kongres - Slovensko združenje za gastroenterologijo in hepatologijo

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kongres - Slovensko združenje za gastroenterologijo in hepatologijo
Revija Slovenskega zdru`enja za gastroenterologijo in hepatologijo
Journal of Slovenian Association of Gastroenterology and Hepatology
Gastroenterolog
Letnik 17, suplement 2, junij 2013 / Volume 17, Supplement 2, June 2013
SLOVENSKO ZDRUŽENJE
ZA GASTROENTEROLOGIJO
IN HEPATOLOGIJO
3
SLOVENSKEGA ZDRUŽENJA ZA
GASTROENTEROLOGIJO IN HEPATOLOGIJO
KONGRES
Z MEDNARODNO UDELEŽBO
Ljubljana, 5.-8. junij 2013
Uvodnik / Introduction
Slovensko združenje za gastroenterologijo in hepatologijo je v sodelovanju Univerzitetnih kliničnih centrov v Ljubljani in v Mariboru, skupaj s tujimi strokovnjaki pripravilo sodoben pregled
gastroenterološke vede s poudarkom na zgodnjem
odkrivanju, zdravljenju in celostni obravnavi starostnika z boleznijo prebavil in bolnikov z rakom
prebavil.
Gastroenterologija je multidisciplinarna veda, v kateri sodelujejo gastroenterologi in abdominalni kirurgi, skupaj z internisti, kirurgi, radiologi, patologi
in pediatri, usmerjenimi v gastroenterologijo. Veda
obsega širok spekter benignih in malignih bolezni
prebavil, od tistih najbolj pogostih, ki prizadenejo
skoraj vsakega človeka vsaj enkrat v življenju, do tistih, ki zahtevajo obravnavo bolnika v univerzitetnih ustanovah.
Število bolnikov z boleznimi prebavil narašča zaradi
staranja prebivalstva, čezmernega jemanja zdravil,
kroničnih vnetij, škodljivih razvad, nepravilne in neuravnotežene prehrane, premajhne telesne dejavnosti in
zaradi vse večje incidence raka prebavil, obenem pa
tudi zaradi večanja našega znanja, novih tehničnih
zmožnosti in daljšega preživetja bolnikov.
Združenje za gastroenterologijo in hepatologijo je
bilo ustanovljeno leta 1967. leta v Rogaški Slatini.
Od samega začetka je delovalo multidisciplinarno,
kar dokazuje tudi stroka njenih predsednikov ves
čas obstoja. Prvi predsednik s petletnim mandatom
je bil internist gastroenterolog, prof. dr. Jože Satler,
drugi, kirurg, prof. dr. Mitja Kovič.
The Slovenian Association for Gastroenterology
and Hepatology - in cooperation with the University
Medical Centre Ljubljana and University Medical
Centre Maribor and in collaboration with foreign
experts - prepared an update of gastroenterology
with the emphasis on early detection, treatment
and comprehensive approach to elderly patients
suffering from digestive diseases and patients with
digestive cancer.
Gastroenterology is a multidisciplinary science associating gastroenterologists and abdominal surgeons as well as internists, surgeons, radiologists,
pathologists and paediatricians dealing with gastroenterology. It covers a wide range of benign and
malignant diseases of digestive system, from the
most common ones that affect almost every person
at least once in their lives to those that need to be
treated in university centres.
The number of patients with digestive diseases is
increasing due to population aging, excessive use of
medications, chronic inflammatory conditions,
unhealthy habits, unhealthy and unbalanced diet,
insufficient physical activity and due to increasingly
high incidence of digestive cancer. The number of
patients with digestive diseases has also increased
due to improved knowledge and new technical capabilities for disease detection and longer survival
times of patients.
The Slovenian Association for Gastroenterology
and Hepatology was established in 1967 in Rogaška
Slatina. From the very beginning on, its activities
GASTROENTEROLOG
V 45 letih svojega delovanja je SZGH pripravilo 86 domačih strokovnih srečanj in 11 mednarodnih srečanj.
Najpomembnejše naloge združenja so stalno strokovno izobraževanje, priprava smernic za diagnostiko
in zdravljenje, urejanje specializacije iz gastroenterologije, širjenje mreže specialistov gastroenterologov,
postavljanje normativov za diagnostične posege in
zdravljenje ter skrb za vrednotenje gastroenterološkega dela.
V zadnjih letih se je vsakodnevno delo gastroenterologov, predvsem tistih na sekundarnem in terciarnem zdravstvenem nivoju, spremenilo. Vse večji
je poudarek na hepatologiji, transplantaciji, zdravljenju z biološkimi zdravili pri bolnikih s kronično
vnetno črevesno bolezenijo, zdravljenje s kemoterapevtiki in tarčnimi zdravili pri bolnikih z raki prebavil, še posebej raki hepatobiliarniga in pankreatičnega sistema. Ob tem se uporablja vse več zelo
zahtevnih, specifičnih diagnostičnih in terapevtskih
endoskopskih posegov.
V prvem dnevu 3. gastroenterološkega kongresu z
mednarodno udeležbo smo želeli predstaviti novosti
v diagnostiki, zdravljenju in paliativni oskrbi bolnikov z boleznimi prebavil. Na tem mestu se moramo
zahvaliti naši farmacevtski družbi KRKA, da je omogočila udeležbo na kongresu 70 gastroenterologom
iz srednje in južne Evrope.
Drugi dan kongresa smo po plenarnih predavanjih, s pomočjo farmacevtske družbe ABBVIE pripravili internacionalni IBD simpozij, na katerem
sodelujejo poznani evropski profesorji za področje
IBD in slušatelji iz 17 držav iz Evrope in S Afrike.
Predavanja, razširjene abstrakte in abstrakte smo
objavili v supplementu revije Gastroenterolog, ki je
revija Slovenskega združenja za gastroenterologijo
in hepatologijo in redno izhaja od leta 1997. Objavljeni prispevki v zborniku so nelektorirani vendar
so bili strokovno recenzirani s strani uredništva.
Zahvaljujem se vsem predavateljem, gostom, sodelavcem in sponzorjem, ki so omogočili pripravo
GASTROENTEROLOG
were multidisciplinary what was reflected in specialities of its presidents throughout its existence. The
first president with a five-year term was an internist
gastroenterologist, prof. dr. Jože Satler, and the second
a surgeon, prof. dr. Mitja Kovič.
In 45 years of its existence the Slovenian Association of Gastroenterology and Hepatology organized
86 national expert meetings and 11 international
meetings. Its most important tasks are expert education, development of guidelines for diagnostics
and treatment, directing gastroeneterology specialisation, broadening the network of gastroenterology
specialists, setting standards for diagnostic procedures and treatment as well as evaluation of gastroenterological work.
In the recent years everyday clinical practice of gastroenterologists, particularly those at the secondary
and tertiary levels, has changed. There is an increased emphasis on hepatology, transplantation,
biological therapy in IBD, chemotherapy and targeted anti-cancer treatment, especially for hepatobiliary and pancreatic cancer. The number of highly
demanding diagnostic and therapeutic endoscopic
procedures has increased as well.
On the first day of the 3rd International Gastroenterology Congress new methods of diagnostics, treatment and palliative care of patients with digestive diseases are presented. We would like to take this
opportunity to thank our pharmaceutical company
KRKA, which allowed 70 gastroenterologists from
Central and South Europe to attend the congress.
On the second day of the congress we prepared –
with the help of the pharmaceutical company ABBVIE – an international IBD symposium, in which
well-known European IBD professors and attendants from 17 countries of Europe and North
Africa will participate.
The lectures, extended abstracts and abstracts are
published in the supplement of the Gastroeneterolog
journal, which is the journal of the Slovenian Associ-
3. kongresa. Zaradi številnih uglednih mednarodnih strokovnjakov in tujih udeležencev, bosta prva
dva dni kongresa v angleškem jeziku. Prepričani
smo, da so strokovni prispevki na visokem strokovnem nivoju in da bodo tudi v pomoč pri vsakdanjem delu ter vzpodbuda za dobro klinično,
znanstveno in raziskovalno delo na področju gastroenterologije in hepatologije.
Prof. dr. Borut Štabuc, dr. med.
Predsednik slovenskega združenja za
gastroenterologijo in hepatologijo
ation for Gastroenterology and Hepatology that has
regularly been published since 1997. The contributions published in the congress book were scientifically reviewed by the editorial board but not edited.
I would like to thank all the lecturers, guests, colleagues and sponsors that contributed to the organization of the 3rd congress. Since several renowned
international experts and foreign attendants will
participate in the congress, the first two days of the
congress will be held in English. We believe that the
contributions are at a high expert level and that
they will facilitate our everyday work as well as give
impetus to good clinical practice and scientific and
research work in the field of gastroenterology and hepatology.
Professor Borut Štabuc, MD, PhD
President of the Slovenian Association for
Gastroenterology and Hepatology
GASTROENTEROLOG
Gastroenterolog
ISSN 1408-2756
Gastroenterolog je uradno glasilo Slovenskega
združenja za gastroenterologijo in hepatologijo.
Objavlja prispevke v slovenskem in angleškem jeziku.
Gastroenterolog is the official journal of the Slovene
Association for Gastroenterology and Hepatology.
It publishes contributions in the Slovene and English
language.
Naslov uredništva / Editorial office
Klinični center Ljubljana
Klinični oddelek za gastroenterologijo
Japljeva 2, 1525 Ljubljana
Glavni urednik / Editor-in-Chief
Borut Štabuc
Uredniki / Editors
Verica Ferlan-Marolt, Eldar Gadžijev, Saša Markovič,
Alojz Pleskovič, Milan Stefanovič, Bojan Tepeš
Uredniški odbor / Editorial Board
David Drobne, Franc Jelenc, Dimitrij Kuhelj,
Živa Mrevlje, Rok Orel, Samo Plut, Peter Popovič,
Stojan Potrč, Pavel Skok, Valentin Sojar,
Lojze M. Šmid
Uredniški svet / Editorial Council
Anton Cerar, Borut Kocijančič, Pavel Košorok,
Miran Koželj, Mirko Omejc, Tatjana Puc Kous,
Miran Rems, Marjeta Sedmak, Marjan Skalicky,
Bor Urbančič, Mihael Zajec, Dragan Stanisavljevič
Priprava za tisk in tisk / Desk-top publishing and
printing
Studio N, Tina Noč, s. p.
Izdajatelj / Publisher
Slovensko združenje za gastroenterologijo in
hepatologijo
Zavod GastroOnko
Gastroenterolog izhaja dvakrat letno.
Letna naročnina za člane Slovenskega združenja za
gastroenterologijo in hepatologijo je vključena v
članarino.
Naklada 600 izvodov.
The journal appears regularly twice yearly.
Yearly subscription for members of the Slovene Society
for gastroenterology and hepatology is included in the
membership fee.
Printed in 600 copies.
GASTROENTEROLOG
Kazalo / Contents
Uvodnik / Editorial
Borut Štabuc
Gastroenterologija v Sloveniji
Gastroenterology in Slovenia ..................................................................................................... 1
Jernej Brecelj
Cistična fibroza in trebušna slinavka
Cystic fibrosis and pancreas ...................................................................................................... 5
Grosek J., Tomazic A., Omejc M., Jelenc F., Djokic M.
Vloga laparoskopije pri obravnavi akutnega divertikulitisa sigme (ADS)
The role of laparoscopy in management of acute sigmoid diverticulitis (ADS) .............................. 11
Andrej Gruden
Endoultrazvočno vodene tankoigelne biopsije cističnih lezij trebušne slinavke
Endoscopic ultrasound guided fine needle aspiration of cystic lesions of the pancreas .................. 16
Matjaž Homan
Eozinofilni ezofagitis pri otrocih - novosti
Eosinophilic esophagitis in children: recent updates .................................................................... 18
Yves Horsman
Portal hypertension: its management in 2013.............................................................................. 22
Arpad Ivanecz, Tomaž Jagrič, Matjaž Horvat, Stojan Potrč
Kako napovedati izid zdravljenja jetrnih zasevkov raka debelega črevesa in danke?
How to predict the treatment outcome of colorectal liver metastases? ........................................... 23
Rado Janša
»Zdravljenje napredovalega HCC – slovenske izkušnje«
Management of advanced HCC - Slovenian experience................................................................ 25
Franc Jelenc, Robert Juvan
Laparoskopske resekcije raka debelega črevesa in danke
Laparoscopic surgery for colorectal cancer.................................................................................. 30
Jera Jeruc
Benigni in maligni tumorji pri 700 zaporednih apendektomijah
Benign and malignant tumors in 700 consecutive appendectomies ............................................... 35
Matjaž Horvat, A. Ivanecz, T. Jagrič, S. Potrč
Kako operirati rak želodca pri starostniku?
How to operate gastric cancer in elderly patients ........................................................................ 39
Pavle Košorok, Matic Bunič, Kristina Fujs Komloš, Boštjan J. Kocjan,
Marija Gačić Štotl, Mario Poljak
Vloga HPV okužbe pri raku zadnjika
The role of HPV infection in anal cancer .................................................................................... 44
Bojan Krebs, Miran Koželj, Stojan Potrč
Protektivne stome po operacijah nizkega raka danke
Protective stoma after low anterior resection for rectal cancer...................................................... 48
GASTROENTEROLOG
Gregor Norčič
Laparaskopska ventralna rektopeksija
Laparosopic ventral rectopexy.................................................................................................... 51
Mirko Omejc
Zdravljenje lokalno napredovalega raka danke
Treatment of locally advanced rectal cancer ............................................................................... 54
Rok Orel
Probiotiki pri vnetni črevesni bolezni
Probiotics in Inflammatory Bowel Disease.................................................................................. 56
Cvetka Pernat Drobež, Andreja Ocepek
Zdravljenje bolnikov z ulceroznim kolitisom: naše izkušnje z adalimumabom
Treatment of ulcerative colitis: our experience with adalimumab ................................................. 64
Popovič Peter, Rok Dežman, Miha Štabuc, Manca Garbajs
Vloga MR-enterografije pri obravnavi bolnikov s Crohnovo boleznijo
MR-Enterography in the management of patients with Crohn‘s disease ........................................ 68
Stojan Potrc, Matjaz Horvat, Arpad Ivanecz, Tomaz Jagric,
Marko Hazabent, Bojan Iljevec
Zapleti pri kirurškem zdravljenju raka trebušne slinavke
Complications in surgical treatment of pancreatic cancer............................................................. 73
Stojan Potrc, Matjaz Horvat, Arpad Ivanecz, Tomaz Jagric, Bojan Iljevec,
Irena Oblak, Vaneja Velenik, Janja Ocvirk
Napredovali rak želodca – kirurška taktika
Advanced gastric cancer – surgical tactic.................................................................................... 76
Primož Sever
Gastrointestinalni stromalni tumorji (GIST)-indikacije in principi kirurškega zdravljenja
Gastrointestinal stromal tumors (GISTs)-indications and princples of surgical treatment................ 87
Milan Stefanovič, Bojan Tepeš, Borut Štabuc, Dominika Novak Mlakar,
Jožica Maučec Zakotnik, Matej Bračko, Snežana Frkovič Grazio
Zagotavljanje kakovosti v presejanju - nadzor in resni neželeni učinki
Assuring quality in screening- control and severe adverse events .................................................. 91
Borut Štabuc, Lojze M. Šmid
Obsevanje in sistemsko zdravljenje raka trebušne slinavke
Radiotherapy and systemic treatment of pancreatic cancer..........................................................101
Milan Stefanovič
Varna terapevtska kolonoskopija
Safe therapeutic colonoscopy......................................................................................................107
Bojan Tepeš
Helicobacter pylori - diagnostika, zdravljenje in rezistenca na antibiotike v Sloveniji
Helicobacter pylori - diagnostics, treatment and antimicrobial resistance in Slovenia ....................114
Blaž Trotovšek
Kirurško zdravljenje tumorjev sotočja jetrnih vodov
Surgical treatment for hilar cholangiocarcinoma.........................................................................120
Manfred Mervic, Samo Plut
Varikozne krvavitve iz zgornjih prebavil
Upper gastrointestinal variceal hemorrhage ................................................................................130
GASTROENTEROLOG
Metka Volavšek, Nina Zidar
Kaj storiti pri nevidnem karcinomu v reseciranem želodcu?
How to deal with invisible carcinoma in the resected stomach?....................................................135
Nina Zidar, Katja Tepeš
Zakaj je diagnoza okužbe s citomegalovirusom v prebavilih težavna?
Why is it difficult to diagnose cytomegalovirus infection in gastrointestinal tract? .........................138
Borut Štabuc, B. Tepeš, P. Skok, M. Vujasinovič, A. Blinc, M. Čerček, M. Tomšič
Slovenske smernice za preprečevanje neželenih učinkov nesteroidnih protivnetnih zdravil,
antiagregacijskih in antikoagulantnih učinkovin na prebavila in srčno žilni sistem
Slovenian guidelines for prevention of non-steroidal anti-inflammatory,
anti-aggregation and anticoagulant agents related adverse effects
on gastrointestinal and cardiovascular system ............................................................................142
Povzetki posterjev / Poster abstracts
Andreja Ocepek, Cvetka Pernat Drobež
Vnetne in rakaste bolezni kože zaradi anti-tnf zdravil pri bolnikih s
kroničnimi vnetnimi črevesnimi boleznimi
Inflammatory and cancerous skin lesions in inflammatory bowel disease
patients treated with anti-tnf therapy..........................................................................................146
Miroslav Vujasinović, Slobodan Vujasinović, Nebojša Djurišić, Tajda Keber
The sign of Leser-Trélat - a case report ........................................................................................149
Miroslav Vujasinović, Apolon Marolt, Bojan Tepeš, Jana Makuc,
Zdenko Kikec, Nace Robač
Vpliv klinične poti na izid zdravljenja bolnikov z akutnim pankreatitisom
Impact of clinical pathway on treatment outcome in patients with acute pancreatitis....................150
Milica Miljković, Miroslav Vujasinović, Martin Tretjak, Apolon Marolt,
Bojan Tepeš, Karmen Klančnik
Ali so bolniki na antikoagulantni terapiji ustrezno zaščiteni
pred krvavitvijo iz zgornjih prebavil?
Are patients on anticoagulants adequately protected against upper gastrointestinal bleeding? .........153
Nace Robač, Miroslav Vujasinović, Apolon Marolt, Martin Tretjak
Rezultati obravnave bolnikov z akutno krvavitvijo iz zgornjih prebavil v splošni bolnišnici:
analiza dveletnega obdobja
Audit of the menagement of acute upper gastrointestinal bleeding in general hospital:
two-year retrospective analysis ...................................................................................................155
Miroslav Vujasinović, Karmen Klančnik, Gregor Kunst, Simona Lavre
Biliarni ileus – prikaz dveh primerov
Biliary ileus – report of two cases ..............................................................................................159
Betka Popič, Miroslav Vujasinović, Jelka Zaletel, Jana Makuc, Metka Epšek Lenart,
Marjana Predikaka, Bojan Tepeš
Seroprevalenca celiakije pri bolnikih s sladkorno boleznijo tipa 1
Seroprevalence of celiac disease among patients with type 1 diabetes mellitus ..............................161
Miroslav Vujasinović, Jelka Zaletel, Bojan Tepeš, Betka Popič, Jana Makuc,
Metka Epšek Lenart, Marjana Predikaka, Saša Rudolf
Eksokrina insuficienca pankreasa pri bolnikih s sladkorno boleznijo
Exocrine pancreatic insufficiency in patients with diabetes mellitus .............................................163
GASTROENTEROLOG
Miroslav Vujasinović, Bojan Tepeš, Saša Rudolf
Eksokrina insuficienca pankreasa pri bolnikih s celiakijo
Exocrine pancreatic insufficiency in patients with celiac disease ..................................................165
Miroslav Vujasinović, Bojan Tepeš, Jana Makuc,
Jelka Zaletel, Tjaša Vidmar, Saša Rudolf
Eksokrina in endokrina insuficienca pankreasa po akutnem pankreatitisu
Exocrine and endocrine pancreatic insufficiency after acute pancreatitis......................................167
Miroslav Vujasinović, Nace Robač, Samo Jeverica, Urša Dolinar, Bojan Tepeš
Helicobacter pylori eradication rate in carinthian region of Slovenia, 2011-2012..........................170
Miroslav Vujasinović
Is adherence to guidelines in treatment of patients with celiac disease satisfactory? ......................171
Katja Novak, Katja Zaletel, Vita Dolžan, Aleksandra Markovič
In Slovenian patients with primary biliary cirrhosis genetic polymorphism
of glutation s-transferase (GSTP1) contribute to higher prevalence
of concomitant autoimmune thyroid disease................................................................................173
R. Janša, J. Tišler-Štuflek, G. Novak, J. Osredkar
Permeabilnostni indeks pri bolnikih s celiakijo
Permeability index in celiac disease patients ...............................................................................175
Betka Popič, Karmen Klančnik, Miroslav Vujasinović
Z liraglutidom povzročen akutni pankreatitis: prikaz primera
Liraglutide-induced acute pancreatitis: case report ......................................................................177
Miroslav Vujasinović, Petra Kaplan
Hematemeza zaradi erozivnega duodenitisa pri maratoncih – prikaz dveh primerov
Hematemesis due to erosive duodenitis in marathon runners – a report of two cases.....................179
Rok Orel, Jakob Zapušek, Gregor Nosan, Marjeta Sedmak, Tanja Kersnik Levart
ARC sindrom – klinični primer...................................................................................................180
Miroslav Vujasinović, Martin Tretjak, Bojan Tepeš, Apolon Marolt,
Milica Miljković, Karmen Klančnik
Ustreznost predpisovanja zaviralcev protonske črpalke
Appropriateness of proton pump inhibitors prescribing.................................................................183
Miroslav Vujasinović, Zdenko Kikec, Cirila Slemenik Pušnik
S kapecitabinom povzročen transmuralni miokardni infarkt – prikaz primera
Capecitabine-induced transmural myocardial infarction – case report ..........................................185
Vanesa Anderle, Nejc Sever, Nataša Smrekar
Serious adverse events associated with ferric carboxymaltose administration
in patients with inflammatory bowel disease treated with anti-TNF drugs ....................................187
GASTROENTEROLOG
Gastroenterologija v Sloveniji
Gastroenterology in Slovenia
Borut Štabuc*
KO za gastroenterologijo, UKC Ljubljana
Gastroenterolog 2013; suplement 2: 1–4
Gastroenterologija je multidisciplinarna veda, v kateri
sodelujejo gastroenterologi in abdominalni kirurgi,
skupaj z internisti, kirurgi, radiologi, patologi in
pediatri, usmerjenimi v gastroenterologijo. Benigne
in maligne bolezni prebavil predstavljajo eno tretjino
vseh bolezni v Sloveniji. Najpogostejše benigne bolezni
so gastroezofagealna refluksna bolezen, dispepsija,
holecistolitiaza in sindrom razdražljivega črevesa.
Najpogostejše maligne bolezni prebavil so rak debelega
črevesa in danke, gastroenteropankreatični nevroendokrini tumorji, rak želodca in rak trebušne slinavke.
Zaradi vse večjega števila bolnikov in novih diagnostičnih ter terapevtskih metod se je delo gastroenterologov na sekundarnem in terciarnem nivoju spremenilo. Ob spremenjeni zahtevnejši patologiji so
diagnostične obdelave vse hitrejše, hospitalizacije
vse krajše, zato je nujno potrebno dobro sodelovanje
z drugimi specialisti še posebej s specialisti družinske
medicine.
Leta 2012 je bilo v Sloveniji, ki ima 2 miljona prebivalcev v 10 regionalnih bolnišnicah in v dveh univerzitetnih klinikah zaposlenih 59 specialistov gastroenterologov in 23 specializantov iz gastroenterologije.
Obenem je je bilo v teh ustanovah zaposlenih 61 abdominalnih kirurgov oz splošnih kirurgov, ki so usmerjeni v abdominalno kirurgijo ter 21 specializantov za
področje abdominalne kirurgije. V Sloveniji v 10 ambu-
Gastroenterology is a multidisciplinary science,
which involves collaboration between gastroenterologists and abdominal surgeons as well as
general internal medicine specialists, surgeons, radiologists, pathologists and pediatricians focused on
gastroenterology. Benign and malignant gastrointestinal diseases represent one third of all diseases
in Slovenia. The most common benign diseases are
gastroesophageal reflux disease, dyspepsia, cholecystolithiasis and irritable bowel syndrome. The
most common malignant gastrointestinal diseases
are colorecal cancer, gastroenteropancreatic neuroendocrine tumors, gastric cancer and pancreatic
cancer. Due to the increasing number of patients
and new diagnostic and therapeutic methods, the
work of gastroenterologists on the secondary and
tertiary level has changed. Newer diagnostic modalities have enabled advanced and faster diagnostics
and therefore shorter hospitalisation stay. In light
of this good cooperation with other specialists as
well as general practicioners is essential.
The population in Slovenia in 2012 was 2 million.
Its public health system included ten regional and
two university hospitals. Alltogether these hospitals employed 59 gastroenterology specialists (or
general internal medicine specialists focused on
gastroenterology) and 61 abdominal surgeons (or
* Prof. dr. Borut Štabuc, dr. med.
KO za gastroenterologijo, UKC Ljubljana
Japljeva 2, 1000 Ljubljana
GASTROENTEROLOG 1
lantah oz. diagnostičnih centrih deluje 17 specialistov
gastroenterologov zasebnikov v 3 ambulantah pa 4
abdominalni kirurgi zasebniki. V UKC ljubljana, ki
pokriva 2/3 Slovenije je zaposlenih 20 specialistov
gastroenterologov in 23 specialistov, abdominalnih
kirurgov. V UKC Maribor je zaposlenih 8 specialistov
gastroenterologov in 12 specialistov abdominalnih
kirurugov.
Med tem ko so v obeh terciarnih ustanovah specialisti usmerjeni večinoma v gastroednterologijo,
v regionalnih bolnišnicah gastroenterologi vsaj
tretjino svojega časa namenijo splošni interni medicini. Vse bolnišnice imajo organizirano 24 urno
urgentno gastroenterološko službo.
V letu 2012 je bilo zaradi bolezni prebavil hospitaliziranih 12.000 bolnikov na okoli 300 bolniških
posteljah Povprečna hospitalizacija je bila 7.5 dni.
V ambulantah je bilo zabeleženih 25.000 obravnav
od tega je bilo 18000 bolnikov prvič pregledanih.
V zasebnih ambulantah je bilo pregledanih še okoli
5000 bolnikov Narejenih je bilo okoli 30.000
gastroskopij od tega 5.500 v zasebnih ambulantah,
16.500 rednih kolonoskopij (5500 zasebniki) in
okoli 10.000 kolonoskopij v državnem programu
presejanja SVIT. Skupno je bilo narejenih okoli
2000 ERCP od tega 1000 v UKC Ljubljana 300 v
Diagnostičnem centru Bled, ostalo v 8 regijskih
bolnišnicah. V 7 ustanovah je bilo skupno narejenih okoli 2000 EUZ in 80 EUZ vodenih citoloških
punkcij. V 8 ustanovah so gastroenterologi opravili
17.000 ambulantnih UZ preiskav. V 4 bolnišnicah
opravljajo abdominalni UZ radiologi. Žal za leto
2012 nimamo podatkov o opravljenem številu operacij oziroma obravnav zaradi benignih in
malignih bolezni prebavil.
Zdravljenje zahtevnih kirurških in gastroenteroloških bolnikov je v zadnjih letih centralizirano.
Tako so radikalne operacije za rake prebavil večinoma v specializiranih ustanovah oziroma v
ustanovah, kjer operirajo izkušeni operaterji z velikim številom operacij. Transplantacija jeter in
trebušne slinavke se izvaja le v UKC Ljubljana.
2 GASTROENTEROLOG
general surgeons focused on abdominal surgery).
There were 23 gastroenterology and 21 abdominal
surgery residents in training. 17 gastroenterology
specialists were employed in private out-patient
clinics or diagnostic centers. 4 abdominal surgery
specialists were employed in 3 out-patient clinics.
UKC Ljubljana provides medical care to about 2/3 of
Slovenian population. It employs 20 gastroenterologists
and 23 abdominal surgeons. UKC Maribor employs
8 gastroenteologists and 12 abdominal surgeons.
Tertiary clinical center employed physicians focus
mainly on clinical gastroenterology, while internal
medicine specialists (focused on gastroenterology) in
regional hospitals deal with general internal medicine
cases in about a third of time. In all hospitals a 24-hour
emergency gastroenterology service is organized.
In 2012, 12,000 patients were admitted due to gastrointestinal pathology. About 300 hospital beds
were available on gastroenterology departments,
average in-patient hospitalization stay was 7.5 days.
25,000 out-patient visits (18,000 of which for the
first time) were recorded, another 5,000 patients
were seen at private out-patient clinics or diagnostic
centers. 30,000 gastroscopies (5,500 of which were
in private clinics) and 16,500 colonoscopies (5,500
of which were in private cinics) were performed.
Additional 10,000 colonoscopies were performed in
the national screening program SVIT. The total of
about 2000 ERCPs were performed, about 1000 at
the University Medical Centre Ljubljana, 300 at the
Diagnostic Centre Bled, the remainder in 8 regional
hospitals. Seven institutions made a combined total
of about 2000 EUS and 80 EUS-guided FNA. In
eight institutions, gastroenterologists performed
17,000 ultrasound examinations, in four hospitals
abdominal ultrasound is performed by radiologists.
Unfortunately no data is available on number of
surgical procedures for benign and malignant gastrointestinal diseases.
Treatment of complex surgical and gastroenterological patients in recent years was centralized.
Thus, radical surgery for gastrointestinal cancers
Na Gastroenterološki kliniki v Ljubljani je bil ustanovljen oddelek za hepatologijo in transplantacijo jeter,
oddelek za KVČB in biološko zdravljenje bolnikov s
KVČB, enota za specifično onkološko zdravljenje
tumorjev prebavil, gastroenteropankreatičnih nevroendokrinih tumorjev in GISTov, ob endoskopskem
oddelku pa še enota za EUZ in EUZ vodene citološke
punkcije in enota za funkcionalno diagnostiko.
V okvirih Združenja za gastroenterologijo in hepatologijo smo po priporočilih UEMS a izdelali natančen
program šest letne specializacije iz gastroenterologije
in si pridobili akreditacijo učnih centrov. Specializacija ima skupno deblo splošne interne medicine, ki
traja 2 leti, 3 leta obveznega izobraževanja v klinični
in endoskopski gastroenterologiji, zadnje, šesto leto je
namenjeno induvidualnemu programu dodatnega
učenja iz hepatologije, kronične vnetne črevesne bolezni, endoskopije ali internistične onkologije. Odločitev
o izbiri je prepuščena izboru specializanta, njegovega
mentorja in državnega koordinatorja za področje
gastroenterologije.
Glede na čakalne dobe za prvi pregled in endoskopske preiskave menimo da je mreža gastroenterologov zasedaj zadovoljivo pokrita in jo bomo v
bodoče le počasi poviševali. Glede na povprečno
starost slovenskih gastroenterologov, 51 let zadnji
dve leti in v bodoče večamo število specializacij iz
gastroenterologije.
Združenje za gastroenterologijo in hepatologijo je bilo
ustanovljeno leta 1967. leta v Rogaški Slatini. V 45
letih svojega delovanja je SZGH pripravilo 86 domačih strokovnih srečanj in 11 mednarodnih srečanj.
Najpomembnejša naloga združenja so stalno strokovno
izobraževanje, priprava smernic za diagnostiko in
zdravljenje, urejanje specializacije iz gastroenterologije,
širjenje mreže specialistov gastroenterologov, postavljanje normativov za diagnostične posege in zdravljenje
ter skrb za vrednotenje gastroenterološkega dela.
V bodoče si želimo glede na potrebe in ekonomske
zmožnosti dokončno izdelati mrežo specialistov
gastroenterologov, abdominalnih kirurgov, inter-
is performed mostly in specialized institutions or
in institutions providing experienced surgeons
with a large number of operations. Liver and pancreas transplantation is performed only at the UKC
Ljubljana.
Several subspecialized departments were established at Gastroenterology clinic in Ljubljana:
Department of Hepatology and Liver Transplantation, Department of IBD and biological treatment,
the unit for specific oncological treatment of tumors
of gastrointestinal tract, neuroendocrine tumors
and gastroenteropancreatic GIST, the endoscopic
department consists of a separate EUS and EUS-FNA
unit and a functional diagnostics unit.
Slovenian Association of Gastroenterology and
Hepatology accepted a rigorous program of six-year
specialization in gastroenterology according to the
recommendations in the Blue book of UEMS. Local
learning centers were accredited. Specialization
includes a 2 years common trunk of general internal
medicine, 3 years of compulsory education in clinical and endoscopic gastroenterology and elective
year (individual additional training in hepatology,
inflammatory bowel disease, endoscopy or medical
oncology).
As the curent waiting time for first examination and
endoscopy is acceptable, we believe that the network
of gastroenterologists is at the moment sufficient
and will only slowly expand in the future. Due to the
average age of Slovenian gastroenterologists being
51 years, the number of residents in training in the
last two years was increased with another increase
being planned in the near future.
Association of Gastroenterology and Hepatology
was established in 1967 in Rogaška Slatina. In 45
years of its operation SZGH organized 86 national
professional meetings and 11 international meetings. The most important tasks of the association
are continuous professional education, development of national guidelines for the diagnosis and
treatment, management of gastroenterology trainGASTROENTEROLOG 3
nistov, kirurgov, radiologov, patologov in pediatrov
usmerjenih v gastroenterologijo. Glede na znane
normative specialista za zagotavljanje kakovostnega dela z bolniki, še posebej pri bolnikih, kjer so
potrebni zahtevni posegi si bomo prizadevali smotrno delitev dela in centralizacijo posameznih
obravnav v tri do štiri specializirane centre. Obenem si bomo prizadevali za tesno sodelovanje z
vsemi drugimi strokami, še posebej s specialisti
družinske medicine, saj na tem temelji napredek,
smotrno načrtovanje diagnostike in zdravljenja ter
racionalizacija oskrbe bolnika z boleznijo prebavil.
4 GASTROENTEROLOG
ing, expanding the network of gastroenterology
specialists, setting the standards and evaluation of
diagnostic interventions and treatment as well as
assuring adequate financial compensation.
In the future, we plan to finalize the network of specialists gastroenterologists, abdominal surgeons,
internists, surgeons, radiologists, pathologists and
pediatricians focused on gastroenterology according
to patient needs and economic capacity. Complex
procedures should be refferred to 3 or 4 specialized
centers. We will strive to work closely with all other
disciplines, especially with family medicine specialists, since only good cooperation enables optimal
diagnosis and treatment planning as well as rational
streamline patient care with gastrointestinal disease.
Cistična fibroza in trebušna slinavka
Cystic fibrosis and pancreas
Jernej Brecelj*
Klinični oddelek za gastroenterologijo, hepatologijo in nutricionistiko, Pediatrična klinika,
Univerzitetni klinični center Ljubljana in Medicinska fakulteta, Univerza v Ljubljani
Gastroenterolog 2013; suplement 2: 5–10
Ključne besede: eksokrina insuficienca trebušne slinavke,
klinična slika, diagnostika, zdravljenje.
Keywords: exocrine pancreatic insufficiency, the clinical
picture, diagnosis and treatment.
POVZETEK
ABSTRACT
Cistična fibroza je najpogostejša monogenska
genetska bolezen kavkaške rase, ki skrajša življenje. Deduje se avtosomno recesivno. Povzročajo jo
številne mutacije gena za klorov kanalček CFTR.
Prizadene različne organe, najpogosteje pljuča, trebušno slinavko, jetra in črevo. Bolezen trebušne
slinavke v okviru cistične fibroze se pri dojenčkih
in otrocih najpogosteje kaže z insuficienco eksokrinega delovanja. Posledica je mekonijski ileus ali
sindrom malabsorpcije, ki se kaže kot steatoreja,
nepridobivanje telesne teže in pomanjkanje vitaminov, topih v maščobah. S trajanjem bolezni se
pri najstnikih in mladih odraslih v 30 % razvije še
sladkorna bolezen. Bolniki s cistično fibrozo z
ohranjenim delovanjem trebušne slinavke in
zdravi prenašalci ene od mutacij gena za cistično
fibrozo imajo večje tveganje za vnetje trebušne slinavke. Poleg klasičnega nadomestnega zdravljenja
z encimi trebušne slinavke in inzulina pri sladkorni bolezni, razvijajo nove načine zdravljenja z
modulatorji klorovih kanalčkov, genskim zdravljenjem in presaditvijo trebušne slinavke. Cistična
fibroza je zelo raziskovana bolezen in služi tudi kot
model za preizkušanje novih načinov zdravljenja,
ki so navedeni v tem prispevku.
Cystic fibrosis is the most common monogenic
genetic disorder in Caucasians that affects patients’
lifespan. The inheritance pattern is autosomal recessive. It is caused by a number of mutations in the
gene for the chloride transmembrane ion channel CFTR. It affects various organs, most commonly the
lungs, pancreas, liver and intestine. The involvement
of the pancreatic gland is most often reflected by
exocrine pancreatic insufficiency in infants and children. It results in meconium ileus or malabsorption
syndrome, with steatorrhoea, failure to thrive and
deficiencies of lipid soluble vitamins. During the
course of the disease one third of teenagers and
young adults develop diabetes. Patients with cystic
fibrosis with preserved pancreatic function and
healthy carriers of a mutation of the gene for cystic
fibrosis have an increased risk of pancreatitis. In addition to conventional replacement therapy with pancreatic enzymes and insulin for diabetes, new treatment approaches with chlorine channel modulators,
gene therapy and transplantation of the pancreas are
currently in experimental phases. Cystic fibrosis is a
widely studied disease and serves as a model for testing new treatment approaches, which are also listed
in this review.
*asist. mag. Jernej Brecelj, dr. med.
Klinični oddelek za gastroenterologijo, hepatologijo in nutricionistiko, Pediatrična klinika
Univerzitetni klinični center Ljubljana in Medicinska fakulteta, Univerza v Ljubljani, Ljubljana, Slovenija.
GASTROENTEROLOG 5
UVOD
Cistična fibroza je najpogostejša monogenska bolezen kavkaške rase, ki skrajša življenjsko dobo. Od
leta 1989 je znano, da jo povzroča mutacija gena
za transmembranski kanalček (beljakovina CFTR;
angl. cystic fibrosis transmembrane regulator protein),
ki izloča klor in bikarbonat. Okvara kanalčka povzroča slabšo topnost mucinov in s tem gostejše
izločke pljuč, črevesa, žolčnih izvodil in trebušne
slinavke. Deduje se avtosomno recesivno (1).
Cistična fibroza se pojavlja pri 1 na 3.000 prebivalcev severne Evrope in njihovih potomcev (npr.
američani evropskega porekla), med južnoameričani pri 1 na 4.000–10.000, med afroameričani pri
1 na 15.000–20.000, najredkeje pa se pojavlja na
Japonskem pri 1 na 350.000 (1).
Znanih je že več kot 1.500 različnih mutacij gena
CFTR, ki jih, glede na stopnjo okvare kanalčka
CFTR, razdelimo v 5 razredov. Klinična slika in
teža bolezni sta odvisni od obeh mutacij na genih
za CFTR in modificirajočih genov. Najpogostejša
mutacija je odsotnost fenilalanina na mestu 508
(mutacija Phe508del ali po starem imenovanju deltaF508), ki je prisotna pri približno dveh tretjinah
bolnikov kavkaške rase (1). V Centru za cistično
fibrozo na Pediatrični kliniki v Ljubljani, ki vodi
70 bolnikov s cistično fibrozo, jih ima 52 % mutacijo Phe508del na obeh in 33 % na enem alelu (2).
Klinična slika cistične fibroze je raznovrstna. Pri
15 % otrok se takoj po rojstvu pokaže z zaporo črevesa
z mekonijem (mekonijski ileus). V prvem letu so
pri bolnikih, ki imajo eksokrino insuficienco trebušne slinavke, najpogostejši znaki malabsorpcije
maščobe s posledicami kot so steatoreja, nepridobivanje telesne teže, podhranjenost, dehidracija,
hipoalbuminemija in znaki pomanjkanja vitaminov topnih v maščobah in cinka. Po prvem letu pa
je praviloma v ospredju bolezen pljuč, ki se kaže
predvsem z okužbami pljuč z bakterijo Pseudomonas aeruginosa in drugimi povzročitelji. Pri 5 %
bolnikov je vodilna jetrna bolezen - fokalna biliarna
6 GASTROENTEROLOG
ciroza. Kadar se znaki cistične fibroze pojavijo šele
v najstniškem ali odraslem obdobju, so to predvsem: vnetje obnosnih votlin in nosni polipi,
bronhiektazije, hemoptiza, recidivantni pankreatitisi, portalna hipertenzija in moška nepolodnost
zaradi neprehodnosti semenovodov (1,3).
Pri osebah z značilnimi simptomi in znaki diagnosticiramo cistično fibrozo, če je koncentracija
kloridnih ionov v znoju (iontoforeza) večja kot 60
mmol/l znoja. Diagnozo dodatno potrdimo z genetsko analizo. Z usmerjeno analizo najpogostejših
mutacij (običajno 30–40) potrdimo diagnozo pri
90 % bolnikov. Če s to preiskavo ne najdemo 2
mutacij, ki povzročata bolezen, pa je potrebno še
sekvencioniranje celega gena CFTR (1). Edini laboratorij, ki opravlja vso diagnostiko cistične fibroze
v Sloveniji, od iontoforeze do sekvencioniranja
gena CFTR, je na Pediatrični kliniki v Ljubljani.
Nekatere navedene preiskave pa so na voljo tudi v
drugih bolnišnicah.
Zdravljenje je celovito in obsega pogosto in dolgotrajno dajanje parenteralnih in inhalacijskih antibiotikov v visokih odmerkih in s tem preprečitev
trajne kolonizacije pljuč z bakterijo Pseudomonas aeruginosa in nekaterimi drugimi bakterijami, fizioterapijo dihal, telesno dejavnost in skrb za dobro
prehranjenost bolnikov s cistično fibrozo (1, 3).
Zdravljenje bolezni trebušne slinavke je navedeno
v nadaljevanju.
Zaradi potrebe po celostni obravnavi, ki obsega različna
medicinska področja, pa tudi psihološko in socialno
obravnavo, je skrb za bolnike s cistično fibrozo najboljša
v centrih, ki združujejo vse potrebne strokovnjake (3).
Pričakovana življenjska doba se povečuje. V Veliki
Britaniji se je v prvem desetletju tega stoletja
mediano preživetje podaljšalo z 31 na 37 let (1). Pri
otrocih rojenih v sedanjem času pa je predvideno
mediano preživetje 41,4 leta (4). To je pomembno
zaradi načrtovanja obravnave bolnikov s cistično
fibrozo v odrasli dobi in seznanjanje zdravnikov
ustreznih specializacij o cistični fibrozi.
Namen prispevka je predstaviti bolezen trebušne slinavke pri cistični fibrozi: patogenezo, diagnostiko,
zaplete, uveljavljene in novejše načine zdravljenja.
s cistično fibrozo koncentracije vitaminov A, E, D,
cinka, selena ter protrombinski čas za oceno preskrbljenosti z omenjenimi vitamini in minerali (3).
MEHANIZEM NASTANKA BOLEZNI
Tabela 1: Posledice pomanjkanja nekaterih vitaminov in
mineralov zaradi malabsorpcije pri cistični fibrozi (3, 7).
Beljakovina CFTR je transmembranski celični
kanalček, ki se tvori v endoplazmatskem retikulumu in se v normalnih razmerah vgradi celično
membrano. Za to sta odgovorna 2 dela, ki večkrat
prehajata skozi membrano. V notranjosti celice sta
dve področji za vezavo nukleotidov, ki preko fosforilacije uravnavata odpiranje kanalčka in s tem
izločanje kloridnih in bikarbonatnih ionov. Kadar
kanalček CFTR ne deluje, se klor in bikarbonat ne
izločata. Sluz se zgosti in v trebušni slinavki zapira
izvodila, kar vodi v kronično fibrozo in nadomeščanje funkcionalnega tkiva z maščevjem (5, 6).
KLINIČNA SLIKA
Pri 85–90 % bolnikov s cistično fibrozo je prizadet
eksokrini del trebušne slinavke, kar se pri propadu
večine funkcionalnega tkiva trebušne slinavke pokaže
s steatorejo. Ta je predvsem posledica pomanjkanja
lipaze. Maščobe se ne razgradijo v maščobne kisline,
da bi se vsrkale. Blata je veliko, je mastno in izrazito
smrdeče, saj nerazgrajene maščobe razgrajujejo črevesne bakterije v svetlini črevesa. Zaradi izgube
energije lahko otrok hujša, nekateri pa izgube z
blatom nadomestijo z izrazito povečanim vnosom
živil in ohranjajo telesno težo (1, 3).
Pomanjkljivo vsrkavanja maščob povzroči energetsko pomanjkanje, kar se kaže kot podhranjenost;
kasneje se lahko pojavijo tudi hipoalbuminemija in
otekline. Malabsorpcija maščob povzroči pomanjkanje vitaminov, topnih v maščobah, cinka in
selena. Sprva so odstopanja lahko le laboratorijska,
sčasoma pa se klinično izrazijo. Zaradi pomanjkanja cinka niso redke kožne spremembe (1,3).
Najpogostejša pomanjkanja vitaminov in mineralov pri cistični fibrozi in njihove posledice so
navedene v Tabeli 1. V okviru razširjenih laboratorijskih preiskav določamo enkrat letno pri bolnikih
Snov
Posledice pomanjkanja
Vitamin A
nočna slepota, keratomalacija,
hiperkeraotza, nagnjenost k okužbam
Vitamin D
rahitis, osteomalacija, osteoporoza,
bolečine v kosteh, zmanjšana mišična moč
Vitamin E
hemolitična anemija, retinopatija,
nevropatija
Vitamin K
nagnjenost h krvavitvam, osteoporoza
Cink
zaostanek v rasti in spolnem razvoju,
izpadanje las, dermatitis, moteno delovanje
imunskega sistema, driska, vnetje jezika
Selen
kardiomiopatija, zmanjšana mišična moč,
bolečine v mišicah
DIAGNOSTIKA
Delovanje eksokrinega dela trebušne slinavke preverjamo z direktnimi in indirektnimi testi.
Direktni temeljijo na analizi aktivnosti pankreatičnih encimov v pankreatičnem soku, ki ga dobimo
po stimulaciji s sekretinom in holecitsokininom
neposredno iz pankreatičnega izvodila. Preiskava
je izvazivna zato se le redko izvaja v omejenem številu centrov (8). Indirektni testi so lažje dostopni,
a so manj senzitivni in specifični, posebno pri bolnikih z blažjo insuficienco trebušne slinavke.
Razdelimo jih v 3 kategorije (8):
1. Določanje snovi (v krvi ali urinu), ki so jih
hidrolizirali pankreatični encimi (npr. test s
pankreolaurilom, ki se določa po zaužitju v
zbranem urinu).
2. Merjenje neprebavljenih in nevsrkanih hranil
v blatu (npr. analiza izločenih maščob z blatom
v 72h) ali njihovih oksidacijskih produktov v
izdihanem zraku z dihalnimi testi.
3. Merjenje aktivnosti pankreatičnih encimov v
blatu (npr. himotripsin, elastaza).
GASTROENTEROLOG 7
Najuporabnejši neinvazivni test za oceno eksokrine insuficience pankreasa je določanje elastaze
v blatu. Test je specifičen za človeško elastazo, zato
nanj jemanje encimov trebušne slinavke ne vpliva,
kot to velja npr. za določanje himotripsina, ki ga
uporabljamo predvsem za ugotavljanje sodelovanja
bolnika pri zdravljenju (kompliance) (8, 9).
Trebušna slinavka ima veliko funkcionalno rezervo,
zato eksokrina insuficienca blage in zmerne stopnje ne
povzročita nujno tudi steatoreje. Hkrati pa je vsrkavanje maščob odvisno tudi od drugih dejavnikov, kot so
žolčne kisline, črevesna vsebina in črevesna sluznica.
Standardni test za ugotavljanje steatoreje je analiza izločenih maščob z blatom v 72h. Bolnik beleži zaužito
prehrano in z enodnevnim zamikom zbira izločeno
blato v posodo, ki ga do analize hrani v zamrzovalniku.
Iz razlike zaužite in izločene maščobe izračunamo
količnik absorpcije maščob. Pri dojenčkih je normalna
vrednost nad 85 %, pri otrocih in odraslih pa nad 93 %.
Preiskava je zamudna, zahtevna in neprijetna ter se zato
uporablja le v izbranih primerih (8).
Pri sodelujočih otrocih in odraslih lahko ugotavljamo stopnjo hidrolize maščob z dihalnim testom
z označenim ogljikom (C13). Po standardiziranem
označenem obroku merimo vsake pol ure označen
ogljik v izdihanem zraku. V raziskavi D. C. Herzog
in sod. so potrdili, da preiskava loči med zdravimi
otroci in otroci s cistično fibrozo in eksokrino insuficienco pankreasa, so pa ugotavljali precejšnje
razlike med različnimi meritvami pri istih preiskovancih (10). Preiskava je zamudna, saj traja 6h.
Med meritvami morajo biti preiskovanci pri miru,
kar je pri otrocih pogosto težko. Potencialna uporabnost je predvsem ugotavljanje ustreznosti
nadomeščanja pankreatičnih encimov (8).
ZDRAVLJENJE
Zdravljenje eksokrine insuficience trebušne slinavke
je ustrezno odmerjanje pankreatičnih encimov glede
na zaužite maščobe. Odmerek lipaze se največkrat
giblje med 500–4.000 enotami na 1 gram zaužitih
maščob (3). Poleg uveljavljenega pripravka encimov
8 GASTROENTEROLOG
trebušne slinavke živalskega izvora v obliki mikrosfer
zaščitenih z ovojem, ki je odporen na želodčno kislino,
in je dokazano učinkovit in varen tudi pri mlajših otrocih (11), je v tretji fazi kliničnih preskusov tudi
pripravek, ki je pridobljen z genskim inženiringom
(12). Njegova učinkovitost in varnost je že dokazana
pri otrocih, starejših od 7 let, primerjalnih raziskav
med obema vrstama zdravila pa še ni.
Ker nadomeščanje pankreatičnih encimov ni
idealno, mora bolnik s cistično fibrozo uživati s
prehrano večje količine vitaminov, topnih v maščobah, cinka in selena, ter vsaj priporočene
odmerke ostalih vitaminov in mikroelementov
(13). To dosežemo s posebej prilagojenimi pripravki za bolnike s cistično fibrozo z vitamini in
minerali, ki pa so primerni tudi za bolnike z drugimi vzroki za eksokrino insuficienco trebušne
slinavke in s holestatskimi boleznimi jeter.
ZAPLETI BOLEZNI TREBUŠNE
SLINAVKE PRI CISTIČNI FIBROZI
Cistični fibrozi pridružena sladkorna
bolezen
Propadanje tkiva trebušne slinavke lahko povzroči tudi
pomanjkljivo izločanje inzulina, ki se kaže najprej kot
motena toleranca za glukozo, kasneje pa kot sladkorna
bolezen. S starostjo se prevalenca veča. Med najstniki
so ugotavljali moteno toleranco za glukozo pri 40 %
bolnikov s cistično fibrozo. Pogostejša je pri dekletih.
V skupini bolnikov starih 25 let jih je imelo sladkorno
bolezen 30 % (1). Zgodnje ugotavljanje razvoja sladkorne bolezni in zdravljenje z inzulinom vpliva tudi na
izboljšano delovanje pljuč, zato opravijo bolniki po 10.
letu vsako leto oralni glukozotolerančni test. V zadnjem
času pa vse več tudi občutljivejšo nekajdnevno kontinuirano merjenje glukoze v medceličnini (3).
Podhranjenost
Podhranjenost je neodvisen dejavnik za slabši potek
bolezni. Pomen dobre prehranjenosti so potrdili v
skupini 584 bolnikov s cistično fibrozo z mediano
starostjo 21 let, ki so jih spremljali 45 mesecev. Petletno preživetje je bilo boljše (84 %) v skupini
bolnikov, ki so imeli težo večjo od 85 % idealne, kot
pri tistih z manjšo težo (53 %) (14). Za ustrezno prehranjenost je ključno pravilno nadomeščanje
pankreatičnih encimov. Pomembna je tudi zdrava
kalorično obogatena prehrana in tudi zdravljenje
ostalih organov, ki jih prizadene cistična fibroza (15).
Novotvorbe trebušne slinavke
Z raziskavami so potrdili nekoliko večje tveganje za
nastanek karcinoma trebušne slinavke in tudi drugih delov prebavil pri bolnikih s cistično fibrozo.
Patogenetski mehanizem ni znan. Z daljšim preživetjem pa se bo incidenca večala. Preprečevanje
temelji na odsvetovanju kajenja (kar je še pomembnejše za pljučno bolezen) in zdravi prehrani bogati z
antioksidanti, kot sta vitamin E in selen. V sklopu
sekundarne preventive, ki obsega presejanje, pa
veljajo zaenkrat enaka priporočila kot za splošno
populacijo (16, 17).
NOVA ZDRAVLJENJA
Modulacija mutiranih CFTR
V letu 2011 je odmevala novica o izboljšanju delovanja mutiranih kanalčkov CFTR s potenciatorjem
ivakaftorjem, ki povzroči izboljšano delovanje
kanalčka CFTR pri določeni mutaciji (G551D).
Jemlje se dvakrat dnevno peroralno. Z dvojno-slepo
raziskavo pri bolnikih s cistično fibrozo starejših od
12 let, so z 48-tedenskim zdravljenjem potrdili
izboljšanje forsiranega ekspiratornega volumna v
prvi sekundi (FEV1) za dobrih 10 %, povišanje telesne teže za 2,7 kg, zmanjšanje koncentracije klora
v znoju in izboljšanje kakovosti življenja (19). Neposredno izboljšanje delovanja trebušne slinavke z
ivakaftorjem še ni bilo dokazano (20).
Razvijajo tudi korektorje kanalčkov CFTR in zaviralce prezgodnje prekinitve prepisovanja gena za
CFTR, ki pa še niso v klinični uporabi (20).
Presaditev trebušne slinavke
Pankreatitis
Pankreatitis se pojavlja pogosteje pri najstnikih in
mladih odraslih s cistično fibrozo, ki imajo ohranjeno delovanje trebušne slinavke. V raziskavi, ki je
zajela več kot 10.000 bolnikov s cistično fibrozo iz
29 držav je imelo pankreatitis kadarkoli v življenju
1,24 %. Pogostejši je bil v skupini bolnikov z ohranjenim delovanjem trebušne slinavke (10,3 %), kot
pri tistih z eksokrino insuficienco (0,5 %). Povezave
z določeno mutacijo niso ugotovili (18).
Kar pri 43 % bolnikov z rekurentnim akutnim
pankreatitisom ali kroničnim pankreatitisom so
dokazali mutacijo vsaj enega gena za CFTR, 11 %
pa jih je imelo mutacije na obeh alelih. Po dodatnih preiskavah jih je 21 % izpolnjevalo kriterije za
postavitev diagnoze cistična fibroza (17).
Presaditve trebušne slinavke pri bolnikih s cistično
fibrozo so dveh vrst. Možna je presaditev celotne
trebušne slinavke in vspostavitve anastomoze s
tankim črevesom, kar izboljša ali normalizira delovanje eksokrinega in endokrinega dela pankreasa.
Opisujejo tudi samo presaditev pankreatičnih otočkov. Obe vrsti presaditev sta redki, saj obstaja
učinkovito nadomestno zdravljenje s pankreatičnimi encimi in inzulinom. Običajno jih združijo
s presaditvijo drugih organov, ki so prizadeti zaradi
cistične fibroze, kot so npr. pljuča ali jetra (1,22).
Gensko zdravljenje
Učinkovitega in varnega genskega zdravljenja cistične fibroze kljub številnim poskusom še niso razvili
(20). Z največjo raziskavo genskega zdravljenja cistične fibroze pri 130 bolnikih so začeli letos v Veliki
Britaniji. Gen za CFTR v liposomih bodo z inhalacijami prenašali v pljuča mesečno v obdobju enega
leta in spremljali učinek na pljuča (23).
GASTROENTEROLOG 9
ZAKLJUČKI
Cistična fibroza okvari trebušno slinavko na različne
načine. Najpogosteje okvari njeno eksokrino delovanje, ki z nadomeščanjem funkcionalnega tkiva s
fibrotičnim vodi pogosto tudi v endokrino motnjo
delovanja, ki se kaže kot sladkorna bolezen. Pri bolnikih z blažjimi mutacijami ali prenašalci mutacije za
cistično fibrozo pa se kaže z nagnjenostjo za nastanek
pankreatitisa. Novi načini zdravljenja cistične fibroze
obetajo nove pristope tudi za zdravljenje bolezni trebušne slinavke. Do njihove uveljavitve ostaja zelo
učinkovito nadomestno zdravljenje eksokrine motnje
delovanja z dodajanjem pankreatičnih encimov in
endokrine z zdravljenjem z inzulinom. Presaditev trebušne slinavke v celoti ali samo otočkov se izvaja le
redko v sklopu presaditve drugih organov.
LITERATURA
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AJ, et al. Wasting as an independent predictor of mortality in
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Dřevínek P et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med 2011; 365(18):
1663–72.
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Vloga laparoskopije pri obravnavi
akutnega divertikulitisa sigme (ADS)
The role of laparoscopy in management of acute
sigmoid diverticulitis (ADS)
Grosek J.*, Tomazic A., Omejc M., Jelenc F., Djokic M.
Univerzitetni klinični center Ljubljana, Klinični oddelek za abdominalno kirurgijo
Gastroenterolog 2013; suplement 2: 11–15
Ključne besede: divertikulitis, divertikuloza, laparoskopija,
Hinchey, Kohler, resekcija debelega črevesa, Hartmannova
resekcija
Keywords: diverticulitis, diverticulosis, laparoscopy,
Hinchey, Kohler, colonic resection, Hartmann`s procedure
POVZETEK
ABSTRACT
Približno 1 % vseh bolnikov z divertikulozo sigme
potrebuje operativno zdravljenje. Diskontinuitetna
resekcija sigme (t.i. Hartmannova resekcija) je še
vedno temelj urgentne kirurške oskrbe pri bolnikih
s Hinchey III ali IV divertikulitisom sigme. Tovrstne
operacije imajo relativno visoko morbiditeto in mortaliteto, tudi delež ponovnih vzpostavitev kontinuitete
črevesa je majhen. Izkušeni kolorektalni kirurgi se
zaradi tega pogosto odločajo za kontinuitetno resekcijo, kot alternativa resekciji pri Hinchey III ADS pa
pridobiva na veljavi laparoskopska lavaža. V prispevku
predstavljamo naše izkušnje in rezultate z zdravljenjem
ADS v 5-letnem obdobju od 2008–2012. Laparoskopska lavaža pri Hinchey III ADS bo svoje pravo
mesto dobila le z dobro pripravljenimi, randomiziranimi prospektivnimi raziskavami z dovolj dolgim
spremljanjem operiranih bolnikov. Trenutno v
Evropi potekajo štiri tovrstne raziskave.
About 1% of people with colonic diverticulosis need
some sort of operation. Hartmann`s procedure still
represents the basis for urgent surgical treatment of
patients with generalized peritonitis (Hinchey III or IV).
These procedures, while simple and efficient, bring
along quite high levels of perioperative morbidity and
mortality. This is why there has recently been a trend
toward a more conservative approach to avoid the risk
of high postoperative morbidity and definitive stoma,
i.e. laparascopic lavage without colonic resection. Well
prepared, prospective, randomized studies with proper
follow up are needed. There are 4 such studies conducted in different European centers at this moment.
*Grosek J.
Univerzitetni klinični center Ljubljana, Klinični oddelek za abdominalno kirurgijo
GASTROENTEROLOG 11
UVOD
Divertikuloza debelega črevesa je bila včasih izredno
redka, sedaj pa se ocenjuje, da je prisotna že pri več
kot polovici ljudi v razvitem svetu. Prevalenca narašča
s starostjo, oba spola pa sta približno enakomerno
prizadeta. V vsaj 75 % je prizadet le sigmoidni del
debelega črevesa, v 5–10 % pa so divertikli prisotni
po celotnem debelem črevesu3.
Divertikli so večinoma klinično nemi in jih naključno
odkrijemo pri različnih preiskavah (kolonoskopija,
irigografija) zaradi drugih težav. Pri bolnikih, ki
jim divertikli povzročajo težave, prevladuje blaga,
nespecifična klinična slika, za katero so značilne
občasne krčevite bolečine v spodnjem delu trebuha
in napihnjenost. Do divertikulitisa, ki nastane zaradi
predrtja posameznega divertikla in okolne vnetne
reakcije, pride pri 20–30 % bolnikov. Spekter klinične slike zaključuje krvavitev iz divertiklov, do
katere lahko pride pri do 15 % bolnikov. Tovrstna
krvavitev običajno nastane nenadoma, je precej
obilna, svetlo rdeča in se večinoma ustavi sama3,7.
–
–
Generalizirani gnojni peritonitis (nastane
kot posledica predrtja poprej omejenega
abscesa)
Generalizirani sterkoralni peritonitis
Kljub temu, da so različni avtorji predlagali oziroma
še predlagajo številne druge klasifikacije akutnega
divertikulitisa sigme, pa je Hincheyeva klasifikacija kljub starosti še vedno aktualna in omogoča v
kombinaciji s Kohlerjevo klasifikacijo izvrstno in
racionalno podlago za izbiro najustreznejšega
načina zdravljenja.
RAZDELITEV
Obstajajo številne razdelitve akutnega divertikulitisa
sigme. Zelo uporabna je klasifikacija Kohlerja in
sodelavcev iz leta 1999, ki bolezen deli v 3 skupine2:
– Simptomatski nekomplicirani divertikulitis
– Ponavljajoči nekomplicirani divertikulitis
– Komplicirani divertikulitis
Krvavitev
Absces/Flegmona
Fistula
Perforacija
Striktura
Gnojni/ Sterkoralni peritonitis
Temelj današnjemu razumevanju bolezni pa je že
leta 1978 postavil Hinchey s sodelavci, ki je divertikulitis z abscesom razdelil v 4 skupine1:
– Perikolični absces ali flegmona
– Medenični, intraabdominalni, retroperitonealni absces
12 GASTROENTEROLOG
Slika 1. Hincheyeva razdelitev (Iz: Hinchey EJ,
Schaal PGH, Richards GK. Treatment of perforated
diverticular disease of the colon. Adv Surg 1978)
KLINIČNA SLIKA, DIAGNOSTIKA
Bolečina v levem spodnjem kvadrantu, lahko slabost z ali brez bruhanja, zmerno povišana telesna
temperatura, spremenjeno odvajanje blata in porast
laboratorijskih kazalcev vnetja so temeljni klinično
in laboratorijski parametri, ki opredeljujejo blago
sliko nekompliciranega divertikulitisa, ne glede na
časovno komponento (akutni oz. ponavljajoči) 3,7.
Povsem na drugem koncu spektra so bolniki z
generaliziranim sterkoralnim peritonitisom (Hinchey IV), ki ga povzroči večja perforacija divertikla,
okolni organi/strukture predrtja ne zamejijo, končna posledica pa je izlitje črevesne vsebine po vsej
trebušni votlini. Bolniki so hudo prizadeti, difuzno
peritonitični in septični. Takšno stanje, v odsotnosti ustreznega zdravljenja ali pa če je le to prepozno,
vodi v šokovno stanje in smrt. Med obema opisanima skrajnostima pa je raznolika klinična slika.
Praktično vedno imajo bolniki povišano telesno
temperaturo in porast vnetnih kazalcev v laboratoriju. Če je absces pod trebušno steno, je prisotna
tudi močna lokalna občutljivost z mišičnim defansom. Tega ni, če je absces retroperitonealno ali
globoko v mali medenici (Hinchey 2). Pride lahko
do spontanega predrtja abscesov. V tem primeru se
gnojna vsebina razlije po trebušni votlini in pride
do difuznega peritonitisa s sepso. Stanje bolnikov
se dramatično poslabša in potrebno je takojšnje
ukrepanje (Hinchey 3) 1,2,3,7.
Če imamo opraviti s kompliciranim divertikulitisom (klasifikacija po Kohlerju), so prisotni dodatni
klinični znaki in simptomi. V primeru, da vnetni
tumor zapre svetlino črevesa, pride do klasične
slike obstruktivnega ileusa debelega črevesa. Pnevmaturija, fekalurija in pogoste okužbe sečil so
značilnost fistulacije vnetnega tumorja v sečni
mehur. Fistulacija v vagino pa privede do umazanega in smrdečega vaginalnega izcedka2,7.
Za diagnozo divertikulitisa so polega anamnestičnih podatkov in zgoraj opisane klinične slike
pomembne tudi laboratorijske preiskave (levkocitoza s pomikom v levo, C reaktivni protein,
prokalcitonin, pregled urina) in pa slikovna diagnostika. Najpogosteje naredimo UZ trebuha, ki
pokaže zadebeljeno steno sigme, prosto tekočino z
ali brez omejenih abscesov. Vedno pogosteje se
odločimo za CT trebuha, ki odkrije tudi abscese,
ki jih včasih zaradi zaplinjenosti trebuha ali same
lokacije abscesov na UZ preiskavi spregledamo
(retroperitonealno, globoko v mali medenici). CT
preiskava pa je zlati standard pri diagnostiki kompliciranih divertikulitisov, pri katerih je prišlo do
fistulacij v druge organe. RTG abdomna je pogosto prva slikovna preiskava pri neznačilnih
kliničnih manifestacijah (zaprtje,...) ali pri bolnikih, pri katerih se divertikulitis pokaže bodisi kot
ileus debelega črevesa ali kjer sumimo na prosti
zrak intraperitonealno7.
Diferencialno diagnostično moramo pomisliti na
različna bolezenska stanja: apendicitis, vnetje sečil,
sindrom iritabilnega kolona, nefrolitiazo, ginekološka obolenja, infekcijski/ishemični kolitis, kronično
vnetno črevesno bolezen in malignom sigme7.
ZDRAVLJENJE
Večina divertikulitisov poteka v blagi, nekomplicirani obliki. Sem sodi tudi Hinchey I, kjer je absces
manjši in lociran perikolično. Tovrstne oblike zdravimo konzervativno, ambulantno ali hospitalno.
Potrebna je bodisi popolna karenca, bodisi zgolj
tekoča dieta s počitkom. Uvedemo empirično antibiotično dvotirno terapijo (gentamicin, metronidazol),
pogosto boleč predel tudi lokalno hladimo. Dva do
tri mesece po sanaciji vnetja je pri bolnikih potrebno
opraviti kolonoskopijo za izključitev malignoma7.
Pri divertikulitisih z omejenimi večjimi abscesi je
poleg opisanega konzervativnega zdravljenja potrebna
tudi drenaža abscesov. Ob ustrezni lokaciji le teh je
najbolje abscese drenirati perkutano, večinoma pod
kontrola ultrazvoka. Če takšna drenaža ni možna
ali pa ni uspešna, je potrebna kirurška drenaža,
bodisi laparoskopska bodisi klasična7.
Komplicirani divertikulitisi s fistulami v sečni
mehur ali vagino zahtevajo kirurško zdravljenje.
Pri takšnih operacijah poleg abdominalnih kirurgov sodelujejo tudi urologi ali ginekologi. Prizadeti
del črevesa je potrebno resecirati, fistulo ekscidirati in defekt na drugem organu prešiti. Resecirani
del črevesa pošljemo na histološki pregled8.
Divertikulitisi, pri katerih je prišlo do difuznega
peritonitisa (Hinchey III in IV), zahtevajo urgentno
kirurško zdravljenje. Že vrsto let je zlati standard t.i.
Hartmannova resekcija sigme, kjer oboleli del debeGASTROENTEROLOG 13
lega črevesa reseciramo, krn zgornje danke s
pomočjo linearnega spenjalnika slepo zapremo ter
prosti konec descendensa izpeljemo navzven skozi
trepanacijo v trebušni steni v levem mezogastriju
kot končno kolostomo. Preteklo je že skoraj 100 let,
odkar je Henri A. Hartmann prvič opisal ta poseg,
kljub temu pa ima ta operacija zaradi svoje enostavnosti in velike učinkovitosti še vedno pomembno
mesto v urgentni abdominalni kirurgiji. Po drugi
strani pa imajo tovrstne operacije relativno visoko
morbiditeto in mortaliteto, tudi delež ponovnih
vzpostavitev kontinuitete črevesa je majhen. Izkušeni kolorektalni kirurgi se zaradi tega pogosto
odločajo za kontinuitetno resekcijo, kot alternativa
resekciji pri Hinchey III ADS pa pridobiva na veljavi
laparoskopska lavaža. Pri Hinchey IV divertikulitisu
pa je pravilna oskrba še vedno Hartmannova resekcija sigme8,9.
Zdravljenje divertikuloze zaradi ponavljajočih divertikulitisov je kirurško, večinoma laparoskopsko.
Prizadeti del črevesa reseciramo in napravimo primarno anastomozo. Odločitev o načinu operacije ni
težka, ključna dilema je, kdaj oziroma ali sploh operirati. Hinchey III ali IV divertikulitis je praktično
vedno posledica prvega napada bolezni, tako da
tega hudega stanja s preventivno resekcijo črevesa
praktično ni možno preprečiti. Večinoma se avtorji
zatorej strinjajo, da je potrebna individualna obravnava vsakega bolnika posebej7,10.
V zadnjem času se je v strokovni literaturi pojavilo
več prispevkov (10 člankov, 267 vključenih bolnikov), v katerih avtorji opisujejo laparoskopsko
lavažo pri Hinchey III divertikulitisu kot enakovredno alternativo klasični Hartmannovi resekciji
sigme. Princip te metode je laparoskopski pristop,
pri katerem zgolj speremo trebušno votlino, vstavimo abdominalne drene in nadaljujemo z
antibiotično terapijo. Čez nekaj mesecev se potem
praviloma odločimo za (laparoskopsko) resekcijo
črevesa s primarno anastomozo. Zagovorniki te
metode menijo, da na ta način spremenimo purulentno okužbo v flegmonozni divertikulitis, ki ga
nato lahko pozdravimo konzervativno. Vprašanje
14 GASTROENTEROLOG
pa je seveda, ali ni obolelo črevo, ki pri tej metodi
ostane »in situ«, stalen vir okužbe. Avtorji tak pristop ocenjujejo kot odličen z zanemarljivim
deležem konverzij in drugih zapletov. Vendar pa
nekoliko bolj kritična analiza pokaže na številne
pomankljivosti teh prispevkov. Večina teh študij je
retrospektivnih, nerandomiziranih, vključenih je
relativno majhno število bolnikov v dolgih časovnih
intervalih. Skupine bolnikov so zelo heterogene,
terapevtski algoritmi niso ustrezno razloženi3-8.
DELO IN METODE
Ker tudi na našem kliničnem oddelku (enota Zaloška/ Vodnikova- BPD) zdravimo bolnike z akutnim
divertikulitisom sigme, smo želeli retrospektivno
zbrati podatke za krajše obdobje (2008–2012), z
namenom kritično ovrednotiti obseg pa tudi kakovost našega dela.
Klinični oddelek za abdominalno kirurgijo v Bolnišnici Petra Držaja je dislocirana enota našega
kirurškega oddelka, ki poleg svoje redne dejavnosti
opravlja tudi dejavnost urgentne abdominalne
kirurgije za odrasle bolnike. Zaradi tega je večina
bolnikov z ADS napotenih v to ustanovo. Na Kliničnem oddelku za abdominalno kirurgijo v UKC
pa smo zdravili oziroma zdravimo predvsem dve
skupini bolnikov z ADS, in sicer bolnike s kompliciranimi oblikami bolezni ter bolnike, ki zaradi
drugih pridruženih bolezni potrebujejo oskrbo v
terciarni ustanovi.
V petletnem obdobju (2008–2012) smo retrospektivno zbrali naslednje podatke:
1. Povprečno število zdravljenih bolnikov
2. Povprečna starost bolnikov
3. Delež žensk/ moških
4. Povprečen čas hospitalizacije
5. Razdelitev bolezni po Hincheyevi klasifikaciji
6. Delež operiranih bolnikov
7. Vrsta resekcije (Hartmann/ anastomoza)
8. Način operacije (Klasično/ laparoskopsko)
9. Stopnja morbiditete/ mortalitete pri operiranih
bolnikih
REZULTATI
ZAKLJUČEK
Klinični oddelek za abdominalno
kirurgijo, enota UKC
Večina bolnikov z divertikli debelega črevesa nima
težav oziroma so te blage. Večji del divertikulitisov
poteka v blagi, nekomplicirani oblikami in jih pozdravimo konzervativno. Približno 1/4 bolnikov (nekateri
menijo, da celo manj- tako govorijo tudi naši rezultati) potrebuje urgentno kirurško zdravljenje.
Temelj tega zdravljenja je že davnega leta 1921
prvič opisana Hartmann-ova resekcija sigme, ki je
relativno enostavna in ima dobre rezultate. Kljub
navdušenju nekaterih kirurgov nad tehniko laparoskopske lavaže brez resekcije črevesa bi bilo
mnogo preuranjeno trditi, da je takšen pristop enakovreden uveljavljeni, to je Hartmannovi operaciji.
Laparoskopska lavaža pri Hinchey III ADS bo svoje
pravo mesto dobila le z dobro pripravljenimi, randomiziranimi prospektivnimi raziskavami z dovolj
dolgim spremljanjem operiranih bolnikov. Trenutno v Evropi potekajo štiri tovrstne raziskave.
Povprečno smo zdravili 12 bolnikov letno. To so
bili večinoma bolniki s kompliciranimi oblikami
bolezni oziroma polimorbidni bolniki, ki so potrebovali zdravljenje v terciarnem centru. Povprečna
starost je bila 62 let, povprečen čas hospitalizacije
pa 13 dni. Hinchey I je bil prisoten pri 30 % bolnikov,
Hinchey II pri 46 %, Hinchey III pri 12 % in Hinchey IV prav tako pri 12 % bolnikov. 2/3 bolnikov je
bilo operiranih. V 15 % je bila narejena laparoskopska
lavaža brez resekcije. V 85 % je bila narejena klasična
resekcija obolelega dela debelega črevesa, in sicer
v polovici primerov s primarno anastomozo, v polovici primerov pa je bila narejena Hartmannova
resekcija. Pooperativna morbiditeta je bila 18 %,
pooperativna smrtnost pa 11 %.
Klinični oddelek za abdominalno
kirurgijo, enota Bolnica Petra Držaja
Povprečno smo zdravili 70 bolnikov letno. Povprečna
starost je bila 64 let, povprečen čas hospitalizacije
pa 6 dni. Bilo je približno enako število žensk in
moških. Hinchey I je bil prisoten pri večini, to je
82 % bolnikov, Hinchey II pri 4 %, Hinchey III pri
7 % in Hinchey IV prav tako pri 7 % bolnikov. 14 %
bolnikov je bilo operiranih. V 1/3 primerov je bila
narejena laparoskopska lavaža brez resekcije. V 2/3
primerov je bila narejena klasična resekcija obolelega
dela debelega črevesa, in sicer v 2/3 primerov s primarno anastomozo, v 1/3 primerov pa je bila narejena
Hartmannova resekcija. Pooperativna morbiditeta je
bila 20 %, pooperativna smrtnost pa 10 %.
LITERATURA
1. Hinchey EJ, Schaal PG, Richards GK: Treatment of perforated
diverticular disease of the colon. Adv Surg 12:85–109, 1978
2. Kohler L, Suaerland S, Neugebauer E: Diagnosis and treatment
of diverticular disease: results of a consensus development conference. Surg Endosc 13: 430–6, 1999
3. Parra-Blanco A: Colonic diverticular disease: patophysiology and
clinical picture. Digestion 73 (suppl 1): 47–57, 2006
4. Alamili M, Gogenur I, Rosenberg J: Acute complicated diverticulitis managed by laparoscopic lavage. Dis Colon Rectum 52:
1345–1349, 2009
5. Myers E, Hurley M, et al: Laparoscopic peritoneal lavage for generalized peritonitis due to perforated diverticulitis. Br J Surg 95:
97–101, 2008
6. Bretagnol F, Pautrat K, et al: Emergency laparoscopic management of perforated sigmoid diverticulitis: A promising alternative
to more radical procedures. J Am Coll Surg 206:654:657, 2008
7. Rafferty J, et al: Practice parameters for sigmoid diverticulitis.
Dis Colon Rectum 49(7): 939–44, 2006
8. Abbas S: Resection and primary anastomosis in acute complicated
diverticulitis, a systematic review of the literature. Int J Colorectal
Dis 22(4):351–7, 2007
9. Seah DW, Ibrahim S, Tay KH: Hartmann procedure: is it still relevant
today? ANZ J Surg 75(6):436–40, 2005
10. Janes S, Meagher A, Frizelle FA: Elective surgery after acute
diverticulitis. Br J Surg 92:133–42, 2005
GASTROENTEROLOG 15
Endoultrazvočno vodene tankoigelne
biopsije cističnih lezij trebušne slinavke
Endoscopic ultrasound guided fine needle
aspiration of cystic lesions of the pancreas
Andrej Gruden*
Klinični oddelek za gastroenterologijo, Interna klinika, Univerzitetni klinični Center, Ljubljana
Gastroenterolog 2013; suplement 2: 16–17
Ključne besede: ciste pankreasa, endoskopski ultrazvok,
tankoigelna aspiracijska biopsija
Keywords: endoscopic ultrasound, pancreatic cyst, fine
needle aspiration
POVZETEK
ABSTRACT
Z vse pogostejšo uporabo diagnostičnih tehnik
(UZ, CT, MRI) ugotavljamo tudi čedalje več pankreatičnih cist.
Pankreatične ciste so lahko ciste, pseudociste ali cistične neoplazme, ki jih nadalje delimo v serozne
cistadenome, mucinozne cistične neoplazme (MCN),
intraduktalne papilarne mucinozne neoplazme
(IPMN) in solidne pseudopapilarne neoplazme. Nekatere pankreatične ciste so benigne, nekatere imajo maligni potencial.
Endoskopski ultrazvok s tankoigelno aspiracijsko
biopsijo omogoča boljšo detekcijo in karakterizacijo
pankreatičnih cist.
An increased number of pancreatic cysts are being
diagnosed due to the increased use of cross-sectional
imaging. Pancreatic cysts can be either true cysts,
pseudocysts or cystic neoplasms, while these are further subdivided into serous cystadenomas, mucinous cystic neoplasms (MCN), intraductal papillary
mucinous neoplasms (IPMN) and solid psedopapillary neoplasm. Some pancreatic cyst are benign,
others have malignant potential.
Endoscopic ultrasound with FNA (fine needle aspiration) cytology and analysis of cystic fluid have led
to a better detection and characterization of the cysts.
INTRODUCTION
into serous cystadenomas, mucinous cystic neoplasms
(MCN), intraductal papillary mucinous neoplasms
(IPMN) and solid pseudoapillary neoplasms.
As a result of incresased use of cross-sectional imaging (US, CT, MRI), increased number of pancreatic
cysts are being diagnosed.
Most studies report the prevalence of pancreatic
cysts around 2,5% (1, 2). In some studies (3), the prevalence of pancreatic cyst was higher, up to 13,5%.
Pancreatic cysts can be true cysts, pseudocysts or
cystic neoplasms, while these are further subdivided
*Andrej Gruden, dr. med.
Klinični oddelek za gastroenterologijo, Interna klinika,
Univerzitetni klinični Center, Ljubljana
16 GASTROENTEROLOG
Some of pancretic cysts are benign, like pancreatic
pseudocyst or serous cystadenoma and do not require
resection when asymptomatic. Others like mucinous
cysts or intraductal papillary mucinous neoplasms
have malignant potential and in these cases surgical
resection is often indicated (4).
IMAGING
Diagnostic methods that are usually used in detection
and evaluation of pancreatic cysts include radiologic
imaging techniques such as ultrasound (US), computed
tomography (CT) and magnetic resonance imaging (MRI).
The primary problem with imaging alone in the evaluation of pancreatic cysts is that there are no clearly
differentiating features that allow a high degree of diagnostic accuracy and that imaging alone is inaccurate in
differentiating each of the types of pancreatic cysts (5).
EUS-FNA FOR PANCREATIC CYSTIC
FLUID ASPIRATION
Difficulties in establishing an accurate diagnosis with
imaging alone have promoted EUS as an useful diagnostic technique in the evaluation of pancreatic
cysts. EUS can provide fine detail on the characterisation of the cyst because of the very high spatial resolution. An advantage of the EUS is the possibility to
perform FNA for analysis of the cyst fluid (4, 5, 6).
The technique of cyst aspiration is relatively straightforward. Cyst is localised under EUS control, needle
is inserted via instrument and cyst is targeted. Ussualy single pass with a needle is performed and cyst
fluid is aspirated and sent to laboratory for cytology
examination and biochemical analysis. If there is any
solid component of the cyst, or intracystic mural nodules, it is punctured as well.
Cytological evaluation of pancreatic cyst fluid is
widely used. Several studies report a sensitivity to be
around 50% for the differentiation between mucinous and nonmucinous neoplasms (4, 5, 6).
Biochemical analysis of the fluid have been evaluated
for seveal years with the underlying thought that
markers secreted into the cyst fluid identify the epithelial lining. Amylase is usualy elevated in psedocyst
and IPMN and low in MCN and serous cystadenoma.
Of the tumor markers, CEA is considered to be the
best discriminant marker between a mucinous and
nonmucionous cyst. A low CEA level (<5 ng/ml) has
been shown to have a sensitivity between 50 and
100% and specificity 77–95% to differentiate between
mucinous and nonmucinous cysts. Pseudocysts and
serous cystadenomas generally have a low CEA value.
The most widely used cutoff for an elevated CEA is
192 ng/ml. This cutoff has sensitivity of 75% and
specificity 84% to discriminate between mucinous and
nonmucinous cysts (4). Howewer, 25% of mucinous
cysts will have CEA level lower than 192 ng/ml (7).
It may be possible to improve the analysis of the cyst
fluid by combining CEA level and molecular analysis
(DNA quantity, K-ras mutation, and allelic imbalance
mutations) (7).
In most hospital laboratories, 1 to 2 ml of liquid is
needed to perform CEA analysis. With some fluid
nedeed for citological examination, cyst should be at
least 1 to 2 cm in size to obtain sufficient fluid (5).
EUS FNA is considered as safe technique to obtain
pancreatic cyst fluid with rare, mostly mild complication, but infection, pancretitis and intracystic hemorrhage have been reported in about 2.4% (5).
REFERENCES
1. de Jong K, Nio CY, Hermnas JJ, et al. High prevalence of pancreatic
cysts detected by screening magnetic resonance imaging examinations.
Clinical gastroenterology and Hepatology. 2010;8(9):806–811
2. Laffan TA, Horton KM, Klein AP, et al. Prevalence of unsuspected
pancreatic cysts on MDCT. American Journal of Roentgenology.
2008;191 (3):802–807
3. Lee KS, Sekhar A, Rofsky NM, Pedrosa I. Prevalence of incidental
pancreatic cysts in the adult population on MR imaging. American
Journal of Gastroenterology.2010;105(9):2079–2084
4. de Jong K, Bruno Mj, Fockens P. Epidemiology, Diagnosis, and
management of Cystic lesions of the Pancreas. Gastroenterol Res
Pract 2012;2012:147465
5. Hawes RH, Clancy J, Hasan M. Endoscopic Ultrasound-Guided
Fine Needle Aspiration in Cystic Pancreatic Lesions. Clin Endosc.
2012 June; 45(2):128–31
6. Khalid A, Brugge W. ACG practice guidelines for the diagnosis
and management of neoplastic pancreatic cysts. Am J Gastroenterol 2007; 102:2339–49.
7. Bhutani MS, Gupta V, Guha S, Gheonea DI, Saftoiu A. Pancreatic
Cyst Fluid Analysisi- A Reviev. Gastrointestin Liver Dis. 2011
Jun;20(2):175–80
Image 1 Needle in the cyst lumen
GASTROENTEROLOG 17
Eozinofilni ezofagitis pri otrocih - novosti
Eosinophilic esophagitis in children: recent updates
Matjaž Homan*
Pediatrična klinika Ljubljana
Gastroenterolog 2013; suplement 2: 18–21
Ključne besede: eozinofilni granulociti, eozinofilni
ezofagitis, sluznica prebavil, biološka zdravila.
POVZETEK
Eozinofilni ezofagitis je kronična imunsko/antigensko
pogojena vnetna bolezen požiralnika, ki se lahko
pojavi kadarkoli v življenju. Za dokončno potrditev
bolezni je potrebno dokazati prekomerno kopičenje
eozinofilnih granulocitov v vsaj enem histološkem preparatu sluznice požiralnika tudi po zdravljenju z
visokimi odmerki zaviralcev protonske črpalke. Bolezen odkrivamo vse pogosteje, tako se incidenca
eozinofilnega ezofagitisa približuje incidenci kronične
vnetne črevesne bolezni. Zdravljenje s hipoalergično
dieto je še vedno najpogostejši način terapije. Topični
kortikosteroid budezonid z razliko od flutikazona
popolnoma obnovi sluznico požiralnika pri bolnikih
z eozinofilnim vnetjem. Zdravljenje je dolgotrajno, v
primerih, ko ni učinkovito, lahko pride do zoženja
požiralnika. V tem primeru je potrebna balonska dilatacija požiralnika, pri čemer število zapletov ni večje
kot v primeru zoženja požiralnika druge etiologije.
UVOD
Eozinofilni ezofagitis (EoE) je kronična bolezen požiralnika, ki je bila prvič opisana pred komaj 30 leti (1).
Bolezen sploh ni redka, saj jo diagnosticiramo pri 6 %
endoskopiranih bolnikov zaradi kakršne koli simptomatike in pri 15 % bolnikov, ki so imeli opravljeno
*Doc. dr. Matjaž Homan, dr. med.
Pediatrična klinika Ljubljana,
Bohoričeva 20, 1000 Ljubljana
18 GASTROENTEROLOG
gastroskopijo zaradi težkega požiranja (2). Kot drugod
v razvitem delu sveta tudi v Sloveniji prepoznamo
vsako leto več bolnikov z EoE. Večino otrok z EoE v
Sloveniji vodimo na Pediatrični kliniki v Ljubljani in
po pregledu podatkov zdravimo trenutno 26 otrok z
EoE. Ob pogostejšem prepoznavanju bolnikov raste z
logaritmično krivuljo tudi število objavljenih raziskav
o EoE. Kljub številnim objavam še vedno ostaja veliko
nejasnosti glede etiologije bolezni, prognoze in zapletov
nezdravljene bolezni, vrste vzdrževalnega zdravljenja
itd. V prispevku bom predstavil najnovejša priporočila
in pregled trenutnega znanja o EoE pri otrocih.
ZNAČILNOSTI EOZINOFILNEGA
EZOFAGITISA
EoE je kronična imunsko/antigensko pogojena vnetna
bolezen požiralnika, za katero je značilna refluksna
simptomatika in prisotnost eozinofilne infiltracije v
steni požiralnika (3). Ob tem je potrebno izključiti
bolezni, kot so gastroezofagealna refluksna bolezen
požiralnika in eozinofilna infiltracija požiralnika,
odzivna na zdravljenje z inhibitorji protonske črpalke.
Diagnoza še vedno temelji na histološkem dokazu
> 15 eozinofilnih granulocitov na polje velike povečave
v epiteliju požiralnika v vsaj enem izmed histoloških
odvzemov, s to razliko, da mora biti prekomerna prisotnost eozinofilnih granulocitov prisotna tudi po
dvomesečnem zdravljenju z visokimi odmerki zaviralcev protonske črpalke. Glede na posodobljena
priporočila v posameznih primerih lahko govorimo o
EoE, tudi če je so v histopatološkem izvidu opisani
eozinofilni mikroabsces ali ekstracelularne eozinofilne granule, bazalno celično hiperplazija in široki
medcelični prostori. Ob tem je potrebno poudariti, da
je nujno potrebno med gastroskopijo odvzeti vsaj dva
vzorca sluznice spodnjega dela požiralnika in dva
vzorca sluznice zgornjega dela požiralnika. Če odvzamemo pet vzorcev požiralnika, postane občutljivost
preiskave skoraj 100 % (4). Pogostost EoE narašča. Če
je bilo do leta 2007 opisanih 212 primerov bolnikov z
EoE, v zadnjih letih opisujejo prevalenco 0,02 % v
Švici (5), 0,44 % v ZDA (6) in 1 % na Švedskem (7).
Bolezen se pojavlja pogosteje pri moških. Gen TSLP,
ki nosi zapis za citokin, ki vpliva na odgovor Th2, se
nahaja na kromosomu X, s čimer lahko deloma razložimo nagnjenost moških k razvoju EoE (8). Poleg
mutacije gena TSLP najdemo pri bolnikih z EoE
pogosto še mutacijo gena filagrin in gena, ki se nahaja
na 5q22 mestu genoma (9, 10). Etiologija EoE še ni
popolnoma jasna. Večinoma sprožijo eozinofilno vnetje v steni požiralnika alergeni iz hrane ali zraka. Z
alergološkimi testi najpogosteje dokažemo preobčutljivost na beljakovine kravjega mleka, pšenice, soje in
rži (11). EoE se najverjetneje lahko razvije tudi po virusni okužbi, po kemični poškodbi sluznice požiralnika
in po dolgotrajni terapiji z zaviralci protonske črpalke
(23, 13). Klinična slika je nespecifična in je odvisna od
starosti. Majhni otroci so neješči, njihova telesna teža
počasneje napreduje, pri šolskih otrocih pa prevladujeta bolečina v zgornjem delu trebuha in za prsnico
ter bruhanje. Bolečine pri požiranju, zatikanje hrane
in zagozdenje kosa hrane v zgornji prebavni cevi se
značilno pojavljajo pri adolescentih in odraslih bolnikih. Pri pogovoru z bolnikom in s starši moramo biti
natančni, saj otroci lahko z določenimi prehrambnimi
navadami zakrijejo težave pri požiranju; izogibajo se
npr. čvrste hrane, režejo kose hrane na zelo majhne
koščke, zalivajo hrano s tekočino. Med pregledom je
potrebno oceniti rast in razvoj otroka, ki se zaradi
same bolezni ali dietnega zdravljenja lahko upočasnita
(3). Endoskopija zgornjih prebavil z odvzemom bioptov ostaja ‘zlati standard‘ pri diagnostiki EoE. Značilen
endoskopski izvid brez histološke potrditve ne zadošča
diagnostičnim kriterijem. Bolniki z EoE imajo pogosto tipičen endoskopski izgled sluznice požiralnika, ki
je granulirana, razbrazdana ali obročaste strukture. V
primeru intenzivnega vnetja so prisotne bele obloge.
Izgled sluznice požiralnika je lahko ob endoskopski
preiskavi tudi popolnoma normalen. Hirano s sod. je
predlagal endoskopsko klasifikacijo EoE z namenom
enotne ocene stopnje vnetja in ocene odziva na zdravljenje (14). Otroci z EoE obolevajo pogosto še za
drugimi atopičnimi boleznimi, kot so astma, atopični
dermatitis, seneni nahod in alergični konjunktivitis in
so pogosto preobčutljivi na alergene iz zraka. Pri
obravnavi otroka z EoE je zato nujna alergološka
obravnava, vključno s krvnimi, kožnimi in krpičnimi
alergološkimi testi. EoE in poslabšanja bolezni se
pogosteje pojavljajo v določenih mesecih v letu, kar je
najverjetneje posledica pridružene alergije na alergene
iz zraka. Ob primerno zdravljenih pridruženih boleznih alergične etiologije je tudi možnost za poslabšanje
EoE manjša (15). Z izjemo invazivne endoskopske diagnostike s histopatološko obravnavo bioptov ni druge
metode, s katero bi opredelili stopnjo alergičnega ezofagitisa. Vrednosti celokupnih IgE, koncentracije
eozinofilnih granulocitov v krvi, citokinov IL-5 in
IL-13 ne korelirajo zanesljivo s stopnjo eozinofilnega
vnetja, zato je potrebno pri otrocih endoskopske preiskave pogosto ponavljati. Furuta s sod. je pred letom
dni predstavil Enterotest, ki s pomočjo vrvice, ki jo
napeljemo v požiralnik, na različnih dolžinah izmeri z
ELISA metodo koncentracijo beljakovin, ki se sprostijo pri degranulaciji eozinofilnih granulocitov v steni
požiralnika (major basic protein-1, eosinophil-derived
neurotoxin, eosinophil cationic protein, eosinophil
peroxidase) (16). Enterotest bo mogoče v prihodnosti
nadomestil kontrolne endoskopije zgornjih prebavil,
saj koncentracije beljakovin dobro korelirajo s stopnjo
eozinofilnega vnetja pri bolnikih z EoE.
ZDRAVLJENJE EOZINOFILNEGA
EZOFAGITISA
Uspešnost zdravljenja EoE je potrebno preveriti z endoskopijo in biopsijo zgornjih prebavil. Tudi če bolnik z
EoE nima več težav, to še ne zagotavlja remisije alergiGASTROENTEROLOG 19
čnega vnetja sluznice požiralnika. O uspešni terapiji
lahko govorimo, če število eozinofilnih granulocitov po
zdravljenju ne preseže 15 celic na polje velike povečave.
Zdravljenje s hipoalergično dieto je še vedno najpogostejši način terapije, ki jo uporabljamo pri otrocih z
EoE. V primeru da z alergološkimi krvnimi, kožnimi
ali krpičnimi testi dokažemo preobčutljivost na
določene prehranske alergene, uvedemo ciljano hipoalergično dieto. Uspešnost terapije preverimo z
endoskopijo zgornjih prebavil 8 do 12 tednov po
uvedbi diete. Če je stena požiralnika še prekomerno
infiltrirana z eozinofilnimi granulociti, bolnika zdravimo z ’dieto šest‘, ki ne vsebuje beljakovin mleka, jajc,
soje, pšenice, morske hrane in oreščkov. Če se dieta
brez šestih skupin živil izkaže kot neučinkovita, predlagamo elementarno prehrano. Elementarna prehrana
je najprimernejša terapija za dojenčke in majhne
otroke s številnimi alergijami in EoE (3). Če ima otrok
težave in se ne strinja oziroma se ne zmore prehranjevati z izključno elementarno prehrano, ga zdravimo z
zdravili. Če ga zdravimo z izključno elementarno prehrano, lahko opravimo kontrolno endoskopijo že po 4
do 6 tednih in nato postopno uvajamo manj alergogene vrste hrane. Pri prehranskem zdravljenju je nujno
potrebno v obravnavo vključiti dietetika. Če za določeno vrsto hrane s provokacijo dokažemo, da sproži
zagon EoE, bo najverjetneje potrebna ciljana dieta do
konca življenja (15).
Med zdravili so najučinkovitejši sistemski kortikosteroidi. Pri 90 % bolnikov z EoE pride leto dni po
prenehanju zdravljenja do ponovitve vnetja. Tako je pri
otrocih z EoE potrebno vzdrževalno zdravljenje z nizkimi odmerki kortikosteroidov, ki pogosto povzročijo
stranske učinke. Zaradi tega zdravimo bolnike z EoE
s sistemsko obliko kortikosteroidov v odmerku 1 mg
na kg TT le v primerih izrazito oteženega požiranja,
dehidracije, pomembne izgube TT in zoženja požiralnika (3). Topični ali lokalno delujoči kortikosteroidi v
obliki pršila ali tekočine viskozne gostote so najpogosteje predpisana zdravila pri zdravljenju EoE. Razen
glivičnega vnetja ustne sluznice to zdravljenje nima
stranskih učinkov in je dokaj uspešno. Ob prekinitvi
terapije z lokalnimi kortikosteroidi pride pogosto do
ponovitve bolezni. Do leta 2007 se je pri opisanem
20 GASTROENTEROLOG
zdravljenju uporabljal izključno flutikazon v obliki
pršila, v zadnjih letih pa ga je nadomestil budezonid v
obliki viskozne tekočine. Raziskave so pokazale, da je
budezonid enako učinkovit kot flutikazon, poleg tega
pa povzroči popolno regeneracijo sluznice požiralnika
(17). Odmerek flutikazona je od 88–440 μg 2–4-krat
dnevno za otroke in 440–880 μg dvakrat dnevno za
adolescente in odrasle bolnike (3). Budezonid je potrebno prejemati v odmerku 1 mg na dan za otroke do
desetega leta starosti in 2 mg dnevno za ostale bolnike.
V primeru, da učinka ne dosežemo, lahko zvišamo
odmerek do 2.8 mg dnevno pri otrocih do desetega
leta starosti in do 4 mg dnevno pri starejših od 10 let
(18). Topični kortikosteroidi so učinkovitejši pri mlajših otrocih in pri bolnikih, ki nimajo dokazanih
alergij (19). Kot pri zdravljenju s sistemskimi kortikosteroidi tudi po ukinitvi topičnih kortikosteroidov
pride do zagona EoE. Straumann s sod. je v raziskavi
ugotovil, da je bilo 50-tedensko vzdrževalno zdravljenje z nizkimi odmerki topičnega budezonida pri 28
odraslih bolnikih z EoE učinkovito le pri nekaj več kot
tretjini bolnikov (20).
Med novejše načine zdravljenja bolnikov z EoE sodijo
zdravljenje z antagonisti leukotrienskih receptorjev,
azatioprinom, 6-merkaptopurinom in z biološkimi
zdravili. Izmed naštetih zdravil so najbolj obetavna biološka zdravila. Med najpomembnejše citokine, ki
sodelujejo v nastanku in vzdrževanju vnetja, spada
IL-5. Protitelesa proti citokinu IL-5 (mepolizumab) so
že uporabili v posameznih kliničnih raziskavah pri
bolnikih s hudimi oblikami EoE (21). Reslizumab je
humanizirano protitelo, ki neutralizira citokinske
učinke IL-5. V raziskavo so vključili 226 otrok z EoE,
prejeli so 4 odmerke biološkega zdravila. Do kliničnega
izboljšanja v večini primerov ni prišlo, zmanjšalo pa se
je število eozinofilnih granulocitov v steni požiralnika
(22). Bolj ali manj neuspešno so poskušali uporabiti v
zdravljenju še omalizumab in infliksimab (23, 24).
Če se kljub zdravljenju kot posledica kroničnega vnetja razvije zoženje požiralnika, je potrebna balonska
dilatacija. Dolgo časa je veljalo, da je pogostnost zapletov po balonski dilataciji večja pri bolnikih z EoE.
Rezultati zadnje metaanalize pa so pokazali, da je šte-
vilo teh zapletov podobno kot v primeru drugih indikacij za širjenje požiralnika s pomočjo endoskopa
(25). Res pa je, da je pogostnost predrtja požiralnika
po dilataciji večje pri bolnikih z EoE, ki imajo zoženje v zgornji tretjini požiralnika in kjer se razvije
skoraj popolna zapora lumna prebavne cevi (26).
9.
10.
11.
ZAKLJUČEK
12.
EoE je kronična bolezen, ki se pojavlja v vseh starostnih
skupinah, najpogosteje pa obolimo do štiridesetega
leta starosti. Glavni diagnostični kriterij je prekomerna
infiltracija stene požiralnika z eozinofilnimi granulociti. EoE in učinek zdravljenja EoE lahko potrdimo
samo z endoskopijo zgornjih prebavil, pri kateri odvzamemo biopte požiralnika. Pogostnost bolezni v razvitem
svetu hitro narašča. Najpogosteje bolezen zdravimo
s hipoalergičnimi dietami, v primeru neuspeha pa uporabimo topično kortikosteroidno terapijo. Tudi če
otrok z EoE nima posebnih težav, je potek EoE potrebno endoskopsko spremljati, če že ne zdraviti, saj
lahko sčasoma povzroči razvoj strikture požiralnika
in motnje peristaltike (27).
13.
14.
15.
16.
17.
18.
19.
Če zdravljenje z dietami in kortikosteroidi pri težje
potekajočem EoE ne bo imelo učinka, bomo v prihodnosti najverjetneje uporabljali biološka zdravila.
LITERATURA
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Cianferoni A, et al. Common variants at 5q22 associate with pediatric eosinophilic esophagitis. Nat Genet. 2010; 42(4): 289–91.
Erwin EA, James HR, Gutekunst HM, Russo JM, Kelleher KJ,
Platts-Mills TA. Serum IgE measurement and detection of food
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Achem SR. Endoscopic assessment of the oesophageal features
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GASTROENTEROLOG 21
Portal hypertension: its management in 2013.
Yves Horsmans*
Head of Internal Medicine Department, Cliniques Universitaires Saint-Luc (U.C.L.), Brussels, Belgium
Gastroenterolog 2013; suplement 2: 22
Portal hypertension remains one of the major complications of liver cirrhosis and is defined as an
hepatic venous pressure gradient (HVPG) of more
than 5 mmHg. Clinically significant portal hypertension is defined as HVPG of 10 mmHg or more.
Development of gastroesophageal varices and variceal
hemorrhage are the most direct consequence of portal hypertension. Over the last decades, significant
advancement in the field has led to standard treatment options.
In this presentation, Baveno V consensus will be presented by outlining the most important steps which
have to be taken into account in the management of
the different stages of portal hypertension.
In the context of primary prophylaxis, the place of
endoscopy, portal pressure gradient measurement,
drugs such as non-selective beta-blockers and treatment
of primary cause of liver disease will be discussed.
At the stage of acute variceal bleeding, the implementation of adequate fluid ressuscitation and transfusion,
antibiotics, vasoactive drugs, therapeutic endoscopy
and transjugular intrahepatic portosystemic shunt
(TIPS) as well as liver transplantation will be put in
perspective. A focus on the differences between
vasoactive drugs will be presented.
Finally, the role of secondary prophylaxis will also
be outlined.
*Yves Horsmans, M.D., PhD
Head of Internal Medicine Department, Cliniques Universitaires Saint-Luc (U.C.L.)
Brussels, Belgium
22 GASTROENTEROLOG
Kako napovedati izid zdravljenja jetrnih
zasevkov raka debelega črevesa in danke?
How to predict the treatment outcome of
colorectal liver metastases?
Arpad Ivanecz*, Tomaž Jagrič, Matjaž Horvat, Stojan Potrč
Oddelek za abdominalno in splošno kirurgijo, Univerzitetni klinični center - Maribor
Gastroenterolog 2013; suplement 2: 23–24
UVOD
BACKGROUND/AIMS
Namen prispevka je ugotoviti, ali lahko z biološkimi označevalci ob znanih kliničnih dejavnikih
tveganja (CRS) pripomoremo k napovedovanju
izida zdravljenja jetrnih zasevkov raka debelega
črevesa in danke (RDČD).
The aim of this study was to assess whether biological markers can provide additional prognostic information to that supplied by clinical risk score (CRS)
for colorectal liver metastases (CRLM).
METHODS
METODE
Opravljen je bil pregled jetrne datoteke našega
oddelka. Bolniki izbrani za analizo so bili zdravljeni
zaradi zasevkov RDČD s potencialno kurativno resekcijo jeter v obdobju od 1996 do 2011. Izražanje p53,
Ki-67 in timidilat sintaze smo določali s tehniko imunohistokemije na izdelanih tkivnih mrežah.
A retrospective review of a prospectively maintained
database was conducted. Patients selected for this study
were treated between 1996 and 2011 with potentially
curative liver surgery. p53, Ki-67, and thymidylate
synthase were assayed using immunohistochemical
techniques on tissue microarrays.
RESULTS
REZULTATI
Izmed 406 bolnikov jih je 98 (24 %) izpolnjevalo kriterije vključitve. Mediani čas sledenja je bil 103 mesece.
Statistična analiza je razkrila korelacijo med prekomerno izraženim p53 in visokim CRS (P = 0.058). Po
multivariatni analizi je samo visoki CRS ostal negativni
napovedni dejavnik preživetja (P = 0.018) in hkrati tudi
pokazatelj zgodnje ponovitve obolenja (P = 0.010).
Med biološkimi označevalci je po multivariatni
analizi samo prekomerno izraženi Ki-67 ostal pozitivni
napovedni dejavnik preživetja (P = 0.038).
A total of 98 (24%) of 406 patients met the inclusion criteria. The median follow-up was 103 months. Analysis
revealed a correlation between p53 protein overexpression and high CRS (P = 0.058). Following multivariate
analysis, only high CRS remained an independent
negative prognostic predictor for survival (P = 0.018) as
well as an indicator of early recurrence of disease
(P = 0.010). Of the biological markers investigated, only
Ki-67 overexpression was identified as a positive predictor of survival on multivariate analysis (P = 0.038).
Arpad Ivanecz*
Oddelek za abdominalno in splošno kirurgijo, Univerzitetni klinični center - Maribor,
Ljubljanska 5, 2000 Maribor, Slovenija
GASTROENTEROLOG 23
ZAKLJUČKI
CONCLUSIONS
Prekomerno izraženi Ki-67 se je pokazal kot pozitivni
napovedni dejavnik preživetja. Samo visoki CRS je
ostal neodvisni negativni napovedni dejavnik.
Ki-67 overexpression was a positive predictor of survival.
Only high CRS remained an independent negative
prognostic predictor.
24 GASTROENTEROLOG
»Zdravljenje napredovalega HCC –
slovenske izkušnje«
Management of advanced HCC - Slovenian
experience
Rado Janša*
Clinical Department of Gastroenterology, University Medical Centre, Ljubljana
Gastroenterolog 2013; suplement 2: 25–29
Ključne besede: jetrnocelični rak, diagnostika, zamejitev
bolezni, napredovala bolezen, naše izkušnje
Key words: hepatocellular carcinoma, diagnosis, staging,
advanced stage of HCC, our experience with systemic treatment
POVZETEK
ABSTRACT
Jetrnocelični karcinom je bolezen dveh stopenj –
ciroze in raka. Pomembno je zdravljenje obeh.
Odločitev za optimalno diagnostiko, zamejitev in
zdravljenje naj sprejme multidisciplinarni konzilij,
ki obravnava vsakega bolnika posebej. Za zamejitev
se priporoča sistem Barcelona Clinic Liver Cancer
(BCLC). Zdravilo izbora za napredovali HCC je
sorafenib. V klinični praksi je ključnega pomena
preudarna izbira bolnikov in načina zdravljenja.
Analiza zdravljenja naših bolnikov z napredovalim
HCC je prikazala, da je zdravljenje s sorafenibom
učinkovito in varno.
HCC is a two stage disease - cirrhosis and tumor. It is
very important to treat both of them. Multidisciplinary groups should decide on the optimal diagnosis,
staging and treatment of the individual patient. It is
important to use single staging system. BCLC staging system is recommended. Sorafenib is standard
of care for advanced HCC. The key point in clinical
practise is careful selection of patients and treatment
of liver diseases and the tumor. In conclusion, our
analysis of group of patients with advanced HCC
demonstrates that the therapy with sorafenib is safe
and effective.
INTRODUCTION
cancer in the world and third most common cause
of cancer-related death worldwide (2).
Hepatocellular carcinoma (HCC) is an epithelial liver
tumor of which the cells are mostly similar with
hepatocytes (1). The incidence of HCC has risen
over the past 2 decades and is expected to increase
over the next decade. HCC presents almost all primary cancer of the liver (over 90%) and is a highly
lethal malignancy. HCC is the fifth most common
World map of the prevalence of HCC is identical to
the distribution of hepatitis B (HBV) and hepatitis C
(HCV) viral infection. Even today, these two etiologic
factors for HCC are very important, although other
causes of cirrhosis are important too.
*Rado Janša
Clinical Department of Gastroenterology,
University Medical Centre, Ljubljana
GASTROENTEROLOG 25
The liver with advanced fibrosis and cirrhosis
undoubtly represents an ideal soil for the development
of a HCC. The annual risk of HCC in patients with cirrhosis ranges from 1%–6% (3). It is very important to
emphasize that HCC is a two state disease – a HCC
TUMOR and an underlying LIVER DISEASE, most
commonly cirrhosis (4, 5).
HCC represents heterogeneous disease in which
dysplastic lesion can evolve into a malignant tumor
(6). In less than 10% of cases, HCC occurs in a normal, non-cirrhotic liver. Molecular classification
system was described and some HCC contain
biliary type cytokeratins (CK7 and/or CK 19) positive cells. This cases have poor prognosis. On the
contrary, fibrolamellar type of HCC occuring in
younger patients without risk factors is a rare
TAB 1: Risk of HCC (Bruix 2010)
variant with a slow growing nature and resistence
to systemic therapy but significantly better prognosis (7 ,8).
Risk factors for development of HCC are different
and individual. They may represent accumulation
of diferent diseases and form the basis for surveillance program for HCC.
Some risk factors represent the cause(s) of liver
disease (HBV, HCV, alcohol, iron overload, fatty
liver), the severity of the liver disease (advanced
fibrosis) and epidemiological factors (male gender,
obesity, diabetes) (2) (TAB 1).
DIAGNOSIS
The diagnosis of HCC is based on the combination of
clinical, laboratory and imaging (sometimes even pathology) examination. Imaging has a great value
especially in cirrhotic liver. Several studies showed that
MRI has a sensitivity and specificity of 75% and 76%
for a diagnosis of HCC, which is better than the sensitivity and specificity of 61% and 66% for triple-phase
spiral CT (9, 10). The presence of washout in arterially
enhancing lesion increases the probability of HCC 65
fold (10). So the main characteristics are arterial hypervascularity and venous or delayed phase washout (9).
Sometimes two contrast enhanced studies should be
done. If the scan doesn‘t show typical features of HCC,
than a second contrast-enhanced study is required.
This reduces the frequency of biopsies.
Threshold
incidence
per year
Incidence
Asian male HBV
carriers > age 40
0.2%
0.4%-0.6% per year
Asian females
HBV carriers
>age 50
0.2%
0.3%-0:6% per year
HBV carrier with
family history of
HCC
0.2%
Incidence than
without family
history
African/North
American Blacks
with HBV
0.2%
HCC occurs at a
younger age
0.2%–1.5%
3%-8% per year
STAGING
Hepatitis C
cirrhosis
1.5%
3%-8% per year
Stage IV PBC with
cirrhosis
1.5%
3%-8% per year
Treatment of HCC depends on the tumor staging, liver
function tests and performance status of the patient.
Genetic
hemochromatosis
and cirrhosis
1.5%
Unkown but probably
>1.5%per year
Alpha 1-antitrypsin
deficiency and
cirrhosis
1.5%
Unkown bur probably
>1.5% per year
Other cirrhosis
1.5%
Unkown
Population group
Cirrhotic HBV
carriers
26 GASTROENTEROLOG
Staging is very important, because ever more treatments of HCC depend on the tumor staging.
Staging systems for HCC have to define our treatment decision and outcome prediction. The BCLC
(Barcelona Clinic Liver Cancer) is recommended
(evidence 2A, recommendation 1B) (4) (TAB2).
TAB 2: BCLC STAGING SYSTEM (BY Liovet 2011)
Until 2007, there wasn’t any systemic drug recommended for patients with advanced stage of HCC.
Treatment with multi-tyrosine kinase inhibitor –
sorafenib is now the standard of care for such
patients since 2007 (in Slovenia since 2008).
- objective response rate was less than 10% (17). The
results of double blind phase III study with the multikinase inhibitor sorafenib were reported. Sorafenib in
Child Pugh A patients with advanced HCC was well
tolerated and showed significant relative improvement
(44%) in overall survival (10,7 months vs 7,9 months)
(16,18). A similar benefit of sorafenib was concluded
in Asian-Pacific study which included patients in
Child Pugh A and B (median OS 6,5 months vs 4,2
months) (17). The most frequently reported drug related side effects were hand-foot-skin reaction, diarrhea,
alopecia, fatigue, hypertension and anorexia. Adverse
events are mostly Grade 1 or 2 (17). In Gideon-Interim analysis 2010 (511 patients) was reported about
8,6 months of median OS in Child Pugh A and 4,0
months in Child Pough B group of patients (19).
The difference between patients with advanced stage
and the intermediate stage of HCC is the presence of
portal vein involvment and/or extrahepatic spread (4).
Sorafenib improves overall survival when compared to
placebo (16). Systemic therapy with classic cytotoxic
drugs did not improve overall survival rate, even more
At University Medical Centre Ljubljana we analysed 71 patients with advanced stage of HCC who
were treated with sorafenib in the period between
2008 - 2012. Out of 71 patients we statistically analysed 59 patients. Our decisions for treatment were
based on BCLC classification of HCC and were
TREATMENT OF ADVANCED HCC OUR EXPERIENCE
The base for treatment of HCC is multidisciplinary
team decision. Treatment depends on the tumor
staging (TAB 3) (11–15).
The majority of patients present with advanced stages
and are therefore not candidates for curative treatment
and/or transarterial chemoembolization (TACE).
GASTROENTEROLOG 27
HCC in cirrhosis
Child-Pugh, PS 0
Very early stage
Single <2cm
Early stage
1 nodule<5cm or
3<3cm
Curave treatments
(resecon, radiofrequency ablaon,
liver transplantaon)
Child-Pugh A-B, PS 0-2
Intermediate stage
Mulnodular, PS 0
Transarterial chemoembolizaon
Child-Pugh C*, PS>2
Advanced stage
Terminal stage
Portal invasion.
nodal involvement
metastases, PS 1-2
Sorafenib*
Symptomac
treatment
TAB 3: Strategy for staging and treatment assignment in patients diagnosed with HCC (adapted from Bruix e et al., 2005) (10).
Abbrevations: PS, performance status, *Poor liver synthetic function due to tumour involvement of the liver.* Only Child-Pugh A.
made in multidisciplinary team. In TAB 4,5 and 6
we can see data for gender, etiology and liver function.
CONCLUSIONS
On the base of our data Kaplan-Meier analysis predicted survival rate and death time rate - TAB 7, TAB 8.
HCC is a two stage disease - cirrhosis and tumor. It is
very important to treat both of them! Multidisciplinary groups should decide on the optimal diagnosis,
staging and treatment of the individual patient. It is
important to use single staging system. BCLC staging system is recommended. Sorafenib is standard
of care for advanced HCC. The key point in clinical
practise is careful selection of patients and treatment
of liver diseases and the tumor. In conclusions, our
analysis of group of patients with advanced HCC
demonstrates that the therapy with sorafenib is safe
and effective.
TAB 4
TAB 5
Mean interval from diagnosis until treatment with
sorafenib was 6,75 months and the duration of
treatment was 10,5 months. Average interval of drug
usage was 9,29 months. Median survival time from
the diagnosis of HCC and those treated with sorafenib (advanced stage HCC, Child Pugh A and B 8)
was 16, 8 months (maximal 47 months, minimal 2
months) (12,357 months).
28 GASTROENTEROLOG
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TAB 6
TAB 7
TAB 8
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GASTROENTEROLOG 29
Laparoskopske resekcije raka debelega
črevesa in danke
Laparoscopic surgery for colorectal cancer
Franc Jelenc*, Robert Juvan
Klinični oddelek za abdominalno kirurgijo, Kirurška klinika, Univerzitetni klinični center Ljubljana
Gastroenterolog 2013; suplement 2: 30–34
Ključne besede: laparoskopske resekcije, rak debelega
črevesa, rak danke
Keywords: laparoscopic resections, colorectal cancer
POVZETEK
ABSTRACT
Laparoskopske resekcije raka debelega črevesa in
danke so se uveljavile v zadnjih dveh desetletjih. V
randomiziranih študijah so potrdili prednost laparoskopskih operacij debelega črevesa zaradi raka pred
odprtimi operacijami. Tudi rezultati preživetja po
laparoskopskih resekcijah so primerljivi z odprtimi
operacijami. Zgodnji rezultati po laparoskopskih
resekcijah raka danke so enakovredni rezultatom po
odprtih resekcijah, za oceno dolgoročnega preživetja
pa bo potrebno več študij. V zadnjih letih se z
napredkom tehnologije uveljavljajo nove laparoskopske tehnike operacij skozi en rez (single incision
laparoscopy) in operiranja s pomočjo robota.
Laparoscopic resections of colorectal cancer have
advantages over open surgical procedures, proven in
randomized trials, and their frequency is increasing
in the last two decades. Early patient survival is comparable to open surgery; long-term survival data is
still scarce and more studies are needed. New laparoscopic techniques are evolving in recent years, such
as single incision laparoscopy and robotically assisted
surgery.
UVOD
sprejete zadržano zaradi zgodnjih poročil o večjem
odstotku metastaz na mestu troakarjev. Postavljala so
se vprašanja prednosti laparoskopske operacije pred
odprto glede na stroške, daljši čas operacije in tehnično zahtevnost. Še bolj pomembno je bilo vprašanje
ali je laparoskopska kirurgija onkološko enakovredna
klasičnim pristopom. Kasnejše študije so pokazale, da
je pogostost ponovitev bolezni in metastaz na mestu
troakarjev enaka kot pri klasičnih operacijah (3). Pred-
Rak debelega črevesa in danke je v Sloveniji po pogostnosti pri ženskah na tretjem mestu in pri moških na
drugem mestu (1). Kirurgija je še vedno temeljni
način zdravljenja raka debelega črevesa in danke. V
začetku devetdesetih let so bile narejene prve laparoskopske resekcije debelega črevesa zaradi raka (2).
Laparoskopske resekcije črevesa zaradi raka so bile
*Doc. dr. Franc Jelenc, dr. med.
Klinični oddelek za abdominalno kirurgijo, Kirurška klinika,
Univerzitetni klinični center Ljubljana
30 GASTROENTEROLOG
nost laparoskopske metode pred klasično operacijo je
v krajši hospitalizaciji, manjši bolečini po operaciji ter
hitrejšem okrevanju. Pri rakavem bolniku je potencialna prednost laparoskopskega pristopa v manjši
kirurški travmi in manjšem vplivu na imunski sistem,
kar naj bi zmanjšalo število ponovitev bolezni in vplivalo na kakovost življenja operiranih bolnikov (4, 5).
RAK DEBELEGA ČREVESA
V velikih randomiziranih multicentričnih študijah kot
so Clinical Outcomes of Surgical Therapy (COST) iz
Severne Amerike, Conventional versus LaparoscopicAssisted Surgery in Colorectal Cacer (CLASICC) iz
Velike Britanije, European Colon Cancer Laparoscopic
or Open Resection (COLOR), Australian Laparoscopic
Colon Cancer Surgical trial (ALCCaS), in v študijah
posameznih centrov v Hong Kongu, Barceloni in Italiji,
so dokazali prednost zgodnjih rezultatov laparoskopskih resekcij pred odprtimi operacijami (6, 7, 8, 9, 10,
11, 12).
Velika prednost laparoskopskega pristopa je krajša
incizija in posledično manjša bolečina in uporaba
analgetikov. Bolniki so po laparoskopskih operacijah
potrebovali tudi do 30 % manj analgetikov kot pri klasičnih operacijah (13). Ohtani je s sodelavci ugotovil,
da se pljučna funkcija pri bolnikih, ki so bili operirani
na laparoskopski način hitreje normalizira (14).
Manjša operativna travma vodi do hitrejše vzpostavitve
motititete črevesa po laparoskopskih resekcijah (9, 11).
Čas hospitalizacije in povratek v normalno aktivnost
je daljši po klasičnih operacijah (13). Čas operacije je
statistično značilno daljši pri laparoskopskih resekcijah zaradi tehnično bolj zahtevnih postopkov (8, 9,
10, 11). Zaradi boljše preglednosti pa je izguba krvi
med operacijo manjša (14).
Preklop iz laparoskopske operacije v odprto je potreben, če ni posega mogoče poseg končati varno za
bolnika, oziroma zadostiti onkološkim principom.
Največkrat so razlogi za preklop preraščajoč tumor,
obsežne prirastline in nejasne anatomske prilike, da
bi lahko prikazali pomembne anatomske strukture
(13). Pomemben dejavnik je tudi izkušenost kirurga,
saj odstotek preklopov pada s številom opravljenih
posegov. V CLASICC študiji so dokazali pomen učne
krivulje, saj se je odstotek preklopov, ki je bil v prvem
letu 38 % zmanjšal na 16 % v šestem letu (7). Da bi
kirurg uspešno operiral na laparoskopski način, naj
bi naredil najmanj 20 laparoskopskih resekcij debelega črevesa, zadosti izkušenj pa naj bi pridobil po
opravljenih 20 do 50 laparoskopskih posegih (14).
Preklop negativno vpliva na zgodnje in pozne rezultate po laparoskopskih resekcijah. Več je zapletov med
operacijo, po operaciji, podaljša se čas hospitalizacije v
primerjavi s posegi, ki so dokončani na laparoskopski
način. Preživetje bolnikov je krajše zaradi pogostejših
lokalnih ponovitev bolezni. V COST in CLASICC študijah je bilo 5-letno preživetje statistično značilno
slabše. Razlog je lahko tudi višji stadiji bolezni v katerih so bili operirani ti bolniki (6, 7).
Zgodnji rezultati
Cochrane analiza 25 randomiziranih kontroliranih
študij, v katerih so primerjali laparoskopske in
odprte posege zaradi benignih in malignih bolezni
debelega črevesa in danke je pokazala, da je bilo statistično značilno manj zapletov po laparoskopskih
operacijah v primerjavi z odprtimi (18,2 proti 23 %).
Značilno manj je bilo vnetij rane, medtem ko je bil
odstotek dehiscenc anastomoz med obema skupinama bolnikov enak. Prav tako je bilo značilno
manj ileusov po laparoskopskih posegih (14, 15).
V študijah niso ugotovili razlike v pooperativni
smrtnosti med laparoskopskimi in odprtimi posegi
zaradi raka debelega črevesa (14, 16).
Radikalnost kirurške resekcije ocenjujemo z številom odstranjenih bezgavk in velikostjo odstranjenega
dela črevesa. Pomenbni so proksimalni, distalni in
cirkumferencialni resekcijski robovi, na podlagi
katerih patolog oceni radikalnost operacije. V študijah ni razlike med številom odstranjenih bezgavk
med laparoskopsko in odprto operacijo (10, 12). V
študiji ALCCaS je bil distalni resekcijski rob značilno daljši kot pri odprti operaciji (9).
GASTROENTEROLOG 31
Pozni rezultati
Kvaliteta življenja
V COST študiji so ugotovili, da po laparoskopskih
resekcijah debelega črevesa ni več lokalnih ponovitev
bolezni kot po odprtih operacijah. Prav tako ni razlike
v 5-letnem preživetju. Ti podatki kažejo, da je laparoskopski poseg enakovreden odprtemu in je onkološko
varen (17). Te rezultate so potrdili tudi tudi v študijah
COLOR in CLASICC. Braga je s sodelavci primerjal
laparoskopske in odprte resekcije zaradi raka leve
strani debelega črevesa. V analizi je zajel skupino 268
bolnikov. Povprečen čas opazovanja je bil 73 mesecev.
5-letno preživetje in prosti interval sta bila podobna v
obeh skupinah. Ni bilo razlike v pojavljanju oddaljenih
metastaz in metastaz na mestu troakarjev. V tej študiji
niso našli razlike med pojavom incizijskih kil, zaporo črevesa in stenozo anastomoz med obema skupinama (12).
Nekatere študije kažejo boljšo kvaliteto življenja po
laparoskopskih resekcijah raka debelega črevesa do
enega leta, kasneje se ti učinki izenačijo z odprtimi
operacijami (22, 23).
V drugi randomizirani študiji Lacyja in sodelavcev, v
kateri je bil mediani čas opazovanja 95 mesecev, je
bilo preživetje bolnikov po laparoskopskih operacijah
statistično značilno daljše kot po odprtih operacijah.
To se je pokazalo predvsem pri bolnikih z rakom
debelega črevesa v stadiju III (18).
Dosedanje študije so obravnavale bolnike z lokalno
omejenim rakom debelega črevesa. Z napredkom
tehnologije, izkušnjami pa raziskujejo tudi vlogo
laparoskopskih resekcij pri napredovalih rakih
debelega črevesa (19).
Vpliv na imunski odgovor organizma
Zaradi manjše poškodbe tkiv pri laparoskopskih
operacijah naj bi se sproščalo manj citokinov.
Posledično naj bi bil zmanjšan imunski odgovor
organizma. Vrednosti interlevkina-6 in endotelijskega
rastnega faktorja so po laparoskopskih posegih nižje
kot po odprtih operacijah. V randomizirani študiji v
Singapurju niso opazili razlike v imunskem odgovoru
med laparoskopskimi in odprtimi operacijami (20).
Verjetno so še drugi mehanizmi, ki vplivajo na imunološki odgovor in posledično boljše preživetje po
laparoskopskih posegih (21).
32 GASTROENTEROLOG
RAK DANKE
Kirurško zdravljenje raka danke se razlikuje od zdravljenja raka debelega črevesa. Če hočemo doseči malo
ponovitev bolezni in dober onkološki rezultat moramo
narediti totalno mezorektalno ekscizijo (TME) z negativnim radiarnim robom. Pri operaciji moramo tudi
paziti na avtonomne živce za ohranitev funkcije
sečnega mehurja in seksualne funkcije. Prospektivni
podatki iz randomiziranih študij ekspertnih centrov
potrjujejo, da so laparoskopske resekcije zaradi raka
danke izvedljive. Na voljo so predvsem zgodnji rezultati teh posegov (24,25). Laparoskopija s povečavo
slike omogoča boljši pregled struktur male medenice
kot ga imamo pri odprti operaciji (24, 26,27).
Zgodnji rezultati
Po podatkih iz literature ima laparoskopski pristop
prednost pred odprtimi operacijami raka danke. Aziz
in sodelavci so v meta-analizi ugotovili, da bolniki po
laparoskopski operaciji hitreje okrevajo, preidejo na
normalno dieto in so manj časa hospitalizirani kot bolniki po odprti operaciji. Manjša je izguba krvi med
operacijo, operacijski čas pa je daljši kot pri odprtih
operacijah (28). Po laparoskopskih posegih je manj
vnetij v rani in manj pljučnih zapletov (29).
Objavljene so tudi študije, v katerih avtorji niso ugotovilli prednosti laparoskopske pred odprto operacijo
v obolevnosti in zgodnji smrtnosti (30, 31).
Po laparoskopskih resekcijah je več dehiscenc anastomoz, kot po odprti operacijah. Prekinitev rektuma
z endoskopskim spenjalnikom je pri nizkih tumorjih
v ozki medenici težavna. Tudi uporaba več polnil za
prekinitev danke poveča tveganje za nastanek dehiscence anastomoze. Neodvisni dejavniki za nastanek
dehiscence anastomoze so nizko ležeč tumor v danki,
TME in moški spol (24).
Merila za onkološko kvaliteto laparoskopske resekcije
raka danke so: kvaliteta kirurške resekcije, lokalna
ponovitev bolezni in dolgoročno preživetje bolnikov.
Najpomembnejša parametra sta distalni in cirkumferencialni resekcijski rob in število odstranjenih bezgav.
Večina študij ne poroča o značilni razliki med številom
odstranjenih bezgavk in distalnem resekcijskem robu
med laparoskopskim in odprtim posegom (29, 30).
Podatki CLASICC študije pa poročajo o večjem odstotku
pozitivnih cirkumferencialnih robov pri laparoskopskih posegih (12 proti 6 % pri odprtih) (7).
Pozni rezultati
Lokalna ponovitev bolezni odraža adekvatnost
TME in nizke resekcije danke. V študijah Laurenta, Lawa in Morina je bilo 5-letno preživetje po
laparoskopskih resekcijah daljše kot po odprtih
operacijah in majhen odstotek lokalnih ponovitev
bolezni (25, 26, 27).
Funkcionalni rezultati
Motnje seksualne funkcije in delovanja mehurja so
pogoste po operacijah raka danke. Kljub upoštevanju
načel TME in ohranitvi živcev zaradi boljše vidljivosti pri laparoskopiji so mnenja nasprotujoča. Quah in
sodelavci poročajo o oslabljeni seksualni funkciji po
laparoskopskih resekciajh v primerjavi z odprto operacijo (32). V korejski študiji so opazovali težave z
mikcijo, ki so po treh mesecih izzvenele (33).
Ovire pri uvajanju laparoskopske
kolorektalne kirurgije
Laparoskopska kirurgija v začetnem obdobju ni bila
primerna za starejše bolnike s pridruženimi boleznimi
zaradi daljšega operacijskega časa in pnevmoperitoneja.
Kasneje so se pokazale prednosti laparoskopije zaradi
hitrejšega okrevanja, manj zapletov s strani srca in pljuč
in nižjo smrtnostjo (34).
Ovira za uvajanje laparoskopije je tudi daljša učna krivulja. Število 30 operacij, ki naj bi jih kirurg izvedel
ob asistenci izkušenega kirurga je manjših ustanovah
težko dosegljivo. Druge ovire so še daljši operacijski
čas, višja cena laparoskopske operacije zaradi opreme
in inštrumentov, ki pa se kompenzirajo s krajšo hospitalizacijo in manj zapleti po operaciji.
V Veliki Britaniji so leta 2007 pričeli z Nacionalnim trening programom laparoskopske kirurgije.
Odstotek laparoskopskih posegov je porastel s 5 %
v letu 2005 na 23 % v letu 2009. V ZDA je ta odstotek
narastel v letu 2009 na 45 % (35, 36)
Nove tehnologije
V zadnjih petih letih so se uveljavile resekcije raka
debelega črevesa in danke skozi eno incizijo (singleincision laparoscopic surgery, SILS). Pri tej metodi
se uvede troakar skozi popek. V troakarju so tri do
štiri vstopna mesta za inštrumente. Huscher in
sodelavci niso opazovali razlike med standardno
laparoskopijo in SILS tehniko po resekcijah raka
debelega črevesa in danke (37).
Kirurgija s pomočjo robota (da Vinci surgical system,
Intuitive Surgical, Sunnivale, CA, USA) se je uveljavila pri radikalni prostatektomiji. Robot se je
uveljavil v kirurgiji raka danke. Prednosti robota
pred standardnim laparoskopskim pristopom so v
tridimenzionalnem vidu, bolj gibljivih inštrumentih
in odsotnosti tremorja. V manjših serijah so potrdili
prednost uporabe robota pred standardno laparoskopijo (38).
ZAKLJUČEK
Laparoskopska kirurgija raka debelega črevesa in
danke je naredila v zadnjih dveh desetletjih velik
napredek. Izboljšani zgodnji rezultati in dobri pozni
rezultati so pokazali, da je laparoskopska resekcija
dobra metoda zdravljenja raka debelega črevesa.
Laparoskopska resekcija raka danke je metoda, ki
daje v specializiranih centrih dobre rezultate. Standardizirana tehnika in dobro usposobljena kirurška
GASTROENTEROLOG 33
ekipa z večjim številom operacij so pomembni pogoji
za varnost bolnikov, manjše število preklopov in dober
izhod laparoskopskih resekcij zaradi raka.
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15. Schwenk W, Haase O, Neudecker JJ et al. Short term benefits for
laparoscopic colorectal resection. Cochrane Database Syst Rev
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16. Abraham NS, Byrne CM, Young JM et al. Meta-analysis of nonrandomized comparative studies of the short-term outcomes of
laparoscopic resection for colorectal cancer. ANZ J Surg
2007;77:508–16.
17. Fleshman J, Sargent DJ, Green E et al. Laparoscopic colectomy
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34 GASTROENTEROLOG
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22. Tjandra JJ, Chan MKY. Systematic review on the short-term outcome of laparoscopic resectionfor colon and rectosigmoid cancer.
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Benigni in maligni tumorji pri
700 zaporednih apendektomijah
Benign and malignant tumors in
700 consecutive appendectomies
Jera Jeruc*
Inštitut za patologijo, Medicinska fakulteta, Univerza v Ljubljani
Gastroenterolog 2013; suplement 2: 35–38
Ključne besede: slepič, appendicitis, tumor slepiča,
nevroendookrini tumor, mucinozna neoplazma, GIST
Key words: appendix, appendicitis, appendiceal neoplasm,
neuroendocrine tumour, mucinous tumour, GIST
POVZETEK
ABSTRACT
Vnetje slepiča (apendicitis) je najpogostejše akutno
trebušno vnetje, ki potrebuje kirurško zdravljenje.
Histološki pregled odstranjenega slepiča običajno
potrdi klinični sum na akutno vnetno dogajanje,
včasih pa pokaže tudi druge pomembne diagnoze.
Namen raziskave je bil ugotoviti pojavnost in histološke značilnosti tumorjev slepiča v naši populaciji.
V raziskavo smo vključili 728 slepičev, ki smo jih v
obdobju sedmih let pregledali v naši ustanovi.
Appendicitis is one of the most common abdominal
inflammatory conditions requiring surgical intervention. Histology usually confirms the clinical suspicion
of acute inflammation, but sometimes other clinically
relevant diagnoses are made. The aim of our study was
to analyse the appendectomies at our institution and to
determine incidence and histological spectrum of
appendiceal tumours in our population. We reviewed
the histopathology results of 728 consecutive appendectomies received in a 7-year period.
Primarni tumor smo ugotovili v 30 (4,1 %) primerih,
kar je nekoliko večja pojavnost kot je opisano v
literaturi. Med njimi je bilo osem nevroendokrinih
tumorjev, pet klasičnih adenomov, 11 primerov mucinozne neoplazme nizke stopnje malignosti (v enem
primeru v povezavi z psevdomiksomom peritoneja)
in trije primeri karcinoma (po en mucinozni, intestinalni in nediferencirani). V enem primeru smo
postavili tudi diagnozo multicističnega mezotelioma
ter v slepiču redkega gastrointestinlnega stromalnega tumorja. Pri večini primerov je bila napotna
diagnoza akutni apendicitis, le pri sedmih, pretežno
velikih tumorjih je sum na tumorsko rast postavil že
kirurg.
Appendiceal tumours were found in 30 cases (4.1%),
which is a higher rate than reported in the literature.
There were eight endocrine tumours, all G1, five cases
of classical adenomas, 11 cases of low-grade appendiceal mucinous neoplasms (one associated with
pseudomyxoma peritonei) and three cases of carcinoma (one mucinous adenocarcinoma, one intestinal
type, one undifferentiated carcinoma). We also diagnosed one case of multicystic mesothelioma and one
gastrointestinal stromal tumour. Most patients presented with acute appendicitis, only in seven patients,
mainly large tumours, the diagnosis was suspected
already by surgeon.
*Doc. dr. Jera Jeruc, dr. med.
Inštitut za patologijo, Medicinska fakulteta, Univerza v Ljubljani,
Korytkova 2, 1000 Ljubljana, Slovenija
GASTROENTEROLOG 35
Histološki pregled odstranjenega slepiča je potrebno opraviti vedno, saj tudi v klinično nesumljivih
primerih lahko odkrije številne klinično pomembne
bolezni ter celo tumorje.
Histopathological examination of appendectomy
specimens may reveal many different conditions not
previously suspected; therefore, it should be performed in all cases.
Introduction
Results
Appendicitis is one of the most common abdominal
conditions demanding surgical intervention. It
affects about 10% of population and is thought to
be initiated by progressive increases in intraluminal
pressure that compromises venous outflow. In 50%
to 80% of cases, acute appendicitis is associated
with overt luminal obstruction, usually by lymphoid
hyperplasia or fecalith (1). Less commonly, symptoms and signs result from other causes such as
inflammation in the setting of Crohn’s disease,
endometriosis or even tumour. Primary appendiceal tumours are rare neoplasms accounting for
0.2–0.5 of all gastrointestinal tumours and < 2% of
all appendectomies (1–7). Neoplastic processes in
the appendix are histologically similar to their
colonic counterparts. However, especially regarding
epithelial neoplasm, the terminology is not standardised among pathologist and reading pathology
reports can be a challenging task for the clinical
doctors.
During the study period, 728 patients had an appendectomy for appendiceal pathology. Appendiceal neoplasm was diagnosed in 31 patients (4.3%). The largest
single group of tumours were low grade appendiceal
mucinous neoplasms (LAMN) comprising 35.5% of
all tumours (Fig. 1A and 1B), followed by neuroendocrine tumours (25.8%) (Fig. 2). The incidence of
different histological entities is presented in Table 1.
The aim of our study was to determine the incidence and histological spectrum of appendiceal
tumours in our population.
Most of the patients presented with acute appendicitis with or without abscess formation, some with
chronic appendicitis. Only occasionally tumour was
Tabela 1. Histološke diagnoze tumorjev slepiča pri
728 zaporednih apendektomijah
Table 1. Histological diagnoses of the appendiceal
tumours in 728 consecutive appendectomies
Type of tumour
No. of
cases (%)
Adenoma
5 (0.7%)
Low-grade
appendiceal
mucinous
neoplasm (LAMN)
11 (1.5%)
1 associated with
pseudomyxoma
peritonei
Adenocarcinoma
3 (0.4%)
1 intestinal type
1 mucinous
1 undifferentiated
Neuroendocrine
tumour
8 (1.1%)
all G1 according to
WHO
2 with lymph node
metastasis
GIST
1 (0.1%)
Multicystic
mesothelioma
1 (0.1%)
Folicular
lymphoma
1 (0.1%)
Metastasis
(urothelial
carcinoma)
1 (0.1%)
Total
31 (4.2%)
Materials and methods
The study included all appendices received for histological evaluation at the Institute of Pathology of
the Medical Faculty at the University of Ljubljana in
a seven year period. Appendectomies performed as
an incidental procedure during some other operation were excluded.
The histology of the appendiceal tumours was evaluated again by experienced pathologists. Demographical
data were collected from the patients’ charts.
36 GASTROENTEROLOG
Figure 2. Neuroendocrine tumour of the appendix
with a characteristic yellow colour.
0.35 to 3.5 cm (mean 1.42 cm), in five patients tumour
was less than 1 cm in greatest diameter. In two cases,
metastases in lymph nodes were detected.
Figure1. Low-grade appendiceal mucinous neoplasm (LAMN).
Abundant mucin causing appendiceal distention (A).
The mean age of patients with colonic-type adenoma
was 59.2 years. There were three tubular adenomas
and, one villous and tubulo-villous adenoma each.
None of them was associated with mucocele and none
of the patients had familial adenomatous polyposis.
Among 11 patients with LAMN there were six women
and five men, mean age of 58.4 years. In six cases herniation of mucin with or without neoplastic epithelium into the muscularis propria was present, and one
of them was associated with pseudomyxoma peritonei.
Figure1. Histology shows filiform villi lined by tall mucinous epithelium displaying low-grade cytologic atypia (B).
suspected already by surgeon: in one of eight neuroendocrine tumours (the largest one), two out of 11
LAMNs and in two out of three carcinomas.
In this series, the mean age of patients with neuroendocrine tumours was 35.4 years with a male-tofemale ratio 1:7. The size of tumours ranged from
GIST measuring 1.0 cm was diagnosed in a 11-year-old
girl, multicystic mesothelioma was found in a 20-year-old
male with clinical signs of acute appendicitis, but without histological signs of inflammation in the appendix.
Discussion
Primary appendiceal neoplasms are uncommon,
being found in approximately 0.5%–1.0% of appendectomy specimens at pathologic evaluation (1–3). In
this study the incidence of primary appendiceal
tumours was 4.3%. This rate is higher compared to
GASTROENTEROLOG 37
most similar studies (2–3, 7–8). Most of previous studies did not include benign and rare types of primary
appendiceal tumours such as classical (colonic type)
adenomas, lymphomas and tumours of mesothelial
origin neither did they include metastatic processes.
The number of examined appendices in our study
increased from 37 in the first year of the study to 266
in the last year. Since the population covered by out
pathology department remained the same during that
period we believe that, in the past, not all appendices
were sent for the histological evaluation, making the
calculated incidence higher.
Although the incidence of appendiceal tumours in our
study was higher, the distribution of histological entities was similar to previous studies with LAMNs being
the most frequent and accounting for more than one
third of cases, followed by neuroendocrine tumours
representing about one quarter of appendiceal neoplasms (7). On the other hand, according to some
authors. neuroendocrine tumours are the most common neoplasms of appendix (9–10). Interestingly, we
have not diagnosed a single case of goblet cell carcinoid although we have encountered a few cases in the
past. Neuroendocrine tumours tend to be diagnosed
at an earlier age than other neoplasms and women
predominate (1, 10–11), as was the case in our series.
Appendiceal neoplasm is typically associated with
acute appendicitis and the diagnosis of tumour is usually difficult to make preoperatively. In our series, a
diagnosis was suspected prior to histology report only
in a few patients, all of them had large tumours or
tumours associated with mucocele. On the other
hand, benign processes associated with mucocele can
sometimes be misinterpreted as tumours by surgeon.
One of three patients with appendiceal carcinoma
(undifferentiated carcinoma) also had a moderately
differentiated adenocarcinoma of the sigmoid colon.
A higher rate of associated cancer in patients with
appendiceal neoplasm, especially of synchronous colon
carcinoma has previously been reported (6).
38 GASTROENTEROLOG
Gastrointestinal stromal tumors (GIST) are rare in
the vermiform appendix. Less than 10 cases have
been reported so far, all in patients over 50 years of
age (12). Interestingly, our patient with appendiceal
GIST was an 11-year-old girl.
In conclusion, appendiceal neoplasm is a rare gastrointestinal malignancy. Most of them are diagnosed only after histological examination of the
resected specimen. Therefore the histological examination of the resected appendix is necessary for
establishing the correct diagnosis and can influence
further clinical decisions. Especially with appendiceal mucinous neoplasm it is important to remove
appendix intact, trying to avoid trauma and possible
rupture of the appendix, as this can affect long term
outcome.
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2. Hananel N, Powsner E, Wolloch Y. Adenocarcinoma of the appendix: an unusual disease. Eur J Surg 1998; 164 (11): 859–62.
3. Connor SJ, Hanna GB, Frizelle FA. Appendiceal tumors: retrospective clinicopathologic analysis of appendiceal tumors from
7,970 appendectomies. Dis Colon Rectum 1998; 41(1): 75–80.
4. Lyss AP. Appendiceal malignancies. Semin Oncol 1988; 15(2):
129–37.
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25(1): 36–9.
6. Bucher P, Mathe Z, Demirag A, Morel P. Appendix tumors in the
era of laparoscopic appendectomy. Surg Endosc 2004; 18(7):
1063–6.
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3,744 appendectomies: a single-institution study. Int J Colorectal
Dis 2011; 26(5): 617–21.
8. O'Donnell ME, Badger SA, Beattie GC, Carson J, Garstin WI.
Malignant neoplasms of the appendix. Int J Colorectal Dis 2007;
22(10): 1239–48.
9. Deschamps L, Couvelard A. Endocrine tumors of the appendix:
a pathologic review. Arch Pathol Lab Med 2010; 134(6): 871–5.
10. Lamm-Himmlin D. Montgomery EA. The neoplastic appendix: a
practical approach. Diagnostic Histopathology 2011; 17(9):
395–403.
11. Carr NJ, Sobin LH. Neuroendocrine tumors of the appendix.
Semin Diagn Pathol 2004; 21(2): 108–19.
12. Agaimy A, Pelz AF, Wieacker P, Roessner A, Wünsch PH,
Schneider-Stock R. Gastrointestinal stromal tumors of the vermiform appendix: clinicopathologic, immunohistochemical, and
molecular study of 2 cases with literature review. Hum Pathol
2008; 39(8): 1252–7.
Kako operirati rak želodca pri
starostniku?
How to operate gastric cancer in elderly patients
Matjaž Horvat*, A. Ivanecz, T. Jagrič, S. Potrč
Oddelek za abdominalno in splošno kirurgijo, Kirurška klinika
Univerzitetni klinični center Maribor
Gastroenterolog 2013; suplement 2: 39–43
Ključne besede: rak želodca, kirurgija, starostniki
Keywords: gastric cancer, surgery, elderly
POVZETEK
ABSTRACT
Analizirali smo podatkovno bazo 20 letnega obdobja
zdravljenja raka na našem oddelku in primerjali starostnike in mlajše bolnike.
Retrospective analysis of gastric cancer surgical
treatment data in our clinical department in 20-year
period was performed and treatment outcome was
compared between younger and older patients.
Bolniki in metode. Pri 847 bolnikih smo od 1992
do 2012 napravili R0 resekcijo zaradi raka želodca.
Bolnike smo razdelili v skupino mlajših od 70 let
in skupino starejših. Primerjali smo predoperativno zdravje in pridruženo obolevnost bolnikov,
karakteristike tumorja, vrsto resekcije, rekonstrukcijo, število in vrsto pooperativnih kirurških
in splošnih zapletov ter preživetje.
Rezultati. Starostniki so imeli slabše zdravje in več
pridruženih obolenj (p<0,05). Najpogostejša pridružena obolenja so bila srčno pljučna, ki jim sledijo
izolirane srčne bolezni in sladkorna bolezen. Pri
podobnih karakteristikah tumorjev in stadijih, smo
pri starostnikih opravili manj totalnih gastrektomij,
manj ekstenzivnih limfadenekomij in splenektomij
(p=0,001, p<0,05, p<0,05). Med skupinama ni bilo
razlik v kirurških zapletih (p=0,563), bilo pa je več
splošnih pooperativnih zapletov pri starostnikih
(p<0,05). Pri skupini starostnikov je bila tudi večja
Patients and methods. In the period between 1992
and 2012, 847 R0 gastric cancer resections were
performed. Preoperative treatment, comorbidities,
tumor characteristics, resection and reconstruction
type, surgical complications and survival were compared between patients bellow and above the age of
70 years.
Results. Comorbidities (p<0.05) were more frequent in older patients. Tumor characteristics did
not differ among groups, however less total gastrectomies, less extensive lymphadenectomies and less
splenectomies were performed in older patients
(p=0,001, p<0,05, p<0,05). The frequency of surgical
complications did not differ among groups (p=0,563),
however general complications were more common
in older patients (p<0,05), with higher 30 and 60 day
mortality (p<0,05) and shorter survival (p<0,05).
* Doc. dr. Matjaž Horvat dr. med.
Oddelek za abdominalno in splošno kirurgijo, Kirurška klinika,
Univerzitetni klinični center Maribor, Ljubljanska 5, 2000 Maribor
GASTROENTEROLOG 39
pooperativna 30- in 60-dnevna umrljivost (p<0,05)
in krajše preživetje (p<0,05).
Zaključki. Operativno zdravljenje starostnikov z <
pooperativne obolevnosti in smrtnosti. Onkološki
principi, ob manjši operativni invazivnosti, ki je v
składu z biološko starostjo, niso ogroženi.
UVOD
Letna incidenca raka želodca je po podatkih Registra
za rak Republike Slovenije iz leta 2006 pri moških
27,18/100.000 in 15,55/100.000 pri ženskah. Bolezen se začne pogosteje pojavljati po 40. letu in
doseže vrh med 60. in 80. letom življenja (1). Po
nekaterih podatkih naj bi bilo kar 30 % bolnikov z
rakom želodca starejših kot 70 let (2). Različne prospektivne in retrospektivne študije so pokazale večjo
obolevnost in smrtnost pri starostnikih v primerjavi
totalnih in subtotalnih gastrektomij, in limfadenektomijami D2 v primerjavi z limfadenektomijami D1
(3–6). Postavlja se ključno vprašanje, kako s predoperativno oceno tveganja izbrati kandidate za manj
ekstenzivno kirurško zdravljenje in s tem znižati
pooperativno obolevnost in smrtnost. Pomembno je
tudi oceniti, ali manj ekstenzivno kirurško zdravljenje
pomeni še spremenljivo krajše preživetje starostnikov
z rakom želodca (7).
Namen naše študije je bil primerjati lastne rezultate
zdravljenja raka želodca pri bolnikih mlajših in starejših od 70 let in vrednotiti njihov izhod zdravljenja.
BOLNIKI IN METODE
Iz prospektivne 20 letne (1992-2012) podatkovne
baze bolnikov, operiranih na Oddelku za abdominalno in splošno kirurgijo UKC Maribor zaradi raka
želodca, smo opravili analizo podatkov starostnikov
(70 in več let) v primerjavi z ostalimi bolniki pri katerih je bila napravljena R0 resekcija želodca. Zanimala
nas je predvsem predoperativna ocena zdravja in število pridruženih obolenj po ASA (klasifikacija po
American Society of Anesthesiologists), kot tudi vrsta
40 GASTROENTEROLOG
Conclusions. Surgical treatment of gastric cancer is
beneficial to older patients and complications and
procedure-related morbidity and mortality is within
expected limits. Reduced surgical invasiveness due
to limits steming form patients biological age is still
fully compatible with expected oncological principles and standards.
pridruženih obolenj in laboratorijski pokazatelji.
Pomemben se nam je zdel tudi obseg resekcije, ki sta
jo pogojevala velikost in lokacija tumorja in histološka klasifikacija po Laurenu, ter njegova patološka
diferenciacija. Nadalje smo med skupinama primerjali stopnjo limfadenektomije in število splenektomij.
Uspeh zdravljenja smo vrednotili s pomočjo pooperativnih zapletov, dolžino ležalne dobe in časom do
eventuelne ponovitve bolezni na podlagi rednega sledenja ter TNM klasifikacije. Primerjavo preživetja
smo izračunali s pomočjo podatkov iz Registra za rak
Republike Slovenije.
Podatke smo statistično obdelali s pomočjo programa SPSS 20.0 in pri tem uporabili teste za
parametrične in neparametrične spremenljivke.
Pri računanju preživetja smo uporabili KaplanMeierjevo metodo. Vrednost P < 0,05 smo smatrali
kot statistično pomembno.
REZULTATI
Na Oddelku za abdominalno kirurgijo UKC Maribor
smo v 20 letih (1992 – 2012) operirali 847 bolnikov
z rakom želodca, pri katerih je bila po patohistološkem pregledu narejena R0 resekcija. Moških je
bilo 533 (62,9 %), žensk pa 314 (37,1 %). Razpon
starosti vseh bolnikov je od 19 do 92 let s povprečno
starostjo 64,7let. Prikaz porazdelitve bolnikov po
starosti prikazuje tabela 1. Bolnikov starejših od 70 let
je bilo 300 (35,4 %), 70 ali mlajših pa 547 (64,6 %).
Tako v skupini mlajših bolnikov, kot starostnikov je
bilo moških več kot žensk. V skupini mlajših bolnikov
je odstotek žensk znašal 35,27 in v skupini starostnikov pa 40,12 kar je bilo statistično pomembno
(p=0,017).
Tabela 1.: bolniki z rakom želodca glede na starost
Pri obeh skupinah je imelo največ bolnikov predoperativno oceno ASA 2 (skupina mlajših 53,38
% in skupina starejših 53,66 %). Občutne razlike
pa obstajajo pri ASA1, kjer je v skupini mlajših
42,96 % bolnikov in pri starostnikih le 6,66 %, kot
tudi pri ASA 3, kjer je stanje obratno. Le majhen
delež mlajših bolnikov je imelo preoperativno
oceno ASA 3 (3,65 %) in občutno večji delež pri
starostnikih (42,96 %). Razlike so statistično
pomembne (p<0,05). Razlike obstajajo tudi pri pridruženih obolenjih, oziroma njihovem številu. Pri
skupini mlajših bolnikov ni imelo pridruženega
obolenja kar 44 % bolnikov, eno ali dve pridruženi
obolenji pa 26 % oziroma 27 % bolnikov. Samo 1,4 %
bolnikov v mlajši skupini je imelo 3 ali več pridruženih obolenj. Slika je obratna pri starostnikih.
Z enim ali dvema pridruženima obolenjema najdemo 79,98 % bolnikov, samo 15,33 % bolnikov ni
imelo nobenega pridruženega obolenja in 4,66 %
je imelo tri ali več pridruženih obolenj, kar je statistično pomembno (p<0,05). Med pridruženimi
obolenji je najpogostejša kombinacija bolezni srca
in pljuč, pri mlajših v 40 % in pri starejših v 36 %.
Na drugem mestu po pogostnosti pridruženih obolenj so bolezni srca v obeh skupinah (mlajši 24 %,
starejši 27 %). Manifesten diabetes je bil pri mlajših prisoten pri 8,1 % in starejših pri 10,6 %
bolnikov. Ostale kombinacije pridruženih obolenj,
kot so obolenja CŽS in jeter ter druge bolezni so
bile redkeje zastopane.
Predoperativna primerjava laboratorijskih vrednosti
krvi ni pokazala pomembnejših odstopanj med skupinama. Razlika se je pokazala pri predoperativnih
vrednostih hemoglobina in celokupnih proteinov. Ti
so bili nižji v skupini starostnikov (hemoglobin povprečno 115 g/L, proteini 66,33 g/L), za razliko od
mlajših bolnikov (hemoglobin povprečno 124,1 g/L,
proteini 69,25 g/L), kar je statistično pomembno
(p<0,05, p<0,05). Med skupinami ni bilo pomembnejših razlik v vrednostih tumorskih označevalcev
karcino embrionalnega antigena (CEA) in tumorskega označevalca CA 19-9 pred operacijo (p=0,986,
p=0,209).
Čeprav je največ tumorjev v obeh skupina lokalizirano v distalni in srednji tretjini želodca in je
število tumorjev v proksimalni tretjini želodca
večje pri mlajši skupini bolnikov (19 % mlajši, 16 %
starejši), vendar razlika ni statistično pomembna
(p=0,304). Pravtako med skupinama ni statistično
pomembne razlike v patohistološki diferenciaciji
tumorjev in velikosti tumorja(p=0,052, p=0,781).
Obstaja pa statistično pomembna razlika pri histološki
diferenciaciji po Laurenu, predvsem na račun večjega
števila intestinalnega tipa pri starostnikih (p=0,033).
Predoperativni slikovni preiskavi za oceno stadija bolezni
(EUZ, CT), ki sta danes obvezen del algoritma preiskav
pred operacijo in osnova za potencialno uvedbo neoadjuvantne terapije zaradi širokega časovnega razpona
opazovanih bolnikov nista bili izvedeni pri 59 % bolnikov
v mlajši skupini in v 63,9 % pri starostnikih. Zadnjih nekaj
let pa ta obvezna diagnostika pred operacijo ne pokaže statistično pomembnih razlik v oceni cTNM klasifikacije.
Najpogostejši predoperativni stadij v obeh skupinah je
cT3cN+ (mlajši bolniki 35 %, starejši bolniki 34,2 %), ostali
stadiji med skupinami so primerljivi in se statistično
pomembno ne razlikujejo (p=0,886).
Obstajajo pomembne razlike med skupinama glede
vrste gastrektomije, predvsem na račun večjega
deleža subtotalnih gastrektomij pri starostnikih
(39,3 %) napram mlajšim bolnikom (28,7 %), manjšega števila totalnih gastrektomij z distalnimi
resekcijami požiralnika (starejši bolniki 3,9 %,
GASTROENTEROLOG 41
mlajši bolniki 6,3 %) in resekcij krna želodca (starejši bolniki 1,9 %, mlajši bolniki 3,6 %). Klinastih
resekcij pri starejših bolnikih je bilo 1 %, pri mlajših bolnikih pa bistveno manj 0,18 %. Pri starejši
skupini je bilo opravljenih tudi več proksimalnih
resekcij želodca (5 %) kot pri mlajši skupini (1,8 %).
Razlike so statistično pomembne (p=0,001).
Povprečna hospitalizacija je pri mlajših bolnikih
15,2 dneva in pri starostnikih 15,5 dneva (p=0,693).
Vrstam gastrektomije sledijo tudi načini rekonstrucij. Pri starejših je več rekonstrukcij po tipu
Bilroth 2 z omega tanko črevesno vijugo in interponatov, pri mlajših pa prednjačijo Roux en Y
ezofagojejuno anastomozo, kar je statistično
pomembno (p<0,05).
Celokupno preživetje je boljše pri skupini mlajših
bolnikov in mediana vrednost znaša 1603 dneva,
pri starostnikih pa je mediana vrednost 1107 dni
(p<0,05). Graf 1.
Perioperativna 30- in 60-dnevna smrtnost je večja
pri starostnikih (8,9 % in 10,3 %), za razliko od
mlajših bolnikov (2,5 % in 3,8 %), kar je statistično
pomembno (p<0,05).
Intenzivnost limfadenektomije je večja pri mlajši skupini bolnikov večja. Pri 16 % bolnikov v mlajši skupini
je bila narejena samo limfadenektomija D1 za razliko
od starostnikov, kjer je samo D1 limfadenektomija
narejena v 29 %. Ekstenzivnejša limfadenektomija D3
je pri mlajših bolnikih narejena v 24 % in pri starejših v
13,5 %. Gre za statistično pomembne razlike (p<0,05).
Splenektomija je bila sestavni del operativnega
posega pri mlajših bolnikih v 38 %, pri skupini starejših bolnikov pa v25,1 %, kar je statistično
pomembno (p<0,05).
Ocena kirurških zapletov pokaže primerljivost obeh
skupin (mlajši 13,3 %, starejši 12,3 %, kar je statistično nepomembno (p=0,387). Največji odstotek
kirurških zapletov predstavljajo abscesi in krvavitve
v obeh skupinah, pri skupini mlajših bolnikov pa še
pankreatits in holecistitis. Med vrstami kirurških
poopertivnih zapletov med skupinama ni statistično
pomembnih razlik (p=0,563). Obstaja pa statistično
pomembna razlika splošnih komplikacij med skupinama na račun večjega števila splošnih zapletov
pri starostnikih (starostniki 18,6 %, mlajši 10,4 %)
(p=0,001). Med skupinama se razlikujejo tudi vrste
splošnih zapletov, kjer pri starostnikih prednjačijo
febrilna stanja, srčna popuščanja in odpovedi in
respiratorni distres, pri mlajših bolnikih pa predvsem
respiratorni distres, srčno popuščanje in febrilna
stanja (p=0,023).
42 GASTROENTEROLOG
Graf 1: prikaz preživetje med skupino starostnikov in mlajših
bolnikov z rakom želodca (R0 resekcija)
RAZPRAVA
V skupini starostnikov najdemo skoraj 80 % bolnikov z enim ali večimi pridruženimi obolenji; več
kot 90 % bolnikov smo uvrstili v skupini ASA 2 in
ASA 3. Ob tem ugotavljamo, da so tako lokalizacija
tumorja glede na tretjine želodca, njegova velikost,
patohistološka diferenciacija in predoperativni stadij primerljivi med obema skupinama. Pri skupini
starejših bolnikov smo opravili manjše število totalnih gastrektomij na račun večjega števila subtotalnih
gatrektomij in bili manj agresivni pri limfadenektomijah in splenektomijah. Podobne številke in rezultate
navajajo v študijah tudi drugi avtorji, ob primerljivih
karakteristikah tumorjev med skupino starostnikov in
mlajših bolnikov z rakom želodca (8–11).
Primerjava pooperativne obolevnosti pokaže nekatere
značilnosti predvsem pri primerjavi zapletov povezanih s kirurškim posegom. V naši študiji smo imeli
primerljivo pooperativno kirurško obolevnost med skupinama in relativno majhno število zapletov puščanj
anastomoz. Najpogostejši kirurški zaplet v naši študiji
predstavljajo abscesi in krvavitve, ki jim sledijo pankreatitisi in holecistitisi. Vrste zapletov med skupinama
so statistično primerljive. Do drugačnih rezultatov pa je
prišel Gretschel v svoji študiji ugotavlja, da je bilo pri
skupini starejših bolnikov pomembno več kirurških
zapletov. Najpogostejši zaplet predstavljajo puščanja
anastomoz, v določenem starostnem intervalu tudi do
9 % (15 bolnikov od 167 v starostnem intervalu od 60
do 75 let) kar sicer ni bilo statistično pomembno. Na
drugem in tretjem mestu števila kirurških zapletov so
pankreatitisi in pankreatične fistule. Vrste kirurških
zapletov v posameznih skupinah so med seboj primerljive (12). Razlago razlik med študijami bi lahko
razložili z relativno manjšo skupino bolnikov z R0
resekcijami (363 bolnikov) vključenih v študijo iz
Berlina, ki so bili razdeljeni v tri starostna obdobja.
Relativno redek zaplet puščanja anastomoz v naši
študiji si razlagamo z ozkim krogom kirurgov v naši
ustanovi, ki se ukvarja s patologijo raka želodca.
Glede nekirurške pooperativne obolevnosti pa tako
v naši študiji kot v študijah ostalih avtorjev po številu zapletov prednjačijo starostniki (5, 7, 8, 12).
Primerjava vzrokov nekirurških pooperativnih
zapletov naše študije z berlinsko pokaže podobnosti
v smislu najpogostejših vzrokov, kot so febrilna stanja z respiratornimi distresi in srčnimi zapleti. V
obeh študijah so bili tako število in vzroki statistično pomembni v primerjavi med skupinami (12).
Več nekirurške pooperativne obolevnosti pri starostnikih je lahko tudi razlog večjo 30- in 60-dnevno
pooperativno umrljivost. Podobne podatke navajajo
tudi drugi avtorji (8, 10, 11, 12).
Čeprav je preživetje skupine starostnikov v naši študiji
pomembno krajše, pa le to ni povezano samo z rakom
želodca. Pričakovana življenska doba starostnikov je
krajša in biologija tumorja pri starostniku drugačna, s
počasnejšo rastjo, kar ima lahko za posledico manjši
delež s tumorjem povezane umrljivosti (13). V naši
študiji smo imeli v skupini starostnikov pomembneje
več intestinalnega tipa raka želodca po Laurenu.
Zaključimo lahko da je operativno zdravljenje starostnika z rakom želodca ob primerni pripravi in izbiri
bolnika smiselno. Starejši bolniki s prikrojenimi kirurškim posegom imajo večjo možnost preživetja, kot
bolniki brez operacije (14). Dejstvo je, da sta biološka
starost in pridružena obolevnost pomembnejši kot
kronološka starost in starost sama ne sme biti izključevalni faktor operativnega posega (15, 16).
LITERATURA
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V, Zakotnik B, et al. Incidenca raka v Sloveniji v letu 2006.
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3. Bozzetti F, Marubini E, Bonfanti G, et al. Subtotal versus total
gastrectomy for gastric cancer: five-year survival rates in a multicenter randomized Italian trial. Italian Gastrointestinal Tumor
Study Group. Ann Surg 1999; 230(2): 170–178.
4. Bonenkamp JJ, Songun I, Hermans J, et al. Randomised comparison of morbidity after D1 and D2 dissection for gastric cancer in 996 Dutch patients [see comments]. Lancet 1995;
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5. Adachi Y, Ogawa Y, Sasaki Y, et al. A clinicopathologic study of
gastric carcinoma with reference to age of patients. J Clin
Gastroenterol 1994; 18(4): 287–290.
6. Tsujitani S, Katano K, Oka A, et al. Limited operation for gastric
cancer in the elderly. Br J Surg 1996; 83(6): 836–839.
7. Enzinger PC, Mayer RJ. Gastrointestinal cancer in older patients.
Semin Oncol 2004; 31(2): 206–219.
8. Oliveira FJ, Furtado E, Ferrao, et al. Total gastrectomy for gastric cancer in elderly patients. Hepatogastroenterology 1999; 46(25): 616–619.
9. Haga Y, Yagi Y, Ogawa M. Less invasive surgery for gastric cancer prolongs survival in patients over 80 years of age. Surg Today
1999; 29(9): 842–848.
10. Wu CW. Lo SS, Shen KH, et al. Surgical mortality, survival, and
quality of life after resection for gastric cancer in the elderly.
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11. Kubota H. Kotoh T, Dhar DK, et al. Gastric resection in the aged
(>or = 80 years) with gastric carcinoma: a multivariate analysis of
prognostic factors. Aust NZ J Surg 2000; 70(4): 254–257.
12. Gretschel S, Estevez-Schwarz L, Huenerbein M, et al. Gastric cancer surgery in elderly patients. World J Surg 2006; 30: 1468–1474.
13. Aral T, Esaki Y, Inoshita N, et al. Pathological charecteristics of gastric cancer in the elderly. A retrospectiv study of 994 surgical
patients. Gastric Cancer 2004; 7(3): 154–159.
14. Matsushita I, hanai H, Kajimura M, et al. Should gastric cancer
patients more than 80 years of age undergo surgery? Comparison
with patients not treated surgically concerning prognosis and
quality of life. J Clin Gastroenterol 2002; 35(1): 29–34.
15. Saidi RF, Bell JL, Dudrick PS. Surgical resection for gastric cancer in elderly patients: is there difference in outcome?. J Surg Res
2004;118(1): 15–20.
16. Piso P, Bektas H, Wener U, et al. Comparison between treatment
results for gastric cancer in younger and elderly patients. Zentralbl
Chir 2002; 127(4): 270–274.
GASTROENTEROLOG 43
Vloga HPV okužbe pri raku zadnjika
The role of HPV infection in anal cancer
Pavle Košorok1*, Matic Bunič1, Kristina Fujs Komloš2, Boštjan J. Kocjan2.
Gačić Štotl Marija1, Mario Poljak2
1
IATROS Medical Centre
2
Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana
Gastroenterolog 2013; suplement 2: 44–47
Ključne besede:Rak zadnjika, okužba s humanim virusom
papiloma, cepljenje, zmanjšana imunska odpornost.
Keywords: Anal cancer, HPV infection, vaccination,
immunodeficiency
POVZETEK
ABSTRACT
Okužba s humanim virusom papiloma (HPV) je vse
pomembnejša. Poleg benigne patologije se vedno
pogostejše tudi maligne spremembe anogenitalnega
predela, med katerimi je najbolj poznan rak materničnega vratu. Intenzivne raziskave so privedle do
uvedbe cepiva, ki v visokem odstotku ščiti pred rakavimi spremembami, ki jih povzročata seva HPV 16 in
18 – rak materničnega vratu, rak anusa, različni raki
v genitalnem predelu in grlu. Cepivo, ki ščiti pred
rakastimi spremembami vsebuje še genotipa HPV 6
in 11, ki povzročata benigne anogenitalne bradavice.
Poznavanje razširjenosti posameznih genotipov v
populaciji je ključno za napoved uspešnosti cepiva.
Na pojav bolezni ne vpliva samo okužba z virusom
ampak tudi spremljajoči dejavniki – število spolnih
partnerjev, homoseksualni in heteroseksualni analni
spolni odnosi, sočasna okužba s spolno prenosljivimi
boleznimi (sifilis, gonoreja, herpes simplex virus, klamidija). Pogosteje se pojavljajo tudi pri bolnikih z
zmanjšano imunsko odpornostjo, pri bolnikih po
kemoterapiji in tistih, ki prejemajo imunosupresivna
zdravila po transplantaciji organov.
Recently, infection with the human papillomavirus
(HPV) became increasingly important. Beside the
benign pathology, malignant changes of ano-genital
region are also increasing, the most known among
them is cervical cancer. Intensive research led to the
introduction of the vaccine which protects the population of cancerous changes caused by HPV strains
16 and 18 - cervical cancer, anal cancer, cancers of
the throat and genital area. The vaccine, which protects against cancer contains also strains HPV 6 and
11, that causes anogenital warts. Knowledge of the
prevalence of certain genotypes in the population is
essential for predicting the performance of the vaccine. The onset of the disease depends not only from
infection, but but also on accompanying circumstances - the number of sexual partners, homosexual and
heterosexual anal sex, co-infection with sexually
transmitted diseases (syphilis, gonorrhea, herpes simplex virus, chlamydia). Increased frequency is also
found in immunodeficient patients, with patients
undergoing chemotherapy and those receiving immunosuppressive drugs after organ transplants. The
virus enters the body through damaged skin epithe-
*Doc. dr. Pavle Košorok, dr. med., spec. krg.
IATROS Medical Centre
Parmova 51 b, 1000 Ljubljana, Slovenia
44 GASTROENTEROLOG
Virus vstopi v telo skozi poškodovati kožni epitelij,
naseli se v bazalnih celicah in se s tem izogne normalnemu imunskemu nadzoru. Razmnožuje se v
spodnjih plasteh ploščatega epitela. Okuženi keratociti proliferirajo na nenormalen način in
povzročijo nastanek genitalnih bradavic (najpogosteje tipa HPV 6 in 11). HPV tipa 16, 18, 31, 33 in
35 povezujemo z nastankom analne displazije in
neoplazije. Onkogeni tipi se naselijo v celičnem
jedru in zlijejo z gostiteljevim dednim materialom.
Pogoste so okužbe z več genotipi virusa naenkrat.
lium and resides in the basal cells and thus avoid
normal immune surveillance. The virus replicates
in the lower layers of flat epithelium. Infected cells
proliferate in an abnormal way and cause the formation of genital warts (usually caused by the types
HPV 6 and 11). HPV types 16, 18, 31, 33 and 35 are
associated with the development of anal dysplasia
and neoplasia. Oncogenic types of genes settle in
the cell nucleus and incorporate in hereditary material. Infections with multiple genotypes of virus are
also frequent.
V naši ustanovi že več let sledimo bolnike, okužene s HPV. Med benignimi najpogosteje najdemo
HPV 6 in 11, med malignimi genotipi pa je najpogostejši HPV 16. Najdeni so tudi drugi benigni in
onkogeni tipi HPV. Pogoste pa so okužbe z več
genotipi naenkrat.
Our institution follows patients infected with HPV for
several years. We usualy confirmed the benign causes
such as HPV 6 and 11. The most common malignant
genotype in our series was HPV 16. We also found
other benign and oncogenic types of HPV. Coexisting
infection with more genotypes were also recorded.
Cepljenje s štirivalentnim cepivom v velikem odstotku
ščiti pred pojavom malignih in benignih obolenj,
povzročenih s HPV.
Vaccination with the quadrivalent vaccine protects
a large percentage of patients from malignant and
benign diseases caused by HPV.
NASTANEK ANALNEGA KARCINOMA
malni episom, medtem, ko se HPV tipa 16 in 18
vgradi v gostiteljevo DNA, kar razloži različno
sposobnost za začetek razvoja raka (3,5). Študije
Palmerja in sodelavcev (6) kažejo na to, da epitelij
prehodne cone analnega kanala kaže embriološke
in histološke podobnosti s prehodno cono materničnega vratu.
Okužba s HPV povzroča analni karcinom na način,
ki ga lahko enačimo z vlogo HPV okužbe pri
nastanku karcinoma materničnega vratu (1,2).
Mnogi bolniki imajo istočasno analne in genitalne
virusne spremembe. Običajno spadajo med populacijo s podobnimi navadami, med drugim tudi
povečanim številom spolnih partnerjev. Analni in
cervikalni karcinomi so praviloma povzročeni z
visokorizičnimi HPV genotipi 16 in 18 (3,4).
Danes je znanih že preko 100 različnih genotipov
HPV, za vsaj 20 od njih vemo, da okužijo anogenitalni predel. Tipa 6 in 11 na splošno povzročata
benigne lezije, kondilome in analno intraepitelialno neoplazijo (AIN) – displazijo nizke stopnje,
ki redko napreduje do karcinoma. Nasprotno,
HPV genotipov 16, 18, 31, 33, 34 in 35 povzročajo
intraepitelijsko displazijo visoke stopnje, carcinoma in situ ter karcinom anusa in materničnega
vratu. HPV tipa 6 in 11 ostaja kot ekstrakromoso-
Imunokomprimirani bolniki, bolniki na imunosupresivni terapiji (transplantacije ledvic, jeter, srca)
in bolniki z rakom po kemoterapiji so izpostavljeni
večjemu tveganju okužbe s HPV in večji verjetnosti
nastanka ploščatoceličnega karcinoma (7, 8). Pri
teh se karcinomi pojavljajo v mlajši dobi, so multifokalni, bolj trdoživi, ponavljajoči in hitro
napredujejo. Pri približno 50 % HIV pozitivnih
bolnikov lahko dokažemo HPV DNA.
Analni karcinom se pojavlja tudi v nerizični populaciji moških in žensk. Zato je treba razmisliti tudi
o drugih načinih prenosa v analni kanal. Možno je,
GASTROENTEROLOG 45
da gre za interakcijo več vzrokov, kot so vplivi okolja,
HPV okužba, imunski status in prisotnost supresivnih genov (9).
DIAGNOSTIKA
V klinični praksi srečujemo bolnike z razvito benigno ali maligno simptomatiko. Pravilno oceno
dobimo s skrbnim pregledom, ki mora zajeti tudi
pregled analnega kanala. Pri tem je omogočen
histološki odvzem na osnovi katerega je nato
možno določiti najboljši način zdravljenja.
V naši ustanovi vedno odvzamemo reprezentativni
vzorec benignih in malignih sprememb, enega od
tipičnih vzorcev pa razdelimo na dva dela od katerih
je eden namenjen histološki preiskavi, drugega pa
vložimo v tekoči dušik za določitev HPV genotipa.
ZDRAVLJENJE
Benigne spremembe odstranimo z ekscizijo in elektrokoagulacijo. Sumljiva mesta prav tako požgemo.
Karcinomske spremembe pa praviloma ekscidiramo z varnostnim robom. Včasih se pokaže, da
imajo tudi navidezno benigne spremembe že malignizirana območja. V takih primerih je potrebna
dodatna kirurška oskrba.
Redko najdemo napredovale maligne spremembe,
kjer je potrebno zdravljenje v sodelovanju z onkologi.
PREVENTIVA
Tako bolnike z benignimi kot malignimi spremembami redno kontroliramo. Iščemo vidne
spremembe. Z brisom analnega kanala pa tako kot
pri brisu cervikalnega kanala (cervikalna intraepitelijska neoplazija – CIN) iščemo spremembe v
smislu analne intraepitelijske neoplazije – AIN.
Posebno skrben nadzor je potreben pri imunokomprimiranih bolnikih in bolnikih okuženih z
virusom HIV (10, 11, 12).
46 GASTROENTEROLOG
REZULTATI NAŠE ŠTUDIJE
V študiji, ki poteka v sodelovanju z Inštitutom za
mikrobiologijo in imunologijo MF UL in Inštitutom
za patologijo MF UL sledimo vse naše paciente in
analiziramo genotipe HPV, ki so prisotni v patoloških
spremembah, ki jih odkrivamo. Najpogosteje odkriti
genotipi so bili HPV 6 in 11 pri bolnikih z benignimi
spremembami, z večjo prevalenco tipa HPV 6 v več
različicah. V posameznih primerih je bila najdena
tudi kombinirana okužba (HPV 6 in 11). Nekateri
HPV pozitivni vzorci so pokazali še druge tipe HPV
kot HPV 26, 40, 42, 54, 57, 61, 62, 73, 74, 84, 91,
CP 6108 in visoko rizični HPV 16 in 52. Pri tkivnih
vzorcih bolnikov z analnim karcinomom je bila
vedno najdena HPV DNA. Najpogostejši genotip je
bil HPV 16. Pri enem od pacientov z malignomom je
bil najdem samo genotip HPV 6, pri enem pa visoko
rizični HPV 52 in istočasna okužba z nizko rizičnim
humanim papiloma virusom HPV 61. (13, 14)
ZAKLJUČEK
Karcinome analnega predela v zadnjem času vse
pogosteje odkrivamo. Dokazan je vpliv okužbe z
humanim papiloma virusom, ki povzroči preskok v
karcinomsko raščo. Obstaja več genotipov HPV, ki
povzročajo spremembe v anogenitalnem predelu.
HPV okužba povzroča spremembe, ki vodijo tudi
do raka materničnega vratu. Najbolj patogene
vrste humanega papiloma virusa sta genotipa 6 in
11, ki praviloma povzročata samo benigne spremembe (anogenitalne bradavice) ter 16 in 18, ki
povzročata rakave spremembe tako na materničnem vratu, kot na zadnjiku. Poleg teh štirih
najpogostejših genotipov so znani še nekateri, ki
jim pripisujejo onkogeno delovanje. Za nastanek
raka zadnjika je v veliki meri odgovorno tudi obnašanje posameznika (vrsta spolnih praks, menjavanje
partnerjev, okužbe s spolno prenosljivimi boleznimi, HIV). Pomembno lahko vpliva tudi zmanjšana
imunska odpornost pri bolnikih s transplantacijo
organov ali ob kemoterapiji.
Poznane so tudi posamezne oblike malignih sprememb, za katere za enkrat ni dokazano, da bi bile
v zvezi s HPV okužbo, potrebno pa jih je poznati
in razlikovati od tistih, kjer je povezava s HPV
okužbo dokazana.
LITERATURA
1. Frisch M. On the etiology of anal squamosum carcinoma. Dan
Med Bull 2002; 49:194–209.
2. Chang GJ, Sheldon A, Welton ML. Epidemiology and natural history of anal HPV infection and ASIL and cancer in the general
population.Semin Colon Rect Surg 2004; 15:210–214
3. Saclarides TJ, Klem D. Genetic alterations and virology of anal
cancer. Semin Colon Rectal Surg 1995; 6:131–134.
4. Shroyer KR, Kim JG, Manos MM, Greer CE, Pearlman NW,
Franklin WA, Papilloma virus found in anorectal squamous carcinoma, not in colon adenocarcinoma. Arch Surg 1992;
127:741–744.
5. Bjorget B, Engeland A, Luostarinen T, et al. Human papilloma virus
infection as a risk factor for anal and perianal skin cancer in a prospective study. Br J Cancer 2002; 87:61–64.
6. ¸Palmer JG, Schoelefield JH, Coates PJ, et al. Anal cancer and
human papilloma viruses. Dis Colon Rectum 1989;
32:1016–1022.
7. Welton ML. Etiology of human papilloma virus infections and the
development of anal squamous intraepithelial lesions. Semin
Colon rectal Surg 2004; 15:193–195.
8. Mullerat J, Northover J. Human papilloma virus and anal neoplastic lesions in the immunocompromised (Transplant) patient.
Semin Colon Rectal Surg 2004; 15:215–217.
9. Deans GT, McAlee JJA, Spence RAJ. Malignant anal tumors. Br
J Surg 1994; 81:501–508.
10. Polefsky JM. Anal squamous intraepithelial lesions in human
immunodefeciency virus–positive men and women. Semin Oncol
2000; 27:471–479.
11. Goldstone SE, Winkler B, Wifford LJ, Alt E, Polefsky JM. High
prevalence of abal squamous intraepithelial lesions and squamous-cell carcinoma in men who have sex with men as seen in a
surgical practice. Dis Colon Rectum 2001; 44:690–698.
12. Goldie SJ, Kuntz KM, Weinstein MC, Freedberg KA, Palefasky
JM. Cost-effectiveness of screening for anal squamous intraepithelial lesions and cancer in human immunodeficiency virusnegative homosexual and bisexual men. Am J Med 2000;
108:634–641.
13. Fujs Komloš K. Molekularna opredelitev humanih virusov papiloma v papilomih grla in analnih ter genitalnih bradavicah.
Doktorska disertacija 2012, Univerza v Ljubljani, Biotehniška
fakulteta.
14. Bunič M, Fujs Komloš K, Kocjan B, Gačić M, Košorok P, Poljak
M. Distribution of HPV genotypes in Slovenian patients with
anogenital warts and anal carcinomas. V: POTOČNIK, Marko
(ur.). 18th Alp-Danube-Adria Congress on Sexually Transmitted
Diseases and Genital Dermatology, Bled, 5–6 October, 2012.
Final program & abstract book. [S. l.]: Agencija Promo, 2012, str.
26–27.
GASTROENTEROLOG 47
Protektivne stome po operacijah nizkega
raka danke
Protective stoma after low anterior resection for
rectal cancer
Bojan Krebs*, Miran Koželj, Stojan Potrč
Oddelek za splošno in abdominalno kirurgijo, Kirurška klinika, UKC Maribor
Gastroenterolog 2013; suplement 2: 48–50
Ključne besede: nizka sprednja resekcija, protektivna stoma,
anastomoza
Keywords: low anterior resection, anastomosis, protective
stoma
POVZETEK
ABSTRACT
Uvod. Rak danke je drugi najpogostejši rak v
Evropi in nizka sprednja resekcija je zlati standard
pri zdravljenju. Najhujši zaplet po taki operaciji je
puščanje anastomoze. Za zmanjšanje tveganja večina
raziskav priporoča izpeljavo protektivne stome. Ta
postopek sicer že sam po sebi predstavlja določeno
tveganje pri primarni operaciji, predvsem pa je
potrebno računati na možne zaplete pri zapiranju.
Introduction. Colorectal cancer is the second most
common cancer in Europe and low anterior resection
is the gold treatment standard. One of the most serious complications after such operation is anastomotic
leakage. To reduce the risk many surgeons recommend fecal derivation with protective stoma. This procedure by itself is not without risk in the time of primary operation, and one must also take in account the
possible complications of protective stoma closing.
Metode. Retrospektivno smo zbrali podatke o bolnikih, pri katerih smo med leti 2003 in 2012 zaprli
protektivno stomo. Bolniki so bili najprej operirani
zaradi procesa na danki in ob nizki sprednji resekciji je bila izpeljana stoma. Pregledali smo podatke o
osnovni operaciji, tipu stome, času in načinu zapiranja stome, hospitalizaciji, zapletih in preživetju.
Rezultati. Med leti 2003 in 2012 smo zaprli stomo
pri 171 bolnikih, ki so bili operirani zaradi raka
danke. Pri 79 bolnikih je bila napravljena transverzostoma, pri 92 pa ileostoma. Povprečen čas do
zapiranja je bil 235 dni po prvi operaciji. V večini
primerov smo napravili resekcijo črevesa in anastomozo (114), v 56 primerih pa samo zapiranje
Methods. We retrospectively collected data on patients
who were operated on closing the stoma between 2003
and 2012. Patients were first operated because of low
rectal cancer and low anterior resection was performed
with derivation stoma. We reviewed the data of the first
operation, type of stoma, time and method of stoma
closure, hospitalization time, and complications.
Results. Between 2003 and 2012, we closed the stoma
in 171 patients who underwent surgery for rectal cancer. In the 79 patients transversostomy and in 92
patients an ileostomy was made. Average time until closure was 235 days after the first operation. In most
cases, we performed bowel resection and anastomosis
*Bojan Krebs, dr. med.
Oddelek za splošno in abdominalno kirurgijo, Kirurška klinika, Univerzitetni klinični center Maribor,
Ljubljanska 5, 2000 Maribor
48 GASTROENTEROLOG
sprednje stene črevesa brez resekcije. Stopnja zapletov je bila 28 %, medtem, ko je bilo zapletov, ki so
zahtevali kirurško ukrepanje 6 %. Trije bolniki (1,8 %)
so umrli.
(114) and in 56 cases, only the closing of the front wall
of intestine without resection was performed.
Complication rate was 28%, while surgical intervention
was needed in 6%. Three patients (1.8%) have died.
Zaključek. Menimo, da je protektivna stoma
potrebna pri operacijah raka spodnjih dveh tretjin
danke, še posebej po preoperativnem obsevanju.
Kljub temu je potrebno biti zelo pazljiv pri zapiranju
le te, saj lahko na prvi pogled enostavna operacija
pripelje do zelo hudih zapletov, vključno s smrtnim
izidom.
Conclusion. We believe that the protective stoma is
required at operations for rectal cancer in the lower
thirds, especially after preoperative oncological therapy. Nevertheless, it is necessary to be very careful
at stoma closing, because such at first glance simple
operation could lead to very serious complications,
including death.
UVOD
torej bolje bolnika intenzivno spremljati in če do
dehiscence pride, izpeljati stomo kasneje.
Eden od večjih zapletov kirurgije raka danke je vsekakor dehiscenca anastomoze. Z raznimi postopki
poskušamo čim bolj zmanjšati verjetnost, da bi do
dehiscence prišlo in če do tega že pride, da bi to
imelo čim manjši vpliv na bolnika. Izpeljava protektivne stome je eden od postopkov, ki po večini
raziskav bistveno zmanjša delež dehiscenc anastomoz (1–3) Prav tako je klinični potek, če do manjše
dehiscence pride, za bolnika bolj ugoden in morda
sploh ne zahteva kirurškega ukrepanja.
Protektivna stoma je bolj priporočljiva pri bolnikh, ki
so prejeli preoperativno obsevanje, pri bolnikih z zelo
nizko anastomozo in pa morda tudi pri moških. Kar
nekaj raziskav je namreč pokazalo, da imajo moški
višjo stopnjo dehiscenc anastomoz. Najverjetneje je
to povezano z ožjo medenico, težjo preparacijo in
tudi zahtevnejšo rekonstrukcijo v takih pogojih.
Nasprotniki tega postopka trdijo, da izpeljava protektivne stome nima bistvenega vpliva na pooperativni
potek (4–6). Stopnja dehiscence anastomoz po nizkih
resekcijah zaradi raka danke je po raznih podatkih od
6–30 %. Če bi izpeljali stome vsem bolnikom po
takih operacijah, bi to pomenilo, da bi 70–94 %
bolnikov imeli stomo po nepotrebnem. Tudi dejstvo,
da stomo imajo, ne bi zagotovo preprečilo hujših
zapletov pri tistih, pri katerih bi resnično prišlo do
dehiscence anastomoze. Po trditvah nasprotnikov je
Potrebno je misliti tudi na to, da je v račun pri izpeljavi
protektivne stome vsekakor potrebno vzeti tudi zaplete
pri drugi operaciji, ko bomo stomo zaprli. Tudi za ta
poseg je potrebna splošna anestezija, sam poseg pa je,
kljub temu, da izgleda relativno enostaven, povezan z
dokaj visoko stopnjo zapletov. Objavljenih je več raziskav o zapiranju protektivnih stom in zapletih (7–9).
METODE
Zbrali smo podatke za vse bolnike, pri katerih smo
zaprli protektivno stomo med leti 2003 in 2012.
Med njimi smo izbrali bolnike, ki so predhodno
bili operirani zaradi nizkega raka danke in izločili
vse ostale. Zanimal nas je spol bolnika, starost,
prvotna operacija, čas do zapiranja protektivne
stome, tip operacije s katero smo stomo zaprli, čas
hospitalizacije po operaciji ter zapleti in reševanje
le teh. Podatke smo vnesli v preglednico in obdelali z računalniškim programom Microsoft Excel.
REZULTATI
V opazovanem obdobju smo zaprli stomo pri 171
bolnikih. Med njimi je bilo 71 žensk in 100 moških.
Pri 79 bolnikih je bila glede na osebno odločitev
operaterja napravljena transversostoma, pri 92 pa
ileostoma. Pred zapiranjem smo pri vseh bolnikih
GASTROENTEROLOG 49
napravili irigografijo s katero smo ocenili prehodnost
anastomoze. Pri 114 bolnikih smo pri zapiranju
napravili resekcijo črevesa in nato termino terminalno
anastomozo in to predvsem pri bolnikih, ki so imeli
predhodno izpeljano ileostomo. Pri 56 bolnikih pa
smo zadnjo steno pustili intaktno in z direktnimi
šivi zašili sprednjo steno črevesa brez resekcije.
Povprečen čas hospitalizacije po operaciji je bil 10 dni
z razponom od 4 do 68 dni. Povprečen čas od primarne operacije do zapiranja stome je bil 232 dni z
razponom od 75 do 753 dni. Stopnja zapletov je bila
28 odstotkov. Na prvem mestu med zapleti je bil
pooperativni ileus pri 25 bolnikih oziroma 14 odstotkih. Večino smo zdravili konzervativno, 7 bolnikov
pa smo zaradi pooperativnega ileusa ponovno operirali.
Pri 11 bolnikih je prišlo do vnetja v rani kar smo zdravili z razprtjem rane. Pri treh bolnikih je prišlo do
dehiscence anastomoze, kar smo zdravili kirurško.
Skupno je pri 6 odstotkih bolnikov prišlo do zapletov, ki so zahtevali kirurško ukrepanje. Trije bolniki
(1,8 %) so umrli. Pri dveh je bil prvotni zaplet ileus,
pri enem pa dehiscenca anastomoze.
RAZPRAVA IN ZAKLJUČEK
V zadnjih letih je vse več raziskav potrdilo, da protektivna stoma zmanjša delež simptomatskih dehiscenc
anastomoz. Glede na te izsledke in naše lastne izkušnje, je izpeljava protektivne stome pri operacijah raka
danke srednje in spodnje tretjine standard že vrsto let
tudi v naši ustanovi. Po drugi strani pa se moramo
zavedati, da je tudi samo zapiranje protektivne stome
zahtevna operacija s svojo stopnjo zapletov.
V letu 2013 je bila objavljena raziskava, kjer Sharma
in sodelavci opozarjajo, da zapiranje ileostome ni tako
imenovana »manjša operacija« in da je potrebna
enaka previdnost kot pri prvi operaciji (10). Obdelali
so podatke za več kot 5000 bolnikov, pri katerih
zaprli protektivno ileostomo. Stopnja velikih (major)
zapletov je bila 9,3 % in stopnja manjših (minor)
zapletov 8,4 %. Smrtnost je bila 0,6 %.
50 GASTROENTEROLOG
Tudi naši rezultati dokazujejo, da je stopnja zapletov po tej operaciji nadpovprečno visoka. Res je,
da je večina zapletov manjših in smo jih uspeli
rešiti konzervativno, vendar pa je tudi stopnja
zapletov, ki so zahtevali ponovno operacijo dokaj
visoka, pa tudi smrtnost ni zanemarljiva.
LITERATURA
1. Montedori A, Cirocchi R, Farinella E, Sciannameo F, Abraha I
(2010) Covering ileo- or colostomy in anterior resection for rectal carcinoma. Cochrane Database Syst Rev CD006878
2. Tan WS, Tang CL, Shi L, Eu KW (2009) Meta-analysis of defunctioning stomas in low anterior resection for rectal cancer. Br J
Surg 96:462–472
3. Chude GG, Rayate NV, Patris V, Koshariya M, Jagad R, Kawamoto J,
Lygidakis NJ.Defunctioning loop ileostomy with low anterior resection for distal rectal cancer: should we make an ileostomy as a routine
procedure? A prospective randomized study.Hepatogastroenterology.
2008 Sep–Oct;55(86–87):1562–7
4. Wong NY, Eu KW. A defunctioning ileostomy does not prevent clinical anastomotic leak after a low anterior resection: a prospective,
comparative study.Dis Colon Rectum. 2005 Nov;48(11):2076–9.
5. Huh JW, Park YA, Sohn SK.A diverting stoma is not necessary
when performing a handsewn coloanal anastomosis for lower rectal cancer.Dis Colon Rectum. 2007 Jul;50(7):1040–6.
6. Pappalardo G, Spoletini D, Proposito D, Giorgiano F, Conte AM,
Frattaroli FM Protective stoma in anterior resection of the rectum:
when, how and why?Surg Oncol. 2007 Dec;16 Suppl 1:S105–8
7. Bada-Yllán O, García-Osogobio S, Zárate X, Velasco L, Hoyos-Tello
CM, Takahashi T.Morbi-mortality related to ileostomy and
colostomy closure.Rev Invest Clin. 2006 Nov-Dec;58(6):555–60.
8. Mansfield SD, Jensen C, Phair AS, Kelly OT, Kelly SB.Complications
of loop ileostomy closure: a retrospective cohort analysis of 123
patients.World J Surg. 2008 Sep;32(9):2101–6.
9. Chen F, Stuart M.The morbidity of defunctioning stomata.Aust
N Z J Surg. 1996 Apr;66(4):218–21.
10. Sharma A, Deeb AP, Rickles AS, Iannuzzi JC, Monson JR, Fleming
FJ.Closure of defunctioning loop ileostomy is associated with considerable morbidity.Colorectal Dis. 2013 Apr;15(4):458–62.*Bojan
Krebs
Laparaskopska ventralna rektopeksija
Laparosopic ventral rectopexy
Gregor Norčič*
KO za abdominalno kirurgijo, UKC Ljubljana
Gastroenterolog 2013; suplement 2: 51–53
Ključne besede: rektopeksija, laparaskopska ventralna
rektopeksija, prolaps rektuma, intususcepcija
Keywords: rectopexy, laparoscopic ventral mesh rectopexy,
prolapse of the rectum, Intussusception
POVZETEK
ABSTRACT
Laparaskopska ventralna rektopeksija z mrežico je
relativno nova kirurška tehnika zdravljenja prolapsa rektuma. Gre za laparaskopsko različico ene
izmed klasičnih transabdominalnih tehnik, ki združuje učinkovitost slednje in minimalno invazivnost.
Glede na rezultate iz literature je laparaskopska ventralna rektopeksija z mrežico povezana z dobrimi
rezultati zdravljenja in nizko incidenco pooperativnih zapletov. Posledično bi lahko šlo za tehniko
izbora pri bolnikih s prolapsom rektuma, ki so sposobni operativnega posega v splošni anesteziji.
Laparoscopic ventral mesh rectopexy is a relatively
new surgical technique for treating rectal prolapse. It
is a laparoscopic version of one of the classic transabdominal techniques that combines its efficiency and
minimal invasiveness. Laparoscopic ventral mesh
rectopexy is associated with good treatment results
and a low incidence of postoperative complications,
according to the available published data. It could
therefore become a technique of choice in patients
with rectal prolapse who are capable of surgical procedure under general anesthesia.
UVOD
Glede na nejasno teorijo in patogenezo prolapsa
rektuma ni presenetljivo, da so se skozi zgodovino
razvile različne kirurške tehnike, s katerimi so
kirurgi poizkušali odpraviti prolaps rektuma in blažiti pridruženo simptomatiko. Tradicionalno se te
kirurške tehnike glede na pristop delijo v dve veliki
skupini: perinealne in transabdominalne tehnike.
Rektopeksija pomeni fiksacijo rektuma na okolišnje
strukture. Gre za kirurško tehniko, ki je namenjena
zdravljenju prolapsa rektuma.
Prolaps rektuma je bolezen zadnjika, ki prizadene
predvsem starejše bolnice. Poleg kozmetične motnje in odvajanja krvi ali sluzi na blato je bolezen
povezana tudi s funkcionalno okvaro, ki se kaže
kot zaprtje (pri okrog 60 % bolnikov) ali inkontinenca
(do 70 % bolnikov). Etiologija prolapsa rektuma ni
povsem pojasnjena, obstajajo različne patogenetske
teorije njegovega nastanka. (1)
Pri perinealnih tehnikah je kirurški poseg omejen
na zadnjik in odpiranje trebušne votline ni potrebno. Posledično se jih lahko izvaja v regionalni
anesteziji. Te tehnike se zato zdijo posebej primerne
za starejše bolnike s pridruženimi boleznimi. Danes
*As. mag. Gregor Norčič, dr. med
Klinični oddelek za abdominalno kirurgijo, Kirurška klinika, Univerzitetni klinični center Ljubljana
Zaloška 2, 1000 Ljubljana
GASTROENTEROLOG 51
se v praksi uporabljata le še dve perinealni tehniki:
perinealna resekcija rektuma po Altemeierju in operacija po Delormu.
Pri transabdominalnih tehnikah se kirurški poseg
zaradi prolapsa rektuma izvede v trebušni votlini.
Transabdominalne tehnike se med sabo razlikujejo
glede na to, ali pri operaciji odstranimo del debelega
črevesa in na kakšen način in kam se fiksira rektum. (2)
TRANSABDOMINALNE KIRURŠKE
TEHNIKE ZARADI PROLAPSA
REKTUMA
Klasične abdominalne operacije zaradi prolapsa
rektuma so: rektopeksija po Ripsteinu, rektopeksija po Wellsu, rektopeksija po Orr-Loygueu, in
resekcija sigmoidnega kolona z rektopeksijo po
Frykman-Goldbergu.
Pri Ripsteinovi operaciji se rektum anteriorno fiksira na presakralno fascijo z neresorbilnimi šivi ali
neresorbilno mrežico.
Pri Wellsovi operaciji se za posteriorno fiksacijo
rektuma uporablja posebna spužva (»Ivalon sponge«)
ali mrežica.
Pri operaciji po Orr-Loygueu se rektum vzdolžno
lateralno fiksira na promontorij sakruma s pomočjo
mrežice.
Operacija po Frykman-Goldbergu je indicirana v primeru dolgega sigmoidnega kolona. Najprej se napravi
resekcija sigme, nato pa še fiksacija rektuma s šivi.
Z razvojem laparaskopske kolorektalne kirurgije so
kirurgi opisane transabdominalne tehnike pričeli
izvajati na minimalno invaziven - laparaskopski
način. Posebej popularna tehnika je postala ventralna laparaskopska rektopeskija z mrežico. Pri tej
tehniki gre pravzaprav za Orr- Loyguevo tehniko
na laparaskopski način.
LAPARASKOPSKA VENTRALNA
REKTOPEKSIJA Z MREŽICO
Tehniko laparaskopske ventralne rektopeksije z mrežico je opisal D’Hoore s sodelavci leta 2004. Bistvo
operacije je laparaskopska mobilizacija rektuma ante52 GASTROENTEROLOG
riorno in lateralno do medeničnega dna, posteriorno
pa se mezorektuma naj ne bi ločevalo od presakralne
fascije. Na ta način naj bi se kirurgi izognili poškodbam avtonomnega živčevja in s tem povezanim
funkcionalnim težavam. Na tako razgaljeno sprednjo
steno ekstraperitonealnega dela rektuma se nato s
posameznimi šivi prišije mrežica. Mrežica je oblikovana v obliko traku, ožji del naj bi bil širok nekoliko
manj od rektuma, po dolžini pa naj bi segala od
medeničnega dna pa do promontorija sakruma. Na
rektum mora biti prišita tako, da poteka od sprednje
stene ekstraperitonealnega rektuma preko desne
lateralne stene do presakralne fascije desno pararektalno v predelu promontorija sakruma. Na tem
mestu se mrežica nato fiksira na presakralno fascijo
s ustreznimi sponkami tako, da se doseže ustrezna
poprava prolapsa rektuma. Čez mrežico se nato s
tekočim šivom rekonstruira peritonej. (3)
REZULTATI ZDRAVLJENJA Z
LAPARASKOPSKO VENTRALNO
REKTOPEKSIJO Z MREŽICO
Številni avtorji poročajo o pozitivnih izidih zdravljenja prolapsa rektuma z laparaskopsko ventralno
rektopeksijo z mrežico. Tehnika naj bi bila povezana
z nizko stopnjo pooperativnih zapletov, visokim
deležem izboljšanja funkcionalnih težav in nizko
stopnjo recidivov prolapsa rektuma.
D’Hoore in sodelavci so prvi poročali o rezultatih
zdravljenja z lapatraskopsko ventralno rektopeksijo z
mrežico. Od 109 operiranih bolnikov je bila potrebna
konverzija iz laparaskopske v klasično tehniko pri
4 bolnikih. Do manjših zapletov je prišlo pri 7 %
bolnikov. Do recidiva prolapsa je prišlo pri 3,66 %
bolnikov. (4)
V preglednem članku, ki zajema 12 nerandomiziranih analiz pri skupaj 728 bolnikih zdravljenih z
laparaskopsko ventralno rektopeksijo so avtorji
ugotavljali recidiv prolapsa pri 0–15,4 %, zmanjšanje
simptomov obstipacije pri 23,9 % in zmanjšanje
inkontinence pri 44,9 % bolnikov. Do zapletov je
prišlo pri 1,4–47 % bolnikov. (5)
Metaanaliza osmih študij pri 467 bolnikih je primerjala laparaskopske tehnike rektopeksije s klasičnimi.
Incidenca recidivov prolapsa je bila pri vseh tehnikah
podobna in se je gibala do 10 %. Pri bolnikih po laparaskopski rektopesiji z mrežico je prišlo do izboljšanja
inkontinence v 27–90 % primerov, do izboljšanja
zaprtja pa v 0–84 % primerov. V posameznih študijah so sicer opisovali tudi poslabšanje obeh simptomov
pri operiranih bolnikih. (6)
Dolgoročni rezultati bolnikov, sledenih po laparaskopski ventralni rektopeksiji v okviru prospektivne
študije, govorijo za recidiv prolapsa pri 6 % bolnikov,
za izboljšanje zaprtja pri 72 % bolnikov in pojav na
novo nastalega zaprtja pri 7 % bolnikov. Pri bolnikih
so po operativnem posegu opažali pomembno izboljšanje kakovosti življenja. (7)
PRIMERJAVA RAZLIČNIH TEHNIK
Obstaja le malo verodostojnih študij, ki bi primerjale različne kirurške tehnike zdravljenja prolapsa
rektuma in njihove rezultate. (2)
Na podlagi omenjene metaanalize študij, ki je primerjala klasične in laparaskopske tehnike med
seboj, lahko zaključimo da so transabdominalne
laparaskopske tehnike najmanj enakovredne transabdominalnim klasičnim tehnikam. Laparaskopske
tehnike niso povezane z višjo stopnjo zapletov, niti z
višjo stopnjo zapletov od klasičnih tehnik. (6)
Multicentrična študija na 293 bolnikih izvedena v
Veliki Britaniji je poizkušala primerjati transabdominalne in perinealne tehnike, nato pa znotraj
obeh skupin še po dve izbrani tehniki: Delormovo
in Altemeierjevo operacijo med perinealnimi tehnikami oziroma rektopeksijo s šivi in resekcijo
sigmoidnega kolona v kombinaciji z rektopeksijo s
šivi. Študija ni pokazala pomembnih razlik med
posameznimi tehnikami, vendar je povezana z določenimi pomanjkljivostmi. Največja pomanjkljivost
je, da je študija dopuščala diskrecijsko pravico
kirurga pri odločitvi za določeno kirurško tehniko.
Posledično je bilo med perinealnimi in transabdominalnimi tehnikami dejansko randomiziranih le
49 bolnikov. Druga velika pomanjkljivost pa je ta,
da od transabdominalnih operacij ni bila izbrana
trenutno najbolj popularna tehnika, to je laparaskopska ventralna rektopeksija z mrežico. (8)
Od leta 2010 je v teku nemška multicentrična randomizirana študija, ki med seboj primerja Delormovo
tehniko in laparaskopsko resekcijo sigmoidnega
kolona v kombinaciji z rektopeksijo s šivi. Rezultate študije še čakamo, vendar tudi ta ne bo dala
neposredne primerjave med najbolj popularno
perinealno in transabdominalno tehniko. (9)
ZAKLJUČEK
Glede na dokaze iz literature je laparaskopska ventralna rektopeksija z mrežico povezana z nizko
incidenco konverzij, nizko incidenco pooperativnih zapletov, nizko incidenco recidiva prolapsa
rektuma in ugodnim funkcionalnim rezultatom
zdravljenja. Bolnike s prolapsom rektuma, ki so
sposobni kirurškega posega v splošni anesteziji je
zato potrebno napotiti h kirurgu, ki obvlada tako
laparskopsko kolorektalno kirurgijo kot tudi perinealne tehnike zdravljenja. Le tako bodo lahko ti
bolniki deležni optimalne kirurške oskrbe.
LITERATURA
1. D’Hoore. Rectal Prolapse, Intussusception, Solitary Rectal
Ulcer. In: Herold A., Lehur P.A., Matzel K.E., O’Connell P.R.:
Coloproctology. Berlin Heidelberg: Springer 2008: 115–119.
2. Melton GB, Kwaan MR. Rectal prolapse. Surg Clin North Am.
2013; 93:187–98.
3. D’Hoore A, Cadoni R, Penninckx F. Long-term outcome of
laparoscopic ventral rectopexy for total rectal prolapse. Br J Surg.
2004; 91:1500–5.
4. D’Hoore A, Penninckx F. Laparoscopic ventral recto(colpo)pexy
for rectal prolapse: surgical technique and outcome for 109 patients.
Surg Endosc. 2006; 20:1919–23.
5. Samaranayake CB, Luo C, Plank AW, Merrie AE, Plank LD,
Bissett IP. Systematic review on ventral rectopexy for rectal prolapse and intussusception. Colorectal Dis. 2010; 12:504–12.
6. Cadeddu F, Sileri P, Grande M, De Luca E, Franceschilli L, Milito
G. Focus on abdominal rectopexy for full-thickness rectal prolapse:
meta-analysis of literature. Tech Coloproctol. 2012; 16:37–53.
7. Maggiori L, Bretagnol F, Ferron M, Panis Y. Laparoscopic ventral
rectopexy: a prospective long-term evaluation of functional
results and quality of life. Tech Coloproctol. 2013 Jan 23. [Epub
ahead of print]
8. Senapati A, Gray RG, Middleton LJ, Harding J, Hills RK,
Armitage NC, et al.. The PROSPER Collaborative Group. PROSPER: a randomised comparison of surgical treatments for rectal
prolapse. Colorectal Dis. 2013 Mar 5. [Epub ahead of print]
9. Rothenhoefer S, Herrle F, Herold A, Joos A, Bussen D, Kieser M,
et al.. DeloRes trial: study protocol for a randomized trial comparing
two standardized surgical approaches in rectal prolapse - Delorme’s
procedure versus resection rectopexy. Trials. 2012; 13:155.
GASTROENTEROLOG 53
Zdravljenje lokalno napredovalega raka
danke
Treatment of locally advanced rectal cancer
Mirko Omejc*
KO za abdominalno kirurgijo, UKC Ljubljana
Gastroenterolog 2013; suplement 2: 54–55
Ključne besede: rak danke, neoadjuvantno zdravljenje,
regresija tumorja
Keywords: rectal cancer, neoadjuvant treatment, tumor
regression
POVZETEK
ABSTRACT
Predoperativno zdravljenje lokalno napredovalega
raka danke v kliničnem stadiju II (cT3-4, N0, M0) in III
(cT1-4, N+, M0) z radiokemoterapijo je postalo standarden način zdravljenja. S tem dosežemo »downsizing« in
»downstaging« tumorja kar omogoča večjo možnost R0
resekcije in izboljša lokalno kontrolo tumorja. V primeru popolne regresije tumorja po neoadjuvantnem
zdravljenju pa to pomeni za bolnika boljšo prognozo kot
pri tumorjih z delno regresijo ali brez regresije tumorja.
Preoperative treatment of advanced rectal cancer in
clinical stage II (cT3-4, N0, M0) and III (cT1-4, N+,
M0) using radiochemotherapy has become standard
treatment approach. Tumor downstaging and downsizing increase R0 resection rates and improve local
control. Complete tumor regression after neoadjuvant treatment carries better prognosis than partial
or no regression.
Namen kirurškega zdravljenja raka danke je zagotoviti
lokalni nadzor nad rakom in tako izboljšati preživetje
ter ohranitev analnega sfinktra, mikcijske in spolne
funkcije in ohraniti oziroma izboljšati kakovost bolnikovega življenja. Za odločitev o načinu zdravljenja so
ključni predoperativni podatki o lokalizaciji in višini
tumorja, globini vraščanja tumorja v steno danke, prizadetosti bezgavk in prisotnosti oddaljenih zasevkov.
Pri tumorjih v stadijih pT1/pT2 pN0 je zdravljenje
samo kirurško. Pri tumorjih, ki rastejo v muskularis
proprijo (T3, T4) in/ali so že zasevali v področne
bezgavke (N1, N2) ali v oddaljene organe (M1), pride
v poštev poleg kirurškega zdravljenja tudi radiokemoterapija. Na osnovi študij objavljenih v zadnjih
letih, ki so dokazale prednost predoperativnega
zdravljenja z radio in kemoterapijo v primerjavi s
pooperativnim zdravljenjem glede lokalne kontrole
tumorja in toksičnosti, se v zadnjih letih vedno bolj
uveljavlja predoperativni pristop (1,2). Izbiro bolnikov za predoperativno zdravljenje nam omogoča
nuklearna magnetna resonanca (MRI), ki omogoča
natančen prikaz mehkih struktur v mali medenici. S
to preiskavo lahko prikažemo radialni rob tumorja in
njegovo oddaljenost od fascije mezorektuma. Pri bolnikih, pri katerih tumor sega v neposredno bližino
fascije ali jo celo prerašča, je lokalnih ponovitev več.
Pri takih tumorjih je zato indicirano predoperativno
oziroma neoadjuvantno zdravljenje (3).
* prof. dr. Mirko Omejc, dr. med.
Klinični oddelek za abdominalno kirurgijo, Kirurška klinika, Univerzitetni klinični center Ljubljana
Zaloška 2, 1000 Ljubljana
54 GASTROENTEROLOG
Uporabljamo dve shemi predoperativne radioterapije. Dolga shema pomeni pet tednov obsevanja in
kemoterapije, ki ji sledi 3- do 8-tedenski premor in
nato operacija. Uporablja se pri bolj razširjenih karcinomih z namenom zmanjšati velikost tumorja
(angl. downsizing) in razširjenost bolezni (angl.
downstaging). Kratka shema radioterapije pa pomeni
en teden radioterapije brez dodatka kemoterapije in
operacija takoj po zaključenem obsevanju. Uporablja
se pri manj razširjenih tumorjih, da bi zmanjšali število lokalnih ponovitev.
Vraščanje tumorja v steno rektuma in razširitev v
regionalne bezgavke sta glavna dejavnika, ki določata
prognozo lokalno napredovalega raka danke. Radioin kemoterapija lahko spremenita patološko T in N
kategorijo, saj v različnem obsegu zmanjšata invazijo
tumorja v steno rektuma in perirektalne bezgavke.
Lahko pride celo do popolnega izginotja tumorskih
celic v črevesni steni in bezgavkah (complete response),
kar je opisano pri 15–30 % bolnikov z lokalno napredovalim rakom danke po takem zdravljenju. S tem
učinkom, »downstaging«, znižanja predoperativnega
kliničnega stadija (kategoriji T/N), v primerjavi z patološkim, merimo odgovor tumorja na predoperativno
zdravljenje (4, 5).
Popolna klinična regresija tumorja (complete clinical regression, cCR), ki pomeni odsotnost klinično
dokazljivega rezidualnega tumorja, pa ne pomeni
tudi patološko popolno regresijo tumorja (pathologic complete regression, pCR), to je popolno
odsotnost vitalnih tumorskih celic. Kljub razvoju
številnih diagnostičnih metod zaenkrat brez operacije in patološkega pregleda resektata, še ni mogoče
zanesljivo potrditi odsotnosti tumorskih celic v steni
črevesa, mezorektumu in bezgavkah. Tudi ob
popolni regresiji tumorja v črevesni steni, obstaja
možnost zasevkov v regionalnih bezgavkah, kar
predstavlja pomemben izziv pri izbiri ustreznega in
ev. manj agresivnega ali neoperativnega zdravljenja.
Patološko potrjena popolna regresija tumorja v steni
črevesa in regionalnih bezgavkah po neoadjuvantnem zdravljenju pomeni za bolnika boljšo prognozo
kot pri tumorjih z delno regresijo ali brez regresije
tumorja, ne glede na klinični stadij bolezni pred
začetkom neoadjuvantnega zdravljenja (7, 8).
Zmanjšanje in regresija tumorja olajšata kirurško zdravljenje, lahko pa tak odgovor pomeni tudi bolj ugoden
biološki potencial tumorja. Ker predoperativna radioin kemoterapija delujeta na tkiva z dobro prekrvavitvijo in oksigenacijo je učinek takšnega zdravljenja boljši
kot pri pooperativnem pristopu in zato delež lokalnih
ponovitev bolezni manjši. Zaradi zmanjšanja tumorja
je v nekaterih primerih možna nizka sprednja resekcija namesto abdominoperinealne ekscizije in s tem
ohranitev kontinuitete prebavne poti. Pomemben je
tudi funkcionalni vidik, saj s predoperativnim obsevanjem prizadenemo tumor in del debelega črevesa, ki ga
pri operaciji odstranimo, ostanejo pa tkiva, ki niso obsevana, kar omogoča rekonstrukcijo z neobsevanim delom
črevesa in zato boljši funkcionalni rezultat (9, 10).
LITERATURA
1. Sebag-Montefiore D, Stephens RJ, Steele R, Monson J, Grieve R,
Khanna S et al. Preoperative radiotherapy versus selective postoperative chemoradiotherapy in patients with rectal cancer (MRC CR07
and NCIC-CTG C016): a multicentre, randomised trial. Lancet 2009;
373: 811–820.
2. Pucciarelli S, Gagliardi G, Maretto I, Lonardi S, Friso ML, Urso E et al.
Long-term oncologic results and complications after preoperative
chemoradiotherapy for rectal cancer: a single-institution experience after
a median follow-up of 95 months. Ann Surg Oncol 2009; 16: 893–899.
3. de Campos-Lobato LF, Stocchi L, da Luz Moreira A, Geisler D, Dietz
DW, Lavery IC et al. Pathologic complete response after neoadjuvant
treatment for rectal cancer decreases distant recurrence and could
eradicate local recurrence. Ann Surg Oncol 2011; 18: 1590–1598.
4. Garcia-Aguilar J, Smith DD, Avila K, Bergsland EK, Chu P, Krieg
RM; Timing of Rectal Cancer Response to Chemoradiation
Consortium. Optimal timing of surgery after chemoradiation for
advanced rectal cancer: preliminary results of a multicenter, nonrandomized phase II prospective trial. Ann Surg 2011; 254: 97–102.
5. Habr-Gama A, Perez RO, Nadalin W, Sabbaga J, Ribeiro U Jr,
Silva e Sousa AH Jr et al. Operative versus nonoperative treatment for stage 0 distal rectal cancer following chemoradiation
therapy: long-term results. Ann Surg 2004; 240: 711–717.
6. Capirci C, Valentini V, Cionini L, De Paoli A, Rodel C, Glynne-Jones
R et al. Prognostic value of pathologic complete response after neoadjuvant therapy in locally advanced rectal cancer: long-term analysis of
566 ypCR patients. Int J Radiat Oncol Biol Phys 2008; 72: 99–107.
7. Shivnani AT, SmallWJr, Stryker SJ, Kiel KD, Lim S, Halverson AL
et al. Preoperative chemoradiation for rectal cancer: results of multimodality management and analysis of prognostic factors. Am J Surg
2007; 193: 389–393.
8. Wheeler JM, Dodds E, Warren BF, Cunningham C, George BD, Jones
AC et al. Preoperative chemoradiotherapy and total mesorectal excision surgery for locally advanced rectal cancer: correlation with rectal
cancer regression grade. Dis Colon Rectum 2004; 47: 2025–2031.
9. Yeo SG, Kim DY, Kim TH, Chang HJ, Oh JH, ParkW et al.
Pathologic complete response of primary tumor following preoperative chemoradiotherapy for locally advanced rectal cancer:
long-term outcomes and prognostic significance of pathologic
nodal status (KROG 09–01). Ann Surg 2010; 252: 998–1004.
10. Maas M, Nelemans PJ, Valentini V, Das P, R¨ odel C, Kuo LJ et
al. Long-term outcome in patients with a pathological complete
response after chemoradiation for rectal cancer: a pooled analysis of individual patient data. Lancet Oncol 2010; 11: 835–844.
GASTROENTEROLOG 55
Probiotiki pri vnetni črevesni bolezni
Probiotics in Inflammatory Bowel Disease
Rok Orel*
Klinični oddelek za gastroenterologijo, hepatologijo in nutricionistiko
Pediatrična klinika, UKC Ljubljana
Gastroenterolog 2013; suplement 2: 56–63
Ključne besede: probiotiki, mikrobiota, kronična vnetna
črevesna bolezen
Keywords: probiotics, microbiota, chronic inflammatory
bowel disease
POVZETEK
ABSTRACT
Nepravilen imunski odziv organizma na črevesne
bakterije je eden ključnih dejavnikov pri patogenezi kroničninh vnetnih črevesnih bolezni.
Zanimivo možnost zdravljenja predstavljalo probiotiki s svojimi številnimi mehanizmi delovanja,
ki vključujejo vpliv na črevesno mikrobioto in
njeno presnovo, preprečevanje naseljevanja patogenih mikroorganizmov, utrjevanje črevesne
pregrade in usmerjanje črevesnega imunskega
odziva. Vendar pa se je potrebno zavedati, da sta
poti nastanka Crohnove bolezni in ulceroznega
kolitisa različni in da so mehanizmi delovanja, s
tem pa tudi klinični učinki probiotikov, specifični
za vsak sev. Namen prispevka je pregled klinične
učinkovitosti probiotikov pri zdravljenju aktivne
oblike ulceroznega kolitisa, paučitisa in Crohnove
bolezni in njihove vloge pri vzdrževanju remisije.
Aberrant immune response to intestinal bacteria is
regarded as crucial factor in the pathogenesis of
inflammatory bowel disease. Probiotics with their
multiple mechanisms of action including influence
on gut microbiota and its metabolism, protection
against environmental pathogens, augmentation of
gut barrier function and regulation of intestinal
immune response represent an interesting therapeutic option. However, it should be reminded that
pathologic mechanisms underlying ulcerative colitis
and Crohn’s disease differ and actions of probiotics
are strain-specific. Therefore, specific probiotic
strains or their combinations revealed to be effective
in different IBD types as well as their stages of activity. The aim of this paper is to review clinical effectiveness of probiotics for the treatment of active
ulcerative colitis, pouchitis and Crohn’s disease and
maintenance therapy for these diseases while they
are in remission. According to results of high-quality
clinical trials the evidence of effectiveness is very
strong for the multispecies probiotic VSL#3 in prevention of pouchitis and maintenance therapy of
ulcerative colitis. For the latter indication non-pathogenic Escherichia coli strain Nissle 1917 can be also
used. There is also a substantial evidence that VSL#3
and maybe E. coli Nissle given simultaneously with
Prof. dr. Rok Orel, dr. med.,
Klinični oddelek za gastroenterologijo, hepatologijo in nutricionistiko, Pediatrična klinika, UKC Ljubljana
Bohoričeva 20, 1525 Ljubljana
56 GASTROENTEROLOG
standard anti-inflammatory drugs are more effective
in treatment of active ulcerative colitis than standard
medical therapy alone. However, at this moment
there is not enough evidence of any probiotic strain
effectiveness in Crohn’s disease to recommend its
routine clinical use.
INTRODUCTION
Listeria monocitogenes or adherent-invasive
Escherichia coli (11). For example, mutations in
NOD2/CARD15 gene recognized as an important
risk factor for CD, result in deficient function of the
key cytoplasmic receptor for recognition of intracellular bacterial peptidoglycan and consequent
ineffective cytokine response and killing of intracellular pathogens (9–11).
Although the exact etiology of inflammatory bowel disease remains unclear, it is believed that these diseases
are the result of aberrant immune responses to intestinal microbes in the gastrointestinal tract in genetically
susceptible host (1). There are many evidences that
support the hypothesis of the involvement of intestinal
microorganisms in the pathogenesis of IBD. In experimental animal models of IBD, genetically engineered
to develop spontaneous chronic gut inflammation
under standard laboratory conditions, this did not happen when they were raised in a germ-free environment
(2, 3). The IBD lesions predominantly occur in the
parts of GI tract with the highest density of bacterial
microbiota such as terminal ileum and colon (4). In
patients with CD, division of the fecal stream proximal
to the inflamed mucosa results in reduction of inflammation in the excluded parts of the gut while relapse
occurs with restoration of fecal stream and reexposure
to luminal contents (5, 6). In addition, antibiotic treatment has been proved to be efficient in specific cases
of IBD and in pouchitis (7). Moreover, a recent metaanalysis by Khan et al. showed a significant benefit of
antibiotics over placebo for induction of remission in
both CD and UC (8).
Despite many evidences that intestinal microorganisms are required for triggering and perpetuation of
inflammation in IBD, it still remains enigmatic
whether a single specific microorganism or a group
of microbial agents sharing distinctive characteristics could be responsible or an aberrant immune
response to the dysbiosis of the commensal intestinal microbiota plays the major role.
Genetic defects found in IBD patients might make
these individuals particularly susceptible for the
infections with intracellular bacteria such as
Mycobacterium avium subspecies paratuberculosis,
In contrast with vast majority of E. coli strains that
inhabit human intestine as a part of a normal commensal microbiota, some strains acquired specific
virulent factors that help them to adhere to intestinal mucosa and invade into it and consequently
induce inflammatory response (11). Increased numbers of invasive mucosa-associated or even intramucosal E. coli, designated as adherent-invasive E.
coli (AIEC), have been reported in patients with
both CD and UC (12–17). AIEC are capable to
adhere to and to invade intestinal epithelial cells
with macropinocytosis-like process and to survive
and replicate within macrophages, inducing the
release of large amount of pro-inflammatory
cytokines such as TNF-by the infected host cell (18).
Even though several specific microorganisms may
play an important role, no specific microorganism
has been generally recognized as a causal factor.
More probably subtle alterations in commensal
microbiota composition and function (dysbiosis) can
be involved in the pathogenesis of IBD. Numerous
studies revealed that fecal microbiota has a different
composition in IBD patients compared with controls, and even differences between CD and UC
were found. The same is true for mucosa-associated
microbiota, a bacterial population present on the
mucosal surface that is in direct interaction with the
intestinal epithelial and immune system cells
(19–22). However, it remains unknown whether the
intestinal microbiota triggers or maintains the
GASTROENTEROLOG 57
chronicity of inflammatory response in IBD, or its
composition is altered as a secondary response to
the intestinal inflammation (23).
microbes from luminal-mucosal interface by a competition for binding sites on epithelial cell surface or
mucus (24, 29).
The conventional therapy of IBD is focused on suppression of inflammation with aminosalicilates,
steroids, immunomodulatory drugs, and anti-tumor
necrosis factor antibodies. Therapeutic strategies
directed towards change or restoration of the balance between intestinal bacteria represent attractive
alternative or adjunct to the conventional therapy.
The effective use of antibiotics to treat perianal CD,
postoperative CD, pouchitis and maybe even UC are
examples of IBD therapy targeting gut bacteria (7,
24, 25). Moreover, efficacy of therapy of active CD
with enteral nutrition can be at least partially attributed to its influence on bacterial microbiota (26).
Probiotics communicate with epithelial cells and different sets of cells implicated in both innate and
acquired immune response via pattern-recognition
receptors (30). They can enhance gut barrier function and reduce intestinal permeability for intestinal
microorganisms and other antigens (31) by increasing mucus production (32, 33), induction of production and secretion of different anti-microbial
peptides such as defensins, lysozyme, lactoferrin or
phospholipase by epithelial cells and enhancement
of tight junctions and reduction of epithelial cell
apoptosis (24, 34, 35).
The potential to manipulate intestinal microbiota
with probiotics and prebiotics for positive therapeutic purposes in IBD is an attractive approach
gaining great interest of both scientific community
and end consumers – patients with IBD.
MECHANISMS OF PROBIOTIC
EFFECTS IN IBD
Probiotics may achieve their therapeutic effect in
IBD through many different mechanisms. They can
influence the composition of intestinal microbiota
and alter metabolic properties of the microbiome
(23). They can produce short-chain fatty acids and
consequently lower the pH the colonic environment
what inhibits the growth of several potentially pathogenic microorganisms. In addition, butyrate plays
a trophic role as a nutrient for colonicytes, enhances
the repair of injured gut epithelium and acts directly
as an anti-inflammatory agent by inactivation of
intracellular transcriptional factor NFκB pathway
and consequently attenuates the synthesis of inflammatory cytokines (27). A great number of probiotic
strains produce antibacterial substances such as
hydrogen peroxide, hydrogen sulphide, lactic acid
and specific bacteriocins which can be active against
pathogenic bacteria (28) and displace deleterious
58 GASTROENTEROLOG
Probiotics can directly or indirectly modulate intestinal immune response. Each probiotic strain may
have distinct immunoregulatory properties. Very
simplified, probiotics can be classified in two groups
regarding their influence on the immune system,
one exhibiting immunostimulating activities and
the other anti-inflammatory properties (36).
Numerous studies revealed several mechanisms by
which probiotics, including those with proven clinical efficacy in the therapy of IBD, down-regulate
inflammatory immune response. Several probiotics
are acting through maturation of intestinal dendritic
cells and strengthening the regulatory T cell (Treg)
response. Tregs are antigen specific T cells which
prevent autoimmunity and preserve tolerance
towards harmless antigens, including intestinal commensal microbiota (30). They can control excessive
NFκB pathway activation and decrease production
of pro-inflammatory cytokines such as TNFα, INFγ
and IL-8, as well as induce a production and secretion of anti-inflammatory cytokines such as IL-10
and TGFβ (30, 36–38).
Regarding facts that pathogenesis of each type of
IBD differs and that mechanisms of probiotics
action are strain specific and can be very different,
it is expectable that for each type and phase of disease different probiotics would be effective.
CLINICAL EVIDENCE OF EFFICACY
OF PROBIOTICS IN IBD
Treatment of active ulcerative colitis
Clinical studies on the efficacy of probiotics for the
induction of remission in ulcerative colitis gave
encouraging, although conflicting results.
There are two reports in the literature of succesfull
use of an enema of the fecal microbiota from a
healthy donor for treatment of active UC (39, 40). It
is interesting that in spite of extremely encouraging
results of these two reports, no other study using bacteriotherapy has been published.
Several studies investigated efficacy of multispecies probiotic VSL#3 containing four strains of lactobacilli
(L. casei, L. plantarum, L. acidophilus, L. delbrueckii
subsp. bulgaricus), three strains of bifidobacteria
(B. longum, B. breve, B. infantis) and one strain of
Streptoccocus (S. Salivarius subsp. thermophilus). In
these randomized, double-blind, placebo controlled trials
they mostly compared VSL#3 as an addition to standard
therapy with aminosalicilates, steroids and imunomodulators with standard therapy alone. Without exception,
they found a supplementation with VSL#3 to be effective
as clinical activity indexes (such as UCAI), as well as
endoscopic appearance/hystology were significantly
better in probiotic treated groups of UC patients (41–46).
In addition, several other probiotic strains (E. coli Nissle
1917 (47), Saccharomyces boulardii (48), Lactobacillus
reuteri ATCC 55730 (49), their combinations
(BIO-THREE, containing Streptococcus faecalis,
Clostridium butyricum and Bacillus mesentericus (50),
Bifidobacteria-fermented milk (BFM), containing
Bifidobacterium breve strain Yakult, B. bifidum and
Lactobacillus acidophilus (51, 52)), or even symbiotic
mixtures (Bifidobacterium longum and a prebiotic
Synergy 1 (53), Bifidobacterium breve strain Yakult
and galacto-oligosaccharide (GOS) (54)) were tested for
their capacities of induction remission in active UC.
The results of these studies, many of them too small
to be conclusive, mostly gave positive results.
Several reviews and meta-analyses were performed
regarding induction of remission in ulcerative colitis by
probiotics in recent years (55–58). In earlier reviews,
not enough high-quality studies were found and they
were regarded to heterogenous according to methodology and probiotic strains used to enable any firm
conclusions. In contrast with older reviews, metaanalysis performed by Zigra et al. showed a significant
benefit of probiotic use for induction of remission of
UC with pooled relative risk 2.27 (95% CI: 1.00–5.14,
P = 0.049) (57). In the most recent review by Jonkers
and al. only subgroup-specific meta-analyses per probiotic were performed (58). The only probiotic with
several published randomized controlled studies for
induction of remission in adult patients with UC was
VSL#3. The calculated pooled RR for VSL#3 was 1.69
(95% CI: 1.17–2.43), indicating a significant benefit of
VSL#3 over control in inducing remission in active UC.
Maintenance of remission in ulcerative colitis
There were several published studies in which efficacy
of probiotics Escherichia coli Nissle 1917 (47, 59, 60)
or VSL#3 (46, 61) was compared to either placebo
or standard therapy for maintenance therapy in UC.
They revealed that these probiotic are as effective as
mesalazine and more effective than placebo for
maintenance of remission.
In contrast with this, several other studies using
some other probiotics such as Lactobacillus rhamnosus GG (62), Probio-Tec-AB-25 containing two
probiotic strains, Lactobacillus acidophilus La-5 and
Bifidobacterium animalis subspecies lactis BB-12
(63), Lactobacillus salivarius subspecies salivarius
UCC118 and Bifidobacterium infantis 35624 (64)
did not prove probiotics to be significantly more
effective compared to placebo.
In conclusion, specific probiotics as Escherichia coli
Nissle 1917 and multispecies mixture VSL#3 are
probably as efficient as standard maintenance therapy
with mesalazine and can be therefore used instead
of mesalazine in patients intolerant or allergic to
5-aminosalycilates, or as adjunctive therapy to standard
GASTROENTEROLOG 59
therapy to potentially increase the duration of remission.
In American Recommendations for probiotic use
from 2011 we found a very strong “A” recommendation for the use of two specific probiotics, Escherichia
coli Nissle 1917 and multispecies mixture VSL#3, for
maintenance of remission in UC (65).
American Recommendations for probiotic use from
2011 (65). Clinical guidelines for the management of
pouchitis from 2009 suggest the use of VSL#3 in
patients with recurrence of pouchitis following antibiotic treatment or having several recurrences despite
antibiotic therapy (74).
Treatment and prevention of pouchitis
Treatment of active Crohn’s disease
In some patients with UC in whom the disease do not
respond to medical therapy or develop dysplasia or
cancer, proctocolectomy with a construction of an
ileal pouch-anal anastosis (IPAA) is required. An
inflammation of this ileal reservoir (pouch), called
pouchitis, developed in between 15 and 50% of such
patients. Although the exact etiology of pouchitis is
not clear, host genetic factors, fecal stasis, mucosal
ischemia and bacterial dysbiosis in the pouch seem to
be involved (32, 58). Most patients develop pouchitis
in the first year after operation. Antibiotic therapy is
generally successful, however the discontinuation of
antibiotics is often followed by a recurrence of the disease. Therefore, treatment and prevention of pouchitis with probiotics have been studied extensively.
There are only few published clinical studies addressing treatment of active Crohn’s disease with probiotics.
Although the Cochrane Collaboration review from
2008 concluded that there was insufficient evidence to
make any conclusions about the efficacy of probiotics
for induction of remission in CD because of a lack of
well designed clinical studies (75), two studies using
symbiotics that were not included in this review
revealed very promising results.
Although several probiotics and their combinations
were studied for treatment of pouchitis (66, 67), only
studies using already mentioned multispecies preparation VSL#3 showed to be consistently effective
both for maintaining remission after its induction
with antibiotics or for prevention of pauchitis development after IPAA (68–72). 40–100% of patients taking
VSL#3 stayed in remission for one year period in
compare with 6% to 15% on placebo.
Consequently, the effectiveness of VSL#3 was confirmed by two meta-analysis, revealing that VSL#3 was
significantly more effective than placebo in the
maintenance therapy of chronic pouchitis (97% vs. 3%,
P < 0.0001) and the number needed to treat with VSL#3
to prevent one additional relapse was only 2 (58, 73).
According to these findings, multispecies probiotic
preparation VSL#3 was granted by A level recommendation for the primary prevention and maintenance of remission of pouchitis after IPAA in the
60 GASTROENTEROLOG
In the first, which was unfortunately small open-label
uncontrolled trial including only 10 CD patients resistant to the therapy with aminosalicylates and prednisolone, a symbiotic preparation consisting of 3 prebiotic strains (Bifidobacterium breve, Bifidobacterium
longum and Lactobacillus casei) and prebiotic psyllium (Plantago ovata) was used. In a one-year period
complete response was achieved in 6 patients with 2
able to discontinue corticosteroid therapy completely
(76). In recently published randomized, doubleblind, placebo-controlled trial involving 35 patients
with active CD, they used a symbiotic therapy comprising probiotic Bifidobacterium longum and prebiotic Synergy 1 (oligofructose and inulin) simultaneously with conventional therapy (77). Comparing pre
and post-treatment results there was a significant clinical, endoscopical and histological improvement as
well as decrease in TNFα in symbiotic but not in the
placebo group.
Maintenance of remission in Crohn’s
disease
Only few high-quality studies were performed to
assess the efficacy of probiotics for maintenance of
remission achieved with standard medical therapy
or surgical resection in Crohn’s disease. Unfortunatelly, none of them showed the efficacy of probiotics
(78-83) with an exception of a small trial in which a
combination of Saccharomyces boulardii and mesalamine revealed to be significantly more efficient
than mesalamine alone (84).
In conclusion, at this moment the probiotic use for
maintenance of remission in Crohn’s disease is not
recommended. However, regarding growing awareness
and knowledge about the role of microbiota in the pathogenesis of this disease as well as of the mechanisms
of probiotics action, continuing efforts of scientific
community to find specific probiotic strains with clinical efficacy in this indication can be expected.
CONCLUSIONS
Despite profound knowledge about potential mechanisms of pre and probiotic in IBD, the usable data
from well-designed high-quality clinical are often to
scarce to enable making of clear recommendations
for their practical use. There is a very strong evidence supporting use of multispecies probiotic
VSL#3 in patients with ileal-pouch-anal-anastomosis
for prevention of postoperative pouchitis or its recurrence after induction of remission by antibiotics. In
addition, this probiotic product may be an effective
adjunct to antibiotic treatment for active pouchitis.
Two probiotics, VSL#3 and nonpathogenic strain of
Escherichi coli Nissle 1917, can be recommended for
maintenance therapy in ulcerative colitis in remission,
especially in patients intolerant or allergic to standard
medical maintenance therapy, as they are regarded to be
equally efficient. Results of several studies support the
use of probiotics concomitant with standard medical
treatment for induction of remission in ulcerative colitis. However, the evidence supporting their use is much
weaker than in maintenance therapy. At the moment,
the evidence of efficacy is strongest for VSL#3.
Unfortunately, the results of clinical trials on both treatment of acute Crohn’s disease or maintenance of its
remission with probiotics are disappointing and do not
support their use in this condition. The only exception
is a weak evidence of an advantage of the use of Saccharomyces boulardii simultaneously with medical
therapy in the maintenance treatment.
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GASTROENTEROLOG 63
Zdravljenje bolnikov z ulceroznim
kolitisom: naše izkušnje z adalimumabom
Treatment of ulcerative colitis: our experience
with adalimumab
Cvetka Pernat Drobež*, Andreja Ocepek
Klinični oddelek za gastroenterologijo, Univerzitetni klinični center Maribor
Gastroenterolog 2013; suplement 2: 64–67
POVZETEK
ABSTRACT
Izhodišča. Adalimumab je humano monoklonsko
protitelo proti dejavniku tumorske nekroze alfa. Od
aprila 2012 ga uporabljamo v zdravljenju ulceroznega
kolitisa. Namen naše raziskave je ocena učinkovitosti
adalimumaba pri zdravljenju bolnikov z zmerno do
hudo potekajočim ulceroznim kolitisom.
Background. Adalimumab is a human monoclonal
antibody to tumor necrosis factor alpha. It has been
used in the treatment of ulcerative colitis since April
2012. The aim of our study is to evaluate efficacy of
adalimumab in the treatment of patients with moderate to severe ulcerative colitis.
Bolniki in metode. Med avgustom 2012 in marcem
2013 smo začeli zdravljenje z adalimumabom pri 10
bolnikih z zmerno do hudo potekajočim ulceroznim
kolitisom, kljub sočasnemu ali predhodnemu zdravljenju z imunosupresorji. 7 je bilo žensk in 3 moški,
stari od 21 do 56 let. Ulcerozni pankolitis je bil diagnosticiran pri 4 ženskah in 2 moških. Levostranski
ulcerozni kolitis je bil diagnosticiran pri 3 ženskah
in 1 moškem. Bolniki so pri prvi aplikaciji prejeli
160 mg adalimumaba, po 2 tednih 80 mg in nato
40 mg vsak drugi teden. Osnovni cilj je bila ocena
kliničnega odgovora po 12. tednih zdravljenja.
Patients and methods. Between August 2012 and
March 2013 we begun treatment with adalimumab in
10 patients with moderate to severe active ulcerative
colitis despite concurrent or prior treatment with
immunosuppressants. There were 7 females and 3
males, aged from 21 to 56 years. Ulcerative pancolitis
was diagnosed in 4 females and 2 males and left-sided
ulcerative colitis in 3 females and 1 men. Patients
received adalimumab 160 mg at week 0, 80 mg at
week 2 and then 40 mg every other week. Primary
end point was clinical response at week 12.
Rezultati. Klinični odgovor v 12. tednu je bil dosežen pri 5 ženskah in 2 moških. Resno okužbo sta
razvili 2 ženski.
Results. Clinical response at week 12 was achived in
5 females and 2 males. 2 females developed serious
infection.
* prim. Cvetka Pernat Drobež, dr. med.
Klinika za interno medicino, Oddelek za gastroenterologijo, Univerzitetni klinični center Maribor
Ljubljanska 5, 2000 Maribor
64 GASTROENTEROLOG
Zaključek. Adalimumab je učinkovito zdravilo za
indukcijo kliničnega odgovora pri bolnikih z zmerno
do hudo potekajočim ulceroznim kolitisom, ki se
niso odzvali na zdravljenje s kortikosteroidi in/ali
imunosupresorji.
Conclusion. Adalimumab is effective in inducing
clinical response in patients with moderate to severe
ulcerative colitis, who did not respond to therapy
with corticosteroids and/or immunosuppressants.
UVOD
Cilji zdravljenja so sprožiti in vzdrževati remisijo bolezni brez rabe kortikosteroidov (KS), doseči celjenje
črevesne sluznice, preprečiti zaplete UK, hospitalizacije in operacije ter preprečiti umrljivost povezano z
njim; na ta način bomo izboljšali kvaliteto bolnikovega
življenja. Zdravimo ga z aminosalicilati, kortikosteroidi, imunosupresorji, kot sta azatioprin (AZA) in
6-merkaptopurin (6-MP) ter s tarčnimi zdravili.
Ulcerozni kolitis (UK) je kronična vnetna bolezen
debelega črevesa, ki lahko prizadane celotno debelo
črevo, praviloma je največkrat prizadeta danka.
Bolezen je kronična, običajno doživljenjska, z akutnimi zagoni vnetja ter vmesnimi krajšimi ali daljšimi
remisijami. Obolevajo ljudje v vseh starostnih obdobjih, pogosteje v starosti med 20–30 leti in med
60–80 leti. Glede razširjenosti vnetnega dogajanja razdelimo UK po Montrealski klasifikaciji v ulcerozni
proktitis, levostranski UK in ulcerozni pankolitis (1).
Norveška študija je na osnovi 10-letnega spremljanja
kohorte bolnikov z UK potrdila, da lokalizacija
vnetnega dogajanja ni konstantna, ampak se pri 20 %
bolnikov širi oralno; pri 83 % bolnikov se zagoni bolezni ponavljajo; pankolitis in pospešena sedimentacija
povečujeta tveganje za kolektomijo (2).
Bolezen je kronična, najpogosteje poteka v zagonih,
remisije so lahko dolge tudi po več let. Značilni simptomi so driska, krvavitve iz danke, številna iztrebljanja
krvavkastega sluzavega blata, krčevite bolečine v trebuhu, lažni pozivi k iztrebljanju, povišana telesna
temperatura, slabokrvnost in hujšanje. Resnost simptomov je sorazmerna z razširjenostjo bolezni.
V klinični praksi je pomembno, da pri bolezni opredelimo aktivnost vnetja, saj le tako izberemo
pravilno zdravljenje. Ne obstaja idealna razdelitev
UK po aktivnosti vnetja. V zadnjem času jo ocenjujemo z Mayo točkovnikom, ki upošteva število
iztrebljanj, prisotnost krvavitev iz danke, endoskopsko oceno črevesne sluznice in zdravnikovo
oceno bolnikove bolezni glede prisotnosti ali odsotnosti znakov sistemskega vnetja (3). UK na ta način
opredelimo, kot blago, zmerno in hudo potekajočo
bolezen.
Za zdravljenje UK sta odobreni 2 tarčni zdravili, in sicer
infliximab (IFX) in adalimumab (Ada). Obe sta protitelesi proti vnetnemu citokinu, pomembnem v patogenezi
UK-dejavniku tumorske nekroze alfa. Obe sta indicirani za zdravljenje zmerno do težko potekajočega UK,
neodzivnega na standardno zdravljenje; IFX je indiciran tudi za zdravljenje fulminantno potekajočega UK.
Izbor zdravil za zdravljenje UK je odvisen od aktivnosti vnetnega dogajanja in lokalizacije bolezni.
Blago potekajoči UK: za indukcijo in vzdrževanje
remisije so dovolj učinkoviti oralno ali/in topično
delujoči aminosalicilati.
Zmerno do težko potekajoči UK: za začetno zdravljenje so potrebna močnejša protivnetna zdravila, kot so
KS v optimalnem odmerku. Po umirjanju simptomov,
kar pričakujemo v 1 do 4 tednih, pričnemo odmerek
zmanjševati. Remisijo vzdržuejmo z aminosalicilati in
imunosupresorji. KS uporabljamo najkrajše možno
časovno obdobje.
Bolnike, ki so na KS-neodzivni, je mogoče prepoznati
v 2–4 tednih. Čeprav je pogosta praksa, pa ni dokazov, da bi intravensko dani KS izboljšali odgovor
bolnikov, neodzivnih na peroralne KS. Pri teh bolnikih v zdravljenje uvedemo tarčno zdravilo infliximab
(3) ali adalimumab (4, 5).
GASTROENTEROLOG 65
Pri bolnikih, ki tekom zdravljenja postanejo odvisni od KS, v zdravljenje vključimo imunosupresor
ali AZA ali 6-MP, ki so učinkovita zdravila za
vzdrževanje remisije, potrebujejo pa vsaj 3 mesečno obdobje, da se pokaže njihov optimalni učinek.
Učinkovitost imunosupresorja ocenimo po 12 tednih
(6). Če tudi imunosupresorji niso učinkoviti, v zdravljenje uvedemo tarčno zdravilo.
Fulminantno potekajoči UK: takšne bolnike zdravimo v bolnišnici s parenteralnimi aplikacijami KS.
Če v 3 do 7 dneh ni ustreznega izboljšanja, v zdravljenje vključimo tarčno zdravilo infliximab (7); če
tudi tarčno zdravilo ni učinkovito, pride v poštev
operativno zdravljenje.
OCENA UČINKOVITOSTI
ADALIMUMABA V ZDRAVLJENJU
ZMERNO DO TEŽKO
POTEKAJOČEGA UK; NAŠE IZKUŠNJE
Adalimumab je odobren v ZDA, Evropi in na
Japonskem za zdravljenje Crohnove bolezni, revmatoidnega artritisa, ankilozirajočega spondilitisa,
juvenilnega idiopatskega artritisa, psoriatičnega
artritisa in psoriaze. Študiji ULTRA 1 in ULTRA
2 sta potrdili njegovo učinkovitost tudi v zdravljenju zmerno do težko potekajočega UK (4,5). Tako
je v Evropi Ada od aprila 2012 registriran tudi za
zdravljenje UK. V naši ustanovi smo bolnike z UK
pričeli zdraviti z adalimumabom jeseni 2012.
Tekom zdravljenja smo in bomo tudi v prihodnje
ocenjevali učinkovitost adalimumaba s spremljanjem kliničnega odgovora, klinične remisije in
endoskopske remisije UK.
Bolniki in metode dela
Avgusta 2012 smo začeli zdravljenje z adalimumabom pri bolnikih z zmerno do hudo potekajočim
UK. Vsi ti bolniki imajo UK, neodziven na standardno zdravljenje z imunosupresorji. Aktivnost
bolezni smo ocenili glede na Mayo točkovnik, upoštevali smo število iztrebljanj, prisotnost rektalne
krvavitve, endoskopsko oceno črevesne sluznice in
splošno stanje bolnika (3). Bolniki morajo za zdra66 GASTROENTEROLOG
vljenje z adalimumabom dosegati vsaj 6 od možnih
12 točk po Mayo točkovniku, endoskopski Mayo
mora biti vsaj 2 točki. Diagnoza UK je bila postavljena endoskopsko ob programiranih koloskopijah
in potrjena histološko. Citomegalovirusni (CMV)
kolitis in Clostridium difficile kolitis sta izključena.
Bolniki so praviloma naivni glede zdravljenja s tarčnimi zdravili. Ob uvajanju adalimumaba prejemajo
svojo standardna zdravila; odmerek KS zmanjšujemo po sprejetih smernicah, AZA prejema še 3
mesece, z uživanjem aminosalicilatov nadaljuje. Za
prvi odmerek prejmejo bolniki 160 mg adalimumaba in po 2 tednih 2. odmerek 80 mg - oba v naši
ustanovi, nato si ustrezno poučeni sami aplicirajo
40 mg adalimumaba vsaki drugi teden.
Uspeh zdravljenja smo opredelili kot klinični odgovor, klinično remisijo in zacelitev sluznice. Klinični
odgovor je bil zadovoljiv, če smo zaznali upad Mayo
točk 3 in več, krvavitve iz danke pa so se morale
ustaviti. Klinična remisija je bila opredeljena kot
skupni Mayo 2 in manj, nobena Mayo podtočka ne
sme biti večja od 1. Zacelitev sluznice je opredeljena
kot endoskopski Mayo 0 ali 1.
Bolnike ocenjujemo na začetku zdravljenja po celotnem Mayo točkovniku; 2., 4., 8., in 12. teden jih
ocenjujemo po parcialnem Mayo točkovniku brez
endoskopske ocene. Če do 12. tedna ni kliničnega
odgovora, opravimo ponovno oceno po celotnem
Mayo točkovniku. Če je 12. teden klinični odgovor
po parcialnem Mayo točkovniku zadovoljiv, opravimo oceno po celotnem Mayo točkovniku 24 teden.
Od avgusta 2012 smo ocenili klinični odgovor pri
10 bolnikih z zmerno do hudo potekajočim UK. 7
je bilo žensk in 3 moški, stari od 21 do 56 let. Ulcerozni pankolitis je bil diagnosticiran pri 4 ženskah
in 2 moških. Levostranski UK je bil diagnosticiran
pri 3 ženskah in 1 moškem. Bolniki so prejeli prvič
160 mg adalimumaba, po 2 tednih 80 mg in nato
40 mg vsak drugi teden. Osnovni cilj je bila ocena
kliničnega odgovora 12. teden.
Rezultati
Začetni Mayo je bil pri ženskah od 7 do 10 točk,
pri moških od 9 do 12 točk. Klinični odgovor v 12.
tednu je bil dosežen pri 5 ženskah s parcialnim
Mayo 1 do 4 točke in 2 moških s parcialnim Mayo
2 do 4 točke, skupno pri 70 % bolnikov. Pri 1 ženski z nezadovoljivim kliničnim odgovorom smo v
zdravljenje dodali KS, pri 1 ženski, zdravljeni z
adalimumabom in aminosalicilati, smo zdravljenje
prekinili zaradi pomembnih stranskih učinkov, in
sicer resne okužbe. Pri 1 moškem ni bilo sprememb niti v parcialnem Mayo niti v celotnem
Mayo, po dodatku KS nismo dosegli izboljšanja;
zdravljenje z Ada smo prekinili, bolnika smo prevedli na IFX v kombinaciji z AZA.
Bolniki so zdravljenje z Ada dobro prenašali, stranskih učinkov je bilo malo. Resno okužbo sta razvili 2
ženski: pri 1 ženski je bilo zdravljenje okužbe uspešno, pri 1 smo morali zdravljenje z Ada prekiniti.
RAZPRAVA
Naši rezultati potrjujejo ugotovitve študije ULTRA 1,
ki je potrdila učinkovitost Ada 160 mg 0. teden, 80 mg
2. teden in nato 40 mg vsaka 2 tedna za indukcijo
klinične remisije. Mi smo ocenjevali klinični odgovor
2., 4., 8. in12. teden zdravljenja. Spremljali smo
število iztrebljanj, prisotnost krvavitve iz danke in
upoštevali zdravnikovo globalno oceno prizadetosti
bolnika. Menimo, da je ocena aktivnosti vnetja s
parcialnim Mayo točkovnikom za potrebe klinične
prakse zadostna; v primeru nezadovoljivega kliničnega
odgovora je potrebna tudi endoskopska ocena.
adalimumabom bolnik z zmerno do težko potekajočim UK, neodziven na KS in/ali imunosupresive,
ki je naiven glede zdravljenja s tarčnimi zdravili in
si želi udobja zdravljenja na domu.
Na osnovi naših izkušenj ocenjujemo, da je Ada
učinkovito zdravilo za indukcijo kliničnega odgovora pri bolnikih z zmerno do hudo potekajočim
UK, ki se niso odzvali na zdravljenje s kortikosteroidi in/ali imunosupresorji.
LITERATURA
1. Silverberg MS, Satsangi J, Ahmad T, Arnott ID, Bernstein CN et
al. Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: Report of a Working
Party of the 2005 Montreal World Congress of Gastroenterology.
Can J Gastroenterol. 2005; 19: 5–36.
2. Solberg IC, Lygren I, Jahnsen J, Aadland E, Hřie O et al. Clinical
course during the first 10 years of ulcerative colitis: results from
a population-based inception cohort (IBSEN Study). Scand J
Gastroenterol. 2009;44(4):431–40.
3. Rutgeerts P, Sandborn WJ, Feagan BG, Reinisch W, et al.
Infliximab for induction and maintenance therapy for ulcerative
colitis. N Engl J Med 2005; 353(23): 2462–76.
4. Reinisch W, Sandborn WJ, Hommes DW, D'Haens G, Hanauer
S et al. Adalimumab for induction of clinical remission in moderately to severely active ulcerative colitis: results of a randomised
controlled trial. Gut. 2011 Jun;60(6):780–7.
5. Sandborn WJ, van Assche G, Reinisch W, Colombel JF, D'Haens
G et al. Adalimumab induces and maintains clinical remission in
patients with moderate-to-severe ulcerative colitis. Gastroenterology
2012; 142(2): 257–65.
6. Leung Y, Panaccione R, Hemmelgarn B, Jones J. Exposing the
weaknesses: a systematic review of azathioprine efficacy in ulcerative colitis. Dig Dis Sci 2008; 53(6): 1455–61.
7. Järnerot G, Hertervig E, Friis-Liby I, Blomquist L, Karlén P et
al. Infliximab as rescue therapy in severe to moderately severe
ulcerative colitis: a randomized, placebo-controlled study.
Gastroenterology 2005; 128(7): 1805–11.
Klinično remisijo bomo pri naših bolnikih ocenjevali po 24 tednu zdravljenja. Ugotovitve študije
ULTRA 2 napovedujejo učinkovitost Ada v dolgotrajni klinični remisiji tudi pri naših bolnikih.
Naši bolniki so bili naivni glede zdravljenja s tarčnimi zdravili. Analiza podskupin študije ULTRA 2
je pokazala najmočnejši učinek Ada pri bolnikih,
ki so bili naivni glede zdravljenja s tarčnimi zdravili; ocena je, da je idealen bolnik za zdravljenje z
GASTROENTEROLOG 67
Vloga MR-enterografije pri obravnavi
bolnikov s Crohnovo boleznijo
MR-Enterography in the management of
patients with Crohn‘s disease
Popovič Peter*, Rok Dežman, Miha Štabuc, Manca Garbajs
Klinični inštitut za radiologijo, Univerzitetni klinični center Ljubljana
Gastroenterolog 2013; suplement 2: 68–72
Ključne besede: Crohnova bolezen, slikovna diagnostika,
magnetno resonančna enterografija,
Key words: Crohn’s disease, diagnostic imaging, magnetic
resonance enterography.
POVZETEK
ABSTRACT
Crohnova bolezen (CB) je kronična vnetna črevesna
bolezen, ki lahko zajame vse plasti črevesne stene v
poteku celotnega prebavnega sistema. Najpogosteje
je prizadeto ozko črevo. Magnetno resonančna-enterografija je slikovno preiskovalna metoda, ki se je
uveljavila kot metoda izbora za oceno ozkega črevesja pri bolnikih s Crohnovo boleznijo. V tej vlogi
nadomešča klasično jejunoileografijo in modernejšo
računalniško tomografsko enterografijo. Z magnetno
resonančno-enterografijo lahko potrdimo prisotnost
bolezni, ocenimo njeno aktivnosti in eventualne
zunajčrevesne zaplete (fistule, abscesi). Namen prispevka je predstaviti (1) trenutno vlogo magnetno
resonančne-enterografije pri obravnavi bolnika s
Crohnovo boleznijo, (2) predstaviti protokol in potek
preiskave, (3) primerjati metodo z drugimi slikovno
preiskovalnimi metodami in (4) opisati magnetno
resonančne-značilnosti Crohnove bolezni v akutnem,
penetrantnem in fibrostenozantnem stadiju bolezni.
Crohn’s disease (CD) is a chronic inflammatory bowel
disease. It can involve any part of the gastrointestinal
tract but the small bowel is most commonly involved.
It is characterized histologically by the presence of
trans-mural inflammation of the bowel wall. Magnetic
resonance enterography (MRE) is becoming the
first-line diagnostic imaging modality in evaluation of
the small bowel in patients with CD. It has surpassed
the conventional small-bowel follow-through and
modern computed tomographic enterography. MRE
can confirm the presence of the CD, is able to assess
disease activity and to demonstrate both mural and
extramural complications. The purpose of this review
is to (1) detail the current role of MRE in the management of patients with CD; (2) describe the protocol
of the MRE at our institution; (3) compare MRE
with other imaging modalities; (4) discuss the MRE
findings in patients with CD in inflammatory,
penetrating and stricturing phase of the disease.
* asist. dr. Peter Popovič, dr. med.
Klinični inštitut za radiologijo, Univerzitetni klinični center Ljubljana
Zaloška 2, 1525 Ljubljana
68 GASTROENTEROLOG
UVOD
Crohnova bolezen (CB) je kronična, ponavljajoča se
vnetna bolezen neznane etiologije, ki se običajno pojavi
v zgodnjem otroštvu. Največkrat prizadeta organa sta
ozko (80 %) in široko črevo, lahko pa je prizadet celotni prebavni trakt, od ust do anusa (1). Za bolezen je
značilno vnetje vseh plasti črevesne stene in segmentna
prizadetost prebavne cevi. Bolezenske spremembe najprej prizadanejo sluznico, histološko se kažejo kot vnetje
s prisotnimi nekazeirajočimi granulomi. Pojavijo se erozije ter ulceracije sluznice in pozneje vnetne zožitve.
Razjede sluznice lahko napredujejo v čezstenske razjede, te pa v sinuse, fistule in abscese – v tem stadiju
govorimo o penetrantni bolezni. V kroničnem stadiju
se v steni razrašča vezivo, kar povzroča zožitve črevesja in posledične obstrukcije. Vse naštete spremembe
so lahko v posameznem segmentu črevesne vijuge prisotne istočasno (2). Penetrantni in stenozirajoči stadij
bolezni pogosto zahtevata kirurško zdravljenje in se
tekom življenja razvijeta pri večini bolnikov s CB (3).
MR-ENTEROGRAFIJA
Natančna ocenarazsežnosti CB je pogosto težavna (4),
vendar pomembna za načrtovanje zdravljenja. Ker je
ozko črevo skoraj v celoti nedostopno za endoskopijo,
se je pri oceni tega dela že v preteklosti uveljavila slikovna diagnostika, vendar je veljalo, da je diagnostična
vrednost magnetnoresonančnega slikanja (ang.
magnetic resonance imaging - MRI) zaradi nekaterih
značilnosti (npr. sorazmerno dolg čas preiskave v primejavi s CT) omejena na »stabilne« organe in ni
primerna za oceno sorazmerno mobilnega črevesja.
Z razvojem in uporabo novih, hitrejših sekvenc se je
v zadnjem desetletju razvila magnetnoresonančna
enterografija (MRE) (slika 1, 2). S to preiskavo lahko
ocenjujemo lumen in steno ozkega črevesja ter tudi
okolne strukture (5). Pri preiskavi uporabljamo specifične sekvence MRI, ki omogočajo morfološko oceno
črevesnih vijug in rekonstrukcijo v več ravneh. Z uporabo enteralnega kontrastnega sredstva zagotovimo
razpetost tankočrevesnih vijug, kar omogoča boljšo
oceno črevesnega lumna in stene. Za oceno prekrvljenosti posameznih delov črevesnih vijug uporabljamo
intravensko kontrastno sredstvo (KS). S kombinacijo
vsega naštetega lahko z MRE ocenjujemo prisotnost bolezni in tudi ocenimo stadij, v kateri se bolezen nahaja.
Evropska organizacija za Crohnovo bolezen in ulcerozni kolitis (ang. European Crohn’s and Colitis
Organisation – ECCO) v svojem zadnjem priporočilu
o diagnostiki in zdravljenju CB kot metodi izbora za
oceno prizadetosti ozkega črevesja priporoča MRE in
CT-enterografijo (6). Po priporočilih ECCO je pomemben argument pri izbiri preiskave tudi izpostavljenost
bolnika iozinirajočemu sevanju. Zaradi kombinacije
dobre morfološke ocene črevesja in odsotnosti ionizirajočega sevanja je MRE metoda izbora za oceno
ozkega črevesja pri bolnikih s CB.
PRIMERJAVA Z DRUGIMI
MODALITETAMI
Poleg MRE v Sloveniji za oceno ozkega črevesja
uporabljamo še jejunoileografijo (JIG) in CT- enterografijo (CTE) ter kapsulno endoskopijo (KE).
MR-enterografija ima v primerjavi z jejunoileografijo
(JIG) precej prednosti. V primerjavi z JIG, ki dobro prikaže le lumen in sluznico, MRE omogoča oceno celotne
črevesne stene in tudi oceno zunajčrevesnih struktur,
npr. perienteričnega maščevja in pripadajočega mezenterija, povečanih bezgavk v mezenteriju in prikaz
abscesov. Izometrične sekvence radiologu omogočajo
Slika 1. Poslabšanje znane Crohnove bolezni pri 27-letnem
bolniku. (a) Na prekontrastni VIBE sekvenci je viden
zadebeljen in zožen daljši odsek terminalnega ileuma.
(b) Postkontrastna VIBE sekvenca (60 s po i.v. aplikaciji
gadolinijevega KS) - zadebeljena stena vijuge ima hiperintenziven signal – znak akutnega vnetja (puščica). Vidna
je tudi poudarjena »vasa recta« (zvezdica) in povečane
mezenterialne bezgavke (krajša puščica). Bolnik je bil po
opravljeni diagnostiki zdravljen z biološkimi zdravili.
GASTROENTEROLOG 69
pregled preiskave v več ravneh, zato superpozicija
ne predstavlja problema pri interpretaciji (7).
CTE in MRE sta enakovredni pri diagnostiki CB (8).
CTE je v primerjavi z MRE hitrejša, bolj dostopna
preiskava in je primernejša za bolnike s klavstrofobijo.
Največja prednost MRE je odsotnost ionizirajočega
sevanja (7). Zaradi narave CB so bolniki pogosto
izpostavljeni slikovni diagnostiki, zato je pomembno,
da jih, če se le da, ne izpostavljamo čezmernemu iozinirajočem sevanju (9). MRE omogoča tudi boljši
prikaz mehkih tkiv, tekočine in edema.
Pri KE bolnik poje kapsulo z videokamero. Kapsula
nato s pomočjo peristaltike potuje vzdolž črevesja in
pri tem ob določenih časovnih intervalih zajema slike
črevesne sluznice. Metaanaliza je pokazala, da je
kapsulna endoskopija bolj občutljiva pri odkrivanju
zgodnje CB, ki je omejena le na spremembe sluznice.
KE slabše oceni prizadetost stene črevesja, nemogoča
pa je ocena zunajčrevesne prizadetosti (10).
IZVEDBA PREISKAVE
Priprava bolnika
Bolnik na preiskavo pride tešč, vnos hrane je treba
prekiniti vsaj 6 ur pred začetkom. Pred preiskavo
bolniki peroralno zaužijejo 1–2 litra enteralnega
kontrastnega sredstva, ki pripomore k zadostni razpetosti tankočrevesnih vijug.
Kontrastna sredstva se med sebojj razlikujejo glede na
svoje »obnašanje« na T1 in T2 obteženih sekvencah.
Slika 2. 31-letna bolnica s Crohnovo boleznijo v penetrantnem stadiju. (a) Koronarna T2 HASTE, vidni sta dve intraperitonealni tekočinski kolekciji (puščica) – ob operaciji dokazani abscesni kolekciji. (b) Postkontrastna VIBE - »Zvezdast
vzorec« (puščica), tipičen videz enteroenteralnih fistul.
70 GASTROENTEROLOG
Negativna KS so hipointenzivna (znižan signal) na
obeh sekvencah, medtem ko so pozitivna hiperintenzivna (zvišan signal). Večina ustanov uporablja
bifazična enteralna KS, ki so imajo hiperintenziven
signal na T2 obteženih sekvencah in hipointenziven
signal na T1 obteženih sekvencah. Ta KS zaradi dobre
kontrastnosti med hiperintenzivnim lumnom in hipointenzivno črevesno steno omogočajo oceno debeline
črevesne stene na T2 sekvenci in dobro oceno obarvanja po aplikaciji i.v. KS na T1 sekvencah (11).
Druga lastnost enteralnih KS je njihova osmolarnost
glede na črevesno vsebino. Hiperosmolarna KS v
črevesju delujejo kot osmotsko odvajalo in pripomorejo k boljši razpetosti črevesnih vijug v primerjavi z
izoosmolarnimi (npr. voda) (11).
Protokol, ki ga uporabljamo na KIR UKC LJ, temelji
na priporočilih strokovnih člankov in na lastnih izkušnjah. Bolniki so pred preiskavo tešči 6 ur. V uri pred
preiskavo zaužijejo 1,5 litra enteralnega kontrastnega
sredstva. Uporabljamo 3 % raztopino sorbitola. Tik
pred začetkom preiskave prejmejo intramuskularno
injekcijo glukagona, ki zavre peristaltiko črevesja in
omogoča boljšo tehnično izvedbo preiskave.
Protokol preiskave
Izvedba preiskave se razlikuje med različnimi ustanovami. Na KIR UKC Ljubljana preiskave opravljamo
na 3T MR-napravi. Sama preiskava traja približno
20 minut. Začnemo s koronarno in aksialno sekvenco
HASTE (Half Fourier acquisition single shot turbo
spin echo) celotnega abdomna (slika 2a). Omenjena
sekvenca je uporabna za oceno anatomije abdomna
in širine črevesnih vijug, dobro pa je vidna tudi
zadebeljena stena vijug.
Nadaljujemo z izometrično sekvenco VIBE (Volumetric
Interpolated Breath-hold Examination) pred in po
intravenski aplikaciji gadolinijevega kontrastnega
sredstva (Slika 1a, 1b, 2b). Slikanje v arterijski fazi
opravimo 30 sekund po aplikaciji kontrastnega
sredstva, nato pa opravimo še slikanji po 60 sekundah in 3 minutah. Tako časovno zaporedje je
optimalno za prikaz progresivnega ojačanja čreve-
sne stene, ki je značilno za akutno vnetje v sklopu
CB (slika 1b) (12). Na sekvencah poleg anatomije
in dinamike obarvanja črevesnih vijug ocenjujemo
še stanje mezenterija, mezenterialnega žilja,
bezgavk in ugotavljamo prisotnost fistul ali tekočinskih kolekcij v abdomnu.
Ocena stadija bolezni:
Obravnava bolnika s CB je kompleksna in zahteva
multidisciplinaren pristop gastroenterologa, abdominalnega kirurga in radiologa. Radiolog lahko z
uporabo MRE poda naslednje odgovore: (1) ali je prizadeto tanko črevo in v kolikšni meri, (2) ali je
bolezen v aktivnem ali v kroničnem (fibrostenozantnem) stadiju, (3) ali je prisotna penetrantna
bolezen z ekstraintestinalnimi zapleti, (4) oceno
odgovora na medikametozno terapijo.
Glavna značilnost CB pri MRE je zadebelitev črevesne
stene, ki je po navadi povezana z zožitvijo lumna (slika
1a). Najpogosteje je prizadet terminalni ileum, prizadeti pa so tudi drugi odseki v poteku črevesja z
vmesnimi odseki neprizadetega črevesja (»skip lezije«).
Ključno vprašanje pri vodenju bolnika s CB je ocena
aktivnosti bolezni. Glede na radiološki videz lahko CB
razdelimo v akutni, penetrantni in fibrostenozirajoči
stadij bolezni (13). Ponavadi so pri enem bolniku prisotni različni stadiji bolezni.
edema. Po aplikaciji kontrastnega sredstva se signal
stene prizadetih vijug intenzivno ojača (slika 1b).
Zaradi hipointenzivnega submukoznega edema in
hiperintenzivne mukoze in seroze ima vijuga videz
razslojenosti. Zaradi aktivnega vnetja in posledične
hiperemije je pomnoženo mezenterialno žilje, predvsem vasa recta, kar vidimo kot t.i. znak glavnika
(ang. comb sign) (slika 1b) (14). V priležnem mezenteriju je vidna reaktivna limfadenopatija (slika 1b).
Obravnava akutnega stadija bolezni brez pridruženih penetrantnih ali fibrostenozantnih sprememb
je običajno konservativna/medikamentozna.
Fibrostenozantni stadij – V kroničnem stadiju bolezni se začne v stenah vijug tvoriti vezivno tkivo,
stene postanejo fibrozirane in rigidne. Na mestu
fibroze se lahko tvori zožitev (stenoza) in privede do
obstrukcije črevesja. Zaradi dalj časa trajajočega čez
stenskega vnetja se ob črevesni vijugi začne odlagati
maščevje, ki odriva mezenterično žilje in sosednje
črevesne vijuge – govorimo o hipertrofiji mezenteričnega maščevja (ang. fat–wrapping; slika 3), ki je
pogosto asimetrično izraženo in bolj izrazito na
mezenterielni strani vijug. Videz je specifičen za CB.
V akutnem stadiju bolezni so prizadete vijuge
ozkega črevesja zadebeljene zaradi submukoznega
MR-enterografija lahko loči zožitve, ki so posledica
fibroze, od zožitev, v katerih je prisotno akutno
vnetje. Razločevanje med njimi je pomembno
zaradi različne obravnave; fibrozirana zožitev brez
akutnega vnetja se ne odziva na terapijo z zdravili
in v primeru simptomatske obstrukcije črevesja
zahteva operativno zdravljenje.
Slika 3. Bolnik s Crohnovo boleznijo v kroničnem stadiju.
a) Pomnoženo mezenterično maščevje v področju terminalnega ileuma (puščica). (b) Po aplikaciji KS ni vidnih
znakov za akutno fazo bolezni.
Penetrantni stadij – Z napredovanjem bolezni
lahko razjede v steni napredujejo do perforacije črevesnih vijug in tvorjenja fistul in intraperitonealnih
abscesov. Fistule se tvorijo med vijugami ozkega
črevesja (enteroenteralne fistule), lahko pa tudi med
tankim črevesjem in drugimi deli prebavne cevi
(kolon, želodec), sečnim mehurjem ali s kožo (slika
2b). Pri oceni fistul in sinusov ima MRE visoko
občutljivost (> 75 %) in specifičnost (> 99 %) (15).
Prisotnost in anatomijo fistule ocenjujemo na postkontrastnih T1-VIBE, kjer imajo zaradi dobre
prekrvljenosti hiperintenziven signal (16).
GASTROENTEROLOG 71
Po naših izkušnjah je za oceno abscesov najbolje
primerjati T2-HASTE (slika 2a) in T1-VIBE sekvence.
Na T2-HASTE ima vsebina hiperintenziven signal,
signal stene abscesa pa je na postkontrastnih T1-VIBE
hiperintenziven. Potrditev abscesa spremeni medikamentozno terapijo bolezni in usmeri nadaljnje
zdravljenje v perkutano drenažo oz. operacijo.
Ocena učinkovitosti medikamentoznega
zdravljenja
MRE je učinkovita metoda za oceno učinkovitosti
medikamentozne terapije. Opravimo jo v akutnem
relapsu bolezni in nato v remisiji. Pri učinkovitem
odgovoru na zdravljenje je vidno zmanjšanje debeline
prizadetih segmentov in tudi manjše obarvanje prizadetih segmentov po aplikaciji KS, medtem ko zoženje
lumna lahko ostaja (17). Biološka zdravila, kot so infliximab in adalimumab, se uporabljajo pri zdravljenju
bolnikov s CB, ki je odporna na druge terapije. MRE
se utegne izkazati kot učinkovita metoda za oceno
uspešnosti in načrtovanja zdravljenja z biološkimi
zdravili in bi posledično utegnila zmanjšati prekomerno rabo omenjenih zdravil in stroške zdravljenja
Vloga difuzijskega slikanja pri oceni Crohnove bolezni
V zadnjih petih letih opravljene manjše študije dokazujejo, da je difuzijsko slikanje najverjetneje v pomoč
pri oceni aktivnosti CB v prizadetem črevesju (18).
Ocena difuzije omogoča razlikovanje med aktivnim
vnetjem in fibrostenozantnim stadijem bolezni. Pri
aktivnem vnetju imajo prizadete črevesne vijuge bolj
izraženo restrikcijo difuzije (19) kot segmenti črevesja
brez aktivnega vnetja. S pomočjo difuzijskega slikanja
je zanesljivejše tudi odkrivanje intraabdominalnih abscesov (20). Difuzijsko slikanje bi lahko imelo vlogo pri
oceni učinkovitosti zdravljenja, vendar študij s tega
področja še ni.
ZAKLJUČEK
MR-enterografija se je v svetu in pri nas uveljavila kot
slikovno preiskovalna metoda izbora pri obravnavi
bolnikov s CB. Uporabna je pri potrditvi diagnoze,
oceni razširjenosti bolezni in za oceno aktivnosti
bolezni. Dobro prikaže spremembe tako v steni
72 GASTROENTEROLOG
črevesja kot tudi zunaj črevesja ter zaplete CB kot so
obstrukcija, penetrantna bolezen in formacija abscesov.
Pomembna prednost MR-enterografije je odsotnost
ionizirajočega sevanja, zaradi česar je primerna za
uporabo pri mlajših bolnikih.
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Zapleti pri kirurškem zdravljenju raka
trebušne slinavke
Complications in surgical treatment of
pancreatic cancer
Stojan Potrč*, Matjaž Horvat, Arpad Ivanecz, Tomaž Jagrič, Marko Hazabent, Bojan Iljevec
Oddelek za abdominalno in splošno kirurgijo, Kirurška klinika, UKC Maribor
Gastroenterolog 2013; suplement 2: 73–75
Ključne besede: rak trebušne slinavke, resekcija, zapleti
Key words: pancreatic cancer, resection, complications
POVZETEK
ABSTRACT
Kljub napredku kirurških tehnik je preživetje po
operacijah zaradi raka trebušne slinavke še vedno
slabo. V retrospektivni analizi smo pregledali podatke
286 bolnikov, ki so bili v obdobju od januarja 1999
do decembra 2012 operirani zaradi raka trebušne
slinavke. Samo pri 169 bolnikih (82 moških, 87
žensk: povprečna starost 64,7 let) je bilo mogoče
opraviti resekcijo, Pri ostalih je bilo obolenje neresektabilno. Bolnike smo razdelili v dve zaporedni skupini
obdobja 7 let. Analizirali smo pooperativno obolevnost in umrljivost ter ju primerjali med skupinama.
Skupna pooperativna pogostost kirurških, splošnih
zapletov in umrljivost so bili 21,3 %, 14,2 % in 5,3 %.
Primerjava rezultatov dveh obdobij ni pokazala
pomembno različne stopnje pooperativnih zapletov,
vendar pa je pooperativna umrljivost v zadnjem 7 letnem obdobju pomembno upadla na 2,6 % (p = 0,025).
Tudi dolgoročno preživetje je v zadnjem 7 letnem
obdobju daljše, vendar razlika ni statistično značilna.
Despite the improvements in surgical technique and
the abilities of intensive medical treatment, the
results regarding the long term survival are somehow
disappointing in pancreas cancer patients. In a retrospective study we reviewed the files of 286 patients
operated for pancreatic cancer from January 1999 to
December 2012. Of these only 169 (82 male, 87 female,
mean age 64,7 years) had pancreatic resection for
resectable pancreatic cancer. In the rest the disease
was unresectable. Patients were grouped in two successive 7 year periods and compared for perioperative
morbidity and mortality and long term survival. The
overall incidence of surgical complications, general
complications and mortality were 21,3%, 14,2% and
5,3%. There was no significant difference concerning
the morbidity between the periods however, the perioperative mortality dropped significantly in the last 7
year period on 2,6% (p = 0,025). The long term survival is insignificant longer in the second period.
*Prof. dr. Stojan Potrč, dr. med.
Oddelek za abdominalno in splošno kirurgijo, Kirurška klinika, UKC Maribor,
Ljubljanska 5, 2000 Maribor, Slovenija
GASTROENTEROLOG 73
BACKGROUND
Resection of the appropriate part of the pancreas is
without any doubt the only treatment which can offer
the patient long term survival. However, despite the
improvements in surgical technique and the abilities
of intensive medical treatment, the results concerning the long term survival are somehow disappointing. Perioperative complications accompanied by
high perioperative mortality were very important factors which burdened success of pancreatic resections.
However the reports from many experienced centers
in the last decade are encouraging.
PATIENTS AND METHODS
In a retrospective study we reviewed the files of 286
patients operated for pancreatic cancer from January
1999 to December 2012. Of these only 169 (82 male,
87 female, mean age 64,7 years) had pancreatic
resection for resectable pancreatic cancer. In the
rest, because of locally unresectable or disseminated
disease exploration with or without a palliative procedure was performed.
Resected specimens were examined according to
standard patho-histologic procedure and classified
according to Lauren, Ming, WHO, TNM and UICC
classification as well as according to differentiation
of tumor cells (gradus).
For the purposes of the study, we divided the patients
after resection in two successive 7 year periods and
compared their perioperative morbidity and mortality
and long term survival (period 1: from 1999 to 2005,
n = 55; period 2: from 2006 to 2012, n = 114).
Perioperative and clinicopathological parameters
were evaluated and further compared between the
two groups of patients. The cut-off date of the study
was December 31, 2012. The survival data were
obtained from the Cancer Registry of Slovenia.
Statistical workup was done by statistical program
IBM SPSS 20. For analyses of descriptive variables
74 GASTROENTEROLOG
Chi-Square tests was used and for analyses in
numeric variables a Student’s t test and MannWhitney tests, where appropriate, were performed.
Survival analysis was done by Kaplan-Meier method
and multivariate analysis by Cox regression (9, 10).
RESULTS
The types of resection in these patients were: 39,6%
pylorus preserving Whipple resection of the pancreatic
head, 37,3% Whipple resection of the pancreatic head,
19,5% left pancreatectomy, 3,6% total pancreatectomy.
Overall for pancreatojejunoanastomosis external
transanastomotic stents were used in 33,7%, “lost”
internal drains in 10,1% of resected patients. External
drains were not used any more for the last 7 years.
In 28,2% of patients some form of adjuvant oncological treatment was added. Concerning TNM classification, 13,7% were T1, 21,4% were T2, 60,7%
were T3, 4,3% were T4, 32,2% were N0 and 65,8%
were N1. A curable resection (R0) was possible in
69,2%, the rest (30,8%) were not curable (R1) resections. The univariate survival analysis revealed a
better median survival in R0 than in R1 resections
(20,5 Vs. 12 months, p = 0,008) as well as its dependance on T (p = 0,041) and N (p = 0,035) stage.
Preoperative general condition (ASA), gender, type
of operation and adjuvant oncological therapy did
not impact the long term survival (p = 1,64, p = 0,26,
p = 0,21, p = 0,18). The overall incidence of surgical complications, general complications, perioperative mortality and 5 years survival were 21,3%,
14,2%, 5,3% and 19,2% respectively. Long term survival in patient who survived the perioperative morbidity was comparable to those without perioperative morbidity (p = 0,22). According to Patients after
resections from the period 1 (n = 55) were statistically comparable to those from the period 2 (n = 114)
regarding the age, gender, type of operation, treatment of complications, adjuvant oncological treatment, the stage T and regarding the curability of the
procedure (p = 0,059, p = 0,53, p = 0,30, p = 0,88,
p = 0,91, p = 0,85, p = 0,53). But patients in the group
2 were in poorer general condition (ASA) and had
more often metastases in the lymph nodes (p < 0,001,
p = 0,02 The perioperative surgical and general
morbidity decreased impressively in the second
period from 29% and 18% to 17% and 12% respectively, it didn’t reach the statistical significance though
(p = 0,18 and p = 0,33). The type of complications
(4,1% leak from bilioenteric anastomosis, 4,1% leak
from the pancreatojejuno anastomosis, 3,6% intraabdominal abscesses, 3,6% gastric emptying syndrome, 2,4% perioperative bleeding, 1,8% disrupted
laparotomy, 0,6% colonic ischemia, 0,6% necrotizing
pancreatitis) revealed some differences (less gastric
emptying syndrome and less of leaks from the pancreatojejuno anastomosis) between the periods, but
the difference was only borderline (p = 0,051).
However, the mortality dropped significantly (2,6%)
in the second period of the study (p = 0,025). The
median survival in the second period reveals a slight
increase (from 17 months to 21 months) but it is not
statistically significant (p = 0,19).
CONCLUSION
The main goal of surgical treatment of resectable
pancreatic cancer - to increase the long term survival substantially - is worldwide still not achieved.
In our study only about 20 % of the patients were
alive after 5 years. The results of the comparison
of two periods indicate significant trends toward
lower perioperative morbidity and mortality in the
last 7 year period. A slight but again insignificant
increase in long term survival is very likely the
result of the former factors. In respect to reports
from other centers regarding the prognostic factors, and our results cover with them, it seems
imperative to diagnose and treat the disease in its
early stage. Keeping the perioperative complications and especially the perioperative mortality low
is of paramount importance not to come in situations where the treatment would be worse than the
disease itself.
GASTROENTEROLOG 75
Napredovali rak želodca – kirurška taktika
Advanced gastric cancer – surgical tactic
Stojan Potrc*,1, Matjaz Horvat1, Arpad Ivanecz1, Tomaz Jagric1, Bojan Iljevec1, Irena Oblak2,
Vaneja Velenik2, Janja Ocvirk3
1 Oddelek za abdominalno in splošno kirurgijo, Kirurška klinika, UKC Maribor
2
Oddelek za radioterapijo, Onkološki inštitut Ljubljana
3 Oddelek za internistično onkologijo, Onkološki inšitut Ljubljana
Gastroenterolog 2013; suplement 2: 76–86
Ključne besede: napredoval rak želodca, kirurgija,
multidisciplinarni pristop
Key words: advanced gastric cancer, surgery,
multimodality treatment
POVZETEK
ABSTRACT
Kirurška resekcija ostaja edino morebitno ozdravitveno zdravljenje napredovalega raka želodca. V
zadnjih letih je perioperativna umrljivost vse nižja,
kakovost življenja po posegu višja, srednje preživetje
pa počasi dosega tistega na vzhodu. Poleg kirurgije
sta pri zdravljenju napredovalega raka želodca
pomembni tudi kemo in radioterapija. V prispevku
je povzet pregled pristopa k zdravljenju napredovalega raka želodca in predstavljene naše izkušnje. Od
začetka leta 2012 do konca leta 2013 smo operirali
1108 bolnikov. Primerjava dveh zaporednih obdobij
je pokazala pomembne razlike v razširjenosti resekcij,
limfadenektomij, perioperativni morbiditeti in
mortalitieti in dolgoročnem preživetju; boljše rezultate
dosegamo v kasnejšem obdobju (totalne gastrektomije
77 %, limfadenektomije D1 87 %, 5-letno preživetje
53, srednje preživetje 78 mesecev, perioperativna
umrljivost 3 %).
Potentially curative surgical resection remains the
mainstay treatment for patients with advanced gastric cancer (AGC). The results in term of better long
term survival, acceptable and low perioperative morbidity and mortality as well as the patient’s quality of
life have improved substantially in western world and
are gradually reaching those in the east. Multimodality
treatment is important in AGC management. The
aim of the present article is to review current approach
to AGC treatment and present our treatment results.
We report on 1108 patients operated for gastric cancer in the period from January 1st 1992 to December
31st 2012. Comparison of two chronologically successive groups of patients revealed some significant
differences regarding the extent of resection, extent
of lymphadenectomy, perioperative morbidity and
mortality as well as long term survival, all in terms
of better results in the recent group (total gastrectomies - 77%, D1 lymphadenectomy - 87%, 5-year
survival - 53%; median survival - 78 months, perioperative mortality - 3%).
*prof. dr. Stojan Potrc, dr. med.,
Oddelek za abdominalno in splošno kirurgijo, Kirurška klinika, UKC Maribor,
Ljubljanska 5, 2000 Maribor, Slovenija
76 GASTROENTEROLOG
INTRODUCTION
Potentially curative surgical resection remains the
mainstay treatment for patients with advanced gastric
cancer (AGC). It presents the only unimodal treatment
which itself offers long-term survival. The experiences
with radical surgical approach developed in Eastern
Asia many decades ago, long time rejected by western
surgical society, has now become accepted and implemented also in many high volume centers in Europe.
The results in term of better long term survival, acceptable and low perioperative morbidity and mortality as
well as the patient’s quality of life have improved substantially presently in western world and are gradually
edging those in the east. Unlike the early gastric cancer
where recently less aggressive modalities were implemented, for now, there is only limited space for “tailoring” of surgical procedure regarding extend of stomach
resection and lymphadenectomy. Including some oncological treatment settings, the multimodality becomes an
issue in the global treatment of AGC too. Resection for
palliation doesn’t follow this aim and results regarding
the survival are disappointing. As with other gastroenterological malignancy additional chemo and/or radiotherapy has in recent decade become a standard for
selected groups of patients with AGC in many countries.
However, some controversies regarding the timing type
and combination of these additional settings still exist.
PATIENTS AND METHODS
1108 patients were operated for gastric cancer in the
period from January 1st 1992 to December 31st 2012.
989 patients had a resection of the stomach and
among this group 847 patients had a potentially curative resection (R0), the reminder had gross or microscopically non curable resections (R2 and R1) or a nonresective procedures were performed. Patients with
local carcinosis in the bursa omentalis were included
if an R0 recection was performed (UICC stage 4). As
table 1 shows less than 13% of patients were in favorable early stage, the rest were patients with AGC. In
patients after R0 resection two chronologically successive groups of patients were formed (P1 = 1992–2002
and P2 = 2003–2012). P1 comprised 342 and P2 505
patients. The demographic statistics and results of survival analyses and some significant differences between
two groups are revealed in table 1 and 2. Survival
analyses and comparison between two periods were
separately performed for all R0 resections, for patients
with distal sited tumours and for patients with tumours
in the proximal third of the stomach (table 2).
Regarding the type of resection and extent of lymphadenectomy in potentially curable resections we
mostly obeyed the principals from the high volume
centre’s in west and east as well as domestic experience
by professor Repše in the early nineties in Ljubljana.
Presently our surgical strategy and tactics nicely match
the S3 guidelines in Germany (1–5).
Adjuvant chemo or chemo-radio therapy was started
in 2001 and was indicated in 39,2% patients after R0
resections (P 2). Perioperative chemotherapy was
started in 2011 and was indicated in 8,2% till now (P 2)
(table 1). A subgroup of patients of 99 patients operated
between January 2001 and December 2010 with
chemo-radiotherapy added to surgery was studied for
any survival benefit.
Clinical and pathological data were prospectively
stored in a computerized data base. Data from the
follow-up were obtained by our own outpatient follow-up and by the National cancer registry of
Slovenia. Complete follow-up was obtained as of 31st
of December 2012. The median follow up period
was 94 months. Perioperative mortality was defined
by survival of 30 days irrelevant if patients may have
already been dismissed from the ward.
Resected specimens were examined according to
standard patho-histologic procedure and classified
according to Lauren, Ming, WHO, TNM and UICC
classification as well as according to differentiation
of tumor cells (gradus) (6, 7, 8).
Statistical workup was done by statistical program
IBM SPSS 20. For analyses of descriptive variables
Chi-Square tests was used and for analyses in numeric
variables a Student’s t-test and Mann-Whitney tests
GASTROENTEROLOG 77
where appropriate were performed. Survival analysis was done by Kaplan-Meier method and multivariate analysis by Cox regression (9, 10).
CURABILITY OF THE PROCEDURE
The strategic aim of the of the treatment in AGC must
be a potentially curable resection, however according
to the epidemiological data sourced from the National
Cancer registry of Slovenia only 60% of all patients
registered for gastric cancer received a specific treatment. More than 90% of patients receiving a specific
treatment were treated surgically, however only
75–85% of those received an R0 resection (3, 11). It
is well documented that R0 resection presents the
only unimodal treatment which itself offers long-term
survival in treatment in patients with resectable
advanced gastric cancer (2, 3, 4).
Table 1. Demographic data for all (n= 847) R0 resected patients.
Overall and grouped in two chronologically periods (P1 = 1992-2002; n = 342 and P2 = 2003-2012; n = 505)
Mean age
Gender
Site of the tumour
Differentiation (G)
Lauren classification
UICC stage
Male
Female
Distal third
Middle third
Proximal third
Entire
Gastric stump
G1
G2
G3
G4
Intestinal
Diffuse
Mixed
Ia
Ib
IIa
IIb
IIIa
IIIb
IIIc
IV
Un classified
Metastases in lymph nodes
Mean diamether of the tumour
Neoadj. onco. th. received
Adjuv. onc. th. received
Type of resection
Extent of lymphadenectomy
78 GASTROENTEROLOG
Distal subtotal
Total
Total+dist. esoph.
Proximal
Gastric stump
Wedge
D 1,5 and more
P1
P2
all
p
64,3 y
59,6%
40,4%
49%
33%
12,6%
1,8%
3,2%
15,7%
30,8%
50,9%
2,5%
45,9%
39,3%
14,9%
9,9%
10,5%
12,6%
10,2%
14%
21,6%
2,6%
0,6%
17,8%
62,7%
59 mm
0
2,6%
50,3%
43,2
1,5%
2%
3,2%
0
67,8%
64,9 y
65.1%
34,9%
32,3%
37,2%
22,2%
5,3%
3%
12,9%
27,4%
59%
0,7%
47,2%
31%
21,8%
14,9%
12,3%
10,3%
14,9%
14,9%
16,2%
7,9%
3%
5,7%
63,4%
65 mm
8,3%
39,2%
20,4%
68,6%
8,3%
4%
3%
0,8%
87,2%
64,6 y
62,9%
37,1%
39,1%
35,7%
18,3%
3,9%
3,1%
12,9%
28,3%
56,9%
1,1%
46,7%
31,2%
19,1%
12,9%
11,6%
11,2%
13,0%
14,5%
18,4%
5,8%
2%
10,6%
63,1%
63,6 mm
5%
24,4%
32,5%
55,3%
5,5%
3,2%
3,1%
0,5%
79%
ns
ns
p<0,0001
ns
p=0,015
p<0,0001
ns
p<0,0001
p<0,0001
p<0,0001
Demographic data, main characteristics of the tumour,
results of patohistological workup (Differentiation of
the tumor cells, Lauren classification, UICC stage,
proportion of affected of lymph nodes, mean number
of affected lymph nodes and mean number of harvested lymph nodes) as well as the results regarding
the survival, perioperative morbidity and mortality
from the present trail are given in tables 1 and 2.
Survival analysis revealed a significant longer overall
survival in P2 (49.6 Vs. 31.1 months; p=0.049),
however the statistical significance vanish after the
mortality was excluded from the calculations.
Certainly the prognosis is much impacted by the
stage of the disease. Our trail revealed that R0
resected patients having intestinal type of the
tumor, with well to moderate differentiated tumour
cells (G1 and 2 Vs. G3 and 4), in lower UICC stage,
with less infiltration on stomach wall (T stage) and
without lymph node metastases have significant better long term survival expectation than those with
less favorable differentiation, diffuse Lauren type or
otherwise more progressed disease (G: p<0,0001;
Lauren: p<0,0001; UICC: p<0,0001; T: p<0,0001;
metastases in lymph nodes: p>0,0001). But we must
respect significant relation between diffuse type and
less differentiated tumours with higher UICC, TNM
stages or positive lymph nodes (UICC - G: chi square:
p<0,0001; T – G: chi square: p<0,0001; positive
lymph nodes: chi square: p<0,0001; UICC - Lauren:
chi square: p=0,011; T – Lauren: chi square: p=0,005;
pos. lymph nodes - Lauren: chi square: p=0,039).
Similar tumour site impacts the survival too. Patients
with tumours sited in the distal two thirds have significant better long term survival (p=0.012).
However, second period of the study (P2), younger
age of the patient, low complication score intestinal
type of the tumour, lower T stage, unaffected lymph
nodes lower number of affected lymph nodes and
higher number of harvested lymph nodes at operation present the most important factors by Cox
regression analysis that impact the survival favorably.
Our trail reveals that of altogether 1108 patients
operated for gastric cancer 12.8% were uncurable
R1 and R2 resections. The present and our former
analyses revealed significant higher perioperative
mortality in comparison to other gastrectomised
patients (12%; p = 0.003) whereas the life expectancy
of these patients is extremely poor (median survival
– 6,6 months) and does not differ at all to those having only a non-resection procedure (11). Although
some authors advocate palliative resection in
selected groups of patients, we agree with the opinion that in a palliative situation complications of the
tumor (bleeding, obstuction) should primarily be
treated by interventional or conservative procedures
(2, 12, 13, 14).
Table 2. Results in survival (over all [n=847], for tumours in distal two thirds [n = 600] and proximal third separately[n = 150]) and overall morbidity and mortality in two chronologically successive periods (P1 and P2 [n = 847]);
* perioperative 30 day mortality included, ** perioperative 30 day mortality excluded
Overall 5YS*
Overall median survival*
Overall 5YS**
Overall median survival**
5YS distal 2/3 of the stomach**
Median survival distal 2/3 of the stomach**
5YS proximal third of the stomach**
Median survival proximal third**
Over all morbidity- surg.
Over all morbidity- gen.
Over all 30 day mortality
P1
P2
p
38,6%
31,1 months
41,8%
35,5 months
43,3%
40,5 months
24,4%
22,6 months
14,9%
13,7%
7,6%
46%
49,6 months
47,3%
54,3 months
52,3%
74,4 months
37,8%
28,5 months
11,7%
13,1%
3%
p=0,049
ns
p=0,057
ns
ns
ns
p=0,002
GASTROENTEROLOG 79
EXTENT OF STOMACH RESECTION
According to the present accepted standards the
extent of stomach resection for AGC (total, distal
subtotal, proximal, Trans hiatal extended) is defined
by the site of the tumor and Lauren classification.
It is generally accepted that the distance from the
proximal edge of the tumor to the proximal resection border should be 5 cm in intestinal and 8 cm
in diffuse type (1, 2). Consequently, for most of the
intestinal type tumours sited in the distal two thirds
of the stomach and diffuse type tumours sited in the
distal third a distal subtotal gastrectomy presents an
appropriate extent of the resection (2–5). In most diffuse type tumours located in the proximal two thirds
of the stomach total gastrectomy or in case of
tumours in the cardiac region (AEG II and III) transabdominal total gastrectomy extended to distal
esophagus will be indicated (2, 15, 16, 17). A frozen
section of the proximal resection border on the esophagus must always be done in these types of
resections for tumours of the esophagogastric junction (2). Within these limits some “tailoring” may be
acceptable but only regarding the type of reconstruction (Roux-en-Y, interposition, pouch…) or
surgical approach (open or laparoscopic, trans abdominal or with thoracotomy or combined). It is well
proven that for tumours of esophagogastric junction
(AEG), at least for AEG II and III tumours, the transabdominal approach and a “transhiatal” resection
is superior to combined approach with thoracotomy
(2, 15, 17, 18). Proximal gastrectomy can be an alternative for total gastrectomy in patients with proximal
sited tumours and is favored by some in selected
patients (13). The oncological result concerning long
term survival showed no significance in these studies, but quality of live was supposed to be superior
to those patients after total extended gastrectomy.
Our own experience in this issue is limited to a retrospective nonrandomised study in patients with
proximal sited tumours where we compared groups
of patients after total with a group after proximal
gastrectomy for the quality of life and survival and
found no difference in long-term survival and no
advantage in quality of life in these selected collec80 GASTROENTEROLOG
tive of patients. But due to low patient numbers and
for methodological reasons the value of conclusions
was limited (19).
The type of gastric resections in the present trail is
given in the table 1. Total gastrostomies and total
gastrostomies extended to distal esophagus present
were the most often performed type of resection
(71.7%) in P 2 group of patients. The difference between the periods in this issue is significant. It
partially reflects a higher number of more proximal
sited tumours in the recent decade, however partially
it is the consequence of more principal holding of
the guidelines adopted by our team in P2. The perioperative morbidity and mortality did not show any
significant difference between different types of
resection (table 2). The list most feared surgical complication is given in table 3. There was no significant
difference regarding the perioperative morbidity and
mortality between different types of resection although, after total gastrectomies the incidence of
surgical complications was a bit higher but the perioperative mortality (was insignificant) the lowest
(table 4). The results of our trail regarding the periopaerative morbidity and mortality match frankly
with those of other reports (2, 3, 4, 5, 15, 33).
EXTENT OF LYMPHADENECTOMY
The optimal extent of lymphadenectomy presents
one of the most controversial areas in gastric cancer treatment. Different levels of lymphadenectomy
were determined many decades ago by Japanese
Table 3. Overall incidence of specific surgical complications in P1 and P2 together (n = 847).
Intrabdominal abscess
Duodenal stump leak
Leak from the EEA*
Leak from the GEA*
Leak from the EJA*
Other surg compl.
No surg. Compl
Number of patients in the group
All GEA
All EJA
1,5%
1,1%
0,7
1,8%
0
5,4%
89,5%
568
3,2%
0,7%
0,2%
0
1,2
7,8%
85,9%
275
S3 guidelines in Germany.
The arguments in favor
of extended lymphadeSurgical
General
30 day
nectomy (more than D1)
complications complications
mortality
are that removing a larger
7,8%
11,7%
3,9%
STG
number of nodes more
11,9%
12,5%
2,5%
TG
accurately stages disease
14,6%
19%
2,4%
TG + dist. esophagectomy
extent and that failure to
25%
30%
10%
Proximal resection
0
0
0
Wedge resection
remove these nodes may
6,7%
0
0
Gastric stump resection
leave behind the disease
ns
ns
ns
p
in as many as one-third
of patients, which would
gastric cancer surgeons. The draining lymph nodes
adversely affect survival (21, 22, 23). A consequence
for the stomach can be divided into 16 stations: staof more accurate staging is minimisation of stage
tions 1 to 6 are perigastric, and the remaining 10
migration (23, 24).The resulting improvement in
are located adjacent to major vessels, behind the
stage-specific survival may explain, in part, the better
pancreas, and along the aorta.
results seen in Asian patients.
Table 4. The incidence od perioperative morbidity and mortality regarding differenttypes of resection (STG = subtotal gastrectomy, TG = total gastrectomy)
By Japanese surgeons lymphadenectomy D1 refers
to a limited dissection of only the perigastric
lymph nodes, whereas the D2 lymph node dissection is an extended dissection, entailing removal
of nodes along the hepatic, left gastric, celiac, and
splenic arteries as well as those in the splenic
hilum (stations 1–11). A superextended D3 lymphadenectomy refers for additional harvesting of
lymph nodes in stations 12 to 16 still defined as a
remote disease in the west (18, 19, 20).
But the extent of lymphadenectomy was long under
discussion in the western world because the benefits in long term survival promised by the extended
lymphadenectomies would have been reversed by
high level of complications rate experienced by
some authors in the West. However, after turbulent
discussions between supporters and opponents of
lymphadenectomy and supported by many randomised and nonrandomised controlled studies as well
in Eastern Asia as in the West, a D2 lymphadenectomy (minus station 10) is now getting more and
more adopted as a standard for surgical treatment
of advanced gastric cancer in most centers all over
the continent. Moreover, a “D2–10” presently has
been suggested for the European guidelines for surgical treatment of AGC and is actually included in
As shown in table 1, most of our patients in P2
had more than D1,5 and higher levels of lymphadenectomy. The categorisation of lymphadenectomy
in our collective of patients showed that significant
difference between D1 and D1,5 and more extended
lymphadenectomy since the number of lymph nodes
harvested in D1 was significant higher in the former
group (13 Vs. 23, p<0,0001). The incidence of perioperative complications did not reveal any significant
difference moreover, the perioperative 30 day mortality was even significantly less (p=0,001).
RATIONALE OF SENTINEL NODE AND
MICROMETASTASES
Sentinel node mapping is another issue of research.
The rationale is to improve the nodal stage and by
that to provide more exact treatment (19). It is also
used by some to navigate the lymphadenectomy in
patient with poor general condition or to tailor the
lymphadenectomy in resections for early gastric cancer. The accuracy of more than 98% was reported
from Far East, in particular in early stages (T1-T2)
(25, 26). Moreover, presenting of sentinel node and
searching for micro metastases (present in 30–50%
of N0) might be important in staging as well as for
decision making concerning adjuvant oncological
GASTROENTEROLOG 81
treatment. By definition micro metastases mean the
presence of tumor cells –single or in small clusters–
detected only by cytokeratin specific immunostaining
that could not be detected by ordinary H and E staining
(27, 28). Some authors were able to prove that the
lymph node micrometastasis is an independent prognostic indicator for patients with histologically
node-negative T3 and T4 gastric cancer (27). In addition to the presence of LN micrometastasis, the
number and level of micrometastases in the lymph
nodes were strongly associated with the survival time
of patients (29, 30, 31).
In our former analysis we studied the reliability of
the Rt PCR method to determine the sentinel
node as well as the method of detecting the micrometastases in deemed N0 stages. The results
revealed that in 28% nodes negative by conventional patohistological workup of nodes as a matter
of fact were affected by micrometastases (32).
SPLENECTOMY
It has been well shown that splenectomy does not
add significantly in postoperative mortality and 5-year
survival (34, 35). Splenectomy or/and splenopancreatectomy is not a part of the routine radical resection
with D2 lymphadenectomy any more unless the
tumor invades either organs. It was suggested to
perform splenectomy in case of suspected lymph
nodes in station 10 or in proximal tumors in stage
T3 or more (34, 35). There is no positive impact on
long term survival by splenectomy, moreover, it
impacts conversely the perioperative morbidity as it
was shown in the Dutch DGST and British MRC
studies. (33, 35, 36).
In approximately one third of our patients the splenectomy was added to gastrectomy. In the P2 of our
trail significant less splenectomies were performed
(38% Vs. 29%; p=0.006). Presently we avoid performing splenectomy unless for oncological or operation
technical reasons. The hospital stay was significant
longer in group of patients with splenectomy (16.6
Vs. 14.7; p=0.005) however, the incidence of perio82 GASTROENTEROLOG
perative morbidity and mortality wasn’t different in
comparison to non splenectomy group. The survival
was not impacted in any way by splenectomy.
There are new randomized control studies in progress to clear out the impact of splenectomy in
surgical treatment of AGC but unfortunately the
results are still not available (37).
MULTIORGAN RESECTION
In patients with tumors invading adjacent organs
a multiorgan resection is indicated to achieve R0
resection. By the reports the multiorgan resection
is done in 5–10% of resected patients with advanced gastric cancer (38). Nowadays endoultrasound
and CT can predict the infiltration of the gastric
tumour in the neigbour organs but surgeons still
can meet unclear situations at operation (38, 39).
In multivariate analysis, peritoneal dissemination,
lymph node ratio, and histologic findings were the
predictors of survival (39). Patients with T4 gastric
carcinoma, even with lymph node metastasis, might
have benefited from aggressive surgery with curative
intent. In our experience 60 patients had a multiorgan resection for AGC. The list of additional
resected organs is given in table 5. In 50 patients a
T4a or T4b stage was confirmed by pathologist, 10
patients had N3 stage.
Survival analysis revealed a borderline significant
lower survival for this group of patients comparing
Table 5. Additional organ resected for oncological reasons
Adrenalectomie
Cholecystectomie
Segmental resection of colon
Segmental resection of jejunum
Liver excision
Left pancreatectomy
Left pancreatectomy +adrenalect
Left pancreatectomy +colon res
Whipple resection
Total
n
%
1
8
5
3
10
24
1
5
3
60
1.7
13.3
8.3
5.0
16.7
40.0
1.7
8.3
5.0
100.0
them with all other R0 resected patients (p=0.046),
but when looking in the groups of similar stages (excluded patients with early cancers -T1) the significance
vanished (p=0.289). Although having had more
extended resection these patient didn’t suffer more
surgical complications (12%) comparing to those who
didn’t have a multiorgan resection and also the perioperative mortality was low (1.7%). If our patients with
infiltration to the neighbor organs wouldn’t have
combined resection they didn’t have any chance for
long term survival. That gilts not only for T4 case but
also for some selected patients with N3 stage.
ONCOLOGICAL REGIMENS
Despite potentially curative resection of stomach
cancer, 50% to 90% of patients die of disease relapse.
As with other gastroenterological malignancy additional chemo and/or radiotherapy has in recent
decade become a standard for selected groups of
patients with AGC in many countries. However,
some controversies regarding the timing type and
combination of these additional settings still exist.
Numerous randomised clinical trials (RCTs) have
compared surgery alone with neoadjuvant, adjuvant
or perioperative regimens comprising chemotherapy
(CTX), or chemo-radiotherapy (CRT) but definitive
evidence is lacking (40, 41).
Different types of adjuvant CTX (mono-, polychemotherapy) were studied for patients after R0
resection in compare to resection alone (42).
Recently well designed phase III studies have been
able to show a significant survival benefit if adjuvant CTX was switched to radical gastrectomy with
D2 lymphadenectomy. But also other agents (capecitabine and oxaliplatin) have been studied for
adjuvant CTX (43). In Japan a mono CTX with S1
(an oral fluoropyrimidine) now presents a standard
after R0 resection for AGC (44).
Another philosophy but the same aim advocated
by some is radiotherapy to be added to adjuvant
CTX. In 2001 a randomised control study revealed
a significant survival benefit (median - 9 months)
for patients receiving CRT after radical surgery in
comparison to those with surgery alone (45).
However, even this well-designed study was criticised to have included high number of patients with
insufficient lymphadenectomy (less than D2) and
by that treating inadequate surgery (46). This
oncological regiment has become popular in the
west especially in USA where it presents a standard
adjuvant treatment for patients after gastrectomy
for AGC. Between 2001 and 2011 adjuvant CRT
gradually became a standard adjuvant treatment
for un-disseminated patients with AGC in stages Ib
and more in Slovenia.
Regarding the multimodal treatment we are able to
report our own experience with adjuvant CRT. In
our collective of patients between January 2001 and
December 2010 altogether 141 R0 resected patients
received adjuvant CRT (only) (2.3% in P1 and 26.3%
in P2). The aim the analysis was to figure it out if
there was any survival benefit for patients receiving
adjuvant CRT and to identify possible subgroups in
which the benefit would be present. The inclusion
criteria are given in table 6. In a retrospective trail
patients who met the inclusion criteria were analysed. To achieve as high as possible homogeneity
between the control and CRT group, we included all
potential candidates for CRT from January 1998 to
December 2010. By this we recruited 176 patients.
99 of them received CRT after surgery (CRT-S) and
77 had surgery (S) only. All patients received a fluoropyrimidine based chemotherapy (xeloda only - 35
patients, fluoropyrimidine + cisplatin - 16 patients,
Table 6. Inclusion criteria for the analysis of CRT
• Histologically confirmed adenocarcinoma of the stomach
• Age < 76 years
• No neoadjuvant therapy
• UICC Stage Ib and more
• T>1
• No distant metastases
• R0 resection
• D>1 lymphadenectomie
• Survival > 90 days
• Completed CRT
GASTROENTEROLOG 83
Table 7. Adjuvant chemo-radiotherapy: Comparability between the group
surgery only (S) and chemo-radiotherapy (CRT)
p (S Vs. CRT-S)
Gender
Chi square: ns
Age
Student t-test: ns
ASA
Chi square: ns
Site of the tumour
Chi square: ns
Diameter of the tumour
Student t-test: ns
UICC stage
Chi square: ns
T stage
Chi square: ns
N stage
Chi square: p = 0.042 (more N0 in S)
Harvested LN
Student t-test: p = 0,032 (S:25LN; CTR-S: 29LN)
of the stomach. This matches well
with several studies from the east
and west (37, 40, 41, 42). The very
important limitation of the adjuvant regimens is the possible
impared patients general performance after surgery that can
humper or even prevent adjuvant
CRT.
fluoropyrimidine + leukovorine - 48 patients). The
comparability between the groups (CRT-S Vs. S) is
presented in table 7. Although more patients survived 5 years in the CRT-S group in compare to S
group (42 % Vs. 34 %) the difference was not significant (p=0,075), however observing only patients
with proximal sited tumours the difference in survival became highly significant (p = 0.017; p = 0.004)
(figure 1 and 2). According to this results CRT
added to radical surgery revealed survival benefit
only for patients with proximal sited tumours and
not for those having tumours in the distal two thirds
Neoadjuvant and perioperative
CTX for patients with potentially
resectable AGC is another option.
A Cochrane meta-analysis from 2006 showed a 40%
respond rate for the combination of capecitabine
with epirubicine and cisplatin. The rationale for
this type of oncological management is that in presence of tumor vascularisation the CTX could be
more efficacy in particular for micrometastases.
Down-sizing/staging of the tumour process and by
that a higher R0 are supposed to be the consequence (41). There is some concern regarding the
possible progress while on neoadjuvant treatment.
Based on the superior compliance of neoadjuvant
and/or perioperative settings as compared with
Figure 1. Adjuvant chemo-radiotherapy for tumours sited
in distal two thirds of the stomach: survival of patients
with adjuvant CRT (CRT-S - dotted) and S only (s - clear line)
(p = 0.521).
Figure 2. Adjuvant chemo-radiotherapy for tumours sited
in the proximal third of the stomach: Survival for
patients with adjuvant CRT (CRT-S - dotted) and S only
(s - clear line) (p = 0.017).
84 GASTROENTEROLOG
adjuvant regimens, neoadjuvant and/or perioperative
was adopted as a standard in some west European
countries and became a standard also in Slovenia
since 2011.
CONCLUSIONS
Contemporary aggressive surgical treatment is in experienced centers a save treatment promising solid long
term survival. It remains the milestone treatment,
however it seems that surgery will no more act as unimodal treatment of advanced gastric cancer. Although
with some drawbacks, many randomised controlled
studies have been able to show the potential positive
impact of radical resection with D2 lymphadenectomie as well as combined resections for most advanced
but resectable cases. The addition of neoadjuvant,
adjuvant or perioperative oncological settings (chemotherapy +/- radiotherapy) seems to have positive
impact on long term survival in selected group of
patients and opens the doors towards the multimodal
treatment also in gastric cancer. In some countries
these multimodal principal has already been implicated as a standard praxis.
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Gastrointestinalni stromalni tumorji
(GIST)-indikacije in principi kirurškega
zdravljenja
Gastrointestinal stromal tumors (GISTs)-indications
and princples of surgical treatment
Primož Sever*
Klinični oddelek za abdominalno kirurgijo, Kirurška klinika, Univerzitetni klinični center Ljubljana
Gastroenterolog 2013; suplement 2: 87–90
Ključne besede: Gastrointestinalni stromalni tumor,
kirurgija, tarčna zdravila
Keywords: Gastrointestinal stromal tumor, surgery, targeted
therapy
POVZETEK
ABSTRACT
Gastrointestinalni stromalni tumorji (GIST) so
redki tumorji prebavnega trakta, ki so v zadnjih
desetih letih doživeli revolucijo na področju diagnosticiranja in zdravljenja. Z odkritjem mutacij
genov ki so odgovorni za nastanek GIST, so se razvila nova tarčna zdravila, ki so ob kirurškem
zdravljenju močno izboljšala preživetje obolelih.
Kirurško zdravljenje je trenutno še vedno edino
potencialno kurativno zdravljenje GIST.
Gastrointestinal stromal tumors (GIST) are rare tumors
of alimentary tract. The last decade was a revolution
in diagnosing and treatment of GIST. Gene mutations discoveries responsible for GIST occurrence
led to development of new targeted therapy. Using
them together with surgery prolonged survival in
patients with GIST. Surgical resection is, to date, the
only potentially curative treatment of GISTs.
UVOD
Gastrointestinalni stromalni tumorji (GIST) so najpogostejši mezenhimski tumorji prebavnega
trakta. GIST med novotvorbami prebavnega trakta
predstavljajo 1–2 % vseh novotvorb z incidenco
1,5-2/100.000 pribivalcev. (1) Za nastanek GIST je
odgovorna protoonkogenska mutacija genov proteinov iz družine tirozinskih kinaz (KIT, PDGFRA).
Raste submukozno v steni prebavnega trakta, agre-
sivnost se ocenjuje na podlagi velikosti tumorja in
številu mitoz na 50 polj pri visoki povečavi (HPF).
Kirurško zdravljenje še vedno predstavlja edini
potencialno kurativni način zdravljenja, ki je še
bolj uspešno v kombinaciji s tarčnimi zdravili iz
družine inhibitorjev tirozinskih kinaz.
*Primož Sever, dr. med.
Klinični oddelek za abdominalno kirurgijo, Kirurška klinika, Univerzitetni klinični center Ljubljana
Ljubljana
GASTROENTEROLOG 87
KLINIČNA SLIKA
ZDRAVLJENJE GIST
Bolniki z GIST imajo nespecifične simptome. Približno tretjina je odkritih naključno, ob operativnem
zdravljenju druge patologije trebuha (20 %) in
obdukciji (10 %). 30 % bolnikov ima anemijo ob
krvavitvi, 28 % izgubo telesne teže, 13 % bolečine
v trebuhu. Lahko povzročajo nelagodje v trebuhu,
zgodnjo sitost, ter pri velikih tumorjih tipno rezistenco. (1) Pojavijo se lahko v katerem koli delu
prebavil, najpogosteje na želodcu (50–60 %), tankem črevesu (20–30 %), debelem črevesu (10 %),
požiralniku (5 %), v 5 % pa se pojavijo drugje v trebušni votlini (omentum, mezenterij) (2). Ob odkritju
bolezni ima 15–47 % bolnikov zasevke, najpogosteje
v jetrih, omentumu in peritoneju (3).
Način zdravljenja je rezultat multidisciplinarne
obravnave vsakega bolnika, v kateri sodelujejo
gastroenterolog, kirurg, onkolog, patolog in radiolog. Zdravljenje se prilagodi glede na stadij tumorja.
Za tumorje manjše od 2cm, ki imajo manj kot 5
mitoz na 50 HPF je dovolj kirurška odstranitev. Vsi
bolniki s tumorji večjimi od 5cm, ki imajo več kot 5
mitoz na 5 HPF prejmejo po kirurški odstranitvi še
adjuvantno terapijo z inhibitorji tirozinskih kinaz.
Pri metastatskih GIST bolniki prejmejo neoadjuvantno terapijo z inhibitorji tirozinskih kinaz in so
nato ponovno predstavljeni kirurškemu zdravljenju, predvsem v smislu citoredukcije.
ODKRIVANJE GIST
Najpogosteje je GIST ugotovljen s pomočjo ultrazvoka
ali ezofagogastroduodenoskopije. Za oceno GIST zgornjih prebavil je zelo uporaben endoskopski ultrazvok.
Poleg velikosti, lahko izkušen endoskopist predvidi
tudi malgni potencial tumorja glede na prisotnost
nepravilnih robov in cističnih vključkov (4). Za oceno
tumorja je primerna tudi računalniška tomografija
(CT), ki pokaže tudi eventuelne zasevke. Magnetno
resonančna preiskava (MRI) je uporabna za oceno
zasevkov v jetrih, saj so nekateri povsem enake gostote
po CT-ju kot parenhim jeter, kar jih naredi nevidne na
CT. Pri diagnosticiranju in sledenju se uporablja tudi
pozitronska emisijska tomografija (PET) z F-fluorodeoksiglukozo, ki zlasti pokaže majhne posevke po
omentumu, ki so nevidni na CT-ju.
Vloga biopsije tumorja ni povsem opredeljena.
Pogosto so GIST dobro vaskularizirani, kar predstavlja preveliko tveganje za krvavitev. Tanko-igelna
aspiracijska biopsija lahko povzroči rupturo tumorja
in implantacijo tumorskih celic po poti biopsije. V
primeru postavitve suma na GIST po slikovnih kriterijih in da je le-ta kirurško odstranljiv, biopsija ni
potrebna. Biopsija je potrebna za potrditev diagnoze pri bolnikih z neresktabilnim GIST in z njo
povezanim začetkom zdravljenja s tarčnimi zdravili.
88 GASTROENTEROLOG
Število
mitoz
<5 na 50
HPF
<5 na 50
HPF
Velikost tumorja
v cm
Želodec
(%)
Jejunum/Ileum
(%)
Dvanajstnik
(%)
Rektum
(%)
<2
0
0
0
0
>2-<5
1,9
4,3
8,3
8,5
>5-<10
3,6
24
>10
12
52
34
57
<2
0
50
ni podatka
54
>2-<5
16
73
50
52
>5-<10
55
85
>10
86
90
86
71
-zelo nizko tveganje
visoko tveganje
-nizko tveganje
-srednje tveganje
-
Slika 1. Verjetnost metastaziranja GIST glede na velikost
tumorja, število mitoz ter lokalizacijo po Milettinen in
Lasota (2006) (5).
Adjuvantno terapijo z inhibitorji tirozinskih kinaz
prejmejo vsi bolniki z visokim tveganjem za metastaziranje, tisti z nizkim tveganjem ga ne prejmejo,
bolniki s srednjim tveganjem pa se o adjuvantnem
zdravljenju dogovorijo z lečečim onkologom.
INDIKACIJE ZA KIRURŠKO
ZDRAVLJENJE
Ključno vlogo pri odločitvi za kirurško zdravljenje
GIST predstavljata velikost in maligni potencial
samega tumorja. Vse GIST >2cm je potrebno ne
glede na maligni potencial odresecirati. Konkretnih
smernic za zdravljenje manjših GIST ni. Trenutno se
še ne da predvideti hitrosti rasti, kot tudi ne spreminjanja malignega potenciala tumorja. Tumorje velikosti
med 1 in 2 cm je možno endoskopsko spremljati in
postaviti indikacije za kirurško zdravljenje v primeru
rasti tumorja, ali ko postane ta simptomatski. Optimalni časovni intervali spremljanja še niso določeni,
zato je odločitev za spremljanje velikokrat negotova. Ob odločitvi za spremljanje GIST je potreben
izdaten pogovor z bolnikom glede tveganja in prednosti take obravnave. (6)
Slika 2. Predlagan algoritem obravnave lokaliziranega
GIST (6).
Opisane so uspešne endoskopske resekcije GIST,
vendar niso sprejete zaradi negotovosti glede varnostnega roba, raztrganja tumorja pri trakciji in s
tem razsoja. Klasična endoskopska tehnika ne zagotavlja varne resekcije submukozno rastočih GIST. (7)
KIRURŠKO ZDRAVLJENJE
Kirurško zdravljenje je še vedno edini potencialno
kurativni način zdravljenja GIST. Operativni poseg
je lahko laparoskopski ali po odprti metodi. Pri
mejno resektabilnih tumorjih in tumorjih pri katerih je predvidena razširjena resekcija, je smiselna
predoperativna kemoterapija s tarčnimi zdravili.
Tumor mora biti makroskopsko v celoti odstranjen
z varnostnim robom enega centimetra ter negativnimi histološkimi robovi (R0 resekcija). (8) Tumorji
so lahko zelo krhki z obilo nekrotičnega tkiva, zato
je potrebna previdna manipulacija v izogib raztrganja pseudokapsule tumorja in s tem razsoja po
trebušni votlini. Pseudokapsula tumorja mora biti
ohranjena (9). Za razliko od žleznega raka GIST ne
vrašča v priležne strukture, jih le odriva, zato se ga
lahko odmakne od sosednjih struktur. Ob močni
vnetni komponenti je možen videz preraščanja, ki
zahteva »en bloc« resekcijo. Slednjo zahtevajo tudi
preraščajoči tumorji. Glede na prizadet organ in
lokacijo se izbere vrsto operativnega posega.
Potrebna je natančna eksploracija trebušne votline
zaradi izključitve metastatske bolezni, ki po predoperativni diagnostiki ni bila vidna. Tako je potrebno
biti pozoren na eventuelne posevke po omentumu
in peritoneju. Ob sumu na zasevke v jetrih se opravi
intraoperativni UZ. Večino posegov predstavljajo
ekscizije in segmentne resekcije, v poštev pa pridejo
tudi netipične in obširne resekcije. Tako je potrebno
ob prizadetosti dvanajstnika v predelu papile Vateri
narediti pankreatoduodenektomijo. Poseben izziv
za kirurga predstavljaja GIST rektuma, zaradi prostorske omejitve medeničnega prostora in pogoste
čvrste fiksacije na medenično dno. (10) V primeru
tumorja v distalnem rektumu je potrebna abdominoperinealna ekscizija. »Klasičnim« resekcijam se je
ob dejstvu, da GIST silno redko zaseva v bezgavke,
potrebno izogniti.
Laparoskopska kirurgija je varna kirurgija GIST-a ob
upoštevanju onkoloških načel (11). Pomembno vlogo
pri odločitvi za laparoskopsko odstranitev imata lokacija ter velikost tumorja. Veliki tumorji v predelu
kardije in pilorusa niso primerni za laparoskopsko
obravnavo. Pomembno je nežna manipulacija s
tumorjem z ustreznimi inštrumenti v izogib rupturi
pseudokapsule tumorja. Po eksciziji tumorja z varnostnim robom je potrebno preparat pred
odstranitvijo iz trebušne votline vstaviti v vrečko.
Pogosto pseudokapsula tumorja pri izvleku vrečke
skozi rano v trebušni steni poči, kar je nujno potrebno zabeležiti v patohistološki protokol. V primeru
manjkajočega tega podatka, se lahko bolnika vodi
kot diseminiran GIST. Prednosti laparoskopske
metode so boljši estetski rezultat, manj je bolečin,
krajša je hospitalizacija in hitrejša vrnitev k vsakodnevnim aktivnostim.
Kirurško zdravljenje razširjene bolezni je smiselno,
če so spremembe solitarne in v primeru dobre regresije po kemoterapiji. (12)
GASTROENTEROLOG 89
ZAKLJUČEK
V zadnjih petnajstih letih je viden velik napredek v
zdravljenju bolnikov z GIST. Odkritje protoonkogenske mutacije genov, izboljšana diagnostika,
izboljšana kirurška tehnika z uvedbo minimalno
invazivne kirurgije ter odkritje tarčnih zdravil, je
močno povečalo preživetje bolnikov z GIST. Kirurško zdravljenje primarnega, ponovitvenega ali
metastatskega tumorja v kombinaciji s tarčnimi
zdravili je postal standard zdravljenja GIST. Za
dober uspeh zdravljenja je potrebna multidisciplinarna obravnava tako pri diagnosticiranju,
zdravljenju in nato vodenju bolnikov z GIST.
90 GASTROENTEROLOG
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targeted systemic therapy using kinase inhibitors. J Clin Oncol
2006; 24:2325.
Zagotavljanje kakovosti v presejanju - nadzor
in resni neželeni učinki
Rezultati nadzora Državnega programa presejanja in zgodnjega odkrivanja
predrakavih sprememb in raka na debelem črevesu in danki SVIT v letih
2010-2012: 23 centrov, 51 endoskopistov in 24 382 kolonoskopij
Assuring quality in screening- control and
severe adverse events
Results of the control of the National Colorectal Cancer Screening Programme
SVIT 2010-2012: 23 centres, 51 endoscopists and 24 382 colonoscopies
Milan Stefanovič*1, Bojan Tepeš2, Borut Štabuc3, Dominika Novak Mlakar4, Jožica Maučec Zakotnik4,
Matej Bračko5, Snežana Frkovič Grazio5
1Diagnostični center Bled, Pod skalo 4, 4260 Bled, Slovenia
2AM DC Rogaskač, Prvomajska 29A, 3250 Rogaška Slatina, Slovenia
3
University Clinical Center, KOGE, Japljeva 2, 1000 Ljubljana, Slovenia
4National Institute of Public Health, Trubarjeva 2, 1000 Ljubljana, Slovenia
5University Clinical Centre, CGO, Zaloška 2, 1000 Ljubljana, Slovenia
Gastroenterolog 2013; suplement 2: 91–100
POVZETEK
ABSTRACT
V nasprotju z nekaterimi drugimi presejalnimi programi lahko presejanje za raka na debelem črevesu
in danki (RDČD) preiskovani osebi povzroči neposredno škodo. Lahko pride do zapletov, kot so
krvavitev, perforacija, zaplet zaradi sedacije in neustrezne napotitve na kirurški poseg.
Še posebej pomembno je, da se presejanje za RDČD
pazljivo spremlja v organiziranem programu, kjer
lahko zbiramo podatke o ustreznosti presejanja in
obenem nadzorujemo varnost, kakovost in učinkovitost kolonoskopije znotraj presejalnega programa.
Unlike some other screening programmes, colorectal
cancer screening may cause direct damage to the person who undergoes the examination. Complications
may occur, such as bleeding, perforation, complications due to sedation and inappropriate referral to
surgery. It is particularly important that colorectal
cancer screening is monitored carefully in an organised programme where information about the suitability of screening can be collected, and at the
same time safety, quality and efficiency of
colonoscopy within the screening programme can
be monitored.
Nadzor kakovosti je načrtovan tako, da zajema
strukturni nadzor v endoskopski enoti, nadzor
endoskopske opreme in endoskopskega osebja in
Quality control is planned to cover structural control in the endoscopic unit, equipment, staff and the
procedure of endoscopic intervention, the result as
*Milan Stefanovič
Diagnostični center Bled
Pod skalo 4, 4260 Bled
GASTROENTEROLOG 91
nadzor postopka ali endoskopskega posega ter
rezultata kot posledice endoskopskega delovanja,
ki se kaže v spremembi zdravstvenega stanja posameznika in populacije kot celote.
the consequence of endoscopic activity, shown in
the change of the health status of an individual and
population as a whole.
INTRODUCTION
DISCUSSION
Nowadays, colonoscopy is widely used in diagnosing
and treatment of colorectal diseases. In general, it is
a safe, precise and efficient examination and most
patients can bear it well. Its advantage over other
diagnostic methods is also that it allows simultaneous therapeutic intervention, e.g. polypectomy.
Consequently, colonoscopy is in the centre of the
screening programme. In order to be able to keep
that position, quality must be assured at all times
and endoscopic quality standards have to be raised.
In Slovenia the network of endoscopic units which
carry out colonoscopy for the needs of SVIT is organised by regional approach. In this way we have brought
examinations closer to people who are involved in the
programme. Colonoscopies for the needs of SVIT can
be carried out in outpatient clinics and outside hospitals but those clinics should not be too far from hospitals which provide emergency medical treatment and
surgical treatment. Endoscopists in SVIT programme,
where the primary screening is immunochemical test
that detects occult bleeding from lower digestive system, are expected to detect and endoscopically remove
more advanced neoplasmas. This requires qualified
staff and appropriate equipment, needed for safe and
complete removal of such changes.
Colonoscopy quality assurance in SVIT programme
will ensure our patients and persons who participate in the colorectal cancer screening programme
receive the best colonoscopy, and at the same time
complications and missing something become
much less likely. The quality is assured by following
the guidelines. Programme Council of the National
Colorectal Cancer Screening Programme, hereinafter referred to as SVIT, monitors key quality
indicators and applies them to granting and
extending licences to endoscopists and endoscopic
centres which participate in the implementation of
the programme. The base for control is quality indicators, adopted by the SVIT Programme Council,
responsible for the implementation of the programme at the national level. Information is collected centrally and prospectively and analysed periodically in controls, announced in advance. All
endoscopists and endoscopic centres which participate in the implementation of screening are
informed about the results. In case of deviating
from the set level of quality and in case of serious
shortcomings and/or mistakes extraordinary supervisions are carried out.
92 GASTROENTEROLOG
In screening period between 2010 -2012, colonoscopies for the needs of SVIT programme were carried out in 23 centres. 51 endoscopists carried out
colonoscopies. After the first supervision, two centres ceased to perform the activity for the needs of
SVIT (8%). Four endoscopists, one of which retired,
ceased to work for the needs of SVIT (7.14%). Three
new endoscopists started to work for the needs of
SVIT (two specialists in internal medicine and one
specialist in abdominal surgery). All centres meet
the set criteria regarding minimum standards
regarding the premises, equipment and staff. In
three centres it was necessary to warn about meeting the standards. Two centres complied with them
while the third one left the programme. All centres
clean the apparatus mechanically and use disposable devices. Disinfection is strictly controlled.
Selected key quality indicators which are monitored and
considered decisive in order to find out the quality level
of colonoscopies, carried out within SVIT programme
Indicator 1 Minimum number of colonoscopies
that an endoscopist has to carry out per year.
Justification: the number of performed colonoscopies
is directly proportional to the percentage of total
colonoscopies and inversely proportional to the number of immediate and subsequent complications.
This is the share of colonoscopists who carried out at
least 200 colonoscopies in one year. The number of
colonoscopies that a colonoscopist has to carry out per
year in order to be eligible to participate in the colorectal cancer screening programme must not be lower
than 200. The more colonoscopies a colonoscopist carries out the more experienced he/she is, and consequently the number of total colonoscopies and detected
lesions increases while the complications get less likely.
Numerator: Number of colonoscopists who carry
out at least 200 colonoscopies per year, within or
outside the screening programme.
Denominator: number of all colonoscopists in the
programme
Unit of measurement: colonoscopist (share in per cent)
Colonoscopist: Acceptable: 85% ≥ 200
Desired: 100% > 200
Results: In three-years screening period 24 382
colonoscopies were carried out, of which 7494 in
2010, 7872 in 2011 and 9016 in 2012. The number of colonoscopies by centres is shown in Graph
1 below. One to nine colonoscopists were carrying
out colonoscopies in an individual centre.
Graph 1. Number of colonoscopies per endoscopic centre together between 2010- 2012 (from 232 to 2715).
Number of colonoscopies per endoscopist ranged
from 61 to 1533 (see Graph 2). It should be taken into
account that in addition to screening colonoscopies
endoscopists were carrying out also regular diagnostic
colonoscopies and consequently most of them reach
the number of 200 examinations per year and also the
desired number 300. For those who had not achieved
that indicator, a transitional period was set and heads
of endoscopic centres were advised to organise the
work so that this criterion will be met. Thus seven
colonoscopists are threatened to have their licences
for carrying out colonoscopies for the needs of the
national screening programme withdrawn.
Graph 2. Number of colonoscopies per endoscopist only
within SVIT programme
Indicator 2 Appropriate visibility after intestinal
preparation
Share of colonoscopies with good visibility in relation
to all colonoscopies. The cleanliness is assessed by the
colonoscopist and he/she documents it with either
well or badly cleared. The measure for the assessment
is the size of the polyp that can still be seen. Colon is
well cleaned when it is cleaned and dirty but still visible (visible lesions are larger than 5 mm) while the
colon is badly cleaned when it is dirty and visibility
is poor (lesions smaller than 5 mm are not seen) and
visibility of the colon is poor.
The precondition for quality colonoscopy is suitable
preparation of the colon. The visibility must be good
and it is an important factor in making the decision
about referral to follow-up colonoscopy.
GASTROENTEROLOG 93
Numerator: number of colonoscopies with good
cleanliness or visibility
Denominator: number of colonoscopies carried out
Unit of measurement: colonoscopy (share in per cent)
Colonoscopist: Acceptable: > 90% good visibility,
≤ 10% bad visibility
Desired: ≥ > 95% good visibility, ≤ 5% bad visibility
Results: within SVIT programme cleanliness of the
intestines before the colonoscopy as one of significant
programme quality indicators is monitored regularly.
In three years (2010–2012) 24 382 colonoscopies were
analysed and excellent cleanliness after preparation of
patients with Moviprep was identified in 84.04% of
cases and good cleanliness (possible to detect a polyp
< 5 mm ) was established in 11.45% of patients. Poor
cleanliness of patients (colonoscopy had to be repeated)
was established only in 1.97% of patients.
Indicator 3 Duration of withdrawing the colonoscope
after colonoscopy without the intervention (average,
median, minimum and maximum duration).
Minimum duration of the examination is 8 minutes
which does not include colonoscopies with biopsies and/or
polypectomies. Caecum or terminal ileum must be
reached during the colonoscopy. Duration of withdrawal
with the instrument is closely linked to the rate of detecting adenomas in people who undergo colonoscopy.
The sensitivity for detecting adenomas will be greater
when the examination of the mucous is more careful,
proximally from the haustra, in turns, when the remains
of mucous and liquid are better cleared from the intestines. There is a lot of substantiated proof that when the
duration of withdrawing the instrument is prolonged,
a higher number of adenomas are detected (≥ 6 minutes
for normal result without taking into account the time
for a therapeutic examination, e.g. polypectomy).
Numerator: number of colonoscopies, excluding
interventions and duration of the examination
≥ 8 minutes
Denominator: number of colonoscopies excluding
interventions
Unit of measurement: colonoscopy (share in per cent)
Colonoscopist: ≥ 90% 8 minutes
94 GASTROENTEROLOG
Results: SVIT set 8 min as the minimum duration
of withdrawal and examination, excluding the time
spent on any other intervention. This information is
particularly important for the endoscopists whose
ADR (the rate of detecting adenomas) is below average and when interval carcinoma develops. During
the supervision (since the time is strictly recorded)
no deviations from the set norm were identified.
Indicator 4 Per cent in total, colonoscopies carried
out to the final part of the colon – total colonoscopies.
A) Share of total colonoscopies (reached caecum
or terminal ileum) in relation to the number
colonoscopies carried out.
B) Share of persons who underwent total colonoscopies (reached caecum or terminal ileum)
in relation to the number of persons who
underwent colonoscopies.
Completeness of the examination is the basis for each
screening programme. The percentage of total colonoscopies (for adequate proof photographic documentation of mouth of the appendix, valvula Bauchini as typical sign of the caecum or final part of the small intestine
is required), should be at least 95% or more, which is the
standard, set by the SVIT Programme Council while the
standard set in European guidelines is set at 90% or
more and the achievement of total colonoscopies in
more than 95% is only desired or recommended.
A) Numerator: number of carried out total
colonoscopies where caecum or terminal
ileum is reached, Denominator: number
of colonoscopies carried out
Unit of measurement: colonoscopy (share
in per cent)
B) Numerator: number of persons who underwent at least one total colonoscopy where
caecum or terminal ileum was reached,
Denominator: number of persons who
underwent at least one colonoscopy
Unit of measurement: person (share in
per cent)
Screening cycle /reporting period, sex,
colonoscopist (for the needs of supervising
colonoscopy centres)
Acceptable: > 90%
Desired: ≥ 95%
Results: within SVIT programme this quality indicator
shows that the set standard is achieved. Between 2010
and the end of the year 2012 of 24 382 examinations
that were carried out on average the share of total
colonoscopies was 97.95%. Only three colonoscopists
(5.8%) did not reach the threshold of 90% of total
colonoscopies while 7 endoscopists did not exceed the
desired threshold of ≥ 95% of total colonoscopies.
Indicator 5 Rate of detecting adenomas during a
colonoscopy (ADR)
Justification: At the moment, the rate of detecting adenomas (ADR) is the only quality indicator, associated
with the occurrence of interval carcinoma. The advantage of ADR is that it can be measured, calculated and
monitored in a simple way. It is well tested and
described in practice and also easy to understand. The
achievement of the minimum number (threshold) for
ADR of an individual screening programme where the
age of the screened persons, sensitivity and specifics of
the primary screening test (iFOBT), applied in the programme, is defined. ADR significantly differs by sex.
This cannot be explained only by the fact that more
women than men participate in screening.
The rate of detecting adenomas during first colonoscopies (ADR) is the share of first colonoscopies
which find a histologically proved adenoma(s) in
relation to the total number of first colonoscopies.
Numerator: number of first colonoscopies where
adenoma was detected
Denominator: number of first colonoscopies
Unit of measurement: first colonoscopy
Screening cycle /reporting period, sex, five-year age
classes, colonoscopist, colonoscopy centre
There is no generally accepted reference standard
for colonoscopies, carried out after positive immunochemical test to occult bleeding.
Results: ADR- rate of detecting adenomas. It is undoubtedly the most important indicator for assessing endo-
scopic work. This indicator shows some considerable
deviations among endoscopists. Interesting, the numbers are almost the same through all three years and the
situation is only partially improving which is confirmed
also by the comparison of the situation in 2010, 2011
and 2012. Graph No. 3 shows the rates (ADR) for individual endoscopists separately for 2010, 2011 and 2012,
and total for three-year period, as well as separately ADR
men and ADR women in the three-year screening
period. ADR in SVIT programme in 2010: 54.16%
(63.56% for men and 43.22% for women). In 2011:
52.89% (63.18% for men and 40.45% for women). In
2012: 54.95% (64.34% for men and 42.16% for women).
Total for three years: 54.0% (63.69% for men and
41.94% for women). Mean ADR for individual endoscopists: for year 2010: all patients 51.05% (SD ± 0.10), for
men 64.52% (SD ± 0.13) and women 41.52% (SD ± 0.12),
2011: mean ADR 51.52% (SD ± 0.11), for men 61.83
(SD ± 0.13) and women 39.42% (SD±0.12), 2012: mean
ADR 52.57% (SD ± 0.11), for men 62.36% (SD ± 0.14)
and women 40.97% (SD ± 0.11).
Graph 3: shows average ADR together and separately for
men and women per individual endoscopists in programme SVIT in three years between 2010 and 2012
Indicator 6 The share of detected adenomas in the
left part of the colon in comparison with the share
of detected adenomas in the right part of the colon.
The right hemicolon includes lienal flexure, transverse colon, hepatic flexure, ascending colon, caecum while the left one includes anus, rectum, sigmoid colon and descending colon. According to the
definition all changes (carcinoma and polyps ≥ 1 cm),
detected in the period of two years after screening
colonoscopy, are considered to be interval changes.
GASTROENTEROLOG 95
According to study data it can be concluded that
polypectomy can prevent subsequent occurrence of carcinoma in more than 90% of cases. Study data show a
better protective role of colonoscopy for the occurrence
of interval cancer in the left hemicolon (in 80% of cases)
than in the right hemicolon (12–33%). The rate of overlooked changes in the right hemicolon is 2 to 3 times
higher than in the left hemicolon. The emphasis should
be placed on careful examination of the entire colon.
Numerator: number of adenomas, detected in the
right/left hemicolon
Denominator: number of adenomas, detected in
the entire hemicolon
Unit of measurement: adenoma (share in per cent)
Screening cycle/reporting period, sex
Acceptable: ratio left: right = 65%:35%
Desired: left < 60%, right > 40%
Results: when assessing the quality of colonoscopy it is
helpful to compare the rate of detecting adenomas in
the right and left hemicolon. The desired ratio between
the detections in the right and left hemicolon should
be 40:60. There are considerable differences between
endoscopist and endoscopic centers regarding number
of AP in the left, compared with the number of AP in
the right colon. In SVIT programme the average ratio
for all centres in three year period for mean percentage
was 66.61% (SD ± 0.0824) in the left and 30.69%
(SD ± 0.0776) in the right part of the colon. Graph
No 4. For the endoscopists ratio between the mean
percentage was in 2010: 69.27% (SD ± 0.0965%) in the
left and 27.80% (SD ± 0.0983) in the right colon, in
2011: 66.65% (SD ± 0.10) left and 31.14% (SD± 0.10)
right and in 2012: 64.02% (SD ± 0.10) left and 47.74%
(SD ± 0.91%) right colon. Graph No 5.
Indicator 7 Number of detected adenomas in relation
to the frequency of detection per colonoscopy with
people who have one or more adenomas detected
Justification: because ADR has some shortcomings. It
is not possible to differentiate the detection of one adenoma and detection of several adenomas during a
colonoscopy which means that two colonoscopists with
a similar ADR can detect a very different number of
96 GASTROENTEROLOG
Graph 4: Ratio as a percentage of AP between the left
and right half of the colon for SVIT endoscopic centres
Graph 5: Ratio as a percentage of AP between the left
and right half of the colon for endoscopists participating
in Programme SVIT
adenomas. ADR can lead to a very misleading sense of
"safety" – when the endoscopist detects one adenoma
his/her attention lowers and the efficiency decreases.
However, this does not affect ADR which is still sufficient for achieving the appropriate level of "quality".
The average number of adenomas per first colonoscopy
(mean adenomas per procedure – MAP) and the average
number of adenoma per first positive colonoscopy
(mean adenomas per positive procedure – MAP+) are
two newer colonoscopy quality indicators which, unlike
ADR, take into account also the number of detected
adenoma during colonoscopy.
Numerator: number of all adenomas detected during
first colonoscopies
Denominator: number of all first colonoscopies
(for MAP) or the number of all first colonoscopies
with at least one adenoma detected (for MAP+)
Unit of measurement: first colonoscopy
A graphical presentation of the share of first colonoscopies by the number of detected adenomas in relation to the total number of first colonoscopies (adenomas under the curve or AUC) is being prepared
to support the two indicators.
Results: rate of detecting adenomas per individual
colonoscopy (ADR below the curve) is a more precise
indicator of the quality of endoscopist work than ADR
itself. There are substantial deviations in this indicator.
Graph No. 6 shows the number of detected adenoma
per individual colonoscopy with one or more neoplastic changes detected. Similarly big differences (shown
in Graph No. 5) are seen in the number of neoplastic
changes for all endoscopists who participated in the
programme, regardless of the number of examinations
carried out. The differences are even up to two and a
half times. The average number of detections per programme in 2010: 1.9, in 2011: 2.0, in 2012: 2.0 and
Graph 6. Per cent of colonoscopies with the detection of
one or more neoplasms.
Graph 7. The average number of detected adenomas
during colonoscopy when one or more adenomas were
detected, for each endoscopist.
total for all three years: 2.0. For individual endoscopist
the average MAP+ for all three years was between 1.2
and 3.1 (1.9 ± 0.49) Graph No.7.
Indicator 8 The share of documented completed
colonoscopies in accordance with the rules.
An appropriate colonoscopy has a completed electronic record. The prime objective is to ensure
proper documenting of endoscopic detections and
recommendations, arising from that. The desired
outcome is to improve coordination during care,
mitigate the risk for the patient and save the costs,
incurred by inappropriate interventions.
Numerator: number of colonoscopies with completed electronic result
Denominator: number of colonoscopies carried out
Unit of measurement: colonoscopy (share in per cent)
Screening cycle/reporting period
Desired: > 95%
Results: prompt and periodic data processing for the
need of the national colorectal cancer screening programme is extremely important and a condition for the
success of the programme itself. The results of screening can be evaluated only by centralised approach and
clearly defined quality standards, which is almost
impossible without computer support. Epidemiologic
data are obtained on the basis of these data and the
activity in individual parts of the programme is controlled. Certainly, this does not exclude own control of
each endoscopic unit on the basis of achieving a certain level of quality by individual quality indicators.
They are applied by all endoscopic centres, involved in
screening. Data are collected and analysed centrally.
Supervisions have revealed most irregularities in this
indicator. This is probably partly due to problems,
encountered during the set up and implementation
of the information system. In spite of several trainings for endoscopists and endoscopic personnel,
completing the form is still not appropriate and certain mistakes are repeated. The information system
is constantly being updated and additional trainings,
especially for endoscopists, are necessary.
GASTROENTEROLOG 97
Indicator 9 The share of persons with interval
changes in all persons who underwent colonoscopy
without any changes detected. All changes (carcinoma
and polyps ≥ 1 cm), detected in the period of two years
after screening colonoscopy, are considered to be
interval changes. According to research it can be concluded that polypectomy can prevent subsequent
occurrence of carcinoma in more than 90% of cases.
Colonoscopy is supposed to provide better protection
from the occurrence of interval cancer in the left
hemicolon (in 80% of cases) compared with right
hemicolon (12–33%). The rate of overlooked changes
in the right hemicolon is 2 to 3 times higher than in
the left hemicolon. The reasons for that are not completely clear: they may result from the fact that
changes in the right hemicolon are more aggressive
and grow faster or because they emerge from nonpolypoid changes which are more likely to be overlooked during colonoscopy, particularly in case of poor
visibility when cleanliness is bad.
Numerator: number of persons with interval
lesions (carcinoma and changes ≥ 10 mm)
Denominator: number of persons who underwent
colonoscopy
Unit of measurement: person (share in per cent)
Endoscopic centre, colonoscopist
Interval lesions < 10%
Interval carcinoma 0%
Results: 3 cases of interval cancer have been
recorded until now in SVIT programme. In all cases
we could attribute it to molecular and clinical factors
which contributed to rapid growth of neoplasm. Of
course we do not know that. Undoubtedly, bad visibility, lack of attention by the examiner (duration is
too short) affect the emergence of interval changes
but these are only assumptions. Also due to these
three cases it is necessary to take care about the quality of colonoscopy all the time although unfortunately
it cannot be regarded as 100% protection. We believe
that these three cases are not definitive number.
More reliable data will be available after the processing and publication of data in the Slovenian cancer
registry between the years 2010-2012. Till now the latest data is from the year 2009.
98 GASTROENTEROLOG
Indicator 10 The share of persons referred to additional intervention when a change was detected during colonoscopy. When the colonoscopist doubts
whether he/she will or will be able to remove the
detected change which poses a high risk for endoscopic complications, such change must be properly
documented (including photo documentation) and
marked with a tattoo (SPOT) if needed. Then the
patient has to be referred to another centre where
endoscopic or surgical procedure will take place. The
referral of a patient with a big benign change to surgical intervention and not endoscopic removal may
be the reason and it is associated with a higher level
of complications. Endoscopic unit and/or endoscopists who carry out colonoscopies for the needs of
the programme (patients with a positive faecal occult
blood test are supposed to have more complex pathology), must have appropriate knowledge and technical
abilities to recognise a change and remove it endoscopically, refer the patient to another institution with
more expert knowledge (EMR and ESD). All colonoscopists who participate in the programme, have to
have expert knowledge level 3 (removal of small nonpolypoid changes ≤ 20 mm and bigger polypoid, sessile and polypoid changes, and in case the access to
the change is technically demanding, they may refer
it to a tertiary centre). The fourth level of expert
knowledge is required for tertiary centres. These
regard limit changes, endoscopic/surgical removals
which require a special consensus by the patient.
Unsuccessful endoscopic removal or inappropriate
referral to surgical therapy is regarded as the colonoscopist's mistake or inappropriate action. Photo and
video documentation helps assess the indicator.
Numerator: number of persons referred to polypectomy in the same or another institution
Denominator: number of persons who had a
change detected
Unit of measurement: person (share in per cent)
Screening cycle /reporting period, colonoscopist
(for the needs of supervising colonoscopy centres)
Desired: < 5%
Results: the share of patients where colonoscopy had
to be repeated due to polypectomy of a demanding
change in a tertiary centre was needed, was for the
entire programme SVIT 1.19% or 291 of all colonoscopies. With the exception of two endoscopists
19.5% and 4.2% each, no one exceed 2.5% referral
for polypectomy, to another endoscopic center.
Regular consilium discussions of all problematic
polyps and especially the case when a change, histologically assessed as pT1,N0,M0, was removed endoscopically, are planned regularly within SVIT programme.
cinoma) SVIT National programmes acquires the necessary documentation and then carries out extraordinary supervision. Four such supervisions have
been carried out and the reports are kept in the SVIT
archives. Table 1 shows cases of serious subsequent
complications which occurred after the release from
the endoscopic unit. According to the standards in
force and comparable data from abroad Slovenian
programme does not deviate regarding the number
and seriousness of complications. We can even say
that they are fewer than in comparable series.
Indicator 11 The share of colonoscopies with complications. The indicator is prepared for individual
types of complications during colonoscopy and after
colonoscopy. Serious complications of colonoscopy
are unplanned hospitalization, prolongation of hospitalization, unplanned further treatments, emergency intervention or death. The basis for the definition of complications is MST (Minimal Standard
Terminology) Version 3.0 and ASGE-classification.
The indicator is one of the main parameters for monitoring the quality of colonoscopy. Endoscopist must
have knowledge that allows him to timely recognize
and immediately relieve immediate complications
during screening colonoscopy. For events that occur
up to 30 days after the colonoscopy it is necessary to
collect medical records from other sources
(internists, surgeons, personal physicians selected).
Numerator: the number of complications of colonoscopy
Denominator: number of colonoscopy
Unit of measurement: colonoscopy (Percentage)
Desired: Diagnostic colonoscopy: <0.5% Therapeutic colonoscopy <2.5%
Perforations requiring surgical therapy: <1/1000
Immediate or delayed bleeding requiring surgery:
<1/1000
Results: unfortunately, complications are an integral
and unavoidable part of endoscopy but they are monitored and analysed regularly. In case of serious complications with a patient who is included in the programme (death, perforation, bleeding which requires
transfusion or/and surgical treatment, or interval car-
Table 1. Colonoscopies with serious complications between 2010-2012.
Indicator 12 Analysis of the questionnaire for the
participants after colonoscopy.
Justification: satisfaction of the person who was examined / patient is very important in assessing the quality of colonoscopy. Patients complete the questionnaire after the colonoscopy and on the basis of the
answers the satisfaction can be assessed objectively.
Results: an important role in assessing the quality of
work, following the adopted guidelines and subjective
experience of people in the process of colorectal cancer screening is played by the results of continuous
surveys of screened people, done with the help of
questionnaires that are sent by mail after the procedure has been carried out. Answers for individual
centres and endoscopists are representative as in all
GASTROENTEROLOG 99
cases more than 50% of questionnaires are filled in
and returned. The questions about the attitude of the
endoscopist, staff in the endoscopic unit and personal
experience during colonoscopy are practically all
assessed by 4 or more (1- very bad, 2- bad, 3-good, 4very good and 5- excellent). The explanatory duty
before, during and after the procedure has improved
a lot and there are no major problems. The problem
is the assessment how painful the colonoscopy is and
although the number of answers that people suffered
a very strong and (almost) unbearable pain during the
examination is lower, it is still too high and with some
endoscopists it exceeds 10%. In Slovenia endoscopic
interventions in sedation are carried out selectively,
which has its advantages and disadvantages.
Undoubtedly, when deciding for sedation, financial
aspect plays an important role because this has not
been settled with the payer (Health Insurance
Institute of Slovenia). Higher quality level means also
that sedation is available to everybody who wants it
and not only to people who need it.
Conclusion: Data on the differences in carrying out
colonoscopies, also in Slovenia, show that the results
can be improved, which can be achieved by constant
taking care about the quality by training endoscopists,
use of optimal coloscopy technique, keeping appropriate documentation, explaining pathological result
and planning endoscopic controls.
Only appropriate performance of colonoscopies can optimally decrease mortality and prevent the occurrence of
colorectal cancer. Prompt control and improved quality
have to be a compulsory part of each colorectal cancer
screening programme.
100 GASTROENTEROLOG
REFERENCES
1. ASGE/ACG: Quality in Endoscopy. Gastrointest Endosc
2006;58:S1-S38.
http://www.asge.org/WorkArea/showcontent.aspx?id=3386
2. Stefanovič M. Vloga in zagotavljanje kakovosti kolonoskopije v
državnem programu presejanja in zgodnjega odkrivanja raka na
debelem črevesu in danki. Gastroenterolog 2007;11:22-31.
http://www.program-svit.si.
3. Zorzi, Manuel, Priscilla Sassoli de’ Bianchi, Grazia Grazzini, Carlo
Senore, eds. “Indicatori di qualitŕ per la valutazione dei programmi
di screening dei tumori colorettali - Manuale operativo”. Epidemiol
Prev 2007; 31 (6): 1-56.
http://www.asplazio.it/asp_online/prev_for_doc/files/screening
/files_screening/colon_retto/Indicatori_Di_Qualita_Per_La_Val
utazione_Dei_Programmi_Di_Screening_Dei_Tumori_Colorett
ali.pdf
4. Segnan N, Patrick J, von Karsa L (eds). European guidelines
for quality assurance in colorectal cancer screeining and
diagnosis – first edition. Luxemburg: Publication Office of
the European Union, 2010.
https://www.google.si/url?sa=t&rct=j&q=&esrc=s&source=web
&cd=2&ved=0CDwQFjAB&url=http%3A%2F%2Fbookshop.eu
ropa.eu%2Fen%2Feuropean-guidelines-for-quality-assurance-incolorectal-cancer-screening-and-diagnosis-pbND3210390%2F
downloads%2FND-32-10-390-ENC%2FND3210390ENC_001.pdf
%3Bpgid%3Dy8dIS7GUWMdSR0EAlMEUUsWb0000ut3WHv
eu%3Bsid%3D70fblrp85EbbnOo1Co1FMdhZTYSnxvcf8TU%
3D%3FFileName%3DND3210390ENC_001.pdf%26SKU%3D
ND3210390ENC_PDF%26CatalogueNumber%3DND-32-10390-EN- C&ei=H1CGUfn_B6in4gTH54HYAw&usg=AFQjCNF5AD0
wv-aiE6xONUP_4P1zwdnn6Q&sig2=ul5xnRdwcF1HIyeCmw3z3g
5. Rembacken B, Hassan C, Riemann J.F, Chilton A, Rutter M,
Dumonceau J.-M, Omar M, Ponchon T. Quality in screening
colonoscopy: position statement of the European Society of
Gastrointestinal Endoscopy (ESGE). Endoscopy 2012; 44: 957–68.
https://www.thieme-connect.de/ejournals/pdf/10.1055/s-00321325686.pdf?issue=10.1055/s-003-24431
Obsevanje in sistemsko zdravljenje raka
trebušne slinavke
Radiotherapy and systemic treatment of
pancreatic cancer
Borut Štabuc*, Lojze M. Šmid
1
Klinični oddelek za gastroenterologijo, UKC Ljubljana
Gastroenterolog 2013; suplement 2: 101–106
Keywords: pancreatic cancer, chemotherapy,
radiochemotherapy
Ključne besede: rak trebušne slinavke, kemoterapija,
radiokemoterapija
POVZETEK
ABSTRACT
V Sloveniji je za rakom trebušne slinavke v letu 2009
zbolelo 357 bolnikov, kar predstavlja nadaljevanje
rasti incidence te bolezni v zadnjih letih. Radikalno
kirurško zdravljenje je edino zdravljenje z možnostjo
ozdravitve, adjuvantno onkološko zdravljenje pa
pomembno podaljša čas srednjega preživetja po
kirurškem posegu. Zdravljenje metastatske bolezni
zadnjih 15 let temelji na gemcitabinu. Nedavne raziskave pa so pokazale pomembno podaljšanje preživetja
pri uporabi kombinacije 5-FU, irinotekana in oksaliplatina (FOLFIRINOX) ter kombinacije gemcitabina
z nab-paklitakselom.
The incidence of pancreatic cancer is rising and
357 new patients were recorded in Slovenia in
2009. Surgery remains the only potentially curative treatment and adjuvant therapy brings survival
benefit. Treatment of metastatic disease was based
on gemcitabine monotherapy for the past 15 years.
Recent studies of 5-FU, irinotecan and oxaliplatin
regimen (FOLFIRINOX) and gemcitabine combination with nab-paclitaxel show survival benefit
and are new first-line treatment options for these
patients.
INTRODUCTION
stry data for 2009, the incidence of pancreatic
cancer was 18.5 per 100.000, which means 357
new cases (1).
Pancreatic cancer is the 10th most common cancer diagnosed and the 4th most common cause of
death resulting from cancer. Median survival is
approximately three to six months, and only 2%
of patients will be alive five years after diagnosis.
Incidence rates are virtually identical to mortality rates with a range of 2.1 to 18.5 per 100.000
people. According to the Slovenian Cancer Regi-
The only curative treatment of pancreatic cancer
is radical surgery, however this type of treatment
is possible only with stage I (T1 – T2, N0) and
sometimes stage II (T3 N0, T1 – T3, N1) disease.
It is well known that age is inappropriate criteria
for patient selection and that extended lymphade-
* Prof. dr. Borut Štabuc, dr. med.
KO za gastroenterologijo, UKC Ljubljana
Japljeva 2, 1000 Ljubljana
GASTROENTEROLOG 101
nectomy brings no survival benefit; among 100
patients with pancreatic cancer, radical resection
is possible in 20 patients only. Median survival in
this patient group is 15 months and only four
patients will be alive at five years. On the other
hand, radiation and chemotherapy or best supportive care are the treatment option for 80% of
patients with pancreatic cancer. The medium survival in this group of patients is between three and
six months and only 2% will be alive at three years.
ADJUVANT CHEMOTHERAPY AND
CHEMO-RADIATION THERAPY OF
PANCREATIC CANCER
According to the American Gastroenteorology Association medical position statement from 1999,
adjuvant therapy with 5-FU based chemo-radiation
regimen should be considered after surgical resection(2). This medical position statement was based
on one pivotal study, which supports adjuvant chemoradiotherapy in patients with resected
pancreatic cancer. This small study that enrolled 43
patients and showed a median survival benefit of
20 months versus 11 months with significant fiveyear survival difference (18% versus 8%) in patients
who received bolus 5-FU with radiation therapy for
one year compared to those with who did not (3).
Small sample size was the most important weakness of this study.
motherapy. The chemotherapy-only arm showed statistically significant benefit over the observation
arm in median survival (20.1 months versus 15.5
months; P=0.009), while the chemoradiation therapy arm showed worse median survival (15.9
months versus 17.9 months; p=0.05). The main
weakness of this study was possible selection bias as
patients and clinicians were allowed to select which
arm to enter. Additional concern was suboptimal
radiotherapy, allowing the final radiotherapy dose
to be left to the judgment of the treating radiotherapists (5).
These confusing and inconsistent results of the
published randomized trials, which failed to provide
clear evidence in support to the use of chemoradiation as adjuvant therapy after pancreatic cancer
resection, spawned several new studies. One retrospective study, covering a 30-year period at Mayo
clinic, evaluated overall survival of 472 patients after
radical (R0) resection of pancreatic cancer. Significantly better survival was observed in patients who
received adjuvant chemoradiotherapy (25.2 months)
compared to those with no adjuvant treatment (19.2
months, p=0.001). The difference in survival can not
be attributed to tumor biology - patients receiving
adjuvant therapy had more adverse prognostic factors than those not receiving adjuvant therapy
(p=0.001) (6).
However, EORTC study in 207 patients with pancreatic and ampullary cancer compared treatment
with infusional 5-FU and radiotherapy given in split
curses (40 Gy) or observation only and showed only
a trend towards benefit of chemoradiation in terms
of medium survival (24.5 months versus 19
months; p=0.2008) (4). This study was criticized for
its radiotherapy component - suboptimal lower dose
and split curses.
Analysis of Prospectively Collected Database at the
Johns Hopkins Hospital of 616 patients showed
similar effect of adjuvant concurrent FU-based chemoradiotherapy. Results confirmed significant
improvement in survival after pancreatic cancer
resection. Patients receiving chemoradiotherapy
experienced longer median (21.2 versus 14.4 months;
P < .001), 2-year (43.9% v 31.9%), and 5-year
(20.1% v 15.4%) survival in comparison to those who
received no adjuvant treatment (7).
ESPAC–1 enrolled 541 patients with resected pancreatic cancer comparing, in a complicated trial
design, post operative observation, chemoradiation,
chemotherapy and chemoradiation followed by che-
In a Randomized EORTC-40013-22012/FFCD9203/GERCOR phase II study, 90 patients were
randomly assigned to receive either four cycles of
gemcitabine or gemcitabine for two cycles followed
102 GASTROENTEROLOG
by weekly gemcitabine with concurrent radiation
(50.4 Gy). Median disease free survival was 12
months in the chemoradiotherapy arm and 11
months in the control arm. Median overall survival
was 24 months in both arms. First local recurrence
was less frequent in the CRT arm (11% vs. 24%) (8).
In the CONKO-001 study, Oettle et al. randomized
368 patients with resected pancreatic cancer to
gemcitabine chemotherapy for six months, or
observation only. This trial showed a statistically
significant disease-free survival benefit (13.4
months versus 6.9 months; P<0.001) of gemcitabine versus observation. Adjuvant treatment with
gemcitabine showed a trend toward overall survival benefit (22.1 months versus 20.2 months;
P=0.06), which was later reported statistically
significant (9).
dard treatment after pancreatic cancer resection,
especially in Asian population.
These trials clearly show the benefit of adjuvant chemotherapy; data regarding radiotherapy is less clear as
direct comparisons are rare and it may not be required
for majority of patients. Most importantly - it should be
noted that we still lack good criteria for selection of
patients for surgical treatment. Despite resectability,
we still loose 30% of patients with stage 1 and 2 disease
after radical surgery in first six months.
NEOADJUVANT TREATMENT OF
PANCREATIC CANCER
Neoptolemos et al. report on ESPAC-3 study in
which 1088 patients with an R0/R1 resection for
pancreatic ductal adenocarcinoma were randomized
within 8 weeks of surgery to receive either bolus
5-FU/leucovorin or gemcitabine for 6 months versus observation. The median overall survival of
patients treated with gemcitabine did not differ from
that of patients treated with 5-FU (23.6 months versus 23.0 months; p=0.39) (10). However, safety and
dose intensity favored gemcitabine in this study.
Neoadjuvant therapy has several potential advantages. Better tumor response is aided by delivery of
chemotherapy and /or radiation to an intact and
well-vascularized primary tumor, furthermore it
provides early treatment of micrometastatic diseases
and offers a time interval within which unfavorable tumor biology unmasks and identifies patients
in whom surgery would not be of benefit. It can
reduce the risk of pancreatic leakage after surgical
reconstruction and lower the rate of local recurrences to less than 10%. Despite these advantages,
there is no evidence and no clinical trials that
would support the administration of chemoterapy
and/or chemoradiation in the preoperative period.
Randomized phase III adjuvant chemotherapy study
comparing gemcitabine versus S1 in patients with
resected pancreatic cancer (JASPAC 01) conducted
in Japan enrolled 385 patients. This trial showed
significantly higher overall two-year survival of S1
treated patients in comparison to the gemcitabine
arm (two-year over all survival 70% (95% confidence
interval 63%–76%) versus 53% (46%–60%)). There
was also significant difference in median disease
free survival with 23,2 months (95% confidence
interval 17,5–32 months) in the S1 arm and 11,2
months (9.7–13.5 months) in the gemcitabine arm
(11). Adjuvant chemotherapy with S1 for resected
pancreatic cancer patients was shown to be superior
to gemcitabine and S1 may be considered new stan-
The University of Texas MD Anderson Cancer
Center evaluated neoadjuvant chemoradiation strategies for resectable pancreatic cancer in a series
of nonrandomized phase II trials. The 276 patients
enrolled in these trials met identical eligibility criteria, which included objective, computed tomography
based determination of resectability and histologic
confirmation of PC, and the patients underwent
resection with a uniform surgical technique.
Median overall survival durations as long as 34
months were observed among the 54%–74 % of
enrolled patients who completed all therapy, including surgery; in contrast, patients who did not
complete treatment had median overall survival
times of only 7–11 months (12).
GASTROENTEROLOG 103
TREATMENT OF LOCALLY
ADVANCED PANCREATIC CANCER
The median survival of patients with locally advanced pancreatic cancer is better when compared to
metastatic disease. The question of optimal treatment
for locally advanced disease remains unresolved. Chemotherapy alone and chemoradiation therapy trials
report medium survival of ten months. In the European Union, chemotherapy alone remains standard
of care. One recent meta-analysis suggested gemcitabine based chemoradiation therapy may be both,
more effective and more toxic than 5-FU based chemoradiation (13).
In a recent prospective clinical trial, presented at
ASCO GI 2013, 74 patients with locally advanced
pancreatic cancer were randomized after 4 cycles
of combination chemotherapy to either gemcitabine or capecitabine radiotherapy arm. The split
radiation dose in both arms was 15,4 Gy. Medium
overall survival was significantly higher in patients
with capecitabine radioterapy arm -15,2 months
versus 13,4 months in the Gemcitabine radioterapy arm (p=0. 012). Median progression free
survival was also longer in this arm (20 versus 10.4
months). Furthermore, following induction chemotherapy the combination of radiotherapy with
capecitabine was significantly less toxic than combination with gemcitabine. The benefit was
archived with no compromise in local control and
improvement in overall survival.
TREATMENT OF METASTATIC
PANCREATIC CANCER
In the last 15 years the gemcitabine in dose 1000 mg
per m2 on weekly schedule has been standard treatment for metastatic pancreatic cancer. In prospective
clinical trial conducted by Buris at al in 1997, 126
patients were randomized in two treatment arms with
either 5-FU or gemcitabine. The difference in progression free survival and medium overall survival
was significant across the two arms (medium overall
survival – 5.65 months in gemcitabine versus 4.41
104 GASTROENTEROLOG
months in 5-FU arm, 1 year survival 18 % in gemcitabine and 2% in 5-FU arm, p=0.002). Furthermore,
the survival benefit was accompanied by significant
clinical benefit in gemcitabine arm patients (14).
Several trials with combination chemotherapy
approaches aimed to improve treatment efficacy in
following years. In an attempt to assess the combination of gemcitabine with a fluoropyrimidine,
phase III trial was performed, comparing combination chemotherapy with gemcitabine plus
capecitabine (GemCap) versus single-agent gemcitabine in 319 patients with advanced or metastatic
pancreatic cancer. Patients were randomly assigned to receive either GemCap (oral capecitabine
650 mg/m2 twice daily on days 1 to 14 plus Gem
1,000 mg/m2 by 30-minute infusion on days 1 and 8,
every 3 weeks) or gemcitabine alone. Median overall
survival time was 8.4 and 7.2 months in the GemCap
and gemcitabine arms, respectively (p= 0.234).
Post-hoc analysis in patients with good Karnofsky
performance status (score of 90 to 100) showed a
significant prolongation of median overall survival
in the GemCap arm compared to the gemcitabine
monotherapy arm (10.1 v 7.4 months, respectively;
p=0.014) (15).
Combination chemotherapy trial with gemcitabine
and oxaliplatin in metastatic pancreatic cancer randomized 156 patients into gemcitabine and 157
patients into gemcitabine with oxaliplatin (GemOx)
arm. The combination was found to be significantly
superior to gemcitabine in terms of response rate
(26.8% and 7.1%, respectively; p = 0.044), clinical
benefit (42.3% and 8.3%; p = .01), median progression free survival (5.8 and 3.7 months, p = 0.04).
One-year survival probability was 27.8% in the gemcitabine arm and 34.7% in the GemOx arm (p =0.22).
Median overall survival time did not differ significantly
and was 7.1 months for gemcitabine monotherapy
and 9.0 months for GemOx combination (p=0.13;
HR 1.20; 95 % CI 0.95 to 1.54) (16).
As showed by another trial with 360 enrolled
patients, irinotecan plus gemcitabine combination
does not affect overall survival or time to progression
when compared with gemcitabine monotherapy in
patients with locally advanced or metastatic pancreatic cancer (median overall survival 6.3 months
and 6.6 months, respectively) (17).
The first gemcitabine combination regimen, which
showed modest improvement in overall survival
over gemcitabine monotherapy, was gemcitabine
with erlotinib. One-year overall survival of 24%
versus 17% was reported for the combination and
monotherapy (HR 0.76), respectively. The study
also supported the concept of effective EGFR pathway targeting in pancreatic cancer patients(18).
Recently, gemcitabine monotherapy was compared
to another promising combination in 342 patients
with metastatic pancreatic cancer. They were randomized to either 5-FU, irinotecan, oxaliplatine
(FOLFORINOX) combination or gemcitabine
monotherapy arm and median overall survival was
significantly longer in the FOLFIRINOX arm with
11.1 months as compared with 6.8 months in the
gemcitabine arm (p<0.001). Median progressionfree survival was 6.4 months in the FOLFIRINOX
group and 3.3 months in the gemcitabine group
(p<0.001). Not surprisingly, the FOLFIRINOX
regimen was associated with higher rates of grade
3 and 4 toxicities than gemcitabine and 42.5% of
patients in the experimental arm received G-CSF
and almost 1/4 of the patients had grade 3 or 4
fatigue. 10–15% experienced grade 3 or 4 vomiting,
diarrhea, or neuropathy(19).
MPACT recently compared the combination of nabpaclitaxel with gemcitabine, in a international phase
III study; 842 patients were randomized and significant survival benefit was reported for the
combination in comparison to gemcitabine monotherapy (median overall survival 8.5 versus 6.7
months, respectively). One-year survival was 35% in
the experimental and 22 % in the control arm, a 5 %
relative difference. Hematological toxicity and neuropathy levels were acceptable and manageable and
the combination of gemcitabine with nab-paclitaxel
may be considered a new standard for the treatment
of patients with metastatic pancreatic cancer.
CONCLUSION
Pancreatic cancer remains a malignancy with grave
prognosis. Adjuvant therapy after radical surgery
improves patient survival. In metastatic disease,
gemcitabine monotherapy remained the main
treatment option in the last 15 years. No clear survival benefit was achieved with gemcitabine
combination chemotherapy until modest two-week
median survival improvement was shown by addition of EGFR-targeting erlotinib. FOLFIRINOX
regimen has proven more effective than gemcitabine, however study population selection and
unfavorable toxicity profile prohibit its wide use.
Nab-paclitaxel combination with gemcitabine has
recently emerged as a possible new standard treatment for metastatic pancreatic cancer, which is yet
to be implemented into everyday practice.
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4. Klinkenbijl JH, Jeekel J, Sahmoud T, van Pel R, Couvreur ML,
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curative resection of cancer of the pancreas and periampullary
region: phase III trial of the EORTC gastrointestinal tract cancer
cooperative group. Ann. Surg. 1999 Dec;230(6):776–782; discussion 782–784.
5. Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA,
Hickey H, et al. A randomized trial of chemoradiotherapy and
chemotherapy after resection of pancreatic cancer. N. Engl. J.
Med. 2004 Mar 18;350(12):1200–10.
6. Corsini MM, Miller RC, Haddock MG, Donohue JH, Farnell MB,
Nagorney DM, et al. Adjuvant radiotherapy and chemotherapy
for pancreatic carcinoma: the Mayo Clinic experience
(1975–2005). J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2008
Jul 20;26(21):3511–6.
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et al. Analysis of fluorouracil-based adjuvant chemotherapy and
radiation after pancreaticoduodenectomy for ductal adenocarcinoma of the pancreas: results of a large, prospectively collected
database at the Johns Hopkins Hospital. J. Clin. Oncol. Off. J.
Am. Soc. Clin. Oncol. 2008 Jul 20;26(21):3503–10.
GASTROENTEROLOG 105
8. Van Laethem J-L, Hammel P, Mornex F, Azria D, Van Tienhoven
G, Vergauwe P, et al. Adjuvant gemcitabine alone versus gemcitabine-based chemoradiotherapy after curative resection for pancreatic cancer: a randomized EORTC-40013-22012/FFCD9203/GERCOR phase II study. J. Clin. Oncol. Off. J. Am. Soc.
Clin. Oncol. 2010 Oct 10;28(29):4450–6.
9. Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K,
et al. Adjuvant chemotherapy with gemcitabine vs observation in
patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. Jama J. Am. Med. Assoc. 2007
Jan 17;297(3):267–77.
10. Neoptolemos JP, Moore MJ, Cox TF, Valle JW, Palmer DH,
McDonald AC, et al. Effect of adjuvant chemotherapy with fluorouracil plus folinic acid or gemcitabine vs observation on survival in patients with resected periampullary adenocarcinoma:
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11. Maeda A, Boku N, Fukutomi A, Kondo S, Kinoshita T, Nagino
M, et al. Randomized phase III trial of adjuvant chemotherapy
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14. Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg
ML, Modiano MR, et al. Improvements in survival and clinical
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106 GASTROENTEROLOG
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12;364(19):1817–25.
Varna terapevtska kolonoskopija
Safe therapeutic colonoscopy
Milan Stefanovič*
Diagnostični center Bled
Gastroenterolog 2013; suplement 2: 107–113
Ključne besede: kolonoskopija, varnost, šolanje, polipektomija
Key words: colonoscopy, safety, training, polypectomy.
POVZETEK
ABSTRACT
Tveganje pri izvajanju kolonoskopije je večplastno
in na to vpliva več dejavnikov. Dejavnik tveganja je
lahko endoskopist, endoskopski tim kot celota ali
njegov del in oprema v endoskopski enoti, ki je na
voljo v danem trenutku. Ne nazadnje je lahko dejavnik tveganja tudi bolnik pri katerem se izvaja
poseg. Vloga zdravnika endoskopista je najpomembnejša in odločujoča. Kot vodja tima in nosilec
dejavnosti je zdravnik endoskopist odgovoren za
strukturo in kakovost procesa. Odgovoren je za
eventualne napake v organizaciji in delu endoskopske enote kot celote ali posameznikov s katerimi
sodeluje v timu. Zelo pomembno je njegovo znanje,
izkušnje in stalna praksa. Za opravljanje kolonoskopije je potreben tretji nivo znanja. Nedvomno je
število opravljenih posegov in zahtevnost posegov,
ki jih je sposoben opraviti v soodvisnosti z izidom
zdravljenja. Ne tako redko je tu prisoten tudi konflikt, ko je potrebno pretehtati kje je meja in kaj
lahko naredimo v danih okoliščinah in kje je meja
pri doseganju tehnične odličnosti. Poleg preprečevanje zapletov mora endoskopist biti sposoben
pravočasno prepoznati in razrešiti zaplet(e) in oskrbeti urgentna stanja.
Risks, associated with colonoscopy are multi-layered
and affected by several factors. Risk factors may
include the endoscopist, endoscopic team as a whole or
a part of it, and equipment in the endoscopic unit
which is available at a given moment. The patient who
undergoes colonoscopy may also be a risk factor. The
role of the endoscopist doctor is the most important
and decisive. As the head of the team, the doctor is
responsible for the structure and quality of the process,
including any mistakes in the organisation and work,
done by the endoscopic unit as a whole or individuals
in the team. Consequently, doctor’s knowledge, experience and constant practical work are of utmost importance. Colonoscopy requires the third level of knowledge. Undoubtedly, the number and complexity of procedures that the doctor is able to carry out are interdependent on the outcome of the treatment.
Furthermore, conflicts are often present when it has to
be decided where the boundary is and what can be
done in given circumstances and where is the limit in
the achievement of technical excellence. In addition to
preventing complications the endoscopist has to be
able to recognise and solve complications and take care
of possible emergency conditions in due time.
* Prim. Milan Stefanovič, M.D.
Diagnostični center Bled, Pod skalo 4
4260 Bled
GASTROENTEROLOG 107
INTRODUCTION
The prerequisite for reliable and safe colonoscopy is
an endoscopic unit and/or endoscopists who have the
required knowledge and technical abilities to recognise changes and endoscopically remove them, or
refer such patient to a tertiary institution with more
expert knowledge /EMR and ESD) or to an abdominal surgeon. All endoscopists should have expert
knowledge level 3 (removal of big polypoid, pedunculated and sessile changes, and smaller non-polypoid
changes ≤ 20 mm). The fourth level of expert knowledge is required for tertiary centres. These regard
limit changes, endoscopic/surgical removals which
require a special consensus by the patient (1, 2).
DISCUSSION
Today we have the mechanisms to separate high
quality endoscopic examinations, carried out by an
endoscopist with appropriate theoretical and technical skills from an examination, carried out by an
examiner who lacks such skills. Patients, doctors
and health system require a guarantee that
endoscopy is carried out only by properly qualified
experts (endoscopists). Fortunately, side effects and
complications are rare, and their type, seriousness
and frequency cannot be used for efficient assessment of the quality of the endoscopist’s work.
Certain quality indicators have been selected which
allow for more efficient control and implementation
of measures for keeping and raising the quality level
of colonoscopies (1, 2).
In order to be able to carry out a colonoscopy procedure successfully, the endoscopist must be cognitively
reliable which means that he/she is able to recognise
abnormalities, interpret them and define the strategy
of treatment accordingly. Each type of endoscopy
includes also technical requirements that the endoscopist has to meet after the completion of studies.
The level of competency for carrying out high quality colonoscopy and removal of high-risk changes
depends also on the competency of the endoscopic
108 GASTROENTEROLOG
team and the equipment which is available: highly
qualified team needs suitable equipment and consumables, which means that any problem that
occurs may be solved.
The requisites for safe colonoscopy in an endoscopic unit are:
– employees have the required knowledge and
level of competency;
– unit has all the required equipment; and
– In case of serious complications the patient can
be cared for locally and then safely transferred
to another health care institution which has all
the conditions for further treatment of such
patient.
Shortcomings may be detected by appropriate
assessing and testing of abilities and competencies
and then removed by additional theoretical and practical training, and also by new investments.
The most suitable indicator for assessing whether the
training in the field of gastrointestinal endoscopy was
successful is the level of successful examinations. This
rate and the rate of complications can provide an objective picture of the endoscopist‘s performance, compared with the statistics of experienced endoscopists.
However, it is more difficult to identify and monitor
information about overlooked changes, which means
that appropriate documentation in the form of electronic records and photo documentation is very important. When assessing the performance, the level of satisfaction of people who have undergone the procedure
is also very important as it affects the patient’s decision
about coming to the agreed follow-up endoscopy (4, 5).
According to the information, there are substantial
differences in previous training, number of treated
cases and individual endoscopists among endoscopic units, hospitals and private practices.
The definition of proper qualification of an endoscopist for independent work and individual type of
endoscopy is still difficult. Most endoscopic associations rely on the assessment regarding the number of
procedures carried out, and more or less on the
teacher’s subjective assessment. The number of procedures carried out for individual types of endoscopy
used to be a criterion for the achievement of appropriate knowledge, but in most cases the numbers were
set too low. It was found out that the learning curve is
much slower and gradual, and the number of required
endoscopic procedures which is the condition for
appropriate qualification is much higher than it had
been anticipated. Today’s requirements are probably
higher also due to the application of new, more and
more sophisticated technologies and complex endoscopic procedures. The achieved level of endoscopic
knowledge can be maintained only by constant work
and keeping the routine.
The definition of proper qualification has to be
unified, which is the task of the national association.
Undoubtedly, the number of examinations carried out
is very important for the qualification and performance of an endoscopist, but it is much more important
to meet and achieve the required level of individual
quality indicators. The American Society for Gastrointestinal Endoscopy (ASGE) has defined 21 general quality indicators which refer to the assessment
of quality of the entire Gastrointestinal Endoscopy ()
before, during and after endoscopic procedure. 14
special quality indicators were defined for the needs
of colonoscopy, including the rate of achieving total
colonoscopy to caecum, duration of withdrawal, rate
of detecting adenomas and removal of detected polyps
(6). In Slovenian National Colorectal Cancer Screening Programme (SVIT Programme) among others 12
quality indicators which refer to colonoscopy are
monitored. The acceptable and desired quality levels
have been set for most of them:
1. Share of colonoscopists with the minimum number of colonoscopies carried out
2. Appropriate visibility after intestinal preparation
3. Share of total colonoscopies
4. Duration of examination during the withdrawal of colonoscope
5. Rate of detecting adenomas in people
who undergo colonoscopy
6. Ratio in the rate of detecting adenomas
during colonoscopy of the left and right
part of the colon
7. Rate of detecting adenomas in people who
undergo colonoscopy below the curve where
also the number of detected adenomas per
colonoscopy and average number of adenomas per colonoscopy with adenoma are
taken into account
8. Referral of the patient to polypectomy to
another centre
9. Share of complications after colonoscopy
10. Significant interval changes after colonoscopy with a positive test to occult
bleeding
11. Appropriate documenting of the colonoscopies carried out, and
12. Appropriate referral to follow-up colonoscopy.
In addition to the above, endoscopic units are controlled, which includes assessing the premises, equipment and staff (for extending and issuing accreditation
upon the inclusion into the SVIT programme). Answers
in the questionnaires, filled in by people who participated in SVIT screening programme, are also used in
the assessment. All these measures require prospective
collection for each colonoscopy and for all people who
carry out colonoscopies. Collection itself is not sufficient. Analysis and taking appropriate measures will
contribute to improving the level of quality (7).
Achieving appropriate quality levels in the field of
gastrointestinal endoscopy will ensure preventing
undesired complications and doctors’ errors in the
best possible way.
Some practical advice for safe polypectomy
If we want to remove a polyp we have to find it first!
There is a lot of information which proves that during colonoscopy neoplasms, even cancer, is overlooked. The rate of missed and overlooked changes
differs among endoscopists which confirms that
scrupulous and careful examination, using appropriate colonoscopic equipment is of key importance
GASTROENTEROLOG 109
for ensuring quality colonoscopy which will prevent
overlooking colorectal cancer (8-11).
foration. It has to be checked prior to the
resection whether all the required devices
are available (clips, noradrenaline, loops,
knives, APC catheter).
2. It is important to discuss the matter with the
patient before you begin the procedure.
Patient’s plans after the intervention (important events, longer travelling…) have to be
taken into account.
3. In case of elective removal of complex
polyps it is recommended to make an
action plan, before the procedure, with the
endoscopic staff and make sure that all the
required devices are available. Repeated
preparation is important as well (MoviPrep
in shared dose) even if the change is in the
rectosigmoid part of the colon. Be careful
with antithrombotic medications (follow
the guidelines) (12, 13).
Each endoscopist should aim at safe and total
removal of all colon polyps (without bleeding and
perforation) (without repetition at the place of the
removal). Most polyps are small and not difficult to
remove (> 90%). However, sometimes they may pose
a challenge.
What should we pay special attention to?
1. High risk of bleeding (pedunculated polyps
on thick stalks, big sessile polyps) because
of the high number of veins which feed the
change and which have to be cut during
polypectomy (+ antithrombotic conditions).
2. High risk of perforation (big sessile
polyps, big LSTs and non-polypoid changes in caecum and right hemicolon) due
to a big cut, required for the removal of
such changes.
3. High risk of residue and/or recidivism
(incomplete removal) in certain patients
where some parts of the polyp were not
removed (12, 13).
Some additional useful advice for safe and
successful polypectomy:
–
Electrocauterisation contributes to practically
everything – perforations and most bleedings
during polypectomy. Small polyps can be efficiently removed by cold techniques: biopsy and
loop without electrocauterisation for 1–3 mm
polyps, and loop without electrocauterisation for
3–10 mm polyps, depending on its shape. As
most small polyps are not threatening for the
patient, we have to be careful when deciding for
the removal with ELR and we always have to
consider the risk benefit factor (14–16).
–
When using »cold loop« some millimetres of
the surrounding healthy mucosa can be grabbed into the loop (14).
–
Use of »hot« biopsy forceps is not recommended.
In addition to higher risk of perforation there is no
guarantee (in spite of the general belief) that the
entire polyp will be burnt. It has been shown that
in 16–28 per cent of cases residual neoplastic tissue remains in the colon after such removal (14).
It is not easy to answer the question how to decide
when a complex polyp is detected during screening
colonoscopy.
If you are not ready for therapeutic procedure:
1. Mark the spot with a tattoo (SPOT) one
haustrum from the change; avoid injecting
into the polyp because fibrosis may occur
and prevent later endoscopic removal.
2. Avoid biopsy from flat/non-polypoid change
and refer the patient to a centre with appropriate experience; biopsies cause submucosal
fibrosis and limit rising after injecting into
submucosa and prevent EMR.
If you decide for resection of a complex lesion:
1. The precondition for endoscopic removal
of such change is appropriate knowledge
required for controlling bleeding and per110 GASTROENTEROLOG
–
Use of weak coagulation current is associated
with higher risk of belated bleeding while a
mixed current for cutting, results in immediate
bleeding. At the moment there are several different units on the market and they are all
suitable for endoscopic polypectomies. Some
»surgical« units (ERBE, Olympus) alternate the
current for coagulation with the current for
cutting. The unit constantly calculates the tissue resistance and performs coagulation,
followed by short pulses of cutting current.
When a thick stem is being cut, it is good to
start with the use of pure coagulation and only
then the alternating current because in this
way immediate bleeding is avoided (12).
–
Ligation loops have proved to be efficient in
preventing immediate and belated bleedings
after the ELR of pedunculated polyps. Several
endoscopists say that they are demanding for
use, especially in case of big pedunculated
polyps, when they are needed the most. The
volume of the polyp can be reduced by injecting adrenaline into the head of the polyp (13).
–
When saline-adrenaline solution is injected into
submucosa, immediate bleeding after polypectomy is prevented (1:100.000/1:200.000).
–
Clips should prevent bleeding!? (if fitted correctly). Prophylactic placement of clips is
recommended.
–
–
Submucosal injection should prevent perforation!? Submucosal injection is very important
for successful EMR as it separates mucosa
from muscularis propria and reduces the risk
of bleeding. This is followed by either en-bloc
or resection by parts (piece-meal) (13, 18).
In most cases we inject into the centre of the
change. Proximal injection is applied when the
polyp reaches behind the haustrum – sometimes this is done best in retroflexion. Injecting
by parts (dynamic submucosal injecting) is
applied in case of very big changes which are
removed also by parts (piece-meal). Sometimes
even up to 30–50 cc has to be injected but there
are no special limitations for the volume (19).
–
During ELR of a pedunculated polyp they have
to be (when feasible) grabbed about 1/3 of the
distance of the polyp head from the colon wall.
This means that enough stem is left so that it
can be grabbed in case of bleeding and at the
same time appropriate distance from the polyp
ensures safe resection in case the invasion has
progressed into the stem (malign polyp). It is
recommended to inject diluted adrenaline into
the thick stem prior to the ELR (12, 14).
–
Several big sessile polyps which could have been
removed endoscopically are still removed by surgeons. Endoscopic therapy is better for the patient.
Long-term results of EMR by parts are excellent.
Endoscopic therapy is also cheaper. The rate of
complications is low (no dehiscence, no hernia…).
The disadvantage is that endoscopic controls are
needed (the first after 3 to 4 months) and also the
second one in one year is compulsory). Disadvantages for the endoscopist: the complications
which occur are endoscopist’s complications;
the procedure is not valued correctly (17).
–
Limitations in endoscopic polypectomy of sessile polyps:
–
the polyp grows and extends into the mouth
of the appendix,
–
it expands (grows) into the terminal ileum,
–
a polyp which covers more than 50-60% the
colon circumference in the ascending colon
and rectum and more than 30% in sigma.
–
a polyp which grows over two neighbouring
haustra can be non-resectable when the
area between the haustra is deep and relatively unreachable (12).
GASTROENTEROLOG 111
–
Big non-polypoid changes should not be biopsied as this way (fibrosis) causes false negative
sign of lifting (»non-lifting) during later planned
polypectomy.
–
Adding methylene blue into the solution for submucosal injection during resection by parts
results in better visual limitation of neoplastic
borders. Alternatively, NBI can be used. The
edges can be cut separately with an eccentric
loop (Wilson Cook). Alternatively, Argon plasma
can be used. The depth of the injury in case of
laser depends on the duration of the pulse in
intensity. Low power and short pulse are required in caecum and ascending colon (12).
–
Retroflexion may facilitate access at difficult
areas. Retroflexion is applied without any difficulties on the ascending colon and rectum.
When gastroscope is used, retroflexion can
also be used in left hemicolon.
–
Indian ink (SPOT = pure carbon particles) is
the best for marking. All changes which are
≥ 20 mm should be marked as they are quite
likely to be malign polyps (> 10%), as well as
the changes that the surgeon would find difficult to find as they are so small. Marks should
be some centimetres from the change at least
between two spots (mesenteric and antimesenteric). After injection with saline solution we
make a bubble into which the ink is injected.
Changes in caecum and rectum do not have to
be marked prior to the planned surgery or in
order to control the spot of ELR during subsequent endoscopic controls (13, 20).
–
ESD is a technique, developed in Japan. It is
time-consuming and associated with higher risk
of complications (4.7% of perforations). It is
questionable whether it really has such a big
advantage over peace-meal EMR by which
almost all benign polyps can be removed. ESD
in rectosigma is technically more demanding
than ESD in the stomach. However, it seems
112 GASTROENTEROLOG
that in ideal conditions the method is reasonable and it is definitely better than surgery
which can be even more dangerous and expensive. At the moment the indications are not
clear and defined enough. In Japan the following are the (possible) indications for ESD:
wide base lesions ≥ 2 cm which cannot be
removed en bloc, non-granulated/locked type,
pit pattern V, Sm1 carcinoma, scarred lesions
(submucous fibrosis), sporadic lesions in case
of ulcerative colitis and residual early carcinoma after incomplete previous EMR. The
conditions to start ESD are primarily clearly
defined and acceptable indications, well-qualified and equipped endoscopic team and the rate
of complications have to remain low. Secondary
requisites, which are time and money, have to
be taken into account as well. Japanese results
for Ro + en bloc resection 75.7%, perforations
4.7% (21, 22). The criteria for carrying out ESD
are appropriate experience with the minimum
of 1000 colonoscopies and more than 200 standard EMRs carried out as well as experience in
managing complications. Due to the above reasons the procedure is limited to selected or
tertiary centres.
CONCLUSIONS
The endoscopist must have appropriate technical
knowledge and ability to judge in detecting and removing abnormalities in colon and rectum. Colonoscopy
has to be fast, safe and as little unpleasant as possible,
with enough time for examination, safe removal and
withdrawal of removed changes for subsequent pathohistological examination. During the examination
all abnormalities should be detected and assessed and
the decision for further action should be made. The
procedure is carried out only when and if needed and
all the neoplastic changes are withdrawn.
Such high quality and safe colonoscopy requires
teamwork and appropriate equipment of the endoscopic unit. Nursing staff have to make sure that the
patient is comfortable and under constant supervi-
sion during the examination so that the endoscopist can focus on the procedure itself. Endoscopic
nurses also provide technical support for proper
functioning of the endoscopic equipment and
make sure that the required endoscopic devices are
available at all times. Last but not least they also
provide support in therapeutic procedures, e.g.
polypectomy. Endoscopists and endoscopic nurses
have to constantly analyse their work in the light of
carrying out the procedures, together with pathologists and surgeons if possible so as to optimally
improve the outcome for the patients.
Quality and safe colonoscopy depends also on proper
maintenance and regular servicing of the equipment
and prompt purchasing of devices for the scope and
type of procedures, carried out in the endoscopic unit.
Devices for solving complications after the removal of
high-risk changes, such as bleeding and in some cases
perforations have to be available. Endoscopic equipment is expensive and when it is used constantly it is
exposed to substantial burdening. The equipment has
to be maintained by qualified personnel. Maintenance
and repair of old instruments is sometimes more
expensive than replacement with new instruments.
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GASTROENTEROLOG 113
Helicobacter pylori - diagnostika, zdravljenje
in rezistenca na antibiotike v Sloveniji
Helicobacter pylori - diagnostics, treatment and
antimicrobial resistance in Slovenia
Bojan Tepeš*
FEBG AMDC Rogaška
Gastroenterolog 2013; suplement 2: 114–119
Ključne besede: antimikrobne sheme, Helicobacter pylori,
indikacije za zdravljenje, rezistenca na antibiotike.
Key words: antimicrobial therapy, drug resistance,
Helicobacter pylori, indication for therapy.
POVZETEK
ABSTRACT
Po priporočilih Slovenskega združenja za gastroenterologijo in hepatologijo zdravnik družinske medicine
na osnovi neinvazivnih diagnostičnih metod, urea
dihalnega testa (UBT) ali določanja monoklonalnih
protiteles proti Helicobacter pylori (H. pylori) v blatu,
začne zdravljenje H. pylori okužbe pri bolniki z
znano razjedo dvanajstnika, pri družinskih članih
prvega dednega reda bolnika z rakom želodca in pred
uvedbo dolgotrajnega zdravljenja s salicilati in nesteroidnimi protivnetnimi zdravili. Druge indikacije za
zdravljenje so v domeni gastroenterologa, ki diagnozo
okužbe postavi z invazivnimi testi ob endoskopiji
(hitri ureazni test, histologija, kultura).
Slovenian Society for Gastroenterology and Hepatology
in his recommendations divides indications for
Helicobacter pylori (H. pylori) treatment between general practitioners (GP) and gastroenterologist. GP
makes a diagnosis of H. pylori infection with urea
breath test (UBT) or with monoclonal antibody-based
H. pylori stool antigen test and starts treatment in case
of known duodenal ulcer patient, first grade relatives
of patient with gastric cancer and before starting long
term therapy with nonsteroidal anti-inflammatory
drugs and salicylates. All other treatment indications
are in domain of gastroenterologist who during upper
GI endoscopy use rapid urease biopsy test, histology or
culture to diagnose the infection.
Način zdravljenja je odvisen od podatkov o lokalni
rezistenci H. pylori na antibiotike. V Sloveniji je
rezistenca po zadnjih podatkih iz leta 2012 na klaritromicin 14,3 %, na metronidazol pa 22,2 %. V
primeru, da je rezistenca H. pylori na klaritromicin
manjša kot 15 %–20 %, je začetno zdravljenje sedem
dni z zaviralcem protonske črpalke (ZPČ), amoksicilinom (A) / metronidazolom (M) in klaritromicinom
(K) dvakrat dnevno. Uspeh zdravljenja preverimo
mesec dni po končanem zdravljenju z UBT. Kontrolna
The treatment algorithm is dependent on H. pylori
local resistance data. H. pylori resistance in Slovenia
in 2012 was 14,3% to clarithromycin (C) and 22,2%
to metronidazole (M). In case of C resistance under
15%–20% triple therapy with proton pump inhibitor
(PPI) - C- A (amoxicillin) / M bid seven days is recommended. The eradication success should be controlled with urea breath test or H. pylori stool antigen
test one month or more after treatment. Control
* Prof. dr. Bojan Tepeš, dr. med., specialist internist gastroenterolog
FEBG AMDC Rogaška, Prvomajska 29 A
3250 Rogaška Slatina
114 GASTROENTEROLOG
endoskopija s histologijo je potrebna pri bolnikih z
razjedo želodca ali MALT limfomom.
endoscopy is performed only in gastric ulcer or MALT
lymphoma patients.
V primeru neuspeha zdravljenja je naslednje priporočeno zdravljenje desetdnevno zdravljenje s koloidnim
bizmutom subcitratom - oksitetraciklinom - metronidazolom in ZPČ (štiritirna terapija z bizmutom), ki pa
ga v Sloveniji še nimamo. Druga možnost je desetdnevno zdravljenje ZPČ-A-K-M dvakrat dnevno. Kot
zdravljenje tretjega reda svetujemo desetdnevno zdravljenje ZPČ -A – levofloksacin (L) ali pa zdravljenje
po antibiogramu.
Recommended second line treatment is ten day colloidal bismuth subcitrate (CBS) - oxytetracycline (T)
– M - PPI therapy.This treatment is not available in
Slovenia at the moment. The other second line
treatment is ten day quadruple non bismuth therapy (PPI - A - K- M bid). This four drugs can be prescribed also as a sequential therapy (PPI and A bid
for 5 days followed by PPI- C - M bid for another five
days). Third line treatment is ten day PPI – A – levofloxacin (L) bid or treatment according to the
result of culture and antibiotic susceptibility.
V kolikor je lokalna rezistenca H. pylori na klaritromicin
večja kot 20 %, kot prvo zdravljenje priporočamo štiritirno zdravljenje z bizmutom ali štiritirno zdravljenje
brez bizmuta (ZPČ-A-K-M) dvakrat dnevno ali ista zdravila v obliki sekvenčnega zdravljenja (ZPČ – A pet dni
in nato ZPČ - K - M naslednjih pet dni dvakrat dnevno).
V kolikor je to zdravljenje neuspešno, je zdravljenje drugega izbora z ZPČ - A - L. Zdravljenje tretjega izbora,
v kolikor je potrebno, je vedno po antibiogramu.
Pri bolnikih, ki so alergični na penicillin, je začetno
zdravljenje ZPČ - M - K. V kolikor je rezistenca na
klaritromicin večja kot 20 % je prvo zdravljenje štiritirno zdravljenje z bizmutom. Nadaljna zdravljenja
so po antibiogramu.
DIAGNOSTIKA HELICOBACTER
PYLORI INFEKCIJE
Specialist družinske medicine
V Sloveniji specialist družinske medicine v skladu s
priporočili Slovenskega združenja za gastroenterologijo in hepatologijo (SZGH; 1) diagnosticira in zdravi
okužbo s Helicobacter pylori v sledečih primerih:
1. Bolnik z razjedo na dvanajstniku
2. Sorodniki prvega reda bolnika z rakom
želodca
3. Bolniki pred uvedbo kroničnega zdravljenja s salicilati in nesteroidnimi protivnetnimi
zdravili (NSPVZ)
In case of clarithromycin resistance higher than 20%,
first line is treatment is ten day quadruple bismuth or
nonbismuth therapy (quadruple or sequential). In
case of failure, ten day therapy PPI – A – L bid is recommended. Third line therapy is prescribed according to culture and antibiotic susceptibility.
In patients allergic to penicillin PPI - M - C is recommended. In case of C resistance higher than 20%
CBS quadruple therapy should be used. All further
therapies should be prescribed according to culture
and antibiotic susceptibility.
Kot diagnostično metodo za ugotavljanje okužbe je
potrebno uporabiti urea dihalni test (UBT) ali pa
monoklonalni test ugotavljanja H. pylori v blatu
(HPB; 2). Senzitivnost UBT je med 88 % in 95 %,
specifičnost pa 95 % (3). Senzitivnost HPB je 94 %,
specifičnost pa 92 % (4). HPB je manj natančen
tudi pri bolnikih s krvavitvijo iz zgornjih prebavil
(5). Pred testom za H. pylori bolnik 1 mesec ne
sme jemati antibiotikov, 14 dni pa ne zaviralcev
protonske črpalke (ZPČ; 2).
Dokazovanje okužbe s H. pylori s serološkimi testi
ni natančno in ni nujno odraz prisotne okužbe, saj
so lahko protitelesa prisotna še več let po ozdravitvi okužbe. Senzitivnost seroloških testov je 85 %,
GASTROENTEROLOG 115
specifičnost pa le 79 % (6). Dokazovanje protiteles
proti H. pylori v slini ali urinu ima še slabšo natančnost kot dokazovanje protiteles v serumu (7).
Specialist gastroenterolog
V vseh ostalih primerih indikacijo za ugotavljanje
okužbe s H. pylori in zdravljenje poda gastroenterolog.
Indikacije za zdravljenje so:
1. Bolnik z razjedo želodca ali dvanajstnika z ali
brez komplikacij.
2. Bolnik z MALT limfomom
3. Bolnik z dispepsijo po končani diagnostični
obdelavi
4. Bolnik z zapleti ob jemanju salicilatov ali
NSPVZ
5. Bolniki z prekancerozo želodca (atrofija, intestinalna metaplazija)
6. Bolnik po endoskopski odstranitvi zgodnjega
raka želodca ali delni resekciji želodca zaradi
raka želodca
7. Bolnik pred začetkom dolgotrajnega zdravljenja z ZPČ
8. Bolnik z rezistentno anemijo, idiopatsko trombocitopenično purpuro, kronično urtikarijo.
9. Vsak bolnik okužen s H. pylori.
Okužba z bakterijo H. pylori je odgovorna za vsaj
71 % do 95 % vseh rakov želodca (8). Zato smo v
novih smernicah SZGH, enako kot so to storile tudi
nekatere druge države s srednjo in visoko incidence raka želodca, priporočili uvedbo presejanja
prebivalcev v starosti med 20–30 let na prisotnost
okužbe s H. pylori in zdravljenje okuženih. Le tako
bomo lahko zmanjšali incidenco raka na želodcu (1,
9–11). Da je s takšnim pristopom to mogoče, dokazujejo rezultati iz Tajvana, ki je takšen način
obravnave zdravih nosilcev H. pylori okužbe že uvedel. Ob tem pa se je zmanjšala tudi pojavnost
dispepsije in razjed želodca in dvanajstnika (12).
Gastroenterologi okužbo ugotavljamo z invazivnimi
testi ob endoskopiji zgornjih prebavil. Največkrat
uporabimo hitri urea bioptični test (HUT). Potrebno
116 GASTROENTEROLOG
je odvzeti po dva biopta iz korpusa in antruma.
Senzitivnost testa je med 90 % in 95 %, specifičnost
pa 95 % do 100 %. Drugi invazivni test je histologija, ki nam poleg potrditve prisotnosti okužbe da
podatek o vrsti gastritisa in prisotnosti prekanceroz želodca. Natančnost izvida je odvisna od
izkušenosti preiskovalca. Odvzem vzorcev za kulturo in antibiogram nam poleg potrditve okužbe
da tudi podatke o občutljivosti H. pylori na antibiotike. To metodo uporabljamo po dveh neuspelih
poiskusih zdravljenja (13).
ZDRAVLJENJE OKUŽBE S H. PYLORI
Uspeh zdravljenja je odvisen od rezistence bakterije
H. pylori na antibiotike, sodelovanja bolnika, dolžine
trajanja zdravljenja, vrste in odmerka ZPČ, CYP
2C19 in MDR1 polimorfizmov, ki vplivajo na uspešnost zniževanja kisline z ZPČ, debelosti in kajenja,
vrste seva H. pylori in endoskopske diagnoze (14, 15).
Rezistenca H. pylori na antibiotike v
Sloveniji
Uspeh ozdravitve okužbe s H. pylori pade iz 91 %
pri na metronidazol občutljivih sevih bakterije H.
pylori na 76 % pri na metronidazol rezistentnih
sevih. Rezistenca je relativna, saj jo je mogoče premagati s podaljšanjem zdravljenja in povečanjem
odmerka zdravila (16). Dosti bolj pomembna kot
razistenca na metronidazol je rezistenca H. pylori
na klaritromicin. Eradikacija H. pylori pade iz 95 %
pri na klaritromicin občutljivih sevih na samo 40 %
pri rezistentnih sevih (17).
Zato je nujno potrebno, da poznamo podatke o
nacionalni rezistenci bakterije H. pylori na antibiotike. V Sloveniji se je v zadnjih desetih letih primarna
rezistenca na metronizadol in klaritromicin spremenila. Leta 1999 je bila rezistenca na klaritromicin
3,7 %, na metronidazol pa 18, 5 % (18), leta 2009 pa
je bila na klaritromicin 17,5 %, na metronidazol pa
18,6 % (Tabela 1; 19). Po še neobjavljenih podatkih
za leto 2012 je bila rezistenca na klaritomicin 14,3 %,
Tabela 1. Sprememba rezistence H. pylori na antibiotike
v Sloveniji
Table 1. Change of H. pylori resistance to antibiotics in
Slovenia
Antibiotik
Leto 2000 Leto 2010 Leto 2012
(v %)
(v %)
(v %)
N=27
N=78
N=153
Amoksicilin
0
0
0
Cipro/Levofloksacin
0
2,3
5,6
Klaritromicin
3,7
16,3
14,3
Metronidazol
18,5
17,2
22,2
Rafampicin
/
/
8,1
na metronidazol 22,2 % in na levofloksacin 5,6 %.
Slovenija je v evropskem povprečju glede rezistence
na klaritromicin in metronidazol in pod povprečjem
glede rezistence na levofloksacin (20).
Zdravljenje ob nizki lokalni rezistenci na
klaritromicin
Po priporočilih Maastricht IV naj se klaritromicin
ne uporablja v primeru, ko je lokalna rezistenca na
klaritromicin večja kot 15 %–20 %, metronidzol pa
ne v primeru lokalne rezistence večje kot 40 % (11).
V priporočilih SZGH iz leta 2010 smo glede na
naše podatke o rezistenci še vedno predlagali trotirno shemo (ZPČ - klaritromicin – amoksicilin,
dvakrat dnevno, 7 dni, ZAK) z izjemo, da bi se pri
bolnikih, ki so bili v življenju večkrat zdravljeni z
makrolidi, klaritromicin zamenjal z metronidazolom, ZAM (Tabela 2, 1). Rezultati sedemdnevnega
zdravljenja s shemo ZAK v Sloveniji so bili po objavljenih podatkih 82 % leta 1997 (21) in 80 % leta
2008 (22). Uspehi zdravljenja s shemo ZAM pa so
bili 82,6 % v letu 1997 in 78,6 % v letu 2008.
Uspeh zdravljenja s shemo ZAK se je v zadnjih
letih v nekateri delih Slovenije zmanjšal. Po še
neobjavljenih podatkih iz Koroške je bil uspeh
sheme ZAK v letih 20011 in 2012 med 69 % in
72,1 % (23). Nasprotno pa je bila enaka shema po
preliminarnih rezultatih raziskave SZGH v letu
2012 v Sloveniji še vedno 80 % (24).
Tabela 2. Zdravljenje okužbe s H. pylori prvega izbora po
priporočilih SZGH
Table 2. First line treatment of H. pylori infection according to SZGH
Zdravljenje H pylori okužbe
Predhodno zdravljenje z makrolidi
-
+
ZPČ 2 X stand.odmerek
Klaritromicin 2 X 500 mg
ZPČ 2 X stand. odmerek
Metronidazol 2 x 400 mg
Amoksicilin 2 X 1000 mg
Amoksicilin 2 x 1000 mg
7 dni
7 dni
Uspešnost zdravljenja preverimo mesec dni po končnem zdravljenju z UBT ali HPB. Bolnik mesec dni
pred kontrolo ne sme jemati antibiotikov, 14 dni pa
ne ZPČ (1). Pri približno 20 % bolnikov ne uspemo
odstraniti okužbe po prvem zdravljenju. Uspeh klasičnega trotirnega zdravljenja je mogoče izboljšati z :
a) Zviševanjem odmerka ZPČ. Rezultati meta
analize pokažejo, da se ob dvigu odmerka ZPČ
na 2 X 40 mg uspeh zdravljenja izboljša za
6 %–10 % v primerjavi z nižjimi odmerki (25).
b) Podaljšanje trajanja zdravljenja. Več meta analiz je ugotovilo, da podaljšanje zdravljenja na
10 dni izboljša uspeh zdravljenja za 4 %,
podaljšanje na 14 dni pa za 5–6 % (26–28).
Zdravljenje druge izbire mora biti desetdnevno. Pri
nas smo glede nadaljnih možnosti zdravljenja relativno omejeni. Trenutno ne razpolagamo s preparati
bizmuta in oksitetraciklina. Zato kot možno zdravljenja druge izbire svetujemo sekvenčno terapijo (prvih
pet dni ZPČ in amoksicilin dvakrat dnevno, nato pa
še pet dni ZPČ - klaritromicin - metronidazol dvakrat
dnevno). Druga možnost je štiritirno zdravljenje brez
bizmuta (ZPČ - amoksicilin – metronidazol - klaritromicin dvakrat dnevno) ali pa zdravljenje po
antibiogramu. Preliminarni rezultati sekvenčnega
zdravljenja in štiritirnega zdravljenja v okviru raziskave SZGH (kot prvega zdravljenja) ugotavljajo 94 %
in 95 % uspešnost odstranitve bakterije.
GASTROENTEROLOG 117
Tabela 3. Možnosti zdravljenja H. pylori okužbe po nespelem zdravljenju prvega izbora
Table 3. Treatment options of H. pylori infection after first line treatment failure
Zdravljenje H pylori okužbe
Zdravljenje prvega izbora je neuspešno
Kultura, antibiogram
in usmerjeno
zdravljenje
10 dni
Koloidni bizmut subcitrat
4 X 120 mg
Sekvenčno zdravljenje
Rešilno zdravljenje
ZPČ 2 X st. odm
- ZPČ 2 X stand.odm.
Metronidazol
Amoksicilin
3 X 400 mg
2 x 1000 mg
Oksitetraciklin
5 dni
4 X 500 mg
ZPČ 2 X st. odm
ZPČ 2 X st. odmerek
Klaritromicin
10 dni
2 X 500 mg
Metronidazol
2 x 400 mg
5 dni
Tabela 4. Priporočila za zdravljenje Maastricht IV
Table 4. Maastrich IV treatment recomendation
V naših razmerah bi bila idealna shema drugega reda
zdravljenje s štiritirno shemo z bizmutom (koloidni
bizmut subcitrat (KBS) – oksitetraciklin - metronidazol
in ZPČ dvakrat dnevno), ki pa je trenutno nimamo
na razpolago. V tujini so prva tri zdravila na voljo v
obliki ene kapsule, kar izboljša sodelovanje bolnika.
Štiritirnno zdravljenje z bizmutovimi preparati po
neuspelem zdravljenju prvega reda ima 80 % uspešnost ozdravitve (29, 30).
Levofloksacin je antibiotik, ki je bodisi v trotirni
shemi z ZPČ in amoksicilinom ali v sekvenčni shemi
118 GASTROENTEROLOG
- Amoksicilin
2 x 1000 mg in :
1. Levofloksacin
2 x 500 mg
ali
2. Rifabutin
2 x 150 mg
ali
3. Furazolidon
2 X 200 mg
pokazal dobre rezultate kot terapija drugega izbora. Ker pa H.
pylori hitro razvije rezistenco
nanj, ga v Sloveniji svetujemo
kot reševalno shemo tretjega
reda (31, 32). Druga možnost je
zdravljenje po antibiogramu.
Ob upoštevanju danih priporočil
je skupna uspešnost zdravljenja
H. pylori okužbe v raziskavi
Rokkasa 98,1 % (33), pri nas pa
97,7 % (22).
Zdravljenje ob visoki
rezistenci na
klaritromicin
V državah z več kot 15 %–20 %
rezistenco H. pylori na klaritromicin trotirne klasične sheme
ne smemo uporabljati. V teh
državah je najbolje začeti s štiritirnim zdravljenjem z KBS.
V primeru neuspeha tega zdravljenja se kot drugo zdravljenje
svetuje ZPČ – amoksicilin levofloksacin dvakrat dnevno
(34, 35). V kolikor tudi to zdravljenje ni uspešno, je naslednje
zdravljenje glede na rezultate
antibiograma (Tabela 4).
Večja težava je pri bolnikih, ki so alergični na penicilin.
V tem primeru se svetuje ZPČ -klaritromicin - metronidazol dvakrat dnevno teden dni v državah z nizko
stopnjo rezistence na klaritromicin. V primeru rezistence H. pylori na klaritromicin, ki je večja kot 20 %,
pa štiritirno zdravljenje s KBS (11). Naslednja zdravljenja, v kolikor so potrebna, so po antibiogramu.
Kot možno obliko reševalnega zdravljenja (tretji poizkus) je navedeno tudi zdravljenje z rifampicinom. V
meta analizi je ta shema pokazala 79 % učinkovitost
zdravljenja (36). Kljub temu ga zaradi možnosti
ustvarjanja rezistence in možnih kasnejših težav
zdravljenja mikobakterij ne svetujemo. Ugotavljamo
tudi, da je v Sloveniji rezistenca H. pylori na rifampicin (8,1 %) višja kot v drugih državah.
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GASTROENTEROLOG 119
Kirurško zdravljenje tumorjev sotočja
jetrnih vodov
Surgical treatment for hilar cholangiocarcinoma
Blaž Trotovšek*
Univerzitetni klinični center Ljubljana
Gastroenterolog 2013; suplement 2: 120–129
Ključne besede: Tumor sotočja jeternih vodov, Klatskinov
tumor, kirurško zdravljenje, presaditev jeter, neoadjuvantna
radiokemoterapija.
Key words: hilar cholangiocarcinoma, surgical treatment,
liver transplantation, neoadjuvant radiochemotherapy.
POVZETEK
ABSTRACT
Uvod. Učinkovita diagnostika in zdravljenje bolnikov s
tumorji sotočja jetrnih vodov temelji na sodelovanju
gastroenterologov, interventnih radiologov, onkologov
in kirurgov. Neresektabilni tumorji sotočja jetrnih
vodov imajo slabo prognozo, toda napredek v kirurških
tehnikah nudi vse večjemu številu bolnikov možnost
dolgoročnega preživtja. Članek povzema sodobne
smernice kirurškega zdravljenja in rezultate preživetja
pri bolnikih z maligno zožitvijo visoko v jetrni lini.
Background. Effective diagnosis and treatment of
patients with hilar cholangiocarcinoma is based on
the synergy of endoscopists, interventional radiologists, oncologists, radiotherapists and surgeons.
Unresected hilar cholangiocarcinoma has a dismal
prognosis, but advances in staging and surgical techniques have given well-selected patients a chance of
long-term survival if curative resection is possible.
This review summarizes the state of the art of surgical treatment, and outcome for patients with biliary obstruction at the hilus of the liver.
Metode. Popolna odstranitev rakastega tkiva nudi
bolniku s tumorjem sotočja jetrnih vodov edino
možnost za ozdravitev in dolgo preživetje. Obravnavali smo različne kirurške posege s poudarkom na
perioperativni obolevnosti, umrljivosti, radikalnosti
posega in pogostosti ponovitve bolezni. Ocenili smo
rezultate zdravljenja s pomočjo 5-letnega preživetja.
Rezultati. Desna hemihepatektomija in trisekciektomija z resekcijo 1. segmenta zagotavlja najširše
varnostne robove in najvišjo stopnjo preživetja, še
posebej ob hkratni načrtovani resekciji razcepišča
portalne vene. Desna trisekciektomija z resekcijo
razcepišča portalne vene nudi 72 % 5-letno preži-
* Blaž Trotovšek
Univerzitetni klinični center Ljubljana, Zaloška cesta 7
1525 Ljubljana, Slovenija
120 GASTROENTEROLOG
Methods. Complete removal of all cancerous tissues
offers patients with hilar cholangiocarcinoma the
only chance for cure and long-term survival.
Different surgical procedures were evaluated with
special emphasis on perioperative morbidity, mortality, radicality and recurrence rate. Outcomes of
radical surgical treatment including 5-year survival
were assessed.
Results. Right hemihepatectomy or right trisectionectomy guarantee the highest radicality rate and
the best long-term results, especially when resection of
vetje ob radikalnem posegu. Brez resekcije portalne
vene so rezultati slabši. Ob desni trisekciektomiji
brez resekcije portalne vene je 5-letno preživetje 52 %
in ob desni hemihepatektomiji le 23 %.
Zaključek. Posledici razširjenih kirurških posegov
sta večje število radikalnih resekcij in izboljšano
preživetje bolnikov s tumorji sotočja jetrnih vodov.
Pri bolnikih z nizkim stadijem bolezni, ki zaradi
kronične bolezni jeter ali zajetosti lokalnih žilnih
struktur niso primerni za resekcijsko zdravljenje,
presaditev jeter z neoadjuvantno kemoradioterapijo
omogoča izboljšanje preživetja.Radikalni razširjeni
posegi predstavljajo temelj kirurškega zdravljenja
danes in v bližnji prihodnosti. Vse bolnike s tumorji
sotočja jetrnih vodov mora obravnavati multidisciplinarna skupina strokvnjakov.
INTRODUCTION
Although a relatively rare tumor, hilar cholangiocarcinoma (HC) also known as Klatskin tumor, comprises up to 50–70% of all cases of bile duct carcinomas. Approximately 3–5 new cases per 100,000 are
diagnosed annually in Europe, but the incidence and
mortality are increasing worldwide. The absence of
early symptoms leads to the diagnosis of most HC
tumors at an advanced incurable stage. Only painless
obstructive jaundice indicates rarely earlier stages,
but it is nevertheless often a sign of advanced disease.
Negative resection margins enhanced by major
hepatic resections are associated with improved outcome, but the close vicinity of these tumors to the
portal vein, to the hepatic arteries and the liver
parenchyma is one of the main obstacles to accomplish this goal. There has been a growing recognition
that HC vs. distal cholangiocarcinoma have a distinct
biological behaviour and natural history, as well as a
therapeutic treatment strategy. This has led the latest
(seventh) edition of the American Joint Committee
on Cancer (AJCC) Cancer Staging Manual to divide
perihilar and distal cholangiocarcinoma into distinct
staging subgroups. Distal cholangiocarcinomas have
a close proximity to the pancreatic head; therefore,
portal bifurcation is performed on a regular basis. A
5-year survival of 72% was reported in R0 resected
patients with portal vein resection. Without portal
vein resection 5-year survival was 52% in R0 patients
undergoing right trisectionectomy and 23% in right
hemihepatectomy.
Conclusion. Extended surgical resection resulted in
increased rate of R0 resections and significantly
improved survival. For patients with early stage hilar
cholangiocarcinoma which is unresectable, liver
transplantation with neoadjuvant chemoradiotherapy
provides survival benefit. Extended resections remain
the cornerstone of surgical treatment today and in
near future. Candidates for resection should be considered by a specialized, multidisciplinary team.
their surgical management involves many of the principles applied for pancreatic head cancer.
Intrahepatic cholangiocarcinomas are usually treated
with extended hepatic resection, while surgical management of HC has evolved since its original description due to improvements in preoperative diagnosis
and a multidisciplinary perioperative management.
The improved surgical treatment of HC in the past
decades, not only owes to changed surgical strategy,
but also to better patient selection and improved
preoperative work-up of candidates for resection.
The co-work of endoscopists, interventional radiologists, oncologists and surgeons, has equally contributed to these improved results. Although cholangiocarcinoma can arise anywhere within the biliary
tree, tumors involving the biliary confluence represent the majority of cases, accounting for 50% to
70% of all patients. Patients with HC commonly
present with advanced disease that is not amenable
to surgical treatment, and recurrence rates are high
even after complete resection. However, complete
removal of all cancerous tissues offers HC patients
the only chance for cure and long-term survival.
Almost every patient undergoing potentially curative resection for HC requires a major partial hepaGASTROENTEROLOG 121
tectomy to ensure disease-free resection margins.
However, extensive resections for patients with HC
have been associated with significant morbidity and
mortality rates, which even at high volume centers
are on the order of 10% to 15%.
There appears to be controversy regarding the selection of patients for whom extensive hepatic
resection is indicated, the type of hepatectomy indicated, i.e. right- or left- sided hepatectomy, and
whether routine caudate lobe resection is necessary.
The rationale for surgical treatment requires the
knowledge provided by T-stage of radial and longitudinal malignancy extension, and of N and M
stages. A correct preoperative assessment is often
difficult to achieve. Significant data on lymph node
involvement and correlated prognosis are still lacking in the literature. Surgical choices are now
determined mainly by local extension of disease.
Nowadays resectability criteria differ from those of
the past: vascular involvement with portal and/or
arterial infiltration is not considered any longer as
an absolute contraindication to resection.
The lack of consensus largely arises from the difficulty of diagnosing precisely the proximal
tumour extension before surgical resection or even
during laparotomy. The main purpose of surgical
therapy of HC is to achieve not only curative resection but also to apply the general rules of
oncological surgery which has to succeed in the
following:
– no-touch technique to avoid seeding of the
tumour,
– no intra-operative open tumour biopsy
– liver preserving technique with residual functioning parenchyma of at least 30–40%,
– flank of hepatectomy is indicated by the predominant site of the lesion,
– R0 resection of biliary tract with tumour-free
margin of at least 1 cm on proximal and distal
biliary tract confirmed by frozen section,
– prevention of contamination of the operative
field with bile to avoid cell spreading
– caudate lobe resection, isolated or associated
with extended hepatectomy,
– removal of the lymph nodes and connective
tissues in the hepatoduodenal ligament in
superior retropancreatic space and around the
common hepatic artery.
In the past, hilar cholangiocarcinoma was treated
by biliary tract resection and limited hepatic resection. Recent data in the literature have shown that
associated hepatic resection significantly increases
the rate of R0 resection, with a better long-term
outcome. Postoperative morbidity and mortality
rates after major resection have decreased because
of preoperative improvement of hepatic function
in patients with HC (biliary drainage, portal embolisation), a better selection of patients and an
evolvement of surgical techniques. Surgical option
is determined by tumour stage, and type of procedure selected so, that guarantees a better
probability of curative resection and therefore a
better prognosis.
GENERAL PRINCIPLES
HC remains one of the most difficult management
problems in terms of staging and radical treatment.
It has long been recognised that surgical resection
with complete removal of all cancer tissues offers the
only chance for cure and long-term survival. Several
studies have confirmed the importance of hepatic
resection achieving a negative resection margin.
122 GASTROENTEROLOG
The close relationship of the neoplasm with portal
bifurcation, right hepatic artery and hepatic
parenchyma makes it difficult to achieve the aforementioned principles. Radial spread of the
lesion to surrounding structures is facilitated by
the absence of a muscular layer in the biliary duct.
Infiltrative growth of HC is the most frequent pattern and determines periductal and perineural
extension along the ducts and Glisson spaces.
These are the reasons why wide (>10mm) tumourfree surgical margins must be obtained.
RESECTABILITY ASSESSMENT
Evaluation of patients with HC involves mainly
assessment of resectability, since resection is the
only curative therapy. As a general rule, an R0
resection must be carried out preserving sufficient
vascularised future remnant liver with adequate
biliary drainage.
The definition of resectability has changed in
recent years. Into consideration has to be taken (1):
– physical status of the patient and liver function,
– biliary extent of neoplasm,
– vascular involvement,
– presence of lobe atrophy,
– lymph-node involvement and presence of
distant metastases
margin does not have a statistical significance on survival
compared to negative margin cases (4). When a margin
is positive on frozen section, the biliary resection should
be extend when technically feasible. If HC extends
peripherally to the second segmental ramification of
the second order intrahepatic biliary radicles on both
sides, the patient is considered to be unresectable.
Radial diffusion extends to the hepatoduodenal ligament and to the perivascular connective tissue of
the hepatic artery and portal vein that are close to
the biliary tract. This aspect determines the choice
of type of hepatectomy and likely associated vascular
resection.
VASCULAR INVOLVEMENT
Portal Vein
PATIENT FACTORS
Surgeon has to assess the patient’s general condition
for a major surgical procedure that usually includes
hepatectomy. Resection is generally precluded if the
patient is medically unfit or otherwise unable to tolerate a surgical procedure, or in the presence of
significant co-morbidity and chronic liver disease.
BILIARY EXTENT OF MALIGNANCY
The infiltrative growth of HC includes longitudinal and
radial extension. Longitudinal extension is either mucosal or submucosal and is correlated to the macroscopic
aspect of the neoplasm (2). The former is more frequent
in the papillary or nodular types and can spread 20 mm
beyond the macroscopic margin of the lesion in 40% of
cases; the latter is typical of invasive types and spreads
on average 6 mm. The submucosal invasive type in all
cases spreads less than 10 mm, while the noninvasive
mucosal type is limited to within 20 mm in 90% of the
cases (3). Considering these data, a macroscopic margin
of 10 mm can be considered sufficient for eradication
of invasive HC. However additional removal of any noninvasive component is still required. The presence of invasive carcinoma on the resected margin worsens the
outcome while the presence of carcinoma in situ on the
Portal invasion is generally associated with homolateral
lobar atrophy but it is not considered a contraindication
to resection. Portal resection in advanced cases or in “enbloc” portal resection during extended right hepatectomy
present different results in patient survival.
Portal infiltration may be classified in three histological grades or levels (5):
– Grade 0: no involvement
– Grade I: cancer invasion limited to the tunica
adventitia or media
– Grade II: cancer invasion arriving at the
tunica intima.
Portal resection is a negative prognostic factor but it
improves outcome compared with non-resected
patients. Three and 5-year survival were 26 and 10%,
respectively, in patients with hepatic and portal combined resection, and 54 and 37% in patients who
underwent hepatic resection alone (p<0.0001), respectively. At multivariate analysis, only macroscopic
portal invasion is considered an independent prognostic factor (RR 2.18; p<0.02), while microscopic
invasion is not (5). Portal resection does not increase
complications and mortality rate, which was about
10% (6, 7). More recently similar morbidity rate (48%)
GASTROENTEROLOG 123
was reported in patients who underwent combined
portal resection vs. hepatic resection alone with no
mortality using the “en-bloc resection” technique
before hepatic dissection (8). Neuhaus (7) reported 5year survival of 65% in R0 cases after combined liver
and portal vein resection using the “en-bloc resection”
technique and these results showed that portal resection associated with hepatectomy can improve the
chances of long-term survival. Concerning extension
of portal invasion, the encasement or occlusion of
the main portal vein proximal to its bifurcation, or
bilateral portal venous encasement by cancer are by
most considered a contraindication to resection.
Hepatic Artery
Data on arterial vascular resection are few. Recently
there have been reported cases of hepatic artery
resection, mainly right branch, during extended left
hepatectomy for advanced HC. However, the data on
the prognostic value of such operations are still lacking. Invasion of proper hepatic artery or of the artery
of remnant liver is a contraindication to surgical
resection (9). Although recent reports of major hepatectomy with hepatic artery reconstruction show a
low mortality (0–8%) and that it can be done safely,
this procedure has higher morbidity and mortality
rates than is hepatectomy itself. For this reason, at
present, hepatic artery reconstruction associated
with major hepatectomy is advisable only in the
advanced tumour where R0 resection can be accomplished with arterial resection. The Nagoya study recommends that the only absolute contraindication for
resection is bilateral arterial encasement by HC (6).
Lobar Atrophy
Lobar atrophy is associated with occlusion of the
portal vein supplying the affected liver segment or
section by HC. As s contraindication to surgery is
considered when:
– atrophy of one hepatic lobe with contralateral
portal vein branch encasement or occlusion,
– atrophy of one hepatic lobe with contralateral
tumour extension to secondary biliary radicles,
124 GASTROENTEROLOG
Lymph-Node metastases
Lymph-node metastases are common finding and
are present in more than 50% of the patients with
HC. There was no involvement of lymph nodes in
47% cases, regional and para-aortic involvement was
observed in 35% and 17%, respectively. Survival was
closely related to nodal involvement: 5-year survival
in N0 patients was 31%, 15% in regional N+ and
12% in para-aortic N+ (10). Considering the outcome of patients with para-aortic lymph node metastases, the survival was significantly better in
patients with microscopically positive nodes than in
patients with macroscopically observed involvement
of lymph nodes, with a 5-year survival of 29 vs. 0%,
respectively. Kosuge et al. reported a mean and
median survival of 79 months and 39 months,
respectively, in N0 patients, 52 and 26 months in
regional N+, and 15 and 14 months in N+ beyond
regional. Five-year survival was 38% in N0, 30% in
regional N+ (similar survival, not statistically significant) and 0% at 3-year survival in N+ beyond
regional nodes (11).
To date, performing surgical resection in patients
with wide and macroscopic involvement of nonregional lymph nodes does not appear justified. It
has not yet been proved that extended lymphadenectomy guarantees improvement in survival
in HC but we believe that a methodical nodal dissection of hepatoduodenal ligament and hilum,
proper and common hepatic artery, periduodenal,
retroduodenal, peripancreatic, celiac, paraaortaic
lymph nodes must always be performed associated
with R0 resection, at least until data are more consistent and conclusive.
Extrahepatic Disease
Adjacent extrahepatic organ invasion is not an
absolute contraindication to resection. A concomitant
pancreatic resection is indicated when HC longitudinaly spreads in the lower intrapancreatic bile duct
and/or massive peripancreatic head and pericholedochal lymph nodes metastases are suspected. In
nodal infiltration, pancreatic resection is disputable,
as distant nodal involvement represents a negative
prognostic factor. First reported results of concomitant pancreatic resection for HC had an operative
mortality of 35% and 5-year survival of 6% (12)
mainly because of postoperative hepatic insufficiency, biliary leaks and pancreatic fistula. Two stage
procedure with delayed pancreatic reconstruction was
therefore proposed to decrease the risk of such extensive procedure (13), and mortality rate decreased considerably in small series of patients (14) reported.
Metastatic Disease
Distant metastases diagnosed preoperatively or
intraoperatively presents an absolute contraindication for resection. The only possible exception can
be the occurrence of hepatic metastases limited in
the lobe to be resected, but the prognosis in these
patients is dismal, with no 5-year survival.
Indications for surgical resection
The indication for surgical procedure is based on careful evaluation of the patient’s physical status, hepatic
function and stage of the disease. The strategy of hepatic
resection is defined preoperatively based on knowledge
of longitudinal and radial extension of the malignancy.
Currently, there is no clinical staging system available
that stratifies patients preoperatively into subgroups
based on potential for resection. The modified BismuthCorlette classification (15) stratifies patients based only
on the extent of biliary involvement by tumour, and the
AJCC staging system is based largely on pathological criteria and has little applicability for preoperative staging
or predicting resectability. Jarnagin proposed the preoperative staging system based on local tumour-related
factors that determine resectability: biliary ductal
involvement, vascular involvement, and lobar atrophy.
Unfortunately it does not aid in establishing the type of
resection to perform (16).
Surgical decision-making depends on the assessment of longitudinal infiltration of the biliary duct
that determines which liver segments must be
resected and the type of biliary reconstruction. Vascular invasion is useful for determining the flank
of hepatectomy. The extent of hepatic resection
needs to be evaluated on the basis of the hepatic
function and of the volume of future remnant liver.
Isolated extrahepatic bile duct resection
Isolated extrahepatic resection of the biliary tract
is by some indicated for treatment of Bismuth-Corlette types I and II. The procedure is considered
oncologically inefficient because cholangiography
does not accurately provide information about longitudinal cancer extension and submucosal tumour
extension at proximal margins and skip-type lesions
render assessment by imaging modalities difficult.
Moreover, in the group of patients who undergo
margin-negative resections, hepatic resection is the
only independent predictor of improved survival
on multivariate analysis, suggesting that a more
limited resection is ineffective for complete
tumour clearance (16). There were no 5-year survival among patients who had undergone biliary
resection alone (17). Similar results were reported
by Miyazaki et al with 5-year survival of 0% in
patients with biliary tract resection alone vs. 27%
in patients with additional hepatic resection (18).
In a large series reported by Nimura all patients
who had undergone isolated biliary tract resection
died within 65 months (6). These data were confirmed by others who reported 5-year survival of 0
vs. 35% in patients who had undergone R0 biliary
tract resection alone vs. additional hepatic resection, respectively (19). This type of procedure has
a high recurrence rate (75–90%), mainly on the
proximal resection margin (20).
The indication for this procedure is limited to highrisk patients with tumour in an early stage (T1 and
T2) and accompanied by poor hepatic function. It is
not recommended even as palliative treatment, since
endoscopic and percutaneous drainages are preferred.
GASTROENTEROLOG 125
Autonomous segment 1 resection (S1)
Resection of S1 is always indicated in association with
hepatectomy when the tumour involves biliary confluence. Frequency of involvement of biliary branches of
S1 varies from 48% (21) to 96% (22). Involvement is the
consequence of infiltrative growth along the epithelium
of biliary duct, direct infiltration of parenchyma or
periductal spread in interstitial tissue. The importance
of S1 is now widely accepted (22). 5-year survival of 46%
with hepatectomy and additional S1 resection, and 12%
without S1 resection was reported (23). Isolated S1
resection associated with resection of extrahepatic biliary tract is restricted to the cases with malignancy growing into the biliary bifurcation and is confined between
the right and left hepatic ducts with the sole involvement of the branches to S1. The results of isolated S1
resection do not reach those of more extended hepatic
resections with reported 3-year survival of 30% after isolated S1 resection vs. 75% after right hepatectomy
(p=0.013) (24).
Central hepatic resections
Central hepatectomies consisting of left medial sectionectomy with S1 resection (S1+S4), right anterior
sectionectomy with S1 resection (S1+S5, S8) and central hepatic bisectionectomy with S1 resection (S1+S4,
S5, S8), are proposed mainly by Japanese authors
(6,25). These tissue-sparing hepatectomies should
minimise postoperative risk of hepatic failure in highrisk patients, still maintaining a potentially curative
R0 resection. Resection is generally difficult and time
consuming, while results in two parenchymal section
lines and caudate resection, with increased risk for
bile leak and increased morbidity. Often it is not possible to obtain an adequate length of free margin on
the biliary ducts, because of anatomical realtions.
Preserving the portal bifurcation and especially the
right and left hepatic arteries, leads to oncological
problems of radicality. Right hepatic artery which
runs very close to the biliary confluence presents the
biggest challange for this type of procedure. Biliary
tract reconstruction is complex and requires a greater
number of anastomoses. Shimada et al. compared the
126 GASTROENTEROLOG
results of major hepatectomies with those of central
hepatic resections. Curability rate (R0:R1) was 77%
and 54%, respectively. The results for central resection
were very similar to that of biliary resection alone
(50%). Biliary leaks were more frequent in central
resections (27 vs.3%), caused either by resection line
leaks or by numerous bilio-digestive anastomoses
(4.8±1.8). Mortality rate was 0% in central resections
and 13% in major hepatectomy, and 5-year survival
rates were 15 and 25%, respectively.
The reason for non-curative resection in central resections is almost always inadequate proximal surgical
margin (26) or residual tumour on portal bifurcation
or hepatic artery (27). Central resections should be
limited to high-risk patients in whom the tumour is
confined longitudinally to the right or left hepatic duct
and does not invade any of segmental hepatic ducts.
Extended right resections
When the right hepatic duct or both hepatic ducts are
invaded equally (Bismuth-Corlette types II, IIIa), right
hemihepatectomy or right trisectionectomy are indicated. In cases with hilar infiltration involving right
intrahepatic ducts without extension to segment 4,
right hemihepatectomy with S1resection is indicated.
When infiltration of segment 4 is suspected right trisectionectomy with S1 resection is indicated. These
operations are believed by most authors to guarantee
the highest radicality rate and the best long-term
results, especially when resection of portal bifurcation is performed on a regular basis (19). Right hepatectomy is more likely to be associated with a negative
resection margin because the common bile duct is on
the right side of the hepatoduodenal ligament with
the right hepatic artery close behind its proximal portion. Right hepatic artery is frequently invaded by
cancer at this site, whereas the left and middle
hepatic artery runs on the left side of the ligament
and are not associated with the bile duct until the end
of the transverse portion of the left hepatic duct. The
extrahepatic part of the left hepatic duct is longer (up
to 30 mm), with a more distant segmental ramification, than that of the right hepatic duct.
Therefore dissection is performed away from the
tumour. The portal bifurcation is resected without
dissection close to tumour and an end-to-end anastomosis of the portal trunk to the left portal vein
will result in a straight course of the vessel, reducing the possibility for kinking. The resection line
after right trisectionectomy is short and surface
small. S1 resection can be carried out easily in
patients undergoing right hemihepatectomy. After
portal vein resection, venous reconstruction with
the left than with the right portal vein is technically
less demanding, due to the long umbilical part of
the left portal vein. Implementing “no-touch technique” with right trisectionectomy and portal
resection, Neuhaus et al. reported a 5-year survival
of 72% in R0 resected patients with portal vein
resection vs. 52% in R0 patients with right trisectionectomy and 23% in patients with right hemihepatectomy without portal resection (19).
Extended left resections
The most common indication for left liver resections in HC is spread of the tumour to left segmental biliary ducts thus rendering impossible right trisectionectomy with highest survival rates. When
tumour involves the bifurcation and spreads
towards left intrahepatic ducts left hemihepatectomy with S1 resection is performed. When the
involvement is extended to the right anterior segment left trisectionectomy with S1 resection is the
recommended procedure. Right portal pedicles are
shorter, determining a more demanding portal vein
reconstruction. Right hepatic artery which lies close
to bile duct and tumour, may hamper the procedure
and facilitate tumour seeding during its mobilisation. The right biliary duct is short (5–10 mm)
before its segmental bifurcation, thus reducing the
chance of obtaining an adequate resection margin.
Reported 5-year survival is worse in left-sided procedures than right ones 28 vs. 50% (27) and 34 vs.
44% (22). Most of the studies confirmed those
results and results of survival are significantly better in right than left hepatectomies (p>0.0013) (15).
Liver transplantation for HC
HC was thought to be an ideal indication for liver transplantation in the early days of the transplantation era.
HC as localized lesion in the liver hilum with low
spreading potential, it was thought to be removed completely by extrahepatic bile duct resection combined
with total hepatectomy and replacement of a cadaveric
homograft. Actually, in even palliatively or nontreated
patients a curative resection could be achieved in most
cases by liver transplantation (28,29). Encouraging
oncological surgical results, with perioperative outcome similar to that in patients receiving liver transplantation for other indications, malignant as well as
benign,were followed by disapointing long-term survival. Tumor recurrence was the most common reason
(80%) for death after successful liver transplantation
and there were no survivor 2 years postoperatively (28).
Other authors reported similar results, with high rates
of local tumor recurrence and only a small minority of
patients surviving for more than 2 years (28–30), The
long-term survival was disappointing, even for early
stages of the disease (31). Owing to these disappointing
results and the increasing donor organ shortage,
organs were not allocated to the patients with HC
Based on the biological behavior of hilar cholangiocarcinoma and the rationale of the surgical oncological principle of wide resection margins and “no-touch” technique, the procedure, termed “extended bile duct resection”, was developed. Basically it combined total hepatectomy and liver transplantation with a cephalic pancreatoduodenectomy (32). The surgical radicality of the
procedure was excellent, with a curative resection of 93%
and perioperative mortality of 14%. But, as in series of
cluster transplantation, the majority of the patients in
this study had advanced tumor stages. 60% of patients
treated with this procedure developed tumor recurrence,
mostly local peritoneal carcinomatosis. Compared to the
long-term survival rates after liver transplantation
alone, the long-term survival rate was clearly better, and
reached 45% at 3 years after curative resection (33).
However, due to the improving results after conventional
combined extrahepatic bile duct resection and partial
hepatectomy (34) neither abdominal organ cluster transGASTROENTEROLOG 127
plantation nor extended bile duct resection became commonly used surgical approaches in the treatment of HC.
Current indications for liver
transplantation in HC
Recently reported results have shown increased survival
rates after liver transplantation for hilar cholangiocarcinoma. The latest 1-, 3-, 5- and 10-year-survival rates of
the 201 patients transplanted for hilar cholangiocarcinoma in Europe were 67%, 41%, 31%, and 22%, respectively (35). Iwatsuki et al. reported a series of 27 patients
with hilar cholangiocarcinoma who underwent liver
transplantation, either because of the extent of the
tumor or because of concomitant advanced cirrhosis,
severe sclerosing cholangitis, or both, precluding partial
hepatectomy. The 1-, 3- and 5-year survival rates in
these patients were 59.3%, 36.2%, and 36.2%,respectively. These long-term results included a perioperative
mortality rate of 22.2% (36).
Currently, liver transplantation for the treatment of HC
should be taken into consideration in patients with
underlying liver pathology that precludes liver resection.
In particular, patients with PSC, who have a high incidence of this cancer, may be suitable for transplantation.
Besides the existence of an underlying liver disease or
cirrhosis, the tumor stage may be important for the indication. Recent results have revealed a markedly
improved outcome in patients with early tumor stages
(38). In particular, the absence of nodal involvement and
a locally restricted character of the tumour seems to be
correlated with favorable results after liver transplantation (38,39). However, there are currently no generally
accepted selection criteria for liver transplantation in
patients with HC. Considerations regarding the selection
of patients with malignant hepatic tumors for liver transplantation are largely influenced by the question of
whether such use of cadaveric grafts would penalize
other patients on the waiting list with benign ant other
malignant liver diseases. Living-donor liver transplantation might become one of the answers to this dilemma
in the future. But first the results in the liver-transplanted patients have to justify the risk for the donors.
For further improvement of the results after liver transplantation for HC, interest has been focused on adjuvant and neoadjuvant treatment options over the past
few years. Clinical trials of new protocols in highly
selected patients have shown encouraging results. In a
study patients with lymph node-negative HC received
liver transplantation after neoadjuvant radiochemotherapy. The protocol included brachytherapy delivered
through percutaneous transhepatic catheters and intravenous infusion of 5-FU until transplantation. Five of
the 11 patients (45%) were alive and free of tumor
2.8–14.5 years after transplantation (37).
A study from the Mayo Clinic treated 28 patients with unresectable, localized, and lymph node-negative stage I/II hilar
cholangiocarcinoma with external-beam irradiation,
systemic 5-FU, and brachytherapy with 192-Iridium plus
oral capecitabine before liver transplantation.
Perioperative mortality was 10.7% and recurrence rate
was 14.2%, 22–63 months after transplantation. The 1-,
3- and 5-year survival rates in this cohort were 92%, 82%,
and 82%, respectively, a finding which is comparable to
overall results for liver transplantation and better than survival rates after surgical resection (38). However, only
patients with tumor stages I and II were selected for these
studies. In addition, morbidity after neoadjuvant radiochemotherapy and liver transplantation was considerable.
128 GASTROENTEROLOG
CONCLUSIONS
Surgical resection remains the mainstay of treatment of
HC as of today. Over the last decades, the radicality of
surgery has increased. Since the patient will benefit from
early surgery, the balance of preconditioning and early
surgery is of crucial importance in clinical decision making. Despite the advancement in preoperative diagnosis,
the decision can often only be made intraoperatively.
Right trisectionectomy (segments 4–8 and 1) is a standard procedure for HC Bismuth–Corlette Type III–IV.
This is a straightforward procedure with excellent results
of resectability and survival. However, the function of
liver remnant must often be improved. Portal vein
embolisation helps to achieve hypertrophy of left lateral
section and biliary drainage should be performed also
on remnant liver parenchyma to speed up regeneration
of cholestatic liver remnant. Liver transplantation and
neoadjuvant radiochemotherapy is another step in radicality of surgical treatment of HC. This type of procedure requires vast resources and influences other
patients on a waiting list for liver transplantation. The
results are promising, but further studies are necessary.
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GASTROENTEROLOG 129
Varikozne krvavitve iz zgornjih prebavil
Upper gastrointestinal variceal hemorrhage
Manfred Mervic*, Samo Plut
Klinični oddelek za gastroenterologijo, Interna klinika, UKCL, Ljubljana
Department of gastroenterology, Division of internal medicine, University Medical Centre Ljubljana
Gastroenterolog 2013; suplement 2: 130–134
POVZETEK
ABSTRACT
Varikozna krvavitev iz zgornjih prebavil je najhujši
zaplet portalne hipertenzije. Zdravljenje bolnikov s
krvavitvijo iz varic je zahtevno. Celotno preživetje
bolnikov se je v zadnjih letih izboljšalo, vendar je
umrljivost še vedno tesno povezana z nezmožnostjo
nadzora začetne krvavitve ali zgodnje ponovne
krvavitve. Začetni ukrepi so namenjeni stabiliziranju bolnika: zavarovanje dihalne poti in dovajanje
nadomestkov tekočin. Čim hitreje je treba začeti
zdravljenje z vazoaktivnimi zdravili (terlipresin,
somatostatin in njegovi analogi), saj je zmanjšanje
tlaka v portalnem sistemu povezano z učinkovitejšim nadzorom nad krvavitvijo in olajša kasnejše
endoskopske posege. Pri približno 20 % bolnikov s
krvavitvijo iz varic se med hospitalizacijo razvije
okužba. Antibiotična profilaksa izboljša preživetje.
Zdravila izbora so kinoloni in intravenozni cefalosporini. Endoskopsko zdravljenje izboljša nadzor
nad krvavitvijo in zmanjša tveganje za ponovno
krvavitev ter umrljivost. Ligacija varic je učinkovitejša od skleroterapije. V primeru krvavitve iz varic
želodca so priporočljivi tkivni adhezivi. Pri bolnikih z jetrno cirozo moramo ob postavitvi diagnoze
napraviti gastroskopijo ter ob prisotnosti velikih
varic pričeti s primarno profilakso z zdravili ali
endoskopsko ligaturo (ki jo ponavljamo do eradi-
Variceal bleeding is one of the most severe complications of portal hypertension. Due to high mortality
the management ofvariceal bleeding remains a clinical
challenge.
*Manfred Mervic
Klinični oddelek za gastroenterologijo, Interna klinika, UKCL
Japljeva 2, Ljubljana
130 GASTROENTEROLOG
Although overall survival has improved in recent years,
mortality is still closely related to failure to control initial bleeding or early rebleeding. Initial procedures are
to secure and protect the airway, and administer volume replacement to stabilize the patient. Treatment
with vasoactive drugs should be started as soon as possible, since a reduction in portal pressure is associated
with a better control of bleeding and may facilitate later
endoscopic procedures. Terlipressin, somatostatin and
analogues improve control of bleeding. Approximately
20% of patients with variceal bleeding will suffer from
an infection, when they are hospitalized.
Antibiotic prophylaxis improves survival. Quinolones
or intravenous cephalosporins should be preferred.
Endoscopic therapy increases control of bleeding and
decreases the risks of rebleeding and mortality.
Ligation is more effective than sclerotherapy. In case
of gastric variceal bleeding, tissue adhesives should be
used. Gastroscopy should be performed in all patient
with liver cirrhosis and if large varices are found pri-
kacije). Sekundarno profilakso uvedemo takoj po
končanem zdravljenju akutne varikozne krvavitve.
Zdravili izbora sta propranolol ali karvedilol. Učinkovitost medikamentozne primarne in sekundarne
profilakse je priporočljivo preveriti z invazivnim
merjenjem portalnega tlaka. V sekundarni profilaksi pride v poštev kombinirano zdravljenja in v
primeru neuspešnosti le tega dodatni ukrepi (portosistemski shunt in presaditev jeter).
mary prophilaxis (medical or endoscopical) should be
initiated. Secondary prophylaxis should start as soon
as possible after the discontinuation of the vasoactive
drug used for the treatment of the bleeding episode.
Drugs of choice are propranolol and carvedilol.
Efficacy of prophylaxis should be evaluated by invasive portal pressure measurement. If innitial secondary prophylaxis fails, combination treatment or additional interventions (porto-systemic shunt and liver
transplant) should be considered.
MERILA IN OPREDELITEV PORTALNE
HIPERTENZIJE
Endoskopska ocena varic požiralnika in želodca ali
merjenje HVPG sta diagnostični metodi za odkrivanje klinično pomembne portalne hipertenzije.
Vzrok portalne hipertenzije je v večini primerov ciroza
jeter, manj pogosti vzroki pa so necirotična fibroza
jeter, tromboza portalne vene, obstrukcija jetrnih ven,
policistična bolezen jeter, jetrne metastaze, konstriktivni perikarditis. Najpogostejša vzroka za jetrno cirozo
sta prekomerno uživanje alkohola in virusni hepatitis.
Krvavitev iz varic požiralnika ali želodca je najpomembnejši zaplet portalne hipertenzije. Prva krvavitev
iz varic se v 30 % primerov konča s smrtjo bolnika.
Do zgodnje ponovitve krvavitve v obdobju šestih
tednov po prvi krvavitvi pride pri 40 % bolnikov.
Tveganje ponovitve je največje prvih pet dni, nato
se šest tednov postopoma zmanjšuje in se po tem
obdobju skoraj izenači s tveganjem za krvavitev
pred prvo krvavitvijo. Na tveganje ponovitve močno
vpliva stopnja ciroze in velikost varic.
Tlak v veni porte določimo z vensko kateterizacijo.
Izmerimo prosti tlak v jetrnih venah (Free Hepatic
Venous Pressure - FHVP) in zagozditveni tlak v jetrnih
venah (Wedged Hepatic Venous Pressure - WHVP).
Gradient tlaka jetrnih ven (Hepatic Venous Pressure
Gradient – HPVG) je enak tlaku v portalni veni.
Pri zdravih ljudeh je HPVG < 5 mm Hg, o portalni
hipertenziji pa govorimo, ko se poveča nad to vrednost.
DIAGNOSTIKA PORTALNE
HIPERTENZIJE
Bolnike z jetrno cirozo ob postavitvi diagnoze
gastroskopiramo.
Varice požiralnika in želodca opredelimo kot majhne
(premer < 5 mm) ali velike (premer >5 mm).
Bolnikom s kompenzirano jetrno cirozo brez varic
ponavljamo gastroskopijo na 2-3 leta.
HVPG je trenutno edina učinkovita diagnostična
metoda za spremljenje učinkovitosti farmakološkega zdravljenja portalne hipertenzije.
PREPREČEVANJE NASTANKA VARIC
Dobro zdravljenje osnovne jetrne bolezni lahko
zmanjša portalno hipertenzijo in prepreči njene
zaplete. Spontana regresija varic je redka.
Zdravljenje z neselektivnimi zaviralci receptorjev
beta (Non-selecive Beta-blockers – NSBB) nastanka
varic pri bolnikih s portalno hipertenzijo ne prepreči, zato pri bolnikih brez varic ni priporočljivo.
Klinično pomembna portalna hipertenzija nastane pri
HVPG > 10 mm Hg. Napoveduje nastanek varic požiralnika in želodca in dekompenzacijo jetrne ciroze.
GASTROENTEROLOG 131
PRIMARNA PROFILAKSA
–
Invazivno merjenje HVPG je trenutno edina
učinkovita diagnostična metoda za spremljenje
učinkovitosti farmakološkega zdravljenja portalne hipertenzije. Znižanje HVPG na ≤12 mmHg
ali za ≥ 20 % glede na osnovni tlak, je dokazano
povezano z zmanjšanjem verjetnosti krvavitve.
Povprečni dnevni odmerek s katerimi dosežemo
ciljno zmanšanje HVPG je 80 mg propranolola
in 12,5 mg karvedilola.
–
V centrih, kjer je tovrstna diagnostika na voljo,
je ocena učinkovitosti zdravljenja s NSBB z invazivnim merjenjem HVPG verjetno smiselna.
Vendar pa ker 60 % bolnikov z majhnimi varicami, ki jih zdravimo s NSBB in ciljnega znižanja
HVPG ne dosežemo, v 2 letih ne zakrvavi, invazivna kontrola učinkovitosti v primeru primarne
profilakse ni priporočena. Pri bolnikih z velikimi varicami je invazivno merjenje zaradi
ocene uspešnosti terapije priporočljivo.
–
Ni konsenza o nadaljevanje zdravljenja s
NSBB pri bolnikih, kjer s hemodinamskim
invazivnim merjenjem uspešosti NSBB ne
potrdimo. Vendar pa je možno, da NSBB koristijo tudi pri bolnikih kjer ciljnega znižanja
HVPG ne dosežemo.
Varice požiralnika in želodca opredelimo kot majhne
(premer < 5 mm) ali velike (premer > 5 mm). Dodatne
endoskopske značilnosti (rdeča znamenja) nimajo
prognostične vrednosti in naj ne vplivajo na odločitev
o zdravljenju.
Vse bolnike z velikimi varicami moramo zdraviti z
NSBB ali z endoskopsko ligaturo (Endoscopic Variceal Band Ligation - EVBL). Trenutno ni dokazov ki
bi podpirali kombinirano zdravljenje (NSBB + EVBL)
v smislu primarne profilakse. Primarna profilaksa z
NSBB je (kljub pomanjkanju dokazov) priporočena
tudi pri bolnikih z izoliranimi varicami želodca.
Bolnike s kompenzirano jetrno cirozo in majhnimi
varicami, ki niso zdravljeni z beta blokatorji,
gastrokopiramo vsako leto in spremljemo napredovanje varic. Vendar se lahko tudi pri njih
odločimo za primarno profilakso z NSBB, saj le ta
zmanjša verjetnost krvavitve in napredovanje varic.
Pri bolnikih, ki jih zdravimo z NSBB, endoskopsko presejanje ni potrebno.
Zdravila izbora iz skupine beta zaviralcev sta propranolol ali karvedilol. Podatki kažejo, da je morda
karvedilol učinkovitejši v primarni preventivi varikozne krvavitve. V primeru kontraindikacij za
zdravljenje z NSBB, če jih bolniki ne prenašajo ali
pa le ti niso učinkoviti, je v primeru velikih varic
indicirana EVBL.
Nadzor uspešnosti zdravljenja z NSBB
–
Odmerek NSBB postopno zvišujemo do zmanjšanja srčne frekvence v mirovanju za 25 %
(vendar ne ≤ 50/min) ali dokler ne postanejo
simptomatski do maksimalnega dnevnega
odmerka (propranilol 160 mg/dan, karvedilol
25 mg/dan). Nekateri od teh bolnikov (a ne vsi)
bodo zaščiteni pred krvavitvijo iz varic. Ocena
uspešnosti NSBB z zmanjšanjem srčne frekvence
ne korelira z zmanjšanjem portalnega tlaka ali
manjšo verjetnostjo krvavitve.
132 GASTROENTEROLOG
Endoskopska skleroterapija, vstavitev transjugularnega intrahepatalnega portosistemskega shunta
(TIPSS) ali zdravljenje z isosorbid-5-mononitratom
(ISMN) za primarno profilakso niso priporočeni.
ZDRAVLJENJE AKUTNE KRVAVITVE
IZ VARIC
Osnovni cilji zdravljenja krvavitve iz varic požiralnika
in želodca so:
– korekcija hipovolemije in hemodinamska stabilizacija
– čim hitrejša zaustavitev krvavitve
– preprečevanje ponovne zgodnje krvavitve
(znotraj 72 ur)
– preprečevanje zapletov povezanih s krvavitvijo
Predpogoji za zdravljenje:
– prostori in oprema za stalno hemodinamsko
monitorizacijo bolnika (dobro usposobljeni specializirani intenzivni oddelek)
– stalno merjenje saturacije krvi s kisikom
– nastavitev iv. kanala za hemodinamsko stabilizacijo in zdravljenje šoka
– intubacija pred endoskopskim posegom pri
masivni in hemodinamsko nekontrolirani krvavitvi iz varic, hepatični komi (III. In IV. stopnje),
nezmožnosti vzdrževanja saturacije krvi s kisikom nad 90 %, pri sumu na aspiracijo
Nadomeščanje krvi
– kri nadomeščamo previdno in vzdržujemo koncentracijo hemoglobina med 70–80 g /l oz. več
glede na bolnikovo starost, pridružene bolezni,
hemodinamski status, aktivnost krvavitve.
– sistolni tlak naj bo 90–100 mm Hg, srčna frekvenca 100/min ali manj
– nadomeščanje trombocitov in zdravljenje koagulopatije ni potrebno. Bolnike z močno iztirjeno
koagulacijo T<30000/mikroL ali pč <0,3 lahko
zdravimo z koncentriranimi trombociti ali svežo
zmrznjeno plazmo
– zdravljenje z rekombinantnim faktorjem VIIa
ni smiselno
Antibiotično zdravljenje
– je pomemben del zdravljenja varikozne krvavitve
– krvavitev iz varic je v 30–40 % povezana z okužbo
– preventivno zdravljenje z antibiotiki je priporočljivo takoj ob ugotovitvi krvavitve in pred
endoskopskim zdravljenjem.
– zdravljenje znižuje število bakterijskih okužb,
zmanjšuje možnost ponovne krvavitve in umrljivost
– zdravimo z amoksicilinom in klavulansko kislino
1,2 g/8 ur iv ali z norfloksacinom 2 x 400 mg p.o
ali ceftriaksonom 1g na dan i.v. Zdravljenje naj
traja 7 dni.
Zdravljenje hepatične encefalopatije
– bolnike s prisotno hepatično encefalopatijo zdravimo z laktulozo ali visoko klizmo
–
učinek preventivnega zdravljenja hepatične
encefalopatije z laktulozo ni dokazan
SPECIFIČNI UKREPI
Farmakološko zdravljenje
– pri sumu na krvavitev iz varic začnemo takoj
in pred endoskopskim posegom z zdravljenjem z vazoaktivnimi zdravili
– zdravila dajemo v kontinuirani infuziji ali v
obliki iv injekcij
1. Somatostatin 250 mcg iv v bolusu, nato 250 mcg/h
v infuziji (v primeru hude krvavitve npr. aktivna
krvavitev ob endoskopiji, lahko uporabimo dvojni
odmerek)
2. Oktreotid 50 mcg iv v bolusu, nato 50 mcg/h v
infuziji
3. Terlipresin 2 mg iv/ 4 ur, nato, če bolnik ne krvavi
več po 24 urah 1 mg iv /4 ure
– zdravljenje nadaljujemo do 5 dni po začetku
krvavitve.
Endoskopsko zdravljenje
– bolnike z varikozno krvavitvijo endoskopiramo
čim prej po hemodinamski stabilizacijo oz.
najkasneje 12 ur po sprejemu v bolnišnico
– bolnikom z blago in hemodinamsko nepomembno krvavitvijo, ki ne potrebujejo transfuzije
lahko napravimo elektivno gastroskopijo
– ligacija varic je priporočena metoda zdravljenja. Skleroterapija je primerna, če je ligacija
varic tehnično prezahtevna zaradi pogojev
med posegom
– endoskopsko zdravljenje s tkivnim adhezivom
je priporočeno pri krvavitvi iz varic želodca.
Pri krvavitvi iz varic požiralnika jo uporabimo le v izjemnih primerih nekontrolirane
krvavitve.
– eritromicin lahko izboljša vidljivost med endoskopijo
GASTROENTEROLOG 133
Zgodnja vstavitev TIPS v primeru neuspeha endoskopskega zdravljenja (v prvih 72 urah):
– bolniki z jetrno cirozo Child C in varikozno
krvavitvijo (vendar Child-Pugh score <14)
– bolniki z jetrno cirozo Child B in aktivno varikozno krvavitvijo med endoskopijo kljub
zdravljenju z vazoaktivnimi zdravili in antibiotiki
– bolniki z HVPG ≥20 mm Hg in akutno varikozno krvavitvijo
– pred posegom je potrebno upoštevati standardne
izključitvene kriterije (srčno popuščanje, tehnične
kontraindikacije)
– akutna hepatična encefalopatija ni kontraindikacija za vstavitev TIPS
V primeru kontraindikacij za medikamentozno
zdravljenje, napravimo bolnikom EVBL. Zdravljenje s ISMN ni alternativa NSBB. V primeru kontraindikacij za EVBL je zdravjenje izbora kombinirana terapija z NSBB in ISMN.
Zdravljenje bolnikov, ki so iz varic zakrvaveli
kljub sekundarni profilaksi
–
Pri bolnikih z nizkim tveganjem za ponovno
krvavitev (začetna jetrna bolezen) ponovno
poskusimo napraviti EVBL. Če kljub kombiniranem zdravljenju (NSBB + EBVL) bolnik vsaj
dvakrat ponovno zakrvavi, je indicirana vstavitev
TIPSS. V redkih primerih je potrebna operativna
vzpostavitev portosistemskega shunta. Kirurška
devaskularizacija je rešilna terapija če ostale možnosti niso učinkovite ali možne.
–
Pri bolnikih z visokim tveganjem za ponovno
krvavitev je indicirana vstavitev TIPSS, če
kljub kombiniranem (NSBB + EBVL) zdravljenju vsaj 2x ponovno zakrvavijo. Rekurentne
krvavitve so indikacija za transplanatacijo jeter.
SEKUNDARNA PROFILAKSA
S sekundarno profilakso pričnemo čimprej, idealno
6. dan po krvavitvi (ali prenehanju zdravljenja z
vazoaktivnimi zdravili).
Terapija izbora je kombinirano zdravljenje z NSBB
in EVBL. Podatki pridobljeni iz študij na področju
primarne profilakse kažejo na to, da je karvedilol
verjetno vsaj enako učinkovit kot propranolol.
LITERATURA
Monoterapija z NSBB je zadostno zdravljenje, če
lahko učinek NSBB preverimo z invazivnim merjenjem HVPG. Bolnike, pri katerih s terapijo z NSBB
ne dosežemo zadostnega učinka pride v poštev kombinacija NSBB in ISMN, ob kontoli HVPG. Če
učinek še vedno ni zadosten je potrebna EVBL.
Propranolol titriramo do minimalno 80 mg/dan v
2–3 odmerkih. Karvedilol titriramo do minimalno
12.5 mg/dan v 2 odmerkih. EBVL pričnemo po
2–3 tednih in jih ponavljamo do popolne eradikacije varic. Majhne rezidualne varice po EBVL so še
sprejemljiv rezultat.
Bolniki z napredovalo jetrno boleznijo, ki so krvaveli iz varic, so potencialni kandidati za presaditev
jeter. Z sekundarno profilakso nadaljujemo do presaditve. TIPSS je smiselno napraviti bolnikom
uvrščenim na čakalno listo za presaditev jeter.
134 GASTROENTEROLOG
1. Garcia-Tsao G, Bosch J, Groszmann R. Portal hypertension and
variceal bleeding, unresolved issues. Summary of an American
Association for the study of liver disease and European
Association for the study of the liver single-topic conference.
Hepatology 2008;47:1764–1772.
2. Grace ND, Groszmann RJ, Garcia-Tsao G, Burroughs AK, Pagliaro
L, Makuch RW, et al. Portal hypertension and variceal bleeding: an
AASLD single topic symposium. Hepatology 1998;28:868–880.
3. de Franchis R; Baveno V Faculty. Revising consensus in portal
hypertension: report of the Baveno V consensus workshop on
methodology of diagnosis and therapy in portal hypertension. J
Hepatol. 2010 Oct;53(4):762–8.
4. Austrian Consensus on the Definition and Treatment of Portal
Hypertension and its Complications M. Peck-Radosavljevic1, M.
Trauner2, F. Schreiber2 (for the Austrian Society of Gastroenterology
and Hepatology.Endoscopy 2005; 37(7): 667–673
Kaj storiti pri nevidnem karcinomu v
reseciranem želodcu?
How to deal with invisible carcinoma in the
resected stomach?
Metka Volavšek*, Nina Zidar
Inštitut za patologijo Medicinske fakultete Univerze v Ljubljani
Gastroenterolog 2013; suplement 2: 135–137
Ključne besede: želodec, nevidni rak, biopsijski rak, patologija
Key words: stomach, invisible cancer, biopsy cancer, pathology
POVZETEK
ABSTRACT
Kadar v biopsiji želodčne sluznice odkrijemo karcinom brez makroskopsko (endoskopsko) vidne lezije,
govorimo o »biopsijskem« ali »nevidnem« karcinomu.
Takšni primeri so redki in zahtevajo skrbno obdelavo
ter dobro sodelovanje med klinikom in patologom.
V prispevku predstavljava dva bolnika, pri katerih
je bila ob gastroskopiji odvzeta biopsija in ugotovljen
adenokarcinom. Pri obeh je bila narejena resekcija
želodca, vendar pri rutinskem histopatološkem pregledu v odstranjenem želodcu nismo našli karcinoma.
Po dodatnem odvzemu številnih vzorcev in ponovnem
pregledu prvotnih biopsij smo pri enem bolniku
našli majhen rezidualni intramukozni pečatnocelični adenokarcinom. Pri drugem bolniku kljub
pregledu številnih vzorcev nismo našli karcinoma.
Ponovni pregled biopsije je potrdil nedvomno prisotnost karcinoma, kar je kazalo z veliko verjetnostjo, da
je bil karcinom z endoskopsko biopsijo v celoti
odstranjen. Obravnava bolnikov z nevidnim karcinomom je zahtevna in bo uspešna le ob dobrem
sodelovanju med klinikom in patologom.
When we detect cancer in gastric mucosa biopsy sample without macroscopic (endosopic) visible lesion we
talk about »invisible«or»biopsy«cancer. Such cases are
rare and require a good cooperation between the
clinical physician and pathologist. In this paper we
present two patients, who underwent gastroscopy
and whose biopsy revealed adenocarcinoma. In both
cases, the gastric resection was performed, but the
pathohistological examination of the resected stomach did not confirm the carcinoma. After additional
sample taking and patohistological examination of
a number of samples we found a small residual
intramucosal signet cell adenocarcinoma in one of
the patients. In the case of the second patient we did
not find cancer, despite examination of many additional samples.
Review of the biopsy samples confirmed the presence of carcinoma, which suggests that the cancer
was completely removed. Treatment of patients with
invisible carcinoma is challenging and will only be
successful in a good cooperation between the clinician and pathologist.
*doc. dr. Metka Volavšek, dr. med.
Inštitut za patologijo Medicinske fakultete Univerze v Ljubljani
Korytkova 2, 1000 Ljubljana
GASTROENTEROLOG 135
UVOD
Karcinom želodca je kljub napredku pogosto odkrit
v napredovalem stadiju, zato so uspehi zdravljenja in
preživetje še vedno slabi. Naš cilj je zato odkriti čim
več bolnikov v čim bolj zgodnjem stadiju bolezni (1).
Poseben izziv so zato tisti bolniki, pri katerih je karcinom odkrit tako zgodaj, da še ni makroskopsko
(endoskopsko) vidne lezije. Tak karcinom imenujemo »biopsijski« ali »nevidni« karcinom (iz angl.:
biopsy cancer, invisible cancer) (2). Običajno gre za
bolnike z gastritisom, pri katerih je bila odvzeta biopsija naključno oz. predvsem zaradi opredelitve
gastritisa in morebitne okužbe s helikobaktrom.
O pogostnosti nevidnega (biopsijskega) karcinoma
želodca je v literaturi malo podatkov. Kim in sod. (3)
so v 8-letnem obdobju med 633 bolniki obravnavali 5
takih primerov (0,8 %), napoved bolezni je bila v tej
seriji odlična. Nekateri avtorji menijo, da v takih primerih radikalno kirurško zdravljenje ni vedno nujno
potrebno, svetujejo predvsem endoskopsko mukozno
ali submukozno resekcijo in fotodinamično terapijo (2).
Obravnava takih bolnikov zahteva predvsem dobro
sodelovanje med patologom in klinikom, sicer
lahko pride do neprijetnih zapletov. Predstavljava
dva bolnika, pri katerih v reseciranem želodcu ni
bilo makroskopsko vidnega karcinoma.
Primer št. 1
Pri 45-letnem bolniku je bila zaradi več mesecev trajajočih dispeptičnih težav narejena gastroskopija, odvzeta
sta bila dva biopsijska vzorca antralne sluznice, v katerih je bila blaga fibroza, v epiteliju pa atipije, sumljive
za blago displazijo. Helikobaktrov nismo našli. Čez en
mesec je bila gastroskopija ponovljena, odvzetih je bilo
več biopsij, v katerih smo našli znake blago aktivnega
kroničnega, HP pozitivnega pangastritisa z blago intestinalno metaplazijo. V vzorcih iz angularne gube je bil
prisoten intramukozni pečatnocelični adenokarcinom.
En teden po zadnji gastroskopiji je bila narejena
resekcija želodca. Pri pregledu reseciranega želodca
136 GASTROENTEROLOG
nismo našli makroskopsko vidnega tumorja ali kakih
drugih sprememb. Za histopatološki pregled smo
odvzeli tkivne vzorce po protokolu in vse bezgavke,
vendar tumorja nismo našli, v 34 pregledanih
bezgavkah ni bilo zasevkov. Ponovno smo pregledali
prvotno biopsijo in še enkrat potrdili diagnozo intramukoznega pečatnoceličnega adenokarcinoma.
Odvzeli smo številne dodatne vzorce in v 106. vzorcu
našli droben intramukozni pečatnocelični adenokarcinom, ki je meril v premeru 7 mm.
Primer št. 2
83-letni bolnik z avtoimunskim gastritisom je bil sprejet v bolnišnico zaradi hematemeze. Pri gastroskopiji
so našli dva hemoragična polipa in jih odstranili.
Histološki pregled je pokazal, da gre za erodirana
hiperplastična polipa, v enem je bil prisoten tudi
intramukozni adenokarcinom intestinalnega tipa. Po
odstranitvi polipov se je krvavitev večkrat ponovila,
zato je bila narejena gastrektomija. Pri pregledu reseciranega želodca smo našli nekoliko stanjšano,
zglajeno sluznico v korpusu in več slabo zamejenih
področij zadebeljene sluznice. Makroskopsko vidnega
tumorja nismo našli. Mikroskopski pregled je pokazal spremembe, značilne za avtoimunski gastritis. V
korpusu je bilo tudi več hiperplastičnih polipov, v
antrumu pa nevroendokrini tumor premera do 3 mm
(mikrokarcinoid). Kljub pregledu številnih vzorcev
nismo našli karcinoma ali displazije, v bezgavkah ni
bilo zasevkov. Zaprosili smo za ponovni pregled biopsije, ki je bila opravljena v drugi ustanovi, in še enkrat
potrdili prisotnost intramukoznega adenokarcinoma
intestinalnega tipa v enem od odstranjenih hiperplastičnih polipov. Področje resekcijskega roba je bilo
delno poškodovano, vendar je zelo verjetno potekalo
v zdravem tkivu, kar je kazalo na možnost, da je bil
karcinom odstranjen endoskopsko.
RAZPRAVA IN ZAKLJUČKI
Opisana dva primera kažeta na možne probleme pri
obravnavi bolnikov z nevidnim rakom želodca, pri
katerih je bila na osnovi biopsijsko potrjene diagnoze
narejena kirurška resekcija želodca, v reseciranem
želodcu pa ni bilo makroskopsko (endoskopsko)
vidne lezije.
Da se izognemo neprijetnim zapletom, je potrebno
dobro sodelovanje med patologom in kliničnim
zdravnikom in dosledno upoštevanje strokovne
doktrine (3, 4).
1. Pri vsaki endoskopski biopsiji je nujno potreben podatek o mestu odvzema, če je biopsij
več, morajo biti za vsako lokalizacijo (npr. korpus, antrum, angularna guba) poslane ločeno
in jasno označene.
2. Potrebujemo tudi podatke o predhodni biopsiji: v kateri ustanovi je bila narejena, kje je
bila odvzeta in kakšna je bila histopatološka
diagnoza. Koristno je, če je mesto predhodne
biopsije na resektatu označeno.
Možnih vzrokov, da karcinoma v resektatu ne najdemo, je več (3).
1. Pri zelo majhnem karcinomu je vedno mogoče,
da je bil karcinom odstranjen endoskopsko in
ga zato v reseciranem organu ne najdemo.
2. Čeprav pri vsakodnevnem delu patologi strogo
upoštevamo veljavno strokovno doktrino, v literaturi vsi aspekti niso povsem jasno opredeljeni.
Tako npr. ni jasnih navodil, koliko dodatnih
vzorcev je potrebno, če po pregledu vzorcev v
skladu z veljavno doktrino karcinoma ne najdemo. Ta odločitev je prepuščena patologu.
3. Vedno je potrebno upoštevati tudi možnost, da
je prišlo do zamenjave vzorcev na kateremkoli
nivoju (pri odvzemu biopsije na kliniki ali pri
obdelavi biopsijskih vzorcev in izvidov na
oddelku za patologijo). Če strogo upoštevamo
veljavne protokole, do zamenjave ne sme priti. V
izjemnih primerih lahko s pomočjo genetskih
testov preverimo, ali tkivni vzorec pripada domnevnemu bolniku ali ne. Zanesljivost sodobnih
testov, ki jih pri nas opravljajo na Inštitutu za
sodno medicino Medicinske fakultete v Ljubljani
pa tudi v drugih ustanovah, je približno 98 % (5).
V primeru »biopsijskega« karcinoma, ki je odkrit
naključno, brez makroskopsko vidne lezije, priporočajo čimprejšnjo ponovitev gastroskopije (»second
look ali rescue endoscopy«) in biopsije (6), po možnosti v treh dneh, saj naj bi bilo mesto predhodne
biopsije tri dni po odvzemu še prepoznavno. Pomembno je tudi število odvzetih biopsijskih vzorcev, saj
občutljivost biopsijske diagnostike karcinoma narašča
s številom vzorcev: pri 4 do 6 vzorcih znaša za želodčni karcinom med 93 % in 97 % (7, 8). K uspešnosti
pripomore tudi uporaba sodobne tehnologije (9).
Z opisanimi primeri dveh bolnikov sva želeli opozoriti na pomen natančne obravnave na vseh nivojih,
s katerimi lahko preprečimo neprijetne zaplete pri
obravnavi resekcije večjih organov zaradi zgodnjega
karcinoma in se izognemo napakam, pa tudi nepotrebnim dolgotrajnim in dragim postopkom.
LITERATURA
1. Fuchs CS, Mayer RJ. Gastric carcinoma. N Engl J Med 1995;
333: 32–41.
2. Rabenstein T, May A, Gossner L, Manner H, Pech O, Günter E,
et al. Invisible gastric carcinoma detected by random biopsy:
long-term results after photodynamic therapy. Endoscopy 2008;
40: 899–904.
3. Kim ES, Jeon SW, Park SY, Park YD, Chung YJ, Yoon SJ, et al.
Where has the tumor gone? The characteristics of cases of negative pathologic diagnosis after endoscopic mucosal resection.
Endoscopy 2009; 41: 739–45.
4. Kim, ES, Jeon SW. Unfound gastric signet ring-cell adenocarcinoma after gastric biopsy. Reply. Endoscopy 2009; 42: 430.
5. Solis-Munoz P, Solis-Herruzo J A, Lopez-Alonso G, et al. Unfound
gastric signet ring-cell adenocarcinoma after gastric biopsy.
Endoscopy 2010; 42: 429–30.
6. Simone A, Casadei A, De Vergori E, et al. Rescue endoscopy to
identify site of gastric dysplasia or carcinoma found at random
biopsies. Dig Liver Dis 2011; 43: 721–25.
7. Lal N, Bhasin DK, Malik AK, Gupta NM, Singh K, Mehta SK.
Optimal number of biopsy specimens in the diagnosis of carcinoma of the oesophagus. Gut 1992; 33: 724–6.
8. Voutilainen ME, Juhola MT. Evaluation of the dignostic accuracy
of gastroscopy to detect gastric tumors: clinicopathological features and prognosis of patients with gastric cancer missed in
endoscopy. Eur J Gastroenterol Hepatol 2005; 17: 1345–9.
9. Yalamarthi S, Witherspoon P, McCole D, Auld CD. Missed diagnoses in patients with upper gastrointestinal cancers. Endoscopy
2004; 36: 874–9.
GASTROENTEROLOG 137
Zakaj je diagnoza okužbe s
citomegalovirusom v prebavilih težavna?
Why is it difficult to diagnose cytomegalovirus
infection in gastrointestinal tract?
Nina Zidar*, Katja Tepeš
Inštitut za patologijo Medicinske fakultete Univerze v Ljubljani
Gastroenterolog 2013; suplement 2: 138–141
Ključne besede: citomegalovirus, prebavila, diagnoza,
imunosupresija
Keywords: cytomegalovirus, gastrointestinal tract,
diagnosis, immunosuppression
POVZETEK
ABSTRACT
Citomegalovirus (CMV) je pomemben povzročitelj
bolezni prebavil, zlasti pri imunosuprimiranih bolnikih in pri kritično bolnih, redko tudi pri sicer
zdravih osebah. Klinične in endoskopske značilnosti so nespecifične. Diagnozo postavimo iz
biopsije na podlagi celic velikank z jedrnimi inkluzijami z videzom sovjega očesa, vendar so le-te v
prebavilih, zlasti v debelem črevesu, pogosto maloštevilne in ne povsem značilnega videza. V takih
primerih lahko diagnozo postavimo s pomočjo
imunohistokemične preiskave. Imunohistokemično preiskavo za dokaz CMV je zato potrebo
opraviti pri vseh imunosuprimiranih bolnikih in
pri vseh z nepojasnjenimi ulkusi in erozijami v prebavilih. Zaradi opisanih značilnosti je diagnostika
CMV bolezni v prebavilih zahtevna in bo uspešna
le ob dobrem sodelovanju med kliniki in patologi.
Cytomegalovirus (CMV) is an important human
pathogen affecting gastrointestinal tract. It occurs
mainly in immunocompromised and critically ill
patients, only seldom in otherwise healthy subjects.
Clinical and endoscopic features are nonspecific.
The diagnosis is made by patohistological findings
of giant cells with basophilic nuclear inclusions
(owl’s eye). However, in gastrointestinal tract, particularly in colon mucosa, those findings are often
scarce and lack the characteristic appearance. In
such cases, the diagnosis is made by means of
immunohistology, which should be performed in
all immunocompromised patients as well as in all
patients with etiologically unexplained ulcers and
erosions. Because of these characteristics the diagnosis of CMV infection in the gastrointestinal
tract presents challenge and requires good cooperation between clinicians and pathologists.
*prof. dr. Nina Zidar, dr. med.
Inštitut za patologijo Medicinske fakultete Univerze v Ljubljani
Korytkova 2, 1000 Ljubljana
138 GASTROENTEROLOG
UVOD
Virus citomegalije (CMV), imenovan tudi humani
herpesvirus 5 (HHV-5), spada v poddružino betaherpesvirusov. CMV povzroča okužbe povsod po
svetu, pri osebah vseh starosti, brez sezonskega
nihanja in epidemij. Primarna okužba povzroči pri
osebah z normalnim imunskim odzivom infekcijski
mononukleozi podobno bolezen z neznačilnimi
znaki in simptomi, kot so slabo počutje, zvišana
telesna temperatura, povečane bezgavke, jetra in
vranica ter limfocitoza, ki večinoma mine brez
zapletov. Pri osebah z zmanjšanim imunskim odzivom ima hujši potek in se lahko konča smrtno.
Najslabšo napoved ima intersticijska pljučnica, retinitis, encefalitis, hepatitis in pankreatitis (1, 2).
Po primarni okužbi preide CMV v latentno obliko:
virusna DNK je prisotna v mnogih celicah, npr. v
endotelijskih celicah, makrofagih in mieloidnih
progenitorskih celicah. Virus se lahko kasneje
kadarkoli reaktivira in povzroči simptomatsko bolezen, zlasti v stanjih zmanjšane imunske odzivnosti.
Prekuženost odraslih je visoka, v razvitem svetu
med 40 % in 100 %, in narašča s starostjo (3-5).
Reaktivacija CMV pri zmanjšani imunski odzivnosti lahko prizadene različne organe in vodi v
nastanek pljučnice, hepatitisa, retinitisa, kolitisa,
encefalitisa. Prebavila, še posebej debelo črevo, so
med najpogosteje prizadetimi organi (3). Kljub
mnogim raziskavam je v zvezi s prizadetostjo prebavil pri reaktivaciji CMV še mnogo nejasnosti,
npr. kateri so klinični in histopatološki diagnostični kriteriji, katere diagnostične metode so
optimalne in katere bolnike je potrebno zdraviti s
protivirusnimi zdravili (6, 7).
KLINIČNE, MAKROSKOPSKE IN
MIKROSKOPSKE ZNAČILNOSTI
OKUŽBE S CMV V PREBAVILIH
Okužba s CMV prizadene v prebavilih najpogosteje
debelo črevo, redkeje požiralnik in želodec, izjemoma ustno votlino in žrelo (8-11). Običajno gre
za reaktivacijo virusa. Prizadetost prebavil je lahko
izolirana ali del sistemske CMV bolezni. Ogroženi
so predvsem imunosuprimirani bolniki, npr. po
presaditvi organov ali kostnega mozga, pri zdravljenju s kortikosteroidi, citostatiki, pri okužbi s
HIV, pa tudi kritično bolni (npr. bolniki s sepso,
cirozo, opeklinami (12–14). Posebej ogroženi so
tudi bolniki s kronično vnetno boleznijo, zlasti tisti
z ulceroznim kolitisom, ki so zdravljeni s kortikosteroidi (3, 7). V novejšem času opozarjajo, da
lahko klinično pomembna CMV bolezen v prebavilih prizadene tudi sicer zdrave osebe (15, 16).
Klinična slika je neznačilna. Pri prizadetosti požiralnika je najpogostejši znak bolečina pri požiranju, pri
prizadetosti želodca pa nekateri navajajo kot značilni
znak posturalno bolečino v epigastriju, ki je najbolj
intenzivna v stoječem položaju, blažja v sedečem in
najblažja v ležečem položaju, ter upočasnjeno praznjenje želodca (17, 18). Pri kolitisu je najpogostejši
klinični znak driska, krvavitev in bolečine v trebuhu.
CMV okužbo prebavil pogosto spremljajo tudi slabost,
bruhanje, zvišana telesna temperatura in izguba telesne teže, kot zaplet se lahko razvije perforacija (19).
Makroskopske (endoskopske) spremembe so nespecifične: pri večini bolnikov so prisotne erozije ali ulkusi,
ulkusi so pogosto multipli in veliki (slika 1A in B).
Lahko so prisotni tudi eritem (slika 1A), edem sluznice,
zadebeljene sluznične gube, vnetni polipi (11, 20, 21).
Slika 1. Levo: operacijski preparat sigmoidnega črevesa
pri bolnici z ishemično boleznijo srca in CMV kolitisom:
eritem sluznice in ulkusi. Desno: operacijski preparat
debelega črevesa pri bolnici s Crohnovo boleznijo, pri
kateri je prišlo do reaktivacije CMV in perforacije črevesa: multipli obsežni ulkusi.
GASTROENTEROLOG 139
Mikroskopsko so za CMV bolezen diagnostične
velike celice z bazofilnimi jedrnimi in/ali citoplazmatskimi inkluzijami s halojem (videz sovjega očesa),
ki jih z lahkoto prepoznamo, za potrditev je priporočljivo opraviti imunohistokemično reakcijo (slika
2A in B). Značilne celice velikanke z inkluzijami pa
so v prebavilih, zlasti v debelem črevesu, pogosto
maloštevilne. Kambham in sod. (22) so analizirali
gostoto CMV-pozitivnih celic v debelem črevesu pri
bolnikih z ulceroznim kolitisom z reaktivacijo CMV
in ugotovili nizko gostoto – le 0,01 do 2.65 celic/mm2.
Poleg tega po naših izkušnjah v prebavilih, zlasti v
debelem črevesu, pogosto ne najdemo značilnih celic
velikank z virusnimi inkluzijami. V literaturi na to
značilnost CMV kolitisa opozarjajo le redki avtorji.
Kambham in sod. (22) so pri 10 bolnikih z imunohistokemično potrjenim CMV kolitisom našli značilne
virusne inkluzije pri treh bolnikih, atipične inkluzije
pri treh bolnikih, pri ostalih bolnikih pa v biopsijskih vzorcih niso opazili inkluzij.
Slika 2. CMV gastritis pri bolniku s plazmocitomom in
amiloidozo, zdravljenem s citostatiki. Levo: epitelijska
celica z značilno jedrno inkluzijo in granulirano citoplazmo. Desno: pozitivna imunohistokemična reakcija na
CMV v epitelijski celici z inkluzijo v jedru in citoplazmi.
V biopsijskem vzorcu pogosto vidimo le povsem
neznačilne spremembe, predvsem proliferacijo granulacijskega tkiva v dnu erozij ali ulkusov (slika 3A). V
teh primerih nam pravilno diagnozo omogoči imunohistokemična preiskava, ki je lahko pozitivna tudi v
celicah, ki nimajo jasno vidnih inkluzij ali pa so le-te
majhne in komaj opazne (slika 3B). Imunohistokemično preiskavo na CMV je zato potrebno narediti pri
vseh imunosuprimiranih bolnikih, pa tudi pri tistih,
ki imajo v prebavilih nepojasnjene erozije ali ulkuse.
140 GASTROENTEROLOG
Slika 3. CMV kolitis pri bolnici s Crohnovo boleznijo.
Levo: proliferacija granulacijskega tkiva v dnu ulkusa,
brez značilnih celic z inkluzijami. Desno: pozitivna imunohistokemična reakcija na CMV v endotelijski celici v
eni od kapilar v granulacijskem tkivu.
DIAGNOSTIKA OKUŽBE S CMV V
PREBAVILIH
Za ugotavljanje okužbe s CMV je na voljo več metod
z različno občutljivostjo in specifičnostjo (23), ki jih
lahko izvajamo na vzorcih krvi, seruma, levkocitov,
izoliranih iz periferne krvi, telesnih tekočin ali na
tkivnih vzorcih. Metode, ki se izvajajo na vzorcih
krvi ali levkocitov, imajo v diagnostiki CMV bolezni
v prebavilih omejeno vrednost, ker je CMV bolezen
v prebavilih običajno posledica reaktivacije pri seropozitivnih osebah in ker običajno ni del sistemske
CMV okužbe. Nudijo le podatke o predhodni izpostavljenosti CMV in identificirajo osebe, pri katerih
lahko pride do reaktivacije virusa (24, 25).
Reaktivacijo CMV v prebavilih lahko zanesljivo ugotovimo le s histopatološkim pregledom tkivnega vzorca.
Histopatološka diagnoza temelji na celicah velikankah
z virusnimi inkluzijami. Slabost je predvsem v majhni
občutljivosti (10–87 %) (3), saj so značilne inkluzije
maloštevilne in v biopsiji lahko niso zajete, poleg tega
so v prebavilih pogosto neznačilne (atipične) in jih ne
prepoznamo (25–27). Če ob histopatološkem pregledu
biopsije naredimo tudi imunohistokemijo ali in situ
hibridizacijo, naraste občutljivost na pribl. 93 % (3, 25,
26, 28). Pri tem običajno uporabimo komercialna protitelesa proti zgodnjemu jedrnemu antigenu, ki se
pojavi 9 do 96 ur po okužbi oz. reaktivaciji virusa. Pozitivna imunohistokemična preiskava torej kaže na
zgodnjo aktivno virusno replikacijo (22, 29).
Novejša priporočila svetujejo tudi uvedbo kvantitivne tkivne PCR (verižne reakcije s polimerazo) (25),
ki je sicer najbolj natančna in občutljiva metoda za
dokazovanje virusne okužbe, vendar zaenkrat še ni
jasnih priporočil o uporabi te metode pri CMV bolezni, saj pozitivna reakcija pomeni prisotnost virusa
(latentna okužba), ne pa tudi aktivne bolezni (3, 30).
ZAKLJUČEK
Reaktivacija CMV v prebavilih je pomembne vzrok
obolevnosti in umrljivosti zlasti pri imunosuprimiranih in kritično bolnih, posebej ogroženi so bolniki
s kronično vnetno črevesno boleznijo, zdravljeni s
kortikosteroidi. Klinična in endoskopska slika sta
običajno neznačilni. Zanesljivi način diagnostike reaktivacije CMV v prebavilih je biopsija. Značilne celice
velikanke z virusnimi inkluzijami v prebavilih, zlasti
v debelem črevesu, pogosto niso prisotne, zato je
potrebno narediti imunohistokemično preiskavo za
dokaz CMV pri vseh imunosuprimiranih bolnikih in
pri vseh z nepojasnjenimi ulkusi in erozijami v prebavilih. Zaradi opisanih značilnosti je diagnostika
CMV bolezni v prebavilih zahtevna in bo uspešna le
ob dobrem sodelovanju med kliniki in patologi.
LITERATURA
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8. Lemonovich TL, Watkins RR. Update on cytomegalovirus infections of the gastrointestinal system in solid organ transplant
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et al. Endoscopic diagnosis of cytomegalovirus gastritis after allogeneic hematopoietic stem cell transplantation. World J
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Yamamoto K. Specific endoscopic features of ulcerative colitis
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23. Roblin X, Pillet S, Oussalah A, Berthelot P, Del Tedesco E,
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26. Lawlor G, Moss AC. Cytomegalovirus in inflammatory bowel disease:
pathogen or innocent bystander? Inflamm Bowel Dis 2010; 16: 1620–7.
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factor in refractory and complicated inflammatory bowel disease.
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GASTROENTEROLOG 141
Slovenske smernice za preprečevanje
neželenih učinkov nesteroidnih
protivnetnih zdravil, antiagregacijskih in
antikoagulantnih učinkovin na prebavila
in srčno žilni sistem
Slovenian guidelines for prevention of
non-steroidal anti-inflammatory,
anti-aggregation and anticoagulant agents
related adverse effects on gastrointestinal and
cardiovascular system
Borut Štabuc*, B. Tepeš, P. Skok, M. Vujasinovič, A. Blinc, M. Čerček, M. Tomšič
KO za gastroenterologijo, UKC Ljubljana
Gastroenterolog 2013; suplement 2: 142–145
POVZETEK
ABSTRACT
Neželene učinke nesteroidnih protivnetnih (NSAR),
antiagregacijskih in antikoagulantnih učinkovin
lahko preprečimo s smotrnim predpisovanjem, z
eradikacijo okužbe z bakterijo helikobakter pilori in
z zaviralci protonske črpalke (ZPČ). NSAR ne prepisujemo bolnikom z visokim tveganjem za gastrointestinalne ali srčno žilne zaplete.
Adverse effects of nonsteroidal anti-inflammatory
(NSAIDs), anti-aggregation and anticoagulant agents
can be prevented by rational prescribing, the eradication of infection with the bacterium Helicobacter
pilori and proton pump inhibitors (PPIs). NSAIDs
should not be prescribed to patients at high risk for
gastrointestinal or cardiovascular complications.
Prior to long-term antiplatelet therapy diagnosis and
treatment of infection with Helicobacter pilori is
recommended. Antiplatelet and anticoagulant therapy is generally not interrupted. In patients at
increased risk for adverse effects in the upper
gastrointestinal tract, PPI should be prescribed in
the standard dose of 20 mg of omepazole, esomeprazole or pantoprazole daily or 15 mg of lansopazole daily.
Pred dolgotrajnim antiagregacijskim zdravljenjem se
priporoča ugotavljanje in zdravljenje okužbe s helikobakter pilori. Aniagregacijskega in antikoagulantnega
zdravljenja praviloma ne prekinjamo. Bolnikom z večjim tveganjem za neželene učinke na zgornjih prebavilih preventivno predpisujemo ZPČ v standardnem
odmerku 20 mg/dan omeprazola, esomeprazola in
pantoprazola ali 15 mg/dan lansoprazola.
* Prof. dr. Borut Štabuc, dr. med.
KO za gastroenterologijo, UKC Ljubljana
Japljeva 2, 1000 Ljubljana
142 GASTROENTEROLOG
S povzetkom priporočil, ki so rezultat skupnega
dela gastroenterologov, revmatologov, kardioologov
in družinskih zdravnikov želimo osvežiti znanje
slovenskih zdravnikov pri preprečevanju in predpisovanju tovrstnih učinkovin in ZPČ.
These guidelines are a product of the joint effort of
gastroenterologists, rheumatologists, cardiologists
and family physicians and are intendet to refreshen
the knowledge of Slovenian doctors in the prevention and prescribing of these agents and PPIs.
INTRODUCTION
Most common side effects include dyspepsia, erosions, duodenal/gastric ulcer and gastrointestinal
hemorrhage. Life-threatening complications such as
perforation, peptic ulcer bleeding and gastrointestinal obstruction occur in 1.5% of patients. The overall mortality rate due to NSAID adverse effects on
the gastrointestinal tract is 1 to 2%.
The use of non-steroidal anti-inflammatory (NSAID),
anti-aggregation and anticoagulant agents is associated with many side effects that increase morbidity, mortality and hospital admission rate, especially in elderly patients.
Based on their mechanism of action, NSAIDs are
subclassified into classical (diclofenac, ibuprofen,
indomethacin, naproxen and ketoprofen), which
inhibit cyclooxygenase 1 and 2 (COX-1 and COX-2),
partially selective COX-2 NSAIDs (meloxicam,
nimesulide, etodolac), which in therapeutic doses
inhibit COX-1 at a lesser degree than classical NSAIDs
and COX-2-selective coxibs (celecoxib, etoricoxib),
which selectively inhibit COX-2.
Oral anti-aggregation agents are subclassified into cyclooxygenase inhibitors (ASA), phosphodiesterase
inhibitors (dipyridamole) and ADP receptor P2Y12
blockers (thienopyridines (ticlopidine, clopidogrel,
prasugrel) and ticagrelor). PAR1 thrombin receptor
blockers are beeing developed (currently at the stage
of clinical trials). Glycoprotein receptor IIb/IIIa inhibitors are only available in parenteral form.
Oral anticoagulation medicines are subclassified into
vitamin K antagonists (warfarin) and direct oral
anticoagulants (dabigatran (thrombin inhibitor),
rivaroxaban and apiksaban (factor Xa inhibitor)).
Adverse effects depend of the type of substance, dosage,
combination therapy and duration of treatment.
Incidence and severity of adverse effects is significantly
affected by concomitant treatment with glucocorticoids,
anti-aggregation and anticoagulant agents as well as comorbidity and individual patient characteristics.
All NSAIDs are cardiotoxic and may increase the risk
of arterial hypertension, congestive heart failure,
thrombosis, heart attack and stroke. It is estimated
that 20% of hospital admissions of patients with congestive heat failure is related to NSAIDs usage.
As some NSAIDs (due to competitive binding to
COX-1) prevent acetylsalicylic acid (ASA) to irreversibly bind to COX-1, patients requireing combination therapy should be advised to take ASA at least
2 hours before the traditional NSAIDs.
Prevention of NSAID and ASA related
adverse effects on gastrointestinal system
according to the degree of risk for
cardiovascular complications (table 1).
Risk factors for adverse events include: age over 65
years, history of gastrointestinal symptoms in the
upper gastrointestinal tract, history of peptic ulcer
disease (PUD), history of gastrointestinal bleeding,
maximum dose of NSAID, concomitant administration of ASA (low dose), anticoagulant therapy,
corticosteroids or selective serotonin reuptake inhibitors (SSRI) and infection with bacterium
Helicobacter pylori (HP).
Patients without risk factors for gastrointestinal
adverse events present the low risk group. Those
with one or two risk factors are at medium risk while
GASTROENTEROLOG 143
those with three or more or those who have had an
ulcer complication as well as those receiving concomitant anticoagulation therapy fall into the category
of high risk.
Half of all PUD of the upper gastrointestinal tract is
caused by HP infection. HP infection increases the
risk of NSAID and ASA related complications of ulcer
disease. Slovenian Association of Gastroenterology
and Hepatology therefore recommends HP testing,
eradication therapy as well as confirmation of successful eradication prior to long-term treatment with
NSAID or ASA. All patients recieving NSAID, anticoagulant and anti-aggregation agents with a history
of ulcer disease or complications after an ulcer should
be tested aswell.
Table 1. Prevention of NSAID and ASA related adverse
effects on gastrointestinal system according to the degree
of risk for cardiovascular complications.
Low risk for
cardiovascular
disease
High risk for
cardiovasculat
disease
(concomitant use
of ASA)
Low risk for ulcer
disease
complications
classical NSAID
(HP-eradication)
naproksen <1g +
PPI + HPeradication
Medium risk for
ulcer disease
complications
classical
NSAID+PPI
or coxib
(HP-eradication)
naproksen < 1g +
PPI + HPeradication
High risk for
ulcer disease
complications
coxib + PPI + HP- no NSAID; PPI +
eradication;
HP-eradication;
continuous
continuous
monitoring
monitoring
Prevention of anti-aggregation and
anticoagulant therapy related adverse
effects on gastrointestinal system
Patients on dual antiplatelet therapy are at 2 to 3
fold higher risk of gastrointestinal bleeding (GIB)
compared to those recieving ASA only. PPI significantly reduces the risk of GIB due to clopidogrel
particularly in patients with more than three risk
factors. Recent prospective studies did not confirm
144 GASTROENTEROLOG
the increased risk of cardiovascular complications
(cardiovascular death, myocardial infarction, stroke)
and thrombosis in coronary stents in patients recieving PPI (regardless of the substance) and clopidogrel/prasugrel. CYP2C19 polymorphism does not
correlate with an increased risk of cardiovascular
complications and thrombosis in coronary stents.
Studies have shown that combination therapy of
ASA and heparin or low molecular weight heparin
(LMWH) increase the risk of GIB for 50%.
Triple therapy (ASA, clopidogrel and anticoagulant)
presents a 3.2 to 6.6 fold increased risk of GIB
(when compared to dual antiplatelet therapy) and
should be prescribed only in indications with proven benefits of this type of treatment. In case of tripple therapy including warfarin, international normalised ratio (INR) should be between 2 and 2.5.
In patients with high or very high risk of thromboembolic complications and concomitant high risk invasive
procedure (risk of bleeding), oral anticoagualtion
should be stopped and temporary LMWH should be
temporary introduced. Sometimes intravenous platelet
receptor IIbIIIa inhibitor eptifibatide is used as well, although there are no evidence-based recommendation.
The minimal duration of dual antiplatelet therapy
(ASA and one of the P2Y12 receptor inhibitors) after
an acute coronary syndrome is 1 month in patients
who received a bare metal stent (BMS) and 6 months
in patients who received a drug eluting stent (DES).
As long-term dual antiplatelet therapy is needed after
DES placement, patients with three or more risk factors for GIB should not receive DES. In these
patients, concomitant use of NSAID and glucocorticoids should be avoided. Treatment with standard
dose PPI significantly reduces the risk of bleeding
from the upper gastrointestinal tract (Table 2).
In case of GIB, dual antiplatelet therapy is not interrupted. If however it has already been interrupted, it
should be re-introduced in three or at latest in seven
Table 2. Prevention of anti-aggregation and anticoagulant
therapy related adverse effects on gastrointestinal system
Dual antiplatelet
Dual antiplatelet
therapy +
therapy
anticoaguation*
Low risk for ulcer
disease
complications
PPI
Medium risk for
ulcer disease
complications
PPI
PPI
High risk for
ulcer disease
complications
PPI; continuous
monitoring
PPI; continuous
monitoring,
consider benefit
vs. risk
days. A cardiology consult should be sought before
ommiting antiplatelet therapy. In case of severe and
life threatening GIB, where endoscopical or radiological treatment fails, platelet transfusion could be
beneficial (however there is no clear evidence it is
effective). Use of recombinant factor VIIa is not recommended due to increased risk of stent thrombosis.
In the case of gastrointestinal bleeding in patients on
triple therapy, warfarin should be replaced with
LMWH, clopidogrel and ASA therapy should not be
interrupted. Treatment in such patients should be discussed by a multidisciplinary team of gastroenterologists and cardiologists.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
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GASTROENTEROLOG 145
Vnetne in rakaste bolezni kože zaradi
anti-TNF zdravil pri bolnikih s kroničnimi
vnetnimi črevesnimi boleznimi
Inflammatory and cancerous skin lesions in
inflammatory bowel disease patients treated
with anti-tnf therapy
Andreja Ocepek*, Cvetka Pernat Drobež
Oddelek za gastroenterologijo, Klinika za interno medicino, Univerzitetni klinični center Maribor
Department for gastroenterology, Clinic for internal medicine, University medical center Maribor
Gastroenterolog 2013; suplement 2: 146–148
UVOD
INTRODUCTION
Bolezenske spremembe kože sodijo med najpogostejše stranske učinke zdravljenja z anti-TNF zdravili.
(1–6) Dosedanje raziskave so pokazale, da se pri bolnikih s kroničnimi vnetnimi črevesnimi boleznimi
(KVČB), pojavijo pri približno 20–25 %. (1, 4, 5)
Med kožnimi odzivi na anti-TNF zdravila najpogosteje srečamo reakcije na mestu injiciranja, okužbe
kože, ne-melanomski rak kože in psoriaza, redko pa
pride do pojava sindroma podobnega lupusu, Stevens-Johnsonovega sindroma, eritema multiforme in
toksične epidermalne nekroze. (6) Predstavljamo
skupino bolnikov s KVČB, ki smo jih v naši ustanovi
zdravili z anti-TNF zdravili in pri katerih so se pojavile vnetne in rakaste bolezni kože.
Skin lesions are most frequently observed adverse
reactions to anti-TNF therapy. (1–6) In inflammatory bowel disease (IBD) patients their incidence is
20–25%. (1, 4, 5) Most common skin side effects of
anti-TNF are injection site reactions, cutaneous
manifestations of infusion reactions, cutaneous
infections, non-melanoma skin cancer, and psoriasis.
Rare lesions include lupus-like syndrome, StevensJohnson syndrome, erythema multiforme and toxic
epidermal necrolysis. (6) We present our group of
IBD patients treated with anti-TNF therapy who
developed inflammatory or cancerous skin lesions.
METODE
Medical charts of all IBD patients treated with anti-TNF
therapy from january 2007 to february 2013 were
retrospectively reviwed, in search of inflammatory
or cancerous skin lesions as side effects of therapy.
Opravili smo retrospektivno analizo medicinske
dokumentacije vseh bolnikov s KVČB, ki smo jih
zdravili z anti-TNF zdravili od januarja 2007 do
februarja 2013, s poudarkom na vnetnih in rakastih
boleznih kože kot stranski učinek te vrste zdravljenja.
METHODS
* Andreja Ocepek, dr. med.
Oddelek za gastroenterologijo, Klinika za interno medicino, Univerzitetni klinični center Maribor
Ljubljanska 5, 2000 Maribor
146 GASTROENTEROLOG
REZULTATI
RESULTS
V raziskavo smo zajeli 125 bolnikov, 65 moških in 60
žensk, povprečne starosti 42,2 let (od 24,3 do 70,6 let).
Pri 18 bolnikih (14,4 %), 10 moških (55,6 %) in 8 ženskah (44,4 %), je prišlo do stranskih učinkov na koži.
11 bolnikov (61,1 %) smo zdravili zaradi Chronove bolezni in 7 bolnikov (38,9 %) zaradi ulceroznega kolitisa. Pri 16 bolnikih (12,8 %) so se pojavile vnetne bolezni kože in sicer psoriaziformni izpuščaji pri 7 bolnikih
(38,9 %), ekcematoidni izpuščaji pri 3 bolnikih (16,7 %),
neopredeljene kožne spremembe pri 3 bolnikih (16,7 %)
in druge spremembe (alopecija, hiperkeratoza, bulozni
pemfigoid) pri 3 bolnikih (16,7 %). Pri večini bolnikov
(9 oz. 50 %) smo kožne spremembe opazovali na koži
udov, pri 3 bolnikih (16,7 %) na trupu, 1 bolnik (5,5 %)
je imel spremembe na trupu in udih, 1 bolnica (5,5 %)
na obrazu, pri 2 bolnikih (11 %) je bilo prizadeto lasišče.
Odkrili smo 3 primere bazoceličnega karcinoma
(BCC) pri 2 bolnikih (1,6 %), pri bolniku na infliksimabu
na koži nosu in pri bolnici na adalimumabu na koži
hrbta in ingvinalnega področja. 12 bolnikov (77,8 %)
je prejemalo infliksimab, 4 bolniki (22,2 %) adalimumab, 2 bolnika (11,1 %) pa zaporedno obe zdravili. Povprečni čas od uvedbe anti-TNF zdravila do pojava kožnih sprememb je bil 14,9 mesecev (2 do 39 mesecev).
Vsi bolniki so bili pregledani pri dermatologu, oba bolnika z BCC pa pri plastičnem kirurgu, ki je vse 3 karcinome odstranil v zdravo. Le pri 1 bolniku (5,5 %) z
buloznim pemfigoidom smo morali anti-TNF zdravilo
ukiniti, pri vseh ostalih bolnikih smo zdravljenje nadaljevali, kožne spremembe pa so izginile ali se omilile
po lokalnem dermatološkem zdravljenju.
In study we included 125 IBD patients, 65 male and 60
female, with average age 42,2 years (24,3 to 70,6 years).
18 patients (14,4%), 10 male (55,6%) and 8 female
(44,4%), developed skin side effects. 11 patients
(61,1%) were treated for Chron's disease and 7 patients
(38,9%) for ulcerative colitis. In 16 patients (12,8%) inflammatory skin lesions were found, psoriasiform lesions in 7 patients (38,9%), eczematiform lesions in
3 patients (16,7%), undefined lesions in 3 patients
(16,7%) and other lesions (alopecia, hyperkeratosis, bullous pemphigoid) in 3 patients (16,7%). Most frequently
skin lesions affected arms and legs (in 9 patients or
50%), only trunk was affected in 3 patients (16,7%),
trunk, arms and legs were affected in 1 patient (5,5%),
only face in 1 patient (5,5%) and scalp in 2 patients
(11%). 3 cases of basocellulare carcinoma (BCC) were
discovered in 2 patients (1,6 %), on the nose in a male
patient on infliximab and on the back and in the inguinal region in a female patient on adalimumab. 12
patients with skin side effects (77,8%) were treated with
infliximab, 4 patients (22,2%) with adalimumab and
2 patients (11,1 %) with both drugs consecutively. Skin
lesions developed after a median time of 14,9 months
(2 to 39 months) after initiating anti-TNF therapy. All
patients were refered to a dermatologist, both patients
with BCC were operated by a plastic surgeon, and all
3 lesions were removed with a clean safety margin. In
one patient (5,5%) with bullous pemphigoid anti-TNF
therapy had to be stopped, in all other patients therapy was continued, and skin lesions disappeared or were
alleviated by topical dermatological therapy.
ZAKLJUČEK
CONCLUSIONS
Kožne spremembe so pogost stranski učinek anti-TNF
zdravil. V skupini naših bolnikov s KVČB smo tovrstne
zaplete zdravljenja ugotovili pri 14,4 % bolnikov. Le v 1
primeru (5,5 %) smo morali anti-TNF zdravilo ukiniti,
pri vseh ostalih bolnikih je zadoščalo lokalno dermatološko zdravljenje. Oba bolnika z BCC sta bila uspešno
kirurško zdravljenja in pod rednim nadzorom s strani
plastičnega kirurga nadaljujeta z anti-TNF zdravljenjem.
Skin side effects are frequent in patients treated with
anti-TNF agents. In our group of IBD patients inflammatory and cancerous skin lesions developed in
14,4% of patients. Only in one patient (5,5%) anti-TNF
therapy wos stopped, in all other patients topical dermatological therapy was sufficient. Both patients with
BCC were treated surgicaly and are continuing with
anti-TNF therapy under surgical surveillance.
GASTROENTEROLOG 147
LITERATURA/REFERENCES
1. Cleynen I, Vermeire S. Paradoxical inflammation induced by anti-TNF
agents in patients with IBD. Gastroenterol Hepatol. 2012;9:496–503.
2. Moustou AE, Matekovits A, Dessinioti C, Antoniou C, Sfikakis PP,
Stratigos AJ. Cutaneous side effects of antietumor necrosis factor biologic
therapy: A clinical review. J Am Acad Dermatol. 2009;61(3):486–504.
3. Miehsler W, Novacek G, Wenzl H, Vogelsang H, Knoflach P, et al.
A decade of infliximab: The Austrian evidence based consensus on
the safe use of infliximab in inflammatory bowel disease. J Chrons
Colitis. 2010;4:221–56.
4. Fidder H, Schnitzler F, Ferrante M, Noman M, Katsanos K, et al. Longterm safety of infliximab in the treatment of inflammatory bowel
disease: a single center cohort study. ECCO ABSTRACTs. 2007;3.
5. Guerra I, Algaba A, Pérez-Calle JL, Chaparro M, Marín-Jiménez
I, et al. Induction of psoriasis with anti-TNF agents in patients
with inflammatory bowel disease: A report of 21 cases. J Chrons
Colitis. 2012;6:518–23.
6. Mocci G, Marzo M, Papa A, Armuzzi A, Guidi L. Dermatological
adverse reactions during anti-TNF treatments: Focus on inflammatory bowel disease. J Chrons Colitis. 2013; In Press.
148 GASTROENTEROLOG
The sign of Leser-Trélat - a case report
Miroslav Vujasinović*,1, Slobodan Vujasinović2, Nebojša Djurišić3, Tajda Keber4
1 Slovenj Gradec General Hospital, Department of Internal Medicine
2 Center for Dermatology
3
Izola General Hospital, Department of Dermatology
4 Medical Faculty at the University of Maribor
Gastroenterolog 2013; suplement 2: 149
ABSTRACT
The Leser-Trélat sign is characterized by the sudden
appearance and rapid increase in both the size and
number od seborrheic keratoses. Existence of the sign
of Leser-Trélat should prompt a search for underlying
malignancy.
Adenocarcinoma is the most common malignant
neoplasm (approximately 67%) associated with this
paraneoplastic syndrome (the sign of Leser- Trélat).
The most common primary tumor site is gastrointestinal tract (approximately 72%).
We present a case of Leser-Trélat sign in patient with
colon adenocarcinoma. Sixty-five years old patient
with history of benign prostatic hyperplasia was presented in dermatology ambulance due to the skin
changes on his back. All changes have been operated
and histopathology showed sebborhoic keratosis. Due
to the sudden onset of sebborheic keratosis a further
gastroenterology work-up was suggested. There were
no pathologic findings in internal clinical examination and laboratory tests (including tumor markers).
A colonoscopy was performed and a rectosigmoid
tumor was found. Histology showed adenocarcinoma.
Abdominal ultrasound and plain chest radiography
were normal. Patient underwent operative procedure
without complication. Pathologic staging of adenocarcinoma was T1N0M0. Five years after operation
the patient’s clinical status is normal.
* Miroslav Vujasinović, MD MSc
Department of Internal Medicine, Slovenj Gradec General Hospital, Gosposvetska 1
Slovenj Gradec 2380, Slovenia
GASTROENTEROLOG 149
Vpliv klinične poti na izid zdravljenja
bolnikov z akutnim pankreatitisom
Impact of clinical pathway on treatment
outcome in patients with acute pancreatitis
Miroslav Vujasinović*,1, Apolon Marolt1, Bojan Tepeš2, Jana Makuc1, Zdenko Kikec1, Nace Robač1
1 Department of Internal Medicine, Slovenj Gradec General Hospital
2 Abakus Medico Diagnostic Centre
Gastroenterolog 2013; suplement 2: 150–152
UVOD
INTRODUCTION
Akutni pankreatitis (AP) je eden najpogostejših
razlogov za hospitalizacijo med boleznimi prebavil,
povezan je z visoko stopnjo umrljivosti in visokimi
stroški zdravljenja.
Acute pancreatitis (AP) is one of the most common
reasons for hospitalization among all gastrointestinal
diseases, and is associated with high mortality and costs
of treatment.
BOLNIKI IN METODE
PATIENTS AND METHODS
Opredeliti učinek klinične poti (KP) in nadzor nad
kazalci kakovosti (KK) zaradi ocene uspešnosti
zdravljenja bolnikov z AP.
To determine the impact of clinical pathway (CP) and
control of indicators of quality (IOQ) on the outcome
of treatment in patients with AP.
KP je bila sestavljena iz naslednjih KK: odvzem vseh
potrebnih laboratorijskih preiskav ob sprejemu (vključno z lipidogramom in transferinom z zmanjšanim
deležem ogljikovih hidratov), določitev etiologije AP,
ultrazvok trebuha (UZ) narejen znotraj 24 ur po sprejetju v bolnišnico, opravljena računalniška tomografija
(CT) trebuha v primerih z sumom na nekrozo, vendar
ne prej kot po 48 urah po sprejemu v bolnišnico, uporaba antibiotične terapije, uporaba protibolečinske
terapije, ustreznost hidracije, kontrola vitalnih parametrov in morebitna premestitev v intenzivno enoto
(IU), opravljena endoskopska retrogradna holangio-
CP consisted of the following IOQ: performance of
all laboratory tests on admission (including lipids
and carbohydrate deficient transferrin), determination of etiology of AP, ultrasound of the abdomen
(US) performed in the first 24 hours after admission
to hospital, contrast-enhanced computed tomography (CECT) of the abdomen in all cases of suspected
necrosis but not in the first 48 hours after admission, appropriate use of antibiotic therapy, pain control, appropriate hydration, control of hemodynamic
parameters and transfer to the Intensive Care Unit
(ICU) if necessary, performing of endoscopic retro-
* Miroslav Vujasinović, MD MSc
Department of Internal Medicine, Slovenj Gradec General Hospital, Gosposvetska 1
Slovenj Gradec 2380, Slovenia
150 GASTROENTEROLOG
pankreatikografija (ERCP) pri bolnikih z biliarno etiologijo, morebitno kirurško zdravljenje, nasveti in
spremljanje bolnikov po odpustu.
Po uvedbi klinične poti za AP je vsa medicinska
dokumentacija mesečno analizirana na oddelčnih
sestankih s poudarkom na najpogostejših pomanjkljivostih zdravljenja.
Primerjali smo rezultate dveh časovnih obdobij v
Splošni bolnišnici Slovenj Gradec: pred (2006–2007)
in po (2010–2012) sprejetju klinične poti za AP.
Primerjali smo dolžino ležalne dobe v naši bolnišnici
z ležalno dobo v drugih bolnišnicah.
grade cholangiopancreatography (ERCP) in all patients
with biliary etiology, surgical treatment if necessary,
advice of outpatient follow-up in all patients after
discharge.
All medical records after the introduction of CP are
analyzed monthly and are discussed at the departmental meeting with emphasis on the most common
deficiencies of the treatment.
We compared results of two periods in our centre:
before (2006-2007) and after (2010-2012) implementation of CP.
Comparison of length of stay with that in other
Slovenian hospitals was performed.
REZULTATI
V treh letih po sprejemu klinične poti smo zdravili
139 bolnikov: 81 (58,3 %) moških in 58 (41,7 %)
žensk, povprečne starosti 59,6 ±17,3 let.
Najbolj pogosta etiologija AP je bil alkohol in žolčni kamni (38,8 % oboje), sledi nepojasnjeni AP
(11,5 %), z zdravili povzročen AP, hipertrigliceridemija, zaplet po ERCP (2,9 % vsi) in tumorji (2,2 %).
Povprečna starost bolnikov z alkoholno etiologijo
je bila 50 ±12,6 let in so bili skoraj 17 let mlajši kot
bolniki z etiologijo žolčnih kamnov (t-test=12.819,
p=0,000).
Etiologija bolezni je bila povezana s spolom bolnika
(Fisher exact test = 44.329, p = 0.000): žolčni kamni
so bili značilno več prisotni pri ženskah (61 %) kot pri
moških (39 %); ravno obratno je pri alkoholnem pankreatitisu, ki ga je bistveno več pri moških (89 %) kot pri
ženskah (11 %), Chi-square =39.398, df=3, p=0,000.
Uporaba antibiotikov je po uvedbi klinične poti
pomembno upadla (od 70,3 % na 51,8 %; p=0,003).
Ni bilo statistično pomembne razlike v umrljivosti
(1,8 % proti 2,9 %).
Trajanje hospitalizacije je na našem oddelku v primerjavi s slovenskim povprečjem izrazito krajše
(p=0,018).
RESULTS
There were 139 patients treated in the three-year
period after introduction of CP: 81 (58.3%) male
and 58 (41.7%) female, mean age 59.6±17.3 years.
The most common etiologies were alcoholism and
gallstones (38.8% each), followed by unexplained
(11.5%), drug-induced, hypertriglyceridemia, post
ERCP (2.9% each) and tumors (2.2%).
Mean age of patients with alcoholic etiology was
50±12.6 years and were almost 17 years younger
than patients with etiology of gallstones (t-test = 12.819,
p =0.000).
The etiology of the disease was found to be associated
with gender of the patient (Fisher exact test = 44.329,
p = 0.000): gallstones were found significantly more
often in females (61%) than in males (39%) and alcoholic
pancreatitis was significantly more frequent with males
(89%) than females (11%).
Antibiotic therapy was prescribed in 72 (51.8%) of
patients.
The most frequent morphological condition was
interstitial edematous pancreatitis in 60.4% of
patients, followed by acute peripancreatic fluid collection (25.9%), necrotizing pancreatitis (12.2 ) and
pancreatic pseudocysts (1.4%).
GASTROENTEROLOG 151
ZAKLJUČEK
Uvedba klinične poti za obravnavo AP in nadzor
nad kazalci kakovosti so izboljšali zdravljenje bolnikov z AP v vseh opazovanih parametrih: zmanjšala
se je ležalna doba, manj je nepojasnjenega AP,
upadla je uporaba antibiotikov (brez sprememb v
umrljivosti).
Abdominal US was performed in all patients in the
first 24 hours.
CE CT was performed in 57 (41%) patients.
One hundred and five (75.5%) patients had one
attack of AP.
Thirty-two (23.0 ) patients were treated in ICU.
Four patients died (2.9%).
We found an increase in the number of alcoholic and
gallstone pancreatitis on the account of a decrease in
unexplained etiology in 2010–12, compared to 2006–7.
The differences in the structure are statistically significant (Chi-square =39.398, df= 3, p=0.000).
The use of antibiotics significantly decreased after
implementation of CP (from 70.3% to 51.8%; p=0.003).
There was no statistically significant difference in
mortality between two periods (1.8% vs. 2.9%).
Length of stay in Slovenj Gradec General Hospital is
significantly shorter compared to Slovenian average
(p=0.018).
CONCLUSIONS
Introduction of CP and control of IOQ has improved
the treatment of patients with AP in all observed
parameters: reduced length of stay, reduced percentage of unexplained cases, reduced use of antibiotic
therapy (without changes in total mortality)
152 GASTROENTEROLOG
Ali so bolniki na antikoagulantni terapiji
ustrezno zaščiteni pred krvavitvijo iz
zgornjih prebavil?
Are patients on anticoagulants adequately protected
against upper gastrointestinal bleeding?
Milica Miljković*,1, Miroslav Vujasinović1, Martin Tretjak1, Apolon Marolt1, Bojan Tepeš2, Karmen Klančnik3
1 Department of Internal Medicine, Slovenj Gradec General Hospital
2 Abakus Medico Diagnostic Centre
3
Medical Faculty at the University of Maribor
Gastroenterolog 2013; suplement 2: 153–154
IZHODIŠČA
BACKGROUND
Zaradi velike pojavnosti srčno žilnih obolenj, ki
povzročajo trombembolične zaplete, se bolnikom
pogosto predpiše antikoagulacijsko zdravljenje s
peroralnimi antikoagulacijskimi zdravili (AZ). AZ
so povezana s povečanim tveganjem za krvavitev iz
zgornjih prebavil, še posebej pri starejših bolnikih
s sočasno predpisanimi acetilsalicilno kislino (ASK),
klopidogrelom, kortikosteroidi, nesteroidnimi analgoantirevmatiki (NSAR) in zaviralci privzema
serotonina (SRI). Zaviralci protonske črpalke (ZPČ)
so zdravila, ki omogočajo učinkovito zaščito pred
krvavitvami iz zgornjih prebavil.
Due to the high prevalence of cardiovascular diseases
anticoagulant medications (AC) are commonly prescribed. Treatment with AC is related to an increased
incidence of acute upper gastrointestinal bleeding
(AUGIB) especially in older patients and concomitant
treatment with acetylsalicylic acid (ASA), clopidogrel,
corticosteroids, nonsteroidal anti-inflammatory drugs
(NSAID) and serotonin reuptake inhibitors (SRI).
Proton pump inhibitors (PPI) are drugs with good
protective effect against AUGIB.
NAMEN IN METODE
A retrospective analysis of medical documentation
of 442 consecutive patients with anticoagulant treatment was performed. We analyzed demographic features, indications for treatment with AC, history of
AUGIB and the prescription of PPI.
Opravili smo retrospektivno analizo medicinske
dokumentacije 440 zaporednih bolnikov v ambulanti za trombotične bolezni, ki prejemajo AZ.
Analizirali smo demografske podatke, indikacije za
AZ, anamnestične podatke o krvavitvah iz zgornjih
prebavil in predpis ZPČ.
AIMS AND METHODS
* Milica Miljković, dr. med.
Department of Internal Medicine, Slovenj Gradec General Hospital, Gosposvetska 1,
2380 Slovenj Gradec, Slovenia
GASTROENTEROLOG 153
REZULTATI
RESULTS
Med 440 bolniki je bilo 242 moških in 196 žensk,
povprečna starost je bil 75,8 ± 6,22 let (65-94 let). Indikacija za predpis AZ je bila atrijska fibrilacija pri 282,
prisotnost mehanskih zaklopk pri 59, pljučna embolija pri 52 in globoka venska tromboza pri 47 bolnikih.
There were 442 patiens (189 male and 243 female),
mean age 75,8 ± 6,2 years (range 65-94).
Varfarin je bil predpisan pri 389 (88,4 %), acenokumarol pri 49 (11,1 %) in dabigatran pri 2
bolnikih (0,5 %).
ASK, NSAR, kortikosteroidi in SRI so bili sočasno
predpisani pri 11 (2,5 %), 7 (1,6 %), 3 (0,7 %) in 35
bolnikih (8,0 %).
Osem (1,8 %) bolnikov je imelo v anamnezi podatek o predhodni krvavitvi iz zgornjih prebavil.
Indications for treatment with AC were: atrial fibrillation (AF) and stroke in 284 patients, valve replacement in 59 patients, pulmonary embolism in 52
patients and deep venous thrombosis in 47 patients.
Warfarin was prescribed in 391 (88,4%) patients,
acenocoumarol in 49 (11,1%) patients and dabigatran in 2 (0,5%) patients.
ASA, NSAID, corticosteroids and SRI were concomitantly prescribed in 11 (2,5%), 7 (1,6%), 3
(0,7%) and 35 (8,0%) cases, respectively.
Eight (1,8%) patients had history of AUGIB.
ZPČ so bili predpisani 97 bolnikom (22 %) z AZ v
mononoterapiji, 26 bolnikom (41,3 %) z AZ in sočasno predpisanimi zdravili (17 bolnikov je prejemalo
SRI, 7 NSAR in 2 kortikosteroide) in 2 bolnikoma
(25 %) z AZ in anamnezo predhodne krvavitve.
343 bolnikov (78 %) starejših od 65 let ni imelo
predpisanega ZPČ.
Pri 57 bolnikih (58,5 %) je bil ZPČ predpisan v
ustrezni standardni dozi, pri 26 (26,8 %) je bila doza
previsoka, pri 14 (14,4 %) pa doza ni bila znana.
ZAKLJUČEK
Zaščita zgornjih prebavil pri bolnikih, ki prejemajo
peroralna anitkoagulacijska zdravila, ni zadostna. Vsi
bolniki, ki poleg teh zdravil prejemajo zdravila z dodatnim tveganjem (predvsem ASK in NSAR) bi morali
imeti predpisan ZPČ, še posebej starejši od 65 let in
tisti s predhodno krvavitvijo iz zgornjih prebavil.
Potrebno je pripraviti slovenska priporočila z jasnimi navodili za predpis ZPČ pri bolnikih z AZ in
dodatnimi dejavniki tveganja za krvavitev iz zgornjih prebavil.
154 GASTROENTEROLOG
PPI were prescribed in 97 (22,0%) patients with AC
in monotherapy, in 26 (41,3%) patients with AC and
concomitant therapy (17 with SRI, 7 with NSAR and
2 with corticosteroids) and in 2 patients (25%) with
AC and history of AUGIB. There were 317 (71,7%)
patients (all older than 65 years) without PPI. In
58,8% of patients PPI was prescribed in proper dose
(standard), in 26,8% the prescribed dose of PPI was
too high and in 14,4% the dose was unknown.
CONCLUSIONS
Gastric protection in patients on AC therapy is not
satisfactory.
All patients were older than 65 years which classifies them as a group of patients with higher risk of
AUGIB.
All patients with AC therapy and concomitant
NSAID or/and ASA therapy should be treated with
PPI in standard dose, especially those older than 65
years and history of AUGIB.
Gastric protection in patients with AC therapy without concomitant therapy (ASA, NSAR) and history
of AUGIB should be exactly specified in national
guidelines.
Rezultati obravnave bolnikov z akutno
krvavitvijo iz zgornjih prebavil v splošni
bolnišnici: analiza dveletnega obdobja
Audit of the menagement of acute upper
gastrointestinal bleeding in general hospital:
two-year retrospective analysis
Nace Robač*, Miroslav Vujasinović, Apolon Marolt, Martin Tretjak
Department of internal medicine, Slovenj Gradec General Hospital
Gastroenterolog 2013; suplement 2: 155–158
UVOD
INTRODUCTION
Akutna krvavitev iz zgornjih prebavil (AKZP) je
resen in pogost problem v klinični praksi in je
povezan z visoko stopnjo umrljivosti.
Acute upper gastrointestinal bleeding (AUGIB) is a
serious and common problem in clinical practice
and is associated with a significant mortality rate.
BOLNIKI IN IN METODE
PATIENTSS AND METHODS
Namen študije je bil opredeliti demografske podatke
bolnikov s krvavitvijo iz zgornjih prebavil, indikacije za gastroskopijo, dejavnike tveganja, etiologijo
krvavitve, endoskopske najdbe, prognozo, trajanje
hospitalizacije in izid zdravljenja.
The aim of the study was to determine demographic
characteristics of patients with upper gastrointestinal
bleeding, indications for gastroscopy, risk factors,
etiology of bleeding, endoscopic findings, prognostic
factors, duration of hospital stay and outcome.
Naredili smo retrospektivni pregled medicinske
dokumentacije bolnikov s krvavitvijo iz zgornjih prebavil (novi sprejemi in hospitalizirani bolniki), ki so
se zdravili v Splošni bolnišnici Slovenj Gradec od
januarja 2010 do decembra 2011. V študijo so bili
vključeni bolniki s hematemezo in/ali meleno pri
katerih je bila opravljena endoskopska preiskava
zgornjih prebavil.
We performed a retrospective review of medical documentation of patients with AUGIB (new admissions
and in-hospital patients) treated at our hospital from
January 2010 to December 2011. We included
patients with hematemesis and/or melena in whom
endoscopic examination was performed.
Analizirani so bili naslednji demografski in klinični
podatki: spol, starost, zgodovina jemanja zdravil:
* Nace Robač, MD
Department of internal medicine, Slovenj Gradec General Hospital
Gosposvetska 1, 2380 Slovenj Gradec, Slovenia
GASTROENTEROLOG 155
acetilsalicilna kislina (ASA), klopidogrel, varfarin,
kortikosteroidi, nesteroidni antirevmatiki (NSAR),
nizkomolekularni heparini (NMH), inhibitorji
ponovnega prevzema serotonina (SRI), zaviralci
protonske črpalke (ZPČ), pridružene internistične
bolezni, srčna frekvenca, krvni tlak, sečnina in
hemoglobin.
Analizirani so bili naslednji endoskopski podatki:
endoskopske najdbe in opravljen hemostatski ukrep.
Prisotnost Helicobacter pylori smo dokazali s
histopatološko analizo biopta ali s hitrim ureaznim
testom med endoskopijo.
Vsakega bolnika smo ocenili po Blatchford in
Rockall lestvici.
Izid zdravljenja je bil ocenjen na podlagi števila
ponovnih krvavitev in kirurških intervencij.
The following demographic and clinical data were
analyzed: gender, age, the history of drug intake
(acetylsalicylic acid [ASA], clopidogrel, warfarin, corticosteroids, nonsteroidal anti-inflammatory drugs
[NSAID], low-weight molecular heparins [LWMH],
serotonin reuptake inhibitors [SRI], proton pump
inhibitors [PPI]), concomitant internal diseases,
heart rate, blood pressure, blood urea nitrogen and
hemoglobin concentration.
The following endoscopic data were analyzed: endoscopic findings and hemostatic treatment applied.
Helicobacter pylori status was determined histologically and/or by rapid urease test during endoscopy.
The Rockall and Blatchford scores were calculated
for each patient.
The outcome was analyzed on the basis of rebleeding rate and surgical rate.
REZULTATI
Analiziranih je bilo 191 bolnikov, povprečne starosti
65,3±16,6 let. Razmerje med moškimi (67,5 %) in
ženskami (32,5 %) je bilo 2:1. Moški so bili povprečno 8 let mlajši kot ženske (statistično pomembno:
p = 0,02). Več kot 2/3 bolnikov (67,5 %) je bilo starejših od 61 let.
RESULTS
There were 191 patients, mean age 65.3±16.6 years.
The ratio between men (67.5%) and women (32.5%)
was 2:1. Men were 8 years younger than women (statistically significant; p = 0.002). More than two thirds
(67.5%) of all patients were older than 61 years.
Najbolj pogosti endoskopski najdbi sta bili želodčni in duodenalni ulkus (45 %), sledijo gastritis
(16,8 %) in varice požiralnika (12,6 %).
Gastric and duodenal ulcers were most common
endoscopic findings (45%) followed by gastritis (16.8%)
and esophageal varices (12.6 ).
Polovica bolnikov (50,3 %) je imela pozitivno
anamnezo jemanja enega ali več zdravil, ki bi
lahko povišala možnost krvavitev iz zgornjih prebavil : acetilsalicilna kislina (23 %), klopidogrel
(3,7 %), NSAR (9,9 %), kortikosteroidi (2,1 %), SRI
(5,8 %), antikoagulantna zdravila (17,8 %).
A half of patients (50.3%) had a history of intake of
one or more drugs that have the potential to increase
the risk of AUGIB: ASA (23%), clopidogrel (3.7%),
NSAID (9.9 %), corticosteroids (2.1%), SRI (5.8%)
and anticoagulants (17.8%).
29 bolnikov (15,2 %) je jemalo ZPČ pred nastankom krvavitve iz zgornjih prebavil.
Twenty-nine patients (15.2%) were using PPI prior
to AUGIB (in a half of cases AUGIB has developed
despite PPI use).
Povezava med Rockall in Blatchford lestvico za opredelitev življenjske nevarnosti je srednje močna
(0,573;p=0,000). Pri bolnikih s krvavitvijo iz varic
požiralnika sta bili Blatchford in Rockall lestvici neu-
Correlation between Rockall and Blatchford scores
for the determination of life risk was medium strong
(0.573; p = 0.000). In patients with variceal bleeding
both Blatchford and Rockall scores were useless
156 GASTROENTEROLOG
porabni (statistično nepomembni: r=0,397, p=0,055).
Lestvici sta imeli najboljšo povezavo pri bolnikih z
normalnimi endoskopskimi izvidi (r=0,709; p=0,010),
srednje dobro povezavo pri bolnikih z želodčnimi in
duodenalnimi ulkusi (r=0,429, p=0,000). Srednja
vrednost Bletchford lestvice pri 5 bolnikih ki so umrli,
je bila 12,8±1,3, Rockall lestvice pa 5,8±1,9. Pri
7,3 % bolnikih z vrednostjo Bletchford lestvice 0 ni
bilo potrebno nobeno hemostatsko zdravljenje.
(statistically non-significant: r= 0.397, p= 0.055).
Both scores have best correlation in patients with
normal endoscopic findings (r= 0.709, p= 0.010)
and medium strong correlation in patients with gastric and duodenal ulcers (r= 0.429, p= 0.000). Mean
Blatchford score in 5 patients who died was 12.8±1.3,
and mean Rockall score was 5.8±1.9. In 7.3% of
patients with Blatchford score 0, no hemostatic treatment was necessary.
Melena je bila indikacija za endoskopsko preiskavo
pri 114 bolnikih (59,7 %), hematemeza pri 72 bolnikih (37,7 %), oboje pa pri 5 (2,6 %) bolnikih.
An indication for endoscopy was melena in 114 patients
(59.7%), hematemesis in 72 patients (37.7%) and both
in 5 (2.6%) patients.
Večina bolnikov je bila hospitaliziranih (87,4 %);
12,6 % pa je bilo ambulantnih obravnav.
The majority of patients were hospitalized (87.4%)
and 12.6% were treated as outpatients.
Prisotnost Helicobacter pylori (HP) smo testirali
pri 92 bolnikih (48,2 %): 63 (33 %) je bilo negativnih, 29 (15.2 %) je bilo pozitivnih.
Helicobacter pylori (HP) status was known in 92
patients (48.2): 63 (33%) were negative and 29 (15.2)
were positive.
Pri vseh bolnikih (100 %) je bil ob sprejemu predpisan ZPČ.
In all patients (100 %) PPI were prescribed on admission and endoscopy was carried out within 12 hours.
Endoskopska preiskava je bila pri vseh bolnikih
narejena znotraj 12 ur.
Endoscopy finding was normal in 12 patients (6.3%).
Normalen endoskopski izvid je imelo 12 bolnikov
(6,3 %).
Endoscopic hemostatic treatment was performed in
105 (55%) patients.
The mean hospital stay was 9.3±9.6 days.
Endoskopsko hemostatsko zdravljenje je bilo opravljeno pri 105 bolnikih (55 %).
Povprečje ležalne dobe je bilo 9,3 dni.
Pet bolnikov (2,9 %) je umrlo zaradi gastrointestinalne krvavitve: 4 bolniki so imeli varice požiralnika,
en bolnik je imel želodčni ulkus (povprečna starost
60,6 ± 18,1 let).
Five patients (2.9%) died due to the gastrointestinal
bleeding: 4 patients with esophageal varices and 1
patient with gastric ulcer (mean age 60.6 ±18.1 years).
Mortality due to comorbidity was 7.9%.
Two patients (1.04%) had rebleeding and surgical
treatment.
Umrljivost zaradi komorbidnosti je bila 7,9 %.
Dva bolnika (1,04 %) sta imela ponovno krvavitev
in sta potrebovala kirurško zdravljenje.
GASTROENTEROLOG 157
ZAKLJUČKI
CONCLUSIONS
Smrtnost zaradi AKZP je zelo nizka, posebej pri
krvavitvah, ki nimajo izvora iz varic požiralnika.
Mortality of AUGIB is very low, especially in nonvariceal bleeding.
Krvavitev iz varic požiralnika je najpogostejši
vzrok smrti.
Variceal bleeding is the commonest cause of death.
Smrt po AKZP je redka brez pridruženih komorbidnih stanj.
Najpogostejša endoskopska najdba je bila krvavitev zaradi ulkusa.
Death following AUGIB is unusual in the absence of
co-morbidity.
The commonest endoscopic diagnosis was peptic
ulcer bleeding.
Rebleeding and surgical rates are very low.
Ponovitev kvavitve in kirurški posegi so zelo redki.
Benefits of Rockall and Blatchford scores are limited.
Koristi Blatchford in Rockall lestvic so omejene.
Odstotek opravljenih urgentnih endoskopij znotraj
12 ur je maksimalen (100 %); je izrazito večji v primerjavi z drugimi študijami in je glavni razlog za
dobro prognozo bolnikov z AKZP.
158 GASTROENTEROLOG
The percentage of urgent endoscopies performed
within the first 12 hours is maximal (100%); it is significantly higher in comparison with other studies
and is the main reason for a good outcome in
patients with AUGIB.
Biliarni ileus – prikaz dveh primerov
Biliary ileus – report of two cases
Miroslav Vujasinović*,1, Karmen Klančnik2, Gregor Kunst3, Simona Lavre4
1 Department of Internal Medicine; Slovenj Gradec General Hospital
2 Medical Faculty at the University of Maribor
3
Department of Surgery; Slovenj Gradec General Hospital
4 Department of Radiology; Slovenj Gradec General Hospital
Gastroenterolog 2013; suplement 2: 159–160
POVZETEK
ABSTRACT
Žolčni kamni lahko ulcerirajo skozi žolčnik v dvanajstnik in prehajajo distalno po tankem črevesju.
Za povzročitev mehanske obstrukcije črevesja
morajo biti običajno večji od 2,5 cm.
Gallbladder stones may ulcerate through the gall
bladder into the duodenum and pass down the
small bowel. Stones that cause mechanical small
bowel obstruction are usually larger than 2.5 cm.
Izraz biliarni ileus je prvič uporabil Bartolin leta
1654 v povezavi z mehansko obstrukcijo črevesja,
ki je nastala zaradi zagozditve enega ali več žolčnih
kamnov v gastrointestinalnem traktu.
The term gallstone ileus was first coined by Bartolin
in 1654 and referred to the mechanical intestinal
obstruction due to impaction of one or more large
gallstones within the gastrointestinal tract.
Kronično draženje in konzervativno zdravljenje
akutnih zagonov holecistitisa privedeta ob dekubitusu stene postopno do razvoja notranje biliarne
fistule v prebavni trakt.
Chronic irritation and conservative treatment of
acute cholecystitis, together with decubitus of the
wall, gradually lead to the development of internal
biliary fistula in the digestive tract.
V primeru zagozditve kamna v duodenumu ali
pilorusu govorimo o Bouveretovem sindromu, ki
ga je prvi opisal francoski internist Leon Bouveret
leta 1896.
A gastric outlet obstruction secondary to an
impacted gallstone in the duodenum or pylorus is
called Bouveret syndrome (it was first described in
1896 by the French internist Leon Bouveret).
Postavitev diagnoze biliarnega ileusa je težka, po
navadi temelji na rentgenoloških ugotovitvah.
Riglerjeva triada, ki jo sestavljajo pnevmobilija,
The diagnosis of biliary ileus is difficult, usually
depending on the radiographic findings. The
Rigler’s triad includes pneumobilia, ectopic radio-
* Miroslav Vujasinović, MD MSc
Department of Internal Medicine, Slovenj Gradec General Hospital, Gosposvetska 1
Slovenj Gradec 2380, Slovenia
GASTROENTEROLOG 159
ektopičen radiopačen kamen in črevesna napihnjenost, je diagnostična najdba za biliarni ileus v
primeru, ko sta prisotna vsaj dva od treh kriterijev.
CT abdomna s kontrastom je postal najpomembnejši
način diagnostike biliarnega ileusa zaradi njegove
dobre ločljivosti. Vidimo lahko črevesne vijuge in
prisotnost kamnov v črevesju, brez motenj s strani
kosti ali zraka v črevesju.
Zaradi nizke pojavnosti tega stanja ni enotnega
mnenja kakšen kirurški poseg je najboljši za zdravljenje. Optimalno kirurško zdravljenje je ena
operacija v eni fazi, sestavljena iz enterotomije,
holecistektomije in poprave oz. zapore fistule. V
primerih visoko rizičnih pacientov pa se naredi le
enterotomija z odstranitvijo kamna.
Prikazana sta dva primera biliarnega ileusa.
160 GASTROENTEROLOG
opaque gallstone, and intestinal distention, and is
considered diagnostic for biliary ileus when two of
the three criteria are present. Abdominal contrast
enhance computed tomography becomes the most
important modality in diagnosing biliary ileus
because the visibility of bowel loops and gallstone
within the loops is not obscured with bones and air
in the loops.
There is no uniform surgical procedure for this disease because of its low incidence. Optimal surgical
treatment is one stage procedure: cholecystectomy,
fistula repair and enterotomy with removal of
impacted stone or just an enterotomy with stone
removal in high risk patients.
We describe two cases of biliary ileus.
Seroprevalenca celiakije pri bolnikih s
sladkorno boleznijo tipa 1
Seroprevalence of celiac disease among patients
with type 1 diabetes mellitus
Betka Popič*,1, Miroslav Vujasinović1, Jelka Zaletel2, Jana Makuc1, Metka Epšek Lenart1,
Marjana Predikaka1, Bojan Tepeš3
1 Department of Internal Medicine; Slovenj Gradec General Hospital
2
Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre Ljubljana
3 Abakus Medico Diagnostic Centre
Gastroenterolog 2013; suplement 2: 161–162
UVOD
BACKGROUND
Celiakija (CD) je sistemska, imunsko pogojena
bolezen, ki jo sproži zaužit gluten pri genetsko dovzetnih osebah. Prizadane 0,6–1,0 % svetovne populacije.
Prevalenca pri odraslih je znotraj posameznih
evropskih držav zelo različna, kar ni povsem pojasnjeno. Bolezen se najpogosteje kaže s kronično
drisko, hujšanjem in meteorizmom
Coeliac disease (CD) is a systemic immune-mediated
disorder triggered by dietary gluten in genetically
susceptible persons. It affects 0.6 to 1.0 % of the
population worldwide. Prevalence shows large unexplained differences in adult age across different
European countries. Frequent symptoms and signs
include chronic diarrhea, weight loss, and abdominal distention. CD is one of the most frequent
autoimmune disorders occurring in type 1 diabetes
mellitus (T1DM). HLA class II molecules DQ2 and
DQ8 have been identified as key genetic risk factors
in both diseases. The prevalence of CD in T1DM
varies in different studies - from 2.6 % to 13.8 %. It
is well accepted that much CD remains undiagnosed
in the community.
CD je ena najpogostejših avtoimunskih bolezeni,
ki se pojavljajo pri sladkorni bolezni tipa 1 (SB1).
Obe bolezni sta povezani z nekaterimi HLA
(human leukocyte antigen) aleli in sicer HLA DQ2
in HLA DQ8. Prevalenca CD pri bolnikih s SB1 je
po podatkih različnih študij od 2,6-13,8 %. Znano
je, da velik del CD ostaja neodkrit.
* Betka Popič, MD
Department of Internal Medicine; Slovenj Gradec General Hospital, Gosposvetska 1
2380 Slovenj Gradec, Slovenia
GASTROENTEROLOG 161
CILJI IN METODE
AIMS/METHODS
Cilj študije je bil določiti seroprevalenco CD pri
naših bolnikih s SB1. V raziskavo smo vključili 44
zapovrstnih bolnikov z znano SB1. Določili smo
serumska IgA protitelesa proti tkivni transglutaminazi (IgAtTg). Pridobljene podatke prikazujemo
številčno (procenti) oziroma s srednjo vrednostjo ±
standardna deviacija.
The aim of our study was to determine seroprevalence of CD among our patients with T1DM. Fourty
four eligible consequtive patients with T1DM were
included in the study. Diagnosis of T1DM was established from health records. Diagnosis of CD was
established by IgA tissue transglutaminase antibodies (IgAtTg). Data are shown as numerous ( %) and
mean ± standard deviation.
REZULTATI
44 preiskovancev z znano SB1 smo testirali na
IgAtTg, od tega 20 (45,5 %) žensk in 24 (54,5 %)
moških. Starost bolnikov je bila 47,3±12,5 let, trajanje SB1 pa 26,2±9.0 let. Seropozitivni so bili trije
bolniki (6,8 %), dva moška in ena ženska. Moška
sta bila stara 27 in 30, ženska pa 38 let. Vsi trije
pacienti so zavrnili nadaljnjo diagnostiko (gastroduodenoskopijo z biopsijo in genetsko testiranje).
ZAKLJUČEK
Raziskava je potrdila visoko prevalenco CD pri
odraslih bolnikih s SB1 (6–7- krat pogosteje, kot
pri ostali populaciji). Naši rezultati so primerljivi z
izsledki podobnih študij iz drugih držav. V visokorizičnih skupinah, kot so pacienti s SB1, bi bilo
smiselno aktivno iskati neprepoznano CD.
162 GASTROENTEROLOG
RESULTS
Fourty four adults with T1DM have been screened
for CD. There were 20 (45,5 %) female and 24 (54,5
%) male, mean age 47,3 ± 12,5 years. Mean time of
DM duration was 26,2 ± 9,0 years. Three patients
(two male and one female) had positive IgAtTg (6,8
%). Males were 27 and 30 years old and female was
38 years old. All three patients declined additional
diagnostic methods (gastroduodenoscopy with biopsies and genetic testing).
CONCLUSION
Study confirmed a high prevalence of CD in adult
patients with T1DM (6-7 times more frequent than
in general population). Our data is comparable with
results of similar studies around the world.
Therefore, a strategy of case finding among highrisk populations, such as patients with T1DM may
be an effective way to identify unrecognized CD.
Eksokrina insuficienca pankreasa pri
bolnikih s sladkorno boleznijo
Exocrine pancreatic insufficiency in patients
with diabetes mellitus
Miroslav Vujasinović*,1, Jelka Zaletel2, Bojan Tepeš3, Betka Popič1, Jana Makuc1,
Metka Epšek Lenart1, Marjana Predikaka1, Saša Rudolf4
1 Department of Internal Medicine; Slovenj Gradec General Hospital
2
Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre Ljubljana
3 Abakus Medico Diagnostic Centre Rogaska
4
Department of Radiology, University Medical Centre Maribor
Gastroenterolog 2013; suplement 2: 163–164
Key words: exocrine, pancreatic, insufficiency, diabetes mellitus, fecal elastase-1
UVOD
INTRODUCTION
Pri bolnikih s sladkorno boleznijo (SB) se lahko
pojavi eksokrina insuficienca pankreasa (EPI).
Tako pogostost EPI kot njena klinična pomembnost ostajata sporni. Cilj študije je bil določiti, ali je
pri bolnikih s SB prisotna EPI.
Exocrine pancreatic insufficiency (EPI) can occur in
patients with diabetes mellitus (DM). Incidence of
EPI and its clinical significance remain poorly
defined. The aim of our study was to determine
whether exocrine pancreatic function is impaired in
patients with DM.
BOLNIKI IN METODE
V raziskavo smo vključili 150 zapovrstnih bolnikov
z več kot 5 let trajajočo SB in sicer 50 bolnikov s
SB tipa 1, 50 bolnikov s SB tipa 2, ki se zdravijo z
inzulinom ter 50 bolnikov s SB tipa 2 na peroralni
antidiabetični terapiji. Starost preiskovancev je bila
59,0±12,0 let, trajanje SB pa 15,0±9,9 let. EPI smo
definirali kot koncentracijo elastaze-1 v blatu (E1)
pod 200 μg/g (ELISA metoda).
PATIENTS AND METHODS
One hundred and fifty consecutive patients, mean
age 59.0 (±12.0 years), with DM lasting at least 5
years were included in the study. We included 50
patients with type 1 DM (DM1), 50 insulin-treated
patients DM type 2 (DM2-ins) and 50 non-insulin
treated patients with DM type 2 (DM2-non-ins).
Diagnosis of DM was established from health
records, lasting 15.0±9.9 years on average. EPI was
diagnosed with a fecal elastase-1 concentration
(FE1) of less than 200 μg/g (ELISA).
* Corresponding author: Miroslav Vujasinović, MD MSc
Slovenj Gradec General Hospital, Department of Internal Medicine, Gosposvetska 1, 2380 Slovenj Gradec, Slovenia
Phone: +386 2 8823 400, Fax: +386 2 8823 505
GASTROENTEROLOG 163
REZULTATI
RESULTS
E1 je bila znižana pri 8 bolnikih (5,4 %): pri 4 (2,7 %)
blago (100–200 μg/g) in pri 4 (2,7 %) pomembno
znižana (<100 μg/g). V skupini bolnikov s SB tipa 1
je bila EPI prisotna pri treh, v skupini s SB tipa 2,
ki se zdravijo z insulinom pri petih bolnikih. V
skupini bolnikov s SB tipa 2 na peroralni terapiji
EPI nismo dokazali pri nobenem preiskovancu.
FE1 was reduced in 8 (5.4%) patients: mildly
reduced (100–200 μg/g) in 4 patients (2.7%) and
markedly reduced (< 100 μg/g) in 4 patients (2.7%).
Frequency of EPI was 3 in DM1, 5 in DM2-ins and
none in DM2-non-ins groups.
ZAKLJUČEK
EPI in DM occured less frequently than in previous
studies, probably due to our strict exclusion criteria
(age, alcohol intake). However, these results may
have an impact on the daily work of clinicians from
different fields of medicine (gastroenterology, diabetology and general practice). Follow-up of patients
with DM should also include the evaluation of
exocrine pancreatic function.
EPI se pri naših bolnikih s SB pojavlja redkeje, kot
je bilo opisovano v prejšnjih študijah, najverjetneje
zaradi strogih izključitvenih kriterijev (starost,
vnos alkohola). Kljub temu imajo rezultati lahko
pomemben klinični vpliv pri vsakdanjem delu
različnih specialistov (gastroenterologi, diabetologi, specialisti družinske medicine). Spremljanje
pacientov s SB bi moralo vsebovati tudi oceno tveganja za EPI.
164 GASTROENTEROLOG
CONCLUSIONS
Eksokrina insuficienca pankreasa pri
bolnikih s celiakijo
Exocrine pancreatic insufficiency in patients
with celiac disease
Miroslav Vujasinović*,1, Bojan Tepeš2, Saša Rudolf3
1 Department of Internal Medicine; Slovenj Gradec General Hospital
2 Abakus Medico Diagnostic Centre
3
Department of Radiology, University Medical Centre Maribor
Gastroenterolog 2013; suplement 2: 165–166
UVOD
INTRODUCTION
Povezava med celiakijo (CD) in eksokrino insuficienco pakreasa (EPI) je bila prvič opisana leta
1957. Od takrat je bilo z različnimi diagnostičnimi
metodami opravljenih mnogo raziskav. Cilj študije
je bil ugotoviti, ali je pri naših bolnikih s CD prisotna EPI. Prikazujemo prve podatke.
Since 1957 when it was first reported the association between celiac disease (CD) and exocrine pancreatic insufficiency (EPI) was a topic of many
researches in which different diagnostic methods
were used. The aim of our study was to determine
whether exocrine pancreatic function is impaired in
patients with CD in our population. We are presenting preliminary results.
BOLNIKI IN METODE
Eksokrino funkcijo pankreasa smo določili s koncentacijo elastaze-1 v blatu (E1). Blago insuficienco
smo definirali pri koncentraciji E1 < 200μg/g,
pomembno pa pri koncentraciji <100 μg/g. Diagnozo CD smo postavili z določitvijo IgA protiteles
proti tkivni transglutaminazi (IgAtTg) v serumu in
potrdili z odvzemom biopsije iz dvanajstnika. Preiskovance smo razdelili v tri skupine: A – novoodkrita
CD; B – bolniki z znano CD na brezglutenski dieti;
C – bolniki z znano CD na normalni prehrani
(zavračajo dieto). Pridobljene podatke prikazujemo
številčno (procenti) oziroma s srednjo vrednostjo ±
standardna deviacija.
PATIENTS AND METHODS
Pancreatic exocrine function was determined by the
fecal elastase-1 concentration (FEC) and insufficiency
was classified as moderately (FEC < 200 μg/g) or
severely impaired (FEC < 100 μg/g). CD was diagnosed by serologic testing using IgA anti tissue transglutaminase antibody (IgAtTg) and small bowel biopsy
using Marsh classification. Patients were divided into
three groups: A - newly diagnosed CD; B - known CD
patients on a gluten-free diet (GFD) and C - patients
with known CD on a normal diet (those who refused
medical advice). Data are shown as numerous ( %) and
mean±standard deviation.
* Miroslav Vujasinović, MD MSc
Department of Internal Medicine, Slovenj Gradec General Hospital, Gosposvetska 1
Slovenj Gradec 2380, Slovenia
GASTROENTEROLOG 165
REZULTATI
RESULTS
Trenutno je v raziskavo vključenih 46 bolnikov, 34
žensk (73,9 %) in 12 moških (26,1 %). Starost preiskovancev je 44,4±17,0 let (od 20 – 76), trajanje
CD pa 5,8±7,8 let. 13 bolnikov (28,3 %) je po klasifikaciji po Marshu razvrščenih v tip 3; 9 (19,5 %)
v tip 2; 8 bolnikov (17,4 %) v tip 1; 16 pa je po
Marshu nerazvrščenih (ni podatka o histologiji v
medicinski dokumentaciji). Pri večini vključenih
preiskovancev (n=37; 80,4 %) gre za znano CD na
brezglutenski dieti, manj je novoodkritih (n=5;
10,9 %), najmanj pa tistih, pri katerih je CD že
znana, a zavračajo dieto (n=4; 8,7 %). E1 je bila
znižana pri dveh bolnikih (4,35 %): zmerno znižana (E1 131 μg/g) pri 69 – letnemu moškemu z
novoodkrito CD Marsh 1 in pomembno znižana
(E1 63 μg/g) pri 24 – letni ženski z znano CD
Marsh 3 na brezglutenski dieti.
There are currently 46 patients included in the
study, 34 (73.9 %) female and 12 (26.1 %) male,
mean age 44.4±17,0 years (range 20-76). Mean duration of CD was 5.8±7.8 years. There were 13 (28.3
%) patients with Marsh 3 CD; 9 (19.5 %) patients
with Marsh 2 CD; 8 (17.4 %) patients with Marsh
1CD and 16 (34.8 %) Marsh non-classified patients
(no histology data in medical records). The majority
of patients had known CD on GFD (n=37; 80.4 %)
followed by newly diagnosed CD (n=5; 10.9 %) and
known CD without GFD (n=4; 8.7 %). FEC was
reduced in 2 (4.35 %) patients: moderately reduced
(FEC 131 μg/g) in 69– year-old male with newly
diagnosed CD Marsh 1 and severely reduced (FEC
63 μg/g) in 24–year-old female with known CD
Marsh 3 on GFD.
CONCLUSIONS
ZAKLJUČEK
EPI se pri naših bolnikih pojavlja redkeje, kot je
bilo opisovano v prejšnjih študijah. Kljub temu
imajo rezultati lahko pomemben klinični vpliv.
Spremljanje pacientov s CD bi moralo vsebovati
tudi oceno eksokrine funkcije pankreasa.
166 GASTROENTEROLOG
EPI occurred much less frequently than in previous
studies. However, these results may have an impact
on the daily work of the clinician. Routine follow-up
of patients with CD should include evaluation of
pancreatic exocrine function.
Eksokrina in endokrina insuficienca
pankreasa po akutnem pankreatitisu
Exocrine and endocrine pancreatic
insufficiency after acute pancreatitis
Miroslav Vujasinović*,1, Bojan Tepeš2, Jana Makuc1, Jelka Zaletel3, Tjaša Vidmar1, Saša Rudolf4
1 Department of Internal Medicine; Slovenj Gradec General Hospital
2 Abakus Medico Diagnostic Centre
3
Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre Ljubljana
4 Department of Radiology, University Medical Centre Maribor
Gastroenterolog 2013; suplement 2: 167–169
UVOD
INTRODUCTION
Eksokrina insuficienca pankreasa (EIP) in sladkorna bolezen tipa 3c (SBt3c) se lahko pojavita pri
bolnikih po prebolelem akutnem pankreatitisu
(AP). Incidenca EIP in SBt3c ter njuna klinična
pomembnost ostajata sporni. V prispevku predstavljamo preliminarne rezultate opravljene študije.
Exocrine pancreatic insufficiency (EPI) and type 3c
diabetes mellitus (T3cDM) can occur in patients after
acute pancreatitis (AP). Incidence of EPI and T3cDM
and clinical significance of both remains controversial.
We are presenting preliminary results of our study.
PATIENTS AND METHODS
BOLNIKI IN METODE
Namen raziskave je bil ugotoviti, ali sta eksokrina
in endokrina funkcija pri bolnikih po prebolelem
AP okvarjeni in oceniti njuno povezavo z etiologijo
ter resnostjo AP. Ocena eksokrine funkcije pankreasa
je temeljila na koncentraciji fekalne elastaze-1 (KFE)
in je bila klasificirana kot zmerno (KFE < 200 μg/g)
ali hudo (KFE < 100 μg/g) znižana. Endokrina
funkcija pankreasa pa je bila ocenjena po kriterijih
Diabetološkega združenja Slovenije, ki so skladni
s kriteriji SZO. Stopnja resnosti in morfologija AP
sta bili določeni po revidirani Atlanta klasifikaciji
in definicijah mednarodnega konsenza 2012.
Podatki so prikazani numerično ( %) in kot povprečje±standarna deviacija.
The aim of the study was to determine whether
exocrine and endocrine pancreatic function are
impaired in patients after AP and to evaluate its relationship to etiology and severity of AP. Pancreatic
exocrine function was determined by the fecal elastase1 concentration (FEC) and insufficiency was classified
as moderately (FEC < 200 μg/g) or severely impaired
(FEC < 100 μg/g). Pancreatic endocrine function was
determined by Slovenian Society for Diabetes criteria
which are in accordance with World Health
Organization criteria in patients without prior DM.
The severity and morphology of AP were determined
by a revised Atlanta classification and definitions by
international consensus 2012. Data are shown as
numerous (%) and mean±standard deviation.
* Miroslav Vujasinović, MD MSc
Department of Internal Medicine, Slovenj Gradec General Hospital, Gosposvetska 1
Slovenj Gradec 2380, Slovenia
GASTROENTEROLOG 167
REZULTATI
RESULTS
Trenutno je vključenih 55 bolnikov; 36 (65,5 %)
moških in 19 (34,5 %) žensk, povprečna starost je
56,3±13,4 let.
There are currently included 55 patients; 36 (65.5%)
men and 19 (34.5 %) women, mean age 56.3±13.4 years.
Najpogostejša vzroka AP sta bila alkohol (n=22; 40 %)
in žolčni kamni (n=22; 40 %), sledijo nepojasnjeni
AP (n=6; 10,9 %), AP zaradi hipertrigliceridemije
(n=3; 5,5 %) in z zdravili povzročeni AP (n=2; 3,6 %).
Most common etiologies of AP were alcohol (n=22;
40 %) and gallstones (n=22; 40 %), followed by unexplained (n=6; 10.9 %), hypertriglyceridemia (n=3;
5.5 %) and drug-induced (n=2; 3.6 %). Mean followup after attack was 2.8±4.9 years (range 1-20 years).
Povprečen čas sledenja po AP je bil 2,8±4,9 let
(obdobje 1–20 let).
There are 43 (78.2 %) patients after one attack and
12 (21.8 %) after two or more attacks.
43 (78,2 %) bolnikov je prebolelo eno epizodo AP
in 12 (21,8 %) dve ali več.
In 34 (61.8 %) patients the clinical course of AP was
mild; in 13 (23.6 %) moderately severe and in 8
(14.6 %) severe.
Pri 34 (61,8 %) bolnikih je bil klinični potek blag ;
pri 13 (23,6 %) zmerno hudo ter pri 8 (14.6 %)
hudo potekajoč.
FEC was reduced in 9 (16.4 %) patients: in 2 patients
moderately reduced (100-200 μg/g) and in 7 patients
severely reduced (< 100 μg/g).
KFE je bila zmanjšana pri 9 (16,4 %) bolnikih: pri
2 bolnikih zmerno (100–200 μg/g) in pri 7 bolnikih močno zmanjšana (< 100 μg/g).
T3cDM was present in 7 (12.7 %) patients (2 of them
had both EIP and T3cDM).
SBt3c je bila prisotna pri 7 (12,7 %) bolnikih (2 od
njih sta imela tako EIP kot SBt3c).
EIP was present in 9 patients: in 2 after severe AP;
in 3 after moderately severe AP and in 4 after mild AP.
EIP je bila prisotna pri 9 bolnikih: pri 2 po hudem AP,
pri 3 po zmerno hudem AP in pri 4 po blagem AP.
T3cDM was present in 7 patients: in 2 after severe AP;
in 1 after moderately severe AP and in four after
mild AP.
SBt3c je bila prisotna pri 7 bolnikih: pri 2 po
hudem AP, pri 1 po zmerno hudem AP in pri 4 po
blagem AP.
EIP je bila najpogostejša pri bolnikih z alkoholno
etiologijo AP (7 od 9), sledijo žolčni kamni (2 od 9).
SBt3c je bila prisotna pri 3 bolnikih z žolčnimi
kamni, 2 bolnikih z alkoholno in 2 bolnikih z
hiperlipemično etiologijo.
168 GASTROENTEROLOG
EPI was more common in patients with alcoholic etiology
(7 out of 9) followed by gallstone etiology (2 out of 9).
T3cDM was present in 3 patients with gallstone, 2
patients with alcohol and 2 patients with hyperlipemic
etiology.
ZAKLJUČKI
CONCLUSIONS
EIP in SBt3c sta se pojavljala mnogo redkeje kot v
prejšnjih študijah.
EPI and T3cDM occurred much less frequently than
in previous studies.
EIP je pogostejša pri bolnikih z alkoholno etiologijo AP.
EPI is more common in patients with alcoholic etiology of AP.
SBt3c ni povezana s specifično etiologijo AP.
T3cDM is not related to specific etiology of AP.
Dosedaj nismo odkrili povezave med stopnjo AP,
EIP ter SBt3c. Kljub temu bi rezultati študije lahko
imeli vpliv na vsakodnevno delo zdravnikov v različnih vejah medicine (gastroenterologija, diabetologija,
družinska medicina).
So far we have not found an association between
severity of AP, EIP and T3cDM.
Sledenje bolnikov po AP bi moralo vključevati
oceno eksokrine in endokrine funkcije pankreasa.
However, these results may have an impact on the daily
work of the clinician in different fields of medicine
(gastroenterology, diabetology and general practice).
Follow-up of patients after AP should include evaluation of pancreatic exocrine and endocrine function.
GASTROENTEROLOG 169
Helicobacter pylori eradication rate in
carinthian region of Slovenia, 2011–2012
Miroslav Vujasinović*,1, Nace Robač1, Samo Jeverica2, Urša Dolinar2, Bojan Tepeš3
1
Department of Internal Medicine, Slovenj Gradec General Hospital
2
Institute for Microbiology and Immunology, Medical Faculty Ljubljana
3 Abakus Medico Diagnostic Centre Rogaška
Gastroenterolog 2013; suplement 2: 170
BACKGROUNDS
Antimicrobial resistance is the leading cause for the
treatment failure of Helicobacter pylori (HP) infection. In the majority of countries including Slovenia
the eradication rate of primary therapy is below
80%. So far, we didn’t have any data about HP eradication rate in Carinthian region on the North-East
of Slovenia.
METHODS
Retrospective analysis of all patients who underwent
eradication treatment for HP infection in Slovenj
Gradec General Hospital from 2011 to 2012 was
performed. Demographic characteristics of patients
and eradication rates after different antimicrobial
treatment regimens were analysed. Secondary resistance to antimicrobial agents was calculated from all
cases where antimicrobial susceptibility testing was
performed.
RESULTS
Total of 324 patients were included in the analysis:
60.2% (n=195) female and 39.8% (n=129) male, mean
age 52.1±15.2 years). 7-days triple therapy with proton
pump inhibitor (PPI), amoxicillin and clarithromycin
(PAC) was prescribed in 87.7% (n=284) of patients
as the first-line treatment, 11,7% (n=38) of patients
received 7-days triple therapy with PPI, amoxicillin
and metronidazole (PAM) and 0,6% (n=2) of patients
received 7-days triple therapy with PPI, clarithromycin
and metronidazole (PCM). The eradication rate with
the first-line therapy was 70,7% intention to treat
(ITT) analysis and 70,9% per protocol (PP) analysis.
Cumulative eradication rate for up to four lines of
therapy was 89,9% ITT analysis and 99,7% PP
analysis. Culture and sensitivity was performed in
16,4% (n=53) of patients. Secondary resistance rates
for clarithromycin, metronidazole, levofloxacin,
amoxicillin and tetracycline among patients after
treatment failure were 84,6%, 70,0%, 7,7%, 2,5%
and 0,0%, respectively.
CONCLUSIONS
The eradication rate of the first-line therapy is critically low. However, cumulative eradication rate is
still high, but below the eradication rate in Slovenia
reported in previous studies. Optimization of the
treatment strategies for the HP eradication is
needed. Systematic surveillance of antimicrobial
resistance of HP is mandatory.
* Miroslav Vujasinović, MD MSc
Department of Internal Medicine, Slovenj Gradec General Hospital, Gosposvetska 1
Slovenj Gradec 2380, Slovenia
170 GASTROENTEROLOG
Is adherence of guidelines in treatment
of patients with celiac disease
satisfactory?
Miroslav Vujasinović*
Department of Internal Medicine, Slovenj Gradec General Hospital
Gastroenterolog 2013; suplement 2: 171–172
BACKGROUND
Celiac disease (CD) is a common autoimmune disorder with a prevalence of 1% in western population. Patients affected by CD should be treated and
followed-up by a multidisciplinary team.
betes mellitus, connective tissue diseases, microscopic
colitis, changes in bone mineral density, skin disorders,
pancreatic exocrine insufficiency, liver diseases, neurologic diseases), access to an advocacy group and
screening of family members.
RESULTS
PATIENTS AND METHODS
To determine adherence to treatment of patients with
CD according to international recommendations:
guidelines on the recognition and assessment of CD in
children and adults from the British National Institute
for Health and Clinical Excellence in 2009 (1), the
American Gastroenterological Association 2006 guidelines for the diagnosis and management of celiac disease (2) and Up To Date recomendations on management of CD in adults (3). Medical documentation of 28
consecutive patients (all Slovene, Caucasians) with confirmed CD was analyzed. The following data were
determined: monitoring the response to a gluten-free
diet (GFD) with serologic testing, consultation with a
skilled dietitian including education about the disease,
identification and treatment of nutritional deficiencies
(iron, calcium, phosphorus, folate, vitamin B12, vitamin D), screening for concomitant diseases (autoimmune thyroid disease, lactose intolerance, type 1 dia-
There were 28 patients: 19 (67,9%) female and 9 (32,1%)
male, mean age 39,6 ±16,2 years (range 18–69).
Mean time from diagnosis of CD was 6,3 ±3,5 years
(range 1–23).
All patients were monitoring the response to a
gluten-free diet with serologic testing: 4 patients
(14,3%) had positive IgA tissue transglutaminase
(TTG) due to the non-compliance.
All compliant patients on GFD (24 out of 28 = 85,7%)
are in remission (without gastrointestinal symptoms).
Twenty-three patients (82,1%) had consultation with a
skilled dietitian including education about the disease.
Nutritional deficiencies were found in following percentages: iron deficiency in 6 (21,4%) patients, vita-
* Miroslav Vujasinović, MD MSc
Department of Internal Medicine, Slovenj Gradec General Hospital, Gosposvetska 1
Slovenj Gradec 2380, Slovenia
GASTROENTEROLOG 171
min D deficiency in 22 (78,5%) patients, calcium
deficiency in 1 (3,5%) patient and folate deficiency
in 2 (7,1%) patients.
Concomitant diseases were found in following percentages: lactose intolerance in 16 (57,1%), microscopic
colitis in 2 (7,1%) patients, Hashimoto thyroiditis in
2 (7,1%) patients, pancreatic exocrine insufficiency
in 2 (7,1%) patients, skin disorders in 5 (17,8%) patients
and osteopenia/osteoporosis in 3 (37,5%) patients
(dual-energy X-ray absorptiometry was performed in
only 8 patients).
All patients were advised to join the support group
(Slovene Celiac Society).
Screening of family members were advised in all
patients and CD was found in close relatives in 6
families (21,4%).
172 GASTROENTEROLOG
CONCLUSIONS
Vitamin D defficiency is most common nutritional
defficiency in patients with CD.
Lactose intolerance is most common concomitant
disease in patients with CD.
All patients with good compliance (on GFD) are currently without gastrointestinal complaints.
Adherence to the international guidelines is satisfactory.
REFERENCES
1. National Institutes of Health Consensus Development Conference
Statement. Celiac Disease 2004. Available at:
http://consensus.nih.gov/ (accessed on April 17, 2013).
2. AGA Institute. AGA Institute Medical Position Statement on the
Diagnosis and Management of Celiac Disease. Gastroenterology
2006; 131:1977–80.
3. Ciclitira PJ. Management of celiac disease in adults. In: UpToDate,
Basow DS (edit), UpTodate, Waltham, MA, 2013
In Slovenian patients with primary
biliary cirrhosis genetic polymorphism
of glutation s-transferase (GSTP1)
contribute to higher prevalence of
concomitant autoimmune thyroid disease
Katja Novak*,1, Katja Zaletel2, Vita Dolžan3, Aleksandra Markovič1
1
University Clinical Center Ljubljana, Division of Internal Medicine, Clinical Dep. for Gastroenterology
2
University Clinical Center Ljubljana, Department of Nuclear Medicine, Dep. for Thyroid diseases
3 University of Ljubljana, Faculty of Medicine, Institute of Biochemistry, Pharmacogenetics Laboratory
Gastroenterolog 2013; suplement 2: 173–174
AIM OF STUDY
METHODS
Glutathione S-transferases (GST) are a large family
of isoenzymes that catalyse conjugation reactions of
reduced glutathione. However GST-mu 1 (GSTM1),
GST-theta 1 (GSTT1) and GST-pi l (GSTP1) also
play an important role in cellular protection against
damage caused by reactive oxygen species. Genetic
polymorphisms of genes coding for these enzymes
alter enzyme activity by reducing antioxidant
defense mechanisms, which are known to contribute to the pathogenesis of many autoimmune
diseases. Primary billiary cirrhosis (PBC) is a rare
autoimmune liver disease, characterized by progressive destruction of small intra-hepatic bile ducts
and gradual development of billiary cirrhosis. PBC
is frequently associated with autoimmune thyroid
disease (AITD), which reportedly affects 15 to 25
percent of patients with PBC. The aim of our
research was to determine the influence of GSTM1,
GSTT1 and GSTP1 polymorphisms on concomitant
AITD in Slovenian PBC patients.
The study population consisted of 92 patients (91
females and 1 male) with PBC. All the patients were
examined for the presence of thyroid disease. AITD
was diagnosed in patients with positive specific thyroid
autoantibodies and with characteristic hypoechoic
ultrasound pattern. Polymorphic GSTM1 and GSTT1
genes deletions (null alleles) were identified using
multiplex PCR. Both genes were simultaneously
amplified in a single-step PCR reaction together
with the beta-globin gene as the internal positive
control and PCR products were visualized on a 2%
agarose gel stained with ethidium bromide. Custom
TaqMan SNP genotyping assays were used to determine GSTP1 Ile105Val and Ala114Val polymorphisms. Statistical analysis (Pearson Chi-Square,
Fisher’s Exact Test, Odds Ratio, 95% Confidence
Interval) were performed using IBM SPSS Statistics
version 20.0.
* Katja Novak
University Clinical Center Ljubljana, Division of Internal Medicine, Clinical Dep. for Gastroenterology,
Japljeva 2, 1000 Lubljana, Slovenia
GASTROENTEROLOG 173
RESULTS
CONCLUSIONS
Among 92 PBC patients AITD was confirmed in 30
(32.6%) and excluded in 62 (67.4%). GSTM1 null
and GSTT1 null allele and GSTP1 Ala114Val frequency distribution did not differ between PBC
patients with and without concomitant AITD. GSTP1
Ile105Val genotype distribution significantly differed
between PBC patients with and withouth concomitant AITD (Pearson p=0.007). In particular, PBC
patients with homozygous GSTP1 105Val/105Val
genotype had significantly higher risk for concomitant AITD (Pearson p=0,005, Fisher p=0.010,
OR=8.500, 95% CI=1.571-45.979). (Table 1).
Our results suggest that the presence of GSTP1
105Val allele may contribute to higher prevalence
of AITD in PBC patients.
174 GASTROENTEROLOG
Permeabilnostni indeks pri bolnikih s
celiakijo
Permeability index in celiac disease patients
R. Janša*,1, J. Tišler-Štuflek2, G. Novak1, J. Osredkar2
1 University Medical Centre Ljubljana, Division of Internal Medicine, Department of Gastroenterology
Univerzitetni klinični center Ljubljana, Klinični oddelek za gastroenterologijo
2 University Medical Centre Ljubljana, Clinical Institute of Clinical Chemistry and Biochemistry
Univerzitetni klinični center Ljubljana, Klinični inštitut za klinično kemijo in biokemijo
Gastroenterolog 2013; suplement 2: 175–176
Glavna funkcija tankega črevesja je prebava črevesne vsebine, absorpcija hranil in elektrolitov ter
vzdrževanje vodne homeostaze. Tanko črevo ima
zelo pomembno vlogo kot pregrada med človeškim
organizmom in zunanjim okoljem. Mehanizem
pregrade omogoča selektivno prepustnost za
makromolekul. Nekatere bolezni imajo pomemben vpliv na celovitost tankega črevesja, tako se ta
razlikuje, če primerjamo zdravo populacijo z bolniki s celiakijo. Zaradi izravnave črevesne sluznice
in sprememb tesnih stikov med enterociti kot
posledice vnetja, imajo ljudje s celiakijo običajno
višje vrednosti permeabilnostnega indeksa v urinu.
Višje vrednosti so posledica večje absorbcije laktuloze zaradi sprememb tesnih stikov med eritrociti
in šibke absorpcije manitola zaradi izravnave sluznice.
The primary function of the small intestine is the
digestion of the intestinal contents, the absorption
of nutrients and electrolytes and water homeostasis
maintenance. However, small intestine has a very
important role as a barrier between the human
organism and the external environment. The mechanism of the barrier enables selective permeability
for some macromolecules. Some diseases have an
important influence on small intestine's integrity.
The small intestine's integrity differs when comparing healthy people and people with Coeliac disease. Due to the intestinal mucosa level off and
changes of tight junctions among enterocytes as a
result of the inflammation, people with Coeliac disease express typically higher values of the permeability index in the urine. The higher values are the
result of the intensively absorbed lactulose through
modification in tight junctions among enterocytes
and a weak absorption of mannitol due to the level
off of intestinal mucosa.
* R. Janša
University Medical Centre Ljubljana, Division of Internal Medicine, Department of Gastroenterology
Zaloška cesta 2, 1000 Ljubljana, Slovenia;
GASTROENTEROLOG 175
METODE
METHODS
Permeabilnostni indeks je predlog za novo metodo,
ki temelji na prepustnost tankega črevesa za dve
molekuli različnih velikosti: manjše molekule manitola in večje molekule laktuloze. Naša skupina je
bila sestavljena iz 10 bolnikov in 10 kontrol. Merili
smo koncentracijo sladkorja v peturnem vzorcu
urina po popitju raztopine, ki je vsebovala laktulozo in manitol. Permeabilnostni indeks je
kvocient med koncentracijo laktuloze in manitola
v urinu. Laktulozo in manitol v urinu smo merili z
absorpcijsko spektroskopijo.
The permeability index is a suggestion for a new
method, based on small intestine's permeability for
the two molecules of different sizes: the smaller molecule mannitol and the larger molecule lactulose.
Our group consisted of 10 patients and 10 controls.
We measured the concentration of sugars in fivehour urine samples after drinking a solution containing lactulose and mannitol. The permeability
index is the quotient of the lactulose and mannitol
concentrations. The principle of the detection of lactulose and mannitol in the urine was absorption
spectroscopy.
REZULTATI
Raziskava je pokazala, da so vrednosti permeabilnostnnega indeksa signifikantno razlikujejo med
obema skupinama. Specifičnost metode je 100 %
in občutljivost 60 %. Vrednost AUC pri ROC krivulji je 0,990.
ZAKLJUČKI
Študija dokazuje, da je permeabilnostni indeks primerni marker prepustnosti tankega črevesja pri
ljudeh s celiakijo. Spremenjena prepustnost za
makromolekule je posledica sprememb v Zonulinski proteinski frakciji tesnih stikov in izravnavi
vnete intestinalne sluznice. Kljub malemu vzorcu
je možno zaključiti, da je permeabilnostni indeks
pomemben potencialni diagnostični test pri bolnikih s celiakijo.
176 GASTROENTEROLOG
RESULTS
The study shows that the values of the permeability
index significantly differ between the two groups of
the people. We assessed the diagnostic value (specificity, sensitivity) of the test and compared the
results between groups with the ROC curve. The
specificity of the method was 100 % and the sensitivity 60 %. The AUC value is 0,990.
CONCLUSIONS
The study proves that the permeability index is an
appropriate marker of the small intestine’s permeability when it comes to people with Coeliac disease.
Different permeability is the consequence of
changes in Zonulin protein fraction of tight junctions and result is different permeability for macromolecules. Despite the small samples of the study it
can be concluded that the permeability index is an
important potential diagnostic test when it comes to
people with Coeliac disease.
Z liraglutidom povzročen akutni
pankreatitis
Liraglutide-induced acute pancreatitis
Betka Popič1, Karmen Klančnik2, Miroslav Vujasinović1
1 Department of Internal Medicine, Slovenj Gradec General Hospital
2 Medical Faculty at the University of Maribor
Gastroenterolog 2013; suplement 2: 177–178
UVOD
INTRODUCTION
Zdravila so redko vzrok akutnega pankreatitisa
(AP). Povzročijo ga le v 0,1-2 % primerov. Liraglutid je sintetični analog humanega glukagonu
podobnega peptida-1 (GLP-1), katerega uporabljamo za zdravljenje sladkorne bolezni tipa 2.
Razvščamo ga v skupino agonistov receptorjev
GLP-1. Apliciramo ga podkožno enkrat dnevno.
Klinične študije so pokazale možno povezavo med
GLP-1 analogi in nastankom AP. Prikazujemo primer z liraglutidom povzročenega AP.
Drug-induced acute pancreatitis (AP) is not common.
It has been estimated that only 0,1-2 % of all cases are
drug-induced. Liraglutide is synthetic analogue of
human glucagon-like peptide-1 (GLP-1) for treating
type 2 diabetes mellitus. It is classified as a GLP-1
receptor agonist, developed for once-daily subcutaneous administration. A possible association between
GLP-1 analogues and AP has been suggested.
PRIKAZ PRIMERA
CASE SUMMARY
50-letna ženska z znano sladkorno boleznijo tipa 2
je bila sprejeta na Oddelek za interno medicino
zaradi tri dni trajajoče bolečine v trebuhu. Teden
dni pred sprejemom smo uvedli liraglutid v dnevni
dozi 1,2 mg. Ob sprejemu smo ugotovili naslednje
laboratorijske izvide: lipaza 3,59 μkat/L, amilaza
1,75 μkat/L, C-reaktivni protein 19,3 mg/L, levkociti 12,7x109/L; testi jetrne funkcije, lipidogram,
kalcij in transferin z nizkim deležem ogljikovih
hidratov (CDT) so bili v mejah normale. Ultrazvok
A 50-year old woman with type 2 diabetes mellitus
(DM) was admitted to the Department of Internal
Medicine with three days history of abdominal pain.
One week prior to admission patient’s treatment of
DM was changed and liraglutide was induced at
daily dose of 1,2 mg. At admission the following laboratory values were found: serum lipase 3,59 μkat/L;
amylase 1,75 μkat/L, C-reactive protein 19,3 mg/L,
white blood count 12.7x109/L; normal liver function tests, lipids, calcium and carbohydrate deficient
We present a case of liraglutide-induced AP.
* Betka Popič, MD
Department of Internal Medicine, Slovenj Gradec General Hospital, Gosposvetska 1,
2380 Slovenj Gradec, Slovenia
GASTROENTEROLOG 177
Naknadno je bil narejen endoskopski ultrazvok, ki
je pokazal cistično lezijo v telesu pankreasa premera 7 mm. CT s kontrastom je bil normalen. Leto
dni po prebolelem AP je bolničino klinično stanje
brez posebnosti.
transferrin. Abdominal ultrasound revealed inhomogeneous pancreatic parenchyma with normal
gallbladder and bile ducts. Liraglutide was discontinued and combination of glibenclamide and metformin was introduced. Abdominal pain was alleviated with spasmolytic and analgetic therapy. On the
9th hospital day the patient was discharged to home
care in clinically stable condition. Additionaly, endoscopic ultrasound was performed and cystic lesion
in pancreatic body (7 mm in diameter) was found.
Contrast-enhanced computed tomography was unremarkable. One year after AP her clinical status is
unremarkable.
ZAKLJUČEK
CONCLUSIONS
Liraglutid in drugi analogi GLP-1 so lahko vzrok
za nastanek AP. Bolnike moramo pred uporabo
tega zdravila opozoriti na možne stranske učinke
ter poučiti o simptomih AP.
Liraglutide and other analogues of GLP-1 could be
associated with AP. Patients should be aware of sideeffects and informed about symptoms of AP.
trebuha je pokazal nehomogen parenhim trebušne
slinavke, žolčnik in žolčni vodi so bili brez posebnosti. Ukinili smo liraglutid in uvedli kombinacijo
glibenklamida in metformina. Ob bolečini je prejemala spazmolitično in analgetično terapijo. Devetega
dne zdravljenja je bila bolnica v stabilnem stanju
odpuščena v domačo oskrbo.
178 GASTROENTEROLOG
Hematemeza zaradi erozivnega
duodenitisa pri maratoncih –
prikaz dveh primerov
Hematemesis due to erosive duodenitis in
marathon runners – a report of two cases
Miroslav Vujasinović*,1, Petra Kaplan2
1 Department of Internal Medicine, Slovenj Gradec General Hospital
2 Division of Internal Medicine, Medical Emergency Unit, University Medical Centre Ljubljana
Gastroenterolog 2013; suplement 2: 179
Key words: hematemesis, duodenitis, runners
POVZETEK
ABSTRACT
Gastrointestinalne težave so pogoste med tekačih
na dolge proge. Simptomi se lahko pojavijo med ali
takoj po naporni vadbi. Tek na dolge proge postaja
vse bolj priljubljen s sodelovanjem večjega števila
pripravljenih in manj pripravljenih udeležencev na
tekmovanjih. Leta 2006 je v vseh kategorijah Ljubljanskega maratona sodelovalo 8287 tekačev. Leta
2012 je število udeležencev iz 41 držav poraslo na
Gastrointestinal complaints are common in long distance runners. The symptoms may occur during or
immediately after a strenuous workout. Long distance running is becoming very popular and large
numbers of trained and untrained people participate in competitions. In 2006, a total of 8287 competitors participated in Ljubljana marathon in all
categories and in 2012 that number increased to
16302 runners from 41 countries.
We report two cases of marathon runners who were
presented at the Medical Emergency Unit after having
vomited black gastric content which was Hemoccult
positive. Their previous medical histories were normal; they did not take any medications and denied
any recent illnesses, but before and during the race
they had no fluid intake. An urgent upper
endoscopy showed erosive gastritis and severe erosive bulbitis with no sign of active bleeding. Both
patients were discharged without any sequelae.
Due to a continuous increase in the number of
marathon participants with many of them not properly trained, physicians and first aid teams should
be aware of gastrointestinal compliants in longdistance runners.
16 302. Predstavljamo dva primera maratoncev, ki sta
bila obravnavana na Internistični prvi pomoči zaradi
bruhanja črne želodčne vsebine. Bolnika sta imela
normalno osebno anamnezo, nista uživala zdravil,
pred in tekom tekmovanja pa nista uživala tekočine.
Urgentna endoskopija zgornjih prebavil je pokazala
erozivni gastritis in hudi erozivni duodenitis brez znakov aktivne krvavitve. Oba bolnika sta bila odpuščena
v domačo oskrbo brez trajnih zdravstvenih posledic.
Zaradi stalnega naraščanja števila udeležencev maratona, med katerimi je veliko slabo pripravljenih, se
morajo zdravniki in ekipe nujne pomoči zavedati
gastrointestinalnih težav pri tekačih na dolge proge.
* Corresponding author: Miroslav Vujasinović MD MSc
Slovenj Gradec General Hospital, Department of Internal Medicine
Gosposvetska 1, 2380 Slovenj Gradec, Phone: +386 2 8823400, Fax: +386 2 8823505, E-mail: [email protected]
GASTROENTEROLOG 179
ARC sindrom – klinični primer
Rok Orel*, Jakob Zapušek, Gregor Nosan, Marjeta Sedmak, Tanja Kersnik Levart
Klinični oddelek za gastroenterologijo, hepatologijo in nutricionistiko
Pediatrična klinika, UKC Ljubljana
Gastroenterolog 2013; suplement 2: 180–182
POVZETEK
ABSTRACT
Kratica ARC označuje trojico kliničnih znakov, ki
so značilni za sindrom: Artrogripoza, Renalna
tubulna acidoza s Fanconijevim sindromom in holestaza (ang. Cholestasis). Gre za autosomno
recesivno bolezen, pri kateri se pojavi mutacija
VPS33B gena (15q26), ki kodira regulacijo zlivanja
membran celic preko SNARE proteinov. V klinični
sliki so pogosto pridruženi še huda distrofija,
ihtioza, nagnjenost h krvavitvam zaradi motene
agregacije trombocitov zaradi odsotnost alfa granul,
v 10 % so pridružene tudi malformacije srca. Prisotna
so lahko tudi telesna stigmata z nizko položenimi
ušesi, prominentnim čelom in velikimi palci. Prognoza bolezni je slaba, praviloma otroci umrejo do
drugega leta starosti. Glavna razloga smrti so septična stanja in krvavitve ob diagnostičnih posegih,
zato se bioptična diagnostika pri otrocih s sumom
na ARC sindrom odsvetuje, nadomestiti jo mora
genetska analiza. Predstavljen je klinični primer
dečka, ki je bil voden na Pediatrični kliniki Univerzitetnega kliničnega centra Ljubljana z dokazanim
ARC sindromom.
ARC acronime is used to describe initial letters of clinical signs that are present in patients with this condition. These are Arthrogryposis, Renal tubular acidosis
along with Fanconi syndrome and Cholestasis. It is an
autosomal recesive disorder due to mutation of
VPS33B gene (15q26), that encodes proper membrane fusion by SNARE proteins. This condition is
often associated with severe dystrophy, ichthyosis, tendency for bleeding due to disfunctional platelet aggregation on account of absent alpha granules, in 10 % of
cases cardiac abnormalities may be present. Corporal
stygmata may also be present, often as low seated ears,
prominent forehead and large thumbs. Prognosis is
lethal, death occures till second year of age. Major
causes of death are sepsis and bleedings during invasive diagnostic procedures, this is why genetic analysis should replace organ biopsy as a first line diagnostic test for ARC syndrome. A case report article of
a boy with ARC syndrome, who was treated in
Children’s hospital of University medical centre
Ljubljana, is presented below.
Prof. dr. Rok Orel, dr. med.,
Klinični oddelek za gastroenterologijo, hepatologijo in nutricionistiko, Pediatrična klinika, UKC Ljubljana
Bohoričeva 20, 1525 Ljubljana
180 GASTROENTEROLOG
PRIKAZ PRIMERA
V porodnišnici Postojna se je novembra 2011 rodil
deček, H.A., plod prve nosečnosti, rojen po normalni poti. Porodna teža 3490, porodna dolžina 50
cm, obseg glave 36 cm, Apgar 9/10/10. V družinski anamnezi ni bilo odstopanj, tako oče kot mati
sta bila oba zdrava, doma iz Bosne in Hercegovine,
brez konsangvinitete.
Težave so se pri dečku pričele tretji dan po porodu,
kazale so se kot nenapredovanje na telesni teži,
potreboval je infuzijo, pojavila se je konjugirana
hiperbilirubinemija, policitemija ter metabolna acidoza s pH 7.28 in presežkom baze –12. Presejalni
testi so bili normalni, UZ kolkov D-IIa in L-1a.
Decembra 2011 je bil deček v starosti 7 dni premeščen na neonatalni oddelek Pediatrične klinike
Univerzitetnega kliničnega centra Ljubljana. Ob sprejemu je bil deček hipoton, izražene je imel znake
distrofije, prisoten je bil ikterus, obojestransko se je
izrazil calcaneovalgus in displazija desnega kolka. V
laboratorijskih izvidih je bila v ospredju hiperkloremična metabolna acidoza in proteinurija. V smislu
izključevanja metabolopatij so bili vsi izvidi (laktat,
piruvat, NH3, galaktoza, alfa 1 antitripsin, aminokisline v serumu, organske kisline v serumu in urinu,
iontoforeza) v mejah normale. Morebitne okužbe s
hepatotropnimi patogeni so bile izključene. Opravljen
je bil UZ glave, kjer je bil ob prvem pregledu postavljen sum na krvavitev v horoidni pletež stranskih
ventriklov, kontrolni UZ izvid je bil v mejah normale.
Zaradi tubularne okvare ledvic je že na neonatalnem
oddelku prejemal redno terapijo z NaHCO3.
Poslan je bil vzorec krvi v Birmingham za genetsko
analizo – potrjena VP33B mutacija.
Deček je bil nato voden multidisciplinarno s strani
konziliarnih subspecialistov. Težave so po enem
mesecu postale vse izrazitejše. S strani gastroenterološke obravnave je bila v ospredju vse izrazitejša
distrofija. Deček je bil sprva hranjen z Aptamil ADC
(Allergy digestive care) formulo. Pogosto je hrano
zavračal, nemalokrat tudi bruhal. Zato je imel vstavljeno nazogastrično sondo, po kateri je bil
dohranjevan z MCT (srednjeverižnimi trigliceridnimi)
olji in dodatkom glukoznega polimera in 2 % rižka.
Kljub nazogastrični sondi se težave z nenapredovanjem teže še vedno niso izboljšale. Zato je bil dečku
uveden CVK za parenteralno hranjenje. Na parente-
ralni prehrani ob vzporedni enteralni prehrani preko
nazogastrične sonde je deček začel pridobivati na
teži. Blato na kri je bilo negativno, analiza blata na
prebavljivost pa je pokazala malabsorbcijo maščob in
proteinov. UZ trebuha je bil v mejah normale. Opravi
tudi scintigrafijo jeter (HIDA), ki pokaže intrahepatalno holestazo. Izključen je bil sindrom Allagile.
Hepatalna biopsija je bila glede na genetsko potrjeno
diagnozo kontraindicirana. Uvedena je bila terapija z
ursodeoksiholno kislino.
S strani nefrološke obravnave je bila v ospredju
tubularna okvara ledvic s Fanconijevim sindromom, redno je prejemal terapijo z NaHCO3.
S strani hematološke obravnave je bilo najti v krvi
sive trombocite z odsotnimi alfa granulami. Ob
tem je bila koagulacija normalna.
S strani ortopedske obravnave je deček sprva nosil
mavčne longete, nato opornice po Otto Borlinu.
S strani kardiološke obravnave ni bilo posebnosti,
UZ srca je bil v mejah normale.
Tudi s strani imunološke obravnave ni bilo najti
posebnosti.
Meseca januarja 2012 je bil za dečka opravljen timski konzilij, kjer so bili glede na dečkovo klinično
stanje in potrjeno diagnozo sprejeti naslednji sklepi:
1. Pri dečku so invazivne diagnostične preiskave
kontraindicirane.
2. Operacija po Kasaiu ni smiselna, ker so
ekstrahepatalni vodi prehodni.
3. Ponovno se dečku uvede popolna enteralna
prehrana preko nazogastrične sonde.
4. Sprejet sklep o odstopu od reanimacijskih
postopkov v soglasju s starši.
Deček je bil nato v bolnišnični obravnavi še do meseca
marca 2012, v tem času je prebolel tri sepse, iz hemokultur je dvakrat porasla E. coli in enkrat S. aureus. V
mesecu marcu je bil nato na željo staršev odpuščen v
domačo oskrbo na terapiji z ursodeoksiholno kislino,
NaHCO3 in enteralnim hranjenjem preko nazogastrične sonde z Aptamil ADC (Allergy digestive care)
formulo z dodatki.
Maja 2012 je bil deček zadnjič hospitaliziran, kjer
mu je bila uvedena paliativna terapija s tramadolom in morfijem. Umrl je v starosti 7 mesecev.
GASTROENTEROLOG 181
KLINIČNI PRIMER
• H.A., deček, 1. nosečnost, PT 3490g, PD 50, OG 36,
Apgar 9/10/10
• Družinska anamneza: bp, ni konsangvinitete, starši iz
Bosne in Hercegovine
• Porodnišnica: slabo napredovanje telesne teže, ihtioza,
konjugirana hiperbilirubinemija, policitemija, metabolna
acidoza
ARC SINDROM
Artrogripoza
Renalna tubulna acidoza (Fanconijev sindrom)
Cholestaza z normalnim gGT
• pogosto pridruženo: huda distrofija, ihtioza, nagnjenost h
•
•
•
•
krvavitvam zaradi motene agregacije trombocitov z
odsotnostjo alfa granul, v 10% pridružene malformacije srca
lahko so prisotna telesna stigmata z nizko položenimi
ušesi, prominentnim čelom in velikimi palci
autosomno recesivna bolezen, mutacija VPS33B gena
(15q26), ki kodira regulacijo zlivanja membran celic
preko SNARE proteinov
glavna razloga smrtnosti: septična stanja ter krvavitve ob
diagnostičnih posegih
prognoza: smrt do drugega leta življenja
Neonatalni oddelek Pediatrične klinike
Univerzitetnega kliničnega centra Ljubljana:
• Klinična slika: distrofija, hipotonija, ikterus, bilateralni
calcaneovalgus, displazija D kolka
• Izvidi: hiperkloremična metabolna acidoza, proteinurija.
Metabolni screening, iontoforeza in alfa 1 antitripsin v
mejah normale. Sindrom Allagile izključen.
Okužbe s hepatotropnimi patogeni izključene
• HIDA: intrahepatalna holestaza
• Hepatalna biopsija: kontraindicirana
• DGN: ARC sindrom
• Gastroenterološka obravnava:
Sprva hranjenje z Aptamil ADC (Allergy digestive care)
formulo, nato vstavitev nazogastrične sonde in dodatek
MCT (srednjeverižnih trigliceridnih) olj, glukoznega
polimera in 2% rižka. Zaradi hude distrofije še
parenteralna prehrana. TH: ursodeoksiholna kislina
• Nefrološka obravnava: tubularna okvara ledvic s
Fanconijevim sindromom. TH: NaHCO3
• Hematološka obravnava: Sivi trombociti brez alfa
granul, normalna koagulacija
• Ortopedska obravnava: Mavčne longete, opornice po
Otto Borlinu
• Kardiološka obravnava: Ultrazvok srca v mejah normale
• Imunološka obravnava: Brez odstopanj od normale
• Birmingham: Genetska analiza: Mutiran gen VP33B
Potek bolezni:
• 3 x sepsa - 2x E.coli in 1x Staph. Aureus
Smrt po šestih mesecih od postavitve diagnoze
CASE REPORT
• H.A., boy, 1. pregnancy, BW 3490g, BL 50, HC 36,
Apgar score 9/10/10
• Familial history: normal, no consangvinity, parents from
Bosnia and Herzegovina
• Nursery: failure to thrive, ichthyosis,
hyperbilirubinemia, policythemia, metabolic acidosis
ARC SYNDROME
Arthrogryposis
Renal tubular acidosis (Fanconi syndrome)
Cholestasis with normal gGT
• often associated with: severe dystrophy, ichthyosis,
tendency for bleeding due to disfunctional platelet
aggregation on account of absent alpha granules, in 10%
of cases cardiac abnormalities are present
• corporal stygmata may be present, often as low seated
ears, prominent forehead and large thumbs
• autosomal recesive disorder, mutation of VPS33B gene
(15q26), that encodes proper membrane fusion by
SNARE proteins
• major causes of death: septic states and bleedings during
invasive diagnostic procedures
prognosis: death till second year of age
Department of neonatology, Children's hospital,
University medical centre Ljubljana:
• Chlinical manifestations: dystrophy, hypotonia, icterus,
bilateral calcaneovalgus, displastic right hip joint
• Blood tests: hyperchloremic metabolic acidosis,
proteinuria. Metabolnic screening, iontophoresis and
alpha 1 antitripsine showed no pathological deviations.
Allagile syndrome was excluded. Hepatopatothropic
pathogens were excluded
• HIDA: intrahepatal cholestasis
• Hepatal biopsy: contraindicated
• DGN: ARC syndrome
• Gastroenterological management: firstly fed with
Aptamil ADC (Allergy digestive care) formula, followed
by insertion of nasogastric probe and addition of MCT
(mid – chain trigliceride) oils, glucose polimere and 2%
rice jelly to the diet, followed by parenteral feeding due to
severe dystrophy. TH: ursodeoxycholic acid
• Nephrological management: tubular kidney disfunction
with Fanconi syndrome. TH: NaHCO3
• Hematological management: grey platelets without
alpha granules, normal coagulation tests
• Orthopedic management: leg plasters, Otto Borlin splints
• Cardiological management: cardiac sonography normal
• Imunological management: no disorders found
• Birmingham: genetic analysis: VP33B gene mutation
Disease outcome:
182 GASTROENTEROLOG
• 3 x sepsis - 2x E.coli and 1x Staph. Aureus
Death after six months from diagnosis date
Ustreznost predpisovanja zaviralcev
protonske črpalke
Appropriateness of proton pump inhibitors
prescribing
Miroslav Vujasinović*,1, Martin Tretjak1, Bojan Tepeš2, Apolon Marolt1, Milica Miljković1,
Karmen Klančnik3
1 Department of Internal Medicine, Slovenj Gradec General Hospital
2
Abakus Medico Diagnostic Centre Rogaška
3 Medical Faculty at the University of Maribor
Gastroenterolog 2013; suplement 2: 183–184
IZHODIŠČA
BACKGROUND
Zaviralci protonske črpalke (ZPČ) so glavno z dokazi
podprto zdravilo za zdravljenje obolenj zgornjega
prebavnega trakta, kot so gastroezofagealna refluksna bolezen, dispepsija in ulkusna bolezen. ZPČ so
ena izmed najpogosteje predpisanih zdravil v Sloveniji, ocenjena vrednost predpisanega esomeprazola,
pantoprazola in omeprazola je v letu 2011 znašala
16 milijonov evrov. Objavljenih je bilo več poročil o
neustreznem predpisovanju ZPČ. Raziskava iz
Velike Britanije je pokazala, da ima ZPČ predpisan
24 % bolnikov napotenih v bolnišnici, od teh le 54 %
z ustrezno indikacijo.
Proton pump inhibitors (PPI) are the most important evidence based drugs for treatment of different
upper gastrointestinal tract diseases. They are
among the most often prescribed drugs in Slovenia
with estimated cost of 16 million EUR in 2011.
There have been numerous reports of inappropriate
prescribing. In a British study only 51 % of patients
admitted to a general hospital had an appropriate
indication. We are presenting preliminary results.
Predstavljamo lastne preliminarne rezultate.
NAMEN IN METODE
Za oceno ustreznosti predpisovanja ZPČ glede na
priporočila smo retrospektivno pregledali medicinsko dokumentacijo 500 zaporednih bolnikov, ki
so bili napoteni v ambulanto internistične prve
pomoči Oddelka za interno medicino SB Slovenj
Gradec. Analizirali smo demografske podatke,
AIMS AND METHODS
To evaluate the indications for use of PPI in accordance with the currently recommendations. A retrospective analysis of medical documentation of 500
consecutive patients sent to Department of Internal
Medicine for urgent assessment. We analyzed demographic features, indications and the adequacy of PPI
prescription.
* Miroslav Vujasinović, MD MSc
Department of Internal Medicine, Slovenj Gradec General Hospital, Gosposvetska 1
Slovenj Gradec 2380, Slovenia
GASTROENTEROLOG 183
vzrok napotitve, predpis in indikacijo za predpis
ZPČ ter ustreznost te indikacije.
REZULTATI
Med 500 bolniki je bilo 251 žensk (50,2 %) in 249
(49,8 %) moških. Povprečna starost je bila 63,3 ±
17,4 let (18–95 let). Večina bolnikov je bila napotenih zaradi srčnih bolezni (26 %), preostali zaradi
bolezni prebavil (21,4 %), pljuč (16 %), živčnega
sistema (7,8 %), žilja (7 %) ter drugih obolenj.
ZPČ je imelo predpisanih 121 bolnikov (24,2 %),
tretjina v skupini z boleznimi prebavil. Najpogosteje predpisan ZPČ je bil pantoprazol (v 79,3 %).
Ustrezna indikacija je bila najdena pri 69 bolnikih
(57 %), najpogosteje kot zaščita zgornjih prebavil
ob sočasnem jemanju antiagregacijskih zdravil (33 %),
peroralnih antikoagulacijskih zdravil (23,6 %), kortikosteroidov (9,7 %) in nesteroidnih analgoantirevmatikov
(5,6 %).
Pri 52 bolnikih (43 %) ustrezne indikacije za predpis ZPČ nismo našli.
ZAKLJUČEK
Naši podatki kažejo na visok delež neustrezno
predpisanih ZPČ. V tej skupini bo potrebna nadaljnja
analiza medicinske dokumentacije in pridobitev
podatkov s strani osebnih zdravnikov z namenom
boljšega razumevanje razlogov za neustrezno predpisovanje.
Neustrezno predpisovanje ZPČ dviguje zdravstvene
stroške in bolnike izpostavlja nepotrebnemu tveganju
za stranske učinke. Potrebno bo poskrbeti za skrbnejše
upoštevanje priporočil in redno spremljanje indikacije
za predpis ZPČ pri posameznem bolniku.
184 GASTROENTEROLOG
RESULTS
There were 500 patiens: 251 female (50.2%) and
249 (49.8%) male; mean age 63.3 ± 17.4 years
(range 18–95). The majority of patient were presented due to cardiac disorders (26%), followed by
gastrointestinal (21.4%), pulmonary (16%), neurologic (7.8%), vascular (7%) and other disorders.
121 patients (24.2%) had a PPI therapy (one third
of them were in the group of patients with gastrointestinal disorders). The most often prescribed
PPI was pantoprazole (79.3%).
An appropriate indication for PPI therapy was
found in 69 patients (57%), most often as gastric
protection with concomitant therapy (33.3% were
taking antiplatelet agents, 23.6% anticoagulants,
9.7% corticosteroids and 5.6% NSAID).
In 52 patients (43%) an appropriate indication could
not be found.
CONCLUSIONS
Our study found high rates of patients in whom
appropriate indication for PPI prescribing could not
be found. In that group of patients further analysis of
medical documentation and telephone survey of general practitioners should be performed. Inappropriate
prescribing of PPI raises healthcare cost and exposes
patients to potential harmful side effects.
Effort has to be made to change the PPI prescribing
policy in primary care. Indication for PPI prescription should be assessed periodically. Reasons for
inadequate PPI prescriptions need to
be explored in more depth to tailor interventions
promoting appropriate PPI prescribing.
S kapecitabinom povzročen transmuralni
miokardni infarkt – prikaz primera
Capecitabine-induced transmural myocardial
infarction – case report
Miroslav Vujasinović*, Zdenko Kikec, Cirila Slemenik Pušnik
Department of Internal Medicine, Slovenj Gradec General Hospital
Gastroenterolog 2013; suplement 2: 185–186
IZHODIŠČA
BACKGROUND
Kapecitabin je široko uporabljen kemoterapevtik
iz skupine neantraciklinskih pripravkov. Je peroralna oblika in predzdravilo 5-fluorouracila (5-FU),
ki se uporablja pri zdravljenju raka črevesja in
danke, dojke, želodca in trebušne slinavke v kombinaciji z ostalimi kemoterapevtiki ali samostojno.
Miokardni infarkt je zelo redek neželen učinek.
Predstavljamo primer bolnice brez predhodno znanih kardiovaskularnih simptomov, pri kateri je
prišlo do razvoja transmuralnega miokardnega
infarkta tekom terapije s kapecitabinom.
Capecitabine is a widely used nonanthracycline cancer chemotherapy agent. It is an orally administrated pro-drug of 5-fluorouracil (5-FU) and is used
in the treatment of colorectal, breast, gastric and
pancreatic cancers, both as a single agent and as a
component of a combination chemotherapy.
Myocardial infarction is an uncommon adverse
effect. We present a case of a female patient without
previous cardiovascular symptoms who developed
transmural myocardial infarction during the treatment with capecitabine.
PRIKAZ PRIMERA
CASE REPORT
59-letna bolnica je bila sprejeta na Oddelek za
interno medicino zaradi anamnestičnega podatka o
pet dni trajajoči torakalni bolečini, ki se je razvila
tekom četrtega ciklusa kemoterapije s kapecitabinom. Oktobra 2011 je bila opravljena resekcija
transverzalnega dela debelega črevesa zaradi adenokarcinoma in nato uvedena adjuvantna kemoterapija
s kapecitabinom. Ob sprejemu so bile v elektrokardiogramu vidne elevacije ST veznice v spodnjestenskih
A 59-year-old female was admitted to the
Department of Internal Medicine with a history of
chest pain of 5-days’ duration during the fourth
cycle of capecitabine treatment. In October 2011
she uderwent a surgical resection due to adenocarcinoma of the transversal colon followed by adjuvant
chemotherapy with capecitabine. On admission, the
electrocardiogram showed ST-segment elevation in
inferior leads. The ishaemic changes were addi-
* Miroslav Vujasinović, MD MSc
Department of Internal Medicine, Slovenj Gradec General Hospital, Gosposvetska 1
Slovenj Gradec 2380, Slovenia
GASTROENTEROLOG 185
odvodih. Ishemične spremembe so bile dodatno
potrjene s povišanimi vrednostmi visoko senzitivnega troponina T in z ehokardiografsko preiskavo
srca. Bolnico smo zdravili z nizkomolekularnim
heparinom in antiagregacijsko terapijo.
tionaly confirmed by very high levels of high sensitive troponin T and echocardiographic examination.
The patient was treated with low molecular weight
heparin and anti-agregation therapy.
CONCLUSION
ZAKLJUČEK
Miokardni infarkt je redek neželen učinek pri bolnikih
zdravljenih s kapecitabinom. Spekter s kapecitabinom
povzročenih kardiotoksičnih sprememb je širok in
vključuje: angino, aritmije, miokardni infarkt in
nenadno srčno smrt. Poročajo o 3–9 % incidenci
kardiotoksičnosti. Simptomi se lahko pojavijo drugi
ali tretji dan po uvedbi kapecitabina. Predvideva se,
da so mehanizemi nastanka stranskih učinkov
kapecitabina enaki kot pri intravenski aplikaciji 5FU. Najverjetnejši mehanizmi kardiotoksičnosti so:
toksičen učinek na endotelij koronarnega žilja, toksični miokarditis, spazem koronarnih arterij in
tromboza. Prvi ukrep pri pojavu kardiotoksičnosti
zaradi kapecitabina je takojšnja prekinitev jemanja
zdravila. Zaradi vse večje uporabe v onkološkem
zdravljenju, moramo biti zdravniki pozorni na
pojav kardiotoksičnosti, še posebej pri bolnikih z
znano ishemično boleznijo srca v anamnezi.
186 GASTROENTEROLOG
Myocardial infarction is a rare condition in patients
during treatment with capecitabine. The spectrum of
capecitabine-induced cardiotoxicity is wide and icludes
angina, arrhythmias, myocardial infarction and sudden
death. The reported incidence of cardiotoxicity ranges
from 3 to 9 %. Published case reports indicate that
symptoms may occur within two to three days after the
initiation of capecitabine therapy. It has been postulated that capecitabine has the same mechanism of the
side effect as intravenous 5-FU. Possible mechanisms
are: direct toxic effects on the coronary endothelial
intima, toxic myocarditis, coronary artery vasospasm
and thrombosis. The main treatment of capecitabineinduced cardiotoxicity is withdrawal of the drug. Due
to its increasing use in oncologic therapy, specialists
should be aware of cardiotoxicity especially when used
in patients with the history of ishaemic heart disease.
Serious adverse events associated with
ferric carboxymaltose administration in
patients with inflammatory bowel disease
treated with anti-TNF drugs
Vanesa Anderle*, Nejc Sever, Nataša Smrekar
Clinical Department of Gastroenterology, University Clinical Centre Ljubljana, Japljeva 2, Slovenia
Gastroenterolog 2013; suplement 2: 187–188
INTRODUCTION
METHODS
Iron deficiency anemia is very common among the
patients with a chronic illness. The prevalence
among the inflammatory bowel disease (IBD)
patients is up to 75%. About 20–30% patients present with iron deficiency without anemia. Both conditions are an important cause of chronic fatigue
syndrome in IBD patients. International guidelines
recommend parenteral iron replacement for treating iron deficiency anemia in IBD patients.
However there are more adverse events documented
with parenteral iron compared to oral supplements
especially in patients with an active disease. Ferric
carboxymaltose (FCM) is considered a safe drug.
The medical records of 62 patients who received
parenteral ferric carboxymaltose during the period
from 1.1.2011 to 2.2.3013 were analysed. Data
included the underlying disease, serum iron levels,
CRP, treatment with biologic drugs (anti-tumor
necrosis factor alpha (anti-TNF)) and any observed
adverse events associated with biologic therapy or
FCM application. Serious adverse events were
described as: low blood pressure, chest pain, dyspnea, tachycardia, nausea, generalized urticarial
(hives), excessive sweating and flushing.
* Vanesa Anderle, dr. med.
Clinical Department of Gastroenterology, University Clinical Centre Ljubljana
Japljeva 2, Slovenia
GASTROENTEROLOG 187
RESULTS
The underlying disease distribution is displayed in
a pie chart 1. 25 patients were male and 37 were female.
Of 53 patients with IBD 32 (60,4 %) were treated
with anti-TNF drugs, 16 were receiving infliximab
and 16 patients adalimumab.
Of 62 patients in the study group the adverse events were
observed in 4 (6,5 %) patients (3 female and 1 male).
All of the affected individuals had an inflammatory
bowel disease and were receiving anti-TNF therapy.
Three patients had Crohn’s disease and one ulcerative colitis. Two patients were receiving adalimumab
and two infliximab. Both individuals on adalimumab
were previously treated with infliximab. One individual had a documented allergic reaction to infliximab.
The severity of the underlying disease at the time of
the adverse event is unfortunately not available.
The exact mechanism causing the adverse events is
unclear. Possible mechanism is IgG mediated reaction between the FCM and the anti-TNF drug
(IgG antibody) or between the FCM and antibodies
developed against the biologic drug. Currently there
is a lack of evidence to classify this reaction as anaphylaxis.
CONCLUSION
Serious adverse events associated with ferric carboxymaltose (FCM) were only observed in IBD patients
receiving anti-TNF drugs. All events occurred after
the first administration of FCM. Possible mechanism is cross reaction between FCM and anti-TNF
drug (IgG antibody) or FCM and antibodies developed against the biologic drug. Caution is advised
administering FCM to IBD patients treated with
anti-TNF drugs.
Pie chart 1 - Underlying disease
Cirrhosis; 2%
Coeliac disease; 6%
Diagnostic
evaluation; 6%
Ulcerative colitis;
23%
188 GASTROENTEROLOG
Crohn's disease;
63%