Original Articles Initial Experience with Ablation of the Prostate Absolute Ethanol

Original Articles
C. T. Huang, et al
Initial Experience with Ablation of the Prostate
Using a Transurethral Intraprostatic Injection of
Absolute Ethanol
Chang-Te Huang, Chi-Ping Huang
Division of Urology, St. Joseph Hospital, Huwei, Yunlin, Taiwan, R.O.C.
OBJECTIVES: Despite extensive research involving numerous treatments for benign prostatic hyperplasia (BPH), the
ideal modality has yet to be determined. We clinically evaluated chemoablation of the prostate using a transurethral
intraprostatic absolute ethanol injection (AEI).
MATERIALS AND METHODS: Dehydrated ethanol was injected transurethrally into 22 patients with prostatic
obstruction. The mean patient age was 72.8 ± 9.0 (median, 20.0) years. Injections were performed under cystoscopic
surveillance at bilateral sites of the prostate for an overall amount of 3~30 (mean, 9.9 ± 6.9; median, 6.0) ml of ethanol
for each patient.
RESULTS: There were no intraoperative complications, but postoperative urinary retention occurred in 4 patient
(18.2%). The mean hospital stay was 2.7 ± 2.9 (median, 2.0) days. The mean prostate volume decreased from 51.6 ±
22.3 (median, 50.3) to 29.7 ± 16.9 (median 25.6) g at 3 months postoperatively (p = 0.001; paired-sample t-test). The
mean IPSS score decreased from 26.1 ± 4.2 (median, 26) to 20.7 ± 5.2 (median, 20.0) at 3 months postoperatively (p =
0.022; paired-sample t-test); the mean peak urine flow rate increased from 9.8 ± 5.4 (median, 9.0) to 14.8 ± 6.0 (median,
15) ml/s at 3 months postoperatively (p = 0.035; paired-sample t-test). There were no significant differences at 6 months
when the same parameters were assessed. Pathological findings for all patients showed no evidence of malignancy in the
treated area. Conditions for which the most patients complained about were frequency (21/22), transient difficult micturition (19/22), and acute urinary retention (4/22).
CONCLUSIONS: Our initial results suggest that this technique can be performed with a short hospital stay or as an
outpatient procedure. It can be considered another treatment choice for prostatic obstruction due to benign hyperplasia,
especially when a patient is at high risk. Controlling the postoperative frequency of alcohol-induced prostatitis is still a
problem we cannot ignore. (JTUA 18:17-22, 2007)
Key words: benign prostatic hyperplasia, transurethral intraprostatic absolute ethanol injection, frequency.
INTRODUCTION
Most men 50~80 years old will develop some degree of benign prostatic hyperplasia (BPH); in community-based epidemiological studies, it is reported by almost 25% of men aged ≥ 40 years.1,2 By 60 years of age,
its prevalence is greater than 50%, and by age 85 it is as
high as 90%. Similar to the histologic evidence, the
prevalence of bothersome symptoms also increases with
age.3 The prostate in males is a composite organ whose
glandular tissues comprise 3 histologically and anatomically distinct zones: the peripheral zone, central zone,
and transition zone (TZ). The TZ is the smallest, and
normally makes up 5% of the glandular prostate; it is
Address reprint requests and correspondence to:
Dr. Chang-Te Huang, Division of Urology, Department of Surgery,
St. Joseph Hospital, 74 Xin-Sheng Road, Huwei, Yunlin, Taiwan 632,
R.O.C.
Tel: 886-5-6337333#2321 E-mail: [email protected]
JTUA 2007 18 No. 1
the only zone where BPH develops.4 Detailed autopsy
and radical prostatectomy studies have shown that these
nodules are mainly caused by budding and branching of
the epithelial glandular tissue (i.e., ducts and acini), and
to a lesser degree by glandular unit enlargement or proliferation of prostatic stromal elements (i.e., smooth
muscle and fibroblasts).5 Although the progression of
BPH is slow, some patients deteriorate more rapidly than
others. Trachtenberg reported that an increased symptom severity, a low maximum urinary flow rate, and a
high post-void residual urine volume (PVR) are considered major risk factors for BPH progression by
urologists.6 So whichever we choose, the treatment for
BPH should integrate resolution of symptoms and
stopping, or at least delaying, the underlying progression.
Despite extensive research involving numerous treatments for BPH, the ideal modality has yet to be
determined. We confirm the feasibility, safety, and efficacy of a new approach for treatment by chemoablation
NT
Original Articles
Ablation of the Prostate Using a Transurethral Intraprostatic Injection of Absolute Ethanol
of the prostate with absolute ethanol, which may be an
innovative transurethral procedure for the relief of obstructive BPH.
MATERIALS AND METHODS
Between December 2003 and April 2004, dehydrated ethanol was injected transurethrally into a group
of 22 patients with documented outlet obstruction due
to BPH. The mean age was 72.8 ± 9.0 (range, 55~90)
years. All patients provided informed consent to accept
this elective procedure, and underwent simultaneous preoperative studies for the prostate specific antigen (PSA)
level, peak urinary flow rate (Qmax), International Prostate Symptom Score (IPSS), and prostate volume. The
risk for prostate cancer is elevated when the PSA level
exceeds 4 ng/ml, and a transanal prostatic biopsy was
recommended before these patients joined this study.
The average PSA level was 4.6 ± 4.7 (range, 0.5~38)
ng/ml. Preoperatively, the mean peak urine flow rate was
9.8 ± 5.4 (range, 4~31) ml/s, and the average IPSS symptom score was 26.1 ± 4.2 (range, 17~32). Preoperative
ultrasound estimated the prostate weight to range 22.
3~112 (mean, 51.6 ± 22.3) g. No patients with acute
urinary retention were included in this study. All patients were admitted to the hospital for at least 24 hours.
The mean age was 69.5 (range, 61~84) years.
The transurethral prostatic injection was performed
in the operating room for all patients under intravenous
general anesthesia. The endoscopic injection was performed at 3 to 5 sites in the right and left lobes of the
prostate using an InjecTx endoscopic device (Fig. 1) or
a 0-degree pediatric cystoscope with a 20-gauge, passive deflection, hollow-core needle passing the working channel, then 3 to 30 ml of ethanol was infused into
the tissue. The injection was mainly given at the 3 and 9
o'clock positions for patients with mild BPH. When there
was severe BPH with elongation of the prostatic urethra,
more injections were given at 1 or 2 sites in the bladder
neck, or in the middle lobe for patients with middle lobe
enlargement. The depth of the needle was around 1.5
cm, and the amount of ethanol was 1~5 ml/injection,
which varied with prostate size (Figs, 2, 3). An intraoperative transurethral prostatic biopsy was carried out to
determine the tissue pathology.
Postoperative Foley catheter drainage was temporarily put in place with continuous normal saline
irrigation, to prevent blood clot formation, and this was
removed several days later. The serum alcohol level was
determined 2 hours after surgery to confirm the safety
of the procedure. All patients were given an analgesic
for 48 hours, and were allowed to be discharged if the
NU
color of the hematuria had turned pinkish. The prostate
was serially inspected at weekly intervals for the first
30 days and monthly for another 60 days. On each follow-up visit, the prostate size was measured by
sonography, and symptoms patients were suffering from
were also recorded in detail. The peak urinary flow rate
and IPSS were evaluated at 3-month intervals in all
patients. The period of follow-up ranged from 3 to 11
months. Paired t-test was used for the systematic analysis of changes in these parameters before and after
treatment, and a p value of < 0.05 was considered statistically significant.
Fig. 1. InjecTx endoscopic device that creates a protrusion
of the injection needle and transfusion of absolute
alcohol through the syringe.
Figs. 2, 3.
Endoscopic injection performed at 3 to 5 sites in
the right and left lobes of the prostate using an
InjecTx endoscopic device or a 0-degree pediatric cystoscope with a 20-gauge needle[?].
JTUA 2007 18 No. 1
Original Articles
C. T. Huang, et al
RESULTS
The number of needle punctures for each patient
ranged from 1 to 5 punctures. The total injected amount
of ethanol for each patient in this study ranged from 3 to
30 (average, 9.9 ± 6.9) ml. This total volume of alcohol
was the average equivalent of 19.2% of the calculated
volume of each individual prostate gland. The mean
operative time was 23.9 ± 11.8 (median, 20) minutes.
There were no intraoperative complications, but postoperative urinary retention occurred in 4 patients. Medication (mainly NSAIDs) for pain control was given for
3.2 ± 2.9 (median, 2.0) days.
The mean days with gross hematuria were 2.8 ± 0.9
(median, 3) days, and an indwelling Foley catheter was
left in place to drain the prostate for a mean of 7.2 ± 7.9
(range, 1~32; median, 5) days. The interval of Foley
catheter placement extended for more than 29 days in 2
people (29 and 32 days, respectively) because of severe
urinary retention. The plasma ethanol concentration was
evaluated 120 minutes after the injection in all patients;
the mean serum alcohol level was 3.5 ± 0.9 (median, 3)
mg/dl (the lethal plasma alcohol concentration is > 400
mg/dl). The mean hospital stay was 2.7 ± 2.9 (median,
2.0) days.
The medication (mainly NSAIDs) for pain control
was given for 3.2 ± 2.9 (median, 2.0) days. The mean
prostate [size/weight?] decreased from 51.6 ± 22.3
(median, 50.3) to 29.7 ± 16.9 (median, 25.6) g at 3
months postoperatively. The overall median reduction
was 42% of the pretreatment volume(p = 0.001; pairedsample t-test). The mean IPSS scores decreased from
26.1 ± 4.2 (median, 26) to 20.7 ± 5.2 (median, 20.0) (3
months postoperatively) (p = 0.022; paired-sample tTable 1. Mean prostate volumes, AUA symptom scores, and
peak urine flow rates revealing significant improvement following 3-months of follow-up
mêÉçéÉê~íáîÉ
P=ãçåíÜë=ä~íÉê
9.8
Peak Flowrate
14.8
P=0.035 < 0.05
51.6
Prostate Volume
29.7
P=0.001 < 0.05
26.1
IPSS
20.7
JTUA 2007 18 No. 1
P=0.022 < 0.05
test); the mean peak urine flow rate increased from 9.8
± 5.4 (median, 9.0) to 14.8 ± 6.0 (median, 15) ml/s 3
months postoperatively (p = 0.035; paired-sample t-test)
(Table 1). There were no significant differences at 6
months when the same parameters were assessed. Pathologic findings for all patients showed no evidence of
malignancy in the treated area. The conditions for which
the most patients complained about were frequency (21/
22), difficult micturition (19/22), and acute urinary retention (4/22). No further major side-effects, such as
fever, hematomas, or permanent painful symptoms were
encountered following the ethanol injection, and no subject developed a urinary tract infection. The PSA level
generally remained highly elevated during the 3-month
follow-up period. No symptoms of sexual dysfunction
were reported during our clinical follow-up.
DISCUSSION
During the last century, the treatment for bladder
outlet obstruction in males suffering from LUTS and
progressive disease relating to BPH has largely consisted
of eradicative surgery. Transurethral resection of the
prostate (TURP) has been the gold standard for the treatment of BPH for the past 30 years, and is a very reliable
and straightforward procedure that most urologists are
confident performing. Nevertheless, this procedure can
be associated with a relatively high complication rate
(approximately 15%)7 and a significant impact on postoperative sexual function.8 The paradigm for the management of BPH has undergone substantial change during the last decade. These perceived morbidities as well
as the need for anesthesia and hospitalization were the
impetus to develop more minimally invasive surgical
methods such as transurethral microwave thermotherapy
(TUMT),9 transurethral needle ablation of the prostate
(TUNA),10 high-intensity focused ultrasound (HIFU),12
interstitial laser coagulation (ILC),12,13 water-induced
thermotherapy (WIT),14 and transurethral enzyme ablation of the prostate.15 However, the recognized efficacies of these therapies remain controversial and, at best,
unresolved. An intraprostatic injection for BPH was first
used more than 100 years ago and may be on the verge
of a rebirth.
One of the earliest documented experiences using a
needle intraprostatically was when Sir Brodie in 1832
recommended puncture of the prostate through the
perineum for the treatment of a prostatic abscess.16 In
1930, Lower and Johnston postulated that people might
find some chemical agent which could induce resultant
shrinkage of the gland with noninfectious prostatitis.17
Various chemical agents, including 5%~10% silver
NV
Original Articles
Ablation of the Prostate Using a Transurethral Intraprostatic Injection of Absolute Ethanol
nitrate, 10% sodium hydroxide, Lugol's solution , and
95% alcohol were later selected to reduce the glands by
"fibroblastic replacement".16
Over the past several decades, absolute ethanol has
extensively been used for tissue ablation in several
organs.18-22 To our knowledge, there are no publications
that state the exact mechanism of ethanol chemoablation,
but it appears that as ethanol is distributed through the
tumor interstitium, its cytotoxic mechanisms are exerted
through a combination of cytoplasmic dehydration, denaturation of cellular proteins, and small-vessel
thrombosis, followed by coagulative necrosis and reactive fibrosis. When injected into the prostate, ethanol
has also resulted in tissue retraction and sloughing.23-25
Both the transperineal and transurethral approaches
effectively cause chemoablation of the prostatic tissue
with ethanol. Historically, the earliest attempts at prostatic chemoablation were by a transperineal injection. 26
Chemoablation using this approach initially achieved
promising results; however, serious complications such
as significant perineal pain after the injection and
extraprostatic tissue necrosis with the transperineal approach due to alcohol leakage and contradictory opinions of potency were reported.27-29 As early as 1988,
Littrup et al. noted a towering ratio of external sphincter
necrosis and urinary incontinence flare-ups
postoperatively, because surgeons were unable to definitively target the tissue using a transperineal mode.
Excessive and uncertain tissue necrosis was compounded
by tissue damage owing to retrograde tracking of the
condensed alcohol along the previous transperineal
paths.30 On the other hand, no disruption of the prostatic
capsule or injury to the bladder urothelium or urethral
sphincter was identified when using a transurethral injection in an in vivo canine model.31
Additionally, to our knowledge, a scarcity of literature exists related to transrectal access for intraprostatic
injections. Two conference abstracts were published in
the literature presenting independent transrectal
intraprostatic injection experiences.32,33 Both of them
included a few collected patients, temporary sequelae,
and the administration of a guide with a transrectal ultrasound probe for needle placement into the targeted
area of the prostate. One very serious possible complication with this route of injection is the risk of urethrorectal fistula formation.
The application of transurethral access in humans
was scientifically analyzed in 1999 by Goya et al.34 They
presented 10 patients managed by a transurethral
intraprostatic injection, with an average 3-month followup. Their procedure encompassed the use of a straight
needle and a cystoscopic injection into the bilateral pro-
OM
static lobes. Hopeful results were described. Nevertheless, no meaningful reduction in volume was measured in that cohort. In 2004, they subsequently assessed
the medium-term (3-year) efficacy of transurethral ethanol injection therapy of the prostate. In total, 34 patients
were followed-up for a median of 4.3 years after the
injection. The mean total ethanol dose was 6.4 ml, and a
catheter was required for a mean of 7.6 days
postoperatively. The mean International Prostate Symptom Score was 21.8 points before AEI (in 34 patients)
and had decreased to 13.1 points after 3 years (in 17, p <
0.01). The mean peak flow rate was 8.3 ml/s before AEI
and had increased to 12.7 ml/s after 3 years (p < 0.01).
The mean prostate volume decreased from 49.3 ml before AEI to 45.7 ml after 1 year (p < 0.001), but had
increased to 51.4 ml after 3 years. No major complications were experienced. By 3 years after surgery 59.0%
of patients had required no further treatment.35
In another series reported by Ditrolio et al. in 2002,
significant decreases in the volume of the obstructed
prostatic tissue were measured following the practice.
In total, 15 patients were documented, including 13 who
had then been followed-up for more than 1 year. At 3
months, the mean prostate size had been reduced to
23.3 (range, 7~61) g compared with the preoperative
mean of 47.5 g, a decrease to 49% of the preoperative
volume. At 12 months, while the mean prostate had increased minimally to 26.4 (range, 12~38) g, it was still
only 55% of the preoperative value. The average total
alcohol dose was 13.1 (range, 8~22) ml. This total volume of alcohol was the average equivalent of 27.3% of
the calculated volume (range, 17.3%~42%) of each individual prostate gland. At 1 year postoper-atively, the
average AUA symptom score was only 27% of the preoperative value. The peak urine flow rate was at a mean
of 11.9 (range, 9~21) ml/s compared with the initial mean
of 5.7 ml/s, representing a 2-fold improve-ment.36
In our cohort, a meaningful reduction in the prostate and an improvement in the peak urinary flow rate
were achieved. The measured serum alcohol level was
also very safe and far below the cutoff point for causing
death. Nevertheless, unpleasant lower urinary tract symptoms resulted in an imperfect outcome. Such a description has seldom been given in other series, whereas it
presents a potential concern for this promising alternative treatment.
CONCLUSIONS
After being investigated for more than a century,
the use of injectable materials for prostatic tissue ablation still has a promising future. Our initial series sug-
JTUA 2007 18 No. 1
Original Articles
C. T. Huang, et al
gests that AEI can effectively ablate prostatic tissue in
canines with minimal systemic absorption. The technique
can be performed with a short hospital stay or as an outpatient procedure. It can be considered another treatment choice for prostatic obstruction due to benign hyperplasia or carcinoma, especially when a patient is at
high risk. We need to point out that the postoperative
frequency of alcohol-induced prostatitis is a problem
which must be communicated to patients preoperatively.
In conclusion, we believe that PEI is a cheap, simple,
and safe alternative for the treatment of BPH and can be
performed in 1 or 2 sessions in the majority of cases. It
should be emphasized that most changes occurred in the
initial 3 months, and little improvement was recorded
thereafter. Because the majority of prostate cancers are
located in the peripheral zone, transurethral prostatic
biopsy during surgery was obviously insufficient for
people with a PSA level of > 4 ng/ml, and a transrectal
prostatic biopsy should be scheduled to definitively exclude the possibility of a malignancy. More systematic
laboratory research and clinical trials, some currently
ongoing, need to be completed.
REFERENCES
1. Garraway WM, Collins GN, Lee RJ. High prevalence of
benign prostatic hypertrophy in the community. Lancet
1991;338:469-71.
2. Chute CG, Panser LA, Girman CJ, et al. The prevalence of prostatism: a population-based survey of urinary symptoms. J Urol 1993;150:85-9.
3. R o e h r b o r n C G , M c C o n n e l l J D . E t i o l o g y ,
pathophysiology, epidemiology and natural history of
benign prostatic hyperplasia. In: Campbell's Urology, 8th
ed. PC Walsh, AB Retik, ED Vaughan Jr, AJ Wein,
editors. Philadelphia, PA: WB Saunders, Ch. 38, 2002:
1297-330.
4. McNeal J. Pathology of benign prostatic hyperplasia.
Insight into etiology. Urol Clin North Am 1990;17: 47786..
5. Price H, McNeal JE, Stamey TA. Evolving patterns of
tissue composition in benign prostatic hyperplasia as a
function of specimen size. Hum Pathol 1990;21:57885..
6. Trachtenberg J. Treatment of lower urinary tract symptoms suggestive of benign prostatic hyperplasia in relation to the patient's risk profile for progression. BJU Int
2005;95:6-11.
7. Mebust WK, Hotgrewe HL, Cockett ATK, et al. Transurethral prostatectomy: immediate and postoperative
complications. A cooperative study of 13 participating
institutions evaluating 3,885 patients. J Urol 1989;141:
243-7.
8. Leliefeld HH, Stoevelaar HJ, McDonnell J. Sexual function before and after various treatments for symptomatic benign prostatic hyperplasia. BJU Int 2002;89:208-
JTUA 2007 18 No. 1
13.
9. Albala DM, Fulmer BR, Turk TM, et al. Office-based
transurethral microwave thermotherapy using the
TherMatrx TMx-2000. J Endourol 2002;16:57-61.
10. Naslund MJ. Transurethral needle ablation of the
prostate. Urology 1997;50:167-72..
11. Madersbacher S, Schatzl G, Djavan B, et al. Long-term
outcome of transrectal high-intensity focused ultrasound
therapy for benign prostatic hyperplasia. Eur Urol 2000;
37:687-94..
12. Costello AJ, Agarwal DK, Crowe HR, et al. Evaluation
of interstitial diode laser therapy for treatment of benign
prostatic hyperplasia. Tech Urol 1999;5:202-6..
13. Greenberger M, Steiner MS. The University of Tennessee experience with the Indigo 830e laser device for
the minimally invasive treatment of benign prostatic
hyperplasia: interim analysis. World J Urol 1998;16:38691..
14. Muschter R, Schorsch I, Danielli L, et al. Transurethral
water-induced thermotherapy for the treatment of benign prostatic hyperplasia: a prospective multicenter
clinical trial. J Urol 2000;164:1565-9..
15. Zhang C, Wang LL, Shong C, et al. Ablation of canine
prostate using two-stage intraprostatic hot agarose solution and enzyme injection. Prostate Cancer Prostatic
Dis 2004;7(4):316-20.
16. Plante MK. Folsom JB. Zvara P. Prostatic tissue ablation by injection: a literature review. [Review] [74 refs]
[Journal Article. Review] J Urol 2004;172:20-6.
17. Lower WE , Johnston RL. Studies in hypertrophy of
prostate. Effect of injection of various chemical agents
into prostate gland with especial reference to injection
of iodine. Trans Am Urol Assoc 1930;177-9.
18. Livraghi T, Benedini V, Lazzaroni S, et al. Long term
results of single session percutaneous ethanol injection in patients with large hepatocellular carcinoma.
Cancer 1998;83:48-57.
19. Solbiati L, Giangrande A, De Pra L, et al. Percutaneous
ethanol injection of parathyroid adenomas under US
guidance: treatment for secondary hyperparathyroidism.
Radiology 1985;155:607-10.
20. Iso Y, Kawanaka H, Tomikawa M, et al. Repeated injection sclerotherapy is preferable to combined therapy
with variceal ligation to avoid recurrence of esophageal
varices: a prospective randomized trial.
Hepatogastroenterology 1997; 44:467-71.
21. Bean WJ. Renal cyst: treatment with alcohol. Radiology 1981;138:329-31.
22. Nanni GS, Hawkins IF, Orak JK. Control of hypertension by ethanol renal ablation. Radiology 1983;148:513.
23. Zvara P, Karpman E, Stoppacher R, et al. Ablation of
canine prostate using transurethral intraprostatic absolute ethanol injection. Urology 1999;54:411-5.
24. Livarghi T, Paracchi A. Treatment of autonomous thyroid nodules with percutaneous ethanol injection. Radiology 1990;175:827-9.
25. Shiina S, Tagawa K, Unuma T, et al. Percutaneous ethanol injection therapy for hepatocellular carcinoma: a histopathologic study. Cancer 1991;68:1524-30.
ON
Original Articles
Ablation of the Prostate Using a Transurethral Intraprostatic Injection of Absolute Ethanol
26. Talwar GL, Pande SK. Injection treatment of enlarged
prostate. Br J Surg 1966;53:421-7.
27. Broughton AC, Smith PH. The significance of perineal
pain after injection of the prostate. Br J Urol 1970;42:
73-5.
28. Angell JC. Treatment of benign prostatic hyperplasia
by phenol injection. Br J Urol 1969;41:735-8.
29. Plante MK, Gross AL, Kliment Jr J, et al. Intraprostatic
ethanol chemoablation via transurethral and
transperineal injection. BJU Int 2003;91(1):94-8.
30. Littrup PJ, Lee F, Borlaza GS, et al, Torp-Pedersen S,
Gray JM. Percutaneous ablation of the canine prostate
using transrectal ultrasound guidance absolute ethanol
and Nd:YAG laser. Invest Radiol 1988;23:734-9.
31. Zvara P, Karpman E, Stoppacher R, et al. Ablation of
canine prostate using transurethral intraprostatic absolute ethanol injection. Urology 1999;54(3):411-5.
OO
32. Larson TNPP, Huidobro C. Controlled tissue ablation
using chemo-gel under ultrasound/MRI guidance. J
Endourol 2001;47:11-2.
33. Larson TN, Huidobro C, Palma P. Intraprostatic injection of ETOH gel for treatment of BPH: preliminary clinical results. J Endourol 2001;132:23-6.
34. Goya N, Ishikawa N, Ito F, et al. Ethanol injection therapy
of the prostate for benign prostatic hyperplasia: preliminary report on application of a new technique. J Urol
1999;162:383-6..
35. Goya N, Ishikawa N, Ito F, et al. Transurethral ethanol
injection therapy for prostatic hyperplasia: 3-year results.
J Urol 2004;172(3):1017-20.
36. Ditrolio J, Patel P, Watson RA, et al. Chemo-ablation of
the prostate with dehydrated alcohol for the treatment
of prostatic obstruction. J Urol 2002;167(5):2100-4.
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