Long-Term Oncologic Outcomes from Laparoscopic Gastrectomy for Gastric Cancer: A Single-Center
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Long-Term Oncologic Outcomes from Laparoscopic Gastrectomy for Gastric Cancer: A Single-Center
Long-Term Oncologic Outcomes from Laparoscopic Gastrectomy for Gastric Cancer: A Single-Center Experience of 601 Consecutive Resections Sang-Woong Lee, MD, Eiji Nomura, MD, George Bouras, MRCS, Takaya Tokuhara, MD, Souichiro Tsunemi, MD, Nobuhiko Tanigawa, MD, FACS Laparoscopic gastrectomy (LG) is becoming increasingly popular for management of early gastric cancer (EGC). Although short-term efficacy is proven, reports on long-term effectiveness are still infrequent. STUDY DESIGN: All patients with a diagnosis of gastric cancer undergoing LG from the beginning of our laparoscopic experience were included in the analysis. At our unit, LG is indicated for all cancers up to preoperative stage T2N1. RESULTS: Six-hundred and one laparoscopic resections were included in the analysis. There were 392 men and 209 women. Mean age was 64.2 ⫾ 10.9 years. Distal gastrectomy was performed in 305 patients, pylorus-preserving gastrectomy in 148, segmental gastrectomy in 42, proximal gastrectomy in 53, total gastrectomy in 27, and wedge resection in 26. Histological staging revealed that 478 patients had stage IA disease, 47 had stage IB, 44 had stage IIA, 19 had stage IIB, 8 had stage IIIA, 3 had stage IIIB, and 2 had stage IIIC. Morbidity and mortality rates were 17.6% and 0.3%, respectively. Median follow-up was 35.9 months (range 3 to 113 months). Cancer recurrence occurred in 15 patients and metachronous gastric remnant cancer was detected in 6 patients. The 5-year overall and disease-free survival rates were 94.2% and 89.9%, respectively, for stage IA tumors, 87.4% and 82.7% for stage IB, 80.8% and 70.7% for stage IIA, and 69.6% and 63.1% for stage IIB. CONCLUSIONS: In our experience, long-term oncological outcomes from LG for EGC are acceptable. Wherever expertise permits, LG should be considered as the primary treatment in patients with EGC. (J Am Coll Surg 2010;211:33–40. © 2010 by the American College of Surgeons) BACKGROUND: Since its introduction by Kitano and colleagues in 1994,1 the number of patients undergoing laparoscopic gastrectomy (LG) for early gastric cancer (EGC) has been increasing rapidly in Japan, where there is a high incidence of EGC. Improvements in instruments and laparoscopic technique have allowed for widespread acceptance of LG, not only for distal gastrectomy (DG) but also for other resections, such as proximal gastrectomy (PG) and total gastrectomy (TG).2-5 Advantages of LG over conventional open resection include reduced postoperative pain, earlier recovery, shorter hospital stay, and better cosmesis.6-10 Although there is high-quality evidence to support short-term efficacy of LG for EGC, accounts on long-term survival are still infrequent. The technical feasibility of systematic laparoscopic lymphadenectomy must still be proven in the longterm, and concerns about this approach, such as the oncological effects of pneumoperitoneum, must still be resolved.11,12 Detailed and organized accounts of the long-term oncological efficacy of the LG are necessary to establish this approach as the primary treatment for EGC. Here we present the longterm oncological outcomes from LG, including all patients treated from the beginning of our laparoscopic experience, to determine its long-term effectiveness and patient survival in the context of EGC. Disclosure information: Nothing to disclose. Received February 1, 2010; Revised March 12, 2010; Accepted March 12, 2010. From the Department of General and Gastroenterological Surgery, Osaka Medical College, Takatsuki, Japan (Lee, Nomura, Tokuhara, Tsunemi, Tanigawa) and Upper Gastrointestinal Surgery Unit, Queen Elizabeth Hospital, Edgbaston, Birmingham, UK (Bouras). Correspondence address: Nobuhiko Tanigawa, MD, FACS, Department of General and Gastroenterological Surgery, Osaka Medical College, 2-7 Daigaku-Machi, Takatsuki, Osaka 569-8686, Japan. email: sur001@poh. osaka-med.ac.jp © 2010 by the American College of Surgeons Published by Elsevier Inc. METHODS Patients From April 2000 to October 2009, 1,386 patients with gastric cancer were managed surgically at our unit. Of these, 601 patients underwent LG. 33 ISSN 1072-7515/10/$36.00 doi:10.1016/j.jamcollsurg.2010.03.018 34 Lee et al Oncologic Results of Laparoscopic Gastrectomy J Am Coll Surg Abbreviations and Acronyms DG ⫽ EGC ⫽ LG ⫽ PG ⫽ PPG ⫽ SG ⫽ TG ⫽ distal gastrectomy early gastric cancer laparoscopic gastrectomy proximal gastrectomy pylorus-preserving gastrectomy segmental gastrectomy total gastrectomy Preoperative staging was based on double-contrast upper gastrointestinal x-ray studies, endoscopy, and enhanced CT. Indications for LG at our institute include all tumors confined to the muscularis propria not amenable to endoscopic mucosal resection with lymph node involvement limited to N1. Patients requiring salvage surgery after incomplete endoscopic resection are also included. Operations were converted to open when serosal invasion or extensive lymphadenopathy was detected at laparoscopy. Operative procedure The type of gastric resection was determined according to tumor location, size, and depth of invasion. Modified (limited) gastrectomy with preservation of remnant stomach is indicated for EGC based on Japanese treatment guidelines.13 Pylorus-preserving gastrectomy (PPG) and segmental gastrectomy (SG) are indicated for lesions of the body of stomach limited to the mucosa ⬍4 cm in diameter and submucosa ⬍2 cm. For PPG, enough distal remnant to allow for an antral cuff of at least 4 cm for gastrogastric anastomosis is necessary, and for SG, the right gastroepiploic vessels are preserved to supply a large remnant distal stomach.14,15 PG is indicated for lesions in the upper third of stomach with no evidence of serosal or lymph node involvement.4,16 TG is indicated for locally advanced proximal lesions or multiple lesions for which the distal stomach cannot be preserved.3,17 Finally, wedge resection is indicated for mucosal cancers of any histological type measuring ⬍2 cm in diameter with a low probability of regional lymph node metastases.18,19 The principle of any resection is to achieve en-bloc resection of gastric segment and surrounding lymph nodes to achieve adequate oncological clearance. DG is the most commonly performed resection at our unit. The patient is positioned with hips extended and abducted for the primary surgeon, who stands between the legs. Pneumoperitoneum at 8 mmHg is established through a supraumbilical trocar and liver retraction is achieved using a Penrose drain (Fig. 1). Greater curvature mobilization is performed by dividing the gastrocolic ligament just away from gastroepiploic arcade. The left gastroepiploic vessels are divided Figure 1. Penrose drain liver retractor in position in the abdominal cavity. to reach the proximal resection line, and the distal mobilization is performed up to the duodenum and the right gastroepiploic vessels. After duodenal transection, the right and left gastric vessels are divided and the lesser curve is cleared of its perigastric fat before gastric transection. Lymph node dissection is performed during vascular mobilization according to guidelines taking lymph nodes en bloc on the side of the resection. Vessels are ligated at their roots in most instances. D1⫹␣ (station nos. 7 and 8a) lymph node dissection is performed for cancer limited to the mucosa, and D1⫹ (station nos. 7, 8a, and 9) is performed for those thought to be extending submucosally (Fig. 2). The proximal stomach is divided after confirming the position of the marking tattoo. The specimen is retrieved from the umbilical trocar site in a bag. Reconstruction is by either Billroth-I (Fig. 3A) or Roux-en-Y (Fig. 3B), as determined by size of remnant stomach and potential for tension with a gastroduodenostomy. Intracorporeal anastomoses are fashioned using endoscopic linear staplers.20,21 Follow-up Histological staging was according to the 7th edition of the Union Internationale Contre le Cancer stage classification criteria. Adjuvant chemotherapy in the form of S-1, an oral fluoropyrimidine, was administered for 1 year in patients with disease stage higher than IIA.22 All patients were followed-up prospectively every 6 months for clinical examination and tumor marker measurements (CEA, carbohydrate antigen 19-9), and CT and endoscopy were performed annually. Statistical analysis All statistical tests were performed using the JMP 8 for Windows (SAS Institute Inc.). Differences in categorical Vol. 211, No. 1, July 2010 Lee et al Oncologic Results of Laparoscopic Gastrectomy 35 Figure 2. Dissected lymph nodes for D1⫹  during distal gastrectomy. variables, such as postoperative complications, tumor recurrence, and other clinicopathological factors were analyzed by chi-square test and p value ⬍0.05 was considered significant. Patient survival was calculated by KaplanMeier method. All continuous data are presented as mean with standard deviations. RESULTS Patient characteristics Demographic, operative, and clinicopathological characteristics of patients undergoing LG are presented in Tables 1 and 2. Types of laparoscopic resections Laparoscopic resections consisted of 305 (50.7%) DG, 148 (24.6%) PPG, 42 (7.0%) SG, 53 (8.8%) PG, 27 (4.5%) TG, and 26 (4.3%) wedge resection. Resections were performed either as laparoscopy-assisted, where the gastric transection and reconstruction were performed through minilaparotomy, or totally laparoscopic, where mobilization, resection, and reconstruction were performed intracorporeally. Most of the procedures in our early experience were laparoscopy-assisted but, since November 2003, we have been introducing total laparoscopic procedures starting with stapled intracorporeal reconstruction after DG.20,21 Concomitant resections of other organs were performed in 56 cases (9.3%). This included 35 cholecystectomies for gallstones, 11 colonic resections, 3 rectal resections, 3 oopherectomies for cystic tumors of the ovary, 2 splenecto- Figure 3. (A) Diagram showing intracorporeal stapled Billroth-I reconstruction. (B) Diagram showing intracorporeal stapled Roux-en-Y reconstruction. 36 Lee et al Oncologic Results of Laparoscopic Gastrectomy Table 1. Demographic, Operative and Tumor Characteristics of 601 Patients after Laparoscopic Radical Gastrectomy Patients Age, y* Gender, male/female, n Body mass index* Operation Totally laparoscopic procedure, yes/no, n Type of gastrectomy, DG/PPG/ SG/PG/TG/WR, n Lymph node dissection, D0/D1/ D1⫹␣/D1⫹/D2, n Lymph node yields,* n Resection of other organs, yes/no, n Operation time, min* Tumor Location, U/M/L/W, n Histology, differentiated/ undifferentiated, n Tumor size, cm* Staging,† IA/IB/IIA/IIB/IIIA/IIIB/ IIIC, n 64.2 ⫾ 10.9 392/209 22.4 ⫾ 3.1 297/304 305/148/42/53/27/26 26/42/144/316/73 23.8 ⫾ 13.2 56/545 300.6 ⫾ 84.8 86/320/191/4 342/259 3.2 ⫾ 2.4 478/47/44/19/8/3/2 *Continuous variables are presented as the mean ⫾ standard deviation. † Tumor staging is classified by Union Internationale Contre le Cancer staging. DG, distal gastrectomy; L, low; M, middle; PG, proximal gastrectomy; PPG, pylorus-preserving gastrectomy; SG, segmental gastrectomy; TG, total gastrectomy; U, upper; W, whole; WR, wedge resection. mies as part of D2 dissection, and 2 herniorrhaphies. Some patients were understaged preoperatively, 45 patients had T3-stage disease and 8 patients had T4a-stage disease on histology. Consequently, the final Union Internationale Contre le Cancer stages of the patients were stage IA in 478 (79.5%), stage IB in 47 (7.8%), stage IIA in 44 (7.3%), stage IIB in 19 (3.2%), stage IIIA in 8 (1.3%), stage IIIB in 3 (0.5%) and stage IIIC in 2 (0.3%) patients. Morbidity and mortality Conversion to open surgery occurred in 31 cases (5.2%) because of advanced-stage disease in 9 patients, uncontrollable hemorrhage in 7 patients, peritoneal adhesions in 4 J Am Coll Surg patients, suspected positive proximal resection margins in 3 patients, and jejunal loop torsion during Roux-en-Y reconstruction after DG in 1 patient. Table 3 summarizes the intraoperative and postoperative complications according to type of resection. Intraoperative and postoperative complications occurred in 106 patients (17.6%). There were no associations between the occurrence of complications and demographic factors including gender, age, body mass index, or tumor stage. There were no statistical differences in the incidence of intraoperative complications between different types of resections. Bleeding was the most frequent intraoperative complication. Postoperative complications occurred more frequently after TG and PG (p ⬍ 0.05). Notably, patients undergoing TG had a high rate of pancreatic injury (11.1%) and anastomotic leakage (11.1%). Overall, anastomotic or duodenal stump leakage occurred in 23 patients (3.8%). Leakage after esophagojejunostomy using a circular stapler and handsewn gastroduodenostomy through minilaparotomy occurred in 7 and 4 patients, respectively. Six of these patients required reoperation, and 17 patients had collections that were treated by percutaneous drainage. Gastric stasis occurred in 10 (6.8%) of 148 patients treated with PPG. On contrary, gastric stasis after SG was seen in only 1 (2.4%) of 42 patients. Four patients suffered from postoperative hemorrhage associated with pancreatic inflammation and secondary pseudoaneurysm of the gastroduodenal artery in 3 patients and splenic artery in 1. All patients were successfully treated by endovascular coiling. Two patients died postoperatively (0.3%), 1 from severe acute pancreatitis and another from acute respiratory distress syndrome. Follow-up Median follow-up was 35.9 months (range 3 to 113 months). Distant recurrences occurred in 14 (2.3%) patients, including 8 peritoneal, 4 hepatic, 1 para-aortic, and 1 bone recurrence (Table 4). A left upper quadrant port site recurrence developed 2 years after surgery in 1 patient with stage IIIC (T3N3) disease and was treated with chemotherapy. A bone metastasis developed 4 years after resection in Table 2. Stage Grouping of 601 Patients after Laparoscopic Radical Gastrectomy T1 (mucosa, submucosa), n T2 (muscularis propria), n T3 (subserosa), n T4a (serosa), n T4b (adjacent structure), n n (%) N0 (0) N1 (1ⴚ2) N2 (3ⴚ6) N3 (7ⴚ) n % 478 24 25 3 0 530 (88.2) 23 9 13 3 0 48 (8.0) 10 3 4 0 0 17 (2.8) 0 1 3 2 0 6 (1.0) 511 37 45 8 0 601 85.0 6.2 7.5 1.3 2 100 Staging according to the 7th edition of the Union Internationale Contre le Cancer classification. Vol. 211, No. 1, July 2010 Lee et al Oncologic Results of Laparoscopic Gastrectomy 37 Table 3. Intraoperative and Postoperative Complications in 601 Patients Undergoing Laparoscopic Radical Gastrectomy Complications Morbidity* Intraoperative, n (%) Bleeding, n Organ injury, n Postoperative, n (%) Anastomotic leakage, n Duodenal stump leakage, n Anastomotic stricture, n Anastomotic ulcer, n Stasis, n Pancreatic injury, n Bleeding, n Bowel obstruction, n Wound infection, n Pulmonary infection, n Mortality ARDS, n Severe pancreatitis, n Type of resection SG (n ⴝ 42) PG (n ⴝ 53) DG (n ⴝ 305) PPG (n ⴝ 148) 5 (1.6) 4 1 60 (19.7) 9 3 3 3 8 16 3 2 10 3 0 0 0 25 (16.9) 2 0 2 2 10 4 1 0 3 1 1 (2.4) 1 0 7 (16.7) 2 0 0 0 1 2 0 0 2 0 0 1 0 0 0 0 TG (n ⴝ 27) WR (n ⴝ 26) p Value 1 (1.9) 1 0 17 (32.1) 4 0 2 0 3 2 1 1 2 2 1 (3.7) 1 0 10 (37.0) 3 0 1 0 0 3 0 0 2 1 0 0 0 3 (11.5) 0 0 0 1 0 0 0 0 1 1 NS 0 0 1 0 0 0 ⬍0.05† *There were 130 complications in 106 patients. † Statistical significance. DG, distal gastrectomy; PG, proximal gastrectomy; PPG, pylorus-preserving gastrectomy; SG, segmental gastrectomy; TG, total gastrectomy; WR, wedge resection. 1 patient with stage IA disease, but with a mucosal lesion measuring 90 mm with no lymph node metastases. Four patients underwent palliative reoperation and chemotherapy and an additional 8 received chemotherapy only. The resection margin was positive in 1 case after wedge resection. Local recurrence in the gastric remnant eventually developed in this patient and was treated with DG. Metachronous gastric remnant cancer was encountered in 6 pa- Table 4. Details of Patients with Distant and Local Recurrences after Laparoscopic Radical Gastrectomy Pathologic findings of primary disease Patient no. Age, y/gender Type of LG Intervals after LG, mos Recurrence site 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 56/female 66/female 73/female 67/male 46/female 57/male 69/male 63/male 75/male 57/female 68/male 77/male 69/male 46/female 82/male DG PG PG DG TG PG PG DG WR DG DG SG DG DG WR 30 35 6 46 6 24 7 48 11 27 23 29 5 24 5 P P P Bone H N P H/N H P/N P P H Port/P Locoregional His. Size, mm Depth of invasion ly V N Stage Tub Tub Por Tub Por Pap Tub Tub Tub Por Por Por Tub Por Tub 150 34 95 90 20 45 30 34 16 60 195 39 20 60 23 Subserosa Submucosa Serosa Mucosa Submucosa Muscularis propria Muscularis propria Muscularis propria Muscularis propria Submucosa Subserosa Muscularis propria Muscularis propria Serosa Submucosa (⫹) (⫹) (⫹) (⫺) (⫹) (⫹) (⫹) (⫹) (⫹) (⫹) (⫹) (⫹) (⫺) (⫹) (⫹) (⫺) (⫹) (⫹) (⫺) (⫺) (⫹) (⫹) (⫹) (⫹) (⫺) (⫺) (⫹) (⫹) (⫹) (⫹) N3 N2 N0 N0 N2 N1 N0 N3 N0 N1 N1 N2 N1 N3 N0 IIIB IIA IIB IA IIA IIA IB IIIA IB IB IIB IIB IIA IIIC IA DG, distal gastrectomy; H, liver; LG, laparoscopic gastrectomy; ly, lymphatic invasion; PG, proximal gastrectomy; P, peritoneal disease; Pap, papillary adenocarcinoma; Por, poorly differentiated adenocarcinoma; Port, port site; SG, segmental gastrectomy; TG, total gastrectomy; Tub, tubular adenocarcinoma; V, venous invasion; WR, wedge resection. 38 Lee et al Oncologic Results of Laparoscopic Gastrectomy Figure 4. Kaplan-Meier overall survival curves according to tumor stage based on the 7th edition of the Union Internationale Contre le Cancer classification. Eleven patients with stage III disease have been omitted because of small sample size. tients (1.0%). Three of these underwent partial resection of the remnant stomach, 2 patients had total gastrectomies and 1 patient had endoscopic submucosal dissection of the second lesion. Another primary cancer developed in 17 patients during the follow-up period, and 33 patients died in total. Causes of death included recurrent disease in 11 patients, another primary cancer in 6, chronic pulmonary disease in 4, cardiovascular disease in 2, apoplexy in 2, chronic liver dysfunction in 2, surgery-related complications in 2, diabetes mellitus in 1, chronic renal failure in 1, collagen disease in 1, and systemic infection in 1. Of 601 patients, 181 were followed-up for ⬎5 years or until death. In these patients, 5-year overall and disease-free survival rates were 90.3% and 85.3%, respectively. According to stage, 5-year overall and disease-free survival rates were 94.2% and 89.9% for 478 stage IA disease, 87.4% and 82.7% for 47 stage IB disease, 80.8% and 70.7% for 44 stage IIA disease, and 69.6% and 63.1% for 19 stage IIB disease, respectively (Figs. 4 and 5). According to the depth of tumor invasion, 5-year overall survival rates were 93.4% for 511 T1 tumors, 70.0% for 37 T2 tumors, 76.7% for 45 T3 tumors, and 57.1% for 8 T4a tumor (Fig. 6). Figure 6. Kaplan-Meier overall survival curves according to T stage based on the 7th edition of the Union Internationale Contre le Cancer classification. J Am Coll Surg Figure 5. Kaplan-Meier disease-free survival curves according to tumor stage based on the 7th edition of the Union Internationale Contre le Cancer classification. Eleven patients with stage III disease have been omitted because of small sample size. DISCUSSION Several prospective trials have demonstrated LG to be superior to open surgery because it results in less postoperative pain, faster recovery, and better cosmetic results.7-10 In light of proven short-term efficacy, the current series represents the largest of its kind investigating the long-term effectiveness of LG in the treatment of gastric cancer stages I and II. In the present cohort, operative morbidity and mortality rates were 17.6% and 0.3%, respectively, and comparable with other accounts in the literature reporting complication rates ranging from 2.5% to 26.7%.23-31 Conversion to open operation occurred for oncological reasons as well as after intraoperative complications, but conversion itself was not associated with poor outcomes. Pancreatic inflammation can be secondary to laparoscopic energy devices transmitting heat and causing pancreatic injury during radical lymph node dissection. Such injury can lead to development of serious complications, including anastomotic leakage and hemorrhage that can require surgical or radiological intervention. A particular problem encountered in the current series was the understaging of 8.8% of cases (53 of 601). Although comparable with other reports,2,25,26 such patients with histologically advanced disease had poor outcomes. The inadvertent application of LG in such patients is difficult to avoid, however, as there is still an uncertainty about the oncological efficacy of laparoscopic manipulation in serosa-positive disease, all efforts must be made to prevent preoperative and intraoperative understaging to apply conventional open measures of preventing peritoneal seedling in advanced disease.11,32 The 5-year overall survival rate for the 511 patients with EGC was 93.4% and comparable with accounts of open resection.33-35 Other authors have also published data supporting the oncological efficacy of LG when compared with open resection in EGC.23,28 Although the uncharac- Vol. 211, No. 1, July 2010 teristic distant recurrence in a patient with T1N0 cancer 4 years after surgery raises some concern, such superficially spreading tumors have been known to have a high frequency of metastasis.36 In the present cohort, cancer recurrence developed in 4 patients with EGC (0.8%): 1 hepatic, 1 boney, and 2 peritoneal. These oncological outcomes are comparable with other accounts supporting the oncological efficacy of LG in EGC.33,37,38 For patients in whom metachronous gastric cancers developed, 5 lesions would have been present before the original resection but were not detected because they were presumably too small. In accordance with the literature, additional surgical resection of the second cancer was beneficial to survival.39-41 Kitano and colleagues, in a multicenter retrospective study of 1,294 LGs in 16 institutions, reported that the morbidity and mortality rates were 14.8% and 0%, respectively, and 5-year disease-free survival rate was 99.8% for stage IA disease, 98.7% for stage IB disease, and 85.7% for stage II disease with a median follow-up of 36 months.27 The seemingly excellent long-term survival of this cohort is overshadowed by concerns about missing data and patients lost to follow-up. Fujiwara and colleagues, in a singlecenter study of 94 LGs for EGC, reported that the morbidity and mortality rates were 22.3% and 0%, respectively, and overall survival rate was 90.1%.25 Similar to our experience, such figures might be more realistic benchmarks for LG when applied to EGC. In conclusion, LG for EGC appears safe and feasible with acceptable short-term surgical and long-term oncological outcomes. Based on this evidence, wherever expertise permits, LG should be considered as the primary treatment in patients with EGC. Curative resection for advanced disease is technically possible, however, the current data cannot address oncological efficacy in these patients. The role of LG in advanced disease must be evaluated prospectively in a randomized controlled setting. Author Contributions Study conception and design: Lee, Nomura, Tanigawa Acquisition of data: Lee, Nomura, Bouras, Tokuhara, Tsunemi, Tanigawa Analysis and interpretation of data: Lee, Nomura, Bouras Drafting of manuscript: Lee, Bouras, Tanigawa Critical revision: Lee, Nomura, Bouras, Tokuhara, Tanigawa REFERENCES 1. Kitano S, Iso Y, Moriyama M, Sugimachi K. Laparoscopyassisted Billroth I gastrectomy. Surg Laparosc Endosc 1994;4: 146–148. Lee et al Oncologic Results of Laparoscopic Gastrectomy 39 2. Asao T, Hosouchi Y, Nakabayashi T, et al. Laparoscopically assisted total or distal gastrectomy with lymph node dissection for early gastric cancer. Br J Surg 2001;88:128–132. 3. Mochiki E, Kamimura H, Haga N, et al. The technique of laparoscopically assisted total gastrectomy with jejunal interposition for early gastric cancer. Surg Endosc 2002;16:540–544. 4. Tanimura S, Higashino M, Fukunaga Y, et al. Laparoscopic gastrectomy with regional lymph node dissection for upper gastric cancer. 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