--Manuscript Draft-- Laparoscopic gastrectomy, Postoperative pancreatic fistula, Pancreatic injury. Tokyo Medical and Dental University Tokyo, JAPAN

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1 International Surgery Intraoperative pancreatic injury gives rise to severe postoperative pancreatic fistula: results of a review of unedited videos of the laparoscopic surgical procedures --Manuscript Draft-- Manuscript Number: Full Title: Article Type: Keywords: Corresponding Author: INTSURG-D R1 Intraoperative pancreatic injury gives rise to severe postoperative pancreatic fistula: results of a review of unedited videos of the laparoscopic surgical procedures Original Article Laparoscopic gastrectomy, Postoperative pancreatic fistula, Pancreatic injury Yuya Sato Tokyo Medical and Dental University Tokyo, JAPAN Corresponding Author Secondary Information: Corresponding Author's Institution: Tokyo Medical and Dental University Corresponding Author's Secondary Institution: First Author: Yuya Sato First Author Secondary Information: Order of Authors: Yuya Sato Kazuyuki Kojima Mikito Inokuchi Keiji Kato Hirofumi Sugita Sho Otsuki Kenichi Sugihara Order of Authors Secondary Information: Abstract: Objective To examine risk factors for and causes of severe postoperative pancreatic fistula (spopf) after laparoscopic gastrectomy (LG) Summary of Background Data There are few reports on POPF after LG. Methods Between February 2012 and March 2014, we examined 86 patients who underwent LG comparing them with 33 patients who underwent open gastrectomy (OG) for gastric cancer. Risk factors for severe POPF (spopf) of Clavien-Dindo grade IIIa or higher were examined. To investigate causes of spopf, we reviewed unedited video recordings of laparoscopic surgical procedures. Results spopf occurred to 3 patients (3.5%) after LG and 1 patient (3.0%) after OG, indicating no significant difference (p=0.901). Univariate analysis showed no significant risk factors for spopf after LG. By reviewing video recordings, all 3 patients with spopf after LG had direct pancreatic injury by ultrasonically activated device (USAD) during peripancreatic lymphadenectomy. In 2 of them, pancreas was injured while the contour of pancreas was obscured by bleeding. Durations of drain placement and postoperative hospitalization were longer for patients with spopf than for those without POPF or grades I and II POPF (p = 0.003, 0.018; respectively). Conclusions No risk factors for spopf after LG could be identified. USAD-induced direct pancreatic injury resulted in spopf, which significantly complicated the postoperative clinical Powered by Editorial Manager and ProduXion Manager from Aries Systems Corporation

2 course. Direct pancreatic injury can occur whether patient has previously reported risk factors (i.e. male, high BMI, distal pancreatectomy) or not. To prevent pancreatic injury, surgeons should manage hemostasis and keep good surgical field to recognize the contour of pancreas accurately. Powered by Editorial Manager and ProduXion Manager from Aries Systems Corporation

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4 Title Page Click here to download Title Page Title page R1.docx Title Intraoperative pancreatic injury gives rise to severe postoperative pancreatic fistula: results of a review of unedited videos of the laparoscopic surgical procedures Yuya Sato, MD, 1 Kazuyuki Kojima, MD, 2 Mikito Inokuchi, MD, 1 Keiji kato, MD, 1 Hirofumi Sugita, MD, 1 Sho Otsuki, MD, 1 Kenichi Sugihara, MD, 3 1 Department of Gastric Surgery, Tokyo Medical and Dental University 2 Center for Minimally Invasive Surgery, Tokyo Medical and Dental University 3 Department of Surgical Oncology, Tokyo Medical and Dental University Corresponding author: Yuya Sato, MD Department of Gastric Surgery, Tokyo Medical and Dental University , Yushima, Bunkyo-ku, Tokyo , Japan Yuya.sato.tmdu@gmail.com Phone: , Fax: A short running heading Direct pancreatic injury gives rise to severe POPF The authors have no conflict of interest to declare.

5 Manuscript Click here to download Manuscript renamed_2953b.docx 1 Abstract Objective To examine risk factors for and causes of severe postoperative pancreatic fistula (spopf) after laparoscopic gastrectomy (LG) Summary of Background Data There are few reports on POPF after LG. Methods Between February 2012 and March 2014, we examined 86 patients who underwent LG comparing them with 33 patients who underwent open gastrectomy (OG) for gastric cancer. Risk factors for severe POPF (spopf) of Clavien Dindo grade IIIa or higher were examined. To investigate causes of spopf, we reviewed unedited video recordings of laparoscopic surgical procedures. Results spopf occurred to 3 patients (3.5%) after LG and 1 patient (3.0%) after OG, indicating no significant difference (p=0.901). Univariate analysis showed no significant risk factors for spopf after LG. By reviewing video recordings, all 3 patients with spopf after LG had direct pancreatic injury by ultrasonically activated device (USAD) during peripancreatic lymphadenectomy. In 2 of them, pancreas was injured while the contour of pancreas was obscured by bleeding. Durations of drain placement and postoperative hospitalization were longer for patients with spopf than for those without POPF or grades I and II POPF (p = 0.003, 0.018; respectively). Conclusions No risk factors for spopf after LG could be identified. USAD-induced direct pancreatic injury resulted in spopf, which significantly complicated the postoperative clinical course. Direct pancreatic injury can occur whether patient has previously reported risk factors (i.e. male, high BMI, distal pancreatectomy) or not. To prevent pancreatic injury, surgeons should manage hemostasis and keep good surgical field to recognize the contour of

6 pancreas accurately. 2

7 Key words: Laparoscopic gastrectomy, Postoperative pancreatic fistula, Pancreatic injury 3

8 4 Introduction A randomized controlled trial has shown that radical lymphadenectomy offers a long-term survival benefit to patients with gastric cancer 1. Radical lymphadenectomy (i.e., D2 lymphadenectomy), including peripancreatic lymphadenectomy, is a standard treatment for curable gastric cancer 2. Since Kitano et al. first applied laparoscopy-assisted distal gastrectomy as a treatment for early gastric cancer in , laparoscopic gastrectomy (LG) is widely prevalent, particularly in Japan and Korea. LG for gastric cancer includes peripancreatic lymphadenectomy and is reported to be safe and feasible compared with OG in terms of morbidity and mortality 4, 5. However, there are few reports evaluating the incidence of postoperative pancreatic fistula (POPF) in patients who undergo LG with peripancreatic lymphadenectomy 6, 7.The influence of the surgical procedure in LG, which is different from that in OG, on the incidence of POPF remains unknown. Therefore, this retrospective study aimed to evaluate POPF after LG compared with those after OG in our institute and examine risk factors for and causes of POPF after LG. Materials and Methods Patients Between February 2012 and March 2014, we reviewed the medical records of 119 patients with preoperatively diagnosed gastric cancer who underwent distal gastrectomy or total gastrectomy with radical lymphadenectomy. Patients were excluded if they underwent anything under D1 lymphadenectomy, if they underwent emergency surgery for gastric cancer (i.e. perforation), or if they underwent surgery for postoperative complications other than POPF. Eventually, 86 patients who underwent LG (laparoscopic distal gastrectomy, n = 73; laparoscopic total gastrectomy, n = 13) with radical lymphadenectomy for gastric cancer were compared with 33 patients who underwent OG (open distal gastrectomy, n = 24; open total gastrectomy, n = 9).

9 5 Indications for LG Inclusion in the LG group was based on the preoperative diagnosis of T1N0, T1N1, T2N0, or T3N0 as per the TNM classification, 7th edition 8. Strategy for lymph node dissection The extent of lymph node dissection was determined according to Japanese gastric cancer treatment guidelines 2010 (version 3) 9. In principle, a D1+ lymphadenectomy was indicated for preoperative diagnosis of T1N0 tumors, and D2 is indicated for N+ or T2-T4 tumors. Surgical procedure for LG and OG The procedure for LG has been described previously 10. Peripancreatic lymphadenectomy included dissection of the infrapyloric lymph nodes (No. 6) and suprapancreatic lymph nodes (No. 7, 8a, 9, 11p, 12a). There are several differences in the surgical techniques for lymph node dissections between LG and OG as described below. First, peripancreatic lymphadenectomy is primarily performed with an ultrasonically activated device (USAD) during LG and a mainly electronic cautery device during OG. Second, retraction of the pancreas during peripancreatic lymphadenectomy is done by a laparoscopic sponge grasped by laparoscopic forceps during LG and by a gauze grasped by hand during OG. Finally, an ERBE VIO 300D generator (ERBE Elektromedizin, Tübingen, Germany) is used for hemostasis in LG, but not in OG. To maintain the quality of surgeries, all gastrectomies were performed, as best as possible, by a team of regular surgeons. For laparoscopic gastrectomy in particular, the operating team comprised some fixed members including one or more expert laparoscopic surgeons.

10 6 Classification and definition of POPF The amylase level in the drainage fluid on the 3rd postoperative day (D-AMY) was measured for each patient. We classified POPF after gastrectomy using the Clavien Dindo Classification. Severe POPF (spopf) was defined as POPF grade IIIa or higher according to the Clavien Dindo classification. For each patient, data on demographics, surgical outcomes, and POPF were collected. In addition, unedited video recordings of each laparoscopic surgical procedure were reviewed. Univariate analysis was performed to evaluate risk factors for spopf. The durations of drain placement and postoperative hospitalization were evaluated as indicators of short-term clinical outcomes of POPF after LG. Statistical analysis Categorical data were compared using the Chi squared test or Fisher s exact test as appropriate. Other variables were compared using the Student s t test of Mann Whitney U-test. Values of p < 0.05 were considered to indicate statistical significance. All analyses were performed using the statistical software package SPSS (ver. 20, Chicago, IL, USA). Results Clinical characteristics Table 1 summarizes the clinical characteristics of patients in the two groups. Age, sex, body mass index (BMI), and type of operation (distal gastrectomy or total gastrectomy) were not significantly different between the two groups. D2 lymph node dissection was more frequent in the OG group (23/33; 69.7%) than in the LG group (18/86; 20.9%; p < 0.001). Clinical stage was significantly more advanced in the OG group than in the LG group (p < 0.001). Surgical outcomes

11 7 Table 2 summarizes the surgical outcomes of patients in the two groups. The surgical duration was significantly longer in the LG group (333min; range, min) than in the OG group (280 min; range, min; p < 0.001). The amount of bleeding was lesser in the LG group (78 ml; range, ml) than in the OG group (560 ml; range, ml; p < 0.001). The number of retrieved lymph nodes was not significantly different between the two groups. The durations of drain placement and postoperative hospitalization were significantly shorter in the LG group (4 days; range, 3 42 days and 8 days; range, 5 71 days, respectively) than in the OG group (5 days; range, 4 55 days and 10 days; range, 8 41 days, respectively; p < and p = 0.002, respectively). Evaluation of D-AMY and classification of POPF Table 3 shows D-AMY values and POPF grades in the two groups. D-AMY (IU/L) was 163 (range, ) in the LG group and 123 (range, ) in the OG group, with no significant difference between groups (p = 0.077). Totally, 25 patients (29.1%) in the LG group and 9 (27.3%) in the OG group developed POPF (p = 0.879); of these, 3 patients (3.5%) in the LG group and 1 (3.0%) in the OG group developed spopf, with no significant differences between groups (p = 0.901). Risk factors for spopf Univariate analysis revealed no significant risk factors for spopf after LG (Table 4). Causes of spopf and clinical data of patients with spopf after laparoscopic gastrectomy By a review of unedited videos of the laparoscopic surgical procedures, all 3 patients with spopf in the LG group had direct pancreatic injury by USAD used during peripancreatic lymphadenectomy (during lymphadenectomy of No. 6 in 2 patients and No. 9 in 1). Clinical data of patients with spopf is shown in table 5. In 3 patients with spopf after LG,

12 8 1 was female and BMI was less than 25.0 (kg/m 2 ) in 2 patients. All 3 patients underwent LDG and D1+ lymphadenectomy without combined resection of other organ. In 3 patients, 2 had Grade IIIa POPF and 1 had Grade IIIb POPF. Short-term clinical outcomes of POPF Figure 1 shows the relationship between the development of POPF and short-term clinical outcomes after LG. The duration of drain placement was 4 days (range, 3 8 days) in patients without POPF, 5.5 days (range, 3 8 days) in those with grades I and II POPF, and 41 days (range, days) in those with grades IIIa and IIIb POPF. The duration of postoperative hospitalization was 8 days (range, 5 32 days) in patients without POPF, 9 days (range, 6 71 days) in patients with grades I and II POPF, and 36 days (range, days) in patients with grade IIIa and IIIb POPF. The duration of drain placement was significantly longer in patients with grades I and II POPF than in those without POPF (p < 0.001), Meanwhile both the durations of drain placement and postoperative hospitalization were significantly longer for patients with grade IIIa or higher POPF than for those without POPF or grades I and II POPF (p = and p = 0.018, respectively). Discussion This study was conducted to evaluate POPF after LG compared with those after OG and examine risk factors for and causes of POPF. No risk factors for spopf after LG could be identified in this study. Direct pancreatic injury by USAD during laparoscopic surgery, as determined by a review of unedited video recordings, was a cause of spopf, which in turn resulted in a significantly inferior postoperative course. Male 7, high BMI ( 25.0 kg/m 2 ) 11, high visceral fat area (VFA) ( 100cm 2 ) 12, and node dissection along the distal splenic artery 13 are reported to be risk factors for POPF. In patients with these risk factors, thermal injury caused by a USAD 6 and retraction and mobilization of the pancreas 14, 15 are supposed to be causes of POPF. In this study, a review of video recordings of the

13 9 laparoscopic surgical procedures revealed that retraction and mobilization of the pancreas and thermal injury caused by a USAD did not result in POPF that complicated the postoperative clinical course. The reported rate of POPF is highly variable, ranging from 1.5% to 7.5% after LG 4, 6, 7, 16 and from 1.1% to 49.7% after (OG) 6, 11, 12, These differences may be related to the variability of criteria among studies. To allow for accurate evaluation and comparison of POPF, objective and reproducible criteria are required. There are two objective classifications for POPF after gastrectomy: the International Study Group on Pancreatic Fistula (ISGPF) classification 20 and the Clavien Dindo classification 21. In this study, we used the Clavien Dindo classification. In previous studies on POPF after gastrectomy that used the ISGPF classification, POPF was defined as grade B or higher ISGPF 6, 7, 16, 22, 23. Because ISGPF Grade A POPF has abnormal data, but has little effect on clinical outcome 7. The Clavien Dindo classification includes seven severity grades, with grades III and IV having two subgroups. The Clavien Dindo classification is considered to be a more detailed classification that includes the clinical course of complications and associated therapeutic modalities 22. However, detailed criteria for grades of each complication were not described in the original report 21. ISGPF grades B and C were considered equivalent to Clavien Dindo grades II or higher in a previous report 22. In this study, we assigned patients with ISGPF grade A POPF to Clavien Dindo grade I POPF. This was not incompatible with the original criteria for Clavien Dindo grade I, defined as deviation from normal hospital course, no need for medication or intervention. In order to set a clinically reasonable definition of POPF after LG, we examined the durations of drain placement and postoperative hospitalization as indicators of the short-term clinical outcomes of POPF after LG. The duration of postoperative hospitalization was not significantly different between patients with grades I and II POPF and those without POPF, whereas both the durations of drain placement and postoperative hospitalization were significantly longer for patients with grade IIIa or higher POPF than for those without POPF and grades I and II

14 10 POPF by several fold. These findings indicate the clinical significance of Clavien Dindo grade IIIa or higher POPF. In this study, POPF occurred in as many as 34 patients (28.6%), indicating no difference between the LG and OG groups (p = 0.846). Furthermore, POPF of Clavien Dindo Grades I and II had little influence on short-term outcomes. Therefore, we focused on severe POPF of Grade IIIa or higher. Clinical stage of disease was significantly higher in the OG group than in the LG group according to the different indications. Therefore, D2 lymph node dissection was more frequently performed in the OG group than in the LG group according to the criteria of lymph node dissection 9. The surgical duration was significantly longer and the amount of bleeding was significantly lesser in the LG group than in the OG group, consistent with the findings of several other studies 6, 24. However, the number of retrieved lymph nodes was not different between groups. It can be concluded that LG is not inferior to OG in terms of the quality of lymph node dissection, even if the different extent of lymph node dissection between the two procedures are considered. The durations of drain placement and postoperative hospitalization were significantly shorter in the LG group than in the OG group. The short-term benefits of LG observed in this study are consistent with those reported in previous studies 5, 25, 26. Obama et al. reported that amylase levels in drainage fluid on the 1st postoperative day was approximately 3 times higher after LG than after OG. However, the incidence of POPF after LG did not differ from that after OG 6. In this study, D-AMY and spopf incidence were not significantly different between the two groups. Previously reported risk factors for POPF such as male and high BMI are supposed to make it difficult to accurately recognize the contour of pancreas and to distinguish the pancreatic tissue from the surrounding fat tissue 7, 12. However, these factors were not risk factors for spopf after LG in this study. Saying to risk factors about surgical procedures, Hyeong et al. reported that type of surgery (total gastrectomy) and combined resection of distal pancreas were independent risk factors for POPF and extended (D2) lymph node dissection was more frequent in POPF patients 16. In

15 11 this study, 3 patients with spopf in the LG group had not all these risk factors. By a review of unedited videos of the laparoscopic surgical procedures, all 3 patients with spopf in the LG group had direct pancreatic injury by USAD used during peripancreatic lymphadenectomy. In 2 of 3 patients with spopf, pancreas was injured while the contour of pancreas was obscured by bleeding. Ethical Approval Statement This research was approved by ethics commitee of Tokyo Medical and Dental University. Number/ID of the approval(s) is M All participants gave informed consent before taking part. Conclusions No risk factors for spopf after LG could be identified. Direct pancreatic injury by a USAD during peripancreatic lymphadenectomy was a cause of spopf after LG, which significantly complicated the postoperative clinical course. Direct pancreatic injury can occur to patients without previously reported risk factors (i.e. male, high BMI, distal pancreatectomy). To prevent pancreatic injury, surgeons should manage hemostasis and keep good surgical field to recognize the contour of pancreas accurately.

16 12 References 1. Songun I, Putter H, Kranenbarg EM, Sasako M, van de Velde CJ. Surgical treatment of gastric cancer: 15-year follow-up results of the randomised nationwide Dutch D1D2 trial. Lancet Oncol 2010;11(5): Sasako M, Saka M, Fukagawa T, Katai H, Sano T. Surgical treatment of advanced gastric cancer: Japanese perspective. Dig Surg 2007;24(2): Kitano S, Iso Y, Moriyama M, Sugimachi K. Laparoscopy-assisted Billroth I gastrectomy. Surg Laparosc Endosc 1994;4(2): Katai H, Sasako M, Fukuda H, Nakamura K, Hiki N, Saka M, et al. Safety and feasibility of laparoscopy-assisted distal gastrectomy with suprapancreatic nodal dissection for clinical stage I gastric cancer: a multicenter phase II trial (JCOG 0703). Gastric Cancer 2010;13(4): Kim HH, Hyung WJ, Cho GS, Kim MC, Han SU, Kim W, et al. Morbidity and mortality of laparoscopic gastrectomy versus open gastrectomy for gastric cancer: an interim report--a phase III multicenter, prospective, randomized Trial (KLASS Trial). Ann Surg 2010;251(3): Obama K, Okabe H, Hosogi H, Tanaka E, Itami A, Sakai Y. Feasibility of laparoscopic gastrectomy with radical lymph node dissection for gastric cancer: from a viewpoint of pancreas-related complications. Surgery 2011;149(1): Jiang X, Hiki N, Nunobe S, Kumagai K, Nohara K, Sano T, et al. Postoperative

17 13 pancreatic fistula and the risk factors of laparoscopy-assisted distal gastrectomy for early gastric cancer. Ann Surg Oncol 2012;19(1): Sobin LH, Gospodarowicz MK, Wittekind C. TNM Classification of Malignant Tumours: Wiley; Japanese gastric cancer treatment guidelines 2010 (ver. 3). Gastric Cancer 2011;14(2): Kojima K, Yamada H, Inokuchi M, Kawano T, Sugihara K. A comparison of Roux-en-Y and Billroth-I reconstruction after laparoscopy-assisted distal gastrectomy. Ann Surg 2008;247(6): Kunisaki C, Shimada H, Ono H, Otsuka Y, Matsuda G, Nomura M, et al. Predictive factors for pancreatic fistula after pancreaticosplenectomy for advanced gastric cancer in the upper third of the stomach. J Gastrointest Surg 2006;10(1): Tanaka K, Miyashiro I, Yano M, Kishi K, Motoori M, Seki Y, et al. Accumulation of excess visceral fat is a risk factor for pancreatic fistula formation after total gastrectomy. Ann Surg Oncol 2009;16(6): Katai H, Yoshimura K, Fukagawa T, Sano T, Sasako M. Risk factors for pancreas-related abscess after total gastrectomy. Gastric Cancer 2005;8(3): Ryu KW, Kim YW, Lee JH, Nam BH, Kook MC, Choi IJ, et al. Surgical complications and the risk factors of laparoscopy-assisted distal gastrectomy in

18 14 early gastric cancer. Ann Surg Oncol 2008;15(6): Perko Z, Pogorelic Z, Bilan K, Tomic S, Vilovic K, Krnic D, et al. Lateral thermal damage to rat abdominal wall after harmonic scalpel application. Surg Endosc 2006;20(2): Yu HW, Jung do H, Son SY, Lee CM, Lee JH, Ahn SH, et al. Risk factors of postoperative pancreatic fistula in curative gastric cancer surgery. J Gastric Cancer 2013;13(3): Sano T, Sasako M, Katai H, Maruyama K. Amylase concentration of drainage fluid after total gastrectomy. Br J Surg 1997;84(9): Okabayashi T, Kobayashi M, Sugimoto T, Okamoto K, Matsuura K, Araki K. Postoperative pancreatic fistula following surgery for gastric and pancreatic neoplasm; is distal pancreaticosplenectomy truly safe? Hepatogastroenterology 2005;52(61): Nobuoka D, Gotohda N, Konishi M, Nakagohri T, Takahashi S, Kinoshita T. Prevention of postoperative pancreatic fistula after total gastrectomy. World J Surg 2008;32(10): Bassi C, Dervenis C, Butturini G, Fingerhut A, Yeo C, Izbicki J, et al. Postoperative pancreatic fistula: an international study group (ISGPF) definition. Surgery 2005;138(1): Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new

19 15 proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 2004;240(2): Miki Y, Tokunaga M, Bando E, Tanizawa Y, Kawamura T, Terashima M. Evaluation of postoperative pancreatic fistula after total gastrectomy with D2 lymphadenectomy by ISGPF classification. J Gastrointest Surg 2011;15(11): Kung CH, Lindblad M, Nilsson M, Rouvelas I, Kumagai K, Lundell L, et al. Postoperative pancreatic fistula formation according to ISGPF criteria after D2 gastrectomy in Western patients. Gastric Cancer Gordon AC, Kojima K, Inokuchi M, Kato K, Sugihara K. Long-term comparison of laparoscopy-assisted distal gastrectomy and open distal gastrectomy in advanced gastric cancer. Surg Endosc Inokuchi M, Kojima K, Yamada H, Kato K, Hayashi M, Motoyama K, et al. Long-term outcomes of Roux-en-Y and Billroth-I reconstruction after laparoscopic distal gastrectomy. Gastric Cancer 2013;16(1): Haverkamp L, Weijs TJ, van der Sluis PC, van der Tweel I, Ruurda JP, van Hillegersberg R. Laparoscopic total gastrectomy versus open total gastrectomy for cancer: a systematic review and meta-analysis. Surg Endosc 2013;27(5):

20 16 Figure legends Figure 1 Relationship between postoperative pancreatic fistula (POPF) grades and short-term clinical outcomes after LG (A) Duration of drain placement in patients with each POPF grade (B) Duration of postoperative hospitalization for patients with each POPF grade The duration of drain placement was significantly longer in patients with Grade I and II POPF than in those without POPF (P <0.001). Meanwhile both the durations of drain placement and postoperative hospitalization were significantly longer for patients with Grade IIIa or higher POPF than in those without POPF or Grade I and II POPF (p = 0.003, p =0.018, respectively).

21 Figure Click here to download Figure Figure ppt R1.tif

22 Table Click here to download Table Tables.docx Table 1 Characteristics of patients LG group OG group (n = 86) (n = 33) p value Age, years (mean ± SD) 65.7 ± ± Sex Male Female 27 9 BMI, Kg/m 2 (mean ± SD) 22.7 ± ± Type of operation Distal gastrectomy Total gastrectomy 13 9 Extent of lymph node dissection <0.001 D D Clinical stage <0.001 Stage IA 64 7 Stage IB 10 2 Stage IIA 3 1 Stage IIB 5 7 Stage IIIA 0 6 Stage IIIB 4 6 Stage IIIC 0 3 Stage IV 0 1 LG laparoscopic gastrectomy, OG open gastrectomy, BMI body mass index

23 Table 2 Surgical outcomes LG group OG group (n = 86) (n = 33) p value Surgical duration, min (median (range)) 333 ( ) 280 ( ) <0.001 Bleeding ml (median (range)) 78 (0 790) 560 ( ) <0.001 Number of retrieved LNs (median (range)) 40 (22 85) 41 (16 88) Duration of drain placement, days (median (range)) 4 (3 42) 5 (4 55) <0.001 Postoperative hospital stay, days (median (range)) 8 (5 71) 10 (8 41) LG laparoscopic gastrectomy, OG open gastrectomy, LN lymph node

24 Table 3 Postoperative pancreatic fistula LG group OG group (n = 86) (n = 33) p value D-AMY a, IU/L (median (range)) 163 ( ) 123 ( ) Clavien Dindo Grade I 19 8 Grade II 3 0 Grade IIIa 2 1 Grade IIIb 1 0 Grade IVa 0 0 Grade IVb 0 0 Grade V 0 0 spopf, n (%) 3 (4.2%) 1 (3.3%) LG laparoscopic gastrectomy, OG open gastrectomy, POPF postoperative pancreatic fistula, spopf, severe postoperative pancreatic fistula a amylase concentration of the drainage fluid on the 3rd postoperative day

25 Table 4 Univariate analysis of risk factors for severe postoperative pancreatic fistula after laparoscopic gastrectomy Total spopf percentage of p value spopf Sex Male % Female % Age % < % BMI % < % T stage T % T2, T3, T % N stage N % N1, N2, N % Type of operation Distal gastrectomy % Total gastrectomy % Extent of lymphadenectomy D % D % Number of retrieved LNs % < % Surgical duration min % <300 min % Bleeding ml % <100ml % spopf severe postoperative pancreatic fistula, BMI body mass index, LNs lymph nodes

26 Table 5 Clinical data of patients with severe postoperative pancreatic fistula after laparoscopic gastrectomy. Surgical Combined Pancreatic POPF Age Sex BMI procedure resection injury Grade a D-AMY b Case 1 74 male 21.2 LDG D1+ none No. 9 Grade IIIa Case 2 63 female 23.7 LDG D1+ none No. 6 Grade IIIa Case 3 74 male 27.5 LDG D1+ none No. 6 Grade IIIb 1122 BMI body mass index, LDG laparoscopic distal gastrectomy, POPF postoperative pancreatic fistula a POPF grades are according to Clavien-Dindo classification. b amylase concentration of the drainage fluid on the 3rd postoperative day. (IU/L)

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29 Supplemental tables (not shown) Click here to download Table Supplemental tables R1.docx Supplemental table. 1 Univariate analysis of risk factors for postoperative pancreatic fistula after gastrectomy Total POPF percentage of p value POPF Sex Male % Female % Age % < % BMI % < % T stage T % T2, T3, T % N stage N % N1, N2, N % Approach Open % Laparoscopic % Type of operation Distal gastrectomy % Total gastrectomy % Extent of lymphadenectomy D % D % Number of retrieved LNs % < % Surgical duration min % <300 min % Bleeding ml % <100ml % POPF postoperative pancreatic fistula, BMI body mass index, LNs lymph nodes

30 Supplemental table. 2 Univariate analysis of risk factors for postoperative pancreatic fistula after laparoscopic gastrectomy Total POPF percentage of p value POPF Sex Male % Female % Age % < % BMI % < % T stage T % T2, T3, T % N stage N % N1, N2, N % Type of operation Distal gastrectomy % Total gastrectomy % Extent of lymphadenectomy D % D % Number of retrieved LNs % < % Surgical duration min % <300 min % Bleeding ml % <100ml % POPF postoperative pancreatic fistula, BMI body mass index, LNs lymph nodes

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