Failure to Undergo Resection Following Neoadjuvant Therapy for Resectable Pancreatic Cancer: A Secondary Analysis of SWOG S1505.

BACKGROUND: Neoadjuvant therapy (NT) is increasingly used for patients with pancreatic ductal adenocarcinoma (PDAC), and yet reasons for not undergoing subsequent pancreatectomy are poorly understood. Given the importance of completing multimodality therapy, we investigated factors associated with failure to undergo surgical resection following NT for PDAC. METHODS: SWOG S1505 was a multicenter phase II randomized trial of preoperative mFOLFIRINOX or gemcitabine/nab-paclitaxel prior to planned pancreatectomy for patients with potentially resectable PDAC. Associations between clinical, demographic, and hospital-level characteristics and receipt of surgical resection were estimated via multiple logistic regression. Differences in overall survival from 18 weeks postrandomization (scheduled time of surgery) according to resection status were assessed via Cox regression models. RESULTS: Among 102 eligible patients, 73 (71.6%) underwent successful pancreatectomy, whereas 29 (28.4%) did not, primarily because of progression (n=11; 10.8%) or toxicity during NT (n=9; 8.8%). Weight loss during NT (odds ratio [OR], 0.34; 95% CI, 0.11-0.93) and the hospital's city size (small: OR, 0.24 [95% CI, 0.07-0.80] and large: OR, 0.28 [95% CI, 0.10-0.79] compared with midsize) were significantly associated with a lower probability of surgical resection in adjusted models, whereas age, sex, race, body mass index, performance status, insurance type, geographic region, treatment arm, tumor location, chemotherapy delays/modifications, and hospital characteristics were not. Surgical resection following NT was associated with improved overall survival (median, 23.8 vs 10.8 months; P<.01) even after adjusting for grade 3-5 adverse events during NT, performance status, and body mass index (hazard ratio, 0.55; 95% CI, 0.32-0.95). CONCLUSIONS: Failure to undergo resection following NT was relatively common among patients with potentially resectable PDAC and associated with worse survival. Although few predictive factors were identified in this secondary analysis of the SWOG S1505 randomized trial, further research must focus on risk factors for severe toxicities during NT that preclude surgical resection so that patient-centered interventions can be delivered or alternate treatment sequencing can be recommended.

Optimal surgical management of unifocal vs. multifocal NF-PNETs: a respective cohort study.

BACKGROUND: Pancreatic neuroendocrine tumors (PNETs) represent 1-2% of pancreatic tumors, with recent guidelines recommending active surveillance for non-functioning PNETs (NF-PNETs) smaller than 2 cm. However, the management of multiple NF-PNETs, as well as the influence of tumor number on prognosis, remains under-researched. METHODS: This retrospective study analyzed NF-PNET patients who underwent pancreatic resection at Severance Hospital between February 1993 and August 2023, comparing the characteristics of patients diagnosed with multifocal tumors and those with unifocal tumors. A subgroup analysis of overall survival (OS) and recurrence-free survival (RFS) was performed based on multifocality employing the Kaplan-Meier method and the log-rank test. RESULTS: Of 187 patients, 169 (90.4%) had unifocal and 18 (9.6%) had multifocal tumors. Multifocal tumors were more likely to be diffusely spread, necessitating more total pancreatectomies (diffuse tumor location: 4.7% in unifocal vs. 38.9% in multifocal cases, p < 0.001; total pancreatectomy: 4.1% in unifocal vs. 33.3% in multifocal cases, p < 0.001). In patients with NF-PNET who underwent the same extent of pancreatic resection, no significant difference in the incidence of complication was observed regardless of multifocality. Moreover, no significant difference in OS was seen between the unifocal and multifocal groups (log-rank test: p = 0.93). However, the multifocal group exhibited a poorer prognosis in terms of RFS compared to the unifocal group (log-rank test: p = 0.004) Hereditary syndrome, tumor grade, size, lymphovascular invasion, and lymph node metastasis were key factors in the recurrence. CONCLUSION: This study's findings suggest that the presence of multiple tumors was associated with poorer recurrence-free survival but did not affect long-term survival following surgery. Given the long-term oncologic outcome and quality of life following surgery, resection of tumors over 2 cm is advisable in patients with multifocal PNETs, while a cautious "wait-and-see" approach for smaller tumors (under 2 cm) can minimize the extent of resection and improve the quality of life. In cases with only small multifocal NF-PNETs (< 2 cm), immediate resection may not be crucial, but the higher recurrence rate than that in solitary NF-PNET necessitates intensified surveillance.

Alpha-1 Antitrypsin Augmentation Therapy in Chronic Pancreatitis Patients Undergoing Total Pancreatectomy and Islet Autotransplantation: A Randomized, Controlled Study.

Stress-induced islet graft loss during the peri-transplantation period reduces the efficacy of islet transplantation. In this prospective, randomized, double-blind clinical trial, we evaluated the safety and efficacy of 60 mg/kg human alpha-1 antitrypsin (AAT) or placebo infusion weekly for four doses beginning before surgery in chronic pancreatitis (CP) patients undergoing total pancreatectomy and islet autotransplantation (TP-IAT). Subjects were followed for 12 months post-TP-IAT. The dose of AAT was safe, as there was no difference in the types and severity of adverse events in participants from both groups. There were some biochemical signals of treatment effect with a higher oxygen consumption rate in AAT islets before transplantation and a lower serum C-peptide (an indicator of islet death) in the AAT group at 15 min after islet infusion. Findings per the statistical analysis plan using a modified intention to treat analysis showed no difference in the C-peptide area under the curve (AUC) following a mixed meal tolerance test at 12 months post-TP-IAT. There was no difference in the secondary and exploratory outcomes. Although AAT therapy did not show improvement in C-peptide AUC in this study, AAT therapy is safe in CP patients and there are experiences gained on optimal clinical trial design in this challenging disease.

Cavitron ultrasonic surgical aspirator (CUSA) compared with conventional pancreatic transection in distal pancreatectomy: study protocol for the randomised controlled CUSA-1 pilot trial.

BACKGROUND: Postoperative pancreatic fistula (POPF) remains the most common and serious complication after distal pancreatectomy. Many attempts at lowering fistula rates have led to unrewarding insignificant results as still up to 30% of the patients suffer from clinically relevant POPF. Therefore, the development of new innovative methods and procedures is still a cornerstone of current surgical research.The cavitron ultrasonic surgical aspirator (CUSA) device is a well-known ultrasound-based parenchyma transection method, often used in liver and neurosurgery which has not yet been thoroughly investigated in pancreatic surgery, but the first results seem very promising. METHODS: The CUSA-1 trial is a randomised controlled pilot trial with two parallel study groups. This single-centre trial is assessor and patient blinded. A total of 60 patients with an indication for open distal pancreatectomy will be intraoperatively randomised after informed consent. The patients will be randomly assigned to either the control group with conventional pancreas transection (scalpel or stapler) or the experimental group, with transection using the CUSA device. The primary safety endpoint of this trial will be postoperative complications ≥grade 3 according to the Clavien-Dindo classification. The primary endpoint to investigate the effect will be the rate of POPF within 30 days postoperatively according to the ISGPS definition. Further perioperative outcomes, including postpancreatectomy haemorrhage, length of hospital stay and mortality will be analysed as secondary endpoints. DISCUSSION: Based on the available literature, CUSA may have a beneficial effect on POPF occurrence after distal pancreatectomy. The rationale of the CUSA-1 pilot trial is to investigate the safety and feasibility of the CUSA device in elective open distal pancreatectomy compared with conventional dissection methods and gather the first data on the effect on POPF occurrence. This data will lay the groundwork for a future confirmatory multicentre randomised controlled trial. ETHICS AND DISSEMINATION: The CUSA-1 trial protocol was approved by the ethics committee of the University of Heidelberg (No. S-098/2022). Results will be published in an international peer-reviewed journal and summaries will be provided in lay language to study participants and their relatives. TRIAL REGISTRATION NUMBER: DRKS00027474.

Preoperative zinc status predicts the occurrence and healing time of pancreatic fistula after distal pancreatectomy.

BACKGROUND: There are few studies that examined the relationship between preoperative zinc (Zn) concentrations and postoperative pancreatic fistula (POPF) after distal pancreatectomy (DP). METHODS: Data from 98 patients who underwent DP between January 2016 and April 2022 were retrospectively reviewed. Patients' clinicopathological and surgical outcomes were analyzed, and we examined the relationship between Zn and clinically relevant POPF (CR-POPF) after DP. RESULTS: In this series, 41 (41.8%) patients had POPF and 31 (31.8%) patients had CR-POPF. The cut-off value for the preoperative Zn concentration was 74 µg/dL for POPF and CR-POPF. Patients with low Zn concentrations were significantly related with high age, low albumin concentrations, higher CRP concentrations, higher NLR, lower PNI, higher rates of POPF and CR-POPF, longer POPF healing time, longer hospital stay, and postoperative complications than patients with high Zn concentrations. The healing time of POPF after DP was significantly negatively correlated with serum Zn concentrations. A multivariate logistic regression analysis showed that preoperative lower Zn concentrations and a prolonged operation time were independent predictors of CR-POPF and the healing time of POPF after DP. The POPF healing time in patients with high Zn was significantly shorter than that in patients with low Zn concentrations. CONCLUSIONS: This retrospective study showed the association between the preoperative Zn concentrations and the occurrence of POPF and the healing time after DP. Zn is a simple biomarker for malnutrition, which may lead to POPF after DP.

Efficacy of pancreaticojejunostomy of the pancreatic stump during distal or central pancreatectomy.

BACKGROUND: A stapler is usually used for transection and closure of the pancreas in distal pancreatectomy (DP) or central pancreatectomy (CP). When the pancreas is transected to the right of the portal vein, it is difficult to use a stapler and clinically relevant postoperative pancreatic fistula (CR-POPF) frequently occurs. We report on the efficacy of pancreaticojejunostomy (PJ) of the pancreatic stump for patients in whom stapler use is difficult. METHODS: Patients who underwent DP or CP were enrolled in this study. The pancreas was usually transected by a stapler, and ultrasonic coagulating shears (UCS) were used depending on the tumor situation. When using UCS, hand-sewn closure or PJ was performed for the pancreatic stump. The relationship between clinicopathological factors and the methods of pancreatic transection and closure were investigated. RESULTS: In total, 164 patients underwent DP or CP, and the pancreas was transected with a stapler in 150 patients and UCS in 14 patients. The rate of CR-POPF was higher and the postoperative hospital stay was longer in the UCS group than in the stapler group. PJ of the pancreatic stump, which was performed for 7 patients, did not worsen intraoperative factors. CR-POPF was not seen in these 7 patients, which was significantly less than that with hand-sewn closure. CONCLUSIONS: PJ of the pancreatic stump during DP or CP reduces CR-POPF compared with hand-sewn closure and may be useful especially when the pancreas is transected to the right of the portal vein.

Optimal cutoff values of drain amylase for predicting pancreatic fistula are different between open and laparoscopic distal pancreatectomy.

BACKGROUND: Drainage fluid amylase (DFA) is useful for predicting clinically relevant postoperative pancreatic fistula (CR-POPF) after distal pancreatectomy (DP). However, difference in optimal cutoff value of DFA for predicting CR-POPF between open DP (ODP) and laparoscopic DP (LDP) has not been investigated. This study aimed to identify the optimal cutoff values of DFA for predicting CR-POPF after ODP and LDP. METHODS: Data for 294 patients (ODP, n = 127; LDP, n = 167) undergoing DP at Kobe University Hospital between 2010 and 2021 were reviewed. Propensity score matching was performed to minimize treatment selection bias. Receiver operating characteristic (ROC) analysis was performed to determine the optimal cutoff values of DFA for predicting CR-POPF for ODP and LDP. Logistic regression analysis for CR-POPF was performed to investigate the diagnostic value of DFA on postoperative day (POD) three with identified cutoff value. RESULTS: In the matched cohort, CR-POPF rates were 24.7% and 7.9% after ODP and LDP, respectively. DFA on POD one was significantly lower after ODP than after LDP (2263 U/L vs 4243 U/L, p < 0.001), while the difference was not significant on POD three (543 U/L vs 1221 U/L, p = 0.171). ROC analysis revealed that the optimal cutoff value of DFA on POD one and three for predicting CR-POPF were different between ODP and LDP (ODP, 3697 U/L on POD one, 1114 U/L on POD three; LDP, 10564 U/L on POD one, 6020 U/L on POD three). Multivariate analysis showed that DFA on POD three with identified cutoff value was the independent predictor for CR-POPF both for ODP and LDP. CONCLUSIONS: DFA on POD three is an independent predictor for CR-POPF after both ODP and LDP. However, the optimal cutoff value for it is significantly higher after LDP than after ODP. Optimal threshold of DFA for drain removal may be different between ODP and LDP.

Long-term outcomes after spleen-preserving distal pancreatectomy with splenic vessels preservation or resection: A nationwide survey of the Japanese Society of Pancreatic Surgery.

BACKGROUND: Spleen preserving distal pancreatectomy is achieved by either splenic vessel resection or splenic vessel preservation. However, the long-term outcomes of spleen-preserving distal pancreatectomy with splenic vessel resection and spleen-preserving distal pancreatectomy with splenic vessel preservation are not well known. This study aimed to evaluate the long-term outcomes of spleen-preserving distal pancreatectomy with splenic vessel resection and spleen-preserving distal pancreatectomy with splenic vessel preservation. METHODS: The study included a total of 335 patients who underwent spleen-preserving distal pancreatectomy during the study period and underwent computed tomography or magnetic resonance imaging 3 and 5 years after surgery in the Japan Society of Pancreatic Surgery member institutions. We evaluated the diameter of the perigastric and gastric submucosal veins, patency of the splenic vessels, and splenic infarction. Preoperative backgrounds and short- and long-term outcomes were compared between the 2 groups. RESULTS: Forty-four (13.1%) and 291 (86.9%) patients underwent spleen-preserving distal pancreatectomy with splenic vessel resection and spleen-preserving distal pancreatectomy with splenic vessel preservation, respectively. There were no significant differences in short-term outcomes between the 2 groups. Regarding long-term outcomes, the prevalence of perigastric varices was higher (P = .006), and platelet count was lower (P = .037) in the spleen-preserving distal pancreatectomy with splenic vessel resection group. However, other complications, such as gastric submucosal varices, postoperative splenic infarction, gastrointestinal bleeding, reoperation, postoperative splenectomy, and other hematologic parameters, were not significantly different between the 2 groups 5 years after surgery. In terms of the patency of splenic vessels in spleen preserving distal pancreatectomy with splenic vessel preservation cases, partial or complete occlusion of the splenic artery and vein was observed 5 years after surgery in 19 (6.5%) and 55 (18.9%) patients, respectively. CONCLUSION: Perigastric varices and thrombocytopenia were observed more in spleen-preserving distal pancreatectomy with splenic vessel resection, yet late clinical events such as gastrointestinal bleeding and splenic infarction are acceptable for spleen-preserving distal pancreatectomy with splenic vessel preservation.

Completion pancreatectomy during pancreatoduodenectomy: A lifesaving solution in high-risk patients.

BACKGROUND: Postoperative pancreatic fistula (POPF) is responsible of most major complications and fatalities after PD. By avoiding POPF, TP may improve operative outcomes in high-risk patients. The aim was to compare total pancreatectomy (TP) and pancreatoduodenectomy (PD) in high-risk patients and evaluate results of implementing a risk-tailored strategy in clinical practice. METHODS: Between 2014 and 2023, 139 patients (76 men, median age 67 years) underwent resection of disease located in the head of the pancreas. Starting January 1, 2022, we offered TP to patients at high POPF risks (fistula risk score (FRS) ≥7) and to patients with intermediate POPF risks (FRS: 3-6) and high risks of failure to rescue (age> 75 years, ASA score ≥3). We compared outcomes of TP and PD and evaluated the results of the new strategy implementation on operative outcomes. Propensity score-based analysis was performed to limit bias of between-group comparison. RESULTS: Eventually, 26 (19%) patients underwent TP and 113 (81%) patients underwent PD. Severe complications occurred in 42 (30%) patients and 13 (9%) patients died. TP resulted in shorter lengths of hospital stay (median: 14 days [11; 18] vs. 17 days [13; 24], p = 0.016) and less risks of post-pancreatectomy hemorrhage (PPH) (0% vs. 20%, p < 0.001) compared to PD. Crude and propensity match analysis showed that the implementation of a risk-tailored strategy led to significant reduction of reoperation, POPF, PPH and mortality rates. CONCLUSION: The use of TP as part of a risk-tailored strategy in high-risk patients can be lifesaving.

Postoperative outcomes and costs of laparoscopic versus robotic distal pancreatectomy: a propensity-matched analysis.

BACKGROUND: Minimally invasive distal pancreatectomy (MIDP) has established advantages over the open approach. The costs associated with robotic DP (RDP) versus laparoscopic DP (LDP) make the robotic approach controversial. We sought to compare outcomes and cost of LDP and RDP using propensity matching analysis at our institution. METHODS: Patients undergoing LDP or RDP between 2000 and 2021 were retrospectively identified. Patients were optimally matched using age, gender, American Society of Anesthesiologists status, body mass index, and tumor size. Between-group differences were analyzed using the Wilcoxon signed-rank test for continuous data, and the McNemar's test for categorical data. Outcomes included operative duration, conversion to open surgery, postoperative length of stay, pancreatic fistula rate, pseudocyst requiring intervention, and costs. RESULTS: 298 patients underwent MIDP, 180 (60%) were laparoscopic and 118 (40%) were robotic. All RDPs were matched 1:1 to a laparoscopic case with absolute standardized mean differences for all matching covariates below 0.10, except for tumor type (0.16). RDP had longer operative times (268 vs 178 min, p < 0.01), shorter length of stay (2 vs 4 days, p < 0.01), fewer biochemical pancreatic leaks (11.9% vs 34.7%, p < 0.01), and fewer interventional radiological drainage (0% vs 5.9%, p = 0.01). The number of pancreatic fistulas (11.9% vs 5.1%, p = 0.12), collections requiring antibiotics or intervention (11.9% vs 5.1%, p = 0.12), and conversion rates (3.4% vs 5.1%, p = 0.72) were comparable between the two groups. The total direct index admission costs for RDP were 1.01 times higher than for LDP for FY16-19 (p = 0.372), and 1.33 times higher for FY20-22 (p = 0.031). CONCLUSIONS: Although RDP required longer operative times than LDP, postoperative stays were shorter. The procedure cost of RDP was modestly more expensive than LDP, though this was partially offset by reduced hospital stay and reintervention rate.

Outcome and survival were similar with laparoscopic and open pancreatectomy in 102 solid pseudopapillary neoplasms.

BACKGROUND: Solid pseudopapillary neoplasms of the pancreas (SPNP) are rare tumors predominantly in young women. We report the largest single-center cohort study comparing resection of SPNP by laparoscopic approach (LA) and the open approach (OA). METHOD: Between 2001 and 2021, 102 patients (84% women, median age: 30) underwent pancreatectomy for SPNP and were retrospectively studied. Demographic, perioperative, pathological, early and the long-term results were evaluated between patients operated by LA and those by OA. RESULTS: Population included 40 LA and 62 OA. There were no significant differences in demographics data between the groups. A preoperative biopsy by endoscopic ultrasound was performed in 45 patients (44%) with no difference between the groups. Pancreatoduodenectomy (PD) was less frequently performed by LA (25 vs 53%, p = 0.004) and distal pancreatectomy (DP) was more frequently performed by LA (40 vs 16%, p = 0.003). In the subgroup analysis by surgical procedure, LA-PD was associated with one mortality, less median blood loss (180 vs 200 ml, p = 0.034) and fewer harvested lymph nodes (11 vs 15, p = 0.02). LA-DP was associated with smaller median tumor size on imaging (40 vs 80mm, p = 0.048), shorter surgery (135 vs 190 min, p = 0.028), and fewer complications according to the median comprehensive complication index score (0 vs 8.7, p = 0.048). LA-Central pancreatectomy was associated with shorter surgery (160 vs 240, p = 0.037), less median blood loss (60 vs 200, p = 0.043), and less harvested lymph nodes (5 vs 2, p = 0.025). After a median follow-up of 60 months, two recurrences (2%) were observed and were unrelated to the approach. CONCLUSIONS: The LA for SPNP appears to be safe, should be applied cautiously in case of PD for large lesion, and was not associated with recurrence.

[Current status and considerations on clinical application of function-preserving pancreatic surgery].

For pancreatic neoplasms, the current clinical treatment strategy is mainly using standard surgical methods, including pancreaticoduodenectomy, distal pancreatectomy with splenectomy, and total pancreatectomy. Standard surgical methods require a larger resection, including resection of some surrounding organs and a large amount of pancreatic parenchyma. The endocrine and exocrine functions of the pancreas are easily damaged. Moreover, since the standard surgical procedure involves the reconstruction of the digestive tract at multiple anastomoses, there is a high risk of pancreatic, biliary, and intestinal fistulas occurring postoperatively. Therefore, function-preserving pancreatic surgery is recommended for some benign and low-grade pancreatic neoplasms. This type of surgery can treat pancreatic diseases while preserving more peripancreatic organs, pancreatic parenchyma and relatively complete digestive tract continuity, thereby improving the patient's short-term and long-term quality of life. In addition, with the development of laparoscopy and da Vinci robotic technology, minimally invasive technology-assisted pancreatic surgery has been carried out in clinical practice. They have been shown to be sufficiently safe and effective. This article reviews several common clinical pancreatic function-preserving surgical methods and their corresponding clinical applications and technical development status from the perspectives of preserving more peripancreatic organs, preserving more pancreatic parenchyma, and promoting pancreatic function recovery.

Advances in Surgery and (Neo) Adjuvant Therapy in the Management of Pancreatic Cancer.

A multimodality approach, which usually includes chemotherapy, surgery, and/or radiotherapy, is optimal for patients with localized pancreatic cancer. The timing and sequence of these interventions depend on anatomic resectability and the biological suitability of the tumor and the patient. Tumors with vascular involvement (ie, borderline resectable/locally advanced) require surgical reassessments after therapy and participation of surgeons familiar with advanced techniques. When indicated, venous reconstruction should be offered as standard of care because it has acceptable morbidity. Morbidity and mortality of pancreas surgery may be mitigated when surgery is performed at high-volume centers.

Prophylactic abdominal drainage after distal pancreatectomy (PANDORINA): an international, multicentre, open-label, randomised controlled, non-inferiority trial.

BACKGROUND: Prophylactic passive abdominal drainage is standard practice after distal pancreatectomy. This approach aims to mitigate the consequences of postoperative pancreatic fistula (POPF) but its added value, especially in patients at low risk of POPF, is currently being debated. We aimed to assess the non-inferiority of a no-drain policy in patients after distal pancreatectomy. METHODS: In this international, multicentre, open-label, randomised controlled, non-inferiority trial, we recruited patients aged 18 years or older undergoing open or minimally invasive elective distal pancreatectomy for all indications in 12 centres in the Netherlands and Italy. We excluded patients with an American Society of Anesthesiology (ASA) physical status of 4-5 or WHO performance status of 3-4, added by amendment following the death of a patient with ASA 4 due to a pre-existing cardiac condition. Patients were randomly assigned (1:1) intraoperatively by permuted blocks (size four to eight) to either no drain or prophylactic passive drain placement, stratified by annual centre volume (<40 or ≥40 distal pancreatectomies) and low risk or high risk of grade B or C POPF. High-risk was defined as a pancreatic duct of more than 3 mm in diameter, a pancreatic thickness at the neck of more than 19 mm, or both, based on the Distal Pancreatectomy Fistula Risk Score. Other patients were considered low-risk. The primary outcome was the rate of major morbidity (Clavien-Dindo score ≥III), and the most relevant secondary outcome was grade B or C POPF, grading per the International Study Group for Pancreatic Surgery. Outcomes were assessed up to 90 days postoperatively and analysed in the intention-to-treat population and per-protocol population, which only included patients who received the allocated treatment. A prespecified non-inferiority margin of 8% was compared with the upper limit of the two-sided 95% CI (Wald) of unadjusted risk difference to assess non-inferiority. This trial is closed and registered in the Netherlands Trial Registry, NL9116. FINDINGS: Between Oct 3, 2020, and April 28, 2023, 376 patients were screened for eligibility and 282 patients were randomly assigned to the no-drain group (n=138; 75 [54%] women and 63 [46%] men) or the drain group (n=144; 73 [51%] women and 71 [49%] men). Seven patients in the no-drain group received a drain intraoperatively; consequently, the per-protocol population included 131 patients in the no-drain group and 144 patients in the drain group. The rate of major morbidity was non-inferior in the no-drain group compared with the drain group in the intention-to-treat analysis (21 [15%] vs 29 [20%]; risk difference -4·9 percentage points [95% CI -13·8 to 4·0]; pnon-inferiority=0·0022) and the per-protocol analysis (21 [16%] vs 29 [20%]; risk difference -4·1 percentage points [-13·2 to 5·0]; pnon-inferiority=0·0045). Grade B or C POPF was observed in 16 (12%) patients in the no-drain group and in 39 (27%) patients in the drain group (risk difference -15·5 percentage points [95% CI -24·5 to -6·5]; pnon-inferiority<0·0001) in the intention-to-treat analysis. Three patients in the no-drain group died within 90 days; the cause of death in two was not considered related to the trial. The third death was a patient with an ASA score of 4 who died after sepsis and a watershed cerebral infarction at second admission, leading to multiple organ failure. No patients in the drain group died within 90 days. INTERPRETATION: A no-drain policy is safe in terms of major morbidity and reduced the detection of grade B or C POPF, and should be the new standard approach in eligible patients undergoing distal pancreatectomy. FUNDING: Ethicon UK (Johnson & Johnson Medical, Edinburgh, UK).