Natural History of the Remnant Pancreatic Duct after Pancreatoduodenectomy for Non-Invasive Intraductal Papillary Mucinous Neoplasm: Results from an International Consortium.

BACKGROUND: Little is known about the prognostic significance of pancreatic duct (PD) dilation following pancreatoduodenectomy for intraductal papillary mucinous neoplasms (IPMN). Although PD dilation is typically the hallmark radiographic feature of IPMN, other causes of PD dilation exist, including anastomotic stricture, pancreatitis, senescence, and postsurgical passive dilation. Therefore, PD dilation after pancreatoduodenectomy for IPMN represents a diagnostic and management dilemma. The purpose of this study was to evaluate the significance of PD dilation after pancreatoduodenectomy for noninvasive IPMN. METHODS: All patients who underwent pancreatoduodenectomy for noninvasive IPMN at nine pancreatic academic centers between 2013 and 2018 were included. Variables were entered prospectively into institutional databases and retrospectively reviewed for the purpose of this study. Dilation of the PD remnant was defined as a duct diameter of ≥5 mm, according to international guidelines. RESULTS: Four-hundred and eighty-one patients were included in this study. The mean age of the patients was 66 years (range 30-90). Patients were surveilled for a median of 4.5 (+/-2.3; max 10.6) years. During follow-up, 132 patients (27.4%) developed PD dilation in the remnant tissue after a median of 3.3 years. Multivariable analysis demonstrated that older age at the time of pancreatoduodenectomy (P=0.01) and longer surveillance duration (P=0.002) were predictors of PD dilation. Interestingly, neither the pathological IPMN subtype (branch-duct vs. main duct/mixed, P=0.96) nor the preoperative PD diameter (P=0.14) was associated with an increased risk of PD dilation in the remnant. During follow-up, IPMN recurrence was suspected in the remaining 72 patients (18.4%), solely because of ductal dilation on cross-sectional imaging in 97% (70/72). Completion pancreatectomy was performed in only 16 patients (3.3%), of whom only four (0.8%) had invasive carcinoma. Three of these four patients had high-grade dysplasia in the original pancreatoduodenectomy specimen, whereas only one had a low-grade dysplastic lesion initially. On multivariable analysis, no variable was predictive of IPMN recurrence in the remnant. CONCLUSIONS: New main duct dilation in the pancreatic remnant after pancreatoduodenectomy for IPMN is common, occurring in 27% of the patients. The duration of surveillance is the main factor associated with remnant PD dilation, suggesting that this is likely a physiologic phenomenon. Although recurrence of IPMN in the remnant is often suspected, only 0.8% of patients develop an invasive carcinoma in the pancreatic remnant requiring completion pancreatectomy.

Somatostatin Versus Octreotide for Prevention of Postoperative Pancreatic Fistula: The PREFIPS Randomized Clinical Trial: A FRENCH 007-ACHBT Study.

OBJECTIVE: Pharmacological prevention of postoperative pancreatic fistula (POPF) after pancreatectomy is open to debate. The present study compares clinically significant POPF rates in patients randomized between somatostatin versus octreotide as prophylactic treatment. METHODS: Multicentric randomized controlled open study in patient's candidate for pancreaticoduodenectomy (PD) or distal pancreatectomy (DP) comparing somatostatin continuous intravenous infusion for 7 days versus octreotid 100 µg, every 8 hours subcutaneous injection for 7 days, stratified by procedure (PD vs DP) and size of the main pancreatic duct (>4 mm) on grade B/C POPF rates at 90 days based on an intention-to-treat analysis. RESULTS: Of 763 eligible patients, 651 were randomized: 327 in the octreotide arm and 324 in the somatostatin arm, with comparable the stratification criteria - type of surgery and main pancreatic duct dilatation. Most patients had PD (n=480; 73.8%), on soft/normal pancreas (n=367; 63.2%) with a nondilated main pancreatic duct (n=472; 72.5%), most often for pancreatic adenocarcinoma (n=311; 47.8%). Almost all patients had abdominal drainage (n=621; 96.1%) and 121 (19.5%) left the hospital with the drain in place (median length of stay=16 days). A total of 153 patients (23.5%) developed a grade B/C POPF with no difference between both groups: 24.1%: somatostatin arm and 22.9%: octreotide arm (χ 2 test, P =0.73, ITT analysis). Absence of statistically significant difference persisted after adjustment for stratification variables and in per-protocol analysis. CONCLUSION: Continuous intravenous somatostatin is not statistically different from subcutaneous octreotide in the prevention of grade B/C POPF after pancreatectomy. FINDINGS: In the PREFIPS Randomized Clinical Trial including 651 patients, a total of 153 patients (23.5%) developed a grade B/C POPF with no significant difference between both groups: 24.1%: somatostatin arm and 22.9%: octreotide arm (χ 2 test, P =0.73, ITT analysis). Absence of statistically significant difference persisted after adjustment for stratification variables and in per-protocol analysis.

Enucleation for Sporadic Nonfunctioning Pancreatic Neuroendocrine Tumors Larger than 2 Centimeters Is Associated with Equivalent Morbidity and Survival Compared to Smaller Tumors: A Multi-Institutional Study.

INTRODUCTION: Nonfunctioning pancreatic neuroendocrine tumor (NF-PanNET) ≤2 cm can be observed or resected. Surgery remains recommended for NF-PanNET >2 cm but its extent, enucleation (EN) versus formal resection, remains controversial. METHODS: Multicentric retrospective cohort of sporadic NF-PanNET patients treated with EN. Short- and long-term outcomes were compared according to tumor size on imaging ≤2 cm versus >2 cm. RESULTS: 131 patients underwent EN for NF-PanNET, including 103 (79.0%) ≤2 cm and 28 (21.0%) >2 cm (extremes, 4-55 mm). Patients' characteristics were comparable, and tumor characteristics only differed in their diameter. Clavien III-IV complications were similar (18.4% vs. 17.9%, p = 1.00) with one death in NF-PanNET ≤2 cm. Grade B/C pancreatic fistula were comparable (16.5% vs. 10.7%, p = 0.850). In NF-PanNET >2 cm there were more pT2/3 stage tumors (85.7% vs. 21.4%, p < 0.001), similar rates of grade G2/3 tumors (25% vs. 16.5%, p = 0.408) with a median Ki67 of 2 (interquartile range: 1-3), and of lymphovascular and perineural invasions. Lymph node picking was done in 46 (35.1%) patients, with a higher median number of harvested lymph nodes in NF-PanNET >2 cm (4 vs. 3, p = 0.01). All were pN0. R0 resection rate (78.6% vs. 82.5%, respectively; p = 0.670) was equivalent. Five-year overall (100% vs. 99%, p = 0.602) and 10-year disease-free (96% vs. 92%, respectively; p = 0.532) survivals were comparable. CONCLUSIONS: EN for selected NF-PanNET >2 cm carries equivalent morbidity, overall and disease-free survivals compared to those observed with NF-PanNET ≤2 cm.

Aborted pancreatoduodenectomy after extensive vascular dissection in patients with pancreatic cancer: a word of caution.

BACKGROUND: Difficulties in distinguishing fibrosis from tumor in borderline and locally advanced pancreatic adenocarcinoma (PDAC) justify surgical exploration to assess resectability. This issue is especially relevant after neoadjuvant treatments (NAT) prior to pancreaticoduodenectomy (PD) although outcomes of aborted PD are unknown. OBJECTIVES: This study aimed to evaluate early outcomes after aborted PD in patients with PDAC. METHODS: Data were collected over a ten-year period, in three University Hospitals in France. Perioperative patient management was similar. The causes of intraoperative PD abortions were recorded, and outcomes of patients who underwent early (metastases, carcinomatosis) and late (following extensive vascular dissection) PD abortion were compared. RESULTS: Of 774 PD for PDAC, 131 (17%) were aborted. 97 (74%) patients underwent early PD abortion due to carcinomatosis (n = 14; 14%), liver metastases (n = 32; 33%), aortocaval lymph node invasion (n = 28; 29%) and massive vascular extension (n = 23; 24%). Late PD abortion occurred after extensive vascular dissection in 34 (26%) patients due to invasion of the common hepatic (n = 16; 47%), superior mesenteric (n = 5; 15%) and right hepatic (n = 1; 3%) arteries and nonreconstructable venous invasion (n = 12; 35%). Patients who underwent late PD abortion had higher rates of overall morbidity (n = 22; 65% vs n = 27; 28%, p = 0.0001), severe complications (n = 14; 41% vs n = 11; 11%, p = 0.0005), mortality (n = 4; 12% vs n = 0; 0%, p = 0.003). They also had higher rates of delayed gastric emptying (n = 11; 32% vs n = 6; 6%, p = 0.0003), deep space infections (n = 10; 29% vs n = 7; 7%, p = 0.002), wound infections (n = 5; 15% vs n = 4; 4%, p = 0.05), and bleeding (n = 8; 24% vs n = 0; 0%, p < 0.0001). CONCLUSION: Aborted PD after extensive vascular dissection has high morbidity and mortality rates. Appropriate information and counseling should be delivered to patients with borderline/locally advanced PDAC considered for PD.

Safety and performance of a synthetic sealant patch aimed to prevent postoperative pancreatic fistula after distal pancreatectomy (SHIELDS) - Prospective international multicenter phase II study.

OBJECTIVE: The incidence for clinically relevant postoperative pancreatic fistulas (CR-POPF) in distal pancreatectomy (DP) ranges up to 25%. None of the available sealants significantly reduce CR-POPF. A new biodegradable sealant patch was able to reduce POPF and to achieve bleeding control in a preclinical porcine DP model. The aim of this first-in-human study was to assess the safety and performance of the sealant patch. METHODS: In this multicenter, single-arm study, 40 patients undergoing distal pancreatectomy were prospectively enrolled from 8 centers. Following surgical resection, the transection plane was closed according to the standard of care and manually covered with the sealant patch. As primary endpoint the incidence of CR-POPF up to 30-days postoperatively was evaluated. The secondary endpoints included the assessment of complications and device usability. RESULTS: Among 40 patients after distal pancreatectomy, CR-POPF occurred in 7 (17.5%) up to postoperative day 30. No type C POPF was observed. There was no intraoperative bleeding observed after patch application. CONCLUSION: The results of this international phase II study demonstrate promising results of a new sealant patch regarding the rate of CR-POPF. Randomized studies are now needed to confirm the superiority of the current patch as compared to the best current practice.

Defining Benchmark Outcomes for Distal Pancreatectomy: Results of a French Multicentric Study.

OBJECTIVE: Defining robust and standardized outcome references for distal pancreatectomy (DP) by using Benchmark analysis. BACKGROUND: Outcomes after DP are recorded in medium or small-sized studies without standardized analysis. Therefore, the best results remain uncertain. METHODS: This multicenter study included all patients undergoing DP for resectable benign or malignant tumors in 21 French expert centers in pancreas surgery from 2014 to 2018. A low-risk cohort defined by no significant comorbidities was analyzed to establish 18 outcome benchmarks for DP. These values were tested in high risk, minimally invasive and benign tumor cohorts. RESULTS: A total of 1188 patients were identified and 749 low-risk patients were screened to establish Benchmark cut-offs. Therefore, Benchmark rate for mini-invasive approach was ≥36.8%. Benchmark cut-offs for postoperative mortality, major morbidity grade ≥3a and clinically significant pancreatic fistula rates were 0%, ≤27%, and ≤28%, respectively. The benchmark rate for readmission was ≤16%. For patients with pancreatic adenocarcinoma, cut-offs were ≥75%, ≥69.5%, and ≥66% for free resection margins (R0), 1-year disease-free survival and 3-year overall survival, respectively. The rate of mini-invasive approach in high-risk cohort was lower than the Benchmark cut-off (34.1% vs ≥36.8%). All Benchmark cut-offs were respected for benign tumor group. The proportion of benchmark cases was correlated to outcomes of DP. Centers with a majority of low-risk patients had worse results than those operating complex cases. CONCLUSION: This large-scale study is the first benchmark analysis of DP outcomes and provides robust and standardized data. This may allow for comparisons between surgeons, centers, studies, and surgical techniques.

A Simple Classification of Pancreatic Duct Size and Texture Predicts Postoperative Pancreatic Fistula: A classification of the International Study Group of Pancreatic Surgery.

OBJECTIVE: The aim of this study was to develop a classification system for pancreas-associated risk factors in pancreatoduodenectomy (PD). SUMMARY BACKGROUND DATA: Postoperative pancreatic fistula (POPF) is the most relevant PD-associated complication. A simple standardized surgical reporting system based on pancreas-associated risk factors is lacking. METHODS: A systematic literature search was conducted to identify studies investigating clinically relevant (CR) POPF (CR-POPF) and pancreas-associated risk factors after PD. A meta-analysis of CR-POPF rate for texture of the pancreas (soft vs not-soft) and main pancreatic duct (MPD) diameter was performed using the Mantel-Haenszel method. Based on the results, the International Study Group of Pancreatic Surgery (ISGPS) proposes the following classification: A, not-soft (hard) texture and MPD >3 mm; B, not-soft (hard) texture and MPD ≤3 mm; C, soft texture and MPD >3 mm; D, soft texture and MPD ≤3 mm. The classification was evaluated in a multi-institutional, international cohort. RESULTS: Of the 2917 articles identified, 108 studies were included in the analyses. Soft pancreatic texture was significantly associated with the development of CR-POPF [odds ratio (OR) 4.24, 95% confidence interval (CI) 3.67-4.89, P < 0.01) following PD. Similarly, MPD diameter ≤3 mm significantly increased CR-POPF risk compared with >3 mm diameter MPDs (OR 3.66, 95% CI 2.62-5.12, P < 0.01). The proposed 4-stage system was confirmed in an independent cohort of 5533 patients with CR-POPF rates of 3.5%, 6.2%, 16.6%, and 23.2% for type A-D, respectively ( P < 0.001). CONCLUSION: For future pancreatic surgical outcomes studies, the ISGPS recommends reporting these risk factors according to the proposed classification system for better comparability of results.

Tumor burden in patients with early and intermediate-stage hepatocellular carcinoma undergoing liver resection: a retrospective multicenter study on clinical and oncological outcomes.

BACKGROUND: According to the Barcelona Clinic Liver Cancer (BCLC) staging system, liver resection (LR) is recommended for early-stage (BCLC-A) hepatocellular carcinoma (HCC) but not for intermediate-stage (BCLC-B). This study aimed to assess the outcomes of LR in these patients using a subclassification tumour burden score (TBS). METHODS: All consecutive patients that underwent LR for BCLC-A and BCLC-B HCC between 01/2010 and 12/2020 in 4 tertiary referral centers were included. Clinical outcomes and overall survival (OS) were assessed in relation to TBS and BCLC stages. RESULTS: Among 612 patients included, 562 were classified as BCLC-A and 50 as BCLC-B. The incidence of overall postoperative complications (56.0 vs 41.5%, p = 0.053) and mortality (0 vs 1.6%, p = 1.000) were similar between BCLC-A and BCLC-B patients. OS was significantly higher for BCLC A/low TBS than BCLC B/low TBS (p = 0.009), while patients with medium and high TBS had similar OS, irrespective of BCLC stage (respectively p = 0.103 and p = 0.343). CONCLUSIONS: Patients with medium and high TBS had comparable OS and DFS, irrespective of BCLC A or B stage, and postoperative morbidity was comparable. These results highlight the need for refinement of the BCLC staging system, and LR could be considered for selected intermediate stage (BCLC-B) according to the tumour burden.

Postpancreatectomy Acute Pancreatitis (PPAP): Definition and Grading From the International Study Group for Pancreatic Surgery (ISGPS).

OBJECTIVE: The ISGPS aimed to develop a universally accepted definition for PPAP for standardized reporting and outcome comparison. BACKGROUND: PPAP is an increasingly recognized complication after partial pancreatic resections, but its incidence and clinical impact, and even its existence are variable because an internationally accepted consensus definition and grading system are lacking. METHODS: The ISGPS developed a consensus definition and grading of PPAP with its members after an evidence review and after a series of discussions and multiple revisions from April 2020 to May 2021. RESULTS: We defined PPAP as an acute inflammatory condition of the pancreatic remnant beginning within the first 3 postoperative days after a partial pancreatic resection. The diagnosis requires (1) a sustained postoperative serum hyperamylasemia (POH) greater than the institutional upper limit of normal for at least the first 48 hours postoperatively, (2) associated with clinically relevant features, and (3) radiologic alterations consistent with PPAP. Three different PPAP grades were defined based on the clinical impact: (1) grade postoperative hyperamylasemia, biochemical changes only; (2) grade B, mild or moderate complications; and (3) grade C, severe life-threatening complications. DISCUSSIONS: The present definition and grading scale of PPAP, based on biochemical, radiologic, and clinical criteria, are instrumental for a better understanding of PPAP and the spectrum of postoperative complications related to this emerging entity. The current terminology will serve as a reference point for standard assessment and lend itself to developing specific treatments and prevention strategies.

International Validation of a Nomogram to Predict Recurrence after Resection of Grade 1 and 2 Nonfunctioning Pancreatic Neuroendocrine Tumors.

BACKGROUND: Despite the low recurrence rate of resected nonfunctional pancreatic neuroendocrine tumors (NF-pNETs), nearly all patients undergo long-term surveillance. A prediction model for recurrence may help select patients for less intensive surveillance or identify patients for adjuvant therapy. The objective of this study was to assess the external validity of a recently published model predicting recurrence within 5 years after surgery for NF-pNET in an international cohort. This prediction model includes tumor grade, lymph node status and perineural invasion as predictors. METHODS: Retrospectively, data were collected from 7 international referral centers on patients who underwent resection for a grade 1-2 NF-pNET between 1992 and 2018. Model performance was evaluated by calibration statistics, Harrel's C-statistic, and area under the curve (AUC) of the receiver operating characteristic curve for 5-year recurrence-free survival (RFS). A sub-analysis was performed in pNETs >2 cm. The model was improved to stratify patients into 3 risk groups (low, medium, high) for recurrence. RESULTS: Overall, 342 patients were included in the validation cohort with a 5-year RFS of 83% (95% confidence interval [CI]: 78-88%). Fifty-eight patients (17%) developed a recurrence. Calibration showed an intercept of 0 and a slope of 0.74. The C-statistic was 0.77 (95% CI: 0.70-0.83), and the AUC for the prediction of 5-year RFS was 0.74. The prediction model had a better performance in tumors >2 cm (C-statistic 0.80). CONCLUSIONS: External validity of this prediction model for recurrence after curative surgery for grade 1-2 NF-pNET showed accurate overall performance using 3 easily accessible parameters. This model is available via www.pancreascalculator.com.

Pain management, fluid therapy and thromboprophylaxis after pancreatoduodenectomy: a worldwide survey among surgeons.

BACKGROUND: The aim of this survey was to assess practices regarding pain management, fluid therapy and thromboprophylaxis in patients undergoing pancreatoduodenectomy on a global basis. METHODS: This survey study among surgeons from eight (inter)national scientific societies was performed according to the CHERRIES guideline. RESULTS: Overall, 236 surgeons completed the survey. ERAS protocols are used by 61% of surgeons and respectively 82%, 93%, 57% believed there is a relationship between pain management, fluid therapy, and thromboprophylaxis and clinical outcomes. Epidural analgesia (50%) was most popular followed by intravenous morphine (24%). A restrictive fluid therapy was used by 58% of surgeons. Chemical thromboprophylaxis was used by 88% of surgeons. Variations were observed between continents, most interesting being the choice for analgesic technique (transversus abdominis plane block was popular in North America), restrictive fluid therapy (little use in Asia and Oceania) and duration of chemical thromboprophylaxis (large variation). CONCLUSION: The results of this international survey showed that only 61% of surgeons practice ERAS protocols. Although the majority of surgeons presume a relationship between pain management, fluid therapy and thromboprophylaxis and clinical outcomes, variations in practices were observed. Additional studies are needed to further optimize, standardize and implement ERAS protocols after pancreatic surgery.

Root-cause Analysis of Mortality After Pancreatic Resection (CARE Study): A Multicenter Cohort Study.

OBJECTIVES: Analyze a multicenter cohort of deceased patients after pancreatectomy in high-volume centers in France by performing a root-cause analysis (RCA) to define the avoidable mortality rate. BACKGROUND: Despite undeniable progress in pancreatic surgery for over a century, postoperative outcome remains particularly worse and could be further improved. METHODS: All patients undergoing pancreatectomy between January 2015 and December 2018 and died postoperatively within 90 days after were included. RCA was performed in 2 stages: the first being the exhaustive collection of data concerning each patient from preoperative to death and the second being blind analysis of files by an independent expert committee. A typical root cause of death was defined with the identification of avoidable death. RESULTS: Among the 3195 patients operated on in 9 participating centers, 140 (4.4%) died within 90 days after surgery. After the exclusion of 39 patients, 101 patients were analyzed. The cause of death was identified in 90% of cases. After RCA, mortality was preventable in 30% of cases, mostly consequently to a preoperative assessment (disease evaluation) or a deficient postoperative management (notably pancreatic fistula and hemorrhage). An inappropriate intraoperative decision was incriminated in 10% of cases. The comparative analysis showed that young age and arterial resection, especially unplanned, were often associated with avoidable mortality. CONCLUSIONS: One-third of postoperative mortality after pancreatectomy seems to be avoidable, even if the surgery is performed in high volume centers. These data suggest that improving postoperative pancreatectomy outcome requires a multidisciplinary, rigorous, and personalized management.

Management and Prognosis of Localized Duodenal Neuroendocrine Neoplasms.

INTRODUCTION: The characteristics, prognostic factors, and management of duodenal neuroendocrine neoplasms (dNEN) are ill-defined, given their rarity. Whether nonsurgical management might be appropriate for patients with nonmetastatic dNEN and a good prognosis, as is the case for pancreatic NEN (pNEN), is unknown. We aimed to describe the management and prognosis of nonmetastatic dNEN patients. METHODS: All consecutive patients with nonmetastatic dNEN managed between 1981 and 2018 in 2 expert centers were included. Recurrence-free survival (RFS) and factors associated with recurrence were estimated. RESULTS: A total of 145 patients with dNEN were included. Twenty-eight patients with sporadic, nonfunctioning, small (median 7 mm) dNEN underwent endoscopic resection, with a 5-year RFS rate of 89.4%. Local recurrence occurred in 2 patients, who underwent surgery with no new events. The 5-year RFS rate was 87.9% in patients who underwent surgery. Upon univariate analysis, age, size, Ki67 index, and lymph node involvement (LN+) were significantly associated with worse RFS for all dNEN treated (endoscopy/surgery); multivariate analysis found that age, size, and LN+ were associated with worse RFS. CONCLUSION: Selected nonmetastatic dNEN had a favorable outcome, and a less invasive therapeutic strategy appeared more suitable than oncological surgery.

Acute Pancreatitis as the Initial Presentation of Pancreatic Adenocarcinoma does not Impact Short- and Long-term Outcomes of Curative Intent Surgery: A Study of the French Surgical Association.

BACKGROUND: Acute pancreatitis (AP) can be one of the earliest clinical presentation of pancreatic ductal adenocarcinoma (PDAC). Information about the impact of AP on postoperative outcomes as well as its influences on PDAC survival is scarce. This study aimed to determine whether AP as initial clinical presentation of PDAC impact the short- and long-term outcomes of curative intent pancreatic resection. PATIENTS AND METHODS: From 2004 to 2009, 1449 patients with PDAC underwent pancreatic resection in 37 institutions (France, Belgium and Switzerland). We used univariate and multivariate analysis to identify factors associated with severe complications and pancreatic fistula as well as overall and disease-free survivals. RESULTS: There were 764 males (52,7%), and the median age was 64 years. A total of 781 patients (53.9%) developed at least one complication, among whom 317 (21.8%) were classified as Clavien-Dindo ≥ 3. A total of 114 (8.5%) patients had AP as the initial clinical manifestation of PDAC. This situation was not associated with any increase in the rates of postoperative fistula (21.2% vs 16.4%, P = 0.19), postoperative complications (57% vs 54.2%, P = 0.56), and 30 day mortality (2.6% vs 3.4%, P = 1). In multivariate analysis, AP did not correlate with postoperative complications or pancreatic fistula. The median length of follow-up was 22.4 months. The median overall survival after surgery was 29.9 months in the AP group and 30.5 months in the control group. Overall recurrence rate and local recurrence rate did not differ between groups. CONCLUSION: AP before PDAC resection did not impact postoperative morbidity and mortality, as well as recurrence rate and survival.

Prognostic value of positive histological margins in patients with pancreatic head ductal adenocarcinoma and lymph node involvement: an international multicentric study.

BACKGROUND: Resection margin status and lymph node (LN) involvement are known prognostic factors for patients who undergo pancreatoduodenectomy for pancreatic ductal adenocarcinoma (PDAC). This study aimed to compare overall survival (OS) and disease-free survival (DFS) by resection margin status in patients with PDAC and LN involvement. METHODS: A retrospective international multicentric study was performed including four Western centers. Multivariable Cox analysis was performed to identify prognostic factors of OS and DFS. Median OS and DFS were calculated using Kaplan-Meier curves and compared using log-rank tests. RESULTS: A cohort of 814 PDAC patients with pancreatoduodenectomy were analyzed. A total of 651 patients had LN involvement (80%). On multivariable analysis R1 resection was not an independent factor of worse OS and DFS in patients with LN involvement (HR 1.1, p = 0.565; HR 1.2, p = 0.174). Only tumor size, grade, and adjuvant chemotherapy were associated with OS and DFS. Median OS and DFS were similar between patients with R0 and R1 resections (23 vs. 20 months, p = 0.196; 15 vs. 14 months, p = 0.080). CONCLUSION: Resection status was not identified as predictor of OS or DFS in PDAC patients with LN involvement. Extensive surgery to achieve R0 resection in such patients might not influence the disease course.

Feasibility of an Enhanced Recovery Protocol for Elective Pancreatoduodenectomy: A Multicenter International Cohort Study.

BACKGROUND: The first enhanced recovery after surgery (ERAS) guidelines for pancreatoduodenectomy (PD) were developed in 2012. The study aimed to assess compliance and outcomes of an ERAS protocol for PD, to study correlation between compliance and outcomes, and to identify risk factors for complications. METHODS: Retrospective cohort analysis is based on a prospective database, including all consecutive patients undergoing elective PD within an ERAS program in four centers: Lausanne University Hospital (Switzerland), Carolinas Medical Center (United States), Edouard Herriot Hospital (France), and University Medical Center Hamburg-Eppendorf (Germany). Patients' characteristics, postoperative outcome and ERAS compliance were assessed. Logistic regression analysis was performed to assess predictors of postoperative complications. RESULTS: Between October 2012 and June 2017, 404 consecutive patients underwent PD. Median length of stay was 14 days with 11.3% readmission rate. Mean overall compliance was 62%, with pre-, intra- and postoperative compliance of 93%, 80% and 30%, respectively. Overall compliance ≥ 70% versus < 70% was significantly associated with a reduction in complications (p = 0.029) and length of stay (p < 0.001). Avoidance of postoperative nasogastric tube (OR = 0.31, p = 0.043), mobilization on day of surgery (OR = 0.28, p = 0.043), and mobilization more than 6 h on postoperative day 2 (OR = 0.45, p = 0.001) were independent predictors of reduced overall complications. CONCLUSIONS: Implementation of enhanced recovery for PD is challenging, especially in the postoperative period. Overall compliance with ERAS protocol ≥ 70% was associated with decreased complications and length of stay. Specific ERAS elements, such as avoidance of postoperative nasogastric tube and early mobilization, independently improved outcomes.

Guidelines for Perioperative Care for Pancreatoduodenectomy: Enhanced Recovery After Surgery (ERAS) Recommendations 2019.

BACKGROUND: Enhanced recovery after surgery (ERAS) pathways are now implemented worldwide with strong evidence that adhesion to such protocol reduces medical complications, costs and hospital stay. This concept has been applied for pancreatic surgery since the first published guidelines in 2012. This study presents the updated ERAS recommendations for pancreatoduodenectomy (PD) based on the best available evidence and on expert consensus. METHODS: A systematic literature search was conducted in three databases (Embase, Medline Ovid and Cochrane Library Wiley) for the 27 developed ERAS items. Quality of randomized trials was assessed using the Consolidated Standards of Reporting Trials statement checklist. The level of evidence for each item was determined using the Grading of Recommendations Assessment Development and Evaluation system. The Delphi method was used to validate the final recommendations. RESULTS: A total of 314 articles were included in the systematic review. Consensus among experts was reached after three rounds. A well-implemented ERAS protocol with good compliance is associated with a reduction in medical complications and length of hospital stay. The highest level of evidence was available for five items: avoiding hypothermia, use of wound catheters as an alternative to epidural analgesia, antimicrobial and thromboprophylaxis protocols and preoperative nutritional interventions for patients with severe weight loss (> 15%). CONCLUSIONS: The current updated ERAS recommendations for PD are based on the best available evidence and processed by the Delphi method. Prospective studies of high quality are encouraged to confirm the benefit of current updated recommendations.

Impact of Enhanced Recovery Program after Surgery in Patients Undergoing Pancreatectomy on Postoperative Outcomes: A Controlled before and after Study.

BACKGROUND: Implementation of enhanced recovery after surgery (ERAS) program after pancreatic surgery was associated with decreased length of stay (LOS). However, there were only retrospective uncontrolled before-after study, and care protocols were heterogeneous. We aimed to evaluate the impact of ERAS program on postoperative outcomes after pancreatectomy through a prospective controlled study. METHODS: A before/after study with a contemporary control group was undertaken in patients undergoing pancreatectomy. We compared 2 groups: the intervention hospital that implemented ERAS program and the control hospital that performed traditional care; and 2 periods: the preimplementation and the post-implementation period. A difference-in-differences approach was used to evaluate whether implementation of ERAS program was associated with improved LOS and postoperative morbidity. RESULTS: About 97 and 75 patients were included in intervention and control hospital. In multivariate analysis, implementation of ERAS was associated with a significantly shorten LOS (hazard ratio 1.61; 95% CI 1.07-2.44) and higher compliance rate (OR 1.34; 95% CI 1.18-1.53). Difference-in-differences analysis revealed that LOS, morbidity, and readmission did not differ after ERAS implementation. CONCLUSION: Implementation of ERAS program was safe and effective after pancreatectomy with high compliance rate. LOS was significantly reduced without compromising morbidity.

Benchmarks in Pancreatic Surgery: A Novel Tool for Unbiased Outcome Comparisons.

OBJECTIVE: To use the concept of benchmarking to establish robust and standardized outcome references after pancreatico-duodenectomy (PD). BACKGROUND: Best achievable results after PD are unknown. Consequently, outcome comparisons among different cohorts, centers or with novel surgical techniques remain speculative. METHODS: This multicenter study analyzes consecutive patients (2012-2015) undergoing PD in 23 international expert centers in pancreas surgery. Outcomes in patients without significant comorbidities and major vascular resection (benchmark cases) were analyzed to establish 20 outcome benchmarks for PD. These benchmarks were tested in a cohort with a poorer preoperative physical status (ASA class ≥3) and a cohort treated by minimally invasive approaches. RESULTS: Two thousand three hundred seventy-five (38%) low-risk cases out of a total of 6186 PDs were analyzed, disclosing low in-hospital mortality (≤1.6%) but high morbidity, with a 73% benchmark morbidity rate cumulated within 6 months following surgery. Benchmark cutoffs for pancreatic fistulas (B-C), severe complications (≥ grade 3), and failure-to-rescue rate were 19%, 30%, and 9%, respectively. The ASA ≥3 cohort showed comparable morbidity but a higher in hospital-mortality (3% vs 1.6%) and failure-to-rescue rate (16% vs 9%) than the benchmarks. The proportion of benchmark cases performed varied greatly across centers and continents for both open (9%-93%) and minimally invasive (11%-62%) PD. Centers operating mostly on complex PD cases disclosed better results than those with a majority of low-risk cases. CONCLUSION: The proposed outcome benchmarks for PD, established in a large-scale international patient cohort and tested in 2 different cohorts, may allow for meaningful comparisons between different patient cohorts, centers, countries, and surgical techniques.

Half of Postoperative Deaths After Hepatectomy may be Preventable: A Root-cause Analysis of a Prospective Multicenter Cohort Study.

OBJECTIVE: To perform a retrospective root-cause analysis of the causes of postoperative mortality after hepatectomy. BACKGROUND: Mortality after liver resection has not decreased over the past decade. METHODS: The study population was a prospective cohort of hepatectomies performed at hepatic, pancreatic, and biliary (HPB) centers between October 2012 and December 2014. Of the 1906 included patients, 90 (5%) died within 90 days of surgery. Perioperative data were retrieved from the original medical records. The root-cause analysis was performed independently by a senior HBP-surgeon and a surgical HBP-fellow. The objectives were to record the cause of death and then assess whether (1) the attending surgeon had identified the cause of death and what was it?, (2) the intra- and postoperative management had been appropriate, (3) the patient had been managed according to international guidelines, and (4) death was preventable. A typical root cause of death was defined. RESULTS: The cause of death was identified by the index surgeon and by the root-cause analysis in 84% and 88% of cases, respectively. Intra- and postoperative management procedures were inadequate in 33% and 23% of the cases, respectively. Guidelines were not followed in 57% of cases. Overall, 47% of the deaths were preventable. The typical root cause of death was insufficient evaluation of the tumor stage or tumor progression in a patient with malignant disease resulting in a more invasive procedure than expected. CONCLUSION: Measures to ensure compliance with guidelines and (in the event of unexpected operative findings) better within-team communication should be implemented systematically.