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BACKGROUND: Although prior studies evaluated the role of EUS and EGD for drainage of pancreatic pseudocysts, there are no randomized trials that compared the technical outcomes between both modalities. OBJECTIVE: To compare the rate of technical success between EUS and EGD for transmural drainage of pancreatic pseudocysts. STUDY DESIGN: A prospective randomized trial. SETTING: A tertiary-referral center. PATIENTS: Those with a history of pancreatitis and symptomatic pancreatic pseudocysts that measured greater than 4 cm in size who were referred for endoscopic transmural drainage. Patients with pancreatic abscess or necrosis were excluded. MAIN OUTCOME MEASUREMENTS: Technical success was defined as the ability to access and drain a pseudocyst by placement of transmural stents. Complications were assessed at 24 hours and at day 30. Treatment success was defined as the complete resolution or decrease in size of the pseudocyst to

Early diagnosis and curative resection are significant predictors of survival in patients with pancreatic cancer. We hypothesize that cholecystectomy within 12 months of pancreatic cancer affects 1-year survival. The Surveillance Epidemiology and End Result (SEER) database linked to Medicare data was used to identify patients diagnosed with pancreatic cancer who underwent cholecystectomy 1 to 12 months prior to cancer diagnosis. The SEER database identified 32,569 patients from 1995 to 2002; 415 (1.3%) underwent cholecystectomy prior to cancer diagnosis. Patients who underwent cholecystectomy had a higher proportion of diabetes (40.2% vs 20.5%; P < 0.01), obesity (8.9% vs 3.1%; P < 0.01), jaundice (17.3% vs 0.7%; P < 0.01), cholelithiasis (70.4% vs 4.2%; P < 0.01), choledocholithiasis (0.7% vs 0.0%; P < 0.01), weight loss (17.3% vs 4.7%; P < 0.01), abdominal pain (79.5% vs 22.5%), steatorrhea (0.7% vs 0.0%; P < 0.01), and cholecystitis (32.3% vs 1.7% ; P < 0.0001). After controlling for tumor stage, patient demographics, and symptoms, survival at 1 year was significantly lower in patients undergoing cholecystectomy (OR, 0.75; 95% CI, 0.58-0.97). Recent cholecystectomy is associated with decreased 1-year survival among patients with pancreatic cancer. For patients older than 65 years of age, further evaluation prior to cholecystectomy may be necessary to exclude pancreatic cancer, especially patients with jaundice, weight loss, and steatorrhea. [ABSTRACT FROM AUTHOR]

Pancreatic resection can alleviate pain in properly selected patients with severe chronic pancreatitis (CP), although the apancreatic state causes "brittle" diabetes. Islet auto-transplantation (IAT) after resection can decrease diabetes-related morbidity. Twenty-six consecutive patients with CP who underwent 27 pancreatic resections with IAT from April 2005 to December 2007 were evaluated in this retrospective case control study. Data were collected by chart and operative note reviews and query of hospital databases. Subgroup analysis was performed on 21 cases of total pancreatectomy and six cases of pancreaticoduodenectomy (PD). Mean age was 43.8 years and 46.2 per cent of patients were female. The most common etiology of CP was alcoholism (34.6%), followed by idiopathic causes (30.8%) and pancreatic divisum (23.1%). There was no mortality and the complication rate was 56 per cent. Islet equivalents infused and islet equivalents/gram of pancreas were 82,094 and 2,739 respectively. Mean discharge insulin dose was 10.7 units/day. Mean follow-up was 6.5 months. At 6 months, 80 per cent of patients reporting had decreased or eliminated their use of narcotic medication and all total pancreatectomy patients required insulin (mean 23 units/day). In appropriately selected patients, pancreatic resection with IAT is safe and effective for the treatment of intractable pain associated with CP. [ABSTRACT FROM AUTHOR]

Background: Ampullary adenocarcinoma (AAC) typically presents at an early stage due to biliary obstruction and therefore might be specifically suitable for minimally invasive pancreatoduodenectomy (MIPD). However, studies assessing MIPD specifically for AAC, including the robotic and laparoscopic approach, are limited. The aim of this study is to compare short- and long-term oncological resection and perioperative outcomes of robotic (RPD), laparoscopic (LPD) and open pancreatoduodenectomy (OPD) performed specifically for AAC., Methods: In this multicenter international cohort study, encompassing 35 centers from 11 countries, MIPD versus OPD and subgroup analyses of LPD versus RPD were undertaken. The primary outcomes regarded the oncological resection (R1 resection rate, lymph node yield) and 5-years overall survival. Secondary outcomes were perioperative outcomes (including intra-operative variables, surgical complications and hospital stay)., Results: In total, patients with AAC who underwent OPD (1721) or MIPD (141) were included. After propensity-score matching, 134 patients per cohort were included. The MIPD group consisted of 53 RPDs and 71 LPDs (50 per group after PSM). There was no difference in overall survival between MIPD and OPD (61.6 % vs 56.2 %, P = 0.215). In the MIPD group, operative time was longer (439 vs 360 min, P < 0.001). Between RPD and LPD, overall survival was not significantly different (75.8 % vs 47.4 %, P = 0.098) and lymph node yield was higher in RPD (21 vs 18, P = 0.014)., Conclusion: In conclusion, patients with AAC seem to have comparable oncological resection and perioperative outcomes from MIPD compared to the traditional OPD. Both RPD as LPD appear to be safe alternatives for patients with AAC, which warrants confirmation by future randomized studies., Competing Interests: Conflict of interest Mario Serradilla-Martín received research funding from Baxter S.L.. Patrick Pessaux is co-founder of Virtualisurg; Marc G. Besselink has received grants from Intuitive for the LEARNBOT European robot Whipple training program, the DIPLOMA-2 trial, and the E-MIPS quality registry, from Medtronic for the investigator-initiated DIPLOMA trial and from Ethicon for the PANDORA trial and the E-MIPS quality registry; Mohammed Abu Hilal received funding from Associazione Italiana per la Ricerca sul Cancro (AIRC). All remaining authors (BAU, AM, UB, MM, BGK, RDV, SK, LB, AM, ML, BKPG, MASM, BB, GK, BI, JK, PG, VKM, GKF, RS, AZ, KJR, AA, BAS, MV, DK, ZS, MG, SB, CMV, SWB, JDC) claim no conflicts of interests and no disclosures., (Copyright © 2024. Published by Elsevier Ltd.)

Objective: To investigate the role of intraoperative estimated blood loss (EBL) on development of clinically relevant postoperative pancreatic fistula (CR-POPF) after pancreatoduodenectomy (PD)., Background: Minimizing EBL has been shown to decrease transfusions and provide better perioperative outcomes in PD. EBL is also felt to be influential on CR-POPF development., Methods: This study consists of 5534 PDs from a 17-institution collaborative (2003-2018). EBL was progressively categorized (≤150mL; 151-400mL; 401-1,000 mL; > 1,000 mL). Impact of additive EBL was assessed using 20 3- factor fistula risk score (FRS) scenarios reflective of endogenous CR-POPF risk., Results: CR-POPF developed in 13.6% of patients (N = 753) and median EBL was 400 mL (interquartile range 250-600 mL). CR-POPF and Grade C POPF were associated with elevated EBL (median 350 vs 400 mL, P = 0.002; 372 vs 500 mL, P < 0.001, respectively). Progressive EBL cohorts displayed incremental CR-POPF rates (8.5%, 13.4%, 15.2%, 16.9%; P < 0.001). EBL >400mL was associated with increased CR-POPF occurrence in 13/20 endogenous risk scenarios. Moreover, 8 of 10 scenarios predicated on a soft gland demonstrated increased CR-POPF incidence. Hypothetical projections demonstrate significant reductions in CR-POPF can be obtained with 1-, 2-, and 3-point decreases in FRS points attributed to EBL risk (12.2%, 17.4%, and 20.0%; P < 0.001). This is especially pronounced in high-risk (FRS7-10) patients, who demonstrate up to a 31% reduction (P < 0.001). Surgeons in the lowest-quartile of median EBL demonstrated CR-POPF rates less than half those in the upper-quartile (7.9% vs 18.8%; P < 0.001)., Conclusion: EBL independently contributes significant biological risk to CR-POPF. Substantial reductions in CR-POPF occurrence are projected and obtainable by minimizing EBL. Decreased individual surgeon EBL is associated with improvements in CR-POPF., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Intraperitoneal drain placement decreases morbidity and mortality in patients who develop a clinically relevant postoperative pancreatic fistula (CR-POPF) following pancreaticoduodenectomy (PD). It is unknown whether multiple drains mitigate CR-POPF better than a single drain. We hypothesized that multiple drains decrease the complication burden more than a single drain in cases at greater risk for CR-POPF., Methods: The Fistula Risk Score (FRS), mitigation strategies (including number of drains placed), and clinical outcomes were obtained from a multi-institutional database of PDs performed from 2003 to 2020. Outcomes were compared between cases utilizing 0, 1, or 2 intraperitoneal drains. Multivariable regression analysis was used to evaluate the optimal drainage approach., Results: A total of 4,292 PDs used 0 (7.3%), 1 (45.2%), or 2 (47.5%) drains with an observed CR-POPF rate of 9.6%, which was higher in intermediate/high FRS zone cases compared with negligible/low FRS zone cases (13% vs 2.4%, P < .001). The number of drains placed also correlated with FRS zone (median of 2 in intermediate/high vs 1 in negligible/low risk cases). In intermediate/high risk cases, the use of 2 drains instead of 1 was not associated with a reduced rate of CR-POPF, average complication burden attributed to a CR-POPF, reoperations, or mortality. Obviation of drains was associated with significant increases in complication burden and mortality - regardless of the FRS zone., Conclusion: In intermediate/high risk zone cases, placement of a single drain or multiple drains appears to mitigate the complication burden while use of no drains is associated with inferior outcomes., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: This study aims to present a full spectrum of individual patient presentations of pancreatic fistula risk, and to define the utility of mitigation strategies amongst some of the most prevalent, and vulnerable scenarios surgeons encounter., Background: The FRS has been utilized to identify technical strategies associated with reduced CR-POPF incidence across various risk strata. However, risk-stratification using the FRS has never been investigated with greater granularity. By deriving all possible combinations of FRS elements, individualized risk assessment could be utilized for precision medicine purposes., Methods: FRS profiles and outcomes of 5533 PDs were accrued from 17 international institutions (2003-2019). The FRS was used to derive 80 unique combinations of patient "scenarios." Risk-matched analyses were conducted using a Bonferroni adjustment to identify scenarios with increased vulnerability for CR-POPF occurrence. Subsequently, these scenarios were analyzed using multivariable regression to explore optimal mitigation approaches., Results: The overall CR-POPF rate was 13.6%. All 80 possible scenarios were encountered, with the most frequent being scenario #1 (8.1%) - the only negligible-risk scenario (CR-POPF rate = 0.7%). The moderate-risk zone had the most scenarios (50), patients (N = 3246), CR-POPFs (65.2%), and greatest non-zero discrepancy in CR-POPF rates between scenarios (18-fold). In the risk-matched analysis, 2 scenarios (#59 and 60) displayed increased vulnerability for CR-POPF relative to the moderate-risk zone (both P < 0.001). Multivariable analysis revealed factors associated with CR-POPF in these scenarios: pancreaticogastrostomy reconstruction [odds ratio (OR) 4.67], omission of drain placement (OR 5.51), and prophylactic octreotide (OR 3.09). When comparing the utilization of best practice strategies to patients who did not have these conjointly utilized, there was a significant decrease in CR-POPF (10.7% vs 35.5%, P < 0.001; OR 0.20, 95% confidence interval 0.12-0.33)., Conclusion: Through this data, a comprehensive fistula risk catalog has been created and the most clinically-impactful scenarios have been discerned. Focusing on individual scenarios provides a practical way to approach precision medicine, allowing for more directed and efficient management of CR-POPF., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Irreversible electroporation (IRE) has emerged as a viable consolidative therapy after induction chemotherapy, in which this combination has improved overall survival of locally advanced pancreatic cancer (LAPC). Optimal timing and patient selection for irreversible electroporation remains a clinically unmet need. The aim of this study was to investigate preoperative factors that may assist in predicting progression-free and overall survival following IRE., Methods: A multi-institutional, prospectively maintained database was reviewed for patients with LAPC treated with induction chemotherapy followed by open-technique irreversible electroporation from 7/2015-5/2019. RECIST 1.1 criteria were used to assess tumor response and radiological progression. Overall survival (OS) and progression-free survival (PFS) were recorded. Survival analyses were performed using Kaplan Meier and Cox multivariable regression analyses., Results: 187 LAPC patients (median age 62 years range, 21 - 91, 65% men, 35% women) were treated with IRE. Median PFS was 21.7 months and median OS from diagnosis was 25.5 months. On multivariable analysis, age ≤ 61 (HR 0.41, 95%CI 0.21-0.78, p<0.008) and no prior radiation (HR 0.49, 95%CI 0.26-0.94, p=0.03) were positive predictors of OS after IRE. Age ≤ 61(HR 0.53, 95%CI, 0.28-.99, p=0.046) and FOLFIRINOX followed by gemcitabine/abraxane induction chemotherapy (HR 0.37,95%CI 0.15-0.89, p=0.027) predicted prolonged PFS after IRE. Abnormal CA19-9 values at the time of surgery negatively impacted both OS (HR 2.46, 95%CI 1.28-4.72, p<0.007) and PFS (HR 2.192, 95%CI 1.143-4.201, p=0.018) following IRE., Conclusions: Age, CA 19-9 response, avoidance of pre-IRE radiation, and FOLFIRINOX plus gemcitabine/abraxane induction chemotherapy are prominent factors to consider when referring or selecting LAPC patients to undergo IRE., Competing Interests: RM II, MD, PhD, FACS is an educational consultant for AngioDynamics, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Woeste, Wilson, Kruse, Weiss, Christein, White and Martin.)

Background: The association between intraoperative estimated blood loss and outcomes after pancreatoduodenectomy has, thus far, been rarely explored., Methods: In total, 7,706 pancreatoduodenectomies performed at 18 international institutions composing the Pancreas Fistula Study Group were examined (2003-2020). High estimated blood loss (>700 mL) was defined as twice the median. Propensity score matching (1:1 exact-match) was employed to adjust for variables associated with high estimated blood loss and clinically relevant pancreatic fistula occurrence. The study was powered to detect a 33% clinically relevant pancreatic fistula increase in the high estimated blood loss group, with α = 0.05 and β = 0.2., Results: The propensity score model included 966 patients with high estimated blood loss and 966 patients with lower estimated blood loss; all covariate imbalantces were solved. Patients with high estimated blood loss patients experienced higher clinically relevant pancreatic fistula rates (19.4 vs 12.6%, odds ratio 1.66; P < .001), as well as higher severe complication rates (27.8 vs 15.6%), transfusions (50.1 vs 14.3%), reoperations (9.2 vs 4.0%), intensive care unit transfers (9.9 vs 4.8%) and 90-day mortality (4.7 vs 2.0%, all P < .001). High estimated blood loss was an independent predictor for clinically relevant pancreatic fistula (odds ratio 1.78, 95% confidence interval 1.37-2.32), as were prophylactic Octreotide administration (odds ratio 1.95, 95% confidence interval 1.46-2.61) and soft pancreatic texture (odds ratio 5.32, 95% confidence interval 3.74-5.57; all P < .001). Moreover, a second model including 1,126 pancreatoduodenectomies was derived including vascular resections as additional confounder (14.0% vascular resections performed in each group). On multivariable regression, high estimated blood loss was confirmed an independent predictor for clinically relevant pancreatic fistula reduction (odds ratio 1.80, 95% confidence interval 1.32-2.44; P < .001), whereas vascular resection was not (odds ratio 0.64, 95% confidence interval 0.34-1.88; P = .156)., Conclusion: This study better establishes the relationship between estimated blood loss and outcomes after pancreatoduodenectomy. Despite inherent contributions to blood loss, its minimization is an actionable opportunity for clinically relevant pancreatic fistula reduction and performance optimization in pancreatoduodenectomy. Accordingly, practical insights are offered to achieve this goal., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Pancreatoduodenectomies at high risk for clinically relevant pancreatic fistula are uncommon, yet intimidating, situations. In such scenarios, the impact of individual surgeon experience on outcomes is poorly understood., Methods: The fistula risk score was applied to identify high-risk patients (fistula risk score 7-10) from 7,706 pancreatoduodenectomies performed at 18 international institutions (2003-2020). For each case, surgeon pancreatoduodenectomy career volume and years of practice were linked to intraoperative fistula mitigation strategy adoption and outcomes. Consequently, best operative approaches for clinically relevant pancreatic fistula prevention and best performer profiles were identified through multivariable analysis models., Results: Eight hundred and thirty high-risk pancreatoduodenectomies, performed by 64 surgeons, displayed an overall clinically relevant pancreatic fistula rate of 33.7%. Clinically relevant pancreatic fistula rates decreased with escalating surgeon career pancreatoduodenectomy (-49.7%) and career length (-41.2%; both P < .001), as did transfusion and reoperation rates, postoperative morbidity index, and duration of stay. Great experience (≥400 pancreatoduodenectomies performed or ≥21-year-long career) was a significant predictor of clinically relevant pancreatic fistula prevention (odds ratio 0.52, 95% confidence interval 0.35-0.76) and was more often associated with pancreatojejunostomy reconstruction and prophylactic octreotide omission, which were both independently associated with clinically relevant pancreatic fistula reduction. A risk-adjusted performance analysis also correlated with experience. Moreover, minimizing blood loss (≤400 mL) significantly contributed to clinically relevant pancreatic fistula prevention (odds ratio 0.40, 95% confidence interval 0.22-0.74)., Conclusion: Surgeon experience is a key contributor to achieve better outcomes after high-risk pancreatoduodenectomy. Surgeons can improve their performance in these challenging situations by employing pancreatojejunostomy reconstruction, omitting prophylactic octreotide, and minimizing blood loss., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: Ampullary adenocarcinoma (AAC) is a rare malignancy with great morphological heterogeneity, which complicates the prediction of survival and, therefore, clinical decision-making. The aim of this study was to develop and externally validate a prediction model for survival after resection of AAC., Materials and Methods: An international multicenter cohort study was conducted, including patients who underwent pancreatoduodenectomy for AAC (2006-2017) from 27 centers in 10 countries spanning three continents. A derivation and validation cohort were separately collected. Predictors were selected from the derivation cohort using a LASSO Cox proportional hazards model. A nomogram was created based on shrunk coefficients. Model performance was assessed in the derivation cohort and subsequently in the validation cohort, by calibration plots and Uno's C-statistic. Four risk groups were created based on quartiles of the nomogram score., Results: Overall, 1007 patients were available for development of the model. Predictors in the final Cox model included age, resection margin, tumor differentiation, pathological T stage and N stage (8th AJCC edition). Internal cross-validation demonstrated a C-statistic of 0.75 (95% CI 0.73-0.77). External validation in a cohort of 462 patients demonstrated a C-statistic of 0.77 (95% CI 0.73-0.81). A nomogram for the prediction of 3- and 5-year survival was created. The four risk groups showed significantly different 5-year survival rates (81%, 57%, 22% and 14%, p < 0.001). Only in the very-high risk group was adjuvant chemotherapy associated with an improved overall survival., Conclusion: A prediction model for survival after curative resection of AAC was developed and externally validated. The model is easily available online via www.pancreascalculator.com., Competing Interests: Declaration of competing interest The authors of the abovementioned manuscript have no conflicts of interest to declare., (Copyright © 2020. Published by Elsevier Ltd.)

Background: The optimal treatment and management of locally advanced pancreatic cancer (LAPC) remains unclear and controversial. This study aimed to report the initial outcomes of the AHPBA Registry and evaluate the reproducibility of existing evidence that the addition of Irreversible Electroporation (IRE), a nonthermal ablative treatment, confers survival benefits beyond standard therapeutic options for patients with LAPC., Methods: From December 2015 to October 2017, patients with LAPC were treated with open-technique IRE following the AHPBA Registry Protocols. Patient demographics, long-term outcomes, and adverse events were recorded. Survival analyses were performed using Kaplan-Meier (KM) curves for overall survival (OS), progression free survival (PFS) and time to progression (TTP)., Results: A total of 152 patients underwent successful IRE. Morbidity and mortality were 18% and 2% respectively, with 19 (13%) patients experiencing severe adverse events. Nine (6%) patients presented with local recurrence. Median TTP, PFS, and OS from diagnosis were 27.3 months, 22.8 months, and 30.7 months respectively., Conclusion: The combination of IRE with established multiagent therapy is safe and demonstrates encouraging survival among patients with LAPC. IRE is associated with a low rate of serious adverse events and has been optimized for more widespread adoption through the standardized protocols available through the AHPBA registry., (Copyright © 2019 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Importance: Ampullary adenocarcinoma is a rare malignant neoplasm that arises within the duodenal ampullary complex. The role of adjuvant therapy (AT) in the treatment of ampullary adenocarcinoma has not been clearly defined., Objective: To determine if long-term survival after curative-intent resection of ampullary adenocarcinoma may be improved by selection of patients for AT directed by histologic subtype., Design, Setting, and Participants: This multinational, retrospective cohort study was conducted at 12 institutions from April 1, 2000, to July 31, 2017, among 357 patients with resected, nonmetastatic ampullary adenocarcinoma receiving surgery alone or AT. Cox proportional hazards regression was used to identify covariates associated with overall survival. The surgery alone and AT cohorts were matched 1:1 by propensity scores based on the likelihood of receiving AT or by survival hazard from Cox modeling. Overall survival was compared with Kaplan-Meier estimates., Exposures: Adjuvant chemotherapy (fluorouracil- or gemcitabine-based) with or without radiotherapy., Main Outcomes and Measures: Overall survival., Results: A total of 357 patients (156 women and 201 men; median age, 65.8 years [interquartile range, 58-74 years]) underwent curative-intent resection of ampullary adenocarcinoma. Patients with intestinal subtype had a longer median overall survival compared with those with pancreatobiliary subtype (77 vs 54 months; P = .05). Histologic subtype was not associated with AT administration (intestinal, 52.9% [101 of 191]; and pancreatobiliary, 59.5% [78 of 131]; P = .24). Patients with pancreatobiliary histologic subtype most commonly received gemcitabine-based regimens (71.0% [22 of 31]) or combinations of gemcitabine and fluorouracil (12.9% [4 of 31]), whereas treatment of those with intestinal histologic subtype was more varied (fluorouracil, 50.0% [17 of 34]; gemcitabine, 44.1% [15 of 34]; P = .01). In the propensity score-matched cohort, AT was not associated with a survival benefit for either histologic subtype (intestinal: hazard ratio, 1.21; 95% CI, 0.67-2.16; P = .53; pancreatobiliary: hazard ratio, 1.35; 95% CI, 0.66-2.76; P = .41)., Conclusions and Relevance: Adjuvant therapy was more frequently used in patients with poor prognostic factors but was not associated with demonstrable improvements in survival, regardless of tumor histologic subtype. The value of a multimodality regimen remains poorly defined.

Objective: To identify a clinical fistula risk score following distal pancreatectomy., Background: Clinically relevant pancreatic fistula (CR-POPF) following distal pancreatectomy (DP) is a dominant contributor to procedural morbidity, yet risk factors attributable to CR-POPF and effective practices to reduce its occurrence remain elusive., Methods: This multinational, retrospective study of 2026 DPs involved 52 surgeons at 10 institutions (2001-2016). CR-POPFs were defined by 2016 International Study Group criteria, and risk models generated using stepwise logistic regression analysis were evaluated by c-statistic. Mitigation strategies were assessed by regression modeling while controlling for identified risk factors and treating institution., Results: CR-POPF occurred following 306 (15.1%) DPs. Risk factors independently associated with CR-POPF included: age (<60 yrs: OR 1.42, 95% CI 1.05-1.82), obesity (OR 1.54, 95% CI 1.19-2.12), hypoalbuminenia (OR 1.63, 95% CI 1.06-2.51), the absence of epidural anesthesia (OR 1.59, 95% CI 1.17-2.16), neuroendocrine or nonmalignant pathology (OR 1.56, 95% CI 1.18-2.06), concomitant splenectomy (OR 1.99, 95% CI 1.25-3.17), and vascular resection (OR 2.29, 95% CI 1.25-3.17). After adjusting for inherent risk between cases by multivariable regression, the following were not independently associated with CR-POPF: method of transection, suture ligation of the pancreatic duct, staple size, the use of staple line reinforcement, tissue patches, biologic sealants, or prophylactic octreotide. Intraoperative drainage was associated with a greater fistula rate (OR 2.09, 95% CI 1.51-3.78) but reduced fistula severity (P < 0.001)., Conclusions: From this large analysis of pancreatic fistula following DP, CR-POPF occurrence cannot be reliably predicted. Opportunities for developing a risk score model are limited for performing risk-adjusted analyses of mitigation strategies and surgeon performance.

Objective: The aim of this study was to identify the optimal fistula mitigation strategy following pancreaticoduodenectomy., Background: The utility of technical strategies to prevent clinically relevant postoperative pancreatic fistula (CR-POPF) following pancreatoduodenectomy (PD) may vary by the circumstances of the anastomosis. The Fistula Risk Score (FRS) identifies a distinct high-risk cohort (FRS 7 to 10) that demonstrates substantially worse clinical outcomes. The value of various fistula mitigation strategies in these particular high-stakes cases has not been previously explored., Methods: This multinational study included 5323 PDs performed by 62 surgeons at 17 institutions. Mitigation strategies, including both technique related (ie, pancreatogastrostomy reconstruction; dunking; tissue patches) and the use of adjuvant strategies (ie, intraperitoneal drains; anastomotic stents; prophylactic octreotide; tissue sealants), were evaluated using multivariable regression analysis and propensity score matching., Results: A total of 522 (9.8%) PDs met high-risk FRS criteria, with an observed CR-POPF rate of 29.1%. Pancreatogastrostomy, prophylactic octreotide, and omission of externalized stents were each associated with an increased rate of CR-POPF (all P < 0.001). In a multivariable model accounting for patient, surgeon, and institutional characteristics, the use of external stents [odds ratio (OR) 0.45, 95% confidence interval (95% CI) 0.25-0.81] and the omission of prophylactic octreotide (OR 0.49, 95% CI 0.30-0.78) were independently associated with decreased CR-POPF occurrence. In the propensity score matched cohort, an "optimal" mitigation strategy (ie, externalized stent and no prophylactic octreotide) was associated with a reduced rate of CR-POPF (13.2% vs 33.5%, P < 0.001)., Conclusions: The scenarios identified by the high-risk FRS zone represent challenging anastomoses associated with markedly elevated rates of fistula. Externalized stents and omission of prophylactic octreotide, in the setting of intraperitoneal drainage and pancreaticojejunostomy reconstruction, provides optimal outcomes.

Cholangiocarcinoma (CCA) is a fatal disease with a 5-year survival of <30%. For a majority of patients, chemotherapy is the only therapeutic option, and virtually all patients relapse. Gemcitabine is the first-line agent for treatment of CCA. Patients treated with gemcitabine monotherapy survive ∼8 months. Combining this agent with cisplatin increases survival by ∼3 months, but neither regimen produces durable remissions. The molecular etiology of this disease is poorly understood. To facilitate molecular characterization and development of effective therapies for CCA, we established a panel of patient-derived xenograft (PDX) models of CCA. We used two of these models to investigate the antitumor efficacy and mechanism of action of the bromodomain inhibitor JQ1, an agent that has not been evaluated for the treatment of CCA. The data show that JQ1 suppressed the growth of the CCA PDX model CCA2 and demonstrate that growth suppression was concomitant with inhibition of c-Myc protein expression. A second model (CCA1) was JQ1-insensitive, with tumor progression and c-Myc expression unaffected by exposure to this agent. Also selective to CCA2 tumors, JQ1 induced DNA damage and apoptosis and downregulated multiple c-Myc transcriptional targets that regulate cell-cycle progression and DNA repair. These findings suggest that c-Myc inhibition and several of its transcriptional targets may contribute to the mechanism of action of JQ1 in this tumor type. We conclude that BET inhibitors such as JQ1 warrant further investigation for the treatment of CCA. Mol Cancer Ther; 17(1); 107-18. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Dr. Charles Bernard Puestow (1902-1973) was an American surgeon who is well known for developing the longitudinal pancreaticojejunostomy, which is known as the "Puestow procedure" in his honor. Puestow served in the American military during the Second World War and commanded the 27th Evacuation Hospital, which provided medical and surgical services to wounded individuals in Europe and North Africa. In 1946, he founded the surgical residency training program at the Hines Veterans Hospital, which was the first such program in the United States based at a veterans hospital.

Objective: This multicenter study sought to evaluate the accuracy of the American College of Surgeons National Surgical Quality Improvement Program's (ACS-NSQIP) surgical risk calculator for predicting outcomes after pancreatoduodenectomy (PD) and to determine whether incorporating other factors improves its predictive capacity., Background: The ACS-NSQIP surgical risk calculator has been proposed as a decision-support tool to predict complication risk after various operations. Although it considers 21 preoperative factors, it does not include procedure-specific variables, which have demonstrated a strong predictive capacity for the most common and morbid complication after PD - clinically relevant pancreatic fistula (CR-POPF). The validated Fistula Risk Score (FRS) intraoperatively predicts the occurrence of CR-POPF and serious complications after PD., Methods: This study of 1480 PDs involved 47 surgeons at 17 high-volume institutions. Patient complication risk was calculated using both the universal calculator and a procedure-specific model that incorporated the FRS and surgeon/institutional factors. The performance of each model was compared using the c-statistic and Brier score., Results: The FRS was significantly associated with 30-day mortality, 90-day mortality, serious complications, and reoperation (all P < 0.0001). The procedure-specific model outperformed the universal calculator for 30-day mortality (c-statistic: 0.79 vs 0.68; Brier score: 0.020 vs 0.021), 90-day mortality, serious complications, and reoperation. Neither surgeon experience nor institutional volume significantly predicted mortality; however, surgeons with a career PD volume >450 were less likely to have serious complications (P < 0.001) or perform reoperations (P < 0.001)., Conclusions: Procedure-specific complication risk influences outcomes after pancreatoduodenectomy; therefore, risk adjustment for performance assessment and comparative research should consider these preoperative and intraoperative factors along with conventional ACS-NSQIP preoperative variables.

Background: As payment models evolve, disease-specific risk stratification may impact patient selection and financial outcomes. This study sought to determine whether a validated clinical risk score for post-operative pancreatic fistula (POPF) could predict hospital costs, payments, and profit margins., Methods: A multi-institutional cohort of 1193 patients undergoing pancreaticoduodenectomy (PD) were matched to an independent hospital where cost, in US$, and payment data existed. An analytic model detailed POPF risk and post-operative sequelae, and their relationship with hospital cost and payment., Results: Per-patient hospital cost for negligible-risk patients was $37,855. Low-, moderate-, and high- risk patients had incrementally higher hospital costs of $38,125 ($270; 0.7% above negligible-risk), $41,128 ($3273; +8.6%), and $41,983 ($3858; +10.9%), respectively. Similarly, hospital payment for negligible-risk patients was $42,685/patient, with incrementally higher payments for low-risk ($43,265; +1.4%), moderate-risk ($45,439; +6.5%) and high-risk ($46,564; +9.1%) patients. The lowest 30-day readmission rates - with highest net profit - were found for negligible/low-risk patients (10.5%/11.1%), respectively, compared with readmission rates of moderate/high-risk patients (15%/15.7%)., Conclusion: Financial outcomes following PD can be predicted using the FRS. Such prediction may help hospitals and payers plan for resource allocation and payment matched to patient risk, while providing a benchmark for quality improvement initiatives., (Copyright © 2016 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Purpose: To conduct a telephone survey establishing pancreatic cancer survivors' level of interest in, preferences for, and perceived barriers and facilitators to participating in exercise and diet intervention programming. These data will inform the development of such interventions for newly-diagnosed patients., Methods: Seventy-one survivors treated for resectable pancreatic adenocarcinoma from October 2011 to August 2014 were identified through an institutional cancer registry and contacted via telephone. A telephone survey was conducted to query survivors' level of interest in, preferences for, and perceived barriers and facilitators to participating in an exercise and dietary intervention program shortly after disease diagnosis. Acceptability of a technology-based visual communication (e.g., Skype™, FaceTime®) intervention was also assessed., Results: Fifty participants completed the survey (response rate 71.8 %). Over two-thirds of participants reported interest in exercise and diet intervention programming. Over half reported comfort with a technology-delivered visual communication intervention. Barriers to participation included older age and physical, personal, and emotional problems. The most common facilitator was program awareness. Outcomes for future research important to participants were supportive care and quality of life., Conclusions: Most pancreatic cancer patients are interested in exercise and diet interventions shortly after diagnosis; however, some barriers to program participation exist., Implications for Cancer Survivors: Future research and intervention planning for pancreatic cancer survivors should focus on developing messaging and strategies that provide support for survivorship outcomes, increase survivor awareness, address lack of familiarity with technology, reduce fears about potential barriers, and help survivors overcome these barriers. In so doing, survivorship needs can be better met and quality of life improved in this understudied population.

Background: Evidence suggests externalized trans-anastomotic stents may be beneficial as a fistula mitigation strategy for pancreatoduodenectomy (PD); however, previous studies have not been rigorously risk-adjusted., Methods: From 2001 to 2015, PDs were performed at three institutions, with externalized stents placed at the surgeon's discretion. The Fistula Risk Score (FRS) and the Modified Accordion Severity Grading System were used to analyze occurrence and severity of clinically relevant postoperative pancreatic fistula (CR-POPF) across various risk scenarios., Results: Of 729 PDs, externalized stents were placed during 129 (17.7 %). Overall, CR-POPFs occurred in 77 (10.6 %) patients. The median FRS of patients who received externalized stents was significantly higher compared with patients who did not (6 vs. 3, p < 0.0001). Patients with negligible, low, or moderate CR-POPF risk (FRS 0-6) did not demonstrate improved outcomes with externalized stents; however, among high-risk patients (FRS 7-10), stents were associated with significantly reduced rates of CR-POPF (14.0 vs. 36.4 %, p = 0.031), severe complications (p = 0.039), and hospital stay (p = 0.014) compared with no stents. The average complication burden of CR-POPF was significantly lower for patients with externalized stents (p = 0.035)., Conclusion: This multicenter study, the largest comparative analysis of externalized trans-anastomotic stents versus no stent for PD, demonstrates a risk-stratified benefit to externalized stents.

Background: Pancreatic adenocarcinoma patients have low survival rates due to late-stage diagnosis and high rates of cancer recurrence even after surgical resection. It is important to understand the molecular characteristics associated with survival differences in pancreatic adenocarcinoma tumors that may inform patient care., Results: RNA sequencing was performed for 51 patient tumor tissues extracted from patients undergoing surgical resection, and expression was associated with overall survival time from diagnosis. Our analysis uncovered 323 transcripts whose expression correlates with survival time in our pancreatic patient cohort. This genomic signature was validated in an independent RNA-seq dataset of 68 additional patients from the International Cancer Genome Consortium. We demonstrate that this transcriptional profile is largely independent of markers of cellular division and present a 19-transcript predictive model built from a subset of the 323 transcripts that can distinguish patients with differing survival times across both the training and validation patient cohorts. We present evidence that a subset of the survival-associated transcripts is associated with resistance to gemcitabine treatment in vitro, and reveal that reduced expression of one of the survival-associated transcripts, Angiopoietin-like 4, impairs growth of a gemcitabine-resistant pancreatic cancer cell line., Conclusions: Gene expression patterns in pancreatic adenocarcinoma tumors can distinguish patients with differing survival outcomes after undergoing surgical resection, and the survival difference could be associated with the intrinsic gemcitabine sensitivity of primary patient tumors. Thus, these transcriptional differences may impact patient care by distinguishing patients who would benefit from a non-gemcitabine based therapy., (Copyright © 2016 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)

Objective: To evaluate surgical performance in pancreatoduodenectomy using clinically relevant postoperative pancreatic fistula (CR-POPF) occurrence as a quality indicator., Background: Accurate assessment of surgeon and institutional performance requires (1) standardized definitions for the outcome of interest and (2) a comprehensive risk-adjustment process to control for differences in patient risk., Methods: This multinational, retrospective study of 4301 pancreatoduodenectomies involved 55 surgeons at 15 institutions. Risk for CR-POPF was assessed using the previously validated Fistula Risk Score, and pancreatic fistulas were stratified by International Study Group criteria. CR-POPF variability was evaluated and hierarchical regression analysis assessed individual surgeon and institutional performance., Results: There was considerable variability in both CR-POPF risk and occurrence. Factors increasing the risk for CR-POPF development included increasing Fistula Risk Score (odds ratio 1.49 per point, P < 0.00001) and octreotide (odds ratio 3.30, P < 0.00001). When adjusting for risk, performance outliers were identified at the surgeon and institutional levels. Of the top 10 surgeons (≥15 cases) for nonrisk-adjusted performance, only 6 remained in this high-performing category following risk adjustment., Conclusions: This analysis of pancreatic fistulas following pancreatoduodenectomy demonstrates considerable variability in both the risk and occurrence of CR-POPF among surgeons and institutions. Disparities in patient risk between providers reinforce the need for comprehensive, risk-adjusted modeling when assessing performance based on procedure-specific complications. Furthermore, beyond inherent patient risk factors, surgical decision-making influences fistula outcomes.

We present a cancer nanomedicine based on acidic pH targeted gold nanorods designed for multispectral optoacoustic tomography (MSOT). We have designed gold nanorods coated with mesoporous silica and subsequently capped with chitosan (CMGs). We have conjugated pH-sensitive variant 7 pHLIP peptide to the CMGs (V7-CMG) to provide targeting specificity to the acidic tumor microenvironment. In vitro , treatment of S2VP10 and MiaPaca2 cells with V7-CMG containing gemcitabine resulted in significantly greater cytotoxicity with 97% and 96.5% cell death, respectively than gemcitabine alone 60% and 76% death at pH 6.5 (S2VP10 pH 6.5 p=0.009; MiaPaca2 pH 6.5 p=0.0197). In vivo , the V7-CMGs provided the contrast and targeting specificity necessary for MSOT of retroperitoneal orthotopic pancreatic tumors. In the in vivo S2VP10 model, the V7-CMG particle preferentially accumulated within the tumor at 17.1 MSOT a.u. signal compared with 0.7 MSOT a.u. in untargeted CMG control in tumor ( P = 0.0002). Similarly, V7-CMG signal was 9.34 MSOT a.u. in the S2013 model compared with untargeted CMG signal at 0.15 MSOT a.u. ( P = 0.0004). The pH-sensitivity of the targeting pHLIP peptide and chitosan coating makes the particles suitable for simultaneous in vivo tumor imaging and drug delivery.

Background: Differences in the behavior of postoperative pancreatic fistulas (POPF) have been described after various pancreatic resections. Here, we compare POPFs after pancreatoduodenectomy (PD) and distal pancreatectomy (DP) using the average complication burden (ACB), a quantitative measure of complication burden., Methods: From 2001 to 2014, 837 DPs and 1,533 PDs were performed by 14 surgeons at 4 institutions. POPFs were categorized by International Study Group on Pancreatic Fistula standards as biochemical (grade A) or clinically relevant (CR-POPF; grades B and C). ACB values were derived from fistula severity scores based on the Modified Accordion Severity Grading. The ACB of POPFs was compared between PD and DP., Results: POPFs were more common after DP compared with PD (34.5 vs 27.2%; P < .001); however, the incidence of any complication was greater after PD (64.9 vs 53.2%; P < .001). When POPFs occurred, they were more likely to be the highest-graded complication after DP compared with PD (65.1 vs 51.6%; P < .001). ACB significantly varied between PDs and DPs for grade C POPFs (0.804 vs 0.611; P < .001). POPFs accounted for 31.2% of the overall complication burden after DP compared with 17.5% of the burden after PD. ACB differed significantly across both institutions and surgeons in terms of POPFs, nonfistulous complications, and overall complications (all P < .05)., Conclusion: Although POPFs occur less frequently after PD, they are associated with a greater complication burden compared with DP. ACB varies significantly between health care providers, suggesting the need for risk-adjusted comparisons of complication severity. Using ACB to evaluate a distinct morbidity has the potential to aid in assessing the impact of procedure-specific complications., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The primary aim of this study was to evaluate the antitumor efficacy of the bromodomain inhibitor JQ1 in pancreatic ductal adenocarcinoma (PDAC) patient-derived xenograft (tumorgraft) models. A secondary aim of the study was to evaluate whether JQ1 decreases expression of the oncogene c-Myc in PDAC tumors, as has been reported for other tumor types. We used five PDAC tumorgraft models that retain specific characteristics of tumors of origin to evaluate the antitumor efficacy of JQ1. Tumor-bearing mice were treated with JQ1 (50 mg/kg daily for 21 or 28 days). Expression analyses were performed with tumors harvested from host mice after treatment with JQ1 or vehicle control. An nCounter PanCancer Pathways Panel (NanoString Technologies) of 230 cancer-related genes was used to identify gene products affected by JQ1. Quantitative RT-PCR, immunohistochemistry and immunoblots were carried out to confirm that changes in RNA expression reflected changes in protein expression. JQ1 inhibited the growth of all five tumorgraft models (P<0.05), each of which harbors a KRAS mutation; but induced no consistent change in expression of c-Myc protein. Expression profiling identified CDC25B, a regulator of cell cycle progression, as one of the three RNA species (TIMP3, LMO2 and CDC25B) downregulated by JQ1 (P<0.05). Inhibition of tumor progression was more closely related to decreased expression of nuclear CDC25B than to changes in c-Myc expression. JQ1 and other agents that inhibit the function of proteins with bromodomains merit further investigation for treating PDAC tumors. Work is ongoing in our laboratory to identify effective drug combinations that include JQ1.

Introduction: International Study Group of Pancreatic Fistula (ISGPF) grade C postoperative pancreatic fistulas (POPF) are the greatest contributor to major morbidity and mortality following pancreatoduodenectomy (PD); however, their infrequent occurrence has hindered deeper analysis. This study sought to develop a predictive algorithm, which could facilitate effective management of this challenging complication., Methods: Data were accrued from 4301 PDs worldwide. Demographics, postoperative management, and microbiological characteristics of grade C POPFs were evaluated. American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) preoperative and intraoperative variables were compared between grade C POPFs and a 639-case sample of non-grade C POPFs. Risk factors for grade C POPF formation were identified using regression analysis., Results: Grade C POPFs developed in 79 patients (1.8 %). Deaths (90 days) occurred in 2.0 % (N = 88) of the overall series, with 35 % (N = 25) occurring in the presence of a grade C POPF. Reoperations occurred 72.2 % of the time. The rates of single- and multi-system organ failure were 28.2 and 39.7 %, respectively. Mortality rates escalated with pulmonary, renal, and neurologic organ failure, but they were unaffected by reoperation(s). The median number of complications incurred was four (IQR: 2-5), and the median duration of hospital stay was 32 (IQR: 21-54) days. Warning signs for impending grade C POPFs most often presented on postoperative day (POD) 6. Adjuvant chemotherapy might have benefited 55.7 % of grade C POPF patients, yet it was delayed in 25.6 % and never delivered in 67.4 % of these patients. Predictive models for grade C POPF occurrence based on preoperative factors alone and preoperative and intraoperative factors yielded areas under the receiver operating characteristic curve of 0.73 and 0.84 (both P < 0.000001), respectively., Conclusion: This global study represents the largest analysis of grade C POPFs following PD. It describes the severe burden that grade C POPFs incur on patients, with high rates of reoperation and infection, while also potentially worsening overall survival by causing death and delay/omission of adjuvant therapy. Additionally, aggressive clinical management for these POPFs did not improve or worsen 90-day mortality. Predictive tools developed through these data may provide value in managing this difficult complication.

Purpose: The purpose of this study was to investigate the effect of radiotherapy on local control and mordibity for patients with resected lymph node-positive pancreatic cancer as compared to gemcitabine-based chemotherapy alone., Materials and Methods: Sixty-nine patients received adjuvant therapy for pancreatic adenocarcinoma with lymph node involvement after surgical resection and met the inclusion criteria for this analysis. Forty (58 %) patients received postoperative radiotherapy (PORT) to a median dose of 50.4 Gy with capecitabine or 5-fluorouracil concurrently in all but one case; 15 patients also received gemcitabine prior to PORT. Twenty-nine (42 %) patients received gemcitabine-based chemotherapy without PORT for a median of 6 cycles., Results: The median overall survival for patients receiving PORT was 24.4 months compared to 25.6 months for patients not receiving PORT (p = 0.943). At 2 years, the rate of local control was 57 % for patients receiving PORT compared to 37 % for those who did not (p = 0.034). At 2 years, the rate of palliative local interventions was 16 % for patients receiving PORT compared to 18 % for patients who did not (p = 0.821)., Conclusion: The use of PORT was associated with improved local control in the gemcitabine era for patients with resected, node-positive, pancreatic adenocarcinoma. The rates of overall survival and palliative interventions did not differ between the two groups.

Background: While contemporary studies demonstrate decreasing complication rates following total pancreatectomy (TP), none have quantified the impact of post-TP complications. The Postoperative Morbidity Index (PMI)-a quantitative measure of postoperative morbidity-combines ACS-NSQIP complication data with severity weighting derived from Modified Accordion Grading System. We establish the PMI for TP in a multi-institutional cohort., Methods: Nine institutions contributed ACS-NSQIP data for 64 TPs (2005-2011). Each complication was assigned an Accordion severity weight ranging from 0.110 (grade 1/mild) to 1.00 (grade 6/death). PMI equals the sum of complication severity weights ("Total Burden") divided by total number of patients., Results: Overall, 29 patients (45.3 %) suffered 55 ACS-NSQIP complications; 15 (23.4 %) had >1 complication. Thirteen patients (20.3 %) were readmitted and one death (1.6 %) occurred within 30 days. Non-risk adjusted PMI was 0.151, while PMI for complication-bearing cases rose to 0.333. Bleeding/Transfusion and Sepsis were the most common complications. Discordance between frequency and burden of complications was observed. While grades 4-6 comprised only 18.5 % of complications, they contributed 37.1 % to the series' total burden., Conclusion: This multi-institutional series is the first to quantify the complication burden following TP using the rigor of ACS-NSQIP. A PMI of 0.151 indicates that, collectively, patients undergoing TP have an average burden of complications in the mild to moderate severity range, although complication-bearing patients have a considerable reduction in health utility.

Objective: The study aim was to quantify the burden of complications of pancreatoduodenectomy (PD)., Background: The Postoperative Morbidity Index (PMI) is a quantitative measure of the average burden of complications of a procedure. It is based on highly validated systems--ACS-NSQIP and the Modified Accordion Severity Grading System., Methods: Nine centers contributed ACS-NSQIP complication data for 1589 patients undergoing PD from 2005 to 2011. Each complication was assigned a severity weight ranging from 0.11 for the least severe complication to 1.00 for postoperative death, and PMI was derived. Contribution to total burden by each complication grade was used to generate a severity profile ("spectrogram") for PD. Associations with PMI were determined by regression analysis., Results: ACS-NSQIP complications occurred in 528 cases (33.2%). The non-risk-adjusted PMI was 0.115 (SD = 0.023) for all centers and 0.113 (SD = 0.005) for the 7 centers that contributed at least 100 cases. Grade 2 complications were predominant in frequency, and the most common complication was postoperative bleeding/transfusion. Frequency and burden of complications differed markedly. For instance, severe complications (grades 4/5/6) accounted for only about 20% of complications but for more than 40% of the burden of complications. Organ space infection had the highest burden of any complication. The average burden in cases in which a complication actually occurred was 0.346., Conclusions: This study develops a quantitative non-risk-adjusted benchmark for postoperative morbidity of PD. The method quantifies the burden of types and grades of postoperative complications and should prove useful in identifying areas that require quality improvement.

S100A4 expression is associated with poor clinical outcomes of patients with pancreatic cancer. The effects of loss or gain of S100A4 were examined in pancreatic cancer cell lines. S100A4 downregulation remarkably reduces cell migration and invasion, inhibits proliferation, and induces apoptosis in pancreatic tumor cells. S100A4 downregulation results in significant cell growth inhibition and apoptosis in response to TGF-β1, supporting a non-canonical role of S100A4 in pancreatic cancer. The role of S100A4 in tumor progression was studied by using an orthotopic human pancreatic cancer xenograft mouse model. Tumor mass is remarkably decreased in animals injected with S100A4-deficient pancreatic tumor cells. P27(Kip1) expression and cleaved caspase-3 are increased, while cyclin E expression is decreased, in S100A4-deficient pancreatic tumors in vivo. S100A4-deficient tumors have lower expression of vascular endothelial growth factor, suggesting reduced angiogenesis. Biochemical assays revealed that S100A4 activates Src and focal adhesion kinase (FAK) signaling events, and inhibition of both kinases is required to maximally block the tumorigenic potential of pancreatic cancer cells. These findings support that S100A4 plays an important role in pancreatic cancer progression in vivo and S100A4 promotes tumorigenic phenotypes of pancreatic cancer cells through the Src-FAK mediated dual signaling pathway.

Background: The aim of the study was to compare the outcomes of patients with pancreatic or peripancreatic walled-off necrosis by endoscopy using the conventional approach versus an algorithmic approach based on the collection size, location and stepwise response to intervention., Methods: This was an observational before-after study of consecutive patients managed over two time intervals. In the initial period (2004-2009) symptomatic patients with walled-off necrosis underwent conventional single transmural drainage with placement of two stents and a nasocystic catheter, followed by direct endoscopic necrosectomy, if required. In the later period (2010-2013) an algorithmic approach was adopted based on size and extent of the walled-off necrosis and stepwise response to intervention. The main outcome was treatment success, defined as a reduction in walled-off necrosis size to 2 cm or less on CT after 8 weeks., Results: Forty-seven patients were treated in the first interval and 53 in the second. There was no difference in patient demographics, clinical or walled-off necrosis characteristics and laboratory parameters between the groups, apart from a higher proportion of women and Caucasians in the later period. The treatment success rate was higher for the algorithmic approach compared with conventional treatment (91 versus 60 per cent respectively; P < 0·001). On multivariable logistic regression, management based on the algorithm was the only predictor of treatment success (odds ratio 6·51, 95 per cent c.i. 2·19 to 19·37; P = 0·001)., Conclusion: An algorithmic approach to pancreatic and peripancreatic walled-off necrosis, based on the collection size, location and stepwise response to intervention, resulted in an improved rate of treatment success compared with conventional endoscopic management., (© 2014 BJS Society Ltd. Published by John Wiley & Sons Ltd.)

Background: Most accrued evidence regarding prophylactic octreotide for a pancreatoduodenectomy (PD) predates the advent of the International Study Group of Pancreatic Fistula (ISGPF) classification system for a post-operative pancreatic fistula (POPF), and its efficacy in the setting of high POPF risk is unknown. The Fistula Risk Score (FRS) predicts the risk and impact of a clinically relevant (CR)-POPF and can be useful in assessing the impact of octreotide in scenarios of risk., Methods: From 2001-2013, 1018 PDs were performed at four institutions, with octreotide administered at the surgeon's discretion. The FRS was used to analyse the occurrence and burden of POPF across various risk scenarios., Results: Overall, 391 patients (38.4%) received octreotide. A CR-POPF occurred more often when octreotide was used (21.0% versus 7.0%; P < 0.001), especially when there was advanced FRS risk. Octreotide administration also correlated with an increased hospital stay (mean: 13 versus 11 days; P < 0.001). Regression analysis, controlling for FRS risk, demonstrated that octreotide increases the risk for CR-POPF development., Conclusion: This multi-institutional study, using ISGPF criteria, evaluates POPF development across the entire risk spectrum. Octreotide appears to confer no benefit in preventing a CR-POPF, and may even potentiate CR-POPF development in the presence of risk factors. This analysis suggests octreotide should not be utilized as a POPF mitigation strategy., (© 2014 International Hepato-Pancreato-Biliary Association.)

Background: Accurate assessment of complications is critical in analysing surgical outcomes. The post-operative morbidity index (PMI), derived from the Modified Accordion Severity Grading System and American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP), is a quantitative measure of post-operative morbidity. This study utilizes PMI to establish the complication burden for a distal pancreatectomy (DP)., Methods: From 2005-2011, nine centres contributed ACS-NSQIP complication data for 655 DPs. Each complication was assigned an Accordion severity weight ranging from 0.11 for grade 1 to 1.00 for grade 6 (death). The PMI is the sum of complication severity weights divided by the total number of patients., Results: ACS-NSQIP complications occurred in 177 patients (27.0%). The non risk-adjusted PMI for DP is 0.087. Bleeding/Transfusion and Organ Space Infection were the most common complications. Frequency and burden differed across Accordion grades. While grade 4-6 complications represented only 15.4% of complication occurrences, they accounted for 30.4% of the burden. Subgroup analysis demonstrates that the PMI did not vary based on laparoscopic versus open approach or the performance of a splenectomy., Discussion: This study uses two validated systems to quantitatively establish the morbidity of a DP. The PMI allows estimation of both the frequency and severity of complications and thus provides a more comprehensive assessment of risk., (© 2014 International Hepato-Pancreato-Biliary Association.)

Background: The Fistula Risk Score (FRS), a ten-point scale that relies on weighted influence of four variables, has been shown to effectively predict clinically relevant postoperative pancreatic fistula (CR-POPF) development and its consequences after pancreatoduodenectomy (PD). The proposed FRS demonstrated excellent predictive capacity; however, external validation of this tool would confirm its universal applicability., Methods: From 2001 to 2012, 594 PDs with pancreatojejunostomy reconstructions were performed at three institutions. POPFs were graded by International Study Group on Pancreatic Fistula standards as grades A, B, or C. The FRS was calculated for each patient, and clinical outcomes were evaluated across four discrete risk zones as described in the original work. Receiver operator curve analysis was performed to judge model validity., Results: One hundred forty-two patients developed any sort of POPF, of which 68 were CR-POPF (11.4 % overall; 8.9 % grade B, 2.5 % grade C). Increasing FRS scores (0-10) correlated well with CR-POPF development (p < 0.001) with a C-statistic of 0.716. When segregated by discrete FRS-risk groups, CR-POPFs occurred in low-, moderate-, and high-risk patients, 6.6, 12.9, and 28.6 % of the time, respectively (p < 0.001). Clinical outcomes including complications, length of stay, and readmission rates also increased across risk groups., Conclusion: This multi-institutional experience confirms the Fistula Risk Score as a valid tool for predicting the development of CR-POPF after PD. Patients devoid of any risk factors did not develop a CR-POPF, and the rate of CR-POPF approximately doubles with each subsequent risk zone. The FRS is validated as a strongly predictive tool, with widespread applicability, which can be readily incorporated into common clinical practice and research analysis.

Pancreatic cancer is the one of the deadliest of all malignancies. The five year survival rate for patients with this disease is 3-5%. Thus, there is a compelling need for novel therapeutic strategies to improve the clinical outcome for patients with pancreatic cancer.  Several groups have demonstrated for other types of solid tumors that early passage human tumor xenograft models can be used to define some genetic and molecular characteristics of specific human tumors. Published studies also suggest that murine tumorgraft models (early passage xenografts derived from direct implantation of primary tumor specimens) may be useful in identifying compounds with efficacy against specific tumor types.  Because pancreatic cancer is a fatal disease and few well-characterized model systems are available for translational research, we developed and characterized a panel of pancreatic tumorgraft models for biological evaluation and therapeutic drug testing.  Of the 41 primary tumor specimens implanted subcutaneously into mice, 35 produced viable tumorgraft models.  We document the fidelity of histological and morphological characteristics and of KRAS mutation status among primary (F0), F1, and F2 tumors for the twenty models that have progressed to the F3 generation.  Importantly, our procedures produced a take rate of 85%, higher than any reported in the literature. Primary tumor specimens that failed to produce tumorgrafts were those that either contained <10% tumor cells or that were obtained from significantly smaller primary tumors. In view of the fidelity of characteristics of primary tumor specimens through at least the F2 generation in mice, we propose that these tumorgraft models represent a useful tool for identifying critical characteristics of pancreatic tumors and for evaluating potential therapies.

Background: The Post-operative Morbidity Index (PMI) is a quantitative utility measure of a complication burden created by severity weighting. The Fistula Risk Score (FRS) is a validated model that predicts whether a patient will develop a post-operative pancreatic fistula (POPF). These novel tools might provide further discrimination of the ISGPF grading system., Methods: From 2001 to 2012, 1021 pancreaticoduodenectomies were performed at four institutions. POPFs were categorized by ISGPF standards. PMI scores were calculated based on the Modified Accordion Severity Grading System. FRS scores were assigned according to the relative influence of four recognized factors for developing a clinically relevant POPF (CR-POPF)., Results: In total, 231 patients (22.6%) developed a POPF, of which 54.1% were CR-POPFs. The PMI differed significantly between the ISGPF grades and patients with no or non-fistulous complications (P < 0.001). 64.9% of POPFs and 84.0% of CR-POPFs contributed the highest Accordion grade to the PMI. Overall, the FRS correlated well with PMI (R(2) = 0.81, P < 0.001)., Conclusion: These data quantitatively reinforce the ISGPF grades that were developed qualitatively around the concept of clinical severity. CR-POPFs usually reflect the patient's highest Accordion score whereas biochemical POPFs are often superseded. The correlation between FRS and PMI indicates that risk factors for a fistula contribute to overall pancreaticoduodenectomy morbidity., (© 2013 International Hepato-Pancreato-Biliary Association.)

Objectives: Morbidity after pancreaticoduodenectomy (PD) remains high. Computed tomography (CT) of intra-abdominal tissue has not been thoroughly evaluated to establish associations with the occurrence of complications after PD. The current study sought to determine whether differences in non-enhanced visceral attenuation predicted complications after PD., Methods: Outcomes in patients undergoing PD were analysed according to the Clavien system for classifying complications and the International Study Group on Pancreatic Fistula system for classifying postoperative pancreatic fistula (POPF). Preoperative non-enhanced CT scans were evaluated by a blinded investigator for attenuation of abdominal viscera and fat thickness. Data on pancreatic firmness and pancreatic duct size were collected. Univariate and multivariate analyses were performed., Results: A total of 134 patients underwent PD for malignant and benign disease. Rates of morbidity, mortality and POPF at 90 days were 61%, 4% and 23%, respectively. Patients with a body mass index of > 25 kg/m(2) had higher rates of POPF (P = 0.05) and complications (P < 0.01). In multivariate analysis, patients were more likely to develop any complication as CT attenuation decreased for paraspinus muscle (P < 0.01), spleen (P < 0.03) and liver (P = 0.01) parenchyma., Conclusions: Postoperative complications after PD remain prevalent. Decreased CT attenuation of abdominal viscera is an independent predictor of morbidity after PD and suggests a high-risk patient physiology for pancreatic resection., (© 2013 International Hepato-Pancreato-Biliary Association.)

Background & Aims: Although surgery is the standard technique for drainage of pancreatic pseudocysts, use of endoscopic methods is increasing. We performed a single-center, open-label, randomized trial to compare endoscopic and surgical cystogastrostomy for pancreatic pseudocyst drainage., Methods: Patients with pancreatic pseudocysts underwent endoscopic (n = 20) or surgical cystogastrostomy (n = 20). The primary end point was pseudocyst recurrence after a 24-month follow-up period. Secondary end points were treatment success or failure, complications, re-interventions, length of hospital stay, physical and mental health scores, and total costs., Results: At the end of the follow-up period, none of the patients who received endoscopic therapy had a pseudocyst recurrence, compared with 1 patient treated surgically. There were no differences in treatment successes, complications, or re-interventions between the groups. However, the length of hospital stay was shorter for patients who underwent endoscopic cystogastrostomy (median, 2 days, vs 6 days in the surgery group; P < .001). Although there were no differences in physical component scores and mental health component scores (MCS) between groups at baseline on the Medical Outcomes Study 36-Item Short-Form General Survey questionnaire, longitudinal analysis showed significantly better physical component scores (P = .019) and mental health component scores (P = .025) for the endoscopy treatment group. The total mean cost was lower for patients managed by endoscopy than surgery ($7011 vs $15,052; P = .003)., Conclusions: In a randomized trial comparing endoscopic and surgical cystogastrostomy for pancreatic pseudocyst drainage, none of the patients in the endoscopy group had pseudocyst recurrence during the follow-up period, therefore there is no evidence that surgical cystogastrostomy is superior. However, endoscopic treatment was associated with shorter hospital stays, better physical and mental health of patients, and lower cost., Trial Registration: ClinicalTrials.gov: NCT00826501., (Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Tumorigenesis of pancreatic cancer (PC) and the pathophysiology of type 2 diabetes mellitus (DM2) are emerging as intertwined pathways. As the operative morbidity and mortality of pancreatectomy has improved, incidence has increased and survival has remained mostly unchanged. The diagnosis of DM2 suggests pancreatic dysfunction and possible early carcinogenesis. DM2 is a significant comorbidity predicting worse outcomes in patients undergoing pancreatic resection as part of the treatment of PC. This article examines this phenomena and suggests possible approaches to screening and diagnosis., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Pancreatectomy or drainage has been advocated for pain due to chronic pancreatitis. Islet cell autotransplantation (IAT) may improve quality of life (QOL); optimal patient selection has not been established., Study Design: Outcomes of 100 patients who underwent pancreatectomy with islet isolation between 2005 and 2012 were assessed by etiology (alcoholic pancreatitis [AP] 30%, and nonalcoholic pancreatitis [NAP] 70%). Insulin requirement, Short Form-36, and McGill Pain Questionnaires were assessed. Data were analyzed using SASv9.2., Results: Of the 100 patients, isolation was unsuccessful in 9 patients due to fibrosis. Alcoholic pancreatitis was associated with 7 of 9 failed isolations (23% vs 3%, p < 0.01), and all of these patients are now diabetic. Ninety-one patients (age 44 years, follow-up 19 months, 23% AP) underwent resection with IAT. Total islet yield (islet cell equivalents [IEQ]) and IEQ/kg body weight were less for patients with AP (81,000 vs 150,000, p < 0.01; 1,260 vs 2,190, respectively, p = 0.01) overall and more specifically, for total pancreatectomy (92,000 vs 188,000, respectively, p = 0.02). Twenty-eight (34%) of all patients who had resections and 15% of those undergoing total pancreatectomy are insulin free. Multivariate analysis identified AP as an independent predictor of insulin units/day (p = 0.01). Complete pre- and postoperative QOL and pain surveys were available on 69 patients. Patients with AP had less QOL improvement (1 of 8 vs 5 of 8 domains, p < 0.01) and "present pain" improvement at 2 years from preoperative levels in those with NAP; no improvement in QOL was seen in those with AP (NAP 2.7 to 1.2, p < 0.01; AP 2.7 to 2.2, p > 0.05)., Conclusions: After pancreatic resection with planned IAT, AP resulted in failed isolations, lower yields, higher insulin requirements, poor long-term QOL improvement, and no improvement in pain scores compared with NAP. Further studies should define criteria for resection and IAT for patients with alcoholic chronic pancreatitis., (Copyright © 2013 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

The aim of this study was to assess for any trend in management of pancreatic fluid collections (PFCs) and identify impacting factors. The endoscopy and surgical databases were queried for PFC patients. PFCs were categorized as pseudocysts (PP) or complex collections (CC) that included abscess/necrosis. The outcome measures were to compare the utilization of surgery and endoscopy from 2004 to 2007 (group I) and from 2008 to 2010 (group II) and identify factors impacting practice patterns. A total of 285 patients were treated: group I included 119 and group II 166. Of 119 group I patients, 29 per cent were treated by surgery and 71 per cent by endoscopy. Of 85 endoscopy patients, 42 per cent were drained by conventional transmural drainage and 58 per cent by endoscopic ultrasound (EUS). Of 166 group II patients, 31 per cent were treated surgically and 69 per cent endoscopically. Of the 115 endoscopy patients, 17 per cent were drained by conventional transmural drainage and 83 per cent by EUS. Compared with group I, all pseudocysts in group II were treated by endoscopy (84% vs 100%, P = 0.001). There was no difference in the rate of CC treated by endoscopy between both groups (57.7% vs 56.8%, P = 0.9). PFCs not causing luminal compression (P < 0.0001) or measuring <9 cm in size (P < 0.0001) were more likely to require EUS. There was a significant trend at our institution in the management of PFCs with all pseudocysts presently being treated only by endoscopy. The ability of EUS to access smaller size PFCs and those not causing luminal compression has significantly expanded the role of endoscopy in PFC management.

Objectives: Endoscopy is a minimally invasive technique for the drainage of peripancreatic fluid collections. This study evaluated the clinical outcomes and predictors of treatment success in consecutive patients undergoing endoscopic transmural drainage of peripancreatic fluid collections., Methods: This is a retrospective study of patients who underwent endoscopic drainage of peripancreatic fluid collections over 7 years. Prior to drainage, an ERCP was attempted for stent placement in all patients with a pancreatic duct leak. Drainages were performed using conventional endoscopy or endoscopic ultrasound. Transmural stents and/or drainage catheters were deployed and endoscopic necrosectomy was undertaken when required. Data on clinical outcomes and complications were collected prospectively., Results: A total of 211 patients underwent drainage of peripancreatic fluid collections that was classified as pseudocyst in 45%, abscess in 28%, and necrosis in 27%. Mean diameter of the fluid collection was 100.6 mm, and 34.5% of patients had pancreatic duct stent placement. Median duration of follow-up was 356 days. Treatment success was 85.3% and was higher for pseudocyst and abscess compared to necrosis (93.5% vs. 63.2%, p < 0.0001). Complications were encountered in 17 patients (8.5%) and was higher for drainage of necrosis than pseudocyst or abscess (15.8% vs. 5.2%, p = 0.02). Treatment success was more likely for patients with pseudocyst or abscess than necrosis (adjusted OR = 7.6, 95% CI [2.9, 20.1], p < 0.0001) when adjusted for serum albumin and white cell count, type of endoscopic modality or accessory used, pancreatic duct stenting, luminal compression, size and location of fluid collection., Conclusions: Endoscopic therapy is a highly effective technique for the management of patients with non-necrotic peripancreatic fluid collections.

Background and Aim: The aim of the present study was to evaluate the frequency of complications during endoscopic ultrasound (EUS)-guided drainage of pancreatic fluid collections (PFC), identify contributing factors, and report on management outcomes., Methods: All patients who underwent EUS-guided PFC drainage over 7 years were enrolled. Indications, demographics, technical details, complications, surgical interventions, and final outcomes were prospectively recorded., Results: Of 148 patients who underwent EUS, PFC was located in the pancreatic body in 84 (56.8%), in the tail in 45 (30.4%), in the head in 15 (10.1%), and in the uncinate region in four patients (2.7%). Perforation was encountered at the site of transmural stenting in two patients (1.3%, 95% confidence interval [CI]: 0.41-4.76) with a pseudocyst in the uncinate region that was drained transgastrically. When compared to other locations, perforation was more common with PFC involving the uncinate region (0% vs 50%, P = 0.0005). Other complications included bleeding in one (0.67%, 95% CI: 0.16, 3.68), stent migration in 1 (0.67%, 95% CI: 0.16, 3.68), and infection in four patients (2.7%, 95% CI: 1.09, 6.73). Bleeding occurred in a patient with underlying acquired factor VIII inhibitors, stent migration in a patient who underwent drainage via the gastric cardia, and infection in two patients with pseudocysts and two with necrosis. While two patients who developed post-procedural infection and one with stent migration were managed endoscopically, both perforations required surgery. Surgical debridement was performed in two patients who developed infection with successful outcomes in one, and death from underlying comorbidity in the other., Conclusions: Complications are rare during EUS-guided drainage of PFC and can be managed successfully in most patients., (© 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.)