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Background: Fascial plane blocks (FPBs) are widely used for abdominal surgery with the assumption that liposomal bupivacaine (LB) is more effective than standard bupivacaine (SB)., Methods: This was a single-institution retrospective cohort study of patients administered FPBs with LB or SB ​+ ​admixtures (dexamethasone/dexmedetomidine) for open abdominal cancer surgery. Propensity score matching generated a 2:1 (LB:SB) matched cohort. Opioid use (mg oral morphine equivalents, OME) and severe pain (≥3 pain scores ≥7 in a 24-h period) were compared., Results: Opioid use was >150 ​mg OME in 19.9 ​% (29/146) LB and 16.4 ​% (12/73) SB patients (p ​= ​0.586). Severe pain was experienced by 44 ​% (64/146) LB and 53 ​% (39/73) SB patients (p ​= ​0.198). On multivariable analysis, SB vs LB choice was not associated with high opioid volume >150 ​mg or severe pain., Conclusions: FPBs with standard bupivacaine were not associated with higher 72-h opioid use or more severe pain compared to liposomal bupivacaine., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objectives: Acinar cell carcinoma (ACC) accounts for about 1% of pancreatic cancers. The molecular and clinical features of ACC are less characterized than those of pancreatic ductal adenocarcinoma. Methods : We retrospectively evaluated the clinical and molecular features of ACC patients who underwent germline and/or somatic molecular testing at The University of Texas MD Anderson Cancer Center from 2008 to 2022 and two cases from 2023-2024 who underwent RNA and TME analysis by Boston Gene. Patient information was extracted from our institutional database with the approval of the Institutional Review Board. Results: We identified 16 patients with available molecular testing results. Fourteen patients had metastatic disease, one had borderline resectable disease, and one had localized resectable disease at diagnosis. Fifteen patients were wild type for KRAS (one patient had unknown KRAS status). Somatic/germline mutations of DNA damage repair genes ( BRCA1/2 , PALB2 , and ATM ) were present in 5 of 12 patients tested for these genes. One patient was found to have RET fusion and responded favorably to selpercatinib for over 42 months. The median overall survival (OS) was 24 months for patients with metastatic disease. One of the additional two cases who underwent BostonGene testing was found to have NTRK1 fusion. RNA and TME analysis by Boston Gene of the two cases reported immune desert features and relatively lower RNA levels of CEACAM5, CD47, CD74, and MMP1 and higher RNA levels of CDH6 compared with PDAC.

Adequate sampling is essential to an accurate pathologic evaluation of pancreatectomy specimens resected for pancreatic ductal adenocarcinoma (PDAC) after neoadjuvant therapy (NAT). However, limited data are available for the association between the sampling and survival in these patients. We examined the association of the entire submission of the tumor (ESOT) and the entire submission of the pancreas (ESOP) with disease-free survival (DFS) and overall survival (OS), as well as their correlations with clinicopathologic features, for 627 patients with PDAC who received NAT and pancreaticoduodenectomy. We demonstrated that both ESOT and ESOP were associated with lower ypT, less frequent perineural invasion, and better tumor response ( p < 0.05). ESOP was also associated with a smaller tumor size ( p < 0.001), more lymph nodes ( p < 0.001), a lower ypN stage ( p < 0.001), better differentiation ( p = 0.02), and less frequent lymphovascular invasion ( p = 0.009). However, since ESOP and ESOT were primarily conducted for cases with no grossly identifiable tumor or minimal residual carcinoma in initial sections, potential bias cannot be excluded. Both ESOT and ESOP were associated with less frequent recurrence/metastasis and better DFS and OS ( p < 0.05) in the overall study population. ESOP was associated with better DFS and better OS in patients with ypT0/ypT1 or ypN0 tumors and better OS in patients with complete or near-complete response ( p < 0.05). ESOT was associated with better OS in patients with ypT0/ypT1 or ypN0 tumors ( p < 0.05). Both ESOT and ESOP were independent prognostic factors for OS according to multivariate survival analyses. Therefore, accurate pathologic evaluation using ESOP and ESOT is associated with the prognosis in PDAC patients with complete or near-complete pathologic response and ypT0/ypT1 tumor after NAT.

Background: Although robotic pancreatectomy may facilitate an earlier functional recovery, the impact of a robotic pancreatectomy program during its early experience on the timing of return to intended oncologic therapy (RIOT) after surgery is unknown., Methods: In this retrospective cohort study, we used propensity score matching with a 1:2 ratio to compare patients who underwent robotic or open surgery (distal pancreatectomy or pancreatoduodenectomy) for pancreatic ductal adenocarcinoma (PDAC) during the first 3 years of our robotic pancreatectomy experience (January 2018-December 2021). Generalized estimating equations modeling was used to evaluate the effect of surgical approach on early RIOT, defined as adjuvant chemotherapy initiation within 8 weeks after surgery, and late RIOT, defined as initiation within 12 weeks after surgery., Results: The matched cohort included 26 patients who underwent robotic pancreatectomy and 52 patients who underwent open pancreatectomy. Rates of receipt of adjuvant chemotherapy were 96.2% and 78.9%, respectively. Rate of early RIOT in the robotic group (73.1% was higher than that in the open group (44.2%; P = 0.018). In multivariable analysis, a robotic approach was associated with early RIOT (odds ratio, 3.54; 95% confidence interval 1.08-11.62; P = 0.038). Surgical approach did not impact late RIOT (odds ratio, 3.21; 95% confidence interval 0.71-14.38; P = 0.128)., Conclusions: Compared with open pancreatectomy, robotic pancreatectomy did not delay RIOT. In fact, odds of early RIOT were increased, which supports the oncological safety of our robotic pancreatectomy program during its implementation., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Ten percent of pancreatic neuroendocrine tumors (pNET) are related to inherited syndromes (MEN1, MEN4, VHL, NF1, and TSC). Growing evidence suggests that clinically sporadic pNETs can also harbor germline pathogenic variants. In this study, we report the prevalence of pathologic/likely pathologic (P/LP) germline variants in a high-risk cohort and an unselected cohort. We collected clinical data of patients with pNETs seen at MD Anderson Cancer Center and Johns Hopkins Hospital. The high-risk cohort included (n = 132) patients seen at MD Anderson Cancer Center who underwent germline testing for high-risk criteria (early onset, personal or family history of cancer, and syndromic features) between 2013 and 2019. The unselected cohort included (n = 106) patients seen at Johns Hopkins Hospital who underwent germline testing following their diagnosis of pNETs between 2020 and 2022. In the high-risk cohort (n = 132), 33% (n = 44) had P/LP variants. The majority of the patients had P/LP variants in MEN1 56% (n = 25), followed by DNA repair pathways 18% (n = 8), and 7% (n = 3) in MSH2 (Lynch syndrome). Patients with P/LP were younger (45 vs. 50 years; P = 0.002). In the unselected cohort (n = 106), 21% (n = 22) had P/LP. The majority were noted in DNA repair pathways 40% (n = 9) and MEN1 36% (n = 8). Multifocal tumors correlated with the presence of P/LP (P = 0.0035). MEN1 germline P/LP variants correlated with younger age (40 vs. 56 years; P = 0.0012), presence of multifocal tumors (P < 0.0001), and World Health Organization grade 1 histology (P = 0.0078). P/LP variants are prevalent in patients with clinically sporadic pNET irrespective of high-risk features. The findings support upfront universal germline testing in all patients with pNET. Prevention Relevance: Here, we present germline data from the largest reported cohort of patients with pNET (n = 238), comprising both a high-risk cohort and an unselected cohort. In both cohorts, we identify a high number of P/LPs, including those in the DNA repair pathway. Our findings support universal germline testing in patients with pNET., (©2024 American Association for Cancer Research.)

Objective: Within a learning health system paradigm, this study sought to evaluate reasons for readmission to identify opportunities for improvement., Background: Post-pancreatectomy readmission rates have remained constant despite improved index hospitalization metrics., Methods: We performed a single-institution case-control study of consecutive patients with pancreatectomy (October 2016 to April 2022). Complications were prospectively graded in biweekly faculty and advanced practice provider meetings. We analyzed risk factors during index hospitalization and categorized indications for 90-day readmissions., Results: A total of 835 patients, median age 65 years and 51% (427/835) males, underwent 64% (534/835) pancreatoduodenectomies, 34% (280/835) distal pancreatectomies, and 3% (21/835) other resections. Twenty-four percent (204/835) of patients were readmitted. The primary indication for readmission was technical in 51% (105/204), infectious in 17% (35/204), and medical/metabolic in 31% (64/204) of patients. Procedures were required in 77% (81/105) and 60% (21/35) of technical and infectious readmissions, respectively, while 66% (42/64) of medical/metabolic readmissions were managed noninvasively. During the index hospitalization, benign pathology [odds ratio (OR): 1.8, P =0.049], biochemical pancreatic leak (OR: 2.3, P =0.001), bile/gastric/chyle leak (OR: 6.4, P =0.001), organ-space infection (OR: 3.4, P =0.007), undrained fluid on imaging (OR: 2.4, P =0.045), and increasing white blood cell count (OR: 1.7, P =0.045) were independently associated with odds of readmission., Conclusions: Most readmissions following pancreatectomy were technical in origin. Patients with complications during the index hospitalization, increasing white blood cell count, or undrained fluid before discharge were at the highest risk for readmission. Predischarge risk stratification of readmission risk factors and augmentation of in-clinic resources may be strategies to reduce readmission rates., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Previous studies suggest that besides anatomy (A: resectable, borderline resectable [BR], or locally advanced [LA]) also biologic (B: carbohydrate antigen 19-9 [CA 19-9]) and conditional (C: performance status) factors should be considered when staging patients with localized pancreatic ductal adenocarcinoma (PDAC). The prognostic value of the combined ABC factors has not been quantitatively validated., Methods: In this retrospective cohort study, we evaluated patients with localized PDAC treated with initial (modified) fluorouracil with leucovorin, irinotecan, and oxaliplatin ([m]FOLFIRINOX) at five high-volume pancreatic cancer centers in the United States and the Netherlands (2012-2019). Multivariable Cox proportional hazards analysis was used to investigate the impact of the ABC factors for overall survival (OS)., Results: Overall, 1,835 patients with localized PDAC were included. Tumor stage at diagnosis was potentially resectable in 346 (18.9%), BR in 531 (28.9%), and LA in 958 (52.2%) patients. The baseline CA 19-9 was >500 U/mL in 559 patients (32.5%). Performance status was ≥1 in 1,110 patients (60.7%). Independent poor prognostic factors for OS were BR disease (hazard ratio [HR], 1.26 [95% CI, 1.06 to 1.50]), LA disease (HR, 1.71 [95% CI, 1.45 to 2.02]), CA 19-9 >500 U/mL (HR, 1.36 [95% CI, 1.21 to 1.52]), and WHO performance status ≥1 (HR, 1.31 [95% CI, 1.16 to 1.47]). Patients were assigned 1 point for each poor ABC factor and 2 points for LA disease. The median OS for patients with score 0-4 was 49.7, 29.9, 22.0, 19.1, and 14.9 months with corresponding 5-year OS rates of 47.0%, 28.9%, 19.2%, 9.3%, and 4.8%, respectively., Conclusion: The ABC factors of tumor anatomy, CA 19-9, and performance status at diagnosis were independent prognostic factors for OS in patients with localized PDAC treated with initial (m)FOLFIRINOX. Staging of patients with localized PDAC at diagnosis should be based on anatomy, CA 19-9, and performance status.

Objective: The aim of this study was to compare infectious complications in pancreatoduodenectomy (PD) patients with biliary stents treated with short, medium, or long durations of prophylactic antibiotics., Background: Pre-existing biliary stents have historically been associated with higher infection risk after PD. Patients are administered prophylactic antibiotics, but the optimal duration remains unknown., Methods: This single-institution retrospective cohort study included consecutive PD patients from October 2016 to April 2022. Antibiotics were continued past the operative dose per surgeon discretion. Infection rates were compared by short (≤24 h), medium (>24 but ≤96 h), and long (>96 h) duration antibiotics. Multivariable regression analysis was performed to evaluate associations with a primary composite outcome of wound infection, organ-space infection, sepsis, or cholangitis., Results: Among 542 PD patients, 310 patients (57%) had biliary stents. The composite outcome occurred in 28% (34/122) short, 25% (27/108) medium, and 29% (23/80) long-duration ( P =0.824) antibiotic patients. There were no differences in other infection rates or mortality. On multivariable analysis, antibiotic duration was not associated with infection rate. Only postoperative pancreatic fistula (odds ratio 33.1, P <0.001) and male sex (odds ratio 1.9, P =0.028) were associated with the composite outcome., Conclusions: Among 310 PD patients with biliary stents, long-duration prophylactic antibiotics were associated with similar composite infection rates to short and medium durations but were used almost twice as often in high-risk patients. These findings may represent an opportunity to de-escalate antibiotic coverage and promote risk-stratified antibiotic stewardship in stented patients by aligning antibiotic duration with risk-stratified pancreatectomy clinical pathways., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: We hypothesized that iterative revisions of our original 2016 risk-stratified pancreatectomy clinical pathways would be associated with decreased 90-day perioperative costs., Study Design: From a single-institution retrospective cohort study of consecutive patients with 3 iterations: "version 1" (V1) (October 2016 to January 2019), V2 (February 2019 to October 2020), and V3 (November 2020 to February 2022), institutional data were aggregated using revenue codes and adjusted to constant 2022-dollar value. Grand total perioperative costs (primary endpoint) were the sum of pancreatectomy, inpatient care, readmission, and 90-day global outpatient care. Proprietary hospital-based costs were converted to ratios using the mean cost of all hospital operations as the denominator., Results: Of 814 patients, pathway V1 included 363, V2 229, and V3 222 patients. Accordion Grade 3+ complications decreased with each iteration (V1: 28.4%, V2: 22.7%, and V3: 15.3%). Median length of stay decreased (V1: 6 days, interquartile range [IQR] 5 to 8; V2: 5 [IQR 4 to 6]; and V3: 5 [IQR 4 to 6]) without an increase in readmissions. Ninety-day global perioperative costs decreased by 32% (V1 cost ratio 12.6, V2 10.9, and V3 8.6). Reduction of the index hospitalization cost was associated with the greatest savings (-31%: 9.4, 8.3, and 6.5). Outpatient care costs decreased consistently (1.58, 1.41, and 1.04). When combining readmission and all outpatient costs, total "postdischarge" costs decreased (3.17, 2.59, and 2.13). Component costs of the index hospitalization that were associated with the greatest savings were room or board costs (-55%: 1.74, 1.14, and 0.79) and pharmacy costs (-61%: 2.20, 1.61, and 0.87; all p < 0.001)., Conclusions: Three iterative risk-stratified pancreatectomy clinical pathway refinements were associated with a 32% global period cost savings, driven by reduced index hospitalization costs. This successful learning health system model could be externally validated at other institutions performing abdominal cancer surgery., (Copyright © 2024 by the American College of Surgeons. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Objective: We aimed to determine if advances in neoadjuvant therapy affected recurrence patterns and survival outcomes after pancreatectomy for pancreatic ductal adenocarcinoma (PDAC)., Background: Data are limited on how modern multimodality therapy affects PDAC recurrence and post-recurrence survival., Methods: Patients who received neoadjuvant therapy followed by curative-intent pancreatectomy for PDAC during 1998-2018 were identified. Treatments, recurrence sites and timing, and survival were compared between patients who completed neoadjuvant therapy and pancreatectomy in 1998-2004, 2005-2011, and 2012-2018., Results: The study included 727 patients (203, 251, and 273 in the 1998-2004, 2005-2011, and 2012-2018 cohorts, respectively). Use of neoadjuvant induction chemotherapy increased over time, and regimens changed over time, with >80% of patients treated in 2012-2018 receiving FOLFIRINOX or gemcitabine with nab-paclitaxel. Overall, recurrence sites and incidence (67.5%, 66.1%, and 65.9%) remained stable, and 85% of recurrences occurred within 2 years of surgery. However, compared to earlier cohorts, the 2012-2018 cohort had lower conditional risk of recurrence in postoperative year 1 and higher risk in postoperative year 2. Overall survival increased over time (median, 30.6, 33.6, and 48.7 mo, P < 0.005), driven by improved post-recurrence overall survival (median, 7.8, 12.5, and 12.6 mo; 3-year rate, 7%, 10%, and 20%; P < 0.005)., Conclusions: We observed changes in neoadjuvant therapy regimens over time and an associated shift in the conditional risk of recurrence from postoperative year 1 to postoperative year 2, although recurrence remained common. Overall survival and post-recurrence survival remarkably improved over time, reflecting improved multimodality regimens for recurrent disease., Competing Interests: Conflicts of Interest and Source of Funding: The authors have no conflicts of interest related to the design or execution of this study. The authors have no financial relationships related to the design or execution of this study. Supported in part by the NIH/NCI under award number P30CA016672. SHC is supported by National Institutes of Health T32 CA 009599 and the MD Anderson Cancer Center support grant (P30 CA016672)., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Surgery in selected patients with locally advanced pancreatic cancer after induction chemotherapy may have drawbacks related to surgical risks and breaks or delays in oncological treatment, in particular when curative intent resection is not possible (that is non-therapeutic laparotomy). The aim of this study was to assess the incidence and oncological impact of a non-therapeutic laparotomy in patients with locally advanced pancreatic cancer treated with induction (m)FOLFIRINOX chemotherapy., Methods: This was a retrospective international multicentre study including patients diagnosed with pathology-proven locally advanced pancreatic cancer treated with at least one cycle of (m)FOLFIRINOX (2012-2019). Patients undergoing a non-therapeutic laparotomy (group A) were compared with those not undergoing surgery (group B) and those undergoing resection (group C)., Results: Overall, 663 patients with locally advanced pancreatic cancer were included (67 patients (10.1%) in group A, 425 patients (64.1%) in group B, and 171 patients (25.8%) in group C). A non-therapeutic laparotomy occurred in 28.2% of all explorations (67 of 238), with occult metastases in 30 patients (30 of 67, 44.8%) and a 90-day mortality rate of 3.0% (2 of 67). Administration of palliative therapy (65.9% versus 73.1%; P = 0.307) and median overall survival (20.4 [95% c.i. 15.9 to 27.3] versus 20.2 [95% c.i. 19.1 to 22.7] months; P = 0.752) did not differ between group A and group B respectively. The median overall survival in group C was 36.1 (95% c.i. 30.5 to 41.2) months. The 5-year overall survival rates were 11.4%, 8.7%, and 24.7% in group A, group B, and group C, respectively. Compared with group B, non-therapeutic laparotomy (group A) was not associated with reduced overall survival (HR = 0.88 [95% c.i. 0.61 to 1.27])., Conclusion: More than a quarter of surgically explored patients with locally advanced pancreatic cancer after induction (m)FOLFIRINOX did not undergo a resection. Such non-therapeutic laparotomy does not appear to substantially impact oncological outcomes., (© The Author(s) 2024. Published by Oxford University Press on behalf of BJS Foundation Ltd.)

Introduction: About 25% of patients with localized pancreatic adenocarcinoma have non-elevated serum carbohydrate antigen (CA) 19-9 levels at baseline, hampering evaluation of response to preoperative treatment. Serum carcinoembryonic antigen (CEA) is a potential alternative., Methods: This retrospective cohort study from five referral centers included consecutive patients with localized pancreatic adenocarcinoma (2012-2019), treated with one or more cycles of (m)FOLFIRINOX, and non-elevated CA19-9 levels (i.e., < 37 U/mL) at baseline. Cox regression analyses were performed to assess prognostic factors for overall survival (OS), including CEA level at baseline, restaging, and dynamics., Results: Overall, 277 patients were included in this study. CEA at baseline was elevated (≥5 ng/mL) in 53 patients (33%) and normalized following preoperative therapy in 14 patients (26%). In patients with elevated CEA at baseline, median OS in patients with CEA normalization following preoperative therapy was 33 months versus 19 months in patients without CEA normalization (p = 0.088). At time of baseline, only elevated CEA was independently associated with (worse) OS (hazard ratio [HR] 1.44, 95% confidence interval [CI] 1.04-1.98). At time of restaging, elevated CEA at baseline was still the only independent predictor for (worse) OS (HR 1.44, 95% CI 1.04-1.98), whereas elevated CEA at restaging (HR 1.16, 95% CI 0.77-1.77) was not., Conclusions: Serum CEA was elevated in one-third of patients with localized pancreatic adenocarcinoma having non-elevated CA19-9 at baseline. At both time of baseline and time of restaging, elevated serum CEA measured at baseline was the only predictor for (worse) OS. Therefore, serum CEA may be a useful tool for decision making at both initial staging and time of restaging in patients with non-elevated CA19-9., (© 2024. Society of Surgical Oncology.)

Background: The prognostic utility of Carbohydrate Antigen 19-9 (CA 19-9) and Carcinoembryonic Antigen (CEA) in ampullary adenocarcinoma is unclear. We sought to evaluate the association between initial tumor marker levels and survival in patients with resected ampullary adenocarcinoma., Methods: This was a single-institution, retrospective cohort study of consecutive patients who underwent pancreatoduodenectomy for ampullary adenocarcinoma from 1999 to 2021. CA 19-9 was assessed after biliary decompression. Contal and O'Quigley method determined optimal biomarker cutoff levels which were correlated with overall survival (OS) using the Kaplan-Meier method and Cox Proportional Hazards Regression., Results: A total of 180 patients underwent pancreatoduodenectomy. Patients with CA 19-9 >100 U/mL had a shorter median OS (28 vs. 132 months, p < 0.001) compared to patients with CA 19-9 ≤ 100 U/mL at diagnosis. Survival was similar between pancreaticobiliary and intestinal tumor subtypes when CA 19-9 was >100 U/mL (OS:25 vs. 33 months, p = 0.415). By Cox regression analysis, CA 19-9 >100 U/mL was independently associated with worse OS (HR 2.8, p = 0.001)., Conclusions: Preoperative CA 19-9 >100 U/mL was associated with shorter OS in patients with resected ampullary adenocarcinoma. CA 19-9 may be useful when counseling patients about prognosis or when considering the role of perioperative systemic therapy., (Copyright © 2023. Published by Elsevier Ltd.)

Background: Risk-stratified drain fluid amylase cutoff values for postoperative day 1 (POD1) (DFA1) and POD3 (DFA3) can guide early drain removal after pancreatoduodenectomy (PD). The aim of this study was to evaluate and recalibrate cutoff values instituted in Feb 2019 using a prospective sequential cohort., Methods: We performed a single-institution prospective cohort study of consecutive patients who underwent pancreatoduodenectomy following implementation of institution-specific DFA cutoffs in February 2019 through April 2022. DFA values, drain removal, and clinically relevant postoperative pancreatic fistulas (CR-POPF) were analyzed. Receiver operating characteristic (ROC) curve analysis determined optimal cutoff values., Results: In total, 267 patients, 173 (65%) low-risk and 94 (35%) high-risk, underwent 228 (85%) open and 39 (15%) robotic pancreatoduodenectomies. Seven (4%) low-risk patients and 21 (22%) high-risk patients developed CR-POPF. Drains were removed in 147 (55%) patients before/on POD3, with 1 (0.7%) CR-POPF. In low-risk patients, CR-POPF was excluded with 100% sensitivity if DFA1 < 286 (area under curve, AUC = 0.893, p = 0.001) or DFA3 < 97 (AUC = 0.856, p = 0.002). DFA1 < 137 (AUC = 0.786, p < 0.001) or DFA3 < 56 (AUC = 0.819, p < 0.001) were 100% sensitive in high-risk patients. Previously established DFA1 cutoffs of 100 (low-risk) and < 26 (high-risk) were 100% sensitive, while DFA3 cutoffs of 300 (low-risk) and 200 (high-risk) had 57% and 91% sensitivity., Conclusions: Within a learning health system, we recalibrated post-PD drain removal thresholds to DFA1 ≤ 300 and DFA3 ≤ 100 for low-risk and DFA1 ≤ 100 and DFA3 ≤ 50 for high-risk patients. This methodology is generalizable to other centers for developing institution-specific criteria to optimize safe early drain removal., (© 2023. The Society for Surgery of the Alimentary Tract.)

Importance: Postoperative opioid overprescribing leads to persistent opioid use and excess pills at risk for misuse and diversion. A learning health system paradigm using risk-stratified pancreatectomy clinical pathways (RSPCPs) may lead to reduction in inpatient and discharge opioid volume., Objective: To analyze the outcomes of 2 iterative RSPCP updates on inpatient and discharge opioid volumes., Design, Setting, and Participants: This cohort study included 832 consecutive adult patients at an urban comprehensive cancer center who underwent pancreatic resection between October 2016 and April 2022, comprising 3 sequential pathway cohorts (version [V] 1, October 1, 2016, to January 31, 2019 [n = 363]; V2, February 1, 2019, to October 31, 2020 [n = 229]; V3, November 1, 2020, to April 30, 2022 [n = 240])., Exposures: After V1 of the pathway established a baseline and reduced length of stay (n = 363), V2 (n = 229) updated patient and surgeon education handouts, limited intravenous opioids, suggested a 3-drug (acetaminophen, celecoxib, methocarbamol) nonopioid bundle, and implemented the 5×-multiplier (last 24-hour oral morphine equivalents [OME] multiplied by 5) to calculate discharge volume. Pathway version 3 (n = 240) required the nonopioid bundle as default in the recovery room and scheduled conversion to oral medications on postoperative day 1., Main Outcomes and Measures: Inpatient and discharge opioid volume in OME across the 3 RSPCPs were compared using nonparametric testing and trend analyses., Results: A total of 832 consecutive patients (median [IQR] age, 65 [56-72] years; 410 female [49.3%] and 422 male [50.7%]) underwent 541 pancreatoduodenectomies, 285 distal pancreatectomies, and 6 other pancreatectomies. Early nonopioid bundle administration increased from V1 (acetaminophen, 320 patients [88.2%]; celecoxib or anti-inflammatory, 98 patients [27.0%]; methocarbamol, 267 patients [73.6%]) to V3 (236 patients [98.3%], 163 patients [67.9%], and 238 patients [99.2%], respectively; P < .001). Total inpatient OME decreased from a median 290 mg (IQR, 157-468 mg) in V1 to 184 mg (IQR, 103-311 mg) in V2 to 129 mg (IQR, 75-206 mg) in V3 (P < .001). Discharge OME decreased from a median 150 mg (IQR, 100-225 mg) in V1 to 25 mg (IQR, 0-100 mg) in V2 to 0 mg (IQR, 0-50 mg) in V3 (P < .001). The percentage of patients discharged opioid free increased from 7.2% (26 of 363) in V1 to 52.5% (126 of 240) in V3 (P < .001), with 187 of 240 (77.9%) in V3 discharged with 50 mg OME or less. Median pain scores remained 3 or lower in all cohorts, with no differences in postdischarge refill requests. A subgroup analysis separating open and minimally invasive surgical cases showed similar results in both groups., Conclusions and Relevance: In this cohort study, the median total inpatient OME was halved and median discharge OME reduced to zero in association with a learning health system model of iterative opioid reduction that is freely adaptable by other hospitals. These findings suggest that opioid-free discharge after pancreatectomy and other major cancer operations is realistic and feasible with this no-cost blueprint.

Background: Clinically relevant postoperative pancreatic fistula (CR-POPF) is a major source of morbidity after distal pancreatectomy. This study examined the association between postoperative opioid use and CR-POPF in the context of opioid-sparing postoperative care., Methods: A case-control study was performed on consecutive patients who underwent distal pancreatectomy between October 2016 and April 2022 at a single institution. Patients who developed CR-POPF were compared to controls. Multivariable regression modeling was used to identify factors associated with CR-POPF., Results: A total of 281 patients underwent 187 open, 20 laparoscopic, and 74 robotic-assisted operations. The rate of CR-POPF was 21% (n = 58). CR-POPF rate declined from 32 to 8% over the study period (p < 0.001). Median oral morphine equivalents (OME) administered on POD 0-1 and 0-3 were 94 and 129 mg, respectively, in patients who did not develop a fistula versus 130 and 180 mg in those who did (both p ≤ 0.001). POD 0-3 OME (OR 1.11, p = 0.044) was independently associated with increased odds of CR-POPF, with each additional 50 mg (equivalent to 10 tramadol pills) increasing the relative risk by 11% and absolute risk by 2%., Conclusion: Early postoperative opioid use after distal pancreatectomy was associated with increased odds of CR-POPF. Decreasing perioperative opioid use through enhanced postoperative management is a low-cost and generalizable approach that may reduce rates of CR-POPF after distal pancreatectomy., (© 2023. The Society for Surgery of the Alimentary Tract.)

Purpose: The Borrmann classification system is widely used to classify advanced gastric cancer (GC). No studies have focused on the relationship between Borrmann type and response to preoperative therapy., Methods: Patients with advanced GC who received preoperative therapy followed by curative-intent gastrectomy from September 2016 through September 2021 were identified. Clinicopathologic characteristics were compared by Borrmann type. Logistic regression models were fit to analyze the relationship between Borrmann type and pCR rate., Results: Of the 227 patients who underwent gastrectomy during the period studied, 73 had pretreatment endoscopic images available for analysis. We classified the tumors as follows: Borrmann type 1, 4 (6%); type 2, 17 (23%); type 3, 33 (45%); and type 4, 19 (26%). Nine patients (12%) achieved pCR; 6 of these (67%) had type 1/2 GC and 3 (33%) had type 3. Multivariable logistic regression showed that Borrmann type 3/4 was the only independent factor associated with pCR (odds ratio 0.12; p = 0.023), but 2-year overall survival rates did not differ by Borrmann type (p = 0.216)., Conclusion: Patients with Borrmann type 3/4 advanced GC have a lower likelihood of achieving pCR after preoperative therapy than those with type 1/2 GC. Determining the Borrmann type preoperatively can guide treatment decision-making., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: With increasing implementation of enhanced recovery programs (ERPs) in clinical practice, standardised data collection and reporting have become critical in addressing the heterogeneity of metrics used for reporting outcomes. Opportunities exist to leverage electronic health record (EHR) systems to collect, analyse, and disseminate ERP data. Objectives: (i) To consolidate relevant ERP variables into a singular data universe; (ii) To create an accessible and intuitive query tool for rapid data retrieval. Method: We reviewed nine established individual team databases to identify common variables to create one standard ERP data dictionary. To address data automation, we used a third-party business intelligence tool to map identified variables within the EHR system, consolidating variables into a single ERP universe. To determine efficacy, we compared times for four experienced research coordinators to use manual, five-universe, and ERP Universe processes to retrieve ERP data for 10 randomly selected surgery patients. Results: The total times to process data variables for all 10 patients for the manual, five universe, and ERP Universe processes were 510, 111, and 76 min, respectively. Shifting from the five-universe or manual process to the ERP Universe resulted in decreases in time of 32% and 85%, respectively. Conclusion: The ERP Universe improves time spent collecting, analysing, and reporting ERP elements without increasing operational costs or interrupting workflow. Implications: Manual data abstraction places significant burden on resources. The creation of a singular instrument dedicated to ERP data abstraction greatly increases the efficiency in which clinicians and supporting staff can query adherence to an ERP protocol.

Background: The use of risk-stratified pancreatectomy care pathways (RSPCPs) is associated with reduced length of stay (LOS). This study sought to evaluate the impact of successive pathway revisions with the hypothesis that high-risk patients require iterative pathway revisions to optimize outcomes., Study Design: A prospectively maintained database (October 2016 to December 2021) was evaluated for pancreaticoduodenectomy patients managed with RSPCPs preoperatively assigned based on postoperative pancreatic fistula (POPF) risk. Launched in October 2016 (version [V] 1), RSPCPs were optimized in February 2019 (V2) and November 2020 (V3). Targeted pathway components included earlier nasogastric tube removal, diet advancement, reduced intravenous fluids and opioids, institution-specific drain fluid amylase cutoffs for early day 3 removal, and patient education. Primary outcome was LOS. Secondary outcomes included major complication (Accordion grade 3+), POPF (International Study Group for Pancreatic Surgery Grade B/C), and delayed gastric emptying (DGE)., Results: Of 481 patients, 234 were managed by V1 (83 high-risk), 141 by V2 (43 high-risk), and 106 by V3 (43 high-risk). Median LOS reduction was greatest in high-risk patients with a 7-day reduction (pre-RSPCP, 12 days; V1, 9 days; V2, 7 days; V3, 5 days), compared with low-risk patients (pre-pathway, 10 days; V1, 6 days; V2, 5 days; V3, 4 days). Complications decreased significantly among high-risk patients (V1, 45%; V2, 33%; V3, 19%; p < 0.001), approaching rates in low-risk patients (V1, 21%; V2, 20%; V3, 14%). POPF (V1, 33%; V2, 23%; V3, 16%; p < 0.001) and DGE (V1, 23%; V2, 22%; V3, 14%; p < 0.001) improved among high-risk patients., Conclusions: Risk-stratified pancreatectomy care pathways are associated with reduced LOS, major complication, Grade B/C fistula, and DGE. The easiest gains in surgical outcomes are generated from the immediate improvement in the patients most likely to be fast-tracked, but high-risk patients benefit from successive application of the learning health system model., (Copyright © 2023 by the American College of Surgeons. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To determine the effects of a preoperative, home-based exercise program on fitness and physical function in patients with pancreatic cancer., Background: We previously established a well-tolerated preoperative exercise program after finding a high frequency of sarcopenia and frailty in patients with pancreatic cancer., Methods: In this randomized, controlled trial (NCT03187951), patients with pancreatic cancer were randomized to Arm A: enhanced usual care or Arm B: prescribed aerobic and resistance exercise during neoadjuvant therapy. Patients received nutrition counseling and activity trackers. The primary endpoint was a 6-minute walk distance (6MWD; ≥14 meters improvement was clinically meaningful). Secondary endpoints included additional physical function tests, health-related quality of life, and clinical outcomes., Results: One hundred fifty-one patients were randomized. Objectively measured weekly activity (153.2±135.6 and 159.8±122.8 min in Arm A and B, respectively, P =0.62) and self-reported weekly moderate-to-strenuous physical activity (107.4±160.4 and 129.6±161.6 min in Arm A and Arm B, respectively, P =0.49) were similar, but weekly strength training sessions increased more in Arm B (by 1.8±1.8 vs 0.1±2.4 sessions, P <0.001). 6MWD improved in both Arm A (mean change 18.6±56.8 m, P =0.01) and Arm B (27.3±68.1 m, P =0.002). Quality of life and clinical outcomes did not significantly differ between arms. Pooling patients in both study groups, exercise, and physical activity was favorably associated with physical performance and clinical outcomes., Conclusions: In this randomized trial of prescribed exercise versus enhanced usual care during neoadjuvant therapy for pancreatic cancer, a high volume of physical activity and increased exercise capacity were observed in both arms, highlighting the importance of activity among patients preparing for surgery., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Neoadjuvant therapy (NAT) is increasingly used to treat patients with pancreatic ductal adenocarcinoma (PDAC). Patients with PDAC often show heterogenous responses to NAT with variable clinical outcomes, and the clinicopathologic parameters associated with these variable outcomes remain unclear. In this study, we systematically examined the clinicopathologic characteristics of 60 short-term survivors (overall survival < 15 months) and 149 long-term survivors (overall survival > 60 months) and compared them to 352 intermediate-term survivors (overall survival: 15-60 months) of PDAC who received NAT and pancreatoduodenectomy. We found that the short-term survivor group was associated with male gender ( p = 0.03), tumor resectability prior to NAT ( p = 0.04), poorly differentiated tumor histology ( p = 0.006), more positive lymph nodes ( p = 0.04), higher ypN stage ( p = 0.002), and higher positive lymph node ratio ( p = 0.03). The long-term survivor group had smaller tumor size ( p = 0.001), lower ypT stage ( p = 0.001), fewer positive lymph nodes ( p < 0.001), lower ypN stage ( p < 0.001), lower positive lymph node ratio ( p < 0.001), lower rate of lymphovascular invasion ( p = 0.001) and perineural invasion ( p < 0.001), better tumor response grading ( p < 0.001), and less frequent recurrence/metastasis ( p < 0.001). The ypN stage is an independent predictor of both short-term and long-term survivors by multivariate logistic regression analyses. In addition, tumor differentiation was also an independent predictor for short-term survivors, and tumor response grading and perineural invasion were independent predictors for long-term survivors. Our results may help to plan and select post-operative adjuvant therapy for patients with PDAC who received NAT and pancreatoduodenectomy based on the pathologic data.

Neoadjuvant FOLFIRINOX and gemcitabine/nab-paclitaxel (GemNP) therapies are increasingly used to treat patients with pancreatic ductal adenocarcinoma (PDAC). However, limited data are available on their clinicopathologic prognosticators. We examined the clinicopathologic factors and survival of 213 PDAC patients who received FOLFIRINOX with 71 patients who received GemNP. The FOLFIRINOX group was younger ( p < 0.01) and had a higher rate of radiation ( p = 0.049), higher rate of borderline resectable and locally advanced disease ( p < 0.001), higher rate of Group 1 response ( p = 0.045) and lower ypN stage ( p = 0.03) than the GemNP group. Within FOLFIRINOX group, radiation was associated with decreased lymph node metastasis ( p = 0.01) and lower ypN stage ( p = 0.01). The tumor response group, ypT, ypN, LVI and PNI, correlated significantly with both DFS and OS ( p < 0.05). Patients with the ypT0/T1a/T1b tumor had better DFS ( p = 0.04) and OS ( p = 0.03) than those with ypT1c tumor. In multivariate analysis, the tumor response group and ypN were independently prognostic factors for DFS and OS ( p < 0.05). Our study demonstrated that the FOLFIRINOX group was younger and had a better pathologic response than the GemNP group and that the tumor response group, ypN, ypT, LVI and PNI, are significant prognostic factors for survival in these patients. Our results also suggest that the tumor size of 1.0 cm is a better cut off for ypT2. Our study highlights the importance of systemic pathologic examination and the reporting of post-treatment pancreatectomies.

Neoadjuvant therapy is increasingly used to treat patients with pancreatic ductal adenocarcinoma (PDAC). Pathologic parameters of treated PDAC, including tumor (ypT) and lymph node (ypN) stage, and tumor response grading (TRG) are important prognostic factors in this group of patients. To our knowledge, a multifactorial prognostic score combining pathologic features including ypT, ypN, and TRG in treated PDAC patients has not been reported. Our cohort consisted of 398 PDAC patients who received neoadjuvant therapy and underwent pancreaticoduodenectomy at our institution. All pancreaticoduodenectomy specimens were grossly and microscopically evaluated using a standard protocol. The integrated pathologic score (IPS) was calculated as the sum of the scores for ypT, ypN, and TRG according to either the MD Anderson grading system (IPSMDA) or the College of American Pathologists (CAP) grading system (IPSCAP). The IPSMDA and IPSCAP were correlated with clinicopathologic parameters and patient survival. Using either IPSMDA or IPSCAP, PDAC patients were stratified into 3 distinct prognostic groups for both disease-free survival (DFS) ( P <0.001) and overall survival (OS) ( P <0.001). The IPSMDA and IPSCAP correlated with tumor differentiation, margin status, the American Joint Committee on Cancer (AJCC) stage, and tumor recurrence ( P <0.05). In multivariate analysis, IPSMDA, IPSCAP, margin status, and tumor differentiation were independent prognostic factors for both DFS ( P <0.05) and OS ( P <0.05). However, patients with AJCC stage IB, IIA, or IIB disease had no significant difference in either DFS or OS ( P >0.05). The IPS appears to provide improved prognostic information compared with AJCC staging for preoperatively treated patients with PDAC., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background/purpose: Risk-stratified pancreatectomy clinical pathways using regional anesthesia and multimodality analgesia have decreased overall opioid use, but the additional benefits of robotic surgery in opioid reduction for pancreatoduodenectomy (PD) are unknown. We compared the inpatient opioid use between robotic PD and open PD., Methods: Patients undergoing open PD within a protocol evaluating preincisional regional anesthetic block bundles were compared to consecutively-treated patients undergoing robotic PD identified from a prospectively maintained single-institutional database. Clinical characteristics, operative outcomes, pain scores and inpatient oral morphine equivalent (OME) use were compared between patients treated with robotic or open PD. Patients with a history of continuous-release opioid dependence were excluded., Results: Of 114 total patients, 25 underwent robotic PD and 89 underwent open PD. Intraoperative opioid use was not different (P = .87), nor were cumulative pain scores. Robotic PD patients used significantly fewer OMEs per day on postoperative days 1-4 (P = .039), used fewer total OMEs during hospitalization (robotic: median = 79, IQR 42.5-141; open: median = 126, IQR 61.3-203.8; P = .0036) and were discharged with fewer OMEs (robotic: median = 0, IQR 0-43.8; open: median = 25, IQR 0-75; P = .009) despite a shorter length of stay (robotic: median = 4, open: median = 5, P = .002)., Conclusions: Robotic PD patients required fewer inpatient OMEs than open PD while maintaining similar pain scores. A higher percentage of robotic PD patients tapered off of opioids prior to discharge than open surgery patients treated with a standardized opioid reduction protocol despite a shorter length of stay. These results provide a rationale for choosing robotic PD when feasible to minimize opioid use., (© 2022 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Objective: To characterize associations between carbohydrate antigen 19-9 (CA19-9) dynamics during neoadjuvant therapy (NT) and survival for patients with pancreatic ductal adenocarcinoma (PDAC)., Background: Although normalization of CA19-9 during NT is associated with improved outcomes following PDAC resection, we hypothesize that CA19-9 dynamics during NT can improve prognostication., Methods: Characteristics for patients with PDAC undergoing NT (July 2011-October 2018) with ≥3 CA19-9 results (bilirubin<2mg/dL) were collected and grouped by CA19-9 dynamics. Nonproducers (<1 U/ml) were excluded, and normal was ≤35 U/ml. Postresection survival was compared among groups., Results: Of 431 patients, 166 had eligible CA19-9 values. Median baseline CA19-9 was 98 U/ml. Overall 2-year postresection recurrence-free survival (RFS) and overall survival (OS) were 37% and 63%, respectively. Patients with normalization (53%) had improved 2-year RFS (47% vs. 28%, P = 0.01) and OS (75% vs. 49%, P = 0.01). CA19-9 dynamics during NT were analyzed by shape, direction, and normalization creating response types ("A-B-C-D-E"). Type A was "Always" decreasing to normalization, B "Bidirectional" with eventual normalization, C "Consistently" normal, D any "Decrease" without normalization, and E "Elevating" without normalization. Types A and B responses were associated with the longest postresection 2-year RFS (51% and 56%) and OS (75% and 92%, respectively) whereas Types D and E had the worst outcomes. After adjusting for node-positivity, perineural invasion, and margin-positivity, CA19-9 response types were independently associated with both RFS and OS, and predicted outcomes are better than CA19-9 normalization alone (likelihood ratio test RFS P < 0.001, OS P = 0.01)., Conclusions: This novel A-B-C-D-E classification of CA19-9 dynamics during NT was associated with postresection outcomes more precisely than CA19-9 normalization alone., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: In contrast to pancreatic ductal adenocarcinoma (PDAC), the risks of pancreatectomy for mucinous pancreatic cysts (MCs) are balanced against the putative goal of removing potentially malignant tumors. Despite undergoing similar operations, different rates of perioperative complications and morbidity between MC and PDAC patient populations may affect recommendations for resection. We therefore sought to compare the rates of postoperative complications between patients undergoing pancreatectomies for MCs or PDAC., Methods: A prospectively maintained institutional database was used to identify patients who underwent surgical resection for MCs or PDAC from July 2011 to August 2019. Patient demographics, complications, and perioperative data were compared between groups., Results: A total of 103 patients underwent surgical resection for MCs and 428 patients underwent resection for PDAC. Combined major 90-day postoperative complications were similar between MC and PDAC patients undergoing pancreaticoduodenectomy (PD, 32.5% vs. 20.0%, p = 0.068) or distal pancreatectomy (DP, 30.2% vs. 20.5%, p = 0.172). The most frequent complications were postoperative pancreatic fistula (POPF), abscess, and postoperative bleeding. The incidence of 90-day ISGPS Grade B/C POPF was higher in cyst patients undergoing PD (17.5% vs. 4.1%, p = 0.003) but not DP (25.4% vs. 20.5%, p = 0.473). No significant differences in operative time or length of stay between MCs and PDAC cohorts were observed., Conclusions: POPFs occur more frequently and at higher grades in patients undergoing PD for MCs than for PDAC and should inform patient selection. Accordingly, the perioperative management of MC patients undergoing PD should emphasize POPF risk mitigation., (© 2022. The Society for Surgery of the Alimentary Tract.)

Background: Normal(ization) of serum carbohydrate 19-9 (CA19-9) before/after surgery has not been compared in patients with pancreatic adenocarcinoma (PDAC) treated with neoadjuvant therapy (NT) versus surgery-first (SF)., Methods: Characteristics for patients with PDAC who underwent resection from July 2011 to October 2018 were collected. Patients with pre-/postoperative CA19-9, bilirubin <2 mg/dL, and initial CA19-9 > 1 U/ml were included. Overall survival (OS) and recurrence-free survival (RFS) were compared by pre-/postoperative CA19-9., Results: In patients receiving NT, normal pre/postoperative CA19-9 ("NT nl/nl ") was associated with median RFS and OS (26 and 77mo), followed by those who normalized after surgery ("NT abnl/nl " 16 and 44mo). For SF patients, normal pre-/postoperative CA19-9 ("SF nl/nl ") was associated with median RFS and OS (115 and not estimable mo), followed by those who normalized after resection ("SF abnl/nl " 18 and 49mo). Groups "NT abnl/abnl " and "SF abnl/abnl " with elevated CA19-9 both before and after resection had the worst median RFS and OS durations., Conclusions: While a normal(ized) postoperative CA19-9 may result in similar survival as preoperative normal(ization), postoperative normalization failed to occur in nearly 30% of SF patients. NT should be considered in patients presenting with elevated CA19-9. If considering SF, ideal patients may include those with normal CA19-9 at presentation., (© 2022 Wiley Periodicals LLC.)

Background: Minimally invasive, robotic gastrectomy is associated with better short-term outcomes and quicker functional recovery. However, the degree to which the robotic approach influences postoperative pain and opioid use after gastrectomy is unknown. Our primary aim was to determine whether the robotic approach to gastrectomy reduces postoperative opioid use compared with the open approach., Methods: Patients who underwent gastrectomy (November 2018 to September 2021) were identified retrospectively. Clinical characteristics, short-term surgical outcomes, oral morphine equivalent (OME) use, and pain scores were collected. Both groups were managed through an enhanced recovery program in the perioperative period., Results: Of 81 patients, 50 underwent open and 31 underwent robotic gastrectomy. Compared with open gastrectomy patients, robotic gastrectomy patients had longer surgery time (360 vs. 288 min), less blood loss (50 vs. 138 mL), and shorter hospital stay (4 vs. 6 days) (all medians, P < 0.001). Robotic gastrectomy patients used lower OMEs on postoperative days 0-4 (all P < 0.05) and in total for days 0-4 (total mean dose 65.0 vs. 169.5 mg; P < 0.001) than did open gastrectomy patients. The robotic gastrectomy patients were prescribed a lower mean OME dose than the open gastrectomy patients (19.0 vs. 29.0 mg, respectively; P = 0.001). Multivariable analysis showed that robotic approach was associated with lower opioid use (odds ratio 3.70; 95% CI 1.01-14.3; P = 0.049)., Conclusions: Compared with open gastrectomy, robotic gastrectomy reduces opioid use in the early postoperative period and is associated with fewer OME discharge prescriptions and shorter hospital stay., (© 2022. Society of Surgical Oncology.)

Background: This study aimed to determine the clinical relevance of putative radiographic and serologic metrics of chemotherapy response in patients with localized pancreatic cancer (LPC) who do not undergo pancreatectomy. Studies evaluating the response of LPC to systemic chemotherapy have focused on histopathologic analyses of resected specimens, but such specimens are not available for patients who do not undergo resection. We previously showed that changes in tumor volume and CA 19-9 levels provide a clinical readout of histopathologic response to preoperative therapy., Methods: Our institutional database was searched for patients with LPC who were treated with first-line chemotherapy between January 2010 and December 2017 and did not undergo pancreatectomy. Radiographic response was measured using RECIST 1.1 and tumor volume. The volume of the primary tumor was compared between pretreatment and posttreatment images. The percentage change in tumor volume (%Δvol) was calculated as a percentage of the pretreatment volume. Serologic response was measured by comparing pretreatment and posttreatment CA 19-9 levels. We established 3 response groups by combining these metrics: (1) best responders with a decline in %Δvol in the top quartile and in CA 19-9, (2) nonresponders with an increase in %Δvol and in CA 19-9, and (3) other patients., Results: This study included 329 patients. Individually, %Δvol and change in CA 19-9 were associated with overall survival (OS) (P≤.1), but RECIST 1.1 was not. In all, 73 patients (22%) were best responders, 42 (13%) were nonresponders, and there were 214 (65%) others. Best responders lived significantly longer than nonresponders and others (median OS, 24 vs 12 vs 17 months, respectively; P<.01). A multivariable model adjusting for type of chemotherapy regimen, number of chemotherapy doses, and receipt of radiotherapy showed that best responders had longer OS than did the other cohorts (hazard ratio [HR], 0.35; 95% CI, 0.21-0.58 for best responders, and HR, 0.55; 95% CI, 0.37-0.83 for others)., Conclusions: Changes in tumor volume and serum levels of CA 19-9-but not RECIST 1.1-represent reliable metrics of response to systemic chemotherapy. They can be used to counsel patients and families on survival expectations even if pancreatectomy is not performed.

Background: The value of neoadjuvant radiotherapy (RT) after 5-fluorouracil with leucovorin, oxaliplatin, and irinotecan, with or without dose modifications [(m)FOLFIRINOX], for patients with borderline resectable (BR) pancreatic ductal adenocarcinoma (PDAC) is uncertain., Methods: We conducted an international retrospective cohort study including consecutive patients with BR PDAC who received (m)FOLFIRINOX as initial treatment (2012-2019) from the Trans-Atlantic Pancreatic Surgery Consortium. Because the decision to administer RT is made after chemotherapy, patients with metastases or deterioration after (m)FOLFIRINOX or a performance score ≥2 were excluded. Patients who received RT after (m)FOLFIRINOX were matched 1:1 by nearest neighbor propensity scores with patients who did not receive RT. Propensity scores were calculated using sex, age (≤70 vs >70 years), WHO performance score (0 vs 1), tumor size (0-20 vs 21-40 vs >40 mm), tumor location (head/uncinate vs body/tail), number of cycles (1-4 vs 5-8 vs >8), and baseline CA 19-9 level (≤500 vs >500 U/mL). Primary outcome was overall survival (OS) from diagnosis., Results: Of 531 patients who received neoadjuvant (m)FOLFIRINOX for BR PDAC, 424 met inclusion criteria and 300 (70.8%) were propensity score-matched. After matching, median OS was 26.2 months (95% CI, 24.0-38.4) with RT versus 32.8 months (95% CI, 25.3-42.0) without RT (P=.71). RT was associated with a lower resection rate (55.3% vs 72.7%; P=.002). In patients who underwent a resection, RT was associated with a comparable margin-negative resection rate (>1 mm) (70.6% vs 64.8%; P=.51), more node-negative disease (57.3% vs 37.6%; P=.01), and more major pathologic response with <5% tumor viability (24.7% vs 8.3%; P=.006). The OS associated with conventional and stereotactic body RT approaches was similar (median OS, 25.7 vs 26.0 months; P=.92)., Conclusions: In patients with BR PDAC, neoadjuvant RT following (m)FOLFIRINOX was associated with more node-negative disease and better pathologic response in patients who underwent resection, yet no difference in OS was found. Routine use of RT cannot be recommended based on these data.

Introduction: The initial settings on an intravenous patient-controlled analgesia (IV-PCA) pump can represent a significant source of postoperative opioid exposure. The primary aim of this study was to evaluate the impact of first day IV-PCA use on total inpatient opioid use after open pancreatectomy, before and after standardization of initial dosing., Methods: Inpatient oral morphine equivalents (OMEs) were reviewed for pancreatectomy patients treated with IV-PCA at a single institution before and after (3/2016-8/2017 versus 3/2019-11/2020) implementation of a standardized initial IV-PCA dosing regimen (initial limit 0.1 mg hydromorphone, or 1 mg OME, every 10 min as needed). IV-PCA OME in the first 24 h and the total inpatient OME were compared between cohorts., Results: Of 220 total patients, 132 were in the prestandardization (PRE) historical cohort. A first-24-h IV-PCA use was different (PRE median 95 mg versus poststandardization [POST] 15 mg, P < 0.001). The median total inpatient OME was different (P < 0.001) between PRE (525 mg, interquartile range [IQR] 239-951 mg) and POST patients (129 mg, IQR 65-204 mg) with 77% (median 373 mg) of total inpatient OMEs contributed by IV-PCA in the PRE and 56% (median 64 mg) in the POST cohorts. There were similar patient-reported pain scores between groups., Conclusions: Standardizing initial IV-PCA settings was associated with a reduced first-24-h opioid exposure, proportional and absolute total IV-PCA use, and total inpatient OMEs. Because of the contribution of an IV-PCA to the total inpatient opioid exposure, purposeful reduction or omission of an IV-PCA is critical to perioperative opioid reduction strategies., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Large pragmatic studies of patients who received 5-fluorouracil with leucovorin, irinotecan, and oxaliplatin ([m]FOLFIRINOX) as initial treatment for localized pancreatic ductal adenocarcinoma (PDAC) are lacking. This study aimed to provide realistic estimates of oncologic outcomes in these patients., Methods: This international retrospective cohort study included all consecutive patients presenting with localized PDAC who received at least 1 cycle of (m)FOLFIRINOX as initial treatment in 5 referral centers from the United States and the Netherlands (2012-2019). Primary outcome was median overall survival (OS), calculated from the date of tissue diagnosis, assessed using Kaplan-Meier estimates. Log-rank test was used to compare OS between groups. A Cox proportional hazards regression model was used to assess prognostic baseline factors for OS. All statistical tests were 2-sided., Results: Overall, 1835 patients were included, of whom 958 (52.2%) had locally advanced (LA), 531 (28.9%) had borderline resectable (BR), and 346 (18.9%) had potentially resectable (PR) PDAC. The median number of (m)FOLFIRINOX cycles was 6 (interquartile range = 4-8). Subsequent treatment included second chemotherapy (12.9%), radiotherapy (49.0%), and resection (37.9%). The resection rate was 17.6% for LA, 53.1% for BR, and 70.5% for PR PDAC (P < .001). The margin-negative resection rate (>1 mm) was 55.2% for LA, 62.6% for BR, and 79.2% for PR PDAC (P < .001). The median OS was 18.7 months (95% confidence interval [CI] = 17.7 to 19.9 months) for LA, 23.2 months (95% CI = 21.0 to 25.7 months) for BR, and 31.2 months (95% CI = 26.2 to 36.6 months) for PR PDAC (P < .001). The median OS for 695 patients who underwent a resection was 38.3 months (95% CI = 36.1 to 42.0 months). Independent prognostic factors at baseline for worse OS were more advanced stage, worse performance status, baseline carbohydrate antigen (CA) 19-9 > 500 U/mL, and body mass index ≤18.5 kg/m2., Conclusions: This large international cohort study provides realistic estimates of resection rates and survival in patients with LA, BR, and PR PDAC who started (m)FOLFIRINOX treatment in PDAC referral centers., (© The Author(s) 2022. Published by Oxford University Press.)

Objective: The primary aim was to compare overall survival (OS) between neoadjuvant therapy (NT) and surgery-first (SF) patients with pancreatic adenocarcinoma (PDAC) by nodal stage using the American Joint Commission on Cancer 8th Edition (AJCC8)., Background: Rates of nodal positivity are consistently lower following NT versus SF sequencing. It's unclear whether post-NT nodal stage (ypNx) has similar survival compared to SF (pNx) using AJCC8., Methods: This is a single-institution retrospective cohort study with routine consideration of NT. Patients undergoing PDAC resection from 2010 to 2018 were analyzed and OS compared by nodal stage using AJCC8., Results: Of 450 total patients, 24% were treated with SF and 76% NT. SF patients had potentially resectable disease in 97% of the cases, whereas NT patients had more advanced clinical stages at diagnosis: borderline resectable 34%, locally advanced 5%. NT patients had higher rates of node-negativity (52.4% vs 22.7%) and lower rates of pathologic N2 disease (19.1% vs 43.6%) vs. SF (p < 0.001). For each pathologic nodal stage, SF and NT groups had similar 5-year OS [pN0/ypN0 52.7% vs. 53.6%, p = 0.723], [pN1/ypN1 37.0% vs. 36.7%, p = 0.872], and [pN2/ypN2 16.6% vs. 21.0%, p = 0.508]., Conclusions: AJCC8 stratifies outcomes for each post-NT nodal stage similar to SF counterparts. Despite presenting with more advanced clinical stage, NT patients had lower rates of nodal metastases yet comparable OS when stratified by final nodal status. These data provide both hope for patients with obvious radiographic nodal disease at presentation and further support for considering NT sequencing for most patients diagnosed with localized PDAC., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Planned pancreatoduodenectomy (PD) for pancreatic adenocarcinoma (PDAC) can be aborted due to intraoperative findings. There is little guidance regarding the need for prophylactic bypass following an aborted PD to prevent symptomatic biliary obstruction or gastric outlet obstruction (GOO) postoperatively. The aim of this study was to characterize postoperative interventions and postsurgical survival in patients following aborted PD., Methods: Patients with PDAC treated with neoadjuvant therapy and staging laparoscopy prior to planned PD between 2010 and 2015 were reviewed for aborted PDs. Data on postoperative biliary obstruction, GOO, procedural intervention, and postsurgical survival were analyzed., Results: Of 271 planned PDs, 47 (17.3%) were aborted. Thirty-six patients had ≥ 2 months of follow-up data and were included. Six patients underwent hepaticojejunostomy and nine patients underwent gastrojejunostomy at the time of the aborted PD. Sixteen of 30 patients (53%) without a surgical biliary bypass required endoscopic intervention, but none required palliative surgery. Ten of 27 patients (37%) without an operative gastrojejunostomy required intervention, but none required palliative surgery. Endoscopic or percutaneous therapy was required to treat 13/16 (81%) patients who presented with postoperative biliary obstructions and 6/10 (60%) of GOOs. Median survival following aborted PD was 13.3 months (CI 8.9-17.7). There were no differences in survival when comparing patients who developed a biliary obstruction (p = 0.92) or GOO (p = 0.90) to asymptomatic patients., Conclusions: Following aborted PD, patients commonly develop obstructive symptoms. However, these symptoms can generally be managed without surgical intervention. In asymptomatic patients, preemptive surgical bypasses are not required at the time of aborted PD., (© 2021. The Society for Surgery of the Alimentary Tract.)

Objective: Intra-tumoral expression of the serine hydrolase carboxylesterase 2 (CES2) contributes to the activation of the pro-drug irinotecan in pancreatic ductal adenocarcinoma (PDAC). Given other potential roles of CES2, we assessed its regulation, downstream effects, and contribution to tumor development in PDAC., Methods: Association between the mRNA expression of CES2 in pancreatic tumors and overall survival was assessed using The Cancer Genome Atlas. Cell viability, clonogenic, and anchorage-independent growth assays as well as an orthotopic mouse model of PDAC were used to evaluate the biological relevance of CES2 in pancreatic cancer. CES2-driven metabolic changes were determined by untargeted and targeted metabolomic analyses., Results: Elevated tumoral CES2 mRNA expression was a statistically significant predictor of poor overall survival in PDAC patients. Knockdown of CES2 in PDAC cells reduced cell viability, clonogenic capacity, and anchorage-independent growth in vitro and attenuated tumor growth in an orthotopic mouse model of PDAC. Mechanistically, CES2 was found to promote the catabolism of phospholipids resulting in HNF4α activation through a soluble epoxide hydrolase (sEH)-dependent pathway. Targeting of CES2 via siRNA or small molecule inhibitors attenuated HNF4α protein expression and reduced gene expression of classical/progenitor markers and increased basal-like markers. Targeting of the CES2-sEH-HNF4α axis using small molecule inhibitors of CES2 or sEH reduced cell viability., Conclusions: We establish a novel regulatory loop between CES2 and HNF4α to sustain the progenitor subtype and promote PDAC progression and highlight the potential utility of CES2 or sEH inhibitors for the treatment of PDAC as part of non-irinotecan-containing regimens., (Copyright © 2021 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Background and Objectives: The impact of perioperative blood transfusion (PBT) on outcomes for pancreatic ductal adenocarcinoma (PDAC) patients given multimodality therapy (MMT) remains undefined. We sought to evaluate the association of PBT with survival after PDAC resection., Methods: Pancreatectomy patients (July 2011-December 2017) who received MMT were abstracted from a prospective database. Overall survival (OS) was compared by PBT within 30 days, 24 h (24HR-BT), or 24 h until 30 days (Postop-BT)., Results: Most (76.6%) of 312 MMT patients underwent neoadjuvant therapy (NT). Eighty-nine patients (28.5%) received PBT; 58 (18.6%) 24HR-BT, and 31 (9.9%) Postop-BT. Compared with surgery-first, NT patients received more 24HR-BTs (22.2% vs. 6.8%, p = 0.003) and PBTs overall (32.6% vs. 15.1%, p = 0.004). Overall median OS was 45 months. The association of PBT with shorter median OS appeared limited to first 24-h transfusions (34 months 24HR-BT vs. 48 months Postop-BT vs. 53 months no-PBT, p = 0.009) and was dose-dependent, with a median OS of 52 months for 0 units 24HR-BT, 35 months for 1 unit, and 25 months for ≥2 units (p = 0.004). Independent predictors of OS included node-positivity (hazard ratio [HR]: 1.93, p < 0.001), perineural invasion (HR: 1.64, p = 0.050), postoperative pancreatic fistula (HR: 1.94, p = 0.018), and 24HR-BT (HR: 1.75, p = 0.001)., Conclusions: Transfusions given within 24 h are associated with dose-dependent decreases in survival after pancreatectomy for PDAC., (© 2021 Wiley Periodicals LLC.)

Background: Glucose-regulated protein 78 (GRP78) plays an essential role in protein folding, transportation, and degradation, thus regulates ER homeostasis and promotes cell survival, proliferation and invasion. GRP78 expression in PDAC patients who received neoadjuvant therapy has not been reported., Methods: This retrospective study of resected PDAC patients included 125 patients treated with neoadjuvant therapy (NAT) and 140 patients treated with surgery first (SF). The expression of GRP78 was evaluated by immunohistochemistry on tissue microarrays and the results were correlated with clinicopathologic parameters and survival., Results: GRP78 expression was higher in SF patients compared to NAT patients (P < 0.001). In SF cohort, the median disease-free survival (DFS) and overall survival (OS) for patients with GRP78-positive tumors were 11.2 months and 25.0 months, respectively, compared to DFS of 52.1 months (P = 0.008) and OS of 69.5 months (P = 0.02) for those with GRP78-negative tumors. GRP78 expression correlated with higher frequency of recurrent/metastasis (P = 0.045). In NAT cohort, GRP78 expression correlated with shorter OS (P = 0.03), but not DFS (P = 0.08). GRP78 expression was an independent prognosticator for both DFS (P = 0.02) and OS (P = 0.049) in SF cohort and was an independent prognosticator for OS (P = 0.03), but not for DFS (P = 0.06) in NAT cohort by multivariate analysis., Conclusions: Our study showed that GRP78 expression in NAT cohort is lower than that in SF cohort. GRP78 expression correlated with shorter survival in both SF and NAT patients. Our findings suggest that targeting GRP78 may help to improve the prognosis in PDAC patients., Competing Interests: Declaration of competing interest The authors declare no conflict of interest to this work., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Delayed gastric emptying (DGE) is a frequent complication after pancreaticoduodenectomy (PD) that impairs recovery and quality of life. The purpose of this study was to assess the impact risk-stratified pancreatectomy clinical pathways (RSPCPs) had on delayed gastric emptying (DGE) and identify factors associated with DGE in a contemporary period., Methods: A single-institution, prospective database was queried for consecutive PDs during July 2011-November 2019. Using international definitions, DGE rates were compared between periods before and after RSPCPs were implemented in 2016, classifying patients according to their postoperative pancreatic fistula (POPF) risk. Risk factors were analyzed to identify modifiable targets., Results: Among 724 elective PDs, 552 (76%) were for adenocarcinoma and 172 (24%) for other diagnoses. Of the 197 (27%) patients with DGE, 119 (16%) had type A, 41 (6%) type B, and 38 (5%) type C. In the overall cohort, DGE rates were higher with pylorus-preserving vs. classic hand-sewn reconstruction (odds ratio [OR] - 1.84; p < 0.001), postoperative abscess (OR - 2.54; p = 0.003), and non-white patients (p = 0.007), but lower after implementation of RSPCPs (OR - 0.34, p < 0.001). In the 374 patients treated with RSPCPs, only 17% (n = 65/374) developed DGE. Patients with protocol-compliant NGT removal ≤ 48 h were less likely to experience DGE (OR - 1.46, p = 0.042)., Conclusion: Our data suggest that implementation of preoperatively assigned RSPCPs as a care bundle was the most important factor in decreasing DGE. These gains were accentuated in patients who underwent early nasogastric tube removal and had a classic hand-sewn gastro-jejunostomy reconstruction. Application of these modifiable factors is generalizable with low implementation barriers., (© 2020. The Society for Surgery of the Alimentary Tract.)

Background: CD73, a newly recognized immune checkpoint mediator, is expressed in several types of malignancies. However, CD73 expression and its impact on tumor microenvironment and clinical outcomes in pancreatic ductal adenocarcinoma (PDAC) remain unclear., Methods: This study included two cohorts: 138 patients from our institution (MDA) and 176 patients from TCGA dataset. CD73 expression, CD4 + , CD8 + , CD21 + and CD45RO + tumor infiltrating lymphocytes (TILs) were evaluated by immunohistochemistry using tissue microarrays. The results of CD73 expression were correlated with clinicopathologic parameters, survival and TILs., Results: CD73 overexpression correlated with poor differentiation (P = 0.002) and tumor size (P = 0.049). For CD73-low group, median overall survival (OS) and recurrence-free survival (RFS) were 26.9 ± 3.8 months and 12.6 ± 2.6 months, respectively, compared to 16.9 ± 4.4 months (P = 0.01) and 7.9 ± 1.2 months (P = 0.01), respectively, in CD73-high group. CD73 was an independent predictor for both RFS (P = 0.02) and OS (P = 0.01) by multivariate variate analysis. Similarly, CD73-high tumors had significantly shorter OS than CD73-low tumors in TCGA dataset (P < 0.0001). CD73-high correlated with decreased CD4 + TILs in MDA cohort and decreased CD8A and CR2 (CD21) expression in TCGA cohort., Conclusions: CD73 overexpression is associated with poor differentiation, tumor size, and shorter survival, and is an independent prognostic factor in PDAC patients. CD73 overexpression is associated with decreased CD4 + , CD8 + and CD21 + TILs. Our data support that CD73 plays an important role in immunosuppressive tumor microenvironment and promote tumor progression in PDAC., (Copyright © 2021 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Recent studies defined a potentially important role of the microbiome in modulating pancreatic ductal adenocarcinoma (PDAC) and responses to therapies. We hypothesized that antibiotic usage may predict outcomes in patients with PDAC. We retrospectively analyzed clinical data of patients with resectable or metastatic PDAC seen at MD Anderson Cancer from 2003 to 2017. Demographic, chemotherapy regimen and antibiotic use, duration, type, and reason for indication were recorded. A total of 580 patients with PDAC were studied, 342 resected and 238 metastatic patients, selected retrospectively from our database. Antibiotic use, for longer than 48 hrs, was detected in 209 resected patients (61%) and 195 metastatic ones (62%). On resectable patients, we did not find differences in overall survival (OS) or progression-free survival (PFS), based on antibiotic intake. However, in the metastatic cohort, antibiotic consumption was associated with a significantly longer OS (13.3 months vs. 9.0 months, HR 0.48, 95% CI 0.34-0.7, p = 0.0001) and PFS (4.4 months vs. 2 months, HR 0.48, 95% CI 0.34-0.68, p = <0.0001). In multivariate analysis, the impact of ATB remained significant for PFS (HR 0.59, p = 0.005) and borderline statistically significant for OS (HR 0.69, p = 0.06). When we analyzed by chemotherapy regimen, we found that patients who received gemcitabine-based chemotherapy as first-line therapy (n = 118) had significantly prolonged OS (HR 0.4, p 0.0013) and PFS (HR 0.55, p 0.02) if they received antibiotics, while those receiving 5FU-based chemotherapy (n = 98) had only prolonged PFS (HR 0.54, p = 0.03). Antibiotics-associated modulation of the microbiome is associated with better outcomes in patients with metastatic PDAC., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Administration of dexamethasone to mitigate postoperative nausea and vomiting has been suggested to improve short- and long-term outcomes after pancreatic ductal adenocarcinoma (PDAC) resection. This study aimed primarily to evaluate these hypotheses in a contemporary patient cohort treated with multimodality therapy., Methods: The clinicopathologic and perioperative characteristics of consecutive resected PDAC patients (July 2011 to October 2018) were analyzed from a prospectively maintained database. Intraoperative administration of dexamethasone (4-10 mg) was retrospectively abstracted from the electronic medical record., Results: The majority of 373 patients (59.8%) received intraoperative dexamethasone. Most of these patients underwent neoadjuvant therapy (75.3%), were potentially resectable at presentation (69.7%), and underwent pancreaticoduodenectomy (79.9%). Women were more likely to receive dexamethasone than men (69.9 vs 30.1%; p < 0.001). The cohorts were otherwise clinically similar. Intraoperative dexamethasone was not associated with differences in postoperative major complications (PMCs) (21.1 vs 19.3%; p = 0.68), postoperative pancreatic fistulas (6.3 vs 6.7%; p = 0.88), or composite infectious complications (28.7 vs 24.7%; p = 0.39). Dexamethasone was not associated with any improvement in median recurrence-free survival (RFS) (17 vs 17 months; p = 0.99) or overall survival (OS) (46 vs 43 months; p = 0.90). After adjustment for clinical factors including margin status, clinical classification, tumor size, and dexamethasone, the only factors independently associated with OS were pathologic node-positivity (hazard ratio [HR], 1.80, 95% confidence interval [CI], 1.32-2.47), perineural invasion (HR, 2.02; 95% CI, 1.23-3.31), multimodality therapy (HR, 0.30; 95% CI, 0.13-0.70), and PMCs (HR, 1.64; 95% CI, 1.17-2.29) (all p < 0.006)., Conclusions: Dexamethasone failed to demonstrate any protective advantage in terms of mitigating short-term PMCs or infectious complications, or to confer any long-term survival benefit. Tumor biology, multimodality therapy, and PMCs remain the main prognostic factors after PDAC resection.

Objectives: Tumor size measurement is critical for accurate tumor staging in patients with pancreatic ductal adenocarcinoma (PDAC). However, accurate tumor size measurement is challenging in patients who received neoadjuvant therapy before resection, due to treatment-induced fibrosis and tumor invasion beyond the grossly identified tumor area. In this study, we evaluated the correlation between the tumor size and tumor volume measured on post-therapy computed tomography (CT) scans and the pathological measurement. Also, we investigated the correlation between these measurements and clinicopathological parameters and survival., Materials and Methods: Retrospectively, we evaluated 343 patients with PDAC who received neoadjuvant therapy, followed by pancreaticoduodenectomy and had pre-operative pancreatic protocol CT imaging. We measured the longest tumor diameter (RadL) and the radiological tumor volume (RadV) on the post-therapy CT scan, then we categorized RadL into four radiologic tumor stages (RTS) based on the current AJCC staging (8th edition) protocol and RadV based on the median. Pearson correlation or Spearman's coefficient (δ), T-test and ANOVA was used to test the correlation between the radiological and pathological measurement. Chi-square analysis was used to test the correlation with the tumor pathological response, lymph-node metastasis and margin status and Kaplan-Meier and Cox-proportional hazard for survival analysis. P-value < 0.05 was considered significant., Results: As a continuous variable, RadL showed a positive linear correlation with the post-therapy pathologic tumor size in the overall patient population (Pearson correlation coefficient: 0.72, P < 0.001) and RadV (δ: 0.63, p < 0.0001). However, there was no correlation between RadL and pathologic tumor size in patients with ypT0 and those with pathologic tumor size of ≤1.0 cm. Post-therapy RTS and RadV group correlated with ypT stage, tumor response grades using either CAP or MDA grading system, distance of superior mesenteric artery margin and tumor recurrence/metastasis., Conclusion: Although RadL tends to understage ypT in PDAC patients who had no radiologically detectable tumor or small tumors (RTS0 or RTS1), radiologic measurement of post-therapy tumor size may be used as a marker for the pathologic tumor staging and tumor response to neoadjuvant therapy., (Copyright © 2020 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Purpose: The combination chemotherapy of fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) has provided clinically meaningful improvement for pancreatic ductal adenocarcinoma (PDAC). We previously uncovered a role for the serine hydrolase carboxylesterase 2 (CES2) in mediating intratumoral activation of the prodrug irinotecan, a constituent of FOLFIRINOX. We aimed to further test the predictive value of CES2 for response to irinotecan using patient-derived xenograft (PDX) models and to elucidate the determinants of CES2 expression and response to FOLFIRINOX treatment among patients with PDAC., Methods: PDXs were engrafted subcutaneously into nude mice and treated for 4 weeks with either saline control or irinotecan. CES2 and hepatocyte nuclear factor 4 alpha (HNF4A) expression in PDAC tissues was evaluated by immunohistochemical and Western blot analysis. Kaplan-Meier and Cox regression analyses were applied to assess the association between overall survival and hemoglobin A1C (HbA1C) levels in patients who underwent neoadjuvant FOLFIRINOX treatment., Results: High CES2 activity in PDAC PDXs was associated with increased sensitivity to irinotecan. Integrated gene expression, proteomic analyses, and in vitro genetic experiments revealed that nuclear receptor HNF4A, which is upregulated in diabetes, is the upstream transcriptional regulator of CES2 expression. Elevated CES2 protein expression in PDAC tissues was positively associated with a history of type 2 diabetes (odds ratio, 4.84; P = .02). High HbA1C levels were associated with longer overall survival in patients who received neoadjuvant FOLFIRINOX treatment ( P = .04)., Conclusion: To our knowledge, we provide, for the first time, evidence that CES2 expression is associated with a history of type 2 diabetes in PDAC and that elevated HbA1C, by predicting tumor CES2 expression, may represent a novel marker for stratifying patients most likely to respond to FOLFIRINOX therapy.

Introduction: Short-term outcomes after distal pancreatectomy (DP) for retroperitoneal (RP) tumors are unknown. We sought to identify rates of postoperative pancreatic fistula (POPF) and morbidity after en bloc DP with RP tumor resection., Methods: A retrospective review of 43 patients who underwent DP with RP tumor resection (1/2011-12/2017) was performed., Results: Seventeen patients had RP sarcoma, 12 renal cell carcinoma, 11 gastrointestinal stromal tumor, and 3 adrenocortical carcinoma. Grade III-IV complications occurred in 7 patients. Grade B POPF occurred in 14 patients, grade C POPF in none, and biochemical leak in 6. Of 22 patients who developed radiographically evident peri-pancreatic fluid collections, 7 required percutaneous drainage. The 90-day readmission rate was 33%., Conclusions: DP with RP tumor resection is associated with high rates of clinically relevant POPF compared to historical results for DP for primary pancreatic tumors. Multi-center studies to identify targetable predictors and risk mitigation strategies for POPF in this rare high-risk population are needed., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Evaluation of response to preoperative therapy for patients with pancreatic adenocarcinoma has been historically difficult. Therefore, preoperative regimens have generally been selected on the basis of baseline data such as radiographic stage and serum CA 19-9 level and then typically administered for a pre-specified duration as long as 6 months or more. The decision to proceed with resection following preoperative therapy likewise has rested upon the absence of disease progression rather than evidence for tumor response. This article reviews the basis for the evaluation of therapeutic response after preoperative therapy for pancreatic cancer in the existing scientific literature, and providing updates and new perspectives., (Copyright © 2020 Perri, Prakash and Katz.)

Background: Resection of the superior mesenteric and/or portal vein (SMV-PV) is increasingly performed with pancreatectomy for adenocarcinoma. We sought to analyze the impact of cancer at the transected edge(s) of the vein wall., Methods: Patients who underwent pancreatectomy with vein resection between 2003 and 2015 at a single center were evaluated. R1 resection was defined per guidelines from the American Joint Commission on Cancer and the College of American Pathologists. Specimens were also evaluated for the presence (V+) or absence (V-) of cancer cells at the transected edge(s) and depth of vein invasion., Results: Among 127 evaluated patients, 114 (90%) received preoperative therapy. R-status was categorized as margin-negative (R0)/V- (n = 72, 57%), R0/V+ (n = 19, 15%), margin-positive (R1)/V- (n = 24, 19%), and R1/V+ (n = 12, 9%). Patients with V- specimens had similar median durations of recurrence-free survival (RFS) (12 vs 9 months) and overall survival (OS) (30 vs 28 months) as did patients with V+ specimens (P > 0.05). In contrast, cancer invasion into the lumen was associated with RFS and OS (P < 0.05). Among patients who underwent R0 resection, V-status had no association with OS, RFS, or local control (P > 0.05)., Conclusion: Cancer invasion into the superior mesenteric and/or portal vein was adversely associated with survival, but cancer at the vein edge(s) was not. Transection of the SMV-PV through macroscopically normal vein may be performed to minimize resected vein length without fear of negatively affecting oncologic outcomes.

Purpose of Review: Pancreatic neuroendocrine tumors (pNETs) are a rare, heterogeneous group of pancreatic neoplasms with a wide range of malignant potential. They may manifest as noninfiltrative, slow-growing tumors, locally invasive masses, or even swiftly metastasizing cancers., Recent Findings: In recent years, because of the increasing amount of scientific literature available for pNETs, the classification, prognostic stratification criteria, and available consensus guidelines for diagnosis and therapy have been revised and updated., Summary: The vast majority of new pNET diagnoses consist of incidentally discovered lesions on cross-sectional imaging. The biologic behavior of pNETs is defined by the grade and stage of the tumor. Surgery is the only curative treatment and it, therefore, represents the first therapeutic choice for any localized pNET; however, recent evidence suggests that patients with small (<2 cm), nonfunctioning G1 tumors can be safely observed.An aggressive surgical approach towards liver metastases is recommended in selected cases, as well as liver-directed therapies for disease control. In the presence of unresectable progressive disease, somatostatin analogs, targeted therapies such as everolimus, peptide receptor radionuclide therapy, and systemic chemotherapy are all useful tools for prolonging survival.

Objectives: Neoadjuvant therapy (NT) is used for advanced pancreatic ductal adenocarcinoma (PDAC). No clear guidelines exist for switching therapies when patients do not respond to initial NT. We sought to characterize patients who underwent early switch from FOLFIRINOX to gemcitabine/nab-paclitaxel (GA) as NT for PDAC., Methods: We identified patients at a single institution switched from FOLFIRINOX to GA within the first 4 months of NT for PDAC during 2012-2017. We compared clinicopathologic data and oncologic outcomes., Results: Of 25 patients who met the criteria, 21 showed a serologic or radiographic response to GA; 11 (52%) reached resection. Responders had decreased carbohydrate antigen (CA) 19-9 levels from pretreatment to post-GA (P = 0.036). Resected responders had significantly decreased CA 19-9 comparing preswitch to post-GA (P = 0.048). The only predictor of GA response was prechemotherapy CA 19-9 of less than1000 U/mL (P = 0.021). Predictors of reaching resection were head/uncinate tumor (P = 0.010) and presenting stage lower than locally advanced (P = 0.041)., Conclusions: When patients do not respond to neoadjuvant FOLFIRINOX, early switch to GA should be considered. Future efforts should be directed toward identifying markers that will allow correct choice of initial therapy rather than attempting to rescue patients who respond poorly to first-line therapy.

Background: Perioperative blood transfusion (PBT) during resection of pancreatic adenocarcinoma (PDAC) has been linked to worse short-term and oncologic outcomes. However, little is known about contemporary rates of transfusion utilization among patients requiring pancreaticoduodenectomy with vein resection (PDVR). The primary aims of this study were to evaluate rates of PBT and to identify modifiable factors associated with PBT during PDVR., Methods: Patients with PDAC treated with preoperative therapy and PDVR (2008-15) were analyzed from a prospective, single-institution database., Results: Among 120 total patients, approximately half (52.5%) of all patients received PBT; rates decreased significantly in the most recent years [70.7%, 2008-10 vs. 36.8%, 2014-15 (p = 0.013)]. Lower preoperative hemoglobin, greater intraoperative percent drop in hemoglobin, increased EBL, and advanced age were all associated with PBT (p < 0.01). The only factors independently associated with PBT by multivariable analysis were age [OR-1.08 per year (95% CI 1.02-1.14)] and EBL [OR-1.30 per 100 mL, (95% CI 1.13-1.50)]., Conclusion: PBT for PDVR for PDAC have decreased, with only 1/3 of contemporary patients requiring PBT. As preoperative therapy and PDVR become more ubiquitous, addressing anemia during preoperative therapy and limiting EBL may reduce blood utilization. Re-evaluation of clinical thresholds for transfusions may further reduce transfusion rates., (Copyright © 2018 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background and Objectives: Venous patency rates after pancreaticoduodenectomy (PD) with portal vein (PV) resection are not well established, and the oncologic impact of portal vein thrombosis (PVT) is unknown. The primary aim of this study was to determine rates and predictors of PVT after PD with PV resection for pancreatic adenocarcinoma (PDAC)., Methods: A retrospective cohort study was performed on PDAC patients treated with preoperative therapy and PD with PV resection at a high-volume institution (2008-15). Primary outcomes were early and late PVT (≤ or >90 days of surgery). Secondary outcomes included major complications and OS., Results: Patients undergoing vein resection (N = 120) included 41.7% (N = 50) primary repair or patch venoplasty, 29.2% (N = 35) primary anastomosis, and 29.2% (N = 35) interposition graft. Thirty-four (28.3%) patients developed PVT (early 7.5% [N = 9]; late 20.8% [N = 25]). Late PVT was often detected concurrently with local recurrence (76.0%; N = 19). There was no association of PVT with vascular resection extent or complications (P > 0.05). On multivariable analysis, PVT was associated with worse OS (HR 2.2 [95% CI 1.34-3.5], P < 0.001)., Conclusions: Overall postoperative patency rates following PV resection PDAC were high. PVT is associated with worse OS, which appears less likely related to technical issues, but rather representative of disease biology., (© 2018 Wiley Periodicals, Inc.)