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Objective: The aim of this study was to evaluate the different phases of the learning curve for robotic distal pancreatectomy (RDP) in international expert centers., Summary Background Data: RDP is an emerging minimally invasive approach; however, only limited, mostly single center data are available on its safe implementation, including the learning curve., Methods: Consecutive patients undergoing elective RDP from 16 expert centers across three continents were included to assess the learning curve. Based on the first 100 RDPs at each center, three cutoffs were used to define the learning curve: operative time for competency, major complications (Clavien-Dindo grade ≥III) for proficiency, and textbook outcome for mastery. Clinical outcomes before and after the cutoffs were compared., Results: The learning curve analysis was conducted on 1109 of 2403 RDPs. Competency, proficiency, and mastery, respectively, were reached after 46, 63, and 73 RDP procedures. After competency, operative time decreased from 245 to 235 minutes (P=0.002). Attaining proficiency was reflected by a reduction in the rate of major complications from 20% to 15% (P=0.012), and mastery was associated with a higher proportion of patients with textbook outcome (71% vs. 63%; P=0.028). The postoperative pancreatic fistula rate remained stable along the learning curve, ranging between 18.5% and 21.5%. Previous laparoscopic experience accelerated the learning process by virtue of reduced operative time and an earlier decrease in major complications., Conclusion: Competency, proficiency, and mastery for RDP were reached after 46, 63, and 73 procedures, respectively, at international expert centers. The findings highlight that the learning curves for intraoperative parameters are completed earlier; however, extensive experience is needed to master RDP., Competing Interests: Conflict of interest: The authors declare that they have no conflict of interest. Conflict of interest: The authors declare that no conflict of interest exists. No grants and financial support were received for this study., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To validate the ISGPS definition and grading system of PPAP after pancreatoduodenectomy (PD)., Summary Background Data: In 2022, the International Study Group for Pancreatic Surgery (ISGPS) defined post-pancreatectomy acute pancreatitis (PPAP) and recommended a prospective validation of its diagnostic criteria and grading system., Methods: This was a prospective, international, multicenter study including patients undergoing PD at 17 referral pancreatic centers across Europe, Asia, Oceania, and the United States. PPAP diagnosis required the following three parameters: (1) postoperative serum hyperamylasemia /hyperlipasemia (POH) persisting on postoperative days 1 and 2, (2) radiologic alterations consistent with PPAP, and (3) a clinically relevant deterioration in the patient's condition. To validate the grading system, clinical and economic parameters were analyzed across all grades., Results: Among 2902 patients undergoing PD, 7.5% (n=218) developed PPAP (6.3% grade B and 1.2% grade C). POH occurred in 24.1% of patients. Hospital stay was associated with PPAP grades (No POH/PPAP 10 days (IQR 7-17) days, grade B 22 days (IQR 15-34) days, and grade C 43 days (IQR 27-54) days; P<0.001), as well as intensive care unit admission (No POH/PPAP 5.4%, grade B 12.6%, grade C 82.9%; P<0.010), and hospital readmission rates (No POH/PPAP 7.3%, grade B 16.1%, grade C 18.5%; P<0.05). Costs of grade B and C PPAP were 2 and 11 times greater than uncomplicated clinical course, resp. (P<0.001)., Conclusions: This first prospective, international validation study of the ISGPS definition and grading system for PPAP highlighted the relevant clinical and financial implications of this condition. These results stress the importance of routine screening for PPAP in patients undergoing PD., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background : Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths in the United States. Previous studies have indicated that microsatellite instability and deficient mismatch repair (MMR) may be associated with improved survival in patients with pancreatic cancer. Here, we aim to investigate the impact of deficient MMR (dMMR) status on oncologic outcomes in patients after resection of PDAC and periampullary adenocarcinoma. Methods : This is a single-institution, retrospective study based on a prospectively maintained database. Pancreatic ductal adenocarcinoma (N = 342) and periampullary adenocarcinoma patients (N = 76) who underwent pancreatic resection surgery between 2016 and 2021 were included. Immunohistochemistry staining results of MMR proteins and next-generation sequencing data were recorded. Cancer-type dependent Cox regression analyses were performed to assess overall and disease-free survival, which was complemented with a 1:2 propensity-score matching for each of the cancer types in order to compare oncologic outcomes. Results : A total of 418 pancreatic cancer patients were included in the analysis. Fifteen patients (3.5%) were diagnosed as dMMR (PDAC N = 7 and periampullary adenocarcinoma N = 8). Cox regression modeling of dMMR status interaction with TNM staging and cancer type revealed that dMMR status strongly improves overall survival ( p < 0.05). After propensity-score matching, Cox regression identified dMMR status as a significant marker of improved overall survival (HR = 0.27, 95%CI 0.09-0.88, p = 0.029). Conclusions : Overall, our findings suggest that dMMR status is associated with markedly improved survival outcomes in patients after resection of pancreatic and periampullary cancer. Future large-scale studies are needed to further validate this finding.

Background: Post-operative incisional hernia (IH) is a common complication following abdominal surgery. Data regarding IH after major pancreatic surgery are limited. We aim to evaluate the long-term risk of IH following major pancreatic resection., Methods: A dual-approach study: a large multi-institutional research network (RN) was investigated for IH incidence and risk factors in propensity-score matched survivors after pancreaticoduodenectomy (PD) and distal pancreatectomy (DP), was complemented by a patient-reported questionnaire., Results: RN analysis identified 22,113 patients that underwent pancreatic surgery. 11.0% of PD patients and 8.6% of DP patients developed IH (P < 0.0001). IH rates were higher with open surgery compared with minimally invasive approaches in PD (OR = 1.56, P = 0.03) and DP (OR = 1.94, P = 0.003). BMI>35 was found to correlate with increased IH rates for PD and DP (OR = 1.87, and OR = 1.86, respectively, P < 0.0001 each), as did postoperative intraabdominal infections (P < 0.0001). Patient-based survey of 104 patients, revealed that 16 patients (15%) reported post-operative IH during the follow-up period. BMI≥30, SSI and intra-abdominal abscesses were associated with increased IH risk (P < 0.05)., Conclusion: Improved survival after pancreatic resection has led to an increased prevalence of long-term surgical sequela. In this study, we demonstrate significant rates of IH among long-term survivors and assess potential risk factors., (Copyright © 2024 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Introduction: Endoscopic ultrasound (EUS)-guided lumen-apposing metal stents (LAMS) represent a novel tool in therapeutic endoscopy. However, the presence of LAMS may dissuade surgeons from operations with curative-intent. We report three clinical scenarios with deployment of LAMS in patients that subsequently underwent pancreaticoduodenectomy (PD)., Methods: Six patients identified from our IRB-approved pancreas cancer database had EUS-LAMS placement prior to PD. Patient, tumor, treatment-related variables, and outcomes are herein reported., Results: Two patients underwent a LAMS gastrojejunostomy (GJ) for duodenal obstruction. Another patient underwent LAMS choledochoduodenostomy (CDS) for malignant biliary obstruction. In three patients, a LAMS gastrogastrostomy or jejunogastrostomy was deployed post Roux-en-Y gastric bypass (RYGB) for a EUS-directed transgastric ERCP (EDGE) procedure. The hospital length of stay after LAMS placement was 0-3 days without morbidity. Patients subsequently proceeded to either classic PD (n = 5) or PPPD (n = 1). Interval from LAMS insertion to surgery ranged from 28 to 194 days. Mean PD operative time and EBL were 513 minutes and 560 mL, respectively. Post-PD hospital length of stay was 4-17 days. Clavien-Dindo IIIb morbidity required percutaneous drainage of intra-abdominal collections in two patients. In cases involving LAMS-GJ and CDS, the LAMS directly impacted the surgeon's preference not to perform pylorus preservation., Conclusions: In this case series, PD following EUS-LAMS was feasible with acceptable morbidity. Additional studies with larger patient populations are needed to evaluate LAMS as a bridge to PD with curative-intent., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Thomas Kowalski, MD reports a relationship with Boston Scientific that includes: consulting or advisory. Anand Kumar, MD reports a relationship with Olympus that includes: consulting or advisory. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Importance: Postpancreatectomy hemorrhage is an uncommon but highly morbid complication of pancreaticoduodenectomy. Clinical evidence often draws suspicion to the gastroduodenal artery stump, even without a clear source., Objective: To determine the frequency of gastroduodenal artery bleeding compared to other sites and the results of mitigation strategies., Design, Setting, and Participants: This cohort study involved a retrospective analysis of data for consecutive patients who had pancreaticoduodenectomy from 2011 to 2021 at Memorial Sloan Kettering Cancer Center (MSK) and Thomas Jefferson University Hospital (TJUH)., Exposures: Demographic, perioperative, and disease-related variables., Main Outcomes and Measures: The incidence, location, treatment, and outcomes of primary (initial) and secondary (recurrent) hemorrhage requiring invasive intervention were analyzed. Imaging studies were re-reviewed by interventional radiologists to confirm sites., Results: Inclusion criteria were met by 3040 patients (n = 1761 MSK, n = 1279 TJUH). Patients from both institutions were similar in age (median [IQR] age at MSK, 67 [59-74] years, and at TJUH, 68 [60-75] years) and sex (at MSK, 814 female [46.5%] and 947 male [53.8%], and at TJUH, 623 [48.7%] and 623 male [51.3%]). Primary hemorrhage occurred in 90 patients (3.0%), of which the gastroduodenal artery was the source in 15 (16.7%), unidentified sites in 24 (26.7%), and non-gastroduodenal artery sites in 51 (56.7%). Secondary hemorrhage occurred in 23 patients; in 4 (17.4%), the gastroduodenal artery was the source. Of all hemorrhage events (n = 117), the gastroduodenal artery was the source in 19 (16.2%, 0.63% incidence in all pancreaticoduodenectomies). Gastroduodenal artery hemorrhage was more often associated with soft gland texture (14 [93.3%] vs 41 [62.1%]; P = .02) and later presentation (median [IQR], 21 [15-26] vs 10 days [5-18]; P = .002). Twenty-three patients underwent empirical gastroduodenal artery embolization or stent placement, 7 (30.4%) of whom subsequently experienced secondary hemorrhage. Twenty percent of all gastroduodenal artery embolizations/stents (8/40 patients), including 13% (3/13 patients) of empirical treatments, were associated with significant morbidity (7 hepatic infarction, 4 biliary stricture), with a 90-day mortality rate of 38.5% (n = 5) for patients with these complications vs 7.8% without (n = 6; P = .008). Ninety-day mortality was 12.2% (n = 11) for patients with hemorrhage (3 patients [20%] with primary gastroduodenal vs 8 [10.7%] for all others; P = .38) compared with 2% (n = 59) for patients without hemorrhage., Conclusions and Relevance: In this study, postpancreatectomy hemorrhage was uncommon and the spectrum was broad, with the gastroduodenal artery responsible for a minority of bleeding events. Empirical gastroduodenal artery embolization/stent without obvious sequelae of recent hemorrhage was associated with significant morbidity and rebleeding and should not be routine practice. Successful treatment of postpancreatectomy hemorrhage requires careful assessment of all potential sources, even after gastroduodenal artery mitigation.

Background: Peripancreatic fluid collections after distal pancreatectomy and splenectomy are commonly identified on postoperative cross-sectional imaging. This study aimed to determine the incidence, natural history, and indications for intervention., Methods: We conducted a retrospective review of patients with peripancreatic fluid collections after distal pancreatectomy with or without splenectomy between 2013 and 2018, approved by our institutional review board. The chi-square test was used for categorical variables, the Mann-Whitney U test for continuous variables, and Fisher's exact test was used for values in which the sample size was less than 5 to compare data., Results: During the study period, 235 patients underwent distal pancreatectomy with or without splenectomy, and 182 patients with postoperative imaging were included. In the cohort of patients with postoperative imaging, 83 (46%) had peripancreatic fluid collections, of which 46 (55%) were symptomatic fluid collections (SFCs) and 37 (45%) were asymptomatic fluid collections (AFCs). Those with SFC had a higher incidence of postoperative morbidity (46% vs 8%; P = .0002), most commonly postoperative pancreatic fistula (90%). Of patients with SFC, 34 (74%) underwent treatment via percutaneous drainage (n = 26), endoscopic drainage (n = 7), or antibiotics alone (n = 1). AFCs (n = 37) were observed. Collections that were intervened upon resolved significantly faster than those observed, 3.5 months vs 13.2 months (P < .0001), respectively., Conclusion: Asymptomatic patients may be observed with or without serial imaging and the AFC will typically resolve spontaneously with time. Patients who develop symptoms should generally be intervened upon with drainage if deemed feasible, given that this reduces the time to resolution., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Society for Surgery of the Alimentary Tract. Published by Elsevier Inc. All rights reserved.)

Objective: The impact of pancreaticoduodenectomy on absorption of drugs in the duodenum remains largely unknown. We aim to characterize the pharmacokinetics of apixaban in patients who had previously undergone pancreaticoduodenectomy., Materials and Methods: A single 10-mg dose of apixaban was administered to 4 volunteers who underwent pancreaticoduodenectomy at least 6 months prior. The maximum plasma apixaban concentration (C max ) and area under the plasma concentration time-curve (AUC 0-24 , AUC 0-inf ) were compared against healthy historical control subjects (N = 12). Geometric mean ratios (GMR) with 90% confidence interval (CI) were calculated for determination of comparative bioequivalence., Results: In pancreaticoduodenectomy patients, AUC 0-24 and AUC 0-inf were 1,861 and 2,080 ng×h/mL, respectively. The GMRs of AUC 0-24 and AUC 0-inf between study subjects and healthy controls were 1.27 (90% CI 0.88 - 1.83) and 1.18 (90% CI 0.82 - 1.72). The mean C max of apixaban was 201 ng/mL (SD 15.6) occurring at a median t max of 3.25 hours (range 2.5 - 4 hours). The GMR of C max between study subjects and healthy controls was 1.12 (90% CI 0.77 - 1.63)., Conclusion: The pharmacokinetic characteristics of apixaban in subjects who had undergone pancreaticoduodenectomy are not significantly different from those of healthy controls. Though the sample size of this study is small, results suggest that no change to apixaban dose regimen is needed in patients who have had a pancreaticoduodenectomy.

Background: Delayed gastric emptying (DGE) is a common complication after pancreaticoduodenectomy. There remains an active debate over the effect of gastrointestinal (GI) reconstruction techniques, such as antecolic (AC) or transmesocolic (TMC) reconstruction, on DGE rates. This study compared the rates of DGE between AC reconstruction and TMC reconstruction after pylorus-preserving pancreaticoduodenectomy (PPPD) and classic pancreaticoduodenectomy (PD)., Methods: This was a retrospective analysis of a prospectively maintained pancreatic surgery database in a single, high-volume center. Demographic, perioperative, and surgical outcome data were recorded from patients who underwent a PD or PPPD between 2013 and 2021. DGE grades were classified using the International Study Group of Pancreatic Surgeons (ISGPS) criteria. Postoperatively, all patients were managed using an accelerated Whipple recovery protocol., Results: A total of 824 patients were assessed, with 303 patients undergoing AC reconstruction and 521 patients undergoing TMC reconstruction. The risk of DGE was significantly greater in patients who received an AC reconstruction than in patients who received a TMC reconstruction (odds ratio [OR], 1.51; 95% CI, 1.07-2.15; P < .05). In addition, AC reconstruction was shown to have a greater incidence of severe DGE (ISGPS grades B or C) than TMC reconstruction, with approximately a 2-fold increase in severe DGE (OR, 1.94; 95% CI, 1.10-3.45; P < .05). Logistic regression and propensity score matching have found increased DGE incidence with AC reconstruction (OR: 1.69 and 1.73, respectively; P < .05)., Conclusions: Although the correlation between GI reconstruction methods and DGE remains a subject of ongoing debate, our study indicated that TMC reconstruction may be superior to AC reconstruction in minimizing the development and severity of DGE for patients after PD., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2024 Society for Surgery of the Alimentary Tract. Published by Elsevier Inc. All rights reserved.)

Background: Communication between caregivers and clinical team members is critical for transitional care, but its quality and potential impact on outcomes are not well understood. This study reports on caregiver-reported quality of communication with clinical team members in the postpancreatectomy period and examines associations of these reports with patient and caregiver outcomes., Methods: Caregivers of patients with pancreatic and periampullary malignancies who had undergone pancreatectomy were surveyed. Instrument measures assessed care experiences using the Caregiver Perceptions About Communication with Clinical Team Members (CAPACITY) instrument. The instrument has two main subscales: communication, assessing the extent to which providers helped caregivers comprehend details of clinical visits, and capacity, defined as the extent to which providers assessed whether caregivers were able to care for patients., Results: Of 265 caregivers who were approached, 240 (90.6%) enrolled in the study. The mean communication and capacity subscale scores were 2.7 ± 0.6 and 1.5 ± 0.6, respectively (range, 0-4 [higher = better]). Communication subscale scores were lower among caregivers of patients who experienced (vs. those who did not experience) a 30-day readmission (2.6 ± 0.5 vs. 2.8 ± 0.6, respectively; p = .047). Capacity subscale scores were inversely associated with restriction in patient daily activities (a 0.04 decrement in the capacity score for every 1 point in daily activity restriction; p = .008)., Conclusions: After pancreatectomy, patients with pancreatic and periampullary cancer whose caregivers reported worse communication with care providers were more likely to experience readmission. Caregivers of patients with greater daily activity restrictions were less likely to report being asked about the caregiver's skill and capacity by clinicians., Plain Language Summary: This prospective study used a validated survey instrument and reports on the quality of communication between health care providers and caregivers as reported by caregivers of patients with pancreatic and periampullary cancer after pancreatectomy. In an analysis of 240 caregivers enrolled in the study, lower communication scores (the extent to which providers helped caregivers understand clinical details) were associated with higher odds of 30-day patient readmission to the hospital. In addition, lower capacity scores (the extent to which providers assessed caregivers' ability to care for patients) were associated with greater impairment in caregivers. The strikingly low communication quality and capacity assessment scores suggest substantial room for improvement, with the potential to improve both caregiver and patient outcomes., (© 2023 American Cancer Society.)

Background: Surgeons rarely perform elective total pancreatectomy (TP). Our study seeks to report surgical outcomes in a contemporary series of single-stage (SS) TP patients., Methods: Between the years 2013 to 2023 we conducted a retrospective review of 60 consecutive patients who underwent SSTP. Demographics, pathology, treatment-related variables, and survival were recorded and analyzed., Results: SSTP consisted of 3% (60/1859) of elective pancreas resections conducted. Patient median age was 68 years. Ninety percent of these patients (n = 54) underwent SSTP for pancreatic ductal adenocarcinoma (PDAC). Conversion from a planned partial pancreatectomy to TP occurred intraoperatively in 31 (52%) patients. Fifty-nine patients (98%) underwent an R0 resection. Median length of hospital stay was 6 days. The majority of morbidities were minor, with 27% patients (n = 16) developing severe complications (Clavien-Dindo ≥3). Thirty and ninety-day mortality rates were 1.67% (one patient) and 5% (three patients), respectively. Median survival for the entire cohort was 24.4 months; 22.7 months for PDAC patients, with 1-, 3-, and 5-year survival of 68%, 43%, and 16%, respectively. No mortality occurred in non-PDAC patients (n = 6)., Conclusion: Elective single-stage total pancreatectomy can be a safe and appropriate treatment option. SSTP should be in the armamentarium of surgeons performing pancreatic resection., (© 2024 The Authors. Journal of Surgical Oncology published by Wiley Periodicals LLC.)

Background: Local treatment options for locally recurrent pancreatic adenocarcinoma (LR-PAC) are limited, with median survival time (MST) of 9-13 months (mos) following recurrence. MRI-guided stereotactic body radiation therapy (MRgSBRT) provides the ability to dose escalate while sparing normal tissue. Here we report on the early outcomes of MRgSBRT for LR-PAC., Methods: Patients with prior resection of pancreatic adenocarcinoma with local recurrence treated with MRgSBRT at a single tertiary referral center from 5-2021 to 2-2023 were identified from our prospective database. MRgSBRT was delivered to 40-50 Gy in 4-5 fractions with target and OAR delineation per institutional standards. Endpoints included local control per RECIST v1.1, distant failure, overall survival (OS), and acute and chronic toxicities per Common Terminology Criteria for Adverse Events, v5., Results: Fifteen patients with LR-PAC were identified with median follow-up of 10.6 mos (2.8-26.5 mos) from MRgSBRT. There were 8 females and 7 males, with a median age of 69 years (50-83). One patient underwent neoadjuvant radiation for 50.4 Gy in 28 fractions followed by resection, and one underwent adjuvant radiation for 45 Gy in 25 fractions prior to recurrence. MRgSBRT was delivered a median of 18.8 mos (3.5-52.8 mos) following resection. OS following recurrence at 6 and 12 mos were 87% and 51%, respectively, with a median survival time of 14.1 mos (3.2-27.4 mos). Three patients experienced local failure at 5.9, 7.8, and 16.6 months from MgSBRT with local control of 92.3% and 83.9% at 6 and 12 months. 10 patients experienced distant failure at a median of 2.9 mos (0.3-6.7 mos). Grade 1-2 acute GI toxicity was noted in 47% of patients, and chronic GI toxicity in 31% of patients. No grade > 3 toxicities were noted., Conclusions: This is the first report on toxicity and outcomes of MRgSBRT for LR-PAC in the literature. MRgSBRT is a safe, feasible treatment modality with the potential for improved local control in this vulnerable population. Future research is necessary to better identify which patients yield the most benefit from MRgSBRT, which should continue to be used with systemic therapy as tolerated., Trial Registration: Jefferson IRB#20976, approved 2/17/21., (© 2024. The Author(s).)

Objective: To assess whether long-term survivors of pancreatic surgery show increased risk to develop impaired bone mineral density, osteoporosis, and vitamin D deficiency., Background: Pancreatic resection poses a risk for malabsorption of fat-soluble vitamins and other micronutrients essential for bone mineralization. Here, we evaluated the long-term effects of pancreatic resection on bone mineral density (BMD) and its clinical sequelae., Methods: This was a two-pronged analysis of post-pancreatectomy patients with a follow-up period greater than 3 years comprising (1) a large, propensity score-matched, cohort study based on a multinational federated research network (FRN) and (2) a retrospective single institution review of clinical and radiographic patient data. In the FRN analysis, an initial cohort of 8,423 post-pancreatectomy patients were identified and propensity score-matched with normal controls. The primary endpoint was the 10-year risk of developing osteoporotic pathological fractures and secondary endpoints included diagnosis of osteoporosis, vitamin-D deficiency, and related therapies. The single institution retrospective analysis identified 224 patients who underwent pancreatic resection between 2005 and 2019. BMD was quantified in CT images acquired before and after surgery. BMD trends and related factors were assessed in a time-series mixed effect linear regression model., Results: A total of 8,080 propensity score-matched pairs were included in the FRN analysis. The analysis revealed a 2.4-fold increase in pathological fractures (P<0.0001) and 1.4-1.5 fold increase in osteoporosis/osteomalacia (P<0.0001) and vitamin-D deficiency (P<0.0001) in post-pancreatectomy patients. Vitamin-D supplements were more common in the pancreatectomy group (OR 1.4, 95% CI 1.28-1.53, P<0.0001), as were specific osteoporosis/osteomalacia treatments such as calcitonin, denosumab, romosozumab, abaloparatide, and teriparatide (OR 2.24, 95%CI 1.69-2.95, P<0.0001). Retrospective analysis of CT imaging revealed that BMD declined more rapidly following pancreatic resection compared to normal historical controls (P=0.015). Older age, pancreatic cancer, and pancreaticoduodenectomy were associated with increased rates of BMD loss (P<0.05, each)., Conclusions: After pancreatic resection, patients are at higher risk for BMD loss and subsequent fractures. As the cohort of pancreatic resection survivorship grows, attention will need to be paid to focused prevention efforts to reduce BMD loss, osteoporosis, and fractures in these vulnerable patients, with specific attention to the pancreatic cancer population., Competing Interests: Conflicts of interest: The authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: This meta-analysis investigated the effects of enhanced recovery after surgery (ERAS) protocols compared to conventional care on postoperative outcomes in patients aged 70 years or older undergoing pancreatoduodenectomy (PD)., Methods: Five databases were systematically searched. Comparative studies with available individual patient data (IPD) were included. The main outcomes were postoperative morbidity, length of stay, readmission and postoperative functional recovery elements. To assess an age-dependent effect, the group was divided in septuagenarians (70-79 years) and older patients (≥80 years)., Results: IPD were obtained from 15 of 31 eligible studies comprising 1109 patients. The overall complication and major complication rates were comparable in both groups (OR 0.92 [95% CI: 0.65-1.29], p = .596 and OR 1.22 [95% CI: 0.61-2.46], p = .508). Length of hospital stay tended to be shorter in the ERAS group compared to the conventional care group (-0.14 days [95% CI: -0.29 to 0.01], p = .071) while readmission rates were comparable and the total length of stay including days in hospital after readmission tended to be shorter in the ERAS group (-0.28 days [95% CI: -0.62 to 0.05], p = .069). In the subgroups, the length of stay was shorter in octogenarians treated with ERAS (-0.36 days [95% CI: -0.71 to -0.004], p = .048). The readmission rate increased slightly but not significantly while the total length of stay was not longer in the ERAS group., Conclusion: ERAS in the elderly is safe and its benefits are preserved in the care of even in patients older than 80 years. Standardized care protocol should be encouraged in all pancreatic centers., (© 2024 Japanese Society of Hepato‐Biliary‐Pancreatic Surgery.)

The KRAS proto-oncogene is a major driver of pancreatic tumorigenesis and is nearly ubiquitously mutated in pancreatic ductal adenocarcinoma (PDAC). KRAS point mutations are detected in over 90% of PDAC cases, and these mutations have been shown to be associated with worse therapy response and overall survival. Pathogenic KRAS mutations are mostly limited to codons 12, 13 and 61, with G12D, G12V, G12R, Q61H, and G13D accounting for approximately 95% of the mutant cases. Emerging data have shown the importance of specific mutant subtypes, as well as KRAS variant allele frequency on clinical prognosis. Furthermore, novel technologies and therapies are being developed to target specific mutant subtypes, with encouraging early results. In this paper, we aim to review the recent studies regarding the relative impact of specific mutant KRAS subtypes on oncologic outcomes, the application of variant allele frequency in next generation sequencing analyses, and the ongoing research into therapies targeting specific mutant KRAS subtypes.

Context.—: Mutant KRAS is the main oncogenic driver in pancreatic ductal adenocarcinomas (PDACs). However, the clinical and phenotypic implications of harboring different mutant KRAS alleles remain poorly understood., Objective.—: To characterize the potential morphologic and clinical outcome differences in PDACs harboring distinct mutant KRAS alleles., Design.—: Cohort 1 consisted of 127 primary conventional PDACs with no neoadjuvant therapy, excluding colloid/mucinous, adenosquamous, undifferentiated, and intraductal papillary mucinous neoplasm-associated carcinomas, for which an in-house 42-gene mutational panel had been performed. A morphologic classification system was devised wherein each tumor was assigned as conventional, papillary/large duct (P+LD, defined as neoplastic glands with papillary structure and/or with length ≥0.5 mm), or poorly differentiated (when the aforementioned component was 60% or more of the tumor). Cohort 2 was a cohort of 88 PDACs in The Cancer Genome Atlas, which were similarly analyzed., Results.—: In both cohorts, there was significant enrichment of P+LD morphology in PDACs with KRAS G12V and G12R compared with G12D. In the entire combined cohort, Kaplan-Meier analyses showed longer overall survival (OS) with KRAS G12R as compared with G12D (median OS of 1255 versus 682 days, P = .03) and in patients whose PDACs displayed P+LD morphology as compared with conventional morphology (median OS of 1175 versus 684 days, P = .04). In the adjuvant-only subset, KRAS G12R had the longest OS compared with G12D, G12V, and other alleles (median OS unreached/undefined versus 1009, 1129, and 1222 days, respectively)., Conclusions.—: PDACs with different mutant KRAS alleles are associated with distinct morphologies and clinical outcomes, with KRAS G12R allele associated with P+LD morphology and longer OS when compared with G12D using Kaplan-Meier studies., Competing Interests: The authors have no relevant financial interest in the products or companies described in this article., (© 2024 College of American Pathologists.)

Background: High-volume pancreatic surgery centers require a significant investment in expertise, time, and resources to achieve optimal patient outcomes. A detailed understanding of the economics of major pancreatic surgery is limited among many clinicians and hospital administrators. A greater consideration of these financial aspects may in fact have implications for enhancing clinical care and for a broader sustainability of high-volume pancreatic surgery programs., Methods: In this retrospective observational study, patients who underwent pancreaticoduodenectomy (PD), total pancreatectomy, or distal pancreatectomy at one academic medical center during the fiscal year 2021 were evaluated. Detailed hospital charges and professional fees were obtained for patients using the Qlik perioperative database. Clinical data for the study cohort were gathered from a prospectively maintained, IRB-approved pancreatic surgery database. Charges for the 91-day perioperative period were included. A P < 0.05 was considered significant., Results: During the study period, 159 evaluable patients underwent 1 of 3 designated pancreatic resections included in the analysis. Ninety-seven patients (61%) were diagnosed with adenocarcinoma and 70% (n = 110) underwent PD. The total charges (combined professional and hospital charges) for the cohort encompassing the entire perioperative period were $20,661,759. The median charge per patient was $130,306 (interquartile range [IQR], $34,534). The median direct cost of care was $23,219 (IQR, $6321) and the median contribution margin per case was $10,092 (IQR, $22,949). The median surgeon professional fee charges were $7700 per patient (IQR, $1296) as compared to $3453 (IQR, $1,144) for professional fee receipts (45% of the surgeon charge). The differences between the professional fee charges and receipts per patient were also considerable for other health care professionals such as anesthesiologists ($4945 charges vs $1406 receipts [28%]) and pathologists ($3035 charges vs $680 receipts [22%]). The surgeon professional fees were only 6% of the total charges, while the professional fees for anesthesiology and pathology were 4% and 2% of the total charges, respectively. Supply charges were 3% of the total charges. Longer operative time was correlated with increased hospital and anesthesia charges, without a significant increase in surgeon charges ( P < 0.001, P < 0.001, and P = 0.2, respectively). Male sex, diabetes, and low serum albumin correlated with greater total hospital charges ( P = 0.01, P = 0.01, and P = 0.03, respectively)., Conclusions: The role of the surgeon in the perioperative clinical care of major pancreatic resection patients is crucial and important and is by no means limited to the operative day. Nevertheless, in the context of the current US health care system, the reimbursement to the surgeon in the form of professional fees is a relatively small fraction of the total health care receipts for these patients. This imbalance necessitates a substantial financial partnership between hospitals and their pancreatic surgery units to ensure the long-term viability of these programs., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Mahvash disease is an exceedingly rare genetic disorder of glucagon signaling characterized by hyperglucagonemia, hyperaminoacidemia, and pancreatic α-cell hyperplasia. Although there is no known definitive treatment, octreotide has been used to decrease systemic glucagon levels. We describe a woman who presented to our medical center after three episodes of small-volume hematemesis. She was found to have hyperglucagonemia and pancreatic hypertrophy with genetically confirmed Mahvash disease and also had evidence of portal hypertension (recurrent portosystemic encephalopathy and variceal hemorrhage) in the absence of cirrhosis. These findings established a diagnosis of portosinusoidal vascular disease, a presinusoidal type of portal hypertension previously known as noncirrhotic portal hypertension. Liver transplantation was followed by normalization of serum glucagon and ammonia levels, reversal of pancreatic hypertrophy, and resolution of recurrent encephalopathy and bleeding varices., (Copyright © 2023 Massachusetts Medical Society.)

Background: Recent reports of the utilisation of pyrvinium pamoate (PP), an FDA-approved anti-helminth, have shown that it inhibits pancreatic ductal adenocarcinoma (PDAC) cell growth and proliferation in-vitro and in-vivo in preclinical models. Here, we report about an ongoing phase I open-label, single-arm, dose escalation clinical trial to determine the safety and tolerability of PP in PDAC surgical candidates., Methods and Analysis: In a 3+3 dose design, PP is initiated 3 days prior to surgery. The first three patients will be treated with the initial dose of PP at 5 mg/kg orally for 3 days prior to surgery. Dose doubling will be continued to a reach a maximum of 20 mg/kg orally for 3 days, if the previous two dosages (5 mg/kg and 10 mg/kg) were tolerated. Dose-limiting toxicity grade≥3 is used as the primary endpoint. The pharmacokinetic and pharmacodynamic (PK/PD) profile of PP and bioavailability in humans will be used as the secondary objective. Each participant will be monitored weekly for a total of 30 days from the final dose of PP for any side effects. The purpose of this clinical trial is to examine whether PP is safe and tolerable in patients with pancreatic cancer, as well as assess the drug's PK/PD profile in plasma and fatty tissue. Potential implications include the utilisation of PP in a synergistic manner with chemotherapeutics for the treatment of pancreatic cancer., Ethics and Dissemination: This study was approved by the Thomas Jefferson Institutional Review Board. The protocol number for this study is 20F.041 (Version 3.1 as of 27 October 2021). The data collected and analysed from this study will be used to present at local and national conferences, as well as, written into peer-reviewed manuscript publications., Trial Registration Number: ClinicalTrials.gov: NCT05055323., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Pancreatic adenocarcinoma is an aggressive disease with poor clinical outcomes. Primary pancreatic tumors originating from the head of the pancreas (H) have different prognostic implications than tumors arising from the body and tail (BT). This is thought to be largely due to anatomic differences, as molecular underpinnings of survival have not been fully explored. We hypothesized that differences in the primary site of H and BT tumors might account for differential molecular outcomes and response to chemotherapy., Methods: Retrospective data from a single high-volume academic center were analyzed for hypothesis generation. A large-scale, real-world retrospective cohort of 2015 patients with next-generation sequencing (NGS) results were analyzed from a Real-World Evidence database. Progression-free survival (PFS) was evaluated from the initiation of first line of therapy for advanced disease until discontinuation because of progression. HR and P values were computed via Cox regression between first-line FOLFIRINOX and gemcitabine/nanoparticle albumin-bound (gem/nab) paclitaxel. Differences in frequencies of genomic alterations between H and BT were analyzed by Fisher's exact test., Results: Genomic alterations in the DNA damage response (DDR) pathway (such as BRCA1, BRCA2, and PALB2 ) were enriched (unadjusted P value = .00244) in BT tumors (21.7% of 618) relative to H tumors (15.6% of 942) where BRCA2 was a top contributor within this pathway. Median PFS in BT tumors on first-line FOLFIRINOX was longer than first line gem/nab-paclitaxel ( P = .006393); this difference was not identified in H tumors ( P = .5546)., Conclusion: DDR pathway alterations including BRCA1 / BRCA2 / PALB2 are known predictors of increased benefit from platinum-based chemotherapy. NGS testing for germline and somatic mutations remains important in pancreatic ductal adenocarcinoma, especially in BT tumors where DDR pathway alterations may be more common than in H tumors.

Purpose: Patients with pancreatic and periampullary cancers may experience significant reduction in their quality of life and often rely on family and unpaid caregivers for assistance after surgery. However, as caregivers are not systematically identified, little is known about the nature, difficulty, and personal demands of assistance they provide. We aim to assess the frequency and difficulty of specific assistance caregivers provide and identify potential interventions that could alleviate the caregiving demands., Methods: This was a prospective, multi-institutional study of caregivers accompanying patients with periampullary and pancreatic cancer at their 1-month postpancreatectomy office visit. An instrument that drew heavily on the National Study of Caregiving was administered to caregivers., Results: Of 240 caregivers, more than half (58.3%) of caregivers were the patients' spouse, a quarter (25.8%) were daughters or sons, 12.9% other relatives, and 2.9% nonrelatives. Caregivers least frequently provided assistance with transportation (14.6% every day) and most frequently provided assistance with housework (65.0% every day, P = .003) and diet (56.5% every day, P = .004). Caregivers reported the least difficulty helping patients with exercise (1.5% somewhat difficult). Caregivers reported significantly more difficulty with assisting with housework (14.5% somewhat difficult, P < .001) and diet (14.9% somewhat difficult, P < .001). Caregivers identified the immediate postpancreatectomy and early discharge periods as the most stressful phases. They also reported having received very little information about available services that could have supported their efforts., Conclusion: Caregivers of patients with periampullary or pancreatic cancer provide considerable assistance in the postoperative period and many reported difficulty in assisting with housework and diet. Work is needed to better prepare and support caregivers to better enable them to adequately care for patients with pancreas and periampullary cancer.

Background: While complication rates after pancreaticoduodenectomy (PD) have improved in recent decades, surgical-related death remains a possibility. Postoperative vital signs offer an untapped opportunity to identify predictors of 90-day mortality., Methods: We performed a retrospective chart review interrogating postoperative day (POD 0-7) vital sign measurements from patients undergoing a PD at Thomas Jefferson University Hospital, Philadelphia, PA (2009-2014). Five specific vital signs were examined as predictors of mortality: temperature, heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure. Statistical analyses and logic algorithms were employed to rank vital sign parameters, with cut-points, to identify those associated with the highest risk of mortality and the most clinical relevance., Results: In our cohort, 11/750 patients (1.5%) died within 30 days of surgery, and 21/750 patients (2.8%) died within 90 days of surgery. Vital sign perturbations associated with the highest risk of mortality included mean SBP < 95 mmHg on POD 7 (odds ratio 51.46) and the mean temperature < 96.9℉ on POD 3 (odds ratio 22.63) with specificities exceeding 99%. The most clinically relevant predictor (i.e., a higher sensitivity) was DBP < 60.5 mmHg on POD 7 (odds ratio 12.45, sensitivity of 75%). These predictors remained statistically significant in a multivariable model., Conclusions: Vital signs can be more effectively utilized to predict 90-day mortality after pancreaticoduodenectomy. Values beyond an informative threshold can potentially identify patients for more intensive monitoring with a goal of rescuing patients and preventing death., (© 2023. The Society for Surgery of the Alimentary Tract.)

Background and Objective: Robotic distal pancreatectomy (DP) is an emerging attractive approach, but its role compared with laparoscopic or open surgery remains unclear. Benchmark values are novel and objective tools for such comparisons. The aim of this study was to identify benchmark cutoffs for many outcome parameters for DP with or without splenectomy beyond the learning curve., Methods: This study analyzed outcomes from international expert centers from patients undergoing robotic DP for malignant or benign lesions. After excluding the first 10 cases in each center to reduce the effect of the learning curve, consecutive patients were included from the start of robotic DP up to June 2020. Benchmark patients had no significant comorbidities. Benchmark cutoff values were derived from the 75th or the 25th percentile of the median values of all benchmark centers. Benchmark values were compared with a laparoscopic control group from 4 high-volume centers and published open DP landmark series., Results: Sixteen centers contributed 755 cases, whereof 345 benchmark patients (46%) were included the analysis. Benchmark cutoffs included: operation time ≤300 minutes, conversion rate ≤3%, clinically relevant postoperative pancreatic fistula ≤32%, 3 months major complication rate ≤26.7%, and lymph node retrieval ≥9. The comprehensive complication index at 3 months was ≤8.7 without deterioration thereafter. Compared with robotic DP, laparoscopy had significantly higher conversion rates (5×) and overall complications, while open DP was associated with more blood loss and longer hospital stay., Conclusion: This first benchmark study demonstrates that robotic DP provides superior postoperative outcomes compared with laparoscopic and open DP. Robotic DP may be expected to become the approach of choice in minimally invasive DP., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Postoperative opioid abuse following surgery is a major concern. This study sought to create an opioid reduction toolkit to reduce the number of narcotics prescribed and consumed while increasing awareness of safe disposal in pancreatectomy patients., Methods: Prescription, consumption, and refill request data for postoperative opioids were collected from patients receiving an open pancreatectomy before and after the implementation of an opioid reduction toolkit. Outcomes included safe disposal practice awareness for unused medication., Results: 159 patients were included in the study: 24 in the pre-intervention and 135 in the post-intervention group. No significant demographic or clinical differences existed between groups. Median morphine milliequivalents (MMEs) prescribed were significantly reduced from 225 (225-310) to 75 (75-113) in the post-intervention group (p < 0.0001). Median MMEs consumed were significantly reduced from 109 (111-207) to 15 (0-75), p < 0.0001), as well. Refill request rates remained equivalent during the study (Pre: 17% v Post: 13%, p = 0.9) while patient awareness of safe disposal increased (Pre: 25% v Post: 62%, p < 0.0001)., Discussion: An opioid reduction toolkit significantly reduced the number of postoperative opioids prescribed and consumed after open pancreatectomy, while refill request rates remained the same and patients' awareness of safe disposal increased., (Copyright © 2023 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Pancreatic ductal adenocarcinoma (PDAC) is the 3rd leading cause of cancer mortality in the United States. Hypoxic and hypercapnic tumor microenvironments have been suggested to promote tumor aggressiveness. The objective of this study was to evaluate the association between chronic obstructive pulmonary disease (COPD) and oncologic survival outcomes in patients with early-stage PDAC and periampullary cancers. In this case-control study, patients who underwent a pancreaticoduodenectomy during 2014-2021 were assessed. Demographic, perioperative, histologic, and oncologic data were collected. A total of 503 PDAC and periampullary adenocarcinoma patients were identified, 257 males and 246 females, with a mean age of 68.1 (±9.8) years and a mean pre-operative BMI of 26.6 (±4.7) kg/m 2 . Fifty-two percent of patients (N = 262) reported a history of smoking. A total of 42 patients (8.3%) had COPD. The average resected tumor size was 2.9 ± 1.4 cm and 65% of the specimens (N = 329) were positive for lymph-node involvement. Kaplan-Meier analysis showed that COPD was associated with worse overall and disease-specific survival ( p < 0.05). Cox regression analysis showed COPD to be an independent prognostic factor (HR = 1.5, 95% CI 1.0-2.3, p = 0.039) along with margin status, lymphovascular invasion, and perineural invasion ( p < 0.05 each). A 1:3 nearest neighbor propensity score matching was also employed and revealed COPD to be an independent risk factor for overall and disease-specific survival (OR 1.8 and OR 1.6, respectively; p < 0.05 each). These findings may support the rationale posed by in vitro laboratory studies, suggesting an important impact of hypoxic and hypercapnic tumor respiratory microenvironments in promoting therapy resistance in cancer.

The utilization of endoscopic ultrasound-guided gastrojejunostomy (EUS-GJ) in the setting of an obstructed (ingrown) duodenal stent as a bridge to pancreaticoduodenectomy (PD) remains undescribed. Herein, we report a case study of a 51-year-old patient who underwent EUS-GJ using lumen apposing metal stent (LAMS) for an obstructed duodenal stent during neoadjuvant treatment for duodenal adenocarcinoma. The patient ultimately underwent surgical resection by a classic PD 14 weeks after LAMS placement. EUS-GJ using LAMS represents a potential option as a salvage bridge to surgery for duodenal obstruction in the setting of an obstructed duodenal stent., (© 2023. The Author(s).)

Background: The purpose of this study was to examine the relationship between various respiratory conditions, including hypercapnic respiratory disease, and a multitude of resected pancreatic lesions., Methods: This retrospective case-control study queried a prospectively maintained database of patients who underwent pancreaticoduodenectomy between January 2015 and October 2021. Patient data, including smoking history, medical history, and pathology reports, were recorded. Patients with no smoking history and no concomitant respiratory conditions were designated as the control group., Results: A total of 723 patients with complete clinical and pathological data were identified. Male current smokers showed increased rates of PDAC (OR 2.33, 95% CI 1.07-5.08, p = 0.039). Male patients with COPD had a markedly increased association with IPMN (OR 3.02, CI 1.08-8.41, p = 0.039), while females with obstructive sleep apnea had a four-fold increase in risk of IPMN compared to women in the control group (OR 3.89, CI 1.46-10.37, p = 0.009). Surprisingly, female patients with asthma had a decreased incidence of pancreatic and periampullary adenocarcinoma (OR 0.36, 95% CI 0.18-0.71. p < 0.01)., Conclusion: This large cohort study reveals possible links between respiratory pathologies and various pancreatic mass-forming lesions.

Importance: Despite improvements in perioperative mortality, the incidence of postoperative surgical site infection (SSI) remains high after pancreatoduodenectomy. The effect of broad-spectrum antimicrobial surgical prophylaxis in reducing SSI is poorly understood., Objective: To define the effect of broad-spectrum perioperative antimicrobial prophylaxis on postoperative SSI incidence compared with standard care antibiotics., Design, Setting, and Participants: Pragmatic, open-label, multicenter, randomized phase 3 clinical trial at 26 hospitals across the US and Canada. Participants were enrolled between November 2017 and August 2021, with follow-up through December 2021. Adults undergoing open pancreatoduodenectomy for any indication were eligible. Individuals were excluded if they had allergies to study medications, active infections, chronic steroid use, significant kidney dysfunction, or were pregnant or breastfeeding. Participants were block randomized in a 1:1 ratio and stratified by the presence of a preoperative biliary stent. Participants, investigators, and statisticians analyzing trial data were unblinded to treatment assignment., Intervention: The intervention group received piperacillin-tazobactam (3.375 or 4 g intravenously) as perioperative antimicrobial prophylaxis, while the control group received cefoxitin (2 g intravenously; standard care)., Main Outcomes and Measures: The primary outcome was development of postoperative SSI within 30 days. Secondary end points included 30-day mortality, development of clinically relevant postoperative pancreatic fistula, and sepsis. All data were collected as part of the American College of Surgeons National Surgical Quality Improvement Program., Results: The trial was terminated at an interim analysis on the basis of a predefined stopping rule. Of 778 participants (378 in the piperacillin-tazobactam group [median age, 66.8 y; 233 {61.6%} men] and 400 in the cefoxitin group [median age, 68.0 y; 223 {55.8%} men]), the percentage with SSI at 30 days was lower in the perioperative piperacillin-tazobactam vs cefoxitin group (19.8% vs 32.8%; absolute difference, -13.0% [95% CI, -19.1% to -6.9%]; P < .001). Participants treated with piperacillin-tazobactam, vs cefoxitin, had lower rates of postoperative sepsis (4.2% vs 7.5%; difference, -3.3% [95% CI, -6.6% to 0.0%]; P = .02) and clinically relevant postoperative pancreatic fistula (12.7% vs 19.0%; difference, -6.3% [95% CI, -11.4% to -1.2%]; P = .03). Mortality rates at 30 days were 1.3% (5/378) among participants treated with piperacillin-tazobactam and 2.5% (10/400) among those receiving cefoxitin (difference, -1.2% [95% CI, -3.1% to 0.7%]; P = .32)., Conclusions and Relevance: In participants undergoing open pancreatoduodenectomy, use of piperacillin-tazobactam as perioperative prophylaxis reduced postoperative SSI, pancreatic fistula, and multiple downstream sequelae of SSI. The findings support the use of piperacillin-tazobactam as standard care for open pancreatoduodenectomy., Trial Registration: ClinicalTrials.gov Identifier: NCT03269994.

Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and lethal cancer. Hypercapnic tumor microenvironments were previously shown to promote cancer chemoresistance. In this study, we aimed to investigate the impact of tissue hypercapnia on PDAC prognosis., Study Design: PDAC cancer-cell lines were cultured in normocapnic (5% CO 2 ) and hypercapnic conditions (10% CO 2 ). RNA was extracted, and whole-exome transcriptome was sequenced. Differentially expressed genes were identified and used to construct a "hypercapnic gene set." PDAC transcriptomic patient data from the Tumor Cancer Genome Atlas was used to calculate single-sample gene set enrichment scores based on each patient's tissue expression of the hypercapnic gene set. Tissue hypercapnic scores (HSs) in PDAC patients (TMN stages Ia-IIb) were determined and correlated with clinicopathological parameters and overall survival., Results: A cohort of 135 resected stage I-II PDAC patients were assessed in this study. The average age was 65 ± 11.0 years, and the male:female ratio was 74:61. Median overall survival was 19.5 ± 1.4 months. High HSs were associated with increased tumor stage (p < 0.05) and higher lymph-node ratio (p < 0.05). In active smokers, high HS also correlated with smoking pack-years (p < 0.05). Cox regression analysis revealed high HS to be an independent prognostic factor for overall survival (hazard ratio [HR] 2.66, p = 0.004), along with lymph-node ratio (HR 4.2, p = 0.002) and age at diagnosis (HR 2.63, p = 0.01)., Conclusions: The pancreatic tumor microenvironment plays an integral role in tumor aggressiveness, and our previous in vitro data suggest that hypercapnia promotes an aggressive, more resistant phenotype. Herein, we show that in early-stage pancreatic cancer, hypercapnic tissue signatures corresponded with a worse overall survival., (Copyright © 2023 by the American College of Surgeons. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Background: Euglycemic diabetic ketoacidosis is a metabolic condition characterized by relative euglycemia, ketonemia, and metabolic acidosis that occurs through mechanisms resembling starvation. Pancreaticoduodenectomy is a complex abdominal operation that subjects patients to a prolonged fasting and an inflammatory state. This study examined the incidence of euglycemic diabetic ketoacidosis and potential opportunities for early diagnosis and management in patients undergoing pancreaticoduodenectomy., Methods: A single-institution retrospective review of 350 patients who underwent pancreaticoduodenectomy between 2017 and 2020 was performed. Primary endpoints were peak beta-hydroxybutyrate levels, peak lactate levels, lowest pH, peak base deficits, and urinary output within the first 24 hours, postoperatively. Additional endpoints included incidence of postoperative pancreatic fistula, delayed gastric emptying, total complications, postoperative hospital length of stay, readmission rates, and changes in insulin regimen at discharge., Results: Of the 350 cases reviewed, 39 (11.1%) patients developed euglycemic diabetic ketoacidosis. Male sex and pancreatic cancer were associated with a risk for euglycemic diabetic ketoacidosis (P < .05). Patients with euglycemic diabetic ketoacidosis had significantly higher peak beta-hydroxybutyrate levels than patients without euglycemic diabetic ketoacidosis (mean difference = 19.8 mg/dL, 95% confidence interval = 14.7-24.9, P < .001), and were nearly four times more likely to require insulin at discharge (odds ratio 3.8, 95% confidence interval = 1.1-13.0, P < .05)., Conclusion: This is the first large descriptive study that investigates euglycemic diabetic ketoacidosis after pancreaticoduodenectomy. Euglycemic diabetic ketoacidosis after pancreaticoduodenectomy is associated with significantly higher beta-hydroxybutyrate levels and new or increased insulin requirement at discharge. Our study demonstrates potential markers for euglycemic diabetic ketoacidosis after pancreaticoduodenectomy, offering an opportunity to identify and successfully treat this disease in a timely manner., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Malignant bowel obstruction is a common complication of advanced gastrointestinal, gynecologic, and genitourinary tumors. Patients present with nausea, vomiting, abdominal pain, and constipation. Cross-sectional imaging is essential to make a diagnosis of bowel obstruction. Initial management is conservative with fluid replacement, electrolyte replacement, bowel rest and sometimes nasogastric decompression. Numerous advanced options exist for definitive management, though none are overly promising but nevertheless may improve quality and quantity of life. Surgical bypass, endoscopic stenting, and endoscopic decompression are some of the options with variable efficacy and are employed in select patients. Chemotherapy may be utilized if the bowel obstruction resolves to reduce tumor burden in a limited number of patients. Parenteral nutrition is an option and should typically be used in surgical patients with good functional and nutritional status with limited tumor burden or curative intent. Palliative care and hospice should be discussed in patients with advanced malignancy who present with peritoneal carcinomatosis or multiple levels of obstruction. Overall prognosis of malignant bowel obstruction is poor, and median survival ranges from 26 to 192 days.

Background: Distress screening of cancer patients is mandated by the American College of Surgeons Commission on Cancer. Clinical implementation remains limited, particularly in surgical oncology settings in individuals with pancreaticobiliary cancers., Study Design: This study evaluated differences in mean distress scores based on the National Comprehensive Cancer Network Distress Thermometer & Problem List for patients with pancreaticobiliary cancers, benign pancreatic conditions, and for their significant others (SOs). The distress screening was conducted at the first office visit and postoperatively in a subset of those who had surgery. Distress Thermometer (DT) scores were dichotomized at ≤5 vs >5 and at ≥7 and correlated with Problem List items. The US ZIP Code database was used to correlate income range, percent poverty, and unemployment in the patient's self-identified ZIP code. Regression models were fitted to identify independent predictors of distress., Results: A total of 547 patients and 184 SOs were evaluated. Thirty percent of patients had DT scores >5, with pancreatic adenocarcinoma patients reporting the highest levels of distress. SOs of pancreatic adenocarcinoma patients reported even greater distress than the patients themselves. As the number of pre-existing medical problems increased; so did DT scores. Distress correlated with physical and emotional problems and worry about insurance coverage and transportation. Higher income level predicted higher DT scores, although poverty predicted lower DT scores. Depression was present in 12% of the patients. Distress improved in those undergoing surgery., Conclusions: Distress and depression in pancreaticobiliary cancer patients and SOs are prevalent. The findings of this study have multiple actionable implications and require diagnosis, treatment, and referral to supportive care resources., (Copyright © 2022 by the American College of Surgeons. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Objective: The objective of this study was to determine baseline health-related quality of life (QoL) in patients with pancreatic adenocarcinoma, periampullary cancers, and benign pancreaticobiliary (PB) conditions at the time of the first visit to a PB surgery clinic, and to explore the relationship between QoL, demographics, clinical parameters, complications, and survival., Summary Background Data: Few studies have examined baseline QoL measures, the impact of comorbidities, age, sex, and smoking on subsequent postoperative complications and survival in patients with pancreatic adenocarcinoma, related PB cancers, and with benign PB conditions., Methods: Data were collected from scheduled patients at a PB surgery clinic between 2013 and 2018. The Brief Pain Inventory, Fact-Hepatobiliary Scale, and Facit-Fatigue questionnaires were administered. QoL parameters were compared between PB cancer patients and those with benign disease., Results: A total of 462 individuals with PB cancers and benign diseases exhibited baseline physical well-being, functional well-being, fatigue, and overall QoL at or below the 75th percentile of wellness at the time of the first office visit. Younger age, smoking, and mental health comorbidities contributed significantly to decreased QoL. PA patients were 7 times more likely to die in the follow-up period than the benign disease group. Black patients had higher pain scores and were 3 times more likely to have a postsurgery complication. Sex differences were identified regarding fatigue, pain, and overall QoL., Conclusions: This large cohort of PB cancer and benign disease patients exhibited significantly impaired baseline QoL. GI problems, weight loss, smoking, cardiovascular, pulmonary disease, and history of anxiety and depression contributed significantly to reduced QoL. The study sheds a cautionary light on the burden of PB disease at the time of surgical evaluation and its relationship to diminished QoL., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Family and other unpaid caregivers play an active role in the recovery of individuals with pancreatic and periampullary cancer after pancreatectomy. However, little is known about caregivers' experiences and how to better support them., Methods: Caregivers accompanying patients to 1-month postpancreatectomy visits at 3 hospitals completed an electronic survey between November 2018 and February 2020. We examine measures of absenteeism and work productivity loss among the subset of caregivers who reported working for pay and comparatively assess caregiver experiences by employment status. All analyses were performed as 2-sided tests., Results: Of 265 caregivers approached for study participation, 240 (90.6%) enrolled. Caregivers were primarily female (70.8% female, 29.2% male) and spouses (58.3%) or adult children (25.8%) of patients, with a median age of 60 years. Of the 240 caregivers included in the study, 107 (44.6%) worked for pay. Nearly half (44.4%) of working caregivers reported being absent from work because of caregiving amounting to a 14% loss in work hours. While at work, 58.9% of working caregivers reported increased work difficulty as a result of caregiving. Taken together, an estimated 59.7% loss in work productivity was experienced because of caregiving in the month following pancreatectomy. After adjustment for sociodemographic factors, working (vs nonworking) caregivers reported increased financial (odds ratio [OR] = 2.32; P = .04) and emotional (OR = 1.93; P = .04) difficulties and daily activity restrictions (OR = 1.85; P = .048)., Conclusions: Working caregivers of patients with pancreatic and periampullary cancer experience negative impacts on work and productivity, and caregiving-related financial and emotional difficulties may be amplified. This study highlights the need for workplace policies to support unpaid cancer caregiving., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: Sarcopenia is common in pancreatic cancer patients. Considering the growing adoption of standardized protocols for enhanced recovery after surgery (ERAS), we examined the clinical impact of sarcopenia in pancreaticoduodenectomy (PD) patients in a 5-day accelerated ERAS program, termed the Whipple Accelerated Recovery Pathway., Methods: A retrospective review was conducted of patients undergoing PD from 2017 through 2020 on the ERAS pathway. Preoperative computerized tomographic scans taken within 45 days before surgery were analyzed to determine psoas muscle cross-sectional area (PMA) at the third lumbar vertebral body. Sarcopenia was defined as the lowest quartile of PMA respective to gender. Outcome measures were compared between patients with or without sarcopenia., Results: In this 333-patient cohort, 252 (75.7%) patients had final pathology revealing pancreatic or periampullary cancer. The median age was 66.7 years (16.4-88.4 years) with a 161:172 male to female ratio. Sarcopenia correlated with delayed tolerance of oral intake (OR 2.2; 95%CI 1.1-4.3, P = 0.03), increased complication rates (OR 4.3; 95%CI 2.2-8.5, P < 0.01), and longer hospital length of stay (LOS) (P < 0.05). Preoperative albumin levels, BMI, and history of pancreatitis were also found to correlate with LOS (P < 0.05). Multivariate regression analysis found low PMA, BMI, and male gender to be independent predictors of increased LOS (P < 0.05)., Conclusion: Sarcopenia correlated with increased LOS and postoperative complications in ERAS patients after PD. Sarcopenia can be used to predict poor candidates for ERAS protocols who may require an alternative recovery protocol, promoting a clinical tier-based approach to ERAS for pancreatic surgery., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Next-generation sequencing (NGS) provides information on genetic mutations and mutant allele frequency in tumor specimens. We investigated the prognostic significance of KRAS mutant allele frequency in patients with right-sided pancreatic ductal adenocarcinoma (PDAC) treated with surgical resection., Methods: A retrospective study reviewed patients who underwent surgical resection for PDAC and analyzed tumors with an in-house mutational panel. Microdissected samples were studied using an NGS-based assay to detect over 200 hotspot mutations in 42 genes (Pan42) commonly involved in PDAC., Results: A total of 144 PDAC right-sided surgical patients with a Pan42 panel were evaluated between 2015 and 2020; 121 patients (84%) harbored a KRAS mutation. Detected mutant allele frequencies were categorized as less than 20% (low mKRAS, n = 92) or greater than or equal to 20% (high mKRAS, n = 29). High mKRAS (KRAS ≥ 20%) patients were noted to have shorter disease-free survival after surgery (11.5 ± 2.1 vs. 19.5 ± 3.5 months, p = 0.03), more advanced tumor stage (p = 0.02), larger tumors (3.6 vs. 2.7 cm, p = 0.001), greater tumor cellularity (26% vs. 18%, p = 0.001), and higher rate of distant recurrence (p = 0.03) than low mKRAS patients., Conclusion: This study demonstrates the importance of KRAS mutant allele frequency on pathological characteristics and prognosis in right-sided PDAC treated with surgery., (© 2022 Wiley Periodicals LLC.)

Background: To identify pancreatectomy specific risk factors for myocardial infarction and cardiac arrest (MICA) and to assess whether addition of new information obtained during the hospitalization changes these risk factors., Methods: Analysis was performed on elective pancreatectomy data from the ACS-NSQIP database (2014-2019). Risk factors were grouped into pre-operative, intra-operative, and postoperative phases. Factors were selected using a bootstrap resampling procedure to determine MICA association. Independent significance was assessed by logistic regression., Results: In the first 30 days post-op, 650 of 39779 patients (1.88%) developed MICA. Some of the surgery specific, intra- and post-operative factors that were identified are: delayed gastric emptying (OR: 2.61; 95% CI: 2.12-3.21), total pancreatectomy (OR: 2.16; 95% CI: 1.29-3.42), pancreatic fistula (OR: 1.54; 95% CI: 1.25-1.90), post-operative transfusion (OR: 1.28; 95% CI: 1.03-1.58), and open approach (OR: 1.36; 95% CI: 1.05-1.77). Adding new variables improved statistical model performance and the c-statistic improved from 0.69 to 0.76 in the final analysis., Conclusion: Surgery specific, intra-, and post-operative factors were associated with MICA. Addition of new information during the hospital course changed risk factors and the statistical prediction of MICA risk improved., (Copyright © 2021 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Pseudomyxoma peritonei (PMP) syndrome is a disease process that typically occurs from ruptured appendiceal mucocele neoplasms. PMP syndrome arising from malignant transformation of an ovarian primary mature cystic teratoma (MCT) is a pathogenesis rarely encountered., Case Presentation: Herein, we report a 28-year-old patient evaluated and treated for a right ovarian mass and large volume symptomatic abdominopelvic mucinous ascites. Molecular profiling and genetic analysis revealed mutations in ATM, GNAS, and KRAS proteins while IHC demonstrated gastrointestinal-specific staining for CK20, CDX2, CK7, and SATB2. Peritoneal cytology showed paucicellular mucin. Diffuse peritoneal adenomucinosis (DPAM) variant of PMP arising from a ruptured ovarian primary MCT after malignant transformation to a low-grade appendiceal-like mucinous neoplasm was ultimately confirmed. Treatment included staged therapeutic tumor debulking and right salpingo-oophorectomy followed by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC)., Conclusions: Our report builds upon the existing literature supporting this aggressive treatment option reserved for advanced abdominal malignancies utilized in this patient with a rare clinical entity., (© 2022. The Author(s).)

Background: This individual-patient data meta-analysis investigated the effects of enhanced recovery after surgery (ERAS) protocols compared with conventional care on postoperative outcomes in patients undergoing pancreatoduodenectomy., Methods: The Cochrane Library, MEDLINE, Embase, Scopus, and Web of Science were searched systematically for articles reporting outcomes of ERAS after pancreatoduodenectomy published up to August 2020. Comparative studies were included. Main outcomes were postoperative functional recovery elements, postoperative morbidity, duration of hospital stay, and readmission., Results: Individual-patient data were obtained from 17 of 31 eligible studies comprising 3108 patients. Time to liquid (mean difference (MD) -3.23 (95 per cent c.i. -4.62 to -1.85) days; P < 0.001) and solid (-3.84 (-5.09 to -2.60) days; P < 0.001) intake, time to passage of first stool (MD -1.38 (-1.82 to -0.94) days; P < 0.001) and time to removal of the nasogastric tube (3.03 (-4.87 to -1.18) days; P = 0.001) were reduced with ERAS. ERAS was associated with lower overall morbidity (risk difference (RD) -0.04, 95 per cent c.i. -0.08 to -0.01; P = 0.015), less delayed gastric emptying (RD -0.11, -0.22 to -0.01; P = 0.039) and a shorter duration of hospital stay (MD -2.33 (-2.98 to -1.69) days; P < 0.001) without a higher readmission rate., Conclusion: ERAS improved postoperative outcome after pancreatoduodenectomy. Implementation should be encouraged., (© The Author(s) 2022. Published by Oxford University Press on behalf of BJS Society Ltd. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Pancreatic cancer (PC) is one of the most aggressive and challenging cancer types to effectively treat, ranking as the fourth-leading cause of cancer death in the United States. We investigated if exposures to angiotensin II receptor blockers (ARBs) or angiotensin I converting enzyme (ACE) inhibitors after PC diagnosis are associated with survival., Methods: PC patients were identified by ICD-9 diagnosis and procedure codes among the 3.7 million adults living in the Emilia-Romagna Region from their administrative health care database containing patient data on demographics, hospital discharges, all-cause mortality, and outpatient pharmacy prescriptions. Cox modeling estimated covariate-adjusted mortality hazard ratios for time-dependent ARB and ACE inhibitor exposures after PC diagnosis., Results: 8,158 incident PC patients were identified between 2003 and 2011, among whom 20% had pancreas resection surgery, 36% were diagnosed with metastatic disease, and 7,027 (86%) died by December 2012. Compared to otherwise similar patients, those exposed to ARBs after PC diagnosis experienced 20% lower mortality risk (HR=0.80; 95% CI: 0.72, 0.89). Those exposed to ACE inhibitors during the first three years of survival after PC diagnosis experienced 13% lower mortality risk (HR=0.87; 95% CI: 0.80, 0.94) which attenuated after surviving three years (HR=1.14; 95% CI: 0.90, 1.45)., Conclusions: The results of this large population study suggest that exposures to ARBs and ACE inhibitors after PC diagnosis are significantly associated with improved survival. ARBs and ACE inhibitors could be important considerations for treating PC patients, particularly those with the worst prognosis and most limited treatment options. Considering that these common FDA approved drugs are inexpensive to payers and present minimal increased risk of adverse events to patients, there is an urgent need for randomized clinical trials, large simple randomized trials, or pragmatic clinical trials to formally and broadly evaluate the effects of ARBs and ACE inhibitors on survival in PC patients., (© 2022. The Author(s).)

Objectives: To compare the efficacy and safety of algenpantucel-L [HyperAcute-Pancreas algenpantucel-L (HAPa); IND# 12311] immunotherapy combined with standard of care (SOC) chemotherapy and chemoradiation to SOC chemotherapy and chemoradiation therapy alone in patients with borderline resectable or locally advanced pancreatic ductal adenocarcinoma (PDAC)., Summary Background Data: To date, immunotherapy has not been shown to benefit patients with borderline resectable or locally advanced unresectable PDAC. HAPa is a cancer vaccine consisting of allogeneic pancreatic cancer cells engineered to express the murine α(1,3)GT gene., Methods: A multicenter, phase 3, open label, randomized (1:1) trial of patients with borderline resectable or locally advanced unresectable PDAC. Patients received neoadjuvant SOC chemotherapy (FOLFIRINOX or gemcitabine/nab-paclitaxel) followed by chemoradiation (standard group) or the same standard neoadjuvant regimen combined with HAPa immunotherapy (experimental group). The primary outcome was overall survival., Results: Between May 2013 and December 2015, 303 patients were randomized from 32 sites. Median (interquartile range) overall survival was 14.9 (12.2-17.8) months in the standard group (N = 158) and 14.3 (12.6-16.3) months in the experimental group (N = 145) [hazard ratio (HR) 1.02, 95% confidence intervals 0.66-1.58; P = 0.98]. Median progression-free survival was 13.4 months in the standard group and 12.4 months in the experimental group (HR 1.33, 95% confidence intervals 0.72-1.78; P = 0.59). Grade 3 or higher adverse events occurred in 105 of 140 patients (75%) in the standard group and in 115 of 142 patients (81%) in the experimental group (P > 0.05)., Conclusions: Algenpantucel-L immunotherapy did not improve survival in patients with borderline resectable or locally advanced unresectable PDAC receiving SOC neoadjuvant chemotherapy and chemoradiation., Trial Registration: ClinicalTrials.gov Identifier: NCT01836432., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: We hypothesized that pancreatic and periampullary adenocarcinoma recurrence after surgical resection may be affected by the shedding of malignant epithelial cells during surgical dissection and that this may have implications for disease recurrence and survival., Study Design: In this ongoing, investigator-initiated prospective randomized controlled trial, patients with pancreatic and periampullary adenocarcinoma were randomized intraoperatively, postresection into 3 study arms: peritoneal lavage using 10 L normal saline or distilled water, or control group with no lavage. Peritoneal fluid was sampled for cytologic analysis (cytospin, cellblock, immunohistochemistry-Ber-EP4 antibody) at 4 stages: (1) abdominal entry pre-dissection, (2) resection bed after tumor extirpation, (3) ex vivo resected specimen, and (4) resection bed postlavage., Results: Between April 2016 and May 2018, 193 patients who underwent randomization for the study also underwent the described cytologic sampling. Of these, 167 patients (86.5%) were ultimately found to have pancreatic or periampullary adenocarcinoma. Before dissection (1) on cytospin analysis, 4.9% were positive, which rose to 10.2% intraoperatively (2), 16.7% ex vivo (3), and decreased to 4.3% (4) after lavage. Lymph node metastasis, margin involvement, and perineural invasion did not correlate with locoregional recurrence (LR). Tumor cells in the ex vivo cytospin (3) correlated with LR (odds ratio 3.8 [95% CI 1.6 to 9.2], p = 0.005) and LR disease-free survival (p = 0.007). Cox regression analysis revealed ex vivo cytospin positivity to be strongly associated with poorer LR disease-free survival (hazard ratio 2.26 [95% CI 1.16 to 4.42], p = 0.017)., Conclusions: Cytologic sampling from ex vivo specimen irrigation after surgical resection of pancreatic and periampullary adenocarcinoma may have implications for LR, survival, and treatment, suggesting a possible cancer cell shedding phenotype., (Copyright © 2022 by the American College of Surgeons. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Objective: The aim of this study was to evaluate whether neoadjuvant therapy (NAT) critically influenced microscopically complete resection (R0) rates and long-term outcomes for patients with pancreatic ductal adenocarcinoma who underwent pancreatoduodenectomy (PD) with portomesenteric vein resection (PVR) from a diverse, world-wide group of high-volume centers., Summary of Background Data: Limited size studies suggest that NAT improves R0 rates and overall survival compared to upfront surgery in R/BR-PDAC patients., Methods: This multicenter study analyzed consecutive patients with R/BR-PDAC who underwent PD with PVR in 23 high-volume centers from 2009 to 2018., Results: Data from 1192 patients with PD and PVR were collected and analyzed. The median age was 68 [interquartile range (IQR) 60-73] years and 52% were males. Some 186 (15.6%) and 131 (10.9%) patients received neoadjuvant chemotherapy (NAC) alone and neoadjuvant chemoradiotherapy, respectively. The R0/R1/R2 rates were 57%, 39.3%, and 3.2% in patients who received NAT compared to 46.6%, 49.9%, and 3.5% in patients who did not, respectively (P =0.004). The 1-, 3-, and 5-year OS in patients receiving NAT was 79%, 41%, and 29%, while for those that did not it was 73%, 29%, and 18%, respectively (P <0.001). Multivariable analysis showed no administration of NAT, high tumor grade, lymphovascular invasion, R1/R2 resection, no adjuvant chemotherapy, occurrence of Clavien-Dindo grade 3 or higher postoperative complications within 90 days, preoperative diabetes mellitus, male sex and portal vein involvement were negative independent predictive factors for OS., Conclusion: Patients with PDAC of the pancreatic head expected to undergo venous reconstruction should routinely be considered for NAT., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)