Faculty Bibliography

INTRODUCTION/BACKGROUND:The influence of baseline health-related quality of life (HRQoL) on peri-operative outcomes in pancreatobiliary (PB) patients is not well established. This study investigated the impact of baseline HRQoL on peri-operative outcomes and the effect of surgery on HRQoL. METHODS:A secondary post-hoc analysis of a multicenter trial (2011-2016) assessed PB patients undergoing pancreatectomy. Pre-operative and 30-day post-operative FACT-G surveys were analyzed. Logistic regressions determined associations between baseline HRQoL scores and 60-day major complications. Subgroup analysis evaluated change in HRQoL (pre-operative to 30-day scores). RESULTS:Among 391 patients, higher baseline HRQoL (FACT-G overall OR 0.54,p ​= ​0.04) was associated with decreased likelihood of developing major complications. Surgery resulted in improvement in HRQoL for patients with chronic pancreatitis (10.2 points) compared to other pathologies (-7 to 3.9 points). CONCLUSION/CONCLUSIONS:Baseline HRQoL was associated with post-operative complications and HRQoL significantly improved for patients with chronic pancreatitis, highlighting the importance of HRQoL on patient-centered outcomes.

BACKGROUND:Intraductal papillary mucinous neoplasm (IPMN)-derived pancreatic cancer was previously categorized into tubular, colloid, and oncocytic subtypes. Intraductal oncocytic papillary neoplasms (IOPN) has long been associated with superior prognosis/indolent behavior, however, there is discordant emerging evidence. This study aimed to investigate this conflicting literature. METHODS:Patients with resected IOPN-derived and IPMN-derived pancreatic cancer were identified from six international centers. Log-rank tests compared time to (TtR) and survival after (SAR) recurrence and five-year overall survival (OS). A multivariable mixed model was used to determine hazard ratios (HR) with confidence intervals (95%CI) for five-year survival. RESULTS:Of 879 patients, 20 (2%) had IOPN-derived pancreatic cancer. Most patients had T1 (55%) or N0 (70%) disease. IOPN and colloid IPMN-derived pancreatic cancers had similar recurrence rates (25% vs. 24%), while recurrence was more common in tubular IPMN-derived pancreatic cancer (42%, p < 0.001). IOPN-derived pancreatic cancer displayed a longer TtR and SAR compared to colloid and tubular IPMN-derived pancreatic cancers. IOPN-derived and colloid IPMN-derived cancers demonstrated significantly lower 5-year mortality risks compared to tubular IPMN-derived cancers (74% and 27% risk reduction, respectively; p < 0.05). CONCLUSION/CONCLUSIONS:IOPN-derived pancreatic cancers have excellent OS. However, some patients have poor prognostic factors and are at risk for both local and systemic recurrence. Given more indolent disease progression given delayed TtR and prolonged SAR compared to colloid and tubular IPMN-derived pancreatic cancers, there may be a role for prolonged surveillance.

BACKGROUND:Antithrombotic therapy (AT) aims to strike a balance between preventing thromboembolic and hemorrhagic complications. However, evidence for AT management after pancreatectomy with vascular reconstruction is lacking. We aimed to provide an overview of the current use of AT for pancreatic surgery with vascular reconstructions. PATIENTS AND METHODS/METHODS:A web-based survey was distributed to 123 surgeons from high-volume pancreas centers (>50 pancreatic resections/year). AT management after different types of vascular reconstruction were investigated. An "aggressive" protocol was defined as the use of any AT protocol other than prophylactic heparin, aspirin, or their combination. RESULTS:The survey was completed by 80 surgeons (59% Europe, 30% USA, 11% Asia). In Europe/Asia, prophylactic heparin was the most commonly reported protocol after partial venous resection/end-to-end anastomosis/human graft (71%/65%/50%, respectively), and an "aggressive" protocol (86%) was the most frequently used after prosthetic graft reconstruction. Conversely, in the USA, prophylactic heparin + aspirin was the most commonly reported protocol after all types of venous reconstruction. Following arterial reconstruction, heparin + aspirin was the most commonly reported protocol, regardless of region. An "aggressive" protocol was more frequently used in Europe/Asia (odds ratio (OR) 1.28; p < 0.001) and following vein reconstruction with either human graft (OR 1.2; p = 0.007) or prosthetic graft (OR 1.56, p <0.001), while ultrasound (OR 1.65; p < 0.001) and arterial reconstruction (OR 1.64; p < 0.001) were significantly associated with antiplatelet use. CONCLUSIONS:In an international cohort of high-volume pancreas surgeons, significant variation in the use of AT following pancreatectomy with vascular reconstruction was observed. This variation was driven by geographical differences and the type of vascular reconstructions performed. In an international cohort of high-volume pancreas surgeons, this Worldwide Snapshot Survey analyzed the current use of antithrombotic therapy for pancreatic surgery with vascular reconstruction. A significant heterogeneity in antithrombotic practice was found and it was mainly driven by geographical differences and the type of vascular reconstructions performed.

SUMMARY OF BACKGROUND DATA/BACKGROUND:Intraductal papillary mucinous neoplasm (IPMN)-derived pancreatic cancer is typically managed like pancreatic intraepithelial neoplasia (PanIN)-derived pancreatic cancer. However, in IPMN-derived pancreatic cancer, the role of chemotherapy remains controversial, particularly in the neoadjuvant setting (NAT). OBJECTIVE:To evaluate the role of neoadjuvant chemotherapy in IPMN-derived pancreatic cancer. METHODS:Patients with IPMN-derived pancreatic cancer treated with either upfront surgery (US) or NAT were identified from eight international centers (2000-2023). Clinicopathologic data were compared. Date of first treatment was used for Kaplan-Meier and log-rank tests to compare overall (OS) and recurrence free survival (RFS). Multivariable Cox-regression was performed in patients that underwent NAT. RESULTS:In 1,019 patients, 76 (7%) underwent NAT. Patients who received NAT had higher baseline CA19-9 levels (P<0.001). Of these 76 patients, 27 (36%), 20 (26%), and 29 (38%) had resectable, borderline resectable, or locally advanced pancreatic cancer at diagnosis, respectively. Advanced resectability stage was significantly more common in the NAT patients as compared to those who underwent US (P<0.001). OS for US patients was 38.0 months (95%CI: 33.7.1-44.3), which was not statistically different than those that received NAT [27.5 mo (95%CI: 23.1-46.7), P=0.121]. This was also valid for patients with resectable disease [US: 38.1 mo vs. NAT: 35.6 mo, P=0.920)]. Complete or marked pathological treatment response (P=0.046) and serological CA19-9 normalization after NAT (P=0.017) were associated with improved survival. On Cox-regression for OS, N2 disease [HR: 4.15 (95%CI: 1.71-10.10)], elevated CA19-9 [HR: 2.02 (95%CI:1.06-3.85)] and R1 margin [HR: 2.36 (95%CI:1.20-4.61)] was independently associated with OS after NAT, while resectability status was not. CONCLUSION/CONCLUSIONS:After NAT and resection, advanced resectability stage was not associated with worse OS indicating the value of this approach for borderline resectable and locally advanced IPMN-derived pancreatic cancer. The benefit of NAT in resectable disease is unclear and may require an individualized approach. Biological treatment effect can be assessed with CA19-9 and confirmed by pathologic response.

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

Total pancreatectomy with islet autotransplantation is a therapeutic option to effectively achieve pain relief and improvements in quality of life for selected patients with debilitating pain from chronic pancreatitis. The understanding of the best application and clinical execution of this procedure is in evolution, with outcomes studies and clinical trials in progress.

Islet/β-cell transplantation offers great hope for patients with type 1 diabetes. We assessed the mechanisms of how intrahepatic coinfusion of human α-1 antitrypsin (hAAT)-engineered mesenchymal stromal cells (hAAT-MSCs) improves survival of human islet grafts posttransplantation (PT). Longitudinal in vivo bioluminescence imaging studies identified significantly more islets in the livers bearing islets cotransplanted with hAAT-MSCs compared with islets transplanted alone. In vitro mechanistic studies revealed that hAAT-MSCs inhibit macrophage migration and suppress IFN-γ-induced M1-like macrophages while promoting IL-4-induced M2-like macrophages. In vivo this translated to significantly reduced CD11c+ and F4/80+ cells and increased CD206+ cells around islets cotransplanted with hAAT-MSCs as identified by multiplex immunofluorescence staining. Recipient-derived F4/80+and CD11b+ macrophages were mainly present in the periphery of an islet, while CD11c+ and CD206+ cells appeared inside an islet. hAAT-MSCs inhibited macrophage migration and skewed the M1-like phenotype toward an M2 phenotype both in vitro and in vivo, which may have favored islet survival. These data provide evidence that hAAT-MSCs cotransplanted with islets remain in the liver and shift macrophages to a protective state that favors islet survival. This novel strategy may be used to enhance β-cell survival during islet/β-cell transplantation for the treatment of type 1 diabetes or other diseases.

INTRODUCTION:Distal pancreatectomy has not been well examined in the modern era to guide management for pancreatitis. We evaluated this heterogeneous group and the preoperative factors associated with clinically relevant postoperative pancreatic fistula (CR-POPF). METHODS:Patients undergoing distal pancreatectomy at a single academic institution from August 2012 to January 2020 were evaluated. Univariate and multivariate logistic regressions were conducted between preoperative factors and CR-POPF. RESULTS:One hundred and thirty patients underwent distal pancreatectomy. Indication for operative management included chronic pancreatitis and/or pseudotumor in 24.6% (n = 32), disconnected left pancreatic remnant in 31.5% (n = 41), chronic distal pseudocyst in 20.8% (n = 27), and distal necrosis in 13.8% (n = 18). Significant complications (Clavien-Dindo grade ≥ III) were seen in 34% of patients. After surgery, 34.2% developed diabetes, 40% had persistent opioid use, and 22.3% had CR-POPF. In multivariate analysis, male sex was significantly associated with CR-POPF (odds ratio 3.1, P = 0.037), and having a preoperative, therapeutic endoscopic retrograde cholangiopancreatography was protective (odds ratio 0.28, P = 0.020). CONCLUSIONS:Distal pancreatectomy is undertaken in pancreatitis with high morbidity. Female sex and preoperative, therapeutic endoscopic retrograde cholangiopancreatography were significant protective factors for CR-POPF. The natural history of this approach is relevant for those with distal pancreatitis failing medical management.