Faculty Bibliography

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.

Chronic pancreatitis (CP) is characterized by pancreatic inflammation, fibrosis, and abdominal pain that is challenging to treat. Mesenchymal stromal cells (MSCs) overexpressing human alpha-1 antitrypsin (hAAT-MSCs) showed improved mobility and protective functions over native MSCs in nonobese diabetic mice. We investigated whether hAAT-MSCs could mitigate CP and its associated pain using trinitrobenzene sulfonic acid (TNBS)-induced CP mouse models. CP mice were given native human MSCs or hAAT-MSCs (0.5 × 10⁶ cells/mouse, i.v., n = 6-8/group). The index of visceral pain was measured by graduated von Frey filaments. Pancreatic morphology and pancreatic mast cell count were analyzed by morphological stains. Nociceptor transient receptor potential vanilloid 1 (TRPV1) expression in dorsal root ganglia (DRG) was determined by immunohistochemistry. hAAT-MSC-treated CP mice best preserved pancreatic morphology and histology. MSC or hAAT-MSC infusion reduced abdominal pain sensitivities. hAAT-MSC therapy also suppressed TRPV1 expression in DRG and reduced pancreatic mast cell density induced by TNBS. Overall, hAAT-MSCs reduced pain and mitigated pancreatic inflammation in CP equal to MSCs with a trend toward a higher pancreatic weight and better pain relief in the hAAT-MSC group compared to the MSC group. Both MSCs and hAAT-MSCs might be used as a novel therapeutic tool for CP-related pain.

Several cytokines and chemokines are elevated after islet infusion in patients undergoing total pancreatectomy with islet autotransplantation (TPIAT), including CXCL8 (also known as interleukin-8), leading to islet loss. We investigated whether use of reparixin for blockade of the CXCL8 pathway would improve islet engraftment and insulin independence after TPIAT. Adults without diabetes scheduled for TPIAT at nine academic centers were randomized to a continuous infusion of reparixin or placebo (double-blinded) for 7 days in the peri-transplant period. Efficacy measures included insulin independence (primary), insulin dose, hemoglobin A_1c (HbA_1c ), and mixed meal tolerance testing. The intent-to-treat population included 102 participants (age 39.5 ± 12.2 years, 69% female), n = 50 reparixin-treated, n = 52 placebo-treated. The proportion insulin-independent at Day 365 was similar in reparixin and placebo: 20% vs. 21% (p = .542). Twenty-seven of 42 (64.3%) in the reparixin group and 28/45 (62.2%) in the placebo group maintained HbA_1c ≤6.5% (p = .842, Day 365). Area under the curve C-peptide from mixed meal testing was similar between groups, as were adverse events. In conclusion, reparixin infusion did not improve diabetes outcomes. CXCL8 inhibition alone may be insufficient to prevent islet damage from innate inflammation in islet autotransplantation. This first multicenter clinical trial in TPIAT highlights the potential for future multicenter collaborations.

BACKGROUND:Our objective was to assess the relationship between overall survival (OS) and distance travelled to the treating facility for patients undergoing liver resection for hepatocellular carcinoma and to determine whether this relationship was dependent upon the structural factors of the treating facility. METHODS:Using National Cancer Database, we focused on extremes of travel: Local (<12.5 miles to treating facility) and Travel (≥50 miles). We analyzed OS with Cox models; we estimated stratified models to assess interaction between distance and facility characteristics (volume, academic status). RESULTS:We included 6860 patients. After correction for confounding, distance travelled was not associated with OS (p = 0.444). However, Travel patients treated at high-volume, academic centers had worse OS compared to Local patients (HR 1.54, 95%CI 1.07-2.21); this association was not seen for patients treated at low volume, academic centers (p = 0.708) high volume non-academic centers (p = 0.174) or low volume non-academic centers (p = 515). CONCLUSION/CONCLUSIONS:For those patients treated at high-volume, academic centers, living far from the facility was associated with worse OS. The reasons for this association should be investigated further.

OBJECTIVES:Smoking and alcohol use are risk factors for acute and chronic pancreatitis, and their role on anxiety, depression, and opioid use in patients who undergo total pancreatectomy and islet autotransplantation (TPIAT) is unknown. METHODS:We included adults enrolled in the Prospective Observational Study of TPIAT (POST). Measured variables included smoking (never, former, current) and alcohol abuse or dependency history (yes vs no). Using univariable and multivariable analyses, we investigated the association of smoking and alcohol dependency history with anxiety and depression, opioid use, and postsurgical outcomes. RESULTS:Of 195 adults studied, 25 were current smokers and 77 former smokers, whereas 18 had a history of alcohol dependency (of whom 10 were current smokers). A diagnosis of anxiety was associated with current smoking (P = 0.005), and depression was associated with history of alcohol abuse/dependency (P = 0.0001). However, active symptoms of anxiety and depression at the time of TPIAT were not associated with smoking or alcohol status. Opioid use in the past 14 days was associated with being a former smoker (P = 0.005). CONCLUSIONS:Active smoking and alcohol abuse history were associated with a diagnosis of anxiety and depression, respectively; however, at the time of TPIAT, symptom scores suggested that they were being addressed.

BACKGROUND:Although volume-outcome literature supports regionalization for complex procedures, travel may be burdensome. We assessed the relationship between overall survival and travel distance for patients undergoing pancreatic resection for adenocarcinoma. METHODS:We analyzed the Fall 2018 National Cancer Database Public Use File. We defined distance traveled as a categorical variable (<12.5 miles, 12.5-50mi, and >50mi). We analyzed overall survival (OS) as a function of distance traveled using the log rank test and Cox proportional hazards models; we estimated stratified models to assess for interaction between distance and other relevant covariates. RESULTS:In adjusted analysis of 39,089 patients, greater distance was associated with decreased OS (p = 0.0029). We found interactions between distance and center type, comorbidities, and age. Distance traveled was a negative factor for patients treated at low-volume academic centers (but not high-volume academic or non-academic centers). Additionally, distance traveled was a negative factor for OS in young, healthy patients but not geriatric, ill patients. CONCLUSION:Traveling more than 12.5 miles for pancreatic resection was associated with worse OS. Prior to regionalization, evaluation of local resources may be necessary.