Faculty Bibliography

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.

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.

Chronic pancreatitis (CP) is a complex disease involving pancreatic inflammation and fibrosis, glandular atrophy, abdominal pain and other symptoms. Several rodent models have been developed to study CP, of which the bile duct 2,4,6 -trinitrobenzene sulfonic acid (TNBS) infusion model replicates the features of neuropathic pain seen in CP. However, bile duct drug infusion in mice is technically challenging. This protocol demonstrates the procedure of bile duct TNBS infusion for generation of a CP mouse model. TNBS was infused into the pancreas through the ampulla of Vater in the duodenum. This protocol optimized drug volume, surgical techniques, and drug handling during the procedure. TNBS-treated mice showed features of CP as reflected by bodyweight and pancreas weight reductions, changes in pain-associated behaviors, and abnormal pancreatic morphology. With these improvements, mortality associated with TNBS injection was minimal. This procedure is not only critical in generating pancreatic disease models but is also useful in local pancreatic drug delivery.

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.

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: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.

Circulating microRNAs (miRNAs) can be biomarkers for diagnosis and progression of several pathophysiological conditions. In a cohort undergoing total pancreatectomy with islet autotransplantation (TPIAT) from the multicenter Prospective Observational Study of TPIAT (POST), we investigated associations between a panel of circulating miRNAs (hsa-miR-375, hsa-miR-29b-3p, hsa-miR-148a-3p, hsa-miR-216a-5p, hsa-miR-320d, hsa-miR-200c, hsa-miR-125b, hsa-miR-7-5p, hsa-miR-221-3p, hsa-miR-122-5p) and patient, disease and islet-isolation characteristics. Plasma samples (n = 139) were collected before TPIAT and miRNA levels were measured by RTPCR. Disease duration, prior surgery, and pre-surgical diabetes were not associated with circulating miRNAs. Levels of hsa-miR-29b-3p (P = 0.03), hsa-miR-148a-3p (P = 0.04) and hsa-miR-221-3p (P = 0.01) were lower in those with genetic risk factors. Levels of hsa-miR-148a-3p (P = 0.04) and hsa-miR-7-5p (P = 0.04) were elevated in toxic/metabolic disease. Participants with exocrine insufficiency had lower hsa-miR-29b-3p, hsa-miR-148a-3p, hsa-miR-320d, hsa-miR-221-3p (P < 0.01) and hsa-miR-375, hsa-miR-200c-3p, and hsa-miR-125b-5p (P < 0.05). Four miRNAs were associated with fasting C-peptide before TPIAT (hsa-miR-29b-3p, r = 0.18; hsa-miR-148a-3p, r = 0.21; hsa-miR-320d, r = 0.19; and hsa-miR-221-3p, r = 0.21; all P < 0.05), while hsa-miR-29b-3p was inversely associated with post-isolation islet equivalents/kg and islet number/kg (r = -0.20, P = 0.02). Also, hsa-miR-200c (r = 0.18, P = 0.03) and hsa-miR-221-3p (r = 0.19, P = 0.03) were associated with islet graft tissue volume. Further investigation is needed to determine the predictive potential of these miRNAs for assessing islet autotransplant outcomes.

DESCRIPTION:The purpose of this American Gastroenterological Association (AGA) Institute Clinical Practice Update is to review the available evidence and expert recommendations regarding the clinical care of patients with pancreatic necrosis and to offer concise best practice advice for the optimal management of patients with this highly morbid condition. METHODS:This expert review was commissioned and approved by the AGA Institute Clinical Practice Updates Committee and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership, and underwent internal peer review by the Clinical Practice Updates Committee and external peer review through standard procedures of Gastroenterology. This review is framed around the 15 best practice advice points agreed upon by the authors, which reflect landmark and recent published articles in this field. This expert review also reflects the experiences of the authors, who are advanced endoscopists or hepatopancreatobiliary surgeons with extensive experience in managing and teaching others to care for patients with pancreatic necrosis. BEST PRACTICE ADVICE 1: Pancreatic necrosis is associated with substantial morbidity and mortality and optimal management requires a multidisciplinary approach, including gastroenterologists, surgeons, interventional radiologists, and specialists in critical care medicine, infectious disease, and nutrition. In situations where clinical expertise may be limited, consideration should be given to transferring patients with significant pancreatic necrosis to an appropriate tertiary-care center. BEST PRACTICE ADVICE 2: Antimicrobial therapy is best indicated for culture-proven infection in pancreatic necrosis or when infection is strongly suspected (ie, gas in the collection, bacteremia, sepsis, or clinical deterioration). Routine use of prophylactic antibiotics to prevent infection of sterile necrosis is not recommended. BEST PRACTICE ADVICE 3: When infected necrosis is suspected, broad-spectrum intravenous antibiotics with ability to penetrate pancreatic necrosis should be favored (eg, carbapenems, quinolones, and metronidazole). Routine use of antifungal agents is not recommended. Computed tomography-guided fine-needle aspiration for Gram stain and cultures is unnecessary in the majority of cases. BEST PRACTICE ADVICE 4: In patients with pancreatic necrosis, enteral feeding should be initiated early to decrease the risk of infected necrosis. A trial of oral nutrition is recommended immediately in patients in whom there is absence of nausea and vomiting and no signs of severe ileus or gastrointestinal luminal obstruction. When oral nutrition is not feasible, enteral nutrition by either nasogastric/duodenal or nasojejunal tube should be initiated as soon as possible. Total parenteral nutrition should be considered only in cases where oral or enteral feeds are not feasible or tolerated. BEST PRACTICE ADVICE 5: Drainage and/or debridement of pancreatic necrosis is indicated in patients with infected necrosis. Drainage and/or debridement may be required in patients with sterile pancreatic necrosis and persistent unwellness marked by abdominal pain, nausea, vomiting, and nutritional failure or with associated complications, including gastrointestinal luminal obstruction; biliary obstruction; recurrent acute pancreatitis; fistulas; or persistent systemic inflammatory response syndrome. BEST PRACTICE ADVICE 6: Pancreatic debridement should be avoided in the early, acute period (first 2 weeks), as it has been associated with increased morbidity and mortality. Debridement should be optimally delayed for 4 weeks and performed earlier only when there is an organized collection and a strong indication. BEST PRACTICE ADVICE 7: Percutaneous drainage and transmural endoscopic drainage are both appropriate first-line, nonsurgical approaches in managing patients with walled-off pancreatic necrosis (WON). Endoscopic therapy through transmural drainage of WON may be preferred, as it avoids the risk of forming a pancreatocutaneous fistula. BEST PRACTICE ADVICE 8: Percutaneous drainage of pancreatic necrosis should be considered in patients with infected or symptomatic necrotic collections in the early, acute period (<2 weeks), and in those with WON who are too ill to undergo endoscopic or surgical intervention. Percutaneous drainage should be strongly considered as an adjunct to endoscopic drainage for WON with deep extension into the paracolic gutters and pelvis or for salvage therapy after endoscopic or surgical debridement with residual necrosis burden. BEST PRACTICE ADVICE 9: Self-expanding metal stents in the form of lumen-apposing metal stents appear to be superior to plastic stents for endoscopic transmural drainage of necrosis. BEST PRACTICE ADVICE 10: The use of direct endoscopic necrosectomy should be reserved for those patients with limited necrosis who do not adequately respond to endoscopic transmural drainage using large-bore, self-expanding metal stents/lumen-apposing metal stents alone or plastic stents combined with irrigation. Direct endoscopic necrosectomy is a therapeutic option in patients with large amounts of infected necrosis, but should be performed at referral centers with the necessary endoscopic expertise and interventional radiology and surgical backup. BEST PRACTICE ADVICE 11: Minimally invasive operative approaches to the debridement of acute necrotizing pancreatitis are preferred to open surgical necrosectomy when possible, given lower morbidity. BEST PRACTICE ADVICE 12: Multiple minimally invasive surgical techniques are feasible and effective, including videoscopic-assisted retroperitoneal debridement, laparoscopic transgastric debridement, and open transgastric debridement. Selection of approach is best determined by pattern of disease, physiology of the patient, experience and expertise of the multidisciplinary team, and available resources. BEST PRACTICE ADVICE 13: Open operative debridement maintains a role in the modern management of acute necrotizing pancreatitis in cases not amenable to less invasive endoscopic and/or surgical procedures. BEST PRACTICE ADVICE 14: For patients with disconnected left pancreatic remnant after acute necrotizing mid-body necrosis, definitive surgical management with distal pancreatectomy should be undertaken in patients with reasonable operative candidacy. Insufficient evidence exists to support the management of the disconnected left pancreatic remnant with long-term transenteric endoscopic stenting. BEST PRACTICE ADVICE 15: A step-up approach consisting of percutaneous drainage or endoscopic transmural drainage using either plastic stents and irrigation or self-expanding metal stents/lumen-apposing metal stents alone, followed by direct endoscopic necrosectomy, and then surgical debridement is reasonable, although approaches may vary based on the available clinical expertise.

Islet autotransplantation (IAT) is increasingly being performed to mitigate against the diabetic complications of pancreatic resection in patients with benign inflammatory pancreatic disorders; however, the glycemic benefit of IAT in patients undergoing partial pancreatic resection is not known. We aimed to determine whether IAT improved glycemic outcomes in patients undergoing distal pancreatectomy for benign inflammatory disease. We performed a multicenter, retrospective case-control study of patients who underwent distal pancreatic resection with IAT at two U S tertiary care centers. The primary outcome was the mean change in pre- vs post-operative HgA1c following transplant as well as the development of new post-operative diabetes. Nine patients requiring distal pancreatectomy for benign disease underwent IAT and were compared to 13 historical controls without IAT. Baseline characteristics were similar between groups. With a median follow-up of 22 months, those who received an IAT had a smaller increase in their pre- vs post-operative HgA1c (0.42 vs 2.83, P = .004), and one case patient (14.3%) vs three control patients (23.1%) developed new post-operative diabetes (P = .581). We conclude that patients undergoing distal pancreatic resection for benign inflammatory disease should be considered for IAT, as long-term glycemic outcomes appear to be improved in those undergoing transplant.