One Degree of Separation: John Malone Howard, MD, Father of Pancreatology

Presentation slides for lecture delivered by Nicholas J. Zyromski, MD (Professor of Surgery, Indiana University School of Medicine) on April 19, 2021. John M. Howard, MD (1919-2011) was a giant in surgery and his many contributions include directing the U.S. Army’s MASH research unit during the Korean conflict and expanding this work to developing the U.S. Trauma Systems (for the latter, he was awarded the presidential Legion of Merit). Dr. Howard was an international leader and one of the fathers of pancreatology. His work with the pancreas included describing and highlighting the importance of gallstones in pancreatitis pathogenesis, and perhaps most notably his dedication and tenacity with pancreatic head resection. Dr. Nicholas Zyromski was fortunate to call Dr. Howard a mentor and friend; this talk will touch on some of Dr. Howard’s life highlights, including his passion for scholarship and lifetime lessons. Presentation recording available online: [LINK]https://purl.dlib.indiana.edu/iudl/media/f26811rx4p[/LINK]This event was sponsored by the John Shaw Billings History of Medicine Society, IU School of Medicine History of Medicine Student Interest Group, IUPUI Medical Humanities & Health Studies Program, and the Ruth Lilly Medical Library

Transgastric Pancreatic Necrosectomy: How I Do It

Necrotizing pancreatitis is a serious medical problem that often requires intervention to debride necrotic pancreatic and peripancreatic tissue. Recently, minimally invasive approaches have been applied to pancreatic necrosectomy. The purpose of this report is to review the history of transgastric pancreatic debridement, identify appropriate patient selection criteria, and highlight technical “pearls.” We present this subject matter in the context of our own clinical experience, with a primary focus on a “How I Do It” type of technical description

Post-Pancreatoduodenectomy Outcomes and Epidural Analgesia: A 5-Year Single Institution Experience

Introduction Optimal pain control post-pancreatoduodenectomy is a challenge. Epidural analgesia (EDA) is increasingly utilized despite inherent risks and unclear effects on outcomes. Methods All pancreatoduodenectomies (PD) performed from 1/2013-12/2017 were included. Clinical parameters were obtained from retrospective review of a prospective clinical database, the ACS NSQIP prospective institutional database and medical record review. Chi-Square/Fisher’s Exact and Independent-Samples t-Tests were used for univariable analyses; multivariable regression (MVR) was performed. Results 671 consecutive PD from a single institution were included (429 EDA, 242 non-EDA). On univariable analysis, EDA patients experienced significantly less wound disruption (0.2% vs. 2.1%), unplanned intubation (3.0% vs. 7.9%), pulmonary embolism (0.5% vs. 2.5%), mechanical-ventilation >48hrs (2.1% vs. 7.9%), septic shock (2.6% vs. 5.8%), and lower pain scores. On MVR accounting for baseline group differences (gender, hypertension, pre-operative transfusion, labs, approach, pancreatic duct size), EDA was associated with less superficial wound infections (OR 0.34; CI 0.14-0.83; P=0.017), unplanned intubations (OR 0.36; CI 0.14-0.88; P=0.024), mechanical ventilation >48 hrs (OR 0.22; CI 0.08-0.62; P=0.004), and septic shock (OR 0.39; CI 0.15-1.00; P=0.050). EDA improved pain scores post-PD days 1-3 (P<0.001). No differences were seen in cardiac or renal complications; pancreatic fistula (B+C) or delayed gastric emptying; 30/90-day mortality; length of stay, readmission, discharge destination, or unplanned reoperation. Conclusion Based on the largest single institution series published to date, our data support the use of EDA for optimization of pain control. More importantly, our data document that EDA significantly improved infectious and pulmonary complications

Targeting Ref-1/APE1 Pathway Inhibition in Pancreatic Cancer Using APX3330 for Clinical Trials

poster abstractPancreatic ductal adenocarcinoma is the 4th leading cause of cancer-related mortality in the US. Most patients present with advanced disease and ~95% die within five years, most surviving under six months. Targeted therapies offer modest improvement in survival, albeit at an increase in side effects and unwanted toxicities. Ref-1 regulates transcription factors involved in pancreatic cancer cell survival signaling due to its redox-coactivator activity, such as HIF-1α, NFκB, NRF2 and STAT3. High expression levels of Ref-1 indicate decreased survival in PDAC and other cancers. APX3330, a specific Ref-1 inhibitor, has been shown in multiple in vitro and in vivo pancreatic cancer models to be effective in reducing tumor growth and metastases. The safety and dose administration of APX3330 have been previously established, including toxicology, phase I, and phase II clinical evaluation in non-cancer patients in Japan (Eisai). We have partnered with ApeX Therapeutics to develop APX3330 for cancer treatment (phase I trial anticipated early 2016). We studied interactions of Ref-1, APX3330, convergent pathways; i.e. HIF-1α and STAT3, and downstream targets like CAIX. We performed in vivo studies demonstrating single and combination effects of APX3330 with Gemcitabine (Gem) showing significantly decreased tumor volume in the combination treatments. We also tested single and combination studies of APX3330 in an ex vivo 3-D tumor-stroma model system using patient derived tumor cells along with patient derived cancer-associated fibroblasts. We used the CAIX inhibitor SLC-0111 and JAK2 inhibitor, Ruxolitinib; both in clinical trials. In our system, APX3330 decreases the tumor area and intensity in a dose-dependent manner. The combination of APX3330 with Gem demonstrated an additive enhancement effect in the tumor, and APX3330 with SLC-0111/Ruxolitinib enhanced tumor killing. These data demonstrate APX3330 single agent efficacy in our 3D patient model and enhanced tumor killing when pathways regulated by Ref-1, HIF-1 and STAT3 are blocked

Annular pancreas: endoscopic and pancreatographic findings from a tertiary referral ERCP center

Background and Aims Annular pancreas is a congenital anomaly whereby pancreatic tissue encircles the duodenum. Current knowledge of endoscopic findings of annular pancreas is limited to small case series. The aim of this study was to describe the endoscopic and pancreatographic findings of patients with annular pancreas at a large tertiary care ERCP center. Methods This is a retrospective observational study. Our Institutional Review Board–approved, prospectively collected ERCP database was queried for cases of annular pancreas. The electronic medical records were searched for patient and procedure-related data. Results From January 1, 1994, to December 31, 2016, 46 patients with annular pancreas underwent ERCP at our institution. Index ERCP was technically successful in 42 patients (91.3%), and technical success was achieved in all 46 patients (100%) after 2 attempts, when required. A duodenal narrowing or ring was found in most patients (n = 39, 84.8%), yet only 2 (4.3%) had retained gastric contents. Pancreas divisum was found in 21 patients (45.7%), 18 of which were complete divisum. Pancreatobiliary neoplasia was the indication for ERCP in 7 patients (15.2%). Pancreatographic findings consistent with chronic pancreatitis were noted in 15 patients (32.6%) at the index ERCP. Conclusion This is the largest series describing the endoscopic and pancreatographic findings of patients with annular pancreas. We found that 45.7% of patients had concurrent pancreas divisum. Endoscopic therapy was successful in most patients at our institution after 1 ERCP, and in all patients after a second ERCP. Nearly one-third of patients had findings consistent with chronic pancreatitis at the time of index ERCP. It is unclear whether this may be a feature of the natural history of annular pancreas

Adipocytes enhance murine pancreatic cancer growth via a hepatocyte growth factor (HGF)-mediated mechanism

INTRODUCTION: Obesity accelerates the development and progression of pancreatic cancer, though the mechanisms underlying this association are unclear. Adipocytes are biologically active, producing factors such as hepatocyte growth factor (HGF) that may influence tumor progression. We therefore sought to test the hypothesis that adipocyte-secreted factors including HGF accelerate pancreatic cancer cell proliferation. MATERIAL AND METHODS: Murine pancreatic cancer cells (Pan02 and TGP-47) were grown in a) conditioned medium (CM) from murine F442A preadipocytes, b) HGF-knockdown preadipocyte CM, c) recombinant murine HGF at increasing doses, and d) CM plus HGF-receptor (c-met) inhibitor. Cell proliferation was measured using the MTT assay. ANOVA and t-test were applied; p < 0.05 considered significant. RESULTS: Wild-type preadipocyte CM accelerated Pan02 and TGP-47 cell proliferation relative to control (59 ± 12% and 34 ± 12%, p < 0.01, respectively). Knockdown of preadipocyte HGF resulted in attenuated proliferation vs. wild type CM in Pan02 cells (35 ± 5% vs. 68 ± 14% greater than control; p < 0.05), but proliferation in TGP-47 cells remained unchanged. Recombinant HGF dose-dependently increased Pan02, but not TGP-47, proliferation (p < 0.05). Inhibition of HGF receptor, c-met, resulted in attenuated proliferation versus control in Pan02 cells, but not TGP-47 cells. CONCLUSIONS: These experiments demonstrate that adipocyte-derived factors accelerate murine pancreatic cancer proliferation. In the case of Pan02 cells, HGF is responsible, in part, for this proliferation

Cancer History: A Predictor of IPMN Subtype and Dysplastic Status?

Introduction The aim of this study was to determine the association of PMH and FH of pancreatic (PDAC) and non-pancreatic cancers with IPMN malignant risk. Methods A retrospective review of a prospective database of IPMN patients undergoing resection was performed to assess FH and PMH. Results FH of PDAC was present in 13% of 362 included patients. Of these, 8% had at least one first degree relative (FDR) with PDAC. The rate of PDAC positive FH in non-invasive versus invasive IPMN patients was 14% and 8%, respectively (p = 0.3). In main duct IPMN patients, FH (44%) and PMH of non-pancreatic cancer (16%) was higher than that seen in branch duct IPMN (FH 29%; PMH 6%; p = 0.004 and 0.008). Conclusions FH of PDAC is not associated with IPMN malignant progression. FH and PMH of non-pancreatic cancer is associated with main duct IPMN, the subtype with the highest rate of invasive transformation

Evolving treatment of necrotizing pancreatitis

Background Over the past decade, the treatment of necrotizing pancreatitis (NP) has incorporated greater use of minimally invasive techniques, including percutaneous drainage and endoscopic debridement. No study has yet compared outcomes of patients treated with all available techniques. We sought to evaluate the evolution of NP treatment at our high volume pancreas center. We hypothesized that minimally invasive techniques (medical only, percutaneous, and endoscopic) were used more frequently in later years. Methods Treatment strategy of NP patients at a single academic medical center between 2005 and 2014 was reviewed. Definitive management of pancreatic necrosis was categorized as: 1) medical treatment only; 2) surgical only; 3) percutaneous (interventional radiology – IR) only; 4) endoscopic only; and 5) combination (Surgery ± IR ± Endoscopy). Results 526 NP patients included biliary (45%), alcoholic (17%), and idiopathic (20%) etiology. Select patients were managed exclusively by medical, IR, or endoscopic treatment; use of these therapies remained relatively consistent over time. A combination of therapies was used in about 30% of patients. Over time, the percentage of NP patients managed without operation increased from 28% to 41%. 247 (47%) of patients had operation as the only NP treatment; an additional 143 (27%) required surgery as part of a multidisciplinary management. Conclusion Select NP patients may be managed exclusively by medical, IR, or endoscopic treatment. Combination treatment is necessary in many NP patients, and surgical treatment continues to play an important role in the definitive therapy of necrotizing pancreatitis patients