Medicine and Health Sciences Commons^™

Repurposing The Fda-Approved Anthelmintic Pyrvinium Pamoate For Pancreatic Cancer Treatment: Study Protocol For A Phase I Clinical Trial In Early-Stage Pancreatic Ductal Adenocarcinoma, Francesca M. Ponzini, Christopher W. Schultz, Benjamin E. Leiby, Shawnna Cannaday, T. Yeo, James Posey, Wilbur B. Bowne, Charles Yeo, Jonathan R. Brody, Harish Lavu, Avinoam Nevler

Department of Surgery Faculty Papers

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 …

Adjuvant Nab-Paclitaxel + Gemcitabine In Resected Pancreatic Ductal Adenocarcinoma: Results From A Randomized, Open-Label, Phase Iii Trial, Margaret A. Tempero, Uwe Pelzer, Eileen M. O'Reilly, Jordan Winter, Do-Youn Oh, Chung-Pin Li, Giampaolo Tortora, Heung-Moon Chang, Charles D. Lopez, Tanios Bekaii-Saab, Andrew H. Ko, Armando Santoro, Joon Oh Park, Marcus S. Noel, Giovanni Luca Frassineti, Yan-Shen Shan, Andrew Dean, Hanno Riess, Eric Van Cutsem, Jordan Berlin, Philip Philip, Malcolm Moore, David Goldstein, Josep Tabernero, Mingyu Li, Stefano Ferrara, Yvan Le Bruchec, George Zhang, Brian Lu, Andrew V. Biankin, Michele Reni

Department of Surgery Faculty Papers

PURPOSE

This randomized, open-label trial compared the efficacy and safety of adjuvant nab-paclitaxel + gemcitabine with those of gemcitabine for resected pancreatic ductal adenocarcinoma (ClinicalTrials.gov identifier: NCT01964430). METHODS

We assigned 866 treatment-naive patients with pancreatic ductal adenocarcinoma to nab-paclitaxel (125 mg/m2) + gemcitabine (1,000 mg/m2) or gemcitabine alone to one 30-40 infusion on days 1, 8, and 15 of six 28-day cycles. The primary end point was independently assessed disease-free survival (DFS). Additional end points included investigator-assessed DFS, overall survival (OS), and safety. RESULTS

Two hundred eighty-seven of 432 patients and 310 of 434 patients completed nab …

Reduced Rates Of Post-Transplant Recurrent Hepatocellular Carcinoma In Non-Alcoholic Steatohepatitis: A Propensity Score Matched Analysis, Ryan Lamm, Peter J Altshuler, Keyur Patel, Osama Shaheen, Angel Paulo Amante, Jesse Civan, Warren Maley, Adam Frank, Carlo Ramirez, Jaime Glorioso, Ashesh Shah, Hien Dang, Adam S Bodzin

Department of Surgery Faculty Papers

Non-alcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (HCC) has become the second leading cause of HCC-related liver transplantation in the United States. This study investigated post-transplant recurrence and survival for patients transplanted for NASH-related HCC compared to non-NASH HCC etiologies. Retrospective review of the United Network for Organ Sharing (UNOS) Organ Procurement and Transplantation Network (OPTN) database identified 7,461 patients with HCC—1,405 with underlying NASH and 6,086 with non-NASH underlying diseases. After propensity score matching (PSM) to account for patient- and tumor-related confounders 1,175 remained in each group. Primary outcomes assessed were recurrence rate and recurrence-free survival. Recurrent malignancy at 5 years …

A Standardized Comparison Of Peri-Operative Complications After Minimally Invasive Esophagectomy: Ivor Lewis Versus Mckeown., Andrew M. Brown, Michael J. Pucci, Adam C. Berger, Talar Tatarian, Nathaniel R. Evans Iii, Ernest L. Rosato, Francesco Palazzo

Department of Surgery Faculty Papers

BACKGROUND: While our institutional approach to esophageal resection for cancer has traditionally favored a minimally invasive (MI) 3-hole, McKeown esophagectomy (MIE 3-hole) during the last five years several factors has determined a shift in our practice with an increasing number of minimally invasive Ivor Lewis (MIE IL) resections being performed. We compared peri-operative outcomes of the two procedures, hypothesizing that MIE IL would be less morbid in the peri-operative setting compared to MIE 3-hole.

METHODS: Our institution's IRB-approved esophageal database was queried to identify all patients who underwent totally MI esophagectomy (MIE IL vs. MIE 3-hole) from June 2011 to …

Posttranscriptional Regulation Of Parg Mrna By Hur Facilitates Dna Repair And Resistance To Parp Inhibitors, Saswati N. Chand, Mahsa Zarei, M. J. Schiewer, Akshay R. Sanan, Carmella Romeo, Shruti Lal, Joseph A. Cozzitorto, Avinoam Nevler, Laura Scolaro, Eric R. Londin, Wei Jiang, Nicole Meisner-Kober, Michael J. Pishvaian, Karen E. Knudsen, Charles Yeo, John M Pascal, Jordan M. Winter, Jonathan R. Brody

Department of Surgery Faculty Papers

The majority of pancreatic ductal adenocarcinomas (PDAC) rely on the mRNA stability factor HuR (ELAV-L1) to drive cancer growth and progression. Here, we show that CRISPR-Cas9–mediated silencing of the HuR locus increases the relative sensitivity of PDAC cells to PARP inhibitors (PARPi). PDAC cells treated with PARPi stimulated translocation of HuR from the nucleus to the cytoplasm, specifically promoting stabilization of a new target, poly (ADP-ribose) glycohydrolase (PARG) mRNA, by binding a unique sequence embedded in its 3⁰ untranslated region. HuR-dependent upregulation of PARG expression facilitated DNA repair via hydrolysis of polyADP-ribose on related repair proteins. Accordingly, strategies to …

Crispr Knockout Of The Hur Gene Causes A Xenograft Lethal Phenotype., Shruti Lal, Edwin C, Cheung, Mahsa Zarei, Ranjan Preet, Saswati N. Chand, Nicole C. Mambelli-Lisboa, Carmella Romeo, Matthew C. Stout, Eric Londin, Austin Goetz, Cinthya Y. Lowder, Avinoam Nevler, Charles Yeo, Paul M. Campbell, Jordan M. Winter, Dan A. Dixon, Jonathan Brody

Department of Surgery Faculty Papers

Pancreatic ductal adenocarcinoma (PDA) is the third leading cause of cancer-related deaths in the United States, whereas colorectal cancer is the third most common cancer. The RNA-binding protein HuR (ELAVL1) supports a pro-oncogenic network in gastrointestinal (GI) cancer cells through enhanced HuR expression. Using a publically available database, HuR expression levels were determined to be increased in primary PDA and colorectal cancer tumor cohorts as compared with normal pancreas and colon tissues, respectively. CRISPR/Cas9 technology was successfully used to delete the HuR gene in both PDA (MIA PaCa-2 and Hs 766T) and colorectal cancer (HCT116) cell lines. HuR deficiency has …

Failure Patterns In Resected Pancreas Adenocarcinoma: Lack Of Predicted Benefit To Smad4 Expression., Jordan M. Winter, Laura H. Tang, David S. Klimstra, Weiguo Liu, Irena Linkov, Murray F. Brennan, Michael I. DʼAngelica, Ronald P. Dematteo, Yuman Fong, William R. Jarnagin, Eileen M. OʼReilly, Peter J. Allen

Department of Surgery Faculty Papers

OBJECTIVE: To determine whether SMAD4 expression is associated with recurrence pattern after resection for pancreatic ductal adenocarcinoma (PDA).

BACKGROUND: SMAD4 expression status has been reported to be associated with patterns of failure in PDA, but studies have not examined recurrence patterns after resection.

METHODS: A tissue microarray was constructed including 127 patients with resected PDA and either short-term (<12 >months) or long-term (>30 months) survival. SMAD4 expression was evaluated by immunohistochemistry and categorized as present or lost in tumor cells. Conventional pathologic features (lymph node metastases, positive resection margin, poor grade, and tumor size) were recorded, and disease-specific outcomes …

Altered Drainage Patterns In Patients With Melanoma And Previous Axillary Dissection., Caitlyn M. Johnson, Charles Intenzo, Michael Mastrangelo, Kendra Feeney, Adam C. Berger

Department of Surgery Faculty Papers

The incidence of melanoma is increasing rapidly in the United States. Sentinel lymph node biopsy is an important diagnostic tool in the treatment and staging of melanoma. However, many patients with melanoma will have had lymph node surgery for previous melanoma or breast cancer. We set out to examine alterations in drainage patterns in patients with previous axillary dissection for breast cancer. We reviewed four patients with truncal and/or extremity melanomas and examined their lymphoscintigraphy and drainage patterns. Three patients with truncal melanoma mapped to cervical lymph nodes and a fourth patient with an arm melanoma mapped to her previously …

Major Perioperative Morbidity Does Not Affect Long-Term Survival In Patients Undergoing Esophagectomy For Cancer Of The Esophagus Or Gastroesophageal Junction., Brent T Xia, Ernest L Rosato, Karen A Chojnacki, Albert G. Crawford, Benny Weksler, Adam C. Berger

Department of Surgery Faculty Papers

INTRODUCTION: The incidence of cancer of the esophagus/GE junction is dramatically increasing but continues to have a dismal prognosis. Esophagectomy provides the best opportunity for long-term cure but is hampered by increased rates of perioperative morbidity. We reviewed our large institutional experience to evaluate the impact of postoperative complications on the long-term survival of patients undergoing resection for curative intent.

METHODS: We identified 237 patients who underwent esophagogastrectomy, with curative intent, for cancer between 1994 and 2008. Complications were graded using the previously published Clavien scale. Survival was calculated using Kaplan-Meier methodology and survival curves were compared using log-rank tests. …

Analysis Of Epstein-Barr Virus Reservoirs In Paired Blood And Breast Cancer Primary Biopsy Specimens By Real Time Pcr., R Serene Perkins, Katherine Sahm, Cindy Marando, Diana Dickson-Witmer, Gregory R Pahnke, Mark Mitchell, Nicholas J Petrelli, Irving M Berkowitz, Patricia Soteropoulos, Virginie M Aris, Stephen P Dunn, Leslie J Krueger

Department of Surgery Faculty Papers

INTRODUCTION: Epstein-Barr virus (EBV) is present in over 90% of the world's population. This infection is considered benign, even though in limited cases EBV is associated with infectious and neoplastic conditions. Over the past decade, the EBV association with breast cancer has been constantly debated. Adding to this clinical and biological uncertainty, different techniques gave contradictory results for the presence of EBV in breast carcinoma specimens. In this study, minor groove binding (MGB)-TaqMan real time PCR was used to detect the presence of EBV DNA in both peripheral blood and tumor samples of selected patients. METHODS: Peripheral blood and breast …

Nipple Aspirate Cytology And Pathologic Parameters Predict Residual Cancer And Nodal Involvement After Excisional Breast Biopsy., E R Sauter, H Ehya, A Mammen, G Klein

Department of Surgery Faculty Papers

We previously demonstrated that abnormal nipple aspirate fluid (NAF) cytology predicted residual breast cancer (RC) and tumour size after excisional biopsy (EB), although normal NAF cytology did not exclude RC. Tumour size correlates with the risk of lymph node (LN) metastases. LN metastases provide prognostic information allowing medical and radiation oncologists to determine the need for adjuvant therapy. We hypothesized that pathologic factors known after EB, combined with NAF cytology, would predict with a high degree of accuracy the presence of RC and LN spread. NAF cytology and pathologic parameters: tumour distance from biopsy margins, multifocal and multicentric disease, sub-type …