Oncology 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 …

Chronic Obstructive Pulmonary Disease Is Associated With Worse Oncologic Outcomes In Early-Stage Resected Pancreatic And Periampullary Cancers, Rachel Huang, Emma Hammelef, Matthew Sabitsky, Carolyn Ream, Saed Khalilieh, Nitzan Zohar, Harish Lavu, Wilbur B. Bowne, Charles J. Yeo, Avinoam Nevler

Department of Surgery Faculty Papers

Pancreatic ductal adenocarcinoma (PDAC) is the 3rd leading cause of cancer mortality in the United States. Hypoxic and hypercapnic tumor microenvironments have been suggested to promote tumor aggressiveness. The objective of this study was to evaluate the association between chronic obstructive pulmonary disease (COPD) and oncologic survival outcomes in patients with early-stage PDAC and periampullary cancers. In this case-control study, patients who underwent a pancreaticoduodenectomy during 2014–2021 were assessed. Demographic, perioperative, histologic, and oncologic data were collected. A total of 503 PDAC and periampullary adenocarcinoma patients were identified, 257 males and 246 females, with a mean age of 68.1 (±9.8) …

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 …

Use Of Autoreactive Antibodies In Blood Of Patients With Pancreatic Intraductal Papillary Mucinous Neoplasms (Ipmn) For Grade Distinction And Detection Of Malignancy, Niall Brindl, Henning Boekhoff, Andrea S Bauer, Matthias M Gaida, Hien Dang, Jörg Kaiser, Jörg D Hoheisel, Klaus Felix

Department of Surgery Faculty Papers

(1) Background: A reliable non-invasive distinction between low- and high-risk pancreatic intraductal papillary mucinous neoplasms (IPMN) is needed to effectively detect IPMN with malignant potential. This would improve preventative care and reduce the risk of developing pancreatic cancer and overtreatment. The present study aimed at exploring the presence of autoreactive antibodies in the blood of patients with IPMN of various grades of dysplasia. (2) Methods: A single-center cohort was studied composed of 378 serum samples from patients with low-grade IPMN (n = 91), high-grade IPMN (n = 66), IPMN with associated invasive cancer (n = 30), pancreatic …

Nsg-Pro Mouse Model For Uncovering Resistance Mechanisms And Unique Vulnerabilities In Human Luminal Breast Cancers, Yunguang Sun, Ning Yang, Fransiscus E Utama, Sameer S Udhane, Junling Zhang, Amy R Peck, Alicia Yanac, Katherine Duffey, John F Langenheim, Vindhya Udhane, Guanjun Xia, Jess F Peterson, Julie M Jorns, Marja T Nevalainen, Romain Rouet, Peter Schofield, Daniel Christ, Christopher J Ormandy, Anne Rosenberg, I Chervoneva, Shirng-Wern Tsaih, Michael J Flister, Serge Y Fuchs, Kay-Uwe Wagner, Hallgeir Rui

Department of Surgery Faculty Papers

Most breast cancer deaths are caused by estrogen receptor-α-positive (ER+) disease. Preclinical progress is hampered by a shortage of therapy-naïve ER+ tumor models that recapitulate metastatic progression and clinically relevant therapy resistance. Human prolactin (hPRL) is a risk factor for primary and metastatic ER+ breast cancer. Because mouse prolactin fails to activate hPRL receptors, we developed a prolactin-humanized Nod-SCID-IL2Rγ (NSG) mouse (NSG-Pro) with physiological hPRL levels. Here, we show that NSG-Pro mice facilitate establishment of therapy-naïve, estrogen-dependent PDX tumors that progress to lethal metastatic disease. Preclinical trials provide first-in-mouse efficacy of pharmacological hPRL suppression on residual ER+ human breast cancer …

A Step Towards Personalizing Next Line Therapy For Resected Pancreatic And Related Cancer Patients: A Single Institution's Experience, Cinthya Y. Lowder, Teena Dhir, Austin B. Goetz, Henry L. Thomsett, Joseph Bender, Talar Tatarian, Subha Madhavan, Emanuel F. Petricoin, Edik Blais, Harish Lavu, Jordan M. Winter, James Posey Iii, Jonathan Brody, Michael J. Pishvaian, Charles J. Yeo

Department of Surgery Faculty Papers

Background: There is a lack of precision medicine in pancreatic ductal adenocarcinoma (PDA) and related cancers, and outcomes for patients with this diagnosis remain poor despite decades of research investigating this disease. Therefore, it is necessary to explore novel therapeutic options for these patients who may benefit from personalized therapies.

Objective: Molecular profiling of hepatopancreaticobiliary malignancies at our institution, including but not limited to PDA, was initiated to assess the feasibility of incorporating molecular profiling results into patient oncological therapy planning.

Methods: All eligible patients from Thomas Jefferson University (TJU) with hepatopancreaticobiliary tumors including PDA, who agreed to molecular testing …

Extended Prophylactic Antibiotics For Mastectomy With Immediate Breast Reconstruction: A Meta-Analysis, Yang Hai, Weelic Chong, Melissa Lazar

Department of Surgery Faculty Papers

Background: The risk of surgical site infection (SSI) for breast surgery in patients without additional risk factors is low, below 5%. Evidence shows the risk of SSI is significantly elevated in patients undergoing immediate breast reconstruction (IBR). However, there is no consensus regarding the use of extended antibiotic prophylaxis. We aim to determine the effect of extended antibiotic prophylaxis on the incidence of SSI after IBR.

Methods: PubMed and Scopus were searched by 2 independent reviewers. Data abstracted included types of study, basic characteristics, detailed antibiotic prophylaxis information, SSI event, and other secondary outcomes. We calculated the risk ratio (RR) …

Optimizing Cancer Cure Dialog: An Analysis Of Pancreatic Cancer Patients' Views Regarding Survival And Cure., Avinoam Nevler, Scott W. Keith, Harish Lavu, Theresa P. Yeo, Shawnna Cannaday, Charles J. Yeo, Jordan M. Winter

Department of Surgery Faculty Papers

BACKGROUND: Pancreatic ductal adenocarcinoma (PDA) is a highly lethal cancer. Clinicians commonly refer to surgical therapy as resection with curative intent. However, PDA cure rates after resection remain unknown and the definition of cure remains vague. We investigated how patients (the majority undergoing resection), family members, and clinicians understand the concept of cure, to better inform discussions with patients regarding PDA prognosis.

METHODS: In a prospective survey, cohorts were asked to indicate the best definition of cure from three choices: 5-year survival endpoint (typically used in the literature), a biological endpoint without biochemical or radiographic signs of disease (similar to …

Guidance Of Sentinel Lymph Node Biopsy Decisions In Patients With T1-T2 Melanoma Using Gene Expression Profiling., John T. Vetto, Eddy C. Hsueh, Brian R. Gastman, Larry D. Dillon, Federico A. Monzon, Robert W. Cook, Jennifer Keller, Xin Huang, Andrew Fleming, Preston Hewgley, Pedram Gerami, Sancy Leachman, Jeffrey D. Wayne, Adam C. Berger, Martin D. Fleming

Department of Surgery Faculty Papers

AIM: Can gene expression profiling be used to identify patients with T1-T2 melanoma at low risk for sentinel lymph node (SLN) positivity?

PATIENTS & METHODS: Bioinformatics modeling determined a population in which a 31-gene expression profile test predicted <5% SLN positivity. Multicenter, prospectively-tested (n = 1421) and retrospective (n = 690) cohorts were used for validation and outcomes, respectively.

RESULTS: Patients 55-64 years and ≥65 years with a class 1A (low-risk) profile had SLN positivity rates of 4.9% and 1.6%. Class 2B (high-risk) patients had SLN positivity rates of 30.8% and 11.9%. Melanoma-specific survival was 99.3% for patients ≥55 years with class 1A, T1-T2 tumors and 55.0% for class 2B, SLN-positive, T1-T2 tumors.

CONCLUSION: The 31-gene expression profile test identifies patients …

Nelfe-Dependent Myc Signature Identifies A Unique Cancer Subtype In Hepatocellular Carcinoma., Hien Dang, Yotsawat Pomyen, Sean P. Martin, Dana A. Dominguez, Sun Young Yim, Ju-Seog Lee, Anuradha Budhu, Ashesh P. Shah, Adam S. Bodzin, Xin Wei Wang

Department of Surgery Faculty Papers

The MYC oncogene is dysregulated in approximately 30% of liver cancer. In an effort to exploit MYC as a therapeutic target, including in hepatocellular carcinoma (HCC), strategies have been developed on the basis of MYC amplification or gene translocation. Due to the failure of these strategies to provide accurate diagnostics and prognostic value, we have developed a Negative Elongation Factor E (NELFE)-Dependent MYC Target (NDMT) gene signature. This signature, which consists of genes regulated by MYC and NELFE, an RNA binding protein that enhances MYC-induced hepatocarcinogenesis, is predictive of NELFE/MYC-driven tumors that would otherwise not be identified by gene amplification …

A Sub-Type Of Familial Pancreatic Cancer: Evidence And Implications Of Loss-Of-Function Polymorphisms In Indoleamine-2,3-Dioxygenase-2., Avinoam Nevler, Alexander J. Muller, Joseph A. Cozzitorto, Austin Goetz, Jordan M. Winter, Theresa P. Yeo, Harish Lavu, Charles Yeo, George C. Prendergast, Jonathan Brody

Department of Surgery Faculty Papers

BACKGROUND: Variation in an individual's genetic status can impact the development of pancreatic ductal adenocarcinoma; however, the majority of familial pancreatic cancers (FPC) cannot yet be attributed to a specific inherited mutation. We present data suggesting a correlation between loss-of-function single nucleotide polymorphisms (SNPs) in an immune regulator gene, indoleamine-2,3-dioxygenase-2 (IDO2), and an increased risk of FPC.

STUDY DESIGN: Germline DNA from patients who underwent resection for pancreatic ductal adenocarcinoma (n = 79) was sequenced for the IDO2 SNPs R248W and Y359Stop. Genotypes resulting in inactivation of IDO2 (Y325X homozygous, R248W homozygous) were labeled as homozygous, and the other genotypes …

Quantification And Expert Evaluation Of Evidence For Chemopredictive Biomarkers To Personalize Cancer Treatment., Shruti Rao, Robert A. Beckman, Shahla Riazi, Cinthya S. Yabar, Simina M. Boca, John L. Marshall, Michael J. Pishvaian, Jonathan R. Brody, Subha Madhavan

Department of Surgery Faculty Papers

Predictive biomarkers have the potential to facilitate cancer precision medicine by guiding the optimal choice of therapies for patients. However, clinicians are faced with an enormous volume of often-contradictory evidence regarding the therapeutic context of chemopredictive biomarkers.We extensively surveyed public literature to systematically review the predictive effect of 7 biomarkers claimed to predict response to various chemotherapy drugs: ERCC1-platinums, RRM1-gemcitabine, TYMS-5-fluorouracil/Capecitabine, TUBB3-taxanes, MGMT-temozolomide, TOP1-irinotecan/topotecan, and TOP2A-anthracyclines. We focused on studies that investigated changes in gene or protein expression as predictors of drug sensitivity or resistance. We considered an evidence framework that ranked studies from high level I evidence for randomized …

Impact Of Hur Inhibition By The Small Molecule Ms-444 On Colorectal Cancer Cell Tumorigenesis., Fernando F. Blanco, Ranjan Preet, Andrea Aguado, Vikalp Vishwakarma, Laura E. Stevens, Alok Vyas, Subhash Padhye, Liang Xu, Scott J. Weir, Shrikant Anant, Nicole Meisner-Kober, Jonathan R. Brody, Dan A. Dixon

Department of Surgery Faculty Papers

Colorectal cancer (CRC) is the third most common cancer and a leading cause of cancer-related mortality. Observed during CRC tumorigenesis is loss of post-transcriptional regulation of tumor-promoting genes such as COX-2, TNFα and VEGF. Overexpression of the RNA-binding protein HuR (ELAVL1) occurs during colon tumorigenesis and is abnormally present within the cytoplasm, where it post-transcriptionally regulates genes through its interaction with 3'UTR AU-rich elements (AREs). Here, we examine the therapeutic potential of targeting HuR using MS-444, a small molecule HuR inhibitor. Treatment of CRC cells with MS-444 resulted in growth inhibition and increased apoptotic gene expression, while similar treatment doses …

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 …

Preoperative Fdg-Pet/Ct Is An Important Tool In The Management Of Patients With Thick (T4) Melanoma., Rodrigo Arrangoiz, Pavlos Papavasiliou, Carrie A Stransky, Jian Q Yu, Li Tianyu, Elin R Sigurdson, Adam C. Berger, Jeffrey M Farma

Department of Surgery Faculty Papers

The yield of preoperative PET/CT (PET/CT) for regional and distant metastases for thin/intermediate thickness melanoma is low. Objective of this study is to determine if PET/CT performed for T4 melanomas helps guide management and alter treatment plans. Methods. Retrospective cohort of 216 patients with T4 melanomas treated at two tertiary institutions. Fifty-six patients met our inclusion criteria (T4 lesion, PET/CT and no clinical evidence of metastatic disease). Results. Fifty-six patients (M: 32, F: 24) with median tumor thickness of 6 mm were identified. PET/CT recognized twelve with regional and four patients with metastatic disease. Melanoma-related treatment plan was altered in …

Serum Monocyte Chemoattractant Protein-1 In Pancreatic Cancer., Jennifer Sullivan, Qiaoke Gong, Terry Hyslop, Harish Lavu, Galina Chipitsyna, Charles Yeo, Hwyda A Arafat

Department of Surgery Faculty Papers

Background/Aims. Pancreatic ductal adenocarcinoma (PDA) has etiological association with chronic inflammation. Elevated circulating levels of inflammatory mediators, such as monocyte chemoattractant protein-1 (MCP-1), are found in obese individuals. We hypothesized that serum MCP-1 levels are elevated in obese PDA patients. Methods. ELISA was used to analyze MCP-1 serum levels in PDA (n = 62) and intraductal papillary mucinous neoplasms (IPMN) (n = 27). Recursive partitioning statistical analysis investigated the relationship between log MCP-1 and clinicopathological parameters. Results. Log MCP-1 values were significantly (P < 0.05) elevated in patients with BMI ≥ 37.5. In patients with BMI < 37.5, average log MCP-1 values were significantly elevated in PDA patients when compared to IPMN patients. Within the IPMN group, higher log MCP-1 levels correlated with increased age. Recursive partitioning analysis of IPMN versus PDA revealed a strategy of predicting characteristics of patients who are more likely to have cancer. This strategy utilizes log MCP-1 as the primary factor and also utilizes smoking status, gender, and age. Conclusion. MCP-1 is a promising biomarker in pancreatic cancer. The potential of using MCP-1 to distinguish PDA from IPMN patients must be studied in larger populations to validate and demonstrate its eventual clinical utility.

Pp32 (Anp32a) Expression Inhibits Pancreatic Cancer Cell Growth And Induces Gemcitabine Resistance By Disrupting Hur Binding To Mrnas., Timothy K Williams, Christina L Costantino, Nikolai A Bildzukewicz, Nathan G Richards, David W Rittenhouse, Lisa Einstein, Joseph A Cozzitorto, Judith C Keen, Abhijit Dasgupta, Myriam Gorospe, Gregory E Gonye, Charles J Yeo, Agnieszka K Witkiewicz, Jonathan R Brody

Department of Surgery Faculty Papers

The expression of protein phosphatase 32 (PP32, ANP32A) is low in poorly differentiated pancreatic cancers and is linked to the levels of HuR (ELAV1), a predictive marker for gemcitabine response. In pancreatic cancer cells, exogenous overexpression of pp32 inhibited cell growth, supporting its long-recognized role as a tumor suppressor in pancreatic cancer. In chemotherapeutic sensitivity screening assays, cells overexpressing pp32 were selectively resistant to the nucleoside analogs gemcitabine and cytarabine (ARA-C), but were sensitized to 5-fluorouracil; conversely, silencing pp32 in pancreatic cancer cells enhanced gemcitabine sensitivity. The cytoplasmic levels of pp32 increased after cancer cells are treated with certain stressors, …

Idiopathic Granulomatous Mastitis Masquerading As Carcinoma Of The Breast: A Case Report And Review Of The Literature., Richard Tuli, Brian J O'Hara, Janet Hines, Anne L Rosenberg

Department of Surgery Faculty Papers

BACKGROUND: Idiopathic granulomatous mastitis is an uncommon, benign entity with a diagnosis of exclusion. The typical clinical presentation of idiopathic granulomatous mastitis often mimics infection or malignancy. As a result, histopathological confirmation of idiopathic granulomatous mastitis combined with exclusion of infection, malignancy and other causes of granulomatous disease is absolutely necessary. CASE PRESENTATION: We present a case of a young woman with idiopathic granulomatous mastitis, initially mistaken for mastitis as well as breast carcinoma, and successfully treated with a course of corticosteroids. CONCLUSION: There is no clear clinical consensus regarding the ideal therapeutic management of idiopathic granulomatous mastitis. Treatment options …

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 …