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Pancreatic Neoplasms: HELP
Articles by Mitesh J. Borad
Based on 15 articles published since 2010
(Why 15 articles?)
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Between 2010 and 2020, Mitesh Borad wrote the following 15 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Review Oncolytic virotherapy in upper gastrointestinal tract cancers. 2017

Yokoda, Raquel / Nagalo, Bolni M / Arora, Mansi / Egan, Jan B / Bogenberger, James M / DeLeon, Thomas T / Zhou, Yumei / Ahn, Daniel H / Borad, Mitesh J. ·Division of Hematology/Oncology, Department of Medicine, Mayo Clinic, Scottsdale, AZ. · Department of Molecular Medicine, Center for Individualized Medicine, Mayo Clinic, Rochester, MN. · Department of Oncology, Mayo Clinic Cancer Center, Phoenix, AZ, USA. ·Oncolytic Virother · Pubmed #29616200.

ABSTRACT: Upper gastrointestinal tract malignancies are among the most challenging cancers with regard to response to treatment and prognosis. Cancers of the esophagus, stomach, pancreas, liver, and biliary tree have dismal 5-year survival, and very modest improvements in this rate have been made in recent times. Oncolytic viruses are being developed to address these malignancies, with a focus on high safety profiles and low off-target toxicities. Each viral platform has evolved to enhance oncolytic potency and the clinical response to either single-agent viral therapy or combined viral treatment with radiotherapy and chemotherapy. A panel of genomic alterations, chimeric proteins, and pseudotyped capsids are the breakthroughs for vector success. This article revisits developments for each viral platform to each tumor type, in an attempt to achieve maximum tumor selectivity. From the bench to clinical trials, the scope of this review is to highlight the beginnings of translational oncolytic virotherapy research in upper gastrointestinal tract malignancies and provide a bioengineering perspective of the most promising platforms.

2 Review Immunotherapy in pancreatic cancer treatment: a new frontier. 2017

Thind, Komal / Padrnos, Leslie J / Ramanathan, Ramesh K / Borad, Mitesh J. ·Department of Internal Medicine, Cleveland Clinic Akron General, Akron, OH, USA. · Division of Hematology/Oncology, Mayo Clinic Arizona, Scottsdale, AZ, USA. · Division of Hematology/Oncology, Mayo Clinic Arizona, 5777 E. Mayo Boulevard, Phoenix, AZ 85054, USA. ·Therap Adv Gastroenterol · Pubmed #28286568.

ABSTRACT: Pancreatic cancer is a highly aggressive and lethal cancer characterized by high invasiveness, local and extensive dissemination at time of diagnosis and resistance to treatment. Few therapies have shown efficacy in the past and even standard of care therapies yield only modest improvements in the mortality of patients with advanced or metastatic disease. Efforts have been undertaken to study the pancreatic tumor microenvironment and have established its complex and immunosuppressive nature which could explain the high resistance to chemotherapy. Novel therapies targeting the tumor microenvironment with an aim to decrease this resistance, improve immune tolerance and increase the efficacy of the current treatment have shown some promising preliminary results in preclinical and clinical trials. We review the current advances in the field of immunotherapy and their effectiveness as a potential treatment strategy in the pancreatic cancer.

3 Review Hypoxia-activated prodrugs in the treatment of advanced pancreatic adenocarcinoma. 2017

Babiker, Hani M / Riaz, Irbaz B / Shah, Syed R / Von Hoff, Daniel D / Borad, Mitesh J. ·aVirginia G Piper Cancer Center Clinical Trials, HonorHealth Research Institute bDepartment of Internal Medicine, Division of Hematology-Oncology, Mayo Clinic Cancer Center, Scottsdale cClinical Translational Research Division, Translational Genomics Research Institute (TGen), Phoenix dDepartment of Internal Medicine, Division of Hematology Oncology, University of Arizona Cancer Center eDepartment of Internal Medicine, University of Arizona, Tucson, Arizona fDepartment of Molecular Medicine, Centre for Individualized Medicine, Rochester, Minnesota, USA gDepartment of Medicine, Dow University of Health Sciences, Karachi, Pakistan. ·Anticancer Drugs · Pubmed #27685167.

ABSTRACT: Pancreatic cancer is an aggressive malignancy with poor survival and high mortality rate with 250 000 deaths per year worldwide. The unique pancreatic cancer microenvironment serves as a major obstacle in the effective treatment of this malignancy. The microenvironment consists not only of pancreatic ductal adenocarcinoma cells but also comprises cells of pancreatic cancer stellate, vascular, and immune origin combined with a dense extracellular matrix containing collagen. The aforementioned pathology leads to an increased intratumor pressure combined with an erratic vascular proliferation within the tumor causing hypoxia and decreased drug delivery. This has led both scientists and clinicians to develop and study drugs with unique mechanisms of action to target the pancreatic cancer microenvironment. Herein, we discuss the pancreatic cancer hypoxic microenvironment, development of hypoxia-activated prodrugs, and results of trials utilizing those drugs to target pancreatic cancer.

4 Review Immunotherapeutic and oncolytic viral therapeutic strategies in pancreatic cancer. 2014

Khan, Meaghan L / Halfdanarson, Thorvardur R / Borad, Mitesh J. ·Mayo Clinic Arizona Division of Hematology & Medical Oncology, 13400 E Shea Boulevard, Scottsdale, AZ 85259, USA. ·Future Oncol · Pubmed #24947264.

ABSTRACT: Pancreatic adenocarcinoma is an aggressive disease with dismal outcomes despite recent advances using combination chemotherapeutic regimens. The lack of an adequate immune response to malignant cells has been identified as a factor associated with tumor aggressiveness and refractoriness to systemic treatment. Preclinical and early clinical studies have identified numerous immunotherapeutic and oncolytic viral therapeutic strategies aimed towards amplifying the immune reaction to pancreatic cancer and have established encouraging results. Promising antitumor efficacy has been observed both in vitro and in vivo with many of these approaches. These novel applications have also led to improved understanding of the process of pancreatic tumor growth and invasion, knowledge of the tumor microenvironment and have pioneered further investigations of similar therapies. Here we review both immunotherapeutic and oncolytic viral therapeutic strategies in pancreatic cancer.

5 Review Isolated supraclavicular lymph node metastasis in pancreatic adenocarcinoma: a report of three cases and review of the literature. 2010

Soman, Arundhati D / Collins, Joseph M / DePetris, Giovanni / Decker, G Anton / Silva, Alvin / Moss, Adyr / Greer, Wendy / Ashman, Jonathan / Callister, Matthew / Borad, Mitesh J. ·Department of Hematology/Oncology, Mayo Clinic Arizona, Scottsdale, AZ 85259, USA. ·JOP · Pubmed #21068495.

ABSTRACT: CONTEXT: Supraclavicular lymph nodes represent a rare site of metastasis in pancreatic cancer. We report three cases of pancreatic adenocarcinoma with metastases to supraclavicular lymph nodes. CASE REPORT: A 51-year-old male was diagnosed with locally advanced pancreatic adenocarcinoma on computed tomography (CT) scan. He was recommended neoadjuvant chemotherapy followed by chemoradiation therapy. However, positron emission tomography (PET)/CT scans and subsequent fine needle aspiration cytology showed supraclavicular lymph node metastasis. The patient received systemic chemotherapy for metastatic pancreatic adenocarcinoma. The second patient, a 66-year-old female with pancreatic adenocarcinoma, underwent pancreaticoduodenectomy and was found to have peripancreatic lymph node involvement. She received adjuvant chemotherapy and was followed-up with surveillance CT scans, which did not reveal any metastasis. However, the patient complained of neck swelling. PET/CT scan and biopsy revealed supraclavicular lymph node metastasis from a pancreatic adenocarcinoma primary. The third patient, a 79-year-old male with a past history of thyroid carcinoma who was treated with partial thyroidectomy, developed neck swelling 4 years after his surgery. Fine needle aspiration cytology was consistent with known papillary thyroid carcinoma. Staging evaluations revealed a pancreatic mass for which he underwent subtotal pancreatectomy and splenectomy. Histopathology revealed grade 3 pancreatic adenocarcinoma. Excisional biopsy of a supraclavicular lymph node showed metastatic pancreatic adenocarcinoma. PET/CT results were consistent with these findings. CONCLUSION: In patients with pancreatic adenocarcinoma, supraclavicular lymph node metastasis represents an uncommon, but clinically significant finding that can lead to changes in treatment planning. PET imaging represents a valuable tool in the detection and follow up of these patients.

6 Clinical Trial None 2017

Korn, Ronald L / Von Hoff, Daniel D / Borad, Mitesh J / Renschler, Markus F / McGovern, Desmond / Curtis Bay, R / Ramanathan, Ramesh K. ·Imaging Endpoints Core Lab, 9700 N 91st St, B-200, Scottsdale, AZ, 85258, USA. rkorn@imagingendpoints.com. · Translational Genomics Research Institute and HonorHealth, 445 North Fifth St, Suite 600, Phoenix, AZ, 85004, USA. · Mayo Clinic, 13400 E Shea Blvd, Scottsdale, AZ, 85259, USA. · Celgene Corporation, 86 Morris Ave, Summit, NJ, 07901, USA. · Department of Interdisciplinary Health Sciences, A. T. Still University, 5850 E Still Circle, Mesa, AZ 85206, USA. ·Cancer Imaging · Pubmed #28774338.

ABSTRACT: BACKGROUND: Positron emission tomography (PET) is poised to become a useful imaging modality in staging and evaluating therapeutic responses in patients with metastatic pancreatic cancer (mPC). This analysis from a phase 1/2 study examined the utility of early PET imaging in patients with mPC treated with nab-paclitaxel plus gemcitabine. METHODS: Tumors were measured by [ RESULTS: Fifty-two patients had baseline and ≥1 follow-up PET scan. The median maximum standardized uptake values per pancreatic lesion in the nab-paclitaxel 100 mg/m CONCLUSIONS: The majority of primary pancreatic tumors and their metastases were PET avid, and PET effectively measured changes in tumor metabolic activity at 6 and 12 weeks. These results support the antitumor activity of nab-paclitaxel 125 mg/m TRIAL REGISTRATION: NCT00398086.

7 Clinical Trial Randomized Phase II Trial of Gemcitabine Plus TH-302 Versus Gemcitabine in Patients With Advanced Pancreatic Cancer. 2015

Borad, Mitesh J / Reddy, Shantan G / Bahary, Nathan / Uronis, Hope E / Sigal, Darren / Cohn, Allen L / Schelman, William R / Stephenson, Joe / Chiorean, E Gabriela / Rosen, Peter J / Ulrich, Brian / Dragovich, Tomislav / Del Prete, Salvatore A / Rarick, Mark / Eng, Clarence / Kroll, Stew / Ryan, David P. ·Mitesh J. Borad, Mayo Clinic, Scottsdale · Tomislav Dragovich, Arizona Cancer Center, Tucson, AZ · Shantan G. Reddy, Louisiana State University Health Sciences Center Shreveport, Shreveport, LA · Nathan Bahary, University of Pittsburgh Medical Center, Pittsburgh, PA · Hope E. Uronis, Duke University Medical Center, Durham, NC · Darren Sigal, Scripps Clinic, La Jolla · Peter J. Rosen, Disney Family Cancer Center, Burbank · Clarence Eng and Stew Kroll, Threshold Pharmaceuticals, South San Francisco, CA · Allen L. Cohn, Rocky Mountain Cancer Center, Denver, CO · William R. Schelman, University of Wisconsin Carbone Cancer Center, Madison, WI · Joe Stephenson Jr, Institute for Translational Oncology Research, Greenville, SC · E. Gabriela Chiorean, Indiana University Simon Cancer Center, Indianapolis, IN · Brian Ulrich, Texas Oncology, Wichita Falls, TX · Salvatore A. Del Prete, Hematology Oncology PC, Stamford, CT · Mark Rarick, Kaiser Permanente Northwest Region Oncology Hematology, Portland, OR · and David P. Ryan, Massachusetts General Hospital Cancer Center, Boston, MA. ·J Clin Oncol · Pubmed #25512461.

ABSTRACT: PURPOSE: TH-302 is an investigational hypoxia-activated prodrug that releases the DNA alkylator bromo-isophosphoramide mustard in hypoxic settings. This phase II study (NCT01144455) evaluated gemcitabine plus TH-302 in patients with previously untreated, locally advanced or metastatic pancreatic cancer. PATIENTS AND METHODS: Patients were randomly assigned 1:1:1 to gemcitabine (1,000 mg/m(2)), gemcitabine plus TH-302 240 mg/m(2) (G+T240), or gemcitabine plus TH-302 340 mg/m(2) (G+T340). Randomized crossover after progression on gemcitabine was allowed. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), tumor response, CA 19-9 response, and safety. RESULTS: Two hundred fourteen patients (77% with metastatic disease) were enrolled between June 2010 and July 2011. PFS was significantly longer with gemcitabine plus TH-302 (pooled combination arms) compared with gemcitabine alone (median PFS, 5.6 v 3.6 months, respectively; hazard ratio, 0.61; 95% CI, 0.43 to 0.87; P = .005; median PFS for metastatic disease, 5.1 v 3.4 months, respectively). Median PFS times for G+T240 and G+T340 were 5.6 and 6.0 months, respectively. Tumor response was 12%, 17%, and 26% in the gemcitabine, G+T240, and G+T340 arms, respectively (G+T340 v gemcitabine, P = .04). CA 19-9 decrease was greater with G+T340 versus gemcitabine (-5,398 v -549 U/mL, respectively; P = .008). Median OS times for gemcitabine, G+T240, and G+T340 were 6.9, 8.7, and 9.2 months, respectively (P = not significant). The most common adverse events (AEs) were fatigue, nausea, and peripheral edema (frequencies similar across arms). Skin and mucosal toxicities (2% grade 3) and myelosuppression (55% grade 3 or 4) were the most common TH-302-related AEs but were not associated with treatment discontinuation. CONCLUSION: PFS, tumor response, and CA 19-9 response were significantly improved with G+TH-302. G+T340 is being investigated further in the phase III MAESTRO study (NCT01746979).

8 Clinical Trial Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. 2011

Von Hoff, Daniel D / Ramanathan, Ramesh K / Borad, Mitesh J / Laheru, Daniel A / Smith, Lon S / Wood, Tina E / Korn, Ronald L / Desai, Neil / Trieu, Vuong / Iglesias, Jose L / Zhang, Hui / Soon-Shiong, Patrick / Shi, Tao / Rajeshkumar, N V / Maitra, Anirban / Hidalgo, Manuel. ·TGen/Virginia G Piper Cancer Ctr, 445 N Fifth St, Suite 600, Phoenix, AZ 85004, USA. dvh@tgen.org ·J Clin Oncol · Pubmed #21969517.

ABSTRACT: PURPOSE: The trial objectives were to identify the maximum-tolerated dose (MTD) of first-line gemcitabine plus nab-paclitaxel in metastatic pancreatic adenocarcinoma and to provide efficacy and safety data. Additional objectives were to evaluate positron emission tomography (PET) scan response, secreted protein acidic and rich in cysteine (SPARC), and CA19-9 levels in relation to efficacy. Subsequent preclinical studies investigated the changes involving the pancreatic stroma and drug uptake. PATIENTS AND METHODS: Patients with previously untreated advanced pancreatic cancer were treated with 100, 125, or 150 mg/m(2) nab-paclitaxel followed by gemcitabine 1,000 mg/m(2) on days 1, 8, and 15 every 28 days. In the preclinical study, mice were implanted with human pancreatic cancers and treated with study agents. RESULTS: A total of 20, 44, and three patients received nab-paclitaxel at 100, 125, and 150 mg/m(2), respectively. The MTD was 1,000 mg/m(2) of gemcitabine plus 125 mg/m(2) of nab-paclitaxel once a week for 3 weeks, every 28 days. Dose-limiting toxicities were sepsis and neutropenia. At the MTD, the response rate was 48%, with 12.2 median months of overall survival (OS) and 48% 1-year survival. Improved OS was observed in patients who had a complete metabolic response on [(18)F]fluorodeoxyglucose PET. Decreases in CA19-9 levels were correlated with increased response rate, progression-free survival, and OS. SPARC in the stroma, but not in the tumor, was correlated with improved survival. In mice with human pancreatic cancer xenografts, nab-paclitaxel alone and in combination with gemcitabine depleted the desmoplastic stroma. The intratumoral concentration of gemcitabine was increased by 2.8-fold in mice receiving nab-paclitaxel plus gemcitabine versus those receiving gemcitabine alone. CONCLUSION: The regimen of nab-paclitaxel plus gemcitabine has tolerable adverse effects with substantial antitumor activity, warranting phase III evaluation.

9 Article Phase 1 trial of Vismodegib and Erlotinib combination in metastatic pancreatic cancer. 2020

McCleary-Wheeler, Angela L / Carr, Ryan M / Palmer, Shanique R / Smyrk, Thomas C / Allred, Jacob B / Almada, Luciana L / Tolosa, Ezequiel J / Lamberti, Maria J / Marks, David L / Borad, Mitesh J / Molina, Julian R / Qi, Yingwei / Lingle, Wilma L / Grothey, Axel / Pitot, Henry C / Jatoi, Aminah / Northfelt, Donald W / Bryce, Alan H / McWilliams, Robert R / Okuno, Scott H / Haluska, Paul / Kim, George P / Colon-Otero, Gerardo / Lowe, Val J / Callstrom, Matthew R / Ma, Wen We / Bekaii-Saab, Tanios / Hung, Mien-Chie / Erlichman, Charles / Fernandez-Zapico, Martin E. ·Schulze Center for Novel Therapeutics, Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, MN, USA. · Division of Medical Oncology, Department of Oncology, Mayo Clinic, Rochester, MN, USA. · Department of Hematology and Oncology, Mid-Atlantic Permanente Medical Group, Wood Lawn, MD, USA. · Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA. · Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA. · Department of Medical Oncology, West Cancer Center, Germantown, TN, USA. · Division of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ, USA. · Division of Hematology and Oncology, Mayo Clinic, Jacksonville, FL, USA. · Department of Nuclear Medicine, Mayo Clinic, Rochester, MN, USA. · Department of Radiology, Mayo Clinic, Rochester, MN, USA. · Center for Molecular Medicine and Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan. · Schulze Center for Novel Therapeutics, Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, MN, USA. Electronic address: Fernandez-zapico.martin@mayo.edu. ·Pancreatology · Pubmed #31787526.

ABSTRACT: BACKGROUND/OBJECTIVES: Interplay between the Hedgehog (HH) and epidermal growth factor receptor (EGFR) pathways modulating the outcome of their signaling activity have been reported in various cancers including pancreatic ductal adenocarcinoma (PDAC). Therefore, simultaneous targeting of these pathways may be clinically beneficial. This Phase I study combined HH and EGFR inhibition in metastatic PDAC patients. METHODS: Combined effects of HH and EGFR inhibition using Vismodegib and Erlotinib with or without gemcitabine in metastatic solid tumors were assessed by CT. Another cohort of patients with metastatic PDAC was evaluated by FDG-PET and tumor biopsies-derived biomarkers. RESULTS: Treatment was well tolerated with the maximum tolerated dose cohort experiencing no grade 4 toxicities though 25% experienced grade 3 adverse effects. Recommended phase II dose of Vismodegib and Erlotinib were each 150 mg daily. No tumor responses were observed although 16 patients achieved stable disease for 2-7 cycles. Paired biopsy analysis before and after first cycle of therapy in PDAC patients showed reduced GLI1 mRNA, phospho-GLI1 and associated HH target genes in all cases. However, only half of the cases showed reduced levels of desmoplasia or changes in fibroblast markers. Most patients had decreased phospho-EGFR levels. CONCLUSIONS: Vismodegib and Erlotinib combination was well-tolerated although overall outcome in patients with metastatic PDAC was not significantly impacted by combination treatment. Biomarker analysis suggests direct targets inhibition without significantly affecting the stromal compartment. These findings conflict with pre-clinical mouse models, and thus warrant further investigation into how upstream inhibition of these pathways is circumvented in PDAC.

10 Article Hepatocytes direct the formation of a pro-metastatic niche in the liver. 2019

Lee, Jae W / Stone, Meredith L / Porrett, Paige M / Thomas, Stacy K / Komar, Chad A / Li, Joey H / Delman, Devora / Graham, Kathleen / Gladney, Whitney L / Hua, Xia / Black, Taylor A / Chien, Austin L / Majmundar, Krishna S / Thompson, Jeffrey C / Yee, Stephanie S / O'Hara, Mark H / Aggarwal, Charu / Xin, Dong / Shaked, Abraham / Gao, Mingming / Liu, Dexi / Borad, Mitesh J / Ramanathan, Ramesh K / Carpenter, Erica L / Ji, Ailing / de Beer, Maria C / de Beer, Frederick C / Webb, Nancy R / Beatty, Gregory L. ·Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA. · Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. · Division of Transplant Surgery, Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. · Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA, USA. · Mayo Clinic Cancer Center, Mayo Clinic, Phoenix, AZ, USA. · Merck Research Labs, Rahway, NJ, USA. · Department of Internal Medicine, University of Kentucky, Lexington, KY, USA. · Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY, USA. · Department of Physiology, University of Kentucky, Lexington, KY, USA. · Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, USA. · Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA. gregory.beatty@uphs.upenn.edu. · Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. gregory.beatty@uphs.upenn.edu. ·Nature · Pubmed #30842658.

ABSTRACT: The liver is the most common site of metastatic disease

11 Article Second-line treatment in patients with pancreatic ductal adenocarcinoma: A meta-analysis. 2017

Sonbol, Mohamad Bassam / Firwana, Belal / Wang, Zhen / Almader-Douglas, Diana / Borad, Mitesh J / Makhoul, Issam / Ramanathan, Ramesh K / Ahn, Daniel H / Bekaii-Saab, Tanios. ·Mayo Clinic Cancer Center, Mayo Clinic, Phoenix, Arizona. · University of Arkansas for Medical Sciences, Little Rock, Arkansas. · Evidence-Based Practice Center, Mayo Clinic, Rochester, New York. · Mayo Clinic Libraries, Mayo Clinic, Phoenix, Arizona. ·Cancer · Pubmed #28817187.

ABSTRACT: BACKGROUND: There are limited therapeutic options for treatment-refractory pancreatic ductal adenocarcinoma (PDAC), with a paucity of data to support the best option after progression on gemcitabine-based regimens. The authors performed a meta-analysis to determine the effectiveness of adding oxaliplatin (OX) or various irinotecan formulations to a fluoropyrimidine (FP) after first-line treatment progression in patients with PDAC. METHODS: Different databases, including PubMed, EMBASE, and Cochrane, were searched to identify randomized controlled trials comparing FP monotherapy versus FP combination therapy that included either oxaliplatin (FPOX) or various irinotecan formulations (FPIRI) in patients with PDAC who progressed after first-line treatment. Secondary analyses were planned to assess the effectiveness of FPOX and FPIRI compared with FP. Outcomes of interest included overall survival (OS) and progression-free survival (PFS). RESULTS: Five studies with 895 patients were identified. Patients randomized to receive FPIRI/FPOX had a significantly improved PFS and a trend toward improved OS compared with those who received FP monotherapy. When comparing FPIRI with FP, there was an improvement in both PFS (hazard ratio, 0.64; 95% confidence interval, 0.47-0.87; P = .005) and OS (hazard ratio, 0.70; 95% confidence interval, 0.55-0.89; P = .004) in patients who received the combination. Conversely, FPOX produced only a modest improvement in PFS with no improvement in OS. CONCLUSIONS: Combination chemotherapy with OX or various IRI formulations appears to improve PFS compared with single-agent FP. FPIRI, but not FPOX, appears to confer an OS advantage. The combination of FP with irinotecan formulations appears to be the appropriate next line of treatment upon progression after gemcitabine-based chemotherapy regimens. Cancer 2017;123:4680-4686. © 2017 American Cancer Society.

12 Article Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH-Mutant Molecular Profiles. 2017

Farshidfar, Farshad / Zheng, Siyuan / Gingras, Marie-Claude / Newton, Yulia / Shih, Juliann / Robertson, A Gordon / Hinoue, Toshinori / Hoadley, Katherine A / Gibb, Ewan A / Roszik, Jason / Covington, Kyle R / Wu, Chia-Chin / Shinbrot, Eve / Stransky, Nicolas / Hegde, Apurva / Yang, Ju Dong / Reznik, Ed / Sadeghi, Sara / Pedamallu, Chandra Sekhar / Ojesina, Akinyemi I / Hess, Julian M / Auman, J Todd / Rhie, Suhn K / Bowlby, Reanne / Borad, Mitesh J / Anonymous5350899 / Zhu, Andrew X / Stuart, Josh M / Sander, Chris / Akbani, Rehan / Cherniack, Andrew D / Deshpande, Vikram / Mounajjed, Taofic / Foo, Wai Chin / Torbenson, Michael S / Kleiner, David E / Laird, Peter W / Wheeler, David A / McRee, Autumn J / Bathe, Oliver F / Andersen, Jesper B / Bardeesy, Nabeel / Roberts, Lewis R / Kwong, Lawrence N. ·Departments of Surgery and Oncology, Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, AB T2N 4N1, Canada. · Departments of Genomic Medicine, Melanoma Medical Oncology, Bioinformatics and Computational Biology, Pathology, and Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA. · University of California Santa Cruz, Santa Cruz, CA 95064, USA. · The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. · Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z 4S6, Canada. · Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI 49503, USA. · Departments of Genetics and Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. · Blueprint Medicines, 38 Sidney Street, Cambridge, MA 02139, USA. · Divisions of Gastroenterology and Hepatology and Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. · Memorial Sloan Kettering Cancer Center, New York, NY 10005, USA. · University of Alabama at Birmingham, Birmingham, AL 35294, USA; HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA. · The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA. · Departments of Genetics and Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. · USC/Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA. · Division of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ 85054, USA. · Departments of Hematology and Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. · Departments of Pathology and Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. · National Cancer Institute, Bethesda, MD 20892, USA. · Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. · Biotech Research and Innovation Centre, Department of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark. Electronic address: jesper.andersen@bric.ku.dk. · Departments of Pathology and Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. Electronic address: bardeesy.nabeel@mgh.harvard.edu. · Divisions of Gastroenterology and Hepatology and Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. Electronic address: roberts.lewis@mayo.edu. · Departments of Genomic Medicine, Melanoma Medical Oncology, Bioinformatics and Computational Biology, Pathology, and Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: lkwong@mdanderson.org. ·Cell Rep · Pubmed #28297679.

ABSTRACT: Cholangiocarcinoma (CCA) is an aggressive malignancy of the bile ducts, with poor prognosis and limited treatment options. Here, we describe the integrated analysis of somatic mutations, RNA expression, copy number, and DNA methylation by The Cancer Genome Atlas of a set of predominantly intrahepatic CCA cases and propose a molecular classification scheme. We identified an IDH mutant-enriched subtype with distinct molecular features including low expression of chromatin modifiers, elevated expression of mitochondrial genes, and increased mitochondrial DNA copy number. Leveraging the multi-platform data, we observed that ARID1A exhibited DNA hypermethylation and decreased expression in the IDH mutant subtype. More broadly, we found that IDH mutations are associated with an expanded histological spectrum of liver tumors with molecular features that stratify with CCA. Our studies reveal insights into the molecular pathogenesis and heterogeneity of cholangiocarcinoma and provide classification information of potential therapeutic significance.

13 Article Preoperative chemoradiation and IOERT for unresectable or borderline resectable pancreas cancer. 2013

Ashman, Jonathan B / Moss, Adyr A / Rule, William G / Callister, Matthew G / Reddy, K Sudhakar / Mulligan, David C / Collins, Joseph M / De Petris, Giovanni / Gunderson, Leonard L / Borad, Mitesh. ·Department of Radiation Oncology, Mayo Clinic Cancer Center - Arizona (MCCC-A), Scottsdale/Phoenix, AZ, USA. ·J Gastrointest Oncol · Pubmed #24294506.

ABSTRACT: BACKGROUND AND OBJECTIVES: Pre-operative chemoradiation (preop CRT) plus intraoperative electron irradiation (IOERT) has been used in the multidisciplinary treatment for patients with locally advanced unresectable or borderline resectable pancreas cancer. This review was performed to evaluate survival, relapse patterns and prognostic factors in patients treated with curative intent. METHODS: Between January 2002 and December 2010, 48 patients with locally advanced pancreatic ductal adenocarcinoma received preop CRT prior to an attempt at resection and IOERT. 31/48 (65%) patients proceeded to curative-intent surgical resection. Resection status prior to preop CRT was locally unresectable (20 patients) and borderline resectable (11 patients). Preop CRT (45-50.4 Gy/25-28 Fx in 27/31) was delivered with concurrent 5FU or gemcitabine-based regimens. Subsequent gross total resection was achieved in 16 patients (R0, 11; R1, 5). IOERT was delivered in 28 patients (dose, 10-20 Gy). 16 patients also received adjuvant post-operative systemic chemotherapy. Outcomes evaluated include survival, local failure in the EBRT field (LF), central failure in the IOERT field (CF), and distant metastases. RESULTS: Resection status was predictive for survival and for patterns of relapse. For patients with at least a gross total resection after preop CRT (R0/R1; n=16) vs. no resection (n=15), both median and overall survival were improved (median 23 vs. 10 months; 2-year, 40% vs. 17%; 3-year, 40% vs. 0%; P=0.002). Liver or peritoneal relapse was documented in 22/31 patients (71%); LF/CF in 5/26 (16%). CONCLUSIONS: Long term survival and disease control are achievable in select patients with borderline resectable or locally unresectable pancreas cancer when gross total surgical resection is achieved after preop CRT. Continued evaluation of curative-intent combined modality therapy is warranted in this high risk population, but additional strategies are needed to improve resectability and disease control.

14 Article Genome-wide characterization of pancreatic adenocarcinoma patients using next generation sequencing. 2012

Liang, Winnie S / Craig, David W / Carpten, John / Borad, Mitesh J / Demeure, Michael J / Weiss, Glen J / Izatt, Tyler / Sinari, Shripad / Christoforides, Alexis / Aldrich, Jessica / Kurdoglu, Ahmet / Barrett, Michael / Phillips, Lori / Benson, Hollie / Tembe, Waibhav / Braggio, Esteban / Kiefer, Jeffrey A / Legendre, Christophe / Posner, Richard / Hostetter, Galen H / Baker, Angela / Egan, Jan B / Han, Haiyong / Lake, Douglas / Stites, Edward C / Ramanathan, Ramesh K / Fonseca, Rafael / Stewart, A Keith / Von Hoff, Daniel. ·Translational Genomics Research Institute (TGen), Phoenix, Arizona, United States of America. ·PLoS One · Pubmed #23071490.

ABSTRACT: Pancreatic adenocarcinoma (PAC) is among the most lethal malignancies. While research has implicated multiple genes in disease pathogenesis, identification of therapeutic leads has been difficult and the majority of currently available therapies provide only marginal benefit. To address this issue, our goal was to genomically characterize individual PAC patients to understand the range of aberrations that are occurring in each tumor. Because our understanding of PAC tumorigenesis is limited, evaluation of separate cases may reveal aberrations, that are less common but may provide relevant information on the disease, or that may represent viable therapeutic targets for the patient. We used next generation sequencing to assess global somatic events across 3 PAC patients to characterize each patient and to identify potential targets. This study is the first to report whole genome sequencing (WGS) findings in paired tumor/normal samples collected from 3 separate PAC patients. We generated on average 132 billion mappable bases across all patients using WGS, and identified 142 somatic coding events including point mutations, insertion/deletions, and chromosomal copy number variants. We did not identify any significant somatic translocation events. We also performed RNA sequencing on 2 of these patients' tumors for which tumor RNA was available to evaluate expression changes that may be associated with somatic events, and generated over 100 million mapped reads for each patient. We further performed pathway analysis of all sequencing data to identify processes that may be the most heavily impacted from somatic and expression alterations. As expected, the KRAS signaling pathway was the most heavily impacted pathway (P<0.05), along with tumor-stroma interactions and tumor suppressive pathways. While sequencing of more patients is needed, the high resolution genomic and transcriptomic information we have acquired here provides valuable information on the molecular composition of PAC and helps to establish a foundation for improved therapeutic selection.

15 Unspecified Hepatoid Carcinoma of the Pancreas: Case Report, Next-Generation Tumor Profiling, and Literature Review. 2016

Chang, James M / Katariya, Nitin N / Lam-Himlin, Dora M / Haakinson, Danielle J / Ramanathan, Ramesh K / Halfdanarson, Thorvardur R / Borad, Mitesh J / Pannala, Rahul / Faigel, Douglas / Moss, Adyr A / Mathur, Amit K. ·Division of Transplant and Hepatopancreatobiliary Surgery, Mayo Clinic Arizona, Phoenix, Ariz., USA. · Department of Laboratory Medicine and Pathology, Mayo Clinic Arizona, Phoenix, Ariz., USA. · Division of Hematology/Oncology, Mayo Clinic Arizona, Phoenix, Ariz., USA. · Division of Gastroenterology/Hepatology, Mayo Clinic Arizona, Phoenix, Ariz., USA. ·Case Rep Gastroenterol · Pubmed #27920649.

ABSTRACT: Fewer than 25 cases of hepatoid carcinoma of the pancreas have been reported in the literature. We present a case in a 61-year-old male with a remote history of Hodgkin's lymphoma and gastric neuroendocrine cell hyperplasia. On surveillance endoscopic ultrasound, an 8 × 5 mm cystic lesion was seen in the tail of the pancreas. MRI showed a focal pancreatic duct cut-off with mild ductal dilation. Fine needle aspiration was performed, which was concerning for acinar cell carcinoma. The patient underwent distal pancreatectomy and recovered uneventfully. Final pathology demonstrated a 1.3-cm hepatoid carcinoma of the pancreas, with a final clinicopathological stage of T1N0M0. Next-generation nucleic acid sequencing of the tumor did not suggest a viable adjuvant chemotherapeutic agent, and no adjuvant therapy was administered. The patient has no evidence of disease 6 months following resection. A further characterization and description of the outcomes of these rare tumors is warranted to help guide providers and counsel patients.