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Pancreatic Neoplasms: HELP
Articles by Amanda L. Blackford
Based on 24 articles published since 2010
(Why 24 articles?)
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Between 2010 and 2020, Amanda Blackford wrote the following 24 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Clinical Trial The Role of Stereotactic Body Radiation Therapy for Pancreatic Cancer: A Single-Institution Experience. 2015

Moningi, Shalini / Dholakia, Avani S / Raman, Siva P / Blackford, Amanda / Cameron, John L / Le, Dung T / De Jesus-Acosta, Ana M C / Hacker-Prietz, Amy / Rosati, Lauren M / Assadi, Ryan K / Dipasquale, Shirl / Pawlik, Timothy M / Zheng, Lei / Weiss, Matthew J / Laheru, Daniel A / Wolfgang, Christopher L / Herman, Joseph M. ·Department of Radiation Oncology & Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. ·Ann Surg Oncol · Pubmed #25564157.

ABSTRACT: BACKGROUND: Stereotactic body radiation therapy (SBRT) is a promising option for patients with pancreatic cancer (PCA); however, limited data support its efficacy. This study reviews our institutional experience of SBRT in the treatment of locally advanced (LAPC) and borderline resectable (BRPC) PCA. METHODS: Charts of all PCA patients receiving SBRT at our institution from 2010 to 2014 were reviewed. Most patients received pre-SBRT chemotherapy. Primary endpoints included overall survival (OS) and local progression-free survival (LPFS). Patients received a total dose of 25-33 Gy in five fractions. RESULTS: A total of 88 patients were included in the analysis, 74 with LAPC and 14 with BRPC. The median age at diagnosis was 67.2 years, and median follow-up from date of diagnosis for LAPC and BRPC patients was 14.5 and 10.3 months, respectively. Median OS from date of diagnosis was 18.4 months (LAPC, 18.4 mo; BRPC, 14.4 mo) and median PFS was 9.8 months (95 % CI 8.0-12.3). Acute toxicity was minimal with only three patients (3.4 %) experiencing acute grade ≥3 toxicity. Late grade ≥2 gastrointestinal toxicity was seen in five patients (5.7 %). Of the 19 patients (21.6 %) who underwent surgery, 79 % were LAPC patients and 84 % had margin-negative resections. CONCLUSIONS: Chemotherapy followed by SBRT in patients with LAPC and BRPC resulted in minimal acute and late toxicity. A large proportion of patients underwent surgical resection despite limited radiographic response to therapy. Further refinements in the integration of chemotherapy, SBRT, and surgery might offer additional advancements toward optimizing patient outcomes.

2 Clinical Trial Phase 2 study of erlotinib combined with adjuvant chemoradiation and chemotherapy in patients with resectable pancreatic cancer. 2013

Herman, Joseph M / Fan, Katherine Y / Wild, Aaron T / Hacker-Prietz, Amy / Wood, Laura D / Blackford, Amanda L / Ellsworth, Susannah / Zheng, Lei / Le, Dung T / De Jesus-Acosta, Ana / Hidalgo, Manuel / Donehower, Ross C / Schulick, Richard D / Edil, Barish H / Choti, Michael A / Hruban, Ralph H / Pawlik, Timothy M / Cameron, John L / Laheru, Daniel A / Wolfgang, Christopher L. ·Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland 21231, USA. jherma15@jhmi.edu ·Int J Radiat Oncol Biol Phys · Pubmed #23773391.

ABSTRACT: PURPOSE: Long-term survival rates for patients with resected pancreatic ductal adenocarcinoma (PDAC) have stagnated at 20% for more than a decade, demonstrating the need to develop novel adjuvant therapies. Gemcitabine-erlotinib therapy has demonstrated a survival benefit for patients with metastatic PDAC. Here we report the first phase 2 study of erlotinib in combination with adjuvant chemoradiation and chemotherapy for resected PDAC. METHODS AND MATERIALS: Forty-eight patients with resected PDAC received adjuvant erlotinib (100 mg daily) and capecitabine (800 mg/m(2) twice daily Monday-Friday) concurrently with intensity modulated radiation therapy (IMRT), 50.4 Gy over 28 fractions followed by 4 cycles of gemcitabine (1000 mg/m(2) on days 1, 8, and 15 every 28 days) and erlotinib (100 mg daily). The primary endpoint was recurrence-free survival (RFS). RESULTS: The median follow-up time was 18.2 months (interquartile range, 13.8-27.1). Lymph nodes were positive in 85% of patients, and margins were positive in 17%. The median RFS was 15.6 months (95% confidence interval [CI], 13.4-17.9), and the median overall survival (OS) was 24.4 months (95% CI, 18.9-29.7). Multivariate analysis with adjustment for known prognostic factors showed that tumor diameter >3 cm was predictive for inferior RFS (hazard ratio, 4.01; P=.001) and OS (HR, 4.98; P=.02), and the development of dermatitis was associated with improved RFS (HR, 0.27; P=.009). During CRT and post-CRT chemotherapy, the rates of grade 3/4 toxicity were 31%/2% and 35%/8%, respectively. CONCLUSION: Erlotinib can be safely administered with adjuvant IMRT-based CRT and chemotherapy. The efficacy of this regimen appears comparable to that of existing adjuvant regimens. Radiation Therapy Oncology Group 0848 will ultimately determine whether erlotinib produces a survival benefit in patients with resected pancreatic cancer.

3 Article Surgical Outcomes After Pancreatic Resection of Screening-Detected Lesions in Individuals at High Risk for Developing Pancreatic Cancer. 2019

Canto, Marcia Irene / Kerdsirichairat, Tossapol / Yeo, Charles J / Hruban, Ralph H / Shin, Eun Ji / Almario, Jose Alejandro / Blackford, Amanda / Ford, Madeline / Klein, Alison P / Javed, Ammar A / Lennon, Anne Marie / Zaheer, Atif / Kamel, Ihab R / Fishman, Elliot K / Burkhart, Richard / He, Jin / Makary, Martin / Weiss, Matthew J / Schulick, Richard D / Goggins, Michael G / Wolfgang, Christopher L. ·Division of Gastroenterology and Hepatology, Department of Medicine, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Blalock 407, Baltimore, MD, 21287, USA. mcanto1@jhmi.edu. · Division of Gastroenterology and Hepatology, Department of Medicine, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Blalock 407, Baltimore, MD, 21287, USA. · Department of Surgery, Thomas Jefferson University, Philadelphia, PA, USA. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD, USA. · Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD, USA. · Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD, USA. · Department of Radiology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD, USA. · Department of Surgery, University of Colorado School of Medicine, Denver, CO, USA. ·J Gastrointest Surg · Pubmed #31197699.

ABSTRACT: BACKGROUND: Screening high-risk individuals (HRI) can detect potentially curable pancreatic ductal adenocarcinoma (PDAC) and its precursors. We describe the outcomes of high-risk individuals (HRI) after pancreatic resection of screen-detected neoplasms. METHODS: Asymptomatic HRI enrolled in the prospective Cancer of the Pancreas Screening (CAPS) studies from 1998 to 2014 based on family history or germline mutations undergoing surveillance for at least 6 months were included. Pathologic diagnoses, hospital length of stay, incidence of diabetes mellitus, operative morbidity, need for repeat operation, and disease-specific mortality were determined. RESULTS: Among 354 HRI, 48 (13.6%) had 57 operations (distal pancreatectomy (31), Whipple (20), and total pancreatectomy (6)) for suspected pancreatic neoplasms presenting as a solid mass (22), cystic lesion(s) (25), or duct stricture (1). The median length of stay was 7 days (IQR 5-11). Nine of the 42 HRI underwent completion pancreatectomy for a new lesion after a median of 3.8 years (IQR 2.5-7.6). Postoperative complications developed in 17 HRI (35%); there were no perioperative deaths. New-onset diabetes mellitus after partial resection developed in 20% of HRI. Fourteen PDACs were diagnosed, 11 were screen-detected, 10 were resectable, and 9 had an R0 resection. Metachronous PDAC developed in remnant pancreata of 2 HRI. PDAC-related mortality was 4/10 (40%), with 90% 1-year survival and 60% 5-year survival, respectively. CONCLUSIONS: Screening HRI can detect PDAC with a high resectability rate. Surgical treatment is associated with a relatively short length of stay and low readmission rate, acceptable morbidity, zero 90-day mortality, and significant long-term survival. CLINICAL TRIAL REGISTRATION NUMBER: NCT2000089.

4 Article The Significance of Ascites in Patients With Pancreatic Ductal Adenocarcinoma: A Case-Control Study. 2019

Baretti, Marina / Pulluri, Bhargavi / Tsai, Hua-Ling / Blackford, Amanda L / Wolfgang, Christopher L / Laheru, Daniel / Zheng, Lei / Herman, Joseph / Le, Dung T / Narang, Amol K / de Jesus-Acosta, Ana. ·Department of Medicine, The University of Vermont Medical Center, Burlington, VT. · Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, The Johns Hopkins Biostatistics Center. · Department of Surgery, Johns Hopkins Medical Institutions, Baltimore, MD. · Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. · Departments of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins School of Medicine, Baltimore, MD. ·Pancreas · Pubmed #30817723.

ABSTRACT: OBJECTIVE: Limited data exist on the impact of ascites in pancreatic ductal adenocarcinoma (PDAC). We evaluated the survival outcomes of patients with PDAC and ascites. METHODS: Retrospective, single-institution, case-control study including patients with newly diagnosed PDAC from 2007 to 2016. One hundred fifty-four patients with ascites at diagnosis (case group) and 154 controls were matched on age, sex, stage, Eastern Cooperative Oncology Group performance, surgical treatment, lymph node, and margin status. Ascites was defined as computed tomography-detected fluid in the pelvic/peritoneal cavity. Overall survival was compared between groups via Cox proportional hazards models with a gamma frailty term to account for the correlation between matched pairs on entire cohort and by disease stages for subgroup analysis. RESULTS: The 154 matched cases included 24 resectable, 19 borderline resectable, 51 locally advanced, and 60 metastatic disease. Patients with ascites had higher risk of death compared with those without (conditional hazard ratio, 1.58; 95% confidence interval, 1.23-2.03; P < 0.001). Stratified analysis showed a significant association between ascites and poor prognosis in patients with localized disease (conditional hazard ratio, 1.62; 95% confidence interval, 1.18-2.24; P = 0.003). CONCLUSIONS: Radiographic ascites is a poor prognostic factor in PDAC. Our findings may aid physicians in considering systemic therapy prior to attempting local treatments.

5 Article Risk of Neoplastic Progression in Individuals at High Risk for Pancreatic Cancer Undergoing Long-term Surveillance. 2018

Canto, Marcia Irene / Almario, Jose Alejandro / Schulick, Richard D / Yeo, Charles J / Klein, Alison / Blackford, Amanda / Shin, Eun Ji / Sanyal, Abanti / Yenokyan, Gayane / Lennon, Anne Marie / Kamel, Ihab R / Fishman, Elliot K / Wolfgang, Christopher / Weiss, Matthew / Hruban, Ralph H / Goggins, Michael. ·Department of Medicine (Gastroenterology), The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland; Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. Electronic address: mcanto@jhmi.edu. · Department of Medicine (Gastroenterology), The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland; Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. · Department of Surgery, University of Colorado School of Medicine, Denver, Colorado. · Department of Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania. · Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. · Department of Medicine (Gastroenterology), The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. · The Johns Hopkins Biostatistics Center, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland. · Department of Radiology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. · Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. ·Gastroenterology · Pubmed #29803839.

ABSTRACT: BACKGROUND & AIMS: Screening of individuals who have a high risk of pancreatic ductal adenocarcinoma (PDAC), because of genetic factors, frequently leads to identification of pancreatic lesions. We investigated the incidence of PDAC and risk factors for neoplastic progression in individuals at high risk for PDAC enrolled in a long-term screening study. METHODS: We analyzed data from 354 individuals at high risk for PDAC (based on genetic factors of family history), enrolled in Cancer of the Pancreas Screening cohort studies at tertiary care academic centers from 1998 through 2014 (median follow-up time, 5.6 years). All subjects were evaluated at study entry (baseline) by endoscopic ultrasonography and underwent surveillance with endoscopic ultrasonography, magnetic resonance imaging, and/or computed tomography. The primary endpoint was the cumulative incidence of PDAC, pancreatic intraepithelial neoplasia grade 3, or intraductal papillary mucinous neoplasm with high-grade dysplasia (HGD) after baseline. We performed multivariate Cox regression and Kaplan-Meier analyses. RESULTS: During the follow-up period, pancreatic lesions with worrisome features (solid mass, multiple cysts, cyst size > 3 cm, thickened/enhancing walls, mural nodule, dilated main pancreatic duct > 5 mm, or abrupt change in duct caliber) or rapid cyst growth (>4 mm/year) were detected in 68 patients (19%). Overall, 24 of 354 patients (7%) had neoplastic progression (14 PDACs and 10 HGDs) over a 16-year period; the rate of progression was 1.6%/year, and 93% had detectable lesions with worrisome features before diagnosis of the PDAC or HGD. Nine of the 10 PDACs detected during routine surveillance were resectable; a significantly higher proportion of patients with resectable PDACs survived 3 years (85%) compared with the 4 subjects with symptomatic, unresectable PDACs (25%), which developed outside surveillance (log rank P < .0001). Neoplastic progression occurred at a median age of 67 years; the median time from baseline screening until PDAC diagnosis was 4.8 years (interquartile range, 1.6-6.9 years). CONCLUSIONS: In a long-term (16-year) follow-up study of individuals at high-risk for PDAC, we found most PDACs detected during surveillance (9/10) to be resectable, and 85% of these patients survived for 3 years. We identified radiologic features associated with neoplastic progression.

6 Article Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer. 2018

Klein, Alison P / Wolpin, Brian M / Risch, Harvey A / Stolzenberg-Solomon, Rachael Z / Mocci, Evelina / Zhang, Mingfeng / Canzian, Federico / Childs, Erica J / Hoskins, Jason W / Jermusyk, Ashley / Zhong, Jun / Chen, Fei / Albanes, Demetrius / Andreotti, Gabriella / Arslan, Alan A / Babic, Ana / Bamlet, William R / Beane-Freeman, Laura / Berndt, Sonja I / Blackford, Amanda / Borges, Michael / Borgida, Ayelet / Bracci, Paige M / Brais, Lauren / Brennan, Paul / Brenner, Hermann / Bueno-de-Mesquita, Bas / Buring, Julie / Campa, Daniele / Capurso, Gabriele / Cavestro, Giulia Martina / Chaffee, Kari G / Chung, Charles C / Cleary, Sean / Cotterchio, Michelle / Dijk, Frederike / Duell, Eric J / Foretova, Lenka / Fuchs, Charles / Funel, Niccola / Gallinger, Steven / M Gaziano, J Michael / Gazouli, Maria / Giles, Graham G / Giovannucci, Edward / Goggins, Michael / Goodman, Gary E / Goodman, Phyllis J / Hackert, Thilo / Haiman, Christopher / Hartge, Patricia / Hasan, Manal / Hegyi, Peter / Helzlsouer, Kathy J / Herman, Joseph / Holcatova, Ivana / Holly, Elizabeth A / Hoover, Robert / Hung, Rayjean J / Jacobs, Eric J / Jamroziak, Krzysztof / Janout, Vladimir / Kaaks, Rudolf / Khaw, Kay-Tee / Klein, Eric A / Kogevinas, Manolis / Kooperberg, Charles / Kulke, Matthew H / Kupcinskas, Juozas / Kurtz, Robert J / Laheru, Daniel / Landi, Stefano / Lawlor, Rita T / Lee, I-Min / LeMarchand, Loic / Lu, Lingeng / Malats, Núria / Mambrini, Andrea / Mannisto, Satu / Milne, Roger L / Mohelníková-Duchoňová, Beatrice / Neale, Rachel E / Neoptolemos, John P / Oberg, Ann L / Olson, Sara H / Orlow, Irene / Pasquali, Claudio / Patel, Alpa V / Peters, Ulrike / Pezzilli, Raffaele / Porta, Miquel / Real, Francisco X / Rothman, Nathaniel / Scelo, Ghislaine / Sesso, Howard D / Severi, Gianluca / Shu, Xiao-Ou / Silverman, Debra / Smith, Jill P / Soucek, Pavel / Sund, Malin / Talar-Wojnarowska, Renata / Tavano, Francesca / Thornquist, Mark D / Tobias, Geoffrey S / Van Den Eeden, Stephen K / Vashist, Yogesh / Visvanathan, Kala / Vodicka, Pavel / Wactawski-Wende, Jean / Wang, Zhaoming / Wentzensen, Nicolas / White, Emily / Yu, Herbert / Yu, Kai / Zeleniuch-Jacquotte, Anne / Zheng, Wei / Kraft, Peter / Li, Donghui / Chanock, Stephen / Obazee, Ofure / Petersen, Gloria M / Amundadottir, Laufey T. ·Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, 21231, USA. aklein1@jhmi.edu. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins School of Medicine, Baltimore, MD, 21287, USA. aklein1@jhmi.edu. · Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA. · Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, 06520, USA. · Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. · Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, 21231, USA. · Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. · Genomic Epidemiology Group, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany. · Department of Obstetrics and Gynecology, New York University School of Medicine, New York, NY, 10016, USA. · Department of Population Health, New York University School of Medicine, New York, NY, 10016, USA. · Department of Environmental Medicine, New York University School of Medicine, New York, NY, 10016, USA. · Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins School of Medicine, Baltimore, MD, 21287, USA. · Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, M5G 1×5, Canada. · Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, 94158, USA. · International Agency for Research on Cancer (IARC), 69372, Lyon, France. · Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany. · Division of Preventive Oncology, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany. · National Center for Tumor Diseases (NCT), 69120, Heidelberg, Germany. · Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), 3720 BA, Bilthoven, The Netherlands. · Department of Gastroenterology and Hepatology, University Medical Centre, 3584 CX, Utrecht, The Netherlands. · Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, SW7 2AZ, UK. · Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia. · Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, 02215, USA. · Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA. · Department of Biology, University of Pisa, 56126, Pisa, Italy. · Digestive and Liver Disease Unit, 'Sapienza' University of Rome, 00185, Rome, Italy. · Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy. · Cancer Genomics Research Laboratory, National Cancer Institute, Division of Cancer Epidemiology and Genetics, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA. · Cancer Care Ontario, University of Toronto, Toronto, Ontario, M5G 2L7, Canada. · Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, M5T 3M7, Canada. · Department of Pathology, Academic Medical Center, University of Amsterdam, 1007 MB, Amsterdam, The Netherlands. · Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Bellvitge Biomedical Research Institute (IDIBELL), Catalan Institute of Oncology (ICO), Barcelona, 08908, Spain. · Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, 65653, Brno, Czech Republic. · Yale Cancer Center, New Haven, CT, 06510, USA. · Department of Translational Research and The New Technologies in Medicine and Surgery, University of Pisa, 56126, Pisa, Italy. · Division of Aging, Brigham and Women's Hospital, Boston, MA, 02115, USA. · Boston VA Healthcare System, Boston, MA, 02132, USA. · Department of Basic Medical Sciences, Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, 106 79, Athens, Greece. · Cancer Epidemiology and Intelligence Division, Cancer Council Victoria, Melbourne, VIC, 3004, Australia. · Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, VIC, 3010, Australia. · Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC, 3004, Australia. · Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA. · SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA. · Department of General Surgery, University Hospital Heidelberg, 69120, Heidelberg, Germany. · Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90032, USA. · Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX, 77230, USA. · First Department of Medicine, University of Szeged, 6725, Szeged, Hungary. · Division of Cancer Control and Population Sciences, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. · Department of Radiation Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, 21231, USA. · Institute of Public Health and Preventive Medicine, Charles University, 2nd Faculty of Medicine, 150 06, Prague 5, Czech Republic. · Epidemiology Research Program, American Cancer Society, Atlanta, GA, 30303, USA. · Department of Hematology, Institute of Hematology and Transfusion Medicine, 02-776, Warsaw, Poland. · Department of Epidemiology and Public Health, Faculty of Medicine, University of Ostrava, 701 03, Ostrava, Czech Republic. · Faculty of Medicine, University of Olomouc, 771 47, Olomouc, Czech Republic. · Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany. · School of Clinical Medicine, University of Cambridge, Cambridge, CB2 0SP, UK. · Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH, 44195, USA. · ISGlobal, Centre for Research in Environmental Epidemiology (CREAL), 08003, Barcelona, Spain. · CIBER Epidemiología y Salud Pública (CIBERESP), 08003, Barcelona, Spain. · Hospital del Mar Institute of Medical Research (IMIM), Universitat Autònoma de Barcelona, 08003, Barcelona, Spain. · Universitat Pompeu Fabra (UPF), 08002, Barcelona, Spain. · Department of Gastroenterology, Lithuanian University of Health Sciences, 44307, Kaunas, Lithuania. · Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. · ARC-NET: Centre for Applied Research on Cancer, University and Hospital Trust of Verona, 37134, Verona, Italy. · Department of Epidemiology, Harvard School of Public Health, Boston, MA, 02115, USA. · Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, 96813, USA. · Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Center (CNIO), 28029, Madrid, Spain. · CIBERONC, 28029, Madrid, Spain. · Oncology Department, ASL1 Massa Carrara, Carrara, 54033, Italy. · Department of Public Health Solutions, National Institute for Health and Welfare, 00271, Helsinki, Finland. · Department of Oncology, Faculty of Medicine and Dentistry, Palacky University Olomouc and University Hospital, 775 20, Olomouc, Czech Republic. · Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, 4029, Australia. · Department of General Surgery, University of Heidelburg, Heidelberg, Germany. · Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. · Department of Surgery, Oncology and Gastroenterology (DiSCOG), University of Padua, 35124, Padua, Italy. · Pancreas Unit, Department of Digestive Diseases and Internal Medicine, Sant'Orsola-Malpighi Hospital, 40138, Bologna, Italy. · Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre-CNIO, 28029, Madrid, Spain. · Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, 08002, Barcelona, Spain. · Centre de Recherche en Épidémiologie et Santé des Populations (CESP, Inserm U1018), Facultés de Medicine, Université Paris-Saclay, UPS, UVSQ, Gustave Roussy, 94800, Villejuif, France. · Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA. · Department of Medicine, Georgetown University, Washington, 20057, USA. · Laboratory for Pharmacogenomics, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, 323 00, Pilsen, Czech Republic. · Department of Surgical and Perioperative Sciences, Umeå University, 901 85, Umeå, Sweden. · Department of Digestive Tract Diseases, Medical University of Łodz, 90-647, Łodz, Poland. · Division of Gastroenterology and Research Laboratory, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza", 71013, San Giovanni Rotondo, FG, Italy. · Division of Research, Kaiser Permanente Northern California, Oakland, CA, 94612, USA. · Department of General, Visceral and Thoracic Surgery, University Hamburg-Eppendorf, 20246, Hamburg, Germany. · Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, 21205, USA. · Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, 142 20, Prague 4, Czech Republic. · Department of Epidemiology and Environmental Health, University at Buffalo, Buffalo, NY, 14214, USA. · Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. · Department of Epidemiology, University of Washington, Seattle, WA, 98195, USA. · Perlmutter Cancer Center, New York University School of Medicine, New York, NY, 10016, USA. · Department of Biostatistics, Harvard School of Public Health, Boston, MA, 02115, USA. · Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. · Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. amundadottirl@mail.nih.gov. ·Nat Commun · Pubmed #29422604.

ABSTRACT: In 2020, 146,063 deaths due to pancreatic cancer are estimated to occur in Europe and the United States combined. To identify common susceptibility alleles, we performed the largest pancreatic cancer GWAS to date, including 9040 patients and 12,496 controls of European ancestry from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4). Here, we find significant evidence of a novel association at rs78417682 (7p12/TNS3, P = 4.35 × 10

7 Article Duodenal Involvement is an Independent Prognostic Factor for Patients with Surgically Resected Pancreatic Ductal Adenocarcinoma. 2017

Dal Molin, Marco / Blackford, Amanda L / Siddiqui, Abdulrehman / Brant, Aaron / Cho, Christy / Rezaee, Neda / Yu, Jun / He, Jin / Weiss, Matthew / Hruban, Ralph H / Wolfgang, Christopher / Goggins, Michael. ·Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. mgoggins@jhmi.edu. · Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. mgoggins@jhmi.edu. · Department of Medicine, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. mgoggins@jhmi.edu. · Department of Pathology, Johns Hopkins Medical Institutions, 1550 Orleans Street, Baltimore, MD, 21231, USA. mgoggins@jhmi.edu. ·Ann Surg Oncol · Pubmed #28439733.

ABSTRACT: BACKGROUND: The current staging system for pancreatic ductal adenocarcinoma (PDAC) includes information about size and local extension of the primary tumor (T stage). The value of incorporating any local tumor extension into pancreatic staging systems has been questioned because it often is difficult to evaluate tumor extension to the peri-pancreatic soft tissues and because most carcinomas of the head of the pancreas infiltrate the intra-pancreatic common bile duct. This study sought to evaluate the prognostic implications of having PDAC with local tumor extension. METHODS: A single-institution, prospectively collected database of 1128 patients who underwent surgical resection for PDAC was queried to examine the prognostic significance of extra-pancreatic tumor involvement ("no involvement," "duodenal involvement," and "extensive involvement"; e.g., gastric, colon or major vein involvement). RESULTS: The median overall survival for the patients without extra-pancreatic involvement was 26 months versus 19 months for the patients with duodenal involvement and 16 months for the patients with extensive involvement (p < 0.001). In the multivariable analysis, duodenal and extensive involvement independently predicted increased risk of death compared with no involvement (hazard ratio [HR] 1.30; 95% confidence interval [CI] 1.08-1.57 and 1.78; 95% CI 1.25-2.55, respectively). A multivariable model combining duodenal and extensive extra-pancreatic involvement, tumor grade, lymph node ratio, and other prognostic features had the highest c-index (0.67). CONCLUSIONS: Inclusion of duodenal involvement in the staging of PDAC adds independent prognostic information.

8 Article Circulating Tumor Cells Expressing Markers of Tumor-Initiating Cells Predict Poor Survival and Cancer Recurrence in Patients with Pancreatic Ductal Adenocarcinoma. 2017

Poruk, Katherine E / Blackford, Amanda L / Weiss, Matthew J / Cameron, John L / He, Jin / Goggins, Michael / Rasheed, Zeshaan A / Wolfgang, Christopher L / Wood, Laura D. ·Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Gasteroenterology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland. cwolfga2@jhmi.edu ldwood@jhmi.edu. · Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland. cwolfga2@jhmi.edu ldwood@jhmi.edu. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland. ·Clin Cancer Res · Pubmed #27789528.

ABSTRACT:

9 Article A novel approach for selecting combination clinical markers of pathology applied to a large retrospective cohort of surgically resected pancreatic cysts. 2017

Masica, David L / Dal Molin, Marco / Wolfgang, Christopher L / Tomita, Tyler / Ostovaneh, Mohammad R / Blackford, Amanda / Moran, Robert A / Law, Joanna K / Barkley, Thomas / Goggins, Michael / Irene Canto, Marcia / Pittman, Meredith / Eshleman, James R / Ali, Syed Z / Fishman, Elliot K / Kamel, Ihab R / Raman, Siva P / Zaheer, Atif / Ahuja, Nita / Makary, Martin A / Weiss, Matthew J / Hirose, Kenzo / Cameron, John L / Rezaee, Neda / He, Jin / Joon Ahn, Young / Wu, Wenchuan / Wang, Yuxuan / Springer, Simeon / Diaz, Luis L / Papadopoulos, Nickolas / Hruban, Ralph H / Kinzler, Kenneth W / Vogelstein, Bert / Karchin, Rachel / Lennon, Anne Marie. ·*Drs Masica and Dal Molin contributed equally as first authors. · Department of Biomedical Engineering and the Institute for Computational Medicine, The Johns Hopkins University, Baltimore, Maryland. · Departments of the Sol Goldman Pancreatic Cancer Research Center. · Departments of Pathology. · Departments of Surgery. · Departments of Oncology. · Departments of Medicine. · Departments of Biostatistics and Bioinformatics. · Departments of the Ludwig Center and Howard Hughes Medical Institute at the Sidney Kimmel Cancer Center, The Johns Hopkins Medical Institutions, Baltimore, Maryland. · Departments of Radiology. · †Drs Lennon and Karchin contributed equally as senior authors amlennon@jhmi.edu karchin@jhu.edu. ·J Am Med Inform Assoc · Pubmed #27330075.

ABSTRACT: OBJECTIVE: Our objective was to develop an approach for selecting combinatorial markers of pathology from diverse clinical data types. We demonstrate this approach on the problem of pancreatic cyst classification. MATERIALS AND METHODS: We analyzed 1026 patients with surgically resected pancreatic cysts, comprising 584 intraductal papillary mucinous neoplasms, 332 serous cystadenomas, 78 mucinous cystic neoplasms, and 42 solid-pseudopapillary neoplasms. To derive optimal markers for cyst classification from the preoperative clinical and radiological data, we developed a statistical approach for combining any number of categorical, dichotomous, or continuous-valued clinical parameters into individual predictors of pathology. The approach is unbiased and statistically rigorous. Millions of feature combinations were tested using 10-fold cross-validation, and the most informative features were validated in an independent cohort of 130 patients with surgically resected pancreatic cysts. RESULTS: We identified combinatorial clinical markers that classified serous cystadenomas with 95% sensitivity and 83% specificity; solid-pseudopapillary neoplasms with 89% sensitivity and 86% specificity; mucinous cystic neoplasms with 91% sensitivity and 83% specificity; and intraductal papillary mucinous neoplasms with 94% sensitivity and 90% specificity. No individual features were as accurate as the combination markers. We further validated these combinatorial markers on an independent cohort of 130 pancreatic cysts, and achieved high and well-balanced accuracies. Overall sensitivity and specificity for identifying patients requiring surgical resection was 84% and 81%, respectively. CONCLUSIONS: Our approach identified combinatorial markers for pancreatic cyst classification that had improved performance relative to the individual features they comprise. In principle, this approach can be applied to any clinical dataset comprising dichotomous, categorical, and continuous-valued parameters.

10 Article Obstructive Sleep Apnea and Pathological Characteristics of Resected Pancreatic Ductal Adenocarcinoma. 2016

Dal Molin, Marco / Brant, Aaron / Blackford, Amanda L / Griffin, James F / Shindo, Koji / Barkley, Thomas / Rezaee, Neda / Hruban, Ralph H / Wolfgang, Christopher L / Goggins, Michael. ·Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America. · Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America. · Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America. · Department of Medicine, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America. ·PLoS One · Pubmed #27732623.

ABSTRACT: BACKGROUND: Prospective studies have identified obstructive sleep apnea (OSA) as a risk factor for increased overall cancer incidence and mortality. The potential role of OSA in the risk or progression of specific cancers is not well known. We hypothesized that pathological differences in pancreatic cancers from OSA cases compared to non-OSA cases would implicate OSA in pancreatic cancer progression. METHODS: We reviewed the medical records of 1031 patients who underwent surgical resection without neoadjuvant therapy for pancreatic ductal adenocarcinoma (PDAC) at Johns Hopkins Hospital between 2003 and 2014 and compared the TNM classification of their cancer and their overall survival by patient OSA status. RESULTS: OSA cases were significantly more likely than non-OSA cases to have lymph node-negative tumors (37.7% vs. 21.8%, p = 0.004). Differences in the prevalence of nodal involvement of OSA vs. non-OSA cases were not associated with differences in other pathological characteristics such as tumor size, tumor location, resection margin status, vascular or perineural invasion, or other comorbidities more common to OSA cases (BMI, smoking, diabetes). A logistic regression model found that a diagnosis of OSA was an independent predictor of lymph node status (hazard ratio, 0.051, p = 0.038). Patients with OSA had similar overall survival compared to those without OSA (HR, 0.89, (0.65-1.24), p = 0.41). CONCLUSION: The observed pathological differences between OSA-associated and non-OSA-associated pancreatic cancers supports the hypothesis that OSA can influence the pathologic features of pancreatic ductal adenocarcinoma.

11 Article Circulating Tumor Cell Phenotype Predicts Recurrence and Survival in Pancreatic Adenocarcinoma. 2016

Poruk, Katherine E / Valero, Vicente / Saunders, Tyler / Blackford, Amanda L / Griffin, James F / Poling, Justin / Hruban, Ralph H / Anders, Robert A / Herman, Joseph / Zheng, Lei / Rasheed, Zeshaan A / Laheru, Daniel A / Ahuja, Nita / Weiss, Matthew J / Cameron, John L / Goggins, Michael / Iacobuzio-Donahue, Christine A / Wood, Laura D / Wolfgang, Christopher L. ·*Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD†Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD‡Department of Medical Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD§Department of Radiation Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD¶Department of Gastroenterology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD||Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY. ·Ann Surg · Pubmed #26756760.

ABSTRACT: OBJECTIVE: We assessed circulating tumor cells (CTCs) with epithelial and mesenchymal phenotypes as a potential prognostic biomarker for patients with pancreatic adenocarcinoma (PDAC). BACKGROUND: PDAC is the fourth leading cause of cancer death in the United States. There is an urgent need to develop biomarkers that predict patient prognosis and allow for better treatment stratification. METHODS: Peripheral and portal blood samples were obtained from 50 patients with PDAC before surgical resection and filtered using the Isolation by Size of Epithelial Tumor cells method. CTCs were identified by immunofluorescence using commercially available antibodies to cytokeratin, vimentin, and CD45. RESULTS: Thirty-nine patients (78%) had epithelial CTCs that expressed cytokeratin but not CD45. Twenty-six (67%) of the 39 patients had CTCs which also expressed vimentin, a mesenchymal marker. No patients had cytokeratin-negative and vimentin-positive CTCs. The presence of cytokeratin-positive CTCs (P < 0.01), but not mesenchymal-like CTCs (P = 0.39), was associated with poorer survival. The presence of cytokeratin-positive CTCs remained a significant independent predictor of survival by multivariable analysis after accounting for other prognostic factors (P < 0.01). The detection of CTCs expressing both vimentin and cytokeratin was predictive of recurrence (P = 0.01). Among patients with cancer recurrence, those with vimentin-positive and cytokeratin-expressing CTCs had decreased median time to recurrence compared with patients without CTCs (P = 0.02). CONCLUSIONS: CTCs are an exciting potential strategy for understanding the biology of metastases, and provide prognostic utility for PDAC patients. CTCs exist as heterogeneous populations, and assessment should include phenotypic identification tailored to characterize cells based on epithelial and mesenchymal markers.

12 Article Glucagon-Like Peptide-1 Receptor Expression in Normal and Neoplastic Human Pancreatic Tissues. 2016

Dal Molin, Marco / Kim, Haeryoung / Blackford, Amanda / Sharma, Rajni / Goggins, Michael. ·From the *Department of Pathology, the Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD; †Department of Pathology, Seoul National University College of Medicine, Seoul, South Korea; and the Departments of ‡Oncology and §Medicine, the Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD. ·Pancreas · Pubmed #26495786.

ABSTRACT: OBJECTIVES: Studies have proposed pro-oncogenic effects of glucagon-like peptide-1 receptor (GLP-1R) agonists in the pancreas by promoting GLP-1R overactivation in pancreatic cells. However, the expression of GLP-1R in normal and neoplastic pancreatic cells remains poorly defined, and reliable methods for detecting GLP-1R in tissue specimens are needed. METHODS: We used RNA in situ hybridization to quantify glp-1r RNA in surgically resected human pancreatic specimens, including pancreatic ductal adenocarcinoma (PDAC), preinvasive intraepithelial lesions (pancreatic intraepithelial neoplasia), and non-neoplastic ductal, acinar, and endocrine cells. A mixed-effect linear regression model was used to investigate the relationship between glp-1r signals and all cells, ordered by increasing grade of dysplasia. RESULTS: All cell types had evidence of glp-1r transcripts, with the highest expression in endocrine cells and lowest in ductal cells. The slope of the fitted line was not significantly different from zero (0.07; 95% confidence interval, -0.0094 to 0.244; P = 0.39), suggesting that progression from normal cells to PDAC is not associated with a parallel increase in glp-1r RNA. A series of pairwise comparisons between all cell types with respect to their glp-1r expression showed no significant difference in glp-1r in cancer, pancreatic intraepithelial neoplasia, and acinar and ductal cells. CONCLUSIONS: Our study supports the lack of evidence for GLP-1R overexpression in PDAC.

13 Article Longer Course of Induction Chemotherapy Followed by Chemoradiation Favors Better Survival Outcomes for Patients With Locally Advanced Pancreatic Cancer. 2016

Faisal, Farzana / Tsai, Hua-Ling / Blackford, Amanda / Olino, Kelly / Xia, Chang / De Jesus-Acosta, Ana / Le, Dung T / Cosgrove, David / Azad, Nilofer / Rasheed, Zeshaan / Diaz, Luis A / Donehower, Ross / Laheru, Daniel / Hruban, Ralph H / Fishman, Elliot K / Edil, Barish H / Schulick, Richard / Wolfgang, Christopher / Herman, Joseph / Zheng, Lei. ·*Departments of Oncology, Surgery, and Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, MD †Department of Surgery, University of Colorado School of Medicine, Denver, CO. ·Am J Clin Oncol · Pubmed #24351782.

ABSTRACT: OBJECTIVES: At diagnosis, 30% of patients with pancreatic cancer are unresectable stage 3 locally advanced. The standard treatment for locally advanced pancreatic cancer (LAPC) is not defined. The current study was conducted to assess the roles of chemotherapy and chemoradiation for LAPC treatment. MATERIALS AND METHODS: Between June 2006 and March 2011, 100 patients with LAPC were treated at the Johns Hopkins Hospital. Retrospective analysis was performed to compare cumulative incidence of progression (CIP) and overall survival (OS) among different subgroups. RESULTS: For the 100 patients, the median OS was 15.8 months and the median CIP was 8.4 months. The combination of chemotherapy and chemoradiation before disease progression was significantly associated with improved CIP (P=0.001) and improved OS when compared with chemoradiation alone (median OS: 16.4 vs. 11.1 mo, P=0.03). Among patients receiving combination treatment, patients who received chemotherapy first followed by chemoradiation had a trend toward lower CIP (P=0.09) and improved OS (median OS: 18.1 vs. 11.0 mo, P=0.09). Patients who received >2 cycles of chemotherapy before chemoradiation had a significantly decreased CIP (P=0.008) and a trend toward better OS (median OS: 19.4 vs. 15.7 mo, P=0.10). On multivariate analysis, receiving >2 cycles of chemotherapy before chemoradiation was associated with improved CIP. CONCLUSIONS: Although combination chemotherapy and chemoradiation is favored in the treatment of LAPC, longer induction chemotherapy may play a more important role in sensitization of tumors to subsequent chemoradiation. Our results support treating patients with induction chemotherapy for at least 3 cycles followed by consolidative chemoradiation. These results merit further validation by a prospective study.

14 Article Common variation at 2p13.3, 3q29, 7p13 and 17q25.1 associated with susceptibility to pancreatic cancer. 2015

Childs, Erica J / Mocci, Evelina / Campa, Daniele / Bracci, Paige M / Gallinger, Steven / Goggins, Michael / Li, Donghui / Neale, Rachel E / Olson, Sara H / Scelo, Ghislaine / Amundadottir, Laufey T / Bamlet, William R / Bijlsma, Maarten F / Blackford, Amanda / Borges, Michael / Brennan, Paul / Brenner, Hermann / Bueno-de-Mesquita, H Bas / Canzian, Federico / Capurso, Gabriele / Cavestro, Giulia M / Chaffee, Kari G / Chanock, Stephen J / Cleary, Sean P / Cotterchio, Michelle / Foretova, Lenka / Fuchs, Charles / Funel, Niccola / Gazouli, Maria / Hassan, Manal / Herman, Joseph M / Holcatova, Ivana / Holly, Elizabeth A / Hoover, Robert N / Hung, Rayjean J / Janout, Vladimir / Key, Timothy J / Kupcinskas, Juozas / Kurtz, Robert C / Landi, Stefano / Lu, Lingeng / Malecka-Panas, Ewa / Mambrini, Andrea / Mohelnikova-Duchonova, Beatrice / Neoptolemos, John P / Oberg, Ann L / Orlow, Irene / Pasquali, Claudio / Pezzilli, Raffaele / Rizzato, Cosmeri / Saldia, Amethyst / Scarpa, Aldo / Stolzenberg-Solomon, Rachael Z / Strobel, Oliver / Tavano, Francesca / Vashist, Yogesh K / Vodicka, Pavel / Wolpin, Brian M / Yu, Herbert / Petersen, Gloria M / Risch, Harvey A / Klein, Alison P. ·Department of Epidemiology, Johns Hopkins School of Public Health, Baltimore, Maryland, USA. · Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland, USA. · 1] Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. [2] Department of Biology, University of Pisa, Pisa, Italy. · Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, USA. · Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins School of Medicine, Baltimore, Maryland, USA. · Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA. · Department of Population Health, QIMR Berghofer Medical Research Institute, Kelvin Grove,Queensland, Australia. · Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA. · International Agency for Research on Cancer (IARC), Lyon, France. · Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, US Department of Health and Human Services, Bethesda, Maryland, USA. · Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, Minnesota, USA. · Laboratory for Experimental Oncology and Radiobiology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. · Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany. · 1] Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands. [2] Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, the Netherlands. [3] Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK. [4] Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia. · Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany. · Digestive and Liver Disease Unit, 'Sapienza' University of Rome, Rome, Italy. · Università Vita Salute San Raffaele and Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ospedale San Raffaele, Milan, Italy. · 1] Department of Surgery, University Health Network, University of Toronto, Toronto, Ontario, Canada. [2] Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada. · 1] Cancer Care Ontario, University of Toronto, Toronto, Ontario, Canada. [2] Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada. · Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute and Medical Faculty Masaryk University, Brno, Czech Republic. · 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [2] Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. · Department of Surgery, Unit of Experimental Surgical Pathology, University Hospital of Pisa, Pisa, Italy. · Department of Medical Sciences, Laboratory of Biology, School of Medicine, University of Athens, Athens, Greece. · Department of Radiation Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Institute of Hygiene and Epidemiology, 1st Faculty of Medicine, Charles University in Prague, Prague, Czech Republic. · Department of Preventive Medicine, Faculty of Medicine, Palacky University, Olomouc, Czech Republic. · Cancer Epidemiology Unit, University of Oxford, Oxford, UK. · Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania. · Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA. · Department of Biology, Section of Genetics, University of Pisa, Pisa, Italy. · Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut, USA. · Department of Digestive Tract Diseases, Medical University of Lodz, Lodz, Poland. · Department of Oncology, Azienda USL 1 Massa Carrara, Massa Carrara, Italy. · Laboratory of Toxicogenomics, Institute of Public Health, Prague, Czech Republic. · National Institute for Health Research (NIHR) Pancreas Biomedical Research Unit, Liverpool Clinical Trials Unit and Cancer Research UK Clinical Trials Unit, Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, UK. · Department of Surgery, Gastroenterology and Oncology, University of Padua, Padua, Italy. · Pancreas Unit, Department of Digestive Diseases, Sant'Orsola-Malpighi Hospital, Bologna, Italy. · ARC-NET-Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy. · Nutritional Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, Rockville, Maryland, USA. · Department of General Surgery, University Hospital Heidelberg, Heidelberg, Germany. · Division of Gastroenterology and Research Laboratory, IRCCS Scientific Institute and Regional General Hospital 'Casa Sollievo della Sofferenza', San Giovanni Rotondo, Italy. · Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. · Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Academy of Sciences, Prague, Czech Republic. · 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [2] Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. · Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA. · 1] Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland, USA. [2] Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins School of Medicine, Baltimore, Maryland, USA. ·Nat Genet · Pubmed #26098869.

ABSTRACT: Pancreatic cancer is the fourth leading cause of cancer death in the developed world. Both inherited high-penetrance mutations in BRCA2 (ref. 2), ATM, PALB2 (ref. 4), BRCA1 (ref. 5), STK11 (ref. 6), CDKN2A and mismatch-repair genes and low-penetrance loci are associated with increased risk. To identify new risk loci, we performed a genome-wide association study on 9,925 pancreatic cancer cases and 11,569 controls, including 4,164 newly genotyped cases and 3,792 controls in 9 studies from North America, Central Europe and Australia. We identified three newly associated regions: 17q25.1 (LINC00673, rs11655237, odds ratio (OR) = 1.26, 95% confidence interval (CI) = 1.19-1.34, P = 1.42 × 10(-14)), 7p13 (SUGCT, rs17688601, OR = 0.88, 95% CI = 0.84-0.92, P = 1.41 × 10(-8)) and 3q29 (TP63, rs9854771, OR = 0.89, 95% CI = 0.85-0.93, P = 2.35 × 10(-8)). We detected significant association at 2p13.3 (ETAA1, rs1486134, OR = 1.14, 95% CI = 1.09-1.19, P = 3.36 × 10(-9)), a region with previous suggestive evidence in Han Chinese. We replicated previously reported associations at 9q34.2 (ABO), 13q22.1 (KLF5), 5p15.33 (TERT and CLPTM1), 13q12.2 (PDX1), 1q32.1 (NR5A2), 7q32.3 (LINC-PINT), 16q23.1 (BCAR1) and 22q12.1 (ZNRF3). Our study identifies new loci associated with pancreatic cancer risk.

15 Article Time to progression of pancreatic ductal adenocarcinoma from low-to-high tumour stages. 2015

Yu, Jun / Blackford, Amanda L / Dal Molin, Marco / Wolfgang, Christopher L / Goggins, Michael. ·Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Department of Medicine, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. ·Gut · Pubmed #25636698.

ABSTRACT: OBJECTIVE: Although pancreatic ductal adenocarcinoma is considered a rapidly progressive disease, mathematical models estimate that it takes many years for an initiating pancreatic cancer cell to grow into an advanced stage cancer. In order to estimate the time it takes for a pancreatic cancer to progress through different tumor, node, metastasis (TNM) stages, we compared the mean age of patients with pancreatic cancers of different sizes and stages. DESIGN: Patient age, tumour size, stage and demographic information were analysed for 13,131 patients with pancreatic ductal adenocarcinoma entered into the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) database. Multiple linear regression models for age were generated, adjusting for patient ethnicity, gender, tumour location and neoplastic grades. RESULTS: African-American ethnicity and male gender were associated with an earlier age at diagnosis. Patients with stage I cancers (mean age 64.8 years) were on average 1.3 adjusted years younger at diagnosis than those with stage IV cancers (p=0.001). Among patients without distant metastases, those with T1 stage cancers were on average 1.06 and 1.19 adjusted years younger, respectively, than patients with T3 or T4 cancers (p=0.03 for both). Among patients with stage IIB cancers, those with T1/T2 cancers were 0.79 adjusted years younger than those with T3 cancers (p=0.06). There was no significant difference in the mean adjusted age of patients with stage IA versus stage IB cancers. CONCLUSIONS: These results are consistent with the hypothesis that once pancreatic ductal adenocarcinomas become detectable clinically progression from low-stage to advanced-stage disease is rapid.

16 Article Very Long-term Survival Following Resection for Pancreatic Cancer Is Not Explained by Commonly Mutated Genes: Results of Whole-Exome Sequencing Analysis. 2015

Dal Molin, Marco / Zhang, Ming / de Wilde, Roeland F / Ottenhof, Niki A / Rezaee, Neda / Wolfgang, Christopher L / Blackford, Amanda / Vogelstein, Bert / Kinzler, Kenneth W / Papadopoulos, Nickolas / Hruban, Ralph H / Maitra, Anirban / Wood, Laura D. ·Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Departments of Pathology and Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland. ldwood@jhmi.edu. ·Clin Cancer Res · Pubmed #25623214.

ABSTRACT: PURPOSE: The median survival following surgical resection of pancreatic ductal adenocarcinoma (PDAC) is currently <20 months. However, survival ≥10 years is achieved by a small subset of patients who are defined as very long-term survivors (VLTS). The goal of this study was to determine whether specific genetic alterations in resected PDACs determined very long-term survival. EXPERIMENTAL DESIGN: We sequenced the exomes of eight PDACs from patients who survived ≥10 years. On the basis of the results of the exomic analysis, targeted sequencing of selected genes was performed in a series of 27 additional PDACs from VLTSs. RESULTS: KRAS mutations were identified in 33 of 35 cancers (94%) from VLTSs and represented the most prevalent alteration in our cohort. TP53, SMAD4, and CDKN2A mutations occurred in 69%, 26%, and 17%, respectively. Mutations in RNF43, which have been previously associated with intraductal papillary mucinous neoplasms, were identified in four of the 35 cancers (11%). Taken together, our data show no difference in somatic mutations in carcinomas from VLTSs compared with available data from PDACs unselected for survival. Comparison of clinicopathologic features between VLTSs and a matching control group demonstrated that younger age, earlier stage, well/moderate grade of differentiation, and negative resection margins were associated with VLTS. However, more advanced stage, poor grade, or nodal disease did not preclude long-term survival. CONCLUSIONS: Our results suggest that in most patients, somatic mutations in commonly mutated genes are unlikely to be the primary determinant of very long-term survival following surgical resection of PDAC.

17 Article Intrapancreatic accessory spleen: possibilities of computed tomography in differentiation from nonfunctioning pancreatic neuroendocrine tumor. 2014

Coquia, Stephanie F / Kawamoto, Satomi / Zaheer, Atif / Bleich, Karen B / Blackford, Amanda L / Hruban, Ralph H / Fishman, Elliot K. ·From the *Department of Radiology, †Division of Biostatistics and Bioinformatics, Sidney Kimmel Cancer Center, and ‡Department of Pathology, the Sol Goldman Pancreatic Center Research Center, Johns Hopkins Hospital, Baltimore, MD. ·J Comput Assist Tomogr · Pubmed #24979264.

ABSTRACT: OBJECTIVE: The aim of this study was to evaluate the ability of computed tomography (CT) in differentiating between intrapancreatic accessory spleen (IPAS) from pancreatic neuroendocrine tumor (PanNET). METHODS: Eight IPASs and 12 PanNETs in the pancreatic tail were retrospectively evaluated by 2 radiologists. Readers assigned a diagnosis to each examination and evaluated for the presence or absence of 9 CT findings that may aid in the diagnosis. RESULTS: Reader 1 had a sensitivity of 0.83 and a specificity of 1; reader 2 had a sensitivity of 0.78 and a specificity of 0.86. Three of the 9 CT findings were found to be statistically significant in IPASs: the lesion present along the pancreatic dorsal surface, the lesion demonstrating the same enhancement as the spleen on venous phase, and heterogeneous enhancement during arterial phase. CONCLUSIONS: CT can be used to differentiate between IPAS and PanNET with good specificity and sensitivity. The IPAS mirrors the spleen's enhancement and is usually located along the dorsal surface of the pancreas.

18 Article Endoscopic ultrasound-guided fine needle aspiration improves the pre-operative diagnostic yield of solid-pseudopapillary neoplasm of the pancreas: an international multicenter case series (with video). 2014

Law, Joanna K / Stoita, Alina / Wever, Wallia / Gleeson, Ferga C / Dries, Andrew M / Blackford, Amanda / Kiswani, Vandhana / Shin, Eun Ji / Khashab, Mouen A / Canto, Marcia Irene / Singh, Vikesh K / Lennon, Anne Marie. ·Division of Gastroenterology and Hepatology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, 1800 Orleans St, Suite 7125 J, Baltimore, MD, 21205, USA, jlaw8@jhmi.edu. ·Surg Endosc · Pubmed #24718662.

ABSTRACT: BACKGROUND/OBJECTIVES: Solid-pseudopapillary neoplasms (SPNs) are rare pancreatic tumors, which occur most frequently in young women and are associated with an excellent prognosis. Computed tomography (CT) is used most commonly to identify these lesions, but there are few studies evaluating the role of endoscopic ultrasound (EUS) and fine needle aspiration (EUS-FNA) in the assessment of SPN. The aim of the study was to determine the incremental diagnostic yield of EUS-FNA compared with CT or EUS in the evaluation of patients with SPN. METHODS: A retrospective chart review of consecutive patients diagnosed with SPN who underwent CT, EUS, and EUS-FNA at five centers from three countries from 1998 to 2013. Patient demographics, imaging, endoscopic studies, cytopathology, and histology were reviewed. RESULTS: Thirty-four patients were identified with SPN. There were 31 (91.2 %) females, with a mean age at diagnosis of 37 years (range 16-81). The most common presenting symptom was abdominal pain which was present in 59 %. SPNs were incidentally detected in 14 (41.2 %) of the patients. The median tumor size was 4.2 cm (range 1.9-9.4). No patient had evidence of local or distant metastases. The most common appearance on EUS was of a mixed solid-cystic lesion (67.6 %). The diagnostic yield of CT and EUS alone was 23.5 and 41.2 %, respectively. CT and EUS combined had a diagnostic yield of 52.9 %. The addition of EUS-FNA significantly increased the diagnostic yield to 82.4 % compared with either CT or CT and EUS (p < 0.005). There were no reported adverse events reported. CONCLUSIONS: SPNs are rare pancreatic tumors primarily affecting young women. The addition of EUS-FNA significantly increased the pre-operative diagnostic yield of SPN to 82.4 %.

19 Article Correlation of Smad4 status with outcomes in patients receiving erlotinib combined with adjuvant chemoradiation and chemotherapy after resection for pancreatic adenocarcinoma. 2013

Herman, Joseph M / Fan, Katherine Y / Wild, Aaron T / Wood, Laura D / Blackford, Amanda L / Donehower, Ross C / Hidalgo, Manuel / Schulick, Richard D / Edil, Barish H / Choti, Michael A / Hruban, Ralph H / Pawlik, Timothy M / Cameron, John L / Laheru, Daniel A / Iacobuzio-Donahue, Christine A / Wolfgang, Christopher L. ·Department of Radiation Oncology & Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address: jherma15@jhmi.edu. ·Int J Radiat Oncol Biol Phys · Pubmed #24074918.

ABSTRACT: -- No abstract --

20 Article Institutional experience with solid pseudopapillary neoplasms: focus on computed tomography, magnetic resonance imaging, conventional ultrasound, endoscopic ultrasound, and predictors of aggressive histology. 2013

Raman, Siva P / Kawamoto, Satomi / Law, Joanna K / Blackford, Amanda / Lennon, Anne Marie / Wolfgang, Christopher L / Hruban, Ralph H / Cameron, John L / Fishman, Elliot K. ·From the *Department of Radiology, Johns Hopkins University; †Division of Gastroenterology, Johns Hopkins Hospital; ‡Division of Oncology Biostatistics, Johns Hopkins University School of Medicine; §Department of Surgery, Johns Hopkins University School of Medicine; and ∥The Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD. ·J Comput Assist Tomogr · Pubmed #24045264.

ABSTRACT: OBJECTIVE: Solid pseudopapillary neoplasms (SPNs) are low-grade malignancies with an excellent prognosis, albeit with the potential for metastatic disease. This study details our institution's experience with the diagnosis and treatment of SPN, including clinical presentation, multimodality imaging findings, and potential predictors of aggressive tumor behavior. MATERIALS AND METHODS: The institutional pathology database was searched through for all cases of SPN since 1988, yielding 51 patients. The electronic medical record was searched for clinical and demographic information regarding these patients, including age, sex, presenting symptoms, type of surgery, postoperative length of stay, tumor markers, and postsurgical follow-up. All available imaging data were reviewed, including those of 30 patients who underwent multidetector computed tomography, those of 9 patients who underwent magnetic resonance imaging (MRI), those of 3 patients who underwent conventional ultrasound, and those of 11 patients who underwent endoscopic ultrasound. RESULTS: A total of 84% of patients were females, with a mean age of only 33 years. Prognosis was excellent, with a mean follow-up of 3 years without recurrence. Only 1 of the 51 patients developed metastatic disease to the liver 8 years after the surgery. On computed tomography, lesions tended to be large (5.3 cm), well circumscribed (29/30), round/oval (20/30), and encapsulated (23/30). The lesions often demonstrated calcification (14/30) and typically resulted in no biliary or pancreatic ductal dilatation. The lesions ranged from completely cystic to completely solid. On MRI, the lesions often demonstrated a T2 hypointense or enhancing capsule (6/9) and demonstrated internal blood products (5/9). The lesions tended to be devoid of vascularity on conventional ultrasound. Ten patients were found to have "aggressive" histology at presentation (T3 tumor, nodal involvement, perineural invasion, or vascular invasion). No demographic, clinical, or multidetector computed tomographic imaging features were found to correlate with aggressive histology. CONCLUSIONS: Certain imaging features (eg, well-circumscribed mass with calcification, peripheral capsule, internal blood products, and lack of biliary/pancreatic ductal obstruction) on computed tomography and MRI are highly suggestive of the diagnosis of SPN, particularly when visualized in young female patients. However, it is not possible to predict aggressive histology on the basis of imaging findings, clinical presentation, or patient demographic features.

21 Article Clinicopathological correlates of activating GNAS mutations in intraductal papillary mucinous neoplasm (IPMN) of the pancreas. 2013

Molin, Marco Dal / Matthaei, Hanno / Wu, Jian / Blackford, Amanda / Debeljak, Marija / Rezaee, Neda / Wolfgang, Christopher L / Butturini, Giovanni / Salvia, Roberto / Bassi, Claudio / Goggins, Michael G / Kinzler, Kenneth W / Vogelstein, Bert / Eshleman, James R / Hruban, Ralph H / Maitra, Anirban. ·Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD. · Unit of General Surgery B, Pancreas Institute, Department of Surgery, "G.B. Rossi" Hospital, University of Verona Hospital Trust, Verona, Italy. · Department of General, Visceral, Thoracic and Vascular Surgery, University of Bonn, Bonn, Germany. · Ludwig Center for Cancer Genetics, Johns Hopkins University School of Medicine, Baltimore, MD. · Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD. · Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD. · Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD. ·Ann Surg Oncol · Pubmed #23846778.

ABSTRACT: BACKGROUND: Intraductal papillary mucinous neoplasms (IPMNs) are the most common cystic precursor lesions of invasive pancreatic cancer. The recent identification of activating GNAS mutations at codon 201 in IPMNs is a promising target for early detection and therapy. The purpose of this study was to explore clinicopathological correlates of GNAS mutational status in resected IPMNs. METHODS: Clinical and pathologic characteristics were retrieved on 54 patients in whom GNAS codon 201 mutational status was previously reported ("historical group", Wu et al. Sci Transl Med 3:92ra66, 2011). In addition, a separate cohort of 32 patients (validation group) was included. After microdissection and DNA extraction, GNAS status was determined in the validation group by pyrosequencing. RESULTS: GNAS activating mutations were found in 64% of the 32 IPMNs included in the validation group, compared with a previously reported prevalence of 57% in the historical group. Overall, 52 of 86 (61%) of IPMNs demonstrated GNAS mutations in the two studies combined. Analysis of both groups confirmed that demographic characteristics, tumor location, ductal system involvement, focality, size, grade of dysplasia, presence of an associated cancer, and overall survival were not correlated with GNAS mutational status. Stratified by histological subtype, 100% of intestinal type IPMNs demonstrated GNAS mutations compared to 51% of gastric IPMN, 71% of pancreatobiliary IPMNs, and 0% of oncocytic IPMNs. CONCLUSIONS: GNAS activating mutations can be reliably detected in IPMNs by pyrosequencing. In terms of clinicopathological parameters, only histological subtype was correlated with mutational frequency, with the intestinal phenotype always associated with GNAS mutations.

22 Article Histopathologic findings of multifocal pancreatic intraductal papillary mucinous neoplasms on CT. 2013

Raman, Siva P / Kawamoto, Satomi / Blackford, Amanda / Hruban, Ralph H / Lennon, Ann Marie / Wolfgang, Christopher L / Rezaee, Neda / Edil, Barish / Fishman, Elliot K. ·Department of Radiology, Johns Hopkins University, 601 N Caroline St, JHOC 3251, Baltimore, MD 21287, USA. srsraman3@gmail.com ·AJR Am J Roentgenol · Pubmed #23436845.

ABSTRACT: OBJECTIVE: The criteria for resection of solitary pancreatic side-branch intraductal papillary mucinous neoplasm (IPMN) have been well described by the Sendai consensus statement. However, the management of multiple pancreatic cystic lesions is less certain, with no clear guidelines in the literature to date. The purpose of this study was to evaluate the histopathologic findings in pancreatic IPMNs in patients with multiple (≥ 4) pancreatic cysts. MATERIALS AND METHODS: The CT scans of all patients with a pathologically proven IPMN at our institution were reviewed, and a total of 52 patients with four or more pancreatic cysts were found. Each case was reviewed for the number of cysts and the presence of signs of invasive malignancy including a coexistent solid pancreatic mass, pancreatic ductal dilatation, and mural nodularity. RESULTS: A total of 52 patients (19 men, 33 women; mean age, 71.8 years) were found to have multifocal IPMNs, defined as four or more cysts, on CT. Of these 52 patients, nine also had evidence of a solid pancreatic mass on CT. Retrospective review of the pathologic results for the remaining 43 patients (17 men, 26 women; mean age, 71.76 years) showed 18 cases of an IPMN with either high-grade dysplasia or a coexistent invasive carcinoma. Most important, 37% (7/19 patients) had no CT findings of an invasive malignancy according to the Sendai criteria (i.e., cysts ≥ 3 cm in the axial plane, main pancreatic ductal dilatation ≥ 6 mm, or mural nodularity within a cyst) but were found to have an IPMN with either high-grade dysplasia or invasive carcinoma. When the pancreas contained 10 or more cysts, high-grade dysplasia or invasive carcinoma tended to be more likely than low- or intermediate-grade dysplasia (odds ratio, 3.83; 95% CI, 0.87-16.8; p = 0.075). CONCLUSION: The presence of multiple pancreatic cysts should be looked on with suspicion, particularly when there are a large number of cysts, even when none of the cysts individually meet the imaging criteria for resection according to the Sendai consensus recommendations. At the very least, these patients need to be followed very closely.

23 Article Genetically defined subsets of human pancreatic cancer show unique in vitro chemosensitivity. 2012

Cui, Yunfeng / Brosnan, Jacqueline A / Blackford, Amanda L / Sur, Surojit / Hruban, Ralph H / Kinzler, Kenneth W / Vogelstein, Bert / Maitra, Anirban / Diaz, Luis A / Iacobuzio-Donahue, Christine A / Eshleman, James R. ·Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland 21231, USA. ·Clin Cancer Res · Pubmed #22753594.

ABSTRACT: PURPOSE: Pancreatic cancer is the fourth cause of death from cancer in the western world. Majority of patients present with advanced unresectable disease responding poorly to most chemotherapeutic agents. Chemotherapy for pancreatic cancer might be improved by adjusting it to individual genetic profiles. We attempt to identify genetic predictors of chemosensitivity to broad classes of anticancer drugs. EXPERIMENTAL DESIGN: Using a panel of genetically defined human pancreatic cancer cell lines, we tested gemcitabine (antimetabolite), docetaxel (antimicrotubule), mitomycin C (MMC; alkylating), irinotecan (topoisomerase I inhibitor), cisplatin (crosslinking), KU0058948 (Parp1 inhibitor), triptolide (terpenoid drug), and artemisinin (control). RESULTS: All pancreatic cancer cell lines were sensitive to triptolide and docetaxel. Most pancreatic cancer cells were also sensitive to gemcitabine and MMC. The vast majority of pancreatic cancer cell lines were insensitive to cisplatin, irinotecan, and a Parp1 inhibitor. However, individual cell lines were often sensitive to these compounds in unique ways. We found that DPC4/SMAD4 inactivation sensitized pancreatic cancer cells to cisplatin and irinotecan by 2- to 4-fold, but they were modestly less sensitive to gemcitabine. Pancreatic cancer cells were all sensitive to triptolide and 18% were sensitive to the Parp1 inhibitor. P16/CDKN2A-inactivated pancreatic cancer cells were 3- to 4-fold less sensitive to gemcitabine and MMC. CONCLUSIONS: Chemosensitivity of pancreatic cancer cells correlated with some specific genetic profiles. These results support the hypothesis that genetic subsets of pancreatic cancer exist, and these genetic backgrounds may permit one to personalize the chemotherapy of pancreatic cancer in the future. Further work will need to confirm these responses and determine their magnitude in vivo.

24 Article A multicenter analysis of GTX chemotherapy in patients with locally advanced and metastatic pancreatic adenocarcinoma. 2012

De Jesus-Acosta, Ana / Oliver, George R / Blackford, Amanda / Kinsman, Katharine / Flores, Edna I / Wilfong, Lalan S / Zheng, Lei / Donehower, Ross C / Cosgrove, David / Laheru, Daniel / Le, Dung T / Chung, Ki / Diaz, Luis A. ·Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 1650 Orleans Street, CRB I, Room 590, Baltimore, MD 21231, USA. ·Cancer Chemother Pharmacol · Pubmed #21800112.

ABSTRACT: PURPOSE: Studies treating adenocarcinoma of the pancreas with gemcitabine alone or in combination with a doublet have demonstrated modest improvements in survival. Recent reports have suggested that using the triple-drug regimen FOLFIRINOX can substantially extend survival in patients with metastatic disease. We were interested in determining the clinical benefit of another three-drug regimen of gemcitabine, docetaxel and capecitabine (GTX) in patients with advanced pancreatic adenocarcinoma. PATIENTS AND METHODS: The cases of 154 patients, who received treatment with GTX chemotherapy with histologically confirmed locally advanced or metastatic pancreatic adenocarcinoma, were retrospectively reviewed. All demographic and clinical data were captured including prior therapy, adverse events, treatment response and survival. RESULTS: One hundred and seventeen metastatic and 37 locally advanced cases of adenocarcinoma of the pancreas were reviewed. Partial responses were noted in 11% of cases, and stable disease was observed in 62% of patients. Responses significantly correlated with toxicity (neutropenia, ALT elevation and hospitalizations). Grade 3 or greater hematologic and non-hematologic toxicities were noted in 41% and 9% of cases, respectively. Overall median survival was 11.6 months. Chemotherapy naïve patients with metastatic and locally advanced disease achieved a median survival of 11.3 and 25.0 months, respectively. CONCLUSIONS: We observe a substantial survival benefit with GTX chemotherapy in our cohort of patients with advanced pancreatic cancer. These findings warrant further investigation of this combination in this patient population.