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Pancreatic Neoplasms: HELP
Articles by Marco Dal Molin
Based on 25 articles published since 2010
(Why 25 articles?)
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Between 2010 and 2020, Marco dal Molin wrote the following 25 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Review A systematic review of solid-pseudopapillary neoplasms: are these rare lesions? 2014

Law, Joanna K / Ahmed, Aadil / Singh, Vikesh K / Akshintala, Venkata S / Olson, Matthew T / Raman, Siva P / Ali, Syed Z / Fishman, Elliot K / Kamel, Ihab / Canto, Marcia I / Dal Molin, Marco / Moran, Robert A / Khashab, Mouen A / Ahuja, Nita / Goggins, Michael / Hruban, Ralph H / Wolfgang, Christopher L / Lennon, Anne Marie. ·From the *Division of Gastroenterology, †Department of Pathology, ‡Department of Radiology, Johns Hopkins University School of Medicine, §Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, and ∥Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD. ·Pancreas · Pubmed #24622060.

ABSTRACT: OBJECTIVE: The aim of the study was to determine if there had been any change in the number of solid-pseudopapillary neoplasm (SPN) cases detected and their evaluation or management over time. METHODS: A systematic review of SPN was performed of all articles published in English in PubMed and Scopus. RESULTS: A total of 2744 patients with SPN were identified in 484 studies published between 1961 and 2012; 87.8% of the cases were reported between 2000 and 2012. A total of 2408 (87.8%) were females, and the mean age was 28.5 (SD, 13.7) years. The most common symptom was abdominal pain in 63.6% of the cases and incidentally detected in 38.1% of the cases. There were 2285 patients who underwent pancreatic resection. The mean tumor size was 8.6 (SD, 4.3) cm. Follow-up was reported for 1952 (90.5%) patients, with a mean follow-up of 36.1 (SD, 32.8) months. Disease-free survival was documented in 1866 (95.6%) patients with recurrence in 86 (4.4%) patients; the median time to recurrence was 50.5 months. CONCLUSIONS: The number of SPNs reported in the literature has seen a 7-fold increase in the number of cases reported since 2000 compared with before. Solid-pseudopapillary neoplasms continue to be primarily found in young women and present with nonspecific symptoms. Surgery remains the mainstay of treatment with an excellent long-term prognosis.

2 Review Identification and analysis of precursors to invasive pancreatic cancer. 2013

Matthaei, Hanno / Dal Molin, Marco / Maitra, Anirban. ·Department of Pathology and Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD, USA. ·Methods Mol Biol · Pubmed #23359146.

ABSTRACT: Precursor lesions of pancreatic cancer have been recognized about a century ago. The development of a consistent reproducible nomenclature and classification system for these lesions has been a major advance in the study of these noninvasive precursors. Pancreatic intraepithelial neoplasia (PanIN) as microscopic precursor lesions can be distinguished from mucinous cystic neoplasms (MCNs) and intraductal papillary mucinous neoplasms (IPMN) that are cystic and can often be recognized on imaging. Since precursor lesions harbor the unique chance to treat a patient before a fatal pancreatic cancer can arise a molecular characterization is essential to understand the biology and to find diagnostic and therapeutic targets to fight this disease of near uniform lethality. In order to study precursor lesions on a molecular level a meticulous isolation of the neoplastic cells is inevitable. We present the salient histopathologic and molecular features of precursor lesions of pancreatic cancer as well as methods that have proved to be useful within experimental studies.

3 Article Intraductal Papillary Mucinous Neoplasms Arise From Multiple Independent Clones, Each With Distinct Mutations. 2019

Fischer, Catherine G / Beleva Guthrie, Violeta / Braxton, Alicia M / Zheng, Lily / Wang, Pei / Song, Qianqian / Griffin, James F / Chianchiano, Peter E / Hosoda, Waki / Niknafs, Noushin / Springer, Simeon / Dal Molin, Marco / Masica, David / Scharpf, Robert B / Thompson, Elizabeth D / He, Jin / Wolfgang, Christopher L / Hruban, Ralph H / Roberts, Nicholas J / Lennon, Anne Marie / Jiao, Yuchen / Karchin, Rachel / Wood, Laura D. ·Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland. · McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland. · State Key Lab of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. · Department of Surgery, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Medicine, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address: karchin@jhu.edu. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address: ldwood@jhmi.edu. ·Gastroenterology · Pubmed #31175866.

ABSTRACT: BACKGROUND & AIMS: Intraductal papillary mucinous neoplasms (IPMNs) are lesions that can progress to invasive pancreatic cancer and constitute an important system for studies of pancreatic tumorigenesis. We performed comprehensive genomic analyses of entire IPMNs to determine the diversity of somatic mutations in genes that promote tumorigenesis. METHODS: We microdissected neoplastic tissues from 6-24 regions each of 20 resected IPMNs, resulting in 227 neoplastic samples that were analyzed by capture-based targeted sequencing. Somatic mutations in genes associated with pancreatic tumorigenesis were assessed across entire IPMN lesions, and the resulting data were supported by evolutionary modeling, whole-exome sequencing, and in situ detection of mutations. RESULTS: We found a high prevalence of heterogeneity among mutations in IPMNs. Heterogeneity in mutations in KRAS and GNAS was significantly more prevalent in IPMNs with low-grade dysplasia than in IPMNs with high-grade dysplasia (P < .02). Whole-exome sequencing confirmed that IPMNs contained multiple independent clones, each with distinct mutations, as originally indicated by targeted sequencing and evolutionary modeling. We also found evidence for convergent evolution of mutations in RNF43 and TP53, which are acquired during later stages of tumorigenesis. CONCLUSIONS: In an analysis of the heterogeneity of mutations throughout IPMNs, we found that early-stage IPMNs contain multiple independent clones, each with distinct mutations, indicating their polyclonal origin. These findings challenge the model in which pancreatic neoplasms arise from a single clone. Increasing our understanding of the mechanisms of IPMN polyclonality could lead to strategies to identify patients at increased risk for pancreatic cancer.

4 Article Simple Detection of Telomere Fusions in Pancreatic Cancer, Intraductal Papillary Mucinous Neoplasm, and Pancreatic Cyst Fluid. 2018

Hata, Tatsuo / Dal Molin, Marco / McGregor-Das, Anne / Song, Tae Jun / Wolfgang, Christopher / Eshleman, James R / Hruban, Ralph H / Goggins, Michael. ·Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Medicine, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address: mgoggins@jhmi.edu. ·J Mol Diagn · Pubmed #29229290.

ABSTRACT: Telomere end-to-end fusions are an important source of chromosomal instability that arise in cells with critically shortened telomeres. We developed a nested real-time quantitative PCR method for telomere fusion detection in pancreatic ductal adenocarcinomas, intraductal papillary mucinous neoplasms (IPMNs), and IPMN cyst fluids. Ninety-one pancreatic cancer cell lines and xenograft samples, 93 IPMNs, and 93 surgically aspirated IPMN cyst fluid samples were analyzed. The association between telomere shortening, telomerase activity, and telomere fusion detection was evaluated. Telomere fusions were detected in 56 of 91 pancreatic cancers (61.5%). Telomere fusion-positive cell lines had significantly shorter telomere lengths than fusion-negative lines (P = 0.003). Telomere fusions were undetectable in normal pancreas or IPMNs with low-grade dysplasia (0.0%) and were detected in IPMN with high-grade dysplasia (HGD; 48.0%) (P < 0.001). In IPMN cyst fluids, telomere fusions were more frequent in IPMNs with HGD (26.9%) or associated invasive cancer (42.9%) than IPMN with intermediate-grade dysplasia (15.4%) or low-grade dysplasia (0%) (P = 0.025). Telomerase activity levels were higher in cyst fluids with fusions than in those without (P = 0.0414). Cyst fluid telomere fusion status was an independent predictor of HGD/invasive cancer by multivariate analysis (odds ratio, 6.23; 95% CI, 1.61-28.0). Telomere fusions are detected in later stages of IPMN progression and can serve as a marker for predicting the presence of HGD and/or invasive cancer.

5 Article Multi-institutional Validation Study of Pancreatic Cyst Fluid Protein Analysis for Prediction of High-risk Intraductal Papillary Mucinous Neoplasms of the Pancreas. 2018

Al Efishat, Mohammad A / Attiyeh, Marc A / Eaton, Anne A / Gönen, Mithat / Prosser, Denise / Lokshin, Anna E / Castillo, Carlos Fernández-Del / Lillemoe, Keith D / Ferrone, Cristina R / Pergolini, Ilaria / Mino-Kenudson, Mari / Rezaee, Neda / Dal Molin, Marco / Weiss, Matthew J / Cameron, John L / Hruban, Ralph H / D'Angelica, Michael I / Kingham, T Peter / DeMatteo, Ronald P / Jarnagin, William R / Wolfgang, Christopher L / Allen, Peter J. ·Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY. · Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY. · Department of Pathology, University of Pittsburgh Cancer Institute, Pittsburgh, PA. · Department of Surgery, Massachusetts General Hospital, Boston, MA. · Department of Pathology, Massachusetts General Hospital, Boston, MA. · Department of Surgery, Johns Hopkins Hospital, Baltimore, MD. · Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD. ·Ann Surg · Pubmed #28700444.

ABSTRACT: OBJECTIVE: Preliminary work by our group suggested that proteins within the pancreatic cyst fluid (CF) may discriminate degree of IPMN dysplasia. We sought to externally validate these markers and determine whether their inclusion in a preoperative clinical nomogram could increase diagnostic accuracy. SUMMARY BACKGROUND DATA: IPMN is the most common radiographically identifiable precursor to pancreatic cancer; however, the timing and frequency of its malignant progression are unknown, and there are currently no reliable preoperative tests that can determine the grade of dysplasia in IPMN. METHODS: Clinical and radiographic data, as well as CF samples, were obtained from 149 patients who underwent resection for IPMN at 1 of 3 institutions. High-risk disease was defined as the presence of high-grade dysplasia or invasive carcinoma. Multianalyte bead array analysis (Luminex) of CF was performed for 4 protein markers that were previously associated with high-risk disease. Logistic regression models were fit on training data, with and without adjustment for a previously developed clinical nomogram and validated with an external testing set. The models incorporating clinical risk score were presented graphically as nomograms. RESULTS: Within the group of 149 resected patients, 89 (60%) had low-risk disease, and 60 (40%) had high-risk disease. All 4 CF markers (MMP9, CA72-4, sFASL, and IL-4) were overexpressed in patients with high-risk IPMN (P < 0.05). Two predictive models based on preselected combinations of CF markers had concordance indices of 0.76 (Model-1) and 0.80 (Model-2). Integration of each CF marker model into a previously described clinical nomogram leads to increased discrimination compared with either the CF models or nomogram alone (c-indices of 0.84 and 0.83, respectively). CONCLUSIONS: This multi-institutional study validated 2 CF protein marker models for preoperative identification of high-risk IPMN. When combined with a clinical nomogram, the ability to predict high-grade dysplasia was even stronger.

6 Article Combined circulating tumor DNA and protein biomarker-based liquid biopsy for the earlier detection of pancreatic cancers. 2017

Cohen, Joshua D / Javed, Ammar A / Thoburn, Christopher / Wong, Fay / Tie, Jeanne / Gibbs, Peter / Schmidt, C Max / Yip-Schneider, Michele T / Allen, Peter J / Schattner, Mark / Brand, Randall E / Singhi, Aatur D / Petersen, Gloria M / Hong, Seung-Mo / Kim, Song Cheol / Falconi, Massimo / Doglioni, Claudio / Weiss, Matthew J / Ahuja, Nita / He, Jin / Makary, Martin A / Maitra, Anirban / Hanash, Samir M / Dal Molin, Marco / Wang, Yuxuan / Li, Lu / Ptak, Janine / Dobbyn, Lisa / Schaefer, Joy / Silliman, Natalie / Popoli, Maria / Goggins, Michael G / Hruban, Ralph H / Wolfgang, Christopher L / Klein, Alison P / Tomasetti, Cristian / Papadopoulos, Nickolas / Kinzler, Kenneth W / Vogelstein, Bert / Lennon, Anne Marie. ·The Ludwig Center, The Johns Hopkins Medical Institutions, Baltimore, MD 21287. · Howard Hughes Medical Institute, The Johns Hopkins Medical Institutions, Baltimore, MD 21287. · Sidney Kimmel Cancer Center at Johns Hopkins, The Johns Hopkins Medical Institutions, Baltimore, MD 21287. · The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD 21287. · Department of Biomedical Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. · Department of Surgery, The Johns Hopkins Medical Institutions, Baltimore, MD 21287. · Division of Systems Biology and Personalized Medicine, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3021, Australia. · Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC 3010, Australia. · Department of Medical Oncology, Western Health, Melbourne, VIC 3021, Australia. · Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202. · Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202. · Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10065. · Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065. · Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15260. · Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15260. · Department of Epidemiology, Mayo Clinic, Rochester, MN 55902. · Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea. · Department of Hepatobiliary and Pancreas Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea. · Division of Pancreatic Surgery, Department of Surgery, San Raffaele Scientific Institute Research Hospital, 20132 Milan, Italy. · Department of Pathology, San Raffaele Scientific Institute Research Hospital, 20132 Milan, Italy. · The Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. · Department of Biostatistics, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205. · Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, MD 21287. · Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD 21287. · Department of Epidemiology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205. · Division of Biostatistics and Bioinformatics, Department of Oncology, The Johns Hopkins Medical Institutions, Baltimore, MD 21287. · The Ludwig Center, The Johns Hopkins Medical Institutions, Baltimore, MD 21287; bertvog@gmail.com amlennon@jhmi.edu. · The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD 21287; bertvog@gmail.com amlennon@jhmi.edu. ·Proc Natl Acad Sci U S A · Pubmed #28874546.

ABSTRACT: The earlier diagnosis of cancer is one of the keys to reducing cancer deaths in the future. Here we describe our efforts to develop a noninvasive blood test for the detection of pancreatic ductal adenocarcinoma. We combined blood tests for

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 Predicting the Grade of Dysplasia of Pancreatic Cystic Neoplasms Using Cyst Fluid DNA Methylation Markers. 2017

Hata, Tatsuo / Dal Molin, Marco / Hong, Seung-Mo / Tamura, Koji / Suenaga, Masaya / Yu, Jun / Sedogawa, Hiraku / Weiss, Matthew J / Wolfgang, Christopher L / Lennon, Anne Marie / Hruban, Ralph H / Goggins, Michael G. ·Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea. · Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Medicine, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. mgoggins@jhmi.edu. ·Clin Cancer Res · Pubmed #28148542.

ABSTRACT:

9 Article Targeted DNA Sequencing Reveals Patterns of Local Progression in the Pancreatic Remnant Following Resection of Intraductal Papillary Mucinous Neoplasm (IPMN) of the Pancreas. 2017

Pea, Antonio / Yu, Jun / Rezaee, Neda / Luchini, Claudio / He, Jin / Dal Molin, Marco / Griffin, James F / Fedor, Helen / Fesharakizadeh, Shahriar / Salvia, Roberto / Weiss, Matthew J / Bassi, Claudio / Cameron, John L / Zheng, Lei / Scarpa, Aldo / Hruban, Ralph H / Lennon, Anne Marie / Goggins, Michael / 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 Surgery, The Pancreas Institute, University and Hospital Trust of Verona, Verona, Italy ‡Departments of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland §Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona, Italy ¶Departments of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland ||Departments of Medicine, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland **ARC-Net applied research on cancer center, University and Hospital Trust of Verona, Verona, Italy. ·Ann Surg · Pubmed #27433916.

ABSTRACT: OBJECTIVE: The aim of this study was to characterize patterns of local progression following resection for pancreatic intraductal papillary mucinous neoplasms (IPMN) using targeted next-generation sequencing (NGS). BACKGROUND: Progression of neoplastic disease in the remnant pancreas following resection of IPMN may include development of a new IPMN or ductal adenocarcinoma (PDAC). However, it is not clear whether this progression represents recurrence of the same neoplasm or an independent second neoplasm. METHODS: Targeted-NGS on genes commonly mutated in IPMN and PDAC was performed on tumors from (1) 13 patients who developed disease progression in the remnant pancreas following resection of IPMN; and (2) 10 patients who underwent a resection for PDAC and had a concomitant IPMN. Mutations in the tumors were compared in order to determine the relationship between neoplasms. In parallel, clinical and pathological characteristics of 260 patients who underwent resection of noninvasive IPMN were reviewed to identify risk factors associated with local progression. RESULTS: We identified 3 mechanisms underlying local progression in the remnant pancreas: (1) residual microscopic disease at the resection margin, (2) intraparenchymal spread of neoplastic cells, leading to an anatomically separate but genetically related recurrence, and (3) multifocal disease with genetically distinct lesions. Analysis of the 260 patients with noninvasive IPMNs showed that family history of pancreatic cancer (P = 0.027) and high-grade dysplasia (HGD) (P = 0.003) were independent risk factors for the development of an IPMN with HGD or an invasive carcinoma in the remnant pancreas. CONCLUSIONS: Using NGS, we identify distinct mechanisms for development of metachronous or synchronous neoplasms in patients with IPMN. Patients with a primary IPMN with HGD or with positive family history are at an increased risk to develop subsequent high-risk neoplasms in the remnant pancreas.

10 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.

11 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.

12 Article Cyst Fluid Telomerase Activity Predicts the Histologic Grade of Cystic Neoplasms of the Pancreas. 2016

Hata, Tatsuo / Dal Molin, Marco / Suenaga, Masaya / Yu, Jun / Pittman, Meredith / Weiss, Matthew / Canto, Marcia I / Wolfgang, Christopher / Lennon, Anne Marie / Hruban, Ralph H / Goggins, Michael. ·Department of Pathology, 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 Surgery, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. Department of Medicine, 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 Oncology, 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 Medicine, 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. mgoggins@jhmi.edu. ·Clin Cancer Res · Pubmed #27230749.

ABSTRACT: PURPOSE: Pancreatic cysts frequently pose clinical dilemmas. On one hand, cysts with high-grade dysplasia offer opportunities for cure, on the other hand, those with low-grade dysplasia are easily over treated. Cyst fluid markers have the potential to improve the evaluation of these cysts. Because telomerase activity is commonly activated in malignant cells, we evaluated the diagnostic performance of cyst fluid telomerase activity measurements for predicting histologic grade. EXPERIMENTAL DESIGN: Telomerase activity was measured using telomerase repeat amplification with digital-droplet PCR in surgically aspirated cyst fluid samples from 219 patients who underwent pancreatic resection for a cystic lesion (184 discovery, 35 validation) and 36 patients who underwent endoscopic ultrasound fine-needle aspiration. Methodologic and clinical factors associated with telomerase activity were examined. RESULTS: Telomerase activity was reduced in samples that had undergone prior thawing. Among 119 samples not previously thawed, surgical cyst fluids from cystic neoplasms with high-grade dysplasia ± associated invasive cancer had higher telomerase activity [median (interquartile range), 1,158 (295.9-13,033)] copies/μL of cyst fluid than those without [19.74 (2.58-233.6) copies/μL; P < 0.001)]. Elevated cyst fluid telomerase activity had a diagnostic accuracy for invasive cancer/high-grade dysplasia of 88.1% (discovery), 88.6% (validation), and 88.2% (merged). Among cysts classified preoperatively as having "worrisome features," cyst fluid telomerase activity had high diagnostic performance (sensitivity 73.7%, specificity 90.6%, accuracy, 86.1%). In multivariate analysis, telomerase activity independently predicted the presence of invasive cancer/high-grade dysplasia. CONCLUSIONS: Cyst fluid telomerase activity can be a useful predictor of the neoplastic grade of pancreatic cysts. Clin Cancer Res; 22(20); 5141-51. ©2016 AACRSee related commentary by Allen et al., p. 4966.

13 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.

14 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.

15 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.

16 Article Cyst fluid biomarkers for intraductal papillary mucinous neoplasms of the pancreas: a critical review from the international expert meeting on pancreatic branch-duct-intraductal papillary mucinous neoplasms. 2015

Maker, Ajay V / Carrara, Silvia / Jamieson, Nigel B / Pelaez-Luna, Mario / Lennon, Anne Marie / Dal Molin, Marco / Scarpa, Aldo / Frulloni, Luca / Brugge, William R. ·Department of Surgery, Division of Surgical Oncology; University of Illinois at Chicago, Chicago, IL. Electronic address: amaker@uic.edu. · Digestive Endoscopy Unit, Istituto Clinico Humanitas, Rozzano, Italy. · Department of Surgery, University of Glasgow, Scotland. · Department of Gastroenterology; Instituto Nacional de Ciencias Medicas y Nutrición - School of Medicine - Universidad Nacional Autonoma de Mexico, Mexico City, Mexico. · Department of Medicine, Division of Gastroenterology, Johns Hopkins University, Baltimore, MD. · Department of Pathology, Johns Hopkins University, Baltimore, MD. · Department of Pathology and Diagnostics, University of Verona; Verona, Italy. · Department of Medicine, Section of Gastroenterology, University of Verona; Verona, Italy. · Department of Medicine, Division of Gastroenterology, Massachusetts General Hospital, Boston, MA. ·J Am Coll Surg · Pubmed #25592469.

ABSTRACT: -- No abstract --

17 Article Outcome of superior mesenteric-portal vein resection during pancreatectomy for borderline ductal adenocarcinoma: results of a prospective comparative study. 2014

Selvaggi, Federico / Mascetta, Giuseppe / Daskalaki, Despoina / dal Molin, Marco / Salvia, Roberto / Butturini, Giovanni / Cellini, Carlo / Bassi, Claudio. ·Department of Surgery, "G. d'Annunzio" University, Chieti-Pescara, Italy. ·Langenbecks Arch Surg · Pubmed #24777762.

ABSTRACT: BACKGROUND: Approximately 20 % of patients affected by pancreatic ductal adenocarcinoma are amenable to surgical resection. Several tumours are reported as "borderline resectable" because of their proximity to the major vessels. In the effort to achieve a radical tumour removal, vein resection has been proposed, but its oncological benefits remain debated. METHODS: Our aim is to investigate morbidity, mortality and survival after pancreatectomy with vein resection. RESULTS: Forty patients underwent pancreatectomy and vein resection (group A), and 20 patients (group B) underwent bilio-enteric and/or gastro-entero bypass. In group A, cancer vein invasion was microscopically proven in 14 cases (35 %). Vein infiltration, tumour differentiation and node-positive disease were not adverse prognostic variables. No difference in survival was seen over a 1-year follow-up. After this period, group A showed significant survival benefits with a longer stabilisation of the disease (p = 0.005). Tumour-free resection margins and adjuvant chemoradiotherapy were the most important prognostic factors (p < 0.05). CONCLUSIONS: Suspicion of vein infiltration should not be a contraindication to resection. Pancreatectomy can be safely performed with an acceptable morbidity and better survival trend.

18 Article GNAS sequencing identifies IPMN-specific mutations in a subgroup of diminutive pancreatic cysts referred to as "incipient IPMNs". 2014

Matthaei, Hanno / Wu, Jian / Dal Molin, Marco / Shi, Chanjuan / Perner, Sven / Kristiansen, Glen / Lingohr, Philipp / Kalff, Jörg C / Wolfgang, Christopher L / Kinzler, Kenneth W / Vogelstein, Bert / Maitra, Anirban / Hruban, Ralph H. ·Departments of *Pathology ††Oncology #Surgery, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine ‡Ludwig Center for Cancer Genetics **Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD §Department of Pathology, Microbiology, Immunology, Vanderbilt University Medical Center, Nashville, TN Departments of †General, Visceral, Thoracic and Vascular Surgery ¶Prostate Cancer Research ∥Institute of Pathology, University of Bonn, Bonn, Germany. ·Am J Surg Pathol · Pubmed #24525507.

ABSTRACT: Incipient intraductal papillary mucinous neoplasms (IPMNs) are poorly described subcentimeter pancreatic cysts with papillae and mucin similar to IPMNs. They are larger than pancreatic intraepithelial neoplasia but do not meet the cutoff size for IPMNs (≥ 1 cm). GNAS codon 201 mutations are hallmark genetic alterations of IPMNs. Hence, we sought to determine the GNAS status of incipient IPMNs to better classify these lesions. Incipient IPMNs from 3 institutions were histologically reassessed, manually microdissected, and the genomic DNA was extracted. Using a sensitive digital ligation technique, the mutational status of KRAS at codon 12 and GNAS at codon 201 was determined. We included 21 incipient IPMNs from 7 male and 12 female patients with a median age of 63 years (range, 40 to 76 y). Most patients underwent surgery for pancreatic ductal adenocarcinoma (N = 8) or ampullary adenocarcinoma (N = 3). The median incipient IPMN size was 4 mm (range, 2 to 7 mm), and a majority had gastric-foveolar (N = 11) or intestinal (N = 5) differentiation. The maximum dysplasia observed was intermediate, and most of the lesions had intermediate-grade dysplasia. Mutational analysis revealed KRAS codon 12 mutations in all 21 incipient IPMNs, whereas 7 lesions (33%) in 7 individual patients harbored GNAS codon 201 mutations. The presence of GNAS 201 mutations in incipient IPMNs suggests that a fraction of these cysts are in fact small IPMNs. Morphologically, incipient IPMNs do not appear to be high-risk lesions. Additional studies in a larger cohort are needed to define the relationship of incipient IPMNs to larger IPMNs and, more importantly, to determine their clinical significance.

19 Article miRNA biomarkers in cyst fluid augment the diagnosis and management of pancreatic cysts. 2012

Matthaei, Hanno / Wylie, Dennis / Lloyd, Maura B / Dal Molin, Marco / Kemppainen, Jon / Mayo, Skye C / Wolfgang, Christopher L / Schulick, Richard D / Langfield, Laura / Andruss, Bernard F / Adai, Alex T / Hruban, Ralph H / Szafranska-Schwarzbach, Anna E / Maitra, Anirban. ·Departments of Pathology, Oncology, and Surgery, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. ·Clin Cancer Res · Pubmed #22723372.

ABSTRACT: PURPOSE: The diagnosis of pancreatic cystic lesions has increased dramatically. Most are benign, whereas some, such as intraductal papillary mucinous neoplasms (IPMN), represent precursors of pancreatic adenocarcinoma. Therapeutic stratification of IPMNs is challenging without precise information on dysplasia grade and presence of invasion. We assessed the diagnostic benefit of using miRNAs as biomarkers in pancreatic cyst fluid, focusing on IPMNs because of their frequency and malignant potential. EXPERIMENTAL DESIGN: RNA was extracted from 55 microdissected formalin-fixed, paraffin-embedded (FFPE) IPMN specimens, and 65 cyst fluid specimens aspirated following surgical resection. Expression of 750 miRNAs was evaluated with TaqMan miRNA Arrays using 22 FFPE and 15 cyst fluid specimens. Differential expression of selected miRNA candidates was validated in 33 FFPE and 50 cyst fluid specimens using TaqMan miRNA Assays. RESULTS: We identified 26 and 37 candidate miRNAs that distinguish low-grade from high-grade IPMNs using FFPE and cyst fluid specimens, respectively. A subset of 18 miRNAs, selected from FFPE and cyst fluid data, separated high-grade IPMNs from low-grade IPMNs, serous cystadenomas (SCA) and uncommon cysts, such as solid pseudopapillary neoplasms (SPN) and cystic pancreatic neuroendocrine tumors (PanNET). A logistic regression model using nine miRNAs allowed prediction of cyst pathology implying resection (high-grade IPMNs, PanNETs, and SPNs) versus conservative management (low-grade IPMNs, SCAs), with a sensitivity of 89%, a specificity of 100%, and area under the curve of 1. CONCLUSIONS: We found candidate miRNAs that helped identify patients with high-grade IPMN and exclude nonmucinous cysts. These classifiers will require validation in a prospective setting to ultimately confirm their clinical usefulness.

20 Article Clinicopathological characteristics and molecular analyses of multifocal intraductal papillary mucinous neoplasms of the pancreas. 2012

Matthaei, Hanno / Norris, Alexis L / Tsiatis, Athanasios C / Olino, Kelly / Hong, Seung-Mo / dal Molin, Marco / Goggins, Michael G / Canto, Marcia / Horton, Karen M / Jackson, Keith D / Capelli, Paola / Zamboni, Giuseppe / Bortesi, Laura / Furukawa, Toru / Egawa, Shinichi / Ishida, Masaharu / Ottomo, Shigeru / Unno, Michiaki / Motoi, Fuyuhiko / Wolfgang, Christopher L / Edil, Barish H / Cameron, John L / Eshleman, James R / Schulick, Richard D / Maitra, Anirban / Hruban, Ralph H. ·Department of General, Visceral, Thoracic and Vascular Surgery, University of Bonn, Germany. ·Ann Surg · Pubmed #22167000.

ABSTRACT: OBJECTIVE: To examine the clinicopathologic features and clonal relationship of multifocal intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. BACKGROUND: Intraductal papillary mucinous neoplasms are increasingly diagnosed cystic precursor lesions of pancreatic cancer. Intraductal papillary mucinous neoplasms can be multifocal and a potential cause of recurrence after partial pancreatectomy. METHODS: Thirty four patients with histologically documented multifocal IPMNs were collected and their clinicopathologic features catalogued. In addition, thirty multifocal IPMNs arising in 13 patients from 3 hospitals were subjected to laser microdissection followed by KRAS pyrosequencing and loss of heterozygosity (LOH) analysis on chromosomes 6q and 17p. Finally, we sought to assess the clonal relationships among multifocal IPMNs. RESULTS: We identified 34 patients with histologically documented multifocal IPMNs. Synchronous IPMNs were present in 29 patients (85%), whereas 5 (15%) developed clinically significant metachronous IPMNs. Six patients (18%) had a history of familial pancreatic cancer. A majority of multifocal IPMNs (86% synchronous, 100% metachronous) were composed of branch duct lesions, and typically demonstrated a gastric-foveolar subtype epithelium with low or intermediate grades of dysplasia. Three synchronous IPMNs (10%) had an associated invasive cancer. Molecular analysis of multiple IPMNs from 13 patients demonstrated nonoverlapping KRAS gene mutations in 8 patients (62%) and discordant LOH profiles in 7 patients (54%); independent genetic alterations were established in 9 of the 13 patients (69%). CONCLUSIONS: The majority of multifocal IPMNs arise independently and exhibit a gastric-foveolar subtype, with low to intermediate dysplasia. These findings underscore the importance of life-long follow-up after resection for an IPMN.

21 Article Loss of expression of the SWI/SNF chromatin remodeling subunit BRG1/SMARCA4 is frequently observed in intraductal papillary mucinous neoplasms of the pancreas. 2012

Dal Molin, Marco / Hong, Seung-Mo / Hebbar, Sachidanand / Sharma, Rajni / Scrimieri, Francesca / de Wilde, Roeland F / Mayo, Skye C / Goggins, Michael / Wolfgang, Christopher L / Schulick, Richard D / Lin, Ming-Tseh / Eshleman, James R / Hruban, Ralph H / Maitra, Anirban / Matthaei, Hanno. ·Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University, Baltimore, MD 21231, USA. ·Hum Pathol · Pubmed #21940037.

ABSTRACT: A better molecular characterization of intraductal papillary mucinous neoplasm (IPMN), the most frequent cystic precursor lesion of pancreatic adenocarcinoma, may have a pivotal role in its early detection and in the development of effective therapeutic strategies. BRG1, a central component of the chromatin remodeling complex SWI/SNF regulating transcription, is inactive in several malignancies. In this study, we evaluate the Brg1 expression in intraductal papillary mucinous neoplasm to better understand its role in the pancreatic carcinogenesis. Tissue microarrays of 66 surgically resected IPMNs were immunolabeled for the Brg1 protein. Expression patterns were then correlated with clinicopathologic parameters. Normal pancreatic epithelium strongly immunolabeled for Brg1. Reduced Brg1 expression was observed in 32 (53.3%) of the 60 evaluable IPMN lesions and occurred more frequently in high-grade IPMNs (13 of 17 showed loss; 76%) compared to intermediate-grade (15 of 29 showed loss; 52%) and low-grade IPMNs (4 of 14 showed loss; 28%) (P = .03). A complete loss of Brg1 expression was observed in 5 (8.3%) of the 60 lesions. Finally, a decrease in Brg1 protein expression was furthermore found in a low-passage noninvasive IPMN cell line by Western blot analysis. We did not observe correlation between Brg1 expression and IPMN subtype or with location of the cyst. We provide first evidence that Brg1 expression is lost in noninvasive cystic precursor lesions of pancreatic adenocarcinoma.

22 Article Recurrent GNAS mutations define an unexpected pathway for pancreatic cyst development. 2011

Wu, Jian / Matthaei, Hanno / Maitra, Anirban / Dal Molin, Marco / Wood, Laura D / Eshleman, James R / Goggins, Michael / Canto, Marcia I / Schulick, Richard D / Edil, Barish H / Wolfgang, Christopher L / Klein, Alison P / Diaz, Luis A / Allen, Peter J / Schmidt, C Max / Kinzler, Kenneth W / Papadopoulos, Nickolas / Hruban, Ralph H / Vogelstein, Bert. ·Ludwig Center for Cancer Genetics and Howard Hughes Medical Institutions, Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA. ·Sci Transl Med · Pubmed #21775669.

ABSTRACT: More than 2% of the adult U.S. population harbors a pancreatic cyst. These often pose a difficult management problem because conventional criteria cannot always distinguish cysts with malignant potential from those that are innocuous. One of the most common cystic neoplasms of the pancreas, and a bona fide precursor to invasive adenocarcinoma, is called intraductal papillary mucinous neoplasm (IPMN). To help reveal the pathogenesis of these lesions, we purified the DNA from IPMN cyst fluids from 19 patients and searched for mutations in 169 genes commonly altered in human cancers. In addition to the expected KRAS mutations, we identified recurrent mutations at codon 201 of GNAS. A larger number (113) of additional IPMNs were then analyzed to determine the prevalence of KRAS and GNAS mutations. In total, we found that GNAS mutations were present in 66% of IPMNs and that either KRAS or GNAS mutations could be identified in 96%. In eight cases, we could investigate invasive adenocarcinomas that developed in association with IPMNs containing GNAS mutations. In seven of these eight cases, the GNAS mutations present in the IPMNs were also found in the invasive lesion. GNAS mutations were not found in other types of cystic neoplasms of the pancreas or in invasive adenocarcinomas not associated with IPMNs. In addition to defining a new pathway for pancreatic neoplasia, these data suggest that GNAS mutations can inform the diagnosis and management of patients with cystic pancreatic lesions.

23 Article Elevated microRNA miR-21 levels in pancreatic cyst fluid are predictive of mucinous precursor lesions of ductal adenocarcinoma. 2011

Ryu, Ji Kon / Matthaei, Hanno / Dal Molin, Marco / Hong, Seung-Mo / Canto, Marcia I / Schulick, Richard D / Wolfgang, Christopher / Goggins, Michael G / Hruban, Ralph H / Cope, Leslie / Maitra, Anirban. ·Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. ·Pancreatology · Pubmed #21757972.

ABSTRACT: BACKGROUND: Biomarkers for the diagnostic classification of pancreatic cysts are urgently needed. Deregulated microRNA (miRNAs) expression is widespread in pancreatic cancer. We assessed whether aberrant miRNAs in pancreatic cyst fluid could be used as potential biomarkers for cystic precursor lesions of pancreatic cancer. METHODS: Cyst fluid specimens were prospectively collected from 40 surgically resected pancreatic cysts, and small RNAs were extracted. The 'mucinous' cohort included 14 intraductal papillary mucinous neoplasms (including 3 with an associated adenocarcinoma) and 10 mucinous cystic neoplasms; the 'nonmucinous' cohort included 11 serous cystadenomas and 5 other benign cysts. Quantitative reverse transcription PCR was performed for five miRNAs (miR-21, miR-155, miR-221, miR-17-3p, miR-191), which were previously reported as overexpressed in pancreatic adenocarcinomas. RESULTS: Significantly higher expression of miR-21, miR-221, and miR-17-3p was observed in the mucinous versus nonmucinous cysts (p < 0.01), with the mean relative fold differences being 7.0-, 7.9-, and 5.4-fold, respectively. Receiver operating characteristic curves demonstrated the highest median area under the curve for miR-21, with a median specificity of 76%, at a sensitivity of 80%. CONCLUSION: This pilot study demonstrates that profiling miRNAs in pancreatic cyst fluid samples is feasible and can yield potential biomarkers for the classification of cystic lesions of the pancreas. and IAP.

24 Article Presence of pancreatic intraepithelial neoplasia in the pancreatic transection margin does not influence outcome in patients with R0 resected pancreatic cancer. 2011

Matthaei, Hanno / Hong, Seung-Mo / Mayo, Skye C / dal Molin, Marco / Olino, Kelly / Venkat, Raghunandan / Goggins, Michael / Herman, Joseph M / Edil, Barish H / Wolfgang, Christopher L / Cameron, John L / Schulick, Richard D / Maitra, Anirban / Hruban, Ralph H. ·The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University, Baltimore, MD, USA. ·Ann Surg Oncol · Pubmed #21537863.

ABSTRACT: BACKGROUND: Margin status is one of the strongest prognosticators after resection of pancreatic ductal adenocarcinoma (PDAC). The clinical significance of pancreatic intraepithelial neoplasia (PanIN) at a surgical margin has not been established. METHODS: A total of 208 patients who underwent R0 resection for PDAC between 2004 and 2008 were selected. Intraoperative frozen section slides containing the final pancreatic parenchymal transection margin were evaluated for presence or absence, number, and grade of PanINs. Data were compared to clinicopathologic factors, including patient survival. RESULTS: PanIN lesions were present in margins in 107 of 208 patients (51.4%). Median number of PanINs per pancreatic resection margin was 1 (range, 1-11). A total of 72 patients had PanIN-1 (34.6%), 44 had PanIN-2 (21.1%), and 16 had PanIN-3 (7.2%) at their margin. Overall median survival was 17.9 (95% confidence interval, 14-21.9) months. Neither the presence nor absence of PanIN nor histological grade had any significant correlation with important clinicopathologic characteristics. There were no significant survival differences between patients with or without PanIN lesions at the resection margin or among patients with PanIN-3 (carcinoma in situ) versus lower PanIN grades. However, patients with R1 resection had a significantly worse outcome compared with patients without invasive cancer at a margin irrespective of the presence of PanIN (P=0.02). CONCLUSIONS: The presence of PanINs at a resection margin does not affect survival in patients who undergo R0 resection for PDAC. These results have significant clinical implications for surgeons, because no additional resection seems to be indicated when intraoperative frozen sections reveal even high-grade PanIN lesions.

25 Article Inactivation of Brca2 cooperates with Trp53(R172H) to induce invasive pancreatic ductal adenocarcinomas in mice: a mouse model of familial pancreatic cancer. 2011

Feldmann, Georg / Karikari, Collins / dal Molin, Marco / Duringer, Stephanie / Volkmann, Petra / Bartsch, Detlef K / Bisht, Savita / Koorstra, Jan-Bart / Brossart, Peter / Maitra, Anirban / Fendrich, Volker. ·University of Bonn, Center of Integrated Oncology Cologne-Bonn, Bonn, Germany. ·Cancer Biol Ther · Pubmed #21455033.

ABSTRACT: An inactivating germline mutation in BRCA2 is the most common known genetic basis for familial pancreatic cancer (FPC), accounting for 5-10% of inherited cases. A genetically engineered mouse model of pancreatic ductal adenocarcinoma (PDAC) arising on the backdrop of Brca2 deficiency is likely to elucidate valuable diagnostic and therapeutic insights for FPC. Both Brca2 alleles were conditionally deleted during development within the pancreatic epithelium by generating Pdx1-Cre; Brca2(f/f) (CB) mice; in addition, triple transgenic Pdx1-Cre; Brca2(f/f); LSL-Trp53(R172H) (CBP) mice were generated, in order to determine the impact of p53 deregulation on Brca2-deficient carcinogenesis. Both CB and CBP mice developed non-invasive ductal precursor lesions (murine pancreatic intraepithelial neoplasia or mPanIN), although these were observed at an earlier time point (5 versus 8 months) and with higher prevalence in CBP mice. A minority of CB mice (15%) developed invasive and metastatic PDAC at a latency of 15 months or greater; in contrast, CBP mice of comparable age uniformly developed PDAC with variable histological features. Mortality in the absence of neoplasia in CB and CBP mice was associated with profound loss of pancreatic parenchyma, consistent with progressive elimination of Brca2-deficient cells. Widespread DNA damage, as evidenced by overexpression of the phosphorylated histone H(2)AX(Ser139), was observed in the non-neoplastic exocrine pancreas, as well as in the mPanIN and PDAC lesions of Brca2-deficient mice, independent of p53 status. Loss of Brca2 function predisposes the exocrine pancreas to profound DNA damage, and the frequency of invasive neoplasia is accentuated by the concomitant deregulation of p53.