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Pancreatic Neoplasms: HELP
Articles by Mari Mino-Kenudson
Based on 54 articles published since 2010
(Why 54 articles?)
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Between 2010 and 2020, M. Mino-Kenudson wrote the following 54 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3
1 Guideline Pathologic Evaluation and Reporting of Intraductal Papillary Mucinous Neoplasms of the Pancreas and Other Tumoral Intraepithelial Neoplasms of Pancreatobiliary Tract: Recommendations of Verona Consensus Meeting. 2016

Adsay, Volkan / Mino-Kenudson, Mari / Furukawa, Toru / Basturk, Olca / Zamboni, Giuseppe / Marchegiani, Giovanni / Bassi, Claudio / Salvia, Roberto / Malleo, Giuseppe / Paiella, Salvatore / Wolfgang, Christopher L / Matthaei, Hanno / Offerhaus, G Johan / Adham, Mustapha / Bruno, Marco J / Reid, Michelle D / Krasinskas, Alyssa / Klöppel, Günter / Ohike, Nobuyuki / Tajiri, Takuma / Jang, Kee-Taek / Roa, Juan Carlos / Allen, Peter / Fernández-del Castillo, Carlos / Jang, Jin-Young / Klimstra, David S / Hruban, Ralph H / Anonymous6721124. ·*Department of Pathology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA †Department of Pathology, Massachusetts General Hospital, Boston, MA ‡Department of Pathology, Tokyo Women's Medical University, Tokyo, Japan §Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY ¶Department of Pathology, University of Verona, Verona, Italy ||Department of Surgery, Massachusetts General Hospital, Boston, MA **Department of Surgery, University of Verona, Verona, Italy ††Department of Surgery, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD ‡‡Departments of Surgery, University of Bonn, Bonn, Germany §§Departments of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands ¶¶Department of Surgery, Edouard Herriot Hospital, HCL, Lyon, France ||||Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands ***Departments of Pathology, Technical University, Munich, Germany †††Department of Pathology, Showa University Fujigaoka Hospital, Yokohama, Japan ‡‡‡Department of Pathology, Tokai University Hachioji Hospital, Tokyo, Japan §§§Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea ¶¶¶Department of Pathology, Pontificia Universidad Católica de Chile, Santiago, Chile ||||||Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY ****Department of Surgery, Massachusetts General Hospital, Boston, MA ††††Department of Surgery, Seoul National University Hospital, Seoul, Korea ‡‡‡‡Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD. ·Ann Surg · Pubmed #25775066.

ABSTRACT: BACKGROUND: There are no established guidelines for pathologic diagnosis/reporting of intraductal papillary mucinous neoplasms (IPMNs). DESIGN: An international multidisciplinary group, brought together by the Verona Pancreas Group in Italy-2013, was tasked to devise recommendations. RESULTS: (1) Crucial to rule out invasive carcinoma with extensive (if not complete) sampling. (2) Invasive component is to be documented in a full synoptic report including its size, type, grade, and stage. (3) The term "minimally invasive" should be avoided; instead, invasion size with stage and substaging of T1 (1a, b, c; ≤ 0.5, > 0.5-≤ 1, > 1 cm) is to be documented. (4) Largest diameter of the invasion, not the distance from the nearest duct, is to be used. (5) A category of "indeterminate/(suspicious) for invasion" is acceptable for rare cases. (6) The term "malignant" IPMN should be avoided. (7) The highest grade of dysplasia in the non-invasive component is to be documented separately. (8) Lesion size is to be correlated with imaging findings in cysts with rupture. (9) The main duct diameter and, if possible, its involvement are to be documented; however, it is not required to provide main versus branch duct classification in the resected tumor. (10) Subtyping as gastric/intestinal/pancreatobiliary/oncocytic/mixed is of value. (11) Frozen section is to be performed highly selectively, with appreciation of its shortcomings. (12) These principles also apply to other similar tumoral intraepithelial neoplasms (mucinous cystic neoplasms, intra-ampullary, and intra-biliary/cholecystic). CONCLUSIONS: These recommendations will ensure proper communication of salient tumor characteristics to the management teams, accurate comparison of data between analyses, and development of more effective management algorithms.

2 Guideline Standardized terminology and nomenclature for pancreatobiliary cytology: the Papanicolaou Society of Cytopathology guidelines. 2014

Pitman, Martha B / Centeno, Barbara A / Ali, Syed Z / Genevay, Muriel / Stelow, Ed / Mino-Kenudson, Mari / Fernandez-del Castillo, Carlos / Max Schmidt, C / Brugge, William / Layfield, Lester / Anonymous9540785. ·Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. ·Diagn Cytopathol · Pubmed #24554455.

ABSTRACT: The Papanicolaou Society of Cytopathology has developed a set of guidelines for pancreatobiliary cytology including indications for endoscopic ultrasound (EUS)-guided fine needle aspiration (FNA) biopsy, techniques of EUS-FNA, terminology and nomenclature of pancreatobiliary disease, ancillary testing, and postbiopsy treatment and management. All documents are based on the expertise of the authors, a review of the literature, discussions of the draft document at several national and international meetings over an 18-month period and synthesis of online comments of the draft document on the Papanicolaou Society of Cytopathology web site (www.papsociety.org). This document selectively presents the results of these discussions and focuses on a proposed standardized terminology scheme for pancreatobiliary specimens that correlate cytological diagnosis with biological behavior and increasingly conservative patient management of surveillance only. The proposed terminology scheme recommends a six-tiered system: Nondiagnostic, Negative, Atypical, Neoplastic (benign or other), Suspicious and Positive. Unique to this scheme is the "Neoplastic" category separated into "benign" (serous cystadenoma), or "Other" (premalignant mucinous cysts, neuroendocrine tumors, and solid-pseudopapillary neoplasms). The positive or malignant category is reserved for high-grade, aggressive malignancies including ductal adenocarcinoma, acinar cell carcinoma, poorly differentiated neuroendocrine carcinomas, pancreatoblastoma, lymphoma, and metastases. Interpretation categories do not have to be used. Some pathology laboratory information systems require an interpretation category, which places the cytological diagnosis into a general category. This proposed scheme provides terminology that standardizes the category of the various diseases of the pancreas, some of which are difficult to diagnose specifically by cytology. In addition, this terminology scheme attempts to provide maximum flexibility for patient management, which has become increasingly conservative for some neoplasms.

3 Review Intraductal papillary mucinous neoplasms: does a family history of pancreatic cancer matter? 2012

Nehra, Deepika / Oyarvide, Vicente Morales / Mino-Kenudson, Mari / Thayer, Sarah P / Ferrone, Cristina R / Wargo, Jennifer A / Muzikansky, Alona / Finkelstein, Dianne / Warshaw, Andrew L / Castillo, Carlos Fernández-del. ·Department of Surgery, Massachusetts General Hospital, Boston MA, USA. ·Pancreatology · Pubmed #22898638.

ABSTRACT: BACKGROUND/OBJECTIVES: The purpose of this study is to compare surgically resected intraductal papillary mucinous neoplasms (IPMNs) in patients with and without a family history of pancreatic cancer to gain insight into differences that may suggest the need for differential management. METHODS: A retrospective review of patients who underwent resection of an IPMN at the Massachusetts General Hospital (1990-2011) was conducted. Three hundred and twenty-four patients of whom 45 (13.9%) had a family history of pancreatic cancer were identified. Patients with (PFH) and without (NFH) a family history of pancreatic cancer were compared. RESULTS: There were no differences in demographic characteristics between groups. Extra-pancreatic malignancies diagnosed prior to the IPMN were more common in those with a PFH (35.6% vs 20.1%, p = 0.03). There were no differences in IPMN characteristics between groups including no difference in the presence of invasive disease (p = 0.55). Concurrent pancreatic ductal adenocarcinomas were more common in those with a PFH (11.1% vs 2.9%, p = 0.02). The survival in the PFH group was marginally lower than the NFH group, a difference found to be attributable to the higher prevalence of extra-pancreatic malignancies. CONCLUSION: Characteristics of surgically resected IPMNs are not different between patients with and without a family history of pancreatic cancer. Most importantly, the incidence of invasive disease is not different, suggesting that these lesions may not be more aggressive when they occur in the presence of a family history of pancreatic cancer.

4 Clinical Trial Imaging of pancreatic cystic lesions with confocal laser endomicroscopy: an ex vivo pilot study. 2017

Kadayifci, Abdurrahman / Atar, Mustafa / Yang, Michelle / Fernandez-Del Castillo, Carlos / Mino-Kenudson, Mari / Brugge, William R. ·Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. kadayifci@hotmail.com. · Division of Gastroenterology, University of Gaziantep, University street, 27060, Gaziantep, Turkey. kadayifci@hotmail.com. · Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. · Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, USA. · Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. ·Surg Endosc · Pubmed #28444494.

ABSTRACT: BACKGROUND: The differential diagnosis of pancreatic cystic lesions (PCLs) is an increasingly common clinical challenge. Confocal laser endomicroscopy (CLE) may differentiate PCLs by imaging of the cyst wall. However, clinical experience is still limited, and better image definition and characterization of the cyst wall in a spectrum of cysts are needed. This experimental study aimed to expose detailed imaging characteristics of PCLs by CLE. METHODS: Patients who underwent surgery of a PCL were enrolled. During surgery, intravenous fluorescein (2.5 ml of 10%) was injected just prior to the ligation of blood vessels supplying the pancreas. The freshly excised specimens were transected along the long axis to fully expose the luminal surface. A Gastroflex-UHD CLE probe (pCLE) was used manually to acquire images directly from the surface of cyst wall. The specimen subsequently underwent cross-sectional histology. All recorded data were analyzed by two investigators for predefined and original image findings of PCLs. RESULTS: Ten cases were recruited into the study. All patients underwent surgery because of a mucinous cyst with worrisome features or a symptomatic PCL. Imaging was successful in all patients and differently shaped papillary projections (PP) were visualized in eight patients. Pathological examination of those patients confirmed 6 cases with Intraductal Papillary Mucinous Neoplasm (IPMN) and 2 cases with Mucinous Cystic Neoplasm (MCN). In two patients with serous cystadenoma, typical vascular network was visualized in one patient, and microcystic structures in the other. Three of the IPMNs were malignant. The loss of papillary margin integrity and significant fragmentation together with irregularity was detected in malignant IPMNs by CLE. CONCLUSIONS: Pancreatic cyst epithelial wall can be visualized successfully by pCLE in ex vivo surgical specimens. Different papillary projections have been seen in all cases of IPMNs and MCNs. CLE has potential for identifying IPMN subtypes and for grading dysplasia.

5 Clinical Trial Circulating tumor cells found in patients with localized and advanced pancreatic cancer. 2015

Kulemann, Birte / Pitman, Martha B / Liss, Andrew S / Valsangkar, Nakul / Fernández-Del Castillo, Carlos / Lillemoe, Keith D / Hoeppner, Jens / Mino-Kenudson, Mari / Warshaw, Andrew L / Thayer, Sarah P. ·From the *Department of Surgery and †Andrew L. Warshaw Institute for Pancreatic Cancer Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA; ‡Department of Surgery, University Hospital Freiburg, Freiburg, Germany; §Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA; and ║Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE. ·Pancreas · Pubmed #25822154.

ABSTRACT: OBJECTIVES: Isolation of circulating tumor cells (CTCs) holds the promise of diagnosing and molecular profiling cancers from a blood sample. Here, we test a simple new low-cost filtration device for CTC isolation in patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: Peripheral blood samples drawn from healthy donors and PDAC patients were filtered using ScreenCell devices, designed to capture CTCs for cytologic and molecular analysis. Giemsa-stained specimens were evaluated by a pancreatic cytopathologist blinded to the histological diagnosis. Circulating tumor cell DNA was subjected to KRAS mutational analysis. RESULTS: Spiking experiments demonstrated a CTC capture efficiency as low as 2 cells/mL of blood. Circulating tumor cells were identified by either malignant cytology or presence of KRAS mutation in 73% of 11 patients (P = 0.001). Circulating tumor cells were identified in 3 of 4 patients with early (≤American Joint Committee on Cancer stage IIB) and in 5 of 7 patients with advanced (≥ American Joint Committee on Cancer stage III) PDAC. No CTCs were detected in blood from 9 health donors. CONCLUSIONS: Circulating tumor cells can be found in most patients with PDAC of any stage, whether localized, locally advanced, or metastatic. The ability to capture, cytologically identify, and genetically analyze CTCs suggests a possible tool for the diagnosis and characterization of genetic alterations of PDAC.

6 Clinical Trial Phase I study of preoperative short-course chemoradiation with proton beam therapy and capecitabine for resectable pancreatic ductal adenocarcinoma of the head. 2011

Hong, Theodore S / Ryan, David P / Blaszkowsky, Lawrence S / Mamon, Harvey J / Kwak, Eunice L / Mino-Kenudson, Mari / Adams, Judith / Yeap, Beow / Winrich, Barbara / DeLaney, Thomas F / Fernandez-Del Castillo, Carlos. ·Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. tshong1@partners.org ·Int J Radiat Oncol Biol Phys · Pubmed #20421151.

ABSTRACT: PURPOSE: To evaluate the safety of 1 week of chemoradiation with proton beam therapy and capecitabine followed by early surgery. METHODS AND MATERIALS: Fifteen patients with localized resectable, pancreatic adenocarcinoma of the head were enrolled from May 2006 to September 2008. Patients received radiation with proton beam. In dose level 1, patients received 3 GyE × 10 (Week 1, Monday-Friday; Week 2, Monday-Friday). Patients in Dose Levels 2 to 4 received 5 GyE × 5 in progressively shortened schedules: level 2 (Week 1, Monday, Wednesday, and Friday; Week 2, Tuesday and Thursday), Level 3 (Week 1, Monday, Tuesday, Thursday, and Friday; Week 2, Monday), Level 4 (Week 1, Monday through Friday). Capecitabine was given as 825 mg/m(2) b.i.d. Weeks 1 and 2 Monday through Friday for a total of 10 days in all dose levels. Surgery was performed 4 to 6 weeks after completion of chemotherapy for Dose Levels 1 to 3 and then after 1 to 3 weeks for Dose Level 4. RESULTS: Three patients were treated at Dose Levels 1 to 3 and 6 patients at Dose Level 4, which was selected as the MTD. No dose limiting toxicities were observed. Grade 3 toxicity was noted in 4 patients (pain in 1; stent obstruction or infection in 3). Eleven patients underwent resection. Reasons for no resection were metastatic disease (3 patients) and unresectable tumor (1 patient). Mean postsurgical length of stay was 6 days (range, 5-10 days). No unexpected 30-day postoperative complications, including leak or obstruction, were found. CONCLUSIONS: Preoperative chemoradiation with 1 week of proton beam therapy and capecitabine followed by early surgery is feasible. A Phase II study is underway.

7 Article Cross Validation of the Monoclonal Antibody Das-1 in Identification of High-Risk Mucinous Pancreatic Cystic Lesions. 2019

Das, Koushik K / Geng, Xin / Brown, Jeffrey W / Morales-Oyarvide, Vicente / Huynh, Tiffany / Pergolini, Ilaria / Pitman, Martha B / Ferrone, Cristina / Al Efishat, Mohammad / Haviland, Dana / Thompson, Elizabeth / Wolfgang, Christopher / Lennon, Anne Marie / Allen, Peter / Lillemoe, Keith D / Fields, Ryan C / Hawkins, William G / Liu, Jingxia / Castillo, Carlos Fernandez-Del / Das, Kiron M / Mino-Kenudson, Mari. ·Division of Gastroenterology, Washington University, St Louis, Missouri. Electronic address: k.das@wustl.edu. · Division of Gastroenterology, Rutgers-Robert Wood Johnson Medical School, New Brunswick, New Jersey. · Division of Gastroenterology, Washington University, St Louis, Missouri. · Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts. · Deparment of Pathology, Massachusetts General Hospital, Boston, Massachusetts. · Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York. · Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland. · Department of Surgery Johns Hopkins School of Medicine, Baltimore, Maryland. · Division of Gastroenterology, Johns Hopkins School of Medicine, Baltimore, Maryland. · Department of Surgery, Washington University, St Louis, Missouri. · Deparment of Pathology, Massachusetts General Hospital, Boston, Massachusetts. Electronic address: mminokenudson@partners.org. ·Gastroenterology · Pubmed #31175863.

ABSTRACT: BACKGROUND & AIMS: Although pancreatic cystic lesions (PCLs) are frequently and incidentally detected, it is a challenge to determine their risk of malignancy. In immunohistochemical and enzyme-linked immunosorbent assay (ELISA) analyses of tissue and cyst fluid from pancreatic intraductal papillary mucinous neoplasms, the monoclonal antibody Das-1 identifies those at risk for malignancy with high levels of specificity and sensitivity. We aimed to validate the ability of Das-1 to identify high-risk PCLs in comparison to clinical guidelines and clinical features, using samples from a multicenter cohort. METHODS: We obtained cyst fluid samples of 169 PCLs (90 intraductal papillary mucinous neoplasms, 43 mucinous cystic neoplasms, and 36 non-mucinous cysts) from patients undergoing surgery at 4 tertiary referral centers (January 2010 through June 2017). Histology findings from surgical samples, analyzed independently and centrally re-reviewed in a blinded manner, were used as the reference standard. High-risk PCLs were those with invasive carcinomas, high-grade dysplasia, or intestinal-type intraductal papillary mucinous neoplasms with intermediate-grade dysplasia. An ELISA with Das-1 was performed in parallel using banked cyst fluid samples. We evaluated the biomarker's performance, generated area under the curve values, and conducted multivariate logistic regression using clinical and pathology features. RESULTS: The ELISA for Das-1 identified high-risk PCLs with 88% sensitivity, 99% specificity, and 95% accuracy, at a cutoff optical density value of 0.104. In 10-fold cross-validation analysis with 100 replications, Das-1 identified high-risk PCLs with 88% sensitivity and 98% specificity. The Sendai, Fukuoka, and American Gastroenterological Association guideline criteria identified high-risk PCLs with 46%, 52%, and 74% accuracy (P for comparison to Das-1 ELISA <.001). When we controlled for Das-1 in multivariate regression, main pancreatic duct dilation >5 mm (odds ratio, 14.98; 95% confidence interval, 2.63-108; P < .0012), main pancreatic duct dilation ≥1 cm (odds ratio, 47.9; 95% confidence interval, 6.39-490; P < .0001), and jaundice (odds ratio, 6.16; 95% confidence interval, 1.08-36.7; P = .0397) were significantly associated with high-risk PCLs. CONCLUSIONS: We validated the ability of an ELISA with the monoclonal antibody Das-1 to detect PCLs at risk for malignancy with high levels of sensitivity and specificity. This biomarker might be used in conjunction with clinical guidelines to identify patients at risk for malignancy.

8 Article Mutant GNAS drives pancreatic tumourigenesis by inducing PKA-mediated SIK suppression and reprogramming lipid metabolism. 2018

Patra, Krushna C / Kato, Yasutaka / Mizukami, Yusuke / Widholz, Sebastian / Boukhali, Myriam / Revenco, Iulia / Grossman, Elizabeth A / Ji, Fei / Sadreyev, Ruslan I / Liss, Andrew S / Screaton, Robert A / Sakamoto, Kei / Ryan, David P / Mino-Kenudson, Mari / Castillo, Carlos Fernandez-Del / Nomura, Daniel K / Haas, Wilhelm / Bardeesy, Nabeel. ·Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. · Departments of Medicine, Harvard Medical School, Boston, MA, USA. · Institute of Biomedical Research, Sapporo Higashi Tokushukai Hospital, Sapporo, Hokkaido, Japan. · Asahikawa Medical University, Hokkaido, Japan. · Departments of Nutritional Sciences and Toxicology, Chemistry, and Molecular and Cell Biology, University of California, Berkeley, CA, USA. · Departments of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA. · Department of Genetics, Harvard Medical School, Boston, MA, USA. · Departments of Pathology, Massachusetts General Hospital, Boston, MA, USA. · Department of Pathology, Harvard Medical School, Boston, MA, USA. · Sunnybrook Research Institute, Toronto, Ontario, Canada. · Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada. · MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Scotland, UK. · Nestlé Institute of Health Sciences SA, Lausanne, Switzerland. · Departments of Surgery, Massachusetts General Hospital, Boston, MA, USA. · Department of Surgery, Harvard Medical School, Boston, MA, USA. · Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. Bardeesy.Nabeel@mgh.harvard.edu. · Departments of Medicine, Harvard Medical School, Boston, MA, USA. Bardeesy.Nabeel@mgh.harvard.edu. ·Nat Cell Biol · Pubmed #29941929.

ABSTRACT: G protein α

9 Article Intraductal Papillary Mucinous Neoplasm of the Pancreas in Young Patients: Tumor Biology, Clinical Features, and Survival Outcomes. 2018

Morales-Oyarvide, Vicente / Mino-Kenudson, Mari / Ferrone, Cristina R / Warshaw, Andrew L / Lillemoe, Keith D / Sahani, Dushyant V / Pergolini, Ilaria / Attiyeh, Marc A / Al Efishat, Mohammad / Rezaee, Neda / Hruban, Ralph H / He, Jin / Weiss, Matthew J / Allen, Peter J / Wolfgang, Christopher L / Fernández-Del Castillo, Carlos. ·Department of Surgery, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Wang Ambulatory Care Center 460, Boston, MA, 02114, USA. · Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. · Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. · Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Surgery, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Wang Ambulatory Care Center 460, Boston, MA, 02114, USA. cfernandez@partners.org. ·J Gastrointest Surg · Pubmed #29047068.

ABSTRACT: AIM: The aim of this paper is to describe the characteristics of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas in young patients. METHODS: We evaluated 1693 patients from the Pancreatic Surgery Consortium who underwent resection for IPMN and classified them as younger or older than 50 years of age at the time of surgery. We assessed the relationship of age with clinical, radiological, pathological, and prognostic features. RESULTS: We identified 90 (5%) young patients. Age was not associated with differences in main pancreatic duct size (P = 0.323), presence of solid components (P = 0.805), or cyst size (P = 0.135). IPMNs from young patients were less likely to be of gastric type (37 vs. 57%, P = 0.005), and more likely to be of oncocytic (15 vs. 4%, P = 0.003) and intestinal types (44 vs. 26%, P = 0.004). Invasive carcinomas arising from IPMN were less common in young patients (17 vs. 27%, P = 0.044), and when present they were commonly of colloid type (47 vs. 31% in older patients, P = 0.261) and had better overall survival than older patients (5-year, 71 vs. 37%, log-rank P = 0.031). CONCLUSION: Resection for IPMN is infrequent in young patients, but when they are resected, IPMNs from young patients demonstrate different epithelial subtypes from those in older patients and more favorable prognosis.

10 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.

11 Article Development and Validation of a Multi-institutional Preoperative Nomogram for Predicting Grade of Dysplasia in Intraductal Papillary Mucinous Neoplasms (IPMNs) of the Pancreas: A Report from The Pancreatic Surgery Consortium. 2018

Attiyeh, Marc A / Fernández-Del Castillo, Carlos / Al Efishat, Mohammad / Eaton, Anne A / Gönen, Mithat / Batts, Ruqayyah / Pergolini, Ilaria / Rezaee, Neda / Lillemoe, Keith D / Ferrone, Cristina R / Mino-Kenudson, Mari / Weiss, Matthew J / Cameron, John L / Hruban, Ralph H / D'Angelica, Michael I / DeMatteo, Ronald P / Kingham, T Peter / Jarnagin, William R / Wolfgang, Christopher L / Allen, Peter J. ·Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY. · Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA. · Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY. · Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD. · Department of Pathology, Massachusetts General Hospital, Boston, MA. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD. ·Ann Surg · Pubmed #28079542.

ABSTRACT: OBJECTIVE: Previous nomogram models for patients undergoing resection of intraductal papillary mucinous neoplasms (IPMNs) have been relatively small single-institutional series. Our objective was to improve upon these studies by developing and independently validating a new model using a large multiinstitutional dataset. SUMMARY BACKGROUND DATA: IPMNs represent the most common radiographically identifiable precursor lesions of pancreatic cancer. They are a heterogenous group of neoplasms in which more accurate markers of high-grade dysplasia or early invasive carcinoma could help avoid unnecessary surgery in 1 case and support potentially curative intervention (resection) in another. METHODS: Prospectively maintained databases from 3 institutions were queried for patients who had undergone resection of IPMNs between 2005 and 2015. Patients were separated into main duct [main and mixed-type (MD)] and branch duct (BD) types based on preoperative imaging. Logistic regression modeling was used on a training subset to develop 2 independent nomograms (MD and BD) to predict low-risk (low- or intermediate-grade dysplasia) or high-risk (high-grade dysplasia or invasive carcinoma) disease. Model performance was then evaluated using an independent validation set. RESULTS: We identified 1028 patients who underwent resection for IPMNs [MD: n = 454 (44%), BD: n = 574 (56%)] during the 10-year study period. High-risk disease was present in 487 patients (47%). Patients with high-risk disease comprised 71% and 29% of MD and BD groups, respectively (P <0.0001). MD and BD nomograms were developed on the training set [70% of total (n = 720); MD: n = 318, BD: n = 402] and validated on the test set [30% (n = 308); MD: n = 136, BD: n = 172]. The presence of jaundice was almost exclusively associated with high-risk disease (57 of 58 patients, 98%). Cyst size >3.0 cm, solid component/mural nodule, pain symptoms, and weight loss were significantly associated with high-risk disease. C-indices were 0.82 and 0.81 on training and independent validation sets, respectively; Brier scores were 0.173 and 0.175, respectively. CONCLUSIONS: For patients with suspected IPMNs, we present an independently validated model for the prediction of high-risk disease.

12 Article Diabetes mellitus in intraductal papillary mucinous neoplasm of the pancreas is associated with high-grade dysplasia and invasive carcinoma. 2017

Morales-Oyarvide, Vicente / Mino-Kenudson, Mari / Ferrone, Cristina R / Sahani, Dushyant V / Pergolini, Ilaria / Negreros-Osuna, Adrián A / Warshaw, Andrew L / Lillemoe, Keith D / Fernández-Del Castillo, Carlos. ·Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, USA. · Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, USA. · Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, USA. · Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, USA. Electronic address: cfernandez@partners.org. ·Pancreatology · Pubmed #28890154.

ABSTRACT: BACKGROUND: While the association between Diabetes Mellitus (DM) and pancreatic ductal adenocarcinoma is well recognized, its importance in intraductal papillary mucinous neoplasm of the pancreas (IPMN) is not well-defined. We sought to examine the associations of DM with degree of dysplasia and morphological subtypes in IPMN. METHODS: In 454 patients with resected IPMN, we evaluated associations of DM with high-grade dysplasia (HGD), invasive carcinoma, precursor epithelial subtype (gastric, intestinal, oncocytic, pancreatobiliary), and histological type of invasive carcinomas (tubular, colloid, oncocytic) using logistic regression. We performed multivariate analyses adjusting for worrisome features and high-risk stigmata of malignancy in a subset of 289 patients with annotated radiological characteristics. RESULTS: The prevalence of DM in our study was 34%. DM was significantly associated with HGD (OR 2.02, 95% CI 1.02-4.01, P = 0.045) and invasive carcinoma (OR 2.05, 95% CI 1.08-3.87, P = 0.027) after adjusting for worrisome features. Compared to patients without DM, those with recent-onset DM (≤5 years before surgery) had 6.9-fold (95% CI 2.38-19.92, P < 0.001) higher risk of invasive carcinoma. DM was associated with increased likelihood of intestinal-type precursor epithelium (OR 1.63, 95% CI 1.07-2.47, P = 0.022) and colloid carcinomas (OR 2.46, 95% CI 1.01-5.99, P = 0.047) CONCLUSION: Preoperative DM was associated with significantly higher risk of HGD and invasive carcinoma in resected IPMN, and risk of invasive carcinoma was highest in patients with recent-onset DM. Patients with DM were more likely to harbor intestinal-type IPMN and colloid carcinomas. Our findings suggest that a diagnosis of DM in patients with IPMN may warrant more aggressive surveillance.

13 Article Tumor engraftment in patient-derived xenografts of pancreatic ductal adenocarcinoma is associated with adverse clinicopathological features and poor survival. 2017

Pergolini, Ilaria / Morales-Oyarvide, Vicente / Mino-Kenudson, Mari / Honselmann, Kim C / Rosenbaum, Matthew W / Nahar, Sabikun / Kem, Marina / Ferrone, Cristina R / Lillemoe, Keith D / Bardeesy, Nabeel / Ryan, David P / Thayer, Sarah P / Warshaw, Andrew L / Fernández-Del Castillo, Carlos / Liss, Andrew S. ·Department of Surgery and the Andrew L. Warshaw, MD Institute for Pancreatic Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States of America. · Department of Surgery, Universita' Politecnica delle Marche, Ancona, Italy. · Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States of America. · Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, United States of America. ·PLoS One · Pubmed #28854237.

ABSTRACT: Patient-derived xenograft (PDX) tumors are powerful tools to study cancer biology. However, the ability of PDX tumors to model the biological and histological diversity of pancreatic ductal adenocarcinoma (PDAC) is not well known. In this study, we subcutaneously implanted 133 primary and metastatic PDAC tumors into immunodeficient mice. Fifty-seven tumors were successfully engrafted and even after extensive passaging, the histology of poorly-, moderately-, and well-differentiated tumors was maintained in the PDX models. Moreover, the fibroblast and collagen contents in the stroma of patient tumors were recapitulated in the corresponding PDX models. Analysis of the clinicopathological features of patients revealed xenograft tumor engraftment was associated with lymphovascular invasion (P = 0.001) and worse recurrence-free (median, 7 vs. 16 months, log-rank P = 0.047) and overall survival (median, 13 vs. 21 months, log-rank P = 0.038). Among successful engraftments, median time of growth required for reimplantation into new mice was 151 days. Reflective of the inherent biological diversity between PDX tumors with rapid (<151 days) and slow growth, differences in their growth were maintained during extensive passaging. Rapid growth was additionally associated with lymph node metastasis (P = 0.022). The association of lymphovascular invasion and lymph node metastasis with PDX formation and rapid growth may reflect an underlying biological mechanism that allows these tumors to adapt and grow in a new environment. While the ability of PDX tumors to mimic the cellular and non-cellular features of the parental tumor stroma provides a valuable model to study the interaction of PDAC cells with the tumor microenvironment, the association of successful engraftment with adverse clinicopathological features suggests PDX models over represent more aggressive forms of this disease.

14 Article Critical role for arginase 2 in obesity-associated pancreatic cancer. 2017

Zaytouni, Tamara / Tsai, Pei-Yun / Hitchcock, Daniel S / DuBois, Cory D / Freinkman, Elizaveta / Lin, Lin / Morales-Oyarvide, Vicente / Lenehan, Patrick J / Wolpin, Brian M / Mino-Kenudson, Mari / Torres, Eduardo M / Stylopoulos, Nicholas / Clish, Clary B / Kalaany, Nada Y. ·Division of Endocrinology, Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, MA, 02115, USA. · Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA. · Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA. · Whitehead Institute for Biomedical Research, Cambridge, MA, 02142, USA. · Metabolon Inc, Research Triangle Park, Durham, NC, 27709, USA. · Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Harvard Medical School, Boston, MA, 02215, USA. · Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA. · Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, 01605, USA. · Division of Endocrinology, Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, MA, 02115, USA. Nada.Kalaany@childrens.harvard.edu. · Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA. Nada.Kalaany@childrens.harvard.edu. · Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA. Nada.Kalaany@childrens.harvard.edu. ·Nat Commun · Pubmed #28808255.

ABSTRACT: Obesity is an established risk factor for pancreatic ductal adenocarcinoma (PDA). Despite recent identification of metabolic alterations in this lethal malignancy, the metabolic dependencies of obesity-associated PDA remain unknown. Here we show that obesity-driven PDA exhibits accelerated growth and a striking transcriptional enrichment for pathways regulating nitrogen metabolism. We find that the mitochondrial form of arginase (ARG2), which hydrolyzes arginine into ornithine and urea, is induced upon obesity, and silencing or loss of ARG2 markedly suppresses PDA. In vivo infusion of

15 Article Long-term Risk of Pancreatic Malignancy in Patients With Branch Duct Intraductal Papillary Mucinous Neoplasm in a Referral Center. 2017

Pergolini, Ilaria / Sahora, Klaus / Ferrone, Cristina R / Morales-Oyarvide, Vicente / Wolpin, Brian M / Mucci, Lorelei A / Brugge, William R / Mino-Kenudson, Mari / Patino, Manuel / Sahani, Dushyant V / Warshaw, Andrew L / Lillemoe, Keith D / Fernández-Del Castillo, Carlos. ·Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Department of Surgery, Universita' Politecnica delle Marche, Ancona, Italy. · Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. · Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. · Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. · Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. · Department of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. · Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. · Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. · Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. Electronic address: cfernandez@partners.org. ·Gastroenterology · Pubmed #28739282.

ABSTRACT: BACKGROUND & AIMS: Little is known about the development of branch duct intraductal papillary mucinous neoplasms (BD-IPMNs). We evaluated long-term outcomes of a large cohort of patients with BD-IPMNs to determine risk of malignancy and define a subset of low-risk BD-IPMNs. METHODS: We performed a retrospective analysis of data from 577 patients with suspected or presumed BD-IPMN under surveillance at the Massachusetts General Hospital. Patients underwent cross-sectional imaging analysis at 3 months or later after their initial diagnosis. The diagnosis of BD-IPMN was based on the presence of unilocular or multilocular cysts of the pancreas and a non-dilated main pancreatic duct (<5 mm). We collected demographic, clinical, and pathology data. Cysts were characterized at the time of diagnosis and during the follow-up period. Follow-up duration was time between initial cyst diagnosis and date of last visit or death for patients without development of pancreatic cancer, date of surgery for patients with histologically confirmed malignancy, or date of first discovery of malignancy by imaging analysis for patients with unresectable tumors or who underwent neoadjuvant treatment before surgery. The primary outcome was risk of malignancy, with a focus on patients followed for 5 years or more, compared with that of the US population, based on standardized incidence ratio. RESULTS: Of the 577 patients studied, 479 (83%) were asymptomatic at diagnosis and 363 (63%) underwent endoscopic ultrasound at least once. The median follow-up time was 82 months (range, 6-329 months) for the entire study cohort; 363 patients (63%) underwent surveillance for more than 5 years, and 121 (21%) for more than 10 years. Malignancies (high-grade dysplasia or invasive neoplasm) developed after 5 years in 20 of 363 patients (5.5%), and invasive cancer developed in 16 of 363 patients (4.4%). The standardized incidence ratio for patients with BD-IPMNs without worrisome features of malignancy at 5 years was 18.8 (95% confidence interval, 9.7-32.8; P < .001). One hundred and eight patients had cysts ≤1.5 cm for more than 5 years of follow-up; only 1 of these patients (0.9%) developed a distinct ductal adenocarcinoma. By contrast, among the 255 patients with cysts >1.5 cm, 19 (7.5%) developed malignancy (P = .01). CONCLUSIONS: In a retrospective analysis of patients with BD-IPMNs under surveillance, their overall risk of malignancy, almost 8%, lasted for 10 years or more, supporting continued surveillance after 5 years. Cysts that remain ≤1.5 cm for more than 5 years might be considered low-risk for progression to malignancy.

16 Article Ductal Carcinoma Arising in a Largely Unchanged Presumed Branch-duct IPMN After 10 Years of Surveillance. 2017

Honselmann, Kim C / Patino, Manuel / Mino-Kenudson, Mari / Ferrone, Cristina / Warshaw, Andrew L / Castillo, Carlos Fernandez-Del / Lillemoe, Keith D. ·*Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA †Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA ‡Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA. ·Ann Surg · Pubmed #28338512.

ABSTRACT: -- No abstract --

17 Article The Prevalence and Clinicopathological Characteristics of High-Grade Pancreatic Intraepithelial Neoplasia: Autopsy Study Evaluating the Entire Pancreatic Parenchyma. 2017

Matsuda, Yoko / Furukawa, Toru / Yachida, Shinichi / Nishimura, Makoto / Seki, Atsuko / Nonaka, Keisuke / Aida, Junko / Takubo, Kaiyo / Ishiwata, Toshiyuki / Kimura, Wataru / Arai, Tomio / Mino-Kenudson, Mari. ·From the *Department of Pathology, Tokyo Metropolitan Geriatric Hospital; †Institute for Integrated Medical Sciences, Tokyo Women's Medical University; ‡Division of Cancer Genomics, National Cancer Center Research Institute; §Department of Endoscopy, Tokyo Metropolitan Geriatric Hospital; ∥Research Team for Geriatric Pathology, Tokyo Metropolitan Institute of Gerontology, Tokyo; ¶Department of Gastroenterological, General, Breast & Thyroid Surgery, Faculty of Medicine, Yamagata University, Yamagata, Japan; #Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA. ·Pancreas · Pubmed #28196020.

ABSTRACT: OBJECTIVE: We sought to identify clinicopathological characteristics of high-grade pancreatic intraepithelial neoplasia (PanIN)/carcinoma in situ to facilitate screening for pancreatic ductal adenocarcinoma. METHODS: We evaluated PanIN lesions in 173 consecutive autopsy cases with no evidence of pancreatic ductal adenocarcinoma and/or intraductal papillary mucinous neoplasm (mean age, 80.5 years) by submitting the entire pancreas for microscopic examination. RESULTS: PanIN-3 was found in 4% of examined cases, whereas PanIN-1 and PanIN-2 were present in 77% and 28%, respectively. PanIN-3 was more frequently identified in patients with diabetes mellitus and/or older age. PanIN-3 lesions were always multifocal, and the number of PanIN-3 foci was positively associated with those of PanIN-1 or PanIN-2. PanIN-3 was located more frequently in the pancreatic body and tail than in the head and predominantly involved small interlobular/intralobular ducts rather than the main duct. Notably, 71% of pancreata with PanIN-3 showed cystic changes in PanIN-3 and lower grade PanIN lesions. PanIN-3 was also accompanied by higher grade extralobular fibrosis. CONCLUSIONS: We found that 4% of the examined pancreata harbored PanIN-3 lesions that were associated with several unique clinicopathological features. The cystic change along with fibrotic pancreatic parenchyma may be detected by imaging studies such as endoscopic ultrasound.

18 Article Genomic Characterization of Low- and High-Grade Pancreatic Mucinous Cystic Neoplasms Reveals Recurrent KRAS Alterations in "High-Risk" Lesions. 2017

Conner, James R / Mariño-Enríquez, Adrián / Mino-Kenudson, Mari / Garcia, Elizabeth / Pitman, Martha B / Sholl, Lynette M / Srivastava, Amitabh / Doyle, Leona A. ·From the *Department of Pathology, Brigham and Women's Hospital; †Harvard Medical School; and ‡Department of Pathology, Massachusetts General Hospital, Boston, MA. ·Pancreas · Pubmed #28196015.

ABSTRACT: OBJECTIVES: Pancreatic ductal adenocarcinoma arises from the following 3 distinct precursor lesions: pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasm, and mucinous cystic neoplasm (MCN). Genetic abnormalities in the first 2 precursor lesions have been well characterized, but there are limited data on progression pathways in MCNs. This study aimed to characterize genomic differences between MCNs with low-grade (LG) and high-grade (HG) dysplasia or carcinoma. METHODS: Neoplastic epithelium from surgical resections of 25 MCNs, 16 with LG dysplasia and 9 with HG dysplasia or invasive carcinoma, was analyzed by targeted massively parallel sequencing. RESULTS: KRAS mutations were most frequent, present in 9 HG (100%) and 3 LG (19%) tumors, 2 of the latter also having discrete areas of HG tumor with the same mutation. TP53 mutations and CDKN2A loss were identified in 5 HG tumors (56%) each but not in LG tumors. CONCLUSIONS: The low frequency of KRAS alterations in cysts without a HG component suggests that a subset of MCNs may have a low risk for malignant progression. Novel single-nucleotide variants that occur at a lower rate may help identify this group and provide a substrate for new diagnostic, prognostic, and therapeutic targets.

19 Article Preoperative characteristics and cytological features of 136 histologically confirmed pancreatic mucinous cystic neoplasms. 2017

Scourtas, Aristana / Dudley, Jonathan C / Brugge, William R / Kadayifci, Abdurrahman / Mino-Kenudson, Mari / Pitman, Martha B. ·Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts. · Department of Pathology, Stanford University Medical Center, Palo Alto, California. · Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts. · Division of Gastroenterology, Gaziantep University School of Medicine, Gaziantep, Turkey. ·Cancer Cytopathol · Pubmed #27926784.

ABSTRACT: BACKGROUND: Mucinous cystic neoplasms (MCNs) of the pancreas present a management conundrum. The majority are benign but all are resected due to their malignant potential. Recent studies have recommended nonsurgical management. In the current study, the authors analyzed the preoperative imaging, cytology, and cyst fluid characteristics of 136 histologically confirmed MCNs to assess predictors of a high-risk (HR) cyst for surgical triage. METHODS: MCNs resected at the Massachusetts General Hospital between 1990 and 2014 formed the study cohort. Patient demographics, cyst size, and mural nodules (MNs) by endoscopic ultrasound, cytology, and cyst fluid carcinoembryonic antigen and amylase levels were correlated with histological grade. A HR cyst was defined as high-grade dysplasia or invasive carcinoma on histology. Performance characteristics were assessed for each parameter, with a cyst size ≥3 cm or a MN on imaging and malignant cytology considered to be "true-positive" results for predicting malignancy. RESULTS: Only 15 of the 136 cysts had HR histology (11%). On average, patients with HR cysts were older than those with low-risk cysts (55 years vs 49 years, respectively). High-grade cytology was the most accurate predictor of malignancy (95%) followed by MN and cyst size together (88%) and MN alone (83%). The average carcinoembryonic antigen level (in ng/mL) increased with the grade of dysplasia but the ranges overlapped between low risk and HR cysts. CONCLUSIONS: To the authors' knowledge, the current study is the largest series to date analyzing the cytological features of histologically confirmed MCN. Cytology is insensitive but very specific for detecting a HR MCN and outperformed imaging for the detection of HR MCN. Endoscopic ultrasound-guided fine-needle aspiration and cytology should be performed on any clinically suspected MCN that is being considered for conservative management. Cancer Cytopathol 2017;125:169-177. © 2016 American Cancer Society.

20 Article Does Size Matter in Pancreatic Cancer?: Reappraisal of Tumour Dimension as a Predictor of Outcome Beyond the TNM. 2017

Marchegiani, Giovanni / Andrianello, Stefano / Malleo, Giuseppe / De Gregorio, Lucia / Scarpa, Aldo / Mino-Kenudson, Mari / Maggino, Laura / Ferrone, Cristina R / Lillemoe, Keith D / Bassi, Claudio / Castillo, Carlos Fernàndez-Del / Salvia, Roberto. ·*General and Pancreatic Surgery Department, The Pancreas Institute, University of Verona Hospital Trust, Verona, Italy †General Surgery Department, Massachusetts General Hospital - Harvard Medical School, Boston, MA ‡Department of Pathology, ARC-Net Research Centre, University of Verona Hospital Trust, Verona, Italy §Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA. ·Ann Surg · Pubmed #27322188.

ABSTRACT: OBJECTIVE: To explore the role of pancreatic ductal adenocarcinoma (PDAC) size on surgical and survival outcomes. BACKGROUND: Tumor size is a prognostic factor for the majority of solid cancers, but the role for PDAC in predicting survival is not well delineated affecting the reliability of tumor node metastasis system classification. METHODS: Between 1998 and 2012, 1507 patients with PDAC underwent resection at University of Verona Hospital and the Massachusetts General Hospital. All data were collected prospectively. Tumor size has been measured both at imaging and gross pathology. RESULTS: Among the tumors measured, 21.5% were <20 mm and 78.5% >20 mm. Larger tumors were associated with higher Ca19.9, T3-T4 and N1, higher grade, perineural invasion, R1 resections, more positive lymph nodes, and higher lymph node ratios (P < 0.05). Tumours <20 mm showed a better prognosis (33 vs 23 months; P < 0.01), but worse surgical results with higher pancreatic fistula (21.1% vs 14.6%; P < 0.01) and mortality rates (1.5% vs 0.3%; P = 0.04). PDAC size was associated with worse prognosis (hazard ratio 1.26, P = 0.02), together with Ca19.9, grading, and N1. When measured at imaging, tumor size was underestimated (median 23 vs 30 mm; P < 0.01) and did not influence prognosis CONCLUSIONS:: PDAC size >20 mm, measured at gross pathology, correlates with surgical outcomes and is an independent predictor of poor prognosis. Given that imaging underestimates size by about 20%, perhaps tumors that measure >20 mm at imaging should be considered for neoadjuvant treatment regardless of resectability.

21 Article Multi-institutional Validation Study of the American Joint Commission on Cancer (8th Edition) Changes for T and N Staging in Patients With Pancreatic Adenocarcinoma. 2017

Allen, Peter J / Kuk, Deborah / Castillo, Carlos Fernandez-Del / Basturk, Olca / Wolfgang, Christopher L / Cameron, John L / Lillemoe, Keith D / Ferrone, Cristina R / Morales-Oyarvide, Vicente / He, Jin / Weiss, Matthew J / Hruban, Ralph H / Gönen, Mithat / Klimstra, David S / Mino-Kenudson, Mari. ·*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 Surgery, Massachusetts General Hospital, Boston, MA §Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY ¶Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD ||Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD **Department of Pathology, Massachusetts General Hospital, Boston, MA. ·Ann Surg · Pubmed #27163957.

ABSTRACT: OBJECTIVE: The aim of this study was to evaluate and validate the proposed 8th edition American Joint Committee on Cancer (AJCC) system for T and N staging of pancreatic adenocarcinoma. SUMMARY OF BACKGROUND DATA: Investigators have questioned the clinical relevance and reproducibility of previous AJCC staging for pancreatic adenocarcinoma. METHODS: Prospective databases at Memorial Sloan Kettering (MSK), Massachusetts General Hospital (MGH), and Johns Hopkins Hospital (JHH) were queried for patients who had undergone resection for pancreatic adenocarcinoma. Patients who underwent a margin-negative (R0) resection, and who had previously undergone pathologic review, were included. Patients were staged according to 7th edition AJCC criteria, as well as the proposed 8th edition system that includes different definitions of tumor size (T) and nodal status (N). The dataset was randomly split into training and test sets. RESULTS: Two thousand three hundred eighteen patients were identified who met inclusion criteria. Recursive partitioning on the training set (n = 1551) identified statistically appropriate cutoffs for tumor size (<2.2 cm, ≥4.8 cm,) and nodal status (no positive nodes, 1 to 3 positive nodes, ≥4 positive nodes) that supported the proposed 8th edition changes. Median survival in patients staged as T3, N0 by the 7th edition definitions was different between institutions (median Center 1, 24 mo; Center 2, 37 mo; Center 3, 29 mo; P = 0.054). This difference was not observed when patients were staged as T3, N0 by 8th edition criteria. Stage, and stage-specific outcome (7th edition), on the test set revealed a predominance of patients (68%) within the IIB subgroup, and a concordance probability estimate (CPE) of 0.57 for stage-specific survival. When assessed with 8th edition criteria, no stage subgroup had a majority of patients, and the CPE was 0.58. CONCLUSIONS: The proposed 8th edition changes for T and N classification were statistically valid and may allow a more reproducible system of T staging. This system also stratifies patients more evenly across stages without sacrificing prognostic accuracy.

22 Article Loss of Trefoil Factor 2 From Pancreatic Duct Glands Promotes Formation of Intraductal Papillary Mucinous Neoplasms in Mice. 2016

Yamaguchi, Junpei / Mino-Kenudson, Mari / Liss, Andrew S / Chowdhury, Sanjib / Wang, Timothy C / Fernández-Del Castillo, Carlos / Lillemoe, Keith D / Warshaw, Andrew L / Thayer, Sarah P. ·Department of Surgery, Andrew L. Warshaw Institute for Pancreatic Cancer Research, Massachusetts General Hospital, Boston, Massachusetts. · Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts. · Division of Surgical Oncology and the Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska. · Division of Digestive and Liver Diseases and Irving Cancer Research Center, Columbia University Medical Center, New York, New York. · Department of Surgery, Andrew L. Warshaw Institute for Pancreatic Cancer Research, Massachusetts General Hospital, Boston, Massachusetts; Division of Surgical Oncology and the Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska. Electronic address: sarah.thayer@unmc.edu. ·Gastroenterology · Pubmed #27523981.

ABSTRACT: BACKGROUND & AIMS: Little is known about the origin of pancreatic intraductal papillary mucinous neoplasms (IPMN). Pancreatic duct glands (PDGs) are gland-like outpouches budding off the main pancreatic ducts that function as a progenitor niche for the ductal epithelium; they express gastric mucins and have characteristics of side-branch IPMNs. We investigated whether PDGs are a precursor compartment for IPMNs and the role of Trefoil factor family 2 (TFF2)-a protein expressed by PDGs and the gastric mucosa that are involved in epithelial repair and tumor suppression. METHODS: We obtained pancreatectomy specimens from 20 patients with chronic pancreatitis, 13 with low-grade side-branch IPMNs, and 15 patients with PDAC; histologically normal pancreata were used as controls (n = 18). Samples were analyzed by immunohistochemistry to detect TFF1 and TFF2 and cell proliferation. We performed mitochondrial DNA mutational mapping studies to determine the cell lineage and fate of PDG cells. Pdx1-Cre;LSL-KRAS RESULTS: Histologic analysis of human samples revealed gastric-type IPMN to comprise 2 molecularly distinct layers: a basal crypt segment that expressed TFF2 and overlying papillary projections. Proliferation occurred predominantly in the PDG-containing basal segments. Mitochondrial mutation mapping revealed a 97% match between the profiles of proliferating PDG cells and their overlying nonproliferative IPMN cells. In contrast to KC mice, 2-month-old KC/Tff2 CONCLUSIONS: In histologic analyses of human IPMNs, we found PDGs to form the basal segment and possibly serve as a progenitor compartment. TFF2 has tumor-suppressor activity in the mouse pancreas and prevents formation of mucinous neoplasms.

23 Article Solid pseudopapillary tumors of the pancreas: Specific pathological features predict the likelihood of postoperative recurrence. 2016

Marchegiani, Giovanni / Andrianello, Stefano / Massignani, Marta / Malleo, Giuseppe / Maggino, Laura / Paiella, Salvatore / Ferrone, Cristina R / Luchini, Claudio / Scarpa, Aldo / Capelli, Paola / Mino-Kenudson, Mari / Lillemoe, Keith D / Bassi, Claudio / Castillo, Carlos Fernàndez-Del / Salvia, Roberto. ·Department of General and Pancreatic Surgery, The Pancreas Institute-University of Verona Hospital Trust, Verona, Italy. · Department of General Surgery, Massachusetts General Hospital-Harvard Medical School, Boston, Massachusetts. · Department of Diagnostic and Public Health, ARC-Net Research Centre-University of Verona Hospital Trust, Verona, Italy. · Department of Pathology, Massachusetts General Hospital-Harvard Medical School, Boston, Massachusetts. · Department of General and Pancreatic Surgery, The Pancreas Institute-University of Verona Hospital Trust, Verona, Italy. roberto.salvia@univr.it. ·J Surg Oncol · Pubmed #27471041.

ABSTRACT: BACKGROUND: Since their introduction in the WHO classification, the incidence of solid pseudopapillary tumors (SPTs) of the pancreas has progressively increased, mainly because of the widespread use of cross-sectional imaging. Few recent studies have analyzed the biological behavior of SPTs, but reliable data on long-term follow-up are needed. METHODS: Retrospective analysis of two Institutions with high caseload, The Department of General Surgery-Pancreas Institute, University of Verona Hospital Trust and the Department of General Surgery, Massachusetts General Hospital, Harvard Medical School, was carried out. Data from 131 consecutive resections for SPT performed during the last three decades were collected and analyzed. RESULTS: The majority of patients were female (86.3%) with a median age of 33 (7-68) years. The prevalent location was the pancreatic tail (33.5%). Applying the WHO criteria, 16 (12.2%) SPTs were considered malignant due to the presence of at least pancreatic parenchyma (9.9%), perineural (4.6%), and/or angiovascular invasion (2.3%). After a median of 62 months after surgery, only two patients had a recurrence (1.5%). Both of them fulfilled the WHO criteria for malignant SPT (vs. 10.7% of those who did not recur, P = 0.01), had an infiltrative growth pattern (vs. 10.8%, P = 0.01), pancreatic parenchyma invasion (vs. 9.7%, P = 0.01) and capsular invasion (vs. 4.9%, P = 0.004). CONCLUSION: Overall, SPTs are associated with excellent survival results after surgical resection. Disease recurrence is extremely rare, and might occur if the primary tumor presents with either pancreatic parenchyma or capsule invasion. J. Surg. Oncol. 2016;114:597-601. © 2016 Wiley Periodicals, Inc.

24 Article Phosphatase PPM1A is a novel prognostic marker in pancreatic ductal adenocarcinoma. 2016

Fan, Jie / Yang, Michelle X / Ouyang, Qi / Fu, Deliang / Xu, Zude / Liu, Xiuping / Mino-Kenudson, Mari / Geng, Jiang / Tang, Feng. ·Department of Pathology, Huashan Hospital, Fudan University, Shanghai 200040, China. · Department of Pathology, University of Vermont Medical Center, Burlington, VT 05401. · Department of Pathology, Huadong Hospital; Fudan University, Shanghai 200040, China. · Department of Pancreatic Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China. · Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China. · Department of Pathology, Massachusetts General Hospital, Boston, MA 02114. · Department of Urology, Shanghai 10th People's Hospital, Tongji University, Shanghai 200072, China. Electronic address: gengjiangsn@sina.com. · Department of Pathology, Huashan Hospital, Fudan University, Shanghai 200040, China. Electronic address: tangfeng1996@sina.com. ·Hum Pathol · Pubmed #27195906.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) harbors complex molecular alterations and remains a lethal disease. Aberrant TGF-β/Smads signaling is a well-known mechanism involved in the progression of PDACs. However, loss of Smad4 expression is reported in only ~50% of PDACs and is generally associated with worse prognosis. Investigating additional prognostic markers is warranted. PPM1A is a phosphatase that dephosphorylates TGF-β-activated Smad2/3 and inactivates the TGF-β signaling. Little is known about the clinical significance of PPM1A in PDACs and its functional relationship to Smad4. In this study, PPM1A and Smad4 immunohistochemistry was assessed in 180 R0 resected human PDACs. PPM1A was lost in 41.7% cases, whereas Smad4 was lost in 45.7% cases. The median survival rate with negative and positive PPM1A was 10.9 and 16.8 months, respectively. Loss of PPM1A was significantly associated with larger tumor size and higher stage and was an independent predictor of unfavorable outcomes. Intriguingly, the overall survival of this cohort was divided into 3 groups based on the expression pattern of PPM1A and Smad4, with the Smad4+/PPM1A+ pattern associated with favorable survival, the Smad4+/PPM1A- or Smad4-/PPM1A- pattern associated with unfavorable, and the PPM1A+/Smad4- pattern fell between these 2 groups. In 82 cases with negative Smad4, PPM1A or P-Smad2/3 expression was retained. Using a SMAD4-deficient human PDAC cell line, BxPC3, we further demonstrated that TGF-β1 treatment induced PPM1A and P-Smad2/3 expression in this cell line. PPM1A and Smad4 immunohistochemistry in surgical specimens may provide more accurate prognostic stratification for patients with PDAC.

25 Article Regulation of GLI Underlies a Role for BET Bromodomains in Pancreatic Cancer Growth and the Tumor Microenvironment. 2016

Huang, Yinshi / Nahar, Sabikun / Nakagawa, Akifumi / Fernandez-Barrena, Maite G / Mertz, Jennifer A / Bryant, Barbara M / Adams, Curtis E / Mino-Kenudson, Mari / Von Alt, Kate N / Chang, Kevin / Conery, Andrew R / Hatton, Charlie / Sims, Robert J / Fernandez-Zapico, Martin E / Wang, Xingpeng / Lillemoe, Keith D / Fernández-Del Castillo, Carlos / Warshaw, Andrew L / Thayer, Sarah P / Liss, Andrew S. ·Departments of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, P.R. China. Department of Surgery and the Andrew L. Warshaw, MD, Institute for Pancreatic Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. · Department of Surgery and the Andrew L. Warshaw, MD, Institute for Pancreatic Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. · Division of Oncology Research, Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, Minnesota. · Constellation Pharmaceuticals, Cambridge, Massachusetts. · Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. · Departments of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, P.R. China. Departments of Gastroenterology, Shanghai First People's Hospital, Shanghai Jiatong University School of Medicine, Shanghai, P.R. China. · Department of Surgery and the Andrew L. Warshaw, MD, Institute for Pancreatic Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. aliss@mgh.harvard.edu sarah.thayer@unmc.edu. ·Clin Cancer Res · Pubmed #27169995.

ABSTRACT: PURPOSE: The initiation, progression, and maintenance of pancreatic ductal adenocarcinoma (PDAC) results from the interplay of genetic and epigenetic events. While the genetic alterations of PDAC have been well characterized, epigenetic pathways regulating PDAC remain, for the most part, elusive. The goal of this study was to identify novel epigenetic regulators contributing to the biology of PDAC. EXPERIMENTAL DESIGN: In vivo pooled shRNA screens targeting 118 epigenetic proteins were performed in two orthotopic PDAC xenograft models. Candidate genes were characterized in 19 human PDAC cell lines, heterotopic xenograft tumor models, and a genetically engineered mouse (GEM) model of PDAC. Gene expression, IHC, and immunoprecipitation experiments were performed to analyze the pathways by which candidate genes contribute to PDAC. RESULTS: In vivo shRNA screens identified BRD2 and BRD3, members of the BET family of chromatin adaptors, as key regulators of PDAC tumor growth. Pharmacologic inhibition of BET bromodomains enhanced survival in a PDAC GEM model and inhibited growth of human-derived xenograft tumors. BET proteins contribute to PDAC cell growth through direct interaction with members of the GLI family of transcription factors and modulating their activity. Within cancer cells, BET bromodomain inhibition results in downregulation of SHH, a key mediator of the tumor microenvironment and canonical activator of GLI. Consistent with this, inhibition of BET bromodomains decreases cancer-associated fibroblast content of tumors in both GEM and xenograft tumor models. CONCLUSIONS: Therapeutic inhibition of BET proteins offers a novel mechanism to target both the neoplastic and stromal components of PDAC. Clin Cancer Res; 22(16); 4259-70. ©2016 AACR.

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