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Pancreatic Neoplasms: HELP
Articles by Vikram Deshpande
Based on 43 articles published since 2010
(Why 43 articles?)
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Between 2010 and 2020, V. Deshpande wrote the following 43 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Review Tumefactive Inflammatory Diseases of the Pancreas. 2019

Zen, Yoh / Deshpande, Vikram. ·Department of Diagnostic Pathology, Kobe University, Kobe, Japan. · The James Homer Wright Pathology Laboratories, Massachusetts General Hospital, Boston, Massachusetts. Electronic address: vdeshpande@mgh.harvard.edu. ·Am J Pathol · Pubmed #30558726.

ABSTRACT: Advances in the past two decades have resulted in the recognition of several tumefactive pancreatic lesions that, on histologic evaluation, show a varying combination of inflammation and fibrosis. Autoimmune pancreatitis, the prototypic tumefactive pancreatic fibroinflammatory lesion, is composed of two distinct diseases, type 1 autoimmune pancreatitis and the less common type 2 autoimmune pancreatitis. Although designated as autoimmune pancreatitis, the two diseases show little morphologic or pathogenic overlap. In type 1 disease, subsets of T lymphocytes (type 2 helper T cells, regulatory T cells, and T follicular helper 2 cells) are hypothesized to drive the inflammatory reaction. The B-cell response is characterized by an oligoclonal expansion of plasmablasts, with dominant clones that vary among patients and distinct clones that emerge at the time of relapse. Although the precise role of IgG4 in this condition remains uncertain, recent studies suggest that other IgG subclasses (eg, IgG1) may mediate the immune reactions, whereas IgG4 represents a response to dampen excessive inflammation. A recent study of type 2 autoimmune pancreatitis highlights the role of CXCL8 (alias IL-8), with duct epithelium and infiltrating T lymphocytes expressing this chemokine; the latter may contribute to the distinct form of neutrophilic inflammation in this disease. The review also highlights other forms of mass-forming chronic pancreatitis: follicular pancreatitis, groove pancreatitis, and those associated with rheumatologic diseases.

2 Review Difficult Diagnostic Problems in Pancreatobiliary Neoplasia. 2015

Bledsoe, Jacob R / Shinagare, Shweta A / Deshpande, Vikram. ·From the Department of Pathology, Massachusetts General Hospital, Boston (Drs Bledsoe and Deshpande) · and the Department of Pathology and Laboratory Medicine, Tufts Medical Center, Boston (Dr Shinagare). ·Arch Pathol Lab Med · Pubmed #26125425.

ABSTRACT: CONTEXT: Many common diagnostic dilemmas are encountered in pancreatobiliary pathology, frequently resulting in uncertainty on behalf of the pathologist and referral for a second opinion. OBJECTIVES: To review 4 common diagnostic dilemmas encountered in the practice of pancreatobiliary pathology: (1) pancreatic ductal adenocarcinoma versus chronic pancreatitis; (2) pancreatic ductal carcinoma versus adenocarcinomas arising in the ampulla and intrapancreatic common bile duct; (3) the distinction of uncommon intraductal neoplasms--intraductal oncocytic papillary neoplasm, intraductal tubulopapillary neoplasm, and intraductal acinar cell carcinoma; and (4) intrahepatic cholangiocarcinoma versus metastatic carcinoma. DATA SOURCES: A review of pertinent literature, along with the authors' personal experience, based on institutional and consultation materials. CONCLUSIONS: Important diagnostic features for a few challenging problems in pancreatobiliary pathology are reviewed. Careful study of the microscopic features along with awareness of differential diagnoses and diagnostic pitfalls generally allows distinction of these entities. We also highlight established and novel ancillary studies that help to arrive at an accurate diagnosis.

3 Clinical Trial A phase 1/2 and biomarker study of preoperative short course chemoradiation with proton beam therapy and capecitabine followed by early surgery for resectable pancreatic ductal adenocarcinoma. 2014

Hong, Theodore S / Ryan, David P / Borger, Darrell R / Blaszkowsky, Lawrence S / Yeap, Beow Y / Ancukiewicz, Marek / Deshpande, Vikram / Shinagare, Shweta / Wo, Jennifer Y / Boucher, Yves / Wadlow, Raymond C / Kwak, Eunice L / Allen, Jill N / Clark, Jeffrey W / Zhu, Andrew X / Ferrone, Cristina R / Mamon, Harvey J / Adams, Judith / Winrich, Barbara / Grillo, Tarin / Jain, Rakesh K / DeLaney, Thomas F / Fernandez-del Castillo, Carlos / Duda, Dan G. ·Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. Electronic address: tshong1@partners.org. · Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. · Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. · Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. · Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. · Department of Radiation Oncology, Brigham and Women's Hospital/Dana-Farber Cancer Institute, Boston, Massachusetts. ·Int J Radiat Oncol Biol Phys · Pubmed #24867540.

ABSTRACT: PURPOSE: To evaluate the safety, efficacy and biomarkers of short-course proton beam radiation and capecitabine, followed by pancreaticoduodenectomy in a phase 1/2 study in pancreatic ductal adenocarcinoma (PDAC) patients. METHODS AND MATERIALS: Patients with radiographically resectable, biopsy-proven PDAC were treated with neoadjuvant short-course (2-week) proton-based radiation with capecitabine, followed by surgery and adjuvant gemcitabine. The primary objective was to demonstrate a rate of toxicity grade ≥ 3 of <20%. Exploratory biomarker studies were performed using surgical specimen tissues and peripheral blood. RESULTS: The phase 2 dose was established at 5 daily doses of 5 GyE. Fifty patients were enrolled, of whom 35 patients were treated in the phase 2 portion. There were no grade 4 or 5 toxicities, and only 2 of 35 patients (4.1%) experienced a grade 3 toxicity event (chest wall pain grade 1, colitis grade 1). Of 48 patients eligible for analysis, 37 underwent pancreaticoduodenectomy. Thirty of 37 (81%) had positive nodes. Locoregional failure occurred in 6 of 37 resected patients (16.2%), and distant recurrence occurred in 35 of 48 patients (72.9%). With median follow-up of 38 months, the median progression-free survival for the entire group was 10 months, and overall survival was 17 months. Biomarker studies showed significant associations between worse survival outcomes and the KRAS point mutation change from glycine to aspartic acid at position 12, stromal CXCR7 expression, and circulating biomarkers CEA, CA19-9, and HGF (all, P<.05). CONCLUSIONS: This study met the primary endpoint by showing a rate of 4.1% grade 3 toxicity for neoadjuvant short-course proton-based chemoradiation. Treatment was associated with favorable local control. In exploratory analyses, KRAS(G12D) status and high CXCR7 expression and circulating CEA, CA19-9, and HGF levels were associated with poor survival.

4 Clinical Conference Case records of the Massachusetts General Hospital. Case 33-2012. A 34-year-old woman with episodic paresthesias and altered mental status after childbirth. 2012

Pallais, J Carl / Blake, Michael A / Deshpande, Vikram. ·Department of Medicine, Massachusetts General Hospital, Boston, USA. ·N Engl J Med · Pubmed #23094726.

ABSTRACT: -- No abstract --

5 Article Enhancer signatures stratify and predict outcomes of non-functional pancreatic neuroendocrine tumors. 2019

Cejas, Paloma / Drier, Yotam / Dreijerink, Koen M A / Brosens, Lodewijk A A / Deshpande, Vikram / Epstein, Charles B / Conemans, Elfi B / Morsink, Folkert H M / Graham, Mindy K / Valk, Gerlof D / Vriens, Menno R / Castillo, Carlos Fernandez-Del / Ferrone, Cristina R / Adar, Tomer / Bowden, Michaela / Whitton, Holly J / Da Silva, Annacarolina / Font-Tello, Alba / Long, Henry W / Gaskell, Elizabeth / Shoresh, Noam / Heaphy, Christopher M / Sicinska, Ewa / Kulke, Matthew H / Chung, Daniel C / Bernstein, Bradley E / Shivdasani, Ramesh A. ·Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. · Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA. · Translational Oncology Laboratory, Hospital La Paz Institute for Health Research, Madrid, Spain. · Broad Institute of Harvard and MIT, Cambridge, MA, USA. yotam.drier@mail.huji.ac.il. · Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. yotam.drier@mail.huji.ac.il. · Lautenberg Center for Immunology and Cancer Research, Hebrew University, Faculty of Medicine, Jerusalem, Israel. yotam.drier@mail.huji.ac.il. · Department of Endocrine Oncology, UMC Utrecht Cancer Center, Utrecht, the Netherlands. · Department of Internal Medicine, Amsterdam UMC, Amsterdam, the Netherlands. · Department of Pathology, UMC Utrecht Cancer Center, Utrecht, the Netherlands. · Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. · Broad Institute of Harvard and MIT, Cambridge, MA, USA. · Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Surgical Oncology, UMC Utrecht Cancer Center, Utrecht, the Netherlands. · Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. · Department of Gastroenterology Division, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. · Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA. · Departments of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, USA. · Broad Institute of Harvard and MIT, Cambridge, MA, USA. bernstein.bradley@mgh.harvard.edu. · Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. bernstein.bradley@mgh.harvard.edu. · Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. ramesh_shivdasani@dfci.harvard.edu. · Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA. ramesh_shivdasani@dfci.harvard.edu. · Departments of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, USA. ramesh_shivdasani@dfci.harvard.edu. ·Nat Med · Pubmed #31263286.

ABSTRACT: Most pancreatic neuroendocrine tumors (PNETs) do not produce excess hormones and are therefore considered 'non-functional'

6 Article Stromal Microenvironment Shapes the Intratumoral Architecture of Pancreatic Cancer. 2019

Ligorio, Matteo / Sil, Srinjoy / Malagon-Lopez, Jose / Nieman, Linda T / Misale, Sandra / Di Pilato, Mauro / Ebright, Richard Y / Karabacak, Murat N / Kulkarni, Anupriya S / Liu, Ann / Vincent Jordan, Nicole / Franses, Joseph W / Philipp, Julia / Kreuzer, Johannes / Desai, Niyati / Arora, Kshitij S / Rajurkar, Mihir / Horwitz, Elad / Neyaz, Azfar / Tai, Eric / Magnus, Neelima K C / Vo, Kevin D / Yashaswini, Chittampalli N / Marangoni, Francesco / Boukhali, Myriam / Fatherree, Jackson P / Damon, Leah J / Xega, Kristina / Desai, Rushil / Choz, Melissa / Bersani, Francesca / Langenbucher, Adam / Thapar, Vishal / Morris, Robert / Wellner, Ulrich F / Schilling, Oliver / Lawrence, Michael S / Liss, Andrew S / Rivera, Miguel N / Deshpande, Vikram / Benes, Cyril H / Maheswaran, Shyamala / Haber, Daniel A / Fernandez-Del-Castillo, Carlos / Ferrone, Cristina R / Haas, Wilhelm / Aryee, Martin J / Ting, David T. ·Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. · Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA. · Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA. · Division of Rheumatology, Allergy, and Immunology, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA 02114, USA. · Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Center for Engineering in Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02114, USA. · Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA. · Clinic of Surgery, UKSH Campus Lübeck, Germany. · Institute of Pathology, University Medical Center Freiburg, Germany. · Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. · Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Division of Rheumatology, Allergy, and Immunology, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA 02114, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. · Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA. Electronic address: aryee.martin@mgh.harvard.edu. · Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address: dting1@mgh.harvard.edu. ·Cell · Pubmed #31155233.

ABSTRACT: Single-cell technologies have described heterogeneity across tissues, but the spatial distribution and forces that drive single-cell phenotypes have not been well defined. Combining single-cell RNA and protein analytics in studying the role of stromal cancer-associated fibroblasts (CAFs) in modulating heterogeneity in pancreatic cancer (pancreatic ductal adenocarcinoma [PDAC]) model systems, we have identified significant single-cell population shifts toward invasive epithelial-to-mesenchymal transition (EMT) and proliferative (PRO) phenotypes linked with mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3) signaling. Using high-content digital imaging of RNA in situ hybridization in 195 PDAC tumors, we quantified these EMT and PRO subpopulations in 319,626 individual cancer cells that can be classified within the context of distinct tumor gland "units." Tumor gland typing provided an additional layer of intratumoral heterogeneity that was associated with differences in stromal abundance and clinical outcomes. This demonstrates the impact of the stroma in shaping tumor architecture by altering inherent patterns of tumor glands in human PDAC.

7 Article Predictors of Resectability and Survival in Patients With Borderline and Locally Advanced Pancreatic Cancer who Underwent Neoadjuvant Treatment With FOLFIRINOX. 2019

Michelakos, Theodoros / Pergolini, Ilaria / Castillo, Carlos Fernández-Del / Honselmann, Kim C / Cai, Lei / Deshpande, Vikram / Wo, Jennifer Y / Ryan, David P / Allen, Jill N / Blaszkowsky, Lawrence S / Clark, Jeffrey W / Murphy, Janet E / Nipp, Ryan D / Parikh, Aparna / Qadan, Motaz / Warshaw, Andrew L / Hong, Theodore S / Lillemoe, Keith D / Ferrone, Cristina R. ·Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA. · Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA. · Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA. · Department of Medical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA. ·Ann Surg · Pubmed #29227344.

ABSTRACT: OBJECTIVE: The aim of this study was to determine (1) whether preoperative factors can predict resectability of borderline resectable (BR) and locally advanced (LA) pancreatic ductal adenocarcinoma (PDAC) after neoadjuvant FOLFIRINOX, (2) which patients might benefit from adjuvant therapy, and (3) survival differences between resected BR/LA patients who received neoadjuvant FOLFIRINOX and upfront resected patients. BACKGROUND: Patients with BR/LA PDAC are often treated with FOLFIRINOX to obtain a margin-negative resection, yet selection of patients for resection remains challenging. METHODS: Clinicopathologic data of PDAC patients surgically explored between 04/2011-11/2016 in a single institution were retrospectively collected. RESULTS: Following neoadjuvant FOLFIRINOX, 141 patients were surgically explored (BR: 49%, LA: 51%) and 110 (78%) were resected. Resected patients had lower preoperative CA 19-9 levels (21 vs 40 U/mL, P = 0.03) and smaller tumors on preoperative computed tomography (CT) scan (2.3 vs 3.0 cm, P = 0.03), but no predictors of resectability were identified. Median overall survival (OS) was 34.2 months from diagnosis for all FOLFIRINOX patients and 37.7 months for resected patients. Among resected patients, preoperative CA 19-9 >100 U/mL and >8 months between diagnosis and surgery predicted a shorter postoperative disease-free survival (DFS); Charlson comorbidity index >1, preoperative CA 19-9 >100 U/mL and tumor size (>3.0 cm on CT or >2.5 cm on pathology) predicted decreased OS. DFS and OS were significantly better for BR/LA PDAC patients treated with neoadjuvant FOLFIRINOX compared with upfront resected patients (DFS: 29.1 vs 13.7, P < 0.001; OS: 37.7 vs 25.1 months from diagnosis, P = 0.01). CONCLUSION: BR/LA PDAC patients with no progression on neoadjuvant FOLFIRINOX should be offered surgical exploration. Except size, traditional pathological parameters fail to predict survival among resected FOLFIRINOX patients. Resected FOLFIRINOX patients have survival that appears to be superior than that of resectable patients who go directly to surgery.

8 Article STK38L kinase ablation promotes loss of cell viability in a subset of KRAS-dependent pancreatic cancer cell lines. 2017

Grant, Trevor J / Mehta, Anita K / Gupta, Anamika / Sharif, Ahmad A D / Arora, Kshitij S / Deshpande, Vikram / Ting, David T / Bardeesy, Nabeel / Ganem, Neil J / Hergovich, Alexander / Singh, Anurag. ·Department of Pharmacology and Experimental Therapeutics, Center for Cancer Research, Boston University Graduate School of Medicine, Boston, MA, USA. · University College London, Cancer Institute, London, United Kingdom. · Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA, USA. ·Oncotarget · Pubmed #29108249.

ABSTRACT: Pancreatic ductal adenocarcinomas (PDACs) are highly aggressive malignancies, associated with poor clinical prognosis and limited therapeutic options. Oncogenic

9 Article Primary lymph node gastrinoma: A single institution experience. 2017

Chen, Yufei / Deshpande, Vikram / Ferrone, Cristina / Blaszkowsky, Lawrence S / Parangi, Sareh / Warshaw, Andrew L / Lillemoe, Keith D / Fernandez-Del Castillo, Carlos. ·Department of Surgery, Massachusetts General Hospital, Boston, MA. · Department of Pathology, Massachusetts General Hospital, Boston, MA. · Department of Hematology/Oncology, Massachusetts General Hospital, Boston, MA. · Department of Surgery, Massachusetts General Hospital, Boston, MA. Electronic address: CFERNANDEZ@mgh.harvard.edu. ·Surgery · Pubmed #28705492.

ABSTRACT: BACKGROUND: Gastrinomas are rare neuroendocrine tumors that ectopically secrete gastrin and classically originate within the duodenum or pancreas. The presence of primary lymph node gastrinoma is controversial. We report on a single institution's experience with gastrinoma, with focus on primary lymph node tumors. METHODS: Patients who underwent operative resection of gastrinoma between 1992 and 2016 at a single institution were identified. A diagnosis of primary lymph node gastrinoma was defined as tumor confined to one or more resected peripancreatic lymph nodes, negative localization for any extra-nodal disease and normal gastrin postresection. RESULTS: In the study, 39 consecutive patients underwent operative resection of gastrinoma. Mean age was 53 years and 49% were male. 93% of patients had successful preoperative localization. Furthermore, 19 patients (49%) underwent enucleation of their tumor and 14 (35.9%) a pancreatic resection. Overall 5- and 10-year survival for all patients was 80.8% and 60.7%, respectively. Primary lymph node gastrinoma was identified in 11 cases (28.2%). The presentation of primary lymph node and non-primary lymph node patients were similar. There was no significant difference in operation type, tumor size, or overall survival. At median follow-up of 59 months, patients with primary lymph node gastrinoma were less likely to have persistent or recurrent disease (9.1% vs 42.9%, P = .04). CONCLUSION: This series supports the existence of primary lymph node gastrinomas, and indicates that as many as 1 in 4 patients with gastrinoma have this form of the disease. This entity should be considered when an isolated pathologic lymph node is identified, although thorough exploration is still recommended to exclude other occult disease.

10 Article Use of Angiotensin System Inhibitors Is Associated with Immune Activation and Longer Survival in Nonmetastatic Pancreatic Ductal Adenocarcinoma. 2017

Liu, Hao / Naxerova, Kamila / Pinter, Matthias / Incio, Joao / Lee, Hang / Shigeta, Kohei / Ho, William W / Crain, Jonathan A / Jacobson, Alex / Michelakos, Theodoros / Dias-Santos, Daniella / Zanconato, Andrea / Hong, Theodore S / Clark, Jeffrey W / Murphy, Janet E / Ryan, David P / Deshpande, Vikram / Lillemoe, Keith D / Fernandez-Del Castillo, Carlos / Downes, Michael / Evans, Ronald M / Michaelson, James / Ferrone, Cristina R / Boucher, Yves / Jain, Rakesh K. ·Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. · Leder Human Biology and Translational Medicine, Biology and Biomedical Sciences, Harvard Medical School, Boston, Massachusetts. · Biostatistics Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. · Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts. · Laboratory for Quantitative Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. · Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. · Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. · Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. · Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. · Gene Expression Laboratory, Salk Institute for Biological Studies in La Jolla, La Jolla, California. · Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. yves@steele.mgh.harvard.edu jain@steele.mgh.harvard.edu. ·Clin Cancer Res · Pubmed #28600474.

ABSTRACT:

11 Article Gastric foveolar dysplasia: a survey of reporting habits and diagnostic criteria. 2017

Serra, Stefano / Ali, Rola / Bateman, Adrian C / Dasgupta, Kaushik / Deshpande, Vikram / Driman, David K / Gibbons, David / Grin, Andrea / Hafezi-Bakhtiari, Sara / Sheahan, Kieran / Srivastava, Amitabh / Szentgyorgyi, Eva / Vajpeyi, Rajkumar / Walsh, Shaun / Wang, Lai Mun / Chetty, Runjan. ·Department of Pathology, University Health Network/University of Toronto, Canada. Electronic address: Stefano.serra@uhn.ca. · Department of Pathology, Kuwait University, Kuwait. · Department of Cellular Pathology, University Hospital Southampton NHS Foundation Trust, Southampton, UK. · Department of Pathology, University Hospital of North Tees, UK. · Massachusetts General Hospital, Boston, USA. · Department of Pathology, London Health Sciences Centre/Western University, Canada. · Department of Pathology, St Luke's Hospital, Dublin, Ireland. · Department of Pathology, St Michael's Hospital, Toronto, Canada. · Department of Pathology, University Health Network/University of Toronto, Canada. · Department of Pathology, St Vincent's University Hospital, Dublin, Ireland. · Brigham and Women's Hospital, Boston, USA. · Department of Pathology, Ninewells Hospital, Dundee, UK. · Department of Pathology, Oxford University Hospitals Trust, Oxford, UK. ·Pathology · Pubmed #28438394.

ABSTRACT: This study aimed to ascertain views, incidence of reporting and diagnostic criteria for gastric foveolar dysplasia. A questionnaire, a post-questionnaire discussion and microscopic assessment of selected cases was conducted by gastrointestinal pathologists to explore the above-stated aims. Fifty-four percent of respondents never or rarely diagnosed gastric foveolar-type dysplasia. The general consensus was that round nuclei, lack of nuclear stratification, presence of inflammation/damage and surface maturation favoured reactive change; while architectural abnormalities/complexity and nuclear enlargement mainly were used to separate low-grade from high-grade foveolar dysplasia. Immunohistochemistry was rarely used to make the diagnosis of dysplasia and was thought not to be of help in routine practice. Inter-observer agreement in grading of dysplasia versus reactive, and the type of dysplasia (foveolar versus adenomatous), was substantial/almost perfect amongst 35.7% and 21.4% of participants, respectively. This reflects low reproducibility in making these diagnoses. In conclusion, foveolar dysplasia was a rarely made diagnosis among 14 gastrointestinal pathologists, there are no uniform criteria for diagnosis and there is poor inter-observer agreement in separating low-grade foveolar dysplasia from reactive gastric mucosa and low-grade adenomatous dysplasia. Greater awareness and agreed criteria will prevent misdiagnosis of low-grade foveolar dysplasia as reactive, and vice versa.

12 Article Expression status of folate receptor alpha is a predictor of survival in pancreatic ductal adenocarcinoma. 2017

Cai, Lei / Michelakos, Theodoros / Ferrone, Cristina R / Zhang, Liyuan / Deshpande, Vikram / Shen, Qi / DeLeo, Albert / Yamada, Teppei / Zhang, Gong / Ferrone, Soldano / Wang, Xinhui. ·Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. · Department of Hepatobiliary, Southwest Hospital, Third Military Medical University, Chongqing, China. · Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. · University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, USA. · Department of Orthopaedic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. ·Oncotarget · Pubmed #28430580.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) has one of the poorest prognosis among malignancies. Thus, the identification of markers useful in developing innovative diagnostic and therapeutic methods is an imperative need. Folate receptor alpha (FRα) has been associated with prognosis in several cancers and has served as a target of novel anti-tumor therapies. However, FRα expression in PDAC and its correlation with the clinical course of the disease has not been thoroughly investigated. In this study, we analyzed FRα expression in 140 PDAC specimens and 7 PDAC cell lines in order to define the significance of FRα expression in PDAC and its potential role as a target for immunotherapy. Immunohistochemical analysis demonstrated that FRα expression intensity was low, intermediate and high in 22(16%), 73(52%) and 45(32%) PDACs, respectively. The staining was located in both membrane and cytoplasm in most cases (123, 88%). Lower FRα expression was associated with cigarette smoking (p<0.001), alcohol consumption (p<0.001), and lymphovascular invasion (p=0.002). Additionally, lower FRα expression was associated with poor overall survival (5-year overall survival: low 13%, intermediate 31%, high 33%; p=0.006). FRα expression (HR=0.61; p=0.03) and Charlson Comorbidity Index (HR=1.16; p=0.01) emerged as independent predictors of survival. The analysis by flow cytometry of 7 PDAC cell lines (AsPC-1, Capan-2, MIA PaCa-2, PANC-1, PDAC2, PDAC3, and PDAC5) demonstrated the highest expression of FRα on the PDAC3 cell line (45%). Therefore, a higher FRα expression is predictive of a favorable prognosis in PDAC and FRα may represent a promising target for novel treatments, including immunotherapy.

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

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

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

14 Article Expression of Markers of Hepatocellular Differentiation in Pancreatic Acinar Cell Neoplasms:  A Potential Diagnostic Pitfall. 2016

Askan, Gokce / Deshpande, Vikram / Klimstra, David S / Adsay, Volkan / Sigel, Carlie / Shia, Jinru / Basturk, Olca. ·From the Memorial Sloan Kettering Cancer Center, New York, NY. · Massachusetts General Hospital, Boston. · Emory University, Atlanta, GA. · From the Memorial Sloan Kettering Cancer Center, New York, NY basturko@mskcc.org. ·Am J Clin Pathol · Pubmed #27425386.

ABSTRACT: OBJECTIVES: Pancreatic acinar cell carcinoma (ACC) is a rare tumor that frequently metastasizes to the liver and may present a diagnostic challenge due to its morphologic similarity to hepatocellular carcinoma. We investigated α-fetoprotein (AFP), hepatocyte paraffin antigen 1 (HepPar 1), glypican 3, arginase 1, and albumin messenger RNA (mRNA) in situ hybridization (ISH) in pancreatic neoplasms with ACC differentiation to assess their diagnostic value. METHODS: AFP, HepPar 1, glypican 3, and arginase 1 immunohistochemical staining was performed on 28 ACCs using a tissue microarray. Albumin mRNA ISH was performed on full-faced sections. RESULTS: Fifteen tumors were positive for at least one marker. Glypican 3 was positive in seven of 28, AFP in five 28, and albumin mRNA ISH in five of 20. None expressed arginase 1. CONCLUSIONS: Hepatocellular differentiation markers, including albumin mRNA ISH, may be positive in ACC, but arginase 1 appears to be uniformly negative. Thus, its use may improve the accuracy in distinguishing these neoplasms from hepatocellular carcinoma. If ACC diagnosis is considered, acinar differentiation can be reliably demonstrated by trypsin/chymotrypsin.

15 Article SIRT6 Suppresses Pancreatic Cancer through Control of Lin28b. 2016

Kugel, Sita / Sebastián, Carlos / Fitamant, Julien / Ross, Kenneth N / Saha, Supriya K / Jain, Esha / Gladden, Adrianne / Arora, Kshitij S / Kato, Yasutaka / Rivera, Miguel N / Ramaswamy, Sridhar / Sadreyev, Ruslan I / Goren, Alon / Deshpande, Vikram / Bardeesy, Nabeel / Mostoslavsky, Raul. ·The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; The MGH Center for Regenerative Medicine, Harvard Medical School, Boston, MA 02114, USA. · The MGH Center for Regenerative Medicine, Harvard Medical School, Boston, MA 02114, USA. · Broad Technology Labs (BTL), The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. · The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA. · Department of Molecular Biology, The Massachusetts General Hospital, Boston, MA 02114, USA; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. · The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; The MGH Center for Regenerative Medicine, Harvard Medical School, Boston, MA 02114, USA; The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address: rmostoslavsky@mgh.harvard.edu. ·Cell · Pubmed #27180906.

ABSTRACT: Chromatin remodeling proteins are frequently dysregulated in human cancer, yet little is known about how they control tumorigenesis. Here, we uncover an epigenetic program mediated by the NAD(+)-dependent histone deacetylase Sirtuin 6 (SIRT6) that is critical for suppression of pancreatic ductal adenocarcinoma (PDAC), one of the most lethal malignancies. SIRT6 inactivation accelerates PDAC progression and metastasis via upregulation of Lin28b, a negative regulator of the let-7 microRNA. SIRT6 loss results in histone hyperacetylation at the Lin28b promoter, Myc recruitment, and pronounced induction of Lin28b and downstream let-7 target genes, HMGA2, IGF2BP1, and IGF2BP3. This epigenetic program defines a distinct subset with a poor prognosis, representing 30%-40% of human PDAC, characterized by reduced SIRT6 expression and an exquisite dependence on Lin28b for tumor growth. Thus, we identify SIRT6 as an important PDAC tumor suppressor and uncover the Lin28b pathway as a potential therapeutic target in a molecularly defined PDAC subset. PAPERCLIP.

16 Article A tunable delivery platform to provide local chemotherapy for pancreatic ductal adenocarcinoma. 2016

Indolfi, Laura / Ligorio, Matteo / Ting, David T / Xega, Kristina / Tzafriri, Abraham R / Bersani, Francesca / Aceto, Nicola / Thapar, Vishal / Fuchs, Bryan C / Deshpande, Vikram / Baker, Aaron B / Ferrone, Cristina R / Haber, Daniel A / Langer, Robert / Clark, Jeffrey W / Edelman, Elazer R. ·Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA; Departments of Surgery, Medicine, and Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: lindolfi@mit.edu. · Departments of Surgery, Medicine, and Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Department of Health Sciences, University of Genoa, Genoa, Italy. · Departments of Surgery, Medicine, and Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: dting1@mgh.harvard.edu. · Departments of Surgery, Medicine, and Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. · CBSET Inc., Department of Applied Sciences, Lexington, MA, USA. · Department of Biomedical Engineering, University of Texas at Austin, Austin, TX, USA. · Departments of Surgery, Medicine, and Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA. · Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA; The David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. · Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA; Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. ·Biomaterials · Pubmed #27082874.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is one of the most devastating and painful cancers. It is often highly resistant to therapy owing to inherent chemoresistance and the desmoplastic response that creates a barrier of fibrous tissue preventing transport of chemotherapeutics into the tumor. The growth of the tumor in pancreatic cancer often leads to invasion of other organs and partial or complete biliary obstruction, inducing intense pain for patients and necessitating tumor resection or repeated stenting. Here, we have developed a delivery device to provide enhanced palliative therapy for pancreatic cancer patients by providing high concentrations of chemotherapeutic compounds locally at the tumor site. This treatment could reduce the need for repeated procedures in advanced PDAC patients to debulk the tumor mass or stent the obstructed bile duct. To facilitate clinical translation, we created the device out of currently approved materials and drugs. We engineered an implantable poly(lactic-co-glycolic)-based biodegradable device that is able to linearly release high doses of chemotherapeutic drugs for up to 60 days. We created five patient-derived PDAC cell lines and tested their sensitivity to approved chemotherapeutic compounds. These in vitro experiments showed that paclitaxel was the most effective single agent across all cell lines. We compared the efficacy of systemic and local paclitaxel therapy on the patient-derived cell lines in an orthotopic xenograft model in mice (PDX). In this model, we found up to a 12-fold increase in suppression of tumor growth by local therapy in comparison to systemic administration and reduce retention into off-target organs. Herein, we highlight the efficacy of a local therapeutic approach to overcome PDAC chemoresistance and reduce the need for repeated interventions and biliary obstruction by preventing local tumor growth. Our results underscore the urgent need for an implantable drug-eluting platform to deliver cytotoxic agents directly within the tumor mass as a novel therapeutic strategy for patients with pancreatic cancer.

17 Article Phosphorylated Histone H3 (PHH3) Is a Superior Proliferation Marker for Prognosis of Pancreatic Neuroendocrine Tumors. 2016

Villani, Vincenzo / Mahadevan, Krishnan K / Ligorio, Matteo / Fernández-Del Castillo, Carlos / Ting, David T / Sabbatino, Francesco / Zhang, Irene / Vangel, Mark / Ferrone, Soldano / Warshaw, Andrew L / Lillemoe, Keith D / Wargo, Jennifer / Deshpande, Vikram / Ferrone, Cristina R. ·Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. · Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. · Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. · Department of Medicine and Surgery, University of Salerno, Salerno, Italy. · Doctor of Medicine Program, Harvard Medical School, Boston, MA, USA. · Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. · Department of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. cferrone@mgh.harvard.edu. ·Ann Surg Oncol · Pubmed #27020585.

ABSTRACT: BACKGROUND: The staging of pancreatic neuroendocrine tumors (PNETs) is continuously evolving. Mitotic count, as measured by hematoxylin and eosin (H&E) or Ki67 labeling index (Ki67LI), is the best predictor of disease biology. However, both of these methods have several limitations. Phosphorylated histone H3 (PHH3), a novel mitotic marker, is potentially more accurate and easier to evaluate. This study aimed to evaluate the prognostic impact of PHH3 on patients with PNETs. METHODS: Clinicopathologic data and paraffin-embedded tissue were evaluated for 100 of the 247 PNET patients whose tumors were resected between 1998 and 2010. Mitotic counts were analyzed on H&E-, Ki67-, and PHH3-stained slides by two independent pathologists. Kaplan-Meier curves, log-rank tests, Cox regression models, and time-dependent receiver operative characteristics (ROC) curves were used to evaluate the prognostic power of these markers. An internal data cross-validation was performed to select the best cutoff. RESULTS: Of the 100 PNET patients resected, 53 were men. The median age of the patients was 59 years (range 19-96 years). The median follow-up period was 68 months (range 3-186 months). The median time for evaluation of an H&E- or PHH3-stained slide was 3 min, relative to 15 min for Ki67. The findings showed H&E, Ki67, and PHH3 all to be excellent predictors of disease-specific survival (DSS). However, PHH3 was superior to H&E and Ki67 in predicting both disease-free survival (DFS) (p = 0.006) and DSS (p = 0.001). Evaluation of the PHH3 mitotic count showed 7 mitoses per 10 high-power fields (HPFs) to be the optimal cutoff for differentiating between low- and high-risk PNET patients. CONCLUSIONS: PHH3 is a better predictor of both DFS and DSS than H&E or Ki67 in PNET. In addition, PHH3 appears to be both easier to interpret and more accurate when compared to current prognostic markers.

18 Article Intra-pancreatic Distal Bile Duct Carcinoma is Morphologically, Genetically, and Clinically Distinct from Pancreatic Ductal Adenocarcinoma. 2016

Deshpande, Vikram / Konstantinidis, Ioannis T / Castillo, Carlos Fernandez-Del / Hezel, Aram F / Haigis, Kevin M / Ting, David T / Bardeesy, Nabeel / Goyal, Lipika / Zhu, Andrew X / Warshaw, Andrew L / Lillemoe, Keith D / Ferrone, Cristina R. ·Department of Pathology, Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114, USA. vdeshpande@mgh.harvard.edu. · Department of Surgery, Massachusetts General Hospital, Boston, MA, USA. · Department of Oncology, Massachusetts General Hospital, Boston, MA, USA. · Department of Pathology, Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114, USA. ·J Gastrointest Surg · Pubmed #26956004.

ABSTRACT: PURPOSE: Differentiating intra-pancreatic distal bile duct carcinoma invading the pancreas from pancreatic ductal adenocarcinomas (PDAC) surrounding the distal common bile duct (CBD) can be challenging. Our aim is to identify clinical, morphological, and genetic features characteristic of intra-pancreatic distal bile duct carcinoma. METHODS: Clinicopathologic data of 550 patients undergoing a pancreaticoduodenectomy between September 1990 and May 2008 were reviewed. KRAS status was assessed with mass-spectrometric genotyping. RESULTS: Ninety-seven patients with intra-pancreatic adenocarcinomas surrounding the CBD were identified; slides were available for 80. Two relationships with the CBD were recognized as follows: type I (n = 42): cancer grew concentrically around the CBD and type II (n = 38): cancer grew asymmetrically around the CBD. Type I adenocarcinomas were associated with high-grade biliary dysplasia (45 vs. 13 %; p = 0.003); type II were associated with high-grade pancreatic intra-epithelial neoplasia (PanIN-2 or -3) (39 vs. 9 %; p = 0.003). Type I tumors had a better median survival (46 months) compared to type II (23 months) or other PDAC (20 months) (p < 0.001). Mutated KRAS was identified in 3/26 (11 %) type I and 20/21 (95 %) type II cancers (p < 0.001). There may be poorer survival in the presence of a KRAS mutation than wild-type KRAS (22.9 vs. 41.6 months; p = 0.3). CONCLUSIONS: Distal periductal adenocarcinomas fall into two distinct groups with biologic, morphologic and genetic differences. Those growing symmetrically around the CBD are more likely to be intra-pancreatic distal bile duct carcinomas and are associated with improved survival whereas cancers with asymmetric growth are more likely to have KRAS mutations and to be PDACs. These findings facilitate a more accurate histopathological diagnosis, which could improve patient selection for therapeutic trials.

19 Article Albumin expression distinguishes bile duct adenomas from metastatic adenocarcinoma. 2016

Moy, Andrea P / Arora, Kshitij / Deshpande, Vikram. ·Pathology Service, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. ·Histopathology · Pubmed #26841202.

ABSTRACT: AIMS: Bile duct adenomas may be difficult to distinguish from metastatic carcinomas, particularly well-differentiated pancreatic ductal adenocarcinoma. Prior studies have evaluated the utility of various immunohistochemical markers, although these markers are notable for low sensitivity and/or specificity. The aim of this study was to investigate the utility of albumin and BRAFV600E expression in distinguishing between metastatic pancreatic adenocarcinoma and bile duct adenoma. METHODS AND RESULTS: We studied 26 bile duct adenomas, three bile duct hamartomas, and 158 pancreatic ductal adenocarcinomas. Branched-chain in-situ hybridization (bISH) for albumin was performed; bISH is based on the branched DNA technology, wherein signal amplification is achieved via a series of sequential steps. Additionally, BRAFV600E immunohistochemistry (IHC) was performed on a subset of cases. Twenty-three of 25 (92%) bile duct adenomas were positive for albumin; 18 (72%) showed diffuse staining, and five showed focal staining (20%), including two challenging examples. Two bile duct hamartomas also stained positively. All pancreatic adenocarcinomas were negative for albumin. Seven of 16 (44%) bile duct adenomas and five of 106 (5%) pancreatic ductal adenocarcinomas were positive for BRAFV600E by IHC. The sensitivity and specificity of expression of albumin, as detected by bISH, for distinguishing bile duct adenomas from metastatic pancreatic adenocarcinomas were 92% and 100%, respectively; the sensitivity and specificity of BRAFV600E IHC for distinguishing bile duct adenomas from metastatic pancreatic adenocarcinomas were 43.8% and 95.3%, respectively. CONCLUSIONS: Diagnostically challenging examples of bile duct adenoma may be distinguished from metastatic pancreatic adenocarcinoma by the use of albumin bISH.

20 Article Follicular pancreatitis: a distinct form of chronic pancreatitis-an additional mimic of pancreatic neoplasms. 2016

Gupta, Rajib K / Xie, Bill H / Patton, Kurt T / Lisovsky, Mikhail / Burks, Eric / Behrman, Stephen W / Klimstra, David / Deshpande, Vikram. ·Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, TN, 38163. Electronic address: rajibgupta2011@gmail.com. · Pathology Group of Midsouth (Trumbull Laboratories), Germantown, TN, 38138; Department of Pathology, Baptist Memorial Hospital, Memphis, TN, 38120. Electronic address: hbup@yahoo.com. · Pathology Group of Midsouth (Trumbull Laboratories), Germantown, TN, 38138; Department of Pathology, Baptist Memorial Hospital, Memphis, TN, 38120. Electronic address: kurt_patton@yahoo.com. · Department of Pathology, Dartmouth-Hitchcock Medical Center and Geisel School of Medicine at Dartmouth, Lebanon, NH. Electronic address: mikhail.lisovsky@hitchcock.org. · Department of Pathology, Lahey Hospital, Burlington, MA, 01805. Electronic address: eric.burks@lahey.org. · Division of Surgical Oncology, Department of Surgery, University of Tennessee Health Science Center, Memphis, TN, 38163; Department of Surgery, Baptist Memorial Hospital, Memphis, TN, 38120. Electronic address: sbehrman@uthsc.edu. · Department of Pathology, Memorial Sloan-Kettering Cancer Center and Memorial Hospital for Cancer and Allied Diseases, New York, NY, 10065. Electronic address: klimstrd@mskcc.org. · Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114. Electronic address: Vikramdirdeshpande@gmail.com. ·Hum Pathol · Pubmed #26563969.

ABSTRACT: Follicular pancreatitis is a recently described variant of chronic pancreatitis characterized clinically by the formation of a discrete pancreatic mass and histologically by the presence of florid lymphoid aggregates with reactive germinal centers. Our aim was to study the clinical and histologic features of follicular pancreatitis, as well as to critically examine potential overlap with autoimmune pancreatitis. Immunohistochemistry for Bcl-2, CD21, κ and λ light chains as well as IgG4 and IgG were performed. We found a total of 6 patients (male-female ratio, 2:1; mean age, 57 years) who fulfilled the diagnosis of follicular pancreatitis in our institutions. Four had an incidental diagnosis, while two presented with abdominal pain, fatigue, and elevated liver enzymes. On imaging, 3 patients had a discrete solid mass, whereas 2 cases showed a dilated main pancreatic duct, mimicking an intraductal pancreatic mucinous neoplasm on imaging. One patient had a lesion in the intra-pancreatic portion of the common bile duct. On histopathology, all cases showed numerous lymphoid follicles with Bcl-2-negative germinal centers either in a periductal or in a more diffuse (periductal and intra-parenchymal) fashion, but without attendant storiform fibrosis, obliterative phlebitis, or granulocytic epithelial lesions. IgG4-to-IgG ratio was <40% in 5 cases. A comparison cohort revealed germinal centers in 25% of type 1 autoimmune pancreatitis and 2% of type 2 autoimmune pancreatitis cases, but none were periductal in location. In conclusion, follicular pancreatitis, an under-recognized mimic of pancreatic neoplasms is characterized by intrapancreatic lymphoid follicles with reactive germinal centers.

21 Article Metformin Reduces Desmoplasia in Pancreatic Cancer by Reprogramming Stellate Cells and Tumor-Associated Macrophages. 2015

Incio, Joao / Suboj, Priya / Chin, Shan M / Vardam-Kaur, Trupti / Liu, Hao / Hato, Tai / Babykutty, Suboj / Chen, Ivy / Deshpande, Vikram / Jain, Rakesh K / Fukumura, Dai. ·Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, Massachusetts, United States of America. · Department of Internal Medicine, Hospital S. Joao, Porto, Portugal. · I3S, Institute for Innovation and Research in Heath, Metabolism, Nutrition and Endocrinology group, Biochemistry Department, Faculty of Medicine, Porto University, Porto, Portugal. · Department of Botany and Biotechnology, St. Xaviers College, Thumba, Trivandrum, Kerala, India. · Program of Biology and Biomedical Sciences, Harvard Medical School, Boston, Massachusetts, United States of America. · Department of Surgery, Keio University School of Medicine, Tokyo, Japan. · Department of Zoology, Mar Ivanios College, Nalanchira, Trivandrum, Kerala, India. · School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, United States of America. · Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America. ·PLoS One · Pubmed #26641266.

ABSTRACT: BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a highly desmoplastic tumor with a dismal prognosis for most patients. Fibrosis and inflammation are hallmarks of tumor desmoplasia. We have previously demonstrated that preventing the activation of pancreatic stellate cells (PSCs) and alleviating desmoplasia are beneficial strategies in treating PDAC. Metformin is a widely used glucose-lowering drug. It is also frequently prescribed to diabetic pancreatic cancer patients and has been shown to associate with a better outcome. However, the underlying mechanisms of this benefit remain unclear. Metformin has been found to modulate the activity of stellate cells in other disease settings. In this study, we examine the effect of metformin on PSC activity, fibrosis and inflammation in PDACs. METHODS/RESULTS: In overweight, diabetic PDAC patients and pre-clinical mouse models, treatment with metformin reduced levels of tumor extracellular matrix (ECM) components, in particular hyaluronan (HA). In vitro, we found that metformin reduced TGF-ß signaling and the production of HA and collagen-I in cultured PSCs. Furthermore, we found that metformin alleviates tumor inflammation by reducing the expression of inflammatory cytokines including IL-1β as well as infiltration and M2 polarization of tumor-associated macrophages (TAMs) in vitro and in vivo. These effects on macrophages in vitro appear to be associated with a modulation of the AMPK/STAT3 pathway by metformin. Finally, we found in our preclinical models that the alleviation of desmoplasia by metformin was associated with a reduction in ECM remodeling, epithelial-to-mesenchymal transition (EMT) and ultimately systemic metastasis. CONCLUSION: Metformin alleviates the fibro-inflammatory microenvironment in obese/diabetic individuals with pancreatic cancer by reprogramming PSCs and TAMs, which correlates with reduced disease progression. Metformin should be tested/explored as part of the treatment strategy in overweight diabetic PDAC patients.

22 Article Transcriptional control of autophagy-lysosome function drives pancreatic cancer metabolism. 2015

Perera, Rushika M / Stoykova, Svetlana / Nicolay, Brandon N / Ross, Kenneth N / Fitamant, Julien / Boukhali, Myriam / Lengrand, Justine / Deshpande, Vikram / Selig, Martin K / Ferrone, Cristina R / Settleman, Jeff / Stephanopoulos, Gregory / Dyson, Nicholas J / Zoncu, Roberto / Ramaswamy, Sridhar / Haas, Wilhelm / Bardeesy, Nabeel. ·Center for Cancer Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. · Center for Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. · Department of Medicine, Harvard Medical School, Boston, Massachusetts 02114, USA. · Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. · Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. · Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. · Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, California 94720, USA. ·Nature · Pubmed #26168401.

ABSTRACT: Activation of cellular stress response pathways to maintain metabolic homeostasis is emerging as a critical growth and survival mechanism in many cancers. The pathogenesis of pancreatic ductal adenocarcinoma (PDA) requires high levels of autophagy, a conserved self-degradative process. However, the regulatory circuits that activate autophagy and reprogram PDA cell metabolism are unknown. Here we show that autophagy induction in PDA occurs as part of a broader transcriptional program that coordinates activation of lysosome biogenesis and function, and nutrient scavenging, mediated by the MiT/TFE family of transcription factors. In human PDA cells, the MiT/TFE proteins--MITF, TFE3 and TFEB--are decoupled from regulatory mechanisms that control their cytoplasmic retention. Increased nuclear import in turn drives the expression of a coherent network of genes that induce high levels of lysosomal catabolic function essential for PDA growth. Unbiased global metabolite profiling reveals that MiT/TFE-dependent autophagy-lysosome activation is specifically required to maintain intracellular amino acid pools. These results identify the MiT/TFE proteins as master regulators of metabolic reprogramming in pancreatic cancer and demonstrate that transcriptional activation of clearance pathways converging on the lysosome is a novel hallmark of aggressive malignancy.

23 Article Radiological and surgical implications of neoadjuvant treatment with FOLFIRINOX for locally advanced and borderline resectable pancreatic cancer. 2015

Ferrone, Cristina R / Marchegiani, Giovanni / Hong, Theodore S / Ryan, David P / Deshpande, Vikram / McDonnell, Erin I / Sabbatino, Francesco / Santos, Daniela Dias / Allen, Jill N / Blaszkowsky, Lawrence S / Clark, Jeffrey W / Faris, Jason E / Goyal, Lipika / Kwak, Eunice L / Murphy, Janet E / Ting, David T / Wo, Jennifer Y / Zhu, Andrew X / Warshaw, Andrew L / Lillemoe, Keith D / Fernández-del Castillo, Carlos. ·*Department of Surgery †Department of Radiation Oncology; and ‡Department of Medical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA. ·Ann Surg · Pubmed #25599322.

ABSTRACT: PURPOSE: On the basis of the ACCORD trial, FOLFIRINOX is effective in metastatic pancreatic adenocarcinoma (PDAC), making it a rational choice for locally advanced PDAC (LA). Aims of this study are to evaluate the accuracy of imaging in determining the resectability of PDAC and to determine the surgical and clinicopathologic outcomes of pancreatic resections after neoadjuvant FOLFIRINOX therapy. PATIENTS AND METHODS: Clinicopathologic data were retrospectively collected for surgical PDAC patients receiving neoadjuvant FOLFIRINOX or no neoadjuvant therapy between April 2011 and February 2014. Americas Hepato-Pancreato-Biliary Association/Society of Surgical Oncology/Society for Surgery of the Alimentary Tract consensus guidelines defined LA and borderline. Imaging was reviewed by a blinded senior pancreatic surgeon. RESULTS: Of 188 patients undergoing resection for PDAC, 40 LA/borderline received FOLFIRINOX and 87 received no neoadjuvant therapy. FOLFIRINOX resulted in a significant decrease in tumor size, yet 19 patients were still classified as LA and 9 as borderline. Despite post-FOLFIRINOX imaging suggesting continued unresectability, 92% had an R0 resection. When compared with no neoadjuvant therapy, FOLFIRINOX resulted in significantly longer operative times (393 vs 300 minutes) and blood loss (600 vs 400 mL), but significantly lower operative morbidity (36% vs 63%) and no postoperative pancreatic fistulas. Length of stay (6 vs 7 days), readmissions (20% vs 30%), and mortality were equivalent (1% vs 0%). On final pathology, the FOLFIRINOX group had a significant decrease in lymph node positivity (35% vs 79%) and perineural invasion (72% vs 95%). Median follow-up was 11 months with a significant increase in overall survival with FOLFIRINOX. CONCLUSIONS: After neoadjuvant FOLFIRINOX imaging no longer predicts unresectability. Traditional pathologic predictors of survival are improved, and morbidity is decreased in comparison to patients with clearly resectable cancers at the time of presentation.

24 Article Combined MEK and PI3K inhibition in a mouse model of pancreatic cancer. 2015

Alagesan, Brinda / Contino, Gianmarco / Guimaraes, Alex R / Corcoran, Ryan B / Deshpande, Vikram / Wojtkiewicz, Gregory R / Hezel, Aram F / Wong, Kwok-Kin / Loda, Massimo / Weissleder, Ralph / Benes, Cyril H / Engelman, Jeffrey / Bardeesy, Nabeel. ·Cancer Center, Massachusetts General Hospital, Boston, MA 02114. · Center for Molecular Imaging Research, Massachusetts General Hospital, Boston, MA 02114. · Department of Radiology, Harvard Medical School, Boston, MA 02115. · Department of Medicine, Harvard Medical School, Boston, MA 02115. · Department of Pathology, Massachusetts General Hospital, Boston, MA 02114. · Department of Pathology, Harvard Medical School, Boston, MA 02115. · Department of Medical Oncology, Dana-Farber Cancer Institute, Boston MA 02215. · Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115. ·Clin Cancer Res · Pubmed #25348516.

ABSTRACT: PURPOSE: Improved therapeutic approaches are needed for the treatment of pancreatic ductal adenocarcinoma (PDAC). As dual MEK and PI3K inhibition is presently being used in clinical trials for patients with PDAC, we sought to test the efficacy of combined targeting of these pathways in PDAC using both in vitro drug screens and genetically engineered mouse models (GEMM). EXPERIMENTAL DESIGN: We performed high-throughput screening of >500 human cancer cell lines (including 46 PDAC lines), for sensitivity to 50 clinically relevant compounds, including MEK and PI3K inhibitors. We tested the top hit in the screen, the MEK1/2 inhibitor, AZD6244, for efficacy alone or in combination with the PI3K inhibitors, BKM120 or GDC-0941, in a Kras(G12D)-driven GEMM that recapitulates the histopathogenesis of human PDAC. RESULTS: In vitro screens revealed that PDAC cell lines are relatively resistant to single-agent therapies. The response profile to the MEK1/2 inhibitor, AZD6244, was an outlier, showing the highest selective efficacy in PDAC. Although MEK inhibition alone was mainly cytostatic, apoptosis was induced when combined with PI3K inhibitors (BKM120 or GDC-0941). When tested in a PDAC GEMM and compared with the single agents or vehicle controls, the combination delayed tumor formation in the setting of prevention and extended survival when used to treat advanced tumors, although no durable responses were observed. CONCLUSIONS: Our studies point to important contributions of MEK and PI3K signaling to PDAC pathogenesis and suggest that dual targeting of these pathways may provide benefit in some patients with PDAC. Clin Cancer Res; 21(2); 396-404. ©2014 AACR.

25 Article Single-cell RNA sequencing identifies extracellular matrix gene expression by pancreatic circulating tumor cells. 2014

Ting, David T / Wittner, Ben S / Ligorio, Matteo / Vincent Jordan, Nicole / Shah, Ajay M / Miyamoto, David T / Aceto, Nicola / Bersani, Francesca / Brannigan, Brian W / Xega, Kristina / Ciciliano, Jordan C / Zhu, Huili / MacKenzie, Olivia C / Trautwein, Julie / Arora, Kshitij S / Shahid, Mohammad / Ellis, Haley L / Qu, Na / Bardeesy, Nabeel / Rivera, Miguel N / Deshpande, Vikram / Ferrone, Cristina R / Kapur, Ravi / Ramaswamy, Sridhar / Shioda, Toshi / Toner, Mehmet / Maheswaran, Shyamala / Haber, Daniel A. ·Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02114, USA. · Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; Department of Surgery, Harvard Medical School, Boston, MA 02114, USA; Department of Health Sciences, University of Genoa, 16126 Genoa, Italy. · Center for Engineering in Medicine, Harvard Medical School, Boston, MA 02114, USA; Department of Surgery, Harvard Medical School, Boston, MA 02114, USA. · Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; Department of Radiation Oncology, Harvard Medical School, Boston, MA 02114, USA. · Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; Department of Surgery, Harvard Medical School, Boston, MA 02114, USA; Department of Pathology, Harvard Medical School, Boston, MA 02114, USA. · Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; Department of Pathology, Harvard Medical School, Boston, MA 02114, USA. · Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; Department of Surgery, Harvard Medical School, Boston, MA 02114, USA. · Center for Engineering in Medicine, Harvard Medical School, Boston, MA 02114, USA. · Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; Department of Surgery, Harvard Medical School, Boston, MA 02114, USA. Electronic address: maheswaran@helix.mgh.harvard.edu. · Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02114, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address: haber@helix.mgh.harvard.edu. ·Cell Rep · Pubmed #25242334.

ABSTRACT: Circulating tumor cells (CTCs) are shed from primary tumors into the bloodstream, mediating the hematogenous spread of cancer to distant organs. To define their composition, we compared genome-wide expression profiles of CTCs with matched primary tumors in a mouse model of pancreatic cancer, isolating individual CTCs using epitope-independent microfluidic capture, followed by single-cell RNA sequencing. CTCs clustered separately from primary tumors and tumor-derived cell lines, showing low-proliferative signatures, enrichment for the stem-cell-associated gene Aldh1a2, biphenotypic expression of epithelial and mesenchymal markers, and expression of Igfbp5, a gene transcript enriched at the epithelial-stromal interface. Mouse as well as human pancreatic CTCs exhibit a very high expression of stromal-derived extracellular matrix (ECM) proteins, including SPARC, whose knockdown in cancer cells suppresses cell migration and invasiveness. The aberrant expression by CTCs of stromal ECM genes points to their contribution of microenvironmental signals for the spread of cancer to distant organs.

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