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Pancreatic Neoplasms: HELP
Articles by Stefano Serra
Based on 19 articles published since 2009
(Why 19 articles?)
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Between 2009 and 2019, Stefano Serra wrote the following 19 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Review The spectrum of histopathological changes encountered in pancreatectomy specimens after neoadjuvant chemoradiation, including subtle and less-well-recognised changes. 2016

Kalimuthu, Sangeetha N / Serra, Stefano / Dhani, Neesha / Chetty, Runjan. ·Departments of Pathology, Laboratory Medicine Program and *Medical Oncology, University Health Network and University of Toronto, Toronto, Canada. ·J Clin Pathol · Pubmed #26915370.

ABSTRACT: Preoperative (neoadjuvant) chemoradiation therapy/treatment (NCRT) is emerging as an important treatment modality in borderline resectable pancreatic ductal adenocarcinoma (PDAC). The constellation of histopathological changes secondary to chemoradiation is diverse and has been well documented, particularly in other gastrointestinal organs such as the oesophagus and colorectum. However, the histological changes specific to the pancreas have not been fully characterised and described. This review aims to provide a detailed catalogue of histological features associated with NCRT-treated PDAC and highlight any subtle, less-recognised changes.

2 Review The use of Cytokeratin 19 (CK19) immunohistochemistry in lesions of the pancreas, gastrointestinal tract, and liver. 2010

Jain, Richa / Fischer, Sandra / Serra, Stefano / Chetty, Runjan. ·Department of Pathology, The Toronto General Hospital, University Health Network/University of Toronto, Toronto, Ontario, Canada. ·Appl Immunohistochem Mol Morphol · Pubmed #19956064.

ABSTRACT: Cytokeratin immunostaining forms the bedrock of the immunohistochemical evaluation of tumors. Cytokeratin 19 (CK19) belongs to a family of keratins, which are normally expressed in the lining of the gastroenteropancreatic and hepatobiliary tracts. CK19 immunohistochemistry has been used successfully in thyroid tumors to recognize papillary carcinomas for some time. However, its use in the pancreas, liver, and gastrointestinal tract (GIT) has only recently come to the fore. The purpose of this review is to look at the use of CK19 immunohistochemistry in tumors occurring at these sites. CK19 has been shown to be an independent prognostic factor for pancreatic neuroendocrine tumors, especially the insulin-negative tumors. CK19 positive tumors are associated with poor outcome irrespective of the established pathologic parameters such as size, mitoses, lymphovascular invasion, and necrosis. It is recommended that CK19 be part of the immunohistochemical panel in the work-up of pancreatic endocrine tumors. CK19 is positive in the most of neuroendocrine tumors occurring in the rest of the GIT, except rectal tumors, which are negative. In the liver, CK19 is of prognostic value in hepatocellular carcinomas and is of use in distinguishing cholangiocarcinoma from hepatocellular carcinomas. It can also be used to highlight native ductules in the liver and helps separate conditions such as focal nodular hyperplasia from hepatic adenoma. The vast majority of adenocarcinomas in the GIT and pancreas are CK19 positive.

3 Article Management and surveillance of non-functional pancreatic neuroendocrine tumours: Retrospective review. 2019

Yohanathan, Lavanya / Dossa, Fahima / St Germain, Amelie Tremblay / Golbafian, Faegheh / Moulton, Carol-Anne / McGilvray, Ian D / Greig, Paul D / Serra, Stefano / Wei, Alice C / Jhaveri, Kartik S / Gallinger, Steve / Cleary, Sean P. ·Division of Hepatobiliary and Pancreatic Surgery, Mayo Clinic, Rochester, MN, USA. · Division of General Surgery, University of Toronto, Toronto, ON, Canada. · Department of Surgery, Hotel-Dieu De Levis, Levis, QC, Canada. · Department of Family Medicine, London, ON, Canada. · Division of General Surgery, University of Toronto, Toronto, ON, Canada; Department of Surgery, University Health Network, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada. · Department of Pathology, University Health Network/University of Toronto, Canada. · Department of Surgery, University Health Network, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada. · Joint Department of Medical Imaging, University Health Network, Mount Sinai Hospital and Women's College Hospital, University of Toronto, Toronto, ON, Canada. · Division of General Surgery, University of Toronto, Toronto, ON, Canada; Division of Hepatobiliary and Pancreatic Surgery, Mayo Clinic, Rochester, MN, USA; Department of Surgery, University Health Network, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada. Electronic address: cleary.sean@mayo.edu. ·Pancreatology · Pubmed #30803874.

ABSTRACT: BACKGROUND: /Objective. To determine the outcomes of a non-operative management approach for sporadic, small, non-functional pancreatic neuroendocrine tumours. METHODS: A retrospective chart review of patients with non-functional pancreatic neuroendocrine tumours initially managed non-operatively at a single institution was performed. Patients were identified through a search of radiologic reports, and individuals with ≥2 cross-sectional imaging studies performed >6 months apart from Jan. 1, 2000 to Dec. 31, 2013 were included. Data on tumour size, radiologic characteristics at diagnosis, interval radiologic growth, and surgical outcomes were recorded. RESULTS: Over the thirteen-year study period, 95 patients met inclusion criteria and were followed radiologically for a median of 36 months (18-69 months). Median initial tumour size on first imaging was 14.0 mm (IQR 10-19 mm). Median overall tumour growth rate was 0.03 mm/month (IQR: 0.00-0.14 mm/month). There was no significant relationship between initial tumour size and growth rate for tumours ≤ 2 cm or for lesions between 2 and 4 cm. Thirteen (14%) patients initially managed non-operatively underwent resection during the follow-up period. Reasons for surgery included interval tumour growth, patient anxiety or preference, or diagnostic uncertainty. Median time to surgery was 14 months (IQR 8-19 months). No patients progressed beyond resectability or developed metastatic disease during the observation period. CONCLUSION: For patients with sporadic, small, non-functional pancreatic neuroendocrine tumours, radiologic surveillance appears to be a safe initial approach to management.

4 Article A precision oncology approach to the pharmacological targeting of mechanistic dependencies in neuroendocrine tumors. 2018

Alvarez, Mariano J / Subramaniam, Prem S / Tang, Laura H / Grunn, Adina / Aburi, Mahalaxmi / Rieckhof, Gabrielle / Komissarova, Elena V / Hagan, Elizabeth A / Bodei, Lisa / Clemons, Paul A / Dela Cruz, Filemon S / Dhall, Deepti / Diolaiti, Daniel / Fraker, Douglas A / Ghavami, Afshin / Kaemmerer, Daniel / Karan, Charles / Kidd, Mark / Kim, Kyoung M / Kim, Hee C / Kunju, Lakshmi P / Langel, Ülo / Li, Zhong / Lee, Jeeyun / Li, Hai / LiVolsi, Virginia / Pfragner, Roswitha / Rainey, Allison R / Realubit, Ronald B / Remotti, Helen / Regberg, Jakob / Roses, Robert / Rustgi, Anil / Sepulveda, Antonia R / Serra, Stefano / Shi, Chanjuan / Yuan, Xiaopu / Barberis, Massimo / Bergamaschi, Roberto / Chinnaiyan, Arul M / Detre, Tony / Ezzat, Shereen / Frilling, Andrea / Hommann, Merten / Jaeger, Dirk / Kim, Michelle K / Knudsen, Beatrice S / Kung, Andrew L / Leahy, Emer / Metz, David C / Milsom, Jeffrey W / Park, Young S / Reidy-Lagunes, Diane / Schreiber, Stuart / Washington, Kay / Wiedenmann, Bertram / Modlin, Irvin / Califano, Andrea. ·Department of Systems Biology, Columbia University, New York, NY, USA. · DarwinHealth Inc, New York, NY, USA. · Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Institute for Systems Genetics, New York University Langone Medical Center, New York, NY, USA. · Department of Urology, Columbia University, New York, NY, USA. · Division of Pathology, European Institute of Oncology, Milan, Italy. · Broad Institute of Harvard and MIT, Cambridge, MA, USA. · Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Cedars-Sinai Medical Center, Los Angeles, CA, USA. · Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. · PsychoGenics Inc., Tarrytown, NY, USA. · Department of General and Visceral Surgery, Zentralklinik, Bad Berka, Germany. · Sulzberger Columbia Genome Center, Columbia University, New York, NY, USA. · Wren Laboratories, Branford, CT, USA. · Division of Hematology Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. · Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI, USA. · Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA. · Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA. · Department of Neurochemistry, the Arrhenius Laboratories for Nat. Sci., Stockholm University, Stockholm, Sweden. · Laboratory of Molecular Biotechnology, Institute of Technology, University of Tartu, Tartu, Estonia. · Falconwood Foundation, New York, NY, USA. · Institute of Pathophysiology and Immunology, Medical University of Graz, Graz, Austria. · Department of Pathology, Columbia University, New York, NY, USA. · Department of Pathology, University Health Network, University of Toronto, Toronto, Canada. · Department of Pathology, Vanderbilt University Medical Center, Nashville, TN, USA. · Division of Colon and Rectal Surgery, State University of New York, Stony Brook, NY, USA. · Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, MI, USA. · Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA. · Imperial College London, London, UK. · Medical Oncology, National Center for Tumor Diseases Heidelberg, University Medical Center Heidelberg, Heidelberg, Germany. · Mount Sinai School of Medicine, New York, NY, USA. · Department of Surgery, New York-Presbyterian Hospital, Weill Cornell Medicine, New York, NY, USA. · Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA. · Department of Internal Medicine, Division of Gastroenterology, Charite, Universitätsmedizin Berlin, Berlin, Germany. · Emeritus Professor Gastrointestinal Surgery, School of Medicine, Yale University, New Haven, Connecticut, USA. imodlin@irvinmodlin.com. · Department of Systems Biology, Columbia University, New York, NY, USA. califano@cumc.columbia.edu. · Department of Biomedical Informatics, Columbia University, New York, NY, USA. califano@cumc.columbia.edu. · Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA. califano@cumc.columbia.edu. · J.P. Sulzberger Columbia Genome Center, Columbia University, New York, NY, USA. califano@cumc.columbia.edu. · Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA. califano@cumc.columbia.edu. ·Nat Genet · Pubmed #29915428.

ABSTRACT: We introduce and validate a new precision oncology framework for the systematic prioritization of drugs targeting mechanistic tumor dependencies in individual patients. Compounds are prioritized on the basis of their ability to invert the concerted activity of master regulator proteins that mechanistically regulate tumor cell state, as assessed from systematic drug perturbation assays. We validated the approach on a cohort of 212 gastroenteropancreatic neuroendocrine tumors (GEP-NETs), a rare malignancy originating in the pancreas and gastrointestinal tract. The analysis identified several master regulator proteins, including key regulators of neuroendocrine lineage progenitor state and immunoevasion, whose role as critical tumor dependencies was experimentally confirmed. Transcriptome analysis of GEP-NET-derived cells, perturbed with a library of 107 compounds, identified the HDAC class I inhibitor entinostat as a potent inhibitor of master regulator activity for 42% of metastatic GEP-NET patients, abrogating tumor growth in vivo. This approach may thus complement current efforts in precision oncology.

5 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.

6 Article Association of Distinct Mutational Signatures With Correlates of Increased Immune Activity in Pancreatic Ductal Adenocarcinoma. 2017

Connor, Ashton A / Denroche, Robert E / Jang, Gun Ho / Timms, Lee / Kalimuthu, Sangeetha N / Selander, Iris / McPherson, Treasa / Wilson, Gavin W / Chan-Seng-Yue, Michelle A / Borozan, Ivan / Ferretti, Vincent / Grant, Robert C / Lungu, Ilinca M / Costello, Eithne / Greenhalf, William / Palmer, Daniel / Ghaneh, Paula / Neoptolemos, John P / Buchler, Markus / Petersen, Gloria / Thayer, Sarah / Hollingsworth, Michael A / Sherker, Alana / Durocher, Daniel / Dhani, Neesha / Hedley, David / Serra, Stefano / Pollett, Aaron / Roehrl, Michael H A / Bavi, Prashant / Bartlett, John M S / Cleary, Sean / Wilson, Julie M / Alexandrov, Ludmil B / Moore, Malcolm / Wouters, Bradly G / McPherson, John D / Notta, Faiyaz / Stein, Lincoln D / Gallinger, Steven. ·PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada2Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada3Hepatobiliary/Pancreatic Surgical Oncology Program, University Health Network, Toronto, Ontario, Canada. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada4Informatics and Bio-computing Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada4Informatics and Bio-computing Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada5Department of Statistical Science, University of Toronto, Toronto, Ontario, Canada. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada6Genome Technologies Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. · Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. · Informatics and Bio-computing Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada2Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. · Transformative Pathology, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. · University of Liverpool, Liverpool, England. · Heidelberg University Hospital, Heidelberg, Germany. · Mayo Clinic, Rochester, Minnesota. · Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts. · University of Nebraska Medical Centre, Omaha, Nebraska. · Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada13Molecular Genetics Department, University of Toronto, Toronto, Ontario, Canada. · Division of Medical Oncology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada. · Hepatobiliary/Pancreatic Surgical Oncology Program, University Health Network, Toronto, Ontario, Canada. · Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada15Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada15Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada16Department of Pathology, University Health Network, Toronto, Ontario, Canada17Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada18BioSpecimen Sciences Program, University Health Network, Toronto, Ontario, Canada. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada3Hepatobiliary/Pancreatic Surgical Oncology Program, University Health Network, Toronto, Ontario, Canada. · Theoretical Biology and Biophysics (T-6), Los Alamos National Laboratory, Los Alamos, New Mexico20Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, New Mexico. · Department of Pathology, University Health Network, Toronto, Ontario, Canada. · Genome Technologies Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada17Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. · Informatics and Bio-computing Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada13Molecular Genetics Department, University of Toronto, Toronto, Ontario, Canada. ·JAMA Oncol · Pubmed #27768182.

ABSTRACT: Importance: Outcomes for patients with pancreatic ductal adenocarcinoma (PDAC) remain poor. Advances in next-generation sequencing provide a route to therapeutic approaches, and integrating DNA and RNA analysis with clinicopathologic data may be a crucial step toward personalized treatment strategies for this disease. Objective: To classify PDAC according to distinct mutational processes, and explore their clinical significance. Design, Setting, and Participants: We performed a retrospective cohort study of resected PDAC, using cases collected between 2008 and 2015 as part of the International Cancer Genome Consortium. The discovery cohort comprised 160 PDAC cases from 154 patients (148 primary; 12 metastases) that underwent tumor enrichment prior to whole-genome and RNA sequencing. The replication cohort comprised 95 primary PDAC cases that underwent whole-genome sequencing and expression microarray on bulk biospecimens. Main Outcomes and Measures: Somatic mutations accumulate from sequence-specific processes creating signatures detectable by DNA sequencing. Using nonnegative matrix factorization, we measured the contribution of each signature to carcinogenesis, and used hierarchical clustering to subtype each cohort. We examined expression of antitumor immunity genes across subtypes to uncover biomarkers predictive of response to systemic therapies. Results: The discovery cohort was 53% male (n = 79) and had a median age of 67 (interquartile range, 58-74) years. The replication cohort was 50% male (n = 48) and had a median age of 68 (interquartile range, 60-75) years. Five predominant mutational subtypes were identified that clustered PDAC into 4 major subtypes: age related, double-strand break repair, mismatch repair, and 1 with unknown etiology (signature 8). These were replicated and validated. Signatures were faithfully propagated from primaries to matched metastases, implying their stability during carcinogenesis. Twelve of 27 (45%) double-strand break repair cases lacked germline or somatic events in canonical homologous recombination genes-BRCA1, BRCA2, or PALB2. Double-strand break repair and mismatch repair subtypes were associated with increased expression of antitumor immunity, including activation of CD8-positive T lymphocytes (GZMA and PRF1) and overexpression of regulatory molecules (cytotoxic T-lymphocyte antigen 4, programmed cell death 1, and indolamine 2,3-dioxygenase 1), corresponding to higher frequency of somatic mutations and tumor-specific neoantigens. Conclusions and Relevance: Signature-based subtyping may guide personalized therapy of PDAC in the context of biomarker-driven prospective trials.

7 Article Regression grading in neoadjuvant treated pancreatic cancer: an interobserver study. 2017

N Kalimuthu, Sangeetha / Serra, Stefano / Dhani, Neesha / Hafezi-Bakhtiari, Sara / Szentgyorgyi, Eva / Vajpeyi, Rajkumar / Chetty, Runjan. ·Laboratory Medicine Program, Department of Pathology, University Health Network, University of Toronto, Toronto, Ontario, Canada. · Laboratory Medicine Program, Department of Medical Oncology, University Health Network, University of Toronto, Toronto, Ontario, Canada. ·J Clin Pathol · Pubmed #27681847.

ABSTRACT: AIM: Several regression grading systems have been proposed for neoadjuvant chemoradiation-treated pancreatic ductal adenocarcinoma (PDAC). This study aimed to examine the utility, reproducibility and level of concordance of three most frequently used grading systems. METHODS: Four gastrointestinal pathologists used the College of American Pathologists (CAP), Evans, MD Anderson Cancer Centre (MDA) regression grading systems to grade 14 selected cases (7-20 slides from each case) of neoadjuvant chemoradiation-treated PDAC. A postscoring discussion with each pathologist was conducted. The results were entered into a standardised data collection form and statistical analyses were performed. RESULTS: There was little concordance across the three systems. The Kendall coefficient of concordance agreement scores were: CAP: 2-poor, 2-fair; Evans: 1-fair, 1-moderate, 2-good; MDA: 1-poor, 2-moderate, 1-good. Interpretation in all three grades in the CAP grading system was a source of discrepancy. Furthermore, using fibrosis as a criterion to assess regression was contentious. In the Evans system, quantifying tumour destruction using arbitrary percentage cut-offs (ie, 9% vs 10%; 50% vs 51%, etc) was imprecise and subjective. Although the MDA system generated greatest concordance, this was due to 'oversimplification' surrounding wide, arbitrarily assigned thresholds of 5% of tumour. CONCLUSIONS: All systems lacked precision and clarity for accurate regression grading. Presently the clinical utility and impact of histological regression grading in patient management is questionable. There is a need to re-evaluate regression grading in the pancreas and establish a reproducible, clinically relevant grading system.

8 Article A bleeding umbilical mass. 2016

Guerra, Francesco / Pulighe, Fabio / Sacchetti, Riccardo / Serra, Stefano / De Nisco, Carlo. ·San Francesco Hospital, Nuoro, Italy. ·Gut · Pubmed #26553739.

ABSTRACT: -- No abstract --

9 Article Tumor budding is an independent adverse prognostic factor in pancreatic ductal adenocarcinoma. 2015

O'Connor, Kate / Li-Chang, Hector H / Kalloger, Steven E / Peixoto, Renata D / Webber, Douglas L / Owen, David A / Driman, David K / Kirsch, Richard / Serra, Stefano / Scudamore, Charles H / Renouf, Daniel J / Schaeffer, David F. ·Divisions of *Anatomic Pathology #General Surgery, Vancouver General Hospital †The University of British Columbia ‡Pancreas Centre BC §Division of Medical Oncology, BC Cancer Agency, Vancouver, BC ∥Department of Pathology, Western University, London ¶Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada. ·Am J Surg Pathol · Pubmed #25634751.

ABSTRACT: Tumor budding is a well-established adverse prognostic factor in colorectal cancer. However, the significance and diagnostic reproducibility of budding in pancreatic carcinoma requires further study. We aimed to assess the prognostic significance of tumor budding in pancreatic ductal adenocarcinoma, determine its relationship with other clinicopathologic features, and assess interobserver variability in its diagnosis. Tumor budding was assessed in 192 archival cases of pancreatic ductal adenocarcinoma using hematoxylin and eosin (H&E) sections; tumor buds were defined as single cells or nonglandular clusters composed of <5 cells. The presence of budding was determined through assessment of all tumor-containing slides, and associations with clinicopathologic features and outcomes were analyzed. Six gastrointestinal pathologists participated in an interobserver variability study of 120 images of consecutive tumor slides stained with H&E and cytokeratin. Budding was present in 168 of 192 cases and was associated with decreased overall survival (P=0.001). On multivariable analysis, tumor budding was prognostically significantly independent of stage, grade, tumor size, nodal status, lymphovascular invasion, and perineural invasion. There was substantial agreement among pathologists in assessing the presence of tumor budding using both H&E (K=0.63) and cytokeratin (K=0.63) stains. The presence of tumor budding is an independent adverse prognostic factor in pancreatic ductal carcinoma. The assessment of budding with H&E is reliable and could be used to better risk stratify patients with pancreatic ductal adenocarcinoma.

10 Article Validation of biomarkers that complement CA19.9 in detecting early pancreatic cancer. 2014

Chan, Alison / Prassas, Ioannis / Dimitromanolakis, Apostolos / Brand, Randall E / Serra, Stefano / Diamandis, Eleftherios P / Blasutig, Ivan M. ·Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada. · Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada. · University of Pittsburgh, Division of Gastroenterology, Hepatology & Nutrition, Pittsburgh, Pennsylvania. · Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. Department of Pathology, University Health Network, Toronto, Ontario, Canada. · Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada. Department of Clinical Biochemistry, University Health Network, Toronto, Ontario, Canada. · Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. Department of Clinical Biochemistry, University Health Network, Toronto, Ontario, Canada. ivan.blasutig@uhn.ca. ·Clin Cancer Res · Pubmed #25239611.

ABSTRACT: PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is a significant cause of cancer mortality. Carbohydrate antigen 19.9 (CA19.9), the only tumor marker available to detect and monitor PDAC, is not sufficiently sensitive and specific to consistently differentiate early cancer from benign disease. In this study, we aimed to validate recently discovered serum protein biomarkers for the early detection of PDAC and ultimately develop a biomarker panel that could discriminate PDAC from other benign disease better than the existing marker CA19.9. PATIENTS AND METHODS: We performed a retrospective blinded evaluation of 400 serum samples collected from individuals recruited on a consecutive basis. The sample population consisted of 250 individuals with PDAC at various stages, 130 individuals with benign conditions and 20 healthy individuals. The serum levels of each biomarker were determined by ELISAs or automated immunoassay. RESULTS: By randomly splitting matched samples into a training (n = 186) and validation (n = 214) set, we were able to develop and validate a biomarker panel consisting of CA19.9, CA125, and LAMC2 that significantly improved the performance of CA19.9 alone. Improved discrimination was observed in the validation set between all PDAC and benign conditions (AUCCA19.9 = 0.80 vs. AUCCA19.9+CA125+LAMC2 = 0.87; P < 0.005) as well as between early-stage PDAC and benign conditions (AUCCA19.9 = 0.69 vs. AUCCA19.9+CA125+LAMC2 = 0.76; P < 0.05) and between early-stage PDAC and chronic pancreatitis (CP; AUCCA19.9 = 0.59 vs. AUCCA19.9+CA125+LAMC2 = 0.74; P < 0.05). CONCLUSIONS: The data demonstrate that a serum protein biomarker panel consisting of CA125, CA19.9, and LAMC2 is able to significantly improve upon the performance of CA19.9 alone in detecting PDAC.

11 Article Hormone profiling, WHO 2010 grading, and AJCC/UICC staging in pancreatic neuroendocrine tumor behavior. 2013

Morin, Emilie / Cheng, Sonia / Mete, Ozgur / Serra, Stefano / Araujo, Paula B / Temple, Sara / Cleary, Sean / Gallinger, Steven / Greig, Paul D / McGilvray, Ian / Wei, Alice / Asa, Sylvia L / Ezzat, Shereen. ·Department of Medicine, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. ·Cancer Med · Pubmed #24403235.

ABSTRACT: Pancreatic neuroendocrine tumors (pNETs) are the second most common pancreatic neoplasms, exhibiting a complex spectrum of clinical behaviors. To examine the clinico-pathological characteristics associated with long-term prognosis we reviewed 119 patients with pNETs treated in a tertiary referral center using the WHO 2010 grading and the American Joint Committee on Cancer/International Union Against Cancer (AJCC/UICC) staging systems, with a median follow-up of 38 months. Tumor size, immunohistochemistry (IHC) profiling and patient characteristics-determining stage were analyzed. Primary clinical outcomes were disease progression or death. The mean age at presentation was 52 years; 55% were female patients, 11% were associated with MEN1 (multiple endocrine neoplasia 1) or VHL (Von Hippel-Lindau); mean tumor diameter was 3.3 cm (standard deviation, SD) (2.92). The clinical presentation was incidental in 39% with endocrine hypersecretion syndromes in only 24% of cases. Nevertheless, endocrine hormone tissue immunoreactivity was identified in 67 (56.3%) cases. According to WHO 2010 grading, 50 (42%), 38 (31.9%), and 3 (2.5%) of tumors were low grade (G1), intermediate grade (G2), and high grade (G3), respectively. Disease progression occurred more frequently in higher WHO grades (G1: 6%, G2: 10.5%, G3: 67%, P = 0.026) and in more advanced AJCC stages (I: 2%, IV: 63%, P = 0.033). Shorter progression free survival (PFS) was noted in higher grades (G3 vs. G2; 21 vs. 144 months; P = 0.015) and in more advanced AJCC stages (stage I: 218 months, IV: 24 months, P < 0.001). Liver involvement (20 vs. 173 months, P < 0.001) or histologically positive lymph nodes (33 vs. 208 months, P < 0.001) were independently associated with shorter PFS. Conversely, tissue endocrine hormone immunoreactivity, independent of circulating levels was significantly associated with less aggressive disease. Age, gender, number of primary tumors, and heredity were not significantly associated with prognosis. Although the AJCC staging and WHO 2010 grading systems are useful in predicting disease progression, tissue endocrine hormone profiling provides additional information of potentially important prognostic value.

12 Article Exome sequencing identifies nonsegregating nonsense ATM and PALB2 variants in familial pancreatic cancer. 2013

Grant, Robert C / Al-Sukhni, Wigdan / Borgida, Ayelet E / Holter, Spring / Kanji, Zaheer S / McPherson, Treasa / Whelan, Emily / Serra, Stefano / Trinh, Quang M / Peltekova, Vanya / Stein, Lincoln D / McPherson, John D / Gallinger, Steven. ·Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, M5G 1X5, Canada. ·Hum Genomics · Pubmed #23561644.

ABSTRACT: We sequenced 11 germline exomes from five families with familial pancreatic cancer (FPC). One proband had a germline nonsense variant in ATM with somatic loss of the variant allele. Another proband had a nonsense variant in PALB2 with somatic loss of the variant allele. Both variants were absent in a relative with FPC. These findings question the causal mechanisms of ATM and PALB2 in these families and highlight challenges in identifying the causes of familial cancer syndromes using exome sequencing.

13 Article Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. 2012

Biankin, Andrew V / Waddell, Nicola / Kassahn, Karin S / Gingras, Marie-Claude / Muthuswamy, Lakshmi B / Johns, Amber L / Miller, David K / Wilson, Peter J / Patch, Ann-Marie / Wu, Jianmin / Chang, David K / Cowley, Mark J / Gardiner, Brooke B / Song, Sarah / Harliwong, Ivon / Idrisoglu, Senel / Nourse, Craig / Nourbakhsh, Ehsan / Manning, Suzanne / Wani, Shivangi / Gongora, Milena / Pajic, Marina / Scarlett, Christopher J / Gill, Anthony J / Pinho, Andreia V / Rooman, Ilse / Anderson, Matthew / Holmes, Oliver / Leonard, Conrad / Taylor, Darrin / Wood, Scott / Xu, Qinying / Nones, Katia / Fink, J Lynn / Christ, Angelika / Bruxner, Tim / Cloonan, Nicole / Kolle, Gabriel / Newell, Felicity / Pinese, Mark / Mead, R Scott / Humphris, Jeremy L / Kaplan, Warren / Jones, Marc D / Colvin, Emily K / Nagrial, Adnan M / Humphrey, Emily S / Chou, Angela / Chin, Venessa T / Chantrill, Lorraine A / Mawson, Amanda / Samra, Jaswinder S / Kench, James G / Lovell, Jessica A / Daly, Roger J / Merrett, Neil D / Toon, Christopher / Epari, Krishna / Nguyen, Nam Q / Barbour, Andrew / Zeps, Nikolajs / Anonymous5450740 / Kakkar, Nipun / Zhao, Fengmei / Wu, Yuan Qing / Wang, Min / Muzny, Donna M / Fisher, William E / Brunicardi, F Charles / Hodges, Sally E / Reid, Jeffrey G / Drummond, Jennifer / Chang, Kyle / Han, Yi / Lewis, Lora R / Dinh, Huyen / Buhay, Christian J / Beck, Timothy / Timms, Lee / Sam, Michelle / Begley, Kimberly / Brown, Andrew / Pai, Deepa / Panchal, Ami / Buchner, Nicholas / De Borja, Richard / Denroche, Robert E / Yung, Christina K / Serra, Stefano / Onetto, Nicole / Mukhopadhyay, Debabrata / Tsao, Ming-Sound / Shaw, Patricia A / Petersen, Gloria M / Gallinger, Steven / Hruban, Ralph H / Maitra, Anirban / Iacobuzio-Donahue, Christine A / Schulick, Richard D / Wolfgang, Christopher L / Morgan, Richard A / Lawlor, Rita T / Capelli, Paola / Corbo, Vincenzo / Scardoni, Maria / Tortora, Giampaolo / Tempero, Margaret A / Mann, Karen M / Jenkins, Nancy A / Perez-Mancera, Pedro A / Adams, David J / Largaespada, David A / Wessels, Lodewyk F A / Rust, Alistair G / Stein, Lincoln D / Tuveson, David A / Copeland, Neal G / Musgrove, Elizabeth A / Scarpa, Aldo / Eshleman, James R / Hudson, Thomas J / Sutherland, Robert L / Wheeler, David A / Pearson, John V / McPherson, John D / Gibbs, Richard A / Grimmond, Sean M. ·The Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst, Sydney, New South Wales 2010, Australia. ·Nature · Pubmed #23103869.

ABSTRACT: Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations. We define 16 significantly mutated genes, reaffirming known mutations (KRAS, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1), and uncover novel mutated genes including additional genes involved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM) and other mechanisms (ZIM2, MAP2K4, NALCN, SLC16A4 and MAGEA6). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signalling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. We also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis.

14 Article The FGFR4-G388R single-nucleotide polymorphism alters pancreatic neuroendocrine tumor progression and response to mTOR inhibition therapy. 2012

Serra, Stefano / Zheng, Lei / Hassan, Manal / Phan, Alexandria T / Woodhouse, Linda J / Yao, James C / Ezzat, Shereen / Asa, Sylvia L. ·Departments of Pathology, Campbell Family Institute for Cancer Research, University Health Network, Toronto, Ontario, Canada. ·Cancer Res · Pubmed #22986737.

ABSTRACT: Pancreatic neuroendocrine tumors (pNET), also known as islet cell tumors, exhibit a wide range of biologic behaviors ranging from long dormancy to rapid progression. Currently, there are few molecular biomarkers that can be used to predict recurrence/metastasis or response to therapy. This study examined the predictive and prognostic value of a single nucleotide polymorphism substituting an arginine (R) for glycine (G) in codon 388 of the FGFR4 transmembrane domain. We established the FGFR4 genotype of 71 patients with pNETs and correlated genotype with biologic behavior. We created an in vivo model of pNET with BON1 cells and transfected them with either FGFR4-G388 or FGFR4-R388 to determine the mechanism of action and to examine response to the mTOR inhibitor everolimus. We then validated the predictive results of experimental studies in a group of patients treated with everolimus. FGFR4-R388 is associated with more aggressive clinical behavior in patients with pNETs with a statistically significant higher risk of advanced tumor stage and liver metastasis. Using an orthotopic mouse xenograft model, we show that FGFR4-R388 promotes tumor progression by increasing intraperitoneal spread and metastatic growth within the liver. Unlike FGFR4-G388, FGFR4-R388 BON1 tumors exhibited diminished responsiveness to everolimus. Concordantly, there was a statistically significant reduction in response to everolimus in patients with FGFR4-R388. Our findings highlight the importance of the FGFR4 allele in pNET progression and identify a predictive marker of potential therapeutic importance in this disease.

15 Article Lipid-rich ("clear cell") neuroendocrine tumors of the pancreas in MEN I patients. 2012

Fryer, Eve / Serra, Stefano / Chetty, Runjan. ·Department of Cellular Pathology, Biomedical Research Centre, Nuffield Department of Clinical Laboratory Sciences, Oxford University Hospitals, University of Oxford, Oxford, UK. ·Endocr Pathol · Pubmed #22923265.

ABSTRACT: The presence of "clear" or lipid-rich cells within pancreatic neuroendocrine tumors is thought to be pathognomonic of von Hippel-Lindau (VHL) disease, especially in the context of multiple tumors. However, we encountered the presence of lipid-rich cells in six of 16 patients (eight microadenomas/adenomas) who had multiple endocrine neoplasia type I (MEN I). Three of the lesions (two microadenomas and one adenoma) were composed entirely of lipid-rich cells while the remaining five lesions had a component of lipid-rich cells. All lesions containing lipid-rich cells were negative for α-inhibin, but positive for chromogranin and synaptophysin. In addition, four of the eight lesions were glucagon positive. None of the patients had clinical symptoms related to hormone production. We suggest that lipid-rich cells are not reflexly indicative of VHL, and that they may be encountered in a proportion of cases of MEN I either focally or constituting the entire neuroendocrine lesion.

16 Article Solitary fibrous tumor of the pancreas. 2009

Chetty, Runjan / Jain, Richa / Serra, Stefano. ·Department of Pathology, University Health Network/University of Toronto, Toronto, Ontario, Canada. runjan.chetty@uhn.on.ca ·Ann Diagn Pathol · Pubmed #19751911.

ABSTRACT: A 67-year-old woman was found to have an incidental pancreatic mass on computed tomographic examination of her abdomen in the course of investigation of hematuria. The radiologic features were of a hypervascular mass in the uncinate process of the head of the pancreas, and a preoperative diagnosis of a neuroendocrine tumor was favored. A Whipple procedure was performed. The uncinate process contained a 2.6-cm well-circumscribed mass. Histologic evaluation showed a lesion composed of alternating hypercellular areas made up of spindle-shaped cells and hypocellular areas with hyalinized, keloidal-like fibrous tissue. Occasional dilated vascular channels and entrapped pancreatic tissue were present within the lesion. Immunohistochemistry showed the lesion to be CD34, CD99, and bcl-2 positive. No evidence of atypia was noted, and the overall impression was of a benign solitary fibrous tumor of the pancreas. This is an unusual primary spindle cell neoplasm of the pancreas and should be considered in the differential diagnosis of all spindle cell lesions that occur in the pancreas.

17 Article Intraductal tubular adenoma (pyloric gland-type) of the pancreas: a reappraisal and possible relationship with gastric-type intraductal papillary mucinous neoplasm. 2009

Chetty, Runjan / Serra, Stefano. ·Department of Pathology, University Health Network/University of Toronto, The Toronto General Hospital, 200 Elizabeth Street, 11th Floor, Eaton Wing, Toronto, ON M5G 2C4, Canada. runjan.chetty@uhn.on.ca ·Histopathology · Pubmed #19723141.

ABSTRACT: AIMS: Intraductal tubular adenoma (ITA) is an uncommon intraluminal polypoid lesion that occurs in the main pancreatic duct and involves the main pancreatic duct in the region of head or body. Three cases of ITA are presented, the literature reviewed and their association with intraductal papillary mucinous neoplasm (IPMN) is postulated. METHODS AND RESULTS: ITA is composed of tightly packed tubular structures with focal cystic dilation and papillary areas lined by gastric/pyloric epithelium showing minimal to mild cytological atypia. Pancreatic intraepithelial neoplasia (PanIN) 1A and B was present in smaller ducts of all cases. In addition, in the cases in this report and 50% of cases reported in the literature, an associated gastric-type IPMN was present in the same duct as the ITA or in adjacent ducts. The coexistence of ITA and IPMN and the similarities of their epithelial lining (gastric/pyloric mucosa) suggest a possible pathogenic link. CONCLUSIONS: ITA can occur without (type A) or with (type B) an associated gastric-type IPMN. ITA could represent a localized, polypoid form of gastric-type IPMN.It is a benign lesion with no evidence of invasion and no direct tumour-related deaths. Its relationship to intraductal tubular carcinoma remains to be elucidated.

18 Article CEACAM1 expression in pancreatic endocrine tumors. 2009

Serra, Stefano / Asa, Sylvia L / Bamberger, Ana-Maria / Wagener, Christoph / Chetty, Runjan. ·Department of Pathology, University Health Network, University of Toronto, Toronto, Canada. ·Appl Immunohistochem Mol Morphol · Pubmed #19349857.

ABSTRACT: The aim of this study was to examine the expression of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) in pancreatic endocrine tumors (PETs) and to correlate it with clinicopathologic parameters. Sixty-nine PETs were examined for tumor size, necrosis, local peripancreatic invasion and lymphovascular invasion, lymph node, and liver metastasis. The mitotic count, expressed per 10 high-power fields (HPF) and MIB1 index were assessed and tumors were classified according to the World Health Organization classification. A tissue microarray was constructed and stained with an extensive panel of endocrine markers and CEACAM1. Twenty-nine tumors were from males and 40 from females, age range: 23 to 80 years (mean 52.4 y), tumor size ranged from 0.8 to 11 cm (mean 3.5 cm), 8 patients had multiple endocrine neoplasia 1 syndrome, and 1 had von Hippel-Lindau disease. Twenty tumors demonstrated local invasion, 32 had lymphovascular invasion, 16 had lymph node metastasis, and 10 had liver metastasis. CEACAM1 was positive in 47 cases and negative in 22 cases (31.9%). Ninety percent of the CEACAM1-negative cases had a MIB1 index 2% (P=0.02). 86.4% of the CEACAM1-negative PETs had a mitotic count 2/10 HPF. In addition, 80% of tumors >or=2 cm in diameter were CEACAM positive (P<0.05). CEACAM1-positive tumors were more frequently insulin negative (9 of 10 cases) (P=0.005) and vasoactive intestinal peptide-positive PETs were all CEACAM1 immunopositive (7 of 7 cases) (P=0.005). Benign tumors and PETs of uncertain malignant behavior were more frequently CEACAM1-negative and low-grade malignant cases were CEACAM1 positive (27 of 29 cases) (P=0.001). In addition, CEACAM1-positive tumors were statistically correlated with cytokeratin 19-positive tumors (P<0.05). PETs showing CEACAM1 positivity have a statistically significant correlation with several of the pathologic parameters of aggressive behavior and its overexpression is seen in those cases with increased invasiveness.

19 Minor Loss of expression of E-cadherin in solid pseudopapillary tumors of the pancreas. 2009

Chetty, Runjan / Serra, Stefano. · ·Pancreas · Pubmed #19307928.

ABSTRACT: -- No abstract --