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Pancreatic Neoplasms: HELP
Articles by Lodewijk A. A. Brosens
Based on 29 articles published since 2010
(Why 29 articles?)
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Between 2010 and 2020, L. Brosens wrote the following 29 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Review Liquid Biopsy as Surrogate for Tissue for Molecular Profiling in Pancreatic Cancer: A Meta-Analysis Towards Precision Medicine. 2019

Luchini, Claudio / Veronese, Nicola / Nottegar, Alessia / Cappelletti, Vera / Daidone, Maria G / Smith, Lee / Parris, Christopher / Brosens, Lodewijk A A / Caruso, Maria G / Cheng, Liang / Wolfgang, Christopher L / Wood, Laura D / Milella, Michele / Salvia, Roberto / Scarpa, Aldo. ·Department of Diagnostics and Public Health, Section of Pathology, University of Verona, 37134 Verona, Italy. · National Institute of Gastroenterology-Research Hospital, IRCCS "S. de Bellis", Castellana Grotte, 70013 Bari, Italy. · Department of Surgery, Section of Pathology, San Bortolo Hospital, 36100 Vicenza, Italy. · Applied Research and Technological Development Department, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, 20133 Milano, Italy. · Faculty of Science and Engineering, Anglia Ruskin University, Cambridge CB1 1PT, UK. · Department of Pathology, University Medical Center Utrecht, Utrecht University, 3584CX Utrecht, The Netherlands. · Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6526GA Nijmegen, The Netherlands. · Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA. · Department of Surgery, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21211, USA. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21211, USA. · Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21211, USA. · Department of Medicine, Section of Medical Oncology, University and Hospital Trust of Verona, 37134 Verona, Italy. · Department of General and Visceral Surgery, The Pancreas Institute, University and Hospital Trust of Verona, 37134 Verona, Italy. · Department of Diagnostics and Public Health, Section of Pathology, University of Verona, 37134 Verona, Italy. aldo.scarpa@univr.it. · ARC-Net Research Center, University of Verona, 37134 Verona, Italy. aldo.scarpa@univr.it. ·Cancers (Basel) · Pubmed #31405192.

ABSTRACT: Liquid biopsy (LB) is a non-invasive approach representing a promising tool for new precision medicine strategies for cancer treatment. However, a comprehensive analysis of its reliability for pancreatic cancer (PC) is lacking. To this aim, we performed the first meta-analysis on this topic. We calculated the pooled sensitivity, specificity, positive (LR+) and negative (LR-) likelihood ratio, and diagnostic odds ratio (DOR). A summary receiver operating characteristic curve (SROC) and area under curve (AUC) were used to evaluate the overall accuracy. We finally assessed the concordance rate of all mutations detected by multi-genes panels. Fourteen eligible studies involving 369 patients were included. The overall pooled sensitivity and specificity were 0.70 and 0.86, respectively. The LR+ was 3.85, the LR- was 0.34 and DOR was 15.84. The SROC curve with an AUC of 0.88 indicated a relatively high accuracy of LB for molecular characterization of PC. The concordance rate of all mutations detected by multi-genes panels was 31.9%. LB can serve as surrogate for tissue in the molecular profiling of PC, because of its relatively high sensitivity, specificity and accuracy. It represents a unique opportunity to be further explored towards its introduction in clinical practice and for developing new precision medicine approaches against PC.

2 Review Why is pancreatic cancer so deadly? The pathologist's view. 2019

Hruban, Ralph H / Gaida, Matthias M / Thompson, Elizabeth / Hong, Seung-Mo / Noë, Michaël / Brosens, Lodewijk Aa / Jongepier, Martine / Offerhaus, G Johan A / Wood, Laura D. ·Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of General Pathology, The University Hospital of Heidelberg, Heidelberg, Germany. · Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. · Department of Pathology, The University Medical Center Utrecht, Utrecht, The Netherlands. · Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands. ·J Pathol · Pubmed #30838636.

ABSTRACT: The remarkable aggressiveness of pancreatic cancer has never been fully explained. Although clearly multifactorial, we postulate that venous invasion, a finding seen in most pancreatic cancers but not in most cancers of other organs, may be a significant, underappreciated contributor to the aggressiveness of this disease. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

3 Review Dilemmas for the pathologist in the oncologic assessment of pancreatoduodenectomy specimens : An overview of different grossing approaches and the relevance of the histopathological characteristics in the oncologic assessment of pancreatoduodenectomy specimens. 2018

Soer, Eline / Brosens, Lodewijk / van de Vijver, Marc / Dijk, Frederike / van Velthuysen, Marie-Louise / Farina-Sarasqueta, Arantza / Morreau, Hans / Offerhaus, Johan / Koens, Lianne / Verheij, Joanne. ·Department of pathology, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. e.c.soer@amc.uva.nl. · Department of pathology, University Medical Center, Utrecht, Netherlands. · Department of pathology, Radboud Medical Center, Nijmegen, Netherlands. · Department of pathology, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. · Department of pathology, VU University Medical Center, Amsterdam, Netherlands. · Department of pathology, Erasmus Medical Center, Rotterdam, Netherlands. · Department of pathology, Leiden Medical Center, Leiden, Netherlands. ·Virchows Arch · Pubmed #29589102.

ABSTRACT: A pancreatoduodenectomy specimen is complex, and there is much debate on how it is best approached by the pathologist. In this review, we provide an overview of topics relevant for current clinical practice in terms of gross dissection, and macro- and microscopic assessment of the pancreatoduodenectomy specimen with a suspicion of suspected pancreatic cancer. Tumor origin, tumor size, degree of differentiation, lymph node status, and resection margin status are universally accepted as prognostic for survival. However, different guidelines diverge on important issues, such as the diagnostic criteria for evaluating the completeness of resection. The macroscopic assessment of the site of origin in periampullary tumors and cystic lesions is influenced by the grossing method. Bi-sectioning of the head of the pancreas may offer an advantage in this respect, as this method allows for optimal visualization of the periampullary area. However, a head-to-head comparison of the assessment of clinically relevant parameters, using axial slicing versus bi-sectioning, is not available yet and the gold standard to compare both techniques prospectively might be subject of debate. Further studies are required to validate the various dissection protocols used for pancreatoduodenectomy specimens and their specific value in the assessment of pathological parameters relevant for prognosis.

4 Review Genetic Syndromes with Pancreatic Manifestations. 2016

Pittman, Meredith E / Brosens, Lodewijk A A / Wood, Laura D. ·Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, Starr 1031A, 525 East 68th Street, New York, NY 10065, USA. · Department of Pathology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, CRB2 Room 345, 1550 Orleans Street, Baltimore, MD 21231, USA. Electronic address: ldwood@jhmi.edu. ·Surg Pathol Clin · Pubmed #27926368.

ABSTRACT: Although the pancreas is affected by only a small fraction of known inherited disorders, several of these syndromes predispose patients to pancreatic adenocarcinoma, a cancer that has a consistently dismal prognosis. Still other syndromes are associated with neuroendocrine tumors, benign cysts, or recurrent pancreatitis. Because of the variability of pancreatic manifestations and outcomes, it is important for clinicians to be familiar with several well-described genetic disorders to ensure that patients are followed appropriately. The purpose of this review was to briefly describe the hereditary syndromes that are associated with pancreatic disorders and neoplasia.

5 Review Pathology of Pancreatic Cancer Precursor Lesions. 2016

Noë, Michaël / Brosens, Lodewijk A A. ·Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands. Electronic address: m.p.m.noe@umcutrecht.nl. · Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands. ·Surg Pathol Clin · Pubmed #27926360.

ABSTRACT: To better understand pancreatic ductal adenocarcinoma (PDAC) and improve its prognosis, it is essential to understand its origins. This article describes the pathology of the 3 well-established pancreatic cancer precursor lesions: pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasm, and mucinous cystic neoplasm. Each of these precursor lesions has unique clinical findings, gross and microscopic features, and molecular aberrations. This article focuses on histopathologic diagnostic criteria and reporting guidelines. The genetics of these lesions are briefly discussed. Early detection and adequate treatment of pancreatic cancer precursor lesions has the potential to prevent pancreatic cancer and improve the prognosis of PDAC.

6 Review Surgical and molecular pathology of pancreatic neoplasms. 2016

Hackeng, Wenzel M / Hruban, Ralph H / Offerhaus, G Johan A / Brosens, Lodewijk A A. ·Department of Pathology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Pathology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands. l.a.a.brosens@umcutrecht.nl. ·Diagn Pathol · Pubmed #27267993.

ABSTRACT: BACKGROUND: Histologic characteristics have proven to be very useful for classifying different types of tumors of the pancreas. As a result, the major tumor types in the pancreas have long been classified based on their microscopic appearance. MAIN BODY: Recent advances in whole exome sequencing, gene expression profiling, and knowledge of tumorigenic pathways have deepened our understanding of the underlying biology of pancreatic neoplasia. These advances have not only confirmed the traditional histologic classification system, but also opened new doors to early diagnosis and targeted treatment. CONCLUSION: This review discusses the histopathology, genetic and epigenetic alterations and potential treatment targets of the five major malignant pancreatic tumors - pancreatic ductal adenocarcinoma, pancreatic neuroendocrine tumor, solid-pseudopapillary neoplasm, acinar cell carcinoma and pancreatoblastoma.

7 Review Pancreatic adenocarcinoma pathology: changing "landscape". 2015

Brosens, Lodewijk A A / Hackeng, Wenzel M / Offerhaus, G Johan / Hruban, Ralph H / Wood, Laura D. ·1 Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands ; 2 Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. ·J Gastrointest Oncol · Pubmed #26261723.

ABSTRACT: Pancreatic cancer is a devastating disease. At time of diagnosis the disease is usually advanced and only a minority of patients are eligible for surgical resection. The overall 5-year survival is 6%. However, survival of patients with early stage pancreatic cancer is significantly better. To improve the prognosis of patients with pancreatic cancer, it is essential to diagnose and treat pancreatic cancer in the earliest stage. Prevention of pancreatic cancer by treating noninvasive precursor lesions just before they invade tissues can potentially lead to even better outcomes. Pancreatic carcinogenesis results from a stepwise progression in which accumulating genetic alterations drive neoplastic progression in well-defined precursor lesions, ultimately giving rise to an invasive adenocarcinoma. A thorough understanding of the genetic changes that drive pancreatic carcinogenesis can lead to identification of biomarkers for early detection and targets for therapy. Recent next-generation sequencing (NGS) studies have shed new light on our understanding of the natural history of pancreatic cancer and the precursor lesions that give rise to these cancers. Importantly, there is a significant window of opportunity for early detection and treatment between the first genetic alteration in a cell in the pancreas and development of full-blown pancreatic cancer. The current views on the pathology and genetics of pancreatic carcinogenesis that evolved from studies of pancreatic cancer and its precursor lesions are discussed in this review.

8 Article Comprehensive characterisation of pancreatic ductal adenocarcinoma with microsatellite instability: histology, molecular pathology and clinical implications. 2020

Luchini, Claudio / Brosens, Lodewijk A A / Wood, Laura D / Chatterjee, Deyali / Shin, Jae Il / Sciammarella, Concetta / Fiadone, Giulia / Malleo, Giuseppe / Salvia, Roberto / Kryklyva, Valentyna / Piredda, Maria L / Cheng, Liang / Lawlor, Rita T / Adsay, Volkan / Scarpa, Aldo. ·Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy claudio.luchini@univr.it. · Pathology, University Medical Center, Utrecht, The Netherlands. · Pathology, Radboud University Medical Center, Nijmegen, The Netherlands. · Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA. · Pathology and Immunology, Washington University in Saint Louis School of Medicine, Saint Louis, Missouri, USA. · Pediatrics, Yonsei University College of Medicine, Seoul, The Republic of Korea. · Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy. · General and Pancreatic Surgery, University and Hospital Trust of Verona, Verona, Italy. · Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA. · ARC-Net Research Center, University and Hospital Trust of Verona, Verona, Italy. · Pathology, Koç University Hospital, Istanbul, Turkey. · ARC-Net Research Center and Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy. ·Gut · Pubmed #32350089.

ABSTRACT: OBJECTIVE: Recently, tumours with microsatellite instability (MSI)/defective DNA mismatch repair (dMMR) have gained considerable interest due to the success of immunotherapy in this molecular setting. Here, we aim to clarify clinical-pathological and/or molecular features of this tumour subgroup through a systematic review coupled with a comparative analysis with existing databases, also providing indications for a correct approach to the clinical identification of MSI/dMMR pancreatic ductal adenocarcinoma (PDAC). DESIGN: PubMed, SCOPUS and Embase were searched for studies reporting data on MSI/dMMR in PDAC up to 30 November 2019. Histological and molecular data of MSI/dMMR PDAC were compared with non-MSI/dMMR PDAC and with PDAC reference cohorts (including SEER database and The Cancer Genome Atlas Research Network - TCGA project). RESULTS: Overall, 34 studies with 8323 patients with PDAC were included in the systematic review. MSI/dMMR demonstrated a very low prevalence in PDAC (around 1%-2%). Compared with conventional PDAC, MSI/dMMR PDAC resulted strongly associated with medullary and mucinous/colloid histology (p<0.01) and with a CONCLUSION: PDAC showing typical medullary or mucinous/colloid histology should be routinely examined for MSI/dMMR status using specific tests (immunohistochemistry, followed by MSI-PCR in cases with doubtful results). Next-generation sequencing (NGS) should be adopted either where there is limited tissue or as part of NGS tumour profiling in the context of precision oncology, acknowledging that conventional histology of PDAC may rarely harbour MSI/dMMR.

9 Article Impact of nationwide enhanced implementation of best practices in pancreatic cancer care (PACAP-1): a multicenter stepped-wedge cluster randomized controlled trial. 2020

Mackay, T M / Smits, F J / Latenstein, A E J / Bogte, A / Bonsing, B A / Bos, H / Bosscha, K / Brosens, L A A / Hol, L / Busch, O R C / Creemers, G J / Curvers, W L / den Dulk, M / van Dieren, S / van Driel, L M J W / Festen, S / van Geenen, E J M / van der Geest, L G / de Groot, D J A / de Groot, J W B / Haj Mohammad, N / Haberkorn, B C M / Haver, J T / van der Harst, E / Hemmink, G J M / de Hingh, I H / Hoge, C / Homs, M Y V / van Huijgevoort, N C / Jacobs, M A J M / Kerver, E D / Liem, M S L / Los, M / Lubbinge, H / Luelmo, S A C / de Meijer, V E / Mekenkamp, L / Molenaar, I Q / van Oijen, M G H / Patijn, G A / Quispel, R / van Rijssen, L B / Römkens, T E H / van Santvoort, H C / Schreinemakers, J M J / Schut, H / Seerden, T / Stommel, M W J / Ten Tije, A J / Venneman, N G / Verdonk, R C / Verheij, J / van Vilsteren, F G I / de Vos-Geelen, J / Vulink, A / Wientjes, C / Wit, F / Wessels, F J / Zonderhuis, B / van Werkhoven, C H / van Hooft, J E / van Eijck, C H J / Wilmink, J W / van Laarhoven, H W M / Besselink, M G / Anonymous3511177. ·Department of surgery, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, PO Box 22660, 1100 DD, Amsterdam, the Netherlands. · Department of surgery, University Medical Center Utrecht, Utrecht, the Netherlands. · Department of gastroenterology, Regional Academic Cancer Center Utrecht, University Medical Center Utrecht & St. Antonius Hospital, Nieuwegein, the Netherlands. · Department of surgery, Leiden University Medical Center, Leiden, the Netherlands. · Department of medical oncology, Tjongerschans Hospital, Heerenveen, the Netherlands. · Department of surgery, Jeroen Bosch Hospital, Den Bosch, the Netherlands. · Department of pathology, University Medical Center Utrecht, Utrecht, the Netherlands. · Department of pathology, Radboud University, Nijmegen, the Netherlands. · Department of gastroenterology, Maasstad Hospital, Rotterdam, the Netherlands. · Department of medical oncology, Catharina Hospital, Eindhoven, the Netherlands. · Department of gastroenterology, Catharina Hospital, Eindhoven, the Netherlands. · Department of surgery, Maastricht UMC+, Maastricht, the Netherlands. · Department of gastroenterology, Erasmus Medical Center, Rotterdam, the Netherlands. · Department of surgery, OLVG, Amsterdam, the Netherlands. · Department of gastroenterology, Radboud UMC, Nijmegen, the Netherlands. · Department of Research, Netherlands Comprehensive Cancer Organisation (IKNL), Utrecht, the Netherlands. · Department of medical oncology, University Medical Center Groningen, Groningen, the Netherlands. · Department of medical oncology, Oncology Center Isala, Zwolle, the Netherlands. · Department of Medical Oncology, Regional Academic Cancer Center Utrecht, University Medical Center Utrecht & St. Antonius Hospital, Nieuwegein, the Netherlands. · Department of medical oncology, Maasstad Hospital, Rotterdam, the Netherlands. · Department of nutrition and dietetics, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands. · Department of surgery, Maasstad Hospital, Rotterdam, the Netherlands. · Department of gastroenterology, Oncology Center Isala, Zwolle, the Netherlands. · Department of surgery, Catharina Hospital, Eindhoven, the Netherlands. · Department of gastroenterology, Maastricht UMC+, Maastricht, the Netherlands. · Department of medical oncology, Erasmus Medical Center, Rotterdam, the Netherlands. · Department of gastroenterology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands. · Department of gastroenterology, Cancer Center Amsterdam, Amsterdam UMC, VU Medical Center, Amsterdam, the Netherlands. · Department of medical oncology, OLVG, Amsterdam, the Netherlands. · Department of surgery, Medisch Spectrum Twente, Enschede, the Netherlands. · Department of gastroenterology, Tjongerschans Hospital, Heerenveen, the Netherlands. · Department of medical oncology, Leiden University Medical Center, Leiden, the Netherlands. · Department of surgery, University Medical Center Groningen, Groningen, the Netherlands. · Department of medical oncology, Medisch Spectrum Twente, Enschede, the Netherlands. · Department of surgery, Regional Academic Cancer Center Utrecht, University Medical Center Utrecht & St. Antonius Hospital, Nieuwegein, the Netherlands. · Department of medical oncology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands. · Department of surgery, Oncology Center Isala, Zwolle, the Netherlands. · Department of gastroenterology, Reinier de Graaf Hospital, Delft, the Netherlands. · Department of gastroenterology, Jeroen Bosch Hospital, Den Bosch, the Netherlands. · Department of surgery, Amphia Hospital, Breda, the Netherlands. · Department of medical oncology, Jeroen Bosch Hospital, Den Bosch, the Netherlands. · Department of gastroenterology, Amphia Hospital, Breda, the Netherlands. · Department of surgery, Radboud UMC, Nijmegen, the Netherlands. · Department of medical oncology, Amphia Hospital, Breda, the Netherlands. · Department of gastroenterology and hepatology, Medisch Spectrum Twente, Enschede, the Netherlands. · Department of pathology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands. · Department of gastroenterology, University Medical Center Groningen, Groningen, the Netherlands. · Department of medical oncology, Maastricht UMC+, Maastricht, the Netherlands. · Department of medical oncology, Reinier de Graaf Hospital, Delft, the Netherlands. · Department of gastroenterology, OLVG, Amsterdam, the Netherlands. · Department of surgery, Tjongerschans Hospital, Heerenveen, the Netherlands. · Department of radiology, Regional Academic Cancer Center Utrecht, University Medical Center Utrecht & St. Antonius Hospital, Nieuwegein, the Netherlands. · Department of surgery, Cancer Center Amsterdam, Amsterdam UMC, VU Medical Center, Amsterdam, the Netherlands. · Julius Center for Health Sciences and primary care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands. · Department of surgery, Erasmus Medical Center, Rotterdam, the Netherlands. · Department of surgery, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, PO Box 22660, 1100 DD, Amsterdam, the Netherlands. m.g.besselink@amsterdamumc.nl. ·Trials · Pubmed #32299515.

ABSTRACT: BACKGROUND: Pancreatic cancer has a very poor prognosis. Best practices for the use of chemotherapy, enzyme replacement therapy, and biliary drainage have been identified but their implementation in daily clinical practice is often suboptimal. We hypothesized that a nationwide program to enhance implementation of these best practices in pancreatic cancer care would improve survival and quality of life. METHODS/DESIGN: PACAP-1 is a nationwide multicenter stepped-wedge cluster randomized controlled superiority trial. In a per-center stepwise and randomized manner, best practices in pancreatic cancer care regarding the use of (neo)adjuvant and palliative chemotherapy, pancreatic enzyme replacement therapy, and metal biliary stents are implemented in all 17 Dutch pancreatic centers and their regional referral networks during a 6-week initiation period. Per pancreatic center, one multidisciplinary team functions as reference for the other centers in the network. Key best practices were identified from the literature, 3 years of data from existing nationwide registries within the Dutch Pancreatic Cancer Project (PACAP), and national expert meetings. The best practices follow the Dutch guideline on pancreatic cancer and the current state of the literature, and can be executed within daily clinical practice. The implementation process includes monitoring, return visits, and provider feedback in combination with education and reminders. Patient outcomes and compliance are monitored within the PACAP registries. Primary outcome is 1-year overall survival (for all disease stages). Secondary outcomes include quality of life, 3- and 5-year overall survival, and guideline compliance. An improvement of 10% in 1-year overall survival is considered clinically relevant. A 25-month study duration was chosen, which provides 80% statistical power for a mortality reduction of 10.0% in the 17 pancreatic cancer centers, with a required sample size of 2142 patients, corresponding to a 6.6% mortality reduction and 4769 patients nationwide. DISCUSSION: The PACAP-1 trial is designed to evaluate whether a nationwide program for enhanced implementation of best practices in pancreatic cancer care can improve 1-year overall survival and quality of life. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03513705. Trial opened for accrual on 22th May 2018.

10 Article Genetic Analysis of Small Well-differentiated Pancreatic Neuroendocrine Tumors Identifies Subgroups With Differing Risks of Liver Metastases. 2020

Pea, Antonio / Yu, Jun / Marchionni, Luigi / Noe, Michael / Luchini, Claudio / Pulvirenti, Alessandra / de Wilde, Roeland F / Brosens, Lodewijk A / Rezaee, Neda / Javed, Ammar / Chianchiano, Peter / Gobbo, Stefano / Regi, Paolo / Salvia, Roberto / Bassi, Claudio / He, Jin / Weiss, Matthew J / Cameron, John L / Offerhaus, G Johan A / Hruban, Ralph H / Lawlor, Rita T / Scarpa, Aldo / Heaphy, Christopher M / Wood, Laura D / Wolfgang, Christopher L. ·Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD. · Department of Surgery, The Pancreas Institute, Verona, Italy. · Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD. · Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy. · Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands. · Department of Pathology, Pederzoli Hospital, Peschiera, Italy. · Department of Surgery, Pederzoli Hospital, Peschiera, Italy. · ARC-Net Applied Research on Cancer Center, University and Hospital Trust of Verona, Verona, Italy. ·Ann Surg · Pubmed #30339629.

ABSTRACT: OBJECTIVE: The aim of this study was to investigate the key molecular alterations in small primary pancreatic neuroendocrine tumors (PanNETs) associated with the development of liver metastases. BACKGROUND: Well-differentiated PanNETs with small size are typically indolent; however, a limited subset metastasize to the liver. METHODS: A total of 87 small primary PanNETs (<3 cm), including 32 metastatic cases and 55 nonmetastatic cases after a 5-year follow-up, were immunolabeled for DAXX/ATRX and analyzed for alternative lengthening of telomeres (ALT) by Fluorescence In Situ Hybridization. A subset of these cases, 24 that metastasized and 24 that did not metastasize, were assessed by targeted next-generation sequencing and whole-genome copy number variation. RESULTS: In the entire cohort, high Ki-67 (OR 1.369; 95% CI 1.121-1.673; P = 0.002), N-stage (OR 4.568; 95% CI 1.458-14.312; P = 0.009), and ALT-positivity (OR 3.486; 95% CI 1.093-11.115; P = 0.035) were independently associated with liver metastases. In the subset assessed by next-generation sequencing and copy number variation analysis, 3 molecular subtypes with differing risks of liver metastases were identified. Group 1 (n = 15; 73% metastasized) was characterized by recurrent chromosomal gains, CN-LOH, DAXX mutations, and ALT-positivity. Group 2 (n = 19; 42% metastasized, including 5 G1 tumors) was characterized by limited copy number alterations and mutations. Group 3 (n = 14; 35% metastasized) were defined by chromosome 11 loss. CONCLUSIONS: We identified genomic patterns of small PanNETs associated with a different risk for liver metastases. Molecular alterations, such as DAXX mutations, chromosomal gains, and ALT, are associated with an increased risk of metastasis in small PanNETs. Therefore, targeted sequencing and/or ALT analysis may help in the clinical decisions for these small PanNETs.

11 Article Pancreatic cancer organoids recapitulate disease and allow personalized drug screening. 2019

Driehuis, Else / van Hoeck, Arne / Moore, Kat / Kolders, Sigrid / Francies, Hayley E / Gulersonmez, M Can / Stigter, Edwin C A / Burgering, Boudewijn / Geurts, Veerle / Gracanin, Ana / Bounova, Gergana / Morsink, Folkert H / Vries, Robert / Boj, Sylvia / van Es, Johan / Offerhaus, G Johan A / Kranenburg, Onno / Garnett, Mathew J / Wessels, Lodewyk / Cuppen, Edwin / Brosens, Lodewijk A A / Clevers, Hans. ·Oncode Institute, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands. · Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center Utrecht, 3584 CT Utrecht, The Netherlands. · Center for Molecular Medicine, University Medical Center Utrecht, 3584 CG Utrecht, The Netherlands. · Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands. · Wellcome Sanger Institute, Hinxton CB10 1SA, United Kingdom. · Department of Molecular Cancer Research, Center Molecular Medicine, Oncode Institute, University Medical Center Utrecht, Utrecht 3584 CM, The Netherlands. · Hubrecht Organoid Technology, Utrecht 3584 CM, The Netherlands. · Department of Pathology, University Medical Center Utrecht, Utrecht 3584 CM, The Netherlands. · Utrecht Platform for Organoid Technology, Utrecht Medical Center Utrecht, Utrecht 3584 CM, The Netherlands. · Hartwig Medical Foundation, 1098 XH Amsterdam, The Netherlands. · Center for Personalized Cancer Treatment,University Medical Center Utrecht, Utrecht 3584 CM, The Netherlands. · Oncode Institute, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands; h.clevers@hubrecht.eu. · Princess Maxima Center, Utrecht 3584 CS, The Netherlands. ·Proc Natl Acad Sci U S A · Pubmed #31818951.

ABSTRACT: We report the derivation of 30 patient-derived organoid lines (PDOs) from tumors arising in the pancreas and distal bile duct. PDOs recapitulate tumor histology and contain genetic alterations typical of pancreatic cancer. In vitro testing of a panel of 76 therapeutic agents revealed sensitivities currently not exploited in the clinic, and underscores the importance of personalized approaches for effective cancer treatment. The PRMT5 inhibitor EZP015556, shown to target

12 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'

13 Article Well-differentiated Pancreatic Neuroendocrine Tumor in a Patient With Familial Atypical Multiple Mole Melanoma Syndrome (FAMMM). 2019

Noë, Michaël / Hackeng, Wenzel M / de Leng, Wendy W J / Vergeer, Menno / Vleggaar, Frank P / Morsink, Folkert H M / Wood, Laura D / Hruban, Ralph H / Offerhaus, G Johan A / Brosens, Lodewijk A A. ·Departments of Pathology. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Hospital, Baltimore, MD. · Internal Medicine. · Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, The Netherlands. ·Am J Surg Pathol · Pubmed #31261289.

ABSTRACT: Germline mutations in CDKN2A result in Familial Atypical Multiple Mole Melanoma Syndrome (FAMMM), which is associated with an increased risk for pancreatic ductal adenocarcinoma and melanoma. CDKN2A is somatically inactivated in multiple neoplasms, raising the possibility that, although the data are not conclusive, germline CDKN2A mutation may also impose an increased risk for other neoplasms. We present a patient with a CDKN2A germline mutation (p16-Leiden mutation) and mosaicism for neurofibromatosis type 2, who presented with a small asymptomatic pancreatic lesion, detected during endoscopic ultrasound screening of the pancreas. After resection, the lesion was found to be a well-differentiated pancreatic neuroendocrine tumor (PanNET). Molecular analysis of the tumor showed somatic loss of the second allele, supporting a causal relation of the PanNET to the underlying FAMMM syndrome. Recent data, showing the association between certain single-nucleotide polymorphisms in the CDKN2A gene and an increased incidence for PanNET, further support a role for germline CDKN2A alterations in PanNET risk. We conclude that PanNETs can be a phenotypic expression of FAMMM syndrome. This can have implications for screening and for the diagnosis of pancreatic neoplasms in carriers of germline CDKN2A mutations.

14 Article Pseudomyxoma Peritonei After a Total Pancreatectomy for Intraductal Papillary Mucinous Neoplasm With Colloid Carcinoma in Lynch Syndrome. 2019

Hackeng, Wenzel M / de Guerre, Livia E V M / Kuypers, Karel C / Snoek, Alexander M / Morsink, Folkert H / Offerhaus, G Johan A / Brosens, Lodewijk A A. ·Departments of Pathology and. · Radiology, St Antonius Hospital, Nieuwegein, the Netherlands. ·Pancreas · Pubmed #30531244.

ABSTRACT: We report a case of pseudomyxoma peritonei (PMP) arising in a 62-year-old male patient with Lynch syndrome (LS). The patient's medical history included an adenocarcinoma of the colon for which a right hemicolectomy was performed and a pancreatectomy due to an intraductal papillary mucinous neoplasm (IPMN) with invasive colloid carcinoma. It was considered that the PMP could be a metastasis of the earlier colonic or pancreatic carcinoma. The pancreatic carcinoma, colon carcinoma, and PMP tissues were examined, and immunohistochemical and molecular analyses were performed to determine the PMP origin. Histopathologic examination revealed morphological similarities with the pancreatic colloid carcinoma, and further immunohistochemical and molecular analyses, including a shared GNAS mutation, confirmed the pancreatic origin of the PMP. In conclusion, this is a unique case of a patient with LS presenting with PMP originating from an IPMN with invasive colloid carcinoma, several years after pancreatectomy. The present case has important diagnostic implications. The IPMN should be considered as a rare extracolonic manifestation of LS, and pancreatic carcinoma origin should be considered in patients presenting with PMP. This case report highlights the added value of molecular diagnostics in daily pathology practice.

15 Article PD-1, PD-L1, and CD163 in pancreatic undifferentiated carcinoma with osteoclast-like giant cells: expression patterns and clinical implications. 2018

Luchini, Claudio / Cros, Jerome / Pea, Antonio / Pilati, Camilla / Veronese, Nicola / Rusev, Borislav / Capelli, Paola / Mafficini, Andrea / Nottegar, Alessia / Brosens, Lodewijk A A / Noë, Michaël / Offerhaus, G Johan A / Chianchiano, Peter / Riva, Giulio / Piccoli, Paola / Parolini, Claudia / Malleo, Giuseppe / Lawlor, Rita T / Corbo, Vincenzo / Sperandio, Nicola / Barbareschi, Mattia / Fassan, Matteo / Cheng, Liang / Wood, Laura D / Scarpa, Aldo. ·Department of Diagnostics and Public Health, Section of Pathology, University of Verona, 37134 Verona, Italy. · Department of Pathology, Beaujon Hospital, 92110 Clichy, France; Paris-Diderot School of Medicine, Inflammation Research Center, 75013 Paris, France. · Department of Surgery, University and Hospital Trust of Verona, 37134 Verona, Italy. · Personalized Medicine, Pharmacogenomics, Therapeutic Optimization, Paris-Descartes University, 75006 Paris, France. · National Institute of Gastroenterology-Research Hospital, IRCCS "S. de Bellis," 70013, Castellana Grotte, Bari, Italy. · ARC-Net Research Center, University of Verona, 37134 Verona, Italy. · Department of Surgery, Section of Pathology, San Bortolo Hospital, 36100 Vicenza, Italy. · Department of Pathology, University Medical Center Utrecht, 3508 Utrecht, The Netherlands; Department of Pathology, Radboud University Medical Center, 6500, HB, Nijmegen, The Netherlands. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21211, USA. · Department of Pathology, University Medical Center Utrecht, 3508 Utrecht, The Netherlands. · Surgical Pathology Unit, Santa Chiara Hospital, 38122 Trento, Italy. · Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21211, USA; Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21211, USA. Electronic address: ldwood@jhmi.edu. · Department of Diagnostics and Public Health, Section of Pathology, University of Verona, 37134 Verona, Italy; ARC-Net Research Center, University of Verona, 37134 Verona, Italy. Electronic address: aldo.scarpa@univr.it. ·Hum Pathol · Pubmed #30031096.

ABSTRACT: Undifferentiated carcinoma with osteoclast-like giant cells (UCOGC), a variant of pancreatic ductal adenocarcinoma (PDAC), has a striking genetic similarity to PDAC but a significantly improved overall survival. We hypothesize that this difference could be due to the immune response to the tumor, and as such, we investigated the expression of PD-1, PD-L1, and CD163 in a series of UCOGC. To this aim, 27 pancreatic UCOGCs (11 pure and 16 PDAC-associated), 5 extrapancreatic tumors with osteoclast-like giant cells and 10 pancreatic anaplastic carcinomas were immunostained using antibodies against PD-1, PD-L1, and CD163. In pancreatic UCOGCs, PD-L1 was expressed in neoplastic cells of 17 (63%) of 27 cases, more often in cases with an associated PDAC (P = .04). Expression of PD-L1 was associated with poor prognosis, confirmed by multivariate analysis: patients with PD-L1-positive UCOGCs had a risk of all-cause mortality that was 3 times higher than did patients with PD-L1-negative UCOGCs (hazard ratio, 3.397; 95% confidence interval, 1.023-18.375; P = .034). PD-L1 expression on tumor cells was also associated with aberrant P53 expression (P = .035). PD-1 was expressed on rare lymphocytes in 12 UCOGCs (44.4%), mainly located at the tumor periphery. CD163 was expressed on histiocytes, with a diffuse and strong staining pattern in all UCOGCs. Extrapancreatic tumors with osteoclast-like giant cells showed very similar staining patterns for the same proteins. Anaplastic carcinomas have some similarities to UCOGCs, but PD-L1 has no prognostic roles. Our results may have important implications for immunotherapeutic strategies in UCOGCs; these tumors may also represent a model for future therapeutic approaches against PDAC.

16 Article DNA methylation profiling in MEN1-related pancreatic neuroendocrine tumors reveals a potential epigenetic target for treatment. 2018

Conemans, E B / Lodewijk, L / Moelans, C B / Offerhaus, G J A / Pieterman, C R C / Morsink, F H / Dekkers, O M / de Herder, W W / Hermus, A R / van der Horst-Schrivers, A N / Drent, M L / Bisschop, P H / Havekes, B / Brosens, L A A / Dreijerink, K M A / Borel Rinkes, I H M / Timmers, H Th M / Valk, G D / Vriens, M R. ·Departments of Surgery, University Medical Center Utrecht, Utrecht, The Netherlands. · Departments of Internal Medicine, University Medical Center Utrecht, Utrecht, The Netherlands. · Departments of Section Endocrinology, Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands. · Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands. · Departments of Endocrinology and Metabolism and Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands. · Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. · Department of Endocrinology, Radboud University Medical Center, Nijmegen, The Netherlands. · Department of Endocrinology, University Medical Center Groningen, Groningen, The Netherlands. · Department of Endocrinology and Metabolism, Academic Medical Center, Amsterdam, The Netherlands. · Division of Endocrinology, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands. · Regenerative Medicine Center and Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands. · German Cancer Consortium (DKTK) Partner Site Freiburg, German Cancer Research Center (DKFZ) and Department of Urology, Medical Center-University of Freiburg, Freiburg, Germany. ·Eur J Endocrinol · Pubmed #29903750.

ABSTRACT: OBJECTIVE: Epigenetic changes contribute to pancreatic neuroendocrine tumor (PanNET) development. Hypermethylation of promoter DNA as a cause of tumor suppressor gene silencing is a well-established oncogenic mechanism that is potentially reversible and therefore an interesting therapeutic target. Multiple endocrine neoplasia type 1 (MEN1) is the most frequent cause of inherited PanNETs. The aim of this study was to determine promoter methylation profiles in MEN1-related PanNETs. DESIGN AND METHODS: Methylation-specific multiplex ligation-dependent probe amplification was used to assess promoter methylation of 56 tumor suppressor genes in MEN1-related ( RESULTS: We found promoter methylation of a large number of potential tumor suppressor genes. CMI (median CMI: 912 vs 876, CONCLUSION: Promoter hypermethylation is a frequent event in MEN1-related and sporadic PanNETs. Targeting DNA methylation could be of therapeutic value in MEN1 patients with advanced PanNETs.

17 Article Immunolabeling of Cleared Human Pancreata Provides Insights into Three-Dimensional Pancreatic Anatomy and Pathology. 2018

Noë, Michaël / Rezaee, Neda / Asrani, Kaushal / Skaro, Michael / Groot, Vincent P / Wu, Pei-Hsun / Olson, Matthew T / Hong, Seung-Mo / Kim, Sung Joo / Weiss, Matthew J / Wolfgang, Christopher L / Makary, Martin A / He, Jin / Cameron, John L / Wirtz, Denis / Roberts, Nicholas J / Offerhaus, G Johan A / Brosens, Lodewijk A A / Wood, Laura D / Hruban, Ralph H. ·Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Surgery, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland. · Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland. · Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address: ldwood@jhmi.edu. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address: rhruban@jhmi.edu. ·Am J Pathol · Pubmed #29684363.

ABSTRACT: Visualizing pathologies in three dimensions can provide unique insights into the biology of human diseases. A rapid and easy-to-implement dibenzyl ether-based technique was used to clear thick sections of surgically resected human pancreatic parenchyma. Protocols were applicable to both fresh and formalin-fixed, paraffin-embedded tissue. The penetration of antibodies into dense pancreatic parenchyma was optimized using both gradually increasing antibody concentrations and centrifugal flow. Immunolabeling with antibodies against cytokeratin 19 was visualized using both light sheet and confocal laser scanning microscopy. The technique was applied successfully to 26 sections of pancreas, providing three-dimensional (3D) images of normal pancreatic tissue, pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasms, and infiltrating pancreatic ductal adenocarcinomas. 3D visualization highlighted processes that are hard to conceptualize in two dimensions, such as invasive carcinoma growing into what appeared to be pre-existing pancreatic ducts and within venules, and the tracking of long cords of neoplastic cells parallel to blood vessels. Expanding this technique to formalin-fixed, paraffin-embedded tissue opens pathology archives to 3D visualization of unique biosamples and rare diseases. The application of immunolabeling and clearing to human pancreatic parenchyma provides detailed visualization of normal pancreatic anatomy, and can be used to characterize the 3D architecture of diseases including pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasm, and pancreatic ductal adenocarcinomas.

18 Article The Dutch Pancreas Biobank Within the Parelsnoer Institute: A Nationwide Biobank of Pancreatic and Periampullary Diseases. 2018

Strijker, Marin / Gerritsen, Arja / van Hilst, Jony / Bijlsma, Maarten F / Bonsing, Bert A / Brosens, Lodewijk A / Bruno, Marco J / van Dam, Ronald M / Dijk, Frederike / van Eijck, Casper H / Farina Sarasqueta, Arantza / Fockens, Paul / Gerhards, Michael F / Groot Koerkamp, Bas / van der Harst, Erwin / de Hingh, Ignace H / van Hooft, Jeanin E / Huysentruyt, Clément J / Kazemier, Geert / Klaase, Joost M / van Laarhoven, Cornelis J / van Laarhoven, Hanneke W / Liem, Mike S / de Meijer, Vincent E / van Rijssen, L Bengt / van Santvoort, Hjalmar C / Suker, Mustafa / Verhagen, Judith H / Verheij, Joanne / Verspaget, Hein W / Wennink, Roos A / Wilmink, Johanna W / Molenaar, I Quintus / Boermeester, Marja A / Busch, Olivier R / Besselink, Marc G / Anonymous3030939. · ·Pancreas · Pubmed #29521943.

ABSTRACT: OBJECTIVES: Large biobanks with uniform collection of biomaterials and associated clinical data are essential for translational research. The Netherlands has traditionally been well organized in multicenter clinical research on pancreatic diseases, including the nationwide multidisciplinary Dutch Pancreatic Cancer Group and Dutch Pancreatitis Study Group. To enable high-quality translational research on pancreatic and periampullary diseases, these groups established the Dutch Pancreas Biobank. METHODS: The Dutch Pancreas Biobank is part of the Parelsnoer Institute and involves all 8 Dutch university medical centers and 5 nonacademic hospitals. Adult patients undergoing pancreatic surgery (all indications) are eligible for inclusion. Preoperative blood samples, tumor tissue from resected specimens, pancreatic cyst fluid, and follow-up blood samples are collected. Clinical parameters are collected in conjunction with the mandatory Dutch Pancreatic Cancer Audit. RESULTS: Between January 2015 and May 2017, 488 patients were included in the first 5 participating centers: 4 university medical centers and 1 nonacademic hospital. Over 2500 samples were collected: 1308 preoperative blood samples, 864 tissue samples, and 366 follow-up blood samples. CONCLUSIONS: Prospective collection of biomaterials and associated clinical data has started in the Dutch Pancreas Biobank. Subsequent translational research will aim to improve treatment decisions based on disease characteristics.

19 Article IPMNs with co-occurring invasive cancers: neighbours but not always relatives. 2018

Felsenstein, Matthäus / Noë, Michaël / Masica, David L / Hosoda, Waki / Chianchiano, Peter / Fischer, Catherine G / Lionheart, Gemma / Brosens, Lodewijk A A / Pea, Antonio / Yu, Jun / Gemenetzis, Georgios / Groot, Vincent P / Makary, Martin A / He, Jin / Weiss, Matthew J / Cameron, John L / Wolfgang, Christopher L / Hruban, Ralph H / Roberts, Nicholas J / Karchin, Rachel / Goggins, Michael G / Wood, Laura D. ·Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Department of Surgery, Charité-Universitätsmedizin Berlin, Berlin, Germany. · Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland, USA. · Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, USA. · Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands. · Department of Surgery, University and Hospital Trust of Verona, Verona, Italy. · Department of Surgery, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Department of Surgery, University Medical Center Utrecht, Utrecht, The Netherlands. · Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. ·Gut · Pubmed #29500184.

ABSTRACT: OBJECTIVE: Intraductal papillary mucinous neoplasms (IPMNs) are precursor lesions that can give rise to invasive pancreatic carcinoma. Although approximately 8% of patients with resected pancreatic ductal adenocarcinoma have a co-occurring IPMN, the precise genetic relationship between these two lesions has not been systematically investigated. DESIGN: We analysed all available patients with co-occurring IPMN and invasive intrapancreatic carcinoma over a 10-year period at a single institution. For each patient, we separately isolated DNA from the carcinoma, adjacent IPMN and distant IPMN and performed targeted next generation sequencing of a panel of pancreatic cancer driver genes. We then used the identified mutations to infer the relatedness of the IPMN and co-occurring invasive carcinoma in each patient. RESULTS: We analysed co-occurring IPMN and invasive carcinoma from 61 patients with IPMN/ductal adenocarcinoma as well as 13 patients with IPMN/colloid carcinoma and 7 patients with IPMN/carcinoma of the ampullary region. Of the patients with co-occurring IPMN and ductal adenocarcinoma, 51% were likely related. Surprisingly, 18% of co-occurring IPMN and ductal adenocarcinomas were likely independent, suggesting that the carcinoma arose from an independent precursor. By contrast, all colloid carcinomas were likely related to their associated IPMNs. In addition, these analyses showed striking genetic heterogeneity in IPMNs, even with respect to well-characterised driver genes. CONCLUSION: This study demonstrates a higher prevalence of likely independent co-occurring IPMN and ductal adenocarcinoma than previously appreciated. These findings have important implications for molecular risk stratification of patients with IPMN.

20 Article Prognostic value of WHO grade in pancreatic neuro-endocrine tumors in Multiple Endocrine Neoplasia type 1: Results from the DutchMEN1 Study Group. 2017

Conemans, Elfi B / Brosens, Lodewijk A A / Raicu-Ionita, Gabriela M / Pieterman, Carolina R C / de Herder, Wouter W / Dekkers, Olaf M / Hermus, Ad R / van der Horst-Schrivers, Anouk N / Bisschop, Peter H / Havekes, Bas / Drent, Madeleine L / Timmers, H Th Marc / Offerhaus, G Johan / Valk, Gerlof D / Vriens, Menno R. ·Department of Endocrine Surgical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands; Department of Endocrine Oncology, University Medical Center Utrecht, Utrecht, The Netherlands. · Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands. · Department of Endocrine Oncology, University Medical Center Utrecht, Utrecht, The Netherlands. · Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. · Departments of Endocrinology and Metabolism and Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands. · Department of Endocrinology, Radboud University Medical Center, Nijmegen, The Netherlands. · Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. · Department of Endocrinology and Metabolism, Academic Medical Center, Amsterdam, The Netherlands. · Department of Internal Medicine, Division of Endocrinology, Maastricht University Medical Center, Maastricht, The Netherlands. · Department of Internal Medicine, Section of Endocrinology, VU University Medical Center, Amsterdam, The Netherlands. · Molecular Cancer Research, Regenerative Medicine Center, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands. · Department of Endocrine Surgical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands. Electronic address: mvriens@umcutrecht.nl. ·Pancreatology · Pubmed #28811081.

ABSTRACT: BACKGROUND: The prognostic value of WHO grade in pancreatic neuroendocrine tumors (PanNETs) in patients with Multiple Endocrine Neoplasia Type 1 (MEN1) is unknown. METHODS: We performed a cohort study using the Dutch National MEN1 database, which includes >90% of the Dutch MEN1 population with data collected between 1990 and 2014. Formalin-fixed paraffin embedded tissue blocks from the largest resected PanNET per patient were collected. MIB1 staining was performed and KI67 labeling index (LI) was determined by manual eye-counting under a microscope and by digital image analysis. Mitotic count was evaluated from hematoxylin & eosin stains. Association between WHO grade and (time until) development of liver metastases was calculated. RESULTS: Sixty-nine MEN1 patients who underwent pancreatic surgery were included. Ten patients (14%) developed liver metastases and all had PanNETs ≥3 cm. WHO G1, G2 and G3 PanNETs were seen in 83% (n = 57), 16% (n = 11) and 1% (n = 1) respectively. In non-functioning PanNETs >2 cm, liver metastases occurred in 80% of WHO G2 PanNETs (4/5) compared to 23% (5/22) in WHO G1 PanNETs (p = 0.03) when WHO grade was based on mitotic count only. This significant association was not seen for WHO grade based on Ki67 LI. After five years, liver metastases in non-functioning PanNETs were not seen in tumors ≤2 cm, in 10% of the large WHO G1 (according to mitotic count only) tumors and in 60% of large WHO G2 tumors (p-value 0.000). CONCLUSION: High mitotic count is correlated with poor prognosis in MEN1 patients with large non-functioning PanNETs.

21 Article Pancreatic undifferentiated carcinoma with osteoclast-like giant cells is genetically similar to, but clinically distinct from, conventional ductal adenocarcinoma. 2017

Luchini, Claudio / Pea, Antonio / Lionheart, Gemma / Mafficini, Andrea / Nottegar, Alessia / Veronese, Nicola / Chianchiano, Peter / Brosens, Lodewijk Aa / Noë, Michaël / Offerhaus, G Johan A / Yonescu, Raluca / Ning, Yi / Malleo, Giuseppe / Riva, Giulio / Piccoli, Paola / Cataldo, Ivana / Capelli, Paola / Zamboni, Giuseppe / Scarpa, Aldo / Wood, Laura D. ·Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Verona, Italy. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Surgery, University and Hospital Trust of Verona, Verona, Italy. · Department of Surgery, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · ARC-Net Research Center, University of Verona, Verona, Italy. · National Research Council, Neuroscience Institute, Aging Branch, Padua, Italy. · Institute for Clinical Research and Education in Medicine (IREM), Padua, Italy. · Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands. · Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands. · Sacro Cuore Don Calabria Hospital, Negrar, Verona, Italy. · Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. ·J Pathol · Pubmed #28722124.

ABSTRACT: Undifferentiated carcinoma of the pancreas with osteoclast-like giant cells (UCOGC) is currently considered a morphologically and clinically distinct variant of pancreatic ductal adenocarcinoma (PDAC). In this study, we report clinical and pathological features of a series of 22 UCOGCs, including the whole exome sequencing of eight UCOGCs. We observed that 60% of the UCOGCs contained a well-defined epithelial component and that patients with pure UCOGC had a significantly better prognosis than did those with an UCOGC with an associated epithelial neoplasm. The genetic alterations in UCOGC are strikingly similar to those known to drive conventional PDAC, including activating mutations in the oncogene KRAS and inactivating mutations in the tumor suppressor genes CDKN2A, TP53, and SMAD4. These results further support the classification of UCOGC as a PDAC variant and suggest that somatic mutations are not the determinants of the unique phenotype of UCOGC. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

22 Article Genetic analyses of isolated high-grade pancreatic intraepithelial neoplasia (HG-PanIN) reveal paucity of alterations in TP53 and SMAD4. 2017

Hosoda, Waki / Chianchiano, Peter / Griffin, James F / Pittman, Meredith E / Brosens, Lodewijk Aa / Noë, Michaël / Yu, Jun / Shindo, Koji / Suenaga, Masaya / Rezaee, Neda / Yonescu, Raluca / Ning, Yi / Albores-Saavedra, Jorge / Yoshizawa, Naohiko / Harada, Kenichi / Yoshizawa, Akihiko / Hanada, Keiji / Yonehara, Shuji / Shimizu, Michio / Uehara, Takeshi / Samra, Jaswinder S / Gill, Anthony J / Wolfgang, Christopher L / Goggins, Michael G / Hruban, Ralph H / Wood, Laura D. ·Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York, USA. · Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands. · Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Department of Pathology, Medica Sur Clinic and Foundation, Mexico City, Mexico. · The First Department of Internal Medicine, Mie University School of Medicine, Tsu, Japan. · Department of Human Pathology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan. · Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan. · Center for Gastroendoscopy, Onomichi General Hospital, Onomichi, Japan. · Department of Pathology, Onomichi General Hospital, Onomich, Japan. · Diagnostic Pathology Center, Hakujikai Memorial Hospital, Tokyo, Japan. · Department of Laboratory Medicine, Shinshu University School of Medicine, Matsumoto, Japan. · Department of Gastrointestinal Surgery, Royal North Shore Hospital and Discipline of Surgery, University of Sydney, Sydney, Australia. · Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research Royal North Shore Hospital and University of Sydney, Sydney, Australia. · Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Department of Medicine, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. ·J Pathol · Pubmed #28188630.

ABSTRACT: High-grade pancreatic intraepithelial neoplasia (HG-PanIN) is the major precursor of pancreatic ductal adenocarcinoma (PDAC) and is an ideal target for early detection. To characterize pure HG-PanIN, we analysed 23 isolated HG-PanIN lesions occurring in the absence of PDAC. Whole-exome sequencing of five of these HG-PanIN lesions revealed a median of 33 somatic mutations per lesion, with a total of 318 mutated genes. Targeted next-generation sequencing of 17 HG-PanIN lesions identified KRAS mutations in 94% of the lesions. CDKN2A alterations occurred in six HG-PanIN lesions, and RNF43 alterations in five. Mutations in TP53, GNAS, ARID1A, PIK3CA, and TGFBR2 were limited to one or two HG-PanINs. No non-synonymous mutations in SMAD4 were detected. Immunohistochemistry for p53 and SMAD4 proteins in 18 HG-PanINs confirmed the paucity of alterations in these genes, with aberrant p53 labelling noted only in three lesions, two of which were found to be wild type in sequencing analyses. Sixteen adjacent LG-PanIN lesions from ten patients were also sequenced using targeted sequencing. LG-PanIN harboured KRAS mutations in 94% of the lesions; mutations in CDKN2A, TP53, and SMAD4 were not identified. These results suggest that inactivation of TP53 and SMAD4 are late genetic alterations, predominantly occurring in invasive PDAC. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

23 Article Aberrant Menin expression is an early event in pancreatic neuroendocrine tumorigenesis. 2016

Hackeng, Wenzel M / Brosens, Lodewijk A A / Poruk, Katherine E / Noë, Michaël / Hosoda, Waki / Poling, Justin S / Rizzo, Anthony / Campbell-Thompson, Martha / Atkinson, Mark A / Konukiewitz, Björn / Klöppel, Günter / Heaphy, Christopher M / Meeker, Alan K / Wood, Laura D. ·Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Pathology, University Medical Center Utrecht, Utrecht 3584, CX, the Netherlands. · Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. · Department of Pathology, College of Medicine, University of Florida, Gainesville, FL 32610-0275, USA. · Department of Pathology, College of Medicine, University of Florida, Gainesville, FL 32610-0275, USA; Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL 32610-0275, USA. · Department of Pathology, Technical University Munich, 81675 Munich, Germany. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. Electronic address: ldwood@jhmi.edu. ·Hum Pathol · Pubmed #27342911.

ABSTRACT: Pancreatic neuroendocrine tumors (PanNETs) are the second most common pancreatic malignancy and cause significant morbidity and mortality. Neuroendocrine microadenomas have been proposed as a potential precursor lesion for sporadic PanNETs. In this study, we applied telomere-specific fluorescent in situ hybridization (FISH) to a series of well-characterized sporadic neuroendocrine microadenomas and investigated the prevalence of alterations in known PanNET driver genes (MEN1 and ATRX/DAXX) in these same tumors using immunohistochemistry for the encoded proteins. We identified aberrant Menin expression in 14 of 19 (74%) microadenomas, suggesting that alterations in Menin, at least a subset of which was likely due to somatic mutation, are early events in pancreatic neuroendocrine tumorigenesis. In contrast, none of the microadenomas met criteria for the alternative lengthening of telomeres phenotype (ALT) based on telomere FISH, a phenotype that is strongly correlated to ATRX or DAXX mutations. Two of 13 microadenomas (15%) were noted to have very rare abnormal bright telomere foci on FISH, suggestive of early ALT, but these lesions did not show loss of ATRX or DAXX protein expression by immunohistochemistry. Overall, these data suggest that loss of Menin is an early event in pancreatic neuroendocrine tumorigenesis and that ATRX/DAXX loss and ALT are relatively late events.

24 Article A Revised Classification System and Recommendations From the Baltimore Consensus Meeting for Neoplastic Precursor Lesions in the Pancreas. 2015

Basturk, Olca / Hong, Seung-Mo / Wood, Laura D / Adsay, N Volkan / Albores-Saavedra, Jorge / Biankin, Andrew V / Brosens, Lodewijk A A / Fukushima, Noriyoshi / Goggins, Michael / Hruban, Ralph H / Kato, Yo / Klimstra, David S / Klöppel, Günter / Krasinskas, Alyssa / Longnecker, Daniel S / Matthaei, Hanno / Offerhaus, G Johan A / Shimizu, Michio / Takaori, Kyoichi / Terris, Benoit / Yachida, Shinichi / Esposito, Irene / Furukawa, Toru / Anonymous4670848. ·*Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY ‡Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD §Department of Pathology and Laboratory Medicine, Emory University Hospital, Atlanta, GA §§Department of Pathology, Dartmouth-Hitchcock Medical Center, Lebanon, NH †Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Ulsan, Korea ∥Department of Pathology, Medica Sur Clinic and Foundation, Mexico City, Mexico ¶Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, UK #Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands **Department of Pathology, Jichi Medical University, Shimotsuke ††Department of Pathology, Cancer Institute, Japanese Foundation for Cancer Research ¶¶Department of Pathology, Hakujikai Memorial Hospital †††Division of Cancer Genomics, National Cancer Center Research Institute §§§Institute for Integrated Medical Sciences, Tokyo Women's Medical University, Tokyo ##Department of Surgery, Kyoto University, Kyoto, Japan ‡‡Department of Pathology, Technical University Munich, Munich ∥∥Department of General, Visceral, Thoracic and Vascular Surgery, University of Bonn, Bonn ‡‡‡Institute of Pathology, Heinrich-Heine University and University Hospital of Düsseldorf, Düsseldorf, Germany ***Service d'Anatomie Pathologique, Hôpital Cochin, Paris, France. ·Am J Surg Pathol · Pubmed #26559377.

ABSTRACT: International experts met to discuss recent advances and to revise the 2004 recommendations for assessing and reporting precursor lesions to invasive carcinomas of the pancreas, including pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasm (IPMN), mucinous cystic neoplasm, and other lesions. Consensus recommendations include the following: (1) To improve concordance and to align with practical consequences, a 2-tiered system (low vs. high grade) is proposed for all precursor lesions, with the provision that the current PanIN-2 and neoplasms with intermediate-grade dysplasia now be categorized as low grade. Thus, "high-grade dysplasia" is to be reserved for only the uppermost end of the spectrum ("carcinoma in situ"-type lesions). (2) Current data indicate that PanIN of any grade at a margin of a resected pancreas with invasive carcinoma does not have prognostic implications; the clinical significance of dysplasia at a margin in a resected pancreas with IPMN lacking invasive carcinoma remains to be determined. (3) Intraductal lesions 0.5 to 1 cm can be either large PanINs or small IPMNs. The term "incipient IPMN" should be reserved for lesions in this size with intestinal or oncocytic papillae or GNAS mutations. (4) Measurement of the distance between an IPMN and invasive carcinoma and sampling of intervening tissue are recommended to assess concomitant versus associated status. Conceptually, concomitant invasive carcinoma (in contrast with the "associated" group) ought to be genetically distinct from an IPMN elsewhere in the gland. (5) "Intraductal spread of invasive carcinoma" (aka, "colonization") is recommended to describe lesions of invasive carcinoma invading back into and extending along the ductal system, which may morphologically mimic high-grade PanIN or even IPMN. (6) "Simple mucinous cyst" is recommended to describe cysts >1 cm having gastric-type flat mucinous lining at most minimal atypia without ovarian-type stroma to distinguish them from IPMN. (7) Human lesions resembling the acinar to ductal metaplasia and atypical flat lesions of genetically engineered mouse models exist and may reflect an alternate pathway of carcinogenesis; however, their biological significance requires further study. These revised recommendations are expected to improve our management and understanding of precursor lesions in the pancreas.

25 Article Diagnostic value of a pancreatic mass on computed tomography in patients undergoing pancreatoduodenectomy for presumed pancreatic cancer. 2015

Gerritsen, Arja / Bollen, Thomas L / Nio, C Yung / Molenaar, I Quintus / Dijkgraaf, Marcel G W / van Santvoort, Hjalmar C / Offerhaus, G Johan / Brosens, Lodewijk A / Biermann, Katharina / Sieders, Egbert / de Jong, Koert P / van Dam, Ronald M / van der Harst, Erwin / van Goor, Harry / van Ramshorst, Bert / Bonsing, Bert A / de Hingh, Ignace H / Gerhards, Michael F / van Eijck, Casper H / Gouma, Dirk J / Borel Rinkes, Inne H M / Busch, Olivier R C / Besselink, Marc G H / Anonymous2740828. ·Department of Surgery, University Medical Center Utrecht, Utrecht, The Netherlands; Department of Surgery, Academic Medical Center, Amsterdam, The Netherlands. · Department of Radiology, St. Antonius Hospital, Nieuwegein, The Netherlands. · Department of Radiology, Academic Medical Center, Amsterdam, The Netherlands. · Department of Surgery, University Medical Center Utrecht, Utrecht, The Netherlands. · Clinical Research Unit, Academic Medical Center, Amsterdam, The Netherlands. · Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands. · Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands; Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands. · Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands. · Department of Surgery, University Medical Center Groningen, Groningen, The Netherlands. · Department of Surgery, Maastricht University Medical Center, Maastricht, The Netherlands. · Department of Surgery, Maasstad Ziekenhuis, Rotterdam, The Netherlands. · Department of Surgery, Radboud University Medical Center, Nijmegen, The Netherlands. · Department of Surgery, St. Antonius Hospital, Nieuwegein, The Netherlands. · Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands. · Department of Surgery, Catharina Hospital, Eindhoven, The Netherlands. · Department of Surgery, OLVG, Amsterdam, The Netherlands. · Department of Surgery, Erasmus Medical Center, Rotterdam, The Netherlands. · Department of Surgery, Academic Medical Center, Amsterdam, The Netherlands. · Department of Surgery, Academic Medical Center, Amsterdam, The Netherlands. Electronic address: m.g.besselink@amc.nl. ·Surgery · Pubmed #25921716.

ABSTRACT: INTRODUCTION: Previous studies have shown that 5-14% of patients undergoing pancreatoduodenectomy for suspected malignancy ultimately are diagnosed with benign disease. A "pancreatic mass" on computed tomography (CT) is considered to be the strongest predictor of malignancy, but studies describing its diagnostic value are lacking. The aim of this study was to determine the diagnostic value of a pancreatic mass on CT in patients with presumed pancreatic cancer, as well as the interobserver agreement among radiologists and the additional value of reassessment by expert-radiologists. METHODS: Reassessment of preoperative CT scans was performed within a previously described multicenter retrospective cohort study in 344 patients undergoing pancreatoduodenectomy for suspected malignancy (2003-2010). Preoperative CT scans were reassessed by 2 experienced abdominal radiologists separately and subsequently in a consensus meeting, after defining a pancreatic mass as "a measurable space occupying soft tissue density, except for an enlarged papilla or focal steatosis". RESULTS: CT scans of 86 patients with benign and 258 patients with (pre)malignant disease were reassessed. In 66% of patients a pancreatic mass was reported in the original CT report, versus 48% and 50% on reassessment by the 2 expert radiologists separately and 44% in consensus (P < .001 vs original report). Interobserver agreement between the original CT report and expert consensus was fair (kappa = 0.32, 95% confidence interval 0.23-0.42). Among both expert-radiologists agreement was moderate (kappa = 0.47, 95% confidence interval 0.38-0.56), with disagreement on the presence of a pancreatic mass in 29% of cases. The specificity for malignancy of pancreatic masses identified in expert consensus was twice as high compared with the original CT report (87% vs 42%, respectively). Positive predictive value increased to 98% after expert consensus, but negative predictive value was low (12%). CONCLUSION: Clinicians need to be aware of potential considerable disagreement among radiologists about the presence of a pancreatic mass. The specificity for malignancy doubled by expert radiologist reassessment when a uniform definition of "pancreatic mass" was used.

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