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Pancreatic Neoplasms: HELP
Articles by Giampaolo Tortora
Based on 34 articles published since 2009
(Why 34 articles?)
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Between 2009 and 2019, G. Tortora wrote the following 34 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Editorial Prognostication and response assessment in liver and pancreatic tumors: The new imaging. 2015

De Robertis, Riccardo / Tinazzi Martini, Paolo / Demozzi, Emanuele / Puntel, Gino / Ortolani, Silvia / Cingarlini, Sara / Ruzzenente, Andrea / Guglielmi, Alfredo / Tortora, Giampaolo / Bassi, Claudio / Pederzoli, Paolo / D'Onofrio, Mirko. ·Riccardo De Robertis, Emanuele Demozzi, Gino Puntel, Mirko D'Onofrio, Department of Radiology, Verona Comprehensive Cancer Network, G.B. Rossi Hospital, University of Verona, 37134 Verona, Italy. ·World J Gastroenterol · Pubmed #26078555.

ABSTRACT: Diffusion-weighted imaging (DWI), dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and perfusion computed tomography (CT) are technical improvements of morphologic imaging that can evaluate functional properties of hepato-bilio-pancreatic tumors during conventional MRI or CT examinations. Nevertheless, the term "functional imaging" is commonly used to describe molecular imaging techniques, as positron emission tomography (PET) CT/MRI, which still represent the most widely used methods for the evaluation of functional properties of solid neoplasms; unlike PET or single photon emission computed tomography, functional imaging techniques applied to conventional MRI/CT examinations do not require the administration of radiolabeled drugs or specific equipments. Moreover, DWI and DCE-MRI can be performed during the same session, thus providing a comprehensive "one-step" morphological and functional evaluation of hepato-bilio-pancreatic tumors. Literature data reveal that functional imaging techniques could be proposed for the evaluation of these tumors before treatment, given that they may improve staging and predict prognosis or clinical outcome. Microscopic changes within neoplastic tissues induced by treatments can be detected and quantified with functional imaging, therefore these techniques could be used also for post-treatment assessment, even at an early stage. The aim of this editorial is to describe possible applications of new functional imaging techniques apart from molecular imaging to hepatic and pancreatic tumors through a review of up-to-date literature data, with a particular emphasis on pathological correlations, prognostic stratification and post-treatment monitoring.

2 Review Pancreatic Cancer and Obesity: Molecular Mechanisms of Cell Transformation and Chemoresistance. 2018

Cascetta, Priscilla / Cavaliere, Alessandro / Piro, Geny / Torroni, Lorena / Santoro, Raffaela / Tortora, Giampaolo / Melisi, Davide / Carbone, Carmine. ·Medical Oncology Unit, Azienda Ospedaliera Universitaria Integrata, 37134 Verona, Italy. priscillacascetta@gmail.com. · Medical Oncology Unit, Azienda Ospedaliera Universitaria Integrata, 37134 Verona, Italy. alessandro.cav@hotmail.com. · Digestive Molecular Clinical Oncology Research Unit, Section of Medical Oncology, Department of Medicine, University of Verona, 37134 Verona, Italy. genypiro@hotmail.com. · Digestive Molecular Clinical Oncology Research Unit, Section of Medical Oncology, Department of Medicine, University of Verona, 37134 Verona, Italy. lorena.torroni@univr.it. · Digestive Molecular Clinical Oncology Research Unit, Section of Medical Oncology, Department of Medicine, University of Verona, 37134 Verona, Italy. raffaela.santoro@univr.it. · Medical Oncology Unit, Azienda Ospedaliera Universitaria Integrata, 37134 Verona, Italy. giampaolo.tortora@univr.it. · Medical Oncology, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Roma, Italy. giampaolo.tortora@univr.it. · Medical Oncology Unit, Azienda Ospedaliera Universitaria Integrata, 37134 Verona, Italy. davide.melisi@univr.it. · Digestive Molecular Clinical Oncology Research Unit, Section of Medical Oncology, Department of Medicine, University of Verona, 37134 Verona, Italy. davide.melisi@univr.it. · Digestive Molecular Clinical Oncology Research Unit, Section of Medical Oncology, Department of Medicine, University of Verona, 37134 Verona, Italy. carmine.carbone@univr.it. ·Int J Mol Sci · Pubmed #30366466.

ABSTRACT: Cancer and obesity are the two major epidemics of the 21st century. Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of death, with a five-year overall survival rate of only 8%. Its incidence and mortality have increased in recent years, and this cancer type is expected to be among the top five leading causes of cancer-related death by 2030 in the United States (US). In the last three decades, the prevalence of overweight people has boosted with a consequent increase in obesity-related diseases. Considerable epidemiologic evidence correlates overweight and obese conditions to an increased risk of several types of cancer, including PDAC. Besides being a risk factor for multiple metabolic disorders, the tumor-promoting effects of obesity occur at the local level via inflammatory mediators that are associated with adipose inflammation and metabolic or hormones mediators and microbiota dysbiosis. Although an excess of body mass index (BMI) represents the second most modifiable risk factor for PDAC with an increased cancer related-death of more than 20⁻40%, still little is known about the molecular mechanisms that underlie this strong association. In this review, we focused on the role of obesity as a preventable risk factor of PDAC, discussing the molecular mechanisms linking obesity to cancer initiation and progression. Moreover, we highlighted the role of obesity in defining chemoresistance, showing how a high BMI can actually reduce response to chemotherapy.

3 Review Tumor thrombosis: a peculiar finding associated with pancreatic neuroendocrine neoplasms. A pictorial essay. 2018

De Robertis, Riccardo / Paiella, Salvatore / Cardobi, Nicolò / Landoni, Luca / Tinazzi Martini, Paolo / Ortolani, Silvia / De Marchi, Giulia / Gobbo, Stefano / Giardino, Alessandro / Butturini, Giovanni / Tortora, Giampaolo / Bassi, Claudio / D'Onofrio, Mirko. ·Department of Radiology, P. Pederzoli Hospital, Via Monte Baldo 24, 37019, Peschiera del Garda, Italy. riccardo.derobertis@hotmail.it. · Department of General and Pancreatic Surgery, Pancreas Institute, G.B. Rossi Hospital, Piazzale L.A. Scuro, 10, 37134, Verona, Italy. · Department of Radiology, P. Pederzoli Hospital, Via Monte Baldo 24, 37019, Peschiera del Garda, Italy. · Department of Oncology, P. Pederzoli Hospital, Via Monte Baldo 24, 37019, Peschiera del Garda, Italy. · Department of Gastroenterology, Pancreas Institute, G.B. Rossi Hospital, Piazzale L.A. Scuro, 10, 37134, Verona, Italy. · Department of Pathology, P. Pederzoli Hospital, Via Monte Baldo 24, 37019, Peschiera del Garda, Italy. · Department of Pancreatic Surgery, P. Pederzoli Hospital, Via Monte Baldo 24, 37019, Peschiera del Garda, Italy. · Department of Medical Oncology, Pancreas Institute, G.B. Rossi Hospital, Piazzale L.A. Scuro, 10, 37134, Verona, Italy. · Department of Radiology, Pancreas Institute, G.B. Rossi Hospital, Piazzale L.A. Scuro, 10, 37134, Verona, Italy. ·Abdom Radiol (NY) · Pubmed #28677005.

ABSTRACT: While abutment, encasement or vessel occlusion are identified in most patients with a pancreatic tumor, tumor thrombosis is an uncommon finding. In particular, there are no description in the literature of tumor thrombosis associated with ductal adenocarcinoma, the most common pancreatic tumor. On the other hand, surgical series reveal that tumor thrombosis is associated with about 5% of pancreatic neuroendocrine neoplasms (PanNENs), and literature data suggest that this finding is frequently underreported on pre-operative imaging examinations. Tumor thrombosis may be clinically relevant, causing splenoportomesenteric hypertension, possibly responsible for life-threatening upper gastrointestinal bleeding. Bland thrombosis caused by direct infiltration of peri-pancreatic vessels frequently determines surgical unresectability, even in neuroendocrine tumors; on the opposite, tumor thrombosis associated with PanNENs do not exclude surgery per se, even though both morbidity and mortality can be increased by such condition. Considering the favorable prognosis of PanNENs and the frequent need to treat tumor thrombosis in order to prevent complications or to relieve symptoms, it is of paramount importance for radiologists the knowledge of the variety of findings associated with tumor thrombosis in PanNENs.

4 Review Suppression of mTOR pathway in solid tumors: lessons learned from clinical experience in renal cell carcinoma and neuroendocrine tumors and new perspectives. 2015

Ortolani, Silvia / Ciccarese, Chiara / Cingarlini, Sara / Tortora, Giampaolo / Massari, Francesco. ·Medical Oncology, Azienda Ospedaliera Universitaria Integrata, University of Verona, Piazzale LA Scuro 10, 37124 Verona, Italy. ·Future Oncol · Pubmed #26075448.

ABSTRACT: The PI3K-AKT-mTOR pathway plays role in the regulation of many cellular processes. Hyperactivation of mTOR signaling has been implicated in human carcinogenesis, representing an attractive target for cancer therapy. Among other cancer subtypes, renal cell carcinoma (RCC) and neuroendocrine tumors are relevant settings in which the deregulation of mTOR pathway is of crucial importance. Different mTOR-inhibitory agents have been developed in recent years. Temsirolimus is approved for advanced RCC; everolimus is registered for the treatment of advanced RCC, pancreatic neuroendocrine tumors and postmenopausal, hormone receptor-positive/HER2-negative, advanced breast cancer. This review is focused on the description of the clinical experience with mTOR-inhibitor agents for the treatment of advanced RCC and neuroendocrine tumors, followed by an excursus on the landscape of the ongoing research in this field.

5 Review Metastatic pancreatic cancer: Is there a light at the end of the tunnel? 2015

Vaccaro, Vanja / Sperduti, Isabella / Vari, Sabrina / Bria, Emilio / Melisi, Davide / Garufi, Carlo / Nuzzo, Carmen / Scarpa, Aldo / Tortora, Giampaolo / Cognetti, Francesco / Reni, Michele / Milella, Michele. ·Vanja Vaccaro, Sabrina Vari, Carlo Garufi, Carmen Nuzzo, Francesco Cognetti, Michele Milella, Medical Oncology A, Regina Elena National Cancer Institute, 00144 Rome, Italy. ·World J Gastroenterol · Pubmed #25944992.

ABSTRACT: Due to extremely poor prognosis, pancreatic cancer (PDAC) represents the fourth leading cause of cancer-related death in Western countries. For more than a decade, gemcitabine (Gem) has been the mainstay of first-line PDAC treatment. Many efforts aimed at improving single-agent Gem efficacy by either combining it with a second cytotoxic/molecularly targeted agent or pharmacokinetic modulation provided disappointing results. Recently, the field of systemic therapy of advanced PDAC is finally moving forward. Polychemotherapy has shown promise over single-agent Gem: regimens like PEFG-PEXG-PDXG and GTX provide significant potential advantages in terms of survival and/or disease control, although sometimes at the cost of poor tolerability. The PRODIGE 4/ACCORD 11 was the first phase III trial to provide unequivocal benefit using the polychemotherapy regimen FOLFIRINOX; however the less favorable safety profile and the characteristics of the enrolled population, restrict the use of FOLFIRINOX to young and fit PDAC patients. The nanoparticle albumin-bound paclitaxel (nab-Paclitaxel) formulation was developed to overcome resistance due to the desmoplastic stroma surrounding pancreatic cancer cells. Regardless of whether or not this is its main mechanisms of action, the combination of nab-Paclitaxel plus Gem showed a statistically and clinically significant survival advantage over single agent Gem and significantly improved all the secondary endpoints. Furthermore, recent findings on maintenance therapy are opening up potential new avenues in the treatment of advanced PDAC, particularly in a new era in which highly effective first-line regimens allow patients to experience prolonged disease control. Here, we provide an overview of recent advances in the systemic treatment of advanced PDAC, mostly focusing on recent findings that have set new standards in metastatic disease. Potential avenues for further development in the metastatic setting and current efforts to integrate new effective chemotherapy regimens in earlier stages of disease (neoadjuvant, adjuvant, and multimodal approaches in both resectable and unresectable patients) are also briefly discussed.

6 Review Pancreatic cancer: systemic combination therapies for a heterogeneous disease. 2014

Melisi, Davide / Calvetti, Lorenzo / Frizziero, Melissa / Tortora, Giampaolo. ·Medical Oncology, Department of Medicine, Università degli studi di Verona, Piazzale L. A. Scuro, 10, 37134, Verona, Italy. giampaolo.tortora@univr.it. ·Curr Pharm Des · Pubmed #25341938.

ABSTRACT: Pancreatic cancer is the only human malignancy for which patients' survival has not improved substantially during the past 30 years. Despite advances in the comprehension of the molecular mechanisms underlying pancreatic carcinogenesis, current systemic treatments offer only a modest benefit in tumor-related symptoms and survival. Over the past decades, gemcitabine and its combination with other standard cytotoxic agents have been the reference treatments for advanced pancreatic cancer patients. The recent introduction of the three-drug combination regimen FOLFIRINOX or the new taxane nab-paclitaxel represent key advances for a better control of the disease. Novel agents targeting molecular mechanisms involved in cancer development and maintenance are currently under clinical investigation. This review describes the most important findings in the field of systemic combination therapies for the treatment of pancreatic cancer. We discuss the emerging evidences for the clinical activity of combination treatments with standard chemotherapy plus novel agents targeting tumor cell-autonomous and tumor microenvironment signaling pathways. We present some of the most important advances in the comprehension of the molecular mechanisms responsible for the chemoresistance of pancreatic cancer and the emerging therapeutic targets to overcome this resistance.

7 Review Molecular pathology of pancreatic cancer: from bench-to-bedside translation. 2012

Corbo, Vincenzo / Tortora, Giampaolo / Scarpa, Aldo. ·ARC-NET Research Centre, University Hospital of Verona, Verona, Italy. ·Curr Drug Targets · Pubmed #22458520.

ABSTRACT: Pancreatic ductal adenocarcinoma (referred here as pancreatic cancer) is a lethal disease with the worst prognosis among all solid tumors. Surgical resection represents the only hope for cure but it is possible only in patients that present with local disease (about 20% of cases). Whether dismal prognosis of pancreatic cancer is a result of late diagnosis or early dissemination to distant organ is still a debate. Moreover, this disease shows an intrinsic chemotherapeutic resistance that has been mainly ascribed to the presence of a dense stromal reaction that significantly impairs drugs delivery. Clinical management of pancreatic cancer patients relies on few molecular markers (e.g., the diagnostic marker CA19-9) that, however, present several limitations to their use. The clinical usefulness of somatic alterations in well-characterized genes (such as KRAS and TP53), whose detection is technically feasible in different biological samples, has been extensively investigated leading to inconsistent results. Furthermore, none of the candidate molecular markers identified in recent years has shown an appropriate clinical performance and therefore none is routinely used. This depicts a scenario where the identification of novel and effective clinical biomarkers is mandatory. Very recent genome-wide comprehensive studies have shed light on the high degree of genetic complexity and heterogeneity of the pancreatic cancers. Although far from being introduced into the clinical settings, results from those studies are expected to change definitively the perspective through which we look at the clinical management of pancreatic cancer patients towards a personalized cancer medicine.

8 Review Emerging pathways and future targets for the molecular therapy of pancreatic cancer. 2011

Vaccaro, Vanja / Melisi, Davide / Bria, Emilio / Cuppone, Federica / Ciuffreda, Ludovica / Pino, Maria Simona / Gelibter, Alain / Tortora, Giampaolo / Cognetti, Francesco / Milella, Michele. ·Medical Oncology A, Regina Elena National Cancer Institute, Rome, Italy. ·Expert Opin Ther Targets · Pubmed #21819318.

ABSTRACT: INTRODUCTION: Pancreatic cancer treatment remains a challenge for clinicians and researchers. Despite undisputable advances in the comprehension of the molecular mechanisms underlying cancer development and progression, early disease detection and clinical management of patients has made little, if any, progress in the past 20 years. Clinical development of targeted agents directed against validated pathways, such as the EGF/EGF receptor axis, the mutant KRAS protein, MMPs, and VEGF-mediated angiogenesis, alone or in combination with gemcitabine-based standard chemotherapy, has been disappointing. AREAS COVERED: This review explores the preclinical rationale for clinical approaches aimed at targeting the TGF-β, IGF, Hedgehog, Notch and NF-κB signaling pathways, to develop innovative therapeutic strategies for pancreatic cancer. EXPERT OPINION: Although some of the already clinically explored approaches (particularly EGFR and KRAS targeting) deserve further clinical consideration, by employing more innovative and creative clinical trial designs than the gemcitabine-targeted agent paradigm that has thus far invariably failed, the targeting of emerging and relatively unexplored signaling pathways holds great promise to increase our understanding of the complex molecular biology and to advance the clinical management of pancreatic cancer.

9 Clinical Trial Maintenance Olaparib for Germline 2019

Golan, Talia / Hammel, Pascal / Reni, Michele / Van Cutsem, Eric / Macarulla, Teresa / Hall, Michael J / Park, Joon-Oh / Hochhauser, Daniel / Arnold, Dirk / Oh, Do-Youn / Reinacher-Schick, Anke / Tortora, Giampaolo / Algül, Hana / O'Reilly, Eileen M / McGuinness, David / Cui, Karen Y / Schlienger, Katia / Locker, Gershon Y / Kindler, Hedy L. ·From the Oncology Institute, Sheba Medical Center, Tel Aviv University, Tel Aviv, Israel (T.G.) · Hôpital Beaujon (Assistance Publique-Hôpitaux de Paris), Clichy, and University Paris VII, Paris (P.H.) · IRCCS Ospedale San Raffaele Scientific Institute, Milan (M.R.), Azienda Ospedaliera Universitaria Integrata Verona, Verona (G.T.), and Fondazione Policlinico Universitario Gemelli IRCCS, Rome (G.T.) - all in Italy · University Hospitals Gasthuisberg and KU Leuven, Leuven, Belgium (E.V.C.) · Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology, Barcelona (T.M.) · Fox Chase Cancer Center, Philadelphia (M.J.H.) · Samsung Medical Center, Sungkyunkwan University School of Medicine (J.-O.P.), and Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine (D.-Y.O.) - both in Seoul, South Korea · University College London Cancer Institute, London (D.H.), and AstraZeneca, Cambridge (D.M.) - both in the United Kingdom · Asklepios Tumorzentrum Hamburg Asklepios Klinik Altona, Hamburg (D.A.), St. Josef-Hospital, Ruhr University Bochum, Bochum (A.R.-S.), and Klinikum rechts der Isar, Department of Internal Medicine II, Technische Universität München, Munich (H.A.) - all in Germany · Memorial Sloan Kettering Cancer Center, New York (E.M.O.) · AstraZeneca, Gaithersburg, MD (K.Y.C., G.Y.L.) · Merck, Kenilworth, NJ (K.S.) · and the University of Chicago, Chicago (H.L.K.). ·N Engl J Med · Pubmed #31157963.

ABSTRACT: BACKGROUND: Patients with a germline METHODS: We conducted a randomized, double-blind, placebo-controlled, phase 3 trial to evaluate the efficacy of olaparib as maintenance therapy in patients who had a germline RESULTS: Of the 3315 patients who underwent screening, 154 underwent randomization and were assigned to a trial intervention (92 to receive olaparib and 62 to receive placebo). The median progression-free survival was significantly longer in the olaparib group than in the placebo group (7.4 months vs. 3.8 months; hazard ratio for disease progression or death, 0.53; 95% confidence interval [CI], 0.35 to 0.82; P = 0.004). An interim analysis of overall survival, at a data maturity of 46%, showed no difference between the olaparib and placebo groups (median, 18.9 months vs. 18.1 months; hazard ratio for death, 0.91; 95% CI, 0.56 to 1.46; P = 0.68). There was no significant between-group difference in health-related quality of life, as indicated by the overall change from baseline in the global quality-of-life score (on a 100-point scale, with higher scores indicating better quality of life) based on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (between-group difference, -2.47 points; 95% CI, -7.27 to 2.33). The incidence of grade 3 or higher adverse events was 40% in the olaparib group and 23% in the placebo group (between-group difference, 16 percentage points; 95% CI, -0.02 to 31); 5% and 2% of the patients, respectively, discontinued the trial intervention because of an adverse event. CONCLUSIONS: Among patients with a germline

10 Clinical Trial Development of peripheral neuropathy and its association with survival during treatment with nab-paclitaxel plus gemcitabine for patients with metastatic adenocarcinoma of the pancreas: A subset analysis from a randomised phase III trial (MPACT). 2016

Goldstein, David / Von Hoff, Daniel D / Moore, Malcolm / Greeno, Edward / Tortora, Giampaolo / Ramanathan, Ramesh K / Macarulla, Teresa / Liu, Helen / Pilot, Richard / Ferrara, Stefano / Lu, Brian. ·Prince of Wales Hospital, Department of Oncology, South Eastern Sydney Illawarra, NSW Health, Barker Street, Randwick, NSW 2031, Australia; University of New South Wales, Australia. Electronic address: david.goldstein@sesiahs.health.nsw.gov.au. · Scottsdale Healthcare/TGen, Bisgrove Research Pavilion, 10510 North 92nd Street, Suite 200, Scottsdale, AZ 85258, USA. · Princess Margaret Hospital, 5th Floor 708, 610 University Avenue, Toronto, Ontario M5G2M9, Canada. · University of Minnesota, Division of Hematology, Oncology and Transplantation, 420 Delaware Street SE, MMC 480, Minneapolis, MN 55455, USA. · Azienda Ospedaliera Universitaria Integrata di Verona, Policlinico Borgo Roma, Piazzale L. Scuro, 10, 37134 Verona, Italy. · Mayo Clinic, 13400 E Shea Blvd FL 3, Scottsdale, AZ 85259, USA. · Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), P. Vall d'Hebron 119-129, Barcelona, Spain. · Celgene Corporation, 86 Morris Avenue, Summit, NJ 07901, USA. ·Eur J Cancer · Pubmed #26655559.

ABSTRACT: BACKGROUND: In a phase III trial in patients with metastatic pancreatic cancer (MPC), nab-paclitaxel plus gemcitabine (nab-P/Gem) demonstrated greater efficacy but higher rates of peripheral neuropathy (PN) versus Gem. This exploratory analysis aimed to characterise the frequency, duration, and severity of PN with nab-P/Gem in the MPACT study. PATIENTS AND METHODS: Patients with previously untreated MPC received nab-P/Gem or Gem. PN was evaluated using a broad-spectrum group of Standardised Medical Dictionary for Regulatory Activities Queries (SMQ) and graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0. A case report form was completed by physicians on day 1 of each cycle (also graded by NCI CTCAE version 3.0). RESULTS: In the nab-P/Gem arm, 227/421 patients (54%) experienced any-grade PN and 70 (17%) experienced grade III PN. No grade IV PN was reported. Most early-onset PN events were grade I, and treatment-related grade III PN occurred in 7% of patients who received up to three cycles of nab-P. Of those who developed grade III PN with nab-P/Gem treatment, 30 (43%) improved to grade ≤ I (median time to improvement = 29 days) and 31 (44%) resumed therapy. Development of PN was associated with efficacy; median overall survival in patients with grade III versus 0 PN was 14.9 versus 5.9 months (hazard ratio, 0.33; P < .0001). CONCLUSIONS: nab-P/Gem was associated with grade III PN in a small percentage of patients. PN development was associated with longer treatment duration and improved survival. Grade III PN was reversible to grade ≤ I in many patients (median ≈ 1 month) NCT00844649.

11 Clinical Trial nab-Paclitaxel plus gemcitabine for metastatic pancreatic cancer: long-term survival from a phase III trial. 2015

Goldstein, David / El-Maraghi, Robert Hassan / Hammel, Pascal / Heinemann, Volker / Kunzmann, Volker / Sastre, Javier / Scheithauer, Werner / Siena, Salvatore / Tabernero, Josep / Teixeira, Luis / Tortora, Giampaolo / Van Laethem, Jean-Luc / Young, Rosemary / Penenberg, Darryl Neil / Lu, Brian / Romano, Alfredo / Von Hoff, Daniel D. ·Prince of Wales Hospital, University of New South Wales, Sydney, NSW, Australia (DG) · Royal Victoria Regional Health Centre, Barrie, ON, Canada (RHEM) · Hôpital Beaujon, Clichy, France (PH) · Klinikum Grosshadern, University of Munich, Munich, Germany (VH) · Universitätsklinikum Würzburg, Würzburg, Germany (VK) · Hospital Clinico San Carlos, Madrid, Spain (JS) · Medizinische Universität Wien, Wien, Austria (WS) · Ospedale Niguarda Ca' Granda, Milan, Italy (SS) · Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain (JT) · Hôpital Saint Antoine, Paris, France (LT) · Azienda Ospedaliera Universitaria Integrata and University of Verona, Verona, Italy (GT) · Hôpital Erasme, Brussels, Belgium (JLVL) · Royal Hobart Hospital, Hobart, Australia (RY) · Celgene Corporation, Summit, NJ (DNP) · Celgene Corporation, Summit, NJ (BL) · Celgene Corporation, Boudry, Switzerland (AR) · Virginia G. Piper Cancer Center at Scottsdale Healthcare/TGen, Scottsdale, AZ (DDVH). ·J Natl Cancer Inst · Pubmed #25638248.

ABSTRACT: BACKGROUND: Positive findings from the phase III MPACT trial led to the regulatory approval of nab-paclitaxel plus gemcitabine as a treatment option for patients with metastatic pancreatic cancer. This report is an update of overall survival (OS) based on longer follow-up. METHODS: Patients (n = 861) with metastatic pancreatic cancer and a Karnofsky performance status of 70 or greater were randomly assigned one to one to receive nab-paclitaxel + gemcitabine or gemcitabine alone. Efficacy data for this post hoc analysis were collected through May 9, 2013. Exploratory analyses of carbohydrate antigen 19-9 (CA19-9) and neutrophil-to-lymphocyte ratio (NLR) were conducted. The primary efficacy endpoint was OS, which was analyzed for all randomly assigned patients by the Kaplan-Meier method. All statistical tests were two-sided. RESULTS: The median OS was statistically significantly longer for nab-paclitaxel plus gemcitabine vs gemcitabine alone (8.7 vs 6.6 months, hazard ratio [HR] = 0.72, 95% confidence interval [CI] = 0.62 to 0.83, P < .001). Long-term (>three-year) survivors were identified in the nab-paclitaxel plus gemcitabine arm only (4%). In pooled treatment arm analyses, higher CA19-9 level and NLR at baseline were statistically significantly associated with worse OS. There appeared to be a treatment effect for OS favoring nab-paclitaxel plus gemcitabine over gemcitabine alone in poor-prognosis subgroups defined by these factors (HR = 0.612, P < .001 for CA19-9 level ≥ median and HR = 0.81, P = .079 for NLR > 5). CONCLUSIONS: These data confirm and extend the primary report of OS, supporting the superior efficacy of nab-paclitaxel plus gemcitabine over gemcitabine alone. Subgroup analyses support the relevance of CA 19-9 and NLR as prognostic markers in metastatic pancreatic cancer.

12 Article An Italian cost-effectiveness analysis of paclitaxel albumin (nab-paclitaxel) + gemcitabine vs gemcitabine alone for metastatic pancreatic cancer patients: the APICE study. 2018

Lazzaro, Carlo / Barone, Carlo / Caprioni, Francesco / Cascinu, Stefano / Falcone, Alfredo / Maiello, Evaristo / Milella, Michele / Pinto, Carmine / Reni, Michele / Tortora, Giampaolo. ·a Studio di Economia Sanitaria , Milan , Italy. · b Policlinico Gemelli , Rome , Italy. · c Ospedale S. Martino , Genoa , Italy. · d Policlinico di Modena , Modena , Italy. · e Azienda Ospedaliera Universitaria Pisana , Pisa , Italy. · f Casa Sollievo della Sofferenza , S. Giovanni Rotondo , Italy. · g Istituto Nazionale Tumori Regina Elena , Rome , Italy. · h Ospedale S. Maria Nuova , Reggio Emilia , Italy. · i Ospedale S. Raffaele , Milan , Italy. · j Azienda Ospedaliera Universitaria Integrata Borgo Roma , Verona , Italy. ·Expert Rev Pharmacoecon Outcomes Res · Pubmed #29641931.

ABSTRACT: BACKGROUND: the APICE study evaluates the cost-effectiveness of nanoparticle albumin-bound paclitaxel (nab-paclitaxel - Nab-P) + gemcitabine (G) vs G alone in metastatic pancreatic cancer (MPC) from the Italian National Health Service (INHS) standpoint. RESEARCH DESIGN AND METHODS: A 4-year, 4 health states (progression-free; progressed; end of life; death) Markov model based on the MPACT trial was developed to estimate costs (Euro [€], 2017 values), and quality-adjusted life years (QALYs). Patients were assumed to receive intravenously Nab-P 125 mg/m RESULTS: Nab-P + G totals 0.154 incremental QALYs and €7082.68 incremental costs vs G alone. ICUR (€46,021.58) is lower than the informal threshold value of €87,330 adopted by the Italian Medicines Agency during 2010-2013 for reimbursing oncological drugs. Sensitivity analyses confirmed the robustness of the baseline findings. CONCLUSIONS: Nab-P + G in MPC patients can be considered cost-effective for the INHS.

13 Article MEKK3 Sustains EMT and Stemness in Pancreatic Cancer by Regulating YAP and TAZ Transcriptional Activity. 2018

Santoro, Raffaela / Zanotto, Marco / Carbone, Carmine / Piro, Geny / Tortora, Giampaolo / Melisi, Davide. ·Digestive Molecular Clinical Oncology Research Unit, Department of Medicine, Università degli studi di Verona, Verona, Italy. · Laboratory of Oncology and Molecular Therapy, Department of Medicine, Università degli studi di Verona, Verona, Italy. · Medical Oncology Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy. · Digestive Molecular Clinical Oncology Research Unit, Department of Medicine, Università degli studi di Verona, Verona, Italy davide.melisi@univr.it. ·Anticancer Res · Pubmed #29599309.

ABSTRACT: BACKGROUND/AIM: Pancreatic cancer is one of the most threatening and poorly understood human malignancies. MEKK3 (MAP3K3) is a serine/threonine kinase activated by different signaling pathways. YAP and TAZ are critical oncogenic effectors in pancreatic cancer. We hypothesized that MEKK3 could sustain pancreatic cancer by inducing YAP/TAZ oncogenic activities. MATERIALS AND METHODS: In Panc1 and AsPC1 pancreatic cancer cell lines MEKK3 was knocked-out (KO) by the CRISPR/Cas9 method. These cells were used to evaluate MEKK3 contribution to the expression of YAP/TAZ and their target genes, cell migration, stemness, and in vivo tumor growth. RESULTS: MEKK3 KO reduced both EMT and cell migration, the size of 3D colonies and the percentage of CD44 CONCLUSION: Silencing of MEKK3 represents a valid approach to revert in vivo the aggressiveness of pancreatic cancer by modulating YAP/TAZ transcriptional activities.

14 Article Prognostic impact of early nutritional support in patients affected by locally advanced and metastatic pancreatic ductal adenocarcinoma undergoing chemotherapy. 2018

Trestini, Ilaria / Carbognin, Luisa / Sperduti, Isabella / Bonaiuto, Clelia / Auriemma, Alessandra / Melisi, Davide / Salvatore, Lisa / Bria, Emilio / Tortora, Giampaolo. ·U.O.C. Oncology, University of Verona Azienda Ospedaliera Universitaria Integrata, Verona, Italy. · Department of Biostatistics, Regina Elena National Cancer Institute, Roma, Italy. · U.O.C. Oncology, University of Verona Azienda Ospedaliera Universitaria Integrata, Verona, Italy. emilio.bria@univr.it. ·Eur J Clin Nutr · Pubmed #29581564.

ABSTRACT: BACKGROUND/OBJECTIVES: The aim of this analysis was to determine the risk of malnutrition and the prognostic value of nutritional intervention in patients affected by pancreatic ductal adenocarcinoma (PDAC) undergoing chemotherapy. SUBJECTS/METHODS: Clinical-pathological and nutritional data were correlated with overall survival (OS) using a Cox model. Nutritional status was determined by Malnutrition Universal Screening Tool (MUST), body mass index, weight loss in the past 6 months, presence of nutrition-related symptoms, and current energy intake. Nutritional intervention included appropriate individual dietary counseling. RESULTS: Data from 109 patients were gathered (median age 63 years). The majority of patients (64.2%) presented a MUST value of ≥ 2, corresponding to a high risk of malnutrition. At multivariate analysis for OS in locally advanced and metastatic PDAC patients, the time between the diagnosis and the nutritional intervention (HR 2.22, p = 0.017), the performance status (HR 1.38, p = 0.075), the surgery of the primary (HR 5.89, p = 0.005), and the response to the first line (HR 5.9, p = 0.03) were independent significant predictors of outcome. Furthermore, a weight gain > 2% from the baseline weight was correlated with the time between the diagnosis and the nutritional intervention (p = 0.021): in patients receiving a nutritional support within 3 months from diagnosis, a 2% weight gain was associated with a 2-year OS benefit (50.3% vs. 33.0%, p = 0.04). CONCLUSIONS: This analysis suggests that the early nutritional support may contribute to influence the prognosis of patients affected by advanced PDAC undergoing chemotherapy.

15 Article Can histogram analysis of MR images predict aggressiveness in pancreatic neuroendocrine tumors? 2018

De Robertis, Riccardo / Maris, Bogdan / Cardobi, Nicolò / Tinazzi Martini, Paolo / Gobbo, Stefano / Capelli, Paola / Ortolani, Silvia / Cingarlini, Sara / Paiella, Salvatore / Landoni, Luca / Butturini, Giovanni / Regi, Paolo / Scarpa, Aldo / Tortora, Giampaolo / D'Onofrio, Mirko. ·Department of Radiology, P. Pederzoli Hospital, Via Monte Baldo 24, 37019, Peschiera del Garda, Italy. riccardo.derobertis@hotmail.it. · Department of Computer Science, University of Verona, Strada le Grazie 15, 37134, Verona, Italy. · Department of Radiology, P. Pederzoli Hospital, Via Monte Baldo 24, 37019, Peschiera del Garda, Italy. · Department of Pathology, P. Pederzoli Hospital, Via Monte Baldo 24, 37019, Peschiera del Garda, Italy. · Department of Pathology, G.B. Rossi Hospital - University of Verona, Piazzale L.A. Scuro 10, 37134, Verona, Italy. · Department of Oncology, P. Pederzoli Hospital, Via Monte Baldo 24, 37019, Peschiera del Garda, Italy. · Department of Oncology, G.B. Rossi Hospital - University of Verona, Piazzale L.A. Scuro 10, 37134, Verona, Italy. · Department of Pancreatic Surgery, G.B. Rossi Hospital - University of Verona, Piazzale L.A. Scuro 10, 37134, Verona, Italy. · Department of Pancreatic Surgery, P. Pederzoli Hospital, Via Monte Baldo 24, 37019, Peschiera del Garda, Italy. · Department of Radiology, G.B. Rossi Hospital - University of Verona, Piazzale L.A. Scuro 10, 37134, Verona, Italy. ·Eur Radiol · Pubmed #29352378.

ABSTRACT: OBJECTIVES: To evaluate MRI derived whole-tumour histogram analysis parameters in predicting pancreatic neuroendocrine neoplasm (panNEN) grade and aggressiveness. METHODS: Pre-operative MR of 42 consecutive patients with panNEN >1 cm were retrospectively analysed. T1-/T2-weighted images and ADC maps were analysed. Histogram-derived parameters were compared to histopathological features using the Mann-Whitney U test. Diagnostic accuracy was assessed by ROC-AUC analysis; sensitivity and specificity were assessed for each histogram parameter. RESULTS: ADC CONCLUSIONS: Whole-tumour histogram analysis of ADC maps may be helpful in predicting tumour grade, vascular involvement, nodal and liver metastases in panNENs. ADC KEY POINTS: • Whole-tumour ADC histogram analysis can predict aggressiveness in pancreatic neuroendocrine neoplasms. • ADC entropy and kurtosis are higher in aggressive tumours. • ADC histogram analysis can quantify tumour diffusion heterogeneity. • Non-invasive quantification of tumour heterogeneity can provide adjunctive information for prognostication.

16 Article Adipocytes sustain pancreatic cancer progression through a non-canonical WNT paracrine network inducing ROR2 nuclear shuttling. 2018

Carbone, C / Piro, G / Gaianigo, N / Ligorio, F / Santoro, R / Merz, V / Simionato, F / Zecchetto, C / Falco, G / Conti, G / Kamga, P T / Krampera, M / Di Nicolantonio, F / De Franceschi, L / Scarpa, A / Tortora, G / Melisi, D. ·Digestive Molecular Clinical Oncology Research Unit, Department of Medicine, University of Verona, Verona, Italy. · Laboratory of Oncology and Molecular Therapy, Department of Medicine, University of Verona, Verona, Italy. · Medical Oncology Unit, Department of Medicine, Azienda Ospedaliera Universitaria Integrata, Verona, Italy. · Department of Biology, University of Naples 'Federico II', Naples, Italy. · Neusosciences Biomedicine and Movement Department, Anatomy and Histology Division, University of Verona, Verona, Italy. · Section of Hematology, Department of Medicine, Università Degli Studi di Verona, Verona, Italy. · Department of Oncology, University of Torino, Candiolo, Italy. · Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Italy. · Department of Medicine, University of Verona-AOUI Verona, Verona, Italy. · ARC-Net Research Centre and Department of Pathology and Diagnostics, University of Verona, Verona, Italy. ·Int J Obes (Lond) · Pubmed #29151594.

ABSTRACT: BACKGROUND: Solid epidemiological evidences connect obesity with incidence, stage and survival in pancreatic cancer. However, the underlying mechanistic basis linking adipocytes to pancreatic cancer progression remain largely elusive. We hypothesized that factors secreted by adipocytes could be responsible for epithelial-to-mesenchymal transition (EMT) induction and, in turn, a more aggressive phenotype in models of pancreatic preneoplastic lesions. METHODS: We studied the role of factors secreted by two adipogenic model systems from primary human bone marrow stromal cells (hBMSCs) in an in vitro experimental cell transformation model system of human pancreatic ductal epithelial (HPDE) cell stably expressing activated KRAS (HPDE/KRAS),Results:We measured a significant induction of EMT and aggressiveness in HPDE and HPDE/KRAS cell lines when cultured with medium conditioned by fully differentiated adipocytes (ADIPO CONCLUSIONS: We demonstrated that adipocytes could induce EMT and aggressiveness in models of pancreatic preneoplastic lesions by orchestrating a complex paracrine signaling of soluble modulators of the non-canonical WNT signaling pathway that determine, in turn, the activation and nuclear translocation of ROR2. This signaling pathway could represent a novel target for pancreatic cancer chemoprevention. Most importantly, these factors could serve as novel biomarkers to select a risk population among obese subjects for screening and, thus, early diagnosis of pancreatic cancer.

17 Article A circulating T 2017

Piro, Geny / Simionato, Francesca / Carbone, Carmine / Frizziero, Melissa / Malleo, Giuseppe / Zanini, Silvia / Casolino, Raffaella / Santoro, Raffaela / Mina, Maria Mihaela / Zecchetto, Camilla / Merz, Valeria / Scarpa, Aldo / Bassi, Claudio / Tortora, Giampaolo / Melisi, Davide. ·Digestive Molecular Clinical Oncology Research Unit, Department of Medicine, Università degli studi di Verona, Verona, Italy. · Laboratory of Oncology and Molecular Therapy, Department of Medicine, Università degli studi di Verona, Verona, Italy. · Comprehensive Cancer Center, Azienda Ospedaliera Universitaria Integrata, Verona, Italy. · Unit of Oncology, Azienda Ospedaliera Universitaria Integrata, Verona, Italy. · Unit of General and Pancreatic Surgery, Azienda Ospedaliera Universitaria Integrata, Verona, Italy. · ARC-Net Research Centre and Department of Pathology and Diagnostics, Università degli studi di Verona, Verona, Italy. ·Oncoimmunology · Pubmed #28932629.

ABSTRACT: Surgery is the only potentially curative option for patients with pancreatic ductal adenocarcinoma (PDAC), but metastatic relapse remains common. We hypothesized that the expression levels of inflammatory cytokines could predict recurrence of PDAC, thus allowing to select patients who most likely could benefit from surgical resection. We prospectively collected plasma at diagnosis from 287 patients with pancreatic resectable neoplasms. The expression levels of 23 cytokines were measured in 90 patients with PDAC by using a multiplex analyte profiling assay. Levels higher than cutoff identified of the T

18 Article Perfusion CT Changes in Liver Metastases from Pancreatic Neuroendocrine Tumors During Everolimus Treatment. 2017

D'Onofrio, Mirko / Cingarlini, Sara / Ortolani, Silvia / Crosara, Stefano / DE Robertis, Riccardo / Vallerio, Paola / Grego, Elisabetta / Ciaravino, Valentina / Ruzzenente, Andrea / Landoni, Luca / Scarpa, Aldo / Bassi, Claudio / Tortora, Giampaolo. ·Department of Diagnostic and Public Health, Institute of Radiology, G.B. Rossi Hospital, University of Verona, Verona, Italy mirko.donofrio@univr.it. · Department of Oncology, G.B. Rossi Hospital, University of Verona, Verona, Italy. · Department of Diagnostic and Public Health, Institute of Radiology, G.B. Rossi Hospital, University of Verona, Verona, Italy. · Department of Radiology, Pederzoli Hospital, Peschiera del Garda, Verona, Italy. · Department of Internal Medicine, G.B. Rossi Hospital, University of Verona, Verona, Italy. · Department of Hepato-biliary Surgery, G.B. Rossi Hospital, University of Verona, Verona, Italy. · Department of Pancreatic Surgery, G.B. Rossi Hospital, University of Verona, Verona, Italy. · Department of Pathology, G.B. Rossi Hospital, University of Verona, Verona, Italy. ·Anticancer Res · Pubmed #28314296.

ABSTRACT: AIM: To evaluate modifications of perfusional parameters assessed by perfusion computed tomography (P-CT) of liver metastases (LM) from pancreatic neuroendocrine tumors (PanNETs) during everolimus treatment. PATIENTS AND METHODS: All patients with LMs from G1-2 PanNETs undergoing everolimus treatment between January 2013 and January 2015 were prospectively evaluated with P-CT at baseline, and after 2 and 4 months of therapy. Size, perfusion, blood volume (BV), peak enhancement intensity (PEI) and time to peak for each lesion were calculated. RESULTS: A total of 33 LMs in nine patients with G1-2 PanNETs were prospectively evaluated: 23/33 (69.7%) were responders, 10/33 (30.3%) were non-responders. Among perfusional parameters, only numerical peak enhancement intensity values significantly differed between the two groups at baseline (p=0.043). BV increase was the most significant perfusional modification identifying responding lesions, even at an early stage of treatment, with a high positive predictive value (89.47%). CONCLUSION: P-CT seems to be useful for prediction of response to everolimus of LMs from PanNETs.

19 Article Homeobox B9 Mediates Resistance to Anti-VEGF Therapy in Colorectal Cancer Patients. 2017

Carbone, Carmine / Piro, Geny / Simionato, Francesca / Ligorio, Francesca / Cremolini, Chiara / Loupakis, Fotios / Alì, Greta / Rossini, Daniele / Merz, Valeria / Santoro, Raffaela / Zecchetto, Camilla / Zanotto, Marco / Di Nicolantonio, Federica / Bardelli, Alberto / Fontanini, Gabriella / Tortora, Giampaolo / Melisi, Davide. ·Digestive Molecular Clinical Oncology Research Unit, Department of Medicine, Università degli studi di Verona, Verona, Italy. · Laboratory of Oncology and Molecular Therapy, Department of Medicine, Università degli studi di Verona, Verona, Italy. · Medical Oncology Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy. · Polo Oncologico, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy University of Pisa, Pisa, Italy. · Unit of Oncology 1, Istituto Oncologico Veneto IRCCS, Padova, Italy. · Division of Pathology, Department of Surgical, Medical, Molecular Pathology, and Critical Area, University of Pisa, Pisa, Italy. · Department of Oncology, University of Torino, Candiolo, Italy. · Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Italy. · Digestive Molecular Clinical Oncology Research Unit, Department of Medicine, Università degli studi di Verona, Verona, Italy. davide.melisi@univr.it. ·Clin Cancer Res · Pubmed #28298545.

ABSTRACT:

20 Article Whole-genome landscape of pancreatic neuroendocrine tumours. 2017

Scarpa, Aldo / Chang, David K / Nones, Katia / Corbo, Vincenzo / Patch, Ann-Marie / Bailey, Peter / Lawlor, Rita T / Johns, Amber L / Miller, David K / Mafficini, Andrea / Rusev, Borislav / Scardoni, Maria / Antonello, Davide / Barbi, Stefano / Sikora, Katarzyna O / Cingarlini, Sara / Vicentini, Caterina / McKay, Skye / Quinn, Michael C J / Bruxner, Timothy J C / Christ, Angelika N / Harliwong, Ivon / Idrisoglu, Senel / McLean, Suzanne / Nourse, Craig / Nourbakhsh, Ehsan / Wilson, Peter J / Anderson, Matthew J / Fink, J Lynn / Newell, Felicity / Waddell, Nick / Holmes, Oliver / Kazakoff, Stephen H / Leonard, Conrad / Wood, Scott / Xu, Qinying / Nagaraj, Shivashankar Hiriyur / Amato, Eliana / Dalai, Irene / Bersani, Samantha / Cataldo, Ivana / Dei Tos, Angelo P / Capelli, Paola / Davì, Maria Vittoria / Landoni, Luca / Malpaga, Anna / Miotto, Marco / Whitehall, Vicki L J / Leggett, Barbara A / Harris, Janelle L / Harris, Jonathan / Jones, Marc D / Humphris, Jeremy / Chantrill, Lorraine A / Chin, Venessa / Nagrial, Adnan M / Pajic, Marina / Scarlett, Christopher J / Pinho, Andreia / Rooman, Ilse / Toon, Christopher / Wu, Jianmin / Pinese, Mark / Cowley, Mark / Barbour, Andrew / Mawson, Amanda / Humphrey, Emily S / Colvin, Emily K / Chou, Angela / Lovell, Jessica A / Jamieson, Nigel B / Duthie, Fraser / Gingras, Marie-Claude / Fisher, William E / Dagg, Rebecca A / Lau, Loretta M S / Lee, Michael / Pickett, Hilda A / Reddel, Roger R / Samra, Jaswinder S / Kench, James G / Merrett, Neil D / Epari, Krishna / Nguyen, Nam Q / Zeps, Nikolajs / Falconi, Massimo / Simbolo, Michele / Butturini, Giovanni / Van Buren, George / Partelli, Stefano / Fassan, Matteo / Anonymous7980896 / Khanna, Kum Kum / Gill, Anthony J / Wheeler, David A / Gibbs, Richard A / Musgrove, Elizabeth A / Bassi, Claudio / Tortora, Giampaolo / Pederzoli, Paolo / Pearson, John V / Waddell, Nicola / Biankin, Andrew V / Grimmond, Sean M. ·ARC-Net Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona 37134, Italy. · Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona 37134, Italy. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1QH, UK. · West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow G31 2ER, UK. · The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia. · Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, New South Wales 2200, Australia. · South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, New South Wales 2170, Australia. · QIMR Berghofer Medical Research Institute, Herston Road, Brisbane 4006, Australia. · Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia. · Department of Surgery, Pancreas Institute, University and Hospital Trust of Verona, Verona 37134, Italy. · Medical Oncology, University and Hospital Trust of Verona, Verona, Italy. · Department of Pathology, General Hospital of Treviso, Department of Medicine, University of Padua, Italy. · Department of Medicine, Section of Endocrinology, University and Hospital Trust of Verona, Verona, Italy. · The University of Queensland, School of Medicine, Brisbane 4006, Australia. · Pathology Queensland, Brisbane 4006, Australia. · Royal Brisbane and Women's Hospital, Department of Gastroenterology and Hepatology, Brisbane 4006, Australia. · Institute of Health Biomedical Innovation, Queensland University of Technology, Brisbane, Australia. · School of Environmental &Life Sciences, University of Newcastle, Ourimbah, New South Wales 2258, Australia. · Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Centre for Cancer Bioinformatics, Peking University Cancer Hospital &Institute, Beijing 100142, China. · Department of Surgery, Princess Alexandra Hospital, Ipswich Rd, Woollongabba, Queensland 4102, Australia. · Department of Anatomical Pathology. St Vincent's Hospital, Sydney, New South Wales 2010, Australia. · Academic Unit of Surgery, School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow Royal Infirmary, Glasgow G4 OSF, UK. · Department of Pathology, Queen Elizabeth University Hospital, Greater Glasgow &Clyde NHS, Glasgow G51 4TF, UK. · Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, MS226, Houston, Texas 77030-3411, USA. · Michael E. DeBakey Department of Surgery and The Elkins Pancreas Center, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030-3411, USA. · Children's Hospital at Westmead, Westmead, New South Wales 2145, Australia. · Children's Medical Research Institute, The University of Sydney, Westmead, New South Wales 2145, Australia. · Department of Surgery, Royal North Shore Hospital, St Leonards, Sydney, New South Wales 2065, Australia. · University of Sydney. Sydney, New South Wales 2006, Australia. · Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales 2050, Australia. · School of Medicine, Western Sydney University, Penrith, New South Wales 2175, Australia. · Department of Surgery, Fremantle Hospital, Alma Street, Fremantle, Western Australia 6160, Australia. · Department of Gastroenterology, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia 5000, Australia. · School of Surgery M507, University of Western Australia, 35 Stirling Highway, Nedlands, Western Australia 6009, Australia. · St John of God Pathology, 12 Salvado Rd, Subiaco, Western Australia 6008, Australia. · Bendat Family Comprehensive Cancer Centre, St John of God Subiaco Hospital, Subiaco, Western Australia 6008, Australia. · University of Melbourne Centre for Cancer Research, University of Melbourne, Melbourne, 3010, Victoria, Australia. ·Nature · Pubmed #28199314.

ABSTRACT: The diagnosis of pancreatic neuroendocrine tumours (PanNETs) is increasing owing to more sensitive detection methods, and this increase is creating challenges for clinical management. We performed whole-genome sequencing of 102 primary PanNETs and defined the genomic events that characterize their pathogenesis. Here we describe the mutational signatures they harbour, including a deficiency in G:C > T:A base excision repair due to inactivation of MUTYH, which encodes a DNA glycosylase. Clinically sporadic PanNETs contain a larger-than-expected proportion of germline mutations, including previously unreported mutations in the DNA repair genes MUTYH, CHEK2 and BRCA2. Together with mutations in MEN1 and VHL, these mutations occur in 17% of patients. Somatic mutations, including point mutations and gene fusions, were commonly found in genes involved in four main pathways: chromatin remodelling, DNA damage repair, activation of mTOR signalling (including previously undescribed EWSR1 gene fusions), and telomere maintenance. In addition, our gene expression analyses identified a subgroup of tumours associated with hypoxia and HIF signalling.

21 Article Pancreatic neuroendocrine neoplasms: Magnetic resonance imaging features according to grade and stage. 2017

De Robertis, Riccardo / Cingarlini, Sara / Tinazzi Martini, Paolo / Ortolani, Silvia / Butturini, Giovanni / Landoni, Luca / Regi, Paolo / Girelli, Roberto / Capelli, Paola / Gobbo, Stefano / Tortora, Giampaolo / Scarpa, Aldo / Pederzoli, Paolo / D'Onofrio, Mirko. ·Riccardo De Robertis, Department of Radiology, Casa di Cura Pederzoli, 37019 Peschiera del Garda, Italy. ·World J Gastroenterol · Pubmed #28127201.

ABSTRACT: AIM: To describe magnetic resonance (MR) imaging features of pancreatic neuroendocrine neoplasms (PanNENs) according to their grade and tumor-nodes-metastases stage by comparing them to histopathology and to determine the accuracy of MR imaging features in predicting their biological behavior. METHODS: This study was approved by our institutional review board; requirement for informed patient consent was waived due to the retrospective nature of the study. Preoperative MR examinations of 55 PanNEN patients (29 men, 26 women; mean age of 57.6 years, range 21-83 years) performed between June 2013 and December 2015 were reviewed. Qualitative and quantitative features were compared between tumor grades and stages determined by histopathological analysis. RESULTS: Ill defined margins were more common in G2-3 and stage III-IV PanNENs than in G1 and low-stage tumors ( CONCLUSION: MR features of PanNENs vary according to their grade of differentiation and their stage at diagnosis and could predict the biological behavior of these tumors.

22 Article Role of Combined 68Ga-DOTATOC and 18F-FDG Positron Emission Tomography/Computed Tomography in the Diagnostic Workup of Pancreas Neuroendocrine Tumors: Implications for Managing Surgical Decisions. 2017

Cingarlini, Sara / Ortolani, Silvia / Salgarello, Matteo / Butturini, Giovanni / Malpaga, Anna / Malfatti, Veronica / DʼOnofrio, Mirko / Davì, Maria Vittoria / Vallerio, Paola / Ruzzenente, Andrea / Capelli, Paola / Citton, Elia / Grego, Elisabetta / Trentin, Chiara / De Robertis, Riccardo / Scarpa, Aldo / Bassi, Claudio / Tortora, Giampaolo. ·From the *Department of Oncology, Comprehensive Cancer Center, G.B. Rossi University Hospital of Verona; †Department of Nuclear Medicine, Sacro Cuore Don Calabria Hospital, Negrar; ‡Hepato-Biliary and Pancreas Unit, Pederzoli Hospital, Peschiera; Departments of §Pancreatic Surgery, ∥Radiology, ¶Internal Medicine, #Hepatobiliary Surgery, and **Pathology, Comprehensive Cancer Center, G.B. Rossi University Hospital of Verona, Verona, Italy. ·Pancreas · Pubmed #27906872.

ABSTRACT: OBJECTIVES: Ga-DOTATOC (Ga) positron emission tomography (PET)/computed tomography (CT) is recommended in the workup of pancreas neuroendocrine tumors (PanNETs); evidence suggests that F-FDG (F) PET/CT can also provide prognostic information. Aims of this study were to assess the role of combined Ga- and F-PET/CT in the evaluation of grade (G) 1-2 PanNETs and to test the correlation between F-PET/CT positivity and tumor grade. METHODS: Preoperative Ga- and F-PET/CT of 35 patients with surgically resected G1-2 PanNETs were evaluated. For grading, the 2010 World Health Organization Classification was used; an ancillary analysis with Ki67 cutoffs at 5% to 20% was conducted. Correlation between F-PET/CT positivity (SUVmax > 3.5) and grade was assessed. RESULTS: Of 35 PanNETs, 28.6% and 71.4% were G1 and G2 as per World Health Organization. Ga-PET/CT showed high sensitivity (94.3%) in detecting G1-2 PanNETs. F-PET/CT was positive in 20% and 76% G1 and G2 tumors (P = 0.002). F-PET/CT identified G2 PanNETs with high positive predictive value (PPV, 90.5%). F-PET/CT correlated with tumor grade also in the ancillary analysis (P = 0.009). CONCLUSIONS: The high sensitivity of Ga-PET/CT in NET detection is known. The high PPV of F-PET/CT in the identification of G2 forms suggests its potential role in PanNETs prognostication and risk stratification.

23 Article Digital Subtraction of Magnetic Resonance Images Improves Detection and Characterization of Pancreatic Neuroendocrine Neoplasms. 2017

De Robertis, Riccardo / Tinazzi Martini, Paolo / Cingarlini, Sara / Ortolani, Silvia / Butturini, Giovanni / Regi, Paolo / Landoni, Luca / Tortora, Giampaolo / Pederzoli, Paolo / D'Onofrio, Mirko. ·From the *Department of Radiology, Casa di Cura Pederzoli, Peschiera del Garda; †PhD School in Inflammation, Immunity and Cancer, and ‡Department of Medical Oncology, G. B. Rossi Hospital, University of Verona, Verona; Departments of §Oncology and ∥Pancreatic Surgery, Casa di Cura Pederzoli, Peschiera del Garda; and ¶Department of Radiology, G. B. Rossi Hospital, University of Verona, Verona, Italy. ·J Comput Assist Tomogr · Pubmed #27861198.

ABSTRACT: OBJECTIVE: The aim of this study was to evaluate the usefulness of digital image subtraction of contrast-enhanced magnetic resonance (MR) images for detection and characterization of pancreatic neuroendocrine neoplasms (PanNENs). METHODS: Magnetic resonance examinations of 50 histologically verified PanNENs were retrospectively evaluated by 2 radiologists; 50 ductal adenocarcinomas were included as a control group. Late arterial phase images and correspondent subtracted images were analyzed. Tumor detectability on a subjective 3-point scale and contrast-to-noise ratios were compared across sequences using paired Student t tests. Tumor signal intensity was compared between sequences using χ or Fisher exact tests. RESULTS: Subjective conspicuity and contrast-to-noise ratios of PanNENs were significantly higher on subtracted images compared with correspondent late arterial phase images (P < 0.001 and P = 0.002). The rate of clearly hyperenhancing PanNENs was higher on subtracted images compared with arterial phase images (76% vs 36%). CONCLUSIONS: Digital image subtraction improves tumor conspicuity and allows better characterization of PanNENs compared with late arterial phase images.

24 Article Hypermutation In Pancreatic Cancer. 2017

Humphris, Jeremy L / Patch, Ann-Marie / Nones, Katia / Bailey, Peter J / Johns, Amber L / McKay, Skye / Chang, David K / Miller, David K / Pajic, Marina / Kassahn, Karin S / Quinn, Michael C J / Bruxner, Timothy J C / Christ, Angelika N / Harliwong, Ivon / Idrisoglu, Senel / Manning, Suzanne / Nourse, Craig / Nourbakhsh, Ehsan / Stone, Andrew / Wilson, Peter J / Anderson, Matthew / Fink, J Lynn / Holmes, Oliver / Kazakoff, Stephen / Leonard, Conrad / Newell, Felicity / Waddell, Nick / Wood, Scott / Mead, Ronald S / Xu, Qinying / Wu, Jianmin / Pinese, Mark / Cowley, Mark J / Jones, Marc D / Nagrial, Adnan M / Chin, Venessa T / Chantrill, Lorraine A / Mawson, Amanda / Chou, Angela / Scarlett, Christopher J / Pinho, Andreia V / Rooman, Ilse / Giry-Laterriere, Marc / Samra, Jaswinder S / Kench, James G / Merrett, Neil D / Toon, Christopher W / Epari, Krishna / Nguyen, Nam Q / Barbour, Andrew / Zeps, Nikolajs / Jamieson, Nigel B / McKay, Colin J / Carter, C Ross / Dickson, Euan J / Graham, Janet S / Duthie, Fraser / Oien, Karin / Hair, Jane / Morton, Jennifer P / Sansom, Owen J / Grützmann, Robert / Hruban, Ralph H / Maitra, Anirban / Iacobuzio-Donahue, Christine A / Schulick, Richard D / Wolfgang, Christopher L / Morgan, Richard A / Lawlor, Rita T / Rusev, Borislav / Corbo, Vincenzo / Salvia, Roberto / Cataldo, Ivana / Tortora, Giampaolo / Tempero, Margaret A / Anonymous5740887 / Hofmann, Oliver / Eshleman, James R / Pilarsky, Christian / Scarpa, Aldo / Musgrove, Elizabeth A / Gill, Anthony J / Pearson, John V / Grimmond, Sean M / Waddell, Nicola / Biankin, Andrew V. ·The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia. · QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. · Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia; Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom; Department of Surgery, Bankstown Hospital, Bankstown, Sydney, New South Wales, Australia; South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales Australia, Liverpool, New South Wales, Australia; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; St Vincent's Clinical School, Faculty of Medicine, University of New South Wales Australia, Darlinghurst, New South Wales, Australia. · Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia; Genetic and Molecular Pathology, Adelaide, South Australia, Australia; School of Biological Sciences, The University of Adelaide, Adelaide, South Australia, Australia. · Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. · Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia; St Vincent's Clinical School, Faculty of Medicine, University of New South Wales Australia, Darlinghurst, New South Wales, Australia. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; South Eastern Area Laboratory Services Pathology, Prince of Wales Hospital, Randwick, New South Wales, Australia; Sonic Genetics, Douglass Hanly Moir Pathology, New South Wales, Australia. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; Macarthur Cancer Therapy Centre, Campbelltown Hospital, New South Wales, Australia. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; Department of Anatomical Pathology, SydPath, St Vincent's Hospital, New South Wales, Australia. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; School of Environmental and Life Sciences, University of Newcastle, Ourimbah, New South Wales, Australia. · Department of Surgery, Royal North Shore Hospital, Sydney, New South Wales, Australia; University of Sydney, Sydney, New South Wales, Australia. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; University of Sydney, Sydney, New South Wales, Australia; Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia. · Department of Surgery, Bankstown Hospital, Bankstown, Sydney, New South Wales, Australia; School of Medicine, Western Sydney University, Penrith, New South Wales, Australia. · Department of Surgery, Fiona Stanley Hospital, Murdoch, Washington. · Department of Gastroenterology, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia, Australia. · Department of Surgery, Princess Alexandra Hospital, Woollongabba, Queensland, Australia. · School of Surgery, University of Western Australia, Australia and St John of God Pathology, Subiaco, Washington. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom; Academic Unit of Surgery, School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow Royal Infirmary, Glasgow, United Kingdom. · West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom; Department of Medical Oncology, Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom. · Department of Pathology, Southern General Hospital, Greater Glasgow & Clyde National Health Service, Glasgow, United Kingdom. · Greater Glasgow and Clyde Bio-repository, Pathology Department, Queen Elizabeth University Hospital, Glasgow, United Kingdom. · Cancer Research UK Beatson Institute, Glasgow, United Kingdom; Institute for Cancer Science, University of Glasgow, Glasgow, United Kingdom. · Universitätsklinikum Erlangen, Erlangen, Germany. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, Maryland. · ARC-NET Center for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy; Department of Pathology and Diagnostics, University of Verona, Verona, Italy. · Department of Medicine, University and Hospital Trust of Verona, Verona, Italy. · Division of Hematology and Oncology, University of California, San Francisco, California. · Australian Pancreatic Cancer Genome Initiative. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom. · Universitätsklinikum Erlangen, Department of Surgery, University of Erlangen-Nueremberg, Germany. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom; St Vincent's Clinical School, Faculty of Medicine, University of New South Wales Australia, Darlinghurst, New South Wales, Australia. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; University of Sydney, Sydney, New South Wales, Australia; Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, New South Wales, Australia. · Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia; University of Melbourne Centre for Cancer Research, The University of Melbourne, Melbourne, Victoria, Australia. · QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. Electronic address: nic.waddell@qimrberghofer.edu.au. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom; Department of Surgery, Bankstown Hospital, Bankstown, Sydney, New South Wales, Australia; South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales Australia, Liverpool, New South Wales, Australia; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom. Electronic address: andrew.biankin@glasgow.ac.uk. ·Gastroenterology · Pubmed #27856273.

ABSTRACT: Pancreatic cancer is molecularly diverse, with few effective therapies. Increased mutation burden and defective DNA repair are associated with response to immune checkpoint inhibitors in several other cancer types. We interrogated 385 pancreatic cancer genomes to define hypermutation and its causes. Mutational signatures inferring defects in DNA repair were enriched in those with the highest mutation burdens. Mismatch repair deficiency was identified in 1% of tumors harboring different mechanisms of somatic inactivation of MLH1 and MSH2. Defining mutation load in individual pancreatic cancers and the optimal assay for patient selection may inform clinical trial design for immunotherapy in pancreatic cancer.

25 Article Genomic analyses identify molecular subtypes of pancreatic cancer. 2016

Bailey, Peter / Chang, David K / Nones, Katia / Johns, Amber L / Patch, Ann-Marie / Gingras, Marie-Claude / Miller, David K / Christ, Angelika N / Bruxner, Tim J C / Quinn, Michael C / Nourse, Craig / Murtaugh, L Charles / Harliwong, Ivon / Idrisoglu, Senel / Manning, Suzanne / Nourbakhsh, Ehsan / Wani, Shivangi / Fink, Lynn / Holmes, Oliver / Chin, Venessa / Anderson, Matthew J / Kazakoff, Stephen / Leonard, Conrad / Newell, Felicity / Waddell, Nick / Wood, Scott / Xu, Qinying / Wilson, Peter J / Cloonan, Nicole / Kassahn, Karin S / Taylor, Darrin / Quek, Kelly / Robertson, Alan / Pantano, Lorena / Mincarelli, Laura / Sanchez, Luis N / Evers, Lisa / Wu, Jianmin / Pinese, Mark / Cowley, Mark J / Jones, Marc D / Colvin, Emily K / Nagrial, Adnan M / Humphrey, Emily S / Chantrill, Lorraine A / Mawson, Amanda / Humphris, Jeremy / Chou, Angela / Pajic, Marina / Scarlett, Christopher J / Pinho, Andreia V / Giry-Laterriere, Marc / Rooman, Ilse / Samra, Jaswinder S / Kench, James G / Lovell, Jessica A / Merrett, Neil D / Toon, Christopher W / Epari, Krishna / Nguyen, Nam Q / Barbour, Andrew / Zeps, Nikolajs / Moran-Jones, Kim / Jamieson, Nigel B / Graham, Janet S / Duthie, Fraser / Oien, Karin / Hair, Jane / Grützmann, Robert / Maitra, Anirban / Iacobuzio-Donahue, Christine A / Wolfgang, Christopher L / Morgan, Richard A / Lawlor, Rita T / Corbo, Vincenzo / Bassi, Claudio / Rusev, Borislav / Capelli, Paola / Salvia, Roberto / Tortora, Giampaolo / Mukhopadhyay, Debabrata / Petersen, Gloria M / Anonymous91128 / Munzy, Donna M / Fisher, William E / Karim, Saadia A / Eshleman, James R / Hruban, Ralph H / Pilarsky, Christian / Morton, Jennifer P / Sansom, Owen J / Scarpa, Aldo / Musgrove, Elizabeth A / Bailey, Ulla-Maja Hagbo / Hofmann, Oliver / Sutherland, Robert L / Wheeler, David A / Gill, Anthony J / Gibbs, Richard A / Pearson, John V / Waddell, Nicola / Biankin, Andrew V / Grimmond, Sean M. ·Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK. · The Kinghorn Cancer Centre, 370 Victoria St, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia. · Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, New South Wales 2200, Australia. · South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, New South Wales 2170, Australia. · QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia. · Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA. · Michael DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas 77030, USA. · Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA. · Department of Human Genetics, University of Utah, Salt Lake City, Utah 84112, USA. · Genetic and Molecular Pathology, SA Pathology, Adelaide, South Australia 5000, Australia. · School of Biological Sciences, The University of Adelaide, Adelaide, South Australia 5000, Australia. · Harvard Chan Bioinformatics Core, Harvard T. H. Chan School of Public Health, Boston, Massachusetts 02115, USA. · Macarthur Cancer Therapy Centre, Campbelltown Hospital, New South Wales 2560, Australia. · Department of Pathology. SydPath, St Vincent's Hospital, Sydney, NSW 2010, Australia. · St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, New South Wales 2052, Australia. · School of Environmental &Life Sciences, University of Newcastle, Ourimbah, New South Wales 2258, Australia. · Department of Surgery, Royal North Shore Hospital, St Leonards, Sydney, New South Wales 2065, Australia. · University of Sydney, Sydney, New South Wales 2006, Australia. · Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown New South Wales 2050, Australia. · School of Medicine, University of Western Sydney, Penrith, New South Wales 2175, Australia. · Fiona Stanley Hospital, Robin Warren Drive, Murdoch, Western Australia 6150, Australia. · Department of Gastroenterology, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia 5000, Australia. · Department of Surgery, Princess Alexandra Hospital, Ipswich Rd, Woollongabba, Queensland 4102, Australia. · School of Surgery M507, University of Western Australia, 35 Stirling Hwy, Nedlands 6009, Australia and St John of God Pathology, 12 Salvado Rd, Subiaco, Western Australia 6008, Australia. · Academic Unit of Surgery, School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow Royal Infirmary, Glasgow G4 OSF, UK. · West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow G31 2ER, UK. · Department of Medical Oncology, Beatson West of Scotland Cancer Centre, 1053 Great Western Road, Glasgow G12 0YN, UK. · Department of Pathology, Southern General Hospital, Greater Glasgow &Clyde NHS, Glasgow G51 4TF, UK. · GGC Bio-repository, Pathology Department, Southern General Hospital, 1345 Govan Road, Glasgow G51 4TY, UK. · Department of Surgery, TU Dresden, Fetscherstr. 74, 01307 Dresden, Germany. · Departments of Pathology and Translational Molecular Pathology, UT MD Anderson Cancer Center, Houston Texas 77030, USA. · The David M. Rubenstein Pancreatic Cancer Research Center and Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA. · Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA. · ARC-Net Applied Research on Cancer Centre, University and Hospital Trust of Verona, Verona 37134, Italy. · Department of Pathology and Diagnostics, University of Verona, Verona 37134, Italy. · Department of Surgery, Pancreas Institute, University and Hospital Trust of Verona, Verona 37134, Italy. · Department of Medical Oncology, Comprehensive Cancer Centre, University and Hospital Trust of Verona, Verona 37134, Italy. · Mayo Clinic, Rochester, Minnesota 55905, USA. · Elkins Pancreas Center, Baylor College of Medicine, One Baylor Plaza, MS226, Houston, Texas 77030-3411, USA. · Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK. · Institute for Cancer Science, University of Glasgow, Glasgow G12 8QQ, UK. · University of Melbourne, Parkville, Victoria 3010, Australia. ·Nature · Pubmed #26909576.

ABSTRACT: Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-β, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63∆N transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.

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