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Pancreatic Neoplasms: HELP
Articles by Raphael Maréchal
Based on 24 articles published since 2010
(Why 24 articles?)
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Between 2010 and 2020, R. Maréchal wrote the following 24 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Guideline New strategies and designs in pancreatic cancer research: consensus guidelines report from a European expert panel. 2012

Van Laethem, J-L / Verslype, C / Iovanna, J L / Michl, P / Conroy, T / Louvet, C / Hammel, P / Mitry, E / Ducreux, M / Maraculla, T / Uhl, W / Van Tienhoven, G / Bachet, J B / Maréchal, R / Hendlisz, A / Bali, M / Demetter, P / Ulrich, F / Aust, D / Luttges, J / Peeters, M / Mauer, M / Roth, A / Neoptolemos, J P / Lutz, M / Anonymous1151075. ·Gastrointestinal Cancer Unit, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium. jl.vanlaethem@erasme.ulb.ac.be ·Ann Oncol · Pubmed #21810728.

ABSTRACT: Although the treatment of pancreatic ductal adenocarcinoma (PDAC) remains a huge challenge, it is entering a new era with the development of new strategies and trial designs. Because there is an increasing number of novel therapeutic agents and potential combinations available to test in patients with PDAC, the identification of robust prognostic and predictive markers and of new targets and relevant pathways is a top priority as well as the design of adequate trials incorporating molecular-driven hypothesis. We presently report a consensus strategy for research in pancreatic cancer that was developed by a multidisciplinary panel of experts from different European institutions and collaborative groups involved in pancreatic cancer. The expert panel embraces the concept of exploratory early proof of concept studies, based on the prediction of response to novel agents and combinations, and randomised phase II studies permitting the selection of the best therapeutic approach to go forward into phase III, where the recommended primary end point remains overall survival. Trials should contain as many translational components as possible, relying on standardised tissue and blood processing and robust biobanking, and including dynamic imaging. Attention should not only be paid to the pancreatic cancer cells but also to microenvironmental factors and stem/stellate cells.

2 Review Current standards and new innovative approaches for treatment of pancreatic cancer. 2016

Conroy, Thierry / Bachet, Jean-Baptiste / Ayav, Ahmet / Huguet, Florence / Lambert, Aurélien / Caramella, Caroline / Maréchal, Raphaël / Van Laethem, Jean-Luc / Ducreux, Michel. ·Department of Medical Oncology, Institut de Cancérologie de Lorraine and Lorraine University, 6 avenue de Bourgogne, CS 30519, 54519, Vandoeuvre-lès-Nancy, France. Electronic address: t.conroy@nancy.unicancer.fr. · Department of Hepato-Gastroenterology, Pitié-Salpétrière University Hospital, 47-83 boulevard de l'hôpital, 75651, Paris Cedex 13, France. · Department of Surgery, Nancy University Hospital Lorraine and Lorraine University, rue du Morvan, 54511, Vandoeuvre-lès Nancy, France. · Department of Radiation Therapy, Tenon Hospital, Paris Est University Hospitals, 4 rue de la Chine, 75020, Paris, France. · Department of Medical Oncology, Institut de Cancérologie de Lorraine and Lorraine University, 6 avenue de Bourgogne, CS 30519, 54519, Vandoeuvre-lès-Nancy, France. · Gustave Roussy Cancer Campus Grand Paris, 114 rue Edouard-Vaillant, 94805, Villejuif Cedex, France. · Department of Gastroenterology, Erasme University Hospital-ULB-Brussels, Lennikstreet 808, 1070, Brussels, Belgium. ·Eur J Cancer · Pubmed #26851397.

ABSTRACT: Pancreatic adenocarcinoma remains a devastating disease with a 5-year survival rate not exceeding 6%. Treatment of this disease remains a major challenge. This article reviews the state-of-the-art in the management of this disease and the new innovative approaches that may help to accelerate progress in treating its victims. After careful pre-therapeutic evaluation, only 15-20% of patients diagnosed with a pancreatic cancer (PC) are eligible for upfront radical surgery. After R0 or R1 resection in such patients, evidence suggests a significantly positive impact on survival of adjuvant chemotherapy comprising 6 months of gemcitabine or fluorouracil/folinic acid. Delayed adjuvant chemoradiation is considered as an option in cases of positive margins. Borderline resectable pancreatic cancer (BRPC) is defined as a tumour involving the mesenteric vasculature to a limited extend. Resection of these tumours is technically feasible, yet runs the high risk of a R1 resection. Neoadjuvant treatment probably offers the best chance of achieving successful R0 resection and long-term survival, but the best treatment options should be determined in prospective randomised studies. Gemcitabine has for 15 years been the only validated therapy for advanced PC. Following decades of negative phase III studies, increasing evidence now suggests that further significant improvements to overall survival can be achieved via either Folfirinox or gemcitabine + nab-paclitaxel regimens. Progress in systemic therapy may improve the chances of resection in borderline resectable pancreatic cancer (BRPC) or locally advanced PC. This requires first enhancing knowledge of the genetic events driving carcinogenesis, which may then be translated into clinical studies.

3 Review [Evolution in the therapeutic strategy of localized resectable pancreatic ductal adenocarcinoma]. 2015

Van Daele, D / Puleo, F / Dumont, R / Polus, M / Loly, C / Martinive, P / Meunier, P / Collignon, J / Hendlisz, A / Maréchal, R / Louis, E / Van Laethem, J-L. · ·Rev Med Suisse · Pubmed #26502580.

ABSTRACT: Pancreatic ductal adenocarcinoma is characterized by a high rate of early metastatic relapse. Surgical resection is still recognized as the cornerstone upfront therapy. However, reported 5 years survival rates are inferior to 20-25% even when surgery is followed by chemotherapy. Margins involvement on the surgical specimen (50 to 85%) and lymph node involvement (around 70%) both strongly impact survival. Median survivals are close to those of locally advanced diseases treated by chemotherapy or chemoradiotherapy, 15 to 16 months. This review focuses on adverse prognostic factors, post-operative outcomes and their impact on multimodality therapy completion rates and survivals in patients undergoing upfront surgery. Current data and emerging results from neoadjuvant series could lead to a change in the therapeutic strategy.

4 Review New challenges in perioperative management of pancreatic cancer. 2015

Puleo, Francesco / Maréchal, Raphaël / Demetter, Pieter / Bali, Maria-Antonietta / Calomme, Annabelle / Closset, Jean / Bachet, Jean-Baptiste / Deviere, Jacques / Van Laethem, Jean-Luc. ·Francesco Puleo, Raphaël Maréchal, Annabelle Calomme, Jean Closset, Jacques Deviere, Jean-Luc Van Laethem, Department of Gastroenterology and Digestive Oncology, Erasme Hospital, 1070 Brussels, Belgium. ·World J Gastroenterol · Pubmed #25741134.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death in the industrialized world. Despite progress in the understanding of the molecular and genetic basis of this disease, the 5-year survival rate has remained low and usually does not exceed 5%. Only 20%-25% of patients present with potentially resectable disease and surgery represents the only chance for a cure. After decades of gemcitabine hegemony and limited therapeutic options, more active chemotherapies are emerging in advanced PDAC, like 5-Fluorouracil, folinic acid, irinotecan and oxaliplatin and nab-paclitaxel plus gemcitabine, that have profoundly impacted therapeutic possibilities. PDAC is considered a systemic disease because of the high rate of relapse after curative surgery in patients with resectable disease at diagnosis. Neoadjuvant strategies in resectable, borderline resectable, or locally advanced pancreatic cancer may improve outcomes. Incorporation of tissue biomarker testing and imaging techniques into preoperative strategies should allow clinicians to identify patients who may ultimately achieve curative benefit from surgery. This review summarizes current knowledge of adjuvant and neoadjuvant treatment for PDAC and discusses the rationale for moving from adjuvant to preoperative and perioperative therapeutic strategies in the current era of more active chemotherapies and personalized medicine. We also discuss the integration of good specimen collection, tissue biomarkers, and imaging tools into newly designed preoperative and perioperative strategies.

5 Review Adjuvant pharmacotherapy in the management of elderly patients with pancreatic cancer. 2013

Maréchal, Raphaël / Demols, Anne / Van Laethem, Jean-Luc. ·Department of Gastroenterology, GI Cancer Unit, Erasme University Hospital, Université Libre de Bruxelles, Route de Lennik 808, 1070, Brussels, Belgium. raphael.marechal@erasme.ulb.ac.be ·Drugs Aging · Pubmed #23338795.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is the fourth or fifth leading cause of death from cancer in Western industrialized countries. Surgical resection is the only chance of cure, but only 15-20 % of cases are potentially resectable at presentation, and despite complete resection, the overall prognosis remains relatively poor. Adjuvant therapy has modestly improved cure rates. The majority of patients with pancreatic cancer are over the age of 65 years. But this age group is underrepresented within clinical trials, and it is unknown whether older patients achieve similar results to younger ones in terms of survival and treatment tolerance. In addition, there are no clinical trials dedicated to the elderly. Retrospective studies coming from the non-resectable setting provide some understanding on outcomes in older patients with PDAC. To date, we can reasonably argue that selected elderly patients with PDAC can benefit from curative surgery and postoperative chemotherapy as do their younger counterparts, without a significant increase in morbidity and mortality. Gemcitabine should be preferred to 5-fluorouracil on the basis of a better risk-benefit balance.

6 Review Molecular changes in pancreatic cancer: implications for molecular targeting therapy. 2012

Demetter, P / Maréchal, R / Verset, L / Salmon, I / Bachet, J-B / Van Laethem, J L. ·Department of Pathology, Erasme University Hospital, Université Libre de Bruxelles (ULB), Brussels, Belgium. pieter.demetter@erasme.ulb.ac.be ·Acta Gastroenterol Belg · Pubmed #22870784.

ABSTRACT: Pancreatic ductal adenocarcinoma has a high mortality rate, which is generally related to the initial diagnosis coming at late stage disease combined with a lack of effective treatment options. Gemcitabine has been the most commonly used drug over the past decade and is still the cornerstone of therapy in adjuvant and metastatic settings. Intrinsic or acquired resistance of tumours to gemcitabine is, however, a major clinical problem. New therapeutic strategies are urgently needed whereas we also need to identify new prognostic and predictive biomarkers. This article focuses on gemcitabine resistance, on the role of chemokines and chemokine receptors in pancreatic carcinoma initiation and progression, and on stellate cells as partners in crime with neoplastic epithelial cells.

7 Clinical Trial Asparagine Synthetase Expression and Phase I Study With L-Asparaginase Encapsulated in Red Blood Cells in Patients With Pancreatic Adenocarcinoma. 2015

Bachet, Jean-Baptiste / Gay, Fabien / Maréchal, Raphaël / Galais, Marie-Pierre / Adenis, Antoine / MsC, David Salako / Cros, Jerome / Demetter, Pieter / Svrcek, Magali / Bardier-Dupas, Armelle / Emile, Jean-François / Hammel, Pascal / Ebenezer, Christelle / Berlier, Willy / Godfrin, Yann / André, Thierry. ·From the *Department of Hepato-Gastroenterology, Pitié Salpêtrière Hospital, Paris; and †Erytech Pharma, Lyon, France; ‡Department of Gastroenterology, Erasme University Hospital, Brussels, Belgium; §Department of Oncology, Centre François Baclesse, Caen; ∥Department of Oncology, Centre Oscar Lambret, Lille; and ¶Pathology Department, Beaujon Hospital, Paris, France; #Department of Pathology, Erasme Hospital, Brussels, Belgium; **Department of Pathology, Saint Antoine Hospital; and ††Department of Pathology, Pitié Salpêtrière Hospital, Paris; ‡‡Department of Pathology, Ambroise Paré Hospital, Boulogne-Billancourt; and §§Department of Gastroenterology, Beaujon Hospital; and Departments of ∥∥Medical Oncology and ¶¶Oncology, Saint-Antoine Hospital, Paris, France. ·Pancreas · Pubmed #26355551.

ABSTRACT: OBJECTIVES: Asparaginase encapsulated in erythrocytes (ERY-ASP) is a potentially effective drug in patients with pancreatic adenocarcinoma (PAC) with null/low asparagine synthetase (ASNS) expression. Our aims were to assess ASNS expression in PAC from a large cohort and its prognostic and/or predictive value and to conduct a phase I trial with ERY-ASP in patients with metastatic PAC. METHODS: Asparagine synthetase expression was evaluated using immunohistochemistry in resected PAC (471 patients) and in pairs of primary tumor and metastases (55 patients). Twelve patients were included in the phase I trial and received a single administration of ERY-ASP (25-150 IU/kg). RESULTS: Null/low ASNS expression was found in 79.4% of the resected PAC with a high concordance between primary tumor and metastases. Asparagine synthetase expression was significantly correlated with sex and CXCR4 expression. In the phase I trial, ERY-ASP was well tolerated by patients with metastatic PAC. No patient had DLTs, and 6 patients had at least 1 ERY-ASP causally related adverse event out of the 12 adverse events reported. CONCLUSIONS: Given the high rate of PAC with null/low ASNS expression and the good tolerability profile of ERY-ASP, ERY-ASP should be evaluated in further clinical studies in metastatic PAC.

8 Article Stratification of Pancreatic Ductal Adenocarcinomas Based on Tumor and Microenvironment Features. 2018

Puleo, Francesco / Nicolle, Rémy / Blum, Yuna / Cros, Jérôme / Marisa, Laetitia / Demetter, Pieter / Quertinmont, Eric / Svrcek, Magali / Elarouci, Nabila / Iovanna, Juan / Franchimont, Denis / Verset, Laurine / Galdon, Maria Gomez / Devière, Jacques / de Reyniès, Aurélien / Laurent-Puig, Pierre / Van Laethem, Jean-Luc / Bachet, Jean-Baptiste / Maréchal, Raphaël. ·Medical Oncology Department, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium; Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium. Electronic address: francesco.puleo@bordet.be. · Programme Cartes d'Identité des Tumeurs (CIT), Ligue Nationale Contre Le Cancer, Paris, France. · Department of Pathology, Beaujon Hospital-Paris Diderot University, Clichy, France. · Department of Pathology, Erasme Hospital, Brussels, Belgium. · Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium. · Department of Pathology, Saint-Antoine Hospital, Paris, France. · Centre de Recherche en Cancérologie de Marseille, INSERM U1068, CNRS UMR 7258, Institut Paoli-Calmettes, Aix Marseille Université, Marseille, France. · Department of Gastroenterology and Digestive Oncology, Erasme Hospital, Brussels, Belgium. · Department of Pathology, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium. · Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium; Department of Gastroenterology and Digestive Oncology, Erasme Hospital, Brussels, Belgium. · Université Paris Descartes UMRS-1147; Assistance Publique Hopitaux de Paris Hopital Européen Georges Pompidou, Paris, France. · Sorbonne Universités, UPMC Université, Department of Gastroenterology, Pitié-Salpetriére Hospital, Paris, France. ·Gastroenterology · Pubmed #30165049.

ABSTRACT: BACKGROUND & AIMS: Genomic studies have revealed subtypes of pancreatic ductal adenocarcinoma (PDA) based on their molecular features, but different studies have reported different classification systems. It is a challenge to obtain high-quality, freshly frozen tissue for clinical analysis and determination of PDA subtypes. We aimed to redefine subtypes of PDA using a large number of formalin-fixed and paraffin-embedded PDA samples, which are more amenable to routine clinical evaluation. METHODS: We collected PDA samples from 309 consecutive patients who underwent surgery from September 1996 through December 2010 at 4 academic hospitals in Europe; nontumor tissue samples were not included. Samples were formalin fixed and paraffin embedded. DNA and RNA were isolated; gene expression, targeted DNA sequencing, and immunohistochemical analyses were performed. We used independent component analysis to deconvolute normal, tumor, and microenvironment transcriptome patterns in samples. We devised classification systems from an unsupervised analysis using a consensus clustering approach of our data set after removing normal contamination components. We associated subtypes with overall survival and disease-free survival of patients using Cox proportional hazards regression with estimation of hazard ratios and 95% confidence interval. We used The Cancer Genome Consortium and International Cancer Genome Consortium PDA data sets as validation cohorts. RESULTS: We validated the previously reported basal-like and classical tumor-specific subtypes of PDAs. We identified features of the PDA, including microenvironment gene expression patterns, that allowed tumors to be categorized into 5 subtypes, called pure basal like, stroma activated, desmoplastic, pure classical, and immune classical. These PDA subtypes have features of cancer cells and immune cells that could be targeted by pharmacologic agents. Tumor subtypes were associated with patient outcomes, based on analysis of our data set and the International Cancer Genome Consortium and The Cancer Genome Consortium PDA data sets. We also observed an exocrine signal associated with acinar cell contamination (from pancreatic tissue). CONCLUSIONS: We identified a classification system based on gene expression analysis of formalin-fixed PDA samples. We identified 5 PDA subtypes, based on features of cancer cells and the tumor microenvironment. This system might be used to select therapies and predict patient outcomes. We found evidence that the previously reported exocrine-like (called ADEX) tumor subtype resulted from contamination with pancreatic acinar cells. ArrayExpress accession number: E-MTAB-6134.

9 Article Assessment of response to chemotherapy in pancreatic ductal adenocarcinoma: Comparison between diffusion-weighted MR quantitative parameters and RECIST. 2018

Bali, Maria Antonietta / Pullini, Serena / Metens, Thierry / Absil, Julie / Chao, Shih-Li / Marechal, Raphael / Matos, Celso / Peerboccus, Bibi Mooneera / Van Laethem, Jean-Luc. ·Department of Radiology, Erasme Hospital, Université Libre de Bruxelles, Route de Lennik, 808, 1070 Brussels, Belgium. Electronic address: mbali@ulb.ac.be. · Institute of Diagnostic Radiology, University of Udine, Udine, Italy. Electronic address: serepul@libero.it. · Department of Radiology, Erasme Hospital, Université Libre de Bruxelles, Route de Lennik, 808, 1070 Brussels, Belgium. Electronic address: tmetens@ulb.ac.be. · Department of Radiology, Erasme Hospital, Université Libre de Bruxelles, Route de Lennik, 808, 1070 Brussels, Belgium. Electronic address: Julie.absil@erasme.ulb.ac.be. · Department of Radiology, Institute Jules Bordet, Boulevard de Waterloo, 121, 1000 Brussels, Belgium. Electronic address: chih-li.chao@bordet.be. · Department of Gastroenterology, Erasme Hospital, Université Libre de Bruxelles, Route de Lennik, 808, 1070 Brussels, Belgium. Electronic address: Raphael.Marechal@erasme.ulb.ac.be. · Department of Radiology, Erasme Hospital, Université Libre de Bruxelles, Route de Lennik, 808, 1070 Brussels, Belgium. Electronic address: cmatos@ulb.ac.be. · Department of Radiology, Erasme Hospital, Université Libre de Bruxelles, Route de Lennik, 808, 1070 Brussels, Belgium. Electronic address: Bibi.Peerboccus@erasme.ulb.ac.be. · Department of Gastroenterology, Erasme Hospital, Université Libre de Bruxelles, Route de Lennik, 808, 1070 Brussels, Belgium. Electronic address: JL.VanLaethem@erasme.ulb.ac.be. ·Eur J Radiol · Pubmed #29857866.

ABSTRACT: PURPOSE: To prospectively assess chemotherapy-induced changes in pancreatic ductal adenocarcinoma (PDA) with diffusion-weighted (DW)-MR quantitative metrics, including apparent diffusion coefficient (ADC) and histogram-derived parameters, compared with RECIST 1.1. METHODS: 24 patients underwent DW-MR at baseline, week-2 and week-8 after chemotherapy initiation. Tumour diameter was assessed on T2-weighted images. Regions-of-interest (ROI) were drawn on ADC map for ROI-ADC. Volume segmentation (b = 1000 s/mm RESULTS: 15/24 patients were responders. RECIST 1.1 correctly characterized 6/15 responders at week-8. At week-2, in responders DW-volume decreased (P = .002); ROI-ADC mean H-D increased (P = .047; P = .048;). The 25th percentile H-D increased in responders and decreased in non-responders (P = .016; P = .048). At week-8 in responders DW-volume decreased and ROI-ADC mean, 25th, 50th, 75th percentiles of H-ADC and H-D increased (P < .05). No changes were observed in non-responders (P > .05). At week-2, 25th percentile of H-D and H-PF relative change correctly classified 20/24 patients (P = .003); at week-8, DW-volume relative change correctly classified 22/24 patients (P < .0001). CONCLUSIONS: ROI-ADC, DW-volume and histogram-derived diffusion parameters are more accurate to categorize responding and non-responding PDA patients treated with chemotherapy compared with RECIST 1.1.

10 Article The Relationship between a New Biomarker of Vagal Neuroimmunomodulation and Survival in Two Fatal Cancers. 2018

Gidron, Y / De Couck, M / Schallier, D / De Greve, J / Van Laethem, J L / Maréchal, R. ·Vrije Universiteit Brussel, Center for Neuroscience, Brussels, Belgium. · Scalab, Université Lille 3, Lille, France. · Faculty of Health Care, University College Odisee, Aalst, Belgium. · Mental Health and Wellbeing Research Group, Vrije Universiteit Brussel, Ixelles, Belgium. · Oncological Center, UZ Brussels, Jette, Belgium. · Department of Gastroenterology, Erasme University Hospital, Brussels, Belgium. ·J Immunol Res · Pubmed #29854838.

ABSTRACT: Background: The vagus nerve may slow tumor progression because it inhibits inflammation. This study examined the relationship between a new vagal neuroimmunomodulation (NIM) index and survival in fatal cancers. Method: We retroactively derived markers of vagal nerve activity indexed by heart rate variability (HRV), specifically the root mean square of successive differences (RMSSD), from patients' electrocardiograms near diagnosis. The NIM index was the ratio of RMSSD to C-reactive protein levels (RMSSD/CRP). Sample 1 included 202 Belgian patients with advanced pancreatic cancer (PC), while sample 2 included 71 Belgian patients with non-small cell lung cancer (NSCLC). In both samples, we examined the overall survival, while in sample 2, we additionally examined the survival time in deceased patients. Results: In PC patients, in a multivariate Cox regression controlling for confounders, the NIM index had a protective relative risk (RR) of 0.68 and 95% confidence interval (95% CI) of 0.51-0.92. In NSCLC patients, the NIM index also had a protective RR of 0.53 and 95% CI of 0.32-0.88. Finally, in NSCLC, patients with a higher NIM index survived more days (475.2) than those with lower NIM (285.1) ( Conclusions: The NIM index, reflecting vagal modulation of inflammation, may be a new independent prognostic biomarker in fatal cancers.

11 Article Prevalence of Microsatellite Instability in Intraductal Papillary Mucinous Neoplasms of the Pancreas. 2018

Lupinacci, Renato M / Goloudina, Anastasia / Buhard, Olivier / Bachet, Jean-Baptiste / Maréchal, Raphaël / Demetter, Pieter / Cros, Jérôme / Bardier-Dupas, Armelle / Collura, Ada / Cervera, Pascale / Scriva, Aurélie / Dumont, Sylvie / Hammel, Pascal / Sauvanet, Alain / Louvet, Christophe / Delpéro, Jean-Robert / Paye, François / Vaillant, Jean-Christophe / André, Thierry / Closset, Jean / Emile, Jean-François / Van Laethem, Jean-Luc / Jonchère, Vincent / Abd Alsamad, Issam / Antoine, Martine / Rodenas, Anita / Fléjou, Jean-François / Dusetti, Nelson / Iovanna, Juan / Duval, Alex / Svrcek, Magali. ·INSERM, UMR S 938 - Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancers, Equipe labellisée par la Ligue Nationale contre le Cancer, F-75012, Paris, France; Sorbonne Université, Université Pierre et Marie Curie - Paris 6, Paris, France; Groupe Hospitalier Diaconesses - Croix Saint-Simon, Service de Chirurgie Digestive, Viscérale et Endocrinienne, Paris, France. · INSERM, UMR S 938 - Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancers, Equipe labellisée par la Ligue Nationale contre le Cancer, F-75012, Paris, France; Inovarion F - 75013, Paris, France. · INSERM, UMR S 938 - Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancers, Equipe labellisée par la Ligue Nationale contre le Cancer, F-75012, Paris, France. · Sorbonne Université, Université Pierre et Marie Curie - Paris 6, Paris, France; AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service d'Hépato-Gastro-Entérologie, Paris, France. · Department of Gastroenterology and Digestive Oncology, Erasme Hospital, Brussels, Belgium. · Department of Pathology, Erasme Hospital, Brussels, Belgium. · AP-HP, Service d'Anatomie et Cytologie Pathologiques, Hôpital Beaujon, Clichy, France; Université Paris Diderot - Paris 7, Paris, France. · AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service d'Anatomie et Cytologie Pathologiques, Paris, France. · INSERM, UMR S 938 - Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancers, Equipe labellisée par la Ligue Nationale contre le Cancer, F-75012, Paris, France; Sorbonne Université, Université Pierre et Marie Curie - Paris 6, Paris, France. · INSERM, UMR S 938 - Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancers, Equipe labellisée par la Ligue Nationale contre le Cancer, F-75012, Paris, France; Sorbonne Université, Université Pierre et Marie Curie - Paris 6, Paris, France; AP-HP, Hôpitaux Universitaires Est Parisien, Hôpital Saint-Antoine, Service d'Anatomie et Cytologie Pathologiques, Paris, France. · AP-HP, Hôpitaux Universitaires Est Parisien, Hôpital Saint-Antoine, Service d'Anatomie et Cytologie Pathologiques, Paris, France. · Sorbonne Université, Université Pierre et Marie Curie - Paris 6, Paris, France. · Université Paris Diderot - Paris 7, Paris, France; AP-HP, Hôpital Beaujon, Department of Gastroenterology, Pôle des Maladies de l'Appareil Digestif (PMAD), Clichy, France. · Université Paris Diderot - Paris 7, Paris, France; AP-HP, Hôpital Beaujon, Department of Hepato-Pancreato-Biliary Surgery, Pôle des Maladies de l'Appareil Digestif (PMAD), Clichy, France. · Department of Oncology, Institut Mutualiste Montsouris, Paris, France. · Department of Digestive Surgical Oncology, Paoli Calmettes Institute, Comprehensive Cancer Centre, Marseille, France. · Sorbonne Université, Université Pierre et Marie Curie - Paris 6, Paris, France; AP-HP, Hôpitaux Universitaires Est Parisien, Hôpital Saint-Antoine, Service de Chirurgie Générale et Digestive, Paris, France. · Sorbonne Université, Université Pierre et Marie Curie - Paris 6, Paris, France; AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service de Chirurgie Digestive et Hépato-bilio-pancréatique, Paris, France. · Sorbonne Université, Université Pierre et Marie Curie - Paris 6, Paris, France; Department of Oncology, Hôpital Saint Antoine, Paris, France. · EA4340 and Service d'Anatomie et Cytologie Pathologiques, Hôpital Ambroise Paré, AP-HP and Versailles University, Boulogne, France. · Hôpital Intercommunal de Créteil, Service d'Anatomie et Cytologie Pathologiques, Créteil, France. · Sorbonne Université, Université Pierre et Marie Curie - Paris 6, Paris, France; AP-HP, Hôpitaux Universitaires Est Parisien, Hôpital Tenon, Service d'Anatomie et Cytologie Pathologiques, Paris, France. · Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Parc Scientifique et Technologique de Luminy, Aix-Marseille Université and Institut Paoli-Calmettes, Marseille, France. · INSERM, UMR S 938 - Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancers, Equipe labellisée par la Ligue Nationale contre le Cancer, F-75012, Paris, France; Sorbonne Université, Université Pierre et Marie Curie - Paris 6, Paris, France. Electronic address: alex.duval@inserm.fr. · INSERM, UMR S 938 - Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancers, Equipe labellisée par la Ligue Nationale contre le Cancer, F-75012, Paris, France; Sorbonne Université, Université Pierre et Marie Curie - Paris 6, Paris, France; AP-HP, Hôpitaux Universitaires Est Parisien, Hôpital Saint-Antoine, Service d'Anatomie et Cytologie Pathologiques, Paris, France. Electronic address: magali.svrcek@aphp.fr. ·Gastroenterology · Pubmed #29158190.

ABSTRACT: Microsatellite instability (MSI) caused by mismatch repair deficiency (dMMR) is detected in a small proportion of pancreatic ductal adenocarcinomas (PDACs). dMMR and MSI have been associated with responses of metastatic tumors, including PDACs, to immune checkpoint inhibitor therapy. We performed immunohistochemical analyses of a 445 PDAC specimens, collected from consecutive patients at multiple centers, to identify those with dMMR, based on loss of mismatch repair proteins MLH1, MSH2, MSH6, and/or PMS2. We detected dMMR in 1.6% of tumor samples; we found dMMR in a larger proportion of intraductal papillary mucinous neoplasms-related tumors (4/58, 6.9%) than non- intraductal papillary mucinous neoplasms PDAC (5/385, 1.3%) (P = .02). PDACs with dMMR contained potentially immunogenic mutations because of MSI in coding repeat sequences. PDACs with dMMR or MSI had a higher density of CD8+ T cells at the invasive front than PDACs without dMMR or MSI (P = .08; Fisher exact test). A higher proportion of PDACs with dMMR or MSI expressed the CD274 molecule (PD-L1, 8/9) than PDACs without dMMR or MSI (4/10) (P = .05). Times of disease-free survival and overall survival did not differ significantly between patients with PDACs with dMMR or MSI vs without dMMR or MSI. Studies are needed to determine whether these features of PDACs with dMMR or MSI might serve as prognostic factors.

12 Article PAP/REG3A favors perineural invasion in pancreatic adenocarcinoma and serves as a prognostic marker. 2017

Nigri, Jérémy / Gironella, Meritxell / Bressy, Christian / Vila-Navarro, Elena / Roques, Julie / Lac, Sophie / Bontemps, Caroline / Kozaczyk, Coraline / Cros, Jérôme / Pietrasz, Daniel / Maréchal, Raphaël / Van Laethem, Jean-Luc / Iovanna, Juan / Bachet, Jean-Baptiste / Folch-Puy, Emma / Tomasini, Richard. ·CRCM, INSERM, U1068, 13009, Marseille, France. · Paoli-Calmettes Institute, 13009, Marseille, France. · Aix-Marseille University, UM 105, 13009, Marseille, France. · CNRS, UMR7258, 13009, Marseille, France. · Gastrointestinal and Pancreatic Oncology, Hospital Clinic of Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), IDIBAPS, Barcelona, Catalonia, Spain. · DYNABIO S.A.S, Luminy Biotech Entreprises, 13288, Marseille, France. · Department of Pathology, INSERM U1149, Hospital Beaujon, F-92110, Clichy, France. · INSERM UMR-S1147, University Paris Descartes, Paris, France. · Department of Hepatobiliary and Digestive Surgery, Hospital Pitié Salpêtrière, Paris, France. · Gastrointestinal Cancer Unit, University Clinic of Bruxelles, Erasme Hospital, 1070, Brussels, Belgium. · Sorbonne University, UPMC University, Paris 06, France. · Department of Hepatogastroentérology, Groupe Hospitalier Pitié Salpêtrière, Paris, France. · Experimental Pathology Department, Instituto de Investigación Biomédicas de Barcelona (IIBB-CSIC), CIBEREHD, IDIBAPS, Barcelona, Catalonia, Spain. · CRCM, INSERM, U1068, 13009, Marseille, France. Richard.tomasini@inserm.fr. · Paoli-Calmettes Institute, 13009, Marseille, France. Richard.tomasini@inserm.fr. · Aix-Marseille University, UM 105, 13009, Marseille, France. Richard.tomasini@inserm.fr. · CNRS, UMR7258, 13009, Marseille, France. Richard.tomasini@inserm.fr. · , 163 Avenue de Luminy, Parc scientifique de Luminy, Case 915, 13288, Marseille Cedex 9, France. Richard.tomasini@inserm.fr. ·Cell Mol Life Sci · Pubmed #28656348.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) is a fatal and insidious malignant disease for which clinicians' tools are restricted by the current limits in knowledge of how tumor and stromal cells act during the disease. Among PDA hallmarks, neural remodeling (NR) and perineural invasion (PNI) drastically influence quality of life and patient survival. Indeed, NR and PNI are associated with neuropathic pain and metastasis, respectively, both of which impact clinicians' decisions and therapeutic options. The aim of this study was to determine the impact and clinical relevance of the peritumoral microenvironment, through pancreatitis-associated protein (PAP/REG3A) expression, on PNI in pancreatic cancer. First, we demonstrated that, in PDA, PAP/REG3A is produced by inflamed acinar cells from the peritumoral microenvironment and then enhances the migratory and invasive abilities of cancer cells. More specifically, using perineural ex vivo assays we revealed that PAP/REG3A favors PNI through activation of the JAK/STAT signaling pathway in cancer cells. Finally, we analyzed the level of PAP/REG3A in blood from healthy donors or patients with PDA from three independent cohorts. Patients with high levels of PAP/REG3A had overall shorter survival as well as poor surgical outcomes with reduced disease-free survival. Our study provides a rationale for using the PAP/REG3A level as a biomarker to improve pancreatic cancer prognosis. It also suggests that therapeutic targeting of PAP/REG3A activity in PDA could limit tumor cell aggressiveness and PNI.

13 Article DLL4 expression is a prognostic marker and may predict gemcitabine benefit in resected pancreatic cancer. 2016

Drouillard, A / Puleo, F / Bachet, J B / Ouazzani, S / Calomme, A / Demetter, P / Verset, G / Van Laethem, J L / Maréchal, R. ·Department of Gastroenterology and Digestive Oncology, University Hospital of Dijon, Dijon, France. · Digestive Cancer Registry of Burgundy, INSERM U866, University Hospital of Dijon, Dijon, France. · Department of Gastroenterology and Digestive Oncology, Erasme Hospital, Brussels, Belgium. · Department of Hepatogastroenterology, Pitié Salpêtrière Hospital, APHP, Paris, France. · Department of Pathology, Erasme Hospital, Brussels, Belgium. · Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium. ·Br J Cancer · Pubmed #27755532.

ABSTRACT: BACKGROUND: There is an increasing interest for Notch signalling pathway and particularly Delta-like ligand 4 (DLL4) as potential therapeutic target to improve outcome for patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: Using immunohistochemistry (IHC) and tissue microarray (TMA), we assessed the expression patterns of DLL4, Notch1 and Notch3 in 151 patients from two independent cohorts of resected PDAC. We investigated the prognostic and the predictive significance of these proteins. RESULTS: High IHC DLL4 expression in cancer cells was associated with worse overall survival (OS) and disease-free survival (DFS) than low DLL4 expression (median OS: 12.9 vs 30.4 months, P=0.004 and median DFS: 8.8 vs 17.4 months, P=0.02). High DLL4 expression remained a significant negative prognostic factor in multivariate analysis (HR for OS: 2.1, P=0.02 and HR for DFS: 2.0, P=0.02). Low DLL4 abundance was associated with a longer OS-only for patients who received an adjuvant gemcitabine-based chemotherapy (P<0.001) but not for patients who did not receive gemcitabine (P=0.72). Furthermore, the interaction test for adjuvant gemcitabine therapy was statistically significant (P<0.001). The validating cohort recapitulated the findings of the training cohort. CONCLUSIONS: Low DLL4 abundance in tumour cells may predict the benefit from adjuvant gemcitabine therapy after PDAC resection.

14 Article Feasibility of Immunohistochemistry on Endoscopic Ultrasound Fine-Needle Aspiration Samples for Evaluating Predictive Biomarkers in Pancreatic Cancer Management. 2016

Puleo, Francesco / Demetter, Pieter / Eisendrath, Pierre / Maréchal, Raphaël / Verset, Laurine / Toussaint, Emmanuel / Bachet, Jean-Baptiste / Arvanitakis, Marianna / Mostafa, Ibrahim / Devière, Jacques / Van Laethem, Jean-Luc. ·Department of Gastroenterology and Digestive Oncology Erasme Hospital and Laboratory of experimental gastroenterology Universitè Libre de Bruxelles Brussels, Belgium fpuleo@ulb.ac.be Department of Pathology Erasme Hospital Brussels, Belgium Department of Gastroenterology and Digestive Oncology Erasme Hospital and Laboratory of experimental gastroenterology Universitè Libre de Bruxelles Brussels, Belgium Department of Pathology Erasme Hospital Brussels, Belgium Department of Gastroenterology and Digestive Oncology Erasme Hospital and Laboratory of experimental gastroenterology Universitè Libre de Bruxelles Brussels, Belgium Department of Gastroenterology Pitié-Salpetriére Hospital Paris, France Department of Gastroenterology and Digestive Oncology, Erasme Hospital, and Laboratory of experimental gastroenterology, Université Libre de Bruxelles, Brussels, Belgium. ·Pancreas · Pubmed #27623560.

ABSTRACT: -- No abstract --

15 Article Lysyl oxidase family activity promotes resistance of pancreatic ductal adenocarcinoma to chemotherapy by limiting the intratumoral anticancer drug distribution. 2016

Le Calvé, Benjamin / Griveau, Audrey / Vindrieux, David / Maréchal, Raphaël / Wiel, Clotilde / Svrcek, Magali / Gout, Johann / Azzi, Lamia / Payen, Léa / Cros, Jérôme / de la Fouchardière, Christelle / Dubus, Pierre / Guitton, Jérôme / Bartholin, Laurent / Bachet, Jean-Baptiste / Bernard, David. ·Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France. · CNRS UMR5286, Lyon, France. · Centre Léon Bérard, Lyon, France. · Université de Lyon, Lyon, France. · Present address: URBC-NARILIS, University of Namur, Namur, Belgium. · Department of Gastroenterology and Gastrointestinal Cancer Unit, Erasme Hospital, Université Libre de Bruxelles, Belgium. · Department of Pathology, AP-HP, Hôpitaux Universitaires Est Parisien, Saint-Antoine Hospital, Paris, France. · Sorbonne University, UPMC University, Paris, France. · Service de Biologie des Tumeurs, CHU de Bordeaux Hôpital du Haut Lévêque, Pessac, France. · Hospices Civils de Lyon, Université de Lyon, Lyon, France. · AP-HP, Hôpitaux Universitaires Paris Nord Val de Seine, Beaujon, France. · Paris Diderot University, Paris, France. · Sorbonne University, UPMC University and INSERM, UMRS 1147, Paris Descrates University, Paris, France. · Gastroenterology Department, APHP, Pitié Salpêtrière Hospital, Paris, France. ·Oncotarget · Pubmed #27050073.

ABSTRACT: Solid tumors often display chemotherapy resistance. Pancreatic ductal adenocarcinoma (PDAC) is the archetype of resistant tumors as current chemotherapies are inefficient. The tumor stroma and extracellular matrix (ECM) are key contributors to PDAC aggressiveness and to limiting the efficacy of chemotherapy. Lysyl oxidase (LOX) family members mediate collagen cross-linking and thus promote ECM stiffening. Our data demonstrate increased LOX, LOXL1, and LOXL2 expression in PDAC, and that the level of fibrillar collagen, which is directly dependent of LOX family activity, is an independent predictive biomarker of adjuvant "Gemcitabine-based chemotherapy" benefit. Experimentally in mice, increased LOX family activity through LOXL2 promotes chemoresistance. This effect of LOX family activity seems to be due to decreased gemcitabine intra-tumoral diffusion. This observation might be explained by increased fibrillar collagen and decreased vessel size observed in tumors with increased LOX family activity. In conclusion, our data support that LOX family activity is both a novel target to improve chemotherapy as well as a novel biomarker to predict gemcitabine benefit in PDAC. Beyond the PDAC, it is possible that targeting LOX family activity might improve efficacy of chemotherapies against different kinds of solid tumors.

16 Article Vagal nerve activity predicts overall survival in metastatic pancreatic cancer, mediated by inflammation. 2016

De Couck, Marijke / Maréchal, Raphaël / Moorthamers, Sofie / Van Laethem, Jean-Luc / Gidron, Yori. ·Mental Health and Wellbeing Research Group, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), 103 Laarbeeklaan, 1090 Brussels, Belgium. Electronic address: marijke.de.couck@vub.ac.be. · Department of Gastroenterology, GI Cancer Unit Erasme Universitary Hospital Université Libre de Bruxelles, 808, route de Lennik, 1070 Brussels, Belgium. · Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), 103 Laarbeeklaan, 1090 Brussels, Belgium. ·Cancer Epidemiol · Pubmed #26618335.

ABSTRACT: Recent research findings suggest neuro-modulation of tumors. Finding new modifiable prognostic factors paves the way for additional treatments, which is crucial in advanced cancer, particularly pancreatic cancer. This study examined the relationship between vagal nerve activity, indexed by heart rate variability (HRV), and overall survival (OS) in patients (N=272) with advanced pancreatic cancer. A "historical prospective" design was employed, where vagal activity and other confounders were retroactively obtained from medical charts at diagnosis, and subsequent OS was examined. HRV was obtained from 10 sec ECGs near diagnosis. Levels of C-reactive protein (CRP) were measured as an inflammatory marker. OS and survival date were obtained from medical charts and the Belgian national registry. Patients with high HRV (>20 msec) survived on average more than double the days (133.5) than those with low HRV (64.0). In a multivariate cox regression, higher initial HRV was significantly correlated with lower risk of death, independent of confounders including age and cancer treatments. This relationship was statistically mediated (accounted for) by CRP levels. Importantly, in patients who lived up to one month from diagnosis only, HRV was unrelated to CRP, while in patients surviving longer, HRV was significantly inversely related to CRP (r=-0.20, p<0.05). These results are in line with possible vagal nerve protection in a fatal cancer, and propose that the mechanism may involve neuroimmuno-modulation. Future studies must test whether vagal nerve activation may help patients with advanced cancers.

17 Article Personalized medicine in pancreatic cancer: the revolution has begun. 2015

Maréchal, Raphaël / Puleo, Francesco / Demols, Anne / Verset, Gontran / Laethem, Jean-Luc Van. ·Department of Gastroenterology & Gastrointestinal Cancer Unit, Erasme Hospital, Université Libre de Bruxelles, Route de Lennik 808, 1070 Brussels, Belgium. · Laboratory of Experimental Gastroenterology, Erasme Hospital, Université Libre de Bruxelles, Belgium. ·Per Med · Pubmed #29749894.

ABSTRACT: Pancreatic ductal adenocarcinoma carries a dismal prognosis. Both chemotherapy and targeted therapies have been disappointing when administered to unselected populations. Recently, progress has been made in our understanding of the genomic landscape of this cancer which displays remarkable heterogeneity suggesting a reorientation of management and research strategies based on molecular characterization and adapted personalized therapy. Resectable disease offers new opportunities for translational research through functional imaging response evaluation and tumor tissue acquisition before and after neoadjuvant therapy. There is urgent need for clinical trials based on molecular profiling in pancreatic ductal adenocarcinoma. In this review we discuss opportunities and limitations of these new strategies, underlining the importance of tissue acquisition and integration of molecular biomarkers in future molecularly driven clinical trials.

18 Article Sonic hedgehog and Gli1 expression predict outcome in resected pancreatic adenocarcinoma. 2015

Maréchal, Raphaël / Bachet, Jean-Baptiste / Calomme, Annabelle / Demetter, Pieter / Delpero, Jean Robert / Svrcek, Magali / Cros, Jérôme / Bardier-Dupas, Armelle / Puleo, Francesco / Monges, Geneviève / Hammel, Pascal / Louvet, Christophe / Paye, François / Bachelier, Philippe / Le Treut, Yves Patrice / Vaillant, Jean-Christophe / Sauvanet, Alain / André, Thierry / Salmon, Isabelle / Devière, Jacques / Emile, Jean-François / Van Laethem, Jean-Luc. ·Saint Antoine Department of Gastroenterology and Gastrointestinal Cancer Unit, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium. Laboratory of Experimental Gastroenterology, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium. raphael.marechal@erasme.ulb.ac.be. · Medical University Pierre et Marie Curie, UFR Paris VI, Paris, France. EA4340 "Epidémiologie et oncogènes des tumeurs digestives," Versailles Saint-Quentin-en-Yvelines University, Versailles, France. Department of Hepato-Gastroenterology, Pitié Salpêtrière Hospital, APHP, Paris, France. · Saint Antoine Department of Gastroenterology and Gastrointestinal Cancer Unit, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium. Laboratory of Experimental Gastroenterology, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium. · Department of Pathology, Erasme Hospital, Université Libre de Bruxelles, and DiaPath, Brussels, Belgium. · Department of Surgery, Institute Paoli Calmettes, Marseille, France. Aix Marseille Université, Marseille, France. · Department of Pathology, Saint Antoine Hospital, APHP, Paris, France. · Department of Pathology, Beaujon Hospital, APHP, Clichy, France. · Medical University Pierre et Marie Curie, UFR Paris VI, Paris, France. Department of Pathology, Pitié Salpêtrière Hospital, APHP, Paris, France. · Department of Pathology, Institute Paoli Calmettes, Marseille, France. · Department of Gastroenterology, Beaujon Hospital, APHP, Clichy, France. · Medical University Pierre et Marie Curie, UFR Paris VI, Paris, France. Department of Oncology, Institut Mutualiste Montsouris, Paris, France. · Medical University Pierre et Marie Curie, UFR Paris VI, Paris, France. Department of Surgery, Saint Antoine Hospital, APHP, Paris, France. · Department of Surgery, University Hospital of Hautepierre, Strasbourg, France. · Department of Digestive Surgery, Conception Hospital, Marseille, France. · Medical University Pierre et Marie Curie, UFR Paris VI, Paris, France. Department of Digestive Surgery, Pitié Salpêtrière Hospital, Paris, France. · Department of Digestive Surgery, Beaujon Hospital, APHP, Clichy, France. · Department of Oncology, Saint-Antoine Hospital, APHP, Paris, France. · Department of Pathology, Erasme Hospital, Université Libre de Bruxelles, and DiaPath, Brussels, Belgium. DIAPath - Center for Microscopy and Molecular Imaging (CMMI), Université Libre de Bruxelles, Gosselies, Belgium. · EA4340 "Epidémiologie et oncogènes des tumeurs digestives," Versailles Saint-Quentin-en-Yvelines University, Versailles, France. Department of Pathology, Ambroise Paré Hospital, APHP, Boulogne Billancourt, France. · Saint Antoine Department of Gastroenterology and Gastrointestinal Cancer Unit, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium. ·Clin Cancer Res · Pubmed #25552484.

ABSTRACT: PURPOSE: Aberrant activation of the hedgehog (Hh) pathway is implicated in pancreatic ductal adenocarcinoma (PDAC) tumorigenesis. We investigated the prognostic and predictive value of four Hh signaling proteins and of the tumor stromal density. EXPERIMENTAL DESIGN: Using tissue microarray and immunohistochemistry, the expression of Shh, Gli1, SMO, and PTCH1 was assessed in 567 patients from three independent cohorts who underwent surgical resection for PDAC. In 82 patients, the tumor stromal index (SI) was calculated, and its association with overall survival (OS) and disease-free survival (DFS) was investigated. RESULTS: Shh and Gli1 protein abundance were independent prognostic factors in resected PDACs; low expressors for those proteins experiencing a better OS and DFS. The combination of Shh and Gli1 levels was the most significant predictor for OS and defined 3 clinically relevant subgroups of patients with different prognosis (Gli1 and Shh low; HR set at 1 vs. 3.08 for Shh or Gli1 high vs. 5.69 for Shh and Gli1 high; P < 0.001). The two validating cohorts recapitulated the findings of the training cohort. After further stratification by lymph node status, the prognostic significance of combined Shh and Gli1 was maintained. The tumor SI was correlated with Shh levels and was significantly associated with OS (P = 0.023). CONCLUSIONS: Shh and Gli1 are prognostic biomarkers for patients with resected PDAC.

19 Article Human equilibrative nucleoside transporter 1 testing in pancreatic ductal adenocarcinoma: a comparison between murine and rabbit antibodies. 2015

Svrcek, Magali / Cros, Jérôme / Maréchal, Raphael / Bachet, Jean-Baptiste / Fléjou, Jean-François / Demetter, Pieter. ·Department of Pathology, AP-HP, Hôpitaux Universitaires Est Parisien, Saint-Antoine Hospital, Paris, France; Université Pierre et Marie Curie - Paris 6, Paris, France. ·Histopathology · Pubmed #25298108.

ABSTRACT: AIMS: The human equilibrative nucleoside transporter 1 (hENT1) expression level in pancreatic ductal adenocarcinoma (PDAC) may predict survival in gemcitabine-treated patients after resection. These results have been obtained with a murine anti-hENT1 antibody (10D7G2) that is not commercially available. Another antibody, which is rabbit-derived (SP120), appears to have no predictive value in local, advanced or metastatic PDAC. We aimed to study whether the two antibodies are equivalent. METHODS AND RESULTS: We compared hENT1 expression with both antibodies in resected PDAC. The results were correlated with overall survival (OS) following gemcitabine treatment. Tissues from two sets of patients (n = 147 each) were stained with SP120 by the use of different equipment, with an amplification technique being used for set 2. The rate of 'hENT1 high' cases was lower with SP120 (set 1, 7% versus 48%; set 2, 11% versus 38%). With the amplification technique, the rate of hENT1 high cases was globally similar between both antibodies. However, concordance between the antibodies was found in only 50% of cases. High hENT1 expression was predictive of OS only with 10D7G2 (hazard ratio 0.49; 95% confidence interval 0.24-0.98; P = 0.045). CONCLUSIONS: The two antibodies are not equivalent. Further prospective studies seem to be warranted before hENT1 testing for PDAC is used in daily practise.

20 Article S100A2 is a predictive biomarker of adjuvant therapy benefit in pancreatic adenocarcinoma. 2013

Bachet, Jean-Baptiste / Maréchal, Raphael / Demetter, Pieter / Bonnetain, Franck / Cros, Jérôme / Svrcek, Magali / Bardier-Dupas, Armelle / Hammel, Pascal / Sauvanet, Alain / Louvet, Christophe / Paye, François / Vaillant, Jean-Christophe / André, Thierry / Closset, Jean / Salmon, Isabelle / Emile, Jean-François / Van Laethem, Jean-Luc. ·Medical University Pierre et Marie Curie, UFR Paris VI, 91-105 Boulevard de l'Hôpital, Paris, France. jean-baptiste.bachet@psl.aphp.fr ·Eur J Cancer · Pubmed #23726265.

ABSTRACT: BACKGROUND: Prognosis of patients with pancreatic adenocarcinoma (PAC) remains poor. S100A2 has been recently suggested as a negative prognostic biomarker in PAC. We aimed to investigate its prognostic and/or predictive value in a large independent multicentric cohort of patients with resected PAC. METHODS: Sequential samples of 471 patients were retrospectively collected; 142 patients did not receive adjuvant treatment (30%) and 329 (70%) received an adjuvant treatment. We measured protein levels of S100A2 by semiquantitative immunohistochemistry with tissue microarrays and correlated with patients' overall survival (OS) and disease-free survival (DFS). RESULTS: S100A2 protein status was obtained in 462 (98%) patients. Its expression was low, moderate or high in 59%, 12% and 2% of cases, respectively. It was not correlated with DFS or OS in the whole population, neither in the subgroup of patients who did not receive adjuvant treatment. However among patients who received an adjuvant therapy, moderate/high levels of S100A2 were significantly associated with longer OS and DFS in multivariate analysis (hazard ratios of 0.63, p=0.022 and 0.67, p=0.017, respectively), whereas low S100A2 was not. Interaction tests for adjuvant therapy were statistically significant both for the OS and the DFS (p=0.001 and p=0.023, respectively). On multivariate analysis, S100A2 retained independent predictive values (OS: p<0.001, DFS: p=0.003) with a significant benefit of adjuvant therapy for those patients with moderate/high S100A2. CONCLUSIONS: S100A2 expression predicts longer DFS and OS in patients treated with adjuvant therapy and should be evaluated as a predictive biomarker.

21 Article Towards a tailored therapy in pancreatic cancer. 2013

Maréchal, Raphaël / Van Laethem, Jean-Luc. ·Department of Gastroenterology and Gastrointestinal cancer Unit, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium. raphael.marechal@erasme.ulb.ac.be ·Acta Gastroenterol Belg · Pubmed #23650783.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) remains a major unsolved health problem. As conventional treatments have shown only a modest impact on disease course, development of new therapeutic strategies based on the molecular biology of PDAC must be a high priority. The identification of relevant predictive and prognostic biomarkers which can be used to select patient subgroups that may benefit from conventional treatments and new targeted agents will be of considerable interest. We have demonstrated the ability of the metabolizing gemcitabine protein (the human Equilibrative nucleoside transporter 1 and the deoxycytidine kinase) in predicting the benefit of adjuvant gemcitabine-based therapy in resected PDAC patients. Beside these predictive biomarkers, we have evaluated different molecular factors that may impact on the likely course of this cancer. The chemokine receptor CXCR4 that has been shown to be implicated in PDAC tumorigenicity and aggressiveness could serve as a prognostic marker for survival after a curative-intent surgery and was associated with the pattern of tumour recurrence (distant versus local relapse). Our findings were validated in an independent cohort of patients. Overall our results suggested that (i) the benefit of an adjuvant gemcitabine-based therapy can be predicted based on the tumour expression of hENT1 and dCK, (ii) CXCR4 is an independent negative prognostic factor and an independent predictor of distant relapse suggesting that anti-CXCR4 targeting therapies can be a promising treatment in combination with cytotoxic chemotherapy in the adjuvant setting. These data open new perspectives for designing trials based on a molecular driven strategy.

22 Article Levels of gemcitabine transport and metabolism proteins predict survival times of patients treated with gemcitabine for pancreatic adenocarcinoma. 2012

Maréchal, Raphaël / Bachet, Jean-Baptiste / Mackey, John R / Dalban, Cécile / Demetter, Pieter / Graham, Kathryn / Couvelard, Anne / Svrcek, Magali / Bardier-Dupas, Armelle / Hammel, Pascal / Sauvanet, Alain / Louvet, Christophe / Paye, François / Rougier, Philippe / Penna, Christophe / André, Thierry / Dumontet, Charles / Cass, Carol E / Jordheim, Lars Petter / Matera, Eva-Laure / Closset, Jean / Salmon, Isabelle / Devière, Jacques / Emile, Jean-François / Van Laethem, Jean-Luc. ·Department of Gastroenterology and Gastrointestinal Cancer Unit, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium. Electronic address: raphael.marechal@erasme.ulb.ac.be. · Medical University Pierre et Marie Curie, UFR Paris VI, Paris, France; EA4340 "Epidémiologie et oncogènes des tumeurs digestives," Versailles Saint-Quentin-en-Yvelines University, Saint-Quentin-en-Yvelines, France; Department of Hepato-Gastroenterology, Pitié Salpêtrière Hospital, APHP, Paris, France. · Department of Oncology, University of Alberta, Cross Cancer Institute, Edmonton, Alberta, Canada. · Department of Biostatistics and Epidemiology (EA4184), Georges François Leclerc Center, Dijon, France. · Department of Pathology, Erasme Hospital, Université Libre de Bruxelles, and DIAPATH, Brussels, Belgium. · Department of Pathology, Beaujon Hospital, APHP, Clichy, France. · Department of Pathology, Saint Antoine Hospital, APHP, Paris, France. · Medical University Pierre et Marie Curie, UFR Paris VI, Paris, France; Department of Pathology, Pitié Salpêtrière Hospital, APHP, Paris, France. · Department of Gastroenterology, Beaujon Hospital, APHP, Clichy, France. · Department of Surgery, Beaujon Hospital, APHP, Clichy, France. · Medical University Pierre et Marie Curie, UFR Paris VI, Paris, France; Department of Oncology, Saint Antoine Hospital, APHP, Paris, France. · Medical University Pierre et Marie Curie, UFR Paris VI, Paris, France; Department of Surgery, Saint Antoine Hospital, APHP, Paris, France. · EA4340 "Epidémiologie et oncogènes des tumeurs digestives," Versailles Saint-Quentin-en-Yvelines University, Saint-Quentin-en-Yvelines, France; Department of Digestive Oncology, Hôpital Européen Georges Pompidou, APHP, Paris, France. · EA4340 "Epidémiologie et oncogènes des tumeurs digestives," Versailles Saint-Quentin-en-Yvelines University, Saint-Quentin-en-Yvelines, France; Department of Surgery, Ambroise Paré Hospital, APHP, Boulogne Billancourt, France. · Medical University Pierre et Marie Curie, UFR Paris VI, Paris, France; Department of Hepato-Gastroenterology, Pitié Salpêtrière Hospital, APHP, Paris, France. · Centre de Cancer de Lyon, Lyon, France; Hospices Civils de Lyon, Lyon, France. · Centre de Cancer de Lyon, Lyon, France. · Department of Surgery, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium. · Department of Gastroenterology and Gastrointestinal Cancer Unit, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium. · EA4340 "Epidémiologie et oncogènes des tumeurs digestives," Versailles Saint-Quentin-en-Yvelines University, Saint-Quentin-en-Yvelines, France; Department of Pathology, Ambroise Paré Hospital, APHP, Boulogne Billancourt, France. ·Gastroenterology · Pubmed #22705007.

ABSTRACT: BACKGROUND & AIMS: Patients who undergo surgery for pancreatic ductal adenocarcinoma (PDAC) frequently receive adjuvant gemcitabine chemotherapy. Key determinants of gemcitabine cytotoxicity include the activities of the human equilibrative nucleoside transporter 1 (hENT1), deoxycytidine kinase (dCK), and ribonucleotide reductase subunit 1 (RRM1). We investigated whether tumor levels of these proteins were associated with efficacy of gemcitabine therapy following surgery. METHODS: Sequential samples of resected PDACs were retrospectively collected from 434 patients at 5 centers; 142 patients did not receive adjuvant treatment (33%), 243 received adjuvant gemcitabine-based regimens (56%), and 49 received nongemcitabine regimens (11%). We measured protein levels of hENT1, dCK, and RRM1 by semiquantitative immunohistochemistry with tissue microarrays and investigated their relationship with patients' overall survival time. RESULTS: The median overall survival time of patients was 32.0 months. Among patients who did not receive adjuvant treatment, levels of hENT1, RRM1, and dCK were not associated with survival time. Among patients who received gemcitabine, high levels of hENT1 and dCK were significantly associated with longer survival time (hazard ratios of 0.34 [P < .0001] and 0.57 [P = .012], respectively). Interaction tests for gemcitabine administration and hENT1 and dCK status were statistically significant (P = .0007 and P = .016, respectively). On multivariate analysis of this population, hENT1 and dCK retained independent predictive values, and those patients with high levels of each protein had the longest survival times following adjuvant therapy with gemcitabine. CONCLUSIONS: High levels of hENT1 and dCK in PDAC predict longer survival times in patients treated with adjuvant gemcitabine.

23 Article Contribution of CXCR4 and SMAD4 in predicting disease progression pattern and benefit from adjuvant chemotherapy in resected pancreatic adenocarcinoma. 2012

Bachet, J B / Maréchal, R / Demetter, P / Bonnetain, F / Couvelard, A / Svrcek, M / Bardier-Dupas, A / Hammel, P / Sauvanet, A / Louvet, C / Paye, F / Rougier, P / Penna, C / Vaillant, J C / André, T / Closset, J / Salmon, I / Emile, J F / Van Laethem, J L. ·Medical University Pierre et Marie Curie, UFR Paris VI, Paris. jean-baptiste.bachet@psl.aphp.fr ·Ann Oncol · Pubmed #22377565.

ABSTRACT: BACKGROUND: Prognosis of patients with pancreatic adenocarcinoma is poor. Many prognostic biomarkers have been tested, but most studies included heterogeneous patients. We aimed to investigate the prognostic and/or predictive values of four relevant biomarkers in a multicentric cohort of patients. PATIENTS AND METHODS: A total of 471 patients who had resected pancreatic adenocarcinoma were included. Using tissue microarray, we assessed the relationship of biomarker expressions with the overall survival: Smad4, type II TGF-β receptor, CXCR4, and LKB1. RESULTS: High CXCR4 expression was found to be the only independent negative prognostic biomarker [hazard ratio (HR) = 1.74; P < 0.0001]. In addition, it was significantly associated with a distant relapse pattern (HR = 2.19; P < 0.0001) and was the strongest prognostic factor compared with clinicopathological factors. In patients who did not received adjuvant treatment, there was a trend toward decrease in the overall survival for negative Smad4 expression. Loss of Smad4 expression was not correlated with recurrence pattern but was shown to be predictive for adjuvant chemotherapy (CT) benefit (HR = 0.59; P = 0.002). CONCLUSIONS: CXCR4 is a strong independent prognostic biomarker associated with distant metastatic recurrence and appears as an attractive target to be evaluated in pancreatic adenocarcinoma. Negative SMAD4 expression should be considered as a potential predictor of adjuvant CT benefit.

24 Article Deoxycitidine kinase is associated with prolonged survival after adjuvant gemcitabine for resected pancreatic adenocarcinoma. 2010

Maréchal, Raphaël / Mackey, John R / Lai, Raymond / Demetter, Pieter / Peeters, Marc / Polus, Marc / Cass, Carol E / Salmon, Isabelle / Devière, Jacques / Van Laethem, Jean-Luc. ·Department of Gastroenterology and Hepato-Pancreatology, Free University of Brussels, Brussels, Belgium. rmarecha@ulb.ac.be ·Cancer · Pubmed #20669326.

ABSTRACT: BACKGROUND: Gemcitabine (2',2'-difluorodeoxycytidine) administration after resection of pancreatic cancer improves both disease-free survival (DFS) and overall survival (OS). Deoxycytidine kinase (dCK) mediates the rate-limiting catabolic step in the activation of gemcitabine. The authors of this report studied patient outcomes according to the expression of dCK after a postoperative gemcitabine-based chemoradiation regimen. METHODS: Forty-five patients with resected pancreatic adenocarcinoma received adjuvant gemcitabine based-therapy in the context of multicenter phase 2 studies. Their tumors were evaluated retrospectively for dCK protein expression by immunohistochemistry. A composite score based on the percentage of dCK-positive cancer cells and the intensity of staining was generated, and the results were dichotomized at the median values. RESULTS: The median follow-up was 19.95 months (95% confident interval [CI], 3.3-107.4 months). The lymph node (LN) ratio and dCK protein expression were significant predictors of DFS and OS in univariate analysis. On multivariate analysis, dCK protein expression was the only independent prognostic variable (DFS: hazard ratio [HR], 3.48; 95% CI, 1.66-7.31; P = .001; OS: HR, 3.2; 95% CI,1.44-7.13; P = .004). CONCLUSIONS: dCK protein expression was identified as an independent and strong prognostic factor in patients with resected pancreatic adenocarcinoma who received adjuvant gemcitabine therapy. The authors concluded that it deserves prospective evaluation as a predictive biomarker for patient selection.