Publications by authors named "Barbara Bournet"

46 Publications

Next-Generation Cancer Biomarkers: Extracellular Vesicle DNA as a Circulating Surrogate of Tumor DNA.

Front Cell Dev Biol 2020 2;8:622048. Epub 2021 Feb 2.

Centre Hospitalier Universitaire (CHU) de Toulouse, Toulouse, France.

Extracellular vesicles (EVs) are produced by healthy tissues and tumor cells and are released in various bodily fluids, including blood. They are limited by bilayer phospholipidic membranes, and they carry a rich content in biomolecules. Their release cleanses the cells of their waste or serves as functional local and distant cell-cell communication and molecular exchange particles. This rich and heterogeneous content has been given intense attention in cancer physiopathology because EVs support cancer control and progression. Because of their specific active cargo, they are being evaluated as carriers of liquid biopsy biomarkers. Compared to soluble circulating biomarkers, their complexity might provide rich information on tumor and metastases status. Thanks to the acquired genomic changes commonly observed in oncogenic processes, double-stranded DNA (dsDNA) in EVs might be the latest most promising biomarker of tumor presence and complexity. This review will focus on the recent knowledge on the DNA inclusion in vesicles, the technical aspects of EV-DNA detection and quantification, and the use of EV-DNA as a clinical biomarker.
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http://dx.doi.org/10.3389/fcell.2020.622048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884755PMC
February 2021

Increased Mucosal Thrombin is Associated with Crohn's Disease and Causes Inflammatory Damage through Protease-activated Receptors Activation.

J Crohns Colitis 2021 May;15(5):787-799

IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, CHU Purpan, Toulouse, France.

Background And Aims: Thrombin levels in the colon of Crohn's disease patients have recently been found to be elevated 100-fold compared with healthy controls. Our aim was to determine whether and how dysregulated thrombin activity could contribute to local tissue malfunctions associated with Crohn's disease.

Methods: Thrombin activity was studied in tissues from Crohn's disease patients and healthy controls. Intracolonic administration of thrombin to wild-type or protease-activated receptor-deficient mice was used to assess the effects and mechanisms of local thrombin upregulation. Colitis was induced in rats and mice by the intracolonic administration of trinitrobenzene sulphonic acid.

Results: Active forms of thrombin were increased in Crohn's disease patient tissues. Elevated thrombin expression and activity were associated with intestinal epithelial cells. Increased thrombin activity and expression were also a feature of experimental colitis in rats. Colonic exposure to doses of active thrombin comparable to what is found in inflammatory bowel disease tissues caused mucosal damage and tissue dysfunctions in mice, through a mechanism involving both protease-activated receptors -1 and -4. Intracolonic administration of the thrombin inhibitor dabigatran, as well as inhibition of protease-activated receptor-1, prevented trinitrobenzene sulphonic acid-induced colitis in rodent models.

Conclusions: Our data demonstrated that increased local thrombin activity, as it occurs in the colon of patients with inflammatory bowel disease, causes mucosal damage and inflammation. Colonic thrombin and protease-activated receptor-1 appear as possible mechanisms involved in mucosal damage and loss of function and therefore represent potential therapeutic targets for treating inflammatory bowel disease.
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http://dx.doi.org/10.1093/ecco-jcc/jjaa229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8095389PMC
May 2021

Primary Intestinal Lymphangiectasia: Diagnostic Accuracy of 99mTc-Labeled Human Serum Albumin Nanocolloid SPECT/CT Before Biopsy.

Clin Nucl Med 2021 Jan;46(1):e34-e35

Department of Gastroenterology and Pancreatology, CHU-Rangueil, University Hospital of Toulouse, Toulouse, France.

Primary intestinal lymphangiectasia is an unusual cause of protein losing enteropathy due to either congenital malformation or obstruction of lymphatics of intestine. The disease can affect all or only a small part of the small intestine. Peripheral lymphedema may be associated. The diagnosis is based on endoscopic and histopathological findings. A 30-year-old woman presents lower extremity edema with hypoproteinemia, hypoalbuminemia, and hypogammaglobulinemia. Tc-labeled human serum albumin nanocolloid lymphoscintigraphy of the lower extremity demonstrated a dermal backflow in the right extremity consistent with lymphedema and an unusual ileal uptake on SPECT/CT. Diagnosis is confirmed on histopathological evaluation of biopsy of ileum.
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http://dx.doi.org/10.1097/RLU.0000000000003285DOI Listing
January 2021

Primary Thromboprophylaxis in Ambulatory Pancreatic Cancer Patients Receiving Chemotherapy: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Cancers (Basel) 2020 Jul 24;12(8). Epub 2020 Jul 24.

Internal Medicine, Autoimmune and Vascular Disease Unit, Saint-Louis Hospital, Assistance Publique Hôpitaux de Paris, F-75010 Paris, France.

Patients with pancreatic cancer (PC) carry the highest risk of venous thromboembolism (VTE) amongst all cancer patients. Appropriate use of primary thromboprophylaxis might significantly and safely reduce its burden. We performed a systematic review of published studies and meeting abstracts using MEDLINE and EMBASE through July 2020 to evaluate the efficacy and safety of primary thromboprophylaxis in ambulatory PC patients receiving chemotherapy. The Mantel-Haenszel random effect model was used to estimate the pooled event-based risk ratio (RR) and the pooled absolute risk difference (RD) with a 95% confidence interval (CI). Five randomized controlled studies with 1003 PC patients were included in this meta-analysis. Compared to placebo, thromboprophylaxis significantly decreased the risk of VTE (pooled RR 0.31, 95% CI 0.19-0.51, < 0.00001, I = 8%; absolute RD -0.08, 95% CI -0.12--0.05, < 0.00001, I = 0%), with an estimated number needed to treat of 11.9 patients to prevent one VTE event. Similar reductions of VTE were observed in studies with parenteral (RR 0.30, 95% CI 0.17-0.53) versus oral anticoagulants (RR 0.37, 95% CI 0.14-0.99) and in studies using prophylactic doses of anticoagulants (RR 0.34, 95% CI 0.17-0.70) versus supra-prophylactic doses of anticoagulants (RR 0.27, 95% CI 0.08-0.90). The pooled RR for major bleeding was 1.08 (95% CI 0.47-2.52, = 0.85, I = 0%) and the absolute RD was 0.00 (95% CI -0.02-0.03, = 0.85, I = 0%). Evidence supports a net clinical benefit of thromboprophylaxis in ambulatory PC patients receiving chemotherapy. Adequately powered randomized phase III studies assessing the most effective anticoagulant and the optimal dose, schedule and duration of thromboprophylaxis to be used are warranted.
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http://dx.doi.org/10.3390/cancers12082028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464699PMC
July 2020

Establishment of a pancreatic adenocarcinoma molecular gradient (PAMG) that predicts the clinical outcome of pancreatic cancer.

EBioMedicine 2020 Jul 3;57:102858. Epub 2020 Jul 3.

Centre de Recherche en Cancérologie de Marseille, CRCM, Inserm, CNRS, Institut Paoli-Calmettes, Aix-Marseille Université, Marseille, France.

Background: A significant gap in pancreatic ductal adenocarcinoma (PDAC) patient's care is the lack of molecular parameters characterizing tumours and allowing a personalized treatment.

Methods: Patient-derived xenografts (PDX) were obtained from 76 consecutive PDAC and classified according to their histology into five groups. A PDAC molecular gradient (PAMG) was constructed from PDX transcriptomes recapitulating the five histological groups along a continuous gradient. The prognostic and predictive value for PMAG was evaluated in: i/ two independent series (n = 598) of resected tumours; ii/ 60 advanced tumours obtained by diagnostic EUS-guided biopsy needle flushing and iii/ on 28 biopsies from mFOLFIRINOX treated metastatic tumours.

Findings: A unique transcriptomic signature (PAGM) was generated with significant and independent prognostic value. PAMG significantly improves the characterization of PDAC heterogeneity compared to non-overlapping classifications as validated in 4 independent series of tumours (e.g. 308 consecutive resected PDAC, uHR=0.321 95% CI [0.207-0.5] and 60 locally-advanced or metastatic PDAC, uHR=0.308 95% CI [0.113-0.836]). The PAMG signature is also associated with progression under mFOLFIRINOX treatment (Pearson correlation to tumour response: -0.67, p-value < 0.001).

Interpretation: PAMG unify all PDAC pre-existing classifications inducing a shift in the actual paradigm of binary classifications towards a better characterization in a gradient.

Funding: Project funding was provided by INCa (Grants number 2018-078 and 2018-079, BACAP BCB INCa_6294), Canceropole PACA, DGOS (labellisation SIRIC), Amidex Foundation, Fondation de France, INSERM and Ligue Contre le Cancer.
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http://dx.doi.org/10.1016/j.ebiom.2020.102858DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334821PMC
July 2020

A New Score to Predict the Resectability of Pancreatic Adenocarcinoma: The BACAP Score.

Cancers (Basel) 2020 Mar 25;12(4). Epub 2020 Mar 25.

The Digestive Surgery and Liver Transplantation Department, Toulouse University Hospital, 31400 Toulouse, France.

Surgery remains the only curative treatment for pancreatic ductal adenocarcinoma (PDAC). Therefore, a predictive score for resectability on diagnosis is needed. A total of 814 patients were included between 2014 and 2017 from 15 centers included in the BACAP (the national Anatomo-Clinical Database on Pancreatic Adenocarcinoma) prospective cohort. Three groups were defined: resectable (Res), locally advanced (LA), and metastatic (Met). Variables were analyzed and a predictive score was devised. Of the 814 patients included, 703 could be evaluated: 164 Res, 266 LA, and 273 Met. The median ages of the patients were 69, 71, and 69, respectively. The median survival times were 21, 15, and nine months, respectively. Six criteria were significantly associated with a lower probability of resectability in multivariate analysis: venous/arterial thrombosis ( = 0.017), performance status 1 ( = 0.032) or ≥ 2 ( = 0.010), pain ( = 0.003), weight loss ≥ 8% ( = 0.019), topography of the tumor (body/tail) ( = 0.005), and maximal tumor size 20-33 mm ( < 0.013) or >33 mm ( < 0.001). The BACAP score was devised using these criteria (http://jdlp.fr/resectability/) with an accuracy of 81.17% and an area under the receive operating characteristic (ROC) curve of 0.82 (95% confidence interval (CI): 0.78; 0.86). The presence of pejorative criteria or a BACAP score < 50% indicates that further investigations and even neoadjuvant treatment might be warranted. Trial registration: NCT02818829.
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http://dx.doi.org/10.3390/cancers12040783DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226323PMC
March 2020

Primary Thromboprophylaxis in Pancreatic Cancer Patients: Why Clinical Practice Guidelines Should Be Implemented.

Cancers (Basel) 2020 Mar 6;12(3). Epub 2020 Mar 6.

Institute of Cardiometabolism and Nutrition, Sorbonne Université, INSERM UMRS_1166, GRC 27 GRECO, F-75013 Paris, France.

Exocrine pancreatic ductal adenocarcinoma, simply referred to as pancreatic cancer (PC) has the worst prognosis of any malignancy. Despite recent advances in the use of adjuvant chemotherapy in PC, the prognosis remains poor, with fewer than 8% of patients being alive at 5 years after diagnosis. The prevalence of PC has steadily increased over the past decades, and it is projected to become the second-leading cause of cancer-related death by 2030. In this context, optimizing and integrating supportive care is important to improve quality of life and survival. Venous thromboembolism (VTE) is a common but preventable complication in PC patients. VTE occurs in one out of five PC patients and is associated with significantly reduced progression-free survival and overall survival. The appropriate use of primary thromboprophylaxis can drastically and safely reduce the rates of VTE in PC patients as shown from subgroup analysis of non-PC targeted placebo-controlled randomized trials of cancer patients and from two dedicated controlled randomized trials in locally advanced PC patients receiving chemotherapy. Therefore, primary thromboprophylaxis with a Grade 1B evidence level is recommended in locally advanced PC patients receiving chemotherapy by the International Initiative on Cancer and Thrombosis clinical practice guidelines since 2013. However, its use and potential significant clinical benefit continues to be underrecognized worldwide. This narrative review aims to summarize the main recent advances in the field including on the use of individualized risk assessment models to stratify the risk of VTE in each patient with individual available treatment options.
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http://dx.doi.org/10.3390/cancers12030618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139861PMC
March 2020

Role of oncogenic KRAS in the diagnosis, prognosis and treatment of pancreatic cancer.

Nat Rev Gastroenterol Hepatol 2020 03 31;17(3):153-168. Epub 2020 Jan 31.

INSERM UMR 1037, Toulouse Centre for Cancer Research, University of Toulouse III, Toulouse, France.

Pancreatic ductal adenocarcinoma (PDAC) is predicted to be the second most common cause of death within the next 10 years. The prognosis for this disease is poor despite diagnostic progress and new chemotherapeutic regimens. The oncogenic KRAS mutation is the major event in pancreatic cancer; it confers permanent activation of the KRAS protein, which acts as a molecular switch to activate various intracellular signalling pathways and transcription factors inducing cell proliferation, migration, transformation and survival. Several laboratory methods have been developed to detect KRAS mutations in biological samples, including digital droplet PCR (which displays high sensitivity). Clinical studies have revealed that a KRAS mutation assay in fine-needle aspiration material combined with cytopathology increases the sensitivity, accuracy and negative predictive value of cytopathology for a positive diagnosis of pancreatic cancer. In addition, the presence of KRAS mutations in serum and plasma (liquid biopsies) correlates with a worse prognosis. The presence of mutated KRAS can also have therapeutic implications, whether at the gene level per se, during its post-translational maturation, interaction with nucleotides and after activation of the various oncogenic signals. Further pharmacokinetic and toxicological studies on new molecules are required, especially small synthetic molecules, before they can be used in the therapeutic arsenal for pancreatic ductal adenocarcinoma.
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http://dx.doi.org/10.1038/s41575-019-0245-4DOI Listing
March 2020

Incidence of Venous Thromboembolism in Patients With Newly Diagnosed Pancreatic Cancer and Factors Associated With Outcomes.

Gastroenterology 2020 04 14;158(5):1346-1358.e4. Epub 2019 Dec 14.

Université de Paris, Institut Universitaire d'Hématologie, Paris, France; Assistance Publique Hôpitaux de Paris, Saint-Louis Hospital, Internal Medicine, Autoimmune and Vascular Disease Unit, Paris, France; Department of Medicine, McGill University, Montreal, Québec, Canada. Electronic address:

Background & Aims: Pancreatic ductal adenocarcinoma (PDAC) is associated with the highest incidence of venous thromboembolism (VTE) of any cancer type. However, little is known about risk factors for VTE or its outcomes in patients with PDAC.

Methods: We collected data from a prospective, observational study performed at multiple centers in France from May 2014 through November 2018 (the Base Clinico-Biologique de l'Adénocarcinome Pancréatique [BACAP] study) linked to a database of patients with a new diagnosis of PDAC of any stage. Data were collected from 731 patients at baseline and during clinical follow-up or in the event of symptoms. The primary endpoint was the onset of VTE during follow-up. The secondary endpoints were progression-free survival (PFS) and overall survival (OS) times.

Results: During a median follow-up of 19.3 months, 152 patients (20.79%) developed a VTE. The median time from PDAC diagnosis to the onset of VTE was 4.49 months. Cumulative incidence values of VTE were 8.07% (95% confidence interval [CI], 6.31-10.29) at 3 months and 19.21% (95% CI, 16.27-22.62) at 12 months. In multivariate analysis, PDAC primary tumor location (isthmus vs head: hazard ratio [HR], 2.06; 95% CI, 1.09-3.91; P = .027) and stage (locally advanced vs resectable or borderline: HR, 1.66; 95% CI, 1.10-2.51, P = .016; metastatic vs resectable or borderline: HR, 2.50; 95% CI, 1.64-3.79; P < .001) were independent risk factors for the onset of VTE. Patients who developed VTE during follow-up had shorter times of PFS (HR, 1.74; 95% CI, 1.19-2.54; P = .004) and OS (HR, 2.02; 95% CI, 1.57-2.60; P < .001).

Conclusion: In an analysis of data from the BACAP study, we found that frequent and early onsets of VTE after diagnoses of PDAC are associated with significant decreases in times of PFS and OS. Studies are needed to determine whether primary prophylaxis of VTE in patients with PDAC will improve morbidity and mortality related to VTE. (ClinicalTrials.gov, Number: clinicaltrials.gov as number NCT02818829).
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http://dx.doi.org/10.1053/j.gastro.2019.12.009DOI Listing
April 2020

A prospective clinical and biological database for pancreatic adenocarcinoma: the BACAP cohort.

BMC Cancer 2018 Oct 16;18(1):986. Epub 2018 Oct 16.

The Department of Gastroenterology and Pancreatology, CHU - Rangueil and the University of Toulouse, 1 avenue Jean Poulhès, TSA 50032, 31059, Toulouse Cedex 9, France.

Background: The prognosis for pancreatic cancer remains poor despite diagnostic advances and treatments with new chemotherapeutic regimens. The five year survival rate remains below 3%. Consequently, there is an urgent need for new treatments to significantly improve the prognosis. In addition, there is a big gap in terms of the screening, early diagnosis and prevention of pancreatic cancer the incidence of which is increasing dramatically.

Methods: Design: the BACAP cohort is a prospective multicenter pancreatic cancer cohort (pancreatic ductal carcinoma) with clinical and multiple biological samples; Participating centers: 15 French academic and private hospitals; Study Population: any cytologically and/or histologically proven pancreatic carcinoma regardless of the stage (resectable, borderline, locally advanced or metastatic) or treatment (surgery, palliative chemotherapy, best supportive care). At least 1500 patients will be included. Clinical data collected include: disease presentation, epidemiological and social factors, baseline biology, radiology, endoscopic ultrasound, staging, pathology, treatments, follow-up (including biological and radiological), and survival. All these data are collected and stored through an e-observation system at a centralized data center. Biological samples and derived products (i.e. before any treatment): blood, saliva, endoscopic ultrasound-guided fine needle aspiration materials from the primary tumor, fine needle biopsy of metastases and surgically resected tissue. DNA and RNA are extracted from fine needle aspiration materials and are quantified and characterized for quality. Whole blood, plasma and serum are isolated from blood samples. Frozen tissues were specifically allocated to the cohort. All derived products and saliva are stored at - 80 °C. Main end-points: i) to centralize clinical data together with multiple biological samples that are harmonized in terms of sampling, the post sampling process and storage; ii) to identify new molecular markers for the diagnosis, prognosis and possibly the predictive response to pancreatic cancer surgery and or chemotherapy.

Discussion: The BACAP cohort is a unique prospective biological clinical database that provides the opportunity to identify correlations between the presence/expression of a broad panel of biomarkers (DNA, RNA, miRNA, proteins, etc.), epidemiological and social data, various clinical situations, various stages and the differentiation of the tumor, treatments and survival.

Trial Registration: ClinicalTrials.gov Identifier: NCT02818829 . Registration date: June 30, 2016.
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http://dx.doi.org/10.1186/s12885-018-4906-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6191891PMC
October 2018

Genetic Testing in Young Adult Patients With Idiopathic Acute Pancreatitis.

Am J Gastroenterol 2018 04;113(4):624

Department of Gastroenterology, University Hospital Centre Rangueil-Larrey, University of Toulouse, Toulouse, France.

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http://dx.doi.org/10.1038/ajg.2017.467DOI Listing
April 2018

Clinical profile of cannabis-associated acute pancreatitis.

Dig Liver Dis 2017 11 6;49(11):1284-1285. Epub 2017 Sep 6.

Department of Gastroenterology, University Hospital Centre Rangueil-Larrey, University of Toulouse, Toulouse, France. Electronic address:

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http://dx.doi.org/10.1016/j.dld.2017.08.040DOI Listing
November 2017

Features of Autoimmune Pancreatitis Associated With Inflammatory Bowel Diseases.

Clin Gastroenterol Hepatol 2018 Jan 4;16(1):59-67. Epub 2017 Aug 4.

Departement of Hepato-Gastroenterology, Hôpital Cochin, AP-HP, Paris, France.

Background & Aims: Few people know of autoimmune pancreatitis (AIP), a rare disorder associated with inflammatory bowel diseases (IBD). We aimed to describe phenotype and outcomes of IBD and AIP when associated.

Methods: We performed a retrospective study of cases of AIP in IBD identified from the multicenter Groupe d'Etude Thérapeutique des Affections Inflammatoires du tube Digestif in Belgium and France from July 2012 through July 2015. Patients were diagnosed with AIP based on the International Consensus Diagnostic Criteria for AIP. A definitive AIP diagnosis was based on histological analysis of pancreatic resection specimens or samples collected by fine-needle aspiration during endoscopic ultrasound. Patients with probable type 1 AIP were identified based on imaging findings, clinical and/or radiologic responses to steroids, level of serum immunoglobulin G4, and involvement of other organs. Patients with probable type 2 AIP were identified based on imaging findings, clinical and/or radiologic responses to steroids, and association with IBD. The primary objective was to collect information on the characteristics of AIP in patients with IBD. We also compared features of patients with IBD with and without AIP in a case-control analysis, using multivariate analysis.

Results: We analyzed data from 91 individuals with AIP and IBD (47 women) seen at 23 centers (58 had ulcerative colitis [UC] and 33 Crohn's disease [CD]). Eighty-nine patients had type 2 AIP, and 2 patients had type 1 AIP. The mean age at diagnosis of AIP was 35 ± 12 years, and for IBD it was 32 ± 12 years. AIP preceded IBD in 19 patients (21%). Over a mean follow-up period of 5.7 ± 4.9 years, 31 patients (34%) relapsed, 11 patients (12%) developed diabetes, and 17 patients (19%) developed exocrine pancreatic insufficiency. In patients with UC, factors independently associated with AIP included proctitis (odds ratio [OR], 2.9; 95% confidence interval [CI], 1.3-6.3; P = .007) and colectomy (OR, 7.1; 95% CI, 2.5-20; P = .0003). In patients with CD, AIP was significantly associated with fewer perianal lesions (OR, 0.16; 95% CI, 0.03-0.77; P = .023), non-stricturing non-penetrating CD (OR, 6.7; 95% CI, 1.25-33.3; P = .0029), and higher rate of colectomy (OR, 27.8; 95% CI, 3.6-217; P = .0029).

Conclusions: In a multicenter retrospective analysis of patients with AIP and IBD, followed for an average of 5.7 ± 4.9 years, we found most to have type 2 AIP. Two-thirds of patients have UC, often with proctitis. One-third of patients have CD, often with inflammatory features. Patients with IBD and AIP have higher rates of colectomy than patients with just IBD.
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http://dx.doi.org/10.1016/j.cgh.2017.07.033DOI Listing
January 2018

Gene Therapy for Pancreatic Cancer: Specificity, Issues and Hopes.

Int J Mol Sci 2017 Jun 8;18(6). Epub 2017 Jun 8.

Department of Gastroenterology, CHU Rangueil, 1 avenue Jean Poulhès, Toulouse 31059, France.

A recent death projection has placed pancreatic ductal adenocarcinoma as the second cause of death by cancer in 2030. The prognosis for pancreatic cancer is very poor and there is a great need for new treatments that can change this poor outcome. Developments of therapeutic innovations in combination with conventional chemotherapy are needed urgently. Among innovative treatments the gene therapy offers a promising avenue. The present review gives an overview of the general strategy of gene therapy as well as the limitations and stakes of the different experimental in vivo models, expression vectors (synthetic and viral), molecular tools (interference RNA, genome editing) and therapeutic genes (tumor suppressor genes, antiangiogenic and pro-apoptotic genes, suicide genes). The latest developments in pancreatic carcinoma gene therapy are described including gene-based tumor cell sensitization to chemotherapy, vaccination and adoptive immunotherapy (chimeric antigen receptor T-cells strategy). Nowadays, there is a specific development of oncolytic virus therapies including oncolytic adenoviruses, herpes virus, parvovirus or reovirus. A summary of all published and on-going phase-1 trials is given. Most of them associate gene therapy and chemotherapy or radiochemotherapy. The first results are encouraging for most of the trials but remain to be confirmed in phase 2 trials.
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http://dx.doi.org/10.3390/ijms18061231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5486054PMC
June 2017

Endoscopic ultrasound-guided fine-needle aspiration plus KRAS and GNAS mutation in malignant intraductal papillary mucinous neoplasm of the pancreas.

Endosc Int Open 2016 Dec 10;4(12):E1228-E1235. Epub 2016 Nov 10.

Department of Gastroenterology and INSERM UMR 1037, CHU Toulouse Rangueil, University of Toulouse, Toulouse, France; INSERM UMR 1037, University Institute of Cancer of Toulouse, University of Toulouse, Toulouse, France.

and mutations are common in intraductal papillary mucinous neoplasia of the pancreas (IPMN). The aims of this study were to assess the role of pre-therapeutic cytopathology combined with and mutation assays within cystic fluid sampled by endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) to predict malignancy of IPMN. We prospectively included 37 IPMN patients with clinical and/or imaging predictors of malignancy (men: 24; mean age: 69.5 years). Cytopathology (performed on cystic fluid and/or IPMN nodules), (Exon 2, codon 12) and (Exon 8, codon 201) mutations assays (using TaqMan allelic discrimination) were performed on EUS-FNA material. The final diagnosis was obtained from IPMN resections (n = 18); surgical biopsies, EUS-FNA analyses, and follow-up (n = 19): 10 and 27 IPMN were benign and malignant, respectively. Sensitivity, specificity, positive and negative predictive values, and accuracy of cytopathology alone to diagnose IPMN malignancy were 55 %, 100 %, 100 %, 45 %, and 66 %, respectively. When mutation analysis was combined with cytopathology these values were 92 %, 50 %, 83 %, 71 %, and 81 %, respectively. assays did not improve the performances of cytopathology alone or those of cytopathology plus a assay. In patients with a likelihood of malignant IPMN at pre-therapeutic investigation, testing for mutations in cystic fluid sampling by EUS-FNA improved the results of cytopathology for the diagnosis of malignancy whereas mutation assay did not.
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http://dx.doi.org/10.1055/s-0042-117216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161125PMC
December 2016

Outcomes of patients with hepatocellular carcinoma are determined in multidisciplinary team meetings.

J Surg Oncol 2017 Mar 4;115(3):330-336. Epub 2016 Nov 4.

Service de chirurgie digestive et hépatobiliaire, Centre Hospitalier Universitaire Rangueil, Université Paul Sabatier III, Toulouse, France.

Background And Objectives: To analyze overall survival (OS) rates for the three curative treatments of hepatocellular carcinoma (HCC) on an intention-to-treat (ITT) basis.

Methods: Cohort study based on data from a multidisciplinary team meeting (MDT) dedicated to HCC. From 2006 to 2013, we included every patient with newly diagnosed HCC, for whom curative treatment (liver transplantation (LT), radiofrequency ablation (RFA), surgical resection (SR)) was decided upon.

Results: We included 387 consecutive patients. LT was decided in 136 cases, RFA in 131 cases, SR in 120 cases. Sixty-six percent of patients received the planned treatment. Five-year OS on an ITT basis were: 35% for the LT-group, 32% for the RFA-group, 34% for the SR-group (P = 0.77). In multivariate analyses, the main negative prognostic factors were not following the MDT decision (HR: 0.39, CI95% [0.27-0.54], P < 0.001), elevated alpha-fetoprotein level (HR: 0.63, CI95% [0.45-0.87], P = 0.005), being outside the Milan criteria (HR: 0.45, CI95% [0.31-0.65], P < 0.001). When curative treatment was performed, per-protocol 5-year OS were 64% for LT, 34% for RFA, 40% for SR.

Conclusion: On an ITT basis, OS was similar whatever the type of curative treatment chosen in MDT. Negative prognostic factors were not following the MDT decision, elevated alpha-fetoprotein, being outside the Milan criteria. J. Surg. Oncol. 2017;115:330-336. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/jso.24500DOI Listing
March 2017

KRAS G12D Mutation Subtype Is A Prognostic Factor for Advanced Pancreatic Adenocarcinoma.

Clin Transl Gastroenterol 2016 Mar 24;7:e157. Epub 2016 Mar 24.

Department of Gastroenterology, CHU Toulouse Rangueil, University of Toulouse, Toulouse, France.

Objectives: There is no molecular biomarker available in the clinical practice to assess the prognosis of advanced pancreatic carcinoma. This multicenter prospective study aimed to investigate the role of KRAS mutation subtypes within the primary tumor to determine the prognosis of advanced pancreatic cancer.

Methods: The exon-2 KRAS mutation status was tested on endoscopic ultrasound-guided fine-needle aspiration biopsy material (primary tumor; restriction fragment-length polymorphism plus sequencing and TaqMan allelic discrimination) of patients with proven locally advanced and/or metastatic pancreatic ductal carcinoma. We used the Kaplan-Meier method, log-rank test, and Cox's model to evaluate the impact of KRAS status on the overall survival (OS), adjusting for age, stage of disease, clinical performance status, CA 19-9 levels, and treatment.

Results: A total of 219 patients (men: 116; mean age: 67±9.4 years) were included: 147 harbored a codon-12 KRAS mutation (G12D: 73; G12V: 53; G12R: 21) and 72 had a wild-type KRAS. There was no difference in the OS between patients with a mutant KRAS (8 months; 95% confidence interval (95% CI): 8.7-12.3) and the wild-type (9 months; 95% CI: 8.7-12.8; hazard ratio (HR): 1.03; P=0.82). However, the patients with a G12D mutation had a significantly shorter OS (6 months; 95% CI: 6.4-9.7) compared with the other patients (OS: 9 months; 95% CI: 10-13; HR: 1.47; P=0.003; i.e., wild type: 9 months, G12V: 9 months, G12R: 14 months). Similar results were observed in the subgroup of 162 patients who received chemotherapy (HR: 1.66; P=0.0013; G12D (n=49): 8 months, wild type (n=56): 10 months, G12V (n=38): 10 months, G12R (n=19): 14 months). Multivariate analyses identified KRAS G12D as an independent predictor for worse prognosis within the entire series (HR: 1.44; P=0.01) and in the subgroup of patients that received chemotherapy (HR: 1.84; P=0.02).

Conclusions: The KRAS G12D mutation subtype is an independent prognostic marker for advanced pancreatic ductal carcinoma. Codon and amino-acid-specific mutations of KRAS should be considered when evaluating the prognoses as well as in trials testing drugs that target RAS and downstream RAS pathways.
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http://dx.doi.org/10.1038/ctg.2016.18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4822095PMC
March 2016

Targeting KRAS for diagnosis, prognosis, and treatment of pancreatic cancer: Hopes and realities.

Eur J Cancer 2016 Feb 28;54:75-83. Epub 2015 Dec 28.

Department of Gastroenterology, CHU Toulouse Rangueil, University of Toulouse, Toulouse, France; INSERM UMR 1037, Center for Cancer Research, Institute of Cancer of the University of Toulouse, Toulouse, France. Electronic address:

Mutation of the KRAS oncogene in pancreatic cancer is responsible for permanent activation of the P21 RAS protein and the cascade of signalling pathways. Consequently, multiple cellular processes, such as transformation, proliferation, invasion, and survival are activated. The aim of this review was to present all potential clinical applications of targeting KRAS in terms of diagnosis and management of pancreatic adenocarcinoma. Quantitative polymerase chain reaction technology provides reliable assessment of KRAS mutations, both in tissues and from fine-needle aspiration biopsies. Numerous studies report that the combination of endoscopic ultrasound-guided cytopathology and a KRAS mutation assay can improve the positive and differential diagnosis of pancreatic cancer, differentiating between benign versus malignant solid pancreatic cancer, and reducing false-negative results compared to cytopathology alone. In addition, the presence of a KRAS mutation is frequently associated with a worse prognosis, both in cases of advanced and resected tumours. However, the KRAS mutation assay is not as efficient at predicting a response to both anti-epidermal growth factor receptor treatments and/or chemotherapy. Targeting of KRAS to treat pancreatic adenocarcinoma has been applied at different stages of RAS molecular intracellular processes: at the transcription level with antisense or interference RNA, at the posttranslational level with inhibitors of farnesyl transferase or anti-RAS vaccination peptides, and to target multiple signalling pathways using inhibitors of mitogen-activated protein kinase, phosphoinositide 3-kinase, AKT, mammalian target of rapamycin, RAF. Despite some encouraging results at pre-clinical and phase I stages, no significant clinical benefits have been observed. Combinatory approaches with standard chemotherapy will be welcome.
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http://dx.doi.org/10.1016/j.ejca.2015.11.012DOI Listing
February 2016

Salivary MicroRNA in Pancreatic Cancer Patients.

PLoS One 2015 29;10(6):e0130996. Epub 2015 Jun 29.

Inserm, UMR1037 CRCT, F-31000 Toulouse, France; Université Toulouse III-Paul Sabatier, UMR1037 CRCT, F-31000 Toulouse, France.

Background: Pancreatic cancer is the fourth leading cause of cancer death in Western countries, with the lowest 1-year survival rate among commonly diagnosed cancers. Reliable biomarkers for pancreatic cancer diagnosis are lacking and are urgently needed to allow for curative surgery. As microRNA (miRNA) recently emerged as candidate biomarkers for this disease, we explored in the present pilot study the differences in salivary microRNA profiles between patients with pancreatic tumors that are not eligible for surgery, precancerous lesions, inflammatory disease or cancer-free patients as a potential early diagnostic tool.

Methods: Whole saliva samples from patients with pancreatic cancer (n = 7), pancreatitis (n = 4), IPMN (n = 2), or healthy controls (n = 4) were obtained during endoscopic examination. After total RNA isolation, expression of 94 candidate miRNAs was screened by q(RT)PCR using Biomark Fluidgm. Human-derived pancreatic cancer cells were xenografted in athymic mice as an experimental model of pancreatic cancer.

Results: We identified hsa-miR-21, hsa-miR-23a, hsa-miR-23b and miR-29c as being significantly upregulated in saliva of pancreatic cancer patients compared to control, showing sensitivities of 71.4%, 85.7%, 85,7% and 57%, respectively and excellent specificity (100%). Interestingly, hsa-miR-23a and hsa-miR23b are overexpressed in the saliva of patients with pancreatic cancer precursor lesions. We found that hsa-miR-210 and let-7c are overexpressed in the saliva of patients with pancreatitis as compared to the control group, with sensitivity of 100% and 75%, and specificity of 100% and 80%, respectively. Last hsa-miR-216 was upregulated in cancer patients as compared to patients diagnosed with pancreatitis, with sensitivity of 50% and specificity of 100%. In experimental models of PDAC, salivary microRNA detection precedes systemic detection of cancer cells markers.

Conclusions: Our novel findings indicate that salivary miRNA are discriminatory in pancreatic cancer patients that are not eligible for surgery. In addition, we demonstrate in experimental models that salivary miRNA detection precedes systemic detection of cancer cells markers. This study stems for the use of salivary miRNA as biomarker for the early diagnosis of patients with unresectable pancreatic cancer.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0130996PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4486170PMC
March 2016

[Advance in the biology of pancreatic of cancer].

Bull Cancer 2015 Jun;102(6 Suppl 1):S53-61

Inserm UMR 1037, Centre de recherche en cancérologie de Toulouse 2, avenue Hubert-Curien, Oncopole de Toulouse, CS 53717, 31037 Toulouse cedex 1.

The understanding of the biology of pancreatic carcinoma has greatly benefited from studies of genetic/epigenetic alterations and molecular expression in experimental models as well as precancerous and cancerous tissues by mean of molecular amplification and large-scale transcriptoma analysis. P16, TP53, DPC4/Smad4 tumor suppressor pathways are genetically inactivated in the majority of pancreatic carcinomas, whereas oncogenic k-ras is activated. The activating point mutation of the KRAS oncogene on codon 12 is the major event and occurs early in pancreatic carcinogenesis. At a late stage of tumor development, an increase of telomerase activity, an over expression of growth factors and/or their receptors (EGF, Nerve Growth Factor, gastrin), of pro-angiogenic factors (VEGF, FGF, PDGF), of invasiveness factors (metalloproteinases, tissue plasminogen activators) occurs. The microenvironment plays also a key role in the invasive and metastatic process of pancreatic carcinoma with a strong relationship between cancerous cells and pancreatic stellate cells as well as extracellular matrix. This microenvironment strongly participates to the tumor fibrosis, hypoxia and hypovascularization inducing an inaccessibility of drugs. Nowadays, the targeting of microenvironment takes a special place in the new therapeutic strategies of pancreatic cancer in combination with chemotherapy.
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http://dx.doi.org/10.1016/S0007-4551(15)31218-2DOI Listing
June 2015

Prospective evaluation of the aetiological profile of acute pancreatitis in young adult patients.

Dig Liver Dis 2015 Jul 18;47(7):584-9. Epub 2015 Mar 18.

Department of Gastroenterology, University Hospital Centre Rangueil-Larrey, University of Toulouse, Toulouse, France. Electronic address:

Background: The aetiologies of acute pancreatitis in young adult patients are poorly known.

Aims: To prospectively evaluate the causes of acute pancreatitis in patients aged less than 35 years.

Methods: Overall, 309 consecutive patients admitted to our centre for acute pancreatitis received first-line investigations, including medical history, standard laboratory tests, abdominal ultrasound and computed tomography. If no aetiology was found, second-line investigations were performed, including endoscopic ultrasound, magnetic-resonance cholangiopancreatography and genetic testing in cases of idiopathic pancreatitis.

Results: Overall, 66 patients aged between 16 and 35 years were included. After first-line investigations, 49% of cases of acute pancreatitis remained idiopathic. Second-line investigations reduced this rate to 21%. The frequency of aetiologies for acute pancreatitis significantly differed in adults aged ≤ 35 compared to those aged >35 years: biliary aetiology was less frequent (23% versus 43%, p=0.003) as well as alcohol-related (8% versus 24%, p=0.01); drug-induced was more common (16% versus 4%, p=0.0007), as well as cannabis-related (13% versus 1%, p<0.0001), or genetic (10% versus 1.5%, p=0.003).

Conclusions: The aetiologies of acute pancreatitis significantly differed in adults aged less than 35 years when compared to older patients. Thus, use of medications, exposure to cannabis, and genetic mutations should be actively sought in these patients.
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http://dx.doi.org/10.1016/j.dld.2015.03.009DOI Listing
July 2015

Outcomes of nonresected main-duct intraductal papillary mucinous neoplasms of the pancreas.

World J Gastroenterol 2015 Mar;21(9):2658-67

Mathieu Daudé, Louis Buscail, Barbara Bournet, Department of Gastroenterology, CHU Toulouse Rangueil, University of Toulouse, 31059 Toulouse, France.

Aim: To compare characteristics and outcomes of resected and nonresected main-duct and mixed intraductal papillary mucinous neoplasms of the pancreas (IPMN).

Methods: Over a 14-year period, 50 patients who did not undergo surgery for resectable main-duct or mixed IPMN, for reasons of precluding comorbidities, age and/or refusal, were compared with 74 patients who underwent resection to assess differences in rates of survival, recurrence/occurrence of malignancy, and prognostic factors. All study participants had dilatation of the main pancreatic duct by ≥ 5 mm, with or without dilatation of the branch ducts. Some of the nonsurgical patients showed evidence of mucus upon perendoscopic retrograde cholangiopancreatography or endoscopic ultrasound and/or after fine needle aspiration. For the surgical patients, pathologic analysis of resected specimens confirmed a diagnosis of IPMN with involvement of the main pancreatic duct or of both branch ducts as well as the main pancreatic duct. Clinical and biologic follow-ups were conducted for all patients at least annually, through hospitalization or consultation every six months during the first year of follow-up, together with abdominal imaging analysis (magnetic resonance cholangiopancreatography or computed tomography) and, if necessary, endoscopic ultrasound with or without fine needle aspiration.

Results: The overall five-year survival rate of patients who underwent resection was significantly greater than that for the nonsurgical patients (74% vs 58%; P = 0.019). The parameters of age (< 70 years) and absence of a nodule were associated with better survival (P < 0.05); however, the parameters of main pancreatic duct diameter > 10 mm, branch duct diameter > 30 mm, or presence of extra pancreatic cancers did not significantly influence the prognosis. In the nonsurgical patients, pancreatic malignancy occurred in 36% of cases within a mean time of 33 mo (median: 29 mo; range: 8-141 mo). Comparison of the nonsurgical patients who experienced disease progression with those who did not progress showed no significant differences in age, sex, symptoms, subtype of IPMN, or follow-up period; only the size of the main pancreatic duct was significantly different between these two sub-groups, with the nonsurgical patients who experienced progression showing a greater diameter at the time of diagnosis (> 10 mm).

Conclusion: Patients unfit for surgery have a 36% greater risk of developing pancreatic malignancy of the main-duct or mixed IPMN within a median of 2.5 years.
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http://dx.doi.org/10.3748/wjg.v21.i9.2658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351216PMC
March 2015

Acute Pancreatitis: Extrapancreatic Necrosis Volume as Early Predictor of Severity.

Radiology 2015 Jul 2;276(1):119-28. Epub 2015 Feb 2.

From the Departments of Radiology (O.M., S.L., F.Z.M., H.R., P.O.) and Gastroenterology (B.B., L.B.), CHU Toulouse Rangueil, Avenue du Professeur Jean Poulhès, 31400 Toulouse, France; and Inserm/UPS UMR 1048, I2MC Team 10, Toulouse, France (O.M.).

Purpose: To determine the volume of extrapancreatic necrosis that predicts severe acute pancreatitis and to assess the reliability of this threshold in predicting severe acute pancreatitis compared with current scoring systems and C-reactive protein (CRP) levels.

Materials And Methods: This institutional review board-approved, HIPAA-compliant retrospective study included patients with acute pancreatitis who were examined with computed tomography (CT) 2-6 days after disease onset. Extrapancreatic necrosis volume, Balthazar score, and CT severity index (CTSI) were calculated. CRP levels 48 hours after the onset of symptoms were reviewed. Outcome parameters included organ failure, infection, need for surgery or percutaneous intervention, duration of hospitalization, and/or death. Receiver operating characteristic (ROC) curves were constructed to determine the optimal threshold for predicting clinical outcomes. Pairwise comparisons of areas under ROC curves (AUCs) from the different grading systems were performed. Interobserver and intraobserver agreement in the grading of extrapancreatic necrosis was assessed by using κ statistics.

Results: In 264 patients, significant relationships were found between extrapancreatic necrosis volume and organ failure, infection, duration of hospitalization, need for intervention, and death (P < .001 for all). The optimal threshold for predicting severe acute pancreatitis was 100 mL. Sensitivity and specificity were 95% (19 of 20) and 83% (142 of 172), respectively, for predicting organ failure (vs 100% [20 of 20] and 46% [79 of 172] for the Balthazar score and 25% [five of 20] and 95% [163 of 172] for the CTSI). The extrapancreatic necrosis AUC was the highest for all systems. Interobserver and intraobserver agreement based on the 100-mL threshold was considered to be excellent.

Conclusion: A simple grading system based on an objective criterion such as a threshold of 100 mL of extrapancreatic necrosis provides more reliable information for predicting acute pancreatitis outcomes than do the current scoring systems.
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http://dx.doi.org/10.1148/radiol.15141494DOI Listing
July 2015

First-in-man phase 1 clinical trial of gene therapy for advanced pancreatic cancer: safety, biodistribution, and preliminary clinical findings.

Mol Ther 2015 Apr 14;23(4):779-89. Epub 2015 Jan 14.

1] Université Toulouse III-Paul Sabatier, UMR1037 CRCT, Toulouse, France [2] Inserm, UMR1037 CRCT, Toulouse, France.

This phase 1 trial was aimed to determine the safety, pharmacokinetics, and preliminary clinical activity of CYL-02, a nonviral gene therapy product that sensitizes pancreatic cancer cells to chemotherapy. CYL-02 was administrated using endoscopic ultrasound in 22 patients with pancreatic cancer that concomitantly received chemotherapy (gemcitabine). The maximum-tolerated dose (MTD) exceeded the maximal feasible dose of CYL-02 and was not identified. Treatment-related toxicities were mild, without serious adverse events. Pharmacokinetic analysis revealed a dose-dependent increase in CYL-02 DNA exposure in blood and tumors, while therapeutic RNAs were detected in tumors. No objective response was observed, but nine patients showed stable disease up to 6 months following treatment and two of these patients experienced long-term survival. Panels of plasmatic microRNAs and proteins were identified as predictive of gene therapy efficacy. We demonstrate that CYL-02 nonviral gene therapy has a favorable safety profile and is well tolerated in patients. We characterize CYL-02 biodistribution and demonstrate therapeutic gene expression in tumors. Treated patients experienced stability of disease and predictive biomarkers of response to treatment were identified. These promising results warrant further evaluation in phase 2 clinical trial.
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http://dx.doi.org/10.1038/mt.2015.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4395782PMC
April 2015

MicroRNAs as emerging biomarkers and therapeutic targets for pancreatic cancer.

World J Gastroenterol 2014 Aug;20(32):11199-209

Marion Gayral, Sébastien Jo, Naima Hanoun, Alix Vignolle-Vidoni, Hubert Lulka, Yannick Delpu, Aline Meulle, Marlène Dufresne, Marine Humeau, Maël Chalret du Rieu, Barbara Bournet, Janick Sèlves, Rosine Guimbaud, Nicolas Carrère, Louis Buscail, Jérôme Torrisani, Pierre Cordelier, Cancer Research Center of Toulouse Team 10, UMR INSERM U1037, Université Paul Sabatier, 31100 Toulouse, France.

Despite tremendous efforts from scientists and clinicians worldwide, pancreatic adenocarcinoma (PDAC) remains a deadly disease due to the lack of early diagnostic tools and reliable therapeutic approaches. Consequently, a majority of patients (80%) display an advanced disease that results in a low resection rate leading to an overall median survival of less than 6 months. Accordingly, robust markers for the early diagnosis and prognosis of pancreatic cancer, or markers indicative of survival and/or metastatic disease are desperately needed to help alleviate the dismal prognosis of this cancer. In addition, the discovery of new therapeutic targets is mandatory to design effective treatments. In this review, we will highlight the translational studies demonstrating that microRNAs may soon translate into clinical applications as long-awaited screening tools and therapeutic targets for PDAC.
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http://dx.doi.org/10.3748/wjg.v20.i32.11199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4145758PMC
August 2014

Role of endoscopic ultrasound in the molecular diagnosis of pancreatic cancer.

World J Gastroenterol 2014 Aug;20(31):10758-68

Barbara Bournet, Louis Buscail, Department of Gastroenterology, CHU Toulouse Rangueil, University of Toulouse, 31059 Toulouse, France.

Pancreatic ductal adenocarcinoma remains one of the most deadly types of tumor. Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is a safe, cost-effective, and accurate technique for evaluating and staging pancreatic tumors. However, EUS-FNA may be inconclusive or doubtful in up to 20% of cases. This review underlines the clinical interest of the molecular analysis of samples obtained by EUS-FNA in assessing diagnosis or prognosis of pancreatic cancer, especially in locally advanced tumors. On EUS-FNA materials DNA, mRNA and miRNA can be extracted, amplified, quantified and subjected to methylation assay. Kras mutation assay, improves diagnosis of pancreatic cancer. When facing to clinical and radiological presentations of pseudo-tumorous chronic pancreatitis, wild-type Kras is evocative of benignity. Conversely, in front of a pancreatic mass suspected of malignancy, a mutated Kras is highly evocative of pancreatic adenocarcinoma. This strategy can reduce false-negative diagnoses, avoids the delay of making decisions and reduces loss of surgical resectability. Similar approaches are conducted using analysis of miRNA expression as well as Mucin or markers of invasion (S100P, S100A6, PLAT or PLAU). Beyond the diagnosis approach, the prediction of response to treatment can be also investigated form biomarkers expression within EUS-FNA materials.
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http://dx.doi.org/10.3748/wjg.v20.i31.10758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4138456PMC
August 2014

Rituximab in pure red-cell aplasia secondary to anti-erythropoietin antibodies.

Kidney Int 2014 Jul;86(1):210-1

1] Département de Néphrologie et Transplantation d'Organes , Centre Hospitalo-Universitaire de Rangueil, Toulouse, France [2] Université Toulouse-III, Toulouse, France.

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http://dx.doi.org/10.1038/ki.2014.144DOI Listing
July 2014

Endoscopic ultrasound-guided fine-needle aspiration biopsy coupled with a KRAS mutation assay using allelic discrimination improves the diagnosis of pancreatic cancer.

J Clin Gastroenterol 2015 Jan;49(1):50-6

*Department of Gastroenterology †INSERM UMR 1037, CHU Toulouse Rangueil ‡Department of Pathology, CHU Toulouse Purpan, University of Toulouse, Toulouse, France.

Goals And Background: Mutation of the KRAS oncogene is present in 75% to 95% of pancreatic cancer tissues. This study aimed to evaluate whether endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA), combined with analysis of the KRAS mutation, improves the diagnosis of pancreatic cancer in cases of inconclusive or doubtful cytopathologic analysis.

Patients And Methods: We prospectively included 186 patients with a pancreatic mass (103 men; mean age: 62 y). Cytopathology and KRAS mutations, using TaqMan MGB allelic discrimination, were performed on EUS-FNA material. A final diagnosis was obtained from EUS-FNA analysis and/or a subsequent biopsy if necessary, and/or surgery, and follow-up: these were pancreatic adenocarcinoma (n=104), other malignant pancreatic tumors (n=22), and benign lesions (n=60, including 35 cases of chronic pancreatitis).

Results: Inconclusive or doubtful (low-grade dysplasia or atypia) cytopathology was found in 68 cases. Of these, 29 patients who had adenocarcinoma were subsequently diagnosed, including 19 cases with a former KRAS mutation. Sensitivity, specificity, positive and negative predictive values, and overall accuracy of cytopathology alone to diagnose adenocarcinoma were 73%, 100%, 100%, 75%, and 85%, respectively. When KRAS mutation analysis was combined with pathology, these values reached 88%, 99%, 99%, 89%, and 93%, respectively. The performance of EUS-FNA to diagnose malignancy was similarly improved after the KRAS-mutation assay (negative predictive value increased from 67% to 88%; accuracy increased from 85% to 94%).

Conclusions: EUS-FNA plus KRAS-mutation analysis, using allelic discrimination, is accurate and improves the diagnosis of pancreatic adenocarcinoma when pathology is inconclusive or doubtful.
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http://dx.doi.org/10.1097/MCG.0000000000000053DOI Listing
January 2015

[Kras oncogene and pancreatic cancer: thirty years after].

Med Sci (Paris) 2013 Nov 20;29(11):991-7. Epub 2013 Nov 20.

Inserm UMR U1037, Centre de recherche sur le cancer de Toulouse, CHU Rangueil, 1, avenue Jean Poulhès, BP 84225, 31432 Toulouse Cedex 4, France - Service de gastroentérologie et nutrition, CHU Rangueil-Larrey, 1, avenue Jean Poulhès, TSA 50032, 31059 Toulouse, Cedex 9, France.

Point mutations of the Kras oncogene induce in cancerous cells an uncontrolled increase of cell proliferation and invasiveness. Mutation of Kras appears early during the process of the pancreatic carcinogenesis and is the most frequent genetic alteration in pancreatic adenocarcinoma (75 to 95 % of cases) as well as in precancerous lesions such as PanIN and IMPN. These latter lesions and tumour microenvironment are reproduced in transgenic models developed in mice. These models are induced on the basis of Kras mutation (Pdx1-Cre ; Kras(G12D) mice) associated or not to the inactivation of tumour suppressor genes (TP53, DPC4, INK4A). Kras mutation assay is easily performed in human biological samples, especially in the cellular material sampled in pancreatic masses under endoscopic ultrasound by fine needle aspiration biopsy. In the near future, searching for Kras mutation could be useful in clinical practice either for positive diagnosis of pancreatic adenocarcinoma in case of unconclusive/doubtful cytopathological analysis or for the differential diagnosis with chronic pancreatitis especially in its pseudotumoural form.
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http://dx.doi.org/10.1051/medsci/20132911015DOI Listing
November 2013