Publications by authors named "Louis Buscail"

95 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

Perineal Wound Closure Following Abdominoperineal Resection and Pelvic Exenteration for Cancer: A Systematic Review and Meta-Analysis.

Cancers (Basel) 2021 Feb 10;13(4). Epub 2021 Feb 10.

Department of Plastic and Reconstructive Surgery, Toulouse University Hospital, 31100 Toulouse, France.

Background: Abdominoperineal resection (APR) and pelvic exenteration (PE) for the treatment of cancer require extensive pelvic resection with a high rate of postoperative complications. The objective of this work was to systematically review and meta-analyze the effects of vertical rectus abdominis myocutaneous flap (VRAMf) and mesh closure on perineal morbidity following APR and PE (mainly for anal and rectal cancers).

Methods: We searched PubMed, Cochrane, and EMBASE for eligible studies as of the year 2000. After data extraction, a meta-analysis was performed to compare perineal wound morbidity. The studies were distributed as follows: Group A comparing primary closure (PC) and VRAMf, Group B comparing PC and mesh closure, and Group C comparing PC and VRAMf in PE.

Results: Our systematic review yielded 18 eligible studies involving 2180 patients (1206 primary closures, 647 flap closures, 327 mesh closures). The meta-analysis of Groups A and B showed PC to be associated with an increase in the rate of total (Group A: OR 0.55, 95% CI 0.43-0.71; < 0.01/Group B: OR 0.54, CI 0.17-1.68; = 0.18) and major perineal wound complications (Group A: OR 0.49, 95% CI 0.35-0.68; < 0.001/Group B: OR 0.38, 95% CI 0.12-1.17; < 0.01). PC was associated with a decrease in total (OR 2.46, 95% CI 1.39-4.35; < 0.01) and major (OR 1.67, 95% CI 0.90-3.08; = 0.1) perineal complications in Group C.

Conclusion: Our results confirm the contribution of the VRAMf in reducing major complications in APR. Similarly, biological prostheses offer an interesting alternative in pelvic reconstruction. For PE, an adapted reconstruction must be proposed with specialized expertise.
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http://dx.doi.org/10.3390/cancers13040721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916499PMC
February 2021

The reversion variant (p.Arg90Leu) at the evolutionarily adaptive p.Arg90 site in CELA3B predisposes to chronic pancreatitis.

Hum Mutat 2021 Apr 19;42(4):385-391. Epub 2021 Feb 19.

Univ Brest, Inserm, EFS, UMR 1078, GGB, Brest, France.

A gain-of-function missense variant in the CELA3B gene, p.Arg90Cys (c.268C>T), has recently been reported to cause pancreatitis in an extended pedigree. Herein, we sequenced the CELA3B gene in 644 genetically unexplained French chronic pancreatitis (CP) patients (all unrelated) and 566 controls. No obvious loss-of-function variants were identified. None of the six low-frequency or common missense variants detected showed significant association with CP. Nor did the aggregate rare/very rare missense variants (n = 14) show any significant association with CP. However, p.Arg90Leu (c.269G>T), which was found in four patients but no controls, and affects the same amino acid as p.Arg90Cys, serves to revert p.Arg90 to the human elastase ancestral allele. As p.Arg90Leu has previously been shown to exert a similar functional effect to that of p.Arg90Cys, our findings not only confirm the involvement of CELA3B in the etiology of CP but also pinpoint a new evolutionarily adaptive site in the human genome.
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http://dx.doi.org/10.1002/humu.24178DOI Listing
April 2021

A Novel Imaging Approach for Single-Cell Real-Time Analysis of Oncolytic Virus Replication and Efficacy in Cancer Cells.

Hum Gene Ther 2021 Feb;32(3-4):166-177

Centre de Recherches en Cancérologie de Toulouse (CRCT), Université de Toulouse, Inserm, CNRS, Toulouse, France.

Oncolytic viruses (OVs) are novel cancer gene therapies that are moving toward the forefront of modern medicines. However, their full therapeutic potential is hindered by the lack of convenient and reliable strategies to visualize and quantify OV growth kinetics and therapeutic efficacy in live cells. In this study, we present an innovative imaging approach for single-cell real-time analysis of OV replication and efficacy in cancer cells. We selected SG33 as a prototypic new OV that derives from wild-type Myxoma virus (MYXV). Lausanne Toulouse 1 (T1) was used as control. We equipped SG33 and T1 genomes with the ANCHOR system and infected a panel of cell lines. The ANCHOR system is composed of a fusion protein (OR-GFP) that specifically binds to a short nonrepetitive DNA target sequence (ANCH) and spreads onto neighboring sequences by protein oligomerization. Its accumulation on the tagged viral DNA results in the creation of fluorescent foci. We found that (1) SG33 and T1-ANCHOR DNA can be readily detected and quantified by live imaging, (2) both OVs generate perinuclear replication foci after infection clustering into horse-shoe shape replication centers, and (3) SG33 replicates to higher levels as compared with T1. Lastly, as a translational proof of concept, we benchmarked SG33 replication and oncolytic efficacy in primary cancer cells derived from pancreatic adenocarcinoma (PDAC) both at the population and at the single-cell levels. , SG33 significantly replicates in experimental tumors to inhibit tumor growth. Collectively, we provide herein for the first time a novel strategy to quantify each step of OV infection in live cells and in real time by tracking viral DNA and provide first evidence of theranostic strategies for PDAC patients. Thus, this approach has the potential to rationalize the use of OVs for the benefit of patients with incurable diseases.
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http://dx.doi.org/10.1089/hum.2020.294DOI Listing
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

Analysis of GPRC6A variants in different pancreatitis etiologies.

Pancreatology 2020 Oct 8;20(7):1262-1267. Epub 2020 Aug 8.

Else Kröner-Fresenius-Zentrum für Ernährungsmedizin (EKFZ), Paediatric Nutritional Medicine, Technische Universität München (TUM), Freising, Germany.

Background: The G-protein-coupled receptor Class C Group 6 Member A (GPRC6A) is activated by multiple ligands and is important for the regulation of calcium homeostasis. Extracellular calcium is capable to increase NLRP3 inflammasome activity of the innate immune system and deletion of this proinflammatory pathway mitigated pancreatitis severity in vivo. As such this pathway and the GPRC6A receptor is a reasonable candidate gene for pancreatitis. Here we investigated the prevalence of sequence variants in the GPRC6A locus in different pancreatitis aetiologies.

Methods: We selected 6 tagging SNPs with the SNPinfo LD TAG SNP Selection tool and the functional relevant SNP rs6907580 for genotyping. Cohorts from Germany, further European countries and China with up to 1,124 patients and 1,999 controls were screened for single SNPs with melting curve analysis.

Results: We identified an association of rs1606365(G) with alcoholic chronic pancreatitis in a German (odds ratio (OR) 0.76, 95% confidence interval (CI) 0.65-0.89, p = 8 × 10) and a Chinese cohort (OR 0.78, 95% CI 0.64-0.96, p = 0.02). However, this association was not replicated in a combined cohort of European patients (OR 1.18, 95% CI 0.99-1.41, p = 0.07). Finally, no association was found with acute and non-alcoholic chronic pancreatitis.

Conclusions: Our results support a potential role of calcium sensing receptors and inflammasome activation in alcoholic chronic pancreatitis development. As the functional consequence of the associated variant is unclear, further investigations might elucidate the relevant mechanisms.
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http://dx.doi.org/10.1016/j.pan.2020.08.001DOI Listing
October 2020

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

Circulating Tumor Cell Clusters: United We Stand Divided We Fall.

Int J Mol Sci 2020 Apr 10;21(7). Epub 2020 Apr 10.

Centre Hospitalier Universitaire (CHU) de Toulouse, 31000 Toulouse, France.

The presence of circulating tumor cells (CTCs) and CTC clusters, also known as tumor microemboli, in biological fluids has long been described. Intensive research on single CTCs has made a significant contribution in understanding tumor invasion, metastasis tropism, and intra-tumor heterogeneity. Moreover, their being minimally invasive biomarkers has positioned them for diagnosis, prognosis, and recurrence monitoring tools. Initially, CTC clusters were out of focus, but major recent advances in the knowledge of their biogenesis and dissemination reposition them as critical actors in the pathophysiology of cancer, especially metastasis. Increasing evidence suggests that "united" CTCs, organized in clusters, resist better and carry stronger metastatic capacities than "divided" single CTCs. This review gathers recent insight on CTC cluster origin and dissemination. We will focus on their distinct molecular package necessary to resist multiple cell deaths that all circulating cells normally face. We will describe the molecular basis of their increased metastatic potential as compared to single CTCs. We will consider their clinical relevance as prognostic biomarkers. Finally, we will propose future directions for research and clinical applications in this promising topic in cancer.
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http://dx.doi.org/10.3390/ijms21072653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7177734PMC
April 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

Natural history of SPINK1 germline mutation related-pancreatitis.

EBioMedicine 2019 Oct 15;48:581-591. Epub 2019 Oct 15.

Department of Gastroenterology and Pancreatology, Beaujon Hospital, APHP, Clichy, and Paris-Diderot University, Paris, France. Electronic address:

Background: The aim was to describe genetic, clinical and morphological features in a large, multicentre European cohort of patients with SPINK1 related pancreatitis, in comparison with patients with idiopathic pancreatitis (IP).

Methods: All SPINK1 mutation carriers with pancreatic symptoms from two French and one English centers were included. Patients with IP were included in a control group. Genetic, clinical, radiological and biochemical data were collected.

Findings: 209 and 302 patients were included in the SPINK1 and control groups (median follow-up: 8.3 years (3.7-17.4) vs 5.3 (2.5-8.8)). The median age at onset of symptoms was 20.1 years (17.5-22.8) in the SPINK1 group versus 41.2 (35.2-45.2). The age of exocrine pancreatic insufficiency (EPI) onset in the SPINK1 group was 49.5 (44.5-54.6) years vs. 65.2 (62.1-68.3), p < 0.001. SPINK1 patients with EPI were 5.3%, 14.7%, 28.3% and 52.4% at 20, 30, 40 and 50 years. Diabetes occurred 37.7 (33.3-42.1) years following the onset of symptoms in the SPINK1 group vs. 30.6 (17.3-43.8) (p = 0.002). SPINK1 patients with diabetes were 7.8%, 13.4%, 26.3% and 43.4% at 30, 40, 50 and 60 years. Seven patients (3.3%) developed pancreatic cancer in the SPINK1 group (versus 3 (0.99%), p = 0.1), at a median age of 60 vs 66 years. The cancer risk was 0.8% before 50 years, 11.9%, 27.7%, 51.8% at 60, 70 and 80 years and was 12 times higher than in controls (Cox HR 12.0 (3.0-47.8), p < 0.001).

Interpretation: SPINK1 related pancreatitis is associated with earlier onset and pancreatic insufficiencies. p.N34S SPINK1 may well be associated with cancer.
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http://dx.doi.org/10.1016/j.ebiom.2019.09.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6838417PMC
October 2019

Impact of needle-based confocal laser endomicroscopy on the therapeutic management of single pancreatic cystic lesions.

Surg Endosc 2020 06 13;34(6):2532-2540. Epub 2019 Aug 13.

Hôpital Privé Jean Mermoz, Ramsay Générale de Santé, 4 rue Jacqueline Auriol, 69008, Lyon, France.

Background And Aim: The diagnosis and therapeutic management of large single pancreatic cystic lesions (PCLs) represent major issues for clinicians and essentially rely on endoscopic ultrasound fine-needle aspiration (EUS-FNA) findings. Needle-based confocal laser endomicroscopy (nCLE) has high diagnostic performance for PCLs. This study aimed to evaluate the impact of nCLE on the therapeutic management of patients with single PCLs.

Methods: Retrospective and comparative study. Five independent pancreatic disease experts from tertiary hospitals independently reviewed data from a prospective database of 206 patients with single PCL, larger than 2 cm and who underwent EUS-FNA and nCLE. Two evaluations were performed. The first one included the sequential review of clinical information, EUS report and FNA results. The second one included the same data + nCLE report. Participants had to propose a therapeutic management for each case.

Results: The addition of nCLE to EUS-FNA led to significant changes in therapeutic management for 28% of the patients (p < 0.001). nCLE significantly increased the interobserver agreement of 0.28 (p < 0.0001), from 0.36 (CI 95% 0.33-0.49) to 0.64 (CI 95% 0.61-0.67). nCLE improved the rates of full agreement among the five experts of 24% (p < 0.0001), from 30 to 54%. With nCLE, the surveillance rate of benign SCAs fell by 35%, from 40 (28/70) to 5% (4/76).

Conclusion: The addition of nCLE to EUS-FNA significantly improves reliability of PCL diagnosis and could impact the therapeutic management of patients with single PCLs. ClinicalTrials.gov number, NCT01563133.
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http://dx.doi.org/10.1007/s00464-019-07062-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214514PMC
June 2020

Expression and Role of MicroRNAs from the miR-200 Family in the Tumor Formation and Metastatic Propensity of Pancreatic Cancer.

Mol Ther Nucleic Acids 2019 Sep 29;17:491-503. Epub 2019 Jun 29.

Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain; Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain; CIBERONC, Centro de Investigación Biomédica en Red en Cáncer, Madrid, Spain. Electronic address:

MicroRNAs from the miR-200 family are commonly associated with the inhibition of the metastatic potential of cancer cells, following inhibition of ZEB transcription factors expression and epithelial-to-mesenchymal transition. However, previous studies performed in pancreatic adenocarcinoma revealed a more complex picture challenging this canonical model. To gain better insights into the role of miR-200 family members in this disease, we analyzed the expression of miR-200a, miR-200b, miR-200c, miR-141, miR-429, and miR-205, and ZEB1, ZEB2, and CDH1 in pancreatic tumors and matching normal adjacent parenchyma and patient-derived xenografts. We found that miR-200a, miR-429, and miR-205 are frequently overexpressed in pancreatic tumors, whereas CDH1 is downregulated, and ZEB1 and ZEB2 levels remain unchanged. Furthermore, we measured a positive correlation between miR-200 family members and CDH1 expression, and a negative correlation between ZEB1 and miR-200c, miR-141, and miR-205 expression, respectively. Interestingly, we identified significant changes in expression of epithelial-to-mesenchymal transition regulators and miR-200 members in patient-derived xenografts. Lastly, functional studies revealed that miR-141 and miR-429 inhibit the tumorigenic potential of pancreatic cancer cells. Taken together, this comprehensive analysis strongly suggests that miRNAs from the miR-200 family, and in particular miR-429, may act as a tumor suppressor gene in pancreatic cancer.
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http://dx.doi.org/10.1016/j.omtn.2019.06.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6656921PMC
September 2019

Liquid Biopsy Approach for Pancreatic Ductal Adenocarcinoma.

Cancers (Basel) 2019 Jun 19;11(6). Epub 2019 Jun 19.

Université Fédérale Toulouse Midi-Pyrénées, Université Toulouse III Paul Sabatier, INSERM, CRCT, 31330 Toulouse, France.

Pancreatic cancer is a public health problem because of its increasing incidence, the absence of early diagnostic tools, and its aggressiveness. Despite recent progress in chemotherapy, the 5-year survival rate remains below 5%. Liquid biopsies are of particular interest from a clinical point of view because they are non-invasive biomarkers released by primary tumours and metastases, remotely reflecting disease burden. Pilot studies have been conducted in pancreatic cancer patients evaluating the detection of circulating tumour cells, cell-free circulating tumour DNA, exosomes, and tumour-educated platelets. There is heterogeneity between the methods used to isolate circulating tumour elements as well as the targets used for their identification. Performances for the diagnosis of pancreatic cancer vary depending of the technique but also the stage of the disease: 30-50% of resectable tumours are positive and 50-100% are positive in locally advanced and/or metastatic cases. A significant prognostic value is demonstrated in 50-70% of clinical studies, irrespective of the type of liquid biopsy. Large prospective studies of homogeneous cohorts of patients are lacking. One way to improve diagnostic and prognostic performances would be to use a combined technological approach for the detection of circulating tumour cells, exosomes, and DNA.
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http://dx.doi.org/10.3390/cancers11060852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627808PMC
June 2019

Needle-based confocal laser endomicroscopy of pancreatic cystic lesions: a prospective multicenter validation study in patients with definite diagnosis.

Endoscopy 2019 09 22;51(9):825-835. Epub 2018 Oct 22.

Unité d'Échoendoscopie et d'Endoscopie d'Oncologie Digestive, Institut Paoli Calmettes, Marseille, France.

Background: Needle-based confocal laser endomicroscopy (nCLE) enables observation of the inner wall of pancreatic cystic lesions (PCLs) during an endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA). This study prospectively evaluated the diagnostic performance of nCLE for large, single, noncommunicating PCLs using surgical histopathology or EUS-FNA cytohistopathology as a reference diagnosis.

Methods: From April 2013 to March 2016, consecutive patients referred for EUS-FNA of indeterminate PCLs without evidence of malignancy or chronic pancreatitis were prospectively enrolled at five centers. EUS-FNA and nCLE were performed and cystic fluid was aspirated for cytohistopathological and carcinoembryonic antigen (CEA) analysis. The diagnostic performance of nCLE was assessed against the reference standard and compared with that of EUS and CEA. This study was registered on ClinicalTrials.gov (NCT01563133).

Results: 206 patients underwent nCLE and 78 PCLs (mean size 40 mm, range 20 - 110 mm) had reference diagnoses (53 premalignant and 25 benign PCLs). Post-procedure pancreatitis occurred in 1.3 % of the patients. nCLE was conclusive in 71 of the 78 cases (91 %). The sensitivies and specifities of nCLE for the diagnosis of serous cystadenoma, mucinous PCL, and premalignant PCL were all ≥ 0.95 (with 95 % confidence interval from 0.85 to 1.0). The AUROC was significantly larger for nCLE than for CEA or EUS.

Conclusions: nCLE had excellent diagnostic performance that surpassed that of CEA and EUS for the diagnosis of large, single, noncommunicating PCLs. The nCLE procedure should be considered in patients with indeterminate PCLs to ensure a more specific diagnosis.
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http://dx.doi.org/10.1055/a-0732-5356DOI Listing
September 2019

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

Commentary: Pancreatic cancer: is the worst to come?

Authors:
Louis Buscail

Int J Epidemiol 2017 12;46(6):1774-1775

Department of Gastroenterology, CHU of Toulouse-Rangueil, University of Toulouse III, Medical School of Medicine Rangueil and INSERM UMR 1037, Cancer Research Center of Toulouse, Toulouse, France.

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http://dx.doi.org/10.1093/ije/dyx143DOI Listing
December 2017

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

Pancreatic cancer: Exosomes for targeting KRAS in the treatment of pancreatic cancer.

Authors:
Louis Buscail

Nat Rev Gastroenterol Hepatol 2017 11 6;14(11):636-638. Epub 2017 Sep 6.

Department of Gastroenterology, Centre of Clinical Investigation for Biotherapy and INSERM U1037, Rangueil Hospital, Centre Hospitalier Universitaire of Toulouse and University of Toulouse 3, 1 avenue Jean Poulhès, TSA 50032, 31059 Toulouse, France.

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http://dx.doi.org/10.1038/nrgastro.2017.113DOI Listing
November 2017

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

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

Initial Characterization of Integrase-Defective Lentiviral Vectors for Pancreatic Cancer Gene Therapy.

Hum Gene Ther 2016 Feb;27(2):184-92

1 Inserm, UMR1037 CRCT , Toulouse, France .

The vast majority (85%) of pancreatic ductal adenocarcinomas (PDACs) are discovered at too of a late stage to allow curative surgery. In addition, PDAC is highly resistant to conventional methods of chemotherapy and radiotherapy, which only offer a marginal clinical benefit. Consequently, the prognosis of this cancer is devastating, with a 5-year survival rate of less than 5%. In this dismal context, we recently demonstrated that PDAC gene therapy using nonviral vectors is safe and feasible, with early signs of efficacy in selected patients. Our next step is to transfer to the clinic HIV-1-based lentiviral vectors (LVs) that outshine other therapeutic vectors to treat experimental models of PDAC. However, a primary safety issue presented by LVs that may delay their use in patients is the risk of oncogenesis after vector integration in the host's cell DNA. Thus, we developed a novel anticancerous approach based on integrase-defective lentiviral vectors (IDLVs) and demonstrated that IDLVs can be successfully engineered to transiently deliver therapeutic genes to inhibit pancreatic cancer cells proliferation. This work stems for the use of therapeutic IDLVs for the management of PDAC, in forthcoming early phase gene therapy clinical trial for this disease with no cure.
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http://dx.doi.org/10.1089/hum.2015.151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4779299PMC
February 2016