Institute Of Recherche Contre Les Cancers Of Lappareil Digestif Ircad

Strasbourg, France

Institute Of Recherche Contre Les Cancers Of Lappareil Digestif Ircad

Strasbourg, France
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Kugler M.,University of Strasbourg | Hostettler A.,Institute Of Recherche Contre Les Cancers Of Lappareil Digestif Ircad | Soler L.,Institute Of Recherche Contre Les Cancers Of Lappareil Digestif Ircad | Borzacchiello D.,École Centrale Nantes | And 3 more authors.
Bio-Medical Materials and Engineering | Year: 2017

Mini-invasive surgery restricts the surgeon information to two-dimensional digital representation without the corresponding physical information obtained in previous open surgery. To overcome these drawbacks, real time augmented reality interfaces including the true mechanical behaviour of organs depending on their internal microstructure need to be developed. For the case of tumour resection, we present here a finite element numerical study of the liver mechanical behaviour including the effects of its own vascularisation through numerical indentation tests in order extract the corresponding macroscopic behaviour. The obtained numerical results show excellent correlation of the corresponding force-displacement curves when compared with macroscopic experimental data available in the literature. © 2017 - IOS Press and the authors. All rights reserved.

Grekova S.,Institute Of Recherche Contre Les Cancers Of Lappareil Digestif Ircad | Aprahamian M.,Institute Of Recherche Contre Les Cancers Of Lappareil Digestif Ircad | Schmitt S.,University of Heidelberg | Giese T.,Institute of Immunology | And 5 more authors.
Cancer Biology and Therapy | Year: 2010

Treatment of cancers by means of viruses, that specifically replicate in (oncotropism) and kill (oncolysis) neoplastic cells, is increasingly gaining acceptance in the clinic. Among these agents, parvoviruses have been shown to possess not only direct oncolytic but also immunomodulating properties, serving as an adjuvant to prime the immune system to react against infected tumors. Here, we aimed to establish whether immunomodulating mechanisms participate in the recently reported therapeutic potential of parvoviruses against pancreatic carcinoma. Using adoptive transfer experiments we discovered that the transfer of splenocytes of donor rats harboring H-1PV-treated orthotopic PDAC tumors could significantly prolong the survival of naïve tumor-bearing recipients, compared to those receiving cells from mock-treated donors. Closer investigation of immunological parameters in infected donor rats revealed that virus-induced interferon gamma production and cellular immune response played an important role in this effect. These data have also preclinical relevance since abortive H-1PV infection of human peripheral blood mononuclear cells or cocultivation of these cells with H-1PV-preinfected pancreatic cancer cells, resulted in enhancement of innate and adaptive immune reactivity. Taken together our data reveal that oncolytic H-1PV modulates the immune system into an anticancer state, and further support the concept of using parvoviruses in the fight against pancreatic cancer. © 2010 Landes Bioscience.

Angelova A.L.,German Cancer Research Center | Grekova S.P.,German Cancer Research Center | Heller A.,University of Heidelberg | Kuhlmann O.,German Cancer Research Center | And 11 more authors.
Journal of Virology | Year: 2014

Novel therapies employing oncolytic viruses have emerged as promising anticancer modalities. The cure of particularly aggressive malignancies requires induction of immunogenic cell death (ICD), coupling oncolysis with immune responses via calreticulin, ATP, and high-mobility group box protein B1 (HMGB1) release from dying tumor cells. The present study shows that in human pancreatic cancer cells (pancreatic ductal adenocarcinoma [PDAC] cells; n=4), oncolytic parvovirus H-1 (H-1PV) activated multiple interconnected death pathways but failed to induce calreticulin exposure or ATP release. In contrast, H-1PV elevated extracellular HMGB1 levels by 4.0±0.5 times (58%±9% of total content; up to 100 ng/ml) in all infected cultures, whether nondying, necrotic, or apoptotic. An alternative secretory route allowed H-1PV to overcome the failure of gemcitabine to trigger HMGB1 release, without impeding cytotoxicity or other ICD activities of the standard PDAC medication. Such broad resistance of H-1PV-induced HMGB1 release to apoptotic blockage coincided with but was uncoupled from an autocrine interleukin- 1β (IL-1β) loop. That and the pattern of viral determinants maintained in gemcitabine-treated cells suggested the activation of an inflammasome/caspase 1 (CASP1) platform alongside DNA detachment and/or nuclear exclusion of HMGB1 during early stages of the viral life cycle. We concluded that H-1PV infection of PDAC cells is signaled through secretion of the alarmin HMGB1 and, besides its own oncolytic effect, might convert drug-induced apoptosis into an ICD process. A transient arrest of cells in the cyclin A1-rich S phase would suffice to support compatibility of proliferation-dependent H-1PV with cytotoxic regimens. These properties warrant incorporation of the oncolytic virus H-1PV, which is not pathogenic in humans, into multimodal anticancer treatments. © 2014, American Society for Microbiology.

Mountney P.,Siemens AG | Fallert J.,Imaging Technologies Research | Nicolau S.,Institute Of Recherche Contre Les Cancers Of Lappareil Digestif Ircad | Soler L.,Institute Of Recherche Contre Les Cancers Of Lappareil Digestif Ircad | And 2 more authors.
Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics) | Year: 2014

Augmented reality for soft tissue laparoscopic surgery is a growing topic of interest in the medical community and has potential application in intra-operative planning and image guidance. Delivery of such systems to the operating room remains complex with theoretical challenges related to tissue deformation and the practical limitations of imaging equipment. Current research in this area generally only solves part of the registration pipeline or relies on fiducials, manual model alignment or assumes that tissue is static. This paper proposes a novel augmented reality framework for intra-operative planning: the approach co-registers pre-operative CT with stereo laparoscopic images using cone beam CT and fluoroscopy as bridging modalities. It does not require fiducials or manual alignment and compensates for tissue deformation from insufflation and respiration while allowing the laparoscope to be navigated. The paper's theoretical and practical contributions are validated using simulated, phantom, ex vivo, in vivo and non medical data. © 2014 Springer International Publishing.

Bousserouel S.,University of Strasbourg | Bousserouel S.,Institute Of Recherche Contre Les Cancers Of Lappareil Digestif Ircad | Gosse F.,University of Strasbourg | Gosse F.,Institute Of Recherche Contre Les Cancers Of Lappareil Digestif Ircad | And 5 more authors.
Oncology Reports | Year: 2010

Despite numerous studies aimed at verifying the anti-tumour activity of aspirin on colon carcinogenesis little is known on the molecular targets involved in the anticarcinogenic properties of this drug. We investigated the long-term administration of low dose of aspirin in a model of experimental colon carcinogenesis in rats. Adult Wistar rats received an intraperitoneal injection of azoxymethane (AOM) once a week for two weeks in order to initiate colon carcinogenesis. One week after AOM injection, rats received daily 0.01% aspirin (6 mg/kg body weight) in drinking water for 10 months. Compared to AOM control rats, aspirin treatment for 10 months caused a 50% reduction of the number of aberrant crypt foci associated with a 50% reduction of prostaglandin E2 (PGE2) concentration and suppressed by 80% tumour formation in the colon. RT-PCR quantitative analysis showed that aspirin treatment reduced significantly (P<0.01) the AOM-triggered increase in mRNA levels of soluble inflammatory mediators (TNFα and IL-1β) and metalloproteinases (MMP3 and MMP7). Conversely, we detected an increased expression level of α-defensin-5 (Rd-5, 2 fold) and lipocalin-2 (LCN2, 4 fold), two markers of the innate immunity system. The expression of apoptosis-related genes such as death receptors and their ligands were reduced by aspirin and the Bcl-2/Bax transcript ratio droped, Bcl-2 expression being reduced to the level found in saline control rats. The present study identifies new molecular targets triggered by aspirin in the colonic mucosa and may support the use of non-toxic low dose of aspirin in long-term treatments as a prophylactic approach against colon carcinogenesis.

Hallet J.,Institute Of Recherche Contre Les Cancers Of Lappareil Digestif Ircad | Hallet J.,University of Strasbourg | Hallet J.,Sunnybrook Health science Center | Gayet B.,University of Paris Descartes | And 5 more authors.
Journal of Hepato-Biliary-Pancreatic Sciences | Year: 2015

Abstract Pre-operative simulation using three-dimensional (3D) reconstructions have been suggested to enhance surgical planning of hepatectomy. Evidence on its benefits for hepatectomy patients remains limited. This systematic review examined the use and impact of pre-operative simulation and intraoperative navigation on hepatectomy outcomes. A systematical searched electronic databases for studies reporting on the use and results of simulation and navigation for hepatectomy was performed. The primary outcome was change in operative plan based on simulation. Secondary outcomes included operating time (min), estimated blood loss, surgical margins, 30-day postoperative morbidity and mortality, and study-specific outcomes. From 222 citations, we included 11 studies including 497 patients. All were observational cohort studies. No study compared hepatectomy with and without simulation. All studies performed 3D reconstruction and segmentation, most commonly with volumetrics measurements. In six studies reporting intraoperative navigation, five relied on ultrasound, and one on a resection map. Of two studies reporting on it, the resection line was changed intraoperatively in one third of patients, based on simulation. Virtually predicted liver volumes (Pearson correlation r=0.917 to 0.995) and surgical margins (r=0.84 to 0.967) correlated highly with actual ones in eight studies. Heterogeneity of the included studies precluded meta-analysis.Pre-operative simulation seems accurate in measuring volumetrics and surgical margins. Current studies lack intraoperative transposition of simulation for direct navigation. Simulation appears useful planning of hepatectomies, but further work is warranted focusing on the development of improved tools and appraisal of their clinical impact compared to traditional resection. © 2015 Japanese Society of Hepato-Biliary-Pancreatic Surgery.

Maldonado M.E.,French Institute of Health and Medical Research | Maldonado M.E.,University of Strasbourg | Maldonado M.E.,Institute Of Recherche Contre Les Cancers Of Lappareil Digestif Ircad | Maldonado M.E.,University of Antioquia | And 10 more authors.
Biomedica | Year: 2010

Introduction: The nuclear factor-kappaB (NF-κB) has been shown to upregulate pro-apoptotic mediators such as TRAIL-DR4/-DR5 receptors and the p53 transcription factor depending on the type of stimulus and the cell type involved. Previously, apple procyanidins (Pcy) have been shown to upregulate the expression of TRAIL-DR4/-DR5 and thereby overcoming the resistance of human colon cancer-derived metastatic SW620 cells to TRAIL. Objectives: NF-κB and p53 were investigated for their involvement in the Pcy-triggered apoptosis of human derived-metastatic colon cancer (SW620) cells. Materials and methods: Cell death, p53, TRAIL-DR4/-DR5 proteins were analyzed by flow cytometry. DR4/DR5 mRNA was analyzed by RT-PCR in real time. Activated p50/p65 and p53 forms were studied by ELISA and immunoblotting. Results: Pcy-triggered cell death was prevented by specific inhibitors of NF-κB and of p53: amino-4-(4-phenoxy-phenylethylamino) quinazoline (QNZ) and pifithrin α (Pα), respectively. QNZ and Pα inhibited the Pcy-dependent activation of TRAIL-DR4/-DR5 death receptors. However, the upregulation of TRAIL-DR4 by Pcy was significantly decreased only when NF-κB and p53 inhibitors were used in combination; this effect was not observed with a single inhibitor. This effect was not observed for TRAIL-DR5 and suggested that the expression of each TRAIL-death receptor may be regulated differently. Conclusions: These data suggested that NF-κB and p53 are partially required in Pcy-triggered apoptosis of SW620 cells by up-regulating the expression of TRAIL-DR4/-DR5. In addition, the ratio between TRAIL-DR4/-DR5 may be a determining factor in the activation of TRAIL-death receptor mediated apoptosis.

PubMed | Hopital Europeen Georges Pompidou, Institute Of Recherche Contre Les Cancers Of Lappareil Digestif Ircad, Hopital Hautepierre, University of Paris Descartes and Aix - Marseille University
Type: Journal Article | Journal: Surgical innovation | Year: 2016

Background Fistulas after esophagectomy are a significant cause of morbidity and mortality. Several endoscopic treatments have been attempted, with varying success. An experimental model that could validate new approaches such as cellular therapies is highly desirable. The aim of this study was to create a chronic esophageal enterocutaneous fistula model in order to study future experimental treatment options. Methods Eight pigs (six 35-kg young German and two 50-kg adult Yucatan pigs) were used. Through a left and right cervicotomy, under endoscopic view, 1 (group A, n = 6) or 2 (group B, n = 7) plastic catheters were introduced into the esophagus 30 cm from the dental arches bilaterally and left in place for 1 month. Radiologic and endoscopic fistula tract evaluations were performed at postoperative day (POD; 30) and at sacrifice (POD 45). Results Three fistulas were excluded from the study because of early (POD 5) dislodgment of the catheter, with complete fistula closure. At catheter removal (POD 30), the external orifice was larger in group B (5.2 1.1 mm vs 2.6 0.4 mm) with more severe inflammation (72% vs 33%). At POD 45, the external orifice was closed in all fistulas in group A and in 1/7 in group B. At necropsy, the fistula tract was still present in all animals. Yucatan pigs showed more complex tracts, with a high level of necrosis and substantial fibrotic infiltration. Conclusions In this article, we show a reproducible, safe, and effective technique to create an esophagocutaneous fistula model in a large experimental animal.

Akladios C.Y.,Institute Of Recherche Contre Les Cancers Of Lappareil Digestif Ircad | Bour G.,Institute Of Recherche Contre Les Cancers Of Lappareil Digestif Ircad | Balboni G.,French Institute of Health and Medical Research | Mutter D.,Institute Of Recherche Contre Les Cancers Of Lappareil Digestif Ircad | And 3 more authors.
Bulletin du Cancer | Year: 2011

Animal experimentation is a prerequisite for preclinical evaluation of treatments such as chemotherapy. It's strictly regulated with the purpose of reducing the number of experimental animal as well as their pain. Small animal imaging should provide a painless longitudinal follow up of tumor progression on a single animal. The aim of the study is to validate small animal imaging by microscanner (μscan) in longitudinal follow up of a hepatocellular carcinoma (HCC) and to demonstrate its interest for in vivo evaluation of tumor response to different therapeutics. An HCC model achieved by orthotopic graft of the MH3924A cell line in ACI rats was followed using a Imtek/Siemens microscanner (μscan) with contrast agents (Fenestra® LC/VC). The procedures giving the optimal enhancement of the liver as well as a reliable determination of tumor volumes by μscan were validated. Three protocols for therapeutic assessment through μscan longitudinal follow up were performed. Each consisted in three groups testing a chemotherapy (gemcitabine, gemcitabine-oxaliplatine or sorafenib) versus two control groups (placebo and doxorubicine). Comparison was done on tumor volumes, median and actual survivals. There was a significant correlation between tumor volumes measured by μscan and autopsy. Treatment by sorafenib, at the contrary of gemcitabine alone or with oxaliplatine, resulted in a significant reduction in tumor volumes and prolongation of actuarial survival. These results are consistent with available clinical data for these diverse therapeutics. In conclusion, small animal imaging with μscan is a non-invasive, reliable, and reproducible method for preclinical evaluation of antitumor agents. ©John Libbey Eurotext.

Rahmi G.,University of Paris Descartes | Pidial L.,University of Paris Descartes | Silva A.K.A.,University Paris Diderot | Blondiaux E.,University of Paris Descartes | And 10 more authors.
Theranostics | Year: 2016

Cell sheet technology opens new perspectives in tissue regeneration therapy by providing readily implantable, scaffold-free 3D tissue constructs. Many studies have focused on the therapeutic effects of cell sheet implantation while relatively little attention has concerned the fate of the implanted cells in vivo. The aim of the present study was to track longitudinally the cells implanted in the cell sheets in vivo in target tissues. To this end we (i) endowed bone marrow-derived mesenchymal stem cells (BMMSCs) with imaging properties by double labeling with fluorescent and magnetic tracers, (ii) applied BMMSC cell sheets to a digestive fistula model in mice, (iii) tracked the BMMSC fate in vivo by MRI and probe-based confocal laser endomicroscopy (pCLE), and (iv) quantified healing of the fistula. We show that image-guided longitudinal follow-up can document both the fate of the cell sheet-derived BMMSCs and their healing capacity. Moreover, our theranostic approach informs on the mechanism of action, either directly by integration of cell sheet-derived BMMSCs into the host tissue or indirectly through the release of signaling molecules in the host tissue. Multimodal imaging and clinical evaluation converged to attest that cell sheet grafting resulted in minimal clinical inflammation, improved fistula healing, reduced tissue fibrosis and enhanced microvasculature density. At the molecular level, cell sheet transplantation induced an increase in the expression of anti-inflammatory cytokines (TGF-ß2 and IL-10) and host intestinal growth factors involved in tissue repair (EGF and VEGF). Multimodal imaging is useful for tracking cell sheets and for noninvasive follow-up of their regenerative properties. © Ivyspring International Publisher.

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