Consolidation whole abdomen irradiation following adjuvant carboplatin-paclitaxel based chemotherapy for advanced uterine epithelial cancer: feasibility, toxicity and outcomes

Background: To evaluate feasibility and preliminary outcomes associated with sequential whole abdomen irradiation (WAI) as consolidative treatment following comprehensive surgery and systemic chemotherapy for advanced endometrial cancer. Methods: We conducted a retrospective analysis of patients treated at our institution from 2000 to 2011. Inclusion criteria were stage III-IV endometrial cancer patients with histological proof of one or more sites of extra-uterine abdomen-confined disease, treated with WAI as part of multimodal therapy. Endpoints were feasibility, acute toxicity, late effects, recurrence-free survival (RFS) and overall survival (OS). Twenty patients were identified. Chemotherapy consisted of 3 to 6 cycles of a platinum-paclitaxel regimen in 18 patients. WAI was delivered using conventional technique to a median total dose of 27.5 Gy. Results: No grade 4 toxicities occurred during chemotherapy or radiotherapy. No radiation dose reduction was necessary. Three patients developed small bowel obstruction, all in the context of recurrent intraperitoneal disease. Kaplan-Meier estimates and 95% confidence intervals for RFS and OS at one year were 63% (38–80%) and 83% (56-94%) and at 3 years 57% (33-76%) and 62% (34-81%), respectively. On univariate Cox analysis, stage IVB and serous papillary (SP) histology were found to be statistically significantly (at the p = 0.05 level) associated with worse RFS and OS. The peritoneal cavity was the most frequent site of initial failure. Conclusions: Consolidative WAI following chemotherapy is feasible and can be performed without interruption with manageable acute and late toxicity. Patients with endometrioid adenocarcinoma, especially stage FIGO III, had favorable outcomes possibly meriting prospective evaluation of the addition of WAI following chemotherapy in selected patients. Patients with SP do poorly and do not routinely benefit from this approach

Glial cell line-derived neurotrophic factor-stimulated phosphatidylinositol 3-kinase and Akt activities exert opposing effects on the ERK pathway: importance for the rescue of neuroectodermic cells.

Glial cell line-derived neurotrophic factor (GDNF) plays a crucial role in rescuing neural crest cells from apoptosis during their migration in the foregut. This survival factor binds to the heterodimer GDNF family receptor alpha1/Ret, inducing the Ret tyrosine kinase activity. ret loss-of-function mutations result in Hirschsprung's disease, a frequent developmental defect of the enteric nervous system. Although critical to enteric nervous system development, the intracellular signaling cascades activated by GDNF and their importance in neuroectodermic cell survival still remain elusive. Using the neuroectodermic SK-N-MC cell line, we found that the Ret tyrosine kinase activity is essential for GDNF to induce phosphatidylinositol 3-kinase (PI3K)/Akt and ERK pathways as well as cell rescue. We demonstrate that activation of PI3K is mandatory for GDNF-induced cell survival. In addition, evidence is provided for a critical up-regulation of the ERK pathway by PI3K at the level of Raf-1. Conversely, Akt inhibits the ERK pathway. Thus, both PI3K and Akt act in concert to finely regulate the level of ERK. We found that Akt activation is indispensable for counteracting the apoptotic signal on mitochondria, whereas ERK is partially involved in precluding procaspase-3 cleavage. Altogether, these findings underscore the importance of the Ret/PI3K/Akt pathway in GDNF-induced neuroectodermic cell survival

Phase II study evaluating consolidation whole abdominal intensity-modulated radiotherapy (IMRT) in patients with advanced ovarian cancer stage FIGO III - The OVAR-IMRT-02 Study

<p>Abstract</p> <p>Background</p> <p>The prognosis for patients with advanced FIGO stage III epithelial ovarian cancer remains poor despite the aggressive standard treatment, consisting of maximal cytoreductive surgery and platinum-based chemotherapy. The median time to recurrence is less than 2 years, with a 5-years survival rate of -20-25%. Recurrences of the disease occur mostly intraperitoneally.</p> <p>Ovarian cancer is a radiosensitive tumor, so that the use of whole abdominal radiotherapy (WAR) as a consolidation therapy would appear to be a logical strategy. WAR used to be the standard treatment after surgery before the chemotherapy era; however, it has been almost totally excluded from the treatment of ovarian cancer during the past decade because of its high toxicity. Modern intensity-modulated radiation therapy (IMRT) has the potential of sparing organs at risk like kidneys, liver, and bone marrow while still adequately covering the peritoneal cavity with a homogenous dose.</p> <p>Our previous phase I study showed for the first time the clinical feasibility of intensity-modulated WAR and pointed out promising results concerning treatment tolerance. The current phase-II study succeeds to the phase-I study to further evaluate the toxicity of this new treatment.</p> <p>Methods/design</p> <p>The OVAR-IMRT-02 study is a single-center one arm phase-II trial. Thirty seven patients with optimally debulked ovarian cancer stage FIGO III having a complete remission after chemotherapy will be treated with intensity-modulated WAR as a consolidation therapy.</p> <p>A total dose of 30 Gy in 20 fractions of 1.5 Gy will be applied to the entire peritoneal cavity including the liver surface and the pelvic and para-aortic node regions. Organ at risk are kidneys, liver (except the 1 cm-outer border), heart, vertebral bodies and pelvic bones.</p> <p>Primary endpoint is tolerability; secondary objectives are toxicity, quality of life, progression-free and overall survival.</p> <p>Discussion</p> <p>Intensity-modulated WAR provides a new promising option in the consolidation treatment of ovarian carcinoma in patients with a complete pathologic remission after adjuvant chemotherapy. Further consequent studies will be needed to enable firm conclusions regarding the value of consolidation radiotherapy within the multimodal treatment of advanced ovarian cancer.</p> <p>Trial registration</p> <p>Clinicaltrials.gov: <a href="http://clinicaltrials.gov/ct2/show/NCT01180504">NCT01180504</a></p

Randomized controlled phase I/II study to investigate immune stimulatory effects by low dose radiotherapy in primarily operable pancreatic cancer

<p>Abstract</p> <p>Background</p> <p>The efficiencies of T cell based immunotherapies are affected by insufficient migration and activation of tumor specific effector T cells in the tumor. Accumulating evidence exists on the ability of ionizing radiation to modify the tumor microenvironment and generate inflammation. The aim of this phase I/II clinical trial is to evaluate whether low dose single fraction radiotherapy can improve T cell associated antitumor immune response in patients with pancreatic cancer.</p> <p>Methods/Design</p> <p>This trial has been designed as an investigator initiated; prospective randomised, 4-armed, controlled Phase I/II trial. Patients who are candidates for resection of pancreatic cancer will be randomized into 4 arms. A total of 40 patients will be enrolled. The patients receive 0 Gy, 0.5 Gy, 2 Gy or 5 Gy radiation precisely targeted to their pancreatic carcinoma. Radiation will be delivered by external beam radiotherapy using a 6 MV Linac with IMRT technique 48 h prior to the surgical resection. The primary objective is the determination of an active local external beam radiation dose, leading to tumor infiltrating T cells as a surrogate parameter for antitumor activity. Secondary objectives include local tumor control and recurrence patterns, survival, radiogenic treatment toxicity and postoperative morbidity and mortality, as well as quality of life. Further, frequencies of tumor reactive T cells in blood and bone marrow as well as whole blood cell transcriptomics and plasma-proteomics will be correlated with clinical outcome. An interim analysis will be performed after the enrolment of 20 patients for safety reasons. The evaluation of the primary endpoint will start four weeks after the last patient's enrolment.</p> <p>Discussion</p> <p>This trial will answer the question whether a low dose radiotherapy localized to the pancreatic tumor only can increase the number of tumor infiltrating T cells and thus potentially enhance the antitumor immune response. The study will also investigate the prognostic and predictive value of radiation-induced T cell activity along with transcriptomic and proteomic data with respect to clinical outcome.</p> <p>Trial registration</p> <p>ClinicalTrials.gov - <a href="http://www.clinicaltrials.gov/ct2/show/NCT01027221">NCT01027221</a></p

Adjuvant whole abdominal intensity modulated radiotherapy (IMRT) for high risk stage FIGO III patients with ovarian cancer (OVAR-IMRT-01) – Pilot trial of a phase I/II study: study protocol

<p>Abstract</p> <p>Background</p> <p>The prognosis for patients with advanced epithelial ovarian cancer remains poor despite aggressive surgical resection and platinum-based chemotherapy. More than 60% of patients will develop recurrent disease, principally intraperitoneal, and die within 5 years. The use of whole abdominal irradiation (WAI) as consolidation therapy would appear to be a logical strategy given its ability to sterilize small tumour volumes. Despite the clinically proven efficacy of whole abdominal irradiation, the use of radiotherapy in ovarian cancer has profoundly decreased mainly due to high treatment-related toxicity. Modern intensity-modulated radiation therapy (IMRT) could allow to spare kidneys, liver, and bone marrow while still adequately covering the peritoneal cavity with a homogenous dose.</p> <p>Methods/Design</p> <p>The OVAR-IMRT-01 study is a single center pilot trial of a phase I/II study. Patients with advanced ovarian cancer stage FIGO III (R1 or R2< 1 cm) after surgical resection and platinum-based chemotherapy will be treated with whole abdomen irradiation as consolidation therapy using intensity modulated radiation therapy (IMRT) to a total dose of 30 Gy in 1.5 Gy fractions. A total of 8 patients will be included in this trial. For treatment planning bone marrow, kidneys, liver, spinal cord, vertebral bodies and pelvic bones are defined as organs at risk. The planning target volume includes the entire peritoneal cavity plus pelvic and para-aortic node regions.</p> <p>Discussion</p> <p>The primary endpoint of the study is the evaluation of the feasibility of intensity-modulated WAI and the evaluation of the study protocol. Secondary endpoint is evaluation of the toxicity of intensity modulated WAI before continuing with the phase I/II study. The aim is to explore the potential of IMRT as a new method for WAI to decrease the dose to kidneys, liver, bone marrow while covering the peritoneal cavity with a homogenous dose, and to implement whole abdominal intensity-modulated radiotherapy into the adjuvant multimodal treatment concept of advanced ovarian cancer FIGO stage III.</p

Towards ecosystem-based management: identifying operational food-web indicators for marine ecosystems

Modern approaches to Ecosystem-Based Management and sustainable use of marine resources must account for the myriad of pressures (interspecies, human and environmental) affecting marine ecosystems. The network of feeding interactions between co-existing species and populations (food webs) are an important aspect of all marine ecosystems and biodiversity. Here we describe and discuss a process to evaluate the selection of operational food-web indicators for use in evaluating marine ecosystem status. This process brought together experts in food-web ecology, marine ecology, and resource management, to identify available indicators that can be used to inform marine management. Standard evaluation criteria (availability and quality of data, conceptual basis, communicability, relevancy to management) were implemented to identify practical food-web indicators ready for operational use and indicators that hold promise for future use in policy and management. The major attributes of the final suite of operational food-web indicators were structure and functioning. Indicators that represent resilience of the marine ecosystem were less developed. Over 60 potential food-web indicators were evaluated and the final selection of operational food-web indicators includes: the primary production required to sustain a fishery, the productivity of seabirds (or charismatic megafauna), zooplankton indicators, primary productivity, integrated trophic indicators, and the biomass of trophic guilds. More efforts should be made to develop thresholds-based reference points for achieving Good Environmental Status. There is also a need for international collaborations to develop indicators that will facilitate management in marine ecosystems used by multiple countries.JRC.D.2-Water and Marine Resource

Physiopathologie des troubles de la glycemie - A) Interet de nouvelles classes d'agents pharmacologiques dans le traitement de l'insulinoresistance - B) Role d'autoanticorps diriges contre le recepteur de l'insuline dans le diabete de type 1 et..

SIGLECNRS T Bordereau / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Développement de modèles pour l'étude de la formation osseuse en culture tridimensionnelle et en ingénierie tissulaire osseuse

La culture tridimensionnelle (3D) et l'ingénierie du tissu osseux sont deux thématiques basées sur l'utilisation de matrices permettant de véhiculer des cellules ostéogéniques dans le but d'obtenir une formation osseuse in vitro et in vivo respectivement. La culture 3D est un enjeu important en biologie car elle permet de restaurer certaines propriétés tissulaires perdues en culture bidimensionnelle (2D) sur plastique. De nombreux travaux sont actuellement dédiés à la mise au point de matrices utilisables comme support de culture 3D des cellules osseuses. Sur la base d'une matrice constituée de particules de phosphate de calcium biphasé (BCP) j'ai mis au point un modèle original de culture 3D qui permet le développement d un tissu ostéoïde et la différenciation spontanée d'ostéoblastes humains en ostéocytes. Ce modèle 3D ouvre une nouvelle voie d étude des ostéocytes qui sont les cellules majoritaires du tissu osseux mais les plus mal connues du fait de leur accessibilité difficile et du manque de modèles d'étude disponibles. L'ingénierie tissulaire osseuse a pour but de reconstruire le stock osseux grâce à l'association de matrices, de facteurs ostéoinducteurs et/ou de cellules ostéogéniques. La majorité des travaux menés actuellement dans ce domaine préconisent l utilisation de cellules stromales mésenchymateuses (MSC) pour améliorer les performances de ces matrices. Cependant le mécanisme d action de ces cellules est encore peu documenté. Basé sur l'utilisation des mêmes particules de BCP, j'ai participé à la mise au point d'un nouveau biomatériau développé et breveté au laboratoire et à son utilisation comme véhicule de MSC de souris pour l'étude de la formation osseuse en site ectopique. La mise au point d'une méthode de suivi quantitatif de la survie des cellules implantées a permis de montrer que ces MSC disparaissaient très rapidement, laissant la place aux cellules de l'hôte qui sont à l'origine du tissu osseux. Nous avons conclu que, dans ce modèle, les MSC implantées jouent très probablement un rôle chimiotactique pour les cellules de l'organisme receveur. Une étude préliminaire des molécules impliquées dans ce rôle chimiotactique à été effectuée, permettant de proposer une nouvelle approche pour l ingénierie tissulaire osseuse.Three-dimensional culture (3D) of bone cells and bone tissue engineering are both based on the use of scaffolds to convey osteogenic cells and obtain in vitro and in vivo bone formation respectively. 3D culture is an important field in cell biology, dedicated to reduce the gap between two-dimensional culture and complex tissue architecture. Many works have described various scaffolds as support for the 3D culture of bone cells but in two studies only the presence of osteocyte-like cells have been detected after very long periods of culture. I have engineered an original model of 3D culture in which human primary osteoblasts are seeded within the interspace of calibrated biphasic calcium phosphate particles (BCP). This system results, after one week, in the development of an osteoid matrix and the spontaneous differentiation of the osteoblasts in osteocytes. This model of primary osteocyte differentiation in 3D is a new tool to gain insights into the biology of osteocytes, which compose over 90-95% of bone cells but are difficult to study due to their accessibility and the very rare models available in vitro. The aim of bone tissue engineering is to regenerate the bone stock through a combination of scaffolds, osteogenic factors and / or osteogenic cells. The majority of the studied in this field advocates the use of mesenchymal stromal cells (MSC) but the mechanism of action of these cells is still poorly documented. Based on the use of BCP particles, I have participated to the development of a new bone substitute, which has been patented in our laboratory. I have used this new biomaterial as a vehicle for mouse MSC in a model of ectopic bone formation. Using a method of quantitative tracking of the implanted cells, I have shown that the implanted MSC disappeared very quickly from the implants whereas host cells were progressively recruited suggesting that host cells are responsible for the bone formation. We have concluded that, in this model, MSC play a chemotactic function towards host cells. A preliminary study of the putative molecules involved in this phenomenon was performed with the aim of proposing a newNICE-BU Sciences (060882101) / SudocSudocFranceF