Long-Term Alterations of Cytokines and Growth Factors Expression in Irradiated Tissues and Relation with Histological Severity Scoring

PURPOSE: Beside its efficacy in cancer treatment, radiotherapy induces degeneration of healthy tissues within the irradiated area. The aim of this study was to analyze the variations of proinflammatory (IL-1α, IL-2, IL-6, TNF-α, IFN-γ), profibrotic (TGF-β1), proangiogneic (VEGF) and stem cell mobilizing (GM-CSF) cytokines and growth factors in an animal model of radiation-induced tissue degeneration. MATERIALS AND METHODS: 24 rats were irradiated unilaterally on the hindlimb at a monodose of 30 Gy. Six weeks (n=8), 6 months (n=8) and 1 year (n=8) after irradiation the mediators expression in skin and muscle were analyzed using Western blot and the Bio-Plex® protein array (BPA) technology. Additional histological severity for fibrosis, inflammation, vascularity and cellularity alterations scoring was defined from histology and immnunohistochemistry analyses. RESULTS: A significant increase of histological severity scoring was found in irradiated tissue. Skin tissues were more radio-sensitive than muscle. A high level of TGF-β1 expression was found throughout the study and a significant relation was evidenced between TGF-β1 expression and fibrosis scoring. Irradiated tissue showed a chronic inflammation (IL-2 and TNF-α significantly increased). Moreover a persistent expression of GM-CSF and VEGF was found in all irradiated tissues. The vascular score was related to TGF-β1 expression and the cellular alterations score was significantly related with the level of IL-2, VEGF and GM-CSF. CONCLUSION: The results achieved in the present study underline the complexity and multiplicity of radio-induced alterations of cytokine network. It offers many perspectives of development, for the comprehension of the mechanisms of late injuries or for the histological and molecular evaluation of the mode of action and the efficacy of rehabilitation techniques

Modélisation de dégénérescence tissulaire radio-induite et conceptualisation de réhabilitation des tissus irradiés par thérapie cellulaire

Radiation therapy induced acute and late sequelae within healthy tissue included in the irradiated area. In general, lesions are characterized by ischemia, cell apoptosis and fibrosis. In this context, cell therapy using bone marrow mesenchymal stem cells (BMSC) might represent an attractive new therapeutic approach, based partly on their angiogenic ability and their involvement in the natural processes of tissue repair. The first part of this work consisted in the development of experimental mouse model of radio-induced tissue degeneration similar to that occurring after radiotherapy. The aim was to better understand the physiopathological mechanisms of radiation-induced tissue damage and to determine the best treatment strategy. The second part of this work investigated the feasibility of autologous BMSC therapy on the murine model of radiation previously established with emphasis on two pre-requisites : the retention of the injected cells within the target tissue and the evaluation of the graft on bone metabolism. This preclinical investigation in a mouse model constitutes an essential step allowing an evaluation of the benefit of cell therapy for the treatment of radiation-induced tissue injury. Data from these studies could allow the proposal of clinical studies.La radiothérapie induit des séquelles aigues puis tardives affectant les tissus sains inclus dans le volume irradié. D'une façon générale, le processus lésionnel se caractérise par une ischémie vasculaire, une apoptose cellulaire et une fibrose cicatricielle. Dans ce contexte, la thérapie cellulaire à l'aide de cellules souches mésenchymateuses médullaires CSMM pourrait constituer une nouvelle approche thérapeutique séduisante, les CSMM ayant une capacité intrinsèque à promouvoir l'angiogenèse et une implication dans les processus naturels de réparation tissulaire. La première partie de ce travail a consisté à la mise au point de modèles murins présentant un processus de dégénérescence tissulaire similaire à celui survenant après radiothérapie. L'objectif étant d'affiner la compréhension des mécanismes physiopathologiques des lésions tissulaires radio-induites et de déterminer une stratégie thérapeutique la plus adaptée possible. La seconde partie de ce travail a été consacrée à l'évaluation de la faisabilité d'une autogreffe de CSMM dans le modèle murin d'irradiation précédemment établi en répondant à deux pré-requis : la rétention des cellules injectées au niveau du tissu cible et l'évaluation de la greffe sur le métabolisme osseux. Cette investigation préclinique sur un modèle murin a permis de réaliser une étape essentielle dans l'évaluation du traitement des lésions tissulaires radio-induites par thérapie cellulaire. Les données issues de ces travaux pourraient à terme permettre la mise en place d'études cliniques

Models for radiation-induced tissue degeneration and conceptualization of rehabilitation of irradiated tissue by cell therapy

La radiothérapie induit des séquelles aigues puis tardives affectant les tissus sains inclus dans le volume irradié. D'une façon générale, le processus lésionnel se caractérise par une ischémie vasculaire, une apoptose cellulaire et une fibrose cicatricielle. Dans ce contexte, la thérapie cellulaire à l'aide de cellules souches mésenchymateuses médullaires CSMM pourrait constituer une nouvelle approche thérapeutique séduisante, les CSMM ayant une capacité intrinsèque à promouvoir l'angiogenèse et une implication dans les processus naturels de réparation tissulaire. La première partie de ce travail a consisté à la mise au point de modèles murins présentant un processus de dégénérescence tissulaire similaire à celui survenant après radiothérapie. L'objectif étant d'affiner la compréhension des mécanismes physiopathologiques des lésions tissulaires radio-induites et de déterminer une stratégie thérapeutique la plus adaptée possible. La seconde partie de ce travail a été consacrée à l'évaluation de la faisabilité d'une autogreffe de CSMM dans le modèle murin d'irradiation précédemment établi en répondant à deux pré-requis : la rétention des cellules injectées au niveau du tissu cible et l'évaluation de la greffe sur le métabolisme osseux. Cette investigation préclinique sur un modèle murin a permis de réaliser une étape essentielle dans l'évaluation du traitement des lésions tissulaires radio-induites par thérapie cellulaire. Les données issues de ces travaux pourraient à terme permettre la mise en place d'études cliniques.Radiation therapy induced acute and late sequelae within healthy tissue included in the irradiated area. In general, lesions are characterized by ischemia, cell apoptosis and fibrosis. In this context, cell therapy using bone marrow mesenchymal stem cells (BMSC) might represent an attractive new therapeutic approach, based partly on their angiogenic ability and their involvement in the natural processes of tissue repair. The first part of this work consisted in the development of experimental mouse model of radio-induced tissue degeneration similar to that occurring after radiotherapy. The aim was to better understand the physiopathological mechanisms of radiation-induced tissue damage and to determine the best treatment strategy. The second part of this work investigated the feasibility of autologous BMSC therapy on the murine model of radiation previously established with emphasis on two pre-requisites : the retention of the injected cells within the target tissue and the evaluation of the graft on bone metabolism. This preclinical investigation in a mouse model constitutes an essential step allowing an evaluation of the benefit of cell therapy for the treatment of radiation-induced tissue injury. Data from these studies could allow the proposal of clinical studies

Apport de l'implantologie en secteur irradié

NANCY1-SCD Pharmacie-Odontologie (543952101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Modélisation de dégénérescence tissulaire radio-induite et conceptualisation de réhabilitation des tissus irradiés par thérapie cellulaire

La radiothérapie induit des séquelles aigues puis tardives affectant les tissus sains inclus dans le volume irradié. D'une façon générale, le processus lésionnel se caractérise par une ischémie vasculaire, une apoptose cellulaire et une fibrose cicatricielle. Dans ce contexte, la thérapie cellulaire à l'aide de cellules souches mésenchymateuses médullaires CSMM pourrait constituer une nouvelle approche thérapeutique séduisante, les CSMM ayant une capacité intrinsèque à promouvoir l'angiogenèse et une implication dans les processus naturels de réparation tissulaire. La première partie de ce travail a consisté à la mise au point de modèles murins présentant un processus de dégénérescence tissulaire similaire à celui survenant après radiothérapie. L'objectif étant d'affiner la compréhension des mécanismes physiopathologiques des lésions tissulaires radio-induites et de déterminer une stratégie thérapeutique la plus adaptée possible. La seconde partie de ce travail a été consacrée à l'évaluation de la faisabilité d'une autogreffe de CSMM dans le modèle murin d'irradiation précédemment établi en répondant à deux pré-requis : la rétention des cellules injectées au niveau du tissu cible et l'évaluation de la greffe sur le métabolisme osseux. Cette investigation préclinique sur un modèle murin a permis de réaliser une étape essentielle dans l'évaluation du traitement des lésions tissulaires radio-induites par thérapie cellulaire. Les données issues de ces travaux pourraient à terme permettre la mise en place d'études cliniques.Radiation therapy induced acute and late sequelae within healthy tissue included in the irradiated area. In general, lesions are characterized by ischemia, cell apoptosis and fibrosis. In this context, cell therapy using bone marrow mesenchymal stem cells (BMSC) might represent an attractive new therapeutic approach, based partly on their angiogenic ability and their involvement in the natural processes of tissue repair. The first part of this work consisted in the development of experimental mouse model of radio-induced tissue degeneration similar to that occurring after radiotherapy. The aim was to better understand the physiopathological mechanisms of radiation-induced tissue damage and to determine the best treatment strategy. The second part of this work investigated the feasibility of autologous BMSC therapy on the murine model of radiation previously established with emphasis on two pre-requisites : the retention of the injected cells within the target tissue and the evaluation of the graft on bone metabolism. This preclinical investigation in a mouse model constitutes an essential step allowing an evaluation of the benefit of cell therapy for the treatment of radiation-induced tissue injury. Data from these studies could allow the proposal of clinical studies.NANCY1-Bib. numérique (543959902) / SudocSudocFranceF

A Comparison of the Clinical and Radiological Extent of Denosumab (Xgeva®) Related Osteonecrosis of the Jaw: A Retrospective Study

Medication-related osteonecrosis of the jaw (MRONJ) is a severe side effect of antiresorptive medication. The aim of this study was to evaluate the incidence of denosumab-related osteonecrosis of the jaw and to compare the clinical and radiological extent of osteonecrosis. A retrospective study of patients who received Xgeva® at the Institut de Cancérologie de Lorraine (ICL) was performed. Patients for whom clinical and radiological (CBCT) data were available were divided into two groups: “exposed” for patients with bone exposure and “fistula” when only a fistula through which the bone could be probed was observed. The difference between clinical and radiological extent was assessed. The p-value was set at 0.05, and a total of 246 patients were included. The cumulative incidence of osteonecrosis was 0.9% at 6 months, 7% at 12 months, and 15% from 24 months. The clinical extent of MRONJ was significantly less than their radiological extent: in the “exposed” group, 17 areas (45%) were less extensive clinically than radiologically (p < 0.001) and respectively 6 (67%) for the “fistula” group (p < 0.031). It would seem that a CBCT is essential to know the real extent of MRONJ. Thus, it would seem interesting to systematically perform a CBCT during the diagnosis of MRONJ, exploring the entire affected dental arch

Photodynamic therapy as salvage treatment for recurrent head and neck cancer

Head and neck cancers often lead to disfiguration or functional impairments after treatment. Local recurrence occurs in around 60% of cases and most of them can not be retreated. Photodynamic therapy (PDT) can be an alternative treatment. In a serie of 10 patients with recurrent squamous cell carcinoma of the head and neck that have failed prior therapies and are unsuitable for conventional curative therapy, PDT treatment has been used. Eight patients have shown complete cicatrisation. Seven patients were cured after the follow up period up to 53 months. Three patients died (one outside etiology). Quality of life was considered as very much for 6 out of 10 patients, quite a bit for 1 patient, a little for 2 patients and not at all for 1 patient. Clinical benefit was evaluated as very much for 6 patients out of 10, quite a bit for 2 patients, a little for 1 patient and not at all for 1 patient. PDT can be proposed to patients with head and neck cancer in palliative situation. It could be a therapeutic solution for selected cases with good outcomes. PDT offers patients a unique chance of remission and increased life expectancy compared with palliative treatments

Simplified model of the complex network of interacting processes and signals in the pathogenesis of radio-induced injury.

<p>The main mediators of the four cytokine and growth factor families involved in inter-cellular exchanges during radiation-induced tissue degeneration in skin and muscles are.represented, namely the expression of proinflammatory (IL-1α, IL-2, IL-6, TNF-α, IFN-γ), profibrotic (TGF-β1), proangiogenic (VEGF) and stem cell mobilizing (GM-CSF) mediators.</p