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PURPOSE Patients with locally advanced grade 2-3 extremity/truncal soft tissue sarcomas (STS) are at high risk of recurrence. The objective of this study was to assess the efficacy and feasibility of neoadjuvant concurrent chemoradiotherapy (cCRT) in selected grade 2-3 patients with limb or trunk wall STS, and to compare this schedule to a sequential approach combining neoadjuvant chemotherapy and adjuvant radiotherapy. METHODS We retrospectively included patients who underwent neoadjuvant cCRT at two comprehensive cancer centers from 1992-2016. We then compared these results to those of patients treated with preoperative chemotherapy and postoperative radiotherapy from a third comprehensive cancer center with a propensity score matched analysis. RESULTS A total of 53 patients were treated by neoadjuvant cCRT; 58 patients could be matched with 29 patients in each treatment group after propensity score matching. Disease-free survival and overall survival at 5 years were 54.9 and 63.5%, respectively with neoadjuvant cCRT, with no significant difference when compared to the sequential treatment group. R0 resection rate was higher (90.9 vs 44.8%, p

International audience; Purpose: There are no safety-focused trials on stereotactic body radiotherapy (SBRT) for localized prostate cancer. This prospective 3‑year phase II trial used binomial law to validate the safety and efficacy of SBRT with stringent organ at risk dose constraints that nevertheless permitted high planning target volume doses.Methods: All consecutive ≥ 70-year-old patients with localized prostate adenocarcinoma who underwent SBRT between 2014 and 2018 at the National Radiotherapy Center in Luxembourg were included. Patients with low Cancer of Prostate Risk Assessment (CAPRA) scores (0–2) and intermediate scores (3–5) received 36.25 Gy. High-risk (6–10) patients received 37.5 Gy. Radiation was delivered in 5 fractions over 9 days with Cyberknife-M6™ (Accuray, Sunnyvale, CA, USA). Primary study outcome was Common Terminology Criteria for Adverse Events version 4 (CTCAEv4) genitourinary and rectal toxicity scores at last follow-up. Based on binomial law, SRBT was considered safe in this cohort of 110 patients if there were ≤ 2 severe toxicity (CTCAEv4 grade ≥ 3) cases. Secondary outcomes were biochemical progression-free survival (bPFS) and patient quality of life (QOL), as determined by the IPPS and the Urinary Incontinence QOL questionnaire.Results: The first 110 patients who were accrued in a total cohort of 150 patients were included in this study and had a median follow-up of 36 months. Acute grade ≥ 3 toxicity never occurred. One transient late grade 3 case was observed. Thus, our SBRT program had an estimated severe toxicity rate of

International audience; Objective: To assess the use of a volumetric image display simulation tool (VDST) for the evaluation of applied radiological neuroanatomy knowledge and spatial understanding of radiotherapy technologist (RTT) undergraduates.Methods: Ninety-two third-year RTT students from three French RTT schools took an examination using software that allows visualization of multiple volumetric image series. To serve as a reference, 77 first- and second-year undergraduates, as well as ten senior neuroradiologists, took the same examination. The test included 13 very-short-answer questions (VSAQ) and 21 exercises in which examinees positioned markers onto preloaded brain MR images from a healthy volunteer. The response time was limited. Each correct answer scored 100 points, with a maximum possible test score of 3,400 (VSAQ = 1,300; marker exercise = 2,100). Answers were marked automatically for the marker positioning exercise and semi-automatically for the VSAQs against prerecorded expected answers.Results: Overall, the mean test score was 1,787 (150-3,300) and the standard deviation was 781. Scores were highly significantly different between all evaluated groups (p < 0.001). The interoperator reproducibility was 0.90. All the evaluated groups could be discriminated by VSAQ, marker, and overall total scores independently (p ≤ 0.0001 to 0.001). The test was able to discriminate between the three schools either by VSAQ scores (p < 0.001 to 0.02) or by overall total score (p < 0.001 to 0.05).Conclusion: This software is a high-quality evaluation tool for the assessment of radiological neuroanatomy knowledge and spatial understanding in RTT undergraduates.Key points: • This VDST allows volumetric image analysis of MR studies. • A high reliability test could be created with this tool. • Test scores were strongly associated with the examinee expertise level.

BACKGROUND Validation of the 2016 LANO MRI scorecard for leptomeningeal metastasis failed for multiple reasons. The objective of this joint EORTC Brain Tumor Group and RANO effort was to validate the feasibility of the revised MRI scorecard for assessing response in leptomeningeal metastasis. METHODS Coded paired cerebrospinal MRI of 20 patients with leptomeningeal metastases from solid cancers at baseline and follow-up after treatment and instructions for assessment were provided via the EORTC imaging platform. The kappa coefficient (K) was used to evaluate inter-observer pairwise agreement. Statistical analyses were performed using SAS V9.4 software (Cary, NC). The sponsor of the study was the University Hospital Zurich (2018-00192). RESULTS Thirty-five raters participated, including 9 neuroradiologists, 17 neurologists, 4 radiation oncologists, 3 neurosurgeons and 2 medical oncologists. Among leptomeningeal metastases-related items at baseline, the best median concordance was noted for hydrocephalus (K=0.63), and the worst median for spinal linear enhancing disease (K=0.46). The median concordance for overall response was moderate (K=0.44). Notably, the interobserver agreement for the presence of parenchymal brain metastases at baseline was minimal (K=0.29). Significant differences were observed when considering the specialty of the raters. Only 394 of 700 ratings (56%) were fully completed. Among 394 fully completed ratings, perfect concordance was noted in 293 ratings (74%) when comparing the overall response according to the guidelines provided in the scorecard and the overall response provided by the raters. The main discordances were noted for partial response according to the rater versus stable disease according to the guidelines (n=44), followed by progression according to the raters versus stable disease according to the guidelines (n=23). CONCLUSION Electronic case report forms with "blocking solutions" are probably required to enforce completeness and quality of scoring. These results confirm the necessity of central review and the need for training of MRI assessment in clinical trials.

Well-differentiated papillary mesothelioma of the peritoneum (WDPMP) is a rare entity. Questions regarding management are still being debated as no more than 50 cases have been reported in the literature. We aimed to analyze the clinical, therapeutic, and prognostic data of patients with WDPMP from the RENAPE observational registry. All patients diagnosed with WDPMP and prospectively included in the RENAPE national registry between 2010 and 2018 were also included in our study. Expert pathologists from the RENA-PATH group confirmed all cases. All clinical, therapeutic, postoperative, and prognostic data were extracted and analyzed. We report on 56 patients with a mean age of 52 years (range 21–74). WDPMP was incidentally diagnosed during imaging or surgery in 16% and 36% of patients, respectively, and an association with synchronous malignancy was found in 18% of patients. Nine lesions showed discrete signs of fatty invasion. The median Peritoneal Cancer Index was 11 (range 0–33). Eleven patients were treated with definitive excision, 4 were treated with cytoreductive surgery (CRS) only, 37 were treated with CRS and hyperthermic intraperitoneal chemotherapy (HIPEC), and 2 were treated with CRS plus HIPEC plus early postoperative intraperitoneal chemotherapy. CRS was considered to be complete in 90% of cases. One patient died postoperatively and 16 patients (31%) faced postoperative complications. The median disease-free survival was 144 months; Four patients relapsed, with a median period of 27 months. No prognostic factors could be identified. Our analysis confirms the favorable prognosis of WDPMP. CRS and HIPEC could be a therapeutic option for diffuse, symptomatic, and/or recurrent disease.

NHL-ChirEx is an interprofessional cross-border education project that addresses the potential excess of radiation induced morbidity throughout the radiation planning and treatment process. NHL-ChirEx is supported by ESTRO and the University of the Greater Region and has been recently approved and funded under INTERREG VA Programme.

Simple Summary Early toxicity of radiotherapy (RT) (from the beginning of treatment to 3 months after its end) may compromise cancer treatments and its prediction is a medical, social and economic challenge. Beyond clinical/dosimetric factors, much of the variation in the risk of toxicity is currently unexplained and largely attributed to individual radiosensitivity (IRS). Thus, radiosensitivity tests would help several decision makings for choosing fractionation, preferring surgery to radiation or proton to photons for instance. Numerous initiatives failed in implementing predictive assays of IRS in clinical routine. Here we assess and validate the predictive ability of a new assay RADIODTECT® (RDT), based on phosphorylated ATM protein quantification in lymphocytes, for early toxicity after radiotherapy (RT). This study demonstrated promising results and implementing RTD as an easy managing test in common RT clinical practice for patients can be advisable. Abstract Radiation therapy (RT), either alone or in combination with surgery and/or chemotherapy is a keystone of cancers treatment. Early toxicity is common, sometimes leading to discontinuation of treatment. Recent studies stressed the role of the phosphorylated ATM (pATM) protein in RT-toxicity genesis and its ability in predicting individual radiosensitivity (IRS) in fibroblasts. Here we assessed the reliability of the pATM quantification in lymphocytes to predict IRS. A first retrospective study was performed on 150 blood lymphocytes of patients with several cancer types. Patients were divided into 2 groups, according to the grade of experienced toxicity. The global quantity of pATM molecules was assessed by ELISA on lymphocytes to determine the best threshold value. Then, the binary assay was assessed on a validation cohort of 36 patients with head and neck cancers. The quantity of pATM molecules in each sample of the training cohort was found in agreement with the observed Common Terminology Criteria for Adverse Events (CTCAE) grades with an AUC = 0.71 alone and of 0.77 combined to chemotherapy information. In the validation cohort, the same test was conducted with the following performances: sensitivity = 0.84, specificity = 0.54, AUC = 0.70 and 0.72 combined to chemotherapy. This study provides the basis of an easy to perform assay for clinical use.

Autophagy is a highly regulated multi-step process that occurs at the basal level in almost all cells. Although the deregulation of the autophagy process has been described in several pathologies, the role of autophagy in cancer as a cytoprotective mechanism is currently well established and supported by experimental and clinical evidence. Our understanding of the molecular mechanism of the autophagy process has largely contributed to defining how we can harness this process to improve the benefit of cancer therapies. While the role of autophagy in tumor resistance to chemotherapy is extensively documented, emerging data point toward autophagy as a mechanism of cancer resistance to radiotherapy, targeted therapy, and immunotherapy. Therefore, manipulating autophagy has emerged as a promising strategy to overcome tumor resistance to various anti-cancer therapies, and autophagy modulators are currently evaluated in combination therapies in several clinical trials. In this review, we will summarize our current knowledge of the impact of genetically and pharmacologically modulating autophagy genes and proteins, involved in the different steps of the autophagy process, on the therapeutic benefit of various cancer therapies. We will also briefly discuss the challenges and limitations to developing potent and selective autophagy inhibitors that could be used in ongoing clinical trials.

Background Segmentation is a crucial step in treatment planning that directly impacts dose distribution and optimization. The aim of this study was to evaluate the inter-individual variability of common cranial organs at risk (OAR) delineation in neurooncology practice. Methods Anonymized simulation contrast-enhanced CT and MR scans of one patient with a solitary brain metastasis was used for delineation and analysis. Expert professionals from 16 radiotherapy centers involved in brain structures delineation were asked to segment 9 OAR on their own treatment planning system. As reference, two experts in neurooncology, produced a unique consensual contour set according to guidelines. Overlap ratio, Kappa index (KI), volumetric ratio, Commonly Contoured Volume, Supplementary Contoured Volume were evaluated using Artiview™ v 2.8.2—according to occupation, seniority and level of expertise of all participants. Results For the most frequently delineated and largest OAR, the mean KI are often good (0.8 for the parotid and the brainstem); however, for the smaller OAR, KI degrade (0.3 for the optic chiasm, 0.5% for the cochlea), with a significant discrimination (p Association des Neuro-Oncologue d’Expression Française society performed better in all indicators compared to non-members (p p Conclusion Our study illustrates the heterogeneity in normal structures contouring between professionals. We emphasize the need for cerebral OAR delineation harmonization—that is a major determinant of therapeutic ratio and clinical trials evaluation.

Radiation therapy (RT) is involved in about 50% of cures. However, overall, after a median follow-up of 2.3 years, 3–5% of the treated patients are estimated to suffer from late toxicity that can cause potentially serious sequelae—in absence of therapeutic deviation. These toxicities are essentially cardiovascular, renal, endocrine, and musculoskeletal but also include secondary radiation-induced malignancies. The incidence of late complications continued to increase with the duration of follow-up without reaching a plateau. These late effects are characterized by a clinical latency during which intricated cellular and tissue events take place, as described in the second section. Several patient- and treatment-related cofactors are associated with late effects occurrence including individual radiosensitivity and radiosensitive syndromes. In the fourth section, we provide a clinical description of “deterministic” late effects according to organ/tissue location and radiosensitivity with a specific emphasis on pediatrics. After reviewing the stochastic late effects, we give insights into the current management of radiotherapy-induced sequelae with curative and preventive approaches.

Purpose To investigate clinical outcome and predicting factors of local failures in patients with colorectal cancer treated for unresectable liver metastases with stereotactic body radiation therapy (SBRT). Methods and materials We restrospectively reviewed the medical records of 67 patients treated with the Cyberknife SBRT system for 99 hepatic metastases between January 2007 and December 2015 in our center. In total, 37.5 to 54.0 Gy in 3 to 5 fractions were prescribed to the 80% isodose line. Local control (LC), intrahepatic progression incidence, Progression-Free Survival (PFS), Overall Survival (OS) and toxicity were evaluated. Results The median follow-up was 47 months (IQR, 28–59 months). The median OS was 53 months, the 2-year OS and PFS rates were 81.4% and 54.0%. The 1- and 2-year LC rates were 86.6% and 72.4%. In the multivariate analysis, the degree of differentiation was the only prognostic factor for LC (HR 0.31, 95% CI, 0.10–0.98, P = 0.046). Margin expansion > 5 mm was not associated with a better LC (HR 0.72, 95% CI, 0.38–1.37, P = 0.317). Performans Status ≥ 2 (HR 3.27, 95% CI, 1.07–9.98, P = 0.038), chemotherapy for metastases before SBRT (HR 0.36, 95% CI, 0.18–0.75, P = 0.006) and regional lymph node at diagnosis (HR 2.19, 95% CI, 1.09–4.43, P = 0.029) were independent prognostic factors for OS. We report 2 cases of grade ≥ 3 toxicity (3.0%) – one grade 3 acute nausea and one grade 3 late gastric ulcer. Conclusion Stereotactic body radiation therapy is an effective and well-tolerated treatment that allow high LC for liver metastases from colorectal cancer during the first two years. A prescription dose of 45 Gy in 3 fractions to the 80% isodose line with a risk adapted schedule to respect Organ At Risk constraints allows a low rate of toxicity.

International audience; Background: To report survival, spontaneous prognostic factors, and treatment efficacy in a French monocentric cohort of diffuse low-grade glioma (DLGG) patients over 35 years of follow-up.Methods: A monocentric retrospective study of 339 patients diagnosed with a new DLGG between 01/01/1982 and 01/01/2017 was created. Inclusion criteria were patient age ≥18 years at diagnosis and histological diagnosis of WHO grade II glioma (according to 1993, 2007, and 2016 WHO classifications). The survival parameters were estimated using the Kaplan-Meier method with a 95% confidence interval. Differences in survival were tested for statistical significance by the log-rank test. Factors were considered significant when p ≤ 0.1 and p ≤ 0.05 in the univariate and multivariate analyses, respectively.Results: A total of 339 patients were included with a median follow-up of 8.7 years. The Kaplan-Meier median overall survival was 15.7 years. At the time of radiological diagnosis, Karnofsky Performance Status score and initial tumor volume were significant independent prognostic factors. Oncological prognostic factors were the extent of resection for patients who underwent surgery and the timing of radiotherapy for those concerned. In this study, patients who had delayed radiotherapy (provided remaining low grade) did not have worse survival compared with patients who had early radiotherapy. The functional capabilities of the patients were preserved enough so that they could remain independent during at least three quarters of the follow-up.Conclusion: This large monocentric series spread over a long time clarifies the effects of different therapeutic strategies and their combination in the management of DLGG.

International audience; PurposePostoperative radiation therapy (poRT) of intracranial/skull base chondrosarcomas (CHSs) is standard treatment. However, consensus is lacking for poRT in extracranial CHS (eCHS) owing to their easier resectability and intrinsic radioresistance. We assessed the practice and efficacy of poRT in eCHS.Methods and MaterialsThis multicentric retrospective study of the French Sarcoma Group/Rare Cancer Network included patients with eCHS who were operated on between 1985 and 2015. Inverse propensity score weighting (IPTW) was used to minimize poRT allocation biases.ResultsOf 182 patients, 60.4% had bone and 39.6% had soft-tissue eCHS. eCHS were of conventional (31.9%), myxoid (28.6%; 41 extraskeletal, 11 skeletal), mesenchymal (9.9%), or other subtypes. En-bloc surgery with complete resection was performed in 52.6% and poRT in 36.8% of patients (median dose, 54 Gy). Irradiated patients had unfavorable initial characteristics, with higher grade and incomplete resection. Median follow-up time was 61 months. Five-year incidence of local relapse was 10% with poRT versus 21.6% without (P = .050). Using the IPTW method, poRT reduced the local relapse risk (hazard ratio, 0.27; 95% confidence interval, 0.14-0.52; P < .001). Five-year disease-free survival (DFS) was 71.8% with poRT and 64.2% without (P = .680). Using the IPTW method, poRT improved DFS (hazard ratio, 0.51; 95% confidence interval, 0.30-0.85; P = .010). The benefit of poRT on local relapse and DFS was confirmed after exclusion of the extraskeletal subtype. There was no difference in overall survival. Prognostic factors of poorer DFS in multivariate analysis were deeper location, higher grade, incomplete resection, and no poRT.ConclusionspoRT should be offered in patients with eCHS and high-grade or incomplete resection, regardless of the histologic subtype.

Sarcomas are a common type of tumor within the pediatric population. The utilization of proton therapy as a primary attribute the ability to spare adjacent healthy tissue, therefore, proton therapy has become a preferential indication in pediatrics compared to other photon irradiation modalities. Proton therapy is also a proven and historically validated irradiation technique in the treatment of chondrosarcomas and chordomas of the skull base and spine. Additionally, proton therapy can potentially limit irradiated healthy tissue volumes in adults and limit the risk of acute and late toxicities. The evaluation of the effectiveness of proton therapy in sarcomas is underway in many clinical situations in prospective trials, some of which are randomized.

The ability to identify, before treatment, those patients who will overreact to radiation therapy would have sound positive clinical implications. By focusing on DNA double-strand breaks recognition and repair proteins after irradiation, we recently demonstrated that the maximal number of phosphorylated ATM (pATM) nuclear foci in the first hour (pATMmax) after ex vivo irradiation correlated with postradiation therapy toxicity severity. We performed additional analyses of our whole collection of fibroblast lines to refine the predictive performance of our assay.Immunofluorescence experiments were performed on 117 primary skin fibroblast lines irradiated at 2 Gy. The toxicity response was split into 2 binary classes: 0 if the toxicity grade was2 and 1 otherwise. To assess the relationship between the quantity of pATMmax foci and toxicity grade, we applied a correlation and then a supervised classification analysis. Training data sets from 13 radiosensitive patients randomly drawn using a random undersampling technique were constituted. Receiver operating characteristic analyses were performed using a Monte-Carlo method to estimate the optimal threshold and discriminate the responses for each data set. The discrimination cutoff was estimated as the maximum value of the 10As expected, we confirmed a quasi-linear dependence between toxicity and pATMmax (Pearson correlation coefficient -0.85; P 2.2eThe results of these experiments allowed us to identify pATMmax as a high-performance predictive parameter of patients with postradiation therapy overreactions. Additional studies are in progress to confirm that this radiosensitivity assay reaches the same performance level in any condition to adapt clinical practice.

Background Approximately 900 children/adolescents are treated with radiotherapy (RT) every year in France. However, among the 80% of survivors, the cumulative incidence of long-term morbidity – including second malignancies - reach 73.4% thirty years after the cancer diagnosis. Identifying a priori the subjects at risk for RT sequelae is a major challenge of paediatric oncology. Individual radiosensitivity (IRS) of children/adolescents is unknown at this time, probably with large variability depending on the age when considering the changes in metabolic functions throughout growth. We previously retrospectively showed that unrepaired DNA double strand breaks (DSB) as well a delay in the nucleoshuttling of the pATM protein were common features to patients with RT toxicity. We aim to validate a high performance functional assay for IRS prospectively. Methods/design ARPEGE is a prospective open-label, non-randomized multicentre cohort study. We will prospectively recruit 222 children/adolescents who require RT as part of their routine care and follow them during 15 years. Prior RT we will collect blood and skin samples to raise a primary dermal fibroblast line to carry out in blind the IRS assay. As a primary objective, we will determine its discriminating ability to predict the occurrence of unusual early skin, mucous or hematological toxicity. The primary endpoint is the measurement of residual double-strand breaks 24 h after ex vivo radiation assessed with indirect immunofluorescence (γH2AX marker). Secondary endpoints include the determination of pATM foci at 10 min and 1 h (pATM marker) and micronuclei at 24 h. In parallel toxicity including second malignancies will be reported according to NCI-CTCAE v4.0 reference scale three months of the completion of RT then periodically during 15 years. Confusion factors such as irradiated volume, skin phototype, previous chemotherapy regimen, smoking, comorbities (diabetes, immunodeficiency, chronic inflammatory disease...) will be reported. Discussion ARPEGE would be the first study to document the distribution of IRS in the pediatric subpopulation. Screening hypersensitive patients would be a major step forward in the management of cancers, opening a way to personalized pediatric oncology. Trial registration ID-RCB number: 2015-A00975–44, ClinicalTrials.gov Identifier: NCT02827552 Registered 7/6/2016.

To examine the possibility of predicting clinical radiosensitivity by quantifying the nuclear forms of autophosphorylated ATM protein (pATM) via a specific enzyme-linked immunosorbent assay (ELISA).This study was performed on 30 skin fibroblasts from 9 radioresistant patients and 21 patients with adverse tissue reaction events. Patients were divided into 2 groups: radioresistant (toxicity grade2) and radiosensitive (toxicity grade ≥2). The quantity of nuclear pATM molecules was assessed by the ELISA method at 10 minutes and 1 hour after 2 Gy and compared with pATM immunofluorescence data.The pATM ELISA data were in quantitative agreement with the immunofluorescence data. A receiver operating characteristic analysis was applied first to 2 data sets (a training set [n=14] and a validating [n=16] set) and thereafter to all the data with a 2-fold cross-validation method. The assay showed an area under the curve value higher than 0.8, a sensitivity of 0.8, and a specificity ranging from 0.75 to 1, which strongly documents the predictive power of the pATM ELISA.This study showed that the assessment of nuclear pATM quantity after 2 Gy via an ELISA technique can be the basis of a predictive assay with the highest statistical performance among the available predictive approaches.

International audience; Purpose: To study overall survival, risk of neurological death, local recurrence and development of new brain metastasis in patients treated for brain oligometastases with hypofractionated stereotactic radiotherapy with CyberKnife®, according to the association or not with an additional whole brain irradiation.Patients and methods: Institutional retrospective study of 102 patients treated for one to three brain metastasis: 76 with exclusive hypofractionated stereotactic radiotherapy and 26 with hypofractionated stereotactic radiotherapy and whole brain irradiation. Objectives were assessed and compared between these two groups according to the Kaplan–Meier method and Cox model.Results: Median follow-up was 18.8 months. There were no difference between exclusive hypofractionated stereotactic radiotherapy and hypofractionated stereotactic radiotherapy with whole brain irradiation for overall survival (respective median 21.5 and 20.1 months), risk of neurological death (respectively 9.2% and 15.4% at one year). At one year: the risk of cerebral progressive disease was greater in the group receiving exclusive hypofractionated stereotactic radiotherapy (respectively 43.4% vs. 26.2%, P = 0.043), the risk of local recurrence was 25% versus 17.6% (P = 0.28) and the development of new brain metastasis was 23.7% versus 11.5% (P = 0.27). After salvage treatments, crude local control was similar in the two groups, respectively 78.6% and 73.5%. Whole brain irradiation has been avoided for 72.4% of patients in the group receving exclusive hypofractionated stereotactic radiotherapy.Conclusion: Whole brain irradiation improves local control of brain metastatic disease in addition to hypofractionated stereotactic radiotherapy. Sparing whole brain irradiation for salvage treatments only does not affect overall survival or risk of neurological death in selected patients with favourable prognosis.; Objectifs: Étude de la survie globale, du risque de décès neurologique, de la progression locale et de l’apparition de nouvelles métastases cérébrales chez des patients pris en charge pour des oligométastases cérébrales par irradiation stéréotaxique hypofractionnée par CyberKnife®, selon l’association ou non à une irradiation encéphalique totale complémentaire.Patients et méthodes: Étude rétrospective institutionnelle sur 102 patients pris en charge pour une à trois métastases cérébrales : 76 par irradiation stéréotaxique hypofractionnée exclusive et 26 par irradiation stéréotaxique hypofractionnée et irradiation encéphalique totale. Les objectifs ont été évalués et comparés entre ces deux groupes selon la méthode de Kaplan–Meier et le modèle de Cox.Résultats: Le suivi médian était de 18,8 mois. Il n’y avait pas de différence entre les groupes traités par irradiation stéréotaxique hypofractionnée exclusive et ceux traités par irradiation stéréotaxique hypofractionnée et irradiation encéphalique totale en termes de survie globale (médianes respectives de 21,5 mois et 20,1 mois), ni de risque de décès neurologique (9,2 % et 15,4 % à un an). Le risque de progression cérébrale à un an était plus important dans le groupe traité par irradiation stéréotaxique hypofractionnée exclusive (43,4 % contre 26,2 %, p = 0,043), avec un risque de progression locale de 25 % contre 17,6 % (p = 0,28) et d’apparition de nouvelles métastases cérébrales de 23,7 % contre 11,5 % (p = 0,28). Après traitements de rattrapage, le taux de contrôle local brut était identique entre les deux groupes, respectivement 78,6 % et 73,5 %. La radiothérapie encéphalique totale a pu être évitée pour 72,4 % des patients du groupe traité par irradiation stéréotaxique hypofractionnée exclusive.Conclusion: L’irradiation encéphalique totale améliore le taux de contrôle local de la maladie métastatique cérébrale en complément de l’irradiation stéréotaxique hypofractionnée. Ne pas la réaliser d’emblée pour la réserver aux seuls traitements de rattrapage n’altère ni la survie globale ni le risque de décès neurologique chez les patients sélectionnés, atteints de cancer de pronostic favorable.

Novel paradigms emerge in oncology today. Systemic treatments are more effective and diversified along with an increased life expectancy in oligometastatic patients. Stereotactic radiotherapy using hypofractionation opens new perspectives for local tumour control. The area of radiobiology has expanded with integration of tumour microenvironment in which radiation-induced inflammation mediators and immune system play a major role. Immunity checkpoints inhibitors experience a major development. This rapidly evolving field seems involved in the abscopal effects, especially when radiation is combined with checkpoints inhibitors, as demonstrated in numerous preclinical studies and several clinical trials. Paradoxically, irradiation also produces immunosuppressive effects. This manuscript aims to report the dual effects of ionizing radiation on the immune system and reviews some results of the combination of radiation and immunity chekpoints inhibitors and also research perspectives.

Resume Objectif de l’etude Evaluer prospectivement la toxicite chronique gastro-intestinale chez les patientes atteintes de cancer du col uterin traite par irradiation classique ou avec modulation d’intensite (RCMI). Patientes et methodes Entre juin 2005 et septembre 2013, 109 patientes ont beneficie d’une radiotherapie externe suivie d’une curietherapie pour un cancer du col uterin a l’institut de cancerologie de Lorraine. Chaque patiente prise en charge par RCMI a ete appariee a une patiente traitee par irradiation classique sur les criteres suivants : chimiotherapie concomitante, complement de dose ganglionnaire, traitement de l’aire ganglionnaire lombo-aortique, âge. Le recueil de toxicite etait prospectif selon la classification du Radiation Therapy Oncology Group. L’objectif principal etait de comparer l’incidence de la toxicite digestive chronique entre les deux groupes. L’influence des parametres dosimetriques sur la toxicite digestive chronique a ete etudiee dans un second temps. La comparaison de la toxicite aigue, la toxicite chronique genito-urinaire, la survie globale et la survie sans recidive constituaient des objectifs secondaires. Resultats Soixante-six patientes ont pu etre appariees. La probabilite de survie globale a 36 mois etait de 71 % apres irradiation classique contre 73 % apres RCMI (p = 0,54). Il n’existait significativement pas de difference entre les deux groupes, en termes de toxicite chronique digestive (p = 0,17), ni de toxicite aigue digestive (p = 0,6445) et genito-urinaire (p = 0,5724). La RCMI epargnait significativement des 30 Gy l’intestin grele (p = = 0,0006) et le rectum (p = 0,0046), et la vessie a 45 Gy (p Conclusion Notre etude ne semble pas mettre en evidence de difference significative concernant la survenue de toxicite chronique digestive entre les deux groupes. L’efficacite clinique parait comparable. Des etudes avec un effectif plus important et une duree de suivi plus longue doivent etre menees.

Summary Introduction Suspicious lesions of sarcoma require preoperative biopsies. If surgical biopsies remain the gold standard, radioguided percutaneous microbiopsies are gaining an increasing importance. The purpose of this study was to compare histopathological results of percutaneous biopsies of soft tissues, trunk and retroperitoneal tumors with the histopathological results of operative specimens. Methods This is a retrospective study including 84 patients treated in our institution. The concordance between the results of the microbiopsy and the operative specimen for the benign–malignant differentiation and the histological type was evaluated. The microbiopsy accuracy was calculated. The sensitivity and the specificity of the microbiopsies compared to the operative specimen were also evaluated for the benign–malignant differentiation. Results The concordance was 0.92 [0.79–1] for the benign–malignant differentiation, 0.97 [0.92–1] for the histological type. The accuracy of microbiopsies was therefore 96% (sensibility = 97.0%; specificity = 94.1%) for the benign–malignant detection and 97.8% for the histological type. Conclusion Percutaneous microbiopsies play an important part in the diagnosis of soft tissue tumors of the limbs, trunk and retroperitoneum, in particular as a replacement to more invasive surgical biopsies. This study evidences the increasing importance of the collaboration between radiologist, surgeon and pathologist in the diagnosis of sarcoma.

Analgesic external beam radiation therapy is a standard of care for patients with uncomplicated painful bone metastases and/or prevention of bone complications. In case of fracture risk, radiation therapy is performed after surgery in a consolidation of an analgesic purpose and stabilizing osteosynthesis. Radiotherapy is mandatory after vertebroplasty or kyphoplasty. Spinal cord compression - the only emergency in radiation therapy - is indicated postoperatively either exclusively for non surgical indication. Analgesic re-irradiation is possible in the case of insufficient response or recurrent pain after radiotherapy. Metabolic radiation, bisphosphonates or denosumab do not dissuade external radiation therapy for pain relief. Systemic oncological treatments can be suspended with a period of wash out given the risk of radiosensitization or recall phenomenon. Better yet, the intensity modulated radiotherapy and stereotactic radiotherapy can be part of a curative strategy for oligometastatic patients and suggest new treatment prospects.

Purpose The aim of this study was to evaluate the impact of the time interval (TI) between surgery and adjuvant radiotherapy (RT) in soft tissue sarcoma (STS). Methods and materials Data from 1131 patients treated between 1990 and 2014 were retrospectively reviewed. Inclusion criteria were: limb or superficial trunk wall STS (R0 or R1 resection) and adjuvant RT. The impact of TI on 10-year local relapse-free survival (LRFS) and 10-year overall survival (OS) was analyzed using a Log-rank test and then Cox Model. Results The median TI was 82days (range, 18–346). With a median follow-up of 235months (range, 2–296months), the 10-year LRFS was 57.5% (±2%) and the 10-year OS was 64.2% (±2%). With a TI of 19–39days, 40–79days, 80–119days, and ⩾120days, 10-year LRFSs were 65.3%, 55.5%, 56.9% and 61.2% ( p =0.465), and 10-year OSs were 72.8%, 60.7%, 66.4% and 62.1% ( p =0.347), respectively. After adjustment for the factors significantly ( p ⩽0.05) associated with LRFS and OS, TI did not alter LRFS ( p =0.182) either OS ( p =0.335). Conclusions In this retrospective STS database study, the TI between surgery and start of adjuvant RT did not seem to affect outcomes.

Stereotactic radiotherapy (SRT) is recommended for treatment of brain oligometastasis (BoM) in patients with controlled primary disease. Where contrast enhancement enlargement occurs during follow-up, distinguishing between radionecrosis and progression presents a critical challenge. Without pathological confirmation, decision-making may be inappropriate and delayed. Quantitative imaging features extracted from routinely performed examinations are of interest in potentially addressing this problem. We explored the added value of the radiomics method for the differential diagnosis of these two entities. Twenty patients who received SRT for BoM, from any primary location, were included (8 radionecrosis, 12 progressions, pathologically confirmed). We assessed the clinical relevance of 1,766 radiomics features, extracted using IBEX software, from the first T1-weighted postcontrast magnetic resonance imaging (MRI) after SRT showing a lesion modification. We evaluated seven feature-selection methods and 12 classification methods in terms of respective predictive performance. The classification accuracy was measured using Cohen's kappa after leave-one-out cross-validation. In this work, the best predictive power reached was a Cohen's kappa of 0.68 (overall accuracy of 85%), expressing a strong agreement between the algorithm prediction and the histological gold standard. Prediction accuracy was 75% for radionecrosis, and 91% for progression. The area under a curve reached 0.83 using a bagging algorithm trained with the chi-square score features set. These findings indicated that the radiomics method is able to discriminate radionecrosis from progression in an accurate, early and noninvasive way. This promising study is a proof of concept, preceding a larger prospective study for defining a robust model to support decision-making in BoM. In summary, distinguishing between radionecrosis and progression is challenging without pathology. We built a classification model based on imaging data and machine learning. Using this model, we were able predict progression and radionecrosis in, respectively, 91% and 75% of cases.

International audience; Purpose: 454 patients with prostate adenocarcinoma were accidentally overexposed to radiation in Epinal hospital, France, between August 1999 and January 2007. We aimed toevaluate whether radiation-induced CD4 or CD8 T-lymphocyte apoptosis (RILA) correlates with the severity of radiation toxicity.Methods: Between 2007 and 2013, all patients who received more than 108% of the prescribed radiation dose, after correction of the treatment plan, were convened, and blood was sampled at 6-months follow-up. Maximal Digestive toxicity (MDT) and maximal urinary toxicity (MUT) were graded using the Common Terminology Criteria for Adverse Events (NCI-CTCAE) v3.0 scale. RILA was assessed using flow cytometry.Results: 245 patients were included in our study. After a median follow-up of 4.8 years, the MDT and MUT reached grade 3-4 in 37 patients and 56 patients, respectively. Patients with prostatectomy exhibited a statistically higher grade of MUT compared with those treated with definitive radiotherapy (p=0.03). The median RILA values were 11.8% and 15.3% for CD4 and CD8 T-lymphocytes, respectively. We found no significant correlation between CD4 or CD8 RILA and either MDT or MUT.Conclusion: RILA does not correlate with the inter-individual variation in MDT or MUT in the largest cohort of patients overexposed to radiation. The magnitude of the overdosage probably overrides biological predictors of toxicity, including individual radiosensitivity.

Purpose The purpose of this study was to evaluate, during a national workshop, the inter-observer variability in target volume delineation for primary extremity soft tissue sarcoma radiation therapy. Methods and materials Six expert sarcoma radiation oncologists (members of French Sarcoma Group) received two extremity soft tissue sarcoma radiation therapy cases 1: one preoperative and one postoperative. They were distributed with instructions for contouring gross tumour volume or reconstructed gross tumour volume, clinical target volume and to propose a planning target volume. The preoperative radiation therapy case was a patient with a grade 1 extraskeletal myxoid chondrosarcoma of the thigh. The postoperative case was a patient with a grade 3 pleomorphic undifferentiated sarcoma of the thigh. Contour agreement analysis was performed using kappa statistics. Results For the preoperative case, contouring agreement regarding GTV, gross tumour volume GTV, clinical target volume and planning target volume were substantial (kappa between 0.68 and 0.77). In the postoperative case, the agreement was only fair for reconstructed gross tumour volume (kappa: 0.38) but moderate for clinical target volume and planning target volume (kappa: 0.42). During the workshop discussion, consensus was reached on most of the contour divergences especially clinical target volume longitudinal extension. The determination of a limited cutaneous cover was also discussed. Conclusion Accurate delineation of target volume appears to be a crucial element to ensure multicenter clinical trial quality assessment, reproducibility and homogeneity in delivering RT. radiation therapy RT. Quality assessment process should be proposed in this setting. We have shown in our study that preoperative radiation therapy of extremity soft tissue sarcoma has less inter-observer contouring variability.

Resume Objectif de l’etude L’objectif de ce travail etait d’implementer un outil d’alerte dosimetrique simple dans une etude retrospective portant sur six patients ORL afin de detecter les situations ou une adaptation de traitement etait requise. Materiel et methodes L’outil dosimetrique genere la cartographie tridimensionnelle de deux informations dosimetriques complementaires : une carte de tolerance de variation de dose et une carte de differentielle de dose. La carte de tolerance est calculee a partir de la distribution de dose planifiee sur la scanographie initiale. Elle affiche pour chaque voxel de chaque organe delinee, les variations acceptables de dose au cours des seances d’irradiation sans exceder les contraintes dosimetriques. La carte de difference de dose est generee suite au calcul de dose reelle sur l’image tomographique conique. Les variations de dose entre la distribution planifiee et la distribution reelle sont affichees pour chaque voxel. En comparant les deux cartes, lorsqu’un voxel presente une valeur superieure a la tolerance de variation de dose correspondante, un systeme d’alerte se declenche et la zone anatomique concernee est visuellement indiquee au medecin. Resultats L’implementation de l’outil d’alerte sur six patients atteints de cancer de la sphere ORL, avec une tomographie conique hebdomadaire, a revele l’aptitude de l’outil a detecter les cas justifiant un nouveau plan de traitement. Deux patients chez qui la regression tumorale engendrait une majoration de la dose delivree au canal medullaire au-dela de 45 Gy ont ete detectes. Conclusion Le developpement de cet outil de detection automatique permet d’orienter rapidement, et sans delineation medicale, les patients atteints de cancer ORL vers une strategie de radiotherapie adaptative.

Background Cervical and skull base chordomas may relapse locally, marginally, or in ectopic sites (ie, surgical pathway, lymph nodes, prevertebral space, subdural space, or distant organs). Methods Among 371 patients treated between 1995 and 2010, we matched the initial dosimetry with the 3D imaging of recurrence and selected the patients with isolated ectopic recurrence. Results During our follow-up, we identified 13 patients who developed ectopic relapses (n = 18) in the form of lung metastasis (n = 2), axial dissemination (n = 6), nodal recurrence (n = 2), subcutaneous metastasis (n = 3), and/or seeding along the surgical pathway (n = 5). Despite treatment of these 13 patients with radiation, surgical interventions, and/or chemotherapy, we could only salvage 5 patients with recurrence in surgical pathway, whereas the remaining 8 patients succumbed to a poor prognosis. Conclusion Our study emphasizes an urgent need for prediction and early diagnosis of ectopic relapses in patients with cervical and skull base chordoma to improve accuracy of their aggressive treatments. © 2015 Wiley Periodicals, Inc. Head Neck, 2015

Purpose To evaluate the efficacy and tolerance of adjuvant concurrent chemoradiation (CCRT) as treatment of grade 2 and 3 (G2-3) localized extremity soft tissue sarcomas (STS) by comparing CCRT with standard adjuvant radiation therapy (RT). Patients and methods This monocentric retrospective study included non-pediatric patients (>16 years) treated by adjuvant RT with or without chemotherapy (CT) after conservative resection of non-recurrent G2-3 extremity STS. Results A total of 80 patients were treated between 1990 and 2012: 51 by RT and 29 by CCRT. Of the 29 CCRT patients, 25 received doxorubicin monotherapy (75 mg/m2/3 weeks). The CCRT group contained a greater proportion of grade 3 extremity STS (p Conclusion CCRT could improve local control as part of a limb-preservation strategy. However, with a limited number of patients, CCRT showed no improvement in either distant control or survival and increased toxicity.

La Presse Medicale - In Press.Proof corrected by the author Available online since jeudi 27 aout 2015

Background HELLP syndrome is a combination of symptoms described as hemolysis, elevated liver enzymes and low platelets, that complicates 0.01–0.6 % of pregnancies. HELLP syndrome has been scarcely reported associated with partial moles, another rare complication of pregnancy. This manuscript describes the only reported case of HELLP syndrome associated with a complete invasive hydatiform mole. Case presentation We report a perimenopausal patient in prolonged remission from an uncommon high-risk invasive complete mole. The diagnosis was set in a context of early onset preeclampsia and HELLP syndrome. The development of life-threatening complications required primary hysterectomy. Postoperative hCG quickly returned to normal with EMA/CO multi-agent chemotherapy. Conclusion Our patient is in prolonged remission from a complete mole complicated with EOP and HELLP syndrome. This exceptional case of complicated gestational trophoblastic neoplasia reflects a very rare condition in which several risk factors for placental ischemia are associated. Emergency hysterectomy should be considered as salvage initial treatment in such life-threatening situations.

International audience; Introduction: Radionecrosis (RN) represents the main complication of stereotactic radiotherapy (SRT) for brain metastases. It may be observed in up to 34% of cases at 24 months after treatment and associated with significant morbidity in 10-17%.Areas covered: Our aim is to discuss the results of original studies on RN related to SRT for brain metastases. Expert commentary: Although the development of RN is unpredictable, larger volume of the lesion, prior whole brain irradiation, and higher dose of radiation represent the major risk factors. RN appears on MRI as contrast-enhancing necrotic lesions, surrounded by edema, occurring at least 3 months after SRT, localized within fields of irradiation. No firm criteria are established. Surgery can provide symptomatic relief but is associated with a risk of complications. Corticosteroids are considered the standard of care treatment, despite limited efficacy and many adverse effects. Bevacizumab represents another interesting option that needs to be validated.

Purpose Brachytherapy is a well-known treatment in the management of skin tumors. For facial or scalp lesions, applicators have been developed to deliver non-invasive treatment. We present cases treated with customized applicators with high dose rate system. Material and methods Patients with poor performance status treated for malignant skin lesions of the scalp or the facial skin between 2011 and 2014 were studied. Afterloading devices were chosen between Freiburg® Flap, silicone-mold or wax applicators. The clinical target volume (CTV) was created by adding margins to lesions (10 mm to 20 mm). The dose schedules were 25 Gy in five fractions for postoperative lesions, 30 Gy in six fractions for exclusive treatments and a single session of 8 Gy could be considered for palliative treatments. Results In 30 months, 11 patients received a treatment for a total of 12 lesions. The median age was 80 years. The median follow-up was 17 months and the 2-year local control rate was 91%. The mean CTV surface was 41.1 cm2 with a mean thickness of 6.1 mm. We conceived three wax applicators, used our silicone-mold eight times and the Freiburg® Flap one time. We observed only low-grade radiodermitis (grade I: 50%, grade II: 33%), and no high-grade skin toxicity. Conclusion High dose rate brachytherapy with customized applicators for facial skin and scalp lesions is efficient and safe. It is a good modality to treat complex lesions in patients unfit for invasive treatment.

International audience; PURPOSE: Whereas post-radiation therapy overreactions (OR) represent a clinical and societal issue, there is still no consensual radiobiological endpoint to predict clinical radiosensitivity. Since 2003, skin biopsy specimens have been collected from patients treated by radiation therapy against different tumor localizations and showing a wide range of OR. Here, we aimed to establish quantitative links between radiobiological factors and OR severity grades that would be relevant to radioresistant and genetic hyperradiosensitive cases. METHODS AND MATERIALS: Immunofluorescence experiments were performed on a collection of skin fibroblasts from 12 radioresistant, 5 hyperradiosensitive, and 100 OR patients irradiated at 2 Gy. The numbers of micronuclei, γH2AX, and pATM foci that reflect different steps of DNA double-strand breaks (DSB) recognition and repair were assessed from 10 minutes to 24 hours after irradiation and plotted against the severity grades established by the Common Terminology Criteria for Adverse Events and the Radiation Therapy Oncology Group. RESULTS: OR patients did not necessarily show a gross DSB repair defect but a systematic delay in the nucleoshuttling of the ATM protein required for complete DSB recognition. Among the radiobiological factors, the maximal number of pATM foci provided the best discrimination among OR patients and a significant correlation with each OR severity grade, independently of tumor localization and of the early or late nature of reactions. CONCLUSIONS: Our results are consistent with a general classification of human radiosensitivity based on 3 groups: radioresistance (group I); moderate radiosensitivity caused by delay of nucleoshuttling of ATM, which includes OR patients (group II); and hyperradiosensitivity caused by a gross DSB repair defect, which includes fatal cases (group III)

11041 Background: A subset of metastatic GIST exhibit very long-term survival after imatinib (IM) introduction. The aim of this study was to analyse the clinico-biological characteristics of GIST pts alive > 10 years (yrs) after diagnosis (dx) of metastases (mets) and identify possible factors associated with long-term survival. Methods: Pts were identified from 2 sarcoma databases; NetSarc and ConticaGIST. Clinical data prospectively registered in the databases were supplemented with retrospective review of medical records. Results: We identified 141 pts (75 men, 66 women) with median age 54 (17-84) yrs and median ECOG 0 (0-2). Primary tumors (T) were all CD117+, and mainly gastric or intestinal (64 & 45 pts), with median size 10 (2-40) cm, CD34+ (82 pts), mitoses/50 HPF ≤ 5 (n = 36), or > 5 (n = 81). Genotype was documented in 82 (58%) pts with 73 (89%) KIT mutations (in exons 11,9 and 12 of 69, 3, and 1 pts respectively) and 9 WT KIT. 129 (91%) T were resected, 124 upfront, 5 post IM, with R0/R1/R2 resections in 61, 11, and 10 pts. Mets were mainly hepatic or peritoneal (78 & 51 respectively). 1st line TKI was given to 139 pts: 130 received IM; 88 (63%) within a clinical trial (CT), 41 (29%) had mets resection. Second, 3d and 4th line TKI were given to 81, 51 and 37 pts respectively, comprising 27, 7 and 10 from CT. Median number of TKIs was 2 (0-7), but 60 (44%) pts received only 1st line with no GIST progression within or after 10 yrs. 2 pts never received TKI but had mets resection. After median FU of 14.3 yrs (10-34.5), 104 remain alive, 37 died. Mean and Median OS from initial dx are 24 yrs (CI95% 21.6-27) and 20,8 yrs. Median PFS on TKIs are 127, 29, 21 and 22 mos on 1st, 2d, 3d and 4th line of TKI. In univariate analysis no factor is significantly associated with OS, but T size (≤ 10 vs > 10 cm) and oligometastatic disease (≤5 vs > 5 mets) are borderline significant (p = 0.056 and 0.07), and good PS (ECOG ≤ 1) at 2dline TKI initiation is associated with better PFS (p = 0.03). Conclusions: This large series of long-term ( > 10 yrs) survivors of metastatic GIST shows a high proportion of mets resection and a longer duration of PFS for TKI at any line. In this selected population, no prognostic factor is associated with long OS.

Background To evaluate the MRI features of a tumor response, local control, and predictive factors of local control after stereotactic body radiation therapy (SBRT) for hepatocellular carcinoma (HCC). Methods Thirty-five consecutive patients with 48 HCCs who were treated by SBRT were included in this retrospective study. All patients provided written informed consent to be treated by SBRT, and prior to inclusion they authorized use of the treatment data for further studies. The assessment was made using MRI, with determination of local and hepatic responses according to Response Evaluation Criteria in Solid Tumors (RECIST) and modified RECIST (mRECIST) criteria during a two-year follow-up. Results The local response rate according to mRECIST was higher than with RECIST. A tumor diameter less than 20 mm at baseline was an independent predictive factor for RECIST and mRECIST responses, as was diffusion-weighted signal for RECIST. During follow-up, a tumor diameter of

To evaluate both local outcome and sequelae of non-metastatic spinal Ewing tumours (EWT).A French cohort of patients ≤ 50years with localised spinal EWT treated between 1988 and 2009, was analysed in regard to tumour characteristics (e.g. volume, vertebral compartment, spinal cord compression, paraspinal soft tissue invasion), local treatment modalities (surgery (S) and margin quality, radiotherapy (RT) dose), response to treatment (e.g. histological response to neoadjuvant chemotherapy (CT)), tumour local control (LC) and sequelae.Seventy-five patients treated in successive trials were evaluated for LC: SFOP-EW88 (n=14), SFOP-EW93 (n=17) and EuroEwing99 (n=44). Fifty-seven patients (79%) presented initial neurological compression and 69% had inaugural decompressive S. Local treatment modality was S+RT (n=50), RT alone (n=19) and S alone (n=6). Surgery was mainly intralesional (66%). Local recurrences had occurred in 19 patients (14 local, 5 loco-regional) with a median interval of 25 months (1-50). After a 7 year median follow-up (1-22 years), the 5-year LC, relapse-free survival (RFS) and overall survival (OS) reached 78.0% (95%CI: 62.6-84.6), 57.0% (95%CI: 45.2-68.9) and 70.0% (95%CI: 59.1-81.0), respectively. Vertebral compartment involved was the only prognostic factor (5-year LC rate 100% versus 71% for favourable and unfavourable compartment, p0.03). Among 41 five-year survivors, we observed spinal curvature deformation (35%), growth retardation (28%), spinal reduction mobility (40%), spinal pain (25%) and neurological sequelae (32%) without any significant association with a particular local procedure.RT is the backbone of a successful local treatment of spinal EWT. The place of S remains a pending question. Its actual benefit will likely evolve with new available RT techniques.

Deriving from glial, astrocyte, or dendrocyte cells, gliomas are the most frequent tumors of central nervous system. Unfortunately, most of gliomas are refractory to standard radiotherapy treatments. The median survival for patients bearing grade IV gliomas (glioblastomas) does not exceed one year even after both aggressive surgery and radiotherapy treatment (Behin et al., 2003). A standard of 60 Gy delivered in 30 fractions during six weeks remains the best radiotherapy modality against gliomas (Behin et al., 2003). This last conclusion raises the possibility that human gliomas might be generally more radioresistant than other tumor tissues. However, there is no consensus in literature about a specific radioresistance of human gliomas. Besides, the complexity of the molecular and cellular features of radiation response and the difficulty to define reliable endpoints to account for radiosensitivity whatever the tissue type may have limited the extent of some reports. In addition, three specific features of radiobiology of gliomas can be also evoked: cellular in vitro endpoints like clonogenic survival seem to be less appropriate to predict gliomas radiocurability than that of other tumour types (Taghian et al., 1992, 1993); animal models extensively used in glioma research may not reflect specificities of human gliomas and may bias in anti-glioma strategies (Holland, 2001); DNA repair capacity of gliomas is poorly documented and most of the investigations about genes mutations concern actors of proliferation rather than upstream DNA repair proteins (Zhu & Parada, 2002). In 2004, our group obtained the most protracted survival of rats bearing radioresistant rodent gliomas by using synchrotron X-rays combined with intracerebral cisplatin injection. Such so-called PAT-plat treatment triggers the photoactivation of platinum atoms and produces some additional DNA double-strand breaks (DSBs) at the vicinity of cisplatininduced DNA adducts (Biston et al., 2004). The severity of PAT-Plat-induced DSBs was shown to be due to the inhibition of the major DSB repair pathway in mammalians, namely

Abstract 163 Iron plays a key role as a cofactor in many fundamental metabolic processes, which require heme synthesis and Fe/S cluster assembly in the mitochondria. Defects in the transport of iron into the mitochondria would lead to anemias due to a deficiency in heme and hemoglobin synthesis. Here we describe a zebrafish genetic mutant, pinotage (pnttq209), which exhibits a profound hypochromic, microcytic anemia. Erythrocytes from pnt mutants have a defect in hemoglobinization and decreased red cell indices (mean corpuscular volume and hemoglobin content, hematocrit, hemoglobin concentration). Through positional cloning, we showed that the mitochondrial ATPase Inhibitory Factor 1 (atpif1), which regulates the inner mitochondrial membrane potential, is the gene disrupted in pnt. The identity of the pnt gene was verified by: (a) decreased atpif1 steady-state mRNA in pnt mutants, (b) phenocopying the anemia with anti-sense atpif1 morpholinos, (c) functional complementation of the anemia with atpif1 cRNA, and (d) a genetic polymorphism in the 3'UTR co-segregating with the mutant phenotype that destabilizes the atpif1 mRNA. Consistent with the conserved function of atpif1 in higher vertebrates, the silencing of the murine ortholog of atpif1 in Friend mouse erythroleukemia (MEL) cells showed a defect in hemoglobinization by o-dianisidine staining and reduction of 59Fe incorporation into heme in 59Fe-metabolically labeled cells. Moreover, Atpif1 knockdown destabilizes their mitochondrial membrane potential and volume. Therefore, the identification of atpif1 in pnt functionally demonstrates the role of atpif1 in regulating the proton motive gradient across the inner mitochondrial membrane for mitochondrial iron incorporation in heme biosynthesis. These results uncover a novel hematopoiesis-related function of atpif1, which will directly contribute to our understanding and potential treatment of human congenital and acquired anemias. Disclosures: No relevant conflicts of interest to declare.