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BACKGROUND AND PURPOSE: Diversity, Equity and Inclusion (DEI) in the medical workforce is linked to improved patient care and innovation, as well as employee retention and engagement. The European Society for Radiotherapy and Oncology launched a survey to provide a benchmark of DEI and engagement among radiation oncology (RO) professionals in Europe.METHODS: An anonymous survey was disseminated among RO professionals in Europe. The survey collected demographics and professional information, and participants were asked if they felt they belonged to a minority group. A DEI and workforce engagement questionnaire by Person et al. evaluated 8 inclusion factors. A favourable score was calculated by adding the percentage of "strongly agreed" or "agreed" answers.RESULTS: A total of 812 complete responses were received from 35 European countries. 21% of respondents felt they belonged to a minority group, mostly based on race/ethnicity (5.9%), nationality (4.8%) and age (4.3%). Compared to benchmark data from the United States, scores were lower for most inclusion factors, and to a greater extent for minority groups. The overall favourable score was 58% for those belonging to a minority group, significantly lower than for other respondents (71%, pCONCLUSIONS: Our work indicates that actions to improve DEI and workforce engagement among RO professionals in Europe are urgently needed, in particular among minority groups. This would potentially improve employee wellbeing and retention, promoting high quality care and innovation.

Background and purpose: Quality of automatic contouring is generally assessed by comparison with manual delineations, but the effect of contour differences on the resulting dose distribution remains unknown. This study evaluated dosimetric differences between treatment plans optimized using various organ-at-risk (OAR) contouring methods. Materials and methods: OARs of twenty lung cancer patients were manually and automatically contoured, after which user-adjustments were made. For each contour set, an automated treatment plan was generated. The dosimetric effect of intra-observer contour variation and the influence of contour variations on treatment plan evaluation and generation were studied using dose-volume histogram (DVH)-parameters for thoracic OARs. Results: Dosimetric effect of intra-observer contour variability was highest for Heart Dmax (3.4 ± 6.8 Gy) and lowest for Lungs-GTV Dmean (0.3 ± 0.4 Gy). The effect of contour variation on treatment plan evaluation was highest for Heart Dmax (6.0 ± 13.4 Gy) and Esophagus Dmax (8.7 ± 17.2 Gy). Dose differences for the various treatment plans, evaluated on the reference (manual) contour, were on average below 1 Gy/1%. For Heart Dmean, higher dose differences were found for overlap with PTV (median 0.2 Gy, 95% 1.7 Gy) vs. no PTV overlap (median 0 Gy, 95% 0.5 Gy). For Dmax-parameters, largest dose difference was found between 0–1 cm distance to PTV (median 1.5 Gy, 95% 4.7 Gy). Conclusion: Dose differences arising from automatic contour variations were of the same magnitude or lower than intra-observer contour variability. For Heart Dmean, we recommend delineation errors to be corrected when the heart overlaps with the PTV. For Dmax-parameters, we recommend checking contours if the distance is close to PTV (

Purpose To demonstrate the feasibility of predicting the patient-specific treatment planning Pareto front (PF) for prostate cancer patients based only on delineations of PTV, rectum and body. Material/methods Our methodology consists of four steps. First, using Erasmus-iCycle, the Pareto fronts of 112 prostate cancer patients were constructed by generating per patient 42 Pareto optimal treatment plans with different priorities. Dose parameters associated to homogeneity, conformity and dose to rectum were extracted. Second, a 3D convex function representing the PF spanned by the 42 plans was fitted for each patient using three patient-specific parameters. Third, ten features were extracted from the, aforementioned, structures to train a linear-regressor prediction algorithm to predict these three patient-specific parameters. Fourth, the quality of the predictions was assessed by calculating the average and maximum distances of the predicted PF to the 42 plans for patients in the validation cohort. Results The prediction model was able to predict the clinically relevant PF within 2 Gy for 90% of the patients with a median average distance of 0.6 Gy. Conclusions We demonstrate the feasibility of fast, accurate predictions of the patient-specific PF for prostate cancer patients based only on delineations of PTV, rectum and body.

Objective: Osteoradionecrosis (ORN) is a severe late complication after radiotherapy but current knowledge on ORN risks in the setting of postoperative radiotherapy (PORT) is limited. We studied the incidence and risk factors of ORN in patients with oral cavity cancers (OCC, treated with PORT.Patients and Methods: A retrospective cohort study was conducted including OCC patients (mainly squamous cell) treated with postoperative intensity modulated radiotherapy between 2010 and 2018 with > 1 year disease-free survival. Cumulative incidences of ORN were computed using the Kaplan Meier method. Clinical and dosimetric risk factors for mandibular ORN were evaluated using Cox regression models.Results: Within our cohort (N = 227, median follow-up 49 months) we observed 46 cases of ORN, mainly in the mandible (n = 41). The cumulative incidence of mandibular ORN was 15.9 % (SE 2.5 %) at three years and 19.8 % (SE 3.0 %) at five years. At univariable analysis, smoking, mandibular mandibulotomy or segment resection, mean dose to the mandible, and mandible volume (%) >= 60 Gy (V60) were significantly associated with increased ORN risks. At multivariable analysis, smoking (HR 2.13, 95 %CI 1.12-4.06) and V60 (HR 1.02 per 1 % increase, 95 %CI 1.01-1.04) remained predictive factors. For active smokers with a high V60 >= 40 % we observed rapid ORN development with a 1-year incidence of 29 % vs 6 % for others (p < 0.01).Conclusion: OCC Patients treated with PORT are at high risk for mandibular ORN. We identified the mandibular volume receiving >= 60 Gy as the dominant risk factor, especially in active smokers. Limiting high-dose volumes at treatment planning may decrease ORN risks.

Background/purpose: To determine the efficacy and toxicity profile of a stereotactic body radiotherapy (SBRT) boost as a first line treatment in patients with oropharyngeal squamous cell carcinoma ...

Purpose: The goal of this study was to generate a large treatment plan database for head and neck (H&N) cancer patients that can be considered as the gold standard to train and validate models for knowledge-based (KB) treatment planning and QA. With this dataset, the intrinsic prediction performance, the effect of interorgan dependency, and the impact of dataset inconsistency was investigated for an existing treatment planning QA model. Methods: The CT scans of 108 previously treated oropharyngeal patients were used to establish the plan database. For each patient, 15 Pareto optimal treatment plans with different planning priorities for the parotid glands were generated with fully automatic multicriterial treatment planning (1620 plans in total). For each of the 15 sets of plans in the database, a KB model was trained with 54 patients and validated on the other 54 by comparing the predictions with the achieved doses. The dose prediction accuracy (predicted—achieved) of the KB models was assessed and compared among the different models to characterize the intrinsic performance and effect of interorgan dependency. In addition, the effect of dataset inconsistency with respect to planning prioritizations was investigated by mixing plans with different prioritizations, for the training, the validation dataset, and for both combined. Results: In the case of a high planning priority, the mean SD of the prediction error for the mean dose of the parotid glands was only 0.2 2.2 Gy, but this increased to 1.0 5.0 Gy in the case that the parotid glands had a low planning priority. Dataset inconsistency (in planning priority) led to a large increase in prediction error for the parotid glands (mean SD) from 0.2 2.2 Gy to 2.8 3.3 Gy, 3.2 5.0 Gy or 0.6 5.4 Gy, depending on the way the datasets were mixed. Conclusions: The generated plan database can be used to validate and characterize KB prediction models for H&N cancer and will be made available upon request. The investigated KB model performed well in case the parotid glands had a high planning priority (little dependence on lower priority OARs), but poorly for organs for which the dose strongly depends on other higher priority OARs. To improve the performance of KB prediction models for H&N cancer, interorgan dependency should be modeled and accounted for. Dataset inconsistency has a large negative impact on the prediction errors of KB models and should be avoided as much as possible.

Purpose: To optimize the diffusion-weighting b values and postprocessing pipeline for hybrid intravoxel incoherent motion diffusion kurtosis imaging in the head and neck region. Methods: Optimized diffusion-weighting b value sets ranging between 5 and 30 b values were constructed by optimizing the Cramér-Rao lower bound of the hybrid intravoxel incoherent motion diffusion kurtosis imaging model. With this model, the perfusion fraction, pseudodiffusion coefficient, diffusion coefficient, and kurtosis were estimated. Sixteen volunteers were scanned with a reference b value set and 3 repeats of the optimized sets, of which 1 with volunteers swallowing on purpose. The effects of (1) b value optimization and number of b values, (2) registration type (none vs. intervolume vs. intra- and intervolume registration), and (3) manual swallowing artifact rejection on the parameter precision were assessed. Results: The SD was higher in the reference set for perfusion fraction, diffusion coefficient, and kurtosis by a factor of 1.7, 1.5, and 2.3 compared to the optimized set, respectively. A smaller SD (factor 0.7) was seen in pseudodiffusion coefficient. The sets containing 15, 20, and 30 b values had comparable repeatability in all parameters, except pseudodiffusion coefficient, for which set size 30 was worse. Equal repeatability for the registration approaches was seen in all parameters of interest. Swallowing artifact rejection removed the bias when present. Conclusion: To achieve optimal hybrid intravoxel incoherent motion diffusion kurtosis imaging in the head and neck region, b value optimization and swallowing artifact image rejection are beneficial. The optimized set of 15 b values yielded the optimal protocol efficiency, with a precision comparable to larger b value sets and a 50% reduction in scan time.

IntroductionThe locoregional failure (LRF) rate in human papilloma virus (HPV)-negative oropharyngeal squamous cell carcinoma (OPSCC) remains disappointingly high and toxicity is substantial. Response prediction prior to or early during treatment would provide opportunities for personalised treatment. Currently, there are no accurate predictive models available for correct OPSCC patient selection. Apparently, the pivotal driving forces that determine how a OPSCC responds to treatment, have yet to be elucidated. Therefore, the holistiC early respOnse assessMent for oroPharyngeaL cancer paTiEnts study focuses on a holistic approach to gain insight in novel potential prognostic biomarkers, acquired before and early during treatment, to predict response to treatment in HPV-negative patients with OPSCC.Methods and analysisThis single-centre prospective observational study investigates 60 HPV-negative patients with OPSCC scheduled for primary radiotherapy (RT) with cisplatin or cetuximab, according to current clinical practice. A holistic approach will be used that aims to map the macroscopic (with Intra Voxel Incoherent Motion Diffusion Kurtosis Imaging (IVIM-DKI); before, during, and 3 months after RT), microscopic (with biopsies of the primary tumour acquired before treatment and irradiated ex vivo to assess radiosensitivity), and molecular landscape (with circulating tumour DNA (ctDNA) analysed before, during and 3 months after treatment). The main end point is locoregional control (LRC) 2 years after treatment. The primary objective is to determine whether a relative change in the mean of the diffusion coefficient D (an IVIM-DKI parameter) in the primary tumour early during treatment, improves the performance of a predictive model consisting of tumour volume only, for 2 years LRC after treatment. The secondary objectives investigate the potential of other IVIM-DKI parameters, ex vivo sensitivity characteristics, ctDNA, and combinations thereof as potential novel prognostic markers.Ethics and disseminationThe study was approved by the Medical Ethical Committee of Erasmus Medical Center. The main results of the trial will be presented in international meetings and medical journals.Trial registration numberNL8458.

Artificial intelligence (AI) has the potential to fundamentally alter the way medicine is practised. AI platforms excel in recognizing complex patterns in medical data and provide a quantitative, rather than purely qualitative, assessment of clinical conditions. Accordingly, AI could have particularly transformative applications in radiation oncology given the multifaceted and highly technical nature of this field of medicine with a heavy reliance on digital data processing and computer software. Indeed, AI has the potential to improve the accuracy, precision, efficiency and overall quality of radiation therapy for patients with cancer. In this Perspective, we first provide a general description of AI methods, followed by a high-level overview of the radiation therapy workflow with discussion of the implications that AI is likely to have on each step of this process. Finally, we describe the challenges associated with the clinical development and implementation of AI platforms in radiation oncology and provide our perspective on how these platforms might change the roles of radiotherapy medical professionals.

ObjectivesKnee osteoarthritis (KOA) progression is frequently monitored by calculating the change in knee joint space width (JSW) measurements. Such differences are small and sensitive to measurement error. We aimed to assess the utility of two alternative statistical modelling methods for monitoring KOA.Material and methodsWe used JSW on radiographs from both the control arm of the Strontium Ranelate Efficacy in Knee Osteoarthritis trial (SEKOIA), a 3-year multicentre, double-blind, placebo-controlled phase three trial, and the Osteoarthritis Initiative (OAI), an open-access longitudinal dataset from the USA comprising participants followed over 8 years. Individual estimates of annualised change obtained from frequentist linear mixed effect (LME) and Bayesian hierarchical modelling, were compared with annualised crude change, and the association of these parameters with change in WOMAC pain was examined.ResultsMean annualised JSW changes were comparable for all estimates, a reduction of around 0.14 mm/y in SEKOIA and 0.08 mm/y in OAI. The standard deviation (SD) of change estimates was lower with LME and Bayesian modelling than crude change (SEKOIA SD = 0.12, 0.12 and 0.21 respectively; OAI SD = 0.08, 0.08 and 0.11 respectively). Estimates from LME and Bayesian modelling were statistically significant predictors of change in pain in SEKOIA (LME P-value = 0.04, Bayes P-value = 0.04), while crude change did not predict change in pain (P-value = 0.10).ConclusionsImplementation of LME or Bayesian modelling in clinical trials and epidemiological studies, would reduce sample sizes by enabling all study participants to be included in analysis regardless of incomplete follow up, and precision of change estimates would improve. They provide increased power to detect associations with other measures.

Purpose Treatment plans manually generated in clinical routine may suffer from variations and inconsistencies in quality. Using such plans for validating a DVH prediction algorithm might obscure its intrinsic prediction accuracy. In this study we used a recently published large database of Pareto-optimal prostate cancer plans to assess the prediction accuracy of a commercial knowledge-based DVH prediction algorithm, RapidPlan. The database plans were consistently generated with automated planning using an independent optimizer, and can be considered as aground truth of plan quality. Methods Prediction models were generated using training sets with 20, 30, 45, 55 and 114 Pareto-optimal plans. Model-20 and Model-30 were built using 5 groups of randomly selected training patients. For 60 independent Pareto-optimal validation plans, predicted and database DVHs were compared. Results For model-114, differences between predicted and database mean doses of more than ± 10% in rectum, anus and bladder, occurred for 23.3%, 55.0%, and 6.7% of the validation plans, respectively. For rectum V65Gy and V75Gy, differences outside the ±10% range were observed in 21.7% and 70.0% of validation plans, respectively. For 61.7% of validation plans, inaccuracies in predicted rectum DVHs resulted in a deviation in predicted NTCP for rectal bleeding outside ±10%. With smaller training sets the DVH prediction performance deteriorated, showing dependence on the selected training patients. Conclusion Even when analysed with Pareto-optimal plans with highly consistent quality, clinically relevant deviations in DVH predictions were observed. Such deviations could potentially result in suboptimal plans for new patients. Further research on DVH prediction models is warranted.

Purpose To prospectively investigate the use of an independent DVH prediction tool to detect outliers in the quality of fully automatically generated treatment plans for prostate cancer patients. Materials/methods A plan QA tool was developed to predict rectum, anus and bladder DVHs, based on overlap volume histograms and principal component analysis (PCA). The tool was trained with 22 automatically generated, clinical plans, and independently validated with 21 plans. Its use was prospectively investigated for 50 new plans by replanning in case of detected outliers. Results For rectum Dmean, V65Gy, V75Gy, anus Dmean, and bladder Dmean, the difference between predicted and achieved was within 0.4 Gy or 0.3% (SD within 1.8 Gy or 1.3%). Thirteen detected outliers were re-planned, leading to moderate but statistically significant improvements (mean, max): rectum Dmean (1.3 Gy, 3.4 Gy), V65Gy (2.7%, 4.2%), anus Dmean (1.6 Gy, 6.9 Gy), and bladder Dmean (1.5 Gy, 5.1 Gy). The rectum V75Gy of the new plans slightly increased (0.2%, p = 0.087). Conclusion A high accuracy DVH prediction tool was developed and used for independent QA of automatically generated plans. In 28% of plans, minor dosimetric deviations were observed that could be improved by plan adjustments. Larger gains are expected for manually generated plans.

With the advent of automatic treatment planning options like Pinnacle's Autoplanning (PAP), the challenge arises how to assess the quality of a plan that no dosimetrist did work on. The aim of this study was to assess plan quality consistency of PAP prostate cancer patients in clinical practice.100 prostate cancer patients were included from NKI and 129 from RadboudUMC (RUMC). Per institute a previously developed [1] treatment planning QA model, based on overlap volume histograms, was trained on PAP plans to predict achievable dose metrics which were then compared to the clinical PAP plans. A threshold of 3 Gy (DVH dose parameters)/3% (DVH volume parameters) was used to detect outliers. For the outlier plans, the PAP technique was adjusted with the aim of meeting the threshold.The average difference between the prediction and the clinically achieved value was0.5 Gy (mean dose parameters) and1.2% (volume parameters), with standard deviation of 1.9 Gy/1.5% respectively. We found 8% (NKI)/25% (RUMC) of patients to exceed the 3 Gy/3% threshold, with deviations up to 6.7 Gy (mean dose rectum) and 6% (rectal wall V64Gy). In all cases the plans could be improved to fall within the thresholds, without compromising the other dose metrics.Independent treatment planning QA was used successfully to assess the quality of clinical PAP in a multi-institutional setting. Respectively 8% and 25% suboptimal clinical PAP plans were detected that all could be improved with replanning. Therefore we recommend the use of independent treatment plan QA in combination with PAP for prostate cancer patients.

IMRT planning with commercial Treatment Planning Systems (TPSs) is a trial-and-error process. Consequently, the quality of treatment plans may not be consistent among patients, planners and institutions. Recently, different plan quality assurance (QA) models have been proposed, that could flag and guide improvement of suboptimal treatment plans. However, the performance of these models was validated using plans that were created using the conventional trail-and-error treatment planning process. Consequently, it is challenging to assess and compare quantitatively the accuracy of different treatment planning QA models. Therefore, we created a golden standard dataset of consistently planned Pareto-optimal IMRT plans for 115 prostate patients. Next, the dataset was used to assess the performance of a treatment planning QA model that uses the overlap volume histogram (OVH). 115 prostate IMRT plans were fully automatically planned using our in-house developed TPS Erasmus-iCycle. An existing OVH model was trained on the plans of 58 of the patients. Next it was applied to predict DVHs of the rectum, bladder and anus of the remaining 57 patients. The predictions were compared with the achieved values of the golden standard plans for the rectum D mean, V 65, and V 75, and D mean of the anus and the bladder. For the rectum, the prediction errors (predicted–achieved) were only −0.2 ± 0.9 Gy (mean ± 1 SD) for D mean,−1.0 ± 1.6% for V 65, and −0.4 ± 1.1% for V 75. For D mean of the anus and the bladder, the prediction error was 0.1 ± 1.6 Gy and 4.8 ± 4.1 Gy, respectively. Increasing the training cohort to 114 patients only led to minor improvements. A dataset of consistently planned Pareto-optimal prostate IMRT plans was generated. This dataset can be used to train new, and validate and compare existing treatment planning QA models, and has been made publicly available. The OVH model was highly accurate in predicting rectum and anus DVHs. For the bladder, larger prediction errors were observed.

Objective Epidemiological and experimental studies have suggested that lipid disorders might be involved in the pathophysiology of knee osteoarthritis (OA). Studies assessing the effect of statins on knee OA progression have shown conflicting results. We investigated the impact of statin use on radiological progression in patients with radiological and symptomatic knee OA. Methods In total, 336 patients from the placebo arm of SEKOIA trial completed the 3-year follow-up and were included in this post-hoc analysis. Statin use was recorded at baseline interview. Minimal medial tibiofemoral joint space was measured on plain radiographs by an automated method at baseline and then annually. Radiologic progression was defined as joint space narrowing ≥ 0.5 mm over 3 years. Results Overall, 71 patients were statin users (21.1%). They had a higher BMI (31.1 ± 5.3 vs. 29.3 ± 5.2 kg/m2, P = 0.008), a higher sum of metabolic factors (≥ 3 factors: 43.7% vs 7.2%; P for trend < 0.001) and a higher rate of radiological progression (49.3% vs. 32.1%, P = 0.007) as compared to statin non-users. The significant association between radiological progression and statin use was independent of age, gender, WOMAC global score, disease duration, baseline joint space width, hypertension, type 2 diabetes, obesity (BMI > 30 kg/m2) and cardiovascular diseases [relative risk 1.49 (95% CI: 1.10–2.02), P = 0.010]. Conclusion Among patients with knee OA, statin use was associated with radiological worsening over 3 years, regardless of other potential confounding factors (obesity, type 2 diabetes, hypertension, disease duration, symptom intensity and radiological severity).

Background: To investigate the location of recurrences with respect to the radiation fields in oropharynx cancer after intensity-modulated radiotherapy and stereotactic body radiotherapy (SBRT) boost. Methods: Local and regional recurrences were delineated on diagnostic scans which were rigidly coregistered with treatment planning scans, then classified based on the location of the center of mass (COM) as well as volumetrically. Results: In 195 patients, the 5-year local and regional control were 90% and 93%, respectively. By COM, 76% of local recurrences were in-field; 24% were out-of-field, significantly higher than 0%-5% in the literature for conventional regimens (P < 0.01). Regional recurrences (19 in 12 patients) were largely within unirradiated neck levels (47%) and electively irradiated regions (42%). Conclusions: The regimen with biological equivalent dose intensification provides excellent overall and in-field local control. The highly conformal boost technique was, however, associated with increased out-of-field local failure.

IF 7.191 (2017); International audience; BACKGROUND:Previous studies showed that high and low body mass index (BMI) was associated with worse prognosis in early-stage colorectal cancer (CRC), and low BMI was associated with worse prognosis in metastatic CRC (mCRC). We aimed to assess efficacy outcomes according to BMI.PATIENTS AND METHODS:A pooled analysis of individual data from 2085 patients enrolled in eight FFCD first-line mCRC trials from 1991 to 2013 was performed. Comparisons were made according to the BMI cut-off: Obese (BMI ≥30), overweight patients (BMI ≥ 25), normal BMI patients (BMI: 18.5-24) and thin patients (BMI

Purpose/objective: To develop a method to predict feasible organ-at-risk (OAR) and tumour dose levels of non-small cell lung cancer (NSCLC) patients prior to the start of treatment planning. Materials/methods: Included were NSCLC patients treated with volumetric modulated arc therapy according to an institutional isotoxic dose-escalation protocol. A training cohort (N = 50) was used to calculate the average dose inside the OARs as a function of the distance to the planning target volume (PTV). These dose-distance relations were used in a validation cohort (N = 39) to predict dose-volume histograms (DVHs) of OARs and PTV as well as the maximum individualized PTV dose escalation. Results: The validation cohort showed that predicted and achieved MLD were in agreement with each other (difference: -0.1 +/- 1.9 Gy, p = 0.81). The spinal cord was dose limiting in only two patients, which was correctly predicted. The achieved mean PTV dose varied from 52 to 73 Gy and was predicted correctly with an accuracy better than 2 Gy (i.e. 1 fraction) for 79% of the patients. Conclusion: We have shown that the MLD and the prescribed PTV dose could be accurately predicted for NSCLC patients. This method can guide the treatment planner to achieve optimal OAR sparing and tumour dose escalation. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

Funding: This meeting was founded by the European Society for Clinical and Economics Aspect of Osteoporosis and Osteoarthritis, a not for profit organization from Belgium. Osteoarthritis (OA), a disease affecting different patient phenotypes, appears as an optimal candidate for personalized healthcare. The aim of the discussions of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) working group was to explore the value of markers of different sources in defining different phenotypes of patients with OA. The ESCEO organized a series of meetings to explore the possibility of identifying patients who would most benefit from treatment for OA, on the basis of recent data and expert opinion. In the first meeting, patient phenotypes were identified according to the number of affected joints, biomechanical factors, and the presence of lesions in the subchondral bone. In the second meeting, summarized in the present article, the working group explored other markers involved in OA. Profiles of patients may be defined according to their level of pain, functional limitation, and presence of coexistent chronic conditions including frailty status. A considerable amount of data suggests that magnetic resonance imaging may also assist in delineating different phenotypes of patients with OA. Among multiple biochemical biomarkers identified, none is sufficiently validated and recognized to identify patients who should be treated. Considerable efforts are also being made to identify genetic and epigenetic factors involved in OA, but results are still limited. The many potential biomarkers that could be used as potential stratifiers are promising, but more research is needed to characterize and qualify the existing biomarkers and to identify new candidates. publishersversion published

Summary Purpose Recent studies have suggested that metabolic factors (obesity, diabetes, hypertension and dyslipidemia) and their clustering in metabolic syndrome (MetS) might be involved in the pathophysiology of knee osteoarthritis (OA). We investigated their impact on radiographic progression by an annualised measure of the joint space narrowing (JSN) of the medial tibiofemoral compartment. Methods 559 patients older than 50 years with symptomatic knee OA were recruited for the placebo arm of the SEKOIA trial. The presence of diabetes, hypertension and dyslipidemia was determined at baseline interview. Body mass index (BMI) was calculated, obesity was considered >30 kg/m 2 . MetS was defined by the sum of metabolic factors ≥3. Minimal medial tibiofemoral joint space on plain radiographs was measured by an automated method at baseline and then annually for up to 3 years. Results The mean age of patients was 62.8 [62.2–63.4] years; 392 were women. A total of 43.8% was obese, 6.6% had type 2 diabetes, 45.1% hypertension, 27.6% dyslipidemia and 13.6% MetS. Mean annualised JSN was greater for patients with type 2 diabetes than without diabetes (0.26 [−0.35 to −0.17] vs 0.14 [−0.16 to −0.12] mm; P = 0.001). This association remained significant after adjustment for sex, age, BMI, hypertension and dyslipidemia ( P = 0.018). In subgroup analysis, type 2 diabetes was a significant predictor of JSN in males but not females. The other metabolic factors and MetS were not associated with annualised JSN. Conclusion Type 2 diabetes was a predictor of joint space reduction in men with established knee OA. No relationships were found between MetS or other metabolic factors and radiographic progression.

Background: Proton therapy is becoming increasingly available, so it is important to apply objective and individualized patient selection to identify those who are expected to benefit most from proton therapy compared to conventional intensity modulated radiation therapy (IMRT). Comparative treatment planning using normal tissue complication probability (NTCP) evaluation has recently been proposed. This work investigates the impact of NTCP model and dose uncertainties on model-based patient selection. Material and Methods: We used IMRT and intensity modulated proton therapy (IMPT) treatment plans of 78 oropharyngeal cancer patients, which were generated based on automated treatment planning and evaluated based on three published NTCP models. A reduction in NTCP of more than a certain threshold (e.g. 10% lower NTCP) leads to patient selection for IMPT, referred to as ‘nominal’ selection. To simulate the effect of uncertainties in NTCP-model coefficients (based on reported confidence intervals) and planned doses on the accuracy of model-based patient selection, the Monte Carlo method was used to sample NTCP-model coefficients and doses from a probability distribution centered at their nominal values. Patient selection accuracy within a certain sample was defined as the fraction of patients which had similar selection in both the ‘nominal’ and ‘sampled’ scenario. Results: For all three NTCP models, the median patient selection accuracy was found to be above 70% when only NTCP-model uncertainty was considered. Selection accuracy decreased with increasing uncertainty resulting from differences between planned and delivered dose. In case of excessive dose uncertainty, selection accuracy decreased to 60%. Conclusion: Model and dose uncertainty highly influence the accuracy of model-based patient selection for proton therapy. A reduction of NTCP-model uncertainty is necessary to reach more accurate model-based patient selection.

Purpose: To assess the accumulated dose and the toxicity after reirradiation for tumors in the lung using non-rigid registration. Material and methods: Twenty patients with a tumor in the lung were reirradiated with or after stereotactic radiotherapy. The summed dose distribution was calculated using non-rigid registration. All doses were recalculated to an equivalent dose of 2 Gy per fraction (EQD2). The median follow-up time was 12 months (range 2-52). Results: The median D-max of the lung in the summed plans was 363 Gy(3) (range 123-590). The median accumulated V20 of the lungs was 15.2%. Seven patients had in the heart and the trachea an accumulated dose >= 70 Gy(3), with a median D-max of the heart of 115 Gy(3) and 89 Gy(3) for the trachea. Eight patients had in the esophagus an accumulated dose >= 70 Gy(3), with a median accumulated dose of 85 Gy(3). No grade 3-5 toxicity was observed. Conclusion: Reirradiation of the lung with or after stereotactic radiotherapy is feasible to a median D-max of 363 Gy(3) to the lung, as low toxicity was observed. (c) 2013 Elsevier Ireland Ltd. All rights reserved.

International audience; Microarray-based comparative genomic hybridization (aCGH) is commonly used in diagnosing patients with intellectual disability (ID) with or without congenital malformation. Because aCGH interrogates with the whole genome, there is a risk of being confronted with incidental findings (IF). In order to anticipate the ethical issues of IF with the generalization of new genome-wide analysis technologies, we questioned French clinicians and cytogeneticists about the situations they have faced regarding IF from aCGH. Sixty-five IF were reported. Forty corresponded to autosomal dominant diseases with incomplete penetrance, 7 to autosomal dominant diseases with complete penetrance, 14 to X-linked diseases, and 4 were heterozygotes for autosomal recessive diseases with a high prevalence of heterozygotes in the population. Therapeutic/preventive measures or genetic counselling could be argued for all cases except four. These four IF were intentionally not returned to the patients. Clinicians reported difficulties in returning the results in 29% of the cases, mainly when the question of IF had not been anticipated. Indeed, at the time of the investigation, only 48% of the clinicians used consents mentioning the risk of IF. With the emergence of new technologies, there is a need to report such national experiences; they show the importance of pre-test information on IF.

SummaryBackground We have encountered repeated cases of recessive lethal generalized severe (Herlitz-type) junctional epidermolysis bullosa (JEB gen sev) in infants born to Hungarian Roma parents residing in a small region of Hungary. Objectives To identify the disease-causing mutation and to investigate the genetic background of its unique carrier group. Methods The LAMB3 gene was analysed in peripheral-blood genomic DNA samples, and the pathological consequences of the lethal defect were confirmed by cutaneous LAMB3cDNA sequencing. A median joining haplotype network within the Y chromosome H1a-M82 haplogroup of individuals from the community was constructed, and LAMB3 single-nucleotide polymorphism (SNP) patterns were also determined. Results An unconventional intronic splice-site mutation (LAMB3, c.1133–22G>A) was identified. Thirty of 64 voluntarily screened Roma from the closed community carried the mutation, but none of the 306 Roma from other regions of the country did. The age of the mutation was estimated to be 548 ± 222 years. Within the last year, more patients with JEB gen sev carrying the same unusual mutation have been identified in three unrelated families, all immigrants from the Balkans. Two were compound heterozygous newborns, in Germany and Italy, and one homozygous newborn died in France. Only the French family recognized their Roma background. LAMB3SNP haplotyping confirmed the link between the apparently unrelated Hungarian, German and Italian male cases, but could not verify the same background in the female newborn from France. Conclusions The estimated age of the mutation corresponds to the time period when Roma were wandering in the Balkans.

International audience; BACKGROUND:Metastatic colorectal cancer (mCRC) frequently occurs in elderly patients. However, data from a geriatric tailored randomized trial about tolerance to and the efficacy of doublet chemotherapy (CT) with irinotecan in the elderly are lacking. The benefit of first-line CT intensification remains an issue in elderly patients.PATIENTS AND METHODS:Elderly patients (75+) with previously untreated mCRC were randomly assigned in a 2 × 2 factorial design (four arms) to receive 5-FU (5-fluorouracil)-based CT, either alone (FU: LV5FU2 or simplified LV5FU2) or in combination with irinotecan [IRI: LV5FU2-irinotecan or simplified LV5FU2-irinotecan (FOLFIRI)]. The CLASSIC arm was defined as LV5FU2 or LV5FU2-irinotecan and the SIMPLIFIED arm as simplified LV5FU2 or FOLFIRI. The primary end point was progression-free survival (PFS). Secondary end points were overall survival (OS), safety and objective response rate (ORR).RESULTS:From June 2003 to May 2010, 71 patients were randomly assigned to LV5FU2, 71 to simplified LV5FU2, 70 to LV5FU2-irinotecan and 70 to FOLFIRI. The median age was 80 years (range 75-92 years). No significant difference was observed for the median PFS: FU 5.2 months versus IRI 7.3 months, hazard ratio (HR) = 0.84 (0.66-1.07), P = 0.15 and CLASSIC 6.5 months versus SIMPLIFIED 6.0 months, HR = 0.85 (0.67-1.09), P = 0.19. The ORR was superior in IRI (P = 0.0003): FU 21.1% versus IRI 41.7% and in CLASSIC (P = 0.04): CLASSIC 37.1% versus SIMPLIFIED 25.6%. Median OS was 14.2 months in FU versus 13.3 months in IRI, HR = 0.96 (0.75-1.24) and 15.2 months in CLASSIC versus 11.4 months in SIMPLIFIED, HR = 0.71 (0.55-0.92). More patients presented grade 3-4 toxicities in IRI (52.2% versus 76.3%).CONCLUSION:In this elderly population, adding irinotecan to an infusional 5-FU-based CT did not significantly increase either PFS or OS. Classic LV5FU2 was associated with an improved OS compared with simplified LV5FU2.CLINICALTRIALSGOV:NCT00303771.

Purpose To develop a model to assess the quality of an IMRT treatment plan using data of prior patients with pancreatic adenocarcinoma. Methods The dose to an organ at risk (OAR) depends in large part on its orientation and distance to the planning target volume (PTV). A database of 33 previously treated patients with pancreatic cancer was queried to find patients with less favorable PTV-OAR configuration than a new case. The minimal achieved dose among the selected patients should also be achievable for the OAR of the new case. This way the achievable doses to the OARs of 25 randomly selected pancreas cancer patients were predicted. The patients were replanned to verify if the predicted dose could be achieved. The new plans were compared to their original clinical plans. Results The predicted doses were achieved within 1 and 2 Gy for more than 82% and 94% of the patients, respectively, and were a good approximation of the minimal achievable doses. The improvement after replanning was 1.4 Gy (range 0–4.6 Gy) and 1.7 Gy (range 0–6.3 Gy) for the mean dose to the liver and the kidneys, respectively, without compromising target coverage or increasing radiation dose to the bowel, cord or stomach. Conclusions The model could accurately predict the achievable doses, leading to a considerable decrease in dose to the OARs and an increase in treatment planning efficiency.

Introduction Acute dysphagia is a distressing dose-limiting toxicity occurring frequently during concurrent chemo-radiation or high-dose radiotherapy for lung cancer. It can lead to treatment interruptions and thus jeopardize survival. Although a number of predictive factors have been identified, it is still not clear how these could offer assistance for treatment decision making in daily clinical practice. Therefore, we have developed and validated a nomogram to predict this side-effect. In addition, clinical usefulness was assessed by comparing model predictions to physicians' predictions. Materials and methods Clinical data from 469 inoperable lung cancer patients, treated with curative intent, were collected prospectively. A prediction model for acute radiation-induced dysphagia was developed. Model performance was evaluated by the c-statistic and assessed using bootstrapping as well as two external datasets. In addition, a prospective study was conducted comparing model to physicians' predictions in 138 patients. Results The final multivariate model consisted of age, gender, WHO performance status, mean esophageal dose (MED), maximum esophageal dose (MAXED) and overall treatment time (OTT). The c-statistic, assessed by bootstrapping, was 0.77. External validation yielded an AUC of 0.94 on the Ghent data and 0.77 on the Washington University St. Louis data for dysphagia⩾grade 3. Comparing model predictions to the physicians' predictions resulted in an AUC of 0.75 versus 0.53, respectively. Conclusions The proposed model performed well was successfully validated and demonstrated the ability to predict acute severe dysphagia remarkably better than the physicians. Therefore, this model could be used in clinical practice to identify patients at high or low risk.

Purpose: To correct megavoltage cone-beam CT (MVCBCT) images of the thorax and abdomen for cupping and truncation artefacts to reconstruct the 3D-delivered dose distribution for treatment evaluation. Materials and methods: MVCBCT scans of three phantoms, three lung and two rectal cancer patients were acquired. The cone-beam projection images were iteratively corrected for cupping and truncation artefacts and the resulting primary transmission was used for cone-beam reconstruction. The reconstructed scans were merged into the planning CT scan (MVCBCT+). Dose distributions of clinical IMRT, stereotactic and conformal treatment plans were recalculated on the uncorrected and corrected MVCBCT+ scans using the treatment planning system and compared to the planned dose distribution. Results: The dose distributions on the corrected MVCBCT+ of the phantoms were accurate for 99% of the voxels within 2% or 2 mm. Using this method the errors in mean GTV dose reduced from about 10% to 1% for the patients. Conclusions: The method corrects cupping and truncation artefacts in cone-beam scans of the thorax and abdomen in addition to head-and-neck (demonstrated previously). The corrected scans can be used to calculate the influence of anatomical changes on the 3D-delivered dose distribution.

During limb development, the spatio-temporal expression of sonic hedgehog (SHH) is driven by the Zone of polarizing activity Regulatory Sequence (ZRS), located 1 megabase upstream from SHH. Gain-of-function mutations of this enhancer, which cause ectopic expression of SHH, are known to be responsible for congenital limb malformations with variable expressivity, ranging from preaxial polydactyly or triphalangeal thumbs to polysyndactyly, which may also be associated with mesomelic deficiency. In this report, we describe a patient affected with mirror-image polydactyly of the four extremities and bilateral tibial deficiency. The proband's father had isolated preaxial polydactyly type II (PPD2). Using Sanger sequencing, a ZRS point mutation (NC_000007.14, g.156584153AG, UCSC, Build hg.19) was only identified in the patient. However, pyrosequencing analysis enabled the detection of a 10% somatic mosaic in the blood and saliva from the father. To our knowledge, this is the first description of a ZRS mosaic mutation. This report highlights the complexity of genotype-phenotype correlation in ZRS-associated syndromes and the importance of detecting somatic mosaicism for accurate genetic counselling.

In a 12-year old girl suffering from autosomal recessive axonal Charcot-Marie-Tooth (CMT) neuropathy, pes cavovarus was treated with botulinum toxin injection in the tibialis posterior. The patient underwent a clinical evaluation, video analysis of spatiotemporal gait parameters and dynamic foot plantar pressure assessment before treatment and then two weeks, three months and six months thereafter. The video gait analysis revealed a decrease in varus during the swing phase of gait. The dynamic foot plantar pressure decreased by 50% in the excessive pressure at the side of the foot six months after the injection (maximal pressure=42.6N/cm2 before treatment and 18.9 N/cm2 after 6 month). Botulinum toxin injection appears to be an efficacious means of correcting pes cavovarus in CMT disease. A larger-scale clinical trial is now required to evaluate the putative longer-term preventive effect of this treatment on the pes cavus deformity.

Trimegestone is a novel norpregnane progestin that is being developed, in combination with estradiol, for the treatment of menopausal symptoms. The pharmacological characteristics of trimegestone have been evaluated in both in vitro and in vivo test systems, and compared with reference progestins. Interaction with hormonal steroid receptors from animal tissues and with human recombinant receptors in vitro has demonstrated that trimegestone has a high specificity and potency for the progesterone receptor, no affinity for the estrogen receptor, and weak affinity for androgen, glucocorticoid and mineralocorticoid receptors. With respect to progestomimetic activity in vivo, trimegestone was more potent than reference progestins in the endometrial transformation test in the rabbit, preventing the uterotrophic effect of estradiol in the immature mouse bioassay, and had more effect on traumatic deciduoma formation and greater oral antiovulatory activity in the rat. In vivo, trimegestone effectively maintained pregnancy in the rat, but was devoid of any uterotrophic activity. Trimegestone showed no androgenic, glucocorticoid, antiglucocorticoid or mineralocorticoid activity, but did show some antiandrogenic and antimineralocorticoid activity at higher doses. Administration of trimegestone to ovariectomized rats, in combination with estradiol, inhibited the uterotrophic effects of estradiol. At doses up to 1 mg/kg intravenously and 30 mg/kg orally, trimegestone was not associated with any unwanted pharmacological effects. Overall, the results show trimegestone to have a favorable pharmacological profile with potent progestomimetic activity.

The accuracy of intensity modulated proton therapy (IMPT) is sensitive to range uncertainties. Geometric margins, as dosimetric surrogates, are ineffective and robust optimization strategies are needed. These, however, lead to increased normal tissue dose. We explore here how this dose increase can be reduced by increasing the maximum tumor dose instead. We focus on range uncertainties, modeled by scaling the stopping powers 5% up (undershoot) or down (overshoot) compared to the nominal scenario. Robust optimization optimizes for target dose conformity in the most likely scenario, not the worst, while constraining target coverage for the worst-case scenario. Non-robust plans are also generated. Different maximum target doses are applied (105% versus 120% versus 140%) to investigate the effect on normal tissue dose reduction. The method is tested on a homogeneous and a lung phantom and on a liver patient. Target D99 of the robust plans equals the prescription dose of 60 GyE(4) for all scenarios, but decreases to 36 GyE for the non-robust plans. The mean normal tissue dose in a 2 cm ring around the target is 11% to 31% higher for the robust plans. This increase can be reduced to -8% and 3% (compared to the non-robust plan) by allowing a maximum tumor dose of 120% instead of 105%. Thus robustness leads to more normal tissue dose, but it can be compensated by allowing a higher maximum tumor dose.

Congenital diaphragmatic hernia has a physiopathology unfully understood, and is the cause of an important morbimortality. We report the case of a fetus suffering from a diaphragmatic hernia associated with a EDNRA gene triplication, coding for the endothelin 1 receptor. High-resolution genetic techniques were able to find the possible origin of this pathology, and showed that it was an isolated form with a good prognostic. ET-A receptor over-expression in lung vessels may cause a vascular remodeling and a lung arterial high blood pressure. This lung abnormality would have occurred before the diaphragmatic defect.

Nager syndrome belongs to the group of acrofacial dysostosis, which are characterized by the association of craniofacial and limb malformations. Recently, exome sequencing studies identified the SF3B4 gene as the cause of this condition in most patients. SF3B4 encodes a highly conserved protein implicated in mRNA splicing and bone morphogenic protein (BMP) signaling. We performed SF3B4 sequencing in 14 families (18 patients) whose features were suggestive of Nager syndrome and found nine mutations predicted to result in loss-of-function. SF3B4 is the major gene responsible for autosomal dominant Nager syndrome. All mutations reported predict null alleles, therefore precluding genotype-phenotype correlations. Most mutation-negative patients were phenotypically indistinguishable from patients with mutations, suggesting genetic heterogeneity.

Split hand/foot malformation (SHFM) with long-bone deficiency (SHFLD, MIM#119100) is a rare condition characterized by SHFM associated with long-bone malformation usually involving the tibia. Previous published data reported several unrelated patients with 17p13.3 duplication and SHFLD. Recently, the minimal critical region had been reduced, suggesting that BHLHA9 copy number gains are associated with this limb defect. Here, we report on 13 new families presenting with ectrodactyly and harboring a BHLHA9 duplication.

A novel model of the titanium Rotterdam tandem and ovoid applicator is presented. As titanium produces artefacts in MR images, an MR sequence was sought and optimised for visualisation and accurate applicator reconstruction. The mean inter-observer (8 observers) variability for four patients was only 0.7 mm (maximum 1.7 mm).

Background and purpose: To predict the lowest achievable rectum 035 for quality assurance of IMRT plans of prostate cancer patients. Materials and methods: For each of 24 patients from a database of 47 previously treated patients, the anatomy was compared to the anatomies of the other 46 to predict the minimal achievable rectum D35. The 24 patients were then replanned to obtain maximally reduced rectum D35. Next, the newly derived plans were added to the database to replace the original clinical plans, and new predictions of the lowest achievable rectum D35 were made. Results: After replanning, the rectum D35 reduced by 9.3 Gy +/- 6.1 (average +/- 1 SD; p < 0.001) compared to the original plan. The first predictions of the rectum D35 were 4.8 Gy +/- 4.2 (average +/- 1 SD; p < 0.001) too high when evaluated with the new plans. After updating the database, the replanned and newly predicted rectum D35 agreed within 0.1 Gy +/- 2.8 (average +/- 1 SD; p = 0.89). The doses to the bladder, anus and femoral heads did not increase compared to the original plans. Conclusions: For individual prostate patients, the lowest achievable rectum D35 in IMRT planning can be accurately predicted from dose distributions of previously treated patients by quantitative comparison of patient anatomies. These predictions can be used to quantitatively assess the quality of IMRT plans. (c) 2013 Elsevier Ireland Ltd. All rights reserved.

To elaborate and validate in general population a survey built with self-administered questionnaires in French about evaluation of sexual health for an application to men and women with metabolic disease.Study built with four questionnaires (socio-familial environment [MSPSS scale], self-esteem [Rosenberg scale], anxiety and depression scale [Sigmund and Snaith scale], and male [BISF-M] or female [BISF-W] sexuality) translated in French and distributed to 232 men and 260 women.Hundred and eleven men aged 18 to 56 years and 142 women aged 20 to 60 years answered the self-administered questionnaire. Analysis showed several links between self-esteem, anxiety and depression and the different domains of male sexuality, justifying their association. Comparison between men and women confirmed the differences of sexual approach between the two sexes.Results in our population were concordant with those already reported in literature, indicating the validity and the reliability of our questionnaire and its multiparametric approach. Data obtained in this population will allow to use this multiparametric tool with patients affected by a metabolic disease.

Muscle phosphofructokinase deficiency, the seventh member of the glycogen storage diseases family, is also called Tarui's disease (GSD VII).We studied two patients in two unrelated families with Tarui's disease, analyzing clinical features, CK level, EMG, muscle biopsy findings and molecular genetics features. Metabolic muscle explorations (forearm ischemic exercise test [FIET]; bicycle ergometer exercise test [EE]; 31P-nuclear magnetic resonance spectroscopy of calf muscle [31P-NMR-S]) are performed as appropriate.Two patients, a 47-year-old man and a 38-year-old woman, complained of exercise-induced fatigue since childhood. The neurological examination was normal or showed light weakness. Laboratory studies showed increased CPK, serum uric acid and reticulocyte count without anemia. There was no increase in the blood lactate level during the FIET or the EE although there was a light increase in the respiratory exchange ratio during the EE. 31P-NMR-S revealed no intracellular acidification or accumulated intermediates such as phosphorylated monoesters (PME) known to be pathognomic for GSD VII. Two new mutations were identified.FIET and EE were non-contributive to diagnosis, but 31P-NMR provided a characteristic spectra of Tarui's disease, in agreement with phosphofructokinase activity level in erythrocytes. Muscle biopsy does not always provide useful information for diagnosis. In these two cases, genetic studies failed to establish a genotype-phenotype correlation.The search for phosphofructokinase deficiency should be continued throughout life in adults experiencing fatigability or weakness because of the severe disability for daily life activities caused by the late onset form.

Tuberous sclerosis complex is a genetic multisystem disease characterized by hamartic development of many organs, most notably the brain, heart, kidneys, lungs, and skin. This autosomic dominant disorder results from mutations in one of two genes, TSC1 and TSC2, coding for hamartin and tuberin, respectively. The hamartin-tuberin complex inhibits the mammalian target of rapamycin pathway, which controls cell growth and proliferation. The clinical presentation is highly variable and most features of tuberous sclerosis become evident only in childhood after the child is several years of age, limiting their usefulness for early diagnosis. The aim of this article is to define the pediatric clinical manifestations of tuberous sclerosis in correlation with patient age. Sometimes, a prenatal diagnosis can be made based on fetal ultrasound and MRI, which show cardiac and brain lesions. However, newborns are most often asymptomatic. In the 1st year, seizures are the most common symptoms, with a high incidence of infantile spasms. In children between 2 and 10 years of age, neurological symptoms are the most frequent with epilepsy, mental retardation, and autism, but extraneurological manifestations can be diagnosed. In adolescents, most features of tuberous sclerosis become evident and renal and pulmonary manifestations must be sought. The knowledge of age-dependent clinical features of tuberous sclerosis can provide an earlier diagnosis and improve the management of these patients with a special role for multidisciplinary consultation.

In 1986, a national survey was carried out in France among 4846 drug abusers attending specialised agencies and treatment centres. Data are analysed and compared with the results of a previous study in 1972. Most French drug abusers are men (74%) ranged in age from 20 to 29 years (68%). Data suggest increasing problems with heroin (69%), cocaine (13%), solvents (5%), alcohol (26%) and multiple drug dependence. Women are younger, they have attempted suicide more often than men but have been incarcerated half as often. Concerning drug abuse trends, women appear to use increasingly sedatives in combination with other drugs. Partial data concerning HIV seropositivity reveal a rate of 48% among drug abusers having been tested.

Purpose To characterize the relationship between pre-radiotherapy 18Fluorodeoxyglucose (FDG) uptake in a tumour voxel, radiation dose and the probability to achieve metabolic control in the tumour voxel after radiotherapy. Materials and methods Thirty-nine patients with inoperable stage I-III non-small cell lung cancer, treated with radiotherapy (RT) alone or sequential chemo radiation were analysed retrospectively. Twenty-two showed metabolic active areas in the tumour 3 months post-radiotherapy, which is known to be a surrogate for persistent local tumour failure and worse survival. Pre- and post-RT FDG-PET-CT scans were registered and the metabolic active zones within the tumour after RT were projected on the pre-RT scan. Multi-level logistic regression was performed to determine the relation between the FDG uptake if a voxel pre-RT and its metabolic state after RT. Results The probability that a voxel is metabolically controlled (mVCP), decreased significantly with increasing FDG uptake in a voxel (SUV) (OR = 0.72), increasing tumour volume (20 cm3) (OR = 0.89) and increasing dose (Gy) (OR = 0.99). Inter-patient differences in mVCP were substantial. Conclusion A methodology was presented to derive relationships between FDG uptake, dose and metabolic control. Although no strong dose effect relation was demonstrated, mVCP decreased with increasing FDG uptake and tumour volume.

French medical demography is a true public health issue. The medicine doctor's scarcity announced by many will not appear for the plastic surgeons. In this speciality, problems are an excess staff and irregular sharing out. The aim of the study was to make a very sharp update of the speciality thanks to an actual demographic descriptive and analytic study compared with the one realised in 1998 including a French plastic surgeon's activity study. In 2007, there were 889 plastic surgeons in France, so 235 surgeons more than in 1998 and an average of 26 new plastic surgeons a year. The plastic surgeon's density was 1 for 71,174 people, much more important than the recommended value. The distribution of these surgeons is still unequal and the excess staff is getting worse. The plastic surgeon's activity study based on the Information System Medicalisation Program (ISMP) between 2004 and 2006, including 13 classic plastic surgery's procedures, showed an important decrease of the activity especially for the private sector. The analytic study put together the data concerning the demography and the activity considering the economic side of esthetic surgery. Thanks to these data, plastic surgeons will now be able to choose their working area not only based on geographic reasons but also depending on the activity they want and on the importance of the competition. This work stands for a help for plastic surgeons, in the hope of a fair sharing out of these practioners.

Sturge-Weber syndrome is a neurocutaneous disease associating facial and pial angioma. Focal epilepsy is a common sign. In a few cases, generalized seizures have been reported.We report on a four-year-old girl with Sturge-Weber syndrome. The first focal seizures occurred at three years of age. She developed refractory status epilepticus. At discharge from the PICU, she was on a ketogenic diet and received three antiepileptic drugs. No seizures were observed for four months. The patient then developed several types of seizures: myoclonic seizures, focal clonic seizures, and sudden falls. We were unable to determine the etiology of the falls. Typical myoclonic astatic seizures were identified on video-electroencephalographic recordings.Seizures in Sturge-Weber syndrome are usually focal. Four patients with Sturge-Weber syndrome and myoclonoastatic seizures are reported in the literature. We discuss the pathophysiological mechanisms leading from a focal lesion to generalized myoclonoastatic seizures.

We report three patients (respectively 36, 52 and 52 years old) with a long history of hidradenitis suppurativa associated with pubic lymph oedema.Dramatic pubic oedema was noted, with "rugby-ball and bag-like" tumefaction associated with nodules and fistula. There was no evidence of lymph node involvement or abdominal lymphatic blockade. One patient underwent surgical excision combined with split-thickness graft and complete healing ensued. Pathological examination of the excised tissue showed telangiectasia and fibrosis.Chronic lymphedema affects patients with severe and long-lasting disease. The complication is caused by chronic and recurrent inflammation due to HS with subsequent blockade or destruction of local lymph drainage routes. Once this complication appears, no medical treatment is effective.

Hand and composite tissue allotransplantation (CTA) holds great potential for reconstructive surgery but its development is currently limited by the side effects of the immunosuppressive drugs. Induction of specific tolerance, a situation where the recipient does not mount an immune response against the allograft but remains fully immunocompetent, holds exciting promise. Generation of mixed hematopoietic chimerism by infusing the recipient with donor bone marrow cells has been shown to induce tolerance without chronic immunosuppression. Genetic matching of the donor and the recipient is another option for transplanting composite tissues with only an initial course of immunosuppression. Experiments demonstrated long-term survival of musculoskeletal allografts between MHC-matched miniature swine. Finally, new immunosuppressive agents with a more targeted action will reduce side effects and may prevent the development of chronic rejection. Skin-specific immunosuppression is particularly useful for limb transplants since skin, regarded as the most antigenic component, is easily accessible to topical or irradiation therapies.