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Abstract Background Concomitant chemo-radiotherapy is the reference treatment for non-resectable locally-advanced Non-Small Cell Lung Cancer (NSCLC). Increasing radiotherapy total dose in the whole tumour volume has been shown to be deleterious. Functional imaging with positron emission tomography (PET/CT) offers the potential to identify smaller and biologically meaningful target volumes that could be irradiated with larger doses without compromising Organs At Risk (OAR) tolerance. This study investigated four scenarios, based on 18FDG and 18F-miso PET/CT, to delineate the target volumes and derive radiotherapy plans delivering up to 74Gy. Method Twenty-one NSCLC patients, selected from a prospective phase II trial, had 18FDG- and 18F-miso PET/CT before the start of radiotherapy and 18FDG PET/CT during the radiotherapy (42Gy). The plans were based planned on a standard plan delivering 66 Gy (plan 1) and on three different boost strategies to deliver 74Gy total dose in pre-treatment 18FDG hotspot (70% of SUVmax) (plan 2), pre-treatment 18F-miso target (SUVmax > 1.4) (plan 3) and per-treatment 18FDG residual (40% of SUVmax). (plan 4). Results The mean target volumes were 4.8 cc (± 1.1) for 18FDG hotspot, 38.9 cc (± 14.5) for 18F-miso and 36.0 cc (± 10.1) for per-treatment 18FDG. In standard plan (66 Gy), the mean dose covering 95% of the PTV (D95%) were 66.5 (± 0.33), 66.1 (± 0.32) and 66.1 (± 0.32) Gy for 18FDG hotspot, 18F-miso and per-treatment 18FDG. In scenario 2, the mean D95% was 72.5 (± 0.25) Gy in 18FDG hotspot versus 67.9 (± 0.49) and 67.9 Gy (± 0.52) in 18F-miso and per-treatment 18FDG, respectively. In scenario 3, the mean D95% was 72.2 (± 0.27) Gy to 18F-miso versus 70.4 (± 0.74) and 69.5Gy (± 0.74) for 18FDG hotspot and per-treatment 18FDG, respectively. In scenario 4, the mean D95% was 73.1 (± 0.3) Gy to 18FDG per-treatment versus 71.9 (± 0.61) and 69.8 (± 0.61) Gy for 18FDG hotspot and 18F-miso, respectively. The dose/volume constraints to OARs were matched in all scenarios. Conclusion Escalated doses can be selectively planned in NSCLC target volumes delineated on 18FDG and 18F-miso PET/CT functional images. The most relevant strategy should be investigated in clinical trials. Trial registration (RTEP5, NCT01576796, registered 15 june 2012)

L'optimisation de l'exploitation des gisements d'hydrocarbures est devenue aujourd'hui,avec la grave crise énergétique que nous traversons, le problème numéro un du mondepétrolier. Afin d'améliorer la production on est obligé de mettre en ceuvre des techniques derécupération assistée qui coûtent très cher et dont le choix est basé sur les propriétés physiques du pétrole, de la roche réservoir et l'état d'exploitation même du gisement.Nous avons donc étudié le comportement volumétrique et viscosimétrique de la fraction lourde d'hydrocarbures ainsi que la mise au point d'une technique d'analyse de cette fraction. Nos mesures ont porté essentiellement sur les corps purs suivants : nCe, nC, nC, nC9, nClo, nC12, nC14, nCls, cyclo Ce, cyclo C" cyclo Cs, méthyl cyclo Cg, benzène, toluène, xylène et triméthylbenzène dans un domaine de température et de pression s'étendant de 20 à 120 °C et de la pression atmosphérique à 400 bars.A partir de ces données expérimentales nous avons développé deux modèles prévisionnels : l'un pour la masse volumique des mélanges basé sur l'équation d'état de Redlich-Kwong et l'introduction de coefficients d'interaction binaire, l'autre sur les viscosités des mélanges à partir d'une équation d'Andrade modi-fiée et de la loi de mélange d'Arrhénius. The principal problem facing the petroleum industry during the present severe energy crisis is ta optimise production from hydrocarbon fields. In order to improve production, enhanced recovery techniques must be used. These are extremely expensive and are chosen on the basis of physical properties of the ail, the réservoir rocks and working conditions of the field. The volumetric and viscometric behovior of the heavy hydrocarbon fraction was therefore studied. A technique for analyzing this fraction was also developed. M~asurements essentially concerned the following pure substances : nC, nC, nC, nC, nC1e,nC,,, nC14,nC18, cyclo C,,cycloC,, cyclo Ce, methyl cycIo Cs, benzène, toluene, xylene and trimethylbenzene in temoerature and pressure range from 20 ta 120' C and from on aimospheric pressure to 440 bars. of state and the introduction of binary interaction coefficients, and the other concerned the viscosities of the mixtures on the basis of a modified Andrade equation and the Arrhenius mixing rule.

BackgroundPerioperative anaphylaxis is a rare and acute systemic manifestation of drug-induced hypersensitivity reactions that occurs following anesthesia induction; the two main classes of drugs responsible for these reactions being neuromuscular blocking agents (NMBA) and antibiotics. The sensitization mechanisms to the drugs are not precisely known, and few risk factors have been described. A growing body of evidence underlines a link between occurrence of allergy and microbiota composition. However, no data exist on microbiota in perioperative anaphylaxis. The aim of this study was to compare circulating microbiota richness and composition between perioperative anaphylaxis patients and matched controls.MethodsCirculating 16s rDNA was quantified and sequenced in serum samples from 20 individuals with fully characterized IgE-mediated NMBA-related anaphylaxis and 20 controls matched on sex, age, NMBA received, type of surgery and infectious status. Microbiota composition was analyzed with a published bioinformatic pipeline and links with patients clinical and biological data investigated.ResultsAnalysis of microbiota diversity showed that anaphylaxis patients seem to have a richer circulating microbiota than controls, but no major differences of composition could be detected with global diversity indexes. Pairwise comparison showed a difference in relative abundance between patients and controls for Saprospiraceae, Enterobacteriaceae, Veillonellaceae, Escherichia-Shigella, Pseudarcicella, Rhodoferax, and Lewinella. Some taxa were associated with concentrations of mast cell tryptase and specific IgE.ConclusionWe did not find a global difference in terms of microbiota composition between anaphylaxis patient and controls. However, several taxa were associated with anaphylaxis patients and with their biological data. These findings must be further confirmed in different settings to broaden our understanding of drug anaphylaxis pathophysiology and identify predisposition markers.

Abstract Purpose To determine the impact of the Bayesian penalized likelihood (BPL) reconstruction algorithm in comparison to OSEM on hypoxia PET/CT images of NSCLC using 18F-MIZO and 18F-FAZA. Materials and methods Images of low-contrasted (SBR = 3) micro-spheres of Jaszczak phantom were acquired. Twenty patients with lung neoplasia were included. Each patient benefitted from 18F-MISO and/or 18F-FAZA PET/CT exams, reconstructed with OSEM and BPL. Lesion was considered as hypoxic if the lesion SUVmax > 1.4. A blind evaluation of lesion detectability and image quality was performed on a set of 78 randomized BPL and OSEM images by 10 nuclear physicians. SUVmax, SUVmean, and hypoxic volumes using 3 thresholding approaches were measured and compared for each reconstruction. Results The phantom and patient datasets showed a significant increase of quantitative parameters using BPL compared to OSEM but had no impact on detectability. The optimal beta parameter determined by the phantom analysis was β350. Regarding patient data, there was no clear trend of image quality improvement using BPL. There was no correlation between SUVmax increase with BPL and either SUV or hypoxic volume from the initial OSEM reconstruction. Hypoxic volume obtained by a SUV > 1.4 thresholding was not impacted by the BPL reconstruction parameter. Conclusion BPL allows a significant increase in quantitative parameters and contrast without significantly improving the lesion detectability or image quality. The variation in hypoxic volume by BPL depends on the method used but SUV > 1.4 thresholding seems to be the more robust method, not impacted by the reconstruction method (BPL or OSEM). Trial registration ClinicalTrials.gov , NCT02490696 . Registered 1 June 2015

Abstract Background In FDG-PET, SUV images are hampered by large potential biases. Our aim was to develop an alternative method (ParaPET) to generate 3D kinetic parametric FDG-PET images easy to perform in clinical oncology. Methods The key points of our method are the use of a new error model of PET measurement extracted from a late dynamic PET acquisition of 15 min, centered over the lesion and an image-derived input function (IDIF). The 15-min acquisition is reconstructed to obtain five images of FDG mean activity concentration and images of its variance to model errors of PET measurement. Our approach is carried out on each voxel to derive 3D kinetic parameter images. ParaPET was evaluated and compared to Patlak analysis as a reference. Hunter and Barbolosi methods (Barbolosi-Bl: with blood samples or Barbolosi-Im: with IDIF) were also investigated and compared to Patlak. Our evaluation was carried on K i index, the net influx rate and its maximum value in the lesion (K i,max). Results This parameter was obtained from 41 non-small cell lung cancer lesions associated with 4 to 5 blood samples per patient, required for the Patlak analysis. Compare to Patlak, the median relative difference and associated range (median; [min;max]) in K i,max estimates were not statistically significant (Wilcoxon test) for ParaPET (− 3.0%; [− 31.9%; 47.3%]; p = 0.08) but statistically significant for Barbolosi-Bl (− 8.0%; [− 30.8%; 53.7%]; p = 0.001), Barbolosi-Im (− 7.9%; [− 38.4%; 30.6%]; p = 0.007) or Hunter (32.8%; [− 14.6%; 132.2%]; p

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that typically results in death within 3–5 years after diagnosis. To date, there is no curative treatment and therefore an urgent unmet need of neuroprotective and/or neurorestorative treatments. Due to their spectrum of capacities in the central nervous system—e.g., development, plasticity, maintenance, neurogenesis—neurotrophic growth factors (NTF) have been exploited for therapeutic strategies in ALS for decades. In this review we present the initial strategy of using single NTF by different routes of administration to the use of stem cells transplantation to express a multiple NTFs-rich secretome to finally focus on a new biotherapy based on the human platelet lysates, the natural healing system containing a mix of pleitropic NTF and having immunomodulatory function. This review highlights that this latter treatment may be crucial to power the neuroprotection and/or neurorestoration therapy requested in this devastating disease.

OBJECTIVE: Major trauma is characterized by a pro-inflammatory response, followed by an immunosuppression. Recently, in trauma patients, the lack of recovery of monocyte Human Leukocyte Antigen DR (mHLA-DR, a biomarker of ICU-acquired immunosuppression) between days 1-2 and days 3-4 has been demonstrated to be independently associated with sepsis development. The main objective of this study was to determine whether early measurements of IL-6 (interleukin-6) and IL-10 plasma concentrations (as markers of initial severity) could improve, in association with mHLA-DR recovery, the prediction of sepsis occurrence in severe trauma patients. DESIGN: Prospective observational study over 24 months in a Trauma ICU at university hospital. PATIENTS: Trauma patients with an ISS over 25 and age over 18 were included. MEASUREMENTS AND MAIN RESULTS: mHLA-DR was assessed by flow cytometry, IL-6 and IL-10 concentrations by ELISA. 100 consecutive severely injured patients were monitored (mean ISS 37±10). 37 patients developed sepsis. IL-6 concentrations and slope of mHLA-DR expression between days 1-2 and days 3-4 were significantly different between septic and non-septic patients. IL-10 was not detectable in most patients. After adjustment for usual clinical confounders, when assessed as a pair, multivariate logistic regression analysis revealed that a slope of mHLA-DR expression (days 3-4/days 1-2)≤1.1 and a IL-6 concentration ≥ 67.1 pg/ml remained highly associated with the development of sepsis (adjusted OR 18.4, 95% CI 4.9; 69.4, p = .00002). CONCLUSIONS: After multivariate regression logistic analysis, when assessed as a pair, a high IL-6 concentration and a persistent mHLA-DR decreased expression were found to be in relation with the development of sepsis with the best predictive value. This study underlines the usefulness of daily monitoring of immune function to identify trauma patients at a high risk of infection.

How effective is home-based exercise therapy delivered using advanced telehealth technology (ATT-ET) for people with chronic obstructive pulmonary disease (COPD) compared with: no exercise therapy (ET), in/outpatient ET, and home-based ET without ATT? Systematic review and meta-analysis of randomised trials. People with stable COPD referred for ET. ATT-ET. Exercise capacity, quality of life, functional dyspnoea, cost-effectiveness and various secondary outcomes. Fifteen eligible trials involved 1,522 participants. Compared with no ET, ATT-ET improved exercise capacity (four studies, 6-minute walk test MD 15 m, 95% CI 5 to 24) and probably improved quality of life (four studies, SMD 0.22, 95% CI 0.00 to 0.43) and functional dyspnoea (two studies, Chronic Respiratory Questionnaire-Dyspnoea MD 2, 95% CI 0 to 4). ATT-ET had a similar effect as in/outpatient ET on functional dyspnoea (two studies, SMD –0.05, 95% CI –0.39 to 0.29) and a similar or better effect on quality of life (two studies, SMD 0.23, 95% CI –0.04 to 0.50) but its relative effect on exercise capacity was very uncertain (three studies, 6-minute walk test MD 6 m, 95% CI –26 to 37). ATT-ET had a similar effect as home-based ET without ATT on exercise capacity (three studies, 6-minute walk test MD 2 m, 95% CI –16 to 19) and similar or better effects on quality of life (three studies, SMD 0.79, 95% CI –0.04 to 1.62) and functional dyspnoea (two studies, Chronic Respiratory Questionnaire-Dyspnoea MD 2, 95% CI 0 to 4). ATT-ET had effects on most secondary outcomes that were similar to or better than each comparator. ATT-ET improves exercise capacity, functional dyspnoea and quality of life compared with no ET, although some benefits may be small. Its benefits are generally similar to in/outpatient ET and similar to or better than home-based ET without ATT. PROSPERO CRD42020165773. [ABSTRACT FROM AUTHOR]

Purpose: The high rates of failure in the radiotherapy target volume suggest that patients with stage II or III non-small-cell lung cancer (NSCLC) should receive an increased total dose of radiotherapy. 2-Deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) and [18F]fluoromisonidazole ([18F]FMISO) (hypoxia) uptake on pre-radiotherapy positron emission tomography (PET)/X-ray computed tomography (CT) have been independently reported to identify intratumor subvolumes at higher risk of relapse after radiotherapy. We have compared the [18F]FDG and [18F]FMISO volumes defined by PET/CT in NSCLC patients included in a prospective study.Procedures: Thirty-four patients with non-resectable lung cancer underwent [18F]FDG and [18F]FMISO PET/CT before (pre-RT) and during radiotherapy (around 42 Gy, per-RT). The criteria were to delineate 40 % and 90 % SUVmax thresholds on [18F]FDG PET/CT (metabolic volumes), and SUV > 1.4 on pre-RT [18F]FMISO PET/CT (hypoxic volume). The functional volumes were delineated within the tumor volume as defined on co-registered CTs.Results: The mean pre-RT and per-RT [18F]FDG volumes were not statistically different (30.4 cc vs 22.2; P = 0.12). The mean pre-RT SUVmax [18F]FDG was higher than per-RT SUVmax (12.7 vs 6.5; P < 0.0001). The mean [18F]FMISO SUVmax and volumes were 2.7 and 1.37 cc, respectively. Volume-based analysis showed good overlap between [18F]FDG and [18F]FMISO for all methods of segmentation but a poor correlation for Jaccard or Dice Indices (DI). The DI maximum was 0.45 for a threshold at 40 or 50 %.Conclusion: The correlation between [18F]FDG and [18F]FMISO uptake is low in NSCLC, making it possible to envisage different management strategies as the studies in progress show. [ABSTRACT FROM AUTHOR]

Cardiac troponin (cTn) concentrations are measured routinely in some centers after cardiac surgery as part of risk stratification, but there are no data on how increased cTn concentrations could change patients' management. The aim of this study was to estimate relevant cTnI thresholds and identify potential interventions (additional monitoring/therapeutic interventions) that could be part of management changes of patients with cTnI greater than relevant thresholds. Retrospective, single-center, observational study. Bichat-Claude Bernard Hospital, Paris, France, between January 1, 2009, and December 31, 2012. Consecutive adult patients undergoing cardiac surgery. cTnI was measured on the 20th postoperative hour. Causes of death and possible interventions were determined by analysis of individual medical records. cTnI thresholds for 1-year cardiac mortality with a specificity >80% were calculated. For this study, 3,228 procedures were analyzed; 129 deaths occurred (4%), 83 of which (2.6%) were cardiac deaths. Threshold cTnI values were 4.2 µg/L for coronary artery bypass grafting (95% confidence interval [CI] 3.9-4.5) and 10.7 µg/L for non-coronary artery bypass grafting (95% CI 10.0-11.3). In multivariable analysis, the EuroSCORE II (odds ratio 1.1 [95% CI 1.06-1.13]; p < 0.001) and cTnI concentrations greater than the thresholds (odds ratio 5.62 [95% CI 3.37-9.37]; p < 0.001) were associated with significantly increased risk of death. The additive and absolute Net Reclassification Index were 0.288% and 14.1%, respectively, for a logistic model including cTnI and EuroSCORE II (area under the curve C-index 0.82 [95% CI 0.77-0.87]) compared with a model including only EuroSCORE II (area under the curve C-index 0.80 [95% CI 0.75-0.84]). Fifty-three of the 83 patients who experienced cardiac death (64%) had a cTnI concentration greater than the threshold, and an intervention was deemed possible in 47 of those 53 (89%) (mostly patients with mild postoperative cardiac dysfunction). For noncardiac deaths, 28% of patients had a cTnI concentration greater than the threshold and no interventions were deemed possible. In an attempt to evolve from risk to management stratification, this study's results identified a subgroup of patients with mild cardiac dysfunction and a cTnI concentration greater than the threshold who could be the target for interventions in future validation studies concerning changes in patient management. [ABSTRACT FROM AUTHOR]

Introduction Today, physicians are accustomed to used PET and MR images for contouring target volumes ant organs at risk. In practice, these images have to be registered to the CT scan before the volume delineation. Acquiring images using the same patient position is a mean to improve the contours definition. However, better precision can be obtained by performing the both exams keeping patient in the same position. Materials used and results obtained for pelvis localisation are discussed. Methods This study is performed on a Discovery GE710 PET/CT and Optima MR450w MRI (General Electric®). Both imagers are equipped with lasers and rigid flat panels. The Zephyr XL (Diacor®) system is used for transferring immobilized patients between each modality. This system is a patented hover technology which can be used with various modality and treatments delivery. Images are registered on AW Server 3.2 (General Electric®) using the "Integrated Registration" software. The rigid registration matrix is then used to calculate the pitch and roll. The pitch and roll values obtained (6 patients) are compared to that measured by positioning patient between each modality (10 patients). Results Using Zephyr XL (Diacor®), the pitch and roll median values are 0.06° ± 0.33 and 0.11° ± 0.45, respectively. The corresponding values obtained by positioning the patient between each modality are 0.34° ± 1.75 and −0.23° ± 1, respectively. Conclusion Results show that uncertainties in patient position are reduced significantly using Zephyr XL (Diacor®) which can be particularly useful for improving PET/CT-MR guided radiation therapy workflow. However, further investigations have to be carried out, with a large patient numbers and for various localization, to confirm these results. [ABSTRACT FROM AUTHOR]

Abstract The evaluation of tumor follow-up according to RECIST 1.1 has become essential in clinical practice given its role in therapeutic decision making. At the same time, radiologists are facing an increase in activity while facing a shortage. Radiographic technologists could contribute to the follow-up of these measures, but no studies have evaluated their ability to perform them. Ninety breast cancer patients were performed three CT follow-ups between September 2017 and August 2021. 270 follow-up treatment CT scans were analyzed including 445 target lesions. The rate of agreement of classifications RECIST 1.1 between five technologists and radiologists yielded moderate (k value between 0.47 and 0.52) and substantial (k value = 0.62 and k = 0.67) agreement values. 112 CT were classified as progressive disease (PD) by the radiologists, and 414 new lesions were identified. The analysis showed a percentage of strict agreement of progressive disease classification between reader-technologists and radiologists ranging from substantial to almost perfect agreement (range 73–97%). Analysis of intra-observer agreement was strong at almost perfect (k > 0.78) for 3 technologists. These results are encouraging regarding the ability of selected technologists to perform measurements according to RECIST 1.1 criteria by CT scan with good identification of disease progression.

Abstract Background During the COVID-19 first wave in France, the capacity of intensive care unit (ICU) beds almost doubled, mainly because of the opening of temporary ICUs with staff and equipment from anaesthesia. Objectives We aim to investigate if the initial management in temporary ICU is associated with a change in ICU mortality and short-term prognosis. Design Retrospective single-centre cohort study. Setting Surgical ICU of the Bichat Claude Bernard University Hospital during the COVID-19 “first wave” (from 18 March to 10 April 2020). Patients All consecutive patients older than 18 years of age with laboratory-confirmed SARS-CoV-2 infection and/or typical radiological patterns were included during their first stay in the ICU for COVID-19. Intervention Patients were admitted to a temporary ICU if no room was available in the classical ICU and if they needed invasive mechanical ventilation but no renal replacement therapy or Extracorporeal Membrane Oxygenation (ECMO) in the short term. The temporary ICUs were managed by mixed teams (from the ICU and anaesthesiology departments) following a common protocol and staff meetings. Main outcome measure ICU mortality Results Among the 59 patients admitted, 37 (62.7%) patients had initial management in the temporary ICU. They had the same characteristics on admission and the same medical management as patients admitted to the classical ICU. ICU mortality was similar in the 2 groups (32.4% in temporary ICUs versus 40.9% in classical ICUs; p=0.58). SAPS-II and ECMO use were associated with mortality in multivariate analysis but not admission to the temporary ICU. Conclusion In an overload context of the ICU of a geographical area, our temporary ICU model allowed access to intensive care for all patients requiring it without endangering them.

Summary: Background: Preoperative COVID-19 has been associated with excess postoperative morbi-mortality. Consequently, guidelines were developed that recommended the postponement of surgery for at least 7 weeks after the infection. We hypothesised that vaccination against the SARS-CoV-2 and the large predominance of the Omicron variant attenuated the effect of a preoperative COVID-19 on the occurrence of postoperative respiratory morbidity. Methods: We conducted a prospective cohort study in 41 French centres between 15 March and 30 May 2022 (ClinicalTrials NCT05336110), aimed at comparing the postoperative respiratory morbidity between patients with and without preoperative COVID-19 within 8 weeks prior to surgery. The primary outcome was a composite outcome combining the occurrence of pneumonia, acute respiratory failure, unexpected mechanical ventilation, and pulmonary embolism within the first 30 postoperative days. Secondary outcomes were 30-day mortality, hospital length-of-stay, readmissions, and non-respiratory infections. The sample size was determined to have 90% power to identify a doubling of the primary outcome rate. Adjusted analyses were performed using propensity score modelling and inverse probability weighting. Findings: Of the 4928 patients assessed for the primary outcome, of whom 92.4% were vaccinated against the SARS-CoV-2, 705 had preoperative COVID-19. The primary outcome was reported in 140 (2.8%) patients. An 8-week preoperative COVID-19 was not associated with increased postoperative respiratory morbidity (odds ratio 1.08 [95% CI 0.48–2.13]; p = 0.83). None of the secondary outcomes differed between the two groups. Sensitivity analyses concerning the timing between COVID-19 and surgery, and the clinical presentations of preoperative COVID-19 did not show any association with the primary outcome, except for COVID-19 patients with ongoing symptoms the day of surgery (OR 4.29 [1.02–15.8]; p = 0.04). Interpretation: In our Omicron-predominant, highly immunised population undergoing general surgery, a preoperative COVID-19 was not associated with increased postoperative respiratory morbidity. Funding: The study was fully funded by the French Society of Anaesthesiology and Intensive Care Medicine (SFAR).

Tumor hypoxia is a complex and evolving phenomenon both in time and space. Molecular imaging allows to approach these variations, but the tracers used have their own limitations. PET imaging has the disadvantage of low resolution and must take into account molecular biodistribution, but has the advantage of high targeting accuracy. The relationship between the signal in MRI imaging and oxygen is complex but hopefully it would lead to the detection of truly oxygen-depleted tissue. Different ways of imaging hypoxia are discussed in this review, with nuclear medicine tracers such as [18F]-FMISO, [18F]-FAZA, or [64Cu]-ATSM but also with MRI techniques such as perfusion imaging, diffusion MRI or oxygen-enhanced MRI. Hypoxia is a pejorative factor regarding aggressiveness, tumor dissemination and resistance to treatments. Therefore, having accurate tools is particularly important.

Allergies and atopy have emerged as significant public health concerns, with a progressively increasing incidence over the last two decades. Anaphylaxis is the most severe form of allergic reactions, characterized by a rapid onset and potentially fatal outcome, even in healthy individuals. Due to the unpredictable nature and potential lethality of anaphylaxis and the wide range of allergens involved, clinical studies in human patients have proven to be challenging. Diagnosis is further complicated by the lack of reliable laboratory biomarkers to confirm clinical suspicion. Thus, animal models have been developed to replicate human anaphylaxis and explore its pathophysiology. Whereas results obtained from animal models may not always be directly translatable to humans, they serve as a foundation for understanding the underlying mechanisms. Animal models are an essential tool for investigating new biomarkers that could be incorporated into the allergy workup for patients, as well as for the development of novel treatments. Two primary pathways have been described in animals and humans: classic, predominantly involving IgE and histamine, and alternative, reliant on IgG and the platelet-activating factor. This review will focus essentially on the former and aims to describe the most utilized IgE-mediated anaphylaxis animal models, including their respective advantages and limitations.

Poster: Physics track: Imaging acquisition and processing PO-1714: Multimodalities imaging PET/CT-MR for radiotherapy: study of positioning uncertainties P. Hinault, I. Gardin, P. Gouel, P. Decazes, H. Souchay, P. Vera, D. Gensanne. [Extracted from the article]

PurposeWe aimed to evaluate the accuracy of T1 and T2 mappings derived from a multispectral pulse sequence (magnetic resonance image compilation, MAGiC®) on 1.5-T MRI and with conventional sequences [gradient echo with variable flip angle (GRE-VFA) and multi-echo spin echo (ME-SE)] compared to the reference values for the purpose of radiotherapy treatment planning.MethodsThe accuracy of T1 and T2 measurements was evaluated with 2 coils [head and neck unit (HNU) and BODY coils] on phantoms using descriptive statistics and Bland–Altman analysis. The reproducibility and repeatability of T1 and T2 measurements were performed on 15 sessions with the HNU coil. The T1 and T2 synthetic sequences obtained by both methods were evaluated according to quality assurance (QA) requirements for radiotherapy. T1 and T2in vivo measurements of the brain or prostate tissues of two groups of five subjects were also compared.ResultsThe phantom results showed good agreement (mean bias, 8.4%) between the two measurement methods for T1 values between 490 and 2,385 ms and T2 values between 25 and 400 ms. MAGiC® gave discordant results for T1 values below 220 ms (bias with the reference values, from 38% to 1,620%). T2 measurements were accurately estimated below 400 ms (mean bias, 8.5%) by both methods. The QA assessments are in agreement with the recommendations of imaging for contouring purposes for radiotherapy planning. On patient data of the brain and prostate, the measurements of T1 and T2 by the two quantitative MRI (qMRI) methods were comparable (max difference,

Tetrodotoxin is one of the most potent neurotoxins in the aquatic world. This review of published and unpublished reports aims to describe the poisoning cases that have occurred in mainland France and overseas territories. Six articles were included, with 13 poisoning events, individuals or collective (number (n) = 53 patients). Moreover, 13 unpublished poisoning events from toxicovigilance networks were found (n = 17). All cases happened in overseas territories: French Guyana (n = 7), New Caledonia (n = 11), Reunion (n = 35) and French Polynesia (n = 17). The median age was 36 years. The most frequent signs were neurological (81.8%), digestive (54.5%) and general (52.3%). Three cases of dysgueusia and nine cases of urogenital discomfort were observed in French Polynesia. Twelve severe cases were reported, including seven deaths. Only three events (11.5%) were documented by a tetrodotoxin assay. Two families of fish accounted for 91.6% of the poisonings: 33.3% due to the Diodontidae family and 58.3% to the Tetraodontidae family. Although rare, information and collection campaigns on tetrodotoxin poisoning are, therefore, essential.

Computed tomography (CT) has revolutionized external radiotherapy by making it possible to visualize and segment the tumors and the organs at risk in a three-dimensional way. However, if CT is a now a standard, it presents some limitations, notably concerning tumor characterization and delineation. Its association with functional and anatomical images, that are positron emission tomography (PET) and magnetic resonance imaging (MRI), surpasses its limits. This association can be in the form of a trimodality PET/CT/MRI. The objective of this mini-review is to describe the process of performing this PET/CT/MRI trimodality for radiotherapy and its potential clinical applications. Trimodality can be performed in two ways, either a PET/MRI fused to a planning CT (possibly with a pseudo-CT generated from the MRI for the planning), or a PET/CT fused to an MRI and then registered to a planning CT (possibly the CT of PET/CT if calibrated for radiotherapy). These examinations should be performed in the treatment position, and in the second case, a patient transfer system can be used between the PET/CT and MRI to limit movement. If trimodality requires adapted equipment, notably compatible MRI equipment with high-performance dedicated coils, it allows the advantages of the three techniques to be combined with a synergistic effect while limiting their disadvantages when carried out separately. Trimodality is already possible in clinical routine and can have a high clinical impact and good inter-observer agreement, notably for head and neck cancers, brain tumor, prostate cancer, cervical cancer.

In Parkinson's disease (PD) depletion of dopamine in the nigro-striatal pathway is a main pathological hallmark that requires continuous and focal restoration. Current predominant treatment with intermittent oral administration of its precursor, Levodopa (l-dopa), remains the gold standard but pharmacological drawbacks trigger motor fluctuations and dyskinesia. Continuous intracerebroventricular (i.c.v.) administration of dopamine previously failed as a therapy because of an inability to resolve the accelerated dopamine oxidation and tachyphylaxia. We aim to overcome prior challenges by demonstrating treatment feasibility and efficacy of continuous i.c.v. of dopamine close to the striatum. Dopamine prepared either anaerobically (A-dopamine) or aerobically (O-dopamine) in the presence or absence of a conservator (sodium metabisulfite, SMBS) was assessed upon acute MPTP and chronic 6-OHDA lesioning and compared to peripheral l-dopa treatment. A-dopamine restored motor function and induced a dose dependent increase of nigro-striatal tyrosine hydroxylase positive neurons in mice after 7 days of MPTP insult that was not evident with either O-dopamine or l-dopa. In the 6-OHDA rat model, continuous circadian i.c.v. injection of A-dopamine over 30 days also improved motor activity without occurrence of tachyphylaxia. This safety profile was highly favorable as A-dopamine did not induce dyskinesia or behavioral sensitization as observed with peripheral l-dopa treatment. Indicative of a new therapeutic strategy for patients suffering from l-dopa related complications with dyskinesia, continuous i.c.v. of A-dopamine has greater efficacy in mediating motor impairment over a large therapeutic index without inducing dyskinesia and tachyphylaxia.

IntroductionThe purpose of our present study was to assess the prognostic impact of FDG PET-CT after induction chemotherapy for patients with inoperable non-small-cell lung cancer (NSCLC).Material and methodsThis retrospective study included 50 patients with inoperable stage II/III NSCLC from January 2012 to July 2015. They were treated for curative intent with induction chemotherapy, followed by concomitant chemoradiation therapy or sequential radiation therapy. FDG PET-CT scans were acquired at initial staging (PET1) and after the last cycle of induction therapy (PET2). Five parameters were evaluated on both scans: SUVmax, SUVpeak, SUVmean, TLG, MTV, and their respective deltas. The prognostic value of each parameter for overall survival (OS) and progression-free survival (PFS) was evaluated with Cox proportional-hazards regression models.ResultsMedian follow-up was 19 months. PET1 parameters, clinical and histopathological data were not predictive of the outcome. TLG2 and ΔTLG were prognostic factors for OS. TLG2 was the only prognostic factor for PFS. For OS, log-rank test showed that there was a better prognosis for patients with TLG2< 69g (HR = 7.1, 95%CI 2.8-18, p = 0.002) and for patients with ΔTLG< -81% after induction therapy (HR = 3.8, 95%CI 1.5-9.6, p = 0.02). After 2 years, the survival rate was 89% for the patients with low TLG2 vs 52% for the others. We also evaluated a composite parameter considering both MTV2 and ΔSUVmax. Patients with MTV2> 23cc and ΔSUVmax> -55% had significantly shorter OS than the other patients (HR = 5.7, 95%CI 2.1-15.4, p< 0.01).ConclusionPost-induction FDG PET might be an added value to assess the patients' prognosis in inoperable stage II/III NSCLC. TLG, ΔTLG as well as the association of MTV and ΔSUVmax seemed to be valuable parameters, more accurate than clinical, pathological or pretherapeutic imaging data.

Parkinson's disease (PD) is a complex illness characterized by progressive dopaminergic neuronal loss. Several mechanisms associated with the iron-induced death of dopaminergic cells have been described. Ferroptosis is an iron-dependent, regulated cell death process that was recently described in cancer. Our present work show that ferroptosis is an important cell death pathway for dopaminergic neurons. Ferroptosis was characterized in Lund human mesencephalic cells and then confirmed ex vivo (in organotypic slice cultures) and in vivo (in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model). Some of the observed characteristics of ferroptosis differed from those reported previously. For example, ferroptosis may be initiated by PKCα activation, which then activates MEK in a RAS-independent manner. The present study is the first to emphasize the importance of ferroptosis dysregulation in PD. In neurodegenerative diseases like PD, iron chelators, Fer-1 derivatives and PKC inhibitors may be strong drug candidates to pharmacologically modulate the ferroptotic signaling cascade.

In oncology, texture features extracted from positron emission tomography with 18-fluorodeoxyglucose images (FDG-PET) are of increasing interest for predictive and prognostic studies, leading to several tens of features per tumor. To select the best features, the use of a random forest (RF) classifier was investigated.Sixty-five patients with an esophageal cancer treated with a combined chemo-radiation therapy were retrospectively included. All patients underwent a pretreatment whole-body FDG-PET. The patients were followed for 3 years after the end of the treatment. The response assessment was performed 1 month after the end of the therapy. Patients were classified as complete responders and non-complete responders. Sixty-one features were extracted from medical records and PET images. First, Spearman's analysis was performed to eliminate correlated features. Then, the best predictive and prognostic subsets of features were selected using a RF algorithm. These results were compared to those obtained by a Mann-Whitney U test (predictive study) and a univariate Kaplan-Meier analysis (prognostic study).Among the 61 initial features, 28 were not correlated. From these 28 features, the best subset of complementary features found using the RF classifier to predict response was composed of 2 features: metabolic tumor volume (MTV) and homogeneity from the co-occurrence matrix. The corresponding predictive value (AUC = 0.836 ± 0.105, Se = 82 ± 9%, Sp = 91 ± 12%) was higher than the best predictive results found using the Mann-Whitney test: busyness from the gray level difference matrix (P < 0.0001, AUC = 0.810, Se = 66%, Sp = 88%). The best prognostic subset found using RF was composed of 3 features: MTV and 2 clinical features (WHO status and nutritional risk index) (AUC = 0.822 ± 0.059, Se = 79 ± 9%, Sp = 95 ± 6%), while no feature was significantly prognostic according to the Kaplan-Meier analysis.The RF classifier can improve predictive and prognostic values compared to the Mann-Whitney U test and the univariate Kaplan-Meier survival analysis when applied to several tens of features in a limited patient database.

The role of angiogenesis in acute leukaemia has been discussed since the cloning of the gene of vascular endothelial growth factor (VEGF) from the acute myelogenous leukemia cell line (HL60) and, thereafter, when the first studies reported increased bone marrow vascularity and elevation of angiogenic cytokines in acute lymphoblastic leukaemia (ALL). VEGF and basic fibroblast growth factor (bFGF) are the major proangiogenic cytokines that have been studied, and evaluation of their prognostic impact in childhood ALL has been reported in several studies, though with controversial results. The antiangiogenic response, contributing to the angiogenic balance, has scarcely been reported. The origin of the factors, their prognostic value, and their relevance as good markers of what really happens in the bone marrow are discussed in this paper. The place of antiangiogenic drugs in ALL has to be defined in the global treatment strategy.

Abstract A female patient, with normal familial history, developed at the age of 30 months an episode of diarrhoea, vomiting and lethargy which resolved spontaneously. At the age of 3 years, the patient re-iterated vomiting, was sub-febrile and hypoglycemic, fell into coma, developed seizures and sequels involving right hemi-body. Urinary excretion of hexanoylglycine and suberylglycine was low during this metabolic decompensation. A study of pre- and post-prandial blood glucose and ketones over a period of 24 hours showed a normal glycaemic cycle but a failure to form ketones after 12 hours fasting, suggesting a mitochondrial β-oxidation defect. Total blood carnitine was lowered with unesterified carnitine being half of the lowest control value. A diagnosis of mild MCAD deficiency (MCADD) was based on rates of 1-14C-octanoate and 9, 10-3H-myristate oxidation and of octanoyl-CoA dehydrogenase being reduced to 25% of control values. Other mitochondrial fatty acid oxidation proteins were functionally normal. De novo acylcarnitine synthesis in whole blood samples incubated with deuterated palmitate was also typical of MCADD. Genetic studies showed that the patient was compound heterozygous with a sequence variation in both of the two ACADM alleles; one had the common c.985A>G mutation and the other had a novel c.145C>G mutation. This is the first report for the ACADM gene c.145C>G mutation: it is located in exon 3 and causes a replacement of glutamine to glutamate at position 24 of the mature protein (Q24E). Associated with heterozygosity for c.985A>G mutation, this mutation is responsible for a mild MCADD phenotype along with a clinical story corroborating the emerging literature view that patients with genotypes representing mild MCADD (high residual enzyme activity and low urinary levels of glycine conjugates), similar to some of the mild MCADDs detected by MS/MS newborn screening, may be at risk for disease presentation.

Objectif de l’étude La chimioradiothérapie est le traitement de référence des cancers bronchiques non à petites cellules localement évolués. L’efficacité de ce traitement reste médiocre, avec un taux important de récidives locorégionales. Des essais en cours testent une augmentation de doses dans un volume sélectionné par tomographie par émission de positons (TEP). L’objectif de ce travail était d’évaluer l’impact d’une augmentation de doses de radiothérapie de 74 Gy les volumes définis par une TEP au fluoromisonidazole (F-miso) ou au fluorodésoxyglucose (FDG) préthérapeutique et au FDG pendant la radiothérapie (à 42 Gy). Matériel et méthode Dans le cadre d’une étude ancillaire RTEP5 (programme hospitalier de recherche clinique [PHRC] de 2011), une étude dosimétrique a été réalisée chez les patients atteints de cancer défini comme hypoxiques par la TEP au F-miso préthérapeutique. Quatre dosimétries ont été réalisées par patient : une étude à 66 Gy sur l’ensemble du volume défini par la tomodensitométrie, trois études avec le même volume à 66 Gy et une augmentation de doses à 74 Gy dans des volumes définis par TEP ( biologic target volume [BTV]) : au FDG, préthérapeutique (seuillage à 70 % de la standard uptake value maximale [SUVmax]), au F-miso, préthérapeutique (seuillage à 1,4) et au FDG pendant la thérapeutique à 42 Gy (seuillage à 40 % de la SUVmax). Toutes dosimétries ont été réalisées pour une radiothérapie conformationnelle avec modulation d’intensité (RCMI). Résultats Vingt patients ont été inclus dans cette analyse. Les volumes définis par TEP traités à 74 Gy étaient plus petits que le volume traité à 66 Gy (volume cible anatomoclinique, CTV) avec un volume cible anatomoclinique traité à 66 Gy moyen de 244 cm 3 contre un volume défini par TEP au FDG préthérapeutique de 4,8 cm 3 , un volume défini par TEP au F-miso de 38,8 cm 3 et un volume défini par TEP au FDG perthérapeutique à 36 cm 3 ( p = 0,0001). La planification à 66 Gy délivrait 62,3 Gy à 95 % du volume cible prévisionnel traité à 66 Gy, les dosimétries à 74 Gy délivraient 72,5 Gy dans 95 % (D95) du volume cible prévisionnel défini par TEP au FDG préthérapeutique, 72,2 Gy au volume cible prévisionnel défini par TEP au F-miso et 73 Gy au volume cible prévisionnel perthérapeutique. Les doses délivrées aux poumons (dose moyenne) ( p = 0,2), dans 35 % du cœur (V35) ( p = 0,9), 50 % de l’œsophage (V50) ( p = 0,6) et 2 % du moelle (D2 %) ( p = 0,1) n’étaient pas augmentées significativement lors des différentes planifications avec augmentation de dose. Conclusion Cette étude démontre la possibilité d’augmenter la dose de radiothérapie à différents volumes définis par TEP efficacement sans augmenter la dose aux organes à risque. [ABSTRACT FROM AUTHOR]

Les essais modernes de radiothérapie nécessitent un contrôle qualité rigoureux afin de répondre aux questions, souvent techniques, demandées. Plusieurs essais de radiothérapie récents n’ont pas pu conclure à cause de déviations majeures au protocole (essais du Trans Tasmanian Radiation Oncology Group (TROG) 02.02 pour les cancers ORL, du Radiation Therapy Oncology Group (RTOG) 0617 pour les cancers bronchiques). L’essai français de phase II/III randomisé RTEP7-IFCT-1402 évalue l’intérêt d’une augmentation de dose de radiothérapie à 74 Gy dans un volume hypermétabolique défini à 42 Gy par TEP-scanographie au fluorodésoxyglucose (FDG) contre 66 Gy dans le bras standard pour des cancers broncho-pulmonaires. Afin de mener à bien cet essai associant des techniques de radiothérapie et de médecine nucléaire complexes, un contrôle qualité exhaustif, et a priori, a été mis en place sous l’égide du groupe qualité de la Société française de radiothérapie oncologique (SFRO) et de la Société française des physiciens médicaux (SFPM) et grâce à la plateforme web collaborative Share Place (AQUILAB, Loos, France). Avant d’inclure dans l’essai, chaque centre investigateur réalise un dummy-run de médecine nucléaire (reconstruction de la TEP, contrôle de la standard uptake value [SUV], seuillage de la TEP), du recalage des images (TEP-scanographie avec la scanographie de planification) et de radiothérapie (délinéation et dosimétrie), afin de s’assurer de l’aptitude du centre à inclure suivant le protocole de l’essai. Durant l’essai, tous les patients du bras expérimental à 74 Gy et tous les trois patients du bras « standard » à 66 Gy, bénéficient d’un contrôle prospectif de la radiothérapie, réalisé par un groupe expert composé d’un oncologue radiothérapeute et d’un physicien médical. Un délai maximal de 72 heures a été défini pour effectuer les contrôles prospectifs durant l’essai. La plateforme web collaborative Share Place permet de coordonner les différents échanges de données, d’informer en temps réel chaque centre investigateur et expert des tâches à réaliser, et de garantir la traçabilité des résultats. La complexité technique de l’essai RTEP7 a nécessité la mise en place d’un contrôle qualité rigoureux et prospectif, qui servira de base de travail aux futurs essais français de radiothérapie et de médecine nucléaire. [ABSTRACT FROM AUTHOR]