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Few comparative data exist on early infections secondary to remission-induction therapy (RIT) with rituximab (RTX) versus cyclophosphamide (CYC) in newly diagnosed anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) patients. We compared and analysed the rates and predictors of severe infection in such patients within the first 6 months following RIT. From the Caen University Hospital databases, we included all consecutive adults newly diagnosed with ANCA-positive granulomatosis with polyangiitis or microscopic polyangiitis between January 2006 and December 2019. We compared rates of survival without severe infection and survival without infections of any severity within 6 months of RIT and used a multivariate Cox analysis to identify predictors of infection. We included 145 patients, 27 in the RTX and 118 in the CYC group. Patients in the RTX group more frequently had pneumococcal vaccination (p < 0.01) and creatinine < 150 µmol/L; other characteristics were comparable between the two groups. Overall, 37 severe infections and 65 infections of any severity were recorded. Rates of survival without severe infection were similar in both groups (p = 0.69), but survival without infections of any severity was lower in the RTX group (p = 0.005). In multivariate analysis, risk factors at diagnosis for severe infections included chronic urinary tract disease, dialysis, and absence of trimethoprim–sulfamethoxazole prophylaxis (p < 0.01 each). Within 6 months of RIT, rates of survival without severe infection were similar in newly diagnosed ANCA-positive AAV patients treated with RTX or CYC, but survival rates without infections of any severity appeared to be lower with RTX treatment.

Resume Introduction Le cancer broncho-pulmonaire est l’un des cancers les plus mortels. Les delais de prise en charge peuvent influencer la survie des patients. L’objectif de cette etude etait d’evaluer les delais de prise en charge diagnostique et therapeutique des patients admis dans le service de Pneumologie et d’Oncologie Thoracique du CHU de Caen Normandie. Materiel et methode Il s’agit d’une etude retrospective, monocentrique et observationnelle, portant sur l’ensemble des patients pris en charge pour un Cancer Broncho-Pulmonaire (CBP) de juin 2017 a janvier 2018 du CHU de Caen. Les delais etudies sont : le delai global (imagerie anormale-traitement), le delai d’acces au diagnostic (imagerie anormale- diagnostic) et le delai d’acces au traitement (diagnostic-traitement). Resultats 127 patients sont inclus dans cette etude. Le delai dlobal median etait de 55,5 jours [31,25; 393], le delai d’acces au diagnostic median etait de 22 jours [13 ; 49] et le delai d’acces au traitement median etait 24,5 jours [12,25 ; 45]. Discussion Les delais de prise en charge de notre etude concordent avec ceux de la litterature. Des axes d’amelioration sont en cours d’elaboration en accord avec le plan cancer 2014-2019 afin de creer un parcours de soins specifique pour ces patients au sein de notre institution.

Thiopurines are drugs widely used for the treatment of autoimmune conditions, inflammatory bowel disease or acute lymphoblastic leukemia. Determination of thiopurine methyltransferase activity (TPMT), a major determinant of thiopurines toxicity, has been suggested before implementing thiopurine treatment. An ultraperformance liquid chromatography (UPLC) method was developed and validated for the quantification of TPMT enzyme activity based on the conversion of 6-mercaptopurine (6-MP) to 6-methylmercaptopurine (6-MMP) using S-adenosyl-L-methionine (SAM) as methyl donor in red blood cell lysates (RBC). This method was improved from a previous laborious high performance liquid chromatography (HPLC) method, using a lower volume of injection and with a shorter runtime. After incubation and protein precipitation 6-MMP was separated on a HSS-T3 (2.1 × 50 mm, 1.8 μm) column and monitored by UV detection (290 nm). A change on the organic solvent used to dissolve 6-MP resulted in a reduction of interference by endogenous or non-enzymatic methylated 6-MMP. A full validation of the 6-MMP assay was performed according to the FDA and EMA guidelines. The method was linear from 0.125 to 2 nmol/mL, with acceptable values of accuracy and precision. The method was applied in 106 patients treated with thiopurines whose TPMT activity was previously quantified by HPLC. Evaluation through Bland-Altman plot showed that TPMT activities were in agreement between both methods.

Lung cancer is the leading cause of cancer-related death. Delays may have an impact on patient survival. The objective of this study was to evaluate the diagnostic and therapeutic management times for patients admitted for lung cancer treatment in the Respiratory Department of CHU de Caen Normandie.This is a retrospective, single-center and observational study, conducted on all patients treated for lung cancer from June 2017 to January 2018 in our department of pneumology in the Caen Normandie CHU. The main median times were investigated were: Global Time (abnormal imaging-treatment), Diagnosis time (abnormal imaging-diagnosis) and Treatment Time (diagnosis-treatment).One hundred and twenty-seven (127) patients were included. Median global time was 55.5 days [31,25; 393], median diagnosis time was 22 days [13; 49], and median treatment time was 24.5 days [12,25; 45].Our treatment times are consistent with those previously published. Areas for improvement are being developed in accordance with the 2014-2019 cancer plan, in particularly the creation in our institution of a specific care pathway for patients with lung cancer.

Malignant pleural mesothelioma (MPM) arises from mesothelial cells lining the pleural cavity of asbestos-exposed individuals and rapidly leads to the development of pleural effusion and death. MPM harbours loss-of-function mutations in genes likeBAP1, NF2, CDKN2A, andTP53, but isolated deletion of these genes alone in mice does not cause MPM and mouse models of the disease are sparse. Here we show that a significant proportion of human MPM harbour point mutations and copy number alterations in theKRASproto-oncogene. These mutations are likely pathogenic, since ectopic expression of mutantKRASG12Din the pleural mesothelium of conditional mice causes MPM. Murine MPM cell lines derived from these tumours carry the initiatingKRASG12Dlesions, secondaryBap1alterations, and human MPM-like gene expression profiles. Moreover, they are transplantable and actionable by KRAS inhibition. Our results indicate thatKRASmutations likely play an important and underestimated role in MPM, which warrants further exploration.

Tumor Necrosis Factor Type 1 Receptor Associated Periodic Syndrome (TRAPS) is a rare autosomal dominant autosomal autoinflammatory disease associated with mutations in the TNF type 1 receptor gene (TNFRSF1A). It is characterized by relatively long recurrent febrile seizures with an average duration of 7 days accompanied by arthralgia, myalgia, and usually a rash. In a patient of Mediterranean origin with recurrent fever, familial Mediterranean fever is the first diagnosis to be suspected by argument of frequency.A retrospective observational study was conducted on patients from Mediterranean origin followed for TRAPS and included in the "Juvenile Inflammatory Rheumatism" (JIR) observational cohort in the national French autoinflammatory center. The age of onset of symptoms, age of diagnosis, number of years of wandering and treatments received were collected for each index case.Nine patients from 6 families of Mediterranean origin were included. A molecular diagnosis confirmed TRAPS in all patients. The median age at diagnosis was 26 years, the mean number of years of wandering was 17 years. The diagnosis of FMF was made first in all patients. AA amyloidosis revealed TRAPS in 2 patients. Colchicine was started without any efficacy in all cases. Five patients were treated with interleukin-1 inhibitory biotherapy with 100% efficacy.In a patient of Mediterranean origin presenting with recurrent febrile abdominal pain of AA amyloidosis, the first diagnosis to be suspected is FMF. Long relapses, dominant transmission, a non-Mediterranean relative, and the ineffectiveness of colchicine should evoke TRAPS.

BackgroundMyeloperoxidase (MPO) plays a major role in loss of immunological tolerance leading to tissue destruction in ANCA-associated vasculitis (AAV). Ceruloplasmin is a protein with antiproteinase and antioxidant properties that inhibits MPO activity. Whether serum level of ceruloplasmin at AAV diagnosis has an impact is unknown.ObjectivesThe objective of this study was to evaluate the prognostic impact of serum level of ceruloplasmin at diagnosis in patients with granulomatosis with polyangiitis or microscopic polyangiitis.MethodsWe conducted a retrospective unicentric study at Caen University Hospital, involving consecutive adult patients with granulomatosis with polyangiitis or microscopic polyangiitis between 2010 and 2021 who had available serum at diagnosis. Data was collected using the health records.Ceruloplasmin was measured by standardized nephelometry (normal values: 0.15 – 0.50 g/L). Patients in each subgroup (whole cohort, microscopic polyangiitis and anti-MPO patients) were divided into two groups based on the median serum level of ceruloplasmin.We estimated survival using the Kaplan-Meier survival curve, and between-group differences were evaluated by the log-rank test. The study was approved by the local ethics committee of Caen University Hospital (n° 1947).ResultsNinety-two patients were included, 46 (50%) granulomatosis with polyangiitis (41 anti-proteinase 3 and 5 anti-MPO) and 46 (50%) microscopic polyangiitis (45 anti-MPO and 1 anti-proteinase 3). The median level of ceruloplasmin was 0.44 g/L. No significant differences in the clinical presentation were observed between patients in the two groups (p>0.05). We observed 9 (19.6%) deaths in the low ceruloplasmin group and 5 (10.9%) in the high ceruloplasmin group (p=0.39). Vasculitis relapse occurred in 10/46 patients (22%) and 11/46 patients (24%) (p=1), renal failure leading to dialysis and/or renal transplant in 6/46 patients (13%) and 8/46 patients (17%) (p=0.77), respectively. No significant difference in survival was found (p=0.07). The same analyses were performed between the low and the high ceruloplasmin group with the microscopic polyangiitis subgroup (n=46), and no significant differences were found (p>0.05). However, within the anti-MPO subgroup (n=50), the survival was worse in the low ceruloplasmin group (p=0.03).ConclusionIn anti-MPO AAV patients, serum level of ceruloplasmin at diagnosis seems to be associated with a significant impact on survival.References[1]Baskin E, et al. Ceruloplasmin levels in antineutrophil cytoplasmic antibody-positive patients. Pediatr Nephrol. 2002;17(11):917–9.[2]Ara J, et al. Ceruloplasmin in small vessel vasculitis. Nephrol Dial Transplant. févr 1999;14(2):515-7.isclosure of Interests: None declared

BackgroundDevelopment of Tumor Necrosis Factor blockers (TNFb) whose drug class has several mechanistic and pharmacologic sub-classes, have improved the management of autoimmune and inflammatory diseases, including sarcoidosis. With their increasing use, paradoxical reactions are described and one of the most frequent is sarcoidosis. However, the description of TNFb-induced sarcoidosis (TIS) remains poor, because reported in few and only short case-series.ObjectivesWe aimed to better describe the clinical spectrum of TIS, and the differential involvement of TNFb sub-classes.MethodsFrench pharmacovigilance database was used to collect data on TIS, excluding patients with previous idiopathic sarcoidosis. Statistical analyses were performed using the Mann-Whitney test for quantitative data and Fisher test for qualitative data. A p value < 0.05 was considered statistically significant.ResultsData were obtained from 2002 to 2019 for infliximab, adalimumab, golimumab, certolizumab and etanercept. Thirty-one TIS patients were collected from the database, including 12 women (38.7%). In most cases, TNFb was introduced for ankylosing spondylitis (58%), psoriasis (19.3%) or rheumatoid arthritis (16.1%). Median age at TIS occurrence was 54 [43.5; 61.5] years, with a median time to onset of 24 [6.0; 72.0] months. The most frequent involved TNFb was etanercept (n=21, 67.8%). The two mains clinical TIS manifestations were lymph node (n=27, 87.1%) and lung involvement (n=16, 51.6%). The culprit drug was discontinued in 26 (84%) patients, and a double-barreled inflammatory gun to control both initial and induced disorders was proposed in 19 of them (90.5 %), mostly glucocorticoids (n=13, 68.4%) alone or combined with methotrexate (n=3, 15,8%). Among the 14 patients with the available data, the TIS had completely resolved in 11 (78.6%); for all these lasts, the TNFb was discontinued. No significant differences were observed between the TNFb sub-classes of monoclonal antibodies or fusion proteins, regarding clinical presentation, median time to onset or outcome.ConclusionThis second largest case-series shows that TIS are mostly encountered with etanercept, but without any difference in clinical or prognostic implications with the other TNFb-subclasses.References[1]Aggarwal BB, Gupta SC, Kim JH. Historical perspectives on tumor necrosis factor and its superfamily: 25 years later, a golden journey. Blood. 2012 Jan 19;119(3):651–65.[2]Cohen Aubart F, Lhote R, Amoura A, Valeyre D, Haroche J, Amoura Z, et al. Drug-induced sarcoidosis: an overview of the WHO pharmacovigilance database. J Intern Med. 2019 Oct 15;[3]Daïen CI, Monnier A, Claudepierre P, Constantin A, Eschard J-P, Houvenagel E, et al. Sarcoid-like granulomatosis in patients treated with tumor necrosis factor blockers: 10 cases. Rheumatology (Oxford). 2009 Aug;48(8):883–6.[4]Javot L, Tala S, Scala-Bertola J, Massy N, Trenque T, Baldin B, et al. [Sarcoïdosis and anti-TNF: a paradoxical class effect? Analysis of the French Pharmacovigilance system database and literature review]. Therapie. 2011 Apr;66(2):149–54.[5]Massara A, Cavazzini L, La Corte R, Trotta F. Sarcoidosis appearing during anti-tumor necrosis factor alpha therapy: a new ‘class effect’ paradoxical phenomenon. Two case reports and literature review. Semin Arthritis Rheum. 2010 Feb;39(4):313–9.[6]Valeyre D, Prasse A, Nunes H, Uzunhan Y, Brillet P-Y, Müller-Quernheim J. Sarcoidosis. Lancet. 2014 Mar;383(9923):1155–67.Disclosure of InterestsNone declared

Background:Clinical manifestations are scarce in AA amyloidosis (AAA) and, contrary to other types of amyloidosis, involvement of the peripheral nervous system was rarely reported in AAA. However, the usual absence of hypertension despite chronic renal failure and the digestive involvement may be secondary to dysautonomia, but the autonomic nervous system has rarely been studied in AAA (1). Measure of the electrochemical skin conductance (ESC) is a simple and reproducible method to evaluate the function of eccrine sweat glands, which are innervated by small non-myelinated C fibers, and patients with AL and hereditary transthyretin amyloidoses show decreased ESC values (2,3).Objectives:To evaluate ESC values by Sudoscan in patients with AAA.Methods:Patients diagnosed as having AAA based on positive immunohistochemistry with an anti-serum amyloid A antibody followed at the national reference center for AAA in Tenon Hospital between July, 2017 and September, 2020, were routinely assessed for ESC with FDA approved Sudoscan (Impeto Medical, Paris, France). An ESC value above 60 microSiemens (µS) or 70 µS were considered normal for hands or feet, respectively. Categorical variables are reported as percentages and continuous variables are expressed as means±standard deviation. Correlations between age, body mass index (BMI), hemoglobin levels, C-reactive protein levels, estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration equation (defined as 0 for dialysis patients) and ESC values were calculated using the nonparametric Spearman test. GraphPad Prism Version 7 software (GraphPad Software, San Diego, California, USA) was used for statistical analyses. A p-value Results:Overall, 32 patients (16 women) were included, with a mean age of 57.4±13.6 years and a mean BMI of 25.2±6.8 kg/m2. Six (19%) had diabetes mellitus, and 5 (16%) had a kidney transplantation. The main causes of AAA were: monogenic autoinflammatory diseases (n=11, 34%, including 9 patients with familial Mediterranean fever), chronic and/or recurrent infections (n=5, 16%), obesity (n=3, 9%) and undefined (n=3, 9%). The mean hands’ ESC values was normal at 65.5±21.1 µS, although 8 (25%) patients had ESC values below 60 µS, including 2 diabetic patients. In contrast, the mean feet’s ESC values was abnormal at 62.7±23.7 µS, including half of the patients with ESC values below 70 µS (2 diabetic patients). Eight patients had abnormal ESC values only for feet, and 1 had abnormal values only for hands. Apart from a significant correlation between feet and hands’ ESC values (pConclusion:To our knowledge, this is the first study to assess ESC in AAA. Feet’s ESC values were moderately impaired in half of the patients with AAA. Therefore, this study reinforces the previously reported alterations in the autonomic nervous system in patients with AAA that should probably be searched for in these patients. In addition, the identification of an alteration of the ESC values cannot allow to distinguish the type of amyloidosis.References:[1]Nussinovitch U, Volovitz B, Nussinovitch M, Lidar M, Feld O, Nussinovitch N, et al. Abnormal heart rate variability in AA amyloidosis of familial Mediterranean fever. Amyloid 2011;18:206–10.[2]Montcuquet A, Duchesne M, Roussellet O, Jaccard A, Magy L. Electrochemical skin conductance values suggest frequent subclinical autonomic involvement in patients with AL amyloidosis. Amyloid 2020;27:215–6.[3]Fortanier E, Delmont E, Verschueren A, Attarian S. Quantitative sudomotor test helps differentiate transthyretin familial amyloid polyneuropathy from chronic inflammatory demyelinating polyneuropathy. Clin Neurophysiol 2020;131:1129–33.Disclosure of Interests:None declared

Double-positive vasculitis with anti-polynuclear cytoplasm (ANCA) and anti-glomerular basement membrane (GBM) antibodies is a rare entity of systemic vasculitis defined by the presence of ANCA and anti-GBM antibodies. The gradual accumulation of clinical and therapeutic data shows the usefulness of identifying and differentiating this entity from the two vasculitis respectively associated with the isolated presence of each of these two antibodies. Indeed, the double-positive ANCA and anti-GBM vasculitis appears to associate the characteristics of the demography and the extra-renal and pulmonary involvement of the ANCA-associated vasculitis on the one hand, and of the histological type and severe renal prognosis of the anti-MBG vasculitis on the other hand, with the renal involvement which is the only involvement consistently observed in double-positive vasculitis. The aim of this focus is to describe the epidemiological, clinico-biological, histological and prognostic characteristics of this entity, in light of recent literature and ongoing therapeutic changes in the two eponymous vasculitis.

Introduction L’efficacite cerebrale des associations platine/pemetrexed et carboplatine/paclitaxel/bevacizumab est connue. Le but de notre etude etait d’evaluer l’efficacite et la tolerance cerebrale de l’association platine/pemetrexed/bevacizumab (PPB), chez des patients presentant un CBNPC non epidermoide avec metastases cerebrales (MC). Methodes Cette etude retrospective, multicentrique, a inclus des patients presentant un CBNPC non epidermoide avec MC mesurables (evaluees par scanner ou par IRM) ayant recu au moins deux cycles de chimiotherapie par PPB, suivis d’une eventuelle maintenance (simple ou double). L’objectif principal etait le taux de reponse cerebrale selon les criteres RECIST 1.1 determine apres relecture par l’un des auteurs (SD). Les objectifs secondaires etaient le taux de reponse cerebrale selon l’investigateur, le taux de reponse globale (cerebrale + extra-cerebrale), la survie sans progression (SSP) cerebrale et globale, la survie globale (SG) et le profil de tolerance. Resultats Entre janvier 2010 et janvier 2018, 58 patients ont ete inclus : 53 % d’hommes, de performans status 0 a 1, d’âge median de 59 ans ; 25,5 % presentaient une mutation KRAS, 7,8 % une mutation de l’EGFR et 3,9 % un rearrangement ALK ; 36,2 % presentaient une symptomatologie neurologique. Le diametre median des MC etait de 12 millimetres et 79,4 % des patients n’avaient pas beneficie d’un traitement local prealable. Il s’agissait d’un traitement de premiere ligne chez 82,8 % des patients. Le nombre median de cycles d’induction etait de 4 [4–4] ; 49 patients (84,5 %) ont beneficie d’un traitement de maintenance (nombre median de cycles de maintenance de 6 [3–13]). Le suivi median etait de 428 jours [212–789]. Le taux de reponse cerebrale a l’association PPB etait de 79,3 % selon l’investigateur (58 patients) et de 68,3 % apres relecture (41 patients). Le taux de reponse global etait de 78,9 %. Les SSP cerebrale et globale etaient respectivement de 10,4 mois [8,5–15,0], et de 10,1 mois [7,4–11,9]. La SG etait de 18 mois [14,9–40,8]. Au moins une toxicite de grade 3 et 4 a ete identifiee chez respectivement 33 % et 24,5 % des patients. Une hemorragie intracrânienne, de grade 1, a ete identifiee. Conclusion Chez des patients presentant un CBNPC non epidermoide avec MC, dont un tiers etaient symptomatique sur le plan neurologique, l’association platine/pemetrexed/bevacizumab permet d’observer un taux de reponse cerebrale de 68,3 %, associe a un profil favorable de tolerance.

Introduction Le cancer bronchopulmonaire (CBP) represente en France un des cancers les plus frequents et il est associe a un mauvais pronostic, pouvant etre influence par les delais de prise en charge. L’objectif de cette etude etait d’evaluer les delais de prise en charge diagnostique et therapeutique des patients suivis au sein du service de pneumologie et d’oncologie thoracique du CHU de Caen. Methodes Il s’agissait d’une etude prospective, monocentrique et observationnelle, portant sur l’ensemble des patients pris en charge pour un CBP de juin 2017 a janvier 2018. L’objectif principal etait l’evaluation du delai global (DG) entre la date de la premiere imagerie realisee anormale (quel que soit son lieu de realisation) et la date de mise en traitement (quel qu’il soit). Les objectifs secondaires etaient l’evaluation du Delai d’acces au diagnostic (DD) : entre la date de la premiere imagerie anormale realisee et la date du diagnostic et l’evaluation du delai d’acces au traitement (DT) : entre la date du diagnostic et la date de mise en traitement. Les delais etaient rendus sous la forme de medianes et etaient compares entre eux par un test non parametrique univarie de Mann–Whitney. Resultats Cent vingt-sept patients ont ete inclus, 53,2 % ont debute leur prise en charge en hospitalisation conventionnelle. Le DG etait de 55,5 jours. Les variables allongeant le DG de facon significative etaient la localisation tumorale peripherique, la necessite de realisation d’un Pet-Scanner, d’une ponction sous scanner, et d’une chirurgie thoracique. Le DD etait de 22 jours. Celui entre la consultation avec le specialiste et le diagnostic etait de 12 jours. Le delai de realisation d’une fibroscopie bronchique ou d’une echo-endoscopie etait respectivement de 2,5 et 3,5 jours et de 11,5 jours pour la ponction sous scanner. Six jours etaient necessaires pour obtenir l’anatomopathologie, 5 jours pour realiser le bilan d’extension et 19 jours pour l’obtention d’un Pet-Scanner. Le DT etait de 24,5 jours. Neuf jours separaient la reunion de concertation pluridisciplinaire et le traitement systemique et 57 jours pour le traitement chirurgical. Conclusion Nos delais de prise en charge sont concordants avec ceux retrouves dans la litterature. Des axes d’amelioration sont en cours d’elaboration et d’application au sein de notre etablissement, en accord avec le plan cancer 2014–2019, avec notamment l’identification d’un parcours de soins diagnostic et therapeutique specifique au CBP.

The finding of hardening and thickening of the skin is common and can be encountered in immune mediated, metabolic, neoplastic, toxic, genetic diseases, or associated with protein deposits. The lack of Raynaud's phenomenon, capillaroscopic abnormalities, or scleroderma-specific autoantibodies should question the diagnosis of scleroderma and trigger the search for a scleroderma-like disorder, for which treatment and prognosis differ. This article gives a review of these disorders and their main characteristics.

Introduction La prescription des cephalosporines est en augmentation dans les hopitaux francais. Bien que generalement bien tolerees, elles peuvent etre responsables d’effets secondaires neurologiques affectant le systeme nerveux central. Ces derniers ont ete decrits avec toutes les generations de cephalosporines, affectant des patients de 65 ans d’âge median, insuffisants renaux dans trois quarts des cas, se manifestant principalement par un etat de mal epileptique non convulsif, des myoclonies ou des crises comitiales et un electroencephalogramme pathologique dans la quasi-totalite des cas. Materiels et methodes Nous avons realise une revue systematique de la litterature pour les cephalosporines les plus recentes disponibles en France en pathologie humaine jusqu’en avril 2016, a partir de la base de donnees PubMED via les mots-cles MeSH suivants : (« neurotoxicity Syndromes » [MeSH] ou « brain diseases » [MeSH] ou « neurologic manifestations » [Mesh] ou « meningitis » [MeSH]). Les articles inclus rapportaient des donnees individuelles originales de patients developpant des symptomes neurologiques (de type crise comitiale, troubles de la vigilance, syndrome confusionnel, myoclonies, signes de localisation et/ou hallucinations) apres l’introduction de l’antibiotique. Le score d’imputabilite selon l’echelle de Naranjo a ete calcule pour chaque cas. La posologie a ete consideree comme adaptee a la fonction renale si elle etait conforme aux recommandations du service ICAR. Resultats Sur les articles actuellement identifies pour le cefpirome (19 articles), la ceftaroline (8 articles), le ceftobiprole (1 article) et le ceftozolane (1 article), aucun ne rapportait de neurotoxicite. En revanche, concernant la ceftazidime, sur les 224 articles identifies, 20 ont ete inclus, rapportant 27 patients (65 ans d’âge median, 11 femmes pour 15 hommes). La neurotoxicite survenait dans un delai median de 6,5 jours, d’evolution favorable en 3 jours en mediane apres arret de l’antibiotique. Elle se manifestait par des signes encephalitiques (100 %), avec syndrome confusionnel (56 %), troubles de la vigilance (44 %), crises comitiales (26 %) et hallucinations (15 %) ainsi que des mouvements anormaux (55,5 %). Un facteur favorisant etait retrouve dans la quasi-totalite des cas (92,6 %), de type insuffisance renale (81,5 %) ou anomalie du systeme nerveux central pre-existante (18,5 %). Sur les 16 cas de neurotoxicite avec posologie et fonction renale disponibles, la dose de ceftazidime etait adaptee a la fonction renale dans uniquement 3 cas (18,75 %). Le score median d’imputabilite selon l’echelle de Naranjo etait de 3, correspondant a une causalite possible. Concernant le cefepime, sur les 119 articles identifies, 61 ont ete inclus, rapportant 148 patients (69 ans d’âge median, 73 femmes pour 62 hommes). La neurotoxicite survenait dans un delai median de 4 jours, d’evolution favorable en 2 jours en mediane apres arret de l’antibiotique. Elle se manifestait par des signes encephalitiques (94,6 %), avec syndrome confusionnel (45 %), troubles de la vigilance (45 %), crises comitiales (12 %) et signes focaux (8,8 %), ainsi que des mouvements anormaux (44,6 %). Un facteur favorisant etait retrouve dans la quasi-totalite des cas (93,2 %), de type insuffisance renale (89,1 %) ou anomalie du systeme nerveux central pre-existante (14,3 %). Sur les 112 cas de neurotoxicite avec posologie et fonction renale disponibles, la dose de cefepime etait adaptee a la fonction renale dans 29 cas (25,9 %). Le score median d’imputabilite selon l’echelle de Naranjo etait de 4, correspondant a une causalite possible. L’electroencephalogramme (EEG) retrouvait pour les 2 molecules une activite lente de facon diffuse et symetrique, un rythme delta diffus, des anomalies paroxystiques, a type d’ondes aigues, de pointes-ondes, de complexes lents, d’ondes triphasiques, de decharges epileptiques voire evocatrices d’un etat de mal epileptique non convulsif. Conclusion Les effets secondaires neurologiques affectant le systeme nerveux central de la ceftazidime et du cefepime s’observent volontiers en presence d’une insuffisance renale, avec une posologie rarement adaptee a celle-ci. Ils se manifestent principalement par des mouvements anormaux, mais peu d’hallucinations ou de crises comitiales, contrairement a d’autres s-lactamines. La survenue de myoclonies, de troubles de la vigilance et/ou de crises comitiales chez un patient sous cephalosporines, en particulier en cas d’insuffisance renale, doit faire suspecter un effet secondaire et modifier l’antibiotherapie. L’EEG peut aider au diagnostic, notamment en presence d’un etat de mal epileptique non convulsif. La notification a la pharmacovigilance est legitime pour ameliorer les connaissances sur ces effets indesirables frequents, sources de morbi-mortalite.

A modification of conventional signal processing for the pressure-compensated flow plethysmograph is proposed to correct the nonlinearity of the flow element that appears for high flows as encountered during forced expiration. Woven screens behave as porous media with a viscous and an inertial component in the resistance; this explains the nonlinearity (23% at 15.1.s-1 with a 400-mesh wire screen area = 50 cm2). It was shown that the pressure drop-flow relationship can be described by a second-degree equation, which can be included in the computation of the thoracic signal from the box pressure. The need for such a correction is evidenced by testing the plethysmograph with a flow step input (0-15 l.s-1) equivalent both in amplitude and in frequency to the thoracic flow during a forced expiration. Such correction for nonlinearity avoids an overestimation of the thoracic forced vital capacity of up to 0.5 liter in normal subjects.

The hydroxylation of debrisoquine was investigated in Sprague-Dawley (SD) and Dark-Agouti (DA) rats. Female and male rats were phenotyped in-vivo with debrisoquine six times during their growth. The ratios debrisoquine/4-hydroxydebrisoquine of the female DA rats increased until the 15th week and then decreased; but the values of the metabolic ratios never exceeded 2. Female DA rats cannot be considered as genetically deficient for hydroxylation of debrisoquine in regard to the metabolic ratio, but the percentage of debrisoquine excretion is up to ten fold higher than that in the other strains. Therefore SD and DA rat livers were perfused for 2 h when the clearance of debrisoquine was significantly lower in the female DA group than in the other groups. 4-Hydroxydebrisoquine in the perfusate increased with time, but the amount after 120 min was 12 fold lower in the female DA rat group than in the female SD rat group. The results of the male DA group fell between. This study confirms that female DA rats present a lower debrisoquine 4-hydroxylating capacity than other rats but shows that urinary metabolic ratio is not sufficient to assess the deficiency of debrisoquine hydroxylation.

The hydroxylation of debrisoquine was investigated in Sprague-Dawley (SD) and Dark-Agouti (DA) rats. Female and male rats were phenotyped in-vivo with debrisoquine six times during their growth. The ratios debrisoquine/4-hydroxydebrisoquine of the female DA rats increased until the 15th week and then decreased; but the values of the metabolic ratios never exceeded 2. Female DA rats cannot be considered as genetically deficient for hydroxylation of debrisoquine in regard to the metabolic ratio, but the percentage of debrisoquine excretion is up to ten fold higher than that in the other strains. Therefore SD and DA rat livers were perfused for 2 h when the clearance of debrisoquine was significantly lower in the female DA group than in the other groups. 4-Hydroxydebrisoquine in the perfusate increased with time, but the amount after 120 min was 12 fold lower in the female DA rat group than in the female SD rat group. The results of the male DA group fell between. This study confirms that female DA rats present a lower debrisoquine 4-hydroxylating capacity than other rats but shows that urinary metabolic ratio is not sufficient to assess the deficiency of debrisoquine hydroxylation.

Gastrointestinal tumors; Tyrosine kinase inhibitors Tumores gastrointestinales; Inhibidores de la tirosina cinasa Tumors gastrointestinals; Inhibidors de la tirosina cinasa Gastrointestinal stromal tumor (GIST), the most common sarcoma, is mainly caused by an oncogenic mutation in the KIT receptor tyrosine kinase. Targeting KIT using tyrosine kinase inhibitors, such as imatinib and sunitinib, provides substantial benefit; however, in most patients, the disease will eventually progress due to KIT secondary mutations leading to treatment failure. Understanding how GIST cells initially adapt to KIT inhibition should guide the selection of appropriate therapies to overcome the emergence of resistance. Several mechanisms have been broadly implicated in the resistance to imatinib anti-tumoral effects, including the reactivation of MAPK signaling upon KIT/PDGFRA targeted inhibition. This study provides evidence that LImb eXpression 1 (LIX1), a protein we identified as a regulator of the Hippo transducers YAP1 and TAZ, is upregulated upon imatinib or sunitinib treatment. LIX1 silencing in GIST-T1 cells impaired imatinib-induced MAPK signaling reactivation and enhanced imatinib anti-tumor effect. Our findings identified LIX1 as a key regulator of the early adaptative response of GIST cells to targeted therapies. This work was supported by Inserm Transfert (CoPoc N°; MAT-PI-13315-A-02 to SF), by the Association contre les Myopathies (AFM N° 23800 to SF), and by Ligue Régionale Contre le Cancer Languedoc-Roussillon (2020 to P.d.S.B). SRD is funded by the “Agence Nationale de la Recherche” (ANR-21-CE14-0017). This work was also supported by institutional funds from the University of Montpellier, INSERM, and CNRS.