L'ANSM a alerté sur le risque d'anomalie sévère de la coagulation et d'hémorragie grave sous céfazoline. L'objectif principal était de mesurer la fréquence de survenue d'anomalies de l'hémostase sous céfazoline. Les objectifs secondaires étaient de mesurer la fréquence de survenue de complications hémorragiques et d'identifier des associations entre apparition d'anomalies de l'hémostase et plusieurs paramètres clinico-biologiques. Dans cette cohorte prospective monocentrique observationnelle, tout patient adulte traité par céfazoline pour plus de 48 heures était inclus sauf refus ou état de choc initial. Le patient bénéficiait d'évaluations clinique quotidienne (hémorragie) jusqu'à deux jours de l'arrêt de la céfazoline et biologique deux fois par semaine (hémostase, numération formule sanguine, dosage de céfazoline). Selon le score de gravité de l'International Society on Thrombosis and Haemostasis (ISTH), un saignement grave était un saignement conduisant au décès ou dans une localisation critique, avec perte de plus de 2 g/dL d'hémoglobine ou transfusion de plus de 2 culots globulaires. Un saignement non-grave mais cliniquement pertinent (NGCP) était un saignement non grave nécessitant une intervention médicale. L'inclusion de 120 patients était prévue, selon les capacités de recrutement du centre. Du 15/09/2019 au 17/07/2020, 120 patients, dont 84 (70 %) hommes, âge moyen 59 ans (20) étaient traités par céfazoline, pour une durée moyenne de 8 (5) jours. Trente-deux (26,6 %) patients avaient une complication hémorragique, dont 12 (10 %) graves ou NGCP, plus fréquentes chez les patients graves (qSOFA à l'arrivée 2-3 pour 4/12 (33,3 %) vs 5/108 (4,7 %), P=0.006), traités pour une endocardite (4/12 (33,3 %) vs 7/108 (6,5 %), P=0,01), avec bactériémie (11/12 (91,7 %) vs 52/108 (48,6 %), P=0,005) et/ou sous traitement anticoagulant oral (4/12 (33,3 %) vs 8/108 (7,4 %), P=0,019). Le delta de plaquettes entre l'arrivée et la veille du saignement était de –24 G/L, P=0,32. Le TP était plus bas chez les patients avec saignement grave ou NGCP (69 (16) vs 82 (17), P=0,03). En analyse multivariée, une bactériémie à l'entrée et une anticoagulation curative en cours la veille du saignement étaient associées à la survenue d'un saignement grave (OR 1,12 (1,03 ; 1,23), P=0,03 et 1,1 (1,003 ; 1.21), P=0,09, respectivement). Un décès par choc septique était observé chez un patient sans hémorragie grave. Sous céfazoline, 10 % des patients ont présenté une hémorragie grave ou NGCP. L'identification de facteurs associés à ces évènements (bactériémie et/ou anticoagulation curative) permet de proposer de limiter la surveillance clinique et biologique renforcée à ce sous-groupe de patients. Aucun lien d'intérêt

Les inhibiteurs de mTOR (mammalian target of rapamycin), initialement utilisés comme immunosuppresseurs en transplantation d’organe solide, ont vu leurs indications s’étendre au domaine de l’oncologie médicale en raison de leurs propriétés antitumorales. La toxicité pulmonaire des inhibiteurs de mTOR est rapportée dans les deux indications [1], [2], mais peu d’études ont exploré les différences entre les pneumopathies aux inhibiteurs de mTOR (mTOR-PI) en transplantation (T) et en oncologie (K). L’objectif de notre étude est de comparer les mTOR-PI dans ces deux populations. Notre étude rétrospective monocentrique a été réalisée dans un centre expert en pneumopathies interstitielles, en transplantation et en oncologie (Hôpital Européen Georges Pompidou). Quatre bases de données ont été utilisées afin d’assurer la collecte exhaustive de tous les cas de mTOR-PI entre 2001 et 2020. Toutes les données cliniques, biologiques, radiologiques et pathologiques ainsi que les résultats ont été collectés et analysés. Trente-neuf patients atteints de mTOR-PI ont été diagnostiqués pendant cette période, 24 en transplantation et 15 en oncologie. La posologie moyenne de l’inhibiteur de mTOR était respectivement de 2,7 mg (±1,7) et 8,8 mg (±2,3). La prévalence globale de mTOR-PI était de 6,4 % avec un délai médian de survenue de 7 mois [IQR 3–35 mois]. Les mTOR-PI étaient significativement plus fréquentes (p < 0,001) et survenaient plus précocement (p < 0,001) chez les patients K. Aucune autre différence clinique, fonctionnelle, radiologique, pathologique ou de sévérité n’a été observée entre les deux groupes. Au moment du diagnostic de mTOR-PI, 14/18 (78 %) des patients transplantés avaient un taux résiduel d’éverolimus dans les normes des valeurs thérapeutiques recommandées. Les pneumopathies aux inhibiteurs de mTOR sont comparables en termes de présentation chez les patients T et K, mais elles surviennent significativement plus tôt après l’introduction du médicament chez ces derniers. Cela pourrait être en partie lié aux différences de posologie utilisées dans ces deux populations.

Journal of the European Academy of Dermatology and VenereologyVolume 34, Issue 9 p. e486-e489 Letter To The Editor Extensive cutaneous and muscular mucormycosis complicating insulin pump treatment V. Berot, V. Berot Department of Dermatology, AP-HP, Henri Mondor Hospital, Créteil, FranceSearch for more papers by this authorC. Bernigaud, Corresponding Author C. Bernigaud charlotte.bernigaud@aphp.fr orcid.org/0000-0002-4563-8927 Department of Dermatology, AP-HP, Henri Mondor Hospital, Créteil, France Research Group Dynamyc, EA7380, Faculté de médecine Université Paris-Est Créteil, Ecole nationale vétérinaire d’Alfort, USC ANSES, Créteil, France Correspondence: C. Bernigaud. E-mail: charlotte.bernigaud@aphp.frSearch for more papers by this authorA. Ferchiou, A. Ferchiou Department of Immunology, AP-HP, Henri Mondor Hospital, Créteil, France INSERM U955, Equipe 21, Université Paris-Est, Créteil, FranceSearch for more papers by this authorS. Ingen-Housz-Oro, S. Ingen-Housz-Oro Department of Dermatology, AP-HP, Henri Mondor Hospital, Créteil, FranceSearch for more papers by this authorS. Hüe, S. Hüe Department of Immunology, AP-HP, Henri Mondor Hospital, Créteil, France INSERM U955, Equipe 16, Université Paris-Est, Créteil, FranceSearch for more papers by this authorC. Ajzenberg, C. Ajzenberg Department of Diabetology and Endocrinology, AP-HP, Henri Mondor Hospital, Créteil, FranceSearch for more papers by this authorS. Thomas, S. Thomas Quality and Risks Management, AP-HP, Henri Mondor Hospital, Créteil, FranceSearch for more papers by this authorE. Wieliczko-Duparc, E. Wieliczko-Duparc Regional Coordinator of Medical Device Surveillance, Materiovigilance et Réactovigilance Ile-de-France, AP-HP, Henri Mondor Hospital, Créteil, FranceSearch for more papers by this authorE. Billaud, E. Billaud Department of Pharmacology, AP-HP, European Georges Pompidou Hospital, Paris, FranceSearch for more papers by this authorN. Ait-Ammar, N. Ait-Ammar Research Group Dynamyc, EA7380, Faculté de médecine Université Paris-Est Créteil, Ecole nationale vétérinaire d’Alfort, USC ANSES, Créteil, France Unit of Mycology and Parasitology, Department of microbiology, AP-HP, Henri Mondor Hospital, Créteil, FranceSearch for more papers by this authorN. Ortonne, N. Ortonne orcid.org/0000-0003-0111-7422 Department of Pathology, AP-HP, Henri Mondor Hospital, Créteil, FranceSearch for more papers by this authorF. Botterel, F. Botterel Research Group Dynamyc, EA7380, Faculté de médecine Université Paris-Est Créteil, Ecole nationale vétérinaire d’Alfort, USC ANSES, Créteil, France Unit of Mycology and Parasitology, Department of microbiology, AP-HP, Henri Mondor Hospital, Créteil, FranceSearch for more papers by this authorO. Chosidow, O. Chosidow Department of Dermatology, AP-HP, Henri Mondor Hospital, Créteil, France Research Group Dynamyc, EA7380, Faculté de médecine Université Paris-Est Créteil, Ecole nationale vétérinaire d’Alfort, USC ANSES, Créteil, FranceSearch for more papers by this author V. Berot, V. Berot Department of Dermatology, AP-HP, Henri Mondor Hospital, Créteil, FranceSearch for more papers by this authorC. Bernigaud, Corresponding Author C. Bernigaud charlotte.bernigaud@aphp.fr orcid.org/0000-0002-4563-8927 Department of Dermatology, AP-HP, Henri Mondor Hospital, Créteil, France Research Group Dynamyc, EA7380, Faculté de médecine Université Paris-Est Créteil, Ecole nationale vétérinaire d’Alfort, USC ANSES, Créteil, France Correspondence: C. Bernigaud. E-mail: charlotte.bernigaud@aphp.frSearch for more papers by this authorA. Ferchiou, A. Ferchiou Department of Immunology, AP-HP, Henri Mondor Hospital, Créteil, France INSERM U955, Equipe 21, Université Paris-Est, Créteil, FranceSearch for more papers by this authorS. Ingen-Housz-Oro, S. Ingen-Housz-Oro Department of Dermatology, AP-HP, Henri Mondor Hospital, Créteil, FranceSearch for more papers by this authorS. Hüe, S. Hüe Department of Immunology, AP-HP, Henri Mondor Hospital, Créteil, France INSERM U955, Equipe 16, Université Paris-Est, Créteil, FranceSearch for more papers by this authorC. Ajzenberg, C. Ajzenberg Department of Diabetology and Endocrinology, AP-HP, Henri Mondor Hospital, Créteil, FranceSearch for more papers by this authorS. Thomas, S. Thomas Quality and Risks Management, AP-HP, Henri Mondor Hospital, Créteil, FranceSearch for more papers by this authorE. Wieliczko-Duparc, E. Wieliczko-Duparc Regional Coordinator of Medical Device Surveillance, Materiovigilance et Réactovigilance Ile-de-France, AP-HP, Henri Mondor Hospital, Créteil, FranceSearch for more papers by this authorE. Billaud, E. Billaud Department of Pharmacology, AP-HP, European Georges Pompidou Hospital, Paris, FranceSearch for more papers by this authorN. Ait-Ammar, N. Ait-Ammar Research Group Dynamyc, EA7380, Faculté de médecine Université Paris-Est Créteil, Ecole nationale vétérinaire d’Alfort, USC ANSES, Créteil, France Unit of Mycology and Parasitology, Department of microbiology, AP-HP, Henri Mondor Hospital, Créteil, FranceSearch for more papers by this authorN. Ortonne, N. Ortonne orcid.org/0000-0003-0111-7422 Department of Pathology, AP-HP, Henri Mondor Hospital, Créteil, FranceSearch for more papers by this authorF. Botterel, F. Botterel Research Group Dynamyc, EA7380, Faculté de médecine Université Paris-Est Créteil, Ecole nationale vétérinaire d’Alfort, USC ANSES, Créteil, France Unit of Mycology and Parasitology, Department of microbiology, AP-HP, Henri Mondor Hospital, Créteil, FranceSearch for more papers by this authorO. Chosidow, O. Chosidow Department of Dermatology, AP-HP, Henri Mondor Hospital, Créteil, France Research Group Dynamyc, EA7380, Faculté de médecine Université Paris-Est Créteil, Ecole nationale vétérinaire d’Alfort, USC ANSES, Créteil, FranceSearch for more papers by this author First published: 03 April 2020 https://doi.org/10.1111/jdv.16406 V.B. and C.B. contributed equally to this work as first authors. F.B. and O.C. contributed equally to this work as senior authors. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Volume34, Issue9September 2020Pages e486-e489 RelatedInformation

Phaeochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumors that arise from the adrenal medulla or sympathetic and parasympathetic ganglia. These tumors produce most often catecholamines in excess, causing hypertension and sometimes severe acute cardiovascular complications. The diagnosis is based on plasma or urines metanephrines measurements and on conventional and nuclear medicine imaging. Catecholamines-producing PPGL is very unlikely if levels are normal. The diagnosis of PPGL cannot be made without visualization of a tumor. Therapeutic management consists mostly of surgical excision, after drug preparation, and should be done in referral centers. About 40% of pheochromocytomas and paragangliomas occur in the context of an autosomal inherited syndrome, making genetic testing essential. The follow-up must be prolonged because a metastatic evolution or a recurrence can be observed in about 15% of the cases.

Objective: Adrenal venous sampling (AVS) is the gold standard to assess lateralization of aldosterone secretion in primary aldosteronism (PA). The selectivity index (SIcortisol, adrenal:peripheral cortisol ratio) determines correct catheter positioning. The lateralization index (LIcortisol, aldosterone:cortisol ratios between adrenal veins) distinguishes unilateral aldosterone producing adenoma (APA) from bilateral adrenal hyperplasia (BAH). Cortisol is not always reliable and metanephrine has been alternatively suggested for SI determination. The aim of our study was to assess the performance of SImetanephrine and LImetanephrine. Design and method: This retrospective study conducted at the HEGP ESH excellence center included 245 patients who had 1) AVS with simultaneous adrenal and peripheral vein samplings without cosyntropin stimulation between 07/2013 and 05/2017, 2) adrenal and peripheral vein samples stored at −80°C to measure retrospectively free metanephrine. Receiver operating characteristic (ROC) curves were used to assess the performance of SImetanephrine and LImetanephrine. Results: Based on SIcortisol and LIcortisol, 198/245 patients had successful AVS (SIcortisol above 2) among whom 108 had APA (LIcortisol above 4) and 90 BAH (LIcortisol below 4). 48/245 patients had failed AVS. Among the 245 AVS, 434 adrenal samples had SIcortisol above 2. A SImetanephrine of 16 was the optimal threshold for successful AVS. This cutoff confirms the selectivity of 22 AVS among the 48 considered as non-selective with SIcortisol. 65 patients underwent unilateral adrenalectomy with 6-month follow up confirming PA biochemical cure (PASO criteria). ROC curve analysis of LImetanephrine plotted APA (n = 65) versus BAH (n = 52) (AUC = 0.954). There was a large overlap of LImetanephrine between APA and BAH. A LImetanephrine threshold of 5 had 80% sensitivity and 95% specificity to distinguish between APA from BAH. Conclusions: We confirmed that SImetanephrine is superior to SIcortisol in assessing the selectivity of AVS. A threshold of 16 for SImetanephrine decreased the rate of AVS falsely considered as failed. In contrast, LImetanephrine did not have enough sensitivity/specificity to distinguish between APA and BAH. The lack of a gold standard to confirm BAH may participate in this finding. A prospective study would be needed to confirm these results

Objective: At least 10% of pheochromocytoma and sympathetic paraganglioma (PPGL) are malignant, yet there is no specific biomarker of malignancy. Societies guidelines sugget the use of 3 Methoxytyramines (3MTT) for the diagnosis of malignancy, however few studies evaluated 24H-urinary 3MTT as a predictor of malignancy. The aim of this study was to evaluate the sensitivity/specificity of 24H-Urinary 3MTT for the diagnosis of malignant PPGLDesign and method: We conducted a retrospective study of electronic registers of Hypertension excellence center of Georges Pompidou hospital, from 2012 to 2015 to identify patients who completed PPGL-workup: Measurement of 24H-Urinary metanephrines/Normetanephrines(MTN/NMT) and 24H-Ur 3MTT by LCMS, Imaging exams to confirm/exclude PPGL, histopathological diagnosis of PPGL after surgery. We excluded from our analysis patients without the diagnosis of PPGL, under medications interacting with MTN/NMT/3MTT secretion, or without 24H-Ur 3MTT determination Determination of 24H-Ur MTN/NMT/3MTT was made by LCMS method with validated protocol. We first analysed ROC parameters for 24h-Ur 3MTT, then those of 24H-Ur 3MTT to 24H-Ur creatinine ratio. Results: 47 patients were included in this study:8 malignant PPGL and 39 non malignant PPGL. ROC curve of sensitivity(1-specificity) of 24h-Ur 3MTT for the diagnosis of PPGL malignancy showed an area under curve(AUC) of 0.671[95%CI 0.519–0.801]: The optimal criterion of the curve corresponded to a value of 24h-Ur 3MTT of 4.67 μmol/24 h and showed a specificity of 82.05% and sensitivity of 62.5% for malignancy diagnosis. A value > 12 μmol/24 h of 24h-Ur 3MTT offered 100% specificity with 37.5% of sensitivity ROC curve of sensitivity(1-specificity) of 24h-Ur 3MTT/24h-Ur Creatininuria for the diagnosis of PPGL malignancy showed an AUC of 0.774 [95%CI 0.629–0.883]: The optimal criterion of the curve was 1.25 μmol/mmol with a specificity of 94.87% and a sensitivity of 50% for the diagnosis of malignancy. A value of 24h-Ur 3MTT/Cr > 1.73 μmol/mmol offered 100% specificity with 25% sensitivity. Conclusions: These data sugget that 24h-Urinary 3MTT measured by LCMS and 24h-Ur 3MTT to creatinine ratio could be used as valuable biomarkers for the diagnosis of malignant PPGL. Values superior to 4.67 μmol/l and 1.25 μmol/mmol respectively offered the best compromise between high specificities and average sensitivities.

Les patients diabétiques sont à risque de mucormycose, se manifestant habituellement par des lésions nécrotiques de la face. L'incidence dans cette population a augmenté de 9 % entre 2001 et 2006. Nous rapportons une forme clinique rare de cette pathologie. Un dispositif à délivrance continue sous-cutanée sur 72 h d'insuline (OmniPOD®) était prescrit à une patiente de 64 ans diabétique devant des difficultés d'équilibre glycémique. À 5 mois apparaissait un nodule inflammatoire au site de la pompe puis un placard inflammatoire du bras gauche extensif malgré 3 antibiothérapies successives et des cordons sous-cutanés indurés du sein gauche et du cou. La biopsie cutanée (HES, PAS et Gomori–Grocott) montrait un infiltrat éosinophilique dense dermo-hypodermique avec vascularite oblitérante et multiples filaments mycéliens larges, irréguliers, non septés dans les vaisseaux évoquant une mucormycose. La PCR Mucorales et la culture sur biopsie identifiaient Rhizopus sp (PCR sérique négative). La TEP-IRM montrait une atteinte cutanée, sous-cutanée et musculaire cervicothoracique antérieure et brachiale gauche sans extension endovasculaire ou cérébrale. Un débridement chirurgical était récusé devant l'extension des lésions. Un traitement par amphotéricine B liposomale était débuté. Le dispositif était retiré et le diabète équilibré. Devant une aggravation locale, l'isavuconazole (IZV) IV à 600 mg était ajouté à j11. On observait une rapide réduction des lésions dès j5 de bithérapie sans effet indésirable. L'IZV per os à 200 mg était poursuivi seul après 14 jours de bithérapie. À 6 mois de traitement une rémission clinique et mycologique était observée. Aucun déficit immunitaire humoral (dosage des sous-classes d'IgG) ou cellulaire (test d'explosion oxydative) n'était retrouvé hormis une surexpression de PD-1 sur les lymphocytes TCD8+. Il n'existait pas d'autres cas de mucormycose compliquant l'utilisation d'OmniPOD® après enquête de la matériovigilance (Fig. 1 et 2). Il s'agit du premier cas de mucormycose cutanée suite à l'utilisation de dispositif de délivrance d'insuline ou de lecture de glucose en continu. Une enquête de la matériovigilance a trouvé 2 cas de dermo-hypodermite (germes pyogènes) dont une fasciite nécrosante fatale. Trois cas de mucormycoses ont été publiés suite à des injections itératives d'insuline. Cette présentation clinique à type de dermo-hypodermite est rare. La pénétration de ce champignon de l'environnement semble liée à l'effraction cutanée par l'aiguille. La surexpression de PD-1 retrouvée chez notre patiente est décrite dans un cas de mucormycose disséminée au cours de laquelle une immunothérapie par nivolumab et interféron a permis la guérison. Une mucormycose doit être évoquée devant tout placard inflammatoire survenant lors de l'utilisation de ces nouveaux dispositifs.

Background: Leflunomide is an immunosuppressive agent commercialized for treatment of rheumatoid arthritis. Because of its immunosuppressive and possible antiviral properties, leflunomide has been evaluated in some case series of BKVAN with favorable results, mostly in adult patients. Leflunomide targeted levels are usually between 50 and 100 mg/L in kidney transplant adult patients. Data in pediatric population are scarce. Objective: To assess the effect of leflunomide on BKvirus in kidney-transplanted children. Methods: Therapeutic drug monitoring of leflunomide is routinely performed by measuring its active metabolite, teriflunomide, using a simple HPLC-UV method. Pediatric kidney transplant patients with at least one teriflunomide sample between 2010 and 2017 were retrospectively included in this study. Viremia control was defined as undetectable BK viremia or a decrease of more than 1 log in the viral load from the baseline after two months of treatment. Adverse events were recorded. Results: A total of 7 patients from 3 centers was included. 6 were only kidney transplant recipients; 1 was a lung-kidney transplant recipient with cystic fibrosis. All patients reported high load BK viremia but none developed BKVAN. For 67% of the patients, complete BK viral clearance was observed during leflunomide treatment with drastic immunosuppressive therapy reduction. Mycophenolate was indeed discontinued in almost all patients. Of note, leflunomide concentrations were significantly higher when viremia was controlled. Only 33% of the observed concentrations were >40 mg/L. The patient with cystic fibrosis had lower concentrations with higher drug doses. No hepatotoxicity was observed in this study and no patient experienced graft rejection. Leflunomide was suspected to cause hemolytic anemia and one patient experienced biological pancreatitis. Conclusion: This study evidenced the wide interindividual variability of the exposure and supported the routine practice of leflunomide with a suggested target level of 30-40 mg/L in pediatric kidney transplanted patient. However, because of the very limited number of patients in our series, further investigations are needed to validate this suggestion.

Objective: -To determine reference intervals of plasma metanephrines(pl-MTN) and normetanephrines(pl-NMT) measured by Liquid chromatography with mass-spectrometry(LC-MS), in semi-recumbent standardized position in hypertensive population referred to an excellence center. -To evaluate the sensitivity/specificity of pl-MTN/pl-NMT in semi-recumbent position compared to seated position,and 24 h urinary metanephrines (24hUr-MTN) for the diagnosis of secreting pheochromoctyoma/paraganglioma(PPGL). -To evaluate the correlation between plasma and urinary MTN/NMTby LC-MS method.Design and method: We conducted a retrospective overview of electronic registers of the Hypetension Unit of Georges Pompidou European hospital, from May 2014 to May 2016 to identify patients who completed a PPGL workup: -concomitant determination of plasma and urinary MTN/NMT by LCMS, -Imaging examinations to confirm/exclude PPGL. -The diagnosis of PPGL was made after surgery by histopathology. All patients under medications interacting with MTN/NMT secretion were excluded. 250 patients corresponded to the inclusion criteria, 169 had a pl-MTN/NMT determination after 30 minutes of semi-recumbent standardized position (145 negative/24 positive for PPGL), and 81 were sampled in seated position (69 negative/12 positive for PPGL)(fig1). Reference intervals were established from the (2.5th-97.5th)percentiles in patients without PPGL. Results: -Reference intervals in standardized semi recumbent position were estimated at [0.1–0.47nmol/l] for pl-MTN and [0.23–1.10nmol/l] for pl-NMT -Compared to the seated group, the semi-recumbent group showed a significantly lower mean value of pl-NMT (0.59 ± 0.23 Vs 0.72 ± 0.34nmol/l p = 0.006), with a lower ’upper reference interval value’(URV)[1.10 Vs 1.5nmol/l] -ROC analysis of pl-NMT for the diagnosis of PPGL showed an increased AUC (0.995 Vs 0.958), a higher sensitivity (95.8% Vs 91.6%) and specificity (97.2% Vs 97.1%) at the URV (97.5th percentile)in the semi-recumbent group Vs seated group. -Comparison of ROC paremeters of pl-NMT in semi-recumbent position, 24hUr-NMT and 24hUrNMT/creatininuria at optimal criterions for the diagnosis of PPGL showed the highest combination of sensitivity/specificity for pl-NMT (95.8%/97.2%) vs (94.4%/95.7%) for 24hUr-NMT and (91.6%/96.7%) for 24hUrNMT/Creatininuria. -Pl-NMT correlated to 24hUr-NMT with a correlation coefficient r = 0.971 (p < 0.0001) Conclusions: pl-NMT measured by LC-MS in semi-recumbent position offered high sensitivity/specificity values for the diagnosis of PPGL. Reference intervals described in our study are comparable to those previously reported in the literature. pl-MTN/NMT correlated well to Ur-MTN/NMT.

Objective: Suboptimal drug adherence may prove to be the greatest barrier to the effectiveness of antihypertensive agents (AHT). Thanks to LC-MS/MS technology, urinary drug detection (UDD) may represent an important advancement to monitor non-adherence in routine clinical practice. Our aim was to assess drug adherence by UDD and compare it to the 4-item Morisky Medication Adherence Scale (MMAS-4). Design and method: 169 patients (68 ± 11 yrs, 58 % women) with primary hypertension followed in the out-patient clinic of a university hospital were included. They received a median of 2 AHT (range 1–4) and most had controlled office BP. MMAS-4 was filled out and urine sampling was performed immediately after oscillometric BP measurement by a nurse and before the visit with the physician. Adherence to prescribed AHT was assessed by LC-MS/MS detection in the urine sample. UDD non-adherence was defined as presence of undetected urine levels of at least one prescribed AHT. Patients were not aware of the measurement. MMAS-4 non-adherence was defined as a score > 0. UDD was taken as a reference. Results: UDD full adherence (detection of all AHT) was observed in 157 patients (67 ± 11 yrs, 131 ± 14/ 72 ± 9 mmHg), and non-adherence in 12 patients (7%) only (73 ± 7 yrs, 144 ± 18/74 ± 13 mmHg; p = 0.01 vs full-adherence). MMAS-4 non adherence was observed in 16% patients. Compared to UDD used as a reference, MMAS-4 had a sensitivity of 84.7% and a specificity of 16.7%. A weak agreement was found between UDD and MMAS-4, with 33/162 non concordant tests. In multivariate analysis, the determinants of UDD non-adherence were office SBP (OR 0.95, IC [0.91- 0.99] per 1 mmHg, p = 0.04,) and diuretic + beta-blocker combination (OR 0.1, IC [0.01 – 0.88], p = 0.03) but not MMAS-4. In multivariate analysis, the only determinant of MMAS-4 non-adherence was age (OR 1.04, IC [1.01–1.08], p = 0.02). Conclusions: In conclusion, the Morisky-4 items questionnaire proved a limited effectiveness in detecting non-adherent patients. Objective measurement of non-adherence, such as urinary detection of AHT, is applicable to clinical practice, providing that LCMS/MS technique is available in the clinical center. Multivariate analyses showed that UDD captured the classical predictors of non-adherence.

Objective: Adherence to antihypertensive treatment (AHT) is usually assessed by scales such as Morisky Medication Adherence Scale questionnaire (MMAS-4) but objective urinary drug levels quantification by liquid chromatography mass spectrometry (LCMS-MS) is now available. Our aim was to compare adherence assessed by LCMS-MS or MMAS-4, in patients with resistant hypertension (RH), compared to patients with well controlled hypertension (CH). Design and method: RH cohort consisted in 82 patients with daytime ABPM > 135/85 mmHg after 4 weeks treatment with a standardised triple AHT participating to a clinical trial. The CH cohort consisted in 91 patients followed in a routine care practice with controlled office BP (<140/90 mmHg) by a median of 2 (range 1–4) AHT. Urinary levels of 14 AHT or their metabolites were evaluated by LC/MS-MS. MMAS-4 was only available in CH. Patients were aware (RH) or not (CH) of the measurement. Non-adherence was defined as a urinary level of at least one AHT below the limit of quantification. Results: LCMS-MS results: in the RH cohort, 63 patients (77%) were adherent, 11 (13%) were partly non-adherent and 8 (10%) were fully non-adherent. In the CH cohort, 86 (93%) were adherent, 5 (6%) were partly non-adherent, and 1 (1%) was fully non-adherent. Office SBP in the CH cohort was significantly higher in non-adherent (partially or fully) than in fully adherent patients (median: 140 vs. 130 mmHg, respectively; p = 0.01). Office DBP did not differ. According to LCMS-MS, the full adherence rate was significantly higher in CH compared to RH cohort (p = 0.002). According to MMAS-4 available in 88 CH patients, 76 (86%) were fully adherent, and 12 (14%) were medium or low adherent and no significant difference in office SBP/DBP was observed between the two subgroups. There was low or no agreement between LCMS-MS and MMAS-4, with 15/88 non concordant tests. Conclusions: In conclusion, measurement of urinary AHT by LCMS-MS gives relevant information on adherence to treatment in patients attending an outpatient clinic. This information is not overlapping with questionnaire tests. It confirms the role of objective non-adherence to treatment in resistance to treatment.

Purpose. - The effectiveness of posaconazole (PSZ) prophylaxis on invasive fungal infections, in patients presenting with acute myeloid leukemia (AML), seems to be correlated to its blood plasma concentration. Our goal was to identify the risk factors for underdosing.Patients and methods. - We retrospectively reviewed the records of patients treated for AML treated with PSZ, during a 2-year period. Assays<500 ng/mL were considered as under dosed.Results. - Fifty-nine assays (43 patients) were performed during induction (n=22) or consolidation (n=37) chemotherapy. PSZ treatment was initiated within a median of 3 days before neutropenia with a first assay performed at 8 days (3-28). The median PSZ blood plasma concentration was 375 ng/mL (<200-1900). Forty-one (69%) treatment were maintained until the end of neutropenia. One patient presented with candidemia, 9 with possible invasive aspergillosis, without any significant association with underdosing. The univariate analysis showed that co-administration of proton pump inhibitors (PPIs) (P=0.01) and cause of hospitalization (induction chemotherapy vs consolidation, P=0.008) were associated with underdosing, contrary to feeding difficulties (P=0.07) and digestive disorders (P=0.5). The multivariate analysis confirmed the impact of PPI use (P=0.01) and the cause of hospitalization (P=0.003).Conclusion. - This study highlights the major impact of PPI administration on PSZ blood plasma levels and stresses the risk of non-effective prophylaxis during induction treatment of AML. (C) 2014 Elsevier Masson SAS. All rights reserved.

The in vitro antifungal activities of essential oil from Cuminum cyminum (C. cyminum) and alcoholic extract from Salvadora persica (S. persica) were investigated in order to evaluate their efficacy against C. albicans ATCC 14053, C. dubliniensis ATCC CD60, C. glabrata ATCC 90030, C. krusei ATCC 6258 and C. parapsilosis ATCC 22019.The essential oil was obtained by hydrodistillation in a Clevenger apparatus and analyzed by gas chromatography/mass spectroscopy (GC/MS). The disc diffusion and broth macrodilution methods were used as antifungal susceptibility tests.The GC/MS analysis allowed 17 components to be determined; the main constituents of C. cyminum essential oil were α-pinene (30%), limonene (21%) and 1,8-cineole (18.5%). C. cyminum oil had a broad-spectrum antifungal activity against different pathogenic Candida species. Inhibition zone values ranged from 7 to 50 mm for C. cyminum and 0 to 10 mm for S. persica against the organisms tested. The best minimal inhibitory concentration (MIC) of C. cyminum oil was associated with C. albicans and C. dubliniensis (289 mg/L) and the MICs of S. persica extract were 4.9 mg/mL and 20 mg/mL against C. albicans and C. dubliniensis, respectively.The results suggested the potential substitution of the antifungal chemicals by C. cyminum essential oil and S. persica alcoholic extract as natural inhibitors to control the growth of the most important pathogenic Candida species and alternative therapies for candidiasis.L’activité antifongique in vitro d’huile essentielle de Cuminum cyminum (C. cyminum) et d’extrait alcoolique de Salvadora persica (S. persica) a fait l’objet d’une étude afin d’évaluer leur efficacité contre C. albicans ATCC 14053, C. dubliniensis ATCC CD60, C. glabrata ATCC 90030, C. krusei ATCC 6258 et C. parapsilosis ATCC 22019.L’huile essentielle est obtenue par hydrodistillation des feuilles dans un appareil Clevenger et est analysée par chromatographie en phase gazeuse/spectrométrie de masse (GC/MS). La technique de diffusion avec des disques et de la macrodilution en milieu liquide ont été utilisées comme tests de sensibilité antifongique.L’analyse GC/MS a permis d’analyser 17 composants ; les principaux constituants de l’huile essentielle de C. cyminum étaient α-pinène (30 %), limonène (21 %) et 1,8 -cineole (18,5 %). L’huile de C. cyminum avait un large spectre d’activité antifongique contre différents espèces pathogènes de Candida. Les zones d’inhibition variaient de 7 à 50 mm pour C. cyminum et de 0 à 10 mm pour S. persica contre les organismes testés. Les meilleures concentrations minimales inhibitrices (CMI) de l’huile de C. cyminum étaient associées à C. albicans et C. dubliniensis (289 mg/L) et les CMIs de l’extrait de S. persica étaient de 4,9 mg/mL et 20 mg/mL contre C. albicans et C. dubliniensis, respectivement.Les résultats suggèrent la possibilité de remplacer des produits chimiques antifongiques par de l’huile essentielle C. cyminum et par un extrait alcoolique naturel de S. persica comme inhibiteur de la croissance des plus importantes espèces pathogènes de Candida et comme thérapies alternatives pour la candidose.

Mucormycosis is a rare, invasive and fatal disease that occurs mainly in diabetes mellitus patients with uncontrolled blood glucose levels or in immunocompromised patients. The mortality rate of this disease is as high as 25 to 80%, despite aggressive surgical treatment and antifungal therapy. This high mortality requires alternative treatment approaches. The accepted treatment modality of invasive mucormycosis are amphotericin B lipid formulations. Although echinocandins generally show no activity against Mucorales, it was shown that Rhizopus oryzae expressed the target enzyme for echinocandins, 1,3-beta-glucan synthase. Additionally, there are some experimental studies in a diabetic mouse model and case reports regarding the effects of caspofungin. In this report, we present a rhinocerebral mucormycosis case treated with liposomal amphotericin B and caspofungin. There was regression of the patient's clinical and radiological condition with the addition of caspofungin, but she died due to discontinuation of her treatment and reasons other than mucormycosis.La Mucormycose est une maladie rare, invasive et mortelle qui survient principalement chez les patients atteints de diabète avec une glycémie non maîtrisée ou chez des patients immunodéprimés. Le taux de mortalité de cette maladie peut atteindre 25 à 80 %, malgré la mise en place d’un traitement chirurgical et antifongique. Cette mortalité élevée nécessite des approches thérapeutiques alternatives. Le traitement de la mucormycose invasive est classiquement basé sur l’utilisation des formulations lipidiques de l’amphotéricine B. Bien que les échinocandines ne montrent généralement aucune activité contre la classe des Mucorales, il a été montré que Rhizopus oryzae exprime l’enzyme cible des échinocandines, la 1,3-bêta-glucane synthase. En outre, il existe quelques études expérimentales à partir d’un modèle de souris diabétique et des cas rapportés d’activité de la caspofungine. Dans ce travail, nous présentons un cas de mucormycose rhino-cérébrale traité par l’amphotéricine B liposomale et la caspofungine. Il a été constaté une régression des signes cliniques et radiologiques chez ce patient lors de l’adjonction de la caspofungine. Le décès est cependant intervenu en raison de l’interruption de son traitement et de raisons autres que la mucormycose.