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International audience; Background and aimsTo evaluate the prevalence and prognostic value of metabolic syndrome (MetS) in patients admitted for coronavirus disease 2019 (COVID-19).Methods and resultsIn this monocentric cohort retrospective study, we consecutively included all adult patients admitted to COVID-19 units between April 9 and May 29, 2020 and between February 1 and March 26, 2021. MetS was defined when at least three of the following components were met: android obesity, high HbA1c, hypertension, hypertriglyceridemia, and low HDL cholesterol. COVID-19 deterioration was defined as the need for nasal oxygen flow ≥6 L/min within 28 days after admission.We included 155 patients (55.5% men, mean age 61.7 years old, mean body mass index 29.8 kg/m2). Fifty-six patients (36.1%) had COVID-19 deterioration. MetS was present in 126 patients (81.3%) and was associated with COVID-19 deterioration (no-MetS vs MetS: 13.7% and 41.2%, respectively, p < 0.01). Logistic regression taking into account MetS, age, gender, ethnicity, period of inclusion, and Charlson Index showed that COVID-19 deterioration was 5.3 times more likely in MetS patients (95% confidence interval 1.3–20.2) than no-MetS patients.ConclusionsOver 81.3% of patients hospitalized in COVID-19 units had MetS. This syndrome appears to be an independent risk factor of COVID-19 deterioration.

Background Reduced mortality at 28 days in patients treated with corticosteroids was demonstrated, but this result was not confirmed by certain large epidemiological studies. Our aim was to determine whether corticosteroids improve the outcomes of our patients hospitalized with COVID-19 pneumonia. Methods Our retrospective, single centre cohort study included consecutive patients hospitalized for moderate to severe COVID-19 pneumonia between March 15 and April 15 2020. An early short course of corticosteroids was given during the second phase of the study. The primary composite endpoint was the need for mechanical ventilation or mortality within 28 days of admission. A multivariate logistic regression model was used to estimate the propensity score, i.e. the probability of each patient receiving corticosteroid therapy based on the initial variables. Results About 120 consecutive patients were included, 39 in the “corticosteroids group”, 81 in the “no corticosteroids group”; their mean ages (±SD) were 66.4 ± 14.1 and 66.1 ± 15.2 years, respectively. Mechanical ventilation-free survival at 28 days was higher in the “corticosteroids group” than in the “no corticosteroids group” (71% and 29% of cases, respectively, p

Previous studies have found a correlation between malnutrition and prognosis in respiratory infections. Our objectives were to determine (i) the percentage of malnutrition, and (ii) its prognosis in patients admitted for coronavirus disease 2019 (COVID-19). In this monocentric retrospective study, we consecutively included all adult patients presenting with acute COVID-19 between 9 April and 29 May 2020. Malnutrition was diagnosed on low body mass index (BMI) and weight loss &ge, 5% in the previous month and/or &ge, 10% in the previous six months. The Nutritional Risk Index (NRI) defined nutritional risk. Severe COVID-19 was defined as a need for nasal oxygen &ge, 6 L/min. We enrolled 108 patients (64 men, 62 &plusmn, 16 years, BMI 28.8 &plusmn, 6.2 kg/m2), including 34 (31.5%) with severe COVID-19. Malnutrition was found in 42 (38.9%) patients, and moderate or severe nutritional risk in 83 (84.7%) patients. Malnutrition was not associated with COVID-19 severity. Nutritional risk was associated with severe COVID-19 (p &lt, 0.01, p &lt, 0.01 after adjustment for C reactive protein), as were lower plasma proteins, albumin, prealbumin, and zinc levels (p &lt, 0.01). The main cause of malnutrition was inflammation. The high percentage of malnutrition and the association between nutritional risk and COVID-19 prognosis supports international guidelines advising regular screening and nutritional support when necessary.

Introduction L’obésité et l’hypertension artérielle sont fréquentes en cas de forme sévère de COVID-19. À ce jour la caractérisation de l’obésité associée n’a pas été décrite. Notre objectif était d’évaluer la prévalence et la valeur pronostique des composantes du syndrome métabolique. Matériels et méthodes Nous avons conduit une étude monocentrique rétrospective dans notre hôpital du 9 avril au 29 mai 2020. Étaient inclus tous les patients adultes hospitalisés pour la première fois en service COVID aigu, et atteints d’une pneumopathie à Sars-Cov-2 prouvée (scanner compatible et/ou PCR Sars-Cov-2 positive). Le critère d’évaluation de la sévérité était l’administration d’un débit d’oxygène supérieur à 6 L/minute pendant le séjour, dans la limite de 28 jours. Le syndrome métabolique était défini par la présence d’au moins trois des cinq critères suivants : hyperglycémie à jeun (diabète connu ou découvert pendant l’hospitalisation, ou glycémie à jeun > 6,1 mmol), hypertension artérielle (hypertension artérielle connue ou diagnostiquée pendant l’hospitalisation), hypertriglycéridémie (à jeun > 1,7 mmol/L ou traitement par fibrates), taux abaissé d’HDL cholestérol ( 88 cms [femmes] ou > 102 cms [hommes]). Résultats Cent neuf patients ont été inclus dont 59,6 % étaient des hommes. L’âge moyen était de 61,8 ans. L’indice de masse corporelle moyen était de 28,9 kg/m2. Trente-cinq patients (32,1 %) ont présenté une pneumopathie sévère. Sur les 97 patients dont le statut « syndrome métabolique » était connu, 70 présentaient un syndrome métabolique (72,2 %). Soixante-neuf patients (65,9 %) présentaient une hyperglycémie à jeun, 63 (57,8 %) une hypertension artérielle, 36 (35,6 %) une hypertriglycéridémie, 81 (83,5 %) un taux bas de cholestérol HDL, 67 (65,0 %) un tour de taillé élevé. Sur les 92 patients pour lesquels les cinq critères du syndrome métabolique étaient disponibles, 2 patients (2,2 %) ne présentaient aucun critère, 8 (8,7 %) présentaient un seul critère, 17 (18,5 %) deux critères, 24 (26,1 %) trois critères, 41 (44,6 %) 4 ou 5 critères. Le syndrome métabolique était plus fréquent en cas de pneumopathie sévère que non sévère (93,5 vs 62,1 %, p

Introduction Des études ont montré une corrélation positive entre dénutrition et sévérité des infections pulmonaires. L’objectif de cette étude était de déterminer : (i) la prévalence de la dénutrition ; et (ii) son pronostic chez des patients hospitalisés pour pneumopathie à SARS-Cov-2. Matériels et méthodes Nous avons réalisé une étude monocentrique rétrospective dans notre hôpital en incluant consécutivement tous les adultes présentant une pneumopathie à SARS-Cov-2 (scanner compatible et/ou PCR COVID-19 positive), nécessitant une hospitalisation en service COVID aigu (hors réanimation) du 9 avril au 29 mai 2020. Nous avons recueilli leurs informations phénotypiques, la présentation de l’infection et les données biologiques. La dénutrition était définie selon : (i) des paramètres cliniques considérant l’index de masse corporelle (IMC) et la variation de poids en un et six mois avant l’admission et ; (ii) un marqueur clinicobiologique (Nutritional Risk Index (NRI) : 1,519 × albuminémie (g/L) + 0,417 × (poids actuel/poids usuel) × 100). Le critère de gravité était l’administration d’un débit d’oxygène supérieur à 6 L/min pendant le séjour, dans la limite de 28 jours. Résultats Nous avons inclus 109 patients (65 hommes, 62 ± 16 ans, IMC 29 ± 6 kg/m2, diabète de type 2 : 42 %, hypertension : 56 %), dont 35 ont présenté une forme grave (32 %). La prévalence de la dénutrition clinique était de 39 %, sans différence (p = 0,11) entre formes graves (50 %) ou non (33 %) ; tandis que la dénutrition définie par le NRI (modérée 49 %, sévère 36 %) était plus fréquente en cas de forme grave (p

Vitamin K antagonists (VKA) are drugs with a major risk of side effect. Guidelines have been published in 2008 by the Haute Autorité de santé (HAS) concerning the management of an excessively elevated INR ratio. Our research aimed to assess physicians' adherence to those guidelines.We realized a retrospective, multicentric study. One hundred and ten cases of excessively elevated INR ratio were identified and analyzed.Overall physicians adherence was 58%. However, patients with the most elevated INR, i.e., INR6, were treated according to guidelines in only 33% of the cases. The use of vitamin K was the major source of mistakes. The rate of mortality was 20%.Adherence to HAS guidelines seems finally limited. It is necessary to put in place procedures to secure the behavior of physicians.

Resume Objectifs L’existence de troubles du sommeil, dont le syndrome d’apnee obstructive du sommeil entraine une hyperactivite du systeme nerveux sympathique responsable en partie de l’elevation des chiffres tensionnels et du caractere parfois resistant de l’hypertension arterielle chez les patients traites. Si quelques etudes ont demontre une elevation reversible apres appareillage des derives methoxyles urinaires chez les patients porteurs d’un syndrome d’apnee obstructive du sommeil, les donnees correlant chez les hypertendus, l’index d’apnees-hypopnees a la secretion des derives methoxyles urinaires sont rares. Patients et methodes Vingt patients hypertendus consecutifs admis pour bilan d’hypertension arterielle ayant beneficie au cours de la meme evaluation d’une polygraphie nocturne et d’un dosage des derives methoxyles urinaires des 24 h ont ete inclus. Resultats Patients hypertendus d’âge moyen 51 ± 11 ans (30–76), 68 % d’hommes. Le diagnostic de syndrome d’apnee obstructive du sommeil a ete pose chez 13 d’entre eux a l’issue du bilan. L’index d’apnee-hypopnee moyen etait de 14 ± 9 (2–32). Seules les normetanephrines urinaires de 24 h (1931 ± 1285 vs 869 ± 293 nmol/24 h ; p r = 0,486 ; p = 0,035). Conclusions Cette etude pilote confirme l’existence d’une elevation chronique elective des normetanephrines urinaires/24 h chez les patients hypertendus avec un syndrome d’apnee obstructive du sommeil et objective une correlation significative entre la severite des troubles du sommeil, exprimee par l’index apnee-hypopnee, et l’excretion des derives methoxyles urinaires.

In this study, we compare the responses of downhole magnetometric resistivity (MMR) and downhole electric resistance tomography (ERT) due to changes in electric resistivity consecutive to CO2 injection in a saline aquifer. The results indicate that a smaller volume of CO2 is detectable with MMR, for noise levels inferred from field data. This is attributed to the fact that the MMR method is sensitive to current density variations and not to absolute values of resistivity. Consequently, the MMR response is not affected by the problem of noise in conductive media, as is the case for ERT (very weak electrical potential in conductive environments). Moreover, sensitivity maps show that the sensitivity patterns have broader extents for MMR.

The management of hypertensive patients is greatly influenced by blood pressure levels and accurate measurement of blood pressure is crucial in this context. Mercury sphygmomanometer has been progressively replaced by more precise oscillometric devices that can be widely used in the clinic and ambulatory setting. The purpose of this review was to detail the different methods for evaluating blood pressure, and to refine their indications and clinical benefit. Office blood pressure measurement has a great variability and should follow a strict protocol to give consistent results. National and international guidelines focus on blood pressure measurement in the ambulatory setting. When used by trained patients, home blood pressure monitoring is reproducible and can provide substantial prognostic information, even if ambulatory blood pressure monitoring remains the gold standard. The role of central blood pressure and pulse wave velocity monitoring in the therapeutic strategy of hypertension needs further assessment.

Introduction Les antivitamines K (AVK) sont une cause majeure de iatrogenie medicamenteuse et de morbi-mortalite. Les surdosages sont frequents en milieu hospitalier, en raison des pathologies aigues intercurrentes, et leur gestion a fait l’objet de recommandations qui font reference en France [1] . L’objectif de ce travail a ete de verifier si la prise en charge de ces situations etait en adequation avec les recommandations de bonne pratique de la HAS. Patients et methodes Cette etude retrospective unicentrique a ete menee au sein d’un CHU d’Ile-de-France. Tous les internes y recoivent en debut de semestre une formation adaptee a la prise en charge des surdosages en anticoagulants. Tous les surdosages, definis par un INR > 4, survenus entre le 01/09/2016 et le 22/11/2016 ont etaient recenses par le laboratoire d’hemostase et l’adequation de la prise en charge avec les recommandations de la HAS ete evaluee par 2 investigateurs independants par une relecture des dossiers informatiques et des historiques de prescription. Resultats Cent soixante-douze surdosages en AVK ont ete analyses durant cette periode (pour un total de 102 patients), avec des patients d’âge moyen 79 ± 12 ans (extremes 28/101). Les AVK etaient prescrits pour une cause cardio-embolique dans 77 % des cas. Quatre-vingt-deux pour cent des patients etaient dans un service de medecine, 18 % en urgences/reanimation, aucun en chirurgie. Du fait du caractere retrospectif de l’etude, nous n’avons pas pu determiner l’adherence aux recommandations dans 18 % des cas car la prise en charge n’avait pas ete detaillee dans le dossier medical ou infirmier. Globalement, 48 % des prises en charge etaient en accord avec les recommandations. Neanmoins, pour les surdosages les plus importants, c.-a-d. INR > 6, le taux d’adequation s’etablissait a 30 %. L’erreur la plus frequente etait l’absence d’arret des AVK, dans 12 % des cas, ainsi que l’absence de controle de l’INR a H24 dans 34 % des cas. Le taux de mortalite hospitaliere de la cohorte etait de 27 % (n = 28) dont 1 deces en lien direct avec le surdosage medicamenteux. Conclusion La prise en charge hospitaliere des surdosages en AVK est largement perfectible et represente une source non negligeable d’amelioration des pratiques et de diminution de la iatrogenie medicamenteuse. Des procedures visant a securiser les comportements des prescripteurs pourraient passer par une centralisation et une seniorisation de la decision therapeutique en cas de surdosage severe, a l’instar des prescriptions complexes en infectiologie.

Introduction Les accidents des anticoagulants representent la premiere cause d’accident iatrogene grave. L’indication du traitement dans la fibrillation atriale est a reevaluer en permanence notamment en raison de la survenue d’evenements intercurrents, et en particulier apres la survenue d’un surdosage grave. Il existe neanmoins peu de donnees de suivi de ces patients dans la vie reelle. Patients et methodes L’objectif principal est d’evaluer la morbi-mortalite a 2 ans des patients hospitalises pour un surdosage en anticoagulant, traites pour une fibrillation atriale non valvulaire. Le critere d’evaluation principal etait le pourcentage de patients pour lesquels, au moins, un evenement medical grave est survenu dans les deux ans qui suivent une hospitalisation pour surdosage en anticoagulant. Un evenement medical grave etait defini par la survenue d’un deces, d’une hemorragie grave, d’un surdosage avec un INR superieur a 6, d’un accident vasculaire cerebral, d’une ischemie aigue. Les objectifs secondaires etaient notamment de definir le pourcentage de patients pour lesquels le traitement anticoagulant a ete interrompu ou poursuivi au cours de l’hospitalisation apres une evaluation de la balance benefice risque, definir les caracteristiques des deux groupes et d’evaluer si la decision d’arreter le traitement anticoagulant a ete suivie par les medecins referents du patient a la sortie d’hospitalisation. Il s’agit d’une etude retrospective, monocentrique, observationnelle et descriptive, menee au centre hospitalier universitaire d’Avicenne, portant sur 100 patients consecutifs hospitalises entre 2011 et 2015. Les criteres d’inclusions etaient notamment la fibrillation atriale non valvulaire, tout anticoagulant confondu, un motif d’hospitalisation principal ou associe defini par une hemorragie grave ou un surdosage en anticoagulant avec un INR superieur a 6. Un critere d’exclusion etait une anticoagulation pour tout autre motif qu’une fibrillation atriale non valvulaire. Resultats Cent patients (âge moyen 83 ± 8 ans) ont ete inclus. Quatre-vingt douze pour-cent des patients etaient traites par AVK. Au cours de la periode de suivi, 73 patients ont presente un evenement medical grave et 50 patients sont decedes. Le traitement anticoagulant avait ete interrompu pour 42 patients a l’issue de l’hospitalisation. Les facteurs associes a l’arret du traitement etaient un âge moyen plus eleve (84,7 ans vs 81,7 ans ; p = 0,06) et un score moyen HASBLED plus eleve (p = 0,08), le score CHA2DS2VASc et la proportion de co-morbidites n’etaient pas differents. Il est survenu autant d’evenements medicaux graves dans les deux groupes (31/42 vs 42/58). Il existait une tendance non significative a un taux de mortalite a deux ans plus important dans le groupe arret du traitement (59 % groupe arret, 43 % groupe poursuite). La survenue d’une infection aigue etait la cause de surdosage la plus frequente (36 %). Le traitement a ete plus souvent interrompu en cas d’hemorragie grave a l’admission. En cas de surdosage asymptomatique le traitement etait majoritairement poursuivi a la sortie. La decision d’arret du traitement a ete suivie par les medecins referents dans 74 % des cas. Il est survenu autant d’evenements medicaux graves pour les patients que la consigne d’arret du traitement ait ete suivie ou non. Conclusion Notre etude effectuee dans la vie reelle (hors essais cliniques) montre le pronostic tres pejoratif a moyen terme d’un accident sous anticoagulants, dans la population âgee hospitalisee. Ainsi, la survenue d’un surdosage grave ayant necessite une hospitalisation apparait comme un marqueur puissant de ce risque evolutif, independamment de la decision therapeutique prise a l’issue de l’incident. La reprise ou non des anticoagulants ne doit pas donc reposer uniquement sur l’evaluation des scores classiques, dont la pertinence peut etre discutee dans cette frange de la population.

S 16020, a new 9-OH olivacine derivative, is a novel topoisomerase II inhibitor with activity in cell lines presenting the classical multidrug resistance phenotype. This report summarizes, in addition to pharmacokinetic data, the whole phase I clinical experience of S 16020 using three different infusion schedules. Asthenia and skin toxicity were the main side effects. In an attempt to understand the skin toxicity mechanism, experiments in animals were performed, the results of which are reported. S 16020 showed rapid tumor necrotizing activity in some patients, with soft tissue metastases of epidermoïd tumors and pain at the tumor site. To document the side effects of S 16020 and tumor site reactions (pain, edema, inflammatory signs), inflammatory parameters and some cytokines were measured. In our patients there was no hemolysis and no detection of anti-S 16020 antibodies, confirming the absence of immunogenicity of the compound. Based on the overall data of the three infusion schedules of S 16020, the dose of 100 mg/m(2) over 3 h every 3 weeks was selected for phase II studies.

This study employs a quasi-experimental, before-after, target-comparison group design as a preliminary and exploratory effort to assess the impact of Correctional Emergency Response Teams (C.E.R.T.) on the level of violence and injuries to staff and inmates within jail settings. The analyses are based on monthly data gathered from violent incident reports maintained at two matching central Florida county jails expressing different levels of CERT. The first jail, the target, has a staff fully trained and certified in CERT operations and functions; the second, the comparison jail, employs an ad hoc cell extraction team which is not trained in CERT nor does it employ CERT tactics and strategies. The findings suggest that CERT may indeed be significant in reducing the level of violence and associated injuries within jail settings. However, within the target jail, increases in the proportion of staff CERT trained and certified did not appear to lead to any additional reductions in the monthly levels o...

Resume L'hypothyroidie congenitale d'origine haute, hypothalamohypophysaire est extremement rare. Elle peut echapper au test de depistage neonatal base sur le microdosage de la TSH. Observation - Anthony ne a 37 semaines presente a la naissance une hypotonie, un iclere, une protrusion de la langue… evocateurs d'hypothyroidie congenitale. Le bilan biologique est en faveur d'une orgine hypothalamique (test de depistage par dosage de la TSH normal). Un traitement par L-thyroxine permet une bonne croissance staluroponderale et psychomotrice. Conclusion - Tout signe clinique evocateur d'une hypothyroidie doit faire rechercher cette possibilite, meme si le test de depistage est negatif.

SUMMARY The estimation of the volume of pores available is of prime importance when evaluating the potential of a site for the geological storage of CO2. Sequential Bayesian simulations, using well logs and acoustic impedance cube are completed to model the porosity field and its variability in the Beekmantown Group reservoir of the Saint-Flavien region, Quebec, Canada. We use stochastic seismic inversion to better recover the whole bandwidth of acoustic impedance distribution observed at well logs, needed to reproduce the distribution of porosity observed on well logs. This methodology is of prime importance in the Saint-Flavien context, as the average porosity is extremely low, and only a fraction of the reservoir, identified as Family 3 by Gaussian mixture models, exhibits higher porosity where CO2 injection would be possible. Comparison of the porosity fields simulated using the deterministic acoustic impedance cube and one realisation of a stochastic inverted acoustic impedance cube clearly show that zones of higher porosity are better reproduced by the latter option. The use of stochastic seismic inversion is needed to obtain a more realistic estimate of available pores for CO2 injection in the Beekmantown Group reservoir in the Saint-Flavien region.

An algorithm to perform raytracing on tetrahedral meshes with the shortest path method is presented. Parameterization in terms of unstructured meshes allows better fitting of the discrete model to structures with arbitrary geometries. To build the raytracing graph, the discretization scheme employs primary nodes at the vertexes and secondary nodes on the edges and faces of the tetrahedra. Improvement of the raytracing accuracy is achieved when compared to results obtained with rectilinear grid of comparable (and to some extent larger) cell size. Compared to rectilinear grids, an increased computational effort must however be deployed to generate the graph needed for raytracing. Besides, tests revealed that increasing the number of secondary nodes rather than refining the mesh appears to be the best approach to improve accuracy. The proposed algorithm appears appropriate for traveltime tomography schemes because it allows using meshes coarser than rectilinear grids for the same level of accuracy, thus reducing the size of the inverse system to solve.

Fotemustine and dacarbazine constitute the most active single chemotherapeutic agents in the treatment of melanoma. In this phase II study we evaluated the activity and toxicity of a combination of fotemustine, dacarbazine and vindesine as a means of increasing response rate and survival time. Between September 1989 and November 1993, 43 patients with advanced melanoma were treated with a combination of 100 mg/m2 fotemustine on days 1 and 8, 250 mg/m2 dacarbazine on days 15 and 16 and 2 mg/m2 vindesine on days 15 and 16 as induction treatment. After a 5-week rest period, the patients exhibiting a response or stable disease received the same drugs administered once every 28 days as maintenance therapy until either progression or toxicity was observed. Among 41 evaluable patients, there were six complete responses and eight partial responses. The overall response rate was 32% (95% confidence interval: 18-46%), with 8 months median duration of response. Median survival time was 10 months. This regimen was well tolerated. From this large phase II study, we conclude that such a combination is active against advanced malignant melanoma and seems to be more effective than fotemustine or dacarbazine used alone, especially on visceral metastatic sites.

The pharmacokinetics of high-dose fotemustine followed by autologous bone-marrow transplantation during a phase I-II clinical trial in 24 patients with glioblastoma or astrocytoma (grade III-IV) was investigated. Plasma levels of fotemustine were determined by high-performance liquid chromatography (HPLC) and UV detection. The metabolite, 2-chloroethanol, was simultaneously followed in six patients by gag liquid chromatography and electron capture detection (GLC-ECD) assay. The drug was given as a 1-h infusion on 2 consecutive days. In all, 40 pharmacokinetic determinations of fotemustine were made at dose levels ranging from 2 x 300 to 2 x 500 mg/m2. Plasma drug elimination was best described by a bi-exponential model, with short distribution and elimination half-lives of 4.15 +/- 2.57 and 28.8 +/- 12.1 min being observed, respectively. No significant difference in half-lives or clearance was seen between the first and the second administration. During dose escalation, the mean area under the concentrationtime curve (AUC) increased from 5.96 +/- 2.89 to 12.22 +/- 3.95 mg l-1 h. Drug clearance was independent of the dose given and equal to 109 +/- 65 l/h, indicating no possible saturation of metabolism and elimination mechanisms at these high-dose levels. The metabolite 2-chloroethanol appeared very early in plasma samples. Its elimination was rapid and rate-limited by the kinetics of the parent compound, giving the same apparent terminal half-life. A close relationship between AUC and C45 values was evidenced (r = 0.890). Associated with the stability of fotemustine kinetic parameters, this could be used in future studies for individual dose adjustment, particularly for high-dose fractionated regimens.

Fabry disease (FD) is an X-linked lysosomal storage disease caused by deficient activity of the enzyme alpha-galactosidase A. Although the disease has progressive effects on most organ systems in the body, data is limited regarding skeletal involvement in this rare disorder. We describe four family-related patients, three men and one premenopausal female, sharing a classic phenotype of FD. Dual-energy X-ray was performed in all cases and osteoporosis or osteopenia were found in all patients and osteoporotic fractures in one. One patient also showed both neuropathic joint disease and osteonecrosis. Several mechanisms that may explain osteoporosis and osteoarthropathy in the setting of FD are emphasized.

38 adults with recurrent supratentorial malignant gliomas, including glioblastoma multiforme (21), anaplastic astrocytomas (9), probably transformed low-grade astrocytomas (6), pinealoblastoma (1) and non-metastatic tumour of unknown histology (1), were treated with fotemustine 100 mg/m2 intravenously every week for 3 consecutive weeks followed by a 5-week rest period. Maintenance treatment consisted of one infusion every 3 weeks. Patients were divided into three groups according to treatment effect. 10 objective responses (26%) with a median time without progression of 32.7 weeks, 18 stabilisations (47%) and 10 failures (26%) were observed. Pathological findings of the initial primary tumour and neurological functional status were unequally distributed in these groups. Haematological and liver toxicities were mild, delayed, transient and reversible. Thrombocytopenia and leukopenia were more frequent (30%) in patients treated with prior chemotherapy. Fotemustine is a well tolerated active drug in recurrent malignant gliomas with an original and short treatment schedule.

In order to assess the apparent diffusion coefficient of two nitrosoureas (carmustine and fotemustine) in the brain, a model of planar diffusion was used in the rat brain and in rat and human brain biopsies. Drugs were deposed on the brain surface at a constant concentration for 30 min. At the end of the diffusion time, the concentration gradient was determined with microelectrodes using voltammetry at 5 different depths in the extracellular space of the gray matter (0-304 microns). Voltammetry with microelectrodes measured quantitatively intact drug in the brain extracellular space (CV 4% for the 2 drugs) in the range studied. The same procedure was used for human and rat brain biopsies which were held in a small cup. The apparent diffusion coefficients in living animals were 0.49 x 10(-6) cm2.s-1 for carmustine and 0.23 x 10(-6) cm2.s-1 for fotemustine; in human biopsies, they were 0.84 x 10(-6) cm2.s-1 for carmustine and 0.37 x 10(-6) cm2.s-1 for fotemustine. Significant differences in the apparent diffusion coefficients of the drugs were accounted for by the fact that the intracellular penetration of fotemustine was better than that of carmustine.

Background: The purpose of this study was to carry out two randomised phase II trials of S 16020, a new olivacine derivative, tested as a single agent in patients with recurrent head and neck cancer, using methotrexate as the control arm to validate the results. Patients and methods: S 16020 at either 80 or 100 mg/m(2) was administered as a 3-h infusion every 3 weeks. Methotrexate, 40 or 50 mg/m(2), was given by bolus injection, weekly for a minimum of 6 weeks. In total, 36 patients were entered in the randomised studies (25 in an initial study, 11 in a confirmatory study) of whom 24 received S 16020 and 12 received methotrexate. Results: A scheduled interim analysis showed one patient having a non-confirmed objective response with S16020 and three patients having a confirmed objective response with methotrexate. In the methotrexate group, there were no patients with severe non-haematological toxicity. With S16020, there was a high incidence of severe non-haematological toxicities, including asthenia, oedema of the face, oedema and pain at the turnout sites and erythematous rash; consequently, both studies were stopped. Conclusions: Both studies were stopped due to the poor anticipated benefit/risk ratio for S16020, although time to progression and overall survival time were similar in both treatment arms.

The aims of this phase I study in patients with recurrent malignant gliomas were to determine the maximum tolerated dose (MTD) and toxicity profile of fotemustine when combined with a fixed dose of procarbazine (PCZ), and to evaluate the extent of O6-alkylguanine-DNA alkyltransferase (ATase) depletion in circulating lymphocytes during treatment. Sixteen patients received an induction cycle consisting of 100 mg/day oral PCZ for 12 consecutive days and a 1-h intravenous infusion of fotemustine given 4 h after PCZ on days 5 and 12 at escalated doses (50, 75, 100 and 125 mg/m2/day). After a 6-week rest period, a maximum of 4 maintenance cycles (PCZ 300 mg/day, 4 days; fotemustine, day 4) was given every 4 weeks. ATase activity was measured on days 1, 5 and 12 over 4 h after PCZ intake. Fifteen patients had previously received at least one nitrosourea-based chemotherapy, associated with PCZ in 12 cases. The MTD of fotemustine was 125 mg/m2 (days 5 and 12) with myelosuppression as the dose limiting toxicity (DLT). At this dose level, half of patients experienced grade 3 anemia, neutropenia or thrombopenia. No extra-hematological DLT was observed. No significant depletion of ATase activity by PCZ was evidenced. One partial response and 7 stable diseases were obtained leading to a disease control rate of 50%. The median times to progression and survival were 2.6 and 9.7 months, respectively. This combined regimen of PCZ and fotemustine was well tolerated with a good disease control rate in heavily pretreated glioma patients and merits further investigation in phase II studies.

Fotemustine was investigated in 17 patients with progressive hepatic metastases from colorectal carcinoma to define the maximally tolerated dose for a daily hepatic intra-arterial infusion (HAI) schedule. Haematotoxicity was delayed, dose-dependent and related to pretreatment, with thrombo- and leucocytopenia being dose-limiting. Local side-effects at the liver were mild. Infection (WHO grade III) occurred in 1 patient due to neutropenia. Other side-effects, particularly renal, pulmonal, neurological or cardiac toxicity, mucositis and diarrhoea, hair loss or allergic reactions did not occur. Pharmacokinetic analysis indicated a short plasma half-life (t1/2 = 25.8 ± 11.5 min) and a high body clearance (CL = 2193 ± 870 ml/min) with large inter- and intra-individual variations. Of 15 evaluable patients, one complete and three partial responses were observed (ORR = 27%; CI95% [4.5–49.5%]). All tumour remissions appeared at higher dose levels in previously untreated patients. Considering the absence of mucosal side-effects, such as mucositis/diarrhoea and of hepatic toxicity, this agent was well tolerated. The recommended intra-arterial dose for consecutive phase II trials is 125 mg/m2/day1–3.

Summary Background S9788 is a triazineaminopiperidine derivative capable of reversing multidrug resistance (MDR) in vitro. In preclinical models S9788 was several fold more potent MDR inhibitor than verapamil or cyclosporine. At P-glycoprotein (Pgp) blocking concentrations, S9788 appeared to have only very little toxicity. Patients and methods In a two step phase I trial we treated 39 patients with refractory cancer with S9788 and bolus doxorubicin. The steps differed mainly in the S9788 infusion duration; in the first part 23 patients received the MDR-reversing drug S9788 over 30 minutes, in the second step of the study 16 patients were administered S9788 over 150 minutes. The doses of S9788 were escalated in cohorts of three patients up to a dose level (DL) of 96 mg/m2 on the 30 minutes infusion, and to 144 mg/m2 on the 150 minutes infusion. The pharmacokinetics of S9788 were determined. Results With the 30-minute infusion schedule symptomatic cardiac arrhythmia were found to be dose limiting. In all patients at the highest DL transient cardiac repolarization prolongation with a long QT-interval on ECG was demonstrated. With the 150-minute administration schedule, S9788 could be escalated up to 144 mg/m2 without subjective toxicity. However, transient QT prolongation was present in all patients. A third degree AV-block and a QT increase of about 40% occurred at the highest DL. Asymptomatic torsade de pointe (DL 96 mg/m2) was demonstrated on Holter recording in one patient. Theses repolarization disturbances with QT increase were considered dose limiting toxicity and the trial was closed. No arrhythmia related death was noted. Pharmacokinetics were similar with both infusion schedules with a mean alpha half life of 11.3 and 13.2 minutes, for the 30-minute and 150-minute infusion, and a terminal half life of 13.5 and 15 hours, respectively. QTc prolongation duration appeared to be dose-dependent. Conclusions With the tested infusion schedules, cardiac toxicity, in particular AV-blocks and QT prolongation, leading to ventricular arrhythmia and torsade de pointe, are the dose limiting toxicities of S9788. Our experience together with the observation of asymptomatic torsade de pointe in two other phase I trials of S9788 infused over six hours precluded the further clinical development of S9788.

Congenital hypothyroidism is very rare compared to primary hypothyroidism. Its early diagnosis may escape neonatal mass screening using TSH assay.Anthony was born at 37 weeks, weighing 3,060 g. He presented with hypotony, jaundice, tongue protrusion evoking congenital hypothyroidism. Thyroid function tests favored hypothyroidism central in origin, while the systematic neonatal screening was normal.Clinical signs of congenital hypothyroidism must lead to more specific tests when neonatal screening is normal.

A phase II study was conducted in order to determine the feasibility and toxicity of cisplatin combined with the nitrosourea fotemustine in central nervous system metastases from non-small cell lung cancer. 31 chemotherapy-naive patients were included between November 1990 and April 1993. Computed tomography scan-documented tumour regression in brain metastases was observed in 7 of the 25 evaluable patients, but only 4 of these (16%) lasted more than 4 weeks. In 2 of these 4 patients, the response on central nervous system metastases was considered as complete. The median duration of response was 20.5 weeks and the median survival was 16 weeks overall and 28.5 weeks for responding patients. The limiting toxicity of this regimen was haematological. 2 patients died from infectious pneumonitis while in neutropenia. Treatment delays due to haematological toxicity occurred in 57% of patients. Despite the rather encouraging response rate, such toxicity appears too high when compared to the overall bad prognosis of this population of patients. Cranial radiotherapy remains the standard treatment in this setting and should only be compared in the future to less aggressive schedules.