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Purpose: Diffuse malignant peritoneal mesothelioma (DMPM) is a severe disease with mainly locoregional evolution. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) is the reported treatment with the longest survival. The aim of this study was to evaluate the impact of perioperative systemic chemotherapy strategies on survival and postoperative outcomes in patients with DMPM treated with curative intent with CRS-HIPEC, using a multi-institutional database: the French RENAPE network. Patients and methods: From 1991 to 2014, 126 DMPM patients underwent CRS-HIPEC at 20 tertiary centres. The population was divided into four groups according to perioperative treatment: only neoadjuvant chemotherapy (NA), only adjuvant chemotherapy (ADJ), perioperative chemotherapy (PO) and no chemotherapy before or after CRS-HIPEC (NoC). Results: All groups (NA: n Z 42; ADJ: n Z 16; PO: n Z 16; NoC: n Z 48) were comparable regarding clinicopathological data and main DMPM prognostic factors. After a median follow-up of 61 months, the 5-year overall survival (OS) was 40%, 67%, 62% and 56% in NA, ADJ, PO and NoC groups, respectively (P Z 0.049). Major complications occurred for 41%, 45%, 35% and 41% of patients from NA, ADJ, PO and NoC groups, respectively (P Z 0.299). In multivariate analysis, NA was independently associated with worse OS (hazard ratio, 2.30; 95% confidence interval, 1.07e4.94; P Z 0.033). Conclusion: This retrospective study suggests that adjuvant chemotherapy may delay recurrence and improve survival and that NA may impact negatively the survival for patients with DMPM who underwent CRS-HIPEC with curative intent. Upfront CRS and HIPEC should be considered when achievable, waiting for stronger level of scientific evidence.

Introduction et but de l’etude La sarcopenie, forme de denutrition initialement decrite chez les sujets âges, consiste en une demuscularisation chez des patients plus jeunes atteints de cancer. De plus en plus decrite, cette sarcopenie est a l’origine de complications graves en cours de chimiotherapie ou dans le peri-operatoire que ce soit en terme de complications post operatoires [1] ou de survie sans recidive [2] . De plus, la perte de masse musculaire semble evolutive en cours de chimiotherapie neoadjuvante [3] . Le but de cette etude retrospective, observationnelle sur une periode de 18 mois, est de rechercher la presence d’une eventuelle sarcopenie chez des patientes operees pour chirurgie de debulking pour carcinome ovarien apres chimiotherapie neoadjuvante. Materiel et methodes Vingt deux patientes ont ete incluses entre janvier 2015 et mars 2017. Criteres d’inclusion : patientes entre 18 et 85 ans, chimiotherapie neoadjuvante identique sur l’institut Bergonie, operees par le meme chirurgien pour une chirurgie notee comme optimale, classees GN2 a la consultation d’anesthesie c’est-a-dire non denutries dans les 3 semaines precedent l’acte operatoire. La recherche de la sarcopenie est realisee sur des coupes TDM en L3 de moins de 1 mois en pre chirurgical et analysee avec le logiciel slide o matic pour le calcul de la masse musculaire. L’albuminemie pre operatoire est recherchee systematiquement. Resultats et analyse statistique n = 22 % imc median albuminemie gr/l Âge median Sarcopenique 14 63,6 23,31 35,5 ± 4,7 70 Non sarcopenique 8 36,3 22,6 37,5 ± 7,6 64,5 Conclusion Si les patientes sarcopeniques sont plus âgees que les patientes non sarcopeniques, la frequence de cette forme de denutrition reste cependant tres elevee et surtout meconnue en preoperatoire. Les criteres classiques (perte de poids, albuminemie) utilises pour quantifier la denutrition en pre operatoire sont pris a defaut dans notre etude.

Une patiente de 66 ans, ayant pour principal antecedent une hysterectomie en 2010 (dans un contexte de dysplasie cervicale recidivante) est prise en charge chirurgicalement en 2014 pour un carcinome epidermoide du fond vaginal, suivie d’une curietherapie du fond vaginal realisee a haut debit de dose. Elle rechute en juillet 2015 au niveau ganglionnaire ainsi que localement au niveau du fond vaginal. Cette recidive hypermetabolique en TEP FDG est traitee en septembre 2015 par pelvectomie totale avec anastomose colorectale protegee et enterocystoplastie avec radiochimiotherapie concomitante. Dans les suites, elle presente une infection urinaire avec dilatation pyelo-calicielle, necessitant la mise en place d’une sonde double J par voie antegrade changee tous les 6 mois. Une augmentation du SCC en juillet 2018 (5 ng/mL pour une norme Conclusion La mise en evidence d’un hypermetabolisme ganglionnaire au TEP-FDG en contexte infectieux, d’autant plus s’il est associe a une reaction osteomedullaire diffuse, doit faire suspecter un processus inflammatoire. La connaissance de l’ensemble des donnees cliniques lors de l’exploration metabolique TEP est primordiale pour limiter les faux-positifs.

3,4-Diaminopyridine is used to treat some symptoms met in Lambert-Eaton myasthenia syndrome. It was shown efficient to reduce a form of variable muscle weakness and fatigability typical of the disease and correlated to a block of acetylcholine release. In France, 3,4-diaminopyridine is nowadays given to patients under capsules form and the status of hospital preparation. Whatever the diluant used in the formulation, the stability period could not exceed 12 months. Preliminary studies were made on a salt form in order to test the influence of various stress factors and determine if there is interaction between them. From this study, the most influent stress condition, presence of hydrogen peroxide, was selected and a comparative study was performed to compare the stability of molecular and salt species. Solutions of each species were exposed to 5 or 15% of hydrogen peroxide and analyzed at 8, 24, 72 and 216 h of degradation by HPLC-UV. Fractions of detected impurities were purified and collected by semi-preparative HPLC-UV and analyzed by HPLC-UV-ESI-MS and IR spectroscopy in order to determine their structure hypotheses. Theses experiments demonstrate that the salt species were more stable under oxidative stress condition than molecular species. The two main degradation products were collected and identified as 4-amino, 3-nitropyridine and 3,4-diaminopyridine-N-oxide when the molecular form was degraded whereas only 4-amino, 3-nitropyridine was found in less quantity in the salt solutions. Nitrogen pyridine and pyridine amine could not easily be oxidized by hydrogen peroxide in salt comparatively to molecular species due to the lone pair of electron engaged in a bound with hydrogen in the first case and by resonance change of the pyridine in the second case. This modification of structure promoted different pathways of degradation for the salt form which are more dependent of energy. Owing to the better stability of the salt species, a new pharmaceutical form containing it was developed to assess its stability under ICH standard conditions allowing an industrial manufacture of this drug.

A simple detection system with a high-performance liquid chromatography (HPLC) with positive ionisation-tandem mass spectrometry (ESI-MS/MS) for determining diphemanil methylsulphate (DMS) levels in human plasma using 4-diphemanylmethylene,1-methylpiperidine as an internal standard (I.S.), is proposed. The acquisition was performed with the multiple reactional monitoring (MRM) mode, by monitoring the transitions: m/z 278 > 262 for DMS and m/z 263 > 247 for the I.S. The method involved a simple single-step deproteinisation with acetonitrile. The analyte was chromatographed on a Zorbax® C18 reversed-phase chromatographic column by isocratic elution with 10−3 M ammonium acetate and 10−3 M hexafluorobutyric acid, adjusted to pH 7.0 with ammoniac/acetonitrile (40/60, v/v). The results were linear over the studied range (0.5–50.0 ng mL−1) and the total analysis time for each run was 10 min. The mean extraction apparent recoveries expressed at the 95% intervals of confidence were 94–104% for DMS and 92–106% for the I.S. The intra- and inter-assay precisions were 4.6–8.4% and 2.9–10.6%, respectively. The limit of quantification was 0.15 ng mL−1. The devised assay was successfully applied to the residual concentrations monitoring in infant.

Journal de Gynecologie Obstetrique et Biologie de la Reproduction - Vol. 35 - N° 7 - p. 711-719

In order to quantify a small amount of a drug, 3,4-diaminopyridine (3,4-DAP), in animal plasma samples, an analytical method was developed. It involved an extraction of 3,4-DAP and phenylephrine, used as internal standard (IS), from plasma with solid-phase extraction (SPE) on C18 cartridges. This analytical method is a hyphenated technique based on high-performance liquid chromatography with electrochemical detection (HPLC–EC) whose purpose is to obtain first a sensitive method and second a satisfying separation between 3,4-DAP and phenylephrine. The analytical method is accurate, specific, and linear between 10 and 500 μg of 3,4-DAP per litre. The recovery of 3,4-DAP is estimated at 70.8% with a 95% confidence interval of (66.0–75.6%). Intermediate precision was evaluated on three quality control samples; the intra-day precision was estimated at 13.5, 9.1, 7.8% and the inter-day precision at 17.9, 8.4, 9.3%. The limit of quantification of the method was evaluated at 10 μg l−1. First toxicokinetic parameters determined on dogs plasma samples after one 3,4-DAP oral administration of 1 mg kg−1 were: Cmax=395.7 μg l−1; Tmax=15 min; t1/2=113.6 min; Clearance/F=16.8 ml kg−1 min−1 and Vd/F=2.7 l kg−1.

NDP kinases are the non-specific enzymes which catalyse the synthesis of the NTPs through a transfer reaction using ATP as phosphoryl donor. In addition to their enzymatic activity, they display other not yet explained functions related to cell growth, differentiation and apoptosis, embryonic development, tumour progression and metastasis. In this study, the expression patterns of the three highly related NDP kinases A, B and C isoforms were investigated in the developing human trophoblast. Both NDP kinase A and B were found to be primarily present in the villous and extravillous cytotrophoblasts, while NDP kinase C was found almost exclusively in the syncytiotrophoblast layer. This suggests that NDP kinase A and B could be a marker for the mononuclear stage of differentiation of villous trophoblasts, while NDP kinase C could be a marker of the syncytiotrophoblast layer.

Diphemanil methylsulfate (DMS) is a synthetic antimuscarinic agent classically used in infants for vagal hypertonia-related symptoms. A normal-phase, isocratic liquid chromatographic method was developed for the quantitative determination of DMS in bulk drugs and in pharmaceutical forms. The method has been completely validated and robustness of this method has been studied. The limit of detection (LOD) for DMS impurities namely, impurity 1 and 2 were found to be 11 and 46 ng/ml. The limit of quantitation (LOQ) was found to be 49 and 139 ng/ml for impurity 1 and 2, respectively. The stability studies have been performed for 2 and 10 mg DMS tablets subjected at various temperatures: 25 degrees C (long term storage condition) and 40 degrees C (accelerated storage condition) for 18 and 6 months, respectively. At 25 degrees C, the samples were found to be stable for the study period. At 40 degrees C, 2 and 10 mg DMS tablets showed degradation up to 5 and 10% over a 6-month period.

Methacholine chloride is a powerful cholinergic bronchoconstrictor agent used during bronchial airway hyper-responsiveness diagnosis. Methacholine is susceptible to hydrolysis in aqueous solutions in acetic acid and beta-methylcholine. In the present work, kinetics of hydrolysis with different solvents (water and phosphate-buffered saline (PBS) pH 7.4) at different temperatures have been studied using a newly developed high-performance liquid chromatography. At 4 degrees C, kinetic determination of hydrolysis in methacholine chloride solutions (50 mg/ml) shows no hydrolysis in either aqueous or phosphate-buffered solutions over a 40-day period. At 30 degrees C, concentration of unbuffered methacholine chloride solutions remained unchanged, but buffered methacholine chloride solutions have degradation up to 5.5% over a 40-day period. At 40 degrees C, concentration of unbuffered methacholine chloride has degradation up to 5% and buffered methacholine chloride solutions have degradation up to 10% over a 40-day period. Methacholine chloride solutions are susceptibly to be used in hospital pharmacy at different concentrations. We have studied pH and osmolality for methacholine solutions prepared with different diluents potentially used in hospital pharmacies, i.e. deionized water, 0.9% NaCl and PBS pH 7.4. We have demonstrated that methacholine solutions prepared with deionized water at 50 mg/ml and diluted with PBS pH 7.4 from 5 to 40 mg/ml are isoosmotic and potentially available for inhalation tests to measure non-specific bronchial hyper-responsiveness.

An off-line system is proposed consisting of ion-pair reversed-phase liquid chromatography, collections of fractions at the outflow of the column and furnace atomic absorption spectrometry. The so-called system allowed determination of both arsenic and selenium species mainly found in the environment and in mammals (arsenite, arsenate, monomethylarsonate, dimethylarsinate, selenite, selenate, selenocystamine, selenocystine, selenomethionine and selenoethionine). In order to study the retention behaviour of these compounds and to estimate the optimal conditions for the chromatographic separation, central composite designs were used to evaluate the influence of the eluent parameters such as pH, tetrabutylammonium phosphate (TBA) concentration and sodium hydrogenphosphate amounts. The retention factors of each species and the selectivity were established as response criteria. Response surfaces and isoresponse curves were drawn from the mathematical models and enabled one to determine the optimal conditions and to visualise the method robustness. The predicted optimal zone was situated at pH 5.5-6.5, 4.0 mM Na2HPO4 and 3.0-4.0 mM TBA. Regression models suggested linearity for the studied compounds in the range 25-200 microg selenium and arsenic per litre investigated.

Hydride generation inductively coupled plasma–atomic emission spectrometry (HG ICP–AES) was used as a continuous detection system for the determination of arsenic in the eluate from a high-performance liquid chromatographic (HPLC) system. Four arsenic species [arsenite As(III), arsenate As(V), monomethylarsonate (MMA), and dimethylarsinate (DMA)] present in the urine samples of patients treated intravenously with arsenite, were analyzed separately by HPLC–HG-ICP–AES using a non-polar C18 column. This analytical method allowed the sensitive determination of the arsenic species in the submicrogram per liter range. Urine samples collected on different days after arsenite administration were found to contain arsenite predominantly – monomethylarsonate and dimethylarsinate were also detected.

The interaction of rutin and methyl-β-cyclodextrin in aqueous solution was studied by UV, fluorescence spectroscopy and reversed-phase liquid chromatography. Free solution capillary electrophoresis was also used as a new means of determination. Measurements from different methods yielded the formation constant for the 1:1 complex.

Inclusion of floctafenine, an analgesic drug, within the cavity of methyl-β-cyclodextrin, in aqueous solution, was confirmed independently by fluorescence spectrophotometric method and reversed-phase liquid chromatography. The 1:1 binding constants have been calculated: • - Fluorescence enhancement was observed upon inclusion for floctafenine; a linear relationship between (1 − fo/fm)/c and fo/fm is obtained (c = [Me-β-cyclodextrin]) and fo and fm are the fluorescent intensities in the absence and presence of Me-β-cyclodextrin at concentration c). From the intercept of the line, Kf can be determined. • - In reversed-phase chromatography capacity factor k′ decreases with an increase in the concentration of Me-β-cyclodextrin added in the mobile phase. A plot of the reciprocal of the capacity factor against [Me-β-cyclodextrin] gives a straight line, from the slope of which the dissociation constant of the inclusion complex can be calculated.

A copper(II)-modified silica gel has been used for the high-performances liquid chromatography of small peptides, isomeric dipeptides and glycine oligomers. This packing combines the high selectivity of the ligand-exchange procedure withthe high column efficiency obtained with microparticles of silica (7 μm). The capabilities of this new packing are shown by the separation of fragments of methionine-enkephalin, which is a neuroendocrine pentapeptide (Tyr—Gly—Gly—Phe—Met). Two isocratic systems have been used in conjunction, the first for the separation of Met-enkephalin tetrapeptides, tripeptides and Phe-Met, and the second for that of dipeptides and amino acids. These systems allowed the separation of all possible fragments of Met-enkephalin with an analysis time of about 15 min. It is then easy to observe the appearance and evolution of peptidic fragments following enzymatic degradation. Moreover, direct injection of the enzymatic media can be performed without storage of the frozen samples.

The degradation of the Met-enkephalin by peptidases present in striatum extracts was followed by a new H.P.L.C. method, based on ligand exchange chromatography. An aminopeptidase activity is present in both the soluble and the particulate fractions of mouse striatum. In addition we confirmed the presence, mainly in the particulate fraction, of a carboxydipeptidase releasing TyrGlyGly and PheMet from Met-enkephalin. The tetrapeptide GlyGlyPheMet also appears to be cleaved by the same enzyme activity.

Silica gels modified with copper(II) are currently used in ligand-exchange liquid chromatography. The main species present at the surface of the stationary phase is shown to be (SiO)2Cu(NH3)2(H2O)x. Measurements of the ammonia concentration in the mobile and stationary phases are combined with computer-assisted calculations to determine the following apparent equilibrium constants: for SiOH + NH3 ⇌ SiO−NH+4, log K = −0.2; for (SiO)2Cu + NH3 ⇌ (SiO)2Cu(NH3), log β1 = 2.8; and for (z.tbnd;SiO)2Cu + 2NH3 ⇌ (SiO)2Cu(NH3)2, log β2 = 4.0. A distribution diagram of the different species present at the surfac of copper-modified silica gel is given. Under the usual operating conditions for ligand-exchange chromatography (pNH3 < 1), more than 60% of the silanol groups which fix copper(II) have a silicate structure with two moles of ammonia per mole of copper(II).

In this paper we present a method for improving the practical identifiability for output least squares estimation of parameters in ordinary or partial differential equations. A method of calculation of a weighting factor is presented which orthonormalizes the sensitivity functions and so increases the efficiency of the minimization algorithm. The positiveness of this weight is obtained by regularization. The method has been tested numerically on simple problems of parmeter estimation on a heat equation.