A safety run-in and randomized phase 2 study of cilengitide combined with chemoradiation for newly diagnosed glioblastoma (NABTT 0306).

BACKGROUND: Cilengitide is a selective integrin inhibitor that is well tolerated and has demonstrated biologic activity in patients with recurrent malignant glioma. The primary objectives of this randomized phase 2 trial were to determine the safety and efficacy of cilengitide when combined with radiation and temozolomide for patients with newly diagnosed glioblastoma multiforme and to select a dose for comparative clinical testing. METHODS: In total, 112 patients were accrued. Eighteen patients received standard radiation and temozolomide with cilengitide in a safety run-in phase followed by a randomized phase 2 trial with 94 patients assigned to either a 500 mg dose group or 2000 mg dose group. The trial was designed to estimate overall survival benefit compared with a New Approaches to Brain Tumor Therapy (NABTT) Consortium internal historic control and data from the published European Organization for Research and Treatment of Cancer (EORTC) trial EORTC 26981. RESULTS: Cilengitide at all doses studied was well tolerated with radiation and temozolomide. The median survival was 19.7 months for all patients, 17.4 months for the patients in the 500 mg dose group, 20.8 months for patients in the 2000 mg dose group, 30 months for patients who had methylated O6-methylguanine-DNA methyltransferase (MGMT) status, and 17.4 months for patients who had unmethylated MGMT status. For patients aged ≤70 years, the median survival and survival at 24 months was superior to what was observed in the EORTC trial (20.7 months vs 14.6 months and 41% vs 27%, respectively; P = .008). CONCLUSIONS: Cilengitide was well tolerated when combined with standard chemoradiation and may improve survival for patients newly diagnosed with glioblastoma multiforme regardless of MGMT methylation status. The authors concluded that, from an efficacy and safety standpoint, future trials of this agent in this population should use the 2000 mg dose. Cancer 2012. © 2012 American Cancer Society.

Initial clinical experience with the admiral oxygenator combined with separated suction.

The Admiral, a new microporous membrane oxygenator with a low surface area, decreased priming volume and two separate reservoirs, was tested in 30 adult patients. This study was undertaken to evaluate blood path resistance, gas exchange capabilities and blood trauma in clinical use, with and without shed blood separation. Patients were divided into 3 groups. Group 1 had valve surgery without separation of suction, Group 2 had coronary artery bypass grafting (CABG) with direct blood aspiration and Group 3 had coronary artery bypass grafting with shed blood separation. The suctioned, separated, cardiotomy blood in Group 3 was treated with an autotransfusion device at the end of bypass before being returned to the patient. Theoretical blood flow could be achieved in all cases without problem. The pressure drop through the oxygenator averaged 88 +/- 13 mmHg at 4 l/min and 109 +/- 12 mmHg at 5 l/min. O(2) transfer was 163 +/- 27 ml/min. Free plasma haemoglobin rose in all groups, but significantly less in group 3. Lactate dehydrogenase (LDH) rose significantly in Groups 1 and 2. Platelets decreased in all groups without significant differences. Clinical experience with this new oxygenator was safe, the reduced membrane surface did not impair gas exchange and blood trauma could be minimized easily by separating shed blood, using the second cardiotomy reservoir.

A genome-wide association study of early menopause and the combined impact of identified variants.

Early menopause (EM) affects up to 10% of the female population, reducing reproductive lifespan considerably. Currently, it constitutes the leading cause of infertility in the western world, affecting mainly those women who postpone their first pregnancy beyond the age of 30 years. The genetic aetiology of EM is largely unknown in the majority of cases. We have undertaken a meta-analysis of genome-wide association studies (GWASs) in 3493 EM cases and 13 598 controls from 10 independent studies. No novel genetic variants were discovered, but the 17 variants previously associated with normal age at natural menopause as a quantitative trait (QT) were also associated with EM and primary ovarian insufficiency (POI). Thus, EM has a genetic aetiology which overlaps variation in normal age at menopause and is at least partly explained by the additive effects of the same polygenic variants. The combined effect of the common variants captured by the single nucleotide polymorphism arrays was estimated to account for ∼30% of the variance in EM. The association between the combined 17 variants and the risk of EM was greater than the best validated non-genetic risk factor, smoking.

Application of the combined integral method to Stefan problems

In this paper we present a new, accurate form of the heat balance integral method, termed the Combined Integral Method (or CIM). The application of this method to Stefan problems is discussed. For simple test cases the results are compared with exact and asymptotic limits. In particular, it is shown that the CIM is more accurate than the second order, large Stefan number, perturbation solution for a wide range of Stefan numbers. In the initial examples it is shown that the CIM reduces the standard problem, consisting of a PDE defined over a domain specified by an ODE, to the solution of one or two algebraic equations. The latter examples, where the boundary temperature varies with time, reduce to a set of three first order ODEs.

First-line temozolomide combined with bevacizumab in metastatic melanoma: a multicentre phase II trial (SAKK 50/07).

BACKGROUND: Oral temozolomide has shown similar efficacy to dacarbazine in phase III trials with median progression-free survival (PFS) of 2.1 months. Bevacizumab has an inhibitory effect on the proliferation of melanoma and sprouting endothelial cells. We evaluated the addition of bevacizumab to temozolomide to improve efficacy in stage IV melanoma. PATIENTS AND METHODS: Previously untreated metastatic melanoma patients with Eastern Cooperative Oncology Group performance status of two or more were treated with temozolomide 150 mg/m(2) days 1-7 orally and bevacizumab 10 mg/kg body weight i.v. day 1 every 2 weeks until disease progression or unacceptable toxicity. The primary end point was disease stabilisation rate [complete response (CR), partial response (PR) or stable disease (SD)] at week 12 (DSR12); secondary end points were best overall response, PFS, overall survival (OS) and adverse events. RESULTS: Sixty-two patients (median age 59 years) enrolled at nine Swiss centres. DSR12 was 52% (PR: 10 patients and SD: 22 patients). Confirmed overall response rate was 16.1% (CR: 1 patient and PR: 9 patients). Median PFS and OS were 4.2 and 9.6 months. OS (12.0 versus 9.2 months; P = 0.014) was higher in BRAF V600E wild-type patients. CONCLUSIONS: The primary end point was surpassed showing promising activity of this bevacizumab/temozolomide combination with a favourable toxicity profile. Response and OS were significantly higher in BRAF wild-type patients.

The separate and combined effects of MHC genotype, parasite clone, and host gender on the course of malaria in mice.

BACKGROUND: The link between host MHC (major histocompatibility complex) genotype and malaria is largely based on correlative data with little or no experimental control of potential confounding factors. We used an experimental mouse model to test for main effects of MHC-haplotypes, MHC heterozygosity, and MHC x parasite clone interactions. We experimentally infected MHC-congenic mice (F2 segregants, homo- and heterozygotes, males and females) with one of two clones of Plasmodium chabaudi and recorded disease progression. RESULTS: We found that MHC haplotype and parasite clone each have a significant influence on the course of the disease, but there was no significant host genotype by parasite genotype interaction. We found no evidence for overdominance nor any other sort of heterozygote advantage or disadvantage. CONCLUSION: When tested under experimental conditions, variation in the MHC can significantly influence the course of malaria. However, MHC heterozygote advantage through overdominance or dominance of resistance cannot be assumed in the case of single-strain infections. Future studies might focus on the interaction between MHC heterozygosity and multiple-clone infections.

Combined Ex-PRESS LR-50/IOL implantation in modified deep sclerectomy plus pharmacoemulsification for glaucoma associated with cataract

RAPPORT DE SYNTHESEBUTLe but de cette étude est de suivre prospectivement les résultats d'une sclérectomie profonde (SP) modifiée en utilisant le tube Ex-PRJESS LR-50, associée à une phacoémulsification avec implantation d'une lentille intraoculaire (LIO), dans la chirurgie combinée du glaucome et de la cataracte.METHODENous avons inclus dans l'étude 24 yeux de 24 patients présentant un glaucome médicalement non contrôlé et une cataracte justifiant son ablation.Une phacoémulsification avec implantation d'une LIO est effectuée. Puis le tube Ex-PRESS LR-50 est inséré au niveau du canal de Schlemm, dans la chambre antérieure, sous un volet scléral. Une SP postérieure partielle est ensuite pratiquée afin de créer une bulle de filtration intrasclérale.Le taux de succès complet a été défini par une pression intraoculaire (PIO) <18 mmHg sans traitement et le taux de succès relatif par une PIO <18 mmHg avec ou sans traitement. En cas de fibrose ou de kyste de la bulle de filtration, une injection sous-conjonctivale d'une solution de Mitomycin C à 0.02% est réalisée, avec ou sans needling.RESULTATSLe suivi moyen était de 40.1±10.8 [moyenne±DS] mois. En préopératoire, la PIO se situait à 18.1 ±5.3 mmHg; la meilleure acuité visuelle corrigée (MAVC) était mesurée à 0.6±0.3 (échelle de Snellen) et le nombre de médicaments hypotenseurs oculaires était de 2.3±1.1. La PIO a diminué de 25.4% à 24 mois et de 27.0% à 48 mois. A 24 mois, 19 patients (86.3%) avaient une MAVC supérieure ou égal à 0.5, et à 48 mois la MAVC était mesurée à 0.7±0.3. Lors de la dernière visite, le nombre moyen de médicaments se situait à 0.6±0.8 (p<0.05). Des injections sous conjonctivales d'une solution de Mitomycin C à 0.02% ont été nécessaires dans 5 yeux. Aucune érosion conjonctivale n'a été constatée. Deux complications majeures ont été observées. Une endophtalmie, deux jours après l'intervention chirurgicale avec phtisis secondaire du globe oculaire. Une obstruction du tube Ex-PRESS LR-50 par de la fibrine, ayant justifié son ablation avec SP classique en un autre site.CONCLUSIONLe tube Ex-PRESS LR-50 inséré dans la chambre antérieure avec une SP modifiée réduit efficacement la PIO dans la chirurgie combinée du glaucome et prévient l'érosion conjonctivale, une complication importante lorsque l'implant n'est pas couvert par un volet scléral.

Magnetic resonance imaging determinants of intraindividual variability in the elderly: combined analysis of grey and white matter.

Elderly individuals display a rapid age-related increase in intraindividual variability (IIV) of their performances. This phenomenon could reflect subtle changes in frontal lobe integrity. However, structural studies in this field are still missing. To address this issue, we computed an IIV index for a simple reaction time (RT) task and performed magnetic resonance imaging (MRI) including voxel based morphometry (VBM) and the tract based spatial statistics (TBSS) analysis of diffusion tensor imaging (DTI) in 61 adults aged from 22 to 88 years. The age-related IIV increase was associated with decreased fractional anisotropy (FA) as well as increased radial (RD) and mean (MD) diffusion in the main white matter (WM) fiber tracts. In contrast, axial diffusion (AD) and grey matter (GM) densities did not show any significant correlation with IIV. In multivariate models, only FA has an age-independent effect on IIV. These results revealed that WM but not GM changes partly mediated the age-related increase of IIV. They also revealed that the association between WM and IIV could not be only attributed to the damage of frontal lobe circuits but concerned the majority of interhemispheric and intrahemispheric corticocortical connections.

Use of combined suspension laryngoscopy, flexible bronchoscopy and high frequency jet ventilation for Y-shaped airway stents delivery

La trachée et les bronches proximales sont de fins conduits subtils, ingénieusement structurés par une partie cartilagineuse antérieure résistante aux variations de pression et une partie membraneuse postérieure souple. Par leurs faibles volumes (espace mort) ils délivrent un grand pourcentage de l'air inspiré aux voies distales, puis au parenchyme pulmonaire, permettant les échanges de gaz. Cette belle harmonie respiratoire peut être rapidement mise à mal dès qu'un processus atteint ces voies respiratoires proximales, soit en les comprimant, processus sténosant, soit en affaiblissant leur structure, trachéo-bronchomalacie, soit en ouvrant leur paroi sur les structures médiastinales, fistule trachéo/broncho-médiastinales, pleurales ou autres. Le pronostic vital est alors rapidement engagé au vu de l'absolue nécessité du bon fonctionnement de ces fins conduits, une petite diminution du calibre de leurs fines lumières provoquant une baisse importante de leurs surfaces. Dans ces situations à haut potentiel de complication majeure les interventions endoscopiques pour restaurer l'intégrité de ces conduits sont alors fort risquées, et il est primordial de pouvoir les effectuer dans un cadre sécurisé au maximum. La réalisation de ces gestes par la technique décrite dans notre article « Use of combined suspension laryngoscopy, flexible bronchoscopy and high frequency jet ventilation forY-shaped airway stents delivery" permet la sécurité nécessaire à ces situations instable, en effet -la laryngoscopie en suspension expose les voies proximales en offrant un accès le plus large possible à l'arbre trachéobronchique ce qui permet l insertion de multiples instruments parfois volumineux, -la Jet ventilation assure une oxygénation et une ventilation adéquate par un fin cathéter placé soit dans le poumon sain, soit en distalité de la lésion -la bronchoscopie souple, passant au travers d'endroits exigus et courbes permet le déploiement sous vision direct, au millimètre près, de divers dispositifs. Cette association remplace avantageusement la technique traditionnelle qui insère les stents à l'aveugle, et en apnée, ce qui représente de haut risque de mauvais positionnement des stents avec des conséquences immédiates sur l'oxygénation et la ventilation souvent déjà bien altérées. Perspective et conclusion : cette technique est utile pour l'insertion des stents en Y, centraux, comme décrit dans notre article, et les indications peuvent être étendues aux stents distaux pour lesquels l'accès n'est parfois pas aisé avec le bronchoscope rigide, et pour d'autres interventions endoscopiques, laser, cryothérapie, radiofréquence ou l'insertion de nouveaux dispositifs.

Hepatosplenic schistosomiasis in field-based studies: a combined clinical and sonographic definition

A combined clinical and sonographic classification of hepatosplenic schistosomiasis mansoni to be used in field-based studies is proposed herein. Seven hundred forty one individuals out of 892 (83%), living in an area endemic for schistosomiasis in Brazil, have been ubmitted to clinical and ultrasound examinations. Based on two stool examinations the overall prevalence for schistosomiasis in this area was 73%. Abdominal palpation was performed with patients in dorsal decubit, during deep breath, by two experienced physicians and a portable ultrasound was used for the evaluation of liver fibrosis, portal collaterals and spleen size. Four groups of individuals were identified using data obtained by abdominal palpation and ultrasound examination: (1) palpable spleen and intense periportal thickening in 9 individuals (1.2%); (2) spleen not palpable and intense periportal thickening in 15 (2%); (3) palpable spleen with light to moderate periportal thickening in 32 (4.3%), and (4) palpable spleen with a normal liver on ultrasound in 30 (4%). The definition of hepatosplenic schistosomiasis in field-based studies as the finding of Schistosoma mansoni eggs in the stools in an individual with splenomegaly is not acceptable anymore. Abdominal ultrasound should be combined with clinical examination to accurately identify hepatosplenics in endemic areas for schistosomiasis.

Where will conflicts between alien and rare species occur after climate and land-use change? A test with a novel combined modelling approach

Protecting native biodiversity against alien invasive species requires powerful methods to anticipate these invasions and to protect native species assumed to be at risk. Here, we describe how species distribution models (SDMs) can be used to identify areas predicted as suitable for rare native species and also predicted as highly susceptible to invasion by alien species, at present and under future climate and land-use scenarios. To assess the condition and dynamics of such conflicts, we developed a combined predictive modelling (CPM) approach, which predicts species distributions by combining two SDMs fitted using subsets of predictors classified as acting at either regional or local scales. We illustrate the CPM approach for an alien invader and a rare species associated to similar habitats in northwest Portugal. Combined models predict a wider variety of potential species responses, providing more informative projections of species distributions and future dynamics than traditional, non-combined models. They also provide more informative insight regarding current and future rare-invasive conflict areas. For our studied species, conflict areas of highest conservation relevance are predicted to decrease over the next decade, supporting previous reports that some invasive species may contract their geographic range and impact due to climate change. More generally, our results highlight the more informative character of the combined approach to address practical issues in conservation and management programs, especially those aimed at mitigating the impact of invasive plants, land-use and climate changes in sensitive regions

The effect of nitric oxide combined with fluoroquinolones against Salmonella enterica serovar Typhimurium in vitro

Two regulons, soxRS and marRAB, are associated with resistance to quinolones or multiple antibiotic in Salmonella enterica serovar Typhimurium. These regulons are activated by nitric oxide and redox-cycling drugs, such as paraquat and cause on activation of the acrAB-encoded efflux pump. In this study, we investigated the effect of nitric oxide (NO) alone and in combination with ofloxacin, ciprofloxacin, and pefloxacin against S. typhimurium clinical isolates and mutant strains in vitro. We did not observe synergistic effect against clinical isolates and SH5014 (parent strain of acr mutant), while we found synergistic effect against PP120 (soxRS mutant) and SH7616 (an acr mutant) S. typhimurium for all quinolones. Our results suggest that the efficiencies of some antibiotics, including ofloxacin, ciprofloxacin, and pefloxacin are decreased via activation of soxRS and marRAB regulons by NO in S. enterica serovar Typhimurium. Further studies are warranted to establish the interaction of NO with the genes of Salmonella and, with multiple antibiotic resistance.

Sustained 24-hour blockade of the renin-angiotensin system: a high dose of a long-acting blocker is as effective as a lower dose combined with an angiotensin-converting enzyme inhibitor.

Whether a higher dose of a long-acting angiotensin II receptor blocker (ARB) can provide as much blockade of the renin-angiotensin system over a 24-hour period as the combination of an angiotensin-converting enzyme inhibitor and a lower dose of ARB has not been formally demonstrated so far. In this randomized double-blind study we investigated renin-angiotensin system blockade obtained with 3 doses of olmesartan medoxomil (20, 40, and 80 mg every day) in 30 normal subjects and compared it with that obtained with lisinopril alone (20 mg every day) or combined with olmesartan medoxomil (20 or 40 mg). Each subject received 2 dose regimens for 1 week according to a crossover design with a 1-week washout period between doses. The primary endpoint was the degree of blockade of the systolic blood pressure response to angiotensin I 24 hours after the last dose after 1 week of administration. At trough, the systolic blood pressure response to exogenous angiotensin I was 58% +/- 19% with 20 mg lisinopril (mean +/- SD), 58% +/- 11% with 20 mg olmesartan medoxomil, 62% +/- 16% with 40 mg olmesartan medoxomil, and 76% +/- 12% with the highest dose of olmesartan medoxomil (80 mg) (P = .016 versus 20 mg lisinopril and P = .0015 versus 20 mg olmesartan medoxomil). With the combinations, blockade was 80% +/- 22% with 20 mg lisinopril plus 20 mg olmesartan medoxomil and 83% +/- 9% with 20 mg lisinopril plus 40 mg olmesartan medoxomil (P = .3 versus 80 mg olmesartan medoxomil alone). These data demonstrate that a higher dose of the long-acting ARB olmesartan medoxomil can produce an almost complete 24-hour blockade of the blood pressure response to exogenous angiotensin in normal subjects. Hence, a higher dose of a long-acting ARB is as effective as a lower dose of the same compound combined with an angiotensin-converting enzyme inhibitor in terms of blockade of the vascular effects of angiotensin.