MGMT promoter methylation in malignant gliomas: ready for personalized medicine?

The DNA repair enzyme O(6)-methylguanine-DNA methyltransferase (MGMT) antagonizes the genotoxic effects of alkylating agents. MGMT promoter methylation is the key mechanism of MGMT gene silencing and predicts a favorable outcome in patients with glioblastoma who are exposed to alkylating agent chemotherapy. This biomarker is on the verge of entering clinical decision-making and is currently used to stratify or even select glioblastoma patients for clinical trials. In other subtypes of glioma, such as anaplastic gliomas, the relevance of MGMT promoter methylation might extend beyond the prediction of chemosensitivity, and could reflect a distinct molecular profile. Here, we review the most commonly used assays for evaluation of MGMT status, outline the prerequisites for standardized tests, and evaluate reasons for difficulties in reproducibility. We critically discuss the prognostic and predictive value of MGMT silencing, reviewing trials in which patients with different types of glioma were treated with various chemotherapy schedules, either up-front or at recurrence. Standardization of MGMT testing requires comparison of different technologies across laboratories and prospectively validated cut-off values for prognostic or predictive effects. Moreover, future clinical trials will need to determine, for each subtype of glioma, the degree to which MGMT promoter methylation is predictive or prognostic, and whether testing should become routine clinical practice.

Influenza and Other Respiratory Virus Weekly Activity Report, December 20, 2008, Week 51

Weekly report of the Iowa Influenza Surveillance Network produced by the Iowa Department of Public Health.

Biomasa desovante de anchoveta en la zona norte centro del mar peruano (4o36,5’ – 14o40’s) a finales del invierno austral 2005

La biomasa desovante entre Punta Infiernillos (14O40’S) y Paita (4°36,5S) fue estimada en 6,1 millones de toneladas (límites de confianza del 95% de 42,29%), y un coeficiente de variación de 21,15%. El peso promedio de las hembras (W) fue 16,27 g, la fecundidad parcial (E), 11.386 ovocitos/hembra, con una proporción sexual (R) de 0,51 y una frecuencia de desove de 0,0984.

Síntesi i optimització de la DPTMephos. Complexos de Mo i W

La ruta sintètica del bis(2-((difenilfosfino)metil)fenil)sulfà, Ph2PCH2-(C6H4)S(C6H4)-CH2PPh2 , DPTMephos, involucra 5 reaccions en 4 etapes ben diferenciades. Es per aquest motiu que es fa necessària una optimització de la ruta sintètica per assolir rendiments més elevats. La primera reacció parteix del sulfur de difenil i involucra la formació d’un complex litiat per acabar realitzant una carbonilació amb N,N-DMF per obtindre un dialdehid. El següent pas de la ruta passa per la reducció del producte al diol corresponent. Tot seguit ja es por preparar el substrat mitjanjant una bromació per a que en l’última etapa, s’acobli a l’estructura el grup difenilfosfino. Tant mateix s’han sintetitzat els isòmers de la DPTMephos amb [W(CO)6] i [Mo(CO)6], observant-se la formació tant dels complexos meridionals com facials i la seva interconversió. Tot seguit s’ha desenvolupat la sulfuració de la DPTMephos per obtindre els lligands tant mono com di sulfurats. També s’ha realitzat un estudi de l’espectre de RMN 31P{1H} del complex fac-[Mo(CO)3(DPTMephos)] a temperatura variable per determinar el senyal de cada fòsfor no equivalent a 200K. S’ha realitzat un estudi de forma qualitativa de les conformacions que adopta l’anell quelat de 6 baules en les conformacions tant meridional com facial d’un complex.

Catalogue de miniatures..., tableaux... provenant du cabinet de M. W... [Walferdin] / [expert] Vignères

[Vente. Art. 1860-05-18. Paris]

[80 phot. des îles Shetland, Orcades, Skye, Bute et autres îles du nord-ouest de l'Ecosse, par G.W. Wilson, don E. Saisset en 1886]

Donateur : Saisset, E. (18..-18..?)

Bortezomib(Velcade (R))-Thalidomide-Dexamethasone (VTD) Is Superior to Thalidomide-Dexamethasone (TD) In Patients with Multiple Myeloma (MM) Progressing or Relapsing After Autologous Transplantation.

Introduction: The Thalidomide-Dexamethasone (TD) regimen has provided encouraging results in relapsed MM. To improve results, bortezomib (Velcade) has been added to the combination in previous phase II studies, the so called VTD regimen. In January 2006, the European Group for Blood and Marrow Transplantation (EBMT) and the Intergroupe Francophone du Myélome (IFM) initiated a prospective, randomized, parallel-group, open-label phase III, multicenter study, comparing VTD (arm A) with TD (arm B) for MM patients progressing or relapsing after autologous transplantation. Patients and Methods: Inclusion criteria: patients in first progression or relapse after at least one autologous transplantation, including those who had received bortezomib or thalidomide before transplant. Exclusion criteria: subjects with neuropathy above grade 1 or non secretory MM. Primary study end point was time to progression (TTP). Secondary end points included safety, response rate, progression-free survival (PFS) and overall survival (OS). Treatment was scheduled as follows: bortezomib 1.3 mg/m2 was given as an i.v bolus on Days 1, 4, 8 and 11 followed by a 10-Day rest period (days 12 to 21) for 8 cycles (6 months) and then on Days 1, 8, 15, 22 followed by a 20-Day rest period (days 23 to 42) for 4 cycles (6 months). In both arms, thalidomide was scheduled at 200 mg/Day orally for one year and dexamethasone 40 mg/Day orally four days every three weeks for one year. Patients reaching remission could proceed to a new stem cell harvest. However, transplantation, either autologous or allogeneic, could only be performed in patients who completed the planned one year treatment period. Response was assessed by EBMT criteria, with additional category of near complete remission (nCR). Adverse events were graded by the NCI-CTCAE, Version 3.0.The trial was based on a group sequential design, with 4 planned interim analyses and one final analysis that allowed stopping for efficacy as well as futility. The overall alpha and power were set equal to 0.025 and 0.90 respectively. The test for decision making was based on the comparison in terms of the ratio of the cause-specific hazards of relapse/progression, estimated in a Cox model stratified on the number of previous autologous transplantations. Relapse/progression cumulative incidence was estimated using the proper nonparametric estimator, the comparison was done by the Gray test. PFS and OS probabilities were estimated by the Kaplan-Meier curves, the comparison was performed by the Log-Rank test. An interim safety analysis was performed when the first hundred patients had been included. The safety committee recommended to continue the trial. Results: As of 1st July 2010, 269 patients had been enrolled in the study, 139 in France (IFM 2005-04 study), 21 in Italy, 38 in Germany, 19 in Switzerland (a SAKK study), 23 in Belgium, 8 in Austria, 8 in the Czech republic, 11 in Hungary, 1 in the UK and 1 in Israel. One hundred and sixty nine patients were males and 100 females; the median age was 61 yrs (range 29-76). One hundred and thirty six patients were randomized to receive VTD and 133 to receive TD. The current analysis is based on 246 patients (124 in arm A, 122 in arm B) included in the second interim analysis, carried out when 134 events were observed. Following this analysis, the trial was stopped because of significant superiority of VTD over TD. The remaining patients were too premature to contribute to the analysis. The number of previous autologous transplants was one in 63 vs 60 and two or more in 61 vs 62 patients in arm A vs B respectively. The median follow-up was 25 months. The median TTP was 20 months vs 15 months respectively in arm A and B, with cumulative incidence of relapse/progression at 2 years equal to 52% (95% CI: 42%-64%) vs 70% (95% CI: 61%-81%) (p=0.0004, Gray test). The same superiority of arm A was also observed when stratifying on the number of previous autologous transplantations. At 2 years, PFS was 39% (95% CI: 30%-51%) vs 23% (95% CI: 16%-34%) (A vs B, p=0.0006, Log-Rank test). OS in the first two years was comparable in the two groups. Conclusion: VTD resulted in significantly longer TTP and PFS in patients relapsing after ASCT. Analysis of response and safety data are on going and results will be presented at the meeting. Protocol EU-DRACT number: 2005-001628-35.

Miss Méphistophélès : roman / Fergus W. Hume ; traduit de l'anglais... par Hephell

Collection : Bibliothèque des meilleurs romans étrangers