Thalidomide for previously untreated elderly patients with multiple myeloma: meta-analysis of 1685 individual patient data from 6 randomized clinical trials

The role of thalidomide for previously untreated elderly patients with multiple myeloma remains unclear. Six randomized controlled trials, launched in or after 2000, compared melphalan and prednisone alone (MP) and with thalidomide (MPT). The effect on overall survival (OS) varied across trials. We carried out a meta-analysis of the 1685 individual patients in these trials. The primary endpoint was OS, and progression-free survival (PFS) and 1-year response rates were secondary endpoints. There was a highly significant benefit to OS from adding thalidomide to MP (hazard ratio = 0.83; 95% confidence interval 0.73-0.94, P = .004), representing increased median OS time of 6.6 months, from 32.7 months (MP) to 39.3 months (MPT). The thalidomide regimen was also associated with superior PFS (hazard ratio = 0.68, 95% confidence interval 0.61-0.76, P < .0001) and better 1-year response rates (partial response or better was 59% on MPT and 37% on MP). Although the trials differed in terms of patient baseline characteristics and thalidomide regimens, there was no evidence that treatment affected OS differently according to levels of the prognostic factors. We conclude that thalidomide added to MP improves OS and PFS in previously untreated elderly patients with multiple myeloma, extending the median survival time by on average 20%.     

High-Risk groups for late diagnosis of HIV infection: a need for rethinking testing policy in the general population

The aim of the study was to identify high-risk groups and the determinants of late HIV diagnosis in France in the era of highly active antiretroviral therapy (HAART), from January 1996 to June 2005. Informations were collected from an electronic medical record of all HIV- 1-infected patients who sought care in six HIV reference centers in France, constituting a prospective multicentric cohort. Patients were defined as "late testers" if they had presented with either symptoms of clinical AIDS or a CD4 cell count less than 200/mm(3) during the year of diagnosis, as "nonlate" if their CD4 count was above 200, and as "unknown" if CD4 cell count in the year at the time of diagnosis was not documented. Among the 4516 patients available for analysis, the percentage of late testing was 38% (n = 1718) and decreased after 2003 (31.5% in 2004-2005). This percentage was higher in heterosexual men (48.2%) than in homosexual men (31.7%) or heterosexual women (32.6%) and was higher for patients older than 30. Heterosexual men living in a couple with children had a higher risk of late testing (odds ratio [OR] = 1.65, 95% confidence interval [CI]: 1.03 to 2.66), while heterosexual women in a couple without children had a lower risk (OR = 0.46, 95% CI: 0.25 to 0.83). Among homosexual men, unemployment was associated with late testing (OR = 2.23, 95% CI: 1.14 to 4.36). The proportion of late testing was still high. Groups classically identified as low risk for HIV infection, particularly heterosexual men in a couple with children, were found to be at high risk for late testing. It seems necessary to improve HIV testing policy in the heterosexual population.     

Obstetrical and neonatal characteristics vary with birthweight in a cohort of 100 term newborns with symptomatic arterial ischemic stroke

ObjectivesMany questions remain regarding the mechanism of perinatal stroke.MethodsIn a series of 100 prospectively enrolled term neonates with symptomatic arterial ischemic stroke, we explored family antecedents, pregnancy and delivery conditions and clinical presenting features and distinguished features of the 50 larger infants with the remainder. Cardiac and cervical arterial imaging were performed in 70 and 51 cases.ResultsPrevious fetal loss, first pregnancy, primiparity, twin-gestation, cesarean and traumatic delivery, neonatal distress, male sex and premature rupture of membranes were statistically more common than in the general population. Normal pregnancy proportion and mean birthweight were in the normal range, arguing against a vasculo-placental origin in the majority. Furthermore, there was an excess of large babies. The larger infants were more subject to suffer from acute perinatal events, with a trend for an excess of neonatal distress (p = 0.065) and for more severe presenting features (p = 0.027), while the lighter were more likely to have experienced longstanding obstetrical risk factors such as complicated pregnancy (p = 0.047) and tobacco exposure (p = 0.028). Cervical MR angiography showed an internal carotid occlusion in two babies, whereas echo-Doppler was always normal; in one case the two methods were discordant. Echocardiography was non-informative.InterpretationThe data from this prospective cohort of neonates with stroke confirm that many obstetrical and perinatal factors are risk determinants. They also suggest that birthweight and gender may be biomarkers of two populations of neonates with different pathological mechanisms. MR angiography appears more sensitive than echo-Doppler for the exploration of the neonatal cervical vasculature.     

Distribution and larval habitat characterization of Anopheles moucheti, Anopheles nili, and other malaria vectors in river networks of southern Cameroon

Despite their importance as malaria vectors, little is known of the bionomic of Anopheles nili and Anopheles moucheti. Larval collections from 24 sites situated along the dense hydrographic network of south Cameroon were examined to assess key ecological factors associated with these mosquitoes distribution in river networks. Morphological identification of the III and IV instar larvae by the use of microscopy revealed that 47.6% of the larvae belong to An. nili and 22.6% to An. moucheti. Five variables were significantly involved with species distribution, the pace of flow of the river (lotic, or lentic), the light exposure (sunny or shady), vegetation (presence or absence of vegetation) the temperature and the presence or absence of debris. Using canonical correspondence analysis, it appeared that lotic rivers, exposed to light, with vegetation or debris were the best predictors of An. nili larval abundance. Whereas, An. moucheti and An. ovengensis were highly associated with lentic rivers, low temperature, having Pistia. An. nili and An. moucheti distribution along river systems across south Cameroon was highly correlated with environmental variables. The distribution of An. nili conforms to that of a generalist species which is adapted to exploiting a variety of environmental conditions, Whereas, An. moucheti, Anopheles ovengensis and Anopheles carnevalei appeared as specialist forest mosquitoes.     

A pilot study of nuclear instability in archived renal and upper urinary tract tumours with putative ochratoxin aetiology

DNA ploidy measurement has been applied uniquely to wax-embedded tissue of primary renal cell and metastatic tumours of a key experimental researcher on porcine ochratoxicosis, a control, and four transitional cell carcinomas from cases of Balkan endemic nephropathy. Primary renal tumour was diploid, and hyperdiploid metastasis was within the lower ploidy range for typical renal cell carcinoma. Three Balkan primary tumours showed extensive aneuploidy indicating marked nuclear instability, similar to model rat renal carcinoma caused by ochratoxin A. In contrast, much less nuclear instability in the putative occupational ochratoxicosis case fitted poorly with the ochratoxin A model.     

TPA023 [7-(1,1-dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine], an agonist selective for alpha2- and alpha3-containing GABAA receptors, is a nonsedating anxiolytic in rodents and primates

7-(1,1-Dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine (TPA023) is a triazolopyridazine that binds with equivalent high (subnanomolar) affinity to the benzodiazepine binding site of recombinant human GABA(A) receptors containing an alpha1, alpha2, alpha3, or alpha5 subunit but has partial agonist efficacy at the alpha2 and alpha3 subtypes and essentially antagonist efficacy at the alpha1 and alpha5 subtypes. In rats, TPA023 gave time- and dose-dependent occupancy after oral dosing, with 50% occupancy corresponding to a dose of 0.42 mg/kg. It has anxiolytic-like activity in unconditioned (elevated plus maze) and conditioned (fear-potentiated startle and conditioned suppression of drinking) rat models of anxiety with minimum effective doses (MED; 1-3 mg/kg) corresponding to 70 to 88% occupancy. However, there was no appreciable sedation in a response sensitivity (chain-pulling) assay at a dose of 30 mg/kg, resulting in 99% occupancy. Similarly, TPA023 was robustly anxiolytic in the squirrel monkey conditioned emotional response assay, with a MED of 0.3 mg/kg, but did not produce any sedation in a lever-pressing test of sedation even at 10 mg/kg. TPA023 produced no impairment in performance in the mouse Rotarod assay, and there was only a mild interaction with ethanol. In addition to anxiolytic-like efficacy, TPA023 had anticonvulsant activity in a mouse pentylenetetrazole seizure model. Finally, TPA023 did not cause precipitated withdrawal in mice treated for 7 days with the nonselective agonist triazolam, nor did N-methyl-beta-carboline-3-carboxamide (FG 7142) precipitate withdrawal in mice treated for 7 days with TPA023. In summary, the novel alpha2/alpha3-selective efficacy profile of TPA023 translates into a nonsedating anxiolytic profile that is distinct from nonselective agonists.     

Dexamethasone-based regimens versus melphalan-prednisone for elderly multiple myeloma patients ineligible for high-dose therapy

Dexamethasone alone increases life expectancy in patients with relapsed multiple myeloma (MM); however, no large randomized study has compared dexamethasone and dexamethasone-based regimens with standard melphalan-prednisone in newly diagnosed MM patients ineligible for high-dose therapy. In the Intergroupe Francophone du Myélome (IFM) 95-01 trial, 488 patients aged 65 to 75 years were randomized between 4 regimens of treatment: melphalan-prednisone, dexamethasone alone, melphalan-dexamethasone, and dexamethasone-interferon alpha. Response rates at 6 months (except for complete response) were significantly higher among patients receiving melphalan-dexamethasone, and progression-free survival was significantly better among patients receiving melphalan (P < .001, for both comparisons), but there was no difference in overall survival between the 4 treatment groups. Moreover, the morbidity associated with dexamethasone-based regimens was significantly higher than with melphalan-prednisone, especially for severe pyogenic infections in the melphalan-dexamethasone arm and hemorrhage, severe diabetes, and gastrointestinal and psychiatric complications in the dexamethasone arms. Overall, these results indicated that dexamethasone should not be routinely recommended as first-line treatment in elderly patients with MM. In the context of the IFM 95-01 trial, the standard melphalan-prednisone remained the best treatment choice when efficacy and patient comfort were both considered. These results might be useful in the context of future combinations with innovative drugs.