Description: Background and Purpose— High plasma total homocysteine (tHcy) has been associated with cognitive impairment but lowering tHcy with B-vitamins has produced equivocal results. We aimed to determine whether B-vitamin supplementation would reduce tHcy and the incidence of new cognitive impairment among individuals with stroke or transient ischemic attack ≥6 months previously. Methods— A total of 8164 patients with stroke or transient ischemic attack were randomly allocated to double-blind treatment with one tablet daily of B-vitamins (folic acid, 2 mg; vitamin B6, 25 mg; vitamin B12, 500 μg) or placebo and followed up for 3.4 years (median) in the VITAmins TO Prevent Stroke (VITATOPS) trial. For this prespecified secondary analysis of VITATOPS, the primary outcome was a new diagnosis of cognitive impairment, defined as a Mini-Mental State Examination (MMSE) score 〈24 on ≥2 follow-up visits. Secondary outcomes were cognitive decline, and the mean tHcy and MMSE at final follow-up. Results— A total of 3089 participants (38%) voluntarily undertook the MMSE 〉6 months after the qualifying stroke; 2608 participants were cognitively unimpaired (MMSE ≥24), of whom 2214 participants (1110 B-vitamins versus 1104 placebo) had follow-up MMSEs during 2.8 years (median). At final follow-up, allocation to B-vitamins, compared with placebo, was associated with a reduction in mean tHcy (10.2 μmol/L versus 14.2 μmol/L; P 〈0.001) but no change from baseline in the mean MMSE score (–0.22 points versus –0.25 points; difference, 0.03; 95% confidence interval, –0.13 to 0.19; P =0.726) and no difference in the incidence of cognitive impairment (5.51% versus 5.47%; risk ratio, 1.01; 95% confidence interval, 0.69–1.48; P =0.976), cognitive decline (9.1% versus 10.3%; risk ratio, 0.89; 0.67–1.18; P =0.414), or cognitive impairment or decline (11.0% versus 11.3%; risk ratio, 0.98; 0.75–1.27; P =0.855). Conclusions— Daily supplementation with folic acid, vitamin B6, and vitamin B12 to a self-selected clinical trial cohort of cognitively unimpaired patients with previous stroke or transient ischemic attack lowered mean tHcy but had no effect on the incidence of cognitive impairment or cognitive decline, as measured by the MMSE, during a median of 2.8 years. Clinical Trial Registration— URL: http://www.controlled-trials.com . Unique identifier: ISRCTN74743444; URL: http://www.clinicaltrials.gov . Unique identifier: NCT00097669.

Description: The pneumococcal chromosome encodes about 140 transporters, many of which are predicted to be involved in efflux. In order to critically evaluate pneumococcal efflux, a series of transporter mutants were constructed, and their phenotypes were assayed by disk diffusion, microdilution drug susceptibility testing (MIC testing), growth of cultures at sub-MIC concentrations, and phenotype microarray analysis. Mutants with mutations in seven ATP binding cassette (ABC) transporters, three multiantimicrobial extrusion (MATE) family efflux pumps, and one major facilitator superfamily (MFS) transporter were obtained in Streptococcus pneumoniae strain DP1004. The susceptibility of these 11 mutants to over 250 different substances was compared to that of the parent strain. Of the tested transporters, only the ABC transporter PatAB (SP2073-5) presented a clear multidrug resistance (MDR) profile, as the mutant showed significantly increased susceptibility to ethidium bromide, acriflavine, and berberine. Among the other transporters analyzed, the mutants devoid of the MATE efflux pump SP2065 exhibited reduced susceptibility to novobiocin, and those with mutations of the MATE family DinF transport system (SP1939) exhibited increased susceptibility to moxifloxacin, ciprofloxacin, and levofloxacin. This change in quinolone MIC was found to be independent from the competence-mediated effect of quinolones on the cinA-recA-dinF operon. Furthermore, the dinF mutant, in contrast to the parental strain, allowed selection for quinolone-resistant mutants when exposed to moxifloxacin. These data confirm the clear MDR profile of the PatAB ABC transporter and suggest for the MATE DinF a phenotype associated with quinolone susceptibility, particularly for moxifloxacin.

Description: On November 1, 2013, the U.S. Food and Drug Administration (FDA) approved obinutuzumab (GAZYVA; Genentech, Inc.), a CD20-directed cytolytic antibody, for use in combination with chlorambucil for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL). In stage 1 of the trial supporting approval, patients with previously untreated CD20-positive CLL were randomly allocated (2:2:1) to obinutuzumab + chlorambucil (GClb, n = 238), rituximab + chlorambucil (RClb, n = 233), or chlorambucil alone (Clb, n = 118). The primary endpoint was progression-free survival (PFS), and secondary endpoints included overall response rate (ORR). Only the comparison of GClb to Clb was relevant to this approval and is described herein. A clinically meaningful and statistically significant improvement in PFS with medians of 23.0 and 11.1 months was observed in the GClb and Clb arms, respectively (HR, 0.16; 95% CI, 0.11–0.24; P 〈 0.0001, log-rank test). The ORRs were 75.9% and 32.1% in the GClb and Clb arms, respectively, and the complete response rates were 27.8% and 0.9% in the GClb and Clb arms, respectively. The most common adverse reactions (≥10%) reported in the GClb arm were infusion reactions, neutropenia, thrombocytopenia, anemia, pyrexia, cough, and musculoskeletal disorders. Obinutuzumab was the first Breakthrough Therapy–designated drug to receive FDA approval. Clin Cancer Res; 20(15); 3902–7. ©2014 AACR .

Description: Aims Percutaneous closure of patent foramen ovale (PFO) in cryptogenic cerebrovascular events is an alternative to medical therapy. The interpretation of residual shunts after implantation of different devices for PFO with different morphologies is controversial. Methods and results Transcatheter PFO closure was performed in 123 patients with a history of ≥1 paradoxical embolism using three different devices: Amplatzer ( n = 46), Figulla Occlutech ( n = 41), and Atriasept Cardia ( n = 36). Fifty-six patients presented with simple PFO and 67 patients had complex morphologies. All patients were studied with contrast enhanced transesophageal echocardiography (TEE) before interventional procedure and thereafter at 1 and 6 months and every 6–12 months in case of incomplete closure. Definite closure was confirmed in at least two consecutive TEE studies. Various PFO morphologies were identified by TEE before device implantation. The device size to PFO diameter ratio was significantly increased in patients with complex PFO compared with those patients with a simple PFO morphology ( P 〈 0.05). The difference between the closure rate of S-PFO and C-PFO concerning each device type was significant (Amplatzer P = 0.0027, Figulla P = 0.0043, and Atriasept P 〈 0.01). The mean follow-up period was 3.4 years (median 2.7 years) with a cerebrovascular re-event rate of 2.4% per year. In three patients, thrombi were detected in the 6-month TEE controls and resolved after medical therapy. In three other patients, the implantation of an adjunctive device was necessary for residual shunt. Conclusion In our series of patients, the closure rate was dependent on PFO morphology more than occluder size and type. An adjunctive device was implanted in selected cases.

Description: Background The ROSORC trial, a randomised, phase II trial comparing sorafenib plus interleukin (IL-2) versus sorafenib alone as first-line treatment of metastatic renal cell carcinoma (mRCC) failed to demonstrate differences in progression-free survival (PFS). Updated overall survival (OS) results are reported. Patients and methods In this study, 128 patients were randomised to receive sorafenib 400 mg twice daily plus subcutaneous IL-2 4.5 million international units (MIU) five times per week for 6 weeks every 8 weeks (arm A) or sorafenib alone (arm B). OS was estimated with the Kaplan–Meier method and compared with the two-sided log-rank test. Results After a median follow-up of 58 months (interquartile range: 28–63 months), the median OS was 38 and 33 months in arms A and B, respectively ( P = 0.667). The 5-year OS was 26.3% [95% confidence interval (CI) 15.9–43.5) and 23.1% (95% CI 13.2–40.5) for the combination- and single-agent arm, respectively. Most of the patients who were refractory to first-line treatment were subsequently treated with different targeted agents; they had a median survival greater than expected. Conclusions This outcome suggests a synergistic effect of the subsequent therapies following sorafenib failure. ClinicalTrials.gov Identifier NCT00609401.

Description: Background and Purpose— To determine the effect of B vitamin treatment on the incidence of cancer among patients with stroke or transient ischemic attack. Methods— A total of 8164 patients with recent stroke or transient ischemic attack were randomly allocated to double-blind treatment with 1 tablet daily of placebo or B vitamins (2 mg folic acid, 25 mg vitamin B 6 , 500 μg vitamin B 12 ) and followed for a median of 3.4 years for any cancer as an adverse event. Results— There was no significant difference in the incidence of any cancer among participants assigned B vitamins compared with placebo (4.04% versus 4.59%; risk ratio, 0.86; 95% CI, 0.70–1.07) and no difference in cancer mortality (2.35% versus 2.09%; risk ratio, 1.09; 0.81–1.46). Among 1899 patients with diabetes, the incidence of cancer was higher among participants assigned B vitamins compared with placebo (5.35% versus 3.28%; adjusted risk ratio, 2.21; 1.31–3.73), whereas among 6168 patients without diabetes, the incidence of cancer was lower among participants assigned B vitamins compared with placebo (3.66% versus 5.03%; adjusted risk ratio, 0.67; 0.51–0.87; P for interaction=0.0001). Conclusions— Daily administration of folic acid, vitamin B 6 , and vitamin B 12 to 8164 patients with recent stroke or transient ischemic attack for a median of 3.4 years had no significant effect, compared with placebo, on cancer incidence or mortality. However, a post hoc subgroup analysis raises the hypothesis that folic acid treatment may increase the incidence of cancer among diabetics and reduce the incidence of cancer among nondiabetics with a history of stroke or transient ischemic attack. Clinical Trial Registration— URL: www.clinicaltrials.gov . Unique identifier: NCT00097669. URL: www.controlled-trials.com . Unique identifier: ISRCTN74743444.