Objective To appraise the evidence for comparative efficacy and tolerability of drug treatments in patients with generalised anxiety disorder. Design Systematic review of randomised controlled trials. Primary Bayesian probabilistic mixed treatment metaanalyses allowed pharmacological treatments to be ranked for effectiveness for each outcome measure, given as percentage probability of being the most effective treatment. Secondary frequentist mixed treatment metaanalyses conducted with random effects model; effect size reported as odds ratio and 95% confidence interval. Data sources Medline, Embase, BIOSIS, PsycINFO, Health Economic Evaluations Database, National Health Service Economic Evaluation Database, and Database of Abstracts of Reviews of Effects via DataStar, and Cochrane Database of Systematic Reviews via Cochrane Library (January 1980 to February 2009). Eligibility criteria Double blind placebo controlled randomised controlled trials; published systematic reviews and meta-analyses of randomised controlled trials. Randomised controlled trials including adult participants (aged ≥18) receiving any pharmacological treatment for generalised anxiety disorder. Data abstraction methods Titles or abstracts reviewed initially, followed by review of full text publications for citations remaining after first pass. A three person team conducted screening; an independent reviewer checked a random selection (10%) of articles screened. Data extracted for meta-analysis were also independently reviewed. Main outcome measures Proportion of participants experiencing ≥50% reduction from baseline score on Hamilton anxiety scale (HAM-A) (response), proportion with final HAM-A score ≤7 (remission), proportion withdrawing from trial because of adverse events (tolerability). Results The review identified 3249 citations, and 46 randomised controlled trials met inclusion criteria; 27 trials contained sufficient or appropriate data for inclusion in the analysis. Analyses compared nine drugs (duloxetine, escitalopram, fluoxetine, lorazepam, paroxetine, pregabalin, sertraline, tiagabine, and venlafaxine). In the primary probabilistic mixed treatment meta-analyses, fluoxetine was ranked first for response and remission (probability of 62.9% and 60.6%, respectively) and sertraline was ranked first for tolerability (49.3%). In a subanalysis ranking treatments for generalised anxiety disorder currently licensed in the United Kingdom, duloxetine was ranked first for response (third across all treatments; 2.7%), escitalopram was ranked first for remission (second across all treatments; 26.7%), and pregabalin was ranked first for tolerability (second across all treatments; 7.7%). Conclusions Though the frequentist analysis was inconclusive because of a high level of uncertainty in effect sizes (based on the relatively small number of comparative trials), the probabilistic analysis, which did not rely on significant outcomes, showed that fluoxetine (in terms of response and remission) and sertraline (in terms of tolerability) seem t...

Since chemotherapy for metastatic breast cancer is not curative, consideration of the quality of life is important in selecting a treatment regimen. We conducted a randomized trial comparing continuous chemotherapy, administered until disease progression was evident, with intermittent therapy, whereby treatment was stopped after three cycles and then repeated for three more cycles only when there was evidence of disease progression. Each approach was tested with doxorubicin combined with cyclophosphamide or with cyclophosphamide combined with methotrexate, fluorouracil, and prednisone. Intermittent therapy resulted in a significantly worse response (P = 0.02 by Mann-Whitney test), a significantly shorter time to disease progression (relative risk based on proportional-hazards model, 1.8; 95 percent confidence interval, 1.4 to 2.4), and a trend toward shorter survival (relative risk, 1.3; confidence interval, 0.99 to 1.6). The quality of life was expressed as linear-analogue self-assessment scores for physical well-being, mood, pain, and appetite and as a quality-of-life index. It improved significantly during the first three cycles, when all patients received treatment. Thereafter, intermittent therapy was associated with worse scores for physical well-being (by 23 percent of scale; 95 percent confidence interval, 11 to 35 percent), mood (25 percent; 13 to 37 percent), and appetite (12 percent; 0 to 24 percent) and for the quality-of-life index as indicated by the patient (14 percent; 5 to 23 percent) and the physician (16 percent; 7 to 26 percent). Changes in the quality of life were independent prognostic factors in proportional-hazards models of subsequent survival. We conclude that, as tested, continuous chemotherapy is better than intermittent chemotherapy for advanced breast cancer.

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Summary The value of chemotherapy in advanced non-small cell lung cancer (NSCLC) remains contentious. Because of this two separate but very similar trials were set up in Australia and Southampton (UK). Two hundred and one patients with stage IIIb or IV NSCLC were randomly assigned to cisplatin 120 mg m 2 on days 1 and 29 and vindesine 3 mg m-2 weekly x 6 or to no chemotherapy. Both groups were eligible to receive radiotherapy or other palliative treatment as required. Of 188 evaluable patients, 97 received chemotherapy and 91 were in the control arm. Response was assessed between days 42 and 49. Responders continued chemotherapy at the same doses though cisplatin being given 6 weekly x 4 and the vindesine 2 weekly x 12. The overall response rate to chemotherapy was 28%; there were no significant differences according to major prognostic criteria. Although the overall survival of the chemotherapy group (median 27 weeks) was longer than that of the no chemotherapy group (median 17 weeks) this was not statistically significant (log rank P = 0.33). For patients without dissemination (IlIb), median survival was 45 weeks in the chemotherapy arm and 26 weeks in the non-chemotherapy (log rank P = 0.075). Toxicity was universal and frequently severe: of 17 patients discontinuing chemotherapy after one cycle, 13 did so because of unacceptable toxicity. This chemotherapy cannot be recommended as routine treatment. Further phase III studies of chemotherapy in advanced NSCLC should continue to use a no chemotherapy control and should also attempt to measure quality of life, an issue not addressed effectively in this or other recent trials.

One hundred eight patients with recurrent or metastatic transitional cell carcinoma of the urothelial tract were randomized to receive cisplatin (C) 80 mg/m2 on day 1 every 4 weeks, or methotrexate (M) 50 mg/m2 on days 1 and 15 plus C 80 mg/m2 on day 2 every 4 weeks (C + M). Fifty-three eligible patients were randomized to C + M and 55 to C. In the C + M arm, 45% of patients responded (complete response [CR], 9%) and 31% (CR, 9%) in the C arm (P = .18). In the C arm, 20 patients failing or relapsing after C received M. Two patients responded, and four with progressive disease (PD) and one with a previous partial response (PR) showed no change. The median survival was 8.7 months (C + M arm) and 7.2 months (C arm), P = .7. Relapse-free survival was not significantly different, but C + M was associated with a significantly increased time to disease progression (median, 5.0 months, v 2.8 months for C arm). The response of untreated patients (37%) was not different from those with prior treatment (39%). On the C + M arm, 92% of patients and 96% of patients on the C arm received 85% or more of the scheduled C dose. Significantly more grade 3 or 4 hematological toxicity (27% v 2%; P = .01) and mucositis (20% v 0%; P = .0005) occurred in patients on the C + M arm. Although the initial response rates seen on the combination arm look superior, and the time to disease progression is increased, these effects have not translated into a clinically important increase in the duration of survival and were associated with increased toxicity.

BackgroundAmyotrophic Lateral Sclerosis (ALS) treatment is complicated by the various mechanisms underlying motor neuron degeneration. Recent studies showed that the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB) are compromised in an animal model of ALS due to endothelial cell degeneration. A later study demonstrated a loss of endothelium integrity in the spinal cords of ALS patients. Since circulating endothelial cells (CECs) in the peripheral blood are associated with endothelium damage, being detached dysfunctional endothelial cells, we hypothesized that CEC levels may reflect endothelium condition in ALS patients.Methodology/Principal FindingsCEC levels were estimated in whole blood smears from ALS patients with moderate stage (MALS), severe stage (SALS), and healthy controls by CD146 expression using immunocytochemistry. A significant reduction of CECs was detected in MALS and SALS patients.Conclusions/SignificanceCECs did not predict endothelium state in ALS patients; however, endothelial damage and/or impaired endothelium repair may occur in ALS leading to BBB/BSCB dysfunction. Reduced CECs in peripheral blood of ALS patients may indicate different mechanisms of endothelial damage and repair, rather than only detachment of dysfunctional endothelial cells. Although a potential mechanism of CEC reduction is discussed, establishing a reliable indicator of endothelial dysfunction/damage is important for evaluation of BBB/BSCB status in ALS patients during disease progression.