Nerve fiber layer thinning lags retinal ganglion cell density following crush axonopathy.

PURPOSE: We investigated the progressive nature of neurodegenerative structural changes following injury to retinal ganglion cell (RGC) axons using quantifiable and noninvasive in vivo imaging techniques. METHODS: To track degenerative RGC progression in retinas following optic nerve crush (ONC) injury, spectral-domain optical coherence tomography (SD-OCT) was used to quantitate the RGC nerve fiber layer (NFL) density. The RGC soma cell density (RCD) was measured by confocal scanning laser ophthalmoscopy (CSLO). The RCD counts were performed using blood vessels as landmarks to anatomically track defined progressive changes in enhanced yellow fluorescent fusion protein (EYFP)-labeled RGCs. RESULTS: Following ONC injury, 68% of the observed decrease in RCD measured by CSLO and 54% of the NFL thickness obtained by SD-OCT imaging (N=4 retinas) occurred within the first week. Between days 7 and 14, an additional 22% decrease in RCD was concurrent with a 31% decrease in overall NFL thickness. Finally, between days 14 and 21, an additional 10% decrease in RCD measured in vivo by CSLO and 15% decrease in NFL thickness by SD-OCT was observed. CONCLUSIONS: Our data suggest that in vivo CSLO imaging of EYFP-RGC expression and SD-OCT measured NFL thickness are fast and reliable methods that longitudinally track neurodegenerative progression following ONC injury. Neurodegenerative changes in NFL thickness measured by SD-OCT imaging have the same overall trajectory as those observed by CSLO for RCD; however, changes in NFL thickness initially lag behind in vivo RGC soma counts with a slower decline in overall measurable change.

Treatment success in cancer: industry compared to publicly sponsored randomized controlled trials.

OBJECTIVE: To assess if commercially sponsored trials are associated with higher success rates than publicly-sponsored trials. STUDY DESIGN AND SETTINGS: We undertook a systematic review of all consecutive, published and unpublished phase III cancer randomized controlled trials (RCTs) conducted by GlaxoSmithKline (GSK) and the NCIC Clinical Trials Group (CTG). We included all phase III cancer RCTs assessing treatment superiority from 1980 to 2010. Three metrics were assessed to determine treatment successes: (1) the proportion of statistically significant trials favouring the experimental treatment, (2) the proportion of the trials in which new treatments were considered superior according to the investigators, and (3) quantitative synthesis of data for primary outcomes as defined in each trial. RESULTS: GSK conducted 40 cancer RCTs accruing 19,889 patients and CTG conducted 77 trials enrolling 33,260 patients. 42% (99%CI 24 to 60) of the results were statistically significant favouring experimental treatments in GSK compared to 25% (99%CI 13 to 37) in the CTG cohort (RR = 1.68; p = 0.04). Investigators concluded that new treatments were superior to standard treatments in 80% of GSK compared to 44% of CTG trials (RR = 1.81; p<0.001). Meta-analysis of the primary outcome indicated larger effects in GSK trials (odds ratio = 0.61 [99%CI 0.47-0.78] compared to 0.86 [0.74-1.00]; p = 0.003). However, testing for the effect of treatment over time indicated that treatment success has become comparable in the last decade. CONCLUSIONS: While overall industry sponsorship is associated with higher success rates than publicly-sponsored trials, the difference seems to have disappeared over time.

Uncertainty in the utility of immunohistochemistry in mismatch repair protein expression in epithelial ovarian cancer.

BACKGROUND: Utility of immunohistochemistry (IHC) for mismatch repair (MMR) protein expression has been demonstrated in colorectal cancer but remains incompletely defined in ovarian cancer. We evaluated MMR protein expression in three population-based samples of epithelial ovarian cancers. MATERIALS AND METHODS: IHC staining was performed on full-section (FS) or tissue microarray (TMA) slides for MLH1, MSH2, and MSH6 expression. RESULTS: Out of 487 cases, 147 and 340 were performed through FS and TMA, respectively. Overall, Loss of Expression (LoE) of at least one MMR protein was observed in 12.7% based on an expression score of ≤3 (on a scale of 9). Notably, LoE was significantly higher in TMAs (17.9%) compared to FS cases (0.7%) (p<0.001). CONCLUSION: A substantial proportion of epithelial ovarian cancers have a loss of MMR protein expression. Protein expression results vary significantly by the tissue sampling methodology utilized, raising concerns about the clinical utility of this test for ovarian tumors.

Treatment of patients with multiple myeloma: an overview of systematic reviews.

Individual studies rarely provide definitive answers to questions related to the effects of treatments. Whether the treatment is associated with more good than harm is best answered by considering the totality of evidence on the topic through the methodology of systematic reviews. The objective of this overview is to summarize all existing systematic reviews on treatments in multiple myeloma (MM), which accounts for 14% of new cases of hematological malignancies each year. Therefore, MEDLINE and the Cochrane Database of Systematic Reviews were systematically searched to identify systematic reviews of interventions. Data were extracted on patients, interventions, control and outcomes. Methodological quality of the systematic reviews was assessed using the AMSTAR assessment tool. Eleven systematic reviews on treatment of MM were included in the overview. Ten addressed seven unique questions and also performed a meta-analysis. One addressed 21 clinical questions related to treatment decisions in myeloma. The quality of systematic reviews varied. The results from the overview show that early treatment does not offer survival benefit. Thalidomide is associated with improved survival when added to standard chemotherapy regimens as induction or maintenance therapy but at the expense of an increased risk of serious adverse events, such as venous thromboembolism. High-dose therapy with single autologous hematopoietic stem cell transplant (AHCT) is associated with superior event-free but not overall survival compared to chemotherapy. Tandem AHCT does not prolong survival but is associated with better event-free survival in comparison to single AHCT. In addition, combination treatment with bisphosphonates reduces pathological vertebral fractures and pain, but does not prolong survival. We found no systematic review evaluating the effects of other novel agents, such as bortezomib or lenalidomide, as single agents or in combinations. Several key clinical questions have been successfully answered by conducting systematic reviews. However, currently many questions of importance for the management of patients with myeloma continue to be dealt with in individual studies instead of synthesized evidence. There is urgent need to perform research synthesis of data related to the effects of novel agents.