Neurotrophic factors are agents with a promising ability to retard progression of neurodegenerative diseases and are effective in slowing photoreceptor degeneration in animal models of retinitis pigmentosa. Here we report a human clinical trial of a neurotrophic factor for retinal neurodegeneration. In this Phase I safety trial, human ciliary neurotrophic factor (CNTF) was delivered by cells transfected with the human CNTF gene and sequestered within capsules that were surgically implanted into the vitreous of the eye. The outer membrane of the encapsulated cell implant is semipermeable to allow CNTF to reach the retina. Ten participants received CNTF implants in one eye. When the implants were removed after 6 months, they contained viable cells with minimal cell loss and gave CNTF output at levels previously shown to be therapeutic for retinal degeneration in rcd1 dogs. Although the trial was not powered to form a judgment as to clinical efficacy, of seven eyes for which visual acuity could be tracked by conventional reading charts, three eyes reached and maintained improved acuities of 10 -15 letters, equivalent to two-to three-line improvement on standard Snellen acuity charts. A surgically related choroidal detachment in one eye resulted in a transient acuity decrease that resolved with conservative management. This Phase I trial indicated that CNTF is safe for the human retina even with severely compromised photoreceptors. The approach to delivering therapeutic proteins to degenerating retinas using encapsulated cell implants may have application beyond disease caused by genetic mutations.clinical trial ͉ neurodegeneration ͉ retinitis pigmentosa ͉ photoreceptor ͉ macular degeneration R etinitis pigmentosa (RP) describes a set of neurodegenerative retinal diseases that cause the death of photoreceptor cells and lead to progressive vision loss and blindness. More than 39 genetic loci and genes have been implicated in monogenic forms of RP (1), underscoring the complexity of its pathogenic mechanisms. With the exception of vitamin A nutritional supplementation (2), no treatments have been shown to be effective across the range of these disorders. Regardless of the initial causative genetic defect, the end result is photoreceptor cell death. The multiplicity of mechanisms stimulated a search for therapeutic agents that are effective in slowing photoreceptor death regardless of the causative genetic mutation.Intervention studies have indicated the possibility of using neurotrophic factors as therapeutic agents for RP (3). Specifically, ciliary neurotrophic factor (CNTF) is effective at retarding retinal degeneration in at least 13 animal RP models, including rd-PDE6b mice (4, 5), rds-peripherin mice (4, 6-10), transgenic rats expressing P23H or S334ter mutant rhodopsin (7, 10), Rdy cats (11), rcd1-PDE6b dogs (7), rhodopsin-knockout mice (9), and rd͞rd mice, nr͞nr mice, and Q334ter rhodopsin transgenic mice (4).CNTF also appears effective for retarding cellular and functional losses in neurodegenerative diseases ...

Purpose Prostate cancer patients with locally advanced disease after radical prostatectomy (RP) are candidates for secondary therapy. However, this higher risk population is heterogeneous and many will not metastasize even when conservatively managed. Given the limited specificity of pathologic features to predict metastasis, newer risk-prediction models are needed. This represents a validation study of a genomic classifier (GC) that predicts post-RP metastasis in a high-risk population. Materials and Methods A case-cohort design was used to sample 1,010 post-RP patients at high risk of recurrence treated between 2000-2006. Patients had preoperative PSA >20 ng/mL, Gleason ≥8, pT3b or GPSM score ≥10. Patients with metastasis at diagnosis or any prior treatment for prostate cancer were excluded. 20% random sampling created a subcohort that included all cases with metastasis. 22-marker GC scores were generated for 219 patients with available genomic data. Receiver operating characteristic and decision curves, competing risk, and weighted regression models assessed GC performance. Results GC had area under the curve of 0.79 for predicting 5-year metastasis post-RP. Decision curves showed that net benefit of GC exceeded clinical-only models. GC was the predominant predictor of metastasis in multivariable analysis. Cumulative incidence of metastasis at 5 years post-RP was 2.4%, 6.0% and 22.5% for patients with low (60% of patients), intermediate (21% of patients), and high (19% of patients) GC scores, respectively (p<0.001). Conclusions These results indicate that genomic information from the primary tumor can identify patients with adverse pathology who are most at risk for metastasis and potentially lethal prostate cancer.

Purpose We investigate whether ocular and person-based characteristics are associated with dark adaptation (DA) measured using the AdaptRx™ device (Apeliotus Technologies, Atlanta, GA). Design Cross-sectional, single-center, observational study. Participants 116 participants >50 years with a range in age-related macular degeneration (AMD) severity. Methods Participants underwent best-corrected visual acuity (BCVA) testing, ophthalmoscopic examination and multimodal imaging. Presence of reticular pseudodrusen (RPD) was assessed by masked grading of fundus images and confirmed with OCT. Eyes were also graded for AMD features (drusen, pigmentary changes, late AMD) to generate a person-based AMD severity groups. One eye was designated the study eye for DA testing using the AdaptRx™ device. Nonparametric statistical testing was performed on all comparisons. Main Outcome Measure The primary outcome of this study was the rod-intercept time (RIT) which is defined as the time for a participant's visual sensitivity to recover to a stimulus intensity of 5 × 10−3 cd/m2 (a decrease of 3 log units), or until a maximum test duration of 40 minutes was reached. Results A total of 116 study eyes in 116 participants (mean age=75.4±9.4 years, 58% female) were analyzed. Increased RIT was significantly associated with increasing age (r=0.34, p=0.0002), decreasing BCVA (r=−0.54, p<0.0001), pseudophakia (p=0.03), decreasing subfoveal choroidal thickness (r=−0.27, p=0.003). Study eyes with RPD (15/116, 13%) had a significantly greater mean RIT compared to eyes without RPD in any AMD severity group (p<0.02 for all comparisons) with 80% reaching the DA test ceiling. Conclusion Impairments in DA increase with age, worse visual acuity, presence of RPD, AMD severity and decreased subfoveal choroidal thickness. Analysis of covariance found the multivariable model that best fit our data included age, AMD group, and presence of RPD (R2=0.56) with the presence of RPD conferring the largest parameter estimate.

Objective. To investigate the safety and efficacy of etanercept in the treatment of uveitis associated with juvenile idiopathic arthritis (JIA). Methods. Children who met the American College of Rheumatology diagnostic criteria for JIA with active uveitis, who had anterior chamber cells of >1؉ or requiring topical corticosteroid >3 times daily, and who were on a stable regimen for arthritis treatment were eligible. Study participants received etanercept (0.4 mg/kg) or placebo administered subcutaneously twice weekly for 6 months. All participants received open-label etanercept for an additional 6 months. Results. Five patients received placebo and 7 received etanercept. Three of the 7 patients treated with etanercept and 2 of the 5 placebo-treated patients were considered ophthalmic successes (P ‫؍‬ 1.0). One patient in each treatment group was considered a treatment failure. Three of the 7 etanercept-treated and 2 of the 5 placebo-treated patients were neither successes nor failures by our definition. There were no serious adverse events for any patient during the entire study period. Reports of minor infections were comparable in each treatment group, 71% for etanercept and 60% for placebo (P ‫؍‬ 0.58). Conclusion. In this small pilot study there was no apparent difference in the anterior segment inflammation between patients treated with etanercept and placebo. The stringent criteria used to measure ophthalmic success of treatment and the small patient population limit the implications of our findings.