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Glaucoma is the leading cause of irreversible blindness globally. With an aging population, disease incidence will rise with an enormous societal and economic burden. The treatment strategy revolves around targeting intraocular pressure, the principle modifiable risk factor, to slow progression of disease. However, there is a clear unmet clinical need to find a novel therapeutic approach that targets and halts the retinal ganglion cell (RGC) degeneration that occurs with fibrosis. RGCs are highly sensitive to metabolic fluctuations as a result of multiple stressors and thus their viability depends on healthy mitochondrial functioning. Metformin, known for its use in type 2 diabetes, has come to the forefront of medical research in multiple organ systems. Its use was recently associated with a 25% reduced risk of glaucoma in a large population study. Here, we discuss its application to glaucoma therapy, highlighting its effect on fibrotic signalling pathways, mitochondrial bioenergetics and NAD oxidation.

Summary:The present study examines the nature of humoral and cellular immune reconstitution in 28 patients with advanced breast cancer following high-dose chemotherapy with stem cell rescue. Patients underwent testing of T, B, NK and dendritic cell function at serial time points until 1 year post transplant or until the time of disease progression. Abnormalities in T cell phenotype and function were observed following high-dose chemotherapy that persisted for at least 6-12 months. The vast majority of patients experienced an inversion of the CD4/CD8 ratio and demonstrated an anergic response to candida antigen. Mean T cell proliferation in response to PHA and to co-culture with allogeneic monocytes was significantly compromised. In contrast, mean IgG and IgA levels were normal 6 months post transplant and NK cell yields and function were transiently elevated following high-dose chemotherapy. Dendritic cells generated from peripheral blood progenitors displayed a characteristic phenotype and were potent inducers of allogeneic T cell proliferation in the posttransplant period. The study demonstrates that patients undergoing autologous transplantation for breast cancer experience a prolonged period of T cell dysfunction. In contrast, B, NK, and DC recover more rapidly. These findings carry significant implications for the design of post-transplant immunotherapy. Bone Marrow Transplantation (2000) 26, 169-176.

Background: Biceps tenodesis can be performed via an open or arthroscopic approach, and there is currently no consensus over which method is superior. The purpose of this study was to systematically review the cohort studies available in the literature to ascertain if open or arthroscopic techniques for biceps tenodesis result in superior clinical outcomes.Methods: A systematic search of articles in MEDLINE, Embase, and the Cochrane Library databases was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Cohort studies comparing the open and arthroscopic techniques for biceps tenodesis were included.Results: Seven clinical trials were identified with 598 patients. The mean follow-up was 23.6 months. In all of the included studies, there was no significant difference (p . 0.05) in any of the functional outcome scoring systems used, including, most commonly, the American Shoulder and Elbow Surgeons (ASES) score and the Constant score. Similarly, no study found a significant difference (p . 0.05) in either patient satisfaction or return to sport. However, 2 studies found a slightly higher rate of complications with the arthroscopic technique due to an increased rate of fixation failure in 1 study and stiffness in the other study.Conclusions: This study found that both open tenodesis and arthroscopic tenodesis result in excellent clinical outcomes, with no significant differences between either method.

Glaucoma is the leading cause of irreversible blindness worldwide, and the burden of the disease continues to grow as the global population ages. Currently, the only treatment option is to lower intraocular pressure. A better understanding of glaucoma pathogenesis will help us to develop novel therapeutic options. Oxidative stress has been implicated in the pathogenesis of many diseases. Oxidative stress occurs when there is an imbalance in redox homeostasis, with reactive oxygen species producing processes overcoming anti-oxidant defensive processes. Oxidative stress works in a synergistic fashion with endoplasmic reticulum stress, to drive glaucomatous damage to trabecular meshwork, retinal ganglion cells and the optic nerve head. We discuss the oxidative stress and endoplasmic reticulum stress pathways and their connections including their key intermediary, calcium. We highlight therapeutic options aimed at disrupting these pathways and discuss their potential role in glaucoma treatment.

PURPOSE Mutations in DNA mismatch repair genes and PTEN, diagnostic of Lynch and Cowden syndromes, respectively, represent the only established inherited predisposition genes in endometrial cancer to date. The prevalence of other cancer predisposition genes remains unclear. We determined the prevalence of pathogenic germline variants in unselected patients with endometrial cancer scheduled for surgical consultation. PATIENTS AND METHODS Patients prospectively consented (April 2016 to May 2017) to an institutional review board–approved protocol of tumor-normal sequencing via a custom next-generation sequencing panel—the Memorial Sloan Kettering–Integrated Mutation Profiling of Actionable Cancer Targets—that yielded germline results for more than 75 cancer predisposition genes. Tumors were assessed for microsatellite instability. Per institutional standards, all tumors underwent Lynch syndrome screening via immunohistochemistry (IHC) for mismatch repair proteins. RESULTS Of 156 patients who consented to germline genetic testing, 118 (76%) had stage I disease. In 104 patients (67%), tumors were endometrioid, and 60 (58%) of those tumors were grade 1. Twenty-four pathogenic germline variants were identified in 22 patients (14%): seven (4.5%) had highly penetrant cancer syndromes and 15 (9.6%) had variants in low-penetrance, moderate-penetrance, or recessive genes. Of these, five (21%) were in Lynch syndrome genes (two MSH6, two PMS2, and one MLH1). All five tumors had concordant IHC staining; two (40%) were definitively microsatellite instability–high by next-generation sequencing. One patient had a known BRCA1 mutation, and one had an SMARCA4 deletion. The remaining 17 variants (71%) were incremental findings in low- and moderate-penetrance variants or genes associated with recessive disease. CONCLUSION In unselected patients with predominantly low-risk, early-stage endometrial cancer, germline multigene panel testing identified cancer predisposition gene variants in 14%. This finding may have implications for future cancer screening and risk-reduction recommendations. Universal IHC screening for Lynch syndrome successfully identifies the majority (71%) of high-penetrance germline mutations.

Background/Objectives: Endothelial keratoplasty (EK) is a commonly performed transplant procedure used in the treatment of corneal endothelial dysfunction. The aim of this systematic review and meta-analysis is to evaluate the differences in visual acuity outcomes, endothelial cell density (ECD) and complications between two forms of EK, ultrathin descemet stripping automated endothelial keratoplasty (UT-DSAEK) and descemet membrane endothelial keratoplasty (DMEK). Methods: A comprehensive literature search was conducted to identify studies reporting comparative results of UT-DSAEK versus DMEK. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was used for search strategy. Of 141 titles, 7 studies met the inclusion criteria; best corrected visual acuity (BCVA) (LogMAR), ECD (cells/mm2), and complications were compared, with all statistical analysis performed using Review Manager. Results: A total of 362 eyes were included for analysis. DMEK resulted in significantly better BCVA at 3 months (0.13 vs 0.23, p = 0.003) and 1 year post-op (0.10 vs 0.19, p = 0.0005). UT-DSAEK resulted in significantly lower total complications (25.2% vs 57.3%, p = 0.0001) and rates of re-bubbling (11.0% vs 33.7%, p = 0.004). No differences were found in ECD between the two procedures (1,673.8 vs 1,705.3, p = 0.77). Conclusions: DMEK results in superior visual acuity rates with quicker recovery. However, UT-DSAEK has a more favourable complication profile, particularly regarding lower rates of re-bubbling. Both are valuable options in the treatment of corneal endothelial disease and choice of procedure may depend on surgical expertise.

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