Novel cell adhesion/migration pathways are predictive markers of HDAC inhibitor resistance in cutaneous T cell lymphoma

BACKGROUND: Treatment for Cutaneous T Cell Lymphoma (CTCL) is generally not curative. Therefore, selecting therapy that is effective and tolerable is critical to clinical decision-making. Histone deacetylase inhibitors (HDACi), epigenetic modifier drugs, are commonly used but effective in only ~30% of patients. There are no predictive markers of HDACi response and the CTCL histone acetylation landscape remains unmapped. We sought to identify pre-treatment molecular markers of resistance in CTCL that progressed on HDACi therapy. METHODS: Purified T cells from 39 pre/post-treatment peripheral blood samples and skin biopsies from 20 patients were subjected to RNA-seq and ChIP-seq for histone acetylation marks (H3K14/9 ac, H3K27ac). We correlated significant differences in histone acetylation with gene expression in HDACi-resistant/sensitive CTCL. We extended these findings in additional CTCL patient cohorts (RNA-seq, microarray) and using ELISA in matched CTCL patient plasma. FINDINGS: Resistant CTCL exhibited high levels of histone acetylation, which correlated with increased expression of 338 genes (FDR \u3c 0·05), including some novel to CTCL: BIRC5 (anti-apoptotic); RRM2 (cell cycle); TXNDC5, GSTM1 (redox); and CXCR4, LAIR2 (cell adhesion/migration). Several of these, including LAIR2, were elevated pre-treatment in HDACi-resistant CTCL. In CTCL patient plasma (n = 6), LAIR2 protein was also elevated (p \u3c 0·01) compared to controls. INTERPRETATION: This study is the first to connect genome-wide differences in chromatin acetylation and gene expression to HDACi-resistance in primary CTCL. Our results identify novel markers with high pre-treatment expression, such as LAIR2, as potential prognostic and/or predictors of HDACi-resistance in CTCL. FUNDING: NIH:CA156690, CA188286; NCATS: WU-ICTS UL1 TR000448; Siteman Cancer Center: CA091842

Outcomes of ovulation induction-intrauterine insemination in lean, overweight, and obese women with polycystic ovary syndrome

Objective: To compare pregnancy rates between lean, overweight, and obese women with polycystic ovary syndrome (PCOS) undergoing ovulation induction-intrauterine insemination (OI-IUI). Design: Retrospective cohort study Setting: Academic training program Patient(s): All women with PCOS undergoing OI-IUI from January 2000 to November 2013. Interventions: Ovulation induction-intrauterine insemination with oral (oral OI-IUI) or combined oral and injectable (combined OI-IUI) agents. Main Outcome Measures: Clinical pregnancy rates (CPR) per IUI were compared in 198 women undergoing oral OI-IUI and combined OI-IUI. Multivariate logistic regression was used to calculate the odds of clinical pregnancy while adjusting for potential confounders. Results were expressed as adjusted odds ratios (OR) with 95% confidence intervals (CI), using lean women as the referent population. Results: In lean PCOS patients undergoing combined OI-IUI, the unadjusted CPR was 52%; CPR was comparatively lower in overweight (22%), obese (27%) and morbidly obese (21%) women for all cycles. Adjusting for age and duration of infertility, the odds of clinical pregnancy after combined OI-IUI was significantly diminished in overweight (OR=0.27 CI=0.12-0.63), obese (OR=0.41, CI=0.20-0.83) and morbidly obese women (OR=0.33 CI=0.14-0.78) as compared to the lean PCOS referent. A similar but non-significant trend was identified in women undergoing oral OI-IUI. Conclusion: Lean women with PCOS have a higher CPR after combined OI-IUI as compared to their overweight, obese, and morbidly obese counterparts. Patients with a lean PCOS phenotype may preferentially benefit from this treatment approach

Visual outcomes and subjective experience after bilateral implantation of a new diffractive trifocal intraocular lens

Purpose - To assess clinical outcomes and subjective experience after bilateral implantation of a diffractive trifocal intraocular lens (IOL). Setting - Midland Eye Institute, Solihull, United Kingdom. Design - Cohort study. Methods - Patients had bilateral implantation of Finevision trifocal IOLs. Uncorrected distance visual acuity, corrected distance visual acuity (CDVA), and manifest refraction were measured 2 months postoperatively. Defocus curves were assessed under photopic and mesopic conditions over a range of +1.50 to -4.00 diopters (D) in 0.50 D steps. Contrast sensitivity function was assessed under photopic conditions. Halometry was used to measure the angular size of monocular and binocular photopic scotomas arising from a glare source. Patient satisfaction with uncorrected near vision was assessed using the Near Activity Visual Questionnaire (NAVQ). Results - The mean monocular CDVA was 0.08 logMAR ± 0.08 (SD) and the mean binocular CDVA, 0.06 ± 0.08 logMAR. Defocus curve testing showed an extended range of clear vision from +1.00 to -2.50 D defocus, with a significant difference in acuity between photopic conditions and mesopic conditions at -1.50 D defocus only. Photopic contrast sensitivity was significantly better binocularly than monocularly at all spatial frequencies. Halometry showed a glare scotoma of a mean size similar to that in previous studies of multifocal and accommodating IOLs; there were no subjective complaints of dysphotopsia. The mean NAVQ Rasch score for satisfaction with near vision was 15.9 ± 10.7 logits. Conclusions - The trifocal IOL implanted binocularly produced good distance visual acuity and near and intermediate visual function. Patients were very satisfied with their uncorrected near vision

Management of Worsening Aortic Dilation and Insufficiency in a 20-Week Pregnant Woman: A Case Report

Preexisting aortic disease can worsen during pregnancy as physiologic hemodynamic changes evolve. At a large academic institution, a patient with a remote history of vasculitis presented with a second trimester pregnancy with increasing aortic dilatation and aortic insufficiency. Extensive obstetric discussions encompassed maternal cardiac risks from continuing the pregnancy and fetal risks from maternal cardiac intervention. This patient desired termination of pregnancy to avoid further complications and to expedite surgical aortic repair

Diffuse Reflectance Spectroscopy of Epithelial Tissue with a Smart Fiber-optic Probe

Diffuse reflectance spectroscopy (DRS) with a fiber-optic probe can noninvasively quantify the optical properties of epithelial tissues and has shown the potential as a cost-effective, fast and sensitive tool for diagnosis of early precancerous changes in the cervix and oral cavity. However, current DRS systems are susceptible to several sources of systematic and random errors, such as uncontrolled probe-to-tissue pressure and lack of a real-time calibration that can significantly impair the measurement accuracy, reliability and validity of this technology as well as its clinical utility. In addition, such systems use bulky, high power and expensive optical components which impede their widespread use in low- and middle-income countries (LMICs) where epithelial cancer related death is disproportionately high. In this paper we report a portable, easy-to-use and low cost, yet accurate and reliable DRS device that can aid in the screening and diagnosis of oral and cervical cancer. The device uses an innovative smart fiber-optic probe to eliminate operator bias, state-of-the-art photonics components to reduce size and power consumption, and automated software to reduce the need of operator training. The device showed a mean error of 1.4 ± 0.5% and 6.8 ± 1.7% for extraction of phantom absorption and reduced scattering coefficients, respectively. A clinical study on healthy volunteers indicated that a pressure below 1.0 psi is desired for oral mucosal tissues to minimize the probe effects on tissue physiology and morphology

Low incidence of paradoxical reductions in HDL-C levels in dyslipidemic patients treated with fenofibrate alone or in combination with ezetimibe or ezetimibe/simvastatin

<p>Abstract</p> <p>Background</p> <p>Fibrates have been reported to cause paradoxical decreases in HDL-C in certain patients.</p> <p>Design and methods</p> <p>This post-hoc analysis explored the frequency/magnitude of HDL-C reductions in a pooled database of mixed dyslipidemic patients (LDL-C:3.4-5.7 mmol/L;TG:1.7-5.7 mmol/L) receiving placebo (PBO), fenofibrate (FENO), ezetimibe plus FENO (EZE+FENO), or EZE/simvastatin plus FENO (EZE/SIMVA+FENO) for 12 weeks.</p> <p>Results</p> <p>PBO-treated patients had the highest incidence of HDL-C reductions from baseline (45%) compared with patients taking FENO (14%), EZE+FENO (9%), or EZE/SIMVA+FENO (9%). Reductions <30% reflected natural variability since the largest reduction in HDL-C approached 30% in the PBO group. Only 3 patients exhibited HDL-C reductions ≥30% (i.e., 2 patients in the FENO group and 1 in the EZE+FENO group). There were no differences in demographic/biochemical characteristics between patients with and without HDL-C reductions.</p> <p>Conclusions</p> <p>The incidence of paradoxical HDL-C reductions was low in mixed dyslipidemic patients receiving FENO alone or combined with EZE or EZE/SIMVA.</p> <p>Trial registrations</p> <p>Clinicaltrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00092560">NCT00092560</a> and <a href="http://www.clinicaltrials.gov/ct2/show/NCT00092573">NCT00092573</a></p

Clinical outcomes after implantation of a new hydrophobic acrylic toric IOL during routine cataract surgery

PURPOSE: To assess the clinical outcomes after implantation of a new hydrophobic acrylic toric intraocular lens (IOL) to correct preexisting corneal astigmatism in patients having routine cataract surgery. SETTING: Four hospital eye clinics throughout Europe. DESIGN: Cohort study. METHODS: This study included eyes with at least 0.75 diopter (D) of preexisting corneal astigmatism having routine cataract surgery. Phacoemulsification was performed followed by insertion and alignment of a Tecnis toric IOL. Patients were examined 4 to 8 weeks postoperatively; uncorrected distance visual acuity (UDVA), corrected distance visual acuity, manifest refraction, and keratometry were measured. Individual patient satisfaction with uncorrected vision and the surgeon’s assessment of ease of handling and performance of the IOL were also documented. The cylinder axis of the toric IOL was determined by dilated slitlamp examination. RESULTS: The study enrolled 67 eyes of 60 patients. Four to 8 weeks postoperatively, the mean UDVA was 0.15 logMAR G 0.17 (SD) and the UDVA was 20/40 or better in 88% of eyes. The mean refractive cylinder decreased significantly postoperatively, from -1.91 +/- 1.07 D to -0.67 +/- 0.54 D. No significant change in keratometric cylinder was observed. The mean absolute IOL misalignment from the intended axis was 3.4 degrees (range 0 to 12 degrees). The good UDVA resulted in high levels of patient satisfaction. CONCLUSION: Implantation of the new toric IOL was an effective, safe, and predictable method to manage corneal astigmatism in patients having routine cataract surgery

The Direct Medical Costs of Undiagnosed Chronic Obstructive Pulmonary Disease

AbstractObjectiveTo estimate the costs of undiagnosed chronic obstructive pulmonary disease (COPD) by describing inpatient, outpatient, and pharmacy utilization in the years before and after the diagnosis.MethodsA total of 6864 patients who were enrolled in the Lovelace Health Plan for at least 12 months during the study period (January 1, 1999 through December 31, 2004) were identified. The first date that utilization was attributed to COPD was considered the first date of diagnosis. Each COPD case was matched to up to three age- and sex-matched controls. All utilization and direct medical costs during the study period were compiled monthly and compared based on the time before and after the initial diagnosis.ResultsTotal costs were higher by an average of $1182 per patient in the 2 years before the initial COPD diagnosis, and$2489 in the 12 months just before the initial diagnosis, compared to matched controls. Most of the higher cost for undiagnosed COPD was attributable to hospitalizations. Inpatient costs did not increase after the diagnosis was made, but approximately one-third of admissions after the diagnosis were attributed to respiratory disease. Outpatient and pharmacy costs did not differ substantially between cases and matched controls until just a few months before the initial diagnosis, but remained 50% to 100% higher than for controls in the 2 years after diagnosis.ConclusionsUndiagnosed COPD has a substantial impact on health-care costs and utilization in this integrated managed care system, particularly for hospitalizations