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The authors discuss the four programmed death receptor-1/programmed death-ligand 1 (PD-L1) targeted immunotherapies approved by the U.S. Food and Drug Administration for the treatment of patients with locally-advanced or metastatic urothelial cancer. Topics mentioned include the estimated number of patients who die from urothelial cancer annually in the U.S., ineligibility of patients for cisplatin-based therapy, and PD-L1 assays included in the labels of three products for second-line use.

Until recently in the United States, no products were approved for second-line treatment of advanced urothelial carcinoma. On May 18, 2016, the U.S. Food and Drug Administration approved atezolizumab for the treatment of patients with locally advanced or metastatic urothelial carcinoma whose disease progressed during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. Atezolizumab is a programmed death-ligand 1 (PD-L1) blocking antibody and represents the first approved product directed against PD-L1. This accelerated approval was based on results of a single-arm trial in 310 patients with locally advanced or metastatic urothelial carcinoma who had disease progression after prior platinum-containing chemotherapy. Patients received atezolizumab 1,200 mg intravenously every 3 weeks until disease progression or unacceptable toxicity. Key efficacy measures were objective response rate (ORR), as assessed by Independent Review per RECIST 1.1, and duration of response (DoR). With a median follow-up of 14.4 months, confirmed ORR was 14.8% (95% CI: 11.1,19.3) in all treated patients. Median DoR was not reached and response durations ranged from 2.1+ to 13.8+ months. Of the 46 responders, 37 patients had an ongoing response for ≥ 6 months. The most common adverse reactions (≥20%) were fatigue, decreased appetite, nausea, urinary tract infection, pyrexia, and constipation. Infection and immune-related adverse events also occurred, including pneumonitis, hepatitis, colitis, endocrine disorders, and rashes. Overall, the benefit-risk assessment was favorable to support accelerated approval. The observed clinical benefits need to be verified in confirmatory trial(s). [ABSTRACT FROM AUTHOR]

On November 23, 2015, the U.S. Food and Drug Administration approved nivolumab (OPDIVO, Bristol-Myers Squibb Company) for patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy. The approval was based on efficacy and safety data demonstrated in an open-label, randomized study of 821 patients with advanced RCC who progressed after at least one anti-angiogenic therapy. Patients were randomized to nivolumab or everolimus and followed for disease progression. The primary end point was overall survival. Subsequent therapies, including everolimus for patients who developed progressive disease on the nivolumab arm, were allowed, but no cross-over was permitted. The median overall survival was 25.0 months on the nivolumab arm and 19.6 months on everolimus arm (hazard ratio: 0.73; 95% confidence interval: 0.60-0.89). The confirmed response rates were 21.5% versus 3.9%; median durations of response were 23.0 versus 13.7 months, and median times to response were 3.0 versus 3.7 months in the nivolumab and everolimus arms, respectively. A statistically significant improvement in progression-free survival was not observed in this trial. The safety profile of nivolumab in renal cell cancer was similar to that in other disease settings. However, the incidence of immune-mediated nephritis appeared to be higher in patients with RCC. [ABSTRACT FROM AUTHOR]

The U.S. Food and Drug Administration approved enzalutamide for the treatment of patients with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC). At the prespecified interim analysis, a statistically significant improvement in overall survival was demonstrated for patients in the enzalutamide arm compared with patients in the placebo arm. The overall benefit-risk profile supports the expanded indication for enzalutamide. On September 10, 2014, the U.S. Food and Drug Administration approved enzalutamide for the treatment of patients with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC). Enzalutamide was initially approved in 2012 for use in patients with mCRPC who had previously received docetaxel. The current approval was based on the results of a randomized, placebo-controlled, double-blind trial conducted in 1,717 asymptomatic or minimally symptomatic patients with chemotherapy-naïve mCRPC. Patients were assigned to receive either enzalutamide 160 mg or placebo orally once daily. The coprimary endpoints were overall survival (OS) and radiographic progression-free survival (rPFS), which was assessed by independent central radiology review. At the prespecified interim analysis, a statistically significant improvement in OS was demonstrated for patients in the enzalutamide arm compared with patients in the placebo arm (hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.60-0.84).The median OS was 32.4 and 30.2 months in the enzalutamide and placebo arms, respectively. A statistically significant prolongation of rPFS was observed in patients in the enzalutamide arm (HR, 0.17; 95% CI, 0.14-0.21). In addition, the time to initiation of cytotoxic chemotherapy was prolonged in the enzalutamide arm (HR, 0.35; 95% CI, 0.30-0.40), with median times of 28.0 and 10.8 months in the enzalutamide and placebo arms, respectively. The safety profile was similar to that previously reported for enzalutamide. Adverse reactions of interest included seizure, hypertension, and falls. Enzalutamide should be discontinued if a seizure occurs during treatment. The overall benefit-risk profile supports the expanded indication for enzalutamide. [ABSTRACT FROM AUTHOR]

Testicular cell proliferation and differentiation is critical for development of normal testicular function and male reproductive maturity. The objective of the current study was to evaluate histoarchitecture and expression of genes marking specific cells and important functions as well as testosterone production of the developing goat testes. Testes were harvested from Alpine bucks at 0, 2, 4, 6, and 8 mo of age (n = 5/age group). Paired testes weight increased from 2 to 4 ( P c 0.001) and 4 to 6 mo (P < 0.01). The greatest increases in seminiferous tubule and lumen diameters and height of the seminiferous epithelium occurred between 2 and 4 mo (P < 0.001). Genes expressed in haploid germ cells (Protaminel [PRMl], Outer Dense Fiber protein 2 [ODF2], and Stimulated by Retinoic Acid gene 8 [S77M5]) increased dramatically at the same time (P < 0.001). Expression of other genes decreased (P < 0.05) during testicular maturation. These genes included P450 side chain cleavage (iCYP11A1), Sex determining region Y-box 9 (SOX9), Insulin-like Growth Factor 1 Receptor (.IGF1R), and Heat Shock Protein A8 (HSPA8). The Glutathione S-Transferase A3 (GSTA3) gene, whose product was recently recognized as a primary enzyme involved in isomerization of androstenedione in man and livestock species including goats, sheep, cattle, pigs, and horses, uniquely peaked in expression at 2 mo (P < 0.05). Follicle- Stimulating Hormone Receptor (FSHR) mRNA abundance tended to steadily decrease with age (P = 0.1 ), while Luteinizing Hormone Receptor (LHCGR) mRNA abundance in testes was not significantly different across the ages. Testosterone content per gram of testicular tissue varied among individuals. However, testosterone content per testis tended to increase at 6 mo (P = 0.06). In conclusion, major changes in cellular stmcture and gene expression in goat testes were observed at 4 mo of age, when spermatogenesis was initiated. Male goats mature rapidly and represent a good model species for the study of agents that enhance or impair development of testicular functions. [ABSTRACT FROM AUTHOR]

Introduction: Optimal risk factor control is integral to managing patients with proven coronary heart disease (CHD+) and for those at risk of coronary heart disease (CHD−). The primary aim of the study was to assess the success rate of reaching lipid risk factor targets in a multiple risk factor clinic. Methods: A retrospective audit was conducted in 488 patients (CHD+, n = 112; CHD−, n = 376) who attended the Cardiovascular Risk Factor Clinic at Tallaght Hospital, Dublin in 2009 and 2010. Results: Risk factor targets achieved in CHD+ and CHD− patients were LDLc (54/62 %), HDLc (67/67 %), systolic blood pressure (35/38 %), diastolic blood pressure (82/75 %), smoking cessation (27/26 %), BMI ≤ 30 (39/50 %) and normal waist circumference (27/39 %). Patients not reaching LDLc targets were found to be receiving fewer lipid-lowering drugs and having higher LDL levels at the initial clinic visit than those reaching targets. Discussion: This retrospective audit highlights gaps in achieving target lipid levels at a multiple risk factor clinic level. High initial LDLc levels and lack of drug titration are evident. Guideline changes, staff rotation, clinic visit frequency and multiplicity of targets may be contributory. More emphasis needs to be placed on education and algorithm-based strategies to achieve better risk factor control. [ABSTRACT FROM AUTHOR]

Lipid guidelines typically focus on total cholesterol +/- low-density lipoprotein cholesterol levels with less emphasis on high-density lipoprotein cholesterol (HDL-C) or triglyceride assessment, thus potentially underestimating cardiovascular (CV) risk and the need for lifestyle or treatment optimization. In this article, we highlight how reliance on isolated total cholesterol assessment may miss prognostically relevant lipid abnormalities; we describe from the European Systematic COronary Risk Evaluation (SCORE) data set how incorporation of HDL-C may improve estimation of CV risk; and, finally, we critically evaluate the evidence base surrounding triglycerides and CV risk. [ABSTRACT FROM AUTHOR]

Aim:We investigated whether anthropometric measurements or metabolic risk factors correlated more with vascular changes associated with obesity.Methods:One hundred never smoking subjects (71 women, 29 men) without vascular events, with blood pressure (BP) <140/90 mm Hg, LDL cholesterol <4 mmol/l, glucose <6.2 mmol/l participated. Anthropometric measurements (body mass index (BMI), waist/hip ratio (WHR), waist circumference (WC) and Waist/height ratio WHTR) and metabolic risk factors (glucose, insulin, lipid and uric acid levels plus BP) were assessed. Subjects underwent vascular measurements (Carotid intima-media thickness (IMT) using duplex ultrasonography, vascular stiffness assessment (Augmentation Index) by applanation tonometry and brachial artery reactivity tests).Results:Risk factors were in the ‘normal distribution’. BMI, WHR, WC, WHTR correlated significantly with triglyceride, HDL, LDL, insulin, glucose, uric acid and systolic BP levels (P<0.001). IMT correlated with WHTR, BMI, WC, Glucose (P<0.001), Homoeostasis Model Assessment (HOMA) and cholesterol levels (P<0.05). Only Age, WHTR or BMI were significant correlates of IMT in a multivariate analysis (P<0.01) including WHTR or BMI, with age, sex, systolic BP, HDLc and HOMA. Augmentation Index correlated with age (P<0.0001), WHTR and WC (P<0.0005) but with age only in a multivariate analysis. Brachial reactivity did not correlate with any anthropometric or metabolic parameters. Anthropometric cutoff points, (BMI 25, WC 102 cm men, 88 cm women, WHR 0.9 men, 0.8 women and WHTR 0.5 men and women) significantly differentiated normal from abnormal metabolic and vascular measurements. The WHTR ratio 0.5 was as reliable as the BMI cutoff 25 in determining metabolic and vascular abnormalities. BMI and WHTR were strongly associated with 89% agreement (P<0.0001).Conclusion:These results demonstrated that in ‘healthy individuals’, anthropometric parameters and metabolic risk factors correlated with each other, but anthropometric parameters were the only significant correlates of carotid IMT. A waist/height ratio 0.5 predicts both early vascular and metabolic changes. These data support a risk factor independent vasculotrophic effect of obesity.International Journal of Obesity (2009) 33, 136–143; doi:10.1038/ijo.2008.254; published online 9 December 2008 [ABSTRACT FROM AUTHOR]

Lipid measurements are essential in cardiovascular disease management in primary care. However, utilizing hospital laboratories may result in excess patient travel, sample loss and repeat clinic visits. Point of care (POC) lipid measurement would overcome these difficulties but has not been validated in an Irish setting. To compare POC lipid profile measurements using a cholestech LDX analyser with a hospital reference laboratory (Lab). One-hundred subjects (30 men, 70 women) participated. Finger prick and venous samples were analysed directly by Cholestech LDX and the Lab. A broad range of lipid values were measured. Absolute differences between POC and Lab measurements were insignificant except for a small over-estimation by the POC method of triglyceride 0.25mmol/l (95% CI 0.17 to 0.24), and an underestimation of HDLc — 0.11mmol/l (95% CI −0.143 to −0.078). There were significant correlations between POC and Lab. levels; total cholesterol r=0.92, triglyceride r=0.93, HDLc r=0.92 and LDLc r=0.86 (all p< 0.0001). These results validate the use of the Cholestech LDX® analyser for point of care lipid measurements in clinical practice, provided well trained operators are supported by a hospital laboratory delivering quality assurance support. [ABSTRACT FROM AUTHOR]

Background: There is growing interest in the use of dendritic cells (DCs) for treatment of malignancy and infectious disease. Our goal was to develop a clinicalscale method to prepare autologous DCs for cancer clinical trials. Methods: PBMC were collected from normal donors or cancer patients by automated leukapheresis, purified by counterflow centrifugal elutriation and placed into culture in polystyrene flasks at 1 × 10[sup 6] cells/mL for 5-7 days at 37°C, with 5% CO[sub 2], with IL-4 and GM-CSF. Conditions investigated included media formulation, supplementation with heatinactivatedallogeneicAB serum or autologous plasmaandtime to harvest (Day 5 or Day 7). DCs were evaluated for morphology, quantitative yield, viability, phenotype and function, including mixed leukocyte response and recall response to tetanus toxoid and influenza virus. Results: DCs with a typical immature phenotype (CD14-negative, CD1a-positive, mannose receptor-positive, CD80-positive, CD83-negative) were generated most consistently in RPMI 1640 supplemented with 10% allogeneic AB serum or 10% autologous plasma. Cell yield was higher at Day 5 than Day 7, without detectable differences in phenotype or function. In pediatric sarcoma patients, autologous DCs had enhanced function compared with monocytes from which they were generated. In this patient group, starting with 8.0 ± 3.7 × 10[sup 8] fresh or cryopreserved autologous monocytes, DC yield was 2.1 ± 1.0 × 10[sup 8] cells, or 29% of the starting monocyte number. Discussion: In the optimized clinical-scale method, purified peripheral monocytes are cultured for 5 days in flasks at 1 × 10[sup 6] cells/mL in RPMI 1640, 10% allogeneic AB serum or autologous plasma, IL-4 and GM-CSF. This method avoids the use of FBS and results in immature DCs suitable for clinical trials. [ABSTRACT FROM AUTHOR]

Americans have recently had thrust into their faces multiple media borne medical and social ethics dilemmas ranging from Dr. Kevorkian's euthanizing a patient on national television to payments by managed care providers for experimental medical treatments, to the nationally telecast situation which this paper will attempt to address. The case at hand concerns a minor in need of a repeat (third) kidney transplant who has been offered a kidney by her father. He also provided a kidney for her second kidney transplant some years ago. The teenage girl went into her current kidney failure/organ rejection state because, feeling well, she stopped taking her antirejection medications. Her father appears to understand the consequences of this offer and is willing nonetheless to donate his remaining kidney to his daughter. His ex-wife and daughter want the kidney and will take it knowing what it will do to him. Of additional interest is that he is incarcerated as a prisoner for a crime for which he will be eligible for parole in the not distant future. This means that although altruistically self-induced, the State will become financially responsible for his medical care and dialysis treatments. This paper will attempt to analyze the competing issues presented by this dilemma and address the underlying conflict between the parameters patient autonomy, parental beneficence and the deontologically based responsibilities of the state and of the health care team. [ABSTRACT FROM AUTHOR]

The use and construction of an automatic gas tank switching system are described. This device monitors the gas pressure in a CO incubator gas system and automatically switches to a reserve tank when the main supply tank is depleted. The unit contains an alarm system that signals either a loss of power or of gas pressure in the supply system. [ABSTRACT FROM AUTHOR]

This study investigates the relationship between Type 2 (non-insulin-dependent) diabetes mellitus and hypercholesterolaemia with regard to delivery of cholesterol to cells and regulation of endogenous cholesterol synthesis. The ability of LDL, from hypercholesterolaemic and Type 2 diabetic patients, to suppress cellular cholesterologenesis and to enhance mitogen-stimulated lymphocyte proliferation was compared. Cholesterol synthesis was estimated by measuring [C]-acetate incorporation into cholesterol and lymphocyte proliferation was assessed by [H]-thymidine incorporation into mitogen-stimulated normal lymphocytes. The results indicate that LDL from both Type 2 diabetic patients in poor metabolic control and hypercholesterolaemic patients was significantly less effective ( p < 0.001) than LDL from non-diabetic normocholesterolaemic subjects in suppressing cholesterol synthesis in lymphocytes. LDL from all hypercholesterolaemic patients enhanced lymphocyte proliferation to a greater extent than LDL from normocholesterolaemic subjects and this effect was significantly increased using LDL from Type 2 diabetic, hypercholesterolaemic patients. Both suppression of [C]-acetate incorporation and enhancement of [H]-thymidine uptake could be related to an increased esterified/free cholesterol ratio in the LDL particle. The fact that cholesterol synthesis and cell proliferation were markedly altered by the above changes in LDL composition suggests a mechanism for cellular cholesterol accumulation in the Type 2 diabetic patient, even in the absence of elevated serum cholesterol levels. [ABSTRACT FROM AUTHOR]

Point mutations in oncogene products such as ras may create neoantigenic determinants recognizable by T lymphocytes as tumor antigens, that could be marshalled to eliminate a tumor by inducing specific cytotoxic T lymphocytes (CTL) with an appropriate vaccine. Peptide-pulsed dendritic cells are a promising new approach to cancer vaccines. For such an approach to work, the determinant must be appropriately processed to the right size fragment and be presented by an appropriate HLA molecule. We have investigated both of these issues for a series of ras codon 12 and 13 point mutations that contain sequences predicted to bind to HLA-A2.1, the most common class I HLA molecule. We find that not only do the different mutations affect binding to HLA-A2.1, but also they affect extracellular antigen processing in two ways: by influencing the trimming of flanking residues from the longer sequence and by influencing the susceptibility of the optimal decamer to further proteolytic degradation. The influence of internal residues on cleavage of flanking residues downstream demonstrates the importance of distant interactions between separated amino acid side chains and/or conformational effects in determining antigen processing. These results may be important in designing an effective vaccine to induce mutant ras-specific tumor immunity. [ABSTRACT FROM AUTHOR]

An abstract of the article "Mortality in Patients With Heart Failure Is Associated With Lower Body Weight and Functional Capacity Independent of LV Function and Weight Changes," by S. Fall and colleagues is presented.

An abstract of the article "A Comparison of Medium- and High-Intensity, 8-Week Cardiac Rehabilitation Programmes in Low-Risk Males," by J. Walsh and colleagues is presented.