Olaparib combined with abiraterone in patients with metastatic castration-resistant prostate cancer: a randomised, double-blind, placebo-controlled, phase 2 trial

Background Patients with metastatic castration-resistant prostate cancer and homologous recombination repair (HRR) mutations have a better response to treatment with the poly(ADP-ribose) polymerase inhibitor olaparib than patients without HRR mutations. Preclinical data suggest synergy between olaparib and androgen pathway inhibitors. We aimed to assess the efficacy of olaparib plus the androgen pathway inhibitor abiraterone in patients with metastatic castration-resistant prostate cancer regardless of HRR mutation status. Methods We carried out this double-blind, randomised, placebo-controlled phase 2 trial at 41 urological oncology sites in 11 countries across Europe and North America. Eligible male patients were aged 18 years or older with metastatic castration-resistant prostate cancer who had previously received docetaxel and were candidates for abiraterone treatment. Patients were excluded if they had received more than two previous lines of chemotherapy, or had previous exposure to second-generation antihormonal drugs. Patients were randomly assigned (1:1) using an interactive voice or web response system, without stratification, to receive oral olaparib 300 mg twice daily or placebo. All patients received oral abiraterone 1000 mg once daily and prednisone or prednisolone 5 mg twice daily. Patients and investigators were masked to treatment allocation. The primary endpoint was investigator-assessed radiographic progression-free survival (rPFS; based on Response Evaluation Criteria in Solid Tumors version 1.1 and Prostate Cancer Clinical Trials Working Group 2 criteria). Efficacy analyses were done in the intention-to-treat population, which included all randomly assigned patients, and safety analyses included all patients who received at least one dose of olaparib or placebo. This trial is registered with ClinicalTrials.gov, number NCT01972217, and is no longer recruiting patients. Findings Between Nov 25, 2014, and July 14, 2015, 171 patients were assessed for eligibility. Of those, 142 patients were randomly assigned to receive olaparib and abiraterone (n=71) or placebo and abiraterone (n=71). The clinical cutoff date for the final analysis was Sept 22, 2017. Median rPFS was 13·8 months (95% CI 10·8–20·4) with olaparib and abiraterone and 8·2 months (5·5–9·7) with placebo and abiraterone (hazard ratio [HR] 0·65, 95% CI 0·44–0·97, p=0·034). The most common grade 1–2 adverse events were nausea (26 [37%] patients in the olaparib group vs 13 [18%] patients in the placebo group), constipation (18 [25%] vs eight [11%]), and back pain (17 [24%] vs 13 [18%]). 38 (54%) of 71 patients in the olaparib and abiraterone group and 20 (28%) of 71 patients in the placebo and abiraterone group had grade 3 or worse adverse events, including anaemia (in 15 [21%] of 71 patients vs none of 71), pneumonia (four [6%] vs three [4%]), and myocardial infarction (four [6%] vs none). Serious adverse events were reported by 24 (34%) of 71 patients receiving olaparib and abiraterone (seven of which were related to treatment) and 13 (18%) of 71 patients receiving placebo and abiraterone (one of which was related to treatment). One treatment-related death (pneumonitis) occurred in the olaparib and abiraterone group. Interpretation Olaparib in combination with abiraterone provided clinical efficacy benefit for patients with metastatic castration-resistant prostate cancer compared with abiraterone alone. More serious adverse events were observed in patients who received olaparib and abiraterone than abiraterone alone. Our data suggest that the combination of olaparib and abiraterone might provide an additional clinical benefit to a broad population of patients with metastatic castration-resistant prostate cancer

T-cell subpopulations αβ and γδ in cord blood of very preterm infants : The influence of intrauterine infection

Open Access: This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are creditedPreterm infants are very susceptible to infections. Immune response mechanisms in this group of patients and factors that influence cord blood mononuclear cell populations remain poorly understood and are considered insufficient. However, competent immune functions of the cord blood mononuclear cells are also described. The aim of this work was to evaluate the T-cell population (CD3+) with its subpopulations bearing T-cell receptor (TCR) αβ or TCR γδ in the cord blood of preterm infants born before 32 weeks of gestation by mothers with or without an intrauterine infection. Being a pilot study, it also aimed at feasibility check and assessment of an expected effect size. The cord blood samples of 46 infants age were subjected to direct immunofluorescent staining with monoclonal antibodies and then analyzed by flow cytometry. The percentage of CD3+ cells in neonates born by mothers with diagnosis of intrauterine infection was significantly lower than in neonates born by mothers without infection (p = 0.005; Mann-Whitney U test). The number of cells did not differ between groups. Infection present in the mother did not have an influence on the TCR αβ or TCR γδ subpopulations. Our study contributes to a better understanding of preterm infants' immune mechanisms, and sets the stage for further investigations.Peer reviewedFinal Published versio

Assessment of Primary Colorectal Cancer Heterogeneity by Using Whole-Tumor Texture Analysis : Contrast-enhanced CT Texture as a Biomarker of 5-year Survival

To determine if computed tomographic (CT) texture features of primary colorectal cancer are related to 5-year overall survival ratePeer reviewedFinal Published versio

Assessment of tumor heterogeneity by CT texture analysis : Can the largest cross-sectional area be used as an alternative to whole tumor analysis?

To determine if there is a difference between contrast enhanced CT texture features from the largest cross-sectional area versus the whole tumor, and its effect on clinical outcome prediction. Methods: Entropy (E) and uniformity (U) were derived for different filter values (1.0–2.5: fine to coarse textures) for the largest primary tumor cross-sectional area and the whole tumor of the staging contrast enhanced CT in 55 patients with primary colorectal cancer. Parameters were compared using nonparametric Wilcoxon test. Kaplan–Meier analysis was performed to determine the relationship between CT texture and 5-year overall survival. Results: E was higher and U lower for the whole tumor indicating greater heterogeneity at all filter levels (1.0–2.5): median (range) for E and U for whole tumor versus largest cross-sectional area of 7.89 (7.43–8.31) versus 7.62 (6.94–8.08) and 0.005 (0.004–0.01) versus 0.006 (0.005–0.01) for filter 1.0; 7.88 (7.22–8.48) versus 7.54 (6.86–8.1) and 0.005 (0.003–0.01) versus 0.007 (0.004–0.01) for filter 1.5; 7.88 (7.17–8.54) versus 7.48 (5.84–8.25) and 0.005 (0.003–0.01) versus 0.007 (0.004–0.02) for filter 2.0; and 7.83 (7.03–8.57) versus 7.42 (5.19–8.26) and 0.005 (0.003–0.01) versus 0.006 (0.004–0.03) for filter 2.5 respectively (p ≤ 0.001). Kaplan–Meier analysis demonstrated better separation of E and U for whole tumor analysis for 5-year overall survival.Peer reviewe

Disease-specific predictive formulas for energy expenditure in the dialysis population

Copyright © 2014 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.OBJECTIVE: Metabolic rate is poorly understood in advanced kidney disease because direct measurement is expensive and time-consuming. Predictive equations for resting energy expenditure (REE) are needed based on simple bedside parameters. Algorithms derived for normal individuals may not be valid in the renal population. We aimed to develop predictive equations for REE specifically for the dialysis population.DESIGN: Two-hundred subjects on maintenance dialysis underwent a comprehensive metabolic assessment including REE from indirect calorimetry. Parameters predicting REE were identified, and regression equations developed and validated in 20 separate subjects.RESULTS: Mean REE was 1,658 ± 317 kCal/day (males) and 1,380 ± 287 kCal/day (females). Weight and height correlated positively with REE (r(2) = 0.54 and 0.31) and negatively with age older than 65 years (r(2) = 0.18). The energy cost of a unitary kilogram of body weight increased nonlinearly for lower body mass index (BMI). Existing equations derived in normal individuals underestimated REE (bias 50-114 kCal/day for 3 equations). The novel derived equation was REE(kCal/day) = -2.497·Age·Factorage+0.011·height(2.023) + 83.573·Weight(0.6291) + 68.171·Factorsex, where Factorage = 1 if 65 years or older and 0 if younger than 65, and Factorsex = 1 if male and 0 if female. This algorithm performed at least as well as those developed for normals in terms of limits of agreement and reduced bias. In validation with the Bland-Altman technique, bias was not significant for our algorithm (-22 ± 96 kCal/day). The 95% limits of agreement were +380 to -424 kCal/day.CONCLUSION: Existing equations for REE derived from normal individuals are not valid in the dialysis population. The relatively increased REE in those with low BMI implies the need for higher dialysis doses in this subgroup. This disease-specific algorithm may be useful clinically and as a research tool to predict REE.Peer reviewe

Primary Esophageal Cancer Heterogeneity as a Potential Prognostic Biomarker in Patients Treated with Definitive Chemoradiation

To determine the association between tumor heterogeneity, morphologic tumor response, and overall survival in primary esophageal cancer treated with chemotherapy and radiation therapy (CRT)Peer reviewe

Lithium influences whole‐organism metabolic rate in Drosophila subobscura

Lithium is widely used to treat bipolar disorder. However, the efficacy and vulnerability as to its side effects are known to differ. Although the specific biochemical mechanism of action is still elusive, lithium may influence mitochondrial function, and consequently, metabolism. Lithium exposure in this study was conducted on a unique set of mito-nuclear introgression lines of Drosophila subobscura to disentangle the independent effects of mitochondrial DNA (mtDNA) against a common nuclear DNA background. The study addressed three issues: (a) whether lithium has a dose-dependent effect on whole-organism metabolic rate, (b) whether mtDNA haplotypes show divergent metabolic efficiency measured by metabolic rate to lithium exposure and (c) whether lithium influences the whole-organism metabolic rate across sexes. The results confirm that lithium influenced the whole-organism metabolic rate, showing a subtle balance between efficacy and adverse effects within a narrow dose range. In addition, lithium exposure was found to influence metabolism differently based on mtDNA haplotypes and sex. This preliminary research may have a range of biological implications for the role of mitochondrial variability in psychiatric disease and treatment by contributing to the understanding and predicting of the lithium treatment response and risk for toxic side effects

PAR-1 antagonist vorapaxar favorably improves global thrombotic status in patients with coronary disease

To assess the effect of vorapaxar on global thrombotic and thrombolytic status. The propensity for thrombus formation is determined by the balance between prothrombotic factors and endogenous thrombolysis. Impaired thrombolytic status increases cardiovascular risk. Vorapaxar is a novel, oral, protease-activated receptor-1 antagonist that inhibits thrombin-induced platelet activation. In the TRACER and TRA 2°P-TIMI 50 studies, patients with acute coronary syndromes and established atherosclerosis were randomized to vorapaxar 2.5 mg daily or placebo, in addition to standard care. In 57 patients enrolled in a single center, blood was tested with the point-of-care global thrombosis test, on and off treatment. This automated test employs non-anticoagulated blood to assess thrombotic and thrombolytic status, measuring the time required to form a shear-induced thrombus under physiological conditions (occlusion time, OT), and subsequently, the time to achieve endogenous lysis of the thrombus (lysis time, LT). Patients on vorapaxar exhibited longer OT on vs. off treatment [median 561 s (interquartile range 422-654) vs. 372 s(338-454), P = 0.003] and shorter LT on treatment than off [1,158 s(746-1,492) vs. 1,733 s(1,388-2,230), P = 0.016]. Patients on placebo showed no difference in OT [419 s(343-514) vs. 411 s(346-535), P = 0.658] or LT [1,236 s(985-1,594) vs. 1,400 s(1,092-1,686), P = 0.524] on and off treatment. During treatment, OT was longer in patients taking vorapaxar [561 s(422-654) vs. 419 s(343-514), P = 0.009], but LT was similar in vorapaxar and placebo arms [1,158 s(746-1,492) vs. 1,236 s(985-1,594), P = 0.277]. Vorapaxar prolongs OT and shortens LT, with favorable effects on thrombotic and thrombolytic status. In addition to its antiplatelet effect, vorapaxar may enhance endogenous thrombolysis, which is frequently impaired in coronary disease.Peer reviewe

Children\u27s, physical activity assessed with wrist- and hip-worn accelerometers

Background: Recently, triaxial raw acceleration accelerometers have become available from GENEActiv and ActiGraph; both are designed for wrist and hip wear. It is important to determine whether the output from these monitors is comparable with the wealth of data already collected from the hip-worn, epoch-based, uniaxial ActiGraph. Purpose: This study aimed to assess the concurrent validity of measures of total activity and time spent at different activity intensities from the GENEActiv relative to the ActiGraph GT3X+. Methods: Fifty-eight children age 10-12 yr wore two accelerometers at the hip (ActiGraph GT3X+ and GENEActiv) and one at the wrist (GENEActiv) for 7 d. Wear time was matched for all monitors before analysis. Results: Mean daily accelerometer output, time spent sedentary, and time in moderate-to-vigorous physical activity (MVPA) from the hip- or wrist-worn GENEActiv were strongly correlated with the corresponding output from the hip-worn ActiGraph (r \u3e 0.83, P \u3c 0.001). However, less time was estimated to be sedentary and more time was estimated to be MVPA using the hip- or wrist-worn GENEActiv (Phillips cut points) than that when using the Evenson vertical axis cut points with the hip-worn ActiGraph. Output from the vertical axis ActiGraph cut points could be predicted with 95% limits of agreement, equating to 23%-28% and 33%-35% of the mean value, by the hip- and wrist-worn GENEActiv, respectively. Conclusions: The assessment of children\u27s activity level, time spent sedentary, and time in MVPA estimated from the hip- or wrist-worn GENEActiv seems to be comparable with that of the uniaxial ActiGraph. On the basis of the strong linear correlations, ActiGraph output can be predicted from the hip- or wrist-worn GENEActiv for comparative purposes at the group level. However, because of relatively wide limits of agreement, individual-level comparisons are not recommended