European experts consensus: BRCA/homologous recombination deficiency testing in first-line ovarian cancer

Background: Homologous recombination repair (HRR) enables fault-free repair of double-stranded DNA breaks. HRR deficiency is predicted to occur in around half of high-grade serous ovarian carcinomas. Ovarian cancers harbouring HRR deficiency typically exhibit sensitivity to poly-ADP ribose polymerase inhibitors (PARPi). Current guidelines recommend a range of approaches for genetic testing to identify predictors of sensitivity to PARPi in ovarian cancer and to identify genetic predisposition. Design: To establish a European-wide consensus for genetic testing (including the genetic care pathway), decision making and clinical management of patients with recently diagnosed advanced ovarian cancer, and the validity of biomarkers to predict the effectiveness of PARPi in the first-line setting. The collaborative European experts’ consensus group consisted of a steering committee (n = 14) and contributors (n = 84). A (modified) Delphi process was used to establish consensus statements based on a systematic literature search, conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Results: A consensus was reached on 34 statements amongst 98 caregivers (including oncologists, pathologists, clinical geneticists, genetic researchers, and patient advocates). The statements concentrated on (i) the value of testing for BRCA1/2 mutations and HRR deficiency testing, including when and whom to test; (ii) the importance of developing new and better HRR deficiency tests; (iii) the importance of germline non-BRCA HRR and mismatch repair gene mutations for predicting familial risk, but not for predicting sensitivity to PARPi, in the first-line setting; (iv) who should be able to inform patients about genetic testing, and what training and education should these caregivers receive. Conclusion: These consensus recommendations, from a multidisciplinary panel of experts from across Europe, provide clear guidance on the use of BRCA and HRR deficiency testing for recently diagnosed patients with advanced ovarian cancer

Increased maternal TSH and decreased maternal FT4 are associated with a higher operative delivery rate in low-risk pregnancies: A prospective cohort study

Background:  The increasing number of operative deliveries is a topic of major concern in modern obstetrics. Maternal thyroid function is of known influence on many obstetric parameters. Our objective was to investigate a possible relation between maternal thyroid function, and operative deliveries. Secondary aim was to explore whether thyroid function was related to specific reasons for operative deliveries. Methods:  In this prospective cohort study, low-risk Caucasian women, pregnant of a single cephalic fetus were included. Women with known auto-immune disease, a pre-labour Caesarean section, induction of labour, breech presentation or preterm delivery were excluded. In all trimesters of pregnancy the thyroid function was assessed. Differences in mean TSH and FT4 were assessed using t-test. Mean TSH and FT4 levels for operative deliveries were determined by one way ANOVA. Repeated measurement analyses were performed (ANOVA), adjusting for BMI, partiy, maternal age and gestational age at delivery. Results:  In total 872 women were included, of which 699 (80.2 %) had a spontaneous delivery. At 36 weeks gestation women who had an operative delivery had a significantly higher mean TSH (1.63mIU/L versus 1.46mIU/L, p = 0.025) and lower mean FT4 (12.9pmol/L versus 13.3pmol/L, p = 0.007)) compared to women who had a spontaneous delivery. Mean TSH was significantly higher (p = 0.026) and mean FT4 significantly lower (p = 0.030) throughout pregnancy for women with an operative delivery due to failure to progress in second stage of labour, compared to women with a spontaneous delivery or operative delivery for other reasons. Conclusion:  Increased TSH and decreased FT4 seem to be associated with more operative vaginal deliveries and Caesarean sections. After adjusting for several confounders the association remained for operative deliveries due to failure to progress in second stage of labour, possibly to be explained by less efficient uterine action

Prospective Observational Study of Pazopanib in Patients with Advanced Renal Cell Carcinoma (PRINCIPAL Study)

Background: Real-world data are essential to accurately assessing efficacy and toxicity of approved agents in everyday practice. PRINCIPAL, a prospective, observational study, was designed to confirm the real-world safety and efficacy of pazopanib in patients with advanced renal cell carcinoma (RCC). Subjects, Materials, and Methods: Patients with clear cell advanced/metastatic RCC and a clinical decision to initiate pazopanib treatment within 30 days of enrollment were eligible. Primary objectives included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), relative dose intensity (RDI) and its effect on treatment outcomes, change in health-related quality of life (HRQoL), and safety. We also compared characteristics and outcomes of clinical-trial-eligible (CTE) patients, defined using COMPARZ trial eligibility criteria, with those of non-clinical-trial-eligible (NCTE) patients. Secondary study objectives were to evaluate clinical efficacy, safety, and RDI in patient subgroups. Results: Six hundred fifty-seven patients were enrolled and received ≥1 dose of pazopanib. Median PFS and OS were 10.3 months (95% confidence interval [CI], 9.2–12.0) and 29.9 months (95% CI, 24.7 to not reached), respectively, and the ORR was 30.3%. HRQoL showed no or little deterioration over time. Treatment-related serious adverse events (AEs) and AEs of special interest occurred in 64 (9.7%), and 399 (60.7%) patients, respectively. More patients were classified NCTE than CTE (85.2% vs. 14.8%). Efficacy of pazopanib was similar between the two groups. Conclusion: PRINCIPAL confirms the efficacy and safety of pazopanib in patients with advanced/metastatic RCC in a real-world clinical setting. Implications for Practice: PRINCIPAL is the largest (n = 657) prospective, observational study of pazopanib in patients with advanced/metastatic renal cell carcinoma, to the authors’ knowledge. Consistent with clinical trial results that often contain specific patient types, the PRINCIPAL study demonstrated that the effectiveness and safety of pazopanib is similarly safe and effective in patients with advanced kidney cancer in a real-world clinical setting. The PRINCIPAL study showed that patients with advanced kidney cancer who are treated with first-line pazopanib generally do not show disease progression for approximately 10 months and generally survive for nearly 30 months

The nature of face expertise in visual working memory: Observations from the other race effect

Several recent visual working memory studies have suggested that face expertise is reflected in a greater capacity for face stimuli, others would suggest that the locus of face expertise can be identified in the fidelity/quality of the facial representation. This study investigated face memory by manipulating expertise, both between object categories (faces, shaded cubes), and within face category (Chinese, Western Caucasian). The research design was a quasi-experimental 3 factor study, looking at the effects associated with participant ethnicity, face stimulus ethnicity. When both participant and face ethnicity factors were collapsed, the results indicated that an advantage of faces over shaded cubes was present only in the within-category change condition. The full factorial analysis revealed an interaction between participant ethnicity and face ethnicity, indicating an advantage for own race face, in both within and between category conditions. The results are considered within current conceptualisations of face representation within visual work memory

Nicotinic Acetylcholine Receptor-Mediated Protection of the Rat Heart Exposed to Ischemia Reperfusion

Abstract Reperfusion injury following acute myocardial infarction is associated with significant morbidity. Activation of neuronal or non-neuronal cholinergic pathways in the heart has been shown to reduce ischemic injury, and this effect has been attributed primarily to muscarinic acetylcholine receptors. In contrast, the role of nicotinic receptors, specifically α-7 subtype (α7nAChR), in the myocardium remains unknown, which offers an opportunity to potentially repurpose several agonists/modulators that are currently under development for neurologic indications. Treatment of ex vivo and in vivo rat models of cardiac ischemia/reperfusion (I/R) with a selective α7nAChR agonist (GTS21) showed significant increases in left ventricular developing pressure and rates of pressure development, without effects on heart rate. These positive functional effects were blocked by co-administration with methyllycaconitine (MLA), a selective antagonist of α7nAChRs. In vivo, delivery of GTS21 at the initiation of reperfusion reduced infarct size by 42% (p < 0.01) and decreased tissue reactive oxygen species (ROS) by 62% (p < 0.01). Flow cytometry of MitoTracker Red-stained mitochondria showed that mitochondrial membrane potential was normalized in mitochondria isolated from GTS21-treated compared with untreated I/R hearts. Intracellular adenosine triphosphate (ATP) concentration in cultured cardiomyocytes exposed to hypoxia/reoxygenation was reduced (p < 0.001), but significantly increased to normoxic levels with GTS21 treatment, which was abrogated by MLA pretreatment. Activation of stress-activated kinases JNK and p38MAPK was significantly reduced by GTS21 in I/R. We conclude that targeting myocardial α7nAChRs in I/R may provide therapeutic benefit by improving cardiac contractile function through a mechanism that preserves mitochondrial membrane potential, maintains intracellular ATP and reduces ROS generation, thus limiting infarct size