Adavosertib in Combination with Olaparib in Patients with Refractory Solid Tumors: An Open-Label, Dose-Finding, and Dose-Expansion Phase Ib Trial.

Background: Adavosertib is a first-in-class, selective small-molecule inhibitor of Wee1. Olaparib is an inhibitor of poly(ADP-ribose) polymerase (PARP). Preclinical data suggest that adavosertib enhances the antitumor effect of PARP inhibitors.

Systematic review of time to subsequent therapy as a candidate surrogate endpoint in advanced solid tumors.

Time to subsequent therapy (TST) is an end point that may complement progression-free survival (PFS) and overall survival (OS) in determining the treatment effect of anticancer drugs and may be a potential surrogate for PFS and OS. We systematically reviewed the correlation between TST and both PFS and OS in published phase 2/3 studies in advanced solid tumors. Trial-level correlational analyses were performed for TST versus PFS (by investigator and/or central review) and TST versus OS.

Phase I study to assess the effect of adavosertib (AZD1775) on the pharmacokinetics of substrates of CYP1A2, CYP2C19, and CYP3A in patients with advanced solid tumors.

Purpose: Adavosertib may alter exposure to substrates of the cytochrome P450 (CYP) family of enzymes. This study assessed its effect on the pharmacokinetics of a cocktail of probe substrates for CYP3A (midazolam), CYP2C19 (omeprazole), and CYP1A2 (caffeine).

Methods: Period 1: patients with locally advanced or metastatic solid tumors received 'cocktail': caffeine 200 mg, omeprazole 20 mg, and midazolam 2 mg (single dose); period 2: after 7- to 14-day washout, patients received adavosertib 225 mg twice daily on days 1-3 (five doses), with cocktail on day 3.

The development of a health-promoting employment intervention with physical activity for young people Not in Education, Employment or Training (NEET): NEXT STEP-on the path to education and job.

Background: In the EU, approx. 16.5% of the 20-34-year-olds are Not in Education, Employment or Training (NEET).

The effect of 5 years of team sport on elderly males' health and social capital-An interdisciplinary follow-up study.

Background And Aims: Floorball training induces positive effects on health among untrained older adults. However, the effect of long-term participation (>2 years) in floorball training among elderly males has not been investigated. The aim of the present study was to examine the effect of 5 years of floorball training on risk factors for lifestyle diseases, fitness, physical function, and social capital of elderly males and compare to a control group that continued their usual lifestyle.

Impact of MET status on treatment outcomes in papillary renal cell carcinoma: A pooled analysis of historical data.

Background: Papillary renal cell carcinoma (PRCC) represents 15% of RCCs but has no indicated therapies, with limited biomarker-based data to inform targeted treatment. MET alterations may be key; > 80% of PRCC tumours show MET upregulation. The objective of this study was to assess MET status in PRCC and its impact on clinical outcomes.

A Comprehensive Methodology to Systematically Identify Drug Hypersensitivity and Anaphylactic Reactions in Clinical Trial Databases.

Background: The incidence of drug hypersensitivity or anaphylactic reactions in clinical trial databases is thought to be underestimated due to variable clinical presentations and lack of clear definitions.

Objective: Our objective was to develop a more comprehensive, systematic methodology for retrospectively identifying potential hypersensitivity or anaphylactic reactions reported in patients treated with investigational drugs in clinical trials and to accurately assess and characterise the risk.

Methods: A three-step approach was developed to identify hypersensitivity or anaphylactic reactions: clinical trial database search, medical review, and adjudication to confirm or rule out cases.

Effect of food on the pharmacokinetics of the WEE1 inhibitor adavosertib (AZD1775) in patients with advanced solid tumors.

Purpose: To support future dosing recommendations, the effect of food on the pharmacokinetics of adavosertib, a first-in-class, small-molecule reversible inhibitor of WEE1 kinase, was assessed in patients with advanced solid tumors.

Methods: In this Phase I, open-label, randomized, two-period, two-sequence crossover study, the pharmacokinetics of a single 300 mg adavosertib dose were investigated in fed versus fasted states.

Results: Compared with the fasted state, a high-fat, high-calorie meal (fed state) decreased adavosertib maximum plasma concentration (C) by 16% and systemic exposure (area under the plasma concentration-time curve [AUC]) by 6%; AUC decreased by 7% and time to maximum plasma concentration was delayed by 1.

Efficacy of Savolitinib vs Sunitinib in Patients With MET-Driven Papillary Renal Cell Carcinoma: The SAVOIR Phase 3 Randomized Clinical Trial.

Importance: Papillary renal cell carcinoma (PRCC) is the most common type of non-clear cell RCC. Because some cases of PRCC are MET-driven, MET inhibition could be a targeted treatment approach. In previous studies, savolitinib (AZD6094, HMPL-504, volitinib), a highly selective MET-tyrosine kinase inhibitor, demonstrated antitumor activity in this patient group.

Osimertinib plus savolitinib in patients with EGFR mutation-positive, MET-amplified, non-small-cell lung cancer after progression on EGFR tyrosine kinase inhibitors: interim results from a multicentre, open-label, phase 1b study.

Background: Preclinical data suggest that EGFR tyrosine kinase inhibitors (TKIs) plus MET TKIs are a possible treatment for EGFR mutation-positive lung cancers with MET-driven acquired resistance. Phase 1 safety data of savolitinib (also known as AZD6094, HMPL-504, volitinib), a potent, selective MET TKI, plus osimertinib, a third-generation EGFR TKI, have provided recommended doses for study. Here, we report the assessment of osimertinib plus savolitinib in two global expansion cohorts of the TATTON study.

Physical Fitness and Body Composition in 10-12-Year-Old Danish Children in Relation to Leisure-Time Club-Based Sporting Activities.

This study investigated whether the physical fitness and body composition of 10-12-year-old Danish children are related to participation in leisure-time club-based sporting activities. The study involved 544 Danish 10-12-year-old 5th-grade municipal schoolchildren (269 boys and 275 girls, 11.1 ± 0.

The social and psychological health outcomes of team sport participation in adults: An integrative review of research.

The aim of this article was to review the international scientific research literature about the social and psychological health outcomes associated with participation in team sport and to synthesise the key issues about team sport as a health-promoting activity. : The methodological framework guiding the review process is the integrative research review. A search of 10 key electronic databases was conducted to identify both quantitative and qualitative studies addressing the social and/or psychological health outcomes from participation in a team sport.

Health Effects of 12 Weeks of Team-Sport Training and Fitness Training in a Community Health Centre for Sedentary Men with Lifestyle Diseases.

This study compares the effects of team-sport training, for sedentary men with lifestyle diseases, with fitness training in a pragmatic set-up in a community health centre (CHC). Thirty-two men in the fitness group (FiG) and 36 men in the team-sport group (TsG) completed the training and trained for 60-90 min, two times/week for 12-16 weeks. In FiG and TsG, mean heart rate (HR) during training was 73.

A Phase I/II Multicenter Study of Single-Agent Foretinib as First-Line Therapy in Patients with Advanced Hepatocellular Carcinoma.

This phase I/II single-arm study evaluated the safety, pharmacokinetics, pharmacodynamics, and activity of foretinib, an oral multikinase inhibitor of MET, ROS, RON, AXL, TIE-2, and VEGFR2, in the first-line setting in advanced hepatocellular carcinoma patients. In the phase I part, advanced hepatocellular carcinoma patients were dose escalated on foretinib (30-60 mg) every day using the standard 3+3 design. Once the maximum tolerated dose (MTD) was determined, an additional 32 patients were dosed at the MTD in the phase II expansion cohort for assessment of efficacy and safety.

Evaluating a Nationwide Recreational Football Intervention: Recruitment, Attendance, Adherence, Exercise Intensity, and Health Effects.

The present study evaluated a nationwide exercise intervention with Football Fitness in a small-scale society. In all, 741 adult participants (20-72 yrs) were successfully recruited for Football Fitness training in local football clubs, corresponding to 2.1% of the adult population.

'FIFA 11 for Health' for Europe. 1: effect on health knowledge and well-being of 10- to 12-year-old Danish school children.

Aim: To modify the 'FIFA 11 for Health' programme to the European situation, and to assess its effects on health knowledge and well-being in Danish school children.

Method: A two-cohort study with seven intervention and two control schools. Of the 546 Danish children (boys 269; girls 277) of mean age 11.

A phase I, dose escalation, pharmacodynamic, pharmacokinetic, and food-effect study of α2 integrin inhibitor E7820 in patients with advanced solid tumors.

Unlabelled: Introduction E7820 is an orally administered sulfonamide that inhibits alfa-2-integrin mRNA expression. Pre-clinically E7820 showed tumor anti-angiogenic effects in various tumor cell lines and xenograft mouse models. Human daily dosing of 100 mg QD had previously been shown to be safe and tolerable.

Population pharmacokinetics modeling and analysis of foretinib in adult patients with advanced solid tumors.

Foretinib is a multikinase inhibitor that inhibits multiple receptor tyrosine kinases, including MET and VEGFR, with the potential for treatment of solid tumors. Hepatocellular carcinoma (HCC) pathogenesis is associated with overexpression of MET, and physiologic changes in the livers of HCC patients may decrease CYP3A isozyme-mediated metabolism of foretinib. A population pharmacokinetic model of foretinib was developed to explore the effect of tumor type, formulation, and other covariates.

A multicenter phase I study of pazopanib in combination with paclitaxel in first-line treatment of patients with advanced solid tumors.

This study was designed to evaluate the safety, pharmacokinetics, and clinical activity of pazopanib combined with paclitaxel to determine the recommended phase II dose in the first-line setting in patients with advanced solid tumors. Patients were enrolled in a 3+3 dose-escalation design to determine the maximum tolerated regimen (MTR) of once daily pazopanib plus paclitaxel administered every 3 weeks at four dose levels (DL1-4). Safety, pharmacokinetics, pharmacogenetics, and disease assessments were performed.

Football Fitness - a new version of football? A concept for adult players in Danish football clubs.

This article explores a new Danish football-based activity for health called Football Fitness (FF). Data are from quantitative and qualitative methods, and the theoretical framework for the analysis of the organizational form of FF is the theory of path dependency (Mahoney) and first- and second-order change (Watzlawick et al.).

An open-label, multicenter, randomized, phase II study of pazopanib in combination with pemetrexed in first-line treatment of patients with advanced-stage non-small-cell lung cancer.

Introduction: This randomized open-label phase II study evaluated the efficacy, safety, and tolerability of pazopanib in combination with pemetrexed compared with the standard cisplatin/pemetrexed doublet in patients with previously untreated, advanced, nonsquamous non-small-cell lung cancer.

Methods: Patients were randomized (2:1 ratio) to receive pemetrexed 500 mg/m(2) intravenously once every 3 weeks plus either oral pazopanib 800 mg daily or cisplatin 75 mg/m(2) intravenously once every 3 weeks up to six cycles. All patients received folic acid, vitamin B12, and steroid prophylaxis.

Total synthesis and stereochemical assignment of baringolin.

The thiopeptide antibiotic baringolin has been synthesized, and its structure and stereochemistry have been confirmed. The use of a strategy based on palladium-catalyzed cross-couplings permitted a modular construction of this natural product.

Phase I study of pazopanib in patients with advanced solid tumors and hepatic dysfunction: a National Cancer Institute Organ Dysfunction Working Group study.

Purpose: Pazopanib is a potent, multitargeted receptor tyrosine kinase inhibitor; however, there is limited information regarding the effects of liver function on pazopanib metabolism and pharmacokinetics. The objective of this study was to establish the maximum-tolerated dose (MTD) and pharmacokinetic profile of pazopanib in patients with varying degrees of hepatic dysfunction.

Experimental Design: Patients with any solid tumors or lymphoma were stratified into four groups based on the degree of hepatic dysfunction according to the National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) criteria.