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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. 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. 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. 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. AstraZeneca.

Objective methods like accelerometers are feasible for large studies and may quantify variability in day-to-day physical activity better than self-report. The variability between days suggests that day of the week cannot be ignored in the design and analysis of physical activity studies. The purpose of this paper is to investigate the optimal number of days needed to obtain reliable estimates of weekly habitual physical activity using the wrist-worn GENEActiv accelerometer. Data are from a subsample of the Mitchelstown cohort; 475 (44.6% males; mean aged 59.6±5.5 years) middle-aged Irish adults. Participants wore the wrist GENEActiv accelerometer for 7-consecutive days. Data were collected at 100Hz and summarised into a signal magnitude vector using 60s epochs. Each time interval was categorised according to intensity based on validated cut-offs. Spearman pairwise correlations determined the association between days of the week. Repeated measures ANOVA examined differences in average minutes across days. Intraclass correlations examined the proportion of variability between days, and Spearman-Brown formula estimated intra-class reliability coefficient associated with combinations of 1-7 days. Three hundred and ninety-seven adults (59.7±5.5yrs) had valid accelerometer data. Overall, men were most sedentary on weekends while women spent more time in sedentary behaviour on Sunday through Tuesday. Post hoc analysis found sedentary behaviour and light activity levels on Sunday to differ to all other days in the week. Analysis revealed greater than 1 day monitoring is necessary to achieve acceptable reliability. Monitoring frame duration for reliable estimates varied across intensity categories, (sedentary (3 days), light (2 days), moderate (2 days) and vigorous activity (6 days) and MVPA (2 days)). These findings provide knowledge into the behavioural variability in weekly activity patterns of middle-aged adults. Since Sunday differed from all other days in the week this suggests that day of the week cannot be overlooked in the design and analysis of physical activity studies and thus should be included in the study monitoring frames. Collectively our data suggest that six days monitoring, inclusive of Saturday and Sunday, are needed to reliably capture weekly habitual activity in all activity intensities using the wrist-worn GENEActiv accelerometer.

Background: Despite advances in the treatment of early triple-negative breast cancer (TNBC), patients with residual invasive disease after neoadjuvant therapy have a high risk of disease recurrence and worse survival outcomes than those who have pathological complete response (pCR). Improving outcomes in early TNBC remains an unmet need requiring new adjuvant treatment approaches. Datopotamab deruxtecan (Dato-DXd) is an antibody–drug conjugate comprising a humanized anti-trophoblast cell-surface antigen 2 immunoglobulin G1 (IgG1) monoclonal antibody attached via a plasma-stable, cleavable linker to a potent topoisomerase I inhibitor payload, with activity observed in advanced TNBC. Objectives: TROPION-Breast03 is an ongoing phase III study evaluating the efficacy and safety of Dato-DXd alone or combined with durvalumab versus standard-of-care therapy as adjuvant treatment in patients with stage I–III TNBC with residual invasive disease at surgical resection following neoadjuvant treatment. Methods and design: Eligible patients, aged ⩾18 years, will be randomized in a 2:1:2 ratio to receive Dato-DXd [6 mg/kg intravenously (IV) every 3 weeks (Q3W); eight cycles] and durvalumab (1120 mg IV Q3W; nine cycles), Dato-DXd monotherapy (6 mg/kg IV Q3W), or investigator’s choice of therapy (ICT; capecitabine, pembrolizumab, or capecitabine and pembrolizumab). The primary endpoint is invasive disease-free survival (iDFS) for Dato-DXd and durvalumab versus ICT. Key secondary endpoints include safety, distant disease-free survival, and overall survival for Dato-DXd and durvalumab versus ICT and iDFS for Dato-DXd monotherapy versus ICT. Ethics: TROPION-Breast03 will be approved by the independent ethics committees or institutional review boards at each study site. All study participants will provide written informed consent. Discussion: TROPION-Breast03 will help define the potential role of Dato-DXd in the treatment of patients with early-stage TNBC who do not have pCR after neoadjuvant therapy. Trial registration: ClinicalTrials.gov identifier: NCT05629585 (registration date: 29 November 2022). Plain language summary TROPION-Breast03: a clinical trial designed to assess the effectiveness and safety of Dato-DXd, alone or in combination with durvalumab, in patients with triple-negative breast cancer who have cancer cells remaining at the time of surgery after initial systemic therapy Triple-negative breast cancer (TNBC), in which cells do not have estrogen or progesterone receptors or high levels of human epidermal growth factor receptor 2, is the most aggressive breast cancer subtype. TNBC is difficult to treat and associated with high risk of recurrence despite standard systemic therapy (treatment targeting the entire body), which can include chemotherapy alone or in combination with immunotherapy (treatment targeting the immune system). To reduce the risk of recurrence, standard systemic treatment is often followed by surgical removal of the patient’s tumors and additional systemic treatment. Dato-DXd is an antibody-drug conjugate, which is an anticancer drug (DXd) connected to an antibody (datopotamab) by a stable linker. Datopotamab binds to TROP2, a protein found on breast cancer cells, and is taken into the tumor cell where the linker breaks, releasing DXd to kill the cell. By delivering DXd directly to cancer cells, Dato-DXd reduces exposure in the rest of the body, reducing the risk of side effects. Since Dato-DXd can recruit immune cells to cancer sites, it may work better combined with durvalumab, a drug that blocks the activity of a protein called PD-L1, making cancer cells more susceptible to being killed by immune cells. The TROPION-Breast03 study will compare Dato-DXd, alone or combined with durvalumab, with standard-of-care therapy in patients with TNBC that has not spread to parts of the body away from the original tumor site(s), but with cancer cells remaining at the time of surgery after initial systemic therapy. It will assess how well each treatment works and describe any side effects. We plan to recruit 1,075 eligible adults who will be randomly assigned in a 2:1:2 ratio to: • Dato-DXd + durvalumab • Dato-DXd alone • Standard-of-care therapy • Patients will receive treatment until they complete the planned course of therapy (8 or 9 cycles), their cancer returns, side effects become unacceptable, or they choose to stop.

Background: Despite treatment advances for patients with early-stage triple-negative breast cancer (TNBC) and hormone receptor (HR)-low/human epidermal growth factor receptor 2-negative (HER2−) breast cancer, treatments that improve clinical outcomes while mitigating toxicity are needed. Datopotamab deruxtecan (Dato-DXd), a TROP2-directed antibody-drug conjugate consisting of a humanized IgG1 monoclonal antibody attached via a plasma-stable cleavable linker to a topoisomerase-I inhibitor payload, has shown efficacy alone or in combination with durvalumab, a selective, high-affinity anti-programmed cell death ligand 1 antibody, in early-phase clinical studies. Objectives: The primary objective of TROPION-Breast04 is to evaluate the efficacy and safety of neoadjuvant Dato-DXd plus durvalumab followed by adjuvant durvalumab with or without chemotherapy versus standard of care in patients with previously untreated early-stage TNBC or HR-low/HER2− breast cancer. Design: This is an ongoing, international, phase III, open-label, randomized controlled study. Methods and analysis: Approximately 1728 patients (aged ⩾18 years) will be randomized 1:1 to eight cycles of neoadjuvant Dato-DXd (6 mg/kg intravenously (IV) every 3 weeks (Q3W)) plus durvalumab (1120 mg IV Q3W) followed by nine cycles of adjuvant durvalumab (1120 mg IV Q3W) with or without chemotherapy versus eight cycles of pembrolizumab (200 mg IV Q3W) plus chemotherapy followed by nine cycles of adjuvant pembrolizumab (200 mg IV Q3W) with or without chemotherapy. Dual primary endpoints are pathological complete response by blinded central review and event-free survival by investigator assessment. Secondary endpoints include overall survival (key), distant disease-free survival, patient-reported outcomes, and safety. Ethics: The study is approved by independent ethics committees and/or institutional review boards at each study site. All patients will provide written informed consent. Discussion: This study will evaluate the potential use of neoadjuvant Dato-DXd plus durvalumab followed by adjuvant durvalumab with or without chemotherapy versus standard of care in patients with previously untreated early-stage TNBC or HR-low/HER2− breast cancer. The findings of this trial could lead to promising treatment options for these patients. Trial registration: ClinicalTrials.gov identifier: NCT06112379. Plain language summary TROPION-Breast04: a clinical study comparing datopotamab deruxtecan (Dato-DXd) plus durvalumab before surgery followed by durvalumab with or without chemotherapy after surgery, versus standard of care treatment in people with triple-negative breast cancer (TNBC) or hormone receptor (HR)-low/human epidermal growth factor receptor 2-negative (HER2−) breast cancer who have not received previous treatment People with TNBC have neither estrogen receptors and/or progesterone receptors nor a protein called HER2 expressed on their cancer cells. Standard treatment for early-stage TNBC that has not spread to other parts of the body and can be removed by surgery is pembrolizumab (a drug that makes cancer cells more susceptible to being killed by the immune system) plus chemotherapy before surgery, and pembrolizumab after surgery. People with HR-low/HER2− breast cancer (BC) do not have HER2 but have low levels of estrogen/progesterone receptors on their cancer cells and may be treated similarly to those with TNBC. Some people with high-risk early-stage TNBC or HR-low/HER2− BC experience a recurrence of their cancer after standard treatment. Therefore, new therapies that stop cancer returning and improve long-term outcomes are needed. Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate that consists of an antibody (datopotamab) and an anticancer drug payload (DXd), joined via a stable cleavable linker. In people with TNBC that has spread to other parts of the body, promising outcomes have been observed with Dato-DXd alone or in combination with durvalumab (a drug that makes cancer cells more susceptible to being killed by the immune system). In the TROPION-Breast04 study, approximately 1700 people with early-stage TNBC or HR-low/HER2– BC who have not received previous treatment will be randomly assigned in equal numbers to receive Dato-DXd plus durvalumab followed by surgery and durvalumab with or without chemotherapy, or pembrolizumab plus chemotherapy followed by surgery and pembrolizumab with or without chemotherapy. TROPION-Breast04 will show if Dato-DXd plus durvalumab before surgery followed by durvalumab with or without chemotherapy after surgery can help people with early-stage TNBC and HR-low/HER2– BC live longer without their cancer returning versus pembrolizumab plus chemotherapy before surgery followed by pembrolizumab with or without chemotherapy.

Preterm 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^sup +^) with its subpopulations bearing T-cell receptor (TCR) [alpha][beta] 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^sup +^ 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 [alpha][beta] or TCR γδ subpopulations. Our study contributes to a better understanding of preterm infants' immune mechanisms, and sets the stage for further investigations.[PUBLICATION ABSTRACT]

Preterm 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.