Aims  Fractional flow reserve (FFRCT) using computed tomography coronary angiography (CTCA) determines both the presence of coronary artery disease and vessel-specific ischaemia. We tested whether an evaluation strategy based on FFRCT would improve economic and clinical outcomes compared with standard care. Methods and results  Overall, 1400 patients with stable chest pain in 11 centres were randomized to initial testing with CTCA with selective FFRCT (experimental group) or standard clinical care pathways (standard group). The primary endpoint was total cardiac costs at 9 months; secondary endpoints were angina status, quality of life, major adverse cardiac and cerebrovascular events, and use of invasive coronary angiography. Randomized patients were similar at baseline. Most patients had an initial CTCA: 439 (63%) in the standard group vs. 674 (96%) in the experimental group, 254 of whom (38%) underwent FFRCT. Mean total cardiac costs were higher by £114 (+8%) in the experimental group, with a 95% confidence interval from −£112 (−8%) to +£337 (+23%), though the difference was not significant (P = 0.10). Major adverse cardiac and cerebrovascular events did not differ significantly (10.2% in the experimental group vs. 10.6% in the standard group) and angina and quality of life improved to a similar degree over follow-up in both randomized groups. Invasive angiography was reduced significantly in the experimental group (19% vs. 25%, P = 0.01). Conclusion  A strategy of CTCA with selective FFRCT in patients with stable angina did not differ significantly from standard clinical care pathways in cost or clinical outcomes, but did reduce the use of invasive coronary angiography.

Background: Geographical inequalities in overweight and obesity prevalence among children are well established in cross-sectional research. We aimed to examine how environmental area characteristics at birth are related to these outcomes in childhood. Methods: Anonymised antenatal and birth data recorded by University Hospital Southampton linked to schoolmeasured weight and height data for children within Southampton, UK, were utilised (14,084 children at ages 4-5 and 5637 at ages 10-11). Children's home address at birth was analysed at the Lower and Middle layer Super Output Area (LSOA/MSOA) levels (areas with average populations of 1500 and 7000, respectively). Area-level indices (walkability, relative density of unhealthy food outlets, spaces for social interaction), natural greenspace coverage, supermarket density and measures of air pollution (PM 2.5 , PM 10 and NO x) were constructed using ArcGIS Network Analyst. Overweight/obesity was defined as a body mass index (BMI; kg/m 2) greater than the 85th centile for sex and age. Population-average generalised estimating equations estimated the risk of being overweight/obese for children at both time points. Confounders included maternal BMI and smoking in early pregnancy, education, ethnicity and parity. We also examined associations for a subgroup of children who moved residence between birth and outcome measurement. Results: There were mixed results between area characteristics at birth and overweight/obesity at later ages. MSOA relative density of unhealthy food outlets and PM 10 were positively associated with overweight/obesity, but not among children who moved. LSOA greenspace coverage was negatively associated with the risk of being overweight/obese at ages 10-11 in all children (relative risk ratio 0.997, 95% confidence interval 0.995-0.999, p = 0.02) and among children who moved.

and PFS (RECIST v1.1; blinded, independent central review) were assessed by the stratified log-rank test in the ITT population. The protocol-specified first interim analysis (IA1) was planned to occur when w255 deaths occurred and w12 months after the last participant was randomized. Nonbinding futility criteria at IA1 were differences in the restricted mean survival time (RMST) between pembroeipi and pembroeplacebo of 0.2 at the maximum observation time and 0.1 at 24 months of follow-up. Results: Between 12-January-2018 and 22-August-2019, 568 participants were randomized to pembroeipi (n¼284; 282 treated) and pembroeplacebo (n¼284; 281 treated). As of 01-September-2020, median (range) study follow-up was 20.6 months (12.4-31.7), treatment was ongoing in 21.3% in the pembroe ipi arm vs 23.8% in the pembroeplacebo arm, and median number of treatment cycles was 10 vs 15. Baseline characteristics were balanced between arms. With 272 deaths, median OS was 21.4 months for pembroeipi vs 21.9 months for pembroeplacebo (HR, 1.08 [95% CI, 0.85-1.37]; P ¼ 0.74). RMST differences were e0.56 at the maximum observation time and e0.52 at 24 months, which met the futility criteria. With 372 events, median PFS was 8.2 months for pembroeipi vs 8.4 months for pembroeplacebo (HR, 1.06 [95% CI, 0.86-1.30]; P ¼ 0.72). ORR was 45.4% in both arms; median DOR was 16.1 months for pembroeipi vs 17.3 months for pembroeplacebo. Treatment-related AEs occurred in 76.2% of pembroeipi recipients vs 68.3% of pembroeplacebo recipients, were of grade 3-5 in 35.1% vs 19.6%, led to death in 2.5% vs 0%, and led to discontinuation of any treatment in 25.2% vs 10.7%. Immune-mediated AEs and infusion reactions occurred in 44.7% of pembroeipi recipients vs 32.4% of pembroe placebo recipients, were grade 3-5 in 20.2% vs 7.8%, led to death in 2.1% vs 0%, and led to discontinuation of any treatment in 14.9% vs 5.3%. Based on the observed efficacy and safety, the external data monitoring committee recommended that the study be stopped due to futility and that participants discontinue ipi/placebo. Conclusion: Adding ipilimumab to pembrolizumab does not improve efficacy and is associated with greater toxicity than pembrolizumab alone as first-line therapy for metastatic NSCLC with PD-L1 TPS 50% and no targetable EGFR or ALK aberrations. These data confirm pembrolizumab monotherapy as a standard-of-care for this population.

PURPOSE Capivasertib is a pan-AKT inhibitor. Preclinical data indicate activity in metastatic castration-resistant prostate cancer (mCRPC) and synergism with docetaxel. PATIENTS AND METHODS ProCAID was a placebo controlled randomized phase II trial in mCRPC. Patients received up to ten 21-day cycles of docetaxel (75 mg/m2 intravenous, day 1) and prednisolone (5 mg twice daily, oral, day 1-21) and were randomly assigned (1:1) to oral capivasertib (320 mg twice daily, 4 days on/3 days off, from day 2 each cycle), or placebo, until disease progression. Treatment allocation used minimization factors: bone metastases; visceral metastases; investigational site; and prior abiraterone or enzalutamide. The primary objective, by intention to treat, determined if the addition of capivasertib prolonged a composite progression-free survival (cPFS) end point that included prostate-specific antigen progression events. cPFS and overall survival (OS) were also assessed by composite biomarker subgroup for PI3K/AKT/PTEN pathway activation status. RESULTS One hundred and fifty patients were enrolled. Median cPFS was 7.03 (95% CI, 6.28 to 8.25) and 6.70 months (95% CI, 5.52 to 7.36) with capivasertib and placebo respectively (hazard ratio [HR], 0.92; 80% CI, 0.73 to 1.16; one-sided P = .32). Median OS was 31.15 (95% CI, 20.07 to not reached) and 20.27 months (95% CI, 17.51 to 24.18), respectively (HR, 0.54; 95% CI, 0.34 to 0.88; two-sided P = .01). cPFS and OS results were consistent irrespective of PI3K/AKT/PTEN pathway activation status. Grade III-IV adverse events were equivalent between arms (62.2%). The most common adverse events of any grade deemed related to capivasertib were diarrhea, fatigue, nausea, and rash. CONCLUSION The addition of capivasertib to chemotherapy did not extend cPFS in mCRPC irrespective of PI3K/AKT/PTEN pathway activation status. The observed OS result (a secondary end point) will require prospective validation in future studies to address potential for bias.

ObjectivesTo investigate socioeconomic inequalities, using maternal educational attainment, maternal and partner employment status, and lone motherhood indicators, in the risk of small-for-gestational-age (SGA) births, their time trend, potential mediation by maternal smoking and body mass index, and effect modification by parity.DesignPopulation-based birth cohort using routine antenatal healthcare data.SettingBabies born at University Hospital Southampton, UK, between 2004 and 2016.Participants65 909 singleton live births born to mothers aged ≥18 years between 24-week and 42-week gestation.Main outcome measuresSGA (birth weight <10th percentile for others born at the same number of completed weeks compared with 2013/2014 within England and Wales).ResultsBabies born to mothers educated up to secondary school level (adjusted OR (aOR) 1.32, 99% CI 1.19 to 1.47), who were unemployed (aOR 1.27, 99% CI 1.16 to 1.38) or with unemployed partners (aOR 1.27, 99% CI 1.13 to 1.43), were at greater risk of being SGA. There was no statistically significant change in the magnitude of this risk difference by these indicators over time between 2004 and 2016, as estimated by linear interactions with year of birth. Babies born to lone mothers were not at higher risk compared with partnered mothers after adjusting for maternal smoking (aOR 1.05, 99% CI 0.93 to 1.20). The inverse association between maternal educational attainment and SGA risk appeared greater in multiparous (aOR 1.40, 99% CI 1.10 to 1.77) compared with primiparous women (aOR 1.28, 99% CI 1.12 to 1.47), and the reverse was true for maternal and partner’s unemployment where the association was stronger in primiparous women.ConclusionsSocioeconomic inequalities in SGA risk by educational attainment and employment status are not narrowing over time, with differences in association strength by parity. The greater SGA risk in lone mothers was potentially explained by maternal smoking. Preventive interventions should target socially disadvantaged women, including preconception and postpartum smoking cessation to reduce SGA risk.

Background: Nearly a third of children in the UK are overweight, with the prevalence in the most deprived areas more than twice that in the least deprived. The aim was to develop a risk identification model for childhood overweight/obesity applied during pregnancy and early life using routinely collected population-level healthcare data. Methods: A population-based anonymised linked cohort of maternal antenatal records (January 2003 to September 2013) and birth/early-life data for their children with linked body mass index (BMI) measurements at 4-5 years (n = 29, 060 children) in Hampshire, UK was used. Childhood age-and sex-adjusted BMI at 4-5 years, measured between September 2007 and November 2018, using a clinical cutoff of ≥ 91st centile for overweight/obesity. Logistic regression models together with multivariable fractional polynomials were used to select model predictors and to identify transformations of continuous predictors that best predict the outcome. Results: Fifteen percent of children had a BMI ≥ 91st centile. Models were developed in stages, incorporating data collected at first antenatal booking appointment, later pregnancy/birth, and early-life predictors (1 and 2 years). The area under the curve (AUC) was lowest (0.64) for the model only incorporating maternal predictors from early pregnancy and highest for the model incorporating all factors up to weight at 2 years for predicting outcome at 4-5 years (0.83). The models were well calibrated. The prediction models identify 21% (at booking) to 24% (at~2 years) of children as being at high risk of overweight or obese by the age of 4-5 years (as defined by a ≥ 20% risk score). Early pregnancy predictors included maternal BMI, smoking status, maternal age, and ethnicity. Early-life predictors included birthweight, baby's sex, and weight at 1 or 2 years of age. Conclusions: Although predictive ability was lower for the early pregnancy models, maternal predictors remained consistent across the models; thus, high-risk groups could be identified at an early stage with more precise estimation as the child grows. A tool based on these models can be used to quantify clustering of risk for childhood obesity as early as the first trimester of pregnancy, and can strengthen the long-term preventive element of antenatal and early years care.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. The REMoDL-B phase III adaptive trial compared rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) versus R-CHOP + bortezomib (RB-CHOP) in patients with diffuse large B-cell lymphoma (DLBCL), stratified by molecular subtype. Primary analysis at a median follow-up of 30 months found no effect of bortezomib on progression-free survival (PFS) or overall survival (OS). Retrospective analysis using a gene expression–based classifier identified a molecular high-grade (MHG) group with worse outcomes. We present an updated analysis for patients successfully classified by the gene expression profile (GEP). Eligible patients were age older than 18 years with untreated DLBCL, fit enough for full-dose chemotherapy, and with adequate biopsies for GEP. Of 1,077 patients registered, 801 were identified with Activated B-Cell (ABC), Germinal Center B-cell, or MHG lymphoma. At a median follow-up of 64 months, there was no overall benefit of bortezomib on PFS or OS (5-year PFS hazard ratio [HR], 0.81; P = .085; OS HR, 0.86; P = .32). However, improved PFS and OS were seen in ABC lymphomas after RB-CHOP: 5-year OS 67% with R-CHOP versus 80% with RB-CHOP (HR, 0.58; 95% CI, 0.35 to 0.95; P = .032). Five-year PFS was higher in MHG lymphomas: 29% versus 55% (HR, 0.46; 95% CI, 0.26 to 0.84). Patients with ABC and MHG DLBCL may benefit from the addition of bortezomib to R-CHOP in initial therapy.

Although survival rates for pediatric acute lymphoblastic leukemia are now excellent, this is at the expense of prolonged chemotherapy regimens. We report the long‐term immune effects in children treated according to the UK Medical Research Council UKALL 2003 protocol. Peripheral blood lymphocyte subsets and immunoglobulin levels were studied in 116 participants, at six time points, during and for 18‐month following treatment, with 30‐39 patients analyzed at each time point. Total lymphocytes were reduced during maintenance chemotherapy and remained low 18 months following treatment completion. CD4 T cells remained significantly reduced 18 months after treatment, but CD8 cells and natural killer cells recovered to normal values. The fall in naïve B‐cell numbers during maintenance was most marked, but numbers recovered rapidly after cessation of treatment. Memory B cells, particularly nonclass‐switched memory B cells, remained below normal levels 18 months following treatment. All immunoglobulin subclasses were reduced during treatment compared to normal values, with IgM levels most affected. This study demonstrates that immune reconstitution differs between lymphocyte compartments. Although total B‐cell numbers recover rapidly, disruption of memory/naïve balance persists and T‐cell compartment persist at 18 months. This highlights the impact of modern chemotherapy regimens on immunity, and thus, infectious susceptibility and response to immunization.