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Indications for immune checkpoint inhibitor therapy are increasing. As the population ages, many patients receiving such drugs will be older adults. Such patients are under-represented in clinical trials, and therefore the safety of immune checkpoint inhibitors in this population has not been adequately assessed. A retrospective multicenter analysis of toxicities was performed in patients with advanced or metastatic solid cancers receiving anti-programmed cell death protein 1 (anti-PD-1) and/or anti-CTLA4 antibodies across three age cohorts (<65 years, 65–74 years and ≥75 years) using univariable and multivariable analyzes. Eligible patients (n=448) were divided into age cohorts: <65 years (n=185), 65–74 years (n=154) and ≥75 years (n=109). Fewer patients in the oldest cohort (7.3%) received an anti-CTLA4 antibody containing regimen compared with the younger cohorts (21.1% and 17.5%). There was no significant difference overall in all grade or ≥G3 toxicities between age cohorts. Significantly fewer patients in the older (65–74 years and ≥75 years) age cohorts discontinued treatment because of toxicity (10.1% and 7.4%) compared with in the <65 years cohort (20.5%; p=0.006). Using logistic regression, only treatment type (ipilimumab containing) was significantly associated with all grade toxicity. However, there was a significantly lower incidence of all-grade endocrine toxicity in the oldest cohort (11.0%) compared with the youngest cohort (22.7%, p=0.02; OR 0.43, 95% CI 0.21 to 0.87), while all-grade dermatological toxicity showed the reverse trend (28.4% vs 18.9%; OR 1.85, 95% CI 1.04 to 3.30). Results were corroborated in the sensitivity analysis using only data from patients who received PD-1 inhibitor monotherapy. This multicenter, real-world cohort demonstrates that immune checkpoint inhibitor therapy is safe and well tolerated regardless of age, with no appreciable increase in adverse events in older adult patients.

Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer, but a comprehensive description of its genomic landscape is lacking. We report the whole genome sequencing of 778 ccRCC patients enrolled in the 100,000 Genomes Project, providing for a detailed description of the somatic mutational landscape of ccRCC. We identify candidate driver genes, which as well as emphasising the major role of epigenetic regulation in ccRCC highlight additional biological pathways extending opportunities for therapeutic interventions. Genomic characterisation identified patients with divergent clinical outcome; higher number of structural copy number alterations associated with poorer prognosis, whereas VHL mutations were independently associated with a better prognosis. The observations that higher T-cell infiltration is associated with better overall survival and that genetically predicted immune evasion is not common supports the rationale for immunotherapy. These findings should inform personalised surveillance and treatment strategies for ccRCC patients. The genomic landscape of clear cell renal cell carcinoma (ccRCC) remains to be comprehensively characterised. Here, whole genome sequencing of 778 ccRCC patients enrolled in the 100,000 Genomes Project was used to identify potential drivers and clinical correlations to inform the development of therapies.

BackgroundEthnicity recording within primary care computerised medical record (CMR) systems is suboptimal, exacerbated by tangled taxonomies within current coding systems.ObjectiveTo develop a method for extending ethnicity identification using routinely collected data.MethodsWe used an ontological method to maximise the reliability and prevalence of ethnicity information in the Royal College of General Practitioner’s Research and Surveillance database. Clinical codes were either directly mapped to ethnicity group or utilised as proxy markers (such as language spoken) from which ethnicity could be inferred. We compared the performance of our method with the recording rates that would be identified by code lists utilised by the UK pay for the performance system, with the help of the Quality and Outcomes Framework (QOF).ResultsData from 2,059,453 patients across 110 practices were included. The overall categorisable ethnicity using QOF codes was 36.26% (95% confidence interval (CI): 36.20%–36.33%). This rose to 48.57% (CI:48.50%–48.64%) using the described ethnicity mapping process. Mapping increased across all ethnic groups. The largest increase was seen in the white ethnicity category (30.61%; CI: 30.55%–30.67% to 40.24%; CI: 40.17%–40.30%). The highest relative increase was in the ethnic group categorised as the other (0.04%; CI: 0.03%–0.04% to 0.92%; CI: 0.91%–0.93%).ConclusionsThis mapping method substantially increases the prevalence of known ethnicity in CMR data and may aid future epidemiological research based on routine data.

[...]we evaluated omicron nAbT in four patients with a history of breakthrough delta infection after two vaccine doses. The exact correlates of immune protection against VOC remain undefined; however, multiple studies have shown that higher nAbT correlate with reduced risk of symptomatic infection.10,11 Finally, we did not evaluate vaccine-induced cellular responses to omicron as we had for other VOCs.2 We note that emerging reports suggest T-cell responses against omicron remain comparable to ancestral variants in the general population without cancer.12,13 In conclusion, we show that most of the patients with cancer in the CAPTURE cohort lacked detectable nAbT against omicron following two vaccine doses, independent of the vaccine type. CS is funded by CRUK (TRACERx, PEACE and CRUK Cancer Immunotherapy Catalyst Network), the CRUK Lung Cancer Centre of Excellence (C11496/A30025), the Rosetrees Trust, Butterfield and Stoneygate Trusts, the Novo Nordisk Foundation (ID16584), a Royal Society Professorship Enhancement award (RP/EA/180007), the National Institute of Health Research (NIHR) Biomedical Research Centre at University College London Hospitals, the CRUK University College London Centre, the Experimental Cancer Medicine Centre and the Breast Cancer Research Foundation (BCRF 20-157). ST is funded by Cancer Research UK (A29911); the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC10988), the UK Medical Research Council (FC10988), and the Wellcome Trust (FC10988); the NIHR Biomedical Research Centre at the Royal Marsden Hospital and Institute of Cancer Research (grant reference number A109), the Royal Marsden Cancer Charity, The Rosetrees Trust (A2204), Ventana Medical Systems (grant reference numbers 10467 and 10530), the National Institute of Health (U01 CA247439) and Melanoma Research Alliance (686061).

Coronavirus disease 2019 (COVID-19) antiviral response in a pan-tumor immune monitoring (CAPTURE) ( NCT03226886 ) is a prospective cohort study of COVID-19 immunity in patients with cancer. Here we evaluated 585 patients following administration of two doses of BNT162b2 or AZD1222 vaccines, administered 12 weeks apart. Seroconversion rates after two doses were 85% and 59% in patients with solid and hematological malignancies, respectively. A lower proportion of patients had detectable titers of neutralizing antibodies (NAbT) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOC) versus wild-type (WT) SARS-CoV-2. Patients with hematological malignancies were more likely to have undetectable NAbT and had lower median NAbT than those with solid cancers against both SARS-CoV-2 WT and VOC. By comparison with individuals without cancer, patients with hematological, but not solid, malignancies had reduced neutralizing antibody (NAb) responses. Seroconversion showed poor concordance with NAbT against VOC. Previous SARS-CoV-2 infection boosted the NAb response including against VOC, and anti-CD20 treatment was associated with undetectable NAbT. Vaccine-induced T cell responses were detected in 80% of patients and were comparable between vaccines or cancer types. Our results have implications for the management of patients with cancer during the ongoing COVID-19 pandemic.

Driver mutations in IDH1 and IDH2 are initiating events in the evolution of chondrosarcoma and several other cancer types. Here, we present evidence that mutant IDH1 is recurrently lost in metastatic central chondrosarcoma. This may reflect either relaxed positive selection for the mutant IDH1 locus, or negative selection for the hypermethylation phenotype later in tumor evolution. This finding highlights the challenge for therapeutic intervention by mutant IDH1 inhibitors in chondrosarcoma.

SummaryPathological response is a surrogate marker of efficacy of neoadjuvant therapy in various tumour types, but there is no consensus on reporting pathological response for renal cell carcinoma. We aimed to assess the status of pathological response reporting in renal cell carcinoma and develop a recommendation on tissue preparation and response reporting for neoadjuvant treatment. We conducted a systematic review of publications on the PubMed and Web of Science databases to identify manuscripts reporting response to pre-surgical therapy in renal cell carcinoma. 119 eligible papers were identified. Only five (4%) studies included details of how pathological response had been assessed. Qualitative statements on residual tumour were common (55 [46%] studies), but only eight (7%) studies used a quantitative assessment of pathological response. Guidelines for tissue preparation and pathological response reporting were reviewed at an international workshop held at the Netherlands Cancer Institute in October, 2024, and further developed through expert discussions. To assess neoadjuvant pathological response, nephrectomy specimens should be sampled with the use of a standardised baseline approach with consideration for more extensive sampling. Microscopic assessment should quantify the residual viable tumour in 10% intervals and greatest linear extent. Clinical details, including the neoadjuvant therapy received, should accompany the pathological assessment. In this systematic review, we describe a standardised method for assessment and reporting pathological response, initially intended for use in clinical trials or research settings. These guidelines will help investigators to assess whether the degree of pathological response is linked to survival outcomes and will inform future standard reporting practices.

Despite initial responses to hormone treatment, metastatic prostate cancer invariably evolves to a lethal state. To characterize the intra-patient evolutionary relationships of metastases that evade treatment, we perform genome-wide copy number profiling and bespoke approaches targeting the androgen receptor (AR) on 167 metastatic regions from 11 organs harvested post-mortem from 10 men who died from prostate cancer. We identify diverse and patient-unique alterations clustering around the AR in metastases from every patient with evidence of independent acquisition of related genomic changes within an individual and, in some patients, the co-existence of AR -neutral clones. Using the genomic boundaries of pan-autosome copy number changes, we confirm a common clone of origin across metastases and diagnostic biopsies, and identified in individual patients, clusters of metastases occupied by dominant clones with diverged autosomal copy number alterations. These autosome-defined clusters are characterized by cluster-specific AR gene architectures, and in two index cases are topologically more congruent than by chance ( p -values 3.07 × 10 −8  and 6.4 × 10 −4 ). Integration with anatomical sites suggests patterns of spread and points of genomic divergence. Here, we show that copy number boundaries identify treatment-selected clones with putatively distinct lethal trajectories. The heterogeneity of androgen receptor ( AR ) gene alterations across metastases in prostate cancer remains unresolved. Here, the authors characterise AR genomic complexity across spatially separated lethal metastases from 10 prostate cancer patients and investigate how AR alterations evolve.

Patients with cancer have higher COVID-19 morbidity and mortality. Here we present the prospective CAPTURE study, integrating longitudinal immune profiling with clinical annotation. Of 357 patients with cancer, 118 were SARS-CoV-2 positive, 94 were symptomatic and 2 died of COVID-19. In this cohort, 83% patients had S1-reactive antibodies and 82% had neutralizing antibodies against wild type SARS-CoV-2, whereas neutralizing antibody titers against the Alpha, Beta and Delta variants were substantially reduced. S1-reactive antibody levels decreased in 13% of patients, whereas neutralizing antibody titers remained stable for up to 329 days. Patients also had detectable SARS-CoV-2-specific T cells and CD4 + responses correlating with S1-reactive antibody levels, although patients with hematological malignancies had impaired immune responses that were disease and treatment specific, but presented compensatory cellular responses, further supported by clinical recovery in all but one patient. Overall, these findings advance the understanding of the nature and duration of the immune response to SARS-CoV-2 in patients with cancer.

IntroductionTreatment options for type 2 diabetes are becoming increasingly complex with people often prescribed multiple medications, and may include both oral and injectable therapies. There is ongoing debate about which drug classes provide the optimum second-line and third-line treatment options. In the real world, patient adherence and persistence determines medication effectiveness. A better understanding of adherence may help inform the choice of second-line and third-line drug classes.Methods and analysisThis systematic review will compare adherence and persistence rates across the different classes of medication available to people with type 2 diabetes. It will include all identified studies comparing medication adherence or persistence between two or more glucose-lowering medications in people with type 2 diabetes. Research databases (MEDLINE, EMBASE, The Cochrane Library, The Register of Controlled Trials, PsychINFO and CINAHL) will be searched for relevant articles, using a comprehensive search strategy. All identified medication trials and observational studies will be included which compare adherence or persistence across classes of diabetes medication. The characteristics and outcomes of all the included studies will be reported along with a study quality grade, assessed using the Cochrane Risk Assessment Tool. The quality of adjustment for confounders of adherence or persistence will be reported for each study. Where multiple (n ≥3) studies provide compare adherence or persistence across the same 2 medication classes, a meta-analysis will be performed.Ethics and disseminationNo ethics approval is required. This review and meta-analysis (where possible) will provide important information on the relative patient adherence and persistence, with the different classes of diabetes therapies. Once complete, the results will be made available by peer-reviewed publication.Trial registration numberCRD42015027865.