The Benchmarking Exercise Programme for Older People (BEPOP): Design, Results and Recommendations from The First Wave of Data Collection.

Objectives: The Benchmarking Exercise Programme for Older People (BEPOP) service improvement project seeks to determine and promote the exercise training characteristics associated with positive outcomes for resistance exercise for older people living with, or at risk of, sarcopenia or physical frailty. Methods: Mixed-methods service improvement project. Ten UK National Health Service physiotherapist-led therapy services delivering exercise interventions for older people submitted anonymized data for up to 20 consecutive patients. A multidisciplinary expert panel generated a report and recommendations with site-specific benchmarking data and feedback. In parallel, participating physiotherapy team members were interviewed to elicit feedback on BEPOP rationale, processes and perceived value. Results: Data from 188 patients were included, mean age 80 years (range 60-101). 115 (61%) received objective assessment of strength-based physical performance. Bodyweight exercises (173 [92%]) and resistance bands (49 [26%]) were the commonest exercise modalities. Exercises progressed predominantly through increased repetitions (163 [87%]) rather than increased load. 50 (30%) had no reassessment of outcomes; only 68 (41%) were signposted to follow-on exercise services. Staff interviews identified themes around knowledge, diagnosis, data collection and practice reflection. Conclusion: BEPOP was feasible to deliver and generated actionable insights for service improvement via improved diagnosis, measurement and progression of resistance exercise.

A Phase I First-in-Human Study of ABBV-011, a Seizure-Related Homolog Protein 6-Targeting Antibody-Drug Conjugate, in Patients With Small Cell Lung Cancer.

PURPOSE: Seizure-related homolog protein 6 (SEZ6) is a novel target expressed in small cell lung cancer (SCLC). ABBV-011, a SEZ6-targeted antibody conjugated to calicheamicin, was evaluated in a phase I study (NCT03639194) in patients with relapsed/refractory SCLC. We report initial outcomes of ABBV-011 monotherapy. PATIENTS AND METHODS: ABBV-011 was administered intravenously once every 3 weeks (Q3W) during dose escalation (0.3-2 mg/kg) and expansion. Patients with SEZ6-positive tumors (≥25% of tumor cells with ≥1+ staining intensity by immunohistochemistry) were preselected for expansion. Safety, tolerability, antitumor activity, and pharmacokinetics were evaluated. RESULTS: As of August 2022, 99 patients received ABBV-011 monotherapy (dose escalation, n=36; Japanese dose evaluation, n=3; dose expansion, n=60 [1 mg/kg, n=40]); median age was 63 years (range, 41-79). Thirty-two percent, 41%, and 26% of patients received 1, 2, and ≥3 prior therapies, respectively. The maximum tolerated dose was not reached through 2.0 mg/kg. Most common treatment-emergent adverse events (TEAEs) were fatigue (50%), nausea (42%), and thrombocytopenia (41%). Most common hepatic TEAEs were increased aspartate aminotransferase (22%), increased g-glutamyltransferase (21%), and hyperbilirubinemia (17%); 2 patients experienced veno-occlusive liver disease. Objective response rate (ORR) was 19% (19/98). In the 1-mg/kg dose-expansion cohort (n=40), ORR was 25%; median response duration was 4.2 months (95% CI, 2.6-6.7) and median progression-free survival was 3.5 months (95% CI, 1.5-4.2). CONCLUSIONS: ABBV-011 1.0 mg/kg Q3W monotherapy was well tolerated and demonstrated encouraging antitumor activity in heavily pretreated patients with relapsed/refractory SCLC. SEZ6 is a promising novel SCLC target and warrants further investigation.

Randomized trial of anetumab ravtansine and pembrolizumab compared to pembrolizumab for mesothelioma.

PURPOSE: The mesothelin-targeting antibody-drug conjugate anetumab ravtansine was evaluated in combination with the programmed cell death-1 (PD-1) inhibitor pembrolizumab based on the common expression of mesothelin and reports of activity in mesothelioma. PATIENTS AND METHODS: A phase 1 safety run-in of the combination of anetumab ravtansine (6.5 mg/kg iv q3weeks) and pembrolizumab (200 mg, IV q3weeks) was conducted, followed by a phase 2 randomization to the combination or pembrolizumab alone at medical centers across the United States and Canada in the National Cancer Institute's Experimental Therapeutics Clinical Trials Network. Patients with pleural mesothelioma that expressed mesothelin and had previously received platinum-based therapy were eligible. RESULTS: In phase 1 (n = 12) only one dose limiting toxicity was observed and the rules for dose reduction were not met. In phase 2, there was no difference in the confirmed response rates between the combination group (n = 18, 2 partial responses [PR], 11 %) and the pembrolizumab group (n = 17, 1 PR, 6 %; z = -0.5523, p = 0.29116). The median PFS was 12.2 months (95 % CI 5.1-not evaluable [NE]) for the combination, and 3.9 months for pembrolizumab (95 % CI 2.1-NE)(HR=0.55, p = 0.20). Patients with high baseline levels of soluble mesothelin who received anetumab ravtansine had a median PFS of 5 months. CONCLUSIONS: The numeric difference in PFS between treatment groups was not statistically significant, likely related to a smaller than planned sample size. High levels of soluble mesothelin should potentially be considered to select against the use of mesothelin-targeting therapies in development that are neutralized by soluble mesothelin.

Cancer research provides a model for advancing clinical trials in dementia in the era of disease-modifying Alzheimer's-type dementia therapies.

Dementia and cancer are multifactorial, widely-feared, age-associated clinical syndromes that are increasing in prevalence. There have been major breakthroughs in clinical cancer research leading to some effective treatments, whereas the field of dementia has achieved comparatively limited success in clinical research. The lessons of cancer research may help those in the dementia research field in confronting some of the dilemmas faced when the clinical care regimen is not entirely safe or efficacious. Cancer clinical trials have assumed that untreated individuals with cancer are at high risk for morbidity and mortality after primary diagnoses. Thus, patients deserve a choice of clinical interventions, either standard of care or experimental, even if the benefits are not certain and the therapy's side effects are potentially severe. The prognosis for many individuals at risk for dementia carries a correspondingly high level of risk for both mortality and severe morbidity, particularly if one focuses on "health-span" rather than lifespan. Caregivers and patients can be strongly impacted by dementia and the many troubling associated symptoms that often go well beyond amnesia. Polls, surveys, and a literature on "dementia worry" strongly underscore that the public fears dementia. While there are institutional and industry hurdles that complicate enrollment in randomized trials, the gravity of the future morbidity and mortality inherent in a dementia diagnosis may require reconsideration of the current protective stance that limits the freedom of at-risk individuals (either symptomatic or asymptomatic) to participate and potentially benefit from ongoing clinical research. There is also evidence from both cancer and dementia research that individuals enrolled in the placebo arms of clinical trials have unexpectedly good outcomes, indicating that participation in clinical trial can have medical benefits to enrollees. To highlight aspects of cancer clinical research that may inform present and future dementia clinical research, this review highlights three main themes: the risk of side effects should be weighed against the often dire consequences of non-treatment; the desirability of long-term incremental (rather than "magic bullet") clinical advances; and, the eventual importance of combination therapies, reflecting that the dementia clinical syndrome has many underlying biological pathways.

Recurrent patellar dislocation: personalised therapy or operative treatment? The REPPORT randomised trial protocol.

INTRODUCTION: Recurrent patellar dislocation is a debilitating musculoskeletal condition, affecting mainly adolescents and adults under the age of 30. It can persist for many decades, causing pain and cartilage and soft-tissue damage, potentially leading to osteoarthritis. Recurrent patellar dislocation can be managed with physiotherapy or surgery. However, it is not known which treatment is most effective. METHODS AND ANALYSIS: Recurrent Patellar Dislocation: Personalised Therapy or Operative Treatment (REPPORT) is a pragmatic, multicentre, two-arm, superiority, randomised controlled trial. It will compare the clinical and cost-effectiveness of an initial management strategy of personalised, phased and progressive rehabilitation, termed personalised knee therapy versus surgery for recurrent patellar dislocation.The trial's target sample size is 276 participants who will be recruited from approximately 20 sites across the UK. Participants will be randomly allocated to the two treatment groups via a central computer-based minimisation system. Treatment allocation will be in a 1:1 ratio, stratified by age, presence of patella alta and recruitment site.The primary outcome is participant-reported function using the Knee injury and Osteoarthritis Outcome 4-domain score at 18 months post randomisation. Health economic evaluation will be conducted from a healthcare system and personal social services perspective. Secondary outcome data including patellar instability, health utility, work/education status, satisfaction with social roles and treatment, health resource use and adverse events will be collected at 6, 12, 18 and 24 months. Analysis will be on an intention-to-treat basis and reported in-line with the Consolidated Standards of Reporting Trials statement. ETHICS AND DISSEMINATION: The trial was approved by the East Midlands-Nottingham 2 Research Ethics Committee on 30 March 2023.Results will be disseminated via peer-reviewed publications, presentations at national and international conferences, in lay summaries, and using the REPPORT website and social media channels. TRIAL REGISTRATION NUMBER: ISRCTN17972668.

Loss, shame and secrecy in women's experiences of a vulval skin condition: A qualitative study.

Vulval lichen sclerosus (LS) is a chronic dermatological condition affecting the anogenital area, causing intense itching, pain and bleeding. It can change the terrain of the vulva, causing loss of vulval anatomy and altered texture and appearance of the skin. There has been little research into how women experience the materialities of a dermatological vulval disease. We aimed to understand experiences of living with LS, using a feminist lens to examine the influence of societal attitudes towards women's bodies and the vulva. We conducted qualitative interviews with 20 women with vulval LS, taking a critical feminist grounded theory approach. While we found that women's experiences of vulval LS symptoms was normalised as a part of womanhood, there was a silencing of speech about the vulva generally, and vulval symptoms more specifically. This caused profound shame and loneliness, and was a barrier to disclosing and seeking help for vulval symptoms, leading to delayed diagnosis and disease progression. Loss of vulval architecture resulted in a loss of (feminine) self and the sense of a body which was whole.

A Probabilistic Approach to Estimate the Temporal Order of Pathway Mutations Accounting for Intra-Tumor Heterogeneity.

The development of cancer involves the accumulation of somatic mutations in several essential biological pathways. Delineating the temporal order of pathway mutations during tumorigenesis is crucial for comprehending the biological mechanisms underlying cancer development and identifying potential targets for therapeutic intervention. Several computational and statistical methods have been introduced for estimating the order of somatic mutations based on mutation profile data from a cohort of patients. However, one major issue of current methods is that they do not take into account intra-tumor heterogeneity (ITH), which limits their ability to accurately discern the order of pathway mutations. To address this problem, we propose PATOPAI, a probabilistic approach to estimate the temporal order of mutations at the pathway level by incorporating ITH information as well as pathway and functional annotation information of mutations. PATOPAI uses a maximum likelihood approach to estimate the probability of pathway mutational events occurring in a specific sequence, wherein it focuses on the orders that are consistent with the phylogenetic structure of the tumors. Applications to whole exome sequencing data from The Cancer Genome Atlas (TCGA) illustrate our method's ability to recover the temporal order of pathway mutations in several cancer types.

'The unexpected journey': a qualitative interview study exploring patient and health professionals experiences of participating in the knee arthroplasty versus joint distraction study (KARDS).

OBJECTIVE: The aim of the knee arthroplasty versus joint distraction (KARDS) randomised trial was to investigate whether knee joint distraction (KJD) is non-inferior to knee arthroplasty, also known as knee replacement (KR). Here we report the findings from qualitative interviews that were part of the planned KARDS process evaluation. DESIGN AND METHODS: Semi-structured qualitative interviews with staff and participants in secondary care. Data were analysed using thematic content analysis. FINDINGS: We were unable to complete the full-planned KARDS process evaluation as recruitment to the trial was closed early but key common themes emerged.Eleven members of staff were interviewed from two KARDS sites (eight initial interviews just after site opening and three follow-up interviews at 12 months). Eleven KARDS participants (six KR and five KJD) were interviewed. One overarching theme emerged: 'An unexpected journey'. This incorporated subthemes including 'an important research question', 'a roller coaster ride', 'lessons learnt', 'managing expectations' and 'a slow recovery'. These encapsulate experiences of both staff and participants. CONCLUSION: The information that we were able to collect highlights that providing adequate and comprehensive information about all aspects of treatment including estimated timelines of recovery are essential in clinical trials of novel interventions. Incorporating a comprehensive rehabilitation package following KJD was a key learning. Process evaluations in these complex trials are essential to determine issues as early as possible so appropriate changes can be made to ensure participants have a smooth journey through the trial experience. TRIAL REGISTRATION NUMBER: ISRCTN14879004.

Multicellular immune ecotypes within solid tumors predict real-world therapeutic benefits with immune checkpoint inhibitors.

Background: Cancer initiation, progression, and immune evasion depend on the tumor microenvironment (TME). Thus, understanding the TME immune architecture is essential for understanding tumor metastasis and therapy response. This study aimed to create an immune cell states (CSs) atlas using bulk RNA-seq data enriched by eco-type analyses to resolve the complex immune architectures in the TME. Methods: We employed EcoTyper, a machine-learning (ML) framework, to study the real-world prognostic significance of immune CSs and multicellular ecosystems, utilizing molecular data from 1,610 patients with multiple malignancies who underwent immune checkpoint inhibitor (ICI) therapy within the ORIEN Avatar cohort, a well-annotated real-world dataset. Results: Our analysis revealed consistent ICI-specific prognostic TME carcinoma ecotypes (CEs) (including CE1, CE9, CE10) across our pan-cancer dataset, where CE1 being more lymphocyte-deficient and CE10 being more proinflammatory. Also, the analysis of specific immune CSs across different cancers showed consistent CD8+ and CD4+ T cell CS distribution patterns. Furthermore, survival analysis of the ORIEN ICI cohort demonstrated that ecotype CE9 is associated with the most favorable survival outcomes, while CE2 is linked to the least favorable outcomes. Notably, the melanoma-specific prognostic EcoTyper model confirmed that lower predicted risk scores are associated with improved survival and better response to immunotherapy. Finally, de novo discovery of ecotypes in the ORIEN ICI dataset identified Ecotype E3 as significantly associated with poorer survival outcomes. Conclusion: Our findings offer important insights into refining the patient selection process for immunotherapy in real-world practice and guiding the creation of novel therapeutic strategies to target specific ecotypes within the TME.

Meniscal Transplant surgery or Optimised Rehabilitation full randomised trial (MeTeOR2): a study protocol.

INTRODUCTION: Pain and disability after meniscectomy can be a substantial lifelong problem. There are few treatment options, especially for young people. Non-surgical management (rehabilitation) is an option but increasingly surgeons are performing meniscal allograft transplants (MATs) for these individuals. However, this is still an uncommon procedure, and availability and usage of MAT vary widely both in the UK and internationally. It is not known which treatment option is the most effective and cost-effective. METHODS AND ANALYSIS: The Meniscal Transplant surgery or Optimised Rehabilitation trial is an international, multicentre, randomised controlled trial. The aim is to compare the clinical and cost effectiveness of MAT versus an optimised package of individualised, progressive, rehabilitation that we have called personalised knee therapy (PKT).Participants will be recruited from sites across the UK, Australia, Canada and Belgium. The planned 144 participants provide at least 90% power to detect a 10-point difference in the Knee injury and Osteoarthritis Outcome Score (KOOS4) at 24-months post randomisation (primary outcome). A prospectively planned economic evaluation will be conducted from a healthcare system and personal social services perspective. Secondary outcome data including health utility, occupational status, sports participation, mental well-being, further treatment, and adverse events will be collected at 3, 6, 12, 18, and 24 months. Analysis will be on an intention-to-treat basis and reported in-line with the Consolidated Standards of Reporting Trials statement. ETHICS AND DISSEMINATION: The trial was approved by the London-Bloomsbury Research Ethics Committee on 19 August 2022 (22/LO/0327) and Northern Sydney Local Health District Human Research Ethics Committee, NSW, Australia on the 13 March 2023 (2022/ETH01890).Trial results will be disseminated via peer-reviewed publications, presentations at international conferences, in lay summaries and using social media as appropriate.This protocol adheres to the recommended Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) checklist. TRIAL REGISTRATION NUMBER: ISRCTN87336549.

Trends in Oral Tongue Cancer Incidence in the US.

Importance: Oral tongue cancer (OTC) incidence has increased rapidly among young (<50 years) non-Hispanic White individuals in the US during the past 2 decades; however, it is unknown if age-associated trajectories have persisted. Objective: To examine US trends in OTC incidence and project future case burden. Design, Setting, and Participants: This cross-sectional analysis of OTC incidence trends used the US Cancer Statistics Public Use Database, which covers approximately 98% of the US population, and included individuals with an OTC diagnosis reported to US cancer registries between January 1, 2001, and December 31, 2019. Exposures: Sex, race and ethnicity, and age. Main Outcomes and Measures: Estimated average annual percentage change in OTC incidence from 2001 to 2019. Given the substantial incidence rate increases among non-Hispanic White individuals compared with those of racial and ethnic minority groups, subsequent analyses were restricted to non-Hispanic White individuals. Forecasted OTC incidence trends and case burden among non-Hispanic White individuals to 2034. Results: There were 58 661 new cases of OTC identified between 2001 and 2019. Male individuals (57.6%), non-Hispanic White individuals (83.7%), those aged 60 years or older (58.0%), and individuals with localized stage disease at diagnosis (62.7%) comprised most cases. OTC incidence increased across all age, sex, and racial and ethnic groups, with marked increases observed among non-Hispanic White individuals (2.9% per year; 95% CI, 2.2%-3.7%). Increases among female individuals aged 50 to 59 years were most notable and significantly outpaced increases among younger non-Hispanic White female individuals (4.8% per year [95% CI, 4.1%-5.4%] vs 3.3% per year [95% CI, 2.7%-3.8%]). While all non-Hispanic White birth cohorts from 1925 to 1980 saw sustained increases, rates stabilized among female individuals born after 1980. Should trends continue, the burden of new OTC cases among non-Hispanic White individuals in the US is projected to shift more toward older individuals (from 33.1% to 49.3% among individuals aged 70 years or older) and female individuals (86% case increase vs 62% among male individuals). Conclusions and Relevance: The results of this cross-sectional study suggest that the period of rapidly increasing OTC incidence among younger non-Hispanic White female individuals in the US is tempering and giving way to greater increases among older female individuals, suggesting a birth cohort effect may have been associated with previously observed trends. Recent increases among non-Hispanic White individuals 50 years or older of both sexes have matched or outpaced younger age groups. Continuing increases among older individuals, particularly female individuals, may be associated with a shift in the OTC patient profile over time.

Attitudes Toward Proactive Topical Corticosteroid Use Among Women With Vulval Lichen Sclerosus.

OBJECTIVES: Some practitioners are adopting proactive topical corticosteroid (TCS) therapy for vulval lichen sclerosus (VLS). We sought to understand patient attitudes toward proactive TCS therapy for VLS in a context in which proactive therapy is adopted. METHODS: Four online focus group discussions with 12 participants. Data analysis was informed by social constructionist grounded theory. RESULTS: All participants had accepted a proactive regimen. Three themes were developed from the analysis: "Coming to accept proactive therapy," "Motivators to maintaining a proactive regimen," and "The importance of a routine that fits me." Within each theme are subthemes illustrating different dimensions of the theme. CONCLUSIONS: Accepting proactive TCS therapy for VLS requires incorporating regular TCS use into a patient's identity, unlearning previous understandings regarding the safety of long-term TCS use, and adopting a regimen that fits within patients' lives and minimizes the loss of autonomy.

"Pathways": A hope-enhancing intervention for patients undergoing treatment for advanced lung cancer.

OBJECTIVE: Observational data suggest hope is associated with the quality of life and survival of people with cancer. This trial examined the feasibility, acceptability, and preliminary outcomes of "Pathways," a hope intervention for people in treatment for advanced lung cancer. METHODS: Between 2020 and 2022, we conducted a single-arm trial of Pathways among participants who were 3-12 weeks into systemic treatment. Pathways consisted of two individual sessions delivered during infusions and three phone calls in which participants discussed their values, goals, and goal strategies with a nurse or occupational therapist. Participants completed standardized measures of hope and goal interference pre- and post-intervention. Feasibility was defined as ≥60% of eligible patients enrolling, ≥70% of participants completing three or more sessions, ≥70% of participants completing post-assessments, and mean acceptability ratings ≥7 out of 10 on intervention relevance, helpfulness, and convenience. Linear regression fixed effects models with covariates modeled pre-post changes in complete case analysis and multiple imputation models. RESULTS: Fifty two participants enrolled: female (59.6%), non-Hispanic White (84.6%), rural (75.0%), and with low educational attainment (51.9% high school degree or less). Except for enrollment (54%), feasibility and acceptability markers were surpassed (77% adherence, 77% retention, acceptability ratings ≥8/10). There was moderate improvement in hope and goal interference from pre-to post-intervention (d = 0.51, p < 0.05 for hope; d = -0.70, p < 0.005 for goal interference). CONCLUSIONS: Strong feasibility, acceptability, and patient-reported outcome data suggest Pathways is a promising intervention to increase hope and reduce cancer-related goal interference during advanced lung cancer treatment.

Impact of individual level uncertainty of lung cancer polygenic risk score (PRS) on risk stratification.

BACKGROUND: Although polygenic risk score (PRS) has emerged as a promising tool for predicting cancer risk from genome-wide association studies (GWAS), the individual-level accuracy of lung cancer PRS and the extent to which its impact on subsequent clinical applications remains largely unexplored. METHODS: Lung cancer PRSs and confidence/credible interval (CI) were constructed using two statistical approaches for each individual: (1) the weighted sum of 16 GWAS-derived significant SNP loci and the CI through the bootstrapping method (PRS-16-CV) and (2) LDpred2 and the CI through posteriors sampling (PRS-Bayes), among 17,166 lung cancer cases and 12,894 controls with European ancestry from the International Lung Cancer Consortium. Individuals were classified into different genetic risk subgroups based on the relationship between their own PRS mean/PRS CI and the population level threshold. RESULTS: Considerable variances in PRS point estimates at the individual level were observed for both methods, with an average standard deviation (s.d.) of 0.12 for PRS-16-CV and a much larger s.d. of 0.88 for PRS-Bayes. Using PRS-16-CV, only 25.0% of individuals with PRS point estimates in the lowest decile of PRS and 16.8% in the highest decile have their entire 95% CI fully contained in the lowest and highest decile, respectively, while PRS-Bayes was unable to find any eligible individuals. Only 19% of the individuals were concordantly identified as having high genetic risk (> 90th percentile) using the two PRS estimators. An increased relative risk of lung cancer comparing the highest PRS percentile to the lowest was observed when taking the CI into account (OR = 2.73, 95% CI: 2.12-3.50, P-value = 4.13 × 10-15) compared to using PRS-16-CV mean (OR = 2.23, 95% CI: 1.99-2.49, P-value = 5.70 × 10-46). Improved risk prediction performance with higher AUC was consistently observed in individuals identified by PRS-16-CV CI, and the best performance was achieved by incorporating age, gender, and detailed smoking pack-years (AUC: 0.73, 95% CI = 0.72-0.74). CONCLUSIONS: Lung cancer PRS estimates using different methods have modest correlations at the individual level, highlighting the importance of considering individual-level uncertainty when evaluating the practical utility of PRS.

Feasibility and Clinical Utility of Reporting Hereditary Cancer Predisposition Pathogenic Variants Identified in Research Germline Sequencing: A Prospective Interventional Study.

PURPOSE: Patients with cancer frequently undergo research-grade germline sequencing but clinically actionable results are not routinely disclosed. The objective of this study is to evaluate the feasibility of reporting clinically relevant secondary findings (SF) identified in germline research sequencing using the institutional molecular tumor board (MTB) and the treating oncology physician. METHODS: This prospective, interventional cohort study enrolled Total Cancer Care participants with any cancer diagnosis at a single institution. Patients underwent research-grade germline whole-exome sequencing, with bioinformatic analysis in a Clinical Laboratory Improvement Amendments-certified laboratory to verify pathogenic/likely pathogenic germline variants (PGVs) in any American College of Medical Genomics and Genetics SF v2.0 genes. After a protocol modification in consenting patients, the MTB reported PGVs to treating oncology physicians with recommendations for referral to a licensed genetic counselor and clinical confirmatory testing. RESULTS: Of the 781 enrolled participants, 32 (4.1%) harbored cancer predisposition PGVs, 24 (3.1%) were heterozygous carriers of an autosomal recessive cancer predisposition syndrome, and 14 (1.8%) had other hereditary disease PGVs. Guideline-directed testing would have missed 37.5% (12/32) of the inherited cancer predisposition PGVs, which included BRCA1, BRCA2, MSH6, SDHAF2, SDHB, and TP53 variants. Three hundred fifteen participants consented to reporting results; results for all living patients were reported to the clinical team with half referred to a licensed genetic counselor. There was concordance between all research variants identified in patients (n = 9) who underwent clinical confirmatory sequencing. CONCLUSION: MTB reporting of research-grade germline sequencing to the clinical oncology team is feasible. Over a third of PGVs identified using a universal testing strategy would have been missed by guideline-based approach, suggesting a role for expanding germline testing.

Lung Cancer in Ever- and Never-Smokers: Findings from Multi-Population GWAS Studies.

BACKGROUND: Clinical, molecular, and genetic epidemiology studies displayed remarkable differences between ever- and never-smoking lung cancer. METHODS: We conducted a stratified multi-population (European, East Asian, and African descent) association study on 44,823 ever-smokers and 20,074 never-smokers to identify novel variants that were missed in the non-stratified analysis. Functional analysis including expression quantitative trait loci (eQTL) colocalization and DNA damage assays, and annotation studies were conducted to evaluate the functional roles of the variants. We further evaluated the impact of smoking quantity on lung cancer risk for the variants associated with ever-smoking lung cancer. RESULTS: Five novel independent loci, GABRA4, intergenic region 12q24.33, LRRC4C, LINC01088, and LCNL1 were identified with the association at two or three populations (P < 5 × 10-8). Further functional analysis provided multiple lines of evidence suggesting the variants affect lung cancer risk through excessive DNA damage (GABRA4) or cis-regulation of gene expression (LCNL1). The risk of variants from 12 independent regions, including the well-known CHRNA5, associated with ever-smoking lung cancer was evaluated for never-smokers, light-smokers (packyear ≤ 20), and moderate-to-heavy-smokers (packyear > 20). Different risk patterns were observed for the variants among the different groups by smoking behavior. CONCLUSIONS: We identified novel variants associated with lung cancer in only ever- or never-smoking groups that were missed by prior main-effect association studies. IMPACT: Our study highlights the genetic heterogeneity between ever- and never-smoking lung cancer and provides etiologic insights into the complicated genetic architecture of this deadly cancer.

Identification of genetically predicted DNA methylation markers associated with non-small cell lung cancer risk among 34,964 cases and 448,579 controls.

BACKGROUND: Although the associations between genetic variations and lung cancer risk have been explored, the epigenetic consequences of DNA methylation in lung cancer development are largely unknown. Here, the genetically predicted DNA methylation markers associated with non-small cell lung cancer (NSCLC) risk by a two-stage case-control design were investigated. METHODS: The genetic prediction models for methylation levels based on genetic and methylation data of 1595 subjects from the Framingham Heart Study were established. The prediction models were applied to a fixed-effect meta-analysis of screening data sets with 27,120 NSCLC cases and 27,355 controls to identify the methylation markers, which were then replicated in independent data sets with 7844 lung cancer cases and 421,224 controls. Also performed was a multi-omics functional annotation for the identified CpGs by integrating genomics, epigenomics, and transcriptomics and investigation of the potential regulation pathways. RESULTS: Of the 29,894 CpG sites passing the quality control, 39 CpGs associated with NSCLC risk (Bonferroni-corrected p ≤ 1.67 × 10-6 ) were originally identified. Of these, 16 CpGs remained significant in the validation stage (Bonferroni-corrected p ≤ 1.28 × 10-3 ), including four novel CpGs. Multi-omics functional annotation showed nine of 16 CpGs were potentially functional biomarkers for NSCLC risk. Thirty-five genes within a 1-Mb window of 12 CpGs that might be involved in regulatory pathways of NSCLC risk were identified. CONCLUSIONS: Sixteen promising DNA methylation markers associated with NSCLC were identified. Changes of the methylation level at these CpGs might influence the development of NSCLC by regulating the expression of genes nearby. PLAIN LANGUAGE SUMMARY: The epigenetic consequences of DNA methylation in lung cancer development are still largely unknown. This study used summary data of large-scale genome-wide association studies to investigate the associations between genetically predicted levels of methylation biomarkers and non-small cell lung cancer risk at the first time. This study looked at how well larotrectinib worked in adult patients with sarcomas caused by TRK fusion proteins. These findings will provide a unique insight into the epigenetic susceptibility mechanisms of lung cancer.

CYP2A6 Activity and Cigarette Consumption Interact in Smoking-Related Lung Cancer Susceptibility.

Cigarette smoke, containing both nicotine and carcinogens, causes lung cancer. However, not all smokers develop lung cancer, highlighting the importance of the interaction between host susceptibility and environmental exposure in tumorigenesis. Here, we aimed to delineate the interaction between metabolizing ability of tobacco carcinogens and smoking intensity in mediating genetic susceptibility to smoking-related lung tumorigenesis. Single-variant and gene-based associations of 43 tobacco carcinogen-metabolizing genes with lung cancer were analyzed using summary statistics and individual-level genetic data, followed by causal inference of Mendelian randomization, mediation analysis, and structural equation modeling. Cigarette smoke-exposed cell models were used to detect gene expression patterns in relation to specific alleles. Data from the International Lung Cancer Consortium (29,266 cases and 56,450 controls) and UK Biobank (2,155 cases and 376,329 controls) indicated that the genetic variant rs56113850 C>T located in intron 4 of CYP2A6 was significantly associated with decreased lung cancer risk among smokers (OR = 0.88, 95% confidence interval = 0.85-0.91, P = 2.18 × 10-16), which might interact (Pinteraction = 0.028) with and partially be mediated (ORindirect = 0.987) by smoking status. Smoking intensity accounted for 82.3% of the effect of CYP2A6 activity on lung cancer risk but entirely mediated the genetic effect of rs56113850. Mechanistically, the rs56113850 T allele rescued the downregulation of CYP2A6 caused by cigarette smoke exposure, potentially through preferential recruitment of transcription factor helicase-like transcription factor. Together, this study provides additional insights into the interplay between host susceptibility and carcinogen exposure in smoking-related lung tumorigenesis. SIGNIFICANCE: The causal pathway connecting CYP2A6 genetic variability and activity, cigarette consumption, and lung cancer susceptibility in smokers highlights the need for behavior modification interventions based on host susceptibility for cancer prevention.

A multi-professional survey of UK practice in the use of intra-articular corticosteroid injection for symptomatic first metatarsophalangeal joint osteoarthritis.

BACKGROUND: The first metatarsophalangeal joint is the most common site of osteoarthritis (OA) in the foot and ankle. Intra-articular corticosteroid injections are widely used for this condition, but little is known about their use in practice. This study explored current practice within the UK National Health Service (NHS) relating to the administration of intra-articular corticosteroids for people with painful first metatarsophalangeal joint (MTPJ) OA. METHODS: A cross-sectional survey using Qualtrics online survey platform (Qualtrics, Provo, UT, USA), distributed through professional bodies, special interest groups, and social media. RESULTS: One hundred forty-four healthcare professionals responded, including podiatrists (53/144; 39%), orthopaedic surgeons (28/144; 19%), podiatric surgeons (26/144; 17%) and physiotherapists (24/144; 16%). Half of respondents administered up to 25 corticosteroid injections per year (67/136; 49%) but some administered more than fifty (21/136; 15%). Injections were administered across the healthcare system but were most common in hospital settings (64/136; 44%) followed by community (38/136; 26%), with less delivered in primary care (11/136; 8%). Half of respondents routinely used image-guidance, either ultrasound or x-ray/fluoroscopy (65/136; 48%) although over one third used none (52/136; 38%). Imaging guidance was more common amongst medical professionals (21/31; 68%) compared to non-medical health professionals (45/105; 43%). Overall, methylprednisolone acetate was the most common corticosteroid used. Medical professionals mostly injected methylprednisolone acetate (n = 15/27; 56%) or triamcinolone acetonide (n = 11/27; 41%), whereas premixed methylprednisolone acetate with lidocaine hydrochloride was the most common preparation used by non-medical health professionals (41/85; 48%). When injecting non premixed steroid, lidocaine hydrochloride (15/35; 43%) was the most common choice of local anaesthetic for non-medical health professionals but medical professionals showed more variation between lidocaine hydrochloride (8/23; 35%) levobupivacaine hydrochloride (9/23; 39%) and bupivacaine hydrochloride (5/23; 22%). CONCLUSIONS: Multiple professional groups regularly administer intra-articular corticosteroids for symptomatic first MTPJ OA across a range of NHS healthcare settings. Overall, methylprednisolone acetate was the most commonly administered steroid and lidocaine hydrochloride the most common local anaesthetic. There was large variation in the use of imaging guidance, type and dose of steroid, local anaesthetic, and clinical pathways used in the intra-articular injection of corticosteroids for people with first MTPJ OA.

Structural rather than catalytic role for mitochondrial respiratory chain supercomplexes.

Mammalian mitochondrial respiratory chain (MRC) complexes are able to associate into quaternary structures named supercomplexes (SCs), which normally coexist with non-bound individual complexes. The functional significance of SCs has not been fully clarified and the debate has been centered on whether or not they confer catalytic advantages compared with the non-bound individual complexes. Mitochondrial respiratory chain organization does not seem to be conserved in all organisms. In fact, and differently from mammalian species, mitochondria from Drosophila melanogaster tissues are characterized by low amounts of SCs, despite the high metabolic demands and MRC activity shown by these mitochondria. Here, we show that attenuating the biogenesis of individual respiratory chain complexes was accompanied by increased formation of stable SCs, which are missing in Drosophila melanogaster in physiological conditions. This phenomenon was not accompanied by an increase in mitochondrial respiratory activity. Therefore, we conclude that SC formation is necessary to stabilize the complexes in suboptimal biogenesis conditions, but not for the enhancement of respiratory chain catalysis.