BMJ oncology最新文献

{"title":"First-in-human phase 1 study of the arginase inhibitor INCB001158 alone or combined with pembrolizumab in patients with advanced or metastatic solid tumours","authors":"A. Naing, K. Papadopoulos, M. Pishvaian, Osama Rahma, G. J. Hanna, Elena Garralda, Omar Saavedra, Sven Gogov, H. Kallender, LuLu Cheng, Michael Smith, Xuejun Chen, Emil Kuriakose, Todd Bauer","doi":"10.1136/bmjonc-2023-000249","DOIUrl":"https://doi.org/10.1136/bmjonc-2023-000249","url":null,"abstract":"The arginase inhibitor INCB001158 was evaluated for safety (primary endpoint) in locally advanced or metastatic solid tumours; pharmacokinetics, pharmacodynamics and efficacy were also assessed.In this non-randomised, open-label, three-part phase 1 study, INCB001158 was orally administered two times per day as monotherapy or in combination with intravenous pembrolizumab 200 mg every 3 weeks. Dose expansion was conducted in tumour-type cohorts (with or without prior anti−PD-1/PD-L1 (programmed death protein 1/programmed death ligand 1) therapy).A total of 107 patients received INCB001158 50–150 mg two times per day as monotherapy, and 153 patients, including 6 with moderate renal impairment, received INCB001158 50–100 mg two times per day combined with pembrolizumab. INCB001158 exposure was similar between groups (median, 56 days (monotherapy); 84 days (combination)). 49 patients (45.8%) on monotherapy and 76 (51.7%) on combination therapy experienced grade ≥3 treatment-emergent adverse events (AEs). The most common INCB001158-related AEs were fatigue (n=10/107 (9.3%)) and nausea (n=10/107 (9.3%)) with monotherapy and diarrhoea (n=24/147 (16.3%)) and fatigue (n=22/147 (15.0%)) with combination therapy. The highest response rate was seen in the anti–PD-1/PD-L1–naive combination therapy group with head/neck squamous cell carcinoma (overall response rate, 19.2%; 4/26 partial responses, 1/26 complete response). Consistent with arginase inhibition activity, plasma arginine dose-dependently increased. Arginase 1 expression in the tumour microenvironment did not correlate with response.INCB001158 was generally well tolerated. Response rates did not exceed background for given tumour types despite demonstrable pharmacodynamic activity. Overall, the limited antitumour activity of arginase inhibition observed suggests that the role of arginine depletion in cancer is multifaceted.NCT02903914.","PeriodicalId":72436,"journal":{"name":"BMJ oncology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141049227","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In pursuit of parity: addressing gender disparities in global cancer research","authors":"Kristina Jenei","doi":"10.1136/bmjonc-2024-000414","DOIUrl":"https://doi.org/10.1136/bmjonc-2024-000414","url":null,"abstract":"","PeriodicalId":72436,"journal":{"name":"BMJ oncology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140785603","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Postprogression therapy and confounding for the estimated treatment effect on overall survival in phase III oncology trials","authors":"Alexander D Sherry, P. Msaouel, Timothy A. Lin, J. Abi Jaoude, R. Kouzy, Esther J Beck, Avital M Miller, Adina H Passy, Gabrielle S Kupferman, Eugene J Koay, C. D. Fuller, Charles R Thomas, Zachary McCaw, E. Ludmir","doi":"10.1136/bmjonc-2024-000322","DOIUrl":"https://doi.org/10.1136/bmjonc-2024-000322","url":null,"abstract":"Estimations of the treatment effect on overall survival (OS) may be influenced by post-progression therapies (PPTs). It is unclear how often OS analyses account for PPT effects. The purpose of this cross-sectional analysis was to determine the prevalence of OS analyses accounting for PPT effects in phase III oncology trials.We screened two-arm, superiority design, phase III, randomised, oncology trials reporting OS from ClinicalTrials.gov. The primary outcome was the frequency of OS analyses adjusting for PPT confounding. Logistic regressions computed ORs for the association between trial-level covariates and the outcome.A total of 334 phase III trials enrolling 265 310 patients were included, with publications between 2004 and 2020. PPTs were reported in 47% of trials (157 of 334), and an analysis accounting for PPTs was performed in only 12% of trials (N=41). PPT adjustments were often prespecified (N=23, 56%), and appeared to be more likely in cross-over studies (OR 5.04, 95% CI 2.42 to 10.38) and studies with discordant surrogate-OS findings (OR 2.26, 95% CI 1.16 to 4.38). In key subgroup analyses, PPT analyses were infrequent, including 8% of trials among those studying locoregional/first-line therapy and 11% of trials among those powered for OS.Although time on PPTs is an important component of OS, PPTs are rarely considered in OS analyses, which may introduce confounding on estimates of the treatment effect on OS. PPTs and methods to account for their effects on OS estimates should be considered at the time of trial design and reporting.","PeriodicalId":72436,"journal":{"name":"BMJ oncology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140774471","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterisation of clinical response and transcriptional profiling of proliferating CD8 T cells in the blood of cancer patients after PD-1 monotherapy or combination therapy","authors":"Rebecca C. Obeng, T. Nasti, Kylee Martens, Peng Li, Annapaola Mariniello, Daniel Y Chang, Christiane S Eberhardt, Donald McGuire, H. Kissick, Candace Z. Daugherty, Yuzi Zhang, Andreas Wieland, Zhengjia Chen, Jeffrey M Switchenko, R. Pillai, Alice O. Kamphorst, Warren J. Leonard, Rafi Ahmed, Suresh S Ramalingam","doi":"10.1136/bmjonc-2024-000328","DOIUrl":"https://doi.org/10.1136/bmjonc-2024-000328","url":null,"abstract":"Immune checkpoint inhibitors (ICI) that block the programmed cell death 1 (PD-1) pathway have shown promise with limited benefit. We and others have shown in small patient cohorts that an early proliferative CD8 T-cell response in the blood may be predictive of clinical response. However, these studies lack detailed analyses and comparisons between monotherapy and combination therapies.We analysed longitudinal blood samples from 103 patients with cancer who received αPD-1 monotherapy or combined with anti-cytotoxic T lymphocyte-associated protein 4 (αCTLA-4) or chemotherapy. Transcriptional analysis of CD8 T cells after the first treatment cycle with effector cells generated following yellow fever virus (YFV-17D) vaccine-induced infection was also compared.An early proliferative (Ki-67+) CD8 T-cell response was observed after cycle 1 in 60 patients (58.3%). Patients with early-and-sustained proliferative responses (cycle 1 and beyond) had better clinical responses and survival than patients with an early-but-limited response (p=0.02). The proliferating cells had an effector-like phenotype. The transcriptional profiles of the effector-like CD8 T cells were similar irrespective of treatment type or clinical response but distinct from that of YFV-specific effector CD8 T cells.Our data suggest that early proliferative CD8 T-cell response in the blood is predictive, and that an early-and-sustained proliferative response may further identify patients with prolonged survival. The ICI-induced effector-like CD8 T cells are transcriptionally distinct from highly functional YFV-specific cells, suggesting opportunities for improved T-cell effector function with combination therapies for better clinical outcome.","PeriodicalId":72436,"journal":{"name":"BMJ oncology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140764073","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex and authorship in global cancer research","authors":"M. Mutebi, Grant Lewison, D. Mukherji, Nazik Hammad, V. Vanderpuye, Erica Liebermann, Winnie K W So, Julie Torode, Richard Sullivan, Ophira Ginsburg","doi":"10.1136/bmjonc-2023-000200","DOIUrl":"https://doi.org/10.1136/bmjonc-2023-000200","url":null,"abstract":"Research is an essential pillar of cancer control and key in shaping regional cancer control agendas. Imbalances in science and technology in terms of lack of female participation have been well documented. However, there is little evidence about country-level female participation in cancer research.Through a complex filter, cancer research papers were identified and grouped by countries and sex of the first and last authors of each paper and analysed by the percentage of females in these positions alongside other parameters.Our analysis of 56 countries’ outputs, in 2009, revealed that females were the first authors in 37.2% and last authors in 23.3% of papers. In 2019, females were the first author in 41.6% and last author in 29.4% of papers. Females increased as first authors by 26%, and as last authors by 12% between these two time periods. The top performing countries in terms female/male parity for first or last authorship were in Eastern and Southern Europe as well as Latin American countries.From 2009 to 2019, the highest proportion of females as first and last authors were from low-income and middle-income countries in Latin America and Eastern Europe.Females were more likely to publish in lower impact journals and were less likely to be cited compared to males.Globally, progress in female’s authorship in oncology research has been uneven. More research is needed to understand the reasons behind this. Advancing diversity and equity in research leadership and authorship will be essential to address the complex challenges of cancer globally.","PeriodicalId":72436,"journal":{"name":"BMJ oncology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140760182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tale of two zones: investigating the clinical outcomes and research gaps in peripheral and transition zone prostate cancer through a systematic review and meta-analysis","authors":"Amin Ali, T. Elumalai, BhanuPrasad Venkatesulu, Lauren Hekman, Hitesh Mistry, Ashwin Sachdeva, Pedro Oliveira, Noel Clarke, Esther Baena, Ananya Choudhury, Robert G Bristow","doi":"10.1136/bmjonc-2023-000193","DOIUrl":"https://doi.org/10.1136/bmjonc-2023-000193","url":null,"abstract":"To assess pathological characteristics, clinical features and outcomes of patients diagnosed with peripheral zone (PZ) and transition zone (TZ) prostate cancer after prostatectomy.We systematically reviewed PubMed, EMBASE and MEDLINE. Primary endpoints were biochemical relapse-free survival (bRFS) and distant metastases rate; secondary endpoints included clinical and pathological features.Ten retrospective cohort studies were identified, six reported HRs for bRFS between PZ and TZ tumours. Patients with TZ tumours had significantly better bRFS (pooled HR 0.57 (0.47, 0.68)) than those with PZ tumours. Two studies reported a lower proportion of distant metastasis in patients diagnosed with TZ tumours compared with PZ tumours (1.5% vs 4.9% (median follow-up 7.0 years) and 0% vs 5% (median follow-up 7.8 years)). PZ tumours presented higher Gleason group and T staging more frequently, while TZ tumours were associated with higher prostate specific antigen levels at diagnosis.PZ tumours were associated with poorer prognostic clinical features and outcomes. Despite adjusting for poor prognostic clinical features, PZ tumours consistently showed worse clinical outcomes than TZ tumours. Our systematic review underscores the need for further research comparing PZ and TZ prostate cancer to understand the underlying differences and refine clinical practice.","PeriodicalId":72436,"journal":{"name":"BMJ oncology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140786499","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HealthCare Access Barrier (HCAB) framework for the barriers to cancer care during conflicts: perspective from Iraq","authors":"Kouther Mohsin, L. Mula-Hussain, Richard Gilson","doi":"10.1136/bmjonc-2023-000252","DOIUrl":"https://doi.org/10.1136/bmjonc-2023-000252","url":null,"abstract":"The Iraqi population has lived under four decades of conflicts, warfare and political instability. The health consequences of the protracted conflict continue to persist. This work critically analyses Iraq’s barriers to delivering and accessing cancer care during the conflicts that Iraq passed through from 1980 to 2017. To identify the barriers to accessing and delivering cancer care services, we used the HealthCare Access Barriers framework, which categorises the barriers into three groups: financial, structural and cognitive. Moreover, a structured search was performed in multidisciplinary databases. To produce a comprehensive body of literature, further materials were retrieved using alternative methods, such as hand-searching and snowballing. The key findings and themes identified in the literature were issues related to funding and affordability (within the financial), destruction and inaccessibility of facilities, therapeutic and diagnostic shortages, workforce and human resources and lack of national guidelines and awareness programmes (within the structural), awareness and knowledge and finally attitudes and beliefs (within the cognitive). These results demonstrated that the barriers to cancer care delivery are complex and inter-related. The financial and structural barriers were particularly intertwined with the protracted conflict, but this relationship was not demonstrable within the findings of the cognitive barriers. We concluded that the barriers facing the delivery and access to cancer care in Iraq are intertwined mainly with its protracted conflict. To ensure that future generations do not continue to pay the price of war, improved reconstructive efforts and further research are necessary.","PeriodicalId":72436,"journal":{"name":"BMJ oncology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140086736","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mismatch repair deficiency and microsatellite instability in urothelial carcinoma: a systematic review and meta-analysis.","authors":"Elias B A Chandran, Giovanni Maria Iannantuono, Saad O Atiq, Dilara Akbulut, Ninet Sinaii, Nicholas I Simon, Abdul Rouf Banday, Salah Boudjadi, Sandeep Gurram, Amin H Nassar, Jonathan E Rosenberg, Gisela Butera, Min Yuen Teo, Guru Sonpavde, Jonathan A Coleman, Andrea B Apolo","doi":"10.1136/bmjonc-2024-000335","DOIUrl":"10.1136/bmjonc-2024-000335","url":null,"abstract":"<p><strong>Background: </strong>Mismatch repair deficiency (dMMR) and microsatellite instability-high (MSI-H) occur in a subset of cancers and have been shown to confer sensitivity to immune checkpoint inhibition (ICI); however, there is a lack of prospective data in urothelial carcinoma (UC).</p><p><strong>Methods and analysis: </strong>We performed a systematic review to estimate the prevalence of dMMR and MSI-H in UC, including survival and clinical outcomes. We searched for studies published up to 26 October 2022 in major scientific databases. We screened 1745 studies and included 110. Meta-analyses were performed if the extracted data were suitable.</p><p><strong>Results: </strong>The pooled weighted prevalences of dMMR in bladder cancer (BC) and upper tract UC (UTUC) were 2.30% (95% CI 1.12% to 4.65%) and 8.95% (95% CI 6.81% to 11.67%), respectively. The pooled weighted prevalences of MSI-H in BC and UTUC were 2.11% (95% CI 0.82% to 5.31%) and 8.36% (95% CI 5.50% to 12.53%), respectively. Comparing localised versus metastatic disease, the pooled weighted prevalences for MSI-H in BC were 5.26% (95% CI 0.86% to 26.12%) and 0.86% (95% CI 0.59% to 1.25%), respectively; and in UTUC, they were 18.04% (95% CI 13.36% to 23.91%) and 4.96% (95% CI 2.72% to 8.86%), respectively. Cumulatively, the response rate in dMMR/MSI-H metastatic UC treated with an ICI was 22/34 (64.7%) compared with 1/9 (11.1%) with chemotherapy.</p><p><strong>Conclusion: </strong>Both dMMR and MSI-H occur more frequently in UTUC than in BC. In UC, MSI-H occurs more frequently in localised disease than in metastatic disease. These biomarkers may predict sensitivity to ICI in metastatic UC and resistance to cisplatin-based chemotherapy.</p>","PeriodicalId":72436,"journal":{"name":"BMJ oncology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11203074/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141861835","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Repurposing radiosensitising medicines for radiotherapy: an overview","authors":"Jie Man Low, G. Rodriguez-Berriguete, Geoff S Higgins","doi":"10.1136/bmjonc-2023-000192","DOIUrl":"https://doi.org/10.1136/bmjonc-2023-000192","url":null,"abstract":"Repurposing established non-cancer drugs for the treatment of cancer offers potential benefits such as speed of clinical translation and financial efficiencies. In this study, we assess the landscape of repurposing drugs for combined use with radiotherapy (RT) based on their capacity to increase tumour radiosensitivity. Using a literature-based approach, we identified 42 radiosensitising drugs with varied non-cancer indications and mechanisms of action, that have entered or completed clinical trials in combination with RT or with chemoradiotherapy. Two compounds, nicotinamide and nimorazole, have entered routine but limited clinical use in combination with radiotherapy. We provide an overview on these successfully repurposed drugs, and highlight some examples of unsuccessful repurposing efforts and drug candidates with an uncertain prospect of success. Upon reviewing the trials, we identified some common themes behind the unsuccessful efforts, including poor trial reporting, absence of biomarkers and patient selection, sub-optimal pharmacological properties, inappropriate trial design, lack or inadequate consideration of pre-clinical and clinical data, and limited funding support. We point out future directions to mitigate these issues and increase the likelihood of success in repurposing drug treatments for radiotherapy.","PeriodicalId":72436,"journal":{"name":"BMJ oncology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139635176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Artificial intelligence across oncology specialties: current applications and emerging tools","authors":"John Kang, Kyle Lafata, Ellen Kim, Christopher Yao, Frank Lin, Tim Rattay, Harsha Nori, Evangelia Katsoulakis, Christoph Ilsuk Lee","doi":"10.1136/bmjonc-2023-000134","DOIUrl":"https://doi.org/10.1136/bmjonc-2023-000134","url":null,"abstract":"Oncology is becoming increasingly personalised through advancements in precision in diagnostics and therapeutics, with more and more data available on both ends to create individualised plans. The depth and breadth of data are outpacing our natural ability to interpret it. Artificial intelligence (AI) provides a solution to ingest and digest this data deluge to improve detection, prediction and skill development. In this review, we provide multidisciplinary perspectives on oncology applications touched by AI—imaging, pathology, patient triage, radiotherapy, genomics-driven therapy and surgery—and integration with existing tools—natural language processing, digital twins and clinical informatics.","PeriodicalId":72436,"journal":{"name":"BMJ oncology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139639244","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}