Functional precision approach in patients with very high risk acute lymphoblastic leukaemia in India: a single-centre cohort study

Background Persistence of measurable residual disease (MRD) and high-risk cytogenetics are established predictors of relapse in childhood acute lymphoblastic leukaemia (ALL). Methods Outcomes of children with ALL treated with the ICiCLe-ALL-2014 protocol at a single centre, between August 2013 and May 2023 were analysed. Co-culture ex-vivo drug response profiling (DRP) was performed on diagnostic or relapsed samples. Patients classified as very high risk (VHR) received DRP guided therapeutic modifications. Event free (EFS) and overall (OS) survival were compared across risk categories. Findings Among 715 patients, at a median 55 (50-58) months, the 3-year EFS for standard-risk, intermediate-risk, high-risk B, T-ALL and VHR were 71% (64%-78%), 67% (58%-75%), 77% (70%-82%), 81% (71%-88%), and 38% (24%-52%) respectively (p < 0.0001). Persistent MRD at end of consolidation was associated with inferior EFS (40.3%, p <= 0.0001). Drug sensitivity scores from DRP performed on 112 samples identified panobinostat (median DSS 23.4), venetoclax (20.7), daunorubicin (17.9), selinexor (12.7) and bortezomib (12.1) as effective in VHR or relapsed ALL. From November 2020, 25 VHR patients received a modified treatment block incorporating venetoclax and bortezomib. At 1.5-year, landmark EFS was 81.8% (58%-93%) with the modified regimen vs 67.7% (49-81) with standard therapy (p = 0.0324). Venetoclax sensitivity correlated with MRD clearance (p = 0.0070). Interpretation DRP enabled identification of effective agents for integration into therapy of VHR paediatric ALL. The addition of venetoclax and bortezomib was well tolerated and associated with improved early survival outcomes. These findings support prospective evaluation of DRP-guided treatment regimens in VHR ALL. Funding DBT-Wellcome India Alliance, Tata Consultancy Services. Copyright (c) 2025 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

Distant recurrence and margin involvement in invasive breast cancer

The effect of involved margins after breast cancer surgery on distant recurrence (DR) is unknown. We determined the association between margin width or involvement, DR and cancer deaths. PATIENTS AND METHODS: Greater Manchester (GM) and the National Cancer Registry (NCRAS) cohorts were analysed. Margin status after curative surgery was measured. Cox-proportional hazards investigated factors associated with LR, DR and breast cancer deaths. RESULTS: In GM (2010-2014), 2295 (70.2%) patients had clear margins ( > 2 mm), 302 (9.2%) close (1-2 mm) and 673 (20.6%) involved ( 1 mm. After BCS, in 5246 patients who underwent chemotherapy after BCS, involved margins 1 mm were associated with lower DR and cancer deaths. Guidelines should recommend a minimum margin clearance of 1 mm

Twelve tips on how to put together a successful applications for ASPIRE award for assessment of students

This paper provides twelve practical tips for institutions preparing to submit successful applications for the ASPIRE Award in the category of Assessment of Students, part of AMEE's global initiative to recognize excellence in health professions education. This paper emphasizes the importance of achieving institutional buy-in, aligning assessment systems with the school's mission and context, assembling a strong submission team, and providing explanation of the award criteria. It highlights the collection and presentation of comprehensive evidence, including metrics like psychometric analysis and construct alignment, to demonstrate standards of excellence. Engaging students in the application process is critical, as their perspectives enhance transparency, equity, and accountability. Institutions are encouraged to address inconsistencies, demonstrate impact through quality improvement cycles, and showcase their commitment to continuous learning and professional development. The tips also include the value of engaging with the ASPIRE Academy for expert support and collaboration during the application process. This paper highlights that the ASPIRE award is an opportunity to foster reflection, collaboration, and innovation, while contributing to global standards of excellence in assessment in health professions education

Biology and clinical management of non-V600 BRAF alterations in NSCLC

BRAF mutations are detected in approximately 3% to 8% of patients with NSCLC. In contrast to melanoma, in which most BRAF mutations occur at the V600 codon, only approximately 35% of BRAF-mutant NSCLC tumors harbor V600 mutations. Among the remaining cases, 60% to 70% present non-V600 mutations, primarily in exons 11 and 15. BRAF mutations are classified into three classes according to their kinase activity and their dependence on RAS activation. Compared with class I (V600), patients with class II and class III mutations are associated with poorer clinical outcomes partly due to the lack of effective targeted therapeutic strategies. Indeed, although dual BRAF and MEK inhibition has demonstrated clinical benefit in BRAF V600-mutant NSCLC, there is currently no consensus on treatment strategies for patients with class II and class III mutations. Beyond point mutations, other BRAF alterations (e.g., gene fusions, deletions, and amplifications) have been identified in treatment-naive tumors and in the context of acquired resistance to targeted therapies in other oncogene-driven NSCLC subtypes. However, the biology and clinical implications of these alterations remain poorly characterized. In this review, we provide a comprehensive overview on the biology, epidemiology, and therapeutic strategies of class II/III BRAF mutations, fusions, deletions, and amplifications in NSCLC. We highlight current challenges in the clinical management of BRAF-mutant NSCLC, emerging inhibitors, and combinatorial therapeutic strategies developed to treat non-V600E BRAF-driven cancers. Finally, we briefly discuss BRAF alterations in the context of resistance to targeted therapies in other oncogene-driven NSCLC

Cancer diagnoses, referrals, and survival in people with a learning disability in the UK: a population-based, matched cohort study

Background People with a learning disability (LD, also known as intellectual disability) face poorer health outcomes, yet the burden of cancer in this population is poorly understood. This study investigated cancer-related outcomes in people with a LD compared to the general population. Methods A matched cohort study was conducted using linked primary care, hospital, mortality, and cancer registry data from Clinical Practice Research Datalink (CPRD) Aurum. In total, 180,911 individuals with a LD were matched with 3,405,467 controls. Outcomes included urgent suspected cancer (USC) referrals, cancer diagnoses, treatment within six months, and overall survival (OS) post-diagnosis. Findings Individuals with a LD had fewer USC referrals within 28 days of possible cancer symptoms (adjusted risk ratio [aRR] 0.52, 95% confidence interval [CI] 0.49-0.55). LD was associated with several cancers, including sarcoma (adjusted hazard ratio [aHR] 1.98, 1.65-2.39), central nervous system (aHR 3.42, 2.99-3.90), testicular (aHR 2.06, 1.61-2.62), and uterine cancers (aHR 1.69, 1.40-2.05) as well as cancer before age 50 years (aHR 1.74, 1.63-1.86). Absolute incidence was lower in individuals with a LD compared to without (3396 [1.9%] vs 67,506 [2.0%]) due to increased all-cause mortality (aHR 3.19, 3.12-3.27). LD was associated with fewer diagnoses via USC referrals (aRR 0.81, 0.76-0.86), fewer treatments within six months (aRR 0.83, 0.80-0.85) and shorter OS (median 4.4 years, 95% CI 3.9-5.1 vs 9.1 years, 8.8-9.5; aHR 1.73, 1.65-1.83). Melanoma, breast, and prostate cancers were less common but had up to a fourfold increased risk of death after diagnosis in individuals with a LD. Interpretation Individuals with a LD have higher cancer risk, more diagnoses outside USC pathways, fewer treatments, and poorer prognosis. Fewer diagnoses of some cancers, alongside worse outcomes, may indicate under-investigation. As premature all-cause mortality improves, cancer burden in this population may rise disproportionately. (c) 2025 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

Camizestrant in combination with capivasertib for women with ER-positive, HER2-negative advanced breast cancer: results from SERENA-1

BACKGROUND: Camizestrant, the next-generation oral selective estrogen receptor degrader and complete estrogen receptor (ER) antagonist, has previously demonstrated superiority over fulvestrant in patients with ER-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. Capivasertib is a selective AKT inhibitor recommended with fulvestrant for patients with PIK3CA/AKT1/PTEN-altered ER-positive, HER2-negative advanced breast cancer. Here, we report data from Parts I and J of SERENA-1 (NCT03616587), evaluating the safety, tolerability, pharmacokinetics and efficacy for the combination of camizestrant and capivasertib. PATIENTS AND METHODS: SERENA-1 is a phase I, open-label, multi-part trial of camizestrant alone and in combination with other anticancer agents in women with ER-positive, HER2-negative advanced breast cancer. In parts I and J, participants received oral camizestrant 75 mg (once daily) in combination with oral capivasertib 400 mg (4 days on, 3 days off). RESULTS: Participants (n = 29) had a median of two previous lines of therapy in the advanced setting; 55.2% had received fulvestrant and 89.7% had received a cyclin-dependent kinase 4/6 inhibitor. Camizestrant in combination with capivasertib had a well-tolerated safety profile, with diarrhea (75.9%) and nausea (44.8%) being the most common adverse events. Median t(max) was achieved ∼4 hours and ∼2 hours post dose for camizestrant and capivasertib, respectively. Clinical benefit at 24 weeks was seen in 51.7% of participants, and median progression-free survival was 8.3 months. CONCLUSION: In these pretreated participants, camizestrant 75 mg in combination with capivasertib 400 mg was well tolerated, with a side effect profile consistent with each drug as monotherapy, and showed encouraging evidence of clinical efficacy

External evaluation of the Manchester score in a contemporary SCLC cohort

OBJECTIVES: The Manchester Score, a prognostic model developed in 1987, was used to stratify patients with Small Cell Lung Cancer (SCLC) by mortality risk, including stage, performance status, and three blood tests as risk factors. Many tools have since been developed for this purpose, but few have seen clinical use, with lack of robust external validation frequently cited as a barrier. In this study we apply a robust and pragmatic external validation approach to the Manchester Score to understand if it remains valid in an unselected modern patient cohort. METHODS: SCLC patients treated in an academic centre between 2013 and 2022 (N = 1783) were included in the validation cohort. Discrimination was assessed using Kaplan-Meier curves, AUC, and Harrell's C-index for the Manchester score and its underlying Cox model. Three levels of Cox model updating were used to address missing baseline hazard data: recalibration, recalibration with rescaling, and model refitting. Calibration was then evaluated with optimism adjustment at 6-, 12-, and 24-months post-diagnosis. RESULTS: The Manchester score shows good discrimination in the modern patient cohort. There is clear separation between risk groups in the Kaplan-Meier curves, with AUC = 0.75 and C-index = 0.68 for the Manchester Score and (AUC = 0.79, C-index = 0.70) for the underlying Cox model. Median survival in the 'good' prognostic group (meeting < 2/5 risk criteria) has increased compared to that from 1987. All model updating methods reported good calibration, with recalibration alone providing the best observed-to-expected ratio at 6 months (1.012 [0.978,1.045]). CONCLUSION: The original Manchester Score prognostic groups remain discriminative of survival, and when updated can predict survival probability at multiple timepoints

Bladder preservation strategies in muscle-invasive bladder cancer: recommendations from the International Bladder Cancer Group

Background and objective: Patient-centric management necessitates providing care aligned with patients' values, preferences, and expressed needs. Therefore, critical assessment of bladder preservation therapies (BPTs) as alternatives to radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC) and practical recommendations on the optimal selection of patients for BPTs are needed urgently. Methods: A global committee of bladder cancer experts was assembled to develop BPT recommendations for MIBC. Working groups reviewed the literature and drafted recommendations, which were voted on by International Bladder Cancer Group (IBCG) members using a modified Delphi process. During a live meeting in August 2023, voting results and supporting evidence were presented, and recommendations were refined based on discussions. Final recommendations achieved >= 75% agreement during the meeting, with further refinements through web conferences and e-mail discussions. Key findings and limitations: Patients with newly diagnosed MIBC should be offered evaluation in a multidisciplinary setting for consideration of BPTs. The main alternative to RC is trimodal therapy (TMT), and favorable prognostic factors for TMT include unifocal cT2 stage, lack of hydronephrosis, and no multifocal carcinoma in situ (CIS). Other options should be reserved for very select patients who are ineligible for or who decline TMT or RC after thorough consideration of benefits versus risks. These include partial cystectomy (PC) for urachal adenocarcinoma and PC or radical transurethral resection alone for solitary tumors amenable to resection with adequate margins and without concomitant CIS or histologic subtypes. Conclusions and clinical implications: The IBCG consensus recommendations provide practical guidance on BPTs for MIBC. (c) 2025 European Association of Urology. Published by Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies