The Christie School of Oncology: Christie Research Publications Repository
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The telomerase vaccine UV1 combined with ipilimumab and nivolumab versus ipilimumab and nivolumab in advanced melanoma (INITIUM): a randomized open-label phase 2 study
No full textPurpose: Immune checkpoint inhibitor (ICI) combinations have improved outcomes in patients with advanced melanoma; however, long term survival remains poor. The addition of therapeutic cancer vaccines to ICI combinations represents a promising strategy to enhance efficacy. Methods: In this phase 2, randomized, open-label trial, 156 patients with unresectable or metastatic melanoma were randomized 1:1 to receive 4 cycles of ipilimumab 3mg/kg and nivolumab 1mg/kg with or without UV1, a telomerase-targeted therapeutic cancer vaccine, followed by maintenance nivolumab 480 mg every 4 weeks. The primary endpoint was progression-free survival (PFS) based on blinded independent central review. Secondary endpoints included overall survival (OS), response assessments, and safety. Results: At a minimum follow-up of 18 months, the projected median PFS was 34.3 months (95 % confidence interval [CI], 7.95 to NR) with ipilimumab-nivolumab-UV1 and 38.4 months (95 % CI, 8.15-38.37) with ipilimumab-nivolumab (hazard ratio, 0.95 [95 % CI, 0.59-1.55]). PFS at 12 months was 57 % (95 % CI, 45.0-68.1) and 57 % (95 % CI, 44.6-67.0) in the ipilimumab-nivolumab-UV1 and ipilimumab-nivolumab arms, respectively. Objective response rates were 59.7 % (ipilimumab-nivolumab-UV1) and 59.2 % (ipilimumabnivolumab; odds ratio, 1.12; 95 % CI, 0.58-2.16). Median overall survival was not reached in either arm (hazard ratio, 1.15 [95 % CI, 0.60-2.20]). Grade >3 treatment-emergent adverse events were reported in 64.5 % and 65.4 % of patients respectively. Conclusion: For patients with treatment na & iuml;ve advanced melanoma, the addition of UV1 to ipilimumabnivolumab did not result in improved efficacy compared with ipilimumab-nivolumab alone
External evaluation of the Manchester score in a contemporary SCLC cohort
No full textOBJECTIVES: 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
Uncovering the role of LINE-1 in the evolution of lung adenocarcinoma
No full textUnderstanding lung cancer evolution can identify tools for intercepting its growth(1,2). Here, in a landscape analysis of 1,024 lung adenocarcinomas (LUADs) with deep whole-genome sequencing integrated with multiomic data, we identified 542 LUADs with a diverse clonal architecture. In this group, we observed divergent evolutionary trajectories based on tobacco smoking exposure, ancestry and sex. LUAD from smokers showed an abundance of tobacco-related C:G>A:T driver mutations(3) in KRAS and short subclonal diversification. LUAD in people who have never smoked (hereafter, never-smokers) showed early occurrence of copy-number alterations and EGFR mutations associated with SBS5 and SBS40a mutational signatures. Tumours containing EGFR mutations exhibited long latency, particularly in female individuals of European-ancestry. Tumours from Asian never-smokers showed a short clonal evolution. Importantly, we found that the mutational signature ID2(4) is a marker of a previously unrecognized mechanism for LUAD evolution. Tumours with ID2 showed short latency and high long interspersed nuclear element-1 (LINE-1, hereafter L1) retrotransposon activity linked to L1 promoter demethylation. These tumours exhibited an aggressive phenotype with genomic instability, elevated hypoxia scores, low neoantigen burden, metastasis propensity and poor overall survival. Reactivated L1-retrotransposition-induced mutagenesis probably contributes to the mutational signature ID2, including through the regulation of the transcriptional factor ZNF695, a member of the KZFP family(5). The complex nature of LUAD evolution creates both challenges and opportunities for screening and treatment plans
British Association of Urological Surgeons (BAUS) consensus document on male genital augmentation and enhancement procedures
No full textObjective: To critically appraise the safety and efficacy of male genital augmentation and enhancement procedures, and to formulate consensus recommendations for urologists and medical professionals.Methods: A systematic search of the literature published between 2000 and 2025 was conducted. Outcomes of interest focused on penile length and girth changes, complications, and validated patient-reported outcomes. Risk of bias was assessed using Cochrane RoB-2 for randomised controlled trials (RCTs) and the Newcastle-Ottawa Scale (NOS) for non-randomised studies. Evidence was synthesised qualitatively by intervention type. Consensus recommendations were generated through structured group appraisal by the British Association of Urological Surgeons (BAUS) Section of Andrology and Genitourethral Surgery (AGUS), integrating the evidence base with expert opinion, quality assessments, and patient safety considerations.Results: Thirty-six studies (n = 3748) were included: 12 injectable fillers and 24 surgical. Injectable fillers produced short-term girth gains with mild, transient complications. Surgical procedures demonstrated modest increases in length and girth, though complicated by infection, fibrosis, and/or device removal. Across the eligible evidence, the risk of bias was high, the quality of evidence was low, and expert opinion was consistently low.Conclusion: Evidence quality remains poor, heterogeneous, and methodologically limited. As such, five key recommendations were generated by the BAUS AGUS committee on genital augmentation and enhancement with either injectable fillers or surgical procedures.Level of evidence:
Unveiling regions associated with acute and late breast side-effects from breast radiotherapy using voxel-wise image-based data mining analysis
No full textBACKGROUND AND PURPOSE: Side-effects after breast cancer treatment, including radiotherapy (RT), can drastically affect a patient's quality of life. This study aims to identify anatomical regions where RT dose is related to breast side-effects using the voxel-wise image-based data mining (IBDM) technique. MATERIALS AND METHODS: Data of 922 patients included in the REQUITE study and who underwent RT after breast-conserving surgery were analysed. All patients were treated supine. We analysed breast pain, oedema, atrophy, induration, and nipple retraction, scored before and after RT by clinicians and patients. We investigated the toxicity burden using the area under the curve for toxicity over time (ToxT-AUC) and applied IBDM by normalising all dose distributions to three reference anatomies. To do so, we established a spatial normalisation pipeline, ensuring that the ipsilateral breast was aligned (flipping all left-side treatments laterally). Dose distributions were converted to equivalent dose in 2 Gy-fraction (EQD(2), α/β = 1.7 Gy and 3 Gy) to account for different RT fractionations. To determine the relevance of each identified region, we used multivariable ordinal regression, including patient-specific factors and clinical variables. RESULTS: Significant regions associated with each breast side-effect were found in different breast quadrants. The regions showed higher mean EQD(2) than the complete breast contour, particularly for grade 2+ (p < 0.01). Dosimetric parameters extracted from the region were significant in multivariable analysis. CONCLUSION: We found regions within the breast where the local dose associates with breast side-effects after breast RT. This result opens a new hypothesis which could help reduce side-effects after breast radiotherapy
Informative censoring in maintenance therapy trials for advanced ovarian cancer: an empirical assessment of its impact on treatment benefit
No full textINTRODUCTION: A considerable proportion of patients in ovarian cancer maintenance trials may be censored in progression-free survival (PFS) analyses, the primary study endpoint. Such censoring is often informative, reflecting discontinuation due to toxicity, preference, or early switch to alternative therapies, potentially biasing results toward overestimating PFS benefit. We aimed to quantify the impact of informative censoring on PFS in these trials. METHODS: Double-blind, placebo-controlled maintenance therapy trials were selected, and individual patient data reconstructed from published survival curves. A sensitivity analysis reclassified varying proportions of all censored events as progressions to model scenarios from 0 % to 100 % informative censoring. Hazard ratios (HRs) were re-estimated and compared with the originally reported values. Duration of therapy was compared with PFS. RESULTS: Twenty-two trial units (N = 8256) were included. Nineteen reported statistically significant results, falling to 14 (74 %) at the upper limit of analysis. HRs diminished progressively, with a 6 % reduction at 10 % censoring and 29 % at 100 %. In nine PARP inhibitor trials, treatment duration was shorter than PFS (mean of medians = 12.5 vs 17.6 months). Results were consistent when limited to PARP inhibitor studies. No correlation was observed between adverse events and censoring. CONCLUSIONS: Informative censoring can substantially distort PFS benefit estimates in ovarian cancer maintenance trials. Transparent reporting of censoring rates and their causes is essential for meaningful clinical interpretation and should be standard in all randomised maintenance therapy trials
Nucleophosmin supports WNT-driven hyperproliferation and tumor initiation
No full textNucleophosmin (NPM1), a nucleolar protein frequently mutated in hematopoietic malignancies, is overexpressed in several solid tumors with poorly understood functional roles. Here, we demonstrate that Npm1 is upregulated after APC loss in WNT-responsive tissues and supports WNT-driven intestinal and liver tumorigenesis. Mechanistically, NPM1 loss induces ribosome pausing and accumulation at the 5'-end of coding sequences, triggering a protein synthesis stress response and p53 activation, which mediate this antitumorigenic effect. Collectively, our data identify NPM1 as a critical WNT effector that sustains WNT-driven hyperproliferation and tumorigenesis by attenuating the integrated stress response and p53 activation. Notably, NPM1 expression correlates with elevated WNT signaling and proliferation in human colorectal cancer (CRC), while CRCs harboring NPM1 deletions exhibit preferential TP53 inactivation, underscoring the clinical relevance of our findings. Being dispensable for adult epithelial homeostasis, NPM1 represents a promising therapeutic target in p53-proficient WNT-driven tumors, including treatment-refractory KRAS-mutant CRC, and hepatic cancers
Functional precision approach in patients with very high risk acute lymphoblastic leukaemia in India: a single-centre cohort study
No full textBackground 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/)
Author Correction: Mcm10 associates with the loaded DNA helicase at replication origins and defines a novel step in its activation
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Uncovering the role of LINE-1 in the evolution of lung adenocarcinoma
No full textUnderstanding lung cancer evolution can identify tools for intercepting its growth(1,2). Here, in a landscape analysis of 1,024 lung adenocarcinomas (LUADs) with deep whole-genome sequencing integrated with multiomic data, we identified 542 LUADs with a diverse clonal architecture. In this group, we observed divergent evolutionary trajectories based on tobacco smoking exposure, ancestry and sex. LUAD from smokers showed an abundance of tobacco-related C:G>A:T driver mutations(3) in KRAS and short subclonal diversification. LUAD in people who have never smoked (hereafter, never-smokers) showed early occurrence of copy-number alterations and EGFR mutations associated with SBS5 and SBS40a mutational signatures. Tumours containing EGFR mutations exhibited long latency, particularly in female individuals of European-ancestry. Tumours from Asian never-smokers showed a short clonal evolution. Importantly, we found that the mutational signature ID2(4) is a marker of a previously unrecognized mechanism for LUAD evolution. Tumours with ID2 showed short latency and high long interspersed nuclear element-1 (LINE-1, hereafter L1) retrotransposon activity linked to L1 promoter demethylation. These tumours exhibited an aggressive phenotype with genomic instability, elevated hypoxia scores, low neoantigen burden, metastasis propensity and poor overall survival. Reactivated L1-retrotransposition-induced mutagenesis probably contributes to the mutational signature ID2, including through the regulation of the transcriptional factor ZNF695, a member of the KZFP family(5). The complex nature of LUAD evolution creates both challenges and opportunities for screening and treatment plans