The Christie School of Oncology: Christie Research Publications Repository
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Corrigendum to 'towards estimating the carbon footprint of external beam radiotherapy' [Physics Medica. 112 (2023) 102652]
No full textThe prognostic significance of sarcopenia in patients treated with definitive radiotherapy: a systematic review
No full textSarcopenia describes the degenerative loss of muscle mass and strength, and is emerging as a pan-cancer prognostic biomarker. It is linked with increased treatment toxicity, decreased survival and significant healthcare financial burden. Systematic analyses of sarcopenia studies have focused on outcomes in patients treated surgically or with systemic therapies. There are few publications concerning patients treated with radiotherapy. This manuscript presents a pan-cancer systematic review of the association between sarcopenia and survival outcomes in patients treated with definitive (chemo-)radiotherapy. A literature search was performed, with 26 studies identified, including a total of 5,784 patients. The prognostic significance of sarcopenia was mixed. This may reflect lack of consensus in methods used to measure skeletal muscle mass and define sarcopenia. Many papers analyse small samples and present sarcopenia cutoffs optimised on the local population, which may not generalise to external populations. Recent advances in artificial intelligence allow for automatic measurement of body composition by segmenting the muscle compartment on routinely collected imaging. This provides opportunity for standardisation of measurement methods and definitions across populations. Adopting sarcopenia diagnosis into clinical workflows could reduce futile treatments and associated financial burden, by reducing treatment toxicities, and improving treatment completion, patient survival, and quality-of-life after cancer
Evaluating cost efficiency in healthcare: a comparative analysis of the one stop lung cancer clinic and pre-implementation pathway
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Fractionated radiation alters the extracellular matrix produced by muscle-invasive bladder cancer cells
No full textThe mutagenic forces shaping the genomes of lung cancer in never smokers
No full textLung cancer in never smokers (LCINS) accounts for around 25% of all lung cancers(1,2) and has been associated with exposure to second-hand tobacco smoke and air pollution in observational studies(3-5). Here we use data from the Sherlock-Lung study to evaluate mutagenic exposures in LCINS by examining the cancer genomes of 871 treatment-naive individuals with lung cancer who had never smoked, from 28 geographical locations. KRAS mutations were 3.8 times more common in adenocarcinomas of never smokers from North America and Europe than in those from East Asia, whereas a higher prevalence of EGFR and TP53 mutations was observed in adenocarcinomas of never smokers from East Asia. Signature SBS40a, with unknown cause(6), contributed the largest proportion of single base substitutions in adenocarcinomas, and was enriched in cases with EGFR mutations. Signature SBS22a, which is associated with exposure to aristolochic acid(7,8), was observed almost exclusively in patients from Taiwan. Exposure to secondhand smoke was not associated with individual driver mutations or mutational signatures. By contrast, patients from regions with high levels of air pollution were more likely to have TP53 mutations and shorter telomeres. They also exhibited an increase in most types of mutations, including a 3.9-fold increase in signature SBS4, which has previously been linked with tobacco smoking(9), and a 76% increase in the clock-like(10) signature SBS5. A positive dose-response effect was observed with air-pollution levels, correlating with both a decrease in telomere length and an increase in somatic mutations, mainly attributed to signatures SBS4 and SBS5. Our results elucidate the diversity of mutational processes shaping the genomic landscape of lung cancer in never smokers
The REFRACT trial: implementation of Bayesian power priors in a randomised, sequential phase II adaptive platform trial
No full textBACKGROUND: REFRACT is a randomised trial aimed at rapidly evaluating multiple novel therapies against standard treatment for relapsed or refractory follicular lymphoma (rrFL) using a minimal number of patients. To this end, we designed a prospective, adaptive, sequentially randomised clinical trial to allow multiple novel therapies to be assessed sequentially against a control arm of investigator choice standard therapy (ICT). METHODS: REFRACT uses a Bayesian power priors approach enabling the sharing of control arm data from previous treatment rounds. The design allows for the randomisation ratio to be changed and fixed to 1:4 in later treatment rounds resulting in fewer patients being recruited to the control arm. RESULTS: Following extensive simulations, we arrived at the selected design of three sequential treatment rounds, each with a control group and a novel experimental arm assessed for the primary outcome of complete metabolic response (CMR) at 24 weeks. Patients in Round 1 are randomised using a 1:1 allocation, with Rounds 2 and 3 randomised using a 1:4 allocation, in favour of experimental treatment. Using Bayesian power priors, data from control patients in earlier rounds will be shared to improve the operating characteristics in the current round. Previous control arm patients will be weighted at 75% of an active control patient within the prior, with opportunities for adjustment should control treatments change over time. CONCLUSIONS: With the use of power priors and an adaptive design this trial will sequentially evaluate three novel treatment regimens in a disease that urgently requires additional treatment options. REFRACT opened to recruitment in July 2023. TRIAL REGISTRATION: EudraCT: 2022-000677-75; 10-Feb-2022. CLINICALTRIALS: gov: NCT05848765; 08-May-2023
Skin radiotherapy as part of a training programme for dermatology residents in UK-2024 update
No full textBlood-based detection of MMP11 as a marker of prostate cancer progression regulated by the ALDH1A1-TGF-β1 signaling mechanism
No full textBACKGROUND: Prostate cancer (PCa) is the second most common type of tumor diagnosed in men and the fifth leading cause of cancer-related death in male patients. The response of metastatic disease to standard treatment is heterogeneous. As for now, there is no curative treatment option available for metastatic PCa, and the clinical tests capable of predicting metastatic dissemination and metastatic response to the therapies are lacking. Our recent study identified aldehyde dehydrogenases ALDH1A1 and ALDH1A3 as critical regulators of PCa metastases. Still, the exact mechanisms mediating the role of these proteins in PCa metastatic dissemination remain not fully understood, and plasma-based biomarkers of these metastatic mechanisms are not available. METHODS: Genetic silencing, gene overexpression, or treatment with different concentrations of the retinoic acid (RA) isomers, which are the products of ALDH catalytic activity, were used to modulate the interplay between retinoic acid receptors (RARs) and androgen receptor (AR). RNA sequencing (RNAseq), reporter gene assays, and chromatin immunoprecipitation (ChIP) analysis were employed to validate the role of RARs and AR in the regulation of the transforming growth factor-beta 1 (TGFB1) expression. Gene expression levels of ALDH1A1, ALDH1A3, and the matrix metalloproteinase 11 (MMP11) and their correlation with pathological parameters and clinical outcomes were analysed by mining several publicly available patient datasets as well as our multi-center transcriptomic dataset from patients with high-risk and locally advanced PCa. The level of MMP11 protein was analysed by enzyme-linked immunosorbent assay (ELISA) in independent cohorts of plasma samples from patients with primary or metastatic PCa and healthy donors, while plasma proteome profiles were obtained for selected subsets of PCa patients. RESULTS: We could show that ALDH1A1 and ALDH1A3 genes differently regulate TGFB1 expression in a RAR- and AR-dependent manner. We further observed that the TGF-β1 pathway contributes to the regulation of the MMPs, including MMP11. We have confirmed the relevance of MMP11 as a promising clinical marker for PCa using several independent gene expression datasets. Further, we have validated plasma MMP11 level as a prognostic biomarker in patients with metastatic PCa. Finally, we proposed a hypothetical ALDH1A1/MMP11-related plasma proteome-based prognostic signature. CONCLUSIONS: TGFB1/MMP11 signaling contributes to the ALDH1A1-driven PCa metastases. MMP11 is a promising blood-based biomarker of PCa progression
Camidanlumab tesirine for relapsed or refractory classic Hodgkin lymphoma: a phase 2 study
No full textOutcomes in classic Hodgkin lymphoma (cHL) have steadily improved; however, additional therapies are needed for patients who relapse or do not respond to novel agents. Here, we report the efficacy and safety of camidanlumab tesirine (Cami), an anti-CD25 antibody-drug conjugate, in patients with relapsed/refractory cHL after brentuximab vedotin/programmed cell death protein 1 inhibitor therapies from the phase 2 ADCT-301-201 study. Eligible patients were adults with cHL who had received >= 3 previous lines of systemic therapy (or >= 2 if ineligible for hematopoietic stem cell transplant). Patients received 45 mu g/kg Cami (IV, once every 3 weeks) in cycles 1 to 2, followed by 30 mu g/kg IV once every 3 weeks for <= 1 year. The primary end point was overall response rate (ORR) per 2014 Lugano classification. Secondary end points included complete response rate (CRR), progression-free survival (PFS), and overall survival (OS). In total, 117 patients were enrolled with a median age of 37.0 years (range, 19-87). The ORR was 70.1% (95% confidence interval [CI], 60.9-78.2), with a CRR of 33.3% (95% CI, 24.9-42.6). The median PFS was 9.13 months (95% CI, 5.3-15.0); median OS was not reached. Thirty-three (28.2%) patients discontinued treatment because of treatment-emergent adverse events; the most common reasons were skin and subcutaneous tissue disorders (n = 10 [8.5%] patients), infections and infestations (n = 5 [4.3%]), and nervous systems disorders (n = 5 [4.3%]). Guillain-Barre-type or polyradiculopathy-type events occurred in 8 (6.8%) patients. Cami was efficacious in this heavily pretreated population; however, the efficacy was overshadowed by substantial issues with the safety profile. This trial was registered at www.clinicaltrials.gov as #NCT04052997