The Christie School of Oncology: Christie Research Publications Repository
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KDM6A, ARID1A and SETD2 loss-of-function mutations as prognostic biomarkers and their association with sites of metastatic progression in locally-advanced, recurrent or metastatic adenoid cystic carcinoma
No full textOBJECTIVES: Recurrent/metastatic (R/M) adenoid cystic carcinoma (ACC) is typically slow growing however, some patients have more rapid progression. We sought to classify mutations in chromatin regulating genes in ACC to determine the impact of chromatin regulatory disfunction on clinical outcomes. MATERIALS AND METHODS: Matched clinical-genomic data from 271 pts with non-resectable or R/M ACC were included in this study. 132 pts were recruited locally. 139 ACC pts were included from cBioPortal for analysis. Mutations were classified as pathogenic using standardised bioinformatic pipelines. Analyses was performed to determine the impact of one or more mutations on overall survival from recurrence (OSr) and site of metastases. RESULTS: KDM6A mutations were seen in 12 % of patients, followed by ARID1A 9 %, EP300 6 %, CREBBP 5 %, KMT2D 5 %, SETD2 2.6 %, an KMT2C 1.8 %. While 15 % of patients harboured activating NOTCH1/2 mutations, which co-occurred with mutations in KDM6A, ARID1A, and CREBBP. NOTCH activation (8.4 v 2.3 years, p= <0.005), KDM6A (6.6 v 4.6 years, p = 0.008) and SETD2 (5.9 v 3.8 years, p = 0.04) mutations were associated with worse OSr. In NOTCH wild-type patients, median OSr for KDM6A 9.2 v 4.8 years (p = 0.07) and SETD2 was 9.8 v 3.2 years (p = 0.04). KDM6A (OR 4.5, 95 % CI 1.7-13.2, p = 0.002) mutations were significantly associated with bone metastasises and ARID1A mutations were associated with bone (OR 3.5, 95 % CI 1.2-11.8, p = 0.025) and liver (OR 3.0, 95 % CI 1.0-9.1, p = 0.053) in NOTCH wild-type patients. CONCLUSIONS: ARID1A, KDM6A and SETD2 loss of function mutations negatively impact clinical outcomes in R/M-ACC irrespective of NOTCH status
T-cell engager toxicity in clinical phase trials; a systematic review and meta-analysis
No full textEngineered to activate a patient's own immune response, T Cell Engagers (TCEs) are positioned to mediate T cell directed cytotoxicity through targeted engagement of a tumour antigen. Despite their attractive properties TCE therapies have yet to be widely used in the treatment of solid tumours with several obstacles that include adverse toxicity profiles. This systematic review and meta-analysis assessed the toxicity associated with T-cell engagers (TCEs) in the treatment of solid tumours. Papers were sourced from MEDLINE, Cochrane Library, CINHL, EMBASE, Web of Knowledge, Scopus. Prevalence data from the identified primary studies was pooled using an inverse variance method with a restricted maximum likelihood estimator. Freeman-Tukey double arcsine transformation to determine toxicity prevalence and confidence intervals. A total of 1147 publications were identified of which 30 were included for systematic review. Toxicity profiles from 17 TCEs, comprising 9 different ligands that utilised the CD3, CD40, CD28 or CD64 signalling pathways were characterised in this study. Of these studies, 21 publications were included for meta-analysis, focussing on four TCEs: catumaxomab, ertumaxomab, tebentafusb, and MDX-H210. Meta-analysis found that the most prevalent toxicities were gastrointestinal and inflammatory. Subgroup analysis revealed that Gastrointestinal toxicity (GI) toxicity was independent of tumour type or ligand. Cytokine Release Syndrome (CRS) is potentially being under-reported due to challenges of differentiation of CRS from other inflammatory mediated constituent symptoms, although Fc-independent TCEs were linked to lower inflammatory toxicity. The review highlights TCE-dependent toxicity profiles and highlights key features that may ameliorate TCE tolerance
18F-FDG-PET scanning following T-cell deplete RIC allogeneic transplantation for relapsed Hodgkin Lymphoma: a single-centre experience
No full textCurrent gynaecological management of women and girls with bleeding disorders in the United Kingdom: a UKHCDO haemophilia treatment centre survey and evaluation of real-world clinical practice for the British Journal of Haematology
No full textGirls and women with bleeding disorders (GWBD) comprise more than half of all registered patients with bleeding disorders in the UK National Haemophilia Database. The gynaecological care of GWBD, until recently, has not been prioritised despite high health burdens, where four of every five patients experience heavy menstrual bleeding (HMB). We report the results of a national survey exploring gynaecological health-care services offered across haemophilia centres in the United Kingdom, with a focus on HMB. We combine these results with a retrospective cohort analysis of individual patient care records, across a 3-year period. Of 65 haemophilia centres, 41 responded, covering 90% of the UK GWBD population. Six hundred and ninety-seven individual patient care records were included, from 13 centres. Our results show that immediate clinical care offered to GWBD experiencing HMB is adequate, despite infrastructure deficiencies (such as lack of joint-gynaecology input and few centres having named clinical leads for GWBD). We recommend several areas for immediate prioritisation within haemophilia centres which will improve the equity of care for GWBD. These include direct access to gynaecological services; universal testing of iron status; and more broadly, a shift towards clinical practices that recognise and address the impact HMB has on patients' psycho-social, sexual and overall quality of life
ABC-12: exploring the microbiome in patients with advanced biliary tract cancer in a first-line study of durvalumab (MEDI4736) in combination with cisplatin/gemcitabine
No full textUntil recently, cisplatin/gemcitabine was standard of care for the first-line treatment of patients with advanced biliary tract cancer (BTC). The addition of durvalumab, an immune checkpoint inhibitor, to the combination of cisplatin/gemcitabine has demonstrated an overall survival (OS) benefit and is now a standard of care first-line treatment option. BTCs exhibit immunogenic features may develop through an accumulation of genetic and epigenetic alterations, and can be influenced by microbial exposure. Microbiota can influence inflammation and immunity, and its disruption may impair tumor response to immunotherapy and chemotherapy. Here, the rationale and design of the multi-center, single-arm ABC-12 trial (ISRCTN11210442) is described, which investigates the role of the microbiome in patients with advanced BTC in a first-line study of durvalumab (MEDI4736) in combination with cisplatin/gemcitabine. The primary objective is to determine the difference in baseline alpha diversity between 'responders' (partial or complete response) and 'non-responders' at 18 weeks (RECIST 1.1) in patients treated with cisplatin/gemcitabine/durvalumab. Secondary objectives include investigating the association between microbiome parameters and objective response rate, tumor control (partial, complete response, and stable disease), progression-free and OS, and investigating the interaction between treatment effect and microbiome parameters on clinical outcomes
Radiation exposure of breast tissue in lymphoma radiotherapy: a systematic review of breast dose metrics published since 2000
No full textBACKGROUND AND PURPOSE: We present a systematic review of breast dose metrics reported in lymphoma patients receiving radiotherapy and provide reporting recommendations for breast dose in future publications. METHODS AND MATERIALS: Studies reporting breast doses in lymphoma radiotherapy published between January 2000 and May 2023 were included. Frequency of reporting factors likely to affect breast dose were calculated. Doses for the most frequently reported metrics (mean breast dose (MBD) (Gy, percentage of prescription), V5Gy and V10Gy (%)) were calculated across articles and compared for target volume approaches, radiotherapy techniques, and inclusion of the axilla. RESULTS: Thirty-four distinct breast dose metrics were found across 57 articles. MBD was the most commonly reported. Axilla irradiation significantly increased MBD, V5Gy and V10Gy, yet 21 articles reported breast doses for a mixed cohort with respect to axillary irradiation. Forty-eight of 57 articles did not report the breast contouring guidelines used. Among articles reporting MBD for proton or butterfly-volumetric modulated arc therapy (VMAT), there was no significant reduction in breast radiation dose for protons compared to butterfly-VMAT. INTERPRETATION: A wide variety of breast dose metrics are reported in the literature, making it challenging to pool breast tissue exposure data in lymphoma radiotherapy. Factors shown in individual studies to affect breast dose should be reported more systematically to enable large scale analysis. Reporting the presence/absence of axillary irradiation is crucial, due to the significant effect on breast dose. We provide reporting recommendations for breast dose metrics to improve research into radiotherapy-induced breast cancer
Recurrent morphoeic basal cell carcinoma with metastatic progression in a 34-year-old patient: a case report
No full textOverall survival according to timing of immune checkpoint inhibitors administration in patients with advanced cancer: Results from a large single-centre cohort analysis
No full textSALVOVAR: a pragmatic randomized phase III trial comparing the SALVage weekly dose-dense regimen to the standard 3-weekly regimen in patients with poor prognostic OVARian cancers
No full textBACKGROUND: Patients with epithelial ovarian cancer (EOC) receiving neoadjuvant platinum-based chemotherapy (NACT) who remain ineligible for complete interval cytoreductive surgery (ICS) due to poor chemosensitivity (CA-125 KELIM™ score <1.0) have a poor prognosis (~20% 5-year survival). A weekly dose-dense carboplatin-paclitaxel regimen may improve outcomes in this high-risk subgroup. OBJECTIVES: To demonstrate the superiority of a salvage weekly dose-dense carboplatin-paclitaxel regimen over continuation of the standard 3-weekly regimen in poor-prognosis EOC patients after 3-4 cycles of standard NACT. DESIGN: SALVOVAR is a pragmatic, open-label, multicenter, international, randomized phase III trial. METHODS AND ANALYSIS: Patients with stages III-IV high-grade EOC are eligible if they present (1) an unfavorable standardized KELIM score <1.0, and (2) a disease not amenable to complete ICS after 3-4 cycles of standard 3-weekly carboplatin-paclitaxel. Patients are randomized (1:1) to either the experimental arm (dose-dense carboplatin AUC5 day 1 plus paclitaxel 80 mg/m(2) on days 1, 8, and 15, every 3 weeks) or the control arm (continuation of the standard regimen) for 3 cycles. Bevacizumab use is allowed at investigator discretion. Stratification factors include planned bevacizumab administration, BRCA mutation status, and KELIM strata. The two co-primary endpoints are (1) improvement in late complete cytoreduction rates (from 5% in the control arm to 20% in the experimental arm), and (2) overall survival (target hazard-ratio, 0.61). Total 250 patients will be randomized. Secondary endpoints include objective response rate, progression-free survival, and safety. Additional planned analyses include quality-of-life, cost-effectiveness, surgical standardization, human sciences, and biology studies. ETHICS: The protocol was approved by the national ethics committee and health authorities. DISCUSSION: SALVOVAR will evaluate whether chemotherapy densification improves outcomes in poorly chemosensitive advanced EOC. If positive, this pragmatic strategy could be implemented in large-scale studies, independent of resource setting. TRIAL REGISTRATION: ClinicalTrials.gov NCT06476184 (June-2024). Available at: https://clinicaltrials.gov/study/NCT06476184
