The Christie School of Oncology: Christie Research Publications Repository
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Tumour hypoxia in driving genomic instability and tumour evolution
No full textIntratumour hypoxia is a feature of all heterogenous solid tumours. Increased levels or subregions of tumour hypoxia are associated with an adverse clinical prognosis, particularly when this co-occurs with genomic instability. Experimental evidence points to the acquisition of DNA and chromosomal alterations in proliferating hypoxic cells secondary to inhibition of DNA repair pathways such as homologous recombination, base excision repair and mismatch repair. Cell adaptation and selection in repair-deficient cells give rise to a model whereby novel single-nucleotide mutations, structural variants and copy number alterations coexist with altered mitotic control to drive chromosomal instability and aneuploidy. Whole-genome sequencing studies support the concept that hypoxia is a critical microenvironmental cofactor alongside the driver mutations in MYC, BCL2, TP53 and PTEN in determining clonal and subclonal evolution in multiple tumour types. We propose that the hypoxic tumour microenvironment selects for unstable tumour clones which survive, propagate and metastasize under reduced immune surveillance. These aggressive features of hypoxic tumour cells underpin resistance to local and systemic therapies and unfavourable outcomes for patients with cancer. Possible ways to counter the effects of hypoxia to block tumour evolution and improve treatment outcomes are described
Validation of a cancer population derived AKI machine learning algorithm in a general critical care scenario
No full textPURPOSE: Acute Kidney Injury (AKI) is the sudden onset of kidney damage. This damage usually comes without warning and can lead to increased mortality and inpatient costs and is of particular significance to patients undergoing cancer treatment. In previous work, we developed a machine learning algorithm to predict AKI up to 30 days prior to the event, trained on cancer patient data. Here, we validate this model on non-cancer data. METHODS/PATIENTS: Medical Information Mart for Intensive Care (MIMIC) is a large, freely available database containing de-identified data from patients who were admitted to the critical care units of the Beth Israel Deaconess Medical Center. Data from 28,498 MIMIC patients were used to validate our algorithm, non-availability of Total Protein measure being the largest removal criterion. RESULTS AND CONCLUSIONS: Applying our algorithm to MIMIC data generated an AUROC of 0.821 (95% CI 0.820-0.821) per blood test. Our cancer derived algorithm compares positively with other AKI models derived and/or tested on MIMIC, with our model predicting AKI at the longest time frame of up to 30 days. This suggests that our model can achieve a good performance on patient cohorts very different to those from which it was derived, demonstrating the transferability and applicability for implementation in a clinical setting
Low-risk febrile neutropenia: does combined chemotherapy/immune checkpoint inhibitor necessitate a change in approach?
No full textPURPOSE: Management of patients with low-risk febrile neutropenia in an outpatient setting guided by the MASCC score is proven to be safe and effective. Most patients on ambulatory low-risk febrile neutropenia pathways are undergoing treatment for breast cancer. Recent data has shown benefit of the addition of immune checkpoint inhibitor therapy to cytotoxic chemotherapy in the neoadjuvant setting for patients with early triple-negative breast cancer. We examined whether the addition of ICI therapy altered the clinical severity of febrile neutropenia in this cohort and the ability to manage these patients in an ambulatory setting. METHODS: An observational analysis was performed at a specialist oncology hospital in the North West of England. We compared patients with triple negative breast cancer presenting with febrile neutropenia following treatment with PC-EC/pembrolizumab to those treated with PC-EC in the neoadjuvant setting. RESULTS: In the study periods, 152 patients received PC-EC and 151 PC-EC/Pembro. Twenty-five patients presented with FN in the PC-EC/Pembro group compared to 16 in those receiving PC-EC (16% vs 11%, p > 0.05). Patients with febrile neutropenia treated with PC-EC/Pembro had more severe clinical presentations as assessed by the MASCC score (18 vs 24; p = 0.01), had worse physiological parameters (NEWS2 at presentation 3 vs 2; p = 0.023) and had a longer length of hospital stay (median 5 days vs 0 days; p = 0.044). There were no deaths at 30 or 90 days in either cohort. CONCLUSION: Triple-negative breast cancer patients receiving neoadjuvant pembrolizumab in addition to PC-EC appear to have more severe presentations with febrile neutropenia. This may necessitate greater caution in pathways for ambulatory management for this cohort
Immune-mediated hepatitis requiring second-line immunosuppression: how long is required? an observational study
No full textBACKGROUND: Immune-mediated hepatitis is a common toxicity and accounts for ⁓20% of immune checkpoint inhibitor (ICI) related deaths. There is broad consensus as to the current approach for acute management for immune-mediated hepatitis. There is little data regarding the duration of immunosuppression in severe immune-mediated hepatitis. METHODS: A prospective observational analysis was performed at a specialist oncology hospital in England from 20th May 2018 to 19th April 2024. The need for second-line immunosuppression, the agents used and their duration were analyzed. The primary outcome was duration of second-line immunosuppression and whether there was a relapse in immune-mediated hepatitis following their cessation. RESULTS: During the study period, 82 patients presented with grade ≥3 immune-mediated hepatitis. Thirty-five (42.7%) had grade 3 hepatitis with 47 (57.3%) having grade 4 hepatitis. All patients received corticosteroids as first line treatment. Twenty-six (31.7%) patients required second-line immunosuppression therapy with mycophenolate mofetil. Four of those required further immunosuppression with a calcineurin inhibitor. The cohort requiring second-line immunosuppression had higher transaminases (mean alanine aminotransferase (ALT) = 889 u/L vs 677 u/L) at presentation. The median duration of therapy was 3 months (6 weeks to 22 months); all patients except for one had stopped their immunosuppression at 6 months. Ten patients who initially received combination ICI therapy had a rechallenge with maintenance nivolumab without a relapse of their hepatitis. CONCLUSION: Most patients with ICI-mediated hepatitis respond to first line immune suppression but approximately one third require second line therapy. Most patients discontinued immune suppression within 3 months. Key messages What is already known on this topic: Hepatitis is a common complication of immune checkpoint inhibition often requiring treatment with steroids and immunosuppression. What this study adds: This prospective observational study of patients presenting with severe ICI induced hepatitis found 26 (31.7%) patients required second-line immunosuppression therapy with a further four requiring third-line agents. The median duration of therapy was 3 months. How this study might affect practice: Most patients with ICI induced hepatitis respond to first line immune suppression but approximately one third require second line therapy, which can often be stopped 3 months post initiation
Tislelizumab (TIS) plus chemotherapy (CT) vs placebo (PBO) plus CT in patients (pts) with locally advanced (LA) esophageal squamous cell carcinoma (ESCC): RATIONALE-306 subgroup analysis
No full textMacro microscopic comparison of tumor thickness and anatomical levels of invasion in resected penile carcinomas
No full textPatient specific verification of steep dose gradients in proton therapy using 3D-printed phantom and Gafchromic film
No full textNorth of England Women's Diet and ActivitY - After Breast Cancer (NEWDAY-ABC) intervention in women diagnosed with early oestrogen-positive, HER2-negative breast cancer: a randomised controlled feasibility study
No full textBACKGROUND: Excess body weight is associated with higher breast cancer mortality rate. This study assessed the feasibility of a co-designed weight loss intervention (NEWDAY-ABC) versus standard care in early-stage oestrogen receptor-positive, human epidermal growth factor receptor 2-negative breast cancer patients. METHODS: This was a two-arm, parallel group, randomised controlled feasibility study. Twenty-one ER + ve, HER2-ve stages I-III breast cancer patients, within 3 years of completing primary treatment (excluding endocrine therapy), were recruited from two UK National Health Service Breast Care Units and randomised (2:1) to intervention plus standard care or standard care alone. The intervention was co-designed with patients and comprised small group-based Support & Skills workshops delivered remotely via teleconference by trained lifestyle advisors and dieticians. Feasibility outcomes included recruitment rate, data quality, intervention acceptability and adherence. Exploratory clinical outcomes included weight loss, anthropometric measures, dietary change, physical activity and patient-reported outcomes. RESULTS: Twenty-one women consented to the study, and 1 withdrew prior to randomisation, leaving 13 in the intervention group and 7 standard care controls, with 11 participants being followed up for 6 months. The overall attendance rate for intervention sessions was 79.6% (74/93 sessions completed). Body weight (candidate primary outcome for a fully powered randomised controlled trial) was reduced in the intervention group by 3.3 kg from baseline to 6 months, versus a 1.1 kg loss of body weight in the standard care control group. Furthermore, the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC-QLQ30) breast module symptom scale scores for breast and arm symptoms improved in the intervention arm only, accompanied by positive changes in physical activity and dietary behaviours. CONCLUSION: The NEWDAY-ABC intervention is feasible and showed preliminary evidence of efficacy in terms of weight loss and other important health outcomes in women with early-stage breast cancer. The clinical and cost-effectiveness of the intervention versus standard care now needs to be robustly evaluated via an adequately powered clinical trial. TRIAL REGISTRATION NUMBER: ISRCTN15088551, registered 3 February 2020
Senolysis by ABT-263 is associated with inherent apoptotic dependence of cancer cells derived from the non-senescent state
No full textCellular senescence is a stress response that cells can employ to resist cell death. Senescent cells rely on anti-apoptotic signaling for their survival, which can be targeted by senolytic agents, like the BCL-XL, BCL-2, BCL-W inhibitor ABT-263. However, the response to ABT-263 of senescent cancer cells ranges from highly sensitive to refractory. Using BH3 profiling, we identify here apoptotic blocks in cancer cells that are resistant to this senolytic treatment and discover a correlation between mitochondrial apoptotic priming and cellular sensitivity to ABT-263 in senescence. Intriguingly, ABT-263 sensitivity correlates with overall mitochondrial apoptotic priming, not only in senescence but also in the parental state. Moreover, we confirm that ABT-263 exposure increases dependency on MCL-1, which is most enhanced in ABT-263 sensitive cells. ABT-263 resistant cells however upregulate MCL-1, while sensitive cells exhibit low levels of this anti-apoptotic protein. Overall, our data indicate that the response of senescent cells to ABT-263 is predetermined by the mitochondrial apoptotic priming state of the parental cells, which could serve as a predictive biomarker for response to senolytic therapy
