The Christie School of Oncology: Christie Research Publications Repository
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Impact of assumptions in causal inference: estimating the effect of mean dose to the medulla oblongata on dysphagia after head and neck radiotherapy
No full textMolecular profiling success in advanced cholangiocarcinoma (CCA) based on tumour acquisition method
No full textGlucagon-like peptide-1 (GLP-1) receptor agonists and cancer prevention: methodological pitfalls in observational studies
No full textBACKGROUND: Obesity, commonly approximated by body mass index (BMI) ≥ 30 kg/m(2), is causally associated with at least 13 cancer types (obesity-related cancers) but it is unclear whether weight loss interventions among obese individuals result in risk reduction of cancer. Recently, several trials of short-term use of glucagon-like peptide-1 (GLP-1) receptor agonists, originally designed for use as anti-diabetes medications, have shown substantial weight loss outcomes compared with placebo. Notably, high-dose semaglutide is associated with approximately 15% weight loss in individuals with obesity without diabetes. With these impressive results, hypotheses are emerging that these drugs might have a role in the prevention of obesity-related cancers, mediated through weight loss. OBJECTIVES/METHODS: The aim of this opinion paper is to critically appraise the methodological challenges and pitfalls associated with studying the question 'does weight loss through use of GLP-1 receptor agonists reduce cancer risk' through observational studies, and exemplify this through critique of a recent study published in this journal. RESULTS: We modified the ROBINS-E framework for assessing risk of bias, identifying seven methodological criteria specific to this research question, against which data should be interpreted. These include adequate adjustment for key parameters of body fatness; immortal time bias; treatment allocation bias; survival bias; cumulative drug dose effect; sufficient sojourn time between drug intervention and cancer presentation; and treatment effect specific to obesity-related cancers. We found that 6 out of 7 methodological criteria were at high risk of bias. CONCLUSIONS: Cancer prevention through GLP-1 receptor agonist use should be explored; however, there are several methodological challenges to overcome in understanding this link before it can inform clinical practice and policy
Impaired plasma membrane calcium ATPase activity and mitochondrial dysfunction contribute to calcium dysregulation in Fabry disease-related painful neuropathy
No full textNeuropathic pain is a hallmark symptom in Fabry disease (FD), a hereditary X-linked lysosomal storage disorder caused by a reduced activity of alpha-galactosidase A (alpha-Gal A). The alpha-Gal A deficiency results in the progressive accumulation of globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3) in the body fluids and lysosomes of various cell types, including sensory ganglia. The FD neuropathy affects the small thinly myelinated A delta fibers and unmyelinated C fibers leading to the loss of intra-epidermal neuronal terminations, along with altered thermal and mechanical perception. Lipid accumulation, such as Gb3 and lyso-Gb3, is implicated in various cellular dysfunctions, including the alteration of ionic currents. It has been shown that administration of Gb3 to human umbilical vein endothelial cells leads to the downregulation of the calcium (Ca2+)-activated K+ channel KCa3.1, whereas lyso-Gb3 evokes cytosolic Ca2+ transients and an enhancement of voltage-activated Ca2+ currents in murine dorsal root ganglia. Therefore, we examined the mechanism underlying Ca2+ regulation in primary afferent neurons from the alpha-Gal A (-/0) mouse model. The obtained results suggest that other transport proteins participate in Ca2+ homeostasis in FD and their dysfunction may be directly involved in nociception. In this context, plasma-membrane Ca2+ ATPases exhibited reduced activity in FD, leading to an increased resting [Ca2+]i in sensory neurons. The reduced activity was associated with a decrease of cytosolic pH which weakened the PMCA-dependent calcium extrusion. We finally evaluated the contribution of mitochondria to the Ca2+ signalling and we observed impairment of the mitochondrial buffer capacity, as well as dysfunctional mitochondria and enhanced autophagy/mitophagy. These findings provide a basis for future insights into the alterations of calcium signalling underlying the onset of neuropathic symptoms in FD
Glucocorticoids unleash immune-dependent melanoma control through inhibition of the GARP/TGF β axis
No full textHalf of patients with advanced melanoma fail to benefit from immune checkpoint blockade, and novel treatments are urgently required. Testing topical medications for anticancer activity in an immunotherapy-resistant murine melanoma model, we found that, counterintuitively, glucocorticoids (GCs) elicit rapid cytotoxic T lymphocyte (CTL)-dependent tumor control. Genetic ablation of the GC receptor in different cellular compartments revealed that GCs acted not on immune cells but directly on tumor cells to downregulate the expression of glycoprotein A repetitions predominant (GARP). This inhibited TGF β signaling and unleashed CTL killing. In agreement, GCs stimulated tumor control in multiple cancer models but only if the tumors also responded to pharmacologic inhibition of TGF β signaling. Furthermore, patients with melanoma with high GC receptor expression or signaling showed improved prognosis and lower TGF β signaling in tumor-infiltrating CTLs. Additionally, elevated GARP expression correlated with reduced survival, including in immunotherapy-treated patients. Thus, the GARP/TGF β axis emerges as a GC-sensitive cancer cell-intrinsic immune-evasive mechanism. SIGNIFICANCE: This study uncovers a surprising role for GCs in triggering CD8+ T cell-dependent tumor control through downregulation of GARP and thus TGF β signaling. Analysis of samples from patients with melanoma suggested that GARP expression may serve as both a biomarker of poor antitumor immunity and a therapeutic target to improve the response to immunotherapy
A patient reported outcome measure for rectal cancer patients eligible for organ preservation: Development and validation of a Watch-and-Wait module for the Assessment of Burden of disease in ColoRectal Cancer (ABCRC) tool
No full textAIM: The Assessment of Burden of ColoRectal Cancer (ABCRC)-tool is an integrated tool, developed in conjunction with colorectal cancer (CRC) patients, that measures the experienced burden of disease and lifestyle parameters and visualizes the results. To provide tailored follow-up care for watch-and-wait (WW) patients, in line with their specific needs and preferences, a WW module for the ABCRC-tool was developed. In this paper we describe the development and validation process of the WW module. METHODS: This study followed a multistep approach. First, a three-round Delphi survey was conducted with both patients and healthcare professionals (HP). Participants were asked to score common RC outcomes that emerged from qualitative interviews with patients and a targeted literature review. Based on included items, appropriate questions were formulated. Reliability was tested by assessing test-retest reliability, defined by Intra Class Correlation. Construct validity was evaluated by hypothesis testing. RESULTS: A total of 128 participants (75 patients and 53 HP) from four countries (UK, Brazil, Portugal and Netherlands) participated in the Delphi survey which included 41 items. After the consensus meeting seven outcomes and appropriate questions (including anxiety, fear of recurrence, fear of surgery, fear of stoma, fecal incontinence, urgency and happiness) were included in the WW module. Validity and reliability testing was completed by 50 Dutch WW patients. The ABCRC-WW module demonstrated sound construct validity and reliability. CONCLUSION: This study demonstrates good psychometric properties of the ABCRC-WW tool. This tool has the potential to facilitate patient-clinician communication, enhance patients' understanding of their condition, and enable individualized care through direct feedback
Randomised phase-2 screening trial of intermittent energy restriction plus resistance exercise versus resistance exercise alone during chemotherapy for advanced breast cancer
No full textBACKGROUND: Weight control and energy restriction could improve survival in patients with advanced breast cancer (ABC) but randomised data are lacking. A randomised screening trial was conducted to assess an intermittent energy restricted diet and resistance exercise intervention (IER + RE) vs RE alone (RE) on progression free survival (PFS), toxicity and Quality of Life (QoL) during chemotherapy for ABC. METHODS: Sixty-eight women were randomised to IER + RE (n = 35) or RE (n = 33) with one-sided significance assessed at the 20% threshold. The primary end point was PFS secondary endpoints included chemotherapy toxicity, weight change and QoL. RESULTS: The adjusted hazard rate for progression comparing IER + RE vs RE was 0.729 (0.391-1.361) and the median PFS 42.0 vs 26.1 weeks respectively (p = 0.160). Toxicity was low and comparable between groups. Comparing IER + RE vs RE alone at cycle 3 the median (interquartile range) changes were: weight -1.8 kg (-4.2 to -0.7) vs +0.2 kg (-0.74, 2.59) (p < 0.001), FACT-B + 4.0 (-0.8, 11) vs +1.0 (-4.0, 4.0) (p = 0.031) and Hospital Anxiety Depression Score -2.0 (-3.5, +0.5) vs +1.0 (-2, 3.5) (p = 0.022). CONCLUSION: IER + RE improved PFS and QoL without evidence of harms warranting a further larger randomised study in ABC. TRIAL REGISTRATION: https://www.isrctn.com/ISRCTN12841416
Pembrolizumab in patients with advanced clear cell gynecological cancer: a phase 2 nonrandomized clinical trial
No full textIMPORTANCE: Advanced clear cell gynecological cancers (CCGCs) have a poor prognosis, with response rates to second-line chemotherapy less than 8%. Preliminary clinical activity with programmed cell death 1 protein (PD-1) inhibitors reported in CCGC merits further investigation. OBJECTIVE: To assess the clinical benefit of pembrolizumab in patients with previously treated advanced CCGC. DESIGN, SETTING, AND PARTICIPANTS: The PEACOCC trial is a single-arm multicenter phase 2 trial conducted at 5 UK centers investigating the clinical benefit and safety of pembrolizumab. PD-1 inhibitor-naive patients with histologically confirmed advanced CCGC, radiological disease progression following 1 or more prior courses of chemotherapy, and an Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0 to 1 were included. Patients were enrolled from March 2019 to October 2021, with data collected until July 2024. INTERVENTIONS: Pembrolizumab, 200 mg, intravenously every 21 days up to 2 years until progression, discontinuation due to toxic effects, or patient/clinician decision. Up to 1 year of retreatment on diseases progression, if stable disease, partial response, or complete response at 2 years. MAIN OUTCOMES AND MEASURES: The primary end point was progression-free survival (PFS) rate at 12 weeks using Response Evaluation Criteria in Solid Tumors version 1.1 to detect a 12-week PFS rate of 33% or greater and exclude a PFS rate of less than 15%, with 90% power and 1-sided 5% significance level. Secondary end points included objective response rate, duration of response, PFS, overall survival, safety, and quality of life. RESULTS: A total of 48 patients were eligible. The median (range) age was 58.5 (32-77) years, and 26 (54%) had an ECOG PS score of 0 and 22 (46%) had an ECOG PS score of 1; 41 (85%) had ovarian, 6 (13%) had endometrial, and 1 (2%) had cervical advanced CCGC. The median (range) courses prior therapy was 3 (1-6); 19 patients (40%) received prior anti-angiogenic therapy, and 19 (40%) had a platinum-free interval of more than 12 months. Grade 3 treatment-related adverse events were observed in 9 patients (19%), and no patients had grade 4 or 5 adverse events. A total of 45 of 46 patients (98%) had mismatch repair-proficient tumors. The 12-week PFS rate was 42% (95% CI, 28-57), and the best objective response rate was 25% (95% CI, 14-40), with 12 partial responses. After a median follow-up of 46.9 months (95% CI, 43.4-55.0), the median PFS was 2.7 months (95% CI, 1.3-5.4), and the median overall survival was 14.8 months (95% CI, 6.7-28.2). CONCLUSIONS AND RELEVANCE: The PEACOCC trial showed clinical benefit with pembrolizumab in patients with previously treated advanced CCGC, of whom all except 1 had MMR-proficient disease. Clinical outcomes were durable with an overall tolerable safety profile, justifying further evaluation of pembrolizumab monotherapy for advanced CCGC in a randomized clinical trial. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03425565
Testing patterns, patient and tumour characteristics and survival by NRAS and KIT genotype in melanoma
No full textBACKGROUND: NRAS and KIT mutations in melanoma bring implications for prognosis, follow-up, selection into trials and potential future treatment with targeted therapies. The frequency of NRAS/KIT mutations and their association with patient/tumour characteristics and survival is poorly documented. OBJECTIVES: To report national data from England on, (1) the frequency of NRAS and KIT mutations, (2) the association of patient/tumour characteristics with NRAS and KIT mutations, and (3) survival of patients with NRAS and KIT mutations. METHODS: This retrospective cohort study identified all new melanomas diagnosed in England from 2016-2021 and molecular NRAS/KIT testing using data from the National Disease Registration Service. Multivariate logistic regression determined the association between a) NRAS and KIT testing with patient/tumour characteristics, b) NRAS genotype with patient/tumour characteristics. Age-standardised net survival (NS) analysed melanoma-specific mortality by NRAS and KIT genotype. RESULTS: Of new melanomas diagnosed, 6.6% (6045/91415) and 3.0% (2705/91415) had a NRAS and KIT test registered. The proportion of successfully tested tumours NRAS and KIT mutated were 30.8% (1811/5887) and 5.8% (148/2560). East of England NRAS tested the highest proportion of cutaneous tumours (11.2% (1114/9950)) compared to the lowest in the North West (1.4% (172/12296)). Elderly patients were more likely to have NRAS mutations (OR 1.01, 95%CI 1.01-1.02). Females (OR 0.81, 95%CI 0.71-0.91) and head/neck melanomas (OR 0.37, 95%CI 0.31-0.44) were less likely to have NRAS mutations. There was no significant difference in 5-year NS between all-stage NRAS WT and mutated tumours (WT NS 62.3%, 95%CI 58.9-65.9 vs mutated NS 58.5%, 95%CI 54.0-63.4). Similarly, there was no significant difference in 5-year NS between KIT WT and mutated tumours (WT NS 50.4%, 95% CI 44.7-57.3 vs mutated NS 52.1%, 95% CI 37.1-73.2). CONCLUSIONS: This is the largest national dataset on melanoma NRAS and KIT status published to date. Variations in NRAS/KIT testing by geographic/demographic factors drives initiatives to ensure consistent care. NRAS mutated melanoma had high incidence which emphasises the unmet need to develop therapies and trials for NRAS mutated melanoma. This study increases our understanding of biomarkers NRAS and KIT and provides a foundation for optimising melanoma care, contributing to advancements in precision oncology