The Christie School of Oncology: Christie Research Publications Repository
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LCNEC Foundations: defining care and improving UK outcomes for high grade pulmonary large cell neuro-endocrine carcinomas (LCNEC)
No full textSix at sixty. malignant peripheral nerve sheath tumours in NF1: 20-year review of a highly cited paper
No full textResponse to 'letter to editor-in-chief' and 'redefining resectability: bridging perspectives in stage III NSCLC management'
No full textAvelumab first-line (1L) maintenance therapy in advanced urothelial carcinoma: Final analysis from a real-world study in the UK
No full textConsensus and controversies about diagnosing GH deficiency: a Delphi survey by the GH research society
No full textPURPOSE: Biochemical tests are required for diagnosing GH-deficiency in children and adults, but controversies remain regarding diagnostic criteria and type of biochemical tests. The aim of the study is to map the clinical practices of GHD diagnosis in children and adults. METHODS: The Growth Hormone Research Society members initiated a Delphi survey of the diagnosis of GHD in children and adults. Pediatric (n = 18) and adult (n = 25) endocrinologists from 14 countries participated and rated their extent of agreement with 61 statements using a Likert-type-scale (1-7). Consensus was predefined as ≥ 80% of panelists rating their agreement unidirectionally as either ≥ 5 (agreement) or ≤ 3 (disagreement). RESULTS: The pediatric panel reached consensus on 17 of 29 (59%) statements on diagnosis in children, whereas the adult panel reached consensus on 28 of 32 (88%) statements on adult patients. There was general agreement to test for GHD in an appropriate clinical context and also on the timing of testing for GHD in both children and adults. A subnormal IGF-I level was considered diagnostic in both children and adults with panhypopituitarism. In children, there was consensus to recommend the arginine stimulation test and the glucagon test. The insulin tolerance test (ITT) was considered gold standard in adults and there was also consensus to recommend the macimorelin test. A stimulated GH cut-off < 5μg/l was consistent with severe GHD in children, whereas test-specific cut-offs were recommended in adults. CONCLUSION: Consensus on the GHD diagnosis was lower in pediatric practice, mainly with respect to choice and interpretation of GH stimulation tests
Evaluating variant pathogenicity prediction tools to establish African inclusive guidelines for germline genetic testing
No full textBACKGROUND: Genetic germline testing is restricted for African patients. Lack of ancestrally relevant genomic data perpetuated by African diversity has resulted in European-biased curated clinical variant databases and pathogenic prediction guidelines. While numerous variant pathogenicity prediction tools (VPPTs) exist, their performance has yet to be established within the context of African diversity. METHODS: To address this limitation, we assessed 54 VPPTs for predictive performance (sensitivity, specificity, false positive and negative rates) across 145,291 known pathogenic or benign variants derived from 50 Southern African and 50 European men matched for advanced prostate cancer. Prioritising VPPTs for optimal ancestral performance, we screened 5.3 million variants of unknown significance for predicted functional and oncogenic potential. RESULTS: We observe a 2.1- and 4.1-fold increase in the number of known and predicted rare pathogenic or benign variants, respectively, against a 1.6-fold decrease in the number of available interrogated variants in our European over African data. Although sensitivity was significantly lower for our African data overall (0.66 vs 0.71, p = 9.86E-06), MetaSVM, CADD, Eigen-raw, BayesDel-noAF, phyloP100way-vertebrate and MVP outperformed irrespective of ancestry. Conversely, MutationTaster, DANN, LRT and GERP-RS were African-specific top performers, while MutationAssessor, PROVEAN, LIST-S2 and REVEL are European-specific. Using these pathogenic prediction workflows, we narrow the ancestral gap for potentially deleterious and oncogenic variant prediction in favour of our African data by 1.15- and 1.1-fold, respectively. CONCLUSION: Although VPPT sensitivity favours European data, our findings provide guidelines for VPPT selection to maximise rare pathogenic variant prediction for African disease studies
Integration of dose surface maps and genetic data identifies the lower posterior rectum as a key region for toxicity after prostate cancer radiotherapy
No full textPurpose: Genome-wide association studies are the gold standard for identifying SNP associated with rectal toxicity after prostate cancer radiotherapy. However, they often neglect the radiotherapy dose distribution, which is a key contributor to toxicity risk. Here, we combined rectal dose surface maps with genetic data to identify rectal regions in which variants influence dose-toxicity relationships. Experimental Design: Data were analyzed from 1,293 patients with prostate cancer from the REQUITE study. Deep learning rectum contouring ensured consistent segmentation, and rectum lengths were standardized to generate two-dimensional dose surface maps. Patients were categorized based on the presence of risk alleles for three candidate SNP (rs1801516, rs17055178, and rs17630638). Propensity score matching accounted for age, rectal volume, prostate volume, and hormone therapy. Voxel-wise Cox proportional hazards models with permutation testing assessed dose-toxicity associations. Results: Voxel-wise Cox proportional hazards models revealed significant (P < 0.05) dose-toxicity associations in risk allele carriers for all SNP for bowel urgency. Risk regions were consistently in the lower posterior rectum. Higher risk of acute bowel control was identified among carriers of the risk allele for rs17630638. For this SNP, carriers of the risk allele showed a higher risk for late rectal bleeding but a reduced risk for acute rectal bleeding. Conclusions: This study identified genotype-driven toxicity patterns using spatial dose mapping. By revealing consistent high-risk rectal regions, this approach strengthens the link between genomics and radiotherapy planning. Importantly, modern radiotherapy planning makes it feasible to reduce dose in genetically sensitive patients and move toward more personalized treatment
An Advanced Clinical Practitioner And Specialist Clinical Pharmacist-Led Outpatient Service To Deliver Maintenance Poly (ADP-Ribose) Polymerase Inhibitors Therapies To Treat Women With Advanced-Stage Or Relapsed, Platinum-Sensitive High-Grade Epithelial Ovarian Cancer
No full textDNGR-1 regulates proliferation and migration of bone marrow dendritic cell progenitors
No full textConventional dendritic cells (cDCs) are sentinel cells that play a crucial role in both innate and adaptive immune responses. cDCs originate from a progenitor (pre-cDC) in the bone marrow (BM) that travels via the blood to seed peripheral tissues before locally differentiating into functional cDC1 and cDC2 cells, as part of a process known as cDCpoiesis. How cDCpoiesis is regulated and whether this affects the output of cDCs is poorly understood. In this study, we show that DNGR-1, an innate immune receptor expressed by cDC progenitors and type 1 cDCs, can regulate cDCpoiesis in mice. In a competitive chimera setting, cDC progenitors lacking DNGR-1 exhibit increased proliferation and tissue migratory potential. Compared with their WT counterparts, DNGR-1-deficient cDC progenitor cells display superior colonization of peripheral tissues but an altered distribution. These findings suggest that cDCpoiesis can be regulated in part by precursor cell-intrinsic processes driven by signals from innate immune receptors such as DNGR-1 that may respond to alterations in the BM milieu
Correction to 'New systemic treatment paradigms in advanced biliary tract cancer and variations in patient access across Europe' [The Lancet Regional Health - Europe, volume 50, March 2025, 101170]
No full text[This corrects the article DOI: 10.1016/j.lanepe.2024.101170.]