The Christie School of Oncology: Christie Research Publications Repository
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Deciphering lung adenocarcinoma evolution and the role of LINE-1 retrotransposition
No full textUnderstanding lung cancer evolution can identify tools for intercepting its growth. In a landscape analysis of 1024 lung adenocarcinomas (LUAD) with deep whole-genome sequencing integrated with multiomic data, we identified 542 LUAD that displayed diverse clonal architecture. In this group, we observed an interplay between mobile elements, endogenous and exogenous mutational processes, distinct driver genes, and epidemiological features. Our results revealed divergent evolutionary trajectories based on tobacco smoking exposure, ancestry, and sex. LUAD from smokers showed an abundance of tobacco-related C:G>A:T driver mutations in KRAS plus short subclonal diversification. LUAD in never smokers showed early occurrence of copy number alterations and EGFR mutations associated with SBS5 and SBS40a mutational signatures. Tumors harboring EGFR mutations exhibited long latency, particularly in females of European-ancestry (EU_N). In EU_N, EGFR mutations preceded the occurrence of other driver genes, including TP53 and RBM10. Tumors from Asian never smokers showed a short clonal evolution and presented with heterogeneous repetitive patterns for the inferred mutational order. Importantly, we found that the mutational signature ID2 is a marker of a previously unrecognized mechanism for LUAD evolution. Tumors with ID2 showed short latency and high L1 retrotransposon activity linked to L1 promoter demethylation. These tumors exhibited an aggressive phenotype, characterized by increased genomic instability, elevated hypoxia scores, low burden of neoantigens, propensity to develop metastasis, and poor overall survival. Reactivated L1 retrotransposition-induced mutagenesis can contribute to the origin of the mutational signature ID2, including through the regulation of the transcriptional factor ZNF695, a member of the KZFP family. The complex nature of LUAD evolution creates both challenges and opportunities for screening and treatment plans
Author Correction: Dose escalation and expansion cohorts in patients with advanced breast cancer in a Phase I study of the CDK7-inhibitor samuraciclib
No full textHSD3B1 and overall survival (OS) in high-risk non-metastatic (M0) and metastatic (M1) prostate cancer starting androgen deprivation therapy (ADT) in the enzalutamide (ENZ) and abiraterone acetate plus prednisolone (AAP) STAMPEDE phase 3 trial
No full textInitial results of a CRUK phase I/II, first in human trial of the CAR t-cell engager protein aleta-001 in patients who have received anti-CD19 CAR t-cell therapy for the treatment of b-cell malignancies
No full textHello healthcare: evaluating the impact of a healthcare conference for secondary school pupils
No full textBACKGROUND: There are over 350 careers within healthcare. However, in the United Kingdom, opportunities are limited for secondary school pupils to learn about a variety of healthcare careers. We aimed to address this by delivering an in-person regional conference on healthcare careers for Year 10 pupils from widening participation (WP) backgrounds. This 'Hello Healthcare Conference' enabled pupils to gain insight into a range of careers within healthcare. We explored the impact of the conference on pupils' self-reported knowledge, skills, and attitudes to healthcare careers. METHODS: We conducted a pre-test-post-test study of 44 pupils from WP backgrounds who attended Hello Healthcare to evaluate the effectiveness of the conference. A five-point Likert scale confidence questionnaire was used to evaluate the impact of Hello Healthcare on school pupils' self-reported knowledge, skills, and attitude to healthcare careers. A Shapiro-Wilk test revealed a lack of normal distribution (p < 0.05); therefore, the pre-test-post-test results for each pupil were compared using a Wilcoxon signed-rank test. RESULTS: 44 Year 10 pupils from WP backgrounds across 4 schools were included in this study. Self-reported knowledge of most healthcare careers improved after the conference. Pupils' perception of having the necessary skills for a healthcare career significantly increased, with Z = -5.78, p < 0.001, and large effect size (r = -0.87). Pupils' perception that they could successfully apply for a healthcare course increased (Z = -5.52, p < 0.001, r =-0.83). CONCLUSIONS: The Hello Healthcare conference was beneficial in improving pupils' awareness and attitudes towards healthcare careers and demonstrated an effective method by which to address the limited perceived knowledge WP pupils may have. Government and universities need to support and invest in the Hello Healthcare conference concept to replicate the impact of the intervention in other regions of the UK
Performance against quality indicators in the initial assessment of patients with respiratory infections in acute medicine services
No full textINTRODUCTION: Hospital attendances due to respiratory infection peak in winter, contributing to pressures within acute services. We assessed the prevalence of suspected respiratory infection within acute medical admissions during winter and evaluated performance against recommendations for initial assessment. METHODS: Data were collected through the Society for Acute Medicine (SAM) Benchmarking Audit, comprising a hospital-level survey and 24-hour patient-level data collection for unplanned acute medical attendances on 22 February 2024. Performance metrics assessed included those from the SAM's clinical quality indicators (CQI) for medical admissions, and British Thoracic Society (BTS) guidelines for community acquired pneumonia. RESULTS: Data were available for 4390 patients at 76 hospitals. Suspected respiratory infections accounted for 22.8% of all unplanned medical attendances; these patients were older (age ≥70 years: 58.2% vs 44.7%, p<0.001) and had higher National Early Warning Score 2 (NEWS2) scores (NEWS2 ≥3: 63.8% vs 23.8%, p<0.001) than those without respiratory infection; they were more likely to be assessed in the emergency department (80.8% vs 63.7%, p<0.001), and had lower rates of discharge without overnight admission (14.9% vs 35.9%, p<0.001). 71.0% of patients underwent a chest X-ray within 4 hours of arrival; 27.0% were reported within 12 hours. Antibiotics were administered ≥4 hours from arrival in 32.9%. Performance against these indicators varied between hospitals. Nine hospitals (12.7%) had a separate respiratory admission service; this was not associated with improved performance against SAM CQIs or BTS guidance. CONCLUSION: Respiratory infections contribute significantly to acute medical attendances via the emergency department. There remains significant scope to improve key steps in initial assessment and management
Skin radiotherapy as part of a training programme for dermatology residents in the UK: 2024 update
No full textA new prognostic index (CLIPI) for advanced cutaneous lymphoma enables precise patient risk stratification
No full textAdvanced mycosis fungoides (MF) and Sézary syndrome (SS) have a poor overall survival (OS) of 60 years (P < .001), raised serum lactate dehydrogenase (P = .005), and large-cell transformation in skin (P = .006). Modeling these 4 independent risk factors into a CLIPI found that there was a worse OS in high- vs low-risk (P < .001), high- vs intermediate-risk (P = .002) and intermediate- vs low-risk (P = .010) groups. Five-year OS was 63.3%, 44.7%, and 18.3% in the low-, intermediate-, and high-risk groups, respectively. In this advanced stage cohort there was a low 5-year survival and increasing stage was not associated with worsening survival. The use of CLIPI to stratify patients into risk groups has the potential to improve outcomes and aid optimal treatment selection. This trial was registered at www.ClinicalTrials.gov as #NCT02848274
Prevalence of contralateral lymphatic drainage patterns during sentinel lymph node biopsy for truncal melanoma: a retrospective, observational study
No full textBACKGROUND AND PURPOSE: This study aimed to examine the prevalence, patterns, and outcomes of contralateral lymphatic drainage during sentinel lymph node biopsy (SLNB) in patients with truncal melanoma. Understanding this phenomenon is crucial for improving surveillance and management strategies for melanoma patients. SUBJECTS AND METHODS: This retrospective cohort study analysed 1308 consecutive patients aged 18 years and over who underwent wide local excision (WLE) for truncal melanoma followed by SLNB at The Christie Hospital, Manchester, UK, between October 2006 and November 2024. Exclusions included non-truncal melanoma and cases without lymphoscintigraphy data. SLNB evolved from intradermal injections of blue dye to include radiolabelled Technetium-99m-nano colloid. Contralateral drainage was defined as sentinel lymph nodes draining exclusively to the opposite side of the coronal midline relative to the WLE scar. Data were correlated with imaging results and patient outcomes. MAIN FINDINGS: Contralateral drainage occurred in 14 patients (1.1%). This subgroup had melanoma thicknesses ranging from 0.80 to 6.40 mm and included 8 males and 6 females (ages 26-72 years). Notably, 10 cases involved posterior torso melanomas, with 6 located on the lower back. Three patients (21.4%) experienced melanoma recurrence during follow-up, all on the ipsilateral side. One patient treated in 2007 died following recurrence, while 2 patients treated in 2018 and 2021 remain alive following immunotherapy. CONCLUSIONS: Contralateral sentinel lymph node drainage, though rare, highlights the need for tailored surveillance strategies for patients with truncal melanoma, particularly those with posterior torso lesions. These findings underscore the importance of incorporating this data into patient consent and individualised care plans