Cancer Services

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Research outputs from Cancer Services at the RD&E.

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Now showing 1 - 5 of 24
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    Selection of patients with malignant melanoma for pelvic lymph node dissection (PLND) using CT-PET
    (Elsevier, 2023-12-01) Ali, T.; Powell, R.; Short, J.; Scatchard, K.; Stone, C.
    OBJECTIVES: In melanoma patients with positive pelvic nodes, pelvic lymph node dissection (PLND) to achieve fully resected disease status facilitates adjuvant-dose systemic therapy and avoids higher treatment doses with greater toxicity. This study aimed to test the accuracy of prediction of nodal involvement of the 2010 joint BAPRAS/BAD guidance compared with Positron Emission Tomography (CT-PET). METHODS: A retrospective review was undertaken of 26 melanoma patients undergoing PLND by a single surgeon between July 2012 and July 2020. The indications for performing PLND were in accordance with the 2010 guidance, but this was supplemented by CT-PET in 16/26 patients. RESULTS: Of the 26 patients undergoing PLND, 10 underwent surgery based upon the 2010 criteria alone and 16 underwent supplementary CT-PET. 17 patients had positive nodes on histology; of these, 13 had a positive CT-PET. Amongst node-negative patients, only one had a false positive CT-PET. CT-PET was 100% sensitive for pelvic nodal disease and 75% specific, with a positive predictive value for nodal involvement of 92%. Of the 10 patients who underwent PLND without CT-PET, only 4 had positive nodes while 6 patients had negative nodes. CONCLUSIONS: The 2010 guidelines remain broad and contributed to negative PLND in a third of our patients (9/26). Hence, the indications for performing PLND need to be revisited. Our series supports PET-CT as being 100% sensitive in the identification of pelvic nodal disease and 75% specific. We recommend that a positive PET-CT should be considered as the primary indication for PLND in melanoma patients.
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    Use of cytology fluid samples for predictive biomarker testing in lung cancer patients
    (Wiley, 2023-12-01) Hawkins, P.; Stevenson, T.; Powari, M.
    OBJECTIVE: To provide a method of directly using cytology fluid samples for predictive biomarker testing in lung cancer patients and to determine the efficacy of a variety of fluid sample types. METHOD: A review of our in-house data from a range of cytology samples including endobronchial ultrasound (EBUS) fine-needle aspirate (FNA) needle washings (NW) and serous effusions tested on the Biocartis Idylla platform. All fluid samples were originally tested using Sanger sequencing. RESULTS: Using our method for fluid samples all of our cytology samples tested for epithelial growth factor receptor (EGFR) yielded valid results on this platform and all variant cases identified. The data showed serous fluids provided the best quality DNA, and variant genotype reports were obtained within 150 minutes. CONCLUSION: Cytology fluid samples can be used for predictive biomarker testing for lung cancer patients to provide in-house results with all fluids providing good-quality DNA.
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    Tamoxifen for the treatment of myeloproliferative neoplasms: A Phase II clinical trial and exploratory analysis
    (Nature, 2023-11-25) Fang, Z.; Corbizi Fattori, G.; McKerrell, T.; Boucher, R. H.; Jackson, A.; Fletcher, R. S.; Forte, D.; Martin, J. E.; Fox, S.; Roberts, J.; Glover, R.; Harris, E.; Bridges, H. R.; Grassi, L.; Rodriguez-Meira, A.; Mead, A. J.; Knapper, S.; Ewing, J.; Butt, N. M.; Jain, M.; Francis, S.; Clark, F. J.; Coppell, J.; McMullin, M. F.; Wadelin, F.; Narayanan, S.; Milojkovic, D.; Drummond, M. W.; Sekhar, M.; ElDaly, H.; Hirst, J.; Paramor, M.; Baxter, E. J.; Godfrey, A. L.; Harrison, C. N.; Méndez-Ferrer, S.
    Current therapies for myeloproliferative neoplasms (MPNs) improve symptoms but have limited effect on tumor size. In preclinical studies, tamoxifen restored normal apoptosis in mutated hematopoietic stem/progenitor cells (HSPCs). TAMARIN Phase-II, multicenter, single-arm clinical trial assessed tamoxifen's safety and activity in patients with stable MPNs, no prior thrombotic events and mutated JAK2(V617F), CALR(ins5) or CALR(del52) peripheral blood allele burden ≥20% (EudraCT 2015-005497-38). 38 patients were recruited over 112w and 32 completed 24w-treatment. The study's A'herns success criteria were met as the primary outcome ( ≥ 50% reduction in mutant allele burden at 24w) was observed in 3/38 patients. Secondary outcomes included ≥25% reduction at 24w (5/38), ≥50% reduction at 12w (0/38), thrombotic events (2/38), toxicities, hematological response, proportion of patients in each IWG-MRT response category and ELN response criteria. As exploratory outcomes, baseline analysis of HSPC transcriptome segregates responders and non-responders, suggesting a predictive signature. In responder HSPCs, longitudinal analysis shows high baseline expression of JAK-STAT signaling and oxidative phosphorylation genes, which are downregulated by tamoxifen. We further demonstrate in preclinical studies that in JAK2V617F+ cells, 4-hydroxytamoxifen inhibits mitochondrial complex-I, activates integrated stress response and decreases pathogenic JAK2-signaling. These results warrant further investigation of tamoxifen in MPN, with careful consideration of thrombotic risk.
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    Influence of family history on penetrance of hereditary cancers in a population setting
    (Elsevier, 2023-10-14) Jackson, L.; Weedon, M. N.; Green, H. D.; Mallabar-Rimmer, B.; Harrison, J. W.; Wood, A. R.; Ruth, K. S.; Tyrrell, J.; Wright, C. F.
    BACKGROUND: We sought to investigate how penetrance of familial cancer syndromes varies with family history using a population-based cohort. METHODS: We analysed 454,712 UK Biobank participants with exome sequence and clinical data (data collected between March 2006 and June 2021). We identified participants with a self-reported family history of breast or colorectal cancer and a pathogenic/likely pathogenic variant in the major genes responsible for hereditary breast cancer or Lynch syndrome. We calculated survival to cancer diagnosis (controlled for sex, death, recruitment centre, screening and prophylactic surgery). FINDINGS: Women with a pathogenic BRCA1 or BRCA2 variant had an increased risk of breast cancer that was higher in those with a first-degree family history (relative hazard 10.3 and 7.8, respectively) than those without (7.2 and 4.7). Penetrance to age 60 was also higher in those with a family history (44.7%, CI 32.2-59.3 and 24.1%, CI 17.5-32.6) versus those without (22.8%, CI 15.9-32.0 and 17.9%, CI 13.8-23.0). A similar pattern was seen in Lynch syndrome: individuals with a pathogenic MLH1, MSH2 or MSH6 variant had an increased risk of colorectal cancer that was significantly higher in those with a family history (relative hazard 35.6, 48.0 and 9.9) than those without (13.0, 15.4 and 7.2). Penetrance to age 60 was also higher for carriers of a pathogenic MLH1 or MSH2 variant in those with a family history (30.9%, CI 18.1-49.3 and 38.3%, CI 21.5-61.8) versus those without (20.5% CI 9.6-40.5 and 8.3% CI 2.1-30.4), but not for MSH6 (6.5% CI 2.7-15.1 with family history versus 8.3%, CI 5.1-13.2). Relative risk increases were also observed both within and across conditions. INTERPRETATION: Individuals with pathogenic cancer syndrome variants may be at a less elevated risk of cancer in the absence of a first-degree family history, so in the context of results return, family history should be considered when counselling patients on the risks and benefits of potential follow-up care. FUNDING: The current work is supported by the MRC (grant no MR/T00200X/1). The MRC had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
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    Acute Toxicity of Hypofractionated and Conventionally Fractionated (Chemo)Radiotherapy Regimens for Bladder Cancer: An Exploratory Analysis from the RAIDER Trial
    (Elsevier, 2023-09-01) Huddart, R.; Hafeez, S.; Omar, A.; Alonzi, R.; Birtle, A.; Cheung, K. C.; Choudhury, A.; Foroudi, F.; Gribble, H.; Henry, A.; Hilman, S.; Hindson, B.; Lewis, R.; Muthukumar, D.; McLaren, D. B.; McNair, H.; Nikapota, A.; Olorunfemi, A.; Parikh, O.; Philipps, L.; Rimmer, Y.; Syndikus, I.; Tolentino, A.; Varughese, M.; Vassallo-Bonner, C.; Webster, A.; Griffin, C.; Hall, E.
    AIMS: Adding concurrent (chemo)therapy to radiotherapy improves outcomes for muscle-invasive bladder cancer patients. A recent meta-analysis showed superior invasive locoregional disease control for a hypofractionated 55 Gy in 20 fractions schedule compared with 64 Gy in 32 fractions. In the RAIDER clinical trial, patients undergoing 20 or 32 fractions of radical radiotherapy were randomised (1:1:2) to standard radiotherapy or to standard-dose or escalated-dose adaptive radiotherapy. Neoadjuvant chemotherapy and concomitant therapy were permitted. We report exploratory analyses of acute toxicity by concomitant therapy-fractionation schedule combination. MATERIALS AND METHODS: Participants had unifocal bladder urothelial carcinoma staged T2-T4a N0 M0. Acute toxicity was assessed (Common Terminology Criteria for Adverse Events) weekly during radiotherapy and at 10 weeks after the start of treatment. Within each fractionation cohort, non-randomised comparisons of the proportion of patients reporting treatment emergent grade 2 or worse genitourinary, gastrointestinal or other adverse events at any point in the acute period were carried out using Fisher's exact tests. RESULTS: Between September 2015 and April 2020, 345 (163 receiving 20 fractions; 182 receiving 32 fractions) patients were recruited from 46 centres. The median age was 73 years; 49% received neoadjuvant chemotherapy; 71% received concomitant therapy, with 5-fluorouracil/mitomycin C most commonly used: 44/114 (39%) receiving 20 fractions; 94/130 (72%) receiving 32 fractions. The acute grade 2+ gastrointestinal toxicity rate was higher in those receiving concomitant therapy compared with radiotherapy alone in the 20-fraction cohort [54/111 (49%) versus 7/49 (14%), P < 0.001] but not in the 32-fraction cohort (P = 0.355). Grade 2+ gastrointestinal toxicity was highest for gemcitabine, with evidence of significant differences across therapies in the 32-fraction cohort (P = 0.006), with a similar pattern but no significant differences in the 20-fraction cohort (P = 0.099). There was no evidence of differences in grade 2+ genitourinary toxicity between concomitant therapies in either the 20- or 32-fraction cohorts. CONCLUSION: Grade 2+ acute adverse events are common. The toxicity profile varied by type of concomitant therapy; the gastrointestinal toxicity rate seemed to be higher in patients receiving gemcitabine.