Now showing items 1-20 of 4623

    • BH3-mimetics: recent developments in cancer therapy

      Townsend, Paul A; Kozhevnikova, M. V.; Cexus, O. N. F.; Zamyatnin, A. A., Jr.; Soond, S. M.; University of Surrey, Guildford, UK. (2021)
      The hopeful outcomes from 30 years of research in BH3-mimetics have indeed served a number of solid paradigms for targeting intermediates from the apoptosis pathway in a variety of diseased states. Not only have such rational approaches in drug design yielded several key therapeutics, such outputs have also offered insights into the integrated mechanistic aspects of basic and clinical research at the genetics level for the future. In no other area of medical research have the effects of such work been felt, than in cancer research, through targeting the BAX-Bcl-2 protein-protein interactions. With these promising outputs in mind, several mimetics, and their potential therapeutic applications, have also been developed for several other pathological conditions, such as cardiovascular disease and tissue fibrosis, thus highlighting the universal importance of the intrinsic arm of the apoptosis pathway and its input to general tissue homeostasis. Considering such recent developments, and in a field that has generated so much scientific interest, we take stock of how the broadening area of BH3-mimetics has developed and diversified, with a focus on their uses in single and combined cancer treatment regimens and recently explored therapeutic delivery methods that may aid the development of future therapeutics of this nature.
    • On Target 2: updated guidance for image-guided radiotherapy

      McNair, H. A.; Franks, K. N.; van Herk, Marcel; Royal Marsden NHS Foundation Trust, Sutton, UK; Institute of Cancer Research, London, UK (2021)
    • Manchester Intermittent versus Daily Diet App Study (MIDDAS): A pilot randomized controlled trial in patients with type 2 diabetes

      McDiarmid, S.; Harvie, Michelle N; Johnson, R.; Vyas, A.; Aglan, A.; Moran, J.; Ruane, H.; Hulme, A.; Sellers, K.; Issa, B. G.; et al. (2021)
      Aims: To test the feasibility and potential efficacy of remotely supported intermittent low energy diets (ILEDs) and continuous low energy diets (CLEDs) in people with type 2 diabetes (T2D) and the feasibility of a Randomized Controlled Trial (RCT) comparing the two approaches. Materials and methods: Seventy-nine adults with overweight/obesity and T2D (≤8 years duration) were randomized 1:1 to CLED (eight weeks/56 days of daily Optifast 820kcal (3430kJ) diet) or isoenergetic ILED (two days of Optifast and five days of a Mediterranean diet/week for 28 weeks). Weight maintenance/continued weight loss was undertaken for the remainder of the 52 weeks. Both groups received frequent telephone and/or the Oviva app support. Feasibility outcomes included study uptake, retention, app usage, dietary adherence, weight loss, and change in HbA1c at 52 weeks. Results: We enrolled 39 ILED and 40 CLED participants and 27 (69%) ILED and 30 CLED (75%) attended 52-week follow-up. Eighty-nine percent (70/79) started using the app and 86% (44/51) still used the app at 52 weeks. Intention-to-treat analysis at 52 weeks showed percentage weight loss was mean (CI) -5.4% (-7.6, -3.1%) for ILED and -6.0% (-7.9, -4.0%) for CLED. HbA1c<48mmol/mol was achieved in 42% of both groups. Mean (CI) changes in the T2D medication effect score (MES) were 0.0008 (-0.3, 0.3) for ILED and -0.5 (-0.8, -0.3) for CLED. Conclusion: The study demonstrates the feasibility and potential efficacy of remotely delivered ILED and CLED programs for weight loss and HbA1c reduction, and the feasibility of an RCT comparing the two approaches.
    • A prostate cancer proteomics database for SWATH-MS based protein quantification

      Muazzam, Ammara; Chiasserini, D.; Kelsall, J.; Geifman, N.; Whetton, Anthony D; Townsend, Paul A; Manchester Cancer Research Centre, Division of Cancer Sciences, Faculty of Biology, School of Medical Sciences, Medicine and Health, University of Manchester, Wilmslow Road, Manchester M20 4GJ, UK (2021)
      Prostate cancer is the most frequent form of cancer in men, accounting for more than one-third of all cases. Current screening techniques, such as PSA testing used in conjunction with routine procedures, lead to unnecessary biopsies and the discovery of low-risk tumours, resulting in overdiagnosis. SWATH-MS is a well-established data-independent (DI) method requiring prior knowledge of targeted peptides to obtain valuable information from SWATH maps. In response to the growing need to identify and characterise protein biomarkers for prostate cancer, this study explored a spectrum source for targeted proteome analysis of blood samples. We created a comprehensive prostate cancer serum spectral library by combining data-dependent acquisition (DDA) MS raw files from 504 patients with low, intermediate, or high-grade prostate cancer and healthy controls, as well as 304 prostate cancer-related protein in silico assays. The spectral library contains 114,684 transitions, which equates to 18,479 peptides translated into 1227 proteins. The robustness and accuracy of the spectral library were assessed to boost confidence in the identification and quantification of prostate cancer-related proteins across an independent cohort, resulting in the identification of 404 proteins. This unique database can facilitate researchers to investigate prostate cancer protein biomarkers in blood samples. In the real-world use of the spectrum library for biomarker detection, using a signature of 17 proteins, a clear distinction between the validation cohort's pre- and post-treatment groups was observed. Data are available via ProteomeXchange with identifier PXD028651.
    • Somatic driver mutation prevalence in 1844 prostate cancers identifies ZNRF3 loss as a predictor of metastatic relapse

      Fraser, M.; Livingstone, J.; Wrana, J. L.; Finelli, A.; He, H. H.; van der Kwast, T.; Zlotta, A. R.; Bristow, Robert G; Boutros, P. C.; Department of Surgery, Division of Urology, University of Toronto, Toronto, ON, Canada. (2021)
      Driver gene mutations that are more prevalent in metastatic, castration-resistant prostate cancer (mCRPC) than localized disease represent candidate prognostic biomarkers. We analyze 1,844 localized (1,289) or mCRPC (555) tumors and quantify the prevalence of 113 somatic driver single nucleotide variants (SNVs), copy number aberrations (CNAs), and structural variants (SVs) in each state. One-third are significantly more prevalent in mCRPC than expected while a quarter are less prevalent. Mutations in AR and its enhancer are more prevalent in mCRPC, as are those in TP53, MYC, ZNRF3 and PRKDC. ZNRF3 loss is associated with decreased ZNRF3 mRNA abundance, WNT, cell cycle & PRC1/2 activity, and genomic instability. ZNRF3 loss, RNA downregulation and hypermethylation are prognostic of metastasis and overall survival, independent of clinical and pathologic indices. These data demonstrate a strategy for identifying biomarkers of localized cancer aggression, with ZNRF3 loss as a predictor of metastasis in prostate cancer.
    • Proton therapy in supradiaphragmatic lymphoma: predicting treatment-related mortality to help optimize patient selection

      Ntentas, G.; Dedeckova, K.; Andrlik, M.; Aznar, Marianne Camille; Shakir, R.; Ramroth, J.; Begum, R.; Kubeš, J.; Darby, S. C.; Mikhaeel, N. G.; et al. (2021)
      Purpose: In some Hodgkin lymphoma (HL) patients, proton beam therapy (PBT) may reduce the risk of radiation-related cardiovascular disease (CVD) and second cancers (SC) compared with photon radiotherapy (photon-RT). Our aim was to identify those who benefit most from PBT in terms of predicted 30-year absolute mortality risks (AMR30) from CVD and SC, taking into account individual background, chemotherapy, radiation and smoking-related risks. Methods and materials: Eighty patients with supradiaphragmatic HL treated with PBT during 2015-2019 were re-planned using optimal photon-RT. To identify patients predicted to derive the greatest benefit from PBT compared to Photon-RT, doses and AMR30 from CVD and SC of the lung, breast and esophagus were compared for all patients and across patient subgroups. Results: For patients with mediastinal disease below the origin of the left main coronary artery (n=66, 82%), PBT reduced mean dose to heart, left ventricle and heart valves by 1.0, 2.7 and 3.6 Gray (Gy) respectively. Based on US mortality rates, PBT reduced CVD AMR30 by 0.2%, from 5.9% to 5.7%. The benefit was larger if the mediastinal disease overlapped longitudinally with the heart by ≥40% (n=23, 29%), where PBT reduced mean dose to heart, left ventricle and heart valves by 3.2, 5.6, and 5.1Gy respectively, and reduced CVD AMR30 by 0.8%, from 7.0% to 6.2%. For patients with axillary disease (n=25, 31%), PBT reduced mean lung dose by 2.8Gy and lung cancer AMR30 by 0.6%, from 2.7% to 2.1%. Breast and esophageal doses were also lower with PBT but effects on AMR30 were negligible. The effect of smoking on CVD and lung cancer AMR30 was much larger than radiation and chemotherapy and the differences between radiation modalities. Conclusions: The predicted benefit of PBT is not universal and is limited to certain categories of lymphoma patients with lower mediastinal or axillary disease. Smoking cessation should be strongly encouraged in smokers requiring thoracic radiotherapy.
    • A phase I/II study to assess the safety and efficacy of pazopanib and pembrolizumab combination therapy in patients with advanced renal cell carcinoma

      Chowdhury, S.; Infante, J. R.; Hawkins, Robert E; Voss, M. H.; Perini, R.; Arkenau, T.; Voskoboynik, M.; Aimone, P.; Naeije, I.; Reising, A.; et al. (2021)
      Background: This study assessed whether antiangiogenic treatment may potentiate immune checkpoint blockade in patients with advanced renal cell carcinoma. Patients and methods: This was an open-label, two-part, multicenter study involving treatment-naïve patients with advanced renal cell carcinoma. Part 1 consisted of a phase I dose escalation and expansion of pazopanib plus pembrolizumab (combination therapy). Cohorts A and B received pazopanib in combination with pembrolizumab, whereas Cohort C received pazopanib monotherapy for 9 weeks before receiving the combination therapy. Part 2 was planned as a randomized three-arm study but was not conducted. Results: Overall, 42 patients were enrolled (10 each in Cohorts A and B, 22 in Cohort C). The maximum tolerated dose was not reached and the recommended phase II dose was not declared, as Cohort C was closed early because of safety concerns. The overall response rates were 60% and 20% in Cohorts A and B, respectively. In Cohort C, the overall response rates were 33%, 25%, and 0% in the combination therapy, pembrolizumab monotherapy, and pazopanib monotherapy groups, respectively. The median progression-free survival rates were 21.95 months and 41.40 months in Cohorts A and B, respectively. Grade 3 or 4 adverse events (AEs) were observed in 90% of patients in Cohorts A and B. In Cohort C, the frequencies of grade 3 or 4 AEs, serious adverse events, and AEs leading to dose reduction were typically high in the combination therapy group. Conclusions: Despite preliminary signs of efficacy, significant hepatotoxicity was observed in Cohorts A and B. The sequential schedule of pazopanib followed by pazopanib plus pembrolizumab showed reduced hepatotoxicity; however, other safety issues emerged with this approach.
    • The role of circular RNAs in DNA damage response and repair

      Papaspyropoulos, A.; Hazapis, O.; Lagopati, N.; Polyzou, A.; Papanastasiou, A. D.; Liontos, M.; Gorgoulis, Vassilis G; Kotsinas, A.; Molecular Carcinogenesis Group, Department of Histology and Embryology, Medical School, National Kapodistrian University of Athens (NKUA), 75 Mikras Asias Str., Goudi, GR-11527 Athens, Greece (2021)
      Circular RNAs (circRNA) comprise a distinct class of non-coding RNAs that are abundantly expressed in the cell. CircRNAs have the capacity to regulate gene expression by interacting with regulatory proteins and/or other classes of RNAs. While a vast number of circRNAs have been discovered, the majority still remains poorly characterized. Particularly, there is no detailed information on the identity and functional role of circRNAs that are transcribed from genes encoding components of the DNA damage response and repair (DDRR) network. In this article, we not only review the available published information on DDRR-related circRNAs, but also conduct a bioinformatic analysis on data obtained from public repositories to uncover deposited, yet uncharacterized circRNAs derived from components of the DDRR network. Finally, we interrogate for potential targets that are regulated by this class of molecules and look into potential functional implications.
    • Blast cells surviving acute myeloid leukemia induction therapy are in cycle with a signature of FOXM1 activity

      Williams, Mark S; Basma, Naseer J; Amaral, Fabio M R; Wiseman, Daniel H; Somervaille, Tim C P; Leukaemia Biology Laboratory, Cancer Research UK Manchester Institute, Oglesby Cancer Research Building, The University of Manchester, 555 Wilmslow Road, Manchester, M20 4GJ, UK (2021)
      Background: Disease relapse remains common following treatment of acute myeloid leukemia (AML) and is due to chemoresistance of leukemia cells with disease repopulating potential. To date, attempts to define the characteristics of in vivo resistant blasts have focused on comparisons between leukemic cells at presentation and relapse. However, further treatment responses are often seen following relapse, suggesting that most blasts remain chemosensitive. We sought to characterise in vivo chemoresistant blasts by studying the transcriptional and genetic features of blasts from before and shortly after induction chemotherapy using paired samples from six patients with primary refractory AML. Methods: Leukemic blasts were isolated by fluorescence-activated cell sorting. Fluorescence in situ hybridization (FISH), targeted genetic sequencing and detailed immunophenotypic analysis were used to confirm that sorted cells were leukemic. Sorted blasts were subjected to RNA sequencing. Lentiviral vectors expressing short hairpin RNAs were used to assess the effect of FOXM1 knockdown on colony forming capacity, proliferative capacity and apoptosis in cell lines, primary AML cells and CD34+ cells from healthy donors. Results: Molecular genetic analysis revealed early clonal selection occurring after induction chemotherapy. Immunophenotypic characterisation found leukemia-associated immunophenotypes in all cases that persisted following treatment. Despite the genetic heterogeneity of the leukemias studied, transcriptional analysis found concerted changes in gene expression in resistant blasts. Remarkably, the gene expression signature suggested that post-chemotherapy blasts were more proliferative than those at presentation. Resistant blasts also appeared less differentiated and expressed leukemia stem cell (LSC) maintenance genes. However, the proportion of immunophenotypically defined LSCs appeared to decrease following treatment, with implications for the targeting of these cells on the basis of cell surface antigen expression. The refractory gene signature was highly enriched with targets of the transcription factor FOXM1. shRNA knockdown experiments demonstrated that the viability of primary AML cells, but not normal CD34+ cells, depended on FOXM1 expression. Conclusions: We found that chemorefractory blasts from leukemias with varied genetic backgrounds expressed a common transcriptional program. In contrast to the notion that LSC quiescence confers resistance to chemotherapy we find that refractory blasts are both actively proliferating and enriched with LSC maintenance genes. Using primary patient material from a relevant clinical context we also provide further support for the role of FOXM1 in chemotherapy resistance, proliferation and stem cell function in AML.
    • Mutational characterization of cutaneous melanoma supports divergent pathways model for melanoma development

      Millán-Esteban, D.; Peña-Chilet, M.; García-Casado, Z.; Manrique-Silva, E.; Requena, C.; Bañuls, J.; López-Guerrero, J. A.; Rodríguez-Hernández, A.; Traves, V.; Dopazo, J.; et al. (2021)
      According to the divergent pathway model, cutaneous melanoma comprises a nevogenic group with a propensity to melanocyte proliferation and another one associated with cumulative solar damage (CSD). While characterized clinically and epidemiologically, the differences in the molecular profiles between the groups have remained primarily uninvestigated. This study has used a custom gene panel and bioinformatics tools to investigate the potential molecular differences in a thoroughly characterized cohort of 119 melanoma patients belonging to nevogenic and CSD groups. We found that the nevogenic melanomas had a restricted set of mutations, with the prominently mutated gene being BRAF. The CSD melanomas, in contrast, showed mutations in a diverse group of genes that included NF1, ROS1, GNA11, and RAC1. We thus provide evidence that nevogenic and CSD melanomas constitute different biological entities and highlight the need to explore new targeted therapies.
    • Positive attributes of anti-TERT CD4 T-Helper Type 1 immune responses in melanoma

      Nagore, E.; Virós, Amaya; Kumar, R.; Department of Dermatology, Instituto Valenciano de Oncologia, Valencia, Spain (2021)
      Nardin et al's (2021) study on melanoma reports anti-TERT CD4 T helper type (Th) 1 responses in more than half of patients. Besides indicating a trend for improved survival, increased anti-TERT CD4 Th1 responses predicted better outcomes for patients treated with immune checkpoint inhibitors. Thus, harnessing systemic anti-TERT CD4 Th1 responses together with tumor-specific elevation of telomerase can potentially open new avenues for biomarkers and treatment in melanoma.
    • Experimental challenges to modeling prostate cancer heterogeneity

      Flores-Téllez, Teresita; Baena, Esther; Prostate Oncobiology Group, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, Alderley Edge, Macclesfield, SK10 4TG (2022)
      Tumor heterogeneity plays a key role in prostate cancer prognosis, therapy selection, relapse, and acquisition of treatment resistance. Prostate cancer presents a heterogeneous diversity at inter- and intra-tumor and inter-patient levels which are influenced by multiple intrinsic and/or extrinsic factors. Recent studies have started to characterize the complexity of prostate tumors and these different tiers of heterogeneity. In this review, we discuss the most common factors that contribute to tumoral diversity. Moreover, we focus on the description of the in vitro and in vivo approaches, as well as high-throughput technologies, that help to model intra-tumoral diversity. Further understanding tumor heterogeneities and the challenges they present will guide enhanced patient risk stratification, aid the design of more precise therapies, and ultimately help beat this chameleon-like disease.
    • A hypercoagulant tumour microenvironment promotes breast cancer progression, with effects inhibited by anticoagulants

      Blower, Emma; Castle, John; Santiago-Gomez, Angelika; Clarke, Robert B; Kirwan, Cliona C; Manchester Cancer and Thrombosis Team, The Oglesby Cancer Research Building, University of Manchester, Manchester, UK (2021)
      Background: Breast cancer patients have a four-fold increased risk of developing a venous thromboembolism (VTE). VTE is associated with increased mortality despite adjusting for cancer stage. Tissue Factor (TF) is expressed by breast cancer-associated ?broblasts as well as breast cancer epithelial cells. TF signals to promote cancer growth and metastasis. Rivaroxaban, a licensed oral anticoagulant that inhibits this TF-Factor VIIa (FVIIa)-Factor Xa (FXa) complex, could potentially be repurposed to target this procoagulant tumour microenvironment in breast cancer. Methods: Recombinant coagulation factors, lentivirally transduced TF over-expressing ?broblasts (TFF) and their control (CF) or conditioned media (TFFCM and CFCM), were cultured with oestrogen receptor positive (ER+) breast cancer cells (MCF-7) +/- Rivaroxaban or anti-TF antibody 10H10. Proliferation (sulforhodamine-B/EdU assay), migration (scratch/transwell assay) and stem cell activity (mammosphere forming e?ciency (MFE) assay) were assessed. The underlying mechanism was analysed with western blotting and quantitative PCR.Results: Recombinant TF,FVIIa and FXa versus control promoted proliferation and migration in MCF-7 cells (p<0.001), with these e?ects abrogated by Rivaroxaban (p<0.05). Recombinant TF,FVIIa and FXa increased phospho-ERK (p<0.01), CXCL8 (p<0.05) and VEGFA (p<0.0001) expression as compared to control, with CXCL8 and VEGFA inhibited by Rivaroxaban (p<0.01).TFFCM promoted proliferation, migration and stem cell activity in MCF-7 cells (p<0.05) as compared to CFCM, with these e?ects abrogated by 10H10 (proliferation, migration, MFE:p<0.05) and Rivaroxaban (migration, MFE:p<0.05). The cancer-promoting e?ects of TFFCM versus CFCM were associated with increased VEGFA (p<0.05) expression; which was reversed by 10H10 and Rivaroxaban (p<0.05). 3D co-culture of MCF-7s with TFF as compared to CF promoted cancer cell migration (p=0.04) and stem cell activity (MFE:p<0.0001), with these e?ects abrogated by 10H10 (migration:p=0.01, MFE:p=0.0028) and Rivaroxaban (migration:p= 0.0341, MFE:p=0.0003).Conclusion: A procoagulant microenvironment promotes proliferation, migration and stem cell activity in ER+ breast cancer in vitro which can be targeted by anticoagulants. Rivaroxaban could potentially be repurposed as anticancer therapy.
    • CHAMPion and WiSDen studies: investigating the relationship between a stromal wound healing phenotype and breast density

      Castle, John; Blower, Emma; Ogunlayi, H; Kirwan, Cliona C; Manchester Cancer Research Centre (2021)
      Background: Tumour stroma resembles a �wound that will not heal�, with myo?broblasts phenotypically similar to cancer-associated ?broblasts (CAFs). Fibroblasts produce collagen and are hyperactivated in high breast density tissue. Breast cancer ?broblasts show increasing expression of procoagulant and CAF markers in the normal-DCIS (ductal carcinoma in situ, breast cancer precursor)-invasive cancer transition. High mammographic density is associated with an increased risk of breast cancer, but the mechanism for this is unclear.Purpose: We hypothesise that high density breast tissue has a wound-like, procoagulant stroma, causing increased collagen formation (visible mammographic density) and promoting breast cancer development, including the transition from DCIS to invasion. This may provide novel therapeutic options for breast cancer prevention. Methods: Fresh tumour/DCIS tissue plus distant normal tissue are collected from patients undergoing mastectomies at Wythenshawe Hospital with the support of pathologists and the Manchester Cancer Research Centre Biobank. Primary broblasts are grown from these and characterised with their e?ect on established breast cancer cell lines investigated. In the ?nal phase of the study, mammographic density and residual FFPE tissue will be compared to the experimental results. Results: Primary ?broblast culture is achievable for most tissue samples, with a bank of frozen cell stocks, conditioned media, lysates and FFPE built up for later study phases. Initial functional experiments using the modi?ed prothrombin time assay indicate ?broblasts cells and their secreted factors in conditioned media initiate coagulation. Conclusions: Cultured primary ?broblasts have been shown to be functionally procoagulant, as suggested by earlier work on ?xed tissue. Functional experiments with the cultured ?broblasts and comparisons to mammographic density will be carried out in the next phases of this study.
    • Reorganization of the 3D genome pinpoints non-coding drivers of primary prostate tumors

      Hawley, J. R.; Zhou, S.; Arlidge, C.; Grillo, G.; Kron, K. J.; Hugh-White, R.; van der Kwast, T. H.; Fraser, M.; Boutros, P. C.; Bristow, Robert G; et al. (2021)
      Prostate cancer is a heterogeneous disease whose progression is linked to genome instability. However, the impact of this instability on the non-coding genome and its three-dimensional organization to aid progression is unclear. Using primary benign and tumor tissue, we find a high concordance in higher order three-dimensional genome organization. This concordance argues for constraints to the topology of prostate tumor genomes. theless, we identified changes in focal chromatin interactions, typical of loops bridging non-coding cis-regulatory elements, and showed how structural variants can induce these changes to guide cis-regulatory element hijacking. Such events resulted in opposing differential expression of genes found at antipodes of rearrangements. Collectively, these results argue that changes to focal chromatin interactions, as opposed to higher order genome organization, allow for aberrant gene regulation and are repeatedly mediated by structural variants in primary prostate cancer.
    • Prostate cancer

      Sandhu, S.; Moore, C. M.; Chiong, E.; Beltran, H.; Bristow, Robert G; Williams, S. G.; Division of Cancer Medicine, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; (2021)
      The management of prostate cancer continues to evolve rapidly, with substantial advances being made in understanding the genomic landscape and biology underpinning both primary and metastatic prostate cancer. Similarly, the emergence of more sensitive imaging methods has improved diagnostic and staging accuracy and refined surveillance strategies. These advances have introduced personalised therapeutics to clinical practice, with treatments targeting genomic alterations in DNA repair pathways now clinically validated. An important shift in the therapeutic framework for metastatic disease has taken place, with metastatic-directed therapies being evaluated for oligometastatic disease, aggressive management of the primary lesion shown to benefit patients with low-volume metastatic disease, and with several novel androgen pathway inhibitors significantly improving survival when used as a first-line therapy for metastatic disease. Research into the molecular characterisation of localised, recurrent, and progressive disease will undoubtedly have an impact on clinical management. Similarly, emerging research into novel therapeutics, such as targeted radioisotopes and immunotherapy, holds much promise for improving the lives of patients with prostate cancer.
    • Understanding melanoma biology to improve patient care

      Marais, Richard; Cancer Research UK Manchester Institute (2021)
      We have developed mouse models of melanoma driven by human oncogenes and ultraviolet radiation (UVR). These models recapitulate the cardinal pathological and genomic features of human melanoma and begin to reveal how UVR-induced DNA damage cooperates with oncogenes such as V600EBRAF to cause melanoma. By comparing the results from our mouse studies to human melanomas, we have shown that approximately 15% of human common cutaneous melanomas are not driven by UVR. We and others have previously reported that mucosal melanomas are driven by large chromosomal structural variations, but we have recently reported that mucosal melanomas of the conjunctiva are also driven by UVR. These data allow us to postulate that in di?erent microenvironments, melanocytes are subject to speci?c mutational processes that drive melanomagenesis, but that if exposed to UVR, these processes are accelerated. Our data emphasise the importance of also protecting our eyes from the damaging e?ects of UVR and highlight that immunotherapy and targeted therapies could be used for some of the rare forms of melanoma for which they are not currently approved. To re?ne the use of melanoma therapies, we have shown that circulating tumour DNA is a powerful tool for monitoring patient responses to treatment, and we have identi?ed a circulating T cell signature that predicts patient responses to immunotherapy. We have also identi?ed a sub-set of cells that may mediate patient responses to anti-PD1-based immunotherapies. The tools we have developed are exploring how precision immunotherapy could be delivered to melanoma patients
    • Exposure of the oesophagus in breast cancer radiotherapy: A systematic review of oesophagus doses published 2010-2020

      Duane, F. K.; Kerr, A.; Wang, Z.; Darby, S. C.; Ntentas, G.; Aznar, Marianne Camille; Taylor, C. W.; St. Luke's Radiation Oncology Network, St. Luke's Hospital, Dublin, Ireland; School of Medicine, Trinity College Dublin, Ireland; Trinity St James's Cancer Institute, St. James's Hospital, Dublin, Ireland (2021)
      Background and purpose: Breast cancer radiotherapy can increase the risk of subsequent primary oesophageal cancer, with risk increasing according to oesophagus radiation dose. We describe oesophagus exposure from modern breast cancer regimens and discuss the risks of oesophageal cancer for women irradiated recently. Materials and methods: A systematic review was undertaken of oesophagus doses from breast cancer radiotherapy regimens published during 2010-2020. Mean and maximum oesophagus doses were described for different target regions irradiated and different radiotherapy techniques. Results: In 112 published regimens from 18 countries, oesophagus doses varied with target region. For partial breast irradiation, average mean oesophagus dose was 0.2 Gy (range 0.1-0.4) in four regimens; maximum dose was not reported. For breast or chest wall radiotherapy, average oesophagus doses were mean 1.8 Gy (range 0.1-10.4) in 24 regimens and maximum 6.7 Gy (range 0.4-14.3) in seven regimens. For radiotherapy including a nodal region, average oesophagus doses were higher: mean 11.4 Gy (range 1.1-29.3) in 61 regimens and maximum 34.4 Gy (range 3.4-51.3) in 55 regimens. Average mean oesophagus doses were >10 Gy for intensity modulated nodal radiotherapy, but lower for other node techniques. Conclusions: Mean oesophagus doses from partial breast and breast/chest wall regimens were usually less than 2 Gy, hence radiation-risks will be very small. However, for radiotherapy including lymph nodes, average mean oesophagus dose of 11.4 Gy may nearly double oesophageal cancer risk. Consideration of oesophageal exposure during nodal radiotherapy planning may reduce the risks of radiation-related oesophageal cancer for women irradiated today.
    • Weight gain after heart transplantation in adults: systematic review and meta-analysis

      Miura, K.; Yu, R.; Sivapalan, K.; Liyanage, U. E.; Entwistle, T.; McKenzie, S. C.; Green, Adèle C; From the Population Health Department, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia (2021)
      Gain in weight is common after heart transplantation but the magnitude of usual weight gain and whether this varies by country is unknown. We systematically reviewed all relevant studies to quantify weight change among heart transplant recipients (HTRs) in the years after transplantation and assess variation with geographic location. We searched PubMed, Cumulative Index to Nursing and Allied Health Literature, and Excerpta Medica Database databases to September 2020. Eligible studies reported adult HTRs' mean/median weight and/or body mass index (BMI) up to time of transplantation (baseline) and posttransplantation in any language. Weighted mean differences (WMDs) (95% confidence intervals [CIs]) of weight/BMI from baseline to posttransplantation were estimated using a random-effects model. Ten studies met the inclusion criteria. Pooled analysis showed weight gain of 7.1 kg (95% CI, 4.4-9.8 kg) in HTRs 12 months posttransplant, with corresponding BMI increase of 1.69 kg/m2 (95% CI, 0.83-2.55 kg/m2). Greatest weight gain at 12 months posttransplant occurred in US HTRs (WMD weight 10.42 kg, BMI 3.25 kg/m2) and least, in European HTRs (WMD weight 3.10 kg, BMI 0.78 kg/m2). In conclusion, HTRs gain substantial weight in the years after transplantation, but varying widely by geographic location.