Now showing items 21-40 of 4924

    • Understanding the molecular biology of anal squamous cell carcinoma

      Samuel, Robert J; Gilbert, DC; Manchester Cancer Research Centre, National Institute of Health and Research Manchester Biomedical Research Centre, Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine, and Health, University of Manchester, Manchester, UK. (2023)
    • Towards a physiologically relevant lung in vitro model for early cancer biomarkers

      Mitta, E; Gilmore, A; Malliri, Angeliki; Cartmell, S; Cell Signalling, Cancer Research UK Manchester Institute, Alderley Park, Manchester SK10 4TG, UK (2023)
    • The tumor multi-omic landscape of endometrial cancers developed on a germline genetic background of adiposity

      Richenberg, G; Francis, A; Owen, CN; Gray, V; Robinson, T; Gabriel, AA; Lawrenson, K; Crosbie, Emma J; Schildkraut, JM; McKay, JD; et al. (2023)
      High body mass index (BMI) is a causal risk factor for endometrial cancer but the tumor molecular mechanisms affected by adiposity and their therapeutic relevance remain poorly understood. Here we characterize the tumor multi-omic landscape of endometrial cancers that have developed on a background of lifelong germline genetic exposure to elevated BMI. We built a polygenic score (PGS) for BMI in women using data on independent, genome-wide significant variants associated with adult BMI in 434,794 women. We performed germline (blood) genotype quality control and imputation on data from 354 endometrial cancer cases from The Cancer Genome Atlas (TCGA). We assigned each case in this TCGA cohort their genetically predicted life-course BMI based on the BMI PGS. Multivariable generalized linear models adjusted for age, stage, microsatellite status and genetic principal components were used to test for associations between the BMI germline PGS and endometrial cancer tumor genome-wide genomic, transcriptomic, proteomic, epigenomic and immune traits in TCGA. High BMI germline PGS was associated with (i) upregulated tumor gene expression in the IL6-JAK-STAT3 pathway (FDR=4.2×10-7); (ii) increased estimated intra-tumor activated mast cell infiltration (FDR=0.008); (iii) increased single base substitution (SBS) mutational signatures 1 (FDR=0.03) and 5 (FDR=0.09) and decreased SBS13 (FDR=0.09), implicating age-related and APOBEC mutagenesis, respectively; and (iv) decreased tumor EGFR protein expression (FDR=0.07). Alterations in IL6-JAK-STAT3 signaling gene and EGFR protein expression were, in turn, significantly associated with both overall survival and progression-free interval. Thus, we integrated germline and somatic data using a novel study design to identify associations between genetically predicted lifelong exposure to higher BMI and potentially actionable endometrial cancer tumor molecular features. These associations inform our understanding of how high BMI may influence the development and progression of this cancer, impacting endometrial tumor biology and clinical outcomes.
    • The emergence and diversification of a zoonotic pathogen from within the microbiota of intensively farmed pigs

      Murray, GGR; Hossain, Mukarram; Miller, EL; Bruchmann, S; Balmer, AJ; Matuszewska, M; Herbert, J; Hadjirin, NF; Mugabi, R; Li, G; et al. (2023)
      The expansion and intensification of livestock production is predicted to promote the emergence of pathogens. As pathogens sometimes jump between species, this can affect the health of humans as well as livestock. Here, we investigate how livestock microbiota can act as a source of these emerging pathogens through analysis of Streptococcus suis, a ubiquitous component of the respiratory microbiota of pigs that is also a major cause of disease on pig farms and an important zoonotic pathogen. Combining molecular dating, phylogeography, and comparative genomic analyses of a large collection of isolates, we find that several pathogenic lineages of S. suis emerged in the 19th and 20th centuries, during an early period of growth in pig farming. These lineages have since spread between countries and continents, mirroring trade in live pigs. They are distinguished by the presence of three genomic islands with putative roles in metabolism and cell adhesion, and an ongoing reduction in genome size, which may reflect their recent shift to a more pathogenic ecology. Reconstructions of the evolutionary histories of these islands reveal constraints on pathogen emergence that could inform control strategies, with pathogenic lineages consistently emerging from one subpopulation of S. suis and acquiring genes through horizontal transfer from other pathogenic lineages. These results shed light on the capacity of the microbiota to rapidly evolve to exploit changes in their host population and suggest that the impact of changes in farming on the pathogenicity and zoonotic potential of S. suis is yet to be fully realized.
    • Real-time motion management in MRI-guided radiotherapy: current status and AI-enabled prospects

      Lombardo, E; Dhont, J; Page, Dennis; Garibaldi, C; Künzel, LA; Hurkmans, C; Tijssen, RHN; Paganelli, C; Liu, PZY; Keall, PJ; et al. (2023)
      MRI-guided radiotherapy (MRIgRT) is a highly complex treatment modality, allowing adaptation to anatomical changes occurring from one treatment day to the other (inter-fractional), but also to motion occurring during a treatment fraction (intra-fractional). In this vision paper, we describe the different steps of intra-fractional motion management during MRIgRT, from imaging to beam adaptation, and the solutions currently available both clinically and at a research level. Furthermore, considering the latest developments in the literature, a workflow is foreseen in which motion-induced over- and/or under-dosage is compensated in 3D, with minimal impact to the radiotherapy treatment time. Considering the time constraints of real-time adaptation, a particular focus is put on artificial intelligence (AI) solutions as a fast and accurate alternative to conventional algorithms.
    • Reply to: comments on '(pre)treatment risk factors for late fatigue and fatigue trajectories following radiotherapy for breast cancer'

      Rosas, JC; Aguado-Barrera, ME; Azria, D; Briers, E; Elliott, Rebecca; Farcy-Jacquet, MP; Giraldo, A; Gutiérrez-Enríquez, S; Rancati, T; Rattay, T; et al. (2023)
    • pSTAT5 is associated with improved survival in patients with thick or ulcerated primary cutaneous melanoma

      Tan, SX; Chong, S; Rowe, C; Claeson, M; Dight, J; Zhou, C; Rodero, MP; Malt, M; Smithers, BM; Green, Adele C; et al. (2023)
      Identifying prognostic biomarkers to predict clinical outcomes in stage I and II cutaneous melanomas could guide the clinical application of adjuvant and neoadjuvant therapies. We aimed to investigate the prognostic value of phosphorylated signal transducer and activator of transcription 5 (pSTAT5) as a biomarker in early-stage melanoma. This study evaluated all initially staged Ib and II melanoma patients undergoing sentinel node biopsy at a tertiary centre in Brisbane, Australia between 1994 and 2007, with survival data collected from the Queensland Cancer Registry. Primary melanoma tissue from 189 patients was analysed for pSTAT5 level through immunohistochemistry. Cox regression modelling, with adjustment for sex, age, ulceration, anatomical location, and Breslow depth, was applied to determine the association between pSTAT5 detection and melanoma-specific survival. Median duration of follow-up was 7.4 years. High pSTAT5 detection was associated with ulceration and increased tumour thickness. However, multivariate analysis indicated that high pSTAT5 detection was associated with improved melanoma-specific survival (hazard ratio: 0.15, 95% confidence interval: 0.03-0.67) as compared to low pSTAT5 detection. This association persisted when pSTAT5 detection was limited to immune infiltrate or the vasculature, as well as when sentinel node positivity was accounted for. In this cohort, staining for high-pSTAT5 tumours identified a subset of melanoma patients with increased survival outcomes as compared to low-pSTAT5 tumours, despite the former having higher-risk clinicopathological characteristics at diagnosis. pSTAT5 is likely an indicator of local immune activation, and its detection could represent a useful tool to stratify the risk of melanoma progression.
    • Indirect treatment comparison of brexucabtagene autoleucel (ZUMA-2) versus standard of care (SCHOLAR-2) in relapsed/refractory mantle cell lymphoma

      Hess, G; Dreyling, M; Oberic, L; Gine, E; Zinzani, PL; Linton, Kim; Vilmar, A; Jerkeman, M; Chen, JMH; Ohler, A; et al. (2023)
      The SCHOLAR-2 retrospective study highlighted poor overall survival (OS) with standard of care (SOC) regimens among patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL) who failed a covalent Bruton tyrosine kinase inhibitor (BTKi). In the ZUMA-2 single-arm trial, brexucabtagene autoleucel (brexu-cel; autologous anti-CD19 CAR T-cell therapy) demonstrated high rates of durable responses in patients with R/R MCL who had previous BTKi exposure. Here, we compared OS in ZUMA-2 and SCHOLAR-2 using three different methods which adjusted for imbalances in prognostic factors between populations: inverse probability weighting (IPW), regression adjustment (RA), and doubly robust (DR). Brexu-cel was associated with improved OS compared to SOC across all unadjusted and adjusted comparisons. Hazard ratios (95% confidence intervals) were 0.38 (0.23, 0.61) for IPW, 0.45 (0.28, 0.74) for RA, and 0.37 (0.23, 0.59) for DR. These results suggest a substantial survival benefit with brexu-cel versus SOC in patients with R/R MCL after BTKi exposure.
    • Immunobiology of cholangiocarcinoma

      Tomlinson, JL; Valle, John W; Ilyas, SI; Division of Cancer Sciences, University of Manchester & Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom (2023)
      Recent literature has significantly advanced our knowledge and understanding of the tumour immune microenvironment of cholangiocarcinoma. Detailed characterisation of the immune landscape has defined new patient subtypes. While not utilised in clinical practice yet, these novel classifications will help inform decisions regarding immunotherapeutic approaches. Suppressive immune cells, such as tumour-associated macrophages and myeloid-derived suppressor cells, form a barrier that shields tumour cells from immune surveillance. The presence of this immunosuppressive barrier in combination with a variety of immune escape mechanisms employed by tumour cells leads to poor tumour immunogenicity. Broad strategies to re-equip the immune system include blockade of suppressive immune cell recruitment to priming cytotoxic effector cells against tumour antigens. While immunotherapeutic strategies are gaining traction for the treatment of cholangiocarcinoma, there is a long road of discovery ahead in order to make meaningful contributions to patient therapy and survival.
    • Immunotherapy and hypofractionated radiotherapy in older patients with locally advanced cutaneous squamous-cell carcinoma of the head and neck: a proposed paradigm by the international geriatric radiotherapy group

      Nguyen, NP; Thariat, J; Gorobets, O; Vinh-Hung, V; Kim, L; Blanco, SC; Vasileiou, M; Arenas, M; Mazibuko, T; Giap, H; et al. (2023)
      Cutaneous skin carcinoma is a disease of older patients. The prevalence of cutaneous squamous-cell carcinoma (cSCC) increases with age. The head and neck region is a frequent place of occurrence due to exposure to ultraviolet light. Surgical resection with adjuvant radiotherapy is frequently advocated for locally advanced disease to decrease the risk of loco-regional recurrence. However, older cancer patients may not be candidates for surgery due to frailty and/or increased risk of complications. Radiotherapy is usually advocated for unresectable patients. Compared to basal-cell carcinoma, locally advanced cSCC tends to recur locally and/or can metastasize, especially in patients with high-risk features such as poorly differentiated histology and perineural invasion. Thus, a new algorithm needs to be developed for older patients with locally advanced head and neck cutaneous squamous-cell carcinoma to improve their survival and conserve their quality of life. Recently, immunotherapy with checkpoint inhibitors (CPIs) has attracted much attention due to the high prevalence of program death ligand 1 (PD-L1) in cSCC. A high response rate was observed following CPI administration with acceptable toxicity. Those with residual disease may be treated with hypofractionated radiotherapy to minimize the risk of recurrence, as radiotherapy may enhance the effect of immunotherapy. We propose a protocol combining CPIs and hypofractionated radiotherapy for older patients with locally advanced cutaneous head and neck cancer who are not candidates for surgery. Prospective studies should be performed to verify this hypothesis.
    • Higher MDMX expression was associated with hypomethylating agent resistance and inferior survival in MDS patients, inferring it a potential therapeutic target

      Wang, Yu-Hung; Lin, CC; Gurashi, K; Wingelhofer, B; Amaral, Fabio M R; Yao, CY; Hsieh, HT; Liu, MC; Hou, HA; Chou, WC; et al. (2023)
    • Guideline for the diagnosis and management of marginal zone lymphomas: a british society of haematology guideline

      Walewska, R; Eyre, TA; Barrington, S; Brady, J; Fields, P; Iyengar, S; Joshi, A; Menne, T; Parry-Jones, N; Walter, H; et al. (2023)
      SCOPE The objective of this guideline is to provide healthcare professionals with clear guidance on the diagnosis and management of patients with marginal zone lymphoma (MZL). METHODOLOGY These guidelines were compiled according to the BSH process: https://b-s-h.org.uk/media/16732/bsh-guidance-development-process-dec-5-18.pdf. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) nomenclature was used to evaluate levels of evidence and to assess the strength of recommendations. The GRADE criteria can be found at http://www.gradeworkinggroup.org. Recommendations are based on a review of the literature using Medline/Pubmed. Search terms included: marginal zone, MZL, extranodal MZL, MALT, nodal, splenic, treatment, randomised, clinical trial, radioimmunotherapy, hepatitis C, Helicobacter pylori. The search was limited to English language publications and conference abstracts from 1 January 1998 to 20 September 2022. Titles/abstracts obtained were curated and manually reviewed by the writing group, which conducted additional searches using subsection heading terms. The manuscript was reviewed by the BSH Guidelines Haemato-oncology Task Force, the BSH Guidelines Executive Committee and the haemato-oncology sounding board of the BSH.
    • Genomic analysis of advanced breast cancer tumors from talazoparib-treated gBRCA1/2mut carriers in the ABRAZO study

      Turner, NC; Laird, AD; Telli, ML; Rugo, HS; Mailliez, A; Ettl, J; Grischke, EM; Mina, LA; Balmaña, J; Fasching, PA; et al. (2023)
      These analyses explore the impact of homologous recombination repair gene mutations, including BRCA1/2 mutations and homologous recombination deficiency (HRD), on the efficacy of the poly(ADP-ribose) polymerase (PARP) inhibitor talazoparib in the open-label, two-cohort, Phase 2 ABRAZO trial in germline BRCA1/2-mutation carriers. In the evaluable intent-to-treat population (N = 60), 58 (97%) patients harbor ≥1 BRCA1/2 mutation(s) in tumor sequencing, with 95% (53/56) concordance between germline and tumor mutations, and 85% (40/47) of evaluable patients have BRCA locus loss of heterozygosity indicating HRD. The most prevalent non-BRCA tumor mutations are TP53 in patients with BRCA1 mutations and PIK3CA in patients with BRCA2 mutations. BRCA1- or BRCA2-mutated tumors show comparable clinical benefit within cohorts. While low patient numbers preclude correlations between HRD and efficacy, germline BRCA1/2 mutation detection from tumor-only sequencing shows high sensitivity and non-BRCA genetic/genomic events do not appear to influence talazoparib sensitivity in the ABRAZO trial.ClinicalTrials.gov identifier: NCT02034916.
    • Diagnosis and evaluation of prognosis of myelofibrosis: A british society for haematology guideline

      McLornan, DP; Godfrey, AL; Green, A; Frewin, R; Arami, S; Brady, J; Butt, NM; Cargo, C; Ewing, J; Francis, S; et al. (2023)
      SUMMARY AND AIMS This document represents an update of the British Society for Haematology (BSH) guideline on myelofibrosis (MF) first published in 2012 and updated in 2015.1 This guideline aims to provide healthcare professionals with clear guidance on the diagnosis and prognostic evaluation of primary myelofibrosis (PMF), as well as post-polycythaemia vera myelofibrosis (post-PV MF) and post-essential thrombocythaemia myelofibrosis (post-ET MF). A section on prefibrotic MF is also included. A separate BSH Guideline covers the management of MF and is published alongside this guideline. METHODOLOGY These guidelines were compiled according to the BSH process https://b-s-h.org.uk/media/16732/bsh-guidance-development-process-dec-5-18.pdf. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) nomenclature was used to evaluate levels of evidence and to assess the strength of recommendations. The GRADE criteria can be found at http://www.gradeworkinggroup.org. Recommendations are based on a review of the relevant MF-related literature using Medline, PubMed/Medline and Cochrane searches beginning from 2012 up to mid-2022. Filters were applied to include only publications written in English, studies carried out in humans, clinical conferences, congresses, clinical trials, clinical studies, meta-analyses, multicentre studies and randomised controlled trials. Exclusion criteria included papers published in non-English journals and those publications without an abstract. REVIEW OF THE MANUSCRIPT Review of the manuscript was performed by the BSH Guidelines Committee Haemato-oncology Task Force, the BSH Guidelines Committee and the Haemato-oncology sounding board of the BSH. We invited two global expert external reviewers to review contents—Professor Ruben Mesa and Professor Alessandro Vannucchi. This guideline has also been reviewed by patient representatives from MPN Voice.
    • Delphi initiative for early-onset colorectal cancer (DIRECt) international management guidelines

      Cavestro, GM; Mannucci, A; Balaguer, F; Hampel, H; Kupfer, SS; Repici, A; Sartore-Bianchi, A; Seppälä, TT; Valentini, V; Boland, CR; et al. (2023)
      Background & aims: Patients with early-onset colorectal cancer (eoCRC) are managed according to guidelines that are not age-specific. A multidisciplinary international group (DIRECt), composed of 69 experts, was convened to develop the first evidence-based consensus recommendations for eoCRC. Methods: After reviewing the published literature, a Delphi methodology was used to draft and respond to clinically relevant questions. Each statement underwent 3 rounds of voting and reached a consensus level of agreement of ≥80%. Results: The DIRECt group produced 31 statements in 7 areas of interest: diagnosis, risk factors, genetics, pathology-oncology, endoscopy, therapy, and supportive care. There was strong consensus that all individuals younger than 50 should undergo CRC risk stratification and prompt symptom assessment. All newly diagnosed eoCRC patients should receive germline genetic testing, ideally before surgery. On the basis of current evidence, endoscopic, surgical, and oncologic treatment of eoCRC should not differ from later-onset CRC, except for individuals with pathogenic or likely pathogenic germline variants. The evidence on chemotherapy is not sufficient to recommend changes to established therapeutic protocols. Fertility preservation and sexual health are important to address in eoCRC survivors. The DIRECt group highlighted areas with knowledge gaps that should be prioritized in future research efforts, including age at first screening for the general population, use of fecal immunochemical tests, chemotherapy, endoscopic therapy, and post-treatment surveillance for eoCRC patients. Conclusions: The DIRECt group produced the first consensus recommendations on eoCRC. All statements should be considered together with the accompanying comments and literature reviews. We highlighted areas where research should be prioritized. These guidelines represent a useful tool for clinicians caring for patients with eoCRC.
    • Comparing the acceptability of total diet replacement and food-based low energy diets for type 2 diabetes remission amongst South asians: a public and patient involvement activity

      Farhat, G; Majeed, S; Rutter, MK; Issa, B; Harvie, Michelle; UK Division of Cancer Sciences, University of Manchester, Manchester, Manchester, UK. (2021)
      Background: With type 2 diabetes prevalence rising, low energy diets (total diet replacement and food-based low energy diets) are increasingly used to induce weight loss and achieve diabetes remission. The effectiveness of these diets has been primarily tested in the UK white population but not in the south Asian population at high risk of diabetes. Obtaining the opinion of members of the community on what would constitute a culturally acceptable diet is essential for successful interventions aiming to achieve diabetes remission in south Asians. Methods: We organised two patient and public involvement activities in the North West of England to understand views of people from the south Asian population on whether low energy diets (850 Kcal) in the form of total diet replacement or food-based meals, are acceptable dietary interventions to achieve type 2 diabetes remission. Results: Thirteen people, with either type 2 diabetes or having someone with diabetes in the family attended a virtual or a face-to-face meeting. Low energy total diet replacement in the form of soups and shakes was considered unacceptable, while there was a preference for a culturally tailored low energy food-based diet. Ready-made portion controlled catered meals were suggested as a likely approach to improve adherence. Conclusions: This work provided valuable insights to shape a future study looking at the feasibility of a catered meal low-energy dietary intervention to induce T2D remission in primary care within the south Asian population.
    • Crosstalk between small-cell lung cancer cells and astrocytes mimics brain development to promote brain metastasis

      Qu, FF; Brough, SC; Michno, W; Madubata, CJ; Hartmann, GG; Puno, A; Drainas, AP; Bhattacharya, D; Tomasich, E; Lee, MC; et al. (2023)
      Brain metastases represent an important clinical problem for patients with small-cell lung cancer (SCLC). However, the mechanisms underlying SCLC growth in the brain remain poorly understood. Here, using intracranial injections in mice and assembloids between SCLC aggregates and human cortical organoids in culture, we found that SCLC cells recruit reactive astrocytes to the tumour microenvironment. This crosstalk between SCLC cells and astrocytes drives the induction of gene expression programmes that are similar to those found during early brain development in neurons and astrocytes. Mechanistically, the brain development factor Reelin, secreted by SCLC cells, recruits astrocytes to brain metastases. These astrocytes in turn promote SCLC growth by secreting neuronal pro-survival factors such as SERPINE1. Thus, SCLC brain metastases grow by co-opting mechanisms involved in reciprocal neuron-astrocyte interactions during brain development. Targeting such developmental programmes activated in this cancer ecosystem may help prevent and treat brain metastases.
    • Choosing the best systemic treatment sequence for control of tumour growth in gastro-enteropancreatic neuroendocrine tumours (GEP-NETs): What is the recent evidence?

      Passhak, M; McNamara, Miread G; Hubner, RA; Ben-Aharon, I; Valle, Juan W; Division of Cancer Sciences, University of Manchester, Manchester M20 4BX, UK; Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK. (2023)
      Gastro-enteropancreatic neuroendocrine tumours (GEP-NETs) represent a rare and highly heterogeneous entity with increasing incidence. Based on the results obtained from several trials performed in the last decade, various therapeutic options have been established for the treatment of patients with GEP-NETs. The options include somatostatin analogues, targeted therapies (sunitinib and everolimus), chemotherapy (with temozolomide or streptozocin-based regimens), and peptide receptor radionuclide therapy. The treatment choice is influenced by various clinico-pathological factors including tumour grade and morphology, the primary mass location, hormone secretion, the volume of the disease and the rate of tumour growth, as well as patient comorbidities and performance status. In this review, the efficacy and safety of treatment options for patients with GEP-NETs is discussed and the evidence to inform the best sequence of available therapies to control tumour growth, prolong patient survival, and to lower potential toxicity, while maintaining patient quality of life is explored.
    • Characterizing prostate cancer risk through multi-ancestry genome-wide discovery of 187 novel risk variants

      Wang, A; Shen, J; Rodriguez, AA; Saunders, EJ; Chen, F; Janivara, R; Darst, BF; Sheng, X; Xu, Y; Chou, AJ; et al. (2023)
      The transferability and clinical value of genetic risk scores (GRSs) across populations remain limited due to an imbalance in genetic studies across ancestrally diverse populations. Here we conducted a multi-ancestry genome-wide association study of 156,319 prostate cancer cases and 788,443 controls of European, African, Asian and Hispanic men, reflecting a 57% increase in the number of non-European cases over previous prostate cancer genome-wide association studies. We identified 187 novel risk variants for prostate cancer, increasing the total number of risk variants to 451. An externally replicated multi-ancestry GRS was associated with risk that ranged from 1.8 (per standard deviation) in African ancestry men to 2.2 in European ancestry men. The GRS was associated with a greater risk of aggressive versus non-aggressive disease in men of African ancestry (P = 0.03). Our study presents novel prostate cancer susceptibility loci and a GRS with effective risk stratification across ancestry groups.
    • Breast cancer polygenic risk scores derived in white european populations are not calibrated for women of ashkenazi jewish descent (erratum: vol 25, 100846, 2023)

      Roberts, Eleanor; Veen, EMV; Byers, H; Barnett-Griness, O; Gronich, N; Lejbkowicz, F; Pinchev, M; Smith, MJ; Howell, Anthony; Newman, WG; et al. (2023)