Now showing items 1-20 of 4747

    • Contemporary breast cancer treatment-associated thrombosis

      Kirwan, Cliona C; Blower, Emma L; Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, Manchester Cancer Research Centre, University of Manchester, United Kingdom (2022)
      Although cancer-associated thrombosis (CAT) is relatively uncommon in breast cancer compared to other solid cancers, as breast cancer is the most commonly diagnosed cancer in women worldwide, the financial and personal cost of breast cancer associated thrombosis (BrCAT) is significant. This increasing risk of BrCAT over time parallels modern developments in breast cancer management. This review comprehensively reports the evidence for BrCAT in the context of modern breast cancer treatments. The risk of BrCAT is most pronounced within the first 3 months to year of diagnosis. The risk of BrCAT increases with operating time, paralleling the increasing frequency of immediate breast reconstruction. Systemic therapies such as chemotherapy and tamoxifen have well recognised thrombogenic effects, that are exacerbated by surgery and supplementary treatments such as colony-stimulating factors, steroids, and bisphosphonates however risk assessment tools are not designed specifically for this lower-VTE risk cancer. Cyclin-dependent kinases 4 and 6 (CDK4/6) Inhibitors, used in metastatic breast cancer, with trials ongoing in early disease, appear to have a class thrombogenic effect, although there is no increase CAT risk with other breast cancer targeted therapies. Given the numerous prothrombotic treatments facing patients within the first year of diagnosis, from surgery, chemotherapy, targeted therapies and endocrine therapy, a more personalised approach considering the additive effects of each individual patient's pathway, as well as their pre-existing risk factors, needs to be considered.
    • Lifetime sunburn trajectories and associated risks of cutaneous melanoma and squamous cell carcinoma among a cohort of norwegian women

      Lergenmuller, S.; Rueegg, C. S.; Perrier, F.; Robsahm, T. E.; Green, Adèle C; Lund, E.; Ghiasvand, R.; Veierød, M. B.; Oslo Centre for Biostatistics and Epidemiology, Department of Biostatistics, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway (2022)
      Importance: To our knowledge, no study has prospectively investigated sunburn patterns over age periods from childhood to adulthood and their associations with skin cancer risk. Objective: To identify lifetime trajectories of sunburns and compare the association between these trajectories and subsequent risk of cutaneous melanoma and squamous cell carcinoma (cSCC). Design, setting, and participants: This population-based cohort study included participants from the Norwegian Women and Cancer Study, established in 1991, with follow-up through 2018. Baseline questionnaires were issued from 1991 to 2007, with follow-up questionnaires every 5 to 7 years. Data analysis was performed from March 16, 2021, to December 4, 2021. Exposures: Participants reported pigmentation factors, sunbathing vacations, and indoor tanning. Annual frequencies of sunburns were reported for childhood, adolescence, and adulthood. Main outcomes and measures: Information on cancer diagnoses, emigration, and death were obtained through linkage to the Cancer Registry of Norway using the unique personal identification number of Norwegian citizens. Results: Of the 172 472 women (age range, 31-70 years) who returned questionnaires, 169 768 received questions about sunburns at study inclusion. Five classes (stable low, low-moderate-low, low to high, high to low, and stable high) of individual lifetime sunburn trajectories with similar shapes were estimated in 3 samples up to 39 years (n = 159 773), up to 49 years (n = 153 297), and up to 59 years (n = 119 170). Mean follow-up ranged from 14.3 to 19.5 years in the 3 samples, during which 1252 to 1774 women were diagnosed with incident primary melanoma and 739 to 871 women with incident primary cSCC. With hazard ratios (HRs) and 95% CIs estimated using a Cox proportional hazards model, the stable high and high to low trajectories showed statistically significant increased melanoma and cSCC risks compared with the stable low trajectory across all samples (≤39 years for stable high and high to low trajectories: melanoma: HR, 1.50 [95% CI, 1.28-1.75] and HR, 1.44 [95% CI, 1.20-1.73]; cSCC: HR, 1.51 [95% CI, 1.22-1.87] and HR, 1.47 [95% CI, 1.14-1.91]). Other trajectories showed increased risk, though generally weaker and mainly estimates that were not statistically significant. There was no statistically significant heterogeneity between melanoma and cSCC estimates. Conclusion and relevance: This cohort study showed that high sunburn frequency throughout life was associated with increased melanoma and cSCC risk. Furthermore, sunburns in childhood are especially important for subsequent risk of these skin cancers. Avoiding sunburns throughout life, in particular in childhood, is therefore crucial.
    • Implementing risk-stratified breast screening in England: an agenda setting meeting

      McWilliams, L.; Evans, D Gareth R; Payne, K.; Harrison, F.; Howell, Anthony; Howell, Sacha J; French, David P; Manchester Centre for Health Psychology, Division of Psychology & Mental Health, School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Oxford Road, Manchester M13 9PL, UK (2022)
      It is now possible to accurately assess breast cancer risk at routine NHS Breast Screening Programme (NHSBSP) appointments, provide risk feedback and offer risk management strategies to women at higher risk. These strategies include National Institute for Health and Care Excellence (NICE) approved additional breast screening and risk-reducing medication. However, the NHSBSP invites nearly all women three-yearly, regardless of risk. In March 2022, a one-day agenda setting meeting took place in Manchester to discuss the feasibility and desirability of implementation of risk-stratified screening in the NHSBSP. Fifty-eight individuals participated (38 face-to-face, 20 virtual) with relevant expertise from academic, clinical and/or policy-making perspectives. Key findings were presented from the PROCAS2 NIHR programme grant regarding feasibility of risk-stratified screening in the NHSBSP. Participants discussed key uncertainties in seven groups, followed by a plenary session. Discussions were audio-recorded and thematically analysed to produce descriptive themes. Five themes were developed: (i) risk and health economic modelling; (ii) health inequalities and communication with women; (iii); extending screening intervals for low-risk women; (iv) integration with existing NHSBSP; and (v) potential new service models. Most attendees expected some form of risk-stratified breast screening to be implemented in England and collectively identified key issues to be resolved to facilitate this.
    • Colorectal cancer incidences in Lynch syndrome: a comparison of results from the prospective lynch syndrome database and the international mismatch repair consortium

      Møller, P.; Seppälä, T.; Dowty, J. G.; Haupt, S.; Dominguez-Valentin, M.; Sunde, L.; Bernstein, I.; Engel, C.; Aretz, S.; Nielsen, M.; et al. (2022)
      Objective: To compare colorectal cancer (CRC) incidences in carriers of pathogenic variants of the MMR genes in the PLSD and IMRC cohorts, of which only the former included mandatory colonoscopy surveillance for all participants. Methods: CRC incidences were calculated in an intervention group comprising a cohort of confirmed carriers of pathogenic or likely pathogenic variants in mismatch repair genes (path_MMR) followed prospectively by the Prospective Lynch Syndrome Database (PLSD). All had colonoscopy surveillance, with polypectomy when polyps were identified. Comparison was made with a retrospective cohort reported by the International Mismatch Repair Consortium (IMRC). This comprised confirmed and inferred path_MMR carriers who were first- or second-degree relatives of Lynch syndrome probands. Results: In the PLSD, 8,153 subjects had follow-up colonoscopy surveillance for a total of 67,604 years and 578 carriers had CRC diagnosed. Average cumulative incidences of CRC in path_MLH1 carriers at 70 years of age were 52% in males and 41% in females; for path_MSH2 50% and 39%; for path_MSH6 13% and 17% and for path_PMS2 11% and 8%. In contrast, in the IMRC cohort, corresponding cumulative incidences were 40% and 27%; 34% and 23%; 16% and 8% and 7% and 6%. Comparing just the European carriers in the two series gave similar findings. Numbers in the PLSD series did not allow comparisons of carriers from other continents separately. Cumulative incidences at 25 years were < 1% in all retrospective groups. Conclusions: Prospectively observed CRC incidences (PLSD) in path_MLH1 and path_MSH2 carriers undergoing colonoscopy surveillance and polypectomy were higher than in the retrospective (IMRC) series, and were not reduced in path_MSH6 carriers. These findings were the opposite to those expected. CRC point incidence before 50 years of age was reduced in path_PMS2 carriers subjected to colonoscopy, but not significantly so.
    • HMG20B stabilizes association of LSD1 with GFI1 on chromatin to confer transcription repression and leukemia cell differentiation block

      Maiques-Diaz, Alba; Nicosia, Luciano; Basma, Naseer J; Romero-Camarero, Isabel; Camera, Francesco; Spencer, Gary J; Amaral, Fabio M R; Simeoni, Fabrizio; Wingelhofer, Bettina; Williamson, Andrew J K; et al. (2022)
      Pharmacologic inhibition of LSD1 induces molecular and morphologic differentiation of blast cells in acute myeloid leukemia (AML) patients harboring MLL gene translocations. In addition to its demethylase activity, LSD1 has a critical scaffolding function at genomic sites occupied by the SNAG domain transcription repressor GFI1. Importantly, inhibitors block both enzymatic and scaffolding activities, in the latter case by disrupting the protein:protein interaction of GFI1 with LSD1. To explore the wider consequences of LSD1 inhibition on the LSD1 protein complex we applied mass spectrometry technologies. We discovered that the interaction of the HMG-box protein HMG20B with LSD1 was also disrupted by LSD1 inhibition. Downstream investigations revealed that HMG20B is co-located on chromatin with GFI1 and LSD1 genome-wide; the strongest HMG20B binding co-locates with the strongest GFI1 and LSD1 binding. Functional assays demonstrated that HMG20B depletion induces leukemia cell differentiation and further revealed that HMG20B is required for the transcription repressor activity of GFI1 through stabilizing LSD1 on chromatin at GFI1 binding sites. Interaction of HMG20B with LSD1 is through its coiled-coil domain. Thus, HMG20B is a critical component of the GFI1:LSD1 transcription repressor complex which contributes to leukemia cell differentiation block.
    • The architecture of clonal expansions in morphologically normal tissue from cancerous and non-cancerous prostates

      Buhigas, C.; Warren, A. Y.; Leung, W. K.; Whitaker, H. C.; Luxton, H. J.; Hawkins, S.; Kay, J.; Butler, A.; Xu, Y.; Woodcock, D. J.; et al. (2022)
      Background: Up to 80% of cases of prostate cancer present with multifocal independent tumour lesions leading to the concept of a field effect present in the normal prostate predisposing to cancer development. In the present study we applied Whole Genome DNA Sequencing (WGS) to a group of morphologically normal tissue (n = 51), including benign prostatic hyperplasia (BPH) and non-BPH samples, from men with and men without prostate cancer. We assess whether the observed genetic changes in morphologically normal tissue are linked to the development of cancer in the prostate. Results: Single nucleotide variants (P = 7.0 × 10-03, Wilcoxon rank sum test) and small insertions and deletions (indels, P = 8.7 × 10-06) were significantly higher in morphologically normal samples, including BPH, from men with prostate cancer compared to those without. The presence of subclonal expansions under selective pressure, supported by a high level of mutations, were significantly associated with samples from men with prostate cancer (P = 0.035, Fisher exact test). The clonal cell fraction of normal clones was always higher than the proportion of the prostate estimated as epithelial (P = 5.94 × 10-05, paired Wilcoxon signed rank test) which, along with analysis of primary fibroblasts prepared from BPH specimens, suggests a stromal origin. Constructed phylogenies revealed lineages associated with benign tissue that were completely distinct from adjacent tumour clones, but a common lineage between BPH and non-BPH morphologically normal tissues was often observed. Compared to tumours, normal samples have significantly less single nucleotide variants (P = 3.72 × 10-09, paired Wilcoxon signed rank test), have very few rearrangements and a complete lack of copy number alterations. Conclusions: Cells within regions of morphologically normal tissue (both BPH and non-BPH) can expand under selective pressure by mechanisms that are distinct from those occurring in adjacent cancer, but that are allied to the presence of cancer. Expansions, which are probably stromal in origin, are characterised by lack of recurrent driver mutations, by almost complete absence of structural variants/copy number alterations, and mutational processes similar to malignant tissue. Our findings have implications for treatment (focal therapy) and early detection approaches.
    • Margin status and survival outcomes after breast cancer conservation surgery: prospectively registered systematic review and meta-analysis

      Bundred, J. R.; Michael, Sarah; Stuart, B.; Cutress, R. I.; Beckmann, K.; Holleczek, B.; Dahlstrom, J. E.; Gath, J.; Dodwell, D.; Bundred, Nigel J; et al. (2022)
      Objective: To determine if margin involvement is associated with distant recurrence and to determine the required margin to minimise both local recurrence and distant recurrence in early stage invasive breast cancer. Design: Prospectively registered systematic review and meta-analysis of literature. Data sources: Medline (PubMed), Embase, and Proquest online databases. Unpublished data were sought from study authors. Eligibility criteria: Eligible studies reported on patients undergoing breast conserving surgery (for stages I-III breast cancer), allowed an estimation of outcomes in relation to margin status, and followed up patients for a minimum of 60 months. Patients with ductal carcinoma in situ only or treated with neoadjuvant chemotherapy or by mastectomy were excluded. Where applicable, margins were categorised as tumour on ink (involved), close margins (no tumour on ink but <2 mm), and negative margins (≥2 mm). Results: 68 studies from 1 January 1980 to 31 December 2021, comprising 112 140 patients with breast cancer, were included. Across all studies, 9.4% (95% confidence interval 6.8% to 12.8%) of patients had involved (tumour on ink) margins and 17.8% (13.0% to 23.9%) had tumour on ink or a close margin. The rate of distant recurrence was 25.4% (14.5% to 40.6%) in patients with tumour on ink, 8.4% (4.4% to 15.5%) in patients with tumour on ink or close, and 7.4% (3.9% to 13.6%) in patients with negative margins. Compared with negative margins, tumour on ink margins were associated with increased distant recurrence (hazard ratio 2.10, 95% confidence interval 1.65 to 2.69, P<0.001) and local recurrence (1.98, 1.66 to 2.36, P<0.001). Close margins were associated with increased distant recurrence (1.38, 1.13 to 1.69, P<0.001) and local recurrence (2.09, 1.39 to 3.13, P<0.001) compared with negative margins, after adjusting for receipt of adjuvant chemotherapy and radiotherapy. In five studies published since 2010, tumour on ink margins were associated with increased distant recurrence (2.41, 1.81 to 3.21, P<0.001) as were tumour on ink and close margins (1.44, 1.22 to 1.71, P<0.001) compared with negative margins. Conclusions: Involved or close pathological margins after breast conserving surgery for early stage, invasive breast cancer are associated with increased distant recurrence and local recurrence. Surgeons should aim to achieve a minimum clear margin of at least 1 mm. On the basis of current evidence, international guidelines should be revised.
    • Width of excision margins after breast conserving surgery for invasive breast cancer and distant recurrence and survival

      Bundred, Nigel J; Bundred, J. R.; Cutress, R. I.; Dodwell, D.; Manchester University NHS Foundation Trust, Wythenshawe, Manchester, UK (2022)
    • Comparative treatment costs of risk-stratified therapy for childhood acute lymphoblastic leukemia in India

      Mungle, T.; Das, N.; Pal, S.; Gogoi, M. P.; Das, P.; Ghara, N.; Ghosh, D.; Arora, R. S.; Bhakta, N.; Saha, Vaskar; et al. (2022)
    • Amplification of the Plag family genes-Plagl1 and Plagl2-is a key feature of a novel embryonal Cns Tumor Type

      Keck, M. K.; Sill, M.; Wittmann, A.; Kumar, P. J.; Stichel, D.; Sievers, P.; Wefers, A. K.; Roncaroli, F.; Hayden, J.; McCabe, Martin G; et al. (2022)
    • Biological markers of ependymoma in children and adolescents (Biomeca): systematic comparison of methods for the precise evaluation of biomarkers for ependymoma diagnosis and prognostication

      Chapman, R.; Ghasemi, D. R.; LeBlond, P.; Witt, H.; Grill, J.; Kilday, John-Paul; Modena, P.; Varlet, P.; Tauziede-Espariat, A.; Haberler, C.; et al. (2022)
      The identification and validation of prognostic and diagnostic biomarkers is a key element of The SIOP Ependymoma II trial, realised through the Biomarkers of Ependymoma in Children and Adolescents study (BIOMECA). BIOMECA aims to identify and validate biomarkers for prediction of outcome whilst enhancing stratification for the next generation of ependymoma trials. We outline our findings from the first 147 consecutive BIOMECA cases (posterior fossa, PF=111; supratentorial, ST=32; spinal, SP=4). We compared various methods for biomarker assessment, across six European laboratories to determine key analysis methods. Methods included: methylation-based classification (EPIC 850K DNA methylation array) (n=141); immunohistochemistry (IHC) for nuclear p65-RELA (n=32), H3K27me3 (n=115), and Tenascin-C (TNC) (n=147); copy number (CN) analysis by FISH, MLPA (1q, CDKN2A) (n=147), and MIP (molecular inversion probe) and DNA methylation array (1q, CDKN2A, 6q, 11q, 13q, 22q) (n=141); analysis of ZFTA- and YAP1-fusions by RT-PCR, sequencing, Nanostring assays and break-apart FISH (n=32). Using DNA methylation-based classification, 91% (n=101/111) of PF cases classified as PF ependymoma group A (PFA) and 69% (n=22/32) of ST cases as ST ependymoma, ZFTA fusion-positive (ZFTA). Most PFAs demonstrated inter-centre agreement for loss of H3K27me3, and were TNC positive, representing surrogate markers for PFA identification. Combinations of p65-RELA IHC, FISH analysis, and RNA-based methods were suitable to identify ZFTA- and YAP1- fused ST ependymomas. Predictive CN alterations were identified by high-resolution, quantitative MIP technology.The integration of histopathology assessment and molecular typing is now critical as the updated 2021 WHO CNS5 classification of ependymomas lists seven molecularly distinct entities. This study highlights the importance of evaluating different methods in a prospective trial cohort. Here, advanced molecular techniques represent powerful tools for the classification of ependymoma entities (DNA methylation array) and for the detection of CN alterations (MIP) and specific fusions, enabling the correct classification and identification of prognostic markers.
    • Changes in clonal architecture inform MPN disease course in advance of phenotypic manifestations

      Lee, J. S.; Williams, N.; Baxter, J. E.; Godfrey, A. L.; Milne, K.; Mane, K.; Wedge, David C; Campbell, P. J.; Green, A. R.; Nangalia, J.; et al. (2021)
    • Multi-omic analysis of chronic myelomonocytic leukaemia monocytes reveals immune dysregulation mediated By TGF-beta activationb

      Bossenbroek, Hasse M; Somervaille, Tim C P; Wiseman, Daniel H; Batta, Kiran; Division of Cancer Sciences, University of Manchester, Manchester (2021)
    • COX-2 upregulation by tumour cells post-chemotherapy fuels the immune evasive dark side of cancer inflammation

      Bell, Charlotte R; Zelenay, Santiago; Cancer Inflammation and Immunity Group, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, Macclesfield, UK (2022)
      Cytotoxic therapies, such as chemotherapy and radiotherapy, are mainstays of cancer treatment for both early and unresectable, advanced disease. In addition to debulking the tumour mass through direct killing of proliferating tumour cells, these treatments can promote tumour control via immune-stimulating effects. Nonetheless, chemoresistance and tumour relapse remain huge clinical problems, suggesting that induction of anti-cancer immunity post-cytotoxic therapy is often weak, not durable and/or overcome by immune evasive mechanisms. In our recent study (Nat Commun 13:2063), we demonstrate that cancer cell-intrinsic activation of the cyclooxygenase (COX)-2/prostaglandin E2 (PGE2) pathway post-chemotherapy treatment is a prevalent phenomenon which profoundly alters the inflammatory properties of the treated cancer cells. Of particular translational relevance, our findings support a model whereby upregulation of COX-2 expression and activity post-chemotherapy impairs the efficacy of the combination of PD-1 blockade and chemotherapy. Accordingly, pharmacological inhibition of COX-2 with celecoxib, an anti-inflammatory drug already used clinically, unleashed tumour control in preclinical models when given alongside chemoimmunotherapy combinations.
    • Long-term changes in body weight and serum cholesterol in heart transplant recipients

      Miura, K.; Yu, R.; Entwistle, T. R.; McKenzie, S. C.; Green, Adèle C; Population Health Department, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia (2022)
      Introduction: Long-term changes in weight and blood lipids beyond 12 months after heart transplantation are largely unknown. We quantified changes in weight, body mass index (BMI), blood cholesterol, and triglycerides in heart transplant recipients (HTRs) during the 36 months after transplantation, and we assessed the influence of statin therapy on these outcomes. Methods: Retrospective cohort study of adult HTRs, transplanted 1990-2017, in Queensland, Australia. From each patient's medical charts, we extracted weight, total cholesterol, triglycerides, and statin therapy at four time-points: time of transplant (baseline), and 12-, 24-, 36-month post-transplant. Changes in weight and blood lipids were assessed according to baseline BMI. Results: Among 316 HTRs, 236 (median age 52 years, 83% males) with available information were included. During the 36 months post-transplant, all patients gained weight (83.5-90.5 kg; p < .001), especially those with baseline BMI < 25.0 km/m2 (67.9-76.2 kg; p < .001). Mean blood cholesterol (4.60-4.90 mmol/L; p = .004) and mean blood triglycerides (1.79-2.18 mmol/L; p = .006) also increased significantly in all patients, particularly in those with baseline BMI ≥ 25.0 km/m2 but the differences were not significant (total cholesterol 4.42-5.13 mmol/L; triglycerides 1.76-2.47 mmol/L). Total cholesterol was highest in patients not taking statins, and levels differed significantly (p = .010) according to statin dosing changes during the 36 months post-transplant. Conclusion: Patients demonstrate significant rises in weight and blood lipids in the 36 months after heart transplantation.
    • High p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER(+) breast cancer

      Palafox, M.; Monserrat, L.; Bellet, M.; Villacampa, G.; Gonzalez-Perez, A.; Oliveira, M.; Brasó-Maristany, F.; Ibrahimi, N.; Kannan, S.; Mina, L.; et al. (2022)
      CDK4/6 inhibitors combined with endocrine therapy have demonstrated higher antitumor activity than endocrine therapy alone for the treatment of advanced estrogen receptor-positive breast cancer. Some of these tumors are de novo resistant to CDK4/6 inhibitors and others develop acquired resistance. Here, we show that p16 overexpression is associated with reduced antitumor activity of CDK4/6 inhibitors in patient-derived xenografts (n = 37) and estrogen receptor-positive breast cancer cell lines, as well as reduced response of early and advanced breast cancer patients to CDK4/6 inhibitors (n = 89). We also identified heterozygous RB1 loss as biomarker of acquired resistance and poor clinical outcome. Combination of the CDK4/6 inhibitor ribociclib with the PI3K inhibitor alpelisib showed antitumor activity in estrogen receptor-positive non-basal-like breast cancer patient-derived xenografts, independently of PIK3CA, ESR1 or RB1 mutation, also in drug de-escalation experiments or omitting endocrine therapy. Our results offer insights into predicting primary/acquired resistance to CDK4/6 inhibitors and post-progression therapeutic strategies.