• Corrigendum to 'Evaluation of senescent cells in intervertebral discs by lipofuscin staining' [Mech. Ageing Dev. 199 (2021) 1-9/111564]

      Veroutis, D.; Kouroumalis, A.; Lagopati, N.; Polyzou, A.; Chamilos, C.; Papadodima, S.; Evangelou, K.; Gorgoulis, Vassilis G; Kletsas, D.; Molecular Carcinogenesis Group, Department of Histology and Embryology, Medical School, National and Kapodistrian University of Athens, Athens, Greece; Biomedical Research Foundation, Academy of Athens, Athens, Greece (2021)
    • The EHA research roadmap: normal hematopoiesis

      Jaffredo, T.; Balduini, A.; Bigas, A.; Bernardi, R.; Bonnet, D.; Canque, B.; Charbord, P.; Cumano, A.; Delwel, R.; Durand, C.; et al. (2021)
    • Induction of APOBEC3 exacerbates DNA replication stress and chromosomal instability in early breast and lung cancer evolution

      Venkatesan, S.; Angelova, M.; Puttick, C.; Zhai, H. R.; Caswell, D. R.; Lu, W. T.; Dietzen, M.; Galanos, P.; Evangelou, K.; Bellelli, R.; et al. (2021)
    • Lack of consensus identifies important areas for future clinical research: Advanced Prostate Cancer Consensus Conference (APCCC) 2019 findings

      Vogl, U. M.; Beer, T. M.; Davis, I. D.; Shore, N. D.; Sweeney, C. J.; Ost, P.; Attard, G.; Bossi, A.; de Bono, J.; Drake, C. G.; et al. (2021)
    • Whole-genome analysis of Nigerian patients with breast cancer reveals ethnic-driven somatic evolution and distinct genomic subtypes

      Ansari-Pour, N.; Zheng, Y.; Yoshimatsu, T. F.; Sanni, A.; Ajani, M.; Reynier, J. B.; Tapinos, Avraam; Pitt, J. J.; Dentro, S.; Woodard, A.; et al. (2021)
    • BROWSE: A multicentre comparison of nine year outcomes in acellular dermal matrix based and complete submuscular implant-based immediate breast reconstruction-aesthetics, capsular contracture and patient reported outcomes

      Wilson, R. L.; Kirwan, Cliona C; O'Donoghue, J. M.; Linforth, R. A.; Johnson, R. K.; Harvey, James R; Nightingale Centre, Manchester University NHS Foundation Trust, Southmoor Road, Manchester, M23 9LT, UK. (2021)
    • Body mass index and cancer mortality in patients with incident type 2 diabetes: a population-based study of adults in England

      Alam, N. N.; Wright, A. K.; Rutter, M. K.; Buchan, I.; Ashcroft, D. M.; Sperrin, M.; Renehan, Andrew G; Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester (2021)
    • RASSF1A disrupts the NOTCH signaling axis via SNURF/RNF4-mediated ubiquitination of HES1

      Papaspyropoulos, A.; Angelopoulou, A.; Mourkioti, I.; Polyzou, A.; Pankova, D.; Toskas, K.; Lanfredini, S.; Pantazaki, A. A.; Lagopati, N.; Kotsinas, A.; et al. (2021)
    • Different directions for retro-inverso peptides

      Preston, George W; Stoller Biomarker Discovery Centre, Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK (2021)
    • The telomere length landscape of prostate cancer

      Livingstone, J.; Shiah, Y. J.; Yamaguchi, T. N.; Heisler, L. E.; Huang, V.; Lesurf, R.; Gebo, T.; Carlin, B.; Eng, S.; Drysdale, E.; et al. (2021)
    • The effects of ionising and non-ionising electromagnetic radiation on extracellular matrix proteins

      Tuieng, R. J.; Cartmell, S. H.; Kirwan, Cliona. C; Sherratt, M. J.; Division of Cell Matrix Biology & Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, UK (2021)
    • The impact of obesity and bariatric surgery on the immune microenvironment of the endometrium

      Naqvi, A.; MacKintosh, M. L.; Derbyshire, A. E.; Tsakiroglou, A. M.; Walker, T. D. J.; McVey, R. J.; Bolton, J.; Fergie, M.; Bagley, Steven; Ashton, Garry; et al. (2021)
    • Ezh2 is essential for the generation of functional yolk sac derived erythro-myeloid progenitors

      Neo, Wen H; Meng, Y.; Rodriguez-Meira, A.; Fadlullah, Muhammad Z H; Booth, C. A. G.; Azzoni, E.; Thongjuea, S.; de Bruijn, M.; Jacobsen, S. E. W.; Mead, A. J.; et al. (2021)
    • Pharmacological inhibition of LSD1 triggers myeloid differentiation by targeting GSE1 oncogenic functions in AML

      Nicosia, Luciano; Boffo, F. L.; Ceccacci, E.; Conforti, F.; Pallavicini, I.; Bedin, F.; Ravasio, R.; Massignani, E.; Somervaille, Tim C P; Minucci, S.; et al. (2021)
    • MiR-195 and its target SEMA6D regulate chemoresponse in breast cancer

      Baxter, Diana E; Allinson, L. M.; Al Amri, W. S.; Poulter, J. A.; Pramanik, A.; Thorne, J. L.; Verghese, E. T.; Hughes, T. A.; School of Medicine, University of Leeds, Leeds LS9 7TF, UK (2021)
    • Discovery of a first-in-class reversible DNMT1-selective inhibitor with improved tolerability and efficacy in acute myeloid leukemia

      Pappalardi, M. B.; Keenan, K.; Cockerill, Mark; Kellner, W. A.; Stowell, Alexandra; Sherk, C.; Wong, K.; Pathuri, S.; Briand, J.; Steidel, M.; et al. (2021)
    • Multi-trait genetic analysis identifies auto-immune loci associated with cutaneous melanoma

      Liyanage, U.; MacGregor, S.; Bishop, D. T.; Shi, J.; An, J.; Ong, J. S.; Han, X.; Scolyer, R. A.; Martin, N. G.; Medland, S. E.; et al. (2021)
    • Upfront autologous stem cell transplantation (ASCT) versus carfilzomib-cyclophosphamide-dexamethasone (KCd) consolidation with K maintenance in transplant-eligible, newly diagnosed (NDTE) multiple myeloma (MM)

      Yong, K.; Camilleri, M.; Wilson, W.; Ramasamy, K.; Streetly, M. J.; Sive, J.; Bygrave, C.; Chapman, M. A.; De Tute, R.; Chavda, S. J.; et al. (2021)
      Background: Upfront ASCT for NDTE MM remains under evaluation with high MRD rates following novel induction and consolidation (cons) strategies. Current phase 3 trials support ASCT, however these employ lenalidomide maintenance which predominantly benefits standard risk (SR) patients (pts). The CARDAMON trial investigated the role of ASCT using K based induction and maintenance. Methods: NDTE pts received 4 x KCd induction (K 20/56 mg/m2 biweekly, C 500 mg D 1,8,15, d 40mg weekly) before 1:1 randomisation to ASCT or 4 x KCd cons. All received 18 months K maintenance (56mg/m2 D1,8,15). Flow cytometric MRD (10-5) was assessed post induction, pre-maintenance and at 6 months maintenance. Primary endpoints were ≥VGPR post induction and 2-year PFS from randomisation. 210 randomised pts were needed to exclude a 10% non-inferiority margin with 15% 1-sided alpha, 80% power. Results: 281 pts were registered, median age 59y (33–74), 24% high risk [t(4;14), t(14;16), t(14;20) or del(17p)]. Post induction, ≥VGPR rate was 58.5%, ORR was 87% with similar responses for high risk vs SR. 52 pts did not proceed to PBSCH (6 MR, 16 PD, 19 toxicity, 4 deaths: 3 infection, 1 cardiac event, 7 other). 109 were randomised to ASCT, 109 to KCd cons. ≥VGPR rate was 78.5% after cons and 80.0% after ASCT (p = 0.8). Median KCd cons dose was 55.5 mg/m2, 99 (90.8%) pts completed 4 cycles, 104 (95.4%) pts received ASCT. After 2.6 years follow-up, median PFS was not reached for ASCT vs 3.8 years for cons (HR: 0.82 (70% CI 0.65, 1.05, p = 0.4). Observed 2-year PFS for ASCT was 75.5% vs 70.7% for cons; calculated difference in 2-year PFS rate (cons vs ASCT) was -4.5% (70% CI -9.2%, +1.1%, non-inferior). High risk pts had inferior outcomes to SR overall regardless of randomisation (2-year PFS ASCT: 52% vs 82% (HR 4.09); cons 48% vs 77% (HR 2.83)). 2 year PFS did not differ according to randomisation: SR 82% (ASCT) vs 77% (cons) HR: 1.29 (0.71-2.35); high risk: 52% (ASCT) vs 48% (cons) HR: 1.06 (0.50-2.23). MRD negativity post induction was 24.3% and similar by genetic risk. MRD negative rates were higher post ASCT (53.1%) than cons (35.8%) (p = 0.02) independent of genetics: SR 49% (ASCT) vs 36% (cons); high risk: 57% (ASCT) vs 32% (cons). G3+ adverse events to induction were infections (18.7%), hypertension (11.2%), anaemia (10.4%), cardiac disorders (3.6%), vomiting (2.2%), fatigue (2.2%), diarrhoea (1.8%). Conclusions: In NDMM receiving KCd induction and K maintenance, KCd cons was non-inferior to ASCT. High risk pts had inferior outcomes, that were not influenced by ASCT or cons randomisation.
    • Impact of increased hypofractionation on treatment cost

      Defourny, N.; Spencer, K.; Tunstall, D.; Cosgrove, V.; Kirkby, Karen J; Henry, A.; Lievens, Y.; Hall, P.; Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester (2021)
      Purpose or Objective The increased use of hypofractionated radiotherapy (RT) for prostate and breast cancer changes the activity within a department. Ultra-hypofractionation has been an international standard of care in palliative RT, particularly for bone metastases, for over 20 years. While expected to be cost-effective due to reduced attendances, many resources requiring capital investment cannot be released when fractions are forgone. We analyse the extent to which treatment costs are fixed (buildings etc), stepped (linear accelerators), variable (materials) or semi-variable (staff) and how total cost, from a healthcare provider perspective, reacts to change in departmental activity. Materials and Methods Using the treatment of bone metastases (with five differing strategies) as an exemplar, we used a time-driven activity-based approach to estimate the cost of RT in a single, large NHS provider (Leeds Teaching Hospitals NHS Trust). Costs are included from a provider perspective for the 2016/17 financial. Hospital level overhead were included at 15.4%. We estimate the treatment cost of five bone metastasis treatment strategies from the healthcare provider perspective and compare to NHS reimbursement tariff. The share of these costs attributable to fixed, semi-variable, stepped and variable costs was assessed. To consider the consequences of hypofractionation, the departmental fraction activity was systematically reduced (by up to 10,000 fractions per year) to assess the impact of this change upon the total cost of delivering remaining treatments with varying levels of disinvestment from staff and equipment. Results The estimated cost of delivering RT for bone metastases ranges from £376 for a single fraction to £3,700 for a fractionated 45Gy in 25# course. These align closely with NHS reimbursement, except for the SABR strategy where tariff during early commissioning exceeds total provider costs by 15.3%. Whilst semi-variable staff costs account for 28.0-39.5% of the total treatment cost, a somewhat larger proportion (38.5-54.8%) is attributable to fixed and stepped costs (Fig.1). The consequences of reducing fraction activity, upon the cost of remaining treatment courses, are illustrated in Fig.2. The greatest impact is seen in fractionated treatments. Disinvestment from semi-variable (staff) costs has a relatively modest impact upon remaining total costs whilst disinvestment from stepped costs (linear accelerators) has a greater impact on total cost although this can only be realised at thresholds aligning to equipment capacity. Conclusion In the long-term, hypofractionation offers a cost efficient mechanism to treat an increasing number of patients within the existing linear accelerator capacity. As a large majority of treatment costs are fixed/stepped, however, disinvest is complex and short to medium-term imbalances between demand and capacity will result in increased treatment costs. This may act as a disincentive to delivering hypofractionated treatment when reimbursement is on a per fraction basis.
    • Single-cell whole-exome DNA sequencing traces clonal trajectory in paired evolution of MGUS to multiple myeloma

      Ansari-Pour, N.; Salatino, S.; Weston-Bell, N.; Bryant, D.; Moreno, L. Y.; Vacca, A.; Zojer, N.; Zannettino, A.; Bowden, R.; Wedge, D.; et al. (2021)
      Background Accurate measurement of heterogeneity and reconstruction of evolutionary pathways are key to decipher clonal dynamics in tumour origins. Although bulk population genetic sequencing data has been used extensively to understand the life history of tumours, sequencing single cell DNA is likely to provide a much higher resolution of clonal dynamics and yield new insights into competing cellular populations with different genotypes. This is of significant importance when clonal evolution from a benign state to malignant disease is being considered, such as in the clonal evolution of MGUS to multiple myeloma (MM). Methods To this end, we further refined a multiple displacement amplification-based single cell whole-exome sequencing (scWES) protocol and applied it to examine MM cells (2 cases), and in one of these cases, probed evolution from a pre-existing MGUS stage in a paired setting. Single tumour cells were isolated from CD138+CD38+ fluorescence-activated cell sorted populations and CD3+ for T cells as germline controls. We developed a novel computational pipeline to accurately call somatic SNVs/indels and copy number aberration (CNA) events in the form of loss-of-heterozygosity (LOH) and gains in each single cell, identified drivers at the genome-wide level and reconstructed the tumour phylogeny while estimating and accounting for allelic dropout (N=176 single cells, 25× each cell). Results By focusing on the patient that allowed comparison of single cells at pre- and post-malignancy states, we show that pre-malignant subclones can be readily identified, and strikingly that malignant cells arise and expand from one of the MGUS subclones in the combined tumour phylogeny. Conclusions These results suggest that this scWES based method is a pragmatic approach to investigate clonal dynamics by allowing: 1) the analysis of genetic heterogeneity at the genome-wide level (much higher resolution than targeted panels), and 2) at low sequencing costs across large set of cells when compared with whole genome sequencing-based methods.