Now showing items 21-40 of 4358

    • Tailored functionalized magnetic nanoparticles to target breast cancer cells including cancer stem-like cells

      Lazaro-Carrillo, A; Calero, M; Aires, A; A, LC; Simoes, Bruno M; Latorre, A; Somoza, A; Clarke, Robert B; Miranda, R; Villanueva, A; et al. (2020)
      Nanotechnology-based approaches hold substantial potential to avoid chemoresistance and minimize side effects. In this work, we have used biocompatible iron oxide magnetic nanoparticles (MNPs) called MF66 and functionalized with the antineoplastic drug doxorubicin (DOX) against MDA-MB-231 cells. Electrostatically functionalized MNPs showed effective uptake and DOX linked to MNPs was more efficiently retained inside the cells than free DOX, leading to cell inactivation by mitotic catastrophe, senescence and apoptosis. Both effects, uptake and cytotoxicity, were demonstrated by different assays and videomicroscopy techniques. Likewise, covalently functionalized MNPs using three different linkers-disulfide (DOX-S-S-Pyr, called MF66-S-S-DOX), imine (DOX-I-Mal, called MF66-I-DOX) or both (DOX-I-S-S-Pyr, called MF66-S-S-I-DOX)-were also analysed. The highest cell death was detected using a linker sensitive to both pH and reducing environment (DOX-I-S-S-Pyr). The greatest success of this study was to detect also their activity against breast cancer stem-like cells (CSC) from MDA-MB-231 and primary breast cancer cells derived from a patient with a similar genetic profile (triple-negative breast cancer). In summary, these nanoformulations are promising tools as therapeutic agent vehicles, due to their ability to produce efficient internalization, drug delivery, and cancer cell inactivation, even in cancer stem-like cells (CSCs) from patients.
    • Hydroxychloroquine/ chloroquine as a treatment choice or prophylaxis for Covid-19 at the primary care level in developing countries: A Primum non Nocere dilemma

      Medina MT; Moncada, Salvador; Faculty of Medical Sciences, National Autonomous University of Honduras, WFN Regional Director for Latin America, Tegucigalpa, Honduras. (2020)
      The Food and Drug Administration (FDA) warned against the use of Hydroxychloroquine or chloroquine for Covid-19 outside of a hospital or a clinical trial setting due to the risk of QT interval prolongation, ventricular tachycardia and the increased risk of these complications when combined with some antibiotics such as azithromycin. Several studies have reported no benefit of Hydroxychloroquine or chloroquine, when used alone or with a macrolide in COVID-19 hospitalized patients. Despite these warnings, in several developing countries the official guidelines for treatment of Covid-19 patients at the primary care level recommend Hydroxychloroquine and azithromycin, among other treatments, as the first-choice for mild symptomatic Covid-19 patients, asymptomatic contacts or for prophylaxis. In our opinion there is a primum non nocere dilemma during this Covid-19 pandemic. In order to solve this bioethical problem, we strongly recommend that a randomized controlled trial in a primary care setting be carried out as a matter of urgency in these areas of the world. Keywords: Bioethics; Clinical trials; Developing countries; Hydroxychloroquine/ chloroquine; Primary care.
    • Does tamoxifen have a therapeutic role outside of breast cancer? A systematic review of the evidence

      Clifford, RE; Bowden, D; Blower, E; Kirwan, Cliona C; Vimalachandran, D; Institute of Cancer Medicine, The University of Liverpool, UK. (2020)
      Introduction: Tamoxifen is a widely used hormonal based therapy for breast cancer in the adjuvant and metastatic setting, prolonging overall and recurrence-free survival. There has been increasing interest in the potential for novel 'off-target' effects of tamoxifen and its metabolite N-desmethyltamoxifen across a number of cancer types. We aim to review the current literature regarding the potential use of tamoxifen in other primary malignancies. Method: A qualitative systematic review was performed according to the PRISMA guidelines using pre-set search criteria across the PubMed, Cochrane and Scopus databases from 1985 to 2019. Additional results were generated from included papers references. Results: A total of 324 papers were identified, of which 47 were included; a further 29 articles were obtained from additional referencing to give a total of 76 articles. Clinical trials have demonstrated benefits with the use of tamoxifen in isolation and combination, specifically in patients with advanced non-resectable malignancy, however results are not consistent across the literature. In vivo data consistently suggests that off target effects of tamoxifen are mediated through the ceramide pathway or through inhibition of protein kinase C (PKC). Conclusions: With increased focus upon the potential of repurposing drugs, tamoxifen may be a candidate for repurposing in the wider cancer setting. There is evidence to suggest that the ceramide or PKC pathway could act as a therapeutic target for tamoxifen or alternative chemotherapeutics and merits further investigation.
    • The relationship between tumour associated macrophage markers and tumour, demographic & behavioural factors in breast cancer

      Singh, U; Castle, J; Greenhalgh, S; Hussain, U; Descamps, Tine; Nash, S; Wilson, M; Hunt, R; Kirwan, CC; University of Manchester, Manchester (2020)
      BACKGROUND: Tumour associated macrophages (TAMs) are prognostic markers in breast cancer, however the influence of patient demographic and behavioural factors on these inflammatory markers has not been fully appreciated. METHODS: In 201 invasive breast cancer and 58 ductal carcinoma in-situ (DCIS) patients, TAM density (percentage % CD68 [IHC-immunohistochemistry] positive cells) was correlated with tumour factors (grade, proliferation (Ki67), ER, HER2); demographic factors (age, menopausal status, breast density, BMI, diabetes) and behavioural factors (smoking, alcohol). RESULTS: TAM density was increased in invasive breast cancer, compared to DCIS, and normal tissue distant from the tumour (59%, 41% and 6% respectively; p<0.001). In invasive cancer, TAM density increased with increasing tumour grade (Grade 1: 42%, Grade 2: 58%, Grade 3: 72%; p=0.006), high Ki67 (71% vs. 47%; p=0.004), ER negativity (70% vs. 51%; p=0.02) and HER2 (HER2 positive 77% vs. HER2 negative 55%; p=0.055). TAM density was higher in high compared to low/intermediate DCIS (44% % vs 31% respectively). In terms of demographic factors, TAM density did not correlate with age, menopausal status, breast density (BIRADs), BMI or history of diabetes. TAM density was not increased in patients who smoked; however, it was increased in patients who self-reported alcohol intake (non-drinker 43% vs. drinker 62%; p=0.01). CONCLUSION: TAM density shows utility in identifying aggressive breast cancer sub-types. The association reported between TAM density and alcohol intake suggests a possible mechanism for alcohol as a risk factor for breast cancer.
    • Topological features of integrin adhesion complexes revealed by multiplexed proximity biotinylation

      Chastney, MR; Lawless, C; Humphries, JD; Warwood, S; Jones, MC; Knight, D; Jorgensen, Claus; Humphries, MJ; Wellcome Centre for Cell-Matrix Research, Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK. (2020)
      Integrin adhesion complexes (IACs) bridge the extracellular matrix to the actin cytoskeleton and transduce signals in response to both chemical and mechanical cues. The composition, interactions, stoichiometry, and topological organization of proteins within IACs are not fully understood. To address this gap, we used multiplexed proximity biotinylation (BioID) to generate an in situ, proximity-dependent adhesome in mouse pancreatic fibroblasts. Integration of the interactomes of 16 IAC-associated baits revealed a network of 147 proteins with 361 proximity interactions. Candidates with underappreciated roles in adhesion were identified, in addition to established IAC components. Bioinformatic analysis revealed five clusters of IAC baits that link to common groups of prey, and which therefore may represent functional modules. The five clusters, and their spatial associations, are consistent with current models of IAC interaction networks and stratification. This study provides a resource to examine proximal relationships within IACs at a global level.
    • Technical evaluation of commercial mutation analysis platforms and reference materials for liquid biopsy profiling

      Weber, S; Spiegl, B; Perakis, SO; Ulz, CM; Abuja, PM; Kashofer, K; Leest, PV; Azpurua, MA; Tamminga, M; Brudzewsky, D; et al. (2020)
      Molecular profiling from liquid biopsy, in particular cell-free DNA (cfDNA), represents an attractive alternative to tissue biopsies for the detection of actionable targets and tumor monitoring. In addition to PCR-based assays, Next Generation Sequencing (NGS)-based cfDNA assays are now commercially available and are being increasingly adopted in clinical practice. However, the validity of these products as well as the clinical utility of cfDNA in the management of patients with cancer has yet to be proven. Within framework of the Innovative Medicines Initiative (IMI) program CANCER-ID we evaluated the use of commercially available reference materials designed for ctDNA testing and cfDNA derived from Diagnostic Leukaphereses (DLA) for inter- and intra-assay as well as intra- and inter-laboratory comparisons. In three experimental setups, a broad range of assays including ddPCR, MassARRAY and various NGS-based assays were tested. We demonstrate that both reference materials with predetermined VAFs and DLA samples are extremely useful for the performance assessment of mutation analysis platforms. Moreover, our data indicate a substantial variability of NGS assays with respect to sensitivity and specificity highlighting the importance of extensive validation of the test performance before offering these tests in clinical routine practice. Keywords: assay validation; cell-free DNA; cfDNA; circulating tumor DNA; ctDNA; diagnostic leukaphereses; molecular profiling; mutation analysis; performance assessment; reference material.
    • Author Correction: The Aurora B specificity switch is required to protect from non-disjunction at the metaphase/anaphase transition

      Kelly, Joanna; Martini, S; Brownlow, N; Joshi, D; Federico, S; Jamshidi, S; Kjaer, S; Lockwood, N; Rahman, KM; Fraternali, F; et al. (2020)
      The original version of this article contained an error in the spelling of the author Khondaker Miraz Rahman, which was incorrectly given as Khondaker Miraz Rahmen. This has now been corrected in the PDF and HTML versions of the article.
    • Anxiety and depression after diagnosis of high-risk primary cutaneous melanoma: a 4-year longitudinal study

      Beesley, VL; Hughes, MCB; Smithers, BM; Khosrotehrani, K; Malt, MK; von Schuckmann, LA; Green, Adèle C; Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia. (2020)
      Purpose: To quantify the prevalence of anxiety or depression (overall; melanoma-related) among people with high-risk primary melanoma, their related use of mental health services and medications, and factors associated with persistent new-onset symptoms across 4 years post-diagnosis. Methods: A longitudinal study of 675 patients newly diagnosed with tumor-stage 1b-4b melanoma. Participants completed the Hospital Anxiety and Depression Scale and answered questions about fear of cancer recurrence, use of medication, and support, serially over 4 years. We identified anxiety and depression trajectories with group-based trajectories models and factors associated with persistent symptoms with logistic regression. Results: At diagnosis, 93 participants (14%) had melanoma-related anxiety or depression, and 136 (20%) were affected by anxiety and/or depression unrelated to melanoma. After 6 months, no more than 27 (5%) reported melanoma-related anxiety or depression at any time, while the point prevalence of anxiety and depression unrelated to melanoma was unchanged (16-21%) among the disease-free. Of 272 participants reporting clinical symptoms of any cause, 34% were taking medication and/or seeing a psychologist or psychiatrist. Of the participants, 11% (n = 59) had new-onset symptoms that persisted; these participants were more likely aged < 70. Conclusions: Melanoma-related anxiety or depression quickly resolves in high-risk primary melanoma patients after melanoma excision, while prevalence of anxiety or depression from other sources remains constant among the disease-free. However, one-in-ten develop new anxiety or depression symptoms (one-in-twenty melanoma-related) that persist. Implications for cancer survivors: Chronic stress has been linked to melanoma progression. Survivors with anxiety and depression should be treated early to improve patient and, potentially, disease outcomes. Keywords: Anxiety; Depression; Distress; Fear of recurrence; Melanoma.
    • The proportion of cancers attributable to social deprivation: A population-based analysis of Australian health data

      Wilson, LF; Green, Adèle C; Jordan, SJ; Neale, RE; Webb, PM; Whiteman, DC; Population Health Department, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Queensland, 4006, Australia; (2020)
      Background: Cancer is a major disease burden globally and people who are socioeconomically disadvantaged have a higher incidence of many types of cancer. We investigated the potential to reduce socioeconomic disparities in cancer incidence in Australia by lowering the prevalence of exposure to four modifiable causes: smoking, alcohol, overweight/obesity and physical inactivity. Methods: We used cancer incidence data from the Australian Cancer Database and risk factor prevalence data from the Australian National Health Survey to estimate the proportions of cancers attributable to the four factors, by area-level socioeconomic disadvantage. For the three risk factors where prevalence was lowest among the least disadvantaged (smoking, overweight/obesity, physical inactivity), we also estimated the potential impact of reducing prevalence in the most disadvantaged areas to that in the least disadvantaged areas. Results: The proportion of cancer attributable to the four factors in combination ranged from 22 % in the most disadvantaged areas to 14 % in the least disadvantaged areas. If the prevalence of tobacco smoking, overweight/obesity and physical inactivity in the more disadvantaged areas were the same as that in the least disadvantaged, an estimated 19,500 cancers (4 % of all cancers diagnosed) could have been prevented in Australia between 2009 and 2013. Conclusions: Reducing the prevalence of key causal factors in areas of greater social disadvantage would prevent many cases of cancer. Strategies to achieve this in highly disadvantaged areas are needed. Keywords: Alcohol; Cancer; Obesity; Physical inactivity; Population attributable fraction; Potential impact fraction; Socioeconomic disadvantage; Tobacco smoking.
    • Pan-cancer analysis of whole genomes

      Campbell, P. J.; Getz, G.; Korbel, J. O.; Stuart, J. M.; Jennings, J. L.; Stein, L. D.; Perry, M. D.; Nahal-Bose, H. K.; Ouellette, B. F. F.; Li, C. H.; et al. (2020)
      Fibrosis and fat replacement in skeletal muscle are major complications that lead to a loss of mobility in chronic muscle disorders, such as muscular dystrophy. However, the in vivo properties of adipogenic stem and precursor cells remain unclear, mainly due to the high cell heterogeneity in skeletal muscles. Here, we use single-cell RNA sequencing to decomplexify interstitial cell populations in healthy and dystrophic skeletal muscles. We identify an interstitial CD142-positive cell population in mice and humans that is responsible for the inhibition of adipogenesis through GDF10 secretion. Furthermore, we show that the interstitial cell composition is completely altered in muscular dystrophy, with a near absence of CD142-positive cells. The identification of these adipo-regulatory cells in the skeletal muscle aids our understanding of the aberrant fat deposition in muscular dystrophy, paving the way for treatments that could counteract degeneration in patients with muscular dystrophy.
    • Favourable outcomes for high-risk diffuse large b-cell lymphoma (IPI 3-5) treated with front-line r-CODOX-M/R-IVAC chemotherapy: results of a phase 2 UK NCRI Trial

      McMillan, A. K.; Phillips E H; Kirkwood, A. A.; Barrans, S.; Burton, C.; Rule, S.; Patmore, R.; Pettengell, R.; Ardeshna, K. M.; Lawrie, A.; et al. (2020)
      BACKGROUND: Outcomes for patients with high-risk diffuse large B-cell lymphoma (DLBCL) treated with R-CHOP chemotherapy are suboptimal but, to date, no alternative regimen has been shown to improve survival rates. This phase 2 trial aimed to assess the efficacy of a Burkitt-like approach for high-risk DLBCL using the dose-intense R-CODOX-M/R-IVAC regimen. PATIENTS AND METHODS: Eligible pts were aged 18-65 years with stage II-IV untreated DLBCL and an International Prognostic Index (IPI) score of 3-5. Patients received alternating cycles of CODOX-M and IVAC (cyclophosphamide, vincristine, doxorubicin and high-dose methotrexate [CODOX-M] alternating with ifosfamide, etoposide and high-dose cytarabine [IVAC]) chemotherapy plus 8 doses of rituximab. Response was assessed by CT after completing all 4 cycles of chemotherapy. The primary endpoint was 2-year progression-free survival (PFS). RESULTS: 111 eligible patients were registered; median age was 50 years, IPI score was 3 (60.4%) or 4-5 (39.6%), 54% had a performance status /=2 and 9% had central nervous system involvement. 85 patients (76.6%) completed all 4 cycles of chemotherapy. There were 5 treatment-related deaths (4.3%)
    • Map3k1 loss cooperates with Braf(V600E) to drive melanomagenesis

      Trucco, Lucas D; Mundra, Piyushkumar A; Garcia-Martinez, Pablo; Hogan, Kate; Baenke, Franziska; Dhomen, Nathalie; Pavet Valeria; Marais, Richard; Molecular Oncology Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, (2020)
      No abstract available
    • Prognostic gene expression signature for high-grade serous ovarian cancer

      Millstein, J.; Budden, Timothy; Goode, E. L.; Anglesio, M. S.; Talhouk, A.; Intermaggio, M. P.; Leong, H. S.; Chen, S.; Elatre, W.; Gilks, B.; et al. (2020)
      BACKGROUND: Median overall survival (OS) for women with high-grade serous ovarian cancer (HGSOC) is approximately four years, yet survival varies widely between patients. There are no well-established, gene expression signatures associated with prognosis. The aim of this study was to develop a robust prognostic signature for overall survival in HGSOC patients. PATIENTS AND METHODS: Expression of 513 genes, selected from a meta-analysis of 1455 tumours and other candidates, were measured using NanoString technology from formalin-fixed, paraffin-embedded (FFPE) tumour tissue from 3,769 women with HGSOC from multiple studies. Elastic net regularization for survival analysis was applied to develop a prognostic model for 5-year OS, trained on 2702 tumours from fifteen studies and evaluated on an independent set of 1067 tumours from six studies. RESULTS: Expression levels of 276 genes were associated with OS [false discovery rate (FDR) < 0.05] in covariate-adjusted single gene analyses. The top five genes were TAP1, ZFHX4, CXCL9, FBN1, and PTGER3 (P < 0.001). The best performing prognostic signature included 101 genes enriched in pathways with treatment implications. Each gain of one standard deviation in the gene expression score (GES) conferred a greater than two-fold increase in risk of death [HR = 2.35 (2.02, 2.71); P < 0.001]. Median survival by GES quintile was 9.5 (8.3, --), 5.4 (4.6, 7.0), 3.8 (3.3, 4.6), 3.2 (2.9, 3.7) and 2.3 (2.1, 2.6) years. CONCLUSION: The OTTA-SPOT (Ovarian Tumor Tissue Analysis consortium - Stratified Prognosis of Ovarian Tumours) gene expression signature may improve risk stratification in clinical trials by identifying patients who are least likely to achieve 5-year survival. The identified novel genes associated with the outcome may also yield opportunities for the development of targeted therapeutic approaches.
    • Glucocorticoids rapidly inhibit cell migration through a novel, non-transcriptional HDAC6 pathway

      Kershaw, Stephen; Morgan, D. J.; Boyd, J.; Spiller, D. G.; Kitchen, G.; Zindy, E.; Iqbal, M.; Rattray, M.; Sanderson, C. M.; Brass, A.; et al. (2020)
      Glucocorticoids (GCs) act through the glucocorticoid receptor (GR) to regulate immunity, energy metabolism, and tissue repair. Upon ligand binding, activated GR mediates cellular effects by regulating gene expression, but some GR effects can occur rapidly without new transcription. We show GCs rapidly inhibit cell migration, in response to both GR agonist and antagonist ligand binding. The inhibitory effect on migration is prevented by GR knockdown with siRNA, confirming GR specificity, but not by actinomycin D treatment, suggesting a non-transcriptional mechanism. We identified a rapid onset increase in microtubule polymerisation following glucocorticoid treatment, identifying cytoskeletal stabilisation as the likely mechanism of action. HDAC6 overexpression, but not knockdown of alphaTAT1, rescued the GC effect, implicating HDAC6 as the GR effector. Consistent with this hypothesis, ligand-dependent cytoplasmic interaction between GR and HDAC6 was demonstrated by quantitative imaging. Taken together, we propose that activated GR inhibits HDAC6 function and thereby increases the stability of the microtubule network to reduce cell motility. We therefore report a novel, non-transcriptional mechanism whereby GCs impair cell motility through inhibition of HDAC6 and rapid reorganization of the cell architecture.
    • Differences in site-specific incidence and relative survival of cutaneous and mucocutaneous genital squamous cell carcinoma in Germany, 2007-2015

      Stang, A.; Wellmann, I.; Kajuter, H.; Trocchi, P.; Becker, J. C.; Green, Adèle, C; Jockel, K. H.; Khil, L.; Institute of Medical Informatics, Biometry and Epidemiology, University Hospital Essen, Germany. (2020)
      Direct comparisons of the incidence and survival of cutaneous vs mucocutaneous genital squamous cell carcinomas (SCCs) are lacking even though they may bring important insights. We aimed to compare incidence rates and survival of cutaneous and mucocutaneous genital SCCs head-to-head, using the same source population, cancer registry methodology and statistical methods in a population of predominantly white Caucasian descent. Using data (2007-2015) from the population-based cancer registry of North Rhine-Westphalia, (population of 18 million people), we estimated age-specific and age-standardized (old European standard) incidence rates and age-standardized relative 5-year survival of SCC with the period approach for the period 2012 to 2015. Overall, 83 650 SCC cases were registered. The age-standardized incidence rates (per 100 000 person-years) of cutaneous SCCs were 36.5 (SE SE 0.17) and 17.0 (SE 0.11) among men and women respectively with corresponding rates for mucocutaneous genital skin, 1.3 (SE 0.03) and 4.5 (SE 0.06) for men and women respectively. In all age groups, incidence rates of mucocutaneous genital SCCs were higher in women than men. Men had higher cutaneous SCC incidence at all non-genital subsites than women, with the exception of the lower extremities. Five-year relative survival was considerably lower for mucocutaneous genital SCCs (men: 71%, women: 75%), especially of the scrotal skin (67%) and labia majora (62%), than for SCC of non-genital skin (men: 93%, women: 97%). Given their relatively high incidence together with a lower survival probability, future studies are warranted to establish therapies for advanced mucocutaneous genital SCC, such as immune checkpoint inhibition. This article is protected by copyright. All rights reserved.
    • Primary breast tumours but not lung metastases induce protective anti-tumour immune responses after Treg-depletion

      Hughes, Ellyn; Lauder, S. N.; Smart, K.; Bloom, A.; Scott, J.; Jones, E.; Somerville, M.; Browne, M.; Blainey, A.; Godkin, A.; et al. (2020)
      Although metastatic disease is responsible for the majority of cancer deaths, tests of novel immunotherapies in mouse tumour models often focus on primary tumours without determining whether these therapies also target metastatic disease. This study examined the impact of depleting Foxp3(+) regulatory T cells (Treg), on lung metastases, using a mouse model of breast cancer. After Treg-depletion, generation of an immune response to the primary tumour was a critical determinant for limiting development of metastasis. Indeed, resection of the primary tumour abrogated any effect of Treg-depletion on metastases. In addition, whilst the immune response, generated by the primary tumour, prevented metastases development, it had little impact on controlling established disease. Collectively, the data indicate that metastatic cells in the lung are not controlled by immune responses induced by the primary tumour. These findings indicate that targeting Tregs alone will not suffice for treating lung metastases.
    • Abatacept acute graft-versus-host disease prophylaxis is feasible and safe when combined with post-transplant cyclophosphamide in the mobilised peripheral blood haploidentical donor setting

      Yong, J.; Patel, Alkesh; Haematology, Clatterbridge Cancer Centre, Liverpool (2020)
      Acute graft-versus-host disease (aGVHD) remains a major limitation to allogeneic haematopoietic stem cell transplantation (HSCT), associated with high patient morbidity and mortality. Steroid refractory acute GVHD (SR-aGVHD) has the highest mortality (around 80%) despite treatment intensi'cation with available immunosuppressive therapy. This is complicated by poor response rates alongside increased toxicity and infectious complications from profound immunosuppression and prolonged uncontrolled GVHD. Novel immunotherapeutic strategies are therefore urgently needed for treatment of SR-aGVHD. Immunological manipulation of T-cell activation is a novel therapeutic treatment approach for aGVHD. Abatacept, a CTLA4-Ig exerting CD28-CD80/CD86 axis T-cell co-stimulation blockade, has been shown in the phase 1 clinical trial setting to be safe, well tolerated without dose limiting toxicities (DLTs), and ef'cacious in the treatment of heavily pretreated chronic extensive GVHD (cGVHD). Marked improvement in National Institutes of Health cGVHD scores alongside signi'cantly reduced steroid dose requirement in this cohort have led to a phase 2 trial (NCT01954979) and National Comprehensive Cancer Network (NCCN) recommendation. T-cell activation is a key component of aGvHD but it is currently unknown if Abatacept represents a potential therapy for SR-aGVHD. We report the feasibility, safety and ef'cacy of Abatacept added to the management of SR-aGVHD in a cohort of four heavily pretreated patients in a single centre. Institutional compassionate access was granted after exhaustion of all available therapies. Three of the four patients developed aGvHD after donor lymphocyte infusion (DLI), in the absence of pre-DLI conditioning or GVHD prophylaxis. Median overall MAGIC aGVHD score was 4, with two patients having predominant stage 4 gut aGVHD and two patients with predominant stage 4 skin aGVHD. The median prior lines of treatment were 5, including steroid therapy (Prednisolone or Methylprednisolone 2 mg/kg/day), calcineurin or mTOR inhibitor, mycophenolic acid and extracorporeal photophoresis (ECP) with 8methoxypsoralen (8-MOP). Patients with gut aGVHD were also treated with vedolizumab and/or in'iximab. Abatacept 10 mg/kg was administered IV in addition to concurrent treatments for SR-aGVHD at d0, d+14, d+28, d+56, d+72 and d+90. If a clinical response was observed after 6 doses, Abatacept was continued every 4'6 weeks up to 12 doses. Two patients achieved a clinical partial response and one patient a clinical complete response at d+100 after initiation of Abatacept. Importantly all patients achieved a median dose reduction in steroids of 98% by d+100. Three patients had viral reactivation diagnosed prior to Abatacept initiation (median of d'155 before Abatacept). Importantly, no new viral reactivations were detected in any patients after Abatacept initiation. No DLTs were observed; bacterial infections were not considered a DLT if they had already occurred with prior therapies, being attributed to pre-existing severe immunosuppression and SRaGVHD. We observed that patients with less than CR by d+100 developed chronic GVHD of the involved organ. Mortality was observed only in the two patients with gut involvement, as a result of chronic malnutrition and recurrent immunocompromised infection. Our experience suggests that Abatacept for SR-aGvHD is feasible, appears safe and may have ef'cacy in some patients. A prospective clinical trial is planned.
    • Genome-wide association meta-analyses combining multiple risk phenotypes provide insights into the genetic architecture of cutaneous melanoma susceptibility

      Landi, MT; Bishop, D T; MacGregor, S; Machiela, MJ; Stratigos, AJ; Ghiorzo, P; Brossard, M; Calista, D; Choi, J.; Fargnoli, MC; et al. (2020)
      Most genetic susceptibility to cutaneous melanoma remains to be discovered. Meta-analysis genome-wide association study (GWAS) of 36,760 cases of melanoma (67% newly genotyped) and 375,188 controls identified 54 significant (P < 5 x 10(-8)) loci with 68 independent single nucleotide polymorphisms. Analysis of risk estimates across geographical regions and host factors suggests the acral melanoma subtype is uniquely unrelated to pigmentation. Combining this meta-analysis with GWAS of nevus count and hair color, and transcriptome association approaches, uncovered 31 potential secondary loci for a total of 85 cutaneous melanoma susceptibility loci. These findings provide insights into cutaneous melanoma genetic architecture, reinforcing the importance of nevogenesis, pigmentation and telomere maintenance, together with identifying potential new pathways for cutaneous melanoma pathogenesis.
    • Induction oxaliplatin capecitabine followed by switch to carboplatin-paclitaxel based RT versus continuing oxaliplatin capecitabine RT in operable esophageal adenocarcinoma: Survival analysis of the randomized phase II neoscope trial

      Mukherjee, S.; Hurt, C.; Cox, C.; Radhakrishna, Ganesh; Gwynne, S.; Bateman, A. R.; Gollins, S.; Hawkins, M. A.; Canham, J.; Grabsch, H. I.; et al. (2020)
      Background: Initial results of the NEOSCOPE trial comparing pre-operative CarPac vs OxCap based chemoradiotherapy (CRT) in patients with adenocarcinoma of the oesophagus or oesophagogastric junction showed comparable toxicity and improvement in pathological complete response (pCR) in favour of the CarPacRT. Here we report survival after a median follow-up of 40.7 months (95% CI: 45.1-53.6). Methods: NEOSCOPE was an open, randomised, 'pick a winner' phase II trial. Patients with resectable oesophageal adenocarcinoma ' cT3 and/or ' cN1 were randomised to OxCapRT (oxaliplatin 85 mg/m2 day 1, 15, 29; capecitabine 625 mg/m2 bd on days of RT) or CarPacRT (carboplatin AUC2; paclitaxel 50 mg/m2 day 1, 8, 15, 22, 29). RT dose was 45 Gy/25 fractions/5 weeks. Induction OxCap (2 cycles) was given prior to CRT. Surgery was performed 6'8 weeks after CRT.The primary endpoint was pCR, secondary endpoints were toxicity, PFS and OS. Results: Between Oct 2013 and Feb 2015, 85 patients were recruited from 17 UK centres. Median OS was not reached in the CarPacRT group and was 41.72 months (95% CI 19.58-.)in the OxCap group (HR 0.56[95% CI 0.29-1.07]; p=0.079). 3-year and 5-year OS rates were 74% (95% CI 58%-85%) and 54% (95% CI 34%-71%) (CarPacRT), and 52% (95% CI 35%-67%) and 39% (95% CI 21%-56%) (OxCapRT). Median PFS (not reached vs 35.3 months, HR=0.61 [95% CI 0.33-1.12]; p=0.111) and metastatic PFS (not reached vs 39.0 months, HR=0.61 [95% CI 0.32-1.14], p=0.118) both favoured the CarPacRT arm. Local recurrence rate was low (OxCapRT= 10%; CarPacRT= 7%). The OS benefit for CarPacRT was consistent across subgroups but not statistically significant. Conclusions: In this longer term analysis there was some evidence that induction OxCap followed by switch to CarPacRT was superior to continuing OxCapRT, with efficacy similar to that seen in other published studies such as 'CROSS' and 'FLOT?. Taken together with the previously published pCR results CarPacRT rather than OxCapRT warrants inclusion in future trials. Funding: Cancer Research UK (C44694/A14614). Clinical trial information: NCT01843829.
    • Post discharge care needs for patients with treated Primary CNS Lymphoma - a baseline single centre retrospective study

      Omer, E; Linton, Kim M; Cowan, Richard A; Faculty of Biology, Medicine and Health, University of Manchester, (2020)
      Primary central nervous system lymphoma (PCNSL) is a rare lymphoma localised to the brain, leptomeninges or eyes. It is a subtype of diffuse large B-cell lymphoma accounting for 1% of non-Hodgkin lymphoma. It presents with a range of non-speci'c symptoms such as seizure and hemianopia which can be confused with other diseases of the older population hence it takes longer to reach a diagnosis. Modern multiagent induction chemotherapy, MATRix (high-dose methotrexate, cytarabine with thiotepa and rituximab) followed by whole-brain radiotherapy or stem cell transplantation consolidation has signi'cantly improved survival rates and created, in parallel, a survivor population with unmet and poorly de'ned treatment and disease-related care needs. Since there is a lack of research and experience of issues and support needs of these patients so we performed a retrospective analysis to describe the supportive care needs, available services and unmet needs of patients with PCNSL following treatment at a single tertiary care centre. Newly diagnosed patients with PCNSL consecutively treated at The Christie NHS Foundation Trust between January 2012 and December 2018 were identi'ed from hospital records. Patients receiving initial treatment with at least one cycle of multiagent chemotherapy or whole-brain radiotherapy and survived for a minimum of 3 months from the start of treatment were included as this study focused on later manifestations of the condition. Clinical records for 10 randomly selected patients were reviewed to identify the most common care needs during and after completion of planned treatment. Worse grade symptom severity was graded using the common terminology criteria for adverse events grading system version 4.03. Referrals for supportive care in the community following completion of planned treatment and unmet care needs were identified and recorded. Sixty-two patients were identi'ed from the initial search, and 42 met the inclusion criteria. The patient population was made up of 20 males and 22 females with the age ranging from 36 to 91 and peaks at 56 and 66 for males and females respectively. Thirty-six patients received chemotherapy with just under 50% completing the four cycles. In terms of survival, 26 patients were alive as of 1 April 2019 when this study was completed. Poor mobility was the most common support need ' present in 80% of patients ' followed by fatigue in 60%, poor nutrition in 48%, inability to perform activities of daily living in 43% and cognitive problems in 24% of patients. Over 73% of the study population were referred to community support services ' physiotherapy (31 patients), occupational therapy (29 patients), dietician (23 patients) and specialist allied health professionals were directly involved in the care of 15 patients. We also found that in most patients, their needs were met as an inpatient, however, following discharge due to reasons such as weak documentation of symptomatic needs, lack of referral or shortage of services in their area needs were missed. A high proportion of treated PCNSL patients have ongoing care needs following discharge from the hospital, but this information is incompletely and inconsistently recorded in the patient record. We are developing a patient-reported outcomes measures tool to identify common care needs for referral and follow-up. This tool will be prospectively audited and gaps in service provision across Greater Manchester identi'ed for future service development.