• 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.
    • Real-world experience of regorafenib in patients with hepatocellular carcinoma: A multicenter United Kingdom study

      Ross, P. J.; Ma, Y. T.; Palmer, D. H.; Lythgoe, M. P.; Merrick, S.; Samson, A.; Rao, A. R.; Basu, B.; Prasad, D.; Dhillon, T.; et al. (2020)
      Background: Regorafenib was the first treatment to demonstrate a survival benefit in patients with HCC after progression on sorafenib. The RESORCE trial found that regorafenib improved overall survival with acceptable toxicity, in patients with disease progression on sorafenib who tolerated '400mg sorafenib daily and had Child-Pugh A liver function. Methods: We performed a multicentre, retrospective, observational study of patients with HCC receiving regorafenib in the UK, following its availability in April 2018. Results: Data on a total of 104 patients were included from April 2018'August 2019, and 80.8% were male. Age was collected in 85 patients, with a median of 68 years (range 22'86). 23.5% had NAFLD, 21.2% had ALD, 12.9% had HBV, and 3.5% had HCV. Prior management included sorafenib (100%), TACE (30.8%), resection (12.9%). Duration of sorafenib treatment was evaluable in 99/104 patients, and reported a median of 8.7 months (range 1.8'76.6). Duration of regorafenib treatment was evaluable in 92/104 patients, and reported a median of 3.9 months (range 0.0'15.7). Following treatment with regorafenib, 6 patients (5.8%) achieved partial response, 37 (35.6%) achieved stable disease and 45 (43.3%) had progressive disease as the best response. 15 (14.4%) were not assessed and 1 (1.1%) had mixed response. Survival data is immature with 62/101 (61.4%) patients alive at the time of census with median survival currently 6.5 months. Fatigue was the most frequent AE, with 69/88 patients (85.2%) for all grades. 12/88 patients (14.8%) had Grade 3 fatigue. Other significant AEs include hand-foot syndrome (6/85 patients [7.3%] had Grade 3) and diarrhoea (4/83 patients [4.9%] had Grade 3). Conclusions: The population in our real-world experience of regorafenib for HCC had a similar duration of prior sorafenib to those in the RESORCE trial. However, there was different balance of aetiologies with a lower proportion of patients with HBV and HCV. The rate of partial response is similar to the RESORCE trial with fewer patients achieving stable disease. The incidence of fatigue was higher, but the incidence of hand-foot syndrome and diarrhoea were lower. Further expansion and follow-up of this population is warranted.
    • Sex difference in patients with biliary tract cancer receiving chemotherapy: Post hoc analysis of ABC-01,-02,-03,-04, BILCAP

      Suzuki, E.; Bridgewater, J. A.; Valle, Juan W; Primrose, J. N.; Wagner, A. D.; Lopes, A.; Fox, R.; Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan (2020)
      Background: The relationship between toxicity from chemotherapy and clinical outcome in biliary tract cancer (BTC) is uncertain. Aim: This post hoc analysis evaluated differences by sex in the frequency of adverse events (AEs) and overall survival (OS) and its impact on progression-free survival (PFS)/recurrence-free survival (RFS) for BTC patients. Methods: Individual patient data were retrieved from ABC -01, -02, -03, -04, and BILCAP study. AEs were graded according to National Cancer Institute's Common Toxicity Criteria v 4.02 and odds ratios along with 95%CI and p-values derived from logistic regression were used to assess the effect of sex on the risk of AEs. Time to event outcomes were evaluated using Cox regression and plotted using Kaplan-Meier plots. All statistical tests were two-sided. Results: Overall 994 patients-data were examined: 86 in ABC-01, 324 in-02, 124 in -03, 13 in -04 and 447 in BILCAP. A total of 484 (49%) were males (M) and 510 (51%) were females (F). 770 patients were evaluable for AEs because a total of 224 patients in BILCAP study belonged to the observation group. Urinary tract infection (M, 1.6%; F, 5.5%), nausea (M, 50.7%; F, 69.9%), vomiting (M, 29.1%; F, 46.1%), alopecia (M, 11.3%; F, 27.3%), are dominant in F, hyperbilirubinaemia (M, 36.7%; F, 29.1%) and thrombocytopenia (M, 43.1%; F, 34.3%) and hiccups (M, 2.4%; F, 0.5%) are dominant in M at any grade. Vomiting (M, 3.5%; F, 7.0%) and fatigue (M, 4.0%; F, 8.5%) are higher in F than in M for grade 3-5. The median OS (M, 16.2 months (Mo); F, 17.5 Mo), PFS (M, 6.4 Mo; F, 6.5 Mo) and RFS (M, 20.8 Mo; F 19.4 Mo) were similar. Amongst the subgroup of patients with gallbladder, F achieved longer OS (M, 11.5 Mo; F 13.3 Mo, 0.73 (95%CI:0.54,0.99), p = 0.041) and RFS than M (M, 20.8 Mo; median PFS for F not reached, HR:0.52 (95%CI:0.27,1.02), p = 0.057). Conclusions: Females with BTC have tended to have more AEs, especially grade 3+. Although no difference was observed in OS, PFS, and RFS between males and females for the overall cohort of patients, females with gallbladder cancer had an improved OS and RFS compared with males. These findings suggest, in BTC, sex may play a role when designing clinical trials as well as in making treatment decisions.
    • Characterization of a pixelated silicon microdosimeter in micro-beams of light ions

      Pola, A.; Bortot, D.; Mazzucconi, D.; Fazzi, A.; Galer, S.; Kirkby, Karen J; Merchant Michael J; Palmans, H.; Agosteo, S.; Politecnico di Milano, Milano, Italy (2020)
      The monolithic silicon telescope technology allows to produce solid state microdosimeters. A detector constituted by a matrix of pixels (2 'm in thickness) coupled with a deeper stage (about 500 'm in thickness) was designed, developed and characterized by comparing its response against Tissue Equivalent Proportional Counters (TEPCs) in different irradiation fields, showing promising results. Each pixel of the 'E stage is a thin diode of 9 'm in diameter delimited by a guard ring of 14 'm in diameter. The aim of this work is the study of the charge collection efficiency of the single pixel of the silicon microdosimeter by irradiating a prototype at the micro-beam facility of the Ion Beam Center - IBC of the University of Surrey. Different light ions were exploited (protons, lithium ions and carbon ions) and scanned on different positions on and around a single pixel of the detector. The results show that the charge generated by events on the sensitive region of the 'E stage is completely collected, while a charge collection efficiency lower than one characterizes the region between the central pixel and its guard ring. The guard ring delimits properly the sensitive region: no signals arise from events outside the 14 'm in diameter ring. Nevertheless, the microdosimetric distributions of the different charged particles highlight a minor distortion in terms of the absorbed dose. This latter result justifies the good agreement with TEPCs in terms of microdosimetric distributions in different hadrons beams described in previous works.
    • Real-world data of high-grade lymphoma patients treated with CD19 CAR-T in the UK

      Kuhnl, A.; Roddie, C.; Tholouli, E.; Menne, T.; Linton, K.; Lugthart, S.; Chaganti, S.; Sanderson, R.; O'Reilly, M.; Norman, J.; et al. (2020)
      Background: England was the ?rst European country to commission a national service for the delivery of CD19 CAR-T in high-grade lymphoma. Since December 2018, relapsed/refractory (r/r) high-grade lymphoma patients who failed two or more lines of treatment have had access to CD19 CAR-T through the NHSE Cancer Drug Fund (CDF). Treatment is delivered at seven commissioned centres in England (QEHB Birmingham, University Hospital Bristol, KCH London, UCLH, The Christie Manchester, Manchester MRI, Freeman Hospital Newcastle). In addition, CAR-T centres in Glasgow and Cardiff have recently opened, alongside a second wave of centres in England (Cambridge, Leeds, RMH London), allowing more patients access to this specialised treatment in their local area. Treatment is approved through a weekly National CAR-T Clinical Panel (NCCP). Here, we report results of the ?rst 125 lymphoma patients approved by the panel between December 2018 and July 2019.Methods: All patients with r/r high-grade lymphoma referred to the NCCP between December 2018 and July 2019 and deemed eligible for treatment with CD19 CAR-T were analysed. Eligibility was assessed according to CDF criteria and con?rmed at the centre's CAR-T multidisciplinary team meeting. The ?nal decision on patient eligibility was made by consensus through the NCCP independent panel. The choice of CAR-T product (axicabtagene ciloleucel (axicel) or tisagenlecleucel (tisagen)) was at the discretion of the treating centre. Results: A total of 133 cases were submitted to the NCCP of which 125 were approved for treatment with CD19 CAR-T. Seventy-nine patients were selected for axi-cel and 46 for tisagen. In total, 116 patients underwent leukapheresis and 91 proceeded to infusion. In the intention to treat (ITT) population, patients? median age was 62 years (range 18?75), 26% were 65 years or older. 89 (71%) patients had de novo diffuse large B-cell lymphoma, 23 (18%) transformed follicular lymphoma, six (5%) transformed marginal zone lymphoma and seven (6%) primary mediastinal B-cell lymphoma. About 76% of cases were advanced stage, 33% had bulky disease and 58% extranodal involvement. About 53/125 (42%) of patients had received three or more prior lines of treatment, 20 patients had previous autologous transplant, ?ve previous allograft. 72% of patients had stable or progressive disease as best response to the last line of treatment. About 83% patients received bridging therapy between the time of NCCP approval and CAR-T infusion (57% chemotherapy, 16% steroids, 10% radiotherapy). Of the 91 patients infused, 11% experienced grade 3+ cytokine release syndrome, 13% grade 3+ neurotoxicity and 34% of patients required intensive care support. Among 80 evaluable patients, the overall response rate at 3 months was 35% (20% complete responses). About 62?5% of patients showed early progression by 3 months. Two patients died from treatment-related toxicities. With a median follow-up of 4?8 months, the median event-free survival was 3?1 months, the median overall survival (OS) has not been reached. Median OS of the ITT cohort was 9?1 months. Updated ef?cacy analyses will be presented at the meeting. Conclusion: NHSE has successfully implemented a national structure for providing broad and rapid access to licensed CD19 CAR-T products. This unique set-up allows capture of prospective real-world data of CAR-T treated patients in the UK, which will help the understanding of the clinical benefirt and health economic implications of this complex treatment in daily practice.
    • Eight-year outcomes of a phase III randomized trial of conventional versus hypofractionated high-dose intensity modulated radiotherapy for prostate cancer (CRUK/06/016): Update from the CHHiP Trial

      Dearnaley, D. P.; Griffin, C.; Syndikus, I.; Khoo, V.; Birtle, A. J.; Choudhury, Ananya; Ferguson, C.; Graham, J.; O'Sullivan, J.; Panades, M.; et al. (2020)
      Background: CHHiP is a non-inferiority trial to determine efficacy and safety of hypofractionated radiotherapy for localised prostate cancer (PCa). Five year results indicated that moderate hypofractionation of 60 Gray (Gy)/20 fractions (f) was non-inferior to 74Gy/37f (Lancet Oncology, 2016). Moderate hypofractionation is now an international standard of care but with patients remaining at risk of recurrence for many years, information on long-term outcomes is important. Here we report pre-planned analysis of 8 year outcomes. Methods: Between October 2002 and June 2011, 3216 men with node negative T1b-T3a localised PCa with risk of seminal vesical involvement ?30% were randomised (1:1:1 ratio) to 74Gy/37f (control), 60Gy/20f or 57Gy/19f. Androgen deprivation began at least 3 months prior to radiotherapy (RT) and continued until end of RT. The primary endpoint was time to biochemical failure (Phoenix consensus guidelines) or clinical failure (BCF). The non-inferiority design specified a critical hazard ratio (HR) of 1.208 for each hypofractionated schedule compared to 74Gy/37f. Late toxicity was assessed at 5 years by RTOG and LENT-SOM scales. Analysis was by intention-to-treat. Results: With a median follow up of 9.2 years, 8 year BCF-free rates (95% CI) were 74Gy: 80.6% (77.9%, 83.0%); 60Gy: 83.7% (81.2%, 85.9%) and 57Gy: 78.5% (75.8%, 81.0%). For 60Gy/20f, non-inferiority was confirmed: HR60=0.84 (90% CI 0.71, 0.99). For 57Gy/19f, non-inferiority could not be declared: HR57=1.17 (90% CI 1.00, 1.37). Clinician assessments of late toxicity were similar across groups. At 5 years, RTOG grade?2 (G2+) bowel toxicity was observed in 14/879 (1.6%), 18/908 (2.0%) and 17/904 (1.9%) of the 74Gy, 60Gy and 57Gy groups respectively. RTOG G2+ bladder toxicity was observed in 17/879 (1.9%), 14/908 (1.5%) and 17/904 (1.9%) of the 74Gy, 60Gy and 57Gy groups respectively. Conclusions: With BCF rates over 80%, long-term follow-up confirms that 60Gy/20f is non-inferior to 74Gy/37f. Late side effects were very low across all groups. These results support the continued use of 60Gy/20f as standard of care for men with localised PCa. Clinical trial information: 97182923.
    • Multiregion expression profiling of prostate cancer from men randomized in the STAMPEDE trial: Stage I results of a multistage biomarker analysis

      Grist, E.; Parry, M.; Mendes, L.; Lall, S.; Kudahetti, S. C.; Vidal, S. S.; Atako, N. B.; Anjum, M.; Ishaq, S.; Todorovic, T.; et al. (2020)
      Background: The PAM50 gene expression classifier stratifies localized prostate cancer into luminal A/B and basal subtypes: luminal A have superior prognosis compared to luminal B and basal. Drug response scores built using the NCI-60 cell lines predict luminal subtypes are more taxane sensitive compared to basal; luminal B is hypothesized to be the most proliferative and hormone responsive compared to the basal subtype. The STAMPEDE trial provides a framework to validate prognostic and predictive associations of the PAM50 test in tumors from men randomized to androgen deprivation therapy (ADT) alone or with docetaxel or abiraterone. We here present multi-region whole-transcriptome expression array data at completion of Stage I designed to confirm the feasibility of molecular subtyping STAMPEDE tumor blocks. Methods: In collaboration with Decipher Biosciences we generated clinical-grade whole-transcriptome expression array data (Human Exon 1.0 ST GeneChip) performed to CLIA standards on mRNA (from three 10 micron slides) from cancer-enriched areas and applied the PAM50 classifier. Results: As of January 2019, we retrieved blocks from 2012 men from an ITT population of 3879. For Stage I feasibility assessment, we sectioned diagnostic trans-rectal biopsies of the prostate from 50 randomly selected men treated with ADT. We extracted mRNA from 109 cores; > 92% cores (101) from > 94% patients (47/50) passed quality control. The prevalence of PAM50 subtypes was: 31 basal cases (62%), 18 luminal B (36%) and 1 luminal A (2%). 26 cases (52%) were identified as ETS-related gene (ERG) positive. More than one core was interrogated from 35/50 cases (range: 1-6 cores). ERG positive cores were homogeneous across cores from the same patient but PAM50 subtyping identified intra-patient variability across cores from the same case. Conclusions: We confirm the feasibility of expression profiling STAMPEDE tumor blocks and identify a low prevalence of luminal A subtype. Whereas ERG status is consistent across multiple cores, basal and luminal subtypes co-exist in the same prostate. Multi-region analysis will enable further refinement for individual patient classification.
    • Conditional survival of patients with rectal cancer undergoing Watch and Wait: The risk of recurrence over time

      Fernandez, L. M.; Figueiredo, N.; Beets, G.; Van Der Valk, M.; Bahadoer, R.; Hilling, D.; Renehan, Andrew G; Van De Velde, C. J. H.; Habr-Gama, A.; Perez, R. O.; et al. (2020)
      Background: Patients with rectal cancer and complete clinical response (cCR) after neoadjuvant chemoradiation (nCRT) have been offered non-operative management (W&W). Risk factors for local regrowth (RG) include baseline cT and type of nCRT. However, the influence of risk factors for RG over time and the extent in time that patients need to be followed with the rectum in situ after a cCR are unknown. Objective: Analyze the risk of recurrence over time through conditional survival (cDFS/cLRFS) estimates for rectal cancer patients under W&W. Methods: Retrospective analysis of all patients from the largest multicenter database of patients managed non-operatively (International Watch and Wait Database?IWWD). Only patients with cCR after nCRT and W&W with a median of >3 years of follow-up were included. cDFS was used to investigate the evolution of recurrence-odds, as patients remain disease-free after nCRT. 2-year cDFS was estimated at ?x? years after nCRT based on the formula cDFS2=DFS(x+2)/DFS(x). Results: 768 patients treated between 1991-2015 were included. Using cDFSestimates, the probability of remaining disease-free for 2 additional years once cCR was achieved and sustained for 1, 3, and 5 years, were 85%, 97%, and 95%, respectively. These contrast with the actuarial DFS for similar intervals of 70%, 68% and 65% respectively. Baseline cT was associated with the risk of RG at 1 year after a cCR (cT2 aLRFS 89% vs. cT3 82%; p=0.004). However, after sustaining a cCR for 1 year, baseline cT becomes irrelevant at 2 years (cLRFS; 94% vs. 90%; |d| 0.14). Also, total dose of RT (?50 vs >50Gy) was associated with the risk of RG (aLRFS 76% vs 85%; p=0.03) at 1 year. Dose of RT becomes irrelevant (at 2 years; cLRFS 93% vs. 90%; |d| 0.10) once patients sustained a cCR for 1 year. Conclusions: Conditional survival estimates suggests that patients have significantly lower risks (?5%) of developing late RG (at 5 years) after sustaining cCR for 3 years. A sustained cCR over time may be more relevant for long-term risk of RG than cT-stage or RT dose. The present data can have significant consequences for the recommendation of intensive surveillance after sustaining 3ys of cCR.
    • Prognostic factors in advanced seminoma: An analysis from the IGCCCG Update Consortium

      Beyer, J.; Collette, L.; Daugaard, G.; De Wit, R.; Tryakin, A.; Albany, C.; Stahl, O.; Fizazi, K.; Gietema, J. A.; De Giorgi, U.; et al. (2020)
      OBJECTIVE: To evaluate the impact of an editorial intervention to improve completeness of reporting of reports of randomised trials. DESIGN: Randomised controlled trial (RCT). SETTING: BMJ Open's quality improvement programme. PARTICIPANTS: 24 manuscripts describing RCTs. INTERVENTIONS: We used an R Shiny application to randomise manuscripts (1:1 allocation ratio, blocks of 4) to the intervention (n=12) or control (n=12) group. The intervention was performed by a researcher with expertise in the content of the Consolidated Standards of Reporting Trials (CONSORT) and consisted of an evaluation of completeness of reporting of eight core CONSORT items using the submitted checklist to locate information, and the production of a report containing specific requests for authors based on the reporting issues found, provided alongside the peer review reports. The control group underwent the usual peer review. OUTCOMES: The primary outcome is the number of adequately reported items (0-8 scale) in the revised manuscript after the first round of peer review. The main analysis was intention-to-treat (n=24), and we imputed the scores of lost to follow-up manuscripts (rejected after peer review and not resubmitted). The secondary outcome is the proportion of manuscripts where each item was adequately reported. Two blinded reviewers assessed the outcomes independently and in duplicate and solved disagreements by consensus. We also recorded the amount of time to perform the intervention. RESULTS: Manuscripts in the intervention group (mean: 7.01; SD: 1.47) were more completely reported than those in the control group (mean: 5.68; SD: 1.43) (mean difference 1.43, 95% CI 0.31 to 2.58). We observed the main differences in items 6a (outcomes), 9 (allocation concealment mechanism), 11a (blinding) and 17a (outcomes and estimation). The mean time to perform the intervention was 87 (SD 42) min. CONCLUSIONS: We demonstrated the benefit of involving a reporting guideline expert in the editorial process. Improving the completeness of RCTs is essential to enhance their usability. TRIAL REGISTRATION NUMBER: NCT03751878.
    • Patterns of use of chemotherapy with radiotherapy in the treatment of muscle-invasive bladder cancer: Data from the RAIDER randomized trial of adaptive radiotherapy

      Huddart, R. A.; Lewis, R.; Griffin, C.; Alonzi, R.; Birtle, A. J.; Choudhury, Ananya; Cresswell, J.; Foroudi, F.; Hafeez, S.; Henry, A.; et al. (2020)
      Background: Level 1 evidence exists for the use of both neoadjuvant chemotherapy (NAC) and concomitant radiosensitization (CRS) to improve outcomes in patients receiving radical radiotherapy (RT) for muscle invasive bladder cancer, but uptake has been patchy. We report here the current patterns of usage in an ongoing trial of adaptive radiotherapy. Methods: RAIDER is an international randomized phase II trial recruiting patients with unifocal T2-T4a urothelial carcinoma of the bladder suitable for RT (ISCRTN:26779187). Patients are randomized in a 1:1:2 ratio to one of 3 arms: Standard whole bladder RT (control); Standard dose adaptive tumour focused RT; Dose escalated (DE) adaptive tumour boost RT. Standard dose patients are treated to either 64Gy/32f or 55Gy/20f and DE patients to 70Gy in 32f or 60Gy in 20f. Patients are encouraged to receive NAC and CRS. The primary endpoint is the rate of late toxicity 6-18 months post treatment in arm 3, with secondary endpoints of patient reported and disease related outcomes. Results: To August 2019, 285 patients had been recruited. Median age is 72 years (IQR 67-79). Stage of disease is T2 79%, T3 19%, T4 2%; 19% have hydronephrosis. Patients receiving NAC were more likely to be PS 0 at trial entry (70% v 45%). Variation in frequency of CRS use is seen across sites, with some offering to >90% of participants and some <50%. Data on NAC and CRS use is available for 249 patients recruited to date is shown in table. Conclusions: In this ongoing clinical trial the majority of patients are receiving NAC and/or CRS. However, uptake is not universal with ~30% of patients not receiving low dose CRS, including some who have received NAC. Clinical trial information: 26779187.