Now showing items 1-20 of 11501

    • Biodegradable oesophageal stents: a potentially useful adjunct in the treatment of dysphagia in patients undergoing radiotherapy for oesophageal carcinoma

      White, K; Thampy, S; Sheikh, H; Bhatt, Lubna; Mullan, Damian; Laasch, Hans-Ulrich; Manchester NHS Foundation Trust (2019)
      Aim Dysphagia is common in patients presenting with oesophageal malignancy. This study aimed to determine the clinical effectiveness of biodegradable stents to help with malignant dysphagia due to radiotherapy for oesophageal cancer and furthermore to establish the complication and re-intervention rates associated with their use. Methods This was a retrospective, observational study of 22 patients between 2008 and 2013. Complications within 2 weeks and episodes of re-intervention required within 4 months of stent insertion prior to radiotherapy were recorded. Results Pre-stent insertion, the mean O�Rourke dysphagia score was 3�5 (median 3, range 2�5). This improved to a mean score of 2�8 (median 3, range 1�4) 1�3 weeks following stent insertion. Complications occurred in seven patients (32%) in an immediate 2-week period, including: pain (2), dysphagia requiring dilatation (1), food obstruction not requiring intervention (1), food obstruction requiring intervention (2) and upper gastrointestinal bleed not requiring intervention (1). Re-intervention was required in 18% within a 4-month period. Findings We propose that biodegradable oesophageal stents are safe and may have benefit over self-expanding metal stents. We recommend they are placed alongside a radiologically inserted gastrostomy in a combined procedure prior to radiotherapy planning.
    • Timing of high-dose methotrexate CNS prophylaxis in DLBCL: an analysis of toxicity and impact on R-CHOP delivery

      Wilson, M. R.; Eyre, T. A.; Martinez-Calle, N.; Ahearne, M.; Parsons, K. E.; Preston, G.; Khwaja, J.; Schofield, J.; Elliot, Johnathon; Mula Kh, A.; et al. (2020)
      High-dose methotrexate (HD-MTX) is increasingly used as prophylaxis for patients with diffuse large B-cell lymphoma (DLBCL) at high risk of central nervous system (CNS) relapse. However, there is limited evidence to guide whether to intercalate HD-MTX (i-HD-MTX) between R-CHOP-21 (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone given at 21-day intervals) or to give it at the end of treatment (EOT) with R-CHOP-21. We conducted a retrospective, multicenter analysis of 334 patients with DLBCL who received CNS prophylaxis with i-HD-MTX (n = 204) or EOT HD-MTX (n = 130). Primary end points were R-CHOP delay rates and HD-MTX toxicity. Secondary end points were CNS relapse rate, progression-free survival, and overall survival. The EOT group had more patients with a high CNS international prognostic index (58% vs 39%; P < .001) and more concurrent intrathecal prophylaxis (56% vs 34%; P < .001). Of the 409 cycles of i-HD-MTX given, 82 (20%) were associated with a delay of next R-CHOP (median, 7 days). Delays were significantly increased when i-HD-MTX was given after day 9 post-R-CHOP (26% vs 16%; P = .01). On multivariable analysis, i-HD-MTX was independently associated with increased R-CHOP delays. Increased mucositis, febrile neutropenia, and longer median inpatient stay were recorded with i-HD-MTX delivery. Three-year cumulative CNS relapse incidence was 5.9%, with no differences between groups. There was no difference in survival between groups. We report increased toxicity and R-CHOP delay with i-HD-MTX compared with EOT delivery but no difference in CNS relapse or survival. Decisions on HD-MTX timing should be individualized and, where i-HD-MTX is favored, we recommend scheduling before day 10 of R-CHOP cycles.
    • Glioma consensus contouring recommendations from a MR-Linac International Consortium Research Group and evaluation of a CT-MRI and MRI-only workflow

      Tseng, C. L.; Stewart, J.; Whitfield, Gillian A; Verhoeff, J. J. C.; Bovi, J.; Soliman, H.; Chung, C.; Myrehaug, S.; Campbell, M.; Atenafu, E. G.; et al. (2020)
      Introduction: This study proposes contouring recommendations for radiation treatment planning target volumes and organs-at-risk (OARs) for both low grade and high grade gliomas. Methods: Ten cases consisting of 5 glioblastomas and 5 grade II or III gliomas, including their respective gross tumor volume (GTV), clinical target volume (CTV), and OARs were each contoured by 6 experienced neuro-radiation oncologists from 5 international institutions. Each case was first contoured using only MRI sequences (MRI-only), and then re-contoured with the addition of a fused planning CT (CT-MRI). The level of agreement among all contours was assessed using simultaneous truth and performance level estimation (STAPLE) with the kappa statistic and Dice similarity coefficient. Results: A high level of agreement was observed between the GTV and CTV contours in the MRI-only workflow with a mean kappa of 0.88 and 0.89, respectively, with no statistically significant differences compared to the CT-MRI workflow (p = 0.88 and p = 0.82 for GTV and CTV, respectively). Agreement in cochlea contours improved from a mean kappa of 0.39 to 0.41, to 0.69 to 0.71 with the addition of CT information (p < 0.0001 for both cochleae). Substantial to near perfect level of agreement was observed in all other contoured OARs with a mean kappa range of 0.60 to 0.90 in both MRI-only and CT-MRI workflows. Conclusions: Consensus contouring recommendations for low grade and high grade gliomas were established using the results from the consensus STAPLE contours, which will serve as a basis for further study and clinical trials by the MR-Linac Consortium. Keywords: Consensus contouring recommendations; Glioma; MR-linac; Organs-at-risk; Radiotherapy.
    • Chronic myelomonocytic leukaemia stem cell transcriptomes anticipate disease morphology and outcome

      Wiseman, Daniel H; Baker, S. M.; Dongre, Arundhati V|Gurashi, Kristian; Storer, Joanna A; Somervaille, Tim CP; Batta, Kiran; Epigenetics of Haematopoiesis Laboratory, Division of Cancer Sciences, The University of Manchester, Manchester M20 4GJ, UK. (2020)
      Background: Chronic myelomonocytic leukaemia (CMML) is a clinically heterogeneous stem cell malignancy with overlapping features of myelodysplasia and myeloproliferation. Over 90% of patients carry mutations in epigenetic and/or splicing genes, typically detectable in the Lin-CD34+CD38- immunophenotypic stem cell compartment in which the leukaemia-initiating cells reside. Transcriptional dysregulation at the stem cell level is likely fundamental to disease onset and progression. Methods: We performed single-cell RNA sequencing on 6826 Lin-CD34+CD38-stem cells from CMML patients and healthy controls using the droplet-based, ultra-high-throughput 10x platform. Findings: We found substantial inter- and intra-patient heterogeneity, with CMML stem cells displaying distinctive transcriptional programs. Compared with normal controls, CMML stem cells exhibited transcriptomes characterized by increased expression of myeloid-lineage and cell cycle genes, and lower expression of genes selectively expressed by normal haematopoietic stem cells. Neutrophil-primed progenitor genes and a MYC transcription factor regulome were prominent in stem cells from CMML-1 patients, whereas CMML-2 stem cells exhibited strong expression of interferon-regulatory factor regulomes, including those associated with IRF1, IRF7 and IRF8. CMML-1 and CMML-2 stem cells (stages distinguished by proportion of downstream blasts and promonocytes) differed substantially in both transcriptome and pseudotime, indicating fundamentally different biology underpinning these disease states. Gene expression and pathway analyses highlighted potentially tractable therapeutic vulnerabilities for downstream investigation. Importantly, CMML patients harboured variably-sized subpopulations of transcriptionally normal stem cells, indicating a potential reservoir to restore functional haematopoiesis. Interpretation: Our findings provide novel insights into the CMML stem cell compartment, revealing an unexpected degree of heterogeneity and demonstrating that CMML stem cell transcriptomes anticipate disease morphology, and therefore outcome. Funding: Project funding was supported by Oglesby Charitable Trust, Cancer Research UK, Blood Cancer UK, and UK Medical Research Council. Keywords: CMML; Leukaemia; Stem cells; sc-RNA Seq.
    • Randomised clinical trial of a gastrointestinal care bundle to reduce symptoms in patients with pelvic cancer undergoing chemoradiotherapy

      White, K. L.; Henson, C. C.; Hann, M.; Eden, M.; Burden, S. T.; Lal, S.; Davidson, Susan E; McLaughlin, J. T.; Gastroenterology, Manchester Foundation Trust, Wythenshawe Hospital, Manchester, UK. (2020)
      Objective: Pelvic radiotherapy is used to treat 17 000 people in the UK each year. Eight in 10 develop difficult bowel problems during pelvic treatment, especially diarrhoea, urgency and incontinence. Some cannot complete treatment, reducing the chance of cancer cure. Undertaking gastroenterologist-led investigation and management during pelvic radiotherapy has never been evaluated. In this study, we aimed to assess whether patients could successfully receive a novel gastrointestinal (GI) care bundle during chemoradiotherapy (feasibility aim) and would experience reduced symptom severity (clinical impact aim). Design: This randomised controlled trial recruited patients with cervical and bladder cancers undergoing radical chemoradiotherapy. Participants were randomised to intervention or control groups. Questionnaire and anthropometric data were collected. All intervention group patients received individualised dietary counselling weekly throughout treatment, and if bowel symptoms developed they were offered rapid-access investigation and treatment for any identified pathology: lactose intolerance, bacterial overgrowth or bile acid malabsorption. Results: Feasibility: 50 participants were recruited, 24 were randomised to the intervention group and 26 to the control group. All completed 20 fractions of external beam pelvic radiotherapy. It was possible to perform 57/72 (79%) of proposed intervention tests with no disruption of oncological management. Clinical impact: All participants developed GI symptoms during radiotherapy. The median symptom score for each group increased from baseline at 6 weeks. This was from 0.156 (0.000-0.333) to 0.600 (0.250-1.286) in the control group, and from 0.00 (0.000-0.300) to 0.402 (0.000-0.667) in the intervention group. Conclusion: It was feasible to recruit to and deliver a randomised controlled trial of interventions in patients undergoing pelvic chemoradiotherapy. Lower median bowel scores were reported in the intervention group at 6 weeks, with fewer patients experiencing symptoms overall. Trial registration number: ISRCTN783488. Keywords: cancer; clinical trials; radiation enteritis; radiotherapy.
    • Identifying the radioresponsive genome for genomics-guided radiotherapy

      West, Catharine ML; Division of Cancer Studies, University of Manchester, Manchester Academic Health Science Centre, The Christie NHS Foundation Trust Hospital, Manchester, M20 4BX, UK. (2020)
    • Multinational Association of Supportive Care in Cancer (MASCC) 2020 clinical practice recommendations for the management of immune-mediated cardiovascular, rheumatic, and renal toxicities from checkpoint inhibitors

      Suarez-Almazor, M. E.; Pundole, X.; Abdel-Wahab, N.; Johnson, D. B.; Gupta, D.; Glezerman, I.; Cooksley, Timothy J; Anderson, R.; Blidner, A.; Choi, J.; et al. (2020)
      Immune checkpoint inhibitors (ICIs) have emerged as the newest pillar of cancer treatment. Immune-mediated toxicities, stemming from increased activity within the T cell lineage, range from asymptomatic or mild complications to those that are fulminant and potentially fatal. Although they are of variable occurrence, cardiovascular, rheumatic, and renal immune-mediated toxicities are among the most serious of these adverse events. We present MASCC recommendations with respect to the workup and management of cardiovascular, rheumatic, and renal immune-mediated toxicities with a focus on presentations that require treatment with immunomodulating agents. Keywords: Arthralgia; Arthritis; Cardiomyopathy; Corticosteroids; Immunomodulation agents; Myocarditis; Myositis; Other immunosuppressive agents; Polymyalgia.
    • When what you see is not always what you get: raising the bar of evidence for new diagnostic imaging modalities

      Sundahl, N.; Gillessen, Silke; Sweeney, C.; Ost, P.; Department of Radiation Oncology, Ghent University Hospital, Ghent, Belgium; Division of Radiotherapy and Imaging, Institute of Cancer Research, London, UK. (2020)
      Even though prostate-specific membrane antigen (PSMA)-positron emission tomography (PET)-computed tomography (CT) is more accurate than conventional imaging in prostate cancer patients, its impact on patient-relevant outcomes is unknown. We argue that more evidence is required before using PSMA-PET-CT as the standard of care for staging.
    • Radiation fractionation schedules published during the COVID-19 pandemic: a systematic review of the quality of evidence and recommendations for future development

      Thomson, David J; Yom, S. S.; Saeed, H.; El Naqa, I.; Ballas, L.; Bentzen, S. M.; Chao, S. T.; Choudhury, Ananya; Coles, C. E.; Dover, L.; et al. (2020)
      Purpose: Numerous publications during the COVID-19 pandemic recommended the use of hypofractionated radiation therapy. This project assessed aggregate changes in the quality of the evidence supporting these schedules to establish a comprehensive evidence base for future reference and highlight aspects for future study. Methods and materials: Based on a systematic review of published recommendations related to dose fractionation during the COVID-19 pandemic, 20 expert panelists assigned to 14 disease groups named and graded the highest quality of evidence schedule(s) used routinely for each condition and also graded all COVID-era recommended schedules. The American Society for Radiation Oncology quality of evidence criteria were used to rank the schedules. Process-related statistics and changes in distributions of quality ratings of the highest-rated versus recommended COVID-19 era schedules were described by disease groups and for specific clinical scenarios. Results: From January to May 2020 there were 54 relevant publications, including 233 recommended COVID-19-adapted dose fractionations. For site-specific curative and site-specific palliative schedules, there was a significant shift from established higher-quality evidence to lower-quality evidence and expert opinions for the recommended schedules (P = .022 and P < .001, respectively). For curative-intent schedules, the distribution of quality scores was essentially reversed (highest levels of evidence "pre-COVID" vs "in-COVID": high quality, 51.4% vs 4.8%; expert opinion, 5.6% vs 49.3%), although there was variation in the magnitude of shifts between disease sites and among specific indications. Conclusions: A large number of publications recommended hypofractionated radiation therapy schedules across numerous major disease sites during the COVID-19 pandemic, which were supported by a lower quality of evidence than the highest-quality routinely used dose fractionation schedules. This work provides an evidence-based assessment of these potentially practice-changing recommendations and informs individualized decision-making and counseling of patients. These data could also be used to support radiation therapy practices in the event of second waves or surges of the pandemic in new regions of the world.
    • The rare YAP1 subtype of SCLC revisited in a biobank of 39 circulating tumor cell patient derived explant models: a brief report

      Pearsall, Sarah M; Humphrey, Sam; Revill, Mitchell; Morgan, Derrick; Frese, Kristopher K; Galvin, Melanie; Kerr, Alistair; Carter, Mathew; Priest, Lynsey; Blackhall, Fiona H; et al. (2020)
      Introduction: Recent consensus defines four SCLC subtypes on the basis of transcription factor expression: ASCL1, NEUROD1, POU2F3, and YAP1. The rare YAP1 subtype is associated with "neuroendocrine (NE)-low" cells among SCLC cell lines and patient samples. We evaluated YAP1 in 39 patients with phenotypically diverse circulating tumor cell-derived explant (CDX) models and revisited YAP1 in terms of prevalence, cell phenotype, and intertumor and intratumor heterogeneity. Methods: YAP1 transcript and protein expression were assessed by RNA sequencing and immunohistochemistry or multiplexed immunofluorescence of NE and non-NE CDX subpopulations. Physically separated NE and non-NE CDX ex vivo culture lysates were Western blotted for YAP1, NE marker SYP, and AXL. Results: RNA sequencing normalized for the four subtype transcription factors identified YAP1 expression in 14 of 39 CDX. A total of 10 CDX expressed YAP1 protein, and eight had strong YAP1 expression confined to rare non-NE cell clusters. This was confirmed in ex vivo CDX cultures in which adherent non-NE cells lacking SYP expression expressed YAP1. However, in two CDX, weaker cellular YAP1 expression was observed, widely dispersed in SYP-positive NE cells. Conclusions: YAP1 was predominantly expressed in non-NE cell clusters in SCLC CDX, but two of 39 CDX expressed YAP1 in NE cells. CDX22P, with relatively high YAP1 expression, is an ASCL1 NE subtype with a low NE score and an outlier within this subtype in our CDX biobank. These descriptive data reveal subtly different YAP1 expression profiles, paving the way for functional studies to compare YAP1 signaling in non-NE and low NE cell contexts for potentially personalized therapeutic approaches. Keywords: Intratumoral heterogeneity; Neuroendocrine; Nonneuroendocrine; Small cell lung cancer (SCLC); YAP1.
    • BRIGHTLIGHT researchers as 'dramaturgs': creating There is a Light from complex research data

      Taylor, R. M.; Lobel, B.; Thompson, K.; Onashile, A.; Croasdale, M.; Hall, N.; Gibson, F.; Martins, A.; Wright, David; Morgan, S.; et al. (2020)
      Background: BRIGHTLIGHT is a national evaluation of cancer services for young people aged 13-24 years in England. It is a mixed methods study with six interlinked studies aiming to answer the question: do specialist cancer services for teenagers and young adults add value? Young people have been integral to study development and management, working as co-researchers, consultants and collaborators throughout. We aimed to share results in a way that was meaningful to young people, the public, and multidisciplinary professionals. This paper reports the development of 'There is a Light: BRIGHTLIGHT', a theatrical interpretation of study results by young people, and offers insight into the impact on the cast, researchers and audiences. Methods: The BRIGHTLIGHT team collaborated with Contact Young Company, a youth theatre group in Manchester. Twenty members of Contact Young Company and four young people with cancer worked together over an eight-week period during which BRIGHTLIGHT results were shared along with explanations of cancer, healthcare policy and models of care in interactive workshops. Through their interpretation, the cast developed the script for the performance. The impact of the process and performance on the cast was evaluated through video diaries. The research team completed reflective diaries and audiences completed a survey. Results: 'There is a Light' contained five acts and lasted just over an hour. It played 11 performances in six cities in the United Kingdom, to approximately 1377 people. After nine performances, a 30-min talk-back between members of the cast, creative team, an expert healthcare professional, and the audience was conducted, which was attended by at least half the audience. Analysis of cast diaries identified six themes: initial anxieties; personal development; connections; cancer in young people; personal impact; interacting with professionals. The cast developed strong trusting relationships with the team. Professionals stated they felt part of the process rather than sitting on the periphery sharing results. Both professional and lay audiences described the performance as meaningful and understandable. Feedback was particularly positive from those who had experienced cancer themselves. Conclusions: Using theatre to present research enabled BRIGHTLIGHT results to be accessible to a larger, more diverse audience. Keywords: Adolescents; Art; BRIGHTLIGHT; Cancer; Dissemination; Patient and public involvement; Teenagers; Theatre; Young adults.
    • Investigating the importance of B cells and antibodies during Trichuris muris infection using the IgMi mouse

      Sahputra, R.; Murphy, E. A.; Forman, R.; Mair, I.; Fadlullah, Muhammad ZH; Waisman, A.; Muller, W.; Else, K. J.; Division of Infection, Immunity and Respiratory Medicine, Lydia Becker Institute for Immunology, The University of Manchester, Manchester, UK. (2020)
      The IgMi mouse has normal B cell development; its B cells express an IgM B cell receptor but cannot class switch or secrete antibody. Thus, the IgMi mouse offers a model system by which to dissect out antibody-dependent and antibody-independent B cell function. Here, we provide the first detailed characterisation of the IgMi mouse post-Trichuris muris (T. muris) infection, describing expulsion phenotype, cytokine production, gut pathology and changes in T regulatory cells, T follicular helper cells and germinal centre B cells, in addition to RNA sequencing (RNA seq) analyses of wild-type littermates (WT) and mutant B cells prior to and post infection. IgMi mice were susceptible to a high-dose infection, with reduced Th2 cytokines and elevated B cell-derived IL-10 in mesenteric lymph nodes (MLN) compared to controls. A low-dose infection regime revealed IgMi mice to have significantly more apoptotic cells in the gut compared to WT mice, but no change in intestinal inflammation. IL-10 levels were again elevated. Collectively, this study showcases the potential of the IgMi mouse as a tool for understanding B cell biology and suggests that the B cell plays both antibody-dependent and antibody-independent roles post high- and low-dose T. muris infection. KEY MESSAGES: During a high-dose T. muris infection, B cells are important in maintaining the Th1/Th2 balance in the MLN through an antibody-independent mechanism. High levels of IL-10 in the MLN early post-infection, and the presence of IL-10-producing B cells, correlates with susceptibility to T. muris infection. B cells maintain gut homeostasis during chronic T. muris infection via an antibody-dependent mechanism. Keywords: B cells; IgMi mouse; Interleukin-10; Intestinal pathology; Th1/Th2; Trichuris muris.
    • Reprint of: Practice recommendations for risk-adapted head and neck cancer radiotherapy during the COVID-19 pandemic: An ASTRO-ESTRO consensus statement

      Thomson, David J; Palma, D.; Guckenberger, M.; Balermpas, P.; Beitler, J. J.; Blanchard, P.; Brizel, D.; Budach, W.; Caudell, J.; Corry, J.; et al. (2020)
      Purpose: Because of the unprecedented disruption of health care services caused by the COVID-19 pandemic, the American Society of Radiation Oncology (ASTRO) and the European Society for Radiotherapy and Oncology (ESTRO) identified an urgent need to issue practice recommendations for radiation oncologists treating head and neck cancer (HNC) in a time of limited resources and heightened risk for patients and staff. Methods and materials: A panel of international experts from ASTRO, ESTRO, and select Asia-Pacific countries completed a modified rapid Delphi process. Topics and questions were presented to the group, and subsequent questions were developed from iterative feedback. Each survey was open online for 24 hours, and successive rounds started within 24 hours of the previous round. The chosen cutoffs for strong agreement (?80%) and agreement (?66%) were extrapolated from the RAND methodology. Two pandemic scenarios, early (risk mitigation) and late (severely reduced radiation therapy resources), were evaluated. The panel developed treatment recommendations for 5 HNC cases. Results: In total, 29 of 31 of those invited (94%) accepted, and after a replacement 30 of 30 completed all 3 surveys (100% response rate). There was agreement or strong agreement across a number of practice areas, including treatment prioritization, whether to delay initiation or interrupt radiation therapy for intercurrent SARS-CoV-2 infection, approaches to treatment (radiation dose-fractionation schedules and use of chemotherapy in each pandemic scenario), management of surgical cases in event of operating room closures, and recommended adjustments to outpatient clinic appointments and supportive care. Conclusions: This urgent practice recommendation was issued in the knowledge of the very difficult circumstances in which our patients find themselves at present, navigating strained health care systems functioning with limited resources and at heightened risk to their health during the COVID-19 pandemic. The aim of this consensus statement is to ensure high-quality HNC treatments continue, to save lives and for symptomatic benefit.
    • The evolving practice of palliative radiotherapy

      Rembielak, Agata; Dennis, K.; The Christie NHS Foundation Trust, Wilmslow Road, Manchester, M20 4BX, UK; The University of Manchester, Oxford Road, Manchester, M13 9PL, UK (2020)
    • Tebentafusp, a TCR/anti-CD3 bispecific fusion protein targeting gp100, potently activated anti-tumor immune responses in patients with metastatic melanoma

      Middleton, M. R.; McAlpine, C.; Woodcock, V. K.; Corrie, P.; Infante, J. R.; Steven, N. M.; Evans, T. R. J.; Anthoney, A.; Shoushtari, A. N.; Hamid, O.; et al. (2020)
      Purpose: Tebentafusp is a first-in-class bispecific fusion protein designed to target gp100 (a melanoma-associated antigen) through a high affinity T cell receptor binding domain, and an anti-CD3 T cell engaging domain which redirects T cells to kill gp100-expressing tumor cells. Here we report from a multicentre Phase 1/2 trial of tebentafusp in metastatic melanoma (NCT01211262) focusing on the mechanism of action of tebentafusp Experimental Design: 84 patients with advanced melanoma received tebentafusp. Treatment efficacy, treatment-related AEs and biomarker assessments were performed for blood-derived and tumor biopsy samples obtained at baseline and on-treatment Results: Tebentafusp was generally well tolerated and active in both metastatic uveal melanoma (mUM) and metastatic cutaneous melanoma (mCM) patients. A 65% 1-year overall survival rate was achieved for both patient cohorts. On-treatment cytokine measurements were consistent with the induction of IFNg pathway-related markers in the periphery and tumor. Notably, tebentafusp induced an increase in serum CXCL10 (a T cell attractant), and a reduction in circulating CXCR3+ CD8+ T cells together with an increase in cytotoxic T cells in the tumor microenvironment. Furthermore, increased serum CXCL10 or the appearance of rash, (likely due to cytotoxic T cells targeting of gp100-expressing skin melanocytes) showed a positive association with patient survival. Conclusions: These data suggest that re-directing T cells using a gp100-targeting T cell receptor/anti-CD3 bispecific fusion protein may provide benefit to patients with metastatic melanoma. Furthermore, the activity observed in these two molecularly disparate melanoma classes hints at the broad therapeutic potential of tebentafusp.
    • ESMO consensus conference recommendations on the management of locoregional melanoma: the ESMO Guidelines Committee

      Michielin, O.; van Akkooi, A.; Lorigan, Paul C; Ascierto, P. A.; Dummer, R.; Robert, C.; Arance, A.; Blank, C. U.; Sileni, V. C.; Donia, M.; et al. (2020)
      The European Society for Medical Oncology (ESMO) held a consensus conference on melanoma on 5-7 September 2019 in Amsterdam, The Netherlands. The conference included a multidisciplinary panel of 32 leading experts in the management of melanoma. The aim of the conference was to develop recommendations on topics that are not covered in detail in the current ESMO Clinical Practice Guideline and where available evidence is either limited or conflicting. The main topics identified for discussion were: (i) the management of locoregional disease; (ii) targeted versus immunotherapies in the adjuvant setting; (iii) targeted versus immunotherapies for the first-line treatment of metastatic melanoma; (iv) when to stop immunotherapy or targeted therapy in the metastatic setting; and (v) systemic versus local treatment of brain metastases. The expert panel was divided into five working groups in order to each address questions relating to one of the five topics outlined above. Relevant scientific literature was reviewed in advance. Recommendations were developed by the working groups and then presented to the entire panel for further discussion and amendment before voting. This manuscript presents the results relating to the management of locoregional melanoma, including findings from the expert panel discussions, consensus recommendations and a summary of evidence supporting each recommendation. All participants approved the final manuscript. Keywords: adjuvant; consensus; immunotherapy; melanoma; targeted therapy; treatment.
    • MILO/ENGOT-ov11: binimetinib versus physician's choice chemotherapy in recurrent or persistent low-grade serous carcinomas of the ovary, fallopian tube, or primary peritoneum

      Monk, B. J.; Grisham, R. N.; Banerjee, S.; Kalbacher, E.; Mirza, M. R.; Romero, I.; Vuylsteke, P.; Coleman, R. L.; Hilpert, F.; Oza, A. M.; et al. (2020)
      Purpose: Low-grade serous ovarian carcinomas (LGSOCs) have historically low chemotherapy responses. Alterations affecting the MAPK pathway, most commonly KRAS/BRAF, are present in 30%-60% of LGSOCs. The purpose of this study was to evaluate binimetinib, a potent MEK1/2 inhibitor with demonstrated activity across multiple cancers, in LGSOC. Methods: This was a 2:1 randomized study of binimetinib (45 mg twice daily) versus physician's choice chemotherapy (PCC). Eligible patients had recurrent measurable LGSOC after ? 1 prior platinum-based chemotherapy but ? 3 prior chemotherapy lines. The primary end point was progression-free survival (PFS) by blinded independent central review (BICR); additional assessments included overall survival (OS), overall response rate (ORR), duration of response (DOR), clinical-benefit rate, biomarkers, and safety. Results: A total of 303 patients were randomly assigned to an arm of the study at the time of interim analysis (January 20, 2016). Median PFS by BICR was 9.1 months (95% CI, 7.3 to 11.3) for binimetinib and 10.6 months (95% CI, 9.2 to 14.5) for PCC (hazard ratio,1.21; 95%CI, 0.79 to 1.86), resulting in early study closure according to a prespecified futility boundary after 341 patients had enrolled. Secondary efficacy end points were similar in the two groups: ORR 16% (complete response [CR]/partial responses[PRs], 32) versus 13% (CR/PRs, 13); median DOR, 8.1 months (range, 0.03 to ? 12.0 months) versus 6.7 months (0.03 to ? 9.7 months); and median OS, 25.3 versus 20.8 months for binimetinib and PCC, respectively. Safety results were consistent with the known safety profile of binimetinib; the most common grade ? 3 event was increased blood creatine kinase level (26%). Post hoc analysis suggests a possible association between KRAS mutation and response to binimetinib. Results from an updated analysis (n = 341; January 2019) were consistent. Conclusion: Although the MEK Inhibitor in Low-Grade Serous Ovarian Cancer Study did not meet its primary end point, binimetinib showed activity in LGSOC across the efficacy end points evaluated. A higher response to chemotherapy than expected was observed and KRAS mutation might predict response to binimetinib.
    • Patient-centered outcomes in ARIEL3, a phase III, randomized, placebo-controlled trial of rucaparib maintenance treatment in patients with recurrent ovarian carcinoma

      Oza, A. M.; Lorusso, D.; Aghajanian, C.; Oaknin, A.; Dean, A.; Colombo, N.; Weberpals, J. I.; Clamp, Andrew R; Scambia, G.; Leary, A.; et al. (2020)
      Purpose: To investigate quality-adjusted progression-free survival (QA-PFS) and quality-adjusted time without symptoms or toxicity (Q-TWiST) in a post hoc exploratory analysis of the phase III ARIEL3 study of rucaparib maintenance treatment versus placebo. Patients and methods: Patients with platinum-sensitive, recurrent ovarian carcinoma were randomly assigned to rucaparib (600 mg twice per day) or placebo. QA-PFS was calculated as progression-free survival function � the 3-level version of the EQ-5D questionnaire (EQ-5D-3L) index score function. Q-TWiST analyses were performed defining TOX as the mean duration in which a patient experienced grade ? 3 treatment-emergent adverse events (TEAEs) or the mean duration in which a patient experienced grade ? 2 TEAEs of nausea, vomiting, fatigue, and asthenia. Q-TWiST was calculated as ?TOX � TOX + TWiST, with ?TOX calculated using EQ-5D-3L data. Results: The visit cutoff was Apr 15, 2017. Mean QA-PFS was significantly longer with rucaparib versus placebo in the intent-to-treat (ITT) population (375 randomly assigned to rucaparib v 189 randomly assigned to placebo; difference, 6.28 months [95% CI, 4.85 to 7.47 months]); BRCA-mutant cohort (130 rucaparib v 66 placebo; 9.37 months [95% CI, 6.65 to 11.85 months]); homologous recombination deficient (HRD) cohort (236 rucaparib v 118 placebo; 7.93 months [95% CI, 5.93 to 9.53 months]); and BRCA wild-type/loss of heterozygosity (LOH) low patient subgroup (107 rucaparib v 54 placebo; 2.71 months [95% CI, 0.31 to 4.44 months]). With TOX defined using grade ? 3 TEAEs, the difference in mean Q-TWiST (rucaparib v placebo) was 6.88 months (95% CI, 5.71 to 8.23 months), 9.73 months (95% CI, 7.10 to 11.94 months), 8.11 months (95% CI, 6.36 to 9.49 months), and 3.35 months (95% CI, 1.66 to 5.40 months) in the ITT population, BRCA-mutant cohort, HRD cohort, and BRCA wild-type/LOH low patient subgroup, respectively. Q-TWiST with TOX defined using select grade ? 2 TEAEs also consistently favored rucaparib. Conclusion: The significant differences in QA-PFS and Q-TWiST confirm the benefit of rucaparib versus placebo in all predefined cohorts.
    • Prostate cancer heterogeneity assessment with multi-regional sampling and alignment-free methods

      Murphy, R. G.; Roddy, A. C.; Srivastava, S.; Baena, Esther; Waugh, D. J.; J, M. O. S.; McArt, D. G.; Jain, S.; LaBonte, M. J.; Movember FASTMAN Centre of Excellence, Patrick G Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast BT9 7AE, UK. (2020)
      Combining alignment-free methods for phylogenetic analysis with multi-regional sampling using next-generation sequencing can provide an assessment of intra-patient tumour heterogeneity. From multi-regional sampling divergent branching, we validated two different lesions within a patient's prostate. Where multi-regional sampling has not been used, a single sample from one of these areas could misguide as to which drugs or therapies would best benefit this patient, due to the fact these tumours appear to be genetically different. This application has the power to render, in a fraction of the time used by other approaches, intra-patient heterogeneity and decipher aberrant biomarkers. Another alignment-free method for calling single-nucleotide variants from raw next-generation sequencing samples has determined possible variants and genomic locations that may be able to characterize the differences between the two main branching patterns. Alignment-free approaches have been applied to relevant clinical multi-regional samples and may be considered as a valuable option for comparing and determining heterogeneity to help deliver personalized medicine through more robust efforts in identifying targetable pathways and therapeutic strategies. Our study highlights the application these tools could have on patient-aligned treatment indications.
    • Mechanisms of drug resistance mediated by long non-coding RNAs in non-small-cell lung cancer

      La Montagna, Manuela; Ginn, Lucy; Garofalo, Michela; Transcriptional Networks in Lung Cancer Group, Cancer Research UK Manchester Institute, University of Manchester, Alderley Park, Manchester, SK10 4TG, UK. (2020)
      Non-small-cell lung cancer (NSCLC) is the most prevalent form of lung cancer and has a poor five-year survival rate of 15%. Chemotherapy and targeted therapies have significantly improved patients' prognosis. Nevertheless, after a successful initial response, some patients relapse when cancer cells become resistant to drug treatments, representing an important clinical limitation. Therefore, investigating the mechanisms of drug resistance is of significant importance. Recently, considerable attention has been given to long non-coding RNAs (lncRNAs), a heterogeneous class of regulatory molecules that play essential roles in tumorigenesis by modulating genes and signalling pathways involved in cell growth, metastasis and drug response. In this article, we review recent research findings on the role of lncRNAs in drug resistance in NSCLC, highlighting their mechanisms of action.