• 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.
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  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.
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  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.
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  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.

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