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Friday 20 December 2019

CCC publication: A Systematic Review of Lenvatinib and Sorafenib for Treating Progressive, Locally Advanced or Metastatic, Differentiated Thyroid Cancer After Treatment With Radioactive Iodine

Citation: BMC Cancer. 2019, 19(1), 1209
Author: Nigel Fleeman, Rachel Houten, Marty Chaplin, Sophie Beale, Angela Boland, Yenal Dundar, Janette Greenhalgh, Rui Duarte, Aditya Shenoy
Abstract: Background:  Treatment with radioactive iodine is effective for many patients with progressive, locally advanced or metastatic, differentiated thyroid cancer. However, some patients become refractory to treatment. These types of patients are considered to have radioactive iodine refractory differentiated thyroid cancer (RR-DTC).
Methods:  We searched Embase, MEDLINE, PubMed and the Cochrane Library from January 1999 through January 2017. Reference lists of included studies and ongoing trial registries were also searched. Reports of randomized controlled trials (RCTs), prospective observational studies, and systematic reviews/indirect comparisons were eligible for inclusion. In the absence of direct clinical trial evidence comparing lenvatinib versus sorafenib, we assessed the feasibility of conducting an indirect comparison to obtain estimates of the relative efficacy and safety of these two treatments.
Results:  Of 2364 citations, in total, 93 papers reporting on 2 RCTs (primary evidence), 9 observational studies and 13 evidence reviews (supporting evidence) were identified. Compared to placebo, RCT evidence demonstrated improvements with lenvatinib or sorafenib in median progression-free survival (PFS) and objective tumour response rate (ORR). Overall survival (OS) was confounded by high treatment crossover (≥75%) in both trials. Adverse events (AEs) were more common with lenvatinib or sorafenib than with placebo but the most common AEs associated with each drug differed. Primarily due to differences in the survival risk profiles of patients in the placebo arms of the RCTs, we considered it inappropriate to indirectly compare the effectiveness of lenvatinib versus sorafenib. ORR and AE findings for lenvatinib and sorafenib from the supporting evidence were broadly in line with RCT evidence. Health-related quality of life (HRQoL) data were limited.
Conclusions:  Lenvatinib and sorafenib are more efficacious than placebo (a proxy for best supportive care) for treating RR-DTC. Uncertainty surrounds the extent of the impact on OS and HRQoL. Lenvatinib could not reliably be compared with sorafenib. Choice of treatment is therefore likely to depend on an individual patient's circumstances.
Keywords:  Clinical effectiveness; Lenvatinib; Sorafenib; Systematic review; Thyroid cancer; Tyrosine kinase inhibitor.

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CCC publication: Olaparib in Patients With Metastatic Castration-Resistant Prostate Cancer With DNA Repair Gene Aberrations (TOPARP-B): A Multicentre, Open-Label, Randomised, Phase 2 Trial

Citation: The Lancet. Oncology. 2020, 21(1), 162-174. 2019 Dec 2 [Online ahead of print]
Author: Joaquin Mateo, Nuria Porta, Diletta Bianchini, Ursula McGovern, Tony Elliott, Robert Jones, Isabel Syndikus, Christy Ralph, Suneil Jain, Mohini Varughese, Omi Parikh, Simon Crabb, Angus Robinson, Duncan McLaren, Alison Birtle, Jacob Tanguay, Susana Miranda, Ines Figueiredo, George Seed, Claudia Bertan, Penny Flohr, Berni Ebbs, Pasquale Rescigno, Gemma Fowler, Ana Ferreira, Ruth Riisnaes, Rita Pereira, Andra Curcean, Robert Chandler, Matthew Clarke, Bora Gurel, Mateus Crespo, Daniel Nava Rodrigues, Shahneen Sandhu, Aude Espinasse, Peter Chatfield, Nina Tunariu, Wei Yuan, Emma Hall, Suzanne Carreira, Johann S de Bono
Abstract: Background:  Metastatic castration-resistant prostate cancer is enriched in DNA damage response (DDR) gene aberrations. The TOPARP-B trial aims to prospectively validate the association between DDR gene aberrations and response to olaparib in metastatic castration-resistant prostate cancer.
Methods:  In this open-label, investigator-initiated, randomised phase 2 trial following a selection (or pick-the-winner) design, we recruited participants from 17 UK hospitals. Men aged 18 years or older with progressing metastatic castration-resistant prostate cancer previously treated with one or two taxane chemotherapy regimens and with an Eastern Cooperative Oncology Group performance status of 2 or less had tumour biopsies tested with targeted sequencing. Patients with DDR gene aberrations were randomly assigned (1:1) by a computer-generated minimisation method, with balancing for circulating tumour cell count at screening, to receive 400 mg or 300 mg olaparib twice daily, given continuously in 4-week cycles until disease progression or unacceptable toxicity. Neither participants nor investigators were masked to dose allocation. The primary endpoint of confirmed response was defined as a composite of all patients presenting with any of the following outcomes: radiological objective response (as assessed by Response Evaluation Criteria in Solid Tumors 1.1), a decrease in prostate-specific antigen (PSA) of 50% or more (PSA50) from baseline, or conversion of circulating tumour cell count (from ≥5 cells per 7·5 mL blood at baseline to <5 cells per 7·5 mL blood). A confirmed response in a consecutive assessment after at least 4 weeks was required for each component. The primary analysis was done in the evaluable population. If at least 19 (43%) of 44 evaluable patients in a dose cohort responded, then the dose cohort would be considered successful. Safety was assessed in all patients who received at least one dose of olaparib. This trial is registered at ClinicalTrials.gov, NCT01682772. Recruitment for the trial has completed and follow-up is ongoing.
Findings:  711 patients consented for targeted screening between April 1, 2015, and Aug 30, 2018. 161 patients had DDR gene aberrations, 98 of whom were randomly assigned and treated (49 patients for each olaparib dose), with 92 evaluable for the primary endpoint (46 patients for each olaparib dose). Median follow-up was 24·8 months (IQR 16·7-35·9). Confirmed composite response was achieved in 25 (54·3%; 95% CI 39·0-69·1) of 46 evaluable patients in the 400 mg cohort, and 18 (39·1%; 25·1-54·6) of 46 evaluable patients in the 300 mg cohort. Radiological response was achieved in eight (24·2%; 11·1-42·3) of 33 evaluable patients in the 400 mg cohort and six (16·2%; 6·2-32·0) of 37 in the 300 mg cohort; PSA50 response was achieved in 17 (37·0%; 23·2-52·5) of 46 and 13 (30·2%; 17·2-46·1) of 43; and circulating tumour cell count conversion was achieved in 15 (53·6%; 33·9-72·5) of 28 and 13 (48·1%; 28·7-68·1) of 27. The most common grade 3-4 adverse event in both cohorts was anaemia (15 [31%] of 49 patients in the 300 mg cohort and 18 [37%] of 49 in the 400 mg cohort). 19 serious adverse reactions were reported in 13 patients. One death possibly related to treatment (myocardial infarction) occurred after 11 days of treatment in the 300 mg cohort.
Interpretation:  Olaparib has antitumour activity against metastatic castration-resistant prostate cancer with DDR gene aberrations, supporting the implementation of genomic stratification of metastatic castration-resistant prostate cancer in clinical practice.
Funding:  Cancer Research UK, AstraZeneca, Prostate Cancer UK, the Prostate Cancer Foundation, the Experimental Cancer Medicine Centres Network, and the National Institute for Health Research Biomedical Research Centres.
Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

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CCC publication: Weekly Dose-Dense Chemotherapy in First-Line Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Carcinoma Treatment (ICON8): Primary Progression Free Survival Analysis Results From a GCIG Phase 3 Randomised Controlled Trial

Citation: Lancet. 2019, 394(10214), 2084-95
Author: Andrew R Clamp, Elizabeth C James, Iain A McNeish, Andrew Dean, Jae-Weon Kim, Dearbhaile M O'Donnell, Jane Hook, Christopher Coyle, Sarah Blagden, James D Brenton, Raj Naik, Tim Perren, Sudha Sundar, Adrian D Cook, Gosala S Gopalakrishnan, Hani Gabra, Rosemary Lord, Graham Dark, Helena M Earl, Marcia Hall, Susana Banerjee, Rosalind M Glasspool, Rachel Jones, Sarah Williams, Ann Marie Swart, Sally Stenning, Mahesh Parmar, Richard Kaplan, Jonathan A Ledermann
Abstract: Background:  Carboplatin and paclitaxel administered every 3 weeks is standard-of-care first-line chemotherapy for epithelial ovarian cancer. The Japanese JGOG3016 trial showed a significant improvement in progression-free and overall survival with dose-dense weekly paclitaxel and 3-weekly carboplatin. In this study, we aimed to compare efficacy and safety of two dose-dense weekly regimens to standard 3-weekly chemotherapy in a predominantly European population with epithelial ovarian cancer.
Methods:  In this phase 3 trial, women with newly diagnosed International Federation of Gynecology and Obstetrics stage IC-IV epithelial ovarian cancer were randomly assigned to group 1 (carboplatin area under the curve [AUC]5 or AUC6 and 175 mg/m2 paclitaxel every 3 weeks), group 2 (carboplatin AUC5 or AUC6 every 3 weeks and 80 mg/m2 paclitaxel weekly), or group 3 (carboplatin AUC2 and 80 mg/m2 paclitaxel weekly). Written informed consent was provided by all women who entered the trial. The protocol had the appropriate national research ethics committee approval for the countries where the study was conducted. Patients entered the trial after immediate primary surgery, or before neoadjuvant chemotherapy with subsequent planned delayed primary surgery. The trial coprimary outcomes were progression-free survival and overall survival. Data analyses were done on an intention-to-treat basis, and were powered to detect a hazard ratio of 0·75 in progression-free survival. The main comparisons were between the control group (group 1) and each of the weekly research groups (groups 2 and 3).
Findings:  Between June 6, 2011, and Nov 28, 2014, 1566 women were randomly assigned to treatment. 72% (365), completed six protocol-defined treatment cycles in group 1, 60% (305) in group 2, and 63% (322) in group 3, although 90% (454), 89% (454), and 85% (437) completed six platinum-based chemotherapy cycles, respectively. Paclitaxel dose intensification was achieved with weekly treatment (median total paclitaxel dose 1010 mg/m2 in group 1; 1233 mg/m2 in group 2; 1274 mg/m2 in group 3). By February, 2017, 1018 (65%) patients had experienced disease progression. No significant progression-free survival increase was observed with either weekly regimen (restricted mean survival time 24·4 months [97·5% CI 23·0-26·0] in group 1, 24·9 months [24·0-25·9] in group 2, 25·3 months [23·9-26·9] in group 3; median progression-free survival 17·7 months [IQR 10·6-not reached] in group 1, 20·8 months [11·9-59·0] in group 2, 21·0 months [12·0-54·0] in group 3; log-rank p=0·35 for group 2 vs group 1; group 3 vs 1 p=0·51). Although grade 3 or 4 toxic effects increased with weekly treatment, these effects were predominantly uncomplicated. Febrile neutropenia and sensory neuropathy incidences were similar across groups.
Interpretation:  Weekly dose-dense chemotherapy can be delivered successfully as first-line treatment for epithelial ovarian cancer but does not significantly improve progression-free survival compared with standard 3-weekly chemotherapy in predominantly European populations.
Funding:  Cancer Research UK, Medical Research Council, Health Research Board in Ireland, Irish Cancer Society, Cancer Australia.
Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.

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CCC publication: Long-term Results From the IDEAL-CRT Phase 1/2 Trial of Isotoxically Dose-Escalated Radiation Therapy and Concurrent Chemotherapy for Stage II/III Non-Small Cell Lung Cancer

Citation: International Journal of Radiation Oncology, Biology, Physics. 2020, 106(4), 733-742
Author: J D Fenwick, D B Landau, A Baker, A T Bates, C Eswar, A Garcia-Alonso, S V Harden, M C Illsley, V Laurence, Z Malik, W P M Mayles, E Miles, N Mohammed, J Spicer, P Wells, S Vivekanandan, A M Mullin, L Hughes, L Farrelly, Y Ngai, N Counsell
Abstract: Purpose:  The XTRIAL phase 1/2 multicenter trial of isotoxically dose-escalated concurrent chemoradiotherapy for stage II/III non-small cell lung cancer (NSCLC) investigated two 30-fraction schedules of 5 and 6 weeks duration. We report toxicity, tumor response, progression-free survival (PFS) and overall survival (OS) for both schedules, with long-term follow-up for the 6-week schedule.
Patients and methods:  Patients received isotoxically-individualized tumor radiation doses of 63-71 Gy in 5 weeks or 63-73 Gy in 6 weeks, delivered concurrently with two cycles of cisplatin and vinorelbine. Eligibility criteria were the same for both schedules.
Results:  120 patients (6% stage IIB, 68% IIIA, 26% IIIB, 1% IV) were recruited from 9 UK centers, 118 starting treatment. Median prescribed doses were 64.5 and 67.6 Gy for the 36 and 82 patients treated using the 5- and 6-week schedules. Grade ≥3 pneumonitis and early esophagitis rates were 3.4% and 5.9% overall, and similar for each schedule individually. Late grade 2 esophageal toxicity occurred in 11.1% and 17.1% of 5- and 6-week patients. Grade ≥4 adverse events occurred in 17 (20.7%) 6-week patients but no 5-week patients. Four adverse events were grade 5, with two considered RT-related. After 51.8 and 26.4 months median follow-up for the 6- and 5-week schedules, median OS was 41.2 and 22.1 months respectively, and median PFS was 21.1 and 8.0 months. In exploratory analyses, OS was significantly associated with schedule (HR=0.56, 95%CI: 0.32-0.98, p=0.04) and fractional clinical/internal target volume receiving ≥95% of the prescribed dose (HR=0.88, 95%CI: 0.77-1.00, p=0.05). PFS was also significantly associated with schedule (HR=0.53, 95%CI: 0.33-0.86, p=0.01).
Conclusions:  Toxicity in XTRIAL was acceptable. Survival was promising for 6-week patients, and significantly longer than for 5-week patients. Survival might be further lengthened by following the 6-week schedule with an immune agent, motivating further study of such combined optimized treatments.
Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.

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CCC publication: A Novel Panel of Differentially-Expressed microRNAs in Breast Cancer Brain Metastasis May Predict Patient Survival

Citation: Scientific Reports. 2019, 9(1), 18518
Author: Athina Giannoudis, Kim Clarke, Rasheed Zakaria, Damir Varešlija, Mosavar Farahani, Lucille Rainbow, Angela Platt-Higgins, Stuart Ruthven, Katherine A Brougham, Philip S Rudland, Michael D Jenkinson, Leonie S Young, Francesco Falciani, Carlo Palmieri
Abstract: Breast cancer brain metastasis (BCBM) is an area of unmet clinical need. MicroRNAs (miRNAs) have been linked to the metastatic process in breast cancer (BC). In this study, we aim to determine differentially-expressed miRNAs utilising primary BCs that did not relapse (BCNR, n = 12), primaries that relapsed (BCR) and their paired (n = 40 pairs) brain metastases (BM) using the NanoString™ nCounter™ miRNA Expression Assays. Significance analysis of microarrays identified 58 and 11 differentially-expressed miRNAs between BCNR vs BCR and BCR vs BM respectively and pathway analysis revealed enrichment for genes involved in invasion and metastasis. Four miRNAs, miR-132-3p, miR-199a-5p, miR-150-5p and miR-155-5p, were differentially-expressed within both cohorts (BCNR-BCR, BCR-BM) and receiver-operating characteristic curve analysis (p = 0.00137) and Kaplan-Meier survival method (p = 0.0029, brain metastasis-free survival; p = 0.0007, overall survival) demonstrated their potential use as prognostic markers. Ingenuity pathway enrichment linked them to the MET oncogene, and the cMET protein was overexpressed in the BCR (p < 0.0001) and BM (p = 0.0008) cases, compared to the BCNRs. The 4-miRNAs panel identified in this study could be potentially used to distinguish BC patients with an increased risk of developing BCBM and provide potential novel therapeutic targets, whereas cMET-targeting warrants further investigation in the treatment of BCBM.

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WUTH publication: Programmed death ligand 1 expression in EBUS aspirates of non-small cell lung cancer: Is interpretation affected by type of fixation?

Citation: Cancer Cytopathology. 2020, 128(2), 100-106. Epub 2019 Dec 18
Author: Gosney JR, Haragan A, Chadwick C, Giles TE, Grundy S, Tippett V, Gumparthy KP, Wight A, Tan HG
Abstract: BACKGROUND: Much of the reluctance about using cytology specimens rather than histology specimens to assess programmed death ligand 1 (PD-L1) expression for guiding the use of immune modulating drugs in the management of non-small cell lung cancer (NSCLC) is based on the belief that the alcohol-based fixatives favored by cytopathologists might reduce the antigenicity of PD-L1 and lead to artifactually low expression levels and false-negative reporting. Therefore, this study was performed to determine whether there is any difference in PD-L1 expression between endobronchial ultrasound (EBUS)-guided aspirates of NSCLC fixed in alcohol-based fixatives and those fixed in neutral buffered formalin (NBF), the standard laboratory fixative for histology specimens.
METHODS: The expression of PD-L1 was compared in 50 paired EBUS aspirates of NSCLC taken from the same lymph node during the same procedure. One aspirate of each pair was fixed in an alcohol-based fixative, and the other was fixed in NBF.
RESULTS: In none of the 50 pairs was there any significant difference, qualitative or quantitative, in the strength, pattern, or extent of PD-L1 expression. In the great majority, the expression was identical, regardless of fixation.
CONCLUSIONS: There is no evidence from this study showing that the use of alcohol-based fixatives has any effect on the expression of PD-L1 or its interpretation. Notwithstanding the general challenges in accurately assessing such expression in cytology specimens, pathologists should feel able to interpret them with confidence, and clinicians should feel able to rely on the results.
© 2019 American Cancer Society.
KEYWORDS: cytology; fixation; immunochemistry; lung cancer; programmed death ligand 1 (PD-L1)

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Thursday 19 December 2019

Research Scholars Programme - Cohort 3 - We're Recruiting!

The Research Scholars Programme is aimed at research-interested individuals who may or may not have NIHR clinical research experience already.  We are encouraging applications from the whole cross section of clinical staffing roles including doctors, nurse’s pharmacists, radiographers, occupational therapists, physiologists, physiotherapists, radiotherapists and biomedical scientists. The Programme is an interactive developmental programme aimed at equipping tomorrow's clinical research leaders with the skills, knowledge and experience needed to become the Principal and Chief Investigators of the future.  Successful candidates receive funding (half funded by the CRN NWC award and the other half 'match' funded by the applicants employer) to cover one full day per week as dedicated time for research.  Scholars commit to attending a day per month at the CRN NWC offices in Liverpool for an exciting programme of face-to-face sessions.
The Research Scholars Programme offers the following benefits:
·         Protected & funded time to enable you to support and deliver NIHR Funded research within your service
·         A development pathway towards becoming a Principal or Chief investigator
·         Full support from CRN NWC & your employer
·         Support & guidance from being matched with a mentor who is an experienced Principal or Chief Investigator
Am I eligible to apply?
The Research Scholars Programme is an initiative to develop early career researchers. In order to be eligible for the Programme you should be:
·         New Consultants or General Practitioners within the last 5 years of taking up their post
·         Nurses (usually Band 7 or above)
·         Allied Health Professionals (usually Band 7 or above)

To apply to be part of the programme, please email rspadmin@nihr.ac.uk for an application form. Applications will be accepted until Monday 27th January 2020 and interviews will be held on Monday 24th and Tuesday 25th February 2020. 

Course Lead: Professor Enitan Carrol, MBChB, MRCP, FRCPCH, MD, FHEA, PG Cert (Higher Education)
Course Co-Lead: Dr Chris Smith, Deputy Chief Operating Officer, CRN North West Coast
Course administrator: Mrs Clare Donnelly, Research Administrator, CRN North West Coast

The Research Scholars Programme
The NWC region has a diverse range of research leaders, but it is recognised to increase its outputs this leadership community requires investment and support to further flourish. Without this medium and longer-term support the region’s ability to attract and participate in a larger proportion of the national NIHR research portfolio would be limited. This is already evidenced by the fact that the NWC region has a proportionately lower number of Chief Investigators leading studies on the NIHR portfolio than other Local Clinical Research Networks (LCRNs) across the country. Given the size of CRN NWC and the inherent health challenges across the local population, it is key this is addressed if the region is to ensure it remains competitive in the future.

The Research Scholars Programme (RSP) is designed to develop ‘research-interested’ individuals in the earlier phase of their clinical research careers. Such individuals may not have previously been involved in NIHR portfolio research or they may have had some involvement in delivery of NIHR trials but not in a significant leadership role. The RSP is open to medical consultants and General Practitioners in the first five years (career breaks excluded) of their careers as well as established colleagues from across other clinical professions such as Allied Health Professionals and Nursing, Physiotherapy, Occupational therapy, Radiography and Pharmacy.

The aim of the programme is to provide successful applicants with remunerated time to enable recruitment into NIHR research studies and establish themselves as Principal Investigators / future Chief Investigators. The RSP award will provide protected time to support the generation of research outputs including trial delivery and the development of research collaborations / future NIHR grant submissions. Successful scholars will be allocated a two-year award to support research career development and NIHR research delivery from NIHR CRN NWC.

The RSP is a collaborative initiative that is being offered in partnership with NHS stakeholders across the CRN NWC region. CRN NWC will provide SPA funding (or equivalent value in other professions) of 1.0 SPA per week (equivalent for AHP’s and nurses), which will be matched by NHS partners/employers supporting the scheme. It is the intention that after the initial two year period, sufficient experience will have been generated for the scholar to sustain the sessional time for research within their employing organisation and may become eligible to apply for further developmental funding from NIHR.

The course content is based on the Vitae Researcher Development Framework (RDF). The RDF is a new approach to researcher development, to enhance research capacity in the UK workforce, develop world-class researchers and build the UK research base. It is a professional development framework for planning, promoting and supporting the personal, professional and career development of researchers in higher education. It articulates the knowledge, behaviours and attributes of successful researchers and encourages them to realise their potential. The four domains are; Engagement, influence and impact, Knowledge and intellectual abilities, Research governance and organisation and Personal effectiveness. https://www.vitae.ac.uk/researchers-professional-development/about-the-vitae-researcher-development-framework

Time commitment
The scholars have protected time of one day a week to conduct research, which includes time to fulfil their Principal Investigator roles at their respective NHS Trusts (industry or NIHR studies developed by others), and to develop proposals for grant funding. In addition, there is a mandatory monthly face-to-face teaching day at the CRN Liverpool office, the delivery of which includes lectures, workshops, and action learning sets. 80 % attendance is mandatory, dates provided in advance.

Assessment
Year1: Promotional video of research profile, Dragon’s Den presentation in front of external panel, Summative Year 1 review presentation (review of achievements in year 1 and goals for year 2).
Year 2: Submission of a 4-page research proposal to include: background and rationale, aims and objectives, research plan, dissemination and impact, research timetable, ethics, patient and public involvement and lay summary, Summative Year 2 review presentation (review of achievements in year 2), Co-development of an NIHR application as co-applicant, lead applicant, co-Chief Investigator or deputy Chief Investigator, to be submitted within 6 months of course completion.

Feedback
Scholars are required to sign in and out of each face-to face session and complete course feedback after each face-to-face session.

Monday 2 December 2019

WUTH publication: Tuberous Sclerosis Complex (TSC): Expert Recommendations for Provision of Coordinated Care

Citation: Frontiers in nerology. 2019 Nov 6, eCollection 2019.
Author: Annear NMP, Appleton RE, Bassi Z, Bhatt R, Bolton PF, Crawford P, Crowe A, Tossi M, Elmslie F, Finlay E, Gale DP, Henderson A, Jones EA, Johnson SR, Joss S, Kerecuk L, Lipkin G, Morrison PJ, O'Callaghan FJ, Cadwgan J, Ong ACM, Sampson JR, Shepherd C, Kingswood JC
Abstract: KEYWORDS: United Kingdom; clinics; commissioning; guidelines; rare disease; service specification; surveillance; tuberous sclerosis complex

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Friday 29 November 2019

CCC publication: A randomised assessment of image guided radiotherapy within a phase 3 trial of conventional or hypofractionated high dose intensity modulated radiotherapy for prostate cancer

Citation: Radiotherapy and Oncology. 2020, 142, 62-71
Author: Murray, Julia; Griffin, Clare; Gulliford, Sarah; Syndikus, Isabel; Staffurth, John; Panades, Miguel; Scrase, Christopher; Parker, Chris; Khoo, Vincent; Dean, Jamie; Mayles, Helen; Mayles, Philip; Thomas, Simon; Naismith, Olivia; Baker, Angela; Mossop, Helen; Cruickshank, Clare; Hall, Emma; Dearnaley, David; CHHiP Investigators
Abstract: BACKGROUND AND PURPOSE: Image-guided radiotherapy (IGRT) improves treatment set-up accuracy and provides the opportunity to reduce target volume margins. We introduced IGRT methods using standard (IGRT-S) or reduced (IGRT-R) margins in a randomised phase 2 substudy within CHHiP trial. We present a pre-planned analysis of the impact of IGRT on dosimetry and acute/late pelvic side effects using gastrointestinal and genitourinary clinician and patient-reported outcomes (PRO) and evaluate efficacy.
MATERIALS AND METHODS: CHHiP is a randomised phase 3, non-inferiority trial for men with localised prostate cancer. 3216 patients were randomly assigned to conventional (74 Gy in 2 Gy/fraction (f) daily) or moderate hypofractionation (60 or 57 Gy in 3 Gy/f daily) between October 2002 and June 2011. The IGRT substudy included a second randomisation assigning to no-IGRT, IGRT-S (standard CTV-PTV margins), or IGRT-R (reduced CTV-PTV margins). Primary substudy endpoint was late RTOG bowel and urinary toxicity at 2 years post-radiotherapy.
RESULTS: Between June 2010 to July 2011, 293 men were recruited from 16 centres. Median follow-up is 56.9(IQR 54.3-60.9) months. Rectal and bladder dose-volume and surface percentages were significantly lower in IGRT-R compared to IGRT-S group; (p < 0.0001). Cumulative proportion with RTOG grade ≥ 2 toxicity reported to 2 years for bowel was 8.3(95% CI 3.2-20.7)%, 8.3(4.7-14.6)% and 5.8(2.6-12.4)% and for urinary 8.4(3.2-20.8)%, 4.6(2.1-9.9)% and 3.9(1.5-9.9)% in no IGRT, IGRT-S and IGRT-R groups respectively. In an exploratory analysis, treatment efficacy appeared similar in all three groups.
CONCLUSION: Introduction of IGRT was feasible in a national randomised trial and IGRT-R produced dosimetric benefits. Overall side effect profiles were acceptable in all groups but lowest with IGRT and reduced margins.
ISRCTN: 97182923.
Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.
KEYWORDS: Dosimetry; Image-guided radiotherapy; Prostate; Toxicity

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CCC publication: The efficacy and safety of venetoclax therapy in elderly patients with relapsed, refractory chronic lymphocytic leukaemia

Citation: British Journal of Haematology. 2019 Nov 4 [Epub ahead of print]
Author: Eyre, Toby A; Roeker, Lindsey E; Fox, Christopher P; Gohill, Satyen H; Walewska, Renata; Walter, Harriet S; Forconi, Francesco; Broom, Angus; Arumainathan, Arvind; Brander, Danielle M; Allan, John N; Schuster, Stephen J; Hill, Brian T; Lansigan, Frederick; Cheson, Bruce D; Lamanna, Nicole; Coombs, Catherine C; Barr, Paul M; Skarbnik, Alan P; Shadman, Mazyar; Ujjani, Chaitra S; Pearson, Laurie; Pagel, John M; Jacobs, Ryan; Mato, Anthony R
Abstract: Elderly chronic lymphocytic leukaemia (CLL) patients treated outside of trials have notably greater toxicity with the Bruton's tyrosine kinase inhibitor ibrutinib compared to younger patients. It is not known whether the same holds true for the B-cell lymphoma 2 inhibitor venetoclax. We provide a comprehensive analysis of key safety measures and efficacy in 342 patients comparing age categories ≥75 and <75 years treated in the relapsed, refractory non-trial setting. We demonstrate that venetoclax has equivalent efficacy and safety in relapsed/refractory CLL patients who are elderly, the majority of whom are previous ibrutinib-exposed and therefore may otherwise have few clear therapeutic options.
© 2019 British Society for Haematology and John Wiley & Sons Ltd.

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CCC publication: Reply to: Considerations on “impact of centralization of services on outcomes in a rare tumour: Retroperitoneal sarcomas”

Citation: European Journal of Surgical Oncology. 2020, 46(Part A), 708
Author: R. Kalaiselvan, A.K. Malik, R. Rao, K. Wong, N. Ali, M. Griffin, C.R. Chandrasekar, S.F. Fenwick, G.J. Poston, H. Malik,

CCC publication: CD8+ Tcell integrin alpha4beta7expression: A potential predictor of severity and steroid sensitivity in checkpoint inhibitor induced colitis

Citation: Journal for ImmunoTherapy of Cancer. 2019, 7
Author: Olsson-Brown A. (acob@liv.ac.uk); Sacco J.; Cachinho S.; Jolly C.; Fontana V.; Lord R.; Pirmohamed M.; Coles M.

CCC publication: Induction of serum CXCL10 by tebentafusp, a gp100-CD3 bispecific fusion protein, was associated with survival in uveal melanoma in a Phase I/II Study

Citation: Source Journal for ImmunoTherapy of Cancer. 2019, 7
Author: Butler M.; Higgs B. (brandon.higgs@immunocore.com); McAlpine C.; Sacco J.; Hassel J.; Abdullah S.; Ranade K.; Carvajal R.

CCC publication: Treatment beyond four cycles of first line Platinum and Etoposide chemotherapy in real-life patients with stage IV Small Cell Lung Cancer: a retrospective study of the Merseyside and Cheshire Cancer network

Citation: BMC pulmonary medicine. 2019, 19(1), 195
Author: Sallam, Mostafa; Wong, Helen; Escriu, Carles
Abstract: BACKGROUND: Dose intensity and dose density of first line Platinum and Etoposide (PE) do not influence Overall Survival (OS) of Small Cell Lung Cancer (SCLC) patients. The effect of treatment length, however, remains unclear. Current guidelines recommend treating beyond 4 cycles -up to 6-, in patients that respond to and tolerate systemic treatment. This has led to variable practice both in clinical practice and clinical research. Here we aimed at quantifying the possible clinical benefit of the extended regimen in our real-life patients treated with PE doublet.
METHODS: Of all patients with SCLC treated in our network with non-concurrent first line PE chemotherapy between 2008 and 2015, we identified and described patients that received 4 cycles (4c) or more (> 4c), and analysed patients with stage IV disease.
RESULTS: Two hundred forty-one patients with stage IV had 4c and 69 had > 4c. The latter were more likely to have sequential thoracic radiotherapy, which suggested a lower metastatic burden. Nevertheless, there were no statistically significant differences when comparing clinical outcomes. The median Duration of Response (DoR; time from last chemotherapy cycle to progression) was 5 months in both groups (HR 1.22; 95% CI 0.93-1.61). Median Progression Free Survival (PFS; time from diagnosis to radiological progression) was 8 months (4c) versus 9 months (> 4c) (HR 0.86; 95% CI 0.66-1.13) and median OS was 11 versus 12 months (HR 0.86, 95% CI 0.66-1.14).
CONCLUSION: Our results highlight a lack of clinical benefit by extending first line PE treatment in stage IV disease, and support limiting treatment to 4 cycles until superiority of a longer regimen is identified in a randomised study.
KEYWORDS: Antineoplastic combined chemotherapy protocols; Drug therapy; Lung neoplasm; Observational study; Small cell lung carcinoma

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CCC publication: Window of opportunity treatment in breast cancer

Citation: ANZ Journal of Surgery. 2019 Nov 26 [Epub ahead of print]
Author: Chen, Julia; Easwaralingam, Neshanth; Warrier, Sanjay; Ong, Andrew; Carson, Emma-Kate; Mak, Cindy; Snook, Kylie; Middleton, Kate; Parker, Andrew; Palmieri, Carlo; Spillane, Andrew; Mann, G Bruce; Lim, Elgene; Segara, Davendra
Abstract: Window of opportunity therapies, which involve short-term administration of systemic therapy between cancer diagnosis and surgery, have raised significant interest in recent years as a mean of assessing the sensitivity of a patient's cancer to therapy prior to surgery. There is now compelling evidence that in patients with early stage hormone-receptor positive breast cancer, a 2-week preoperative treatment with standard hormone therapies in a preoperative window period provides important prognostic information, which in turn helps to aid decision-making regarding treatment options. Changes in short-term biomarker endpoints such as cell proliferation measured by Ki-67 can act as surrogate markers of long-term outcomes. Paired tissues obtained pre- and post-investigational treatment, without having to subject the patient to additional biopsies, can then be used to conduct translational research to investigate predictive biomarkers and pharmacodynamics. In this review, we will examine the utility and challenges of window of opportunities therapies in breast cancer in the current literature, and the current Australian and international trial landscape in this clinical space.
© 2019 Royal Australasian College of Surgeons.

Link to PubMed record

CCC publication: Integrated treatment of brain metastases

Citation: Current Opinion in Oncology. 2019, 31(6), 501-7
Author: Rosenfelder N
Abstract: PURPOSE OF REVIEW: Optimal treatment of brain metastases has been limited to local treatment with few systemic options. Increasing use of systemic targeted therapies, chemotherapy and immunotherapy and combination of local and systemic treatments has resulted in plethora of publications. We review the existing evidence for individual treatments and new evidence for the integration of systemic and combination of local treatments.
RECENT FINDINGS: Encouraging efficacy of systemic therapies supports combination of systemic and local treatment albeit with little randomized trial data. Efficacy particularly of targeted agents provides an opportunity to delay local treatments including radiosurgery and whole brain radiotherapy. Randomized trials testing the integration of surgery, radiotherapy and radiosurgery are reviewed with emphasis on patient relevant endpoints to guide the clinician in the choice and sequence of treatments and integrating systemic and local therapies.
SUMMARY: There is increasing tendency to use focused radiation for single and oligometastases with or without surgery and decline in whole brain radiotherapy which is limited to multiple metastases in tumours without effective systemic options. Systemic therapies have promising intracranial efficacy and the sequence and combination with localized radiation is awaiting trials. Changes in practice with a move to primary systemic treatment for brain metastases without radiation, should be undertaken with caution and close monitoring.

Link to PubMed record

CCC publication: The First Supra-Regional Contact X-Ray Brachytherapy (Papillon) MDT: An Analysis of Treatment Decisions And Patient Choice

Citation: European Journal of Surgical Oncology. 2019, 45(11), 2222
Author: Fretwell V.; Wong H.; Myint A.S.

Monday 11 November 2019

WUTH publication: Breast conservation surgery by round block mammoplasty

Citation: European Journal of Surgical Oncology. 2020, 46(2) 240-44. Epub 2019 Oct 28
Author: Burrah R, James K, Lund J, Vinayagam R
Abstract: BACKGROUND: Round block mammoplasty (RBM) is a type of Oncoplastic procedure to facilitate breast conservation surgery for breast cancer.
METHODS: Retrospective study of 270 patients who underwent this surgery. The surgical and oncological outcomes of RBM were studied.
RESULTS: The median age was 61 years and median follow-up 39 months. Most cancers (59%) were screen-detected. The location of the cancer was commonly in the upper outer quadrant followed by upper inner quadrant (20%). The average tumor size was 18 mm and in 48% of patients the whole tumor size increased to 23.5 mm due to associated DCIS. The median specimen weight was 41 gm. Forty patients (14.8%) had positive margins. Postoperative complications were seen in 18 patients (6.6%). There were 4 local and 1 axillary recurrences, and 8 distant metastasis. Contralateral symmetrising surgery was required in 13 patients (4.8%).
CONCLUSION: RBM is a robust and easily adaptable technique which provides good exposure for a safe oncological excision. The surgical and oncological outcomes are good and contralateral symmetrising surgery is rarely required.
Copyright © 2019 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.
KEYWORDS: Mammoplasty; Oncoplastic surgery; Round block

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Friday 8 November 2019

WUTH publication: A rare case of a diverticular perforation associated with colo-urachal fistula presenting as anaphylaxis

Citation: Annals of the Royal College of Surgeons of England. 2020, 102(3), e51-e53. Epub 2019 Nov 7.
Author: Yang D, Pearson D, Smith D
Abstract: Diverticular disease is a common clinical condition among Western populations, which increases with age. It can present in a variety of manners and has myriad of potential disease complications. We present a rare case of an adult patient with an extraperitoneal complications of a diverticular perforation presenting with facial swelling due to a colo-urachal fistula associated with a patent urachal remnant. Perforation should be considered in patients presenting with surgical emphysema with background of diverticular disease.
KEYWORDS: Colorectal surgery; Diverticular disease; Diverticular perforation; Surgical emphysema; Urachal remnant

Link to PubMed record

Tuesday 5 November 2019

WUTH publication: Medium-term outcome of posterior surgery in the treatment of non-tuberculous bacterial spinal infection

Citation: Journal of Orthopaedics. 2019, 16(6), 569-75
Author: Aljawadi A, Sethi G, Imo E, Arnall F, Choudhry MN, George KJ, Tambe A, Verma R, Yasin MN, Mohammed S, Siddique I
Abstract: OBJECTIVE: to evaluate the outcome of posterior spinal stabilization surgery for the management of bacterial spinal infection.
METHODS: 21 patients with bacterial infection were managed surgically with posterior stabilization. Outcome measures included neurological status. Follow-up data collected using Spine Tango COMI questionnaires and Euro Qol EQ-5D.
RESULTS: The mean improvement in neurological deficits was 0.91 Frankel grade. Residual symptoms of pain had no or minor effect on the work or usual activities in 52% of subjects, with 88% reported having either no or mid problems with mobility.
CONCLUSION: Posterior surgery can improve neurological outcome in approximately half of the patients.
© 2019 Professor P K Surendran Memorial Education Foundation. Published by Elsevier B.V. All rights reserved.
KEYWORDS: Discitis; Infection; Spine; Spondylodiscitis; Surgery

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Monday 4 November 2019

WUTH publication: Training opportunities in thoracic ultrasound for respiratory trainees: are current guidelines practical?

Citation: BMJ open respiratory research. 2019, 6(1), e000390
Author: Stanton AE, Evison M, Roberts M, Latham J, Clive AO, Batalla-Duran E, Bhatnagar R, Asciak R, Diggins B, Bintcliffe OJ, Lees D, Parsonage M, Denny P, Gow K, Avram C, Gautam M, Rahman NM
Abstract: INTRODUCTION: Respiratory trainees in the UK face challenges in meeting current Royal College of Radiologists (RCR) Level 1 training requirements for thoracic ultrasound (TUS) competence, specified as attending 'at least one session per week over a period of no less than 3 months, with approximately five scans per session performed by the trainee (under supervision of an experienced practitioner)'. We aimed to clarify where TUS training opportunities currently exist for respiratory registrars.
METHODS: Data were collected (over a 4-week period) to clarify the number of scans (and therefore volume of training opportunities) within radiology departments and respiratory services in hospitals in the South West, North West deaneries and Oxford.
RESULTS: 14 hospitals (including three tertiary pleural centres) provided data. Of 964 scans, 793 (82.3%) were conducted by respiratory teams who performed a mean of 17.7 scans per week, versus 3.1 TUS/week in radiology departments. There was no radiology session in any hospital with ≥5 TUS performed, whereas 8/14 (86%) of respiratory departments conducted such sessions. Almost half (6/14) of radiology departments conducted no TUS scans in the period surveyed.
CONCLUSIONS: The currently recommended exposure of regularly attending a list or session to undertake five TUS is not achievable in radiology departments. The greatest volume of training opportunities exists within respiratory departments in a variety of scheduled and unscheduled settings. Revision of the competency framework in TUS, and where this is delivered, is required.
© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
KEYWORDS: Imaging/CT MRI etc; pleural disease

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Wednesday 30 October 2019

Let's Talk Research 2020 - Call for papers is now open!

NHS Research and Development North West are pleased to announce the Call for Papers for Lets Talk Research 2020 - The Time is Now!

Thursday 25th June 2020, The Monastery, Gorton

Let’s Talk Research celebrates the exemplary work of early career NHS researchers that is laying the foundations for the methods and practices of the future and asks us to consider what we want research and innovation in the NHS to look like in 2050 and beyond.
We would like to invite presenters to submit abstracts for innovative workshops, alternative format presentations and 'Research Has Got Talent' 3 minute paper presentations for Let’s Talk Research 2020 – The Time is Now
The conference provides a multidisciplinary platform to critically articulate research, development and innovation in health and social care across the region.
We want to hear about how your research is going to change the future of health and social care.  
We particularly welcome contributions from clinicians, early career researchers, clinical academics, patients involved in research and members of the public.




The submission deadline is 5pm Friday 27th March 2020.

FOR MORE INFORMATION AND TO BOOK YOUR PLACE TODAY, CLICK HERE! 

CONFIRMED SPEAKERS SO FAR...
 

Prof Soo Downe, Professor in Midwifery Studies, UcLan

Click here to watch Prof Downe’s recent Wonder Woman podcast video where she shares with us her career journey from clinical midwife to practising researcher
Simon R. Stones
Simon is a postgraduate researcher based in the School of Healthcare at the University of Leeds. He is a passionate patient advocate, consultant and ambassador for young people living with musculoskeletal diseases, inspired by his own journey with arthritis, fibromyalgia, and Crohn’s disease since childhood.

Prof Dave Jones, Dean, NIHR Academy

Professor Dave Jones is responsible for assisting NIHR and universities in the leadership training and career management of all trainees funded through NIHR Integrated Academic Training Schemes and NIHR Personal Awards Schemes

Dr Justin Jagosh, Director, Centre for Advancement in Realist Evaluation & Synthesis, University of Liverpool

Justin is an Honorary Research Associate at the University of Liverpool and Director for the Centre for Advancement in Realist Evaluation and Synthesis – CARES.  He is an advisor on numerous research contracts involving realist methodology and delivers training workshops in the UK and Internationally, including an annual CARES Summer School.
(as Justin is based in Canada his keynote will be done by live feed – something not to be missed!!!)

“What a brilliant conference, really loved the creative element and it really stood out as one of the best conferences I've ever been to! A day well spent!''
Delegate 2016 
“Rarely have I learnt so much and had so much fun at a conference before - i'd recommend this to anyone!'' 
Delegate 2017 

Thursday 24 October 2019

CCC publication: Addition of docetaxel to hormonal therapy in low- and high-burden metastatic hormone sensitive prostate cancer: long-term survival results from the STAMPEDE trial

Citation: Annals of Oncology. 2019, 30(12), 1992-2003. 2019 Sep 27 [Epub ahead of print]
Author: M D; Matheson, D; Millman, R; Parker, C C; Ritchie, A W S; Rush, H; Russell, J M; Brown, J; Beesley, S; Birtle, A; Capaldi, L; Gale, J; Gibbs, S; Lydon, A; Nikapota, A; Omlin, A; O'Sullivan, J M; Parikh, O; Protheroe, A; Rudman, S; Srihari, N N; Simms, M; Tanguay, J S; Tolan, S; Wagstaff, J; Wallace, J; Wylie, J; Zarkar, A; Sydes, M R; Parmar, M K B; James, N D
Abstract: BACKGROUND: STAMPEDE has previously reported that the use of upfront docetaxel improved overall survival (OS) for metastatic hormone naïve prostate cancer patients starting long-term androgen deprivation therapy. We report on long-term outcomes stratified by metastatic burden for M1 patients.
METHODS: We randomly allocated patients in 2 : 1 ratio to standard-of-care (SOC; control group) or SOC + docetaxel. Metastatic disease burden was categorised using retrospectively-collected baseline staging scans where available. Analysis used Cox regression models, adjusted for stratification factors, with emphasis on restricted mean survival time where hazards were non-proportional.
RESULTS: Between 05 October 2005 and 31 March 2013, 1086 M1 patients were randomised to receive SOC (n = 724) or SOC + docetaxel (n = 362). Metastatic burden was assessable for 830/1086 (76%) patients; 362 (44%) had low and 468 (56%) high metastatic burden. Median follow-up was 78.2 months. There were 494 deaths on SOC (41% more than the previous report). There was good evidence of benefit of docetaxel over SOC on OS (HR = 0.81, 95% CI 0.69-0.95, P = 0.009) with no evidence of heterogeneity of docetaxel effect between metastatic burden sub-groups (interaction P = 0.827). Analysis of other outcomes found evidence of benefit for docetaxel over SOC in failure-free survival (HR = 0.66, 95% CI 0.57-0.76, P < 0.001) and progression-free survival (HR = 0.69, 95% CI 0.59-0.81, P < 0.001) with no evidence of heterogeneity of docetaxel effect between metastatic burden sub-groups (interaction P > 0.5 in each case). There was no evidence that docetaxel resulted in late toxicity compared with SOC: after 1 year, G3-5 toxicity was reported for 28% SOC and 27% docetaxel (in patients still on follow-up at 1 year without prior progression).
CONCLUSIONS: The clinically significant benefit in survival for upfront docetaxel persists at longer follow-up, with no evidence that benefit differed by metastatic burden. We advocate that upfront docetaxel is considered for metastatic hormone naïve prostate cancer patients regardless of metastatic burden.
© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
KEYWORDS: STAMPEDE trial; docetaxel; hormone naive; metastatic; prostate cancer; randomised control trial

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CCC publication: Transanal endoscopic microsurgery for rectal lesions in a specialist regional early rectal cancer centre: the Mersey experience

Citation: Colorectal Disease. 2019, 21(10), 1164-74
Author: Ondhia, M; Tamvakeras, P; O'Toole, P; Montazerri, A; Andrews, T; Farrell, C; Ahmed, S; Slawik, S; Merseyside Early Rectal Cancer Network
Abstract: AIM: Organ-preserving local excision by transanal endoscopic microsurgery (TEM) for early rectal cancer offers significantly lower morbidity as compared to formal rectal cancer resection with acceptable outcomes. This study presents our 6-year experience of TEM for rectal lesions referred to a specialist early rectal cancer centre in the UK.
METHOD: Data were collected for all patients referred for TEM of suspected early rectal cancer to a regional specialist early rectal cancer multidisciplinary team (MDT) over a 6-year period.
RESULTS: One hundred and forty-one patients who underwent full-thickness TEM for suspected or confirmed early rectal cancer were included. Thirty patients were referred for TEM following incomplete endoscopic polypectomy. Final pathology was benign in 77 (54.6%) cases and malignant in 64 (45.4%). Of the 61 confirmed adenocarcinomas, TEM resections were pT0 in 17 (27.9%), pT1 in 32 (51.7%), pT2 in 11 (18.0%) and pT3 in 1 (1.6%). Thirty-eight of 61 patients (62.3%) had one or more poor histological prognostic features and these patients were offered further treatment. Twenty-three of 61 (37.7%) patients with rectal adenocarcinoma required no further treatment following TEM. Forty-three cases of rectal adenocarcinoma were available for establishing recurrence rates. Two of 43 patients (4.7%) developed a recurrence at a median follow-up of 28.7 months (12.1-66.5 months). The overall estimated 5-year overall survival rate was 87.9% and the disease-free survival rate was 82.9%.
CONCLUSION: Acceptable outcomes are possible for TEM surgery with appropriate patient selection, effective technique, expert histopathology, appropriate referral for adjuvant treatment and meticulous follow-up. This can be achieved through an early rectal cancer MDT in a dedicated specialist regional centre.
Colorectal Disease © 2019 The Association of Coloproctology of Great Britain and Ireland.
KEYWORDS: Early rectal cancer; local excision rectal cancer

Link to PubMed record

CCC publication: ALK immunohistochemistry positive, FISH negative NSCLC is infrequent, but associated with impaired survival following treatment with crizotinib

Citation: Lung Cancer. 2019, 138, 13-18
Author: Mellemgaard, A; Dingemans, A M C; Speel, E J M; de Langen, A J; Hashemi, S M S; Bahce, I; van der Drift, M A; Looijen-Salamon, M G; Gosney, J; Postmus, P E; Samii, S M S; Duplaquet, F; Weynand, B; Durando, X; Penault-Llorca, F; Finn, S; Grady, A O; Oz, B; Akyurek, N;  Buettner, R; Wolf, J; Bubendorf, L; Duin, S; Marondel, I; Heukamp, L C; Timens, W; Schuuring, E M D; Pauwels, P; Smit, E F
Abstract: OBJECTIVE: Metastasized non-small cell lung cancer (NSCLC) with an anaplastic lymphoma kinase (ALK) rearrangement is usually sensitive to a range of ALK-tyrosine kinase inhibitors. ALK-positive NSCLC have been identified in pivotal phase III trials with fluorescence in situ hybridization (ALK FISH+). These tumors are also expressing the fusion product (ALK immunohistochemistry (IHC)+). However, discrepant cases occur, including ALK IHC + FISH-. The aim of this study was to collect ALK IHC + cases and compare within this group response to crizotinib treatment of ALK FISH + cases with ALK FISH- cases.
MATERIALS AND METHODS: In this European prospective multicenter research study patients with Stage IV ALK IHC + NSCLC treated with crizotinib were enrolled. Tumor slides were validated centrally for ALK IHC and ALK FISH.
RESULTS: Registration of 3523 ALK IHC tests revealed a prevalence of 2.7% (n = 94) ALK IHC + cases. Local ALK FISH analysis resulted in 48 concordant (ALK IHC+/FISH+) and 16 discordant (ALK IHC+/FISH-) cases. Central validation revealed 37 concordant and 7 discordant cases, 5 of which had follow-up. Validation was hampered by limited amount of tissue in biopsy samples. The PFS at 1 year for ALK concordant and discordant was 58% and 20%, respectively (HR = 2.4; 95% CI: 0.78-7.3; p = 0.11). Overall survival was significantly better for concordant cases than discordant cases after central validation (HR=4.5; 95% CI= 1.2-15.9; p=0.010.
CONCLUSION: ALK IHC + FISH- NSCLC is infrequent and associated with a worse outcome on personalized treatment. A suitable predictive testing strategy may be to screen first with IHC and then confirm with FISH instead of considering ALK IHC equivalent to ALK FISH according to the current guidelines.
Copyright © 2019 Elsevier B.V. All rights reserved.
KEYWORDS: alk; fluorescence in situ hybridisation; immunohistochemistry; non-small cell lung cancer; prognosis; treatment

Link to PubMed record

CCC publication: A prognostic model to personalize monitoring regimes for patients with incidental asymptomatic meningiomas

Citation: Neuro-oncology. 2019 Oct 11 [Epub ahead of print]
Author: Islim, Abdurrahman I; Kolamunnage-Dona, Ruwanthi; Mohan, Midhun; Moon, Richard D C; Crofton, Anna; Haylock, Brian J; Rathi, Nitika; Brodbelt, Andrew R; Mills, Samantha J; Jenkinson, Michael D
Abstract: BACKGROUND: Asymptomatic meningioma is a common incidental finding with no consensus on the optimal management strategy. We aimed to develop a prognostic model to guide personalized monitoring of incidental meningioma patients.
METHODS: A prognostic model of disease progression was developed in a retrospective cohort (2007-2015), defined as: symptom development, meningioma-specific mortality, meningioma growth or loss of window of curability. Secondary endpoints included non-meningioma-specific mortality and intervention.
RESULTS: Included were 441 patients (459 meningiomas). Over a median of 55 months (interquartile range, 37-80), 44 patients had meningioma progression and 57 died (non-meningioma-specific). Forty-four had intervention (at presentation, n = 6; progression, n = 20; nonprogression, n = 18). Model parameters were based on statistical and clinical considerations and included: increasing meningioma volume (hazard ratio [HR] 2.17; 95% CI: 1.53-3.09), meningioma hyperintensity (HR 10.6; 95% CI: 5.39-21.0), peritumoral signal change (HR 1.58; 95% CI: 0.65-3.85), and proximity to critical neurovascular structures (HR 1.38; 95% CI: 0.74-2.56). Patients were stratified based on these imaging parameters into low-, medium- and high-risk groups and 5-year disease progression rates were 3%, 28%, and 75%, respectively. After 5 years of follow-up, the risk of disease progression plateaued in all groups. Patients with an age-adjusted Charlson comorbidity index ≥6 (eg, an 80-year-old with chronic kidney disease) were 15 times more likely to die of other causes than to receive intervention at 5 years following diagnosis, regardless of risk group.
CONCLUSIONS: The model shows that there is little benefit to rigorous monitoring in low-risk and older patients with comorbidities. Risk-stratified follow-up has the potential to reduce patient anxiety and associated health care costs.
© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.
KEYWORDS: asymptomatic; incidental; meningioma; prognosis; risk score

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CCC publication: Ambulatory emergency oncology: A key tenet of future emergency oncology care

Citation: International Journal of Clinical Practice. 2020, 74(1), e13436. 2019 Oct 21 [Epub ahead of print]
Author: Cooksley, Tim; Marshall, Will; Ahn, Shin; Lasserson, Daniel S; Marshall, Ernie; Rice, Terry W; Klotz, Adam
Abstract: The challenges of emergency oncology alongside its increasing financial burden has led to an interest in developing optimal care models for meeting patients' needs. Ambulatory care is recognized as a key tenet in ensuring the safety and sustainability of acute care services. Increased access to ambulatory care has successfully reduced ED utilization and improved clinical outcomes in high risk non-Oncological populations. Individualised management of acute cancer presentations is a key challenge for emergency oncology services so that it can mirror routine cancer care. There are an increasing number of acute cancer presentations, such as low risk febrile neutropenia and incidental pulmonary embolism, that can be risk assessed for care in an emergency ambulatory setting. Modelling of ambulatory emergency oncology services will be dependent on local service deliveries and pathways, but are key for providing high quality, personalised and sustainable emergency oncology care. These services will also be at the forefront of much needed emergency oncology to define the optimal management of ambulatory-sensitive presentations.
© 2019 John Wiley & Sons Ltd.
KEYWORDS: Ambulatory Care; Emergency Oncology; Febrile neutropenia; Incidental pulmonary embolism; MASCC

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CCC publication: Radiographer non-medical prescribing: independence and implications for practice

Citation: Journal of Prescribing Practice. 2019, 1(10) 506-11
Author: Cain
Abstract: Non-medical prescribing is not a new initiative in healthcare. The modernisation of the NHS, strained workforces in radiotherapy and clinical oncology and the recognition that the role of the radiographer extends across the entire patient pathway has motivated development of therapeutic radiographer roles. For advanced, expert and consultant radiographers, this includes non–medical, supplementary, and independent prescribing authority. Limitations in current prescribing legislation have the potential to negatively impact these services. However, the overall benefits of non-medical prescribing for the patient, professional and entire workforce are undeniable. Radiographer non-medical prescribing is pertinent to the maintenance and continued improvement of cancer services.

Thursday 17 October 2019

WUTH publication: The Supracondylar Process: A Rare Case of Ulnar Nerve Entrapment and Literature Review

Citation: Journal of hand and microsurgery. 2019, 11(Suppl 1), S06-S10
Author: May-Miller P, Robinson S, Sharma P, Shahane S
Abstract: A fit and well 33-year-old male mechanic was referred to the clinic complaining of locking of right elbow and paraesthesia and pain affecting the forearm and hand. Radiographs demonstrated a right-sided supracondylar process. The patient had locking of his right elbow, which caused shooting pains both distally and proximally. The ulnar nerve was irritable proximal to the cubital tunnel, and there was some weakness of the ulnar nerve supplied muscles of the hand and forearm. The patient had a subjective feeling of altered sensation over the medial one and a half digits. The magnetic resonance imaging (MRI) suggested that there was anomalous anatomy around the elbow and that compression of the ulnar and or the median nerve by a fibrous band appeared to be the cause of his symptoms. A surgical exploration was arranged. The incision was posterior to the medial epicondyle. A fascial/muscular band was identified from the tip of the supratrochlear spur to the olecranon and was seen to kink the ulnar nerve. This was corrected upon its release. The supratrochlear spur was excised with an osteotome, and bone wax applied to the humerus. On review 6 weeks postoperatively, his function had returned to normal.
© Thieme Medical Publishers.
KEYWORDS: ligament of Struthers; supracondylar process; ulnar nerve

Link to PubMed record

Tuesday 15 October 2019

WUTH publication: Assessment of steroid use as a key performance indicator in inflammatory bowel disease-analysis of data from 2385 UK patients

Citation: Alimentary pharmacology and therapeutics. 2019, 50(9), 1009-18 Epub 2019 Oct 8
Author: Selinger CP, Parkes GC, Bassi A, Limdi JK, Ludlow H, Patel P, Smith M, Saluke S, Ndlovu Z, George B, Saunders J, Adamson M, Fraser A, Robinson J, Donovan F, Parisi I, Tidbury J, Gray L, Pollok R, Scott G, Raine T
Abstract: BACKGROUND: Patients with IBD are at risk of excess corticosteroids.
AIMS: To assess steroid excess in a large IBD cohort and test associations with quality improvement and prescribing.
METHODS: Steroid exposure was recorded for outpatients attending 19 centres and associated factors analysed. Measures taken to avoid excess were assessed.
RESULTS: Of 2385 patients, 28% received steroids in the preceding 12 months. 14.8% had steroid excess or dependency. Steroid use was significantly lower at 'intervention centres' which participated in a quality improvement programme (exposure: 23.8% vs 31.0%, P < .001; excess 11.5% vs 17.1%, P < .001). At intervention centres, steroid use fell from 2015 to 2017 (steroid exposure 30.0%-23.8%, P = .003; steroid excess 13.8%-11.5%, P = .17). Steroid excess was judged avoidable in 50.7%. Factors independently associated with reduced steroid excess in Crohn's disease included maintenance with anti-TNF agents (OR 0.61 [95% CI 0.24-0.95]), treatment in a centre with a multi-disciplinary team (OR 0.54 [95% CI 0.20-0.86]) and treatment at an intervention centre (OR 0.72 [95% CI 0.46-0.97]). Treatment with 5-ASA in CD was associated with higher rates of steroid excess (OR 1.72 [95% CI 1.24-2.09]). In ulcerative colitis (UC), thiopurine monotherapy was associated with steroid excess (OR 1.97 [95% CI 1.19-3.01]) and treatment at an intervention centre with less steroid excess (OR 0.72 [95% CI 0.45-0.95]).
CONCLUSIONS: This study validates steroid assessment as a meaningful quality measure and provides a benchmark for this performance indicator in a large cohort. A programme of quality improvement was associated with lower steroid use.

Link to PubMed record

Monday 7 October 2019

WUTH publication: Xanthogranulomatous pyelonephritis with associated renal cell carcinoma

Citation: BMJ Case Reports. 2019, 12(10), e232097
Author: Moss BF, Potter L, Cliff A, Kumar M
Abstract: Xanthogranulomatous pyelonephritis is associated with obstruction, stones and infection. CT is the mainstay of diagnosis, but appearances can mimic other conditions, including renal cell carcinoma. Nephrectomy is commonly recommended, but conservative treatment with antibiotics has been described after tissue diagnosis. We present a case of xanthogranulomatous pyelonephritis with concomitant renal cell carcinoma, which was an association that was suggested in 1988 and supported by subsequently reported cases. Conservative management of biopsy or cytology proven xanthogranulomatous pyelonephritis is unsafe, as an area of synchronous malignant tumour may be missed: we recommend it only in patients unfit for nephrectomy.
© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.
KEYWORDS: oncology; renal intervention; renal medicine; urological surgery; urology

Link to PubMed record

Friday 4 October 2019

WUTH publication: Need for A Central Renal Registry in Pakistan

Citation: Therapeutic apheresis and dialysis. 2019 Oct 3 [Epub ahead of print]
Author: Abid A, Abid H, Jamil A
Abstract: KEYWORDS: Acute kidney injury, Chronic kidney disease, Nephrology, Public health, Pakistan, Renal registry

Link to PubMed record

Monday 30 September 2019

WUTH publication: Short-term outcome of surgical arthrodiastasis of the ankle with Ilizarov frame in a cohort of children and young people with juvenile idiopathic arthritis

Citation: Rheumatology Advances in Practice. 2019, 3(2)
Author: Cleary G, Pain C, McCann L, Mahmood K, Brookes-Fazakerley S, Robinson S, Walton R, Highcock A, Landes C, Barnes N, Roberts I, James L
Abstract: OBJECTIVES: Despite medical advances, life-changing articular damage may still occur in patients with JIA. We report a cohort with destructive arthropathy of the ankle treated by surgical arthrodiastasis.
METHODS: Eight patients (nine ankles) received arthrodiastasis by means of an Ilizarov frame between 2009 and 2013. Patient- and clinician-reported outcome measures were collated prospectively, with retrospective analysis of demographics, disease and pre-surgical treatment.
RESULTS: Pre-surgery, all patients received IA CS (mean 0.8 injections/year) and MTX (mean diagnosis to treatment 3.8 years; two of eight started within 3 months). Seven of eight patients received biologic drugs. Pain scores improved by 56 and 29% (P < 0.005) at 6 and 12 months post-frame removal. American Academy Orthopaedic Foot and Ankle Society ankle-hindfoot scale, Oxford Ankle Foot Questionnaire-Child and Oxford Ankle Foot Questionnaire-Parent scores improved by 171, 62 and 80%, respectively (P < 0.005) at 12 months post-frame removal. Patients remained satisfied with surgical treatment for a mean of 13.3 months. There was transient pin site infection in three patients, and all patients had radiological improvement in joint space.
CONCLUSION: Arthrodiastasis with an Ilizarov frame is a safe, well-tolerated technique that should be considered as a short-term joint-preserving procedure to improve pain and function when damage has occurred. Delays to systemic medical treatment in this cohort would be considered out-with standard modern practice but, although less prevalent, destructive ankle arthropathy continues to occur in JIA, and we believe this study to be relevant. The ankle is particularly susceptible to damage and, even if localized, should be treated early and aggressively with DMARDs and rapid progression to biologic therapies.
LEVELOF EVIDENCE: Level IV.
KEYWORDS: ankle; arthrodiastasis; functional outcome; juvenile idiopathic arthritis; pain

Link to PubMed record

Wednesday 25 September 2019

CCC publication: Patterns of Recurrence After Resection of Pancreatic Ductal Adenocarcinoma: A Secondary Analysis of the ESPAC-4 Randomized Adjuvant Chemotherapy Trial

Citation: JAMA Surgery. 2019 Sep 4. [Epub ahead of print]
Author: Jones RP, Psarelli EE, Jackson R, Ghaneh P, Halloran CM, Palmer DH, Campbell F, Valle JW, Faluyi O, O'Reilly DA, Cunningham D6, Wadsley J, Darby S, Meyer T, Gillmore R, Anthoney A, Lind P, Glimelius B, Falk S, Izbicki JR, Middleton GW, Cummins S, Ross PJ, Wasan H, McDonald A, Crosby T, Ting Y, Patel K, Sherriff D, Soomal R, Borg D, Sothi S, Hammel P, Lerch MM, Mayerle J, Tjaden C, Strobel O, Hackert T, Büchler MW, Neoptolemos JP; European Study Group for Pancreatic Cancer
Abstract: Importance: The patterns of disease recurrence after resection of pancreatic ductal adenocarcinoma with adjuvant chemotherapy remain unclear.
Objective: To define patterns of recurrence after adjuvant chemotherapy and the association with survival.
Design, Setting, and Participants: Prospectively collected data from the phase 3 European Study Group for Pancreatic Cancer 4 adjuvant clinical trial, an international multicenter study. The study included 730 patients who had resection and adjuvant chemotherapy for pancreatic cancer. Data were analyzed between July 2017 and May 2019.
Interventions: Randomization to adjuvant gemcitabine or gemcitabine plus capecitabine.
Main Outcomes and Measures: Overall survival, recurrence, and sites of recurrence.
Results: Of the 730 patients, median age was 65 years (range 37-81 years), 414 were men (57%), and 316 were women (43%). The median follow-up time from randomization was 43.2 months (95% CI, 39.7-45.5 months), with overall survival from time of surgery of 27.9 months (95% CI, 24.8-29.9 months) with gemcitabine and 30.2 months (95% CI, 25.8-33.5 months) with the combination (HR, 0.81; 95% CI, 0.68-0.98; P = .03). The 5-year survival estimates were 17.1% (95% CI, 11.6%-23.5%) and 28.0% (22.0%-34.3%), respectively. Recurrence occurred in 479 patients (65.6%); another 78 patients (10.7%) died without recurrence. Local recurrence occurred at a median of 11.63 months (95% CI, 10.05-12.19 months), significantly different from those with distant recurrence with a median of 9.49 months (95% CI, 8.44-10.71 months) (HR, 1.21; 95% CI, 1.01-1.45; P = .04). Following recurrence, the median survival was 9.36 months (95% CI, 8.08-10.48 months) for local recurrence and 8.94 months (95% CI, 7.82-11.17 months) with distant recurrence (HR, 0.89; 95% CI, 0.73-1.09; P = .27). The median overall survival of patients with distant-only recurrence (23.03 months; 95% CI, 19.55-25.85 months) or local with distant recurrence (23.82 months; 95% CI, 17.48-28.32 months) was not significantly different from those with only local recurrence (24.83 months; 95% CI, 22.96-27.63 months) (P = .85 and P = .35, respectively). Gemcitabine plus capecitabine had a 21% reduction of death following recurrence compared with monotherapy (HR, 0.79; 95% CI, 0.64-0.98; P = .03).
Conclusions and Relevance: There were no significant differences between the time to recurrence and subsequent and overall survival between local and distant recurrence. Pancreatic cancer behaves as a systemic disease requiring effective systemic therapy after resection.
Trial Registration: Clinicaltrials.gov Identifier: NCT00058201, EudraCT 2007-004299-38, and ISRCTN 96397434.

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