• UBE2QL1 is disrupted by a constitutional translocation associated with renal tumor predisposition and is a novel candidate renal tumor suppressor gene.

      Wake, N; Ricketts, C; Morris, M; Prigmore, E; Gribble, S; Skytte, A-B; Brown, Michael D; Clarke, Noel W; Banks, R; Hodgson, S; et al. (2013-12)
      Investigation of rare familial forms of renal cell carcinoma (RCC) has led to the identification of genes such as VHL and MET that are also implicated in the pathogenesis of sporadic RCC. In order to identify a novel candidate renal tumor suppressor gene, we characterized the breakpoints of a constitutional balanced translocation, t(5;19)(p15.3;q12), associated with familial RCC and found that a previously uncharacterized gene UBE2QL1 was disrupted by the chromosome 5 breakpoint. UBE2QL1 mRNA expression was downregulated in 78.6% of sporadic RCC and, although no intragenic mutations were detected, gene deletions and promoter region hypermethylation were detected in 17.3% and 20.3%, respectively, of sporadic RCC. Reexpression of UBE2QL1 in a deficient RCC cell line suppressed anchorage-independent growth. UBE2QL1 shows homology to the E2 class of ubiquitin conjugating enzymes and we found that (1) UBE2QL1 possesses an active-site cysteine (C88) that is monoubiquitinated in vivo, and (2) UBE2QL1 interacts with FBXW7 (an F box protein providing substrate recognition to the SCF E3 ubiquitin ligase) and facilitates the degradation of the known FBXW7 targets, CCNE1 and mTOR. These findings suggest UBE2QL1 as a novel candidate renal tumor suppressor gene.
    • UGT1A1*28 genotype predicts gastrointestinal toxicity in patients treated with intermediate-dose irinotecan.

      Ferraldeschi, Roberta; Minchell, Laura J; Roberts, Stephen A; Tobi, Simon; Hadfield, Kristen D; Blackhall, Fiona H; Mullamitha, Saifee A; Wilson, Gregory; Valle, Juan W; Saunders, Mark P; et al. (2009-05)
      AIMS: Variants in UGT1A1 have previously been associated with toxicity from irinotecan chemotherapy. We conducted a pragmatic prospective cohort study to establish the relevance of UGT1A1 variants in the prediction of severe diarrhea and neutropenia in patients with colorectal cancer receiving irinotecan in a routine clinical setting. MATERIALS & METHODS: Genotyping of UGT1A1*28 and c.-3156G>A was undertaken in an unselected, prospective cohort of 96 individuals treated with irinotecan at a single major UK oncology centre. Data on cytotoxic drugs received, and toxicity for all irinotecan treatment cycles were collected from case notes. Over 95% (92/96) of patients received an intermediate dose of irinotecan (180 mg/m(2), twice weekly). Irinotecan was given in combination with other cytotoxic drugs in 93/96 subjects and Grade 3 or 4 toxicity occurred in 23% of subjects. RESULTS: No association was found between UGT1A1*28 or c.-3156G>A and neutropenia. However, individuals carrying two copies of UGT1A1*28 (p = 0.04; OR: 14; 95% CI: 1.1-185) or c.-3156G>A (p = 0.03) had a significantly increased risk of diarrhea over all cycles. CONCLUSION: Our findings indicate that UGT1A1 genotyping is not a good predictor of hematological toxicity in patients treated with intermediate irinotecan doses. However, it may be useful in the identification of patients at risk of severe diarrhea.
    • UICC postgraduate courses in clinical cancer chemotherapy: a teaching experience outside Europe.

      Brunner, K; Crowther, Derek; Eckhardt, S; Monfardini, S; Olive, A D; Reed, D W (1980)
    • The UK at the forefront of innovative drug-radiotherapy combination clinical trials: introducing the CONCORDE platform

      Faivre-Finn, Corinne; Brown, S; Ryan, A; Greystoke, A; The Christie NHS Foundation Trust/University of Manchester, Manchester, UK (2020)
    • UK consensus statement on safe clinical prescribing of Bexarotene for patients with cutaneous T-cell lymphoma.

      Scarisbrick, J; Morris, S; Azurdia, R; Illidge, Timothy M; Parry, Eileen; Graham-Brown, R; Cowan, Richard A; Gallop-Evans, E; Wachsmuth, R; Eagle, M; et al. (2012-09-10)
      Background:  Bexarotene is a synthetic retinoid from the subclass of retinoids called rexinoids which selectively activate retinoid X receptors. It has activity in cutaneous T-cell lymphoma and has been approved by the European Medicines Agency since 1999 for treatment of the skin manifestations of advanced stage (IIB-IVB) cutaneous T-cell lymphoma in adult patients refractory to at least one systemic treatment. In vivo bexarotene produces primary hypothyroidism which may be managed with thyroxine replacement. It also affects lipid metabolism typically resulting in raised triglycerides which requires prophylactic lipid modification therapy. Effects on neutrophils, glucose and liver function may also occur. These side effects are dose dependent and may be controlled with corrective therapy or dose adjustments. Objectives:  To produce a UK statement outlining a bexarotene dosing schedule and monitoring protocol to enable bexarotene prescribers to deliver bexarotene safely for optimal effect. Methods:  Leaders from UK supraregional centres have produced this consensus statement after a series of meetings and review of the literature. Results:  The statement outlines a bexarotene dosing schedule and monitoring protocol. This gives instruction on monitoring and treating thyroid, lipid, liver, blood count, creating kinase, glucose and amylase abnormalities. This statement also includes algorithms for a bexarotene protocol and lipid management which may be used in the clinical setting. Conclusion:  Clinical prescribing of bexarotene for patients with cutaneous T-cell lymphoma requires careful monitoring to allow bexarotene to be given safely at optimal dose.
    • The UK experience in treating relapsed childhood acute lymphoblastic leukaemia: a report on the medical research council UKALLR1 study.

      Lawson, S E; Harrison, G; Richards, S; Oakhill, A; Stevens, R; Eden, Tim O B; Darbyshire, P J; Department of Haematology, Birmingham Children's Hospital, Birmingham, UK. isaac.lawson@btinternet.com (2000-03)
      We have examined the toxicity and overall outcome of the Medical Research Council UKALL R1 protocol for 256 patients with relapsed childhood acute lymphoblastic leukaemia (ALL). Second remission was achieved in over 95% of patients. Two patients died during induction and seven patients died of resistant disease. The overall actuarial event-free survival (EFS) at 5 years for all patients experiencing a first relapse was 46% (95% CI 40-52). Duration of first remission, site of relapse, age at diagnosis and sex emerged as factors of prognostic significance. Five-year EFS was only 7% for children relapsing in the bone marrow within 2 years of diagnosis, but was 77% for those relapsing without bone marrow involvement > 2.5 years from diagnosis. All analyses in this report are by treatment received. For those receiving chemotherapy alone, the 5-year EFS was 48%; for autologous bone marrow transplantation (BMT), the 5-year EFS was 47%; for unrelated donor BMT, it was 52%; and for related donor BMT, the 5-year EFS was 45%. The groups, however, were not comparable with respect to risk factor profile, and therefore direct comparison of EFS is misleading. Adjustment for time to transplant and prognostic factors was used to reduce the effects of biases between treatment groups, but did not suggest benefit for any particular treatment. There was failure of our planned randomization scheme in this trial with only 9% of those eligible being randomized, which highlights the difficulties in running randomized trials especially in patients who have relapsed from a previous trial. The optimal treatment for relapsed ALL therefore remains uncertain. Alternative approaches are clearly needed for those with early bone marrow relapse if outcome is to improve.
    • UK experience of hypofractionated radiotherapy for ductal carcinoma in situ

      Barker, Claire L; Kelly, Claire L; Anandadas, Carmel N; Magee, Brian; Department of Clinical Oncology, The Christie NHS Foundation Trust, Manchester, UK (2019)
    • UK guidelines for the safe delivery of intensity-modulated radiotherapy.

      Mackay, Ranald I; Staffurth, J; Poynter, A; Routsis, D; The Christie NHS Foundation Trust, Manchester, UK. ranald.mackay@physics.cr.man.ac.uk (2010-10)
      This paper outlines the guidelines for the development of intensity-modulated radiotherapy (IMRT) in the UK. The guidelines are designed to cover the complete implementation of IMRT, with guidelines in the following categories: commissioning, quality, clinical, audit, and training and education. These guidelines have been compiled by the Radiotherapy Development Board of the Royal College of Radiologists and will support the safe application of IMRT in the UK.
    • UK guidelines on oesophageal dilatation in clinical practice.

      Sami, S; Haboubi, H; Ang, Y; Boger, P; Bhandari, P; de Caestecker, J; Griffiths, H; Haidry, R; Laasch, Hans-Ulrich; Patel, P; et al. (2018-02-24)
      These are updated guidelines which supersede the original version published in 2004. This work has been endorsed by the Clinical Services and Standards Committee of the British Society of Gastroenterology (BSG) under the auspices of the oesophageal section of the BSG. The original guidelines have undergone extensive revision by the 16 members of the Guideline Development Group with representation from individuals across all relevant disciplines, including the Heartburn Cancer UK charity, a nursing representative and a patient representative. The methodological rigour and transparency of the guideline development processes were appraised using the revised Appraisal of Guidelines for Research and Evaluation (AGREE II) tool.Dilatation of the oesophagus is a relatively high-risk intervention, and is required by an increasing range of disease states. Moreover, there is scarcity of evidence in the literature to guide clinicians on how to safely perform this procedure. These guidelines deal specifically with the dilatation procedure using balloon or bougie devices as a primary treatment strategy for non-malignant narrowing of the oesophagus. The use of stents is outside the remit of this paper; however, for cases of dilatation failure, alternative techniques-including stents-will be listed. The guideline is divided into the following subheadings: (1) patient preparation; (2) the dilatation procedure; (3) aftercare and (4) disease-specific considerations. A systematic literature search was performed. The Grading of Recommendations Assessment, Develop-ment and Evaluation (GRADE) tool was used to evaluate the quality of evidence and decide on the strength of recommendations made.
    • The UK lung SABR survey on behalf of the Advanced Radiotherapy Technologies Network

      Brown, Sean; Beasley, M; McNair, H; Faivre-Finn, Corinne; Franks, K; Murray, L; van Herk, Marcel; Henry, A; The Christie NHS Foundation Trust, Radiotherapy Related Research, Manchester (2019)
    • A UK multi-centre pilot study of speech and swallowing outcomes following head and neck cancer.

      Radford, K; Woods, Helen; Lowe, D; Rogers, S N; Speech and Language Therapy Department, City Hospital, Sandwell and West Birmingham Trusts, Birmingham, UK. (2004-08)
      Speech and swallowing are important components of health-related quality of life following head and neck cancer treatment. The aim of this study was to demonstrate the value of prospective multi-centre evaluation by Speech and Language Therapists and to compare health-related quality of life with speech and swallowing impairments. The University of Washington Head and Neck questionnaire version 4 (UW-QOL) and Therapy Outcome Measures (TOM) were rated before and 6 months after cancer treatment in 95 patients from 12 centres. There was deterioration in TOM scores at 6 months. Pretreatment UW-QOL swallowing was ranked equal first, with speech fourth. At 6 months speech was first and swallowing second. There were positive correlations between UW-QOL swallowing and TOM dysphagia and between UW-QOL speech and TOM laryngectomy, voice, phonology and dysarthria disorders. Both outcome measures are suitable for routine practice. Adaptation of TOM scales for use with head and neck cancer patients may improve sensitivity, validity and therapist compliance.
    • UK national audit of extracorporeal photopheresis in CTCL.

      Sanyal, S; Child, F; Alfred, A; Callaghan, T; Alband, N; Whittaker, S; Wain, M; Morris, S; Malladi, R; Cowan, Richard A; et al. (2017-08-07)
      We performed a national audit of extracorporeal photopheresis (ECP) in cutaneous T-cell lymphoma (CTCL) to gather information on number of treatment cycles, treatment duration and reason for stopping. UK Consensus Guidelines and European ECP Guidelines recommend that ECP can be considered for first-line treatment for erythrodermic CTCL patients with blood involvement [1,2,3]. Publications have shown effectiveness of ECP in early-stage MF, stage IA-IIA [4,5] and ECP is listed as a systemic treatment option in refractory early-stage MF in the National Comprehensive Cancer Network Guidelines [6]. This article is protected by copyright. All rights reserved.
    • The UK national breast cancer screening programme for survivors of Hodgkin lymphoma detects breast cancer at an early stage.

      Howell, Sacha J; Searle, C; Goode, Valerie; Gardener, T; Linton, Kim M; Cowan, Richard A; Harris, Maggie A; Hopwood, Penelope; Swindell, Ric; Norman, Alison; et al. (2009-08-18)
      BACKGROUND: Supradiaphragmatic radiotherapy (SRT) to treat Hodgkin's lymphoma (HL) at a young age increases the risk of breast cancer (BC). A national notification risk assessment and screening programme (NRASP) for women who were treated with SRT before the age of 36 years was instituted in the United Kingdom in 2003. In this study, we report the implementation and screening results from the largest English Cancer Network. METHODS: A total of 417 eligible women were identified through cancer registry/hospital databases and from follow-up (FU) clinics. Screening results were collated retrospectively, and registry searches were used to capture BC cases. RESULTS: Of the 417 women invited for clinical review, 243 (58%) attended. Of these 417 women, 23 (5.5%) have been diagnosed with BC, a standardised incidence ratio of 2.9 compared with the age-matched general population. Of five invasive BCs diagnosed within the NRASP, none involved axillary lymph nodes compared with 7 of 13 (54%) diagnosed outside the programme (P<0.10). The mean latency for BC cases was 19.5+/-8.35 years and the mean FU duration for those unaffected by BC was 14.6+/-9.11 years (P<0.01), suggesting that those unaffected by BC remain at high risk. Recall and negative biopsy rates were acceptable (10.5 and 0.8%, respectively). CONCLUSIONS: The NRASP appears to detect BC at an early stage with acceptable biopsy rates, although numbers are small. Determination of NRASP results on a national basis is required for the accurate evaluation of screening efficacy in women previously treated with SRT.
    • A UK national phase I/II clinical trial of a MEK1/2 inhibitor combined with highly active anti-retroviral therapy for HIV-associated Kaposi's sarcoma

      Young, R; Poyser, C; Crack, L; Dockrell, D; Bowman, C; Billingham, L; Bower, M; Westwell, S; Leahy, Michael G; Woll, P; et al. (2015)
    • UK Quantitative WB-DWI Technical Workgroup: consensus meeting recommendations on optimisation, quality control, processing and analysis of quantitative whole-body diffusion weighted imaging for cancer.

      Barnes, A; Alonzi, R; Blackledge, M; Charles-Edwards, G; Collins, D; Cook, G; Coutts, Glyn; Goh, V; Martin, G; Kelly, C; et al. (2017-10-27)
      Application of whole body diffusion weighted MRI (WB-DWI) for oncology are rapidly increasing within both research and routine clinical domains. However, WB-DWI as a quantitative imaging biomarker (QIB) has significantly slower adoption. To date challenges relating to accuracy and reproducibility, essential criteria for a good QIB, have limited widespread clinical translation. In recognition, a UK workgroup was established in 2016 to provide technical consensus guidelines (to maximise accuracy and reproducibility of WB-MRI QIBs) and accelerate the clinical translation of quantitative WB-DWI applications for oncology.
    • The UK Standardisation of Breast Radiotherapy (START) trials of radiotherapy hypofractionation for treatment of early breast cancer: 10-year follow-up results of two randomised controlled trials.

      Haviland, J; Owen, J; Dewar, J; Agrawal, R; Barrett, J; Barrett-Lee, P; Dobbs, H; Hopwood, P; Lawton, P; Magee, Brian; et al. (2013-10)
      5-year results of the UK Standardisation of Breast Radiotherapy (START) trials suggested that lower total doses of radiotherapy delivered in fewer, larger doses (fractions) are at least as safe and effective as the historical standard regimen (50 Gy in 25 fractions) for women after primary surgery for early breast cancer. In this prespecified analysis, we report the 10-year follow-up of the START trials testing 13 fraction and 15 fraction regimens.
    • UK Vessel Health and Preservation (VHP) Framework: a commentary on the updated VHP 2021

      Hallam, C.; Denton, A.; Weston, V.; Dunn, H.; Jackson, T.; Keeling, S; Hill, Steve; AC Independent Nursing Consultants, Huddersfield, (2021)
      Background: In 2016, a UK vessel health and preservation (VHP) framework was developed to support healthcare staff to select the most appropriate vascular access device for patients requiring intravenous therapy. The VHP framework was based on available evidence and expert consensus. The VHP was based on available evidence and expert consensus. Development of the vhp 2020 framework: A multidisciplinary team reviewed the original UK VHP framework and considered new published evidence, national and international guidelines and expert opinion. A literature search was performed using Cinahl and Medline, incorporating a variety of terms linked to vascular access devices, assessment and selection. Articles published in and after 2014 in English were included. Twelve articles were found to be relevant including three evidence-based guidelines, two randomised control trials and one systematic review. Findings: Three main studies provided the evidence for the update: the MAGIC study that assessed the appropriateness of peripherally inserted central catheters in patients; a study that utilised the 'A-DIVA scale' to predict the likelihood of difficult venous access; and a study that incorporated an 'I-DECIDED tool' for peripheral intravenous catheter assessment and decision-making for device removal. In addition, published guidelines provided evidence that the original advice on appropriate osmolarity of medicines for peripheral administration needed updating. Conclusion: The 2020 UK VHP framework reflects latest evidence-based research and guidelines, providing healthcare staff updated guidance to assist in maintaining good practice in vascular access assessment and device selection and patient safety.