Now showing items 1-20 of 6882

    • Two truncating variants in FANCC and breast cancer risk

      Dork, T; Peterlongo, P; Mannermaa, A; Bolla, MK; Wang, Q; Dennis, J; Ahearn, T; Andrulis, IL; Anton-Culver, H; Arndt, V; et al. (2019)
      Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC, has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95%CI 0.44-1.33, p?=?0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1, BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are differences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants.
    • STEM: SFX-01 in the treatment and evaluation of metastatic breast cancer

      Ross, SL; Morris, T; Campone, M; Cortes, J; Duhoux, FP; Howell, Sacha J; Evgen Pharma PLC, Wilmslow, Cheshire (2019)
    • A phase II study to assess the safety and efficacy of the dual mTORC1/2 inhibitor vistusertib in relapsed, refractory DLBCL

      Eyre, TA; Hildyard, C; Hamblin, A; Ali, AS; Houlton, A; Hopkins, L; Royston, D; Linton, Kim M; Pettitt, A; Rule, S; et al. (2019)
      Patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who are unfit for or relapsed postautologous stem-cell transplantation have poor outcomes. Historically, mTORC1 inhibitors have produced responses in approximately 30% of patients in this setting. mTORC1 inhibitor efficacy may be limited by resistance mechanisms including AKT activation by mTORC2. To date, dual mTORC1/2 inhibitors targeting both the TORC1 and TORC2 complexes have not been investigated in DLBCL. This phase II trial investigated the oral dual mTORC1/2 inhibitor vistusertib in an intermittent dosing schedule of 125 mg b.d. for 2 days per week. Thirty patients received vistusertib and six received vistusertib-rituximab for up to six cycles (28-day cycles). Two partial responses were achieved on monotherapy. Durations of response were 57 and 62 days, respectively, for these patients. 19% had stable disease within six cycles. In the monotherapy arm, the median progression-free survival was1.69 (95% confidence interval [CI] 1.61-2.14) months and median overall survival was 6.58 (95% CI 3.81-not reached) months, respectively. The median duration of response or stable disease across the trial duration was 153 days (95% CI 112-not reached). Tumour responses according to positron emission tomography/computed tomography versus computed tomography were concordant. There were no differences noted in tumour volume response according to cell of origin by either gene expression profiling or immunohistochemistry. Vistusertib ± rituximab was well tolerated; across 36 patients 86% of adverse events were grade (G) 1-2. Common vistusertib-related adverse events were similar to those described with mTORC1 inhibitors: nausea (47% G1-2), diarrhoea (27% G1-2, 6% G3), fatigue (30% G1-2, 3% G3), mucositis (25% G1-2, 6% G3), vomiting (17% G1-2), and dyspepsia (14% G1-2). Dual mTORC1/2 inhibitors do not clearly confer an advantage over mTORC1 inhibitors in relapsed or refractory DLBCL. Potential resistance mechanisms are discussed within.
    • Association of mismatch repair proteins with Merkel cell polyomavirus status and prognosis in Merkel cell carcinoma

      Wardhani, LO; Matsushita, M; Iwasaki, T; Kuwamoto, S; Nonaka, Daisuke; Nagata, K; Kato, M; Kitamura, Y; Hayashi, K; Clinical Pathology Department, Medical Faculty, Sebelas Maret University, Indonesia (2019)
    • The expression of Notch signalling pathway in Merkel cell carcinoma

      Matsushita, M; Wardhani, LO; Iwasaki, T; Kuwamoto, S; Nonaka, Daisuke; Nagata, K; Kato, M; Kitamura, Y; Hayashi, K; Division of Molecular Pathology, Department of Pathology, Tottori University Faculty of Medicine, Yonago, Japan, (2019)
    • Body mass index trajectories across adulthood and smoking in relation to prostate cancer risks: the NIH-AARP Diet and Health Study

      Kelly, Scott P; Lennon, Hannah; Sperrin, Matthew; Matthews, Charles; Freedman, Neal D; Albanes, Demetrius; Leitzmann, Michael F; Renehan, Andrew G; Cook, Michael B; Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda (2019)
      BACKGROUND: Previously we showed that adulthood body mass index (BMI) trajectories that result in obesity were associated with elevated risks of fatal prostate cancer (PCA). To further explore this relationship, we conducted a study within the NIH-AARP Diet and Health Study. METHODS: Among 153 730 eligible men enrolled in the NIH-AARP cohort from 1995 to 1996 (median follow-up?=?15.1?years), we identified 630 fatal PCA cases and 16 896 incident cases. BMI was assessed for ages 18, 35 and 50 and at study entry, enabling examination of latent class-identified BMI trajectories. Hazard ratios (HRs) and 95% confidence intervals (CI) were estimated using Cox proportional hazards regression. RESULTS: BMI at study entry (mean age?=?63, HR?=?1.12; 95% CI?=?1.01, 1.24, per 5-unit increase) and maximum BMI during adulthood (HR?=?1.12; 95% CI?=?1.02, 1.24, per 5-unit increase) shared modest associations with increased risk of fatal PCA. Smoking status likely modified the relationship between BMI trajectories and fatal PCA (Pinteraction = 0.035 via change-in-estimate variable section, P?=?0.065 via full a priori model). Among never-smokers, BMI trajectory of normal weight to obesity was associated with increased risk of fatal disease (HR?=?2.37; 95% CI?=?1.38, 4.09), compared with the maintained normal weight trajectory, whereas there was no association among former or current-smokers. Total and non-aggressive PCA exhibited modest inverse associations with BMI at all ages, whereas no association was observed for aggressive PCA. CONCLUSIONS: Increased BMI was positively associated with fatal PCA, especially among never-smokers. Future studies that examine PCA survival will provide additional insight as to whether these associations are the result of biology or confounding.
    • Metastatic Hormone-Sensitive Prostate Cancer: Clinical Decision Making in a Rapidly Evolving Landscape of Life-Prolonging Therapy

      VanderWeele, DJ; Antonarakis, ES; Carducci, MA; Dreicer, R; Fizazi, K; Gillessen, Silke; Higano, CS; Morgans, AK; Petrylak, DP; Sweeney, CJ; et al. (2019)
    • Integration of early supportive and palliative care in a patient's journey with cancer

      Lyon, J; Cook, Natalie; Lawrie, I; Faculty of biology, medicine and health, University of Manchester (2019)
    • Safety and efficacy of nivolumab in patients with rare melanoma subtypes who progressed on or after ipilimumab treatment: a single arm, open-label, phase II study

      Nathan, P; Ascierto, PA; Haanen, J; Espinosa, E; Demidov, L; Garbe, C; Guida, M; Lorigan, Paul C; Chiarion-Sileni, V; Gogas, H; et al. (2019)
      BACKGROUND: Nivolumab has been widely studied in non-acral cutaneous melanoma; however, limited data are available in other melanoma subtypes. We report outcomes by melanoma subtype in patients who received nivolumab after progression on prior ipilimumab. PATIENTS AND METHODS: CheckMate 172 was a phase II, single-arm, open-label, multicentre study that evaluated nivolumab in patients with advanced melanoma who progressed on or after ipilimumab. Patients received 3 mg/kg of nivolumab, every 2 weeks for up to 2 years. The primary end-point was incidence of grade ³3, treatment-related select adverse events (AEs). RESULTS: Among 1008 treated patients, we report data on patients with non-acral cutaneous melanoma (n = 723 [71.7%]), ocular melanoma (n = 103 [10.2%]), mucosal melanoma (n = 63 [6.3%]), acral cutaneous melanoma (n = 55 [5.5%]) and other melanoma subtypes (n = 64 [6.3%]). There were no meaningful differences in the incidence of grade ³3, treatment-related select AEs among melanoma subtypes or compared with the total population. No new safety signals emerged. At a minimum follow-up of 18 months, median overall survival was 25.3 months for non-acral cutaneous melanoma and 25.8 months for acral cutaneous melanoma, with 18-month overall survival rates of 57.5% and 59.0%, respectively. Median overall survival was 12.6 months for ocular melanoma and 11.5 months for mucosal melanoma, with 18-month overall survival rates of 34.8% and 31.5%, respectively. CONCLUSIONS: The safety profile of nivolumab after ipilimumab is similar across melanoma subtypes. Compared with non-acral cutaneous melanoma, patients with acral cutaneous melanoma had similar survival outcomes, whereas those with ocular and mucosal melanoma had lower median overall survival. CLINICALTRIALS.
    • Implementing the Royal College of Radiologists' Radiotherapy Target Volume Definition and Peer Review Guidelines: More Still To Do?

      Mercieca, S; Belderbos, J; Gilson, D; Dickson, J; Pan, Shermaine; van Herk, Marcel; Faculty of Health Science, University of Malta, Msida, Malta (2019)
    • Validation of the IPF-specific version of St. George's Respiratory Questionnaire

      Prior, TS; Hoyer, N; Shaker, SB; Davidsen, JR; Yorke, Janelle; Hilberg, O; Bendstrup, E; Department of Respiratory Diseases and Allergy, Aarhus University Hospital, Aarhus, Denmark. (2019)
      BACKGROUND: Patients with idiopathic pulmonary fibrosis (IPF) have impaired health-related quality of life (HRQL). To measure HRQL, an IPF-specific version of the St. George's Respiratory Questionnaire (SGRQ-I) was developed, but not sufficiently validated. This study aimed to assess the validity (i.a. known-groups validity and concurrent validity) and test-retest reliability of SGRQ-I in IPF patients with different disease durations. METHODS: Patients with IPF were consecutively recruited and completed SGRQ, SGRQ-I, King's Brief Interstitial Lung Disease questionnaire (K-BILD), University of California, San Diego Shortness of Breath Questionnaire (SOBQ) and Short Form-36 (SF-36) along with pulmonary function tests and a 6-min walk test (6MWT) at baseline. After two weeks, SGRQ-I and Global Rating of Change Scales (GRCS) were completed. RESULTS: At baseline and after two weeks, 150 and 134 patients completed the questionnaires, respectively. The internal consistency of SGRQ-I was high (Cronbach's ??=?0.92). Good concurrent validity was demonstrated by high intraclass correlation coefficients (ICC?=?0.97), Bland-Altman plots and moderate to strong correlations to K-BILD, SOBQ and SF-36 (r?=?-?0.46 to 0.80). High ICC (0.92) and a Bland-Altman plot indicated good test-retest reliability. SGRQ-I was good at discriminating between patients with different stages of disease (?score >?18.1, effect sizes >?0.10). Validity was similar across groups of different disease duration. CONCLUSIONS: SGRQ-I proved to be valid at distinguishing between different disease severities, valid compared to other HRQL instruments, applicable across different disease durations and reliable upon repetition. SGRQ-I is a valid option for measuring HRQL in patients with IPF. TRIAL REGISTRATION: The study was registered at ( NCT02818712 ) on 15 June 2016.
    • Duodenal neuroendocrine tumour associated with minimal change glomerulonephritis

      Montague, E; Hockenhull, Kimberley; Lamarca, Angela; Al-Sayed, Tamer; Hubner, Richard A; Medical Oncology, Christie NHS Foundation Trust, Manchester, UK (2019)
      Paraneoplastic glomerular disease is an increasingly well-recognised entity, and a wide range of both solid and haematological malignancies have been implicated. The most common glomerular disease associated with cancer is membranous nephropathy. Only a few case reports have described an association between neuroendocrine tumours (NETs) and glomerulonephritis and only one paediatric case in relation to minimal change disease. A 76-year-old woman with a well-differentiated duodenal NET presented with nephrotic syndrome and renal biopsy was suggestive of minimal change glomerulonephritis. Standard therapy with corticosteroids brought little benefit, but a dramatic improvement was seen following initiation of systemic anticancer therapy with lanreotide, a somatostatin analogue. Less than 1?month after initiation of lanreotide, the patient was no longer in a nephrotic state, and after a further 2 months of follow-up had shown no sign of relapse.
    • Chromosome instability syndromes

      Taylor, AMR; Rothblum-Oviatt, C; Ellis, NA; Hickson, ID; Meyer, Stefan; Crawford, TO; Smogorzewska, A; Pietrucha, B; Weemaes, C; Stewart, GS; et al. (2019)
      Fanconi anaemia (FA), ataxia telangiectasia (A-T), Nijmegen breakage syndrome (NBS) and Bloom syndrome (BS) are clinically distinct, chromosome instability (or breakage) disorders. Each disorder has its own pattern of chromosomal damage, with cells from these patients being hypersensitive to particular genotoxic drugs, indicating that the underlying defect in each case is likely to be different. In addition, each syndrome shows a predisposition to cancer. Study of the molecular and genetic basis of these disorders has revealed mechanisms of recognition and repair of DNA double-strand breaks, DNA interstrand crosslinks and DNA damage during DNA replication. Specialist clinics for each disorder have provided the concentration of expertise needed to tackle their characteristic clinical problems and improve outcomes. Although some treatments of the consequences of a disorder may be possible, for example, haematopoietic stem cell transplantation in FA and NBS, future early intervention to prevent complications of disease will depend on a greater understanding of the roles of the affected DNA repair pathways in development. An important realization has been the predisposition to cancer in carriers of some of these gene mutations.
    • Determinants Of The Growth Hormone Nadir During Oral Glucose Tolerance Test In Adults - commentary

      Trainer, Peter J; Monaghan, Phillip J; Endocrinology, Christie Hospital, Manchester, M20 4BX, (2019)
    • Immune checkpoint blockade in small cell lung cancer

      Tay, Rebecca Y; Heigener, D; Reck, M; Califano, Raffaele; Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester (2019)
      Despite the highly immunogenic potential of small cell lung cancer (SCLC), progress in evaluating the therapeutic value of immune checkpoint agents has lagged behind that of non-small cell lung cancer. Results from a number of phase I-III clinical trials that specifically address the use of anti-PD-1, anti-PD-L1 and anti-CTLA-4 agents in SCLC have now been reported. This review will focus on the available evidence for immune checkpoint blockade in SCLC and review current biomarker strategies with the aim of providing perspective and interpretation of this data for clinical practice.
    • Electrochemotherapy and Ablative Therapies in Non-melanoma Skin Cancer

      O'Donoghue, N; Mowatt, David J; Sykes, Andrew J; Salford Royal NHS Foundation Trust Hospital, Salford, UK (2019)
      Although surgery and radiotherapy remain the most commonly used treatments for non-melanoma skin cancer, there are a variety of alternatives. Here we discuss the use of electrochemotherapy and ablative treatments and examine the evidence for their effectiveness against a number of non-melanoma skin cancers.
    • Radiotherapy for metastatic prostate cancer-Authors' reply

      Parker, CC; James, ND; Brawley, CD; Clarke, Noel W; Parmar, MKB; Academic Urology Unit, Royal Marsden Hospital, London, SM2 5PT, UK. (2019)
    • Non-Melanoma Skin Cancer - An Underestimated Global Health Threat?

      Rembielak, Agata; Ajithkumar, T; Department of Clinical Oncology, The Christie NHS Foundation Trust, Manchester, UK; The University of Manchester, Manchester, UK. (2019)