• An open-label, multicentre safety study of vemurafenib in patients with BRAFV600-mutant metastatic melanoma: final analysis and a validated prognostic scoring system

  Larkin, J; Brown, M; Arance, A; Hauschild, A; Queirolo, P; Vecchio, M; Ascierto, P; Krajsová, I; Schachter, J; Neyns, B; Garbe, C; Sileni, VC; Mandalà, M; Gogas, H; Espinosa, E; Hospers, G; Lorigan, Paul C; Nyakas, M; Guminski, A; Liszkay, G; Rutkowski, P; Miller, W; Donica, M; Makrutzki, M; Blank, C; Royal Marsden NHS FT, London (2019)

  BACKGROUND: The oncogenic BRAF inhibitor vemurafenib improves outcomes for patients with advanced BRAFV600 mutation-positive melanoma compared with cytotoxic chemotherapy. Vemurafenib is now approved for use in this patient population. PATIENTS AND METHODS: In this open-label, multicentre study, patients with previously treated or untreated melanoma and the BRAFV600 mutation received vemurafenib 960 mg twice daily. The primary endpoint was safety. In a post hoc analysis, overall survival (OS) was analysed according to a prognostic scoring system developed using Eastern Cooperative Oncology Group performance status, existence of brain metastases and baseline serum lactate dehydrogenase level. The index was validated using data from patients treated with vemurafenib or dacarbazine in three clinical trials and data from patients treated with vemurafenib plus cobimetinib in two studies. The study is registered with ClinicalTrials.gov (NCT01307397). RESULTS: Between March 2011 and January 2013, 3224 patients were enrolled, and 3219 patients received ?1 dose of vemurafenib (safety population); median follow-up time was 33.4 months. Vemurafenib's long-term benefits were confirmed, and no new safety signals identified. The prognostic index showed between-group differences in OS, with tight, non-overlapping confidence intervals. Validation in a pooled group of 666 vemurafenib-treated clinical trial patients revealed a similar pattern; the pattern was similar in 280 patients treated with vemurafenib plus cobimetinib. CONCLUSIONS: Final results from the vemurafenib safety study confirm vemurafenib's tolerability in BRAFV600 mutation-positive patients and resemble those seen in real-world clinical practice. This index may be useful in patients on combination therapy and as a basis for further.
• Cancelled operations: a 7-day cohort study of planned adult inpatient surgery in 245 UK National Health Service hospitals

  Nariani, Jaya; Clark, Sam; Duniec, Larysa; Health Services Research Centre,National Institute of Academic Anaesthesia (2018)

  BACKGROUND: Cancellation of planned surgery impacts substantially on patients and health systems. This study describes the incidence and reasons for cancellation of inpatient surgery in the UK NHS. METHODS: We conducted a prospective observational cohort study over 7 consecutive days in March 2017 in 245 NHS hospitals. Occurrences and reasons for previous surgical cancellations were recorded. Using multilevel logistic regression, we identified patient- and hospital-level factors associated with cancellation due to inadequate bed capacity. RESULTS: We analysed data from 14 936 patients undergoing planned surgery. A total of 1499 patients (10.0%) reported previous cancellation for the same procedure; contemporaneous hospital census data indicated that 13.9% patients attending inpatient operations were cancelled on the day of surgery. Non-clinical reasons, predominantly inadequate bed capacity, accounted for a large proportion of previous cancellations. Independent risk factors for cancellation due to inadequate bed capacity included requirement for postoperative critical care [odds ratio (OR)=2.92; 95% confidence interval (CI), 2.12-4.02; P<0.001] and the presence of an emergency department in the treating hospital (OR=4.18; 95% CI, 2.22-7.89; P<0.001). Patients undergoing cancer surgery (OR=0.32; 95% CI, 0.22-0.46; P<0.001), obstetric procedures (OR=0.17; 95% CI, 0.08-0.32; P<0.001), and expedited surgery (OR=0.39; 95% CI, 0.27-0.56; P<0.001) were less likely to be cancelled. CONCLUSIONS: A significant proportion of patients presenting for surgery have experienced a previous cancellation for the same procedure. Cancer surgery is relatively protected, but bed capacity, including postoperative critical care requirements, are significant risk factors for previous cancellations.
• Sun protection behavior after diagnosis of high-risk primary melanoma and risk of a subsequent primary

  von Schuckmann, L; Wilson, L; Hughes, M; Beesley, L; Janda, M; van der Pols, J; Smithers, B; Khosrotehrani, K; Green, Adèle C; Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia (2019)

  BACKGROUND: Melanoma survivors are at high risk of further primary melanomas. OBJECTIVE: To assess sun behavior after melanoma diagnosis and in relation to further primary melanomas. METHODS: We applied repeated measures latent class analysis to reported primary prevention behavior at time of diagnosis and every 6 months for 2 years after diagnosis in patients with clinical stage IB or II melanoma. Correlates of behavior trajectories and risk of subsequent primaries were determined by using multivariable logistic and Cox regression analyses, respectively. RESULTS: Among the 448 male and 341 female patients, sunscreen use fell into 3 trajectories: stable never-use (26% of males and 12% of females), stable sometimes-use (35% of males and 29% of females), and increased to often-use (39% of males and 59% of females). Most reduced their weekend sun exposure, but in 82% of males and 69% of females it remained increased. Males, smokers, the less educated, those who tanned, and those not self-checking their skin were more likely to have trajectories of inadequate protection. Patients with a history of melanoma before the study doubled their risk of another primary melanoma in the next 2 years if sunscreen use in that time was inadequate (hazard ratio, 2.45; 95% confidence interval, 1.00-6.06). LIMITATIONS: Patient-reported data are susceptible to recall bias. CONCLUSION: Our results may assist clinicians in identifying patients not using adequate sun protection and providing information for patient counseling.
• Do airline pilots and cabin crew have raised risks of melanoma and other skin cancers? Systematic review and meta-analysis.

  Miura, K; Olsen, C; Rea, S; Marsden, J; Green, Adèle C; Population Health Department, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Queensland, 4006, Australia (2018)

  BACKGROUND: Airline pilots and cabin crew are potentially exposed to hazardous ultraviolet (UV) and cosmic radiation that may increase their risk of melanoma and other skin cancers. OBJECTIVES: To establish precise risks of melanoma and keratinocyte cancer (KC) for airline pilots and for cabin crew based on all studies published to date. METHODS: We searched Medline, ISI science citation index, EMBASE, SCOPUS, and CINAHL to June 2018. All studies of melanoma and KC risk and mortality in airline pilots and cabin crew compared with the general population were eligible. Standardised incidence ratios (SIRs) and mortality ratios (SMRs) were pooled using random effects models. RESULTS: From 5866 articles, we reviewed 44 full-text articles, of which 12 studies whose data were collected mostly between the 1970s-1990s, were eligible for inclusion. The pooled SIR (pSIR) for melanoma in pilots was 2.03 (95% confidence interval (CI) 1.71-2.40) and in cabin crew was 2.12 (95% CI 1.71-2.62). For pilots, pSMR for melanoma was 1.99 (95% CI 1.17-3.40) and for cabin crew was 1.18 (95% CI 0.73-1.89). For KC, the pSIR was 1.86 (95% CI 1.54-2.25) in pilots and 1.97 (95% CI 1.25-2.96) in cabin crew. There was no evidence of study heterogeneity. CONCLUSIONS: Available evidence shows that airline pilots and cabin crew have about twice the risk of melanoma and other skin cancers compared with the general population, with pilots more likely to die from melanoma. However, most of evidence was collected several decades ago and their relevance to contemporary levels of risk is uncertain.
• Fluoromethylcyclopropylamine derivatives as potential in vivo toxicophores - a cautionary disclosure

  Acton, Ben; Small, Helen F; Smith, Kate M; McGonagle, Alison E; Stowell, Alexandra I; James, Dominic I; Hamilton, Nial M; Hamilton, Nicola S; Hitchin, James R; Hutton, Colin P; Waddell, Ian D; Ogilvie, Donald J; Jordan, Allan M; Drug Discovery Unit, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, Macclesfield SK10 4TG, UK (2019)

  Fluorination of metabolic hotspots in a molecule is a common medicinal chemistry strategy to improve in vivo half-life and exposure and, generally, this strategy offers significant benefits. Here, we report the application of this strategy to a series of poly-ADP ribose glycohydrolase (PARG) inhibitors, resulting in unexpected in vivo toxicity which was attributed to this single-atom modification.

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