Targeting the centrosome and polo-like kinase 4 in osteosarcoma.

It has been historically uncertain if extra centrosomes are a cause or consequence of tumorigenesis. Experiments have recently established that overexpression of polo-like kinase 4 (PLK4) promotes centrosome amplification with consequential promotion of cellular aneuploidy. Furthermore, centrosome amplification drives spontaneous tumorigenesis in mice. Tissues lacking normal functional p53 tolerate extra centrosomes, whereas p53 proficient tissues initiate proliferative arrest in this circumstance. Extra centrosomes trigger activation of the multi-protein PIDDosome complex, with Caspase-2 effecting cleavage of the p53-negative regulator mouse double minute 2, consequent stabilization of p53 and p21-dependent arrest of the cell cycle. The co-occurrence of cellular aneuploidy, complex chromosomal rearrangements and p53 dysfunction is a striking feature of some osteosarcomas. It is postulated that small-molecule PLK4 inhibitors such as CFI-400945, which are in development, may have utility in osteosarcoma given these findings.

Neo-adjuvant Vismodegib followed by radiation in locally advanced basal cell carcinoma.

Basal cell carcinomas occur in up to 39% of Caucasian men and 28% of women. Rarely it can present a management dilemma in patients with neglected locally advanced disease of large dimension or involvement of critical structures. The Hedgehog pathway is constitutively active in almost all basal cell carcinomas and patients with Naevoid Basal Cell Carcinoma Syndrome have germline mutations in the Patched tumor suppressor gene, a Hedgehog pathway component, on chromosome 9q. This case describes an elderly patient with an untreated sporadic Basal cell carcinoma whose dimensions precluded local management approaches. The Hedgehog pathway inhibitor Vismodegib had a dramatic response allowing definitive treatment to be pursued.

Professional burnout, work patterns and career satisfaction in medical oncologists in Ireland.

BACKGROUND: Burnout is an occupational syndrome frequently encountered within the healthcare profession. It is characterised by emotional exhaustion (EE), depersonalisation (DP) and a low sense of personal accomplishment (PA). Its negative impact extends to the physician, patient and overall service provision. AIMS: The aim of this study was to evaluate work patterns, the prevalence of burnout and its associations in medical oncology consultants and specialist registrars (SpRs) in Ireland. METHODS: Participants were invited to partake in an anonymised online survey. Burnout domains were measured using the validated Maslach Burnout Inventory. Associations between variables were evaluated using the Mann-Whitney U and Kruskal-Wallis tests (continuous), and chi-square and Fisher's exact testing (categorical). RESULTS: Seventy-four physicians were contacted to participate, 44 (59%) completed the survey. The majority (71%) work ≥ 50 h a week, with 57% having additional on-call commitments of ≥ 5 days/month. Burnout is defined by a high score in EE combined with a high DP and/or low PA was identified in 45% of consultants and 20% of SpRs. Longer working hours (≥ 60 h/ week) were found to be associated with both high EE (p = 0.049) and DP (p = 0.019). Higher EE scores were demonstrated in those ≥ 40 years (p = 0.04). The majority (86%) reported they would become an oncologist again. CONCLUSION: One or more of the symptoms of burnout is highly prevalent in medical oncologists in Ireland. With increasing pressure on resources, burnout is expected to increase. Attention to strategies for prevention needs to be prioritised within our healthcare system.