Geographic remoteness from a multidisciplinary team is associated with an increased clinical staging of head and neck cancer: a Newcastle (Australia) study.

The purpose of this study was to investigate the relationship between a patient's residential distance from a tertiary referral regional multidisciplinary team (MDT) and the clinical staging of their head and neck cancer (HNC) at presentation. A retrospective cohort study was performed of all attendees with HNC who had undergone an MDT assessment. The period of study was January 2016 to January 2017. The primary predictor variable was the patient's residential distance from the MDT. Demographic and clinicopathological factors were recorded. The primary outcome variable was the clinical staging conferred by the MDT. Descriptive and ordinal logistical regression analyses were conducted to examine the data. There were 286 observations; 230 patients were male and 56 were female. The mean age of the cohort was 66.52 years. The average residential distance from the MDT was 68.16 km. Regression analysis, while not statistically significant, indicated that those living more than 100 km (range 102-592 km) from the MDT had a 1.49 times increased risk of being diagnosed with an advanced stage of cancer when compared to those living less than 100 km away. This study provides insights into the potential adverse effect geographic remoteness has on initial staging of HNC and the need for further strategies to serve this at-risk population.

The leukemia-associated cytoplasmic nucleophosmin mutant is an oncogene with paradoxical functions: Arf inactivation and induction of cellular senescence.

Mutations leading to aberrant cytoplasmic localization of Nucleophosmin 1 (NPM1) have been recently identified as the most frequent genetic alteration in acute myelogenous leukemia. However, the oncogenic potential of this nucleophosmin mutant (NPMc+) has never been established, which casts doubt on its role in leukemogenesis. By performing classical transformation assays, we find that NPMc+, but not wild-type NPM, cooperates specifically with adenovirus E1A to transform primary mouse embryonic fibroblasts in soft agar. We demonstrate that NPMc+ blocks the p19(Arf) (Arf) induction elicited by E1A. Surprisingly, however, we find that NPMc+ induces cellular senescence and that E1A is able to overcome this response. We propose a model whereby the NPMc+ pro-senescence activity needs to be evaded for oncogenic transformation, even though NPMc+ can concomitantly blunt the Arf/p53 pathway. These findings identify for the first time NPMc+ as an oncogene and shed new unexpected light on its mechanism of action.

Dyskerin expression influences the level of ribosomal RNA pseudo-uridylation and telomerase RNA component in human breast cancer.

Dyskerin is a nucleolar protein, altered in dyskeratosis congenita, which carries out two separate functions, both fundamental for proliferating cells. One function is the pseudo-uridylation of ribosomal RNA (rRNA) molecules, necessary for their processing, and the other is the stabilization of the telomerase RNA component, necessary for telomerase activity. A significant feature of dyskeratosis congenita is an increased susceptibility to cancer; so far, however, no data have been reported on dyskerin changes in human tumours. Therefore, in this study, the distribution of dyskerin in a large series of human tumours from the lung, breast, and colon, as well as from B-cell lymphomas, was analysed by immunohistochemistry. Dyskerin proved never to be lost or delocalized outside the nucleolus. A quantitative analysis of dyskerin mRNA expression was then performed in 70 breast carcinomas together with the evaluation of telomerase RNA component levels and rRNA pseudo-uridylation. Dyskerin mRNA levels were highly variable and directly associated with both telomerase RNA component levels and rRNA pseudo-uridylation. Dyskerin gene silencing in the MCF-7 human breast carcinoma cell line reduced telomerase activity and rRNA pseudo-uridylation. Significantly, patients with low dyskerin expression were characterized by a better clinical outcome than those with a high dyskerin level. These data indicate that dyskerin is not lost in human cancers and that the levels of its expression and function are associated with tumour progression.