Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies.

Cellular senescence is a key component of human aging that can be induced by a range of stimuli, including DNA damage, cellular stress, telomere shortening, and the activation of oncogenes. Senescence is generally regarded as a tumour suppressive process, both by preventing cancer cell proliferation and suppressing malignant progression from pre-malignant to malignant disease. It may also be a key effector mechanism of many types of anticancer therapies, such as chemotherapy, radiotherapy, and endocrine therapies, both directly and via bioactive molecules released by senescent cells that may stimulate an immune response. However, senescence may contribute to reduced patient resilience to cancer therapies and may provide a pathway for disease recurrence after cancer therapy. A new group of drugs, senotherapies, (drugs which interact with senescent cells to interfere with their pro-aging impacts by either selectively destroying senescent cells (senolytic drugs) or inhibiting their function (senostatic drugs)) are under active investigation to determine whether they can enhance the efficacy of cancer therapies and improve resilience to cancer treatments. Senolytic drugs include quercetin, navitoclax, and fisetin and preclinical and early phase clinical data are emerging of their potential role in cancer treatments, although none are yet in routine use clinically. This article provides a review of these issues.

Inter-observer variability in the histological assessment of colorectal polyps detected through the NHS Bowel Cancer Screening Programme.

AIMS: Although effective clinical management of colorectal polyps detected through the National Health Service (NHS) Bowel Cancer Screening Programme (BCSP) is dependent on the quality of pathological diagnosis, there have been few attempts to formally evaluate inter-observer variability in histological assessment. The aim of this study was to examine the impact of inter-observer variability on the reported prevalence of prognostic features in a large series of screen-detected colorectal polyps. METHODS AND RESULTS: A retrospective series of 1329 screen-detected polyps (2008-10) was identified from computerized records at two histopathology departments participating in the NHS BCSP. Slides from a sample of 239 polyps were exchanged between centres for independent review and measurement of inter-observer (kappa) agreement. There were significant between-centre differences in the prevalence of polyps with high-risk histological features. Diagnostic review demonstrated good reliability with respect to the assessment of adenomatous change (κ = 0.83), excision margin status (κ = 0.74), high-grade dysplasia (0.61) and invasive malignancy (κ = 0.84). By contrast, there were significant inter-observer differences in the classification of villous lesions (0.18) despite recent efforts to standardize reporting practice. CONCLUSIONS: Inter-observer variability in the assessment of screen-detected colorectal polyps limits the prognostic value of histological subtyping and highlights the need for clarification of existing diagnostic criteria.

An elastic Van Gieson stain is unnecessary for the histological diagnosis of giant cell temporal arteritis.

BACKGROUND: Elastic Van Gieson (EVG) stain is used routinely to identify the internal elastic lamina in biopsy specimens from clinically suspected cases of giant cell arteritis (GCA). It is widely recognised, however, that disruption of the internal elastic lamina is not specific for GCA. Evidence suggests that routine use of special stains in temporal artery biopsies does not increase diagnostic sensitivity and current American College of Rheumatology guidelines do not include structural changes to the vessel wall in their recommended diagnostic criteria. Objective To assess whether use of EVG stain contributes to the diagnosis of GCA, compared with standard H&E stained sections alone. METHODS: A retrospective case series of 105 temporal artery biopsies positive for GCA between 1999 and 2009 were retrieved and reviewed histologically. Comparable diagnostic information was extracted from reports for 406 negative biopsies over the same period. RESULTS: Review of H&E stained sections showed diagnostic features of GCA in 97.2% (n=102) of positive cases. Disruption or reduplication of the internal elastic lamina was apparent in 96.1% (n=101) of EVG stained sections, but was also reported as present in nearly two-thirds of negative biopsies. CONCLUSIONS: An EVG stain does not contribute to recognition of diagnostic features in a majority of cases and should therefore be reserved for use as a supplementary investigation. Inclusion of pre-biopsy treatment on histology request forms would assist in the interpretation of equivocal biopsies.