Mortality during marathons: a narrative review of the literature.

BACKGROUND: Millions of community-dwelling individuals run marathons each year. There are infrequent deaths, which are often reported widely, and may create unnecessary alarm about the potential risks. Equally, sensible planning for such eventualities is important when staging an event. OBJECTIVE: The aim of the review was to determine the risk of death from running a marathon and the likely location of such deaths in order to inform the public of the likely risks and improve planning for such events. DESIGN: Narrative review. DATA SOURCES: Primary: PubMed. Secondary: contact was made with the organisers and medical teams of specific marathons and online data sought where necessary. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Studies had to report the number of participants and deaths during, or within 24 hours of completing the marathon. Results relevant to half marathons or ultramarathons or other endurance events, such as triathlons, were not included. Deaths due to terrorist activity were not included. RESULTS: The risk of death estimated by these studies was approximately 0.67 per 100 000 finishers, that is, 1 death per 149 968 participants. From those studies that reported deaths by sex, the rate of male deaths was 0.98/100 000 (1 per 102 503) vs 0.41/100 000 (1 per 243 879) in females. Deaths tended to occur in the last quarter of the race. SUMMARY/CONCLUSION: The risk of death from participating in a marathon is small. Men are more at risk than women. Deaths tend to occur later in the race.

Institutional quality assurance for breast cancer HER2 immunohistochemical testing: identification of outlier results and impact of simultaneous fluorescence in situ hybridization cotesting.

The College of American Pathologists Accreditation Checklist requires comparison of laboratory predictive results with published benchmarks but does not require analysis of individual pathologists. With the availability of targeted human epidermal growth factor receptor 2 (HER2) protein therapy, uniform reporting of HER2 protein status by immunohistochemistry (IHC) is essential. Our aim was to compare HER2 IHC results among pathologists in routine clinical practice within a single institution and assess the impact of simultaneous IHC and fluorescence in situ hybridization (FISH) ordering. We reviewed reports from 928 consecutive breast needle biopsies from 2008 to 2012 at a tertiary academic medical center in which HER2 IHC and HER2 FISH were ordered. There was a significant association between breast pathologist and IHC result (negative, 49.8%-83.2%; positive, 8.7%-14.1%; equivocal, 5.2%-41.5%; P < .0001) but not breast pathologist and FISH result (P = .69). For 1 pathologist, IHC signed out with FISH had an equivocal rate nearly 2-fold lower than IHC results that were reported first (10.5% versus 20.9%) (P = .04). Institutions should be aware that although overall HER2 IHC reporting may be consistent with guidelines, there can be significant variation among practitioners. In addition to aggregate data, we recommend comparing the rates from individual pathologists to standards. Furthermore, routine simultaneous ordering of both IHC and FISH could impact interpretation of test results and may inappropriately encourage less confidence in IHC results among pathologists.

Dual EZH2 and EHMT2 histone methyltransferase inhibition increases biological efficacy in breast cancer cells.

BACKGROUND: Many cancers show aberrant silencing of gene expression and overexpression of histone methyltransferases. The histone methyltransferases (HKMT) EZH2 and EHMT2 maintain the repressive chromatin histone methylation marks H3K27me and H3K9me, respectively, which are associated with transcriptional silencing. Although selective HKMT inhibitors reduce levels of individual repressive marks, removal of H3K27me3 by specific EZH2 inhibitors, for instance, may not be sufficient for inducing the expression of genes with multiple repressive marks. RESULTS: We report that gene expression and inhibition of triple negative breast cancer cell growth (MDA-MB-231) are markedly increased when targeting both EZH2 and EHMT2, either by siRNA knockdown or pharmacological inhibition, rather than either enzyme independently. Indeed, expression of certain genes is only induced upon dual inhibition. We sought to identify compounds which showed evidence of dual EZH2 and EHMT2 inhibition. Using a cell-based assay, based on the substrate competitive EHMT2 inhibitor BIX01294, we have identified proof-of-concept compounds that induce re-expression of a subset of genes consistent with dual HKMT inhibition. Chromatin immunoprecipitation verified a decrease in silencing marks and an increase in permissive marks at the promoter and transcription start site of re-expressed genes, while Western analysis showed reduction in global levels of H3K27me3 and H3K9me3. The compounds inhibit growth in a panel of breast cancer and lymphoma cell lines with low to sub-micromolar IC50s. Biochemically, the compounds are substrate competitive inhibitors against both EZH2 and EHMT1/2. CONCLUSIONS: We have demonstrated that dual inhibition of EZH2 and EHMT2 is more effective at eliciting biological responses of gene transcription and cancer cell growth inhibition compared to inhibition of single HKMTs, and we report the first dual EZH2-EHMT1/2 substrate competitive inhibitors that are functional in cells.

Do amount of variant differentiation and mitotic rate in bladder cancer change with neoadjuvant chemotherapy?

Neoadjuvant chemotherapy (NAC) is currently recommended to all candidate patients with muscularis propria-invasive bladder cancer. However, NAC is effective in only a subset of patients, and predictors of response are lacking. Our study aimed to characterize tumoral changes with NAC usage and to identify features at bladder biopsy/transurethral resection (Bx/TUR) that may predict response. A retrospective search was performed to identify patients with bladder cancer that were pT2 at Bx/TUR upon whom a radical cystectomy (RC) was performed from 2007 to 2010. A blinded slide review of the Bx/TUR and RC was conducted. Presence, type, percent of tumor variant morphology, and tumoral mitotic rate were assessed. Ninety RC patients with slides available were identified (46 NAC, 44 non-NAC). In NAC-treated patients, there was a significantly higher percentage of nonurothelial variant differentiation in the RC compared with Bx/TUR, whereas there was no difference in the non-NAC subgroup. Percent variant differentiation at Bx/TUR was not a predictor of response. There was a significant decrease in mitotic rate between Bx/TUR and RC in NAC patients, whereas there was no difference in the non-NAC subgroup, although mitotic rate was not a predictor of response. In conclusion, percent variant differentiation and mitotic rate changed significantly from Bx/TUR to RC with NAC usage, although neither predicted response. Pathologists should be aware that variant differentiation is common in bladder cancer, with increased presence after NAC, in order to improve recognition and documentation of these findings.

Trends in prostatic adenocarcinoma tumor volume by visual estimation in prostatectomy specimens.

We retrospectively reviewed 1792 consecutive radical prostatectomies (RP) from 2003 to 2006 at a single institution to establish tumor volume reference values, to determine current trends in visually estimated prostate adenocarcinoma tumor volume, and to characterize cases with no residual cancer on RP. Tumor volumes were recorded and subsequently stratified as very low, 0-1%; low, 1.1-10%; intermediate, 10.1-20%; high, 20.1-50%; and very high, >50%, with incidences of 11.7%, 52.1%, 21.5%, 13.2%, and 1.5%, respectively. The incidence of very low volume tumors increased within the time period (p=0.04). Seminal vesicle involvement was detected in 5.0% of cases and lymph node metastasis occurred in 1.4%. Volume categories statistically correlated with seminal vesicle invasion (p=0) and lymph nodes metastases (p=0). Eleven cases of no residual cancer (0.6%) were identified with a non-statically significant increase during the study (p=0.07). The rising incidence of very low volume tumors should be considered by clinicians when discussing treatment options with patients. A discrete tumor volume should be provided for RP specimens as it may be an important prognostic factor.

An oxidative burst of superoxide in embryonic axes of recalcitrant sweet chestnut seeds as induced by excision and desiccation.

Recalcitrant seeds are intolerant of desiccation and cannot be stored in conventional seed banks. Cryopreservation allows storage of the germplasm of some recalcitrant seeded species, but application to a wide range of plant diversity is still limited. The present work aimed at understanding the stresses that accompany the first steps in cryopreservation protocols, wounding and desiccation, both of which are likely to lead to the formation of reactive oxygen species (ROS). Extracellular ROS production was studied in isolated embryonic axes of sweet chestnut (Castanea sativa). Axis excision was accompanied by a burst of superoxide (O(2)(*-)), demonstrated by a colorimetric assay using epinephrine, electron spin resonance and staining with nitroblue tetrazolium. Superoxide was immediately produced on the cut surface after isolation of the axis from the seed, with an initial 'burst' in the first 5 min. Isolated axes subjected to variable levels of desiccation stress showed a decrease in viability and vigour and increased electrolyte leakage, indicative of impaired membrane integrity. The pattern of O(2)(*-) production showed a typical Gaussian pattern in response to increasing desiccation stress. The results indicate a complex interaction between excision and subsequent drying and are discussed with a view of manipulating ROS production for optimisation of cryopreservation protocols.

The Effect of Intradermal Injection of GM-CSF and TNF-α on the Accumulation of Dendritic Cells in Ovine Skin.

Abstract- Intradermal recombinant ovine (rov) GM-CSF was associated with the accumulation over 5 DAys of MHC Class-II+ dendritic cells at the injection site, as well as increased numbers of neutrophils, eosinophils and lymphocytes when compared to control injection sites receiving heat-inactivated cytokines. Most of the dendritic cells were adjacent to the epidermis and dermal structures such as hair follicles, sweat glands and blood vessels. Fewer than 10% of the accumulating MHC Class-II+ dendritic cells expressed the CD1 antigen and none expressed detectable CD lib or CD lie antigens. They did not appear to be proliferating. Injection of rov TNF-α was associated with an increase in MHC Class-II+ dendritic cells that was significant only in the epidermis and only at 2 DAys following the first of four daily injections. Increased numbers of neutrophils and lymphocytes, but not eosinophils, were also recorded. Injection of rov TNF-α together with rov GM-CSF enhanced the accumulation of the MHC Class-II+, CD1+ subpopulation of dendritic cells compared to either cytokine alone. GM-CSF in particular is involved in an in vivo pathway supporting the accumulation of predominantly MHC Class-II+ CD1- dendritic cells which are a minor population in unchallenged skin. Résumé- Des injections intradermiques de GM-CSF recombinant ovin sont associées à l'accumulation en 5 jours de cellules dendritiques MHC classe II(+) au site de l'injection, ainsi qu'à une augmentation du nombre de neutrophiles, éosinophiles et lymphocytes, comparativement à ce qui est observe aux points d'injection témoins qui ont reçu des cytokines inactivées par la chaleur. La plupart des cellules dentritiques sont adjacentes à l'épiderme, aux follicules pileux, aux glandes sudoripares et aux vaisseaux sanguins. Moins de 10% des cellules dendritiques MHC classe II(+) accumulées expriment l'antigène CD1 et aucune n'exprime les antigènes CD11b et CD11c. Elles ne semblent pas proliférer. L'injection de TNF alpha recombinant ovin est associée à une augmentation des cellules dendritiques MHC classe II(+) qui est significative seulement dans l'épiderme, et seulement 2 jours suivant la première des quatre injections. Une augmentation du nombre de neutrophiles et de lymphocytes, mais pas des éosinophiles est également notée. L'injection simultanée de TNF alpha recombinant ovin et de GM-CSF recombinant ovin favorise l'accumulation d'une sous population de cellules dendritiques MHC classe II(+), CD1(+), comparativement à ce qui est observé en utilisant les cytokines séparément. GM-CSF en particulier est in vivo à l'origine de l'accumulation de cellules dendritiques MHC classe II(+), CD1(-) qui forment une population mineure dans la peau. [Haig, D. M., Hutchison, G., Green, I., Sargan, D., Reid, H. W. The effect of intradermal injection of GM-CSF and TNF-α on the accumulation of dendritic cells in ovine skin (Effect de l'injection intradermique de GM-CSF et de TNF alpha sur l'accumulation de cellules dentritiques dans la peau du mouton).