Do diagnostic delays in cancer matter?

background: The United Kingdom has poorer cancer outcomes than many other countries due partly to delays in diagnosing symptomatic cancer, leading to more advanced stage at diagnosis. Delays can occur at the level of patients, primary care, systems and secondary care. There is considerable potential for interventions to minimise delays and lead to earlier-stage diagnosis. methods: Scoping review of the published studies, with a focus on methodological issues. results: Trial data in this area are lacking and observational studies often show no association or negative ones. This review offers methodological explanations for these counter-intuitive findings. conclusion: While diagnostic delays do matter, their importance is uncertain and must be determined through more sophisticated methods

High Levels of Exosomes Expressing CD63 and Caveolin-1 in Plasma of Melanoma Patients

BACKGROUND: Metastatic melanoma is an untreatable cancer lacking reliable and non-invasive markers of disease progression. Exosomes are small vesicles secreted by normal as well as tumor cells. Human tumor-derived exosomes are involved in malignant progression and we evaluated the presence of exosomes in plasma of melanoma patients as a potential tool for cancer screening and follow-up. METHODOLOGY/PRINCIPAL FINDINGS: We designed an in-house sandwich ELISA (Exotest) to capture and quantify exosomes in plasma based on expression of housekeeping proteins (CD63 and Rab-5b) and a tumor-associated marker (caveolin-1). Western blot and flow cytometry analysis of exosomes were used to confirm the Exotest-based findings. The Exotest allowed sensitive detection and quantification of exosomes purified from human tumor cell culture supernatants and plasma from SCID mice engrafted with human melanoma. Plasma levels of exosomes in melanoma-engrafted SCID mice correlated to tumor size. We evaluated the levels of plasma exosomes expressing CD63 and caveolin-1 in melanoma patients (n = 90) and healthy donors (n = 58). Consistently, plasma exosomes expressing CD63 (504+/-315) or caveolin-1 (619+/-310) were significantly increased in melanoma patients as compared to healthy donors (223+/-125 and 228+/-102, respectively). While the Exotest for CD63+ plasma exosomes had limited sensitivity (43%) the Exotest for detection of caveolin-1+ plasma exosomes showed a higher sensitivity (68%). Moreover, caveolin-1+ plasma exosomes were significantly increased with respect to CD63+ exosomes in the patients group. CONCLUSIONS/SIGNIFICANCE: We describe a new non-invasive assay allowing detection and quantification of human exosomes in plasma of melanoma patients. Our results suggest that the Exotest for detection of plasma exosomes carrying tumor-associated antigens may represent a novel tool for clinical management of cancer patients

S-100B Concentrations Predict Disease-Free Survival in Stage III Melanoma Patients

Elevation of the tumor marker S-100B in melanoma patients is a highly specific indicator of recurrence. The role of S-100B in disease-free survival (DFS) was evaluated in stage III melanoma patients (staged with fluorodeoxyglucose positron emission tomography [FDG-PET] and computed tomography [CT]) with palpable lymph node metastases who underwent therapeutic lymph node dissection. S-100B and LDH were measured on the day before surgery (d = -1) and on days 1, 2, and 7 postoperatively. Multivariate logistic regression was used to study factors associated with preoperative elevation of S-100B. Univariate (log-rank test) and multivariate (Cox regression) survival analyses were performed to identify factors associated with DFS. Between 2004 and 2008, 56 patients (median age 57, range 24-93) years, 27 males (48%) and 29 females (52%) entered the study. Preoperative S-100B elevation was found in 27 patients (48%) and elevated LDH in 20 patients (36%). No association was found between these two markers at any time. Multivariate analysis showed that elevated S-100B preoperatively (hazard ratio [HR] 2.7, P = .03) was associated with DFS. S-100B elevation was associated with increased tumor size (odds ratio [OR] 3.40; P = .03). Elevated S-100B preoperatively in patients with optimally staged clinical stage III melanoma is associated with decreased disease-free survival. S100-B could be used as a prognostic marker in the stratification of new adjuvant trials to select stage III melanoma patients for adjuvant systematic treatment

Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148

Genome wide association studies (GWAS) have mapped multiple independent cancer susceptibility loci to chr5p15.33. Here, we show that fine-mapping of pancreatic and testicular cancer GWAS within one of these loci (Region 2 in CLPTM1L) focuses the signal to nine highly correlated SNPs. Of these, rs36115365-C associated with increased pancreatic and testicular but decreased lung cancer and melanoma risk, and exhibited preferred protein-binding and enhanced regulatory activity. Transcriptional gene silencing of this regulatory element repressed TERT expression in an allele-specific manner. Proteomic analysis identifies allele-preferred binding of Zinc finger protein 148 (ZNF148) to rs36115365-C, further supported by binding of purified recombinant ZNF148. Knockdown of ZNF148 results in reduced TERT expression, telomerase activity and telomere length. Our results indicate that the association with chr5p15.33-Region 2 may be explained by rs36115365, a variant influencing TERT expression via ZNF148 in a manner consistent with elevated TERT in carriers of the C allele

Pathway-Based Analysis of a Melanoma Genome-Wide Association Study: Analysis of Genes Related to Tumour-Immunosuppression

Systemic immunosuppression is a risk factor for melanoma, and sunburn-induced immunosuppression is thought to be causal. Genes in immunosuppression pathways are therefore candidate melanoma-susceptibility genes. If variants within these genes individually have a small effect on disease risk, the association may be undetected in genome-wide association (GWA) studies due to low power to reach a high significance level. Pathway-based approaches have been suggested as a method of incorporating a priori knowledge into the analysis of GWA studies. In this study, the association of 1113 single nucleotide polymorphisms (SNPs) in 43 genes (39 genomic regions) related to immunosuppression have been analysed using a gene-set approach in 1539 melanoma cases and 3917 controls from the GenoMEL consortium GWA study. The association between melanoma susceptibility and the whole set of tumour-immunosuppression genes, and also predefined functional subgroups of genes, was considered. The analysis was based on a measure formed by summing the evidence from the most significant SNP in each gene, and significance was evaluated empirically by case-control label permutation. An association was found between melanoma and the complete set of genes (pemp = 0.002), as well as the subgroups related to the generation of tolerogenic dendritic cells (pemp = 0.006) and secretion of suppressive factors (pemp = 0.0004), thus providing preliminary evidence of involvement of tumour-immunosuppression gene polymorphisms in melanoma susceptibility. The analysis was repeated on a second phase of the GenoMEL study, which showed no evidence of an association. As one of the first attempts to replicate a pathway-level association, our results suggest that low power and heterogeneity may present challenges

Particulate matter exposure during pregnancy is associated with birth weight, but not gestational age, 1962-1992: a cohort study

<p>Abstract</p> <p>Background</p> <p>Exposure to air pollutants is suggested to adversely affect fetal growth, but the evidence remains inconsistent in relation to specific outcomes and exposure windows.</p> <p>Methods</p> <p>Using birth records from the two major maternity hospitals in Newcastle upon Tyne in northern England between 1961 and 1992, we constructed a database of all births to mothers resident within the city. Weekly black smoke exposure levels from routine data recorded at 20 air pollution monitoring stations were obtained and individual exposures were estimated via a two-stage modeling strategy, incorporating temporally and spatially varying covariates. Regression analyses, including 88,679 births, assessed potential associations between exposure to black smoke and birth weight, gestational age and birth weight standardized for gestational age and sex.</p> <p>Results</p> <p>Significant associations were seen between black smoke and both standardized and unstandardized birth weight, but not for gestational age when adjusted for potential confounders. Not all associations were linear. For an increase in whole pregnancy black smoke exposure, from the 1^st(7.4 μg/m³) to the 25^th(17.2 μg/m³), 50^th(33.8 μg/m³), 75^th(108.3 μg/m³), and 90^th(180.8 μg/m³) percentiles, the adjusted estimated decreases in birth weight were 33 g (SE 1.05), 62 g (1.63), 98 g (2.26) and 109 g (2.44) respectively. A significant interaction was observed between socio-economic deprivation and black smoke on both standardized and unstandardized birth weight with increasing effects of black smoke in reducing birth weight seen with increasing socio-economic disadvantage.</p> <p>Conclusions</p> <p>The findings of this study progress the hypothesis that the association between black smoke and birth weight may be mediated through intrauterine growth restriction. The associations between black smoke and birth weight were of the same order of magnitude as those reported for passive smoking. These findings add to the growing evidence of the harmful effects of air pollution on birth outcomes.</p

Heterogenous effects of histamine on isolated rat coronary arteries.

A

Year-round patterns of mineral lick use by Moose (Alces americanus), deer, and Elk (Cervus canadensis) in north-central British Columbia

Natural mineral licks are important to the physiological ecology of several species of ungulates in North America and abroad. Information on year-round patterns of mineral lick use by ungulates in Canada is poorly understood. We used camera traps to record patterns of mineral lick use by four ungulate species visiting five naturally occurring mineral licks located within the John Prince Research Forest and surrounding area, near Fort St. James, British Columbia, Canada. Our cameras detected over 1800 mineral lick visits by ungulates from February 2017 to January 2018. Mineral licks were visited year-round, however, most visits were made between May and September during morning hours. We observed variable lick visitations among sites, species, and sex and age classes. The species observed in descending number of lick visits included Moose (Alces americanus), White-tailed Deer (Odocoileus virginianus), Elk (Cervus canadensis), and Mule Deer (Odocoileus hemionus). Some licks were visited by all four species, while others were visited by fewer. Female ungulates were recorded at licks more frequently than males or juveniles, which likely reflected the underlying sex and age structure of the population. Elk spent more time at licks than Moose and deer and there was no difference in visit durations between Moose and deer. Most visits were made by single animals, but group visits were also observed. Our findings provide evidence that mineral licks are used year-round by ungulates and appear to be important habitat features on the landscape