Chance mechanisms affecting the burden of metastases

BACKGROUND: The burden of cancer metastases within an individual is commonly used to clinically characterize a tumor's biological behavior. Assessments like these implicitly assume that spurious effects can be discounted. Here the influence of chance on the burden of metastasis is studied to determine whether or not this assumption is valid. METHODS: Monte Carlo simulations were performed to estimate tumor burdens sustained by individuals with cancer, based upon empirically derived and validated models for the number and size distributions of metastases. Factors related to the intrinsic metastatic potential of tumors and their host microenvironments were kept constant, to more clearly demonstrate the contribution from chance. RESULTS: Under otherwise identical conditions, both the simulated numbers and the sizes of metastases were highly variable. Comparable individuals could sustain anywhere from no metastases to scores of metastases, and the sizes of the metastases ranged from microscopic to macroscopic. Despite the marked variability in the number and sizes of the metastases, their respective growth times were rather more narrowly distributed. In such situations multiple occult metastases could develop into fully overt lesions within a comparatively short time period. CONCLUSION: Chance can have a major effect on the burden of metastases. Random variability can be so great as to make individual assessments of tumor biology unreliable, yet constrained enough to lead to the apparently simultaneous appearance of multiple overt metastases

Recent trends in breast cancer incidence in US white women by county-level urban/rural and poverty status

<p>Abstract</p> <p>Background</p> <p>Unprecedented declines in invasive breast cancer rates occurred in the United States between 2001 and 2004, particularly for estrogen receptor-positive tumors among non-Hispanic white women over 50 years. To understand the broader public health import of these reductions among previously unstudied populations, we utilized the largest available US cancer registry resource to describe age-adjusted invasive and <it>in situ </it>breast cancer incidence trends for non-Hispanic white women aged 50 to 74 years overall and by county-level rural/urban and poverty status.</p> <p>Methods</p> <p>We obtained invasive and <it>in situ </it>breast cancer incidence data for the years 1997 to 2004 from 29 population-based cancer registries participating in the North American Association of Central Cancer Registries resource. Annual age-adjusted rates were examined overall and by rural/urban and poverty of patients' counties of residence at diagnosis. Joinpoint regression was used to assess trends by annual quarter of diagnosis.</p> <p>Results</p> <p>Between 2001 and 2004, overall invasive breast cancer incidence fell 13.2%, with greater reductions among women living in urban (-13.8%) versus rural (-7.5%) and low- (-13.0%) or middle- (-13.8%) versus high- (-9.6%) poverty counties. Most incidence rates peaked around 1999 then declined after second quarter 2002, although in rural counties, rates decreased monotonically after 1999. Similar but more attenuated patterns were seen for <it>in situ </it>cancers.</p> <p>Conclusion</p> <p>Breast cancer rates fell more substantially in urban and low-poverty, affluent counties than in rural or high-poverty counties. These patterns likely reflect a major influence of reductions in hormone therapy use after July 2002 but cannot exclude possible effects due to screening patterns, particularly among rural populations where hormone therapy use was probably less prevalent.</p

Predictors of survival after hepatic resection among patients with colorectal liver metastasis

Studies suggest improved survival following resection of colorectal cancer liver metastases (CLMs). We investigated predictors of survival among patients with CLM who underwent hepatic resection using the SEER-Medicare database to identify patients ⩾65 years diagnosed with CLM, 1991–2003, who underwent hepatectomy. Cox proportional hazards models were used to identify factors associated with survival after hepatectomy. Of 923 patients with CLM who underwent hepatectomy, 514 were stages I–III and developed CLM>6 months after diagnosis (metachronous), and 409 were stage IV with CLM at diagnosis (synchronous). From the date of hepatectomy, 5 year survival was 22%; younger age, being married, female gender, surgery in an NCI-designated cancer centre, fewer comorbidities, fewer positive lymph nodes, and lower grade were associated with improved survival. Both 5-fluorouracil (5FU)-based chemotherapy and hepatic arterial infusion (HAI) of floxuridine-based chemotherapy following hepatectomy improved survival (HR=0.62, 95% CI: 0.50–0.78; HR=0.51, 95% CI: 0.28–0.97, respectively) in the synchronous, but not metachronous, group. The HR for overall mortality was higher in hospitals with a high vs low procedure volume (0.75, 95% CI: 0.58–0.94). A substantial subgroup of patients with CLM who undergo hepatectomy experiences long-term survival. High hospital procedure volume and use of 5FU-based or HAI-based chemotherapy after resection were associated with improved prognosis

Genetic Effects at Pleiotropic Loci Are Context-Dependent with Consequences for the Maintenance of Genetic Variation in Populations

Context-dependent genetic effects, including genotype-by-environment and genotype-by-sex interactions, are a potential mechanism by which genetic variation of complex traits is maintained in populations. Pleiotropic genetic effects are also thought to play an important role in evolution, reflecting functional and developmental relationships among traits. We examine context-dependent genetic effects at pleiotropic loci associated with normal variation in multiple metabolic syndrome (MetS) components (obesity, dyslipidemia, and diabetes-related traits). MetS prevalence is increasing in Western societies and, while environmental in origin, presents substantial variation in individual response. We identify 23 pleiotropic MetS quantitative trait loci (QTL) in an F16 advanced intercross between the LG/J and SM/J inbred mouse strains (Wustl:LG,SM-G16; n = 1002). Half of each family was fed a high-fat diet and half fed a low-fat diet; and additive, dominance, and parent-of-origin imprinting genotypic effects were examined in animals partitioned into sex, diet, and sex-by-diet cohorts. We examine the context-dependency of the underlying additive, dominance, and imprinting genetic effects of the traits associated with these pleiotropic QTL. Further, we examine sequence polymorphisms (SNPs) between LG/J and SM/J as well as differential expression of positional candidate genes in these regions. We show that genetic associations are different in different sex, diet, and sex-by-diet settings. We also show that over- or underdominance and ecological cross-over interactions for single phenotypes may not be common, however multidimensional synthetic phenotypes at loci with pleiotropic effects can produce situations that favor the maintenance of genetic variation in populations. Our findings have important implications for evolution and the notion of personalized medicine

The Human Phenotype Ontology in 2024: phenotypes around the world

\ua9 The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research. The Human Phenotype Ontology (HPO) is a widely used resource that comprehensively organizes and defines the phenotypic features of human disease, enabling computational inference and supporting genomic and phenotypic analyses through semantic similarity and machine learning algorithms. The HPO has widespread applications in clinical diagnostics and translational research, including genomic diagnostics, gene-disease discovery, and cohort analytics. In recent years, groups around the world have developed translations of the HPO from English to other languages, and the HPO browser has been internationalized, allowing users to view HPO term labels and in many cases synonyms and definitions in ten languages in addition to English. Since our last report, a total of 2239 new HPO terms and 49235 new HPO annotations were developed, many in collaboration with external groups in the fields of psychiatry, arthrogryposis, immunology and cardiology. The Medical Action Ontology (MAxO) is a new effort to model treatments and other measures taken for clinical management. Finally, the HPO consortium is contributing to efforts to integrate the HPO and the GA4GH Phenopacket Schema into electronic health records (EHRs) with the goal of more standardized and computable integration of rare disease data in EHRs