Bayesian analysis of a rat formaldehyde DNA-protein cross-link model.

As the initial effort in a multi-step uncertainty analysis of a biologically based cancer model for formaldehyde, a Markov chain Monte Carlo (MCMC) analysis was performed for a compartmental model that predicts DNA-protein cross-links (DPX) produced by formaldehyde exposure. The Bayesian approach represented by the MCMC analysis integrates existing knowledge of the model parameters with observed, formaldehyde-DPX-specific data, providing a statistically sound basis for estimating model output uncertainty. Uncertainty and variability were evaluated through a hierarchical structure, where interindividual variability was considered for all model parameters and that variability was assumed to be uncertain on population levels. The uncertainty of the population mean and that of the population variance were significantly reduced through the MCMC analysis. Our investigation highlights several issues that must be dealt with in many real-world analyses (e.g., issues of parameters' nonidentifiability due to limited data) while demonstrating the feasibility of conducting a comprehensive quantitative uncertainty evaluation. The current analysis can be viewed as a case study, for a relatively simple model, illustrating some of the constraints that analysts will face when applying Bayesian approaches to biologically or physiologically based models of increasing complexity.

Teratocarcinosarcoma of the nasal cavity and paranasal sinuses: report of 3 cases with assessment for chromosome 12p status.

Sinonasal teratocarcinosarcoma (SNTCS) is a rare malignant neoplasm with 63 reported cases to date. Patients are exclusively adults, with a mean age of 60 years and marked male predominance. Histologically, these tumors are characterized by the presence of admixed epithelial and mesenchymal components. The histogenesis of SNTCS remains uncertain and genetic studies have not been reported to date. Two SNTCSs from the archives of Memorial Sloan-Kettering Cancer Center and one submitted from St Luke's-Roosevelt Hospital Center were evaluated by fluorescent in situ hybridization for amplification of chromosome12p, an event usually associated with the genesis of bona fide germ cell neoplasms (including mediastinal and testicular teratomas). Microscopic examination revealed admixed epithelial and mesenchymal elements in all 3 cases; benign squamous and glandular epithelium and neuroepithelial tissue were identified, the squamous epithelium demonstrating "fetal-like" cytoplasmic clearing. Mesenchymal proliferations were recognized ranging from well-differentiated smooth muscle to high-grade sarcoma. A malignant germ cell component was not identified in any of the cases. Fluorescent in situ hybridization evaluation demonstrated only 2 copies of chromosome 12 per case. Although the histogenesis of SNTCS remains uncertain, we have found an absence of 12p amplification in 3 cases. Our findings suggest that 12p amplification, if it occurs at all in this setting, is exceptional and that SNTCS is a somatic-type neoplasm exhibiting divergent differentiation rather than a germ cell tumor.