Identification of novel CHD1-associated collaborative alterations of genomic structure and functional assessment of CHD1 in prostate cancer.

A clearer definition of the molecular determinants that drive the development and progression of prostate cancer (PCa) is urgently needed. Efforts to map recurrent somatic deletions in the tumor genome, especially homozygous deletions (HODs), have provided important positional information in the search for cancer-causing genes. Analyzing HODs in the tumors of 244 patients from two independent cohorts and 22 PCa xenografts using high-resolution single-nucleotide polymorphism arrays, herein we report the identification of CHD1, a chromatin remodeler, as one of the most frequently homozygously deleted genes in PCa, second only to PTEN in this regard. The HODs observed in CHD1, including deletions affecting only internal exons of CHD1, were found to completely extinguish the expression of mRNA of this gene in PCa xenografts. Loss of this chromatin remodeler in clinical specimens is significantly associated with an increased number of additional chromosomal deletions, both hemi- and homozygous, especially on 2q, 5q and 6q. Together with the deletions observed in HEK293 cells stably transfected with CHD1 small hairpin RNA, these data suggest a causal relationship. Downregulation of Chd1 in mouse prostate epithelial cells caused dramatic morphological changes indicative of increased invasiveness, but did not result in transformation. Indicating a new role of CHD1, these findings collectively suggest that distinct CHD1-associated alterations of genomic structure evolve during and are required for the development of PCa.

Issues in the assessment of prostate-specific antigen immunoassays. An update.

Prostate-specific antigen (PSA) immunoassays continue to provide unique and valuable information in the early diagnosis and clinical management of prostate cancer. During the past few years there has been considerable progress in the standardization of routine PSA assays and an emergence of PSA assays with novel applications. The authors discuss these developments and provide some insight when assessing the nuances of assay performance and clinical value.

Issues in the assessment of PSA immunoassays.

The physician and laboratorian have several proven PSA assays from which to choose, and several more are likely to achieve FDA approval soon. Furthermore, an assay that is FDA approved offers considerable reassurance that the many aspects of assay design and manufacturing processes meet an acceptable standard. This will become even more critical as assays report values in the ultrasensitive range. We have attempted to review here some of the most important issues related to PSA assay performance and standardization. Standardization particularly is a complex problem for which solutions are just now appearing. Yet efforts must continue to minimize controversies, because many more assays will be forthcoming and because newer applications of PSA determinations will place more pressure on proper assay evaluations. For example, measurement of free PSA, PSA-ACT complexes, and the ratio of one to the other are intriguing possibilities for added clinical benefit. Also, ultrasensitive PSA assays add a new dimension to the detection of residual disease and may provide unique opportunities for the implementation of new therapies and their timely evaluation. In our opinion, the impact of PSA on the management of prostate cancer is still growing, and the opportunities for better and new assays are still great.

On the possibility of 'real-time' Monte Carlo calculations for the estimation of absorbed dose in radioimmunotherapy.

Dosimetry calculations of monoclonal antibodies (MABs) are made difficult because the focus of radioactivity is targeted for a nonstandard volume in a nonstandard geometry, precluding straightforward application of the MIRD formalism. The MABDOS software addresses this shortcoming by interactive placement of a spherical perturbation into the Standard Man geometry for each tumor focus. S tables are calculated by a Monte Carlo simulation of photon transport for each organ system (including tumor) that localizes activity. Performance benchmarks are reported that measure the time required to simulate 60,000 photons for each penetrating radiation in the spectrum of 99mTc and 131I using the kidney as source organ. Results indicate that calculation times are probably prohibitive on current microcomputer platforms. Mini and supercomputers offer a realistic platform for MABDOS patient dosimetry estimates.