© 2005 Oxford University Press
IN THIS ISSUE
Risk of Thyroid Cancer After Exposure to 131I in ChildhoodAfter the Chernobyl nuclear power plant accident in April 1986, the incidence of childhood thyroid cancer increased in contaminated areas. Most radiation exposure to the thyroid was from iodine isotopes, especially 131I. To evaluate thyroid cancer risk after exposure to radioactive iodine in childhood and to investigate environmental and host factors that may modify this risk, Cardis et al. (p. 724) carried out a population-based case–control study of thyroid cancer in Belarus and the Russian Federation. They found a strong dose–response relationship between radiation dose to the thyroid received in childhood and thyroid cancer risk. The radiation- related risk was three times higher in iodine-deficient areas than elsewhere, and administering potassium iodide reduced this risk by a factor of 3. The authors conclude that exposure to 131I during childhood was associated with an increased risk of thyroid cancer and that both iodine deficiency and iodine supplementation may modify this risk.
In an editorial, Boice (p. 703) notes that the thyroid gland of children, but not that of adults, is especially sensitive to the carcinogenic action of radiation and that for 131I this action was increased by iodine-deficient diets and decreased by iodine supplements even if taken months after the exposure, which is remarkable. Boice concludes by raising questions for future research to further the understanding of the association between thyroid cancer and exposure to 131I in childhood.
Targeted Coagulation in the Tumor Vasculature
Tumors require blood flow to grow and thrive, and disrupting blood flow therefore has the potential to be an effective anticancer therapy. One strategy to deprive tumors of blood flow is to specifically target their blood vessels. To this end, Dienst et al. (p. 733) developed a recombinant fusion protein that combines the extracellular domain of soluble tissue factor, which induces coagulation, and an antibody directed against vascular cell adhesion molecule 1 (VCAM-1), a transmembrane glycoprotein that is expressed by tumor vasculature and some tumor cells but not generally by normal blood vessels. The fusion protein bound to VCAM-1 and induced coagulation in vitro. Injection of the fusion protein into mice bearing tumors of human origin resulted in increased tumor necrosis relative to injection with vehicle, in tumor growth delay, and in tumor regression. The fusion protein was well tolerated, with no evidence of systemic coagulation events.
In an editorial, Narazaki and Tosato (p. 705) note that this work shows that strategies aimed at producing vascular occlusion in tumors can be effective and selective. They point out that VCAM-1 is one of several tumor vessel–associated molecules that have been identified and that it will be important to determine which has the greatest tumor specificity and whether there are differences among tumor types.
Recall Rate and Screen Detection of Breast Cancer
Breast cancer screening programs aim to improve the detection of early-stage cancers without increasing the rate of false positives. To investigate how recall rate— the rate at which women who undergo mammography are recalled for additional assessment—relates to detection and false positivity rates, Otten et al. (p. 748) had 15 radiologists review screening mammograms for women with interval and screen-detected cancers in the Dutch breast screening program. The authors first used a linear mixed model to estimate mean detection sensitivities at various false-positive rates and then extrapolated these results to the entire Dutch screening program to calculate the effect of adjusting recall rates on earlier detection of cancers (i.e., shift from interval to screen detected) and on numbers of false positives. For programs with recall rates of 1% to 4%, lowering the threshold for recall resulted in a substantial number of earlier-detected breast cancers. However, at higher recall rates, lowering the recall threshold resulted in a disproportionate increase in false-positive outcomes.
Premenopausal Sex Steroid Levels and Breast Cancer Risk
Contrasting etiologic hypotheses about the role of endogenous sex steroids in breast cancer development among premenopausal women implicate ovarian androgen excess and progesterone deficiency, estrogen excess, estrogen and progesterone excess, and both an excess or lack of adrenal androgens as risk factors. Kaaks et al. (p. 755) conducted a nested case–control study to examine associations of premenopausal serum concentrations of sex steroids and subsequent breast cancer risk. They found that elevated serum concentrations of testosterone, androstenedione, and dehydroepiandrosterone sulfate were associated with an increased risk of breast cancer, whereas elevated serum progesterone concentrations were associated with a reduced risk of breast cancer, but no clear associations were found between breast cancer risk and premenopausal serum levels of estrone or estradiol.
The Apoptosome-Mediated Pathway as a Therapeutic Target
How to induce apoptosis in tumor cells, especially those that are p53-defective, is unclear. Mashima et al. (p. 765) measured p53 status and activity of the apoptosome, a protein complex that forms when cytochrome c is released from the mitochondria and that initiates cell death, in a series of normal tissues and cancer cell lines and found that many p53-defective tumor cell lines had higher apoptosome activity than the normal cell lines and tissues. The authors identified Triacsin c as an inhibitor of acyl-CoA synthetase, an enzyme that regulates cytochrome c release. Triacsin c induced apoptosome-mediated cell death in tumor cells and suppressed the growth of xenograft human lung tumors in athymic mice. The authors conclude that acyl-CoA synthetase inhibition may be a novel strategy to induce p53-defective tumor cell death.
Development and Use of Cancer Prediction Models
Because cancer researchers, clinicians, and the public are increasingly interested in statistical models designed to predict the occurrence of cancer, interest has also increased in ensuring that the models are appropriately applied, correctly developed, and rigorously evaluated. Freedman et al. (p. 715) report on a workshop sponsored by the National Cancer Institute to identify strengths and limitations of cancer and genetic susceptibility prediction models that are currently in use and under development. Participants also explored methodologic issues related to their development, evaluation, and validation. They concluded by identifying future research priorities and resources.
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