© 2003 by Oxford University Press
Journal of the National Cancer Institute, Vol. 95, No. 1, 1,
January 1, 2003
© 2003 Oxford University Press
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Randomized controlled trials of new disease treatments, including some treatments for cancer, often include a placebo control arm. It is well known that patients given a placebo often show some relief from disease symptoms, but the extent to which placebo treatment of cancer patients leads to improvement in symptoms or quality of life, or in tumor responses, is not known. To investigate this question, Chvetzoff and Tannock (p. 19) searched the literature for randomized controlled trials in oncology with a placebo arm or a best supportive care arm. Their analysis of the outcomes of these trials (37 of the first type and 10 of the second) indicates that placebos are sometimes associated with some improvement in control of symptoms such as pain and appetite but are rarely associated with positive tumor responses. Conversely, substantial improvements in symptom control or quality of life are unlikely to be the result of placebo effects.
In an editorial, Temple (p. 2) notes that Chvetzoff and Tannock’s analysis is potentially useful in considering trials that do not have a concurrent control group, which are common in oncology.
Postmenopausal Hormone Use and Mammographic Density
Mammographic density is a risk factor for breast cancer. Postmenopausal hormone use is associated with an increase in mammographic density, but the magnitude of the density increase is unknown. Greendale et al. (p. 30) analyzed digitized baseline and 12-month mammograms for 571 women, aged 45–65 years who were randomly assigned to receive placebo or conjugated equine estrogens either alone or combined with three different progestin regimens. They found that the absolute mean 12-month change in mammographic percent density for women in the combined treatment groups was greater than that for women in the placebo group and that estrogen alone was not associated with as great an increase in mammographic density as was estrogen combined with progestin. They conclude that greater mammographic density is associated with the use of estrogen/progestin combination therapy, regardless of how the progestin was given, but not with the use of estrogen only.
In an editorial, Chlebowski and McTiernan (p. 4) stress that how changes in breast density with postmenopausal hormone use affects subsequent changes in breast cancer risk remains to be resolved. They outline the predictions and status of ongoing randomized clinical trials that address this issue.
SV40 Exposure and Pleural Mesothelioma Incidence
Poliovirus vaccines that were used during the late 1950s and early 1960s were contaminated with the tumorigenic monkey virus, simian virus 40 (SV40). SV40 DNA sequences have been detected in some human cancers, especially pleural mesotheliomas. Strickler et al. (p. 38) examined the relationship between SV40-contaminated poliovirus vaccine exposure and subsequent rates of pleural mesothelioma in the United States. They found that the age-standardized pleural mesothelioma incidence rates for 1975 through 1997 increased the most among males who were at least 75 years old, the age group least likely to have been immunized against poliovirus, whereas the rates among males in the age groups most heavily exposed to SV40-contaminated poliovirus vaccine remained stable or decreased during this time period. They observed similar age-specific trends among females. The authors conclude that the age-specific trends in U.S. pleural mesothelioma incidence rates are not consistent with an effect of exposure to SV40-contaminated poliovirus vaccine.
Pap and HPV Testing and Cervical Cancer Risk
In the United States, annual Pap smear screening has been favored over less frequent screening to minimize the risk of cervical cancer. Sherman et al. (p. 46) evaluated whether simultaneous one-time screening with Pap and human papillomavirus (HPV) tests is useful for assessing the future risk for cervical intraepithelial neoplasia 3 (CIN3) or cervical cancer. They found that women with negative Pap and HPV baseline tests were at low risk for CIN3 or cancer in the subsequent 45 months, largely because a negative HPV test was associated with a relatively low future risk of cervical neoplasia. They conclude that negative combined test results should provide added reassurance for lengthening the screening interval among low-risk women, and positive results identify a relatively small group of women who require more frequent surveillance.
Pitfalls in the Use of Microarrays
With the use of DNA microarray technology becoming increasingly common among researchers, determining what is biologically relevant from tens of thousands of noisy data points has proven to have unique challenges. In their commentary, Simon et al. (p. 14) explain how the experimental objectives of microarray analyses drive the design and the analysis in class prediction studies, such as those involved in diagnostic testing and prognostic stratification. The authors state that, for class prediction problems, the analysis should use the class information and not cluster analysis methods, which are appropriate only when there are no predefined classes. The authors stress the importance of cross-validating the predictor by using a training data set and a validation data set, the importance of providing accurate error rates, and the need to compare new prediction algorithms with standard prediction methods before making strong claims regarding predictor efficacy.
Oltipraz Induction of Glutathione-S-Transferase
Chemopreventive agents, such as the dithiolthione oltipraz, can transcriptionally induce genes whose protein products can protect cells from chemical-induced carcinogenesis. Oltipraz is thought to exert its chemopreventive effects through the induction of glutathione-S-transferase (GST). To identify the molecular signals that stimulate this induction, Kang et al. (p. 53) investigated the role of the CCAAT/enhancer binding protein (C/EBP) in the induction of GSTA2 (alpha form) and the enhancer element(s) responsible for GSTA2 expression. They found that oltipraz induced the expression of GSTA2 mRNA in a time and dose-dependent manner, the beta form of C/EBP (C/EBP
) translocated into the nucleus and bound to the consensus sequence of C/EBP in oltipraz treated cells, and phosphatidylinositol-3 kinase (PI3-kinase) was required for C/EBP induction of GSTA2 by oltipraz. The authors conclude that oltipraz-induced GSTA2 expression is dependent on PI3-kinase-mediated nuclear translocation and binding of C/EBP to the C/EBP enhancer element in the GSTA2 gene promoter.
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