© Oxford University Press 2006.
IN THIS ISSUE
Isotretinoin and Prevention of Second Primary TumorsHigh-dose isotretinoin (13-cis-retinoic acid) has produced encouraging results in patients with head and neck squamous cell cancer (HNSCC). However, the toxic effects of high-dose isotretinoin are substantial. Khuri et al. (p. 441) conducted a phase III randomized trial of low-dose isotretinoin (30 mg/day) versus placebo in 1190 early-stage HNSCC patients to assess its effect on second primary tumor incidence and survival. After 3 years of study drugs and up to 4 years of additional follow-up, isotretinoin did not reduce the rate of second primary tumors or increase survival. Among isotretinoin-treated patients, current smokers had a higher rate of second primary tumors than never or former smokers. The authors conclude that low-dose isotretinoin does not reduce the rate of second primary tumors or overall or smoking-related disease–free survival and that smoking increases the rate of second primary tumors and death among patients receiving low-dose isotretinoin.
In an editorial, Freemantle et al. (p. 426) review the evidence of a potential role for retinoids in cancer chemoprevention and discuss factors that may contribute to the paradoxical lack of isotretinoin clinical chemopreventive activity. They suggest that future trials of retinoids include validated biomarker endpoints to verify drug activity.
Vitamin D Status and Cancer Risk in Men
Giovannucci et al. (p. 451) investigated multiple determinants of vitamin D exposure in relation to cancer risk among men in the Health Professionals Follow-Up Study. An increment of 25 nmol/L in predicted plasma 25-hydroxy-vitamin D [25(OH)D] level was associated with a 17% reduction in total cancer incidence, a 29% reduction in total cancer mortality, and a 45% reduction in digestive system cancer mortality. For men in the bottom and top deciles of predicted 25(OH)D, the absolute annual rate of total cancer was 758 and 674 per 100,000 men, respectively, total cancer mortality was 326 and 277 per 100,000 men, and digestive cancer mortality was 128 and 78 per 100,000 men. The authors conclude that low levels of vitamin D may be associated with increased cancer incidence and mortality in men, particularly for digestive system cancers.
In an editorial, Schwartz and Blot (p. 428) note the strong biologic and epidemiologic evidence that vitamin D has chemopreventive activity. Although heavy sun exposure can be harmful, moderate exposure produces enough vitamin D for healthy bones in light-skinned individuals, and vitamin D supplements are readily available. The authors suggest speedy evaluation of vitamin D as a chemopreventive agent in randomized clinical trials.
Soy Intake and Breast Cancer Risk
Epidemiologic studies of soy intake and breast cancer risk have produced varying results. In this issue, Trock et al. (p. 459) performed a meta-analysis of 18 epidemiologic studies of soy exposure and breast cancer risk that were published from 1978 through 2004. High soy intake was modestly associated with reduced breast cancer risk among all women, but the association was not statistically significant among Asian women. The risk reduction among Western women was inconsistent with their low exposure levels and lacked a dose response, making it difficult to rule out artifact as an explanation for the observed association. The authors conclude that the available data do not provide a clear answer to the role of soy in breast cancer risk and that recommendations for high-dose isoflavone supplementation to prevent breast cancer or its recurrence are premature.
In an editorial, Martínez et al. (p. 430) discuss the variations in the design of studies that examined associations between soy foods and their nutrients and breast cancer risk. They note the consequences of adjusting for this variance in the conduct and interpretation of the meta-analysis.
Gene Expression Profiling and Melanoma Outcome
To identify differentially expressed genes involved in melanoma progression and prognosis, Winnepenninckx et al. (p. 472) investigated the relationship between gene expression profiles and clinical outcome in patients with primary melanoma. They identified 254 genes (including genes involved in activating DNA replication origins) that were associated with survival of patients with primary melanoma and thus metastatic dissemination. When 23 of these genes were studied at the protein level in a validation set, expression of five genes was statistically significantly associated with survival. When adjusted for tumor thickness, ulceration, age, and sex, expression of two of these genes was still statistically significantly associated with survival. The authors conclude that these 254 genes may elucidate molecular mechanisms underlying poor prognosis in melanoma patients.
Serum Retinol and Hepatocellular Carcinoma Risk
Retinoids are antioxidants that enhance cellular differentiation and reduce inflammation. To determine whether serum concentrations of retinol, its derivative retinoids, and antioxidants are associated with risk of HCC, Yuan et al. (p. 482) estimated risk of HCC by levels of micronutrient among a cohort of Chinese men from 1986 through 2001 who provided blood samples, information on risk-related behaviors, hepatitis B status, and self-reported history of physician-diagnosed hepatitis or cirrhosis at enrollment. The authors found that men with the highest levels of serum retinol had a lower risk of HCC compared with men with the lowest levels. Hepatitis B-positive men with the lowest levels of serum retinol had a greater than 70-fold higher risk than hepatitis B-negative men with the highest levels. The authors conclude that a high prediagnostic serum level of retinol is associated with a decreased risk of HCC in this Chinese population of men.
Grb7 Peptide Inhibitor and Pancreatic Cancer Metastasis
Tanaka et al. (p. 491) evaluated growth receptor–bound protein 7 (Grb7) as a molecular target for metastatic pancreatic cancer and a Grb7 peptide inhibitor as a therapeutic agent for metastatic pancreatic cancer. They found that 61% of pancreatic cancer specimens had higher levels of Grb7 than corresponding normal pancreatic tissue. Grb7 expression was different between specimens from patients with and without lymph node metastasis. A selective Grb7 peptide inhibitor blocked the interaction between Grb7 and focal adhesion kinase and the phosphorylation of Grb7 protein and attenuated cell migration and peritoneal metastasis of pancreatic cells in a mouse model. The authors conclude that the Grb7 peptide inhibitor is a promising therapeutic agent against metastatic pancreatic cancer.
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