Does worry about breast cancer predict screening behaviors? A meta-analysis of the prospective evidence

OBJECTIVE: Many women worry about the possibility of developing breast cancer, but there is conflicting evidence concerning whether cancer worry acts as a facilitator or inhibitor of breast cancer screening. METHOD: We conducted a meta-analysis of 12 prospective studies that measured worry about breast cancer at baseline and subsequent breast self-examination (BSE) or mammography utilization among 3342 high-risk and general population women. RESULTS: The data consistently show that breast cancer worry has a small but reliable (r = 0.12) association with breast cancer screening behavior, such that greater worry predicts a greater likelihood of screening. We also found that the means for breast cancer worry were consistently in the lower third of the scales, despite differences in measurement approaches, sample utilization, or the date that the study was conducted. CONCLUSION: The meta-analysis supports the contention that breast cancer worry may motivate screening behavior, and that high levels of breast cancer worry are uncommon.     

Measuring urbanization pattern and extent for malaria research: A review of remote sensing approaches

Within the next 30 years, the proportion of urban dwellers will rise from under half to two thirds of the world's population. Such a shift will entail massive public health consequences, and most of this urban transition will occur in low-income regions of the world. Urban populations face very different health risks compared to those in rural areas, particularly in terms of malaria. To target effective and relevant public health interventions, the need for clear, consistent definitions of what determines urban areas and urban communities is paramount. Decision makers are increasingly seeing remote sensing as a cost-effective solution to monitoring urbanization at a range of spatial scales. This review focuses on the progress made within the field of remote sensing on mapping, monitoring, and modeling urban environments and examines existing challenges, drawbacks, and future prospects. We conclude by exploring' some of the particular relevance of these issues to malaria and note that they are of more general relevance to all those interested in urban public health.     

DNA-targeted 1,2,4-benzotriazine 1,4-dioxides: potent analogues of the hypoxia-selective cytotoxin tirapazamine

Tirapazamine (TPZ, 1,2,4-benzotriazin-3-amine 1,4-dioxide) is a bioreductive hypoxia-selective cytotoxin, currently in phase II/III clinical trials in combination with radiotherapy and with cisplatin-based chemotherapy. We have prepared a series of 1,2,4-benzotriazine 1,4-dioxide (BTO) analogues of TPZ where a DNA-targeting chromophore is attached at the 3-position via a flexible linker. DNA binding affinity was modified through variation of the chromophore or the pK(a) of the linker chain. The association constants (K(DNA)) for calf thymus DNA ranged from 1 x 10(2) to 5.6 x 10(5) M(-1) (ionic strength of 0.01 M). DNA binding affinity was dependent on the presence of a positive charge, either in the linker chain or in the chromophore, and (for a series of 4-acridine carboxamide chromophore analogues) correlated strongly with linker chain pK(a). The efficacy of these BTOs in killing aerobic and hypoxic mouse SCCVII tumor cells in vitro was determined by clonogenic survival. Cytotoxicity was measured as the concentration required to reduce plating efficiency to 10% of controls (C(10)), and the hypoxic cytotoxicity ratio (HCR) for each BTO was calculated as C(10)(aerobic)/C(10)(hypoxic). BTOs bearing a positive charge showed increased hypoxic cytotoxicity (1.5-56-fold) compared to TPZ and mostly modest HCRs (8-51), but some excellent (>167 and 400) values. There was a strong correlation between K(DNA) and hypoxic cytotoxicity but no correlation between K(DNA) and HCR. Cytotoxicity in HT-29 human colon carcinoma cells, determined using IC(50) assays, showed similar relationships with a correlation between K(DNA) and hypoxic cytotoxicity but no correlation between K(DNA) and HCR. In this cell line, a higher proportion of compounds (7 of 11) had HCRs greater than or equal to that of TPZ. The data confirm that DNA targeting is a useful concept for increasing potency while maintaining hypoxic selectivity and provide a direction for the further development of DNA-targeted analogues of TPZ.     

Selective potentiation of the hypoxic cytotoxicity of tirapazamine by its 1-N-oxide metabolite SR 4317

Tirapazamine (TPZ), a bioreductive drug with selective toxicity for hypoxic cells in tumors, is currently in Phase III clinical trials. It has been suggested to have a dual mechanism of action, both generating DNA radicals and oxidizing these radicals to form DNA breaks; whether the second (radical oxidation) step is rate-limiting in cells is not known. In this study we exploit the DNA radical oxidizing ability of the 1-N-oxide metabolite of TPZ, SR 4317, to address this question. SR 4317 at high, but nontoxic, concentrations potentiated the hypoxic (but not aerobic) cytotoxicity of TPZ in all four of the human tumor cell lines tested (HT29, SiHa, FaDu, and A549), thus providing a 2-3-fold increase in the hypoxic cytotoxicity ratio. In potentiating TPZ, SR 4317 was 20-fold more potent than the hypoxic cell radiosensitizers misonidazole and metronidazole but was less potent than misonidazole as a radiosensitizer, suggesting that the initial DNA radicals from TPZ and radiation are different. SR 4317 had favorable pharmacokinetic properties in CD-1 nude mice; coadministration with TPZ provided a large increase in the SR 4317 plasma concentrations relative to that for endogenous SR 4317 from TPZ. It also showed excellent extravascular transport properties in oxic and anoxic HT29 multicellular layers (diffusion coefficient 3 x 10(-6) cm(2)s(-1), with no metabolic consumption). Coadministration of SR 4317 (1 mmol/kg) with TPZ at a subtherapeutic dose (0.133 mmol/kg) significantly enhanced hypoxic cell killing in HT29 tumor xenografts without causing oxic cell killing, and the combination at its maximum tolerated dose was less toxic to hypoxic cells in the retina than was TPZ alone at its maximum tolerated dose. This study demonstrates that benzotriazine mono-N-oxides have potential use for improving the therapeutic utility of TPZ as a hypoxic cytotoxin in cancer treatment.     

Cost effectiveness of treating low HDL-cholesterol in the primary prevention of coronary heart disease

BACKGROUND: A low serum level of high-density lipoprotein (HDL)-cholesterol is an independent risk factor for coronary heart disease (CHD). Fibrates, particularly gemfibrozil, have been shown to raise HDL-cholesterol levels and reduce the incidence of CHD. The literature on fibrate cost effectiveness is quite limited. OBJECTIVE: The objective of this analysis is to determine the cost effectiveness of the fibrates gemfibrozil and fenofibrate in the primary prevention of CHD. The target population includes patients with low levels of HDL-cholesterol, but without pre-existing CHD or other CHD risk factors sufficiently elevated to indicate drug therapy. STUDY DESIGN AND METHODS: From a societal perspective, a lifetime incremental cost-effectiveness model was developed to calculate baseline and treatment costs, life-years gained and QALYs gained. Model parameter values were taken from existing literature. In this 'backward induction' model, the expected costs and outcomes for each 5-year time-interval are utilised in subsequent 5-year time period calculations over the patient's entire lifetime. The study population consisted of a hypothetical cohort of males and females in the US aged 45-74 years, with low levels of HDL-cholesterol and no prior history of CHD. The base-case CHD risk factors for this population were obtained from the VA-HIT (Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial) population baseline characteristics, but assuming no prior CHD history. Estimates for the reduction in CHD risk associated with fibrate therapy reduction are also taken from the VA-HIT study. RESULTS: Using a societal cost-effectiveness threshold of US$50, 000 per QALY, primary prevention of CHD in patients with low HDL-cholesterol levels using generic gemfibrozil therapy is cost effective for all age and sex categories, in contrast to fenofibrate therapy, which is cost effective for males, but not for females at baseline risks levels. In the base-case scenario, because of their higher CHD lifetime risk, it is more cost effective to treat males than females with either gemfibrozil or fenofibrate. For males and females the cost per QALY decreases with age for most age intervals. Gemfibrozil is more cost effective than fenofibrate for all age-sex categories because of the assumed equal efficacy and the higher fenofibrate drug cost. In the comparison scenario, generic lovastatin was more cost effective than gemfibrozil for men except at age 45 years and women at all ages, and more cost effective than fenofibrate for both men and women. CONCLUSIONS: This analysis suggests that fibrate therapy, particularly with generic gemfibrozil, is cost effective in the primary prevention of CHD in individuals with low HDL-cholesterol levels, with or without elevated triglyceride levels. Certain patient subgroups, such as those with elevated triglyceride levels, smokers and those with diabetes mellitus are likely to achieve both CHD risk reduction and overall savings in net expected medical care costs. Comparable cost-effectiveness results are also shown for lovastatin therapy in the target patient population. Gemfibrozil dominates fenofibrate because of the lower cost of therapy (direct and indirect costs). These conclusions are robust to reasonable changes in model parameter values.     

Toluidine blue staining identifies high-risk primary oral premalignant lesions with poor outcome

There is a pressing need for the development of visual aids that will facilitate the detection of oral premalignant lesions (OPLs) with a high-risk of progression. Preliminary data suggest that toluidine blue stain may be preferentially retained by OPLs with high-risk molecular clones. In this study, we monitored OPLs from 100 patients without any history of oral cancer for an average of 44 months in order to evaluate the association of toluidine blue status with clinicopathologic risk factors, molecular patterns (microsatellite analysis on seven chromosome arms: 3p, 9p, 4q, 8p, 11q, 13q, and 17p) and outcome. Toluidine blue-positive staining correlated with clinicopathologic risk factors and high-risk molecular risk patterns. Significantly, a >6-fold elevation in cancer risk was observed for toluidine blue-positive lesions, with positive retention of the dye present in 12 of the 15 lesions that later progressed to cancer (P = 0.0008). This association of toluidine blue status with risk factors and outcome was evident even when the analysis was restricted to OPLs with low-grade or no dysplasia. Our results suggest the potential use of toluidine blue in identifying high-risk OPLs.     

Carotid artery stenosis in asymptomatic patients who have received unilateral head-and-neck irradiation

PURPOSE: To determine the prevalence of carotid artery stenosis in patients who have received ipsilateral head-and-neck radiotherapy and have no symptoms of cerebrovascular disease. METHODS AND MATERIALS: Forty patients underwent ultrasound and computed tomography angiography of their carotid arteries. The vessels on the irradiated side were compared with those on the unirradiated side in a matched-pair analysis with regard to any stenosis, stenosis > or =60% in the internal carotid artery/carotid bulb, intima medial thickness (IMT), and grade of wall abnormalities. History, physical, and fasting blood levels were taken to detect risk factors for carotid disease. RESULTS: Fourteen irradiated carotid trees bore one or more stenosis vs. five in the unirradiated ones (p = 0.03). There were six bulb/internal carotid artery stenoses > or =60% in the irradiated carotids vs. one in the unirradiated (OR 6:1, p = 0.13). IMT and grade of vessel wall abnormality were higher in the irradiated carotids, but only at doses > or =50 Gy, and only at measurement points that lay within the radiation portals. CONCLUSION: Radiation appears to cause carotid artery stenosis. There may be a dose threshold for carotid wall changes, which has relevance for radiotherapy in several tumor sites.