Arnold Engel

Cortical Tuber Count: A Biomarker Indicating Neurologic Severity of Tuberous Sclerosis Complex

The relationship between the number of cortical tubers observed by magnetic resonance imaging (MRI) and the severity of cerebral dysfunction of tuberous sclerosis patients has been examined in a meta-analysis of the published literature. The literature review has identified five independent studies for examining the association. These studies consistently reveal that the cortical tuber count detected on MRI scans is increased among those with more severe cerebral disease. Severity of the cerebral dysfunction is measured by the seizure status and its control and by the developmental status and the level of mental retardation. Meta-analysis demonstrates that within a study population, the MRI-detected cortical tuber count is six times more likely to be above the median count for tuberous sclerosis patients with severe cerebral dysfunction (poor seizure control or moderate-severe retardation or both) than more mildly affected tuberous sclerosis patients. Similarly, across studies, moderately to severely affected patients are five times more likely to have greater than seven MRI-detected cortical tubers than those more mildly affected. These associations are both statistically significant and strong. The cortical tuber count is a biomarker that reasonably predicts the severity of cerebral dysfunction of tuberous sclerosis. Cortical tubers of tuberous sclerosis form in the early gestational period. The embryologic disruption determining the clinical severity of the cortical dysfunction of tuberous sclerosis is set in the early gestational period. (J Child Neurol 1997;12:85-90).

Arsenic in drinking water and bladder cancer mortality in the United States: an analysis based on 133 u.s.counties and 30 years of observation.

This study analyzes the relationship between arsenic exposure through drinking water and bladder cancer mortality. The county-specific white male bladder cancer mortality data (1950–1979) and county-specific groundwater arsenic concentration data were obtained for 133 U.S. counties known to be exclusively dependent on groundwater for their public drinking water supply. No arsenic-related increase in bladder cancer mortality was found over the exposure range of 3 to 60 &mgr;g/L using stratified analysis and regression analyses (both unweighted and weighted by county population and using both mean and median arsenic concentrations). These results, which provide a direct estimate of arsenic-related cancer risk for U.S. residents, exclude the National Research Council’s 2001 risk estimate that was based on Southwest Taiwan data and required adjusting for differences between the body mass and water consumption rates of U.S. and Taiwanese residents.

Human breast sarcoma and human breast implantation: A time trend analysis based on SEER data (1973–1990)

Since the demonstration in the 1940s of foreign body induction of sarcomas in rodents, the safety of artificial implants in humans has been a matter of concern. In this study, we assess the risk for the development of breast sarcomas in women with silicone breast implants. Our analysis is based on the National Cancer Institutes Surveillance, Epidemiology, and End Results (SEER) Program database for the years 1973-1990 and on estimates of breast implantation rates from about 1960 onward. We have divided the SEER data into two equal time periods, 1972-1981 and 1982-1990. For each time period, we estimated the average annual number of women in the United States who had received breast implants 10 or more years earlier. This analysis allows for a 10 year latency period for the induction of breast sarcoma. We calculated that the average number of women in the U.S. 10 or more years post breast implantation was 55,000 for the 1973-1981 period and 509,000 for the 1982-1990 period. We then examined the SEER data to observe whether there was a concomitant rise in the female breast sarcoma incidence rates between these two time periods. We found the mean age-adjusted incidence rate of breast sarcomas was 0.13 per 100,000 women for the initial 9-year period, 1973-1981, and 0.12 per 100,000 women for the latter 9-year period, 1981-1990.(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic myelogenous leukemia and benzene exposure: A systematic review and meta-analysis of the case–control literature☆

Benzene exposure is well demonstrated as a cause of acute myelogenous leukemia, but not of chronic myelogenous leukemia. Previous literature reviews based on case series and cohort studies have not shown an association. We have now conducted a literature search for case-control studies that examine the association between benzene exposure and chronic myelogenous leukemia. Six case-control studies have been found. These derive from occupational groups, cancer registries, and a clinical laboratory. Their exposure ascertainments are all based on job histories, job-exposure matricies, or industrial hygiene data. The odds ratios (ORs) for individual studies range from 0.73 to 1.2. The pooled OR is 1.003 with 95% confidence interval (CI) of 0.94-1.07 (p=0.98) for both a fixed effects model and a random effects model. The case-control literature indicates that chronic myelogenous leukemia does not appear to be related to benzene exposure.

Goitrogens in the Environment

No less than 200 million members of the world’s human population have the thyroid enlargements known as goiters and associated disorders, resulting in a public health and socioeconomic problem of major proportions (1,2). It is clear that the greatest goitrogenic factor among the world’s population is iodine deficiency. Seventy-five percent of people with goiter live in less developed countries where iodine deficiency is prevalent. The role of iodine deficiency as an environmental determinant in the development of endemic goiter is firmly established. However, iodine deficiency does not always result in endemic goiter (3), and iodine supplementation does not always result in complete eradication and prevention of goiter (1,3–9). Even in the presence of extreme iodine deficiency there is an unequal geographic distribution of goiter.

Cancer Risks Associated with Arsenic: Lamm et Al. Respond

We thank Guo for his comments and additional information. As indicated by Guo in his letter, three of the six southwest Taiwan townships in in the internal cancer study of Wu et al. (1989) (townships 2, 4, and 6) show significant dose–response relationships for bladder and lung cancer standardized mortality ratios (SMRs) with respect to the median village well arsenic levels, whereas the other three townships (townships 0, 3, and 5) show high background rates for these cancers and no significant dose–response relationship with village arsenic level. Figure 1 demonstrates that the township-specific inverse linear regression lines for townships 2, 4, and 6 all meet the no increased risk level of SMR = 100 (inflection point) at arsenic exposure levels of approximately 125–150 μg/L, which is consistent with a threshold model. That is the same inflection point range seen for skin cancer prevalence in southwest Taiwan (Byrd et al. 1996) and in Inner Mongolia (Lamm et al., in press). Figure 1 SMRs for bladder and lung cancer by median village well arsenic level for the 42 villages in the six townships in the southwest Taiwan study of Wu et al. (1989) with linear regression analysis by township. SMR = 100 is the level of no increased risk with ... In contrast, the data for townships 0, 3, and 5 are indicative of high background bladder and lung cancer rates (SMRs > 250 at low arsenic levels) that are independent of the arsenic level. We inferred from these analyses the presence of a second (non-arsenic) carcinogenic factor and speculated that it might be related to the nonarsenic etiological factors for blackfoot disease, a condition uniquely reported for this area. On the basis of ongoing analyses, we are currently less inclined to believe that the “township” factor is related to blackfoot disease. Guo inquires whether exposure heterogeneity within the villages has affected the accuracy of the risk estimates based on the village medians and suggests using alternative exposure indicators. We have examined this. The analytic fits to the models demonstrated in Figure 1 are quite similar whether the median or the mean is used as the summary exposure indicator for the villages; Table 1 shows the robustness of the arsenic concentration of the inflection point with the use of a variety of exposure indicators. The table demonstrates that the inflection point for this group of townships and its 95% confidence interval (CI) for these townships is also robust, based on 20 villages. The lower confidence limit of the inflection point is 40μg/L arsenic. Table 1 Inflection points (SMR = 100) in the inverse linear regression model. In spite of the uncertainties in the exposure assessments, the analytic findings are quite robust. They best fit a nonlinear or threshold carcinogenic risk model for arsenic with an inflection point at 150 μg/L (Taiwan) with the presence of at least one additional confounding risk factor. Further analysis will follow the deciphering of the village code. However, interpretation should be cautious because the Wu et al. (1989) study contained data for only about one-third of the villages in the six-township area.