Temporal variability in urinary concentrations of phthalate metabolites, phytoestrogens and phenols among minority children in the United States.

BACKGROUND: Exposure to endocrine disruptors (EDs), including some phthalates, phytoestrogens and phenols can be quantified using biomarkers of exposure. However, reliability in the use of these biomarkers requires an understanding of the timeframe of exposure represented by one measurement. Data on the temporal variability of ED biomarkers are sparse, especially among children. OBJECTIVE: To evaluate intraindividual temporal variability in 19 individual urinary biomarkers (eight phthalate metabolites from six phthalate diesters, six phytoestrogens (two lignans and four isoflavones) and five phenols) among New York City children. METHODS: Healthy Hispanic and Black children (N=35; 6-10 years old) donated several urine samples over 6 months. To assess temporal variability we used three statistical methods: intraclass correlation coefficient (ICC), Spearman correlation coefficients (SCC) between concentrations measured at different timepoints, and surrogate category analysis to determine how well the tertile categories based on a single measurement represented a 6-month average concentration. RESULTS: Surrogate category analysis indicated that a single sample provides reliable ranking for all analytes; at least three of four surrogate samples predicted the 6-month mean concentration. Of the 19 analytes, the ICC was >0.2 for 18 analytes and >0.3 for 10 analytes. Correlations among sample concentrations throughout the 6-month period were observed for all analytes; 14 analyte concentrations were correlated at 16 weeks. CONCLUSIONS: The reasonable degree of temporal reliability and the wide range of concentrations of phthalate metabolites, phytoestrogens and phenols suggest that these biomarkers are appropriate for use in epidemiologic studies of environmental exposures in relation to health outcomes in children.

Interactions among GSTM1, GSTT1 and GSTP1 polymorphisms, cruciferous vegetable intake and breast cancer risk.

Isothiocyanates are anticarcinogenic phytochemicals found in cruciferous vegetables that both induce and are substrates for the gluthatione S-transferases (GSTs). The GSTs are phase II metabolizing enzymes involved in metabolism of various bioactive compounds. Functional polymorphisms in GST genes have been identified and may interact with cruciferous vegetable intake to affect cancer risk. We examined this hypothesis using data from the Long Island Breast Cancer Study Project, a population-based case-control study conducted in Long Island, NY, from 1996 to 1997. Cruciferous vegetable intake in the previous year was assessed via modified Block food frequency questionnaire. DNA was extracted from blood samples (n = 1052 cases and n = 1098 controls) and genotyped for GSTM1 deletion, GSTT1 deletion and GSTP1 Ile105Val using multiplex polymerase chain reaction and Taqman assays. Unconditional logistic regression was used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CI). We found an 86% increase in the OR for breast cancer among carriers of the GSTM1 null, GSTT1 null and GSTP 105Ile/Ile genotypes (OR = 1.86, 95% CI = 1.12, 3.08) and a 36% decrease in the OR among carriers of GSTM1 present, GSTT1 null and GSTP1 105Ile/Val + Val/Val genotypes (OR = 0.64, 95% CI = 0.42, 0.97) compared with GSTM1 present, GSTT1 present and GSTP1 105Ile/Ile carriers. We found no joint effects among GST polymorphisms and cruciferous vegetable intake and breast cancer risk. In conclusion, we found associations between specific combinations of three GST gene polymorphisms and breast cancer risk but these did not modify the association between cruciferous vegetable intake and breast cancer. Additional studies are needed to confirm the associations observed.

Lactose and benign ovarian tumours in a case-control study.

We investigated the relation between benign ovarian tumours and lactose among 746 case women identified at seven New York metropolitan hospitals and 404 community controls, age and hospital frequency matched to the expected case distribution. No increase in risk was found for lactose (highest quartile versus lowest: adjusted odds ratio = 0.82 (95% CI 0.57-1.20) or for any other lactose foods.

Breast cancer risk in relation to adipose concentrations of organochlorine pesticides and polychlorinated biphenyls in Long Island, New York.

To assess a possible etiological role of organochlorine compounds in breast cancer development on Long Island, a high-risk region of New York State, concentrations of organochlorine pesticides and polychlorinated biphenyls (PCBs) were measured in the adipose tissue of 232 women with breast cancer and 323 hospital controls admitted to surgery for benign breast disease or non-breast-related conditions. Seven pesticide residues and 14 PCB congeners were assayed via a supercritical fluid extraction method followed by gas chromatography with electron capture detection. After adjustment for age and body mass index, which were strongly correlated with organochlorine levels, adipose concentrations of 1,1-dichloro-2,2-di(4-chlorophenyl)ethylene, total pesticides, and total polychlorinated biphenyls (PCBs) did not differ significantly between cases and controls. The relative abundance of individual pesticide species and PCB congeners was similar in cases and controls. Odds ratios adjusted for age, BMI, hospital, and race gave no evidence of a dose-response for 1,1-dichloro-2,2-di(4-chlorophenyl)ethylene, total pesticides, or total PCBs, whether stratified by estrogen receptor status or not. Breast cancer risk among Long Island residents was not elevated compared with residents of the adjacent New York City borough of Queens. We did not confirm a previously reported association between breast cancer risk and levels of PCB congener 118 (2,3',4,4',5-pentachlorobiphenyl), nor did we observe an association with the most abundant congener 153 (2,2',4,4',5,5'-hexachlorobiphenyl), a strong inducer of phase I enzymes that was reported recently to have estrogenic properties. Only PCB congener 183 (2,2',3,4,4',5',6-heptachlorobiphenyl), which is also an inducer, was significantly associated with risk, with an adjusted odds ratio of 2.0 (95% confidence interval, 1.2-3.4) in women with adipose levels >5.67 ng/g; the biological importance of this observation is unclear without confirmation in additional studies. Although neither the present nor other studies have provided convincing evidence of an association between body burden of 1,1,1-trichloro-2,2-bis(4-chlorophenyl)ethane and PCBs with cancer of the breast, these compounds are rated as "possible" and "probable" human carcinogens, respectively, by the International Agency for Research on Cancer. Investigations of associations with cancer at other sites should be carried out.

Oral contraceptive and benign ovarian tumors.

Whether use of combined oral contraceptives (OC) protects against benign ovarian tumors is unknown. A case-control study of pathologically confirmed benign ovarian tumors was conducted in the New York City area and included cases diagnosed from January 1, 1992, to December 31, 1993, and controls identified by random digit dialing. There were 196 cases with serous adenomas, 176 with teratomas, 311 with endometriomas, and 65 with mucinous adenomas. Interview data were used to determine contraceptive use. Ever use of OC was associated with a decreased risk of these benign tumors (age- and hospital-adjusted odds ratio = 0.79, 95% confidence interval: 0.60, 1.05). In histologic subgroup analyses, the risk of ovarian tumors was reduced for both current and past OC users. Among tumor subtypes, the risk reduction was greatest for women who had endometriotic lesions. The risk reduction also was greater for women who had used OC for more than 24 months. Protection against benign ovarian tumors may be an additional noncontraceptive benefit of OC use.

Diet and benign ovarian tumors (United States).

OBJECTIVES: The relation between benign ovarian tumors (BOTs) and nutrients, primarily dietary fat, was examined using case-control data. METHODS: 746 cases were diagnosed from 1 January 1992 to 31 December 1993. The 404 age- and hospital frequency-matched community controls were identified by random digit dialing. Six hundred seventy-three cases and 351 controls provided dietary information. RESULTS: The risk of BOTs was elevated for the highest vs. lowest quartile of intake of total, vegetable, saturated, monounsaturated, and polyunsaturated fat. The corresponding age-, hospital-, total energy-, and body mass index-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) are 1.3 (0.9-1.9), 1.7 (1.2-2.5), 1.2 (0.8-1.8), 1.3 (0.9-1.8), and 1.6 (1.1-2.3). After adjustment for polyunsaturated fat, the risk of BOTs only remained elevated for vegetable fat (highest vs. lowest quartile OR and 95% CI = 1.4 (0.8-2.3)). Elevated risks were observed for higher intakes of polyunsaturated fat with endometrioid, serous, and teratoma tumors. Higher intakes of vegetable fat, adjusted for polyunsaturated fat, increased the risk of endometrioid, mucinous, and serous tumors. Only the risk of serous BOTs was consistently lower for higher intakes of micronutrients, with the strongest reduction observed for sources of vitamin A. Estimates were not confounded by non-nutrient covariates. CONCLUSIONS: Polyunsaturated and vegetable fat may increase the risk of BOTs, while vitamin A may lower the risk of serous BOTs; however, these findings and lack of associations for other nutrients should be replicated.

Magnetic resonance spectroscopy in the evaluation of neurotoxicity following cranial irradiation for childhood cancer.

In order to evaluate the role of proton MR spectroscopy (1H-MRS) in the diagnosis and assessment of long-term radiation-related neurotoxicity, 14 children who had received cranial irradiation for the treatment of childhood leukaemia (n = 6) or brain tumours (n = 8) underwent 1H-MRS, MRI and neuropsychological assessment. Short-term effects at 2 months following treatment were studied in a further three patients. MRI abnormalities were observed in nine patients. No statistically significant differences between patients and controls (n = 17) were seen in any of the calculated 1H-MRS metabolite ratios, in any of the three patient groups. On multivariate logistic regression analysis there was a correlation between the choline/water ratio and a low IQ. It is concluded that any systematic radiation-induced changes in the 1H MRS metabolites must be below the detection threshold of this study.

Characteristics associated with recent recreational exercise among women 20 to 44 years of age.

Data on 1,501 control women from a multi-center, population-based, case-control study of breast cancer were used to examine characteristics associated with recreational exercise during the year prior to the interview among women 20 to 44 years of age. In a univariate analysis, higher levels of recreational exercise were associated with: higher education; higher family income; white race; previous participation in recreational exercise above the median level at ages 12 to 13 and at age 20; being nulliparous; ever lactating; being a never or past smoker; having a low current Quetelet's index (QI: weight in kilograms divided by height in meters squared); and living in Atlanta or Seattle (compared to New Jersey). In a multiple linear regression model, independent predictors of higher levels of recreational exercise were: participation in higher levels of exercise at 20 years of age; having a low current QI; and never having smoked. Though all women should be encouraged to participate in exercise, these findings identity subgroups of women that may need targeting when developing exercise intervention programs.

Overexpression of cyclin D1 occurs in both squamous carcinomas and adenocarcinomas of the esophagus and in adenocarcinomas of the stomach.

Increased expression of the cyclin D1 gene frequently occurs in human squamous carcinomas of the esophagus. However, the expression of cyclin D1 has not been previously examined in detail in adenocarcinomas of the esophagus or stomach. Therefore, we examined, in parallel, the expression of cyclin D1 in both squamous and adenocarcinomas of the esophagus and in adenocarcinomas of the stomach. The level of expression of the cyclin D1 protein was assessed by immunohistochemistry in 39 esophageal and 34 gastric carcinomas and correlated with clinical and pathology parameters. Within the esophagus, 71% of the squamous carcinomas and 64% of the adenocarcinomas were positive for increased cyclin D1 nuclear staining. For adenocarcinomas of the stomach, the overall positive rate was 47%; in the gastric cardia, the rate was 44%, and in other regions of the stomach, it was 50%. In esophageal and gastric adenocarcinomas of the intestinal type, increased expression of cyclin D1 was seen in 70% of the samples, whereas with the diffuse type only 13% were positive (P < .01). Tumors from patients older than the median age of 67 years were more frequently positive than tumors from patients younger than 67 years (74% v 42%, respectively) (P < .01). Positive staining was also seen more frequently in well and moderately differentiated tumors than in poorly differentiated tumors (74% v 49%, respectively) (P < .05). Cytoplasmic staining for cyclin D1 was noted in 22% of the tumors, of various types. Therefore, increased expression of cyclin D1 frequently occurs in both adenocarcinomas and squamous carcinomas of the esophagus, and in adenocarcinomas of the stomach. The increased expression in adenocarcinomas is especially frequent in the intestinal-type lesions.

Electric blanket use and breast cancer risk among younger women.

To investigate whether use of electric blankets, one of the largest sources of electromagnetic field exposure in the home, is associated with the risk of female breast cancer, the authors analyzed data from a population-based US case-control study. The 2,199 case patients were under age 55 years and had been newly diagnosed with breast cancer between 1990 and 1992. The 2,009 controls were frequency-matched to cases by 5-year age group and geographic area. There was little or no risk associated with ever having used electric blankets, mattress pads, or heated water beds among women under age 45 years (adjusted odds ratio = 1.01, 95% confidence interval 0.86-1.18) or among women aged > or =45 years (adjusted odds ratio = 1.12, 95% confidence interval 0.87-1.43). There was no substantial variation in risk with duration of use; with whether the appliance was used only to warm the bed or used throughout the night; with menopausal status; or with the cases' hormone receptor status or stage of disease. Potential breast cancer risk factors that were associated with electric blanket use did not substantially confound the associations under investigation. These data do not support the hypothesis that electric blanket use increases breast cancer risk among women under age 55 years.

Amyloid angiopathy causing widespread miliary haemorrhages within the brain evident on MRI.

The case of a 70-year-old woman with cerebral amyloid angiopathy (CAA) is presented. MRI of the head showed widespread miliary foci of haemorrhage within the cerebrum and cerebellum, with some additional linear lesions within the cerebral cortex and patchy lesions in the white matter. This is in contrast to the more usual pattern of intracranial haemorrhage in CAA, i.e., a lobar haematoma.

Recreational physical activity and breast cancer risk among women under age 45 years.

To evaluate whether recreational physical activity is associated with breast cancer among young women, the authors analyzed data from a population-based case-control study. Cases (n = 1,668) were women under age 45 years who had been newly diagnosed with breast cancer between 1990 and 1992 in Atlanta, Georgia, central New Jersey, or Seattle, Washington. Controls (n = 1,505) were frequency-matched to cases by 5-year age group and geographic area of residence. Breast cancer was not associated with recreational activity in any of the three time periods assessed (highest quartile of activity vs. lowest: age- and center-adjusted odds ratio (OR) = 0.94 (95% confidence interval (CI) 0.77-1.15) at ages 12-13 years, OR = 1.08 (95% CI 0.88-1.32) at age 20 years, and OR = 1.18 (95% CI 0.97-1.44) during the past year), with the average of the three time periods (OR = 1.02, 95% CI 0.84-1.25), or with daily climbing of at least two flights of stairs (without stopping) during the past year (daily climbing vs. never climbing: OR = 1.03, 95% CI 0.86-1.23). Estimates were not modified or confounded by body mass index, menopausal status, or caloric intake during the past year. These results do not support a protective role for physical activity in the risk of breast cancer among young women.

Recreational and occupational physical activities and risk of breast cancer.

Physical activity has been hypothesized to reduce breast cancer risk, but an inverse association has not been consistently reported. In this review, we critically evaluate for coherence, validity, and bias the epidemiologic studies on recreational or occupational physical activity, discuss the biologic plausibility of the association, and identify areas for future research. Results from seven of nine studies suggest that higher levels of occupational physical activity may be associated with a reduction in risk, at least among a subgroup of women. Eleven of 16 investigations on recreational exercise reported a 12%-60% decrease in risk among premenopausal and postmenopausal women, although a dose-response trend was not evident in most of the studies. The reduction in risk associated with exercise was more likely to be observed in case-control studies than in cohort studies. Most investigations incompletely assessed physical activity, which contributed to conflicting findings on the optimal time period, duration, frequency, or intensity of activity to minimize risk. Physical activity may exert its effects through changes in menstrual characteristics, reduced body size, or alterations in immune function. In summary, most epidemiologic studies of physical activity reported a reduction in the risk of breast cancer among physically active women. Future research studies should focus on using a cohort design to rule out recall bias as a possible explanation for the decrease in risk associated with exercise, on improving assessment of lifetime physical activity from all sources to clarify whether there is a dose-response relation or an optimal time period, duration, frequency, or intensity of activity, and on elucidating the underlying mechanisms for the inverse association.

Treatment for breast cancer and blood levels of chlorinated hydrocarbons.

Small studies have examined, with conflicting results, whether breast cancer risk is increased among women exposed to high levels of chlorinated hydrocarbons, as measured in breast fat tissue or peripheral blood collected prior to treatment (pretreatment blood). For a population-based, case-control study, collection of pretreatment blood is a labor-intensive effort. An alternative is to collect blood from cases at interview, as is done for controls, after breast cancer treatment has commenced (posttreatment blood). It is unknown whether treatment affects blood levels of the organochlorines 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE) or polychlorinated biphenyls (PCBs). The purpose of this study was to determine whether pretreatment versus posttreatment blood samples yielded significantly different estimates of cumulative exposure to DDE and PCBs among newly diagnosed breast cancer patients. Two-ml blood samples were collected prior to and after treatment for breast cancer from 22 nonfasting women, ages 45-87 years, newly diagnosed with invasive disease. Treatment was defined as major surgery (mastectomy or node removal), radiation, hormones (tamoxifen), or chemotherapy. Pretreatment and posttreatment blood samples were assayed for DDE and PCBs in blinded, matched pairs. The reported concentrations (volume basis) were adjusted for estimated total plasma lipids. For DDE, mean differences in unadjusted [0.99 ng/ml; 95% confidence interval (CI), -0.36 to 2.34 ng/ml] and lipid-adjusted (0.05 microgram/g lipid; 95% CI, -0.04 to 0.13 microgram/g lipid) levels were small. For PCBs, the unadjusted (0.68 ng/ml; 95% CI, 0.05 to 1.30 ng/ml) and adjusted (0.070 microgram/g lipid; 95% CI, -0.009 to 0.149 microgram/g lipid) mean differences were of borderline statistical significance. The mean percent change in lipid-adjusted organochlorine levels did not vary substantially between treatment groups, except for those patients receiving chemotherapy [n = 5; 15.8% (DDE), 29.4% (PCBs)]. Adjusted mean differences also increased with increasing time between the pretreatment and posttreatment blood draws. In multiple regression models that included treatment, age, race, stage, and time between blood draws, only chemotherapy appeared to predict the percent change in adjusted pretreatment and posttreatment levels of DDE or PCBs (P = 0.10 and 0.06, respectively). Posttreatment blood samples drawn within 3 months of pretreatment samples, with the exception of those drawn after the commencement of chemotherapy, provide similar measures of DDE body burden levels among breast cancer cases. The use of blood samples collected after treatment, rather than before treatment, for characterizing PCB levels may lead to misclassification of exposure.

Down syndrome and moyamoya disease: presentation with subarachnoid hemorrhage.

Moyamoya disease in childhood is frequently accompanied by manifestations of ischemia; cerebral hemorrhage is unusual in patients younger than 15 years of age. Previous studies suggest an association of childhood moyamoya disease, which is often bilateral, with Down syndrome. Possible etiologic factors of moyamoya disease in Down syndrome are discussed.

Changes in cytomorphology of childhood lymphoblastic leukaemia at the time of disease relapse. Childhood Leukaemia Working Party of the United Kingdom Medical Research Council.

AIMS: Children in a United Kingdom national trial for relapsed non-B lymphoblastic leukaemia (ALL) had their diagnostic and relapse marrow cytomorphology compared to see what changes occur during the evolution of the disease. METHODS: Each relapse slide was assessed blindly for French American British (FAB) type and other morphological features by a panel of three independent microscopists without reference to each other or any diagnostic material. Diagnostic slides had been assessed by the same panel on an earlier occasion. RESULTS: A total of 134 consecutive children was studied. Six (5%) were classified as FAB type L2 at diagnosis, compared with 18 (13%) at relapse (a difference of 9%). Twenty two (16%) changed their FAB type, 17 (13%) from L1 to L2 and five (4%) from L2 to L1. The FAB score fell at relapse in 34 children and rose in 14, a difference of 14%. Cell size was the commonest feature to change (increasing in 22 and diminishing in nine) followed by prominent nucleoli (appearing in 21 and disappearing in six). Forty four (33%) children had vacuolated blasts at diagnosis, compared with 48 (36%) at relapse. Twenty five changed their vacuole score substantially, 14 gaining > 10% and 11 falling < 10%. CONCLUSIONS: These findings reflect the variability of lymphoblast cytomorphology, but also show a trend for cells to have more prominent nucleoli and greater size at relapse. Factors controlling these features of the FAB type are unknown, but they may simply be related to the growth fraction of a particular disease and not to any lineage specific biological feature.

Adult postrepair myelomeningocoele and tethered cord syndrome: good surgical outcome after abrupt neurological decline.

Adults who have had repair of an open myelomeningocoele at birth are susceptible to a variant of adult onset tethered cord syndrome (ATCS). Precipitous and profound loss of lower extremity motor function occurred in two postrepair adult patients, but was not seen in any of our 12 cases of adult tethered cord with any other aetiologies. Both postrepair ATCS patients made a good recovery after surgical release of the tether. For the patients with other aetiologies, surgery yielded improvement or recovery of urinary continence in 57%, relief from pain in 78% and improved strength in 80%. Evidence of retethering was observed in 25% of the operated patients at intervals ranging from 1 to 9 years postoperatively. We conclude that surgical release of tether can reverse incontinence in ATCS of any aetiology and that in the post-myelomeningocoele repair patient, both dexamethasone and surgical intervention are helpful in reversing acute neurological deterioration.

Prospective evaluation of cerebral angiography and computed tomography in cerebral haematoma.

One hundred and two consecutive patients with cerebral haematoma were prospectively allocated to one of two groups according to their CT on admission. Group 1 patients were thought to have a high probability of an underlying structural lesion and underwent cerebral angiography acutely. If normal, this was repeated at three months. Group 2 patients were thought not to have such a lesion and underwent angiography at three months. Patients older than the mean age of the study population, and hypertensive patients were much less likely to harbour an aneurysm or arteriovenous malformation than younger or normotensive patients (p < 0.01; sensitivity 87.9%, specificity 88.6%). An aneurysm or arteriovenous malformation was the cause of haemorrhage in 12.8% of hypertensive patients, in 30.9% of patients with haematoma involving the basal ganglia, and 18.2% of those with posterior fossa haemorrhage. Features of CT in isolation give a sensitivity of 77.2% and a specificity of 84.2%. Follow up angiography in group 1 showed an arteriovenous malformation in one of seven patients in whom the original study was normal. These results contrast sharply with data from previous retrospective studies. The decision to investigate a patient with cerebral haematoma should be primarily based on the patient's clinical condition, rather than on the site of haemorrhage.

Periodic acid Schiff reaction in childhood lymphoblastic leukaemia. The Medical Research Council Working Party on Childhood Leukaemia.

AIMS: To assess the prevalence and degree of periodic acid Schiff (PAS) positivity in blast cells from children with lymphoblastic leukaemia (ALL); its association with other disease characteristics; and its clinical importance in predicting the outcome of treatment. METHODS: Marrow slides from entrants to a large United Kingdom multicentre ALL trial (UKALL X) were batch processed and assessed blind for PAS positivity by one morphologist. Patients were classified into groups A, B, and C, corresponding to less than 1% PAS positive cells, 1-10%, and over 10%, respectively. Their PAS pattern was then compared with other clinical and pathological features of ALL and with treatment outcome. RESULTS: Slides from 921 children were examined of which 371 (40%) were categorised as group A, 324 (35%) as group B, and 226 (25%) as group C. There was a clear association between the presence of blast cell vacuoles on Romanowsky staining and PAS positivity. Group A (PAS negative) patients included a disproportionate excess of those with L2 morphology, those under 2 or over 6 years of age, those with an initial white cell count over 50 x 10(9)/l, those with a T or null cell immunophenotype, and those with chromosomal abnormalities other than "high hyperdiploidy". Four years from diagnosis, group C patients had an 8% disease free survival advantage over those in group A (2p = 0.01). This was irrespective of initial white cell count, but not of immunophenotype or the presence of vacuoles. CONCLUSIONS: Strong PAS positivity is a feature of "common" ALL and is particularly associated with blast cell vacuoles. It does occasionally occur in other disease subtypes with or without vacuoles. It predicts a better response to current treatment, but not independently of other cell characteristics.