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Background parenchymal enhancement measured quantitatively at breast MRI is associated with increased odds of breast cancer for both premenopausal and postmenopausal women after accounting for breast cancer risk factors.

Genome-wide association studies (GWAS) have transformed our understanding of glioma susceptibility, but individual studies have had limited power to identify risk loci. We performed a meta-analysis of existing GWAS and two new GWAS, which totaled 12,496 cases and 18,190 controls. We identified five new loci for glioblastoma (GBM) at 1p31.3 (rs12752552; P = 2.04 × 10−9, odds ratio (OR) = 1.22), 11q14.1 (rs11233250; P = 9.95 × 10−10, OR = 1.24), 16p13.3 (rs2562152; P = 1.93 × 10−8, OR = 1.21), 16q12.1 (rs10852606; P = 1.29 × 10−11, OR = 1.18) and 22q13.1 (rs2235573; P = 1.76 × 10−10, OR = 1.15), as well as eight loci for non-GBM tumors at 1q32.1 (rs4252707; P = 3.34 × 10−9, OR = 1.19), 1q44 (rs12076373; P = 2.63 × 10−10, OR = 1.23), 2q33.3 (rs7572263; P = 2.18 × 10−10, OR = 1.20), 3p14.1 (rs11706832; P = 7.66 × 10−9, OR = 1.15), 10q24.33 (rs11598018; P = 3.39 × 10−8, OR = 1.14), 11q21 (rs7107785; P = 3.87 × 10−10, OR = 1.16), 14q12 (rs10131032; P = 5.07 × 10−11, OR = 1.33) and 16p13.3 (rs3751667; P = 2.61 × 10−9, OR = 1.18). These data substantiate that genetic susceptibility to GBM and non-GBM tumors are highly distinct, which likely reflects different etiology.

Introduction Deficiencies in cellular responses to DNA damage can predispose to cancer. Ionizing radiation can cause cluster damage and double-strand breaks (DSBs) that pose problems for cellular repair processes. Three genes (ATM, BRCA1, and BRCA2) encode products that are essential for the normal cellular response to DSBs, but predispose to breast cancer when mutated.Design To examine the joint roles of radiation exposure and genetic susceptibility in the etiology of breast cancer, we designed a case-control study nested within five population-based cancer registries. We hypothesized that a woman carrying a mutant allele in one of these genes is more susceptible to radiation-induced breast cancer than is a non-carrier. In our study, 700 women with asynchronous bilateral breast cancer were individually matched to 1400 controls with unilateral breast cancer on date and age at diagnosis of the first breast cancer, race, and registry region, and counter-matched on radiation therapy. Each triplet comprised two women who received radiation therapy and one woman who did not. Radiation absorbed dose to the contralateral breast after initial treatment was estimated with a comprehensive dose reconstruction approach that included experimental measurements in anthropomorphic and water phantoms applying patient treatment parameters. Blood samples were collected from all participants for genetic analyses.Conclusions Our study design improves the potential for detecting gene–environment interactions for diseases when both gene mutations and the environmental exposures of interest are rare in the general population. This is particularly applicable to the study of bilateral breast cancer because both radiation dose and genetic susceptibility have important etiologic roles, possibly by interactive mechanisms. By using counter-matching, we optimized the informativeness of the collected dosimetry data by increasing the variability of radiation dose within the case–control sets and enhanced our ability to detect radiation–genotype interactions.

The role of ataxia-telangiectasia mutated (ATM) heterozygosity in cancer is uncertain. In vitrostudies of cells from ATMheterozygotes provide strong evidence of radiation sensitivity. Some, but not all, clinical studies suggest an increased risk of breast cancer among ATMgene carriers, and this risk may be greater among those exposed to radiation. This possible excess risk of breast cancer associated with ATMheterozygosity constitutes the basis for several genetic epidemiological studies designed to clarify the role that the ATMgene plays in the etiology of breast and other cancers. The primary focus of this international, multidisciplinary, National Cancer Institute-sponsored workshop was to discuss ongoing and planned epidemiologic studies aimed at understanding the complexities of the ATMgene and its role in carcinogenesis. The invited participants were from diverse disciplines including molecular and clinical genetics, radiation biology and physics, epidemiology, biostatistics, pathology, and medicine. In the present meeting report, the aims of each project are described.

Tumor characteristics are strong predictors of survival among women with breast carcinoma, yet the variability in prognosis among women presenting with similar stages suggests other factors may also play an important role. We examine the prognostic significance of etiologic risk factors for breast carcinoma to determine whether factors that influence the development of breast carcinoma also affect the course of the disease among a prospective cohort of young women with bilateral breast carcinoma. The 369 U.S. women included in this study were from the Cancer and Steroid Hormone Study who were diagnosed with an invasive first primary breast carcinoma between 1980 and 1982 and a second primary breast carcinoma before 1999. Cox proportional hazards models were used to evaluate factors known and suspected to be associated with breast carcinoma and with survival, based on reporting at the time of the first primary. One hundred sixty women died during the 16–18-year follow-up period. The adjusted 1, 5, 10, and 15-year survival rates following diagnosis of second primary breast carcinoma were 94%, 70%, 55%, and 49%, respectively. Survival rates werepoorest among the youngest women, those diagnosed with a second primary within 5 years of their first, poor African American women, women with either primary diagnosed at a later stage, those with less than 12 years of school, single women, and those with major weight gain between age 18 and adulthood. This study provided little evidence that important etiologic factors for breast carcinoma predict mortality following diagnosis of a second primary breast carcinoma. Cancer 2002;95:2051–8. © 2002 American Cancer Society. DOI 10.1002/cncr.10950

All 62 coding exons of the ATM gene, along with 10–20 bases of the intronic region flanking each exon, were screened for DNA base sequence alterations by using denaturing high-performance liquid chromatography (DHPLC) in a series of 52 breast cancer patients. Six (12%) of these patients exhibited a total of eight different novel germ-line mutations that do not represent common polymorphisms. Of these, three patients possessed four nonconservative missense mutations while two conservative missense and two synonymous mutations were detected in the other three patients. In addition, 43 patients were found to have a total of 141 DNA sequence variations representing 21 different common polymorphisms and rare variants. An analysis of the relationship between the presence of a novel ATM mutation and either patient demographics or tumor properties demonstrated a significant difference between African Americans (3/7 = 43%) and other ethnic groups (3/45 = 7%, P = 0.026). None of the other characteristics examined was found to be related to mutation status. Environ. Mol. Mutagen. 38:200–208, 2001. © 2001 Wiley-Liss, Inc.

All 62 coding exons of the ATMgene, along with 10–20 bases of the intronic region flanking each exon, were screened for DNA base sequence alterations by using denaturing high‐performance liquid chromatography (DHPLC) in a series of 52 breast cancer patients. Six (12%) of these patients exhibited a total of eight different novel germ‐line mutations that do not represent common polymorphisms. Of these, three patients possessed four nonconservative missense mutations while two conservative missense and two synonymous mutations were detected in the other three patients. In addition, 43 patients were found to have a total of 141 DNA sequence variations representing 21 different common polymorphisms and rare variants. An analysis of the relationship between the presence of a novel ATMmutation and either patient demographics or tumor properties demonstrated a significant difference between African Americans (3/7 = 43%) and other ethnic groups (3/45 = 7%, P= 0.026). None of the other characteristics examined was found to be related to mutation status. Environ. Mol. Mutagen. 38:200–208, 2001. © 2001 Wiley‐Liss, Inc.

Based upon the results of several epidemiologic studies, it has been suggested that women who are carriers for a mutation in the ataxia telangiectasia-mutated (ATM) gene are susceptible for the development of breast cancer. Therefore, 37 consecutive breast cancer patients were screened for the presence of a germline ATMmutation using a non-isotopic RNase cleavage-based assay (NIRCA). This paper reports the first use of NIRCA for detection of ATMmutations in breast cancer patients. Using this assay, no ATMmutations were found in our patient population. This result is similar to the findings of other studies that have employed approaches complementary to NIRCA.

• The impact of maternal opiate dependency on birth weight and head circumference of offspring was studied in 150 mother-infant pairs and 150 controls. Mean birth weight and head circumference of drug-dependent offspring were reduced symmetrically compared with drug-free controls of similar socioeconomic status. Although mean gestational ages and rates of prematurity were similar, intrauterine growth retardation occurred in 20% of passively addicted infants vs 4% of controls. A longer period of methadone maintenance was associated with longer gestation and increased birth weight, while higher methadone dosages were associated with higher birth weights and larger head circumferences. Smoking was associated with reduced birth weight by an average of 160 g per pack of cigarettes smoked per day; longer duration of smoking was associated with reductions in both birth weight and head circumference. These data suggest therapeutic strategies to improve these fetal growth characteristics and perhaps improve neurobehavioral outcome of drug-dependent newborns.(AJDC 1987;141:1163-1167)

• Early weight-change patterns were studied in 101 passively addicted neonates. Newborns showing mild abstinence and not requiring pharmacologic treatment lost an average of 4.0% of birth weight, reached a weight nadir on day 3, and regained birth weight by days 7 to 8. Newborns treated with either paregoric or phenobarbital for more severe signs of abstinence lost an average of 6.3% of birth weight, reached a nadir on days 6 to 7, and regained birth weight only by days 13 to 14. Despite comparable birth weights and energy intakes, treated newborns weighed 95 g less than untreated neonates on day 10 when the untreated neonates were discharged. In light of abnormal early weight-change patterns seen with more severe abstinence, both strict control of abstinence and provision of additional individualized nutritional support seem warranted.(AJDC 1986;140:829-832)

To determine the clinical significance of the occurrence of hemodynamic deterioration after the administration of calcium channel blocking drugs, nifedipine (20 mg orally) was administered to 29 patients with severe left ventricular dysfunction. Thirteen patients showed hemodynamic improvement with the drug (Group 1), as shown by a notable increase in cardiac index associated with a modest decrease in mean arterial pressure. The other 16 patients exhibited hemodynamic deterioration after nifedipine (Group 2), as reflected by a decline in right and left ventricular stroke work indexes accompanied by a marked hypotensive response. These differences were not related to differences in the peripheral vascular response to nifedipine, because both groups showed similar decreases in systemic and pulmonary vascular resistances.

A consecutive group of 67 patients (70 eyes) with senile cataract underwent extracapsular cataract extraction and implantation of a Shearing posterior chamber intraocular lens. After two years of follow-up, there was an 11% + 2% decrease in central cell density (P<.001), a 20% + 2% decrease in superior cell density (P<.001), and a 5% + 3% decrease in inferior cell density (P<,005). Complications included corneal edema requiring a corneal transplant (one patient), a sterile nonhealing ulcer that required a conjunctival flap (one patient), and secondary glaucoma (one patient). Nine patients had visual acuities poorer than 20/40 but none had cystoid macular edema. Primary or secondary capsulotomy did not significantly increase endothelial cell loss. Central endothelial cell loss from extracapsular cataract extraction with Shearing posterior chamber intraocular lens implantation was correlated with age, as well as with preoperative superior endothelial cell density (P<.05).

One hundred and twentynine workers chronically exposed to asbestos were interviewed regarding their perceived health status and concerns, their health behaviors, particularly their smoking behavior, and their psychologic wellbeing. In contrast to a nonexposed comparison group of postal workers, asbestos workers exhibited significantly elevated levels of somatic concern P < .03, and significantly lower levels of mental health functioning only when experiencing high levels of stress P < .01. Despite feeling significantly more susceptible to developing cancer P < .0001, 34 of asbestos workers were cigarette smokers compared to 32 of the postal group and longterm mask usage was minimal. Asbestos workers' increased sensitivity to stress and changes in health status along with the lack of adaptation of healthpromotive behaviors indicate the need for interventions to attend to the psychologic effects of increased risk status.

Magnesium abnormalities are common in patients with congestive heart failure but the clinical and prognostic significance of an abnormal serum magnesium concentration in this disorder has not been investigated. Therefore, the relation between serum magnesium concentration and the clinical characteristics and long-term outcome of 199 patients with chronic heart failure was evaluated. The serum magnesium concentration was &lt;1.6 mEq/liter in 38 patients (19%), within the normal range in 134 patients (67%) and >2.1 mEq/liter in 27 patients (14%).

Germline mutations in the BRCA1and BRCA2genes confer a marked increase in risk of breast cancer. Loss-of-function mutations have been identified in the PALB2gene that also increase the risk of breast cancer. PALB2interacts with BRCA1and BRCA2genes. In previous studies, the risk of breast cancer was estimated to be 2 to 4 times higher among carriers of PALB2loss-of-function mutations as the risk among nonmutation carriers. Prior to the present study, the exact lifetime risk of breast cancer conferred by such mutations was unknown.

Introduction: Deficiencies in cellular responses to DNA damage can predispose to cancer. Ionizing radiation can cause cluster damage and double-strand breaks (DSBs) that pose problems for cellular repair processes. Three genes (ATM, BRCA1, and BRCA2) encode products that are essential for the normal cellular response to DSBs, but predispose to breast cancer when mutated. Design: To examine the joint roles of radiation exposure and genetic susceptibility in the etiology of breast cancer, we designed a case-control study nested within five population-based cancer registries. We hypothesized that a woman carrying a mutant allele in one of these genes is more susceptible to radiation-induced breast cancer than is a non-carrier. In our study, 700 women with asynchronous bilateral breast cancer were individually matched to 1400 controls with unilateral breast cancer on date and age at diagnosis of the first breast cancer, race, and registry region, and counter-matched on radiation therapy. Each triplet comprised two women who received radiation therapy and one woman who did not. Radiation absorbed dose to the contralateral breast after initial treatment was estimated with a comprehensive dose reconstruction approach that included experimental measurements in anthropomorphic and water phantoms applying patient treatment parameters. Blood samples were collected from all participants for genetic analyses. Conclusions: Our study design improves the potential for detecting gene–environment interactions for diseases when both gene mutations and the environmental exposures of interest are rare in the general population. This is particularly applicable to the study of bilateral breast cancer because both radiation dose and genetic susceptibility have important etiologic roles, possibly by interactive mechanisms. By using counter-matching, we optimized the informativeness of the collected dosimetry data by increasing the variability of radiation dose within the case–control sets and enhanced our ability to detect radiation–genotype interactions.

The impact of maternal drug dependency on neonatal morphometrics was studied in 150 mother-infant and 150 concurrent control pairs. The maternal population included 121 methadone-maintained women, of whom 80 abused other drugs concomitantly; the remaining 29 women used multiple street drugs. Mean birth weight of the passively addicted neonates(PA)(2.80 kg ± 0.55) (SD) differed significantly from controls(C)(3.25 kg ± 0.59)(p<.001). Mean head circumference of PA infants(32.6 cm ± 1.8)also differed significantly from C(33.8 cm ± 1.7)(p < .001). Mean weight and head circumference of PA newborns fell at the 25th percentile for gestational age, differing from the C group value(50-75th percentile)(p<001). Mean gestational age(PA 38.9 wks ± 2.2 vs C 39.3 wks ± 2.3) and prematurity rates(10% PA vs 7% C)did not differ, but IUGR was increased to 20% in the PA group vs 4% C(P < .001). Within the PA group, selected perinatal variables of maternal age, parity, weight gain during pregnancy, polydrug abuse, methadone dosage, and duration of drug and alcohol use were not significantly associated with either birth weight or head circumference.This demonstration of symmetrical IUGR in PA infants and the known association of small head size at birth with reduced neurobehavioral outcome mandates greater concern for “optimal” methadone maintenance during pregnancy.

The impact of maternal drug dependency on weight changes after birth was assessed in 131 passively addicted infants. The maternal population included 40% who took methadone alone and 56% who abused other drugs concurrently with methadone. Abstinence was treated with phenobarbital (PH) in 53 infants and with paregoric (PA) in 45 infants by random design; the remaining 33 infants (C) did not require treatment to control mild abstinence signs. The three groups were comparable as to sex ratio, ethnic distribution, gestational age, and birth weight.Adjusting for birth weight and caloric intake, both PA and PH treated groups of addicted infants lost more weight than the untreated group on days 9-10, at which point untreated babies were discharged; PH-C=94 grams(p <.01),PA-C=96 grams(p<.01). On day 21 the PH group had gained significantly more weight than the PA group(p<.01). When patterns of weight loss and gain were corrected for abstinence severity based on a standard scoring system, both significant differences disappeared completely (r2=.91 on day 9, r2=.86 on day 21). These findings are consistent with the concept that severity of abstinence directly affects weight loss and gain within the first month of life. Infants requiring treatment for moderate or severe abstinence should receive caloric supplementation during that period.