Friedreich's ataxia cardiomyopathy: case based discussion and management issues.

Cardiac involvement is common in Friedreich's Ataxia and is a common cause of premature death. Evidence regarding treatment of congestive heart failure in patients with Friedreich's Ataxia is lacking. The case of a 31-year-old male with advanced Friedreich's Ataxia who presented with an acute diarrhoeal illness and features of acute heart failure is discussed. We then review the reported cardiac manifestations of Friedreich's Ataxia and discuss management options.

Menopause and breast cancer risk.

PIP: Age at menopause and type of menopause from hospital records of breast cancer patients were compared with similar information reported by a national probability sample of women. The national sample comprised 3581 women who responded to the 1960-1962 National Health Examination Survey. The cancer series consisted of 3887 patients selected from those reported to the Connecticut Cancer Registry between 1950 and 1959. No substantial bias was identified when the validity of the comparison and the effect of the relatively large number of breast cancer patients whose menopause histories were deficient were evaluated. Overall, surgically induced menopause was associated with a reduction in breast cancer risk to about 60% of that experienced by women having natural menopause induced before age 35, but induction up to age 50 was protective. There was little effect in the 10 years following the surgical procedure, but substantial reduction occurred in all subsequent periods. Among women with menopause induced before age 35, breast cancer risk stayed as low as 1/3 that expected 30 and more years later. Relative risk of breast cancer increased with age at natural menopause. Women with natural menopause at age 55 or older had twice the breast cancer risk experienced by those whose menopause occurred before age 45. The relative risk of breast cancer associated with late natural menopause was greatest after age 70.^ieng

Socioeconomic status, urine estrogens, and breast cancer risk.

Urine estrogens were measured in 46 women students, ages 15-18, at a middle-class high school in Athens and in 40 women of the same age residing at one of three orphanages in the same city. The lower socioeconomic status (SES) of the latter group was documented by their lower mean height (by 5.2 cm) and weight (by 5.3 kg) relative to the high school students. Both in follicular and luteal phases of the menstrual cycle, the women with lower SES had 50% higher estriol ratios (ratio of the concentration of estriol to the sum of the concentrations of estrone and estradiol). In luteal specimens the concentration of all three major estrogens was higher in the group with low SES than in the women in the other group, but the concentration of estriol was most increased. There was also an indication of less frequent anovular cycles among the women with low SES. These findings are consistent with hypotheses linking either the estriol ratio or the frequency of anovular cycles to breast cancer risk.

PIP: Urine estrogen levels were measured in 46 women students, ages 15-18, at a middle-class high school in Athens, Greece and in 40 women of the same age residing at 1 of 3 orphanages in the same city. The lower (SES) socioeconomic status of the latter group was documented by their lower mean height (by 5.2 cm) and weight (by 5.3 kg) relative to the high school students. Both in follicular and luteal phases of the menstrual cycle, the women with lower SES had 50% higher estriol ratios (ratio of the concentration of estriol to the sum of the concentrations of estrogens and estradiol). In luteal specimens, the concentration of all 3 major estrogens was higher in the group with low SES than in the women in the other group, but the concentration of estriol was most increased. There was also an indication of less frequent anovulan cycles among the women with low SES. These findings are consistent with hypotheses linking either the estriol ratio or the frequency of anovular cycles to breast cancer risk.

Association of breast cancer risk with age at first and subsequent births: a study in the population of the Estonian Republic.

Information on reproductive history was obtained from 362 urban breast cancer patients attending the oncological dispensaries at Tallinn and Tartu, Estonian Republic, and from 694 urban women participating in gynecologic screening programs offered by the same centers. The 2 groups were compared by means of Mantel-Haenszel and logistic regression procedures to estimate age-adjusted odds ratios. Women whose first birth occurred before 20 years of age had a breast cancer risk less than one-third the risk of nulliparous women. Risk increased with increase in age at first birth (AFB) but remained below 1.0 (relative to nulliparae), even in the highest AFB categories. The fertility rate in Estonia during the period of this study was relatively low, which facilitated an evaluation of the effect of births subsequent to the first. After adjustment for AFB, it appeared that in this population subsequent births had a protective effect additional to that conferred by the first birth. Moreover, for women who had only 2 children, the age at the time of birth of the second child was a determinant of that effect. Compared to nulliparous women, the breast cancer odds ratio for uniparous women who had their child before age 25 was 0.62, and the ratio for duoparous women who had both their children under that age was 0.18. Neither lactation nor menarche was a risk factor for breast cancer in this pouplation.

Smoking and hepatitis B-negative primary hepatocellular carcinoma.

Smoking histories were obtained from 79 patients with primary hepatocellular carcinoma (PHC) (of whom 40 were negative and 39 positive for serum hepatitis B surface antigen), 39 patients with liver cancer not primary in the liver (LCNP), and 204 hospitalized controls. All subjects were Caucasians of Greek nationality and residence. No significant difference in smoking habits was found between controls and either PHC patients positive for serum hepatitis B surface antigen or LCNP patients. In contrast, there was a highly significant association between smoking and PHC negative for serum hepatitis B surface antigen (P less than 10(-4)); this association was not accounted for by the greater alcohol consumption of smokers. The risk ratios were 1.3, 2.5, 3.7, and 8.4 for current smokers of 1-10, 11-20, 21-30, and 30+ cigarettes per day.

Endogenous sex hormones, prolactin, and breast cancer in premenopausal women.

Forty-one women with breast cancer and 119 controls participated in a case-control study of the relation of endogenous sex hormones to breast carcinoma in premenopausal women. During the follicular phase of the menstrual cycle, one overnight urine specimen was collected. During the luteal phase, urine and blood specimens were obtained. 17 beta-Estradiol, sex hormone-binding globulin, progesterone, and prolactin were measured in plasma, whereas estrogen metabolites (estrone, estradiol, and estriol) and pregnanediol were assessed in the urine. Breast cancer was associated with high-plasma estradiol and prolactin and with low progesterone. Similar but weaker associations were observed for urinary estrogens and pregnanediol in the luteal phase.

Estrogen profiles of primiparous and nulliparous women in Athens, Greece.

Urine estrogens of 144 primiparous women and 122 nulliparous women of similar age were measured. The primiparae were at least 6 months post pregnancy. The ratio of the estriol concentration to the sum of the concentrations of estrone and estradiol (the estriol ratio) was higher among primiparous women under 25 years of age than among nulliparous women of the same age. The difference was greater in specimens collected in the luteal phase of the menstrual cycle than in those collected in the follicular phase and was statistically significant (P less than 0.05, one-tailed t-test) only in the luteal phase. The high estriol ratios of the primiparous women did not decline with increasing interval after pregnancy, at least up to 24 months. Among the younger women, significantly lower levels of pregnanediol, suggestive of a higher frequency of anovular menstrual cycles, were also seen in the nulliparous women. The findings were consistent with the hypothesis that the protective effect against breast cancer of a full-term pregnancy at an early age operates either through a change in the pattern of estrogen metabolism induced by the pregnancy or through a change in the frequency of ovular cycles.

Elevated urine estrogen and pregnanediol levels in daughters of breast cancer patients.

Urine levels of three major estrogens and of pregnanediol were measured for 76 nulliparous daughters of breast cancer patients and for 115 control women of similar age and parity. Concentrations of estrone and estradiol tended to be higher in the daughters of breast cancer patients than in the controls; total estrogens were elevated in both phases than in the controls; total estrogens were elevated in both phases of the menstrual cycle and significantly so in the luteal phase. There was little difference between the daughters and the controls in estriol ratios--the ratios of the concentration of estriol to the sum of the concentrations of estrone and estradiol. Pregnanediol levels were higher in the daughters than in the controls.

Oral contraceptive use and fibrocystic breast disease of different histologic classifications.

The relationship between oral contraceptive (OC) use and occurrence of fibrocystic breast disease (FBD) of different histologic classifications was evaluated with data from a cohort study. Biopsy specimens from 232 women with FBD were classified into different atypia categories. In 96 matched pairs of OC users and nonusers, atypia scores were lower in users than in nonusers. Women without breast diseases (500 OC users and 500 nonusers) were sampled from the original cohort to form a two-stage "anamorphic" study with the 232 cases of FBD. The previously shown inverse association between OC use and FBD occurrence was present and increased with increased length of OC use. However, the "protective effect" of OC use did not vary for different histologic classifications of FBD. The findings from both paired and anamorphic analyses of the data are not consistent with the hypothesis that the use of OC is associated with decreased frequency only of FBD with minimal epithelial atypia.

Urine estrogens, frequency of ovulation, and breast cancer risk: case-control study in premenopausal women.

Urine specimens from 94 premenopausal women with breast cancer and from 70 control women have been compared with respect to concentration of the three major estrogen fractions and to frequency of ovulation as assessed by urine pregnanediol. The probability of anovulation (0.14 in the breast cancer patients and 0.09 among the controls) was not significantly higher among the women with breast cancer (P approximately 0.30). However, there was a positive association between urine estrogen concentration and breast cancer risk. The association was statistically significant (P less than 0.05) for each of the three estrogens measured and in both the follicular and the luteal phases of the menstrual cycle; the relative risk increased from 1 in the referent category (less than 5 micrograms estrogen/g creatinine) to about 3 in the highest category (greater than or equal to 15 micrograms estrogen/g creatinine). The association between urine estrogens and breast cancer risk was consistently stronger when the comparison was restricted to specimens collected in menstrual cycles during which ovulation occurred.

Risk of breast cancer in relation to lifetime alcohol consumption.

BACKGROUND: Although an association between alcohol consumption and risk of breast cancer has been observed in many studies, questions of major importance remain, including the nature of the dose-response relationship and the effects of drinking at various periods in life. PURPOSE: Our goal was to address the issues listed above with a large case-control study. METHODS: We conducted a population-based case-control study in Maine, Massachusetts (excluding the four counties that include metropolitan Boston), New Hampshire, and Wisconsin. Case patients were eligible if their diagnosis of invasive breast cancer was first reported to one of the four statewide cancer registries during the period of 1988 through 1991. During the accrual period, 11,879 potentially eligible case patients and 16,217 control subjects were identified. After excluding ineligible women from the study, telephone interviews were obtained from 6888 case patients and 9424 control subjects. Complete data for recent alcohol consumption, and thus final eligibility for study participation, were determined for 6662 case patients and 9163 control subjects. The average age at time of interview was 58.7 years. The questions on alcohol use addressed average consumption during five periods of the subjects' lives: ages 16-19, 20-29, 30-39, 40-59, and 60-74 years. Similar responses from 211 control subjects upon reinterview 6-12 months later were taken to be indicative of the reliability of the questionnaire used in this study. RESULTS: Lifetime average alcohol consumption (measured as the average grams per day consumed from age 16 to the recent past) and recent alcohol consumption (average grams per day consumed in the previous age interval) were associated with risk of developing breast cancer. The multivariate relative risk of breast cancer, in those who drink compared with abstainers, associated with average lifetime consumption of 12-18 g/day of alcohol (about one drink) was 1.39 (95% confidence interval [CI] = 1.16-1.67), of 19-32 g/day (about two drinks) was 1.69 (95% CI = 1.36-2.10), of 33-45 g/day (about three drinks) was 2.30 (95% CI = 1.51-3.51), and of greater than or equal to 46 g/day (four or more drinks) was 1.75 (95% CI = 1.16-2.64) (P for trend < .0001). The multivariate relative risk per 13 g/day (about one drink) of alcohol consumed before 30 years of age was 1.09 (95% CI = 0.95-1.24), whereas the relative risk associated with recent consumption of 13 g/day was 1.21 (95% CI = 1.09-1.34). CONCLUSIONS: In these data, alcohol consumption was clearly related to breast cancer risk. Risk appeared to increase even at moderate levels of consumption. For women of all ages combined, consumption before 30 years of age was not an important determinant of risk.

Maternal age and birth rank of women with breast cancer.

Data from a large international case-control study of breast cancer suggested that women born to young mothers had a 25% lower risk of breast cancer. The association was not secondary to a tendency for these women themselves to have had children at early ages. The data provided no indication of a meaningful association between breast cancer risk and birth rank. Confounding was controlled by stratification according to a summary confounder score.

Estrogen profiles of premenopausal women with breast cancer.

Population surveys have demonstrated an inverse relationship between breast cancer incidence rates and the urine "estriol ratio," the concentration of estriol relative to the sum of the concentrations of estrone and estradiol. In this study, the urine estriol ratio was evaluated in premenopausal breast cancer patients and control women from Boston and San Francisco. Although at least 2 years had passed since last use of oral contraceptives, women with a history or oral contraceptive use for 19 months or longer excreted estrogen in low concentrations compared to nonusers and so were excluded. Among the remaining 73 cases and 55 controls, the cases had lower estriol ratios and higher estrone and estradiol levels than did controls. However, these differences, which averaged about 10%, were not statistically significant. Thus the hypothesis that a low estriol ratio is a cause of breast cancer is given only minimal support. Among women in their 40's, the excretion of estrogens is subject to many influences and is difficult to study. The many determinants of estrogen excretion, including age and oral contraceptive use, should be accommodated in the design of future studies of the estriol ratio.

The incidence of seizures among children with autistic symptoms.

The authors examined 183 children with autistic symptoms and found that the age-specific incidence rates of seizures in this sample were between 3 and 28 times the rates for children in the general population. The subjects classified as totally autistic were at high risk of developing seizure from early childhood well into adolescence, but especially so at puberty. The partially autistic children had an increased risk of seizures only up to age 10. The authors suggest that the high incidence of seizures at puberty observed in this study may be specific to children with total autistic symptomatology and may represent a distinct pathological process associated with autism.

A prospective cohort study of nutrient intake and age at menarche.

A cohort of 213 girls (aged 10 y, range +/- 9 mo) whose parents reported their dietary intakes (including nutritional supplements) using a semiquantitative food frequency questionnaire, was followed for 4 y until 82% of the 194 parents who responded to follow-up letters had reported that their daughters had had their first menstrual periods. The relative risk (RR) of menarche before age 12.5 y was 2.0 [95% confidence interval (CI) = 1.1-3.8] for the tallest girls (greater than 150 cm) compared with the shortest girls (less than 130 cm). The RR was 2.1 (95% CI = 1.1-3.8) for the fattest girls [Quetelet's index of relative weight (in kg/m2) greater than 19] vs the leanest girls (less than 15). After adjusting for height and Quetelet's index, menarcheal age was not associated with intake of energy nor energy-adjusted intake of protein, fat, or carbohydrate. The overall results are consistent with the hypothesis that nutritional factors influence age at menarche mainly through their effects on accumulation of adipose tissue.

Overview of studies on endometrial cancer and other types of cancer in humans: perspectives of an epidemiologist.

The epidemiologic studies relevant to the hypothesis that exposure to tamoxifen is associated with risk of cancer of the endometrium and perhaps other organs are described, summarized, and evaluated. One large body of data comes from the randomized trials of tamoxifen as a therapeutic agent against established breast cancer. With respect to endometrial cancer, these studies suggest that an association with tamoxifen use exists. However, the evidence is far from conclusive: the association is not seen in all the reported randomized trials, there appears to be a deficit of endometrial cancer in the comparison groups in two of the most important studies, none of the studies has adequately addressed the problems of confounding by prior hysterectomy and/or hormone replacement therapy, and none addresses the issue of detection bias. One nonrandomized cohort study shows findings similar to those from the randomized studies but also has similar problems, in addition to the problems associated with the lack of randomization of exposure. Case control studies were also considered, with the conclusion that they show results similar to those from the cohort studies (randomized and nonrandomized); that is, that the evidence leans toward the view that there is an association between tamoxifen use and endometrial cancer risk, but that it is incomplete and inconclusive. The issues of detection bias and potential confounding variables are better dealt with in the case control studies than in the cohort studies. One important question raised in one of the major case control studies is whether the apparent association is stronger with total dose of tamoxifen or with duration of use. Some investigators have reported an association between tamoxifen use and cancers other than those of the endometrium, but for none of these cancers is the evidence consistent between studies and the associations lack the theoretical underpinning that might be invoked for endometrial cancer, if in fact the existence of an association were established empirically for the latter site.

Some recent issues in low-exposure radiation epidemiology.

Three areas of activity in the field of low-level radiation epidemiology have been reviewed. They concern the questions of cancer risk related to antenatal X-ray exposure, occupational radiation exposure, and residence in areas of real or supposed increased levels of radiation. Despite the a priori unlikelihood of useful information developing from studies in any of these areas, such investigations are being pursued, and the results are proving to be stimulating. Much important information will be forthcoming in the near future.

A code of ethical conduct for epidemiologists?

The absence of a written code of ethics in epidemiology does not imply that epidemiologists have been behaving unethically. Rather, there are unwritten standards taught by precept and enforced at the level of science (e.g. through funding, publication, etc.) and the courts. The question is whether it would be desirable to have a set of guidelines in written form. Those epidemiologists pressing for a written code perceive the theoretical advantage of one. Those opposed are concerned with the feasibility of developing an effective, enforceable code. Although I do not underestimate the difficulty of the task, the benefit of having written guidelines seems to me comparable to that of having written laws, albeit incomplete and imperfect--i.e. to inform the individual how his or her actions would be viewed in terms of professional norms. Steps have already been taken by the Society for Epidemiologic Research in cooperation with the American College of Epidemiology to draft a code of ethics for epidemiologists. Broad participation in this endeavor will be required if it is to succeed.

Radiation dose and second cancer risk in patients treated for cancer of the cervix.

The risk of cancer associated with a broad range of organ doses was estimated in an international study of women with cervical cancer. Among 150,000 patients reported to one of 19 population-based cancer registries or treated in any of 20 oncology clinics, 4188 women with second cancers and 6880 matched controls were selected for detailed study. Radiation doses for selected organs were reconstructed for each patient on the basis of her original radiotherapy records. Very high doses, on the order of several hundred gray, were found to increase the risk of cancers of the bladder [relative risk (RR) = 4.0], rectum (RR = 1.8), vagina (RR = 2.7), and possibly bone (RR = 1.3), uterine corpus (RR = 1.3), cecum (RR = 1.5), and non-Hodgkin's lymphoma (RR = 2.5). For all female genital cancers taken together, a sharp dose-response gradient was observed, reaching fivefold for doses more than 150 Gy. Several gray increased the risk of stomach cancer (RR = 2.1) and leukemia (RR = 2.0). Although cancer of the pancreas was elevated, there was no evidence of a dose-dependent risk. Cancer of the kidney was significantly increased among 15-year survivors. A nonsignificant twofold risk of radiogenic thyroid cancer was observed following an average dose of only 0.11 Gy. Breast cancer was not increased overall, despite an average dose of 0.31 Gy and 953 cases available for evaluation (RR = 0.9); there was, however, a weak suggestion of a dose response among women whose ovaries had been surgically removed. Doses greater than 6 Gy to the ovaries reduced breast cancer risk by 44%. A significant deficit of ovarian cancer was observed within 5 years of radiotherapy; in contrast, a dose response was suggested among 10-year survivors. Radiation was not found to increase the overall risk of cancers of the small intestine, colon, ovary, vulva, connective tissue, breast, Hodgkin's disease, multiple myeloma, or chronic lymphocytic leukemia. For most cancers associated with radiation, risks were highest among long-term survivors and appeared concentrated among women irradiated at relatively younger ages.