Association between HIV infection and cervical neoplasia: implications for clinical care of women at risk for both conditions.

OBJECTIVE: Both AIDS and cervical neoplasia (CN) can result from sexual transmission of HIV infection and may affect similar groups of women. Available data on the association between AIDS and CN have practical implications for gynecological care. We review these data to provide an estimate of the magnitude of the association between CN and HIV infection. DESIGN: Twenty-one studies were reviewed, including reports and abstracts published from January 1986 to July 1990. Of these, five included a comparison group and had sufficient data for inclusion in the analysis. RESULTS: All five controlled studies reported a significant association between HIV infection and CN. One included women with both intraepithelial and invasive lesions; the other four considered women with intraepithelial lesions only. The summary odds ratio indicated that the odds of HIV-infected women having CN are 4.9 (95% confidence interval, 3.0-8.2) times that of HIV-negative women. CONCLUSIONS: Research is needed to clarify etiological relationships and the role of human papillomavirus in the causal pathway of the observed association. Meanwhile, available data are sufficient to encourage regular Papanicolaou's smear screening of HIV-infected women, and HIV testing and counseling of women with CN considered at risk for HIV infection.

Menstrual timing of treatment for breast cancer.

Although the hormone dependency of breast cancer has been recognized for nearly a century, the influence on disease progression of cyclical hormonal levels among premenopausal women has not been extensively researched. The findings of recent studies, assessing the effect on prognosis of the hormonal milieu at the time of surgery, have been conflicting. However, several reports have noted improved survival among patients with positive, axillary lymph nodes surgically treated in the later phase of the menstrual cycle when progesterone levels are elevated. Biologic support for the influence of menstrual timing is provided by cyclical patterns of cell division and cell death observed in normal breast tissue as well as potential tumor cell dissemination during surgery among patients with positive axillary nodes. Immune parameters, which also respond to cycling endogenous hormones, may influence the metastatic potential of circulating tumor cells. Comparisons among studies of menstrual timing of surgery have been complicated by differences in cycle divisions, extent of primary surgery, frequency of adjuvant therapy, duration of follow-up, and analytic procedures. Although several clinicians are now scheduling breast surgery of premenopausal women in relation to day of the menstrual cycle, a majority of surgeons have deferred consideration of menstrual timing until additional research is available. While waiting 5-10 years for the results of prospective studies, additional retrospective analyses, using carefully collected data, may provide clinical guidance. With increasing concern for issues related to women's health, multidisciplinary studies will be required to adequately characterize the influence of the menstrual cycle and other aspects of women's reproductive physiology on breast cancer and other medical conditions.

One-year follow-up of infants with abstinence-associated seizures.

Fourteen infants with neonatal abstinence-associated seizures were assessed neurodevelopmentally during the first year of life. Despite abnormal neurologic examination results in eight of 12 infants at 2 to 4 months of age, nine of 12 infants had normal neurologic examination results at follow-up (two infants were unavailable for follow-up; one infant died of acquired immunodeficiency syndrome). Nine neonatal electroencephalograms were abnormal; seven of eight of these abnormal tracings normalized during the follow-up period. Bayley developmental scores remained normal during the first year of life and did not differ from either passively addicted infants without seizures or from published population norms. This short-term favorable prognosis for abstinence-associated seizures differs from that associated with neonatal seizures due to other causes. This observed improvement in neurologic function may be based on replenishment of neurotransmitters following transient depletion in the neonatal period.

p53 haplotype determination in breast cancer.

Inheritance of certain germ line haplotypes consisting of three biallelic polymorphisms of p53 has been proposed as a risk factor for breast cancer and colorectal cancer [A. Själander et al., Carcinogenesis (Lond.), 17: 1313-1316, 1996, and Carcinogenesis (Lond.), 16: 1461-1464, 1995]. In their studies, pairwise haplotypes of these three polymorphisms were estimated. Extended haplotypes were further projected from the pairwise combinations. To overcome the necessity to estimate pairwise and extended haplotype frequencies, a PCR method has been developed to determine the absolute extended p53 haplotypes in diploid genomes. The method requires allele-specific PCR, confirmed by restriction analysis, and successive amplicon analysis. It has been applied to a nested case-control study of breast cancer (284 subjects; 99 cases and 185 controls; 182 Caucasians, 56 Hispanics, and 46 African-Americans). Evidence is presented that minor variants of the intron 3, codon 72, and intron 6 polymorphisms were moderately elevated in Caucasian breast cancer cases (intron 3, P = 0.03 for genotype and P = 0.01 for allelic frequency; codon 72, P = 0.07 for genotype and P = 0.054 for allelic frequency; and intron 6, P = 0.02 for genotype and P = 0.02 for allele frequency). Accordingly, analysis of haplotype distributions suggested an association of minor p53 haplotypes with breast cancer risk in Caucasians (P = 0.07). The relative allelic frequencies in breast cancer cases compared with controls also differed by age and menopausal status; the 1-2-1 haplotype was overrepresented in postmenopausal cases (P = 0.02) and cases older than 50 years (P = 0.02), whereas the other minor haplotypes (1-1-2 and rare variants) were overrepresented in premenopausal cases (P = 0.003) and cases 50 years of age and younger (P = 0.02). Genotype distributions at each locus and for all control groups were consistent with Hardy-Weinberg equilibria. Differences in haplotype distribution were associated with ethnicity (Caucasians versus African-Americans and Caucasians versus Hispanics, P < 0.001). The new haplotyping method may be useful in the study of gene-environment interactions.

The relationship between body mass and breast cancer among women enrolled in the Cancer and Steroid Hormone Study.

We examined the relationship between body mass [weight (kg)/height (m)2] and breast cancer using data from the Cancer and Steroid Hormone Study. The study compared 4323 women aged 20-54 years with newly diagnosed breast cancer identified through population-based tumor registries with 4358 women randomly selected from the general population of the same geographic areas. Among naturally menopausal women, risk of breast cancer increased with increasing body mass index (BMI); those severely overweight (BMI greater than or equal to 32.30) had nearly 3-fold higher risk of breast cancer compared with women in the leanest category (BMI less than 20.00). This positive association appeared stronger with increasing years since menopause and in women who had ever used estrogen replacement therapy. A positive association between body mass and breast cancer risk also was observed among premenopausal women; however, risk estimates were substantially lower. Substantial weight gain from adolescence to adulthood was a more important risk factor than lifelong obesity. Prevalence of obesity increases with age; our results suggest that interventions that prevent this trend could have an important effect on breast cancer risk, especially during the menopausal years.

Early abortion and breast cancer risk among women under age 40.

In New York State, incidence of cancer and fetal death are reportable health events mandated by state law. These data enabled a population-based record linkage study of the effect of early pregnancy termination on breast cancer risk to be conducted. In upstate New York 1451 cases under age 40 were reported to the Cancer Registry during 1976-1980. Cases were matched with 1451 population controls by year of birth and by residence using zip codes. All names including those changed by marriage were matched with the reports of fetal deaths occurring between 1971 and 1980. Matched pairs analyses revealed an excess of early pregnancy terminations among cases in all categories. Odds ratios (OR) were significantly elevated among those with an induced abortion (OR = 1.9) and a spontaneous abortion (OR = 1.5). Elevated risks were also noted for consecutive abortion events without intervening livebirths.

Epidemiology of breast carcinoma: Age, menstrual status, and exogenous hormone usage in patients with lobular carcinoma in situ.

Lobular carcinoma in situ (LCIS) of the breast is a neoplastic condition associated with premenopausal women and it is largely for this reason that LCIS has been considered to be an estrogen-dependent lesion. In this report we present the results of a study of age at diagnosis, menstrual status, and exogenous hormone usage in 59 women with LCIS and in 190 patients with duct carcinoma. When LCIS was associated with duct carcinoma, 46% of patients were postmenopausal and in the group that also had infiltrating lobular carcinoma 71% were postmenopausal. Nine of 39 (23%) patients whose only carcinoma was LCIS were postmenopausal, 56% were premenopausal and 21% were menopausal. Seven of the nine postmenopausal women had never used a hormone-containing medication. In a comparison group with only duct carcinoma, 59.4% were postmenopausal and 35.2% had taken a hormone preparation. The high proportion of postmenopausal patients with LCIS leaves considerable doubt as to whether all lesions termed LCIS are equally dependent on estrogens at all stages in their evolution. We found no evidence to link LCIS with exogenous hormone usage in postmenopausal women. Prospective studies of hormone levels in patients with LCIS and in their relatives may provide an explanation for persistence of the lesion in postmenopausal women and could aid in identifying women at risk of developing invasive carcinoma.

Health promotion and disease prevention in HMOs: a survey of newly established IPAs in New York City.

Independent Practice Associations (IPAs) are the fastest growing segment of the Health Maintenance Organization (HMO) industry, but little is known about their provision of health promotion and disease prevention to subscribers. To examine the extent to which IPA policies encourage health promotion and disease prevention, we interviewed medical directors and other senior administrators of six newly developing IPA-HMOs in New York City. We also reviewed promotional literature to assess how extensively health promotion and disease prevention were marketed to the potential subscriber. Although medical protocols for preventive screening exist in most IPAs, compliance with guidelines is left largely to the individual physician's judgment for implementation. IPA respondents suggested that their physician panels are oriented toward prevention, but there is uncertain evidence in this regard, and incentive payments could discourage referrals for screening. Health education programs are sporadic. Health promotion and disease prevention do not appear to be a high priority among six newly established IPAs in New York City. We recommend several steps that would encourage IPA-HMOs to increase their health promotion activities.

Clinical and demographic features of patients admitted to a new chemical dependency program in New York City.

We reviewed the clinical and demographic features of all 128 patients who were admitted to a new 28-day in-patient chemical dependency program in New York City during the first six months of operation. The medical records were reviewed retrospectively. Alcohol, cocaine, heroin, marijuana and diazepam were the most common substances abused. Parenteral drug abuse at any time was reported by 51 (40%) of the 128 patients, and 42 (33%) were current parenteral drug abusers. Abusers of alcohol only were significantly older than parenteral drug abusers or non-parenteral drug abusers. Patients who were employed at admission had a significantly longer mean length of stay and a higher rate of completion of the program than those who were not employed. We conclude that: (1) parenteral drug abuse is likely to be commonly seen in chemical dependency programs serving middle-income patients in urban areas, (2) alcohol abusers are older than abusers of other drugs, (3) a higher educational level is associated with successful completion of the chemical dependency program, and (4) evaluation programs are needed in all types of chemical dependency treatment.

The timing of breast cancer surgery during the menstrual cycle.

A number of recent studies have suggested that survival among premenopausal women after primary treatment of breast cancer may be affected by the estimated hormonal milieu at the time of surgery, especially in those with axillary lymph node metastases. The concept has created considerable controversy and has resulted in the publication of many negative reports. However, several biological mechanisms have been suggested for the observed survival advantage. These include cyclical patterns of immune function, as well as cell division and cell death, that correlate with hormonal fluctuations of the menstrual cycle. Comparisons among studies of timing have been complicated by differences in menstrual cycle divisions, variability in the sources of study populations, limited availability of menstrual history data, and changes over the past 2 decades in primary and adjuvant breast cancer therapy. Several recent publications have been enhanced by the availability of serum collected at the time of surgery that enables accurate measurement of the hormonal milieu. In these studies, the likelihood of misclassification by menstrual cycle phase is reduced, and dependence on recalled menstrual history is eliminated. High progesterone levels have been associated with improved survival. These findings have encouraged some to suggest that perioperative administration of progesterone or tamoxifen (Nolvadex) may provide a preventive avenue comparable to scheduling surgery during the luteal phase. Further multidisciplinary studies are needed, however, to clarify the influence of the naturally occurring or medically induced hormonal milieu at the time of breast cancer surgery on survival in premenopausal women.

Validation study of the LAMBDA model for predicting the BRCA1 or BRCA2 mutation carrier status of North American Ashkenazi Jewish women.

LAMBDA is a model that estimates the probability an Ashkenazi Jewish (AJ) woman carries an ancestral BRCA1 or BRCA2 mutation from her personal and family cancer history. LAMBDA is relevant to clinical practice, and its implementation does not require a computer. It was developed principally from Australian and UK data. We conducted a validation study using 1286 North American AJ women tested for the mutations 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2. Most had a personal or family history of breast cancer. We observed 197 carriers. The area under the receiver operator characteristic (ROC) curve (a measure of ranking) was 0.79 [95% confidence interval (CI) = 0.77-0.81], similar to that for the model-generating data (0.78; 95% CI = 0.75-0.82). LAMBDA predicted 232 carriers (18% more than observed; p = 0.002) and was overdispersed (p = 0.009). The Bayesian computer program BRCAPRO gave a similar area under the ROC curve (0.78; 95% CI = 0.76-0.80), but predicted 367 carriers (86% more than observed; p < 0.0001), and was substantially overdispersed (p < 0.0001). Therefore, LAMBDA is comparable to BRCAPRO for ranking AJ women according to their probability of being a BRCA1 or BRCA2 mutation carrier and is more accurate than brcapro which substantially overpredicts carriers in this population.

Possible related risks to breastfeeding.

Animal studies have identified a mouse mammary tumor agent transmitted through lactation that increases the incidence and reduces the age for tumor development in offspring. A similar viral particle has been detected with greater frequency in the milk of humans with a family history of breast carcinoma than in the milk of those with no history. Animal studies also indicate that a male offspring who has been breastfed, at low risk himself, could possibly transmit the agent through seminal fluid. The health team is encouraged to consider these factors when discussing infant feeding methods with women who have a positive family history of breast carcinoma.

Atypical carcinoid tumor of the larynx. A critical review of the literature.

To better characterize the clinical and pathological features of the laryngeal atypical carcinoid (LAC), 127 of the published cases were analyzed. The LAC had a predilection for males (3 m:1 f), with a peak incidence in the 6th and 7th decades of life. Seventy-eight percent of patients with a relevant clinical history were smokers. Most tumors presented in the supraglottic larynx (96%) and the mean size of the measured primary lesions was 1.6 cm. The tumors were frequently argyrophil (97% of those so stained), rarely argentaffin (2 cases), and on immunohistochemistry were often reactive when stained for keratins (96%), chromogranin A (94%), and calcitonin (80%). Surgical resection was the principal modality of treatment. Of the 127 cases, metastasis to neck nodes were found in 43%, to skin or subcutaneous sites in 22%, and to distant sites in 44%. Of the 119 patients with follow-up, 49% died with tumor. The cumulative proportion surviving was 48% at 5 years and 30% at 10 years, and there were significantly worse survival rates among patients with tumors larger than 1 cm, and for patients developing tumor involvement of skin and subcutaneous tissues. Adjuvant radiation did not affect survival rates.

Evaluation of glare in normal and pseudophakic subjects.

It has been difficult to document the subjective complaint of glare. Devices to quantify this problem include the Miller-Nadler glare tester (MNGT) and the brightness acuity tester (BAT). We used these devices to evaluate a group of pseudophakic subjects (15 eyes with posterior-chamber intraocular lenses) and a group of normal subjects (32 low myopic eyes). A subject's ability to discern contrast with a background glare source is measured as a percentage with the MNGT. The number of lines lost on the Snellen chart as a light is brightened progressively over the line of vision is the BAT score. A Wilcoxon signed-ranks test showed no significant change without correction (SC) to with correction (CC) with the BAT but was significant at P less than .001 with the MNGT. The BAT scores for the normal group CC (mean, 0.59) compared with the intraocular lens group CC (mean, 3.0) with the Mann-Whitney U test showed a statistically significant difference (P less than .001). There also was a difference with the MNGT between normal group CC (mean, 5.1%) and pseudophakic group CC (mean, 8.9%) at P less than .001). These results suggest that pseudophakic subjects have marked visual dysfunction secondary to glare. The BAT, however, showed a more easily quantifiable change unaffected by spectacle correction.

Association of vaginal smear cytology with menstrual status in breast cancer.

The relationship of clinically defined menstrual categories and an independent measure of hormonal stimulation, maturation index of vaginal smear cytology, was studied. Analysis of 596 smears obtained at the time of breast cancer diagnosis revealed a statistically significant association between menstrual status and maturation index. However, within each menstrual group varying levels of maturation were noted. Estrogenic effect in the absence of exogenous hormone administration was found in 11% of patients following bilateral oophorectomy and among 24% of women whose natural menopause occurred 20 years or longer prior to diagnosis. Endogenous estrogen production appears to continue for many years among some women. Clinical factors such as obesity, diabetes and/or hypertension may stimulate high squamous maturation in some patients. Others of the same age and with similar clinical histories were found to have atrophic smears. The differences in maturation index may be due to individual variations in: endogenous hormone levels; sensitivity of the vaginal mucosa to similar hormonal stimuli; use of certain medications; or unidentified exogenous factors. The maturation index was found to be significantly associated with the following prognostic factors: weight relative to height, tumor size and estrogen receptor content of the primary tumor. These findings indicate that vaginal smear cytology may define specific subsets within menstrual categories which may be relevant to therapy and prognosis in breast cancer.

Neonatal neurologic and electroencephalographic effects of intrauterine cocaine exposure.

Thirty-nine infants with intrauterine exposure to cocaine were examined for neurologic and electroencephalographic (EEG) abnormalities. Of the 39 infants, 34 displayed central nervous system irritability, but only two of the infants required sedation. The EEGs were abnormal in 17 of 38 infants during the first week of life; abnormalities were characterized as showing central nervous system irritability. The EEG abnormalities could not be predicted on the basis of clinical neurologic dysfunction or perinatal variables. On follow-up, 9 of the 17 abnormal EEGs remained abnormal during the second week of life. One infant had an abnormal first EEG at 13 days of age. By 3 to 12 months of age, however, 9 of the 10 previously abnormal tracing had normalized and one is pending. These transient clinical and EEG abnormalities may be the result of changes in neurotransmitter availability and function.

Carcinoma of the male breast: analysis of prognosis compared with matched female patients.

BACKGROUND: Considerable debate exists concerning the prognosis of breast cancer in male patients compared with that in female patients. Some studies have observed worse prognosis for men; others suggested the higher mortality rates were primarily due to delayed diagnosis. METHODS: Survival time from diagnosis with invasive disease to death resulting from breast cancer of 58 men treated between 1973 and 1989 was compared with survival of 174 women treated between 1976 and 1978 who were matched by stage of disease and age at diagnosis. All patients were treated by mastectomy and axillary dissection. RESULTS: Tumors were < or = 2 cm in 70% of cases and 55% were free of axillary metastases. The histology of the tumors differed significantly by gender (p < 0.05). Significantly more men had estrogen receptor-positive tumors (87%) than did women (55%, p < 0.001). Survival at 10 years was similar for male and female patients. Multivariate analysis controlling for tumor size, number of positive axillary lymph nodes, age at diagnosis, histology, and receptor status indicated no significant difference in survival of male compared with female patients. CONCLUSIONS: These data conflict with the conventional wisdom that breast cancer in men carries a worse prognosis than the disease in women. Although histology of the tumor and receptor status differed by gender, these factors did not have an impact on survival in these paired patients. Our data indicate that breast carcinoma in males is not biologically more aggressive than in females.

Obesity at diagnosis of breast carcinoma influences duration of disease-free survival.

OBJECTIVE: To study disease-free survival at 10 years in relation to obesity at the time of diagnosis. DESIGN: A prospective study of consecutively treated patients with primary breast cancer. SETTING: Memorial Sloan-Kettering Cancer Center, New York. PATIENTS: Nine hundred twenty-three women treated by mastectomy and axillary dissection. MAIN RESULTS: Women who were obese (25% or more over optimal weight for height) at the time of primary breast cancer treatment were at significantly greater risk for recurrence (42%) compared with nonobese patients (32%) 10 years after diagnosis (P less than 0.01). In multivariate analyses, obesity remained a statistically significant prognostic factor after controlling for measured tumor size, number of positive axillary lymph nodes, age at diagnosis, and adjuvant chemotherapy with a hazard ratio of 1.29 (95% CI, 1.0 to 1.67). When analyses were restricted to the 557 patients free of lymph node metastases, the hazard ratio of recurrence associated with obesity was 1.59 (CI, 1.06 to 2.39); 32% of obese patients developed recurrent disease compared with 19% of nonobese women. CONCLUSIONS: Obesity at the time of diagnosis is a significant prognostic factor that may limit the reduction in breast cancer mortality attainable through detection at an early stage of disease. Because obesity and the risk for breast cancer increase with age, interventions that encourage weight control may influence breast cancer survival rates.