The impact of musculoskeletal ill health on quality of life and function after critical care: a multicentre prospective cohort study.

Physical disability is a common component of post-intensive care syndrome, but the importance of musculoskeletal health in this population is currently unknown. We aimed to determine the musculoskeletal health state of intensive care unit survivors and assess its relationship with health-related quality of life; employment; and psychological and physical function. We conducted a multicentre prospective cohort study of adults admitted to intensive care for > 48 h without musculoskeletal trauma or neurological insult. Patients were followed up 6 months after admission where musculoskeletal health state was measured using the validated Musculoskeletal Health Questionnaire score. Of the 254 participants, 150 (59%) had a musculoskeletal problem and only 60 (24%) had received physiotherapy after discharge. Functional Comorbidity Index, Clinical Frailty Scale, duration of intensive care unit stay and prone positioning were all independently associated with worse musculoskeletal health. Musculoskeletal health state moderately correlated with quality of life, rs = 0.499 (95%CI 0.392-0.589); anxiety, rs = -0.433 (95%CI -0.538 to -0.315); and depression, rs = -0.537 (95%CI -0.631 to -0.434) (all p < 0.001). Patients with a musculoskeletal problem were less physically active than those without a problem (median (IQR [range]) number of 30 min physical activity sessions per week 1 (0-3.25 [0-7]) vs. 4 (1-7 [0-7]), p < 0.001, respectively). This study found that musculoskeletal health problems were common after intensive care unit stay. However, we observed that < 25% of patients received physical rehabilitation after discharge home. Our work has identified potential high-risk groups to target in future interventional studies.

Gentamicin Applied to the Oval Window Suppresses Vestibular Function in Guinea Pigs.

Intratympanic gentamicin therapy is widely used clinically to treat the debilitating symptoms of Ménière's disease. Cochleotoxicity is an undesirable potential side effect of the treatment and the risk of hearing loss increases proportionately with gentamicin concentration in the cochlea. It has recently been shown that gentamicin is readily absorbed through the oval window in guinea pigs. The present study uses quantitative functional measures of vestibular and cochlea function to investigate the efficacy of treating the vestibule by applying a small volume of gentamicin onto the stapes footplate in guinea pigs. Vestibular and cochlea function were assessed by recording short latency vestibular evoked potentials in response to linear head acceleration and changes in hearing threshold, respectively, 1 and 2 weeks following treatment. Histopathology was analyzed in the crista ampullaris of the posterior semi-circular canal and utricular macula in the vestibule, and in the basal and second turns of the cochlea. In animals receiving gentamicin on the stapes footplate, vestibular responses were significantly suppressed by 72.7 % 2 weeks after treatment with no significant loss of hearing. This suggests that the vestibule can be treated directly by applying gentamicin onto the stapes footplate.

Influence of cochleostomy and cochlear implant insertion on drug gradients following intratympanic application in Guinea pigs.

Locally applied drugs can protect residual hearing following cochlear implantation. The influence of cochlear implantation on drug levels in the scala tympani (ST) after round window application was investigated in guinea pigs using the marker trimethylphenylammonium (TMPA) measured in real time with TMPA-selective microelectrodes. TMPA concentration in the upper basal turn of the ST rapidly increased during implantation and then declined due to cerebrospinal fluid entering the ST at the cochlear aqueduct and exiting at the cochleostomy. The TMPA increase was found to be caused by the cochleostomy drilling if the burr tip partially entered the ST. TMPA distribution in the second turn was less affected by implantation procedures. These findings show that basal turn drug levels may be changed during implantation and the changes may need to be considered in the interpretation of therapeutic effects of drugs in conjunction with implantation.

Gentamicin administration on the stapes footplate causes greater hearing loss and vestibulotoxicity than round window administration in guinea pigs.

Clinically, gentamicin has been used extensively to treat the debilitating symptoms of Mèniére's disease and is well known for its vestibulotoxic properties. Until recently, it was widely accepted that the round window membrane (RWM) was the primary entry route into the inner ear following intratympanic drug administration. In the current study, gentamicin was delivered to either the RWM or the stapes footplate of guinea pigs (GPs) to assess the associated hearing loss and histopathology associated with each procedure. Vestibulotoxicity of the utricular macula, saccular macula, and crista ampullaris in the posterior semicircular canal were assessed quantitatively with density counts of hair cells, supporting cells, and stereocilia in histological sections. Cochleotoxicity was assessed quantitatively by changes in threshold of auditory brainstem responses (ABR), along with hair cell and spiral ganglion cell counts in the basal and second turns of the cochlea. Animals receiving gentamicin applied to the stapes footplate exhibited markedly higher levels of hearing loss between 8 and 32 kHz, a greater reduction of outer hair cells in the basal turn of the cochlea and fewer normal type I cells in the utricle in the vestibule than those receiving gentamicin on the RWM or saline controls. This suggests that gentamicin more readily enters the ear when applied to the stapes footplate compared with RWM application. These data provide a potential explanation for why gentamicin preferentially ablates vestibular function while preserving hearing following transtympanic administration in humans.

Direct entry of gadolinium into the vestibule following intratympanic applications in Guinea pigs and the influence of cochlear implantation.

Although intratympanic (IT) administration of drugs has gained wide clinical acceptance, the distribution of drugs in the inner ear following IT administration is not well established. Gadolinium (Gd) has been previously used as a marker in conjunction with magnetic resonance imaging (MRI) to visualize distribution in inner ear fluids in a qualitative manner. In the present study, we applied gadolinium chelated with diethylenetriamine penta-acetic acid (Gd-DTPA) to the round window niche of 12 guinea pigs using Seprapack(TM) (carboxlmethylcellulose-hyaluronic acid) pledgets which stabilized the fluid volume in the round window niche. Gd-DTPA distribution was monitored sequentially with time following application. Distribution in normal, unperforated ears was compared with ears that had undergone a cochleostomy in the basal turn of scala tympani and implantation with a silastic electrode. Results were quantified using image analysis software. In all animals, Gd-DTPA was seen in the lower basal scala tympani (ST), scala vestibuli (SV), and throughout the vestibule and semi-circular canals by 1 h after application. Although Gd-DTPA levels in ST were higher than those in the vestibule in a few ears, the majority showed higher Gd-DTPA levels in the vestibule than ST at both early and later time points. Quantitative computer simulations of the experiment, taking into account the larger volume of the vestibule compared to scala tympani, suggest most Gd-DTPA (up to 90%) entered the vestibule directly in the vicinity of the stapes rather than indirectly through the round window membrane and ST. Gd-DTPA levels were minimally affected by the implantation procedure after 1 h. Gd-DTPA levels in the basal turn of scala tympani were lower in implanted animals, but the difference compared to non-implanted ears did not reach statistical significance.

Breast cancer risk in women with abnormal cytology in nipple aspirates of breast fluid.

BACKGROUND: We previously showed that women with abnormal cytology in breast fluid obtained by nipple aspiration had an increased relative risk (RR) of breast cancer compared with women from whom fluid was not obtained and with women whose fluid had normal cytology. This study extends the follow-up in the original study group (n = 4046) and presents the first follow-up for a second group of women (n = 3627). METHODS: We collected nipple aspirate fluid from women in the San Francisco Bay Area during the period from 1972 through 1991, classified the women according to the most severe epithelial cytology observed in fluid specimens, and determined breast cancer incidence through March 1999. We estimated RRs for breast cancer using Cox regressions, adjusting for age and year of study entry. All statistical tests were two-sided. RESULTS: For women in the first and second study groups, the median years of follow-up were 21 years and 9 years, respectively, and breast cancer incidences were 7.8% (285 cases in the 3633 women for whom breast cancer status could be determined) and 3.5% (115 of 3271), respectively. Compared with women from whom no fluid was obtained, whose incidences of breast cancer were 4.7% (39 of 825) and 3.3% (65 of 1950) for those in group 1 and group 2, respectively, incidences and adjusted RRs were 8.1% (34 of 422), with RR = 1.4 (95% confidence interval [CI] = 0.9 to 2.3), and 0% (0 of 31), respectively, for those with unsatisfactory aspirate specimens and 8.2% (148 of 1816), with RR = 1.6 (95% CI = 1.1 to 2.3), and 3.1% (25 of 811), with RR = 1.2 (95% CI = 0.8 to 2.0), respectively, for those with normal cytology in aspirates. Compared with women from whom no fluid was obtained, incidences and adjusted RRs for women in group 1 with epithelial hyperplasia and atypical hyperplasia in aspirates were 10.8% (52 of 483), with RR = 2.4 (95% CI = 1.6 to 3.7), and 13.8% (12 of 87), with RR = 2.8 (95% CI = 1.5 to 5.5), respectively, while those for women in group 2 were 5.5% (25 of 457) and 0% (0 of 22), respectively, with a combined RR = 2.0 (95% CI = 1.3 to 3.3). CONCLUSION: The results obtained with the newly followed women independently confirmed previous findings that women with abnormal cytology in nipple aspirates of breast fluid have an increased risk of breast cancer.

Ductal lavage for detection of cellular atypia in women at high risk for breast cancer.

BACKGROUND: Breast cancer originates in breast epithelium and is associated with progressive molecular and morphologic changes. Women with atypical breast ductal epithelial cells have an increased relative risk of breast cancer. In this study, ductal lavage, a new procedure for collecting ductal cells with a microcatheter, was compared with nipple aspiration with regard to safety, tolerability, and the ability to detect abnormal breast epithelial cells. METHODS: Women at high risk for breast cancer who had nonsuspicious mammograms and clinical breast examinations underwent nipple aspiration followed by lavage of fluid-yielding ducts. All statistical tests were two-sided. RESULTS: The 507 women enrolled included 291 (57%) with a history of breast cancer and 199 (39%) with a 5-year Gail risk for breast cancer of 1.7% or more. Nipple aspirate fluid (NAF) samples were evaluated cytologically for 417 women, and ductal lavage samples were evaluated for 383 women. Adequate samples for diagnosis were collected from 111 (27%) and 299 (78%) women, respectively. A median of 13,500 epithelial cells per duct (range, 43-492,000 cells) was collected by ductal lavage compared with a median of 120 epithelial cells per breast (range, 10-74,300) collected by nipple aspiration. For ductal lavage, 92 (24%) subjects had abnormal cells that were mildly (17%) or markedly (6%) atypical or malignant (<1%). For NAF, corresponding percentages were 6%, 3%, and fewer than 1%. Ductal lavage detected abnormal intraductal breast cells 3.2 times more often than nipple aspiration (79 versus 25 breasts; McNemar's test, P<.001). No serious procedure-related adverse events were reported. CONCLUSIONS: Large numbers of ductal cells can be collected by ductal lavage to detect atypical cellular changes within the breast. Ductal lavage is a safe and well-tolerated procedure and is a more sensitive method of detecting cellular atypia than nipple aspiration.

Stimulatory influence of soy protein isolate on breast secretion in pre- and postmenopausal women.

Soy foods have been reported to have protective effects against premenopausal breast cancer in Asian women. No studies have been reported on potential physiological effects of dietary soy consumption on breast gland function. We evaluated the influence of the long-term ingestion of a commercial soy protein isolate on breast secretory activity. We hypothesized that the features of nipple aspirate fluid (NAF) of non-Asian women would be altered so as to resemble those previously found in Asian women. At monthly intervals for 1 year, 24 normal pre- and postmenopausal white women, ages 30 to 58, underwent nipple aspiration of breast fluid and gave blood and 24-h urine samples for biochemical studies. No soy was administered in months 1-3 and 10-12. Between months 4-9 the women ingested daily 38 g of soy protein isolate containing 38 mg of genistein. NAF volume, gross cystic disease fluid protein (GCDFP-15) concentration, and NAF cytology were used as biomarkers of possible effects of soy protein isolate on the breast. In addition, plasma concentrations of estradiol, progesterone, sex hormone binding globulin, prolactin, cholesterol, high density lipoprotein-cholesterol, and triglycerides were measured. Compliance was assessed by measurements of genistein and daidzein and their metabolites in 24-h urine samples. Excellent compliance with the study protocol was obtained. Compared with NAF volumes obtained in months 1-3, a 2-6-fold increase in NAF volume ensued during months 4-9 in all premenopausal women. A minimal increase or no response was found in postmenopausal women. No changes were found in plasma prolactin, sex hormone binding globulin, cholesterol, high density lipoprotein cholesterol, and triglyceride concentrations. Compared with concentrations found in months 1-3 (no soy), plasma estradiol concentrations were elevated erratically throughout a "composite" menstrual cycle during the months of soy consumption. No significant changes were seen in plasma progesterone concentrations. No significant changes were found in plasma estrogen levels in postmenopausal women. A moderate decrease occurred in the mean concentration of GCDFP-15 in NAF in premenopausal women during the months of soy ingestion. Of potential concern was the cytological detection of epithelial hyperplasia in 7 of 24 women (29.2%) during the months they were consuming soy protein isolate. The findings did not support our a priori hypothesis. Instead, this pilot study indicates that prolonged consumption of soy protein isolate has a stimulatory effect on the premenopausal female breast, characterized by increased secretion of breast fluid, the appearance of hyperplastic epithelial cells, and elevated levels of plasma estradiol. These findings are suggestive of an estrogenic stimulus from the isoflavones genistein and daidzein contained in soy protein isolate.

Association of abnormal nipple aspirate cytology and mammographic pattern and density.

The pattern and density of mammograms have been shown to be associated with proliferative histopathology and an increased risk of breast cancer. We recently found that epithelial atypia in nipple aspirate fluid obtained 10-18 years earlier was associated with an increased risk of breast cancer. In the present study we examined the association between the cytology of nipple aspirate fluid and mammographic patterns in 588 volunteers recruited from the mammography clinic at the University of California. Nipple aspirate fluid cytology was classified according to the most severe epithelial change present and mammograms were classified by the Wolfe method and the percentage area of density. A direct relationship was found between mammographic density and cytological abnormality. When controlled for age, body mass index, previous biopsy, and calcification, the odds ratios of high density mammograms (over 50%) with nipple aspirate fluid cytological atypia was 4.4 (95% confidence interval, 0.9-21.5; P = 0.08) when normal cytology was the referent. These preliminary findings indicate that highly dense mammograms are associated with cytological atypia and are consistent with studies reporting an association of histological hyperplasia and atypical hyperplasia with severe mammographic findings. If confirmed by further studies, nipple aspirate cytology may be a useful adjunct to mammographic patterns in the prediction of breast cancer risk, especially among premenopausal women.

Gross cystic disease fluid protein in nipple aspirates of breast fluid of Asian and non-Asian women.

Gross cystic disease fluid protein 15 (GCDFP-15) is universally present in the apocrine metaplastic epithelium of cystic breast disease and breast cancer, but it is rarely found in normal breast epithelium. Therefore GCDFP-15 detected in nipple aspirates of breast fluid (NAF) could serve as a biochemical marker of the presence and possibly extent of apocrine metaplasia within the breast. GCDFP-15 levels were measured in NAF from 37 Asian and 78 non-Asian women using radioimmunoassay. GCDFP-15 (range, 0-81,643 micrograms/ml) was found in the NAF of all but 1 woman and was highly correlated between right and left breasts. Mean concentrations of GCDFP-15 were significantly lower in NAF from Asian compared with non-Asian women. Markedly reduced levels of GCDFP-15 were found in the 17 women who had been parous in the previous 2 years. In women not parous within the prior 2 years, no relationship was found between GCDFP-15 levels and age, weight, age at menarche, first-degree family history of breast cancer, parity, oral contraceptive use, or smoking history. High concentrations of GCDFP-15 were found in the NAF of women with a history of a benign breast biopsy. Because similarly high levels of GCDFP-15 were found in NAF in over 40% of women without a history of benign breast biopsy, and because GCDFP-15 in the breast is produced only by apocrine metaplastic epithelium, we infer that the breasts of these women likely contain a significant degree of apocrine metaplasia.(ABSTRACT TRUNCATED AT 250 WORDS)

Breast cancer risk associated with abnormal cytology in nipple aspirates of breast fluid and prior history of breast biopsy.

The authors previously reported an increased risk of breast cancer in women from the San Francisco Bay Area first enrolled between 1973 and 1980 with proliferative cytologic findings (hyperplasia, moderate hyperplasia, and atypia) compared with women with normal cytologic findings in breast fluids obtained by nipple aspiration and with women from whom breast fluid could not be obtained. To look for factors which might modify the risks associated with cytology, the authors examined several standard breast cancer risk factors: parity, age at first pregnancy, age at menarche, family history of breast cancer, and prior history of breast biopsy. Among women aged 30 years or over, only prior biopsy modified the effect of proliferative cytologic findings on the risk of breast cancer (p < 0.10). For those women with no prior biopsy, breast cancer incidence was 5% (47 of 985) among women with normal cytology and 5% (13 of 277) among women with proliferative findings, whereas among those women with normal cytology and 18% (11 of 62) among women with proliferative cytology. Age-adjusted as well as multivariate-adjusted relative risks indicated that the increased risk of breast cancer associated with proliferative cytologic findings was largely confined to women who had a prior history of breast biopsy.

Breast cancer incidence in women with abnormal cytology in nipple aspirates of breast fluid.

This is a prospective study of breast cancer risk in relation to nipple aspirate fluid cytology in 2,701 volunteer white women from the San Francisco Bay Area first enrolled between 1973 and 1980. The women were not pregnant or lactating and were free of breast cancer within 6 months of entry into the study. The breast cancer status of this cohort was determined between June 1988 and April 1991. Follow-up was complete for 87% (n = 2,343) of the cohort, representing 29,961 person-years and an average of 12.7 years of follow-up. The overall breast cancer incidence was 4.4% (104 of 2,343) and rose with fluid cytology findings as follows: no fluid obtained, 2.6% (9 of 352); unsatisfactory specimen, 4.8% (15 of 315); normal cytology, 4.3% (56 of 1,291); epithelial hyperplasia, 5.5% (18 of 327); and atypical hyperplasia, 10.3% (6 of 58). Relative risks for breast cancer and their 95% confidence intervals were estimated by Cox regression, adjusting for age and year of entry. Compared with the relative risk for women who yielded no fluid, relative risks were: unsatisfactory specimen, relative risk (RR) = 1.4 (95% confidence interval (CI) 0.6-3.3); normal cytology, RR = 1.8 (95% CI 0.9-3.6); epithelial hyperplasia, RR = 2.5 (95% CI 1.1-5.5); and atypical hyperplasia, RR = 4.9 (95% CI 1.7-13.9). These findings were strongest for and were mainly confined to women aged 25-54 years. Women with atypical hyperplasia and a first-degree family history of breast cancer were six times more likely to develop breast cancer than were women with atypical hyperplasia but without a family history of breast cancer (95% CI 1.0-30.2). These findings provide strong support for our hypothesis that hyperplasia and atypical hyperplasia diagnosed in nipple aspirates of breast fluid are associated with an increased risk of breast cancer.

Characterization by image cytometry of duct epithelial proliferative disease of the breast.

To develop a morphometric model of premalignant breast epithelium, we evaluated 120 lesions classified as nonproliferative disease (n = 20), hyperplasia (n = 20), moderate hyperplasia (n = 20), atypical hyperplasia (n = 20), carcinoma in situ (n = 20), and carcinoma (n = 20) in tissue from surgical biopsy or mastectomy. Atypical hyperplasia, a component of duct epithelial proliferative disease, has frequently been described in breasts with carcinoma. Atypical hyperplasia is generally viewed as premalignant or as a marker of increased risk for breast cancer. Measurements of nuclei in breast lesions were obtained with the Leitz TAS Plus on 4-microns sections stained for DNA with the Azure A Feulgen reaction. Nuclei of duct epithelial lesions had morphometric features that displayed changes from nonproliferative disease to carcinoma. The morphometric data from each lesion were compared among the six disease groups. Means of nuclear area, perimeter, maximum and minimum diameter, and large dark and large light intranuclear areas increased with higher degrees of proliferative abnormality. When the six groups of lesions were compared using the means of the first four nuclear features, atypical hyperplasia was significantly different (P less than 0.05) from carcinoma and non-proliferative lesions, but not from hyperplasia, moderate hyperplasia, or carcinoma in situ. These findings suggest that objective morphometric descriptors for characterizing significant proliferative lesions can be established using image cytometry. The progressive increases also suggest that proliferative breast disease is a continuum that includes premalignant lesions.

Cerumen phenotype and proliferative epithelium in breast fluids of U.S.-born vs. immigrant Asian women: a possible genetic-environmental interaction.

To determine whether a genetic-environmental interaction exists between the breast, a modified apocrine gland, its secretions, and the genetic polymorphic phenotypes of wet and dry cerumen, we examined nipple aspirate fluid (NAF) for proliferative disease in 172 U.S.-born and immigrant Chinese and Japanese women. Cytologic evidence of proliferative epithelial cells (benign hyperplasia and/or atypical hyperplasia) was found in the NAF of 36 women (20.9%). A significantly higher incidence of proliferative epithelial cells was present in the NAF of U.S.-born than in immigrant Asian women (28.6% vs. 16.5%) (p = 0.05). A higher proportion of U.S.-born Asian women with wet cerumen than women with dry cerumen had proliferative epithelial cells in NAF: 39.3% vs. 20.0% (p = 0.08). No significant difference in NAF proliferative cells was found between immigrant women with wet and dry cerumen: 15.8% vs. 17.3%; p = 0.50. A strong association of proliferative epithelial cells and cerumen phenotype was found in parous U.S.-born women (wet = 47.6% vs. dry = 16.0%; p = 0.002). No significant association with wet and dry cerumen phenotype was found in parous immigrant women (wet = 12.2% vs. dry = 20%). These findings support the hypothesis that an apocrine genetic polymorphic trait differentially influences susceptibility of the breast to proliferative disease in Asian women born in environments presumed to be of high risk for breast cancer compared to women from low risk environments.

Adenocarcinoma with a neuroendocrine component arising in the urachus. A case report.

The clinical, cytologic, histologic and ultrastructural findings in a mixed adenocarcinoma and neuroendocrine carcinoma of the urinary bladder urachus, an extremely rare tumor only recently described, are presented for a 31-year-old woman who died of widespread metastatic disease six months following the initial diagnosis and treatment. Cytologic study of voided urine and bladder washings disclosed the presence of malignant cells with the features of a small cell carcinoma; retrospectively, scarce adenocarcinoma cells were also identified in those specimens. Histologic study of resection specimens, including the use of special stains and electron microscopy, confirmed the presence of a small cell component, consistent with the poor prognosis in this case. Image analysis measurements of the malignant cells suggested a high proliferation rate.

Factors associated with obtaining nipple aspirate fluid: analysis of 1428 women and literature review.

Studies of cytologic and biochemical constituents of nipple aspirates of breast fluid have contributed to understanding the natural history of benign and malignant breast disease. We conducted multivariate analyses using 1428 women from a recent case-control study of breast disease to determine which factors were independently associated with the ability to obtain breast fluid from nonlactating women. We then compared results from these analyses to the results from five previous studies that also used the aspiration technique of Sartorius. Four factors were consistently associated across studies with increased ability to obtain breast fluid: 1) age up to 35 to 50 years; 2) earlier age at menarche; 3) non-Asian compared to Asian ethnicity; and 4) history of lactation. Exogenous estrogen use, endogenous estrogen concentrations, phase of menstrual cycle, family history of breast cancer, type of menopause, and less than full-term pregnancy consistently did not influence ability to obtain fluid. New findings from this study shed light on some apparently contradictory findings from the previous studies. In particular, this study showed that the effects of age on ability to obtain fluid appeared to be independent of the effects of menopause. Furthermore, discrepancies in previous findings on the effects of parity on ability to obtain fluid may be explained by our finding that the increased ability to obtain fluid from parous compared to nulliparous women applied only to parous women who had breastfed.

Breast fluid cholesterol and cholesterol beta-epoxide concentrations in women with benign breast disease.

Because cholesterol 5,6-epoxides have been reported to be mutagenic, carcinogenic, and cytotoxic, we investigated the relationship of these substances in breast fluid to histopathologically defined breast disease. We measured cholesterol and its oxidation product, 5 beta,6 beta-epoxide, in breast fluids from 68 women with biopsied benign breast disease (BBD) and 135 women with no history of breast disease (controls). Each biopsy was classified according to the most severe epithelial change: (a) nonproliferative epithelia; (b) hyperplasia without atypia; or (c) hyperplasia with atypia. Similar to our previous findings in control women, breast fluid cholesterol and beta-epoxide concentrations in women with BBD were associated with factors of interest in relation to breast cancer: concentrations increased with age and were higher in white than nonwhite women and in women who were past or current smokers; concentrations were lower in women who had given birth or breastfed within 2 yr. Increased breast fluid cholesterol and beta-epoxide concentrations were significantly associated with proliferative BBD (hyperplasia with or without atypia) compared to controls. After adjustment for covariates, the odds ratio for proliferative BBD associated with detectable versus nondetectable beta-epoxide concentrations was 8.5 (95% confidence intervals, 1.1, 68.8). Our findings suggest that the histological progression from normal epithelium to hyperplasia without atypia to atypical hyperplasia is associated with progressively increasing concentrations of both cholesterol and cholesterol beta-epoxide.

Image cytometric classification of premalignant breast disease in fine needle aspirates.

Image cytometry for the classification of fine needle aspirate (FNA) biopsies was evaluated in samples from 39 women. Eighteen of them had benign lesions, seven had premalignant lesions, nine had carcinoma in situ, and five had carcinoma. The term, premalignant, here refers to lesions with an increased risk of developing into breast cancer (atypical hyperplasia and, to a lesser extent, moderate or florid hyperplasia). The classifications by cytometry were compared with the microscopic diagnoses of the same FNA samples and of tissue from a subsequent surgical biopsy of the same area. One slide from each breast FNA sample was restained in Azure-A Feulgen. Breast epithelial cells were measured using a texture analysis program on the Leitz TAS-plus. The mean, standard deviation (SD), and interquartile range were calculated for each of 12 nuclear parameters from 200 cells per slide. A discriminant analysis was used to develop a statistical model for classifying individual samples. Six of seven atypical proliferative lesions (atypical hyperplasia and moderate hyperplasia) were identified by image cytometry, but were unrecognized by conventional microscopic examination.

Association of breast fluid coloration with age, ethnicity, and cigarette smoking.

Nipple aspirates of breast fluid (NAF) occur with different colorations (colorless, white, pale yellow, dark yellow, brown, green, and black). Increasing concentrations of cholesterol, cholesterol 5,6-epoxides, estrogens, and fluorescent products of lipid peroxidation have been positively associated with the dark colorations (dark yellow, brown, green, and black). Because of the absence of data on these variations in breast fluid coloration, we made an exploratory study of their possible associations with age, ethnicity, clinical breast status, and breast cancer risk factors. Dark NAF colorations increased with age among white women from 22.5% at 20-29 years to 49.2% at 50-59 years. Among Chinese and Japanese women, the overall proportion of dark breast fluids was significantly lower (highest proportion 23.5%). A positive association of dark NAF coloration was found with current cigarette smoking (odds ratio = 1.64 [1.04-2.59]). A dose response between amount smoked and dark coloration was found in women less than 50 years of age, with women who smoked more than one pack per day having an odds ratio of 2.31 (1.30-4.67). No significant association of dark NAF was found with the major breast cancer risk factors or with actual benign or malignant breast disease. The dark colorations may represent pigmented products of apocrine gland secretion, lipofuscin complexes of peroxidated lipoprotein, breakdown products of hemoglobin, and possibly, diet-related secretory products.

Benign and malignant breast disease: initial study results of serum and breast fluid analyses of endogenous estrogens.

Design, methods, and study population of a long-term multidisciplinary investigation of benign and malignant breast disease were reported. This initial report focused on the relation of menstrual, reproductive, and other factors to serum and breast fluid estrogen measures [estradiol (E2), estrone (E1), percent free estrogen, and sex hormone binding globulin] among control women. After adjustment for the factors found to be related to the various estrogen measures, estrogen levels in women with benign and malignant disease were compared to those of controls. Findings were as follows: a) little evidence of any relation of most breast cancer risk factors with the various serum estrogen parameters studied; b) differences in breast fluid estrogen levels that may be relevant to the protective effect of parity on breast cancer risk; c) markedly higher levels of E2 and E1 in breast fluid than in serum and no evidence of a correlation of serum with breast fluid measures; d) no support for the hypothesis that breast cancer patients have higher serum percent free E2 than controls or women with benign breast disease; and e) higher breast fluid E2 and E1 levels in women with biopsied benign breast disease than in controls.