Does the Motor Cortex Want the Full Story? The Influence of Sentence Context on Corticospinal Excitability in Action Language Processing.

The reading of action verbs has been shown to activate motor areas, whereby sentence context may serve to either globally strengthen this activation or to selectively sharpen it. To investigate this issue, we manipulated the presence of manual actions and sentence context, assessing the level of corticospinal excitability by means of transcranial magnetic stimulation. We hypothesized that context would serve to sharpen the neural representation of the described actions in the motor cortex, reflected in context-specific modulation of corticospinal excitability. Participants silently read manual action verbs and non-manual verbs, preceded by a full sentence (rich context) or not (minimal context). Transcranial magnetic stimulation pulses were delivered at rest or shortly after verb presentation. The coil was positioned over the cortical representation of the right first dorsal interosseous (pointer finger). We observed a general increase of corticospinal excitability while reading both manual action and non-manual verbs in minimal context, whereas the modulation was action-specific in rich context: corticospinal excitability increased while reading manual verbs, but did not differ from baseline for non-manual verbs. These findings suggest that sentence context sharpens motor representations, activating the motor cortex when relevant and eliminating any residual motor activation when no action is present.

Increased blood pressure visit-to-visit variability in patients with systemic lupus erythematosus: association with inflammation and comorbidity burden.

BACKGROUND: Blood pressure visit-to-visit variability is a novel risk factor for deleterious long-term cardiac and renal outcomes in the general population. We hypothesized that patients with systemic lupus erythematosus (SLE) have greater blood pressure visit-to-visit variability than control subjects and that blood pressure visit-to-visit variability is associated with a higher comorbidity burden. METHODS: We studied 899 patients with SLE and 4172 matched controls using de-identified electronic health records from an academic medical center. We compared blood pressure visit-to-visit variability measures in patients with SLE and control subjects and examined the association between blood pressure visit-to-visit variability and patients' characteristics. RESULTS: Patients with SLE had higher systolic blood pressure visit-to-visit variability 9.7% (7.8-11.8%) than the control group 9.2% (7.4-11.2%), P < 0.001 by coefficient of variation. Additional measures of systolic blood pressure visit-to-visit variability (i.e. standard deviation, average real variation, successive variation and maximum measure-to-measure change) were also significantly higher in patients with SLE than in control subjects. In patients with SLE, blood pressure visit-to-visit variability correlated significantly with age, creatinine, CRP, triglyceride concentrations and the Charlson comorbidity score (all P < 0.05). Hydroxychloroquine use was associated with reduced blood pressure visit-to-visit variability (P < 0.001), whereas the use of antihypertensives, cyclophosphamide, mycophenolate mofetil and corticosteroids was associated with increased blood pressure visit-to-visit variability (P < 0.05). CONCLUSION: Patients with SLE had higher blood pressure visit-to-visit variability than controls, and this increased blood pressure visit-to-visit variability was associated with greater Charlson comorbidity scores, several clinical characteristics and immunosuppressant medications. In particular, hydroxychloroquine prescription was associated with lower blood pressure visit-to-visit variability.

Aging mice have increased chromosome instability that is exacerbated by elevated Mdm2 expression.

Aging is thought to negatively affect multiple cellular processes including the ability to maintain chromosome stability. Chromosome instability (CIN) is a common property of cancer cells and may be a contributing factor to cellular transformation. The types of DNA aberrations that arise during aging before tumor development and that contribute to tumorigenesis are currently unclear. Mdm2, a key regulator of the p53 tumor suppressor and modulator of DNA break repair, is frequently overexpressed in malignancies and contributes to CIN. To determine the relationship between aging and CIN and the role of Mdm2, precancerous wild-type C57Bl/6 and littermate-matched Mdm2 transgenic mice at various ages were evaluated. Metaphase analyses of wild-type cells showed a direct correlation between age and increased chromosome and chromatid breaks, chromosome fusions and aneuploidy, but the frequency of polyploidy remained stable over time. Elevated levels of Mdm2 in precancerous mice increased both the numerical and the structural chromosomal abnormalities observed. Chromosome and chromatid breaks, chromosome fusions, aneuploidy and polyploidy were increased in older Mdm2 transgenic mice compared with wild-type littermates. Unexpectedly, chromosome fusions, aneuploidy and polyploidy rates in Mdm2 transgenic mice, but not chromosome and chromatid breaks, showed cooperation between Mdm2 overexpression and age. Notably, Mdm2 overexpression promoted gains in one or more chromosomes with age, while it did not affect the rate of chromosome loss. Therefore, aging increased specific forms of genomic instability, and elevated Mdm2 expression cooperated with aging to increase the likelihood of gaining certain chromosomal abnormalities of the kind thought to lead to cancer development.

Immunohistochemical analysis of receptor tyrosine kinase signal transduction activity in chordoma.

AIMS: Currently, there are no effective chemotherapeutic protocols for chordoma. Reports of receptor tyrosine kinase (RTK) expression in chordoma suggest that these tumours may respond to kinase inhibitor therapy. However, RTK signalling activity has not been extensively investigated in chordoma. METHODS: A tissue microarray containing 21 cases of chordoma was analysed for expression of a number of proteins involved in signal transduction from RTKs by immunohistochemistry. RESULTS: Platelet-derived growth factor receptor-beta, epidermal growth factor receptor (EGFR), KIT and HER2 were detected in 100%, 67%, 33% and 0% of cases, respectively. Platelet-derived growth factor receptor-beta staining was of moderate-to-strong intensity in 20 of 21 cases. In contrast, KIT immunoreactivity was weak and focal in each of the seven positive cases. Total EGFR staining was variable; weak staining for phosphorylated EGFR was detected in nine cases. Phosphorylated isoforms of p44/42 mitogen-activated protein kinase, Akt and STAT3, indicative of tyrosine kinase activity, were detected in 86%, 76% and 67% of cases, respectively. CONCLUSIONS: Chordomas commonly express RTKs and activated signal transduction molecules. Although there were no statistically significant correlations between the expression of any of the markers studied and disease-free survival or tumour location, the results nonetheless indicate that chordomas may respond to RTK inhibitors or modulators of other downstream signalling molecules.

Estimating the undetected burden of influenza hospitalizations in children.

During the 2004-2005 influenza season two independent influenza surveillance systems operated simultaneously in three United States counties. The New Vaccine Surveillance Network (NVSN) prospectively enrolled children hospitalized for respiratory symptoms/fever and tested them using culture and RT-PCR. The Emerging Infections Program (EIP) and a similar clinical-laboratory surveillance system identified hospitalized children who had positive influenza tests obtained as part of their usual medical care. Using data from these systems, we applied capture-recapture analyses to estimate the burden of influenza related-hospitalizations in children aged<5 years. During the 2004-2005 influenza season the influenza-related hospitalization rate estimated by capture-recapture analysis was 8.6/10,000 children aged<5 years. When compared to this estimate, the sensitivity of the prospective surveillance system was 69% and the sensitivity of the clinical-laboratory based system was 39%. In the face of limited resources and an increasing need for influenza surveillance, capture-recapture analysis provides better estimates than either system alone.

Efficacy of inactivated and cold-adapted vaccines against influenza A infection, 1985 to 1990: the pediatric experience.

BACKGROUND: Influenza is a common and potentially serious infection in children. Although there is interest in broadening the use of influenza vaccine in healthy children, there are few large, randomized, controlled trials that evaluate the safety and efficacy of inactivated vaccine in the pediatric population. METHODS: From 1985 through 1990 a randomized, controlled trial of cold-adapted and inactivated vaccines for the prevention of influenza A disease was conducted at Vanderbilt University, and the cumulative results from this trial in patients of all ages have been previously published. We reanalyzed the data from this trial in the subset of patients who were younger than 16 years at the time of their participation. We determined vaccine safety, immunogenicity and efficacy, based on culture-positive illness and seroconversion, in this subset of patients. RESULTS: During the 5 years of the study, 791 children younger than 16 years received 1809 doses of either inactivated or cold-adapted vaccine or placebo. The vaccines were well-tolerated, and there were no serious reactions. Inactivated trivalent influenza vaccines were 91.4 and 77.3% efficacious in preventing symptomatic, culture-positive influenza A H1N1 and H3N2 illness, respectively. The efficacy of the inactivated vaccine based on hemagglutination inhibition assay seroconversion was 67.1 and 65.5%, respectively, for H1N1 and H3N2 serotypes. CONCLUSIONS: Inactivated trivalent influenza A vaccines are well-tolerated and efficacious in the prevention of influenza A disease in children 1 to 16 years old.

Prognostic value of morphometry in patients with normal breast tissue or usual ductal hyperplasia of the breast.

Women with usual ductal hyperplasia have a relative risk of 1.6-1.9 of subsequent breast cancer development. This slightly increased risk is generally not considered sufficiently high to justify (chemo)preventive therapy. It is therefore important to identify high-risk ductal hyperplastic lesions that would benefit from such a treatment. Nuclear morphometric features have been shown in previous work to be useful for objectively describing morphologic features associated with high risk in (pre)invasive breast lesions. The aim of this study was to evaluate whether such morphometric features can also predict subsequent invasive cancer development in patients with the common pattern of usual ductal hyperplasia or a normal breast biopsy. The present case-control study included 423 women with normal breast biopsies (n = 89) or biopsies containing usual ductal hyperplasia (n = 334). Of these 423 women, 132 developed invasive breast cancer during follow-up (mean 16.7 +/- 7.0 years). On the original hematoxylin and eosin-stained sections, nuclear morphometry was performed with a digitizing video overlay system, and mitotic and apoptotic indices were assessed. Patients with mean nuclear feature values for area, perimeter, diameter or longest axis above the 75th percentile had 1.6-1.7 times the breast cancer risk of women with mean nuclear feature values below this value. Pairwise combinations of these features yielded slightly higher cancer risks for the fourth quartile patients, with the highest risk (1.9) for patients with SD of nuclear area and perimeter values above the 75th percentile. The number of apoptotic or mitotic cells had no prognostic value for patients with apparently normal tissue or usual ductal hyperplasia. Our results give a first indication that normal breast tissue or usual ductal hyperplasia harbor nuclear morphologic changes that, when assessed by morphometry, may be used to predict breast cancer development. It is worthwhile studying this further in independent groups of patients with long-term follow-up.

No elevation in long-term breast carcinoma risk for women with fibroadenomas that contain atypical hyperplasia.

BACKGROUND: The authors previously showed that women with a fibroadenoma have a relative risk of invasive breast carcinoma of approximately 2.0 compared with women of similar age from the general population. This relative risk approaches 1.0 when family history and proliferative changes in the adjacent parenchyma are removed and rises to > 3.0 if the fibroadenoma has complex histology. The risk for developing breast carcinoma in women with atypical lobular hyperplasia (ALH) and atypical ductal hyperplasia (ADH) or their minimal variants within a fibroadenoma is unknown. METHODS: The authors conducted a long-term, retrospective cohort study of 1834 women with adequate follow-up who presented with fibroadenoma at three local hospitals between 1950 and 1968. Histology was reviewed using established criteria, and the patients were categorized with ALH, ADH, minimal atypia, or no atypia. RESULTS: The overall prevalence of ALH or ADH within fibroadenomas was 0.81%. Minimal or true atypia within a fibroadenoma appeared to be correlated with proliferative disease in the adjacent parenchyma but could not predict for the presence there of well-established atypia. Only 7% of women with well-developed atypia developed invasive carcinoma on follow-up. Three women with minimal atypia developed invasive carcinoma. CONCLUSIONS: In this study of a large cohort of women with fibroadenoma, the authors found that atypia within a fibroadenoma cannot predict for the presence of atypia within adjacent breast parenchyma. They also found that atypia confined to a fibroadenoma does not incur a clinically meaningful risk of future breast carcinoma development greater than that of fibroadenoma alone.

Multifactor-dimensionality reduction reveals high-order interactions among estrogen-metabolism genes in sporadic breast cancer.

One of the greatest challenges facing human geneticists is the identification and characterization of susceptibility genes for common complex multifactorial human diseases. This challenge is partly due to the limitations of parametric-statistical methods for detection of gene effects that are dependent solely or partially on interactions with other genes and with environmental exposures. We introduce multifactor-dimensionality reduction (MDR) as a method for reducing the dimensionality of multilocus information, to improve the identification of polymorphism combinations associated with disease risk. The MDR method is nonparametric (i.e., no hypothesis about the value of a statistical parameter is made), is model-free (i.e., it assumes no particular inheritance model), and is directly applicable to case-control and discordant-sib-pair studies. Using simulated case-control data, we demonstrate that MDR has reasonable power to identify interactions among two or more loci in relatively small samples. When it was applied to a sporadic breast cancer case-control data set, in the absence of any statistically significant independent main effects, MDR identified a statistically significant high-order interaction among four polymorphisms from three different estrogen-metabolism genes. To our knowledge, this is the first report of a four-locus interaction associated with a common complex multifactorial disease.

Hypoproteinemia predicts acute respiratory distress syndrome development, weight gain, and death in patients with sepsis. Ibuprofen in Sepsis Study Group.

OBJECTIVE: Starling's equation indicates that reduced oncotic pressure gradients will favor edema formation, and the current consensus definition of acute respiratory distress syndrome (ARDS) excludes only the hydrostatic pressure contribution. We hypothesized that low serum total protein levels might correlate with the likelihood of ARDS in at-risk patients because serum total protein is the chief determinant of oncotic pressure in humans. DESIGN: Regression analysis to compare outcomes in patients with low serum total protein levels with outcomes in patients with normal serum total protein levels with respect to weight change, development of ARDS, and mortality. SETTING: Intensive care units (ICUs) of seven clinical centers in North America. PATIENTS: A total of 455 ICU patients who met consensus criteria for severe sepsis (178 of whom developed ARDS) from a recently completed prospective clinical trial. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: We found that 92% of the patients developing ARDS had low or borderline serum total protein levels (<6 g/dL). Logistic and multiple regression analyses confirmed that of 18 clinical variables, initial serum total protein level and protein change over time were the most statistically significant predictors of weight gain, prolonged mechanical ventilation, ARDS development, and mortality in the study population. This correlation remained significant after adjustment for the other major predictors of outcome present at baseline (ie, Acute Physiology and Chronic Health Evaluation II score). CONCLUSIONS: Hypoproteinemia is significantly correlated with fluid retention and weight gain, development of ARDS and poor respiratory outcome, and mortality in patients with sepsis. Prospective, randomized trials of serum protein manipulation are needed to establish whether there is a cause-effect relationship to this association.

Histologic grading of breast cancer: linkage of patient outcome with level of pathologist agreement.

In the histologic grading of invasive breast cancer with the Nottingham modification of the Scarff-Bloom-Richardson grading scheme (NSBR), it has been found that when pathologists disagree, they tend not to disagree by much. However, if tumor grade is to be used as an important parameter in making treatment decisions, then even this generally small degree of pathologist variability in assessing grade needs to be correlated with patient outcome. Findings from the Nottingham/Tenovus Primary Breast Cancer Study were used for patient outcome data. Kaplan-Meier survival curves were constructed for NSBR scores grouped according to the level at which pathologists tend to agree in assessing grade, from a reproducibility perspective. For example, if a given tumor were assessed by several pathologists as having either an NSBR score of 5 or 6, then what is the correct score--the intermediate-grade Score 6 assessments or the low-grade Score 5 assessments? By "regrouping" the Nottingham outcome data such that data from patients with Score 5 tumors are grouped with patients having Score 6 tumors (a 5-6 group), then the level in which the pathologists agreed with each other (that the tumor was either score 5 or 6) is better matched with patient outcome. In response to the above example, it was not surprising to find that patients with Score 5-6 tumors had a probability of survival between the established low and intermediate NSBR final combined grades. However, it is the discussion of this approach that highlights that optimal use of grading requires awareness of the level of pathologist agreement and understanding the value of pathologists' reaching consensus in assessments. Also, knowledge of possible clinical decision thresholds can help in providing relevant interpretations of grading results.

Mediastinal fibrosis is associated with human leukocyte antigen-A2.

OBJECTIVE: To determine the association between mediastinal fibrosis and human leukocyte antigen (HLA) genes. DESIGN: Case-control study. SETTING: Vanderbilt University Medical Center. SUBJECTS: Nineteen consecutive patients with mediastinal fibrosis who presented to the pulmonary clinic at Vanderbilt University Medical Center from 1987 to 1996. The control subjects were 21,086 whites who were cadaveric kidney donors from October 1987 through December 1993. MEASUREMENTS: HLA testing was performed on blood samples from all 19 cases. Information on HLA typing for the control subjects was obtained from the United Network for Organ Sharing. Frequency of HLA class I and II antigens found in the cases was compared with the frequency in the control subjects. RESULTS: The relative risk of mediastinal fibrosis among subjects with the HLA-A2 antigen was 3.32 times that of those who lacked this antigen (95% confidence interval, 1.19 to 9. 2). CONCLUSION: HLA-A2 was strongly associated with mediastinal fibrosis, suggesting that an abnormal immune response is important in the pathogenesis of this disease. Key words: Histoplasma capsulatum; human leukocyte antigen-A2; mediastinal fibrosis

Loss of expression of transforming growth factor beta type II receptor correlates with high tumour grade in human breast in-situ and invasive carcinomas.

AIMS: Loss of transforming growth factor beta type II receptor (TGFbeta-RII) expression has been associated with resistance to TGFbeta-mediated inhibition of cell proliferation and tumour progression. We investigated whether the expression of TGFbeta-RII is related to the progression of human breast cancer and whether there is a correlation between TGFbeta-RII expression and phenotypic markers of biological aggressiveness. METHODS AND RESULTS: Immunohistochemical methods were used to detect TGFbeta-RII in archival breast samples including benign proliferative lesions, ductal carcinoma in situ (DCIS) and invasive mammary carcinomas (IMC). Neoplastic cells showed reduced expression of TGFbeta-RII in comparison to the normal breast tissue and benign lesions. There was a significant inverse correlation between loss of TGFbeta-RII expression and tumour grade within both DCIS (P = 0.004) and IMC (P = 0.001) groups. There was an inverse correlation between TGFbeta-RII expression and both mitotic count (P = 0.001) and clinical stage (P = 0.004). Oestrogen receptor (P = 0.07) and lymph node status (P = 0.10) were not significantly associated with TGFbeta-RII expression. CONCLUSIONS: These data indicate that decreased expression of TGFbeta-RII may contribute to breast cancer progression and is related to a more aggressive phenotype in both in-situ and invasive carcinomas.

Historical and epidemiologic background of human premalignant breast disease.

Premalignant breast disease in humans is a concept that admits to a broad range of elements and possible determinants predicting the likelihood of developing breast cancer. Most of these elements are relative, such as the risk of breast cancer for women that is 130 times that of men and peaks at a younger age by about 10 years. Breast cancer is clearly a stochastic, multifactorial process that evolves over many years in which we must make predictions by likelihood. This review will present the most specially defined and reliably proven of these elements, highlighting anatomic and molecular factors.

Androgen receptor CAG repeat lengths in ductal carcinoma in situ of breast, longest in apocrine variety.

CAG repeat number in the androgen receptor (AR) has been associated with decreased prostate cancer risk, and AR expression has been found in female breast cancer, often associated with apocrine differentiation. Because trinucleotide expansion can alter gene expression and protein function, we hypothesized that it might occur in breast neoplasms. We used a repeat expansion detection technique to determine CAG repeat lengths in DNA from breast biopsies. Three lesion types were microdissected: fibroadenoma (48 cases), ductal carcinoma in situ (DCIS, 24 cases), and invasive mammary carcinoma (18 cases). The maximum number of CAG repeats in either allele of each patient in these three groups was compared. Microsatellite repeat lengths in DCIS were longer than in fibroadenomas or invasive carcinomas (P= 0.017 comparing DCIS vs invasive carcinomas). Two cases of apocrine DCIS had very long repeat lengths, both exhibiting microsatellite lengths at the longest range of normal (32 and 33). Inherited differences in AR CAG length might influence the transition from DCIS to invasive breast cancer, perhaps by modulating function of AR in breast tissue. AR microsatellite polymorphisms could influence cellular differentiation in DCIS lesions, promoting formation of the apocrine subtype in the presence of longer CAG repeats.

Transforming growth factor-beta and breast cancer risk in women with mammary epithelial hyperplasia.

BACKGROUND: Transforming growth factors-beta (TGF-betas) regulate mammary epithelial cell division. Loss of expression of TGF-beta receptor II (TGF-beta-RII) is related to cell proliferation and tumor progression. Breast epithelial hyperplastic lesions lacking atypia (EHLA) are associated with a mild elevation in breast cancer risk. We investigated the expression of TGF-beta-RII in EHLA and the risk of subsequent invasive breast cancer. METHODS: We conducted a nested case-control study of women with biopsy-confirmed EHLA who did not have a history of breast cancer or atypical hyperplasia of the breast. Case patients (n = 54) who subsequently developed invasive breast cancer were matched with control patients (n = 115) who did not. Formalin-fixed, paraffin-embedded sections of breast biopsy specimens of all 169 patients with EHLA were studied by immunohistochemical analysis with antibodies against TGF-beta-RII. All P values are two-sided. RESULTS: Women with breast EHLA and 25%-75% TGF-beta-RII-positive cells or less than 25% TGF-beta-RII-positive cells had odds ratios of invasive breast cancer of 1.98 (95% confidence interval [CI] = 0.95-4.1) or 3.41 (95% CI = 1.2-10.0), respectively (P for trend =.008). These risks are calculated with respect to women with EHLA that had greater than 75% TGF-beta-RII expression. Women with a heterogeneous pattern of TGF-beta-RII expression in their normal breast lobular units and either greater than 75%, 25%-75%, or less than 25% positive cells in their EHLA had odds ratios for breast cancer risk of 0.742 (95% CI = 0.3-1.8), 2.85 (95% CI = 1.1-7.1), or 3.55 (95% CI = 1.0-10.0), respectively (P for trend =.003). These risks are relative to women with a homogeneous pattern of expression in their normal lobular units and greater than 75% positive cells in their EHLA. CONCLUSION: This study indicates that loss of TGF-beta-RII expression in epithelial cells of EHLA is associated with increased risk of invasive breast cancer.

Effects of ibuprofen on the physiology and survival of hypothermic sepsis. Ibuprofen in Sepsis Study Group.

OBJECTIVES: The objective was to compare the clinical and physiologic characteristics of febrile septic patients with hypothermic septic patients; and to examine plasma levels of cytokines tumor necrosis factor alpha (TNF-alpha and interleukin 6 (IL-6) and the lipid mediators thromboxane B2 (TxB2) and prostacyclin in hypothermic septic patients in comparison with febrile patients. Most importantly, we wanted to report the effect of ibuprofen treatment on vital signs, organ failure, and mortality in hypothermic sepsis. SETTING: The study was performed in the intensive care units (ICUs) of seven clinical centers in the United States and Canada. PATIENTS: Four hundred fifty-five patients admitted to the ICU who met defined criteria for severe sepsis and were suspected of having a serious infection. INTERVENTION: Ibuprofen at a dose of 10 mg/kg (maximum 800 mg) was administered intravenously over 30 to 60 mins every 6 hrs for eight doses vs. placebo (glycine buffer vehicle). MEASUREMENTS AND MAIN RESULTS: Forty-four (10%) septic patients met criteria for hypothermia and 409 were febrile. The mortality rate was significantly higher in hypothermic patients, 70% vs. 35% for febrile patients. At study entry, urinary metabolites of TxB2, prostacyclin, and serum levels of TNF-alpha and IL-6 were significantly elevated in hypothermic patients compared with febrile patients. In hypothermic patients treated with ibuprofen, there was a trend toward an increased number of days free of major organ system failures and a significant reduction in the 30-day mortality rate from 90% (18/20 placebo-treated patients) to 54% (13/24 ibuprofen-treated patients). CONCLUSIONS: Hypothermic sepsis has an incidence of approximately 10% and an untreated mortality twice that of severe sepsis presenting with fever. When compared with febrile patients, the hypothermic group has an amplified response with respect to cytokines TNF-alpha and IL-6 and lipid mediators TxB2 and prostacyclin. Treatment with ibuprofen may decrease mortality in this select group of septic patients.

Estrogen replacement therapy in women with a history of proliferative breast disease.

BACKGROUND: Little information is available regarding the invasive breast carcinoma risk associated with estrogen replacement therapy (ERT) in women with histories of histologically defined breast lesions. METHODS: A retrospective cohort study of a consecutive series of women who underwent breast biopsies that proved to be benign between 1952-1978 was conducted. Follow-up data were obtained for 9494 women (87.6% of women eligible for follow-up). To investigate the effect of ERT on invasive breast carcinoma risk, the analysis was restricted to women with premenopausal breast disease whose follow-up extended through menopause and who did not develop premenopausal breast carcinoma. Relative risks were calculated with respect to women who took ERT but whose benign breast biopsies had neither atypical hyperplasia (AH), complex fibroadenoma (CFA), nor proliferative disease without atypia (PDWA). RESULTS: During 190,845 woman-years of follow-up there were 444 confirmed cases of invasive breast carcinoma in the entire cohort. Women with a history of AH had relative risks of invasive breast carcinoma of 2.87 (95% confidence interval [95% CI], 1.3-6.3) and 2.53 (95% CI, 1.0-6.3) if they did or did not take ERT, respectively. For women with a history of CFA these risks were 1.57 (95% CI, 0.72-3.4) and 1.46 (95% CI, 0.53-4.0), respectively, whereas for women with a history of PDWA they were 1.37 (95% CI, 0.88-2.1) and 1.13 (95% CI, 0.69-1.9), respectively. CONCLUSIONS: ERT does not significantly elevate the risk of invasive breast carcinoma in women with previous histologically defined benign breast disease. Therefore, ERT is not contraindicated in these women.

Monoclonality in fibroadenomas with complex histology and phyllodal features.

Fibroadenoma is a common cause of benign breast masses in young women. These women have a slightly increased risk of subsequent breast cancer, particularly if their tumors have complex histologic patterns. We assessed monoclonality in fibroadenomas and correlated the results with histologic analysis. We performed a clonal analysis of 52 fibroadenomas from 43 patients using X-chromosome inactivation studies. The cases included fibroadenomas with complex and simple histology. Areas examined were predominantly stroma but epithelium was also present. DNA was isolated from paraffin-embedded tissue and was subjected to polymerase chain reaction amplification of the human androgen receptor gene with and without predigestion of the DNA with Hha 1. If a monoclonal process was identified, the epithelial and stromal components were subsequently microdissected and reanalyzed. 36/43 (83.7%) women were heterozygous. We studied 45 tumors in these 36 informative women. 1/20 (5% complex fibroadenomas and 1/25 (4%) simple fibroadenomas were monoclonal. The epithelial component of both monoclonal fibroadenomas was polyclonal. The one monoclonal simple fibroadenoma was also the only one with mixed features to contain a phyllodes component. In this case, monoclonality was found in the stroma of both the fibroadenoma and phyllodes regions. Monoclonality has been previously associated with phyllodes phenotype, but not with fibroadenomas, except for 3 fibroadenomas that recurred as phyllodes tumor. We report that monoclonality may also be seen occasionally in complex fibroadenomas, and was found in a tumors with mixed fibroadenoma/phyllodes features without clinical recurrence for 4 years.