Pathological and epidemiological factors associated with advanced stage at diagnosis of breast cancer.

BACKGROUND: Breast cancer is a highly heterogeneous disease, but the stage at presentation significantly influences outcome. It is important to dissect the pathobiological and epidemiological factors that influence the stage at presentation in order to develop effective strategies to improve clinical outcome. SOURCES OF DATA: PubMed references relating to breast cancer subtypes, molecular classification of breast cancer, genetic susceptibility, young women and breast cancer. AREAS OF AGREEMENT: HER-2 positive, basal-like tumours and inflammatory breast cancers (IBC) more frequently present as late stage disease. Socioeconomic, cultural and ethnic background also influence stage at presentation. AREAS OF CONTROVERSY: The biology of IBC is poorly understood. Relative contribution of social and genetic factors in certain ethnic groups. GROWING POINTS Molecular determinants of breast cancer behaviour. Genetic and biological factors influencing disease phenotype in different ethnic groups. AREAS TIMELY FOR DEVELOPING RESEARCH: Biology of basal-like tumours and IBC. Role of predisposition of genetic variants in determining breast cancer phenotypes. Biological differences in breast cancer from different ethnic groups.

Molecular subtyping of DCIS: heterogeneity of breast cancer reflected in pre-invasive disease.

BACKGROUND: Molecular profiling has identified at least four subtypes of invasive breast carcinoma, which exhibit distinct clinical behaviour. There is good evidence now that DCIS represents the non-obligate precursor to invasive breast cancer and therefore it should be possible to identify similar molecular subtypes at this stage. In addition to a limited five-marker system to identify molecular subtypes in invasive breast cancer, it is evident that other biological molecules may identify distinct tumour subsets, though this has not been formally evaluated in DCIS. METHODS: Tissue microarrays were constructed for 188 cases of DCIS. Immunohistochemistry was performed to examine the expression patterns of oestrogen receptor (ER), progesterone receptor (PR), Her2, EGFR, cytokeratin (CK) 5/6, CK14, CK17, CK18, ß4-integrin, ß6-integrin, p53, SMA, maspin, Bcl-2, topoisomerase IIα and P-cadherin. Hierarchical clustering analysis was undertaken to identify any natural groupings, and the findings were validated in an independent sample series. RESULTS: Each of the intrinsic molecular subtypes described for invasive breast cancer can be identified in DCIS, though there are differences in the relative frequency of subgroups, in particular, the triple negative and basal-like phenotype is very uncommon in DCIS. Hierarchical cluster analysis identified three main subtypes of DCIS determined largely by ER, PR, Her2 and Bcl-2, and this classification is related to conventional prognostic indicators. These subtypes were confirmed in an analysis on independent series of DCIS cases. CONCLUSION: This study indicates that DCIS may be classified in a similar manner to invasive breast cancer, and determining the relative frequency of different subtypes in DCIS and invasive disease may shed light on factors determining disease progression. It also demonstrates a role for Bcl-2 in classifying DCIS, which has recently been identified in invasive breast cancer.

Predictive markers in breast cancer--the present.

Breast cancer is a heterogeneous disease and there is a continual drive to identify markers that will aid in predicting prognosis and response to therapy. To date, relatively few markers have established prognostic power. Oestrogen receptor (ER) is probably the most powerful predictive marker in breast cancer management, both in determining prognosis and in predicting response to hormone therapies. Progesterone receptor (PR) is also a widely used marker, although its value is less well established. HER-2 status has also become a routine prognostic and predictive factor in breast cancer. Given the importance of these biological markers in patient management, it is essential that assays are robust and quality controlled, and that interpretation is standardized. Furthermore, it is important to be aware of the limitations in their predictive power, and how this may be refined through addition of further biological markers. The aim of this review is to provide an overview of the established role of ER, PR and HER-2 in patient management, the current standards for assessing these markers, as well as highlighting the controversies that still surround their use and methods of assessment.

Early onset of breast cancer in a group of British black women.

Since there are no published data on breast cancer in British black women, we sought to determine whether, like African-American women, they present at a younger age with biologically distinct disease patterns. The method involved a retrospective review of breast cancer to compare age distributions and clinicopathological features between black women and white women in the UK, while controlling for socioeconomic status. All women presented with invasive breast cancer, between 1994 and 2005, to a single East London hospital. Black patients presented significantly younger (median age of 46 years), than white patients (median age of 67 years (P=0.001)). No significant differences between black and white population structures were identified. Black women had a higher frequency of grade 3 tumours, lymph node-positive disease, negative oestrogen receptor and progesterone receptor status and basal-like (triple negative status) tumours. There were no differences in stage at presentation; however, for tumours of < or =2 cm, black patients had poorer survival than white patients (HR=2.90, 95% CI 0.98-8.60, P=0.05). Black women presented, on average, 21 years younger than white women. Tumours in younger women were considerably more aggressive in the black population, more likely to be basal-like, and among women with smaller tumours, black women were more than twice as likely to die of their disease. There were no disparities in socioeconomic status or treatment received. Our findings could have major implications for the biology of breast cancer and the detection and treatment of the disease in black women.

Positive and negative aspects of sentinel lymph node biopsy in breast cancer.

The sentinel lymph node (SLN) is the first lymph node to receive lymphatic drainage from a tumor. SLN biopsy has become a mainstay of breast cancer management and is used when the axilla is clinically clear of disease. Staging of the axilla in breast cancer is used to predict prognosis and in planning adjuvant treatment. SLN biopsy is not used where there has been previous axillary or breast radiotherapy or surgery, locally advanced or inflammatory disease and stage IV disease. Controversies remain in several specific clinical situations, including management of the axilla following detection of a positive SLN. There are no sufficiently robust predictive tumor features to prevent completion axillary dissection in these cases. However, there is evidence that immediate axillary surgery for operable, clinically node-negative breast cancer provides no survival benefit and may be unnecessary for many women. SLN biopsy may have a role after neoadjuvant chemotherapy, sparing some women from axillary node dissection. Further work is required to ascertain SLN biopsy sensitivity prior to its routine use in the clinic for multicentric and multifocal disease.

A review of the ethnic differences in breast cancer.

Women of African descent have a lower incidence of breast cancer than their white counterparts; however, the overall age-adjusted breast cancer mortality rates are higher. They also present at a younger age, and have more advanced disease that exhibits poor prognostic features including significantly larger tumors of higher grade, higher rates of estrogen receptor and progesterone receptor negativity and a higher rate of p53 mutations and HRAS1 proto-oncogene expression, all of which confer a poor prognosis. While there are many possible contributory factors to the discrepancies in outcome in women of African descent, there is no satisfactory explanation as to why women of African origin tend to present at a younger age with hormone receptor-negative tumors and more adverse prognostic features.

Evidence for the role of gonadotropin hormones in the development of Alzheimer disease.

Differences in the prevalence and age of onset of Alzheimer disease (AD) in men and women, and observations that hormone replacement therapy (HRT) may prevent the development of AD, caused many to hypothesize that estrogen deficiency contributes to AD. However, recent trials using estrogen failed to show any benefit in preventing or alleviating the disease. To address this and other inconsistencies in the estrogen hypothesis, we suspect that another hormone of the hypothalamic-pituitary-gonadal axis, luteinizing hormone (LH), as a major factor in AD pathogenesis. Individuals with AD have elevated levels of LH when compared with controls, and both LH and its receptor are present in increased quantities in brain regions susceptible to degeneration in AD. LH is also known to be mitogenic, and could therefore initiate the cell cycle abnormalities known to be present in AD-affected neurons. In cell culture, LH increases amyloidogenic processing of amyloid-beta protein precursor, and in animal models of AD, pharmacologic suppression of LH and FSH reduces plaque formation. Given the evidence supporting a pathogenic role for LH in AD, a trial of leuprolide acetate, which suppresses LH release, has been initiated in patients.

Novel therapeutic strategies for Alzheimer's disease based on the forgotten reproductive hormones.

The relationship between hormones and Alzheimer's disease (AD) has been intensely researched. While the majority of this work has focused on the sex steroids, estrogens, and more recently androgens, a serendipitous patient encounter led one of us (R.L.B.) to question whether other hormones of the hypothalamic-pituitary-gonadal axis might play a role in the pathogenesis of AD. The age-related decline in reproductive function results in a dramatic decrease in serum estrogen and testosterone concentrations and an equally dramatic compensatory increase in serum gonadotropin concentrations. Indeed, there is growing evidence that the gonadotropin luteinizing hormone, which regulates serum estrogen and testosterone concentrations, is an important causative factor in the development of AD. This review provides information supporting the 'gonadotropin hypothesis'. We put forth a novel mechanism of how changes in serum luteinizing hormone concentrations could contribute to the pathogenesis of AD and discusses potential therapeutic anti-gonadotropin compounds.

Human adenovirus-36 is associated with increased body weight and paradoxical reduction of serum lipids.

BACKGROUND: Human adenovirus-36 (Ad-36) increases adiposity and paradoxically lowers serum cholesterol and triglycerides in chickens, mice, and non-human primates. The role of Ad-36 in human obesity is unknown. OBJECTIVES: To determine the prevalence of Ad-36 antibodies in obese and nonobese humans. To evaluate the association of Ad-36 antibodies with body mass index (BMI) and serum lipids. DESIGN: Cohort study. Volunteers from obesity treatment programs, communities, and a research study. SUBJECTS: Obese and nonobese volunteers at the University of Wisconsin, Madison, WI, and the Bowen Center, Naples, Florida. Obese and thin volunteer research subjects and 89 twin pairs at Columbia University, New York. INTERVENTIONS: Study 1: 502 subjects; serum neutralization assay for antibodies to Ad-2, Ad-31, Ad-36, and Ad-37; serum cholesterol and triglycerides assays. Study 2: BMI and %body fat in 28 twin pairs discordant for Ad-36 antibodies. MAIN OUTCOME MEASURES: Presence of antibodies to adenoviruses, BMI, serum cholesterol and triglycerides levels. RESULTS: Significant (P < 0.001) association of obesity and positive Ad-36 antibody status, independent of age, sex, and collection site. Ad-36 antibodies in 30% of obese, 11% of nonobese. Lower serum cholesterol and triglycerides (P < 0.003) in Ad-36 antibody-positive vs -negative subjects. Twin pairs: antibody-positive twins had higher BMIs (24.5+/-5.2 vs 23.1+/-4.5 kg/m2, P < 0.03) and %body fat (29.6+/-9.5% vs 27.5+/-9.9%, P < 0.04). No association of Ad-2, Ad-31, or Ad-37 antibodies with BMI or serum lipids. CONCLUSIONS: Ad-36 is associated with increased body weight and lower serum lipids in humans. Prospective studies are indicated to determine if Ad-36 plays a role in the etiology of human obesity.

Elevated gonadotropin levels in patients with Alzheimer disease.

OBJECTIVE: To determine whether gonadotropin levels are elevated in patients with Alzheimer disease (AD). PATIENTS AND METHODS: We measured luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels from stored plasma samples from 284 patients seen at a tertiary care center. We also reviewed their medical charts to record age and estrogen use in the women. The primary aim of our study was to determine whether gonadotropin levels were elevated in 134 patients with AD compared with levels from 45 patients with frontotemporal dementia (FTD) and 105 cognitively normal controls. RESULTS: Although overlap between LH and FSH levels was considerable, LH (P=.046) and FSH (P=.007) were significantly elevated in estrogen-free women with AD (LH: median, 26.3 IU/L; interquartile range, 14.9-34.6 IU/ L; FSH: median, 62.0 IU/L; interquartile range, 45.9-78.5 IU/L) compared with normal controls (LH: median, 20.1 IU/L; interquartile range, 13.7-25.3 IU/L; FSH: median, 47.7 IU/L; interquartile range, 34.1-57.5 IU/L). Levels of LH were also significantly higher (P=.03) in estrogen-free women with AD compared with women with FTD (LH: median, 20.7 IU/L; interquartile range, 19.0-28.5 IU/L; FSH: median, 53.3 IU/L; interquartile range, 27.6-77.9 IU/ L). When we controlled for age, no differences in LH and FSH were observed in men with AD compared with normal controls. CONCLUSIONS: Gonadotropin levels are elevated in some patients with AD, ie, women not taking estrogen. Elevated gonadotropin levels may have a role in the production of amyloid-beta protein, which is related to formation of senile plaques. Therefore, elevated gonadotropin levels may be involved in the pathogenesis of AD.

MALDI-TOF MS analysis of a library of polymerizable cyclodextrin derivatives.

Polymerizable cyclodextrin derivatives (PCDs) have been proposed as candidates for use in dental therapeutics (Bowen, 1996; Bowen and Reed, 1997). Here, PCD "libraries" were synthesized by quasi-random reactions of 6 moles of methacrylic anhydride plus 6 moles of cyclic glutaric anhydride per mole of beta-cyclodextrin (BCD) in solution. BCD has 21 reactive sites on each of its molecules. These proportions were based on probability calculations, which predicted that the products should have a minimum of 2 polymerizable substituents and acidic ligand groups on practically every one of the diverse product molecules. Matrix-assisted laser desorption/ionization (MALDI) time of flight (TOF) mass spectrometry (MS) gave valuable information regarding the masses of molecular ions representing the molecules that made up the PCD libraries. For the MALDI-TOF MS analyses, small samples were analyzed by the successive application of 3 solutions to the sample holder: the matrix in acetone, the products in water, and sodium trifluoroacetate in water. The resulting spectra had > 40 envelopes of mass peaks above background. The ionic-abundance peak heights had quasi-Gaussian configurations, with central peaks having masses in the neighborhood of 2000 g/mol (Daltons). Regardless of structural permutations within each peak, the range of these peaks was between about 1500 g/mol and 2900 g/mol. This range of masses was in accord with, but perhaps somewhat more narrow than, that predicted by the statistical method, which was based on equal reactivity of all hydroxyl groups. Analysis by MALDI-TOF MS gave valuable data regarding the masses, structures, and characteristics of the products formed and provided unanticipated information to facilitate improvements in future PCD syntheses.

An association of elevated serum gonadotropin concentrations and Alzheimer disease?

Alzheimer disease affects almost 4 million Americans and costs $65 billion annually. The disease is more common in women than in men, and studies suggest that oestrogen may have a protective effect. Oestrogen replacement lowers circulating concentrations of gonadotropins. When gonadotropins are added to rat granulosa cells in culture, the number of low density lipoprotein (LDL) receptors and the rate of uptake of low density lipoprotein increases. Many proteins found in Alzheimer disease plaques are ligands for low density lipoprotein receptors (LDLR) on central nervous system (CNS) neurones. This study evaluated whether gonadotropins may be associated with Alzheimer disease. Circulating concentrations of follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels in 40 male residents of long-term care facilities with the primary diagnosis of dementia were compared to 29 age-matched controls. Serum concentrations of FSH and LH were significantly higher in dementia patients. We speculate they may play an aetiologic role in the deposition of abnormal proteins, particularly those associated with low density lipoprotein receptors, in CNS neurones.

Echocardiographic assessment of patients receiving long-term treatment with anorexiant medications.

OBJECTIVE: To describe the prevalence and evaluate the risk of echocardiogram-determined valvulopathy in patients who received fenfluramine and phentermine in an effort to lose weight, in comparison with normal control subjects. METHODS: A historical cohort study was conducted in a clinical obesity-management practice. A total of 164 patients (88% women) who were treated with fenfluramine-phentermine for weight loss had echocardiographic evaluations. A subsample was cross-validated. RESULTS: The prevalence of mild or greater aortic regurgitation was 18.3%, and the prevalence of moderate or greater mitral regurgitation was 3.7%. The prevalences of mild or greater tricuspid and pulmonary valve regurgitation, valve thickening, and pulmonary hypertension were 23.2%, 5.5%, 10.4%, and 6.7%, respectively. No significant increases in risk were found for moderate or greater regurgitation of any valve. Patients had at least a 3-fold risk for mild or greater aortic regurgitation (standardized morbidity ratio [SMR] = 3.03; 95% confidence interval [CI] = 2.05 to 4.33) and a 2-fold risk for tricuspid regurgitation (SMR = 2.24; 95% CI = 1.58 to 3.06) in comparison with normal healthy adults. Age and duration of drug therapy predicted increased risk for aortic regurgitation. Four patients who had moderate or greater aortic regurgitation had taken the fenfluramine-phentermine combination continuously for 454, 615, 645, and 984 days. CONCLUSION: Use of serotonergic anorexiant medications may increase risk for mild or greater aortic and tricuspid regurgitation, although selection bias and obesity as causes of the association cannot be ruled out. Age and duration of drug therapy were predictors of aortic valvulopathy. Population-based studies are needed to confirm these preliminary findings.

New surface-active comonomer for adhesive bonding.

Previous studies have indicated that chemical and physical characteristics of aromatic amines can be influenced by the nature of their substituents. The experimental question examined in the present study relates to the effects of replacing specific hydrogen atoms with methyl groups in a surface-active comonomer utilized in adhesive bonding protocols. N-2-propionic acid-N-3-(2-hydroxy-1-methacryloxy)propyl-3,5-dimethylaniline sodium salt (N35A) was synthesized by an addition reaction of glycidyl methacrylate with the sodium salt of N-reaction of glycidyl methacrylate with the sodium salt of N-(3,5-dimethylphenyl)alanine, which was formed by alkaline hydrolysis of ethyl-N-(3,5-dimethylphenyl)alanate that was prepared by condensation of ethyl-2-bromopropionate with 3,5-dimethylaniline. 1H and 13C NMR spectra and analysis by mass spectroscopy were consistent with N35A after it had been recrystallized from acetone. Color stability and adhesion-promoting capability of N35A were compared with those of N-2-acetic acid-N-3-(2-hydroxy-1-methacryloxy)propyl-4-methylanaline sodium salt (Na-NTG-GMA), the latter being widely used in commercial bonding formulations. Both N35A and Na-NTG-GMA polymerized within a few minutes at 23 degrees C when dissolved in aliquots from a stock solution containing benzene 85 wt%, ethanol 14 wt%, and benzoyl peroxide 1.0 wt%; but with each at 0.018 molal concentration, the N35A suspension was more color-stable than that of the Na-NTG-GMA. In the protocol used, shear bond strengths of a hybrid composite to human dentin with N35A were 30.2 MPa, SD = 7.5 MPa, and with Na-NTG-GMA, 29.7 MPa, SD = 11.8 MPa(n = 7 each; t test, p = 0.93).

Physical and chemical properties of resin-reinforced calcium phosphate cements.

OBJECTIVES: The purpose of this study was to improve the handling and physical properties of a self-setting, water-based calcium phosphate cement by combining it with polymerizable resins and to study the setting reactions involved. METHODS: Dual-cured composite cements were prepared from a calcium phosphate cement powder and dental monomers that contain carboxylated hydrophilic resins or resin/water mixtures. The setting reaction of the calcium phosphate cement in the presence of the resins was evaluated by pH measurements, infrared spectroscopy, diametral tensile strength, x-ray diffraction analysis, and scanning electron microscopy. RESULTS: Carboxylated resins were chosen because they can form ionic bonds to the mineral filler, which was confirmed by appearance of an infrared absorbance peak at 1552 cm-1 within 24 h after mixing due to the formation of a carboxylate salt. Hydroxyapatite did not develop in composites prepared from resin and calcium phosphate cement. However, composites from calcium phosphate cement, resin and water showed approximately 40% hydroxyapatite. The resulting composite cements have moderately high DTS of 14-15 MPa and high pH. SIGNIFICANCE: Hydrophilic acidic resins allows mixing with water and/or allow rapid diffusion of water into the resinous cement so that the dissolution and reprecipitation processes required for the conversion of the calcium phosphate components to hydroxyapatite can occur. The characteristics of the resulting composite cements suggest that the materials may be useful in pulp capping and/or cavity lining.

An esthetic glass-ceramic for use in composite restoration inserts.

The objective of the preliminary work reported here was to prepare an improved formulation of intrinsically colored microcrystalline glass-ceramic. Applications could include "megafillers" for direct composite restorations, precision castings, and CAD-CAM prostheses. The experimental glass-ceramic reported here contained SiO2 56.9, AI2O3 19, LiO2 7, ZnO 6, MgO 5, TiO22, ZrO22, P2O52, and CeO20.1 mole%. The batch materials were melted and stirred at 1,610 degrees C for 2 h, quenched in water and also formed into a block of a clear, slightly yellow glass. To identify the crystalline phases that developed during transformation of the glass to the ceramic, x-ray diffraction was used on ten aliquots taken during 15 h of stepwise heating from 750 to 1050 degrees C. With heating, the yellow color deepened to a very translucent "dark yellow" dental shade, then lightened with gradually increasing opacity during formation of secondary crystalline phases. X-ray opacity was approximately equivalent to that of dental enamel. The refractive index of the glass, nD1.554, increased during nucleation and growth of the crystalline phases to a maximum of 1.586. Intrinsic coloration of these glass-ceramic materials can be controlled by varying the heat treatment and/or composition to match typical dental shades.

Adhesion of composites to dentin and enamel.

Extrapolations based on the history of the development of composites and an adhesion system for bonding dental resins and composites to hard tooth tissues can rightfully be the basis for strong optimism regarding future improvements in esthetic and conservative treatment modalities. Improved understanding of mechanisms of action and the clinical application steps common to current adhesion systems will certainly lead to improved oral healthcare.