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We present unconditionally energy-stable second-order time-accurate schemes for diffuse-interface (phase-field) models; in particular, we consider the Cahn-Hilliard equation and a diffuse-interface tumor-growth system consisting of a reactive Cahn-Hilliard equation and a reaction-diffusion equation. The schemes are of the Crank-Nicolson type with a new convex-concave splitting of the free energy and an artificial-diffusivity stabilization. The case of nonconstant mobility is treated using extrapolation. For the tumor-growth system, a semi-implicit treatment of the reactive terms and additional stabilization are discussed. For suitable free energies, all schemes are linear. We present numerical examples that verify the second-order accuracy, unconditional energy-stability, and superiority compared with their first-order accurate variants.
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Modelos Teóricos , Neoplasias/metabolismo , Algoritmos , Simulación por Computador , HumanosRESUMEN
AIM: Sentinel lymph node (SLN) biopsy is an accepted alternative to axillary lymph node dissection to assess the axillary tumour status in breast cancer patients. Memorial Sloan-Kettering Cancer Center (MSKCC) developed a nomogram to predict the likelihood of SLN metastases in breast cancer patients. Nomogram performance was tested on a Dutch population. METHODS: Data of 770 breast cancer patients who underwent successful SLN biopsy were collected. SLN metastases were present in 222 patients. A receiver operating characteristic (ROC) curve was drawn and the area under the curve was calculated to assess the discriminative ability of the MSKCC nomogram. A calibration plot was drawn to compare actual versus nomogram-predicted probabilities. RESULTS: The area under the ROC curve for the predictive nomogram was 0.67 (95% confidence interval 0.63-0.72) as compared to 0.75 in the original population. The nomogram was well-calibrated in the Dutch population. CONCLUSIONS: In a Dutch population, the MSKCC nomogram estimated risk of sentinel node metastases in breast cancer patients well (i.e. calibration) with reasonable discrimination (area under ROC curve). Nomogram performance on core needle biopsy data has to be evaluated prospectively.
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Neoplasias de la Mama/patología , Metástasis Linfática , Nomogramas , Biopsia del Ganglio Linfático Centinela , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Persona de Mediana Edad , Países Bajos , Ciudad de Nueva York , Estudios Prospectivos , Curva ROCRESUMEN
Genetic polymorphisms of host defense genes might increase risk for periodontitis. This case-control study investigated whether 102 single-nucleotide polymorphisms (SNPs) in Fc gamma receptor (FCGR) genes are associated with chronic periodontitis. Cases were 190 Hong Kong Chinese patients with severe chronic periodontitis, and there were 169 periodontitis-free individuals as controls. Genotype CC and allele C of rs445509 (p < 0.0001, OR = 0.30) of FCGR3A were significantly more prevalent among control individuals than among cases, after adjustment for age, sex, and smoking. Smoking was significantly associated with chronic periodontitis (p = 0.003, OR = 3.35). Within the limitations of this study, SNP rs445509 of FCGR3A seem to be negatively associated, while smoking was positively associated, with severe chronic periodontitis among Hong Kong Chinese.
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Periodontitis Crónica/genética , Polimorfismo de Nucleótido Simple/genética , Receptores de IgG/genética , Adenina , Adulto , Factores de Edad , Alelos , Estudios de Casos y Controles , Citosina , Femenino , Genotipo , Guanina , Haplotipos , Hong Kong , Humanos , Masculino , Persona de Mediana Edad , Factores Sexuales , Fumar , TiminaRESUMEN
BACKGROUND AND OBJECTIVE: Polymorphisms of host defence genes might increase one's risks for periodontitis. This study investigated whether tagging single nucleotide polymorphisms (SNPs) of the gene encoding complement component 5 (C5) are associated with periodontitis in a Hong Kong Chinese population. MATERIAL AND METHODS: Eleven tagging SNPs of 229 patients with at least moderate periodontitis and 207 control subjects without periodontitis were genotyped using an i-plexGOLD MassARRAY mass-spectrometry system. RESULTS: Genotype AG of SNP rs17611 was more prevalent in the group of periodontitis patients than in the controls (54.6% vs. 41.7%, p = 0.007). The haplotype CGCA of the haplotype block consisting of rs1035029, rs17611, rs25681 and rs992670 was significantly associated with periodontitis in a dominant model (p = 0.001). The SNP rs17611 showed high linkage disequilibrium with rs1035029, rs25681 and rs992670. Smoking was also significantly associated with periodontitis (p = 0.006). CONCLUSION: The tagging SNP rs17611 of the C5 gene and smoking may be associated with periodontitis among the Hong Kong Chinese population.
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Complemento C5/genética , Factores Inmunológicos/genética , Periodontitis/inmunología , Polimorfismo de Nucleótido Simple/genética , Adenina , Adolescente , Adulto , Factores de Edad , Periodontitis Agresiva/genética , Periodontitis Agresiva/inmunología , Estudios de Casos y Controles , Periodontitis Crónica/genética , Periodontitis Crónica/inmunología , Citosina , Femenino , Frecuencia de los Genes/genética , Variación Genética/genética , Genotipo , Guanina , Haplotipos , Hong Kong , Humanos , Intrones/genética , Desequilibrio de Ligamiento/genética , Masculino , Persona de Mediana Edad , Periodontitis/genética , Factores de Riesgo , Factores Sexuales , Fumar , Adulto JovenRESUMEN
Periodontal disease is considered to be an opportunistic infection as a result of interactions between the causative agents (dental plaque) and the host responses which may be modulated by genetic, environmental and acquired risk factors. Besides being a well-confirmed risk factor in a number of systemic diseases, tobacco smoking has also been associated with periodontal disease. Over the past 10-15 years, more and more scientific data on the impact of smoking on various aspects of periodontal disease and the underlying mechanisms has been published. The purpose of this review was to provide an overview of the available data in order to give practitioners a better understanding of the relationship between smoking and periodontal disease. Subsequently, they can use some of the information in treatment decisions and give advice to patients who are smokers suffering from periodontal disease.
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Enfermedades Periodontales/etiología , Fumar/efectos adversos , Placa Dental/microbiología , Encía/irrigación sanguínea , Humanos , Planificación de Atención al Paciente , Enfermedades Periodontales/inmunología , Factores de Riesgo , Fumar/inmunologíaRESUMEN
BACKGROUND: Completion axillary lymph node dissection (ALND) remains the standard of care for patients with disease-positive sentinel lymph nodes (SLN). However, approximately two-thirds will have no additional disease-positive nodes. To identify the patient's individual risk for non-SLN metastases, the Memorial Sloan-Kettering Cancer Center (MSKCC) developed a nomogram. METHODS: The records of 182 breast cancer patients who underwent SLN and ALND were selected. Serial hematoxylin and eosin (HE) analysis and immunohistochemistry were routinely performed on each sentinel node. For application of the nomogram, the detection method was assigned in two ways: for all metastases visible by serial HE, the method of detection was scored as "serial HE" (method 1), independent of the tumor size, and by a combination of size and staining method (method 2); so macrometastasis were scored as detected by routine HE, micrometastasis by serial HE, and isolated tumor cells by immunohistochemistry. A receiver operating characteristic curve (ROC) was drawn, and the area under the curve was calculated to assess the discriminative power of the nomogram. RESULTS: The area under the ROC was .71 (range, .64-.79) according to method 1 and .75 (range, .67-.88) according to method 2. CONCLUSIONS: Because the variable "method of detection" in the MSKCC nomogram is a surrogate for SLN metastasis size, the size category of the SLN metastasis can be used in applying the nomogram to patients in whom the SLN histologic analysis is performed by a much different procedure than that used to develop the MSKCC nomogram. This results in an improved predictive accuracy.
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Neoplasias de la Mama/patología , Ganglios Linfáticos/patología , Nomogramas , Adulto , Anciano , Anciano de 80 o más Años , Axila , Femenino , Humanos , Metástasis Linfática , Persona de Mediana Edad , Curva ROC , Estudios Retrospectivos , Factores de Riesgo , Biopsia del Ganglio Linfático CentinelaRESUMEN
OBJECTIVE: To evaluate the adjunctive effect of a low-power He-Ne laser in the non-surgical periodontal treatment of patients with moderate to advanced chronic periodontitis. BACKGROUND DATA: Laser applications in dental treatment are now more common in the literature. However, limited data are available on the potential effects of the low-power laser as an adjunct to non-surgical periodontal therapy for managing patients with moderate to advanced periodontal disease. MATERIALS AND METHODS: Sixteen patients with probing pocket depth (PPD) > or =5 mm and comparable bone defects on both sides of the mouth were recruited. Supragingival plaque (PL), bleeding on probing (BOP), PPD, and probing attachment level (PAL) were recorded at baseline and at 3, 6, 9, and 12 mo, while gingival crevicular fluid (GCF) samples and standardized intra-oral radiographs for digital subtraction radiography were taken at baseline and at 1, 3, 6, 9, and 12 mo. After non-surgical mechanical periodontal treatment, the test sites were selected randomly and irradiated with a low-power He-Ne laser (output power 0.2 mW) for 10 min for a total of eight times in the first 3-mo period, while the control sites received no additional treatment. RESULTS: PL percentage (83-16%) and BOP percentage (95-34%) decreased significantly after 12 mo. Statistically significant changes in reductions of PPD and GCF volume, gain in PAL, and increase in recession were seen in both test and control sites when compared to baseline (p < 0.05). No statistically significant differences in any clinical parameters or radiographic findings were found between the test and control sites. Changes in GCF volume were significant only at 3 mo in the test sites. CONCLUSION: Within the limits of this pilot study, the use of the low-power He-Ne laser as an adjunct to non-surgical periodontal therapy in patients with moderate to advanced chronic periodontitis did not seem to provide additional clinical benefit.
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Periodontitis Crónica/radioterapia , Terapia por Luz de Baja Intensidad , Adulto , Periodontitis Crónica/diagnóstico por imagen , Femenino , Humanos , Láseres de Gas , Masculino , Persona de Mediana Edad , Bolsa Periodontal/radioterapia , Proyectos Piloto , RadiografíaRESUMEN
Image registration is one of the image processing methods which is widely used in computer vision, pattern recognition, and medical imaging. In digital subtraction radiography, image registration is one of the important prerequisites to match the reference and subsequent images. In this paper, we propose an automatic non-rigid registration method namely curvature-based registration that relies on a curvature based penalizing term and its application on dental radiography. The regularizing term of this intensity-based registration approach provides affine linear transformation so that pre-registration step is no longer necessary. This leads to faster and more reliable solutions. The implementation of this approach is based on the numerical solution of the underlying Euler-Lagrange equations. In addition, a comparison between this algorithm and Linear Alignment Method (LAM) with 20 image pairs is presented.
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Sample groups of children (n=50) and adults (n=38) were selected from pools of 207 children, (11-13-year olds from two primary schools) and 94 adults (25-44-year olds from four governmental agencies) who were the subjects of an oral health survey among Tibetans living in Lhasa, Tibet Autonomous Region. Mean ages of the study groups of children (38% females) and adults (61% females) were 11.6+/-0.9 and 37.1+/-6.1 years, respectively. All had lived in Tibet since birth. Oral rinse samples were selective cultured to isolate, quantify and speciate aerobic and facultatively anaerobic Gram-negative rods (using the API 20E kit) and yeasts (using API 20C AUX and API ZYM kits). For children, the isolation rates for oral coliform bacteria and yeasts were 84 and 14%, respectively, for adults, the respective rates were 26 and 40%. The corresponding quantities of coliforms/yeasts for children and adults were 0.4+/-1.6 x 10(3)c.f.u./15.8+/-72.3 and 0.2+/-0.6 x 10(3)c.f.u./57.2+/-137.5c.f.u. per millilitre oral rinse, respectively. Aerobic and facultatively anaerobic Gram-negative rods and Stenotrophomonas maltophilia, a free-living saprophytic and ubiquitous bacterial species of wide geographic distribution, were significantly more frequently recovered from the children's oral rinses. The isolation rates of facultatively anaerobic Gram-negative rods in adults and yeasts in both groups were similar to those found in similar cohorts from southern China in earlier studies. Randomly amplified polymeric DNA analysis showed that the S. maltophilia spp. isolated from children were of several different clonal types and were school specific. This study shows that the colonisation rate of facultatively anaerobic Gram-negative rods in adults and yeasts in both groups are similar to those in populations living at lower altitudes, the native young, urban Tibetans appear to exhibit a high oral carriage rate of S. maltophilia spp.
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Bacilos Gramnegativos Anaerobios Facultativos/aislamiento & purificación , Bacilos Grampositivos/aislamiento & purificación , Boca/microbiología , Adolescente , Adulto , Niño , Cryptococcus/aislamiento & purificación , Enterobacteriaceae/aislamiento & purificación , Femenino , Humanos , Masculino , Pseudomonas/aislamiento & purificación , Saccharomyces/aislamiento & purificación , Stenotrophomonas maltophilia/aislamiento & purificación , Tibet/epidemiologíaRESUMEN
OBJECTIVES: To calibrate and validate a digital subtraction radiography system using scanned images for quantification of alveolar bone changes by means of computer-assisted densitometric image analysis (CADIA) in vitro. MATERIALS AND METHODS: Noise levels were determined using 10 standardized periapical radiographs of the same lower molar region in a human dry skull. For validation of the system, radiographs were taken before and after bovine bone particles in measures with increments of 2 mg weighing from 2 to 20 mg were added into each socket of three dry skulls. Radiographs were developed and scanned into a computer with a flatbed scanner. After digitization, the images were subjected to alignment, normalization and subtraction. Appropriate regions of interest (ROIs) were selected and their CADIA values were calculated for the determination of noise levels, and correlations between the CADIA values and the actual bone mass were performed. RESULTS: When the threshold value was 7, the percentage of pixels deviating from the set threshold value was small (0-11.3%). There were statistically significant correlations between the actual bone mass and the CADIA value for anterior sockets (p<0.001, r2=0.89) and posterior sockets (p<0.001, r2=0.9). For pooled data of both anterior and posterior sockets, the correlation was also statistically significant (p<0.001, r2=0.88). CONCLUSIONS: A high and statistically significant correlation between the actual bone mass and CADIA value was obtained, which suggests that the system could be suitable for the detection of small alveolar bone changes.
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Pérdida de Hueso Alveolar/diagnóstico por imagen , Radiografía Dental Digital , Técnica de Sustracción , Alveolo Dental/diagnóstico por imagen , Absorciometría de Fotón , Animales , Artefactos , Calibración , Bovinos , Humanos , Análisis de los Mínimos Cuadrados , Interpretación de Imagen Radiográfica Asistida por Computador , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
Internal mammary lymph-node (IMN) metastases in breast carcinomas have a major influence on survival, comparable with the influence of axillary lymph-node metastases (ALNM). Prospective, randomized trials have demonstrated that complete IMN dissection as part of extended radical mastectomy does not improve overall or disease-free survival. In the subset of patients with tumours 1cm or less in size and no ALNM, information on IMN status would provide important information. In these cases, the presence of IMN metastases would change the staging from stage I to stage IIIB, according to the current tumour, node and metastasis classification. More importantly, it would influence these patients' adjuvant treatment. Lymphatic mapping for sentinel lymph-node (SLN) biopsy has demonstrated extra-axillary drainage in up to 35% of patients. Recent reports have demonstrated the feasibility of internal mammary sentinel lymph-node (IM-SLN) biopsy. Here we review the general prognostic and clinical significance of tumor location and lymph-node metastases in breast cancer and discuss the specific factors associated with IMN identification, metastases and treatment in the pre-SLN and SLN eras. Based on our review, we propose an algorithm for a selective approach to IM-SLN in breast cancer.
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Algoritmos , Neoplasias de la Mama/patología , Ganglios Linfáticos/patología , Biopsia del Ganglio Linfático Centinela , Femenino , Humanos , Metástasis Linfática , Arterias Mamarias , Estadificación de Neoplasias , Selección de Paciente , Pronóstico , Salud de la MujerRESUMEN
AIMS: The purpose was to identify the independent predictive factors of axillary lymph-node metastases (ALNM) in infiltrating ductal carcinoma (IFDC) and to create a prospective, validated statistical model to predict the likelihood of ALNM in patients in the present era of sentinel lymph-node (SLN) biopsy and enhanced histopathology. METHODS: Univariate and multivariate analyses of 13 clinicopathological variables (including tumour location) were performed to determine predictors of ALNM in 1659 eligible SLN biopsy procedures. A logistic regression model was developed and then prospectively validated on a second population of 187 subsequent consecutive procedures. RESULTS: Age, pathological tumour size, palpability, lymphovascular invasion (LVI), histological grade, nuclear grade, ductal histological subtype, tumour location (quadrant) and multifocality were associated with ALNM in univariate analyses (P < 0.001). Of these, only palpability and histological grade were not statistically associated with ALNM in the multivariate analysis (P> 0.05). The frequency of ALNM in upper-inner-quadrant (UIQ) tumours was 20.6%, compared with 33.2% for all other quadrants (P<0.0005). There was no statistical difference between UIQ and other-quadrant tumours in any clinicopathological variables analysed. The logistic regression model, developed based on the population of 1659, had the same accuracy, sensitivity, specificity, positive predictive value and negative predictive value when applied prospectively to the second population. CONCLUSION: Tumour size, LVI, age, nuclear grade, histological subtype, multifocality and location in the breast were independent predictive factors for ALNM in IFDC. ALNM is less frequent in UIQ tumours than in other-quadrant tumours. Our prospectively validated predictive model could be valuable in pre-operative patient discussions, although staging of the axilla in the individual patient remains necessary.
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Ganglios Linfáticos/patología , Metástasis Linfática/diagnóstico , Metástasis Linfática/patología , Biopsia del Ganglio Linfático Centinela , Adulto , Anciano , Axila , Neoplasias de la Mama/diagnóstico , Carcinoma Ductal de Mama/diagnóstico , Carcinoma Lobular/diagnóstico , Femenino , Humanos , Persona de Mediana Edad , Análisis Multivariante , Estadificación de Neoplasias , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Sesgo de Selección , Sensibilidad y Especificidad , Salud de la MujerAsunto(s)
Enfermedades Periodontales/epidemiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Periodontitis Agresiva/epidemiología , Asia/epidemiología , Pueblo Asiatico , Niño , Preescolar , Servicios de Salud Dental/estadística & datos numéricos , Recesión Gingival/epidemiología , Gingivitis Ulcerosa Necrotizante/epidemiología , Estado de Salud , Humanos , Renta/estadística & datos numéricos , Persona de Mediana Edad , Higiene Bucal/estadística & datos numéricos , Islas del Pacífico/epidemiología , Pérdida de la Inserción Periodontal/epidemiología , Índice Periodontal , Pobreza/estadística & datos numéricos , Prevalencia , Factores de Riesgo , Clase Social , Pérdida de Diente/epidemiología , Población BlancaAsunto(s)
Neoplasias de la Mama/cirugía , Escisión del Ganglio Linfático/métodos , Metástasis Linfática/patología , Mastectomía Radical/métodos , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Femenino , Humanos , Estadificación de Neoplasias , Biopsia del Ganglio Linfático Centinela , Tasa de SupervivenciaAsunto(s)
Neoplasias de la Mama/patología , Carcinoma in Situ/patología , Carcinoma Intraductal no Infiltrante/patología , Biopsia con Aguja , Neoplasias de la Mama/diagnóstico , Carcinoma Intraductal no Infiltrante/diagnóstico , Femenino , Humanos , Estadificación de Neoplasias , Sensibilidad y EspecificidadRESUMEN
In a study among 72 nurses, the affective consequences of social comparison were examined and related to neuroticism (N) and to social comparison orientation (SCO). Participants were confronted with a bogus interview with an upward versus a downward comparison target. Positive affect and identification were higher, and negative affect was lower, in the upward than in the downward comparison condition. Independent of their SCO, the higher individuals were in N, the less they identified with the upward comparison target, the more they identified with the downward comparison target, and the less positive affect they showed following confrontation with the upward comparison target. In contrast, independent of their level of N, the higher individuals were in SCO, the more negative affect they showed following confrontation with the downward comparison target. The effects on negative affect stayed the same when controlling for positive affect, and the effects on positive affect stayed the same when controlling for negative affect. These effects were also obtained when perceived direction was used as a predictor instead of the experimentally manipulated direction. It is concluded that, although N and SCO are correlated, these variables seem to have independent and distinct effects upon the responses to social comparison information.
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Afecto , Trastornos Neuróticos/diagnóstico , Personalidad , Deseabilidad Social , Trabajo , Adulto , Conducta Competitiva , Femenino , Humanos , Masculino , Persona de Mediana Edad , Trastornos Neuróticos/epidemiología , Enfermeras y Enfermeros/psicología , Determinación de la Personalidad , Distribución AleatoriaRESUMEN
The aim of this study was to investigate the salivary immunoglobulin A concentration in rapid and slow plaque formers. After 3 days of oral hygiene abstinence, 49 healthy volunteers were screened using the plaque index (PI) to assess their plaque formation rates. Five subjects with the highest, and five with the lowest mean PI were selected as rapid and slow plaque formers, respectively. Unstimulated whole saliva was collected from each of these ten subjects and the levels of salivary IgA assessed using a conventional ELISA technique. Reference curves for salivary IgA were established by testing serial dilutions of human IgA with known concentrations. When the differences between the two groups were compared, almost a twofold increase in the mean salivary IgA concentration in the slow (16 microg/ml +/- 4) compared with the rapid (9 microg/ml +/- 3) plaque formers was recorded (p < 0.05). These findings, reported for the first time, imply that salivary IgA may play a crucial role in regulating the pioneer plaque development on enamel surfaces.
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Índice de Placa Dental , Placa Dental/inmunología , Inmunoglobulina A Secretora/metabolismo , Saliva/inmunología , Adulto , Femenino , Humanos , Masculino , Proyectos PilotoRESUMEN
OBJECTIVE: The purpose of this study was to evaluate the outcomes of bracketing wire placement during preoperative breast needle localization. SUBJECTS AND METHODS: We prospectively examined mammograms of 1057 consecutive lesions that had preoperative needle localization and surgical excision and classified the lesions according to Breast Imaging Reporting and Data System (BI-RADS) final assessment categories. Bracketing wires, defined as multiple wires placed to delineate the boundaries of a single lesion, were used in 103 (9.7%) of 1057 lesions. Medical records, imaging studies, and histologic findings in these 103 lesions were reviewed. RESULTS: Of 103 bracketed lesions, median lesion size was 3.5 cm (range, 1.5-9.5 cm). Ninety-three lesions (90.3%) contained calcifications; 65 lesions (63.1%) were BI-RADS category 5 (highly suggestive of malignancy); and 33 lesions (32.0%) were percutaneously proven cancers. The median number of wires placed was two (range, 2-5). Surgical histologic findings were carcinoma in 75 lesions (72.8%), atypical hyperplasia in eight lesions (7.8%), and benign in 20 lesions (19.4%). Of 42 calcific lesions that were bracketed and had postoperative mammograms available for review, complete removal of suspicious calcifications was accomplished in 34 (81.0%). Of 75 cancers that were bracketed, clear histologic margins of resection were obtained in 33 (44.0%). CONCLUSION: Bracketing wires were used during preoperative needle localization primarily for larger calcific lesions that were proven cancers or were highly suggestive of malignancy (BI-RADS category 5). Bracketing wires may assist the surgeon in achieving complete excision of calcifications, but bracketing wires do not ensure clear histologic margins of resection.
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Biopsia/instrumentación , Neoplasias de la Mama/diagnóstico por imagen , Mamografía/instrumentación , Mastectomía Segmentaria/instrumentación , Adulto , Anciano , Mama/patología , Neoplasias de la Mama/patología , Neoplasias de la Mama/cirugía , Calcinosis/diagnóstico por imagen , Calcinosis/patología , Calcinosis/cirugía , Carcinoma Ductal de Mama/diagnóstico por imagen , Carcinoma Ductal de Mama/patología , Carcinoma Ductal de Mama/cirugía , Carcinoma Intraductal no Infiltrante/diagnóstico por imagen , Carcinoma Intraductal no Infiltrante/cirugía , Carcinoma Lobular/diagnóstico por imagen , Carcinoma Lobular/patología , Carcinoma Lobular/cirugía , Diagnóstico Diferencial , Femenino , Enfermedad Fibroquística de la Mama/diagnóstico por imagen , Enfermedad Fibroquística de la Mama/patología , Enfermedad Fibroquística de la Mama/cirugía , Humanos , Hiperplasia , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
PURPOSE: Clinically undetectable micrometastases may account for disease recurrence in breast cancer patients after variable disease-free intervals. However, little is known about the cellular mechanisms controlling human breast cancer micrometastases. We compared tumor proliferation rate, apoptotic index, and angiogenesis in human breast cancer micrometastases with those of macroscopic axillary lymph node metastases. EXPERIMENTAL DESIGN: Seven breast cancer micrometastases (<2 mm) obtained from the sentinel nodes of seven patients were compared with 13 macrometastases (lymph node replaced with tumor) obtained from 13 patients. The tissue was fixed in formalin, embedded in paraffin, serially sectioned, and evaluated by H&E and immunohistochemistry for cytokeratin. Tumor proliferation rate was assessed as the number of Ki-67-positive nuclei/total number of tumor nuclei. Tumor vascularity was quantified using antibody to factor VIII to identify microvessels per high-power field (at x400). Apoptosis was quantified using the terminal deoxynucleotidyl transferase (Tdt)-mediated nick end labeling method. Results were analyzed with the Wilcoxon rank-sum test. RESULTS: Median size of micrometastases was 0.5 mm (range, 0.4-1.0), and the median number of tumor nuclei/section was 143 (range, 90-312). Median proliferation rate for macrometastases was greater than for micrometastases (35% versus 12%; P = 0.003). Median microvessel density/high-power field for macrometastases was greater than for micrometastases (17 versus 1; P < 0.001). There was no difference in apoptotic index between macrometastases and micrometastases (1.1% versus 0.7%; P = not significant). CONCLUSIONS: Human breast cancer micrometastases have lower tumor proliferation rates and angiogenesis than breast cancer macrometastases. These characteristics may explain their differential growth patterns.
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Neoplasias de la Mama/patología , Metástasis de la Neoplasia/patología , Adulto , Anciano , Apoptosis , Neoplasias de la Mama/irrigación sanguínea , Neoplasias de la Mama/metabolismo , División Celular , Humanos , Inmunohistoquímica , Antígeno Ki-67/análisis , Persona de Mediana Edad , Neovascularización Patológica/patología , Factor de von Willebrand/análisisRESUMEN
Gossypol has demonstrated in vitro effects on cell cycle regulation and anti-tumor activity against mammary carcinoma cell lines. This Phase I/II study assesses both the effect of gossypol on cell cycle regulatory proteins in vivo and the clinical effect. Twenty women with refractory metastatic breast cancer received oral gossypol at daily doses between 30 and 50 mg per day. Gossypol plasma levels were measured (n = 8) and the modulation of the retinoblastoma (Rb) gene protein and Cyclin D1 was assessed by serial biopsies (n = 4). Grade I-II toxicities with gossypol treatment included nausea in 30% of patients, fatigue 15%, emesis 15%, altered taste sensation 15% and diarrhea in 10% of patients. Two of the three patients receiving 50 mg/day experienced dose limiting dermatologic toxicity (grade III). One patient had a minor response and two patients had stable disease with > 50% decline in serial assessments of the serum tumor markers. Immunohistochemical analysis of cyclin D1 and Rb expression in serial biopsies of four patients revealed both a concurrent decrease in cyclin D1 expression and an increase in nuclear Rb expression in three patients. The maximal tolerated dose (MTD) of gossypol was 40 mg/day. Gossypol appears to affect the expression of Rb protein and cyclin D1 in breast cancer metastases at doses achievable, yet had negligible antitumor activity against anthracycline and taxane refractory metastatic breast cancer. The cell cycle regulatory effects of gossypol suggest a potential role for gossypol as a modulating agent in conjunction with other cell cycle specific compounds.