Prognostic value of bcl-2 expression among women with breast cancer in Libya.

We studied the association of the immunohistochemical bcl-2 expression in Libyan breast cancer with clinicopathological variables and patient outcome. Histological samples from 170 previously untreated primary Libyan breast carcinoma patients were examined. In immunohistochemistry, the NCL-L-bcl-2-486 monoclonal antibody was used. Positive expression of bcl-2 was found in 106 patients (62.4 %). The bcl-2 expression was significantly associated with estrogen receptor (p<0.0001) and progesterone receptor positive tumors (p=0.002), small tumor size (p<0.0001), low tumor grade (p<0.0001), negative axillary lymph nodes (p<0.0001), early stages (p=0.001), and low risk of metastasis (p<0.0001). Positive expression was also associated with older patients (>50 years; p=0.04). Histological subtypes and family history of breast cancer did not have significant relationship with bcl-2. Patients with positive expression of bcl-2 had lower recurrence rate than bcl-2-negative patients and better survival after median follow-up of 47 months. Patients with high bcl-2 staining were associated with the best survival. The role of bcl-2 as an independent predictor of disease-specific survival was assessed in a multivariate survival (Cox) analysis, including age, hormonal status, recurrence, histological grade, and clinical stage variables. Bcl-2 (p<0.0001) and clinical stage (p=0.016) were independent predicators of disease-specific survival. For analysis of disease-free survival, the same variables were entered to the model and only bcl-2 proved to be an independent predictor (p=0.002). Patients with positive expression of bcl-2 were associated with low grade of malignancy, with lower recurrence rate, with lower rate of death, and with longer survival time. Bcl-2 is an independent predictor of breast cancer outcome, and it provides useful prognostic information in Libyan breast cancer. Thus, it could be used with classical clinicopathological factors to improve patient selection for therapy.

Loss of MUC2 expression predicts disease recurrence and poor outcome in colorectal carcinoma.

Clinical staging and histological grading after surgery have been the "gold standard" for predicting prognosis and planning for adjuvant therapy of colorectal cancer (CRC). With the recent development of molecular markers, it has become possible to characterize tumors at the molecular level. This is important for stage II and III CRCs, in which clinicopathological features do not accurately predict heterogeneity, e.g., in their tumor response to adjuvant therapy. In the present study, archival samples from 141 patients with stage I, II, III, or IV CRC treated during 1981-1990 at Turku University Hospital (Finland) were used (as microarray blocks) to analyze MUC2 expression by immunohistochemistry. Altogether, 49.7 % of all tumors were positive for MUC2. There was no significant correlation between MUC2 expression and age (P < 0.499), tumor invasion (P < 0.127), tumor staging (P < 0.470), histological grade (P < 0.706), lymph node involvement (P < 0.854), or tumor metastasis (P < 0.586). However, loss of MUC2 expression was significantly associated with disease recurrence (P < 0.031), tumor localization (P < 0.048), and with borderline significance with gender (P < 0.085). In univariate (Kaplan-Meier) survival analysis, positive MUC2 significantly predicted longer disease-free survival (DFS) and disease-specific survival (DSS) as well. However, in multivariate (Cox) survival analysis, MUC2 lost its power as an independent predictor of DFS and DSS. Our results implicate the value of MUC2 expression in predicting disease recurrence and long-term survival in CRC.

Prognostic significance of DNA image cytometry in Libyan breast cancer.

BACKGROUND: We evaluated the relation of nuclear DNA content and clinicopathological features and prognosis in primary breast cancer of female Libyan patients with variable stage and grade and different treatment regimes. PATIENTS AND METHODS: Histological samples from 104 patients of breast carcinoma were retrospectively studied by computerized nuclear DNA cytometry. Isolated nuclei from paraffin sections were stained with Feulgen stain and DNA was measured using a computer-assisted image analysis cytometry system. In each case, 200 nuclei were measured and the DNA histograms, S phase fraction (SPF) and number of cells above 5c and 9c were determined. We applied different approaches in the analysis of DNA to compare the DNA histograms with different clinicopathological features and survival. RESULTS: The mean of DNA ploidy mode for all tumors was 3.43; 82.7% of tumors were aneuploid and 17.3% were diploid. The median SPF was 3.5% for DNA diploid and 13.5% for DNA aneuploid tumors. DNA aneuploid tumors and high SPF were associated with advanced stage, distant metastasis, high histological grade and lymph node involvement. The SPF was also associated with large tumor size and with younger patients (<50 years). In the overall population (median follow-up 51 months), patients with aneuploid DNA histograms and high SPF values had shorter survival times than those with diploid DNA histograms and low SPF values (p = 0.001, p < 0.0001, respectively). Also, short survival was associated with a multiploid DNA histogram and with DNA aneuploid cells ≥5 cells (p < 0.0001, p = 0.001, respectively). In a Cox multivariate analysis, DNA ploidy (p = 0.010), age (p = 0.038) and clinical stage (p = 0.001) were independent predictors of overall survival, and DNA ploidy (p = 0.018) and clinical stage (p = 0.001) also proved to be independent predictors of disease-specific survival. The SPF cutoff point of 11% might be applied to separate patients into good and poor prognosis groups. CONCLUSIONS: DNA image cytometry with careful analysis of the histograms may provide valuable prognostic information in Libyan breast cancer, with potential clinical implications in patient management, particularly in predicting the patients at high risk for metastasis and recurrence who should be considered as candidates for combined adjuvant therapy.

Apoptotic activity in Libyan breast cancer.

BACKGROUND: We evaluated the relationship of the apoptotic activity index (AI) and the standardized mitotic-apoptotic ratio (SMI/AI) with clinicopathological features and prognosis in Libyan female breast cancer (BC) patients. We then compared our results with corresponding results in Finnish and Nigerian female BC patients. METHODS: Histological samples of breast carcinoma from 130 patients were retrospectively studied: an estimation of the apoptotic activity per square millimeter (expressed as apoptotic activity index (AI)), and standardized mitotic-apoptotic ratio (SMI/AI) was made, and the results compared with the clinicopathological features and the patient's survival. RESULTS: There was a statistically significant correlation between the AI and most of the clinicopathological features; the strongest association was observed for clinical stage lymph node (LN) status (P = 0.005). There were also correlations between AI and histological grade (P = 0.035), large tumor size (P = 0.011) and the clinical stage (P = 0.009). There were, however, prominent AI differences between Libyan, Nigerian and Finnish populations. The mean values of AI and SMI/AI in Libyan BC patients were 12.8 apoptotic figures per square millimeter and 2.8, respectively. The Libyan AI is slightly higher than in Nigeria, but much higher than in Finland. The differences between countries are seen throughout the samples as well as being present in certain subgroups. The survival analysis indicated that short survival time was associated with high apoptotic indices values and so can identify aggressive tumors and provide significant prognostic support. The cutoff (4 and 18 apoptosis/mm2) of AI might be applied as a quantitative criterion for Libyan BC to separate the patients into good, moderate and bad prognosis groups. CONCLUSIONS: The results indicated that the differences in AI among the three countries may be due to the known variation in the distribution of genetic markers in these populations. Improvement in health care and introduction of screening programs, however, could be very helpful in the Libyan population.

MMP-9 (gelatinase B) expression is associated with disease-free survival and disease-specific survival in colorectal cancer patients.

Extracellular matrix degradation is required for invasion and metastasis formation in colorectal carcinoma (CRC), therefore, we have examined matrix metalloproteinases MMP-9 expression in tumors from patients with CRC. The study comprises of 360 patients who underwent bowel resection for stage II, III, IV tumors. Paraffin-embedded CRC tissue samples were used for immunohistochemical staining. Negative MMP-9 expression levels correlated with longer survival time as evaluated by disease-free survival and disease-specific survival (p =.023, p =.006). In multivariate survival (Cox) analysis, MMP9 was a significant independent predictor of DFS (p =.014), but not of DSS, which was independently predicted by disease recurrence, stage and localization. The detection of MMP-9 expression may be valuable in finding patients who are at high risk of developing disease recurrence.

Correlation of nuclear morphometry of breast cancer in histological sections with clinicopathological features and prognosis.

BACKGROUND: The relation of nuclear morphometry measurements with clinicopathological features was evaluated along with prognosis in invasive female breast carcinoma in Libyan patients. Data was compared with corresponding results on Finnish, and Nigerian female breast cancer patients. PATIENTS AND METHODS: Histological samples from 131 patients of breast carcinoma were retrospectively studied by computerized nuclear morphometry. In each case, 50 nuclei were measured and the mean nuclear morphometric features were calculated and compared with different clinicopathological features, and patient's survival. RESULTS: There was statistically significant correlation between the mean nuclear area (MNA) and most clinicopathological features, with the strongest association observed for nuclear grade (p<0.0001). There was also correlation between nuclear area and tumor stage (p<0.04), tumor size (p<0.03) and lymph node (LN) status (p<0.001). A corresponding relationship was found between other size related features and clinical factors. The univariate analysis and survival analysis indicated that short survival time was associated with high nuclear morphometric values. MNA had negative correlation with length of survival (Pearson's test r=-0.29, p=0.019). Morphometric shape features did not show significant association with clinical features or survival. CONCLUSION: The results indicated that nuclear size features are reliable prognostic indicators in Libyan female breast carcinomas, as they were among Finnish and Nigerian females. The nuclear morphometric parameters can identify the aggressive tumor phenotype and provide significant prognostic information in predicting survival and tumors at risk of progression. The cut-off (71.0 mum(2)) of MNA might be applied as quantitative criterium for Libyan nuclear grading to separate patients into good and poor prognosis groups.

Nuclear morphometry in FNABs of breast disease in Libyans.

BACKGROUND: Nuclear morphometry can be expected to improve the distinction between benign and malignant lesions. PATIENTS AND METHODS: Forty fine-needle aspiration biopsy (FNAB) samples fixed in 50% ethanol were collected at the African Oncology Institute, Sabratha, Libya, during the period 2004-2007. All diagnoses reported were confirmed histologically. There were 23 cases of infiltrating ductal carcinoma and 17 of benign breast disease. Two different assessment methods were applied: measurements made on cell groups, and those made on free cells. Apocrine metaplasia was excluded. Five different size parameters (include mean nuclear area, MNA) and 6 shape factors were measured. RESULTS: The size parameters showed significant differences between benign and malignant cases. The mean, median and 95% percentiles of nuclear area in both types of assessment were especially significant. The shape parameters were not significant. CONCLUSION: The study suggests that interactive computerized nuclear morphometry is an efficient and successful tool in distinguishing between cases of benign and malignant disease. Combination of our data with earlier free cell data gave the following diagnostic guidelines: Range of overlap in free cell samples: MNA 55 microm2 - 71 micro2. Cut-off values for diagnostic purposes: 100% detection of malignant cases: MNA > 54 microm2 (specificity 84%), 100% detection of benign cases: MNA < 72 microm2 (sensitivity 91%).

VEGF-1 expression in colorectal cancer is associated with disease localization, stage, and long-term disease-specific survival.

BACKGROUND: Angiogenesis plays an important role in progression of colorectal carcinoma (CRC). Evidence from preclinical and clinical studies indicates that vascular endothelial growth factor (VEGF) is the predominant angiogenic factor in CRC. Indeed, VEGF is expressed in approximately 50% of CRCs, with minimal to no expression in normal colonic mucosa and adenomas. In this study, the expression of VEGF-1 was examined in stage I-IV CRCs to determine its clinicopathological correlates, and association with the response to treatment and disease outcome. PATIENTS AND METHODS: The present series consisted of tissue samples obtained from 360 patients with stage I, II, III, or IV CRC who had undergone large bowel resection during 1981-1990 at Turku University Hospital. Archival paraffin-embedded CRC tissue samples were used to build up tissue microarray (TMA) blocks and VEGF-1 expression was assessed immunohistochemically using an automated staining system. Three different grading systems were applied to evaluate the expression of VEGF-1. RESULTS: Seventy percent of patients with stage IV CRC had positive VEGF-1 expression, while 50% and 47%, respectively of patients with stage II and III CRC had positive VEGF-1 expression (p = 0.005). VEGF-1 expression in the left colon and rectum was significantly higher than that in the right colon (61% vs. 45%, respectively) (p = 0.006). Significant statistical correlation (p = 0.04) was found between VEGF-1 and 10-year disease-specific survival: patients who died of the disease more frequently had a VEGF-1-expressing tumour than did those who survived for 10 years. CONCLUSION: Quantification of VEGF-1 expression seems to provide valuable prognostic information in CRC, particularly in selecting those patients at high risk for disease progression who are likely to benefit from adjuvant therapy.

Loss of cholinergic neurons in the pedunculopontine nucleus in Parkinson's disease is related to disability of the patients.

We investigated neuronal number and size in the pars compacta of the pedunculopontine nucleus (PPN) in Parkinson's disease (PD). In PD, the number of Luxol fast blue (LFB) neurons was reduced by 27% from the mean control value (p=0.04) and the cholinergic (choline acetyltransferase, ChAT-positive) neuron number was reduced by 36% (p=0.03). In addition to neuronal loss, the remaining neurons in the PPN in PD were smaller than in controls. The profile area of LFB neurons was reduced by 14% (p=0.009) and that of ChAT-positive neurons by 26% (p=0.001). There was more severe loss of ChAT-positive neurons with a more severe stage of the disease, evaluated by the modified Hoehn and Yahr scale (r=-0.66, p=0.03). The neuron number decreased much more than could be expected on the basis of decrease in cell size alone.

Up-regulation of alpha-catenin is associated with increased lymph node involvement in colorectal cancer.

AIM: To investigate the changing pattern of alpha-catenin expression and its relationship to clinical and pathological features of colorectal cancer (CRC) patients. METHODS: Archival tumor samples were analyzed using immunohistochemistry (IHC) for alpha-catenin in 91 patients with advanced CRC. RESULTS: The values of alpha-catenin membrane index (MI) and cytoplasmic index (CI) were significantly related to the depth of tumor invasion (P = 0.027, P = 0.020, respectively), high indices being associated with increased depth of the primary tumor invasion (T3 and T4). Similarly, patients with high alpha-catenin expression had a significantly increased risk of lymph node metastasis (32/39 vs 37/52 for MI and 37/45 vs 32/46 for CI) (P = 0.001, P = 0.0001, respectively, for LNN status). An altered expression (i.e., cytoplasmic pattern) was also related (P = 0.047) to the response to chemotherapy; patients with low CI were more responsive (CR: 7/46) than patients with high CI values (CR: 0/45). There was a marginal effect on survival in patients time with metastases (SWM) (P = 0.087); patients with low CI showing slightly longer SWM, but no such effect on disease free survival (DFS) or disease specific survival (DSS). As to co-expression with another member of the adhesion complex (beta-catenin), high alpha-catenin/beta-catenin MI index was of marginal significance in predicting longer DSS (P = 0.063, log-rank). CONCLUSION: The results implicate that high alpha-catenin expression is intimately involved in the key regulatory mechanisms leading to invasive phenotype, lymph node metastases, and progressive disease in CRC.

Nuclear beta-catenin expression as a prognostic factor in advanced colorectal carcinoma.

AIM: To investigate the changing pattern of beta-catenin expression and its prognostic value in advanced colorectal cancer (CRC). METHODS: Archival tumor samples were analyzed for beta-catenin using immunohistochemistry (IHC) in 95 patients with advanced CRC. RESULTS: Membranous beta-catenin expression was found in the normal colorectal epithelium. Almost 100% of CRC cases showed membranous and cytoplasmic expression, and 55 (58%) cases showed nuclear expression. In univariate (Kaplan-Meier) survival analysis, only the nuclear index (NI) was a significant predictor of disease free survival (DFS) (P = 0.023; n = 35), with a NI above the median associated with longer DFS (34.2 mo) than those with a NI below the median (15.5 mo) (P = 0.045, ANOVA). The other indices were not significant predictors of DFS, and none of the three tested indices (for membranous, cytoplasmic, or nuclear expression) predicted disease-specific survival (DSS). However, when dichotomized as positive or negative nuclear expression, the former was a significant predictor of more favorable DFS (P = 0.041) and DSS (P = 0.046). CONCLUSION: Nuclear beta-catenin expression provides additional information in predicting patient outcome in advanced CRC.

Genomic changes of the 55 kDa subunit of DNA polymerase epsilon in human breast cancer.

BACKGROUND: DNA polymerases (Pols) represent potential candidates for cancer genes because of their central functions in DNA metabolism. Defects of some DNA Pols have shown cancer associations, but data on DNA polymerase (Pol) epsilon is limited. MATERIALS AND METHODS: Twenty-four human breast cancer DNA samples and four control DNA samples were examined for possible mutation in the entire coding region of the 55 kDa small subunit of the human DNA Pol epsilon gene using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis of the DNA and sequence analysis. In addition, 20 control DNAs were studied with PCR-SSCP for the end of intron 18 and exon 19 region. RESULTS: An AATT deletion was found at one location in intron 18 in 2 out of the 24 breast cancer cases (8%), but in none of the control cases. In addition, a single base transition was found in the cancer DNAs in intron 14, but the same changes were also found in the control DNAs, suggesting polymorphism. CONCLUSION: Specific changes might occur in the 55 kDa small subunit DNA sequence of DNA Pol epsilon in breast cancer. The deletion at the region of intron-exon junction may not affect the protein code, but could potentially influence splicing efficiency and expression levels, possibly impairing the function of Pol epsilon DNA.

The effect of vascular endothelial growth factor-1 expression on survival of advanced colorectal cancer patients.

Colorectal cancer is third leading cause of cancer mortality. About 60% of patients had already developed metastasis at the time of diagnosis. Vascular endothelial growth factor (VEGF) is crucial for the development of neovascularization and hence metastasis. This study aimed at investigating the relation between the expression of VEGF in biopsies from surgically dissected colon cancer and the survival of those patients. Biopsies were collected from 86 patients with advanced colon cancer and sections were stained by immunohistochemistry for VEGF. Patients received chemotherapy after the operation and were followed up for disease progression and survival. The clinical data were statistically analyzed with respect to the immunohistochemistry results. The survival of the patients was significantly longer in the patients for whom biopsies showed negative or weak expression of VEGF in comparison to those with moderate to high expression (p-value = 0.04). The expression of VEGF was more frequent in the patients who died as a consequence of the disease in comparison to the 10-year survivors. In conclusion, VEGF could be related to the survival of the patients with colorectal carcinoma and should be considered as a predictor of the prognosis.

Nuclear size as prognostic determinant in stage II and stage III colorectal adenocarcinoma.

BACKGROUND: The prognostic value of morphometric nuclear features was assessed in stage II and stage III colorectal cancer (CRC). MATERIALS AND METHODS: Primary tumors from 123 CRC patients were analyzed using an image overlay drawing system for the following nuclear size features: area, perimeter, diameter and form features. RESULTS: The nuclear area (NA) was significantly different in tumors at different localizations (p=0.029). A large NA was a significant predictor of recurrent disease, with overall response (OR) 3.09 (1.37-6.95) (p =0.006). The NA was significantly larger in recurrent cases (106.3 microm2) than in non-recurrent ones (96.6 microm2) (p=0.007) and was a significant predictor of disease-free survival (DFS) in univariate (Kaplan-Meier) analysis (log-rank p=0.0239). However, lymph node involvement was the most powerful predictor of DFS in multivariate analysis, with OR 3.371 (95%CI 1.17-9.65) (p=0.024) and disease recurrence the only independent predictor of disease-specific survival (DSS), with OR 48.4 (95%CI 6.30-371.73). CONCLUSION: Quantitative measurement of the NA seems to accurately discriminate the patients, among stage II and III colorectal cancer, who are likely to develop disease recurrence. Image morphometry seems to be a useful adjunct tool in examining the subgroup of lymph node-negative patients to predict the risk of disease recurrence and indications for adjuvant therapy.

E-cadherin expression pattern in primary colorectal carcinomas and their metastases reflects disease outcome.

AIM: To investigate the changes that occur in E-cadherin expression during the process of metastasis in colorectal cancer. METHODS: E-cadherin expression was detected by immunohistochemistry and two indices of expression were calculated which reflected the level of expression and the locations (membrane and cytoplasm). Univariate and multivariate survival analyses were used to assess the value of these two E-cadherin indices as predictors of both disease-free (DFS) and disease-specific (DSS) survival. RESULTS: E-cadherin membrane index (MI), but not cytoplasmic index (CI), was significantly higher in primary tumors than their metastases (P = 0.0001). Furthermore, both primary tumor MI and CI were higher among the patients who developed subsequent metastasis (P = 0.022 and P = 0.007, respectively). Interestingly, both indices were higher in liver metastase compared to other anatomic sites (MI, P = 0.034 and CI, P = 0.022). The CI of the primary tumors was a significant predictor of DFS (P = 0.042, univariate analysis), with a strong inverse correlation between CI and DFS (P = 0.006, multivariate analysis). Finally, the MI of primary tumor proved to be a significant independent predictor of DSS, with higher indices being associated with a more favorable outcome (P = 0.016). CONCLUSION: Examination of E-cadherin expression and distribution in colorectal tumors can be extremely valuable in predicting disease recurrence. The observation that aberrant cytoplasmic expression of E-cadherin can predict disease recurrence is obviously of great importance for both patients and clinicians, and significantly affects decisions concerning the therapy and management of the patients.

Neurofibromin Expression is Associated with Aggressive Disease and Poor Outcome in Colorectal Carcinoma.

AIM: To assess the predictive and prognostic value of neurofibromin (NF) expression in colorectal carcinoma (CRC). MATERIALS AND METHODS: The present series consists of archival samples from 191 patients with stage I, II, III, or IV CRC treated between 1981 and 1990 at the Turku University Hospital (Finland). Tumor biopsies as microarray blocks were analyzed for expression of NF by immunohistochemistry. Different grading systems were tested for NF expression. RESULTS: A significant correlation between NF expression and tumor localization was found, with tumors arising in the colon showing intense NF expression more often than those arising in the rectum (p=0.014). Higher expression of NF was more common in tumors not responding to treatment (p=0.004). Tumors with multiple metastases showed higher expression of NF than those with single metastasis only (p=0.025). Furthermore, NF expression showed a borderline (p=0.068) correlation with gender; tumors of women showed higher NF expression that those of males. On the other hand, NF expression was not significantly associated with tumor recurrence, age, lymph node involvement, tumor grade and tumor stage or disease outcome. CONCLUSION: Positive NF expression in CRC is a sign of aggressive disease and poor outcome.

Immunohistochemical staining of estrogen and progesterone receptors: aspects for evaluating positivity and defining the cutpoints.

BACKGROUND: Estrogen (ER) and progesterone (PgR) receptors are predictive and prognostic factors in breast cancer. The most suitable immunohistochemical cutpoints for dividing the tumors in hormone receptor-negatives and -positives may, however, need more consideration. We examined the association between breast cancer survival and cutpoints assessed by four different models. We looked for evidence for which patient subgroups could be handled best through applying different cutpoints. MATERIALS AND METHODS: Three hundred and twenty-four samples of invasive breast cancer were immunohistochemically stained for ER and PgR, bcl-2 and erbB2. Fractions of ER- and PgR-positive cells and also ER and PgR staining scores were assessed. The fractions of stained cells and staining scores, respectively, were determined on the whole section area, and the area of most intense staining. Candidate cutpoints, dividing the patients into good and poor prognosis groups, were tested among all patients group, N+ and N- groups, premenopausal and postmenopausal patient groups. The correlation between immunohistochemistry results of ER, PgR, bcl-2 and erbB2 as well as SMI (standardized mitotic index), patient age, tumor size and axillary lymph node status were tested. RESULTS: The ER score was correlated with age, SMI and bcl-2 positivity. The PgR score was correlated with erbB2 and bcl-2. Lobular carcinomas had higher staining scores of ER and PgR than ductal carcinomas. CONCLUSION: In this material, ER was correlated with factors reflecting the differentiation of the tumor. On the basis of the ER and PgR immunohistochemistry cutpoint analysis, we found that the optimal cutpoints in different patient groups may not be the same.

Nuclear area is a prognostic determinant in advanced colorectal cancer.

BACKGROUND: The prognostic value of morphometric nuclear features in Dukes' Stages B/C and D colorectal cancer (CRC) was assessed. PATIENTS AND METHODS: Primary tumours from 86 CRC patients were analysed, using an image overlay drawing system (Prodit Morphometry Program), for the following nuclear features: area, perimeter, diameter, form factor, roundness. RESULTS: The median nuclear area (NA) was 104.6 microm2 (range 57.2 - 237.2 microm2). The NA was larger in patients with lymph node metastasis (p < 0.02). Altogether, 43% of the patients showed clinical response to irinotecan-based chemotherapy. All six patients with complete response (CR) had a NA above the median (p < 0.03). The disease-specific survival of the patients with a NA above the median was significantly better than in patients with smaller NA (p < 0.02). CONCLUSION: Using the median NA as the cut-off value seems to effectively discriminate patients who are likely to respond to irinotecan-based chemotherapy (with improved prognosis) from those who are non-responsive and develop progressive disease.

Enterolactone inhibits the growth of 7,12-dimethylbenz(a)anthracene-induced mammary carcinomas in the rat.

The inverse association between a high enterolactone (ENL) concentration in both urine and serum, and the risk of breast cancer found in epidemiological studies suggests a chemopreventive action for ENL. However, no causal relationship has been established in clinical studies or in experimental models for breast cancer. In the present study, the potential chemopreventive action of p.o. administered ENL (1 or 10 mg/kg of body weight) was tested in 7,12-dimethylbenz(a)anthracene-induced mammary cancers of the rat. Rats were maintained on a standard open-formula chow diet. Daily p.o. administration of ENL at a dose of 10 mg/kg of body weight for 7 weeks significantly inhibited tumor growth. The growth-inhibitory effect of ENL was more pronounced on the new tumors, which developed during the treatment period, but ENL also inhibited the growth of those tumors established before the start of the lignan administration. The rat serum concentration of ENL, which illustrated a permanent positive effect on breast cancer growth, was 0.4 microM, which is >10-fold as compared with the serum concentrations found in the general human population. The effect of ENL was not restricted to any specific histological tumor type. ENL was demonstrated to act as a weak aromatase inhibitor in vitro and to reduce the relative uterine weight of the 7,12-dimethylbenz(a)anthracene-treated nonovariectomized rats. However, in a short-term assay ENL had no effect on the uterine growth of the intact or androstenedione-treated immature rats. Thus, the mechanism of the ENL action and its minimum or optimal daily dose remains to be clarified.

Apocrine change in fine-needle aspiration biopsy: nuclear morphometry and DNA image cytometry.

The aim of this study was to investigate the potential of computerized nuclear morphometry and DNA image cytometry in characterizing the apocrine change of mammary epithelium in fine-needle aspiration biopsy (FNAB). The effect of two different sample processing techniques on the results was also studied. Mean nuclear areas in air-dried smears ranged from 59.0 microm2 to 151.0 microm2 and in ethanol-fixed samples from 32.3 microm2 to 63.4 microm2. The DNA histograms of apocrine cells usually showed a dominant peak in the diploid region. In some cases the mode of the peak was slightly shifted to the right or left in respect to the control peak. One case had a tetraploid cell population, suggesting atypical apocrine change. After histological investigation this case was diagnosed as infiltrating carcinoma. The patient had earlier been treated with x-ray irradiation for a mediastinal lymphoma. Findings of nuclear morphometry and DNA cytometry in apocrine metaplasia are here described in a systematic study for the first time. The data suggest that these methods may help in distinguishing premalignant and malignant apocrine lesions from typical apocrine metaplasia of mammary epithelial cells.