Epithelial hyperproliferation and transglutaminase 1 gene expression in Stevens-Johnson syndrome conjunctiva.
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In Stevens-Johnson syndrome, pathological keratinization of the ordinarily nonkeratinized corneal and conjunctival mucosal epithelia results in severe visual loss. We examined conjunctiva covering cornea in five eyes in the chronic cicatricial phase of Stevens-Johnson syndrome. Normal conjunctiva from five age-matched individuals was studied also. The number of epithelial cells in Stevens-Johnson syndrome conjunctiva that were immunoreactive with a monoclonal antibody, Ki-67, to a nuclear antigen found only in proliferating cells was greater than normal (93.8+/-19.8 cells above 100 basal cells versus 12.8+/-0.5 cells above 100 basal cells; P = 0.009). In addition, although clinical inflammation was mild, massive lymphocytic infiltration was seen in the substantia propria of conjunctiva covering cornea. In situ hybridization documented transglutaminase 1 (keratinocyte transglutaminase) mRNA in suprabasal cells of the abnormally thickened conjunctival epithelium in all Stevens-Johnson syndrome patients. In contrast, no message was detected in normal conjunctival or corneal epithelia. Transglutaminase 1 is expressed during the terminal differentiation of keratinocytes where it helps synthesize cornified cell envelopes. We speculate that in Stevens-Johnson syndrome, epithelial hyperproliferation, and transglutaminase 1 gene expression lead to the pathological keratinization of ocular surface mucosal epithelia. (+info)
Circadian variation in the expression of cell-cycle proteins in human oral epithelium.
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At the tissue level, there is experimental and clinical data to suggest a cytokinetic coordination of the cell cycle with a greater proportion of cycling cells entering S-phase and mitosis at specific times of the day. The association of certain cell-cycle proteins with defined events in the cell cycle is well established and may be used to study the timing of cell-cycle phases over 24 hours. In this study oral mucosal biopsies were obtained from six normal human volunteers at 4-hour intervals, six times over 24 hours. Using immunohistochemistry, the number of positive cells expressing the proteins p53, cyclin-E, cyclin-A, cyclin-B1, and Ki-67 was determined for each biopsy and expressed as the number of positive cells per mm of basement membrane. We found a statistically significant circadian variation in the nuclear expression of all of these proteins with the high point of expression for p53 at 10:56 hours, cyclin-E at 14:59 hours, cyclin-A at 16:09 hours, cyclin-B1 at 21:13 hours, and Ki-67 at 02:50 hours. The circadian variation in the nuclear expression of cyclins-E (G1/S phase), -A (G2-phase), and -B1 (M-phase) with a normal physiological progression over time suggests a statistically significant circadian variation in oral epithelial cell proliferation. The finding of a circadian variation in the nuclear expression of p53 protein corresponding to late G1 is novel. This information has clinical implications regarding the timing of chemotherapy and radiotherapy. (+info)
Immunologic proliferation marker Ki-S2 as prognostic indicator for lymph node-negative breast cancer.
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BACKGROUND: Proper treatment of lymph node-negative breast cancer depends on an accurate prognosis. To improve prognostic models for this disease, we evaluated whether an immunohistochemical marker for proliferating cells, Ki-S2 (a monoclonal antibody that binds to a 100-kd nuclear protein expressed in S, G2, and M phases of the cell cycle), is an accurate indicator of prognosis. METHODS: We studied 371 Swedish women with lymph node-negative breast cancer; the median follow-up time was 95 months. The fraction of tumor cells in S phase was assessed by flow cytometry, and tumor cell proliferation was measured immunohistochemically with the monoclonal antibodies Ki-S2 and Ki-S5 (directed against the nuclear antigen Ki-67). A combined prognostic index was calculated on the basis of the S-phase fraction, progesterone receptor content, and tumor size. RESULTS: In multivariate analyses that did or did not (263 and 332 observations, respectively) include the S-phase fraction and the combined prognostic index, the Ki-S2 labeling index (percentage of antibody-stained tumor cell nuclei) emerged as the most statistically significant predictor of overall survival, disease-specific survival, and disease-free survival (all two-sided P<.0001). In the risk group defined by a Ki-S2 labeling index of 10% or less, life expectancy was not statistically significantly different from that of age-matched women without breast cancer, whereas the group with a high Ki-S2 labeling index had an increased risk of mortality of up to 20-fold. CONCLUSIONS: Cellular proliferation is a major determinant of the biologic behavior of breast cancer. Prognosis is apparently best indicated by the percentage of cells in S through M phases of the cell cycle. Measurement of the Ki-S2 labeling index of a tumor sample may improve a clinician's ability to make an accurate prognosis and to identify patients with a low risk of recurrence who may not need adjuvant therapy. (+info)
Comparison of the Ki-67 score and S-phase fraction as prognostic variables in soft-tissue sarcoma.
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Immunohistochemically determined Ki-67 scores and flow cytometrically determined S-phase fractions were successfully evaluated from the primary tumours of 123 patients with soft-tissue sarcoma. All patients had either limb or superficial trunk tumours. Ki-67 score correlated strongly with ploidy, S-phase fraction and grade. Ki-67 did not correlate with the size of the primary tumour. When analysed as a continuous variable, Ki-67 was a stronger predictor of both metastasis-free survival and disease-specific overall survival (P = 0.003 and 0.04 respectively) than was the S-phase fraction (P = 0.06 and 0.07 respectively). We tested the relevance of different cut-point values by dividing the whole material into two parts at every 10% (e.g. 10% of patients vs. the remaining 90%, 20% vs. 80%, etc.). We counted the relative risk and confidence interval at all these cut-off points. Ki-67 had good prognostic discriminating power irrespective of the cut-point value, but S-phase fraction lost its prognostic power at higher cut-point values. In conclusion, we found that Ki-67 is a useful prognostic tool in the treatment of soft-tissue sarcoma patients irrespective of the cut-point value. S-phase fraction can be used at lower cut-point values. (+info)
Androgen receptor expression in male breast carcinoma: lack of clinicopathological association.
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Androgen receptor (AR) expression was retrospectively analysed in 47 primary male breast carcinomas (MBCs) using a monoclonal antibody on formalin-fixed, paraffin-embedded tissues. AR immunopositivity was detected in 16 out of 47 (34%) cases. No association was found with patient age, tumour stage, progesterone receptor (PGR) or p53 protein expression. Well-differentiated MBCs tended to be AR positive more often than poorly differentiated ones (P = 0.08). A negative association was found between ARs and cell proliferative activity: MIB-1 scores were higher (25.4%) in AR-negative than in AR-positive cases (21.11%; P = 0.04). A strong positive association (P = 0.0001) was found between ARs and oestrogen receptors (ERs). In univariate analysis, ARs (as well as ERs and PGRs) were not correlated with overall survival; tumour histological grade (P = 0.02), size (P = 0.01), p53 expression (P = 0.0008) and MIB-1 scores (P = 0.0003) had strong prognostic value. In multivariate survival analysis, only p53 expression (P = 0.002) and histological grade (P = 0.02) retained independent prognostic significance. In conclusion, the lack of association between AR and most clinicopathological features and survival, together with the absence of prognostic value for ER/PGR status, suggest that MBCs are biologically different from female breast carcinomas and make it questionable to use antihormonal therapy for patients with MBC. (+info)
Continuous perivascular L-arginine delivery increases total vessel area and reduces neointimal thickening after experimental balloon dilatation.
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The aim of this study was to evaluate whether vascular remodeling and neointimal thickening occur after balloon dilatation of the nonatherosclerotic rabbit carotid artery, and whether both processes are influenced by continuous perivascular delivery of L-arginine or the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME). In the first experiment, histological and morphometric evaluation of arteries was performed at different time points after balloon dilatation: 10 minutes (n=7), and 1 (n=7), 2 (n=9), 3 (n=20), or 10 (n=5) weeks. Neointimal thickening progressively contributed to luminal narrowing for at least 10 weeks after angioplasty. During the first 2 weeks after dilatation, a significant decrease of the total vessel area was measured. Ten weeks after dilatation, both the neointimal and total vessel area were increased without further changing of the luminal area. In the second experiment, endothelial injured rabbits were randomly assigned to receive 2 weeks of continuous local perivascular physiological salt solution (n=6), L-arginine (n=8), or L-NAME (n=7), starting immediately after balloon dilatation (ie, local drug delivery during the first phase of the biphasic vascular remodeling process). Perivascular L-arginine delivery significantly reduced the neointimal area, despite an increased number of neointimal Ki-67-positive smooth muscle cells. Both the luminal area and total vessel area were significantly increased. Serum L-arginine levels remained unchanged. L-NAME administration had no effect on the neointimal area, nor on the luminal and total vessel area. Neointimal formation and biphasic vascular remodeling occur after experimental balloon dilatation of the nonatherosclerotic rabbit carotid artery, and can be influenced by continuous local perivascular delivery of L-arginine. (+info)
Tumor extension and cell proliferation in adenocarcinomas of the lung.
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To elucidate the mechanism of tumor extension in human pulmonary adenocarcinoma, we immunohistochemically investigated the expression of cell cycle regulator proteins in 54 small adenocarcinomas less than 3 cm in diameter. The Ki-67-labeling index was significantly higher in the periphery of the tumor nodule than in the center. This proliferative potential correlated well with coexpression of cdk2 and cyclin A. p27, one of the cdk inhibitors, was highly expressed in normal bronchial epithelial cells. Peripherally located tumor cells expressed p27 at an intermediate level, but at a higher frequency and level than those in the center. Expression of p21 was also predominant in the periphery. Furthermore, the expression patterns of p21 and p27 were reciprocal. In vitro kinase assays further demonstrated higher cdk2 kinase activity in the periphery. These results suggest that: (i) within an emerging extension made up of peripherally located tumor cells, their high proliferative potential gradually wanes as their relative topographical position becomes more central in the expanding tumor; (ii) peripherally located tumor cells maintain their proliferative potential by higher cyclin A-cdk2 complex activity; and (iii) intermediate expression of p21/p27 in the peripherally located cells promotes higher cyclin A-cdk2 kinase activity, whereas high p21/p27 expression in nonneoplastic cells inhibits kinase activity. (+info)
Comparison of mitotic index, in vitro bromodeoxyuridine labeling, and MIB-1 assays to quantitate proliferation in breast cancer.
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PURPOSE: To investigate the hypothesis that in vitro bromodeoxyuridine (BrDu) labeling might be superior to MIB-1 immunostaining for prognostic value, because it more selectively labels cells during the S phase. METHODS: Four hundred eighty-six patients with breast cancers (59% lymph node-negative, 41% lymph node-positive) surgically excised between 1988 and 1993 (median follow-up, 62 months) were evaluated for cellular proliferation using prospective in vitro BrDu uptake assays, retrospective mitotic indices, and MIB-1 labeling. RESULTS: MIB-1, BrDu labeling, and mitotic index-derived proliferation data were highly correlated. Each was similarly associated with most other markers of prognosis, although these relationships were not identical. By univariate analysis, nodal status was the most significant prognostic variable for all patients. Higher BrDu labeling index, MIB-1 immunolabeling, and mitotic index were also associated with shortened disease-free survival (DFS) and disease-specific survival for the entire patient group, as well as for node-negative patients. The association between cellular proliferation and survival was much weaker for node-positive patients. Multivariate models confirmed that nodal status, tumor size, and proliferation data predicted survival in all patients as well as those with node-negative disease, although MIB-1 was somewhat more closely associated with outcome than mitotic index or in vitro BrDu data. For patients with T1NOMO disease (n = 172), the only significant predictors of DFS were proliferation rate (mitotic index or MIB-1) and tumor grade. CONCLUSIONS: Proliferation rate predicts recurrence and survival in breast cancer. This effect is more pronounced in node-negative patients. In vitro BrDu data are not superior to MIB-1 and mitotic counting. (+info)