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Proliferative activity has been proposed as a prognostic and predictive marker for breast cancer; Ki-67 is one of the most frequently used markers to assess proliferative activity. In the current study, Ki-67 immunoreactivity was comparatively assessed, even in terms prognostic relevance, with 3H-thymidine labeling index as a reference standard for proliferation in 126 patients with stage I and II breast cancer. There was a significant but weak correlation between Ki-67 values and the 3H-thymidine labeling index (r = 0.19, P = 0.03). Analysis of variance showed that the mean 3H-thymidine labeling index values were not statistically different in terms of pathologic size (T1, T2. T3, T4), number of pathologically positive axillary nodes (neg, pos 1-3, pos > 3), and grading classes (1, 2, 3), but significantly and inversely correlated with estrogen receptor status (P = 0.033) and progesterone receptor status (P = 0.08). The Ki-67 values significantly correlated with N status (P = 0.041), estrogen receptor status (P < 0.001), progesterone receptor status (P < 0.001), and grading (P < 0.001). The median follow-up was 37 months. In terms of prognosis, Ki-67 was associated significantly with overall survival (P = 0.01) and marginally with disease-free survival (P = 0.095). A significant difference in prognosis was found for both disease-free survival (P = 0.024) and overall survival (P = 0.040) when a 3H-thymidine labeling index cut-off of 6.5% was used (P = 0.024). The results suggest that, although both are indicators of proliferative activity, 3H-thymidine labeling index and Ki-67 seem to identify breast cancers with different phenotypes.
Appl Immunohistochem Mol Morphol 2002 Dec
PMID:Relationship between the thymidine labeling and Ki-67 proliferative indices in 126 breast cancer patients. 1260 97

Young women with breast cancer have a more unfavorable outcome and advanced disease than older women. This study was initiated to determine the difference in tumor biology between younger and older groups. One hundred fifty-five patients with invasive ductal carcinoma, not otherwise specified, comprised the study group, including 50 women aged less than 35 years, 50 aged 36 to 50 years, and 55 aged more than 50 years. Histopathologic parameters, including tumor size, combined histologic grade, and axillary lymph node status, were studied. Biomarkers, including estrogen receptor status, tumor proliferation rate as determined by Ki-67, and gene expressions of c-erbB-2, p53, bcl-2, and BRCA1, were determined by immunohistochemistry. Comparisons of the distribution of these parameters in three age groups were performed. Breast cancer occurring in women aged less than 35 years had a significantly higher incidence of large tumor, high proliferation rate, and loss of nuclear BRCA1 expression (44.0% versus 22.0% or 23.6%) than in the two older age groups. Breast cancer in women aged less than 35 years also had higher histologic grade and higher frequency of bcl-2-negative tumor than that found in the 36- to 50-year age group. No difference was found in lymph node status and c-erbB-2 and p53 gene expressions between the age groups. Loss of BRCA1 nuclear expression significantly correlated with higher histologic grade and high Ki-67 index (P < 0.05) in group A. These findings suggested that women aged less than 35 years have frequent loss of nuclear BRCA1 expression, which may be responsible for the specific tumor biology different from older women. However, c-erbB-2 and p53 gene expressions seem to have no important role in the adverse tumor behavior of breast cancer in young women.
Appl Immunohistochem Mol Morphol 2002 Dec
PMID:Frequent loss of BRCA1 nuclear expression in young women with breast cancer: an immunohistochemical study from an area of low incidence but early onset. 1260 98

DP-1 is a G1 cell cycle-related protein that forms heterodimers with E2F, a family of transcriptional factors regulating the expression of genes important for G1 to S progression. Although the exact role of DP-1 is not well understood, it has been shown to stabilize DNA binding of E2F proteins. By immunohistochemistry, the authors examined the expression of DP-1 in lymphoid tissues, including 8 cases of reactive follicular hyperplasia and 69 cases of B-cell non-Hodgkin lymphoma. The expression of the cell cycle-related proteins E2F-1 and Ki-67 was also assessed. Scoring was based on the proportion of labeled nuclei (1-10%, 11-25%, 26-50%, and > 50%). In reactive follicular hyperplasia, staining for DP-1, E2F-1, and Ki-67 was largely confined to the germinal centers. All 25 cases of follicular lymphoma, regardless of grade, had a high proportion (> 50%) of DP-1-positive cells but a lower proportion of cells marking for E2F-1 and Ki-67 (P < 0.001). The diffuse large B-cell lymphomas (n = 24) had high DP-1 and Ki-67 scores but low E2F-1 scores (P < 0.001). Small lymphocytic (n = 10), marginal zone (n = 3), and mantle cell lymphomas (n = 5) contained relatively low proportions of cells labeled for all three markers. Precursor B-cell lymphoblastic lymphoma (n = 2) displayed high proportions of cells positive for DP-1, Ki-67, and E2F-1 (> 50% in both cases). Except in follicular center cell lesions, DP-1 expression generally correlated with that of Ki-67. However, the expression of DP-1 was discordant with that of E2F-1 in benign and malignant follicular center cells, suggesting that DP-1 may have functions other than facilitating E2F-1-dependent gene regulation and cell cycle progression in these neoplasms.
Appl Immunohistochem Mol Morphol 2002 Dec
PMID:Immunohistochemical expression of the transcription factor DP-1 and its heterodimeric partner E2F-1 in non-Hodgkin lymphoma. 1260

Mutated tumor suppression gene p53 is a common genetic abnormality in most papillary or invasive transitional cell carcinomas (TCC). In these cases, overexpression of p53 protein is detectable in nuclei by immunohistochemical methods. Nuclear antigen Ki-67, a marker of cellular proliferation, has been shown to correlate with the growth of many human neoplasms, including TCC. Since overexpression of p53 protein and increased Ki-67 proliferative activity have been a consistent finding in TCC, p53 and Ki-67 expression may be used as markers of urothelial cells with significant genetic alterations. In this study, the authors have investigated whether there is increased p53 and Ki-67 expression in varying grades of urothelial dysplasia. Staining for p53 and Ki-67 using formalin-fixed, paraffin-embedded sections was performed using a Dako Autostainer, followed by counting positive cells using an automatic cellular imaging system (ACIS). The high-grade dysplasia/CIS group (n = 16) had a similar high percentage and intensity of p53 staining (45.3 +/- 4.3%; 28.2 +/- 6.1 arbitrary units [AU]) as the TCC group (n = 16. 53.6 +/- 3.9%; 36.8 +/- 5.7 AU), but revealed a significantly higher percentage and intensity of p53 staining than the low-grade dysplasia (n = 14, 25.6 +/- 3.3%; 12.2 +/- 2.0 AU) and benign group (n = 10, 10.0 +/- 3.3%; 5.8 +/- 1.7 AU). Percentage of p53-positive cells counted by ACIS was similar to that obtained by manual counting. In addition, expression of Ki-67 in all four groups paralleled p53 expression. The authors' data showing overexpression of p53 and Ki-67 in high-grade urothelial dysplasia/CIS similar to that observed in TCC support the notion that high-grade urothelial dysplasia/CIS is a precursor of invasive TCC.
Appl Immunohistochem Mol Morphol 2002 Dec
PMID:p53 protein and Ki-67 overexpression in urothelial dysplasia of bladder. 1260 1

Unconstrained cell proliferation is characteristic of tumors. It is caused by the functional disorders of proteins that constitute the cell cycle mechanism. The cell cycle is controlled by cyclins, cyclin-dependent kinases, and cyclin-dependent kinase inhibitors. Many reports have proved, in cancers, that cyclins, cyclin-dependent kinases, and cyclin-dependent kinase inhibitors are out of control. Cyclin A is a protein that regulates critical transition of the cell cycle. The expression of cyclin A in meningiomas by immunohistochemical method was investigated. Furthermore, the correlation among cyclin A expression, clinical course, and proliferative potential were also evaluated. Seventy-seven meningiomas were studied. The mean cyclin A labeling indices were as follows: benign meningiomas, 1.01% +/- 0.62%; atypical meningiomas, 4.23% +/- 1.82%; and anaplastic meningiomas, 7.72% +/- 0.88%. Analyses of variance showed that significant differences existed between tumor grades for cyclin A labeling indices. A linear positive correlation between the cyclin A labeling index and bromodeoxyuridine labeling index was observed. The multivariate analysis using Cox's hazards model showed a high cyclin A labeling index (>3%) was a significant risk factor for recurrence. A high Ki-67 labeling index (>5%) and high tumor grade (World Health Organization grade II, III) were also significant risk factors for recurrence. These results suggested that the evaluation of cyclin A expression in meningiomas provides significant clinical information, especially as an independent prognostic indicator.
Appl Immunohistochem Mol Morphol 2003 Mar
PMID:Prognostic significance of cyclin a expression in meningiomas. 1261 Mar 50

We tested a recently developed flexible method of separation and quantification of immunohistochemical staining by means of color image analysis. An algorithm was recently developed to deconvolve the color information acquired with RGB cameras, to calculate the contribution of each of the applied stains, based on the stain-specific RGB absorption. The algorithm was tested using a set of lung-tumor samples labeled for the detection of Ki-67, an antigen expressed in proliferating cells, covering a wide range of staining levels. Quantification of the labeling was compared with HSI-based segmentation and manual analysis of the same samples. The recently developed deconvolution method performed significantly better than the HSI based system when compared to manual counting as gold standard. The deconvolution system showed significantly reduced variability in the LI determination, especially of highly labeled control samples. This resulted in significant increase in sensitivity of classification of samples with increased KI-67 labeling without changing the specificity, when compared to the HSI based method.
Appl Immunohistochem Mol Morphol 2003 Mar
PMID:Comparison of quantification of histochemical staining by hue-saturation-intensity (HSI) transformation and color-deconvolution. 1261 Mar 62

A change in the balance between proliferation and apoptosis in the course of hepatocellular carcinoma (HCC) development and progression has been suspected. We wanted to identify related genes whose mRNA levels could provide markers of severity and prognosis after resection. The extent of cell apoptosis, proliferation, and differentiation was measured with a terminal deoxynucleotidyl transferase-mediated deoxyuridine 5-triphosphate-biotin nick-end labeling assay, and the Ki-67 index was determined in paired tumor and cirrhotic tissue samples from patients who had undergone HCC resection after diagnosis of hepatitis C-related or alcoholism-related cirrhosis. These patients included two groups with highly versus poorly differentiated tumor cells, and the latter was split into two subgroups of those with versus without early recurrence. The mRNA levels for various apoptosis-related or proliferation-related genes and those for the growth factor/receptor systems were measured by quantitative reverse transcriptase-polymerase chain reaction in paired tumor and cirrhotic liver samples from every patient, and some of the corresponding proteins were detected by immunohistochemistry. In all instances, protein expression was highly heterogeneous within groups and similar between groups. In contrast, some differences in mRNA level between tumor and cirrhotic tissues were quite informative. Low levels of hepatocyte growth factor and transforming growth factor alpha mRNAs were found concomitantly in highly differentiated tumors, whereas overexpression of mRNAs for the cognate receptors c-met and epidermal growth factor receptor were found in poorly differentiated tumors and primarily in patients with early tumor recurrence. These results argue for growth factor-dependent HCC development and provide novel and combined prognosis markers after HCC surgery.
Mol Carcinog 2003 Mar
PMID:Hepatocyte growth factor, transforming growth factor alpha, and their receptors as combined markers of prognosis in hepatocellular carcinoma. 1261 35

We reported previously a significant increase in survival of nude rats harboring orthotopic A549 human non-small cell lung cancer tumors after treatment with a combination of exisulind (Sulindac Sulfone) and docetaxel (D. C. Chan, Clin. Cancer Res., 8: 904-912, 2002). The purpose of the current study was to determine the biochemical mechanisms responsible for the increased survival by an analysis of the effects of both drugs on A549 orthotopic lung tumors and A549 cells in culture. Orthotopic A549 rat lung tissue sections from drug-treated rats and A549 cell culture responses to exisulind and docetaxel were compared using multiple apoptosis and proliferation analyses [i.e., terminal deoxynucleotidyl transferase-mediated nick end labeling, active caspase 3, the caspase cleavage products cytokeratin 18 and p85 poly(ADP-ribose) polymerase, and Ki-67]. Immunohistochemistry was used to determine cyclic GMP (cGMP) phosphodiesterase (PDE) expression in tumors. The cGMP PDE composition of cultured A549 cells was resolved by DEAE-Trisacryl M chromatography and the pharmacological sensitivity to exisulind, and additional known PDE inhibitors were determined by enzyme activity assays. Exisulind inhibited A549 cell cGMP hydrolysis and induced apoptosis of A549 cells grown in culture. PDE5 and 1 cGMP PDE gene family isoforms identified in cultured cells were highly expressed in orthotopic tumors. The in vivo apoptosis rates within the orthotopic tumors increased 7-8-fold in animals treated with the combination of exisulind and docetaxel. Exisulind increased the in vivo apoptosis rates as a single agent. Docetaxel, but not exisulind, decreased proliferative rates within the tumors. The data indicate that exisulind-induced apoptosis contributed significantly to the increased survival in rats treated with exisulind/docetaxel. The mechanism of exisulind-induced apoptosis involves inhibition of cGMP PDEs, and these results are consistent with a cGMP-regulated apoptosis pathway.
Mol Cancer Ther 2003 May
PMID:Exisulind-induced apoptosis in a non-small cell lung cancer orthotopic lung tumor model augments docetaxel treatment and contributes to increased survival. 1274 10

Lymphoepithelioma-like carcinoma (LELC) of the stomach is reported to be associated with Epstein-Barr virus (EBV) and to have a better prognosis than typical adenocarcinoma. However, the incidence of EBV and its association with Helicobacter pylori is controversial. In our series, 9 of 370 (2.4%) cases of gastric adenocarcinoma were LELC. Formalin-fixed, paraffin-embedded LELC tissue was immunostained with monoclonal antibodies against CD3, CD20, and Ki-67. Warthin-Starry stain for H. pylori and in situ hybridization for EBV were performed. As a control, 21 cases of adenocarcinoma with prominent lymphoid stroma were compared with LELC. The most common location of LELC was the body of the stomach (five cases), followed by the cardia (two cases), whereas the antrum was the most common site for the control group. There were no significant differences in age, sex, or lymph node metastasis between the LELC and control groups. The mean Ki-67 index was similar (38.2% in LELC versus 35.3% in control). H. pylori was found in 2 LELC cases (22%) and 6 controls (28.5%). EBV was positive in 7 LELC cases (77.8%) and 4 controls (19.0%). All patients with LELC are alive and well, whereas three patients have died of their disease in the control group. Although EBV appeared to be a contributing factor, H. pylori had a minor role in LELC. There were no clinicopathologic differences between LELC and the control group, except for the location of the tumor in the body of the stomach and the tendency toward a better prognosis in LELC.
Appl Immunohistochem Mol Morphol 2003 Jun
PMID:Gastric carcinoma with lymphoid stroma: incidence of EBV and Helicobacter pylori infection. 1277 99

It is unclear how expression of the FHIT (fragile histidine triad) gene by the colorectal neoplasm correlates with histogenesis and progression of the disease. We studied the association between expression of Fhit protein and development of colorectal carcinoma (CRC). We also examined relations between Fhit protein expression, macroscopic type, Ki-67 labeling index (LI), and p53 overexpression in carcinoma in situ. We examined 27 colorectal adenomas, 82 carcinomas in situ and 21 invasive CRCs resected endoscopically or surgically. The carcinomas in situ comprised three macroscopic types: polypoid (n=27), superficial (flat elevated, n=27; depressed, n=10) and granulonodular laterally spreading tumor (G-LST, n=23). Fhit, Ki-67, and p53 overexpression were examined immunohistochemically. Levels of Fhit protein were lower in invasive CRC than in adenoma and carcinoma in situ (p<0.01). In carcinoma in situ, reduced Fhit expression was observed in 7 of 22 (31.8%) polypoid types, 13 of 27 (48.1%) superficial flat elevated types, 8 of 10 (80%) superficial depressed types and 7 of 23 (30.4%) G-LST. Frequencies of reduced Fhit expression were significantly higher in the polypoid type and G-LST lesions than in the depressed type (p<0.05). Reduced expression of Fhit protein was related significantly to Ki-67 LI and p53 overexpression in carcinoma in situ (p<0.01). The present findings suggest that reduced expression of Fhit protein is related to development of colorectal neoplasm. Polypoid CRC and G-LST appear to differ from superficial depressed CRC in terms of Fhit expression.
Int J Mol Med 2003 Oct
PMID:Clinical significance of Fhit expression in development of colorectal carcinoma of various macroscopic types. 1296 15


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