4288

MKI67

marker of proliferation Ki-67;MKI67;marker of proliferation Ki-67

antigen KI-67|antigen identified by monoclonal antibody Ki-67|proliferation-related Ki-67 antigen|protein phosphatase 1, regulatory subunit 105

10q26.2

protein-coding

Breast cancer is often relatively slow growing, but at diagnosis about 40% of patients have regional spread to at least one axillary node. It has been shown that unrelated clones are in primary breast carcinomas. There is possibility that only a small subpopulation of the cells of the primary tumour (PT) metastasis. It has been shown that Ki-67 protein is a useful marker in histopathology, which is present during all active phases of the cell cycle and making possibility to assess growth fraction of tumour cells. The purpose of the study was to evaluate the expression of Ki-67 and comparison between the PTs and MRLNs as well as to estimate the relationships between Ki-67 and the chosen anatomoclinical features of the breast cancer. Immunohistochemical analyses for Ki-67 were performed on the PTs (69 cases without primary chemotherapy) and MRLNs (33 cases) of breast cancer. Increased expression of Ki-67 in PTs significantly correlated with pT2 stage of tumours (p < 0.05) and grade G3 (p < 0.04), but there was not relationship with lymph node status. expression of Ki-67 positively correlated between PTs and MRLNs (p < 0.001). Comparison between PTs and matching MRLNs revealed that 23 (69.7%) cases showed a convergence between PTs and matching MRLNs with regard to negative or positive staining. We would like to emphasize the importance of studies concerning the proteins involved in proliferation in MRLNs, because knowledge about heterogeneity between PTs and MRLNs could shed light on tumour biology and may lead to development of more effective anti-cancer therapies.

Breast cancer is a heterogeneous disease, so therapeutic predictive biological markers need to be identified. To date an accurate evaluation of predictive markers is mainly done at the primary site; however, the main goal of adjuvant therapy for breast cancer is the control of micrometastases. The aim of this study is to assess as therapeutic and/or prognostic marker, the proliferation status of primary tumors and involved nodes as measured by Ki67 and thymidylate synthase (TS) expression, in 30 breast cancer node positive patients. TS is the main target of 5-fluorouracil (5-FU) activity, and its overexpression is one of the mechanisms of 5-FU drug resistance; however, in some studies its absence is responsible for a worse response to 5-FU. Our results show that malignant cells of involved nodes were in a post mitotic phase of the cell cycle, and show a low proliferation index and TS expression, while the primary tumours and controls, were strongly positive. On these basis we can hypothesize that these cells could be less sensitive to 5-FU. Further studies are necessary to identify other mechanisms responsible for their metastasing capability and/or for their aggressiveness.

BACKGROUND: Ki-67 overexpression has been reported to be related to a poor prognosis for early stage breast cancer. We analyzed whether Ki-67 has a prognostic impact on risk subgroups based on the recommendations at St. Gallen in 2007. METHODS: To determine the impact of Ki-67 on each risk group, a retrospective analysis was performed in patients with breast cancer who underwent curative surgery. Ki-67 was examined by immunohistochemistry with a predefined cutoff level of 10%. RESULTS: A total of 1,166 patients were eligible for this analysis. During the follow-up period, distant metastasis was observed in 164 patients (14.1%), and 80 patients (6.9%) died. Ki-67 overexpression (Ki-67 >/= 10%) was identified as an independent prognostic factor for distant-metastatic-free survival (DFS) and overall survival (OS) by univariate and multivariate analysis. In the intermediate-risk group, the difference between Ki-67 overexpression and no overexpression was statistically significant in 5-year DFS (90.9 vs. 83.4%, p = 0.002) and OS (98.1 vs. 95.8%, p = 0.002). However, in both the low- and high-risk groups, Ki-67 overexpression was not an independent prognostic factor for either 5-year DFS or OS. CONCLUSIONS: Ki-67 overexpression indicates an unfavorable prognostic impact for DFS and OS. However, this impact is restricted only to those patients classified at intermediate risk.

We examined whether baseline Ki67 expression in estrogen receptor-positive (ER+) primary breast cancer correlates with clinical benefit and time to progression on first-line endocrine therapy and survival in metastatic disease. Ki67 values and outcome information were retrieved from a prospectively maintained clinical database and validated against the medical records; 241 patients with metastatic breast cancer were included--who had ER+ primary cancer with known Ki67 expression level--and received first-line endocrine therapy for metastatic disease. Patients were assigned to low (<10 %), intermediate (10-25 %), or high (>25 %) Ki67 expression groups. Kaplan-Meier survival curves were plotted and multivariate analysis was performed to assess association between clinical and immunohistochemical variables and outcome. The clinical benefit rates were 81, 65, and 55 % in the low (n = 32), intermediate (n = 103), and high (n = 106) Ki67 expression groups (P = 0.001). The median times to progression on first-line endocrine therapy were 20.3 (95 % CI, 17.5-38.5), 10.8 (95 % CI, 8.9-18.8), and 8 (95 % CI, 6.1-11.1) months, respectively (P = 0.0002). The median survival times after diagnosis of metastatic disease were also longer for the low/intermediate compared to the high Ki67 group, 52 versus 30 months (P < 0.0001). In multivariate analysis, high Ki67 expression in the primary tumor remained an independent adverse prognostic factor in metastatic disease (P = 0.001). Low Ki67 expression in the primary tumor is associated with higher clinical benefit and longer time to progression on first-line endocrine therapy and longer survival after metastatic recurrence.

INTRODUCTION: Ki-67 expression is a biomarker for proliferation. Its prognostic value is recognized in breast cancer (BC) patients with negative axillary nodes, but is less clear in BC patients with positive axillary lymph nodes. METHODS: We retrospectively reviewed the medical records of 1131 Chinese BC patients treated from January 2002 to June 2007 and 450 patients met the inclusion criteria: positive nodes, adjuvant therapy, and complete biomarker profile (estrogen receptor (ER), progesterone receptor (PR), HER2, p53, Ki-67). Univariate and multivariate regression analysis were used to correlate biomarkers and tumor characteristics with metastasis free survival (MFS) and overall survival (OS). RESULTS: Median follow-up time was 46 months (range 5-76 months). The Ki-67 expression was associated significantly with histological grade, ER, PR, HER2, and P53 status (P<0.05). tumor stage, nodal stage, and ER status were independent prognostic factors for MFS. Ki-67 status was associated significantly with OS but not MFS. To determine whether the extent of LN involvement in the BC patients influenced the role of Ki-67 in survival rates, we compared these variables in patients with 1-3 positive lymph nodes (N1) to those of patients with >/= 4 positive lymph nodes. Ki-67 status was an independent prognostic factor for MFS (Hazard Ratio, 3.27, P = 0.026) and overall survival (HR, 10.64, P = 0.007) in patients with 1-3 positive nodes (N1). CONCLUSIONS: The possibility that Ki-67 expression together with clinical factors can improve prediction of the prognosis of BC patients with 1 approximately 3 positive axillary lymph nodes warrants further studies.

BACKGROUND & OBJECTIVE: Bmi-1, a putative oncogene, is a member of the polycomb group genes, and is expressed in many human tumors. Ki67 is an important nuclear antigen associated with cell proliferation. This study was to investigate the expression, significance and correlation of Bmi-1 and Ki67 in colorectal carcinoma (CRC) tissues. METHODS: Protein expressions of Bmi-1 and Ki67 in sixty CRC, 30 adenomas and 20 normal colorectal mucosal tissues were detected using immunohistochemistry. Correlations of the expression of Bmi-1 and Ki67 to clinicopathological features and survival of patients were analyzed. RESULTS: The expression rates of Bmi-1 and Ki67 were 25.0%, 6.7%, 0% and 18.3%, 3.3% and 0% in CRC, adenomas and normal colorectal mucosal tissues, respectively. The expression of Bim-1 and Ki67 were significantly higher in CRC than in adenomas and normal colorectal mucosal tissues (P<0.05). Chi-square test revealed that the overexpression of Bmi-1 protein in CRC was correlated to distant metastasis (P<0.01) and TNM stage (P<0.05), while the overexpression of Ki67 protein was associated with age, distant metastasis and TNM stage (P<0.05). Further logistic regression analysis showed that only distant metastasis was correlated with Bmi-1 overexpression (P<0.01,OR>1), and only age was correlated with Ki67 overexpression(P<0.05, OR<1). Kaplan-Meier survival analysis showed that the survival was significantly shorter in CRC patients with overexpression than low expression of Bmi-1 and Ki67 (P<0.05). CONCLUSIONS: Overexpression of Bmi-1 and Ki67 protein are significantly correlated with tumorigenesis, metastasis and prognosis of CRC. Bmi-1 and Ki67 might be used to predict the prognosis of CRC. Bmi-1 might regulate the expression of Ki67 indirectly in CRC patients.

The liver is the most common and critical site for the development of colon cancer metastases. tumor angiogenesis in liver metastasis from colon carcinoma is a controversial subject. Liver microenvironment, immunophenotypical and morphological particularities of hepatic vessels are only few aspects, which establish difficulties in quantification of tumor vascularisation from liver metastasis. The aim of this work is to study the distribution of CD105 positive vessels and the proliferation rate of endothelial cells from liver metastasis of colon carcinoma based on double immunostaining CD105/Ki67. In liver metastasis from well-differentiated adenocarcinoma we found a high number of CD105+/Ki67- vessels. On the other hand, in liver metastasis from poorly differentiated adenocarcinoma we noticed rare CD105+/Ki67+ vessels. It is hypothesized that neoangiogenesis of liver metastasis is performed through intussusceptive mechanism rather than sprouting and could be supported by the presence of kissing phenomenon, CD105 positive transcapillary pillars and the absence of endothelial cells proliferation in this vessels. We conclude that in liver metastasis principal mechanism of neovascularisation formation is based on intussusception.

BACKGROUND: The aim of this study was to compare mitotic count (MC) and Ki-67 proliferation index as prognostic markers in pancreatic and midgut neuroendocrine neoplasms (NENs). METHODS: Two hundred eighty-five patients with metastatic NENs were recruited. Concordance between histological grade according to either Ki-67 or MC as defined by the European Neuroendocrine tumour Society guidelines was assessed and the prognostic significance of Ki-67 or MC were evaluated. RESULTS: There was a discrepancy of 44 and 38% in grade assignment when using Ki-67 or MC in pancreatic and midgut NENs, respectively. In multivariate analysis, grade using Ki-67, but not MC, was a significant prognostic factor in determining overall survival (hazard ratios: midgut G2 2.34, G3 15.1, pancreas G2 2.08, G3 11.3). The prognostic value of Ki-67 was improved using a modified classification (hazard ratios: midgut G2 3.02, for G3 22.1, pancreas G2 5.97, G3 33.8). CONCLUSION: There is a lack of concordance between Ki-67 and MC in assigning tumour grade. Grade according to Ki-67 was a better prognostic marker than MC for metastatic pancreatic and midgut NENs. We suggest that Ki-67 alone should be used for grading pancreatic and midgut NENs and that the current threshold for classifying G1/G2 tumours should be revised from 2 to 5%.

Oral cancer is the eighth most prevalent cancer worldwide. It causes significant mortality and morbidity rates, which have motivated the search for prognostic factors to better tailor the individual management of oral squamous cell carcinoma patients. Nucleophosmin is a multifunctional protein that is involved in many cellular activities, such as, regulation of the tumor suppressor genes TP53 and p14(ARF) and is associated with proliferative and growth suppressive roles in the cell. Nucleophosmin is overexpressed in many solid tumors in human, including tumors of the colon, liver, stomach, ovary, and prostate. In this study, we analyzed the expression of nucleophosmin, Ki-67, and p53 by immunohistochemistry in oral squamous cell carcinomas. Less than 10% of nuclear staining was observed in 90.3%, 50.6%, and 65.3% of the cases for nucleophosmin, p53, and Ki-67, respectively. expression of p53 was not significantly associated with any of the clinicopathologic parameters analyzed. Increased expression of Ki-67 was associated with the presence of lymph node metastasis (P < .0001), advanced stages of disease (P = .0030), tumors occurring in the floor of mouth (P = .0018), and moderately/well-differentiated tumors (P = .0287). Local recurrence was associated with higher expression of nucleophosmin (P = .0233), and disease-free survival rate was significantly better in patients with low expression of nucleophosmin. Multivariate analysis suggested that expression of nucleophosmin could be an independent prognostic factor for oral squamous cell carcinoma patients.

Vitamin D, in addition to its effects on bone, is important in cell cycle regulation. Vitamin D receptor (VDR) has been identified in breast, prostate, and colon cancers, as well as in canine and human osteosarcoma (OS) cell lines; however, it has not been well investigated in human OS-archived specimens. We correlated VDR, retinoid X receptor (RXR), and MIB-1 (Ki-67) expression in 110 archived OS cases with several clinicopathologic parameters including patient's age, sex, tumor location, tumor grade, and type and metastatic status. The expression of VDR and RXR was identified in human OS tissue obtained from primary and metastatic OS archival tissue. No statistically significant difference was found in VDR expression in relation with tumor grade, type, age, sex, or location. The expression of RXR was highest in higher-grade (P = .0006) and metastatic tumors but remained unchanged when correlated with tumor type, age, sex, or location. The expression of MIB-1 was statistically elevated in higher-grade tumors (P = .001), patients 25 years or younger (P = .04), tumors located in extremities (P = .005), and metastatic lesions, but was not impacted by tumor type or patient's sex. Proliferative activity was significantly reduced after treatment, as the mean MIB-1 expression dropped from 11% in primary biopsy samples to 6% in resection specimens. There appears to be a relationship between proliferative tumor activity and tumor grade, location, and metastasis. Additional studies on the analysis of the effects of vitamin D and RXR on OS proliferation, apoptosis, and differentiation are critical to further evaluate their potential role in OS treatment.

OBJECTIVE: To analyze the expressions of Ki67, PCNA and mitotic index in ovarian epithelial tumors and their relationship with clinical pathological features. METHODS: The expressions of Ki67, PCNA protein and mitotic index in ovarian tissues from 20 patients with normal ovarian tissues, 28 patients with ovarian benign tumors, 20 patients with borderline tumors and 109 (73 metastatic ovarian cancer) patients with malignant tumors were retrospectively tested using the American GBI immunohistochemistry two-step method. The expressions of Ki67 and PCNA mRNA were also detected by in situ hybridization (ISH) in ovarian tissues from 37 patients with primary ovarian cancer, 14 patients with borderline tumors, 11 patients with benign tumors and 12 patients with normal ovarian tissues. The relationship between clinical pathologic parameters and the expressions of Ki67 and, PCNA and mitotic index in human ovarian tumors was analyzed. RESULTS: (1) The expressions of Ki67 mRNA and protein in ovarian epithelial tumors was higher than in the controls (P = 0.003; P = 0.009; P = 0.001; P = 0.001). But no significant differences appeared in the expression and overexpression of PCNA mRNA and pratein (P = 0.327; P = 0.718; P = 0.123; P = 0.125). Positive correlations between the expressions of mRNA and protein for Ki67 and PCNA were found (r = 0.449, P = 0.025; r = 0.484, P = 0. 014). (2) The expression of Ki67 in ovarian epithelial was higher in low differential carcinoma and at FIGO III-IV stage (P = 0.008; P = 0.007). The expression of Ki67 protein in serous tumor tissues was high, but low or missed in other types of tumor tissues such as malignant mixed mullerian tumor and transitional cell carcinoma (P = 0. 018). No significant differences in other clinicopathological features were found. The high expression of PCNA did not coincide with histological grading, clinical stage and histological types (P = 0.447; P = 0.763; P = 0.657). There were 72 patients with high mitotic index (66.1%). The high expression of mitotic index coincided with histological grading and clinical stage, but not with histological types (P = 0.002; P = 0.040). (3) The combined overexpression of Ki67 and high mitotic index occurred in 57 patients, which coincided with histological grading, clinical stage and histological types (P = 0.018; P = 0.001; P = 0.020). (4) In the 73 patients with metastatic ovarian cancers, the expressions of Ki67 (58.9%), PCNA protein (91.8%) and high MI (61.6%) in primary cancer tissues were greater than in the metastatic cancer tissues (peritoneum and epiploon, Ki67 41.4%, P = 0.031; PCNA 74%, P = 0.004; high MI 38.4%, P = 0.005). The positive intensity of Ki67 protein expression in primary ovarian cancers was significantly higher than in metastatic ovarian cancers (P = 0.040). There was no significant difference in positive intensity of PCNA between primary and metastatic ovarian cancers (P = 0.514). CONCLUSION: Ki67 and mitotic index can serve as biomolecular markers for predicting the proliferation of malignant ovarian epithelial tumors. PCNA can not discriminate between benign and malinant ovarian tumors.

BACKGROUND: The aim of this study was to compare mitotic count (MC) and Ki-67 proliferation index as prognostic markers in pancreatic and midgut neuroendocrine neoplasms (NENs). METHODS: Two hundred eighty-five patients with metastatic NENs were recruited. Concordance between histological grade according to either Ki-67 or MC as defined by the European Neuroendocrine tumour Society guidelines was assessed and the prognostic significance of Ki-67 or MC were evaluated. RESULTS: There was a discrepancy of 44 and 38% in grade assignment when using Ki-67 or MC in pancreatic and midgut NENs, respectively. In multivariate analysis, grade using Ki-67, but not MC, was a significant prognostic factor in determining overall survival (hazard ratios: midgut G2 2.34, G3 15.1, pancreas G2 2.08, G3 11.3). The prognostic value of Ki-67 was improved using a modified classification (hazard ratios: midgut G2 3.02, for G3 22.1, pancreas G2 5.97, G3 33.8). CONCLUSION: There is a lack of concordance between Ki-67 and MC in assigning tumour grade. Grade according to Ki-67 was a better prognostic marker than MC for metastatic pancreatic and midgut NENs. We suggest that Ki-67 alone should be used for grading pancreatic and midgut NENs and that the current threshold for classifying G1/G2 tumours should be revised from 2 to 5%.

Clinical outcome of penile squamous cell carcinoma (PSCC) largely depends on the presence of lymph node metastasis. In search of a valuable marker predicting the risk for metastasis, the expression of Ki67 was investigated immunohistochemically in primary tumors and compared to presence of inguinal lymph node metastasis. As human papilloma virus (HPV) is thought to affect Ki67 expression, we evaluated whether occurrence of HPV DNA correlates to Ki67 score or metastatic potential. Samples originated from patients subjected to resection of invasive SCC of penis. Immunohistochemistry was done on paraffin-embedded sections using a monoclonal antibody against Ki67. After DNA isolation from paraffin embedded tissue the presence of HPV 6/11, HPV 16 and HPV 18 DNA was analyzed by PCR. Statistical analysis was done using two tail unpaired t test and Chi-square test. Four of 28 patients showed a weak Ki67 expression, without displaying lymph node metastasis. Among 17 patients showing an intermediate Ki67 index, eight exhibited metastases while in all seven patients with a strong expression of Ki67 lymph node metastases were found. The median Ki67 expression in metastastic lesions was significantly different (50.3%) from tumors without lymph node metastasis (31.8%) (p=0.024). Furthermore, a correlation between presence of HPV DNA and strong Ki67 expression was determined (p=0.009). Since our study demonstrated a strong Ki67 labeling index significantly associated to positive lymph nodes, we suggest Ki67 expression as a prognostic marker for lymph node metastasis in penile squamous carcinoma.

PURPOSE: Proliferative activity defined by Ki-67 staining index (SI) has been correlated with progression and prognosis in a number of malignant tumors including prostate cancer. However, few studies have examined Ki-67 SI in pretreatment diagnostic material from patients treated with definitive radiotherapy. In a prior study, we found that a Ki-67 SI of >3.5% was associated with poorer patient outcome. The goals of this analysis were to validate the prognostic value of Ki-67 SI and this cut point. EXPERIMENTAL DESIGN: Of 456 assessable patients in Radiation Therapy Oncology Group Protocol 86-10, diagnostic material from 108 patients was available for Ki-67 analysis using MIB-1 antibody. Sixty patients were treated with external beam radiotherapy (EBRT) alone, and 48 patients were treated with short-term androgen deprivation + EBRT. Median follow-up was 9 years for those living. The relationship of Ki-67 with distant metastasis (DM), disease-specific survival (DSS), and overall survival (OS) was examined. RESULTS: The median Ki-67 SI was 7.1% (range, 0.2-45.5%). The 7.1% cut point was associated with DM and DSS; however, the 3.5% cut point was as strong a determinant and was the focus of this analysis. In Cox proportional hazards regression, Ki-67 SI was independently associated with DM and DSS. When the Ki-67 SI was 3.5%, the 5-year risk of DM was 13.5% and 50.8% (P = 0.0005), respectively, and the 5-year risk of DSS was 97.3% and 67.7% (P = 0.0039), respectively. No association of Ki-67 SI with OS was observed. CONCLUSIONS: Higher Ki-67 SI was significantly associated with a greater risk of DM and DSS in locally advanced prostate cancer after definitive EBRT or AD + EBRT.

The study was aimed to determine the role of ki- 67 and vimentin markers in choosing the tactics of surgical treatment of patients with metastatic kidney cancer. The analysis of the results of treatment of 71 patients with metastatic renal cell carcinoma was performed. The first group included 16 (22.5%) patients, who underwent complete removal of distant metastases after nephrectomy. The second group consisted of 55 (77.5 %) patients who underwent cytoreductive nephrectomy only. Immunohistochemical analyses of tissues removed were performed in all patients for the evaluation of ki-67 and vimentin expression levels. When comparing the outcomes of patients after complete removal of metastases depending on the vimentin and ki-67 expression levels (< 10% and > 10%), a significant increase in the cumulative survival in the case of absence of vimentin and ki-67 expression of <10 % (log - rank test, P = 0.0001) was revealed. The same pattern was noted in the group of patients who underwent nephrectomy only. In the absence of expression of vimentin and ki-67 < 10%, survival rate in patients who underwent metastasectomy after nephrectomy was significantly higher compared with patients who underwent nephrectomy only (P = 0.001). In the case of positive expression of vimentin and ki-67 > 10%, differences in survival rate in these groups were not observed (P > 0.082). Thus, an association between the vimentin and ki-67 expression levels and the degree of spread of metastatic renal cell carcinoma was identified: the high level of expression of these markers precludes the increase of life expectancy of patients after removal of all metastases.