Apoptotic and proliferation indexes in primary superficial bladder tumors

Whether apoptotic index [AI] and/or Ki-67 labeling index [Ki-67LI] add prognostic information in bladder cancer remains unclear. Mean AI and Ki-67 LI increased with grade and stage in 147 superficial bladder tumors. AI (>1.7%) correlated with tumor size, grade and proliferation. Ki-67 LI (>10%) correlated with higher grade and stage. Tumor size and Ki-67 LI were independent predictors of disease-free and progression-free survival, respectively. Tumor size, patient's age and tumor's recurrence predicted overall survival. We conclude that conventional clinical parameters and Ki-67 LI define risk groups of bladder tumors, while AI has limited value.     

Decreasing of p27(Kip1)and cyclin E protein levels is associated with progression from superficial into invasive bladder cancer

The p27(Kip1)(p27) protein is a cyclin-dependent kinase inhibitor of the transition from G1 to S phase. It has been reported that decreased p27 protein level is a negative prognostic indicator in human tumours including bladder cancer. We studied the relationship between protein levels of p27, cyclin E and Ki-67 and clinicopathological features of 145 consecutive Japanese patients with transitional cell carcinoma of the bladder using immunohistochemical staining. Low protein levels of p27 were associated with low staining of cyclin E (P = 0.0302), high Ki-67 index (P = 0.0306), poorly differentiated grade (P = 0.0006), muscle invasion (P = 0.0019) and lymph node metastsis (P = 0.0002). Low staining of cyclin E and high Ki-67 index correlated with poorly differentiated grade, muscle invasion and lymph node metastsis. Cyclin E protein levels was inversely related with Ki-67 index (P = 0.0002). Kaplan-Meier plots of survival rate in patients with low versus high p27 staining showed that low protein levels of p27 were associated with a shortened disease-free and overall survival (P< 0.0001 and P< 0.0001, respectively). Similarly, low staining of cyclin E and high Ki-67 index correlated with a shortened disease-free and overall survival. On multivariate analysis using Cox proportional hazards model, low protein levels of p27 and high Ki-67 index were independent predictors of shortened disease-free (P< 0.0001, P = 0.0031, respectively), and low protein levels of p27, low staining of cyclin E and high Ki-67 index of overall survival (P = 0.0017, P = 0.0009, P = 0.0003, respectively). In superficial bladder tumours (Ta, T1; 86 patients), significant correlations were observed between low p27 staining and high Ki-67 index and early recurrence (P = 0.0048, P = 0.0178, respectively). Among the recurrenced superficial tumours (35 patients), the tumours which remained at a low stage showed high protein levels of p27 and cyclin E, and the tumours which progressed to invasive disease showed a gradual decrease in p27 and cyclin E protein levels over time. Our findings suggest that decreased protein levels of p27 and cyclin E play a role in the progression of bladder cancer and to evaluate these protein levels may be useful in management of the diseases.     

The prognostic value of KI-67 proliferation index in transitional cell carcinoma of renal pelvis and ureter

The investigation deals with Ki-67 immunoreactivity assay in upper urinary tract transitional cell carcinoma (TCC) with respect to grade, stage and survival after radical surgery. In a retrospective study (5yrs) of 37 patients with TCC of the renal pelvis and ureter, who had undergone radical nephroureterectomy and bladder resection, pT1-pT4 lesions and G1-G3 tumors were identified. Ki-67 expression was evaluated by immunohistological staining (1:100; MIB-1; Immunotech. Inc., Westbrook, USA). By using fifteen x600 visual fields, Ki-67 labeling index (number of positive cells per 100 tumor cells) was found (mean +SD--29.7 +/- 9.22). There was a correlation between the index and tumor stage (p < 0.001) and grade (p = 0.002). The Ki-67 values in excess of 27 corresponded to high risk of bladder recurrence (p < 0.001) and short duration of recurrence development (p = 0.067) whereas, for the index of under 22, five-year progression-free survival was more frequent (p < 0.001). Having been tested in that study, discriminative modeling yielded the following parameters: sensitivity and specificity for bladder recurrence was 93% and 79% while for 5-year progression-free survival- 89% and 100%.     

Predictive factors for overall and progression-free survival,and dissemination in oligodendroglial tumors

The pattern of recurrence and predictive factors for tumor progression, dissemination and survival in oligodendroglial tumors were investigated. 56 consecutive patients with oligodendroglial tumors were retrospectively analyzed to determine the predictive significance of various factors, including World Health Organization grade, loss of chromosomes 1p and 19q, and immunohistochemical features of TP53, O⁶-methylguanine-deoxyribonucleic-acid-methyltransferase, CD44H, nestin, and Ki-67. Eleven patients developed dissemination, and had significantly shorter post-progression survival compared to ten patients with local recurrence. Univariate analysis showed that retention of chromosome 1p or 19q, Ki-67 labeling index ≥ 25%, diffuse expression of nestin, and p53 labeling index ≥ 10% were unfavorable factors for overall, progression-free, and dissemination-free survival. Multivariate analysis showed that Ki-67 labeling index ≥ 25% and diffuse expression of nestin were significant for dissemination-free survival. In conclusion, post-progression survival shows significant differences between patients with local and disseminated recurrence. Ki-67 labeling index and nestin expression pattern are useful markers to predict dissemination.     

Expression of cell-cycle regulatory proteins and their prognostic value in superficial low-grade urothelial cell carcinoma of the bladder.

AIMS: Cell-cycle regulatory proteins are important indicators in determining progression trough the cell-cycle and progression to invasive cancer in patients presenting with superficial bladder cancer. We performed an immunohistochemical study in order to evaluate the prognostic value of the expression of p16, p27, pRb, p53 and Ki-67 in superficial grade I and II papillary urothelial cell carcinoma of the bladder. METHODS: p16, p27, p53, pRb and Ki-67 immunoexpression was studied in 14 pTa, 35 pT1a and 7 pT1b bladder tumours at presentation and at recurrence of their tumours. The recurrence-free survival and the progression-free survival were analysed according to these regulatory cell-cycle proteins expression. RESULTS: For survival in univariate analysis a high Ki-67 labelling index was a poor prognostic factor for recurrence-free and progression-free survival (P=0.0014 and P=0.012, respectively). Ki-67 labelling index was also an independent recurrence-free survival prognostic factor (P=0.0005). The p16, p27, p53 and pRb immunoreactivity was not significantly associated with recurrence or progression rate in this group of bladder carcinomas. CONCLUSIONS: These data suggest that the Ki-67 labelling index can be a reliable marker in predicting recurrence and/or progression in superficial low-grade bladder carcinomas and may be relevant in planning adjuvant therapy.     

Predictive value of cell cycle markers p53, MDM2, p21, and Ki-67 in superficial bladder tumor recurrence.

The aim of the study was to determine whether the expression of the cell cycle markers p53, MDM2, p21, and Ki-67 was predictive of superficial bladder cancer recurrence and to compare the relative predictive power for tumor recurrence of a cell cycle index based on the number of abnormally expressed cell cycle markers with a clinicopathological index based on primary clinical tumor characteristics. The expression of p53, MDM2, and p21 proteins and the value of the Ki-67 index were analyzed for 244 patients. One hundred ninety-four lesions were determined to be superficial papillary tumors (pTa), whereas 50 tumors invaded the lamina propria (pT1). Tumor grade was noted low (grade 1) in 83 cases and high (grades 2-3) in 161 cases. An avidin-biotin peroxidase method was performed using monoclonal antibodies against p53, MDM2, p21, and Ki-67 antigens after antigen retrieval treatment of formalin-fixed specimens. The cell cycle marker index was created using the number of abnormally expressed cell cycle markers according to the following cutoff points: p53 (>5%), MDM2 (>20%), p21 (<5%), and Ki-67 (>10%). The clinicopathological index was created using the following adverse tumor characteristics: grades G2-G3, stage pT1, multifocality, and diameter of tumors > 3 cm. Cox regression models were used to calculate the relative risks and their 95% confidence intervals associated with disease recurrence for the clinicopathological index and the cell cycle marker index. The chi2 test was performed to describe the correlation between the Ki-67 index and p53, MDM2, and p21 protein expression. Kaplan-Meier survival curves were generated to demonstrate the disease-free survival according to these two prognostic indexes. The clinicopathological index was a strong, independent predictor of disease recurrence where tumors with three or four adverse tumor characteristics at initial resection had over four times the risk of recurrence than tumors with no risk factors (P for trend = 0.0001). A strong correlation was observed between the Ki-67 index >10% and both MDM2 and p21 proteins. MDM2 was overexpressed in 106 tumors (43%), and p53 was overexpressed in 47 (19%); Ki-67 was >10% in 171 cases (70%). Thirty-nine tumors (16%) were p21 negative. The risk of recurrence increased slightly with the number of abnormally expressed cell cycle markers, but when the clinicopathological index was taken into account in multivariate analysis, the cell cycle marker index was not predictive of disease recurrence (P for trend = 0.72). The cell cycle markers studied provided no added prognostic information on disease recurrence after initial resection of papillary superficial tumors when the clinicopathological parameters were taken into account.     

Ki-67 immunostaining and other prognostic factors including tobacco smoking in patients with resected nonsmall cell lung carcinoma

BACKGROUND: To estimate the effectiveness of expression of the tumor proliferative marker Ki-67 antigen (Ki-67) as a postoperative prognostic marker, the authors analyzed Ki-67 expression and its correlation with postoperative survival and other clinicopathologic factors, including preoperative smoking habits, in patients with resected nonsmall cell lung carcinoma (NSCLC). METHODS: A total of 156 patients with resected NSCLC at the study institution were investigated. Postoperative survival rates were estimated based on demographic and clinicopathologic factors, including Ki-67 expression and preoperative tobacco smoking habits. RESULTS: The overall postoperative 5-year survival rate in patients with high Ki-67 labeling indices (>/= 20%) was 39.6% compared with 67.7% in patients with low Ki-67 labeling indices. This finding was significant for all resected cases and for each pathologic disease stage (P < 0.05). The postoperative 5-year survival rate in patients with a history of heavy smoking (>/= 30 pack-years) was 47.6% compared with 62.5% for other patients (P = 0.027). This result was especially significant in patients with International Union Against Cancer Stage I disease and in patients with nonsquamous cell carcinoma (P < 0.03). The authors also observed a positive correlation between the Ki-67 labeling index and preoperative smoking habits (P = 0.0002). Multivariate analysis demonstrated that lymph node involvement, tumor differentiation, and Ki-67 labeling index were significant prognostic factors in NSCLC (P < 0.01). CONCLUSIONS: Tumor Ki-67 expression is a strong prognostic factor in NSCLC, especially adenocarcinoma. It may be hypothesized that tobacco mutagenicity may play a role in the growth and extension of NSCLC, which is one of the major impediments to postoperative survival in patients with a history of heavy smoking.     

Ki-67 index enhances the prognostic accuracy of the urothelial superficial bladder carcinoma risk group classification

Approximately 80% of bladder tumors are urothelial superficial papillary carcinomas (USPC). Despite a generally good prognosis, these tumors have a strong propensity to recur and about 1/3 of them compared to disease progression. Histological assessment of these superficial tumors is not sufficiently discriminator in predicting prognosis; therefore, we decided to evaluate the prognostic significance of p53 and Ki-67 immunoexpression in low-grade (GI-II) USPC in order to predict the potential outcome of these tumors. P53 and Ki-67 immunoexpression were studied in function of recurrence-free and progression-free survival in 159 primary superficial bladder tumors. A prognostic risk model based on grade, stage and multifocality was also evaluated. P53 accumulation was significantly related to tumor progression (p=0.006). High Ki-67 index (>/=18%) and multifocality were significantly related to recurrence (both p=0.0001) and progression-free survival (both p=0.0001) and were independent prognostic factors in the multivariate analysis. The prognostic risk model based on grade, stage and multifocality was not an efficient discriminator of outcome. Adding the Ki-67 index into the risk model, single pTa/T1-GI Ki-67 positive tumors, usually classified as low risk, were reclassified as of intermediate risk. After this reclassification, the risk group model identified a subgroup of pTa/T1-G1 with a high risk of recurrence and progression. Ki-67 index is a reliable prognostic marker in urothelial superficial bladder carcinoma and, when included into a risk profile classification of the low-grade USPC, the accuracy of the prognostic discrimination is enhanced.     

Apoptosis and Survival in High-grade Astrocytomas as Related to Tumor Fas (APO-1/CD95) Expression

Although a majority of high-grade gliomas express the apoptosis-inducing receptor Fas, little is known about the extent of apoptosis or prognostic significance of Fas expression in these tumors. In situ labeling of apoptotic cells and Ki-67 immunohistochemistry were performed on 51 high-grade human astrocytomas previously characterized for Fas expression. Survival data was compiled from patient records and correlated with tumor grade, apoptotic index (AI) and Fas expression. A significant correlation was found between tumor grade and the AI and Ki-67 labeling index (LI); however, only the AI increased significantly with Fas expression. The AI increased from 0.39 ± 0.12% to 0.82 ± 0.10% in grade III vs. IV astrocytomas (P = 0.003). The Ki-67-LI increased from 3.64 ± 1.5% to 11.35 ± 2.1% in grade III vs. IV astrocytomas (P = 0.004). Additionally, tumors expressing higher Fas levels had a greater AI than those expressing lower levels (0.81 ± 0.11% vs. 0.43 ± 0.11%) (P = 0.017). Despite longer median survivals for patients with tumors exhibiting high Fas expression, statistical significance was not achieved. Patients with grade III astrocytomas demonstrated a median survival of 20 vs. 18 months for tumors with high vs. low Fas expression (P = 0.51). Patients with grade IV astrocytomas demonstrated a median survival of 9 vs. 7.4 months for tumors with high vs. low Fas expression, respectively (P = 0.77). Although the degree of Fas expression in high-grade astrocytomas appears to correlate with the apoptotic rate, no overall differences in survival could be demonstrated between tumors expressing high vs. low Fas levels.     

124例三阴性乳腺癌临床病理因素与预后分析

目的:三阴性乳腺癌（triple-negative breast cancer,TNBC）预后差,易复发转移,缺乏有效的治疗手段。本文回顾性分析TNBC及基底细胞型的临床病理因素与预后的关系。方法:纳入江苏省肿瘤医院124例TNBC,Fisher法分析临床病理因素之间的相关性,Kaplan-Meier法分析Ki-67/p53与无进展生存期的相关性,COX回归模型分析无进展生存期的预后因素。结果:TNBC肿块大小与腋窝淋巴结转移相关,Ki-67高表达与腋窝淋巴结转移相关,p53阳性与病理分级相关。TNBC及基底细胞型中,Ki-67高增殖与p53阳性患者具有相对较差的无病生存期（P＜0.05）。临床分期、腋窝淋巴结转移阳性、Ki-67高增殖与p53阳性是TNBC无病生存的独立预后因素。结论:本文证实Ki-67及p53是TNBC生存预后的预测因子,为TNBC延长生存、改善预后提供依据。     

Ki-67: a prognostic factor for low-grade glioma?

PURPOSE: Immunohistochemical techniques were used to detect the expression of Ki-67, a nuclear proliferation marker, in 180 low-grade glioma tumor specimens to determine whether Ki-67 is a prognostic predictor of survival or tumor recurrence. MATERIALS AND METHODS: A clinical database of 180 low-grade glioma patients (35 children aged /=5%. An average Ki-67 value of >/=5% was prognostically significant for reduced cause-specific survival (CSS, p = 0.05) and a Ki-67 level >/=10% was strongly significant of a poor survival outcome (p = 0.009). Ki-67 was not prognostically significant for progression-free survival. Other prognostically significant factors for CSS included age (p = 0.05), Karnofsky performance status (p = 0.0001), radiation dose (p = 0.02), extent of surgical resection (biopsy vs. others, p = 0.004), and timing of radiation (p = 0.0005). Ki-67 did not remain an independent statistically significant factor for CSS on multivariate analysis. Age and Ki-67 positivity (both maximal and average values) directly correlated (i.e., advancing age was associated with a higher Ki-67 index). When the patient group was further subdivided by age and timing of RT (postoperative vs. deferred), the prognostic significance of Ki-67 for CSS was lost. Within the deferred RT subgroup, a maximal Ki-67 >2% was associated with a worsened CSS. Within the pediatric population, Ki-67-negative patients had a 5-year CSS and progression-free survival of 100%. The 5-year CSS and progression-free survival declined significantly to 84% and 67% for patients with tumors demonstrating any degree of Ki-67 positivity (p = 0.005 and p = 0.006, respectively). CONCLUSION: Ki-67 is a useful predictor of CSS in low-grade gliomas; however, it is not independent of other prognostic factors, particularly age. Although Ki-67 was not helpful in predicting which adult patients were likely to benefit from postoperative RT, the results of the present study indicate a possible utility in the selection of pediatric patients for RT and in the selection of poorer prognosis patients for clinical trials.     

Prognostic and predictive value of changes in tumour cell proliferation in locally advanced breast cancer primarily treated with doxorubicin

We previously reported that high tumour cell proliferation evaluated by Ki-67 expression, high mitotic frequency and high histological grade were associated with resistance to primary doxorubicin monotherapy in locally advanced breast cancer harbouring wild-type (wt) TP53. The aim of our present study was to evaluate the predictive and prognostic impact of proliferation parameters assessed in tumour tissue obtained after chemotherapy, and alterations induced in tumour cell proliferation. While we found a significant reduction in Ki-67 expression and mitotic frequency in tumours with wtTP53 (p=0.001 and p=0.008, respectively), no significant change was recorded in tumours expressing mutant TP53. For histological grade there was no significant change in either group. There was a direct correlation between pre- and post-treatment values for Ki-67 and mitotic frequency in tumours harbouring wtTP53 (p=0.0001 for both), but no correlation in tumours harbouring mutated TP53. High post-treatment Ki-67 expression and mitotic frequency were found to predict doxorubicin resistance only in patients with wtTP53 (p=0.04 and p=0.03, respectively). The prognostic importance of proliferation markers and histological grade was found to be similar whether they were determined in the pre- or post-treatment samples (Ki-67; pre: p=0.02; post: p=0.03; mitotic frequency; p=0.002 and p=0.01, respectively; histological grade; p=0.0001 and p=0.002, respectively). While the reduction in mitotic frequency was associated with improved survival (p=0.03), no significant associations between changes in other parameters and outcome were recorded.     

肾癌细胞Ki-67免疫组化染色指数与预后的关系

 为探索肾癌预后较好的估价指标，41例肾癌根治标本Ki—67免疫组化染色。复发组的Ki—67染色指数显著高于未复发组（P相似文献   

Prognostic value of proliferation, apoptosis, defective DNA mismatch repair, and p53 overexpression in patients with resected Dukes' B2 or C colon cancer: a North Central Cancer Treatment Group Study.

PURPOSE: Molecular studies of colon cancer have provided insights into pathogenesis, yet it is unclear how important these markers are in predicting prognosis. This study investigated the prognostic significance of TUNEL, bcl-2, p53, proliferation marker Ki-67 and DNA mismatch repair (MMR) status in patients with Dukes' stage B2 and C colorectal adenocarcinomas. PATIENTS AND METHODS: Tumor tissue from 366 patients (75% Dukes' C, 25% Dukes' B2) from four randomized North Central Cancer Treatment Group phase III surgical adjuvant trials were used. Eighty-one percent of patients received adjuvant treatment, which was primarily fluorouracil (FU) based (90%). Tumor location was predominantly (87%) the colon. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL), Ki-67, p53, bcl-2, and MMR were assayed using immunohistochemistry. Stage, grade, MMR, Ki-67, and previously determined flow cytometry markers (ploidy and S phase) were explored for associations with each other and with overall survival (OS) and disease-free survival (DFS). RESULTS: Univariately, stage B2, low grade, diploid, Ki-67 more than 27%, normal p53, and FU-based adjuvant treatment were significantly associated with improved OS and DFS (P <.05). After adjusting for stage, grade, and ploidy in multivariate analysis, Ki-67 remained significantly related to both OS and DFS (P <.01). Active FU-based adjuvant treatment was significant only for OS in this multivariate model. Neither bcl-2 nor TUNEL were significant. CONCLUSION: This retrospective study indicates that Ki-67 and ploidy may have stronger prognostic impact on OS and DFS than other parameters investigated after adjusting for stage and tumor grade. Prospective studies to elucidate the mechanism and prognostic significance of these findings are necessary.     

High-throughput tissue microarray analysis of COX2 expression in urinary bladder cancer

To investigate whether protein expression of cyclooxygenase 2 (COX2) is associated with tumor phenotype, immunohistochemical alterations, and clinical outcome in urinary bladder cancer (BC). Tissue microarrays (n = 776) were used to analyze COX2, P53 and the Ki-67 labeling index immunohistochemically. A monoclonal mouse antibody was used after heat-induced antigen retrieval. COX2 expression was scored semiquantitatively (0-3+). COX2 expression was detected in 60% (368/617) of urothelial BC. Positive COX2 staining was seen in 77.8% (140/182) of muscle invasive urothelial BC, compared to 35% (7/20) of muscle invasive squamous cell carcinomas (p < 0.001). COX2 protein expression was associated with advanced tumor stage (p < 0.0001), high-grade histology (p < 0.0001), solid growth pattern in invasive BC (pT1-4, p = 0.02), high Ki-67 labeling index (p < 0.0001), and positive P53 IHC (p < 0.001). COX2 expression was not associated with survival, recurrence, and progression in clinically relevant subgroups (pTa, pT1, pT2-4). Expression of COX2 is common in advanced BC with poor prognostic characteristics, supporting efforts to initiate clinical trials on the efficacy of COX2 inhibitors in the adjuvant treatment of high-risk urinary BC.     

Significance of spontaneous apoptosis during colorectal tumorigenesis

To determine if apoptosis is involved in colorectal tumorigenesis and its progression, colorectal adenomas (n = 63), carcinomas (n = 49), and normal mucosa were investigated by using in situ end-labeling (TUNEL) method. The expression of Ki-67 was also analyzed immunohistochemically. TUNEL labeling index (TLI) and Ki-67 labeling index (KLI) were determined. TLI/KLI was significantly higher in the adenomas of small size and/or of low and middle grade atypia than those of large size and/or of high grade atypia. No difference was observed in the indices between adenomas and carcinomas and among the cancer groups classified on the basis of their clinicopathological features. The results indicate that the reduction of susceptibility to apoptosis plays an important role in the early stage of the adenoma-carcinoma sequence. Apoptosis can explain the enormous cell loss thought to exist in normal colorectal mucosa and in the tumor growth process. © 1996 Wiley-Liss, Inc.     

MIB-1 as a proliferative marker in transitional cell carcinoma of the bladder: clinical significance and comparison with other prognostic factors

BACKGROUND: Staging and grading of transitional cell carcinoma of the bladder are generally viewed as indicators of prognosis and form the basis of therapy, but they do not predict outcome accurately. This study was designed to evaluate the value for predicting recurrence, progression, and survival of proliferation fraction in transitional cell carcinoma of the bladder determined by immunostaining of histopathologic specimens with the monoclonal antigen MIB-1. METHODS: In a prospectively followed group of 301 patients with transitional cell carcinoma of the bladder, formalin fixed tumor specimens were immunostained and the MIB-1 labeling index was determined. Crude survival, progression free survival, and recurrence free survival (for patients with Ta and T1 tumors) were assessed in univariate and multivariate analysis according to stage, grade, mitotic index of the tumor, and patient age. The median value of continuous variables was used as a cutoff point in statistical analysis. RESULTS: In univariate analysis there was a strong association between all included factors and crude survival, progression free survival, and recurrence free survival with a median follow-up period of 60 months. In multivariate analysis, crude survival and progression free survival were determined by stage (P = 0.0001) and age (P = 0.0001). Recurrence free survival for patients with Ta and T1 tumors was determined by MIB-1 labeling index (P = 0.0317), mitotic index (P = 0.0229), and age (P = 0.0001). CONCLUSIONS: MIB-1 immunostaining in transitional cell carcinoma of the bladder correlated well with grade, stage, and clinical outcome. In multivariate analysis, proliferation fraction had prognostic value in predicting recurrence free survival for patients with Ta and T1 tumors, whereas stage and age appeared to be predictors of progression free survival.     

Low expression of p27(Kip1), a cyclin-dependent kinase inhibitor, is a marker of poor prognosis in synovial sarcoma

BACKGROUND: Low expression of p27(kip1), a dominant cyclin-dependent kinase inhibitor involved in G1-S transition of the cell cycle, recently has been reported to be associated with aggressive tumor growth. It has been shown that active cell proliferation alludes to poor prognosis in patients with synovial sarcoma. However, to the authors' knowledge, little is known about the clinicopathologic significance of p27(kip1) in synovial sarcoma. METHODS: p27(kip1) expression was examined immunohistochemically in 55 cases of primary synovial sarcoma, and the relations between p27(kip1) expression and several cell proliferation markers, i.e., mitotic index (MI), Ki-67 labeling index (Ki-67 LI), and clinicopathologic parameters related to poor prognosis, were determined. Univariate and multivariate survival analyses were performed to evaluate the prognostic significance of p27(kip1) expression in synovial sarcomas. RESULTS: p27(kip1) labeling index (p27(kip1) LI) correlated inversely with MI (r = -0.44, P = 0.0007) and Ki-67 LI (r = -0.63, P < 0.0001). Of the clinicopathologic parameters examined, tumor necrosis (P = 0.019) and American Joint Committee on Cancer (AJCC) stage (P = 0.021) correlated significantly with p27(kip1) LI. Survival analysis showed that p27(kip1) LI was an independent prognostic factor for overall survival in patients with synovial sarcoma (P = 0.0031). CONCLUSIONS: The study results suggested that low expression of p27(kip1) may be useful as a marker of poor-prognosis synovial sarcoma.     

Clinicopathologic and molecular correlations of necrosis in the primary tumor of patients with renal cell carcinoma

BACKGROUND: The presence of histologic necrosis in the primary tumor of patients with renal cell carcinoma (RCC) has been suggested to be an important predictor of survival. The authors investigated the relation of tumor necrosis to other clinicopathologic factors known to be important prognostic indicators for patients with RCC. METHODS: The records of 311 patients undergoing treatment for RCC were evaluated for basic clinicopathologic information including TNM classification, nuclear grade, Eastern Cooperative Oncology Group (ECOG) performance status (PS), disease recurrence, and survival. The presence and extent of histologic necrosis of the primary tumors was recorded and correlated with clinicopathologic factors, carbonic anhydrase IX and Ki-67 expression, disease recurrence, and survival. RESULTS: The presence of necrosis in the primary tumor of patients with RCC compared with patients with RCC without necrosis was associated with higher T classification (P < 0.0001), the presence of lymph node disease (P = 0.009), the presence of metastases (P < 0.0001), higher grade (P < 0.0001), greater mean tumor size (P < 0.0001), an ECOG PS score > or = 1 (P = 0.007), higher University of California-Los Angeles Integrated Staging System (UISS) category (P < 0.0001), and higher Ki-67 expression (P < 0.0001). The extent of necrosis in the primary tumor was associated with the presence of lymph node disease (P = 0.009) and the presence of metastases (P < 0.0001), and correlated with higher T classification (sigma = 0.31, P < 0.0001), poorer ECOG PS (sigma = 0.18, P = 0.002), higher grade (sigma = 0.33, P < 0.0001), greater tumor size (sigma = 0.40, P < 0.0001), higher UISS category (sigma = 0.37, P < 0.0001), and higher Ki-67 staining (sigma = 0.32, P < 0.0001). Patients with the presence of necrosis in the primary tumor demonstrated a lower 5-year disease-specific survival compared with patients without necrosis in the primary tumor (36% vs. 75%; P < 0.0001). Multivariate analysis demonstrated that T classification (P < 0.0001), distant metastases (P < 0.0001), and ECOG PS (P < 0.0001) were independent predictors of DSS, whereas the presence of necrosis was not (P = 0.1100). Substratification into localized and metastatic disease demonstrated that the presence of necrosis was an independent predictor of survival in patients with localized (P = 0.025), but not metastatic (P = 0.44), disease. The extent of necrosis was not an independent predictor of survival (P > 0.05). Patients with the presence of necrosis in the primary tumor had a lower 5-year disease recurrence-free rate compared with patients without the presence of necrosis (62% vs. 92%, P < 0.0001). CONCLUSIONS: The presence of necrosis in the primary tumor was associated with adverse prognostic factors such as high T classification, presence of lymph node disease and metastases, high grade, large tumor size, and poor ECOG PS. The extent of necrosis was found to be associated with the presence of lymph node disease and metastases and correlated with higher T classification, higher grade, greater tumor size, poorer ECOG PS, and higher UISS category. The presence of this histologic variant was an independent predictor of poor survival in patients with localized, but not metastatic, disease. In addition, Ki-67 expression served as a valuable surrogate marker for the presence of histologic tumor necrosis.     

IDH1/2 mutation status combined with Ki-67 labeling index defines distinct prognostic groups in glioma

The current World Health Organization (WHO) classification of human gliomas is mainly based on morphology. However, it has limitations in prognostic prediction. We examined whether combining isocitrate dehydrogenase (IDH) 1/2 mutation status with the Ki-67 labeling index would improve the definition of prognostically distinct entities. We investigated the correlation of Ki-67 expression with IDH1/2 mutation status and their impact on clinical outcome in 703 gliomas. Low Ki-67 expression closely overlapped with IDH1/2 mutation in our cohort (P < 0.0001). Patients with IDH1/2 mutation survived significantly longer than patients with wild-type IDH1/2 did (P < 0.0001); higher Ki-67 expression was associated with shorter progression-free survival and overall survival (OS) (P < 0.0001). IDH1/2 combined with Ki-67 was used to re-classify glioma patients into five groups. IDH1/2 mutant patients with low and moderate Ki-67 expression (Group1) had the best prognosis, whereas patients with wild-type IDH1/2 and high Ki-67 expression (Group5) had the worst prognosis (Median OS = 1527 vs. 355 days, P < 0.0001). To summarize, our new classification model distinguishes biologically distinct subgroups and provides prognostic information regardless of the conventional WHO grade. Classification based on IDH1/2 mutation status and Ki-67 expression level could be more convenient for clinical application and guide personalized treatment in malignant gliomas.