MIB-1 Score Research Articles

Oncogenes and male breast carcinoma: c-erbB-2 and p53 coexpression predicts a poor survival.

To investigate the prognostic value of biomarkers in male breast carcinoma (MBC). Fifty patients (mean age, 62.2 years) with invasive ductal carcinoma were retrospectively studied. All patients received surgery; 35 had adjuvant postoperative therapy. The median follow-up was 59 months (range, 1 to 230 months). c-myc, c-erbB-2, p53, and bcl-2 proteins were immunohistochemically detected on sections from formalin-fixed, paraffin-embedded tissues using 9E11, CB11, DO7, and bcl-2 124 monoclonal antibodies (mAbs). Estrogen, progesterone, and androgen receptors were detected using specific mAbs. Cell proliferation was assessed by MIB-1 mAb. In univariate analysis, c-myc, c-erbB-2, and p53 protein overexpression was significantly correlated with prognosis. The median survival was 107 months for c-myc-negative and 52 months for c-myc-positive patients (P =.01), 96 months for c-erbB-2-negative and 39 months for c-erbB-2-positive patients (P =.02), and 100 months for p53-negative and 33 months for p53-positive patients (P =.0008). Tumor histologic grade (P =.01), tumor size (P =.02), patient age at diagnosis (P =.03), and MIB-1 scores (P =.0004) also had prognostic value. In multivariate analysis, only c-erbB-2 and p53 immunoreactivity retained independent prognostic significance. All nine patients who did not express c-erbB-2 and p53 proteins were alive after 58 months, whereas none of the 14 patients expressing both proteins survived at 61 months follow-up (P =.0002). Overexpression of c-myc, c-erbB-2, and p53 proteins may be regarded as an additional prognostic factor in MBC. The combination of c-erbB-2 and p53 immunoreactivity can stratify patients into different risk groups.

Esophageal small cell carcinomas: clinicopathologic parameters, p53 overexpression, proliferation marker, and their impact on pathogenesis.

To evaluate the clinicopathologic features and the roles of p53 and MIB-1 in esophageal small cell carcinoma. Twenty patients (14 men and 6 women) with esophageal small cell carcinoma treated in our hospital from 1982 through 1996 were studied. The clinicopathologic features, treatment received, and survival data of these patients were documented. Representative tissue was collected from each tumor, and immunohistochemical preparations for p53 protein and MIB-1 were made. Small cell carcinoma accounted for 1.3% of all esophageal malignant tumors. The median age of patients at presentation was 60 years. On gross examination, the tumors were large ulcerative lesions (median length, 7.5 cm). In 17 patients in whom p53 immunohistochemical study was performed, p53 protein was detected in 65% (9 of 17). All stage IV tumors were negative for p53 expression. The median tumor cell MIB-1 score was high at 855 (range, 810-964) positive cells per 1000. Overall median survival was 3.4 months. In patients who underwent chemotherapy, there was significant response. Esophageal small cell carcinoma is an aggressive tumor. Overexpression of p53 is associated with early stages of carcinogenesis. The high proliferative index, as defined by the MIB-1 immunohistochemical method, may be related to aggressive behavior and high sensitivity to chemotherapy and radiotherapy.

Prognostic Relevance of a Histological Grading System Using MIB-1 for Adult Soft-Tissue Sarcoma

Several histological grading systems have been proposed and found as strong indicators of outcome in soft-tissue sarcomas. However, a putative independent prognostic influence of recently developed biological and molecular markers remains to be established. This study investigated the prognostic relevance of a histological grading system based on the assessment of proliferative activity in adult soft-tissue sarcomas of the extremities, trunk, head, and neck. Tissue blocks from 95 of 108 patients without distant metastases or regional lymph node involvement were available. Immunohistochemical staining for MIB-1 and p53 was done on paraffin-embedded sections. All clinicopathologic and immunohistochemical variables and patient survival were assessed using univariate and multivariate analyses. Variables included histological grading based on the modified Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) system using the MIB-1 score for the estimation of the proliferative potential of the tumors. Variables associated with overall survival were tumor site in the trunk, head and neck, mitosis count, necrosis, MIB-1 score, FNCLCC grade, modified FNCLCC grade using the MIB-1 score, and stage (all p values <0.05). In multivariate analysis, the modified grade proved to be the most significant predictor of shortened overall survival, in addition to tumor site in the trunk, head, and neck. Overexpression of p53 did not correlate with increased risk of tumor mortality. Using MIB-1 to replace mitosis counts in the FNCLCC system improves grading of soft-tissue sarcomas, and this in conjunction with other important factors appear to be more accurate prognostic factors for survival, and for patient selection in investigational adjuvant treatment trials.

Immunohistochemical localization of metallothionein in endometrial lesions.

Metallothioneins (MTs) are a group of ubiquitous low-molecular-weight proteins essential for the protection of cells against heavy metal ion toxicity. The immunohistochemical expression of MT was studied by immunohistochemistry using a monoclonal antibody (E9) against a conserved epitope of I and II isoforms in a series of 89 endometrial carcinomas, 34 cases of hyperplasia, and 32 samples of normal endometrium. In secretory phase endometrium, extensive MT expression was detected in most cases (92.4%). In contrast, MT immunoreactivity was confined to small foci in 22.2% of proliferative phase cases. The MT values in normal endometrium were inversely correlated with oestrogen receptor (ER) content (p<0.0001), progesterone receptor (PgR) content and with PCNA (p<0.0001) and MIB1 (p=0.001) scores. In hyperplastic lesions, MT expression was detected only in 3.3% of cases, while in the group of carcinomas it was observed in 23.1%. A statistically significant difference of MT expression was observed between carcinomas and simple hyperplasias (p=0.03). In carcinomas, MT expression was positively correlated with grade (p=0.0065), MIB1 (p=0.022), and p53 (p=0.006) expression, and inversely with PgR (p=0.03). A trend of inverse correlation between MT and ER receptor was also detected (p=0.07). These data suggest that MT expression seems to be under hormonal control in normal endometrium; that it may modify p53 expression; and that it could be used as an additional biological marker indicating aggressive behaviour in endometrial lesions.

Antiapoptotic Bcl-2 family protein expression increases with progression of oligodendroglioma.

Altered expression of Bcl-2 family proteins has been associated with tumorigenesis and tumor progression as well as resistance to radiotherapy and chemotherapy. In the current study, Bcl-2 family protein expression was examined in oligodendrogliomas and anaplastic oligodendrogliomas, and an attempt was made to determine whether these proteins accumulate during disease progression and to search for protein expression patterns predictive of time to progression and overall survival. A total of 42 oligodendroglioma tissue samples, 26 de novo World Health Organization (WHO) Grade 2 oligodendrogliomas, and 16 de novo WHO Grade 3 anaplastic oligodendrogliomas were studied. Nineteen Grade 2 tumors progressed: 10 again were Grade 2 oligodendrogliomas and 8 had progressed to higher grade lesions. Eight anaplastic oligodendrogliomas progressed: five again were WHO Grade 3 tumors and three were glioblastoma multiforme. Expression of Bcl-2, Bax, Bcl-X, and Mcl-1 proteins and of the proliferation marker Ki-67 was evaluated by immunohistochemistry. Apoptotic cells were quantified by in situ nick translation (ISNT). De novo WHO Grade 2 oligodendrogliomas had higher Bcl-2 scores (P = 0.037), lower MIB-1 scores (P = 0.0012), and lower ISNT scores (P = 0.049) compared with de novo WHO Grade 3 anaplastic oligodendrogliomas. In de novo oligodendrogliomas, low numbers of Bax positive cells were associated with a short time to disease progression (P = 0.043). In de novo anaplastic oligodendrogliomas, low numbers of Bcl-2 positive cells correlated with short survival (P = 0.029). In tumors that had progressed from WHO Grade 3 anaplastic oligodendrogliomas, the authors found significantly more Bcl-X positive (P = 0.005), Mcl-1 positive (P = 0.002), and Bax positive (P = 0.03) cells. The results of the current study show that progression of oligodendrogliomas and anaplastic oligodendrogliomas is associated with an enhanced expression of antiapoptotic Bcl-2 family proteins.

Prognostic Value of MIB-1 Score, p53, EGFr, Mitotic Index and Papillary Status in Primary Superficial (Stage pTa/T1) Bladder Cancer: A Prospective Comparative Study

Objective: A prospective randomized study was undertaken to determine whether cell proliferation indices (M/V index, MIB1), papillary status, the expression of p53 and epidermal growth factor receptor (EGFr) have prognostic value in superficial (pTa–pT1) bladder cancer (SBC). Methods: 207 patients with primary SBC were followed up over a period of 4.9 (range 3.7–6.0) years. M/V index and papillary status were assessed by light microscopy, and expression of MIB1, p53 and EGFr was assessed by immunohistochemistry. The results of histopathological analyses were related to the survival data of the patients. Results: Using univariate analysis, stage (p < 0.001), grade (p < 0.001), papillary status (p < 0.001), MIB1 (p < 0.001), M/V index (p < 0.001), EGFr (p < 0.001) and p53 (p = 0.002) were significant predictors of progression. Using multivariate analysis, MIB-1 score and papillary status were independent predictors of progressive disease and cancer-specific survival. Tumor grade was the only independent predictor of recurrence. Conclusion: Evaluation of tumor cell proliferation rate by M/V index or by MIB1 immunohistochemistry and assessment of papillary status by light microscopy are useful prognostic tools in tailoring treatment and follow-up schedule of patients with SBC.

Serum alpha-fetoprotein levels in patients with chronic hepatitis C. Relationships with serum alanine aminotransferase values, histologic activity index, and hepatocyte MIB-1 scores.

Patients with chronic viral hepatitis and cirrhosis often have elevated serum alpha-fetoprotein (AFP) values, the causes of which are unclear. We studied 81 patients with chronic hepatitis C and the relationships of serum AFP and alanine aminotransferase (ALT) values, hepatic histologic features, and hepatocyte proliferation activity scores. Twenty-two patients had nil to mild fibrosis, 34 had moderate fibrosis, and 25 had marked fibrosis-cirrhosis. The mean serum AFP value was significantly greater in patients with more fibrosis. Serum ALT values were slightly greater in the marked fibrosis-cirrhosis patient group. The differences in the HAI and in hepatocyte MIB-1 scores were not significant. Among all patients, increasing serum AFP values significantly correlated with increasing ALT values. However, there were no significant correlations with serum ALT or HAI and serum AFP values. There was no association between serum AFP values and immunohistochemical staining for AFP within hepatocytes. These results suggest that elevated serum AFP values are the result of altered hepatocyte-hepatocyte interaction and loss of normal architectural arrangements. The presence of marked fibrosis or cirrhosis, a state of significant altered hepatocyte architecture, may be the underlying cause of increased serum AFP, rather than necrosis or active regeneration.

Prolonged neoadjuvant combined androgen blockade leads to a further reduction of prostatic tumor volume: three versus six months of endocrine therapy

Objectives. In most clinical trials that have investigated the potential beneficial effects of neoadjuvant combined androgen blockade (CAB) in clinically localized prostate cancer, CAB has been given for 3 months, but no data are available on the influence of a longer duration of neoadjuvant CAB on the pathologic features of prostate cancer. Methods. Prostatectomy specimens of 40 patients, randomized to 3 (n = 18) or 6 (n = 22) months of neoadjuvant CAB, were blindly evaluated with regard to tumor volume, pathologic stage, and surgical margins. The morphologically most vital tumor areas were investigated for nucleolar size and MIB-1 defined proliferative activity. Results. The patients treated for 6 months had a median tumor volume 60% lower than the 3-month treatment group ( P = 0.005). In the 6-month treatment group, no residual tumor could be found in 2 cases, but the proportion of prostatectomy specimens with seminal vesical invasion and positive surgical margins was not statistically different from that after 3 months. Compared with untreated controls, tumor proliferative activity assessed by MIB-1 immunoreactivity was significantly lower at 3 and 6 months of neoadjuvant CAB ( P = 0.01). However, in 2 of 17 examined tumors that had been treated for 6 months, high MIB-1 scores suggested a development toward therapy-resistant cancer. Conclusions. Prolonged neoadjuvant CAB for 6 months leads to a further decrease in prostatic tumor volume compared with the findings after 3 months. In a few instances, residual tumor areas with substantial MIB-1 defined proliferative activity persist at 6 months, thus indicating that in at least some cases, despite the overall decrease in tumor size, cancer cells can continue the cell cycle under CAB.

Cell proliferation measured by MIB1 and timing of surgery for breast cancer.

We have investigated the use of the antibody MIB1 as a proliferative and prognostic marker in breast cancer and whether changes in proliferative activity could account for differences in prognosis of premenopausal women operated on during different phases of the menstrual cycle. MIB1 expression was strongly correlated with S-phase fraction and histological grade. There was no difference in MIB1 scores between different phases of the menstrual cycle. Both MIB1 score and timing of surgery correlated significantly with duration of survival, while the two together were even stronger predictors of overall survival. Women with slowly proliferating tumours surgically removed in the luteal phase had a very good prognosis, whereas women with rapidly proliferating tumours excised at other times of the cycle had a worse prognosis.

Adenoid cystic carcinoma of the breast: value of histologic grading and proliferative activity.

Adenoid cystic carcinoma of the breast is an uncommon carcinoma with a distinctive histology. Prognosis is favorable, although recurrence and distant metastases have been described. We assessed whether histologic features and proliferative activity can identify aggressive neoplasms. We studied 31 cases of adenoid cystic carcinoma (age range of patients, 33 to 74 years). Three histologic grades were defined: grade I: completely glandular; grade II: < 30% solid areas, and grade III: > or = 30% solid pattern. In 19 of 31 cases, immunohistochemical stains for estrogen receptor were available. Twelve of 31 cases were immunohistochemically stained for Ki-67 antigen using MIB1 antibody. Ten of 20 tumors were subareolar. All tumors were grossly circumscribed; however, 12 of 20 (60%) had focal infiltration peripherally. Five of 19 tumors were estrogen receptor positive. There was no statistical correlation between MIB1 score and histologic grade, nuclear grade, infiltration of the adjacent fat or breast parenchyma, or estrogen receptor status. All patients were alive with no evidence of disease after a median follow-up of 7 years. Neither histologic or nuclear grading nor proliferative activity were useful prognosticators. None of the tumors had lymph node metastases. Therefore, axillary lymph node dissection may not be necessary. Because more than half of adenoid cystic carcinomas are infiltrative focally, the most important therapeutic goal is complete tumor removal with uninvolved margins of excision.

TUMOR CELL PROLIFERATION AND SURVIVAL IN PATIENTS WITH PROSTATE CANCER FOLLOWED EXPECTANTLY

Purpose Prostate cancers have different biological potentials, and aggressive tumors are difficult to identify when still localized. Tumor cell proliferation determined by MIB-1 expression has been suggested as an important predictor for outcome in several human cancers including the prostate. We test the possible prognostic value of tumor cellular proliferation in prostate cancer patients treated with no intent to cure. Materials and Methods Formalin fixed, paraffin embedded tumor tissue obtained at the time of diagnosis from 221 patients originating from a well known complete Danish prostate cancer population was immunohistochemically investigated. The tumor cell proliferation rate was determined using the MIB-1 antibody. Tumors were clinically localized in 57% of the patients. Results Tumor cell proliferation rate expressed by the MIB-1 score significantly correlated with tumor stage (p <0.001) and malignancy grade (p <0.001). The MIB-1 score, divided into low and high by the median value, showed significant association with disease specific survival in the entire study population (p <0.0001), as well as in the 125 patients suffering from clinically localized disease (p = 0.018). Multivariate analyses showed that MIB-1 was a significant (p = 0.0003) prognostic factor in the entire population, including advanced disease stages. However, in the theoretically curable clinically localized subpopulation MIB-1 was not significant (p = 0.08) contrary to histopathological grade (p = 0.02), erythrocyte sedimentation rate (p = 0.02) and T classification (p = 0.035). Conclusions Prostate tumor cell proliferation, expressed by MIB-1 immunoreactivity, demonstrated significant association with disease specific survival. However, MIB-1 is a close alternative to histopathological grade in describing the natural history of clinically localized prostate cancer. The additional prognostic value and the practical consequence of tumor cell proliferation remain to be clarified.

Prognostic significance of MIB-1 proliferative activity in thin melanomas and immunohistochemical analysis of MIB-1 proliferative activity in melanocytic tumors.

Metastasis from thin melanomas is rare and unpredictable. In order to assess the prognostic value of the proliferation marker, MIB-1, immunohistochemical staining was evaluated in a retrospective case-control study of 11 thin melanomas with documented metastasis and 11 control tumors that failed to metastasize. Tumors selected were < 1-mm thick and were individually matched for tumor thickness, date of excision, and patient age and sex. Analysis of MIB-1 expression as both a mean and a maximum level for the case and control groups revealed no association with metastasis. Wilcoxon's matched-pairs signed-rank test had p-values of 0.45 for the maximum values and 0.79 for the mean values. For the 11 thin melanomas that metastasized, there was a weak, yet statistically insignificant, correlation between the proportion of cells positive for MIB-1 and the length of the relapse-free period [Spearman's correlation coefficient = 0.20 for the maximum level (p = 0.56) and 0.19 for the mean level (p = 0.58)]. These results suggest that MIB-1 expression may be of limited value as a prognostic marker for increased risk of metastasis in patients with thin melanomas. MIB-1 immunohistochemistry was also performed on 25 benign and 70 malignant paraffin-embedded melanocytic tumors to evaluate the level of MIB-1 expression at different stages of tumor progression. A progressive increase in MIB-1 expression was seen from benign tumors through to primary melanomas, with the highest level seen in metastatic melanomas. Within the group of primary melanomas, the MIB-1 score was shown to correlate significantly with tumor thickness and Clark's level of invasion (Spearman's correlation coefficient = 0.71 for level and 0.77 for thickness).

Appraisal of intratumoral microvessel density, MIB-1 score, DNA content, and p53 protein expression as prognostic indicators in patients with locally confined renal cell carcinoma.

The prognostic values of intratumoral microvessel density (iMVD), tumor cell proliferation rate, DNA content (ploidy), and p53 protein expression are controversial or have not been well studied in patients with renal cell carcinoma (RCC) confined to the kidney. A uniform group of 52 clear cell (conventional) RCCs confined to the kidney (classified as T1N0M0 or T2N0M0) were analyzed for iMVD, MIB-1 score, DNA content, S-phase fraction, and p53 protein expression by immunohistochemical methods or flow cytometry. iMVD was evaluated in a single area (X200, 1.15 mm2) representative of the highest MVD (neovascular "hot spot") after independently highlighting endothelial cells with antibodies specific for factor VIII-related antigen (F8/86) and CD31 (JC/70A). The MIB-1 antibody (Ki-67 antigen) score was used as a marker for the tumor cell proliferation rate. DNA content and S-phase fraction were determined by flow cytometry using paraffin embedded tissue. p53 expression was assessed using the D07 antibody. The median time of clinical follow-up was > 9 years. Eleven patients died of disease; the median time to death was 26 months. iMVD counts using antifactor VIII and anti-CD31 were tightly correlated (correlation coefficient = 0.89). S-phase fraction was higher in aneuploid tumors than in diploid tumors (mean, 12.4% vs. 4.3%; P = 0.01). Using univariate survival analyses, tumor size (stage classification pT1 vs. PT2; P = 0.01) and nuclear grade (P = 0.04) were associated with shortened survival. No statistically significant differences in survival were found for iMVD, MIB-1 score, DNA content, S-phase fraction, or p53 expression. Only two cases strongly expressed p53 protein; both tumors were of high nuclear grade. Using multivariate survival analyses, nuclear grade and tumor size were the only independent prognostic factors (best model P = 0.002). In this study, nuclear grade and tumor size were found to be independent predictors of survival in locally confined clear cell (conventional) RCC, as has been shown previously for locally confined RCC in general. MIB-1 score, iMVD counts, DNA content, S-phase fraction, and p53 expression did not contribute additional prognostic information.

The prognostic value of p53 nuclear overexpression and MIB-1 as a proliferative marker in transitional cell carcinoma of the bladder

There is controversy regarding the value of biologic markers as prognostic indicators independent of clinicopathologic parameters in transitional cell carcinoma (TCC) of the bladder. The authors examined the prognostic value of p53 tumor suppressor gene expression and the proliferative marker MIB-1 in TCC of the bladder. Fresh frozen samples from 114 TCCs of the bladder and 13 normal bladders were studied by immunohistochemistry, using monoclonal antibodies MIB-1 for proliferation and PAb 1801 for p53 nuclear overexpression. Scores were determined in each case by counting at least 500 nuclei per slide in 3-5 selected regions. Patients were stratified for both markers into two groups for time-event analysis, according to the median number of nuclei stained. Patients with nuclear staining below the median value of the score were considered negative in the statistical analysis. Quantitative immunostaining was analyzed in relation to the time to recurrence, progression, and cancer death, and compared with clinical and pathologic parameters for prognostic significance in univariate and multivariate analysis (stepwise logistic regression). Median nuclear overexpression of p53 was 22% and that of MIB-1 28%. There was a strong association between proliferation and p53 nuclear overexpression (P < 0.0001). Progression free and disease specific survival rate estimates (log rank test) were significantly lower in patients with p53 or MIB-1 scores above 22% and 28%, respectively. Multivariate analysis indicated that stage as well as p53 and MIB-1 immunostaining provided independent prognostic information. Quantitative immunohistochemical evaluation of nuclear p53 and MIB-1 immunostaining inexpensively provides prognostic indicators in cases of TCC of the bladder.

Cell proliferation, bcl-2, c-myc, p53 and apoptosis as indicators of different aggressiveness in small lymphocytic lymphoma (SLL).

Cell proliferation activity, by MIB1 mAb, expression of bcl-2, c-myc and p53 gene proteins and apoptotic index (AI) were assessed in 54 cases of SLL and compared to the morphological subtypes of this disorder, defined by Lennert on the basis of amount and distribution of small and larger activated lymphocytes as diffuse, tumor-forming and pseudofollicular subtypes (DS, TFS, PFS). MIB1 scores showed significant differences between DS, PFS and TFS (5.5%, 16.61% and 24.14%, respectively; p < 0.0001). Worth noting, the MIB1 score did not differ significantly when comparing DS with the diffuse areas of PFS, or TFS with the pseudofollicles of PFS. The mean bcl-2 gene protein score was displayed to a high extent in all subtypes, but less extensively by larger activated lymphocytes that, conversely, expressed c-myc. MIB1 score correlated negatively with bcl-2 and positively with c-myc protein scores. These findings suggest that lymphocytes protected from apoptosis by bcl-2 would be exponed to cell activation and growth acceleration provided by c-myc. This condition would account for a different aggressiveness of morphologically activated subtypes, such as TFS and PFS with larger pseudofollicles. The survival analysis, performed in 23 cases, showed a trend of association of cell proliferation and c-myc expression with a more aggressive progression of the disease. Overexpression of p53 and apoptosis were found only in a minority of cases, unrelated to the subtypes. In conclusion, cell growth fraction, bcl-2 and c-myc assessment may be of help in predicting the aggressiveness of different subtypes of SLL. This approach should be most conveniently applied to PFS, which represents a continuum between DS and TFS, in order to distinguish, in this heterogeneous subtype, more indolent from more aggressive disorders.

Immunohistochemical Expression of Ki-67 to Predict Lymph Node Involvement in Clinical Stage I Nonseminomatous Germ Cell Tumors

Purpose Primary archival tumor tissues of 89 patients with clinical stage I nonseminomatous germ cell tumors were analyzed for MIB-1 expression and histological parameters such as percentage embryonal carcinoma and presence of vascular invasion to determine the value of these parameters to predict absence or presence of occult lymph node disease. Materials and Methods A monoclonal antibody (MIB-1) developed for application in paraffin-embedded tissues was used to measure immunohistochemical expression of Ki-67 for the overall tumor (total MIB-1) and for each malignant cell type present. In addition, the primary tumors were examined for the presence of vascular invasion and determination of quantitative histology. Univariate and multivariate logistic regression models were used for statistical analysis. Results Univariate analysis neither revealed total MIB-1 score nor MIB-1 score in the highest area of staining of the different cell types to significantly predict pathological stage I or stage II disease. However, the presence of vascular invasion (p <0.001) and the percentage of embryonal carcinoma (p <0.0001) were significant risk factors for occult nodal disease. Multivariate logistic regression analysis revealed the combination of vascular invasion and the percentage of embryonal carcinoma to be the best model to predict pathological stage II correctly (86.5%). Discussion The determination of immunohistochemical MIB-1 expression did not correlate with pathological stage in clinical stage I nonseminomatous germ cell tumors (NSGCT). We were not able to define high risk or low risk groups for occult nodal disease based on MIB-1 staining results. However, percentage of embryonal carcinoma and presence of vascular invasion accurately predicted absence or presence of lymph node metastasis in clinical stage I NSGCT. Our study underlines that a prospective multicenter trial is urgently needed to accurately assess the role of MIB-1 staining in management of clinical stage I NSGCT.

Predicting renal outcome in IgA nephropathy.

Immunoglobulin A (IgA) nephropathy, the most common form of glomerulonephritis worldwide, is characterized by a heterogeneous clinical course. In this study, multivariate analysis was performed to identify histopathologic and clinical features that most accurately predict adverse outcome from a dataset of 148 individuals with IgA nephropathy who underwent renal biopsy at our institution between 1973 and 1995. A semiquantitative scoring system was developed for assessment of six glomerular, eight interstitial, and six vascular histopathologic features of IgA nephropathy. Glomerular and interstitial proliferative activity was evaluated by immunostaining archival biopsy specimens with Mib-1, an antibody directed against the Ki-67 antigen. Kaplan-Meier survival analysis was performed, with renal failure being defined as onset of dialysis or transplantation. A number of clinicopathologic factors were univariately associated with adverse outcome, including elevated serum creatinine levels; the presence of hypertension; proteinuria; component and total histopathologic scores; and positive glomerular or interstitial Mib-1 scores. The total glomerular score, consisting of the arithmetic sum of each of the six component scores, was the strongest histopathologic predictor of adverse outcome. Total interstitial and vascular scores also provided more prognostic information than did individual component scores. By multivariate analysis, high total glomerular scores, increased serum creatinine levels at diagnosis, and younger age were significant (P < 0.01) independent predictors of renal failure. Our studies provide a rational basis for the inclusion of composite histopathologic scores in clinical intervention studies of patients with IgA nephropathy and other glomerular disorders.

Immunoreactivity of bcl-2, p53 and EGFr is associated with tumor stage, grade and cell proliferation in superficial bladder cancer. Finnbladder III Group.

Immunoreactivity of bcl-2, p53, the epidermal growth factor (EGFr) and Ki-67 (MIB-1) proteins was assessed by immunohistochemistry in 185 patients with superficial bladder cancer (SBC) in order to evaluate their usefulness as indicators of tumor progression. Forty-one percent of the tumors were bcl-2 positive, 36% of them were positive for p53 (over 20% of nuclei), while 41% were positive for EGFr, and 30% of the tumors were MIB-1 positive (proliferation index > 15%). Immunoreactivity of all analyzed proteins was highly significantly related to tumor grade and stage. Tumors which were bcl-2, p53 or EGFr positive were also rapidly proliferative (MIB-1 score >15%). The obtained results suggest that all analyzed proteins may have prognostic significance in SBC. The prognostic value of the abnormal immunolabeling of the analyzed proteins will be established after an adequate follow-up period of this same cohort of patients.

DNA ploidy and p53 expression correlate with survival and cell proliferative activity in male breast carcinoma

DNA flow cytometry and the monoclonal antibody D07 were applied in formalin-fixed, paraffin-embedded specimens from 34 primary male breast carcinomas to verify whether DNA ploidy and p53 expression were associated with survival and proliferative activity. They were compared with tumor clinicopathologic features, sex steroid hormone receptors and cell proliferative activity, assessed by the counts of the argyrophilic nucleolar organizer regions (AgNORs), the monoclonal antibody PC10 against the proliferating cell nuclear antigen and the monoclonal antibody MIB-1. A significant correlation was found between survival and tumor ploidy (median survival, 77 months for diploid but only 38 months for aneuploid cases; P = .03) and p53 expression (median survival, 95 months for cases with p53 scores ⩽ 14.06% versus 33 for cases with p53 scores > 14.06%; P = .0004; median survival, 99 months for p53 negative vs 39 for positive cases; P = .007). Tumor histological grade ( P = .006), AgNOR counts ( P = .0001), PC10 scores ( P = .002), and MIB-1 scores ( P = .001) were also associated with prognosis. In the multivariate analysis, only p53 scores ( P = .001) or p53 immunopositivity ( P = .003) and AgNOR counts ( P = .022) retained an independent prognostic significance. Aneuploid tumors had higher AgNOR counts ( P = .002), PC10 ( P = .007), MIB-1 ( P = .006), and p53 scores ( P = .01) than diploid cases. A linear relationship was observed between p53 scores and AgNOR counts ( r = .41; P = .014), PC10 ( r = .46; P = .005), and MIB-1 scores ( r = .44; P = .011). These results indicate that DNA ploidy and p53 expression are associated with survival and cell proliferative activity in male breast carcinoma. Quantitative parameters, such as DNA ploidy, p53 scores, AgNOR counts, PC10, and MIB-1 scores substantially improve the prognostic significance of the traditional parameters in male breast carcinoma.

Expression of MIB-1, mitotic index and S-phase fraction as indicators of cell proliferation in superficial bladder cancer. Finnbladder Group.

Cell proliferation of transitional cell bladder cancer (TCC) was determined by MIB-1 immunolabeling, volume-corrected mitotic index (M/V index) and S-phase fraction measurement in 207 patients with superficial (Ta-T1) bladder cancer. The results were compared to T category, WHO grade and DNA-ploidy. The MIB-1 score was related to T category (P < 0.001), WHO grade (P < 0.001), DNA ploidy (P < 0,0001), M/V index (P < 0.0001) and fraction of cells in S phase (P < 0.0001). The mean MIB-1 score was 6.37% for G1, 14.59% for G2 and 28.59% for G3 carcinomas (P < 0.001). The MIB-1 score for Ta tumors was 9.24% and for T1 tumors 25.34% (P < 0.001). The M/V index was 3.9 for G1, 11.5 for G2 and 25.9 for G3 tumors (P < 0.0001). The M/V index for Ta tumors was 6.4 and 25.3 for T1 tumors (P < 0.0001). WHO grade 1 tumors had 7.7%, grade 2 tumors 13.8% and grade 3 tumors 21.8% of cells in S phase (P < 0.001). Of grade 1 tumors, 97% were diploid and 3% aneuploid, and 78% of grade 2 tumors were diploid and 22% aneuploid. Of grade 3 tumors, 30% were diploid and 70% aneuploid (P < 0.001). Of Ta tumors, 92% were diploid and 8% aneuploid, respectively, whereas 40% of T1 tumors were diploid and 60% aneuploid (P < 0.0001). The results show that quantitative cell proliferation indices are associated with T category and WHO grade in superficial bladder cancer. The prognostic value of the S-phase fraction and mitotic index has been demonstrated in several previous analyses of prognostic factors while the value of MIB-1 score on bladder cancer prognosis remains to be established in further follow-up studies.