KI67 proliferation index in tumors of the upper urinary tract as related to established prognostic factors and long-term survival.

OBJECTIVE: Nephroureterectomy is the standard treatment for tumors of the renal pelvis and ureter. Conservative management or indication of adjuvant treatment in these neoplasms is based mainly in histological grade and stage. The aim of this study is to assess the relation of Ki67 index with other established prognostic factors and to define its predictive value for long term survival, which could be useful in selecting the best treatment for each individual case. METHODS: 81 patients with urothelial tumors of the renal pelvis and ureter, diagnosed and treated between 1975 and 1993, comprised the present study. Ki67 immunostaining was performed in paraffin-embedded tissue. A cut-off limit of 20% was chosen. Tumor location, histological grade, histological pattern, local (T), nodal (N), vascular and perineural invasion and stage (TNM) were assessed in relation to the proliferation index and as prognostic criteria for survival in both univariate and multivariate analysis. RESULTS: The Ki67 proliferation index was found to be related to grade (p < 0.001), T (T0 vs T1-4; p < 0.01), N (p < 0.038), TNM categories (stage 0 vs I-IV; p < 0.048) and perineural invasion (p < 0.01). There was a marginal relation to vascular invasion (p < 0.11). Survival was better for the patients with low proliferating tumors (90%) than for high proliferating ones (67%) (p < 0.02). In the multivariate analysis only T stage was statistically significant (p < 0.01) but a highly suggestive trend was found for the Ki67 index (p < 0.07). CONCLUSIONS: Tumor proliferation assessed by Ki67 immunostaining is related to the progression of the disease and proved to be of predictive value for long-term survival in tumors of the renal pelvis and ureter. The Ki67 index is able to detect high-risk patients that could not be cured by radical surgery alone, raising the need for some type of aduvant treatment in these cases. The treatment predictive effect observed in low grade-low stage cases suggests its possible utility in patients managed conservatively.

The role of Ki67 proliferation assessment in predicting local control in bladder cancer patients treated by radical radiation therapy.

PURPOSE: To assess whether tumour proliferation as measured by Ki67 immunostaining has any predictive value for local control in bladder cancer patients treated by radiotherapy. PATIENTS AND METHODS: Fifty-five patients suffering from infiltrating bladder carcinoma recommended for radical radiotherapy (66 Gy/6-7 weeks) were included in this study. Paraffin-embedded pre-treatment tumour sections were stained with the Ki67 antibody. The percentage of Ki67-positive nuclei was correlated with established prognostic factors, local control and survival. RESULTS: The Ki67 index was not related to local control in our patients when the median was selected as the cut-off value. Patients with tumours with a very low (<27%) Ki67 index had better local control at 5 years (69%) than patients with tumours with greater (>27%) Ki67 expression indices (31.5%) (P<0.05; log-rank test). CONCLUSIONS: Ki67 immunostaining was a feasible method to estimate tumour proliferation. Patients with very low proliferating tumours seemed to achieve better local control after fractionated radiotherapy compared to other patients. Further studies are needed with a greater number of patients to accurately define the role of Ki67 expression in predicting tumour repopulation during fractionated radiotherapy.

Prognostic value of the expression of p53, bcl-2, and bax oncoproteins, and neovascularization in patients with radically resected non-small-cell lung cancer.

PURPOSE: To assess the prognostic value of p53, bcl-2, bax, and neovascularization in radically resected non-small-cell lung cancer (NSCLC) patients. PATIENTS AND METHODS: Tumors from 116 patients were assessed by immunohistochemistry for expression of p53 (DO7 and PAb1081), bcl-2, and the quantification of microvessel density (CD-31). In addition, the expression of bax was assessed in 61 stage I tumors. The median levels of expression of each marker were used as cutoff points. RESULTS: p53 was not correlated to any patient or tumor characteristic, whereas bcl-2 showed higher expression in squamous cell carcinomas (P < .001). bax expression was significantly related with male sex (P = .006) and adenocarcinoma type (P = .0013). p53 status, assessed with one monoclonal antibody (MoAb), was not predictive for survival; however, the combination of staining results obtained with two MoAbs identified the DO7-/PAb1801+ tumors as those with the worst prognosis. bcl-2 expression was associated with longer survival in stage I patients (P = .0169). The combined group expressing p53+(PAb1801)/bcl-2- had the worst survival in stage I patients (P = .034) and in the whole series in comparison with the other combinations of the two oncoproteins. bax expression alone had no influence on survival of stage I patients, but patients with bax+/bcl-2- tumors had the worst prognosis (P = .02 in comparison with bax+/bcl-2+). Tumor neovascularization was not related with other factors, and patients with CD-31+ tumors had a shorter survival duration than those with CD-31- tumors only in stage II (P = .0283). By multivariate analysis including all patients, the presence of p53+/ bcl-2- tumor expression and large tumor diameter (> or = 4cm) were independent prognostic factors for shorter survival duration. For stage I, only the presence of bax+/ bcl-2- tumor expression had a significant negative influence on survival. CONCLUSION: The interaction and the regulation of new biologic markers, such as those involved in the apoptotic pathway, are complex. Combinations of the expression of several of them may give more valuable information than the study of just one. Prognostic influence of p53 staining varied depending on the choice of antibody and the combination of bcl-2- together with p53+ (PAb1801) or with bax+ had the worst influence on survival for patients with stage I NSCLC.

Overexpression of p53 in transitional cell carcinoma of the renal pelvis and ureter. Relation to tumor proliferation and survival.

BACKGROUND: Clinical management of patients with tumors of the upper urinary tract is based mainly on histologic grade and stage of the tumors. In recent years, tumor proliferation has also proved to be an important factor in determining the prognosis of these and other transitional cell tumors. The aim of this study was to assess the role of p53 in regulating cell proliferation and tumor progression and to define its value in predicting the long term survival of patients with these tumors. Such information could be of use in selecting treatment in individual cases. METHODS: Eighty-three patients with urothelial tumors of the renal pelvis and ureter diagnosed and treated between 1975 and 1993 were included in this study. p53 immunostaining was performed on paraffin embedded tissue. Tumor location, histologic grade, histologic pattern, tumor proliferation by Ki-67, local (T classification), lymph node (N classification), vascular and perineural invasion, and clinical stage (TNM) were assessed in relation to p53 overexpression (Mann-Whitney U test and analysis of variance comparisons) and as prognostic factors for survival in both univariate analysis (log rank test) and multivariate analysis (Cox proportional hazards model). RESULTS: Overexpression of p53 was related to tumor proliferation as assessed by Ki-67 (P < 0.01), T classification (Ta vs. T1-4; P < 0.01), N classification (P < 0.054), and TNM staging (Stage 0 vs. I-IV; P < 0.01). There was also a statistically significant relation to vascular (P < 0.002) and perineural invasion (P < 0.04). Fifteen-year actuarial survival for the whole group was 75%. Patients having tumors with low p53 overexpression (< 30% of stained nuclei) had a better survival rate (88%) than those having tumors with high (> 30%) p53 overexpression (65%) (P < 0.02), and this effect reached statistical significance with high grade (P < 0.02) and infiltrating tumors (P < 0.04). Patients with low p53 and Ki-67 expression had a 15-year survival rate of 100%; in contrast, patients with overexpression of both markers had a 15-year survival rate of 61% (P < 0.003). In a multivariate analysis, only T classification (P < 0.001) and p53-Ki-67 expression (P < 0.026) were statistically significant. CONCLUSIONS: Overexpression of p53 is related to increased tumor proliferation and disease progression and is of value in determining the long term survival of patients with tumors of the renal pelvis and ureter. p53 immunostaining can be used to distinguish low risk patients in the theoretically unfavorable high grade, high stage group, and when used together with Ki-67 index, it is a predictive factor for survival.

Expression of the human major vault protein LRP in human lung cancer samples and normal lung tissues.

BACKGROUND: The recently discovered LRP protein has been shown to be involved in drug resistance and possibly in detoxification processes. MATERIALS AND METHODS: To study the relation between LRP expression and exposure to cigarette smoke, LRP immunoreactivity was evaluated in 39 paraffin embedded normal lung tissues derived from patients operated on for pneumothorax, and related to amount of pack years smoked. We also studied the LRP protein expression in 36 non-small-cell lung cancer (NSCLC) samples and related the expression to patient characteristics and survival. Furthermore 17 lung tumor samples (10 NSCLC and 7 SCLC) derived from patients treated with chemotherapy were analysed in order to investigate the relation between LRP or MRP expression and the patient's response to chemotherapy. RESULTS: In the normal lung tissues, LRP intensity levels were not correlated to the amount of pack years smoked, although a trend was seen for higher LRP intensity levels in patients who smoked more than 10 pack years. LRP expression was significantly higher in NSCLC samples than in SCLC samples, and all SCLC samples displayed very low LRP expression. Within NSCLC, squamous cell and adenocarcinomas had higher LRP expression than large cell undifferentiated and mixed tumors. In NSCLC patients LRP expression was not a prognostic factor for survival. At initial analysis LRP expression levels did not predict for the response to chemotherapy. Only 3 out of 17 patients expressed MRP, and all SCLC samples were MRP negative. CONCLUSIONS: Striking different expression levels were seen between NSCLC and SCLC for both LRP and MRP. In a preliminary analysis LRP expression was not predictive for response to chemotherapy in lung cancer patients. In pneumothorax patients LRP levels were not correlated with the amount of pack years smoked.