Cytokine levels in cystic renal masses associated with renal cell carcinoma

PURPOSE: We compared cytokine levels in fluid from renal cysts with and without renal cell carcinoma. MATERIALS AND METHODS: Fluid was aspirated from 18 renal cysts without (benign) and 21 with renal cell carcinoma (malignant). Serum from patients with renal cell carcinoma and healthy controls was collected and cytokines were measured by enzyme-linked immunosorbent assay. RESULTS: Interleukin-6 (IL-6) and basic fibroblast growth factor concentrations were higher in malignant than benign cysts or serum (p <0.006). Epidermal growth factor levels were significantly higher in malignant cysts and serum than in benign cysts (p <0.01). IL-6 levels in malignant cysts positively correlated with the erythrocyte sedimentation rate (R=0.80) and C-reactive protein (R=0.86), and they were higher in grade 3 than in grade 2 tumors. Basic fibroblast growth factor levels were significantly higher in malignant cysts associated with hypervascular than hypovascular tumors (p=0.029). CONCLUSIONS: Cytokine levels in aspirated fluid may help to identify malignant renal cysts and indicate the characteristics of coexisting tumors.     

Serum interleukin-6 levels in metastatic renal cell carcinoma before treatment with interleukin-2 correlates with paraneoplastic syndromes but not patient survival

PURPOSE: We sought to determine the frequency of interleukin-6 (IL-6) expression in renal cancer cell lines, the frequency of the detection of IL-6 in the serum of patients with metastatic renal cell carcinoma, whether serum IL-6 level correlates with the development of paraneoplastic syndromes and whether serum IL-6 level in patients with metastatic renal cancer correlates with response to treatment with interleukin-2 (IL-2) or patient survival. MATERIALS AND METHODS: Conditioned media from 21 cell lines from 20 patients were examined for IL-6. We identified 2 matched groups of patients with metastatic renal cancer (30 responders and 29 nonresponders) to IL-2 based immunotherapy. Stored pretreatment serum specimens were evaluated for IL-6. Medical records were reviewed to determine the presence of paraneoplastic syndromes. RESULTS: IL-6 was detected in 19 of 21 renal cancer cell lines (90%) obtained from 20 patients with metastatic renal cancer as well as in the serum of 33 of 59 patients (56%) with metastatic renal cell carcinoma. A significant association between serum IL-6 level and anemia (p = 0.0032), elevated platelet count (p = 0.01), decreased albumin (p = 0.034) and elevated alkaline phosphatase (p = 0.04) was found. A trend was noted of the association of increased serum IL-6 level and fever (p = 0.051). No correlation was found between pretreatment serum IL-6 level and survival or response to IL-2. CONCLUSIONS: IL-6 was frequently secreted by renal cancer cell lines but it was only present in the serum of approximately half of the patients with metastatic renal cancer. Elevations of serum IL-6 were associated with paraneoplastic manifestations frequently seen in patients with renal cancer, including anemia, thrombocytosis, decreased albumin and elevations of alkaline phosphatase (Stauffer's syndrome). A weak relationship was noted between serum IL-6 level and fever but none was noted between that and survival or response to IL-2.     

Clinicopathological study of incidental renal cell carcinoma

BACKGROUND: The objective of this study is to evaluate the clinicopathological features of incidental renal cell carcinoma, compared with non-incidental carcinoma. METHODS: Between July 1st, 1984 and June 30, 1994, 87 renal cell carcinoma patients were treated at our hospital; 56 had non-incidental renal cell carcinoma and 31 had incidental carcinoma. The clinicopathological features were examined. RESULTS: The incidence of incidental cancer ranges from 0 to 66%, and the incidence has increased in recent years. The median value of maximal tumor size was 4.0cm (1.5 approximately 8.0cm) for incidental cancer, and 8.0cm (3.0 approximately 16cm) for incidental cancer, and 8.0cm (3.0 approximately 16cm) for non-incidental cancer, i.e., the incidental cancer was significantly smaller than the non-incidental one (p < 0.001). The pathological stage of the resected non-incidental renal cell carcinoma (n = 47) was pT1, pT2, pT3 and pT4 in 0, 23, 21 and 3 patients, respectively. For the resected incidental renal cell carcinoma (n = 31) 3, 26, 2 and 0 patients showed pathological stages pT1, pT2, pT3 and pT4, respectively; the pathological stage of incidental renal cell carcinoma was significantly lower than that of non-incidental carcinoma (p < 0.001). Eighteen and 29 resected non-incidental renal cell carcinoma were grades 1 and 2, respectively, whereas 17 and 14 resected incidental renal cell carcinomas were in grades 1 and 2, respectively. Vascular invasion by tumor cells was shown in 31 (66.0%) and 8 (25.8%) patients with non-incidental and incidental renal cell carcinomas, respectively; the incidence of vascular invasion in incidental cancer being significantly lower than in non-incidental cancer (p < 0.001). The performance status and general condition in patients with incidental renal cell carcinoma were superior to those in patients with the non-incidental cancer. The 1, 3 and 5-year survival rate of all 87 renal cell carcinoma patients was 81, 62 and 57%, respectively. These rates for patients with non-incidental renal cell carcinoma were 72, 48 and 41%, respectively, and those for incidental cancer patients were 100%. The survival of patients with incidental renal cell carcinoma was significantly better than that of non-incidental carcinoma patients (p < 0.005). CONCLUSION: Our results suggest that the detection of incidental renal cell carcinoma will increase, and that the prognosis for renal cell carcinoma will improve. However, even in incidental renal cell carcinoma, careful long-term follow up may be necessary, since some tumors are comparatively large and exhibit vascular invasion.     

Electrical stimulation of the trigeminal nerve root for the treatment of chronic facial pain

BACKGROUND: Alterations of the p53 gene are involved in the development of diverse human malignancies, but their incidence and clinicopathologic features are still not well characterized for endometrial carcinoma. METHODS: To investigate the clinicopathologic significance of p53, mutations and loss of heterozygosity (LOH) in endometrial carcinoma in 92 patients with this disease were examined. RESULTS: Mutations of p53 were detected in 20 (22%) of the 92 patients with carcinoma, and LOH was detected in 23 (32%) of the 72 patients in whom heterozygosity of the gene was available. There was a significant correlation between the occurrence of mutation and LOH. Mutations and LOH were more frequent in patients with Grade 3 tumors than in those with Grades 1 and 2 tumors (P = 0.0498, P = 0.0051, respectively). Patients with LOH had a poorer postoperative survival than those without LOH (P = 0.0022, log-rank test), and patients with both LOH and mutation showed the worst prognosis (P < 0.0001, log rank test). Loss of heterozygosity of the p53 gene showed a significant relation to prognosis that was independent of tumor stage, histologic grade, and muscular invasion. CONCLUSIONS: Mutation and LOH of the p53 gene are prognostic indicators in patients with endometrial carcinoma, suggesting that alterations of p53 may play an important role in the development of this cancer.     

Circulating antibodies against p53 protein in patients with ovarian carcinoma. Correlation with clinicopathologic features and survival

BACKGROUND: Genetic alterations of the p53 tumor suppressor protein are the most frequent molecular events in human carcinogenesis. For as yet unknown reasons, mutant p53 often acts as an immunogen for autoantibody generation. These autoantibodies can be detected in the serum of cancer patients. The presence of such antibodies has been identified in a subset of patients with ovarian carcinoma, but their clinical significance has not been investigated. METHODS: Serum samples from patients with ovarian carcinoma were quantitatively analyzed for the presence of p53 autoantibodies with a time-resolved immunofluorometric procedure. Tumor p53 overexpression was assessed by immunohistochemical analysis of tissue sections. Kaplan-Meier survival curves were calculated for p53 antibody positive and negative patients, and the Cox model was used to evaluate the strength of the associations between the presence of serum p53 antibodies and cancer relapse or death, and also between the presence of such antibodies and other clinicopathologic features. RESULTS: p53 antibodies were detected in the serum of 41 of 174 patients with ovarian carcinoma (24%). Antibody levels ranged from a few hundred to 9 x 10(6) arbitrary Units/L, and fluctuated during the course of the disease. p53 antibody positive patients tended to have tumors overexpressing p53, but the association between the two parameters was not statistically significant (P = 0.13). There was also no association between the presence of p53 antibodies and clinical stage, tumor histologic type, or overall patient survival. However, these antibodies were more frequently present in patients older than 50 years (P = 0.001), in patients with moderately or poorly differentiated tumors (P = 0.001), and in patients who received chemotherapy (P = 0.015), and who suffered relapse after surgery (P = 0.018). In univariate analysis, p53 antibody positive patients were at an increased risk for relapse but not death. In multivariate analysis, the differences in disease free and overall survival between patients who were p53 antibody positive or negative were not statistically significant. CONCLUSIONS: p53 autoantibodies are found frequently in the serum of patients with ovarian carcinoma. The presence of such autoantibodies was associated with older patient age, more aggressive tumors, and reduced patient disease free survival. In multivariate analysis the prognostic value of p53 autoantibodies was not statistically significant.     

Prevalence, morphology and biology of renal cell carcinoma in von Hippel-Lindau disease compared to sporadic renal cell carcinoma

PURPOSE: Renal cell carcinoma occurs as a sporadic tumor but may be part of the autosomal dominant von Hippel-Lindau disease, characterized by retinal and central nervous system hemangioblastoma, pheochromocytoma, pancreatic cysts and renal cell carcinoma. We determine the prevalence of von Hippel-Lindau disease in a series of unselected renal cell carcinoma cases by molecular genetic analysis, and compare sporadic to von Hippel-Lindau renal cell carcinoma with respect to morphology and biology. MATERIALS AND METHODS: We established registers comprising 63 subjects with von Hippel-Lindau renal cell carcinoma, belonging to 30 distinct families (register A), and 460 unselected patients operated on for renal cell carcinoma in an 11-year period (register B). Molecular genetic analysis of the von Hippel-Lindau gene was performed for living patients of register A, representing 80% of von Hippel-Lindau families, and register B, 62% living patients, to identify von Hippel-Lindau germline mutations. In addition, register B was evaluated by a questionnaire (95% response) for familial occurrence of von Hippel-Lindau disease. RESULTS: The prevalence of von Hippel-Lindau renal cell carcinoma was 1.6% in 189 consenting unselected renal cell carcinoma patients. Risk factors for occult germline von Hippel-Lindau gene mutations in register B included familial renal cell carcinoma in 3 of 3 patients (100%), multifocal or bilateral renal cell carcinoma in 1 of 10 (10%) and age younger than 50 years at diagnosis in 1 of 33 (3%). Compared to sporadic von Hippel-Lindau renal cell carcinoma was characterized by an occurrence 25 years earlier, association with renal cysts, multifocal and bilateral tumors, cystic organization and low grade histology, and a better 10-year survival (p < 0.001 each). In von Hippel-Lindau disease metastases occurred only in tumors larger than 7 cm. CONCLUSIONS: von Hippel-Lindau differs from sporadic renal cell carcinoma in morphology and biology. Our data provide arguments for planning surgery for von Hippel-Lindau renal cell carcinoma and should stimulate future investigations.     

Induction of human IgE synthesis in B cells by a basophilic cell line, KU812

OBJECTIVES: Tumors are thought to metastasize by a process involving tumor cell attachment to extracellular matrix, degradation of matrix components by tumor-associated proteases, and cellular movement into the area modified by protease activity. Type IV collagen comprises the major element tumor cells must degrade to gain access to the rest of the body. Renal cancer cell line progelatinase A (E.C. 3.4.24.24; 72-kDa type IV collagenase; MMP-2) mRNA expression was correlated with patient survival. METHODS: Total cellular mRNA was extracted from tumor cell lines derived from patients with metastatic renal cell carcinoma. The results of the densitometric analysis of Northern blots were correlated with patient survival. Formalin-fixed, paraffin-embedded tissue sections of primary renal cancers were examined for immunohistochemical expression of MMP-2. RESULTS: Cell lines established from 23 primary renal tumors and six metastatic sites in 26 patients with metastatic renal carcinoma were studied. Variable expression of progelatinase A, relative to A2058 melanoma cells (mean +/- SEM, 0.60 +/- 0.21; median, 0.082; range, 0 to 4.78), was found. There was a significant inverse association between patient survival and the log of the MMP-2 expression (P = 0.045 by the Cox proportional-hazards model). Using a cutoff value of 0.10, the closest round number to the median expression of MMP-2, a significant difference between survival of patients with lower and higher MMP-2 expression in their primary renal cell line was found (P = 0.0054). Cell lines with low, intermediate, and high expression of MMP-2 mRNA all had primary tumors with high tissue immunohistochemical expression of MMP-2. CONCLUSIONS: These studies demonstrate an inverse relationship between renal cancer cell line MMP-2 mRNA expression and patient survival. Immunohistochemical studies of the primary tumors from which the cell lines were derived uniformly showed high MMP-2 expression. Previous work suggests local renal factors upregulate cellular expression of MMP-2 in the primary tumor, and are not active at extrarenal sites.     

Clinical comparison of the Alcon 20,000 Legacy and 10,000 Master phacoemulsification units

OBJECTIVES: To determine the relationship between angiogenesis and various histopathologic features as well as clinical outcome in patients with localized renal cell carcinoma (RCC). METHODS: Microvessel density was quantified by using immunocytochemical staining of endothelial cells for factor VIII-related antigen of 36 specimens taken from patients with pathologic Stage pT1 or pT2 RCC. All patients underwent radical nephrectomy and were followed for a mean time of 97.3 months. RESULTS: No association was noted between microvessel count (MVC) and either cell type, architecture, or tumor size. Inverse correlation was noted between MVC and nuclear area (P = 0.006), nuclear elipticity (P = 0.016), nuclear roughness (P = 0.039), and histologic grade (P = 0.047). Patients having tumors with low MVC had significantly better survival rate compared with those with high MVC neoplasms (P = 0.0014, by Cox proportional hazards method). CONCLUSIONS: Despite lack of correlation with known predictors of survival, MVC provides independent prognostic information for patients with localized RCC.     

Pulmonary metastasectomy for testicular germ cell tumors: a 28-year experience

BACKGROUND: The role of surgery in patients with pulmonary metastatic germ cell tumors has been evolving since the 1970s. To evaluate the results of pulmonary resection, we reviewed our 28-year experience. METHODS: Between July 1967 and May 1995, 157 patients with testicular germ cell tumors underwent pulmonary resections for suspected metastases. Their clinical and pathological data were reviewed. Kaplan-Meier and Cox regression models were used to analyze prognostic factors for survival after resection of metastatic disease. RESULTS: All patients were male with median age of 27 years (range 15-65). Complete resection was accomplished in 155 (99%) patients. Viable carcinoma was present in 44% (70) of the patients. Forty-one (26%) patients had metastases to other sites after pulmonary metastasectomy. The overall actuarial survival 5 years after pulmonary resection was 68% for the entire group and 82% for patients diagnosed after 1985. On multivariate analysis, the adverse prognostic factors were metastases to nonpulmonary visceral sites (p = 0.0069) and the presence of viable carcinoma in the resected specimen (p < 0.0001). CONCLUSIONS: With current chemotherapy regimens, almost 85% of the patients with testicular germ cell tumors undergoing complete resection of their pulmonary metastases can be expected to achieve long-term survival.     

Prognostic parameters of renal cell carcinoma. Clinicopathologic and DNA image cytometric analysis in 133 pT3a cases

In 133 cases of patients with renal cell carcinoma which infiltrated locally into the renal fatty tissue (stage pT3a, TNM classification of 1987), the prognostic potential of the following parameters was investigated: symptoms, patient's age at the time of operation, tumor size and localization, grade of malignancy, cell type, growth pattern, and prognostic score according to St?rkel et al. [Eur Urol 1990;18(suppl 2):36]. Additionally, automated image analysis DNA cytometry was performed on 110/133 carcinomas. After an average observation period of 3.6 years (maximum 10.1 years), 59 (44.4%) of the patients died of their tumors. The cause-specific 5- and 10-year survival rates were 51.3 and 29.1%, respectively. Statistically significant differences (p < 0.05) within the individual parameters were found only for the grade of malignancy and the corresponding prognostic score. Using DNA cytometry, 13 types of renal cell carcinoma were differentiated; 90% of the tumors contained aneuploid cells. Significant differences between these relative to prognosis did not exist. In the case of locally advanced renal cell carcinoma, the DNA histogram does not seem to be superior to conventional prognostic criteria.     

Sarcomatoid renal carcinoma

OBJECTIVE: Sarcomatoid carcinoma of the kidney is a unique, uncommon variety of parenchymatous tumors and is considered to have a worse prognosis by stage than the other histological types. Our experience is reviewed and compared with the larger series reported in the literature. METHODS: Of 101 cases of renal carcinoma submitted to surgery at our department from January, 1990 to December, 1996, there were 4 cases of sarcomatoid carcinoma of the kidney. We compared our cases with the larger series (91 cases in total) reported in the literature for incidence, age, distribution according to sex, tumor size, location, form of presentation, stage and survival. RESULTS: Sarcomatoid renal carcinoma accounts for 1% to 6% of parenchymatous tumors of the kidney according to the different series. The mean age at presentation was 48 years (range 27-61) in our series; there was no prevalence according to sex or location; the renal capsule was not compromised in 3 out of the 4 cases; only one case showed regional lymph node involvement and no case showed distant metastasis at the time of diagnosis. Although these tumors are diagnosed in the advanced stages, two of our cases were incidentally discovered in the early stages (one died 13 months thereafter and the other is alive at 42 months). Patients that are alive and disease-free can only be found in the patient group with stage I or II tumor. All patients with tumor stage III and IV have died. This histological type has a worse prognosis. Most of the series report a mean survival of 5 months. CONCLUSIONS: Sarcomatoid renal carcinoma accounts for 1%-6% of all renal carcinomas. It can present at any age and has a very poor prognosis, with a mean survival of 6 months.     

Prognostic significance of S-phase fraction detected by antithymidine antibodies in epidermoid cervix carcinomas

PURPOSE: To assess the predictive value of pretreatment proliferative activity of epidermoid cervix carcinoma cells with respect to short- and long-term results of radiotherapy. METHODS AND MATERIALS: The proliferative activity of 25 epidermoid cervix carcinomas was evaluated as the immunofluorescent labeling index (LI) by rabbit antithymidine antibodies reacting specifically with single-stranded DNA of replication forks in S-phase cells. The short-term clinical outcome was estimated at 3-6 months after treatment by visual and palpatory examination. Three-year follow-up data were obtained through hospital charts and correspondence with referring physicians for only 19 patients. RESULTS: There was no statistically significant association between LI and such conventional prognostic factors as clinical stage. The LI value of cervix carcinomas was significantly associated with complete regression at 3-6 months after radiotherapy and 3-year disease-free survival. Complete regression at 3-6 months was observed in 87.5% patients with fast proliferating tumors (LI > 7.0%), and only in 41.2% patients with slowly proliferating tumors (p = 0.03). Probability of 3-year disease-free survival was 85.7% in patients with fast proliferating tumors and 50.0% in those with slowly proliferating tumors (p = 0.05). CONCLUSIONS: The immunofluorescent LI of epidermoid cervix carcinoma is able to provide prognostic information on short-term tumor response to radiotherapy and disease-free survival.     

The benefits of mammography are not limited to women of ages older than 50 years

BACKGROUND: Although the benefits of mammography are established in women age < or = 50 years, its use in women age < 50 years is controversial. It is the purpose of this study to determine whether the better outcome in mammographically detected breast carcinoma compared with clinically detected breast carcinoma observed in women age > or = 50 years also is observed in women age < 50 years. METHODS: The authors analyzed 869 cases of Stage I and II breast carcinoma in women treated with breast-conserving therapy between 1984-1994. The median follow-up was 43 months (range, 3-128 months). Three hundred and eighteen patients (37%) presented with mammographic abnormalities without clinical signs of disease and 551 patients (63%) presented with clinical signs of disease. The median age of the patients was 56 years (range, 22-88 years). Three hundred and four patients (35%) were age < 50 years. RESULTS: Mammographically detected tumors in women age < 50 years were of similar size to those in women age > or = 50 years (median 1.1 cm vs. 1.0 cm). Axillary lymph node involvement and tumor grade were not significantly different between these two groups. However, in women age < 50 years the clinically detected tumors were found to be significantly larger, more likely to be axillary lymph node positive, and of higher grade compared with tumors in older women. Consequently, in patients with mammographically detected tumors, there was no significant difference in recurrence free survival (RFS) between women age < 50 years compared with women age > or = 50 years (90% and 92%, respectively; P=0.4), whereas in patients with clinically detected tumors there was a significant difference in 5-year RFS (77% vs. 87%, respectively; P=0.02). CONCLUSIONS: Mammography results in the diagnosis of smaller and lower grade breast carcinoma. If mammographically detected, there appears to be no difference in RFS between women age < 50 years and those women age > or = 50 but there is a difference if the tumors are clinically detected. If left to grow to the size necessary for clinical detectability, the disease appears to be more aggressive in younger women.     

Epidermal growth factor family and renal cell carcinoma: expression and prognostic impact

OBJECTIVE: Expression and prognostic impact of some exponents of the epidermal growth factor (EGF) family in renal cell carcinoma (RCC) were examined. MATERIALS AND METHODS: EGF, transforming growth factor-alpha (TGF-alpha), EGF receptor (EGF-R), and c-erb B-2 were determined immunohistochemically in formalin-fixed paraffin-embedded tumor samples of 30 patients with locally confined RCCs. The prognostic significance of these growth factors and their receptors as well as of tumor stage and malignancy grade was examined with respect to survival and tumor recurrence by following up the fate of the patients after nephrectomy (mean follow-up time 5.2 years). RESULTS: The members of the EGF family and their receptors studied were expressed to a variable degree in all RCCs investigated. However, using log-rank tests in Kaplan-Meier plots only tumor stage (p < 0.0007) and malignancy grade (p < 0.007) but none of the growth factors or receptors studied (p > 0.05, respectively) exhibited prognostic significance with respect to both survival and disease-free period. On the contrary, there was a significant correlation between EGF and TGF-alpha (p < 0.001), EGF and EGF-R (p = 0.028), EGF-R and c-erb B-2 (p = 0.0009), and-inversely related-between TGF-alpha and tumor stage (p = 0.047) and between EGF-R and malignancy grade (p = 0.03). The coexpression of the factors studied also showed no prognostic relevance. CONCLUSION: The expression of these members of the EGF family seems not to bear evaluable prognostic information for clinical use in the case of RCC.     

p53 and c-jun expression in urinary bladder transitional cell carcinoma: correlation with proliferating cell nuclear antigen (PCNA) histological grade and clinical stage

OBJECTIVE: To investigate p53 and c-jun oncoproteins and proliferating cell nuclear antigen (PCNA) in transitional cell urinary bladder carcinomas (TCCs) and to determine their relationships to tumour grade, stage and survival. MATERIALS AND METHODS: The expression of p53, c-jun and PCNA was studied using immunohistochemistry in formalin-fixed, paraffin-embedded tissues in a series of 110 TCCs. RESULTS: 58% of our cases were positive for p53 and 88% for c-jun. A statistically very significant correlation (p < 0.0001) was observed between p53 and c-jun (r = 0.781), p53 and PCNA (r = 0.772), c-jun and PCNA (r = 0.831) as well as between each of the two oncoproteins and the histological grade and clinical stage (p < 0.001). There was no correlation of either p53, PCNA or c-jun with clinical outcome in terms of patients survival. CONCLUSION: p53 and c-jun proteins' overexpression are strongly related to rapid tumour cell proliferation and hence with aggressive growth in urinary bladder TCC. PCNA score remains an important prognostic index in transitional cell carcinoma of the bladder.     

Effect of ramipril on heart rate variability in digitalis-treated patients with chronic heart failure

Bilharzial-related bladder carcinoma (BBC) is the most common malignant neoplasm in Egypt, also occurring with a high incidence in other regions of the Middle East and East Africa. The clinical and pathological features of BBC are different than those described for the conventional transitional cell carcinoma of the bladder, including the high incidence of squamous cell carcinoma reported in BBC and the fact that over 90% of BBC cases at presentation are advanced-stage tumors (P3 and P4). This study was conducted to better define the phenotypic alterations associated with BBC affecting the p53 cell cycle control pathway, including altered patterns of expression of downstream effector proteins such as mdm2 and p21/WAF1. A well-characterized cohort of 125 patients affected with bilharzial-related bladder tumors was studied. Tumors were classified as squamous carcinomas (n = 68), transitional cell carcinomas (n = 55), or adenocarcinomas (n = 2). The products encoded by TP53, mdm2, and p21/WAF1 genes were analyzed by immunohistochemistry. Furthermore, the patterns of expression of these molecules were correlated with the Ki67 proliferative index. In addition, the microanatomical distribution of programmed cell death was assessed in a subset of tumors, using the so-called terminal deoxynucleotidyl transferase-mediated nick end labeling method. p53 nuclear overexpression was identified in 25 (20%) of 125 cases. Nuclear overexpression of mdm2 was detected in 74 (59.2%) of 125 cases. There was a statistically significant association between coexpression of both p53 and mdm2 and detection of lymph node metastases (P = 0.04). p21/WAF1 expression was detected in 87 (72%) of 121 evaluable cases. A high Ki67 proliferative index was observed in 99 (86%) of 115 evaluable cases. There was a statistically significant association between high Ki67 proliferative index and mdm2-positive phenotype (P = 0.005) and deep muscle invasion (P3b; P = 0.026) as well as lymph node metastases (P = 0.039). Apoptosis was observed in terminally differentiated tumor cells identified in the superficial layers of well-differentiated squamous carcinoma or exfoliating cells in transitional lesions. However, only rare apoptotic tumor cells were found in basal or suprabasal layers as well as in the invasive elements of the neoplasms studied. These results suggest that the frequency of p53 nuclear overexpression in BBC is lower than that reported for conventional transitional cell carcinoma. Nevertheless, tumors with p53 alterations have a greater propensity to progress. The prominent number of cases displaying an mdm2-positive phenotype suggests that this may be an early incident in BBC and should be regarded as a potential oncogenic phenomenon. This is supported by the significant correlation between high Ki67 proliferative index and mdm2 overexpression. The association of an aggressive clinical course with the coexpression of both p53 and mdm2 products might be viewed as a cooperative effect that develops in tumor progression.     

Detection of cytokine gene expression in human monocytes and lymphocytes by fluorescent in situ hybridization in cell suspension and flow cytometry

OBJECTIVES: Previous reports indicate that up to 10% of patients with localized renal cell carcinoma have direct intracaval neoplastic extension. Many patients with locally confined tumors and small intracaval tumor extensions can be surgically cured. Few studies have documented long-term survival after radical surgery for renal cell carcinoma involving higher vena caval tumor extension. We report the follow-up of 34 consecutive patients undergoing radical nephrectomy and intrahepatic or supradiaphragmatic intracaval thrombectomy for renal cell carcinoma. METHODS: From October 1982 through January 1993, 34 consecutive patients with a mean age of 60 years were identified as having clinical Stage T3 renal cell carcinoma (mean diameter 9.5+/-4.0 cm) with intrahepatic (41%) or supradiaphragmatic (59%) intracaval neoplastic extension. Patients underwent radical nephrectomy with intrahepatic caval thrombectomy (38%) or supradiaphragmatic caval thrombectomy using cardiac bypass with hypothermia and circulatory arrest (62%). Clinical outcome was assessed during a mean follow-up of 30 months (range 1 to 182). RESULTS: A total of 24 (71%) of 34 tumors demonstrated capsular penetration, and 22 (65%) of 34 had significant perinephric extension into Gerota's fascia by pathologic analysis. Metastatic disease was identified in 35% of patients either at the time of surgery or by pathologic analysis. Using Kaplan-Meier actuarial analysis, the likelihood of survival for all 34 consecutive patients after surgery was 68% (95% confidence interval [CI] 49% to 81%) at 1 year, 32% (95% CI 18% to 48%) at 2 years, 14% (95% CI 5% to 28%) at 5 years, and 9% (95% CI 2% to 24%) at 10 years. Neither capsular penetration, perinephric extension, the level of intracaval extension of tumor, nor the use of cardiopulmonary bypass significantly affected survival. CONCLUSIONS: In patients with renal cell carcinoma and intrahepatic or supradiaphragmatic intracaval extension of tumor, the presence of metastases is a frequent occurrence and, if present, greatly diminishes survival. Improvements in the preoperative detection of occult metastases are needed if surgery alone is to improve survival.     

Epidermal growth factor receptor expression is associated with rapid tumor cell proliferation in renal cell carcinoma

Epidermal growth factor receptor (EGF-r) expression and tumor cell proliferation rate have been proposed as potential prognostic parameters in renal cell carcinoma (RCC). In this study, immunohistochemical stains using antibodies to EGF-r and the cell proliferation marker Ki-67 (MIB-1) were used to study the relationship between EGF-r expression, tumor cell proliferation, and prognosis in 50 non-papillary RCC extending beyond the renal capsule (pT3). A high Ki-67 labeling index (LI) was associated with poor patient prognosis (P < .05). Thirty-eight cases (76%) expressed strong cell membrane immunoreactivity for EGF-r. There was a tendency toward a shortened survival for EGF-r-positive tumors (P = .08). Tumor growth fraction (Ki-67 LI) was significantly higher in EGF-r-positive tumors than in EGF-r-negative tumors (P < .05), suggesting that rapid tumor proliferation might be responsible for the poor prognosis associated with EGF-r-positive RCC.     

Multiple primary malignancies in renal cell carcinoma

PURPOSE: We determine the incidence and nature of multiple primary malignancies in patients with renal cell carcinoma, and whether these patients have an increased risk of a second primary malignancy. MATERIALS AND METHODS: Between July 1989 and January 1997, 551 patients underwent an operation for renal cell carcinoma. The incidence of other primary malignancies was determined and classified as antecedent, synchronous or subsequent. The observed number of subsequent malignancies after diagnosis of renal cell carcinoma was compared to the expected number based on age, race and sex specific 1990 to 1994 incidence rates from the United States Surveillance, Epidemiology and End Results data using the Poisson test. RESULTS: The number of primary malignancies, including cutaneous malignancies, was at least 1 in 148 patients (26.9%), at least 2 in 34 (6.2%), at least 3 in 6 (1.1%) and 4 in 1 (0.2%). Other malignancies were antecedent in 85 cases (45.0%), synchronous in 74 (39.4%) and subsequent in 30 (16.0%). The most common other primary malignancies were breast, prostate, colorectal and bladder cancer, and non-Hodgkin's lymphoma. Only men with renal cell carcinoma had an increased risk of bladder cancer (standardized incidence ratio 4.3, p = 0.0067). CONCLUSIONS: Breast, prostate, colorectal and bladder cancer as well as non-Hodgkin's lymphoma were the most common other primary malignancies. Men with renal cell carcinoma have an increased risk of subsequent bladder cancer.     

Expression of Fas in renal cell carcinoma

We have investigated whether the Fas-mediated cell death pathway is functional in renal cell carcinoma. The expression of Fas in surgical specimens and cell lines of renal cell carcinoma was examined. Fas expression was positive in six out of 18 tumors measured by flow cytometry and was prominent in advanced tumors. Three out of the six Fas-positive tumors had already metastasized at the time of surgery. A significant correlation was found between the tumor volume and the percentage of Fas-positive cells in a tumor (r = 0.70, P = 0.0007). Fas-positive tumors were larger than Fas-negative tumors [mean tumor volume (ml) +/- SD, Fas(+), 265.6 +/- 136.8; Fas(-), 65.8 +/- 80.9, P = 0.0012]. All human renal carcinoma cell lines tested (ACHN, Caki-1, SMKT-R-2, SMKT-R-3 and SMKT-R-4) expressed Fas abundantly, as Fas-positive cells accounted for > 50% in all cell lines by flow cytometry. Treatment with anti-Fas antibody caused apoptosis in Fas-positive renal cell carcinoma cell lines. However, the effectiveness of apoptosis induction in individual cell lines was not correlated with the level of Fas expressed. These data suggest that Fas targeting may be a therapeutic option for treatment of advanced renal cell carcinoma which is refractory to either chemotherapy or irradiation.