Expression of cyclooxygenase-2 in primary superficial bladder cancer tissue may predict risk of its recurrence after complete transurethral resection.

A new modality is necessary to prevent recurrence of superficial bladder cancer after complete transurethral resection (TUR) because of the high recurrence rate even with current prophylaxis protocols. Prostaglandins (PGs) are known to be produced more in transitional cell carcinoma, and etiologically bladder cancer risk is negatively associated with the intake of non-steroidal anti-inflammatory drugs (NSAIDs), which inhibit cyclooxygenase (COX), the rate-limiting enzyme of the PG production. We have shown the chemopreventive effect of piroxicam, an NSAID, on the N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN)-induced rat bladder cancer model. To avoid gastrointestinal side effects of regular NSAIDs, we also showed the chemopreventive effect of nimesulide, a selective inhibitor of the second isoform of COX, COX-2, which does not affect COX-l house-keeping activity in gastrointestinal mucosa on the same model. We also observed induction of COX-2 protein in the rat bladder tumor. In this study, we screened COX-2 protein expression in primary superficial bladder cancer tissues, to elucidate if COX-2 selective inhibitors can be a candidate chemopreventive agent for bladder cancer recurrence. Five and 6 samples of superficial bladder cancer cases with and without recurrence after complete TUR were examined by immunohistochemical analysis. We found more COX-2 protein positive samples in the cases with recurrence than in cases without recurrence. Even though the number of cases examined is small, this result supports our hypothesis that COX-2 contributes to superficial bladder cancer recurrence, thus, selective COX-2 inhibitors can be a candidate chemopreventive agent for the recurrence.

Detection of circulating MN/CA9 positive renal cell carcinoma cells during operation.

Our previous study demonstrated the clear detection of MN/CA9 mRNA in peripheral blood samples from RCC patients. However, approximately 30 % of control blood samples from healthy volunteers showed MN/CA9 expression. We have developed a new primer set and optimized the PCR conditions, now resulting in a specificity of 100 %. In tissue samples, all clear cell type carcinomas but none of the spindle cell type and pleomorphic cell type tumors expressed the MN/CA9 message. Analysis of MN/CA9 messages in peripheral blood samples from RCC patients gave positive results for 0/2, 1/9, 0/4 and 4/12 of stage I, II, III and IV cases, respectively. RT-PCR analysis using preoperative renal venous blood samples resulted in clear detection of MN/CA9 positive cells in 2/4, 3/13, 2/6 and 1/1 of stage I, II, III and IV cases, respectively. Our results suggest that assessment of MN/CA9 expression by RT-PCR is a promising method for detecting cancer cells in the circulation of patients with RCC.

Transurethral needle ablation of the prostate: an initial Japanese clinical trial.

OBJECTIVES: Transurethral needle ablation of the prostate is a new alternative endoscopic thermal therapy that uses a low-energy radio frequency delivered into the prostatic adenoma. Herein is reported the initial clinical experience by multiple institutes in Japan of transurethral needle ablation of the prostate for the treatment of symptomatic benign prostatic hyperplasia. METHODS: A total of 93 patients were treated with this technique. Transurethral needle ablation of the prostate was generally performed under low-spinal anesthesia. Before and after the procedure, international symptom score (IPSS), quality of life (QOL) score, peak urinary flow rate (Qmax), postvoid residual urine volume and prostate size were evaluated. RESULTS: There was a reduction of IPSS of more than 50% when compared with that of pretreatment, being 51.3% (57/93 patients) and 60.2% (56/93 patients) at 3 months and 6 months after the procedure, respectively. Sixty-seven patients who were available for a 12-month follow-up period demonstrated a markedly decreased mean IPSS when compared with that measured before the treatment for a statistically significant difference (P < 0.01). Fifty-eight patients who were available for uroflowmetric study at 12 months exhibited a notably increased mean Qmax of 11.2 +/- 4.5 mL/s, which was a statistically significant increase when compared with that found before treatment (P < 0.05). Although all patients suffered some degree of gross hematuria after the procedure, none of them required any specific treatment for complications. CONCLUSION: Transurethral needle ablation technique for the treatment of symptomatic benign prostatic hyperplasia is safe and effective. However, a much longer follow-up study is essential for fully evaluating the extended effectiveness of this technique.

Treated natural history of superficial bladder cancer.

BACKGROUND: The present study was conducted to examine the natural history of superficial bladder cancer. METHODS: One hundred and forty-four patients with superficial bladder cancer who had been treated with transurethral resection of bladder tumor (TURBt) alone were analyzed. RESULTS: The non-recurrence rate was 64.8% at 36 months and 61.2% at 60 months after TURBt. When the non-recurrence rate after TURBt was analyzed by background variables, the rate differed significantly between the solitary tumor group and the multiple tumor group. The tumor recurrence hazard curves for the entire population had one high peak before 500 days and another slight peak around 1500 days after TURBt. CONCLUSIONS: These results will provide basic information useful when evaluating new regimens of intravesical instillation therapy for prophylaxis of superficial bladder cancer after our complete TURBt in the Nara Uro-Oncology Research Group.

A prospective randomized multicenter study of chlormadinone acetate versus flutamide in total androgen blockade for prostate cancer.

BACKGROUND: A randomized multicenter study was conducted to investigate the efficacy of total androgen blockade (TAB) for patients with previously untreated prostate cancer using the steroidal anti-androgen chlormadinone acetate (CMA) and the non-steroidal anti-androgen flutamide. We also compared the liver dysfunction in these two arms. METHODS: From November 1995 to October 1997, 71 patients were registered into this study and 70 of them were eligible. RESULTS: There was no significant difference in the efficacy of TAB between CMA and flutamide at 24 weeks. The testosterone and prostate-specific antigen (PSA) levels in patients administered flutamide (Group II) increased significantly 3 days after the first dose of LH-RH analog, whereas no such increase was observed in patients administered CMA (Group I), indicating that CMA prevented the flare-up. Parameters of liver function, serum GOT and GPT levels, which were normal at the baseline, became abnormal in 30.0% and 35.3%, respectively, of patients in Group II. These figures were significantly higher than the corresponding figures of 6.3% and 12.5%, respectively, in Group I. When the degree of change in each of these parameters was analyzed, both GOT and GPT levels showed a significantly greater increase in Group II than in Group I. CONCLUSION: These results indicate that attention must be paid to changes in liver function during the administration of flutamide in patients with prostate cancer even if their baseline liver function is normal. It is also suggested that CMA may be better tolerated from the viewpoint of the drug effects on liver function.

[The problem of a long-term follow up in patients with renal cell carcinoma].

PURPOSE: We investigated on a problem of long-term follow up in patients with renal cell carcinoma. PATIENTS AND METHODS: A total of 287 patients with renal cell carcinoma treated in Nara Medical University and affiliated facilities from January 1980 to December 1990 were examined. And we investigated the trend of explanation to patients including 287 patients from 1991 to 1995. RESULTS: Up to December 1995, there are 76 patients (26.5%) unable to be followed and 211 patients able to be followed. The former group patients were less declared cancer rather than the latter group patients. Of 76, 22 patients (28.9%) might misunderstand completely recovering from the cancer disease. For the recent 5 years, those patients who were declared cancer increased, and those patients who were explained benign disease decreased. CONCLUSION: These results suggested that declaration of cancer is important for patients with renal cell carcinoma to be followed for a long-term.

A comparative study of terazosin and tamsulosin for symptomatic benign prostatic hyperplasia in Japanese patients.

OBJECTIVE: To compare the efficacy and safety of an incremental-dose regimen of terazosin (1-2 mg daily) and a fixed-dose regimen of tamsulosin (0.2 mg daily), on Japanese patients with symptomatic benign prostatic hyperplasia (BPH). PATIENTS AND METHODS: This multicentre, single-blind, randomized trial compared terazosin and tamsulosin over 4 weeks, in 61 patients with symptomatic BPH randomly assigned to terazosin (n = 31) or tamsulosin (n = 30). Terazosin 0.5 mg twice daily was administered for 2 weeks, followed by 1 mg twice daily for 2 weeks. Tamsulosin (0.2 mg) was administered once daily for 4 weeks. Symptoms were evaluated using the International Prostate Symptom Score (IPSS), and quality of life (QOL) was assessed subjectively before treatment, and again after 2 and 4 weeks of treatment. Objective measurements taken before and after the treatment period were the maximum (Qmax) and average (Qave) urinary flow rates, and the percentage residual urine volume. Improvement was defined as a 25% decrease from baseline in IPSS, > 1 point increase in QOL score, and > 2.5 mL/s increase in Qmax. Adverse reactions potentially related to the study drugs were recorded throughout the treatment period. RESULTS: Both terazosin and tamsulosin produced statistically significant improvements in subjective and objective variables. Neither treatment affected systolic or diastolic blood pressure or pulse rate. Adverse reactions were noted in four patients (three in the terazosin group and one in the tamsulosin group). However, there was no statistically significant difference in the incidence of adverse effects between the groups. CONCLUSIONS: Despite the limitations of small sample size and relatively short treatment periods, terazosin and tamsulosin were equally effective in the treatment of symptomatic BPH in Japanese patients, using relatively lower doses than those used in Western countries.

Different regulation of vascular endothelial growth factor expression by the ERK and p38 kinase pathways in v-ras, v-raf, and v-myc transformed cells.

Here we show that vascular endothelial growth factor (VEGF) mRNA expression is up-regulated in oncogene transformed rat liver epithelial (RLE) cell lines and that the extracellular signal-regulated kinase (ERK) and p38 kinase differentially regulate the oncogene-mediated stimulation of VEGF. The highest level of VEGF mRNA expression was observed in the v-H-ras transformed RLE cell line, followed by the v-raf and v-myc transformed lines. The PD98059 MEK inhibitor was used to block the ERK pathway and SB203580 inhibitor to block the p38 pathway. The parent and the v-H-ras transformed RLE cell lines showed up-regulation of VEGF RNA expression through the ERK pathway and down-regulation of VEGF through the p38 pathway. VEGF was regulated in a comparable manner in a human breast carcinoma cell line. In the v-raf and v-myc transformed RLE lines, positive regulation of VEGF was transduced through the p38 pathway. These findings suggest that (1) oncogenic ras differs from raf and myc in the recruitment of the MAPK signaling pathways for VEGF regulation; (2) that VEGF is regulated in ras transformed and human cancer cell lines in a positive and negative manner by the ERK and p38 signaling pathways.

[Late phase II clinical study for bropirimine (U-54461S) in situ carcinoma of the bladder: follow-up investigation. Bropirimine Study Group].

A follow-up investigation was conducted on a Late Phase II clinical study of bropirimine for carcinoma in situ (CIS) of the bladder. We previously reported that 48 patients were enrolled and 17 patients achieved complete remission (CR) in the Late Phase II study. Of the 17 CR patients, 5 had recurrence, but 9 were recurrence free for a year and 5 have remained so for more than 2 years (median follow-up: 29.1 +/- 4.2 months). The 1-year and 2-year recurrence-free rates calculated using the Kaplan-Meier method were 70.3% and 61.5% respectively. Of all the 47 bropirimine-treated patients, 11 underwent total cystectomy (median follow-up: 31.8 +/- 5.2 months). The rates of bladder preservation after 1 year, 2 years, and 3 years calculated using the Kaplan-Meier method were 87.2%, 80.7%, and 74.0% respectively. Of the 39 patients who did not respond to bropirimine or suffered from recurrence after bropirimine treatment, 19 received subsequent intravesical bacillus Calmette-Guerin (BCG) therapy and 13 achieved CR (68.4%). This suggests that bropirimine does not decrease the efficacy of BCG therapy. In the present study, the prognosis was confirmed to be favorable after bropirimine therapy. Bropirimine would thus seem to be a useful oral anticancer agent for bladder CIS.

Increased expression of cyclooxygenase-2 protein in rat urinary bladder tumors induced by N-butyl-N-(4-hydroxybutyl) nitrosamine.

The anti-inflammatory drugs, aspirin and piroxicam, are known to possess chemopreventive potential against rat superficial urinary bladder carcinogenesis induced by N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN). Recently, we found similar inhibitory effects with a selective cyclooxygenase (COX)-2 inhibitor, nimesulide. In order to clarify the inhibitory mechanisms, we have further studied the expression of COX-2 protein in urinary bladder tumors induced by BBN in Fischer 344 male rats. For comparison, papillomatosis caused by uracil-induced urolithiasis, and normal epithelial cells, were also investigated. Western blot analysis revealed COX-2 protein to be barely expressed in the normal epithelial cells, whereas it was increased 13-22-fold in varying sizes of urinary bladder tumors and 7-fold in papillomatosis. Immunohistochemically, COX-2 protein was diffusely expressed in transitional cell carcinomas and nodulo-papillary hyperplasia but weakly expressed only in basal cells in simple hyperplasia and normal-looking surrounding epithelia. In papillomatosis, it was moderately expressed only in endothelial cells in stroma. These results indicate that COX-2 plays important roles in the development of preneoplastic and neoplastic lesions in the rat urinary bladder, and therefore could be a good target for chemoprevention of superficial lesions.

Diagnostic usefulness of endorectal magnetic resonance imaging with dynamic contrast-enhancement in patients with localized prostate cancer: mapping studies with biopsy specimens.

BACKGROUND: New diagnostic criteria for dynamic magnetic resonance (MR) imaging in prostate cancer are presented. The diagnostic usefulness of endorectal MR imaging with dynamic contrast-enhancement in localized prostate cancer and the validity of these criteria were evaluated. METHODS: Eighteen untreated patients who were suspected of localized prostate cancer were included in the study. They received endorectal dynamic MR imaging before systematic sextant needle biopsy. First. a mapping study with the findings of MR images and histopathology of biopsy specimens was performed in eight patients out of 18 to compare the difference in T2-weighted images with the endorectal coil and the body coil in the same individuals. Second, another mapping study was performed in all 18 patients by analyzing the findings of endorectal dynamic MR images. For the diagnosis of prostate cancer in MR imaging, we offered diagnostic criteria from our experience in addition to those in plain T2-weighted images from the literature. RESULTS: The overall diagnostic rates of endorectal dynamic MR imaging were 88.9% in accuracy, 100% in sensitivity, and 81.8% in specificity. In the comparison of the endorectal and body coils in T2-weighted images in eight patients, there was no difference in the diagnostic rates except for one more histopathologic false positive portion in endorectal MR imaging. In the second mapping study in 18 patients, the diagnostic rates were 92.6% in accuracy, 88.9% in sensitivity and 93.3% in specificity. Endorectal dynamic imaging raised the diagnostic sensitivity from 77.8 to 88.9%. CONCLUSION: The data demonstrated the validity of this diagnostic criteria and the diagnostic usefulness of endorectal dynamic MR imaging in localized prostate cancer.

[Intra-arterial chemotherapy for invasive bladder cancer].

The present investigation was conducted to examine the effects of intra-arterial chemotherapy (IAC) for patients with invasive bladder cancer. A total of 37 patients were treated with IAC at Nara Medical University and its affiliated hospitals between January, 1993 and August, 1997. There were 27 patients in the poor risk group. The remaining 10 patients underwent anti-tumor IAC. Thirty of the 37 patients received chemotherapeutic agents via a reservoir, and the remaining 7 patients received a one-shot injection of agents followed by transcatheter arterial embolization (TAE). In the reservoir group, there were 18 patients who received IAC in combination with radiation therapy. As a result, reduction of tumor size was noted in 53%, and the 3-year cause-specific survival rate was 54% in all cases. There was a significant difference in the 3-year survival rate between the radiation-treated group and the group without radiation. The adverse events included anemia, leukopenia, thrombocytopenia and gastrointestinal symptoms, but none of them were severe. The results of the present study indicate that IAC is useful in the treatment of invasive bladder cancer for poor risk patients.

E-cadherin and alpha-, beta- and gamma-catenin expression in prostate cancers: correlation with tumour invasion.

The E-cadherin-catenin complex plays an important role in establishing and maintaining intercellular connections and morphogenesis and reduced expression of its constituent molecules is associated with invasion and metastasis. In the present study, we examined E-cadherin and alpha-, beta- and gamma-catenin levels in tumour tissues obtained by radical prostatectomy in order to investigate the relationship with histopathological tumour invasion. Immunohistochemical findings for 45 prostate cancer specimens demonstrated aberrant expression of each molecule to be associated with dedifferentiation and, in addition, alteration of staining patterns for the three types of catenin was significantly correlated with capsular but not lymphatic or vascular invasion. The data thus suggest that three types of catenin may be useful predictive markers for biological aggressiveness of prostate cancer.

A new parameter in decision making for transurethral electroresection of benign prostate hyperplasia.

OBJECTIVE: In this study, the clinical usefulness of transition zone (TZ) volume (TZV) measured by transrectal ultrasonography (TRUS) was investigated as a new parameter for the preoperative prediction of the treatment efficacy of transurethral resection of the prostate (TURP). METHODS: Fifty-six men with symptomatic benign prostatic hyperplasia (BPH; age 68.6 +/- 9.7 years) underwent TURP and were evaluated based on ordinary BPH parameters such as the international prostatic symptom score (I-PSS), quality of life (QOL) score, peak urine flow and entire prostate volume (PV), as well as the new TZV parameters and calculation of the TZ index. Relative risks were adjusted simultaneously for potentially confounding variables by multiple logistic regression analysis after adjustment for age, QOL, I-PSS, Qmax and residual urine. RESULTS: The adjusted relative risk for TURP at a TZ index of 0.1 increased to 4.5 (95% confidence interval 2.3-8.78). In general, poor responses were observed in patients with less symptomatic scores or lower values prior to operation, but there was a weak correlation between treatment outcome and preoperative scores or values of ordinary parameters. The volume parameters of BPH and PV did not predict treatment efficacy preoperatively, but TZV and the TZ index correlated with the treatment efficacy of TURP. CONCLUSION: TZV and the TZ index seem to be useful new parameters in preoperative decision-making with regard to TURP.

Goserelin acetate with or without antiandrogen or estrogen in the treatment of patients with advanced prostate cancer: a multicenter, randomized, controlled trial in Japan. Zoladex Study Group.

OBJECTIVE: The aims of this randomized, controlled study were to investigate the efficacy and safety of long-term monotherapy with the luteinizing hormone-releasing hormone agonist goserelin acetate compared with both short- and long-term combined androgen blockade. METHODS: Patients with advanced prostate cancer (n = 371) were randomized to treatment with goserelin acetate alone or a combination of goserelin acetate plus either long-term or short-term antiandrogen (chlormadinone acetate) or short-term estrogen (diethylstilbestrol diphosphate). RESULTS: There were no significant differences between the treatment groups with respect to objective progression, overall survival or disease-specific survival. Nevertheless, subgroup analysis suggested that patients with minimal disease or a good prognosis might benefit more from combined androgen blockade than other patients. Combined androgen blockade significantly reduced the incidence of disease flare compared with goserelin acetate treatment alone. CONCLUSIONS: Neither short- nor long-term combined androgen blockade had a survival advantage over goserelin acetate alone.

Prevention by 1'-acetoxychavicol acetate of the induction but not growth of putative preneoplastic, glutathione S-transferase placental form-positive, focal lesions in the livers of rats fed a choline-deficient, L-amino acid-defined diet.

The effects of 1'-acetoxychavicol acetate (ACA) on endogenous rat liver carcinogenesis because of chronic feeding of a choline-deficient, L-amino acid-defined (CDAA) diet were examined. Male Fischer 344 rats, 6 weeks old, received the CDAA diet containing ACA at doses of 0, 0.005, 0.010 and 0.050% for 12 weeks and were then killed. ACA decreased the numbers of putative preneoplastic, glutathione S-transferase placental form (GST-P)-positive, focal lesions developing in the livers of rats fed the CDAA diet but did not alter their sizes. At the same time, ACA reduced the levels of 8-hydroxyguanine, a parameter of oxidative DNA damage, but did not significantly affect generation of 2-thiobarbituric acid-reacting substances, indicators of oxidative extra-DNA damage, or hepatocyte proliferation. Furthermore, ACA did not exert any significant effects on the numbers or sizes of GST-P-positive lesions in the livers of rats when administered between weeks 2 and 8 after initiation with a single i.p. dose of 200 mg/kg body wt of N-nitrosodiethylamine. These results indicate that ACA prevents the CDAA diet-associated induction of putative preneoplastic lesions by reduction of oxidative DNA damage but does not affect their subsequent growth.

[Nuclear matrix protein 22 levels in patients with renal transplantation].

BACKGROUND: Nuclear matrix protein 22 (NMP22) is a parameter of cell death including apoptosis. To evaluate the clinical efficacy of NMP22 as a marker for rejection after renal transplantation, we measured serum and urinary NMP22. PATIENTS AND METHODS: We measured the concentrations of serum NMP22 by Konica-Matritech NMP22 kit, and CD3, 4, 8 which are surface markers of lymphocyte, in 11 patients with renal transplantation. The patients consisted of 10 males and 1 females whose serum creatinine ranged 1.0 to 2.7 mg/dl. Additionally, 9 healthy adults were employed as control subjects. And serum and urinary NMP22 were measured after transplantation sequentially in 5 of the patients. RESULTS: 1) In the patients, serum NMP22 values were higher than those in control subjects, statistically (p < 0.01). 2) There were not significant correlations between serum NMP22 and CD3, 4, 8, 3) At the periods of acute tubular necrosis and acute rejection, serum NMP22 values were higher than those at the stable periods. CONCLUSIONS: These results suggest that serum NMP22 is useful parameter of rejection in renal transplantation patients.

Chemopreventive effects of nimesulide, a selective cyclooxygenase-2 inhibitor, on the development of rat urinary bladder carcinomas initiated by N-butyl-N-(4-hydroxybutyl)nitrosamine.

The chemopreventive potential of a selective cyclooxygenase-2 inhibitor, nimesulide (NIM), against the development of rat superficial urinary bladder carcinomas after initiation with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) was examined. Six-week-old Fischer 344 male rats were given 0.05% BBN in their drinking water for 8 weeks, followed by diets supplemented with 0, 100, 200, or 400 ppm NIM for 12 weeks, and they were then sacrificed. NIM decreased, in a dose-dependent manner, the incidence of transitional cell carcinoma (TCC) to 12 of 20 (60.0%), 8 of 16 (50.0%), and 5 of 19 (26.3%) and the multiplicity of TCCs to 0.75 +/- 0.79, 0.56 +/- 0.63, and 0.37 +/- 0.78 per rat at 100, 200, and 400 ppm, respectively, as compared with the BBN alone group values of 18 of 20 (90.0%) and 2.35 +/- 1.23. NIM did not significantly affect the cell differentiation or invasiveness of TCCs. These results indicate clear chemopreventive potential of a selective cyclooxygenase-2 inhibitor against postinitiation development of superficial rat urinary bladder carcinomas.

[Results of clinical study with epirubicin hydrochloride injectable solution for superficial bladder cancer. IMI28 Injectable Solution Study Group for Superficial Bladder Cancer].

A 7-center cooperative clinical study with a new formulation of epirubicin hydrochloride injectable solution (Epirubicin-RTU) was conducted in patients with superficial bladder carcinoma. Epirubicin-RTU at the dose of 60 mg/30 ml was administered by intravesical instillation once daily for three (3) consecutive days and a 4-day drug-free interval followed; then the above intravesical instillation of Epirubicin-RTU was repeated for three consecutive days. All 20 registered cases were eligible, and 18 cases completed the whole course of the study. In 18 completers, CR was observed in 12 cases and PR was observed in one (1) case, for an efficacy rate of 72.2%. The primary adverse reaction was bladder irritation including pollakiuria 85.0% (17/20), miction pain 85.0% (17/20), and hematuria 80.0% (16/20), which were all reversible and tolerable. In urinalysis, urinary sediment showed leukocytes and erythrocytes, and proteinuria was observed. All were reversible. From the above results, this new formulation of Epirubicin-RTU was considered useful for the treatment of superficial bladder carcinoma.

Prognostic value of nm23 protein expression in renal cell carcinomas.

In the present study, an analysis of whether expression of nm23-H1 and nm23-H2 proteins has prognostic significance was performed. A series of 95 renal cell carcinomas was analyzed for nuclear grade, tumor size (larger than 50 mm or not), staging in the Robson system and expression of nm23-H1 and nm23-H2, as well as patient survival. Immunohistochemical staining of nm23-H1 and nm23-H2 was found in 68.4 and 50.5% of the cases, respectively. Significant differences in nm23-H1, but not nm23-H2 expression were noted with regard to nuclear grade and tumor size. The patients with nm23-H1-expression-negative tumors sized < or = 50 mm had a significantly poorer prognosis than their positive counterparts. Multivariate analysis using the Cox proportional hazards regression model indicated that the staging in the Robson system and expression of nm23-H1 were significant and independent prognostic factors for survival. However, no significant correlation between the incidence of metastasis and expression of nm23-H1 or nm23-H2 was found. The results imply that reduced expression of nm23-H1 influences the prognosis of patients with renal cell carcinomas, but not the likelihood of metastasis. In small tumors sized < or = 50 mm, reduced expression of nm23-H1 protein was suggested to be an especially strong predictor of a poor prognosis.