Early Efficacy of an α1 Adrenoceptor Antagonist, Naftopidil, against Lower Urinary Tract Symptoms Suggestive of Benign Prostatic Hyperplasia.

OBJECTIVES: The present study investigated the early efficacy of naftopidil against lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH). METHODS: Subjects comprised patients with LUTS suggestive of BPH who were followed prospectively for 8 weeks. Inclusion criteria were: (i) international prostate symptom score (IPSS) ≥8; (ii) no previous treatment for BPH; and (iii) eligibility for naftopidil monotherapy. IPSS and quality of life index were evaluated, and uroflowmetry and residual urine volume were determined optionally. In the previous study, patients who demonstrated a decrease in total American Urological Association symptom score of 25% or more from baseline were considered responders. The ratio of onset of efficacy of naftopidil was calculated by the ratio of the number of responder in each group with the starting dose. RESULTS: Naftopidil efficacy was analyzed for 243 patients. Significant improvement of IPSS was achieved within 1-3 days after medication. Starting dosage and average dosage were identified as factors associated with the period until onset of naftopidil efficacy. Onset of efficacy was significantly quicker with a starting dosage of 50 mg/day as compared with 25 mg/day (P = 0.0047). However, ratios of onset of efficacy with starting dosages of 25, 50 and 75 mg/day were 77.9, 76.7 and 85.7%, respectively, showing no significant difference between groups (P = 0.7463). Duration to onset of efficacy with naftopidil dosage ≥50 mg/day was 11.2 days, significantly early compared to dosage <50 mg/day. Incidence of adverse effect was 3.8%. CONCLUSION: Naftopidil showed early effects against LUTS suggestive of BPH within a few days.

The mobile phone decreases fructose but not citrate in rabbit semen: a longitudinal study.

The negative impact of mobile phones on sperm motility has been previously described. Both fructose and citrate are important components in semen that facilitate sperm motility. To date, no studies have investigated the effect of exposure to electromagnetic radiation emitted from the mobile phone on their levels.. Therefore, a longitudinal study using the adult rabbit as a model was undertaken. A total of 30 adult male rabbits were randomly divided into three groups. The first (phone) group was placed in specially designed cages, and exposed to radio frequency emitted from a mobile phone (900 MHz) kept in standby mode and positioned adjacent to the genitalia for 8 h daily for 12 weeks. The other two groups served as controls; the stress group which was housed in the same kind of cages to evaluate any cage-induced anxiety, and the control group which was housed in the conventional roomy cages. Semen samples were retrieved weekly. Sperm motility and viability, semen fructose and citrate, and serum testosterone were measured. Histological sections from the prostatic complex, ampulla, and vesicular gland were evaluated. A significant drop in both fructose levels (257 +/-11.6 vs. 489 +/- 8.4 mg %, the baseline level) and number of motile sperms (50 vs. 72%) was observedin the phone group at the 10th week. However, no correlation was found between the two values. The stress control animals showed a similar but significantly less decline in motility No significant changes in citrate levels or other study parameters were seen in the three animal groups throughout the study. In conclusion, the pulsed radio frequency emitted by the mobile phone kept in the standby position longitudinally affected sperm motility and fructose but not citrate levels in rabbit semen.

Current status of endocrine therapy for prostate cancer in Japan analysis of primary androgen deprivation therapy on the basis of data collected by J-CaP.

BACKGROUND: Based on the data of current status of endocrine therapy for prostate cancer registered in the Japan Study Group of Prostate Cancer (J-CaP), we conducted an analysis of primary androgen deprivation therapy (PADT) and an interim analysis of the prognosis. METHODS: Of the 26 272 cases registered in the server of J-CaP, the 19 409 cases initially receiving PADT were included in this study. The initial therapy was divided into eight categories according to its features. RESULTS: Of the 19 409 patients, 1513 (7.8%) were given anti-androgen monotherapy, 955 patients (4.9%) surgical castration only, 1001 patients (5.2%) surgical castration + anti-androgen, 3015 patients (15.5%) LHRH monotherapy, 1658 patients (8.5%) LH-RH + short-term anti-androgen, 10 434 patients (53.8%) LH-RH + anti-androgen, 37 patients (0.2%) watchful waiting and 796 patients (4.1%) other therapy. In progression-free survival, the prognosis was slightly better following maximum androgen blockade (MAB) in each stage. CONCLUSIONS: The pattern of PADT is more typical in Japan compared with that in the United States. Patients who received MAB accounted for 59.0% of all the patients. MAB tends to be more often selected for patients who are rated as being at high risk on the basis of high Gleason score or PSA level upon diagnosis in each clinical stage of the disease. Investigations of the outcome are on-going and they will make clear the significance of this trend in Japan.

STAT3 polymorphism predicts interferon-alfa response in patients with metastatic renal cell carcinoma.

PURPOSE: To clarify the effect of genetic polymorphisms on the response to interferon alfa (IFN-alpha) for metastatic renal cell carcinoma (MRCC), and to find a reliable molecular marker to select those patients with MRCC who would benefit from IFN-alpha immunotherapy. PATIENTS AND METHODS: We carried out an association study in which 463 single nucleotide polymorphisms (SNPs) in 33 candidate genes were genotyped in 75 Japanese patients who had received IFN-alpha for MRCC. RESULTS: After adjusting for lung metastasis, stepwise logistic regression analysis revealed that the SNPs in signal transducer and activator 3 (STAT3) were most significantly associated with better response to IFN-alpha. Linkage disequilibrium mapping revealed that the SNP in the 5' region of STAT3, rs4796793, was the most significant predictor of IFN-alpha response (odds ratio [OR] = 2.73; 95% CI, 1.38 to 5.78). The highest OR was shown in the CC genotype at rs4796793 compared to the GG + GC genotypes (OR = 8.38, 95% CI, 1.63 to 42.96). Genotype-dependent expressions of STAT3 in B lymphocyte cell lines and the enhanced growth inhibitory effects of IFN- by STAT3 suppression in an RCC cell line supported the results of the present association study. CONCLUSION: The present study suggested that the STAT3 polymorphism is a useful diagnostic marker to predict the response to IFN-alpha therapy in patients with MRCC. An efficient response marker for IFN-alpha needs to be utilized to establish individual optimal treatment strategies, even when newer drug therapies are used as first line treatments for MRCC.

Unusual trivial trauma may end with extrusion of a well-functioning penile prosthesis: a case report.

BACKGROUND: Diabetes mellitus (DM) is the most common indication for insertion of a penile prosthesis and is a risk factor for infection of such prostheses. CASE PRESENTATION: Two patients presented with infected prostheses following unusual trivial penile trauma. Both patients underwent exploration and removal of the prostheses with uneventful recovery. CONCLUSION: Appropriate sizing of the prosthesis should be taken into account to ensure good concealment and avoid easy exposure of the penis to unexpected trauma. Use of the newly designed antibiotic-coated prostheses appears preferable. As soon as signs of prosthesis infection appeared, extrusion of the device should be expedited.

The case for androgen deprivation as primary therapy for early stage disease: results from J-CaP and CaPSURE.

PURPOSE: We analyzed the outcome of primary androgen depletion therapy, which has gained more attention as a potential therapeutic option in patients with localized or locally advanced prostate cancer as it has been increasingly implemented despite limited data on its therapeutic impact in Japan and the United States. MATERIALS AND METHODS: We analyzed data from CaPSURE and the Japanese Prostate Cancer study. RESULTS: In Japan primary androgen depletion therapy has long been the treatment of choice for localized and locally advanced prostate cancer. Based on CaPSURE data the frequency of primary androgen depletion therapy being chosen to treat localized and locally advanced disease is also increasing in clinical practice in the United States. A study of the outcomes of endocrine therapy is currently being performed in Japan by the Japanese Prostate Cancer Study Group. CONCLUSIONS: It is important to obtain such information about the role of primary androgen depletion therapy for localized and locally advanced prostate cancer from studies of natural history and clinical trials. It is also important to update practical treatment guidelines.

Lack of association between the incidence of testicular germ cell tumors and Y-chromosome haplogroups in the Japanese population.

BACKGROUND: Despite being relatively uncommon, testicular germ cell tumors (TGCT) are the most common malignant disease in young men. Epidemiological studies concerning patients with testicular cancer indicate that the most of them have poor semen quality or testicular dysgenesis. However, many studies have shown that the Y chromosome harbors many candidate genes responsible for spermatogenesis process and development and maintenance of the germ cells. The Y chromosome is thought to have a relationship with the formation and progression of TGCT. MATERIALS AND METHODS: To verify this relationship, we investigated if there is any correlation between the Y chromosome structural variations presented as different haplogroups and the occurrence of TGCT in the Japanese population. Using combined haplogroups based on typing of three Y chromosome polymorphic binary markers, we analyzed 68 TGCT derived from Japanese patients together with randomly selected 104 unrelated healthy Japanese matched male controls who were confirmed as residents of the same geographic area. RESULTS: Our findings showed a lack of association between the incidence of TGCT and the different Y- chromosome haplogroups in Japanese population. CONCLUSION: We concluded that there are no significant variations in males from different Y chromosome lineages regarding their susceptibility or resistance for developing TGCT. The previously hypothesized role of the Y chromosome in the development of TGCT is still uncertain and needs further verification.

Altered expression of members of the IGF-axis in clear cell renal cell carcinoma.

Renal cell carcinoma (RCC) is a heterogeneous disease and its biology is poorly understood. The commonest subtype identified is clear cell RCC. The insulin-like growth factor axis is intimately involved with many cellular roles including that of renal development. Dysregulation of this axis has frequently been demonstrated in cancer. In this study, we examine the expression of several IGF-axis components, including receptors, ligands, and binding proteins in clear cell renal cell carcinoma. A series of clear cell RCCs with matched normal kidney from the same individuals were obtained. Total RNA was extracted and expression levels of genes examined using RNase protection analysis. We confirm the dysregulation of the IGF-axis within clear cell renal cell carcinoma including the upregulation of IGFBP-3, which is further validated by immunohistochemical staining on a tissue array containing 50 RCC: positive staining in 29/30 clear cell; 1/10 papillary and 0/10 chromophobe. In addition, we demonstrate that the expression of the A isoform of the insulin receptor is significantly upregulated, while that of IGFBP-5 are significantly downregulated in this tumour subtype.

Expression of angiopoietin-1 and -2, and its clinical significance in human bladder cancer.

OBJECTIVE: To investigate the relationship between angiopoietin-1 and -2 expression and the clinicopathological variables and clinical outcome in patients with bladder cancer treated by surgical resection, as both have been recently identified as antagonistic angiogenic factors which regulate tumour growth. MATERIALS AND METHODS: The expression of angiopoietin-1 and -2 were assessed by immunohistochemistry in tissue sections from 52 transitional cell carcinomas of the bladder (33 grade 1, 15 grade 2, four grade 3, including two associated with carcinoma in situ; 22 were stage Ta, 19 T1 and 11 T2 tumours). Normal bladder specimens were also resected during each operation as controls. The expression angiopoietins were related to the clinicopathological variables of the tumours. RESULTS: Positive immunostaining was detected in 18 samples (35%) for angiopoietin-1 and in 23 (44) for angiopoietin-2. There was no significant difference in survival according to tumour angiopoietin-1 status in the patients, but in contrast the overall survival of patients with angiopoietin-2-positive tumours was significantly lower than for those with angiopoietin-2-negative tumours (P < 0.05). Positive angiopoietin-2 expression was significantly correlated with histological grade (P = 0.026), histological stage (P = 0.009) and poor prognosis (P < 0.05). On multivariate analysis, positive angiopoietin-2 expression was an independent negative predictor for survival (P = 0.042). CONCLUSIONS: These results suggest that angiopoietin-2 overexpression is associated with tumour progression, thereby indicating a poor prognosis for some patients treated by surgical resection for bladder carcinoma.

Nitrite-derived nitric oxide formation following ischemia-reperfusion injury in kidney.

Nitric oxide (NO) is synthesized from l-arginine by nitric oxide synthase (NOS), and nitrite and nitrate are believed to be waste forms of NO. We previously reported an enzyme-independent pathway of NO generation from nitrite in acidic conditions. In this study, we show nitrite-derived NO formation in renal ischemia-reperfusion injury using electron paramagnetic resonance (EPR) spectroscopy. In this experiment, we utilized a stable isotope of [(15)N]nitrite as a source of nitrite to distinguish l-arginine-derived NO from [(15)N]nitrite-derived (15)NO. Intravenous infusion of a stable isotope of [(15)N]nitrite ((15)NO(2)(-)) facilitated the formation of Hb(15)NO during renal ischemia, which demonstrated that the origin of NO was nitrite. The EPR signal of Hb(15)NO in kidney appeared after 40 min of renal ischemia, and renal reperfusion decreased the Hb(15)NO level in the kidney and increased it in blood by contrast. In addition, the amount of HbNO was nitrite concentration dependent, and this formation was NOS independent. Our findings suggest that nitrite can be an alternative source of NO in ischemic kidney and that it binds with hemoglobin and then is spread by the circulation after reperfusion.

Characteristics of patients with prostate cancer who have initially been treated by hormone therapy in Japan: J-CaP surveillance.

OBJECTIVE: Hormone therapy for prostate cancer has empirically prevailed in Japan. We planned to evaluate the trends and outcome of hormone therapy for establishing an adequate guideline. METHODS: Patients with prostate cancer who were initially treated by hormone therapy were registered through the J-CaP registration system. This report summarizes the background factors. RESULTS: From January 2001 to October 2003, 17,872 patients were registered from 395 institutes throughout Japan. The background factors of 17,312 patients were analyzed. The 17,872 patients were estimated as composing more than half of newly diagnosed prostate cancer patients in Japan. Of these, 22.9, 35.1, 32.9 and 8.6% belonged to T1, T2, T3 and T4, respectively. For the purposes of hormone therapy, 77.5% was primary hormone therapy. Neoadjuvant setting and adjuvant setting were 18.1 and 4.3%, respectively. About 60% of the hormone therapy was combined hormone therapy with LH-RHa plus anti-androgens. CONCLUSION: Irrespective of patients' age, TNM, stage of illness, or histological background, the majority of prostate cancer patients in Japan are receiving hormone therapy. It is necessary to evaluate whether this trend is merely a continuation of past experience of Japanese urologists or if there is a difference in the profile of effect and side-effect in the case of Japanese patients compared to therapy given in Westerners.

Robust classification of renal cell carcinoma based on gene expression data and predicted cytogenetic profiles.

Renal cell carcinoma (RCC) is a heterogeneous disease that includes several histologically distinct subtypes. The most common RCC subtypes are clear cell, papillary, and chromophobe, and recent gene expression profiling studies suggest that classification of RCC based on transcriptional signatures could be beneficial. Traditionally, however, patterns of chromosomal alterations have been used to assist in the molecular classification of RCC. The purpose of this study was to determine whether it was possible to develop a classification model for the three major RCC subtypes that utilizes gene expression profiles as the bases for both molecular genetic and cytogenetic classification. Gene expression profiles were first used to build an expression-based RCC classifier. The RCC gene expression profiles were then examined for the presence of regional gene expression biases. Regional expression biases are genetic intervals that contain a disproportionate number of genes that are coordinately up- or down-regulated. The presence of a regional gene expression bias often indicates the presence of a chromosomal abnormality. In this study, we demonstrate an expression-based classifier can distinguish between the three most common RCC subtypes in 99% of cases (n = 73). We also demonstrate that detection of regional expression biases accurately identifies cytogenetic features common to RCC. Additionally, the in silico-derived cytogenetic profiles could be used to classify 81% of cases. Taken together, these data demonstrate that it is possible to construct a robust classification model for RCC using both transcriptional and cytogenetic features derived from a gene expression profile.

The neuronal and endothelium-dependent relaxing responses of human corpus cavernosum under physiological oxygen tension last longer than previously expected.

BACKGROUND: Intracavernosal oxygen tension varies greatly in the process of erection. Blood extracted from the human penis demonstrates an increase from approximately 30 mmHg Po(2) in the flaccid state to 100 mmHg in the erect state of the penis. In the present study, using these levels as a guide, we investigate how the NO-dependent relaxation of human corpus cavernosum changed under physiological oxygen tensions ranging from approximately 30 to 100 mmHg. METHODS: Human penile tissue specimens were obtained at penile surgery with informed consent from the patients. The preparations were mounted in Krebs solution in an organ bath and the isometric tension was recorded. Krebs solutions of various oxygen tensions were prepared by bubbling 5% CO(2) in N(2) and O(2). The NO-dependent relaxation caused by electrical field stimulation (EFS) and acetylcholine (ACh) was studied, and the amplitude and duration of relaxation evaluated. RESULTS: The amplitude of relaxation induced by EFS was significantly decreased under physiological oxygen tension conditions (P < 0.01). The duration of the relaxant response induced by EFS and ACh was significantly prolonged in physiological oxygen tension conditions than in high oxygen tension (P < 0.01). However, there was no correlation between the duration of relaxation induced by EFS and each physiological oxygen tension level. The duration of relaxation induced by ACh was most prolonged at 60-69 mmHg oxygen tension. CONCLUSION: Physiologically, the effect of NO may last longer than was previously thought. In addition, it would seem that there is an optimal physiological oxygen tension for maximum ACh-induced relaxation.

[Mass screening for prostate cancer in Tokushima City: the results of 2001].

PURPOSE: Screening with prostate specific antigen (PSA) only to detect prostate cancer was started in Tokushima City from 2001 as one of health check lists. We evaluated the first year result. MATERIALS AND METHODS: Fifty-five years old or elder men living in Tokushima City who wants to measure serum PSA level to screen for prostate cancer were entered to screening program. The men whose PSA levels detected as over normal; range were recommended to visit to urologists for further examination to detect prostate cancer include prostate biopsy. The results of further examination were reported to Tokushima City and evaluated. RESULTS: The population of fifty-five or elder men in Tokushima City was 25,416 and 9,019 (35.5%) men were measured serum PSA levels. In 801 (8.9%) men, PSA levels were over normal range, and recommended further examination to detect prostate cancer. 451 (56.3%) men visited to urologists for further examination, and prostate biopsy was performed in 231 (51.2%) men. Finally, 121 men were diagnosed as prostate cancer, 52.1% of 231 men performed prostate biopsy, 26.7% of 451 men visited to urologist for further examination, 1.34% of 9,019 men measured serum PSA levels. Patient number for each clinical stages were 49 in B0, 16 in B1, 16 in B2, 29 in C, one in D1, and 10 in D2. Patients number in each age range were 3 in 55-59, 11 in 60-64, 22 in 65-69, 37 in 70-74, 33 in 75-79, 15 in 80 or elder. Patient number of Stage B and 74 years old or younger was 48 (39.7%). CONCLUSION: Prostate cancer was detected in 1.34% of 9,019 men who measured serum PSA levels, and early stage B was two thirds. PSA screening to detect prostate cancer as one of health check-lists in Tokushima City was useful to detect early prostate cancer.

Infrequent alteration in the p53R2 gene in human transitional cell carcinoma of the urinary tract.

OBJECTIVE: Functional defects in DNA repair have been shown to be associated with genomic instability followed by cancer. Recently, p53R2 [p53-inducible ribonucleotide reductase (RR) small subunit 2 homologous] was identified as a novel RR gene which is directly regulated by p53 protein in the G1 and G2 phases of the cell cycle supplying nucleotides to repair damaged DNA. METHODS: We performed genetic analyses of p53R2 to determine whether p53R2 alterations play significant roles in urothelial tumorigenesis. Genomic DNA from 108 primary transitional cell carcinomas (TCCs; 81 of the urinary bladder and 27 of the renal pelvis or ureter) was analyzed for mutation in the p53R2 gene by direct sequencing. We focused on three domains of the p53R2 gene: one RR small subunit signature involving codons 120-146 (region 1) and two putative nuclear localization signal sequences, involving codons 149-155 (region 2) and codons 163-169 (region 3). In addition, a p53-binding site of 20 nucleotides in intron 1 of p53R2 was also analyzed. RESULTS: One renal pelvic TCC (0.9%: 1/108) had a single-base substitution in p53R2 with a G to T transversion resulting in the amino acid substitution Glu136 --> Asp. This base substitution was localized within the domain of exon 4 encoding the RR small subunit signature, and causes an amino acid substitution in one of the most highly conserved regions of p53R2, in which human R2 and yeast RNR2 and RNR4 proteins are highly homologous. CONCLUSION: This finding provides the in vivo evidence for the infrequent involvement of alterations in p53R2 inhuman urothelial TCCs.

CD29 and CD7 mediate galectin-3-induced type II T-cell apoptosis.

Galectin (Gal)-3, a M(r) 31000 member of the beta-galactoside-binding protein family, is a multifunctional protein implicated in a variety of biological functions, including tumor cell adhesion, proliferation, differentiation, angiogenesis, apoptosis, cancer progression, and metastasis. Here, we report that secreted extracellular Gal-3 can signal apoptosis of human T leukemia cell lines, human peripheral blood mononuclear cells, and activated mouse T cells after binding to cell surface glycoconjugate receptors through carbohydrate-dependent interactions because the apoptotic effect was found to be inhibited by lactose, specific sugar inhibitor, and to be dose dependent. However, the apoptosis sensitivity to Gal-3 varied among the different cell lines tested. We report that Gal-3-null Jurkat, CEM, and MOLT-4 cells were significantly more sensitive to exogenous Gal-3 than SKW6.4 and H9 cells, which express Gal-3, suggesting a cross-talk between the antiapoptotic activity of intracellular Gal-3 and proapoptotic activity of extracellular Gal-3. Furthermore, Gal-3-transfected CEM cells were found to be more resistant to C(2)-ceramide-induced apoptosis than the control CEM cells. Identification of Gal-3 cell surface receptors revealed that Gal-3 binding to CD7 and CD29 (beta(1) integrin) induced apoptosis. Gal-3 binding to its cell surface receptors results in activation of mitochondrial apoptosis events including cytochrome c release and caspase-3 activation, but not caspase-8 activation. Taken together, these results suggest that the induction of T-cell apoptosis by secreted Gal-3 may play a role in the immune escape mechanism during tumor progression through the induction of apoptosis to cancer-infiltrating T cells. The induction of T-cell apoptosis by secreted Gal-3 is dependent in part on the presence or absence of cytoplasmic Gal-3, providing a new insight for the immune escape mechanism of cancer cells.

Amiloride and urinary trypsin inhibitor inhibit urothelial cancer invasion.

OBJECTIVE: To determine the contribution of urokinase-type plasminogen activator (uPA) and plasmin in the invasion of highly invasive urothelial cancer cells. METHODS: We compared expression levels of mRNA and protease activity of uPA and plasmin formation in primary cultures of the noninvasive transitional cell carcinoma, UCT-1, and in the highly invasive type, UCT-2. By using in vitro cell invasion assay system, we evaluated the effects of amiloride and urinary trypsin inhibitor (UTI), which inhibit uPA and plasmin, respectively, on invasion by both cell lines. RESULTS: Expression levels of mRNA, protein, and activities of uPA were significantly higher (p<0.005) and resulted in more plasminogen activation in UCT-2 than in UCT-1. Amiloride and UTI significantly inhibited plasmin formation and the invasion of both cell lines (p<0.001). CONCLUSIONS: High expression levels of mRNA, activities of uPA and high plasmin formation significantly potentiated the invasiveness of urothelial cancer cells. Thus, inhibitors of uPA and plasmin, such as amiloride and UTI, respectively, could be useful therapeutic tools with which to treat urothelial cancer.

The t(1;3) breakpoint-spanning genes LSAMP and NORE1 are involved in clear cell renal cell carcinomas.

By positional cloning, we identified two breakpoint-spanning genes in a familial clear cell renal cell carcinoma (CCRCC)-associated t(1;3)(q32.1;q13.3): LSAMP and NORE1 (RASSF1 homolog). Both genes are downregulated in 9 of 9 RCC cell lines. While the NORE1A promoter predominantly presents partial methylation in 6 of the cell lines and 17/53 (32%) primary tumors, the LSAMP promoter is completely methylated in 5 of 9 cell lines and in 14/53 (26%) sporadic and 4 familial CCRCCs. Expression of LSAMP and NORE1A proteins in CCRCC cell lines inhibited cell proliferation. These characteristics indicate that LSAMP and NORE1A may represent new candidate tumor suppressors for CCRCC.

Molecular subclassification of kidney tumors and the discovery of new diagnostic markers.

We analysed the expression profiles of 70 kidney tumors of different histological subtypes to determine if these subgroups can be distinguished by their gene expression profiles, and to gain insights into the molecular mechanisms underlying each subtype. In all, 39 clear cell renal cell carcinomas (RCC), seven primary and one metastatic papillary RCC, six granular RCC from old classification, five chromophobe RCC, five sarcomatoid RCC, two oncocytomas, three transitional cell carcinomas (TCC) of the renal pelvis and five Wilms' tumors were compared with noncancerous kidney tissues using microarrays containing 19,968 cDNAs. Based on global gene clustering of 3560 selected cDNAs, we found distinct molecular signatures in clear cell, papillary, chromophobe RCC/oncocytoma, TCC and Wilms' subtypes. The close clustering in each of these subtypes points to different tumorigenic pathways as reflected by their histological characteristics. In the clear cell RCC clustering, two subgroups emerged that correlated with clinical outcomes, confirming the potential use of gene expression signatures as a predictor of survival. In the so-called granular cell RCC (terminology for a subtype that is no longer preferred), none of the six cases clusters together, supporting the current view that they do not represent a single entity. Blinded histological re-evaluation of four cases of 'granular RCC' led to their reassignment to other existing histological subtypes, each compatible with our molecular classification. Finally, we found gene sets specific to each subtype. In order to establish the use of some of these genes as novel subtype markers, we selected four genes and performed immunohistochemical analysis on 40 cases of primary kidney tumors. The results were consistent with the gene expression microarray data: glutathione S-transferase alpha was highly expressed in clear cell RCC, alpha methylacyl racemase in papillary RCC, carbonic anhydrase II in chromophobe RCC and K19 in TCC. In conclusion, we demonstrated that molecular profiles of kidney cancers closely correlated with their histological subtypes. We have also identified in these subtypes differentially expressed genes that could have important diagnostic and therapeutic implications.