Sex-related differences in the associations between maternal dioxin-like compounds and reproductive and steroid hormones in cord blood: The Hokkaido study.

BACKGROUND: Prenatal exposure to dioxin-like compounds (DLCs) irreversibly affects fetal reproductive and steroid hormone synthesis. OBJECTIVE: This study aimed to assess the relationships between maternal DLCs and cord blood reproductive and steroid hormones. METHODS: Participants in this study were pregnant women who enrolled in the Sapporo Cohort of the Hokkaido Study between 2002 and 2005. We quantified 29 DLCs during the 2nd and 3rd trimesters in maternal blood. Additionally, we measured the concentrations of progesterone, estradiol (E2), testosterone (T), androstenedione, dehydroepiandrosterone (DHEA), cortisol, cortisone, sex hormone-binding globulin (SHBG), luteinizing hormone (LH), follicle-stimulating hormone (FSH), prolactin, inhibin B, and insulin-like factor-3 (INSL3) in cord blood samples. RESULTS: Data from 183 mother-child pairs were analyzed. We observed sex-dependent associations of DLCs on T/E2 ratios, DHEA, cortisol, cortisone, adrenal androgen/glucocorticoid (AA/GC: sum of DHEA and androstenedione)/(sum of cortisol and cortisone) ratios and SHBG. An increase in maternal DLCs related to decreased T/E2 ratios and SHBG and inhibin B levels, and increased AA/GC ratios and FSH and DHEA levels in male cord blood samples. However, an increase in maternal mono-ortho polychlorinated biphenyls related to increased cortisol, cortisone, and SHBG levels, and decreased DHEA levels and AA/GC ratios in female cord blood samples. CONCLUSIONS: Prenatal exposure to DLCs alters steroidogenesis and suppresses the secretion of inhibin B in male cord blood. Relationships between maternal DLCs and cord blood hormones differ between boys and girls. Further studies are required to clarify whether the effects of in utero exposure to DLCs on adrenal hormones extend into infancy and puberty.

Impact of posterior urethral diameter/external urethral sphincter diameter as a new tool to predict detrusor pressure in the voiding phase.

PURPOSES: We measured posterior urethra diameter (PUD) and external urethral sphincter diameter (EUSD), which can also be measured by voiding cystourethrography (VCUG) and investigated the relationship between PUD/EUSD and detrusor pressure (Pdet) during voiding by videourodynamics (VUDS). METHODS: Sixty-three children, who were 3 years old or less and underwent VUDS, were enrolled in the present study. We measured PUD and EUSD in addition to detrusor pressure at the time of the widest EUS during voiding (Pdet-voiding) by VUDS, and PUD/EUSD was investigated compared to Pdet-voiding. RESULTS: Seventy-eight VUDS were performed in 63 patients, and the median age at VUDS was 10.2 months. These studies revealed a significant correlation between PUD/EUSD and Pdet-voiding (r = 0.641, p < 0.001). However, a significant correlation was not observed between PUD/EUSD and age (r = 0.180). We defined Pdet-voiding of more than 80 cmH2O as a high voiding pressure, and a PUD/EUSD of 2.4 was a good predictor for the cutoff value for high voiding pressure. Pdet-voiding was significantly higher in children with a PUD/EUSD of ≥ 2.4 (p < 0.001). In 19 children who had neurological diseases, a significant correlation was found between PUD/EUSD and Pdet-voiding (r = 0.842, p < 0.001), and a PUD/EUSD of 2.4 was a useful cutoff value for high voiding pressure. CONCLUSIONS: PUD/EUSD is a valuable tool to predict high voiding pressure in pediatric patients. A PUD/EUSD of ≥ 2.4 in VCUG indicates the need to perform more invasive tests, such as VUDS, in pediatric patients aged 3 and under with neuropathic diseases.

Aldo-keto reductase 1C1 induced by interleukin-1ß mediates the invasive potential and drug resistance of metastatic bladder cancer cells.

In treating bladder cancer, determining the molecular mechanisms of tumor invasion, metastasis, and drug resistance are urgent to improving long-term patient survival. One of the metabolic enzymes, aldo-keto reductase 1C1 (AKR1C1), plays an essential role in cancer invasion/metastasis and chemoresistance. In orthotopic xenograft models of a human bladder cancer cell line, UM-UC-3, metastatic sublines were established from tumors in the liver, lung, and bone. These cells possessed elevated levels of EMT-associated markers, such as Snail, Slug, or CD44, and exhibited enhanced invasion. By microarray analysis, AKR1C1 was found to be up-regulated in metastatic lesions, which was verified in metastatic human bladder cancer specimens. Decreased invasion caused by AKR1C1 knockdown suggests a novel role of AKR1C1 in cancer invasion, which is probably due to the regulation of Rac1, Src, or Akt. An inflammatory cytokine, interleukin-1ß, was found to increase AKR1C1 in bladder cancer cell lines. One particular non-steroidal anti-inflammatory drug, flufenamic acid, antagonized AKR1C1 and decreased the cisplatin-resistance and invasion potential of metastatic sublines. These data uncover the crucial role of AKR1C1 in regulating both metastasis and drug resistance; as a result, AKR1C1 should be a potent molecular target in invasive bladder cancer treatment.

Association of perfluoroalkyl substances exposure in utero with reproductive hormone levels in cord blood in the Hokkaido Study on Environment and Children's Health.

BACKGROUND: Exposure to perfluoroalkyl substances (PFASs) may disrupt reproductive function in animals and humans. Although PFASs can cross the human placental barrier, few studies evaluated the effects of prenatal PFAS exposure on the fetus' reproductive hormones. OBJECTIVE: To explore the associations of prenatal exposure to perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) with cord blood reproductive hormones. METHODS: In the prospective birth cohort (Sapporo cohort of the Hokkaido study), we included 189 mother-infant pairs recruited in 2002-2005 with both prenatal maternal and cord blood samples. PFOS and PFOA levels in maternal blood after the second trimester were measured via liquid chromatography-tandem mass spectrometry. We also measured cord blood levels of the fetuses' reproductive hormones, including estradiol (E2), total testosterone (T), progesterone (P4), inhibin B, insulin-like factor 3, steroid hormone binding globulin, follicle-stimulating hormone, and luteinizing hormone, and prolactin (PRL). RESULTS: The median PFOS and PFOA levels in maternal serum were 5.2ng/mL and 1.4ng/mL, respectively. In the fully adjusted linear regression analyses of the male infants, maternal PFOS levels were significantly associated with E2 and positively, and T/E2, P4, and inhibin B inversely; PFOA levels were positively associated with inhibin B levels. Among the female infants, there were significant inverse associations between PFOS levels and P4 and PRL levels, although there were no significant associations between PFOA levels and the female infants' reproductive hormone levels. CONCLUSIONS: These results suggest that the fetal synthesis and secretion of reproductive hormones may be affected by in utero exposure to measurable levels of PFOS and PFOA.

The inflammatory cytokine IL-1ß is involved in bladder remodeling after bladder outlet obstruction in mice.

AIMS: We investigated the relationship between IL-1ß and morphological and functional changes following partial bladder outlet obstruction (pBOO). METHODS: Female wild-type C57/BL6 mice (WT) and IL-1ß-/- mice (KO) were used. Animals were sacrificed either 1 or 3 weeks after pBOO or sham surgery, and their bladders were harvested to determine bladder weight, for RT-PCR to measure interleukin-1ß (IL-1ß), insulin growth factor-1 (IGF-1), and transforming growth factor-ß (TGF-ß) levels, and for histological analysis with Hematoxylin-Eosin (HE) staining. Cystometry was performed on conscious animals 3 weeks after surgery to evaluate urodynamic parameters. IGF-1 was also administered intraperitoneally to KO with pBOO, and bladder weight was then investigated. RESULTS: IL-1ß-mRNA levels were significantly higher in WT-pBOO than in WT-sham. IGF-1-mRNA and TGF-ß-mRNA levels were also significantly higher in WT-pBOO than in WT-sham; however, these increases were smaller in KO-pBOO than in WT-pBOO. Bladder weight was significantly higher in WT-pBOO than in WT-sham, while increases in bladder weight were significantly suppressed in KO-pBOO. HE staining revealed the thickened bladder wall in WT-pBOO, and this phenomenon was less in KO-pBOO than in WT-pBOO. Regarding the urodynamic parameters examined, micturition pressure and bladder capacity were significantly higher in WT-pBOO than in WT-sham, but remained unchanged in KO-pBOO. The administration of IGF-1 to KO-pBOO led to similar increases in bladder weight and the thickened bladder wall as those observed in WT-pBOO. CONCLUSION: IL-1ß has the potential to induce bladder remodeling and deteriorate urodynamic parameters in pBOO.

Diagnostic outcome of ureteroscopy in urothelial carcinoma of the upper urinary tract: Incidence of later cancer detection and its risk factors after the first examination.

BACKGROUND: To determine the incidence of later cancer detection and its risk factors after the first diagnostic ureteroscopy. METHODS: One hundred and sixty-six patients undergoing diagnostic ureteroscopy based on the suspicion of urothelial carcinoma of the upper urinary tract (UC of the UUT) between 1995 and 2012 were included. We examined the diagnostic outcome of the initial ureteroscopy. Thereafter, we collected follow-up data on patients who had not been diagnosed with UC of the UUT at the first examination, and evaluated the incidence of later cancer detection and its risk factors using Cox hazard models. RESULTS: Of the 166 patients, 76 (45.8%) were diagnosed with UC of the UUT at the first diagnostic ureteroscopy. The remaining 90 (54.2%) were diagnosed with other malignancies (n = 22), non-malignant disorders (n = 18), or without disorders (n = 50). Of these 90 patients, follow-up data were available in 65 patients (median: 41 months, range: 3-170). During the follow-up, carcinoma was detected in 6 patients (6/65, 9.2%) at a median of 43.5 months (range: 10-59). Episodes of gross hematuria (p = 0.0048) and abnormal cytological findings (p = 0.0335) during the follow-up and a male sex (p = 0.0316) were adverse risk factors. CONCLUSION: Later cancer detection of UC of the UUT was not uncommon after the first examination. The risk analysis revealed the aforementioned characteristics.

[The significance of metastasectomy in patients with metastatic renal cell carcinoma].

We conducted a retrospective study to clarify the clinical significance of metastasectomy in patients with metastatic renal cell carcinoma (mRCC). Of 83 mRCC patients who were treated at our hospital between 2005 and 2010, 19 patients who underwent metastasectomy during the treatment course were the subjects of the present study. By the purpose and timing of metastasectomy, we classified the 19 patients into three groups : (1) patients who immediately underwent metastasectomy at diagnosis of metastasis (primary group), (2) patients who underwent resection of clinically problematic metastatic lesions for the relief of their symptoms (palliative group), and (3) patients who underwent complete resection of all metastatic lesions after sufficient systemic therapies (consolidation group). In the primary group (n=5), four patients had lung metastasis and one had metastases to limbs and the adrenal gland. Overall survival at 3 years was 100%. In the palliative group (n=4), 3 patients underwent resection of brain metastasis and one underwent resection of skin metastasis. The symptoms associated with metastasis clearly improved. In the consolidation group (n=10), the metastasized organ was the lung in 5 patients, pancreas in 4, and liver in one. Preoperative systemic therapy included sunitinib or sorafenib in 5 patients, interferon-α in 4, and S-1 in one. After metastasectomy, systemic therapies were discontinued in 9 patients, 4 of whom did not experience RCC recurrence, with a median follow-up of 35 months. Overall survival at 3 years was 60%. Metastasectomy would be a good treatment option in patients with mRCC.

Adaptor protein CRK induces epithelial-mesenchymal transition and metastasis of bladder cancer cells through HGF/c-Met feedback loop.

We have previously reported that an adaptor protein CRK, including CRK-I and CRK-II, plays essential roles in the malignant potential of various aggressive human cancers, suggesting the validity of targeting CRK in molecular targeted therapy of a wide range of cancers. Nevertheless, the role of CRK in human bladder cancer with marked invasion, characterized by distant metastasis and poor prognosis, remains obscure. In the present study, immunohistochemistry indicated a striking enhancement of CRK-I/-II, but not CRK-like, in human bladder cancer tissues compared to normal urothelium. We established CRK-knockdown bladder cancer cells using 5637 and UM-UC-3, which showed a significant decline in cell migration, invasion, and proliferation. It is noteworthy that an elimination of CRK conferred suppressed phosphorylation of c-Met and the downstream scaffold protein Gab1 in a hepatocyte growth factor-dependent and -independent manner. In epithelial-mesenchymal transition-related molecules, E-cadherin was upregulated by CRK elimination, whereas N-cadherin, vimentin, and Zeb1 were downregulated. A similar effect was observed following treatment with c-Met inhibitor SU11274. Depletion of CRK significantly decreased cell proliferation of 5637 and UM-UC-3, consistent with reduced activity of ERK. An orthotopic xenograft model with bioluminescent imaging revealed that CRK knockdown significantly attenuated not only tumor volume but also the number of circulating tumor cells, resulted in a complete abrogation of metastasis. Taken together, this evidence uncovered essential roles of CRK in invasive bladder cancer through the hepatocyte growth factor/c-Met/CRK feedback loop for epithelial-mesenchymal transition induction. Thus, CRK might be a potent molecular target in bladder cancer, particularly for preventing metastasis, leading to the resolution of clinically longstanding critical issues.

Concurrent occurrence of renal cell carcinoma with rhabdoid features in a married couple: a case report.

BACKGROUND: Renal cell carcinoma (RCC) with rhabdoid features is a rare histology and exhibits clinically aggressive behavior. We report a case of a married couple in whom RCC with rhabdoid features concurrently occurred. The rarity of this event suggests that environmental factors may contribute to the etiology of RCC with rhabdoid features. CASE PRESENTATION: A 76-year-old Japanese woman was diagnosed with a hypervascular mass in the right kidney and tumor thrombus extending into the right atrium by enhanced computed tomography (CT). She underwent radical nephrectomy and tumor thrombectomy following systemic therapy with the tyrosine kinase inhibitor sunitinib. The histological evaluation denoted clear cell RCC with rhabdoid features. The patient died of cancer 12 months postoperatively. A 76-year-old man, her husband, presented with gross hematuria 2 weeks after his wife had undergone surgery. He had a long history of asbestos exposure. An abdominal CT scan revealed a hypervascular mass in the right kidney and tumor thrombus extending into the inferior vena cava. He also underwent radical nephrectomy and tumor thrombectomy. The histological evaluation also showed clear cell RCC with rhabdoid features. Bone metastasis occurred 12 months postoperatively, but he died of an unrelated cause 18 months after surgery. CONCLUSION: Concurrent occurrence of RCC with rhabdoid features may not to be coincidental. Although further studies are warranted, asbestos exposure may contribute to the etiology of clear cell RCC with rhabdoid features.

Early discontinuation of antibiotic prophylaxis in patients with persistent primary vesicoureteral reflux initially detected during infancy: outcome analysis and risk factors for febrile urinary tract infection.

PURPOSE: We retrospectively assessed the incidence of and risk factors for febrile urinary tract infection in children during active surveillance after early discontinuation of antibiotic prophylaxis. MATERIALS AND METHODS: We retrospectively evaluated 9 females and 61 uncircumcised males diagnosed with primary vesicoureteral reflux before age 1 year who had persistent reflux on followup voiding cystourethrogram and were subsequently followed under active surveillance without continuous antibiotic prophylaxis. Patients with secondary vesicoureteral reflux or associated urological abnormality were excluded. Clinical outcomes, including incidence of febrile urinary tract infection and new scar formation, were evaluated. Risk factors for febrile urinary tract infection were also analyzed. RESULTS: Mean age at stopping continuous antibiotic prophylaxis was 21 months, and mean followup was 61 months. During active surveillance 21 patients had febrile urinary tract infection, and the 5-year infection-free rate under active surveillance was 67.5%. One or 2 foci of minimal new scarring developed in 4 of 16 patients who underwent followup dimercapto-succinic acid scan after febrile urinary tract infection. On multivariate analysis dilated vesicoureteral reflux on followup voiding cystourethrogram was the only significant risk factor for febrile urinary tract infection. CONCLUSIONS: This study revealed that about two-thirds of patients with persistent vesicoureteral reflux were free of febrile urinary tract infection during 5 years of active surveillance. Those with dilated vesicoureteral reflux on followup voiding cystourethrogram are at significantly greater risk for febrile urinary tract infection. Accordingly active surveillance, especially in patients with nondilated vesicoureteral reflux on followup voiding cystourethrogram, seems to be a safe option even in children who have not yet been toilet trained.

Postoperative detrusor contractility temporarily decreases in patients undergoing pelvic organ prolapse surgery.

OBJECTIVES: To assess the postoperative lower urinary tract function in patients undergoing pelvic organ prolapse surgery. METHODS: A total of 24 women with advanced anterior vaginal wall prolapse underwent transvaginal repair using a polypropylene mesh. The preoperative, 1-week and 3-month postoperative evaluations were carried out by urodynamics. Maximal flow rate detrusor pressure at maximal flow rate, voided volume and bladder contractility index were measured. A value of P < 0.05 was considered to be statistically significant. RESULTS: The mean age of patients was 73.5 years (range 49-84 years). The mean postoperative maximal flow rate, voiding efficiency and bladder contractility index decreased significantly after the operation compared with the preoperative values (P < 0.05). No significant differences were observed between preoperative and 3-month postoperative parameters. Of the patients, 33.3%, 11.1% and 50% were classified as having normal/strong contractility preoperative, 1 week and 3 months, respectively. The proportion of normal/strong contractility decreased significantly after the operation, and it recovered 3 months postoperatively. The grade of obstruction did not change significantly. CONCLUSIONS: Patients undergoing pelvic organ prolapse surgery present temporary impaired detrusor contractility, which improves significantly during the midterm postoperative period.

Outcome of regional lymphadenectomy in accordance with primary tumor location on laparoscopic nephroureterectomy for urothelial carcinoma of the upper urinary tract: a prospective study.

PURPOSE: To determine the appropriate template of regional lymph node dissection (LND) at the time of laparoscopic nephroureterectomy (LNU) for patients with clinically node- negative urothelial carcinoma of the upper urinary tract. PATIENTS AND METHODS: This prospective study included 45 patients undergoing LND with LNU in accordance with our prospective rules regarding the area of LND. Perioperative, pathologic, and follow-up data were collected. Micrometastasis in lymph nodes (LNs) was later evaluated by immunohistochemistry (IHC). Recurrence-free survival (RFS) was calculated with the Kaplan-Meier method. RESULTS: The median number of LNs removed was 14 (range 1-33). One patient with pT3 disease had node metastasis based on routine pathologic examination, and IHC revealed micrometastases in two additional patients (pT2 in one and pT3 in one). Therefore, 15% (3/20) of patients with ≥pT2 disease had node disease. After surgery, six patients experienced minor complications (Grade 1 or 2), and Grade 5 gastrointestinal bleeding after aspiration pneumonia developed in one elderly male patient on the 45th postoperative day, which was not considered to be associated with LND. At the last follow-up, lung metastasis developed in four patients (pT1 in one, pT2 in one, and pT3 in two), and presacral lymph node metastasis developed in one patient with a lower ureteral tumor (pT2), which was not included in our prospective template for a lower ureteral tumor. LN recurrence within/ near the LND area was not observed in patients with pelvic/upper ureteral carcinoma. The 2-year nonurothelial RFS rate was 84%. CONCLUSIONS: We consider that the present template represents regional LNs for patients with clinically node-negative pelvic/upper ureteral carcinoma, while presacral LNs may be incorporated into the regional LND template for patients with clinically node-negative lower ureteral carcinoma.

Association between maternal exposure to di(2-ethylhexyl) phthalate and reproductive hormone levels in fetal blood: the Hokkaido study on environment and children's health.

Prenatal di(2-ethylhexyl) phthalate (DEHP) exposure can produce reproductive toxicity in animal models. Only limited data exist from human studies on maternal DEHP exposure and its effects on infants. We aimed to examine the associations between DEHP exposure in utero and reproductive hormone levels in cord blood. Between 2002 and 2005, 514 pregnant women agreed to participate in the Hokkaido Study Sapporo Cohort. Maternal blood samples were taken from 23-35 weeks of gestation and the concentration of the primary metabolite of DEHP, mono(2-ethylhexyl) phthalate (MEHP), was measured. Concentrations of infant reproductive hormones including estradiol (E2), total testosterone (T), and progesterone (P4), inhibin B, insulin-like factor 3 (INSL3), steroid hormone binding globulin, follicle-stimulating hormone, and luteinizing hormone were measured from cord blood. Two hundred and two samples with both MEHP and hormones' data were included in statistical analysis. The participants completed a self-administered questionnaire regarding information on maternal characteristics. Gestational age, birth weight and infant sex were obtained from birth records. In an adjusted linear regression analysis fit to all study participants, maternal MEHP levels were found to be associated with reduced levels of T/E2, P4, and inhibin B. For the stratified analyses for sex, inverse associations between maternal MEHP levels T/E2, P4, inhibin B, and INSL3 were statistically significant for males only. In addition, the MEHP quartile model showed a significant p-value trend for P4, inhibin B, and INSL3 decrease in males. Since inhibin B and INSL3 are major secretory products of Sertoli and Leydig cell, respectively, the results of this study suggest that DEHP exposure in utero may have adverse effects on both Sertoli and Leydig cell development in males, which agrees with the results obtained from animal studies. Comprehensive studies investigating phthalates' exposure in humans, as well as their long-term effects on reproductive development are needed.

Identification of novel targets for antiangiogenic therapy by comparing the gene expressions of tumor and normal endothelial cells.

Targeting tumor angiogenesis is an established strategy for cancer therapy. Because angiogenesis is not limited to pathological conditions such as cancer, molecular markers that can distinguish between physiological and pathological angiogenesis are required to develop more effective and safer approaches for cancer treatment. To identify such molecules, we determined the gene expression profiles of murine tumor endothelial cells (mTEC) and murine normal endothelial cells using DNA microarray analysis followed by quantitative reverse transcription-polymerase chain reaction analysis. We identified 131 genes that were differentially upregulated in mTEC. Functional analysis using siRNA-mediated gene silencing revealed five novel tumor endothelial cell markers that were involved in the proliferation or migration of mTEC. The expression of DEF6 and TMEM176B was upregulated in tumor vessels of human renal cell carcinoma specimens, suggesting that they are potential targets for antiangiogenic intervention for renal cell carcinoma. Comparative gene expression analysis revealed molecular differences between tumor endothelial cells and normal endothelial cells and identified novel tumor endothelial cell markers that may be exploited to target tumor angiogenesis for cancer treatment.

Contribution of bone marrow-derived mesenchymal stem cells to the morphological changes in the bladder after partial outlet obstruction: a preliminary study.

OBJECTIVES: To investigate the contribution of bone marrow-derived mesenchymal stem cells to the changes in bladder morphology in response to partial bladder outlet obstruction. METHODS: Allogenic bone marrow cells were transplanted from transgenic rats expressing green fluorescent protein into female Sprague-Dawley rats 1 day after their bone marrow-derived mesenchymal stem cells had been destroyed by irradiation. This generated chimeric rats in which green fluorescent protein labeled bone marrow-derived mesenchymal stem cells replaced host bone marrow-derived mesenchymal stem cells. The animals received partial bladder outlet obstruction or sham surgery 6 weeks later. The animals were killed 6 weeks after the surgery, and bladder tissue was prepared for immunofluorescence with antibodies against a urothelium marker (AE1/AE3), a myofibroblast marker (vimentin), a smooth muscle marker and green fluorescent protein. RESULTS: More labeled bone marrow-derived mesenchymal stem cells were found in the partial bladder outlet obstruction group than in the in the sham group. Most bone marrow-derived mesenchymal stem cells were present around the basement membrane (laminin) and lamina propria below the urothelium. Bone marrow-derived mesenchymal stem cells were also found in the urothelium layer, and some of them were double-stained with green fluorescent protein and AE1/AE3. Some bone marrow-derived mesenchymal stem cells, which were located in the interstitial tissue, were double-stained with green fluorescent protein and vimentin. Bone marrow-derived mesenchymal stem cells, which migrated into the smooth muscle layer, showed fusiform morphology, and some were double-stained with green fluorescent protein and smooth muscle marker. CONCLUSIONS: Bone marrow-derived mesenchymal stem cells home to the partial bladder outlet obstruction bladder, and these cells have the potential to differentiate into the several components of bladder tissue including the urothelium, myofibroblasts and smooth muscle cells. Thus, bone marrow-derived mesenchymal stem cells contribute to the morphological changes of the bladder in response to partial bladder outlet obstruction.

TRIM29 as a novel prostate basal cell marker for diagnosis of prostate cancer.

Tripartite motif protein 29 (TRIM29) is one of the TRIM family proteins, some of which function as E3 ubiquitin ligases. In this study, we investigated the usefulness of TRIM29 for diagnosis of prostate cancer. Prostate tissues including carcinoma and non-carcinoma tissues obtained by needle biopsy and radical prostatectomy were used. Immunohistochemistry was performed according to standard procedures using an antibody against TRIM29. Immunohistochemical staining with an antibody against 34ßE12, which recognizes cytokeratins 1, 5, 10 and 14, was performed as a control. Basal cells of normal prostatic glands were stained with anti-TRIM29 antibody in all cases, whereas prostate cancer tissues had no or little staining with anti-TRIM29 antibody. TRIM29 is selectively expressed in basal cells of the normal prostate gland, and immunohistochemical staining with anti-TRIM29 antibody showed the same expression pattern as that with 34ßE12 in prostate cancer and its benign mimics. Our data indicate that TRIM29 may be useful for distinguishing prostate cancers from benign tissues.

RENAL nephrometry score is a predictive factor for the annual growth rate of renal mass.

OBJECTIVE: To evaluate the association between the RENAL nephrometry score and annual growth rates of renal masses presumed to be renal cell carcinoma. METHODS: The current study included 47 renal tumors followed up for at least 12 months, of which 26 tumors were found to be pathologically proven renal cell carcinomas. Annual tumor growth rates were calculated from changes in the maximal diameter on computed tomography, and RENAL nephrometry scores were recorded on initial imaging by two senior urologists. The associations between clinical characteristics including the RENAL nephrometry score and annual growth rates were analyzed using a linear regression model. RESULTS: The median tumor size at diagnosis was 1.7 cm (range 0.6-5.8). The median nephrometry score at diagnosis was 7 (range 4-10). Overall, the median tumor growth rate was 0.34 cm per year (range -0.19-2.0). Linear regression analysis showed that the annual tumor growth rate was associated with the RENAL nephrometry score (P < 0.0001), but it was independent of the age at diagnosis, sex and initial tumor size. In addition, the correlation between the RENAL nephrometry score and annual growth rate remained significant in the 26 pathologically proven renal cell carcinomas. CONCLUSIONS: The RENAL nephrometry score is associated with the annual growth rate of renal masses. Our findings further support the association between the RENAL nephrometry score and tumor biology.

Roles of adenosine A1 and A2A receptors in the control of micturition in rats.

AIMS: Adenosine is a neurotransmitter that exerts numerous physiological effects in many organs. However, few studies have focused on the role of adenosine receptors in the control of micturition. Therefore, we examined the role of adenosine A1 and A2A receptors in the control of bladder activity in rats with normal or acetic acid (AA) irritated bladders. METHODS: Cystometrograms during saline or 0.2% AA infusion were recorded under urethane anesthesia in female Sprague-Dawley rats. After a stabilization period, CCPA (A1 receptor agonist) and/or ZM24138 (A2A receptor antagonist) were administered intravenously (i.v.), intrathecally (i.t.), intracerebroventricularly (i.c.v.), or intravesically. Micturition parameters were recorded and compared before and after drug administration. RESULTS: I.v., i.t., or i.c.v. administration of CCPA or ZM24138 significantly increased intercontraction intervals (ICIs) in both saline and AA infusion groups. During AA infusion, the inhibitory effects induced by i.c.v. CCPA or i.t. ZM24138 were significantly greater than those by i.t. or i.c.v. administration, respectively. Intravesical administration of CCPA, but not ZM24138, significantly increased ICI. CONCLUSIONS: These results indicated that: (1) when nociceptive signals from the bladder increase, adenosine A1 receptor-mediated inhibition of micturition is enhanced in the brain, compared to the normal condition, (2) A1 receptor activation also exerts a peripheral inhibitory effect on micturition, and (3) adenosine A2A receptor-mediated excitatory mechanisms are enhanced in the spinal cord following C-fiber bladder afferent stimulation. Thus adenosine A1 receptor agonists and A2A receptor antagonists might be effective for the treatment of overactive bladder and/or bladder hypersensitive disorders, in which C-fiber afferent function is enhanced.

Outcome of metastasectomy for urothelial carcinoma: a multi-institutional retrospective study in Japan.

PURPOSE: We determined prognostic factors associated with prolonged survival after metastasectomy for urothelial carcinoma. MATERIALS AND METHODS: A total of 42 patients who underwent resection of urothelial carcinoma metastases with curative intent at 4 Japanese university hospitals were included in analysis. Of the patients 41 of 42 underwent systemic chemotherapy before and/or after metastasectomy. Overall survival was analyzed using the Kaplan-Meier method. The relationship between clinical characteristics and survival was analyzed using the log rank test. RESULTS: Metastasectomy included lymph node dissection in 20 cases, pulmonary resection in 12, pelvic exenteration in 3, resection of local recurrence in 2, resection of subcutaneous metastasis in 2, liver resection in 1 and other in 2. Median overall survival was 29 months (IQR 19-80) from the initiation of treatment for metastases and 26 months (IQR 11-90) from metastasectomy. The overall 5-year survival rate after metastasectomy was 31%. On univariate analysis patients treated with metastasectomy for a solitary lung or solitary lymph node metastasis had significantly longer survival than the others who underwent metastasectomy (81 vs 19 months, log rank test p = 0.0296). CONCLUSIONS: Long-term cancer control could be achieved in a subgroup of patients who undergo metastasectomy, especially those with a solitary lung or solitary lymph node metastasis.

Successful penile reconstruction after multimodal therapy in patients with primitive neuroectodermal tumor originating from the penis.

We herein present an extremely rare case of primitive neuroectodermal tumor originating in the penis. A 16-year-old male adolescent presented with painful penile swelling. Pathological, immunohistochemical and cytogenetical examinations of the specimens obtained from total penectomy confirmed the diagnosis of primitive neuroectodermal tumor. After total penectomy, the patient received adjuvant chemotherapy with ifosfamide-based regimen for 48 weeks. As a series of therapies, the patient underwent penile reconstruction surgery after completing adjuvant chemotherapy. The patient has not shown any evidence of recurrence for the 7 years after penile reconstruction surgery, and voiding function is completely normal. A favorable outcome was observed by multimodal therapy including aggressive resection for local control, intensive adjuvant chemotherapy, and penile reconstruction with cosmetic and functional success. Similar therapeutic approaches might be selected for children with primary malignant tumors of the penis.