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BACKGROUND Androgen deprivation therapy (ADT) is one of the most effective treatments for advanced prostate cancer (PCa). However, it has been reported that the use of ADT is significantly associated with an increased risk of acute kidney injury (AKI) among patients with newly diagnosed non-metastatic PCa. We investigated changes in renal function that occurred in Japanese patients with PCa after ADT was discontinued. PATIENTS AND METHODS Among 121 patients who underwent prostate biopsies, were pathologically diagnosed with PCa, and received ADT for ≥6 months at our Institution between 2009 and 2014, 60 patients who underwent radiotherapy for stage B or C PCa were eligible for inclusion in this retrospective study. Renal function was assessed using the estimated glomerular filtration rate (eGFR) before treatment and at 1, 3, 6, 9, and 12 months after the initiation of ADT and the rate of change in the eGFR (ΔeGFR) during ADT and after the discontinuation of ADT was investigated. We divided patients into two groups: Group 1 received ADT for 6 months, and group 2 received ADT for 12 months. Age; ΔeGFR; prostate-specific antigen, testosterone and hemoglobin levels; clinical stage; Gleason score; comorbidities; body mass index; heart rate; and the cardiothoracic ratio were analyzed. RESULTS A total of 60 patients (group 1: n=23, group 2: n=37) were analyzed. The Gleason score of group 2 was higher than that of group 1 (p=0.0011). Regarding clinical stage, group 1 had more patients with stage B disease, and group 2 had more with stage C (p

There is no useful predictive marker for reclassification on active surveillance. Thus, we aimed to investigate thresholds of [−2] proPSA (p2PSA)-related parameters to predict reclassification of the first-year protocol biopsy (1-year PBx) and evaluate the influence of clinical decision-making. This was an observational, prospective cohort study conducted at 19 Japanese institutes. The inclusion criteria included clinical stage T1c/T2, prostate-specific antigen (PSA) levels ≤10 ng/mL, PSA density

Analysis of microRNA (miRNA) regulatory networks is useful for exploring novel biomarkers and therapeutic targets in cancer cells. The Cancer Genome Atlas dataset shows that low expression of both strands of pre‐miR‐101 (miR‐101‐5p and miR‐101‐3p) significantly predicted poor prognosis in clear cell renal cell carcinoma (ccRCC). The functional significance of miR‐101‐5p in cancer cells is poorly understood. Here, we focused on miR‐101‐5p to investigate the antitumor function and its regulatory networks in ccRCC cells. Ectopic expression of mature miRNAs or siRNAs was investigated in cancer cell lines to characterize cell function, ie, proliferation, apoptosis, migration, and invasion. Genome‐wide gene expression and in silico database analyses were undertaken to predict miRNA regulatory networks. Expression of miR‐101‐5p caused cell cycle arrest and apoptosis in ccRCC cells. Downstream neighbor of son (DONSON) was directly regulated by miR‐101‐5p, and its aberrant expression was significantly associated with shorter survival in propensity score‐matched analysis (P = .0001). Knockdown of DONSON attenuated ccRCC cell aggressiveness. Several replisome genes controlled by DONSON and their expression were closely associated with ccRCC pathogenesis. The antitumor miR‐101‐5p/DONSON axis and its modulated replisome genes might be a novel diagnostic and therapeutic target for ccRCC., MicroRNA‐101‐5p expression was downregulated in clear cell renal cell carcinoma (ccRCC) tissues and functioned as tumor‐suppressive microRNA. MicroRNA‐101‐5p directly regulated DONSON, which was highly expressed in ccRCC and sunitinib‐resistant RCC tissues. DONSON and other replisome‐related genes have a potential to be diagnostic and therapeutic targets in ccRCC.

A 34-year-old man visited our hospital complaining of a small painless left scrotal mass. His serum alpha-fetoprotein and human chorionic gonadotropin-beta levels were normal. Ultrasonography revealed a solitary 14 mm mass. Magnetic resonance imaging revealed a mass with high intensity on T2-weighted imaging. Computed tomography revealed a heterogeneous tumor in the left scrotum. Left high orchiectomy was performed. The histopathological diagnosis was a teratoma without germ cell neoplasia in situ (GCNIS). Fluorescence in situ hybridization analysis showed no appearance of i(12p). The patient was clinically diagnosed as having a prepubertal-type testicular teratoma. Adult teratomas contain GCNIS and are aggressively treated as malignant germ cell tumors. However, a prepubertal-type teratoma is benign and does not relapse. It is essential to validate the appearance of i(12p) to differentiate prepubertal and postpubertal-type teratoma.

Background/Aim: We investigated the changes in and characteristics of renal function in Japanese patients with high-risk prostate cancer (PCa) who underwent radiotherapy and long-term androgen deprivation therapy (ADT), including those seen after the ADT was discontinued. Patients and Methods: Among 60 patients who were pathologically diagnosed with PCa and received ADT for 24 months and radiotherapy, 36 patients who underwent treatment for stage B or C PCa were eligible. We assessed renal function using the estimated glomerular filtration rate (eGFR) and investigated the rate of change in the eGFR (ΔeGFR) during and after ADT. Univariate and multivariate logistic analyses were carried out to identify clinical factors that were significantly associated with renal dysfunction at 36 months. Results: The incidence of renal dysfunction at 36 months was 75% (27/36). Multivariate analysis showed that the presence/absence of HF was an independent predictor of renal dysfunction at 36 months. Conclusion: Renal function tended to recover after ADT was received for 24 months and subsequently discontinued. The presence/absence of HF represents new and meaningful information for patients receiving ADT, and high-risk PCa patients prior to ADT.

Androgen deprivation therapy is frequently used to treat prostate cancer (PCa), but resistance can occur, a condition known as castration‐resistant prostate cancer (CRPC). Thus, novel approaches for identification of CRPC are important for designing effective PCa treatments. Analysis of microRNA (miRNA) expression signatures by RNA sequencing showed that both passenger and guide strands of the miR‐455‐duplex (miR‐455‐5p and miR‐455‐3p, respectively) acted as antitumor miRNAs in PCa cells. The involvement of miRNA passenger strands in cancer pathogenesis is a novel concept for miRNA functionality. Based on a large patient cohort in The Cancer Genome Atlas, expression of eight miR‐455‐5p/‐3p target genes (PIR: P = 0.0137, LRP8: P = 0.0495, IGFBP3: P = 0.0172, DMBX1: P = 0.0175, CCDC64: P = 0.0446, TUBB1: P = 0.0149, KIF21B: P = 0.0336, and NFAM1: P = 0.0013) was significantly associated with poor prognosis of PCa patients. Here, we focused on PIR (pirin), a highly conserved member of the cupin superfamily. PIR expression was directly regulated by miR‐455‐5p, and PIR overexpression was detected in hormone‐sensitive prostate cancer (HSPC) surgical specimens and CRPC autopsy specimens. Loss‐of‐function assays using siRNA or an inhibitor (bisamide) showed that downregulation of PIR expression blocked cancer cell migration and invasion. Moreover, the miR‐455‐5p/PIR axis contributed to cancer cell aggressiveness. These results suggest that PIR might be a promising diagnostic marker for HSPC and CRPC. Furthermore, CRPC treatment strategies targeting PIR may be possible in the future. Identification of antitumor miRNAs, including miRNA passenger strands, may contribute to the development of new diagnostic markers and therapeutic strategies for CRPC.

Background/aim This study aimed to access the effectiveness of serum neutrophil-to-lymphocyte ratio (NLR) in patients undergoing prostate needle biopsy with a prostate specific antigen (PSA) between 4.0 and 10.0 ng/ml. Patients and methods A total of 633 cases were eligible. We evaluated several factors including age, PSA, PSA-density (PSAD), platelet-to-lymphocyte ratio (PLR) and NLR in the presence or absence of prostate cancer (PCa), retrospectively. We evaluated statistically the associations between each factor and pathological findings or Gleason score. Results A total of 201 were evaluated in this study. Regarding the presence or absence of prostate cancer, there were statistically significant differences in age, PSA levels, PSAD, the PLR and NLR. The mean NLR value of the patients with PCa was significantly lower compared to the entire cohort. Multivariate analysis showed that age, PSAD, and NLR were independent risk factors predicting PCa. Conclusion For patients having a PSA between 4.0 and 10.0 ng/ml, NLR was a predicting factor of PCa prior to prostate needle biopsy and an effective biomarker and useful tool for avoiding unnecessary biopsies.

OBJECTIVES To identify key oncogenes and proteins that are controlled by the microRNA miR-29 family (miR-29a, miR-29b and miR-29c) in renal cell carcinoma pathogenesis. METHODS Genome-wide gene expression and in silico database analyses were carried out. The Cancer Genome Atlas database was used to investigate the clinical significance of gene expression data in renal cell carcinoma patients. Loss-of-function assays were applied to investigate the function of target genes. RESULTS We identified 47 possible target genes that might be regulated by the miR-29 family in renal cell carcinoma cells. Among the targets of the miR-29 family, high expression of 10 genes (ADAMTS14, TRIB13, SERPINH1, FCGR1B, COL1A1, LAIR2, WISP2, TREM1, TNKS1BP1 and GBP2) significantly predicted poor patient prognosis (P

In the human genome, miR-451a, miR-144-5p (passenger strand), and miR-144-3p (guide strand) reside in clustered microRNA (miRNA) sequences located within the 17q11.2 region. Low expression of these miRNAs is significantly associated with poor prognosis of patients with renal cell carcinoma (RCC) (miR-451a: P = .00305; miR-144-5p: P = .00128; miR-144-3p: P = 9.45 × 10-5 ). We previously reported that miR-451a acted as an antitumor miRNA in RCC cells. Involvement of the passenger strand of the miR-144 duplex in the pathogenesis of RCC is not well understood. Functional assays showed that miR-144-5p and miR-144-3p significantly reduced cancer cell migration and invasive abilities, suggesting these miRNAs acted as antitumor miRNAs in RCC cells. Analyses of miR-144-5p targets identified a total of 65 putative oncogenic targets in RCC cells. Among them, high expression levels of 9 genes (FAM64A, F2, TRIP13, ANKRD36, CENPF, NCAPG, CLEC2D, SDC3, and SEMA4B) were significantly associated with poor prognosis (P < .001). Among these targets, expression of SDC3 was directly controlled by miR-144-5p, and its expression enhanced cancer cell aggressiveness. We identified genes downstream by SDC3 regulation. Data showed that expression of 10 of the downstream genes (IL18RAP, SDC3, SH2D1A, GZMH, KIF21B, TMC8, GAB3, HLA-DPB2, PLEK, and C1QB) significantly predicted poor prognosis of the patients (P = .0064). These data indicated that the antitumor miR-144-5p/oncogenic SDC3 axis was deeply involved in RCC pathogenesis. Clustered miRNAs (miR-451a, miR-144-5p, and miR-144-3p) acted as antitumor miRNAs, and their targets were intimately involved in RCC pathogenesis.

Effective treatments for patients with castration‐resistant prostate cancer (CRPC) have not yet been established. Novel approaches for identification of putative therapeutic targets for CRPC are needed. Analyses of RNA sequencing of microRNA (miRNA) expression revealed that miR‐99a‐3p (passenger strand) is significantly downregulated in several types of cancers. Here, we aimed to identify novel miR‐99a‐3p regulatory networks and therapeutic targets for CRPC. Ectopic expression of miR‐99a‐3p significantly inhibited cancer cell proliferation, migration, and invasion in PCa cells. Non‐SMC condensin I complex subunit G (NCAPG) was a direct target of miR‐99a‐3p in PCa cells. Overexpression of NCAPG was detected in CRPC clinical specimens and was significantly associated with shorter disease‐free survival and advanced clinical stage. Knockdown of NCAPG inhibited cancer cell aggressiveness. The passenger strand miR‐99a‐3p acted as an antitumor miRNA in naïve PCa and CRPC. NCAPG was regulated by miR‐99a‐3p, and its overexpression was involved in CRPC pathogenesis. Involvement of passenger strand of miRNA in cancer pathogenesis is novel concept, and identification of antitumor miRNA regulatory networks in CRPC might be provided novel prognostic markers and therapeutic targets for this disease.

Recent analyses of our microRNA (miRNA) expression signatures obtained from several types of cancer have provided novel information on their molecular pathology. In renal cell carcinoma (RCC), expression of microRNA-451a (miR-451a) was significantly downregulated in patient specimens and low expression of miR-451a was significantly associated with poor prognosis of RCC patients (P = .00305) based on data in The Cancer Genome Atlas. The aims of the present study were to investigate the antitumor roles of miR-451a and to identify novel oncogenic networks it regulated in RCC cells. Ectopic expression of miR-451a significantly inhibited cancer cell migration and invasion by RCC cell lines, suggesting that miR-451a had antitumor roles. To identify oncogenes regulated by miR-451a in RCC cells, we analyzed genome-wide gene expression data and examined information in in silico databases. A total of 16 oncogenes and were found to be possible targets of miR-451a regulation. Interestingly, high expression of 9 genes (PMM2, CRELD2, CLEC2D, SPC25, BST2, EVL, TBX15, DPYSL3, and NAMPT) was significantly associated with poor prognosis. In this study, we focused on phosphomannomutase 2 (PMM2), which was the most strongly associated with prognosis. Overexpression of PMM2 was detected in clinical specimens and Spearman's rank test indicated a negative correlation between the expression levels of miR-451a and PMM2 (P = .0409). Knockdown of PMM2 in RCC cells inhibited cancer cell migration and invasion, indicating overexpression of PMM2 could promote malignancy. Analytic strategies based on antitumor miRNAs is an effective tool for identification of novel pathways of cancer.

Our recent determination of a microRNA (miRNA) expression signature in prostate cancer (PCa) revealed that miR-205-5p was significantly reduced in PCa tissues and that it acted as an antitumor miRNA. The aim of this study was to identify oncogenic genes and pathways in PCa cells that were regulated by antitumor miR-205-5p. Genome-wide gene expression analyses and in silico miRNA database searches showed that 37 genes were putative targets of miR-205-5p regulation. Among those genes, elevated expression levels of seven in particular (HMGB3, SPARC, MKI67, CENPF, CDK1, RHOU, and POLR2D) were associated with a shorter disease-free survival in a large number of patients in the The Cancer Genome Atlas (TCGA) database. We focused on high-mobility group box 3 (HMGB3) because it was the most downregulated by ectopic expression of miR-205-5p in PC3 cells and its expression was involved in PCa pathogenesis. Luciferase reporter assays showed that HMGB3 was directly regulated by miR-205-5p in PCa cells. Knockdown studies using si-HMGB3 showed that expression of HMGB3 enhanced PCa cell aggressiveness. Overexpression of HMGB3/HMGB3 was confirmed in naive PCa and castration-resistant PCa (CRPC) clinical specimens. Novel approaches to analysis of antitumor miRNA-regulated RNA networks in PCa cells may provide new insights into the pathogenic mechanisms of the disease.

Analysis of our original microRNA (miRNA) expression signature of patients with advanced renal cell carcinoma (RCC) showed that microRNA-10a-5p (miR-10a-5p) was significantly downregulated in RCC specimens. The aims of the present study were to investigate the antitumor roles of miR-10a-5p and the novel cancer networks regulated by this miRNA in RCC cells. Downregulation of miR-10a-5p was confirmed in RCC tissues and RCC tissues from patients treated with tyrosine kinase inhibitors (TKI). Ectopic expression of miR-10a-5p in RCC cell lines (786-O and A498 cells) inhibited cancer cell migration and invasion. Spindle and kinetochore-associated protein 1 (SKA1) was identified as an antitumor miR-10a-5p target by genome-based approaches, and direct regulation was validated by luciferase reporter assays. Knockdown of SKA1 inhibited cancer cell migration and invasion in RCC cells. Overexpression of SKA1 was observed in RCC tissues and TKI-treated RCC tissues. Moreover, analysis of The Cancer Genome Atlas database demonstrated that low expression of miR-10a-5p and high expression of SKA1 were significantly associated with overall survival in patients with RCC. These findings showed that downregulation of miR-10a-5p and overexpression of the SKA1 axis were highly involved in RCC pathogenesis and resistance to TKI treatment in RCC.

Background: Despite recent advancements, metastatic castration-resistant prostate cancer (CRPC) is not considered curative. Novel approaches for identification of therapeutic targets of CRPC are needed. Methods: Next-generation sequencing revealed 945–1248 miRNAs from each lethal mCRPC sample. We constructed miRNA expression signatures of CRPC by comparing the expression of miRNAs between CRPC and normal prostate tissue or hormone-sensitive prostate cancer (HSPC). Genome-wide gene expression studies and in silico analyses were carried out to predict miRNA regulation and investigate the functional significance and clinical utility of the novel oncogenic pathways regulated by these miRNAs in prostate cancer (PCa). Results: Based on the novel miRNA expression signature of CRPC, miR-145-5p and miR-145-3p were downregulated in CRPC. By focusing on miR-145-3p, which is a passenger strand and has not been well studied in previous reports, we showed that miR-145-3p targeted 4 key molecules, i.e., MELK, NCAPG, BUB1, and CDK1, in CPRC. These 4 genes significantly predicted survival in patients with PCa. Conclusions: Small RNA sequencing for lethal CRPC and in silico analyses provided novel therapeutic targets for CRPC.

Background Although the perioperative management of patients with pheochromocytoma has been improving recently, severe hypotensive episodes can occur that require postoperative catecholamine support and are challenging to manage. Our aim was to identify the clinical factors that predict prolonged postresection hypotension in patients after laparoscopic adrenalectomy for pheochromocytoma. Methods The records of 73 Japanese patients who underwent unilateral laparoscopic adrenalectomy for pheochromocytoma were surveyed retrospectively. Patients were divided into 2 groups according to whether catecholamine support was needed after postoperatively. Clinical and biochemical data were evaluated at baseline and after operation. Results Thirty-four of 73 patients (47%) required continuous infusion of catecholamine to maintain systolic blood pressure >90 mm Hg at the end of the operation. The median duration of postoperative catecholamine support was 17 hours (range, 3–130) in these 34 patients. On multivariate analysis, tumor size >60 mm, urinary epinephrine levels >200 μg/day, and urinary norepinephrine levels >600 μg/day were independent predictors of prolonged hypotension requiring postoperative catecholamine support. Tumor size and urinary norepinephrine levels were significantly correlated with the duration of postoperative catecholamine support. Conclusion Larger tumor size and greater values of urinary epinephrine and norepinephrine levels were significant predictors of prolonged hypotension requiring postoperative catecholamine support. Moreover, tumor size and urinary norepinephrine levels were positively correlated with the duration of postoperative catecholamine support. Clinicians can identify and manage patients more effectively with a greater risk of prolonged hypotension after tumor resection using these preoperative clinical variables.

To identify oncogenes regulated by micro-ribonucleic acid, miR-199a/b-3p, in metastatic castration-resistant prostate cancer.Advanced ribonucleic acid sequencing technologies were applied to construct a micro-ribonucleic acid expression signature using metastatic castration-resistant prostate cancer autopsy specimens. Ectopic expression of mature micro-ribonucleic acids or small-interfering ribonucleic acids were applied to functional assays for cancer cell lines. Genome-wide gene expression and in silico database analyses were carried out to predict micro-ribonucleic acid targets.Ectopic expression of miR-199a/b inhibited cancer cell aggressiveness. The gene coding for non-structural maintenance of chromosomes condensin I complex subunit H was directly regulated by miR-199a/b-3p. High expression of condensin I complex subunit H was significantly associated with poor disease-free survival by The Cancer Genome Atlas database analysis (P 0.0001). Overexpression of condensin I complex subunit H was detected in hormone-sensitive prostate cancer and castration-resistant prostate cancer specimens, and knockdown assays showed that its expression enhanced cancer cell migration and invasive abilities.Small ribonucleic acid sequencing of metastatic castration-resistant prostate cancer specimens showed the presence of several antitumor micro-ribonucleic acids whose targets are involved in hormone-sensitive prostate cancer and metastatic castration-resistant prostate cancer pathogenesis. Condensin I complex subunit H seems to be a promising diagnostic marker and therapeutic target for this disease. Our approach, based on the roles of anti-tumor micro-ribonucleic acids and their targets, will contribute to an improved understanding of the molecular pathogenesis of hormone-sensitive prostate cancer and metastatic castration-resistant prostate cancer.

Background: Our present study of the microRNA (miRNA) expression signature in castration-resistant prostate cancer (CRPC) revealed that the clustered miRNAs microRNA-221 (miR-221) and microRNA-222 (miR-222) are significantly downregulated in cancer tissues. The aim of this study was to investigate the functional roles of miR-221 and miR-222 in prostate cancer (PCa) cells. Methods: A CRPC miRNA signature was constructed by PCR-based array methods. Functional studies of differentially expressed miRNAs were analysed using PCa cells. The association between miRNA expression and overall survival was estimated by the Kaplan–Meier method. In silico database and genome-wide gene expression analyses were performed to identify molecular targets regulated by the miR-221/222 cluster. Results: miR-221 and miR-222 were significantly downregulated in PCa and CRPC specimens. Kaplan–Meier survival curves showed that low expression of miR-222 predicted a short duration of progression to CRPC. Restoration of miR-221 or miR-222 in cancer cells revealed that both miRNAs significantly inhibited cancer cell migration and invasion. Ecm29 was directly regulated by the miR-221/222 cluster in PCa cells. Conclusions: Loss of the tumour-suppressive miR-221/222 cluster enhanced migration and invasion in PCa cells. Our data describing targets regulated by the tumour-suppressive miR-221/222 cluster provide insights into the mechanisms of PCa and CRPC progression.

Many patients with primary aldosteronism (PA) show a significant decline in kidney function after adrenalectomy. Thus, PA patients who undergo surgery are at greater risk of both postoperative renal damage and new-onset metabolic events associated with renal insufficiency. The aim of this study was to explore postoperative changes in serum lipid levels and to identify risk factors associated with postoperative new-onset dyslipidemia in PA patients. The records of 57 Japanese patients who underwent unilateral laparoscopic adrenalectomy for PA were retrospectively surveyed. Clinical and biochemical data were evaluated at baseline and 12 months after surgery. Preoperative and postoperative estimated glomerular filtration (eGFR) and serum lipid profile, including triglycerides, high-density lipoprotein (HDL)-cholesterol and low-density lipoprotein (LDL)-cholesterol levels, were compared. Furthermore, uni- and multivariate analyses were performed to determine the predictors for postoperative new-onset dyslipidemia. A significant decrease in eGFR and deterioration of serum lipid levels was identified postoperatively in most patients. Of the 39 patients without pre-existing dyslipidemia, 18 developed new-onset dyslipidemia postoperatively. Multivariate analysis identified preoperative lower eGFR and higher body mass index as independent predictors for new-onset dyslipidemia after surgery. On univariate analyses, additional factors associated with new-onset dyslipidemia included older age, male sex, higher LDL-cholesterol, and higher LDL/HDL ratio. PA patients had a higher risk of postoperative new-onset or progressive dyslipidemia. Clinicians should pay attention to not only follow-up of renal impairment but also total management of new-onset metabolic events associated with renal insufficiency in PA patients.

Objectives To investigate the functional roles of microRNA-205 in the modulation of novel cancer pathways in prostate cancer cells. Methods Functional studies of microRNA-205 were carried out to investigate cell proliferation, migration and invasion in prostate cancer cell lines (PC3 and DU145) by restoration of mature microRNA. In silico database and genome-wide gene expression analyses were carried out to identify molecular targets and pathways mediated by microRNA-205. Loss-of-function studies were applied to microRNA-205 target genes. Results Restoration of microRNA-205 in cancer cell lines significantly inhibited cancer cell migration and invasion. Our data showed that the centromere protein F gene was overexpressed in prostate cancer clinical specimens and was a direct target of microRNA-205 regulation. Silencing of centromere protein F significantly inhibited cancer cell migration and invasion. Furthermore, MCM7, an oncogenic gene functioning downstream of centromere protein F, was identified by si-centromere protein F transfectants in prostate cancer cells. Conclusions Loss of tumor-suppressive microRNA-205 seems to enhance cancer cell migration and invasion in prostate cancer through direct regulation of centromere protein F. Our data describing pathways regulated by tumor-suppressive microRNA-205 provide new insights into the potential mechanisms of prostate cancer oncogenesis and metastasis.

Our recent studies revealed that dual strands of certain pre-microRNAs, e.g., pre-miR-144, pre-miR-145, and pre-miR-150, act as antitumor microRNAs (miRNAs) in several cancers. The involvement of passenger strands of miRNAs in cancer pathogenesis is a novel concept in miRNA research. The analysis of a miRNA expression signature in clear cell renal cell carcinoma (ccRCC) has revealed that the guide strand of pre-miR-149 is significantly downregulated in cancer tissues. The aims of this study were to investigate the functional significance of miR-149’s guide strand (miR-149-5p) and passenger strand (miR-149-3p), and to identify the oncogenic genes regulated by these miRNAs in ccRCC cells. The ectopic expression of these miRNAs significantly inhibited cancer cell migration and invasion in ccRCC cells. Forkhead box protein M1 (FOXM1) was directly regulated by miR-149-5p and miR-149-3p in ccRCC cells. Knockdown studies using si-FOXM1 showed that the expression of FOXM1 enhanced RCC cell aggressiveness. Interestingly, the analysis of a large number of patients in the The Cancer Genome Atlas (TCGA) database (n = 260) demonstrated that patients with high FOXM1 expression had significantly shorter survival than did those with low FOXM1 expression (p = 1.5 × 10-6). Taken together, dual strands of pre-miR-149 (miR-149-5p and miR-149-3p) acted as antitumor miRNAs through the targeting of FOXM1 in ccRCC cells.

Analysis of our microRNA (miRNA) expression signature in human cancers has shown that guide and passenger strands of pre-miR‑150, i.e., miR‑150‑5p and miR‑150‑3p, are significantly downregulated in cancer tissues. In miRNA biogenesis, the passenger strand of miRNA is degraded and is thought to have no functions. Thus, the aim of this study was to investigate the functional significance of miR‑150‑5p and miR‑150‑3p in naive prostate cancer (PCa) and castration-resistant prostate cancer (CRPC). Ectopic expression assays showed that both strands of miRNAs significantly suppressed cancer cell migration and invasion. Our strategies of miRNA target searching demonstrated that SPOCK1 (SPARC/osteonectin, cwcv and kazal like domains proteoglycan 1) was directly regulated by miR‑150‑5p and miR‑150‑3p. Knockdown of SPOCK1 by siRNA inhibited cancer cell aggressiveness. Moreover, overexpression of SPOCK1 was observed in naive PCa and CRPC tissues. Taken together, dual strands of pre-miR‑150 (miR‑150‑5p and miR‑150‑3p) acted as antitumor miRNAs in naive PCa and CRPC cells. Expression of oncogenic SPOCK1 was involved in naive PCa and CRPC pathogenesis. Novel approaches to analysis of antitumor miRNA-regulated RNA networks in cancer cells may provide new insights into the pathogenic mechanisms of naive PCa and CRPC.

Summary Background The number of antihypertensive drug classes cannot accurately reflect the total consumption of antihypertensive drugs used to control blood pressure. The defined daily dose has been adopted to permit consumption analysis of many prescribed drugs. The aim of the present study was to assess postoperative changes in antihypertensive drug consumption in patients with primary aldosteronism using the defined daily dose as the unit of measurement. Methods This retrospective study included 110 Japanese patients who underwent unilateral laparoscopic adrenalectomy between 1995 and 2012. Antihypertensive drug doses were calculated according to the standard of the defined daily dose recommended by the World Health Organization to compare drug use. After assessing postoperative changes in antihypertensive drug consumption, univariate and multivariate analyses were performed to identify clinical predictors for a 75% or greater decrease in the defined daily dose. Results Consumption of antihypertensive drugs decreased postoperatively in 95.4% of patients. The median decrease in the defined daily dose was 76.8%. A postoperative decrease of 75% or greater in the defined daily dose was confirmed in 52.7% of patients. Multivariate analysis identified no medical history of cardiovascular disease, low body mass index, and short duration of hypertension as independent predictors of a postoperative decrease of 75% or greater in the defined daily dose. Conclusion The defined daily dose is a useful tool for assessing total changes in the consumption of antihypertensive drugs in patients with primary aldosteronism. Using the defined daily dose, clinicians could explain in detail to patients with primary aldosteronism the predicted postoperative change in antihypertensive drug consumption.

// Yusuke Goto 1,2 , Satoko Kojima 3 , Rika Nishikawa 1,2 , Hideki Enokida 4 , Takeshi Chiyomaru 4 , Takashi Kinoshita 1 , Masayuki Nakagawa 4 , Yukio Naya 3 , Tomohiko Ichikawa 2 and Naohiko Seki 1 1 Department of Functional Genomics, Chiba University Graduate School of Medicine, Chiba, Japan 2 Department of Urology, Chiba University Graduate School of Medicine, Chiba, Japan 3 Department of Urology, Teikyo University Chiba Medical Center, Chiba, Japan 4 Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan Correspondence: Naohiko Seki, email: // Keywords : microRNA, miR-23b, miR-27b, miR-24-1, castration-resistant prostate cancer Received : May 27, 2014 Accepted : July 31, 2014 Published : July 31, 2014 Abstract Our recent study of microRNA (miRNA) expression signatures in prostate cancer (PCa) has revealed that all members of the miR-23b/27b/24-1 cluster are significantly downregulated in PCa tissues. The aim of this study was to investigate the effectiveness of these clustered miRNAs as a disease progression marker and to determine the functional significance of these clustered miRNAs in PCa. Expression of the miR-23b/27b/24-1 cluster was significantly reduced in PCa tissues. Kaplan-Meier survival curves showed that low expression of miR-27b predicted a short duration of progression to castration-resistant PCa. Gain-of-function studies using mature miR-23b , miR-27b ,and miR-24-1 significantly inhibited cell proliferation, migration and invasion in PCa cells (PC3 and DU145). To identify the molecular targets of these miRNAs, we carried out gene expression and in silico database analyses. GOLM1 was directly regulated by miR-27b in PCa cells. Elucidation of the molecular targets and pathways regulated by the tumor-suppressive microRNAs should shed light on the oncogenic and metastatic processes in PCa.

Primary aldosteronism is the most common curable cause of secondary hypertension. Despite resection, however, many patients with primary aldosteronism continue to require antihypertensive drugs to control their blood pressure. Although many patients with primary aldosteronism want to know the postoperative probability of hypertension cure before surgery, there are no predictive models calculating its probability. We therefore developed a nomogram to predict hypertension cure in patients with primary aldosteronism after laparoscopic adrenalectomy. We retrospectively surveyed 132 Japanese patients with primary aldosteronism who were treated by unilateral laparoscopic adrenalectomy. Hypertension cure was defined as normal blood pressure (

Our recent studies of microRNA (miRNA) expression signatures revealed that microRNA-29s (miR-29s; including miR-29a/b/c) were significantly downregulated in prostate cancer (PCa) and was a putative tumor-suppressive miRNA family in PCa. Herein, we aimed to investigate the functional significance of miR-29 in cancer cells and to identify novel miR-29s-mediated cancer pathways and target genes involved in PCa oncogenesis and metastasis. Restoration of miR-29s in PC3 and DU145 cell lines revealed significant inhibition of cancer cell migration and invasion. To identify miR-29s-mediated molecular pathways and targets, we used gene expression data and in silico database analysis. Our analysis demonstrated that miR-29s modulated the focal adhesion pathway. Moreover, the laminin γ1 (LAMC1) gene was a candidate target of miR-29s regulation. Luciferase reporter assays showed that miR-29s directly regulated LAMC1. Silencing of LAMC1 significantly inhibited cell migration and invasion in cancer cells, and LAMC1 was upregulated in PCa. miR-29s acted as tumor suppressors, contributing to cancer cell migration and invasion and directly targeting laminin signaling. Recognition of tumor-suppressive miRNA-mediated cancer pathways provides new insights into the potential mechanisms of PCa oncogenesis and metastasis, and suggests novel therapeutic strategies for treating this disease.

Our recent study of the microRNA expression signature of prostate cancer (PCa) revealed that microRNA-224 (miR-224) is significantly downregulated in PCa tissues. Here, we found that restoration of miR-224 significantly inhibits PCa cell migration and invasion. Additionally, we found that oncogenic TPD52 is a direct target of miR-224 regulation. Silencing of the TPD52 gene significantly inhibits cancer cell migration and invasion. Moreover, TPD52 expression is upregulated in cancer tissues and negatively correlates with miR-224 expression. We conclude that loss of tumour-suppressive miR-224 enhances cancer cell migration and invasion in PCa through direct regulation of oncogenic TPD52.

The aim of this study was to retrospectively investigate clinical outcomes by relative dose and dose intensity of docetaxel (DOC) as chemotherapy for Japanese patients with castration-resistant prostate cancer (CRPC).A total of 145 CRPC patients who received more than 4 courses of DOC chemotherapy at 14 hospitals between 2005 and 2011 were enrolled. Patients were divided into two groups--those receiving a higher or lower dose (mg/m(2)) or dose intensity (mg/m(2)/week). Differences between the groups regarding treatment outcomes and adverse events (AEs) were determined. Additionally, prognostic factors predictive of cancer-specific survival (CSS) in these patients were identified by both univariate and multivariate analysis.The total patient group underwent a mean of 11.2 ± 7.4 DOC cycles, and the mean CSS after therapy was 15.6 ± 10.1 months. The higher-dose group had a better prostate-specific antigen (PSA) response than the lower-dose group. However, there was no significant difference between the groups in prognosis after DOC chemotherapy. Leukopenia and neutropenia were observed more frequently in the higher-dose group. Serum biomarkers (including PSA, lactate dehydrogenase and alkaline phosphatase), hemoglobin levels and presence of pain at initiation of chemotherapy, as well as the PSA nadir level on first-line hormone therapy, all were significant predictors of CSS.In the Japanese population, relatively low-dose DOC chemotherapy had no deleterious effect on the CSS of CRPC patients, and a lower incidence of AEs occurred, in spite of a diminished PSA response compared with those receiving a higher dose.

Water-filled laparoendoscopic surgery (WaFLES) has been proposed as a novel surgical system achieving a wide surgical field in the intra- and extraperitoneal space with continuous irrigation of isotonic fluid into the field. Despite its technical feasibility and advantages, the safety of the technique, particularly with respect to physiological functions, has not been evaluated.Various types of minor abdominal surgeries were performed under general anesthesia in nine adult pigs either by conventional laparoscopy (n = 3) or WaFLES (n = 6). In addition to esophageal temperature and body weight, cardiorespiratory variables such as blood pressure, heart rate, and arterial blood gas parameters were compared before and after the surgeries. Blood samples were obtained for assessing changes in biochemical parameters before and after the surgeries.Three to seven hours of various surgeries were completed without critical cardiorespiratory events in all animals. Oxygenation and ventilation were maintained regardless of the techniques used for the surgeries. A minor increase of body weight (2.5% of initial body weight), metabolic acidosis, hyperkalemia, and impaired hepatic function were observed after WaFLES surgeries.The preliminary study indicated no serious immediate adverse effects of the WaFLES technique.

Prostate cancer (PCa) is one of the leading causes of cancer-related death in men. PCa is androgen-dependent, and androgen-deprivation therapy is effective for first-line hormonal treatment, but the androgen-independent phenotype of PCa eventually develops, which is difficult to treat and has no effective cure. Recently, microRNAs have been discovered to have important roles in the initiation and progression of PCa, suggesting their use in diagnosis, predicting prognosis and development of treatment for castration-resistant PCa (CRPC). Understanding the networks of microRNAs and their target genes is necessary to ascertain their roles and importance in the development and progression of PCa. This review summarizes the current knowledge about microRNAs regulating PCa progression and elucidates the mechanism of progression to CRPC.

microRNAs (miRNAs) have key roles in human tumorigenesis, tumor progression and metastasis. miRNAs are aberrantly expressed in many human cancers and can function as tumor suppressors or oncogenes that target many cancer-related genes. This study seeks to identify novel miRNA-regulated molecular pathways in prostate cancer (PCa). The miRNA expression signature in clinical specimens of PCa showed that 56 miRNAs were significantly downregulated in PCa compared with non-PCa tissues. We focused on the top four downregulated miRNAs (miR-187, miR-205, miR-222 and miR-31) to investigate their functional significance in PCa cells. Expression levels of these four miRNAs were validated in PCa specimens (15 PCa tissues and 17 non-PCa tissues) to confirm that they were significantly reduced in these PCa tissues. Gain-of-function analysis demonstrated that miR-222 and miR-31 inhibited cell proliferation, invasion and migration in PCa cell lines (PC3 and DU145), suggesting that miR-222 and miR-31 may act as tumor suppressors in PCa. Genome-wide gene expression analysis using miR-222 or miR-31 transfectants to identify the pathways they affect showed that many cancer-related genes are regulated by these miRNAs in PC3 cells. Identification and categorization of the molecular pathways regulated by tumor suppressive miRNAs could provide new information about the molecular mechanisms of PCa tumorigenesis.

Primary aldosteronism caused by aldosterone-producing adenoma is the most common curable cause of secondary hypertension, but despite resection, many patients continue to require antihypertensive medications to control their blood pressure postoperatively. The Aldosteronoma Resolution Score is a preoperative 4-item predictive model for the complete postoperative resolution of hypertension. Our aim was to validate the accuracy of this model in predicting postoperative resolution of hypertension in Japanese patients.The records of 91 Japanese patients who underwent unilateral adrenalectomy for aldosterone-producing adenoma were surveyed retrospectively. Patients were distributed into 2 groups according to whether blood pressure was normal without antihypertensive medications at 6 months postoperatively. Clinical and biochemical data were evaluated at baseline and after the 6-month follow-up.At 6 months, blood pressure had normalized in 45% of the patients without antihypertensive medications. Multivariate logistic regression analysis revealed that patients who had complete resolution of hypertension were significantly more likely to have been taking ≤2 antihypertensive medications preoperatively, have a duration of hypertension of6 years, and be female. The predictive accuracy of the Aldosteronoma Resolution Score was assessed using the area under the curve of receiver operator characteristics analysis. The value of the area under the curve was 0.81.Our external validation revealed that the Aldosteronoma Resolution Score developed using Western data can identify accurately Japanese individuals with aldosterone-producing adenoma who are likely to have complete resolution of hypertension after adrenalectomy.

Background: Our recent analyses of miRNA expression signatures showed that miR-1 and miR-133a were significantly reduced in several types of cancer. Interestingly, miR-1 and miR-133a are located on the same chromosomal locus in the human genome. We examined the functional significance of miR-1 and miR-133a in prostate cancer (PCa) cells and identified the novel molecular targets regulated by both miR-1 and miR-133a. Methods and Results: The expression levels of miR-1 and miR-133a were significantly downregulated in PCa compared with non-PCa tissues. Restoration of miR-1 or miR-133a in PC3 and DU145 cells revealed significant inhibition of proliferation, migration, and invasion. Molecular target identification by genome-wide gene expression analysis and luciferase reporter assay showed that purine nucleoside phosphorylase (PNP) was directly regulated by both miRNAs. Silencing of the PNP gene inhibited proliferation, migration, and invasion in both PC3 and DU145 cells. Immunohistochemistry detected positive staining of PNP in PCa specimens. Conclusions: Downregulation of miR-1 and miR-133a was a frequent event in PCa and both function as tumour suppressors. The PNP is a novel target gene of both miRNAs and potentially functions as an oncogene. Therefore, identification of novel molecular networks regulated by miRNAs may provide new insights into the underlying causes of PCa oncogenesis.

OBJECTIVES To explore the rate of upgrading in a contemporary cohort from 2 Japanese institutions, and evaluating the predictive accuracy of the nomogram when applied to patients, regardless of race. Previous reports have indicated that a maximum of 43% of men with prostate cancer will show an upgraded Gleason score from biopsy to radical prostatectomy (RP). A preparative nomogram was developed at the University of Hamburg to predict the probability of upgrading from biopsy to RP specimen. METHODS Clinical and pathologic data of 503 patients from 2 Japanese institutions were supplied for validation. Nomogram-predicted probabilities of upgrading from biopsy to RP specimen were compared with actual rate of upgrading. The area under the receiver operating characteristic curve (AUC) was calculated for all patients. Calibration of the nomogram was achieved by comparing the predicted upgrading rate with that of an ideal nomogram. RESULTS Gleason sum upgrading was recorded in 29.8% of patients at RP. Accuracy of the nomogram was 79.2% (confidence interval, 75.1%-83.2%). Overall AUC was 0.79 when applied to the validation dataset, with individual institutional AUCs ranging from 0.79-0.80. Nomogram predictions of upgrading were not within 10% of an ideal nomogram. CONCLUSIONS Gleason sum upgrading between biopsy and final pathology represents an important consideration in treatment decision-making, and nearly one third of patients with prostate cancer will be upgraded. The Hamburg nomogram seems to provide reasonably accurate predictions regardless of minor variations in pathologic assessment, but is not necessarily so accurate when applied to Japanese patient population.

Objective: At present, computed tomography (CT) is used in almost all patients with renal tumors. We aimed to investigate the relationship between visceral adipose tissue (VAT), as assessed by CT, and various other factors in patients with renal cell carcinoma (RCC). Methods: We undertook an examination of VAT in 117 male patients undergoing nephrectomy or partial nephrectomy at Chiba University Hospital using software designed to detect VAT in the horizontal plane of the body cavity. Pathological stage, microvascular invasion, tumor grade, performance status, C-reactive protein, BMI, hypertension, hyperlipemia, hyperglycemia, history of smoking and cause-specific survival rate were examined in relation to VAT, and multivariate Cox regression analysis was used to determine significant predictors of cause-specific survival. Results: VAT in patients with stage I disease was significantly greater than that in patients with more advanced disease (p = 0.0219). VAT in patients with microvascular invasion was significantly smaller than in those without microvascular invasion (p = 0.0260). Patients with high VAT had significantly higher cumulative cause-specific survival when compared to patients with low VAT (p = 0.0257). Conclusion: VAT was associated with better clinical features in patients with RCC. Further study is necessary in order to clarify the role of VAT in RCC.

The relationships between serum level of testosterone (T) and prostate cancer (PCa) are complex. The present study evaluated whether presence of PCa alters serum T levels. Subjects were 125 patients with clinically localized PCa treated using radical prostatectomy (RP), for whom pretreatment T levels were recorded. We investigated clinical and pathological factors such as pretreatment serum T level, age, pretreatment prostate-specific antigen, Gleason score and pathological stage. Serum T and human luteinizing hormone (LH) levels before and after RP were then compared in 118 of the 125 patients. Mean pretreatment T level was significantly higher in patients with organ-confined PCa (pT2; 4.03+/-1.50 ng ml(-1)) than in patients with nonorgan-confined cancer (pT3; 3.42+/-1.06 ng ml(-1); P=0.0438). No association existed between pretreatment serum T level and pathological Gleason score. After RP, serum T level (5.60+/-1.90 ng ml(-1)) was significantly elevated compared to preoperative level (3.89+/-1.43 ng ml(-1); P0.0001). In parallel, significant increases were seen in postoperative serum LH level (6.86+/-3.64 ng ml(-1)) compared to preoperative level (5.11+/-2.47 ng ml(-1); P=0.0001). In contrast, differences in serum T levels according to pathological stage disappeared postoperatively (P=0.5513). Significant increases in serum T and LH levels were seen after RP, compared to preoperative levels in parallel. This study suggests that serum T levels are altered by the presence of PCa, supporting the possibility that PCa may inhibit serum T levels with negative feedback in the hypothalamic-pituitary axis.

Objective The outcome of trial of voiding without catheter in patients treated combination therapy with dutasteride and alpha1-adrenergic receptor blocker for acute urinary retention caused by benign prostatic hyperplasia was not reported. We evaluated the clinical efficacy of combination therapy with dutasteride in patients with unsuccessful trial without catheter after treatment with an alpha1-adrenergic receptor blocker monotherapy for acute urinary retention caused by benign prostatic hyperplasia. Patients and methods Patients with acute urinary retention due to prostatic hyperplasia were catheterized and treated alpha1-adrenergic receptor blocker monotherapy. After two weeks later, patients were put on trial without catheter. 52 patients who were unsuccessful trial without catheter administered combination therapy with dutasteride and alpha1-adrenergic receptor blocker. We use criteria that voiding urine volume over 100 ml and post-void residual urine volume below 100 ml in deciding whether catheter should be removed. Results 33 (63.5%) men did not require re-catheterization within 7 months after combination therapy. The successful rate of Performance Status (PS) 0-1 group was significantly superior to that of PS 2-4 group. Conclusions PS 0-1 men catheterized for AUR can void more successfully after catheter removal than PS 2-4 men if treated with combination therapy.

Aim: The objective of the present study was to clarify the indications, usefulness and limitations of ureterorenoscopy. Material and methods: From January 1998 to June 2004, 72 consecutive patients (48 men and 24 women) with a mean age of 66 years (range, 27–83 years) underwent ureterorenoscopy to diagnose upper urinary tract tumors (UUT). Median follow-up was 24 months (range, 1–73 months). Patients were divided into four subgroups by voided urine cytology and preoperative radiographic findings. Group A (n = 11, 15.3%), positive voided urine cytology and positive preoperative radiographic findings; group B (n = 5, 6.9%), positive cytology and negative radiographic findings; group C (n = 48, 66.7%), negative cytology and positive radiographic findings and group D (n = 8, 11.1%), frank hematuria originating from the UUT but negative cytology and negative radiographic findings. We compared the findings of ureterorenoscopic examination and biopsy with the results of retrograde pyelography and cytology of upper tract urine. For each examination, the following diagnostic indices were assessed: sensitivity, specificity, positive-predictive-value (PPV) and negative-predictive-value (NPV) and accuracy. Statistical analysis was performed using McNemar’s test. Results: For ureterorenoscopy, sensitivity was 94%, specificity 59%, PPV 72%, NPV 92% and accuracy 76%. For biopsy, sensitivity was 77%, specificity 100%, PPV 100%, NPV 80% and accuracy 88%. Accuracy of ureterorenoscopy tended to be superior to that of retrograde pyelography. Ureterorenoscopy was most useful in the group which consisted of 48 patients (66.7%) with negative voided urine cytology and positive preoperative radiographic findings. This group was the only group in which accuracy of ureterorenoscopic biopsy was superior to that of urine cytology, significantly (P = 0.03). Conclusion: Results indicated that ureterorenoscopy is most suitable and gives superior accuracy in patients with positive radiographic findings and negative voiding cytology. Ureterorenoscopic biopsy of the upper urinary tract would provide useful information when considering therapeutic strategies, such as nephron-sparing management.

A 62-year-old man was admitted to our hospital complaining of lower abdominal mass and weight loss. Computed tomography and magnetic resonance imaging studies revealed a large tumor occupying the pelvis and expanding into inferior vena cava, which reached to the renal pedicle. Open biopsy was undergone under general anesthesia. Histopathological diagnosis was inflammatory fibrosarcoma. Five courses of chemotherapy including vincristine, actinomycin-D and cyclophosphamide (VAC) resulted in 35% reduction of the tumor volume in one direction, indicating that VAC could be an alternative effective therapy for inoperable inflammatory fibrosarcoma.

Objective: Laparoscopic surgery for primary aldosteronoma and Cushing's syndrome is well established. We report on our experiences with laparoscopic adrenalectomy for pheochromocytoma, and assess the efficacy and safety of the laparoscopic approach. Methods: Between April 1998 and April 2003, a total of 23 patients underwent laparoscopic adrenalectomy for pheochromocytoma at Chiba University Hospital and Yokohama Rosai Hospital, Japan. We compared the surgical outcomes of these patients with those of 106 patients with adrenal tumors due to other pathologies who underwent laparoscopic adrenalectomy during the same period. Results: The mean tumor size of pheochromocytoma was 4.96 cm. Mean operative time was 192.7 min, and mean estimated blood loss was 130 mL. Neither mean operative time nor mean estimated blood loss was greater for patients with pheochromocytoma. Intraoperative hypertension (systolic blood pressure > 180 mmHg) occurred in 39.1% (9/23) of patients with pheochromocytoma. During the follow-up period, there were no mortalities or recurrences of endocrinopathy. Conclusions: Laparoscopic adrenalectomy for pheochromocytoma is a safe and minimally invasive procedure.

Transurethral surgery is widely accepted as standard therapy for male urethral obstruction. The present study was undertaken to identify and select lesions to be managed by processing endoscopic images of the urethra for assisting less invasive therapy in patients with voiding dysfunction.Cystourethroscopic video files of 25 patients with lower urinary tract symptoms were recorded before and after administration of alpha-1 adrenoceptor antagonists. Each video frame was restored and tagged with information indicating the position in the panoramic image of the urethra. A three-dimensional virtual urethra was created to indicate critical lesions for voiding dysfunction, together with fluid dynamics simulation of urine flow.The urine stream was depicted in the virtual urethras in 19 patients. Before therapy, 17 patients showed vortex formation that was diminished after therapy in nine patients with a significant relationship in improvement of relative energy loss of flow (p=0.025). The narrowing points proximal to the vortex, candidate of lesions, were identified in the panoramic image and linked to the endoscopic image.Therapeutic designing for endoscopic management was possible in patients with voiding dysfunction based on computational fluid dynamics, and would be promising as "focal" therapy for aging males.

Our recent studies of the microRNA (miRNA) expression signature in prostate cancer (PCa) indicated that miRNA-218 (miR-218) was significantly downregulated in clinical specimens, suggesting that miR-218 might act as a tumor-suppressive miRNA in PCa. The aim of the present study was to investigate the functional significance of miR-218 in PCa and to identify novel miR-218-regulated cancer pathways and target genes involved in PCa oncogenesis and metastasis. Restoration of miR-218 in PCa cell lines (PC3 and DU145) revealed that this miRNA significantly inhibited cancer cell migration and invasion. Gene expression data and in silico analysis demonstrated that LIM and SH3 protein 1 (LASP1) is a potential target of miR-218 regulation. LASP1 is a cytoskeletal scaffold protein that plays critical roles in cytoskeletal organization and cell migration. Luciferase reporter assays showed that miR-218 directly regulated expression of LASP1. Moreover, downregulating the LASP1 gene significantly inhibited cell migration and invasion in cancer cells, and the expression of LASP1 was upregulated in cancer tissues. We conclude that loss of tumor-suppressive miR-218 enhanced cancer cell migration and invasion in PCa through direct regulation of LASP1. Our data on pathways regulated by tumor-suppressive miR-218 provide new insight into the potential mechanisms of PCa oncogenesis and metastasis.

Our recent study of microRNA (miRNA) expression signature of prostate cancer (PCa) has revealed that the microRNA-143/145 (miR-143/145) cluster is significantly downregulated in cancer tissues, suggesting that these cluster miRNAs are candidate tumor suppressors. The aim of this study was to investigate the functional significance of the miR-143/145 cluster in PCa cells and to identify novel targets regulated by these cluster miRNAs in PCa. Restoration of miR-143 or miR-145 in PCa cell lines (PC3 and DU145) revealed that these miRNAs significantly inhibited cancer cell migration and invasion. Gene expression data and in silico analysis demonstrated that Golgi membrane protein 1 (GOLM1) resembling a type II golgi transmembrane protein was a potential target of miR-143/145 cluster target gene. Gene expression studies and luciferase reporter assays showed that GOLM1 was directly regulated by the miR-143/145 cluster. Silencing of GOLM1 resulted in significant inhibition of cell migration and invasion in PCa cells. Furthermore, the expression of GOLM1 was upregulated in cancer tissues by immunohistochemistry. Loss of the tumor-suppressive miR-143/145 cluster enhanced cancer cell migration and invasion in PCa through directly regulating GOLM1. Our data on target genes regulated by the tumor-suppressive miR-143/145 cluster provide new insights into the potential mechanisms of PCa oncogenesis and metastasis.

To investigate the hypothesis that 5-alpha-reductase inhibitors exert early ameliorative effects on voiding and storage symptoms in men with lower urinary tract symptom-associated benign prostatic hyperplasia.This was a prospective study involving the participation of eight outpatient clinics in Chiba Prefecture, Japan. The patients received dutasteride (0.5 mg) once daily orally for 24 weeks as an add-on to their ongoing therapy with an alpha-1 blocker. The study patients recorded their urinary symptoms every day for 14 days after starting dutasteride. The International Prostate Symptom Score, prostate volume, uroflowmetry results, and residual urine volume were checked at 3 and 6 months after starting dutasteride.A total of eighty-eight patients participated in the present study; 74 were eligible for analysis of the early effects of dutasteride. The median age was 69.6 years (range 54-89), the median prostate volume was 50.3 mL (range 24.7-103.3) and the median International Prostate Symptom Score was 17.6 (range 8-35). The proportion of patients with International Prostate Symptom Score improvements (≥3 points, or ≥25%) or 3 points or more decreased International Prostate Symptom Score were defined effective, 37 (50.0%) and 47 (63.5%) experienced improvement at 1 month after administration, respectively.This is the first prospective clinical study to show the early beneficial effects of 5-alpha-reductase inhibitors for lower urinary tract symptom-associated benign prostatic hyperplasia. Patients with severe symptoms were found to be responsive to dutasteride. The influence of the placebo effect was not denied. Further study is necessary.

Background: Although the percentage of patients with renal cell carcinoma (RCC) extending into venous systems is unexpectedly high, the prognostic impact and independency of venous tumor thrombus-related factors on overall survival (OS) remain controversial. Furthermore, the prognostic impact of various clinicopathologic factors including tumor thrombus-related factors on OS may change with elapsed years after the intervention and also with follow-up duration of participants. The aim of the study is to explore independent and universal predictive preoperative and intraoperative clinicopathologic factors on OS in patients with RCC extending into venous systems using subgroup analysis in terms of restricted follow-up duration and yearly-based survivors.Methods: Between 1980 and 2009, 292 patients diagnosed with RCC with venous tumor thrombus were retrospectively registered for this study. The prognostic impacts of various clinicopathologic and surgical treatment factors including levels of venous thrombus, venous wall invasion status and likelihood of aggressive cytoreductive operation, were investigated using Kaplan-Meier method and following multivariate Cox proportional hazards model for all patients and those still alive at 1, 2, and 3 years of follow-up. To investigate the impact of follow-up duration on the statistical analyses, multivariate logistic regression analyses were used to explore prognostic factors using restricted data until 1, 2, and 3 years of follow-up.Results: The median follow-up duration was 40.4 months. The 5-year OS was 47.6%. Several independent predictive factors were identified in each subgroup analysis in terms of yearly-based survival and restricted follow-up duration. The presence of tumor thrombus invading to venous wall was independently related to OS in the full-range follow-up data and in survivors at 2 and 3 years of follow-up. Using restricted follow-up data until 1, 2, and 3 years of follow-up, many independent predictive factors changed with follow-up duration, but surgical category could be universal and independent predictive factors.Conclusion: The most universal factors affecting improvement both in short-term and long-term survivals could be cytoreductive surgery and absence of venous wall invasion. It may mean that feasible aggressive cytoreductive operation following more reliable preoperative imaging for predicting venous wall invasion status would improve OS for patients with RCC extending into venous systems., BMC Cancer, 13(1), 447; 2013

Correct interpretation of renal function in patients with primary aldosteronism is difficult before adrenalectomy, because subtle kidney impairment is often masked by glomerular hyperfiltration peculiar to primary aldosteronism. The aim of this study was to investigate postoperative changes in renal function for patients with primary aldosteronism and to identify clinical predictors of chronic kidney disease manifested postoperatively in the patients without pre-existing chronic kidney disease.Records of 78 Japanese patients who underwent unilateral adrenalectomy for primary aldosteronism were retrospectively surveyed. Patients who had been followed up for6 months were excluded. Preoperative and postoperative estimated glomerular filtration rate were compared. Furthermore, uni- and multivariate analyses were carried out to identify clinical predictors for chronic kidney disease manifested postoperatively.Patients with preoperative estimated glomerular filtration rate ≥60 mL/min/1.73 m(2) showed a significant decrease after surgery. Of the 66 patients without pre-existing chronic kidney disease, 24 developed chronic kidney disease postoperatively. Multivariate logistic regression analysis identified a medical history of dyslipidemia as an independent predictor for chronic kidney disease manifested postoperatively. According to univariate analyses, additional factors associated with postoperative manifestation of chronic kidney disease included older age, lower diastolic blood pressure and lower estimated glomerular filtration rate.The interpretation of normal or abnormal renal functions by examining estimated glomerular filtration rate heightened by hyperfiltration alone can mislead clinicians before adrenalectomy. Clinicians should pay attention to patients at greater risk of a significant decline in postoperative renal function.

To examine the efficacy of an alpha-1 blocker and its correlation to structural alteration of the prostatic urethra and the loss of energy in the urine flow using a virtual urethra processed from an endoscopic video image.Video images of the prostatic urethra were recorded during cystourethroscopy in 11 patients with benign prostatic hyperplasia (BPH) before and after treatment with an alpha-1 blocker, naftopidil. The three-dimensional (3D) structure of the prostatic urethra was reproduced from video files. Fluid dynamic analysis and hydraulic energy calculations were performed using the "virtual" 3D urethral images.In 9 of 11 patients studied, an 11% improvement in the loss of energy (range, 1%-82%) was seen. Alpha-1 blocker treatment mediated the disappearance or decrease of the bulky vortex formation in seven patients, which led to an improved urinary stream. A positive correlation was found between improved energy loss and residual urine volume (P=0.0312).Alpha-1 blocker therapy led to a decreased energy loss in the urine flow in the prostatic urethra in relation to the improvement of clinical symptoms. The cystourethroscopy could be a tool to assess the urethral resistance in patients with BPH using image processing methodology.

MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression, primarily at the post-transcriptional level. Growing evidence suggests that miRNAs function as oncogenes or tumor suppressors in human cancers. The down-regulation of miR-145 has been reported in many types of human cancer, including prostate cancer (PC), suggesting that miR-145 functions as a tumor suppressor. Using the PC cell lines, PC3 and DU145, gain-of-function assays revealed that miR-145 transfection inhibited cell proliferation, migration and invasion. Fascin homolog 1 (FSCN1), an actin-bundling protein, is a candidate target gene of miR-145 based on genome-wide gene expression analysis. A luciferase reporter assay showed a significantly decreased signal at two miR-145 target sites at the 3'UTR of FSCN1, suggesting that miR-145 directly regulates FSCN1. In FSCN1 loss-of-function assays, cell growth, migration and invasion were all inhibited, implying that FSCN1 is associated with the progression of PC. The identification of tumor suppressive miRNAs and their target genes could provide new insights into the potential mechanisms of prostate carcinogenesis.

The objective of the present study was to document the treatment efficacy and safety of sorafenib in Japanese patients with advanced renal cell carcinoma (RCC). A retrospective analysis of 50 consecutive patients with metastatic RCC between January 2005 and December 2009 was carried out. Patients received sorafenib after failed cytokine therapy or first-line sorafenib treatment. All received 400 mg of sorafenib orally twice daily. Five of 14 patients with bone metastases were also given bisphosphonates. Tumor response was evaluated every 1-2 months according to the Response Evaluation Criteria in Solid Tumors. Adverse events (AE) were evaluated at each visit during and after treatment, and were recorded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events version 3.0. Dose modification of sorafenib was permitted if grade 3 or 4 AE occurred. Treatment continued until disease progression or treatment intolerance occurred. Partial response, and stable disease as best objective responses were observed in 11 (22%) and 23 (46%) patients, respectively. Median progression-free survival was 7.3 months and median overall survival was 11.9 months. All patients experienced AE and one or more grade 3/4 AE occurred in 43 of 50 (86%) patients. Although it requires close monitoring, sorafenib treatment seemed to be effective in the present study population.

To investigate the benefit of alpha1-adrenoceptor antagonist naftopidil on the quality of life (QOL) of patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia (BPH/LUTS).A total of 99 men with BPH/LUTS were prospectively recruited. The Short Form-8 (SF-8) was used for generic QOL assessment and each parameter was compared with the norm in these patients. Longitudinal changes were evaluated using the SF-8 and the International Prostatic Symptoms Score (I-PSS) at baseline, 4 and 8 weeks after naftopidil administration. The relationship between SF-8 and I-PSS was analyzed.Five of eight components in the SF-8 were significantly lower than the Japanese national norm at baseline. SF-8 score was improved by naftopidil at 4 and 8 weeks in general health (GH) and physical component summary (PCS) in the patients in their 70s. Mental health (MH) and mental component summary (MCS) were improved at 8 weeks in patients in their 60s. When analyzing the whole cohort, SF-8 GH, role emotional (RE) and MH had improved at 8 weeks, which was similar to the norm, and bodily pain (BP) results were better. Compared with the baseline, total I-PSS, storage/voiding symptoms and QOL index scores improved significantly under naftopidil. Each component of I-PSS (except for hesitancy) correlated with SF-8 sub-scales (except for BP) to some extent.BPH/LUTS impairs generic QOL, which is improved by naftopidil treatment. SF-8 can be a useful instrument to assess the efficacy of BPH/LUTS treatment because its simplicity to complete and analyze, and its meaningful relationship to I-PSS.