CHARGE syndrome with both primary and secondary hypogonadism.

Introduction: CHARGE syndrome is a rare disorder that causes congenital abnormalities in multiple organs, including secondary hypogonadism. We report, herein, a unique case of CHARGE syndrome with both primary and secondary hypogonadism and discuss the possible causes and pathogenesis in this patient. Case presentation: A 15-year-old boy with delayed secondary sexual characteristics and non-palpable testes was referred to our hospital. Physical examination and detection of a chromodomain-helicase-deoxyribonucleic acid-binding protein 7 gene mutation confirmed CHARGE syndrome. Hormone stimulation tests suggested both primary and secondary hypogonadism. Laparoscopic bilateral orchiectomy was performed because of decreased testosterone production and atrophy in both testes. Pathological examination of the testes revealed maturation arrest, germ cell neoplasm in situ, and decreased expression of steroid synthase. Conclusion: This appears to be the first report of CHARGE syndrome with both primary and secondary hypogonadism demonstrated in endocrinological and histological examinations.

Evaluation of testicular stiffness in boys with unilateral cryptorchidism after orchiopexy by ultrasound strain elastography.

PURPOSE: We assessed the stiffness of unilateral undescended testes after orchiopexy, examining its value in tracking histopathological changes and fertility potential during postoperative follow-up. Additionally, we explored the optimal timing for surgery based on testicular stiffness. PATIENTS AND METHODS: Thirty-six boys who had been diagnosed with unilateral undescended testis and treated with orchiopexy were included in the study. Testicular stiffness was evaluated several times over respective follow-up periods by ultrasound strain elastography after orchiopexy. The strain ratios were measured as the ratios of the elasticities of the descended testis to those of the operated testes. The patients were divided into two groups based on the age at which they underwent orchiopexy:under < 2 years (Group A) and ≥ 2 years (Group B). RESULTS: The mean strain ratios were 0.90 ± 0.32 and 0.92 ± 0.20 in Groups A and B, respectively. In Group A, the strain ratio was constant regardless of postoperative months (r = 0.01, p = 0.99); however, in Group B, it tended to increase with postoperative months (r = 0.42, p = 0.07). CONCLUSIONS: Evaluation of testicular stiffness may be useful for the estimation of histopathological changes and fertility potential in boys with unilateral undescended testes at follow-up appointments after orchiopexy. Our data indicate that performing orchiopexy as early as possible may be recommended to avoid testicular damage.

The activated complement pathway in the fibrous process of benign prostatic hyperplasia.

BACKGROUND: To elucidate the changes in activated complement pathway in the fibrous process of benign prostatic hyperplasia (BPH), we analyzed the correlation between complement component expression and histological types of fibrosis using human BPH tissue. METHODS: Fifty-six histological BPH patients who underwent prostate needle biopsy at our institution (mean age 68.6 ± 6.5 years), divided into two histological groups, fibromuscular and fibrous, were compared. Inflammatory cell infiltration in BPH tissue was evaluated by immunohistochemical staining using CD45, with complement expression analysis performed using C3, factor B, and C5b-9 antibody, and the occupancy ratio of the stained region was calculated. Further, correlation between the histological types of fibrous components in BPH tissue and lower urinary tract symptoms questionnaires was analyzed. RESULTS: Twenty-seven (48.2%) and 29 (51.8%) cases were classified in the fibromuscular and fibrous groups, respectively. The proportion of CD45-positive cells in BPH tissue was significantly higher in the fibromuscular group. In complement component analysis, factor B did not significantly differ between groups, while C3 (fibromuscular group; 10.7 ± 8.2%, fibrous group; 16.4 ± 12.7%) and C5b-9 (fibromuscular group; 15.9 ± 6.2%, fibrous group; 17.6 ± 9.2%) were significantly higher in the fibrous group (p = 0.04, p = 0.04, respectively). International Prostate Symptom Score Q5 subscore, indicating slow stream, was significantly higher in the fibrous group (p = 0.04). CONCLUSIONS: In fibrous BPH with abundant fibrosis, the late complement pathway in addition to alternative pathway was activated compared to fibromuscular BPH. These results suggested that the alternative and late complement pathways were involved in the histological fibrous process of BPH.

Unilateral adrenalectomy for a drug-resistant bilateral primary aldosteronism with heart failure: pathophysiology and surgical indication.

BACKGROUND: Patients with bilateral primary aldosteronism (PA) generally are treated with antihypertensive drugs, but optimal treatment for patients with complications due to refractory hypertension has not been established. In this report, we present a case with bilateral PA who presented with persistent hypertension, despite treatment with 6 drugs, and left-dominant heart failure, which was improved after unilateral adrenalectomy. CASE PRESENTATION: A 61-year-old man was admitted to our hospital because of severe left-dominant heart failure. His heart rhythm was atrial fibrillation and the left ventricle was diffusely hypertrophic and hypokinetic. Coronary arteries were normal on coronary arteriogram. Primary aldosteronism was suspected based on severe hypokalemia (2.5 mEq/L) and plasma aldosterone concentration (PAC; 1,410 pg/mL). Although computed tomography (CT) showed a single left cortical nodule, adrenal vein sampling (AVS) indicated bilateral PA. Early in the case, heart failure and hyperkalemia in this patient were improved by treatment with a combination of 6 antihypertensive drugs (spironolactone 25 mg/day, eplerenone 100 mg/day, azosemide 60 mg/day, tolvaptan 7.5 mg/day, enalapril 5 mg/day, and bisoprolol fumarate 10 mg/day); however, heart failure relapsed after four months of treatment. We hypothesized that hypertension caused by excess aldosterone was inducing the patient's heart failure. In order to reduce aldosterone secretory tissue, a laparoscopic adrenalectomy was performed for the left adrenal gland, given the higher level of aldosterone from the left gland compared to the right. Following surgery, the patient's heart failure was successfully controlled despite the persistence of high PAC. Treatment with anti-hypertensive medications was reduced to two drugs (eplerenone 100 mg/day and bisoprolol fumarate 10 mg/day). In order to elucidate the mechanism of drug resistance, immunohistochemistry (IHC) and real time-polymerase chain reaction (RT-PCR) assays were performed to assess the expression of steroidogenic factor 1 (SF-1), a regulator of steroid synthesis in adrenal tissue. IHC and RT-PCR demonstrated that the expression of SF-1 in this patient (at both the protein and mRNA levels) was higher than that observed in unilateral PA cases that showed good responsivity to drug treatment. CONCLUSIONS: Unilateral adrenalectomy to reduce aldosterone secretory tissue may be useful for patients with drug-refractory, bilateral PA. Elevated expression of SF-1 may be involved in drug resistance in PA.

PSMA Targeted Molecular Imaging and Radioligand Therapy for Prostate Cancer: Optimal Patient and Treatment Issues.

Theranostics (therapy + diagnosis) targeting prostate-specific membrane antigen (PSMA) is an emerging therapeutic modality that could alter treatment strategies for prostate cancer. Although PSMA-targeted radioligand therapy (PSMA-RLT) has a highly therapeutic effect on PSMA-positive tumor tissue, the efficacy of PSMA-RLT depends on PSMA expression. Moreover, predictors of treatment response other than PSMA expression are under investigation. Therefore, the optimal patient population for PSMA-RLT remains unclear. This review provides an overview of the current status of theranostics for prostate cancer, focusing on PSMA ligands. In addition, we summarize various findings regarding the efficacy and problems of PSMA-RLT and discuss the optimal patient for PSMA-RLT.

Involvement of Mast-Cell-Tryptase- and Protease-Activated Receptor 2-Mediated Signaling and Urothelial Barrier Dysfunction with Reduced Uroplakin II Expression in Bladder Hyperactivity Induced by Chronic Bladder Ischemia in the Rat.

We aimed to investigate the relationship between mast cell (MC) infiltration into the bladder with urothelial barrier dysfunction and bladder hyperactivity in a chronic bladder ischemia (CBI) rat model. We compared CBI rats (CBI group; n = 10) with normal rats (control group; n = 10). We measured the expression of mast cell tryptase (MCT) and protease-activated receptor 2 (PAR2), which are correlated with C fiber activation via MCT, and Uroplakins (UP Ia, Ib, II and III), which are critical to urothelial barrier function, via Western blotting. The effects of FSLLRY-NH2, a PAR2 antagonist, administered intravenously, on the bladder function of CBI rats were evaluated with a cystometrogram. In the CBI group, the MC number in the bladder was significantly greater (p = 0.03), and the expression of MCT (p = 0.02) and PAR2 (p = 0.02) was significantly increased compared to that of the control group. The 10 µg/kg FSLLRY-NH2 injection significantly increased the micturition interval of CBI rats (p = 0.03). The percentage of UP-II-positive cells on the urothelium with immunohistochemical staining was significantly lower in the CBI group than in the control group (p < 0.01). Chronic ischemia induces urothelial barrier dysfunction via impairing UP II, consequently inducing MC infiltration into the bladder wall and increased PAR2 expression. PAR2 activation by MCT may contribute to bladder hyperactivity.

Concurrent Reduced Expression of Contiguous PKD1, TSC2 and NTHL1 Leading to Kidney Diseases and Multiple Diverse Renal Cancers.

BACKGROUND/AIM: Several cases of concurrent reduction of expression of polycystin 1 (PKD1) and Tuberous Sclerosis Complex 2 (TSC2) that are contiguous in chromosome 16p13 have been previously reported. This study newly addresses the concurrent reduction of expression of PKD1, TSC2 and NTHL1, which is adjacent to TSC2 and is a tumor suppressor gene. MATERIALS AND METHODS: We investigated the mRNA expression levels of PKD1, TSC2, PKD2, TSC1 and NTHL1 in blood and renal cell carcinoma (RCC) tissues in a proband with autosomal dominant polycystic kidney disease (ADPKD), tuberous sclerosis complex (TSC) and multiple pathologically diverse RCCs, including clear cell, papillary and chromophobe types. Additionally, we investigated germline variants in blood using whole exome sequencing (WES) in the proband and her four siblings. RESULTS: mRNA expression levels of PKD1, TSC2 and NTHL1 were reduced in the proband's blood and RCCs, compared with control groups. WES identified one novel variant with amino acid changes in the PKD1 exon in the three subjects with ADPKD, including the proband. Moreover, two variants in the TSC2 intron specific to the proband were also identified. CONCLUSION: In this study, we report a novel pathogenic variant in the PKD1 exon which likely led to ADPKD, and two variants in the TSC2 intron, which might have led to reduction in the expression of both TSC2 and NTHL1, consequently leading to TSC and multiple pathologically diverse RCCs.

Impacts of Neoadjuvant Hormonal Therapy Prior to Robot-Assisted Radical Prostatectomy on Postoperative Hormonal- and Sexual-Related Quality of Life - Assessment by Patient-Reported Questionnaire.

PURPOSE: Neoadjuvant hormonal therapy (HT) before radical prostatectomy (RP) is not recommended by current guidelines in terms of oncological outcomes. Despite this, neoadjuvant HT is sometimes conducted before RP for a small proportion of patients in clinical practice. This study evaluated the impacts of neoadjuvant HT on hormonal- and sexual-related quality of life (QOL) among patients who underwent robot-assisted RP (RARP). MATERIALS AND METHODS: Participants comprised 470 patients divided into a non-neoadjuvant HT group (n = 408) and a neoadjuvant HT group (n = 62). Hormonal- and sexual-related QOL were measured using the Expanded Prostate Cancer Index Composite (EPIC) questionnaire. RESULTS: Hormonal summary scores at 6 and 9 months, function scores before and 3, 6, and 9 months and bother score at 6 months after RARP were significantly lower in the neoadjuvant HT group than in the non-neoadjuvant HT group. Sexual function scores were decreased in the neoadjuvant HT group compared to the non-neoadjuvant HT group before and 6 months after RARP. In the neoadjuvant HT group, sexual function at 3 months after RARP was significantly worse in patients with >5 months of neoadjuvant HT than in patients with ≤5 months of neoadjuvant HT. Conversely, sexual bother at 3 months after RARP was significantly worse in patients with ≤5 months of neoadjuvant HT than in patients with >5 months of neoadjuvant HT. CONCLUSION: Vintage neoadjuvant HT prior to RARP should not be recommended due to not only oncological outcomes, but also the impacts on postoperative hormonal- and sexual-related QOL.

Usefulness of the mayo adhesive probability score as a predictive factor for renal function deterioration after partial nephrectomy: a retrospective case-control study.

PURPOSE: Whether the Mayo adhesive probability score, an index of the perinephric fat environment, could be a predictive factor for renal function deterioration after partial nephrectomy was investigated. METHODS: A retrospective case-control study of 78 patients who underwent laparoscopic partial nephrectomy was performed. An estimated glomerular filtration rate preservation rate at ≤ 90% at 3 months after surgery was defined as postoperative renal function deterioration. These patients were divided into two groups (non-deterioration and deterioration groups). Patient factors including Mayo adhesive probability scores (both tumor and unaffected sides) and surgical factors were evaluated to identify the predictors for postoperative renal function deterioration. The statistical analysis used univariate and multivariate logistic regression analyses. RESULTS: Thirty-seven (47.4%) patients had postoperative renal function deterioration after partial nephrectomy. Univariate analysis identified Mayo adhesive probability score on the unaffected side (p = 0.02), and warm ischemia time (p < 0.01) as predictors of postoperative renal function deterioration. On multivariate analyses, Mayo adhesive probability score on the unaffected side (odds ratio: 1.38 [1.05-1.79], p = 0.02) and warm ischemia time (odds ratio: 1.04 [1.01-1.07], p < 0.01) were significantly associated with postoperative renal function deterioration as same as univariate analysis. On receive operating characteristic curve analysis, Mayo adhesive probability score on the unaffected side (cutoff value 1.5; p = 0.02) and warm ischemia time (cutoff value 26.5 min; p = 0.01) were significant predictors of renal function deterioration 3 month after surgery. CONCLUSION: The Mayo adhesive probability score on the unaffected side and warm ischemia time are useful predictors for renal function deterioration after partial nephrectomy. TRIAL REGISTRATION NUMBER: 2019-249, January 21st, 2019, retrospectively registered.

Prevalence and predictors of postoperative detrusor underactivity after robot-assisted radical prostatectomy: A prospective observational study.

OBJECTIVES: To identify the prevalence and predictors of postoperative detrusor underactivity during the early postoperative period after robot-assisted radical prostatectomy. METHODS: We carried out a prospective observational study of 64 patients scheduled for robot-assisted radical prostatectomy using urodynamic study before and 1 month after robot-assisted radical prostatectomy. Detrusor underactivity was defined as maximum flow rate ≤15 mL/s and detrusor pressure at maximum flow rate ≤25 cmH2 O during voiding. Incidences of pre- and postoperative detrusor underactivity were assessed, and predictors of postoperative detrusor underactivity were determined using uni- and multivariate logistic regression analyses. Factors comprised patient characteristics (age, prostate weight etc.), operative factors (surgical duration, nerve sparing etc.) and preoperative urodynamic study parameters (maximum flow rate, bladder contractile index etc.). RESULTS: Pre- and postoperative detrusor underactivity at 1 month after robot-assisted radical prostatectomy were detected in one patient (1.6%) and 24 patients (37.5%), respectively. Univariate analysis selected preoperative maximum flow rate (P = 0.02), detrusor pressure at maximum flow rate (P = 0.04) and bladder contractile index (P < 0.01) as predictors of postoperative detrusor underactivity (odds ratio 0.83, 0.97 and 0.94, respectively). On multivariate analyses, only preoperative bladder contractile index was associated with postoperative detrusor underactivity (P < 0.01; odds ratio 0.94). A cut-off of 102.8 offered optimal accuracy in receiver operating characteristic analysis. Patient characteristics and operative factors were not significantly associated with postoperative detrusor underactivity. CONCLUSIONS: A comparatively high prevalence of postoperative detrusor underactivity is observed in patients at 1 month after robot-assisted radical prostatectomy. Patients with preoperative low bladder contractile index have a higher probability of developing early postoperative detrusor underactivity after robot-assisted radical prostatectomy.

Spindle cell renal cell carcinoma diagnosed after sunitinib treatment for chromophobe renal cell carcinoma.

INTRODUCTION: Chromophobe renal cell carcinoma presents in early pathological stages with a lower risk of metastasis. However, aggressive features and metastasis can occur. A rare case of rapidly progressive disease with histological changes is presented. CASE PRESENTATION: A 56-year-old woman had a right renal tumor with multiple lymph node metastases, and the pathological diagnosis of the biopsy specimens from the primary tumor was chromophobe renal cell carcinoma. After sunitinib treatment, the metastatic lymph node had decreased in size and the numbers of circulating tumor cells were decreased, consequently, cytoreductive nephrectomy was performed. However, rapid progression of lymph node metastases was observed. Histopathological examination showed that the renal tumor was diagnosed as spindle cell renal carcinoma. CONCLUSION: It appears that the primary tumor underwent epithelial-mesenchymal transition; further tissue specimen collection and analysis might be needed.

Morphological change and characteristics of myofibroblasts during the growth process of benign prostatic hyperplasia.

OBJECTIVES: To clarify the morphological change and characteristics of myofibroblast during the growth process of benign prostatic hyperplasia. METHODS: This study examined the characteristics of myofibroblasts during the growth process of the prostate in the stromal component-dominant benign prostatic hyperplasia rat model. Transforming growth factor-ß1 and insulin-like growth factor-binding protein 3 expression were evaluated by western blotting (n = 6). We used double immunohistochemical staining to evaluate the number of myofibroblasts positive for α-smooth muscle actin and vimentin in benign prostatic hyperplasia tissues. Expression and histological analyses of the benign prostatic hyperplasia were also carried out in rats at 2, 3 and 8 weeks after urogenital sinus implantation (n = 6). To evaluate the fine morphological characteristics of myofibroblasts in human benign prostatic hyperplasia tissues, electron microscopy analysis was additionally carried out. RESULTS: There was a significant upregulation of the transforming growth factor-ß1 and insulin-like growth factor-binding protein 3 expression in benign prostatic hyperplasia (P < 0.05). There was a significant increase in the number of myofibroblasts in benign prostatic hyperplasia (P < 0.05) compared with normal prostate, with these abundantly located in the stromal area. The transforming growth factor-ß1 and insulin-like growth factor-binding protein 3 expression and number of myofibroblasts showed a time-dependent increase (P < 0.05), with growth factor expressions preceding the myofibroblast increase. Electron microscopy confirmed that the myofibroblast progenitor cells, which possess abundant stress fibers, were predominantly located around fibrous areas in human benign prostatic hyperplasia. CONCLUSIONS: Differentiation into myofibroblasts induced by transforming growth factor-ß1 and insulin-like growth factor-binding protein 3 actively occurs during the growth process of benign prostatic hyperplasia. Myofibroblast progenitor cells seem to be associated with prostatic fibrosis in human benign prostatic hyperplasia.

Transient renal dysfunction due to rhabdomyolysis after robot-assisted radical prostatectomy.

PURPOSE: The aim of the present study was to investigate whether renal dysfunction following rhabdomyolysis occurs after robot-assisted radical prostatectomy (RARP), and to investigate the factors related to rhabdomyolysis after RARP. METHODS: A total of 180 consecutive patients who underwent RARP at our institution were investigated. Rhabdomyolysis was defined as creatine kinase (CK) > 1050 IU/L after RARP. The association between CK and renal function after RARP was investigated, and the factors related to rhabdomyolysis after RARP were also investigated. RESULTS: Postoperative CK (407 ± 936 IU/L) was significantly higher than preoperative CK (134 ± 75 IU/L) (p < 0.001), and eGFR after RARP was significantly negatively correlated with CK on the day after RARP (correlation coefficient (ρ) = - 0.248, p = 0.007), but the significant negative correlation disappeared on the 7th day after RARP (ρ = - 0.010, p = 0.32). On multivariate analysis, postoperative CK elevation was significantly correlated with console time (p = 0.002). Rhabdomyolysis was observed in 6.1% (11/180), and of the patients with rhabdomyolysis, acute renal failure was transiently observed in 45.5% (5/11). On multivariate analysis, rhabdomyolysis was significantly associated with higher body mass index (BMI) (> 25.7 kg/m2) and longer console time (> 188 min) (p = 0.02 and p = 0.005, respectively). CONCLUSION: Temporary renal dysfunction can occur after RARP due to CK elevation. Thus, sufficient attention must be paid to renal insufficiency after elevation of CK values for several days after RARP. Because rhabdomyolysis after RARP was associated with both obesity and long console time, console time during RARP should be shortened, especially in patients with obesity.

Perioperative Detection of Circulating Tumor Cells in Radical or Partial Nephrectomy for Renal Cell Carcinoma.

BACKGROUND: The current study was conducted to clarify the frequency of systemic circulating tumor cells (CTCs) appearing after surgery for renal cell carcinoma and to evaluate the differences in postoperative CTCs between different surgical procedures. METHODS: This prospective, cohort study included 60 consecutive patients who underwent laparoscopic radical nephrectomy (RN) (n = 22), laparoscopic partial nephrectomy (PN) (n = 19), open RN (n = 8), or open PN (n = 11). In this study CTCs were measured by the FISHMAN-R system, and CTCs drawn from a peripheral artery were collected just before and immediately after surgery. The number of pre- and postoperative CTCs and the perioperative changes in CTCs were measured for each surgical method. RESULTS: Six patients were excluded from the current analyses. Preoperative CTCs did not differ significantly by surgical approach (laparoscopic RN: 3.4 ± 4.2; laparoscopic PN: 3.4 ± 4.1; open RN: 7.7 ± 6.8; open PN: 6.0 ± 7.6; P = 0.19). Open RN resulted in a significantly greater number of postoperative CTCs (laparoscopic RN: 4.8 ± 3.7; laparoscopic PN: 7.9 ± 9.1; open RN: 22.5 ± 26.3; open PN: 6.4 ± 6.3; P < 0.001) and perioperative changes in CTCs (laparoscopic RN: 1.3 ± 5.3; laparoscopic PN: 4.5 ± 9.6; open RN: 14.7 ± 25.0; open PN: 0.4 ± 6.3; P < 0.001). No significant differences in these were observed among the three groups except in the open RN group. In the multivariate analysis, the surgical approach was significantly correlated with the number of postoperative CTCs (P = 0.016) and the perioperative change in CTCs (P = 0.01). CONCLUSIONS: This proof-of-concept study indicated that after surgery, more cancer cells can be expelled into the bloodstream, especially after open RN. Sufficient and careful follow-up assessment for the emergence of distant metastases is needed for patients undergoing open RN.

The preoperative pad test as a predictor of urinary incontinence and quality of life after robot-assisted radical prostatectomy: a prospective, observational, clinical study.

PURPOSE: To assess whether the preoperative 1-h pad test could predict postoperative urinary incontinence and quality of life after robot-assisted radical prostatectomy. METHODS: A total of 329 patients who underwent robot-assisted radical prostatectomy between 2013 and 2016 were prospectively enrolled in this study. These patients were divided into the preoperative urinary continence group and the preoperative urinary incontinence group according to the 1-h pad test. The time to achieve urinary continence, lower urinary tract function evaluated by uroflowmetry and post-voided residual urine volume, and quality of life evaluated by King's Health Questionnaire and International Consultation on Incontinence Questionnaire-Short Form were compared between these two groups. RESULTS: There were 190 patients (58%) in the preoperative urinary continence group (1-h pad test ≤ 2 g) and 139 patients (42%) in the preoperative urinary incontinence group (1-h pad test > 2 g). In the preoperative urinary continence/incontinence groups, 83%/76% of patients achieved continence within 12 months, respectively, and urinary incontinence remained significantly longer in the preoperative incontinence group than in the preoperative continence group (P = 0.042). Although there were no significant differences in all quality of life items between the two groups before surgery, several items were significantly higher in the preoperative urinary continence group. CONCLUSION: Achievement of urinary continence and improvement of urinary quality of life are delayed in patients with preoperative urinary incontinence assessed by the 1-h pad test. The preoperative 1-h pad test could be a useful predictor of prolonged urinary incontinence and poor quality of life after robot-assisted radical prostatectomy.

Usefulness of a novel classification based on perioperative changes of membranous urethral length using hierarchical cluster analysis of urinary incontinence and overactive bladder symptoms after robot-assisted radical prostatectomy: A prospective observational study.

AIMS: The aim of the present study was to construct a novel classification based on perioperative changes of membranous urethral length (MUL) using hierarchical cluster analysis to predict urinary incontinence (UI) and overactive bladder (OAB) symptoms after robot-assisted radical prostatectomy (RARP). METHODS: A total of 299 patients who underwent RARP with complete pre and postoperative MUL data were included in the present study. Hierarchical cluster analysis was performed to identify the groups with similar perioperative MUL and prostate size. UI and OAB symptoms after RARP were evaluated in each cluster for 12 months after RARP. RESULTS: Four groups were identified by the cluster analysis of these factors: preservation of MUL type (cluster 1, n = 92); standard type (cluster 2, n = 137); large prostate type (cluster 3, n = 23); and loss of MUL type (cluster 4, n = 47). Although there was significantly more UI in clusters 3 and 4 than in clusters 1 and 2 up to 3 months after RARP, UI improvement was the most delayed in cluster 3. Improvement of OAB symptoms was also most delayed in cluster 3. Urinary quality of life (QOL) was significantly worse in cluster 4 than in clusters 1 and 2. CONCLUSIONS: Cluster analysis successfully classified patients after RARP into four characteristic groups based on perioperative MUL. Recovery from UI and OAB symptoms and urinary QOL after RARP were significantly different among these groups. This classification based on cluster analysis might be useful to predict recovery from UI and OAB symptoms when following QOL after RARP.

The association between local arteriosclerosis of the prostatic arteries and chronic inflammation in human benign prostatic enlargement.

BACKGROUND: To elucidate the pathogenesis of benign prostatic enlargement (BPE) in humans due to chronic inflammation caused by arteriosclerosis, the relationships between prostate size and the degree of chronic inflammation induced by local arteriosclerosis were investigated. METHODS: The present cohort included 50 subjects who underwent robot-assisted radical prostatectomy (RARP) in a prospective study. The presence or absence of local arteriosclerosis in the prostatic arteries removed during RARP was evaluated by microscopic assessment. Chronic inflammation in the prostate was judged according to both the density and the extent of inflammatory cells. The expression of lectin-like oxidized-low density lipoprotein receptor-1 (LOX-1) and the infiltration of macrophages in the prostate, which are high in arteriosclerosis, were investigated by immunohistochemistry. RESULTS: Local arteriosclerosis was observed in 28% (14/50). Prostate size and the inflammation score were significantly increased in the presence of arteriosclerosis (P = 0.006, P < 0.001, respectively). There was also a significant increase of LOX-1 in the epithelial and stromal cells of the prostate in the presence of arteriosclerosis (all, P < 0.001). Concerning the presence of macrophages, subjects with arteriosclerosis had significantly more positive expression of ionized calcium-binding adapter molecule-1 (IBA-1), a marker of macrophages, than subjects without arteriosclerosis (P < 0.001). CONCLUSIONS: In human surgical specimens, chronic inflammation owing to local arteriosclerosis of the prostatic arteries was significantly related to prostatic enlargement. Given the immunohistochemical analyses, the putative pathogenesis for this relationship is that LOX-1 induces macrophage infiltration, leading to BPE.

Delayed diagnosis of intraperitoneal bladder perforation after blunt trauma.

INTRODUCTION: Intraperitoneal urinary bladder perforation due to blunt trauma in intoxicated patients requires quick and accurate diagnosis. However, this is difficult to correctly diagnose in intoxicated patients because their symptoms can be masked. We describe a rare case of intraperitoneal urinary bladder perforation that occurred after blunt trauma. CASE PRESENTATION: A 66-year-old intoxicated man stumbled, tripped on a stone step and landed on his lower abdomen, but felt no pain at the time. Two days later, he was diagnosed with intraperitoneal urinary bladder perforation, which was repaired by open surgery. CONCLUSION: Urinary bladder perforation should be considered when patients present with abdominal pain and decrease in urine volume following trauma.

Interleukin-6 induces drug resistance in renal cell carcinoma.

Metastatic renal cell carcinoma (mRCC) is a tumor entity with poor prognosis due to limited therapy options. Tyrosine kinase inhibitors (TKIs), the novel targeted agents have been used for the treatment of mRCC and have shown efficacy. Interferon (IFN)-α is also one of the most frequently used agents in immunotherapy. However, drug resistance needs to be overcome to achieve a sufficiently positive effect. Interleukin-6 (IL-6), which induce suppressor of cytokine signaling-3 (SOCS3) expression, is one of the factors associated with poor prognosis of patients with renal cell carcinoma (RCC). To analyze the influence of IL-6 in drug resistance of RCC, anti-IL-6 receptor antibody was used in combination with IFN or TKIs. The SOCS3 mRNA expression level was significantly increased by IFN-α stimulation in 786-O RCC cells which were resistant to IFN, but not in ACHN cells that were sensitive to IFN. The overexpression of SOCS3 by gene transfection in ACHN significantly inhibited the growth-inhibitory effect of IFN-α. An in vivo study demonstrated that co-administration of SOCS3-targeted siRNA promoted INF-α-induced cell death and growth suppression in 786-O cell xenograft. SOCS3 could be a key component in the resistance to interferon treatment of renal cell carcinoma. Because SOCS3 is rapidly up-regulated by IL-6 and a negative regulator of cytokine signaling, IL-6 expression on RCC cells was also analyzed and the 786-O cells showed the high level of IL-6 mRNA expression under the condition of interferon stimulation. IL-6R antibody, tocilizumab, significantly suppressed cell proliferation in 786-O cells by interferon stimulation accompanied with phosphorylation of STAT1 and inhibited SOCS3 expression. The in vivo effects of combination therapy with tocilizumab and interferon showed significant suppression of 786-O tumor growth in a xenograft model. We also hypothesized that TKI resistance and IL-6 secretion are causally connected. And we found that 786-O RCC cells secrete high IL-6 levels after low dose stimulation with the TKIs sorafenib, sunitinib and pazopanib, inducing activation of AKT-mTOR pathway, NFκB, HIF-2α and VEGF expression. Tocilizumab neutralizes the AKT-mTOR pathway activation and results in reduced proliferation. A combination therapy with tocilizumab and TKI suppresses 786-O tumor growth and inhibits angiogenesis in vivo more efficient than TKI alone. Our findings suggest that IL-6 could induce drug resistance on RCC, and combination therapy of IL-6R inhibitors and IFN/TKIs may represent a novel therapeutic approach for RCC treatment.

Suppression of SOCS3 enhances TRAIL-induced cell growth inhibition through the upregulation of DR4 expression in renal cell carcinoma cells.

BACKGROUND: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a tumor-selective apoptosis inducer that is expressed in natural killer cells, whose cytotoxicity is activated by interferon (IFN). We investigated the effect of suppressor of cytokine signaling (SOCS) 3 on the expression of TRAIL receptors (DR4) and on TRAIL sensitivity in renal cell carcinoma (RCC) cells. METHODS: Vector expression, RNA interference and IL-6 receptor antibody tocilizumab were used to investigate the functional role of SOCS3 in DR4 expression. Immunoprecipitation was employed to detect the biochemical interaction between SOCS3 and DR4. The expression of DR4 induced by combination with IFN-α and tocilizumab was also examined by immunohistochemical staining using mice xenograft model. RESULTS: DR4 expression was up-regulated by IFN stimulation in RCC cells. 786-O cells were resistant to TRAIL and showed higher SOCS3 expression. ACHN cells showed higher DR4 expression and lower SOCS3 expression. Suppression of SOCS3 up-regulated DR4 expression and enhanced the TRAIL sensitivity in 786-O cells. In ACHN cells, DR4 expression was down-regulated by transfection with pCI-SOCS3, and the cells became resistant to TRAIL. Immunoprecipitation revealed the biochemical interaction between SOCS3 and DR4. A marked increase in IFN-induced DR4 protein expression after tocilizumab treatment was observed by immunohistochemical staining in the tumor from the mice xenograft model. CONCLUSIONS: Our results indicate that IFN and SOCS3 regulate DR4 expression in RCC cells. Combination therapy with IFN-α, tocilizumab and an anti-DR4 agonistic ligand appears to effectively inhibit advanced RCC cell growth.