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.

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.

The current status of prostate cancer treatment and PSMA theranostics.

In the treatment of cancer, understanding the disease status, or accurate staging, is extremely important, and various imaging techniques are used. Computed tomography (CT), magnetic resonance imaging, and scintigrams are commonly used for solid tumors, and advances in these technologies have improved the accuracy of diagnosis. In the clinical practice of prostate cancer, CT and bone scans have been considered especially important for detecting metastases. Nowadays, CT and bone scans are called conventional methods because positron emission tomography (PET), especially prostate-specific membrane antigen (PSMA)/PET, is extremely sensitive in detecting metastases. Advances in functional imaging, such as PET, are advancing the diagnosis of cancer by allowing information to be added to the morphological diagnosis. Furthermore, PSMA is known to be upregulated depending on the malignancy of the prostate cancer grade and resistance to therapy. Therefore, it is often highly expressed in castration-resistant prostate cancer (CRPC) with poor prognosis, and its therapeutic application has been attempted for around two decades. PSMA theranostics refers to a type of cancer treatment that combines both diagnosis and therapy using a PSMA. The theranostic approach uses a radioactive substance attached to a molecule that targets PSMA protein on cancer cells. This molecule is injected into the patient's bloodstream and can be used for both imaging the cancer cells with a PET scan (PSMA PET imaging) and delivering radiation directly to the cancer cells (PSMA-targeted radioligand therapy), with the aim of minimizing damage to healthy tissue. Recently, in an international phase III trial, the impact of 177Lu-PSMA-617 therapy was studied in patients with advanced PSMA-positive metastatic CRPC who had previously been treated with specific inhibitors and regimens. The trial revealed that 177Lu-PSMA-617 significantly extended both progression-free survival and overall survival compared to standard care alone. Although there was a higher incidence of grade 3 or above adverse events with 177Lu-PSMA-617, it did not negatively impact the patients' quality of life. PSMA theranostics is currently being studied and used primarily for the treatment of prostate cancer, but it has the potential to be applied to other types of cancers as well.

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.

Insights into the development of a new index, vesical adaptation response to diuresis, for understanding lower urinary tract dysfunction.

OBJECTIVES: To clarify how vesical adaptation response, the homeostatic system that constantly changes voided volume to adapt to diuresis, is involved in male lower urinary tract symptoms and bladder storage function. METHODS: We included male patients older than 65 years with lower urinary tract symptoms. Vesical adaptation response to diuresis was defined as a positive correlation between urine output rate and voided volume on 3-day sensory-related frequency volume charts. Patients were divided into two groups according to the presence or absence of vesical adaptation response to diuresis, and characteristics were compared between groups. RESULTS: Ninety-four male patients were finally analyzed. Vesical adaptation response to diuresis was found in 48 patients (51%) and was lacking in 46 patients (49%). Patients without vesical adaptation response to diuresis were significantly more often diagnosed with overactive bladder (P = 0.04). After adjusting for confounders, absence of vesical adaptation response to diuresis was significantly associated with overactive bladder (adjusted odds ratio 3.76, 95% confidence interval 1.34-10.55; P = 0.01) and benign prostatic enlargement (adjusted odds ratio 1.04, 95% confidence interval 1.01-1.07; P = 0.02). CONCLUSIONS: The absence of vesical adaptation response to diuresis, characterized by decreased voided volume during a diuretic phase, can be interpreted as a form of bladder storage dysfunction. Assessment of vesical adaptation response to diuresis may provide a new index of bladder storage function and contribute to a better understanding of the pathophysiology underlying bladder storage dysfunction in patients with lower urinary tract symptoms.

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.

Upregulation of glucocorticoid receptor-mediated glucose transporter 4 in enzalutamide-resistant prostate cancer.

Enzalutamide (Enz) is a second-generation androgen receptor (AR) antagonist for castration-resistant prostate cancer (CRPC) therapy, and it prolongs survival time in these patients. However, during Enz treatment, CRPC patients usually acquire resistance to Enz and often show cross-resistance to other AR signaling inhibitors. Although glucocorticoid receptor (GR) is involved in this resistance, the role of GR has not yet been clarified. Here, we report that chronic Enz treatment induced GR-mediated glucose transporter 4 (GLUT4) upregulation, and that upregulation was associated with resistance to Enz and other AR signaling inhibitors. Additionally, inhibition of GLUT4 suppressed cell proliferation in Enz-resistant prostate cancer cells, which recovered from Enz resistance and cross-resistance without changes in GR expression. Thus, a combination of Enz and a GLUT4 inhibitor could be useful in Enz-resistant CRPC patients.

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.

Comprehensive approach for post-prostatectomy incontinence in the era of robot-assisted radical prostatectomy.

Robot-assisted radical prostatectomy (RARP) has enabled steady and stable surgical procedures due to both meticulous maneuvers and magnified, clear, 3-dimensional vision. Therefore, better surgical outcomes have been expected with RARP than with other surgical modalities. However, even in the RARP era, post-prostatectomy incontinence has a relatively high incidence as a bothersome complication. To overcome post-prostatectomy incontinence, it goes without saying that meticulous surgical procedures and creative surgical procedures, i.e., "Preservation", "Reconstruction", and "Reinforcement" of the anatomical structures of the pelvis, are most important. In addition, medication and appropriate pad usage might sometimes be helpful for patients with post-prostatectomy incontinence. However, patients who have 1) BMI > 26 kg/m2, 2) prostate volume > 70 mL, 3) eGFR < 60 mL/min, or a 4) Charlson comorbidity index > 2 have a tendency to develop post-prostatectomy incontinence despite undergoing the same surgical procedures. It is important for patients who have a high risk for post-prostatectomy incontinence to be given information about delayed recovery of post-prostatectomy incontinence. Thus, not only the surgical procedures, but also a comprehensive approach, as mentioned above, are important for post-prostatectomy incontinence.