CD271 promotes proliferation and migration in bladder cancer.

Bladder cancer is a urothelial cancer and effective therapeutic strategies for its advanced stages are limited. Here, we report that CD271, a neurotrophin receptor, promotes the proliferation and migration of bladder cancer cells. CD271 knockdown decreased proliferation in both adherent and spheroid cultures, and vice versa when CD271 was overexpressed in bladder cancer cell lines. CD271 depletion impaired tumorigenicity in vivo. Migration activity was reduced by CD271 knockdown and TAT-Pep5, a known CD271-Rho GDI-binding inhibitor. Apoptosis was induced by CD271 knockdown. Comprehensive gene expression analysis revealed alterations in E2F- and Myc-related pathways upon CD271 expression. In clinical cases, patients with high CD271 expression showed significantly shortened overall survival. In surgically resected specimens, pERK, a known player in proliferation signaling, colocalizes with CD271. These data indicate that CD271 is involved in bladder cancer malignancy by promoting cell proliferation and migration, resulting in poor prognosis.

Preoperative prognostic model for localized and locally advanced renal cell carcinoma: Michinoku Japan Urological Cancer Study Group.

BACKGROUND: The Modified International Metastatic Renal Cell Carcinoma Dataset Consortium model (mIMDC) is a preoperative prognostic model for pT3cN0M0 renal cell carcinoma (RCC). This study aimed to validate the mIMDC and to construct a new model in a localized and locally advanced RCC (LLRCC). METHODS: A database was established (the Michinoku Japan Urological Cancer Study Group database) consisting of 79 patients who were clinically diagnosed with LLRCC (cT3b/c/4NanyM0) and underwent radical nephrectomy from December 2007 to May 2018. Using univariable and multivariable analyses, we retrospectively analyzed disease-free survival (DFS) and overall survival (OS) in this database, constructed a new prognostic model according to these results, and estimated the model fit using c-index on the new and mIMDC models. RESULTS: Independent poorer prognostic factors for both DFS and OS include the following: ≥ 1 Eastern Cooperative Oncology Group performance status, 2.0 mg/dL C-reactive protein, and > upper normal limit of white blood cell count. The median DFS in the favorable (no factor), intermediate (one factor), and poor-risk group (two or three factors) was 76.1, 14.3, and 4.0 months, respectively (P < 0.001). The 3-year OS in the favorable, intermediate, and poor-risk group were 92%, 44%, and 0%, respectively (P < 0.001). The c-indices of the new and mIMDC models were 0.67 and 0.60 for DFS (P = 0.060) and 0.74 and 0.63 for OS (P = 0.012), respectively. CONCLUSION: The new preoperative prognostic model in LLRCC can be used in patient care and clinical trials.

Prognosis of Japanese metastatic renal cell carcinoma patients in the targeted therapy era.

BACKGROUND: The aims of this study were to investigate prognosis and validate prognostic models [Memorial Sloan-Kettering Cancer Center (MSKCC), International Metastatic Renal Cell Carcinoma Data Consortium (IMDC), and Japanese metastatic renal cancer (JMRC) models] in the targeted therapy era in Japanese patients with metastatic renal cell carcinoma. METHODS: We retrospectively analyzed 692 patients who were diagnosed with mRCC from January 2008 to August 2018 in the Michinoku Japan Urological Cancer Study Group database. Nivolumab as sequential therapy was widely used. Other immune checkpoint inhibitors were excluded from this study. RESULTS: The median overall survival (95% confident interval) in all, MSKCC favorable, intermediate, and poor risk patients was 41.0 months (33.9-46.8), not reached (63.5 to not estimable), 46.8 months (37.1-52.9), and 10.4 months (8.9-14.4), respectively. The median overall survival (95% confident interval) in IMDC favorable, intermediate, and poor risk patients was not reached (61.6 to not estimable), 47.4 months (41.4-56.5), and 11.5 (9.9-16.3), respectively. The c-index of the MSKCC, IMDC, and JMRC models calculated at mRCC diagnosis was 0.680, 0.689, and 0.700, respectively. No statistical differences were found in the c-index among the models. CONCLUSION: While the real-world overall survival in Japanese patients with mRCC in the targeted therapy era improved compared to that previously reported in the cytokine era, there was no clear difference in the survival of poor risk patients between these eras. There were no differences in the superiority among the models.

Importance of Therapeutic Drug Monitoring to Detect Drug Interaction between Pazopanib and Warfarin: A Case Report.

Pazopanib is an orally available multi-tyrosine kinase inhibitor and has been used to treat renal cell carcinoma (RCC). Here, we report the case of a patient with RCC with an increased prothrombin time- international normalized ratio (PT-INR) due to pazopanib therapy. In addition, we have reported the change in the blood levels of pazopanib. A 75-year-old man underwent a left nephrectomy for RCC. Four years later, his cancer recurred and pazopanib therapy was initiated. He was also taking warfarin for atrial fibrillation and his PT-INR was constant at approximately 2. His warfarin dose was reduced from 3.5 mg/day to 3.0 mg/day on day 10 because his PT-INR increased from 2.19 to 3.07 compared to that before starting pazopanib. On day 28, his PT-INR further increased to 4.34, and his aspartate aminotransferase, alanine transaminase, and alkaline phosphatase levels increased. The target concentration of pazopanib was 20.5 to 50.3 µg/mL, but his blood concentrations were 92.1 µg/mL on day 6 and 93.7 µg/mL on day 13. Therefore, both pazopanib and warfarin were discontinued. One week later, his laboratory tests recovered, and hence, warfarin treatment was resumed. However, pazopanib therapy was terminated due to concerns about liver dysfunction. His hepatic dysfunction and increased PT-INR were considered to be due to pazopanib treatment. Pazopanib has been reported to have no effect on the pharmacokinetics of warfarin in clinical patients. In this case, blood levels of pazopanib were abnormally high, possibly causing liver dysfunction and drug interactions, leading to his PT-INR prolongation. TDM monitoring, in addition to the recommended monitoring for pazopanib hepatotoxicity, may help identify patients at risk for drug interactions. For patients receiving concomitant pazopanib and warfarin, close monitoring of PT-INR is warranted.

Clinical predictors of the estimated glomerular filtration rate 1 year after radical nephrectomy in Japanese patients.

PURPOSE: To evaluate renal function 1 year after radical nephrectomy (RN) for renal cell carcinoma, the preoperative predictors of postnephrectomy renal function were investigated by sex, and equations to predict the estimated glomerular filtration rate (eGFR) 1 year after RN were developed. MATERIALS AND METHODS: A total of 525 patients who underwent RN between May 2007 and August 2011 at Tohoku University Hospital and its affiliated hospitals were prospectively evaluated. Overall, 422 patients were analyzed in this study. RESULTS: Independent preoperative factors associated with postnephrectomy renal function were different in males and females. Preoperative eGFR, age, tumor size, and body mass index (BMI) were independent factors in males, while tumor size and BMI were not independent factors in females. The equations developed to predict eGFR 1 year after RN were: Predicted eGFR in males (mL/min/1.73 m2)=27.99-(0.196×age)+(0.497×eGFR)+(0.744×tumor size)-(0.339×BMI); and predicted eGFR in females=44.57-(0.275×age)+(0.298×eGFR). The equations were validated in the validation dataset (R2=0.63, p<0.0001 and R2=0.31, p<0.0001, respectively). CONCLUSIONS: The developed equations by sex enable better prediction of eGFR 1 year after RN. The equations will be useful for preoperative patient counseling and selection of the type of surgical procedure in elective partial or RN cases.

Phosphodiesterase type 5 inhibitor administered immediately after radical prostatectomy temporarily increases the need for incontinence pads, but improves final continence status.

PURPOSE: To evaluate the effects of phosphodiesterase type 5 inhibitor (PDE5i) on urinary continence recovery after bilateral nerve-sparing radical prostatectomy (BNSRP). MATERIALS AND METHODS: Between 2002 and 2012, 137 of 154 consecutive patients who underwent BNSRP in our institution retrospectively divided into 3 groups that included patients taking PDE5i immediately after surgery (immediate PDE5i group, n=41), patients starting PDE5i at an outpatient clinic after discharge (PDE5i group, n=56), and patients taking no medication (non-PDE5i group, n=40). Using self-administered questionnaires, the proportion of patients who did not require incontinence pads (pad-free patients) was calculated preoperatively and at 1, 3, 6, 12, 18, and 24 months after BNSRP. Severity of incontinence was determined based on the pad numbers and then compared among the 3 groups. RESULTS: Proportions of pad-free patients and severity of incontinence initially deteriorated in all of the groups to the lowest values soon after undergoing BNSRP, with gradual improvement noted thereafter. The deterioration was most prominent in the immediate PDE5i group. As compared to the non-PDE5i group, both the PDE5i and immediate PDE5i groups exhibited a better final continence status. CONCLUSIONS: PDE5i improves final continence status. However, administration of PDE5i immediately after surgery causes a distinct temporary deterioration in urinary incontinence.

Impact of Tissue Sealing Sheet on Erectile Dysfunction in a Rat Model of Nerve-Sparing Radical Prostatectomy.

INTRODUCTION: The tissue sealing sheet has recently been used to prevent intraoperative bleeding from the neurovascular bundles in radical prostatectomy. Surgical stress or inflammatory changes likely play a role in erectile dysfunction after cavernous nerve injury. However, the efficacy of a tissue sealing sheet for preventing erectile function after nerve-sparing radical prostatectomy remains unclear. AIM: To evaluate the effect of a tissue sealing sheet on erectile dysfunction after cavernous nerve dissection. METHODS: Male Sprague-Dawley rats were randomly divided into three groups and subjected to sham operation or bilateral cavernous nerve dissection with (sheet group) or without (non-sheet group) a tissue sealing sheet. In the sheet group, cavernous nerves were sealed with a tissue sealing sheet immediately after cavernous nerve dissection. MAIN OUTCOME MEASURES: Erectile function was assessed by measuring intracavernous pressure and arterial pressure during pelvic nerve electrostimulation at 4 weeks after surgery. Expressions of interleukin-6, tumor growth factor-ß1, and heme-oxygenase-1 in the major pelvic ganglion were examined by real-time polymerase chain reaction. RESULTS: Mean intracavernous pressure along with mean arterial pressure in the sheet group were similar to those in the sham group and showed a significant positive response compared with the non-sheet group (P < .05). Furthermore, expressions of interleukin-6, tumor growth factor-ß1, and heme-oxygenase-1 were significantly lower in the sheet group than in the non-sheet group (P < .05). CONCLUSION: Use of a tissue sealing sheet attenuated postoperative inflammatory changes and oxidative stress and improved erectile function after cavernous nerve injury in rats. The tissue sealing sheet might become a useful therapeutic approach to preserve erectile function after nerve-sparing radical prostatectomy.

Urinary straining contributes to inguinal hernia after radical retropubic prostatectomy.

OBJECTIVES: To verify whether abdominal pressure during urination represents an important factor in the postoperative development of inguinal hernia after radical retropubic prostatectomy. METHODS: Participants comprised 228 patients who underwent radical retropubic prostatectomy without prophylaxis for inguinal herniation between 2002 and 2007. Development of inguinal hernia was assessed from clinical records. Straining was rated on a six-point scale (straining score) according to frequency of straining using answers to question 6 of the International Prostate Symptom Score questionnaire preoperatively, and at 1, 3, 6, 12, 18, 24 and 36 months after prostatectomy. Straining scores were compared between patients with and without postoperative inguinal hernia. Multivariate analysis was carried out to identify parameters associated with inguinal hernia development after prostatectomy. Associations between inguinal hernia development and frequency of postoperative urinary straining were also estimated. RESULTS: Straining score in both groups was significantly increased at 1 month after radical retropubic prostatectomy. This increase was significantly greater in the postoperative inguinal hernia group (P < 0.05). Throughout the observation period, postoperative straining scores were higher in the group with postoperative inguinal hernia than in the group without. On multivariate analysis, postoperative urinary straining and previous hernia repair represented significant risk factors for postoperative inguinal hernia. The proportion of patients without inguinal hernia decreased significantly with increasing frequency of postoperative urinary straining. CONCLUSION: Urinary straining is associated with inguinal hernia development after radical retropubic prostatectomy.

Serum luteinizing hormone concentration is significantly associated with recovery of urinary function after radical prostatectomy.

OBJECTIVE: To perform a longitudinal investigation of the correlation between functional recovery and sex hormone concentrations after radical prostatectomy (RP). PATIENTS AND METHODS: A total of 72 consecutive patients undergoing RP between January 2012 and June 2013 were prospectively included and serially followed after surgery for comparative analysis. Their luteinizing hormone (LH) and total testosterone (TT) concentrations were measured before surgery and 3 and 12 months after surgery. They also filled out a health-related quality of life questionnaire before and at 1, 3, 6 and 12 months after surgery. RESULTS: The mean LH concentration increased from 4.28 U/L at baseline to 5.53 U/L at 3 months and remained high at 12 months after RP (both P < 0.001). There were no significant changes in the TT concentration after RP. LH at baseline was negatively correlated with the urinary function (UF) score at 3 and 12 months after RP (P = 0.030 and 0.032, respectively). After RP, subjects with high baseline LH (n = 37) were more likely than those with low LH concentrations to report lower UF scores (P = 0.014). Multivariate analysis of variance in an interaction of time × LH concentration for UF scores indicated a significant relationship between changes in UF score and LH concentration (P = 0.004). CONCLUSIONS: Radical prostatectomy affects sex hormones by increasing LH concentrations, while TT concentrations remain stable after surgery. Baseline LH concentrations are significantly associated with the recovery of urinary outcomes after RP.

[Total penectomy for corpus cavernosum abscess: a case report].

Abscess of corpus cavernosum penis is a rare infection condition. A 69-year-old-man was referred toour hospital with gradual development of penis swelling. T2-weighted magnetic resonance imaging of the pelvis showed abscess formation in the corpus cavernosum. There was no apparent cause of his penile abscess from either history or clinical examination. Open drainage improved his clinical symptoms transiently. However, severe penile pain relapsed, and abscess progressively extended in the corpus cavernosum and spongiosum, necessitating total penectomy. The surgical specimen revealed intensive inflammation and his condition improved immediately after penectomy.

Intravesical seeding of upper urinary tract urothelial carcinoma cells during nephroureterectomy: an exploratory analysis from the THPMG trial.

OBJECTIVE: The Pirarubicin Monotherapy Study Group trial was a randomized Phase II study that evaluated the efficacy of intravesical instillation of pirarubicin in the prevention of bladder recurrence after nephroureterectomy for upper urinary tract urothelial carcinoma. This study conducted further analysis of the Pirarubicin Monotherapy Study Group cohort, focusing on intravesical seeding of cancer cells. METHODS: Using the data from the Pirarubicin Monotherapy Study Group trial, bladder recurrence-free survival rates and factors associated with bladder recurrence in the control group were analyzed. RESULTS: Of 36 patients in the control group, 14 with positive urine cytology had more frequent recurrence when compared with the 22 patients with negative cytology (P = 0.004). Based on the multivariate analysis in the control group, voided urine cytology was an independent predictive factor of bladder recurrence (hazard ratio, 5.54; 95% confidence interval 1.12-27.5; P = 0.036). Of 72 patients in the Pirarubicin Monotherapy Study Group trial, 31 had positive urine cytology. Among the 31 patients, 17 patients who received pirarubicin instillation had fewer recurrences when compared with 14 patients who received control treatment (P = 0.0001). On multivariate analysis, pirarubicin instillation was an independent predictor of better recurrence-free survival rates in the patients with positive urine cytology (hazard ratio, 0.02; 95% confidence interval, 0.00-0.53; P = 0.018). Of 21 patients with bladder recurrence, 17 had recurrent tumor around cystotomy or in the bladder neck compromised by the urethral catheter, supporting the notion that tumor cells seeded in the injured urothelium. CONCLUSIONS: Intravesical instillation of pirarubicin immediately after nephroureterectomy significantly reduced the bladder recurrence rate in patients with positive voided urine cytology. The results suggest that intravesical seeding of upper urinary tract urothelial carcinoma occurs during nephroureterectomy.

Prospective randomized phase II trial of a single early intravesical instillation of pirarubicin (THP) in the prevention of bladder recurrence after nephroureterectomy for upper urinary tract urothelial carcinoma: the THP Monotherapy Study Group Trial.

PURPOSE: We evaluated the efficacy of a single early intravesical instillation of pirarubicin (THP) in the prevention of bladder recurrence after nephroureterectomy for upper urinary tract urothelial carcinoma (UUT-UC). PATIENTS AND METHODS: From December 2005 to November 2008, 77 patients clinically diagnosed with UUT-UC from 11 institutions participating in the Tohoku Urological Evidence-Based Medicine Study Group were preoperatively enrolled in this study. Patients were randomly assigned to receive or not receive a single instillation of THP (30 mg in 30 mL of saline) into the bladder within 48 hours after nephroureterectomy. Cystoscopy and urinary cytology were repeated every 3 months for 2 years or until the occurrence of first bladder recurrence. RESULTS: Seventy-two patients were evaluable for efficacy analysis, 21 of whom had a subsequent bladder recurrence. Significantly fewer patients who received THP had a recurrence compared with the control group (16.9% at 1 year and 16.9% at 2 years in the THP group v 31.8% at 1 year and 42.2% at 2 years in the control group; log-rank P = .025). No remarkable adverse events were observed in the THP-treated group. Based on multivariate analysis, THP instillation (hazard rate [HR], 0.26; 95% CI, 0.07 to 0.91; P = .035) and open surgery (HR, 0.28; 95% CI, 0.09 to 0.84; P = .024) were independently predictive of a reduced incidence of bladder recurrence. CONCLUSION: In this prospective randomized phase II study, a single intravesical instillation of THP seemed to reduce bladder recurrence after nephroureterectomy. A phase III, large-scale, multicenter study is needed to confirm these observations.

[A case report of sarcomatoid carcinoma of the urinary bladder].

A 49-year-old female visited to our department with complaints of gross hematuria and micturition pain. Cystoscopic examination revealed a 5-cm diameter solid broad-based tumor located at the front wall of the bladder. Histologically, the tumor was composed of grade 2 urothelial carcinoma (UC) element and sarcomatous spindle cell element. Immunohistochemical examination demonstrated that both UC and spindle cells were positive for cytokeratin. In addition, spindle cells did not stain for S-100 protein or smooth muscle actin. We diagnosed the tumor as sarcomatoid carcinoma and performed total cystectomy and ileal conduit without chemotherapy and radiation. The patient has remained without any evidence of recurrence for 14 months after operation. Sarcomatoid carcinoma of the bladder has aggressive malignant potential and poor prognosis. An appropriate adjuvant therapy for sarcomatoid carcinoma with metastasis has not been established. Total cystectomy is recommended as soon as possible after pathological diagnosis in the same manner as conventional high grade UC.

Molecular characterization of human and rat organic anion transporter OATP-D.

We have isolated and characterized a novel human and rat organic anion transporter subtype, OATP-D. The isolated cDNA from human brain encodes a polypeptide of 710 amino acids (Mr 76,534) with 12 predicted transmembrane domains. The rat clone encodes 710 amino acids (Mr 76,821) with 97.6% amino acid sequence homology with human OATP-D. Human and rat OATP-D have moderate amino acid sequence homology with LST-l/rlst-1, the rat oatp family, the prostaglandin transporter, and moatl/MOAT1/KIAA0880/OATP-B. Phylogenetic tree analysis revealed that OATP-D is branched in a different position from all known organic anion transporters. OATP-D transports prostaglandin E1 (Km 48.5 nM), prostaglandin E2 (Km 55.5 nM), and prostaglandin F2,, suggesting that, functionally, OATP-D encodes a protein that has similar characteristics to those of the prostaglandin transporter. Rat OATP-D also transports prostaglandins. The expression pattern of OATP-D mRNA was abundant mainly in the heart, testis, brain, and some cancer cells. Immunohistochemical analysis further revealed that rat OATP-D is widely expressed in the vascular, renal, and reproductive system at the protein level. These results suggest that OATP-D plays an important role in translocating prostaglandins in specialized tissues and cells.

Determination of the target ventricular rate in patients with atrial fibrillation by evaluation of ventriculoarterial coupling.

In a pilot study, we determined the target ventricular rate of patients with atrial fibrillation by evaluating their ventriculoarterial coupling. Eleven patients with atrial fibrillation were studied. We recorded M-mode echocardiograms and radial artery blood pressure simultaneously. The left ventricular end-systolic pressure-volume ratio (Emax) and effective arterial elastance (Ea) were calculated for each beat, and the relationship of the preceding R-R interval (pRR) to Emax and Ea was evaluated. There was a significant positive correlation between pRR and Emax, and a significant negative correlation between pRR and Ea in all patients. The pRR that produced maximal stroke work was determined at the point of Emax=Ea, and the pRR that achieved maximal mechanical efficiency was determined at the point of 2Ea=Emax. By evaluating ventriculoarterial coupling in these patients who had atrial fibrillation, we were able to determine that the range between the 2 pRR intervals was the range of the optimal ventricular rate. A narrower range of the 2 pRR intervals was observed in patients with dilated cardiomyopathy than in the patients with no underlying cardiac disease. We conclude that it may be possible to determine the optimal ventricular rate in patients with atrial fibrillation by evaluating ventriculoarterial coupling.