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The Geriatric Nutritional Risk Index (GNRI) has been reported as a screening tool to assess the nutrition-related risk with mortality in older patients and those with the various diseases. However, the prognostic value of GNRI in metastatic renal cell carcinoma (mRCC) patients receiving nivolumab therapy remains unclear.Fifty-six consecutive patients with mRCC receiving nivolumab between September 2013 and August 2020 at our institution were retrospectively analyzed. The survival outcomes and prognostic factors associated with overall survival (OS) were statistically analyzed.Thirteen and forty-three patients were classified with low (GNRI92) and high (GNRI ≥ 92) GNRI, respectively. Patients with low GNRI demonstrated significantly shorter OS (GNRI was a significant prognostic biomarker in mRCC patients receiving nivolumab.

Background/Aim: Immune-related adverse events (irAEs) develop in a subset of patients with metastatic renal cell carcinoma (mRCC) treated with immune-checkpoint-inhibitors (ICIs). Evidence regarding the prognostic impact of irAEs remains limited in these patients. Patients and Methods: Ninety-one consecutive patients with mRCC treated with ICIs were retrospectively analyzed. Overall survival (OS) rates were estimated using the Kaplan–Meier method. In multivariate analysis, predictors of OS were analyzed using the Cox-proportional-hazards-model. Results: Twenty-nine patients were treated with the combination of nivolumab plus ipilimumab. According to International Metastatic RCC Database Consortium risk classification, 27/47/17 patients were classified into favorable/intermediate/poor risk categories. The 1, 3, and 5-year OS-rates were 89, 70, and 57%, respectively. A total of 67 irAEs occurred in 44 patients (48%), including 15 patients with grade 3-4. OS was significantly longer in patients with irAEs (p=0.01). In multivariate analysis, Karnofsky performance status, prior nephrectomy, and irAEs were independent significant predictors of OS. Conclusion: In our study, irAEs were significantly associated with OS in mRCC patients treated with ICIs.

To investigate the tumor shrinkage patterns of patients with metastatic renal cell carcinoma treated with nivolumab monotherapy.Forty-four consecutive patients with metastatic renal cell carcinoma treated with nivolumab monotherapy (81 metastatic and four primary lesions) between September 2013 and December 2020 were retrospectively analyzed. The tumor shrinkage rate of individual visceral and lymph node metastatic lesions and the primary site lesions treated with nivolumab monotherapy, as well as the association between overall survival and pretreatment tumor size, were statistically assessed.Pretreatment tumor size for the total and individual target lesions, which included kidneys, lungs, pancreas, and lymph nodes, were not correlated with tumor shrinkage rate. The tumor shrinkage rate was found to have no significant association with pretreatment tumor size between any organ. In addition, there is no significant difference in tumor shrinkage rate between larger (median value) and smaller (median value) pretreatment tumor size in any organ. Finally, there was no significant difference in overall survival between larger and smaller pretreatment tumor size.Pretreatment tumor size was not associated with the tumor shrinkage rate and overall survival in nivolumab monotherapy.

To clarify the diagnostic performance of the three-dimensional reconstructed virtual image (3D-RVI) in evaluating RENAL nephrometry score (RENAL-NS).This study included 130 patients who underwent preoperative contrast-enhanced computed tomography followed by partial nephrectomy for renal tumors suggestive of renal cell carcinoma. RENAL-NS was calculated prior to the surgery, and tumor resection was performed referring to the score. We retrospectively reviewed preoperative contrast-enhanced computed tomography images. We calculated the inter-observer variability of RENAL-NS using 3D-RVI vs two-dimensional (2D) imaging and compared the ability of RENAL-NS using 3D-RVI vs 2D imaging to predict the risk of opening of the urinary collecting system. We also compared the two modalities for the time required to evaluate RENAL-NS.RENAL-NS evaluated using 3D-RVI showed a higher inter-observer agreement compared to 2D-imaging (rUsing 3D-RVI improves the accuracy, reliability and efficiency of RENAL-NS evaluation in preoperative assessment and can play an important role in preoperative assessment and intraoperative navigation.

In order to search for predictive biomarkers of efficacy of pembrolizumab therapy for metastatic urothelial cancer (UC), we investigated the relationship between treatment outcomes and early neutrophil-lymphocyte ratio (NLR), lactate dehydrogenase (LDH), and C-reactive protein (CRP) responses.Medical records of 101 patients with metastatic UC who started pembrolizumab as a second-line or later treatment were reviewed. NLR, LDH, and CRP were recorded after 3 weeks of therapy. In addition, we investigated whether these factors had an association with prolonged progression-free (PFS) or overall (OS) survival.The objective response rate, median PFS, and median OS were 25.7%, 6.3 months, and 15.2 months, respectively. PFS and OS were significantly shorter in patients with NLR3, LDHupper limit of normal (ULN), and CRP0.5 mg/dl after 3 weeks of pembrolizumab treatment (p0.05). A predictive model comprising these factors (favorable risk group: 0 risk factors; intermediate-risk group: 1-2 risk factors; poor-risk group: 3 risk factors) revealed distinct PFS and OS curves (p0.001). In the favorable risk group, 12-month OS was 79.6%; in the poor-risk group, it was 12.8%. Harrell's C-indices for NLR3, LDHULN, CRP0.5 mg/dl, and all three combined for predicting OS were 0.656, 0.625, 0.633 and 0.678, respectively. Early responses were also non-significantly associated with ORR (p=0.37).Pembrolizumab treatment outcomes are associated with early NLR, LDH, and CRP responses in metastatic urothelial cancer.

Despite the rapid introduction of androgen receptor-targeted agents (ARTA) into clinical practice for castration-resistant prostate cancer (CRPC), the optimal treatment strategy after first-line ARTA remains unclear. The object of this study was to clarify clinical outcomes of second-line therapy for CRPC after first-line ARTA.The medical records of 130 consecutive patients with CRPC with disease progression during first-line ARTA and who started second-line therapy at our Institution between 2014 and 2020 were analyzed.A total of 130 patients with CRPC were identified. Ninety patients underwent ARTA-ARTA treatment, and 40 patients underwent ARTA-docetaxel treatment. The median observation period after second-line ARTA or docetaxel administration was 14.2 months. The prostate-specific antigen response rates overall, and after second-line ARTA, and docetaxel were 26.8%, 24.7%, and 31.6%, respectively. The median progression-free survival (PFS) and 1- and 2-year PFS rates of second-line therapy were 7.9 months and 34.6% and 15.4%, respectively. The median overall survival (OS) and 1- and 2-year OS rates were 27.4 months and 81.8%, and 54.9%, respectively. Multivariate analyses for OS disclosed that a C-reactive protein over the upper limit of normal and time from first-line ARTA to progression under 12 months were associated with shorter OS. Prostate-specific antigen response, PFS and OS of second-line therapy were not significantly different between second-line ARTA and docetaxel.There was no significant difference in OS between ARTA-ARTA and ARTA-docetaxel groups in the present study, suggesting that second-line ARTA might be the preferred treatment after initial failure of ARTA.

Prostate cancer localization is reportedly associated with the laterality of lymph node metastasis. Thus, it may be feasible to predict side-specific lymph node metastasis (LNM) at radical prostatectomy (RP). To investigate whether multiparametric magnetic resonance imaging and biopsy findings can predict side-specific negative LNM and to explore the feasibility of unilateral lymph node dissection (LND) at RP.A total of 500 patients who were diagnosed with prostate cancer with prebiopsy multiparametric magnetic resonance imaging of the prostate and subsequent prostate biopsy and who underwent RP and extended LND without neoadjuvant treatment were enrolled. Multiparametric magnetic resonance imaging, biopsy findings, and LNM were assessed for each side. The negative predictive value (NPV) of multiparametric magnetic resonance imaging or biopsy or both for ipsilateral LNM was examined.LNM was found in 9.2% (46/500) and 15.6% (28/180) of patients in the overall and high-risk cohorts, respectively. Magnetic resonance imaging and biopsy findings were negative in 408 and 262 sides, respectively, in the overall cohort and 144 and 100 sides, respectively, in the high-risk cohort. The NPVs of magnetic resonance imaging, biopsy, and both for ipsilateral LNM were 98.3%, 98.5%, and 99.1%, respectively, in the overall cohort, and 95.8%, 97.1%, and 97.6%, respectively, in the high-risk cohort.Unilateral LND may be indicated based on side-specific LNM risk as assessed by prebiopsy multiparametric magnetic resonance imaging and biopsy.

ObjectiveTo compare renal function (RF) outcomes after bladder-preserving tetramodal therapy against muscle-invasive bladder cancer (MIBC) to those after radical cystectomy (RC).MethodsThis study included 95 patients treated with tetramodal therapy consisting of transurethral bladder tumour resection, chemoradiotherapy and partial cystectomy (PC) and 300 patients treated with RC. The annual change in the estimated glomerular filtration rate (eGFR) was compared using the linear mixed model. Renal impairment was defined as a >25% decrease from the pretreatment eGFR, and renal impairment-free survival (RIFS) was calculated. The association between treatment type and renal impairment was assessed.ResultsThe number of patients who received neoadjuvant chemotherapy was 8 (8.4%) in the tetramodal therapy group and 75 (25.0%) in the RC group. After the inverse probability of treatment weighting adjustments, the baseline characteristics were balanced between the treatment groups. The mean eGFR before treatment in tetramodal therapy and RC groups was 69.4 and 69.6 mL/min/1.73 m2 and declined with a slope of −0.7 and −1.5 mL/min/1.73 m2/year, respectively. The annual deterioration rate of post-treatment eGFR in the tetramodal therapy group was milder than in the RC group. The 5-year RIFS rate in the tetramodal therapy and the RC groups was 91.2 and 85.2%, respectively. Tetramodal therapy was an independent factor of better RIFS compared with RC.ConclusionsRF was better preserved after tetramodal therapy than after radical therapy; however, even after tetramodal therapy, the eGFR decreased, and a non-negligible proportion of patients developed renal impairment.

In this study, we investigated the association between the early response of serum and hematological variables and the outcome of cabazitaxel therapy. The medical records of 59 consecutive patients who had previously received docetaxel chemotherapy for the treatment of metastatic castration-resistant prostate cancer (CRPC) and who received cabazitaxel at our hospital between January 2011 and March 2020 were retrospectively reviewed and statistically analyzed. The median follow-up period after cabazitaxel initiation was 15.2 months. The 30% prostate-specific antigen (PSA) response rate, median PSA progression-free survival period, and overall survival (OS) period were 45.8%, 4.3 months, and 22.6 months, respectively. Within 1 to 2 cycles of cabazitaxel, we were unable to identify hematological or serum kinetics that had a relationship with OS. Analysis of the variables after 3 cycles of cabazitaxel, however, revealed two factors, PSA decline > 30% (p = 0.016) and neutrophil–lymphocyte ratio (NLR) decline > 30% (p = 0.044), as the predictors of favorable outcome for OS. We established a prognostic model for predicting the OS period composed of these two factors, which exhibited distinctly separated OS curves (p = 0.004). The C-index of a model incorporating these two factors was 0.703. This is the first study to demonstrate that PSA and NLR decline 3 cycles after the initiation of cabazitaxel were associated with favorable outcome in patients with CRPC. Also, 3 cycles of cabazitaxel might be necessary to assess the efficacy of cabazitaxel therapy.

Introduction Although the utility of diffusion‐weighted whole‐body imaging with background body signal suppression for assessing lymph node involvement or distant metastasis is renowned in many cancers, only few studies have revealed its utility for germ cell carcinoma. Some metastatic lesions of germ cell carcinomas are difficult to detect by conventional imaging. Case presentation We report a case of a 70‐year‐old man with relapsed retroperitoneal germ cell tumor. Although his human chorionic gonadotropin levels increased, conventional imaging analysis showed no evidence of recurrence. Diffusion‐weighted whole‐body imaging with background body signal suppression was performed to search the metastatic lesion and detected metastatic sacral lesions. The patient responded well to local radiotherapy added to the steroid pulse and salvage chemotherapy and achieved long‐term recurrence‐free survival. Conclusion Diffusion‐weighted whole‐body imaging with background body signal suppression has the potential to detect metastatic lesions not usually detected by conventional imaging methods.

Objective To study the efficacy of phosphodiesterase-5 inhibitor tadalafil in attenuating adverse events after low-dose-rate brachytherapy for prostate cancer. Methods This was a randomized open-label trial, conducted at two institutions. Prostate cancer patients undergoing low-dose-rate brachytherapy were randomly assigned to receive tadalafil (study group) or tamsulosin (control group). The primary endpoint was International Prostate Symptom Score for subjective evaluation of lower urinary tract symptoms. Uroflowmetry, postvoid residual urine volume, and Sexual Health Inventory for Men score were the secondary endpoints. Each clinical variable was evaluated during a follow-up period of 1 year after low-dose-rate brachytherapy. Results A total of 107 patients were enrolled in this study, with a final total of 96 patients analyzed. The mean total International Prostate Symptom Score changes at 1, 3, 6, 9, and 12 months after low-dose-rate brachytherapy were +7.4, +7.1, +4.7, +1.5, and +0.8, respectively, in the tamsulosin group, and +8.5, +9.2, +6.4, +4.1, and +1.6, respectively, in the tadalafil group. There were no statistically significant differences in International Prostate Symptom Score with the exception of the score at 9-month follow-up. Moreover, there were no statistically significant differences in any of the uroflowmetry or postvoid residual urine volume findings. The Sexual Health Inventory for Men score in the tadalafil group was significantly higher than that in the tamsulosin group at 6, 9, and 12 months after low-dose-rate brachytherapy. Conclusions Tadalafil could be an effective option for the management of lower urinary tract symptoms after low-dose-rate brachytherapy.

Background: Several studies have reported the efficacy of cabazitaxel in cancer therapy; however, investigations of its safety are few. The aim of this study was to retrospectively analyze the efficacy and safety of cabazitaxel based on treatment outcome data. Methods: A questionnaire form on the use of cabazitaxel was mailed to hospitals associated with the Shinshu University. Responses were received from 11 institutions regarding 55 cases. Results: Patients received a median of 4 courses of cabazitaxel treatment. Decreases in prostrate-specific antigen (PSA) were observed in 61.5% of cases with declines of 30%, 50%, and 90% in 36.5%, 23.0%, and 7.6% of cases, respectively. PSA progression-free survival was 5.0 months, and overall survival after the start of cabazitaxel was 13.0 months. Forty-five patients received postcabazitaxel treatment; 17 showed decreased PSA. Safety assessment indicated that white blood cell and neutrophil counts were significantly higher in the second than in the first course of treatment and Grade 3 to 4 leukopenia and neutropenia significantly decreased. Twenty-four subjects were aged ≥75 years; 79% of them had their doses reduced at the first administration. The mean dose was 20 mg/m2. However, there was no significant difference in the PSA progression-free survival between the ≥75-year-old and

We compared clinical outcomes and toxicities associated with seed brachytherapy (SEED-BT) alone and SEED-BT plus external-beam radiotherapy (EBRT) for the treatment of intermediate-risk prostate cancer. From 2006 to 2011, 993 patients diagnosed with intermediate-risk prostate cancer were treated with either SEED-BT alone (n = 775) or SEED-BT plus EBRT (n = 158) at 3 tertiary hospitals. One-to-one propensity score matching was performed to compare clinical outcomes between the groups. In the propensity score-matched analysis (102 pairs), median follow-up was 95 months (range: 18–153 months). The 8-year biochemical recurrence-free rate (bRFR) was significantly better with SEED-BT alone than with combined radiotherapy (93.3% vs. 88.4%; HR: 0.396; 95% CI: 0.158 to 0.991). The cumulative incidence of grade 2 or greater late genitourinary toxicity at 8 years was 21.0% for SEED-BT alone and 33.2% for combined radiotherapy. Grade 2 or greater late genitourinary toxicities were significantly fewer with SEED-BT alone than with combined radiotherapy (HR: 0.521; 95% CI: 0.308 to 0.881). Similarly, grade 2 or greater late gastrointestinal toxicities were significantly fewer with SEED-BT alone (0% vs. 12.2%; HR: 0.125; 95% CI: 0.040 to 0.390). Our study implies that SEED-BT alone might be a better disease-management plan than SEED-BT plus EBRT for intermediate-risk prostate cancer.

Background/Aim: To evaluate the relationship between treatment period and overall survival (OS) and to identify clinical factors associated with OS in patients with metastatic renal cell carcinoma (mRCC). Patients and Methods: Two hundred thirteen consecutive patients with mRCC receiving systemic therapy between 2008 and 2020 were divided into two groups: those starting first-line therapy in 2008-2015 (n=133) and those in 2016-2020 (n=80). Clinical factors associated with OS were retrospectively and statistically analyzed. Results: Median OS and one-, three- and five-year OS rates were not reached and 88.7%, 64.9%, and 64.9% in patients treated in 2016-2020; 31.4 months and 78.5%, 42.8% and 34.2% in 2008-2015 (p=0.0013). Multivariate analysis identified the period in which first-line therapy was started as the strongest predictor for OS (p=0.0002). Conclusion: OS was significantly better in mRCC patients treated in 2016-2020 than in 2008-2015. Treatment period was the strongest predictor for OS.

Background We aimed to establish an external validation of the Briganti 2019 nomogram in a Japanese cohort to preoperatively evaluate the probability of lymph node invasion in patients with high-risk, clinically localized prostate cancer. Methods The cohort consisted of 278 patients with prostate cancer diagnosed using magnetic resonance imaging-targeted biopsy who underwent radical prostatectomy and extended pelvic lymph node dissection from 2012 to 2020. Patients were rated using the Briganti 2019 nomogram, which evaluates the probability of lymph node invasion. We used the area under curve of the receiver operating characteristic analysis to quantify the accuracy of the nomogram. Results Nineteen (6.8%) patients had lymph node invasion. The median number of lymph nodes removed was 18. The area under the curve for the Briganti 2019 was 0.71. When the cutoff was set at 7%, 84 (30.2%) patients with extended pelvic lymph node dissection could be omitted, and only 1 (1.2%) patient with lymph node invasion would be missed. Sensitivity, specificity, and negative predictive values at the 7% cutoff were 94.7, 32.0, and 98.8%, respectively. Conclusion This external validation showed that the Briganti 2019 nomogram was accurate, although there may still be scope for individual adjustments.

Aim: To reduce the frequency of the need for hospital visits for patients with prostate cancer (PCa) taking androgen-deprivation therapy during the SARS-CoV-2 (COVID-19) pandemic, we switched them from gonadotropin-releasing hormone (GnRH) antagonist to a long-acting luteinizing hormone-releasing hormone (LH-RH) agonist. Here, we confirmed the efficacy and safety profile of this switching. Patients and Methods: We analyzed the medical records of 32 patients with PCa who received ADT and switched from GnRH antagonist to a long-acting LH-RH agonist during the COVID-19 pandemic, evaluating hematological and serological variables, including serum testosterone and prostate-specific antigen. Results: Before and after the switching from GnRH antagonist to LH-RH agonist, the median serum testosterone levels were 0.22 and 0.18 ng/ml, respectively, and the median serum prostatespecific antigen levels were 0.18 and 0.11 ng/ml, respectively. No changes in the rates of flare-ups of conditions or adverse events were observed. Conclusion: Switching from GnRH antagonist to a long-acting LH-RH agonist appears to be a reasonable option that does not diminish efficacy or exacerbate adverse events.

OBJECTIVES To evaluate the efficacy and safety profiles of first-line etoposide, ifosfamide and cisplatin and primary prophylaxis with pegfilgrastim as first-line chemotherapy for disseminated germ cell cancer. METHODS This study reviewed 154 consecutive patients with previously untreated disseminated germ cell cancer who received first-line etoposide, ifosfamide and cisplatin between 1995 and 2020. Of these, 54 patients were managed with primary prophylaxis using pegfilgrastim (primary prophylaxis group), and 100 were managed with the therapeutic use of short-acting granulocyte colony-stimulating factor (non-primary prophylaxis group). RESULTS The International Germ Cell Cancer Collaborative Group classification identified 90 (58%)/40 (26%)/24 (16%) patients with good/intermediate/poor prognosis, respectively. Overall, 139 patients (90%) were disease free after etoposide, ifosfamide and cisplatin with/without post-chemotherapy surgery. The median relative dose intensity of etoposide, ifosfamide and cisplatin was 96%, and there was a significant difference between the primary prophylaxis and non-primary prophylaxis groups (100% vs 90%, P

Neural cross-sensitization has been postulated as a mechanism underlying overlaps of chronic pelvic pain disorders such as bladder pain syndrome/interstitial cystitis (BPS/IC) and irritable bowel syndrome (IBS). Animals with experimental colitis have been used to study the underlying mechanisms for overlapped pelvic pain symptoms, and shown to exhibit bladder overactivity evidenced by frequent voiding; however, it has not directly been evaluated whether pain sensation derived from the lower urinary tract is enhanced in colitis models. Also, the cross-sensitization between the colon and urethra has not been studied previously. In the present study, we therefore investigated pain behaviors induced by nociceptive stimuli in the lower urinary tract and the involvement of C-fiber afferent pathways using rats with colitis induced by intracolonic application of 2,4,6-trinitrobenzenesulfonic acid (TNBS). In TNBS-induced colitis rats at 10 days, intravesical application of resiniferatoxin (RTx) induced a significantly greater number of episodes of both licking and freezing behaviors, which were reduced by capsaicin-sensitive C-fiber afferent desensitization. Histochemical studies using fluorescent dye tracers injected into the colon, bladder or urethra showed that dichotomized afferent neurons comprised 6.9-14.5% of L1, L6 and S1 dorsal root ganglion (DRG) neurons innervating the colon or the lower urinary tract. Transient receptor potential vanilloid 1 (TRPV1) mRNA expression was significantly increased in, the bladder, urethra and S1 DRG in colitis rats. An increase in myeloperoxidase (MPO) activity was found in the colon, but not in the bladder or urethra after intracolonic TNBS treatment. These results indicate that TNBS-induced colitis increased pain sensitivity in the bladder and urethra via activation of C-fiber afferent pathways due to colon-to-bladder and colon-to-urethral cross-sensitization, suggesting the contribution of pelvic organ cross-sensitization mechanisms to overlapped pain symptoms in BPS/IC and IBS.

Bladder pain syndrome/interstitial cystitis is a disease with lower urinary tract symptoms, such as bladder pain and urinary frequency, which results in seriously impaired quality of life of patients. The extreme pain and urinary frequency are often difficult to treat. Although the etiology of bladder pain syndrome/interstitial cystitis is still not known, there is increasing evidence showing that afferent hyperexcitability as a result of neurogenic bladder inflammation and urothelial dysfunction is important to the pathophysiological basis of symptom development. Further investigation of the pathophysiology will lead to the effective treatment of patients with bladder pain syndrome/interstitial cystitis.

We previously reported the effects of herpes simplex virus (HSV) vector-mediated enkephalin on bladder overactivity and pain. In this study, we evaluated the effects of vHPPE (E1G6-ENK), a newly engineered replication-deficient HSV vector encoding human preproenkephalin (hPPE). vHPPE or control vector was injected into the bladder wall of female rats 2 weeks prior to the following studies. A reverse-transcription PCR study showed high hPPE transgene levels in L6 dorsal root ganglia innervating the bladder in the vHPPE group. The number of freezing behaviors, which is a nociceptive reaction associated with bladder pain, was also significantly lower in the vHPPE group compared with the control group. The number of L6 spinal cord c-fos-positive cells and the urinary interleukin (IL)-1β and IL-6 levels after resiniferatoxin (RTx) administration into the bladder of the vHPPE group were significantly lower compared with those of the control vector-injected group. In continuous cystometry, the vHPPE group showed a smaller reduction in intercontraction interval after RTx administration into the bladder. This antinociceptive effect was antagonized by naloxone hydrochloride. Thus, the HSV vector vHPPE encoding hPPE demonstrated physiological improvement in visceral pain induced by bladder irritation. Gene therapy may represent a potentially useful treatment modality for bladder hypersensitive disorders such as bladder pain syndrome/interstitial cystitis.

Lower urinary tract dysfunction is caused by functional and pathophysiological alterations of the peripheral organs, including the urothelium and detrusor smooth muscle, as well as peripheral and central nervous systems. Recent research in this field has increased our understanding of the mechanisms of lower urinary tract dysfunction, and new drugs have been developed, leading to increased treatment options and changing medical care for lower urinary tract symptoms. Nevertheless, clinicians still often experience refractory and treatment-resistant cases against conventional therapeutic modalities. For such cases, gene therapy targeting for the lower urinary tract and its afferent pathway is anticipated to offer a new therapeutic approach. Therefore, in this article, we review the possibility and current status of gene therapy for lower urinary tract dysfunction.

We investigated the effects of replication-defective herpes simplex virus (HSV) vector expression of interleukin-4 (IL-4) on bladder overactivity and nociception. HSV vector expressing murine interleukin-4 (S4IL4) or the control vector expressing β-galactosidase (SHZ) were injected to the rat bladder wall. At 1 week after viral injection, in cystometry performed under urethane anesthesia, the S4IL4-treated group did not show the intercontraction intervals reduction during intravesical administration of 10 nM resiniferatoxin (RTx). At 2 weeks after viral injection, behavioral studies were performed on vector-injected animals in an awakened state. Freezing behavior induced by 3 μM RTx, administered for 1 min into the bladder, was significantly suppressed in the S4IL4 group compared with the SHZ group. Murine IL-4 levels examined by ELISA were significantly increased in bladder and bladder afferent dorsal root ganglia at 2 weeks after viral injection. The expression of IL-1β and IL-2 and bladder inflammatory responses were significantly suppressed in the RTx-irritated bladder of S4IL4-injected rats. These results indicate that HSV vector-mediated interleukin-4 expression in the bladder and bladder afferent pathways reduces the inflammatory response, bladder overactivity and nociceptive behavior induced by bladder irritation in the rat model. Therefore, IL-4 gene therapy could be a new strategy for treating urinary frequency and/or bladder pain.

A 66-year-old female who underwent a partial urethrectomy complained of severe incontinence due to intrinsic sphincter deficiency. Bone anchor surgical technique was performed, but in 3 years, serious pelvic organ prolapse had occurred. Consequently, anterior and posterior tension-free vaginal mesh operation was planned. Preoperative urodynamic examination predicted postoperative stress incontinence, and concurrent transobturator tape (TOT) surgery was performed. After 3 months, stress incontinence reoccurred, and secondary TOT was performed. Relapse was probably caused by dislocation of the first TOT towards the bladder neck. Thus, the secondary TOT was placed distal to the initial tape towards the external urethral meatus, and proper tension was applied. After the operation, stress incontinence was cured. Thus, a second TOT procedure, with proper positioning and tensioning, can effectively cure stress incontinence that occurs after an initial TOT procedure.

CASE 1 A 28-year-old woman visited a local medical doctor, complaining of abdominal pain, urinary frequency and a sense of residual urine. Magnetic resonance imaging revealed a lower abdominal extraperitoneal tumor, approximately 5 cm in diameter, adjacent to the bladder dome. It was thought to be a urachal tumor, and she was referred to our hospital. A hard hen's egg-sized mass was palpable in the lower abdomen. Urinary analysis was normal. Cytological examination was also negative. Cystoscopy revealed redness in the bladder dome mucosa. Although the preoperative diagnosis was a urachal cancer, the pathological diagnosis on surgery was desmoids, and tumor excision was performed. No recurrence has been seen for 7 years postoperatively. CASE 2 A 71-year-old man complaining of swelling of the lower abdomen was referred to our department because he was suspected to have a urachal tumor, of about 15 cm in diameter, on computed tomography. A hard infant head-sized mass was palpable in the lower abdomen. Urinary analysis was normal. Cystoscopical examination showed a markedly compressed bladder dome, however, no abnormal findings were seen in the mucosa. Although the preoperative diagnosis was a urachal tumor, the intraoperative pathological diagnosis revealed no malignancy. The mass was connected to the bladder dome, and partial cystectomy was conducted. The final pathological diagnosis was a solitary fibrous tumor. No recurrence has been seen for 5 years postoperatively. Because a urachal tumor is highly malignant, radical cystectomy and urinary diversion might be planned preoperatively. However, care should be taken not to be too invasive, considering the possibility of a benign tumor.

Bladder pain syndrome/interstitial cystitis is a disease with lower urinary tract symptoms, such as bladder pain and urinary frequency, which results in seriously impaired quality of life of patients. The extreme pain and urinary frequency are often difficult to treat. Although the etiology of bladder pain syndrome/interstitial cystitis is still not known, there is increasing evidence showing that afferent hyperexcitability as a result of neurogenic bladder inflammation and urothelial dysfunction is important to the pathophysiological basis of symptom development. Further investigation of the pathophysiology will lead to the effective treatment of patients with bladder pain syndrome/interstitial cystitis.

INTRODUCTION AND OBJECTIVES: Bladder pain syndrome/ interstitial cystitis (BPS/IC) is a serious disease whose main symptoms are bladder pain and frequent urination. We examined whether the effects of glycine, an inhibitory neurotransmitter, on pain behavior and bladder overactivity are enhanced by gene transfer of glycine receptors (GlyR) using replication-deficient HSV vectors. METHODS: Female SD rats were used, and 20 l of viral suspension of either GlyR (6.8 10 pfu/ml) or control vector (E1G6) (7.1 10 pfu/ml) was injected to the bladder wall. GlyR vectors also expressed Red Fluorescent Protein (RFP). (1) The bladder and L6 dorsal root ganglia (DRG) were harvested 2 weeks after viral injection. (2) In an awake condition, nociceptive behaviors such as lower abdominal licking (licking) and motionless head-turning (freezing) induced by 3 M resiniferatoxin (RTx) intravesical administration (0.3ml for 1min) through a urethral catheter were scored every 5 sec for 15 min among control virus and GlyR groups (n 7-8). (3) Rats were divided into 4 groups, which were treated with control vector, GlyR, control vector with glycine, or GlyR with glycine. In the glycine administration groups, an osmotic pump filled with 0.9% glycine was placed in the abdomen to administer glycine continuously. Two weeks later, cystometry (n 7-10) was performed under urethane anesthesia. After 2 hours of saline infusion, 10nM RTx was infused to induce bladder overactivity. Intercontraction intervals (ICI) were recorded and compared. RESULTS: (1) RFP positive cells were observed in both L6 DRG and bladder of GlyR injected rats. (2) GlyR-treated rats showed a significant reduction in licking (p 0.05) and freezing behavior (p 0.01) compared to E1G6 rats. (3) Virus (control or GlyR) injection without glycine administration did not alter the ICI reduction rate after RTx intravesical infusion in cystometry. Both control virus and GlyR groups given with glycine also showed a significant reduction in ICI after RTx, with a smaller reduction rate (p 0.05) in GlyR virus-injected rats with glycine. CONCLUSIONS: The GlyR vector intensified the therapeutic effect of glycine on bladder overactivity and pain in rats with RTxinduced cystitis, suggesting that glycine administration with HSV-mediated glycine receptor gene therapy might be effective for treating BPS/IC. In addition, systemic administration of inhibitory transmitters such as glycine in combination with local HSV gene therapy of their receptors could enhance the drug-receptor interaction in target organs.

Glycine is a major inhibitory neurotransmitter in the spinal cord, the concentration of which is regulated by two types of glycine transporters (GlyTs): GlyT1 and GlyT2. We hypothesized that the inhibition of GlyTs could ameliorate bladder overactivity and/or pain sensation in the lower urinary tract.Investigate the effects of GlyT inhibitors on bladder overactivity and pain behavior in rats.Cystometry was performed under urethane anesthesia in cyclophosphamide (CYP)-treated rats. In behavioral studies using conscious rats, nociceptive responses were induced by intravesical administration of resiniferatoxin (3μM). Selective GlyT1 or GlyT2 inhibitors were administered intrathecally to evaluate their effects.Cystometric parameters, nociceptive behaviors (licking and freezing), and messenger RNA (mRNA) levels of GlyTs and glycine receptor (GlyR) subunits in the dorsal spinal cord (L6-S1) were measured.During cystometry in CYP-treated rats, significant increases in intercontraction interval and micturition pressure threshold were elicited by ALX-1393, a selective GlyT2 inhibitor, but not by sarcosine, a GlyT1 inhibitor. These effects were completely reversed by strychnine, a GlyR antagonist. ALX-1393 also significantly suppressed nociceptive behaviors in a dose-dependent manner. In sham rats, GlyT2 mRNA was expressed at a much higher level (23-fold) in the dorsal spinal cord than GlyT1 mRNA. In CYP-treated rats, mRNA levels of GlyT2 and the GlyR α1 and β subunits were significantly reduced.These results indicate that GlyT2 plays a major role in the clearance of extracellular glycine in the spinal cord and that GlyT2 inhibition leads to amelioration of CYP-induced bladder overactivity and pain behavior. GlyT2 may be a novel therapeutic target for the treatment of overactive bladder and/or bladder hypersensitive disorders such as bladder pain syndrome/interstitial cystitis.

cation of ATP. The intravesical infusion of ATP and systemic application of AF-353, a P2X2/3 receptor-specific antagonist, allowed us to evaluate the contribution of P2X2/3 purinergic receptors to the activity of spinal neurons. METHODS: Following anesthesia with isoflurane, suprapubic, venous and tracheal catheters were implanted in female rats. After L1–L2 laminectomy, the cervical spinal cord was transected, rats were mechanically pithed, ventilated, and paralyzed. Urinary bladder pressure was monitored and the neural activity was acquired at a rate of 10 KHz via a computerized data acquisition system. Field potentials in the dorsal horn of the spinal cord were measured via tungsten microelectrodes in response to intravesical pressure steps ranging from 0–60 cm/H2O in A) control (saline in the bladder), B) after stimulation of urothelial purinergic receptors (1mM vesical ATP), C) after i.v. application of AF-353 (10 mg/kg), D) following a second i.v. injection of AF-353 (20 mg/kg), and E) after i.v. suramin (100 mg/kg). Pressure steps were maintained for one minute followed by three minutes of recovery. RESULTS: Only neurons that showed an increased activity during bladder distention were evaluated. Under control conditions, field potentials increased concomitantly with bladder pressure steps. Intravesical application of 1mM ATP produced an increase (27%) in the baseline electrical activity and a greater response (25%) to pressure changes than the saline controls. The first systemic application of AF-353 generated a marked decrease (52%) in electrical activity during isobaric stimulation; further additive inhibition (75%) was achieved after a second application of AF-353 30 minutes later. The application of suramin, following AF-353 treatments, maximally inhibited (87%) the response in neural activity to pressure changes. CONCLUSIONS: Our results suggest that purinergic receptors in the urothelium are important modulators of C-fiber mediated noxious bladder activation of lumbosacral dorsal spinal neurons. Moreover, the marked inhibition evoked by systemic application of AF-353 implicates P2X2/3 sensory purinergic receptors as significant drivers of bladder C-fiber mediated spinal neuronal activity.

A 75-year-old man visited our hospital with the complaint of lumbago due to bilateral hydronephrosis. Computed tomographic (CT) scan revealed a thick and homogeneous retroperitoneal soft-tissue mass with isodensity to the muscle, which extended from around the kidneys to the bladder. His serum IgG4 level was extremely high. He also had proptosis. He was diagnosed as having retroperitoneal fibrosis due to IgG4- related sclerosing disease, and treated with glucocorticoid and azathioprine. After 2 months, partial regression of the mass was observed.

A 39-year-old woman visited our hospital with a complaint of gross hematuria. Cystoscopy revealed a nodular tumor 3 cm in diameter in the posterior wall of the bladder. A transurethral resection was performed. This initial operation was complicated by unexpected intra-operative high blood pressure and visualization was obscured by bleeding. The histological diagnosis was paraganglioma. Therefore, a partial cystectomy was planned. Using cystoscopy, a 10 mm margin was identified and marked using electrocoagulation, followed by an open surgical procedure. After laparotomy, drainage veins were identified and ligated under the guidance of flexible cystoscopy lighting. Intra-operative blood pressure was stable during the operation, and the margin was negative for tumor.

A 33-year-old woman was referred to our hospital for further examination of a right adrenal mass 4.5 cm in diameter. Hormonal findings were normal. Computed tomography, magnetic resonance image and angiograpy demonstrated non-functioning adrenal tumor. Right nephrectomy was performed, because the tumor adhered firmly to the upper pole of the right kidney. The pathological diagnosis was nephroblastoma (nephroblastic type, complex subtype). Postoperative chemotherapy was started for stage III Wilms' tumor. However, peripheral neuropathy such as numbness of the fingers developed. Therefore, chemotherapy was discontinued in the fifth week. The patient is currently alive without recurrence 17 months postoperatively. In adult patients, postoperative chemotherapy for nephroblastoma is often interrupted due to side effects. Further studies on the protocol for adults is necessary.