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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.

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.

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.

Background: We evaluate the role of the Geriatric Nutritional Risk Index (GNRI) as a prognostic factor in metastatic renal cell carcinoma patients receiving nivolumab.Methods: Fifty-six consecutive patients with metastatic renal cell carcinoma receiving nivolumab after tyrosine kinase inhibitor 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. Results: Median follow-up period was 28.6 months. Median progression-free survival (PFS) and 1- and 3-year PFS rates were 26.4 months, 59.7%, and 19.5%, respectively. Median OS and 1- and 3-year OS rates were 48.1 months, 88.9%, and 74.5%, respectively. Thirteen and forty-three patients were classified with low (GNRI p = 0.0002) and PFS (p = 0.045) than those with high GNRI. In multivariate analysis, GNRI at the time of nivolumab (hazard ratio: 4.38, p = 0.013) was extracted as the predictor for OS in addition to duration from diagnosis to treatment (p = 0.0005) and lymphocyte count (p = 0.026). Integration of the GNRI into the International Metastatic Renal Cell Cancer Database Consortium (IMDC) risk classification improved the c-index from 0.761 to 0.833 (combination of GNRI with IMDC risk classification) and to 0.778 (substitution of GNRI with Karnofsky performance status in IMDC risk classification).Conclusions: GNRI was a significant prognostic biomarker in metastatic renal cell carcinoma patients receiving nivolumab. This simple screening tool could be very useful in clinical practice.

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.

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.

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.

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.