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Advanced bladder cancer (BC) (local invasive and/or metastatic) is not curable even with cytotoxic chemotherapy, immune checkpoint inhibitors, and targeted treatment. Targeting GSK-3β is a promising novel approach in advanced BC. The induction of autophagy is a mechanism of secondary resistance to various anticancer treatments. Our objectives were to investigate the synergistic effects of GSK-3β in combination with autophagy inhibitors to evade GSK-3β drug resistance. Small molecule GSK-3β inhibitors and GSK-3β knockdown using siRNA promoted the expression of autophagy-related proteins. We further investigated that GSK-3β inhibition induced the nucleus translocation of transcription factor EB(TFEB). Compared to the GSK-3β inhibition alone, its combination with chloroquine (an autophagy inhibitor) significantly reduced BC cell growth. These results provide that targeting autophagy potentiates GSK-3β inhibition-induced apoptosis and retarded proliferation in BC cells.

Background Sarcomatoid carcinoma is a rare, high-grade malignancy with epithelial and mesenchymal components. It may be a good candidate for immunotherapy because it is associated with overexpression of programmed cell death ligand 1. Sarcomatoid urothelial carcinoma (UC) of the upper urinary tract is extremely rare. Here we report the first case of sarcomatoid UC of the renal pelvis that responded to immunotherapy. Case presentation A 79-year-old man was referred to our hospital complaining of various symptoms, including anorexia and abdominal pain. A computed tomography scan revealed a right atrial tumor, a 9 cm left renal mass with a renal vein tumor thrombus, para-aortic lymphadenopathy, and multiple small lung nodules. The patient underwent resection of the right atrial tumor. Pathological analysis of the tumor did not lead to an accurate diagnosis even after several rounds of immunohistochemistry. He underwent a needle biopsy of the left kidney and was initially diagnosed with collecting duct carcinoma, a rare subtype of renal cell carcinoma (RCC). Following the initial diagnosis, immunotherapy with nivolumab and ipilimumab commenced. Thereafter, almost all lesions, including the left renal tumor, were reduced in size. However, he underwent a left nephrectomy approximately a year after beginning immunotherapy due to repeated left renal bleeding. Histological examination of the nephrectomy specimen revealed two forms of cancer—sarcomatoid UC and conventional high-grade UC. Two months after surgery, the patient was found to have new lung metastases. He underwent chemotherapy with gemcitabine and cisplatin, followed by immunotherapy with pembrolizumab. However, both treatments were ineffective. The patient died of cancer 19 months after his first admission. Conclusions The presented case of sarcomatoid UC of the renal pelvis that partially responded to immunotherapy suggests that immunotherapy can be a promising treatment for sarcomatoid UC.

Background: Despite advances in systemic therapy for renal cell carcinoma (RCC), most metastatic RCCs remain incurable. Therefore, new therapeutic approaches are needed to further improve the outcome of RCC treatment. Methods: We treated cultured RCC cells with a panel of 12 small molecule selective HDAC (histone deacetylase) 6 inhibitors or genetically knocked down HDAC6. Results: HDAC6 expression was confirmed in pathological RCC specimens and cultured RCC cell lines by immunohistochemical staining and western blot respectively. Most of the HDAC6 inhibitors we used decreased cell viability and proliferation in a concentration-dependent manner in the low micromolar range. Furthermore, HDAC6 inhibition induced apoptosis in RCC cells. The major imitation of our study is the lack of in vivo experiments. Conclusions: HDAC6 inhibitors decreased cell viability and proliferation by inducing apoptosis in RCC cells. Our results suggest that HDAC6 inhibitors are promising anti-cancer agents, which should be validated in future in vivo studies.

Immune checkpoint inhibitors (ICI) have dramatically changed the treatment of metastatic renal cell carcinoma (mRCC). Although many studies have reported biomarkers as predicting the efficacy of ICI in mRCC, they remain controversial and have challenges to apply in real-world practice. We evaluated prognostic significance of multiple molecules associated with tumor immunity in patients treated with ICI. The molecules were detected in tumor tissues by immunohistochemical staining. We identified CD8 positive T cells and CD68 positive macrophages infiltrating into the tumor tissue as a significant favorable prognostic factors for ICI treatment. Conversely, high expression of CD4-positive T cells was associated with poor response to ICI. Furthermore, we demonstrated that scoring for the expression status of these three molecules provides a remarkably accurate biomarker in patients with mRCC. Even the classical approach of immunohistochemistry could predict the outcome of ICI treatment by assessing the combined status of tumor-infiltrating immune cells.

The selection of effective therapeutic agents is critical for improving the survival of patients with renal cell carcinoma (RCC). The aim of the present study was to develop an ex vivo drug testing assay using patient-derived tumor organoid (TO) cultures. For this purpose, surgical tumor specimens were obtained from 20 patients with RCC. TOs were developed ex vivo from freshly resected RCC tumors, and their histopathological and molecular characteristics were evaluated using histological staining and whole-exome sequencing (WES). Using a cell viability assay, the therapeutic efficacy of standard of care tyrosine kinase inhibitors in RCC TOs was determined. It was found that TOs recapitulated the histological features of primary RCC tumors. Using WES, a strong concordance was identified at the genetic level between the primary tumors and their corresponding TOs. Using patient-derived TO models, a prototype of an ex vivo drug testing assay was developed, and it was found that RCC TOs exhibited differential responses to sunitinib, pazopanib, cabozantinib, axitinib and sorafenib treatment. On the whole, although the predictive value of the current assay has to be tested and validated in future clinical studies, the findings of the present study demonstrate a novel approach for ex vivo drug testing in patient-derived TO models, which may have potential for use in the personalized treatment of cancer patients.

Introduction: We aimed to assess the outcome of free tube graft urethroplasty for single-stage repair of hypospadias with chordee in children. Materials and Methods: We retrospectively evaluated a series of 56 patients (16 months to 9 years old, median 24 months) who underwent free graft urethroplasty for repair of hypospadias with chordee between May 2005 and November 2017. The median follow-up was 7 years (range 1–11). Results: After releasing the chordee, the hypospadiac orifice was retracted to become penile in 32 patients (57%), penoscrotal in 18 patients (32%), and scrotal in 6 patients (11%). Single-stage repair was achieved without complications in 42 patients (75%). Of the remaining 14 patients with postoperative complications requiring surgical intervention, 2 had meatal stenosis, 9 had urethrocutaneous fistula, 1 had urethral diverticulum without meatal stenosis, and 1 had meatal regression. One patient who complained the urine stream went upwards in an arc underwent cutback meatoplasty to correct the stream. In all patients, a neomeatus with a vertically oriented slit-like appearance was eventually achieved at the tip of the glans. Conclusion: A free graft is an appropriate choice for repairing hypospadias with chordee. Our procedure achieved favorable functional and cosmetic outcomes with a low postoperative morbidity rate.

Background: The management of febrile urinary tract infection (fUTI) in patients with vesicoureteral reflux (VUR) is crucial to prevent renal scarring. Continuous antibiotic prophylaxis (CAP) is the most widely used initial treatment for VUR. However, the optimal duration of CAP is still unclear. We aimed to clarify an appropriate patient population and the optimal timing to discontinue CAP. Methods: We reviewed the records of 247 patients with primary VUR between January 2000 and December 2015. Seventy-two patients who discontinued CAP despite persistent VUR were enrolled. Kaplan-Meier method and Cox proportional hazard model was used in statistical analysis. Results: Following the discontinuation of CAP, fUTI developed in 25 patients after a median of 9 months (range 0–81). VUR resolved spontaneously in 9 out of 47 patients without recurrence during follow-up. Multivariate analysis showed bilateral VUR and duration of CAP of less than 1 year after the last fUTI were significant risk factors for recurrence. Conclusion: Among the risk factors examined, patients administered CAP for less than 1 year after the last fUTI and those with bilateral VUR had significantly more frequent recurrence. Our study suggests that the administration of CAP for more than 1 year after the last fUTI is beneficial in avoiding recurrent fUTI.

Histone deacetylases (HDACs) are enzymes that remove acetyl groups from histones and have attracted attention as potential targets for cancer therapy. Several small molecule inhibitors have been developed to target HDACs; however, clinical trials of pan-HDAC inhibitors have found these types of inhibitors to be inefficient and to be relatively highly toxic. In the present study, the role of one HDAC isozyme, HDAC6, in urothelial cancer was investigated. Protein expression levels and subcellular localization of HDAC6 was identified in surgically resected bladder tumors using immunohistochemistry. The antitumor effects of 12 small molecule HDAC6 inhibitors were also examined in vitro using cultured urothelial cancer cells. The HDAC6 inhibitors decreased cell viability, with IC50 values in the low µM range, as low as 2.20 µM. HDACi D, E and F had the lowest IC50 values. HDAC6 has been previously reported to regulate programmed death-ligand 1 (PD-L1) and PD-L1 expression was found to be a predictor of decreased overall survival time. There was no association between the protein expression level of HDAC6 and PD-L1 in tumor tissues; however, HDAC6 inhibition by specific small molecule inhibitors resulted in decreased expression levels of membranous PD-L1 in cultured urothelial cancer cell lines. The results suggested that inhibition of HDAC6 could be a promising novel approach for the treatment of urothelial cancer.

(Backgrounds) The efficacy of bortezomib for chronic antibody mediated rejection (CAMR) after kidney transplantation is still obscure. (Materials and methods) CAMR were persisted in 5 recipients who were treated with plasma exchange, low dose of IVIG, steroid pulse therapy, and rituximab. 1.3 mg/m2 of bortezomib was administered on days 1, 4, 8, 11. Serum creatinine (sCr) levels, anti-HLA antibodies, and histology were analyzed. (Results) Stable sCr levels were obtained in 3 out of 5 recipients. No one lost renal graft function during follow-up periods. Anti-HLA class I antibodies were significantly decreased after bortezomib treatment, however anti-HLA class II antibodies were not changed. Histology showed no improvement at 6 months after bortezomib administration. Two recipients whose sCr levels increased during follow-up had already had interstitial fibrosis and tubular atrophy (IF/TA) in histology before bortezomib treatment. (Conclusions) The use of bortezomib after IF/TA could be detected in histology may not contribute to stabilize renal graft function in CAMR.

A cecoureterocele is a rare form of ectopic ureterocele that the orifice of the affected ureter is within the bladder, but the cavity of the ureterocele extends beyond the bladder neck into the urethra. We present a case of a newborn boy with a large cecoureterocele with contralateral renal rupture. He required an emergency transurethral incision of the ureterocele for the treatment of acute renal failure and respiratory disorder.

Glycogen synthase kinase-3beta (GSK-3β) is a serine/threonine protein kinase that has been established as a therapeutic target in a broad spectrum of human malignancies. We have previously identified aberrant GSK-3β nuclear expression in bladder cancer (BC), and demonstrated that GSK-3β positively regulated BC cell survival and proliferation. Our objective was to evaluate the antitumor effects of the clinically viable agent 9-ING-41, a maleimide-based ATP-competitive GSK-3 inhibitor, which has broad spectrum antitumor activity and marked activity in reversing chemoresistance in a variety of pre-clinical models of human cancers. We used flow cytometry, Western immunoblotting, quantitative RT-PCR, BrDU incorporation and MTS assays to examine antitumor activity of 9-ING-41 in BC (T24, HT1376, RT4 cell lines). Additionally, we studied combination therapy of 9-ING-41 with gemcitabine and cisplatin, standard agents used for the treatment of patients with advanced BC, with cabozantinib, a multi kinase inhibitor, and with chloroquine, an autophagy inhibitor. A dose-dependent decrease in cancer cell proliferation was observed by MTS assay and BrdU incorporation assay with GI50 0.7μM (T24), 4.7 μM(HT1376), 2.2μM(RT4). Treatment with 9-ING-41 induced prominent cell cycle arrest (predominantly G2 arrest) in BC cells. Expression of cell cycle related proteins, including Cyclin D, and anti-apoptotic proteins, such as XIAP and Bcl-2, were significantly decreased as detected by Western immunoblotting and real time RT-PCR. Treatment with 9-ING-41 significantly potentiated the growth inhibitory effect of cisplatin and gemcitabine in cultured cells. In addition, combination therapy with 9-ING-41 and cabozantinib or chloroquine, significantly potentiated the effect of either single agent. Our data proved that a single treatment using 9-ING-41 is effective in BC cells. Combination treatment of 9-ING-41 with standard chemotherapeutic drugs or novel agents may provide a new therapeutic approaches in BC. These data provide a rational for the inclusion of patients with advanced BC in clinical studies of 9-ING-41. Citation Format: Hiroo Kuroki, Tsutomu Anraku, Vladimir Bilim, Masayuki Tasaki, Daniel Schmitt, Andrew Mazer, Francis J. Giles, Andrey Ugolkov, Yoshihiko Tomita. 9-ING-41, a novel inhibitor of glycogen synthase kinase-3beta (GSK-3β), is active as a single agent and within combination therapies in bladder cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4812.

A 13-year-old girl presented with an occult blood in urine. CT revealed right rudimentary kidney and left hydronephrosis. Renogram demonstrated right poor renal function pattern and left obstructive pattern. She underwent left pyeloplasty. Histologic examination revealed the true ureteral diverticulum. True ureteral diverticulum is a rare congenital anomaly and synonymous with blind-ending bifid ureter. This is a sixth case in the Japanese literature.

The effects of androgen deprivation therapy (ADT) include not only suppression of tumor growth, but also adverse effects on various bodily functions. The aim of this study was to determine the metabolic effects of ADT in patients with nonmetastatic prostate cancer. Forty-nine men with prostate cancer were treated with ADT before beginning radical therapy for 6 months. Body weight, peripheral red blood cell counts, hemoglobin, hematocrit, fasting blood sugar, serum total cholesterol, blood urea nitrogen, uric acid, compensated calcium, inorganic phosphorus, bone-specific alkaline phosphatase, urinary deoxypyridinoline, and radial bone density determined using dual energy x-ray absorptiometry were examined before and 6 months after ADT treatment. Body weight (P = 0.037) and the levels of fasting blood sugar (P = 0.014), serum total cholesterol (P = 0.017), blood urea nitrogen (P = 0.030), compensated calcium (P < 0.001), inorganic phosphorus (P < 0.001), bone-specific alkaline phosphatase (P < 0.001), and compensated urinary deoxypyridinoline (P < 0.001) increased significantly. Peripheral red blood cell counts (P < 0.001), hemoglobin level (P < 0.001), hematocrit (P < 0.001), uric acid (P < 0.001), and radial bone density (P = 0.023) decreased significantly. These effects of ADT on various bodily functions warrant systematic study in clinical trials. We should be aware of the far-reaching consequences of ADT and incorporate strategies for preventing and managing adverse effects into routine practice.