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1.
IJU Case Rep ; 6(4): 211-215, 2023 Jul.
Article in English | MEDLINE | ID: mdl-37405028

ABSTRACT

Introduction: Although immune checkpoint inhibitors offer significant therapeutic benefits to patients with advanced cancer, they can also cause a variety of immune-related adverse events. As immune checkpoint inhibitors are being widely used, rare immune-related adverse events are being reported. Case presentation: A 70-year-old man with advanced salivary duct carcinoma was treated with pembrolizumab following radiotherapy. After receiving two doses of pembrolizumab, the patient experienced symptoms such as micturition pain and hematuria. Immune-related cystitis was suspected, and the patient underwent a bladder biopsy and bladder hydrodistension. Histological analysis revealed non-neoplastic bladder mucosa with CD8-positive lymphocyte-dominant inflammatory cell infiltration, consistent with immune-related cystitis. The patient's bladder symptoms improved postoperatively without steroid administration. Conclusion: Although steroids are commonly administered to treat immune-related adverse events, bladder hydrodistension may be a promising treatment option for immune-related cystitis to avoid administration of steroids, which may impair the therapeutic effect of immune checkpoint inhibitors.

2.
Curr Oncol ; 30(6): 5350-5365, 2023 05 28.
Article in English | MEDLINE | ID: mdl-37366889

ABSTRACT

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


Subject(s)
Urinary Bladder Neoplasms , Humans , Glycogen Synthase Kinase 3 beta/pharmacology , Cell Line, Tumor , Urinary Bladder Neoplasms/drug therapy , Autophagy , Apoptosis/genetics , Cell Proliferation
3.
BMC Urol ; 23(1): 38, 2023 Mar 18.
Article in English | MEDLINE | ID: mdl-36934227

ABSTRACT

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.


Subject(s)
Atrial Fibrillation , Carcinoma, Renal Cell , Carcinoma, Transitional Cell , Kidney Neoplasms , Urinary Bladder Neoplasms , Male , Humans , Aged , Carcinoma, Transitional Cell/therapy , Carcinoma, Transitional Cell/pathology , Atrial Fibrillation/pathology , Urinary Bladder Neoplasms/pathology , Kidney Neoplasms/pathology , Kidney Pelvis/pathology , Carcinoma, Renal Cell/pathology , Immunotherapy
4.
Sci Rep ; 12(1): 20386, 2022 11 27.
Article in English | MEDLINE | ID: mdl-36437290

ABSTRACT

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 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.


Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Humans , Carcinoma, Renal Cell/pathology , Immune Checkpoint Inhibitors/pharmacology , Immune Checkpoint Inhibitors/therapeutic use , Kidney Neoplasms/pathology , Prognosis
5.
IJU Case Rep ; 5(3): 175-178, 2022 May.
Article in English | MEDLINE | ID: mdl-35509791

ABSTRACT

Introduction: Tumors in the fibroma-thecoma group are benign tumors, typically found in the ovaries of postmenopausal women and occasionally develop in the testes. These tumors are mostly treated with radical orchiectomy because preoperative diagnosis confirming the benign nature is difficult. Case presentation: A 40-year-old man was incidentally pointed out to have a right intrascrotal mass, measuring approximately 10 cm on computed tomography. Malignant testicular tumor was suspected based on the location and size of the tumor. The patient underwent right radical orchiectomy. Histologically, the tumor had no evidence of malignancy, and the diagnosis of tumors in the fibroma-thecoma group was made. The patient had no recurrence 8 months after surgery. Conclusion: Intrascrotal tumors in the fibroma-thecoma group are rare benign tumors and mostly treated with radical orchiectomy due to concerns about malignancies. Further investigation is needed for accurate preoperative diagnosis, and we should be aware of these rare tumors.

6.
Oncol Rep ; 46(4)2021 Oct.
Article in English | MEDLINE | ID: mdl-34468011

ABSTRACT

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 patient­derived 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 whole­exome 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 patient­derived 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 patient­derived TO models, which may have potential for use in the personalized treatment of cancer patients.


Subject(s)
Carcinoma, Renal Cell/drug therapy , Organoids/drug effects , Protein Kinase Inhibitors/pharmacology , Cell Line, Tumor , Humans , Receptor Protein-Tyrosine Kinases
7.
Oncol Lett ; 21(1): 64, 2021 Jan.
Article in English | MEDLINE | ID: mdl-33281975

ABSTRACT

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.

8.
Int J Mol Med ; 45(2): 315-323, 2020 Feb.
Article in English | MEDLINE | ID: mdl-31894292

ABSTRACT

Glycogen synthase kinase­3 (GSK­3), a serine/threonine kinase, is involved in a broad range of pathological processes including cancer. GSK­3 has two isoforms, GSK­3α and GSK­3ß, and GSK­3ß has been recognized as a therapeutic target for the development of new anticancer drugs. The present study aimed to investigate the antitumor effects of 9­ING­41, which is a maleimide­based ATP­competitive small molecule GSK­3ß inhibitor active in patients with advanced cancer. In renal cancer cell lines, treatment with 9­ING­41 alone induced cell cycle arrest and apoptosis, and autophagy inhibitors increased the antitumor effects of 9­ING­41 when used in combination. Treatment with 9­ING­41 potentiated the antitumor effects of targeted therapeutics and increased the cytotoxic effects of cytokine­activated immune cells on renal cancer cell lines. These results provided a compelling rationale for the inclusion of patients with renal cancer in studies of 9­ING­41, both as a single agent and in combination with current standard therapies.


Subject(s)
Antineoplastic Agents/pharmacology , Glycogen Synthase Kinase 3 beta/antagonists & inhibitors , Kidney Neoplasms/drug therapy , Maleimides/pharmacology , Protein Kinase Inhibitors/pharmacology , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Glycogen Synthase Kinase 3 beta/metabolism , Humans , Kidney Neoplasms/metabolism , Maleimides/chemistry , Protein Kinase Inhibitors/chemistry
9.
Urol Int ; 104(5-6): 386-390, 2020.
Article in English | MEDLINE | ID: mdl-31801150

ABSTRACT

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.


Subject(s)
Foreskin/transplantation , Hypospadias/surgery , Urethra/surgery , Child , Child, Preschool , Humans , Infant , Male , Postoperative Complications/epidemiology , Retrospective Studies , Urologic Surgical Procedures, Male/methods
10.
Sci Rep ; 9(1): 19977, 2019 12 27.
Article in English | MEDLINE | ID: mdl-31882719

ABSTRACT

Glycogen synthase kinase-3 beta (GSK-3ß), a serine/threonine kinase, has been identified as a potential therapeutic target in human bladder cancer. In the present study, we investigated the antitumor effect of a small molecule GSK-3ß inhibitor, 9-ING-41, currently in clinical studies in patients with advanced cancer, in bladder cancer cell lines. We found that treatment with 9-ING-41 leads to cell cycle arrest, autophagy and apoptosis in bladder cancer cells. The autophagy inhibitor chloroquine potentiated the antitumor effects of 9-ING-41 when tested in combination studies. Our findings also demonstrate that 9-ING-41 enhanced the growth inhibitory effects of gemcitabine or cisplatin when used in combination in bladder cancer cells. Finally, we found that 9-ING-41 sensitized bladder cancer cells to the cytotoxic effects of human immune effector cells. Our results provide a rationale for the inclusion of patients with advanced bladder cancer in clinical studies of 9-ING-41.


Subject(s)
Antineoplastic Agents/pharmacology , Glycogen Synthase Kinase 3 beta/antagonists & inhibitors , Indoles/pharmacology , Maleimides/pharmacology , Protein Kinase Inhibitors/pharmacology , Autophagy/drug effects , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Cisplatin/pharmacology , Drug Synergism , Humans , Urinary Bladder Neoplasms
11.
Urol Int ; 102(4): 462-467, 2019.
Article in English | MEDLINE | ID: mdl-30917379

ABSTRACT

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.


Subject(s)
Anti-Bacterial Agents/administration & dosage , Antibiotic Prophylaxis/methods , Fever/drug therapy , Fever/prevention & control , Urinary Tract Infections/drug therapy , Urinary Tract Infections/prevention & control , Vesico-Ureteral Reflux/drug therapy , Adolescent , Child , Child, Preschool , Drug Administration Schedule , Female , Fever/complications , Humans , Infant , Kaplan-Meier Estimate , Kidney/pathology , Male , Multivariate Analysis , Proportional Hazards Models , Recurrence , Retrospective Studies , Risk Assessment , Risk Factors , Secondary Prevention , Urinary Tract Infections/complications , Vesico-Ureteral Reflux/complications
12.
Nihon Hinyokika Gakkai Zasshi ; 109(2): 68-73, 2018.
Article in Japanese | MEDLINE | ID: mdl-31006744

ABSTRACT

(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.


Subject(s)
Antibodies , Bortezomib/administration & dosage , Graft Rejection/immunology , Graft Rejection/therapy , HLA Antigens/immunology , Kidney Transplantation , Adolescent , Adult , Bortezomib/therapeutic use , Child , Chronic Disease , Female , Graft Rejection/drug therapy , Humans , Infusions, Intravenous , Male , Middle Aged , Treatment Failure , Young Adult
13.
Urol Int ; 97(2): 238-40, 2016.
Article in English | MEDLINE | ID: mdl-27045294

ABSTRACT

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.


Subject(s)
Kidney Diseases/complications , Ureterocele/complications , Urinary Bladder Diseases/complications , Humans , Infant, Newborn , Male , Rupture, Spontaneous , Ureterocele/pathology , Urinary Bladder Diseases/pathology
14.
Nihon Hinyokika Gakkai Zasshi ; 103(3): 569-72, 2012 May.
Article in Japanese | MEDLINE | ID: mdl-22876664

ABSTRACT

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.


Subject(s)
Diverticulum/congenital , Kidney/abnormalities , Ureteral Diseases/congenital , Adolescent , Female , Humans , Hydronephrosis/etiology
15.
J Clin Endocrinol Metab ; 90(2): 657-60, 2005 Feb.
Article in English | MEDLINE | ID: mdl-15562007

ABSTRACT

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.


Subject(s)
Androgen Antagonists/therapeutic use , Flutamide/therapeutic use , Prostatic Neoplasms/metabolism , Absorptiometry, Photon , Aged , Aged, 80 and over , Blood Glucose/metabolism , Blood Urea Nitrogen , Body Weight , Cholesterol/blood , Erythrocyte Count , Humans , Male , Middle Aged , Neoplasm Staging , Orchiectomy , Prostatic Neoplasms/pathology
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