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Osteosarcoma (OS) in humans is characterized by alterations in the TP53 gene. In mice, loss of p53 triggers OS development, for which c-Myc (Myc) oncogenicity is indispensable. However, little is known about which genes are targeted by Myc to promote tumorigenesis. Here, we examined the role of γ-glutamylcyclotransferase (Ggct) which is a component enzyme of the γ-glutamyl cycle essential for glutathione homeostasis, in human and mouse OS development. We found that GGCT is a poor prognostic factor for human OS, and that deletion of Ggct suppresses p53-deficient osteosarcomagenesis in mice. Myc upregulates Ggct directly by binding to the Ggct promoter, and deletion of a Myc binding site therein by genome editing attenuated the tumorigenic potential of p53-deficient OS cells. Taken together, these results show a rationale that GGCT is widely upregulated in cancer cells and solidify its suitability as a target for anticancer drugs., (© 2024 The Author(s). Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

A 76-year-old woman was referred to our department because of high fever and bladder irritative symptoms. Computed tomography revealed the presence of a heterogeneous mass with indistinct borders on the left anterior wall of the bladder. The lesion contained a linear hyperdense shadow. We initially suspected malignancy, such as urachal carcinoma or soft-tissue sarcoma. However, upon review of previous computed tomography scans, it was confirmed that the linear hyperdense shadow had migrated from the intestinal tract to the bladder. Considering the possibility of abscess formation caused by a foreign body, we decided to perform a transurethral biopsy. The results of the pathological analysis showed abscess formation. The patient was diagnosed with perivesical abscess caused by accidental ingestion of a fish bone. Following the administration of antibiotics, the lesion markedly shrank. Although it is difficult to distinguish perivesical abscess from malignant disease, invasive treatment can be avoided by appropriate diagnosis based on imaging studies.

Background/aim: γ-Glutamyl cyclotransferase (GGCT) is up-regulated in various cancer types, including lung cancer. In this study, we evaluated efficacy of gapmer-type antisense oligonucleotides (ASOs) targeting GGCT in an A549 lung cancer xenograft mouse model and studied their mechanisms of action., Materials and Methods: GGCT was inhibited using GGCT-ASOs and cell proliferation was evaluated by dye exclusion test. Western blot analysis was conducted to measure expression of GGCT, p21, p16 and p27, phosphorylation of AMP-activated protein kinase, and caspase activation in A549 cells. Induction of apoptosis and up-regulation of reactive oxygen species were assessed by flow cytometry using annexin V staining and 2',7'-dichlorodihydrofluorescein diacetate dye, respectively., Results: GGCT-ASOs suppressed GGCT expression in A549 cells, inhibited proliferation, and induced apoptosis with activation of caspases. GGCT-ASOs also increased expression of cell-cycle regulating proteins, phospho-AMPK and ROS levels. Systemic administration of GGCT-ASOs to animals bearing A549 lung cancer xenografts showed significant antitumor effects without evident toxicity., Conclusion: GGCT-ASOs appear to be promising as novel cancer therapeutic agents., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Prohibitin-2 (PHB2) is a scaffold protein that has pleiotropic functions, which include interacting with γ -glutamylcyclotransferase (GGCT) in the cytoplasm and repressing the transcriptional activities of the p21 Waf1/Cip ( p21 ) gene in the nucleus. The cytotoxic drug fluorizoline binds to PHB1/2 and exerts antiproliferative actions on cancer cells. However, the precise mechanism underlying the antiproliferative effects of fluorizoline is not fully elucidated. In the present study, we first show that fluorizoline induces p21 expression in several human cancer cell lines, including MCF7 breast cancer cells. Treatment of MCF7 cells with fluorizoline suppressed proliferation and prevented cells from entering into the DNA synthesis phase. Knockdown of p21 rescued the suppressed proliferation, indicating that fluorizoline inhibited MCF7 cell growth via the induction of p21. Overexpression of PHB2 in MCF7 cells prevented the induction of p21 expression by fluorizoline and restored the antiproliferative effects and blockade of cell cycle progression. Moreover, treatment of MCF7 cells with fluorizoline inhibited the interaction between endogenous PHB2 and GGCT proteins and reduced the level of nuclear localization of PHB2 proteins. These results indicate that targeting PHB2 with fluorizoline induces the expression of p21 and consequently blocks proliferation of cancer cells. SIGNIFICANCE STATEMENT: This study shows that fluorizoline may be a promising novel anticancer drug candidate that induces p21 expression and blocks cell-cycle progression in human cancer cell lines. In addition, we show that fluorizoline inhibits the interaction between PHB2 and GGCT and reduces the nuclear localization of PHB2 proteins., (Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics.)

Renal cell carcinoma (RCC) has the high mortality rate among urological malignancies. The development of RCC cannot be effectively reduced by molecular targeted therapies based on nutrient deprivation, such as inhibition of tumor angiogenesis. The objective of this study was to identify predictive biomarkers of poor prognosis and therapeutic molecular targets in patients with RCC. Two independent cohorts were analyzed in the present study. Global transcriptomics were used in the first cohort (43 patients with RCC) to identify biomarker genes. Each identified biomarker was subsequently analyzed using immunohistochemistry in the second cohort (97 patients with RCC). Following transcriptomics, biomarkers were evaluated using receiver operating characteristic curve analysis. Predictive accuracy for poor survivals was assessed using the log-rank test and Cox multivariate analysis. Global transcriptomic analysis in the first cohort focusing on cases with survival periods <2 years after initial diagnosis of metastasis detected seven overexpressed genes, which correlated with poor prognosis. The ADP-ribosylation factor-like 4C (ARL4C) exhibited the best accuracy in the receiver operating characteristic curve analysis and predicted poor survival in the first cohort (log-rank test, P<0.001; Cox multivariate analysis, hazard ratio =167, P=0.005). In the second cohort, the expression of ARL4C was semi-quantitatively evaluated through immunohistochemistry. Twenty-seven cases showed high levels of ARL4C, confirming a significant association with shorter survivals (log-rank test, P<0.001; Cox multivariate analysis, hazard ratio =9.41, P=0.004). ARL4C was shown to be a predictive biomarker for poor prognosis in patients with RCC and may be a novel target in the treatment of RCC., Competing Interests: None.

Selective targeting of drugs to tumor cells is a key goal in oncology. Here, we performed an in vivo phage display to identify peptides that specifically target xenografted prostate cancer cells. This yielded three peptide candidates, LN1 (C-TGTPARQ-C), LN2 (C-KNSMFAT-C), and LN3 (C-TNKHSPK-C); each of these peptides was synthesized and evaluated for binding and biological activity. LN1 showed the highest avidity for LNCaP prostate cancer cells in vitro and was thus administered to tumor-bearing mice to evaluate in vivo binding. Strikingly, LN1 specifically bound to the tumor tissue and exhibited very low reactivity with normal liver and kidney tissues. To demonstrate that LN1 could specifically deliver drugs to prostate cancer tissue, a therapeutic peptide, LN1-KLA (C-TGTPARQ-C-GGG- D [KLAKLAK] 2 ), was prepared and used to treat LNCaP cells in vitro and was also administered to tumor-bearing mice. The therapeutic peptide significantly suppressed growth of the cells both  in vitro and in vivo . Our study shows that a selective homing peptide strategy could facilitate cell-specific targeting of therapeutics while avoiding adverse reactions in normal tissues.

We report a case of drug-induced interstitial lung disease as a result of combined androgen blockade. A 75 year-old male was receiving bicalutamide and reuprorelin acetate treatment for advanced prostate cancer. Two weeks after starting therapy, the patient developed dyspnea due to interstitial lung disease. Based on the clinical diagnosis of drug-induced interstitial lung disease, bicalutamide was withdrawn and steroid therapy was initiated. The patient succumbed 6 days later due to respiratory failure. Drug-induced interstitial lung disease following combined androgen blockade is a rare, but potentially serious adverse effect that requires close attention.

Ureterosciatic hernia is an uncommon condition that can cause ureteral obstruction. Here, we report a case of ureterosciatic hernia successfully treated by ureteral stent placement. A 95-year old woman presented to our emergency department with high fever. An abdominal CT scan revealed mild left hydronephrosis and urinalysis identified pyuria. The patient was subsequently admitted to hospital with a diagnosis of complicated pyelonephritis. No recovery was evident after antimicrobial treatment, a repeat CT scan revealed a ureterosciatic hernia. We indwelled a left ureteral stent and repaired the hernia. We did not opt for a surgical approach because of the patient's age and presence of dementia. The stent was removed after 2 months, but the patient was re-admitted 4 months later because of pyelonephritis. Here, we indwelled a left ureteral stent, and the patient underwent regular ureteral stent exchange. Placement of a ureteral stent for ureterosciatic hernia is an effective treatment for elderly patients and those who are poor surgical candidates.

Gamma-glutamylcyclotransferase (GGCT) was originally identified as a protein highly expressed in bladder cancer tissues by proteomic analysis, and its higher expression in a variety of cancers compared to normal tissues have been shown. Depletion of GGCT in various cancer cells results in antiproliferative effects both in vitro and in vivo ; thus it is considered a promising therapeutic target. Although it has been shown that knockdown of GGCT induces cellular senescence and non-apoptotic cell death, associated with upregulation of cyclin-dependent kinase inhibitors (CDKIs) including p21 WAF1/CIP1 , the cellular events that follow GGCT depletion are not fully understood. Here, we show that GGCT depletion induced autophagy in MCF7 breast and PC3 prostate cancer cells. Conversely, overexpression of GGCT in NIH3T3 fibroblast under conditions of serum deprivation inhibited autophagy and increased proliferation. Simultaneous knockdown of autophagy related-protein 5, a critical effector of autophagy, along with GGCT in MCF7 and PC3 cells led to significant attenuation of the multiple cellular responses, including upregulation of CDKIs, increased numbers of senescence-associated β-galactosidase positive senescent cells, and growth inhibition. Furthermore, we show that autophagy-promoting signaling cascades including activation of the AMPK-ULK1 pathway and/or inactivation of the mTORC2-Akt pathway were triggered in GGCT-depleted cells. These results indicate that autophagy plays an important role in the growth inhibition of cancer cells caused by GGCT depletion., Competing Interests: None.

Previous studies show that gamma-glutamylcyclotransferase (GGCT) is expressed at high levels in various cancer tissues and that its knockdown inhibits MCF7 cancer cell growth via upregulation of p21 WAF1/CIP1 (p21). However, the detailed underlying mechanism is unclear. Here, we used yeast two-hybrid screening and co-immunoprecipitation to identify Prohibitin-2 (PHB2) as a novel protein that interacts with GGCT. We also show that nuclear expression of PHB2 in MCF7 cells falls upon GGCT knockdown, and that overexpression of PHB2 inhibits p21 upregulation. A chromatin immunoprecipitation assay revealed that nuclear PHB2 proteins bind to the p21 promoter, and that this interaction is abrogated by GGCT knockdown. Moreover, knockdown of PHB2 alone led to significant upregulation of p21 and mimicked the cellular events induced by GGCT depletion, including G0/G1 arrest, cellular senescence, and growth inhibition, in a p21 induction-dependent manner. Taken together, the results indicate that PHB2 plays a central role in p21 upregulation following GGCT knockdown and as such may promote deregulated proliferation of cancer cells by suppressing p21., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: The Kidney Disease: Improving Global Outcomes group (KDIGO) defined acute kidney injury (AKI) as an elevation of serum creatinine (sCR) exceeding 0.3 mg/dl within 48 h. The widely used adverse events criteria for chemotherapy, Common Toxicity Criteria for Adverse Events Version 4.0 (CTCAE v4.0), also defined AKI as sCR exceeding 0.3 mg/dl, but with no provision of a time course. Here, we attempted to clarify the impact of AKI (CTCAE v4.0) during cisplatin-based chemotherapy on clinical outcome of patients with advanced urothelial cancer (UC)., Methods: This multicenter retrospective study included 230 UC patients who received cisplatin-based chemotherapy., Results: During the first chemotherapy course, AKI (CTCAE v4.0) episodes were observed in 61 patients (26.5 %), whereas only four patients (1.5 %) experienced AKI (KDIGO) episodes. Both the pretreatment estimated glomerular filtration rate (eGFR) and creatinine clearance by Cockcroft-Gault formula were not efficient predictors for the development of AKI (CTCAE v4.0). AKI (CTCAE v4.0) impacted renal function: at the start of second-course chemotherapy, the average eGFR of the patients with AKI (CTCAE v4.0) was 54.1 ml/min/1.73 m 2 , significantly lower than that of patients without AKI (CTCAE v4.0) (63.4 ml/min/1.73 m 2 ). As a result, only 57.4 % of patients with AKI (CTCAE v4.0) received the planned treatment at the second course. The survival of the patients who developed AKI (CTCAE v4.0) was significantly worse than that of the patients who did not. The 3-year OSs were 10.3 and 21.4 %, respectively (P = 0.02)., Conclusion: The present study demonstrated that AKI (CTCAE v4.0) during chemotherapy had a negative impact on both the intensity of subsequent chemotherapy and oncological outcomes.

An ectopic kidney is a common congenital anomaly of the urogenital system, but malignant tumor in an ectopic kidney has been rarely reported. We report a case of ureteral carcinoma arising from an ectopic kidney in an 83-year-old male. He visited a hospital complaining of gross hematuria. Computed tomography revealed right ectopic kidney, right ureteral tumor and bladder tumor around the right ureteral orifice. Transurethral resection of the bladder tumor was performed and histopathological diagnosis was urothelial carcinoma. He was referred to our clinic for surgery of the right ureteral tumor. We performed open right nephroureterectomy and partial cystectomy. The histopathological diagnosis was a high grade urothelial carcinoma of the right ureter, pT3N0. Four months postoperatively, there was no evidence of recurrence. We discuss the clinical and pathological features of the malignancy in an ectopic kidney.

Background: The standard regimen of systemic chemotherapy for patients with advanced urothelial cancer (UC) changed from methotrexate, vinblastine, adriamycin, and cisplatin (MVAC) to gemcitabine and cisplatin (GC) in 2008 when the use of gemcitabine for UC began to be reimbursed by public health insurance in Japan. We examined its influence on the chemotherapy trend in elderly patients aged ≥80 years., Methods: Among 345 patients included in our previous multicenter retrospective cohort study (chemotherapy for urothelial carcinoma: renal function and efficacy study; CURE study), the outcome of 30 patients aged ≥80 years was reviewed before and after 2008 and compared with 315 young patients., Results: There were only 7 (4.6 %) elderly individuals among all registered patients before 2008, whereas the number increased to 23 (12 %) after 2008. Before 2008, only one elderly patient received MVAC, while GC (whose rate was similar to the rate in young patients) was administered to 13 patients (56.5 %) after 2008. The chemotherapeutic effect and overall survival (OS) rate was not significantly different between young and elderly patients. In the elderly treated with the GC regimen, the renal impairment rate after the first cycle was significantly higher, and the presence of distant metastases and renal impairment were independent prognostic factors in a multivariate analysis., Conclusion: Since GC was approved as the standard regimen for first-line chemotherapy in UC, selected elderly patients have been able to safely receive systemic chemotherapy like young patients. The clinical response rate and OS rate were similar to the young, but we need to monitor changes in renal function more closely in the elderly treated with GC.

Dormant cancer cells are deprivation-resistant, and cause a number of problems for therapeutic approaches for cancers. Renal cell carcinomas (RCCs) include deprivation-resistant cells that are resistant to various treatments. In this study, the specific characteristics of deprivation-resistant cells were transcriptionally identified by next generation sequencing. The hypoxia-inducible factors (HIF) transcription factor network was significantly enhanced in deprivation-resistant RCCs compared to the sensitive RCCs. Deprivation-resistant RCCs, that had lost Von Hippel-Lindau tumor suppressor expression, expressed hydroxyl-HIF2-alpha in the nucleus, but not sensitive-RCCs. Hydroxyl-HIF-alpha was also expressed in nuclei of RCC tissue samples. Knockdown for HIF2-alpha, but not HIF1-alpha, induced cell death related to a reduction in HIF-related gene expression in deprivation-resistant RCC cells. Chetomin, a nuclear HIF-inhibitor, induced marked level of cytotoxicity in deprivation-resistant cells, similar to the knockdown of HIF2-alpha. Therefore, hydroxyl-HIF2-alpha might be a potential therapeutic target for RCCs.

A 67-year-old man presented at our hospital with severe edema on the left side of his neck, chest and brachial regions. He had a history of right radical nephrectomy due to renal cell carcinoma (RCC, clear cell subtype, stage II) 15 years earlier. Thereafter, metastases to the pancreatic tail and right lung, and left lung metastasis were removed at 8 years and 11 years, respectively, after the nephrectomy. Four years earlier, he had also undergone total gastrectomy for gastric carcinoma (poorly differentiated adenocarcinoma, stage IV) and subsequent maintenance chemotherapy for gastric carcinoma. Follow-up computed tomography (CT) disclosed bilateral lung metastases and a pancreatic head metastasis. Cytology of pleural effusion on admission suggested pleuritis carcinomatosa from RCC. Clinical diagnosis was bilateral lung and pancreatic head metastases, pleuritis carcinomatosa and left subclavian vein thrombosis due to RCC metastasis. Maintenance chemotherapy for gastric carcinoma was replaced by Sunitinib 50 mg for RCC but he died of progressive disease 20 days later. Immunohistochemical study of the tissue from autopsy revealed lung metastasis and pancreatic head metastasis from both RCC and gastric carcinoma as well as multiple visceral metastases, pleuritis carcinomatosa and left subclavian vein thrombosis due to gastric carcinoma. Cause of death was acute respiratory failure due to pulmonary tumor embolism and pulmonary edema. Immunohistochemical study from autopsy was able to reveal the exact diagnosis, and immunohistochemical studies may be helpful in diagnosing the exact origin of metastasis and selecting appropriate treatmentsin patientswith multiple cancers.

Objective: There has been no clear evidence supporting similar chemo-responses for upper and lower urothelial carcinomas., Methods: We conducted a multicenter retrospective cohort study to analyze urothelial carcinoma patients who underwent systemic chemotherapy at 17 centers from 2004 to 2010. A total of 298 patients with either urothelial carcinoma of the bladder (N = 151) or upper tract urothelial carcinoma (N = 147) were included. Differences in tumor location (urothelial carcinoma of the bladder vs. upper tract urothelial carcinoma) were evaluated in relation to the patient backgrounds and clinical responses to systemic chemotherapy., Results: Overall 216 patients were treated with cisplatin-based chemo-regimens (gemcitabine and cisplatin in 92, or methotrexate, vinblastine, adriamycin and cisplatin/methotrexate, epirubicin and cisplatin in 124). Among 186 initially metastatic patients, the incidences of lung metastasis and liver metastasis were 39.2 and 34.1%, respectively, in upper tract urothelial carcinoma patients, and were significantly higher than those with urothelial carcinoma of the bladder (22.4% for lung; 8.4% for liver metastasis). Among 112 post-surgical recurrent/metastatic patients, age was significantly higher and estimated glomerular filtration rate at baseline was significantly lower in upper tract urothelial carcinoma patients than those with urothelial carcinoma of the bladder. No significant differences were observed in overall clinical response rates for systemic chemotherapy between urothelial carcinoma of the bladder (45.8%) and upper tract urothelial carcinoma (38%) in initially metastatic patients or between urothelial carcinoma of the bladder (43.2%) and upper tract urothelial carcinoma (44.1%) in post-surgical recurrent/metastatic patients. Tumor location was not independently associated with cancer-specific survival in either initially metastatic or post-surgical recurrent/metastatic urothelial carcinoma patients., Conclusions: No significant difference was observed in response rates of urothelial carcinoma of the bladder and upper tract urothelial carcinoma to systemic chemotherapy, suggesting that a similar chemo-regimen can be applied to metastatic urothelial carcinoma patients regardless of tumor location (upper vs. lower)., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

A 25-year-old man presented complaining of a painful, left scrotal swelling. He first noticed a mass in his left scrotum during childhood, but, in the absence of clinical symptoms, did not seek medical attention. We detected a left testicular tumor which was elastic, firm and smooth. Serum levels of alpha-fetoprotein (AFP), human chorionic gonadotropin (hCG), and lactate dehydrogenase (LDH) were all within normal range. Magnetic resonance imaging (MRI) and ultrasound revealed a solid tumor with cysts accompanied by intracystic hemorrhage and calcified walls. From the above findings, the tumor was suspected to be benign and, we therefore planned testis-sparing surgery. We performed tumor enucleation under cold ischemia. Since an intraoperative frozen section revealed the tumor to be benign, we preserved the remaining testis as planned. The final pathologic diagnosis was a mature teratoma without a malignant germ cell component. Evidence of recurrence has not been observed five years after the operation. In conclusion, when a mature teratoma that has been present since prepuberty is suspected in an adult, testis-sparing surgery should be considered.

Leiomyoma is a benign smooth muscle tumor which is rarely found in the paraurethral region. We report a case of paraurethral leiomyoma in a 44-year-old female who visited a clinic complaining of urinary retention. Magnetic resonance imaging revealed a 9 cm mass adjacent to the urethra. She was referred to our department. Transvaginal needle biopsy was performed and the histopathological diagnosis was leiomyoma. The mass was completely excised transperitoneally and transvaginally. The resected specimen was 8 × 7 × 4.5 cm in size and 194 g in weight. Histopathological diagnosis was leiomyoma and the tumor cells demonstrated immunoreactivity for estrogen receptors and progesterone receptors. Herpost operative course was uneventful and she gained normal voiding function. In a follow-up after 3 months, there was no evidence of recurrence. We discuss the clinical and pathological features of the paraurethral leiomyoma.

A 6-month-old boy was referred to our hospital with left scrotal swelling. Scrotal ultrasound examination revealed a 2 cm cystic mass without solid component in left testicular parenchyma. Serum AFP, hCG and LDH levels were within normal limits. Although we suspected a simple cyst of the testis or a benign testicular tumor, the left testicle was explored via an inguinal incision in case of malignancy. Since intraoperative frozen section revealed benign, we preserved the remaining testis. The wall of cystic mass had a small solid lesion. The definitive pathological examination of the cyst wall showed mature teratoma including squamous epithelium, glandular epithelium of enteric type and cartilage. At 4 years of follow up, he was free of recurrence without testicular atrophy.

Objective: The aim of the study is to clarify the clinical effects of first-line chemotherapy regimens for advanced urothelial cancer on clinical responses and survival of patients grouped by renal function., Methods: In this multicenter retrospective cohort study, 345 urothelial cancer patients received systemic chemotherapy for metastatic or unresectable disease in 17 centers (2004-10)., Results: Two hundred and forty-one patients were treated with methotrexate, vinblastine, doxorubicin and cisplatin/methotrexate, epirubicin and cisplatin (n = 136) or gemcitabine and cisplatin (n = 105) followed by carboplatin-based treatments, non-platinum treatments or other regimens. After 2008, gemcitabine and cisplatin was the most frequently used regimen in patients with an estimated glomerular filtration rate < 60 ml/min/1.73 m(2) and in those with estimated glomerular filtration rate ≥ 60 ml/min/1.73 m(2). The gemcitabine and cisplatin patients' complete response rate was 10.5% and their response rate was 52.4%, which was highest among all regimens. Gemcitabine and cisplatin demonstrated a better 3-year overall survival when the estimated glomerular filtration rate was ≥ 60 ml/min/1.73 m(2) (31.4%), but it tended to be worse when the estimated glomerular filtration rate was < 60 ml/min/1.73 m(2) (14.1%). In the latter cases, the dose reduction rate of gemcitabine and cisplatin was high (43.9%). Among the patients with estimated glomerular filtration rate < 60 ml/min/1.73 m(2), the 1-year overall survival of the patients treated with a reduced dose of gemcitabine and cisplatin was significantly lower than that of those treated with standard-dose gemcitabine and cisplatin (26.2 vs. 60.3%, respectively, P = 0.0108)., Conclusions: Gemcitabine and cisplatin provided favorable responses and survival in patients with estimated glomerular filtration rate ≥ 60 ml/min/1.73 m(2) but unsatisfactory oncological outcomes in patients with estimated glomerular filtration rate < 60 ml/min/1.73 m(2), especially when treated with a reduced dose. Alternative regimens might be optimal rather than reduced-dose gemcitabine and cisplatin in patients with estimated glomerular filtration rate < 60 ml/min/1.73 m(2)., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Sunitinib has been approved for the treatment of metastatic renal cell carcinoma (RCC). Sunitinib pharmacokinetics shows a large interpatient variability., Patients and Methods: A retrospective, observational clinical study of 21 patients with RCC was performed. Sunitinib was administered for 4 weeks of a 6-week cycle for the first cycle. We evaluated the association of sunitinib-induced toxicities and clinical outcomes with the trough total sunitinib concentration in a steady state during the first cycle., Results: The median total sunitinib concentration was 91.8 ng/mL (range, 49.8-205 ng/mL). There was an association between total sunitinib concentration and the severity of thrombocytopenia, anorexia, and fatigue. Patients with ≥ 100 ng/mL total sunitinib (n = 8), compared with patients with < 100 ng/mL (n = 13), had a greater incidence of Grade ≥ 3 toxicities (6 patients [75.0%] vs. 3 patients [23.1%]). Patients with < 100 ng/mL total sunitinib had significantly longer time to treatment failure (TTF) and progression-free survival (PFS) time than patients with ≥ 100 ng/mL (median TTF, 590 vs. 71 days; P = .04; median PFS, 748 vs. 238 days; P = .02)., Conclusion: Results of this study suggest that therapeutic drug monitoring of sunitinib could be useful for avoiding severe toxicities. Dose reduction might be needed, especially when the total sunitinib concentration is ≥ 100 ng/mL, to avoid unnecessary early discontinuation of treatment., (Copyright © 2015 Elsevier Inc. All rights reserved.)

In all creatures including humans, the molecules that function in accordance with the genetic code are mainly proteins. After completing the sequencing of the human genome, rapid progress has been made in proteome analysis. The primary structures of almost all proteins were determined by the human genome sequence. However, the whole picture of proteins cannot be elucidated because of alternative splicing and post-translational modifications. Therefore, genomic as well as systematic and comprehensive information of proteins is required. Modern methods of proteomics have dramatically improved the quality and speed of protein analysis. Developments in both bioinformatics and mass spectrometry have contributed to the technical improvement, making it possible to identify proteins in a short time with high accuracy even from a very small sample. In the field of cancer research, many studies of useful diagnostic and prognostic biomarkers using these proteomic technologies have been reported, and target molecules for treatment have been explored. The aim of the present review was to summarize the basic technologies of proteomics and recent research in the field of urothelial cancer obtained using proteomic methods., (© 2015 The Japanese Urological Association.)

Six regional medical associations in Shiga prefecture agreed to cooperate in an investigation of medical care for male gonococcal and chlamydial urethritis. In June 2011, we sent a questionnaire to 372 medical offices in Shiga prefecture, and analyzed replies of respondents. Ten urologists and 175 non-urologists responded to the survey (response rate 49.7%). Among 185 physicians, 52 (10 urologists and 42 nonurologists) have treated male patients with gonococcal and chlamydial urethritis. More than 20% (42/175) of non-urological clinics are involved in the medical management. At initial diagnosis for sexually transmitted male urethritis, all urologists select the nucleic acid amplification method (100%), whereas many non-urologists do not (35%). For the treatment of chlamydial urethritis, non-urologists select levofloxacin (LVFX, 52.8%) rather than azithromycin (AZM, 22.0%), whereas urologists use AZM (78.0%) mostly but do not use LVFX (0%) (p = 0.023). For the treatment of gonococcal urethritis, non-urologists prefer oral new quinolones (53.1%) compared to urologists (25.0%) (p = 0. 74). For cure judgment of gonoccocal and chlamydial urethritis, many non-urologists rely on the improvement of subjective symptoms (50 and 47%), but urologists do not (10 and 0%) (p = 0.022 and 0.026, respectively). As for recognition of the clinical guideline for sexually transmitted disease, most urologists (90%) know it, but few non-urologists (13%) do (p < 0.001). We found that non-urological clinics make a great contribution to the medical treatment for male gonococcal and chlamydial urethritis in Shiga prefecture. It is important to standardize the medical care for sexually transmitted male urethritis by familiarizing non-urological practitioners with the clinical guideline.

We report a repair of a right ureteral stenosis with the appendix as a ureteral substitute. A 20-year-old male suffered a traumatic injury in a motorcycle accident. He underwent an emergency operation for right hemothorax, intraabdominal hemorrhage, and bone fracture of right leg. Three weeks later, right hydronephrosis and urinoma were identified. Combined retrograde and antegrade pyelography demonstrated a severe 7 cm long stenosis in the right upper ureter. After an indwelling right nephrostomy catheter was placed, he returned to the hospital for a ureteral reconstruction. We planned to substitute the appendix to bridge the stenotic ureter. After transecting the appendix from the cecum, the mesoappendix was spatulated from mesoileum. Ureteral tissue was resected and appendix was interposed. Three weeks later, ureteral stent was removed. DTPA diuretic renogram scintigraphy demonstrated no evidence of obstruction five weeks later. Two years postoperatively, the patient was asymptomatic and his renal function was normal. Although only few cases of ureteral repair with appendix are known, uretero-appandix replacement is less invasive and complicated, and recommended in some cases.

A 52-year-old man who had been treated with sorafenib for lung metastasis of renal cell carcinoma (RCC) presented to our hospital with iron-deficiency anemia. He had undergone right nephrectomy for RCC (clear cell carcinoma, pT1bN0M0) 11 years ago and lung metastasis developed 6 years after the surgery. Although upper gastrointestinal endoscopy and colonoscopy were performed on suspicion of gastrointestinal bleeding, no abnormality was detected. Capsule endoscopy and single balloon small bowel endoscopy disclosed a hemorrhagic submucosal tumor in the jejunum. Laparoscopic partial jejunectomy was performed, and pathological examination indicated metastatic RCC to the small intestine. After the operation, anemia improved but he died 8 months later because of intrabronchial bleeding from the metastatic lesion of the lung. Metastatic RCC of the small intestine is relatively rare, its diagnosis is difficult. Recently, new diagnostic tools such as capsule endoscopy and balloon-assisted endoscopy have been developed, and they are useful in diagnosing gastrointestinal bleeding (OGIB) which can not be detected by traditional enteroscopy. If patients with advanced RCC show gastrointestinal bleeding of uncertain etiology, we should perform aggressive examination of the digestive tract with these diagnostic tools.

Human chromosome 7 ORF 24 (C7orf24) has been identified as a tumor-related protein, and shown to be a γ-glutamyl cyclotransferase. In the current study, we characterized the promoter region of the human C7orf24 gene to explore the transcriptional regulation of the gene. We revealed that the human C7orf24 promoter is a TATA-less promoter, containing five CCAAT boxes aligned in a forward orientation. By performing a luciferase reporter assay with 5'-deleted and site-directed mutated constructs in HeLa, MCF-7 and IMR-90 cells, we found that three proximal CCAAT boxes are important for basal transcription. Electrophoretic mobility gel shift assay and chromatin immunoprecipitation assay demonstrated that NF-Y specifically bound to all three CCAAT boxes. In addition, the mRNA and protein expression levels of C7orf24 were significantly reduced in HeLa cells depleted of NF-YB, a subunit of NF-Y. These results suggested that NF-Ys bound to the three proximal CCAAT boxes play a central role in the transcription of the gene. Furthermore, as in the case of other genes transcribed under the control of multiple NF-Ys, such as human E2f1 and cyclin b1, the C7orf24 gene expression profile oscillated during the cell cycle, implying that C7orf24 is a novel cell cycle-associated gene., (© 2011 The Authors Journal compilation © 2011 FEBS.)

A 65-year-old man presented with gross hematuria in 2004. Computed tomography (CT) showed a left renal mass, and he underwent laparoscopic radical nephrectomy. Pathological diagnosis was clear cell carcinoma (pT2N0M0, G2＞G3). Four years later, a right adrenal tumor was disclosed by follow-up CT. Then laparoscopic adrenectomy was performed. Histology showed metastasis of the renal clear cell carcinoma. In 2009, he noticed gross hematuria, and cystoscopy revealed a 2cm solitary, non-papillary tumor at the anterior wall of the bladder. At the same time, small solitary liver metastasis (6 mm) was observed on abdominal CT. Transurethral resection of the bladder tumor and resection of liver tumor was performed, and pathological diagnosis was clear cell carcinoma both in vesical and hepatic masses. Nine months after the last surgery, he is living with no obvious tumor recurrence. To our knowledge this case is the 34th case of bladder metastasis from renal cell carcinoma in the Japanese literature. We reviewed literature and discuss the clinical features of bladder metastasis of renal cell carcinoma.

Chemotherapy with docetaxcel (DTX) plus estramustine (EMP) for castration-resistant prostate cancer (CRPC) was started 30 months after the patient, a 65-year-old man, was diagnosed as having advanced prostate cancer cT3aN1M1 (OSS) with an initial PSA of 490 ng/ml. Prostate biopsy specimens revealed moderately differentiated adenocarcinoma, Gleason's sum 4＋5. He was treated with DTX 30 mg/m2 on day 2 and oral EMP 560 mg/day days 1-3 weekly for 3 out of 4 weeks. PSA at start of DTX plus EMP was 81.7 ng/ml, and that after 59 months was 66.6 ng/ml. No objective change in computed tomography and bone scan were observed. He also had no cancer-related symptoms and activity of daily life was good. Chemotherapy was interrupted twice because of pleural effusion and dyspnea by DTX, at 3 and 4 months, respectively, long-term disease stabilization was obtained by this treatment. Other adverse events including interstitial pneumonia, cardiovascular disorders and myelosuppression were not observed. He was maintained on the same chemotherapy. DTX plus EMP chemotherapy is an effective treatment for CRPC patients. Continuing this therapy it is important to survey and control adverse events caused by DTX and EMP carefully.

Background: Up-regulation of the expression of the gene C7orf24, encoding γ-glutamyl cyclotransferase, is a common event in cancers derived from various tissues, but its involvement in osteosarcomas (OS) has not yet been demonstrated., Materials and Methods: The expression of C7orf24 was analyzed in human OS cell lines and primary tumor samples. The biological effects of C7orf24 on growth, motility, and invasion in the OS cell lines were investigated using siRNA for C7orf24. Genes related to the function of C7orf24 were sought by genome-wide gene expression profiling., Results: The level of C7orf24 expression was much higher in the OS cell lines and OS primary tumors than in normal osteoblasts. Down-regulation of C7orf24 expression inhibited the growth of the cell lines in association with enhancement of cell-clustering. Treatment with C7orf24-siRNA inhibited cell motility and invasion. Gene ontology suggested the function of C7orf24 to be related to cell adhesion and protein transport., Conclusion: C7orf24 is also involved in the growth of OS, and is a potential biomarker for this type of tumor.

A 28-year-old male presented with a small painless lump in his left hemiscrotum. A physical examination revealed a non-tender mass that was palpable on the tail of left epididymis, and the testis and spermatic cord were normal. Ultrasonography showed an isoechoic round shaped tumor, 16 mm in diameter. An exploration of the scrotum was performed, based on a preoperative diagnosis of a left epididymal tumor. The tumor was located below the tail of epididymis, and had a whitish capsule, which looked similar to tunica albuginea testis. A frozen section revealed testicular tissue without any malignant change, and therefore polyorchidism was diagnosed. The accessory testis was resected because there was no connection with the epididymis and vas deferens. Polyorchidism is a rare congenital anomaly with 24 cases reported in the Japanese literature. The indications for the resection of an accessory testis are controversial. Patients with intrascrotal polyorchidism might be recommended to undergo a resection of the accessory testes if there are signs of dysplasia during an intraoperative biopsy. Patients must be followed up with regular clinical and ultrasonic examinations when accessory testes are preserved. However, extrascrotal supernumerary testes should be managed by an orchiectomy because of the increased risk of malignancy.

We report a case of renal arteriovenous fistula (RAVF) following blunt renal trauma. An 84-year-old woman who presented with massive gross hematuria after striking her right flank region on the corner of a table was transferred to neighboring hospital on October 24, 2006. Plain computerized tomography (CT) revealed a small subcapsular hematoma on the right kidney, corresponding to a type I renal injury according to the classification of the Japanese Association for the Surgery of Trauma. However, subsequent enhanced CT demonstrated the migration of injected contrast material from the main trunk of the right renal artery to the inferior vena cava in the early phases. Because these findings suggested the occurrence of RAVF, the patient was referred to our hospital for further evaluation and therapy. Selective right renal arteriography enabled observation of trauma-induced RAVF in the upper pole of the affected kidney. Consecutively, transcatheter arterial embolization was performed with a metal coil, after which the shunt blood flow was successfully stopped. RAVF associated with blunt renal injury is extremely rare : only four cases have been previously reported in the literature.

Crossed renal ectopia with fusion is a rare anomaly of the kidney. The present case report describes a 67-year-old man with renal tumor who had been diagnosed as having a crossed ectopic kidney with fusion for 25 years. The pathological diagnosis of the primary tumor specimen was Wilms' tumor with favorable histology. Upon tumor recurrence, molecular detection of SYT-SSX2 fusion transcripts lead to the diagnosis of synovial sarcoma of the kidney. To our knowledge, this is the first case of primary synovial sarcoma arising from a crossed ectopic kidney with fusion.

Objectives: To evaluate the potential suitability of calreticulin (CRT) as a urinary marker for bladder cancer., Methods: Urine specimens were collected from patients with histologically confirmed bladder urothelial carcinoma (Group 1; n = 109), urological patients without urothelial carcinoma (Group 2; n = 60), and non-urological patients (Group 3; n = 40). We developed an enzyme-linked immunosorbent assay (ELISA) procedure using commercially available anti-CRT mono/polyclonal antibodies, and then measured the concentration of urinary CRT., Results: Urinary CRT concentration of group 1 was significantly higher than group 2 and 3 (Mann-Whitney U-test, P < 0.001). Groups 2 and 3 were joined together and considered as a non-bladder cancer group (n = 100), and a cutoff value (2.85 ng/mL) was determined using receiver operating characteristic (ROC) analysis. The sensitivity, specificity, and the area under the curve were 67.9%, 80.0%, and 0.742, respectively. The overall sensitivity of voided urine cytology (VUC) was 39.0% (n = 105), and the sensitivity of urinary CRT was significantly superior to VUC (McNemar test, P < 0.001). Higher sensitivity was observed especially in Ta, G1-2, and

We report a case of retroperitoneal schwannoma treated by laparoscopic surgery. A 32-year-old woman presented with a mass in the retroperitoneal space that was incidentally revealed by abdominal echography. Computed tomography and magnetic resonance imaging showed a mass 95 mm in diameter in the retroperitoneal cavity which had a cystic component. With a diagnosis of retroperitoneal tumor, laparoscopic resection was performed. Pathological diagnosis was retroperitoneal benign schwannoma consisting of Antoni A and B types. Our case is the largest retroperitoneal schwannoma tumor which was removed by laparoscopic surgery.

Priapism is rare and usually unpredictable. High-flow priapism is caused by unregulated arterial inflow. Antecedent trauma is the most commonly described etiology. This condition does not require emergent treatment. The initial management of high-flow priapism should be observation, because treatment-related erectile dysfunction may appear. We report a case of high-flow priapism by perineal trauma in a 27-year-old man. His corpora were typically tumescent, but not completely rigid. He could not have sexual intercourse. Blood from the corpus cavernosum was normally oxygenated. Color duplex ultrasonography was performed in the lithotomy position, scanned at the perineum, showed pseudoaneurysmal appearance. Selective internal pudendal arteriography showed a right cavernous arterial extravasation. Superselective embolization of right internal pudendal arteries was performed with an autologous clot. After the procedure, detumescence was achieved as well as erectile function. We recommend superselective arterial embolization as the management of high flow priapism to patients who request treatment.

Objectives: Vesicoureteral reflux (VUR) is the most common congenital urinary tract anomaly. This disease can pose a major threat to the kidneys as twenty percent of patients with endstage renal disease are reported to have VUR. Although genetic studies for uroplakin III (UPIII) have been reported recently, no study has focused on UPIII gene expression in VUR patients. We describe here the up-regulation of UPIII mRNA in exfoliated urinary cells from primary VUR patients., Methods: A real-time RT-PCR for UPIII mRNA was performed on exfoliated urothelial cells from 18 primary VUR and 38 control samples. UPIII mRNA copies were calculated for each sample. The statistical differences were assessed by the Mann-Whitney U test. Receiver operator characteristic curves were constructed for analysis of the diagnostic values., Results: UPIII mRNA was found to be up-regulated to a greater extent in VUR than in control exfoliated urinary cells (mean +/- SE: 497.0 +/- 178.5 copies vs. 69.0 +/- 10.0 copies, respectively, P < 0.001). In evaluating the measurement of urinary UPIII mRNA as a screening test for VUR, the sensitivity was 77.8% and the specificity was 76.3% by the best diagnostic cutoff point., Conclusions: This is the first report demonstrating up-regulation of UPIII in mRNA levels in VUR patients. We submit that the quantitative measurement of urinary UPIII mRNA has a potential of developing into the first non-invasive screening test for VUR.

Purpose: Interstitial cystitis remains a poorly understood urological condition characterized by chronic pelvic pain and increased urinary frequency in the absence of any known etiology. Urothelial dysfunction and other abnormalities are presumed to be involved in the disease. Uroplakins that are expressed by urothelial cells are thought to have an important role as major barrier proteins on the apical surface of the urothelium., Materials and Methods: Gene expression of uroplakin Ia, Ib, II, III and III-delta4 was quantitatively measured in bladder biopsy samples from 29 patients with interstitial cystitis and 16 control subjects using real-time reverse transcriptase-polymerase chain reaction., Results: The mRNA levels of the uroplakin Ia, Ib and II genes were relatively low and uroplakin III was relatively high in interstitial cystitis bladders compared to normal controls, although not significantly. Uroplakin III-delta4, a splicing variant of uroplakin III, was significantly up-regulated in interstitial cystitis samples (p <0.001). When patients with interstitial cystitis were divided into those with and without ulcerative changes, the uroplakin III and III-delta4 genes were significantly up-regulated only in patients with nonulcerative interstitial cystitis. Even more interesting was the finding that up-regulation of uroplakin III-delta4 was much more prominent than that of uroplakin III, that is 26.5 vs 5.6-fold compared to the median values of normal subjects., Conclusions: Although the clinical implications of the over expression of uroplakin III and III-delta4 in nonulcerative interstitial cystitis bladders remains to be clarified, from the diagnostic viewpoint uroplakin III-delta4 is a potential marker for identifying nonulcerative interstitial cystitis.

Proteome analysis of bladder cancer with narrow-range pH 2-DE has identified a novel protein on chromosome 7 encoded by ORF 24 (C7orf24) as one of the highly expressed proteins in cancer cells. C7orf24 is currently registered in the protein database as a hypothetical protein with unknown function. The homologs of C7orf24 in other animals have also been registered as putative protein genes. Western blot analysis using a mAb against C7orf24 confirmed its higher expression in bladder cancer compared with normal tissue. Several other cancer cell lines were also found to express C7orf24. However, the introduction of C7orf24 into Rat-1 or NIH3T3 cells did not cause malignant transformation. A stable transfectant of NIH3T3 cells with recombinant retrovirus vector was produced for a growth rate assay, and a higher growth rate was observed in C7orf24-expressing cells compared with the controls. Six kinds of small interfering RNAs (siRNAs) were then produced, and C7orf24-siRNA#5 showed a strong knockdown effect on protein expression and significant antiproliferative effects on cancer cell lines were demonstrated by the MTT assay. Therefore, C7orf24 may have an important role in cancer cell proliferation, and may be an appropriate therapeutic target molecule against cancer., (Copyright © 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Small cell carcinoma (SCC) originating from the prostate is rare. We report three cases of SCC of the prostate. Case 1: A 29-year-old man with large pelvic mass and pelvic lymph node metastases was diagnosed as having pure SCC of the prostate. Chemo-radiotherapy resulted in a great reduction of the tumor volume. However, the disease recurred immediately, and he died of disease 17 months after diagnosis. Case 2: A 65-year-old man presented with pure prostatic SCC with lung metastases. Although cystoprostatectomy combined with pre- and post-operative chemotherapy ended with no evidence of disease, he died after 16 months because of multiple metastases and local recurrence. Case 3: A 73-year-old man was diagnosed as having SCC and poorly differentiated adenocarcinoma of the prostate simultaneously. Chemo-endocrine therapy and pelvic irradiation were performed, achieving partial remission. However, he developed multiple distant metastases, and died of disease 15 months after diagnosis. We reviewed 82 cases previously reported in Japan. Patient's ages ranged from 24 to 86 years (mean 68.7 years). Many patients had lymph node or distant metastases (stage D, 73%). Thirty-seven (45%) were pure SCCs and 45 (55%) were associated with adenocarcinoma. The prognosis after the recognition of SCC is very poor, and the 1- and 2-year survival rates were 27% and 10%, respectively. Survival did not differ in patients with pure SCC or mixed glandular and small cell carcinoma. Higher elevation of pretreatment serum NSE value was associated with the poor prognosis.

The mainstay in the management of invasive bladder cancer continues to be radical cystectomy. With regard to improvement of quality of life, however, therapies that preserve the bladder are desirable. We investigated the use of intravesical PLK-1 small interfering RNA (siRNA) against bladder cancer. Patients with bladder cancers expressing high levels of PLK-1 have a poor prognosis compared with patients with low expression. Using siRNA/cationic liposomes, the expression of endogenous PLK-1 could be suppressed in bladder cancer cells in a time- and dose-dependent manner. As a consequence, PLK-1 functions were disrupted. Inhibition of bipolar spindle formation, accumulation of cyclin B1, reduced cell proliferation, and induction of apoptosis were observed. In order to determine the efficacy of the siRNA/liposomes in vivo, we established an orthotopic mouse model using a LUC-labeled bladder cancer cell line, UM-UC-3(LUC). PLK-1 siRNA was successfully transfected into the cells, reduced PLK-1 expression, and prevented the growth of bladder cancer in this mouse model. This is the first demonstration, to our knowledge, of inhibition of cancer growth in the murine bladder by intravesical siRNA/cationic liposomes. We believe intravesical siRNA instillation against bladder cancer will be useful as a therapeutic tool.