A phase III multicenter, randomized, controlled study of combined androgen blockade with versus without zoledronic acid in prostate cancer patients with metastatic bone disease: results of the ZAPCA trial.

OBJECTIVE: To examine the antitumor activity of zoledronic acid (ZA) combined with androgen deprivation therapy (ADT) for men with treatment-naive prostate cancer and bone metastasis. METHODS: We enrolled 227 men with treatment-naive prostate cancer and bone metastasis. Participants were randomly assigned (1:1 ratio) to receive combined androgen blockade alone (CAB group) or ZA with combined androgen blockade (CZ group). Time to treatment failure (TTTF), time to the first skeletal-related event (TTfSRE), and overall survival (OS) rates were estimated using the Kaplan-Meier method. Hazard ratios (HRs) were calculated using the Cox proportional hazards model. Median follow-up duration was 41.5 months. RESULTS: Median TTTFs were 12.4 and 9.7 months for the CZ and CAB groups, respectively (HR 0.75; 95 % CI 0.57-1.00; p = 0.051). For men with baseline prostate-specific antigen levels <200 ng/mL, median TTTFs were 23.7 and 9.8 months for the CZ and CAB groups, respectively (HR 0.58; 95 % CI 0.35-0.93; p = 0.023). Median TTfSREs were 64.7 and 45.9 months for the CZ and CAB groups, respectively (HR 0.58; 95 % CI 0.38-0.88; p = 0.009). OS was similar between the groups. CONCLUSIONS: This study failed to demonstrate that combined use of ZA and ADT significantly prolonged TTTF in men with treatment-naive prostate cancer and bone metastasis. However, it generates a new hypothesis that the combined therapy could delay the development of castration resistance in a subgroup of patients with low baseline prostate-specific antigen values <200 ng/mL. The treatment also significantly prolonged TTfSRE but did not affect OS.

[Locally Advanced Ureteral Cancer Seen in an Ectopic Kidney : A Case Report].

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.

[A Case of Synchronous Multiple Metastases in which the Origin Could Not Be Identified by Routine Examination].

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.

[Questionnaire survey on medical care for male urethritis in community clinics in Shiga prefecture].

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.

Magnetic resonance voiding cystourethrography (MRVCUG): a potential alternative to standard VCUG.

PURPOSE: To evaluate the accuracy and feasibility of magnetic resonance voiding cystourethrography (MRVCUG), with or without contrast medium, in detecting vesicoureteral reflux (VUR) by comparison with conventional voiding cystourethrography (VCUG). MATERIALS AND METHODS: Seventy-five patients underwent a series of 55 indirect MRVCUG (I-MRVCUG) and 61 direct MRVCUG (D-MRVCUG) between 2003 and 2009. We retrospectively compared the results from I-MRVCUG and D-MRVCUG with those from VCUG on 150 kidney-ureter units. Ratios of successful completion of the two types of MRVCUG were analyzed in 116 examinations according to sex, age, and among the two groups, with or without sedation. RESULTS: D-MRVCUG was superior to I-MRVCUG in detecting VUR (sensitivity: 96.8% vs. 76.9%; specificity: 96.3% vs. 88.7%; agreement: 96.6% vs. 83.7%; kappa: 0.83 [95% confidence interval (CI): 0.72, 0.94] vs. 0.55 [95% CI: 0.41, 0.69]). The overall ratio of successful completion of the two types of MRVCUG was 76.7% (89/116): there was no significant difference between I-MRVCUG and D-MRVCUG. The successful completion rate was significantly lower in MRVCUG in toddlers compared with preschoolers, infants, schoolchildren, and adults (P < 0.001). CONCLUSION: The two types of MRVCUG (I-MRVCUG and D-MRVCUG) are promising tests without radiation exposure. Both I-MRVCUG and D-MRVCUG are feasible for children except for toddlers.

Recurrent rhabdomyosarcoma after adjuvant chemotherapy for stage I non-seminomatous germ cell tumor with malignant transformation.

We report a rare case of stage I non-seminomatous testicular germ cell tumor with malignant transformation. The patient received two cycles of chemotherapy (cisplatin, bleomycin and etoposide) tailored to testicular germ cell tumors as an adjuvant therapy after orchiectomy. However, 22 months later, the patient developed a metastasis in the occipital region that consisted of solely rhabdomyosarcoma through malignant transformation of a teratoma component. This case highlights an issue related to adjuvant chemotherapy for testicular germ cell tumors with components of malignant transformation.

[Repair of right ureteral stenosis by traumatic injury with appendiceal interposition: a case report].

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.

Methylation profile of DNA repetitive elements in human testicular germ cell tumor.

Testicular germ cell tumors (TGCTs) have a unique epigenetic profile distinct from that of other types of cancer. To further evaluate epigenetics of TGCTs, this study examines DNA methylation patterns of DNA repetitive elements in TGCTs. Bisulfite genomic sequencing and combined bisulfite restriction analysis (COBRA) were used to analyze the methylation patterns of DNA repetitive elements (LINE1 and Alu repeats) in embryonal carcinoma (EC) derived cell lines, primary TGCT tissues, noncancerous testicular tissues adjacent to TGCTs and cancer cells derived from somatic tissues (testicular malignant lymphoma tissues and renal cell carcinoma cell lines). Through both bisulfite genomic sequencing and COBRA, LINE1 was extensively hypomethylated in both seminomatous and nonseminomatous TGCT tissues as well as EC cell lines. We studied two Alu repeats locating in the 5' end of E-cadherin and XIST by bisulfite genomic sequencing. These two Alu elements were extensively hypomethylated in seminomatous TGCTs, but methylated in nonseminomatous TGCTs, including two EC derived cell lines. This increased unmethylated profile in seminomatous TGCTs was observed also by COBRA for Alu repeats. Although partial demethylation of DNA repetitive elements was observed in cancer cells of somatic tissue origin, the degree of demethylation was more pronounced in TGCTs than in cancer cells of somatic tissue origin. We observed abnormal demethylation of DNA repetitive elements in some of the tissues adjacent to TGCTs. The results indicate that the underlying mechanisms to undergo or maintain demethylation of DNA repetitive sequences differ between TGCTs and cancer cells of somatic tissue origin.

Therapeutic potential of SOX2 inhibition for embryonal carcinoma.

PURPOSE: Some nonseminomatous germ cell tumors are resistant to any type of chemotherapy. Control of embryonal carcinoma cells is crucial to manage nonseminomatous germ cell tumors. We established SOX2 targeting therapy in an embryonal carcinoma model. MATERIALS AND METHODS: SOX2 expression was evaluated in a series of testicular germ cell tumor tissue samples. The antitumor effect of SOX2 knockdown was analyzed in vitro and in vivo using an embryonal carcinoma model. RESULTS: In testicular germ cell tumor tissue SOX2 was expressed in the foci of embryonal carcinoma but negative in seminoma and yolk sac tumors. In an embryonal carcinoma model SOX2-siRNA induced apoptotic cell death in vitro and significant growth suppression in vivo. CONCLUSIONS: This study shows the therapeutic potential of SOX2 silencing for embryonal carcinoma. However, further improvements are needed in SOX2-siRNA delivery to the tumor.

[Small intestinal metastasis from renal cell carcinoma: a case report].

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.

[Change in concepts of urolithiasis: recent advances in pathogenesis, assessment, treatment and prophylaxis].

A nationwide survey of urolithiasis in Japan conducted in 2005 disclosed its steady increase in incidence and the life-long risk was estimated to be 15% in men and 6% in women. The recurrence rate has also increased, to 70 -80% in the extracorporeal shock wave lithotripsy (ESWL) era from around 50% previously. Although urolithiasis is very common and highly recurrent, the impact and concern of stone disease are not necessarily as high as expected either medically or socially, because of its benign nature and easy accessibility to treatments by ESWL and/or endourological procedures. Dramatic progress is taking place both experimentally and clinically in this field, such as development of a simple method of measuring metastable limits using a microplate, clarifying altered oxalate metabolism due to insulin resistance and close relationship between stone disease and metabolic syndrome, elucidating the exact role of osteopontin in an experimental model at a molecular level, prophylaxis of stone disease by angiotensin II type I receptor blocker, and addition of a new modality of fiberscopic transurethral lithotripsy (f-TUL) to the conventional endourological treatments. We hope that "change and future perspective" in the field of urolithiasis will be discussed and clarified in this symposium.

[Long-term disease stabilization by docetaxel plus estramustine for castration-resistant prostate cancer : report of a case].

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.

[Bladder metastasis of renal cell carcinoma : report of a case].

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.

Primary synovial sarcoma arising from a crossed ectopic kidney with fusion.

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.

A rare case of multiple schwannomas presenting with scrotal mass: a probable case of schwannomatosis.

We report a rare case of multiple schwannomas presenting with scrotal mass. In the present case, a scrotal schwannoma developed in a 66-year-old man with a history of brain tumor surgery. Investigating the patient's past history lead to the diagnosis as probable schwannomatosis. Patients with schwannomatosis are at increased risk of developing multiple schwannomas and these patients need regular surveillance. In this regard, the present case highlights the importance of thorough history taking in patients with scrotal schwannoma.

[Renal arteriovenous fistula induced by blunt renal trauma : a case report].

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.

[Efficacy of naftopidil for nocturia and consequent sleep disturbance in patients with benign prostatic hyperplasia].

Nocturnal urinary frequency is a predominant complaint among males presenting with benign prostatic hyperplasia (BPH), which markedly impacts quality of life (QOL) and often causes sleep disturbance. We studied the efficacy of naftopidil an alpha 1-adrenoreceptor antagonist used for treatment of BPH for improvement of nocturia and consequent sleep disturbance. Twenty-five patients diagnosed with BPH were administered daily oral doses of naftopidil (50 or 75 mg/day) for eight weeks. The symptoms were assessed quantitatively using the following criteria : International Prostate Symptoms Score (I-PSS), QOL index, frequency volume chart, and Pittsburgh Sleep Quality Index (PSQI). After treatment, the mean+/-SD of total I-PSS and nocturia decreased from 16.9+/-5.2 to 10.3+/-4.9 (p<0.001) and 3.5+/-1.2 to 2.3+/-1.3 (p<0.001), respectively. In addition, all categories of storage symptoms in I-PSS were also significantly improved. PSQI results were obtained in 21 of the 25 patients, and decreased from 6.4+/-4.2 to 5.3+/-3.5 (p=0.026) (normal range: less than 5.5). This is the first report of a quantitative analysis of the effect of naftopidil on sleep quality in BPH patients. In conclusion, naftopidil appears to be an effective agent not only for nocturia and other urinary storage symptoms, but also for improving the quality of sleep.

[Polyorchidim: a case report and review of the literature].

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.

Cyclin D1b variant promotes cell invasiveness independent of binding to CDK4 in human bladder cancer cells.

Alternative splicing in the cyclin D1 gene produces cyclin D1b variant which lacks a C-terminal region containing the threonine-286 (T286) phosphorylation site required for nuclear export. We have shown that the expression of the cyclin D1b variant is detected in about 60% of human bladder cancer tissues (15/26) and cell lines (3/5). To examine the role of the cyclin D1b variant in bladder carcinogenesis, we introduced wild-type cyclin D1a, cyclin D1b variant or mutant cyclin D1-T286A cDNAs into a human bladder cancer cell line, SBT991, in which cyclin D1b transcript was not expressed, and compared their oncogenic activities. Ectopic expression of cyclin D1b promoted cell invasiveness and anchorage-independent growth of the cancer cells. On the other hand, cyclin D1-T286A enhanced anchorage-independent growth, but did not promote cell invasiveness. The amount of nuclear-localized cyclin D1b and cyclin D1-T286A was higher than that of nuclear-localized cyclin D1a. In addition, introduction of siRNA specific for cyclin D1b into cells of the T24 bladder cancer cell line, in which cyclin D1b transcript was expressed, significantly suppressed cell invasiveness. Immunoprecipitation analysis revealed that cyclin D1a and cyclin D1-T286A could bind to cyclin-dependent kinase 4 (CDK4) but cyclin D1b has lost its capacity to associate with CDK4. Unlike cyclin D1a and cyclin D1-T286A, expression of cyclin D1b did not enhance phosphorylation of Rb protein in SBT991 cells. These results indicate that cyclin D1b promotes cell invasiveness independent of binding to CDK4 to enhance Rb phosphorylation.

Suppression of cell invasiveness by periostin via TAB1/TAK1.

We have previously shown that the expression of periostin is significantly downregulated in human bladder cancer tissues and that periostin suppresses cell invasiveness and metastasis of cancer cells. To clarify the molecular mechanism of this suppression by periostin, we searched for periostin-binding proteins and identified TAB1, which interacts with and activates TAK1, by mass analysis of proteins co-precipitated with periostin in 293T cells expressing periostin. The association between periostin and TAB1 was confirmed by a pulldown assay in 293T cells co-tranfected with expression plasmids of periostin, TAB1 and TAK1. TAK1 was also co-precipitated with periostin in this assay. Co-transfection experiments in 293T also showed that periostin could activate TAK1. Introduction of siRNA for TAB1 suppressed TAK1 activation by periostin. Analyses with deletion mutants of periostin revealed that the C-terminal region of periostin was necessary and sufficient for the association with TAB1 and the TAK1 activation. The suppression of invasiveness by periostin was attenuated by siRNA targeting TAK1 or TAB1 in 293T (human embryonic kidney) and T24 (human bladder carcinoma) cell lines. These findings indicate that periostin is involved in the suppression of cell invasiveness via the TAB1/TAK1 signaling pathway.