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1.  Establishment of an ASPL-TFE3 renal cell carcinoma cell line (S-TFE) 
Cancer Biology & Therapy  2013;14(6):502-510.
Xp11 translocation renal cell carcinoma is a rare disease diagnosed in children and adolescents in the advanced stage with an aggressive clinical course. Various gene fusions including the transcription factor E3 (TFE3) gene located on chromosome X cause the tumor. We established an Xp11 translocation renal cell carcinoma cell line from a renal tumor in a 18-y-old Japanese female and named it “S-TFE.” The cell line and its xenograft demonstrated definite gene fusion including TFE3. They showed strong nuclear staining for TFE3 in immunohistochemistry, TFE3 gene rearrangement in dual-color, break-apart FISH analysis and ASPL-TFE3 type 1 fusion transcripts detected by RT-PCR and direct DNA sequencing. Although many renal cell carcinoma cell lines have been established and investigated, only a few cell lines are recognized as Xp11.2 translocation carcinoma. S-TFE will be useful to examine the characteristics and drug susceptibility of Xp11 translocation renal cell carcinoma.
doi:10.4161/cbt.24344
PMCID: PMC3813566  PMID: 23760492
renal neoplasm; cell line; TFE3; Xp11.2; translocation; tumorigenesis; FISH
2.  Comparison of Laparoscopic, Hand-Assisted, and Open Surgical Nephroureterectomy 
Background and Objectives:
The aim of this study was to compare oncologic outcomes after laparoscopic nephroureterectomy, hand-assisted laparoscopic nephroureterectomy, and open nephroureterectomy for upper urinary tract urothelial cancer.
Methods:
Between April 1995 and August 2010, 189 patients underwent laparoscopic nephroureterectomy, hand-assisted laparoscopic nephroureterectomy, or open nephroureterectomy for upper urinary tract urothelial cancer. Of these patients, 110 with no previous or concurrent bladder cancer or any metastatic disease were included in this study. Cancer-specific survival, recurrence-free survival, and intravesical recurrence-free survival rates were analyzed by the Kaplan-Meier method and compared with the log-rank test. The median follow-up period for the cohort was 70 months (range, 6–192 months).
Results:
The 3 groups were well matched for tumor stage, grade, and the presence of lymphovascular invasion and concomitant carcinoma in situ. The estimated 5-year cancer-specific survival rates were 81.1%, 65.6%, and 65.2% for laparoscopic nephroureterectomy, hand-assisted laparoscopic nephroureterectomy, and open nephroureterectomy, respectively (P = .4179). The estimated 5-year recurrence-free survival rates were 33.8%, 10.0%, and 41.2% for laparoscopic nephroureterectomy, hand-assisted laparoscopic nephroureterectomy, and open nephroureterectomy, respectively (P = .0245). The estimated 5-year intravesical recurrence-free survival rates were 64.8%, 10.0%, and 76.2% for laparoscopic nephroureterectomy, hand-assisted laparoscopic nephroureterectomy, and open nephroureterectomy, respectively (P < .0001).
Conclusion:
Although there was no significant difference in cancer-specific survival rate among the laparoscopic nephroureterectomy, hand-assisted laparoscopic nephroureterectomy, and open nephroureterectomy groups, hand-assisted laparoscopic nephroureterectomy may be inferior to laparoscopic nephroureterectomy or open nephroureterectomy with regard to recurrence-free survival and intravesical recurrence-free survival rates.
doi:10.4293/108680813X13794522666842
PMCID: PMC4035642  PMID: 24960495
Nephroureterectomy; Laparoscopic; Hand-assisted laparoscopic
3.  Potential Survival Benefit of Anti-Apoptosis Protein: Survivin-Derived Peptide Vaccine with and without Interferon Alpha Therapy for Patients with Advanced or Recurrent Urothelial Cancer—Results from Phase I Clinical Trials 
We previously identified a human leukocyte antigen (HLA)-A24-restricted antigenic peptide, survivin-2B80–88, a member of the inhibitor of apoptosis protein family, recognized by CD8+cytotoxic T lymphocytes (CTL). In a phase I clinical trial of survivin-2B80-88 vaccination for metastatic urothelial cancer (MUC), we achieved clinical and immunological responses with safety. Moreover, our previous study indicated that interferon alpha (IFNα) enhanced the effects of the vaccine for colorectal cancer. Therefore, we started a new phase I clinical trial of survivin-2B80–88 vaccination with IFNα for MUC patients. Twenty-one patients were enrolled and no severe adverse event was observed. HLA-A24/survivin-2B80–88 tetramer analysis and ELISPOT assay revealed a significant increase in the frequency of the peptide-specific CTLs after vaccination in nine patients. Six patients had stable disease. The effects of IFNα on the vaccination were unclear for MUC. Throughout two trials, 30 MUO patients received survivin-2B80–88 vaccination. Patients receiving the vaccination had significantly better overall survival than a comparable control group of MUO patients without vaccination (P = 0.0009). Survivin-2B80–88 vaccination may be a promising therapy for selected patients with MUC refractory to standard chemotherapy. This trial was registered with UMIN00005859.
doi:10.1155/2013/262967
PMCID: PMC3863714  PMID: 24363758
4.  Long-term safety, efficacy, and tolerability of imidafenacin in the treatment of overactive bladder: a review of the Japanese literature 
Imidafenacin is an antimuscarinic agent with high affinity for the M3 and M1 muscarinic receptor subtypes and low affinity for the M2 subtype, and is used to treat overactive bladder. Several animal studies have demonstrated that imidafenacin has organ selectivity for the bladder over the salivary glands, colon, heart, and brain. In Phase I studies in humans, the approximately 2.9-hour elimination half-life of imidafenacin was shorter than that of other antimuscarinics such as tolterodine and solifenacin. Imidafenacin was approved for clinical use in overactive bladder in Japan in 2007 after a randomized, double-blind, placebo-controlled Phase II study and a propiverine-controlled Phase III study conducted in Japanese patients demonstrated that imidafenacin 0.1 mg twice daily was clinically effective for treating overactive bladder and was not inferior to propiverine for reduction of episodes of incontinence, with a better safety profile than propiverine. Several short-term clinical studies have demonstrated that imidafenacin also improves sleep disorders, nocturia, and nocturia-related quality of life. In addition, it is speculated that addon therapy with imidafenacin is beneficial for men with benign prostatic hyperplasia whose overactive bladder symptoms are not controlled by alpha-1 adrenoceptor antagonists. No cognitive impairment or influence of imidafenacin on the QTc interval has been observed. Although there have been very few relevant long-term clinical studies, the available information suggests the long-term efficacy, safety, and tolerability of imidafenacin, with less frequent severe adverse events, such as dry mouth and constipation. In addition, imidafenacin can be used safely for a long time even for cognitively vulnerable elderly patients with symptoms of overactive bladder. Thus, it is highly likely that imidafenacin is safe, efficacious, and tolerable to control symptoms of overactive bladder even over the long term. However, it remains unknown if the practical effectiveness of imidafenacin is applicable to ethnic groups other than Japanese.
doi:10.2147/PPA.S28160
PMCID: PMC3564458  PMID: 23390360
overactive bladder; antimuscarinics; imidafenacin; long-term efficacy
5.  Clinical outcomes of surgical treatment and longitudinal non-surgical observation of patients with subclinical Cushing's syndrome and nonfunctioning adrenocortical adenoma 
Aims:
To investigate the outcomes of the surgical management and longitudinal assessment of patients with subclinical Cushing's syndrome (SCS) and nonfunctioning adrenocortical adenoma (NFA).
Materials and Methods:
Between the years 1995 and 2008, 73 patients with asymptomatic adrenocortical adenoma were enrolled. They were informed of the risks and benefits of adrenalectomy and conservative management, and then chose the treatment.
Results:
SCS was observed in 13 patients (17.8%) and NFA in 60 patients (82.2%). Tumor size in SCS was significantly larger than that in NFA (34.6 ± 9.7 mm vs. 24.5 ± 8.0 mm in diameter, P=0.001). Of the SCS patients, 7 also suffered from hypertension (HT), 2 from diabetes mellitus (DM) and 3 from hyperlipidemia (HL). After adrenalectomy, the insulin dose could be reduced in 2 (100%) patients with DM, in 5 (71.4%) of those with HT and in 2 (66.7%) of those with HL. In the NFA surveillance group, 1 (2.6%) case developed into SCS 3 years after the initial presentation and an increase in size of the tumor was observed in 1 (2.6%), with a mean follow-up of 51.2 months.
Conclusions:
Surgical resection may be beneficial for the control of SCS and is likely to provide improvement of concomitant HT, DM and HL. Although NFA can be managed conservatively, its size and hormonal activities may change longitudinally. Thus, long-term follow-up is necessary for NFA.
doi:10.4103/0970-1591.98461
PMCID: PMC3424895  PMID: 22919134
Adrenal incidentalomas; adrenalectomy; conservative management; nonfunctioning adrenocortical adenoma; subclinical Cushing's syndrome
6.  Peritoneal dissemination of prostate cancer due to laparoscopic radical prostatectomy: a case report 
Introduction
Peritoneal dissemination with no further metastases of prostate cancer is very rare, with only three cases reported in the available literature. We report the first case of iatrogenic peritoneal dissemination due to laparoscopic radical prostatectomy.
Case Presentation
A 59-year-old Japanese man underwent laparoscopic radical prostatectomy for clinical T2bN0M0 prostate cancer, and the pathological diagnosis was pT3aN0 Gleason 3+4 adenocarcinoma with a negative surgical margin. Salvage radiation therapy was performed since his serum prostate-specific antigen remained at a measurable value. After the radiation, he underwent castration, followed by combined androgen blockade with estramustine phosphate and dexamethasone as each treatment was effective for only a few months to a year. Nine years after the laparoscopic radical prostatectomy, computed tomography revealed a peritoneal tumor, although no other organ metastasis had been identified until then. He died six months after the appearance of peritoneal metastasis. An autopsy demonstrated peritoneal dissemination of the prostate cancer without any other metastasis.
Conclusion
Physicians should take into account metastasis to unexpected sites. Furthermore, we suggest that meticulous care be taken not to disseminate cancer cells to the peritoneum during laparoscopic radical prostatectomy.
doi:10.1186/1752-1947-5-355
PMCID: PMC3175179  PMID: 21819588
7.  The Efficacy and Safety of Propiverine Hydrochloride in Patients with Overactive Bladder Symptoms Who Poorly Responded to Previous Anticholinergic Agents 
Advances in Urology  2011;2011:714978.
Objectives. To prospectively examine the efficacy and safety of propiverine hydrochloride in patients with overactive bladder (OAB) symptoms who poorly responded to previous treatment with solifenacin, tolterodine or imidafenacin. Methods. Patients aged ≥20 with persisting OAB symptoms (≥6 in OAB symptom score (OABSS)) even after at least 4-week treatment using solifenacin, tolterodine or imidafenacin were enrolled. Propiverine 20 mg/day was administered for 12 weeks to 70 patients who desired the further improvement of OAB symptoms and 3 who had intolerable adverse events of previous drugs. The OABSS and postvoid residual urine volume (PVR) were determined before and at 4 and 12 weeks of treatment. Results. Of 73 patients enrolled (29 males and 44 females, median age 71 years), 52 completed the protocol treatment. The OABSS was significantly improved by propiverine treatment (9.0 at baseline, 6.2 at 4 weeks, 6.3 at 12 weeks (P < 0.001)). The scores of OAB symptoms (nighttime frequency, urgency and urge incontinence) except daytime frequency also improved significantly. No increase in PVR was observed. The most frequent adverse event was dry mouth (13.7%), followed by constipation (6.8%). Conclusions. Propiverine is useful to improve OAB for patients who poorly respond to solifenacin, tolterodine or imidafenacin.
doi:10.1155/2011/714978
PMCID: PMC3130959  PMID: 21747845
8.  Naftopidil for the treatment of urinary symptoms in patients with benign prostatic hyperplasia 
Naftopidil, approved only in Japan, is an α1-adrenergic receptor antagonist (α1-blocker) used to treat lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH). Different from tamsulosin hydrochloride and silodosin, in that it has higher and extremely higher affinity respectively, for the α1A-adrenergic receptor subtype than for the α1D type, naftopidil has distinct characteristics because it has a three times greater affinity for the α1D-adrenergic receptor subtype than for the α1A subtype. Although well-designed large-scale randomized controlled studies are lacking and the optimal dosage of naftopidil is not always completely determined, previous reports from Japan have shown that naftopidil has superior efficacy to a placebo and comparable efficacy to other α1-blockers such as tamsulosin. On the other hand, the incidences of ejaculatory disorders and intraoperative floppy iris syndrome induced by naftopidil may be lower than for tamsulosin and silodosin having high affinity for the α1A-adrenergic receptor subtype. However, it remains unknown if the efficacy and safety of naftopidil in Japanese is applicable to white, black and Hispanic men having LUTS/BPH in western countries.
doi:10.2147/TCRM.S13883
PMCID: PMC3132093  PMID: 21753885
benign prostatic hyperplasia; lower urinary tract symptoms; α1-blocker; naftopidil
9.  The Add-On Effect of Solifenacin for Patients with Remaining Overactive Bladder after Treatment with Tamsulosin for Lower Urinary Tract Symptoms Suggestive of Benign Prostatic Obstruction 
Advances in Urology  2010;2010:205251.
Objectives. To investigate the add-on effect of solifenacin for Japanese men with remaining overactive bladder (OAB) symptoms after tamsulosin monotherapy for lower urinary tract symptoms (LUTS) suggestive of benign prostatic obstruction (BPO) in real-life clinical practice. Methods. Patients aged ≥ 50 having remaining OAB symptoms (≥ 3 of OAB symptom score (OABSS) with ≥2 of urgency score) after at least 4 weeks treatment by 0.2 mg of tamsulosin for BPO/LUTS received 2.5 or 5.0 mg of solifenacin for 12 weeks. The International Prostate Symptom Score (IPSS), QOL index and OABSS, maximum flow rate (Qmax) and postvoid residual urine volume (PVR) were determined. Results. A total of 48 patients (mean age 72.5 years) completed the study. There were significant improvement in IPSS (15.1 to 11.2) and QOL index (4.2 to 3.0) by add-on of solifenacin. Although the IPSS storage symptom score was significantly improved, there were no changes observed in the IPSS voiding symptom score. The OABSS showed significant improvement (8.0 to 4.8). No changes were observed in Qmax and PVR. Conclusions. Under the supervision of an experienced urologist, the additional administration of solifenacin to patients with BPO/LUTS treated with tamsulosin, is effective in controlling remaining OAB symptoms.
doi:10.1155/2010/205251
PMCID: PMC2964005  PMID: 20981257
10.  Aberrant expression and potency as a cancer immunotherapy target of alpha-methylacyl-coenzyme A racemase in prostate cancer 
Alpha-methylacyl-CoA racemase (AMACR) is an enzyme playing an important role in the beta-oxidation of branched-chain fatty acids and fatty acid derivatives. High expression levels of AMACR have been described in various cancers, including prostate cancer, colorectal cancer and kidney cancer. Because of its cancer-specific and frequent expression, AMACR could be an attractive target for cytotoxic T-lymphocyte (CTL)-based immunotherapy for cancer. In the present study, we examined the induction of AMACR-specific CTLs from prostate cancer patients' peripheral blood mononuclear cells (PBMCs) and determined HLA-A24-restricted CTL epitopes.
RT-PCR and immunohistochemical analysis revealed that AMACR was strongly expressed in prostate cancer cell lines and tissues as compared with benign or normal prostate tissues. Four AMACR-derived peptides carrying the HLA-A24-binding motif were synthesized from the amino acid sequence of this protein and analyzed to determine their binding affinities to HLA-A24. By stimulating patient's PBMCs with the peptides, specific CTLs were successfully induced in 6 of 11 patients. The peptide-specific CTLs exerted significant cytotoxic activity against AMACR-expressing prostate cancer cells in the context of HLA-A24. Our study demonstrates that AMACR could become a target antigen for prostate cancer immunotherapy, and that the AMACR-derived peptides might be good peptide vaccine candidates for HLA-A24-positive AMACR-expressing cancer patients.
doi:10.1186/1479-5876-7-103
PMCID: PMC2797764  PMID: 20003233
11.  Late Recurrence and Second Primary Malignancy among 139 Patients with Germ Cell Tumors: Long-term Outcome of the Disease in a Single-center Experience 
Objective
We retrospectively evaluated long-term oncological outcomes in patients with germ cell tumors (GCTs) primarily treated at our institution and assessed late recurrence and second primary malignancies.
Methods
This study included a total of 139 males with newly diagnosed GCTs of the testis or extragonadal origin who received treatment, including surgery, chemotherapy and radiation therapy, at our hospital between 1980 and 2005. We reviewed late recurrence that occurred at least 2 years after the initial disease-free status and secondary malignancies as well as oncological outcomes.
Results
In patients with seminoma, 5-year progression-free survival and cause-specific survival rates were 87.2% and 100% for Stage I, 88.9% and 100% for Stage II, and 50.0% and 50.0% for Stage III, respectively, whereas in those with non-seminomatous GCTs, they were 79.1% and 96.3% for Stage I, 89.5% and 89.4% for Stage II, and 85.7% and 78.4% for Stage III, respectively. Late recurrence was found in five (3.6%) patients and all of them responded to salvage treatment and achieved disease-free status. Second primary hematological neoplasms occurred in three (2.2%), although they had a long-term free of the primary disease. All died of the second primary disease.
Conclusions
Late recurrence was successfully managed with appropriate treatments, although its incidence was not negligible. Periodic follow-up may be necessary for >5 years in patients with GCTs for early detection of late recurrence. In addition, care should be taken to watch for the development of life-threatening second primary malignant disease during long-term follow-up.
doi:10.1093/jjco/hyp142
PMCID: PMC2813544  PMID: 19906660
urology; urologic-med; urologic-radOncol
12.  Treatment Strategy According to Findings on Pressure-Flow Study for Women with Decreased Urinary Flow Rate 
Advances in Urology  2009;2009:782985.
Purpose. In women who reported a weak urinary stream, the efficacy of treatment chosen according to the urodynamic findings on pressure-flow study was prospectively evaluated. Materials and Methods. Twelve female patients with maximum flow rates of 10 mL/sec or lower were analyzed in the present study. At baseline, all underwent pressure-flow study to determine the degree of bladder outlet obstruction (BOO) and status of detrusor contractility on Schäfer's diagram. Distigmine bromide, 10 mg/d, was given to the patients with detrusor underactivity (DUA) defined as weak/very weak contractility, whereas urethral dilatation was performed using a metal sound for those with BOO (linear passive urethral resistance relation 2–6). Treatment efficacy was evaluated using the International Prostate Symptom Score (IPSS), uroflowmetry, and measurement of postvoid residual urine volume. Some patients underwent pressure-flow study after treatment. Results. Urethral dilatation was performed for six patients with BOO, while distigmine bromide was given to the remaining six showing DUA without BOO. IPSS, QOL index, and the urinary flow rate were significantly improved in both groups after treatment. All four of the patients with BOO and one of the three with DUA but no BOO who underwent pressure-flow study after treatment showed decreased degrees of BOO and increased detrusor contractility, respectively. Conclusions. Both BOO and DUA cause a decreased urinary flow rate in women. In the short-term, urethral dilatation and distigmine bromide are efficacious for female patients with BOO and those with DUA, respectively.
doi:10.1155/2009/782985
PMCID: PMC2762086  PMID: 19841751
13.  Membrane-Anchored CD14 Is Important for Induction of Interleukin-8 by Lipopolysaccharide and Peptidoglycan in Uroepithelial Cells 
We investigated the induction of interleukin-8 (IL-8) by bacterial lipopolysaccharide (LPS) and peptidoglycan (PGN) in the bladder cancer cell lines T24, 5637, UM-UC-3, and HT1197. T24 and 5637 cells strongly induced IL-8 after stimulation with LPS or PGN in a dose- and time-dependent manner, whereas UM-UC-3 and HT1197 cells did so very weakly. The expression of CD14 at the mRNA, total cellular protein, and cell surface protein levels differed among these cell lines, but the expression levels of Toll-like receptors 2 and 4 (TLR2 and TLR4) were not significantly different. The CD14 expression levels were found to correlate with the inducibility of IL-8 by LPS or PGN. Treatment of T24 and 5637 cells with phosphatidylinositol-specific phospholipase C to eliminate CD14 from the cell surface dramatically suppressed the induction of IL-8. On the other hand, UM-UC-3 cells transfected with CD14 cDNA expressed membrane-anchored CD14 and showed more efficent induction of IL-8 by LPS stimulation than untransfected controls. These results suggest that the presence of the membrane-anchored, but not the soluble, form of CD14 is a strong factor in IL-8 induction in bladder epithelial cells in response to bacterial components. The presence of the membrane-anchored form of CD14 may thus be a determinant for the inflammatory response of uroepithelial cells.
doi:10.1128/CDLI.11.5.969-976.2004
PMCID: PMC515273  PMID: 15358661
14.  The Loss of TGF-β Signaling Promotes Prostate Cancer Metastasis1 
Neoplasia (New York, N.Y.)  2003;5(3):267-277.
Abstract
In breast and colon cancers, transforming growth factor (TGF)-β signaling initially has an antineoplastic effect, inhibiting tumor growth, but eventually exerts a proneoplastic effect, increasing motility and cancer spread. In prostate cancer, studies using human samples have correlated the loss of the TGF-β type II receptor (TβRII) with higher tumor grade. To determine the effect of an inhibited TGF-β pathway on prostate cancer, we bred transgenic mice expressing the tumorigenic SV40 large T antigen in the prostate with transgenic mice expressing a dominant negative TβRII mutant (DNIIR) in the prostate. Transgene( s) and TGF-β1 expression were identified in the prostate and decreased protein levels of plasminogen activator inhibitor type I, as a marker for TGF-β signaling, correlated with expression of the DNIIR. Although the sizes of the neoplastic prostates were not enlarged, increased amounts of metastasis were observed in mice expressing both transgenes compared to age-matched control mice expressing only the large T antigen transgene. Our study demonstrates for the first time that a disruption of TGF-β signaling in prostate cancer plays a causal role in promoting tumor metastasis.
PMCID: PMC1502411  PMID: 12869309
transforming growth factor-β; prostate cancer; metastasis; probasin; transgenic mice

Results 1-14 (14)