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1.  Ureteral Reconstruction With Bowel Segments: Experience With Eight Patients in a Single Institute 
Korean Journal of Urology  2014;55(11):742-749.
Purpose
Although replacement of the ureter with a bowel segment is indicated for large ureteral defects, it is still a challenging technique for urologists. We present our experience and outcome of ureteral reconstruction using bowel segments.
Materials and Methods
Ureteral reconstruction with bowel segments was performed in eight patients in our institute between 1969 and 2009. We investigated the position and length of the ureteral defect and methods of reconstruction as well as the patients' backgrounds, postoperative complications, and clinical outcomes.
Results
Five patients underwent ureteral replacement with isolated ileal segments alone. In one patient, the ureter was reconstructed by using the Yang-Monti procedure with the ileum. A colon segment was used in two patients who required bladder augmentation for tuberculous contracted bladder at the same time. Metabolic acidosis occurred in three patients having a solitary kidney and the ureter had to be replaced by a relatively long intestinal segment. Two patients who received preoperative radiation therapy were required to undergo additional operations. Long-term cancer-free survival was achieved in one patient who underwent ileal substitution for low-grade renal pelvic cancer.
Conclusions
Although ureteral replacement with a bowel segment is a challenging and useful procedure, attention must be paid to the possibility of metabolic acidosis, which is likely to occur in patients having a solitary kidney with renal insufficiency or in patients requiring a long intestinal segment for reconstruction. In addition, preoperative radiation therapy for the pelvic organs may cause postoperative complications.
doi:10.4111/kju.2014.55.11.742
PMCID: PMC4231152  PMID: 25405017
Colon; Ileum; Reconstructive surgical procedures; Ureter
2.  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
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.  Efficacy and Safety of Axitinib Versus Sorafenib in Metastatic Renal Cell Carcinoma: Subgroup Analysis of Japanese Patients from the Global Randomized Phase 3 AXIS Trial 
Objective
Axitinib is a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors 1, 2 and 3. The efficacy and safety of axitinib in Japanese patients with metastatic renal cell carcinoma were evaluated.
Methods
A subgroup analysis was conducted in Japanese patients enrolled in the randomized Phase III trial of axitinib versus sorafenib after failure of one prior systemic therapy for metastatic renal cell carcinoma.
Results
Twenty-five (of 361) and 29 (of 362) patients randomized to the axitinib and sorafenib arms, respectively, were Japanese and included in this analysis. Median progression-free survival in Japanese patients was 12.1 months (95% confidence interval 8.6 to not estimable) for axitinib and 4.9 months (95% confidence interval 2.8–6.6) for sorafenib (hazard ratio 0.390; 95% confidence interval 0.130–1.173; stratified one-sided P = 0.0401). The objective response rate was 52.0% for axitinib and 3.4% for sorafenib (P = 0.0001). The common all-causality adverse events (all grades) in Japanese patients were dysphonia (68%), hypertension (64%), hand–foot syndrome (64%) and diarrhea (56%) for axitinib, and hand–foot syndrome (86%), hypertension (62%) and diarrhea (52%) for sorafenib. The safety profiles of axitinib and sorafenib in Japanese patients were generally similar to those observed in the overall population, with the exceptions of higher incidences of hypertension, dysphonia, hand–foot syndrome, hypothyroidism and stomatitis.
Conclusions
Axitinib is efficacious and well tolerated in Japanese patients with previously treated metastatic renal cell carcinoma, consistent with the results in the overall population, providing a new targeted therapy for these Japanese patients.
doi:10.1093/jjco/hyt054
PMCID: PMC3664320  PMID: 23630366
axitinib; renal cell carcinoma; vascular endothelial growth factor receptors; clinical trial; phase III
5.  Semen quality of fertile Japanese men: a cross-sectional population-based study of 792 men 
BMJ Open  2013;3(1):e002223.
Objectives
To establish a base line for future studies on temporal trends, to describe potential geographical differences in semen quality and reference values for studies of men from the general population.
Design
Cross-sectional study of fertile men from four areas in Japan. Inclusion criteria were: age 20–45 years at the time of invitation, and both the man and his mother had to be born in Japan. Additionally, the current pregnancy of the female partner had to be achieved by normal sexual relations without any fertility treatment.
Setting
Four Japanese study centres at urban areas located in Sapporo, Osaka, Kanazawa and Fukuoka.
Participants
792 men, median age 31.4 years, included from 1999 to 2002.
Outcome measures
Semen volume, sperm concentration, total sperm count, sperm motility and sperm morphology.
Results
Semen volumes, percentages of motile spermatozoa and morphologically normal spermatozoa differed slightly between the four groups, whereas no differences in sperm concentrations or total sperm counts were found. In total, 1.2% of men had a sperm concentration below 5 million/ml, 2.1% below 10 million/ml, 3.5% below 15 million/ml and 16.3% below 40 million/ml. For morphology, 14.7% had less than 5% normal spermatozoa. Reproductive hormone levels varied significantly, however, only little from a biological point of view.
Conclusions
This is the first cross-sectional study on semen quality covering fertile men from the major regions of Japan. It showed that semen quality of fertile Japanese men is comparable to that of the best in European regions. The results may serve as reference values for studies of men from the general population.
doi:10.1136/bmjopen-2012-002223
PMCID: PMC3563117  PMID: 23355656
6.  Evaluation of primary androgen deprivation therapy in prostate cancer patients using the J-CAPRA risk score 
Prostate International  2013;1(2):81-88.
Purpose:
To determine the influence of maximal androgen blockade (MAB) and non-MAB hormonal therapy with an luteinizing hormone releasing hormone (LHRH) analog on overall survival of prostate cancer patients in the Japan Study Group of Prostate Cancer (J-CaP) registry according to risk, as assessed using the novel J-CAPRA risk instrument. To undertake a multivariate analysis combining J-CAPRA risk score, type of hormonal therapy and comorbidities, in order to assess their impact on overall survival.
Methods:
The J-CaP database includes men in Japan diagnosed with any stage of prostate cancer between 2001 and 2003 and treated with primary androgen deprivation therapy (PADT), as monotherapy or in combination. A total of 26,272 men were enrolled and of these 19,265 were treated with PADT. This analysis was undertaken using the latest data set (30 April, 2010) including a total of 15,727 patients who received PADT and had follow-up data for periods ranging from 0 to 9.2 years.
Results:
MAB for prostate cancer patients with intermediate- or high-risk disease has a significant benefit in terms of overall survival compared with LHRH analog monotherapy or surgical castration alone. Better results may be achieved in older (≥75 years) patients. Patient comorbidities are an important factor in determining overall survival, notably in older patients, and should be considered when selecting therapy.
Conclusions:
Based on large-scale registry data, this report is the first to analyze the outcomes of MAB therapy in patients with prostate cancer at a wide range of disease stages. MAB therapy may provide significant survival benefits in intermediate- and high-risk patients.
doi:10.12954/PI.12016
PMCID: PMC3814111  PMID: 24223407
Prostate neoplasms; Maximal androgen blockade; Overall survival; Primary androgen deprivation therapy; Risk scoring
7.  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
8.  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
9.  Immunotherapy for Urothelial Carcinoma: Current Status and Perspectives 
Cancers  2011;3(3):3055-3072.
Intravesical instillation of bacillus Calmette Guérin (BCG) for the treatment of urothelial carcinoma (UC) of the bladder is based on the BCG-induced immune response, which eradicates and prevents bladder cancer. The results of recent studies have suggested that not only major histocompatibility complex (MHC)-nonrestricted immune cells such as natural killer cells, macrophages, neutrophils, etc., but also MHC-restricted CD8+ T cells play an important role and are one of the main effectors in this therapy. Better understanding of the mechanism of BCG immunotherapy supports the idea that active immunotherapy through its augmented T cell response can have great potential for the treatment of advanced UC. In this review, progress in immunotherapy for UC is discussed based on data from basic, translational and clinical studies. We also review the escape mechanism of cancer cells from the immune system, and down-regulation of MHC class I molecules.
doi:10.3390/cancers3033055
PMCID: PMC3759186  PMID: 24212945
immunotherapy; urothelial cancer; cancer vaccine
10.  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
11.  Rectourinary Fistula after Radical Prostatectomy: Review of the Literature for Incidence, Etiology, and Management 
Prostate Cancer  2011;2011:629105.
Although rectourinary fistula (RUF) after radical prostatectomy (RP) is rare, it is an important issue impairing the quality of life of patients. If the RUF does not spontaneously close after colostomy, surgical closure should be considered. However, there is no standard approach and no consensus in the literature. A National Center for Biotechnology Information (NVBI) PubMed search for relevant articles published between 1995 and December 2010 was performed using the medical subject headings “radical prostatectomy” and “fistula.” Articles relevant to the treatment of RUF were retained. RUF developed in 0.6% to 9% of patients after RP. Most cases required colostomy, but more than 50% of them needed surgical fistula closure thereafter. The York-Mason technique is the most common approach, and closure using a broad-based flap of rectal mucosa is recommended after excision of the RUF. New techniques using a sealant or glue are developing, but further successful reports are needed.
doi:10.1155/2011/629105
PMCID: PMC3216010  PMID: 22110993
12.  Copy number alterations in urothelial carcinomas: their clinicopathological significance and correlation with DNA methylation alterations 
Carcinogenesis  2010;32(4):462-469.
The aim of this study was to clarify the genetic backgrounds underlying the clinicopathological characteristics of urothelial carcinomas (UCs). Array comparative genomic hybridization analysis using a 244K oligonucleotide array was performed on 49 samples of UC tissue. Losses of 2q33.3–q37.3, 4p15.2–q13.1 and 5q13.3–q35.3 and gains of 7p11.2–q11.23 and 20q13.12–q13.2 were correlated with higher histological grade, and gain of 7p21.2–p21.12 was correlated with deeper invasion. Losses of 6q14.1–q27 and 17p13.3–q11.1 and gains of 19q13.12–q13.2 and 20q13.12–q13.33 were correlated with lymph vessel involvement. Loss of 16p12.2–p12.1 and gain of 3q26.32–q29 were correlated with vascular involvement. Losses of 5q14.1–q23.1, 6q14.1–q27, 8p22–p21.3, 11q13.5–q14.1 and 15q11.2–q22.2 and gains of 7p11.2–q11.22 and 19q13.12–q13.2 were correlated with the development of aggressive non-papillary UCs. Losses of 1p32.2–p31.3, 10q11.23–q21.1 and 15q21.3 were correlated with tumor recurrence. Unsupervised hierarchical clustering analysis based on copy number alterations clustered UCs into three subclasses: copy number alterations associated with genome-wide DNA hypomethylation, regional DNA hypermethylation on C-type CpG islands and genome-wide DNA hypo- and hypermethylation were accumulated in clusters A, B1 and B2, respectively. Tumor-related genes that may encode therapeutic targets and/or indicators useful for the diagnosis and prognostication of UCs should be explored in the above regions. Both genetic and epigenetic events appear to accumulate during urothelial carcinogenesis, reflecting the clinicopathological diversity of UCs.
doi:10.1093/carcin/bgq274
PMCID: PMC3066412  PMID: 21177765
13.  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
14.  Phase III Trial of Everolimus in Metastatic Renal Cell Carcinoma: Subgroup Analysis of Japanese Patients from RECORD-1 
Objective
To assess the efficacy and safety of everolimus in Japanese patients with metastatic renal cell carcinoma.
Methods
A subgroup analysis of the pivotal Phase III, randomized, double-blind, placebo-controlled trial of everolimus 10 mg/day in patients with disease progression after treatment with sorafenib, sunitinib or both assessed outcomes in Japanese participants. Results were compared with those for the overall study population.
Results
The final trial analysis included 24 Japanese patients (everolimus, n= 15; placebo, n = 9). Median progression-free survival in the Japanese subpopulation was 5.75 months (95% confidence interval, 4.90 months to not reached) with everolimus and 3.61 months (95% confidence interval, 1.91–9.03 months) with placebo (hazard ratio, 0.19; 95% confidence interval, 0.05–0.83). Median overall survival was not reached with everolimus and was 14.9 months (95% confidence interval, 11.0–16.8 months) with placebo (hazard ratio, 0.30; 95% confidence interval, 0.07–1.27). Overall, efficacy and safety were similar when comparing the Japanese and overall populations. In the Japanese subpopulation, the most common adverse events with everolimus were stomatitis, infections and rash. Four Japanese subjects (27%) developed Grade 1 (n = 2) or 2 (n = 2) pneumonitis (all reversible and allowing for continuation of therapy, after interruption, steroids and dose reduction for both Grade 2 cases), with a lower pneumonitis incidence of 14% in the overall population (albeit associated with a Grade 3 incidence of 4%).
Conclusions
These findings suggest that the demonstrated benefits of everolimus in the overall trial population are similar in Japanese patients with metastatic renal cell carcinoma.
doi:10.1093/jjco/hyq166
PMCID: PMC3012894  PMID: 20965941
everolimus; renal cell carcinoma; mTOR
15.  Identification of a set of genes associated with response to interleukin-2 and interferon-α combination therapy for renal cell carcinoma through genome-wide gene expression profiling 
Interleukin (IL)-2 and interferon (IFN)-α combination therapy for metastatic renal cell carcinoma (RCC) improves the prognosis for a subset of patients, while some patients suffer from severe adverse drug reactions with little benefit. To establish a method to predict responses to this combination therapy (approximately 30% response rate), the gene expression profiles of primary RCCs were analyzed using an oligoDNA microarray consisting of 38,500 genes or ESTs, after enrichment of the cancer cell population by laser micro-beam microdissection. The analysis of 10 responders and 18 non-responders identified 24 genes that exhibited significant differential expression between the two groups. In addition, the patients whose tumors did not express HLA-DQA1 or HLA-DQB1 molecules demonstrated poor clinical response. Exclusion of patients with tumors lacking either of these two genes is likely to improve the response rate to IL-2 and IFN-α combination therapy from 30 to 67%, indicating that a simple pretreatment test provides useful information with which to subselect patients with renal cancer in order to improve the efficacy of this treatment and reduce unnecessary medical costs.
doi:10.3892/etm.2010.148
PMCID: PMC3445972  PMID: 22993625
interleukin-2 and interferon-α combination therapy; HLA-DQA1; HLA-DQB1
16.  Herpes simplex virus vector-mediated delivery of neurturin rescues erectile dysfunction of cavernous nerve injury 
Gene therapy  2008;16(1):26-33.
Summary
Neurturin (NTN), a member of glial cell line-derived neurotrophic factor (GDNF) family, is known as an important neurotrphic factor for penis-projecting neurons. We recently demonstrated significant protection from erectile dysfunction (ED) following a replication defective herpes simplex virus (HSV) vector-mediated GDNF delivery to the injured cavernous nerve. Herein we applied HSV vector-mediated delivery of NTN to this ED model. Rat cavernous nerve was injured bilaterally using a clamp and dry ice. For HSV-treated groups, 20μl of vector stock was administered directly to the damaged nerve. Delivery of an HSV vector expressing both green fluorescent protein (GFP) and lacZ (HSV-LacZ) was used as a control. Intracavernous pressure along with systemic arterial pressure (ICP/AP) was measured 2 and 4 weeks after the nerve injury. Fluorogold (FG) was injected into the penile crus 7 days before sacrifice to assess neuronal survival. Four weeks after nerve injury, rats treated with HSV-NTN exhibited significantly higher ICP/AP compared to untreated or control vector treated groups. The HSV-NTN group had more FG-positive MPG neurons than control group following injury. HSV vector-mediated delivery of NTN could be a viable approach for improvement of erectile dysfunction following cavernous nerve injury.
doi:10.1038/gt.2008.132
PMCID: PMC2615792  PMID: 18668142
Erectile Dysfunction; Neurturin; Gene Therapy; HSV
17.  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
18.  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
19.  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
20.  Prognostic biomarkers of renal cell carcinoma: Recent advances 
Recent advances in understanding the characteristics of renal cell carcinoma (RCC) have brought to our attention many prognostic markers that affect and predict the survival outcome of patients with the disease. For the moment, however, patients with RCC have not received any benefit from such markers. If a patient is diagnosed as “high risk” by using such prognostic markers, there is no promising systemic therapy available. In this review we mainly focus on biomarkers of RCC that can be applied for therapeutic use reported in recent publications. Several issues and limitations in the reported studies are also highlighted and discussed. Developing biomarkers from the viewpoint of therapeutic application will lead to improvement of the prognosis of RCC patients.
doi:10.4103/0970-1591.38596
PMCID: PMC2684243  PMID: 19468351
Biomarker; prognosis; renal cell carcinoma
21.  The 6-Fluoro-8-Methoxy Quinolone Gatifloxacin Down-Regulates Interleukin-8 Production in Prostate Cell Line PC-3▿  
Fluoroquinolones exhibit immunomodulatory effects on monocytes and macrophages, in addition to their bactericidal activities. It remains unknown even whether the quinolones act directly on the prostate. This study was based on the understanding of the molecular mechanisms of the actions of the fluoroquinolones that can be used for the treatment of chronic prostatitis/chronic pelvic pain syndrome. We investigated whether the 6-fluroro-8-methoxy quinolone gatifloxacin (GFLX) affected the production and secretion of interleukin-8 (IL-8) in the prostate cell line PC-3. GFLX decreased the level of IL-8 release from unstimulated PC-3 cells. GFLX also attenuated IL-8 secretion from PC-3 cells stimulated with peptidoglycan, Mycoplasma hominis, phorbol ester, and tumor necrosis factor alpha (TNF-α), indicating that GFLX exhibits an anti-inflammatory effect on the prostate cell line. However, GFLX failed to alter activation of the NF-κB and AP-1 elicited by these stimulants. GFLX significantly attenuated the expression of IL-8 mRNA in TNF-α-stimulated PC-3 cells and down-regulated the transcriptional activity of the 5′-flanking region of the IL-8 gene from −1481 to +44 bp. The deletion construct without the 5′-flanking region from −1481 to −170 bp but not the construct without the region from −1481 to −188 bp reversed the suppressive effect of GFLX on IL-8 promoter activity. These results demonstrate that GFLX suppresses IL-8 expression in the prostate cell line by decreasing the promoter activity of the IL-8 gene.
doi:10.1128/AAC.00395-06
PMCID: PMC1797650  PMID: 17043111
22.  Escherichia coli Isolates Associated with Uncomplicated and Complicated Cystitis and Asymptomatic Bacteriuria Possess Similar Phylogenies, Virulence Genes, and O-Serogroup Profiles▿  
Journal of Clinical Microbiology  2006;44(12):4589-4592.
The genetic and serological characteristics of Escherichia coli isolates from patients with uncomplicated cystitis (UC), complicated cystitis (CC), and complicated asymptomatic bacteriuria (CASB) were determined. Phylogenetic group B2 was predominant in all categories. The prevalences of 14 out of 18 virulence factor genes were similar among the three categories, while pap, iha, ompT, and PAI were more frequently seen in isolates associated with UC than CC or CASB.
doi:10.1128/JCM.02070-06
PMCID: PMC1698404  PMID: 17065267
23.  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

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