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1.  Use of alpha-1 adrenoceptor antagonists in patients who underwent low-dose-rate brachytherapy for prostate cancer - a randomized controlled trial of silodosin versus naftopidil - 
To evaluate the effect of two different alpha-1 adrenoceptor antagonists on lower urinary tract symptoms in patients who underwent LDR-brachytherapy.
A total of 141 patients who had been clinically diagnosed with localized prostate cancer and underwent LDR-brachytherapy were enrolled. Patients were randomized and allocated to two groups (silodosin 8 mg vs. naftopidil 75 mg). The primary endpoint was a change in the international prostate symptom score (IPSS) at 3 months after seed implantation. Secondary endpoints included the recovery rate of IPSS at 12 months after seed implantation, the change in IPSS and overactive bladder symptom score, uroflowmetric parameters, and frequency volume chart (FVC). To determine independent variables that can predict IPSS recovery, logistic regression analysis was carried out.
The mean change in the IPSS at 3 months after seed implantation in both groups was ⊿10.6 (naftopidil) and ⊿10.4 (silodosin), respectively. There was not a significant difference between the two groups (p=0.728). An increase in urinary frequency and a decrease in total urinated volume and mean voided volume were observed in FVC for 12 months after seed implantation. Multivariate analysis revealed that the urethral dose (UD30) was an independent predictive parameter of IPSS recovery. Patients with UD30 < 200Gy showed a higher recovery rate of IPSS at 12 months after seed implantation.
There was no significant difference of serial change in IPSS between silodosin and naftopidil during the first year after seed implantation. A lower dose on the urethra was an independent predictor of IPSS recovery at 12 months after seed implantation.
PMCID: PMC4300048  PMID: 25544509
Prostate cancer; LDR-brachytherapy; Alpha-1 adrenoceptor antagonist; Urinary morbidity; Randomized controlled study
2.  Salvage brachytherapy for seminal vesicle recurrence after initial brachytherapy for prostate cancer: a case report 
BMC Research Notes  2014;7(1):760.
To report the efficacy and safety of salvage brachytherapy for seminal vesicle recurrence after initial brachytherapy in a patient with prostate cancer. As far as we know, this is a first report of salvage brachytherapy for seminal vesicle recurrence in Japan.
Case presentation
A 70-year-old Japanese man with low-risk prostate cancer received low-dose-rate brachytherapy. Forty-two months after the seed implantation, he showed biochemical recurrence based on the nadir + 2 ng/mL definition. The prostate specific antigen (PSA) level was 5.11 ng/mL at 58 months after seed implantation. A saturation biopsy of the prostate showed no recurrence. Systemic screening also showed no distant metastases. However, T2-weighted magnetic resonance imaging (MRI) demonstrated a low intensity area at the base of the right seminal vesicle, which was strongly suggestive of recurrence. Sixty months after the initial therapy, a seminal vesicle biopsy confirmed recurrence with a Gleason score of 4 + 3 before salvage brachytherapy was performed. The prescribed dose was 145 Gy, the same as the dose of the initial therapy. One month later, the PSA level had rapidly declined to 0.898 ng/mL without androgen deprivation therapy. Ten months after the salvage brachytherapy, the PSA level reached 0.078 ng/mL. No adverse events were seen during the follow-up period.
We experienced a patient who was successfully treated with salvage brachytherapy for seminal vesicle recurrence. Salvage brachytherapy is one of the promising therapeutic options for recurrence after initial brachytherapy.
PMCID: PMC4216847  PMID: 25344831
Salvage brachytherapy; Seminal vesicle recurrence; Prostate cancer
3.  Proposed salvage treatment strategy for biochemical failure after radical prostatectomy in patients with prostate cancer: a retrospective study 
Treatment options for patients with recurrent disease after radical prostatectomy include salvage radiotherapy of the prostatic bed and/or androgen deprivation therapy. To establish an effective treatment strategy for recurrent disease after radical prostatectomy, we retrospectively analyzed the outcome of salvage radiation monotherapy in such cases.
Data from 61 men who had undergone salvage radiation monotherapy for biochemical recurrent disease after radical prostatectomy were retrospectively reviewed. In all patients, salvage radiotherapy consisted of iraradiation to the prostatic bed (70 Gy) using three-dimensional conformal radiotherapy techniques. Treatment outcome was analyzed to identify predictive factors of salvage radiotherapy.
The biochemical recurrence-free survival after salvage radiation monotherapy at 2 and 5 years was 55% and 38%, respectively. Cox proportional regression models revealed that the independent predictive factors for biochemical recurrence were Gleason Score ≥ 8, negative surgical margin, and PSA velocity ≥ 0.38 ng/mL/year. Negative surgical margin and PSA velocity ≥ 0.8 ng/mL/year were significantly associated with poor response in the serum PSA levels after salvage radiotherapy.
Based on our findings, we propose a treatment strategy for biochemical recurrent disease after radical prostatectomy. Patients with Gleason score ≤ 7, positive surgical margin, and PSA velocity < 0.38 ng/mL/year are categorized the most favorable group, so that eradication by salvage radiation monotherapy could be expected. Other patients could be divided to two groups depending on surgical margin status and PSA velocity: 1) patients who might require combination of SRT and short-term androgen deprivation therapy and 2) patients who should be treated by androgen deprivation monotherapy.
PMCID: PMC4283125  PMID: 25331298
Prostate cancer; Biochemical failure; Salvage radiotherapy; Prostate-specific antigen; PSA doubling time; PSA velocity
4.  Temporary cognitive impairment related to administration of newly developed anticholinergic medicines for overactive bladder: two case reports 
BMC Research Notes  2014;7(1):672.
Cognitive impairment is one of the side effects of using anticholinergic medicines for overactive bladder; however, its incidence has not been fully reported. We experienced two elderly Japanese patients with overactive bladder who had temporary cognitive impairment caused by anticholinergic medicines.
Case presentation
The first case was a 79-year-old female patient to whom imidafenacin (0.2 mg) was administered daily to control her frequent micturition and urgency. She was taking the following medicines: etizolam, triazolam, captopril, bisoprolol, and amlodipine besylate. Her Hasegawa dementia rating scale-revised was impaired from 26/30 to 17/30 and recovered to 25/30 after the imidafenacin treatment was stopped. The second case was an 82-year-old female patient to whom imidafenacin (0.2 mg) was administered daily for frequent micturition and urgency. She was taking the following medicines: losartan potassium and clenbuterol. Her Hasegawa dementia rating scale-revised decreased from 28/30 to 19/30 and recovered to 24/30 after the imidafenacin treatment was stopped. In our patients who were taking multiple medicines, there is a possibility that medicines other than anticholinergics may have caused cognitive impairment. We need to keep in mind that many elderly people take multiple medicines because of comorbidity.
Anticholinergic medicines can cause cognitive impairment in elderly people, and attention should be paid to cognition when elderly overactive bladder patients are treated with anticholinergic medicines.
PMCID: PMC4180548  PMID: 25252702
Overactive bladder; Anticholinergic medicine; Cognition
5.  Photodynamic diagnosis of shed prostate cancer cells in voided urine treated with 5-aminolevulinic acid 
BMC Urology  2014;14:59.
Past attempts at detecting prostate cancer (PCa) cells in voided urine by traditional cytology have been impeded by undesirably low sensitivities but high specificities. To improve the sensitivities, we evaluate the feasibility and clinical utility of photodynamic diagnosis (PDD) of prostate cancer by using 5-aminolevulinic acid (5-ALA) to examine shed prostate cancer cells in voided urine samples.
One hundred thirty-eight patients with an abnormal digital rectal exam (DRE) and/or abnormal prostate-specific antigen (PSA) levels were recruited between April 2009 and December 2010. Voided urine specimens were collected before prostate biopsy. Urine specimens were treated with 5-ALA and imaged by fluorescence microscopy and reported as protoporphyrin IX (PPIX) positive (presence of cells demonstrating simultaneous PPIX fluorescence) or PPIX negative (lack of cells demonstrating fluorescence).
Of the 138 patients, PCa was detected on needle biopsy in 81 patients (58.7%); of these 81 patients with PCa, 60 were PPIX-positive (sensitivity: 74.1%). Although 57 patients did not harbor PCa by conventional diagnostic procedures, 17 of these at-risk patients were found to be PPIX-positive (specificity: 70.2%). PPIX–PDD was more sensitive compared with DRE and transrectal ultrasound and more specific compared with PSA and PSA density. The incidence of PPIX–PDD positivity did not increase with increasing total PSA levels, tumor stage or Gleason score.
To our knowledge, this is the first successful demonstration of PPIX in urine sediments treated with 5-ALA used to detect PCa in a noninvasive yet highly sensitive manner. However, further studies are warranted to determine the role of PPIX–PPD for PCa detection.
PMCID: PMC4130698  PMID: 25086448
5-aminolevulinic acid; Prostate cancer; Photodynamic diagnosis; Urine cytology
6.  The biochemical recurrence-free rate in patients who underwent prostate low-dose-rate brachytherapy, using two different definitions 
To assess the biochemical recurrence (BCR)-free rate in patients who underwent prostate low-dose-rate brachytherapy (LDR-brachytherapy), using two different definitions (Phoenix definition and PSA ≥ 0.2 ng/mL).
Two hundreds and three patients who were clinically diagnosed with localized prostate cancer (cT1c-2cN0M0) and underwent LDR-brachytherapy between July 2004 and September 2008 were enrolled. The median follow-up period was 72 months. We evaluated the BCR-free rate using the Phoenix definition and the PSA cut-off value of 0.2 ng/mL, as in the definition for radical prostatectomy. To evaluate an independent variable that can predict BCR, Cox’s proportional hazard regression analysis was carried out.
The BCR-free rate in patients using the Phoenix definition was acceptable (5-year: 92.8%). The 5- year BCR-free rate using the strict definition (PSA ≥ 0.2 ng/mL) was 74.1%. Cox’s proportional hazard regression analysis showed that a higher biological effective dose (BED) of ≥180 Gy2 was the only independent variable that could predict BCR (HR: 0.570, 95% C.I.: 0.327-0.994, p = 0.048). Patients with a higher BED (≥180 Gy2) had a significantly higher BCR-free rate than those with a lower BED (<180 Gy2) (5-year BCR-free rate: 80.5% vs. 67.4%).
A higher BED ≥180 Gy2 promises a favorable BCR-free rate, even if the strict definition is adopted.
PMCID: PMC4029825  PMID: 24885896
Prostate cancer; LDR-brachytherapy; Biochemical recurrence-free rate; BED
7.  Nadir PSA level and time to nadir PSA are prognostic factors in patients with metastatic prostate cancer 
BMC Urology  2014;14:33.
Primary androgen deprivation therapy (PADT) is the most effective systemic therapy for patients with metastatic prostate cancer. Nevertheless, once PSA progression develops, the prognosis is serious and mortal. We sought to identify factors that predicted the prognosis in a series of patients with metastatic prostate cancer.
Two-hundred eighty-six metastatic prostate cancer patients who received PADT from 1998 to 2005 in Nara Uro-Oncology Research Group were enrolled. The log-rank test and Cox’s proportional hazards model were used to determine the predictive factors for prognosis; rate of castration-resistant prostate cancer (CRPC) and overall survival.
The median age, follow-up period and PSA level at diagnosis were 73 years, 47 months and 174 ng/mL, respectively. The 5-year overall survival rate was 63.0%. The multivariable analysis showed that Gleason score (Hazard ratio [HR]:1.362; 95% confidence interval [C.I.], 1.023-1.813), nadir PSA (HR:6.332; 95% C.I., 4.006-9.861) and time from PADT to nadir (HR:4.408; 95% C.I., 3.099-6.271) were independent prognostic factors of the incidence of CRPC. The independent parameters in the multivariate analysis that predicted overall survival were nadir PSA (HR:5.221; 95% C.I., 2.757-9.889) and time from PADT to nadir (HR:4.008; 95% C.I., 2.137-7.517).
Nadir PSA and time from PADT to nadir were factors that affect both CRPC and overall survival in a cohort of patients with metastatic prostate cancer. Lower nadir PSA level and longer time from PADT to nadir were good for survival and progression.
PMCID: PMC4018264  PMID: 24773608
Prostate cancer; Metastasis; Risk factors
8.  Novel missense mutation in the FH gene in familial renal cell cancer patients lacking cutaneous leiomyomas 
BMC Research Notes  2014;7:203.
Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a rare tumor predisposition syndrome characterized by cutaneous and uterine leiomyomas and papillary type 2 renal cell cancer. Germline mutation of the fumarate hydratase (FH) gene is known to be associated with HLRCC.
Case presentation
We describe a 64-year-old father and his 39-year-old son with HLRCC who developed papillary type 2 RCCs lacking cutaneous leiomyomas at any site. A common missense mutation in the FH gene, (c.1021G > A, p.D341N) in exon 7, was detected in the 2 cases. Functional prediction with the bioinformatics programs, SIFT and Polyphen-2, reported “damaging (SIFT score 0.00)” and “probably damaging (PSIC score 1.621)” values, respectively. In 162 healthy individuals, there were no cases of a G transition to any base. Finally, (c.1021G > A) in exon 7, was identified as a point mutation.
We report a family with HLRCC in which a novel missense mutation was detected. A familial papillary type 2 renal cancer should be considered HLRCC unless typical cutaneous leiomyomas do not occur.
PMCID: PMC3978052  PMID: 24684806
Familial renal cell cancer; Papillary renal cell cancer; Fumarate hydratase; Missense mutation
9.  Follow-up study of unilateral renal function after nephrectomy assessed by glomerular filtration rate per functional renal volume 
To evaluate the clinical usefulness of estimated glomerular filtration rate (eGFR) divided by functional renal volume (FRV) measured by three-dimensional image reconstruction (eGFR/FRV) for the prediction of functional outcomes after nephrectomy.
Eighty-three patients who underwent nephrectomy were enrolled. The FRV of each patient was measured before surgery. Preoperative medical information on proteinuria, blood pressure, blood glucose level, body mass index (BMI), hemoglobin level and serum cholesterol level were also obtained. We evaluated the relationships between eGFR/FRV and each of these parameters before surgery. We also assessed the potential relationship between eGFR/FRV and the 3-year postoperative eGFR. Stepwise multiple regression analyses were conducted to elucidate independent factors.
The median FRV and eGFR were 310.15 cm3 and 79.0 ml/min/1.73 m2 before surgery, respectively. The correlation between FRV and eGFR was statistically significant (r = 0.465, P < 0.001). The median eGFR/FRV was 0.24 ml/min/1.73 m2/cm3. Stepwise multiple regression analysis showed that the independent parameters (multiple correlation coefficient, r = 0.389, P = 0.031) associated with eGFR/FRV were proteinuria, BMI, age and hypertension. Proteinuria was statistically associated with eGFR/FRV, and the independent parameters (multiple correlation coefficient, r = 0.694, P < 0.001) associated with the 3-year postoperative eGFR were age, BMI and eGFR/FRV. The eGFR/FRV was statistically associated with the 3-year postoperative eGFR (r = 0.559, P < 0.001).
The present results demonstrated that patients with proteinuria are expected to have a lower eGFR/FRV than those without proteinuria. The present study also supports the notion that eGFR/FRV is the primary determinant of the long-term functional outcome after nephrectomy. It should be taken into consideration that patients with a low eGFR/FRV may develop chronic kidney disease after nephrectomy.
PMCID: PMC3995114  PMID: 24641796
Functional renal parenchymal volume; eGFR; Proteinuria; Renal surgery
10.  Trends of risk classification and primary therapy for Japanese patients with prostate cancer in Nara Uro-Oncological Research Group (NUORG)–a comparison between 2004-2006 and 2007-2009 
BMC Cancer  2013;13:588.
To assess the trends of risk classification and primary therapy in Japanese patients who were diagnosed with prostate cancer between 2004-2006 and 2007-2009.
A total of 4752 patients who were newly diagnosed with prostate cancer at Nara Medical University and its 23 affiliated hospitals between 2004 and 2009 were enrolled. The differences in risk classification and primary therapy were compared in patients who were newly diagnosed between 2004-2006 (prior period) and 2007-2009 (latter period).
The proportion of patients with a high or greater risk significantly decreased in the latter period compared to the prior period (p < 0.001). The proportion of primary androgen deprivation therapy (PADT) was 50% in the prior period, and 40% in the latter period. On the other hand, the proportion of radiation therapy was 14% in the prior period, but 24% in the latter period. The proportion of radical prostatectomy was the same in the two periods (30%). The primary therapy was significantly different between the two periods (p < 0.001).
Higher risk patients significantly decreased in the latter period compared to the prior period. The use of PADT also significantly decreased in the latter period. However, there were still higher risk patients in Japan, and the use of PADT was still common in patients with localized prostate cancer or locally advanced prostate cancer in Japan.
PMCID: PMC4028809  PMID: 24325407
Primary therapy; Primary androgen deprivation therapy; Radical prostatectomy; Radiation therapy; Risk classification; Active surveillance
11.  Diagnostic markers of urothelial cancer based on DNA methylation analysis 
BMC Cancer  2013;13:275.
Early detection and risk assessment are crucial for treating urothelial cancer (UC), which is characterized by a high recurrence rate, and necessitates frequent and invasive monitoring. We aimed to establish diagnostic markers for UC based on DNA methylation.
In this multi-center study, three independent sample sets were prepared. First, DNA methylation levels at CpG loci were measured in the training sets (tumor samples from 91 UC patients, corresponding normal-appearing tissue from these patients, and 12 normal tissues from age-matched bladder cancer-free patients) using the Illumina Golden Gate methylation assay to identify differentially methylated loci. Next, these methylated loci were validated by quantitative DNA methylation by pyrosequencing, using another cohort of tissue samples (Tissue validation set). Lastly, methylation of these markers was analyzed in the independent urine samples (Urine validation set). ROC analysis was performed to evaluate the diagnostic accuracy of these 12 selected markers.
Of the 1303 CpG sites, 158 were hyper ethylated and 356 were hypo ethylated in tumor tissues compared to normal tissues. In the panel analysis, 12 loci showed remarkable alterations between tumor and normal samples, with 94.3% sensitivity and 97.8% specificity. Similarly, corresponding normal tissue could be distinguished from normal tissues with 76.0% sensitivity and 100% specificity. Furthermore, the diagnostic accuracy for UC of these markers determined in urine samples was high, with 100% sensitivity and 100% specificity.
Based on these preliminary findings, diagnostic markers based on differential DNA methylation at specific loci can be useful for non-invasive and reliable detection of UC and epigenetic field defect.
PMCID: PMC3691617  PMID: 23735005
Urothelial cancer; DNA methylation; Pyrosequencing; ROC; Piagnostic accuracy
12.  The Effects of Chlormadinone Acetate on Lower Urinary Tract Symptoms and Erectile Functions of Patients with Benign Prostatic Hyperplasia: A Prospective Multicenter Clinical Study 
Advances in Urology  2013;2013:584678.
Purpose. To evaluate the effects of chlormadinone acetate (CMA), progesterone-derived antiandrogen, on lower urinary tract symptoms (LUTS) and erectile functions of benign prostatic hyperplasia (BPH). Methods. A multicenter, single-cohort prospective study was conducted. A total of 114 patients received CMA for 16 weeks. The endpoints were changes in International Prostate Symptom Scores (IPSS), IPSS-QOL, International Index of Erectile Function-5, Qmax prostate volume, and residual urine volume. Results. Significant improvements were observed in IPSS from week 8 to week 48 (32 weeks after treatment). IPSS-QOL improvements were also significant from week 8 to week 48. Qmax increased to a maximum at Week 16 and remained elevated throughout the study. Moreover, a decrease of 25% in prostate volume was observed at Week 16. IPSS, QOL, and Qmax changes during the study were not different between the previously treated and untreated patients. IPSS storage subscore changes differed between the age groups. Few severe adverse reactions were observed, except for erectile dysfunction. Conclusions. CMA rapidly and significantly reduced prostate volume and improved voiding and storage symptoms and QOL. Our results suggest that CMA is safe and beneficial, especially for elderly patients with LUTS associated with BPH.
PMCID: PMC3671298  PMID: 23762042
13.  Periodical assessment of genitourinary and gastrointestinal toxicity in patients who underwent prostate low-dose-rate brachytherapy 
To compare the periodical incidence rates of genitourinary (GU) and gastrointestinal (GI) toxicity in patients who underwent prostate low-dose-rate brachytherapy between the monotherapy group (seed implantation alone) and the boost group (in combination with external beam radiation therapy (EBRT)).
A total of 218 patients with a median follow-up of 42.5 months were enrolled. The patients were divided into 2 groups by treatment modality, namely, the monotherapy group (155 patients) and the boost group (63 patients). The periodical incidence rates of GU and GI toxicity were separately evaluated and compared between the monotherapy group and the boost group using the National Cancer Institute - Common Terminology Criteria for Adverse Events, version 3.0. To elucidate an independent factor among clinical and postdosimetric parameters to predict grade 2 or higher GU and GI toxicity in the acute and late phases, univariate and multivariate logistic regression analyses were carried out.
Of all patients, 78.0% showed acute GU toxicity, and 7.8% showed acute GI toxicity, while 63.8% showed late GU toxicity, and 21.1% showed late GI toxicity. The incidence rates of late GU and GI toxicity were significantly higher in the boost group. Multivariate analysis showed that the International Prostate Symptom Score (IPSS) before seed implantation was a significant parameter to predict acute GU toxicity, while there were no significant predictive parameters for acute GI toxicity. On the other hand, combination with EBRT was a significant predictive parameter for late GU toxicity, and rectal volume (mL) receiving 100% of the prescribed dose (R100) was a significant predictive parameter for late GI toxicity.
The boost group showed higher incidence rates of both GU and GI toxicity. Higher IPSS before seed implantation, combination with EBRT and a higher R100 were significant predictors for acute GU, late GU and late GI toxicity.
PMCID: PMC3570431  PMID: 23363647
Prostate cancer; LDR-brachytherapy; GU toxicity; GI toxicity
14.  Inhibition of COX-2 expression by topical diclofenac enhanced radiation sensitivity via enhancement of TRAIL in human prostate adenocarcinoma xenograft model 
BMC Urology  2013;13:1.
COX-2 inhibitors have an antitumor potential and have been verified by many researchers. Treatment of cancer cells with external stressors such as irradiation can stimulate the over-expression of COX-2 and possibly confer radiation resistance. In this study, we tested if topical diclofenac, which inhibits both COX-1 and COX-2, administration rendered prostate tumor cells sensitize to the effects of radiation.
LNCaP-COX-2 and LNCaP-Neo cells were treated with 0 to 1000 μM diclofenac. Next, a clonogenic assay was performed in which cells were subjected to irradiation (0 to 4 Gy) with or without diclofenac. COX-2 expression and other relevant molecules were measured by real-time PCR and immunohistochemistry after irradiation and diclofenac treatment. In addition, we assessed the tumor volumes of xenograft LNCaP-COX-2 cells treated with topical diclofenac with or without radiation therapy (RT).
LNCaP-COX-2 and LNCaP-Neo cell lines experienced cytotoxic effects of diclofenac in a dose related manner. Clonogenic assays demonstrated that LNCaP-COX-2 cells were significantly more resistant to RT than LNCaP-Neo cells. Furthermore, the addition of diclofenac sensitized LNCaP-COX-2 not but LNCaP-Neo cells to the cytocidal effects of radiation. In LNCaP-COX-2 cells, diclofenac enhanced radiation-induced apoptosis compared with RT alone. This phenomenon might be attributed to enhancement of RT-induced TRAIL expression as demonstrated by real-time PCR analysis. Lastly, tumor volumes of LNCaP-COX-2 cells xenograft treated with diclofenac or RT alone was >4-fold higher than in mice treated with combined diclofenac and radiation (p<0.05).
These in vitro and in vivo findings suggest that conventional COX inhibitor, diclofenac enhances the effect of RT on prostate cancer cells that express COX-2. Thus, diclofenac may have potential as radiosensitizer for treatment of prostate cancer.
PMCID: PMC3561196  PMID: 23289871
Prostate cancer; Radiation therapy; COX-2; TRAIL; Apoptosis; Topical therapy; Radiosensitizer; Diclofenac; Radioresistance
15.  Improvement of the surgical curability of locally confined prostate cancer including non-organ-confined high-risk disease through retropubic radical prostatectomy with intentional wide resection 
Retropubic radical prostatectomy with intentional wide resection (RRP-WR), which enables clear location of the prostate apex and the performance of posterolateral wider resection to remove extraprostatic extension, was introduced to our institutions. The aim of this study is to assess the feasibility and the efficacy of RRP-WR as a surgical intervention for locally confined prostate cancer.
A total of 90 Japanese patients with pathologically proven and clinically locally confined hormone-naïve prostate cancer were treated through RRP-WR, and the surgical morbidity was assessed. The patients were observed without immediate treatment until biochemical recurrence (BCR).
The surgical morbidities were comparable to conventional procedures. No positive surgical margin (pSM) was pathologically identified in pT2 cases from prostatectomy specimens. It was identified in only 14.3% of pT3a cases, 36.4% of pT3b cases and 100% of pT4 cases. No apical pSM was found except for one of the pT4 cases in the levator ani muscle. PSA was at an undetectable level in 80.0% of all cases, 90.0% of pT2 cases, and 67.5% of pT3 and pT4 cases after surgery. The BCR-free survival rate in all cases was 82.4% and that of high-risk cases without pSM was 76.9% at a median follow-up of 19.3 months (3.3 to 59.2).
RRP-WR is feasible and effective in removing organ-confined prostate cancer as well as extraprostatic extension without pSM. Thus, it is worthwhile to evaluate if this procedure improves the clinical outcome of locally confined prostate cancer including high-risk conditions treated by surgical intervention.
PMCID: PMC3523069  PMID: 23158926
Prostate; Neoplasms; Prostatectomy
16.  Minimal percentage of dose received by 90% of the urethra (%UD90) is the most significant predictor of PSA bounce in patients who underwent low-dose-rate brachytherapy (LDR-brachytherapy) for prostate cancer 
BMC Urology  2012;12:28.
To clarify the significant clinicopathological and postdosimetric parameters to predict PSA bounce in patients who underwent low-dose-rate brachytherapy (LDR-brachytherapy) for prostate cancer.
We studied 200 consecutive patients who received LDR-brachytherapy between July 2004 and November 2008. Of them, 137 patients did not receive neoadjuvant or adjuvant androgen deprivation therapy. One hundred and forty-two patients were treated with LDR-brachytherapy alone, and 58 were treated with LDR-brachytherapy in combination with external beam radiation therapy. The cut-off value of PSA bounce was 0.1 ng/mL. The incidence, time, height, and duration of PSA bounce were investigated. Clinicopathological and postdosimetric parameters were evaluated to elucidate independent factors to predict PSA bounce in hormone-naïve patients who underwent LDR-brachytherapy alone.
Fifty patients (25%) showed PSA bounce and 10 patients (5%) showed PSA failure. The median time, height, and duration of PSA bounce were 17 months, 0.29 ng/mL, and 7.0 months, respectively. In 103 hormone-naïve patients treated with LDR-brachytherapy alone, and univariate Cox proportional regression hazard model indicated that age and minimal percentage of the dose received by 30% and 90% of the urethra were independent predictors of PSA bounce. With a multivariate Cox proportional regression hazard model, minimal percentage of the dose received by 90% of the urethra was the most significant parameter of PSA bounce.
Minimal percentage of the dose received by 90% of the urethra was the most significant predictor of PSA bounce in hormone-naïve patients treated with LDR-brachytherapy alone.
PMCID: PMC3487947  PMID: 22974428
Prostate cancer; Brachytherapy; PSA bounce; Post-dosimetry; UD90 (%)
17.  Calculated Tumor Volume Is an Independent Predictor of Biochemical Recurrence in Patients Who Underwent Retropubic Radical Prostatectomy 
Advances in Urology  2012;2012:204215.
Purpose. The purpose of this study is to investigate whether the clinicopathological biopsy findings can predict the oncological outcome in patients who undergo radical prostatectomy. Materials and Methods. Between January 1997 and March 2006, 255 patients with clinically localized adenocarcinoma of the prostate (clinical T1-3N0M0) who had undergone retropubic radical prostatectomy were enrolled in this study. None of the patients received neoadjuvant or adjuvant therapy. Clinicopathological parameters were assessed to determine a predictive parameter of biochemical recurrence. Results. Of the total 255 patients, 77 showed biochemical recurrence during the follow-up period. The estimated 5-year overall survival, 5-year cause-specific survival, and 5-year biochemical recurrence-free survival rates were 97.7%, 99.5%, and 67.3%, respectively. Multivariate analysis using the Cox proportional hazards model showed that calculated cancer volume was an independent predictor among the preoperative clinicopathological parameters (P < 0.05). SVI and PSM were independent predictors among the postoperative parameters (SVI; P < 0.001, PSM; P = 0.049). Among the significant preoperative and postoperative parameters, calculated cancer volume remained an independent predictive parameter in multivariate analysis (P < 0.01). Conclusions. Tumor volume, as calculated by preoperative parameters, is an independent predictor of biochemical recurrence in patients who had undergone radical prostatectomy.
PMCID: PMC3359669  PMID: 22654901
18.  5-fluorouracil enhances the antitumor effect of sorafenib and sunitinib in a xenograft model of human renal cell carcinoma 
Oncology Letters  2012;3(6):1195-1202.
Sorafenib and sunitinib are multi-kinase inhibitors with antitumor activity in patients with advanced renal cell carcinoma (RCC). Several studies have evaluated the effect of sorafenib/sunitinib in combination with chemotherapeutic agents in different types of tumor. However, few studies have addressed the activity of fluorinated pyrimidine in combination with sorafenib/sunitinib. In this study, we examined the potential of combination therapy with 5FU and sorafenib/sunitinib in human RCC cell lines. Three human RCC cell lines, ACHN, Caki-1 and Caki-2, were used to assess sensitivity to 5-fluorouracil (5FU), sorafenib and sunitinib alone or in combination using an in vitro cell survival assay. Caki-2 cells demonstrated significantly higher resistance to 5FU and sorafenib as compared to ACHN and Caki-1. Additive antitumor effects of the combination therapy were observed in the in vitro study. There was a tendency for a positive correlation between the sensitivity to sunitinib and platelet-derived growth factor β (PDGFR-β) expression levels, which were examined by reverse transcription polymerase chain reaction. Caki-1 xenograft models were prepared by inoculating cells subcutaneously into nude mice, which were divided randomly into six groups: control, 5FU (8 mg/kg/day, intraperitoneally), sorafenib (15 mg/kg/day, orally), sunitinib (20 mg/kg/day, orally), and 5FU with sorafenib or sunitinib. The treatments were administered on 5 days each week, and tumor growth was monitored for 42 days following inoculation of cells. Synergistic antitumor effects of the combination therapy were observed in an in vivo study. The resected tumors were evaluated using the Ki-67 labeling index and microvessel density. Both the Ki-67 labeling index and microvessel density were decreased in tumors treated with the combination therapy compared to those treated with sorafenib/sunitinib alone. These findings suggest that the combination therapy of 5FU with sorafenib/sunitinib may be an effective therapeutic modality for advanced RCC patients.
PMCID: PMC3392575  PMID: 22783417
renal cell carcinoma; 5-fluorouracil; sorafenib; sunitinib; angiogenesis
19.  Transverse testicular ectopia with disorders of sex development 
Transverse testicular ectopia (TTE) is a rare congenital anomaly. Although TTE often coexists with abnormalities such as inguinal hernia and persistent Mullerian duct syndrome, disorders of sex development (DSD) in combination with TTE is extremely rare. We report a case of DSD with sex chromosomal abnormality in combination with TTE. To our knowledge, this case report is a first presentation of such anomaly.
PMCID: PMC3339796  PMID: 22557726
Disorders of sex development; laparoscopy; transverse testicular ectopia
20.  ROS generation via NOX4 and its utility in the cytological diagnosis of urothelial carcinoma of the urinary bladder 
BMC Urology  2011;11:22.
Reactive oxygen species (ROS) production via NADPH oxidase (NOX) contributes to various types of cancer progression. In the present research, we examined the pathobiological role of NADPH oxidase (NOX)4-mediated generation of reactive oxygen species (ROS) in urothelial carcinoma (UC) of the urinary bladder, and demonstrated the utility of ROS labeling in urine cytology.
NOX4 gene was silenced in vivo and in vitro by NOX4 siRNA transfection with or without atlocollagen. Cell cycle and measurement of ROS were analyzed by flowcytometry. Orthotopic implantation animal model was used in vivo experiment. NOX4 expression in urothelial carcinoma cells was observed by immunohistochemical analysis using surgical specimens of human bladder cancer. Urine cytology was performed after treatment with ROS detection reagents in addition to Papanicolaou staining.
NOX4 was overexpressed in several UC cell lines and the NOX inhibitor, diphenylene iodonium reduced intracellular ROS and induced p16-dependent cell cycle arrest at the G1 phase. Moreover, silencing of NOX4 by siRNA significantly reduced cancer cell growth in vivo as assessed in an orthotopic mouse model. Immunohistochemistry demonstrated high expression of NOX4 in low grade/non-invasive and high grade/invasive UC including precancerous lesions such as dysplasia but not in normal urothelium. Then, we assessed the usefulness of cytological analysis of ROS producing cells in urine (ROS-C). Urine samples obtained from UC cases and normal controls were treated with fluorescent reagents labeling the hydrogen peroxide/superoxide anion and cytological atypia of ROS positive cells were analyzed. As a result, the sensitivity for detection of low grade, non-invasive UC was greatly increased (35% in conventional cytology (C-C) vs. 75% in ROS-C), and the specificity was 95%. Through ROS-C, we observed robust improvement in the accuracy of follow-up urine cytology for cases with previously diagnosed UC, especially in those with low grade/non-invasive cancer recurrence (0% in C-C vs. 64% in ROS-C).
This is the first report demonstrating that ROS generation through NOX4 contributes to an early step of urothelial carcinogenesis and cancer cell survival. In addition, cytology using ROS labeling could be a useful diagnostic tool in human bladder cancer.
PMCID: PMC3215170  PMID: 22032647
21.  Cyclooxygenase 2-dependent and independent activation of Akt through casein kinase 2α contributes to human bladder cancer cell survival 
BMC Urology  2011;11:8.
Survival rate for patients presenting muscle invasive bladder cancer is very low, and useful therapeutic target has not been identified yet. In the present study, new COX2 downstream signals involved in urothelial carcinoma cell survival were investigated in vitro and in vivo.
COX2 gene was silenced by siRNA transfection. Orthotopic implantation animal model and transurethral instillation of siRNA with atelocollagen was constructed to examine the effects of COX2 knockdown in vivo. Cell cycle was examined by flowcytoketry. Surgical specimens derived from patients with urinary bladder cancer (all were initially diagnosed cases) were used for immunohistochemical analysis of the indicated protein expression in urothelial carcinoma cells.
Treatment with the COX2 inhibitor or knockdown of COX2 reduced expression of casein kinase (CK) 2 α, a phophorylated Akt and urokinase type plasminogen activator (uPA), resulting in p27 induction, cell cycle arrest at G1 phase and cell growth suppression in human urothelial carcinoma cell lines expressing COX2. Silencing of CK2α exhibited the similar effects. Even in UMUC3 cells lacking the COX2 gene, COX2 inhibition also inhibited cell growth through down-regulation of the CK2α-Akt/uPA axis. The mouse orthotropic bladder cancer model demonstrated that the COX2 inhibitor, meloxicam significantly reduced CK2α, phosphorylated Akt and uPA expression, whereas induced p27 by which growth and invasiveness of bladder cancer cells were strongly inhibited. Immunohistochemically, high expression of COX2, CK2α and phosphorylated form of Akt was found in high-grade, invasive carcinomas as well as carcinoma in situ, but not in low-grade and noninvasive phenotypes.
COX2-dependent and independent activation of CK2α-Akt/uPA signal is mainly involved in urothelial carcinoma cell survival, moreover, not only COX2 but also CK2α could be direct targets of COX2 inhibitors.
PMCID: PMC3111585  PMID: 21592330
cyclooxygenase 2; urothelial carcinoma; casein kinase 2α; Akt
22.  The primary therapy chosen for patients with localized prostate cancer between the university hospital and its affiliated hospitals in Nara Uro-oncological research group registration 
BMC Urology  2011;11:6.
We investigated the differences between the preferential primary therapy conceived by the primary doctors and the primary therapy actually conducted for prostate cancer patients in Nara, Japan.
The distribution of primary therapy and clinical characteristics of 2303 prostate cancer patients - diagnosed between 2004 and 2006 at Nara Medical University and its 23 affiliated hospitals - were assessed. Moreover, the preferential primary therapy for the patients at each clinical stage (cT1-T3bN0M0) conceived by the primary doctors was investigated and compared to the actual therapy.
Of all patients, 51% received primary androgen deprivation therapy (PADT), 30% underwent radical prostatectomy (RP), and 14% received radiation therapy (RT). The preferential primary therapy for cT1-2N0M0 was RP (92%) while 38% of the patients actually received PADT (RP: 40%). For cT3aN0M0, the preferential primary therapy was both RP and external beam radiation therapy (EBRT) while 58% of the patients actually received PADT (RP: 16%, EBRT: 24%). For cT3bN0M0, the most preferential primary therapy was EBRT (46%) while 67% of the patients actually received PADT (EBRT: 21%). This trend was more notable in the affiliated hospitals than in the University hospital. The hospitals with lower volume of RP per year significantly conducted PADT compared with those with higher volume of RP.
PADT was commonly used to treat localized prostate cancer as well as locally advanced prostate cancer in Japan. There was a definite discrepancy between the preferential primary therapy conceived by the primary doctors and the actual therapy provided to the patients.
PMCID: PMC3095576  PMID: 21524283

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