Masayoshi Zaitsu

Comparative Evaluation of the Safety and Efficacy of Long-Term Use of Imidafenacin and Solifenacin in Patients with Overactive Bladder: A Prospective, Open, Randomized, Parallel-Group Trial (the LIST Study)

Objectives. Overactive bladder (OAB) is a chronic disease, but comparative trials of anticholinergics, which are commonly used for treatment of OAB, have generally been performed for up to 12 weeks only. There is no comparative study of a long-term intervention. Methods. We conducted a 52-week prospective randomized comparative study to evaluate the efficacy and tolerability of two anticholinergics. Results. Forty-one Japanese patients with untreated OAB were randomly assigned to imidafenacin and solifenacin groups. There was no difference in OABSS and KHQ scores between the two groups, but the severity and incidence of adverse events caused by the anticholinergics showed increased differences between the groups with time. The severity of dry mouth and the incidence of constipation were significantly lower in the imidafenacin group (P = 0.0092 and P = 0.0013, resp.). Conclusions. This study is the first long-term trial to show differences in the properties of anticholinergics that were not detected in short-term studies. Since OAB is a chronic disease, we conclude that imidafenacin is preferable to solifenacin from a perspective of safety.

Surgical castration in hormone-refractory metastatic prostate cancer patients can be an alternative for medical castration.

Background. Most patients with metastatic prostate cancer are endocrinologically treated with LHRH agonist, but finally castration-refractory and hormone-refractory cancers occur. Serum testosterone levels get low to “the castration level” by LHRH agonists but may not get low enough against castration-refractory prostate cancer. Methods. As case series, twelve patients suffering from hormone-refractory prostate cancer continuously on LHRH agonist underwent surgical castration. Additionally, one hundred and thirty-nine prostate cancer patients on LHRH agonist or surgical castration were tested for serum total testosterone levels. Results. Surgical castration caused decrease in serum PSA in one out of 12 hormone-refractory prostate cancer patients with PSA reduction rate 74%. Serum total testosterone levels were below the sensitivity threshold (0.05 ng/mL) in 40 of 89 (44.9%) medically castrated patients and 33 of 50 (66.0%) surgically castrated patients (P = .20). Conclusion. Even hormone-refractory prostate cancer patients are candidates for surgical castration because of endocrinological, oncological, and economical reasons.

Detection of AR-V7 mRNA in whole blood may not predict the effectiveness of novel endocrine drugs for castration-resistant prostate cancer

A splice variant of androgen receptor (AR), AR-V7, lacks in androgen-binding portion and leads to aggressive cancer characteristics. Reverse transcription-polymerase chain reactions (PCRs) and subsequent nested PCRs for the amplification of AR-V7 and prostate-specific antigen (PSA) transcripts were done for whole blood of patients with prostate cancer and male controls. With primary reverse transcription PCRs, AR-V7 and PSA were detected in 4.5% and 4.7% of prostate cancer, respectively. With nested PCRs, AR-V7 messenger RNA (mRNA) was positive in 43.8% of castration-sensitive prostate cancer and 48.1% of castration-resistant prostate cancer (CRPC), while PSA mRNA was positive in 6.3% of castration-sensitive prostate cancer and 18.5% of CRPC. Whole-blood samples of controls showed AR-V7 mRNA expression by nested PCR. Based on multivariate analysis, expression of AR-V7 mRNA in whole blood was not significantly correlated with clinical parameters and PSA mRNA in blood, while univariate analysis showed a correlation between AR-V7 mRNA and metastasis at initial diagnosis. Detection of AR-V7 mRNA did not predict the reduction of serum PSA in patients with CRPC following abiraterone and enzalutamide administration. In conclusion, AR-V7 mRNA expression in normal hematopoietic cells may have annihilated the manifestation of aggressiveness of prostate cancer and the prediction of the effectiveness of abiraterone and enzalutamide by the assessment of AR-V7 mRNA in blood.

Experience with imidafenacin in the management of overactive bladder disorder

Overactive bladder (OAB) is a chronic syndrome defined by symptoms of urinary urgency with no underlying medical causes. First-line treatment of OAB comprises fluid intake advice and bladder training, supplemented by anticholinergic drugs if necessary. Owing to the chronic nature of OAB, the ideal anticholinergic treatment should have good long-term efficacy and tolerability. There are many anticholinergics available, although some of these are not specific for the bladder and can cause adverse effects such as dry mouth, constipation, blurred vision or cognitive impairment. Imidafenacin (a newer anticholinergic which has been marketed in Japan since 2007) was developed to improve the tolerability of anticholinergic therapy. This article summarizes the pharmacological properties, pharmacokinetics, clinical efficacy and tolerability of imidafenacin in the treatment of OAB. Data from key clinical studies of imidafenacin show that it has a fast onset of action and is effective for the treatment of OAB. It selectively binds to muscarinic receptors in the bladder and is associated with a good safety profile compared with other anticholinergics. The clinical efficacy, superior tolerability and adjustable dosing of imidafenacin make it a good anticholinergic for the treatment of OAB.

A Dual 5α-Reductase Inhibitor Dutasteride Caused Reductions in Vascular Density and Area in Benign Prostatic Hyperplasia

Objectives. Dutasteride, a dual 5α-reductase inhibitor, is used to treat benign prostatic hyperplasia. Nevertheless, its histopathological effects on the morphometrics of blood vessels and glands are still controversial. The aim here was to assess the histopathological effects of dutasteride in cases of benign prostatic hyperplasia in a retrospective study. Methods. Patients with benign prostatic hyperplasia more than 40 cm3 in prostatic volume were administered 0.5 mg of dutasteride daily or left untreated prior to receiving a transurethral resection of the prostate. Images of sections stained with hematoxylin/eosin and with anti-CD31 antibody were analyzed. Results. In the dutasteride-treated group, the duration of administration was 16.3 ± 8.1 weeks. Artery/arteriole density and vein/venule density in benign prostatic tissue were both lower in the dutasteride-treated group than in the control group. The vein/venule area as a percentage of the whole area was also lower in the dutasteride-treated group, while the artery/arteriole area did not show a significant difference. Glandular/CD31-expressing vessel densities as well as glandular/CD31-expressing vessel areas were comparable between the two groups. Conclusions. Dutasteride reduced the artery/arteriole and vein/venule densities and the proportion of vein/venule area in the tissue of patients with benign prostatic hyperplasia.

Alcohol consumption and risk of upper-tract urothelial cancer

BACKGROUND Upper-tract urothelial cancer (UTUC), which includes renal pelvic cancer and ureter cancer, is a rare cancer and its prognosis is poor. Smoking and high-risk occupations (e.g., printing and dyestuff working which involves exposure to aniline dyes) are well-known risk factors for UTUC. However, the risk of alcohol consumption in UTUC remains unclear. This study aimed to determine whether alcohol consumption is an independent risk factor for UTUC. METHODS The study was a case-control study which used the nationwide clinical inpatient database of the Rosai Hospital group in Japan. We identified 1569 cases and 506,797 controls between 1984 and 2014. We estimated the odds ratio (OR) and 95% confidence interval (95%CI) of alcohol consumption for UTUC - never, up to 15g/day, >15-30g/day, or >30g/day - using unconditional logistic regression. We adjusted for the following covariates: age, sex, study period, hospital, history of smoking, and high-risk occupation. RESULTS The risk of UTUC was significantly higher in ever-drinkers compared with never-drinkers (OR=1.23, 95%CI, 1.08-1.40; P=0.001). Compared with never-drinkers, the risk threshold for UTUC was >15g of alcohol consumption per day (equivalent to 6 ounces of Japanese sake containing 23g of alcohol). A dose-response was observed (P<0.001). CONCLUSION Alcohol consumption may be an independent risk factor for UTUC, with a low-risk threshold of 15g of alcohol per day.

Overexpression of Aquaporin 1 in the Tunica Vaginalis May Contribute to Adult-Onset Primary Hydrocele Testis

To investigate the cause of the adult-onset primary noncommunicating hydrocele testis, protein expressions of water channel aquaporins (AQPs) 1 and 3 in the tunica vaginalis were assessed. Frozen tunica vaginalis specimens from patients with adult-onset primary hydrocele testis and control male nonhydrocele patients were subjected to Western blot analysis for the detection of AQP1 and AQP3 proteins. Paraffin-embedded sections of tunica vaginalis specimens were histochemically stained with anti-AQP1 and anti-AQP3 antibodies as well as an anti-podoplanin antibody to stain lymphatic endothelia. Hydrocele fluid was subjected to biochemical analysis. AQP1 protein expression in the tunica vaginalis was significantly higher in patients with adult-onset hydrocele testis than in the controls. The AQP3 protein was not detected in the tunica vaginalis. Histochemically, AQP1 expression in the tunica vaginalis was localized in vascular endothelial and smooth muscle cells. The densities of AQP1-expressing capillaries and lymphatic vessels were similar between the tunica vaginalis of the controls and those of hydrocele patients. Sodium levels were higher in the hydrocele fluid than in the serum. In conclusion, overexpression of the AQP1 protein in individual capillary endothelial cells of the tunica vaginalis may contribute to the development of adult-onset primary noncommunicating hydrocele testis as another aquaporin-related disease.

Participation in Community Group Activities Among Older Adults: Is Diversity of Group Membership Associated With Better Self-rated Health?

Background Participation in community activities (eg, sports and hobby groups or volunteer organizations) is believed to be associated with better health status in the older population. We sought to (1) determine whether a greater diversity of group membership is associated with better self-rated health and (2) identify the key dimension of the membership diversity (eg, gender, residential area, or age). Methods We performed a cross-sectional study of 129,740 participants aged 65 years and older who were enrolled in the Japan Gerontological Evaluation Study in 2013. We assessed the diversity of group membership using (1) a continuous variable (range 0–4) accounting for the total degree of each diversity dimension or (2) dummy variables for each dimension. We estimated prevalence ratios (PRs) and 95% confidence intervals (CIs) for better self-rated health according to the diversity of group membership, using Poisson regression and robust variance with multiple imputation, adjusted for other covariates. Results The participants involved in social groups with greater diversity had better self-rated health: the PR per one point unit increase in diversity was 1.03 (95% CI, 1.02–1.04). Participation in gender-diverse groups was associated with the best profile of health (PR 1.07; 95% CI, 1.04–1.09). Conclusions Among the older population in Japan, higher group diversity is associated with better self-rated health. Gender is the key dimension of diversity that is associated with better self-rated health.

Occupational class and risk of renal cell cancer

We sought to examine the association between occupational class linked to job stress and the risk of renal cell cancer. To identify potential mediators, we additionally examined whether any observed associations persisted even after controlling for the contribution of stress‐related factors (eg, smoking, hypertension, and obesity).

A single nucleotide polymorphism in kidney anion exchanger 1 gene is associated with incomplete type 1 renal tubular acidosis

Various conditions including distal renal tubular acidosis (dRTA) can induce stone formation in the kidney. dRTA is characterized by an impairment of urine acidification in the distal nephron. dRTA is caused by variations in genes functioning in intercalated cells including SLC4A1/AE1/Band3 transcribing two kinds of mRNAs encoding the Cl−/HCO3− exchanger in erythrocytes and that expressed in α-intercalated cells (kAE1). With the acid-loading test, 25% of urolithiasis patients were diagnosed with incomplete dRTA. In erythroid intron 3 containing the promoter region of kAE1, rs999716 SNP showed a significantly higher minor allele A frequency in incomplete dRTA compared with non-dRTA patients. The promoter regions of the kAE1 gene with the minor allele A at rs999716 downstream of the TATA box showed reduced promoter activities compared that with the major allele G. Patients with the A allele at rs999716 may express less kAE1 mRNA and protein in the intercalated cells, developing incomplete dRTA.