Yukio Homma

Integrated molecular analysis of clear-cell renal cell carcinoma

Clear-cell renal cell carcinoma (ccRCC) is the most prevalent kidney cancer and its molecular pathogenesis is incompletely understood. Here we report an integrated molecular study of ccRCC in which ≥100 ccRCC cases were fully analyzed by whole-genome and/or whole-exome and RNA sequencing as well as by array-based gene expression, copy number and/or methylation analyses. We identified a full spectrum of genetic lesions and analyzed gene expression and DNA methylation signatures and determined their impact on tumor behavior. Defective VHL-mediated proteolysis was a common feature of ccRCC, which was caused not only by VHL inactivation but also by new hotspot TCEB1 mutations, which abolished Elongin C–VHL binding, leading to HIF accumulation. Other newly identified pathways and components recurrently mutated in ccRCC included PI3K-AKT-mTOR signaling, the KEAP1-NRF2-CUL3 apparatus, DNA methylation, p53-related pathways and mRNA processing. This integrated molecular analysis unmasked new correlations between DNA methylation, gene mutation and/or gene expression and copy number profiles, enabling the stratification of clinical risks for patients with ccRCC.

Silodosin, a new α1A‐adrenoceptor‐selective antagonist for treating benign prostatic hyperplasia: results of a phase III randomized, placebo‐controlled, double‐blind study in Japanese men

This section contains papers from Japan, Austria, the UK, and joint papers from France, Denmark, Switzerland, Australia and the USA. A wide variety of lower urinary tract topics is covered, from BPH to overactive bladder and urodynamic stress incontinence.

Age-related changes in cholinergic and purinergic neurotransmission in human isolated bladder smooth muscles.

We evaluated the correlation among age, cholinergic and purinergic neurotransmissions in the electrical field stimulation-induced contractions in human isolated urinary bladder smooth muscles, using the muscle bath technique. Human bladder specimens were divided into three groups (G1, under 50years; G2, 51-70years; G3, over 70years old), and each muscle strip was suspended in a thermostatically controlled organ bath filled with oxygenated Krebs-Henseleit solution, connected to an isometric force displacement transducer, and an isometric tension development was recorded. The contractile responses induced by KCl, carbachol, adenosine triphosphate (ATP) and electrical field stimulation, and the effects of atropine and alpha, beta methylene ATP on electrical field stimulation-induced contractions were observed. The contractile response to KCl and concentration-response curves for carbachol and ATP, and frequency-response curves for electrical field stimulation were not significantly different among the three groups. The atropine sensitive and resistant parts of contraction induced by electrical field stimulation were decreased and increased with age, respectively. There are significant positive and negative correlations between age and the purinergic, and age and the cholinergic neurotransmissions in human isolated bladder smooth muscles, respectively. The age-related changes in neurotransmissions may contribute to the changes in bladder function in the elderly.

An epidemiological survey of overactive bladder symptoms in Japan

To report an epidemiological survey of lower urinary tract symptoms (LUTS) to determine the prevalence of overactive bladder (OAB) symptoms (defined as a symptom complex of daily urinary frequency of eight or more times and urgency once or more per week) in Japan.

INCREASED INCIDENTAL DETECTION AND REDUCED MORTALITY IN RENAL CANCER—RECENT RETROSPECTIVE ANALYSIS AT EIGHT INSTITUTIONS

A retrospective survey of renal cell carcinoma between 1975 and 1993 at eight collaborating institutions was conducted with special reference to the incidental detection and mortality of renal cancer. The analysis demonstrated a recent dramatic increase in the frequency of incidental renal cancer, which now comprises two‐thirds of all renal cancers, and a simultaneous recession in non‐incidental or suspected renal cancer. Incidental renal cancer has remained unchanged during the last decade as far as patient demographics, occasion and method of detection, and the degree of tumor extension are concerned. On the other hand, the annual number of deaths from renal cancer has significantly decreased, and kidney‐sparing surgery has been more frequently performed. These results indicate that incidental renal cancers are now in the majority, and earlier detection may contribute to improving the mortality and morbidity from the disease as a whole.

Androgen-responsive long noncoding RNA CTBP1-AS promotes prostate cancer

High‐throughput techniques have identified numerous antisense (AS) transcripts and long non‐coding RNAs (ncRNAs). However, their significance in cancer biology remains largely unknown. Here, we report an androgen‐responsive long ncRNA, CTBP1‐AS, located in the AS region of C‐terminal binding protein 1 (CTBP1), which is a corepressor for androgen receptor. CTBP1‐AS is predominantly localized in the nucleus and its expression is generally upregulated in prostate cancer. CTBP1‐AS promotes both hormone‐dependent and castration‐resistant tumour growth. Mechanistically, CTBP1‐AS directly represses CTBP1 expression by recruiting the RNA‐binding transcriptional repressor PSF together with histone deacetylases. CTBP1‐AS also exhibits global androgen‐dependent functions by inhibiting tumour‐suppressor genes via the PSF‐dependent mechanism thus promoting cell cycle progression. Our findings provide new insights into the functions of ncRNAs that directly contribute to prostate cancer progression.

Clinical guidelines for interstitial cystitis and hypersensitive bladder syndrome.

A clinical guideline and algorism for interstitial cystitis and hypersensitive bladder syndrome has been developed by a group of East Asian urologists as a revised form of the Japanese guideline for interstitial cystitis. The guideline defines interstitial cystitis (IC) as a disease of the urinary bladder diagnosed by 3 requirements; 1) a characteristic complex of lower urinary tract symptoms, 2) bladder pathology such as Hunners ulcer and bladder bleeding after overdistension, and 3) exclusions of confusable diseases. The characteristic symptom complex is termed as hypersensitive bladder syndrome (HBS), which is defined as bladder hypersensitivity, usually associated with urinary frequency, with or without bladder pain. For the definite diagnosis of IC, cytoscopy or hydrodistension is crutial; HBS is the diagnosis when IC is suspected but not confirmed by the 3 requirements. Numerous therapeutic options are available; however, most of them lack in high level of evidence, leaving a few as recommended therapies. Etiology of IC are multifactorial; the interaction among nervous, immune and endocrine factors forms a vicious cycle, provocating and maintaining inflammatory reactions in the bladder. The inclusion and efficacy criteria for clinical trials should be standardized to enhance the clinical research for this disabling disease, which has proved to be more prevalent than previously believed.

A survey on incidental adrenal tumors in Japan.

A nationwide Japanese survey of 210 cases from 116 collaborating institutions demonstrated a dramatic increase in incidentally detected adrenal tumor from 4 cases in 1980 to 54 in 1988. The most common diagnosis was nonfunctioning cortical adenoma (69 cases), followed by pheochromocytoma (49). A total of 14 malignant tumors (6.7%) and 16 functioning benign cortical lesions was also found. Histological study revealed that functioning tumors were small and found in relatively young female patients, nonfunctioning cortical adenomas were of similar size but found in older patients, and all malignant tumors were larger than 6.5 cm. in diameter and occurred in patients 58 years or younger. These results indicate an increase in the occurrence of incidental adrenal tumor and the complexity of pathology.

Clinical guidelines for overactive bladder

Department of Urology, Fukushima Medical University, Fukushima, Department of Urology, Shinshu University School of Medicine, Matsumoto, Nagano, Department of Urology, University of Yamanashi Interdisciplinary Graduate School of Medicine and Engineering, Chuo, Yamanashi, Department of Urology, University of Fukui Faculty of Medicine, Fukui, Department of Urology, University of Tokyo Faculty of Medicine, Tokyo, Department of Urology, Asahikawa Medical College, Asahikawa, Hokkaido, Department of Urology, Niigata University School of Medicine, Niigata, Department of Urology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Department of Urology, Graduate School of Medical Science, Kyushu University, Fukuoka, Department of Urology, Graduate School of medical Science, Kumamoto University, Kumamoto, Japan

Clinical efficacy and tolerability of extended-release tolterodine and immediate-release oxybutynin in Japanese and Korean patients with an overactive bladder: a randomized, placebo-controlled trial

To compare extended‐release (ER) tolterodine and immediate‐release (IR) oxybutynin with placebo in Japanese and Korean patients with an overactive bladder (OAB).