Raizo Yamaguchi

Reduction of 8-hydroxyguanine in human leukocyte DNA by physical exercise

We investigated the effect of physical exercise on the level of 8-hydroxyguanine (8-OH-Gua), a form of oxidative DNA damage, and its repair activity in human peripheral leukocytes. Whole blood samples were collected by venipuncture from 21 healthy male volunteers (10 trained athletes and 13 untrained men), aged 19-50 years, both before and after physical exercise. Trained athletes showed a lower level of 8-OH-Gua (2.4+/-0.5/10(6) Gua, p = 0.0032) before exercise when compared to that of untrained men (6.2+/-3.5). The mean levels of 8-OH-Gua of untrained subjects decreased significantly (p = 0.0057) from 6.2+/-3.5/10(6) Gua (mean+/-SD/10(6) Gua) to 3.3+/-1.4/10(6) Gua after physical exercise. On the other hand, the mean levels of repair activity of untrained subjects significantly increased after exercise (p = 0.0093) from 0.037+/-0.024 (mean DNA cleavage ratio+/-SD) to 0.056+/-0.036. In the trained athletes 8-OH-Gua level and its repair activity were not changed before and after the exercise. We also observed inter-individual differences in 8-OH-Gua levels and its repair activities. These results suggest that physical exercise causes both rapid and long-range reduction of oxidative DNA damage in human leukocytes, with individually different efficiencies.

Increase in 8-hydroxyguanine and its repair activity in the esophagi of rats given long-term ethanol and nutrition-deficient diet

Epidemiological studies have shown that an increased risk of esophageal cancer is associated with the chronic consumption of alcoholic beverages, although alcohol itself is not a carcinogen in animal models. Reactive oxygen species produced by the metabolism of ethanol or by chronic inflammation may play an important role in the carcinogenic process. In this study, we analyzed one type of oxidative DNA damage, 8‐hydroxyguanine (8‐OH‐Gua), and its repair activity in the esophagus as indicators of cellular oxidative stress in rats given long‐term ethanol and an autoclaved diet (nutrition‐deficient diet). Three‐week‐old male Sprague‐Dawley rats were fed an ethanol beverage whose concentration was increased from 12 to 70% over 20 weeks. When the concentration reached 50%, the diet of one group was changed from the regular diet to an autoclaved diet. At the feeding periods of 20, 25, 30, and 35 weeks, the rats were sacrificed and the 8‐OH‐Gua levels and repair activities within the esophagi were measured. After 30 weeks of ethanol‐ and autoclaved diet‐feeding, significant increases of 8‐OH‐Gua and its repair activity were observed in the esophagi, but not in those of the ethanol‐ and normal diet‐fed rats. This result indicates that the combined effects of long‐term ethanol consumption and nutritional deficiency may be involved in inducing oxidative stress in the rat esophagus.

Impact of aging and comorbidity on the efficacy of low-intensity shock wave therapy for erectile dysfunction

To evaluate the efficacy of low‐intensity shock wave therapy and to identify the predictive factors of its efficacy in Japanese patients with erectile dysfunction.

Feasibility and accuracy of computational robot-assisted partial nephrectomy planning by virtual partial nephrectomy analysis

To evaluate the feasibility and accuracy of virtual partial nephrectomy analysis, including a color‐coded three‐dimensional virtual surgical planning and a quantitative functional analysis, in predicting the surgical outcomes of robot‐assisted partial nephrectomy.

Testosterone promotes DNA damage response under oxidative stress in prostate cancer cell lines.

Sustained chronic inflammation and oxidative stress in the prostate promote prostate carcinogenesis. The process of oncogenic transformation leads to enhanced DNA damage and activates the checkpoint network that functions as an inducible barrier against cancer progression. Here, we analyzed the effects of testosterone on the DNA damage response in prostate cancer cells to assess whether testosterone functions a barrier to cancer progression under the oxidative stress.

Feasibility of multiparametric prostate magnetic resonance imaging in the detection of cancer distribution: histopathological correlation with prostatectomy specimens

Purpose To prevent overtreatment, it is very important to diagnose the precise distribution and characteristics of all cancer lesions, including small daughter tumors. The purpose of this study was to evaluate the efficacy of T2-weighted magnetic resonance imaging (T2W), diffusion-weighted magnetic resonance imaging (DWI), magnetic resonance spectroscopy (1H-MRS), and prostate biopsy (PBx) in the detection of intraprostatic cancer distribution. Methods All patients underwent T2W, DWI, 1H-MRS, and PBx followed by radical prostatectomy (RP). Individual prostates were divided into 12 segmental regions, each of which was examined for the presence or absence of malignancy on the basis of T2W, DWI, 1H-MRS, and PBx, respectively. These results were compared with the histopathological findings for RP specimens. Results We included 54 consecutive patients with biopsy-proven prostate cancer (mean age, 62.7 years; median prostate-specific antigen level, 5.7 ng/mL) in this study. We could detect cancer in 247 of 540 evaluable lesions. The area under the receiver operator characteristic curve analysis yielded a higher value for DWI (0.68) than for T2W (0.65), 1H-MRS (0.54), or PBx (0.56). In 180 cancerous regions of RP specimens with false-negative PBx results, T2W+DWI had the highest positive rate (53.3%) compared with that of each sequence alone, including T2W (45.6%), DWI (41.1%), and 1H-MRS (30.0%). Conclusions Multiparametric magnetic resonance imaging (T2W, 1H-MRS, DWI) enables the detection of prostate cancer distribution with reasonable sensitivity and specificity. T2W+DWI was particularly effective in detecting cancer distribution with false-negative PBx results.

The Impact of Increased Bladder Blood Flow on Storage Symptoms after Holmium Laser Enucleation of the Prostate

In order to investigate how holmium laser enucleation of the prostate (HoLEP) improves urinary storage symptoms, we assessed blood flow in the urinary bladder mucosa of patients with benign prostatic hyperplasia (BPH) before and after laser surgery. Seventy-four consecutive patients with BPH (median age 69 years, range; 53–88) underwent HoLEP at our institution and are included in this study. We prospectively assessed the International Prostate Symptom Score (IPSS), IPSS-QOL Score, the Overactive Bladder Symptom Score (OABSS), uroflowmetry, and blood flow in the urinary bladder, before and after surgery. Blood flow in the bladder mucosa was measured using the OMEGA FLOW (OMEGAWAVE, Tokyo, Japan) laser Doppler flowmeter. The median volume of the enucleated adenomas was 45.0 g (range: 25.0 to 83.2). The median IPSS improved significantly from 20 (range: 6–35) to 3 (0–22) (p<0.001; Wilcoxon signed-rank test), as did the storage symptoms score, which decreased from 13 (2–20) to 3 (1–8) (p<0.001). Median bladder blood flow increased at the trigone from 9.57±0.83 ml/sec to 17.60±1.08 ml/sec. Multiple regression analysis for the improved storage symptom score eliminated all explanatory variables except increased bladder perfusion. The data suggest that HoLEP improves blood flow in the bladder mucosa, which independently leads to the improvement of storage symptoms.

Serum level of follicle-stimulating hormone is associated with extraprostatic extension of prostate cancer

Purpose: To determine whether serum follicle-stimulating hormone (FSH) can be used to predict the aggressiveness of prostate cancer prior to radical prostatectomy. Methods: Ninety-six patients who underwent radical prostatectomy for biopsy proved cT1c-T2N0M0 prostate cancer between 2003 and 2008 were identified for retrospective analysis. Using univariate regression analysis, potential variables of extraprostatic tumor extension were identified, including prostate-specific antigen (PSA), luteinizing hormone, FSH, testosterone, biopsy findings, and age. These variables of interest were analyzed by logistic and linear regression analysis to determine if serum FSH is predictive of extraprostatic extension. Results: Extraprostatic extension was pathologically confirmed in 18 of 96 patients (18.8%). Statistical analysis confirmed that serum FSH was significantly associated with extraprostatic extension (P=0.04). However, age, PSA level, Gleason score, number of tumors, and serum testosterone level were not found to be independent predictors of extraprostatic extension. Conclusions: Selective expression of FSH receptor on the surface of blood vessels of prostate cancers has recently been reported. Measuring serum FSH preoperatively in patients with prostate cancer may provide clinically relevant information about extraprostatic spread of tumor.

Phase I study of highly selective inhibitor of VEGFR tyrosine kinase, tivozanib, in Japanese patients with solid tumors

Tivozanib is a potent and selective inhibitor of vascular endothelial growth factor receptor (VEGFR) tyrosine kinases. A previous clinical trial in the EU and USA indicated that tivozanib at the maximum tolerated dose of 1.5 mg/day showed an antitumor activity in patients with renal cell carcinoma. This Japanese phase I study was designed to determine the recommended phase II dose of tivozanib for Japanese patients; secondary objectives included pharmacokinetic/pharmacodynamic profiles and preliminary efficacy. Daily treatment with tivozanib in a 3‐weeks‐on/1‐week‐off cycle was examined in nine Japanese patients with advanced solid tumors in the 3 + 3 design (Level 1, 1.0 mg; Level 2, 1.5 mg). No dose‐limiting toxicity was observed throughout the study, and the maximum tolerated dose was not reached. The most commonly observed drug‐related adverse events were diarrhea, dysphonia, rash, thyroid stimulating hormone increase, and with severity grade ≥3, hand‐foot skin reaction, hypertension, and proteinuria. Those adverse events were generally well‐manageable and mostly resolved within the tolerability evaluation period. Serum exposure to tivozanib resulted in t1/2 of more than >60 h. Increase of plasma VEGF and decrease of plasma VEGFR‐1 and VEGFR‐2 were observed 1–3 weeks after tivozanib treatment. Although no complete or partial response was observed, long‐term stable disease continuing more than 170 days was observed in three renal cell carcinoma patients who had failed prior VEGFR inhibitors. In conclusion, 1.5 mg/day of tivozanib in a 3‐weeks‐on/1‐week‐off setting was tolerable in Japanese patients, and was recommended for further clinical trials in the Japanese population. Clinical trial Registration No: JapicCTI‐090854.

Maintenance monotherapy with gemcitabine after standard platinum-based chemotherapy in patients with advanced urothelial cancer.

To investigate the outcomes of gemcitabine maintenance monotherapy treatment for metastatic urothelial cancer.