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Objectives: To clarify clinical predictors for a prostate-specific antigen decrease � 50% in response to alternative non-steroidal antiandrogen therapy and to develop a nomogram to predict the prostate-specific antigen decrease � 50% in response to alternative non-steroidal antiandrogen therapy in patients with advanced prostate cancer that relapsed after initial combined androgen blockade. We previously reported that combined androgen blockade with an alternative non-steroidal antiandrogen is effective for advanced prostate cancer that has relapsed after initial combined androgen blockade. Methods: We enrolled 161 patients from 14 medical institutions with histologically confirmed prostate cancer who had been treated with combination therapy and in whom cancer progressed after first-line combined androgen blockade therapy. A nomogram for the prostatespecific antigen decrease � 50% from baseline prostate-specific antigen in response to alternative non-steroidal antiandrogen therapy was developed based on the final logistic regression model. Results: Overall prostate-specific antigen decreased � 50% in 75 of 161 patients (46.6%) in response to alternative non-steroidal antiandrogen therapy. Using five independent risk factors (initial serum level of prostate-specific antigen, hemoglobin, C-reactive protein, prostate-specific antigen nadir to second hormone therapy and Gleason sum), a nomogram was developed for the prediction of prostate-specific antigen decrease � 50% in response to alternative nonsteroidal antiandrogen therapy. The receiver operating characteristic curve showed that the accuracy of the predicted probability was 72.5% for the model. Conclusions: This predictive nomogram could predict the prostate-specific antigen decrease � 50% in response to alternative non-steroidal antiandrogen therapy and might be of benefit to determine the sequential treatment strategy in patients with relapse after first combined androgen blockade.

Background: Cannabinoid receptor subtype 1 (CB1) has a relationship to the proliferation of various cells including malignant tumoral cells. We investigated and compared the expression of CB1 in benign and malignant human prostate tissues and in benign and malignant human prostate cell lines, as well as its function for the proliferation of human prostate cancer cells. Methods: Real-time quantitative PCR was performed to compare its expressions in human prostate tissues (normal, benign hyperplasia, and cancer) and prostate cell lines (3 normal and 3 malignant). For localization of CB1, immunofluorescent staining with rabbit anti-CB1 polyclonal antibodies and tetramethyl isothiocyanate (TRITC)-labeled swine anti-rabbit immunoglobulin (DAKO) were used under fluorescence microscope. To further analyze whether cell death was induced by anandamide (non-selective agonist for CB1/CB2) via a receptor dependent mechanism, the viability of DU145 cells, which is known as androgen-insensitive prostate cancer cell, was measured using MTT assay. Results: CB1mRNA was found to be expressed in the all 3 human prostate tissues, however, CB1 protein was expressed in BPH and low grade malignant PC tissues, but not in high grade malignant PC tissues. CB1 as for cell lines, the expression of CB1 was low in malignant cell lines except for DU145. Anandamide elicited cell death, which was significantly inhibited by AM251 (selective antagonist for CB1), indicating that cell death induced by anandamide in DU145 cells was mediated by CB1. Anandamide time-dependently elicits up-regulation of CB1 in DU145 cells. Conclusions: CB1 may be an inhibitory regulator of androgen-insensitive human prostate cancer epithelial cell growth.

【目的】糖尿病合併透析症例の血糖管理の現況をグリコアルブミン（GA）で評価し，予後に対する影響を検討した．【方法】対象は2004年1月1日から2009年12月31日までに山梨厚生病院で維持血液透析をした糖尿病合併症例87例．年齢65.9±10.9歳，男60例，女27例．観察期間中GAを毎月計測して平均した（平均GA）．Cox比例ハザードモデルで平均GAの生存への影響を検討した．また平均GAで対象を4群に分割し，Kaplan-Meier法で生存分析を行った．【結果】観察期間は3.1±2.0年で，30名が死亡した．平均GAは21.9±4.1％．平均GAと年齢が有意に死亡を規定した（平均GA：比例ハザード1.108，95％信頼区間1.013～1.213，p＝0.026，年齢：比例ハザード1.035，95％信頼区間1.001～1.070，p＝0.046）．平均GA 24.23％以上の群は19.05～24.02％の群に比べて有意に生存が不良であった（p＝0.496，log-rang test）．【結論】糖尿病合併血液透析症例の血糖管理不良は死亡危険因子である．これらの症例の透析導入後の血糖管理が重要である．

Introduction: We investigated how generic and disease-specific measures differ in estimating the quality of life (QoL) impact of lower urinary tract symptoms (LUTS). Materials and Methods: A total of 172 men and 67 women ≧40 years old who attended the public lectures completed the questionnaire comprising the International Prostate Symptom Score, benign prostatic hyperplasia impact index and SF-36 Health Survey. The multiple regression analysis was performed to evaluate the QoL impact of LUTS. Results: Both storage and voiding symptoms showed significant correlations with disease-specific QoL. Among men, voiding symptom correlated more closely with disease-specific QoL than storage symptom did, and this finding was reversed among women. Storage but not voiding symptoms showed a significant correlation with generic QoL. Among men, storage symptom correlated more closely with mental health than physical health, and the reversed finding was obtained among women. Generic QoL, especially physical health, was significantly influenced by some comorbid diseases, but disease-specific QoL was not. Conclusions: The QoL impact of LUTS was differentially estimated by disease-specific and generic measures with sex differences.

Aim: We examine the expression of mRNA of G protein-coupled receptor kinase (GRK) subtypes and muscarinic acetylcholine receptor (M) subtypes in the detrusor smooth muscle of the human urinary bladder. Furthermore, we confirm the presence and the localization of GRK proteins in the detrusor smooth muscle of the obstructed bladder in comparison with the control bladder. Methods: Detrusor smooth muscle tissues of the human urinary bladder were obtained from 12 male patients; 6 patients did not have bladder outlet obstruction, and the other 6 patients had bladder outlet obstruction. Portions of the dome or anterior wall of the urinary bladder were used for the present study. Reverse transcription/polymerase chain reaction for GRK2, M2 and M3 was performed using total RNA extracted from human urinary bladder detrusor. Antibodies to GRK2, GRK3 and GRK4 were used to confirm the presence of the protein product in the human urinary bladder using immunohistochemical staining and the western blotting technique. Results: All complementary DNA (cDNA) transcribed from three different mRNA (M2, M3 and GRK2) were successfully amplified and size-fractionated. The expression of GRK2 protein was strong in the human bladder detrusor, but was significantly weakened by western blotting in obstructed bladder in comparison with control bladder. Conclusions: Failure in desensitization mechanisms of muscarinic acetylcholine receptors might be related to storage symptom elicited by overactivity in obstructed bladder with benign prostatic hyperplasia.

Aim: The expression of the telomerase subunits such as human telomerase reverse transcriptase (hTERT) and human telomerase RNA component (hTR) may be associated with tumor development and progression. We evaluated the relationship between mRNA quantification of both hTERT and hTR and clinicopathologic parameters in bladder cancer. Methods: We examined the mRNA expression of hTERT and hTR in 29 specimens with bladder cancer (Grade: Grade I, 9 cases; Grade II, 13 cases and Grade III, 7 cases. Stage: pTa-pT1, 18 cases; pT2-T4, 11 cases). We immediately froze all of specimens obtained during TUR-Bt and isolated the total RNA from each specimen. We measured the quantity of hTERT, hTR and GAPDH mRNA by a real-time reverse transcription–polymerase chain reaction method based on TaqMan technology. Results: The hTERT/GAPDH mRNA ratio and hTERT mRNA/total RNA in superficial bladder tumor was significantly lower than in invasive bladder tumor. The hTR/GAPDH mRNA ratio and hTR mRNA/total RNA in superficial tumor were significantly lower than in invasive bladder tumor. The hTERT mRNA expression significantly correlated with tumor grade, but the hTR mRNA expression did not correlate with tumor grade. There was no significant difference in the hTERT/GAPDH mRNA ratio and hTR mRNA/total RNA according to multiplicity of bladder tumor. Conclusions: Our results demonstrated that the expression of hTERT mRNA correlated with the progression of stage and grade in bladder cancer. The quantitative analysis of hTERT and hTR mRNA might be a marker for clinicopathologic parameters in bladder cancer.

Prostaglandin E1 leads to penile erection, mainly via prostaglandin E2 (EP) receptors. This study aimed to identify the expression profile of EP receptor genes in human corpus cavernosum. Using the quantitative real-time reverse transcription polymerase chain reaction, the mRNA levels of EP receptor subtypes were measured. In addition, expressions of EP receptor subtype proteins were determined by immunohistochemical method. Among the four subtypes, EP4 receptor mRNA expression was the highest, and EP2 receptor mRNA followed, whereas EP1 and EP3 receptor mRNAs were hardly observed. Expression level of EP4 receptor mRNA was significantly higher than that of EP2 receptor mRNA. Expression of both EP2 and EP4 receptor proteins were clearly detected in the cavernous smooth muscle. These results may suggest that EP4 receptor plays an important role among four EP receptor subtypes for relaxation of smooth muscle in the human corpus cavernosum.

Between 1996 and 2003, ten patients with small renal tumors underwent retroperitoneoscopic partial nephrectomy without renal ischemia, nine patients with small renal tumors underwent open partial nephrectomy via a retroperitoneal approach. Both groups were operated on using a microwave tissue coagulator. We compared the results of retroperitoneoscopic group with those of a retroperitoneal open surgery group. Retroperitoneoscopic partial nephrectomy without renal ischemia was performed without any major or minor complications in any patient. The mean operation time for retroperitoneoscopic surgery significantly longer than that for open partial nephrectomy. However, the mean estimated blood loss for retroperitoneoscopic surgery was less than that for open partial nephrectomy. In addition, the retroperitoneoscopic group seemed to recover more rapidly than the open surgery group. This endoscopic surgery is feasible as minimally invasive procedure. It results in saving renal function, minimal blood loss and rapid recovery.

Summary Introduction: Despite the beneficial immunosuppressive effects of FK506 during small intestine transplantation, FK506 appears to have direct toxic effects on the intestine. The mechanisms of FK506-induced intestinal damage is unclear, and whether nitric oxide (NO) is involved in the mechanism has not been well defined. This study was designed to evaluate the effects of N G -Nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthase, on small intestinal damage in rats treated with FK506. Materials and methods: Wistar rats weighing 240—260 g, aged 11 weeks, were administered FK506 (5 mg/kg/day i.m) and/or L-NAME (5 mg/dl in drinking water) for 10 days. Body weight gain, diarrhoea and mortality were observed during experiment. At the end of experiment, the intestinal specimens were excised for histological evaluation. In addition, the effects of L-aginine treatment (1 g/dl in drinking water) were evaluated in this study. Results: L-NAME administration time-dependently induced diarrhoea and high mortality in the rats treated with FK506. At the end of 10 days treatment, 7 of 12 rats (58.3%) suffered from diarrhoea and 5 of 12 rats (41.7%) died in the FK506 + L-NAME group (vs. FK506 group, p = 0.05). A significant loss of body weight was also found in the rats treated with FK506 + L-NAME (—52.2±28.8 g, in FK506 % L-NAME group vs. —14.3±8.7g in FK506 group, p = 0.001). In parallel with the severe diarrhoea and high mortality, the loss of villi, hemorrhage and necrosis (grade 5 of pathological damage) was seen in the small intestinal mucosa of rats treated with FK506 + L-NAME. L-arginine treatment in part prevented diarrhoea, mortality and pathological damage of small intestinal mucosa induced by L-NAME. Conclusions: Inhibition of NOS induces intestinal mucosal damage and increases mortality in rats treated with FK506. L-arginine treatment can in part prevent the injury induced L-NAME. The present study suggests that NO, as an important protective factor, may be involved in the FK506-induced intestinal damage.

Large meta-analyses have documented that maximum androgen blockade with nonsteroidal antiandrogens for advanced prostate cancer confers survival benefits, although it remains controversial. Also, we and others have reported the effectiveness of second line hormonal therapy for prostate cancer that relapses after initial hormone therapy. However, there is little clinical evidence of the effectiveness of the latter treatment strategy. Therefore, in this multicenter trial in Japan we analyzed clinical outcomes following alternative changing from 1 nonsteroidal antiandrogen to another, ie bicalutamide to flutamide and flutamide to bicalutamide, for advanced prostate cancer that relapsed after initial maximum androgen blockade.The study included 232 patients with advanced prostate cancer who were initially treated with maximum androgen blockade, including surgical or medical castration combined with nonsteroidal antiandrogens. If a patient relapsed while on first line therapy, we discontinued antiandrogen and evaluated the patient for antiandrogen withdrawal syndrome. We then administered an alternative antiandrogen and evaluated its effect.The incidence of antiandrogen withdrawal syndrome after initial maximum androgen blockade was 15.5% for bicalutamide and 12.8% for flutamide. A prostate specific antigen decrease after antiandrogen withdrawal was a prognostic factor. Nonsteroidal antiandrogens as alternative therapy in patients with relapse after the initial maximum androgen blockade were effective (prostate specific antigen decrease greater than 50%) as second line maximum androgen blockade. Of 232 patients 142 (61.2%) showed a prostate specific antigen decrease in response to an alternative antiandrogen. These responders had significantly better survival than nonresponders, suggesting that responsiveness to second line therapy predicts increased survival.Following maximum androgen blockade with an alternative nonsteroidal antiandrogen is effective for advanced prostate cancer that has relapsed after initial maximum androgen blockade. Even a partial response to second line maximum androgen blockade was associated with improved survival. Our data support the notion that responders to second line regimens are androgen independent but still hormonally sensitive.

We examine the expression of mRNA of G protein-coupled receptor kinase (GRK) subtypes and muscarinic acetylcholine receptor (M) subtypes in the detrusor smooth muscle of the human urinary bladder. Furthermore, we confirm the presence and the localization of GRK proteins in the detrusor smooth muscle of the obstructed bladder in comparison with the control bladder.Detrusor smooth muscle tissues of the human urinary bladder were obtained from 12 male patients; 6 patients did not have bladder outlet obstruction, and the other 6 patients had bladder outlet obstruction. Portions of the dome or anterior wall of the urinary bladder were used for the present study. Reverse transcription/polymerase chain reaction for GRK2, M2 and M3 was performed using total RNA extracted from human urinary bladder detrusor. Antibodies to GRK2, GRK3 and GRK4 were used to confirm the presence of the protein product in the human urinary bladder using immunohistochemical staining and the western blotting technique.All complementary DNA (cDNA) transcribed from three different mRNA (M2, M3 and GRK2) were successfully amplified and size-fractionated. The expression of GRK2 protein was strong in the human bladder detrusor, but was significantly weakened by western blotting in obstructed bladder in comparison with control bladder.Failure in desensitization mechanisms of muscarinic acetylcholine receptors might be related to storage symptom elicited by overactivity in obstructed bladder with benign prostatic hyperplasia.

The expression of the telomerase subunits such as human telomerase reverse transcriptase (hTERT) and human telomerase RNA component (hTR) may be associated with tumor development and progression. We evaluated the relationship between mRNA quantification of both hTERT and hTR and clinicopathologic parameters in bladder cancer.We examined the mRNA expression of hTERT and hTR in 29 specimens with bladder cancer (Grade: Grade I, 9 cases; Grade II, 13 cases and Grade III, 7 cases. Stage: pTa-pT1, 18 cases; pT2-T4, 11 cases). We immediately froze all of specimens obtained during TUR-Bt and isolated the total RNA from each specimen. We measured the quantity of hTERT, hTR and GAPDH mRNA by a real-time reverse transcription-polymerase chain reaction method based on TaqMan technology.The hTERT/GAPDH mRNA ratio and hTERT mRNA/total RNA in superficial bladder tumor was significantly lower than in invasive bladder tumor. The hTR/GAPDH mRNA ratio and hTR mRNA/total RNA in superficial tumor were significantly lower than in invasive bladder tumor. The hTERT mRNA expression significantly correlated with tumor grade, but the hTR mRNA expression did not correlate with tumor grade. There was no significant difference in the hTERT/GAPDH mRNA ratio and hTR mRNA/total RNA according to multiplicity of bladder tumor.Our results demonstrated that the expression of hTERT mRNA correlated with the progression of stage and grade in bladder cancer. The quantitative analysis of hTERT and hTR mRNA might be a marker for clinicopathologic parameters in bladder cancer.

We have developed a novel modification of previous approaches to donor nephrectomy and herein review our original operative procedure. First, the posterior aspect of the kidney was dissected retroperitoneoscopically and dissection of the renal artery, ureter and gonadal vein was almost completed. Second, the anterior aspect of the kidney was dissected with transperitoneal hand-assistance, and dissection of the renal pedicle from the anterior surface was accomplished easily and safely. This operative procedure was successfully performed for two donors with no intraoperative or postoperative complications. Our modified endoscopic donor nephrectomy is feasible as a minimally invasive procedure because of its safety, and its ability to preserve renal function and establish an excellent operative field for both posterior and anterior aspects of the kidney.

Lower urinary tract symptoms (LUTS) are associated with lower urinary tract dysfunction. Symptoms are the subjective indicator of a disease or change in condition as perceived by the patient, caregiver, or partner and may lead the individual to seek help from health care professionals. LUTS are usually qualitative and, therefore, cannot usually be used to make a definitive diagnosis. LUTS also can indicate pathologies other than lower urinary tract dysfunction, such as urinary infection. LUTS are divided into 7 groups: storage, voiding (obstructive), postmicturition symptoms and 4 others. Voiding symptoms, which are caused by lower urinary tract obstruction, include slow stream, splitting or spraying, intermittency, hesitancy, straining, and terminal dribble. Postmicturition symptoms, which are experienced immediately after micturition, consist of the feeling of incomplete emptying and postmicturition dribble. Postmicturition dribble describes the involuntary loss of urine immediately after the individual has finished passing urine; in men, usually after leaving the toilet and in women, after rising from the toilet. Hence, postmicturition dribble is elicited by different situations or is considered as having different implications. For example, although postmicturition dribble usually implies incomplete emptying (voiding symptoms) in elderly men with benign prostatic hyperplasia, postmicturition dribble is often considered as urinary incontinence (a storage symptom) in many patients, even with bladder outlet obstruction. In such cases, detailed history taking and further evaluation, such as urinary flowmetry, postvoid residual volume, and comprehensive urodynamic evaluation, should be performed as appropriate. If no urodynamic abnormalities of either the detrusor or the outlet can be detected despite significant LUTS, factors unrelated to the lower urinary tract may be responsible for the voiding symptoms.

We examined the influence of aging on bladder function in men and women.Using the International Prostate Symptom Score questionnaire with an additional question on urinary incontinence lower urinary tract symptoms were evaluated in all outpatients who first visited our urological department from June 2001 to December 2002. In 550 of the 1,201 patients who completed the questionnaire any pathological conditions that might cause micturition disorder could not be detected with urological examinations. Symptom scores of these patients without underlying disease causing micturition disorder were the basis of this study.In men and women total and storage symptom scores but not the voiding symptom score increased significantly with age. In each age group total, storage and voiding symp-tom scores were not significantly different between men and women. Women 50 to 69 years old had significant higher incontinence scores than men of the same age, whereas a significant increase in the incontinence score with age was found only in men. The quality of life score increased with age in men but not in women. However, the 2 sexes did not significantly differ in quality of life score.Lower urinary tract symptoms, especially storage symptoms, showed age related alterations in the 2 sexes without any underlying disease causing micturition disorder. The prevalence of urinary symptoms was not different between men and women. Therefore, bladder function in each sex might be subject to a gender independent aging process.

A 69-year-old-man undergoing hemodialysis for 8 years developed metastatic urothelial carcinoma and received combination chemotherapy with paclitaxel and carboplatin. Paclitaxel 175 mg/m2 was given as a 3-hour intravenous infusion, and carboplatin was dosed to the area under the plasma concentration-time curve (AUC) of 5 mg.min/ml calculated according to the Calvert formula as a 30-minute intravenous infusion immediately after paclitaxel. Hemodialysis was started 1 hour after carboplatin, then their pharmacokinetics was determined in the patient. The AUC of paclitaxel and carboplatin were 15.2 and 64.56 micrograms.h/ml, respectively. The metastatic tumor size was reduced by more than 20% after 3 courses of this chemotherapy. Grade 3 neutropenia and grade 1 thrombopenia were observed. This is the first report that the combination of paclitaxel and carboplatin is feasible in a patient with metastatic urothelial carcinoma undergoing hemodialysis, with low toxicity and safety.

It is ideal to use not a transperitoneal but a retroperitoneal approach for both open and endoscopic partial nephrectomy. We compared the results of retroperitoneoscopic nephron-sparing surgery for small renal tumors using a microwave tissue coagulator without renal pedicle clamping with those of a retroperitoneal open procedure.Between 1996 and 2002, eight patients with small renal tumors underwent retroperitoneoscopic partial nephrectomy without renal ischemia, and nine patients with small renal tumors underwent open partial nephrectomy via a retroperitoneal approach. Both groups were operated on using a microwave tissue coagulator.Retroperitoneoscopic partial nephrectomy without renal ischemia was performed without any major or minor complications in any patient. The mean operation time for retroperitoneoscopic surgery was significantly longer than that for open partial nephrectomy (221.9 minutes v 145.9 minutes; P = 0.0004). However, the mean estimated blood loss for retroperitoneoscopic surgery was less than that for open partial nephrectomy (137.5 mL v 334.8 mL; P = 0.012). In addition, the retroperitoneoscopic group seemed to recover more rapidly than the open surgery group.Retroperitoneoscopic nephron-sparing surgery of small renal tumors using a microwave tissue coagulator without renal ischemia is feasible as minimally invasive procedure. It results in saving renal function, minimal blood loss, and rapid recovery.

To study the limitations of lymphangiography in the detection of early lymphatic spread of pelvic malignancies, we evaluated 587 lymph nodes from 23 patients with stages pNO to 2 carcinoma of the bladder or prostate. Pelvic lymphadenectomy was performed 5 to 10 days after bipedal lymphangiography. Excised lymph nodes were separated one by one and an x-ray of each node was taken (lymphnodegram). The individual lymphnodegram was compared to the histological findings. Interpretations of lymphnodegrams from all 17 nodes with metastases were positive in 5, suspicious in 1, negative in 9 and radiolucent in 2. False negative judgments occurred chiefly because metastatic foci were microscopic. Two lymph nodes without metastasis were interpreted as positive for disease because of fat replacement of the nodes. These results indicated that lymphangiography is not suitable for the detection of early lymphatic metastases of carcinoma of the bladder or prostate.