Seiichiro Ozono

Prognosis of Japanese Metastatic Renal Cell Carcinoma Patients in the Cytokine Era: A Cooperative Group Report of 1463 Patients

BACKGROUNDnIncidence rate of renal cell carcinoma (RCC) differs among countries. The rates of Asian countries are lower than those of countries in North America or Europe but are exceptionally high in Japanese males. Approximately 30% of patients with RCC have metastasis at initial diagnosis, and another 30% have metastasis after nephrectomy. Clinical studies of risk factors in patients with metastatic RCC (mRCC) are mainly based on data from non-Asian patients.nnnOBJECTIVESnWe aimed to investigate the prognosis of Japanese patients and their prognostic factors.nnnDESIGN, SETTING, AND PARTICIPANTSnThe subjects of this study were 1463 patients who were clinically diagnosed with RCC with metastasis in 40 Japanese hospitals between January 1988 and November 2002.nnnMEASUREMENTSnThe primary end point was overall survival calculated from first diagnosis of mRCC to death or last follow-up. We also investigated the relationship between survival and clinical features.nnnRESULTS AND LIMITATIONSnThe median overall survival time was 21.4 mo. The estimated survival rates at 1, 3, 5, and 10 yr were 64.2%, 35.2%, 22.5%, and 9.1%, respectively; they contrasted with data from the United States of 54%, 19%, 10%, and 6%, respectively for the same periods. A high percentage of patients had undergone nephrectomy (80.5%) and metastasectomy (20.8%), both of which were shown to prolong survival.nnnCONCLUSIONSnThe median survival time in the present study was approximately twice as long as that of previous studies from North America or Europe. Early diagnosis of metastasis, nephrectomy, metastasectomy, and cytokine-based therapy seemed to improve the prognosis of RCC patients in the present study.

Alternative Nonsteroidal Antiandrogen Therapy for Advanced Prostate Cancer That Relapsed After Initial Maximum Androgen Blockade

PURPOSEnLarge 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.nnnMATERIALS AND METHODSnThe 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.nnnRESULTSnThe 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.nnnCONCLUSIONSnFollowing 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.

Inhibitory Effect of Tomato Juice on Rat Urinary Bladder Carcinogenesis after N-Butyl-N-(4-hydroxybutyl)nitrosamine Initiation

The effects of tomato juice on urinary bladder carcinogenesis were studied in male Fischer 344 rats initiated with N‐butyl‐N‐(4‐hydroxybutyl)nitrosamine (BBN) in rats. The animals (6 weeks old) were given 0.05% BBN in their drinking water for 8 weeks, followed by diluted tomato juice for 12 weeks, and killed at 20 weeks after the beginning of the experiment. Lycopene concentrations in the livers of rats given tomato juice were elevated. Histopathological analysis of urinary bladder lesions revealed the numbers, but not incidences, of urinary bladder transitional cell carcinomas (TCCs) to be decreased in the group given tomato juice. No influence on the incidence of simple and nodullopapillary hyperplasias, invasion or differentiation of TCC was noted. These results indicate that tomato juice, presumably the contained lycopene and other anti‐oxidants in combination, exerts an inhibitory effect on the development of TCCs in the rat urinary bladder.

Bladder Cancer Working Group Report

EPIDEMIOLOGY OF BLADDER CANCER: Bladder cancer is the 7th most common cancer in men and the 17th most common in women in the world. The incidence of bladder cancer varies considerably among countries, with the highest incidence rates seen in Western countries and the lowest rates in Asian countries. In recent years, the mortality rate due to bladder cancer has been stable or decreased gradually. LIFESTYLE AND UROTHELIAL CARCINOMA: Occupational risks, environmental risks, dietary habits and cigarette smoking are lifestyle factors known to influence the development of urothelial carcinoma. Although the relative risk of bladder cancer associated with occupations is small, the public health impact may be significant. The Western pattern of diet is associated with a significant increase in the risk of bladder cancer. It has been found that smoking accounts for more than 50% of bladder cancers in men and 30% in women. Urological patients awareness of smoking as a risk factor for bladder cancer is lower than their awareness regarding other smoking-related disease entities. Counseling patients regarding the risk of tobacco is a role for urologists. GENETIC SUSCEPTIBILITY TO UROTHELIAL CARCINOMA: Recent single-nucleotide polymorphism genetic studies in relation to bladder carcinogenesis have revealed several associated genetic polymorphisms of detoxification or DNA repair genes, such as NAT2, GST and OGG1. That information is important in relation to environmental risk factors and ethnic differences and will help predict the prognosis of patients with bladder cancer. Further studies are needed to confirm potential gene-gene and gene-environmental interactions leading to bladder carcinogenesis.

Maintenance therapy with bacillus Calmette-Guérin Connaught strain clearly prolongs recurrence-free survival following transurethral resection of bladder tumour for non-muscle-invasive bladder cancer.

Study Type – Therapy (RCT)

Late recurrence of renal cell carcinoma: retrospective and collaborative study of the Japanese Society of Renal Cancer.

OBJECTIVESnTo evaluate in collaboration the clinical features of late recurrence of renal cell carcinoma (RCC). Late recurrence is one of the specific biologic behaviors of RCC; however, the clinical and pathologic features of the late recurrence of RCC are not fully understood.nnnMETHODSnA total of 470 patients who had undergone curative treatment of RCC and had not developed recurrence within 10 years of follow-up were documented from 13 institutions of the board members of the Japanese Society of Renal Cancer. Multivariate analysis with Cox proportional hazards model was used to determine the pathologic and clinical factors affecting the late recurrence and survival of patients with RCC ≥10 years after surgery. Survival analysis was performed using the Kaplan-Meier method.nnnRESULTSnDuring the 10-28-year (median 13.2) observation period, 30 patients (6.4%) developed a late recurrence. The disease-free survival rate at 15 and 20 years was 89.5% and 78.4%, respectively. Multivariate analysis showed that lymph node metastasis was the only factor to predict for late recurrence (P = .0334). Age at nephrectomy was the only prognostic factor for overall survival on multivariate analysis (P < .0001). Of the 470 patients, 30 had developed late recurrence in 44 sites, including the lung (36.4%), kidney (25%), and bone (13.6%), followed by the brain, pancreas, adrenal gland, lymph nodes, and liver. Late recurrences in the lung or kidney were observed at any time ≥10 years after nephrectomy.nnnCONCLUSIONSnLate recurrence of RCC after initial treatment is not a rare event, and lifelong follow-up is necessary.

Positive response to ice water test associated with high-grade bladder outlet obstruction in patients with benign prostatic hyperplasia

OBJECTIVESnTo elucidate the clinical significance of detrusor overactivity (DO) that is probably due to C-fiber activation caused by bladder outlet obstruction (BOO), we examined the responses to the ice water test (IWT) in patients with benign prostatic hyperplasia (BPH) and assessed the results with reference to the clinical manifestations and urodynamic findings.nnnMETHODSnA total of 127 patients without neurologic disease, who were older than 50 years of age, with an International Prostate Symptom Score of 8 points or greater and a quality of life index of 2 or more points, were enrolled in this study. We tested the response to ice water instillation by monitoring the intravesical pressure in all cases and assessed the results with reference to the findings of International Prostate Symptom Score and quality of life index questionnaires, BOO indexes, 48-hour frequency volume charts, prostate volume, and data from free-flowmetry and pressure flow studies for detecting DO. Twenty patients with neurogenic bladder dysfunction underwent IWT as a control group.nnnRESULTSnThe responders to the IWT accounted for 14 (70%) of the 20 patients with neurogenic bladder dysfunction and 35 (27%) of the 127 patients without neurologic disease. All of these responders showed DO on the pressure flow studies. The patients without neurologic disease who responded to the IWT had higher BOO indexes than did the nonresponders and had a smaller volume at a maximal desire to void on the urodynamic studies. The largest single-voided volume recorded from the 48-hour frequency volume charts was also smaller for the responders than for the nonresponders.nnnCONCLUSIONSnThe patients with BPH clearly showed that DO was mainly due to active C-fibers stimulated by high-grade BOO and that DO was a cause of urgency and frequency-related symptoms with decreased bladder capacity. It will be necessary to assess the inhibitory effect of capsaicin on DO caused by activation of C-fibers and the reversibility of C-fiber activation after surgical treatment for BPH, so that the criteria for decision-making for the treatment of BPH may be clarified with the aid of the IWT.

Reversibility of adenine-induced renal failure in rats

AbstractBackground. A renal failure model prepared from rats fed on an adenine diet provides valuable information about the pathomechanism of various complications associated with a persistent uremic state. To establish an animal experimental model in which the animals survive in a persistent uremic state, it is essential to settle a point of no return, i.e., an irreversible point. We investigated an irreversible point using the rat renal failure model induced by adenine treatment.nMethods. Rats were fed on a diet containing 0.75% adenine for 2, 4, or 6 weeks, and they were then fed an adenine-free diet for an additional 4 weeks to evaluate the degree of recovery from renal dysfunction.nResults. The rats fed on the adenine diet for 2 weeks showed a decrease in mean serum creatinine(s-Cr) from 1.8 mg/dl before to 0.7 mg/dl after the observation period, with mild anemia. The rats fed on the adenine diet for 4 weeks showed persistent renal dysfunction. Although the mean s-Cr decreased from 2.7 to 2.0 mg/dl, it continued to be higher than the normal range, and the anemia worsened. In the rats fed on the adenine diet for 6 weeks, the mean s-Cr increased from 3.4 to 3.6 mg/dl. Hypoproteinemia was also observed and some animals died.nConclusion. Based on the above results, it was concluded that to prepare a model of chronic renal failure in rats compatible to chronic renal failure seen clinically, the administration of a 0.75% adenine diet for 4 weeks is most appropriate.

Clinical guideline for male lower urinary tract symptoms

Abstract:u2003 This article is a shortened version of the clinical guideline for lower urinary tract symptoms (LUTS), which has been developed in Japan for symptomatic men aged 50u2003years and over irrespective of presumed diagnoses. The guideline was formed on the PubMed database between 1995 and 2007 and other relevant sources. The causes of male LUTS are diverse and attributable to diseases/dysfunctions of the lower urinary tract, prostate, nervous system, and other organ systems, with benign prostatic hyperplasia, bladder dysfunction, polyuria, and their combination being most common. The mandatory assessment should comprise medical history, physical examination, urinalysis, and measurement of serum prostate‐specific antigen. Symptom and quality of life questionnaires, bladder diary, residual urine measurement, urine cytology, urine culture, measurement of serum creatinine, and urinary tract ultrasonography would be optional tests. The Core Lower Urinary Tract Symptom Score Questionnaire may be useful in quickly capturing important symptoms. Severe symptoms, pain symptoms, and other clinical problems would indicate urological referral. One should be careful not to overlook underlying diseases such as infection or malignancy. The treatment should be initiated with conservative therapy and/or medicine such as α1‐blockers. Treatment with anticholinergic agents should be reserved only for urologists, considering the risk of urinary retention. The present guideline should help urologists and especially non‐urologists treat men with LUTS.

Aggressive angiomyxoma in the scrotum expressing androgen and progesterone receptors

Abstractu2002 Aggressive angiomyxoma is a rare benign mesenchymal myxoid tumor that arises from the pelvic soft tissues and perineum in relatively young females. This tumor has the ability to infiltrate locally and has a high risk of local recurrence after extirpation, but no potential to metastasize. We report here a rare case of aggressive angiomyxoma that developed in the scrotum of a 47‐year‐old male. Immunostaining of the resected specimen revealed that the tumor cell nuclei stained strongly and diffusely for androgen receptors (80% of the tumor cells), and moderately and partly for progesterone receptors (20% of the tumor cells). However, staining was negative for estrogen receptors. It is highly suggested that the growth of aggressive angiomyxoma in males may depend on androgen manipulation, contrary to its frequent and close association with estrogen receptor expression, which has been reported in females.