Kazuyuki Sagiyama

Postoperative UFT Adjuvant and the Risk Factors for Recurrence in Renal Cell Carcinoma: A Long-Term Follow-Up Study

Background Radical nephrectomy is the standard therapy for low‐stage renal cell carcinoma. However, recurrence sometimes develops even in patients who are considered to have undergone a curative resection of the primary tumor. The purpose of this study was to evaluate the usefulness of UFT (a 1: 4 mixture of tegafur and uracil) adjuvant and the risk factors for recurrence in renal cell carcinoma.

Genotypic Evolution in a Quinolone-Resistant Neisseria gonorrhoeae Isolate from a Patient with Clinical Failure of Levofloxacin Treatment

Recently, a reduction in the antimicrobial susceptibility of clinical isolates of Neisseria gonorrhoeae to newer fluoroquinolones including levofloxacin in vitro has been recognized in Japan. We examined the quinolone resistance mechanisms in N. gonorrhoeae isolates from a patient with clinical failure of levofloxacin treatment. Man with gonococcal urethritis was treated with oral 100 mg levofloxacin 3 times daily for 7 days. However, clinical failure of the treatment was observed. The minimum inhibitory concentration of levofloxacin for the posttreatment isolate (4.0 μg/ml) was 4-fold higher than that for the pretreatment isolate (1.0 μg/ml). To analyze quinolone resistance mechanisms in the set of isolates, we performed DNA sequencing of the quinolone reisistance-determining regions within the gyrA and parC genes. Moreover, we assayed the intracellular levofloxacin and norfloxacin accumulation level in these isolates. The pretreatment isolate contained three substitutions compared to susceptible wild-type isolate, including serine to phenylalanine at position 91 and aspartic acid to asparagine at position 95 in the GyrA protein, and serine to proline at position 88 in the ParC protein. The posttreatment isolate had four substitutions, including the same three substitutions and an additional glutamic acid to glutamine substitution at position 91 in ParC. There was no significant difference in the level of accumulation of levofloxacin and norfloxacin between the pretreatment and posttreatment isolates. Our results indicate that levofloxacin selects a mutant having an additional alteration within the gene cording for the ParC protein during treatment, which may have enhanced quinolone resistance in the organism.

Treatment of advanced hormone-refractory prostate carcinoma with a combination of etoposide, pirarubicin and cisplatin

A total of 20 patients with hormone-refractory prostate carcinoma entered a pilot study of combination chemotherapy based on the EAP (etoposide, Adriamycin and cisplatin) regimen, in which Adriamycin was replaced by pirarubicin, a less cardiotoxic derivative of Adriamycin. The response was assessed by criteria modified from those of the National Prostatic Cancer Project: prostate-specific antigen was employed instead of acid phosphatase. Of 18 evaluable patients, 6 achieved a partial response, 5 had stable disease, and in 7 the disease had progressed during therapy; thus, the overall response rate was 33.3% [95% confidence interval (CI) 11.5–55.1%]. Significant pain alleviation and performance status improvement were obtained in 5 of 12 patients (41.7%; CI 13.8–69.6%) and 3 of 13 patients (23.1%; CI 0.2–46.0%), respectively. Although myelosuppression was moderate to severe, no chemotherapy-related deaths or bacteriologically documented sepsis occurred; nor was there any clinical cardiotoxicity. All the responding patients received maintenance chemotherapy with etoposide thereafter. At present, the median duration of response is 33 weeks (range: 23–91 weeks) and the median survival period for all patients is 42 weeks (range: 27+ −136 weeks), with 12 deaths. In spite of the small number of patients treated, these results suggest that this chemotherapy regimen is active in advanced hormone-refractory prostate carcinoma.

Early intravesical instillation of adriamycin with oral administration of 5-fluorouracil after transurethral resection for superficial bladder cancer: preliminary results.

SummaryIn all, 199 patients were entered in this study by 21 collaborating hospitals. Patients with superficial transitional cell carcinoma of the bladder were randomized postoperatively into four groups. Group A received early (immediately and 2 days after transurethral resection) instillation of adriamycin (30 mg/30 mg); group B received early instillation of adriamycin with oral administration of 5-fluorouracil (200 mg/day); group C received delayed (7 days after transurethral resection) instillation of adriamycin (30 mg/30 ml); and group D received delayed instillation of adriamycin with oral administration of 5-fluorouracil (200 mg/day). All patients subsequently received instillations weekly for 2 more weeks, and then every 2 weeks for a further 14 weeks. After 4 months, they received one instillation per month for 8 months. 5-Fluorouracil was administered p. o. for 1 year. The postoperative follow-up period was 12 months. After 3 and 6 months there were significant differences in the non-recurrence rates between groups B and C. After 12 months the overall nonrecurrence rates were 87.9% in group A, 83.5% in group B, 89.2% in group C, and 82,8% in group D, and there were no significant differences among the four groups. The number of patients entered and the follow-up period are not adequate for firm conclusions, and further studies are necessary. The main side effect was bladder irritation, which was observed in 38.8% of patients in the early instillation groups and in 26.3% of those in the delayed instillation groups. No severe systemic side effects were observed in this study.

“Two route infusion chemotherapy” usingcis-diamminedichloroplatinum (II) and its antidote, sodium thiosulfate, for metastatic liver tumors in rats

We studied the effects of combination chemotherapy of an antitumor drugcis-diamminedichloroplatinum (II) (DDP) and its potent antidote, sodium thiosulfate (STS) in rat liver tumor systems. This therapy was given to female WKA rats with metastatic liver tumors 13 days after inoculation of syngeneic hepatoma cells through the mesenteric vein. DDP and STS were administeredvia two different routes, hepatic artery and femoral vein, respectively (we call this treatment “two route infusion chemotherapy”). The antitumor effects were evaluated 21 days after the treatment by calculating the tumor weight from the total weight of the liver. Tumor weights of rats treated with 20 mg/kg of intra-arterial DDP plus 1,054 mg/kg of systemic STS (group A), 5 mg/kg of intra-arterial DDP alone (group B), and 5 mg/kg of systemic DDP alone (group C) were, about one fifth two fifths and three fifths of the tumor weights in the untreated controls, respectively. In group A, no rats died despite administration of a 4-fold higher DDP dose than in the latter two groups B and C in which 14–18 per cent of the rats died, due to DDP-induced toxicity. The patterns of body weight gain in the three groups after the chemotherapy were much the same. Our results clearly indicate that the antitumor effect of DDP on metastatic liver tumors in rats can remarkably be enhanced by the “two route infusion chemotherapy” of DDP and STS.

Intravesical Therapy with Adriamycin plus Verapamil in Patients with Superficial Bladder Cancer: A Pilot Study

Nineteen patients with histologically proven superficial bladder cancer (Ta, T1) were treated with intravesical instillation of 30 mg of adriamycin (ADM) dissolved in 24 ml physiological saline plus 15 mg of verapamil (VR) (6 ml) every day for 10 days. In spite of the short period of treatment, 6 of the 18 evaluable patients (33.3%) showed complete response (CR) and a further 5 (27.8%) showed partial response (PR). Five of the 6 patients with CR were recurrent cases who had previously received prophylactic intravesical instillation chemotherapy including ADM. Irritative urinary symptoms were observed in 11 of the 19 patients (57.9%). However, these symptoms were mild in the majority of patients and the treatment was completed without interruption in all but 1 patient. There was no significant absorption of ADM and VR into the systemic circulation. No clinical evidence of systemic toxicity was observed. These results suggest that combination of ADM and VR has a possibility to be a useful prophylactic intravesical instillation chemotherapy after endoscopic resection of not only primary but also recurrent chemoresistant bladder cancers.

Adjuvant chemotherapy with early intravesical instillation of Adriamycin and long-term oral administration of 5-fluorouracil in superficial bladder cancer

SummaryA randomized controlled trial was performed to study the efficiency of adjuvant chemotherapy with carly intravesical instillation of Adriamycin and long-term oral administration of 5-fluorouracil in 275 patients with superficial bladder cancer. All of the patients were randomized into four groups. Group A received early (immediately and 2 days after transurethral resection) instillation of Adriamycin alone; Group B received early instillation of Adriamycin with oral administration of 5-fluorouracil; Group C received delayed (7 days after transurethral resection) instillation of Adriamycin alone; and group D received delayed instillation of Adriamycin with oral administration of 5-fluorouracil. All patients subsequently received instillations weekly for 2 weeks and then every 2 weeks for a further 14 weeks. After 4 months, they received monthly instillations for 8 months. 5-Fluorouracil (groups B and D) was given daily p.o. for 1 year. Evaluation was possible in 187 patients. The postoperative follow-up period for determination of non-recurrence rates was 36 months, during which no significant difference was detected among the four groups. Moreover, no statistically significant difference was found between the early-and delayed-instillation groups. However, the non-recurrence rates obtained in the groups undergoing early instillation were higher than those determined in the delayed-instillation groups during the 36-month follow-up period, and this difference was especially significant at 4 and 5 months. In addition, the early-instillation groups showed significantly higher non-recurrence rates than did the delayed-instillation groups in terms of primary cases (P<0.01), tumor size of <1 cm (P<0.05), multiple tumors (P<0.01), pathological stage pTa (P<0.01), and histological grades G1 and G2 (P<0.05). Groups B and D, which were treated by intravesical instillation of Adriamycin with oral administration of 5-fluorouracil, showed no significant prophylaxis of recurrence during the 36-month follow-up as compared with groups A and C, which received intravesical instilations alone. The main side effect, which required discontinuation of the treatment, was bladder irriation. However, no significant difference in its incidence was found between the early-and delayed-instillation groups. No severe systemic side effect was encountered in this study. These results suggest that early as well as repeated intravesical instillation of Adriamycin is clinically tolerable and may be effective in preventing the recurrence of superficial bladder cancer.

Significance of the Preoperative Intravesical Instillation of Doxorubicin and the Oral Administration of 5‐Fluorouracil in Preventing Recurrence After a Transurethral Resection of Superficial Bladder Cancer

Background: The postoperative intravesical instillation of doxorubicin (ADM) has a preventative effect on recurrence after a transurethral resection (TUR) of superficial bladder cancer. However, the significance of preoperative ADM instillation remains unclear. Although the oral administration of 5‐fluorouracil (5‐FU) has been observed to show some clinical response against bladder cancer, its preventative effect on the recurrence of superficial bladder cancer after TUR is unknown. Methods: Patients were randomized into 4 groups. All 4 groups received postoperative ADM instillation. In addition, patients in groups C and D received preoperative ADM instillation, whereas patients in groups B and D additionally received oral 5‐FU postoperatively. The nonrecurrence rate and side effects were both compared among the 4 groups.

Evaluation of a commercial DNA probe assay for the detection of Neisseria gonorrhoeae

The diagnostic value of a prototype ribosomal RNA-directed DNA probe system for Neisseria gonorrhoeae was evaluated in 119 men with urethritis. All 15 patients with positive results on Thayer-Martin culture were also positive with the DNA probe, while all 63 patients who had negative results on Thayer-Martin culture were also negative with the DNA probe. Thus the rate of agreement between the two tests was 100%. Positive DNA probe results were obtained in all 14 patients who were positive on an enzyme immunoassay, while negative DNA probe results were obtained in all 27 patients who were negative on the enzyme immunoassay. The agreement rate between these two tests was also 100%. The results of this study indicate that the DNA probe assay is a reasonable, noncultural alternative for directly detecting N gonorrhoeae in urogenital samples.

Holmium laser enucleation for the large (220 ml) prostatic adenoma

A 63-year-old male with symptomatic benign prostatic enlargement (220 ml as estimated by transrectal ultrasonography) was underwent transurethral holmium laser enucleation. Total operative time was 211 minutes and actual weight of tissue enucleated was 156 grams. There was no perioperative hyponatremia and a blood transfusion. The duration of catheterization was 3 days and the hospital stay was 5 days. Three months after treatment, the international prostate symptom score (IPSS) decreased from 19 preoperatively to 1. The quality of life (QOL) index decreased from 6 preoperatively to 1, whilst the maximum flow rate (Qmax) increased from 7 ml/sec preoperatively to 58 ml/sec.