Drug interactions between tacrolimus and phenytoin in Japanese heart transplant recipients: 2 case reports.

OBJECTIVE: The purpose of the study was to demonstrate how the interaction between phenytoin and tacrolimus (FK 506) can be managed clinically and to characterize the change in FK 506 levels after discontinuation of phenytoin in two Japanese heart transplant recipients with different dosing periods ofphenytoin. METHODS: A drug interaction between phenytoin and FK 506 was investigated in 2 patients. The concentration-dose ratios (CDR: trough blood FK 506 level (ng/ml)/FK 506 dose (mg/day) on the previous day) were calculated as an index of the induction of the CYP3A4 enzyme during and after phenytoin therapy. RESULTS: About 2- to 3-fold dosages of FK 506 were required to maintain the required blood level when phenytoin was used concomitantly in the two cases examined. The FK 506 dose was constant within 21 days after discontinuing phenytoin in Patient 1 who had 36 days of phenytoin therapy. In Patient 2 with 21-day phenytoin therapy, the FK 506 doses and CDR varied for 10 days after discontinuing phenytoin, and expected FK 506 C0 levels were achieved within 11 days. CONCLUSIONS: The persistence of CYP induction after discontinuing phenytoin is dependent on the history of administration and, perhaps, on the dosing period in particular.

Correlation of c-myc expression with nuclear pleomorphism in human renal cell carcinoma.

The expression of the c-myc gene product in renal cell carcinomas was examined by immunostaining with monoclonal antibody (mAb) MYC-1. The effects of preservation and fixation of tissues on staining were first examined. In cryostat sections fixed with 4% buffered formalin for 15 min, staining was observed in the nucleus. On the other hand, in paraffin sections after fixation with 10% formalin, staining was observed in the cytoplasm, but not in the nucleus. Because c-myc protein has been shown to be a nuclear protein, the finding that c-myc protein was not detectable in the nucleus appeared to be due to the preservation or fixation procedures used. Therefore, cryostat sections fixed with 4% formalin were used to investigate the correlation between the reaction of MYC-1 mAb and nuclear pleomorphism in primary and metastatic renal cell carcinomas. Among 41 primary tumors, positive staining was observed in 2 of 17 tumors (12%) of grade 1, 17 of 21 (81%) of grade 2, and all 3 (100%) of grade 3. Among 17 metastatic tumors, positive staining was not observed in any of the 5 (0%) of grade 1 but was observed in 2 of 4 (50%) of grade 2 and all 8 (100%) of grade 3. Thus, the frequency of the positive reaction with MYC-1 mAb was correlated with nuclear pleomorphism in primary and metastatic renal cell carcinomas. The reaction of Ki-67 mAb, which recognized a nuclear antigen present in proliferating cells, was also correlated with nuclear pleomorphism. These findings suggest that the c-myc gene product plays a role in cell proliferation in renal cell carcinomas.

Characterization of an established cell line from human renal carcinoma.

A cell line, designated as OUR-10, has been established from a renal carcinoma in a Japanese woman. This cell line forms monolayers of polygonal epithelial cells with scattered round or dendritic cells and exhibits multilayering. With electron microscopy, differentiated surface structures that resemble the microvilli characteristic of renal carcinomas can be seen even at the 60th transfer. The cells have a hypodiploid karyotype with modal numbers of 39 and 40. No marker chromosomes were seen, but definite nonrandom loss of three chromosomes in Group D and one in Group E were recognized. The doubling time was estimated as approximately 32 hr in exponentially growing cultures, and the cells formed colonies in soft agar with an average efficiency of 25%. Heterotransplantation into the cheek pouch of immunosuppressed hamsters produced tumors that were histologically similar to the original cancerous tissue. The electrophoretic mobility of gamma-glutamyl transpeptidase extracted from the cells coincided with that of a novel isozyme found in human renal carcinoma tissue, and the genetic phenotype of the glucose-6-phosphate dehydrogenase was proved to be the B phenotype. The antigenic structure of HLA was determined as HLA-A2, 11; B5, 40, which was the same as that of peripheral blood lymphocytes of the woman with renal carcinoma.

Alteration of hexosaminidase isozymes in human renal carcinoma.

The activity and isozyme patterns of hexosaminidase in human renal carcinoma were studied in comparison with those of normal kidney. Hexosaminidase in extracts from normal kidney and renal carcinoma tissue could be separated into two major forms [hexosaminidase A (Hex A) and hexosaminidase B (Hex B)] by Cellogel electrophoresis or by diethylaminoethyl cellulose column chromatography. All of 10 renal carcinoma tissues showed a low activity ratio of Hex A to Hex B, as compared with the ratio in normal kidney; the ratio in renal carcinoma tissue was between 0.61 and 2.21 (mean, 1.30), while that in normal kidney was between 2.50 and 4.52 (mean, 3.46). Hexosaminidase activity and the ratio of Hex A to Hex B in renal carcinoma tissue were independent of the cell type and the differentiation grade of carcinoma tissue. Hex A and Hex B of renal carcinoma tissue differed from each other in physicochemical properties such as pH dependence of enzyme activity, thermostability, and Km's for two synthetic substrates, but each isozyme maintained its same physicochemical properties whether from normal or from carcinoma tissue. The isozyme patterns of cultured renal carcinoma cells and placenta were similar to those of the carcinoma tissue. The results presented here indicate that hexosaminidase isozymes in renal carcinoma tissue express at least oncoplacental patterns.

A dose-escalation and pharmacokinetic study of subcutaneously administered recombinant human interleukin 12 and its biological effects in Japanese patients with advanced malignancies.

A pilot dose-escalation study of recombinant human interleukin 12 (rhIL-12) was conducted in Japanese patients with advanced malignancies. Cohorts of three patients received escalating doses of rhIL-12 that increased from 50 to 300 ng/kg/day s.c. three times a week for 2 weeks followed by 1-week rest. The same dosage and schedule was repeated for two additional courses. Sixteen previously treated patients were registered, and 15 were evaluated. Common toxicities were fever and leukopenia; the abnormality of laboratory tests included elevations in aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, C-reactive protein, and beta2-microglobin. Dose-limiting toxicity was the grade 3 elevation of aminotransferases, and was observed in two of six patients at the 300-ng/kg dose level after the first course in one patient and after the third course in the other. Leukopenia was observed at all of the dose levels; two of six patients at 300 ng/kg experienced grade 3 leukopenia. Thus, 300 ng/kg was determined to be the maximum acceptable dose. Peak plasma levels of rhIL-12 decreased in the second courses, but the areas under the curve were almost the same in the first and second courses. Biological effects included increases of plasma levels of IFN-gamma, tumor necrosis factor-alpha, IL-6, IL-10, and neopterin. In two patients with renal cell carcinoma, complete response and partial response of metastatic tumors were observed with 50 and 300 ng/kg; the responses lasted for 5 and 3.5 months, respectively. Although immunological response to rhIL-12 varies depending on administration route and schedule and on patients' physiological conditions, the recommended dose for Phase II studies is 300 ng/kg s.c. three times a week for 2 weeks followed by 1-week rest.

Combination salvage chemotherapy using cisplatin and teniposide for patients with refractory germinal testicular tumors.

Ten patients with refractory germ-cell tumors were treated with a chemotherapy regimen consisting of teniposide and cisplatin (VM-26 and CDDP; P-VM therapy). Three patients (30%) achieved a complete remission (CR) after chemotherapy alone, and another three subjects (30%) attained a CR following chemotherapy and radiation therapy. Three of the six complete responders relapsed but were rendered disease-free by re-salvage therapy. Among the responders, six patients (60%) are alive and remain disease-free after follow-up periods ranging from 18 to 84 months (median, 48 months). However, the toxicity of P-VM therapy was high, with severe myelosuppression being observed in nine patients; nevertheless, all side effects were reversible. We concluded that the P-VM regimen seems to be effective in the treatment of refractory testicular cancers.

Combination chemotherapy including adriamycin for advanced transitional cell carcinoma of the urinary tract.

Thirty-three patients with advanced transitional cell carcinoma of the urinary tract (23 bladder cases, 8 ureter cases, and 2 renal pelvis cases) were treated by three-drug combination chemotherapy using two protocols (protocol I: Adriamycin 50 mg/m2, cyclophosphamide 500 mg/m2, and 5-fluorouracil 500 mg/m2, protocol II: Adriamycin 50 mg/m2, cyclophosphamide 500 mg/m2, and cis-platinum 50 mg/m2). Protocol I induced responses in three of 19 patients (16%), (1 complete response, 2 partial responses), and protocol II (I complete response, 4 partial responses) in five of 14 patients (36%). The overall response rate was 24%. The duration of response was relatively short (median duration 5.1 months). The combination therapy was relatively well tolerated except in three patients, including two mortalities. In our study, three-drug combination chemotherapy with Adriamycin, especially that including cis-platinum, was effective against transitional cell carcinoma of the urinary tract, but the results were not completely satisfactory.

Postoperative systemic adjuvant chemotherapy for bladder cancer.

Forty-six patients with bladder cancer without distant metastasis (M0) were treated by chemotherapy as an adjuvant after total cystectomy using three protocols (protocol I: adriamycin 50 mg/m2, cyclophosphamide 500 mg/m2, and cis-platinum 50 mg/m2 i.v., starting at least 2 weeks after surgery every 3 weeks for three cycles; protocol II: adriamycin 30 mg/m2 on the 1st postoperative day, cyclophosphamide 300 mg/m2 on the 1st and the 7th days; protocol III: FT-207 60 mg/m2, p.o. every day for 1 year). Average follow-up periods after surgery by protocol were 18 months for protocol I, 31 for protocol II, and 43 for protocol III. Analysis of the survival curves showed no statistically significant differences among the three groups or between a historical control group of 106 patients and the entire patient population examined in the present study. The histopathological grades recorded in the 46 patients were G1, G2, and G3 in 1, 22, and 23, respectively. However, from a study of 48 pT3 and pT4 cases, the survival rate of 10 patients receiving protocol I therapy was statistically significantly higher than those of 12 patients treated according to protocol II and of 26 historical controls, at 1 year and 2 years, respectively. Toxic effects, with gastrointestinal symptoms including nausea and vomiting and myelosuppression (including leukopenia and anemia) were more frequent with protocol I. Alopecia occurred in about 80%-90% of patients treated according to either protocol I or II. Almost all patients could tolerate adjuvant chemotherapy, and none of them died as a result of these regimens. The results recorded in this study justify the evaluation of combination adjuvant chemotherapy with adriamycin, cyclophosphamide and cis-platinum in a prospectively randomized trial.

Phase II study of cis-diammine(glycolato)platinum, 254-S, in patients with advanced germ-cell testicular cancer, prostatic cancer, and transitional-cell carcinoma of the urinary tract. 254-S Urological Cancer Study Group.

A multicenter cooperative study was conducted to evaluate the clinical efficacy and safety of cis-diammine(glycolato)platinum (254-S), a second-generation anticancer platinum complex, in the treatment of genitourinary cancers. 254-S was given i.v. at 100 mg/m2 at 4-week intervals. As a result, 2 complete responses (CRs) and 8 partial responses (PRs) were obtained in 35 patients with transitional-cell carcinoma (TCC) of the urinary bladder or pyeloureter, 3 PRs were obtained in 16 subjects with prostatic cancer, and 6 CRs and 6 PRs were obtained in 15 patients with testicular cancer, generating objective response rates of 28.6% [95% confidence interval (CI), 14.6%-46.3%], 18.8% (95% CI, 4.0%-45.6%), and 80.0% (95% CI, 51.9%-95.7%), respectively. Bone marrow suppression was the dose-limiting toxicity, although it was reversible. Although no hydration was performed in approx. 40% of the patients, the incidence of nephrotoxic effects was low and most of those encountered were mild, the exception being one patient who showed severe renal insufficiency after the first treatment. Nausea and vomiting occurred in approx. 70% of the patients, but most gastrointestinal toxicities were controlled without antiemetic treatment. In addition, liver-function impairment was rarely observed. We conclude that 254-S is a promising cisplatin analogue for the treatment of genitourinary cancers and is worthy of further investigation in large-scale, randomized comparative studies with other platinum derivatives in both single-agent and combination regimens.

Effect of recombinant granulocyte colony-stimulating factor (rG-CSF) on chemotherapy-induced neutropenia in patients with urogenital cancer.

The effects of recombinant granulocyte colony-stimulating factor (rG-CSF) on the myelosuppression, especially neutropenia, induced by cancer chemotherapy in patients with urogenital cancer were investigated in a randomized, controlled clinical study. In this study, rG-CSF was given subcutaneously at a dose of 2 micrograms/kg per day for 14 consecutive days. Changes in neutrophil counts were compared between the first (no rG-CSF) and second cycles (rG-CSF treatment period) of chemotherapy. rG-CSF administration was found to be effective in reducing the duration of neutropenia, in elevating the neutrophil nadir, and in reducing recovery time. Based on comparisons between the randomized rG-CSF treatment group (with rG-CSF) and the control group, treatment with rG-CSF resulted in the moderation or prevention of neutropenia and the acceleration of recovery. These results demonstrate that in chemotherapy of patients with urogenital cancer, in which neutropenia is a dose- or schedule-limiting factor, the concomitant use of rG-CSF may enable an increase in the dose (higher single dose or increased dose per unit of time) or shorten the chemotherapy period.

Adjuvant and neoadjuvant chemotherapy for invasive bladder cancer.

A total of 20 patients with primary invasive bladder cancer who underwent radical cystectomy received postoperative adjuvant chemotherapy using a CAP (cyclophosphamide, doxorubicin, and cisplatin) or modified M-VAC (methotrexate, vinblastine, pirarubicin, and cisplatin) regimen. In all, 16 of the patients were treated with CAP and 4 received the modified M-VAC regimen. Of the 20 patients, 17 had transitional-cell carcinoma with or without non-transitional-cell elements. All of the patients had tumors with a histological grade of G2 (6 cases) or G3 (14 cases). As for lymph-node metastasis, there were ten N0 cases, three N1 cases, six N2 cases, and one N3 case. Adjuvant chemotherapy was usually commenced 2 weeks after the surgery and was given every 3-4 weeks for two or three cycles. The 5-year survival rate of these 20 patients was 65.9%, whereas that of 49 patients who did not receive any adjuvant chemotherapy was 30.2%. Regarding toxicity, both of the adjuvant chemotherapy regimens used in this study were generally well tolerated. The most common toxic effects were gastrointestinal symptoms, alopecia, and myelosuppression. Another 19 patients with invasive transitional-cell carcinoma of the bladder received 2 or 3 cycles of neoadjuvant chemotherapy using the modified M-VAC or MEC (methotrexate, epirubicin, and cisplatin) regimen. Of 18 pathologically evaluable patients who underwent radical cystectomy or partial cystectomy, the stage was pT0 in 3 cases (17%), pTis in 3 (17%), pT1 in 3 (17%), and pT2 or higher in 9 (50%). The 4-year survival rate of 18 patients who received neoadjuvant chemotherapy was 71.5%. Regarding toxicity, one patient died of a bowel complication after surgery, and the complication was suggested to be drug-induced.

Long-term results of intravesical chemoprophylaxis of superficial bladder cancer: experience of the Japanese Urological Cancer Research Group for Adriamycin.

Long-term results were analyzed in terms of tumor progression and survival in patients with superficial bladder cancer who were enrolled in the second intravesical chemoprophylactic study of the Japanese Urological Cancer Research Group for Adriamycin, which was started in July 1982. This study was a prospective, randomized, controlled trial conducted on primary tumors treated with a long-term instillation regimen that involved control versus intravesical instillations of Adriamycin or mitomycin C given once a week for the first 2 weeks, once every other week for 14 weeks, once a month for 8 months, and once every 3 months for 1 year, for a total of 21 instillations in 2 years. An analysis of the prophylactic effects of such treatment on bladder tumors after TUR has previously been performed, and the results have been published elsewhere. The present study represents a follow-up of the above trial. Of the 671 cases previously analyzed with regard to tumor prophylaxis, 158 cases (23.5%) were eligible to be followed for tumor progression and survival. A detailed comparison of the background factors between these 158 patients and the other 513 cases revealed no statistically significant difference. Thus, the 158 evaluable cases might reasonably be considered to represent all patients enrolled in the second study, and the results were thought to be reasonable enough to reflect the long-term efficacy of the long-term instillation regimen adopted in this study. The median follow-up for these 158 cases was 6.6 years. Tumor progression in terms of the disease stage and/or grade occurred in 43 of 127 patients who received prophylactic instillations and in 12 of 31 control cases. No significant difference in the incidence of tumor progression was found between the treatment and the control groups. In addition, no difference in survival was observed between the treatment group and the control group. Survival was also compared between patients who showed tumor progression and those who did not. All patients whose tumors did not progress survived, whereas the 7-year survival of those exhibiting tumor progression was less than 90%.

The 4th study of prophylactic intravesical chemotherapy with adriamycin in the treatment of superficial bladder cancer: the experience of the Japanese Urological Cancer Research Group for Adriamycin.

A multicentric randomised trial was conducted for the purpose of investigating the efficacy of intravesical chemoprophylaxis of superficial bladder cancers. A total of 443 patients (number of evaluable patients, 284) were registered from July 1987 to December 1989 and randomised into 3 groups. Group A received 21 intravesical instillations of Adriamycin (ADM) at 20 mg/40 ml physiological saline for 2 years after undergoing transurethral resection (TUR); group B was given the same dose as group A but received 6 intravesical instillations for 2 weeks before undergoing TUR; and group C served as a control and underwent TUR only. Better prophylactic effects were obtained in group A. The overall non-recurrence rates calculated for groups A and B differed significantly (P less than 0.05) on day 240, and those determined for groups A and C were also significantly different (P less than 0.01) on day 480. No benefit was obtained using intravesical instillation prior to TUR (group B). The major side effects encountered were pollakisuria and miction pain, which occurred in 32% of the patients in group A and in 52% of those in group B.

Evaluation of systemic chemotherapy with methotrexate, vinblastine, adriamycin, and cisplatin for advanced bladder cancer. The Japanese Urological Cancer Research Group for Adriamycin.

In a cooperative study of the Japanese Urological Cancer Research Group for Adriamycin, the usefulness of chemotherapy with methotrexate, vinblastine, Adriamycin, and cisplatin (M-VAC therapy) in treating advanced or recurrent bladder cancer was examined. Evaluation of the clinical responses obtained in 86 evaluable patients revealed 13 complete responses, 29 partial responses, 4 minor responses, 19 cases of no change, and 21 cases of progressive disease. The overall response rate was 48.8% (42/86). The rate of response to M-VAC therapy at each disease site was as low as 21.4% (3/14) in bone lesions but exceeded 40% in the primary lesion, the lymph nodes, the lung, the liver, and other lesions. The clinical response to M-VAC therapy was not significantly influenced by the performance status of the patients, the dose intensity, or previous therapy. The median duration of response for the 42 responders was 22.7 weeks (range, 8.1-134.1 weeks), and the median duration of survival for the 86 evaluable patients was 9.8 months. Side effects were frequently encountered; the patients experienced anorexia, nausea, vomiting, malaise, alopecia, and leukopenia, but all of these symptoms were tolerable.

Prophylactic chemotherapy with intravesical instillation of adriamycin and oral administration of 5-fluorouracil after surgery for superficial bladder cancer. The Japanese Urological Cancer Research Group for Adriamycin.

The Japanese Urological Cancer Research Group for Adriamycin has conducted a series of clinical trials to investigate the efficacy and safety of prophylactic intravesical chemotherapy for superficial bladder cancer. In the third trial, reported herein, patients with recurrent bladder cancer or multiple primary cancer were selected and randomized to one of four groups using the envelope method after complete resection of the original tumors. Group A was given Adriamycin alone, group B received oral 5-fluorouracil (5-FU), group C was given Adriamycin and oral 5-FU, and group D served as the control group. Of the 544 patients registered, 331 were evaluable for the purpose of this study. The administration of 5-FU (group B) failed to prevent the recurrence of bladder tumors. Although group C (both Adriamycin and 5-FU) did not fare better than group A (Adriamycin only), Adriamycin was effective in preventing the recurrence of tumors, especially in high-risk patients with recurrent and multiple tumors. The risk of recurrence was reduced to 0.21 (95% confidence interval, 0.10-0.44) relative to the control group. There was no indication of a synergistic effect between 5-FU and Adriamycin. As side effects, cystitis syndrome was observed in 23%-30% of the patients in the Adriamycin groups and mild myelosuppression was observed in the 5-FU groups.

Phase II trial of carboplatin in patients with advanced germ-cell testicular tumors and transitional cell carcinomas of the urinary tract.

Carboplatin, an analog of cisplatin, was evaluated in a phase II study involving 25 patients with advanced testicular tumor and 45 with transitional cell carcinoma (TCC) of the urinary tract; 21 and 38 cases, respectively, were evaluable for response. Prior treatment with cisplatin-based chemotherapy had occurred in 7 of the testicular cancer patients and in 11 with TCC. The response rate (complete + partial response) in testicular tumors was 47.6%. The best response rate was observed in seminomas (70.0%), whereas the response rate in nonseminomas was 27.3%. The seminoma patients had mainly stage IIIA or less than IIIA disease, with metastatic lesions restricted to the lymph nodes. Three responses were seen in patients previously treated with cisplatin. In TCC, the response rate was 18.4%. Good-risk patients were treated with a dose of 400 mg/m2 every 4 weeks, whereas poor-risk patients received a lower dose of 300 mg/m2. The response rates for good-risk patients were 50.0% in testicular lesions and 26.1% in TCC. For poor-risk patients, the response rates were 40.0% and 6.7%, respectively. Carboplatin was well tolerated, with no significant renal impairment or ototoxicity detected. Nausea and vomiting were experienced by 51.7% of patients, but the severity was low; half of these patients demonstrated WHO grade I toxicity. However, myelosuppression was severe. In conclusion, carboplatin demonstrated activity in both testicular tumors and TCC and is worthy of further study, especially in combination with other active drugs.

Phase III trial of the Japanese Urological Cancer Research Group for Adriamycin: cyclophosphamide, adriamycin and cisplatinum versus cyclophosphamide, adriamycin and 5-fluorouracil in patients with advanced transitional cell carcinoma of the urinary bladder.

A non-randomized clinical study on systemic combination chemotherapy was conducted by the Japanese Urological Cancer Research Group for Adriamycin to compare the effectiveness of CAP (cyclophosphamide 200-500 mg/m2, adriamycin 30-50 mg/m2 and cisplatin 30-50 mg/m2) and CAF (cyclophosphamide 200-500 mg/m2, adriamycin 30-50 mg/m2 and 5-fluorouracil 250 mg/m2) in 123 patients (104 evaluable) with advanced and/or metastatic cancer of the urinary bladder. Among 96 patients who were non-randomly selected to receive CAP, 4 achieved complete remission, 12 achieved partial remission, 7 achieved minor response, 30 had stable disease, and 43 had disease progression. The response in the 8 patients who received CAF were: partial remission in 1 and progressive disease in 7. The overall response rate to CAP therapy was 17%, as against 13% for CAF therapy. The median duration of survival with CAP was 29 weeks and with CAF, 22 weeks. The differences between the two groups in duration of survival and response rate were not statistically significant. Complete and/or partial remissions were observed in the lymph nodes, lung and liver in 32%, 24%, and 57% of cases, respectively. There was no objective response in bone metastasis. The main side effects of CAP were anorexia (88%), nausea and/or vomiting (81%), alopecia (65%), leukopenia (72%), anemia (48%), and renal dysfunction (17%). No patients died as a result of toxicity of these combination chemotherapy modalities.

Comparative analysis of short-term and long-term prophylactic intravesical chemotherapy of superficial bladder cancer. Prospective, randomized, controlled studies of the Japanese Urological Cancer Research Group.

The Japanese Urological Cancer Research Group has conducted three randomized clinical studies on intravesical chemoprophylaxis of superficial bladder cancers. This paper presents a comparative analysis of the first and second of these. The protocol used in the first study was a so-called short-term schedule in which drugs (for group A, ADM 30 mg/30 ml; group B, ADM 20 mg/40 ml; group C, MMC 20 mg/40 ml; and group D, control) were administered twice a week for 4 weeks after transurethral resection (TUR), and in the second study a long-term schedule was used, in which drugs (for group E, ADM 30 mg/30 ml; group F, ADM 20 mg/40 ml; group G, MMC 20 mg/40 ml; and group H, control) were administered twice a week for 1 week, every 2 weeks for 7 weeks, monthly for 8 months, and finally once every 3 months for 1 year. In the first study 575 patients were evaluated and followed up for 5 years. The second study started 28 months later, and 607 patients were evaluated. A generally good prophylactic effect was obtained in the second study when the patients' backgrounds were adjusted in combination with the history and number of the tumors. The second study did not reveal any promoting or inhibitory effect on the progression of the recurrent tumors. There were no significant side effects in either study. The indications and the schedule for prophylactic intravesical chemotherapy should be more carefully studied.

A multivariate analysis of prognostic factors related to recurrence and progression of superficial bladder cancer.

Prognostic factors related to the recurrence and progression of superficial primary bladder cancers were analyzed by Cox's proportional hazards regression model. We followed 75 patients (stage Ta, 49 cases; T1, 26 cases; grade G1, 42 cases; G2, 29 cases; G3, 4 cases) after transurethral resection for 10 to 74 months (median 38 months). The antibodies reactive with the products of oncogenes [anti-c-myc oncoprotein (MYC-1); anti-c-erbB-2 oncoprotein], tumor suppressor gene [anti-p53 mutant protein (BP53-12)], growth factor receptor [anti-transferrin receptor (HBT-2)], proliferation [anti-proliferatioe nuclear antigen (Ki-67)], and malignant transformation (B1.4) were used for immunohistochemical staining. The reactivities of mAb B1.4, HBT2, and BP53-12 were significantly increased according to the grade, and those of mAb Ki-67, MYC-1, and c-erbB-2 were not. The reactivities of all antibodies were not significantly different between stages Ta and T1. As prognostic factors, stage, grade, tumor number, urinary cytology, and reactivities of the above six antibodies were used for the analysis. Urinary cytology, multifocality, and the reactivity of mAb Ki-67 showed a relative but significant high risk for recurrence, and the reactivities of mAb HBT2, mAb B1.4, and mAb Ki-67 showed a significant high risk for progression in the multivariate analysis. These results suggest that mAb B1.4 may be useful as a new prognostic factor for the progression of superficial bladder cancer.

A novel gamma-glutamyl transpeptidase in renal carcinoma in comparison with normal kidney enzyme.

A novel gamma-glutamyl transpeptidase was found in a renal carcinoma tissue. This enzyme electrophoresed more quickly than that of normal kidney, but more slowly than normal liver enzyme. Their Rf values are 0.46, 0.33, and 0.52 for the renal carcinoma, normal kidney and normal liver enzyme, respectively. After treatment of the renal carcinoma and normal kidney enzyme with neuraminidase, the renal carcinoma gamma-glutamyl transpeptidase still electrophoresed slightly faster than that of normal kidney. The catalytic properties of the renal carcinoma gamma-glutamyl transpeptidase were almost the same as those of normal kidney except for molecular weight; the molecular weight for the renal carcinoma was estimated to be about 130 000, while that of normal kidney was about 90 000. These results may mean that the enzyme of the renal carcinoma is different from that of normal kidney in chemical constituents other than sialic acid. Of 10 patients with renal carcinoma examined electrophoretically, 5 posessed this novel enzyme in their renal carcinoma tissues.