Equivalent efficacy of mitomycin C plus doxorubicin instillation to bacillus Calmette-Guerin therapy for carcinoma in situ of the bladder.

BACKGROUND: To elucidate the most efficient topical therapy for carcinoma in situ of the bladder, the efficacy of intravesical mitomycin C plus doxorubicin therapy was compared with bacillus Calmette-Guerin (BCG) therapy. The clinical behavior of the tumor was analysed according to the histological grade. METHODS: Forty-two patients with carcinoma in situ of the bladder were randomized to intravesical BCG (21 patients) or mitomycin C plus doxorubicin sequential therapy (21 patients) as first line treatment. The non-responders underwent the subsequent instillation of the other intravesical therapy alternately. Of the patients, 27 had grade 2 and 15 had grade 3 cancer. RESULTS: Both topical therapies were equally effective with initial response rates of 86% (18/21) for BCG and 81% (17/21) for mitomycin C plus doxorubicin, irrespective of the tumor grade. Of seven initial non-responders, five patients achieved a complete response by subsequent instillation, resulting in a total response rate of 95%. After a mean follow-up of 47 months, five patients (12%) developed disease progression. The progression rates were not different between the topical therapies, but were significantly higher in grade 3 than in grade 2 cases. CONCLUSION: It appears likely that mitomycin C plus doxorubicin instillation has an equivalent efficacy to BCG as the initial therapy of carcinoma in situ and the combination of them would be the most efficient treatment for the disease. Moreover, histological grading would be clinically useful in defining the tumor characteristics and behavior of carcinoma in situ of the bladder.

Successful treatment of metastatic adenocarcinoma of the urachus: report of 2 cases with more than 10-year survival.

Metastatic urachal cancer is often considered lethal. We report 2 cases of metastatic urachal carcinoma successfully treated with surgical excision followed by combinations of surgery, radiation, and chemotherapy against local recurrence and/or distant metastases, with a recurrence-free survival period of more than 10 years. These cases provide support for multimodal treatments of metastatic urachal cancer.

Combination chemotherapy with ifosfamide, 5-fluorouracil, etoposide and cisplatin for metastatic urothelial cancer.

PURPOSE: To investigate the activity of combination chemotherapy with ifosfamide, 5-fluorouracil, etoposide and cisplatin in patients with metastatic urothelial cancer. METHODS: A group of 29 patients were treated with 2000 mg/m2 ifosfamide, 750 mg/m2 5-fluorouracil, 100 mg/m2 etoposide and 20 mg/m2 cisplatin. All four drugs were given intravenously on days 1 through 3 and the treatment was repeated every 3 weeks. Of the 29 patients, 14 had lymph node metastasis alone, and 15 had visceral lesions. RESULTS: An objective response was achieved in 17 patients (59%). There was no difference in response rates according to metastatic site including osseous lesions, which responded well in four of six patients. The 3-year survival rate for all patients was 16% with four patients who had undergone salvage surgery being alive with no evidence of disease 15 to 61 months after initiation of the treatment. A good performance status, lymph node metastasis alone and administration of chemotherapy at the full dosage had a significantly favorable impact on patient survival. Bone marrow toxicity was significant and one patient died of treatment-related sepsis. CONCLUSIONS: Ifosfamide, 5-fluorouracil, etoposide and cisplatin combination chemotherapy appeared to be active in the treatment of metastatic urothelial cancer. Although bone marrow toxicity was significant, the treatment was well tolerated by the majority of the patients. Further study may be warranted.

[Low dose CVD chemotherapy as a tumor dormancy therapy for extra-adrenal malignant pheochromocytoma: a case report].

A 38 year-old man presented with upper abdominal mass and hypertension pointed out at a medical examination. Blood pressure was 170/90 under medication of an alpha-blocker. Abdominal CT scan showed an 8 x 8 cm inter-aortocaval mass displacing pancreas head ventrally, and further a 4 x 4 cm mass at the aortic bifurcation, but there was no tumorous lesion in bilateral adrenal glands. Plasma nor-epinephrine level and urinary VMA excretion were excessive but plasma adrenaline level was within normal limits. MIBG scintigram showed hot spots in the 4th and 9th thoracic vertebrae. The destructive change of the 9th vertebra on magnetic resonance imaging strongly suggested metastasis of the tumor. Histologic and immunohistochemical findings of the biopsy specimen taken from the lower abdominal tumor in addition to the above clinical data led to the diagnosis of extra-adrenal malignant pheochromocytoma with spinal metastases. Since 2 cycles of full dose CYVADIC chemotherapy had no effects on lowering the high blood pressure and reducing the tumor size, low dose (60% of the full dose) CVD (cyclophosphamide, vincristine and dacarbazine) was given as a palliative chemotherapy on an out-patient clinic approximately every 4 weeks. After 4 cycles of the chemotherapy, his backache due to spinal metastasis markedly improved, hypertension as well as the plasma dopamine level was normalized and nor-epinephrine level was markedly decreased, though the tumor size was not reduced. Thereafter, no medication for hypertension was necessary. During 3 years and 6 months until now, 36 cycles of the chemotherapy has been repeated with no significant side effects. He has been at full-time work with quality of life being well preserved. Low dose CVD regimen appears to be an effective tumor dormancy therapy for advanced extra-adrenal pheochromocytoma.

The serum level of the amino-terminal propeptide of type I procollagen is a sensitive marker for prostate cancer metastasis to bone.

OBJECTIVE: To assess the level of a bone-formation marker, the amino-terminal propeptide of type I procollagen (PINP), for its utility in indicating bone metastasis in patients with prostate cancer. PATIENTS AND METHODS: Several bone formation markers, i.e. PINP, the carboxy-terminal propeptide of type I procollagen (PICP), bone-specific alkaline phosphatase (BALP), and bone Gla protein (BGP), a bone resorption marker (pyridinoline cross-linked carboxy-terminal telopeptide, ICTP), and prostate specific antigen (PSA) were measured in 40 patients without and 25 patients with bone metastasis. No patient had undergone previous treatment, except for six who developed bone metastasis while undergoing hormone therapy. RESULTS: All markers except BGP were significantly higher in patients with bone metastasis than in those without. The levels of PINP correlated best with the extent of disease, although the levels of PSA, BALP and ICTP also correlated well. While PINP had the largest area under the receiver-operator characteristic curve, PSA, BALP and ICTP also produced useful curves. CONCLUSION: The bone formation marker PINP seems to be useful for discriminating patients with and without bone metastasis. PINP may help in the early and accurate diagnosis of bone metastasis in such patients.

Retroperitoneal cystic metastasis from a small clear cell renal carcinoma.

A 39-year-old housewife was referred to our hospital for the treatment of a small renal tumor. A 25 x 35 mm cystic mass that had been detected by computerized tomography scan just caudal to the renal hilus proved to be a metastasis from the renal carcinoma of clear cell type. The pathogenesis may have been due to tumor cells obstructing a lymphatic vessel draining the kidney. Cystic metastasis from renal cell carcinoma is very rare and this appears to be the second published case in the world.

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.

[Treatment and prognosis of testicular seminoma].

Although testicular germ cell tumor is a relatively uncommon disease, it is a relatively common type of malignant tumor among young men. Seminoma accounts for approximately 50% of all germ cell testicular tumors. Since the vast majority of patients with seminoma present with early-stage disease and the disease responds well to treatment, almost all of the patients are cured. Patients who have stage I disease without obvious metastatic lesions have two treatment options, surveillance or adjuvant retroperitoneal radiotherapy, following inguinal orchiectomy. Stage IIA disease with a relatively small retroperitoneal lymph node metastasis is generally treated by retroperitoneal radiation therapy, although systemic chemotherapy with carboplatin is an alternative treatment. For patients with bulky retroperitoneal lymph node or distant metastases (stage IIB, III), systemic chemotherapy including cisplatin and etoposide appears to be the standard approach. Recently, 85% to 90% of patients with stage III disease are cured. Thus, the current therapeutic goal is cure of the disease with the minimum of treatment sequelae.

[Treatment results of VIP (etoposide, ifosfamide and cisplatin) chemotherapy as a first-line therapy in metastatic germ cell tumors].

PURPOSE: We investigated the effectiveness and toxicity of VIP therapy as a first-line chemotherapy for patients with metastatic germ cell tumor. PATIENTS AND METHODS: From March 1994 to October 1997, we treated 16 patients with VIP therapy consisting of etoposide (100 mg/m2), ifosfamide, (1.2 g/m2) and cisplatin (20 mg/m2), all of which were generally given daily for 5 consecutive days every 3 weeks. Of the 16 patients, 6 were classified into a good, 5 into an intermediate, and 5 into a poor prognostic group according to the International Germ Cell Consensus Classification. RESULTS: Thirteen patients (81%) achieved complete response with VIP alone or VIP plus surgery. Three-year survival rate was 100% in good and intermediate prognostic group, while 40% in poor prognostic group. Although all patients had Grade 3 or higher myelosuppression, the treatment was well tolerated and no patient died of treatment-related complications. CONCLUSIONS: VIP appears to be an effective and safe regimen as an induction chemotherapy for good and intermediate risk patients with germ cell tumor. However, more intensive regimen may be necessary for poor-risk patients.

MDP77: A novel neurite-outgrowth-promoting protein predominantly expressed in chick muscles.

A 4.7 kb chick cDNA clone that coded for the novel muscle-derived protein, MDP77, was isolated from a cDNA library of the denervated crus muscles using an antibody which inhibited the neurite outgrowth activity. MDP77 consisted of 676 aa with a calculated molecular mass of 77 k. The deduced amino acid sequence exhibited an extended coiled-coil domain and a leucine zipper motif. A recombinant protein promoted the neurite-outgrowth from the cultured chick neurons of the spinal cord in a dose-dependent manner. Northern blotting and in situ hybridization revealed that MDP77 was predominantly expressed in the cardiac and the skeletal muscles. In the COS-7 cells transfected with the cDNA of the epitope-tagged MDP77, the expressed protein was detected in the culture medium, suggesting that the MDP77 was secreted.

Cellular senescence of a human bladder carcinoma cell line (JTC-32) induced by a normal chromosome 11.

Human chromosome 11 is expected to carry tumor suppressor genes for a variety of human cancers, including bladder carcinoma. To examine the functional role of a putative tumor suppressor gene(s) on this chromosome in the development of bladder carcinoma, we performed microcell-mediated transfer of chromosome 11 into the bladder carcinoma cell line, JTC-32. Fifteen of 20 colonies formed by the transfer experiment showed a remarkable change in cell morphology. They flattened and ceased growing, or senesced, prior to 10 population doublings. The presence of transferred chromosome 11-derived fragments in the growth-arrested cells was confirmed by PCR-based polymorphism analyses. The remaining 5 microcell hybrid clones exhibited a parental cell-like morphology, and presumably escaped from senescence, which was accompanied by deletions and/or rearrangements of the transferred chromosome 11. On the other hand, a transferred normal chromosome 7 neither changed the cell morphology nor arrested the cell growth. These results support the hypothesis that chromosome 11 contains a gene or genes which restore the senescence program lost during the immortalization process of JTC-32 cells.

Influence of TNF microsatellite polymorphisms (TNFa) on age-at-onset of insulin-dependent diabetes mellitus.

The TNF-alpha gene is located in the HLA region and has been implicated in the pathogenesis of Type I (insulin-dependent) diabetes mellitus (IDDM). We investigated the frequency of TNFa microsatellite alleles in 76 young-onset IDDM patients, 65 adult-onset IDDM patients, and 90 control subjects. We also examined the association of these TNFa alleles with HLA-DRB1 alleles, HLA-class I alleles, and TNF-alpha production. The frequency of the TNFa2 and TNFa9 alleles was increased in the young-onset IDDM patients compared to control subjects, but the increased frequency of TNFa2 was not significant after the correction for the number of comparisons was made. We did not find any association of TNFa2 or TNFa9 with any of the HLA-DRB1 alleles. In contrast, the frequency of the TNFa13 allele was decreased in both the young-onset and the adult-onset IDDM patients compared to the control subjects, but the difference lost significance after the correction was made in the adult-onset IDDM. The TNFa13 allele was strongly associated with DRB1*1502. Patients with TNFa2 or TNFa9 had greater TNF-alpha production, while those positive for TNFa13 had lower TNF-alpha production than patients with non-TNFa2, a9, and a13 alleles. These results suggest that TNFa polymorphisms are associated with age-at-onset of IDDM and influence the inflammatory process of pancreatic beta cell destruction in the development of IDDM.

Late recurrence and progression after a long tumor-free period in primary Ta and T1 bladder cancer.

OBJECTIVE: To determine the probability and risk factors of recurrence and progression (to T2 or worse) after a long tumor-free period in patients with superficial (stage Ta and T1) bladder cancer. PATIENTS AND METHODS: A consecutive series of 100 patients with superficial bladder cancer who remained tumor-free for longer than 4 years after initial treatment were reviewed. The rates of recurrence and progression were statistically assessed and the significance of risk factors was determined. RESULTS: Of the 100 patients, 24 (24. 0%) recurred within 15 years after the initial treatment. The 10- and 15-year recurrence-free rates were 76.0 and 59.6%, respectively. Among the clinicopathological variables examined, intravesical chemotherapy was determined by a log-rank test to be a significant unfavorable risk factor for late recurrence (p < 0.001). Progression of the tumor occurred in 5 patients. Four variables including presence of multiple tumors, involvement of the bladder neck, positive urine cytology, and intravesical chemotherapy were found by a univariate analysis to be significant risk factors for late progression (p < 0.05). Among these factors, initial presence of multiple tumors (3 or more) was determined by a multivariate analysis to be an independent risk factor for late progression. CONCLUSION: Recurrence and progression continue to occur in patients with superficial bladder cancer even after long periods of dormancy. Regular follow-up urological assessments should be continued until at least 15 years of tumor-free existence, especially in patients treated by intravesical chemotherapy or those initially having multiple tumors.

[Metastatic testicular tumor requiring inferior vena cava resection with polytetrafluoroethylene graft replacement: a case report].

A 31 year-old man with a biopsy-proved retroperiotoneal yolk sac tumor was referred to our clinic. Physical examination revealed a thum- tip sized left supra-clavicular mass, a huge right abdominal mass and a tiny hard mass of the right testis. On CT scan, the abdominal tumor, 13 cm in diameter, encircled the inferior vena cava. Serum levels of LDH, AFP and hCG-beta were 2,585 U/l, 19,922 ng/ml and 6.6 ng/ml, respectively. No visceral metastasis was found. Following the right high orchiectomy, 4 cycles of VIP chemotherapy consisting of ifosfamide, etoposide and cisplatin were given, which resulted in partial response of the retroperitoneal mass and complete regression of the supraculavicular node with normalization of all tumor markers. Thus, retroperitoneal lymph node dissection was carried out. Because of the marked adhesion to the tumor, the inferior vena cava was segmentally resected together with the tumor, which was followed by reconstruction of the vena cava using a 16 cm long polytetrafluoroethylene graft, since no collateral venous route was found on the pretreatment venacavography. Histologically, the tumor was nearly necrotic with mature teratoma in small part. Postoperative clinical course was uneventful except feeling of numbness at the right tip toe, and the inferior vena cava has been patent 18 months after the operation with no evidence of recurrence.

[Two cases of giant testicular tumor with widespread extension to the spermatic cord: usefulness of upfront chemotherapy].

The first case was a 55-year-old man with biopsy-proven seminoma of the left inguinal undescended testis. The tumor, 10 x 9 x 9 cm in size, with a calculated weight of 520 g invaded the left spermatic cord up to the level of the renal hilum and metastasized to the retroperitoneal lymph nodes (13 x 10 cm). The serum level of lactate dehydrogenase (LDH) and beta human chorionic gonadotropin (beta-hCG) was 3,669 U/l and 1.3 ng/ml, respectively. The second case was a 38-year-old man with non-seminoma of the left testis. The testicular tumor, 32 x 28 x 28 cm in size, with a calculated weight of 7,000 g invaded the left spermatic cord up to the level of the aortic-bifurcation and metastasized to the retroperitoneal and the left supraclavicular lymph nodes. The serum level of LDH, alphafetoprotein (AFP) and beta-hCG was 2,040 U/l, 240 ng/ml and 5.6 ng/ml, respectively. Both patients were initially treated with VIP chemotherapy (etoposide, ifomide and cis-platinum), 4 cycles for the 1st case and 3 for the 2nd, and followed by high orchiectomy and retroperitoneal lymph node dissection. Histologic section of all resected specimens revealed only necrosis and fibrosis. The patients have been free of recurrence for 15 and 13 months, respectively, after the operation. In the Japanese literature, 42 cases of giant testicular tumor (> 400 g) including these two cases have been reported. To our knowledge, our second case is the largest among the non-seminomatous tumors. For giant testicular tumor with extensive invasion to the spermatic cord, initial chemotherapy followed by surgical resection appears to be a better management.

Clinical significance of "cannibalism" in urinary cytology of bladder cancer.

OBJECTIVE: To investigate the cytologic characteristics and clinical significance of "cannibalism" (cytophagocytosis), a characteristic histologic finding associated with malignancy, found in urinary cytology samples during the diagnosis of bladder cancer. STUDY DESIGN: The subjects were 252 patients with bladder cancer initially treated from 1981 to 1991. For their pretreatment urine samples, membrane filtration was performed to determine the presence and amount of cannibalism, a tumor cell within a tumor cell. The urinary cytologic findings were then correlated with the histologic findings of primary bladder cancer. RESULTS: Only cells from urinary cytology-positive specimens demonstrated cannibalism. The positive rate of cannibalism was significantly higher in grade 3 (25%) than grade 1 (0%) or 2 (8%) superficial papillary cancer (P < .01) and also higher in muscle-invading bladder cancer (57%) than grade 3 superficial papillary cancer (P < .01). The rate did not differ significantly between muscle-invading cancer and superficial nonpapillary cancer (44%). In 198 patients with superficial bladder cancer, progression was observed in 19 (10%) during a mean follow-up of 72 months. All of them showed positive urinary cytology results in pretreatment samples, and among the patients with positive urinary cytology, the progression rate was significantly higher when cannibalism was present than when it was absent (38% vs. 17%, P < .05). Moreover, in high grade cases, cannibalism had significant predictive value for progression. By multivariate analysis, cannibalism was an independent factor for prediction of progression, as were tumor grade and stage. CONCLUSION: Cannibalism in urinary cytology appears to be an indicator of both the anaplastic grade and invasiveness of transitional cell carcinoma of the bladder. Furthermore, cannibalism may provide a reliable predictor of progression of superficial bladder cancer.