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BACKGROUND This study aimed to determine the clinical benefit of neoadjuvant methotrexate, doxorubicin, vinblastine, and cisplatin (MVAC) in patients with muscle-invasive bladder cancer (MIBC) treated with radical cystectomy. PATIENTS AND METHODS Patients with MIBC (T2-4aN0M0) were randomised to receive two cycles of neoadjuvant MVAC followed by radical cystectomy (NAC arm) or radical cystectomy alone (RC arm). The primary end point was overall survival (OS). Secondary end points were progression-free survival, surgery-related complications, adverse events during chemotherapy, proportion with no residual tumour in the cystectomy specimens, and quality of life. To detect an improvement in 5-year OS from 45% in the RC arm to 57% in the NAC arm with 80% power, 176 events were required per arm. RESULTS Patients (N = 130) were randomly assigned to the RC arm (N = 66) and the NAC arm (N = 64). The patient registration was terminated before reaching the initially planned number of patients because of slow accrual. At the second interim analysis just after the early stoppage of patient accrual, the Data and Safety Monitoring Committee recommended early publication of the results because the trial did not have enough power to draw a confirmatory conclusion. OS of the NAC arm was better than that of the RC arm, although the difference was not statistically significant [hazard ratio 0.65, multiplicity adjusted 99.99% confidence interval 0.19-2.18, one-sided P = 0.07]. In the NAC arm and the RC arm, 34% and 9% of the patients had pT0, respectively (P < 0.01). In subgroup analyses, OS in almost all subgroups was in favour of NAC. CONCLUSIONS This trial showed a significantly increased pT0 proportion and favourable OS of patients who received neoadjuvant MVAC. NAC with MVAC can still be considered promising as a standard treatment. UMIN CLINICAL TRIALS REGISTRY IDENTIFIER C000000093.

Alfa fetoprotein (AFP), human chorionic gonadotropin (HCG), beta HCG and lactate dehydrogenase (LDH) are powerful markers of germ cell tumors. The role of tumor markers is very important in the diagnosis, treatment and follow-up of germ cell tumors, respectively. We can often deduce the histological typing of germ cell tumors by tumor marker elevation before surgery. Tumor markers also frequently provide clues as to outcome in individual cases before treatment. The half-life of tumor markers during chemotherapy indicate the effect of the treatment. The optimal regimen of chemotherapy should therefore be selected based on the half-life of tumor markers. Normalized tumor markers designate the phase of discussion on surgical indications. Determination of tumor markers is important in following patients after treatment of germ cell tumors. The elevation of serum tumor markers denotes recurrence and is often the first sign of treatment failure.

The experience with hepatectomy for metastatic renal cell carcinoma (RCC) has been very rarely reported, because multiple organ metastases ordinarily coexist when hepatic metastases are found out. Three patients who underwent hepatectomy for metastatic RCC are presented here. Radical nephrectomy was performed for the primary renal lesions in all the patients, and their hepatic metastases were resected simultaneously in one of them with a solitary tumor, and about one month later in two of them with multiple (3 and 6) tumors. These operations produced no distinct complications. The patients with 1 and 3 hepatic metastatic lesions survived without tumor recurrence for 12 and 21 months, respectively, while the patient with 6 hepatic metastatic lesions had tumor-free interval of only 2 months and died 10 months after hepatectomy due to lung metastasis. Hepatectomy may be the only promising treatment for hepatic metastases from RCC, but the indication for surgery should be evaluated according to the number of hepatic metastases.

The presence of mRNAs for vascular endothelial growth factor (VEGF) and a VEGF-related protein, placenta growth factor (PIGF) was examined in 29 cases of renal cell carcinoma tissues and adjacent normal kidney tissues and in 4 human renal cell carcinoma cell lines. Northern blot analysis showed that 26 of 27 hypervascular renal cell carcinoma tissues (96%) exhibited a markedly elevated level (3-13 fold) of VEGF mRNA compared to the adjacent normal kidney tissues. Even tumors of small size, whenever they were hypervascular, overexpressed VEGF mRNA. We also demonstrated that mRNA for PIGF was expressed in 21 of 23 hypervascular renal cell carcinoma tissues (91%) but was not detected in the adjacent normal kidney tissues. Two hypovascular carcinoma tissues neither overexpressed VEGF mRNA nor had PIGF mRNA. VEGF mRNA was detected in four human renal cell carcinoma cell lines, while PIGF mRNA was not. There was no difference in the level of basic fibroblast growth factor mRNA between tumor tissues and normal kidney tissue, although our previous study demonstrated elevated basic fibroblast growth factor protein in the serum of renal cell carcinoma patients (K. Fujimoto et al., Biochem. Biophys. Res. Commun., 180: 386-392, 1991). Taken together, these results suggest that VEGF, PIGF, and basic fibroblast growth factor are cooperatively working to increase the angiogenesis in renal cell carcinoma in vivo.

The East Japan Testicular Tumor Study group has studied advanced testicular tumors. Treatment and prognosis of the patients who did not achieved complete response on the primary chemotherapy were discussed in this paper. Also 8 patients who had once reached complete response by primary treatments and relapsed later have been clinically analyzed. 1. Concerning the patients non-achieving complete response on the primary chemotherapy: Two cases who had resection of the residual tumors and 4 cases who had radiation therapy had reached NED in 7 cases of seminoma stage II. Nine of 10 cases in non-seminoma stage II reached NED on resection of the residuals. Moreover, 10 out of 17 cases in stage III showed NED on excision of the residuals. On the other hand, recuperating was very difficult in the cases who could not have excision of residual tumor. The histological findings of the residual tumors after chemotherapy were necrosis and fibrosis in 13 cases, viable cells in 4 cases, teratoma in 6 cases and other 2 cases were not clear. Five out of 15 who had teratoma in the primary lesion had teratoma in the resected residuals on metastatic lesion. On the other hand 5 patients who did not have teratoma originally had no any teratoma elements in the residuals. 2. Concerning the relapse cases by primary treatments: Although relapses were possible in any stages, they were more common with stage IIIB and IIIC cases. Those who achieved complete response after chemotherapy alone fewer relapse than those who had partial response after chemotherapy and there after had excision of residual tumor.(ABSTRACT TRUNCATED AT 250 WORDS)

The clinicopathological findings of 154 patients with initially superficial (stage pTa or pT1) transitional cell carcinoma in the bladder were analyzed to study risk factors for tumor recurrence or progression in grade and/or stage of the low grade tumor. The number, size, grade and stage of tumor at the first presentation were the significant predictors for the first tumor recurrence. However, only the tumor grade and size at the first recurrence were the predictors for the second recurrence. In 19 (33%) of 57 patients with recurrence, low grade superficial tumor progressed in tumor grade and/or muscle invasion. The progression of low grade tumor correlated with short tumor free intervals and tumor size. Grade and/or stage progression was observed in 14% of the tumor of 1 cm or less in diameter, whereas in 42% of the tumor more than 1 cm in diameter (Chi-square test: p0.25). These results indicate that tumor grade and size are important predictors for recurrences. Short tumor free intervals and sizes of tumors in the second recurrence are significant predictors for grade and/or stage progression in low grade superficial cancer.

A twenty-four-year-old male patient with stage III advanced extragonadal germ-cell tumor obtained complete remission after comprehensive treatment including high-dose combination chemotherapy with autologous bone marrow transplantation. He had massive tumors in cervical, mediastinal, abdominal and inguinal lymph nodes, bilateral lungs and liver. Ascites, plural effusion and pericardial effusion were also noted. Cancer cells were demonstrated from his bloody sputum, pericardial drainage and an aspirate from supraclavicular tumor. His tumor produced hCG, AFP, placental ALP and LDH, and hCG was the best marker for the diagnosis and monitoring. The initial serum hCG level was high at 460,000 mIU/ml, but fell to 13 mIU/ml after 3 courses of PVP therapy. However, it rose ten-fold in a week. After ultra-high dose combination chemotherapy with autologous BMT, the patient's hCG fell to 1.8 mIU/ml and remained at that level thereafter. He has remained well with no sign of recurrence after 25 months.

The ideal course of multidisciplinary treatment of disseminated germ cell tumors was shown with special reference to the role of the tumor markers for 1) diagnosis of pathological elements and risk factors, 2) appropriate selection of the protocol before and during the chemotherapeutic treatment, 3) timely resection of residual tumor and 4) monitoring of the recurrence after treatment. The practical role of tumor markers for evaluation of chemotherapeutic effectiveness, the following reconsideration of the appropriate protocol and timely indication of surgical intervention for residual mass after chemotherapy were emphasized by demonstrating the clinical courses of 2 patients with advanced nonseminomatous testicular germ cell tumors.

Prognostic factors of chemotherapy against advanced testicular cancer were analysed in 33 cases studied by East Japan Testicular Tumor Study Group. In this study a discriminant analysis of quantification theory (a multivariate analysis) was adapted, taking 7 factors as comparative variables. The significant factors for complete tumor response were clinical stage, histology, and tumor markers (HCG-beta, AFP). Prognostic score was calculated in each case by quantification theory, which correctly discriminated the group with CR from that without CR, at a probability of 90.1%. The results of our study indicate that the outcome of chemotherapy on advanced testicular cancer may be predicted with probability, by patients' status and adopted treatment. It may enable one to make an adequate treatment schedule for each patient.

We have developed a method of in vitro stimulation of TIL and PBL using immobilized anti CD3 antibody instead of autologous tumors. After this treatment, proliferation of T cells was greatly enhanced. Separated TILs were cultured by OKT3 coated 96 well culture plate for about one week with 10% human serum and 1,000U/ml of rIL-2 supplemented RPMI-1640 medium, and then transferred to plain vessels. TIL increased in number by more than 5,000-fold after 3 weeks. PBLs obtained from 10 ml of peripheral blood were cultured in OKT3-coated culture flask (75 cm2) with 10 ml of medium for about one week, and then in plain flasks and finally expanded by culture in gas-permeable culture bags. PBL proliferated by more than 1,000-fold after 2 weeks. TIL or PBL cultured by this method contained over 90% activated T cells positive for the Leu4 marker, and HLA-DR. About 60% of these were CD8-positive and about 40% were CD4-positive. Only a small number of Leu 11-positive cells were detected in every case.

A 52-year-old male was admitted to this hospital as stage D2 prostatic carcinoma. He had been previously treated with transurethral resection of prostate and hormonal therapy. Rectal examination revealed the prostate bigger than a hen-egg with stony-hard nodules. Both whole body bone X-ray and bone scintigram showed multiple bone metastasis. Total cysto-prostatectomy and pelvic lymph node dissection were performed because the patient was relatively young, was in good general status and the tumor was not sensitive to hormonal therapy. In addition, he was expected to have obstructive uropathy soon and the reported results of radiotherapy for local control of advanced prostate cancer were unsatisfactory. He was followed by bone X-ray and bone scintigram every six months. Osteoplastic area diminished in size and hot lesions in bone scintigram disappeared gradually. The patient is very active in his daily life without evidence of local recurrence or new metastasis more than seven years after operation. The validity of mass reduction surgery for hormone-resistant stage D2 prostatic carcinoma is discussed.

Herein we report a 36-year-old man with hyperparathyroidism and a past history of internal irradiation to the thyroid. Twelve years previously at age 24 years he had received 8 mCi of radioactive iodine for Graves' disease. An additional dose of 4 mCi was required 3 years later. A right lower parathyroid adenoma (28 X 23 X 20 mm, 5.7 g) was found at neck exploration. Although the association of external ionizing radiation to the head and neck and the subsequent development of hyperfunctioning parathyroid glands has been described in recent years, there are only 4 cases in the literature of parathyroid surgery for hyperparathyroidism secondary to earlier treatment with radioactive iodine for Graves' disease. In a long-term follow-up of 180 patients treated with radioactive iodine for Graves' disease, neither hypercalcemia nor hypophosphatemia was found. Whether internal radiation therapy can be a causative factor in the development of hyperparathyroidism should be elucidated in future. However, it seems reasonable to suggest that patients whose hyperthyroidism has been treated with radioactive iodine should have their serum calcium levels examined at 5-year intervals.

Ultrasound-guided renal cyst puncture was performed on 22 cysts which were then 95% ethanol instilled to prevent recurrence of cystic fluid. Cystic lesions disappeared on the ultrasonogram in the follow-up period of 3 to 28 months. On CT, cystic lesions became smaller size but did not disappear. Average CT numbers of the cyst were 8.75 +/- 3.83 before and 12.96 +/- 3.27 after ethanol instillation. The cystic wall became thicker. Caliceal distortion and/or pelvis compression by cystic lesions improved on IVP 2 to 3 days after ethanol instillation. The renal image on Tc-99m-DMSA scintigram showed morphological improvement and DMSA renal uptake rate increased slightly but significantly 2 to 4 weeks after ethanol instillation. There were no major complications with this procedure except for one case in which the tip of the catheter became stuck in the cyst and broke off when the catheter was removed. A slight local irritable pain was noticed in all cases. Half of the patients had hot flushes and/or somewhat drunken sense but these symptoms were only temporary. Antabuse phenomenon appeared in one case with concomitant use of a cephem antibiotics after ethanol instillation. This method of therapy is a safe non-surgical approach to treat renal cysts. 95% ethanol instillation in the cyst seems to prevent recurrence of cystic fluid.

Bladder cancer is believed to develop through reversible premalignant stages followed by irreversible steps, and ending in invasive cancer giving rise to distant metastases. Because of the variation in the clinical course it has also been suggested that different forms of cancer develop along different molecular pathways leading to tumor presentations of various malignant potential. Today we treat and prognosticate bladder cancer on the basis of clinical and histologic findings that are insufficient to assess all the biologic potential of these tumors. Understanding the pathogenesis of bladder cancer might lead to a more precise identification of particular tumors with regard to clinical aggressiveness, resulting in individualized strategies for treatment and prophylaxis. Bladder cancer is seldom diagnosed in its preclinical stage, it is instead detected at cystoscopy and virtually never recognized as an incidental finding on autopsy. Therefore its "natural history" largely reflects that of "treated" disease. The true incidence of premalignant and malignant epithelial changes is not known. Incidences of hyperplasia and dysplasia of approximately 10% and approximately 5%, respectively and only occasional findings of cancer itself were reported in two autopsy series. Urothelial dysplasia is generally believed to be premalignant and a putative precursor of invasive cancer but unfortunately there has been a lack of standardization in terms of terminology and diagnosis. There is also a need for an agreed definition of the boundary between premalignancy, i.e. urothelial changes that have some but not all the features of carcinoma in situ, and malignancy, especially when considering potentially harmful treatments to prevent this transition. Most new diagnostic tools available and being tested today compare new detection techniques with traditional methods such as cytology or conventional histology of malignant rather than premalignant changes. There is probably also a short preclinical latency, as implied by the incidental findings of bladder cancer at autopsy, which makes it necessary to define how and when to promote early detection and treatment. Future studies therefore have to concentrate on methods for early detection of disease as well as characterization of host susceptibility, evaluation of exposure to carcinogens and potential effects of preventive measures. It is also likely that the improved tools of molecular prognostication will allow us to design trials more precisely in order to tailor therapeutic strategies.