Kazuo Gohji

Elevation of serum levels of urokinase-type plasminogen activator and its receptor is associated with disease progression and prognosis in patients with prostate cancer.

Several investigators have revealed that urokinase‐type plasminogen activator (uPA) and its receptor (uPAR) are overexpressed in serum as well as in tumor tissues in patients with various types of cancer. In this study, we examined whether the serum levels of uPA and uPAR could be used as predictors of the progression and prognosis of prostate cancer.

Serum matrix metalloproteinase-2 and its density in men with prostate cancer as a new predictor of disease extension.

We examined whether the serum matrix metalloproteinase‐2 (MMP‐2) level and MMP‐2 density could be predictors of the development and extension of prostate cancer. Serum samples were collected before any clinical treatment from 98 patients with prostate cancer and from 76 patients with benign prostatic hyperplasia (BPH). Control sera were obtained from 70 healthy men. The serum level of MMP‐2 was determined by 1‐step enzyme immunoassay. A newly defined MMP‐2 density parameter was determined by dividing the serum level of MMP‐2 by the prostate volume, which was measured by ultrasonography. The mean serum level of MMP‐2 in prostate cancer patients was significantly higher than in the control and BPH groups. Furthermore, the serum MMP‐2 levels in prostate cancer patients with metastasis were highly elevated compared with those without metastases. The MMP‐2 density in pathologically organ‐confined prostate cancer was significantly higher than that in BPH. There was a statistically significant difference in the MMP‐2 density between pT2N0M0 and pT1N0M0 prostate cancers. Moreover, the serum MMP‐2 level correlated well with the clinical course of prostate cancer with bone metastasis. Our results suggest that MMP‐2 plays an important role in the development and extension of prostate cancer and that the serum level of MMP‐2 and the MMP‐2 density indicate prostate cancer extension and are, therefore, useful for the followup of prostate cancer patients. Int. J. Cancer (Pred. Oncol.) 79:96–101, 1998.

Overexpression of Bcl-2 in bladder cancer cells inhibits apoptosis induced by cisplatin and adenoviral-mediated p53 gene transfer

To investigate the effects of the expression of Bcl-2 protein in bladder cancer on the apoptosis induced by cisplatin or adenoviral-mediated p53 gene (Ad5CMV-p53) transfer, we transfected the bcl-2 gene into KoTCC-1, a human bladder cancer cell line that does not express the Bcl-2 protein. The Bcl-2-transfected KoTCC-1 (KoTCC-1/B) exhibited significantly higher resistance to both cisplatin and Ad5CMV-p53 transfer than did either the parental KoTCC-1 (KoTCC-1/P) or the vector-only transfected cell line (KoTCC-1/C). The flow cytometric analysis of the propidium iodide-stained nuclei and DNA fragmentation analysis after cisplatin or Ad5CMV-p53 treatment revealed DNA degradation in both KoTCC-1/P and KoTCC-1/C, whereas KoTCC1/B showed a marked inhibition of DNA degradation. Following the treatment with cisplatin or Ad5CMV-p53, the accumulation of p53 protein was highly detectable for a long period in KoTCC-1/B compared to that in KoTTC-1/P and KoTCC-1/C. Furthermore, the cisplatin and Ad5CMV-p53 treatments each reduced the volume of the subcutaneous tumors established in nude mice formed by KoTCC-1/P or KoTCC-1/C; in contrast, their reductive effects on the tumors formed by KoTCC-1/B were significantly suppressed. The intraperitoneal tumor cell implantation model revealed that the prognoses of mice injected with KoTCC-1/B were significantly inferior to those of the mice injected with either KoTCC-1/P or KoTCC-1/C after treatment with cisplatin or Ad5CMV-p53. These findings suggest that the expression of Bcl-2 in bladder cancer cells interferes with the therapeutic effects of cisplatin and Ad5CMV-p53 through the inhibition of the apoptotic pathway.

Increased angiogenin expression in the tumor tissue and serum of urothelial carcinoma patients is related to disease progression and recurrence.

The progression of solid tumors is at least partly dependent on angiogenesis, the induction of which is mediated by several angiogenic factors, including angiogenin (ANG). The authors evaluated the expression of ANG in the tumor tissue and serum of patients with urothelial carcinoma.

MULTIFOCAL RENAL CELL CARCINOMA IN JAPANESE PATIENTS WITH TUMORS WITH MAXIMAL DIAMETERS OF 50 MM. OR LESS

PURPOSEnWe determined the risk of local recurrence in 64 Japanese patients a median of 69 years old with renal cell carcinoma who were possible candidates for nephron sparing surgery and who underwent radical nephrectomy.nnnMATERIALS AND METHODSnA total of 64 kidneys in which tumors 50 mm. or less were resected were prospectively examined pathologically in 3 mm. sections. The incidence of satellite tumors and the relationship between the pathological findings of the primary and satellite tumors were evaluated.nnnRESULTSnSatellite tumors were identified in 10 of the 64 kidneys (15.6%), a rate similar to that reported in the United States. The correlation of histological findings between primary and satellite tumors was 70% for tumor grade. Satellite tumor grade was less than that of the primary lesion in 3 cases. In 60% of the specimens with multifocal renal cancer satellite tumors were within 10 mm. of the margin of the primary tumor. At this distance, if partial nephrectomy had been performed, the satellite lesions would have been missed in 4 of these 10 patients (40%). Of the 10 kidneys with satellite renal tumors 8 (80%) had vascular invasion of the primary tumor. Multiple logistic regression analysis demonstrated that vascular invasion was a significant predictor of multifocality of renal cell carcinoma.nnnCONCLUSIONSnOur results suggest that vascular invasion is a risk factor for multifocality in Japanese patients with renal cell carcinoma. Therefore, careful and long-term followup is necessary in patients with renal cell carcinoma who have undergone nephron sparing surgery, especially those with vascular invasion of the primary tumor.

Synergistic antitumor effects of interleukin-12 gene transfer and systemic administration of interleukin-18 in a mouse bladder cancer model

Abstract We introduced the interleukin-12 (IL-12) gene into the mouse bladder cancer cell line (MBT2) to establish sublines that secrete bioactive IL-12. IL-12-secreting MBT2 (MBT2/IL-12) sublines were completely rejected when subcutaneously implanted into immunocompetent syngeneic C3H mice. Although this antitumor effect did not change when IL-12-secreting cells were injected into immunodeficient mice whose CD8+ T or CD4+ T cells had been depleted by the corresponding antibody, it was abrogated when natural killer cells were depleted by anti-asialoGM1 antibody. In addition, when parental MBT2 cells mixed with MBT2/IL-12 cells were subcutaneously injected into mice, admixed MBT2/IL-12 inhibited the growth of the parental tumor. Furthermore, this antitumor effect was enhanced by systemic IL-18 administration. This synergism was abrogated when the mice were treated with interferon-γ-neutralizing antibody inu2009vivo. In conclusion, local secretion of IL-12 led to effective antitumor activity that was enhanced by systemic administration of IL-18. Interferon-γ plays an important role in the synergism of IL-12 gene transduction and systemic administration of IL-18.

Conservative therapy for stage T1b, grade 3 transitional cell carcinoma of the bladder

OBJECTIVESnTo retrospectively evaluate the usefulness of transurethral resection of bladder tumor (TURBT) and intravesical instillation for pT1bG3 transitional cell carcinoma of the urinary bladder.nnnMETHODSnBetween May 1984 and May 1997, 45 patients with pT1bG3 transitional cell carcinoma of the urinary bladder underwent TURBT and intravesical instillation with bacillus Calmette-Guerin (BCG) or other anticancer agents. Random biopsy was carried out in 37 patients. The recurrence-free survival rate was determined by tumor size, number of tumors, lymphovascular invasion, and drugs used for intravesical instillation. The median follow-up period was 63 months (range 4 to 145) after the initial TURBT.nnnRESULTSnOf 37 patients who underwent random biopsy, concomitant carcinoma in situ was detected in 18 patients (48.6%). The incidence of concomitant CIS was significantly higher in patients with multiple tumors (P = 0.029). Vesical recurrence was noted in 16 patients (35.6%). The overall 1-, 3-, and 5-year recurrence-free survival rates were 88.5%, 66.7%, and 66.7%, respectively. Progression (muscular invasion) occurred in only 2 patients (4.4%). Total cystectomy was performed in 4 patients, including the 2 patients with progressive disease, and 2 patients with recurrent CIS that resisted BCG therapy. None of the patients died of bladder cancer.nnnCONCLUSIONSnOur results suggest that aggressive attempts at initial or subsequent TURBT combined with BCG therapy achieved good control of pT1bG3 transitional cell carcinoma of the urinary bladder.

Expression of basic fibroblast growth factor is associated with resistance to cisplatin in a human bladder cancer cell line

To clarify the role of basic fibroblast growth factor (FGF-2) in the drug resistance of bladder cancer, we transfected the FGF-2 gene into HT1376, an FGF-2 negative human bladder cancer cell line. The FGF-2-transfected cell lines exhibited three- to four-fold higher resistant potential to cisplatin than the vector-only transfected control cell lines in vitro. When cisplatin was injected intraperitoneally after s.c. implantation of HT1376 sublines into nude mice, FGF-2 transfectants formed tumors about twice as large as did controls. In contrast, there was no significant difference in either cell proliferation in vitro or tumor growth in vivo among these cell lines without cisplatin treatment. Furthermore, DNA degradation following cisplatin treatment was markedly suppressed in FGF-2 transfectants compared to control cells. These results suggest that the expression of the FGF-2 gene plays an important role in the acquisition of the cisplatin-resistant phenotype of bladder cancer, probably through the protection against cisplatin-induced apoptosis.

Elevation of serum level of vascular endothelial growth factor as a new predictor of recurrence and disease progression in patients with superficial urothelial cancer

OBJECTIVESnTo determine whether the serum vascular endothelial growth factor (VEGF) level in patients with urothelial cancer could be used as a predictor of recurrence and disease progression.nnnMETHODSnSerum levels of VEGF in 51 healthy controls and 135 patients with urothelial cancer (81 superficial and 54 invasive cancers) were measured using a sandwich enzyme immunoassay, and the results were analyzed with respect to several clinicopathologic factors.nnnRESULTSnSignificant differences in the serum VEGF level were observed between healthy controls and patients with superficial urothelial cancer (34+/-12 pg/mL versus 49+/-27 pg/mL, P<0.001) and between healthy controls and patients with invasive cancer (34+/-12 pg/mL versus 51+/-35 pg/mL, P<0.001), whereas there was no significant difference in the serum VEGF level between superficial and invasive cancers (49+/-27 pg/mL versus 51+/-35 pg/mL, P = 0.31). Among patients with superficial cancer, the disease-free survival rate of patients with elevated serum levels of VEGF was significantly lower than that of patients with normal levels (P<0.05). The progression-free survival rate of superficial cancer patients with elevated serum levels of VEGF was also significantly lower than that of patients with normal levels (P<0.01). In addition, Coxs multivariate analysis revealed that the elevation of serum VEGF level was strongly associated with disease-free survival and progression-free survival in patients with superficial cancer (P<0.05).nnnCONCLUSIONSnThe results of this study suggest that the elevation of serum VEGF level could be used as a new independent predictor of recurrence and disease progression in patients with superficial urothelial cancer.

Preoperative Computerized Tomography Detection of Extensive Invasion of the Inferior Vena Cava by Renal Cell Carcinoma: Possible Indication for Resection with Partial Cardiopulmonary Bypass and Patch Grafting

The relationship of the diameter of the inferior vena cava as measured by computerized tomography (CT) and tumor invasion of the inferior vena caval wall was determined in patients with renal cell carcinoma. In addition, the indications and usefulness of surgery using partial cardiopulmonary bypass and a polytetrafluoroethylene (Gore-Tex) patch graft are discussed. In all 7 patients with an inferior vena caval diameter of 40 mm. or larger on CT tumor had extensively invaded the vessel wall macroscopically and microscopically. Therefore, resection of the inferior vena caval wall and repair with a patch graft were necessary. Partial cardiopulmonary bypass was used in 6 of these 7 patients. On the other hand, of 11 patients with an inferior vena cava less than 40 mm. in diameter only 2 with extensive tumor invasion of the vessel wall underwent a patch graft procedure without partial cardiopulmonary bypass. One patient who had massive hemorrhage before bypass was started died while in a coma. The survival of the remaining patients ranged from 6 to 131 months (median 19 months). Blood loss in patients who underwent surgery with partial cardiopulmonary bypass was much less than that in patients without bypass. In our series, there were no complications related to the graft itself and graft patency was excellent. Our results indicate that an inferior vena caval diameter of 40 mm. or more on CT probably indicates extensive tumor invasion. Although further experience and observation are necessary to evaluate whether partial cardiopulmonary bypass and/or a patch graft improves the prognosis of patients with extensive inferior vena caval invasion by renal cell carcinoma, this method was relatively safe and decreased blood loss.