Akihiko Okuyama

Clinical Study of Brain Metastasis of Renal Cell Carcinoma

Objectives: To evaluate the natural history and the efficacy of treatments for renal cell carcinoma (RCC) with brain metastasis, we reviewed 18 patients with this disease. Methods: Out of 325 cases with RCC treated at Osaka University Hospital from 1957 to 1993, 18 (5.5%, male:female ratio 16:2) cases developed brain metastases. Median follow-up was 44 months after the initial treatment of the primary lesion. Twelve patients had surgical resection of brain metastases (surgical group), and 7 of them received adjuvant radiotherapy. Six patients with poor performance status were treated with supportive therapy alone (nonsurgical group). Results: Of 18 RCC patients with brain metastasis, 16 were male and 2 female. All brain metastases except for 1 case were symptomatic. Median interval between the initial treatment of the primary lesion and the diagnosis of brain metastasis was 19 months. The most frequent metastatic site prior to brain was the lung, which was detected in 7 cases (38.9%). Median survival of the entire group, measured from the onset of brain metastasis, was 9.5 months. One-year survival rate after the diagnosis of brain metastasis was 43.2% (64.8% in surgical group, 0% in nonsurgical group), 3-year 18.5% and 5-year 0%. Among 109 metastatic RCC, 14 patients were treated by lymphokine-activated killer (LAK) therapy. Out of 14 metastatic RCC patients treated by LAK therapy, 3 (21.4%) developed brain metastases. On the other hand, out of 95 metastatic RCC patients without LAK therapy, 15 (15.8%) had brain metastases. There was no significant difference in the rate of brain metastases between these two groups. Conclusion: There was a trend for prognosis of the surgical group to be better compared to that of the nonsurgical group, although it is not statistically significant. The optimum treatment for brain metastasis of RCC remains undefined, but our data suggested surgical resection in selected patients might contribute to prolonged survival of patients with brain metastasis. LAK therapy was not necessarily the risk factor of the brain metastasis.

Soluble Fas in serum from patients with renal cell carcinoma.

OBJECTIVESnFas/APO- 1 is an apoptosis-signaling cell-surface receptor belonging to the tumor necrosis factor receptor family. The Fas-Fas ligand system plays an important role in cytotoxic T-lymphocyte-mediated or natural killer cell-mediated cytotoxicity against tumor cells. Soluble Fas (sFas), generated by alternative splicing, has been reported to antagonize the interaction of cell-surface Fas with Fas ligand. This study examined the level of sFas in the serum of patients with renal cell carcinoma (RCC) and investigated the correlation between the sFas level and clinicopathologic parameters of RCC.nnnMETHODSnUsing reverse transcriptase-polymerase chain reaction, we examined the production of sFas messenger RNA (mRNA) from the cultured human RCC cell lines ACHN and OUR-10 and from surgical specimens. We also measured sFas levels in the serum of 31 patients with RCC before and after nephrectomy using an sFas-specific enzyme-linked immunosorbent assay.nnnRESULTSnmRNA of sFas was identified both in cultured ACHN cells and human RCC tissues, although mRNA of wild-type Fas was exclusively predominant. The level of sFas in the serum of patients with RCC was significantly higher than that of normal controls, but sFas was not detectable in the supernatant of cultured renal cancer cells. Preoperative and postoperative serum sFas levels did not clearly correlate with the patients age or sex or with histologic stage, grade, or cell type of RCC. The serum sFas level in patients with RCC correlated with tumor size. In 24 of the 31 cases, radical nephrectomy reduced the serum sFas level within 3 months.nnnCONCLUSIONSnOur results suggest that the elevated serum sFas level in patients with RCC might not be derived from the tumor itself but might reflect an immune response to the tumor burden. Serum sFas may be a useful indicator of tumor burden in patients with RCC.

Extent and zonal distribution of prostatic intraepithelial neoplasia in patients with prostatic carcinoma in Japan: analysis of whole-mounted prostatectomy specimens.

Prostatic intraepithelial neoplasia (PIN), an intraluminar proliferation of epithelial cells in ducts and acini, is divided into high‐grade (HGPIN) and low‐grade (LGPIN), based on morphologies. HGPIN is considered to be a putative precursor of prostatic adenocarcinoma (PCA). Information on PIN has been limited in Japan, because PIN had not been regarded as a precursor lesion for PCA.

EFFECTS OF EPIDERMAL GROWTH FACTOR ON THE INVASION ACTIVITY OF THE BLADDER CANCER CELL LINE

PURPOSEnEpidermal growth factor (EGF) is excreted in high concentrations in the urine and stimulates urothelial cell growth. The cultured bladder cancer cell line KU-1 was used to study the molecular mechanisms by which EGF affects urothelial tumor growth and invasion activity.nnnMATERIALS AND METHODSnKU-1 cells were grown in cell culture in the presence or absence of EGF. Anchorage-independent cell growth assays and Matrigel invasion assays were performed. Expression of cytokeratins was examined by Northern and Western blot analyses. Chloramphenicol acetyltransferase assays were used to determine whether EGF stimulated matrix metalloproteinase expression.nnnRESULTSnEGF enhanced anchorage-independent growth in soft agar and increased the number of cells penetrating into a Matrigel membrane. A transient transfection assay revealed that EGF increased the promoter activities of the matrix metalloproteinase 1 and 9 genes in KU-1 cells. Moreover, the morphology of KU-1 cells changed after the addition of EGF to the culture medium. Western and Northern blot analyses demonstrated that EGF decreased cytokeratin 19 expression, but did not affect expression of cytokeratin 8 or 18.nnnCONCLUSIONnEGF increased the invasive activity of KU-1 bladder cancer cells in part by increasing the secretion of matrix metalloproteinases. Morphologic changes may result from altered composition of cytoskeletal proteins.

SUSCEPTIBILITY TO IDIOPATHIC AZOOSPERMIA IN JAPANESE MEN IS LINKED TO HLA CLASS I ANTIGEN

PURPOSEnApproximately 15 to 20% of infertile men have azoospermia. In the Y chromosome a deletion, termed the azoospermic factor, has been found in some cases of idiopathic azoospermia. We investigate the relationship of factors in autosomal chromosomes (HLA class I antigens) to spermatogenesis failure in idiopathic azoospermia.nnnMATERIALS AND METHODSnWe evaluated 65 infertile Japanese men with idiopathic azoospermia. The frequency of the HLA allele reported in 1,216 healthy Japanese men was used as a control. HLA class I typing was performed by the National Institutes of Health standard serological method or polymerase chain reaction-sequence specific primer analysis. Allele frequencies were calculated. We determined statistical significance in the frequency of each allele in patients and controls using the chi-square test. The relationship of HLA antigens to idiopathic azoospermia was expressed as relative risk.nnnRESULTSnIn Japanese men with idiopathic azoospermia the frequency of HLA-A33, B13 and B44 was significantly increased compared with controls. The relative risk of HLA-B44 was 8.4, an extremely high value compared with that of other diseases and HLA antigens.nnnCONCLUSIONSnWe suggest that HLA class I antigens are important genetic markers that represent a risk factor for idiopathic azoospermia.

Enhancement of interleukin-2-induced lymphokine-activated killer activity by interleukin 7 against autologous human renal cell carcinoma.

Adjuvant immunotherapy with interferons and/or interleukin 2 (IL-2) is widely used for advanced kidney cancer. However, the results are not satisfactory so far. The purpose of this study is to evaluate the inducible activity of lymphokine-activated killer (LAK) cells against autologous human renal cell carcinoma. The effect of interleukin 7 (IL-7) on IL-2-induced LAK activity was assessed by the autologous assay system which we have established. Peripheral blood lymphocytes from patients with renal cell carcinoma were stimulated with IL-2 and/or IL-7, and tested for antitumor activity against autologous renal cell carcinoma. In all 10 cases tested, IL-7 alone induced LAK activity. Moreover, IL-2-induced LAK activity was augmented by the concomitant addition of IL-7. Flow cytometry revealed an increase in IL-2-receptor-positive lymphocytes following incubation with IL-7. These results suggest that combination therapy using IL-2 and IL-7 may be a useful treatment for patients with advanced renal cell carcinoma.

HLA-DRB genotypes in Japanese patients with renal cell carcinoma.

Objectives: Several clinical features, such as the spontaneous regression of some renal cell carcinoma (RCC) metastases after nephrectomy, suggest immune involvement in tumor destruction. Patients and Methods: We investigated the role of genetic variation at the HLA class II loci in RCC by analyzing the HLA-DR antigen and HLA-DRB1, DRB3, DRB4 and DRB5 alleles in 55 patients using the polymerase chain rection. Results: No statistically significant differences were observed in the frequency of the HLA-DR antigen or HLA-DRB3, DRB4, or DRB5 genes between the patients and a healthy control group. On the other hand, the HLA-DRB1*0403 and *1202 alleles were significantly more frequent in the patients than in the controls (p < 0.001 and p < 0.01, respectively). Conclusion: RCC might be linked to these two alleles in Japanese patients.

Antitumor Effect of Irinotecan Hydrochloride (CPT‐11) on Human Renal Tumors Heterotransplanted in Nude Mice

Background: There has been a paucity of antitumor drugs that are active against renal tumors. Irinotecan hydrochloride (CPT‐11), a DNA topoisomerase type 1 inhibitor, has demonstrated antitumor activity against human tumors, however, no antitumor effect of CPT‐11 on renal tumors has been reported. The antitumor effect of CPT‐11 was investigated on 2 human renal tumors (OUR‐10 and OUR‐20) heterotransplanted into nude mice.