RENAL TUMORS, RETROPERITONEUM, URETER, AND URINARY DIVERSION AND RECONSTRUCTION

months in both groups (P = 0.49), and there was no significant difference in median survival (12.2 months with interferon vs. 15.7 months with placebo, P = 0.52).

NO difference in outcome was observed in patients with metastatic renal-cell carcinoma who were treated with interferon gamma-lb as compared with placebo. These results emphasize the necessity of testing the efficacy of immunomodulators in randomized studies. Reprinted with permission from Massachusetts Medical Society.

Editorial Comment: Variable response rates have been reported with immunotherapy in the treatment of metastatic renal cell carcinoma. The authors investigate the use of interferon gamma in a blinded, placebo controlled study. There was no difference in the overall response rate, time to disease progression or survival in the treatment versus placebo groups. Interest- ingly, grades 1 and 2 toxicity were reported in both groups with 76% of the placebo group reporting at least grade 1 toxicity. Although interferon will undoubtedly be used in association with other immunotherapies, it does not appear effective as a single agent.

Fray F. Marshall, M.D.

Two North American Families With Hereditary Papillary Renal Carcinoma and Identical Novel Mutations in the MET Proto-Oncogene

L. SCHMIDT, K. JUNKER, G. WEIRICH, G. GLENN, P. CHOW, I. LUBENSKY, Z. ZHUANG, M. JEFFERS, G. VANDE WOLJDE, H. NEUMA", M. WALTHER, W. M. LINEHAN AND B. ZBAR, Intramural Research Support Program, Science Applications International Corporation-Frederick, Advanced Biosciences Laboratories-Basic Re- search Program and Laboratory of Immunobiology, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, Urologic Oncology and Genetic Epidemiology Branches, and Labo- ratory of Pathology, National Cancer Institute and Department of Diagnostic Radiology, National Insti- tutes of Health, Bethesda, Maryland, and Albert Ludwig University Freiburg, Freiburg, Germany

1737

Conclusions

Cancer Res., 58: 1719-1722, 1998 Hereditary papillary renal carcinoma (HPRC) is a newly recognized inherited disorder characterized by

a predisposition to develop multiple bilateral papillary renal carcinomas. Individuals affected with HPRC have been shown to have germ-line mutations in the tyrosine kinase domain of the MET proto-oncogene. We identified a novel mutation in exon 16 of the MET gene in two large North American HPRC families. The H1112R MET mutation segregated with the disease, was not present in 320 normal chromosomes, and caused malignant transformation of NIH 3T3 cells. By examining individuals with the H1112R mutation, we determined the age-dependent penetrance of this mutation and identified additional nonrenal malig- nancies that occurred in mutation carriers. Affected members of the two families shared the same haplotype within and immediately distal to the MET gene, suggesting a founder effect. The identification of the H1112R mutation will facilitate predictive testing in HPRC and guide future studies of the MET gene in human neoplasia.

Editorial Comment: Abnormalities of chromosome 3p were identified with clear cell renal cell carcinoma phenotype, and more recently the hereditary papillary renal cell carcinoma gene was found on chromosome 7q. In this study a novel mutation on exon 16 of the MET proto-oncogene was identified in 2 families. There was a predisposition for papillary renal cell carcinoma. Interestingly, this mutation was identical in both families, which suggested a common ancestor. There was a base change of amino acid histidine to arbnine. There appeared to be a disparity in the number of tumors in individuals of the same age who had the mutation, which suggests that other genes may modify the expression of the mutation in the MET gene.

Fray F. Marshall, M.D.

Minimal Recruitment and Activation of Dendritic Cells Within Renal Cell Carcinoma A. J. TROY, K. L. SUMMERS, P. J. T. DAVIDSON, C. H. ATKINSON AND D. N. J . HART, Hematology/Immunology

Research Group, Department of Urology and Oncology Service, Christchurch Hospital, Christchurch, New Zealand

Clin. Cancer Res., 4: 585-593, 1998 Dendritic cells (DCs) are predicted to participate in natural tumor immunity by migrating into tumors,

where they acquire antigen, undergo activation, and migrate to lymph nodes to initiate a T-lymphocyte response against tumor-associated antigens. The presence of DCs using defined lineage markers and their function in human tumors has not been assessed previously. The monoclonal antibodies against CMRF-44 and CD83, which a re differentiatiodactivation antigens on DCs, were used in immunohistological and flow cytometry studies to analyze the DC subtypes infiltrating 14 cases of human renal cell carcinoma (RCC). The functional immunocompetence of the DCs isolated from RCC was assessed by testing their ability to stimulate a n allogeneic mixed leukocyte reaction. The majority of leukocytes present within the RCC were macrophages (62% 2 14.7) or T lymphocytes (19% ? 9.5), with CD45 ' HLA-DR' lineage-negative putative DCs accounting for less than 10% of the leukocytes present. Of these, a subset, comprising less than 1% of total leukocytes, had a n activated CMRF-44 + or CD83 + DC phenotype. Activated CMRF-44' and CD83'

1738 RENAL TUMORS, RETROPERITONEUM, URETER, AND URINARY DIVERSION AND RECONSTRUCTION

DCs were more evident outside the tumor in association with T-lymphocyte clusters. The number of CMRF-44' DCs correlated closely with the number of S-100-positive DCs. Isolation of DCs from eight RCCS was achieved, and flow cytometry studies confirmed the small proportion of activated CMRF-44' DCs. The CMRF-44 ' DCs stimulated an allogeneic mixed leukocyte reaction, but the CMRF-44- DCs (normal tissue DC precursors and other cells) failed to do so. These results suggest that RCCs recruit few DCs into the tumor substance, and the tumor environment fails to initiate the expected protective activation of DCS. These two mechanisms, amongst others, may contribute to tumor escape from immunosurveillance. In vitro loading of DCs with tumor-associated antigens may be a useful therapeutic maneuver.

Editorial Comment: Immunotherapy has been used for some time in the treatment of renal cell carcinoma. It is not clear why some patients respond and others do not. The tumor may escape immunosurveillance. In this study dendritic cells, which are associated with antigenic recog- nition, do not appear stimulated in the presence of tumor. Various cytokines may suppress dendritic cell response. For example, vascular endothelial growth factor has been reported to suppress dendritic cell production. As we gain understanding of antigenic recognition, immu- nosurveillance of tumors will be better understood.

Fray F. Marshall, M.D.

Over-Expression of Glutathione S-Transferase Yp Isozyme and Concomitant Down-Regulation of Ya Isozyme in Renal Cell Carcinoma of Rats Induced by Ferric Nitrilotriacetate

T. TANAKA, Y. NISHIYMIA, K. OKADA, K. SATOH, A. FUKUDA, K. UCHIDA, T. OSAWA, H. HIAL AND S. TOYOKUNI, Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Kyoto, Second Department of Biochemistry, Hirosaki University School of Medicine, Hirosaki, and Laboratory of Food and Biodynamics, Nagoya University School of Agriculture, Nagoya, Japan

Carcinogenesis, 1 9 897-903, 1998 An iron chelate, ferric nitrilotriacetate (Fe-NTA), induces renal proximal tubular damage, a consequence

of iron-catalysed Fenton-like reactions, that finally leads to a high incidence of renal cell carcinoma (RCC) in rodents. Glutathione S-transferase (GST) is a family of enzymes that play an important role in detoxi- fication of hydrophobic and electrophilic molecules, and has been associated with putative preneoplastic foci of rat hepatocarcinogenesis and chemotherapy-resistance of human cancers. Our previous study revealed an induction of r-class glutathione S-transferase (Yp) mRNA in the kidney 3 h after administration of Fe-NTA. In the present study, expression of GST isozymes were further investigated in the Fe-NTA-induced RCCs of rats which are characterized by (1) high incidence of metastasis and invasion, ( 2 ) high incidence of tumour-associated mortality, and (3) possible involvement of reactive oxygen species in carcinogenesis. In the Fe-NTA-induced RCCs, the levels of a-class GST (Ya) mRNA and proteins were markedly decreased with no apparent change in the copy number of the gene. In contrast, GST-Yp mRNA and proteins were significantly increased in the RCCs while the total GST enzymatic activity was decreased. Immunohisto- chemical analysis revealed intense staining of GST-Yp not only in the primary RCCs and its metastatic sites, but also in their non-tumorous part of proximal tubules. The contrastive expression of GST isozymes in this renal carcinogenesis model suggests an alteration of its transcription mechanisms and warrants further investigation of this particular detoxifying enzyme from the viewpoint of reactive oxygen species- induced carcinogenesis.

Editorial Comment: An iron chelate, ferric nitrilotriacetic acid induces a high incidence of renal cell carcinoma in rodents. Glutathione S-transferase represents a group of enzymes that have an important role in detoxification of electrophilic molecules. Mutated glutathione S-transferase pi is an early defect that occurs in prostate cancer. Expression of glutathione S-transferase-Yp was significantly increased in the renal cell carcinoma model and glutathione S-transferase-Ya was almost completely suppressed. The total glutathione S-transferase enzymatic activities appeared lower in rats with renal cell carcinoma. This model of reactive oxygen species induced carcinogenesis allows investigation of the important role of detoxification enzyme systems. Ultimately, patients at risk may be prophylactically treated with agents that may prevent or reduce the later development of renal cancer.

Fray F. Marshall, M.D.

A Rat Model of Chemical-Induced Polycystic Kidney Disease With Multistage Tumors F. ITO, H. TOMA, Y. YAMAGUCHI, H. NAWAWA, s. ONlTSUKA AND Y. HASHIMOTO, Department of Urology, Tokyo

Women's Medical College and Department of Pathology, Jikei University School of Medicine, Tokyo, Japan Nephron, 7 9 73-79, 1998

Permission to Publish Abstract Not Granted

Editorial Comment: Diphenylthiazole induces polycystic kidney disease in the rat and N-nitmsomorpholine is a carcinogen that induces renal cell carcinoma. Interestingly, the incidence of tumors appeared higher in rats treated with both agents. Renal failure is increasingly a major