Multi-cytokine therapy for advanced renal cell carcinoma: determination of the minimal effective dose.

A low-dose cytokine combination therapy was given continuously for as extended period to seven patients with advanced renal cell carcinoma to investigate adverse reactions and anti-cancer effectiveness. These cases were: five patients with metastasis; one whose surgical removal of metastatic foci resulted in a non-curative operation; and one patient administered our regimen as postoperative treatment for locally-advanced cancer. Our regimen was started with a subcutaneous injection of a two-drug combination: 6x10(6) units interferon-alfa (IFN-alpha) and 1x10(6) units interferon-gamma (IFN-gamma) to per week iwall our patients; subcutaneous injection of 1.4x10(6) units interleukin-2 (IL-2) per week was added for three patients who showed insufficient therapeutic effects. The combination therapy was performed for 31 months maximum. Objective adverse reactions were very slight in all patients, thus they could be treated as outpatients. Therapeutic outcomes of IFN-alpha and IFN-gamma combination therapy were assessed as CR in one, PR in one, NC in 2 and PID in one patient. One patient showed NC for 27 months. Three patients, one PR case, one NC case and one PD case, were shifted to the three-drug combination therapy and the results after shifting were assessed as 2 PR cases and one PD case. These 2 PR cases are still under treatment with a good quality of life after 31 and 24 months, respectively. These results suggest the possibility of prolonging survival-time by combining continuous low-dose cytokine with conventional local treatments.

Clinical effects of tumor-associated macrophages and dendritic cells on renal cell carcinoma.

Several reports have documented infiltration of many monocytes in renal cell carcinoma (RCC). Since few studies have examined the relationship between monocyte infiltration and clinical prognosis in RCC, we clinically investigated this relationship by semi-quantitative analysis of monocyte infiltration and tumor angiogenesis. The following six parameters were measured immunohistologically in 98 RCC patients who underwent nephrectomy between 1987 and 1997: tumor-associated macrophage (TAM), microvessel density (MVD), S-100 protein-positive cells (S-100(+) cells), HLA-DR-positive cells, apoptosis index and proliferative index (PI). We then assessed intercorrelations among parameters and correlations to prognosis. Significant positive correlations were identified for TAM, MVD and PI, with a tendency for higher parameter values to reflect poorer prognosis. The prognosis of patients without metastasis was poor for the high TAM group even when levels of MVD were low. These findings suggest that TAM facilitates the growth of RCC via angiogenesis and other mechanisms. Prognosis was significantly better in metastatic RCC patients who underwent interferon-alpha (IFN-alpha) therapy when the levels of S-100(+) cells were high. Nonetheless, the levels of S-100(+) cells among these IFN-treated patients did not correlate with other parameters, and none of the other parameters correlated with prognosis. One of the antitumor effects of IFN-alpha for RCC could therefore be mediated by dendritic cells.

[A clinical study on tumor-associated monocyte lineage cells in renal cell carcinoma].

To investigate the relationship between the ratio of monocytes infiltrating renal cell carcinoma (RCC) and prognosis, in 78 patients who underwent nephrectomy, the positive rate of the following parameters was assessed immunohistochemically under light microscopy: tumor-associated macrophage (TAM), microvessel density (MVD), S-100 cell, HLA-DR cell, apoptosis index (AI) and proliferative index (PI). The relationship between the positive rate of these parameters and prognosis, and intercorrelations among these parameters were analyzed. A positive correlation with prognosis was observed in patients positive for TAM, MVD or PI (r = 0.625). Prognosis was poor for patients with high levels of these parameters. Furthermore, the number of S-100-positive cells was a prognostic factor only in patients with metastatic RCC. Although the role of TAM as a prognostic factor in RCC is clear, no linear relationship was identified between prognosis and other monocytes.