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Bowen's disease is a squamous cell carcinoma in situ that rarely invades into the underlying dermis. In order to evaluate the relationship between the cytological properties of the tumor cells and the host immune response, we have examined the expression of p53 and proliferating cell nuclear antigen (PCNA), and the number of mitotic cells, clumping cells, koilocytes, Langerhans cells (LCs) and dermal lymphoid cell infiltration in 18 cases of anogenital Bowen's disease. When compared with normal anogenital skins (n = 10), a statistically significant number of p53-positive cells, PCNA-positive cells, mitotic cells, clumping cells, koilocytes and dermal lymphoid cells was observed in the cases of Bowen's disease. Importantly, there existed a very strong correlation between the number of PCNA-positive tumor cells and the number of infiltrated dermal lymphoid cells. Moreover, the number of mitotic cells significantly correlated with the number of intratumoral LCs. The in situ hybridization technique for human papilloma virus (HPV) demonstrated that the HPV-infected Bowen's disease showed a similar histological and immunohistological pattern as the HPV-non-infected counterparts, except for increased koilocyte formation and decreased p53 positivity. The present data suggest that the proliferative activity of Bowen's disease significantly correlates with the host immune reaction, and that the host immune system may differentially recognize the different cytological properties of tumor cells in the Bowen's disease.

The lymphocytes isolated from perfused or non-perfused circulations before, during, and after hyperthermic isolated limb perfusion (HILP) in the four patients with malignant melanoma were analysed for the expression of CD54 (ICAM-1), CD58 (LFA-3), CD4, CD8, HLA class I and class II in order to investigate the mechanism(s) of the activation of such immunocompetent cells as natural killer (NK)-cells or T-lymphocytes by HILP. It was thus found that the lymphocyte populations expressing CD54 increased significantly 1 day after HILP in the four patients examined. The lymphocyte populations expressing CD58 apparently increased. It was also found that the NK-cell and T-lymphocyte activities increased during or after HILP in the present four cases as observed previously in the other melanoma patients. These results indicate that our HILP system may augment the immunological activities through the mechanisms of the induction of CD54 or CD58 expression in the peripheral lymphocytes of the melanoma patients who receive HILP.

Although ethanol injection in combination with microwaval hyperthermia and systemic administration of interleukin-2 was found to be very effective in suppressing the growth of B16 melanoma nodules with a size of less than 7 mm in diameter in our previous experiments, the growth of B16 melanomas with a size of greater than 10 mm in diameter was very difficult to control with any of the therapeutic modalities examined. In subsequent experiments, we investigated whether ethanol injection (150 microliters/injection) in combination with local injection of beta-interferon (2 x 10(4) IU/injection) and local microwaval hyperthermia at 43 degrees C for 15 min was able to suppress the growth of melanoma nodules and to prolong survival times of melanoma-burdened mice. The results were that we successfully suppressed the growth of melanoma nodules of that size for the first time with combinations of the therapeutic modalities described above. Infiltration of immunocompetent cells such as T lymphocytes and NK cells was clearly observed in the melanoma tissues treated with the therapeutic combination. These experimental results should be applied to the treatment of human melanomas in advanced stages which have no indications for surgical operation.

Previous studies from our laboratories have shown that UV-B irradiation at the site of an intradermal infection of herpes simplex virus (HSV) resulted in a higher incidence of zosteriform lesions and suppressed cellular immune responses to HSV in mice. In order to determine whether the production of T-cell-derived cytokine (IFN-gamma, IL-2 and IL-4) by immune cells from irradiated mice is also suppressed, we examined the production of cytokines by lymph node cells and spleen cells taken from UV-B irradiated, HSV type 1 (HSV-1)-infected mice. UV-B irradiation (120 mJ/cm2) prior to HSV-1 infection was found to markedly suppress IFN-gamma production compared to that of the non-irradiated control. IL-4 production was enhanced compared to IL-2 in the UV-B irradiated mice. These results suggest that alteration(s) in the cytokine production profile may therefore be involved in the development of severe skin lesions caused by HSV infection in UV-B irradiated mice.

A malignant schwannoma in the left calf of a 37-year-old man with type 1 neurofibromatosis is herein reported. Since it is known that capillaries in benign neurofibromas are accompanied by hypertrophic pericytes expressing an abundant amount of smooth muscle alpha-actin (SMAA), we examined the immunohistochemical reactivity of SMAA within this malignant tumor and then compared it with that in surrounding benign areas. In the nests of malignant cells, decreased SMAA staining was found in the capillary walls. In the benign tissues around the malignant tumor, various extents of SMAA could be visualized in the vessels and myofibroblasts. Platelet-derived growth factor (PDGF) was also detected in the tumor, suggesting that cytokines secreted by malignant cells may have an influence on the expression of SMAA as well as on the alteration of the structure of blood vessels.

Using immunohistochemical technique and Western blot analysis, we demonstrated the increased expression of the c-fos oncogene in the infiltrative type of solid basal cell carcinoma (BCC), but low or no expression in the circumscribed type of solid BCC. The infiltrative type is called aggressive BCC and had been shown to exhibit a higher rate of recurrence than the circumscribed type. Our results indicate that increased expression of the fos oncogene is closely related to the invasive ability of the tumor cells.

Murine B16-F10 melanoma was treated with local microwave hyperthermia, local injection of murine recombinant interferon-beta (rIFN-beta) or a combination of both in order to investigate the augmentation of anti-proliferative effects with this combination treatment. Concerning the local modulation of immunological reactions of the host, local hyperthermia at 43 degrees C for 15 min on murine melanoma caused remarkable infiltration of natural killer cells and local injection of rIFN-beta led to considerable infiltration of T cells. When these two modalities were combined, the infiltration of NK cells completely disappeared and, instead, remarkable augmentation of T cell infiltration occurred. Synergistic suppressive effects on melanoma growth with occasional scar formation were seen with this combined modality. These results indicate that local hyperthermia with a combination of rIFN-beta modulates local immune reactions of the host, and probably this immune reaction is partly involved in the course of the suppression of tumor growth.

Expression of the c-fos oncogene in B16 melanoma with high and low metastatic abilities was investigated. In Northern blot analysis, a highly metastatic B16-F10 melanoma cell line showed a higher extent of transcription of the fos gene than did a low metastatic B16-F1 cell line. Immunohistochemical studies revealed that B16-F10 cells stained more strongly than B16-F1 cells, both in vitro and in vivo, using the antibody against fos proteins. These results suggest that fos product may be involved in the regulation of gene expressions related to metastasis of B16 melanoma.