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Background: Imiquimod, an immune response modifier that is used topically to treat different types of skin cancer, induces the production of proinflammatory cytokines that stimulate an antitumor immune response. We assessed characteristics of the imiquimod-induced immune activation in epithelial and lymphoproliferative neoplasias of human skin. We focused on plasmacytoid predendritic cells (PDCs), the primary producer of interferon a (IFN-[alpha]) after imiquimod activation in vitro. Methods: We used Affymetrix oligonucleotide arrays to compare gene expression profiles from tumors from 16 patients, 10 with superficial basal cell carcinomas (sBCCs), five with cutaneous T-cell lymphomas (CTCLs), and one with Bowen's disease, before and after topical imiquimod treatment. We used quantitative immunohistochemistry with PDC-specific antibodies against BDCA-2 and CD123 to characterize the PDC population before and after imiquimod treatment in these specimens. Activation status of PDCs from four sBCC patients was assessed by intracellular IFN-[alpha] staining and flow cytometry. Results: Expression of various IFN-[alpha]-inducible genes (e.g., CIG5, G1P2, OASL, IFIT1, STAT1, IFI35, OAS1, ISG20, MxA, and IRF7), the so-called IFN-[alpha] signature, was increased similarly in both sBCC and CTCL lesions after imiquimod treatment. PDCs were recruited and activated in both lesion types, and they produced IFN-[alpha] after imiquimod treatment in vivo (mean percentage of PDCs producing IFN-[alpha] = 14.5%, 95% confidence interval [CI] = 4.9% to 24%; range = 3.3%-27%, n = 4 lesions). Imiquimod induced similar immune activation patterns in all three diseases, and these patterns were associated with the number of PDCs recruited to the treatment site. Two imiquimod-treated sBCC patients who did not mount an inflammatory response to imiquimod and whose lesions lacked the IFN-[alpha] signature after treatment had fewer PDCs in treated lesions compared with other treated patients with such a response. Conclusions: Imiquimod induces immune activation patterns that relate to the number of the PDCs recruited to the treatment site, thus supporting the role of PDC in responsiveness to imiquimod in humans.

Background. Anatomic location has been identified by several investigators as a significant prognostic factor for patients with primary cutaneous melanoma (CM). However, the best determination of higher and lower risk sites is still controversial, and the biologic significance of tumor site in the course of primary CM is unknown. The aim of the present study was to identify higher and lower risk sites based on multivariate analysis. Methods. A series of 5093 patients with invasive primary cutaneous melanoma followed from 1970 to 1988 at four university centers in Germany was investigated using the multivariate Cox proportional hazard model to analyze the importance of anatomic location for survival probability. Results. The anatomic location was found to be a highly significant prognostic factor for patients with primary melanoma by multivariate analysis (P < 0.0001). An optimized classification into sites of higher and lower risk with respect to survival was evaluated by multivariate analysis controlling for the possible confounding effects of the other significant prognostic factors. Relative to the lower leg as the prognostically favorable baseline, the following locations were associated with a significantly higher risk of death caused by primary cutaneous melanoma: back and breast (thorax), upper arm, neck, and scalp (TANS regions). The lower trunk, thigh, lower leg, foot, lower arms, hands, and face were identified as lower risk sites. Conclusions. Anatomic location was confirmed as an independent prognostic factor for patients with primary cutaneous melanoma. The TANS regions were identified as high risk sites, and the lower trunk, thigh, lower leg, foot, lower arms, hands, and face were identified as intermediate sites. Cancer 1995; 75:2492-8. Key words: primary cutaneous melanoma, anatomic location, prognostic classification, multivariate analysis.

Background, Numerous investigations have examined prognostic factors for patients with primary cutaneous melanoma. However, only a few studies have been published on the definition of prognostic groups. The first aim of the present study was to determine the relative importance of different prognostic factors in a large collective study. The second aim was to define prognostic groups of patients based on combinations of prognostic factors and to define a model that allows the estimation of individual survival probability. Methods. Long term follow-up of 5264 patients with invasive primary cutaneous melanoma was performed from 1970 to 1988 at four German University Departments of Dermatology (Berlin-Steglitz, Munster-Hornbeide, Tubingen, and Wurzburg). The multivariate Cox model was used to analyze 5093 patients, and 4371 patients with complete information were included in a classification and regression tree analysis (CART). Results. Tumor thickness, sex, anatomic location, and level of invasion were highly significant prognostic factors according to the multivariate analysis (P < 0.0001). However, histologic subtype and age influenced prognosis less significantly (P 0.05). The CART analysis resulted in 12 groups defined mainly by tumor thickness, sex, and anatomic location, which were combined into five prognostic groups. The prognostic stratification defined by the five groups was superior compared with the standard TNM model. Ten-year survival rates of the five groups ranged from 97% to 14% (P < 0.0001), and an equation was used to calculate individual survival probabilities based on the significant factors of the Cox model. Conclusions. Consideration of all significant prognostic factors of patients with primary cutaneous melanoma investigated in the present study allows for the definition of prognostic groups with a more reliable estimation of prognosis than by previous staging systems and also enables calculation of individual survival probabilities. Cancer 1995; 75:2484-91. Key words: primary cutaneous melanoma, prognostic groups, individual prognosis, multivariate analysis.

Background. Maximum tumor thickness and level of invasion are known to be the most important prognostic factors for patients with primary cutaneous melanoma. However, the classification of tumor thickness and the question of whether the combination of tumor thickness and level of invasion provides a better prognostic classification than tumor thickness alone are still matters of debate. The present study examined the relationship between tumor thickness and survival probability to define cutoff points of tumor thickness. Secondly, it investigated the prognostic value of the combination of tumor thickness and level of invasion as proposed in the current TNM classification system. Methods. A series of 5093 patients with invasive primary cutaneous melanoma followed from 1970 to 1988 at four University centers in Germany (Departments of Dermatology in Tubingen, Wurzburg, Berlin-Steglitz, and at the Fachklinik) were analyzed by multivariate Cox models. Results. The relationship between tumor thickness and relative risk of death caused by melanoma was found to be almost linear to a tumor thickness of 6 mm. For tumors greater than 6 mm, no further marked increase in relative risk was observed. The stratification of tumor thickness with endpoints at 1, 2, and 4 mm resulted in the best fit to the authors' data among all classifications with three endpoints, but differences were only slight. By multivariate analysis, the combination of tumor thickness and level of invasion as proposed by the current TNM classification were found to be prognostically less significant than tumor thickness alone. The prognostic influence of level of invasion was proved statistically only for tumor thickness less than or equal to 1 mm. Conclusions. The proposed stratification of tumor thickness with cutoff points at 1, 2, and 4 mm was supported by multivariate statistical analysis. The analysis of the current TNM staging system indicates the precedence of tumor thickness for the staging of patients with primary cutaneous melanoma in the case of discordance between tumor thickness and level of invasion. Cancer 1995; 75:2499-2506. Key words: Primary cutaneous melanoma, Breslow's tumor thickness, Clark's level of invasion, optimized cutoff points, prognostic classification.

Background. Treatment of patients with metastatic melanoma with either dacarbazine or recombinant interleukin-2 (rIL-2) resulted in a response rate of approximately 15%. This study investigates the possible synergism of this chemoimmunotherapy combination. Methods. Fifty-seven patients with metastatic malignant melanoma received 135 treatment cycles. Treatment consisted of dacarbazine (Days 1-5) at 250 mg/[m.sup.2] by a 30-minute slow infusion, and interleukin-2 by constant intravenous infusion (Days 21-25 and 28-32) at 18 x [10.sup.6] IU/[m.sup.2]/24 hours. After this treatment cycle, a 1-week rest was scheduled, and in the absence of undue toxicity or tumor progression, patients received a second cycle as described. Maximum treatment consisted of two induction and four maintenance cycles. In a subgroup of patients, immunoparameters were analyzed to identify prognostic factors. Standard supportive care was given. Results. Common toxicities included fever, hypotension, nausea/vomiting, anemia, leukopenia, thrombocytopenia, an increase in serum lactic dehydrogenase levels and diarrhea. The objective response rate was 15.8% (one complete response and eight partial responses). In 14 patients, the disease stabilized. For patients who had an objective response, median response duration was 13.9 months (6.3-[39.0.sup.+]), and median survival was 19.0 months (6.3-[39.0.sup.+]); overall survival was 9.3 months (0.8-[39.0.sup.+]). Immunomonitoring did not reveal any relevant prognostic factors for overall response. Conclusions. Sequential treatment with dacarbazine and rIL-2 is feasible and produces long-lasting responses in a minority of patients. Cancer 1995;75:1038-44.

When infiltration of lymphoma cells into the skin occurs, a careful pathologic analysis is required. Conservative therapy may be adequate for low-grade lymphomas, while high-grade lymphomas may require aggressive treatment. The classification system for lymphoma grades is not entirely satisfactory; some cases that appear to be benign can have the same poor outcome as those involving malignant lymphoma. A study was undertaken to determine if DNA cytometry can be useful in evaluating cutaneous lymphomas. The principle behind cytometry involves the use of optical methods to measure the amount of DNA in individual cells. Often, tumors with abnormal amounts of DNA are more aggressive and result in a worse prognosis. Flow cytometry is often used in such measurements, but it is also possible to make these measurements using microscopic slides and a computerized image analysis system, which was done in the present study. An evaluation of 49 non-Hodgkin's lymphomas with either primary or predominant skin involvement was made, and an index reflecting the variation of nuclear DNA was developed. This index, called 2cDI, correlated strongly with the malignancy of the lymphoma. Patients with 2cDI less than 0.5 experienced no disease progression in the year following the analysis. In contrast, disease progression was observed in 57 percent of the patients with intermediate values, and in 64 percent of the patients with a 2cDI exceeding 1.0. The distribution of DNA within lymphoma cells may prove to be a valuable indicator of malignancy in cutaneous lymphoma. (Consumer Summary produced by Reliance Medical Information, Inc.)

Lymphomatoid papulosis is the development of pimple-like lesions in the lymph system, and may resemble certain features of Hodgkin's disease. Hodgkin's disease is characterized by the enlargement of lymph nodes and the infiltration or accumulation of lymph cells in blood vessels, bone marrow, liver, and spleen. Patients with Hodgkin's disease have Reed-Sternberg cells, which are giant connective tissue cells with one or two large nuclei. Lymphomatoid papulosis and Hodgkin's disease may develop in the same patient. The abnormal cells in these two disorders share similar physical features; the clinical association of these two diseases and physical similarity of atypical cells in lymphomatoid papulosis and Hodgkin's disease suggests that these two disorders may be related. The immunologic similarity between lymphomatoid papulosis and Hodgkin's disease was assessed by examining the antigens on the Reed-Sternberg cells of Hodgkin's disease and the atypical cells from lesions of lymphomatoid papulosis. Antigens are components of the cells which are capable of provoking an immune response. Both cell types had CD30, CD45 T cell-restricted, and CD15 antigens, but lacked CD45 B cell-restricted antigens and the enzyme lysozyme. In addition, CD30, CD2, CD3, and CD25 antigens were detected in both types of atypical cells, but not B cell and macrophage antigens. The similarity of immune features in the Reed-Sternberg cells of Hodgkin's disease and cells of lymphomatoid papulosis suggest that the malignant cells in both conditions may be derived from activated immune T cells, and that these two disease are closely related. (Consumer Summary produced by Reliance Medical Information, Inc.)