[Adjuvant interferon-alpha therapy of malignant melanoma. Position of the Dermatologic Oncology Working Group].
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Chemotherapy, Adjuvant↗
Biomedical subjects
R Dummer
Publications and source records attributed to R Dummer.
Expression of melanoma-associated antigens in short-term melanoma cultures detected by RT-PCR and subsequent ELISA.
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Antigens, CD↗
Cost-effectiveness of whole-body PET imaging in non-small cell lung cancer and malignant melanoma.
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Carcinoma, Non-Small-Cell Lung↗
Immune stimulatory potential of B7.1 and B7.2 retrovirally transduced melanoma cells: suppression by interleukin 10.
The immunostimulatory capacities of B7.1-and B7.2- expressing melanoma cells were investigated. A365, 960306 and 950504 melanomas, established from nodular melanoma lesions, were retrovirally transduced. Irradiated B7-, B7.1+ and B7.2+ melanoma cells were co-cultured with autologous or allogeneic peripheral blood mononuclear cells (PBMCs). Proliferation was assessed by [3H]thymidine uptake. mRNA encoding for interleukin 2 (IL-2), IL-4, IL-10 and interferon gamma (IFN-gamma) was determined. IFN-gamma, IL-2, IL-4 and IL-10 secretion were quantitated by ELISA. B7.1+ and B7.2+ melanomas induced proliferation of PBMCs and mRNA for IL-2 and IFN-gamma. After co-incubation of transduced melanoma cells with PBMCs, high levels of IL-10 were detectable in the supernatant. The presence of neutralizing anti-IL-10 antibodies resulted in enhanced proliferation and IL-2 and IFN-gamma secretion. Our data indicate that B7.1- and B7.2-transduced melanoma cells trigger lymphocytic proliferation with transcription of IL-10, IL-2 and IFN-gamma. Blocking of IL-10 augments these effects. Gene therapy protocols using tumour cells as a vaccine have to consider the adverse effects of IL-10.
Adult↗
Vaccination of melanoma patients with peptide- or tumor lysate-pulsed dendritic cells.
Melanoma is the main cause of death in patients with skin cancer. Cytotoxic T lymphocytes (CTLs) attack melanoma cells in an HLA-restricted and tumor antigen-specific manner. Several melanoma-associated tumor antigens have been identified. These antigens are suitable candidates for a vaccination therapy of melanoma. Dendritic cells (DCs) are antigen-presenting cells (APCs) specialized for the induction of a primary T-cell response. Mouse studies have demonstrated the potent capacity of DCs to induce antitumor immunity. In the present clinical pilot study, DCs were generated in the presence of granulocyte/macrophage-colony stimulating factor (GM-CSF) and interleukin 4 (IL-4) and were pulsed with tumor lysate or a cocktail of peptides known to be recognized by CTLs, depending on the patient's HLA haplotype. Keyhole limpet hemocyanin (KLH) was added as a CD4 helper antigen and immunological tracer molecule. Sixteen patients with advanced melanoma were immunized on an outpatient basis. Vaccination was well tolerated. No physical sign of autoimmunity was detected in any of the patients. DC vaccination induced delayed-type hypersensitivity (DTH) reactivity toward KLH in all patients, as well as a positive DTH reaction to peptide-pulsed DCs in 11 patients. Recruitment of peptide-specific CTLs to the DTH challenge site was also demonstrated. Therefore, antigen-specific immunity was induced during DC vaccination. Objective responses were evident in 5 out of 16 evaluated patients (two complete responses, three partial responses) with regression of metastases in various organs (skin, soft tissue, lung, pancreas) and one additional minor response. These data indicate that vaccination with autologous DCs generated from peripheral blood is a safe and promising approach in the treatment of metastatic melanoma. Further studies are necessary to demonstrate clinical effectiveness and impact on the survival of melanoma patients.
Adult↗
Higher frequency of selective losses of HLA-A and -B allospecificities in metastasis than in primary melanoma lesions.
Expression of HLA class I molecules is essential for the recognition of tumor cells by CD8+ T cells. In this study, 48 bioptic samples of 42 patients in all stages of melanoma were investigated after short-time cultivation of tumor cells. To confirm melanocytic origin of cultured cells, samples were screened for mRNA expression of melanoma markers gp100, tyrosinase, MAGE-3, MelanA, and MUC18 by reverse transcriptase-polymerase chain reaction. Surface expression of specific HLA-A and -B allospecificities on melanoma cells were analyzed with a standard microcytotoxicity assay after stimulation with interferon (IFN)-alpha and compared with the background found in peripheral blood mononuclear cells from the corresponding patients. Immunohistochemistry and flow cytometry confirmed specific losses in cases where the appropriate monoclonal antibodies were available. The level of expression of HLA-I, HLA-II, and intercellular adhesion molecule 1 antigens on melanoma cells cultured in the presence or absence of IFN-alpha and IFN-gamma was determined cytofluorometrically. All cell cultures tested were found to be positive for one or more melanocytic markers by reverse transcriptase-polymerase chain reaction. The specific HLA-I alleles on the cultured cells were detectable in 45 of 48 samples. In 11 cases a specific loss of one HLA-I allele was observed (2 x A2, B7, B8, B18, 4XB44, B47, B49). Ten of these samples were derived from locoregional lymphnode metastases or from distant metastatic tumors. Only one sample from a primary melanoma showed a specific loss of HLA-I (B47). IFN-alpha upregulated expression of HLA-I up to 4-fold. IFN-gamma enhanced the appearance of HLA-II up to 35-fold and the expression of intercellular adhesion molecule 1 up to 40-fold. Selective loss of HLA-I allospecificities might be a major step in tumor progression.
Antigen-Antibody Reactions↗
Melan A/MART-1 immunoreactivity in formalin-fixed paraffin-embedded primary and metastatic melanoma: frequency and distribution.
Monoclonal antibody (MAb) A103 specifically detects Melan A/MART-1 protein expression. Melan A/MART-1-derived peptides are recognized by CD8+ T-cells and are used in immunotherapy. We examined formalin-fixed paraffin-embedded tissue from 57 melanomas (34 primary, 23 metastatic) and 39 control cases (junctional, dermal, compound, Spitz, Reed and balloon-cell naevi) using the alkaline phosphatase and anti-alkaline phosphatase immunochemical method after antigen retrieval. Immunoreactivity was rated as low, medium or high, and staining pattern as homogeneous or heterogeneous. Staining with MAb A103 showed a sensitivity of 88% for melanoma, with a very high specificity for melanocytic cells. Immunopositivity decreased along with clinical stage, with stage I showing 100%, stage II 88%, stage III 90% and stage IV 75% immunoreactivity. Staining changed from an exclusively homogeneous pattern in the early clinical stages to a more heterogeneous pattern in the later stages. Melanocytic control tissues consisting of naevi of different subtypes all showed weak to moderate homogeneous immunoreactivity, with polarity towards the epidermis. Analysis of short-term melanoma cell cultures using reverse transcription-polymerase chain reaction (RT-PCR) enzyme-linked immunosorbent assay (ELISA) demonstrated mRNA expression in only one third of the originally immunopositive tumours, suggesting rapid mRNA expression loss in culture. MAb A103 allows the detection of melanoma-associated Melan A/MART-1 protein expression in routine archival tissue and thus enables the profiling of melanomas suited for immunotherapy approaches involving Melan A/MART-1 derived epitopes.
Antibodies, Monoclonal↗
Tyrosinase immunoreactivity in formalin-fixed, paraffin-embedded primary and metastatic melanoma: frequency and distribution.
Monoclonal antibody T311 specifically detects tyrosinase protein expression. Tyrosinase-derived peptides are recognized by CD8+ T-cells and applied in immunotherapy. We examined formalin-fixed paraffin-embedded tissue of 50 melanoma (primary n=31, metastatic n=19) and 41 control cases (junctional, dermal, compound, Spitz, Reed, balloon-cell nevi) by immunochemistry using the alkaline phosphatase-anti-alkaline phosphatase method after antigen retrieval. Staining with mAb T311 showed a sensitivity of 94% for melanoma with a very high specificity for melanocytic cells. Immunopositivity (94% of melanomas overall) correlated inversely with clinical stage: clinical stage I and stage II showed 100%, stage III and stage IV 86% immunoreactivity each. Staining changed from an exclusively homogeneous pattern in early stages to a more heterogeneous pattern in later stages. Melanocytic control tissue like nevi of different subtypes all showed weak to moderate, homogeneous immunoreactivity with polarity towards the epidermis. RT-PCR ELISA analysis of short-term melanoma cell cultures displayed mRNA expression in only half of the originally immunopositive tumors only, suggesting rapid mRNA expression loss in culture. mAb T311 allows detection of melanoma-associated tyrosinase protein expression and thus profiling of melanomas using routine archival tissue suited for immunotherapy approaches involving tyrosinase derived epitopes.
Antibodies, Monoclonal↗
Comparative analysis of histological and immunohistological features in mycosis fungoides and Sézary syndrome.
Mycosis fungoides (MF) and Sézary syndrome (SS) are closely related cutaneous T-cell lymphomas, which differ in several clinical aspects. We compared histological and immunophenotypical features of these two entities, which could be implicated in the dermotropism and epidermotropism, characteristic for both of them. Thirteen biopsy specimens from patients with established plaque-stage MF and 13 from SS patients were examined retrospectively, and 21 histological criteria were assessed. Further, 9 cryosections from MF lesions and 9 from SS lesions were stained for LFA, ICAM1, CD40, CD40-ligand, CD28, CD80, CTLA-4, CD86, FAS, FAS-ligand, CLA and CD15s. The only histological criteria that showed persistent differences were acanthosis (in 12 of 13 SS and in 7 of 13 MF specimens) and Pautrier collections (detected in 6 SS and 11 MF biopsies). Patterns of staining with the antibodies mentioned above were found to be similar. Our results indicate that these interaction molecules seem to be involved in the pathogenesis of MF and SS, but their immunohistochemical distribution does not contribute to the differentiation between the two entities.
Abatacept↗
Pseudo-melanoma after laser therapy.
A 44-year-old woman had several congenital melanocytic nevi that were treated with a CO2 laser. Six weeks after the laser treatment one lesion repigmented and was therefore excised. The initial histological diagnosis of malignant melanoma was revised to 'pseudo-melanoma' after re-evaluation of the history, the clinical presentation and the histology. We conclude that pseudo-melanoma is a complication of laser therapy that has to be recognised in order to avoid unnecessary surgical procedures.
Adult↗
Comparison of 8-MOP aqueous bath and 8-MOP ethanolic lotion (Meladinine) in local PUVA therapy.
BACKGROUND AND OBJECTIVE: Local PUVA (psoralen plus UVA light) is an effective outpatient treatment for patients with palmoplantar eczema or psoriasis. In this study, the efficacy, applicability and patient acceptance of two local forms of 8-methoxypsoralen (8-MOP) PUVA therapy were compared. METHODS: The study design was a left-right comparison (n = 37): the left hand or foot was treated with (aqueous) 8-MOP bath PUVA whereas the right received (ethanolic) 8-MOP lotion PUVA. After 1 month, the more successful treatment was continued on both sides until lesions cleared. RESULTS: Both therapies were effective and both useful for particular clinical applications: patients with erosive lesions and rhagades appreciated the gentleness of bath PUVA. Those with pustules or hyperkeratotic lesions appreciated the greater effectiveness of 8-MOP lotion PUVA. The total UVA dose and number of sessions to clearance were smaller with 8-MOP lotion. There was no difference in the length of the relapse-free period. Therapy nonresponders usually became apparent within the first 12 sessions. CONCLUSIONS: The difference between bath PUVA and lotion PUVA can be described as 'gentle' versus 'strong' therapy. The better therapy depends on clinical indication.
Administration, Cutaneous↗
Treatment of vascular lesions using the VersaPulse variable pulse width frequency doubled neodymium:YAG laser.
BACKGROUND: The flashlamp-pumped dye laser is considered the treatment of choice for vascular lesions including port-wine stains. However, this treatment is associated with an intensive postoperative purpura and considerable pain. OBJECTIVE: We tested a newly developed laser device with a 532-nm neodymium:YAG laser with variable pulse widths between 2 and 10 ms. METHODS: Forty-two consecutive patients from our laser clinics were treated with the new laser system delivering energy through a chilled tip by means of circulating water (cooling temperature was between 4 and 5.5 degreesC). Forty of them had been pre-treated with an argon laser and an argon-pumped dye laser. RESULTS: Out of the 42 patients, 1 patient had a complete clearing, 11 had an excellent result (more than 80% clearing), 21 patients had a good result (51-75% clearing), weak responses were seen in 9 patients. Significant success was already seen after 1 or 2 treatments. Side effects were rare. There was no purpura after treatment. Local anesthesia was only applied in 6 out of 42 patients. CONCLUSION: The variable pulse width frequency doubled neodymium:YAG laser seems to be an alternative to the flashlamp-pumped dye laser and deserves to be investigated in comparative trials.
Adolescent↗
Results of interleukin-2-based treatment in advanced melanoma: a case record-based analysis of 631 patients.
PURPOSE: In patients with stage IV melanoma, durable responses have been reported with treatment regimens that involve high-dose interleukin-2 (IL-2). We analyze long-term results of 631 melanoma patients from 12 institutions who had received IL-2 alone, in combination with interferon alfa 2a or 2b (IFNalpha), or with cytotoxic drugs. METHODS: Case records that contained pretreatment parameters, response data, and updated survival information were collected. After univariate analysis, the multivariate evaluation of the impact of pretreatment parameters on response and survival was performed by logistic regression and Cox's regression, respectively. RESULTS: Patients were divided into four groups according to treatment: IL-2 alone (n=117), IL-2 and chemotherapy (n=49), IL-2 and IFNalpha (n=153), and IL-2, chemotherapy, and IFNalpha (n=312). The median survival of all patients was 10.5 months and the 2- and 5-year survival rates were 19.9% and 10.4%, respectively. Independent prognostic factors for response and survival were entirely different, treatment group being the only significant factor for response, and serum lactate dehydrogenase (LDH), metastatic site, and performance predicting survival. The addition of IFNalpha to IL-2 was associated with prolonged survival, but the effect of additional chemotherapy was less obvious. CONCLUSION: Serum LDH, metastatic site, and performance status are useful stratification factors for randomized trials in metastatic melanoma. The improved long-term survival rates observed in melanoma patients treated with IL-2/IFNalpha-containing regimens are notable in contrast to the reported 5-year survival rates of 2% to 6% achieved with chemotherapy, but because selection bias cannot be ruled out, the impact of IL-2, as well as all other components of the treatment regimens, on survival needs to be confirmed in prospective randomized trials.
Adult↗
Sézary syndrome, T-helper 2 cytokines and accessory factor-1 (AF-1).
Mycosis fungoides and the Sézary Syndrome are characterized by clonal accumulation of well differentiated T-helper memory cells in the skin and, in the case of the Sézary Syndrome, also in the blood and lymph nodes. Well known immunological abnormalities in patients with MF and SS include reduced delayed type hypersensitivity, decreased proliferation upon stimulation with mitogens of the peripheral blood mononuclear cells, elevated IgE or IgA serum levels and eosinophilia. These abnormalities can be explained by the predominance of T-helper 2 cytokines. Clonal T-lymphocytes purified from the peripheral blood of SS patients transcribe mainly IL-10 and IL-5. They can be CD7 positive or negative. These clonal T cells express the accessory factor-1 (AF-1) or Interferon gamma receptor beta-chain that is essential for Interferon gamma signalling. These results imply perspectives for new therapeutical approaches, such as IL-12 or chimeric fusion proteins.
Humans↗
[Therapy of cutaneous melanoma].
Therapy of melanoma considers the individual prognosis. Primary low-risk melanomas with tumor-thickness below 1 mm can be treated by surgery with a safety margin of 1 cm. If the tumor-thickness is more than 2 mm the safety margin should be 3 cm. Elective lymph node dissection for melanomas at the extremities is widely substituted by the sentinel lymph node procedure. This new technique shall be applied only in specialised centers in the context of clinical trials. After the resection of lymph node metastases adjuvant treatment using Interferon-alpha should be considered. Palliative therapy of metastases includes surgery, radiotherapy and chemo-immunotherapy depending on the number and location of the metastases. Recent progress in understanding the immunobiology of melanoma and the development of gene therapy has offered new perspectives for future therapeutical intervention including peptide vaccination alone or loaded on dendritic cells and gene therapy.
Antineoplastic Agents↗
[Cutaneous lymphomas. Quality Assurance Committee of the German Society of Dermatology and the Professional Organization of German Dermatologists e. V].
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Germany↗
Prognostic value of serum 5-S-cysteinyldopa for monitoring human metastatic melanoma during immunochemotherapy.
The melanin metabolite 5-S-cysteinyldopa (5-S-CD) has been reported to be helpful in detecting occult melanoma metastases and as a prognostic marker in B16 melanoma-bearing mice. The goal of our study was to analyze the significance of the serum 5-S-CD level for the biochemical detection of metastases in human malignant melanoma (MM) and for monitoring the progression or the immunochemotherapeutically induced regression of MM. From 11 patients with metastatic MM observed between 1991 and 1995, serum samples were collected before and after each cycle of immunotherapy or immunochemotherapy. Samples were analyzed for 5-S-CD by automated high performance liquid chromatography with electrochemical detection. Cycles of immunochemotherapy consisted of human interleukin 2 and IFN-alpha (four patients) or of human interleukin 2, IFN-alpha, and dacarbazine (seven patients). Serum value of 5-S-CD in our normal controls was 1.9 +/- 0.6 ng/ml. All patients with metastatic MM showed 5-S-CD serum levels above the upper normal limit of 3.2 ng/ml (10 nM) and ranged from 2.3-fold (4.3 +/- 3.9 ng/ml) of the normal control values in early stages of metastases to more than 50-fold (94.3 +/- 220.3 ng/ml) of the normal control values in advanced stages of the disease. In 28 of 41 (68%) immunochemotherapeutical cycles, a decrease of 5-S-CD was seen during therapy, and in 13 cycles (31.7%), an increase was seen. Patients with more than 68% decreasing cycles (defined as responders; n = 5) showed significantly longer survival times (P = 0.008) than patients with less than 68% decreasing cycles (nonresponders; n = 6). High levels of 5-S-CD were also observed in metastasizing amelanotic melanoma. Serum 5-S-CD is a useful marker for monitoring the clinical course of MM patients, for discriminating between responders and nonresponders to immunochemotherapy, and as a prognostic factor concerning survival time and death risk.
Adult↗
Interleukin-10 is a growth factor for human melanoma cells and down-regulates HLA class-I, HLA class-II and ICAM-1 molecules.
IL-10 is a cytokine which shows various effects including inhibition of T-cell proliferation or HLA-dependent antigen presentation. In this study, we analysed the effects of exogenous or autocrine IL-10 on proliferation and expression of immunocritical surface molecules. Fourteen cultures of human melanoma cells were established from primary melanomas, locoregional lymph-node or distant metastases. In 5 melanoma cell cultures, proliferation in the presence of IL-10, anti-IL-10 antibodies (Ab) or control Ab was assessed with colorimetric and [3H]thymidine uptake assays. Flow cytometric analysis was used to quantify the expression of human leukocyte antigen (HLA) class-I, HLA class-II and intercellular adhesion molecule (ICAM)-1 and the IL-10 receptor (IL-10R). IL-10 production of melanoma cells was documented by RT-PCR and IL-10 protein was detected in the supernatants by means of ELISA. IL-10 enhanced proliferation and prolonged survival of melanoma cells in 5 out of 5 cultures. Anti-IL-10 Ab decreased proliferation. IL-10R expression was found in 12 out of 14 (86%) melanoma cell cultures. The expression of HLA-I, HLA-II and ICAM-1 on all melanoma cells that were positive for IL-10R showed a reduction of 10-60% by IL-10, whereas the surface levels of HLA-I, HLA-II and ICAM-1 in 5 out of 5 cell cultures revealed an increase of 10-170% by anti-IL-10 Ab. These findings suggest that IL-10 is an autocrine growth factor with significant impact on immunocritical molecules in melanoma. IL-10 effects have to be considered when planning therapeutic immunointerventions in melanoma patients.
Antibodies, Monoclonal↗