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R Dummer

Publications and source records attributed to R Dummer.

At least 145 records · Page 8Linked to original sources
PubMed1996

Sézary syndrome T-cell clones display T-helper 2 cytokines and express the accessory factor-1 (interferon-gamma receptor beta-chain).

Sézary syndrome (SS) is a leukemic variant of low-grade cutaneous T-cell lymphomas (CTCLs). The clonal T cells in this lymphoproliferative disorder are poorly characterized. Using antibodies against the variable region of the T-cell receptor (TCR V alpha/beta), we identified four predominant T-cell clones (two V beta 8+ clones, one V beta 5.1+, and one V alpha 2(a)+) in peripheral blood mononuclear cells (PBMC) of SS patients. Their phenotype was CD3+, CD4+, CD5+, CD45RO+. Clonal T cells were purified, and cytokine transcription and secretion was analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR) followed by hybridization with biotinylated probes and enzyme-linked immunosorbent assays (ELISAs). The interleukin-10 (IL-10) PCR product was cloned and sequenced and found to be identical to the published cDNA sequence. The presence of accessory factor-1 (AF-1, or interferon-gamma [IFN-gamma] receptor beta-chain) encoding mRNA was assessed by RT-PCR and immunostaining using serum of rabbits immunized with the extracellular domain of a recombinant human AF-1 protein followed by APAAP staining. Clonal T cells transcribe and secrete mainly T-helper 2 cytokines (IL-10, -5, and -13). mRNA from purified SS clones but not mRNA from SS total PBMC was positive for AF-1 in an agarose gel and/or after hybridization. AF-1 transcription was associated with membrane-bound immunoreactivity for AF-1 in SS clones. SS-derived T-cell clones display T-helper 2 cytokines. This weakens cell-mediated immunosurveillance, and explains the clinical and immunologic abnormalities in SS patients. The T-helper 2 cytokine spectrum of all clones investigated is associated with overexpression of AF-1. This suggests that AF-1 is a potential marker for these clones (and eventually other T-helper 2 lymphocytes) and might represent a target for treatment of the disease.

Base Sequence↗
PubMed1996

Farnesyltransferase activity and mRNA expression in human skin basal cell carcinomas.

Ras oncogene encode a protein p2l which in its mutated form transforms mammalian cells only after membrane anchoring by a series of enzymatic reactions where the initial step is catalyzed by farnesyltransferase (FTase). For this reason, FTase has become an attractive target for the development of novel anticancer agents. Virtually nothing is known about FTase activity and the association between the expression of its alpha and beta subunit genes with respect to the processing of Ras p21 in human cancers. In this study, we found that compared to normal skin, FTase activity and levels of both cytosolic and membrane-bound Ha-Ras p21 were significantly higher in human skin basal cell carcinomas (BCCs). In addition, the expression of both alpha and beta subunit genes was significantly higher in BCCs than the normal skin. These results suggest an association between enhanced FTase activity and the processing of overexpressed Ras p21 in such tumor type. This may have a bearing on the pathogenesis of activated Ras oncogene containing human malignancies.

Alkyl and Aryl Transferases↗
PubMed1996

Incidence and in-vivo relevance of anti-interferon antibodies during treatment of low-grade cutaneous T-cell lymphomas with interferon alpha-2a combined with acitretin or PUVA.

Interferon-alpha combined with retinoid or PUVA is used for the treatment of cutaneous T-cell lymphoma. Anti-IFN-alpha antibodies (IFN ab) occur regularly during IFN-alpha treatment. We investigated the incidence of neutralizing and binding IFN ab and analysed their relationship with clinical and immunological parameters. A group of 17 CTCL patients were treated with IFN alpha-2a three times weekly subcutaneously at a dose of 3 Mill. I.U. combined either with retinoid (acitretin, Neotigason; 0.5 mg/kg bodyweight) daily or with 5-methoxypsoralen (1.2 mg/kg bodyweight) plus UVA radiation three times weekly. Prior to and during treatment we monitored stage, skin involvement by a tumour burden index, serum levels of beta 2-microglobulin, neopterin, binding and neutralizing IFN ab, Interleukin-6 (IL-6), soluble IL-2 receptors (sIL-2r) and the CD4/CD8 ratio of peripheral blood mononuclear cells. We observed two complete, two partial and six minor responses, four patients with stable disease and three patients with progressive disease. Of the 17 patients, 7 developed binding IFN ab, but only 2 had neutralizing IFN ab which were associated with high titres of binding IFN ab. IFN ab formation was more frequent in patients with normal CD4/CD8 ratios and a high tumour burden index and showed a trend to be more frequent in PUVA-cotreated patients than in retinoid-cotreated patients. Responses were more frequently seen in IFN ab-negative patients. IFN ab developed in patients treated with PUVA or retinoid combined with IFN. Binding as well as neutralizing IFN ab may have an impact on the treatment success in CTCL patients.

Acitretin↗
PubMed1996

Detection of elevated levels of IL-4, IL-6, and IL-10 in blister fluid of bullous pemphigoid.

Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease with autoantibodies directed against antigens associated with hemidesmosomes of basal keratinocytes. In addition to autoantibodies and activated complement, cellular mechanisms are crucial for blister formation in this disease. Mononuclear cells, which are the first cells infiltrating BP lesions, mainly belong to CD3, CD4+ T-helper (Th) cells. Elevated concentrations of IL-2, IFN gamma, TNF beta, and IL-5 have been recently demonstrated in BP blister fluid. In this study, we were interested in levels of other Th-type cytokines, including IL-3, IL-4, IL-6, IL-10, and GM-CSF in blister fluid of BP. Cytokines were determined by ELISA or bioassay. Levels in the blister fluid from ten BP patients were compared with those in serum samples taken at the time of blister puncture and with those in suction blister fluid of ten healthy volunteers. In blister fluid of BP, we found significantly elevated concentrations of IL-4, IL-6, and IL-10 relative to both concurrent serum samples and suction blister fluid from controls. No differences were detected for either IL-3 or GM-CSF. Our results suggest that IL-4, IL-6, and IL-10 are released at the site of blister formation in BP.

Adolescent↗
PubMed1996

Detection of IL-1 alpha, IL-1 beta and IL-1 receptor antagonist in blister fluid of bullous pemphigoid.

Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease. In addition to autoantibodies, complement activation and inflammatory cells are necessary for lesion formation. In this study, we investigated the potential involvement of IL-1, secreted by various inflammatory and non-inflammatory cells, in BP lesions. We determined IL-1 alpha IL-1 beta and IL-1 receptor antagonist in both blister fluid and concurrent serum samples of 10 BP patients by ELISAs. For comparison, we assayed experimentally generated suction blisters from 10 healthy volunteers. IL-1 beta levels were significantly elevated in BP blisters, whereas levels of IL-1 alpha were decreased relative to those in controls. In concurrent serum samples, no IL-1 alpha or IL-1 beta were detected in patients or controls. Levels of IL-1 receptor antagonist were significantly higher in BP blisters in relation to both concurrent sera and suction blisters. Our data indicate the release of IL-1 beta, IL-1 receptor antagonist, and to a lesser extent, of IL-1 alpha, at the site of blister formation in BP and support the notion that cell-mediated immune mechanisms may contribute to blister formation in this disease.

Aged↗
PubMed1996

MIB-1 immunoreactivity correlates with metastatic dissemination in primary thick cutaneous melanoma.

BACKGROUND: The proliferation rate of transformed cells is a putative prognostic indicator. MIB-1 is a murine monoclonal antibody to a Ki-67 epitope that detects a nuclear antigen found only in proliferating cells. OBJECTIVE: The aim of this study was to test for a correlation between MIB-1 immunoreactivity and the metastatic potential of malignant melanoma. METHODS: MIB-1 reactivity (% total tumor nuclei) was assessed in 34 formalin-fixed, paraffin-embedded primary cutaneous melanomas and correlated with metastatic potential and overall survival (follow-up, 10.5 +/- 1.8 years). RESULTS: Whereas no correlation was found between MIB-1 reactivity and metastases in primary thin cutaneous melanoma (Breslow thickness, < 0.75 mm; mean thickness, 0.39 +/- 0.16 mm), good correlation was found (p = 0.0001) in primary thick cutaneous melanoma (Breslow thickness, > 1.5 mm; mean thickness, 3.0 +/- 1.3 mm). MIB-1 reactivity was 12.3% +/- 7.7% and 0.7% +/- 1.3% with and without metastases, respectively, and was highest in the primary melanomas that later metastasized. However, overall survival in patients with thick cutaneous melanoma and metastases did not correlate with MIB-1 reactivity. CONCLUSION: MIB-1 proliferative activity is a useful prognostic indicator in primary cutaneous melanomas thicker than 1.5 mm and may predict the development of metastases.

Antibodies, Monoclonal↗
PubMed1996

Circulating interleukin-2 receptors are a group of multimeric proteins with immunoreactivity for interleukin-2 receptor alpha, beta, and gamma chains.

Soluble interleukin-2 receptor (sIL-2R) alpha chain serum levels as determined by enzyme-linked immunosorbant assay (ELISA) are commonly used to monitor various inflammatory and neoplastic disorders associated with lymphocytic proliferation and activation. The in vivo structure of this soluble receptor species, however, is not characterized. We investigated sera with elevated sIL-2R serum levels of patients with histologically proven cutaneous T cell lymphoma (CTCL) and high-dose IL-2-treated melanoma patients and healthy donors. Purified recombinant IL-2R alpha and beta chain molecules, produced by transfection of NIH/3T3 fibroblasts and CHO cells, served as positive controls for purification and detection procedures. For selective enrichment of IL-2R molecules from supernatants and sera, affinity columns were prepared by coupling recombinant IL-2 or monoclonal antibodies against the alpha and the beta chain of the IL-2R complex to cyanogen bromide-activated Sepharose. Western blotting with affinity-purified fractions under reducing and nonreducing conditions revealed proteins that showed immunoreactivity for IL-2R alpha, beta, and gamma chain using several detection antibodies against these molecules. We conclude that the composition of sIL-2R in vivo is more complex than that of recombinant sIL-2R and can include all three IL-2R chains.

Antineoplastic Agents↗
PubMed1996

Malignant blue naevus with distant subcutaneous metastasis.

Malignant blue naevus is a distinct but rarely documented variant of malignant melanoma, and we describe the triple recurrence of a suprapatellar cellular blue naevus over 12 years in a middle-aged woman. Staging investigations revealed a distant subcutaneous metastasis of the right thigh. Immunohistochemistry of the primary lesion and all recurrences showed S-100, HMB-45, NKI/C-3 and Ki-67 positive cells. However, non-malignant cellular blue naevi from five consecutive other patients were all Ki-67 negative. The change from negative to positive Ki-67 responsivity may therefore be a valuable marker of malignant and metastatic potential in early cellular blue naevi.

Female↗
PubMed1996

T-cell receptor beta variable region (V beta) usage in cutaneous T-cell lymphomas (CTCL) in comparison to normal and eczematous skin.

Cutaneous T-cell lymphomas (CTCL) are a heterogeneous group of lymphoproliferative disorders. We investigated the variable region (V beta) of the T-cell receptor (TCR) repertoire in CTCL and compared it to the V beta repertoire in normal and eczematous skin. We used a panel of 21 anti-V beta antibodies and investigated 84 biopsies of 71 CTCL patients (4 parapsoriasis en grandes plaques (PA), 1 lymphomatoid papulosis, 29 mycosis fungoides (MF), 13 Sezary syndrome (SS), 1 CD8+ CTCL, 11 pleomorphic CTCL (PLEO), 12 CTCL nor classified). Six biopsies of normal skin and 6 of eczematous skin lesions served as controls. We determined the frequency of the V beta in normal and inflamed skin and compared it to the percentage of the respective V beta in the malignant clone of the CTCL patients. The percentage of the V beta positive CD4+ cells in relation to the total number of T cells in normal skin and inflamed skin differed from the distribution of the V beta families in the peripheral blood mononuclear cells (PBMC). Out of 71 CTCL cases, the clone was identified in 23 (32%). We identified the following clones: 1 V beta 3.1 (16MF), 7 V beta 5.1 (1 CD8+ CTCL, 1 CTCL not classified, 1 MF, 1 PA, 3 SS), 1 V beta 6.7 (1 SS), 7 V beta 8.1/8.2 (2 CTCL not classified, 1 PLEO, 2 MF, 2 SS), 1 V beta 12.1 (1 PLEO), 3 V beta 17.1 (2 CTCL not classified, 1 MF), 2 V beta 22.1 (1 CTCL not classified, 1 MF), 1 TCR delta (SS). The frequency of the malignant clone V beta usage corresponded well to the repertoire of V beta in eczematous skin but not to the repertoire in PBMC. In 6 patients, the malignant clone was mainly localized in the epidermis. In 17 cases, the clone-specific cells were distributed in epidermis and dermis equally. A retrospective analysis showed that preferential epidermal homing of the clone was associated with a non-aggressive clinical course. The V beta usage of CTCL and eczema suggests a special cutaneous microenvironment which might be co-created by certain (bacterial?) superantigens. A preferential epidermal homing of the clone might have prognostic implications.

Adolescent↗
PubMed1996

Lack of expression of dopamine D2 receptors in malignant melanoma: evidence for interaction of iodobenzofurans with melanin.

OBJECTIVES: (1) To compare scintigraphy using the new dopamine D2 receptor binding radioligand iodobenzofuran (IBF) versus whole-body positron emission tomography (PET) in demonstrating metastasizing melanoma, and (2) to determine, for the first time using a panel of histochemical techniques, whether the ability of D2 receptor binding radioligands to detect melanoma metastases is due to tumor-expressed D2 receptors. METHODS: Seven patients with metastatic melanoma were examined using 123I-IBF scintigraphy. Findings were compared to the results of PET and metastasis histochemistry: D2 receptor mRNA assay (metastases: n = 5; melanoma cell lines: n = 4) using the reverse transcriptase polymerase chain reaction (RT-PCR) versus D2 receptor-transfected Chinese hamster ovary cell controls: in vitro 125I-IBF binding (n = 19), and immunohistochemical staining for dopamine D2 receptor protein (n = 19). RESULTS: IBF scintigraphy detected 2/10 melanoma metastases detected by PET (sensitivity 20%). No dopamine D2 receptor mRNA was found in melanoma cells using RT-PCR. The binding of 125I-IBF correlated with the amount of melanin present in the metastases; two amelanotic melanomas both failed to bind 125I-IBF. Immunohistochemical staining was negative in all metastases. CONCLUSION: Melanoma cells do not appear to express dopamine D2 receptors. Although IBF had high dopamine D2 receptor affinity, its ability to detect melanoma metastases is more likely explained by low affinity binding to melanin than by the presence of dopamine receptors.

Adult↗
PubMed1996

A primary cutaneous non-T, non-B CD4+, CD56+ lymphoma.

BACKGROUND: Cutaneous lymphomas are heterogeneous clonal lymphoproliferative disorders originating from B or T lymphocytes. OBSERVATION: We describe a patient with a unique primary cutaneous lymphoma characterized by a bruise-like aspect of the skin lesions, a CD4+, CD43+, CD56+, CD2-, CD3-, CD8-, T-cell receptor-negative phenotype of the medium-sized to large lymphoid tumor cells and an undetermined genotype (T-cell receptor beta and immunoglobulin heavy chain in germline configuration, no clonal T-cell receptor gamma population as detected after analysis with polymerase chain reaction combined with denaturing gradient gel electrophoresis) and fast relapse after radiotherapy. CONCLUSIONS: This non-B, non-T cutaneous lymphoma cannot be classified by any current lymphoma classification. It seems to represent a new disease entity with peculiar clinical, histologic, and molecular features.

Antigens, Neoplasm↗
PubMed1995

[Are skin tumors on the increase?].

The skin is the most common site of malignancy. Epithelial tumors, i.e., basalioma and squamous-cell carcinoma, are among the most frequent skin tumors but have a good prognosis if detected early. Prognosis of metastatic melanoma however is bad. Due to increased UV-exposure the frequency of all three tumors has much increased in recent years. Cutaneous lymphomas and kaposi sarcoma are rare skin tumors. The latter is nowadays of increased interest because of its association with HIV infection. An overview of the current epidemiologic data on malignant skin tumors is presented.

Basal Cell Carcinoma↗
PubMed1995

[How do melanoma cells circumvent the immune response? Consequences for future therapy attempts and current biopsy processing].

Malignant melanoma can be recognized by the immune system via HLA-associated tumor-associated antigens. Nevertheless, melanoma cells circumvent immune response in most cases. The mechanisms which may be responsible are defects in the expression of HLA-class I molecules, release of soluble adhesion molecules, and secretion of immunosuppressive cytokines such as interleukin-10. Using modern techniques the individual melanoma cells can be cultured and characterized by immunological and molecular biological methods. An exact characterization of the individual tumors will result in specific immunotherapy for the individual patient.

Antigens, Neoplasm↗
PubMed1995

A multicenter phase II clinical trial using dacarbazine and continuous infusion interleukin-2 for metastatic melanoma. Clinical data and immunomonitoring.

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/m2 by a 30-minute slow infusion, and interleukin-2 by constant intravenous infusion (Days 21-25 and 28-32) at 18 x 10(6) IU/m2/24 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+), and median survival was 19.0 months (6.3-39.0+); overall survival was 9.3 months (0.8-39.0+). 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.

Adult↗
PubMed1995

New perspectives in experimental and clinical research for cutaneous T cell lymphomas.

Cutaneous T cell lymphomas (CTCL) are lymphoproliferative disorders, which can be classified by an adaptation of the Kiel classification. The most common CTCL, Mycosis fungoides (MF) and Sézary syndrome (SS), are monoclonal T helper memory lymphomas. They belong to the group of peripheral T cell lymphomas. However, CTCL includes other disease entities such as granulomatous slack skin, pagetoid reticulosis, and lipotropic CTCL. Polymerase chain reaction of the T cell receptor (TCR)-gamma and screening of the PCR products for sequence-specific mobility in acrylamide gels has increased the detection limit for clonal T cells in the skin. This method will help to define the relationship of CTCL to other lymphoproliferative disorders and may contribute to the early diagnosis of CTCL. In SS, the malignant CTCL clone secretes a T helper-2 cytokine pattern, which might be responsible for the systemic immunosuppression in CTCL patients. New treatment modalities (IL-12) might correct these immunologic abnormalities. Cutaneous B cell lymphomas mostly are follicular center cell derived and usually have a good prognosis. Therapy of cutaneous lymphomas should take into account prognostic factors, the most reliable of which in CTCL is the tumor mass expressed by the tumor burden index.

Cytokines↗
PubMed1995

[Strategies for gene therapy of melanoma].

Active unspecific immunotherapy in an adjuvant or palliative setting has been shown to enhance survival in melanoma patients, and gene therapy now offers new perspectives for active specific immunotherapy. Gene therapy includes the transfer of genetic material performed by either viral or non-viral methods and in vivo or ex vivo. For melanoma the following approaches are suggested: vaccination with tumour-specific, HLA-associated antigens using peptides or 'naked DNA', vaccination with melanoma cells transfected with cytokine genes or B7, adoptive immunotherapy with specific T-lymphocytes or transfected tumour-infiltrating lymphocytes, or transfection of tumour cells with a tumour suppressor gene whose dysfunction plays a crucial role in melanoma.

Cytokines↗