Search Results - (Author, Cooperation:R. Dummer)

2013-01-11

Nature Publishing Group (NPG)

0028-0836

1476-4687

Biology

Chemistry and Pharmacology

Medicine

Natural Sciences in General

Physics

Animals ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Disease Models, Animal ; Drug Administration Schedule ; Drug Resistance, Neoplasm/*drug effects ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Humans ; Indoles/*administration & dosage/*adverse effects/pharmacology ; MAP Kinase Signaling System/drug effects ; Melanoma/*drug therapy/genetics/*pathology ; Mice ; Mitogen-Activated Protein Kinase Kinases/metabolism ; Mutation ; Neoplasm Transplantation ; Proto-Oncogene Proteins B-raf/chemistry/genetics/metabolism ; Subcutaneous Tissue ; Sulfonamides/*administration & dosage/*adverse effects/pharmacology ; Time Factors ; Xenograft Model Antitumor Assays

2015-09-12

American Association for the Advancement of Science (AAAS)

0036-8075

1095-9203

Biology

Chemistry and Pharmacology

Computer Science

Medicine

Natural Sciences in General

Physics

Adult ; Aged ; Aged, 80 and over ; Antibodies, Monoclonal/*pharmacology/therapeutic use ; Antigens, Neoplasm/*genetics ; *Biomarkers, Pharmacological ; CTLA-4 Antigen/*antagonists & inhibitors ; Cell Cycle Checkpoints/genetics/immunology ; Cohort Studies ; DNA Mutational Analysis ; Drug Resistance, Neoplasm/genetics ; Exome ; Female ; Genomics ; HLA Antigens/genetics ; Humans ; Male ; Melanoma/*drug therapy/*genetics/secondary ; Middle Aged ; Mutation ; Skin Neoplasms/*drug therapy/*genetics/pathology ; Tumor Microenvironment/drug effects/immunology ; Young Adult

2018-08-09

American Association for the Advancement of Science (AAAS)

2375-2548

Natural Sciences in General

1365-2230

Blackwell Publishing Journal Backfiles 1879-2005

Medicine

Analyses of the karyotype and genome of cutancous T-cell lymphoma (CTCL) cells have shown that they contain chromosome breaks and translocations. The sequence analyses of such DNA breakpoints found in various kinds of leukaemias have suggested chat some of the observed translocations have been caused by illegitimate V(D)J (v = Variability; D = diversity; J = joining) recombination. To study whether illegitimate Y(D)J recombination is responsible for the continuously increasing number of DNA breaks in CTCL, we used reverse transcriptase polymerase chain reaction (RT-PCR) to analyse three CTCL cell lines and biopsies from 14 CTCI. patients for the expression of the RAG-1 and RAG-2 genes which are essential for V(D)J recombination, We found no RAG gene expression in any of the 17 samples analysed, indicating that illegitimate V(D)J recombination may not be the reason for the increased number of chromosomal aberrations and trans-locations in CTCL cells.

Electronic Resource

1365-2133

Blackwell Publishing Journal Backfiles 1879-2005

Medicine

Electronic Resource

1365-2133

Blackwell Publishing Journal Backfiles 1879-2005

Medicine

Electronic Resource

1365-3083

Blackwell Publishing Journal Backfiles 1879-2005

Medicine

Non-specific antibody production usually accompanies the T-cell-regulated B-cell response. In this papaer the Machanisms involved in non-MHC-restricted T-cell interaction were studied. As previously shown for NK cells, activated B cells induce IFN-α and TNFα production in non MHC-restricted cytotoxic T lymphocytes (NrCTL). Using an in vitro model system, we demonstrate that direct cell cell interactions are required to induce these cytokines in NrCTL. Receptor ligand systems involed are leucocyte function antigen-1/intercellular adhesion molecule-1 (LFA-1/ICAM-1)(CDlla, CD18/CDM).Tn/LFA-3(CD2, CD58), andtheclonoty-pic T-cell receptor (TCR) strueture NKTa of JT9/JTI0 with ils no!i-MHC-related target antigen TNKtar(4F2), Cytokine produclion can be induced by activating motiockmahmtibodics against CD2R, Antibodies againsi the elonotypic TCR (NKTa) or CD3 had no cylokine-iiiduciiig effect on NrCTL cullured alone, but were able to retrieve the effect of blocking the target antigen on co-cuhured B eells. We eould lurther demonstrate that the inhibition of the TCR/targel antigen interaction eould be overcome by elose cell cell contae! culture conditions. From these findings il i s concluded that the role of the TCR in non-MHC-reslricted cell cell interaction is to facilitate LFA-l. lCAM-1-mediated elfectorlarget adhesion in a specific way rather than lo mediate direct activating signals upon lymphokine produclion or cytoxicity.

Electronic Resource

1365-2230

Blackwell Publishing Journal Backfiles 1879-2005

Medicine

Basal cell carcinoma (BCC) of the skin represents the most common malignancy in the fair-skinned population worldwide. HLA-G is one of the molecules implicated in immunotolerance. To investigate the role of HLA-G in recurring BCCs, we constructed a tissue microarray containing 38 primary BCCs that underwent radiotherapy and 14 secondary BCCs recurring on the primary site after radiotherapy, and evaluated the HLA-G protein expression by immunohistochemistry. The HLA-G protein was most frequently expressed in aggressive sclerosing BCCs. Nodular BCC demonstrated the strongest HLA-G expression. Interestingly, tumor infiltrating mononuclear cells (TIMC) expressed the HLA-G molecule in BCCs that showed no recurrence. After comparing primary BCCs and BCCs relapsed after radiotherapy, we observed decreased HLA-G expression on tumor cells and the loss of HLA-G expression on TIMC in relapsed BCCs. After radiotherapy, immunobiology of BCC may change resulting in the down-regulation of HLA-G expression on tumor and on tumor-infiltrating cells.

Electronic Resource

1600-0560

Blackwell Publishing Journal Backfiles 1879-2005

Medicine

Mycosis fungoides (MF) and Sezary syndrome (SS) are closely related cutaneous T-cell lymphotmas, 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 CD 15s. 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.

Electronic Resource

1600-0625

Blackwell Publishing Journal Backfiles 1879-2005

Medicine

Abstract The practical value of the detection of clonality within the T-cell receptor gamma locus by polymerase chain reaction for the diagnosis of cutaneous T-cell lymphomas is well known. However, studies dealing with this subject so far, with special emphasis on the sensitivity of the technique in comparison to, for example, Southern blotting have used mixtures of DNA in various concentrations instead of using mixtures of the cells involved, which would reflect the in vivo situation in a more realistic scope. The purpose of this study was therefore to determine the sensitivity and the limitations of the PCR assay by dilution experiments, using mixtures of cells. Furthermore we studied its applicability to cutaneous T-cell proliferative disorders. Two clonal T-cell lines (MyLa and Jurkat) served as positive control. Dilutions of MyLa cells, cultured normal human keratinocytes and peripheral blood mononuclear cells from lymphoma negative volunteers were used to assess the sensitivity of the PCR-DGGE assay. Skin samples from 4 patients with cutaneous T-cell lymphoma, 1 lesional lymph node, 2 blood samples from a patient with Sézary syndrome and 4 lymphoma-negative tissue samples were analysed. Two samples were uncertain for diagnosis of lymphoma. The PCR-DGGE assay consisted of a 2-round nested PCR with consensus primers within the TCR-gamma locus followed by electrophoretic separation of the product along a denaturing urea/formamide gradient gel. PCR-DGGE sensitivity was, to our knowledge, for the first time investigated for mixtures of lymphocytes (clonal and polyclonal) and keratinocytes. Clonal T-cells were detected in a concentration between 1–0.1% in keratinocytes, whereas the sensitivity was generally lower upon dilution in peripheral blood mononuclear cells or in a mixture of keratinocytes and peripheral blood mononuclear cells. Nevertheless, T-cell clonality was detected in 2 blood samples of a patient with Sézary syndrome, which were negative by Southern blot analysis. The crucial point of this work was the new approach to establish the sensitivity of the PCR-DGGE, in a way which more closely mimics the condition of clinical specimens. Instead of mixing and amplifying DNA extracted from clonal T-cell lines and polyclonal bone marrow cells, we amplified DNA from clonal and polyclonal cells which had been mixed in various ratios before DNA extraction. Polymerase chain reaction in conjunction with denaturing gradient gel electrophoresis is a sensitive and versatile molecular tool for the assessment of clonality of suspect cutaneous lesions. The determination of sensitivity using DNA extracted from premixed cells more closely corresponds to the actual test situation when testing skin samples.

Electronic Resource

1600-0560

Blackwell Publishing Journal Backfiles 1879-2005

Medicine

Purpose: Commercially available polyclonal antibodies against a mixture of bovine brain S100 proteins have become an established marker for immunohistochemical characterization of malignant melanoma. However, the commercially available antibodies used are undefined and to date, 13 different human S100 proteins are known. The purpose of this study was to examine the expression of 4 newly available polyclonal antibodies against the human recombinant Ca2+-binding S100 proteins, S100A1, S100A2, S100A4 and S100A6, in cutaneous melanoma and to correlate these findings with the standard S100 staining as well as with the metastatic potential of the primary. Methods: 39 formalin-fixed paraffin-embedded primary cutaneous melanomas were incubated with polyclonal antibodies against recombinant human S100 proteins using the APAAP method. The extent of staining was qualitatively assessed and a staining index was calculated. Findings were correlated to the metastatic potential and the overall survival in all patients. Results: Staining with antibodies against human S100A6 as well as with antibodies against conventional bovine S100 proteins was positive in all specimens. No correlation was found between the extent of protein expression and patients' outcome for standard S100 staining as well as for S100A6. S100A1, S100A2 and S100A4 stainings could not be used for statistical analysis due to their low expression in melanoma. Conclusion: Staining was positive using S100A6 antibodies in all specimens, the quality being inferior to the commercially available SI00 antibody. Highly specific and well characterized antibodies against the individual S100 proteins are now available for future immunohistochemical characterization studies in melanomas.Böni R, Heizmann CW, Dogouglu A, Ilg EC, Schäfer BW, Dummer R, Burg G. Ca+2-binding proteins S100A6 and S100B in primary cutaneous melanoma.

Electronic Resource

1365-2133

Blackwell Publishing Journal Backfiles 1879-2005

Medicine

Summary T-zone lymphoma (TZL) is a rare subtype of nodal peripheral T-cell lymphoma characterized by a clonal expansion of T-zone lymphocytes accompanied by a proliferation of other T-zone constituents. Non-specific cutaneous alterations are seen in about one-third of all cases, but specific cutaneous involvement is extremely rare. We present a case of TZL with secondary skin infiltration, review the literature on cutaneous manifestations of TZL and discuss the differential diagnosis of TZL.

Electronic Resource

1365-2133

Blackwell Publishing Journal Backfiles 1879-2005

Medicine

Electronic Resource

1365-2133

Blackwell Publishing Journal Backfiles 1879-2005

Medicine

Tyrosine is a precursor of melanin synthesis and might thus present a valuable marker for melanoma. The aim of this study was to evaluate the uptake of alpha-methyl-tyrosine(AMT) in melanoma cell cultures and to assess its usefulness as a radiopharmaceutical for staging melanoma patients with whole-body scintigraphy. Melanoma (M19-cell lines) and fibroblast (negative control) cell cultures were incubated with125I-AMT and the radioactive uptake in the cell lines was measured in a gamma-counter over 24h. For in vivo studies, planar whole-body scintigraphy and single photon emission computed tomography (SPECT) of the tumour region was performed following injection of 250–350 MBq123I-AMT in six patients with known melanoma metastases. Findings were compared with results of whole-body positron emission tomography using 18F-fluorodeoxyglucose (FDG-PET) as a standard of reference. Fibroblasts showed an unchanged uptake of (mean±SD)0.56±0.09% 15min and 0.066±0.09% 24h, respectively, after incubation of 125I-AMT, whereas there was an increased uptake in melanoma cell cultures over time from 0.9±0.05% to 7.5±1.6%. In staging melanoma patients, the sensitivity of whole-body AMT-scintigraphy compared with FDG-PET was 37%(10 of 27 metastases). AMT is transported and metabolized to a high extent in melanoma cells and 123I-AMT is accumulated in melanoma metastases. Owing to its low sensitivity, however, the clinical use of whole-body AMT scintigraphy cannot be recommended.

Electronic Resource

1365-2230

Blackwell Publishing Journal Backfiles 1879-2005

Medicine

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, NK1/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.

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1365-2133

Blackwell Publishing Journal Backfiles 1879-2005

Medicine

An 81-year-old man presented with a generalized maculopapular rush, lymphadenopathy, conjunctivitis and arthritis. Vasculitis was confirmed by skin biopsy and by direct immunofluorescence, which showed perivascular C3 and granular IgM accumulauon. Histology of an inguinal lymph node was diagnostic for angioimmunoblastic lymphadenopalhy with dysproteinaemia (AILD), and this was confirmed by the finding of hypergammaglobulinaemia and elevated IgE levels. Immuno-histology on a lymph node biopsy showcd a T-helper cell (CD4) intiltrale expressing the intcrleukin (ILJ-2 receptor alpha and beta chains. While recciving prednisone 100mg/day, the patient developed new lesions. mimicking a relapse of vasculitis, which were subsequently shown to be necrotizing herpes zoster. Serum IL-2 and IL-6 levels were elevated. To our knowledge, this is the tirsl report of simultaneouselevation of IL-2 and IL-6 in AILD: IL-2 may be involved in proliferation of the malignant cell clone. and IL-6 in the pathogenesis of both the vasculitis (via endothelial cell activations and the hypergammaglobulinaemia.

Electronic Resource

1365-2133

Blackwell Publishing Journal Backfiles 1879-2005

Medicine

Summary Metastatic melanoma was staged in l5 patients using whole-body positron emission tomography (PET) and the radiopharmaceutical 2-fluorine-18-fluoro-2-deoxy-D-glucose (FDG). PET correctly demonstrated 30 metastases in lung, brain, pancreas, nasal cavity, skin and subcutaneous tissue, and lymph nodes. It detected 97% of all metastases exceeding its spatial resolution (〉5mm). Two cutaneous metastases (approximately 3 mm) did not show increased FDG uptake; the overall detection sensitivity was 91%. Two false-positive lesions in one patient were due to severe wound infection. PET correctly excluded malignancy in four cases where suspicious lesions were found with conventional cross-sectional imaging modalities but later ruled out by fine-needle biopsy.PET therefore proved to be an excellent method for staging of metastatic melanoma. Due to its high sensitivity for malignant lesions and the possibility of covering the whole body in one examination, it can replace staging techniques employing multiple imaging modalities: chest X-ray, ultrasonography and computed tomography. Furthermore, it provides information on the malignant potential of the detected lesion.

Electronic Resource

1365-2133

Blackwell Publishing Journal Backfiles 1879-2005

Medicine

Peripheral blood mononuclear cells (PBMC) were taken by leukapheresis from a patient with melanoma skin metastases and stimulated in vitro using 1000 IU recombinant interleukin 2 (IL-2)/ml to generate lymphokine-activated killer cells (LAK cells). Two-colour immunofluorescence analysis demonstrated an IL-2-induced up-regulation of CD25 on natural killer cells (CD56+) as well as on T lymphocytes (CD3+). After radiolabelling with indium-111, the cells were reinfuse. Gamma-camera imaging revealed an enrichment at the tumour sites. Immunostaining of tumour tissue taken before and after scintigraphy demonstrated CD25+ Tlymphocytes (CD2+, CD3+), but no natural killer cells (CD16+, CD56+) infiltrating the metastases.LAK cell enrichment at melanoma metastases in vivo did not involve natural killer cells, but was characterized by increased numbers of activated T lymphocytes in this patient.

Electronic Resource

1365-2133

Blackwell Publishing Journal Backfiles 1879-2005

Medicine

Imiquimod is a topical immune response modifier that binds to Toll-like receptor-7 and -8, inducing interferon-α. We treated superficial basal cell carcinomas (BCC) with imiquimod 5% cream daily for 5–8 days. The BCC lesions were biopsied before treatment and following imiquimod treatment, when the lesion showed the signs of erosion. We applied histology, immunohistochemistry and gene array technology (AffymetrixTM) to gain further insight into the mode of action of imiquimod. Our findings demonstrate that imiquimod-induced BCC regression is associated with a strong activity of the innate immune response, mediated by cells of macrophage–monocyte origin and is associated with the induction of apoptosis.

Electronic Resource

1365-2133

Blackwell Publishing Journal Backfiles 1879-2005

Medicine

We report three patients with blastic natural killer (NK)-cell lymphoma of the skin associated with myelodysplastic syndrome (MDS) (two patients) or subacute myelomonocytic leukaemia (one patient). In two patients MDS was diagnosed before skin lesions; the patient with leukaemia initially presented with skin lesions. Our patients had several clinical features in common, namely multiple skin lesions with a bruise-like appearance, involvement of the oral mucosa, and good general status at presentation but very rapid deterioration in the course of the disease. All patients died of disease 4–14 months after the diagnosis. Histopathologically, there were cutaneous infiltrates of slightly pleomorphic medium-sized cells expressing CD4, CD56, terminal deoxynucleotidyl transferase (focally) and being negative for surface CD3, cytotoxic molecules, B-cell-associated markers and myelomonocytic markers. Erythrocyte extravasation was seen in all patients. T-cell receptor genes were in germline configuration. MDS was classified as refractory cytopenia with multilineage dysplasia and ring sideroblasts and refractory anaemia with transition to refractory anaemia with excess of blasts. We reviewed similar cases reported in the literature showing coexistence of blastic NK-cell lymphoma/leukaemia and MDS or myelogenous leukaemia. We conclude that given an overall limited number of reported cases of blastic NK-cell lymphoma/leukaemia, its association with various myelodysplastic/myeloproliferative disorders seen in a subset of patients (≈ 15–20%) is more than coincidental and may indicate their common origin.

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