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Biomedical subjects

Claudia S Vetter

Publications and source records attributed to Claudia S Vetter.

7 recordsLinked to original sources
PubMed2006

The carcinogenic potential of tacrolimus ointment beyond immune suppression: a hypothesis creating case report.

BACKGROUND: Since tacrolimus ointment was approved by the U.S. Food and Drug Administration (FDA) as a promising treatment for atopic dermatitis, it has been approved in more than 30 additional countries, including numerous European Union member nations. Moreover, in the current clinical routine the use of this drug is no longer restricted to the approved indication, but has been extended to a wide variety of inflammatory skin diseases including some with the potential of malignant transformation. So far, the side-effects reported from the topical use of tacrolimus have been relatively minor (e.g. burning, pruritus, erythema). Recently, however, the FDA reviewed the safety of topical tacrolimus, which resulted in a warning that the use of calcineurin inhibitors may be associated with an increased risk of cancer. CASE PRESENTATION: Oral lichen planus (OLP) was diagnosed in a 56-year-old women in February 1999. After several ineffective local and systemic therapeutic measures an off-label treatment of this recalcitrant condition using Tacrolimus 0.1% ointment was initiated in May 2002. After a few weeks of treatment most of the lesions ameliorated, with the exception of the plaques on the sides of the tongue. Nevertheless, the patient became free of symptoms which, however, reoccurred once tacrolimus was weaned, as a consequence treatment was maintained. In April 2005, the plaques on the left side of the tongue appeared increasingly compact and a biopsy specimen confirmed the suspected diagnosis of an oral squamous cell carcinoma. CONCLUSION: The suspected causal relationship between topical use of tacrolimus and the development of a squamous cell carcinoma prompted us to test the notion that the carcinogenicity of tacrolimus may go beyond mere immune suppression. To this end, tacrolimus has been shown to have an impact on cancer signalling pathways such as the MAPK and the p53 pathway. In the given case, we were able to demonstrate that these pathways had also been altered subsequent to tacrolimus therapy.

Administration, Topical↗
PubMed2005

STAT5 contributes to interferon resistance of melanoma cells.

BACKGROUND: Malignant melanoma is a highly aggressive neoplastic disease whose incidence is increasing rapidly. In recent years, the use of interferon alpha (IFNalpha) has become the most established adjuvant immunotherapy for melanoma of advanced stage. IFNalpha is a potent inhibitor of melanoma cell proliferation, and the signal transducer and activator of transcription STAT1 is crucial for its antiproliferative action. Although advanced melanomas clinically resistant to IFNalpha are frequently characterized by inefficient STAT1 signaling, the mechanisms underlying advanced-stage interferon resistance are poorly understood. RESULTS: Here, we demonstrate that IFNalpha activates STAT5 in melanoma cells and that in IFNalpha-resistant cells STAT5 is overexpressed. Significantly, the knockdown of STAT5 in interferon-resistant melanoma cells restored the growth-inhibitory response to IFNalpha. When STAT5 was overexpressed in IFNalpha-sensitive cells, it counteracted interferon-induced growth inhibition. The overexpressed STAT5 diminished IFNalpha-triggered STAT1 activation, most evidently through upregulation of the inhibitor of cytokine-signaling CIS. CONCLUSIONS: Our data demonstrate that overexpression and activation of STAT5 enable melanoma cells to overcome cytokine-mediated antiproliferative signaling. Thus, overexpression of STAT5 can counteract IFNalpha signaling in melanoma cells, and this finally can result in cytokine-resistant and progressively growing tumor cells. These findings have significant implications for the clinical failure of IFNalpha therapy of advanced melanoma because they demonstrate that IFNalpha induces the activation of STAT5 in melanoma cells, and in STAT5-overexpressing cells, this contributes to IFNalpha resistance.

Antineoplastic Agents↗
PubMed2005

Cytoplasmic and nuclear expression of survivin in melanocytic skin lesions.

Survivin, a member of the inhibitors of apoptosis protein family, regulates both cellular proliferation and apoptotic cell death. While the human survivin gene is highly expressed in the developing fetus, in adults its expression is restricted to highly proliferating normal tissues and neoplastic tumors tissues. In the present study, we compared the expression of survivin in melanoma and benign melanocytic lesions such as junctional, compound, dermal, congenital, blue and spitz nevi. This analysis reveals a heterogeneous expression of survivin with respect to both the intensity, frequency and cellular localization. In junctional, compound and blue nevi, survivin was present in nuclear localization, whereas in spitz nevi survivin was detectable in the cytoplasm. In dermal and congenital nevi, survivin was present in both localizations with predominance of the nuclear compartment. Interestingly, this distribution was similar to that observed in primary melanoma; whereas in metastatic melanoma the predominance of the nuclear localization of survivin was lost. Our data demonstrate that although survivin is expressed in a large number of benign nevi, the balance between its cytoplasmic and nuclear expression was immensely heterogeneous between lesions with suspected different developmental origins.

Cell Nucleus↗
PubMed2004

B-Raf specific antibody responses in melanoma patients.

BACKGROUND: Mutations of the BRAF gene are the most common genetic alteration in melanoma. Moreover, BRAF mutations are already present in benign nevi. Being overexpressed and mutated, B-Raf is a potential target for the immune system and as this mutation seems to be an early event, a humoral immune response against this antigen might serve as a diagnostic tool for detection of high risk patients. METHODS: 372 sera of 148 stage IV melanoma patients and 119 sera of non-melanoma patients were screened for B-Raf, B-Raf V599E and C-Raf specific antibodies by an ELISA assay. Sera were screened for specific total Ig and for IgG. Serum titers were compared with a two tailed Mann-Whitney U test. Sera with titers of 1:300 or higher were termed positive and groups were compared with a two tailed Fisher's exact test. RESULTS: B-Raf specific antibodies recognizing both B-Raf and B-Raf V599E were detected in 8.9% of the sera of melanoma patients and in 2,5% of the control group. Raf specific IgG was detected in some patients at very low levels. B-Raf specific antibody responses did not correlate with clinical parameters but in some cases, B-Raf antibodies emerged during disease progression. CONCLUSION: These findings imply that B-Raf is immunogenic in melanoma patients and that it might serve as a potential target for immunotherapy. However, B-Raf specific antibodies emerge at rather late stages of melanoma progression and are present only with a low frequency indicating that spontaneous B-Raf specific antibodies are not an early marker for melanoma, but rather may serve as a therapeutic target.

Antibodies, Neoplasm↗
PubMed2002

Differential expression of inhibitory or activating CD94/NKG2 subtypes on MART-1-reactive T cells in vitiligo versus melanoma: a case report.

Selection and activation of T cells is tightly regulated by both antigen-specific receptors and co-receptors to ensure that responses to self antigens are largely avoided. By T cell receptor clonotypic mapping and staining with tetrameric HLA-peptide complexes, we demonstrate the presence of melanocyte differentiation antigen MART-1 specific T cells in the areas of destruction of both neoplastic and normal melanocytic cells in a case of a primary melanoma and its associated hypopigmentation. These self reactive T cells expressed CD94/NKG2 major histocompatibility complex class I specific C-type lectin-like receptors. This family of receptors includes both activating and inhibitory isoforms. Thus, we performed a detailed analysis that revealed the exclusive presence of inhibitory NKG2-A/B receptors in the vitiligo-like leukoderma, whereas both the inhibitory receptors and the activating NKG2-C/E isoforms were present within the tumor. Our data suggest the differential expression of killer inhibitory receptors as a possible mechanism to regulate T cell responses to self antigens.

Antigens, CD↗
PubMed2002

Expression of stress-induced MHC class I related chain molecules on human melanoma.

Cellular immune responses to melanoma are tightly regulated and include specific T cell responses to self antigens such as Mart-1 and gp100. Thus, additional signals apart from those mediated by the T cell receptor are needed to ensure T cell activation. Recently, the stress inducible major histocompatibility complex molecules, MHC class I related chain, were identified as an activator of both natural killer and T cells via interaction with their receptor NKG2D. Herein, we report the expression of MIC in 31 of 40 primary cutaneous melanomas and in 13 of 20 metastatic lesions. Moreover, lymphocytes infiltrating the tumor were found to express NKG2D. Detailed analysis identified both CD3+ T cells as well as CD56+ natural killer cells contributing to this NKG2D+ tumor infiltrating lymphocyte population present.

Adult↗