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Biomedical subjects

W Tilgen

Publications and source records attributed to W Tilgen.

At least 55 records · Page 3Linked to original sources
PubMed2001

Increased soluble CD95 (sFas/CD95) serum level correlates with poor prognosis in melanoma patients.

Functional impairment of the Fas/CD95 receptor-ligand system is associated with the development and progression of malignancies. One possible cause might be the inhibition of the formation of a functional Fas/CD95-FasL complex by soluble Fas/CD95 molecules (sFas/CD95). In the present study we determined sFas/CD95 serum concentration in 125 melanoma patients of different clinical stages of disease compared with 30 healthy controls using an ELISA. sFas/CD95 serum level was significantly elevated (P < 0.0005) in melanoma patients (mean +/- SE = 8.60 +/- 0.26 ng/ml) compared with healthy controls (mean +/- SE = 6.27 +/- 0.25 ng/ml). Univariate analysis revealed a correlation of sFas/CD95 serum concentration with advanced stages of disease (P = 0.009). Only a slight increase in sFas/CD95 serum level (P = 0.057) could be observed in regard to the tumor burden. Patients undergoing current treatment with cytostatics (n = 18) revealed a strong increase in sFas/CD95 serum level (P < 0.0005), whereas treatment with IFN-alpha alone or combined with cytostatics (n = 19) showed no change in serum sFas/CD95 concentration. According to univariate analysis, elevated sFas/CD95 serum levels were associated with a poor overall (P < 0.005) and a progression-free (P < 0.0005) survival. Multivariate analysis revealed sFas/CD95 serum concentration as an independent predictive factor for progression-free (P = 0.011), but not overall (P = 0.078), survival. Our results show a prognostic relevance of serum sFas/CD95 in melanoma patients, indicating that the evaluation of sFas/CD95 serum level may be important for the selection of therapeutic strategies.

Biomarkers, Tumor↗
PubMed2001

[Olmsted syndrome].

BACKGROUND: The Olmsted syndrome is a rare congenital disorder with palmoplantar keratoderma and hyperkeratotic periorifical plaques. Only 19 cases were reported in the literature. Other cutaneous and organic findings have been reported with different frequencies. CASE REPORT: A 17-year-old girl presented with genital, perigenital and perianal hyperkeratotic plaques extending to the thighs, palmoplantar keratoderma and nail dystrophy. A small erythematokeratotic plaque was localized below the lower lip. Improvement of the palmoplantar and genital lesions was noted after one month of treatment with 25 mg acitretine daily. Further substantial improvement of the palmoplantar and ungueal lesions was observed during the next 7 months. However, discrete erythematous perianal and perigenital lesions persisted in these areas 2 years later. DISCUSSION: Efficacy of retinoids in the Olmsted syndrome is controversially discussed in the literature. However, acitretin seems to be the treatment of choice of this syndrome in adults.

Acitretin↗
PubMed2000

Immunohistochemical analysis of DNA mismatch repair enzyme hMSH-2 in normal human skin and basal cell carcinomas.

We have analysed the expression and distribution of the DNA mismatch repair enzyme hMSH-2 in normal skin and basal cell carcinomas. hMSH-2 protein was investigated immunohistochemically (normal human skin: n = 10; basal cell carcinomas: n = 16) on frozen sections using a highly sensitive streptavidin-peroxidase technique and a specific mouse monoclonal antibody (clone FE11). In normal human skin, we found nuclear immunoreactivity for hMSH-2 in epidermal keratinocytes of the basal and first 1-3 suprabasal cell layers. All basal cell carcinomas analysed revealed strong nuclear imunoreactivity that was pronounced in peripheral tumour cells and cells of the palisade. Expression of hMSH-2 protein was consistently and strongly upregulated in tumour cells of the carcinomas as compared to adjacent unaffected epidermis or epidermis of normal human skin. Twelve of the sixteen carcinomas analysed revealed no visual correlation in comparing the labelling patterns for hMSH-2 with the labelling pattern for the proliferation marker Ki-67. Our findings indicate that (a) hMSH-2 is expressed in human epidermal keratinocytes, predominantly in lower cell layers of the viable epidermis; (b) expression of hMSH-2 protein is strongly upregulated in basal cell carcinomas as compared to unaffected epidermis; (c) the level of hMSH-2 proteins in the carcinomas is not exclusively regulated by the proliferative activity of these tumour cells; (d) inactivating mutations of the hMSH-2 gene may in the carcinomas not be involved in the carcinogenesis or microsatellite instability secondary to replication errors; (e) expression of hMSH-2 may be of importance for the genetic stability of basal cell carcinomas in vivo.

Adenosine Triphosphatases↗
PubMed2000

Immunoreactivity of six monoclonal antibodies directed against 1,25-dihydroxyvitamin-D3 receptors in human skin.

Using confocal laser scanning microscopy, we tested the suitability of five monoclonal mouse antibodies (IVA7E7, IVB12G12, IVG9C11, VD2F12, and VIIID8C12) that had been raised against different domains of the porcine intestinal 1,25-dihydroxyvitamin-D3 receptor (VDR), for the immunohistological detection of VDR in human skin. The VDR immunoreactivity of these antibodies was compared with the well-characterized VDR-staining pattern of the mouse monoclonal antibody 9A7gamma raised against chick intestinal VDR. All six antibodies revealed strong nuclear and qualitatively similar immunoreactivity in all cell layers of the viable epidermis. Our data demonstrate that the five mouse monoclonal antibodies are suitable for immunohistochemical detection of VDR in frozen sections. These antibodies show comparable staining patterns in human skin even though they had been raised against different functional domains of the 1,25-dihydroxyvitamin-D3 receptor.

Animals↗
PubMed2000

Accumulation of CD4+CD7- T cells in inflammatory skin lesions: evidence for preferential adhesion to vascular endothelial cells.

The CD7- subset of CD4+ memory T cells reflects a stable differentiation state of post-thymic helper T cells and represents a small subpopulation in circulating blood. We here demonstrate that CD7- T cells preferentially accumulate in skin lesions under chronic inflammatory conditions irrespective of the particular disease. As adhesion to vascular endothelial cells (EC) is required for migration of circulating lymphocytes into tissues, we analysed the adherence of purified subsets of CD4+ memory T cells to endothelial cells in vitro. Compared with CD4+CD7+ T cells, cells of the CD4+CD7- subset preferentially adhere to EC, which is moreover increased after prestimulation of EC with tumour necrosis factor-alpha (TNF-alpha). Stimulated EC increase expression of intercellular adhesion molecule-1 (CD54) and E-selectin (CD62E), the ligand of which, cutaneous lymphocyte-related antigen (CLA), is highly expressed in CD4+CD7- T cells but not in CD4+CD7+ T cells. LFA-1 is expressed in a bimodal distribution on CD4+CD7- T cells in contrast to CD4+CD7+ cells, whereas VLA-1, VLA-3, and VLA-5 are nearly similarly expressed in both T cell subsets. Our results imply that the preferred adherence of CD4+CD7- memory T cells to vascular EC, which is increased after long-term EC stimulation with TNF-alpha, is likely to facilitate their accumulation in various inflammatory skin lesions.

Antigens, CD7↗
PubMed2000

Use of high-dose methylprednisolone pulse therapy in patients with progressive and stable vitiligo.

BACKGROUND: Although there are several treatment options available for patients with generalized vitiligo, their efficacy is still a matter of debate. Although shown to be effective, corticosteroids applied either systemically or topically carry the risk of significant side-effects in long-term therapy. We evaluated the effectiveness of intravenous methylprednisolone (8 mg/kg body weight) administered on three consecutive days in patients with generalized vitiligo. MATERIALS AND METHODS: A total of 14 patients with progressive or static vitiligo were included in a prospective, open, clinical study. RESULTS: Eighty-five per cent of the patients presenting with progressive disease showed cessation of disease progression after the infusion therapy. Repigmentation was observed in 71% of patients with progressive vitiligo. None of the six patients presenting with static disease showed any repigmentation in response to this form of treatment. The therapy was well tolerated in all but one patient who developed intermittent arterial hypertension during therapy. CONCLUSIONS: High-dose glucocorticoid pulse therapy may represent a therapeutic option in patients with generalized progressive vitiligo, and should be further evaluated in a prospective, randomized, clinical trial.

Adolescent↗
PubMed2000

Interferon-alpha-associated development of bullous lesions in mycosis fungoides.

We report a 67-year-old woman with mycosis fungoides (MF) who was receiving subcutaneous injections of recombinant interferon alpha-2b (IFN-alpha). After 2 months of IFN-alpha treatment, bullous lesions appeared on her trunk and extremities. A skin biopsy specimen from the trunk revealed histopathologic features of bullous MF. Bullous lesions with specific infiltrates of MF are very rare; to the best of our knowledge, this is the first case showing specific bullous lesions of MF developed under IFN-alpha treatment.

Aged↗
PubMed2000

Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma.

PURPOSE: To compare, in 305 patients with advanced metastatic melanoma, temozolomide and dacarbazine (DTIC) in terms of overall survival, progression-free survival (PFS), objective response, and safety, and to assess health-related quality of life (QOL) and pharmacokinetics of both drugs and their metabolite, 5-(3-methyltriazen-1-yl)imidazole-4-carboximide (MTIC). PATIENTS AND METHODS: Patients were randomized to receive either oral temozolomide at a starting dosage of 200 mg/m(2)/d for 5 days every 28 days or intravenous (IV) DTIC at a starting dosage of 250 mg/m(2)/d for 5 days every 21 days. RESULTS: In the intent-to-treat population, median survival time was 7.7 months for patients treated with temozolomide and 6.4 months for those treated with DTIC (hazards ratio, 1.18; 95% confidence interval [CI], 0.92 to 1.52). Median PFS time was significantly longer in the temozolomide-treated group (1.9 months) than in the DTIC-treated group (1.5 months) (P =.012; hazards ratio, 1.37; 95% CI, 1.07 to 1.75). No major difference in drug safety was observed. Temozolomide was well tolerated and produced a noncumulative, transient myelosuppression late in the 28-day cycle. The most common nonhematologic toxicities were mild to moderate nausea and vomiting, which were easily managed. Temozolomide therapy improved health-related QOL; more patients showed improvement or maintenance of physical functioning at week 12. Systemic exposure (area under the curve) to the parent drug and the active metabolite, MTIC, was higher after treatment with oral temozolomide than after IV administration of DTIC. CONCLUSION: Temozolomide demonstrates efficacy equal to that of DTIC and is an oral alternative for patients with advanced metastatic melanoma.

Adult↗
PubMed1999

Heterogenous susceptibility to CD95-induced apoptosis in melanoma cells correlates with bcl-2 and bcl-x expression and is sensitive to modulation by interferon-gamma.

The expression and functionality of the Fas receptor (CD95/APO-1) play an important role for the maintenance of tissue homeostasis. Various types of tumor cells have been shown to escape immune recognition by constitutive resistance to CD95-mediated apoptosis. Furthermore, several apoptosis-related proteins have been reported to influence CD95 sensitivity. We tested an unselected panel of 11 melanoma cell lines for sensitivity to CD95 and the corresponding expression of CD95, CD95L, bcl-2, bcl-x, bcl-xS, bax and FLIP proteins. Despite detection of CD95 cell-surface expression in 9 out of the 11 cell lines tested, only 3 melanoma cell lines were sensitive to anti-CD95-MAb-induced cell death. Apoptosis-related proteins CD95L, bcl-2, bcl-x, bcl-xS and bax were found to be heterogenously expressed in different melanoma cell lines tested. The susceptibility of melanoma cells to anti-CD95-MAb-mediated apoptosis was associated with low protein expression of both bcl-2 and bcl-x. The level of CD95 cell-surface expression in melanoma cells was no indicator for CD95 sensitivity. Furthermore, FLIP protein was detectable in 7 out of the 11 cell lines, but showed no correlation to CD95 sensitivity. Certain cytokines have been described as modulating the susceptibility of tumor cells to CD95-induced cell death. Since IFN-alpha was proved to be clinically efficient in melanoma therapy, we tested whether interferons have the ability to induce sensitivity to CD95 in primarily resistant melanoma cell lines. Here we show that IFN-gamma, but not IFN-alpha, is able to increase the susceptibility of sensitive cell lines and to induce CD95 sensitivity in resistant melanoma cell lines, accompanied by up-regulation of the protein expression level of CD95 and/or bcl-xS.

Apoptosis↗
PubMed1999

Analysis of 1,25-dihydroxyvitamin D(3) receptors (VDR) in basal cell carcinomas.

We have analyzed expression of 1,25-dihydroxyvitamin D(3) receptor (VDR) protein and mRNA in basal cell carcinomas (BCC) of human skin. VDR immunoreactivity in BCCs was compared with the staining pattern of the proliferation marker Ki-67 in the same tumors. Additionally, VDR staining was compared to staining pattern of apoptotic cells by terminal UTP nucleotide end labeling assay. Frozen sections of superficial type, nodular type, and fibrosing type BCCs were consistently immunoreactive for VDR (mAb 9A7gamma) with almost every tumor cell labeled (n = 15). In general, VDR staining was pronounced in peripheral tumor cells. VDR immunoreactivity was consistently stronger in tumor cells than in adjacent or unaffected epidermis. No visual correlation was found in BCCs comparing labeling patterns of Ki-67-positive or apoptotic cells and mAb 9A7gamma. VDR mRNA was increased in BCCs (n = 6) compared to normal human skin (n = 5), as revealed by reverse transcription-polymerase chain reaction analysis. Our findings indicate that VDR is strongly expressed in BCCs and may be involved in the growth regulation of this tumour, and VDR mRNA and protein are increased in BCCs as compared to normal human epidermis.

Antibodies, Monoclonal↗
PubMed1999

Treatment of progressive pigmented purpura with oral bioflavonoids and ascorbic acid: an open pilot study in 3 patients.

BACKGROUND: Bioflavonoids and ascorbic acid have been shown to increase capillary resistance and to mediate potent antioxidative radical scavenging activities. OBJECTIVE: We evaluated the clinical effect of oral bioflavonoids and ascorbic acid in patients with chronic progressive pigmented purpura (PPP). METHODS: In an open pilot study, oral rutoside (50 mg twice a day) and ascorbic acid (500 mg twice a day) were administered to 3 patients with chronic PPP. RESULTS: At the end of the 4-week treatment period, complete clearance of the skin lesions was achieved in all 3 patients. No adverse reactions were noted. All patients remained free of lesions at the end of 3 months after treatment. CONCLUSION: Our results suggest a beneficial effect of bioflavonoids in combination with ascorbic acid on PPP. Because the disease is mostly resistant to other treatment modalities, placebo-controlled studies are necessary to determine the usefulness of this therapy in PPP.

Administration, Oral↗
PubMed1999

Immunohistochemical analysis of DNA 'mismatch-repair' enzyme human Mut-S-Homologon-2 in ovarian carcinomas.

The human Mut-S-Homologon-2 (hMSH-2) gene product is a member of a highly conserved family of proteins involved in postreplication mismatch repair. We have analysed hMSH-2 expression in normal ovarian tissue (n = 15) and ovarian carcinomas (n = 40). hMSH-2 protein was investigated immunohistochemically on frozen sections using a highly sensitive streptavidin-peroxidase technique and a specific mouse monoclonal antibody (clone FE11). A hMSH-2-immunoreactivity score (hMSH-2-IRS) for semiquantitative analysis of hMSH-2 expression is presented. In normal ovarian tissue, we only found weak nuclear immunoreactivity for hMSH-2 in 60%, while the remaining 40% were hMSH-2 negative (mean hMSH-2-IRS: 0.73; SD: +/-0.70). All ovarian carcinomas analysed revealed moderate to strong nuclear immunoreactivity (mean hMSH-2-IRS: 8.05; SD: +/-3.65). hMSH-2 staining was heterogeneous, with visual differences between individual tumour cells. Expression of hMSH-2 protein was consistently and strongly upregulated in tumour cells of ovarian carcinomas as compared to normal ovarian tissue. No statistically significant correlation in comparing the labelling patterns for hMSH-2 with the labelling patterns for Ki-67 (mean percentage of Ki-67 positive tumour cells: 25.88%; SD: +/-18.43) was observed in ovarian carcinomas. Furthermore, no statistical significant correlations between hMSH-2-IRS and histological grading (p = 0.47), histological type of carcinoma (p = 0.706) or FIGO-classification (p = 0.054) were found. Our findings indicate that (a) hMSH-2 is expressed in normal human ovarian tissue, (b) expression of hMSH-2 is increased in ovarian carcinomas, (c) expression of hMSH-2 may be of importance for the genetic stability of ovarian carcinomas in vivo, (d) hMSH-2 mutations may not cause microsatellite instability in ovarian carcinomas, (e) hMSH-2 may contribute to mechanisms responsible for resistance to anticancer drugs.

Adenocarcinoma↗
PubMed1999

Specific lysis of melanoma cells by receptor grafted T cells is enhanced by anti-idiotypic monoclonal antibodies directed to the scFv domain of the receptor.

Malignant transformation of melanocytes is frequently associated with abnormalities in antigen processing and in human leukocyte antigen class I antigen expression. Here, we evaluated a human leukocyte antigen class I antigen-independent approach to target cytotoxic T lymphocytes to melanoma cells by grafting cytotoxic T lymphocytes with a chimeric receptor that consists of both a domain binding to high molecular weight-melanoma associated antigen and a cellular activation domain. The binding domain is a single-chain antibody fragment (scFv) derived from the monoclonal anti-high molecular weight-melanoma associated antigen antibody 763.74 by phage display techniques. The cellular activation domain is the signaling unit of the FcepsilonRI receptor gamma chain. Both domains constitute the chimeric receptor scFv763.74-gammaR. Cytotoxic MD45 T cells grafted with the scFv763.74-gammaR receptor bind specifically to high molecular weight-melanoma associated antigen-positive melanoma cells and lyse melanoma cells in a human leukocyte antigen class I independent fashion. Pre-incubation of receptor grafted T cells with immobilized anti-idiotypic (id) monoclonal antibody MK2-23 binding to the scFv domain of the receptor enhanced the lysis of melanoma cells indicating that the specific cytolytic activity of receptor grafted T cells can be increased by costimulation with cross-linked anti-idiotypic monoclonal antibodies that recognize the antigen binding domain of the chimeric receptor.

Amino Acid Sequence↗
PubMed1999

Successful treatment of progressive vitiligo with high-dose intravenous methylprednisolone 'pulse' therapy.

We report on the successful therapy of rapid progressive generalized vitiligo in a 24-year-old woman. After intravenous injection of 500 mg of methylprednisolone on 3 consecutive days, the disease progression was stopped and repigmentation was induced. The treatment was repeated monthly and after 6 cycles, repigmentation was achieved on vast parts of most vitiligo lesions. The treatment was well tolerated by the patient, and no side effects were noted. We conclude that high-dose glucocorticoid pulse therapy may represent a therapeutic alternative in selected patients with generalized rapid progressive vitiligo.

Adult↗