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C Garbe

Publications and source records attributed to C Garbe.

At least 37 records · Page 2Linked to original sources
PubMed1996

K+ channels and the intracellular calcium signal in human melanoma cell proliferation.

K+ channels, membrane voltage, and intracellular free Ca2+ are involved in regulating proliferation in a human melanoma cell line (SK MEL 28). Using patch-clamp techniques, we found an inwardly rectifying K+ channel and a calcium-activated K+ channel. The inwardly rectifying K+ channel was calcium independent, insensitive to charybdotoxin, and carried the major part of the whole-cell current. The K+ channel blockers quinidine, tetraethylammonium chloride and Ba2+ and elevated extracellular K+ caused a dose-dependent membrane depolarization. This depolarization was correlated to an inhibition of cell proliferation. Charybdotoxin affected neither membrane voltage nor proliferation. Basic fibroblast growth factor and fetal calf serum induced a transient peak in intracellular Ca2+ followed by a long-lasting Ca2+ influx. Depolarization by voltage clamp decreased and hyperpolarization increased intracellular Ca2+, illustrating a transmembrane flux of Ca2+ following its electrochemical gradient. We conclude that K+ channel blockers inhibit cell-cycle progression by membrane depolarization. This in turn reduces the driving force for the influx of Ca2+, a messenger in the mitogenic signal cascade of human melanoma cells.

Animals↗
PubMed1996

Oral hairy leukoplakia in 71 HIV-seropositive patients: clinical symptoms, relation to immunologic status, and prognostic significance.

BACKGROUND: Oral hairy leukoplakia (OHL) is a benign hyperplasia of the oral mucosa that is induced by Epstein-Barr virus. It occurs nearly exclusively in men infected with HIV. OHL is a marker of moderate to advanced immunodeficiency and disease progression in patients with HIV infection. OBJECTIVE: We attempted to determine the clinical characteristics of OHL in a large group of patients infected with HIV and to analyze its relation to immune status and prognosis. METHODS: A total of 456 patients with HIV-associated skin disorders were evaluated during the years 1982 through 1992. All patients had an oral examination. CD4+ cell counts were obtained within 3 months of the examination. RESULTS: OHL was diagnosed in 15.6% of 456 patients. The median age of the patients was 35 years. OHL was found most often on the lateral aspect of the tongue; in one patient the lesion covered the entire dorsal surface of the tongue. Significant immunosuppression was present in the majority of patients at the time of OHL diagnosis (median CD4+ T-lymphocyte count, 235/microliter; median CD4+/CD8+ ratio, 0.3). The median survival time was 20 months in patients with OHL. In patients with a higher CD4 cell count (CD4+ T lymphocyte count, > or = 300/microliter) the diagnosis of OHL was associated with shorter survival times (median survival time, 25 months) compared with other patients with HIV (median survival time, 52 months). CONCLUSION: OHL is a frequent finding in patients with HIV and indicates advanced immunosuppression. Even in patients with more than 300/microliter CD4+ T lymphocytes, OHL is associated with a poor prognosis.

AIDS-Related Opportunistic Infections↗
PubMed1996

Failure of gadopentetate dimeglumine-enhanced, high-resolution magnetic resonance imaging to differentiate among melanin-containing skin tumors.

RATIONALE AND OBJECTIVES: We evaluated the diagnostic potential of gadopentetate dimeglumine-enhanced, high-resolution magnetic resonance (MR) imaging to differentiate benign from malignant melanin-containing skin tumors. METHODS: Forty-five patients were prospectively examined using high-resolution MR imaging at 1.5 T using a 2.5-cm surface coil. For tumor assessment, T1-weighted and T2-weighted transverse spin-echo sequences were acquired. After intravenous administration of gadopentetate dimeglumine (0.1 mmol/kg), the T1-weighted transverse sequence was repeated. Contrast enhancement was quantitatively determined as the percentage increase of signal intensity. Histologic findings were correlated using the Wilcoxon signed-ranks test. The quality of contrast enhancement was assessed by three independent investigators who were unaware of the patients' history and histologic data. The signal-to-noise ratio (SNR) was calculated in the T2-weighted sequence. Significance was tested using the Wilcoxon signed-ranks test. RESULTS: In all tumors, contrast enhancement was visually discernible. Half of the cases were enhanced inhomogeneously. The percentage of contrast enhancement did not correlate with histologic findings. Malignant melanomas could not be differentiated from benign melanocytic nevi with the use of gadopentetate dimeglumine. Determination of the SNR in T2-weighted sequences revealed no significant difference for histologic subgroups or tumor type. CONCLUSION: Gadopentetate dimeglumine-enhanced MR imaging does not differentiate malignant melanomas from benign melanocytic nevi. Determination of the SNR in the T2-weighted sequences revealed no significant difference for histologic subgroups.

Adolescent↗
PubMed1996

Increase of melanocytic nevus counts in children during 5 years of follow-up and analysis of associated factors.

OBJECTIVES: To investigate nevus development in childhood and to examine causative related factors such as pigment phenotype and the role of sun exposure in the development of melanocytic nevi. DESIGN AND PARTICIPANTS: Nevus counts were performed in kindergarteners (n = 866) before the age of 7 years and again 5 years later (n = 377). Eligible for analysis were 357 children who were examined twice. Possible related factors were searched for by standardized interviews with parents. RESULTS: The mean number of nevi measuring 1 mm or more was 9 in the first examination and the number measuring 2 mm or more, 4. Five years later, the mean number of nevi measuring 1 mm or more was 40 and the number measuring 2 mm or more was 16. Children with poor sun tolerance had statistically significant more nevi (relative risk, 3.7;95% confidence interval, 1.9-7.2). The presence of freckles was a strong predictor for a high increase of melanocytic nevi (relative risk, 2.1; 95% confidence interval, 1.3-3.3). The number of days per year with intensive solar exposure was an independent prognostic factor. The relative risk for the development of melanocytic nevi was increased by a factor of 1.6 in children who had more than 21 days of intensive sun exposure per year (95% confidence interval, 1.0-2.5). CONCLUSION: The development of melanocytic nevi in childhood is strongly related to characteristics of pigmentation associated with poor sun tolerance. In addition, we found evidence for the influence of UV radiation on the number of acquired melanocytic nevi in childhood.

Child↗
PubMed1995

Overall and site-specific risk of malignant melanoma associated with nevus counts at different body sites: a multicenter case-control study of the German Central Malignant-Melanoma Registry.

A large number of benign melanocytic nevi is the major risk factor for malignant melanoma (MM). In a multicenter case-control study, the number of common (CN) and clinically atypical (AN) nevi were counted separately at individual sites in 278 melanoma patients and 278 age- and gender-matched non-melanoma controls. Relative risk (RR) adjusted for age and sex was calculated. In men as well as women, the number of CN on the legs was the best predictor of overall melanoma risk. In men, RR for developing MM when > or = 1 AN were present on the trunk was 4-fold (vs. none). In women, presence of AN on the arms increased RR 9.5-fold. For men and women combined, after adjusting for age and gender, the RR for developing MM on the trunk and on the legs was best predicted by counts of CN at the respective body region. However, high counts of CN on the arms were associated with high melanoma risk on the legs (somewhat lower on the trunk). For AN, no site-specificity of melanoma risk was found. Our data suggest that nevus counts of the legs are the best predictor of overall melanoma risk if total body nevus counts are not feasible. Although high counts of CN on the trunk and legs are associated with a higher risk of developing MM at the respective site than at another site, our data do not unequivocally support a direct site-specific melanoma risk.

Arm↗
PubMed1995

Primary cutaneous melanoma. Identification of prognostic groups and estimation of individual prognosis for 5093 patients.

BACKGROUND: Numerous investigations have examined prognostic factors for patients with primary cutaneous melanoma. However, only a few studies have been published on the definition of prognostic groups. The first aim of the present study was to determine the relative importance of different prognostic factors in a large collective study. The second aim was to define prognostic groups of patients based on combinations of prognostic factors and to define a model that allows the estimation of individual survival probability. METHODS: Long term follow-up of 5264 patients with invasive primary cutaneous melanoma was performed from 1970 to 1988 at four German University Departments of Dermatology (Berlin-Steglitz, Münster-Hornheide, Tübingen, and Würzburg). The multivariate Cox model was used to analyze 5093 patients, and 4371 patients with complete information were included in a classification and regression tree analysis (CART). RESULTS: Tumor thickness, sex, anatomic location, and level of invasion were highly significant prognostic factors according to the multivariate analysis (P < 0.0001). However, histologic subtype and age influenced prognosis less significantly (P < 0.05). The CART analysis resulted in 12 groups defined mainly by tumor thickness, sex, and anatomic location, which were combined into five prognostic groups. The prognostic stratification defined by the five groups was superior compared with the standard TNM model. Ten-year survival rates of the five groups ranged from 97% to 14% (P < 0.0001), and an equation was used to calculate individual survival probabilities based on the significant factors of the Cox model. CONCLUSIONS: Consideration of all significant prognostic factors of patients with primary cutaneous melanoma investigated in the present study allows for the definition of prognostic groups with a more reliable estimation of prognosis than by previous staging systems and also enables calculation of individual survival probabilities.

Age Factors↗
PubMed1995

Primary cutaneous melanoma. Prognostic classification of anatomic location.

BACKGROUND: Anatomic location has been identified by several investigators as a significant prognostic factor for patients with primary cutaneous melanoma (CM). However, the best determination of higher and lower risk sites is still controversial, and the biologic significance of tumor site in the course of primary CM is unknown. The aim of the present study was to identify higher and lower risk sites based on multivariate analysis. METHODS: A series of 5093 patients with invasive primary cutaneous melanoma followed from 1970 to 1988 at four university centers in Germany was investigated using the multivariate Cox proportional hazard model to analyze the importance of anatomic location for survival probability. RESULTS: The anatomic location was found to be a highly significant prognostic factor for patients with primary melanoma by multivariate analysis (P < 0.0001). An optimized classification into sites of higher and lower risk with respect to survival was evaluated by multivariate analysis controlling for the possible confounding effects of the other significant prognostic factors. Relative to the lower leg as the prognostically favorable baseline, the following locations were associated with a significantly higher risk of death caused by primary cutaneous melanoma: back and breast (thorax), upper arm, neck, and scalp (TANS regions). The lower trunk, thigh, lower leg, foot, lower arms, hands, and face were identified as lower risk sites. CONCLUSIONS: Anatomic location was confirmed as an independent prognostic factor for patients with primary cutaneous melanoma. The TANS regions were identified as high risk sites, and the lower trunk, thigh, lower leg, foot, lower arms, hands, and face were identified as intermediate sites.

Arm↗
PubMed1995

Primary cutaneous melanoma. Optimized cutoff points of tumor thickness and importance of Clark's level for prognostic classification.

BACKGROUND: Maximum tumor thickness and level of invasion are known to be the most important prognostic factors for patients with primary cutaneous melanoma. However, the classification of tumor thickness and the question of whether the combination of tumor thickness and level of invasion provides a better prognostic classification than tumor thickness alone are still matters of debate. The present study examined the relationship between tumor thickness and survival probability to define cutoff points of tumor thickness. Secondly, it investigated the prognostic value of the combination of tumor thickness and level of invasion as proposed in the current TNM classification system. METHODS: A series of 5093 patients with invasive primary cutaneous melanoma followed from 1970 to 1988 at four University centers in Germany (Departments of Dermatology in Tübingen, Würzburg, Berlin-Steglitz, and at the Fachklinik) were analyzed by multivariate Cox models. RESULTS: The relationship between tumor thickness and relative risk of death caused by melanoma was found to be almost linear to a tumor thickness of 6 mm. For tumors greater than 6 mm, no further marked increase in relative risk was observed. The stratification of tumor thickness with endpoints at 1, 2, and 4 mm resulted in the best fit to the authors' data among all classifications with three endpoints, but differences were only slight. By multivariate analysis, the combination of tumor thickness and level of invasion as proposed by the current TNM classification were found to be prognostically less significant than tumor thickness alone. The prognostic influence of level of invasion was proved statistically only for tumor thickness less than or equal to 1 mm. CONCLUSIONS: The proposed stratification of tumor thickness with cutoff points at 1, 2, and 4 mm was supported by multivariate statistical analysis. The analysis of the current TNM staging system indicates the precedence of tumor thickness for the staging of patients with primary cutaneous melanoma in the case of discordance between tumor thickness and level of invasion.

Age Factors↗
PubMed1995

Production of cytokines by human melanoma cells and melanocytes.

Experimental animal models have shown that various cytokines, depending of their specific properties, may support growth and metastasis of tumor cells or even lead to tumor rejection. The analysis of expression of cytokine genes by melanoma cell lines indicated that melanoma cells constitutively produce both autostimulatory and inhibitory cytokines. Using reverse transcriptase polymerase chain reaction analysis, simultaneous expression of several cytokines, including interleukin-1 beta (IL-1 beta), IL-6, IL-8, tumor necrosis factor-alpha, and granulocyte-macrophage colony-stimulating factor, by melanoma cells was found. The same cytokine transcripts were detected in melanocytes, suggesting that cells of the melanocytic lineage express a specific pattern of cytokines in vitro. All these cytokines are known to be able to stimulate effector cells of the host. Additionally, production of mRNA for IL-10, a cytokine with potential immunosuppressive properties, was detected in melanoma cells and melanocytes. These and other cytokines are likely to be involved in the immune response to cancer and at this time it is unknown what the net effects of multiple cytokines are on the outcome of the host response to tumor.

Cells, Cultured↗
PubMed1995

Growth control of melanoma cells and melanocytes by cytokines.

Aberrant proliferation of tumor cells characterizes cancer growth. Investigations of cellular growth control mechanisms have contributed to our understanding of carcinogenesis and to the identification of compounds with specific antitumor activity. Many cytokines have been found to act on melanoma tumors, either produced by the tumor cells themselves or by infiltrating host cells. Purified cytokines allowed direct comparison of the growth response between normal human melanocytes and malignant melanoma cells. The present paper summarizes results of a series of our own experiments not yet published and data from a review of the recent literature. Proliferation of normal human melanocytes is enhanced by several cytokines, including basic fibroblast growth factor (bFGF), melanoma growth stimulatory activity (MGSA), hepatocyte growth factor (HGF), and mast cell growth factor (MGF). Melanoma cells are additionally stimulated by epidermal growth factor (EGF)/transforming growth factor alpha (TGF-alpha) and nerve growth factor (NGF). Tumor necrosis factor alpha (TNF-alpha), transforming growth factor beta 1 (TGF-beta 1), and interleukin (IL)-6 are all potent inhibitors of melanocyte growth, but they are less effective on melanoma cells or even stimulate their growth. Interferon (IFN)-alpha and IFN-gamma inhibited proliferation of melanoma cells but not of melanocytes, whereas IFN-beta showed antiproliferative effects in both cell types. These findings suggest an alteration in growth control mechanisms during melanocyte transformation and possibly play a role in melanoma pathogenesis.

Autoreceptors↗
PubMed1995

Role of elective lymph node dissection in stage I malignant melanoma: evaluation by matched pair analysis.

The role of elective lymph node dissection (ELND) in clinical stage I malignant melanoma continues to be controversial. We present a matched pair analysis of 375 patients treated in the Department of Dermatology in Kassel between 1979 and 1991 by wide local excision (WLE) plus ELND. Multivariate analysis revealed tumor thickness, level of invasion, age, sex, and localization as independent prognostic factors, and 375 patients treated by WLE alone were matched as controls to the patients treated by ELND and WLE. There was no significant benefit from WLE plus ELND compared to WLE alone in the total group as shown by the 5-year survival rates (87.3% versus 86.4%) and 10-year survival rates (80.1% versus 77.82%). Increased survival rates were noted for tumor thicknesses 1.51-4.0 mm for the WLE plus ELND group, as shown by the 10-year survival rates of 73.1% versus 60.3%. However, these data were not significant (p = 0.14). Disease-free survival rates were significantly higher in the group treated by additional ELND for all tumor thicknesses (p < 0.05) and even more in intermediate tumor thicknesses of 1.51-4.0 mm (p < 0.001). A significant benefit of elective lymph node dissection was detected for malignant melanoma of the trunk (all tumor thicknesses), as shown by the 5-year survival rates of 92.0% versus 79.7% and 10-year survival rates of 80.4% versus 45.16% (p < 0.05). Malignant melanoma of the extremities revealed no significant differences in survival rates. We conclude that there is a certain benefit from ELND in clinical stage I malignant melanoma for tumor thicknesses of 1.51-4.00 mm. Especially in malignant melanoma of the trunk, WLE plus ELND was more beneficious than WLE alone.

Actuarial Analysis↗
PubMed1995

Perspectives of cytokine treatment in malignant skin tumors.

Cytokines have been tested in the treatment of different skin cancers during the last decade, and treatment schedules have been established or proposed for several malignant skin tumors. Preferentially, the interferons and interleukin-2 were found to be effective in treating skin cancers. Interferons alpha and beta have been approved for the treatment of human immunodeficiency virus (HIV)-associated Kaposi's sarcoma, cutaneous T cell lymphoma, and malignant melanoma in several countries. Interferon alpha was found to be most effective in cutaneous T cell lymphoma with 40%-60% overall responses. When combining interferon alpha with psoralens and ultraviolet A (PUVA) or with retinoids, even higher response rates up to 60%-90% were reported, and long-term remissions have been described. A considerable activity of interferon alpha was found in HIV-associated Kaposi's sarcoma with response rates of 30%-50%. The effectiveness of Kaposi's sarcoma's treatment was further improved by combining interferon alpha and zidovudine. Responses to interferon alpha in metastatic malignant melanoma are rather seldom (10%-15%), but a stabilization of the disease with prolonged survival was reported after interferon alpha treatment. Additionally, interleukin-2 was found to be active in metastatic melanoma, with overall response rates of about 20%, and both biological agents were found to have an additive efficacy in combination. Several combined regimens of interferon alpha, interleukin-2, and polychemotherapy have been described in metastatic melanoma, and overall response rates higher than 50% were found with these combined treatment modalities. Interferon alpha and beta were also intralesionally injected into basal cell carcinomas and other epithelial skin cancers, and complete responses were found in more than 80% of tumors treated. Local applications of interferons and interleukin-2 were likewise found to be effective in the treatment of cutaneous melanoma metastases and cutaneous manifestations of Kaposi's sarcoma. Cytokines and their combination with other treatment modalities has greatly enriched the treatment facilities in malignant skin tumors during recent years, and additional new cytokines will be introduced in skin cancer treatment in near future.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Photodynamic action of ultraviolet A: induction of cellular hydroperoxides.

Long-wavelength ultraviolet radiation (UVA) can cause cancer. A carcinogenic mechanism involved may be the induction of harmful reactive oxygen species resulting from photodynamic effects. UVA is generally assumed to induce photodynamic effects, but evidence from experiments with viable biological materials has been indirect until present. Here we measured the induction of (lipid) hydroperoxides as direct indicators of photodynamic reactions. Cultured human fibroblasts were irradiated with 10J UVA/cm2. The induced hydroperoxides were measured by an enzymatic method using glutathione peroxidase and glutathione reductase (GR). Additionally, reduced glutathione (GSH) was determined as parameter for the constitutive antioxidant defense. UVA was found to increase lipid hydroperoxides in fibroblasts by 116% (p < 0.001), when compared to nonirradiated controls. Conversely GSH was decreased in the irradiated cells by 51% (p < 0.001). Because of the induced hydroperoxides, it is concluded that the UVA effects were mediated by a photodynamic mechanism. The photodynamic mechanism resulted in the formation of reactive oxygen species and the consumption of constitutive antioxidants. This suggests a role for antioxidants during the photodynamic mechanism. Photodynamic mechanisms may play a crucial role in carcinogenic events, especially after UVA.

Antioxidants↗
PubMed1995

Protein patterns of benign and malignant human melanocytes show consistent changes in gene expression.

For human malignant melanoma, no pattern of oncogene activation has yet been identified which consistently occurs in the malignant cells. In order to better understand the transformation process, we studied the overall gene expression at the protein level in human melanoma cells in vitro by two-dimensional gel electrophoresis. For that, four established cell lines, MEWO, M5, SKMEL13, and IGR39, were used and compared with newly established cultures of normal human melanocytes. Considerable variations in the protein patterns of the different melanoma cell lines were found, whereas the patterns of normal human melanocytes correlated fairly well with each other. With respect to the expression of single proteins, we identified four major proteins which were consistently found in cultured melanocytes and stringently repressed in the four melanoma cell lines examined. On the other hand, induction of new proteins in the different melanoma cell lines was found to be less stringent and also less uniform. We propose that malignant transformation of melanocytes may be more associated with the suppression of melanocytic proteins rather than with new expression of melanoma specific proteins.

Cells, Cultured↗
PubMed1995

Identification of genes specifically regulated in human melanoma cells.

In order to improve the characterization of human malignant melanoma cells and their variant gene expression in vitro, a search for specifically regulated genes was performed. Four melanoma cell lines (M5, MEWO, IGR39, SKMEL13) and newly cultured normal human melanocytes were included in a comparative hybridization (differential screening) of a human melanoma cDNA-library. Six cDNAs were isolated showing a stronger expression (four genes) or a weaker expression (two genes) in melanoma cells than in normal human melanocytes. Quantification of the expression patterns of the two repressed genes in Northern blots revealed general expression in all melanocyte cultures examined, no expression in three cell lines (M5, IGR39, SKMEL13) and weak expression in MEWO. The four induced genes were found to be only weakly expressed in normal human melanocytes, but showed an elevated expression in all of the four melanoma cell lines tested. Thus, using the technique of differential screening, consistent gene regulation at the messenger RNA level was identified, which distinguishes the four melanoma cell lines tested from normal melanocytes. We conclude from the expression patterns that specific gene regulation in melanoma cells in vitro is characterized both by strong repression of some melanocyte genes, as well as by the induction of other genes, but there was no indication of new expression of genes specific for melanoma cells. Because of the uniform induction or repression in different melanoma cell lines, it is conceivable that the cloned genes may be involved in the malignant transformation of melanocytic cells.

Base Sequence↗
PubMed1995

Tumour necrosis factors and several interleukins inhibit the growth and modulate the antigen expression of normal human melanocytes in vitro.

In the present study the action of various cytokines as regulators of human melanocyte growth and differentiation was examined in vitro. Primary melanocyte cultures were obtained in complete medium free of 12-O-tetradecanoylphorbol-13-acetate or serum. First passage melanocytes were treated with various concentrations of recombinant tumour necrosis factor alpha and beta (rTNF-alpha, rTNF-beta), as well as with various recombinant interleukins (rIL-1a, rIL-1b, rIL-2, rIL-3, rIL-4 and rIL-6) for 6 days in complete medium and for 6 and 12 days in a mitogen-reduced medium variant. The 4-methylumbelliferyl heptanoate fluorometric microassay and Ki-67 staining were used for assessing cell proliferation, and the immunophenotype was evaluated using various monoclonal antibodies. Melanocyte proliferation in complete medium was inhibited by rTNF-alpha (-24%), rTNF-beta (-17%), rIL-1a (-21%), rIL-1b (-18%) and rIL-6 (-29%); in contrast, rIL-2, rIL-3 and rIL-4 had no antiproliferative effect. Measurements of Ki-67-positive nuclei confirmed these results. In the reduced medium variant, none of the above cytokines inhibited melanocyte proliferation. Recombinant TNF-alpha and rTNF-beta markedly reduced the expression of the pigment cell-associated antigens HMB-45 and K.1.2, and they enhanced the expression of VLA-2, ICAM-1 and HLA class I antigens and strongly induced HLA-DR. Similar changes were induced by rIL-1a, rIL-b and rIL-6, and rIL-2 decreased the expression of HLA class I antigens and of ICAM-1. In conclusion, several cytokines inhibited the growth and modulated the phenotype of melanocytes in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

Antigens↗