[Skin diseases as indicators of cancer]. / Hauterkrankungen als Hinweis auf Neoplasien.

In contrast to the obligatory paraneoplasias, which are usually rare, diseases such as Sweet's syndrome, thrombophlebitis or herpes zoster are more common. But they are less frequently associated with neoplasia. The risk of overlooking an associated neoplasm is therefore greater. In this article, prototypic diseases are presented with their clinical appearance, possible pathogenesis and treatment options; this is accompanied by raising awareness of potential associations with cancer. The emphasis on the distinct features of the neoplasm-associated forms should enable more reliable detection of these variants and hopefully contribute to an earlier diagnosis of associated neoplasms. These peculiarities include the jumping or wandering thrombophlebitis occurring as Trousseau's syndrome, recurrent, severe courses with involvement of the oral mucosa in Sweet's syndrome or the necrotizing, gangrenous clinical course, often with a multisegment distribution pattern of herpes zoster. Studies on the association of facultative cutaneous paraneoplasias with certain tumors are presented. However, no general recommendation for tumor screening in patients with herpes zoster, Sweet's syndrome or thrombophlebitis can be given. In atypical courses, particularly severe manifestations or the absence of other causes, more extensive diagnostic procedures appear appropriate in order not to miss possibly associated neoplasms.

Fluticasone/formoterol dry powder versus budesonide/formoterol in adults and adolescents with uncontrolled or partly controlled asthma.

UNLABELLED: This 12-week study compared the efficacy and safety of a fixed combination of fluticasone propionate plus formoterol (FL/F) 250/12 µg b.i.d. administered via a dry powder inhaler (DPI) (Libbs Farmacêutica, Brazil) to a combination of budesonide plus formoterol (BD/F) 400/12 µg b.i.d. After a 2-week run-in period (in which all patients were treated exclusively with budesonide plus formoterol), patients aged 12-65 years of age (N = 196) with uncontrolled asthma were randomized into an actively-controlled, open-labeled, parallel-group, multicentre, phase III study. The primary objective was to demonstrate non-inferiority, measured by morning peak expiratory flow (mPEF). The non-inferiority was demonstrated. A statistically significant improvement from baseline was observed in both groups in terms of lung function, asthma control, and the use of rescue medication. FL/F demonstrated a statistical superiority to BD/F in terms of lung function (FEV(1)) (p = 0.01) and for asthma control (p = 0.02). Non-significant between-group differences were observed with regards to exacerbation rates and adverse events. In uncontrolled or partly controlled asthma patients, the use of a combination of fluticasone propionate plus formoterol via DPI for 12-weeks was non-inferior and showed improvements in FEV(1) and asthma control when compared to a combination of budesonide plus formoterol. ( CLINICAL TRIAL NUMBER: ISRCTN60408425).

[In vitro diagnosis and monitoring of Hymenoptera venom hyposensitization]. / In-vitro-Diagnostik und Monitoring bei Insektengifthyposensibilisierung.

Specific immunotherapy (SIT) of hymenoptera venom allergy, in particular, has become an example for the effectiveness of the treatment of IgE-mediated allergic diseases. In vitro diagnostic procedures and the measurement of serum tryptase for risk assessment are well-established in the process of diagnose finding and therapy preparation. For monitoring and validation of the effectiveness of the SIT, however, in vitro diagnostic procedures remain controversial. Potentially useful approaches include detection of specific IgE, specific IgG4, basophile activation - represented by the CD 63 expression - and the lymphocyte proliferation and its IL10 release. Preliminary data suggest that the latter method appear appropriate, whereas the detection of basophile activation did not produce definite results.

Expression and induction of cytochrome p450 isoenzymes in human skin equivalents.

Organotypic skin models are frequently used for a wide range of applications and latterly also for dermatotoxicological studies. To evaluate their practicability for the investigation of xenobiotic metabolism in human skin we compared three types of organotypic skin models, acquired by purchase from different manufacturers, to a self-constructed in-house model with regard to cytochrome P450 (CYP) isoenzyme expression on mRNA and protein level and the inducibility of these enzymes by aryl hydrocarbon receptor ligands. To induce enzyme activity, models were treated with benzanthracene, liquor carbonis detergens, pix lithanthracis or dimethyl sulfoxide as a solvent control. RNA was isolated by phenol-chloroform extraction and purified. Gene expression patterns were studied by cDNA microarray analysis. Microarray data were confirmed by real-time PCR. For quality control of the models and to detect and localize enzyme expression, immunofluorescence staining was performed with antibodies against CYPs and structure proteins. The immunofluorescence staining demonstrated the regular structure of our models. We could provide evidence for the expression of CYP types 1A1, 1B1, 2E1, 2C and 3A5 in organotypic skin models. The expression of CYP1A1 and CYP1B1 was highly inducible by treatment with liquor carbonis detergens. The proof of the expression and inducibility of CYP enzymes in organotypic skin models suggests that skin equivalents are a valuable tool that can emulate CYP-dependent metabolism of drugs and other xenobiotics in human skin.

[Imaging of actinic porokeratosis by optical coherence tomography (OCT)]. / Bildgebende Diagnostik der aktinischen Porokeratose mittels optischer Kohärenztomographie (OCT).

Disseminated superficial actinic porokeratosis (DSAP) is a rare, genetically heterogeneous skin disorder. We report a case of a 73-year-old female patient who was diagnosed with DSAP by optical coherence tomography (OCT) and histology. During the last 4 years prior to diagnosis, she had developed numerous (pre)malignant lesions of the skin of the lower legs including actinic keratoses, squamous cell carcinomas and Bowen's disease. DSAP lesions and actinic keratoses were resistant to topical treatment with imiquimod and retinoids, but improved with photodynamic therapy (PDT).

Determination of interleukin-5 secretion from drug-specific activated ex vivo peripheral blood mononuclear cells as a test system for the in vitro detection of drug sensitization.

BACKGROUND: In vitro detection of drug sensitization is still limited. The lymphocyte transformation test, which determines drug-specific proliferation, is the only in vitro test for detecting drug sensitization at the cellular level irrespective of the reaction's clinical phenotype. Accumulation of eosinophils following IL-5 secretion from drug-specific stimulated T cells is a characteristic histological feature of drug-induced skin eruptions. OBJECTIVE: We determined whether in vitro drug-specific activation of ex vivo peripheral blood mononuclear cells from 10 patients with drug-induced maculopapular exanthems and three patients with severe skin reactions results in secretion of IL-5, IL-10 or IFN-gamma and assessed the sensitivity and specificity of drug-specific IL-5 secretion as a test system compared with the lymphocyte transformation test and patch tests. Furthermore, the subsets of CD4+ and CD8+ T cells involved in drug-specific proliferation, IL-5 secretion and mRNA expression were examined in three patients. METHODS: Drug-specific proliferation of peripheral blood mononuclear cells in the lymphocyte transformation test was investigated by 3H-thymidine uptake, and culture supernatants taken after 5 days were analysed for IL-5, IL-10 and IFN-gamma concentrations by ELISA technique. IL-5 mRNA expression was determined by RT-PCR. RESULTS: Drug-specific activation of peripheral blood mononuclear cells consistently resulted in IL-5 and to a lesser extent in IL-10 and IFN-gamma secretion. The sensitivities of the patch test, lymphocyte transformation test and assessment of drug-specific IL-5 secretion for the detection of drug sensitization were 55%, 75% and 92%, respectively. CONCLUSION: These data suggest a role for the determination of drug-specific IL-5 secretion by ex vivo peripheral blood mononuclear cells for the in vitro detection of drug-sensitization in drug-induced maculopapular exanthems.

Expression of multiple cytochrome p450 enzymes and multidrug resistance-associated transport proteins in human skin keratinocytes.

Cytochrome P450 enzymes metabolize various endogenous and exogenous small molecular weight compounds. Transport-associated proteins, such as P-glycoprotein, multidrug resistance-associated protein and lung resistance protein are overexpressed in drug-resistant cell lines, as well as in human tumors from various histologic origins, including malignant melanoma. Little is known about the expression and function of cytochrome enzymes and multidrug resistance-associated transport proteins in human skin; therefore, the aim of this study was to analyze the expression pattern of cytochrome enzymes and multidrug resistance-associated transport proteins in proliferating human epidermal keratinocytes under constitutive conditions and after induction with various inducers. Reverse transcription-polymerase chain reaction revealed constitutive expression of cytochromes 1A1, 1B1, 2B6, 2E1, and 3A5 in keratinocytes and showed expression of cytochrome 3A4 after incubation with dexamethasone. The expression of cytochrome 1A1 was enhanced on the mRNA level after induction with benzanthracene. Reverse transcription-polymerase chain reaction analysis of the multidrug resistance-associated transport proteins revealed constitutive expression of multidrug resistance-associated proteins 1 and 3-6, and lung resistance protein in human epithelial keratinocytes and was negative for multidrug resistance 1 and 2. Expression of 1 was seen after induction with dexamethasone. Reverse transcription-polymerase chain reaction results were confirmed by immunoblots which showed expression of cytochromes 1A1, 2B6, 2E1, and 3A, multidrug resistance-associated proteins 1, 3, and 5 as well as multidrug resistance 1 after induction with dexamethasone. Immunohistology showed positive immunofluorescence in skin specimens for cytochromes 1A1, 2B6, 2E1, and 3A and multidrug resistance-associated protein 1 and multidrug resistance 1. Constitutive activity of cytochrome 1A1, 2B, 2E1, and 3A enzymes was measured by catalytic assays. These results show that keratinocytes of the human skin express various transport-associated enzymes and detoxifying metabolic enzymes. Previous studies have revealed that cytochrome enzymes and transport-associated proteins play complementary parts in drug disposition by biotransformation (phase I) and anti-transport (phase III) and act synergistically as a drug bioavailability barrier.

Analysis of tumor cell evolution in a melanoma: evidence of mutational and selective pressure for loss of p16ink4 and for microsatellite instability.

Tumorigenesis and tumor progression can be considered an evolutionary process. In order to deduce information on the mutational and selective pressures during melanoma progression we performed microsatellite analysis at 42 autosomal and two X-linked loci in a microdissected primary melanoma and its nine metastases. Loss of heterozygosity at locus D9S259 was the only genetic change observed in all metastases. The pattern of loss of heterozygosity at loci D9S162 and D9S171 within the region of common loss on chromosome 9p21 which encompasses the tumor suppressor gene p16ink4 enabled the distinction of four genetically different tumor cell populations. Three cell lineages showed homozygous loss of the p16ink4 gene, which evolved independently in each tumor cell population within the primary tumor. Additional allele losses could be demonstrated at markers D14S53 and DXS998. The fourth lineage did not demonstrate loss of heterozygosity at loci D9S162 and D9S171 and contained the wild type p16ink4 gene but was characterized by abundant microsatellite instability. The evolutionary approach towards tumorigenesis and tumor progression used in this study thus confirms the role of p16ink4 inactivation for melanoma progression but not for melanoma initiation; it suggests the existence of additional putative tumor suppressor genes located on 9p as well as on the long arm of chromosome 14 and shows that microsatellite instability may represent an alternative pathway of tumor cell evolution in malignant melanoma.