M. Wosnitza

Active transport of contact allergens and steroid hormones in epidermal keratinocytes is mediated by multidrug resistance related proteins.

TO THE EDITOR The phenomenon of multidrug resistance (MDR) is defined as the ability of a cell to show resistance to a wide variety of structurally and functionally unrelated molecules and is, in large part, related to membrane efflux transporters because its principal mechanism is the active transport of substrates out of the cell (Higgins, 2007). Multidrug transporters have broad specificity for a wide range of chemically unrelated agents (Higgins, 2007). One superfamily of active membrane transporters is the family of ATP-binding cassette (ABC) transport proteins that use the energy of ATP hydrolysis to transport large organic molecules either directly or, in case of many natural substrates, conjugated to acidic ligands, such as glutathione, glucuronate, or sulfate out of the cell (König et al., 1999). Although most ABC transporters were discovered as drug transporters, they frequently transport a wide range of physiological substrates, including peptides, steroids, and inflammatory lipid mediators (Robbiani et al., 2000; Borges-Walmsley et al., 2003; Reid et al., 2003). Therefore, it is further understood that these efflux pumps have, in addition to conferring resistance of tumor cells to various chemotherapeutic drugs, crucial physiological roles (Piddock, 2006). Several studies have been carried out to investigate the expression, regulation, and specific substrates of ABC efflux transport proteins, such as P-glycoprotein (P-gp) and multidrug resistance-associated proteins (MRP, gene name: ATP binding cassette C transporters, ABCC) (Flens et al., 1996; Ishikawa et al., 2000). Earlier it has been shown that cells of the skin express a specific pattern of several efflux proteins (Sleeman et al., 2000; Baron et al., 2001; Colone et al., 2008). Gene expression analysis of normal human epidermal keratinocytes (NHEK) showed constitutive expression of MRP1 (ABCC1) as well as MRP 3–7 (ABCC3–7), but was negative for MDR1 and MRP2 (ABCC2) (Baron et al., 2001). With regard to the regulatory mechanisms of these transport proteins in skin cells, it was shown that the expression of different MRP family members can be significantly enhanced by IL-6-type cytokines. Furthermore, upregulation of MRP expression was found in lesional skin samples collected from patients with inflammatory skin disorders such as psoriasis and lichen planus (Dreuw et al., 2005). In this study, we provide evidence for the functional MRP-mediated efflux activity of NHEKs using an in vitro transport assay. Therefore, the efflux transport of various radiolabeled compounds, including eugenol (4-allyl-2methoxyphenol), isoeugenol, estradiol 17beta-D-glucuronid (E217bG), oestrone3-sulfate, cyclosporine, and dexpanthenol, was inhibited by the specific MRP inhibitors, such as indomethacin (Figure 1) (Draper et al., 1997; Zhou et al., 2008) or MK571 (Figure 2) (Skazik et al., 2008; Zhou et al., 2008), and the intracellular accumulation of these substrates was determined after 15, 30, and 60 minutes. Cells not treated with the inhibitor served as a control. Treatment with indomethacin at a concentration of 1 mM decreased the efflux transport of [H]E217bG up to 6.5-fold and of [H]oestrone-3sulfate up to 3.6-fold in NHEKs in comparison with control transport measured in the absence of the inhibitor (Figure 1a and b). Treatment of NHEKs with MK571 decreased the efflux of [H]E217bG in a concentrationdependent manner at a concentration of 25 mM up to 4.1-fold and at a concentration of 100mM up to 5.1-fold (Figure 2a). MK571 strongly reduced the efflux of [H]oestrone-3-sulfate as well in a concentration-dependent manner, as the cells accumulated this steroid hormone up to 3.2-fold using 25 mM of MK571 and up to 6.1-fold using 100mM of the inhibitor (Figure 2b) in comparison with control transport that is measured in the absence of the inhibitor. Indomethacin blocked the efflux transport of [H]eugenol up to 1.6-fold compared with control cells without indomethacin treatment (Figure 1c). Treatment of cells with indomethacin increased intracellular concentration of [H]isoeugenol only slightly up to 1.1-fold (Figure 1d). Treatment of NHEKs with MK571 at concentrations of 100mM and 25 mM decreased efflux transport of [H]eugenol and [H]isoeugenol, respectively, to 1.6-fold after 60 minutes of incubation (Figure 2c and d). Time course experiments show stronger effects of both inhibitors on the accumulation of E217bG, oestrone-3-sulfate, eugenol, and isoeugenol (Figures 1a–d and 2a–d) in the cell after 60 minutes compared with 15 or 30 minutes. This adds to the suggestion that these effects are due to the inhibition of efflux transport and not due to influx transport. Treatment of cells with indomethacin or MK571

Kontaktsensibilisierung gegen Azol-Antimykotika

Contact sensitization to azole antimycotics is rare, even though they are widely used. We present the case of a man who developed allergic contact dermatitis due to topical application of a variety of antimycotics. Patch testing revealed positive reactions to clotrimazole, croconazole, oxiconazole and tioconazole. Cross-sensitivity was possible, but multiple sensitizations could not be excluded.ZusammenfassungKontaktsensibilisierungen gegen Azol-Antimykotika sind trotz ihrer weiten Verbreitung sehr selten. Wir berichten über einen Patienten mit allergischer Kontaktdermatitis nach lokaler Anwendung verschiedener Antimykotika. In der Epikutantestung zeigten sich positive Reaktionen auf Clotrimazol, Croconazol, Oxiconazol und Tioconazol. Hierbei handelt es sich möglicherweise um Kreuzreaktionen. Multiple Sensibilisierungen konnte anamnestisch jedoch nicht ausgeschlossen werden.AbstractContact sensitization to azole antimycotics is rare, even though they are widely used. We present the case of a man who developed allergic contact dermatitis due to topical application of a variety of antimycotics. Patch testing revealed positive reactions to clotrimazole, croconazole, oxiconazole and tioconazole. Cross-sensitivity was possible, but multiple sensitizations could not be excluded.

Contact sensitization to azole antimycotics.

Contact sensitization to azole antimycotics is rare, even though they are widely used. We present the case of a man who developed allergic contact dermatitis due to topical application of a variety of antimycotics. Patch testing revealed positive reactions to clotrimazole, croconazole, oxiconazole and tioconazole. Cross-sensitivity was possible, but multiple sensitizations could not be excluded.ZusammenfassungKontaktsensibilisierungen gegen Azol-Antimykotika sind trotz ihrer weiten Verbreitung sehr selten. Wir berichten über einen Patienten mit allergischer Kontaktdermatitis nach lokaler Anwendung verschiedener Antimykotika. In der Epikutantestung zeigten sich positive Reaktionen auf Clotrimazol, Croconazol, Oxiconazol und Tioconazol. Hierbei handelt es sich möglicherweise um Kreuzreaktionen. Multiple Sensibilisierungen konnte anamnestisch jedoch nicht ausgeschlossen werden.AbstractContact sensitization to azole antimycotics is rare, even though they are widely used. We present the case of a man who developed allergic contact dermatitis due to topical application of a variety of antimycotics. Patch testing revealed positive reactions to clotrimazole, croconazole, oxiconazole and tioconazole. Cross-sensitivity was possible, but multiple sensitizations could not be excluded.

The PAPA Syndrome

The PAPA syndrome is a very rare autoinflammatory disorder and is a clinically allotropic syndrome affecting both joints and skin (OMIM #604416). Depending on the clinical manifestations, some authors use the term familial recurrent arthritis (FRA) as a synonym for PAPA syndrome, if early childhood arthritis and joint destruction are the dominant clinical features [1].

Merkel cell carcinoma

ZusammenfassungEin 67-jähriger Patient entwickelte innerhalb kurzer Zeit mehrere hautfarbene Knoten an seinem linken Handrücken. Das histologische Gutachten ergab ein Merkel-Zell-Karzinom (MCC). Das MCC ist ein äußerst aggressiv wachsender kutaner Tumor, der von neuroendokrinen Zellen der Basalschicht der Epidermis ausgeht. Bekannte Risikofaktoren sind ein fortgeschrittenes Alter, Immunsuppression und UV-Exposition. Aktuelle Studien konnten ein neues Polyomavirus (MCPyV) in 75–85% der Neoplasien nachweisen, das eine zentrale Rolle in der Entstehung des MCC zu spielen scheint. Hier erhofft man sich neue und wirksamere Therapieoptionen.AbstractA 67-year old patient developed multiple flesh-colored nodules on the back of his left hand. Histological examination led to the diagnosis of a Merkel cell carcinoma (MCC). This highly aggressive primary cutaneous tumor is classified as a neuroendocrine carcinoma. It affects mostly elderly and immunosuppressed patients. Recently, a new polyomavirus (MCPyV) has been detected in about 75–85% of MCC and seems to play an important role in their pathogenesis. This new finding may help to develop new therapeutic options for MCC.A 67-year old patient developed multiple flesh-colored nodules on the back of his left hand. Histological examination led to the diagnosis of a Merkel cell carcinoma (MCC). This highly aggressive primary cutaneous tumor is classified as a neuroendocrine carcinoma. It affects mostly elderly and immunosuppressed patients. Recently, a new polyomavirus (MCPyV) has been detected in about 75-85% of MCC and seems to play an important role in their pathogenesis. This new finding may help to develop new therapeutic options for MCC.

Merkel-Zell-Karzinom des Handrückens

ZusammenfassungEin 67-jähriger Patient entwickelte innerhalb kurzer Zeit mehrere hautfarbene Knoten an seinem linken Handrücken. Das histologische Gutachten ergab ein Merkel-Zell-Karzinom (MCC). Das MCC ist ein äußerst aggressiv wachsender kutaner Tumor, der von neuroendokrinen Zellen der Basalschicht der Epidermis ausgeht. Bekannte Risikofaktoren sind ein fortgeschrittenes Alter, Immunsuppression und UV-Exposition. Aktuelle Studien konnten ein neues Polyomavirus (MCPyV) in 75–85% der Neoplasien nachweisen, das eine zentrale Rolle in der Entstehung des MCC zu spielen scheint. Hier erhofft man sich neue und wirksamere Therapieoptionen.AbstractA 67-year old patient developed multiple flesh-colored nodules on the back of his left hand. Histological examination led to the diagnosis of a Merkel cell carcinoma (MCC). This highly aggressive primary cutaneous tumor is classified as a neuroendocrine carcinoma. It affects mostly elderly and immunosuppressed patients. Recently, a new polyomavirus (MCPyV) has been detected in about 75–85% of MCC and seems to play an important role in their pathogenesis. This new finding may help to develop new therapeutic options for MCC.A 67-year old patient developed multiple flesh-colored nodules on the back of his left hand. Histological examination led to the diagnosis of a Merkel cell carcinoma (MCC). This highly aggressive primary cutaneous tumor is classified as a neuroendocrine carcinoma. It affects mostly elderly and immunosuppressed patients. Recently, a new polyomavirus (MCPyV) has been detected in about 75-85% of MCC and seems to play an important role in their pathogenesis. This new finding may help to develop new therapeutic options for MCC.

Merkel-Zell-Karzinom des Handrückens@@@Merkel cell carcinoma

ZusammenfassungEin 67-jähriger Patient entwickelte innerhalb kurzer Zeit mehrere hautfarbene Knoten an seinem linken Handrücken. Das histologische Gutachten ergab ein Merkel-Zell-Karzinom (MCC). Das MCC ist ein äußerst aggressiv wachsender kutaner Tumor, der von neuroendokrinen Zellen der Basalschicht der Epidermis ausgeht. Bekannte Risikofaktoren sind ein fortgeschrittenes Alter, Immunsuppression und UV-Exposition. Aktuelle Studien konnten ein neues Polyomavirus (MCPyV) in 75–85% der Neoplasien nachweisen, das eine zentrale Rolle in der Entstehung des MCC zu spielen scheint. Hier erhofft man sich neue und wirksamere Therapieoptionen.AbstractA 67-year old patient developed multiple flesh-colored nodules on the back of his left hand. Histological examination led to the diagnosis of a Merkel cell carcinoma (MCC). This highly aggressive primary cutaneous tumor is classified as a neuroendocrine carcinoma. It affects mostly elderly and immunosuppressed patients. Recently, a new polyomavirus (MCPyV) has been detected in about 75–85% of MCC and seems to play an important role in their pathogenesis. This new finding may help to develop new therapeutic options for MCC.A 67-year old patient developed multiple flesh-colored nodules on the back of his left hand. Histological examination led to the diagnosis of a Merkel cell carcinoma (MCC). This highly aggressive primary cutaneous tumor is classified as a neuroendocrine carcinoma. It affects mostly elderly and immunosuppressed patients. Recently, a new polyomavirus (MCPyV) has been detected in about 75-85% of MCC and seems to play an important role in their pathogenesis. This new finding may help to develop new therapeutic options for MCC.

Kontaktsensibilisierung gegen Azol-Antimykotika@@@Contact sensitization to azole antimycotics

Contact sensitization to azole antimycotics is rare, even though they are widely used. We present the case of a man who developed allergic contact dermatitis due to topical application of a variety of antimycotics. Patch testing revealed positive reactions to clotrimazole, croconazole, oxiconazole and tioconazole. Cross-sensitivity was possible, but multiple sensitizations could not be excluded.ZusammenfassungKontaktsensibilisierungen gegen Azol-Antimykotika sind trotz ihrer weiten Verbreitung sehr selten. Wir berichten über einen Patienten mit allergischer Kontaktdermatitis nach lokaler Anwendung verschiedener Antimykotika. In der Epikutantestung zeigten sich positive Reaktionen auf Clotrimazol, Croconazol, Oxiconazol und Tioconazol. Hierbei handelt es sich möglicherweise um Kreuzreaktionen. Multiple Sensibilisierungen konnte anamnestisch jedoch nicht ausgeschlossen werden.AbstractContact sensitization to azole antimycotics is rare, even though they are widely used. We present the case of a man who developed allergic contact dermatitis due to topical application of a variety of antimycotics. Patch testing revealed positive reactions to clotrimazole, croconazole, oxiconazole and tioconazole. Cross-sensitivity was possible, but multiple sensitizations could not be excluded.

Ekkrines Adenokarzinom bei einer Patientin mit familiärem Mammakarzinom

A 67-year-old patient developed a subcutaneous, non-tender nodule in her left groin over a period of about seven years. The patient underwent surgery and 4 procedures were required to obtain complete excision. The histopathologic findings showed eccrine adenocarcinoma, a member of the heterogeneous group of sweat gland tumors which occur primarily in adults with a peak of 50-60 years of age. Sweat gland carcinomas are extremely rare neoplasms of the skin and exhibit a slow growth rate with a rather high local recurrence rate. The tumor has a disposition to metastasize and shows a poor response rate to adjuvant therapy regimens. Therefore wide, deep surgical excision with an excision margin of 2-3 cm is the treatment of choice. Nevertheless there are some case reports on successful therapy of a metastasized sweat gland carcinoma with 5-fluorouracil and tamoxifen. Here further studies are needed to achieve a better survival rate for patients with metastatic disease.

Eccrine adenocarcinoma in a patient with familial breast carcinoma

A 67-year-old patient developed a subcutaneous, non-tender nodule in her left groin over a period of about seven years. The patient underwent surgery and 4 procedures were required to obtain complete excision. The histopathologic findings showed eccrine adenocarcinoma, a member of the heterogeneous group of sweat gland tumors which occur primarily in adults with a peak of 50-60 years of age. Sweat gland carcinomas are extremely rare neoplasms of the skin and exhibit a slow growth rate with a rather high local recurrence rate. The tumor has a disposition to metastasize and shows a poor response rate to adjuvant therapy regimens. Therefore wide, deep surgical excision with an excision margin of 2-3 cm is the treatment of choice. Nevertheless there are some case reports on successful therapy of a metastasized sweat gland carcinoma with 5-fluorouracil and tamoxifen. Here further studies are needed to achieve a better survival rate for patients with metastatic disease.