Brigitte Almond-Roesler

Current Use and Future Potential Role of Retinoids in Dermatology

SummarySince their introduction 15 years ago, retinoids have been increasingly used for topical and systemic treatment of psoriasis and other hyperkeratotic and parakeratotic skin disorders, keratotic genodermatoses, severe acne and acne-related dermatoses, and also for therapy and/or chemoprevention of skin cancer and other neoplasia. Oxidative metabolites of vitamin A (retinol) are natural retinoids present at low levels in the peripheral blood. Synthetic retinoids are classified into 3 generations including nonaromatic, monoaromatic and polyaromatic compounds. They are detectable in plasma 30–60 minutes after systemic administration, and reach maximum concentrations 2 to 4 hours later. Elimination half-life is 10 to 20 hours for isotretinoin, 80 to 175 days for etretinate and 2 to 4 days for trans-acitretin; the latter, however, partially converts into etretinate. Retinoid concentrations in skin are rather low in contrast to subcutaneous fat tissue.Intracellularly, retinoids interact with cytosolic proteins and specific nuclear receptors. Two classes of nuclear receptors have been suggested to mediate retinoid activity at the molecular level, RARs and RXRs. The expression of retinoid receptors is tissue specific; skin mainly espresses RARγ and RXRα. Retinoids affect epidermal cell growth and differentiation as well as sebaceous gland activity and exhibit immunomodulatory and anti-inflammatory properties.Current retinoid research targets the development of receptor-selective retinoids for tailoring and/or improving their therapeutic profile. Currently, tretinoin is used systemically for acute promyelocytic leukaemia, etretinate and acitretin for psoriasis and related disorders, as well as other disorders of keratinisation, and isotretinoin for seborrhoea, severe acne, rosacea and acneiform dermatoses. Systemic retinoids are also applied for chemoprevention of epithelial skin cancer and cutaneous T cell lymphoma. The major adverse effect of retinoids is teratogenicity; all other adverse effects are dose-dependent and controllable. Contraception is, therefore, essential during retinoid treatment in women of child-bearing age. Clinical monitoring requires physical examination for adverse effects every 3 to 4 weeks and proper laboratory investigations, also including analysis of retinoid bioavailability in selected cases. Topical retinoids are rapidly developing at present and seem promising for the future; their clinical application includes acne, aging, photodamage, precanceroses, skin cancer and disorders of skin pigmentation. The development of receptor-specific retinoids for topical treatment of psoriasis and/or acne may lead to interesting new compounds based on our current concepts of retinoid function.

Merkel cell carcinoma: Report of ten cases with emphasis on clinical course, treatment, and in vitro drug sensitivity

BACKGROUND Merkel cell carcinoma (MCC) is an uncommon primary neuroendocrine skin tumor most often seen in the elderly. The clinical course varies. Treatment is controversial and few data on drug sensitivity are available. OBJECTIVE We evaluated the clinical course and treatment of 10 MCC patients and determined MCC chemosensitivity. METHODS Clinical records as well as laboratory and histopathologic data from 10 patients with MCC treated in our department were examined. Chemosensitivity to various chemotherapeutic agents and interferons of MCC cells from four patients was determined in a soft agar clonogenic assay. RESULTS MCC behaved as an aggressive tumor with early and frequent local relapses (4 of 10 patients at a 2.2-month average), regional (4 of 10 patients at 2.5 months), and distant metastases (5 of 10 patients 9.6 months after excision of the primary tumor). In all but one patient, regional metastases preceded distant ones. Metastatic spread was associated with an average survival of 21 months from the initial diagnosis. Long-term survival (53+ and 65+ months) was observed in two women. Wide excision of the primary tumor, alone or combined with adjuvant chemotherapy and radiotherapy, was the most effective treatment. In advanced disease, chemotherapy and radiotherapy were not able to induce long-term remission. In vitro assays for MCC drug sensitivity revealed cisplatin, doxorubicin, and vindesine to be the most active. CONCLUSION MCC has a poor prognosis in advanced stages; therefore the primary tumor should be aggressively treated. The in vitro clonogenic assay may help to identify the chemosensitivity profile of MCC and to optimize chemotherapy protocols.

Cultured dermal papilla cells of the rat vibrissa follicle. Proliferative activity, adhesion properties and reorganization of the extracellular matrix in vitro

Abstract The dermal papilla of the mammalian hair follicle plays an important role in regulating and controlling the hair cycle. Distinct functional stages of dermal papilla cells (DPC) are involved in this process, thus suggesting that the dermal papilla is a highly specialized suborgan of the pilosebaceous unit. The aim of the present study was to investigate the functional properties of cultured DPC in various assays and to compare their functional properties with those of dermal fibroblasts (DFB). In monolayer cell cultures DPC showed an aggregative growth pattern, different to that of DFB, and lower proliferation rates, as compared to the controls. Adhesion assays performed using a 51 [Cr]labelling method showed strong adhesion of both cell populations to collagen types I and IV, fibronectin and laminin, but DPC in vitro showed significantly higher adhesiveness to collagen type IV, a major component of the basement membrane of dermal papillae in vivo. The capacity of DPC to reorganize extracellular matrix components, as measured by gel contraction with three-dimensional collagen type I lattices, proved to be significantly lower than that of DFB and, moreover, DPC lysed the collagen lattices completely after 48 h in culture. The funtional differences between DPC and DFB were paralleled by higher surface expression and synthesis levels of the ‚ 1 , · 1 , and · 5 chains of integrin adhesion receptors in DPC, as detected by fluorescence-activated cell-sorter analysis and radioimmunoprecipitation. These findings provide evidence that DPC are a highly specialized cell population, which clearly differs from another mesenchymal cell type, DFB. After their isolation and cultivation in vitro, DPC still preserve functional properties related to important steps of cell-matrix interaction involved in the hair cycle.

Growth and characterization of a cell line from a human primary neuroendocrine carcinoma of the skin (Merkel cell carcinoma) in culture and as xenograft.

The primary neuroendocrine carcinoma of the skin or Merkel cell carcinoma (MCC) is a skin tumor with aggressive biological behaviour. Experimental models for investigating the biological properties of the tumor are prerequisite for developing new therapeutic approaches. In this study, we report the establishment and characterisation of a cell line derived from the lymph‐node metastasis of a patient with highly aggressive MCC. Merkel carcinoma cells (MCC‐1) grew as floating aggregates in suspension cultures for more than two years and over 70 subcultures. The proliferation rate in suspension cultures was rather moderate with a population doubling time of 69 h. The immunocytochemical pattern of the cultured MCC‐1 was similar to that of the original tumor with expression of cytokeratin 18, neuron‐specific enolase, neurofilaments, and synaptophysin. In addition, reverse transcriptase polymerase chain reaction (RT‐PCR) revealed presence of chromogranin A mRNA in the MCC‐1 cell line. Furthermore, electron microscopy yielded the rare finding of neuroendocrine granules in the cytoplasm of the cultured cells. The cell line MCC‐1 was able to form colonies in soft agar. Nude mice developed solid tumors with similar histology to the original tumor after subcutaneous and intravenous injections of cultured MCC‐1, and malignant ascites was seen after intraperitoneal injection. Also, two MCC‐1 sublines were established by reculturing cells from the xenografts grown in vivo and immunocytochemistry confirmed their neuroendocrine origin. The MCC‐1 line may thus serve as a model for studying the biology and the metastatic potential of Merkel cell carcinoma.

Kontaktallergien auf Kortikosteroide Prävalenz, Kreuzsensibilisierung und Nachweismöglichkeiten

ZusammenfassungLokale Kortikosteroide (KS) werden therapeutisch zur Behandlung allergischer Erkrankungen der Haut eingesetzt, daher bleibt ihr eigenes sensibilisierendes Potential häufig unentdeckt. In den letzten 10 Jahren wurden vermehrt KS-Kontaktallergien beschrieben, sodaß inzwischen für >50 Kortikosteroide Kontaktallergien bekannt geworden sind. Nach neuesten Untersuchungen gehören KS zu den eher häufigen Kontaktallergenen, wobei die Prävalenz bei Frauen 2mal höher ist als bei Männern. Klinisch imponiert die KS-Kontaktallergie als chronisch persistierende, therapierefraktäre Dermatitis. KS-Allergien gehören zu den Typ-I- und/oder den Typ-IV-Reaktionen, wobei durch die enge chemische Strukturverwandtschaft einzelner Kortikosteroidmoleküle (z.B. Hydrokortison und Tixocortol-Pivalat) Kreuzallergien beobachtet werden. Überempfindlichkeitsreaktionen auf KS können verzögert auftreten und mit Hilfe von Epikutan-, Intrakutan- und Gebrauchs-Testen unter Beachtung verlängerter Ablesezeiten (bis zu 120 h nach Testbeginn) nachgewiesen werden. Für die Routinetestung empfiehlt es sich, das vom Patienten verwendete Präparat sowie zum Vergleich Tixocortol-Pivalat und Budesonid als Markersubstanzen heranzuziehen. Die Entwicklung weiterer Markersubstanzen für den Nachweis von Überempfindlichkeitsreaktionen auf KS ist Ziel aktueller Untersuchungen.SummaryTopical corticosteroids (CS) are frequently used to treat of allergic contact dermatitis, so that their own potential for sensitization is rarely detected. However, increasing numbers of hypersensitivity reactions to corticosteroids have been reported during the last 10 years, and allergic skin reactions to over 50 particular compounds have been observed. CS must now be regarded as a rather frequent contact allergen, the prevalence being twice as high in women as in men. Contact allergy to CS is clinically characterized by a chronic and persistent, corticosteroid-resistant dermatitis. In general, hypersensitivity to CS is a type I and/or type IV mediated allergic reaction. Cross-sensitivity between individual corticosteroid preparations has been described owing to their closely related chemical structures (e.g. hydrocortisone and tixocortol pivalate). Contact allergy to CS can be confirmed by patch-tests, intradermal injection tests or application tests; because of the delayed appearance of positive skin reactions a prolonged evaluation period of up to 120 h is recommended. For routine screening the use of the patients own material and of tixocortol pivalate and budesonide as test marker substances seems appropriate. The development of further marker substances is a target for ongoing research.

Psoriatische Onycho-Pachydermo- Periostitis (POPP)

ZusammenfassungWir berichten über einen Patienten mit psoriatischer Diathese ohne manifeste Psoriasis, bei dem eine Vergrößerung und schmerzhafte Schwellungen beider Großzehen in Kombination mit Nagelwachstumsstörungen und partieller Onycholyse an den Großzehennägeln aufgetreten waren. Unlängst sind solche Krankheitsbilder in der Literatur als psoriatische Onycho-Pachydermo-Periostitis (POPP) zusammengefaßt worden. Anhand unseres Patienten stellen wir diese neue Entität u. W. erstmalig in der deutschsprachigen Literatur vor und diskutieren die Stellung der POPP im Verhältnis zu anderen Formen der Psoriasis arthropathica.SummaryWe describe a patient with painful enlargement and severe nail deformity of both great toes. The patient furthermore presented with some minor diagnostic criteria for psoriasis such as nail pitting and had a positive family history of the disease. In the recent literature, such cases have been recognized as a new entity termed psoriatic onycho-pachydermo-periostitis (POPP). In this case report, POPP is discussed in relationship to other forms of psoriatic arthropathy and with special emphasis regarding its diagnostic criteria and therapeutic implications.

Trans-Acitretin wird in Etretinat rückmetabolisiert Bedeutung für die orale Retinoidtherapie

ZusammenfassungDas orale Retinoid trans-Acitretin (t-Acitretin, Neotigason) wird seit 1992 anstelle der Muttersubstanz Etretinat (Tigason) v.a. in der Psoriasis-Therapie auf der Basis seiner kürzeren Halbwertszeit und der Annahme eingesetzt, daß ein Vorteil bei der notwendigen Antikonzeptionsdauer abzuleiten ist. Nach Einführung des Metaboliten wurde jedoch überraschend festgestellt, daß im Blut von Kranken, die mit t-Acitretin behandelt waren, wiederum Etretinat auftrat. Bis heute wurde eine solche Rückführung des t-Acitretins in Etretinat bei mindestens 83 Patienten beobachtet, sodaß auch beim neu eingeführten Präparat die ursprünglich angenommene notwendige Antikonzeptionsdauer von nur 2 Monaten nach Beendigung der oralen Einnahme auf 2 Jahre ausgedehnt werden mußte, wie beim Etretinat.In dieser Übersicht werden die Metabolisierungswege von t-Acitretin unter besonderer Berücksichtigung der Etretinat-Bildung beschrieben. Anhand der vorliegenden Studien an Probanden, Patienten und am Tiermodell werden mögliche Hypothesen zur Rückmetabolisierung des t-Acitretins in Etretinat erörtert und praktische Schlußfolgerungen für die orale Retinoidtherapie gezogen. Eine metabolische Rückveresterung von t-Acitretin in Etretinat auf enzymatischem Wege erscheint wahrscheinlich, wobei die Einnahme von Alkohol offenbar als Co-Faktor eine fördernde Wirkung auf die Rückveresterung hat. Umstritten bleibt, ob die Einführung des t-Acitretins anstelle von Etretinat für den Patienten einen nennenswerten Vorteil bringt. In diesem Rahmen gewinnt die Notwendigkeit einer Überwachung der Retinoidtherapie mittels Blutspiegel-Bestimmungen in therapeutisch schwierigen Fällen oder mit dem Ziel der Konzeptionserlaubnis an Bedeutung.SummaryThe oral retinoid etretinate (Tigason) has recently been replaced by trans-acitretin (Neotigason) in the treatment of severe psoriasis, primarily because of its short half-life and the assumption that a shorter period of subsequent contraception would be required. After introduction of the new drug, however, circulating quantities of etretinate were detected in patients treated with trans-acitretin. Thus far, re-esterification has been detected in at least 83 cases. The 2-month period of strict contraception initially recommended after oral intake of trans-acitretin has been extended to 2 years, as with etretinate. We review some aspects of trans-acitretin metabolism, with special emphasis on etretinate formation. Re-esterification of trans-acitretin into etretinate takes place under varying conditions in volunteers and patients, as well as in animal models. Ethanol is a co-factor for the enzymatic re-esterification of trans-acitretin. It is unclear whether the introduction of trans-acitretin has been of any significant benefit to patients. Monitoring of plasma retinoid levels during and after retinoid therapy remains of decisive importance in managing difficult cases and or in approving decisions for pregnancy.

Granulomatosis disciformis Miescher

ZusammenfassungWir berichten über eine 57jährige Patientin mit Granulomatosis disciformis Miescher, die an der Haut ein typisches morphologisches Bild zeigte: neben scheibenförmigen Plaques mit zarter zentraler Sklerose fanden sich Läsionen, die einer Necrobiosis lipoidica bzw. einem Granuloma anulare ähnelten. Die histologische Untersuchung zeigte ein makrophagenreiches lymphomononukleäres Infiltrat, kleinere Areale nekrobiotischen Kollagens und stellenweise einen mäßiggradigen Kollagenanbau. Anhand unseres Falles geben wir einen kurzen Überblick über die kontrovers geführte Diskussion zur nosologischen Stellung der Granulomatosis disciformis und schließen uns der vorherrschenden Meinung an, daß die Granulomatosis disciformis eine charakteristische Variante aus dem Formenkreis der nichtinfektiösen kutanen Granulomatosen ist, die im Spektrum dieser Erkrankungen zwischen dem generalisierten Granuloma anulare und der typischen, an den Unterschenkeln lokalisierten Necrobiosis lipoidica steht.SummaryWe describe granulomatosis disciformis Miescher in a 57-year old female patient with typical clinical manifestation: disc-shaped plaques with slight central sclerosis and lesions resembling necrobiosis lipoidica and granuloma anulare. Histology revealed an infiltrate mainly composed of macrophages and lymphocytes and small foci of necrobiotic collagen and of new collagen formation. We review the literature on granulomatosis disciformis and nosology, concluding – as do most authors – that granulomatosis disciformis is a characteristic variant within the spectrum of cutaneous noninfectious granulomatous disease lying in between generalized granuloma anulare and necrobiosis lipoidica.

Tumors of the Pilosebaceous Unit

Appendage tumors of the pilosebaceous apparatus are relatively rare, and their clinical aspect is usually nonspecific. In most cases pilosebaceous tumors are benign; however, malignant neoplasias (e.g. trichilemmal carcinoma, malignant pilomatricoma) have been described. In the present review we propose the classification of pilosebaceous tumors by degree and by direction of differentiation and by histological configuration. Three different histological patterns have to be distinguished: tumors with central dilated hair follicle, tumors consisting of epithelial islands and keratotic cysts in the corium and neoplasias with predominantly mesenchymal components surrounding epithelial formations. Careful histopathological examination of pilar appendage tumors will help to classify the wide range of clinically and histologically different tumors and to establish the exact diagnosis.

The phospholipid analogue hexadecylphosphocholine (HePC) inhibits proliferation of keloid fibroblasts in vitro and modulates their fibronectin and integrin synthesis

Hexadecylphosphocholine (HePC), a topically effective compound, exerts a strong antiproliferative effect on neoplastic cells. In the present study we investigated (1) the antiproliferative effect of HePC on benign mesenchymal cells in vitro, using as examples normal and keloid fibroblasts, and (2) the influence of HePC on various functional properties of these cells, including phosphatidylcholine biosynthesis, their capacity to reorganize a three-dimensional collagen-I matrix, and their expression and synthesis of fibronectin and subunits of the β1 integrin family. Fibroblasts derived from keloids (kelfib) and from normal skin (nfib) were cultured in serum-containing medium and treated in the third passage with 50 μmol/l HePC. Proliferative activity was significantly (P < 0.05) more strongly inhibited in kelfib than in nfib under HePC treatment, whereas their phosphatidylcholine synthesis was inhibited to a similar extent. However, the ability of fibroblasts to contract a three-dimensional collagen-I lattice was significantly (P < 0.05) enhanced only in kelfib treated with HePC. These functional differences following treatment with HePC were paralleled by an upregulation of the α2- and β1-integrin chains, and a downregulation of fibronectin synthesis and the α5-subunit. Our results indicate a differential modulation of kelfib metabolism by HePC, suggesting a possible new therapeutic approach for keloid and hypertrophic scars in vivo.