Georgios Gaitanis

The Malassezia Genus in Skin and Systemic Diseases

SUMMARY In the last 15 years, the genus Malassezia has been a topic of intense basic research on taxonomy, physiology, biochemistry, ecology, immunology, and metabolomics. Currently, the genus encompasses 14 species. The 1996 revision of the genus resulted in seven accepted taxa: M. furfur, M. pachydermatis, M. sympodialis, M. globosa, M. obtusa, M. restricta, and M. slooffiae. In the last decade, seven new taxa isolated from healthy and lesional human and animal skin have been accepted: M. dermatis, M. japonica, M. yamatoensis, M. nana, M. caprae, M. equina, and M. cuniculi. However, forthcoming multidisciplinary research is expected to show the etiopathological relationships between these new species and skin diseases. Hitherto, basic and clinical research has established etiological links between Malassezia yeasts, pityriasis versicolor, and sepsis of neonates and immunocompromised individuals. Their role in aggravating seborrheic dermatitis, dandruff, folliculitis, and onychomycosis, though often supported by histopathological evidence and favorable antifungal therapeutic outcomes, remains under investigation. A close association between skin and Malassezia IgE binding allergens in atopic eczema has been shown, while laboratory data support a role in psoriasis exacerbations. Finally, metabolomic research resulted in the proposal of a hypothesis on the contribution of Malassezia-synthesized aryl hydrocarbon receptor (AhR) ligands to basal cell carcinoma through UV radiation-induced carcinogenesis.

Skin diseases associated with Malassezia yeasts: Facts and controversies

The implication of the yeast genus Malassezia in skin diseases has been characterized by controversy, since the first description of the fungal nature of pityriasis versicolor in 1846 by Eichstedt. This is underscored by the existence of Malassezia yeasts as commensal but also by their implication in diseases with distinct absence of inflammation despite the heavy fungal load (pityriasis versicolor) or with characteristic inflammation (eg, seborrheic dermatitis, atopic dermatitis, folliculitis, or psoriasis). The description of 14 Malassezia species and subsequent worldwide epidemiologic studies did not reveal pathogenic species but rather disease-associated subtypes within species. Emerging evidence demonstrates that the interaction of Malassezia yeasts with the skin is multifaceted and entails constituents of the fungal wall (melanin, lipid cover), enzymes (lipases, phospholipases), and metabolic products (indoles), as well as the cellular components of the epidermis (keratinocytes, dendritic cells, and melanocytes). Understanding the complexity of their interactions will highlight the controversies on the clinical presentation of Malassezia-associated diseases and unravel the complexity of skin homeostatic mechanisms.

Drug-induced bullous pemphigoid in diabetes mellitus patients receiving dipeptidyl peptidase-IV inhibitors plus metformin

Background  Preclinical data and reports of adverse skin reactions in patients treated with dipeptidyl peptidase‐IV inhibitors (gliptins) have increased awareness towards skin‐targeting side‐effects of these anti‐hyperglycaemic drugs. Bullous pemphigoid (BP), sometimes drug‐induced, is the most commonly acquired autoimmune blistering dermatosis in western countries, typically a disease of the elderly people with significant morbidity and excess mortality.

Malassezia‐derived indoles activate the aryl hydrocarbon receptor and inhibit Toll‐like receptor‐induced maturation in monocyte‐derived dendritic cells

Background  The aryl hydrocarbon receptor (AhR) is a nuclear receptor and transcriptional regulator with pleiotropic effects. The production of potent AhR ligands by Malassezia yeasts, such as indirubin, indolo[3,2‐b]carbazole (ICZ), tryptanthrin and malassezin, has been associated with the pathogenesis of seborrhoeic dermatitis and pityriasis versicolor. Antigen‐presenting cells in the skin can encounter microbes in the presence of these bioactive metabolites that could potentially modulate their function.

Immunocryosurgery for basal cell carcinoma: results of a pilot, prospective, open-label study of cryosurgery during continued imiquimod application.

Background/aim  Theoretical considerations support the combination of cryosurgery and topical imiquimod to treat basal cell carcinomas (BCC). The aim of the present study was to test the feasibility and efficacy of ‘cryosurgery during continued imiquimod application’ (‘immunocryosurgery’) to treat ‘high‐risk‐for‐recurrence’ BCCs.

Advances in the in Vivo Raman Spectroscopy of Malignant Skin Tumors Using Portable Instrumentation.

Raman spectroscopy has emerged as a promising tool for real-time clinical diagnosis of malignant skin tumors offering a number of potential advantages: it is non-intrusive, it requires no sample preparation, and it features high chemical specificity with minimal water interference. However, in vivo tissue evaluation and accurate histopathological classification remain a challenging task for the successful transition from laboratory prototypes to clinical devices. In the literature, there are numerous reports on the applications of Raman spectroscopy to biomedical research and cancer diagnostics. Nevertheless, cases where real-time, portable instrumentations have been employed for the in vivo evaluation of skin lesions are scarce, despite their advantages in use as medical devices in the clinical setting. This paper reviews the advances in real-time Raman spectroscopy for the in vivo characterization of common skin lesions. The translational momentum of Raman spectroscopy towards the clinical practice is revealed by (i) assembling the technical specifications of portable systems and (ii) analyzing the spectral characteristics of in vivo measurements.

Treatment of Toxic Epidermal Necrolysis with the Combination of Infliximab and High-Dose Intravenous Immunoglobulin

Background: Therapeutic evidence for toxic epidermal necrolysis (TEN) is indicative for high-dose intravenous immunoglobulin yet inconclusive for corticosteroids. Objective: To describe the combination of corticosteroids, infliximab and a high-dose intravenous immunoglobulin course for TEN. Patients and Methods: In three patients (SCORTEN survival probabilities: 41.7%, 64.2%, 41.7%) disease control was evaluated by (a) employing quantitative image analysis to measure progression of skin detachment and (b) patients’ outcome (complete re-epithelization). Published cases of TEN treatments with infliximab were retrieved from PubMed. Results: Within 48 h skin disease progression was arrested in all patients. Two patients were discharged after 3 weeks without any sequels from skin or conjunctivae. One patient passed away on the ninth day, however with noticeably improved skin (mortality rate: 33% observed vs. 50% expected). A PubMed search retrieved five TEN patients treated successfully with infliximab. Conclusion: The described combination presents a feasible therapeutic alternative for TEN that warrants further evaluation.

High-dose intravenous immunoglobulin in the treatment of adult patients with bullous pemphigoid

High-dose intravenous immunoglobulin (IVIg) has only been sporadically used in the treatment of bullous pemphigoid (BP), as it is suggested as an adjuvant to systemic corticosteroids in progressive disease or when life-threatening complications are of concern with other therapeutic interventions. The aim of the present study was to report our observations in the treatment of adult BP patients with IVIg, in association with a focused literature review. In our Department we identified five patients (4 women, 1 man) who had received IVIg for BP relatively early in the course of their disease. These cases were added to the 36 adequately documented ones reported in the literature. Most of these patients (33/41) responded to treatment with IVIg and 7/33 responders remained clear one year after the onset of IVIg. However, the time for effective disease control after IVIg treatment depended positively on disease duration before treatment (P<0.01). In conclusion, despite the limited experience with its use, IVIg seems to be a useful therapeutic alternative to conventional modalities for selected BP patients, particularly if it is initiated promptly after BP diagnosis.

Imiquimod can be combined with cryosurgery (immunocryosurgery) for locally advanced periocular basal cell carcinomas

Recent reports of case series support the efficacy and safety of topical imiquimod in the treatment of periocular skin tumours.1 2 Cryosurgery is an established ‘non-surgical’ treatment modality for these tumours, particularly for eyelid basal cell carcinomas (BCCs).3 Ongoing studies from our group indicate that the targeted combination of cryosurgery with imiquimod is a highly efficacious modality for BCCs and Bowens disease of the skin.4 5 This letter aims to contribute to the current discussion on imiquimod-based treatment modalities for the management of skin tumours involving eye structures.1 2 We present three patients with biopsy proven, locally advanced periocular BCCs, who refused surgery and were treated with the combination ‘cryosurgery during continuing imiquimod application’ (immunocryosurgery).4 For immunocryosurgery, a commercial imiquimod 5% cream formulation (Aldara®, MEDA) was prescribed, and the patients were instructed to apply a tiny quantity (approximately 20–30% of the sachet content) on the tumour (including an ∼0.5 cm zone of healthy skin around it) every night at bedtime and wash it with tap water the following morning. Cryosurgery was performed by the open spray liquid N2 method employing a Cry-Ac (Brymill, UK) cryogun, with a tip B, under eye surface tetracain anaesthesia. Daily imiquimod application was not interrupted—even at the evening of the day that cryosurgery was performed. We have observed that omitting daily application of …

Could Malassezia yeasts be implicated in skin carcinogenesis through the production of aryl-hydrocarbon receptor ligands?

UNLABELLED Malassezia yeasts are found on the skin of all humans and many warm-blooded animals. In vitro they have the ability to synthesize potent ligands (indolo[3,2-b]carbazole, malassezin and indirubin) of the aryl-hydrocarbon receptor (AhR; synonym: dioxin receptor) when the sweat contained L-tryptophan is used as the single nitrogen source. The production of these AhR-ligands has been associated with pathogenic strains of a certain Malassezia species (Malassezia furfur) but recent evidence shows that this property is widely distributed in almost all currently known Malassezia species. AhR is associated with carcinogenesis and the potential connection of these ubiquitous skin symbionts, and putative pathogens, with skin neoplasia should be evaluated mainly focusing on mechanisms related to the distinctive ability of the yeast to produce potent AhR ligands. HYPOTHESIS Synthesis of available pertinent data show a possible link between Malassezia produced AhR ligands and skin carcinogenesis, particularly of basal cell carcinoma (BCC). BCCs are almost exclusively observed in animal species colonized by Malassezia. In humans and animals there is overlapping in the skin regions colonized by this yeast and affected by BCC. The potent AhR ligands synthesized by pathogenic Malassezia strains could contribute to tumor promotion by: modification of the UV radiation carcinogenesis, alterations in the salvage/survival of initiated tumor cells, inhibition of cell senescence, interaction with vitamin D metabolism, promotion of immune tolerance and finally pro-carcinogenic modulation of cell cycle progression and apoptosis.