[Imiquimod in the treatment of recalcitrant warts: a new therapy option?]. / Imiquimod in der Behandlung von therapieresistenten Verrucae -- eine neue Therapieoption?

Recalcitrants viral warts can pose a therapeutic challenge to the treating physician. In a clinical study, we documented the effect of imiquimod 5% cream (Aldara) on recalcitrants warts in 22 patients. A complete and partial clearing of the warts was achieved in 41% and 50%, respectively. In only 9% of patients no improvement could be observed. Beside the very often observed perilesional erythema, which correlated well with good treatment response, no relevant side effects were documented. Imiquimod 5% cream (Aldara) is an efficient, easy to perform ambulatory treatment modality for recalcitrants HPV induced warts with few side effects.

[Venous stasis--chronic leg ulcer]. / Venöse Stase--das offene Bein.

Chronic venous leg ulcer is a major health problem, affecting principally the elderly. The natural history of the disease is of a continuous cycle of healing and breakdown over decades and recurrence is common. In the present manuscript a survey of the management of venous leg ulcers is given.

Morbidity and outcome after sentinel lymph node dissection in patients with early-stage malignant cutaneous melanoma.

OBJECTIVE: Prospective analysis of the morbidity and outcome of the sentinel lymph node (SLN) technique in a consecutive series of patients with early-stage melanoma. METHODS: Between 1997 and 1998, 60 patients with stage IB-II malignant melanoma underwent SLN dissection. Preoperative dynamic lymphoscintigraphy with mapping of the lymph vessels and lymph nodes and location of the sentinel node was performed the day before SLN dissection. SLN was identified by use of the blue dye technique. SLN was assessed for histopathological and immunohistochemical examination. Postoperative morbidity and mortality were recorded. Follow-up consisted of repetitive clinical examination with lymph nodes status, laboratory and radiologic findings. RESULTS: Tumor-positive SLN was observed in 18% of the patients and stage II disease was found in 91% of the patients with positive SLN. Breslow thickness was the only significant factor predicting involvement of a SLN (p = 0.02). In 36% of the positive SLN, metastases could be assessed only by immunohistochemical examination. Postoperative complications after SLN dissection were observed in 5% in comparison with 36% after elective lymph node dissection. After a mean follow-up of 32 months, recurrence was observed in 3% with a mean disease-free survival of 8 months. Overall survival was 82% and 90% in patients with positive and negative SLN, respectively. Overall mortality was 15%, due to distant metastases in 78% of the cases. CONCLUSIONS: Staging of early-stage melanoma with the SLN dissection by use of the blue dye technique combined to lymphoscintigraphy and immunohistochemistry is reliable and safe, with less morbidity than elective lymphadenectomy. Long-term follow-up is mandatory to establish the exact reliability of SLN dissection.

[Paraneoplastic dermatoses in the area of the head]. / Paraneoplastische Dermatosen im Kopfbereich.

Paraneoplastic dermatoses or cutaneous paraneoplastic syndroms are non neoplastic skin changes closely related to and in their manifestation influenced by an underlying malignancy. The ability to identify these skin changes is of particular importance. Thus, recognition is useful in the early diagnosis of an otherwise asymptomatic malignancy and may significantly affect survival. In this paper important clinical characteristics and commonly associated malignancies of paraneoplastic dermatoses also affecting the head are reported.

CD1a-positive dendritic cells transport the antigen DNCB intracellularly from the skin to the regional lymph nodes in the induction phase of allergic contact dermatitis.

Dendritic cells are potent stimulators of T cell-mediated immune responses. In contact hypersensitivity reactions in animals dendritic cells have been reported to transport antigens to the regional lymph nodes. In this study we investigated whether skin-derived dendritic cells transport contact antigens via the afferent lymph in humans. By means of a microsurgical technique lymph cells were collected after painting a defined skin region with a 2% concentration of the sensitizing agent 2,4-dinitrochlorobenzene on the leg of 14 volunteers. There was no significant change in flow, output or composition of cells after antigen painting. Using flow cytometric analysis we were able to detect the antigen in CD1a+ dendritic cells of the afferent lymph 15-25 h after antigen application. The antigen could only be detected after permeabilizing the dendritic cells, indicating that the main part of the antigen is transported intracellularly and not on the surface of these cells. Further analysis of cell surface antigens such as CD80, CD86, HLA-DR, CD11a, CD14, CD23, CD25 and CD54 revealed that in the course of cutaneous sensitization the phenotype of the dendritic cells was not altered in the afferent lymph. These results provide direct evidence that during the induction phase of allergic contact dermatitis in humans antigen-bearing dendritic cells internalize the antigen and migrate from the skin via the afferent lymph vessels to the lymph nodes.

[Clinical aspects and etiology of erythroderma: an analysis of 64 cases]. / Klinik und Atiologie der Erythrodermie: Eine Analyse von 64 Fällen.

The difficulty of exfoliative dermatitis lies in the finding of underlying causes. In the present study the profile of 64 patients with erythroderma diagnosed between 1.1.1990 and 31.12.1999 were analysed. Clinical, histological and laboratory findings and their relationship to the aetiology were investigated. A masculine:feminine ratio of 2.6:1 was found. Among these patients the most common causative factors were pre-existing dermatoses (58%) and drugs (16%). In about eleven percent of the patients exfoliative dermatitis was associated with malignancy. Six out of seven malignancies were found in males, five of them suffering from pre-existing dermatosis. In 16 percent of the patients no aetiology of erythroderma could be found. No laboratory or clinical findings were indicative for an underlying malignant condition. Since we demonstrated underlying neoplastic disorders in seven (11%) of the cases, five of them also suffering from pre-existing dermatosis, we consider it absolutely necessary to screen for such diseases in the presence of the diagnosis exfoliative dermatitis.

Successful induction of immune responses against mutant ras in melanoma patients using intradermal injection of peptides and GM-CSF as adjuvant.

The rapidly increasing incidence and mortality rate of malignant melanoma, together with the lack of efficient treatment of the late stages, makes it a serious threat to public health. Innovative new treatments are needed. The proteins of the ras-family of proto-oncogenes, functioning as relay switches for signalling pathways between cell surface and nucleus, are involved in cell proliferation, differentiation, apoptosis and transformation. If over-expressed or mutated they can induce and/or maintain a transformed state of a cell. Codon 61 mutations of N-ras seem to be involved in melanoma development on sun exposed sites. In order to induce an immune response towards mutated N-ras proteins we performed a phase 1 feasibility study. Ten melanoma patients were immunized intradermally 6 times with N-ras peptides (residue 49-73) with 4 codon 61 mutations using GM-CSF as adjuvant. HLA typing was not used as an inclusion criterion. Eight patients responded with strong delayed type hypersensitivity reactions. In 2 of the patients an in vitro response to the vaccine could also be detected. The specificity of the reaction could be confirmed by cloning of peptide-specific CD4 positive T cells from peripheral blood of the patients. Intradermal injection of ras peptides using GM-CSF as adjuvant is simple to perform and seems to be efficient in inducing cellular immune responses. Since a majority of the patients showed positive skin reactions and 2 of the patients analysed showed a T-helper response to this melanoma specific antigen, these promiscuous HLA class II binding mutant ras peptides may be candidates for inclusion into vaccine cocktails containing various established CTL epitopes.

Cutaneous leukocytoclastic vasculitis in dermatomyositis suggests malignancy.

BACKGROUND: Dermatomyositis (DM) is a rare connective tissue disease which has been shown to be associated with an underlying malignancy. OBJECTIVE: Evaluation of the prevalence of malignancy in DM at our clinic and search for characteristics of the paraneoplastic form of disease. METHODS: Retrospective review of patient files and histology reports over the period from 1991 to 1998. RESULTS: 23 patients (14 women and 9 men) with DM could be identified in this time period with a median age at diagnosis of 48 years. Malignancies were found in 5 (22%) cases. The skin biopsies of all patients showed features of DM; in 7 cases, a leukocytoclastic vasculitis was detected. Four of the 5 cases with an associated malignancy demonstrated histologically a vasculitis in lesional skin, compared to only 3 out of 18 cases without malignancy (p < 0.05, Fisher's exact test). CONCLUSION: Our data suggest that vasculitis in lesional skin biopsies has a predictive value for the presence of underlying malignancy.

A comparative study of the expression of cytotoxic proteins in allergic contact dermatitis and psoriasis: spongiotic skin lesions in allergic contact dermatitis are highly infiltrated by T cells expressing perforin and granzyme B.

Recent reports indicate that cytotoxic T cells are critically involved in contact hypersensitivity reactions in animals. In this study we sought to investigate the in vivo expression of cytotoxic granule proteins in the elicitation phase of allergic contact dermatitis in humans. Skin biopsy specimens were obtained from patients with allergic contact dermatitis (n = 8) and psoriasis (n = 6) and from controls with normal skin (n = 6). Expression of perforin and granzyme B was investigated by in situ hybridization and immunohistochemistry. In contrast to normal skin and psoriasis, a significant enhancement of perforin and granzyme B gene expression and immunoreactivity was observed in the mononuclear cell infiltrate of allergic contact dermatitis. Immunoreactivity for perforin and granzyme B was mainly found in the cytoplasm of lymphocytic cells, which were located in the dense perivascular infiltrate as well as at sites of marked spongiosis in the epidermis. Double immunostaining revealed that both CD4+ and CD8+ T cells are capable of expressing perforin and granzyme B. In conclusion, our data suggest that T-cell-mediated mechanisms involving cytotoxic granule proteins may elicit epidermal cell injury in vivo and thereby strongly contribute to the development of allergic contact dermatitis in humans.

Isolation of dendritic cells from human afferent lymph.

The skin acts as a mechanical, physicochemical, and immunological control and defense system. The efficient operation of the skin immune system involves cytokine production and adhesion molecule expression by both infiltrating and resident cutaneous cells, and thus depends upon a system of cell homing, based on interactions between cell-surface properties and soluble mediators.

[Immunotherapy in malignant melanoma]. / Immuntherapie beim malignen Melanom.

The malignant melanoma is because of its ability to form metastasis even at early stages of disease the deadliest of all skin tumors. Its incidence rises faster than that of any other human tumor. Today, treatment of melanoma is based on surgical removal, and depending on the stage, chemotherapy and/or biological response modifiers. The response and cure rates are, however, not satisfactory and there is, therefore, ongoing research for other approaches. The identification of melanoma antigenic peptides like Melan-A, gp100 and ras peptides has opened new possibilities in the treatment of malignant melanoma. The research on generating mainly T cell mediated immune responses against malignant melanoma using many different approaches like injection of dendritic cells pulsed with melanoma specific peptides, injection of in vitro with cytokines stimulated T cells, immunization with peptides in the presence of different adjuvants, immunization with genetically modified melanoma cells etc. has produced many encouraging results. However, the future of tumor-vaccine development still lies in generation of more potent vaccination protocols.

Down-regulation of IL-12 by topical corticosteroids in chronic atopic dermatitis.

BACKGROUND: Previous reports indicate that IL-12 may be involved in the development of chronic atopic dermatitis. However, the cellular source of this cytokine in the skin and its expression during successful treatment of the skin lesions are not known. OBJECTIVE: Our purpose was to delineate the precise in situ localization of IL-12 and its modulation under topical treatment with corticosteroids. METHODS: Skin biopsy specimens were obtained from nonlesional, lesional, and treated skin of patients with atopic dermatitis and from healthy skin of nonatopic control subjects. IL-12 was investigated by real-time quantitative reverse transcriptase-PCR and immunohistochemistry. RESULTS: Expression of IL-12 p40 mRNA was significantly enhanced in lesional skin from atopic dermatitis and strongly down-regulated after treatment with topical corticosteroids for 9 to 10 days. In contrast, similar levels of IL-12 p35 transcripts were found in all the samples without any significant differences after treatment. In addition, a strong enhancement of IL-12 immunoreactivity was observed on the mononuclear cell infiltrate in the lesional skin samples, which was also markedly reduced after treatment. IL-12 immunoreactivity was mainly located in the cytoplasm of dermal dendritic cells and macrophages as well as some Langerhans cells. CONCLUSION: Our data suggest that the enhanced local production of IL-12 in dendritic cells and macrophages may be responsible for up-regulating production of IFN-gamma in chronic lesions and strengthen the idea that IL-12 may have a pivotal role in promoting inflammation in atopic dermatitis.

Typical features of calciphylaxis in a patient with end-stage renal failure, diabetes mellitus and oral anticoagulation.

We report a multimorbid patient with end-stage renal failure showing a large necrosis and livedo racemosa on the right thigh. Histology revealed medial calcification of the small arteries typical of calciphylaxis. We found the typical features of the disease with different risk factors like elevated calcium-phosphate product, diabetes mellitus and oral anticoagulation. On account of the location of the skin lesions, a bad prognosis was expected. In spite of therapeutical measures with lowering of the calcium and phosphate levels, the patient died 1 month after the diagnosis had been made.

[Transitory acantholytic dermatosis (Grover disease). An analysis of the clinical spectrum based on 21 histologically assessed cases]. / Transitorische akantholytische Dermatose (M. Grover). Eine Analyse des klinischen Spektrums anhand von 21 histologisch erfassten Fällen.

BACKGROUND AND OBJECTIVE: In 1970 Ralph W. Grover described a clinicopathologic entity characterized by pruritic keratotic papules and papulovesicles predominantly on the trunk, disappearing spontaneously after a few weeks or months and demonstrating the histological features of epidermal acantholysis. The etiology remains unknown; sweating, heat and sunlight are suspected trigger factors. In our survey the clinical spectrum of the disease will be examined. PATIENTS AND METHODS: We have analyzed 21 cases of Grover's disease histologically diagnosed in Berne in 1997 and 1998. RESULTS: In most cases we observed isolated papules disseminated on the trunk. The predominant histological type was the Darier-type; presumably there is no correlation between histological type and clinical features. At the time of diagnosis the skin disorder had been present on average for 83 months. There was a strong association with sweating and heat. Topical steroids were successful in 50% of patients. CONCLUSIONS: Our 21 cases reflect in general the literature. Nevertheless, the long persistence of the skin lesions was striking perhaps making the term transient somewhat inaccurate.

Human afferent lymph from normal skin contains an increased number of mainly memory / effector CD4(+) T cells expressing activation, adhesion and co-stimulatory molecules.

We investigated the T cell population in the afferent lymph and the peripheral blood with regard to expression of activation, adhesion and co-stimulatory molecules and cytokine profile by immunohistochemistry and flow cytometry. The majority of the lymphoid cell population in the afferent lymph were CD4(+), CD45RO(+) T cells expressing the alpha beta TCR. An increased percentage of the T cells expressed activation molecules like HLA-DR, CD25, CD26, CD69 as well as adhesion and co-stimulatory molecules like CD54, CD154 / 40 ligand. Furthermore, T cells in the afferent lymph predominantly expressed the type 1 cytokine IFN-gamma, whereas type 2 cytokines such as IL-4, IL-5, IL-10 were not or barely detectable. Interestingly, dendritic cells expressing IL-12 were also found in close association with some lymphocytes, indicating that these contacts may be important in promoting Th 1 cells. In conclusion, an increased number of mainly CD4(+) memory / effector T cells, expressing activation, adhesion and co-stimulatory molecules migrate through the afferent skin-derived lymph in humans. Furthermore, our data demonstrate the dominance of a type 1 cytokine profile in these T cells and suggest that they have an important function in the immune surveillance against pathogens or other antigens in the skin and its associated lymphoid tissue.

Antigen-presenting cells and keratinocytes express interleukin-12 in allergic contact dermatitis.

Interleukin-12 (IL-12) has previously been suggested as playing a major rôle in the activation of cytotoxic lymphocytes. Recent reports indicate that cytotoxic CD8+ cells are critically involved in the elicitation phase of contact hypersensitivity reactions. In this study, the in situ expression of IL-12 was investigated in normal human skin and in allergic contact dermatitis by immunohistochemistry. Skin biopsy specimens were obtained from allergic patch test reactions after 3 days, and from normal skin in 8 subjects. In contrast to normal skin, a strong enhancement of IL-12 immunoreactivity was observed in the mononuclear cell infiltrate of allergic contact dermatitis. IL-12 immunoreactivity was mainly located in the cytoplasm of dermal dendritic cells and macrophages as well as of some Langerhans cells. IL-12-positive cells were often found in close apposition to lymphocytes. Furthermore, positive immunostaining was also detected in keratinocytes at sites of marked exocytosis and spongiosis in the epidermis. In conclusion, the enhanced in situ expression of IL-12 may contribute to the activation of cytotoxic lymphocytes and thereby represent an important factor in the pathogenesis of contact hypersensitivity reactions in humans.

The HECA-452 epitope is highly expressed on lymph cells derived from human skin.

The cutaneous lymphocyte-associated antigen (CLA), recognized by the monoclonal antibody HECA-452, is a cell surface glycoprotein that binds specifically to E-selectin. CLA is present on most T cells at sites of cutaneous immune response and has been shown to be important in lymphocyte homing to the skin. It is expressed only by a minor subset of peripheral T cells and is absent on thymocytes. We have analysed (using a FACScan flow cytometer) the expression of CLA on human lymph cells derived from normal skin, from ultraviolet (UV)-irradiated skin and from allergic contact dermatitis. Whereas in the peripheral blood CLA was expressed on < 20% of CD4 +, CD8 + and CD56 + cells (natural killer cells), > 60% of CD4 +, CD8 + and CD56 + cells isolated from skin-derived lymph expressed CLA. Furthermore, > 90% of CD1a + dendritic lymph cells were positive for CLA. UV irradiation of the skin and induction of an allergic contact dermatitis did not change CLA expression on lymph cells, although lymph flow and cell output increased. These results provide further evidence for an important role of CLA in cell homing to the skin.

Awareness and early detection of cutaneous melanoma: an analysis of factors related to delay in treatment.

Factors associated with the detection of cutaneous melanomas and reasons for delay in diagnosis were investigated in 429 patients with histologically proven melanoma operated on between January 1993 and June 1996. Patients were interviewed using a standardized questionnaire. In 25% of patients, treatment was delayed for more than 1 year from the time they first noticed a suspicious pigmented lesion. Melanoma was detected by the patients themselves in 67% of women and 45% of men. The three predominant clinical symptoms of melanoma were change in colour (darker), increase in size and increase in elevation of a pigmented lesion. The role of sun exposure and of naevi as risk factors for melanoma, as well as the potential benefit of early treatment, were known by 87%, 66% and 82% of the patients, respectively. However, melanoma awareness had no impact on the time period between first observation of skin changes and treatment. Among the factors associated with delay in melanoma diagnosis, an initial incorrect diagnosis as a benign lesion by the physician first visited (in 18% of all cases) had the highest significance. Patients detecting their lesions themselves were treated significantly later than patients in whom others had remarked on changes in a naevus. Furthermore, melanomas of the head and neck were treated later than melanomas at other body sites. Further efforts to educate both the public and the medical profession are essential to ensure earlier treatment for cutaneous melanomas.

[Drug-induced papular-purpuric gloves and socks syndrome]. / Medikamentös induziertes papulopurpurisches Gloves-and-socks-Syndrom.

The papular-purpuric "gloves and socks" syndrome (PPGSS) was first described in 1990 by Harms et al. The syndrome is characterised by fever, an itchy erythema with edema, confluent papules and purpura of the hands and feet in a "gloves and socks" distribution. The skin lesions may be associated with purpura and superficial erosions of the oral mucosa. Viral infections, in particular parvovirus B19, are the most likely trigger. In the present case PPGSS developed after taking trimethoprim/sulfamethoxazole. Since the patient developed identical symptoms after accidental re-challenge with the same drug, this case strongly suggests medications as another factor in the pathogenesis of PPGSS.