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Background All iodinated radiocontrast media (RCM) may cause hypersensitivity reactions, either immediate-type within 5–10 min of RCM injection or delayed-type, which become apparent more than 1 h after RCM exposure. Delayed-type hypersensitivity to RCM may pose a problem for future radiologic investigations because due to possible immunological cross-reactivity all iodinated RCM are usually avoided. Objective The aim of this study was not only to identify the causal RCM for the exanthema but also to demonstrate that patients may receive alternative iodinated RCM despite a history of RCM-induced allergic exanthema. Methods We evaluated 32 patients with a history of exanthema after RCM application using standardized patch, prick and intradermal skin testing. In case of positive skin tests intravenous challenges with skin-test-negative RCM were performed to identify non-ionic monomer RCM which are tolerated. Results In 6 out of 32 patients skin tests strongly suggested a delayed-type non-IgE-mediated allergic hypersensitivity to the RCM iomeprol (3 x), iopromide (2×), and iopamidol. In 4 patients alternative non-ionic monomer RCM (2× iosarcol, iopromide, and iomeprol) were identified by controlled challenge tests. Conclusions The evaluation of patients with RCM-associated exanthema should always include appropriate skin tests ensuring that patients with a delayed-type allergic RCM-induced exanthema are not missed. Moreover, allergologic testing may identify alternative RCM of the group of non-ionic monomers, which are tolerated in future radiologic investigations.

Behçet's disease is a chronic relapsing systemic vasculitis of unknown etiology, affecting predominantly oral and genital mucocutaneous tissues and also the eyes. The disease is spread worldwide with a higher prevalence rate in countries along the ancient Silk Route, but it is rare (1-10/100,000) in Central and Northern Europe. Genetic, environmental, immunologic, inflammatory and rheologic factors are involved in the pathogenesis and the course of the disease. Any vascularized organ may be affected. Eye involvement is frequent, and may eventually result in loss of vision. Further important complications are cerebral manifestations, thrombotic syndromes, and arterial aneurysms with a high risk of rupture. Diagnosis and therapy of Behçet's disease are best managed by an interdisciplinary team. Skin lesions may be controlled by systemic treatment with colchicine, alternatively with dapsone, and in severe cases with thalidomide. Active systemic disease should be treated more aggressively using immunosuppressants. Despite advances in treatment relapses are still frequent, and systemic disease remains associated with an adverse prognosis.

Background: Combination of temozolomide (TMZ) with nonpegylated interferon alfa is associated with increased efficacy in terms of response rates compared with monotherapy. A multicenter phase II study was carried out to assess the activity and toxicity of TMZ plus pegylated interferon alfa-2b (peg-IFNa-2b), hypothesizing improved efficacy due to modified pharmacokinetic properties of the novel interferon (IFN) formulation. Patients and methods: In all, 124 patients with stage IV melanoma without prior chemotherapy and no cerebral metastases were treated with 100 lg peg-IFNa-2b s.c. per week and oral TMZ 200 mg/m 2 (days 1–5, every 28 days). Primary study end point was objective response, and secondary end points were overall and progression-free survival (PFS) and safety. Results: In all, 116 patients were assessable for response: 2 (1.7%) had a complete response and 19 (16.4%) a partial response (overall response rate 18.1%). Of total, 25.0% achieved disease stabilization and 56.9% progressed. Overall survival was 9.4 months; PFS was 2.8 months. Grade 3/4 thrombocytopenia occurred in 20.7% and grade 3/4 leukopenia in 23.3%. Conclusions: The efficacy of TMZ plus peg-IFNa-2b in this large phase II study is moderate and comparable to published results of the combination of TMZ with non-peg-IFN. Likewise, the safety profile of peg-IFNa-2b seems to be similar to non-peg-IFN when combined with TMZ.

Contains fulltext : 70584.pdf (Publisher’s version ) (Closed access) BACKGROUND: The transplantation of keratinocytes suspended in fibrin carrier represents a candidate regimen for chronic ulcer treatment in an outpatient setting. We evaluated the integration and survival of autologous individualized keratinocytes applied within fibrin matrix onto chronic venous leg ulcers in vivo. Parallel in vitro culture was used to validate keratinocyte survival and apoptosis in fibrin compared to collagen matrix carrier. METHODS: Seven patients with chronic venous leg ulcers were transplanted with autologous keratinocytes suspended in fibrin sealant after isolation and expansion from full-skin biopsy. The fibrin carrier was removed in three patients after 7 days, whereas four patients served as control with fibrin remaining. In parallel in vitro cultures, primary keratinocyte movement in fibrin as well as viability in three-dimensional (3D) fibrin versus collagen lattices was examined. RESULTS: Complete ulcer healing was observed in four of seven ulcers after a mean duration of 14.5 weeks. If the fibrin layer was removed, complete wound healing occurred in three of three patients, compared to one of four in the control group. In vitro, keratinocytes formed a monolayer underneath but remained isolated and nonmobile within the fibrin matrix, suggesting reepithelialization along the lower fibrin interphase. Keratinocyte culture in 3D fibrin at clinically used concentration (90 mg/mL) caused high levels of apoptosis, similar to 3D collagen, which was prevented by diluting fibrin concentration to 3 mg/mL. CONCLUSIONS: Transplantation of autologous keratinocytes suspended in fibrin is efficient in the treatment of chronic venous leg ulcers. Due to an antimigratory and survival-compromising effect, the presently used fibrin carrier should be removed after a few days of transplantation.

Abundant mucin deposition is an unusual finding for melanocytic lesions. This notion, however, should be toned down since mucin may be present in distinct melanocytic lesions. Indeed, following the first description of mucin depositions in neural differentiated naevi by Maize and Ackerman in 1987 1 this phenomenon was repeatedly observed.2,3,4,5 Especially in blue naevi mucin deposition is a peculiar observation. For blue naevi 5 variants are distinguished to avoid the misdiagnosis of melanoma with stromal mucin deposition6: (i) neural nevus, (ii) myxoid intradermal nevus, (iii) alveolar cellular blue nevus, (iiii) ancient melanocytic nevus, (v) sclerosing blue nevus. In 2003, Rongioletti and Innocenzi described the first two examples of sclerosing blue naevi with an abundant mucinous stroma. Herein, we describe the third case of this rare entity. It should be noted, that particularly this uncommon variant of a blue naevus is easily mistaken as desmoplastic-neurotropic melanoma in which the present stromal deposition of mucin is a more typical finding. A specimen from the right lower leg of a 53-year old man was referred to our dermatopathology department with the clinical diagnosis of a dermatofibroma. Clinically, the tumor appeared as a brown lesion with a regular and sharp border. The histopathological work up revealed a symmetrical, well circumscribed papule; the fibro-mucinous stroma contained spindle-shaped and dendritic melanocytes, which sometimes were arranged in whorls (Fig. 1A). Orderly arranged melanocytes in the periphery were characterized by pigmentation, as confirmed by melanin-staining. Melanophages were present as clearly seen in the reaction against CD68. Alcian blue staining confirmed the mucin deposition within the tumor and excluded an intradermal component (Fig. 1B). Immunohistochemical staining with Mart-1 (Fig. 1D) and S-100 confirmed both the nature and the distribution of the melanocytes. Notably no reaction was found against MIB-1 excluding a high proliferation rate (Fig. 1C). Thus all criteria for the diagnosis of a sclerosing mucinous blue naevus were fulfilled, and the differential diagnosis of a malignant melanoma was excluded. Moreover, the clinical diagnosis of a dermatofibroma was ruled out by lack of either epidermal changes or typical infiltrating pattern. Hemosiderin deposits which mimic melanin were excluded by special staining. Figure 1. (A) Fibro-mucinous stroma with spindle-shaped and dendritic melanocytes, which sometimes were arranged in whorls. Melanophages were present (20x Hematoxylin and Eosin). (B) Alcian blue staining confirmed the mucin deposition within the tumor (20x Mucin). ... The cause of mucin deposition in melanocytic lesions remains elusive. It was attributed to a partial involution of the respective lesions. Interestingly, the dermoscopy of the presented sclerotic blue nevus revealed a hypopigmented center; a notion which has been described before.7 In line with this hypothesis it is well established that cellularity of naevi decrease which age, whereupon melanocytes are replaced by fibrous matrix, mucin and sometimes fat.8 With the present case report we like to raise the awareness for this rare entity because of the momentous differential diagnosis. Further reports of such cases would help to learn more about its clinical, dermoscopic and histological features.

An angiostatic approach was used to assess the impact of anti-inflammatory therapy in combination with metronomic low-dose chemotherapy. A randomized multi-institutional phase II trial was designed to select metronomic chemotherapy (arm A: trofosfamide 50 mg orally three times daily, day 1+) or combined anti-inflammatory/angiostatic treatment (arm B: trofosfamide as above mentioned plus rofecoxib 25 mg orally, day 1+, and pioglitazone 60 mg orally, day 1+) for further evaluation. A total of 76 patients, mostly (60%) refractory to at least one previous chemotherapy with maximum tolerated doses, and progression of metastatic melanoma were included. The estimated progression-free survival (PFS) rates at one year were 0% for metronomic chemotherapy (A), but 9% for additional anti-inflammatory therapy (B). Vice versa the hazard ratio for the intent-to-treat analysis of A versus B was 1.9 (P=0.008). By Cox analysis, the impact of anti-inflammatory therapy on PFS achieved significance (P=0.016) as well as C-reactive protein response on overall survival (P=0.045). WHO grade 3 (no grade 4) toxicities were reported in arm A/B in 19 and 28%, respectively. In conclusion, control of tumour-associated inflammatory processes (C-reactive protein response) is associated with longer PFS than achieved with metronomic chemotherapy alone in metastatic melanoma.

Purpose: The microphthalmia-associated transcription factor (MITF) is regarded as a key oncogene of the melanocytic lineage since it was detected by a genome-wide analysis to be strongly amplified in 15% to 20% of metastatic melanomas. MITF gene amplification was shown to be associated with a reduced survival in metastatic melanoma patients, and reduction of MITF activity was shown to sensitize melanoma cell lines to chemotherapeutics, suggesting the intratumoral MITF gene copy number as a predictive biomarker of response and survival after chemotherapy. Patients and Methods: To validate this hypothesis, we investigated MITF gene amplification in tumor tissues obtained from 116 metastatic melanoma patients before an individualized sensitivity-directed chemotherapy using quantitative real-time PCR. MITF amplification rates were correlated with tumor chemosensitivity quantified by an ATP-based luminescence assay and with chemotherapy outcome in terms of response and survival. Results: Of 116 tumor tissues, 104 were evaluable for MITF gene amplification. Strong amplification (≥4 copies per cell) was detected in 24 of 104 tissues (23%), whereas 62 of 104 tissues (60%) harbored >3 copies per cell. Strong MITF gene amplification was associated with a reduced disease-specific survival (P = 0.031). However, no correlation was found between MITF copy number and in vitro chemosensitivity or in vivo chemotherapy response. Conclusion: Our findings suggest that strong amplifications of the melanoma oncogene MITF affects patient survival but does not influence tumor chemosensitivity and chemotherapy response. Thus, the MITF gene copy number seems a useful prognostic marker in metastatic melanoma but could not be confirmed as a predictive marker of chemosensitivity and chemotherapy response.

Rituximab has been established as an effective and safe therapy for cutaneous B-cell lymphoma (CBCL). Different survival pathways, that is the Raf/MEK/Erk- or the p38MAPK cascade, have been suggested as downstream mediators of rituximab and may be involved in treatment failure. Biopsies from four patients, suffering from different subtypes of CBCL, which were obtained at various time points of relapse during or after therapy with 375 mg rituximab per m2 of body surface area, were analysed for the expression of CD20, CD3, Ki-67, Raf-kinase inhibitory protein (RKIP) and bcl-2 by immunohistochemistry. No CD20-loss variants, that is the suggested main tumour escape mechanism to rituximab therapy, were observed in any specimen of relapsing CBCL. Notably, the expression of proapoptotic RKIP remained increased in these tumour samples. This was concomitated by a constant to slightly reduced proliferation status as demonstrated by Ki-67 staining. However, relapsing CBCL exhibited a strong upregulation of the antiapoptotic molecule bcl-2 in comparison to pretherapeutic levels. The immunohistochemical analyses of this case series of rituximab refractory CBCL suggest that upregulation of bcl-2 may play a major role in therapy resistance.

Background Aromatic anticonvulsant agents such as carbamazepine and phenytoin can induce anticonvulsant hypersensitivity syndrome (AHS) at a frequency of 1 in 10,000 to 1 in 1,000 treated patients. The hypersensitivity syndrome is a potentially life-threatening adverse drug reaction with multiorgan involvement, and incidental reexposure must be strictly avoided. Patients and treating physicians must be informed and educated about the causal drug and its potential immunologic or toxicologic cross-reactivity with other compounds. It has been well established that for future antiepileptic drug therapy, carboxamides (carbamazepine and oxcarbazepine), phenytoin, and barbiturates (phenobarbital and primidone) have to be avoided owing to their high degree of cross-reactivity. Other anticonvulsant agents, such as valproic acid, benzodiazepines, and gabapentin, may be prescribed. Objectives To present the clinical data for and to describe the potential cross-reactivity between aromatic anticonvulsant and tricyclic antidepressant agents in patients with carbamazepine- and phenytoin-induced AHS. Methods The knowledge of cross-reactivity among aromatic anticonvulsant agents mainly emerged from clinical experience and observations because diagnostic challenge tests are not advisable. Thirty-six patients with the diagnosis of AHS were instructed to contact our unit if the symptoms relapsed. Results Despite better knowledge of AHS, one third of the patients had avoidable recurrences after exposure to cross-reactive drugs. Besides the known cross-reactivity among aromatic anticonvulsant agents, we observed a recurrence of the hypersensitivity syndrome in 5 patients after the administration of tricyclic antidepressant agents. Conclusion The important potential cross-reactivity between aromatic anticonvulsant and tricyclic antidepressant drugs should be brought to the attention of treating physicians.

RESENTATION n attempt to lose weight can have unexpected conseuences, but a rash is surely one of the least expected. In his case, a 38-year-old female was referred by her family octor because of spreading skin eruptions that had started pproximately 6 weeks prior with single lesions on the rms. She had been diabetic (type II) for 5 years and was urrently being treated with metformin, repaglinide, and nsulin. For the last 8 weeks she had been attempting to ose weight on a diet that included umeboshi, a very salty ickled Japanese plum and had therefore increased her ntake of carbohydrate-rich drinks. She also complained f headache and dizziness but experienced no gastroinestinal symptoms.

Sterile eosinophilic folliculitis, a clinical entity first described by Ofuji in 1970, is a rather rare skin disorder, in particular in the non-Asian population. We report the first case of eosinophilic folliculitis associated with toxocariasis in a Caucasian patient. Topical and systemic anti-inflammatory and antiphlogistic therapy along with systemic antihelminthic treatment resulted in complete remission of the skin lesions. In addition, there was a marked decrease of antibodies to Toxocara antigens in the patient's serum following antihelminthic therapy. Given that (I) some cases of eosinophilic folliculitis have been reported which were associated with infestation with metazoan parasites; (2) infestations with the roundworm Toxocara canis are known to induce eosinophilic reactions in some tissues; and (3) therapy-induced remission of eosinophilic folliculitis was accompanied by a decrease of Toxocara-directed antibodies in the patient's serum, we propose that there is an aetiopathogenic link between toxocariasis and eosinophilic folliculitis in this patient.

As proposed by Hanahan and Weinberg (2000. Cell 100, 57–70) carcinogenesis requires crucial events such as (i) genomic instability, (ii) cell cycle deregulation, (iii) induction of a telomere length maintenance mechanism, and (iv) an angiogenic switch. By comparing the expression of p53, cyclin D1, p16, hTERT, and TSP-1 in spontaneously regressing keratoacanthoma (KA) as a paradigm of early neoplasia, with malignant invasive cutaneous squamous cell carcinoma (SCC) as a paradigm of advanced tumour development, we are now able to assign the changes in the expression of these proteins to specific stages and allocate them to defined roles in the multi-step process of skin carcinogenesis. We show that mutational inactivation of the p53 gene, and with that the onset of genomic instability is the earliest event. Individual p53-positive cells are already seen in “normal” skin, and 3/5 actinic keratoses (AKs), 5/22 KAs, and 13/23 SCCs contain p53-positive patches. Cell cycle deregulation was indicated by the overexpression of the cell cycle regulator cyclin D1, as well as by the loss of the cell cycle inhibitor p16. Interestingly, overexpression of cyclin D1 – observed in 80% of KAs and SCCs, respectively – showed a cell cycle-independent function in HaCaT cell transplants on nude mice. Cyclin D1 overexpression was associated with a massive inflammatory response, finally leading to tissue destruction. Loss of the cell cycle inhibitor p16, on the other hand, correlated with SCCs. Thus, it is tempting to suggest that overexpression of cyclin D1 is an early change that in addition to growth stimulation leads to an altered epithelial–mesenchymal interaction, while functional p16 is able to control this deregulated growth and needs to be eliminated for malignant progression. Another requirement for uncontrolled growth is the inhibition of telomere erosion by up-regulating telomerase activity. As measured by hTERT protein expression, all of the KAs and SCCs studied were positive, with a similar distribution of the protein in both groups and an expression pattern resembling that of normal epidermis. Thus, telomerase may not need to be increased significantly in skin carcinomas. Finally, we show that the angiogenesis inhibitor TSP-1 is strongly expressed in most KAs, and mainly by the tumour cells, while in SCCs the generally weak expression is restricted to the tumour–stroma. Furthermore, we provide evidence that the loss of a copy of chromosome 15 is responsible for reduced TSP-1 expression and thereby this aberration contributes to tumour vascularisation (i.e. the angiogenic switch) required for malignant growth.

Summary Background. Pemphigus vulgaris is a life-threatening autoimmune blistering skin disease, usually treated with high-dose corticosteroids in combination with other immunosuppressants. However, this regimen may prove inadequate in severe cases and can cause dangerous side-effects. We have recently reported protein A immunoadsorption (PAIA) to be an effective adjuvant treatment for induction of remission in severe pemphigus. However, in a significant number of cases, the disease rapidly recurred once PAIA and immunosuppressive medication were tapered. Aims. The aim of the present study was to develop a PAIA-based therapeutic regimen that would result in a more prolonged remission of pemphigus. Methods. Nine patients with pemphigus vulgaris were treated with a modified protocol characterized by a combination of PAIA with a higher initial dose of systemic methylprednisolone (2 mg/kg). In addition, azathioprine or mycophenolate mofetil was administered as a steroid-sparing agent. Results. In all nine patients treated with this regimen, we observed a sharp decline of circulating autoantibody levels and dramatic improvement of cutaneous and mucosal lesions within 4 weeks of therapy. The patients remained free of clinical disease for up to 26 months after PAIA treatment was discontinued. Conclusion. The improved treatment protocol appears to combine highly effective induction of clinical remission in severe or treatment-resistant pemphigus with a prolonged subsequent symptom-free interval.

Non-melanoma skin cancers, in particular keratoacanthomas (KAs) and squamous cell carcinomas (SCCs), have become highly frequent tumor types especially in immune-suppressed transplant patients. Nevertheless, little is known about essential genetic changes. As a paradigm of ‘early’ changes, that is, changes still compatible with tumor regression, we studied KAs by comparative genomic hybridization and show that gain of chromosome 11q is not only one of the most frequent aberration (8/18), but in four tumors also the only aberration. Furthermore, 11q gain correlated with amplification of the cyclin D1 locus (10/14), as determined by fluorescence in situ hybridization, and overexpression of cyclin D1 protein (25/31), as detected by immunohistochemistry. For unraveling the functional consequence, we overexpressed cyclin D1 in HaCaT skin keratinocytes. These cells only gained little growth advantage in conventional and in organotypic co-cultures. However, although the control vector-transfected cells formed a well-stratified and orderly differentiated epidermis-like epithelium, they showed deregulation of tissue architecture with an altered localization of proliferation and impaired differentiation. The most severe phenotype was seen in a clone that additionally upregulated cdk4 and p21. These cells lacked terminal differentiation, exhibited a more autonomous growth in vitro and in vivo and even formed tumors in two injection sites with a growth pattern resembling that of human KAs. Thus, our results identify 11q13 gain/cyclin D1 overexpression as an important step in KA formation and point to a function that exceeds its known role in proliferation by disrupting tissue organization and thereby allowing abnormal growth.

Background: This randomized phase III trial was designed to demonstrate the superiority of autologous peptide-loaded dendritic cell (DC) vaccination over standard dacarbazine (DTIC) chemotherapy in stage IV melanoma patients. Patients and methods: DTIC 850 mg/m 2 intravenously was applied in 4-week intervals. DC vaccines loaded with MHC class I and II-restricted peptides were applied subcutaneously at 2-week intervals for the first five vaccinations and every 4 weeks thereafter. The primary study end point was objective response (OR); secondary end points were toxicity, overall (OS) and progression-free survival (PFS). Results: At the time of the first interim analysis 55 patients had been enrolled into the DTIC and 53 into the DC-arm (ITT). OR was low (DTIC: 5.5%, DC: 3.8%), but not significantly different in the two arms. The Data Safety & Monitoring Board recommended closure of the study. Unscheduled subset analyses revealed that patients with normal serum LDH and/or stage M1a/b survived longer in both arms than those with elevated serum LDH and/or stage M1 c. Only in the DC-arm did those patients with (i) an initial unimpaired general health status (Karnofsky = 100) or (ii) an HLA-A2+/ HLA-B44- haplotype survive significantly longer than patients with a Karnofsky index

A 70-year-old patient presented erosions on the oral mucosa and skin, predominantly in perianal and inguinal areas. Histopathologically, subepidermal blistering was observed. By direct immunofluorescence microscopy, linear deposits of IgG and C 3 were seen at the dermal-epidermal junction. By indirect immunofluorescence microscopy, binding of IgG autoantibodies to the dermal side of NaCl-split skin was detected. These autoantibodies were shown to target both the non-processed and processed α 3 - as well as the β 3 -subunit of laminin 5 by immunoblot analysis using extracellular matrix of cultured human keratinocytes. Based on these results, the diagnosis of an anti-laminin 5 mucous membrane pemphigoid was established. Oral treatment with dapsone, combined with intravenous dexamethasone pulses, led to a rapid improvement.

Background Since tacrolimus ointment was approved by the U.S. Food and Drug Administration (FDA) as a promising treatment for atopic dermatitis, it has been approved in more than 30 additional countries, including numerous European Union member nations. Moreover, in the current clinical routine the use of this drug is no longer restricted to the approved indication, but has been extended to a wide variety of inflammatory skin diseases including some with the potential of malignant transformation. So far, the side-effects reported from the topical use of tacrolimus have been relatively minor (e.g. burning, pruritus, erythema). Recently, however, the FDA reviewed the safety of topical tacrolimus, which resulted in a warning that the use of calcineurin inhibitors may be associated with an increased risk of cancer. Case presentation Oral lichen planus (OLP) was diagnosed in a 56-year-old women in February 1999. After several ineffective local and systemic therapeutic measures an off-label treatment of this recalcitrant condition using Tacrolimus 0.1% ointment was initiated in May 2002. After a few weeks of treatment most of the lesions ameliorated, with the exception of the plaques on the sides of the tongue. Nevertheless, the patient became free of symptoms which, however, reoccurred once tacrolimus was weaned, as a consequence treatment was maintained. In April 2005, the plaques on the left side of the tongue appeared increasingly compact and a biopsy specimen confirmed the suspected diagnosis of an oral squamous cell carcinoma. Conclusion The suspected causal relationship between topical use of tacrolimus and the development of a squamous cell carcinoma prompted us to test the notion that the carcinogenicity of tacrolimus may go beyond mere immune suppression. To this end, tacrolimus has been shown to have an impact on cancer signalling pathways such as the MAPK and the p53 pathway. In the given case, we were able to demonstrate that these pathways had also been altered subsequent to tacrolimus therapy.

siveness to purified protein derivative of tuberculin. Arch Dermatol 1993:129:469-73. 5. Kuramoto Y, Aiba S, Tagami H, et al. Erythema induramm of Bazin as a type of tuberculid. J Am Acad Dermatol 1990;22:612-6. 6. Schneider JW, Geiger DH. Rossouw DJ, et al. Mycobacteriurn tuberculosis DNA in erythema induratum of Bazin. Lancet 1993:342:747-8. 7. Degitz K, Stein M, Thomas P. et al. Aetiology of tuberculids. Lancet 1993;341:239-40. 8. Eisenach KD, Cave MD, Bates JH. et al. Polymerase chain reaction amplification of a repetitive DNA sequence specific for Mycobacterium tuberculosis. J Infect Dis 1990: 161:977-81. 9. Irgang S. Nodose erythema induramm (Bazin's disease). N Y State J Med 1964;64:2580-3. 10. Feiwel M, Munro DD. Diagnosis and treatment of erythema induramm (Bazin). BMJ 1965;1:1109-11. 11. Lebel M. Lassonde M. Erythema induratum of B azin. J Am Acad Dermatol 1986; 14:738-42. 12. Webster GF, Toso SM, Hegemann L. Inhibition of a model of in vitro granuloma formation by tetracyclines and ciprofloxacin: involvement of protein kinase C. 1994:130:74852. 13. Tefford ED. Lesions of the skin and subcutaneous tissue in diseases of the peripheral circulation. Arch Dermatol Syph 1937;36:952-63. 14. Eberhartinger C Das Problem des Erythema Induramm Bazin. Arch Klin Exp Dermatol 1963;217:196-254. 15. Van der Lug L. Some remarks about tuberculosis of the skin and tuberculids. Dermatologica 1965;131:266-75. 16. Forstrom L. Hannuksela K. Antituberculous treatment of erythema induratum of Bazin. Acta Derm Venereol (Stockh) 1970:50:143-7.

The expression of BP180 has previously been demonstrated to be influenced by both calcium (Ca(2+)) concentration and binding of anti-BP180-antibodies in cultured keratinocytes of the skin squamous cell carcinoma line DJM-1. Here, BP180 expression was studied in cultured normal human epidermal keratinocytes by confocal laser scanning microscopy. We exploited an experimental system, in which BP180 was previously shown to mediate, upon incubation with anti-BP180 antibodies, a specific signal-transducing event that leads to the release of inflammatory mediators, such as IL-8 from cultured normal human epidermal keratinocytes (NHEK). We found that without addition of BP180-specific IgG, BP180 is predominantly expressed on the cell surface irrespective of the Ca(2+) concentration. In contrast, cell surface BP180 was greatly reduced in NHEK kept in high Ca(2+) medium after incubation with BP180-specific IgG for 12 h compared to low Ca(2+) medium. This effect was seen with antibodies to both N- and C-terminal fragments of the BP180 ectodomain, respectively. In addition, a slightly higher BP180 expression was found in NHEK cultured in low compared to high Ca(2+) medium by Western blotting. Interestingly, in contrast to NHEK kept under low Ca(2+ )conditions, in NHEK grown in high Ca(2+) medium, no elevated levels of IL-8 were released after treatment of cells with anti-BP180 IgG compared to normal IgG. Our data indicate that the Ca(2+)-modulated expression of BP180 is functionally relevant. This finding sheds further light on the complex pathomechanism in blister formation of BP180-related autoimmune blistering skin diseases.

The skin and the mucosa of the respiratory and gastrointestinal tracts are continuously exposed to microorganisms, but only a limited number of these enter the body and cause disease. To resist microbial infection, the host has developed a multitude of defense mechanisms involving the innate and adaptive immune systems. Dendritic cells (DCs) provide the link between these arms of the immune system. The initiation of an immune response is critically dependent on the activation of DCs, which can discriminate between different classes of microorganisms and elicit tailored antimicrobial immune responses. They have an extraordinary capacity to stimulate naive T cells and initiate primary immune responses. In turn, some pathogens interfere with DC function to block or delay their elimination by the host. Progress in understanding the role of DCs in the host response to microbes is reviewed.

Morbus Köhlmeier-Degos is a rare systemic disease characterized by pathognomonic cutaneous lesions with typical histology. We report the case of a 22-year-old woman with a benign course of this disease and discuss therapeutical options. The patient presented with whitish papules on neck, trunk and extremities that slowly developed within seven months. Examination of the skin revealed about 20 papules of 2-5 mm size. The lesions were partly skin-colored, partly with an erythematous rim and showed a central porcelain-like atrophy. Histology showed an interface-dermatitis and a wedge-shaped mucin deposition with sclerosis of the upper reticular dermis. Organ manifestation was absent. The patient was started on a daily therapy of 300 mg acetyl salicylic acid. Over the course of 24 months single new lesions appeared at a reduced frequency. Apart from the malignant form of Morbus Köhlmeier-Degos there exists a benign course which may be successfully controlled with anti-platelet therapy. We speculate that the lack of vessel occlusion in the histology could be a hallmark of a benign form of this rare disease.

Scleromyxoedema is a rare disease of unknown aetiology that is characterized by deposition of mucin and sclerotic induration of the skin; it is associated with paraproteinaemia. Patients suffer from progressive disability due to immobilization and cosmetic disfigurement. Treatment of scleromyxoedema is a therapeutic challenge. The antimalarial hydroxychloroquine has a rapid and reliable effect in reticular erythematous mucinosis.Four consecutive patients (two women, two men; median age: 50 years) with scleromyxoedema, three of them with IgG lambda paraprotein, were treated with hydroxychloroquine. Treatment was initiated with 600 mg p.o. for 10 days, followed by 400 mg for at least 4 weeks, and 200 mg thereafter.Complete remission of skin manifestations was achieved in one patient, whereas three patients achieved a partial remission of 61+, 5 and 25 months' duration. Notably, three patients felt increased mobility and reduced firmness of skin during the first week of treatment, which was reflected in a rapid reduction in dermal thickness. In one patient, dysphagia was reverted as evidenced by normalization of oesophageal clearance. Paraproteinaemia was not influenced at all. Side effects included one case of electroretinogram abnormalities after 19 months of therapy and one case of leucopenia after 3 months.Hydroxychloroquine is an effective form of therapy for scleromyxoedema, leading to rapid and prolonged alleviation of symptoms.

Recent results from basic and translational research on the causes and mechanisms of melanoma genesis and progression will impact on future therapeutic approaches. The increasing understanding of the molecular pathology of malignant disease and the detailed analysis of the signal transduction pathways involved allows specific intervention with these oncogenic events. These interventions address the molecules associated with or responsible for the malignant transformation and have therefore been termed "targeted therapy". The present review focuses on the therapeutic options involving modulation of the Ras/MAPK- and PI3K/AKT-signal transduction pathways.

Malignant melanoma of the skin preferentially metastasises via the lymphatic system. Novel molecular biomarkers, which are involved in malignant transformation, proliferation, angiogenesis and lymphangiogenesis, are currently under investigation to elucidate the risk for lymph node metastasis. To this end, the vascular endothelial growth factors VEGF-C and VEGF-D have been identified to promote lymphangiogenesis and lymphatic spread through activation of its receptor, Vascular endothelial growth factor receptor-3 (VEGFR-3). Prompted by this assumption, we estimated the degree of lymphangiogenesis by semiquantitative immunohistochemical analysis of the expression of VEGFR-3 and the panvascular marker CD31 in primary cutaneous melanoma (n=26) and correlated these findings with the sentinel lymph node (SLN) status. The cohort was selected for matched prognostic markers in SLN-positive and SLN-negative patients. In contrast to other studies, we observed an inverse correlation between expression of these markers with lymph node metastases. Additionally, no difference between intratumoral versus peritumoral CD31- or VEGFR-3 expression on blood vessels versus lymphatic capillaries could be detected. Interestingly, VEGFR-3 upregulation was not restrained to vascular structures but also appeared on tumor cells. In summary, in our series VEGFR-3/CD31 immunohistochemical staining of primary melanoma does not serve as a valid marker to predict lymph node involvement. As lymphatic spread is a complex, multi-step process, several different biomarkers have to be combined to define new prognostic subgroups in cutaneous melanoma.

Bullous delayed pressure urticaria (DPU) is a rare variant of DPU. Treatment of DPU is difficult and the underlying pathogenic mechanism of DPU remains elusive. We report a 72-year-old man with DPU and associated chronic urticaria as well as delayed urticarial dermographism. Pressure challenge gave rise to a deep weal covered by multiple vesicles and bullae after 24 h. Histological examination of a skin biopsy specimen obtained 24 h after pressure challenge demonstrated intraepidermal bullae filled with eosinophils accompanied by a dense, predominantly eosinophilic infiltrate in the dermis. Whereas the numbers and morphology of mast cells were unaltered, the extracellular deposition of eosinophil cationic protein revealed evidence for eosinophil activation. Concomitantly, both CD4+ and CD8+ T lymphocytes were present in the infiltrate and expressed interleukin 5. As bullous DPU may represent the maximal variant of DPU, the investigation of the cellular infiltrate and the chemokines/cytokines released may reveal potential pathogenic mechanisms. A possible effector role of eosinophilic granulocytes, T-cell subsets and mast cells is discussed.

Immunotherapy has been widely investigated for its potential use in cancer therapy and it becomes more and more apparent that the selection of target antigens is essential for its efficacy. Indeed, limited clinical efficacy is partly due to immune evasion mechanisms of neoplastic cells, e.g. downregulation of expression or presentation of the respective antigens. Consequently, antigens contributing to tumor cell survival seem to be more suitable therapeutic targets. However, even such antigens may be subject to immune evasion due to impaired processing and cell surface expression. Since development and progression of tumors is not only dependent on cancer cells themselves but also on the active contribution of the stromal cells, e.g. by secreting growth supporting factors, enzymes degrading the extracellular matrix or angiogenic factors, the tumor stroma may also serve as a target for immune intervention. To this end several antigens have been identified which are induced or upregulated on the tumor stroma. Tumor stroma-associated antigens are characterized by an otherwise restricted expression pattern, particularly with respect to differentiated tissues, and they have been successfully targeted by passive and active immunotherapy in preclinical models. Moreover, some of these strategies have already been translated into clinical trials.

In the medical community lectures and publications about nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity have led to an increasing awareness and diagnosis of this condition. Frequently, the diagnosis NSAID hypersensitivity is based only on history, which is a vague and unreliable indicator. A two-stage diagnostic procedure with skin tests (to exclude IgE-mediated allergy) followed by single-blinded, placebo-controlled oral challenges was carried out on patients attending our clinic from 1997 to 2003 with the diagnosis of a NSAID hypersensitivity. Out of 260 patients tested, 61.5% described their NSAID hypersensitivity as cutaneous (urticaria, angioedema), 24.2% had respiratory symptoms (asthma, rhinitis), 3.5% had anaphylactoid reactions, and 10.8% described uncertain signs. In fact 55.0% of all patients previously labelled as NSAID sensitive tolerated NSAID when assessed by oral challenge, whereas 13.8% were truly NSAID sensitive. In 31.2% of patients the challenge test with the suspicious drug was either not done or rejected by the patient; but all showed a proven tolerance of alternative NSAID. Our study demonstrates that oral challenge tests are safe, practical and useful in ruling out NSAID hypersensitivity in approximately 50% of the patients who have previously been labelled as such.

It is generally believed that priming of efficient T-cell responses takes place in peripheral lymphoid tissues. Although this notion has been rigidly proven for infectious diseases, direct evidence for lymph node priming of in vivo T-cell responses against tumors is still lacking. In the present study, we conducted a full and nonbiased comparison of T-cell clonotypes in melanoma lesions and corresponding sentinel lymph nodes. Whereas most tumor lesions comprised a high number of T-cell clonotypes, only a small number of clonally expanded T cells were detected in the draining lymph nodes. Comparative clonotype mapping demonstrated the presence of identical T-cell clonotypes in the tumors and the respective sentinel lymph nodes, only when tumor cells were present in the latter. However, taking advantage of clonotype specific PCR amplification, TCR sequences representing clonally expanded T cells at the tumor site could be detected in the lymph nodes draining the tumors even in the absence of tumor cells. Evidence for the tumor-specific characteristics of these cells was obtained by in situ staining with peptide/HLA class I complexes demonstrating the presence of MART-1/HLA-A2- and MAGE-3/HLA-A2-reactive T cells at the tumor site, as well as in the draining lymph node. Our data indicate that T-cell responses to melanoma are primed in the sentinel lymph node by cross presentation of tumor antigens by dendritic cells.

Background: Asthma is an inflammatory airway disease associated with infiltration of T cells and eosinophils, increased levels of pro-inflammatory cytokines, and shedding of bronchial epithelial cells (EC). We have recently shown that T cells and eosinophils cooperate in inducing bronchial EC apoptosis in asthma through secretion of IFN-γ and TNF-α. Since EC shedding is a histologic hallmark of asthma, the intercellular junction of EC may be a target of pro-inflammatory cytokines. Methods: Bronchial EC, cultured and exposed to IFN-γ and TNF-α, were studied for the expression of adhesion molecules and apoptosis. In addition, the epithelial layer of bronchial biopsies from asthma patients was evaluated for apoptosis, shedding, and expression of adhesion molecules. Results: We demonstrate that the induction of EC apoptosis is accompanied by loss of E-cadherin. In situ examination of E-cadherin in asthma revealed a reduction in its expression on EC membranes. In contrast, the in vitro and in vivo expression of β1-integrins and intercellular adhesion molecule-1 (ICAM-1) increased on EC during asthmatic airway inflammation. Conclusions: Loss of cadherin-mediated intercellular adhesion and apoptosis could account for fragility and shedding of EC in asthma, especially since this occurs between columnar and basal EC.

The skin and the eye share vulnerabilities to various autoimmune and immunopathogenic disorders, yet display immunity in strikingly different ways. This book presents up-to-date information on disorders and explores the mechanisms by which immunological processes affect these two organ systems.

We describe a patient who developed an exclusively perianal-intergluteal vesicular eruption after receiving a course of ampicillin/sulbactam. Direct immunofluorescence microscopy of perilesional skin demonstrated linear deposits of IgA along the dermal-epidermal junction. Circulating IgA autoantibodies against the 120-kd soluble ectodomain of bullous pemphigoid antigen 180 (LAD-1 autoantigen) were detected by immunoblotting. Discontinuation of the antibiotics resulted in a rapid resolution of the skin lesions. This is a most unusual case of localized drug-induced linear IgA disease.

Background Mutations of the BRAF gene are the most common genetic alteration in melanoma. Moreover, BRAF mutations are already present in benign nevi. Being overexpressed and mutated, B-Raf is a potential target for the immune system and as this mutation seems to be an early event, a humoral immune response against this antigen might serve as a diagnostic tool for detection of high risk patients. Methods 372 sera of 148 stage IV melanoma patients and 119 sera of non-melanoma patients were screened for B-Raf, B-Raf V599E and C-Raf specific antibodies by an ELISA assay. Sera were screened for specific total Ig and for IgG. Serum titers were compared with a two tailed Mann-Whitney U test. Sera with titers of 1:300 or higher were termed positive and groups were compared with a two tailed Fisher's exact test. Results B-Raf specific antibodies recognizing both B-Raf and B-Raf V599E were detected in 8.9% of the sera of melanoma patients and in 2,5% of the control group. Raf specific IgG was detected in some patients at very low levels. B-Raf specific antibody responses did not correlate with clinical parameters but in some cases, B-Raf antibodies emerged during disease progression. Conclusion These findings imply that B-Raf is immunogenic in melanoma patients and that it might serve as a potential target for immunotherapy. However, B-Raf specific antibodies emerge at rather late stages of melanoma progression and are present only with a low frequency indicating that spontaneous B-Raf specific antibodies are not an early marker for melanoma, but rather may serve as a therapeutic target.

Background: IgE-mediated allergy to grapes has very rarely been reported in patients from the Mediterranean area. Recently, endochitinase 4 and a lipid transfer protein (LTP) have been identified as major allergens in grape-allergic patients who do not have an associated pollinosis. The purpose of this case study was to identify the allergens responsible for severe anaphylactic reactions after consumption of wine, fresh grapes and raisins in a German patient. Methods: Prick-to-prick tests and the basophil activation test (BAT) were performed to confirm allergy. Specific IgE was further analyzed by immunoblotting and inhibition tests for the determination of crossreactivity. The IgE-binding protein was subjected to N-terminal microsequencing. Results: Prick-to-prick tests were positive to fresh and cooked white and blue grapes, to raisins, to white and red wine, and to grape extract. Specific IgE against grapes (f259) was 2.43 kU/l (class 2). The BAT showed specific IgE-mediated activation of basophils after stimulation with grape extract. IgE binding to a 15-kDa protein was completely inhibited by pre-incubation with recombinant cherry LTP Pru av 3. N-terminal sequencing identified this 15-kDa protein as grape LTP Vit v 1. Conclusion: Our data show that sensitization to LTP can occur outside the Mediterranean area causing severe fruit allergy without association to pollinosis.

Results from in vitro chemosensitivity testing recommend treosulfan/gemcitabine chemotherapy for the treatment of stage IV uveal melanoma. Twenty patients received treosulfan 3,500 mg/m2 followed by gemcitabine 1,000 mg/m2 on day 1 and day 8 repeated on day 29. In cases of prior chemotherapy only 75% of these dosages were used. Without any patient achieving an objective response, 25% of patients (95% confidence interval, 8.6–49.1%) had stabilisation of disease. This stabilisation was associated with a prolonged median overall survival of 17 months compared with 7 months for the patients with progressive disease. First-line treatment was not associated with better response or survival although prognostic parameters did not significantly differ from that of other patients. The results are disappointing and question the value of individualized chemotherapy based on in vitro assays.

Tumour necrosis factor (TNF)-alpha is thought to play a major role in the pathophysiology of psoriasis. Good clinical responses of psoriasis to anti-TNF-alpha-based therapies have recently been demonstrated. We studied the effect of infliximab, a monoclonal antibody against TNF-alpha, on chemokine expression in pustular psoriasis. A 61-year-old man with a 2-year history of severe pustular psoriasis of von Zumbusch type who did not respond to conventional therapies responded rapidly to treatment with infliximab. The clinical response was reflected by an immediate and effective reduction of the neutrophil-attractant chemokines interleukin (IL)-8 and growth-related oncogene (Gro)-alpha as well as of monocyte chemoattractant protein (MCP)-1, as determined by mRNA in situ hybridization of lesional skin. No expression before or after treatment was seen for monokine induced by interferon (IFN)-gamma (MIG) and IFN-inducible protein (IP)-10. Thus, in pustular psoriasis the chemokine expression pattern is dominated by neutrophil-attractant chemokines and MCP-1 while, in contrast to plaque psoriasis, IFN-gamma-inducible lymphocyte-attractant chemokines such as IP-10 and MIG are not abundant. We conclude that anti-TNF-alpha treatment with infliximab is an effective therapy in severe pustular psoriasis which is reflected by downregulation of disease-promoting chemokines such as IL-8, Gro-alpha and MCP-1.

SUMMARY In bullous pemphigoid (BP), the binding of BP180-specific antibodies to their hemidesmosomal target antigen is not sufficient for blister formation, but must be accompanied by the release of proteases. Using plasminogen activator (PA) knock-out mice, the PA system has previously been shown to be a prerequisite for blister formation in experimental murine BP. Here, we found elevated levels of plasmin and tPA, but not of uPA, in blister fluid from BP patients (n = 7) compared to blisters from patients with toxic epidermal necrolysis (n = 4) and suction blisters in healthy controls (n = 7). Subsequently, we addressed the question whether keratinocytes release PA in response to the binding of anti-BP180 antibodies. Treatment of cultured normal human keratinocytes with BP IgG, but not with control IgG, led to both increased protein and mRNA levels of tPA, but not of uPA, as determined by ELISA and RT-PCR, respectively. The specificity of this finding was confirmed using BP180-deficient keratinocytes from a patient with generalized atrophic benign epidermolysis bullosa, where no tPA release was observed after stimulation with BP IgG. Our results show the elevated expression and release of tPA from normal human keratinocytes upon stimulation with antibodies to human BP180. Keratinocytes, by secreting tPA, may thus play an active role in blister formation of BP.

Alterations of skin and hair pigmentation are important features that have warranted treatment from ancient history on up to modern time. In some cultures, even today patients with vitiligo are regarded as social outcasts and are affected considerably both emotionally and physically. This article presents current options and future directions for the treatment of hypopigmentary disorders. Whereas with congenital disorders, such as albinism and phenylketonuria, no causal therapy has been established up to now, several treatment options for acquired hypopigmentary disorders have been investigated. In particular, in vitiligo, one of the most prevalent hypopigmentary disorders, a number of treatment modalities have been employed in the past 30 years. However, most of them are only able to palliate, not cure, the disease. Depending on the distribution of the hypopigmented lesions (localised or generalised) and the state of the disease (active or stable), several therapeutic options, for example phototherapy, surgical skin grafts, autologous melanocyte transplantation and immunomodulators, can be applied alone or in combination. For phototherapy, because of unfavourable results and adverse effects, ultraviolet (UV) A has been largely replaced by narrow-band UVB for repigmentation of generalised vitiligo. Although immunomodulators, such as corticosteroids, have been used both topically and systemically over the past 3 decades for the treatment of disseminated vitiligo, they are only suitable for the treatment of acrofacial and localised forms because of adverse effects. Hence, new immunomodulatory agents, such as calcineurin antagonists, have recently been introduced as new promising tools to treat acquired hypopigmentary disorders. However, all therapeutic approaches are hampered by the fact that the pathophysiology of hypopigmentary disorders is still poorly understood.

ejd.2013.1966 Auteur(s) : Sabrina C. Lang1 Lang_S@klinik.uni-wuerzburg.de, Sophie Glas2, Matthias Scheich2, Henning Hamm1, Andreas Kerstan1, Eva-B Brocker1 1 Department of Dermatology, Venereology and Allergology 2 Department of Otorhinolaryngology, University Hospital of Wurzburg Josef-Schneider-Str. 2 D - 97080 Wurzburg Hyalinosis cutis et mucosae (lipoid proteinosis) is a rare autosomal recessive disorder caused by loss-of-function mutations in the extracellular matrix protein 1 gene (ECM1) [...]

Expression of matrix metalloproteinases (MMPs) and their activation in tumor cells, as well as tumor surrounding stromal cells have been implicated in tumor cell invasion and metastasis. By means of a syngeneic tumor model for either experimental or spontaneous metastases, the differential expression of MMPs and tissue inhibitors of MMPs (TIMPs) in relation to the microenvironment and the way of metastasis induction was characterized. In vitro characterization revealed that increased levels of secreted MMP-2, MMP-9, and TIMP-1 were only detectable in the most aggressive cell line, B16G3.12BM2. Remarkably, active MMP-2 was restricted to this cell line, whereas TIMP-2 and membrane type (MT) 1-MMP expression was comparable in all three of the spontaneously metastasizing melanoma cell lines investigated. In vivo analysis demonstrated that MMP-2, MMP-9, and MT1-MMP were predominantly expressed at the tumor-stroma border of s.c. tumors. Furthermore, functional active MMP-2 was restricted to this invasive front. In spontaneous lymph node or lung metastases, however, MMP-9 was expressed both in the center and the periphery of tumors; these areas were largely negative for MMP-2 and MT1-MMP. Notably, tumor cells of experimental lung metastases did not express MMP-9 at all. These results indicate that expression of MMPs in melanoma metastases is not only influenced by their localization but also the nature of tumor induction, suggesting that individual MMPs serve specific roles during the different stages of metastasis formation.