[Differential diagnose of angioedema. Acute edematous scleromyxedema]. / Differenzialdiagnose Angioödem. Akut ödematöses Skleromyxödem.

A woman presented in the emergency room with the diagnosis of angioedema refractory to treatment. She had soft, compressible periorbital edema, as well as edema of her hands and lower arms. She also complained of severe pain in her hands including sensations of numbness and tingling. The history, course and examination results eliminated several possible differential diagnostic considerations like an acute histamine- or bradykinin-mediated angioedema or superior vena cava syndrome. Histological examination confirmed the diagnosis of scleromyxedema.

Adjuvant treatment of recalcitrant bullous pemphigoid with immunoadsorption.

Elimination of pathogenic autoantibodies by immunoadsorption (IA) has been described as an effective adjuvant treatment in severe bullous autoimmune diseases, especially in pemphigus. There is much less experience in the treatment of bullous pemphigoid (BP). BP was diagnosed in a 62-year-old Caucasian woman presenting a pruritic rash with multiple tense blisters. Standard treatments with topical and oral corticosteroids, steroid-sparing agents including dapsone, azathioprine, mycophenolate mofetil (MMF) and intravenous immunoglobulins were ineffective or had to be discontinued due to adverse events. An immediate clinical response could be achieved by two treatment cycles of adjuvant protein A immunoadsorption (PA-IA) in addition to continued treatment with MMF (2 g/day) and prednisolone (1 mg/kg/day). Tolerance was excellent. Clinical improvement remained stable after discontinuation of IA and went along with sustained reduction of circulating autoantibodies. Our data demonstrate that PA-IA might be a safe and effective adjuvant treatment in severe and recalcitrant BP.

[Maculo-papular exanthem with acute renal failure. Drug-induced hypersensitivity syndrome]. / Makulopapulöses Exanthem mit akuter Niereninsuffizienz. Arzneimittelinduziertes Hypersensitivitätssyndrom.

Acute renal failure caused by interstitial nephritis as part of a drug hypersensitivity syndrome constitutes a rare, but potentially life-threatening adverse drug reaction. We describe a patient with a mild maculo-papular rash accompanied by eosinophilia after prolonged treatment with meropenem, vancomycin, and moxifloxacin. Subsequently, a rapidly progressing renal failure developed which dominated the clinical picture. Upon cessation of all suspected drugs and therapy with high-dose steroids for 6 weeks, the renal function slowly returned to normal.

[Muir-Torre syndrome. An interdisciplinary challenge]. / Muir-Torre-Syndrom. Eine interdisziplinäre Herausforderung.

Muir-Torre syndrome (MTS) is a rare autosomal dominant tumor syndrome characterized by the occurrence of tumors of the sebaceous glands and/or multiple keratoacanthomas in addition to internal neoplasia. Skin tumors include not only sebaceous adenomas and sebaceomas but also sebaceous carcinomas which are associated with colorectal carcinomas in over 50%, less commonly with carcinomas of the remaining gastrointestinal, urinary or genital tract. The underlying pathogenesis is a defect of the DNA mismatch repair system introducing microsatellite instability in tumor tissue.

[Persistent swelling after flushing of an abscess with Octenisept®]. / Persistierende Schwellung nach Spülung eines Abszesses mit Octenisept®.

We report the case of a long-lasting cutaneous side effect after inappropriate use of Octenisept® solution (containing octenidine and phenoxyethanol). Following lavage of an abscess in the inguinal region, a painful erythematous induration mimicking cellulitis persisted for several months. Manual lymphatic drainage considerably improved the symptoms. Octenisept® shows considerable tissue toxicity in vivo including - but not restricted to - blood vessel damage. Deterioration of endothelial cells followed by oedema and continued tissue damage can be seen histologically. Despite the fact that there is a circular letter issued by the manufacturer as well as a boxed warning on the bottles, the awareness to avoid this misuse of Octenisept® is still lacking.

[Dithiols as chelators. A cause of bullous skin reactions]. / Chelatbildner mit Thiolaktivität. Auslöser bullöser Hautreaktionen.

Chelation therapy with (RS)-2,3-Bis(sulfonyl)propane-1-sulfonic acid (DMPS) after an occupational lead exposure led to the development of a severe bullous drug eruption. Skin tests and histology/immunohistology of the test reactions indicated a T-cell-mediated immune response against DMPS. Metal-binding thiol groups as in DMPS are chemically highly reactive and therefore effectively mediate the development of immunogenic hapten (DMPS)-protein complexes. Therefore, the pharmacological effects and sensitization potential of dithiols are tightly connected. Cross-reactivity of DMPS to other chelators like D-penicillamine is possible; the indications for chelation therapy should be weighed carefully.

Vaccination with mage-3A1 peptide-pulsed mature, monocyte-derived dendritic cells expands specific cytotoxic T cells and induces regression of some metastases in advanced stage IV melanoma.

Dendritic cells (DCs) are considered to be promising adjuvants for inducing immunity to cancer. We used mature, monocyte-derived DCs to elicit resistance to malignant melanoma. The DCs were pulsed with Mage-3A1 tumor peptide and a recall antigen, tetanus toxoid or tuberculin. 11 far advanced stage IV melanoma patients, who were progressive despite standard chemotherapy, received five DC vaccinations at 14-d intervals. The first three vaccinations were administered into the skin, 3 x 10(6) DCs each subcutaneously and intradermally, followed by two intravenous injections of 6 x 10(6) and 12 x 10(6) DCs, respectively. Only minor (less than or equal to grade II) side effects were observed. Immunity to the recall antigen was boosted. Significant expansions of Mage-3A1-specific CD8(+) cytotoxic T lymphocyte (CTL) precursors were induced in 8/11 patients. Curiously, these immune responses often declined after the intravenous vaccinations. Regressions of individual metastases (skin, lymph node, lung, and liver) were evident in 6/11 patients. Resolution of skin metastases in two of the patients was accompanied by erythema and CD8(+) T cell infiltration, whereas nonregressing lesions lacked CD8(+) T cells as well as Mage-3 mRNA expression. This study proves the principle that DC "vaccines" can frequently expand tumor-specific CTLs and elicit regressions even in advanced cancer and, in addition, provides evidence for an active CD8(+) CTL-tumor cell interaction in situ as well as escape by lack of tumor antigen expression.

Diagnostic testing in suspected fluoroquinolone hypersensitivity.

BACKGROUND: Because of their broad antibacterial activity in the gram-negative and gram-positive spectrum, high oral bioavailability, and good tissue penetration, fluoroquinolone antibiotics are widely used. Besides direct drug-related side-effects, fluoroquinolones may cause hypersensitivity reactions. OBJECTIVE: The aim of this retrospective analysis was to present the results of diagnostic testing in cases of clinically suspected fluoroquinolone-induced immediate or delayed hypersensitivity. METHODS: We studied 101 patients with a history of immediate or delayed hypersensitivity symptoms in temporal relation to treatment with a fluoroquinolone antibiotic using standardized skin testing, followed by oral challenges. Patients with anaphylaxis symptoms were further evaluated with in vitro tests. RESULTS: Fluoroquinolone hypersensitivity was excluded in 71 patients by tolerated oral challenge tests. During positive challenge tests, six patients (three out of these had positive and three had negative skin prick tests) developed anaphylaxis symptoms but the presumed IgE-mediated mechanism could not be confirmed by in vitro tests. Patch testing was constantly negative; however, in two patients a rash was induced by the challenge tests. CONCLUSION: History alone leads clearly to a considerable over-estimation of fluoroquinolone hypersensitivity. Moreover, skin or in vitro tests do not seem to be very useful in identifying hypersensitive patients. Challenge tests appear to be necessary for definitely confirming or ruling out fluoroquinolone hypersensitivity.

Superimposed linear psoriasis: differential therapeutic response of linear and nonlinear lesions.

Linear psoriasis is a very unusual clinical variation of psoriasis. Typical clinical features include early onset of erythematosquamous lesions along Blaschko's lines, ability to elicit psoriatic features, absence of pruritus and positive family history for psoriasis. Recently, the term 'superimposed linear psoriasis' was coined for cases with development of nonlinear psoriatic lesions at predilection sites in later life. We report a 19-year-old woman meeting all criteria for the diagnosis of superimposed linear psoriasis including typical histological features. Remarkably, treatment with topical steroids and dithranol cleared the psoriatic lesions on predilection sites whereas the linear lesions were resistant to topical therapy. Linear psoriatic lesions are believed to be caused by genetic alterations in early embryogenesis leading to loss of heterozygosity at a gene locus involved in the pathogenesis of psoriasis. Comparison of mosaic keratinocytes derived from linear lesions with wild-type keratinocytes from the same person may therefore allow identification of key regulatory genes.

Temozolomide plus pegylated interferon alfa-2b as first-line treatment for stage IV melanoma: a multicenter phase II trial of the Dermatologic Cooperative Oncology Group (DeCOG).

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-IFNalpha-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 mug peg-IFNalpha-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-IFNalpha-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-IFNalpha-2b seems to be similar to non-peg-IFN when combined with TMZ.

A high school gym-induced disease.

Physical exercise may induce upper and lower airway symptoms such as rhinitis and asthma. Rhinitis symptoms are often neglected although runny nose and nasal congestion may interfere with performance of the affected individual. A detailed history regarding locality and time of symptoms is of most significance for taking the appropriate diagnostic measures and identifying, as in this case, an uncommon form of allergic rhinitis to airborne spores from moulds.

Gain of 11q/cyclin D1 overexpression is an essential early step in skin cancer development and causes abnormal tissue organization and differentiation.

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.

Clonal T cell responses in tumor infiltrating lymphocytes from both regressive and progressive regions of primary human malignant melanoma.

The T cell receptor (TCR) BV variable (V) gene repertoire of tumor infiltrating lymphocytes (TIL) found in progressive and regressive regions of the same primary human melanomas were characterized by reverse transcription coupled polymerase chain reaction (RT-PCR). After surgery, the tumors were divided into different parts which were judged as regressive or progressive regions by visual inspection. Subsequently this diagnosis was confirmed by histology. From a total of four primary melanomas analyzed, 2 were drawn to be HLA-A2+. Only relatively few BV-gene families were expressed at significant levels in each of the samples. Comparison of the BV-expression in regressive versus progressive regions of the same tumor revealed major differences in all cases examined. Direct sequencing of RT-PCR products indicated that highly expressed BV-gene families were of clonal origin in both the regressive and progressive regions. Together, these data strongly suggest the occurrence of clonal T cell responses in both regressive and progressive areas of the same primary tumor. The differences in expression of certain BV-genes may correlate with the functional activity of certain populations of tumor-infiltrating T cells.

T cell-mediated Fas-induced keratinocyte apoptosis plays a key pathogenetic role in eczematous dermatitis.

Clinical and histologic similarities between various eczematous disorders point to a common efferent pathway. We demonstrate here that activated T cells infiltrating the skin in atopic dermatitis (AD) and allergic contact dermatitis (ACD) induce keratinocyte (KC) apoptosis. KCs normally express low levels of Fas receptor (FasR) that can be substantially enhanced by the presence of IFN-gamma. KCs are rendered susceptible to apoptosis by IFN-gamma when FasR numbers reach a threshold of approximately 40,000 per KC. Subsequently, KCs undergo apoptosis induced by anti-FasR mAb's, soluble Fas ligand, supernatants from activated T cells, or direct contact between T cells and KCs. Apoptotic KCs show typical DNA fragmentation and membrane phosphatidylserine expression. KC apoptosis was demonstrated in situ in lesional skin affected by AD, ACD, and patch tests. Using numerous cytokines and anti-cytokine neutralizing mAb's, we found no evidence that cytokines other than IFN-gamma participate in this process. In addition, apoptosis-inducing pathways other than FasR triggering were ruled out by blocking T cell-induced KC apoptosis by caspase inhibitors and soluble Fas-Fc protein. Responses of normal human skin and cultured skin equivalents to activated T cells demonstrated that KC apoptosis caused by skin-infiltrating T cells is a key event in the pathogenesis of eczematous dermatitis.

Chemoimmunotherapy for cutaneous melanoma with dacarbazine and epifocal contact sensitizers: results of a nationwide survey of the German Dermatologic Co-operative Oncology Group.

PURPOSE: To scrutinize published data from small mono-centric studies and case reports which implicated high response rates and promising survival times for a combination therapy consisting of epifocal dinitrochlorobenzene (DNCB) and dacarbazine (DTIC) for metastasized melanoma. This therapy merges the effects of an allergic contact dermatitis elicited at the site of a cutaneous metastasis, and systemic chemotherapy. METHODS: We performed a retrospective survey with nine German centers and evaluated 72 patients treated from 1993 to 2005. RESULTS: The objective response rate in stage III melanoma (n = 39) was 62%. In contrast, only 9% objective responses were observed in 33 stage IV patients. Interestingly, more than half of patients with objective remissions remained progression-free for more than 1 year irrespective of the stage of disease. CONCLUSIONS: Epifocal DNCB combined with DTIC is effective in patients with regionally metastasized melanoma not amenable to surgery or isolated limb perfusion, whereas in stage IV disease in spite of few durable remissions the addition of DNCB does not improve the therapeutic efficacy of DTIC.

Targeted combined anti-inflammatory and angiostatic therapy in advanced melanoma: a randomized phase II trial.

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.

Functional hierarchy of simultaneously expressed adhesion receptors: integrin alpha2beta1 but not CD44 mediates MV3 melanoma cell migration and matrix reorganization within three-dimensional hyaluronan-containing collagen matrices.

Haptokinetic cell migration across surfaces is mediated by adhesion receptors including beta1 integrins and CD44 providing adhesion to extracellular matrix (ECM) ligands such as collagen and hyaluronan (HA), respectively. Little is known, however, about how such different receptor systems synergize for cell migration through three-dimensionally (3-D) interconnected ECM ligands. In highly motile human MV3 melanoma cells, both beta1 integrins and CD44 are abundantly expressed, support migration across collagen and HA, respectively, and are deposited upon migration, whereas only beta1 integrins but not CD44 redistribute to focal adhesions. In 3-D collagen lattices in the presence or absence of HA and cross-linking chondroitin sulfate, MV3 cell migration and associated functions such as polarization and matrix reorganization were blocked by anti-beta1 and anti-alpha2 integrin mAbs, whereas mAbs blocking CD44, alpha3, alpha5, alpha6, or alphav integrins showed no effect. With use of highly sensitive time-lapse videomicroscopy and computer-assisted cell tracking techniques, promigratory functions of CD44 were excluded. 1) Addition of HA did not increase the migratory cell population or its migration velocity, 2) blocking of the HA-binding Hermes-1 epitope did not affect migration, and 3) impaired migration after blocking or activation of beta1 integrins was not restored via CD44. Because alpha2beta1-mediated migration was neither synergized nor replaced by CD44-HA interactions, we conclude that the biophysical properties of 3-D multicomponent ECM impose more restricted molecular functions of adhesion receptors, thereby differing from haptokinetic migration across surfaces.

Modes of binding and internalization of monoclonal antibodies to human melanoma cell lines.

The process of monoclonal antibody (MAb) binding to tumor cells is greatly influenced by the biology of the respective antigen. This was concluded from an analysis of binding and release of MAbs and MAb fragments to melanoma cells at different concentration levels and different temperatures. With an antigen known to be stably expressed at the cell surface (i.e., Mr 97,000 protein) rapid binding of MAbs was observed at both 0 degrees C and 37 degrees C, and this was reversed by treatment with isoosmolar acid buffer. With another group of antigens, MAb binding increased continuously up to considerable levels at 37 degrees C, but not at 0 degrees C. Concomitantly, the portion of radioactive MAb not desorbable by acid buffer treatment increased, pointing to temperature-dependent internalization. With still another group of (glycolipid) antigens, the highest MAb binding was obtained with fixed cells at 0 degrees C. In this situation MAb release was particularly rapid, thus pointing to a shedding process.

Regulation of tumor necrosis factor-related apoptosis-inducing ligand sensitivity in primary and transformed human keratinocytes.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been shown to exert potent cytotoxic activity against many tumor cell lines but not against normal cells. It has been hypothesized that this difference in TRAIL sensitivity between normal and transformed cells might be due to the expression of the non-death-inducing TRAIL receptors (TRAIL-R) TRAIL-R3 and TRAIL-R4, presumably by competition for limited amounts of TRAIL. To assess the regulation of resistance versus sensitivity to TRAIL in primary as well as transformed keratinocytes, we examined TRAIL sensitivity, TRAIL receptor expression, and intracellular signaling events induced by TRAIL. Although TRAIL induced apoptosis in primary as well as transformed keratinocytes, a marked difference in sensitivity could be observed with primary keratinocytes (PK) being 5-fold less sensitive to TRAIL than transformed keratinocytes (TK). Yet both cell types exhibited similar TRAIL receptor surface expression, suggesting that expression of TRAIL-R3 and TRAIL-R4 may not be the main regulator of sensitivity to TRAIL. Biochemical analysis of the signaling events induced by TRAIL revealed that PK could be sensitized for TRAIL and, similarly, for TRAIL-R1- and TRAIL-R2-specific apoptosis by pretreatment of the cells with cycloheximide (CHX). This sensitization concomitantly resulted in processing of caspase-8, which did not occur in TRAIL-resistant PK. These data indicate that an early block of TRAIL-induced apoptosis was present in PK compared with TK or PK treated with CHX. Interestingly, cellular FLICE inhibitory protein (cFLIP) levels, high in PK and low in TK and several other squamous cell carcinoma cell lines, decreased rapidly after treatment of PK with CHX, correlating with the increase in TRAIL sensitivity and caspase-8 processing. Furthermore, ectopic expression of cFLIP long (cFLIP(L)) in TK by transfection with a cFLIP(L) expression vector resulted in resistance to TRAIL-mediated apoptosis of these cells. Thus, our results demonstrate that TRAIL sensitivity in PK is primarily regulated at the intracellular level rather than at the receptor level.