In vitro evidence for senescent multinucleated melanocytes as a source for tumor-initiating cells.

Oncogenic signaling in melanocytes results in oncogene-induced senescence (OIS), a stable cell-cycle arrest frequently characterized by a bi- or multinuclear phenotype that is considered as a barrier to cancer progression. However, the long-sustained conviction that senescence is a truly irreversible process has recently been challenged. Still, it is not known whether cells driven into OIS can progress to cancer and thereby pose a potential threat. Here, we show that prolonged expression of the melanoma oncogene N-RAS(61K) in pigment cells overcomes OIS by triggering the emergence of tumor-initiating mononucleated stem-like cells from senescent cells. This progeny is dedifferentiated, highly proliferative, anoikis-resistant and induces fast growing, metastatic tumors. Our data describe that differentiated cells, which are driven into senescence by an oncogene, use this senescence state as trigger for tumor transformation, giving rise to highly aggressive tumor-initiating cells. These observations provide the first experimental in vitro evidence for the evasion of OIS on the cellular level and ensuing transformation.

[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.

The telomere profile distinguishes two classes of genetically distinct cutaneous squamous cell carcinomas.

The incidence of skin cancer is increasing worldwide and cutaneous squamous cell carcinomas (SCCs) are associated with considerable morbidity and mortality, particularly in immunosuppressed individuals ('carcinomatous catastrophy'). Yet, molecular mechanisms are still insufficiently understood. Besides ultraviolet (UV)-indicative mutations, chromosomal aberrations are prominent. As telomeres are essential in preserving chromosome integrity, and telomere erosion as well as aberrant spatial telomere distribution contribute to genomic instability, we first established telomere length profiles across the whole tissue and identified normal skin (10/30) harboring discrete epidermal sites (stem cell territories) of evenly short telomeres. Precancerous actinic keratoses (AKs) (17) and SCCs (27) expressed two telomere phenotypes: (i) tissue-wide evenly short to intermediate and (ii) longer and tissue-wide heterogeneous telomere lengths, suggesting two modes of initiation, with one likely to originate in the epidermal stem cells. Although tumor histotype, location, patient gender or age failed to distinguish the two SCC telomere phenotypes, as did telomerase activity, we found a trend for a higher degree of aberrant p53 and cyclin D1 expression with long/heterogeneous telomeres. In addition, we established an association for the short/homogeneous telomeres with a simpler and the heterogeneous telomeres with a more complex karyotype correlating also with distinct chromosomal changes. SCCs (13) from renal transplant recipients displayed the same telomere dichotomy, suggesting that both telomere subtypes contribute to 'carcinomatous catastrophy' under immunosuppression by selecting for a common set (3, 9p and 17q) and subtype-specific aberrations (e.g., 6p gain, 13q loss). As a second mechanism of telomere-dependent genomic instability, we investigated changes in telomere distribution with its most severe form of telomeric aggregates (TAs). We identified a telomere length-independent but progression-dependent increase in cells with small telomere associations in AKs (17/17) and additional TAs in SCCs (24/32), basal cell carcinomas (30/31) and malignant melanomas (15/15), and provide evidence for a reactive oxygen species-dependent mechanism in this UV-induced telomere organization-dependent genomic instability.

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.

Decisive role of tumor necrosis factor-α for spongiosis formation in acute eczematous dermatitis.

Apoptosis of single keratinocytes (KC) is a characteristic feature of spongiosis formation, the histopathologic hallmark of acute eczematous dermatitis. In acute eczema, activated dermis-infiltrating T cells secrete several proinflammatory cytokines which might be decisive for KC apoptosis or survival. We analyzed the role of tumor necrosis factor alpha (TNF-α) in the determination of KC fate during spongiosis formation in acute eczematous dermatitis. Supernatants of activated human CD4(+) T cells induced apoptosis in primary KC, which could be fully inhibited by individual blockade of interferon-γ (IFN-γ) and CD95 but not by neutralization of TNF-α activity. As compared to CD95-triggering alone, synchronous CD95 and TNF receptor cross-linking in the presence of IFN-γ only marginally enhanced KC apoptosis. Importantly, pre-treatment of KC with TNF-α followed by CD95 stimulation, but not vice versa, significantly amplified KC apoptosis as compared to CD95 stimulation alone. This TNF-α-mediated sensitization to CD95-induced KC cell death could be abrogated by blocking TNF receptor 1 (TNF-R1) but not TNF-R2 mAb. In eczematous dermatitis, the CD95 receptor was expressed throughout the epidermis, whereas immunohistological detection of TNF-R1 was rather restricted to KC around spongiotic vesicle formation. Thus, TNF-α primes KC for CD95-mediated signals which results in an increased susceptibility to apoptosis. TNF-R1 expression and spatial action of TNF-α restricted to spongiotic vesicles promote both CD95-induced KC apoptosis and limitation of spreading KC damage.

[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.

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.

[Spectroscopic imaging of the human liver using 3D CSI: optimization and application in patients with metastatic uvea melanoma]. / Spektroskopische bildgebung der menschlichen leber mittels 3D-CSI: etablierung und anwendung bei patienten mit metastasiertem aderhautmelanom.

PURPOSE: (31)P MR spectroscopy (MRS) allows the noninvasive assessment of metabolic alterations in tumors. Due to physical as well as technical limitations, mostly large and single voxels are used. We used a spatially resolved (31)P MRS technique to characterize metabolic abnormalities inside and adjacent to liver metastases of patients with uvea melanoma. MATERIALS AND METHODS: Optimization of 3D chemical shift imaging (3D CSI) was performed in healthy volunteers (n = 19; voxel size 25 ml). Patients (n = 8) with liver metastases were then examined. Cross sectional imaging was available for all patients. RESULTS: Compared to healthy volunteers, the PME/PDE ratios of patients with liver metastasis were significantly higher (0.56 +/- 0.30 vs. 0.39 +/- 0.21; p < 0.05). A trend towards increased PME/beta ATP ratios (2.07 +/- 1.83 vs. 1.02 +/- 0.45; p = 0.12) and decreased Pi/PME ratios (0.57 +/- 0.29 vs. 1.06 +/- 0.58; p = 0.06) was also observed. Patients with metastases > or = 5 cm showed significantly higher PME/PDE ratios (0.68 +/- 0.17 vs. 0.45 +/- 0.03; p < 0.05). Liver parenchyma adjacent to metastases did not show any significant changes compared to non-diseased tissue. CONCLUSION: 3D CSI allows the simultaneous analysis of metabolic alterations in diseased as well as in healthy human liver. Metastases show significant metabolic alterations. Thus, (31)P MRS opens new possibilities for therapeutic monitoring.

Linear variant of chronic cutaneous lupus erythematosus: a clue for the pathogenesis of chronic cutaneous lupus erythematosus?

Lesions of chronic cutaneous lupus erythematosus usually occur in a discoid pattern as erythematous, well-defined, scaly patches affecting face and scalp. The linear variant of chronic cutaneous lupus erythematosus is an exceptional clinical variation with band-like arranged lesions along the lines of Blaschko which represent the developmental growth pattern of embryonic ectodermal cells. Therefore, this unusual clinical observation may provide additional clues for the pathogenesis of chronic cutaneous lupus erythematosus. It is intriguing to hypothesize that linear lesions of chronic cutaneous lupus erythematosus may be caused by increased susceptibility of resident skin cells due to mutations of genes in early embryogenesis.

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.

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.