Acute febrile neutrophilic dermatosis (Sweet's syndrome) in childhood and adolescence: two new patients and review of the literature on associated diseases.

OBJECTIVES: The objectives of this study were to analyse the literature on Sweet's syndrome in childhood focussing on associated diseases and to suggest possible screening procedures for this group of patients. Furthermore, two new patients with Sweet's syndrome are reported. METHODS: A literature search was performed on Pub med using search terms "sweet* syndrome*" and neutrophil* dermatos*. Patients were subdivided into the following groups: classic/idiopathic, paraneoplastic, and parainflammatory Sweet's syndrome. RESULTS: The literature search revealed 64 patients (including our two patients) who were diagnosed with Sweet's syndrome in childhood and adolescence; 27 (42%) patients were categorized as "classic/idiopathic Sweet's syndrome". In 37 patients (58%) chronic associated diseases were reported. Out of these, 21 (33%) patients were categorized as "parainflammatory Sweet's syndrome" including chronic recurrent multifocal osteomyelitis, vasculitis with aortitis, recurrent infections due to immunodeficiencies, arthritis, and systemic lupus erythematosus. Sixteen (25%) patients were categorized as "paraneoplastic Sweet's syndrome" comprising both malignant and premalignant diseases like leukemia, aplastic anaemia, and Fanconi anaemia. As all five (8%) patients treated with drugs (granulocyte-colony stimulating factor, retinoid acid) suffered from malignant, premalignant, or parainflammatory diseases, these patients were categorized according to the underlying disease. Two new children with Sweet's syndrome and associated diseases are presented here, one of them suffering from recurrent infections and trisomy 21, while the other was diagnosed with CNS vasculitis 5(1/2) years after the primary diagnosis. CONCLUSIONS: Sweet's syndrome should be considered in differential diagnosis of prolonged fever with cutaneous involvement. As most cases of pediatric Sweet's syndrome are associated with other diseases we suggest careful screening and monitoring of these patients especially concerning malignant/premalignant diseases, immunodeficiencies, cardiovascular involvement, autoimmune diseases, and drug associations.

[Type IV-allergy due to corticosteroids. Rare and paradoxical]. / Typ-IV-Allergie auf Kortikosteroide. Selten und paradox.

HISTORY AND CLINICAL FINDINGS: A 48-year-old woman developed a skin rash after taking glucocorticoids. INVESTIGATIONS: Positive patch tests revealed type IV allergy (delayed reaction) to several glucocorticoids. In addition an eczema-like rash was produced by an oral provocation test with triamcinolone, although the patch test for this drug had been negative. TREATMENT AND COURSE: We recommended avoidance of the positively-tested corticosteroids and issued a corresponding allergy pass. CONCLUSION: Type IV allergy to glucocorticoids is rare but should be considered whenever patients develop a skin rash after the use of corticosteroids.

Multiple vascular abnormalities and a paradoxical combination of vitamin B12 deficiency and thrombocytosis in a case with POEMS syndrome.

POEMS/Crow-Fukase syndrome is a rare multisystem disorder associated with elevated vascular endothelial growth factor (VEGF), which clinically presents with polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes. We report a case of POEMS syndrome due to a gammopathy of undetermined significance with thrombocytosis, vitamin B(12) deficiency, highly elevated VEGF and in addition to glomeruloid angiomas two previously undescribed proliferative vascular lesions: a spinal arteriovenous fistula and a plexogenic pulmonary arteriopathy, which ultimately resulted in lethal pulmonary hypertension. We assume that the high VEGF levels caused the vascular abnormalities observed in our patient.

Combination chemotherapy with or without s.c. IL-2 and IFN-alpha: results of a prospectively randomized trial of the Cooperative Advanced Malignant Melanoma Chemoimmunotherapy Group (ACIMM).

The purpose of this randomized trial was to evaluate the efficacy of combination chemoimmunotherapy compared with chemotherapy alone. A total of 124 patients were randomized to receive intravenous cisplatin (35 mg m(-2), days 1-3), carmustine (150 mg m(-2), day 1, cycles 1 and 3 only), dacarbacine (220 mg m(-2), days 1-3) and oral tamoxifen (20 mg m(-2), daily) in combination with (n=64) or without (n=60) sequential subcutaneous IL-2 and IFN-alpha. In those patients who received sequential immunotherapy, each cycle of chemotherapy was followed by outpatient s.c. IL-2 (10 x 10(6) IU m(-2), days 3-5, week 4; 5 x 10(6) IU m(-2), days 1, 3, 5, week 5) and s.c. IFN-alpha (5 x 10(6) IU m(-2), day 1, week 4; days 1, 3, 5, week 5). The overall response rate of patients treated with the combination of chemotherapy and IL-2/IFN-alpha was 34.3% with seven complete responses (10.9%) and 15 partial responses (23.4%). In patients treated with chemotherapy, only, the overall response rate was 29.9% with eight complete responses (13.3%) and 10 partial responses (16.6%). There was no significant difference in median progression free survival (0 months vs 4 months) and in median overall survival (12 months vs 13 months) for combined chemoimmunotherapy and for chemotherapy, respectively.

Is psoriasis a T-cell disease?

The etiology and pathogenesis of psoriasis--one of the most common chronic, inflammatory, hyperproliferative skin disorders of man--have long fascinated dermatologists, pathologists and biologists alike. Here, we have a model disease that offers to study neuroectodermal-mesenchymal interactions in the widest sense possible. Epithelial, endothelial, and hematopoietic cells as well as neurons projecting into the skin apparently all interact with each other to generate the characteristic psoriatic lesion. For decades, the ongoing controversy on the molecular nature, choreography and hierarchy of these complex interactions e.g. between epidermal keratinocytes, T cells, neurotrophils, endothelial cells and sensory nerves has served as a driving force propelling investigative dermatology to ever new horizons. This debate has not only been at the heart of our quest to develop more effective forms of therapy for this socially crippling disease, but it also has profoundly influenced how we view the skin as a whole: the numerous competing theories on the pathogenesis of psoriasis published so far also are reflections on the evolution of mainstream thought in skin biology over the last decades. These days, conventional wisdom infatuated with a T-cell-centered approach to inflammatory skin diseases-- portrays psoriasis as an autoimmune disease, where misguided T lymphocyte activities cause secondary epithelial abnormalities. And yet, as this CONTROVERSIES feature reminds us, some authoritative "pockets of academic resistance" are still quite alive, and interpret psoriasis e.g. as a genetically determined, abnormal epithelial response pattern to infectious and/or physicochemical skin insults. Weighing the corresponding lines of argumentation is not only an intriguing, clinically relevant intellectual exercise, but also serves as a wonderful instrument for questioning our own views of the skin universe and its patterns of deviation from a state of homeostasis.

Reduction of tumor burden and stabilization of disease by systemic therapy with anti-CD20 antibody (rituximab) in patients with primary cutaneous B-cell lymphoma.

BACKGROUND: Primary cutaneous B-cell lymphoma (CBCL) is characterized by restriction to the skin, a high incidence of recurrence after various treatment modalities, and a variable but mostly favorable prognosis. METHODS: Ten patients with long standing primary CBCL (3 with follicular CBCL, 5 with cutaneous, large B-cell lymphoma, 1 with diffuse large cell lymphoma, and 1 with extranodal large cell lymphoma) were treated by intravenous application of a chimeric antibody against the CD20 transmembrane antigen that is present on malignant and normal B-cells. In 6 of 10 patients, several treatment attempts either had failed or could not be used due to severe side effects or underlying disease. RESULTS: The treatment regimen resulted in two complete regressions, five partial responses, and one mixed response, and two patients did not respond to the treatment. No severe side effects occurred, except for slight pain in the nodules after infusion and an urticarial reaction at the tumor sites. A prolonged, complete disappearance of B-cells from the peripheral blood was observed. The immunoglobulin serum levels and inflammatory markers were unchanged. Histologic examination of biopsies from two regressing tumor nodes showed necrotic tumor cells and infiltration with CD8 positive cells. CONCLUSIONS: Intravenous therapy with the anti-CD20 antibody rituximab is a nontoxic and effective treatment for patients with primary cutaneous B-cell lymphoma.

Mage-3 and influenza-matrix peptide-specific cytotoxic T cells are inducible in terminal stage HLA-A2.1+ melanoma patients by mature monocyte-derived dendritic cells.

Dendritic cell (DC) vaccination, albeit still in an early stage, is a promising strategy to induce immunity to cancer. We explored whether DC can expand Ag-specific CD8+ T cells even in far-advanced stage IV melanoma patients. We found that three to five biweekly vaccinations of mature, monocyte-derived DC (three vaccinations of 6 x 106 s.c. followed by two i.v. ones of 6 and 12 x 106, respectively) pulsed with Mage-3A2.1 tumor and influenza matrix A2. 1-positive control peptides as well as the recall Ag tetanus toxoid (in three of eight patients) generated in all eight patients Ag-specific effector CD8+ T cells that were detectable in blood directly ex vivo. This is the first time that active, melanoma peptide-specific, IFN-gamma-producing, effector CD8+ T cells have been reliably observed in patients vaccinated with melanoma Ags. Therefore, our DC vaccination strategy performs an adjuvant role and encourages further optimization of this new immunization approach.

Treatment of erythrodermic cutaneous T-cell lymphoma with intermittent chlorambucil and fluocortolone therapy.

BACKGROUND: Erythrodermic cutaneous T-cell lymphomas (CTCL) including Sézary syndrome have been successfully treated with daily administration of chlorambucil and prednisone (Winkelmann regimen). OBJECTIVES: Our purpose was to determine the efficacy and safety of a low-dose pulse chemotherapy with chlorambucil and fluocortolone in this stage of the disease. Fluocortolone has the same potency as prednisone but lacks a mineralocorticoid effect. PATIENTS/METHODS: Thirteen patients with erythrodermic CTCL (stages III-IVb) were treated with chlorambucil and fluocortolone therapy (chlorambucil 10-12 mg day-1 for 3 days and fluocortolone, first day 75 mg, second day 50 mg and third day 25 mg) as primary therapy in an uncontrolled pilot study. Treatment was started with pulses every 2 weeks; subsequently, the intervals were prolonged according to the clinical status. Clinical outcome, side-effects and long-term survival were assessed. RESULTS: Seven patients achieved a complete remission and six had a partial response (improved significantly). The mean duration of remissions was 16.5 (median 12) months. The mean number of cycles necessary during the first year was one cycle every 5 weeks. No treatment-related severe side-effects occurred. The long-term follow-up (mean 31.5, median 27 months) showed that six patients remained in complete remission and three showed a stable partial remission. Four patients died, two of them from their lymphoma. CONCLUSIONS: We conclude that pulse chemotherapy with chlorambucil and fluocortolone is effective and safe in the treatment of erythrodermic CTCL and should be considered as an alternative to the classical Winkelmann treatment scheme.

Pyoderma gangrenosum in a patient with autoimmune haemolytic anaemia and complement deficiency.

About 50% of cases of pyoderma gangrenosum (PG) are associated with a variety of systemic diseases. We describe a patient with severe PG on both legs who suffered from an autoimmune haemolytic anaemia in association with a congenital deficiency of complement factors C2 and C4. To the best of our knowledge, this constellation has not been previously reported.

Dapsone and colchicine inhibit adhesion of neutrophilic granulocytes to epidermal sections.

A frozen section adhesion assay was used to study the influence of dapsone and colchicine on cell-cell adhesion between neutrophils and epidermal cells. Sections were prepared from small punch biopsies from healthy donors after preincubation with IFN-A. Freshly prepared neutrophils were activated with TNF-. or PAF after exposure to dapsone or colchicine, incubated on these sections, and the adhered cells were enumerated after washing. In the presence of dapsone (at concentrations of 0.1-80 Ig/ml) adherence of neutrophils could be blocked dose-dependently and 50% inhibition of adhesion was achieved at a concentration of 10 Ig/ml. Colchicine at concentrations of 10-200 ng/ml inhibited neutrophil binding with a clear correlation between inhibition and colchicine concentration. At a colchicine concentration of 110 ng/ml, 50% blocking was achieved. Since the function of CD11b/ paragraph signCD18 is necessary for neutrophil adhesion in this assay, we monitored CD11b expression on neutrophils after dapsone and colchicine exposure. CD11b expression on neutrophils was significantly reduced 5 h after incubation with dapsone at a concentration of 80 Ig/ paragraph signml, whereas no effects of colchicine on CD11b expression could be demonstrated. Our study showed that both drugs significantly inhibited adhesion between neutrophils and the epidermis.

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.

Modulation of irritation-induced increase of E-selectin mRNA in vivo by topically applied corticosteroids.

There is a continuous need for methods to evaluate the biologic effects of topically applied drugs in the skin. Irritation of the epidermis with sodium dodecyl sulfate leads to an upregulation of E-selectin on endothelial cells and E-selectin mRNA can be detected in vivo within a short time. This study was aimed to investigate whether this biologic response can be used as a read-out for the anti-inflammatory effect of topically administered corticosteroids. We investigated skin of healthy volunteers treated according to the two following experimental protocols: (i) topical application of different corticosteroids (versus basic ointments as controls) for 12 h and irritation with sodium dodecyl sulfate 1% for 4 h; (ii) irritation with sodium dodecyl sulfate 1% for 12 h and application of the corticosteroids for 5 h. The biopsy specimens were subjected to RNA extraction and reverse transcription and competitive reverse transcriptase-polymerase chain reaction was performed using defined concentrations of a pre-constructed mimic DNA. As result, we found strong positive signals for wild-type E-selectin mRNA in all biopsies pretreated with basic ointments, whereas in biopsies from areas pretreated with corticosteroids the bands for wild-type E-selectin DNA could be detected at 10-1000 lower levels of mimic DNA concentrations. The reverse experiment, application of corticosteroids after the irritation, again yielded significantly reduced signals for E-selectin mRNA. In both experimental settings, the different strength of the topical corticosteroids used was reflected by significant differences in the amount of E-selectin mRNA found in the biopsies. This study demonstrates the pharmacologic effect of topical corticosteroids on the irritation-induced E-selectin mRNA expression on dermal endothelial cells in vivo using very small tissue samples and this approach may be of value for further pharmaceutical studies.