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.

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.

Infiltration of both T cells and neutrophils in the skin is accompanied by the expression of endothelial leukocyte adhesion molecule-1 (ELAM-1): an immunohistochemical and ultrastructural study.

Various inducible adhesion molecules on human endothelial cells like the endothelial leukocyte adhesion molecule-1 (ELAM-1) seem to be the basis of mechanisms that allow peripheral blood leukocytes to enter precisely areas of inflamed tissue. Because in vitro data had shown that ELAM-1 plays a central role in neutrophil as well as memory T-cell endothelium interactions, we analyzed in vivo at the light and electron microscopic level its expression in various benign and malignant skin diseases, which differ in the composition of the cellular infiltrates. The expression of ELAM-1 on endothelial cells at different anatomical sites could be demonstrated independently from the cell type (neutrophils/memory T cells) infiltrating the surrounding tissue. On the ultrastructural level we demonstrate that the expression of ELAM-1 is restricted to certain segments of post-capillary venules exhibiting distinctive morphologic features. The ELAM-1-positive endothelia are identical to those vessels that are currently described to be the preferred sites of lymphocyte trafficking in diseased skin.

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.

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.

Idiopathic recurrent palmoplantar hidradenitis in children. Report of 22 cases.

BACKGROUND: Idiopathic recurrent palmoplantar hidradenitis (IRPH) is characterized by tender erythematous plaques and nodules on the soles and, less often, the palms of young patients. To date, 10 cases of IRPH have been documented in the literature. OBSERVATIONS: We describe 22 pediatric patients with characteristic cutaneous and histologic findings of IRPH. Their mean age was 6 years (age range, 1.5-15 years). The onset of the disease clustered in 2 peaks, in autumn and spring. All patients had complete resolution of their lesions within 3 weeks, in 16 cases without any treatment. Ten of the 22 patients experienced more than 1 episode of IRPH. CONCLUSIONS: Our study represents the largest number of cases of IRPH collected to date. Based on our data, the clinical picture is so characteristic that a histopathologic examination may not be necessary in every case. We suggest that there is a seasonality in the occurrence of this always benign and limited disease.

Adhesion of neutrophils to epidermal cells: prerequisites for and blocking by anti-CD11b antibodies.

Immigration of neutrophils into the epidermis is a hallmark of several so-called neutrophilic dermatoses. In this study we used a frozen section adhesion assay to study the impact of different activation procedures as well as of CD11 integrins on cell-cell adhesion between neutrophils and epidermal cells. Serial sections from punch biopsies of healthy donors were incubated with freshly prepared neutrophils for 40 min and adherent cells were counted after washing. We found that preactivation of the biopsies with interferon-gamma in vitro is a prerequisite for neutrophil binding. Activation of neutrophils with N-formyl-methionyl-leucyl-phenylalanine (fMLP), tumor necrosis factor-alpha (TNF-alpha) or platelet activating factor (PAF) then leads to a three- to sixfold increase in neutrophil adhesion. This enhanced binding could be blocked by anti-CD11b monoclonal antibodies, whereas anti-CD11a and anti-CD11c antibodies exerted no significant effect. At a temperature of 6 degrees C, 50% inhibition of neutrophil binding was observed. Complement factor C3 and fibrinogen, known ligands for CD11b/CD18, could not be detected on epidermal cells by immunohistochemistry. In summary, our study showed that enhanced binding of neutrophils to epidermal sections can be achieved by prestimulation of both the keratinocytes with interferon-gamma and the neutrophils with fMLP, TNF-alpha and PAF. This adhesion was furthermore revealed to be dependent on the function of the leucocyte integrin CD11b/CD18.

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.

Expression of integrin receptors and ICAM-1 on keratinocytes in vivo and in an in vitro reconstructed epidermis: effect of sodium dodecyl sulphate.

Several integrin heterodimers such as alpha 2 beta 1, alpha 6 beta 4 and alpha v beta 5 are expressed on basal keratinocytes of the epidermis. Because overexpression of these integrins as well as induction of the intercellular adhesion molecule-1 (ICAM-1) have been found in inflammatory dermatoses, we sought to determine whether these modulations could be used as markers of skin irritation. In normal epidermis, topical application of 1% sodium dodecyl sulphate (SDS) for 24 h caused an upregulation of alpha 3, beta 1, alpha 6, beta 4, alpha v, beta 5 and to a lesser extent alpha 2 integrin chains as well as an induction of ICAM-1. To investigate whether these parameters could also be used for evaluation of skin irritancy in vitro, SDS was applied for 24 h to reconstructed epidermis on de-epidermized dermis (RE-DED). In RE-DED, integrin overexpression and aberrant alpha 5 expression was seen under normal in vitro culture conditions and topical application of SDS caused only marginal additional upregulation. We could not detect any ICAM-1 reactivity on either normal or irritated RE-DED. Our results demonstrate that the modulation of integrin and ICAM-1 expression can be used as markers of irritation of the epidermis in vivo, but not in vitro.

CD36 (OKM5) antigen expression on human mucosal epithelia is associated with keratinization type.

The glycoprotein CD36 functions as a thrombospondin receptor and is expressed on a variety of cell types, including platelets, monocyte/macrophages, and endothelial cells. In human skin, the presence of CD36 on keratinocytes was initially found in lesional areas of T-cell mediated inflammatory dermatoses. Controversy still exists on the interpretation of this expression as an inflammatory or differentiation-associated marker. So far, only limited data are available on CD36 expression in oral epithelia. The present immunohistochemical study was therefore performed to determine the presence of CD36 on keratinocytes of healthy and disease-affected epithelia of the oral cavity in 80 biopsy specimens. As results, we found an inflammation-independent strong expression of CD36 in oral epithelia with ortho- and parakeratinization, such as the oral side of the gingiva, the hard palate, and the back of the tongue. Non-keratinized epithelia such as the gingival pocket epithelium, the soft palate, the lip, the buccal mucosa, and the side of the tongue were CD36 negative. We therefore suggest that CD36 expression in keratinocytes from oral epithelia is an epithelial differentiation marker.

Sweet's syndrome: clinical spectrum and associated conditions.

We report six cases of acute neutrophilic dermatosis (Sweet's syndrome). Clinical and laboratory data as well as the results of further examination of the patients are presented. Unusually associated disorders, such as Crohn's disease together with an erythema nodosum or adenocarcinoma of the colon, were diagnosed in these patients.

Cutaneous pleomorphic large cell lymphoma.

The case of a primary cutaneous pleomorphic large cell lymphoma occurring in a twenty-one-year-old woman who presented with a blue-reddish nodule on her left cheek of three months' duration is presented. The tumor consisted of pleomorphic blast cells showing high mitotic activity. On immunohistochemical examination, the majority of the tumor cells expressed CD 3 (Leu-4), CD 4 (Leu-3), HLA-DR CD 30 (Ki-1/Ber-H 2), and CD 25 (IL2 receptor). Twenty-two months after excision of the tumor there is no detectable systemic spread of the lymphoma. This case provides further evidence for recent observations that primary cutaneous Ki-1-positive large cell lymphomas without lymph node involvement may have a favorable prognosis after local treatment despite showing histologic pattern of malignancy.

Pseudocoarctation of the abdominal aorta.

The case of an asymptomatic pseudocoarctation of the abdominal aorta is reported. Pronounced kinking of the abdominal aorta was seen on angiograms, without stenosis or collateral circulation. Angiography revealed normal renal arteries originating from the malformated aortal segment. The possible etiology and the need for the therapeutical intervention are discussed.

[Inspiration-triggered vasoconstrictive episodes in healthy subjects, in patients with diabetes mellitus and in patients with clinically manifest polyneuropathy of variable origin. A simple Doppler ultrasound test to assess the autonomic vascular functional unit of the upper extremity]. / Inspirationsgetriggerte vasokonstriktorische Episoden bei Gesunden, bei Patienten mit Diabetes mellitus sowie bei Patienten mit klinisch manifester Polyneuropathie unterschiedlicher Genese. Ein einfacher Ultraschall-Doppler-Test zur Prüfung der autonomvaskulären Funktionseinheit an der oberen Extremität.

BACKGROUND: A cost- and time efficient ultrasound-Doppler-test is introduced to evaluate the function of autonomic innervation of the upper limb. A voluntary inspiratory vasoconstrictor episode (VICE) after a provoked deep inspiration, transmitted via sympathetic nervous system, can be demonstrated at the radial artery using basic Doppler equipment. PATIENTS AND METHOD: VICEs were investigated in 30 healthy subjects (group A), in 20 patients with diabetes mellitus without clinical signs of polyneuropathy (group B) and in 20 patients with clinically manifest polyneuropathy (group C). RESULTS: In all healthy subjects a two minutes arterial occlusion led to a decrease of resistance index (RI) lower than 0.9 indicating sufficient hyperemia. RI during VICE increased to 1.0 in all healthy subjects. In 50% of the patients of group B as well as in 50% of the patients of group C the test revealed abnormal findings suggesting a disorder of the functional peripheral neurovascular unity.