Tobacco smoke-induced immunologic changes may contribute to oral carcinogenesis.

OBJECTIVE: The objective of this study was to determine if tobacco smoke (TS), a risk factor for cancers of the aerodigestive tract, may contribute to oral carcinogenesis, in part, by suppressing local immunity. METHODS: Mice were placed in Plexiglas holders in which they breathed TS through the nose and mouth for 1 hour daily for 21 days. Control mice breathed room air in the same manner. One day after the last exposure, mice were immunized by application of oxazolone to each buccal mucosa. Control mice were mock immunized by application of vehicle alone. Five days later, all mice were challenged on the ears with oxazolone, and 24-hour ear swelling assessed as contact hypersensitivity. RESULTS: Mice exposed to TS had a significantly smaller contact hypersensitivity response compared with controls. When subsequently reimmunized on the glabrous skin, mice originally primed through TS-exposed mucosa could not be fully immunized, indicating induction of immunologic tolerance by exposure to hapten through TS-perturbed mucosa. Immunocompetent mice exposed to TS in this manner and challenged by submucosal placement of a syngeneic malignant tumor had significantly increased tumor growth over time compared with controls. No difference in growth rate was observed when the experiment was performed with natural killer cell-deficient, SCID (severe combined immunodeficiency) mice. In addition, exposure of epidermal Langerhans cells in vitro to an aqueous extract of TS impaired their ability to undergo maturation and to present antigen to responsive T cells. CONCLUSIONS: Immunologic changes induced in the oral cavity by exposure to TS may play a role in the development of oral cancers.

N-acetyl-S-farnesyl-l-cysteine suppresses chemokine production by human dermal microvascular endothelial cells.

Isoprenylcysteine (IPC) molecules modulate G-protein-coupled receptor signalling. The archetype of this class is N-acetyl-S-farnesyl-l-cysteine (AFC). Topical application of AFC locally inhibits skin inflammation and elicitation of contact hypersensitivity in vivo. However, the mechanism of these anti-inflammatory effects is not well understood. Dermal microvascular endothelial cells (ECs) are involved in inflammation, in part, by secreting cytokines that recruit inflammatory cells. We have previously shown that the sympathetic nerve cotransmitter adenosine-5'-triphosphate (ATP) and adenosine-5'-O-(3-thio) triphosphate (ATPγS), an ATP analogue that is resistant to hydrolysis, increase secretion of the chemokines CXCL8 (interleukin-8), CCL2 (monocyte chemotactic protein-1) and CXCL1 (growth-regulated oncogene α) by dermal microvascular ECs. Production of these chemokines can also be induced by the exposure to the proinflammatory cytokine TNFα. We have now demonstrated that AFC dose-dependently inhibits ATP-, ATPγS- and TNFα-induced production of CXCL1, CXCL8 and CCL2 by a human dermal microvascular EC line (HMEC-1) in vitro under conditions that do not affect cell viability. Inhibition of ATPγS- or TNFα-stimulated release of these chemokines was associated with reduced mRNA levels. N-acetyl-S-geranyl-l-cysteine, an IPC analogue that is inactive in inhibiting G-protein-coupled signalling, had greatly reduced ability to suppress stimulated chemokine production. AFC may exert its anti-inflammatory effects through the inhibition of chemokine production by stimulated ECs.

Serum levels of glycoprotein Dickkopf-1 in patients with cutaneous malignant melanoma: a prospective pilot study.

BACKGROUND: Dickkopf-1 (Dkk-1) glycoprotein is an inhibitor of the canonical Wnt pathway. Recent studies have demonstrated elevated Dkk-1 serum levels in patients with diverse malignancies. In vitro studies with melanoma cell lines showed that loss of Dkk-1 expression may contribute to tumor progression. OBJECTIVE: The present study is the first in vivo investigation of Dkk-1 serum levels in patients with cutaneous malignant melanoma. METHODS: We analyzed serum levels of Dkk-1 protein in 82 patients with cutaneous melanoma. RESULTS: Serum levels were significantly increased (mean 83.01 pmol/l) in comparison to healthy controls (mean 29.36 pmol/l). No statistical difference in Dkk-1 serum levels neither between patients without or with lymph node metastases (p = 0.719) nor between patients with or without visceral metastases (p = 0.929) was found. Patients before excision had moderately higher Dkk-1 serum levels than after excision or with florid metastases. CONCLUSION: Our data suggest that increased Dkk-1 expression is an early event in melanoma, decreasing in later tumor stages. It was shown previously that Dkk-1 activates cell death in melanoma cells. Our in vivo data indicate that a decrease in Dkk-1 could be a sign of loss of tumor control.

Value of micromorphometric criteria of sentinel lymph node metastases in predicting further nonsentinel lymph node metastases in patients with melanoma.

Patients with metastases in the sentinel node (SN) are advised to undergo complete lymph node dissection, although the majority of them will have no further metastatic disease. Some of these patients undergo unnecessary surgery. In this study, we tried to predict the likelihood of further non-SN metastases on the basis of earlier published micromorphometric classifications of SN metastases. Metastases in the SN were re-evaluated on the basis of the microanatomic location of the lesions according to the Dewar's criteria, the S-classification of SN, and tumor burden in accordance with the Rotterdam criteria. The results of these classifications were correlated with the presence of further non-SN metastases. Specimens of 124 positive-SN basins and subsequent complete lymph node dissection were investigated. Further metastases in non-SNs were found in 30 lymph node basins (24.2%). All of the above-mentioned classification systems were significantly correlated with non-SN tumor status. Especially, in patients with SN metastases in subcapsular location, a maximum depth of invasion of less than 0.3 mm (stage I according to the S-classification) or metastases of less than 0.1 mm in diameter had a very low probability of further non-SN metastases (0-5%). The validity of earlier published classifications of SN metastases-based on the micromorphometric criteria in predicting non-SN status was confirmed. Especially, in patients with subcapsular metastases, SI stage metastases or metastases of less than 0.1 mm had a very low risk of further non-SN metastases.

Intravascular large B-cell lymphoma of the skin: typical clinical manifestations and a favourable response to rituximab-containing therapy.

Intravascular large B-cell lymphoma (IVBCL) is a rare malignant neoplasm characterized by the proliferation of large B cells within the blood vessels. The disease can be limited to the skin, but involvement of other organs is common. We report a case of cutaneous IVBCL in a 62-year-old man with minimal histological changes in contrast to prominent skin lesions. The patient was successfully treated with rituximab in combination with CHOP chemotherapy.

Study on the Prevention of Allergy in Children in Europe (SPACE): allergic sensitization at 1 year of age in a controlled trial of allergen avoidance from birth.

Several studies have demonstrated that early intervention may modulate the natural course of atopic disease. The objective of this study was to prevent sensitization to house dust mite and food allergens, as well as development of atopic symptoms, during infancy. To achieve this we employed the combination of an educational package with the use of mite allergen-impermeable mattress encasings. A multi-center European, population-based, randomized controlled study of children at increased atopic risk [study on the prevention of Allergy in Children in Europe (SPACE)] was performed in five countries (Austria, Germany, Greece, Great Britain, Lithuania) and included three cohorts of schoolchildren, toddlers and newborns. We report on the newborn cohort. A total of 696 newborns were included in Austria, Great Britain and Germany. Inclusion criteria were a positive history of parental allergy and a positive skin-prick test or specific immunoglobulin E (IgE) of >or= 1.43 kU/l against at least one out of a panel of common aeroallergens in one or both parents. At 1 year of age the overall sensitization rate against the tested allergens [dust mite allergens: Dermatophagoides pteronyssinus and D. farinae (Der p and Der f, respectively)] and food allergens (egg, milk) in the prophylactic group was 6.21% vs. 10.67% in the control group. The prevalence of sensitization against Der p was 1.86% in the prophylactic group vs. 5% in the control group. In conclusion, we demonstrated, in a group of newborns at risk for atopic diseases, that the sensitization rate to a panel of aero- and food allergens could be effectively decreased through the use of impermeable mattress encasings and the implementation of preventive measures that were easy to perform.