Prognosis of patients with metastatic melanoma is poor (Ketcham and Balch, 1985;Tafra et al, 1995), with an annual risk of death of about 20% during the first 3 years (Slingluff et al, 1992). The second most common site for metastatic spread is the lung (Balch and Milton, 1985), and the annual probability of developing pulmonary metastases increases progressively from 10% at 5 years to 17% at 15 years. Overall long-term survival for such patients is poor, with only 4% of patients alive at 4 years (Harpole et al, 1992).As effective chemotherapy for metastatic melanoma is not available, surgery can represent the only prospect of cure for highly selected patients (Wong et al, 1993;Karakousis et al, 1994). However only 10-12% of cases are suitable for surgery with curative intent (Cahan, 1973;Mountain et al, 1984;Thayer and Overholt, 1985;Pogrebniak et al, 1988;Gorenstein et al, 1991). Moreover, surgical results are still controversial as the majority of published studies are based on a small number of cases with relatively short follow-up.Two large series have already confirmed the prognostic value of factors such as radicality, number of resected metastases and disease-free interval (DFI) after pulmonary metastasectomy (Harpole et al, 1992;Tafra et al, 1995) but it remains unclear how these data can be used for preoperative patient selection.The purpose of this study is to evaluate the long-term results of surgery in melanoma pulmonary metastases from the International Registry of Lung Metastases (IRLM) data, with the aim of defining the subset of patients that really benefit from surgery. PATIENTS AND METHODSOf the 5206 patients recorded in the International Registry of Lung Metastases in the period 1945-1995, 328 (6.3%) had operations for pulmonary stage IV melanoma. The aims of the Registry, methodology of data collection and analysis have been published previously (Pastorino et al, 1997). In summary, all patients who had undergone resection of pulmonary metastases with curative intent were eligible for inclusion if their primary tumour, as well as metastases in other organs, had been effectively treated. Eighteen major centres from Europe, the USA and Canada took part in the project. Data analysisSurvival time was calculated from first metastasectomy to the last date of follow-up, by means of the Kaplan-Meier estimate. Mean follow-up of patients alive was 42 months.The impact on survival of the following variables was tested: age, sex, radicality of metastasectomy, time to pulmonary metastases (time from surgery of primary melanoma to diagnosis of pulmonary metastases, TPM), number of pathologically confirmed metastases, resection volume, nodal involvement, delay of surgery from diagnosis of metastases to metastasectomy, chemotherapy, Lung metastases from melanoma: when is surgical treatment warranted? Summary Surgical treatment of lung metastases from melanoma is highly controversial as the expected outcome is much poorer than for other primary tumours and a reliable system for selecting patients is lacking. ...

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The cAMP signaling pathway regulates growth of many cell types, including somatotrophs, thyrocytes, melanocytes, ovarian follicular granulosa cells, adrenocortical cells, and keratinocytes. Mutations of partners from the cAMP signaling cascade are involved in tumor formation. Thyroid-stimulating hormone (TSH) receptor and Gs␣ activating mutations have been detected in thyroid autonomous adenomas, Gs␣ mutations in growth hormone-secreting pituitary adenomas, and PKAR1A mutations in Carney complex, a multiple neoplasia syndrome. To gain more insight into the role of cAMP signaling in tumor formation, human primary cultures of thyrocytes were treated for different times (1.5, 3, 16, 24, and 48 h) with TSH to characterize modulations in gene expression using cDNA microarrays. This kinetic study showed a clear difference in expression, early (1.5 and 3 h) and late (16 -48 h) after the onset of TSH stimulation. This result suggests a progressive sequential process leading to a change of cell program. The gene expression profile of the long-term stimulated cultures resembled the autonomous adenomas, but not papillary carcinomas. The molecular phenotype of the adenomas thus confirms the role of long-term stimulation of the TSH-cAMP cascade in the pathology. TSH induced a striking up-regulation of different negative feedback modulators of the cAMP cascade, presumably insuring the oneshot effect of the stimulus. Some were down-or nonregulated in adenomas, suggesting a loss of negative feedback control in the tumors. These results suggest that in tumorigenesis, activation of proliferation pathways may be complemented by suppression of multiple corresponding negative feedbacks, i.e., specific tumor suppressors.cyclic AMP ͉ microarrays ͉ papillary tumors ͉ thyrotropin T ight regulation of the second messenger cAMP is of crucial importance for cells because it regulates function, differentiation, and proliferation (1). In cells in which cAMP stimulates growth, activating mutations in partners of this pathway induce uncontrolled growth. In most benign thyroid autonomous adenomas, activating mutations have been found in the thyroidstimulating hormone (TSH) receptor (TSHR) (2) and, to a lesser extent, in the Gs␣ protein, an activator of the cAMP-producing adenylyl cyclase (1, 3). These mutations result in a TSHindependent growth and lead to hyperfunction (1). In addition, activating mutations of the Gs␣ protein have been detected in growth hormone-secreting pituitary adenomas (4) and inactivating mutations in the type I-␣ regulatory subunit inhibiting protein kinase A (PKAR1A) in Carney complex, a multiple neoplasia syndrome (5).Our knowledge of the genes regulated by the cAMP-protein kinase A cascade and its uncontrolled activation is still sketchy (6). To gain more insight into the cAMP-activated signal transduction cascade in tumors, human primary cultures of thyrocytes treated for different times with the TSH growth and differentiation stimulus were used as a model. Thyrocytes in primary culture are expected to be better mod...

BackgroundType II alveolar epithelial cells (AECII) are well known for their role in the innate immune system. More recently, it was proposed that they could play a role in the antigen presentation to T lymphocytes but contradictory results have been published both concerning their surface expressed molecules and the T lymphocyte responses in mixed lymphocyte cultures. The use of either AECII cell line or fresh cells could explain the observed discrepancies. Thus, this study aimed at defining the most relevant model of accessory antigen presenting cells by carefully comparing the two models for their expression of surface molecules necessary for efficient antigen presentation.MethodsWe have compared by flow cytometry the surface expression of the major markers involved in the immunological synapse on the A549 cell line, the most popular model of type II alveolar epithelial cells, and freshly isolated cells. HLA-DR, CD80, CD86, ICOS-L, CD54, CD58 surface expression were studied in resting conditions as well as after IFN-γ/TNF-α treatment, two inflammatory cytokines, known to modulate some of these markers.ResultsThe major difference found between the two cells types was the very low surface expression of HLA-DR on the A549 cell line compared to its constitutive expression on freshly isolated AECII. The surface expression of co-stimulatory molecules from the B7 family was very low for the CD86 (B7-2) and ICOS-L (B7-H2) and absent for CD80 (B7-1) on both freshly isolated cells and A549 cell line. Neither IFN-γ nor TNF-α could increase the expression of these classical co-stimulatory molecules. However CD54 (ICAM-1) and CD58 (LFA-3) adhesion molecules, known to be implicated in B7 independent co-stimulatory signals, were well expressed on the two cell types.ConclusionsConstitutive expression of MHC class I and II molecules as well as alternative co-stimulatory molecules by freshly isolated AECII render these cells a good model to study antigen presentation.