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1.  Genetic and morphologic features for melanoma classification 
Pigment cell & melanoma research  2010;23(6):763-770.
Melanoma is comprised of biologically distinct subtypes. The defining clinical, histomorphologic and molecular features are not fully established. This study sought to validate the association between genetic and histomorphologic features previously described, determine their reproducibility, and association with important clinical variables.
Detailed clinical and histomorphologic features of 365 primary cutaneous melanomas were assessed by 11 pathologists and correlated with mutation status of BRAF and NRAS. There was substantial agreement in the quantitative assessment of histomorphologic features showing similar or better interobserver reproducibility than the established WHO classification scheme. We confirmed that melanomas with BRAF mutations showed characteristic morphologic features (p<0.0001) and metastasized more frequently to regional lymph nodes (p=0.046). Importantly, melanomas without mutations were a heterogeneous group, with a subset having very similar features clinical and morphological features than those with BRAF mutation raising the possibility that they are biologically related.
Our study confirms an association between histomorphologic features, mutation status and pattern of metastasis, providing criteria for a refined melanoma classification aimed at defining biologically homogeneous disease subgroups.
PMCID: PMC3107973  PMID: 20874733
melanoma; BRAF; mutation; classification; histomorphology
2.  Prognostic value of angiogenesis evaluated with high-frequency and colour Doppler sonography for preoperative assessment of primary cutaneous melanomas: correlation with recurrence after a 5 year follow-up period 
Cancer Imaging  2006;6(1):24-29.
Objective: To study the value of high-frequency sonography (HFS) and colour Doppler sonography (CDS) in evaluating the 5 year metastatic potential of primary cutaneous melanomas (CM). Materials and methods: 111 CM were studied before surgical resection and 107 were depicted on HFS. The maximal HFS thickness was measured and compared with the Breslow thickness. A CDS study was performed in each tumour. Results: HFS thickness ranged from 0.26 to 8.0 mm and Breslow thickness from 0.15 to 8.0 mm. HFS and Breslow thickness correlated strongly (r>0.93). Intratumour vessels were depicted in 43 of the 107 CM, of which 40 were thicker than 2 mm. The median follow-up was 61 months and 27 patients developed relapses. In the univariate analyses, neovascularization visualized with CDS, sonographic thickness and the Breslow thickness were significantly linked to relapses (p<0.0001), as were lymph node status and ulceration (p=0.007 and 0.004). Conclusion: Vascularization was observed mainly in thick primary melanoma. A median follow-up of 5 years showed the prognostic value of angiogenesis evaluated by CDS.
PMCID: PMC1693780  PMID: 16644502
Melanoma; angiogenesis; Doppler sonography; ultrasonography; histology
3.  Vaccination of metastatic melanoma patients with autologous dendritic cell (DC) derived-exosomes: results of thefirst phase I clinical trial 
DC derived-exosomes are nanomeric vesicles harboring functional MHC/peptide complexes capable of promoting T cell immune responses and tumor rejection. Here we report the feasability and safety of the first Phase I clinical trial using autologous exosomes pulsed with MAGE 3 peptides for the immunization of stage III/IV melanoma patients. Secondary endpoints were the monitoring of T cell responses and the clinical outcome.
Patients and methods
Exosomes were purified from day 7 autologous monocyte derived-DC cultures. Fifteen patients fullfilling the inclusion criteria (stage IIIB and IV, HLA-A1+, or -B35+ and HLA-DPO4+ leukocyte phenotype, tumor expressing MAGE3 antigen) were enrolled from 2000 to 2002 and received four exosome vaccinations. Two dose levels of either MHC class II molecules (0.13 versus 0.40 × 1014 molecules) or peptides (10 versus 100 μg/ml) were tested. Evaluations were performed before and 2 weeks after immunization. A continuation treatment was performed in 4 cases of non progression.
The GMP process allowed to harvest about 5 × 1014 exosomal MHC class II molecules allowing inclusion of all 15 patients. There was no grade II toxicity and the maximal tolerated dose was not achieved. One patient exhibited a partial response according to the RECIST criteria. This HLA-B35+/A2+ patient vaccinated with A1/B35 defined CTL epitopes developed halo of depigmentation around naevi, a MART1-specific HLA-A2 restricted T cell response in the tumor bed associated with progressive loss of HLA-A2 and HLA-BC molecules on tumor cells during therapy with exosomes. In addition, one minor, two stable and one mixed responses were observed in skin and lymph node sites. MAGE3 specific CD4+ and CD8+ T cell responses could not be detected in peripheral blood.
The first exosome Phase I trial highlighted the feasibility of large scale exosome production and the safety of exosome administration.
PMCID: PMC554765  PMID: 15740633
exosomes; dendritic cells; phase I trial; cancer vaccine; immunotherapy
4.  Novel mode of action of c-kit tyrosine kinase inhibitors leading to NK cell–dependent antitumor effects 
Journal of Clinical Investigation  2004;114(3):379-388.
Mutant isoforms of the KIT or PDGF receptors expressed by gastrointestinal stromal tumors (GISTs) are considered the therapeutic targets for STI571 (imatinib mesylate; Gleevec), a specific inhibitor of these tyrosine kinase receptors. Case reports of clinical efficacy of Gleevec in GISTs lacking the typical receptor mutations prompted a search for an alternate mode of action. Here we show that Gleevec can act on host DCs to promote NK cell activation. DC-mediated NK cell activation was triggered in vitro and in vivo by treatment of DCs with Gleevec as well as by a loss-of-function mutation of KIT. Therefore, tumors that are refractory to the antiproliferative effects of Gleevec in vitro responded to Gleevec in vivo in an NK cell–dependent manner. Longitudinal studies of Gleevec-treated GIST patients revealed a therapy-induced increase in IFN-γ production by NK cells, correlating with an enhanced antitumor response. These data point to a novel mode of antitumor action for Gleevec.
PMCID: PMC489961  PMID: 15286804

Results 1-4 (4)