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Meldola, Italy

Testori A.,Istituto Europeo di Oncologia | Chiarion-Sileni V.,Veneto Institute of Oncology | Stanganelli I.,Scientific Institute of Romagna for the Study and Treatment of Tumors | Rossi C.R.,University of Padua | And 5 more authors.
Dermatology | Year: 2013

Follow-up is managed internally in 94% of centers and is programmed according to international guidelines in 52% of high-volume hospitals (>25 melanoma diagnoses per year); the remainder use internal guidelines; fewer low-volume centers (≤25 diagnoses per year) have internal guidelines (25%, p = 0.001). Instrumental examinations for stage III and IV disease are similar, while the examination interval changes from 3/4 months for stage III to 2/3 months for stage IV, and use of PET/CT increases from 44 to 54%. Overall, thoracic and abdominal CT is used most for follow-up in stage III (83%), while bone scintigraphy is used more commonly in low-volume centers (41 vs. 19%, p = 0.003), despite similar use of PET/CT (48 vs. 41%). Brain CT or MRI is more common in high-volume centers (63 vs. 39%, p > 0.0001), as is echography of draining lymph nodes (71 vs. 52%, p = 0.01). Hepatic/abdominal echography and thoracic radiography are used in about 50% of centers, regardless of type. In stage IV, use of bone scintigraphy is similar among groups (ca. 40%); brain CT/NMR use increases from 51 to 64% and is more common in high-volume centers (p = 0.03). Lymph node echography is more common in high-volume centers (56 vs. 39%, p = 0.03). Copyright © 2013 S. Karger AG, Basel.

Gatti L.,Molecular Pharmacology Unit | Sevko A.,German Cancer Research Center | Sevko A.,University of Mannheim | de Cesare M.,Molecular Pharmacology Unit | And 14 more authors.
Oncotarget | Year: 2014

Target-specific agents used in melanoma are not curative, and chemokines are being implicated in drug-resistance to target-specific agents. Thus, the use of conventional agents in rationale combinations may result in optimization of therapy. Because histone deacetylases participate in tumor development and progression, the combination of the pan-inhibitor SAHA and temozolomide might provide a therapeutic advantage. Here, we show synergism between the two drugs in mutant BRAF cell lines, in association with decreased phosphorylation of cell survival proteins (e.g., C-Jun-N-terminal-kinase, JNK). In the spontaneous ret transgenic mouse melanoma model, combination therapy produced a significant disease onset delay and down-regulation of Chemokine (C-C motif) ligand 2 (CCL2), JNK, and of Myeloid-derived suppressor cell recruitment. Co-incubation with a CCL2-blocking-antibody enhanced in vitro cell sensitivity to temozolomide. Conversely, recombinant CCL2 activated JNK in human tumor melanoma cells. In keeping with these results, the combination of a JNK-inhibitor with temozolomide was synergistic. By showing that down-regulation of CCL2-driven signals by SAHA and temozolomide via JNK contributes to reduce melanoma growth, we provide a rationale for the therapeutic advantage of the drug combination. This combination strategy may be effective because of interference both with tumor cell and tumor microenvironment.

Chiarion-Sileni V.,Veneto Oncology Institute | Guida M.,Italian National Cancer Institute | Romanini A.,University of Pisa | Bernengo M.G.,University of Turin | And 8 more authors.
Dermatology | Year: 2013

Melanoma incidence and mortality rates are rising in Italy, indicating that more effective treatments are required both in the adjuvant and metastatic settings. We analyzed clinical practices in the adjuvant and metastatic settings by conducting a nationwide survey of clinicians responsible for managing melanoma treatment and follow-up in a representative sample of Italian hospitals. 95% of participating hospitals completed the panel of questions on adjuvant and metastatic treatment, making it likely that these results give a realistic picture of treatment and follow-up of melanoma patients in Italy. In low-volume hospitals (<25 new melanoma diagnoses yearly) adjuvant therapy was significantly more used than in large-volume hospitals for patients in stage III and IV (82 versus 66% and 56 versus 30%, respectively), and only 11% of patients were enrolled in clinical trials. In the metastatic setting dacarbazine was the preferred first-line treatment (32%) followed by polychemotherapy (23%); 12% of patients were enrolled in clinical trials and less than 10% received interleukin-2, usually subcutaneously. The information provided by this study was used by the Italian Melanoma Intergroup to improve the quality of care and to redirect financial resources. Copyright © 2013 S. Karger AG, Basel.

De Rosa F.,Immunotherapy Unit | Guidoboni M.,Immunotherapy Unit | Amadori D.,Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori | Ridolfi R.,Immunotherapy Unit | And 2 more authors.
Melanoma Research | Year: 2014

MicroRNAs are increasingly being recognized to play an important role in finely tuning gene expression; therefore, their dysregulation in cancer has been investigated extensively. In terms of melanoma, they are involved in the regulation of many genes and pathways impacting invasiveness, dissemination, and disease progression. Many microRNAs also target genes regulating ontogenesis and functions of the immune system. Indeed, fine-tuning of gene expression by microRNAs is necessary for normal differentiation of the various components of the immune system and for mounting an effective innate and cell-mediated response, which has been shown to be able to control tumor growth. Dendritic cells, by presenting antigens to and activating naive T cells, constitute a critical aspect and have been therefore been used in many studies of cancer vaccination with promising results. Many genes regulating functions and plasticity of dendritic cells are indeed targeted by microRNAs, whose expression is also dependent on maturation status. Therefore, microRNAs could provide new potential therapeutic targets both on the tumor and on the immune system, and could also be used to characterize dendritic cells utilized in immunotherapy trials. © 2014 Wolters Kluwer Health.

Vergani E.,Immunotherapy Unit | Vallacchi V.,Immunotherapy Unit | Frigerio S.,Immunotherapy Unit | Deho P.,Immunotherapy Unit | And 8 more authors.
Neoplasia | Year: 2011

PLX4032/vemurafenib is a first-in-class small-molecule BRAFV600E inhibitor with clinical activity in patients with BRAF mutant melanoma. Nevertheless, drug resistance develops in treated patients, and strategies to overcome primary and acquired resistance are required. To explore the molecular mechanisms involved in primary resistance to PLX4032, we investigated its effects on cell proliferation and signaling in a panel of 27 genetically characterized patient-derived melanoma cell lines. Cell sensitivity to PLX4032 was dependent on BRAFV600E and independent from other gene alterations that commonly occur in melanoma such as PTEN loss, BRAF, and MITF gene amplification. Two cell lines lacking sensitivity to PLX4032 and harboring a different set of genetic alterations were studied as models of primary resistance. Treatment with the MEK inhibitor UO126 but not with PLX4032 inhibited cell growth and ERK activation. Resistance to PLX4032 was maintained after CRAF down-regulation by siRNA indicating alternative activation of MEK-ERK signaling. Genetic characterization by multiplex ligation-dependent probe amplification and analysis of phosphotyrosine signaling by MALDI-TOF mass spectrometry analysis revealed the activation of MET and SRC signaling, associated with the amplification of MET and of CTNNB1 and CCND1 genes, respectively. The combination of PLX4032 with drugs or siRNA targetingMET was effective in inhibiting cell growth and reducing cell invasion and migration in melanoma cells with MET amplification; similar effects were observed after targeting SRC in the other cell line, indicating a role for MET and SRC signaling in primary resistance to PLX4032. Our results support the development of classification of melanoma in molecular subtypes for more effective therapies. © 2011 Neoplasia Press, Inc.

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