Publications (25)201.67 Total impact
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Article: DIAGNOSTIC AND PROGNOSTIC VALUE OF IMMUNOCYTOCHEMISTRY AND BRAF MUTATION ANALYSIS ON LIQUID BASED BIOPSIES OF THYROID NEOPLASMS SUSPICIOUS FOR CARCINOMA.
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ABSTRACT: OBJECTIVE: In the field of Fine Needle Aspiration Cytology (FNAC), the category of suspicious for malignancy (SM) thyroid lesions which bears 55-85% risk of malignant histology, is a challenging topic in which morphology alone is not always able to make a correct diagnosis. Recently, immunocytochemistry (ICC) has been referred as helpful in differentiating low and high malignant risk lesions and BRAF activating mutations have been identified in a significant amount of papillary thyroid carcinomas (PTC). The introduction of the liquid-based cytology (LBC) may simplify the application of these techniques to thyroid cytology.DESIGN Our aim is to evaluate the diagnostic and prognostic role of both ICC and BRAF mutation for the SM category on LBC.METHODS From October 2010 through June 2011, 113 LBC cytological cases (including 37 SM and 76 PTC) underwent surgery. All cases were studied for BRAF mutation and ICC.RESULTS In detail, ICC resulted positive in 26 (86.6%) histologically malignant SM with 15 of which (40.5%) expressed a BRAF mutation. Overall 63 cases showed a BRAF mutation histological resulting as PTC.Concerning the prognostic role of BRAF mutation for the two categories, we reported a significant correlation with multifocality, nodal involvement and extracapsular invasion (p<0.0001).CONCLUSIONS Special techniques such as ICC and molecular might be successfully carried out on LBC- processed material. For both categories, ICC is more sensitive whereas BRAF analysis is an interesting support due to its high specificity adding a prognostic value in both SM and PTCs.European Journal of Endocrinology 03/2013; · 3.42 Impact Factor -
Article: Targeted therapy with bevacizumab and erlotinib tailored to the molecular profile of patients with recurrent glioblastoma. Preliminary experience.
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ABSTRACT: BACKGROUND: Advances in comprehension of molecular biology of glioblastoma (GBM) have led to the development of targeted therapies. The aim of the present study was to evaluate the efficacy and safety of a targeted therapeutic approach in which administration of bevacizumab and erlotinib was tailored on the molecular profile of recurrent GBM. METHODS: We prospectively enrolled ten adult patients suffering from recurrent GBM who had undergone surgical resection and standard chemo-radiotherapy. Tumor tissue was assessed for the expression of EGFRvIII and MGMT promoter methylation by RT-PCR, and for PTEN and VEGF expression by immunohistochemistry. Normal PTEN status was required for inclusion. Patients with VEGF overexpressing tumors (10/10) were treated with bevacizumab (10 mg/kg iv every 2 weeks in 6-week cycles); patients whose tumor expressed EGFRvIII (4/10) added erlotinib (150 mg/day orally; 300 mg/day if on enzyme-inducing antiepileptic drugs). Therapy was continued until disease progression or unacceptable toxicity. Primary endpoints of the study were response rate (RR), 6-month progression-free survival (PFS-6), and safety profile. RESULTS: The RR and PFS-6 were 100 % (4/4) and 50 % (3/6) in patients treated with bevacizumab+erlotinib (n = 4) and bevacizumab (n = 6), respectively. In the whole cohort (n = 10), RR and PFS-6 were both 70 % (7/10); median PFS and overall survival (OS) were 8.0 (3.0-31.0) and 9.5 (5.0-31.0) months, respectively. No grade 3/4 adverse events were observed; three patients treated with bevacizumab+erlotinib displayed grade 1/2 rash not requiring dose reduction; one patient treated with bevacizumab developed intratumoral hemorrhage requiring treatment discontinuation. CONCLUSION: To our knowledge, this is the first study on recurrent GBM in which administration of bevacizumab and erlotinib was tailored on the molecular profile of the patient's tumor. Although we treated a limited number of patients, we obtained significantly higher RR and PFS-6 than those reported in a previous trial lacking molecular tumor analysis.Acta Neurochirurgica 11/2012; · 1.52 Impact Factor -
Article: Epigenetic silencing of Id4 identifies a glioblastoma subgroup with a better prognosis as a consequence of an inhibition of angiogenesis.
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ABSTRACT: BACKGROUND: Inhibitors of DNA binding/differentiation (Id1 to Id4) are a family of helix-loop-helix transcription factors, which are highly expressed during embryogenesis and at lower levels in mature tissues. Id4 plays an important role in neuronal stem cell differentiation, and its deregulation has been implicated in glial neoplasia. METHODS: The methylation status of Id4 was analyzed by methylation-specific polymerase chain reaction (PCR) in 62 glioblastoma (GBM) cases and in 20 normal brain tissues. Methylation status of Id4 was confirmed by sequencing after subcloning and messenger RNA (mRNA) and protein expression. We also evaluated the mRNA expression of MGP (matrix GLA protein), TGF-β1 (transforming growth factor beta 1), and VEGF (vascular endothelial growth factor) by real-time PCR analysis. Clinical and histological assessment of tumor angiogenesis was performed by evaluating the relative enhancing tumor ratio on magnetic resonance imaging and microvessel density on von Willebrand factor-stained sections, respectively. RESULTS: The promoter of Id4 was methylated in 23 of 62 (37%) GBMs. In methylated GBMs, Id4 mRNA was significantly reduced, compared with unmethylated GBMs (P = .0002). A significant reduction of protein expression was detected in all hypermethylated cases. GBMs with methylated Id4 showed a significant reduction of MGP, TGF-β1, and VEGF mRNA expression and had significantly lower relative enhancing tumor ratio (P = .0108) and microvessel density (P = .0241) values with respect to unmethylated GBMs. Finally, Id4 methylation was significantly associated with a favorable clinical outcome (P = .0006). CONCLUSIONS: These data suggest that methylation of Id4 may be involved in the pathogenesis of GBM and in the resistance of this neoplasm to conventional treatment throughout MGP-mediated neoangiogenesis. Cancer 2012. © 2012 American Cancer Society.Cancer 11/2012; · 4.77 Impact Factor -
Article: Prognostic relevance of c-Myc and BMI1 expression in patients with glioblastoma.
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ABSTRACT: Although the c-Myc oncogene is frequently deregulated in human cancer, its involvement in the pathogenesis of glioblastoma is not clear. We conducted immunohistochemical analysis of the expression of c-Myc, polycomb ring finger oncogene (BMI1), and acetylation of the lysine 9 (H3K9Ac) of histone 3 in 48 patients with glioblastoma who underwent surgery followed by radiotherapy and temozolomide treatment. The expression of c-Myc, BMI1, and H3K9ac was correlated with clinical characteristics and outcome. We found that overexpression of c-Myc was significantly associated with that of BMI1 (P = .009), and that patients who harbored glioblastomas overexpressing c-Myc and BMI1 showed significantly longer overall survival (P < .0001 and P = .0009, respectively). Our results provide the first evidence of the prognostic value of c-Myc and associated genes in patients with glioblastoma. The favorable effect of c-Myc and BMI1 expression on survival is likely mediated by the sensitization of cancer cells to radiotherapy and temozolomide through the activation of apoptotic pathways.American Journal of Clinical Pathology 09/2012; 138(3):390-6. · 2.60 Impact Factor -
Article: Von hippel-lindau disease and erythrocytosis.
Journal of Clinical Oncology 03/2012; 30(13):e137-9. · 18.37 Impact Factor -
Article: Expression of EGFRvIII in glioblastoma: prognostic significance revisited.
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ABSTRACT: The epidermal growth factor receptor variant III (EGFRvIII) is associated with increased proliferation of glioma cells. However, the impact of EGFRvIII on survival of patients with glioblastoma (GBM) has not been definitively established. In the present study, we prospectively evaluated 73 patients with primary GBM treated with surgical resection and standard radio/chemotherapy. The EGFRvIII was assessed by reverse transcription-polymerase chain reaction (PCR), O(6)-methylguanine methyltransferase (MGMT) promoter methylation was assessed by methylation-specific PCR, and phosphatase and tension homolog (PTEN) expression was assessed by immunohistochemistry. In 14 patients of this series, who presented with tumor recurrence, EGFRvIII was determined by real-time PCR. Sensitivity to temozolomide (TMZ) was assessed in vitro on GBM neurosphere cell cultures with different patterns of EGFRvIII expression. Age 60 years or younger, preoperative Karnofsky Performance Status score of 70 or higher, recursive partitioning analysis score III and IV, methylated MGMT, and Ki67 index of 20% or less were significantly associated with longer overall survival (OS; P = .0069, P = .0035, P = .0007, P = .0437, and P = .0286, respectively). EGFRvIII identified patients with significantly longer OS (P = .0023) and the association of EGFRvIII/Ki67 of 20% or less, EGFRvIII/normal PTEN, EGFRvIII/methylated MGMT, and EGFRvIII/normal PTEN/methylated MGMT identified subgroups of GBM patients with better prognosis. In recurred GBMs, EGFRvIII expression was approximately two-fold lower than in primary tumors. In vitro, the EGFRvIII-negative GBM neurosphere cells were more resistant to TMZ than the positive ones. In conclusion, in contrast with previous studies, we found that EGFRvIII is associated with prolonged survival of GBM patients treated with surgery and radio/chemotherapy. Depletion of EGFRvIII in recurrent GBMs as well as differential sensitivity to TMZ in vitro indicates that the EGFRvIII-negative cell fraction is involved in resistance to radio/chemotherapy and tumor repopulation.Neoplasia (New York, N.Y.) 12/2011; 13(12):1113-21. · 5.48 Impact Factor -
Article: Is there a role for IGF1R and c-MET pathways in resistance to cetuximab in metastatic colorectal cancer?
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ABSTRACT: The KRAS mutation is not responsible for all cases of resistance to anti-epidermal growth factor receptors (EGFRs) in metastatic colorectal cancer (mCRC), and new predictive and prognostic factors are actively being sought. We retrospectively evaluated the efficacy of a cetuximab-containing treatment in 73 patients with mCRC according to KRAS and BRAF mutational status as well as PTEN, c-MET, and insulin-like growth factor receptor (IGF1R) expression. Overall response rate (ORR), median progression-free survival (mPFS), and median overall survival (mOS) were significantly lower in patients with KRAS mutation than in patients with KRAS wild-type; among the population with KRAS wild-type, only 2 patients with BRAF mutations were found and neither of them achieved a response. No significant association was found between PTEN and clinical outcome. Compared with low/normal expression, c-MET overexpression significantly correlated with shorter mPFS and mOS: 3 vs. 5 months (P = .018) and 11 vs. 10 months (P = .037), respectively. In patients with high IGF1R expression, mOS was significantly longer than in those with low/normal expression (14 vs. 8 months; P = .015). KRAS mutation significantly correlates with a worse outcome in patients treated with cetuximab, whereas no definitive inference can be drawn about the role of BRAF mutation and PTEN loss of expression. Instead, c-MET overexpression might represent a negative prognostic factor in mCRC and may have a role in resistance to anti-EGFR therapy. Interestingly, IGF1R overexpression seems a favorable prognostic factor in mCRC.Clinical Colorectal Cancer 05/2011; 10(4):325-32. · 1.68 Impact Factor -
Article: The viral load of Epstein-Barr virus (EBV) DNA in peripheral blood predicts for biological and clinical characteristics in Hodgkin lymphoma.
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ABSTRACT: The Epstein-Barr virus (EBV) is present in the malignant Hodgkin/Reed-Sternberg (HRS) cells of 20% to 40% cases of Hodgkin lymphoma (HL) in Western countries. We were interested in the detection and quantification of cell-free plasma EBV-DNA as an indicator of biological and clinical characteristics in EBV-associated HL. EBV was detected in peripheral blood compartments (whole blood, plasma, and mononuclear cells) at diagnosis by real-time PCR for the EBNA (EB nuclear antigen) region (n = 93) and in HRS cells by in situ hybridization for EBV-encoded small RNAs (EBER; n = 63). These data were correlated to histological and clinical characteristics, EBV serology, circulating cell-free DNA, and interleukin (IL)-6 levels. Detection of EBV-DNA in plasma had a high specificity (90%), but a relatively low sensitivity (65%) to predict for EBV association. The viral load was higher in patients with advanced stage disease, older age in the presence of B-symptoms, and international prognostic score more than 2. The presence of EBV in HRS cells and higher plasma EBV-DNA copy numbers correlated to an increased frequency of tumor-infiltrating CD68+ macrophages in lymph node biopsies. Plasma EBV-DNA load correlated to circulating cell-free DNA and IL-6 levels, and inversely correlated to lymphocyte counts and EBNA1 antibody titers. Although the presence of EBV-DNA in peripheral blood cannot be regarded as a surrogate marker for EBER, the plasma EBV-DNA load at HL diagnosis is an indicator of disease activity and biological characteristics associated with negative prognosis. Moreover, the inverse correlation to EBNA1 antibody titers and lymphocyte counts may indicate a reduction in immunosurveillance, favoring the expansion of EBV-HRS cells in HL.Clinical Cancer Research 05/2011; 17(9):2885-92. · 7.74 Impact Factor -
Article: Epigenetic silencing of SOCS3 identifies a subset of prostate cancer with an aggressive behavior.
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ABSTRACT: Chronic inflammation and subsequent tissutal alterations may play a key role in prostate carcinogenesis. In this way, molecular alterations of the suppressor of cytokine signaling 3 (SOCS3), one of the most important inhibitory molecule of inflammatory signal transduction circuitries, could contribute to explain the pleiotropic role of interleukin-6 (IL-6) in this type of cancer. We analyzed the methylation status and mRNA expression of SOCS3 in 20 benign prostate hyperplasias (BPH) and in 51 prostate cancer specimens. We analyzed the SOCS3 methylation status using methylation-specific PCR. Hypermethylation was confirmed by sequencing after subcloning. Epigenetic silencing of this gene was also demonstrated by real-time PCR and by immunohistochemistry. Results and correlation with clinical data were statistically analyzed. We found that the promoter of SOCS3 was methylated in 39.2% of prostate cancer. On the contrary, all BPH and normal controls had an unmethylated pattern. Real-time analysis showed that in methylated cases SOCS3 mRNA expression was reduced by three and four folds as compared to BPH and unmethylated cases, respectively. Interestingly, SOCS3 mRNA level was higher in unmethylated prostate cancer than in BPH. The immunohistochemical staining analysis for SOCS 3 confirmed mRNA results. Moreover, methylation of SOCS3 promoter significantly associated with intermediate-high grade Gleason score (P = 0.0007) and with an unfavorable clinical outcome (P = 0.0019). Our data suggest that SOCS3 hypermethylation may be involved in the pathogenesis of prostate cancer and could identify a tumor subset with an aggressive behavior.The Prostate 02/2011; 71(3):318-25. · 3.48 Impact Factor -
Article: Expression of the stem cell marker CD133 in recurrent glioblastoma and its value for prognosis.
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ABSTRACT: Experimental data suggest that glioblastoma cells expressing the stem cell marker CD133 play a major role in radiochemoresistance and tumor aggressiveness. To date, however, there is no clinical evidence that the fraction of CD133-positive cells in glioblastoma that recurs after radiochemotherapy may be relevant for prognosis. The authors used immunohistochemistry to assess CD133 expression in 37 paired glioblastoma samples, including 1 primary tumor sample and 1 recurrent tumor sample, after patients received adjuvant radiochemotherapy. To assess the actual composition of the CD133-positive glioblastoma cell population, fluorescence-associated cell sorting (FACS) analysis was used to sort CD133-positive/CD45-negative cells that were assayed for tumor-specific chromosomal aberrations using interphase fluorescence in situ hybridization. To rule out endothelial precursor cells, CD133-positive fractions also were assayed with anti-CD34 by FACS. In recurrent glioblastomas, the percentage of CD133-positive cells was increased by 4.6-fold compared with the percentage in primary glioblastomas, although, in some tumors, it increased up to 10-fold and 20-fold. Unexpectedly, the increase in CD133 expression was associated significantly with longer survival after tumor recurrence. An analysis of tumor-specific chromosomal aberrations and in vivo studies revealed that the CD133-positive cell compartment of recurrent glioblastoma was composed of both cancer stem cells and nontumor neural stem cells. The latter cells represented from 20% to 60% of the CD133-positive cell population, and their relative percentage favorably affected the survival of patients with recurrent glioblastoma. Endothelial CD133-positive/CD34-positive precursors did not contribute to the CD133-positive cell population. The authors hypothesized that, similar to the phenomenon described in glioblastoma models, neural stem/progenitor cells that are recruited by the tumor from surrounding brain may exert an antitumorigenic effect.Cancer 01/2011; 117(1):162-74. · 4.77 Impact Factor -
Article: Endothelial progenitor cells are clonal and exhibit the JAK2(V617F) mutation in a subset of thrombotic patients with Ph-negative myeloproliferative neoplasms.
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ABSTRACT: In this study we investigated whether neoplastic transformation occurring in Philadelphia (Ph)-negative myeloproliferative neoplasms (MPNs) could involve also the endothelial cell compartment. We evaluated the level of endothelial colony-forming cells (E-CFCs) in 42 patients (15 with polycythemia vera, 12 with essential thrombocythemia, and 15 with primary myelofibrosis). All patients had 1 molecular abnormality (JAK2(V617F) or MPL(W515K) mutations, SOCS gene hypermethylation, clonal pattern of growth) detectable in their granulocytes. The growth of colonies was obtained in 22 patients and, among them, patients with primary myelofibrosis exhibited the highest level of E-CFCs. We found that E-CFCs exhibited no molecular abnormalities in12 patients, had SOCS gene hypermethylation, were polyclonal at human androgen receptor analysis in 5 patients, and resulted in JAK2(V617F) mutated and clonal in 5 additional patients, all experiencing thrombotic complications. On the whole, patients with altered E-CFCs required antiproliferative therapy more frequently than patients with normal E-CFCs. Moreover JAK2(V617F)-positive E-CFCs showed signal transducer and activator of transcription 5 and 3 phosphorylation rates higher than E-CFCs isolated from healthy persons and patients with MPN without molecular abnormalities. Finally, JAK2(V617F)-positive E-CFCs exhibited a high proficiency to adhere to normal mononuclear cells. This study highlights a novel mechanism underlying the thrombophilia observed in MPN.Blood 01/2011; 117(9):2700-7. · 9.90 Impact Factor -
Article: Expression of the stem cell marker CD133 in recurrent glioblastoma and its value for prognosis
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ABSTRACT: BACKGROUND:Experimental data suggest that glioblastoma cells expressing the stem cell marker CD133 play a major role in radiochemoresistance and tumor aggressiveness. To date, however, there is no clinical evidence that the fraction of CD133-positive cells in glioblastoma that recurs after radiochemotherapy may be relevant for prognosis.METHODS:The authors used immunohistochemistry to assess CD133 expression in 37 paired glioblastoma samples, including 1 primary tumor sample and 1 recurrent tumor sample, after patients received adjuvant radiochemotherapy. To assess the actual composition of the CD133-positive glioblastoma cell population, fluorescence-associated cell sorting (FACS) analysis was used to sort CD133-positive/CD45-negative cells that were assayed for tumor-specific chromosomal aberrations using interphase fluorescence in situ hybridization. To rule out endothelial precursor cells, CD133-positive fractions also were assayed with anti-CD34 by FACS.RESULTS:In recurrent glioblastomas, the percentage of CD133-positive cells was increased by 4.6-fold compared with the percentage in primary glioblastomas, although, in some tumors, it increased up to 10-fold and 20-fold. Unexpectedly, the increase in CD133 expression was associated significantly with longer survival after tumor recurrence. An analysis of tumor-specific chromosomal aberrations and in vivo studies revealed that the CD133-positive cell compartment of recurrent glioblastoma was composed of both cancer stem cells and nontumor neural stem cells. The latter cells represented from 20% to 60% of the CD133-positive cell population, and their relative percentage favorably affected the survival of patients with recurrent glioblastoma. Endothelial CD133-positive/CD34-positive precursors did not contribute to the CD133-positive cell population.CONCLUSIONS:The authors hypothesized that, similar to the phenomenon described in glioblastoma models, neural stem/progenitor cells that are recruited by the tumor from surrounding brain may exert an antitumorigenic effect. Cancer 2011. © 2010 American Cancer Society.Cancer 12/2010; 117(1):162 - 174. · 4.77 Impact Factor -
Article: Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells.
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ABSTRACT: Glioblastoma is a highly angiogenetic malignancy, the neoformed vessels of which are thought to arise by sprouting of pre-existing brain capillaries. The recent demonstration that a population of glioblastoma stem-like cells (GSCs) maintains glioblastomas indicates that the progeny of these cells may not be confined to the neural lineage. Normal neural stem cells are able to differentiate into functional endothelial cells. The connection between neural stem cells and the endothelial compartment seems to be critical in glioblastoma, where cancer stem cells closely interact with the vascular niche and promote angiogenesis through the release of vascular endothelial growth factor (VEGF) and stromal-derived factor 1 (refs 5-9). Here we show that a variable number (range 20-90%, mean 60.7%) of endothelial cells in glioblastoma carry the same genomic alteration as tumour cells, indicating that a significant portion of the vascular endothelium has a neoplastic origin. The vascular endothelium contained a subset of tumorigenic cells that produced highly vascularized anaplastic tumours with areas of vasculogenic mimicry in immunocompromised mice. In vitro culture of GSCs in endothelial conditions generated progeny with phenotypic and functional features of endothelial cells. Likewise, orthotopic or subcutaneous injection of GSCs in immunocompromised mice produced tumour xenografts, the vessels of which were primarily composed of human endothelial cells. Selective targeting of endothelial cells generated by GSCs in mouse xenografts resulted in tumour reduction and degeneration, indicating the functional relevance of the GSC-derived endothelial vessels. These findings describe a new mechanism for tumour vasculogenesis and may explain the presence of cancer-derived endothelial-like cells in several malignancies.Nature 12/2010; 468(7325):824-8. · 36.28 Impact Factor -
Article: Thrombopoietin receptor activation, thrombopoietin mimetic drugs, and hereditary thrombocytosis: remarks on bone marrow fibrosis.
Journal of Clinical Oncology 07/2010; 28(19):e317-8. · 18.37 Impact Factor -
Article: Hereditary thrombocytosis caused by MPLSer505Asn is associated with a high thrombotic risk, splenomegaly and progression to bone marrow fibrosis.
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ABSTRACT: Background The MPL(Ser505Asn) mutation has been reported to be a cause of hereditary thrombocythemia. Recently, we detected this mutation in a large proportion of children with familial thrombocythemia, suggesting that in Italy the incidence of MPL(Ser505Asn) mutation could be underestimated. DESIGN AND METHODS: We extended the search for this mutation to all patients with essential thrombocythemia who had a positive family history for thrombocytosis or essential thrombocythemia. We identified eight Italian families positive for the MPL(Ser505Asn) mutation. Clinical and hematologic data were available for members of seven families, including 21 patients with a proven mutation and 20 relatives with thrombocytosis. RESULTS: Fifteen major thrombotic episodes, nine of which were fatal, were recorded among 41 patients. The thrombotic manifestation was stroke in four cases, myocardial infarction in seven cases, fetal loss in two cases, deep vein thrombosis of the leg in one case and Budd Chiari syndrome in one case. Almost all patients over 20 years old had splenomegaly and bone marrow fibrosis, while these were rarely observed in patients under 20 years old, suggesting that these manifestations are associated with aging. Finally, the life expectancy of family members with thrombocytosis was significantly shorter than that of members without thrombocytosis (P=0.003). Conclusions Patients with familial thrombocytosis caused by a MPL(Ser505Asn) mutation have a high risk of thrombosis and, with aging, develop splenomegaly and bone marrow fibrosis, significantly affecting their life expectancy.Haematologica 09/2009; 95(1):65-70. · 6.42 Impact Factor -
Article: The mutant JAK2 allele burden in children with essential thrombocythemia.
British Journal of Haematology 03/2009; 145(3):430-2. · 4.94 Impact Factor -
Article: The mutant JAK2V617F allele burden in children with essential thrombocythemia
British Journal of Haematology 02/2009; 145(3):430 - 432. · 4.94 Impact Factor -
Article: Prognostic relevance of SOCS3 hypermethylation in patients with glioblastoma multiforme.
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ABSTRACT: Alterations in the signal transduction pathways are key mechanisms in the pathogenesis of de novo glioblastoma multiforme (GBM), which are also involved in the resistance to chemo- and radiotherapy. Here, we analyzed the methylation status and mRNA expression of suppressor of cytokine signaling (SOCS)1-2-3, 3 of the most important inhibitory molecules of the signal transduction circuitry, in 46 GBM specimens. The relationship between methylation status of SOCS1-2-3 and clinical outcome was investigated. Using methylation-specific PCR (MS-PCR) and sequencing, after bisulphite modification, we found that the promoter of SOCS1-2-3 was methylated in 24, 6.5 and 35% of GBM, respectively. Real-time analysis showed that in methylated GBM, mRNA expression for SOCS1-2-3 was reduced by 5, 3 and 7-folds, respectively, when compared with unmethylated GBM. Moreover, methylation of SOCS3 promoter significantly associated with an unfavorable clinical outcome (p < 0.0002). Our data suggest that methylation of SOCS3 may be involved in the pathogenesis of GBM and in the resistance of this neoplasm to conventional treatment.International Journal of Cancer 09/2008; 123(12):2955-60. · 5.44 Impact Factor -
Article: A novel heterozygous HIF2AM535I mutation reinforces the role of oxygen sensing pathway disturbances in the pathogenesis of familial erythrocytosis.
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ABSTRACT: HIF2A transcription factor plays a central role in the regulation of the hypoxia responding pathway in mammalian cells, by modulating erythropoiesis and angiogenesis. Molecular alterations of oxygen sensing pathway constituents are implicated in hereditary erythrocytosis. Here we show that 2 members of a family with idiopathic erythrocytosis exhibited a new heterozygous G to A mutation at base 1605 of the exon 12 of hypoxia-inducible factor-2A (HIF2A) gene. This mutation determines the replacement of methionine by isoleucine at the position 535, very close to the position 531, where the hydroxyl acceptor prolyne is located. In addition, we found that mRNA expression of erythropoietin receptor, vascular endothelial growth factor, transferrin receptor, adrenomedullin and N-myc downstream regulated gene 1, up-regulated by HIF2A or hypoxia, were significantly higher in patients carrying the mutation than in normal controls. These results suggest that the HIF2A(M535I) gene mutation could induce hereditary erythrocytosis at a young age.Haematologica 08/2008; 93(7):1068-71. · 6.42 Impact Factor -
Article: Epigenetic alteration of SOCS family members is a possible pathogenetic mechanism in JAK2 wild type myeloproliferative diseases.
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ABSTRACT: In polycythemia vera (PV) and essential thrombocythemia (ET) specific JAK2 mutations constitutively activate the JAK-STAT pathway, explaining biologic findings such as endogenous erythroid colony (EECs) growth or PRV-1 RNA overexpression. Since these markers are detected also in JAK2 wild type patients, we hypothesized that, in these cases, the activation of the JAK-STAT pathway could be produced by a deregulation of the suppressor of cytokine signaling (SOCS) protein system. Eighty-one patients with PV and ET (53 adults and 28 children) were investigated for the methylation status of the SOCS-1, SOCS-2 and SOCS-3 CpG islands and for several myeloproliferative markers (including JAK2 and MPL mutations and clonality of hematopoiesis). SOCS-1 or SOCS-3 hypermethylation was identified in 23 patients and was associated with a significant decrease of SOCS-1 or SOCS-3 RNA and protein levels. The gene expression was restored by exposing cells to the demethylating agent 2-deoxyazacytidin. Interestingly, SOCS-1 or SOCS-3 hypermethylation was detected in 6 female patients, proved negative for JAK2 or MPL mutations and exhibiting monoclonal hematopoiesis. In conclusion, SOCS-1 or SOCS-3 hypermethylation can activate the JAK-STAT signaling pathway in alternative or together with JAK2 mutations. These alterations might represent a potential therapeutic target.International Journal of Cancer 08/2008; 123(7):1586-92. · 5.44 Impact Factor
Top co-authors
Top Journals
Institutions
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2011–2012
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Università Cattolica del Sacro Cuore
- Institute of Pathological Anatomy
Milano, Lombardy, Italy
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2010
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National Research Council - Italy
Roma, Latium, Italy
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2007–2009
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The Catholic University of America
Washington, D. C., DC, USA
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2008
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Sacred Heart University
Fairfield, CT, USA
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