Iacopo Petrini

National Cancer Institute (USA), Maryland, United States

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Publications (24)114.58 Total impact

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    ABSTRACT: We analyzed 28 thymic epithelial tumors (TETs) using next-generation sequencing and identified a missense mutation (chromosome 7 c.74146970T>A) in GTF2I at high frequency in type A thymomas, a relatively indolent subtype. In a series of 274 TETs, we detected the GTF2I mutation in 82% of type A and 74% of type AB thymomas but rarely in the aggressive subtypes, where recurrent mutations of known cancer genes have been identified. Therefore, GTF2I mutation correlated with better survival. GTF2I β and δ isoforms were expressed in TETs, and both mutant isoforms were able to stimulate cell proliferation in vitro. Thymic carcinomas carried a higher number of mutations than thymomas (average of 43.5 and 18.4, respectively). Notably, we identified recurrent mutations of known cancer genes, including TP53, CYLD, CDKN2A, BAP1 and PBRM1, in thymic carcinomas. These findings will complement the diagnostic assessment of these tumors and also facilitate development of a molecular classification and assessment of prognosis and treatment strategies.
    Nature genetics. 06/2014;
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    Simone Pacini, Iacopo Petrini
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    ABSTRACT: Recent investigations have made considerable progress in the understanding of tissue regeneration driven by mesenchymal stromal cells (MSCs). Data indicate the anatomical location of MSC as residing in the “perivascular” space of blood vessels dispersed across the whole body. This histological localization suggests that MSCs contribute to the formation of new blood vessels in vivo. Indeed, MSCs can release angiogenic factors and protease to facilitate blood vessel formation and in vitro are able to promote/support angiogenesis. However, the direct differentiation of MCSs into endothelial cells is still matter of debate. Most of the conflicting data might arise from the presence of multiple subtypes of cells with heterogeneous morpho functional features within the MSC cultures. According to this scenario, we hypothesize that the presence of the recently described Mesodermal Progenitor Cells (MPCs) within the MSCs cultures is responsible for their variable angiogenic potential. Indeed, MPCs are Nestin-positive CD31-positive cells exhibiting angiogenic potential that differentiate in MSC upon proper stimuli. The ISCT criteria do not account for the presence of MPC within MSC culture generating confusion in the interpretation of MSC angiogenic potential. In conclusion, the discover y of MPC gives new insight in defining MSC ancestors in human bone marrow, and indicates the tunica intima as a further, and previously overlooked, possible additional source of MSC.
    Frontiers in Cell and Developmental Biology 05/2014; 2.
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    ABSTRACT: In non-small-cell lung cancer, the molecular diagnosis of somatic mutations is instrumental for the choice of the most appropriate treatment. However, despite an initial response, resistance to tyrosine kinase inhibitors occurs and thereafter tumors progress. For this reason, next generation inhibitors able to overcome acquired resistances are currently in development. Therefore, the identification of the molecular determinants of resistance is needed to adapt treatment accordingly. The analysis of circulating cell-free tumor DNA represents a powerful tool to monitor the somatic changes induced by treatment. This review focuses on the most recent advantages in the diagnosis of acquired resistance in circulating cell-free tumor DNA and underlines the strategies ready to be translated in the clinical practice.
    Expert Review of Molecular Diagnostics 04/2014; · 4.09 Impact Factor
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    ABSTRACT: Genetic alterations and etiology of thymic epithelial tumors (TETs) are largely unknown, hampering the development of effective targeted therapies for patients with TETs. Here TETs of advanced-stage patients enrolled in a clinical trial of molecularly-guided targeted therapies were employed for targeted sequencing of 197 cancer-associated genes. Comparative sequence analysis of 78 TET/blood paired samples obtained from 47 thymic carcinoma (TC) and 31 thymoma patients revealed a total of 86 somatic non-synonymous sequence variations across 39 different genes in 33 (42%) TETs. TCs (62%; 29/47) showed higher incidence of somatic non-synonymous mutations than thymomas (13%; 4/31; p < 0.0001). TP53 was the most frequently mutated gene in TETs (n = 13; 17%), especially in TCs (26%), and was associated with a poorer overall survival (p < 0.0001). Genes in histone modification [BAP1 (n = 6; 13%), SETD2 (n = 5; 11%), ASXL1 (n = 2; 4%)], chromatin remodeling [SMARCA4 (n = 2; 4%)], and DNA methylation [DNMT3A (n = 3; 7%), TET2 (n = 2; 4%), WT1 (n = 2; 4%)] pathways were recurrently mutated in TCs, but not in thymomas. Our results suggest a potential disruption of epigenetic homeostasis in TCs, and a substantial difference in genetic makeup between TCs and thymomas. Further investigation is warranted into the roles of epigenetic dysregulation in TC development and its potential for targeted therapy.
    Scientific reports. 01/2014; 4:7336.
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    ABSTRACT: Purposes: To determine if the deregulation of genes relevant for normal thymus development can contribute to the biology of thymic epithelial tumors. EXPERIMENTAL DESIGN: Using array comparative genomic hybridization, we evaluated the copy number aberrations of genes regulating thymus development. The expression of genes most commonly involved in copy number aberrations was evaluated by immunohistochemistry and correlated with patients' outcome. Correlation between FOXC1 copy number loss and gene expression was determined in a confirmation cohort. Cell lines were used to test the role of FOXC1 in tumors. RESULTS: Among 31 thymus development-related genes, PBX1 copy number gain and FOXC1 copy number loss were presented in 43.0% and 39.5% of the tumors respectively. Immunohistochemistry on a series of 132 thymic epithelial tumors including those evaluated by comparative genomic hybridization, revealed a correlation between protein expression and copy number status only for FOXC1 but not for PBX1. Patients with FOXC1-negative tumors had a shorter time to progression and a trend for a shorter disease related survival. The correlation between FOXC1 copy number loss and mRNA expression was confirmed in a separate cohort of 27 thymic epithelial tumors. Ectopic FOXC1 expression attenuated anchorage-independent cell growth and cell migration in vitro. CONCLUSION: Our data support a tumor suppressor role of FOXC1 in thymic epithelial tumors.
    Clinical Cancer Research 02/2013; · 7.84 Impact Factor
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    ABSTRACT: Molecular pathology of thymomas is poorly understood. Genomic aberrations are frequently identified in tumors but no extensive sequencing has been reported in thymomas. Here we present the first comprehensive view of a B3 thymoma at whole genome and transcriptome levels. A 55-year-old Caucasian female underwent complete resection of a stage IVA B3 thymoma. RNA and DNA were extracted from a snap frozen tumor sample with a fraction of cancer cells over 80%. We performed array comparative genomic hybridization using Agilent platform, transcriptome sequencing using HiSeq 2000 (Illumina) and whole genome sequencing using Complete Genomics Inc platform. Whole genome sequencing determined, in tumor and normal, the sequence of both alleles in more than 95% of the reference genome (NCBI Build 37). Copy number (CN) aberrations were comparable with those previously described for B3 thymomas, with CN gain of chromosome 1q, 5, 7 and X and CN loss of 3p, 6, 11q42.2-qter and q13. One translocation t(11;X) was identified by whole genome sequencing and confirmed by PCR and Sanger sequencing. Ten single nucleotide variations (SNVs) and 2 insertion/deletions (INDELs) were identified; these mutations resulted in non-synonymous amino acid changes or affected splicing sites. The lack of common cancer-associated mutations in this patient suggests that thymomas may evolve through mechanisms distinctive from other tumor types, and supports the rationale for additional high-throughput sequencing screens to better understand the somatic genetic architecture of thymoma.
    PLoS ONE 01/2013; 8(4):e60572. · 3.53 Impact Factor
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    ABSTRACT: BACKGROUND: The WHO-classification was shown to be an independent prognostic marker in some but not all retrospective studies possibly due to lack of reproducibility. We investigated the reproducibility of the WHO-classification and its prognostic implication using a large series of resected thymomas. METHODS: Four independent pathologists histologically classified a surgical series of 129 thymic tumors in a blinded fashion. Fleiss' kappa-coefficient was used to assess the pathologists' overall agreement, and Cohen-Kappa to assess the agreement between two observers. Disease-related-survival (DRS) and progression-free-survival (PFS) curves were generated by Kaplan-Meier method and compared by log-rank test. RESULTS: In 63/129 (48.8%) cases there was a complete agreement; in 43/129 (33.3%) cases 3/4 pathological diagnoses were identical; in 15/129 (11.6%) cases the diagnoses were identical by pair; in 8/129 (6.2%) cases three different pathological diagnoses were on record. The Kappa-correlation coefficient was only moderate (0.53). A following web review carried out on the 23 cases with at least two different diagnoses reached a complete consensus. The histotype showed a statistically significant impact on PFS and DRS in the classification provided by only two pathologists. CONCLUSIONS: In this study, the agreement on WHO classification of thymomas was only moderate and this impacted on patients management. Web consensus conference on the diagnosis, more stringent diagnostic criteria or the adoption of referral diagnostic centres may substantially reduce discrepancies.
    Lung cancer (Amsterdam, Netherlands) 12/2012; · 3.14 Impact Factor
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    ABSTRACT: Arsenic Trioxide (ATO) is effective in about 20% of patients with myelodysplasia (MDS); its mechanisms of action have already been evaluated in vitro, but the in vivo activity is still not fully understood. Since ATO induces apoptosis in in vitro models, we compared the expression of 93 apoptotic genes in patients' bone marrow before and after ATO treatment. For this analysis, we selected 12 patients affected by MDS who received ATO in combination with Ascorbic Acid in the context of the Italian clinical trial NCT00803530, EudracT Number 2005-001321-28. Real-time PCR quantitative assays for genes involved in apoptosis were performed using TaqMan® Assays in 384-Well Microfluidic Cards "TaqMan® Human Apoptosis Array".Quantitative RT-PCR for expression of EVI1 and WT1 genes was also performed. Gene expression values (Ct) were normalized to the median expression of 3 housekeeping genes present in the card (18S, ACTB and GAPDH). ATO treatment induced up-regulation of some pro-apoptotic genes, such as HRK, BAK1, CASPASE-5, BAD, TNFRSF1A, and BCL2L14 and down-regulation of ICEBERG. In the majority of cases with stable disease, apoptotic gene expression profile did not change, whereas in cases with advanced MDS more frequently pro-apoptotic genes were up-regulated. Two patients achieved a major response: in the patient with refractory anemia the treatment down-regulated 69% of the pro-apoptotic genes, whereas 91% of the pro-apoptotic genes were up-regulated in the patient affected by refractory anemia with excess of blasts-1. Responsive patients showed a higher induction of BAD than those with stable disease. Finally, WT1 gene expression was down-regulated by the treatment in responsive cases. These results represent the basis for a possible association of ATO with other biological compounds able to modify the apoptotic pathways, such as inhibitors of the BCL2 family.
    Journal of Hematology & Oncology 09/2012; 5:53. · 4.46 Impact Factor
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    ABSTRACT: Sorafenib improves overall survival and time to progression of advanced hepatocellular (aHCC) patients such as demonstrated in 2 phase III trials. However, aHCC patients' outcome is still poor despite these results. In order to improve the efficacy of systemic treatment for aHCC, we evaluated the combination of sorafenib plus 5-fluorouacil infusion in a phase II trial. Patients with aHCC not eligible for loco-regional therapies, Child-Pugh A-B, ECOG-PS 0-1, and without history of anti-cancer systemic treatment were enrolled. Treatment schedule was: sorafenib 400 mg/bid continuously and continuum infusion of 5-fluorouracil 200 mg/sqm/daily day 1-14 every 3 weeks. Thirty-nine patients were enrolled: ECOG-PS 0-1: 29-10, Child-Pugh A-B: 36-3. Grade 3/4 (%) toxicities included: diarrhea 5.1/0, mucositis 20.5/2.6, hand foot skin reaction 20.5/0, skin rash 10.5/0, hypertension 10.3/0, hyperbilirubinemia 5.1/2.6, glutamic-oxaloacetic transaminase increase 10.3/0, glutamic-pyruvic transaminase increase 7.7/0, cardiac toxicity (one heart failure, two atrial fibrillation cases) 7.7/0, and bleeding (melena) in 2.6/0. One partial response was observed. Stable disease was obtained in 46.2% of patients with a median duration of 16.2 months. Median time to progression was 8 months (CI 95% = 5.7-10.4), and median overall survival was 13.7 months (CI 95% = 9.5-17.9). The results show an encouraging disease control rate, time to progression, and overall survival. The combination of sorafenib and 5-fluorouracil was feasible, and the side effects were manageable for patients carefully selected for liver function and performance status.
    Cancer Chemotherapy and Pharmacology 03/2012; 69(3):773-80. · 2.80 Impact Factor
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    ABSTRACT: The molecular pathology of thymic epithelial tumors (TETs) is largely unknown. Using array comparative genomic hybridization (CGH), we evaluated 59 TETs and identified recurrent patterns of copy number (CN) aberrations in different histotypes. GISTIC algorithm revealed the presence of 126 significant peaks of CN aberration, which included 13 cancer-related genes. Among these peaks, CN gain of BCL2 and CN loss of CDKN2A/B were the only genes in the respective regions of CN aberration and were associated with poor outcome. TET cell lines were sensitive to siRNA knockdown of the anti-apoptotic molecules BCL2 and MCL1. Gx15-070, a pan-BCL2 inhibitor, induced autophagy-dependent necroptosis in TET cells via a mechanism involving mTOR pathways, and inhibited TET xenograft growth. ABT263, an inhibitor of BCL2/BCL-XL/BCL-W, reduced proliferation in TET cells when administered in combination with sorafenib, a tyrosine kinase inhibitor able to downregulate MCL1. Immunohistochemistry on 132 TETs demonstrated that CN loss of CDKN2A correlated with lack of expression of its related protein p16(INK4) and identified tumors with poor prognosis. The molecular markers BCL2 and CDKN2A may be of potential value in diagnosis and prognosis of TETs. Our study provides the first preclinical evidence that deregulated anti-apoptotic BCL2 family proteins may represent suitable targets for TET treatment.
    Cell Death & Disease 01/2012; 3:e351. · 6.04 Impact Factor
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    ABSTRACT: Pancreatic cancer is the fourth leading cause of cancer-related death, and studies on the clinical relevance of its genomic imbalances are warranted. Recurrent copy number alterations of cytobands and genes were analyzed by array comparative genomic hybridization (aCGH) in 44 resected pancreatic cancer specimens. Prognostic markers identified by aCGH were validated by PCR gene copy number assay in an independent validation cohort of 61 resected pancreatic cancers. The functions of gene identified were evaluated by proliferation, cell cycle, and migration assays in pancreatic cancer cells. We showed recurrent copy number gains and losses in the first cohort. Loss of 18q22.3 was significantly associated with short-term overall survival in the first cohort (P = 0.019). This cytoband includes the carboxypeptidase of glutamate-like (CPGL) gene. CPGL gene deletion was associated with shorter overall survival in the validation cohort (P = 0.003). CPGL deletion and mutations of TP53 or Kras seem to be independent events. A Cox model analysis of the two cohorts combined showed that loss of 18q22.3/deletion of the CPGL gene was an independent poor prognostic factor for overall survival (HR = 2.72, P = 0.0007). Reconstitution of CPGL or its splicing variant CPGL-B into CPGL-negative pancreatic cancer cells attenuated cell growth, migration, and induced G(1) accumulation. Loss of 18q22.3/deletion of the CPGL gene is a poor prognostic marker in resected pancreatic cancer, and functional studies suggest the CPGL gene as growth suppressor gene in pancreatic cancer.
    Clinical Cancer Research 11/2011; 18(2):524-33. · 7.84 Impact Factor
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    ABSTRACT: A key challenge in the treatment of thymoma and thymic carcinoma (TC) is in improving our understanding of the molecular biology of these relatively rare tumors. In recent years, significant efforts have been made to dissect the molecular pathways involved in their carcinogenesis. Here we discuss the results of large-scale genomic analyses conducted to date and review the most active chemotherapies and targeted treatments. We reviewed the literature for chemotherapeutic trials in the last 20 years and trials involving targeted therapies between 1999 and 2010. The search was supplemented by a review of abstracts presented at the annual meetings of the American Society of Clinical Oncology (from 1999 to 2010), at the first International Conference on Thymic Malignancies in 2009, and at a follow-up meeting of the newly formed International Thymic Malignancies Interest Group in 2010. Surgery remains the treatment of choice for operable tumors, whereas chemotherapy is standard in locally advanced and metastatic disease. Thus far, targeted therapies have been developed empirically. Histone deacetylase inhibitors have shown some activity in thymoma whereas sunitinib may be active in TC. There are no data to support the use of HER2- or EGFR-targeted therapies in thymic malignancies. Drug development for the treatment of thymic malignancies is difficult because of the rarity of these tumors. Ethnic differences are becoming apparent, with aggressive subtypes being observed in Asians and African Americans. Incremental improvements in our understanding of tumor biology suggest that molecular profiling-directed therapies may be the preferred route of investigation in the future.
    Journal of Clinical Oncology 11/2011; 29(36):4820-7. · 18.04 Impact Factor
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    ABSTRACT: Melanoma is an immunogenic tumour but, despite the wide range of immunotherapies tested, only few promising results have been reported to date. Both in vitro and in xenograft models, γδ lymphocyte-mediated cytotoxicity against melanoma cells has been reported. IL-2/zoledronate treatment can expand γδ cells in vitro and in animal models. This could represent an immunotherapeutic strategy against melanoma. To evaluate the feasibility of this approach, we studied γδ lymphocyte phenotype from patients with melanoma, their ability to be expanded by IL-2/zoledronate and their cytotoxic activity against SK-MEL-30 cell line. Peripheral blood samples were collected from 30 patients with melanoma and 10 healthy donors. Percentage of γδ lymphocytes and CD45RO+CD27+, CD45RA+CD27-, CD57+, Vγ9Vδ2 subpopulations were evaluated by flow cytometry. IL-2/zoledronate γδ cell expansion rate and their cytotoxicity against SK-MEL-30 cell line were studied. A percentage decrease in circulating Vγ9Vδ2 and an increase in CD45RA+CD27- and CD57+ γδ lymphocytes were observed in melanoma. IL-2/zoledronate expansion rate did not differ between controls and patients with melanoma but cytotoxicity against SK-MEL-30 appeared reduced. Our results show that γδ cell function is impaired in patients with advanced melanoma and suggest a possible role in tumour progression.
    European Journal of Clinical Investigation 11/2011; 41(11):1186-94. · 3.37 Impact Factor
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    ABSTRACT: Eur J Clin Invest 2012; 42 (5): 575–576
    European Journal of Clinical Investigation 10/2011; 42(5):575-6. · 3.37 Impact Factor
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    ABSTRACT: Thymic malignancies are rare tumors. The insulin-like growth factor-1 (IGF-1)/IGF-1 receptor (IGF-1R) system is involved in the development of the thymus. IGF-1R expression in thymic epithelial malignancies is unknown. The authors investigated the expression of IGF-1R and phosphorylated AKT serine 473 (p-AKT) by using immunohistochemistry and examined the clinicopathologic correlations in a retrospective, single-institution surgical series of 132 patients with thymic epithelial malignancies. Earlier disease stage, less aggressive histologic types, and complete resection were significant positive prognostic factors for disease-related survival and progression-free survival, and being a woman was a better prognostic factor for disease-related survival. IGF-1R and p-AKT protein levels were expressed in 20% and 36% of thymic tumors, respectively. Both markers were expressed more commonly in recurrent disease than in primary tumors, in more aggressive subtypes, and in more advanced disease stages. There was a trend toward better survival and progression-free survival in patients who were negative for IGF-1R or p-AKT expression in the whole series. When only the 91 primary tumors, IGF1R expression was associated with worse progression-free survival (P < .001). The current retrospective analysis demonstrated that disease stage, tumor histology, sex, and resection type were major prognostic factors in the survival of patients with thymic malignancies. The expression levels of IGF-1R and p-AKT in thymic tumors suggested that IGF-1R is a potential target for treatment.
    Cancer 10/2010; 116(20):4686-95. · 5.20 Impact Factor
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    ABSTRACT: This study determined whether expression levels of a panel of biologically relevant microRNAs can be used as prognostic or predictive biomarkers in patients who participated in the International Adjuvant Lung Cancer Trial (IALT), the largest randomized study conducted to date of adjuvant chemotherapy in patients with radically resected non-small cell lung carcinoma (NSCLC). Expression of miR-21, miR-29b, miR-34a/b/c, miR-155, and let-7a was determined by quantitative real-time PCR in formalin-fixed paraffin-embedded tumor specimens from 639 IALT patients. The prognostic and predictive values of microRNA expression for survival were studied using a Cox model, which included every factor used in the stratified randomization, clinicopathologic prognostic factors, and other factors statistically related to microRNA expression. Investigation of the expression pattern of microRNAs in situ was performed. We also analyzed the association of TP53 mutation status and miR-34a/b/c expression, epidermal growth factor receptor and KRAS mutation status, and miR-21 and Let-7a expression. Finally, the association of p16 and miR-29b expression was assessed. Overall, no significant association was found between any of the tested microRNAs and survival, with the exception of miR-21 for which a deleterious prognostic effect of lowered expression was suggested. Otherwise, no single or combinatorial microRNA expression profile predicted response to adjuvant cisplatin-based chemotherapy. Together, our results indicate that the microRNA expression patterns examined were neither predictive nor prognostic in a large patient cohort with radically resected NSCLC, randomized to receive adjuvant cisplatin-based chemotherapy versus follow-up only.
    Cancer Research 10/2010; 70(21):8288-98. · 9.28 Impact Factor
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    ABSTRACT: Overexpression of c-kit, a tyrosine kinase receptor protein encoded by the protooncogene kit, has been previously reported in thymic epithelial tumors and in other neoplasms such as gastrointestinal stromal tumors, myeloproliferative disorders, melanoma, and seminoma. Mutations in the kit gene have been related to response to imatinib in gastrointestinal stromal tumor and one case report of thymic carcinoma. We studied expression of c-kit in a large retrospective series of thymic epithelial malignancies and sequenced the whole gene in a subset of patients. Thymic epithelial tumors from 120 patients (13 thymic carcinomas and 107 thymomas) were examined. Immunohistochemical staining with an antic-kit polyclonal antibody was performed on a tissue microarray. Mutation analyses of exons 1 to 20 were conducted by direct DNA sequencing of polymerase chain reaction products in eight thymic carcinomas, five thymomas, and one thymic carcinoma cell line. The percentage of c-kit positive cells was significantly higher in thymic carcinoma (46%) than in thymoma (4%). Decreased disease-related survival and progression-free survival were observed in c-kit positive tumors. No mutations were detected. c-kit expression is strongly but not exclusively related to thymic carcinoma histotype, and it is of prognostic value. Mutations are very rare.
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 09/2010; 5(9):1447-53. · 4.55 Impact Factor
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    ABSTRACT: Multipotent mesenchymal stromal cells (MSCs) exert a relevant immunosuppressive activity by inhibiting T- and B-lymphocytes, natural killer (NK) cells and dendritic cell expansion. Nevertheless, a possible activity on gamma/delta T cells has still not been evaluated. Gamma-delta T lymphocytes play an important role in the control of cancer and they have been shown to be implicated in graft-vs.-host disease. Thus, modulation of activation and proliferation of these cells could be relevant for therapeutic purposes. Peripheral blood mononuclear cells from 21 healthy donors were used as source for gamma-delta T cells, expanded in presence of 10 IU mL(-1) interleukin-2 (IL-2) and 1 microM zoledronate. MSCs were recovered from patients undergoing routine total hip replacement surgery, and characterised by flow cytometry. Cytotoxicity on multiple myeloma and melanoma cell lines was assessed by measuring dilution of the carboxyfluorescein diacetate succinimydylester dye (CFSE). Gamma-delta T cells were then incubated with MSCs in contact cultures, and with addition of MSC-conditioned medium. In this article we confirmed that (1) in vitro expanded gamma-delta T cells play a significant anti-proliferative effect on multiple myeloma and melanoma cells and (2) multipotent mesenchymal stromal cells effectively suppress the ex vivo expansion of T cells carrying a specific T-cell receptor gene (TCR) rearrangement, Vgamma9/Vdelta2, induced by the combination of IL-2 and zoledronate, without interfering with their cytotoxic activity. These findings contribute to explain the activity of ex vivo expanded mesenchymal cells, suggesting that MSCs would interact with gamma-delta T lymphocytes. This effect could be relevant in separating graft-vs.-host from the graft-vs.-tumour effect, especially considering the possibility of modulating T-lymphocytes activity by the immunomodulating drugs now available.
    European Journal of Clinical Investigation 07/2009; 39(9):813-8. · 3.37 Impact Factor
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    ABSTRACT: The triple drug combination consisting of irinotecan, oxaliplatin and 5-fluorouracil (FOLFOXIRI) has demonstrated higher activity and efficacy compared to the doublet FOLFIRI. 5-Fluorouracil could be substituted in FOLFOXIRI regimen by capecitabine, an oral fluoropyrimidine with similar efficacy. Recently, a dose-finding trial has demonstrated the feasibility of the combination of irinotecan, oxaliplatin and capecitabine (XELOXIRI) and established their recommended doses. The aim of this study was to evaluate the activity of XELOXIRI. A total of 36 patients with unresectable metastatic colorectal cancer received irinotecan 165 mg m(-2) and oxaliplatin 85 mg m(-2) on day 1 plus capecitabine 2000 mg m(-2) per day orally in two doses from day 1 to day 7, every 2 weeks. Grade 3-4 toxicities were infrequent, expect for neutropenia and diarrhoea, which were each observed in 30% of patients. Two complete and twenty-two partial responses were obtained, corresponding to an overall response rate of 67% (95% CI 51.4-82%). After a median follow-up of 17.7 months, the median progression-free and overall survival were 10.1 and 17.9 months, respectively. The substitution of 5-fluorouracil with capecitabine, in combination with irinotecan and oxaliplatin, is feasible and does not impair the activity of the regimen. However, the XELOXIRI combination is associated with a high incidence of diarrhoea and, therefore, should be considered as a not preferable alternative to FOLFOXIRI.
    British Journal of Cancer 06/2009; 100(11):1720-4. · 5.08 Impact Factor
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    ABSTRACT: PTEN, AKT, and KRAS are epidermal growth factor receptor (EGFR) downstream regulators. KRAS mutations confer resistance to cetuximab. This retrospective study investigated the role of PTEN loss, AKT phosphorylation, and KRAS mutations on the activity of cetuximab plus irinotecan in patients with metastatic colorectal cancer (mCRC). A cohort of patients with irinotecan-refractory mCRC who were treated with cetuximab plus irinotecan was tested for PTEN immunoreactivity (ie, immunohistochemistry; IHC), pAKT IHC, and KRAS mutations. Analyses were performed both on primary tumors and on related metastases, and the association among IHC, mutational results, and treatment outcomes was investigated. One-hundred two patients were eligible. Ninety-six primary tumors, 59 metastases, and 53 paired samples were available. Forty-nine primary tumors (58% of assessable samples) had a preserved PTEN expression (PTEN-positive), whereas 35 (40% of assessable samples) were pAKT-positive. Levels of concordance between primary tumors and metastases were 60%, 68%, and 95% for PTEN, pAKT, and KRAS, respectively. PTEN status on primary tumors and pAKT status both on primary tumors and on metastases did not predict response or progression-free survival (PFS). On metastases, 12 (36%) of 33 patients with PTEN-positive tumors were responders compared with one (5%) of 22 who had PTEN-negative tumors (P = .007). The median PFS of patients with PTEN-positive metastases was 4.7 months compared with 3.3 months for those with PTEN-negative metastases (hazard ratio [HR], 0.49; P = .005). Patients with PTEN-positive metastases and KRAS wild type had longer PFS compared with other patients (5.5 months v 3.8 months; HR, 0.42; P = .001). PTEN loss in metastases may be predictive of resistance to cetuximab plus irinotecan. The combination of PTEN IHC and KRAS mutational analyses could help to identify a subgroup of patients with mCRC who have higher chances of benefiting from EGFR inhibition.
    Journal of Clinical Oncology 05/2009; 27(16):2622-9. · 18.04 Impact Factor

Publication Stats

361 Citations
114.58 Total Impact Points

Institutions

  • 2012–2014
    • National Cancer Institute (USA)
      • Medical Oncology Branch and Affiliates
      Maryland, United States
  • 2006–2014
    • Università di Pisa
      • • Department of Clinical and Experimental Medicine
      • • Department of Biology
      Pisa, Tuscany, Italy
  • 2010–2013
    • National Institutes of Health
      • Branch of Medical Oncology Branch and Affiliates
      Bethesda, MD, United States
    • Istituto Clinico Humanitas IRCCS
      Rozzano, Lombardy, Italy
  • 2008
    • Santa Chiara Hospital
      Trient, Trentino-Alto Adige, Italy