P A Zucali

National Institutes of Health, Bethesda, MD, United States

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Publications (78)361.16 Total impact

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    ABSTRACT: Quantitative analyses on FDG PET for response assessment are increasingly used in clinical studies, particularly with respect to tumours in which radiological assessment is challenging and complete metabolic response is rarely achieved after treatment. A typical example is malignant pleural mesothelioma (MPM), an aggressive tumour originating from mesothelial cells of the pleura. We present our results concerning the use of semiquantitative and quantitative parameters, evaluated at the baseline and interim PET examinations, for the prediction of treatment response and disease outcome in patients with MPM. We retrospectively analysed data derived from 131 patients (88 men, 43 women; mean age 66 years) with MPM who were referred to our institution for treatment between May 2004 and July 2013. Patients were investigated using FDG PET at baseline and after two cycles of pemetrexed-based chemotherapy. Responses were determined using modified RECIST criteria based on the best CT response after treatment. Disease control rate, progression-free survival (PFS) and overall survival (OS) were calculated for the whole population and were correlated with semiquantitative and quantitative parameters evaluated at the baseline and interim PET examinations; these included SUVmax, total lesion glycolysis (TLG), percentage change in SUVmax (ΔSUVmax) and percentage change in TLG (ΔTLG). Disease control was achieved in 84.7 % of the patients, and median PFS and OS for the entire cohort were 7.2 and 14.3 months, respectively. The log-rank test showed a statistically significant difference in PFS between patients with radiological progression and those with partial response (PR) or stable disease (SD) (1.8 vs. 8.6 months, p < 0.001). Baseline SUVmax and TLG showed a statistically significant correlation with PFS and OS (p < 0.001). In the entire population, both ΔSUVmax and ΔTLG were correlated with disease control based on best CT response (p < 0.001). ΔSUVmax was significantly correlated with PFS in the entire population (p = 0.02) and with both PFS and OS in patients not undergoing talc pleurodesis (n = 65; p < 0.01 for PFS, p = 0.03 for OS), and in patients without pleurodesis presenting a SD and/or PR at CT after two cycles. These results confirm the role of FDG PET in the assessment of disease prognosis and treatment efficacy in MPM patients receiving first-line pemetrexed-based chemotherapy. In particular, metabolic response evaluated using ΔSUVmax can be used to predict outcome in MPM patients not undergoing talc pleurodesis who achieve SD and/or PR at the interim CT evaluation.
    European journal of nuclear medicine and molecular imaging 11/2014; · 5.11 Impact Factor
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    ABSTRACT: Purpose This phase I study evaluated the safety, tolerability, maximum tolerated dose (MTD), and recommended phase II dose (RP2D) of tivantinib combined with sorafenib in patients with advanced solid tumors. Materials and Methods A standard 3 + 3 dose escalation design was used. At the RP2D, expansion cohorts in 5 tumor types could be enrolled. Pharmacogenetic and pharmacodynamic analysis were performed. Results Eighty-seven patients received the study treatment. The combination had no unexpected toxicities. The most common treatment-related adverse events (AE) were rash (40 %), diarrhea (38 %), and anorexia (33 %). The RP2D was tivantinib 360 mg BID and sorafenib 400 mg BID for all cancer histologies, except in hepatocellular carcinoma (HCC) patients tivantinib was 240 mg BID plus sorafenib 400 mg BID. The overall response rate was 12 % in all patients, 26 % in melanoma, 15 % in renal cell carcinoma (RCC), 10 % in HCC, and 0 % in other patients. Disease control rate (CR, PR and SD ≥8 weeks) was 58 % in all patients, 90 % in RCC, 65 % in HCC, 63 % in melanoma, 40 % in breast cancer, and 8 % in NSCLC patients. Conclusions The combination treatment could be administered at full standard single-agent doses in all patients except those with HCC, where tivantinib was lowered to 240 mg BID. Preliminary evidence of anticancer activity was observed in patients with RCC, HCC, and melanoma, including patients refractory to sorafenib and/or other anti-VEGF pathway therapies. The combination treatment has therapeutic potential in treating a variety of solid tumors.
    Investigational New Drugs 10/2014; · 3.50 Impact Factor
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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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    ABSTRACT: Background:The incidence of malignant pleural mesothelioma (MPM) in elderly patients is increasing. There are no specific guidelines for their management.Methods:The clinical records of elderly patients (⩾70 years old) with MPM referred from January 2005 to November 2011 to six Italian Centres were reviewed. Age, gender, histology, International Mesothelioma Interest Group (IMIG) stage, Eastern Cooperative Oncology Group Performance Status (ECOG-PS), Charlson Comorbidity Index (CCI) and treatment modalities were analysed and correlated to overall survival (OS).Results:In total, 241 patients were identified. Charlson Comorbidity Index was ⩾1 in 92 patients (38%). Treatment was multimodality therapy including surgery in 18, chemotherapy alone in 180 (75%) and best supportive care in 43 cases (18%). Chemotherapy was mainly pemetrexed based. Median OS was 11.4 months. Non-epithelioid histology (HR 2.32; 95% CI 1.66-3.23, P<0.001), age ⩾75 years (HR 1.44; 95% CI 1.08-1.93, P=0.014), advanced (III-IV) stage (HR 1.47; 95% CI 1.09-1.98, P=0.011) and CCI⩾1 (HR 1.38; 95% CI 1.02-1.85, P=0.034) were associated to a shorter OS. Treatment with pemetrexed was associated with improved OS (HR 0.40; 95% CI 0.28-0.56, P<0.001).Conclusions:Non-epithelioid histology, age ⩾75 years, advanced IMIG stage and presence of comorbidities according to CCI were significant prognostic factors in elderly patients with MPM. Treatment with pemetrexed-based chemotherapy was feasible in this setting. Prospective dedicated trials in MPM elderly patients selected according to prognostic factors including comorbidity scales are warranted.British Journal of Cancer advance online publication, 10 June 2014; doi:10.1038/bjc.2014.312 www.bjcancer.com.
    British Journal of Cancer 06/2014; · 5.08 Impact Factor
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    ABSTRACT: not applicable.
    Clinical Cancer Research 05/2014; · 7.84 Impact Factor
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    ABSTRACT: Pemetrexed-platinum chemotherapy is the standard first-line treatment of unresectable malignant pleural mesothelioma (MPM). At progression, patients are generally selected to experimental trials, when available, or, in every-day clinical practice, they are offered second-line chemotherapy. The optimal treatment has not yet been defined. The aim of this retrospective, single-center study was to evaluate the activity and toxicity of vinorelbine administered to a consecutive series of pemetrexed-pretreated MPM patients. Vinorelbine 25mg/m(2) was administered intravenously as a single agent on days 1, 8 every three weeks, either as second-line (2L) or further-line (>2L) therapy. Treatment was repeated for a maximum of 6 cycles, until progression, or unacceptable toxicity. Fifty-nine patients were included in this analysis. Vinorelbine was given to 34 patients as 2L, and to 25 as >2L treatment. The median age was 69 years (range 45-80). Forty-two patients (71.2%) had a good EORTC prognostic score. Partial response was observed in 9 (15.2%) cases, stable disease in 20 (33.9%). The overall disease control rate (DCR) was 49.1%. Median progression-free survival (PFS) and overall survival (OS) were 2.3 and 6.2 months, respectively. ECOG performance status (PS) (HR0 vs. 1-2 0.50; 95%CI: 0.3-0.8; p=0.014) and PFS≥6 months following first-line (FL) chemotherapy (HRFL-PFS>6ms vs. <6ms 0.50; 95%CI: 0.3-0.9; p=0.031) were significantly associated to OS in multivariate analysis. No difference was observed in terms of DCR, PFS, and OS in relation to age, histology, sex, line of vinorelbine therapy, or response to FL treatment. Hematological toxicity was acceptable, with grade 3/4 neutropenia occurring in 5 (8.4%) patients, and there were no cases of febrile neutropenia. The main non-hematological toxicities were grade 2 fatigue in 17 (28.8%) and constipation in 7 (11.8%) patients. Vinorelbine was moderately active in pemetrexed-pretreated MPM patients, with an acceptable toxicity profile, particularly in patients with ECOG-PS0 and FL-PFS ≥6 months.
    Lung cancer (Amsterdam, Netherlands) 11/2013; · 3.14 Impact Factor
  • Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 08/2013; 8(8):e79-80. · 4.55 Impact Factor
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    ABSTRACT: Background:The aim of this open label phase II study (NCT00407459) was to assess the activity of the vascular endothelial growth factor (VEGF) inhibitor bevacizumab combined with pemetrexed and carboplatin in patients with previously untreated, unresectable malignant pleural mesothelioma (MPM).Methods:Eligible patients received pemetrexed 500 mg m(-2), carboplatin area under the plasma concentration-time curve (AUC) 5 mg ml(-1) per minute and bevacizumab 15 mg kg(-1), administered intravenously every 21 days for six cycles, followed by maintenance bevacizumab. The primary end point of the study was progression-free survival (PFS). A 50% improvement in median PFS in comparison with standard pemetrexed/platinum combinations (from 6 to 9 months) was postulated.Results:Seventy-six patients were evaluable for analysis. A partial response was achieved in 26 cases (34.2%, 95% CI 23.7-46.0%). Forty-four (57.9%, 95% CI 46.0-69.1%) had stable disease. Median PFS and overall survival were 6.9 and 15.3 months, respectively. Haematological and non-haematological toxicities were generally mild; however, some severe adverse events were reported, including grade 3-4 fatigue in 8% and bowel perforation in 4% of patients. Three toxic deaths occurred.Conclusion:The primary end point of the trial was not reached. However, due to the limitation of a non-randomised phase II design, further data are needed before drawing any definite conclusion on the role of bevacizumab in MPM.British Journal of Cancer advance online publication 16 July 2013; doi:10.1038/bjc.2013.368 www.bjcancer.com.
    British Journal of Cancer 07/2013; · 5.08 Impact Factor
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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: Background:The mesenchymal-epithelial transition factor (MET) receptor is dysregulated in hepatocellular carcinoma (HCC), and tivantinib (ARQ 197) is an oral, selective, MET inhibitor.Methods:This Phase-1b study assessed tivantinib safety as primary objective in patients with previously treated HCC and Child-Pugh A or B liver cirrhosis. Patients received oral tivantinib 360 mg twice daily until disease progression or unacceptable toxicity.Results:Among 21 HCC patients, common drug-related adverse events (AEs) were neutropaenia, anaemia, asthenia, leucopaenia, anorexia, diarrhoea, and fatigue. No drug-related worsening of liver function or performance status occurred, but one Child-Pugh B patient experienced drug-related bilirubin increase. Four patients had drug-related serious AEs, including one neutropaenia-related death. Haematologic toxicities were more frequent than in previous tivantinib studies but were manageable with prompt therapy. Best response was stable disease (median, 5.3 months) in 9 of 16 evaluable patients (56%). Median time to progression was 3.3 months.Conclusion:Tivantinib demonstrated a manageable safety profile and preliminary antitumour activity in patients with HCC and Child-Pugh A or B cirrhosis.British Journal of Cancer advance online publication, 3 January 2013; doi:10.1038/bjc.2012.556 www.bjcancer.com.
    British Journal of Cancer 01/2013; · 5.08 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: Background:NGR-hTNF exploits the peptide asparagine-glycine-arginine (NGR) for selectively targeting tumour necrosis factor (TNF) to CD13-overexpressing tumour vessels. Maximum-tolerated dose (MTD) of NGR-hTNF was previously established at 45 μg m(-2) as 1-h infusion, with dose-limiting toxicity being grade 3 infusion-related reactions. We explored further dose escalation by slowing infusion rate (2-h) and using premedication (paracetamol).Methods:Four patients entered each of 12 dose levels (n=48; 60-325 μg m(-2)). Pharmacokinetics, soluble TNF receptors (sTNF-R1/sTNF-R2), and volume transfer constant (K(trans)) by dynamic imaging (dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI)) were assessed pre- and post-treatment.Results:Common related toxicity included grade 1/2 chills (58%). Maximum-tolerated dose was not reached. Both C(max) (P<0.0001) and area under the plasma concentration-time curve (P=0.0001) increased proportionally with dose. Post-treatment levels of sTNF-R2 peaked significantly higher than sTNF-R1 (P<0.0001). Changes in sTNF-Rs, however, did not differ across dose levels, suggesting a plateau effect in shedding kinetics. As best response, 12/41 evaluable patients (29%) had stable disease. By DCE-MRI, 28/37 assessed patients (76%) had reduced post-treatment K(trans) values (P<0.0001), which inversely correlated with NGR-hTNF C(max) (P=0.03) and baseline K(trans) values (P<0.0001). Lower sTNF-R2 levels and greater K(trans) decreases after first cycle were associated with improved survival.Conclusion:asparagine-glycine-arginine-hTNF can be safely escalated at doses higher than MTD and induces low receptors shedding and early antivascular effects.British Journal of Cancer advance online publication, 20 November 2012; doi:10.1038/bjc.2012.506www.bjcancer.com.
    British Journal of Cancer 11/2012; · 5.08 Impact Factor
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    ABSTRACT: BACKGROUND: The epidermal growth factor receptor (EGFR) and ERBB2 (HER2) pathways and vascular endothelial growth factor (VEGF)-dependent angiogenesis have a pivotal role in cancer pathogenesis and progression. Robust experimental evidence has shown that these pathways are functionally linked and implicated in acquired resistance to targeted therapies making them attractive candidates for joined targeting. We undertook this phase I trial to assess the safety, the recommended dose for phase II trials (RPTD), pharmacokinetics (PK), pharmacodynamics (PD), and the preliminary antitumour activity of the combination of lapatinib and sorafenib in patients with advanced refractory solid tumours. METHODS: Four cohorts of at least three patients each received lapatinib once daily and sorafenib twice daily together on a continuous schedule. Doses of lapatinib and sorafenib were escalated based on dose-limiting toxicities (DLTs) in the first treatment cycle following a traditional 3+3 design until the RPTD was reached. Additional patients were treated at the RPTD to characterise PK profiles of this combination and to investigate the potential interaction between lapatinib and sorafenib. Serum samples were collected at baseline and then prospectively every two cycles to assess changes in PD parameters. This trial is registered with ClinicalTrials.gov, number NCT00984425. FINDINGS: Thirty patients with advanced refractory solid tumours were enroled. DLTs were grade three fatigue and grade 3 atypical skin rash observed at dose levels 3 and 4, respectively. The higher dose level explored (lapatinib 1250mg/day and sorafenib 400mg twice daily) represented the RPTD of the combination. The most common drug-related adverse events were fatigue (68%), hypocalcemia (61%), diarrhoea (57%), lymphopaenia (54%), anorexia (50%), rash (50%), and hypophosphatemia (46%). PK analysis revealed no significant effect of sorafenib on the PK profile of lapatinib. Of the 27 assessable patients for clinical activity, one achieved a confirmed complete response, four (15%) had a partial response, and 12 (44%) achieved disease stabilisation. The disease control rate overall was 63%. INTERPRETATION: Combination treatment with lapatinib and sorafenib was feasible with promising clinical activity and without significant PK interactions. Long term tolerability seems to be challenging.
    European journal of cancer (Oxford, England: 1990) 11/2012; · 4.12 Impact Factor
  • Giovanni Luca Ceresoli, Paolo Andrea Zucali
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    ABSTRACT: INTRODUCTION: Malignant pleural mesothelioma (MPM) is a disease with a dismal prognosis. Currently available treatments have modest results. Therefore, new agents and new treatment strategies are eagerly awaited by patients and clinicians. Preclinical and clinical studies have shown that angiogenesis plays a very important role in MPM. Therefore, a great hope has been placed in the use of anti-angiogenic agents in this disease. AREAS COVERED: Studies regarding anti-angiogenic treatments in MPM with bevacizumab, tyrosine-kinase inhibitors (TKIs) and other agents were critically analyzed, with an overview of ongoing trials and future perspectives, including research on biomarkers. EXPERT OPINION: The clinical use of angiogenesis inhibitors in MPM patients has resulted more challenging than anticipated. The intrinsic complexity of neo-angiogenesis, and its redundant regulatory mechanisms, suggests that multiple and different biomarkers are needed to predict efficacy of anti-angiogenic agents and to monitor their biological and therapeutic effects. The growing understanding of the molecular alterations and key pathways that underlie the resistance to VEGF inhibitors will allow to design studies of the combination of agents targeting these pathways with anti-VEGF therapies. Only a tight integration of preclinical and clinical studies will allow to achieve a real progress in MPM patients with this therapeutic strategy.
    Expert Opinion on Investigational Drugs 04/2012; 21(6):833-44. · 4.74 Impact Factor
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    ABSTRACT: Thymic carcinomas represent the most aggressive histotype of thymic epithelial tumors (TETs). The 2004 World Health Organization classification has assigned a subgroup of thymic carcinomas as t(15;19) carcinomas based on the presence of t(15;19), a translocation found in poorly differentiated and highly aggressive NUT midline carcinomas. These tumors are characterized byrearrangement of the NUT (nuclear protein in testis) gene on chromosome 15q14, which in most cases fuses to the bromodomain containing 4 (BRD4) gene on chromosome 19 p13.1 through reciprocal t(15;19) translocation, resulting in constitutive BRD4-NUTfusion protein expression. To our knowledge, NUT translocation has been reported only in four thymic carcinomas. Due to the rarity of TETs, the prevalence of NUT rearrangement in TETs has however never been systematically explored. Formalin-fixed paraffin-embedded samples of histologically confirmed TETs were evaluated for NUT expression and rearrangement by immunohistochemistry and fluorescence in situ hybridization, respectively. A series of 148 TETs (37 carcinomas and 111 thymomas) were examined for NUT expression and rearrangement. Only one thymic carcinoma (2.7% of thymic carcinomas or 0.68% of TETs) was found positive for NUT expression and rearrangement. Rearrangement of NUT is infrequent in TETs. We propose that caution should be taken to distinguish t(15;19) thymic carcinoma from other mediastinal carcinomas, as NUT midline carcinomas are often associated with dreadful prognosis or overt lethality.
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 04/2012; 7(4):744-50. · 4.55 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: Although pemetrexed, a potent thymidylate synthase (TS) inhibitor, enhances the cytoytoxic effect of platinum compounds against malignant pleural mesothelioma (MPM), novel combinations with effective targeted therapies are warranted. To this end, the current study evaluates new targeted agents and their pharmacological interaction with carboplatin-pemetrexed in human MPM cell lines. We treated H2052, H2452, H28 and MSTO-211H cells with carboplatin, pemetrexed and targeted compounds (gefitinib, erlotinib, sorafenib, vandetanib, enzastaurin and ZM447439) and evaluated the modulation of pivotal pathways in drug activity and cancer cell proliferation. Vandetanib emerged as the compound with the most potent cytotoxic activity, which interacted synergistically with carboplatin and pemetrexed. Drug combinations blocked Akt phosphorylation and increased apoptosis. Vandetanib significantly downregulated epidermal growth factor receptor (EGFR)/Erk/Akt phosphorylation as well as E2F-1 mRNA and TS mRNA/protein levels. Moreover, pemetrexed decreased Akt phosphorylation and expression of DNA repair genes. Finally, most MPM samples displayed detectable levels of EGFR and TS, the variability of which could be used for patients' stratification in future trials with vandetanib-pemetrexed-carboplatin combination. Vandetanib markedly enhances pemetrexed-carboplatin activity against human MPM cells. Induction of apoptosis, modulation of EGFR/Akt/Erk phosphorylation and expression of key determinants for pemetrexed and carboplatin activity contribute to this synergistic interaction, and, together with the expression of these determinants in MPM samples, warrant further clinical investigation.
    British Journal of Cancer 11/2011; 105(10):1542-53. · 5.08 Impact Factor
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    ABSTRACT: The pemetrexed-cisplatin chemotherapy is standard of care in first-line (FL) treatment of malignant pleural mesothelioma (MPM). The second-line (SL) chemotherapy is considered, but the optimal treatment has not been defined yet. The aim of this study was to evaluate the clinical outcomes of SL-therapy in a series of MPM-patients included in a retrospective multicenter database. Clinical records of MPM-patients who received SL-treatment from 1996 to 2008 were reviewed. Study endpoints were response, overall-survival (OS), and progression-free-survival (PFS) for SL, stratified for patient characteristics, FL-outcomes, and type of SL. Out of 423 patients, 181 with full clinical data were identified. Patients' characteristics: median-age 64 years (range: 36-85); male gender 115 (63.5%); good EORTC-score 109 (60.2%); epithelial histology 135 (74.6%). After FL, 147 (81.2%) patients achieved disease-control (DC) and 45 had a time-to-progression≥12 months (TTP≥12). After SL, 95 patients (52.6%) achieved DC (21 response; 74 stable-disease); median PFS and OS were 4.3 and 8.7 months, respectively. According to multivariate analysis, DC after SL-therapy was significantly related to pemetrexed-based treatment (OR: 2.46; p=0.017) and FL-TTP≥12 (OR: 3.50; p=0.006). PFS was related to younger age (<65 years) (HR: 0.70; p=0.045), ECOG-PS0 (HR: 0.67; p=0.022), and FL-TTP≥12 (HR: 0.45; p<0.001). OS was significantly related to ECOG-PS0 (HR: 0.43; p<0.001) and to FL-TTP≥12 (HR: 0.54; p=0.005). In pemetrexed pre-treated patients, re-treatment with a pemetrexed/platinum combination significantly reduced the risk-of-death than pemetrexed alone (HR: 0.11; p<0.001). In conclusion, SL-chemotherapy seems to be active in MPM-patients, particularly in younger patients with ECOG-PS0 and prolonged TTP after FL-pemetrexed-based chemotherapy. In selected patients, re-challenge with pemetrexed-based regimens, preferentially associated with platinum-compound, appears to be an option for SL-setting. Considering the important limitations of this study, due to retrospective nature and the possible selection bias, prospective clinical trials are warranted to clarify these issues.
    Lung cancer (Amsterdam, Netherlands) 09/2011; 75(3):360-7. · 3.14 Impact Factor
  • Journal of Clinical Oncology 06/2011; 29(18):e529-31. · 18.04 Impact Factor
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    ABSTRACT: The current study investigates whether or not functional polymorphisms in the ATP-binding cassette transporter gene ABCG2 might affect gefitinib activity and/or toxicity in non-small-cell lung cancer (NSCLC) patients. Towards this end, ABCG2 polymorphisms and expression were assessed in DNA and tumors from 94 NSCLC patients treated with gefitinib, whereas their associations with toxicity/response and time-to-progression/overall survival were evaluated using Pearson-χ(2) and log-rank-test, respectively. Patients carrying an ABCG2 -15622T/T genotype or harboring at least one TT copy in the ABCG2 (1143C/T, -15622C/T) haplotype developed significantly more grade 2/3 diarrhea (p < 0.01). No associations were found between polymorphisms and outcome. Consistently, ABCG2 protein levels in tumors were not significantly different between patients harboring different ABCG2 variants. The ABCG2 -15622C/T polymorphism and ABCG2 (1143C/T, -15622C/T) haplotype resulted in a gefitinib-dependent, moderate-to-severe diarrhea suggesting that these pharmacogenetic markers should be considered to optimize NSCLC treatment.
    Pharmacogenomics 02/2011; 12(2):159-70. · 3.86 Impact Factor

Publication Stats

1k Citations
361.16 Total Impact Points

Institutions

  • 2010–2013
    • National Institutes of Health
      • Branch of Medical Oncology Branch and Affiliates
      Bethesda, MD, United States
  • 2009–2013
    • Humanitas Gavazzeni - Bergamo
      Bérgamo, Lombardy, Italy
  • 2006–2013
    • VU University Medical Center
      Amsterdamo, North Holland, Netherlands
    • Istituto di Cura e Cura a Carattere Scientifico Basilicata
      Rionero in Vulture, Basilicate, Italy
  • 2002–2012
    • Istituto Clinico Humanitas IRCCS
      Rozzano, Lombardy, Italy
  • 2008
    • National Cancer Institute (USA)
      • Center for Cancer Research
      Bethesda, MD, United States