Paolo A Zucali

Istituto Clinico Humanitas IRCCS, Rozzano, Lombardy, Italy

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Publications (92)577.07 Total impact

  • Cancer Research 08/2015; 75(15 Supplement):4335-4335. DOI:10.1158/1538-7445.AM2015-4335 · 9.33 Impact Factor
  • G L Ceresoli · F De Vincenzo · M G Sauta · M Bonomi · P A Zucali
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    ABSTRACT: Prostate cancer (PC) is a heterogeneous disease, whose growth is driven by androgens and androgen receptors. Androgen deprivation therapy (ADT) is the standard treatment of hormone-naïve metastatic disease. The majority of patients are treated with medical castration with GnRH agonists or antagonists, which usually determines a profound PSA decline and a radiological and clinical benefit. However, essentially all patients experience progression to castration-resistant prostate cancer (CRPC), and overall prognosis remains disappointing. Early targeting of cells that survive hormonal therapy may potentially prevent the development of CRPC. Several trials have explored the use of combination therapy with ADT and chemotherapy, targeting both the androgen dependent and independent cells simultaneously. Docetaxel was administered in combination with ADT to men with hormone-naïve metastatic prostate cancer, in the attempt to improve the duration and quality of patient survival. Three large randomized trials (the GETUG-15, CHAARTED and more recently the STAMPEDE study) have assessed these endpoints, with partially conflicting results. Overall, the results from these trials seem to support the use of early docetaxel combined with ADT in selected hormone-naïve metastatic PC patients. Full publication of the results of all studies, with longer follow-up, and the results of other ongoing trials in this setting will hopefully further define the role and the indications of this therapeutic strategy.
    The quarterly journal of nuclear medicine and molecular imaging: official publication of the Italian Association of Nuclear Medicine (AIMN) [and] the International Association of Radiopharmacology (IAR), [and] Section of the Society of.. 07/2015; · 2.03 Impact Factor
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    ABSTRACT: ABSTRACT Surgical resection remains the cornerstone of therapy for early-stage thymic epithelial tumors (TETs), while in advanced or recurrent forms, a multimodality approach incorporating radiation and chemotherapy is required. Given the absence of effective treatment options for metastatic/refractory TETs and the poor related prognosis, there is a compelling need to identify promising 'drugable' molecular targets. Initial reports of activity from targeted agents in TETs derived from anecdotal cases have been often associated with specific activating mutations. Only in recent years, several agents have been formally investigated into prospective clinical trials, with varying success rates. We reviewed the literature on targeted therapy in TETs along with two cases of thymoma achieving striking responses to sorafenib in combination with lapatinib.
    Future Oncology 04/2015; 11(8):1223-32. DOI:10.2217/fon.14.318 · 2.48 Impact Factor
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    ABSTRACT: We are getting used to referring to instrumentally detectable biological features in medical language as "imaging biomarkers". These two terms combined reflect the evolution of medical imaging during recent decades, and conceptually comprise the principle of noninvasive detection of internal processes that can become targets for supplementary therapeutic strategies. These targets in oncology include those biological pathways that are associated with several tumour features including independence from growth and growth-inhibitory signals, avoidance of apoptosis and immune system control, unlimited potential for replication, self-sufficiency in vascular supply and neoangiogenesis, acquired tissue invasiveness and metastatic diffusion. Concerning brain tumours, there have been major improvements in neurosurgical techniques and radiotherapy planning, and developments of novel target drugs, thus increasing the need for reproducible, noninvasive, quantitative imaging biomarkers. However, in this context, conventional radiological criteria may be inappropriate to determine the best therapeutic option and subsequently to assess response to therapy. Integration of molecular imaging for the evaluation of brain tumours has for this reason become necessary, and an important role in this setting is played by imaging biomarkers in PET and MRI. In the current review, we describe most relevant techniques and biomarkers used for imaging primary brain tumours in clinical practice, and discuss potential future developments from the experimental context.
    European journal of nuclear medicine and molecular imaging 12/2014; 42(4). DOI:10.1007/s00259-014-2971-8 · 5.38 Impact Factor
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    ABSTRACT: Malignant pleural mesothelioma (MPM) is a lethal disease with scarce therapeutic options, and preclinical studies on new targeted-agents are warranted. Because previous studies reported high c-Met expression and alterations in the microtubules network in most MPM samples, we evaluated the activity of the tivantinib, which has been recently suggested to affect microtubule polymerization in addition to inhibiting c-Met. In four MPM cell lines tivantinib inhibited both c-Met activity and microtubule polymerization, resulting in inhibition of cell-growth with IC50s ranging between 0.3 µM (MSTO-211H) and 2.4 µM (H2052). Furthermore tivantinib synergistically enhanced the antiproliferative and pro-apoptotic activity of pemetrexed, as detected by sulforhodamine-B-assay and flow cytometry. The synergistic interaction was associated with reduction of thymidylate synthase expression and inhibition of migratory activity. In aggregate, these data show the ability of tivantinib to specifically target key pathways in MPM cells and synergistically interact with pemetrexed, supporting further studies on this therapeutic approach.
    Current Drug Targets 12/2014; 15(14). DOI:10.2174/1389450116666141205160924 · 3.02 Impact Factor
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    ABSTRACT: Thymic epithelial tumors (TETs) are rare primary mediastinal tumors arising from thymic epithelium. Their rarity and complexity hinder investigations of their causes and therapy development. Here we summarize the existing knowledge regarding medical treatment of these tumors, and thoroughly review the known genetic aberrations associated with TETs and the present status of potential biological treatments. Epidermal growth factor receptor (EGFR), stem cell factor receptor (KIT), insulin-like growth factor-1 receptor (IGF1R), and vascular endothelial growth factors (VEGF-A, VEGF-B, and VEGF-2) are overexpressed in TETs. EGFR overexpression in TETs is associated with higher stage, and IGF-1R overexpression has poor prognostic value. Data indicate that anti-IGF1R monoclonal antibodies, and inhibitors of angiogenesis, somatostatin (SST) receptors, histone deacetylase (HDAC), mammalian target of rapamycin (mTOR), and cyclin-dependent kinases (CDK) may be active against TETs. Continued investigations in this field could lead to advancement of targeted and biological therapies for TETs. © The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email:
    Annals of Oncology 11/2014; 26(5). DOI:10.1093/annonc/mdu527 · 7.04 Impact Factor
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    ABSTRACT: Purpose 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. Methods 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). Results 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
    European journal of nuclear medicine and molecular imaging 11/2014; 42(5). DOI:10.1007/s00259-014-2960-y · 5.38 Impact Factor
  • European Journal of Cancer 11/2014; 50:176. DOI:10.1016/S0959-8049(14)70668-9 · 5.42 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; 33(1). DOI:10.1007/s10637-014-0167-5 · 2.92 Impact Factor
  • 39th ESMO Congress (ESMO); 09/2014
  • Clinical Cancer Research 07/2014; 20(13). DOI:10.1158/1078-0432.CCR-13-3256 · 8.72 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; 46(8). DOI:10.1038/ng.3016 · 29.35 Impact Factor
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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 06/2014; 111(2). DOI:10.1038/bjc.2014.312 · 4.84 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; 84(3). DOI:10.1016/j.lungcan.2013.11.011 · 3.96 Impact Factor
  • Elisa Giovannetti · Godefridus J Peters · Paolo A Zucali
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 08/2013; 8(8):e79-80. DOI:10.1097/JTO.0b013e318293e45b · 5.28 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 07/2013; 109(3). DOI:10.1038/bjc.2013.368 · 4.84 Impact Factor
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    ABSTRACT: Purposes: To determine whether the deregulation of genes relevant for normal thymus development can contribute to the biology of thymic epithelial tumors (TET). 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 TETs, 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 TETs. Ectopic FOXC1 expression attenuated anchorage-independent cell growth and cell migration in vitro. Conclusion: Our data support a tumor suppressor role of FOXC1 in TETs.
    Clinical Cancer Research 02/2013; 19(8). DOI:10.1158/1078-0432.CCR-12-3260 · 8.72 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 01/2013; 108(1). DOI:10.1038/bjc.2012.556 · 4.84 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; 79(3). DOI:10.1016/j.lungcan.2012.11.015 · 3.96 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 (Ktrans) 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 Cmax (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 Ktrans values (P<0.0001), which inversely correlated with NGR–hTNF Cmax (P=0.03) and baseline Ktrans values (P<0.0001). Lower sTNF-R2 levels and greater Ktrans 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 11/2012; 108(1). DOI:10.1038/bjc.2012.506 · 4.84 Impact Factor

Publication Stats

2k Citations
577.07 Total Impact Points


  • 2002–2013
    • Istituto Clinico Humanitas IRCCS
      • • Department of Oncology and Hematology
      • • Department of Urology
      Rozzano, Lombardy, Italy
  • 2011
    • Università di Pisa
      Pisa, Tuscany, Italy
  • 2006
    • VU University Medical Center
      Amsterdamo, North Holland, Netherlands
  • 2005
    • Leiden University
      Leyden, South Holland, Netherlands