Paolo Zucali | Università degli Studi di Milano - State University of Milan (Italy) (original) (raw)

Papers by Paolo Zucali

Annals of Oncology, 2008

Background: Approximately 10% of unselected non-small-cell lung cancer (NSCLC) patients responded... more Background: Approximately 10% of unselected non-small-cell lung cancer (NSCLC) patients responded to the epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) treatment. However, resistance mechanisms are not well understood. We evaluated several potential biological markers of intrinsic EGFR-TKIs-resistance in NSCLC.

Urologic Oncology: Seminars and Original Investigations, 2015

The prognosis of younger patients with prostate cancer is unclear, and the very few studies asses... more The prognosis of younger patients with prostate cancer is unclear, and the very few studies assessing those with metastatic castration-resistant prostate cancer (mCRPC) have mainly involved patients treated with older therapies. The aim of this observational study was to evaluate the clinical outcomes of a contemporary series of docetaxel-treated patients with mCRPC who were 60 years and younger. We retrospectively identified 134 patients who were 60 years and younger who were treated with docetaxel in 25 Italian hospitals and recorded their predocetaxel history of prostate cancer, their characteristics at the start of chemotherapy, and their postdocetaxel treatment history and outcomes. Most of the 134 consecutive patients with mCRPC received the standard 3-week docetaxel schedule; median progression-free survival (PFS) was 7 months, and 90 patients underwent further therapies after progression. The median overall survival (OS) from the start of docetaxel treatment was 21 months, but OS was significantly prolonged by the postprogression treatments, particularly those based on the new agents such as cabazitaxel, abiraterone acetate, or enzalutamide. OS was significantly shorter in the patients with a shorter interval between the diagnosis of prostate cancer and the start of docetaxel treatment; those who received hormonal treatment for a shorter period; those with shorter prostate-specific antigen doubling times; and those with lower hemoglobin levels, a worse performance status, and higher lactate dehydrogenase levels before starting treatment with docetaxel. The findings of this first study of clinical outcomes in a contemporary series of younger patients with mCRPC showed that their survival is similar to that expected in unselected patients with mCRPC who were of any age.

British journal of cancer, Jan 8, 2008

The incidence of malignant pleural mesothelioma (MPM) in elderly patients is increasing. In this ... more The incidence of malignant pleural mesothelioma (MPM) in elderly patients is increasing. In this study, pooled data from two phase II trials of pemetrexed and carboplatin (PC) as first-line therapy were retrospectively analysed for comparisons between age groups. Patients received pemetrexed 500 mg m(-2) and carboplatin AUC 5 mg ml(-1) min(-1) intravenously every 21 days with standard vitamin supplementation. Elderly patients were defined as those >or=70 years old. A total of 178 patients with an ECOG performance status of <or=2 were included. Median age was 65 years (range 38-79), with 48 patients >or=70 years (27%). Grade 3-4 haematological toxicity was slightly worse in >or=70 vs <70-year-old patients, with neutropenia observed in 25.0 vs 13.8% (P=0.11), anaemia in 20.8 vs 6.9% (P=0.01) and thrombocytopenia in 14.6 vs 8.5% (P=0.26). Non-haematological toxicity was mild and similar in the two groups. No significant difference was observed in terms of overall disease...

Expert Opinion on Medical Diagnostics, 2007

The EGF receptor (EGFR) is one of the most important targets for cancer treatment implicated in t... more The EGF receptor (EGFR) is one of the most important targets for cancer treatment implicated in the control of cell survival, proliferation and metastasis. In the last few years different EGFR molecular antagonists have been evaluated in the clinical setting and some of these drugs have demonstrated clinical efficacy in a subset of non-small cell lung cancer (NSCLC) patients. Gefitinib or erlotinib are a new class of compounds able to inhibit the tyrosine kinase domain of EGFR (EGFR TKI) and, during recent years, clinical and biologic predictors for TKI sensitivity have been identified. Among clinical features, never-smoking history has emerged as the most relevant clinical characteristic predictive of response to TKIs in NSCLC, and EGFR gene mutation or EGFR increased gene copy number represent critical biologic variables associated with an improved outcome for patients exposed to these agents. Unfortunately, cancer cells possess escape mechanisms to overcome inhibition of cell proliferation leading to drug resistance. There are several mechanisms that have been identified as responsible for intrinsic or acquired resistance. The aim of the present review is to analyze available data in order to identify an optimal paradigm for patient selection.

European Journal of Cancer Supplements, 2009

Clinical Cancer Research, 2014

Cancer Treatment Reviews, 2007

Most patients with malignant pleural mesothelioma (MPM) are candidates for chemotherapy during th... more Most patients with malignant pleural mesothelioma (MPM) are candidates for chemotherapy during the course of their disease. Assessment of the response with conventional criteria based on computed tomography (CT) measurements is challenging, due to the circumferential and axial pattern of growth of MPM. Such difficulties hinder an accurate evaluation of clinical study results and make the clinical management of patients critical. Several radiological response systems have been proposed, but neither WHO criteria nor the more recent RECIST unidimensional criteria nor hybrid uni-and bidimensional criteria seem to apply to tumor measurement in this disease. Recently, modified RECIST criteria for MPM have been published. Although they are already being used in current clinical trials, they have been criticized based on the high grade of inter-observer variability and on theoretical studies of mesothelioma growth according to non-spherical models. Computer-assisted techniques for CT measurement are being developed. The use of FDG-PET for prediction of response and, more importantly, of survival outcomes of MPM patients is promising and warrants validation in large prospective series. New serum markers such as osteopontin and mesothelin-related proteins are under evaluation and in the future might play a role in assessing the response of MPM to treatment.

Ejc Supplements, 2007

The extend of lymph node involvement in patients with non-small cell lung cancer (NSCLC) is the m... more The extend of lymph node involvement in patients with non-small cell lung cancer (NSCLC) is the most important prognostic factor and influences multimodality treatment. We studied safety, accuracy and characteristics of intraoperative ultrasound (US) guided systematic mediastinal nodal dissection in patients with resected NSCLC. Methods: Intraoperative hand held ultrasound probe was used in systematic mediastinal nodal dissection in 54 patients after radical surgery for NSCLC. Mapping of the lymph nodes by their number and station followed by histopathologic evaluation was performed. Data were compared with 58 patients who underwent lung resections and systematic mediastinal nodal dissection for NSCLC within the same time period at our institution. Statistical analysis was carried out. Results: The surgical procedure used depended on the extent of the disease, as well as the cardiopulmonary reserve of the patients and was comparable in both groups. Operating time was prolonged for 12 (6−20) minutes in patients with US guided mediastinal nodal dissection, but number and stations of evaluated lymph nodes was significantly higher (p > 0.001) at the same group of patients. Skip nodal metastases were found in 24% of patients without N1 nodal involvement. Standard staging system seemed to be improved in US guided mediastinal lymphadenectomy patients. Complications rate showed no difference between analyzed groups of patients. Conclusion: Higher number and location of analyzed mediastinal nodal stations in patients with resected NSCLC using hand held ultrasound probe suggested to be of great oncology significance. Procedure showed improved safety and higher accuracy. Our results indicate that intraoperative US may have important staging implication.

Nature Genetics, 2014

We analyzed 28 thymic epithelial tumors (TETs) using next-generation sequencing and identified a ... more We analyzed 28 thymic epithelial tumors (TETs) using next-generation sequencing and identified a missense mutation (chromosome 7 c.74146970T&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;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.

The Breast, 1998

S U MMA R Y. In a consecutive series of 241 women with operable breast cancer and clinically nega... more S U MMA R Y. In a consecutive series of 241 women with operable breast cancer and clinically negative axillary lymph nodes, 99mTc was injected on the day before surgery, and scintigraphic images were taken. During breast surgery a handheld gamma ray detector was used to locate the sentinel node and facilitate its removal separately via a small axillary incision. Complete axillary lymphadenectomy was then performed. The sentinel node accurately predicted axillary lymph node status in 232 (97.5%) of the 238 patients in whom a sentinel node was identified, and in all of the cases with a tumour cl.2 cm in diameter (38 patients). Of the 109 cases with metastatic axillary nodes, in 39 (35.8%) the only positive node was the sentinel node. In the great majority of patients, lymphoscintigraphy and gamma probe-guided surgery can locate the sentinel node in the axilla, obtaining important information on the status of axillary nodes.

Molecular Cancer Therapeutics, 2010

EGFR mutations are strongly predictive of epidermal growth factor receptor (EGFR)-tyrosine kinase... more EGFR mutations are strongly predictive of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor activity in non-small cell lung cancer (NSCLC), but resistance mechanisms are not completely understood. The interindividual variability in toxicity also points out to the need of novel pharmacogenetic markers to select patients before therapy. Therefore, we evaluated the associations between EGFR and AKT1 polymorphisms and outcome/toxicity in gefitinib-treated NSCLC patients. Polymorphic loci in EGFR, and AKT1, and EGFR and K-Ras mutations were assessed in DNA isolated from blood samples and/or paraffin-embedded tumor from 96 gefitinib-treated NSCLC patients. Univariate and multivariate analyses compared genetic variants with clinical efficacy and toxicity using Fisher's, log-rank test, and Cox's proportional hazards model. AKT1-SNP4 association with survival was also evaluated in 127 chemotherapy-treated/gefitinib-naive patients, whereas its relationship with AKT1 expression and gefitinib cytotoxicity was studied in 15 NSCLC cell lines. AKT1-SNP4 A/A genotype was associated with shorter time-to-progression (P = 0.04) and overall survival (P = 0.007). Multivariate analyses and comparison with the gefitinib-nontreated population underlined its predictive significance, whereas the in vitro studies showed the association of lower AKT1 mRNA levels with gefitinib resistance. In contrast, EGFR-activating mutations were significantly correlated with response, longer time-to-progression, and overall survival, whereas EGFR −191C/A (P < 0.001), −216 G/T (P < 0.01), and R497K (P = 0.02) polymorphisms were strongly associated with grade >1 diarrhea. AKT1-SNP4 A/A genotype seems to be a candidate biomarker of primary resistance, whereas EGFR −191C/A, −216G/T, and R497K polymorphisms are associated with diarrhea when using gefitinib in NSCLC patients, thus offering potential new tools for treatment optimization.

Lung Cancer, 2006

The epidermal growth factor receptor (EGFR) is overexpressed in many epithelial malignancies, aga... more The epidermal growth factor receptor (EGFR) is overexpressed in many epithelial malignancies, against which some antitumoral drugs have been developed. There is a lack of information as to EGFR expression in malignant pleural mesothelioma (MPM), an aggressive and fatal cancer poorly responsive to current oncological treatments. Our aim was to: (a) compare EGFR immunohistochemical expression with mRNA levels measured by real time PCR; (b) assess the relationships between EGFR expression and clinico-pathological data including survival; (c) analyze the EGFR mutations.

Journal of Thoracic Oncology, 2010

Overexpression of c-kit, a tyrosine kinase receptor protein encoded by the protooncogene kit, has... more 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 the American Geriatrics Society, 2000

Investigational New Drugs, 2008

The aim of this study was to evaluate retrospectively the response rate, progression-free surviva... more The aim of this study was to evaluate retrospectively the response rate, progression-free survival and median duration of response to dacarbazine as second/third-line chemotherapy for refractory soft tissue sarcomas. We studied 40 valuable patients with refractory soft tissue sarcomas and confirmed progressive disease (median age 54 years; range 24-73) treated between May 1997 and October 2005: 30 (75%) with metastases, and 23 (57.5%) with grade 3 disease. Dacarbazine was given as second-line chemotherapy to 29 patients (72.5%) every 21 days using three different schedules: dacarbazine 800 mg/m2 on day 1 (26 patients); dacarbazine 400 mg/m2 on days 1 and 2 (five patients); and dacarbazine 300 mg/m2 on days 1, 2 and 3 (nine patients). There were no complete responses, three (7.5%) partial responses and five (12.5%) cases of stable disease, for an overall disease control rate of 20%. Median progression-free survival was 2 months and median response duration 9 months. The 3- and 6-month progression-free rates were, respectively, 25% (SE 6.85%) and 20% (SE 6.32%). There were no cases of grade 3-4 hematological and non-hematological toxicity. In conclusion, our results suggest that second/third-line therapy with dacarbazine leads to satisfactory disease control in refractory soft tissue sarcomas; its activity seems to be comparable with other treatments, such as high dose ifosfamide or ecteinascidin-743, but it has a better toxicity profile.

Expert Review of Pharmacoeconomics & Outcomes Research, 2007

Gemcitabine is a novel pyrimidine nucleoside antimetabolite agent that is active, either as monot... more Gemcitabine is a novel pyrimidine nucleoside antimetabolite agent that is active, either as monotherapy or in association with other cytotoxic compounds, in pancreatic, ovarian, breast, bladder and non-small-cell lung cancer. The drug has an acceptable toxicity profile with myelosuppression being the most common adverse event. Pharmacoeconomic assessments have been performed in order to determine whether gemcitabine is a cost effective cancer treatment. Several cost analyses have investigated gemcitabine in association with cisplatin in the treatment of non-small-cell lung cancer, indicating that the combination is cost effective when compared with either old- or new-generation platinum-based treatments. Results in other malignancies are not corroborated by the same quality of evidence, therefore more extensive analyses are warranted. Overall, available data indicate that accurate selection of patients and careful cost analyses should be included in the development of new anticancer drugs for an appropriate use of limited healthcare resources.

European Journal of Cancer, 1998

The particle or hadron beams deployed in radiotherapy (protons, neutrons and helium, carbon, oxyg... more The particle or hadron beams deployed in radiotherapy (protons, neutrons and helium, carbon, oxygen and neon ions) have physical and radiobiological characteristics which differ from those of conventional radiotherapy beams (photons) and which offer a number of theoretical advantages over conventional radiotherapy. After briefly describing the properties of hadron beams in comparison to photons, this review discusses the indications for hadrontherapy and analyses accumulated experience on the use of this modality to treat mainly neoplastic lesions, as published by the relatively few hadrontherapy centres operating around the world. The analysis indicates that for selected patients and tumours (particularly uveal melanomas and base of skull/spinal chordomas and chondrosarcomas), hadrontherapy produces greater disease-free survival. The advantages of hadrontherapy are most promisingly realised when used in conjunction with modern patient positioning, radiation delivery and focusing techniques (e.g. on-line imaging, three-dimensional conformal radiotherapy) developed to improve the efficacy of photon therapy. Although the construction and running costs of hadrontherapy units are considerably greater than those of conventional facilities, a comprehensive analysis that considers all the costs, particularly those resulting from the failure of less effective conventional radiotherapy, might indicate that hadrontherapy could be cost effective. In conclusion, the growing interest in this form of treatment seems to be fully justified by the results obtained to date, although more efficacy and dosing studies are required.