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Polo V.,Gustave Roussy | Polo V.,Instituto Oncologico Veneto IRCCS | Besse B.,Gustave Roussy
Annals of Oncology | Year: 2014

Four to six cycles of platinum-based chemotherapy are currently recommended for the first-line treatment of advanced non-small-cell lung cancer (NSCLC). Several studies have assessed the benefit of maintenance therapy following platinum- based first-line therapy, to improve disease control, and thus, progression-free and overall survival with minimal toxicity and maintenance or improvement of quality of life of patients. We review here clinical trials evaluating continuation maintenance therapy or switch maintenance therapy in locally advanced or metastatic NSCLC, to highlight the achievements made and critical issues faced. Based on the available results and limitations of these trials, maintenance therapy should be considered a good treatment strategy for a limited subgroup of patients. Maintenance therapy should be personalised according to the characteristics of patients and their disease, taking into account the data available for the agents used in this setting. © The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.


Dieci M.V.,University of Padua | Mathieu M.C.,Gustave Roussy | Guarneri V.,University of Padua | Guarneri V.,Instituto Oncologico Veneto IRCCS | And 6 more authors.
Annals of Oncology | Year: 2015

Background: Tumor-infiltrating lymphocytes (TILs) are emerging as strong prognostic factor for early breast cancer patients, especially in the triple-negative subtype. Here, we aim to validate previous findings on the prognostic role of TIL in the context of two randomized adjuvant trials and to investigate whether lymphocyte infiltrates can predict benefit from adjuvant anthracyclines. Patients and methods: A total of 816 patients enrolled and treated at the Gustave Roussy in the context of two multicentric randomized trials comparing adjuvant anthracyclines versus no chemotherapy were included in the present analysis. Primary end point was overall survival (OS). Hematoxilin and eosin slides of primary tumors were retrieved and evaluated for the percentage of intratumoral (It) and stromal (Str) TIL. Each case was also defined as high-TIL or low-TIL breast cancer adopting previously validated cutoffs. Results: TIL were assessable for 781 of 816 cases. High-TIL cases were more likely grade 3 and estrogen receptor (ER)-negative (P < 0.001). In multivariate analysis, both continuous It-TIL and Str-TIL were strong prognostic factors for OS [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77-0.95 P = 0.003; HR 0.89, 95% CI 0.81-0.96, P = 0.005 for It-TIL and Str-TIL, respectively]. The prognostic effect of continuous TIL was limited to triple-negative and HER2-positive patients. Ten-year OS rates were: 89% and 68% for triple-negative high-TIL and low-TIL, respectively (HR 0.44, 95% CI 0.18-1.10, P = 0.07) and 78% and 57% for HER2-positive high-TIL versus low-TIL, respectively (HR 0.46, 95% CI 0.20- 1.11, P = 0.08). Either continuous or binary TIL variables did not predict for the efficacy of anthracyclines. Test for interaction P value was not significant in the whole study population and in subgroups (ER+/HER2-, HER2+, ER-/HER2-). Conclusions: We confirmed the prognostic role of TIL in triple-negative early breast cancer and suggested a prognostic impact in HER2+ patients as well. Basing on our data, TIL should not be used as a parameter to select patients for anthracyclines chemotherapy. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.


Indraccolo S.,Instituto Oncologico Veneto IRCCS
Advances in experimental medicine and biology | Year: 2013

While it is well established that an angiogenic switch marks escape from tumor dormancy in xenograft models, the molecular pathways involved in the control of tumor cell proliferation or survival by angiogenesis remain substantially uncharted. We recently demonstrated that signals stemming from angiogenic endothelial cells (EC) regulate the behavior of dormant cancer cells. Specifically, we observed that the Notch ligand Dll4, induced by angiogenic factors in EC, triggers Notch3 activation in neighboring tumor cells and promotes a tumorigenic phenotype. Evidence that Notch signaling is involved in tumor dormancy was further strengthened by the observation that MKP-1 levels-a broadly expressed phosphatase-are controlled by Notch3 by regulation of protein ubiquitination and stability. Notch3 and MKP-1 levels are consistently low in dormant tumors, and this is accompanied by relatively high levels of phosphorylated p38, a canonical MKP-1 target previously associated with maintenance of tumor dormancy. These results elucidate a novel angiogenesis-driven mechanism involving the Notch and MAPK pathways that controls tumor dormancy. More in general, angiogenic EC could form part of the vascular niche, a specialized microenvironment which appears to regulate metastatic outgrowth and future studies are needed to clarify the contribution of EC in the regulation of cancer stem cell behavior in the niche.The notion that EC could communicate signals to tumor cells raises questions about the possibility of achieving tumor dormancy by counteracting angiogenesis. In experimental tumors, anti-VEGF drugs typically prune the newly formed vasculature, thus reducing microvessel density, blood flow, and perfusion. These drugs eventually increase hypoxia and cause tumor necrosis but dormancy is rarely observed. Our group recently reported that anti-VEGF therapy causes a dramatic depletion of glucose and an exhaustion of ATP levels in tumors. Moreover, we found that the central metabolic checkpoint LKB1/AMPK-a cellular sensor of ATP levels that supports cell viability in response to energy stress-is activated by anti-VEGF therapy in experimental tumors and it has a key role in induction of sustained tumor regression. These functional links between activation of the LKB1/AMPK by anti-angiogenic therapy and tumor dormancy suggest a role for metabolism in the regulation of this phenomenon.


Carron M.,University of Padua | Freo U.,University of Padua | Zorzi M.,Instituto Oncologico Veneto IRCCS | Ori C.,University of Padua
Journal of Critical Care | Year: 2010

Purpose: The study aimed to investigate cardiorespiratory parameters potentially predictive of failure of noninvasive ventilation (NIV) in severe community-acquired pneumonia (CAP). Patients and Methods: Sixty-four consecutive patients with severe CAP entered the study and underwent NIV with a helmet. Arterial blood gases, Pao 2/FIo 2, and oxygenation index (OI; mean airway pressure × FIo 2 × 100/Pao 2) were determined before and after a 1-hour trial of NIV. Results: Noninvasive ventilation succeeded in 28 patients (43%) and failed in 36 patients (56%). Patients who avoided intubation had significantly (P < .05) shorter stays in ICU and lower rates of mortality in ICU and in hospital. Patients who failed NIV had higher Simplified Acute Physiology Score II at ICU admission (33 ± 11 versus 29 ± 9) and lower pH before NIV trial (7.37 versus 7.44). Furthermore, patients who required intubation failed to improve or worsened arterial blood gases during NIV trial and, by the end of the trial, had lower (P < .05) pH (7.34 versus 7.44) and Pao 2/FiO 2 (177 versus 228) and higher OI (8.6 versus 5.0) and respiratory rate (28 versus 23 breaths/min). In a multivariate analysis, post-NIV to pre-NIV deltas of Pao 2/FiO 2 and of OI were independent predictors of NIV failure, with OI delta being significantly more accurate. Conclusions: Noninvasive ventilation failed in approximately half patients with severe CAP. Posttrial to pretrial deltas of Pao 2/FiO 2 and OI may help to guide decision about endotracheal intubation. © 2010 Elsevier Inc.


Bonanno L.,Instituto Oncologico Veneto Irccs
Translational Lung Cancer Research | Year: 2013

The backbone of first-line treatment for Epidermal Growth Factor (EGFR) wild-type (wt) advanced Non-small cell lung cancer (NSCLC) patients is the use of a platinum-based chemotherapy combination. The treatment is characterized by great inter-individual variability in outcome. Molecular predictive markers are extremely needed in order to identify patients most likely to benefit from platinumbased treatment and resistant ones, thus optimizing chemotherapy approach in NSCLC. Several components of DNA repair response (DRR) have been investigated as potential predictive markers. Among them, high levels of expression of ERCC1, both at protein and mRNA levels, have been associated with resistance to cisplatin in NSCLC. In addition, low levels of expression of RRM1, a target for gemcitabine, have been associated with improved OS in advanced NSCLC patients treated with cisplatin and gemcitabine. Preclinical data and retrospective analyses showed that BRCA1 is able to induce resistance to cisplatin and sensitivity to antimicrotubule agents. In addition, the mRNA levels of expression of RAP80, encoding for a protein cooperating with BRCA1 in homologous recombination (HR), have demonstrated to further subclassify low BRCA1 NSCLC tumors, improving the predictive model. On the basis of biological knowledge on DNA repair pathway and recent controversial results from clinical validation of potential molecular markers, integrated analysis of multiple DNA repair components could improve predictive information and pave the way to a new approach to customized chemotherapy clinical trials. © Translational lung cancer research. All rights reserved.


Zorzi M.,Instituto Oncologico Veneto IRCCS
Epidemiologia e prevenzione | Year: 2010

We present the main results from the fifth survey of the Italian screening programmes for colorectal cancer carried out by the National Centre for Screening Monitoring (Osservatorio Nazionale Screening, ONS) on behalf of the Ministry of Health. By the end of 2008, 87 programmes were active (14 had been activated during the year), and 52,9%of Italians aged 50- 69 years were residing in areas covered by organised screening programmes (theoretical extension). Ten Regions had their whole population covered. In the South of Italy and Islands, 12 new programmes were activated in 2008, including those of Abruzzo and Molise Regions, with an increase of theoretical extension from 7% to 21%. The majority of programmes employ the faecal occult blood test (FOBT), while some have adopted flexible sigmoidoscopy (FS) once in a lifetime, or a combination of both. Overall, about 2,593,000 subjects were invited to undergo FOBT, 71%of those to be invited within the year. The adjusted attendance rate was 47.5% and approximately 1,171,000 subjects were screened. Large differences in the attendance rate were observed among Regions, with 10% of programmes reporting values lower than 30%. Positivity rate of FOBT programmes was 5.9% at first screening (range 2.0-11%) and 4% at repeat screening (range 2.9-6.5%). The average attendance rate for total colonoscopy (TC) was 81.3% and in three Regions it was lower than 70%. Completion rate of TC was 92.2%. Among the 665,264 subjects attending screening for the first time, the detection rate (DR) per 1,000 screened subjects was 2.7 for invasive cancer and 13.1 for advanced adenomas (AA, adenomas with a diameter ≥1 cm, with villous/ tubulo-villous type or with high-grade dysplasia). As expected, the corresponding figures in the 552,391 subjects at repeat screening were lower (1.3‰ and 8.3‰ for invasive cancer and AA, respectively). The DR of cancer and adenomas increased with age and was higher among males. Many programmes reported some difficulties in guaranteeing TC in the appropriate time frame to FOBT+ subjects: in 16.0% of cases the waiting time was longer than two months. Seven programmes employed FS as the screening test: 58.8% of the target population (about 50,000 subjects) were invited and 8,135 subjects were screened, with an attendance rate of 27.2%. Overall, 83% of FS were classified as complete. Overall TC referral rate was 13.5% and the DR per 1,000 screened subjects was 4.7 and 47.5 for invasive cancer and AA, respectively.


Novelletto B.F.,Societa Italiana di Medicina Generale Padua | Guzzinati S.,Instituto Oncologico Veneto Irccs | Avogaro A.,University of Padua
Metabolic Syndrome and Related Disorders | Year: 2012

Background: Cardiovascular disease (CVD) is more frequent in adults with metabolic syndrome than in those without. We wished to assess the prevalence of the metabolic syndrome and the role of its specific components on prevalent CVD in a large cohort of subjects from the general population. Methods: Seventy-eight general practitioners among 3,542 were identified and participated in this study. Personal, anthropometric, and lifestyle data were obtained as was data relevant to CVD [coronary heart disease (CHD) or stroke or both]. A stratified random sample of 6,347 subjects taken from the population of the Veneto region in northeastern Italy was analyzed. Results: The prevalence [and its 95% confidence limits (CL)] of metabolic syndrome by gender and age classes was higher in men than women (21.9% vs. 16.8) and it increased with age (29.8% in ages 60-69 vs. 8.0 in ages 30-39). The most frequent triad of metabolic syndrome was waist circumference (WC)-blood pressure (BP)-hyperglycemia (GLYC) (33%). Metabolic syndrome was significantly associated with CVD [odds ratio (OR)=1.53, 95% CL, 1.02-2.29] and gender (men have about six times the risk of women), and the risk of CVD increases with age (11% per additional year of age). High-density lipoprotein (HDL) is the only component of metabolic syndrome associated with CVD: The OR was 2.12 (95% CL, 1.32-3.43) and remains significant in sex-specific models only in men. Conclusions: The prevalence of metabolic syndrome in the Veneto region among subjects ages 30-69 is high. There is a significant association between prevalent CVD and metabolic syndrome, but the biological basis of association is strongly influenced by gender. © 2012, Mary Ann Liebert, Inc.


Pasello G.,Instituto Oncologico Veneto IRCCS | Ceresoli G.L.,Instituto Humanitas Gavazzeni | Favaretto A.,Instituto Oncologico Veneto IRCCS
Cancer Treatment Reviews | Year: 2013

Malignant Pleural Mesothelioma (MPM) is an aggressive tumour with poor prognosis and increasing incidence in industrialized countries because of the previous widespread exposure to asbestos fibres and to the long lag period from time of exposure and the diagnosis of the disease. MPM shows high refractoriety to systemic treatment, single-modality treatment was generally ineffective and did not achieve higher results than supportive care. The incidence of local and distant recurrences after surgery remains high and that was the reason for many centres to perform combined treatments. In the attempt of reducing the incidence of local recurrences, a multimodality approach with surgery followed by adjuvant radiotherapy was explored. Extrapleural pneumonectomy (EPP) allows higher doses of radiotherapy to the whole hemithorax by avoiding pulmonary toxicity and the results of this approach is a significant reduction of loco-regional relapses; although, extrathoracic metastasis represent a major problem in the management of the disease because of the impact on overall survival. The success with surgical resection after neoadjuvant chemotherapy in stage IIIA lung cancer has been the impetus for several groups to apply this strategy in MPM aiming at reducing the incidence of distant relapse after surgery. Platinum-based chemotherapy plus gemcitabine or pemetrexed for 3-4 cycles followed by surgery and postoperative high-dose radiotherapy showed the best results in terms of overall and progression free survival. This review will focus on the main clinical studies and overview the results of different chemotherapy regimens in the neoadjuvant treatment of MPM. © 2012 Elsevier Ltd.


Zhu A.X.,Harvard University | Park J.O.,Sungkyunkwan University | Ryoo B.-Y.,University of Ulsan | Yen C.-J.,National Cheng Kung University | And 16 more authors.
The Lancet Oncology | Year: 2015

Background: VEGF and VEGF receptor-2-mediated angiogenesis contribute to hepatocellular carcinoma pathogenesis. Ramucirumab is a recombinant IgG1 monoclonal antibody and VEGF receptor-2 antagonist. We aimed to assess the safety and efficacy of ramucirumab in advanced hepatocellular carcinoma following first-line therapy with sorafenib. Methods: In this randomised, placebo-controlled, double-blind, multicentre, phase 3 trial (REACH), patients were enrolled from 154 centres in 27 countries. Eligible patients were aged 18 years or older, had hepatocellular carcinoma with Barcelona Clinic Liver Cancer stage C disease or stage B disease that was refractory or not amenable to locoregional therapy, had Child-Pugh A liver disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, had previously received sorafenib (stopped because of progression or intolerance), and had adequate haematological and biochemical parameters. Patients were randomly assigned (1:1) to receive intravenous ramucirumab (8 mg/kg) or placebo every 2 weeks, plus best supportive care, until disease progression, unacceptable toxicity, or death. Randomisation was stratified by geographic region and cause of liver disease with a stratified permuted block method. Patients, medical staff, investigators, and the funder were masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01140347. Findings: Between Nov 4, 2010, and April 18, 2013, 565 patients were enrolled, of whom 283 were assigned to ramucirumab and 282 were assigned to placebo. Median overall survival for the ramucirumab group was 9·2 months (95% CI 8·0-10·6) versus 7·6 months (6·0-9·3) for the placebo group (HR 0·87 [95% CI 0·72-1·05]; p=0·14). Grade 3 or greater adverse events occurring in 5% or more of patients in either treatment group were ascites (13 [5%] of 277 patients treated with ramucirumab vs 11 [4%] of 276 patients treated with placebo), hypertension (34 [12%] vs ten [4%]), asthenia (14 [5%] vs five [2%]), malignant neoplasm progression (18 [6%] vs 11 [4%]), increased aspartate aminotransferase concentration (15 [5%] vs 23 [8%]), thrombocytopenia (13 [5%] vs one [<1%]), hyperbilirubinaemia (three [1%] vs 13 [5%]), and increased blood bilirubin (five [2%] vs 14 [5%]). The most frequently reported (≥1%) treatment-emergent serious adverse event of any grade or grade 3 or more was malignant neoplasm progression. Interpretation: Second-line treatment with ramucirumab did not significantly improve survival over placebo in patients with advanced hepatocellular carcinoma. No new safety signals were noted in eligible patients and the safety profile is manageable. Funding: Eli Lilly and Co. © 2015 Elsevier Ltd.


Contento R.L.,Irccs Instituto Clinico Humanitas | Molon B.,Instituto Oncologico Veneto Irccs
Current Topics in Microbiology and Immunology | Year: 2010

The immunological synapse is a dynamic structure, formed between a T cell and one or more antigen-presenting cells, characterized by lipid and protein segregation, signaling compartmentalization, and bidirectional information exchange through soluble and membrane-bound transmitters. In addition, the immunological synapse is the site where signals delivered by the T-cell receptors, adhesion molecules, as well as costimulatory and coinhibitory receptors are decoded and integrated. Signaling modulation and tunable activation thresholds allow T cells to interpret the context in which the antigen is presented, recognize infectious stimuli, and finally decide between activation and tolerance. In this review, we discuss some strategies used by membrane receptors to tune activation signals in T cells. © 2010 Springer-Verlag Berlin Heidelberg.

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