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Leto S.M.,University of Turin | Leto S.M.,Candiolo Cancer Institute | Sassi F.,Candiolo Cancer Institute | Catalano I.,University of Turin | And 12 more authors.
Clinical Cancer Research | Year: 2015

Purpose: Preclinical studies in HER2-amplified gastrointestinal cancer models have shown that cotargeting HER2 with a monoclonal antibody and a small molecule is superior to monotherapy with either inhibitor, but the underlying cooperative mechanisms remain unexplored. We investigated the molecular underpinnings of this synergy to identify key vulnerabilities susceptible to alternative therapeutic opportunities. Experimental Design: The phosphorylation/activation of HER2, HER3, EGFR (HER receptors), and downstreamtransducers was evaluated inHER2-overexpressing colorectal and gastric cancer cell lines by Western blotting and/or multiplex phosphoproteomics. The in vivo outcome of antibody-mediated HER2 blockade by trastuzumab, reversibleHER2 inhibition by lapatinib, and irreversible HER2 inhibition by afatinib was assessed in patient-derived tumorgrafts and cell-line xenografts by monitoring tumor growth curves and by using antibody-based proximity assays. Results: Trastuzumab monotherapy reduced HER3 phosphorylation, with minor consequences on downstream transducers. Lapatinib alone acutely inhibited all HER receptors and effectors but led to delayed rephosphorylation of HER3 and EGFR and partial restoration of ERK and AKT activity. When combined with lapatinib, trastuzumab prevented HER3/EGFR reactivation and caused prolonged inhibition of ERK/AKT. Afatinib alone was also very effective in counteracting the reinstatement of HER3, EGFR, and downstream signaling activation. In vivo, the combination of trastuzumab and lapatinib-or, importantly, monotherapy with afatinib-resulted in overt tumor shrinkage. Conclusions: Only prolonged inhibition of HER3 and EGFR, achievable by dual blockade with trastuzumab and lapatinib or irreversible HER2 inhibition by single-agent afatinib, led to regression of HER2-amplified gastrointestinal carcinomas. © 2015 American Association for Cancer Research. Source

Rosazza C.,Carlo Besta Institute of Hospitalization | Rosazza C.,Carlo Besta Institute of Hospitalization | Andronache A.,Carlo Besta Institute of Hospitalization | Sattin D.,Disability Unit | And 11 more authors.
Annals of Neurology | Year: 2016

Objective Understanding residual brain function in disorders of consciousness poses extraordinary challenges, and imaging examinations are needed to complement clinical assessment. The default-mode network (DMN) is known to be dysfunctional, although correlation with level of consciousness remains controversial. We investigated DMN activity with resting-state functional magnetic resonance imaging (rs-fMRI), alongside its structural and metabolic integrity, aiming to elucidate the corresponding associations with clinical assessment. Methods We enrolled 119 consecutive patients: 72 in a vegetative state/unresponsive wakefulness state (VS/UWS), 36 in a minimally conscious state (MCS), and 11 with severe disability. All underwent structural MRI and rs-fMRI, and a subset also underwent 18F-fluorodeoxyglucose positron emission tomography (FDG-PET). Data were analyzed with manual and automatic approaches, in relation to diagnosis and clinical score. Results Excluding the quartile with largest head movement, DMN activity was decreased in VS/UWS compared to MCS, and correlated with clinical score. Independent-component and seed-based analyses provided similar results, although the latter and their combination were most informative. Structural MRI and FDG-PET were less sensitive to head movement and had better diagnostic accuracy than rs-fMRI only when all cases were included. rs-fMRI indicated relatively preserved DMN activity in a small subset of VS/UWS patients, 2 of whom evolved to MCS. The integrity of the left hemisphere appears to be predictive of a better clinical status. Interpretation rs-fMRI of the DMN is sensitive to clinical severity. The effect is consistent across data analysis approaches, but heavily dependent on head movement. rs-fMRI could be informative in detecting residual DMN activity for those patients who remain relatively still during scanning and whose diagnosis is uncertain. Ann Neurol 2016;79:841-853 © 2016 American Neurological Association. Source

Radaelli S.,Fondazione Istituto Nazionale Dei Tumori | Stacchiotti S.,Fondazione Istituto Nazionale Dei Tumori | Ruggieri P.,Istituto Ortopedico Rizzoli | Donati D.,Istituto Ortopedico Rizzoli | And 8 more authors.
Spine | Year: 2016

Study Design. Retrospective case series. Objective. To report on the natural history and long-term outcome of a large series of consecutive primary sacral chordoma patients surgically treated at two reference centers. Summary of Background Data. Sacral chordomas are rare tumors with poor long-term prognosis mainly caused by local failure. Till date, a few large series with long follow up are available in literature. Methods. All consecutive patients affected by primary localized sacral chordoma operated on at two Italian reference centers between 1981 and 2012 were included. Overall survival (OS), disease free survival (DFS), crude cumulative incidence (CCI) of local recurrence (LR), and distant metastases (DM) were calculated. Multivariable analyses for OS, DFS, LR, and DM were performed. Results. A total of 99 patients were identified: 65 males and 34 females. Median age was 59 years (range 22-77 yrs), median tumor size was 9cm (range 4-22). Nineteen patients received pre- or postoperative radiotherapy (RT). Wide (R0) surgical margins were achieved in 46 patients, marginal (R1) margins in 43 patients and intralesional (R2) margins in 10 patients. At a median follow up of 8.7 years (range 1-23.8 yrs) 30 patients died of disease, 31 patients developed local relapse, 16 patients developed distant metastasis, whereas 51 patients are alive without disease. OS and DFS at 5, 10, and 15 year were 92% and 63%, 45% and 62%, 36% and 21%, respectively, without any evidence of a plateau in the curves.CCI of LR and DM were 30% and 9% at 5 years, 46% and 18% at 10 years, 56% and 23% at 15 years. Size of the tumor and quality of surgical margins were the only significant predictors of long-term outcome. DFS for 15 years was, in fact, 49% for R0 and 7% for R1, respectively. Conclusion. In this series, long-term outcome of resected sacral chordoma was poor, with less than 25% patients were disease-free at 15 years. Interestingly, only half of the patients treated with R0 resection had no evidence of recurrence at 15 years. When surgical margins are expected to be positive other treatment modalities should be considered, especially when expected sequelae are substantial as in the case of more cephalad levels of resection. Level of Evidence: 3 © Copyright 2016 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Source

Grassi P.,Medical Oncology 1 | Verzoni E.,Medical Oncology 1 | Porcu L.,Laboratory of Methodology for Biomedical Research | Iacovelli R.,Medical Oncology 1 | And 2 more authors.
Therapeutic Advances in Urology | Year: 2015

Background: This study investigated whether the effectiveness of first-line tyrosine-kinase inhibitors was associated with sites of disease in patients with metastatic renal cell carcinoma (mRCC). Methods: A retrospective cohort of consecutive mRCC patients receiving first-line sorafenib (SO) or sunitinib (SU) was analyzed. Results: In total, 203 patients received SO and 99 SU. In patients with liver metastasis, SU was associated with a 18% higher risk of time-to-treatment failure (TTF), and a 39% higher risk of death than SO: conversely, patients without liver metastases who received SU showed a 46% decreased risk of TTF and 62% decreased risk of death. Conclusions: mRCC patients with liver metastases treated with first-line SO showed a better outcome compared with SU, while mRCC patients without liver metastases treated with firstline SU showed a better outcome compared with SO. Source

Polato F.,Laboratory of Molecular Pharmacology | Polato F.,U.S. National Institutes of Health | Rusconi P.,Laboratory of Molecular Pharmacology | Zangrossi S.,Laboratory of Molecular Pharmacology | And 10 more authors.
Journal of the National Cancer Institute | Year: 2014

Background p53 influences genomic stability, apoptosis, autophagy, response to stress, and DNA damage. New p53-target genes could elucidate mechanisms through which p53 controls cell integrity and response to damage. Methods DRAGO (drug-activated gene overexpressed, KIAA0247) was characterized by bioinformatics methods as well as by real-time polymerase chain reaction, chromatin immunoprecipitation and luciferase assays, time-lapse microscopy, and cell viability assays. Transgenic mice (94 p53-/- and 107 p53 +/- mice on a C57BL/6J background) were used to assess DRAGO activity in vivo. Survival analyses were performed using Kaplan-Meier curves and the Mantel-Haenszel test. All statistical tests were two-sided. Results We identified DRAGO as a new p53-responsive gene induced upon treatment with DNA-damaging agents. DRAGO is highly conserved, and its ectopic overexpression resulted in growth suppression and cell death. DRAGO-/- mice are viable without macroscopic alterations. However, in p53-/- or p53+/- mice, the deletion of both DRAGO alleles statistically significantly accelerated tumor development and shortened lifespan compared with p53-/- or p53+/- mice bearing wild-type DRAGO alleles (p53-/-, DRAGO-/- mice: hazard ratio [HR] = 3.25, 95% confidence interval [CI] = 1.7 to 6.1, P <. 001; p53+/-, DRAGO-/- mice: HR = 2.35, 95% CI = 1.3 to 4.0, P <. 001; both groups compared with DRAGO+/+ counterparts). DRAGO mRNA levels were statistically significantly reduced in advanced-stage, compared with early-stage, ovarian tumors, but no mutations were found in several human tumors. We show that DRAGO expression is regulated both at transcriptional- through p53 (and p73) and methylation-dependent control-and post-transcriptional levels by miRNAs. Conclusions DRAGO represents a new p53-dependent gene highly regulated in human cells and whose expression cooperates with p53 in tumor suppressor functions. © The Author 2014. Published by Oxford University Press. All rights reserved. Source

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