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Bracarda S.,San Donato Hospital | Ricci S.,Santa Chiara Hospital | Sacco C.,University of Udine | Ridolfi L.,I.R.S.T | And 3 more authors.
Annals of Oncology | Year: 2013

Background: The ROSORC trial, a randomised, phase II trial comparing sorafenib plus interleukin (IL-2) versus sorafenib alone as first-line treatment of metastatic renal cell carcinoma (mRCC) failed to demonstrate differences in progression-free survival (PFS). Updated overall survival (OS) results are reported. Patients and methods: In this study, 128 patients were randomised to receive sorafenib 400 mg twice daily plus subcutaneous IL-2 4.5 million international units (MIU) five times per week for 6 weeks every 8 weeks (arm A) or sorafenib alone (arm B). OS was estimated with the Kaplan-Meier method and compared with the two-sided log-rank test. Results: After a median follow-up of 58 months (interquartile range: 28-63 months), the median OS was 38 and 33 months in arms A and B, respectively (P = 0.667). The 5-year OS was 26.3% [95% confidence interval (CI) 15.9-43.5) and 23.1% (95% CI 13.2-40.5) for the combination- and single-agent arm, respectively. Most of the patients who were refractory to first-line treatment were subsequently treated with different targeted agents; they had a median survival greater than expected. Conclusions: This outcome suggests a synergistic effect of the subsequent therapies following sorafenib failure. © The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

PubMed | IRST, Irccs Instituto Of Ricerche Farmacologiche Mario Negri, AOU Maggiore della Carita, Ospedale S. Cuore di Gesu and 21 more.
Type: Journal Article | Journal: Oncotarget | Year: 2016

We aimed to identify clinical predictors of long-term response to abiraterone (defined as >12 months drug exposure) in a retrospective cohort of metastatic castration-resistant prostate cancer patients treated in post-docetaxel setting at 24 Italian centers. The Cox proportional hazards model was used to analyze the association between clinical features and the duration of drug exposure. Results were expressed as hazard ratios (HR) with associated 95% confidence intervals (CI). A total of 143 patients met the inclusion criteria. Their median age was 73 years, median Gleason score 8 and median abiraterone exposure 20 months. At the univariate analysis, a significant correlation with the duration of abiraterone exposure was found for Gleason score (HR 0.82, 95% CI 0.71-0.96; p=0.012), PSA (HR 1.10, 95% CI 1.03-1.18; p=0.08) and lactic dehydrogenase levels (HR 1.22, 95% CI 1.02-1.46; p=0.027), while the association between lower alkaline phosphatase levels and treatment duration was marginally significant (HR 1.07, 95% CI 0.99-1.16; p=0.074). Only PSA and Gleason score were predictive of long-term treatment duration in the multivariate analysis. No other clinical factors resulted to be predictive of sustained response to abiraterone, including metastatic disease at diagnosis and visceral disease, suggesting that all subgroups of patients may derive a substantial clinical benefit from abiraterone treatment. These findings need to be validated in prospective, larger studies.

Maltoni M.,I.R.S.T | Scarpi E.,I.R.S.T | Rosati M.,Azienda Unita Sanitaria Locale Of Forli | Derni S.,Azienda Unita Sanitaria Locale Of Forli | And 4 more authors.
Journal of Clinical Oncology | Year: 2012

Purpose: Palliative sedation is a clinical procedure aimed at relieving refractory symptoms in patients with advanced cancer. It has been suggested that sedative drugs may shorten life, but few studies exist comparing the survival of sedated and nonsedated patients. We present a systematic review of literature on the clinical practice of palliative sedation to assess the effect, if any, on survival. Methods: A systematic review of literature published between January 1980 and December 2010 was performed using MEDLINE and EMBASE databases. Search terms included palliative sedation, terminal sedation, refractory symptoms, cancer, neoplasm, palliative care, terminally ill, end-of-life care, and survival. A manual search of the bibliographies of electronically identified articles was also performed. Results: Eleven published articles were identified describing 1,807 consecutive patients in 10 retrospective or prospective nonrandomized studies, 621 (34.4%) of whom were sedated. One case-control study was excluded from prevalence analysis. The most frequent reason for sedation was delirium in the terminal stages of illness (median, 57.1%; range, 13.8% to 91.3%). Benzodiazepines were the most common drug category prescribed. Comparing survival of sedated and nonsedated patients, the sedation approach was not shown to be associated with worse survival. Conclusion: Even if there is no direct evidence from randomized clinical trials, palliative sedation, when appropriately indicated and correctly used to relieve unbearable suffering, does not seem to have any detrimental effect on survival of patients with terminal cancer. In this setting, palliative sedation is a medical intervention that must be considered as part of a continuum of palliative care. © 2012 by American Society of Clinical Oncology.

Maltoni M.,Instituto Scientifico Romagnolo Per Lo Studio E La Cura Dei Tumori Irst | Scarpi E.,Biostatistics and Clinical Trials Unit | Pittureri C.,Palliative Care Unit | Martini F.,Palliative Care Unit | And 7 more authors.
Oncologist | Year: 2012

Purpose. Predicting prognosis in advanced cancer aids physicians in clinical decision making and can help patients and their families to prepare for the time ahead. Materials and Methods. This multicenter, observational, prospective, nonrandomized population-based study evaluated life span prediction of four prognostic scores used in palliative care: the original Palliative Prognostic Score (PaP Score), a variant of PaP Score including delirium (DPaP Score), the Palliative Performance Scale, and the Palliative Prognostic Index. Results. A total of 549 patients were enrolled onto the study. Median survival of the entire group was 22 days (95% confidence intervals [95% CI] = 19 -24). All four prognostic models discriminated well between groups of patients with different survival probabilities. Log-rank tests were all highly significant (p <.0001). The PaP and D-PaP scores were the most accurate, with a C index of 0.72 (95% CI = 0.70-0.73) and 0.73 (95% CI = 0.71-0.74), respectively. Conclusion. It can be confirmed that all four prognostic scores used in palliative care studies accurately identify classes of patients with different survival probabilities. The PaP Score has been extensively validated and shows high accuracy and reproducibility in different settings. © AlphaMed Press.

Fabbri F.,Instituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori IRST | Brigliadori G.,Instituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori IRST | Carloni S.,Instituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori IRST | Ulivi P.,Instituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori IRST | And 4 more authors.
Prostate | Year: 2010

BACKGROUND. The efficacy of current therapy for hormone-refractory prostate cancer is still unsatisfactory and new agents and therapeutic modalities are needed. The aims of the present work were to examine the in vitro activity and mechanisms of action of different antitumor drug combinations in hormone-resistant prostate cancer (HRPC) cell lines. METHODS. The activity of docetaxel (Doc), cisplatin (Cis), oxaliplatin (Oxa), SN-38 and ST1481, singly or in combination, was assessed in different HRPC cell lines (PC3, parental DU145 and taxane-resistant DU145-R) by SRB test. Apoptosis was evaluated by TUNEL and ANN-V assays. Extrusion pump activity was studied by Hoechst 33342 assay, while gene expression related to drug efflux mechanisms and DNA damage repair was analyzed by RT-PCR. RESULTS. Doc induced a high cytocidal effect in the HRPC cells, whereas Cis, Oxa, SN-38 and ST1481 exerted prevalently cytostatic activity. Doc followed by ST1481 proved to be the most effective drug sequence among those investigated, producing an important synergistic effect (R.I. from 2.0 to 5.2) in all the tested cell lines. Moreover, this sequence induced a significant downregulation of xenobiotic extrusion pump and DNA damage repair gene expression. ST1481 synergistically increased the cytocidal effect of Doc, probably through a downregulation of extrusion pump activity and DNA damage repair-related genes. CONCLUSIONS. Our results show that the Doc → ST1481 sequence effectively reduces the cancer cell population and restores Doc activity in taxane-resistant HRPC, indicating its potential usefulness as first- or second-line treatment of hormone-refractory prostate cancer. © 2009 Wiley-Liss, Inc.

Lorenzini C.,University of Bologna | Lamberti C.,University of Bologna | Aquilina M.,IRST
Computing in Cardiology | Year: 2016

The aim of this retrospective study was to detect early cardiotoxicity by speckle tracking analysis. We analyzed 2D and 3D echocardiographic datasets (2DE and 3DE) in 65 patients treated for breast cancer with anthracycline and trastuzumab. We compared the temporal variations of the left ventricular ejection fraction (LVEF) obtained analyzing 2D and 3D datasets and of the strain values computed before, during and after chemotherapy administration. In addition, in a subgroup of 45 patients a complete echocardiographic examination was performed 6 months after completion of therapy. Cardiotoxicity onset definition varies depending on the method used to compute LVEF (16.9% by 2DE and 50.8% by 3DE). Thirty-three patients developed cardiotoxicity. Nine of them showed a reduction of longitudinal and radial strain values before LVEF reduction at the 16th week. Through 3D speckle tracking analysis early diagnosis of the cardio-toxicity onset seems achievable allowing the planning of cardio protective therapy without interrupting chemotherapy administration. © 2015 CCAL.

Lorenzini C.,University of Bologna | Aquilina M.,IRST | Lamberti C.,University of Bologna | Corsi C.,University of Bologna
Computing in Cardiology | Year: 2014

The aim of this study was to evaluate if variability in EF estimate from echocardiographic data acquired with two dimensional (2DE) and three-dimensional (3DE) systems and analyzed using different software packages could affect cardio-toxicity assessment. We analyzed 2DE and 3DE datasets in 94 patients treated for breast cancer with anthracycline and trastuzumab. EF was computed from 2DE and 3DE data using two software packages (EchoPAC, GE Healthcare and TomTec 4D LV analysis). Corresponding estimates were compared. In addition, in a subgroup of 20 patients 3DE data were re-analyzed and intra-observer and inter-observer variability by three investigators were computed, using both software packages. As expected 2DE-based estimates significantly underestimated 3DE-based estimates. Intra-observer and inter-observer variability using both analysis packages showed a huge variability, due to significant differences in end systolic volume and EF. Following clinical definition of cardio-toxicity onset, these variability results could be a confounding factor since variations in EF measurement are in the range of EF decrease due to cardiac adverse effects from cancer therapeutic drugs.

Fabbri F.,Instituto Scientifico Romagnolo Per Lo Studio E La Cura Dei Tumori Irst | Zoli W.,Instituto Scientifico Romagnolo Per Lo Studio E La Cura Dei Tumori Irst | Carloni S.,Instituto Scientifico Romagnolo Per Lo Studio E La Cura Dei Tumori Irst | Ulivi P.,Instituto Scientifico Romagnolo Per Lo Studio E La Cura Dei Tumori Irst | And 6 more authors.
Journal of Cellular Physiology | Year: 2011

The efficacy of therapy for hormone-refractory prostate cancer (HRPC) is still unsatisfactory and new agents and therapeutic modalities are needed. The aims of the present work were to examine the in vitro activity and mechanisms of action of doxorubicin (DX), pegylated liposomal DX (PLDX), and non-pegylated liposomal DX (NPLDX) in DU145 and taxane-resistant DU145-R HRPC cell lines. Drug activity and incorporation, apoptosis, and expression of cell death-related markers were evaluated by SRB test, cytofluorimetric assays, and Western blot, respectively. Among the different DX formulations, NPLDX showed the highest cytotoxic activity in both cell lines, with more than 50% of apoptotic cells at only 1/10 of the plasma peak concentration after 72h exposure. Anthracyclines, in particular NPLDX, were highly concentrated in the Golgi apparatus. Moreover, a significant increase was observed in the expression of CD95 receptor, GD3 ganglioside and, caspase-2 and -8 active forms in both cell lines followed by caspase-3 activation and mitochondrial membrane depolarization. The Golgi apparatus, probably acting as a stress sensor, intensified the conventional apoptotic mechanism induced by anthracyclines. Our data support the hypothesis that organelle-dependent initiation of cell death other than that induced by mitochondria and nucleus is a research area worthy of pursuing and suggest that the Golgi apparatus could be an ideal target for anti-cancer therapy. Of note, the activity of NLPDX in taxane-resistant DU145-R cells warrants further evaluation as second-line treatment of advanced HRPC after taxane failure. © 2011 Wiley-Liss, Inc.

Farolfi A.,Instituto Scientifico Romagnolo Per Lo Studio E La Cura Dei Tumori Irst | Ridolfi L.,Instituto Scientifico Romagnolo Per Lo Studio E La Cura Dei Tumori Irst | Guidoboni M.,Instituto Scientifico Romagnolo Per Lo Studio E La Cura Dei Tumori Irst | Milandri C.,Instituto Scientifico Romagnolo Per Lo Studio E La Cura Dei Tumori Irst | And 4 more authors.
Journal of Chemotherapy | Year: 2011

The liver is the primary site of metastases in most uveal melanoma patients. We retrospectively investigated intraarterial chemotherapy (iAC) as treatment for patients with hepatic melanoma metastases. twenty-three patients (18 with uveal melanoma) received fotemustine (14 patients, 61.9%) or carboplatin (9 patients, 31.1%) via hepatic iAC delivery. the catheter was introduced through percutaneous access to the femoral artery with drugs delivered directly to the hepatic artery, and was removed at the end of each treatment cycle. A total of 3 cycles was planned, repeated every 21 days. However, patients with a clinical response could receive more than 3 cycles, provided that the toxic effects were acceptable. iAC was well tolerated and no catheter-related complications or grade 4 toxicities were reported. Considering only uveal melanoma patients, the overall response rate and disease control rate was 16.7% and 38.9%, respectively. median time to progression was 6.2 months (95% Ci 3.7-10.5) and median overall survival was 21 months (95% Ci 8-39). iAC is well tolerated and is a valid choice for patients with a poor prognosis since median survival rates are among the longest reported. © E.S.I.F.T. srl - Firenze.

LONGUEUIL, QUEBEC--(Marketwired - Dec. 14, 2016) - Héroux-Devtek Inc. (TSX:HRX) ("Héroux-Devtek" or the "Corporation"), a leading international manufacturer of aerospace products, today announced that it has signed a contract with Swedish defence and security company Saab AB ("Saab") for the production of complete landing gear systems for the Gripen E fighter aircraft. Under the terms of the agreement, Héroux-Devtek will manufacture, assemble and deliver complete landing gear systems for the Gripen E. Operations will be mainly carried out from the Corporation's facilities located in the United Kingdom. The design and development of the landing gear is currently being finalized by Héroux-Devtek's U.K.-based engineering team. Based on current program status, this new contract covers a total of 96 aircraft, representing firm orders for the Gripen E for the Swedish and Brazilian air forces. It also includes the provision of spare parts. Deliveries are expected to begin in calendar 2017. The aircraft is also being considered by several other countries and the contract provides an option for Saab to award the manufacturing of additional complete landing gear systems to Héroux-Devtek. "Héroux-Devtek is proud to further enhance its longstanding relationship with Saab. Our U.K. operations have designed and manufactured landing gear systems for previous variants of the Gripen aircraft and this new contract acknowledges their expertise on an important program. This life-cycle contract will generate revenues over an extended period of time and increase our proportion of sales derived from products on which we hold intellectual property or design authority rights. It will also solidify our geographical revenue diversification as well as our balance between commercial and defence programs. We are pleased to continue providing a wide range of complete, high-quality landing gear systems to leading OEMs of the global aerospace industry," said Martin Brassard, Vice-President and Chief Operating Officer of Héroux-Devtek. Saab's Gripen is a multi-role combat aircraft capable of undertaking the full range of air-to-air and air-to-ground missions, including specialist roles such as intelligence, surveillance, target acquisition and reconnaissance (ISTAR) and electronic warfare. Gripen is equipped with the most modern sensors and mission systems, including an active electronically scanned array (AESA) radar and infra-red search and track (IRST) system. It can be armed with any air-launched weapon that a customer requires, and integration of new capabilities is speedy and affordable. Gripen is easily deployable, with a very low maintenance and support footprint coupled with high reliability. Héroux-Devtek Inc. (TSX:HRX) is an international company specializing in the design, development, manufacture and repair and overhaul of landing gear and actuation systems and components for the Aerospace market. The Corporation is the third largest landing gear company worldwide, supplying both the commercial and defence sectors of the Aerospace market with new landing gear systems and components, as well as aftermarket products and services. The Corporation also manufactures hydraulic systems, fluid filtration systems and electronic enclosures. Approximately 80% of the Corporation's sales are outside Canada, including about 55% in the United States. The Corporation's head office is located in Longueuil, Québec with facilities in the Greater Montreal area (Longueuil, Laval and St-Hubert); Kitchener, Cambridge and Toronto, Ontario; Springfield and Strongsville, Ohio; Wichita, Kansas; Everett, Washington; and Runcorn, Nottingham and Bolton, United Kingdom. Saab serves the global market with world-leading products, services and solutions within military defence and civil security. Saab has operations and employees on all continents around the world. Through innovative, collaborative and pragmatic thinking, Saab develops, adopts and improves new technology to meet customers' changing needs. Except for historical information provided herein, this press release may contain information and statements of a forward-looking nature concerning the future performance of the Corporation. These statements are based on suppositions and uncertainties as well as on management's best possible evaluation of future events. Such factors may include, without excluding other considerations, fluctuations in quarterly results, evolution in customer demand for the Corporation's products and services, the impact of price pressures exerted by competitors, and general market trends or economic changes. As a result, readers are advised that actual results may differ from expected results.

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