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Kroger N.,University of Hamburg | Solano C.,Hospital Clinico Universitario | Wolschke C.,University of Hamburg | Bandini G.,S. Orsola Malpighi University Hospital | And 30 more authors.
New England Journal of Medicine | Year: 2016

BACKGROUND Chronic graft-versus-host disease (GVHD) is the leading cause of later illness and death after allogeneic hematopoietic stem-cell transplantation. We hypothesized that the inclusion of antihuman T-lymphocyte immune globulin (ATG) in a myeloablative conditioning regimen for patients with acute leukemia would result in a significant reduction in chronic GVHD 2 years after allogeneic peripheral-blood stem-cell transplantation from an HLA-identical sibling. METHODS We conducted a prospective, multicenter, open-label, randomized phase 3 study of ATG as part of a conditioning regimen. A total of 168 patients were enrolled at 27 centers. Patients were randomly assigned in a 1:1 ratio to receive ATG or not receive ATG, with stratification according to center and risk of disease. RESULTS After a median follow-up of 24 months, the cumulative incidence of chronic GVHD was 32.2% (95% confidence interval [CI], 22.1 to 46.7) in the ATG group and 68.7% (95% CI, 58.4 to 80.7) in the non-ATG group (P<0.001). The rate of 2-year relapse-free survival was similar in the ATG group and the non-ATG group (59.4% [95% CI, 47.8 to 69.2] and 64.6% [95% CI, 50.9 to 75.3], respectively; P = 0.21), as was the rate of overall survival (74.1% [95% CI, 62.7 to 82.5] and 77.9% [95% CI, 66.1 to 86.1], respectively; P = 0.46). There were no significant between-group differences in the rates of relapse, infectious complications, acute GVHD, or adverse events. The rate of a composite end point of chronic GVHD-free and relapse-free survival at 2 years was significantly higher in the ATG group than in the non-ATG group (36.6% vs. 16.8%, P = 0.005). CONCLUSIONS The inclusion of ATG resulted in a significantly lower rate of chronic GVHD after allogeneic transplantation than the rate without ATG. The survival rate was similar in the two groups, but the rate of a composite end point of chronic GVHD-free survival and relapsefree survival was higher with ATG. (Funded by the Neovii Biotech and the European Society for Blood and Marrow Transplantation; ClinicalTrials.gov number, NCT00678275. Copyright © 2016 Massachusetts Medical Society.


Lefebvre J.-L.,Center Oscar Lambret | Andry G.,Institute Jules Bordet | Chevalier D.,Center Hospitalier Regional Claude Huriez | Luboinski B.,Institute Gustave Roussy | And 11 more authors.
Annals of Oncology | Year: 2012

Background: We report the 10-year results of the EORTC trial 24891 comparing a larynx-preservation approach to immediate surgery in hypopharynx and lateral epilarynx squamous cell carcinoma. Material and methods: Two hundred and two patients were randomized to either the surgical approach (total laryngectomy with partial pharyngectomy and neck dissection, followed by irradiation) or to the chemotherapy arm up to three cycles of induction chemotherapy (cisplatin 100 mg/m. 2 day 1 + 5-FU 1000 mg/m. 2 day 1-5) followed for complete responders by irradiation and otherwise by conventional treatment. The end points were overall survival [OS, noninferiority: hazard ratio (preservation/surgery) ≤ 1.428, one-sided α = 0.05], progression-free survival (PFS) and survival with a functional larynx (SFL). Results: At a median follow-up of 10.5 years on 194 eligible patients, disease evolution was seen in 54 and 49 patients in the surgery and chemotherapy arm, respectively, and 81 and 83 patients had died. The 10-year OS rate was 13.8% in the surgery arm and 13.1% in the chemotherapy arm. The 10-year PFS rates were 8.5% and 10.8%, respectively. In the chemotherapy arm, the 10-year SFL rate was 8.7%. Conclusion: This strategy did not compromise disease control or survival (that remained poor) and allowed more than half of the survivors to retain their larynx. © The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.


Bovolato P.,Ospedale Civili Brescia | Bille A.,Fondazione IRCCS Instituto Nazionale dei Tumori | Ardissone F.,San Luigi Hospital | Santambrogio L.,Ospedale Policlinico | And 7 more authors.
Journal of Thoracic Oncology | Year: 2014

BACKGROUND: Surgery with pleurectomy/decortication (P/D) or extrapleural pneumonectomy (EPP) can be an option for selected patients with resectable malignant pleural mesothelioma (MPM). The aim of this study was to investigate the impact of surgical treatment on the outcome of patients with MPM. METHODS: We retrospectively reviewed data from 1365 consecutive patients with histologically proven MPM, treated from 1982 to 2012 in six Institutions. Patients received chemotherapy alone (n = 172), best supportive care (n = 690), or surgical treatment (n = 503), by either P/D (n = 202) or EPP (n = 301) with or without chemotherapy. RESULTS: After a median follow-up of 6.7 years (range, 1.1-14.8), 230 patients (16.8%) were alive; median survival for patients who received palliative treatment or chemotherapy alone, P/D, and EPP were 11.7 (95% CI, 10.5-12.5), 20.5 (95% CI, 18.2-23.1), and 18.8 (95% CI, 17.2-20.9) months, respectively. The 30-day mortality was 2.6% after P/D and 4.1% after EPP (p = 0.401). According to multivariate analysis (n = 1227), age less than 70, epithelial histology, and chemotherapy were independent favorable prognostic factors. In the subset of 313 patients (25.5%) with all favorable prognostic factors, median survival was 18.6 months after medical therapy alone, 24.6 months after P/D, and 20.9 months after EPP (p = 0.596). CONCLUSIONS: Our data suggest that patients with good prognostic factors had a similar survival whether they received medical therapy only, P/D, or EPP. The modest benefit observed after surgery during medical treatment requires further investigation, and a large multicenter, randomized trial, testing P/D after induction chemotherapy versus chemotherapy alone in MPM patients with good prognostic factors, is needed. Copyright © 2014 by the International Association for the Study of Lung Cancer.


Lidove O.,Hopital Bichat | West M.L.,Dalhousie University | Pintos-Morell G.,Germans Trias i Pujol University Hospital | Reisin R.,Hospital Britanico | And 7 more authors.
Genetics in Medicine | Year: 2010

Enzyme replacement therapy with α-galactosidase A has been used to treat Fabry disease since 2001. This article reviews the published evidence for clinical efficacy of the two available enzyme preparations. We focused on heart, kidney, and nervous system manifestations, which impact both quality of life and overall prognosis. A literature search was undertaken to identify prospective open or randomized controlled trials of enzyme replacement therapy in patients with Fabry disease published since 2001. To date, no definitive conclusion can be drawn from studies that have directly compared therapeutic responses between the two commercially available enzyme preparations. Significant clinical benefits of enzyme replacement therapy have been demonstrated, mainly in patients at an early phase of the disease, with beneficial effects on heart, kidneys, pain, and quality of life in treated patients. Incidence of antibodies against agalsidase alfa and agalsidase beta observed during major clinical studies suggests a greater antigenic response to agalsidase beta. Further studies are required to confirm the long-term clinical benefits of enzyme replacement therapy. More studies with female patients are needed as are investigations of early initiation of enzyme replacement therapy to determine the optimal time to start treatment to prevent irreversible organ damage. The value of adjunctive and supportive therapies should also be rigorously analyzed. © 2010 Lippincott Williams & Wilkins.


PubMed | Instituto Auxologico Italiano, University of Milan Bicocca and Ospedale San Gerardo
Type: Journal Article | Journal: European heart journal | Year: 2016

Haemochromatosis (HH) displays a number of circulatory alterations concurring at increase cardiovascular risk. Whether these include sympathetic abnormalities in unknown.In 18 males with primary HH (age: 42.3 10.4 years, mean SD), clinic and beat-to-beat blood pressure (BP, Finapres), heart rate (HR, EKG), and muscle sympathetic nerve activity (MSNA, microneurography) traffic were measured in the iron overload state and after iron depletion therapy. Haemochromatosis patients displayed elevated serum iron indices while other haemodynamic and metabolic variables were superimposable to ones seen in 12 healthy subjects (C). Muscle sympathetic nerve activity was significantly greater in HH than C (64.8 13.3 vs. 37.8 6.7 bs/100 hb, P < 0.01). Iron depletion caused a significant reduction in serum ferritin, transferrin saturation, and MSNA (from 64.8 13.3 to 39.2 9.2 bs/100 hb, P < 0.01) and a significant improvement in baroreflex-MSNA modulation. This was paralleled by a significant increase in the high-frequency HR variability and by a significant reduction in the low-frequency systolic BP variability components. Before after iron depletion therapy, MSNA was significantly and directly related to transferrin saturation, liver iron concentration, and iron removed, while the MSNA reductions observed after the procedure were significantly and inversely related to the baroreflex-MSNA increases detected after iron depletion. In C, all variables remained unchanged following 1 month observation.These data provide the first evidence that in HH iron overload is associated with an hyperadrenergic state and a baroreflex alteration, which are reversed by iron depletion. These findings underline the importance of iron overload in modulating sympathetic activation, possibly participating at the elevated cardiovascular risk reported in HH.


Bianda N.,Ospedale San Giovanni | Di Valentino M.,Ospedale San Giovanni | Priat D.,University of Zürich | Segatto J.M.,Ospedale San Giovanni | And 13 more authors.
European Heart Journal | Year: 2012

Aims The time course of atherosclerosis burden in distinct vascular territories remains poorly understood. We longitudinally evaluated the natural history of atherosclerotic progression in two different arterial territories using high spatial resolution magnetic resonance imaging (HR-MRI), a powerful, safe, and non-invasive tool. Methods and Results We prospectively studied a cohort of 30 patients (mean age 68.3, n= 9 females) with high Framingham general cardiovascular disease 10-year risk score (29.5) and standard medical therapy with mild-to-moderate atherosclerosis intra-individually at the level of both carotid and femoral arteries. A total of 178 HR-MRI studies of carotid and femoral arteries performed at baseline and at 1-and 2-year follow-up were evaluated in consensus reading by two experienced readers for lumen area (LA), total vessel area (TVA), vessel wall area (VWA= TVA-LA), and normalized wall area index (NWI= VWA/TVA). At the carotid level, LA decreased (-3.19/year, P 0.018), VWA increased (3.83/year, P= 0.019), and TVA remained unchanged. At the femoral level, LA remained unchanged, VWA and TVA increased (5.23/year and 3.11/year, both P < 0.01), and NWI increased for both carotid and femoral arteries (2.28/year, P= 0.01, and 1.8/year, P= 0.033). Conclusion The atherosclerotic burden increased significantly in both carotid and femoral arteries. However, carotid plaque progression was associated with negative remodelling, whereas the increase in femoral plaque burden was compensated by positive remodelling. This finding could be related to anatomic and flow differences and/or to the distinct degree of obstruction in the two arterial territories. © 2011 The Author.


Villa F.,Ospedale San Gerardo | Iacca C.,Ospedale San Gerardo | Molinari A.F.,Ospedale San Gerardo | Giussani C.,Ospedale San Gerardo | And 4 more authors.
Critical Care Medicine | Year: 2012

OBJECTIVE: Isoflurane is a volatile anesthetic that has a vasodilating effect on cerebral vessels producing a cerebral blood flow increase. Furthermore, it has been shown in animal studies that isoflurane, when used as a preconditioning agent, has neuroprotective properties, inducing tolerance to ischemia. However, it is not routinely used in neurointensive care because of the potential increase in intracranial pressure caused by the rise in cerebral blood flow. Nevertheless, subarachnoid hemorrhage patients who are at risk for vasospasm may benefit from an increase in cerebral blood flow. We measured regional cerebral blood flow during intravenous sedation with propofol and during sedation with isoflurane in patients with severe subarachnoid hemorrhage not having intracranial hypertension. DESIGN: The study is a crossover, open clinical trial (NCT00830843). SETTING: Neurointensive care unit of an academic hospital. PATIENTS: Thirteen patients with severe subarachnoid hemorrhage, (median Fisher scale 4), monitored on clinical indication with intracranial pressure device and a thermal diffusion probe for the assessment of regional cerebral blood flow. An intracranial pressure >18 mm Hg was an exclusion criterion. INTERVENTIONS: Cerebral and hemodynamic variables were assessed at three steps. Step 1: sedation with propofol 3-4 mg/kg/hr; step 2: after 1hr of propofol discontinuation and isoflurane 0.8%; step 3: after 1hr of propofol at the same previous infusion rate. Cerebral perfusion pressure and arterial PCO2 were maintained constant. Mean cerebral artery flow velocity and jugular vein oxygen saturation were measured at the end of each step. MEASUREMENTS AND MAIN RESULTS: Regional cerebral blood flow increased significantly during step 2 (39.3±29mL/100 hg/min) compared to step 1 (20.8±10.7) and step 3 (24.7±8). There was no difference in regional cerebral blood flow comparing step 1 vs. step 3. No significant difference in intracranial pressure, mean cerebral artery transcranial Doppler velocity, PaCO2, cerebral perfusion pressure between the different steps. CONCLUSIONS: Isoflurane increases regional cerebral blood flow in comparison to propofol. Intracranial pressure did not change significantly in the population not affected by intracranial hypertension. Copyright © 2012 by the Society of Critical Care Medicine and Lippincott Williams and Wilkins.


Radaelli A.,Ospedale San Gerardo | Mancia G.,University of Milan Bicocca | Balestri G.,Ospedale Desio | Rovati A.,Ospedale San Gerardo | And 4 more authors.
Journal of Hypertension | Year: 2014

Objective: After myocardial infarction (MI), baroreflex function is impaired and heart rate (HR) variability is reduced. An impaired baroreflex has been observed also in coronary patients with no previous MI, leading to hypothesize alterations of HR variability also in these patients. The aim of the present work was, therefore, to study whether and to what extent cardiovascular variability is altered in coronary patients with no previous MI. Methods: Thirty-two individuals were studied: eleven patients with coronary artery disease but no previous MI [coronary artery disease (CAD)], eleven patients with a reduced left ventricular ejection fraction [congestive heart failure (CHF)] and ten age-matched controls (CNT). Results: Overall HR variability was significantly and similarly reduced in CAD (630±272 ms2) and CHF patients (594±395 ms2) with respect to CNT (1405±837 ms2), this being the case also for the low and high frequency spectral components. Low-frequency oscillations of blood pressure (BP) were also significantly and similarly less pronounced in CAD (0.7±0.7mmHg2) and CHF patients (0.7±0.7mmHg2) compared with CNT (1.8±1.4mmHg2). Moreover, both CAD and CHF patients showed a significantly reduced baroreflex function and an increased pulse-wave velocity with respect to CNT. Conclusion: Our study shows that in coronary patients with no MI and no left ventricular dysfunction, there is a profound alteration of both HR and BP variability as in CHF patients, presumably because of a marked impairment of the autonomic modulation of the heart and blood vessels.


Pesenti A.,Ospedale San Gerardo | Pesenti A.,University of Milan Bicocca | Patroniti N.,Ospedale San Gerardo | Patroniti N.,University of Milan Bicocca | And 2 more authors.
Critical Care Medicine | Year: 2010

Mechanical ventilation and ventilator-associated lung injury could be avoided by decreasing the ventilatory needs of the patient by extracorporeal carbon dioxide removal. The reasons for the increased ventilatory needs of the patients with acute respiratory distress syndrome are outlined, as well as some of the mechanisms of continuing damage. Extracorporeal gas exchange has been used mainly as a rescue procedure for severely hypoxic patients. Although this indication remains valid, we propose that extracorporeal carbon dioxide removal could control the ventila-tory needs of the patient and allow the maintenance of spontaneous breathing while avoiding intubation and decreasing the concurrent sedation needs. A scenario is depicted whereby an efficient carbon dioxide removal device can maintain blood gas homeostasis of the patient with invasiveness comparable to he-modialysis. High carbon dioxide removal efficiency may be achieved by combinations of hemofiltration and metabolizable acid loads. Copyright © 2010 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins.

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