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Pagliarulo V.,University of Bari | Eisenberger M.A.,Johns Hopkins University | Schroder F.H.,Erasmus Medical Center | Sternberg C.N.,San Camillo Forlanini Hospital | Studer U.E.,University of Bern
European Urology | Year: 2012

Context: Androgen deprivation therapy (ADT) for prostate cancer (PCa) represents one of the most effective systemic palliative treatments known for solid tumors. Although clinical trials have assessed the role of ADT in patients with metastatic and advanced locoregional disease, the risk-benefit ratio, especially in earlier stages, remains poorly defined. Given the mounting evidence for potentially life-threatening adverse effects with short- and long-term ADT, it is important to redefine the role of ADT for this disease. Objective: Review the published experience with currently available ADT approaches in various contemporary clinical settings of PCa and reported serious treatment-related adverse events. This review addresses the level of evidence associated with the use of ADT in PCa, focusing upon survival outcome measures. Furthermore, this paper discusses evolving approaches targeting androgen receptor signaling pathways and emerging evidence from clinical trials with newer compounds. Evidence acquisition: A comprehensive review of the literature was performed, focusing on data from the last 10 yr (January 2000 to July 2011) and using the terms androgen deprivation, hormone treatment, prostate cancer and adverse effects. Abstracts from trials reported at international conferences held in 2010 and 2011 were also evaluated. Evidence synthesis: Data from randomized controlled trials and population-based studies were analyzed in different clinical paradigms. Specifically, the role of ADT was evaluated in patients with nonmetastatic disease as the primary and sole treatment, in combination with radiation therapy (RT) or after surgery, and in patients with metastatic disease. The data suggest that in men with nonmetastatic disease, the use of primary ADT as monotherapy has not shown a benefit and is not recommended, while ADT combined with conventional-dose RT (<72 Gy) for patients with high-risk disease may delay progression and prolong survival. The postoperative use of ADT remains poorly evaluated in prospective studies. Likewise, there are no trials evaluating the role of ADT in patients with biochemical relapses after surgery or RT. In patients with metastatic disease, there is a clear benefit in terms of quality of life, reduction of disease-associated morbidity, and possibly survival. Treatment with bilateral orchiectomy, luteinizing hormone-releasing hormone agonist therapy, with and without antiandrogens has been associated with various serious adverse events, including cardiovascular disease, diabetes, and skeletal complications that may also affect mortality. Conclusions: Although ADT is an effective treatment of PCa, consistent long-term benefits in terms of quality and quantity of life are predominantly evident in patients with advanced/metastatic disease or when ADT is used in combination with RT (<72 Gy) in patients with high-risk tumors. Implementation of ADT should be evidence based, with special consideration to adverse events and the risk-benefit ratio. © 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved.


Scher H.I.,Sloan Kettering Cancer Center | Fizazi K.,University Paris - Sud | Saad F.,University of Montréal | Taplin M.-E.,Dana-Farber Cancer Institute | And 16 more authors.
New England Journal of Medicine | Year: 2012

BACKGROUND: Enzalutamide (formerly called MDV3100) targets multiple steps in the androgen-receptor-signaling pathway, the major driver of prostate-cancer growth. We aimed to evaluate whether enzalutamide prolongs survival in men with castration-resistant prostate cancer after chemotherapy. METHODS: In our phase 3, double-blind, placebo-controlled trial, we stratified 1199 men with castration-resistant prostate cancer after chemotherapy according to the Eastern Cooperative Oncology Group performance-status score and pain intensity. We randomly assigned them, in a 2:1 ratio, to receive oral enzalutamide at a dose of 160 mg per day (800 patients) or placebo (399 patients). The primary end point was overall survival. RESULTS: The study was stopped after a planned interim analysis at the time of 520 deaths. The median overall survival was 18.4 months (95% confidence interval [CI], 17.3 to not yet reached) in the enzalutamide group versus 13.6 months (95% CI, 11.3 to 15.8) in the placebo group (hazard ratio for death in the enzalutamide group, 0.63; 95% CI, 0.53 to 0.75; P<0.001). The superiority of enzalutamide over placebo was shown with respect to all secondary end points: the proportion of patients with a reduction in the prostate-specific antigen (PSA) level by 50% or more (54% vs. 2%, P<0.001), the soft-tissue response rate (29% vs. 4%, P<0.001), the quality-of-life response rate (43% vs. 18%, P<0.001), the time to PSA progression (8.3 vs. 3.0 months; hazard ratio, 0.25; P<0.001), radiographic progression-free survival (8.3 vs. 2.9 months; hazard ratio, 0.40; P<0.001), and the time to the first skeletal-related event (16.7 vs. 13.3 months; hazard ratio, 0.69; P<0.001). Rates of fatigue, diarrhea, and hot flashes were higher in the enzalutamide group. Seizures were reported in five patients (0.6%) receiving enzalutamide. CONCLUSIONS: Enzalutamide significantly prolonged the survival of men with metastatic castrationresistant prostate cancer after chemotherapy. (Funded by Medivation and Astellas Pharma Global Development; AFFIRM ClinicalTrials.gov number, NCT00974311.) Copyright © 2012 Massachusetts Medical Society.


Prantera C.,San Camillo Forlanini Hospital | Lochs H.,Innsbruck Medical University | Grimaldi M.,Alfa Wassermann SpA | Danese S.,Instituto Clinico Humanitas | And 2 more authors.
Gastroenterology | Year: 2012

Background & Aims: Bacteria might be involved in the development and persistence of inflammation in patients with Crohn's disease (CD), and antibiotics could be used in therapy. We performed a clinical phase 2 trial to determine whether a gastroresistant formulation of rifaximin (extended intestinal release [EIR]) induced remission in patients with moderately active CD. Methods: We performed a multicenter, randomized, double-blind trial of the efficacy and safety of 400, 800, and 1200 mg rifaximin-EIR, given twice daily to 402 patients with moderately active CD for 12 weeks. Data from patients given rifaximin-EIR were compared with those from individuals given placebo, and collected during a 12-week follow-up period. The primary end point was remission (Crohn's Disease Activity Index <150) at the end of the treatment period. Results: At the end of the 12-week treatment period, 62% of patients who received the 800-mg dosage of rifaximin-EIR (61 of 98) were in remission, compared with 43% of patients who received placebo (43 of 101) (P =.005). A difference was maintained throughout the 12-week follow-up period (45% [40 of 89] vs 29% [28 of 98]; P =.02). Remission was achieved by 54% (56 of 104) and 47% (47 of 99) of the patients given the 400-mg and 1200-mg dosages of rifaximin-EIR, respectively; these rates did not differ from those of placebo. Patients given the 400-mg and 800-mg dosages of rifaximin-EIR had low rates of withdrawal from the study because of adverse events; rates were significantly higher among patients given the 1200-mg dosage (16% [16 of 99]). Conclusions: Administration of 800 mg rifaximin-EIR twice daily for 12 weeks induced remission with few adverse events in patients with moderately active CD. © 2012 AGA Institute.


Matteocci A.,San Camillo Forlanini Hospital | Pierelli L.,San Camillo Forlanini Hospital | Pierelli L.,University of Rome La Sapienza
Vox Sanguinis | Year: 2014

Red blood cell (RBC) transfusions are a milestone in the treatment for sickle cell anaemia (SSA) and for thalassaemia. RBC alloimmunization remains a major challenge of chronic transfusion therapy, and it can lead to adverse life-threatening events. The alloimmunization risk could depend on multiple factors such as the number of transfusions and, most of all, the genetic background. Different ethnic groups are predisposed to immunization because of a significant degree of RBC antigenic mismatch between donor and recipient. There is no universal agreement and standards for the most appropriate selection of RBC units in chronically transfused subjects. Current practice only deals with compatibility of ABO, Rh and K antigens. Molecular RBC antigenic matching extended to other blood group systems is an innovative strategy to ensure a better quality and effectiveness of transfusion therapy. © 2013 International Society of Blood Transfusion.


Pirker R.,Medical University of Vienna | Pereira J.R.,Arnaldo Vieira Of Carvalho Cancer Institute | Von Pawel J.,Asklepios Fachkliniken | Krzakowski M.,Maria Curie Sklodowska University | And 10 more authors.
The Lancet Oncology | Year: 2012

Background: Findings from the phase 3 First-Line ErbituX in lung cancer (FLEX) study showed that the addition of cetuximab to first-line chemotherapy significantly improved overall survival compared with chemotherapy alone (hazard ratio [HR] 0·871, 95% CI 0·762-0·996; p=0·044) in patients with advanced non-small-cell lung cancer (NSCLC). To define patients benefiting most from cetuximab, we studied the association of tumour EGFR expression level with clinical outcome in FLEX study patients. Methods: We used prospectively collected tumour EGFR expression data to generate an immunohistochemistry score for FLEX study patients on a continuous scale of 0-300. We used response data to select an outcome-based discriminatory threshold immunohistochemistry score for EGFR expression of 200. Treatment outcome was analysed in patients with low (immunohistochemistry score <200) and high (≥200) tumour EGFR expression. The primary endpoint in the FLEX study was overall survival. We analysed patients from the FLEX intention-to-treat (ITT) population. The FLEX study is registered with ClinicalTrials.gov, number NCT00148798. Findings: Tumour EGFR immunohistochemistry data were available for 1121 of 1125 (99·6%) patients from the FLEX study ITT population. High EGFR expression was scored for 345 (31%) evaluable patients and low for 776 (69%) patients. For patients in the high EGFR expression group, overall survival was longer in the chemotherapy plus cetuximab group than in the chemotherapy alone group (median 12·0 months [95% CI 10·2-15·2] vs 9·6 months [7·6-10·6]; HR 0·73, 0·58-0·93; p=0·011), with no meaningful increase in side-effects. We recorded no corresponding survival benefit for patients in the low EGFR expression group (median 9·8 months [8·9-12·2] vs 10·3 months [9·2-11·5]; HR 0·99, 0·84-1·16; p=0·88). A treatment interaction test assessing the difference in the HRs for overall survival between the EGFR expression groups suggested a predictive value for EGFR expression (p=0·044). Interpretation: High EGFR expression is a tumour biomarker that can predict survival benefit from the addition of cetuximab to first-line chemotherapy in patients with advanced NSCLC. Assessment of EGFR expression could offer a personalised treatment approach in this setting. Funding: Merck KGaA. © 2012 Elsevier Ltd.


Sonpavde G.,Baylor College of Medicine | Sternberg C.N.,San Camillo Forlanini Hospital | Rosenberg J.E.,Dana-Farber Cancer Institute | Hahn N.M.,Indiana University | And 2 more authors.
The Lancet Oncology | Year: 2010

Front-line platinum-based combination chemotherapy leads to high response rates but suboptimum overall survival for patients with advanced transitional-cell carcinoma of the urothelium. Bevacizumab is being assessed in combination with platinum-based first-line chemotherapy in a large phase 3 trial. Current second-line systemic therapies, including taxanes, yield disappointing outcomes. Vinflunine, a novel vinca alkaloid, showed some activity and was recently approved in Europe based on results of the first completed phase 3 trial in the second-line setting. Better understanding of molecular biology and the emergence of novel biological agents now offer the possibility of improved outcomes. Neoadjuvant therapy before cystectomy and consolidation therapy with biological agents after first-line therapy provide a framework for the development of new drugs. We propose that trials to approve new drugs target two separate populations; multicentre non-randomised phase 2 trials should include patients with chemotherapy-resistant disease progressing within 6 months of first-line therapy, and randomised trials might be appropriate for chemotherapy-sensitive disease progressing more than 6 months after first-line therapy. A multidisciplinary approach is necessary to make therapeutic advances. This review discusses current second-line therapy and emerging drugs for advanced transitional-cell carcinoma. © 2010 Elsevier Ltd.


Caviglia A.,San Camillo Forlanini Hospital
Il Giornale di chirurgia | Year: 2011

Procedure for Prolapse and Hemorrhoids (PPH or Longo procedure), a stapled circumferential anal mucosectomy, has proven to be very popular as it is considered safe and successful. However, a high haemorrhoid recurrence rate is reported, specially due to insufficient mucosal resection. The authors have come up with a technical modification to the mucoprolapsectomy, notably the Single Stapler Parachute Technique (SSPT), in order to obtain more abundant mucosal resection. In this study they will present the results obtained in 80 patients treated for muco-haemorrhoidal prolapse, 40 of whom underwent traditional PPH, while the remaining 40 patients underwent SSPT, both performed in two different specialised centres located in Rome, Italy.


La Pera G.,San Camillo Forlanini Hospital
Archivio Italiano di Urologia e Andrologia | Year: 2012

The difficulty in correctly identifying the etiologic factors of premature ejaculation (PE) could be due to the fact that the role of the pelvic floor muscles (PFMs) in the voluntary control of ejaculatory reflex has not been elucidated. The aim of the present investigation was to measure the prevalence of awareness of the role and use of PFM contraction in controlling the ejaculatory reflex among PE and non-PE participants. A total of 44 men with PE and 73 men without PE were recruited. In the first part of the study, we validated a test that rendered the participants aware of the PFMs through digital rectal examination and the PFM contraction. In the second part, we posed this multiple-choice question: "Which muscles do you use to delay ejaculation?". Men not answering correctly were considered not to be using the PFMs and also to be unaware that it is necessary to contract the PFMs to control the ejaculatory reflex. Only 3 of 44 subjects (6.8%) with PE and 60 of 73 subjects (82%) without PE answered correctly and used PFMs to control the ejaculatory reflex (Fisher test p < 0.0001). This test has a sensibility of 93%, a specificity of 82%, and an accuracy of 86%. The vast majority of PE subjects were unaware that to inhibit or delay ejaculation it is necessary to contract the PFMs. This association also raises the question whether the difficulties in defining PE and finding effective PE therapies could be due to a nonhomogeneous population of PE patients with different etiopathogenetic factors. More studies are required to confirm these data and to answer this question.


Gristina G.R.,San Camillo Forlanini Hospital | Antonelli M.,Catholic University of the Sacred Heart | Conti G.,Catholic University of the Sacred Heart | Ciarlone A.,San Camillo Forlanini Hospital | And 3 more authors.
Critical Care Medicine | Year: 2011

Background: Mortality is high among patients with hematologic malignancies admitted to intensive care units for acute respiratory failure. Early noninvasive mechanical ventilation seems to improve outcomes. Objective: To characterize noninvasive mechanical ventilation use in Italian intensive care units for acute respiratory failure patients with hematologic malignancies and its impact on outcomes vs. invasive mechanical ventilation. Design, Setting, Participants: Retrospective analysis of observational data prospectively collected in 2002-2006 on 1,302 patients with hematologic malignancies admitted with acute respiratory failure to 158 Italian intensive care units. Measurements: Mortality (intensive care unit and hospital) was assessed in patients treated initially with noninvasive mechanical ventilation vs. invasive mechanical ventilation and in those treated with invasive mechanical ventilation ab initio vs. after noninvasive mechanical ventilation failure. Findings were adjusted for propensity scores reflecting the probability of initial treatment with noninvasive mechanical ventilation. RESULTS:: Few patients (21%) initially received noninvasive mechanical ventilation; 46% of these later required invasive mechanical ventilation. Better outcomes were associated with successful noninvasive mechanical ventilation (vs. invasive mechanical ventilation ab initio and vs. invasive mechanical ventilation after noninvasive mechanical ventilation failure), particularly in patients with acute lung injury/adult respiratory distress syndrome (mortality: 42% vs. 69% and 77%, respectively). Delayed vs. immediate invasive mechanical ventilation was associated with slightly but not significantly higher hospital mortality (65% vs. 58%, p = .12). After propensity-score adjustment, noninvasive mechanical ventilation was associated with significantly lower mortality than invasive mechanical ventilation. LIMITATIONS:: The population could not be stratified according to specific hematologic diagnoses. Furthermore, the study was observational, and treatment groups may have included unaccounted for differences in covariates although the risk of this bias was minimized with propensity score regression adjustment. Conclusions: In patients with hematologic malignancies, acute respiratory failure should probably be managed initially with noninvasive mechanical ventilation. Further study is needed to determine whether immediate invasive mechanical ventilation might offer some benefits for those with acute lung injury/adult respiratory distress syndrome. © 2011 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins.


Iacucci M.,San Camillo Forlanini Hospital
Therapeutic Advances in Gastroenterology | Year: 2011

The focus of effective management of inflammatory bowel disease, especially Crohn's disease, has shifted from short-term symptom control to long-term modification of disease course and complications. Intestinal healing has achieved prominence as a goal of therapy that influences long-term disease course. We review the natural history of inflammatory bowel disease, the markers of disease control that may reflect outcomes and the specific role of mucosal healing. We may aim at better mucosal healing by appropriate choice of therapy, appropriate combinations of therapy and intervening early in the disease course. © The Author(s), 2011.

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