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Cremolini C.,University of Pisa | Loupakis F.,University of Pisa | Antoniotti C.,University of Pisa | Lupi C.,University of Pisa | And 16 more authors.
The Lancet Oncology | Year: 2015

Background: In the TRIBE study, FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) plus bevacizumab significantly improved progression-free survival of patients with metastatic colorectal cancer compared with FOLFIRI (fluorouracil, leucovorin, and irinotecan) plus bevacizumab. In this updated analysis, we aimed to provide mature results for overall survival-a secondary endpoint-and report treatment efficacy in RAS and BRAF molecular subgroups. Methods: TRIBE was an open-label, multicentre, phase 3 randomised study of patients (aged 18-70 years with Eastern Cooperative Oncology Group [ECOG] performance status of 2 or less and aged 71-75 years with an ECOG performance status of 0) with unresectable metastatic colorectal cancer who were recruited from 34 Italian oncology units. Patients were randomly assigned (1:1) via a web-based procedure to receive FOLFIRI plus bevacizumab or FOLFOXIRI plus bevacizumab. Bevacizumab was given as a 5 mg/kg intravenous dose. FOLFIRI consisted of a 180 mg/m2 intravenous infusion of irinotecan for 60 min followed by a 200 mg/m2 intravenous infusion of leucovorin for 120 min, a 400 mg/m2 intravenous bolus of fluorouracil, and a 2400 mg/m2 continuous infusion of fluorouracil for 46 h. FOLFOXIRI consisted of a 165 mg/m2 intravenous infusion of irinotecan for 60 min, followed by an 85 mg/m2 intravenous infusion of oxaliplatin given concurrently with 200 mg/m2 leucovorin for 120 min, followed by a 3200 mg/m2 continuous infusion of fluorouracil for 48 h. Tissue samples for RAS and BRAF mutational status analyses were centrally collected. In this updated analysis, we assessed the secondary endpoint of overall survival in the main cohort and treatment efficacy in RAS and BRAF molecular subgroups. All analyses were by intention to treat. TRIBE was concluded on Nov 30, 2014. The trial is registered with ClinicalTrials.gov, number NCT00719797. Findings: Between July 17, 2008, and May 31, 2011, 508 patients were randomly assigned. At a median follow-up of 48·1 months (IQR 41·7-55·6), median overall survival was 29·8 months (95% CI 26·0-34·3) in the FOLFOXIRI plus bevacizumab group compared with 25·8 months (22·5-29·1) in the FOLFIRI plus bevacizumab group (hazard ratio [HR] 0·80, 95% CI 0·65-0·98; p=0·03). Median overall survival was 37·1 months (95% CI 29·7-42·7) in the RAS and BRAF wild-type subgroup compared with 25·6 months (22·4-28·6) in the RAS-mutation-positive subgroup (HR 1·49, 95% CI 1·11-1·99) and 13·4 months (8·2-24·1) in the BRAF-mutation-positive subgroup (HR 2·79, 95% CI 1·75-4·46; likelihood-ratio test p<0·0001). Treatment effect was not significantly different across molecular subgroups (pinteraction=0·52). Interpretation: FOLFOXIRI plus bevacizumab is a feasible treatment option for those patients who meet the inclusion criteria of the present study, irrespective of baseline clinical characteristics and RAS or BRAF mutational status. Funding: GONO (Gruppo Oncologico del Nord Ovest) Cooperative Group and ARCO Foundation. © 2015 Elsevier Ltd.


Angelucci E.,Hematology | Matthes-Martin S.,Medical University of Vienna | Baronciani D.,Ospedale Oncologico di Riferimento Regionale Armando Businco | Bonanomi S.,Hospital San Gerardo | And 19 more authors.
Haematologica | Year: 2014

Thalassemia major and sickle cell disease are the two most widely disseminated hereditary hemoglobinopathies in the world. The outlook for affected individuals has improved in recent years due to advances in medical management in the prevention and treatment of complications. However, hematopoietic stem cell transplantation is still the only available curative option. The use of hematopoietic stem cell transplantation has been increasing, and outcomes today have substantially improved compared with the past three decades. Current experience world-wide is that more than 90% of patients now survive hematopoietic stem cell transplantation and disease-free survival is around 80%. However, only a few controlled trials have been reported, and decisions on patient selection for hematopoietic stem cell transplantation and transplant management remain principally dependent on data from retrospective analyses and on the clinical experience of the transplant centers. This consensus document from the European Blood and Marrow Transplantation Inborn Error Working Party and the Paediatric Diseases Working Party aims to report new data and provide consensus-based recommendations on indications for hematopoietic stem cell transplantation and transplant management. © 2014 by the Ferrata Storti Foundation.


PubMed | Galliera Hospital, Hospital of Cremona, University of Genoa, Oncology Institute IRCCS Veneto and 10 more.
Type: Clinical Trial, Phase III | Journal: The Lancet. Oncology | Year: 2015

In the TRIBE study, FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) plus bevacizumab significantly improved progression-free survival of patients with metastatic colorectal cancer compared with FOLFIRI (fluorouracil, leucovorin, and irinotecan) plus bevacizumab. In this updated analysis, we aimed to provide mature results for overall survival-a secondary endpoint-and report treatment efficacy in RAS and BRAF molecular subgroups.TRIBE was an open-label, multicentre, phase 3 randomised study of patients (aged 18-70 years with Eastern Cooperative Oncology Group [ECOG] performance status of 2 or less and aged 71-75 years with an ECOG performance status of 0) with unresectable metastatic colorectal cancer who were recruited from 34 Italian oncology units. Patients were randomly assigned (1:1) via a web-based procedure to receive FOLFIRI plus bevacizumab or FOLFOXIRI plus bevacizumab. Bevacizumab was given as a 5 mg/kg intravenous dose. FOLFIRI consisted of a 180 mg/m(2) intravenous infusion of irinotecan for 60 min followed by a 200 mg/m(2) intravenous infusion of leucovorin for 120 min, a 400 mg/m(2) intravenous bolus of fluorouracil, and a 2400 mg/m(2) continuous infusion of fluorouracil for 46 h. FOLFOXIRI consisted of a 165 mg/m(2) intravenous infusion of irinotecan for 60 min, followed by an 85 mg/m(2) intravenous infusion of oxaliplatin given concurrently with 200 mg/m(2) leucovorin for 120 min, followed by a 3200 mg/m(2) continuous infusion of fluorouracil for 48 h. Tissue samples for RAS and BRAF mutational status analyses were centrally collected. In this updated analysis, we assessed the secondary endpoint of overall survival in the main cohort and treatment efficacy in RAS and BRAF molecular subgroups. All analyses were by intention to treat. TRIBE was concluded on Nov 30, 2014. The trial is registered with ClinicalTrials.gov, number NCT00719797.Between July 17, 2008, and May 31, 2011, 508 patients were randomly assigned. At a median follow-up of 481 months (IQR 417-556), median overall survival was 298 months (95% CI 260-343) in the FOLFOXIRI plus bevacizumab group compared with 258 months (225-291) in the FOLFIRI plus bevacizumab group (hazard ratio [HR] 080, 95% CI 065-098; p=003). Median overall survival was 371 months (95% CI 297-427) in the RAS and BRAF wild-type subgroup compared with 256 months (224-286) in the RAS-mutation-positive subgroup (HR 149, 95% CI 111-199) and 134 months (82-241) in the BRAF-mutation-positive subgroup (HR 279, 95% CI 175-446; likelihood-ratio test p<00001). Treatment effect was not significantly different across molecular subgroups (pinteraction=052).FOLFOXIRI plus bevacizumab is a feasible treatment option for those patients who meet the inclusion criteria of the present study, irrespective of baseline clinical characteristics and RAS or BRAF mutational status.


Papaemmanuil E.,Wellcome Trust Sanger Institute | Rapado I.,Hospital Universitario 12 Of Octubre | Li Y.,Wellcome Trust Sanger Institute | Potter N.E.,Institute for Cancer Research | And 36 more authors.
Nature Genetics | Year: 2014

The ETV6-RUNX1 fusion gene, found in 25% of childhood acute lymphoblastic leukemia (ALL) cases, is acquired in utero but requires additional somatic mutations for overt leukemia. We used exome and low-coverage whole-genome sequencing to characterize secondary events associated with leukemic transformation. RAG-mediated deletions emerge as the dominant mutational process, characterized by recombination signal sequence motifs near breakpoints, incorporation of non-templated sequence at junctions, ∼30-fold enrichment at promoters and enhancers of genes actively transcribed in B cell development and an unexpectedly high ratio of recurrent to non-recurrent structural variants. Single-cell tracking shows that this mechanism is active throughout leukemic evolution, with evidence of localized clustering and reiterated deletions. Integration of data on point mutations and rearrangements identifies ATF7IP and MGA as two new tumor-suppressor genes in ALL. Thus, a remarkably parsimonious mutational process transforms ETV6-RUNX1-positive lymphoblasts, targeting the promoters, enhancers and first exons of genes that normally regulate B cell differentiation. © 2014 Nature America, Inc.


Luetz A.,Charité - Medical University of Berlin | Balzer F.,Charité - Medical University of Berlin | Radtke F.M.,Charité - Medical University of Berlin | Jones C.,Whiston Hospital | And 5 more authors.
PLoS ONE | Year: 2014

Analgesia, sedation and delirium management are important parts of intensive care treatment as they are relevant for patients' clinical and functional long-term outcome. Previous surveys showed that despite this fact implementation rates are still low. The primary aim of the prospective, observational multicenter study was to investigate the implementation rate of delirium monitoring among intensivists. Secondly, current practice concerning analgesia and sedation monitoring as well as treatment strategies for patients with delirium were assesed. In addition, this study compares perceived and actual practice regarding delirium, sedation and analgesia management. Data were obtained with a two-part, anonymous survey, containing general data from intensive care units in a first part and data referring to individual patients in a second part. Questionnaires from 101 hospitals (part 1) and 868 patients (part 2) were included in data analysis. Fifty-six percent of the intensive care units reported to monitor for delirium in clinical routine. Fourty-four percent reported the use of a validated delirium score. In this respect, the survey suggests an increasing use of delirium assessment tools compared to previous surveys. Nevertheless, part two of the survey revealed that in actual practice 73% of included patients were not monitored with a validated score. Furthermore, we observed a trend towards moderate or deep sedation which is contradicting to guideline-recommendations. Every fifth patient was suffering from pain. The implementation rate of adequate painassessment tools for mechanically ventilated and sedated patients was low (30%). In conclusion, further efforts are necessary to implement guideline recommendations into clinical practice. The study was registered (ClinicalTrials.gov identifier: NCT01278524) and approved by the ethical committee. Copyright: © 2014 Luetz et al.


PubMed | Hospital San Gerardo, Hopitaux Universitaires Of Geneva, Whiston Hospital, Charité - Medical University of Berlin and Sostana GmbH
Type: Journal Article | Journal: PloS one | Year: 2014

Analgesia, sedation and delirium management are important parts of intensive care treatment as they are relevant for patients clinical and functional long-term outcome. Previous surveys showed that despite this fact implementation rates are still low. The primary aim of the prospective, observational multicenter study was to investigate the implementation rate of delirium monitoring among intensivists. Secondly, current practice concerning analgesia and sedation monitoring as well as treatment strategies for patients with delirium were assesed. In addition, this study compares perceived and actual practice regarding delirium, sedation and analgesia management. Data were obtained with a two-part, anonymous survey, containing general data from intensive care units in a first part and data referring to individual patients in a second part. Questionnaires from 101 hospitals (part 1) and 868 patients (part 2) were included in data analysis. Fifty-six percent of the intensive care units reported to monitor for delirium in clinical routine. Fourty-four percent reported the use of a validated delirium score. In this respect, the survey suggests an increasing use of delirium assessment tools compared to previous surveys. Nevertheless, part two of the survey revealed that in actual practice 73% of included patients were not monitored with a validated score. Furthermore, we observed a trend towards moderate or deep sedation which is contradicting to guideline-recommendations. Every fifth patient was suffering from pain. The implementation rate of adequate pain-assessment tools for mechanically ventilated and sedated patients was low (30%). In conclusion, further efforts are necessary to implement guideline recommendations into clinical practice. The study was registered (ClinicalTrials.gov identifier: NCT01278524) and approved by the ethical committee.


PubMed | Hospital San Gerardo, Italian National Cancer Institute, University of Verona, Arcispedale S.Maria Nuova and 5 more.
Type: | Journal: Computational and mathematical methods in medicine | Year: 2015

The aim of this work was to assess robustness and reliability of an adaptive thresholding algorithm for the biological target volume estimation incorporating reconstruction parameters.In a multicenter study, a phantom with spheres of different diameters (6.5-57.4 mm) was filled with (18)F-FDG at different target-to-background ratios (TBR: 2.5-70) and scanned for different acquisition periods (2-5 min). Image reconstruction algorithms were used varying number of iterations and postreconstruction transaxial smoothing. Optimal thresholds (TS) for volume estimation were determined as percentage of the maximum intensity in the cross section area of the spheres. Multiple regression techniques were used to identify relevant predictors of TS.The goodness of the model fit was high (R(2): 0.74-0.92). TBR was the most significant predictor of TS. For all scanners, except the Gemini scanners, FWHM was an independent predictor of TS. Significant differences were observed between scanners of different models, but not between different scanners of the same model. The shrinkage on cross validation was small and indicative of excellent reliability of model estimation.Incorporation of postreconstruction filtering FWHM in an adaptive thresholding algorithm for the BTV estimation allows obtaining a robust and reliable method to be applied to a variety of different scanners, without scanner-specific individual calibration.


Nicelli E.,San Raffaele Scientific Institute | Gemma M.,San Raffaele Scientific Institute | De Vitis A.,San Raffaele Scientific Institute | Foti G.,Hospital San Gerardo | Beretta L.,San Raffaele Scientific Institute
Head and Neck | Year: 2010

Background. No technique can be considered as a gold standard for ventilation during direct laser CO2 laryngeal microsurgery. We evaluated the feasibility of standard ventilation with laser-safe endotracheal tubes (ETTs) and inspired O2 fraction (FiO2) = 0.21 during direct microlaryngoscopy. Methods. During total intravenous anesthesia, standard mechanical normoventilation was set with FiO2 = 0.21 and 50 mm Hg peak inspiratory pressure limit. If SpO2 was <90% for >2 minutes, FiO2 was increased to 0.3; after 4 minutes it was increased to 0.4; after another 4 minutes, positive endexpiratory pressure (PEEP) could be set at 5 cm H2O; and after another 4 minutes, surgery was stopped if SpO2 remained <90%. Results. We studied 111 consecutive direct microlaryngoscopies on different patients. Four patients (3.6%) suffered minor intraoperative desaturation. Barotrauma was not observed, PEEP was never applied, and surgery was never stopped. Body mass index was independently predictive of the occurrence of intraoperative desaturation. Conclusions. Standard mechanical ventilation with FiO2 = 0.21 through laser-safe ETTs is feasible during direct microlaryngoscopy. © 2009 Wiley Periodicals, Inc.


Giovacchini G.,University of Milan Bicocca | Picchio M.,San Raffaele Scientific Institute | Coradeschi E.,University of Milan Bicocca | Bettinardi V.,San Raffaele Scientific Institute | And 10 more authors.
European Journal of Nuclear Medicine and Molecular Imaging | Year: 2010

Purpose: Detection of recurrence in prostate cancer patients with biochemical failure after radical prostatectomy by [11C]choline PET/CT depends on the prostate-specific antigen (PSA) level. The role of other clinical and pathological variables has not been explored. Methods: A total of 2,124 prostate cancer patients referred to our Institution for [ 11C]choline PET/CT from December 2004 to January 2007 for restaging of disease were retrospectively considered for this study. Inclusion criteria were: previous treatment by radical prostatectomy, and biochemical failure, defined as at least two consecutive PSA measurements of >0.2 ng/ml. These criteria were met for 358 patients. Binary logistic analysis was used to investigate the predictive factors of [11C]choline PET/CT. PET/CT findings were validated using criteria based on histological analysis, and follow-up clinical and imaging data. Receiver operating characteristic (ROC) analysis was used to assess the performance of [11C]choline PET/CT in relation to PSA levels. Results: The mean PSA level was 3.77±6.94 ng/ml (range 0.23-45 ng/ml; median 1.27 ng/ml). PET/CT was positive for recurrence in 161 of 358 patients (45%). On an anatomical region basis, [11C] choline pathological uptake was observed in lymph nodes (107/161 patients, 66%), prostatectomy bed (55/161 patients, 34%), and in the skeleton (46/161 patients, 29%). PET/CT findings were validated using histological criteria (46/358, 13%), and follow-up clinical and imaging criteria (312/358, 87%). Sensitivity, specificity, positive predictive value, negative predictive value, and overall accuracy were, respectively, 85%, 93%, 91%, 87%, and 89%. In multivariate analysis, high PSA levels, advanced pathological stage, previous biochemical failure and older age were significantly (P<0.05) associated with an increased risk of positive PET/CT findings. The percentage of positive scans was 19% in those with a PSA level between 0.2 and 1 ng/ml, 46% in those with a PSA level between 1 and 3 ng/ml, and 82% in those with a PSA level higher than 3 ng/ml. ROC analysis showed that PET/CT-positive and PET/CT-negative patients could be best distinguished using a PSA cut-off value of 1.4 ng/ml. Conclusions: In addition to PSA levels, pathological stage, previous biochemical failure and age should be considered by physicians when referring prostate cancer patients with biochemical failure after radical prostatectomy to [11C]choline PET/CT. © 2009 Springer-Verlag.

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