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OBJECTIVE Recipients of allogeneic hematopoietic stem cell transplantation (allo-HCT) with positive cytomegalovirus (CMV) serology are at increased risk of morbidity and mortality. The primary objective of this study was to assess the association between treated CMV infection and overall mortality within 1 year after allo-HCT in adult CMV-seropositive Recipients (R+). Secondary objectives included overall 5-year mortality after allo-HCT, risk factors for treated CMV infection, associations between treated CMV infection and allo-HCT complications and medical costs. METHODS A multicenter retrospective cohort study was conducted in adult CMV-seropositive recipients (R+) who underwent to allo-HCT between 1st January 2010 and 31st December 2014. RESULTS Five hundred seventy two CMV-seropositive patients (mean age, 50.2 years) undergoing allo-HCT between 2010 and 2014 were included; 55.9% of donors were CMV seropositive. CMV infection treated with antiviral therapy was reported in 227 patients (39.7%) after transplantation. One-year overall mortality was significantly increased in patients with treated CMV infections (hazard ratio, 1.86; 95% CI, 1.16-3.00; P = .011). Mean medical costs during the first post-HCT year were higher in patients with CMV infection (€46 853 vs €31 318; P

Aims Although left ventricular assist devices (LVADs) are currently approved for coverage and reimbursement in France, no French cost-effectiveness (CE) data are available to support this decision. This study aimed at estimating the CE of LVAD compared with medical management in the French health system. Methods and results Individual patient data from the ‘French hospital discharge database’ (Medicalization of information systems program) were analysed using Kaplan–Meier method. Outcomes were time to death, time to heart transplantation (HTx), and time to death after HTx. A micro-costing method was used to calculate the monthly costs extracted from the Program for the Medicalization of Information Systems. A multistate Markov monthly cycle model was developed to assess CE. The analysis over a lifetime horizon was performed from the perspective of the French healthcare payer; discount rates were 4%. Probabilistic and deterministic sensitivity analyses were performed. Outcomes were quality-adjusted life years (QALYs) and incremental CE ratio (ICER). Mean QALY for an LVAD patient was 1.5 at a lifetime cost of €190 739, delivering a probabilistic ICER of €125 580/QALY [95% confidence interval: 105 587 to 150 314]. The sensitivity analysis showed that the ICER was mainly sensitive to two factors: (i) the high acquisition cost of the device and (ii) the device performance in terms of patient survival. Conclusions Our economic evaluation showed that the use of LVAD in patients with end-stage heart failure yields greater benefit in terms of survival than medical management at an extra lifetime cost exceeding the €100 000/QALY. Technological advances and device costs reduction shall hence lead to an improvement in overall CE.

6573 Background: The standard of care non-surgical approach for locally advanced head and neck squamous cell carcinoma (LA HNSCC) patients (pts) is concurrent chemoradiation with high dose cisplatin or cetuximab in case of contra-indication. Older age is a contra-indication to cisplatin, and cetuximab might not improve survival in older pts. It is therefore urgently needed to develop new treatment options for elderly pts with LA HNSCC. NBTXR3 are hafnium oxide nanoparticles that can enhance the efficacy of radiotherapy (RT) by increasing locally the deposited dose. In this phase I clinical trial we aimed to evaluate the feasibility and safety of NBTXR3 administered as intratumoral (IT) injection prior to RT in LA HNSCC elderly pts. Methods: Pts with stage III-IV LA HNSCC of the oropharynx or oral cavity ineligible for platinum-based chemoradiation received a single IT injection of NBTXR3 into a selected primary tumor and intensity modulated RT (IMRT; 70 Gy/35 fractions/7 weeks) [NCT01946867]. A 3+3 dose escalation design, tested NBTXR3 dose levels equivalent to 5, 10, 15, and 22% of baseline tumor volume, followed by a dose expansion at the Recommended Phase II Dose (RP2D). Primary endpoints included RP2D determination, and early dose limiting toxicities (DLT). NBTXR3 intratumoral bioavailability and anti-tumor activity (RECIST 1.1) were also evaluated. Results: Enrollment was completed at all dose escalation levels: 5% (3 pts), 10% (3 pts), 15% (5 pts), and 22% (8 pts). No early DLT or SAE related to NBTXR3 or injection were observed. The median follow-up from NBTXR3 administration is 7.6 months. One AE (Grade 1) related to NBTXR3 and four AEs (Grade 1-2) related to the injection were observed. RT-related toxicity was as expected with IMRT. CT-scan assessment showed a good dispersion of NBTXR3 throughout the injected tumor and not in surrounding healthy tissues. The RP2D was determined to be 22%. Preliminary efficacy was evaluated in pts who received the intended dose of NBTXR3 and RT. A complete response of the injected lesion was observed in 9/13 (69%) evaluable pts at doses ≥10% (2 unconfirmed) and an overall complete response in 5/13 (38%) evaluable pts at doses ≥10%. Preliminary safety and efficacy data of the dose expansion cohort at the RP2D will also be presented. Conclusions: NBTXR3 activated by RT was well tolerated at all tested doses and demonstrated promising preliminary anti-tumor activity. Recruitment is ongoing in the dose expansion cohort. These results demonstrate that further testing of NBTXR3 in this population is warranted. Clinical trial information: NCT01946867 .

Recipients of allogeneic hematopoietic stem cell transplant (HSCT) who have positive cytomegalovirus (CMV) serology are at increased risk for morbidity and mortality after HSCT. However, the exact correlation between early CMV infection and post-HSCT outcomes, notably relapse, is still a source of conflicting data, especially in the era of viral surveillance through polymerase chain reaction (PCR) and preemptive antiviral therapy. We thus decided to retrospectively investigate the clinical impact of early, post-HSCT CMV infection/disease, in a large multi-center cohort of French patients. All consecutive CMV-seropositive adults (≥ 18 years old) who received a first HSCT in 3 French centers between January 1st 2010 and December 31th 2014 were eligible. Cord blood transplantation or a second HSCT were not considered here, as these procedures are associated with a significantly higher risk of morbidity and mortality. Study data were primarily derived from existing electronic health records. The study was conducted in accordance with the Declaration of Helsinki. CMV infection/disease was defined by the initiation of a preemptive and/or a curative anti-CMV treatment in the presence of a CMV viremia detected by a quantitative PCR. The primary objective of this study was to assess the association between CMV infection/disease and overall mortality within the first-year post-transplantation. Secondary clinical endpoints addressed the association between CMV infection/disease and the following outcomes within the first-year of HSCT: graft failure, relapse of the underlying disease, non-relapse mortality (NRM), incidence of acute and chronic graft-versus-host disease (GvHD), and the occurrence of infections other than CMV. Relapse was considered as a competing risk for non-relapse mortality, and death for other events of interest (relapse, incidence of acute and chronic GvHD, and occurrence of infections). Models were adjusted for disease type, disease status at HSCT, age at HSCT, sex, donor type, stem cell source, and conditioning regimen (MAC versus RIC, use of total body irradiation or anti-thymocyte globulin). Five hundred seventy-two patients (54.5% male, 71.2% with Karnofsky >90, and median age 54 years) met the inclusion criteria. Underlying diseases were acute leukemia (33.9%), lymphoid neoplasms (25.9%), and myelodysplastic/ myeloproliferative neoplasms (22.6%). The disease was generally in complete remission at the time of HSCT (56.5%) or stable at the time of HSCT (16.4%). The majority of patients had received a reduced intensity conditioning regimen HSCT (72.5%), and peripheral blood stem cells (71.3%). Donor type was as follows: HLA-matched unrelated donor, 34.1%; HLA-matched relative donor, 46.5%; mismatched unrelated donor, 16.3% and mismatched related donor, 3.10%. CMV infection/disease was observed in 227 patients (39.7%) at a median time of 39.5 days (range, 3-295 days) post-transplant. Overall survival rate as per Kaplan-Meier analysis was 70.9% at 1-year post-HSCT. After adjusting for significant risk factors and considering CMV infection/disease as a time-dependent variable in a Cox model, overall mortality at 1-year was significantly increased in patients developing CMV infection/disease (HR 1.86, [95%CI 1.16 - 3.00], p=0.011). The Fine and Gray competing risk model showed that CMV infection/disease during the first-year post-transplant was significantly associated with higher risk of infections other than CMV (HR 2.34, 95%CI [1.63 - 3.37], p In this large cohort of 572 consecutive CMV-seropositive adults undergoing allo-HSCT, and who were monitored with a PCR-based strategy according to routine clinical practice, we identified that CMV infection/disease were significantly associated with an increased risk of 1-year overall and non-relapse mortality, related to higher rates of infections other than CMV. Therefore, post-HSCT CMV infection/disease seemed to be a major concern in the recent healthcare setting, affecting mortality and morbidity. Disclosures Peffault De Latour: Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Amgen Inc.: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pfizer Inc.: Consultancy, Honoraria, Research Funding. Clement:MSD: Employment. Allavoine:MSD: Employment. Tadmouri:ClinSearch: Employment. Blomkvist:ClinSearch: Employment.

Rhodiola rosea (roseroot) extract is a commercially successful product, primarily used to reduce the effect of fatigue on physical and mental performance. In this perspective we present our investigation of the most recent studies performed on human subjects. With a focus on the statistical methods we found considerable shortcomings in all but one of the studies that claim significant improvement from roseroot extract. Overall, the study designs have not been well explained. Experimental results have been confused and appear to be in some cases incorrect. Some of the conclusions are based on selected results and contradicting data have not been adequately taken into account. We point to other studies of higher quality performed on roseroot, several that found no significant effect and one that did. We conclude that the currently available evidence for the claimed effects is insufficient and that the effect of Rhodiola rosea is in need of further investigation before therapeutic claims can be made.

International audience; OBJECTIVEThe purpose of this study was to systematically review the research on volume and outcome relationships in critical care.METHODSFrom January 1, 2001, to April 30, 2014, MEDLINE and EMBASE were searched for studies assessing the relationship between admission volume and clinical outcomes in critical illness. Bibliographies were reviewed to identify other articles of interest, and experts were contacted about missing or unpublished studies. Of 127 studies reviewed, 46 met inclusion criteria, covering seven clinical conditions. Two investigators independently reviewed each article using a standardized form to abstract information on key study characteristics and results.RESULTSOverall, 29 of the studies (63%) reported a statistically significant association between higher admission volume and improved outcomes. The magnitude of the association (mortality OR between the lowest vs highest stratum of volume centers), as well as the thresholds used to characterize high volume, varied across clinical conditions. Critically ill patients with cardiovascular (n = 7, OR = 1.49 [1.11-2.00]), respiratory (n = 12, OR = 1.20 [1.04-1.38]), severe sepsis (n = 4, OR = 1.17 [1.03-1.33]), hepato-GI (n = 3, OR = 1.30 [1.08-1.78]), neurologic (n = 3, OR = 1.38 [1.22-1.57]), and postoperative admission diagnoses (n = 3, OR = 2.95 [1.05-8.30]) were more likely to benefit from admission to higher-volume centers compared with lower-volume centers. Studies that controlled for ICU or hospital organizational factors were less likely to find a significant volume-outcome relationship than studies that did not control for these factors.CONCLUSIONSCritically ill patients generally benefit from care in high-volume centers, with more substantial benefits in selected high-risk conditions. This relationship may in part be mediated by specific ICU and hospital organizational factors.Volume-outcome relationships are well established in many surgical conditions and high-risk procedures in health care.1 Under these relationships, higher numbers of procedures are thought to lead to better patient outcomes through the development of procedural skill.2 Such observations lend conceptual support to the development of regionalized systems of surgical care, in which patients are selectively referred to high-volume providers.3 Selective referral has substantially improved the quality of care for patients in need of these planned high-risk procedures, with improved outcomes over time due in large part to concentration of care.2Given the current shortage of ICU physicians and the overall complexity of critical illness, critical care is also an attractive target for regionalization. However, unlike in many surgical conditions, the volume-outcome relationship in critical illness is still incompletely characterized.4 In the absence of a well-defined volume-outcome relationship, regionalization of critical care may increase costs while delaying definitive therapy for extremely sick patients in need of rapid diagnosis and treatment. Moreover, regionalization is only one potential strategy for region-wide organization of critical care.5 Without a greater understanding of the mechanism of the volume-outcome relationship, which may in part be determined by organizational factors that are correlated with volume, we may miss out on opportunities to improve outcomes for small-volume providers without large-scale reorganization of care.The goal of this study was to perform a systematic review of literature to assess the volume-outcome relationship among critically ill adult patients. In addition to providing summary information, we sought to understand organizational factors that may be potential mechanisms for this effect by analyzing the differences between positive and negative studies.

The purpose of this study was to systematically review the research on volume and outcome relationships in critical care.From January 1, 2001, to April 30, 2014, MEDLINE and EMBASE were searched for studies assessing the relationship between admission volume and clinical outcomes in critical illness. Bibliographies were reviewed to identify other articles of interest, and experts were contacted about missing or unpublished studies. Of 127 studies reviewed, 46 met inclusion criteria, covering seven clinical conditions. Two investigators independently reviewed each article using a standardized form to abstract information on key study characteristics and results.Overall, 29 of the studies (63%) reported a statistically significant association between higher admission volume and improved outcomes. The magnitude of the association (mortality OR between the lowest vs highest stratum of volume centers), as well as the thresholds used to characterize high volume, varied across clinical conditions. Critically ill patients with cardiovascular (n = 7, OR = 1.49 [1.11-2.00]), respiratory (n = 12, OR = 1.20 [1.04-1.38]), severe sepsis (n = 4, OR = 1.17 [1.03-1.33]), hepato-GI (n = 3, OR = 1.30 [1.08-1.78]), neurologic (n = 3, OR = 1.38 [1.22-1.57]), and postoperative admission diagnoses (n = 3, OR = 2.95 [1.05-8.30]) were more likely to benefit from admission to higher-volume centers compared with lower-volume centers. Studies that controlled for ICU or hospital organizational factors were less likely to find a significant volume-outcome relationship than studies that did not control for these factors.Critically ill patients generally benefit from care in high-volume centers, with more substantial benefits in selected high-risk conditions. This relationship may in part be mediated by specific ICU and hospital organizational factors.

International audience; Background:Periodontal infections are hypothesized to increase the risk of adverse systemic outcomes through inflammatory mechanisms. The magnitude of effect, if any, of anti-infective periodontal treatment on systemic inflammation is unknown, as are the patient populations most likely to benefit. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to test the hypothesis that anti-infective periodontal treatment reduces systemic c-reactive protein (CRP).Methods and Findings:MEDLINE, EMBASE, CENTRAL and CINAHL databases were searched using sensitivity-enhancing search terms. Eligible RCTs enrolled patients with periodontal infection, compared a clearly defined anti-infective periodontal intervention (experimental group) to an "inactive control" (no periodontal intervention) or to an "active control" (lower treatment intensity than the experimental group). Mean differences in final CRP values at the earliest post-treatment time point (typically 1-3 months) between experimental and control groups were analyzed using random-effects regression. Among 2,753 possible studies 20 were selected, which included 2,561 randomized patients(median=57). Baseline CRP values were >3.0 mg/L in 40% of trials. Among studies with a control group receiving no treatment, the mean difference in CRP final values among experimental treatment vs. control groups was -0.37 mg/L [95%CI=-0.64, -0.11], (P=0.005), favoring experimental treatment. Trials for which the experimental group received antibiotics had stronger effects (P for interaction=0.03) and the mean difference in CRP final values among experimental treatment vs. control was -0.75 mg/L [95%CI=-1.17,-0.33]. No treatment effect was observed among studies using an active treatment comparator. Treatment effects were stronger for studies that included patients with co-morbidities vs. studies that included "systemically healthy" patients, although the interaction was not significant (P=0.48).Conclusions:Anti-infective periodontal treatment results in short-term modest reductions in systemic CRP. © 2013 Demmer et al.