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Abstract Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, which is caused by mutations of the NOTCH3 gene, has a large heterogeneous progression, presenting with declines of various clinical scores and occurrences of various clinical event. To help assess disease progression, this work focused on predicting the composite endpoint of stroke-free survival time by comparing the performance of Cox proportional hazards regression to that of machine learning models using one of four feature selection approaches applied to demographic, clinical and magnetic resonance imaging observational data collected from a study cohort of 482 patients. The quality of the modeling process and the predictive performance were evaluated in a nested cross-validation procedure using the time-dependent Brier Score and AUC at 5 years from baseline, the former measuring the overall performance including calibration and the latter highlighting the discrimination ability, with both metrics taking into account the presence of right-censoring. The best model for each metric was the componentwise gradient boosting model with a mean Brier score of 0.165 and the random survival forest model with a mean AUC of 0.773, both combined with the LASSO feature selection method.

Abstract Background Looking for treatment-by-subset interaction on a right-censored outcome based on observational data using propensity-score (PS) modeling is of interest. However, there are still issues regarding its implementation, notably when the subsets are very imbalanced in terms of prognostic features and treatment prevalence. Methods We conducted a simulation study to compare two main PS estimation strategies, performed either once on the whole sample (“across subset”) or in each subset separately (“within subsets”). Several PS models and estimands are also investigated. We then illustrated those approaches on the motivating example, namely, evaluating the benefits of facial nerve resection in patients with parotid cancer in contact with the nerve, according to pretreatment facial palsy. Results Our simulation study demonstrated that both strategies provide close results in terms of bias and variance of the estimated treatment effect, with a slight advantage for the “across subsets” strategy in very small samples, provided that interaction terms between the subset variable and other covariates influencing the choice of treatment are incorporated. PS matching without replacement resulted in biased estimates and should be avoided in the case of very imbalanced subsets. Conclusions When assessing heterogeneity in the treatment effect in small samples, the “across subsets” strategy of PS estimation is preferred. Then, either a PS matching with replacement or a weighting method must be used to estimate the average treatment effect in the treated or in the overlap population. In contrast, PS matching without replacement should be avoided in this setting.

Abstract Background The respective benefits of high and low doses of dexamethasone (DXM) in patients with severe acute respiratory syndrome coronavirus 2 (SARS-Cov2) and acute respiratory failure (ARF) are controversial, with two large triple-blind RCTs reaching very important difference in the effect-size. In the COVIDICUS trial, no evidence of additional benefit of high-dose dexamethasone (DXM20) was found. We aimed to explore whether some specific patient phenotypes could benefit from DXM20 compared to the standard of care 6 mg dose of DXM (DXMSoC). Methods We performed a post hoc exploratory Bayesian analysis of 473 patients who received either DXMSoc or DXM20 in the COVIDICUS trial. The outcome was the 60 day mortality rate of DXM20 over DXMSoC, with treatment effect measured on the hazard ratio (HR) estimated from Cox model. Bayesian analyses allowed to compute the posterior probability of a more than trivial benefit (HR 1.05). Bayesian measures of interaction then quantified the probability of interaction (Pr Interact) that the HR of death differed across the subsets by 20%. Primary analyses used noninformative priors, centred on HR = 1.00. Sensitivity analyses used sceptical and enthusiastic priors, based on null (HR = 1.00) or benefit (HR = 0.95) effects. Results Overall, the posterior probability of a more than trivial benefit and potential harm was 29.0 and 51.1%, respectively. There was some evidence of treatment by subset interaction (i) according to age (Pr Interact, 84%), with a 86.5% probability of benefit in patients aged below 70 compared to 22% in those aged above 70; (ii) according to the time since symptoms onset (Pr Interact, 99%), with a 99.9% probability of a more than trivial benefit when lower than 7 days compared to a

Introduction: COVID-19 disease presentation is heterogeneous, from asymptomatic up to severe life-threatening forms. Getting further insights into patients with specific diseases is of particular interest. We aimed to identify profiles of hematology patients hospitalized with COVID-19 that would be associated with survival and to assess the differences between cohorts Methods: A binational cohort of 263 patients with COVID-19 and hematological disease was studied in Paris, France and São Paulo, Brazil. Patient profiles were based on age, comorbidities, biological measurements, COVID-19 symptoms and hematological disease characteristics. A semi-supervised learning method with a survival endpoint was first used, following which, a classifier was identified to allow the classification of patients using only baseline information Main results: Two profiles of patients were identified, one being young patients with few comorbidities and low C-reactive protein (CRP), D-dimers, lactate dehydrogenase (LDH) and creatinine levels, and the other, older patients, with several comorbidities and high levels of the 4 biology markers. The profiles were strongly associated with survival (p < 0.0001), even after adjusting for age (p = 0.0002). The 30-day survival rate was 77.1% in the first profiles, versus 46.7% in the second. The Brazilian analysis emphasized the importance of age, while the French focused on the comorbidities Conclusion: This analysis showed the importance of CRP, LHD and creatinine in the COVID-19 presentation and prognosis, whatever the geographic origin of the patients.

Juvenile myelomonocytic leukemia (JMML) is an aggressive pediatric myeloproliferative neoplasm requiring hematopoietic stem cell transplantation (HSCT) in most cases. We retrospectively analyzed 119 JMML patients who underwent first allogeneic HSCT between 2002 and 2021. The majority (97%) carried a RAS-pathway mutation, and 62% exhibited karyotypic alterations or additional mutations in SETBP1, ASXL1, JAK3 and/or the RAS pathway. Relapse was the primary cause of death, with a 5-year cumulative incidence of 24.6% (95%CI: 17.1-32.9). Toxic deaths occurred in 12 patients, resulting in treatmentrelated mortality (TRM) of 9.0% (95%CI: 4.6-15.3). The 5-year overall (OS) and event-free survival were 73.6% (95%CI: 65.7-82.4) and 66.4% (95%CI: 58.2-75.8), respectively. Four independent adverse prognostic factors for OS were identified: age at diagnosis >2 years, time from diagnosis to HSCT >6 months, monocyte count at diagnosis >7.2x109/L, and the presence of additional genetic alterations. Based on these factors, we proposed a predictive classifier. Patients with three or more predictors (21% of the cohort) had a 5-year OS of 34.2%, whereas those with none (7%) had a 5-year OS of 100%. Our study demonstrates improved transplant outcomes compared to prior published data, which can be attributed to the synergistic impacts of a low TRM and a reduced yet still substantial relapse incidence. By integrating genetic information with clinical and hematological features, we have devised a predictive classifier. This classifier effectively identifies a subgroup of patients who are at a heightened risk of unfavorable post-transplant outcomes who would benefit novel therapeutic agents and post-transplant strategies.

Abstract Background To improve the efficiency of clinical trials, leveraging external data on control and/or treatment effects, which is almost always available, appears to be a promising approach. Methods We used data from the experimental arm of the Covidicus trial evaluating high-dose dexamethasone in severely ill and mechanically ventilated COVID-19 patients, using published data from the Recovery trial as external data, to estimate the 28-day mortality rate. Primary approaches to deal with external data were applied. Results Estimates ranged from 0.241 ignoring the external data up to 0.294 using hierarchical Bayesian models. Some evidence of differences in mortality rates between the Covidicus and Recovery trials were observed, with an matched adjusted odds ratio of death in the Covidicus arm of 0.41 compared to the Recovery arm. Conclusions These indirect comparisons appear sensitive to the method used. None of those approaches appear robust enough to overcome randomized clinical trial data. Trial registration Covidicus Trial: NCT04344730, First Posted: 14/04/2020; Recovery trial: NCT04381936

Introduction SARS-CoV-2 has been identified as the cause of the disease officially named COVID-19, primarily a respiratory illness. COVID-19 was characterised as a pandemic on 11 March 2020. It has been estimated that approximately 20% of people with COVID-19 require oxygen therapy. Oxygen has been listed on the WHO Model List of Essential Medicines List and Essential Medicines List for Children for almost two decades. The COVID-19 pandemic has highlighted, more than ever, the acute need for scale-up of oxygen therapy. Detailed data on the use of oxygen therapy in low-and-middle income countries at the patient and facility level are needed to target interventions better globally.Methods and analysis We aim to describe the requirements and use of oxygen at the facility and patient level of approximately 4500 patients with COVID-19 in 30 countries. Our objectives are specifically to characterise type and duration of different modalities of oxygen therapy delivered to patients; describe demographics and outcomes of hospitalised patients with COVID-19; and describe facility-level oxygen production and support. Primary analyses will be descriptive in nature. Respiratory support transitions will be described in Sankey plots, and Kaplan-Meier models will be used to estimate probability of each transition. A multistate model will be used to study the course of hospital stay of the study population, evaluating transitions of escalating respiratory support transitions to the absorbing states.Ethics and dissemination WHO Ad Hoc COVID-19 Research Ethics Review Committee (ERC) has approved this global protocol. When this protocol is adopted at specific country sites, national ERCs may make require adjustments in accordance with their respective national research ethics guidelines. Dissemination of this protocol and global findings will be open access through peer-reviewed scientific journals, study website, press and online media.Trial registration number NCT04918875.

Background: As we enter the era of precision medicine, the role of adaptive designs, such as response-adaptive randomisation or enrichment designs in drug discovery and development, has become increasingly important to identify the treatment given to a patient based on one or more biomarkers. Tailoring the ventilation supply technique according to the responsiveness of patients to positive end-expiratory pressure is a suitable setting for such a design. Methods: In the setting of marker-strategy design, we propose a Bayesian response-adaptive randomisation with enrichment design based on group sequential analyses. This design combines the elements of enrichment design and response-adaptive randomisation. Concerning the enrichment strategy, Bayesian treatment-by-subset interaction measures were used to adaptively enrich the patients most likely to benefit from an experimental treatment while controlling the false-positive rate.The operating characteristics of the design were assessed by simulation and compared to those of alternate designs. Results: The results obtained allowed the detection of the superiority of one treatment over another and the presence of a treatment-by-subgroup interaction while keeping the false-positive rate at approximately 5/% and reducing the average number of included patients. In addition, simulation studies identified that the number of interim analyses and the burn-in period may have an impact on the performance of the scheme. Conclusion: The proposed design highlights important objectives of precision medicine, such as determining whether the experimental treatment is superior to another and identifying wheter such an efficacy could depend on patient profile.

Introduction Corticosteroids affect variably survival in sepsis trials, suggesting heterogeneity in patients’ response to corticosteroids. The RECORDS (Rapid rEcognition of COrticosteRoiD resistant or sensitive Sepsis) trial aimed at defining endotypes associated with adults with sepsis responsiveness to corticosteroids.Methods and analysis RECORDS, a multicentre, placebo-controlled, biomarker-guided, adaptive Bayesian design basket trial, will randomly assign to a biomarker stratum 1800 adults with community-acquired pneumonia, vasopressor-dependent sepsis, septic shock or acute respiratory distress syndrome. In each stratum, patients will be randomly assigned to receive a 7-day course of hydrocortisone and fludrocortisone or their placebos. Patients with COVID-19 will be treated with a 10-day standard course of dexamethasone and randomised to fludrocortisone or its placebo. Primary outcome will be 90-day death or persistent organ dysfunction. Large simulation study will be performed across a range of plausible scenarios to foresee power to detect a 5%–10% absolute difference with corticosteroids. We will assess subset-by-treatment interaction by estimating in a Bayesian framework two quantities: (1) measure of influence, relying on the value of the estimation of corticosteroids’ effect in each subset, and (2) measure of interaction.Ethics and dissemination The protocol was approved by the Ethics Committee (Comité de Protection des Personnes, Dijon, France), on 6 April 2020. Trial results will be disseminated at scientific conferences and results will be published in peer-reviewed journals.Trial registration number ClinicalTrials.gov Registry (NCT04280497).

Abstract Background Statistical issues present while evaluating a diagnostic procedure for breast cancer are non rare but often ignored, leading to biased results. We aimed to evaluate the diagnostic accuracy of the fine needle aspiration cytology(FNAC), a minimally invasive and rapid technique potentially used as a rule-in or rule-out test, handling its statistical issues: suspect test results and verification bias. Methods We applied different statistical methods to handle suspect results by defining conditional estimates. When considering a partial verification bias, Begg and Greenes method and multivariate imputation by chained equations were applied, however, and a Bayesian approach with respect to each gold standard was used when considering a differential verification bias. At last, we extended the Begg and Greenes method to be applied conditionally on the suspect results. Results The specificity of the FNAC test above 94%, was always higher than its sensitivity regardless of the proposed method. All positive likelihood ratios were higher than 10, with variations among methods. The positive and negative yields were high, defining precise discriminating properties of the test. Conclusion The FNAC test is more likely to be used as a rule-in test for diagnosing breast cancer. Our results contributed in advancing our knowledge regarding the performance of FNAC test and the methods to be applied for its evaluation.

Abstract Background Adaptive clinical trials have been increasingly commonly employed to select a potential target population for one trial without conducting trials separately. Such enrichment designs typically consist of two or three stages, where the first stage serves as a screening process for selecting a specific subpopulation. Methods We propose a Bayesian design for randomized clinical trials with a binary outcome that focuses on restricting the inclusion to a subset of patients who are likely to benefit the most from the treatment during trial accrual. Several Bayesian measures of efficacy and treatment-by-subset interactions were used to dictate the enrichment, either based on Gail and Simon’s or Millen’s criteria. A simulation study was used to assess the performance of our design. The method is exemplified in a real randomized clinical trial conducted in patients with respiratory failure that failed to show any benefit of high flow oxygen supply compared with standard oxygen. Results The use of the enrichment rules allowed the detection of the existence of a treatment-by-subset interaction more rapidly compared with Gail and Simon’s criteria, with decreasing proportions of enrollment in the whole sample, and the proportions of enrichment lower, in the presence of interaction based on Millen’s criteria. In the real dataset, this may have allowed the detection of the potential interest of high flow oxygen in patients with a SOFA neurological score ≥ 1. Conclusion Enrichment designs that handle the uncertainty in treatment efficacy by focusing on the target population offer a promising balance for trial efficiency and ease of interpretation.

ABSTRACT The ID NOW COVID-19 system (IDNOW) is a point-of-care test (POCT) providing results within 15 min. We evaluated the impact of IDNOW use on patient length of stay (LOS) in an emergency department (ED). In the ED of Saint-Louis Hospital, Paris, France, adult patients requiring a rapid diagnosis of SARS-CoV-2 were tested with Cepheid Xpert Xpress SARS-CoV-2 or FilmArray respiratory panel RP2 in the virology laboratory between 18 October and 3 November 2020 (period 1) and with IDNOW between 4 November and 30 November 2020 (period 2). A total of 676 patients participated in the study, 337 during period 1 and 339 during period 2. The median LOS in ED was significantly higher in period 1 than in period 2 (276 versus 208 min, P

Summary: Background: Administration of convalescent plasma may serve as an adjunct to supportive treatment to prevent COVID-19 progression and death. We aimed to evaluate the efficacy and safety of 2 volumes of intravenous convalescent plasma (CP) with high antibody titers for the treatment of severe cases of COVID-19. Methods: We conducted a Bayesian, randomized, open-label, multicenter, controlled clinical trial in 7 Brazilian hospitals. Adults admitted to hospital with positive RT-PCR for SARS-CoV2, within 10 days of the symptom onset, were eligible. Patients were randomly assigned (1:1:1) to receive standard of care (SoC) alone, or in combination with 200 mL (150–300 mL) of CP (Low-volume), or 400 mL (300–600 mL) of CP (High-volume); infusion had to be performed within 24 h of randomization. Randomization was centralized, stratified by center. The primary outcome was the time until clinical improvement up to day 28, measured by the WHO ten-point scale, assessed in the intention-to-treat population. Interim and terminal analyses were performed in a Bayesian framework. Trial registered at ClinicalTrials.gov: NCT04415086. Findings: Between June 2, 2020, and November 18, 2020, 129 patients were enrolled and randomly assigned to SoC (n = 42), Low-volume (n = 43) or High-volume (n = 44) CP. Donors presented a median titer of neutralizing antibodies of 1:320 (interquartile range, 1:160 to 1:1088). No evidence of any benefit of convalescent plasma was observed, with Bayesian estimate of 28-day clinical improvement of 72.7% (95%CI, 58.8 to 84.7) in the SoC versus 64.1% (95%ci, 53.8 to 73.7) in the pooled experimental groups (mean difference of -8.7%, 95%CI, -24.6 to 8.2). There was one case of cutaneous mild allergic reaction related to plasma transfusion and one case of suspected transfusion-related acute lung injury but deemed not to be related to convalescent plasma infusion. Interpretation: In this prospective, randomized trial of adult hospitalized patients with severe COVID-19, convalescent plasma was not associated with clinical benefits. Funding: Brazilian Ministry of Science, Technology and Innovation, Fundação de Amparo à Pesquisa do Estado de São Paulo.

Abstract Introduction About 30% of patients with Guillain-Barré syndrome become ventilator dependent, of whom roughly 75% develop pneumonia. This trial aimed at assessing the impact of early mechanical ventilation (EMV) on pneumonia occurrence in GBS patients. We hypothesize that EMV will reduce the incidence of pneumonia. Methods This was a single centre, open-label, randomized controlled trial performed on two parallel groups. 50 intensive care unit adults admitted for Guillain-Barré syndrome and at risk for acute respiratory failure. Patients were randomized to early mechanical ventilation via face-mask or endotracheal intubation owing to the presence or absence of impaired swallowing (experimental arm), or to conventional care (control arm). The primary outcome was the incidence of pneumonia up to intensive care unit discharge (or 90 days, pending of which occurred first). Findings Twenty-five patients were randomized in each group. There was no significant difference between groups for the incidence of pneumonia (10/25 (40%) vs 9/25 (36%), P = 1). There was no significant difference between groups for the time to onset of pneumonia (P = 0.50, Gray test). During follow-up, there were 16/25 (64%) mechanically ventilated patients in the control group, and 25/25 (100%) in the experimental arm (P

Abstract Background The evaluation process of French medical students will evolve in the next few years in order to improve assessment validity. Script concordance testing (SCT) offers the possibility to assess medical knowledge alongside clinical reasoning under conditions of uncertainty. In this study, we aimed at comparing the SCT scores of a large cohort of undergraduate medical students, according to the experience level of the reference panel. Methods In 2019, the authors developed a 30-item SCT and sent it to experts with varying levels of experience. Data analysis included score comparisons with paired Wilcoxon rank sum tests and concordance analysis with Bland & Altman plots. Results A panel of 75 experts was divided into three groups: 31 residents, 21 non-experienced physicians (NEP) and 23 experienced physicians (EP). Among each group, random samples of N = 20, 15 and 10 were selected. A total of 985 students from nine different medical schools participated in the SCT examination. No matter the size of the panel (N = 20, 15 or 10), students’ SCT scores were lower with the NEP group when compared to the resident panel (median score 67.1 vs 69.1, p

Background Dexamethasone is standard of care for the treatment of patients with COVID-19 requiring oxygen. The objective is to assess the clinical benefit of adding remdesivir to dexamethasone. Patients and methods A retrospective cohort study of hospitalized patients with COVID-19 pneumonia requesting low-flow oxygen who received dexamethasone. Patients admitted to infectious diseases wards also received remdesivir. Primary outcome was duration of hospitalization after oxygen initiation. Secondary outcomes were in-hospital death, and death and/or transfer to the intensive care unit. To handle potential confounding by indication bias, outcome comparison was performed on propensity score-matched populations. Propensity score was estimated by a multivariable logistic model including prognostic covariates; then 1:1 matching was performed without replacement, using the nearest neighbor algorithm with a caliper of 0.10 fold the standard deviation of the propensity score as the maximal distance. Balance after matching was checked on standardized mean differences. Results From August 15th 2020, to February 28th, 2021, 325 patients were included, 101 of whom received remdesivir. At admission median time from symptoms onset was 7 days, median age: 68 years, male sex; 61%, >1 comorbidity: 58.5%. Overall 180 patients matched on propensity score were analyzed, 90 each received remdesivir plus dexamethasone or dexamethasone alone. Median duration of hospitalization was 9 (IQR: 7–13) and 9 (IQR: 5–18) days with and without remdesivir, respectively (p = 0.37). In-hospital death rates and rates of transfer to the intensive care unit or death were 8.9 and 17.8% (HR: 0.46, 95% CI: 0.21–1.02, p = 0.06) and 20.0 and 35.6% with and without remdesivir, respectively (HR: 0.45, 95% CI: 0.23–0.89, p = 0.015). Conclusion In hospitalized patients with COVID-19 pneumonia receiving low-flow oxygen and dexamethasone, the addition of remdesivir was not associated with shorter hospitalization or lower in-hospital mortality but may have reduced the combined outcome of death and transfer to the intensive care unit.

IntroductionPatients with hyperleukocytic (HL) acute myeloid leukemia (AML) are at higher risk of early death. Initial management of these patients is challenging, not fully codified and heterogenous. Retrospective studies showed that several symptomatic measures might decrease early death rate but long-term data are scarce. We aimed to analyze whether the therapeutic measures carried out urgently at diagnosis may influence the outcome among HL AML patients having achieved who survived inaugural complications.MethodsWe retrospectively reviewed all medical charts from patients admitted to Saint-Louis Hospital between January, 1st 1997 and December, 31st 2018 with newly diagnosed AML and white blood cell (WBC) count above 50x109/L. Outcome measures were cumulative incidence of relapse (CIR), treatment-related mortality (TRM) defined as relapse-free death, and overall survival. Univariate and multivariate analyses were performed using Cox proportional hazards models.ResultsA total of 184 patients with HL AML in complete remission (CR) were included in this study. At 2 years after CR. 62.5% of patients were alive, at 5 years, cumulated incidence of relapse was 55.8%. We found that every therapeutic measure, including life-sustaining therapies carried out in the initial phase of the disease, did not increase the relapse risk. The use of hydroxyurea for more than 4 days was associated with a higher risk of relapse. At the end of the study, 94 patients (51.1%) were still alive including 23 patients out of 44 aged less than 60 yo that were able to return to work.ConclusionWe show that the use of emergency measures including life sustaining therapies does not come at the expense of a higher risk of relapse or mortality, except in the case of prolonged use of hydroxyurea. Patients with HL AML should be able to benefit from all available techniques, regardless of their initial severity.

Graft versus host disease (GvHD) still hinders allogeneic hematopoietic stem cell transplantation. Here, the authors use metabolomics to analyze two cohorts of paired transplant recipients and donors, identifying significant differences in both host- and microbiota-derived metabolites.

Background & Aims: In this study we aimed to analyse the impact of the aetiology of cirrhosis on the incidence, characteristics and prognosis of hepatocellular carcinoma (HCC) diagnosed during a surveillance program. Methods: Individual data from a randomized trial and 2 prospective cohorts of patients with compensated histologically proven cirrhosis recruited between 2000 and 2016 were pooled. The influence of cirrhosis aetiology on survival after HCC detection was assessed using multivariable regression models. Results: Among 3,533 patients (1,926 virus [VIR], 1,167 alcohol [ALC], 440 combined [MIX]), 431 were diagnosed with HCC after a median follow-up of 57.1 months. The 5-year HCC incidence was lowest in ALC (VIR 12.6%, ALC 9.1%, MIX 14.3%, p = 0.04). At the time of diagnosis, tumour burden and Child-Pugh score were comparable across aetiology groups, but early BCLC stages (0/A) were significantly less frequent in ALC (VIR 80%, ALC 37%, MIX 72%) as a result of worse ECOG performance status. However, similar access to first-line curative HCC treatment was reported across aetiology groups (p = 0.68). Median survival after HCC diagnosis was significantly reduced in ALC (VIR 39, ALC 21, MIX 34 months, p = 0.02). However, when adjusting for tumour size, ECOG and Child-Pugh score, the aetiology of the underlying cirrhosis no longer had a significant impact. Conclusion: Compared to patients with virus-related cirrhosis, patients with alcohol-related compensated cirrhosis enrolled in a surveillance program have: i) the lowest 5-year HCC incidence; ii) worse overall prognosis, mostly driven by a poor general condition, despite similar access to first-line curative treatment. Lay summary: It has been suggested that early detection of hepatocellular carcinoma (HCC) may be futile in patients with alcohol-related cirrhosis. By comparing outcomes in more than 3,000 patients with compensated cirrhosis included in surveillance programs, this study suggests that HCC surveillance enables early diagnosis in most patients with alcohol-related cirrhosis despite a higher competing risk of death in these patients. We also report similar access to first-line curative HCC treatment in these patients compared to those with viral cirrhosis, despite higher rates of comorbidities and impaired liver function. Following HCC detection, the later parameters were major drivers of death irrespective of the cause of cirrhosis. Registration: CHC2000 (NCT00190385) and CIRRAL (NCT01213927) cohorts were registered at ClinicalTrials.gov and the full protocols are available at the following links (https://clinicaltrials.gov/ct2/show/NCT00190385) and https://clinicaltrials.gov/ct2/show/NCT01213927, respectively). The full CirVir protocol is available via the ANRS Web site (http://anrs.fr).

Abstract Background Pneumothorax may recur during pulmonary Langerhans cell histiocytosis (PLCH) patients’ follow-up and its management is not standardised. The factors associated with pneumothorax recurrence are unknown. Methods In this retrospective study, PLCH patients who experienced a pneumothorax and were followed for at least 6 months after the first episode were eligible. The objectives were to describe the treatment of the initial episode and pneumothorax recurrences during follow-up. We also searched for factors associated with pneumothorax recurrence and evaluated the effect on lung function outcome. Time to recurrence was estimated by the Kaplan Meier method and the cumulative hazard of recurrence handling all recurrent events was estimated. Univariate Cox models and Andersen-Gill counting process were used for statistical analyses. Results Fourty-three patients (median age 26.5 years [interquartile range (IQR), 22.9–35.4]; 26 men, 39 current smokers) were included and followed for median time of 49 months. Chest tube drainage was the main management of the initial pneumothorax, which resolved in 70% of cases. Pneumothorax recurred in 23 (53%) patients, and overall 96 pneumothoraces were observed during the study period. In the subgroup of patients who experienced pneumothorax recurrence, the median number of episodes per patient was 3 [IQR, 2–4]. All but one recurrence occurred within 2 years after the first episode. Thoracic surgery neither delayed the time of occurrence of the first ipsilateral recurrence nor reduced the overall number of recurrences during the study period, although the rate of recurrence was lower after thoracotomy than following video-assisted thoracic surgery (p = 0.03). At the time of the first pneumothorax, the presence of air trapping on lung function testing was associated with increased risk of recurrence (hazard ratio = 5.08; 95% confidence interval [1.18, 21.8]; p = 0.03). Pneumothorax recurrence did not predict subsequent lung function decline (p = 0.058). Conclusions Our results show that pneumothorax recurrences occur during an “active” phase of PLCH. In this observational study, the time of occurrence of the first ipsilateral recurrence and the overall number of pneumothorax recurrences were similar after conservative and thoracic surgical treatments. Further studies are needed to determine the best management to reduce the risk of pneumothorax recurrence in PLCH patients.

Abstract Background The aim of this study was to assess the benefit of direct ICU admission from the emergency department (ED) compared to admission from wards, in patients with hematological malignancies requiring critical care. Methods Post hoc analysis derived from a prospective, multicenter cohort study of 1011 critically ill adult patients with hematologic malignancies admitted to 17 ICU in Belgium and France from January 2010 to May 2011. The variable of interest was a direct ICU admission from the ED and the outcome was in-hospital mortality. The association between the variable of interest and the outcome was assessed by multivariable logistic regression after multiple imputation of missing data. Several sensitivity analyses were performed: complete case analysis, propensity score matching and multivariable Cox proportional-hazards analysis of 90-day survival. Results Direct ICU admission from the ED occurred in 266 (26.4%) cases, 84 of whom (31.6%) died in the hospital versus 311/742 (41.9%) in those who did not. After adjustment, direct ICU admission from the ED was associated with a decreased in-hospital mortality (adjusted OR: 0.63; 95% CI 0.45–0.88). This was confirmed in the complete cases analysis (adjusted OR: 0.64; 95% CI 0.45–0.92) as well as in terms of hazard of death within the 90 days after admission (adjusted HR: 0.77; 95% CI 0.60–0.99). By contrast, in the propensity score-matched sample of 402 patients, direct admission was not associated with in-hospital mortality (adjusted OR: 0.92; 95% CI 0.84–1.01). Conclusions In this study, patients with hematological malignancies admitted to the ICU were more likely to be alive at hospital discharge if they were directly admitted from the ED rather than from the wards. Assessment of early predictors of poor outcome in cancer patients admitted to the ED is crucial so as to allow early referral to the ICU and avoid delays in treatment initiation and mis-orientation.

Abstract Background Acute respiratory failure is the leading reason for intensive care unit (ICU) admission in immunocompromised patients, and the need for invasive mechanical ventilation has become a major clinical endpoint in randomized controlled trials (RCTs). However, data are lacking on whether intubation is an objective criteria that is used unbiasedly across centers. This study explores how this outcome varies across ICUs. Methods Hierarchical models and permutation procedures for testing multiple random effects were applied on both data from an observational cohort (the TRIAL-OH study: 703 patients, 17 ICUs) and a randomized controlled trial (the HIGH trial: 776 patients, 31 ICUs) to characterize ICU variation in intubation risk across centers. Results The crude intubation rate varied across ICUs from 29 to 80% in the observational cohort and from 0 to 86% in the RCT. This center effect on the mean ICU intubation rate was statistically significant, even after adjustment on individual patient characteristics (observational cohort: p value = 0.013, median OR 1.48 [1.30–1.72]; RCT: p value 0.004, median OR 1.51 [1.36–1.68]). Two ICU-level characteristics were associated with intubation risk (the annual rate of intubation procedure per center and the time from respiratory symptoms to ICU admission) and could partly explain this center effect. In the RCT that controlled for the use of high-flow oxygen therapy, we did not find significant variation in the effect of oxygenation strategy on intubation risk across centers, despite a significant variation in the need for invasive mechanical ventilation. Conclusion Intubation rates varied considerably among ICUs, even after adjustment on individual characteristics.

Abstract Background Mottling score, a tissue perfusion parameter, is correlated with outcome in septic shock patients. However, its predictive value on mortality according to prognostic covariates such as vasopressor dose and other tissue perfusion parameters remains unknown. Methods Mottling score and tissue perfusion parameters were recorded at ICU admission (H0), H-6, H 12, and H-24 and used to assess the predictive value of mottling score on 14-day mortality in a development cohort. Results were then validated in an independent cohort of septic shock patients in Brazil. Results Overall, 259 patients with sepsis or septic shock were included, 14-day mortality was 37%. Factors associated with death were mottling score (OR 2.26 [95% CI, 1.72–2.97]), arterial lactate level (OR 1.29 [1.11–1.5]), and urine output 0.8 μg/kg/min). There was no difference in the effect of mottling score on mortality according to mean arterial pressure, heart rate, cardiac index, and urine output, but we found a significant interaction between arterial lactate level and mottling score (p = 0.04). The predictive value of the mottling score remains significant when using the recent SEPSIS-3 definition of septic shock. Finally, a decrease of mottling score during resuscitation was significantly associated with better outcome after adjustment on SOFA score (p = 0.001). Conclusions Our results support the high prognostic value of mottling score for 14-day mortality in septic patients, whatever vasopressor dosage and other perfusion parameters. Mottling score variations during resuscitation are also predictive of mortality.

Abstract Background It is unclear whether influenza infection and associated co-infection are associated with patient-important outcomes in critically ill immunocompromised patients with acute respiratory failure. Methods Preplanned secondary analysis of EFRAIM, a prospective cohort study of 68 hospitals in 16 countries. We included 1611 patients aged 18 years or older with non-AIDS-related immunocompromise, who were admitted to the ICU with acute hypoxemic respiratory failure. The main exposure of interest was influenza infection status. The primary outcome of interest was all-cause hospital mortality, and secondary outcomes ICU length of stay (LOS) and 90-day mortality. Results Influenza infection status was categorized into four groups: patients with influenza alone (n = 95, 5.8%), patients with influenza plus pulmonary co-infection (n = 58, 3.6%), patients with non-influenza pulmonary infection (n = 820, 50.9%), and patients without pulmonary infection (n = 638, 39.6%). Influenza infection status was associated with a requirement for intubation and with LOS in ICU (P

Abstract Background Providing appropriate support and care for end-of-life patients and their relatives is a major concern and a daily responsibility for intensivists. Bereaved relatives of non-surviving patients in intensive care units (ICUs) often suffer from prolonged grief, posttraumatic stress disorder, anxiety, and depression. A physician-driven intervention, consisting of three meetings with the family, might reduce the post-ICU burden of bereaved family members 6 month after death. The patient’s nurse is actively involved at each step. We hypothesize that this strategy will improve communication in the end-of-life setting and thus, should reduce the post-ICU burden for family members, specifically the development of prolonged grief 6 months after the death. Methods/design The COSMIC-EOL trial is a prospective, multicenter, cluster randomized controlled trial in which centers are allocated to two parallel arms: (1) intervention centers where relatives benefit from three-step physician-driven support during the dying and death process and (2) control centers where, during the dying and death process, relatives receive the standard of care practice. Each of the 36 participating centers will include 25 relatives of patients with a length of stay ≥2 days. Participating relatives will be followed up by phone at 1, 3, and 6 months after the patient’s death to complete questionnaires permitting evaluation of their post-ICU burden. The main outcome is prolonged grief measured 6 months after the death using the PG-13. Other outcomes include evaluation of quality of dying, quality of communication, anxiety, depression, and post-traumatic stress. The estimated duration of the study is 36 months. Discussion The results of the trial will provide information about the effectiveness of physician-driven support for relatives of patients dying in an ICU. The study is expected to demonstrate a decrease in the ICU burden for bereaved relatives who benefitted from this intervention. Trial Registration ClinicalTrials.gov, NCT02955992. Registered on November 3rd 2016.

Despite appealing characteristics for the clinical trials setting, Bayesian inference methods remain scarcely used, especially in randomized controlled clinical trials (RCT). This is particularly true when dealing with a survival endpoint, likely due to the additional complexities to model specifications. We propose to use Bayesian inference to estimate the treatment effect in this setting, using a proportional hazards (PH) model for right-censored data. Implementation of such an estimation process is illustrated on two working examples from cancer RCTs, the ALLOZITHRO and the CLL7-SA trials, both originally analyzed using a frequentist approach. In these two different settings, we show that Bayesian sequential analyses can provide early insight on treatment effect in RCTs. Relying on posterior distributions and predictive posterior probabilities, we find that Bayesian sequential analyses of the ALLOZITHRO trial, which was terminated early due to an unanticipated deleterious effect of the intervention on survival, allow quantifying early that the treatment effect was opposite to what was expected. Then, incorporating historical data in the sequential analyses of the CLL7-SA trial would have allowed the treatment effect to be closer to the protocol hypothesis. These post-hoc results give grounds to advocate for a wider use of Bayesian approaches in RCTs, including those with right-censored endpoints, as informative decision tools.

ObjectivesAlthough some prognostic factors for COVID-19 were consistently identified across the studies, differences were found for other factors that could be due to the characteristics of the study populations and the variables incorporated into the statistical model. We aimed to a priori identify specific patient profiles and then assess their association with the outcomes in COVID-19 patients with respiratory symptoms admitted specifically to hospital wards.MethodsWe conducted a retrospective single-center study from February 2020 to April 2020. A non-supervised cluster analysis was first used to detect patient profiles based on characteristics at admission of 220 consecutive patients admitted to our institution. Then, we assessed the prognostic value using Cox regression analyses to predict survival.ResultsThree clusters were identified, with 47 patients in cluster 1, 87 in cluster 2, and 86 in cluster 3; the presentation of the patients differed among the clusters. Cluster 1 mostly included sexagenarian patients with active malignancies who were admitted early after the onset of COVID-19. Cluster 2 included the oldest patients, who were generally overweight and had hypertension and renal insufficiency, while cluster 3 included the youngest patients, who had gastrointestinal symptoms and delayed admission. Sixty-day survival rates were 74.3%, 50.6% and 96.5% in clusters 1, 2, and 3, respectively. This was confirmed by the multivariable Cox analyses that showed the prognostic value of these patterns.ConclusionThe cluster approach seems appropriate and pragmatic for the early identification of patient profiles that could help physicians segregate patients according to their prognosis.

BackgroundThe prevalence of psychological symptoms and the co-occurrence of substance abuse disorders in adult patients with Langerhans cell histiocytosis (LCH) has not been previously explored. We aimed to use validated scales to evaluate depression and anxiety symptoms experienced by adult LCH patients.MethodsIn this cross-sectional study, all consecutive adult LCH patients seen at our national reference center between January 2012 and January 2013 were asked to complete the following instruments: the Hospital Anxiety and Depression scale (HADS); Barratt Impulsiveness Scale, Version 10 (BIS-10); and Cannabis Use Disorders Identification Test (CUDIT). Self-reported scores on these scales were used to determine the point prevalence of clinically significant psychological symptoms and substance use disorders in LCH patients. Patient profiles in terms of psychological features were assessed by principal component analysis including the HADS and BIS-10 instruments values, followed by hierarchical clustering. Fisher exact tests and Wilcoxon tests were used to examine the associations between disease-related parameters and high levels of anxiety and impulsivity.ResultsSeventy-one adult LCH patients, mainly with pulmonary LCH (PLCH), completed the evaluations. Clinically significant anxiety and depression symptoms were reported by 22 (31%) and 4 (6%) subjects, respectively. Impulsivity was detected in 14% (10/71) of the patients. Seventeen percent (12/71) of the patients used cannabis on a regular basis, with 50% of these individuals (6/12) exhibiting scores consistent with cannabis use disorder. Three derived clusters of patients were identified in the principal component analysis; these patient clusters differed in successful weaning from tobacco at the time of evaluation (p = 0.03). In univariate analyses, isolated PLCH and the use of psychotropic treatments were statistically associated with clinically significant anxiety symptoms.ConclusionsHigh levels of anxiety and impulsivity are common in adult patients with LCH. The consequences of these symptoms for the management of LCH patients warrant further evaluation.

The severe respiratory distress syndrome linked to the new coronavirus disease (COVID-19) includes unbearable dyspneic suffering which contributes to the deterioration of the prognosis of patients in intensive care unit (ICU). Patients are put on mechanical ventilation to reduce respiratory suffering and preserve life. Despite this mechanical ventilation, most patients continue to suffer from dyspnea. Dyspnea is a major source of suffering in intensive care and one of the main factors that affect the prognosis of patients. The development of innovative methods for its management, especially non-drug management is more than necessary. In recent years, numerous studies have shown that transcranial direct current stimulation (tDCS) could modulate the perception of acute or chronic pain. In the other hand, it has been shown that the brain zones activated during pain and dyspnea are close and/or superimposed, suggesting that brain structures involved in the integration of aversive emotional component are shared by these two complex sensory experiences. Therefore, it can be hypothesized that stimulation by tDCS with regard to the areas which, in the case of pain have activated one or more of these brain structures, may also have an effect on dyspnea. In addition, our team recently demonstrated that the application of tDCS on the primary cortical motor area can modulate the excitability of the respiratory neurological pathways. Indeed, tDCS in anodal or cathodal modality reduced the excitability of the diaphragmatic cortico-spinal pathways in healthy subjects. We therefore hypothesized that tDCS could relieve dyspnea in COVID-19 patients under mechanical ventilation in ICU. This study was designed to evaluate effects of two modalities of tDCS (anodal and cathodal) vs. placebo, on the relief of dyspnea in COVID-19 patients requiring mechanical ventilation in ICU.Trial Registration: This protocol is derived from the tDCS-DYSP-REA project registered on ClinicalTrials.gov NCT03640455. It will however be registered under its own NCT number.

INTRODUCTION:The benefit of reducing the time of antibiotic initiation in the emergency department (ED) for neutropenic patients is controversial and the research on the impact of antibiotic adherence to international guidelines in the ED is scarce. We aimed to investigate the effect of antibiotic timing and appropriateness on outcomes in patients with febrile neutropenia (FN) and to assess the performance of the MASCC risk-index to risk-stratify such patients in the ED. METHODS:We prospectively identified patients with FN who presented to our ED and assessed their Multinational Association of Supportive Care in Cancer (MASCC) risk-index. The time to parenteral antibiotic initiation and the appropriateness of the antibiotic regimen according to international guidelines were retrospectively abstracted. The performance of the MASCC risk-index in predicting the absence of complication was assessed with sensitivity, specificity and the area under the receiver operating characteristics curve (AUC). We investigated the effect of the time to antibiotic initiation and the appropriateness of the antibiotic regimen on the outcome (ICU admission or death) by logistic regression analyses. RESULTS:We included 249 patients. Median age was 60 years and 67.9% had hematological malignancies, 26 (10.4%) were admitted to the ICU and 23 (9.8%) died during hospital stay. Among the 173 patients at low risk according to the MASCC risk-index, 56 (32.4%) presented at least one complication including 11 deaths. The MASCC risk-index had a sensitivity and a specificity of 0.78% and 0.43%, respectively, in predicting the absence of complication and the AUC was 0.67. The time to antibiotic initiation in the ED was not associated with the outcome after adjusting for performance status and shock-index. Conversely, an inadequate ED antibiotic regimen was associated with higher ICU admission or death during hospital stay (OR = 3.50; 95% CI = 1.49 to 8.28). CONCLUSION:An inadequate ED antibiotic regimen in patients with FN was significantly associated with higher ICU admission or death during hospital stay.

Abstract Background Multiple imputation by chained equations (MICE) requires specifying a suitable conditional imputation model for each incomplete variable and then iteratively imputes the missing values. In the presence of missing not at random (MNAR) outcomes, valid statistical inference often requires joint models for missing observations and their indicators of missingness. In this study, we derived an imputation model for missing binary data with MNAR mechanism from Heckman’s model using a one-step maximum likelihood estimator. We applied this approach to improve a previously developed approach for MNAR continuous outcomes using Heckman’s model and a two-step estimator. These models allow us to use a MICE process and can thus also handle missing at random (MAR) predictors in the same MICE process. Methods We simulated 1000 datasets of 500 cases. We generated the following missing data mechanisms on 30% of the outcomes: MAR mechanism, weak MNAR mechanism, and strong MNAR mechanism. We then resimulated the first three cases and added an additional 30% of MAR data on a predictor, resulting in 50% of complete cases. We evaluated and compared the performance of the developed approach to that of a complete case approach and classical Heckman’s model estimates. Results With MNAR outcomes, only methods using Heckman’s model were unbiased, and with a MAR predictor, the developed imputation approach outperformed all the other approaches. Conclusions In the presence of MAR predictors, we proposed a simple approach to address MNAR binary or continuous outcomes under a Heckman assumption in a MICE procedure.

Abstract Background Acute respiratory failure (ARF) is the leading reason for intensive care unit (ICU) admission in immunocompromised patients. High-flow nasal oxygen (HFNO) therapy is an alternative to standard oxygen. By providing warmed and humidified gas, HFNO allows the delivery of higher flow rates via nasal cannula devices, with FiO2 values of nearly 100%. Benefits include alleviation of dyspnea and discomfort, decreased respiratory distress and decreased mortality in unselected patients with acute hypoxemic respiratory failure. However, in preliminary reports, HFNO benefits are controversial in immunocompromised patients in whom it has never been properly evaluated. Methods/design This is a multicenter, open-label, randomized controlled superiority trial in 30 intensive care units, part of the Groupe de Recherche Respiratoire en Réanimation Onco-Hématologique (GRRR-OH). Inclusion criteria will be: (1) adults, (2) known immunosuppression, (3) ARF, (4) oxygen therapy ≥ 6 L/min, (5) written informed consent from patient or proxy. Exclusion criteria will be: (1) imminent death (moribund patient), (2) no informed consent, (3) hypercapnia (PaCO2 ≥ 50 mmHg), (4) isolated cardiogenic pulmonary edema, (5) pregnancy or breastfeeding, (6) anatomical factors precluding insertion of a nasal cannula, (7) no coverage by the French statutory healthcare insurance system, and (8) post-surgical setting from day 1 to day 6 (patients with ARF occurring after day 6 of surgery can be included). The primary outcome measure is day-28 mortality. Secondary outcomes are intubation rate, comfort, dyspnea, respiratory rate, oxygenation, ICU length of stay, and ICU-acquired infections. Based on an expected 30% mortality rate in the standard oxygen group, and 20% in the HFNO group, error rate set at 5%, and a statistical power at 90%, 389 patients are required in each treatment group (778 patients overall). Recruitment period is estimated at 30 months, with 28 days of additional follow-up for the last included patient. Discussion The HIGH study will be the largest multicenter, randomized controlled trial seeking to demonstrate that survival benefits from HFNO reported in unselected patients also apply to a large immunocompromised population. Trial registration ClinicalTrials.gov, ID: NCT02739451. Registered on 15 April 2016.

Abstract Background It is well known that the standard doses of a given drug may not have equivalent effects in all patients. To date, the management of depression remains mainly empirical and often poorly evaluated. The development of a personalized medicine in psychiatry may reduce treatment failure, intolerance or resistance, and hence the burden and costs of mood depressive disorders. The Geneva Cocktail Phenotypic approach presents several advantages including the “in vivo” measure of different cytochromes and transporter P-gp activities, their simultaneous determination in a single test, avoiding the influence of variability over time on phenotyping results, the administration of low dose substrates, a limited sampling strategy with an analytical method developed on DBS analysis. The goal of this project is to explore the relationship between the activity of drug-metabolizing enzymes (DME), assessed by a phenotypic approach, and the concentrations of Venlafaxine (VLX) + O-demethyl-venlafaxine (ODV), the efficacy and tolerance of VLX. Methods/design This study is a multicentre prospective non-randomized open trial. Eligible patients present a major depressive episode, MADRS over or equal to 20, treatment with VLX regardless of the dose during at least 4 weeks. The Phenotype Visit includes VLX and ODV concentration measurement. Following the oral absorption of low doses of omeprazole, midazolam, dextromethorphan, and fexofenadine, drug metabolizing enzymes activity is assessed by specific metabolite/probe concentration ratios from a sample taken 2 h after cocktail administration for CYP2C19, CYP3A4, CYP2D6; and by the determination of the limited area under the curve from the capillary blood samples taken 2–3 and 6 h after cocktail administration for CYP2C19 and P-gp. Two follow-up visits will take place between 25 and 40 days and 50–70 days after inclusion. They include assessment of efficacy, tolerance and observance. Eleven french centres are involved in recruitment, expected to be completed within approximately 2 years with 205 patients. Metabolic ratios are determined in Geneva, Switzerland. Discussion By showing an association between drug metabolism and VLX concentrations, efficacy and tolerance, there is a hope that testing drug metabolism pathways with a phenotypical approach would help physicians in selecting and dosing antidepressants. The MARVEL study will provide an important contribution to increasing the knowledge of VLX variability and in optimizing the use of methods of personalized therapy in psychiatric settings. Trial registration ClinicalTrials.gov NCT02590185 (10/27/2015). This study is currently recruiting participants.

Abstract Background The common frequentist approach is limited in providing investigators with appropriate measures for conducting a new trial. To answer such important questions and one has to look at Bayesian statistics. Methods As a worked example, we conducted a Bayesian cumulative meta-analysis to summarize the benefit of patient-specific instrumentation on the alignment of total knee replacement from previously published evidence. Data were sourced from Medline, Embase, and Cochrane databases. All randomised controlled comparisons of the effect of patient-specific instrumentation on the coronal alignment of total knee replacement were included. The main outcome was the risk difference measured by the proportion of failures in the control group minus the proportion of failures in the experimental group. Through Bayesian statistics, we estimated cumulatively over publication time of the trial results: the posterior probabilities that the risk difference was more than 5 and 10%; the posterior probabilities that given the results of all previous published trials an additional fictive trial would achieve a risk difference of at least 5%; and the predictive probabilities that observed failure rate differ from 5% across arms. Results Thirteen trials were identified including 1092 patients, 554 in the experimental group and 538 in the control group. The cumulative mean risk difference was 0.5% (95% CrI: −5.7%; +4.5%). The posterior probabilities that the risk difference be superior to 5 and 10% was less than 5% after trial #4 and trial #2 respectively. The predictive probability that the difference in failure rates was at least 5% dropped from 45% after the first trial down to 11% after the 13th. Last, only unrealistic trial design parameters could change the overall evidence accumulated to date. Conclusions Bayesian probabilities are readily understandable when discussing the relevance of performing a new trial. It provides investigators the current probability that an experimental treatment be superior to a reference treatment. In case a trial is designed, it also provides the predictive probability that this new trial will reach the targeted risk difference in failure rates. Trial registration CRD42015024176 .

Abstract Background Vinblastine is the standard treatment for children with Langerhans cell histiocytosis (LCH). Whether this treatment could be extended to adults with LCH is questionable. This retrospective multicenter study included 35 adult patients (median age 33 years; 23 men; 80% with multisystem LCH) who were treated with vinblastine + steroids as a first-line chemotherapy and followed for a median time of 83 months. The objectives were to determine the overall response rate (based on the Histiocyte Society criteria), disease reactivation rate, toxicity, permanent consequences, and survival rate corresponding to this treatment. The lung involvement outcome was based on serial lung function tests. The distribution of right-censored end points was estimated by the Kaplan-Meier method. Univariate Cox model with time-fixed and time-varying covariates was used for the predictive analysis of reactivation in the responders. Univariate analyses of risk factors for neurotoxicity were based on nonparametric Wilcoxon rank sum tests and exact Fisher tests. Results The median duration of the first course of vinblastine was 7.6 months, with a median cumulative dose of 160 mg [IQR 120–212]. Seventy percent of the patients were responders at the end of this treatment. Subsequently, LCH reactivation occurred with a 5-year cumulative incidence of 40%. During the study, 27 reactivations were observed in 17 patients, and half of these episodes were retreated with vinblastine. At the end of the last vinblastine treatment, 70% of the patients were responders. None of the patients with impaired lung function improved. No grade 3–4 peripheral neuropathy was observed. At the final vinblastine treatment, permanent LCH consequences, primarily pituitary stalk involvement, were present in 15 (43%) patients, and all were present at the time of vinblastine initiation. The 10-year survival rate was 86.2% (95CI, 71.8–100%), and the 2 patients who died from LCH had risk organ localizations. Conclusions Vinblastine is an effective and well-tolerated first-line treatment for adult LCH except in patients with lung involvement and impaired lung function. However, a significant portion of patients experienced LCH reactivation during long-term follow up. As in childhood LCH, the presence of risk organ involvement has a negative impact on patient prognosis.

High-risk myelodysplastic syndrome/acute myeloid leukemia patients have a very poor survival after azacitidine failure. Guadecitabine (SGI-110) is a novel subcutaneous hypomethylating agent which results in extended decitabine exposure. This multicenter phase II study evaluated the efficacy and safety of guadecitabine in high-risk myelodysplastic syndrome and low blast count acute myeloid leukemia patients refractory or relapsing after azacitidine. We included 56 patients with a median age of 75 years [Interquartile Range (IQR) 69-76]. Fifty-five patients received at least one cycle of guadecitabine (60 mg/m2/d subcutaneously days 1-5 per 28-day treatment cycles), with a median of 3 cycles (range, 0-27). Eight (14.3%) patients responded, including two complete responses; median response duration was 11.5 months. Having no or few identified somatic mutations was the only factor predicting response (P=0.035). None of the 11 patients with TP53 mutation responded. Median overall survival was 7.1 months, and 17.9 months in responders (3 of whom had overall survival >2 years). In multivariate analysis, IPSS-R (revised International Prognostic Scoring System) score other than very high (P=0.03) primary versus secondary azacitidine failure (P=0.01) and a high rate of demethylation in blood during the first cycle of treatment (P=0.03) were associated with longer survival. Thus, guadecitabine can be effective, sometimes yielding relatively prolonged survival, in a small proportion of high-risk myelodysplastic syndrome/low blast count acute myeloid leukemia patients who failed azacitidine. (Trial registered at clinicaltrials.gov identifier: 02197676)

The use of antihuman T-lymphocyte immunoglobulin in the setting of transplantation from an HLA-matched related donor is still much debated. Acute and chronic graft-versus-host disease are the main causes of morbidity and mortality after allogeneic hematopoietic stem cell transplantation in patients with myelofibrosis. The aim of this study was to evaluate the effect of antihuman T-lymphocyte immunoglobulin in a large cohort of patients with myelofibrosis (n=287). The cumulative incidences of grade II-IV acute graft-versus-host disease among patients who were or were not given antihuman T-lymphocyte immunoglobulin were 26% and 41%, respectively. The corresponding incidences of chronic graft-versus-host disease were 52% and 55%, respectively. Non-adjusted overall survival, disease-free survival and non-relapse mortality rates were 55% versus 53%, 49% versus 45%, and 32% versus 31%, respectively, among the patients who were or were not given antihuman T-lymphocyte immunoglobulin. An adjusted model confirmed that the risk of acute graft-versus-host disease was lower following antihuman T-lymphocyte immunoglobulin (hazard ratio, 0.54; P=0.010) while it did not decrease the risk of chronic graft-versus-host disease. The hazard ratios for overall survival and non-relapse mortality were 0.66 and 0.64, with P-values of 0.05 and 0.09, respectively. Antihuman T-lymphocyte immunoglobulin did not influence disease-free survival, graft-versus-host disease, relapse-free survival or relapse risk. In conclusion, in the setting of matched related transplantation in myelofibrosis patients, this study demonstrates that antihuman T-lymphocyte immunoglobulin decreases the risk of acute graft-versus-host disease without increasing the risk of relapse.

The randomized, phase III ALFA-0701 trial showed that a reduced and fractionated dose of gemtuzumab ozogamicin added to standard front-line chemotherapy significantly improves event-free survival (EFS) in adults with de novo acute myeloid leukemia (AML). Here we report an independent review of EFS, final overall survival (OS), and additional safety results from ALFA-0701. Patients (n=271) aged 50-70 years with de novo AML were randomized to receive conventional front-line induction chemotherapy (3+7daunorubicin+cytarabine) with/without gemtuzumab ozogamicin 3 mg/m2 on days 1, 4, and 7 during induction. Patients in remission following induction therapy received 2 courses of consolidation therapy (daunorubicin+cytarabine) with/without gemtuzumab ozogamicin (3 mg/m2/day on day 1) according to their initial randomization. The primary end point was investigator-assessed EFS. Secondary end points included OS and safety. A blinded independent review confirmed the investigator-assessed EFS results [August 1, 2011; hazard ratio (HR) 0.66; 95% Confidence Interval (CI): 0.49–0.89; 2-sided P=0.006], corresponding to a 34% reduction in risk of events in the gemtuzumab ozogamicin versus control arm. Final OS at April 30, 2013 favored gemtuzumab ozogamicin but was not significant. No differences in early death rate were observed between arms. The main toxicity associated with gemtuzumab ozogamicin was prolonged thrombocytopenia. Veno-occlusive disease (including after transplant) was observed in 6 patients in the gemtuzumab ozogamicin arm and 2 in the control arm. In conclusion, gemtuzumab ozogamicin added to standard intensive chemotherapy has a favorable benefit/risk ratio. These results expand front-line treatment options for adult patients with previously untreated AML. (Trial registered at clinicaltrials.gov; identifier: 00927498.)

In standard-risk acute promyelocytic leukemia, recent results have shown that all-trans retinoic acid plus arsenic trioxide combinations are at least as effective as classical all-trans retinoic acid plus anthracycline-based chemotherapy while being less myelosuppressive. However, the role of frontline arsenic trioxide is less clear in higher-risk acute promyelocytic leukemia, and access to arsenic remains limited for front-line treatment of standard-risk acute promyelocytic leukemia in many countries. In this randomized trial, we compared arsenic, all-trans retinoic acid and the “classical” cytarabine for consolidation treatment (after all-trans retinoic acid and chemotherapy induction treatment) in standard-risk acute promyelocytic leukemia, and evaluated the addition of arsenic during consolidation in higher-risk disease. Patients with newly diagnosed acute promyelocytic leukemia with a white blood cell count 10x109/L received consolidation chemotherapy with or without arsenic. Overall, 795 patients with acute promyelocytic leukemia were enrolled in this trial. Among those with standard-risk acute promyelocytic leukemia (n=581), the 5-year event-free survival rates from randomization were 88.7%, 95.7% and 85.4% in the cytarabine, arsenic and all-trans retinoic acid consolidation groups, respectively (P=0.0067), and the 5-year cumulative incidences of relapse were was 5.5%, 0% and 8.2%. (P=0.001). Among those with higher-risk acute promyelocytic leukemia (n=214), the 5-year event-free survival rates were 85.5% and 92.1% (P=0.38) in the chemotherapy and chemotherapy plus arsenic groups, respectively, and the corresponding 5-year cumulative incidences of relapse were 4.6% and 3.5% (P=0.99). Given the prolonged myelosuppression that occurred in the chemotherapy plus arsenic arm, a protocol amendment excluded cytarabine during consolidation cycles in the chemotherapy plus arsenic group, resulting in no increase in relapse. Our results therefore advocate systematic introduction of arsenic in the first-line treatment of acute promyelocytic leukemia, but probably not concomitantly with intensive chemotherapy, a situation in which we found myelosuppression to be significant. (ClinicalTrials.gov Identifier: NCT00378365)

Abstract Background Multi-Arm Multi-Stage designs aim at comparing several new treatments to a common reference, in order to select or drop any treatment arm to move forward when such evidence already exists based on interim analyses. We redesigned a Bayesian adaptive design initially proposed for dose-finding, focusing our interest in the comparison of multiple experimental drugs to a control on a binary criterion measure. Methods We redesigned a phase II clinical trial that randomly allocates patients across three (one control and two experimental) treatment arms to assess dropping decision rules. We were interested in dropping any arm due to futility, either based on historical control rate (first rule) or comparison across arms (second rule), and in stopping experimental arm due to its ability to reach a sufficient response rate (third rule), using the difference of response probabilities in Bayes binomial trials between the treated and control as a measure of treatment benefit. Simulations were then conducted to investigate the decision operating characteristics under a variety of plausible scenarios, as a function of the decision thresholds. Results Our findings suggest that one experimental treatment was less efficient than the control and could have been dropped from the trial based on a sample of approximately 20 instead of 40 patients. In the simulation study, stopping decisions were reached sooner for the first rule than for the second rule, with close mean estimates of response rates and small bias. According to the decision threshold, the mean sample size to detect the required 0.15 absolute benefit ranged from 63 to 70 (rule 3) with false negative rates of less than 2 % (rule 1) up to 6 % (rule 2). In contrast, detecting a 0.15 inferiority in response rates required a sample size ranging on average from 23 to 35 (rules 1 and 2, respectively) with a false positive rate ranging from 3.6 to 0.6 % (rule 3). Conclusion Adaptive trial design is a good way to improve clinical trials. It allows removing ineffective drugs and reducing the trial sample size, while maintaining unbiased estimates. Decision thresholds can be set according to predefined fixed error decision rates. Trial registration ClinicalTrials.gov Identifier: NCT01342692 .

Background and objectives: Hip fracture is a major public health issue. Those fractures lead to high costs and a decrease in quality of life. A national French survey was conducted, with the objectives to firstly assess the current management of hip fracture and its prevention, both in the osteoporotic and cancer settings, and secondly to evaluate the opinions of physicians on the potential use of minimally invasive implantable devices to prevent hip fracture in alternative of surgery. Materials and methods: This national survey was conducted in France between April and July 2017. Questionnaires were sent to orthopedic surgeons, interventional radiologists, oncologists, and rheumatologists. Completed questionnaires were analyzed and compared according to two indications: orthopedics-traumatology and oncology. Factors associated with these responses were assessed using univariable analyses, based on chi-square tests or an exact Fisher test, as appropriate. Results: A total of 182 questionnaires were completed and further analyzed. Physicians have highlighted the need for a low re-fracture rate and to improve life expectancy for more than 1 year (50% for responders of the orthopedics-traumatology questionnaire and 80% for the responders interested in both indications), as well as quality of life (12.5% and 31%, respectively), but with no significant differences in the oncologic indication. Most of the experts were willing to use or prescribe implantable devices for prevention (63% in orthopedics-traumatology and 93% in oncology), although limited clinical experience (54 and 58%) and surgical risk (around 30% in each indication) were considered as limits. Conclusions: Prevention of hip fracture remains a concern for physicians. More clinical experience with implantable devices, in particular in cancer patients, is needed, but implemented in a strategy to maximize patient recovery while reducing costs.