Emilie Bérard

Fluoxetine for motor recovery after acute ischaemic stroke (FLAME): a randomised placebo-controlled trial

BACKGROUND Hemiplegia and hemiparesis are the most common deficits caused by stroke. A few small clinical trials suggest that fluoxetine enhances motor recovery but its clinical efficacy is unknown. We therefore aimed to investigate whether fluoxetine would enhance motor recovery if given soon after an ischaemic stroke to patients who have motor deficits. METHODS In this double-blind, placebo-controlled trial, patients from nine stroke centres in France who had ischaemic stroke and hemiplegia or hemiparesis, had Fugl-Meyer motor scale (FMMS) scores of 55 or less, and were aged between 18 years and 85 years were eligible for inclusion. Patients were randomly assigned, using a computer random-number generator, in a 1:1 ratio to fluoxetine (20 mg once per day, orally) or placebo for 3 months starting 5-10 days after the onset of stroke. All patients had physiotherapy. The primary outcome measure was the change on the FMMS between day 0 and day 90 after the start of the study drug. Participants, carers, and physicians assessing the outcome were masked to group assignment. Analysis was of all patients for whom data were available (full analysis set). This trial is registered with ClinicalTrials.gov, number NCT00657163. FINDINGS 118 patients were randomly assigned to fluoxetine (n=59) or placebo (n=59), and 113 were included in the analysis (57 in the fluoxetine group and 56 in the placebo group). Two patients died before day 90 and three withdrew from the study. FMMS improvement at day 90 was significantly greater in the fluoxetine group (adjusted mean 34·0 points [95% CI 29·7-38·4]) than in the placebo group (24·3 points [19·9-28·7]; p=0·003). The main adverse events in the fluoxetine and placebo groups were hyponatraemia (two [4%] vs two [4%]), transient digestive disorders including nausea, diarrhoea, and abdominal pain (14 [25%] vs six [11%]), hepatic enzyme disorders (five [9%] vs ten [18%]), psychiatric disorders (three [5%] vs four [7%]), insomnia (19 [33%] vs 20 [36%]), and partial seizure (one [<1%] vs 0). INTERPRETATION In patients with ischaemic stroke and moderate to severe motor deficit, the early prescription of fluoxetine with physiotherapy enhanced motor recovery after 3 months. Modulation of spontaneous brain plasticity by drugs is a promising pathway for treatment of patients with ischaemic stroke and moderate to severe motor deficit. FUNDING Public French National Programme for Clinical Research.

Hemophagocytic syndrome in patients with acute myeloid leukemia undergoing intensive chemotherapy

Hemophagocytic lymphohistiocytosis is a condition of immune dysregulation characterized by severe organ damage induced by a hyperinflammatory response and uncontrolled T-cell and macrophage activation. Secondary hemophagocytic lymphohistiocytosis typically occurs in association with severe infections or malignancies. Patients with acute myeloid leukemia may be prone to develop hemophagocytic lymphohistiocytosis because of an impaired immune response and a high susceptibility to severe infections. In a series of 343 patients treated by intensive chemotherapy over a 5-year period in our center, we identified 32 patients (9.3%) with fever, very high ferritin levels, and marrow hemophagocytosis (i.e. patients with hemophagocytic lymphohistiocytosis). Compared to patients without hemophagocytic lymphohistiocytosis, these 32 patients had hepatomegaly, pulmonary or neurological symptoms, liver abnormalities, lower platelet count and higher levels of C-reactive protein as well as prolonged pancytopenia. A microbial etiology for the hemophagocytosis was documented in 24 patients: 14 bacterial infections, 9 Herpesviridae infections and 11 fungal infections. The treatment of hemophagocytic lymphohistiocytosis consisted of corticosteroids and/or intravenous immunoglobulins along with adapted antimicrobial therapy. Patients with hemophagocytic lymphohistiocytosis had a median overall survival of 14.9 months, which was significantly shorter than that of patients without hemophagocytic lymphohistiocytosis (22.1 months) (P=0.0016). Hemophagocytic lymphohistiocytosis was significantly associated with a higher rate of induction failure, mainly due to deaths in aplasia. Hemophagocytic lymphohistiocytosis can be diagnosed in up to 10% of patients with acute myeloid leukemia undergoing intensive chemotherapy and is associated with early mortality. Fever, very high ferritin levels and marrow hemophagocytosis represent the cornerstone of the diagnosis. Further biological studies are needed to better characterize and recognize this syndrome in patients with acute myeloid leukemia.

Telaprevir- and boceprevir-based tritherapies in real practice for F3-F4 pretreated hepatitis C virus patients.

AIM To assess, in a routine practice setting, the sustained virologic response (SVR) to telaprevir (TPV) or boceprevir (BOC) in hepatitis C virus (HCV) null-responders or relapsers with severe liver fibrosis. METHODS One hundred twenty-five patients were treated prospectively for 48 wk with TPV or BOC + pegylated-interferon (peg-INF) α2a + ribavirin (PR) according to standard treatment schedules without randomization. These patients were treated in routine practice settings in 10 public or private health care centers, and the data were prospectively collected. Only patients with severe liver fibrosis (Metavir scores of F3 or F4 upon liver biopsy or liver stiffness assessed by elastography), genotype 1 HCV and who were null-responders or relapsers to prior PR combination therapy were included in this study. RESULTS The Metavir fibrosis scores were F3 in 35 (28%) and F4 in 90 (72%) of the patients. In total, 62.9% of the patients were null-responders and 37.1% relapsers to the previous PR therapy. The overall SVR rate at 24 wk post-treatment withdrawal was 59.8%. The SVR was 65.9% in the TPV group and 44.1% in the BOC group. Independent predictive factors of an SVR included a response to previous treatment, relapsers vs null-responders [OR = 3.9; (1.4, 10.6), P = 0.0084], a rapid virological response (RVR) [OR 6.9 (2.6, 18.2), P = 0.001] and liver stiffness lower than 21.3 kPa [OR = 8.2 (2.3, 29.5), P = 0.001]. During treatment, 63 patients (50.8%) had at least one severe adverse event (SAE) of grade 3 or 4. A multivariate analysis identified two factors associated with SAEs: female gender [OR = 2.4 (1.1, 5.6), P = 0.037] and a platelet count below 150 × 10(3)/ mm(3) [OR = 5.3 (2.3, 12.4), P ≤ 0.001]. CONCLUSION More than half of these difficult-to-treat patients achieved an SVR and had SAEs in an actual practice setting. The SVR rate was influenced by the response to previous PR treatment, the RVR and liver stiffness.

Impact of obesity in favorable‐risk AML patients receiving intensive chemotherapy

We assessed the influence of obesity on the characteristics and prognosis of acute myeloid leukemia (AML). Indeed, safety of intensive chemotherapy and outcome of obese AML patients in a real‐life setting are poorly described, and chemotherapy dosing remains challenging. We included 619 consecutive genetically‐defined cases of AML treated with intensive chemotherapy between 2004 and 2012. In this cohort, 93 patients (15%) were classified in the obese category according to WHO classification; 59% of them received capped doses of chemotherapy because of a body surface area above 2 m2. Obese patients were older and presented more often with cardiovascular comorbidities. Although obese patients had more frequently de novo AML, main characteristics of AML including white blood cell count, karyotype and mutations were well‐balanced between obese and non‐obese patients. After induction chemotherapy, early death and complete remission rates were similar. Overall (OS), event‐free (EFS) and disease‐free (DFS) survival were not significantly different compared to non‐obese patients. However, in the European LeukemiaNet (ELN) favorable subgroup, obese patients had lower median OS, EFS and DFS than non‐obese patients (18.4, 16.8 and 17.2 vs. 43.6, 31.8 and 29.7 months, respectively) and obesity showed a significant impact on OS (OR 2.54; P = 0.02) in multivariate models. Although we did not find any significant impact of obesity on outcome in the whole series, this study suggests that special efforts for chemotherapy dose optimization are needed in the ELN favorable subgroup since dose capping may be deleterious. Am. J. Hematol. 91:193–198, 2016.

Intensive chemotherapy, azacitidine, or supportive care in older acute myeloid leukemia patients: An analysis from a regional healthcare network

We assessed in a French regional healthcare network the distribution of treatments, prognostic factors, and outcome of 334 newly diagnosed acute myeloid leukemia patients aged 60 years or older over a 4‐year period of time (2007–2010). Patients were selected in daily practice for intensive chemotherapy (n = 115), azacitidine (n = 95), or best supportive care (n = 124). In these three groups, median overall survival was 18.9, 11.3, and 1.8 months, respectively. In the azacitidine group, multivariate analysis showed that overall survival was negatively impacted by higher age (P = 0.010 for one unit increase), unfavorable cytogenetics (P = 0.001), lymphocyte count <0.5 G/L (P = 0.015), and higher lactate dehydrogenase level (P = 0.005 for one unit increase). We compared the survival of patients treated by azacitidine versus intensive chemotherapy and best supportive care using time‐dependent analysis and propensity score matching. Patients treated by intensive chemotherapy had a better overall survival compared with those treated by azacitidine from 6 months after diagnosis, whereas patients treated by azacitidine had a better overall survival compared with those treated by best supportive care from 1 day after diagnosis. This study of “real life” practice shows that there is a room for low intensive therapies such as azacitidine in selected elderly acute myeloid leukemia patients. Am. J. Hematol. 89:E244–E252, 2014.

Undiagnosed airflow limitation in patients at cardiovascular risk.

BACKGROUND Chronic obstructive pulmonary disease (COPD) and cardiovascular diseases (CVD) share risk factors and impair each others prognosis. AIMS To assess the prevalence of airflow limitation (AL) compatible with COPD in a population at cardiovascular risk and to identify determinants of AL. METHODS All consecutive patients referred to the cardiovascular prevention unit of a university hospital in 2009 were studied in a cross-sectional analysis. Patients answered questionnaires on socioeconomic status, medical history and lifestyle, and underwent extensive physical examinations, biological measures and spirometry testing. AL was defined as FEV1/FVC<0.70, without any history of asthma. Determinants of AL were assessed using logistic regression. RESULTS The sample comprised 493 participants (mean age 57.4±11.1 years); 60% were men, 18% were current smokers, 42% were ex-smokers and 10% of patients had a history of CVD. Ten-year risk of coronary heart disease (CHD) according to the Framingham equation was intermediate (10-20%) for 25% of patients and high (>20%) for 10%. Prevalence of AL was 5.9% (95% confidence interval [CI] 4.0-8.3%) in the whole population and 4.3% (2.6-6.6%) among subjects in primary cardiovascular prevention. AL was independently associated with CVD (adjusted odds ratio 4.18, 95% CI 1.72-10.15; P=0.002) but not with Framingham CHD risk. More than 80% of patients screened with AL had not been diagnosed previously and more than one in two patients was asymptomatic. CONCLUSION Patients with CVD are at increased risk of AL and thus should benefit from AL screening as they are frequently asymptomatic.

Postoperative complications after craniotomy for brain tumor surgery

INTRODUCTION After elective craniotomy for brain tumour surgery, patients are usually admitted to an intensive care unit (ICU) for monitoring. Our goal was to evaluate the incidence and timing of neurologic and non-neurologic postoperative complications after brain tumour surgery, to determine factors associated with neurologic events and to evaluate the timing and causes of ICU readmission. PATIENTS AND METHODS This prospective, observational and analytic study enrolled 188 patients admitted to the ICU after brain tumour surgery. All postoperative clinical events during the first 24hours were noted and classified. Readmission causes and timing were also analysed. RESULTS Twenty-one (11%) of the patients were kept sedated after surgery; the remaining 167 patients were studied. Thirty one percent of the patients presented at least one complication (25% with postoperative nausea and vomiting (PONV), 16% with neurologic complications). The occurrence of neurological complications was significantly associated with the absence of preoperative motor deficit and the presence of higher intraoperative bleeding. Seven patients (4%) were readmitted to the ICU after discharge; 43% (n=3) of them had a posterior fossa surgery. CONCLUSION Postoperative complications, especially PONV, are frequent after brain tumour surgery. Moreover, 16% of patients presented a neurological complication, probably justifying the ICU postoperative stay for early detection. The absence of preoperative motor deficit and intraoperative bleeding seems to predict postoperative neurologic complications. Finally, patients may present complications after ICU discharge, especially patients with fossa posterior surgery, suggesting that ICU hospitalization may be longer in this type of surgery.

Dutch Lipid Clinic Network low-density lipoprotein cholesterol criteria are associated with long-term mortality in the general population.

BACKGROUND Heterozygous familial hypercholesterolaemia (HeFH) is a severe autosomal dominant disease that is underdiagnosed, inadequately treated and has a severe long-term cardiovascular risk. Few studies have evaluated the long-term risk of high low-density lipoprotein cholesterol (LDL-C) concentrations. AIM To evaluate long-term mortality in a large cohort of healthy subjects, according to LDL-C concentrations. METHODS Based on a sample of 6956 subjects visiting a preventive cardiology department, we selected adult subjects without a personal history of cardiovascular disease. From 1995 to 2011, 4930 healthy subjects were examined and followed up until 31 December 2011. All-cause deaths were collected exhaustively. A Cox-based multivariable analysis evaluated long-term total mortality risk according to Dutch Lipid Clinic Network (DLCN) LDL-C concentrations. RESULTS After a mean follow-up of 8.6 years, 123 all-cause deaths were recorded (cumulative mortality rate, 2.5%). In the final multivariable model, major risk factors such as age, sex, tobacco use and diabetes were significantly associated with mortality. After adjustment for age, sex, tobacco use, hypertension, diabetes and statin therapy, and in comparison with subjects with LDL-C<4 mmol/L (<155 mg/dL), subjects with LDL-C between 4 and <5 mmol/L (155 to <190 mg/dL) had a hazard ratio (HR) of 1.99 (95% confidence interval [CI] 1.31-3.02; P=0.001), subjects with LDL-C between 5 and <6.5 mmol/L (190 to <250 mg/dL) had an HR of 1.81 (95% CI, 1.06-3.02; P=0.030), subjects with LDL-C between 6.5 and<8.5 mmol/L (250 to <330 mg/dL) had an HR of 2.69 (95% CI, 1.06-6.88; P=0.038) and subjects with LDL-C ≥ 8.5 mmol/L (≥330 mg/dL) had an HR of 6.27 (95% CI, 0.84-46.57; P=0.073). After excluding patients on statins at baseline, subjects with LDL-C ≥ 8.5 mmol/L (≥330 mg/dL) had an HR of 8.17 (95% CI, 1.08-62.73; P=0.042). CONCLUSIONS The severity of LDL-C elevation is associated with a higher risk of death in healthy subjects. DLCN LDL-C concentrations may be used in daily practice to identify patients with HeFH who warrant aggressive treatment.

Diffusion MRI of the neck of the femur in Legg-Calve-Perthes disease: a preliminary study.

PURPOSE To evaluate diffusion MR imaging of the neck of the femur in Legg-Calve-Perthes disease (LCPD). MATERIAL AND METHODS This is a prospective study in 27 children followed for unilateral LCPD. Forty-six MRIs were carried out with bilateral quantification of the apparent diffusion coefficient (ADC) of the neck of the femur. The intra- and inter-observer variability of the ADC measurements was evaluated. The association between the ADC and age as well as the healthy or pathological status of the neck of the femur and the Catterall classification were looked for. RESULTS Intra- and inter-observer reproducibility of the ADC measurements was excellent. A statistically significant negative correlation between the ADC of the healthy neck of the femur and age was found. There was a significant increase in the ADC of the pathological neck of the femur compared to the healthy neck. The ratio of the pathological neck ADC and the healthy neck ADC was significantly associated with the Catterall classification. CONCLUSION The quantification of the ADC of the neck of the femur is reproducible. This could be useful in the treatment of LCPD, where there is an early and significant increase in the ADC on the pathological side. This increase could have a prognostic value, as it is correlated with the Catterall classification.

14-Year risk of all-cause mortality according to hypoglycaemic drug exposure in a general population.

Purpose Guidelines for management of patients with type 2 diabetes mellitus recommend the use of hypoglycaemic drugs when lifestyle interventions remain insufficient for glycaemic control. Recent trials have provided worrying safety data on certain hypoglycaemic drugs. The aim of this study was to assess 14-year risk of all-cause mortality according to hypoglycaemic drug exposure at baseline, in a general population. Methods Our analysis was based on the observational Third French MONICA survey on cardiovascular risk factors (1995–1997). Vital status was obtained 14 years after inclusion, and assessment of determinants of mortality was based on multivariable Cox modelling. Results There were 3336 participants and 248 deaths over the 14-year period. At baseline, there were 3162 (95%) non-diabetic, 46 (1%) untreated type 2 diabetic and 128 (4%) type 2 diabetic subjects with hypoglycaemic drug treatment (metformin alone (31%), sulfonylureas alone or in combination (49%), insulin alone or in combination (10%), or other treatments (9%)). After adjustment for duration of diabetes, history of diabetes complications, area of residence (centre), age, gender, educational level, alcohol consumption, smoking, blood pressure, LDL and HDL cholesterol, which all were significant and independent determinants of mortality, the hazard ratio for all-cause mortality was 3.22 [95% confidence interval: 0.87–11.9] for untreated diabetic subjects, 2.28 [0.98–5.26] for diabetics treated with metformin alone, 1.70 [0.92–3.16] for diabetics with sulfonylureas and 4.92 [1.70–14.3] for diabetic with insulin versus non-diabetic subjects. Conclusions Our results support the conclusion that until more evidence is provided from randomized trials, a prudent approach should be to restrain use of insulin to situations in which combinations of non-insulin agents have failed to appropriately achieve glycemic control, as it is recommended in the current guidelines for the management of type 2 diabetes.