Sandrine Katsahian

Aortic Stiffness Is an Independent Predictor of Fatal Stroke in Essential Hypertension

Background and Purpose— Pulse pressure is a stronger predictor of cardiovascular events than systolic or diastolic blood pressure in large cohorts of French and North American patients. However, its influence on stroke is controversial. Large-artery stiffness is the main determinant of pulse pressure. The influence of arterial stiffness on the occurrence of stroke has never been demonstrated. Our aim was to establish the relationship between aortic stiffness and stroke death in hypertensive patients. Methods— We included, in a longitudinal study, 1715 essential hypertensive patients who had a measurement of arterial stiffness at entry (ie, between 1980 and 2001) and no overt cardiovascular disease or symptoms. Mean follow-up was 7.9 years. At entry, aortic stiffness was assessed from the carotid-femoral pulse wave velocity. A Cox proportional hazard regression model was used to estimate the relative risk (RR) of stroke and coronary deaths. Results— Mean±SD age at entry was 51±13 years. Twenty-five fatal strokes and 35 fatal coronary events occurred. Pulse wave velocity significantly predicted the occurrence of stroke death in the whole population. There was a RR increase of 1.72 (95% CI, 1.48 to 1.96;P <0.0001) for each SD increase in pulse wave velocity (4 m/s). The predictive value of pulse wave velocity remained significant (RR=1.39 [95% CI, 1.08 to 1.72];P =0.02) after full adjustment for classic cardiovascular risk factors, including age, cholesterol, diabetes, smoking, mean blood pressure, and pulse pressure. In this population, pulse pressure significantly predicted stroke in univariate analysis, with a RR increase of 1.33 (95% CI, 1.16 to 1.51) for each 10 mm Hg of pulse pressure (P <0.0001) but not after adjustment for age (RR=1.19 [95% CI, 0.96 to 1.47];P =0.10). Conclusions— This study provides the first evidence, in a longitudinal study, that aortic stiffness is an independent predictor of fatal stroke in patients with essential hypertension.

High-Dose Therapy and Autologous Blood Stem-Cell Transplantation Compared With Conventional Treatment in Myeloma Patients Aged 55 to 65 Years: Long-Term Results of a Randomized Control Trial From the Group Myelome-Autogreffe

PURPOSE To study the impact of high-dose therapy (HDT) with autologous stem-cell support in patients with symptomatic multiple myeloma (MM) between the ages of 55 and 65 years. PATIENTS AND METHODS One hundred ninety patients between 55 and 65 years old who had newly diagnosed stage II or III MM were randomly assigned to receive either conventional chemotherapy (CCT; ie, monthly courses of a regimen of vincristine, melphalan, cyclophosphamide, and prednisone) or HDT and autologous blood stem-cell transplantation (using either melphalan alone 200 mg/m(2) intravenous [IV] or melphalan 140 mg/m(2) IV plus busulfan 16 mg/kg orally as pretransplantation cytoreduction). RESULTS Within a median follow-up of 120 months, median event-free survival (EFS) times were 25 and 19 months in the HDT and CCT groups, respectively. Median overall survival (OS) time was 47.8 months in the HDT group compared with 47.6 months in the CCT group. A trend to better EFS (P = .07) was observed in favor of HDT, whereas OS curves were not statistically different (P = .91). The period of time without symptoms, treatment, and treatment toxicity (TwiSTT) was significantly longer for the HDT patients than for the CCT patients (P = .03). CONCLUSION With a median follow-up time of approximately 10 years, this randomized trial confirmed a benefit of HDT in terms of EFS and TwiSTT but did not provide evidence for superiority of HDT over CCT in OS of patients aged 55 to 65 years with symptomatic newly diagnosed MM.

Fever control using external cooling in septic shock: a randomized controlled trial.

RATIONALE Fever control may improve vascular tone and decrease oxygen consumption, but fever may contribute to combat infection. OBJECTIVES To determine whether fever control by external cooling diminishes vasopressor requirements in septic shock. METHODS In a multicenter randomized controlled trial, febrile patients with septic shock requiring vasopressors, mechanical ventilation, and sedation were allocated to external cooling (n = 101) to achieve normothermia (36.5-37°C) for 48 hours or no external cooling (n = 99). Vasopressors were tapered to maintain the same blood pressure target in the two groups. The primary endpoint was the number of patients with a 50% decrease in baseline vasopressor dose after 48 hours. MEASUREMENTS AND MAIN RESULTS Body temperature was significantly lower in the cooling group after 2 hours of treatment (36.8 ± 0.7 vs. 38.4 ± 1.1°C; P < 0.01). A 50% vasopressor dose decrease was significantly more common with external cooling from 12 hours of treatment (54 vs. 20%; absolute difference, 34%; 95% confidence interval [95% CI], -46 to -21; P < 0.001) but not at 48 hours (72 vs. 61%; absolute difference, 11%; 95% CI, -23 to 2). Shock reversal during the intensive care unit stay was significantly more common with cooling (86 vs. 73%; absolute difference, 13%; 95% CI, 2 to 25; P = 0.021). Day-14 mortality was significantly lower in the cooling group (19 vs. 34%; absolute difference, -16%; 95% CI, -28 to -4; P = 0.013). CONCLUSIONS In this study, fever control using external cooling was safe and decreased vasopressor requirements and early mortality in septic shock.

Presence of B Cells in Tertiary Lymphoid Structures Is Associated with a Protective Immunity in Patients with Lung Cancer

RATIONALE It is now well established that immune responses can take place outside of primary and secondary lymphoid organs. We previously described the presence of tertiary lymphoid structures (TLS) in patients with non-small cell lung cancer (NSCLC) characterized by clusters of mature dendritic cells (DCs) and T cells surrounded by B-cell follicles. We demonstrated that the density of these mature DCs was associated with favorable clinical outcome. OBJECTIVES To study the role of follicular B cells in TLS and the potential link with a local humoral immune response in patients with NSCLC. METHODS The cellular composition of TLS was investigated by immunohistochemistry. Characterization of B-cell subsets was performed by flow cytometry. A retrospective study was conducted in two independent cohorts of patients. Antibody specificity was analyzed by ELISA. MEASUREMENTS AND MAIN RESULTS Consistent with TLS organization, all stages of B-cell differentiation were detectable in most tumors. Germinal center somatic hypermutation and class switch recombination machineries were activated, associated with the generation of plasma cells. Approximately half of the patients showed antibody reactivity against up to 7 out of the 33 tumor antigens tested. A high density of follicular B cells correlated with long-term survival, both in patients with early-stage NSCLC and with advanced-stage NSCLC treated with chemotherapy. The combination of follicular B cell and mature DC densities allowed the identification of patients with the best clinical outcome. CONCLUSIONS B-cell density represents a new prognostic biomarker for NSCLC patient survival, and makes the link between TLS and a protective B cell-mediated immunity.

Brachial Pressure–Independent Reduction in Carotid Stiffness After Long-Term Angiotensin-Converting Enzyme Inhibition in Diabetic Hypertensives

Hypertension and diabetes are associated with an increased arterial stiffness. A direct blood pressure–independent effect of angiotensin-converting enzyme inhibitors on arterial stiffness has never been unequivocally demonstrated. In this mechanistic study, we used an experimental design in which patients responding to 1 month treatment with 4 mg perindopril were randomized double-blind to either 4 mg perindopril or 8 mg perindopril for 6 months. We determined carotid distensibility with echotracking and applanation tonometry at baseline and after the 7-month treatment period in 57 essential hypertensive patients with type 2 diabetes (age 63±7 years). We monitored ambulatory blood pressure at baseline and after treatment. After 7 months treatment, 24-hour ambulatory blood pressure significantly decreased, with no significant difference between 4 mg and 8 mg perindopril. Carotid distensibility increased more after 8 mg perindopril compared with 4 mg perindopril (8 mg: from 13.1±5.9 to 16.0±6.7 kPa−1×10−3; 4 mg: from 13.2±5.2 to 12.7±5.9 kPa−1×10−3; ANOVA, dose-period interaction, P<0.05). Carotid internal diameter and elastic modulus were significantly lower after 8 mg perindopril compared with 4 mg perindopril, independent of blood pressure reduction. These results indicate a dose-dependent and blood pressure–independent reduction in carotid stiffness under chronic treatment with an angiotensin-converting enzyme inhibitor. They suggest that arterial distensibility was increased through an inward remodeling, leading to a reduction in wall stress, thus reducing elastic modulus. They also suggest that long-term administration of high doses (8 mg) of perindopril is required to improve carotid structure and function in hypertensive patients with type 2 diabetes.

Prospective Evaluation of a Polymerase Chain Reaction–ELISA Targeted to Aspergillus fumigatus and Aspergillus flavus for the Early Diagnosis of Invasive Aspergillosis in Patients with Hematological Malignancies

BACKGROUND Current laboratory and radiological methods for diagnosis of invasive aspergillosis (IA) lack sensitivity and specificity. METHODS We prospectively evaluated the diagnostic value of twice-weekly screening for circulating Aspergillus fumigatus and A. flavus DNA with a polymerase chain reaction-enzyme-linked immunosorbent assay (PCR-ELISA). RESULTS Among the 201 adult patients with hematological malignancies who were included in the study, 55 IA cases were diagnosed. On the basis of the analysis of 1205 serum samples from 167 patients, the sensitivity, specificity, and positive and negative predictive values of the PCR-ELISA for proven and probable IA cases were 63.6%, 89.7%, 63.6%, and 89.7%, respectively, when samples with 2 consecutive positive results were used. The use of a combination of the PCR-ELISA and a galactomannan (GM) assay increased the sensitivity to 83.3%, increased the negative predictive value to 97.6%, and decreased the specificity to 69.8%. In most patients with IA, PCR-ELISA positivity anticipated or was simultaneous with the initiation of antifungal therapy, the abnormalities found by computed tomography, the mycological/histological diagnosis, and the GM positivity. Overall, 56.3% of the patients had at least 1 positive sample, and the false single-positive rate was 44.8%. CONCLUSIONS In addition to serial screening for GM antigenemia and radiological surveillance, PCR-ELISA may improve the rates of early diagnosis of IA and the management of patients with hematological malignancies.

Management of large-vessel vasculitis with FDG-PET: a systematic literature review and meta-analysis.

AbstractWe aimed to clarify the role of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) in the management of large-vessel vasculitis (LVV), focusing on 3 issues which are as follows: describe and determine the different FDG-PET criteria for the diagnosis of vascular inflammation, the performance of FDG-PET for the diagnosis of large-vessel inflammation in giant cell arteritis (GCA) patients, and the performance of FDG-PET to evaluate the disease inflammatory activity in Takayasu arteritis (TA) patients.MEDLINE, Cochrane Library, and EMBASE database were searched for articles that evaluated the value of FDG-PET in LVV, from January 2000 to December 2013. Inclusion criteria were American College of Rheumatology criteria for GCA or TA, definition PET positivity threshold, and >4 cases included. Sensitivity (Se) and specificity (Sp) of FDG-PET for the diagnosis of large-vessel inflammation were calculated from each included individual study, and then pooled for meta-analysis with a random-effects model.Twenty-one studies (413 patients, 299 controls) were included in the systematic review. FDG-PET showed FDG vascular uptake in 70% (288/413) of patients and 7% (22/299) of controls. Only vascular uptake equal to or higher than the liver uptake was significantly different between GCA/TA patients and controls (P < 0.001). The meta-analysis of GCA patients (4 studies, 57 patients) shows that FDG-PET has high Se and Sp for the diagnosis of large-vessel inflammation in GCA patients in comparison to controls, with a pooled Se at 90% (95% confidence interval [CI], 79%–93%) and a pooled Sp at 98% (95% CI, 94%–99%). The meta-analysis of TA patients (7 studies, 191 patients) shows that FDG-PET has a pooled Se at 87% (95% CI, 78%–93%) and Sp at 73% (95% CI, 63%–81%) for the assessment of disease activity in TA, with up to 84% Sp, with studies using National Institutes of Health criteria as the disease activity assessment scale.FDG-PET showed good performances in the diagnosis of large-vessel inflammation, with higher accuracy in GCA patients than in TA patients. Although a vascular uptake equal to or higher than the liver uptake appears to be a good criterion for the diagnosis of vascular inflammation, further studies are needed to define the threshold of significance as well as the clinical significance of the vascular uptake.

Effectiveness of chest physiotherapy in infants hospitalized with acute bronchiolitis: a multicenter, randomized, controlled trial.

Vincent Gajdos and colleagues report results of a randomized trial conducted among hospitalized infants with bronchiolitis. They show that a physiotherapy technique (increased exhalation and assisted cough) commonly used in France does not reduce time to recovery in this population.

Glucose level is a major determinant of carotid intima-media thickness in patients with hypertension and hyperglycemia.

Background A causal relationship has been established between hyperglycemia and cardiovascular diseases, but no threshold has been retained to determine a ‘glycemia-associated’ cardiovascular risk. Carotid intima–media thickness (CIMT) is an independent predictor for cardiovascular events. High blood pressure is a major determinant of CIMT. Objectives To determine the influence of fasting glycemia on CIMT in hypertensive patients with either normal fasting glucose, impaired fasting glucose (IFG) or type 2 diabetes (DM-2). Methods We included 158 essential hypertensive patients with either normal fasting glucose (n = 74), IFG (n = 24) or DM-2 (n = 60) in a cross-sectional study. Common carotid IMT was measured with a high resolution echotracking system. Results CIMT of DM-2 patients was significantly higher than that of IFG and normal fasting glucose patients (809 ± 180, 697 ± 151 and 689 ± 134 μm, respectively; analysis of variance (ANOVA) P < 0.0001). In multivariate analysis in normal fasting glucose patients, local pulse pressure and age were the major determinants of CIMT, whereas glycemia was not. In IFG and DM-2 patients, fasting glycemia was strongly associated with CIMT, explaining 21 and 18% of its variance, respectively. Particularly, in IFG patients, an increase in 1 mmol/l glycemia was associated with a 165 μm increase in CIMT. In hyperglycemic patients, with either IFG or DM-2, age was an important determinant of CIMT, whereas local pulse pressure was not. Conclusion These data suggest that glycemia is a major independent determinant of CIMT in hypertensive hyperglycemic patients, not only in DM-2 patients but also at the earlier stage of IFG, offsetting the mechanical role of local pulse pressure.

A meta-analysis on data from 575 patients with multiple myeloma randomly assigned to either high-dose therapy or conventional therapy

Abstract: Long-term results of high-dose therapy followed by autologous stem cell transplantation (HDT-ASCT) as the first-line treatment for patients with myeloma are still poorly reported. To gain further insight in the long-term benefits of first-line HDT-ASCT compared with conventional therapy in myeloma, we performed a meta-analysis of individual patient data. We selected randomized trials evaluating HDT-ASCT in patients with previously untreated myeloma from 1990 to 1998, all with a median follow-up of 5 years or more. Individual data of the 3 selected trials were obtained from the study authors. Outcomes were survival, treatment-related mortality, and time without symptoms of disease or toxicity of treatment (TWiST). Five hundred seventy-five patients were analyzed, including 435 deaths (104 months of median follow-up). Compared with conventional therapy and adjusting for prognostic covariates, HDT-ASCT did not significantly prolong long-term survival (stratified hazard ratio, 0.887; 95% confidence interval, 0.735-1.072). This was not modified by accounting for heterogeneity in baseline risks, in treatment of relapse, or in outcomes across trials. There was no evidence of interaction between treatment effect on survival and presentation features. In contrast, a mean gain of 14.5 months (95% confidence interval, 9.9-19.1 mo) in TWiST was observed in the HDT-ASCT group compared with conventional therapy. In conclusion, we showed only a trend toward a long-term survival benefit of HDT-ASCT over conventional therapy for first-line treatment of myeloma. However, HDT-ASCT clearly delayed time to relapse, with a resulting 14.5 months benefit in mean TWiST. Abbreviations: CI = confidence interval, HDT-ASCT = high-dose therapy followed by autologous stem cell transplantation, HR = hazard ratio, IFM = Intergroupe Français du Myélome, MAG = Myélome Autogreffe Group, TRM = treatment-related mortality, TWiST = time without symptoms of disease or toxicity of treatment.