Summary Background B lymphocytes are implicated in the pathogenesis of multiple sclerosis. We aimed to assess efficacy and safety of two dose regimens of the humanised anti-CD20 monoclonal antibody ...ocrelizumab in patients with relapsing-remitting multiple sclerosis. Methods We did a multicentre, randomised, parallel, double-blind, placebo-controlled study involving 79 centres in 20 countries. Patients aged 18–55 years with relapsing-remitting multiple sclerosis were randomly assigned (1:1:1:1) via an interactive voice response system to receive either placebo, low-dose (600 mg) or high-dose (2000 mg) ocrelizumab in two doses on days 1 and 15, or intramuscular interferon beta-1a (30 μg) once a week. The randomisation list was not disclosed to the study centres, monitors, project statisticians or to the project team at Roche. All groups were double blinded to group assignment, except the interferon beta-1a group who were rater masked. At week 24, patients in the initial placebo, 600 mg ocrelizumab, and interferon beta-1a groups received ocrelizumab 600 mg; the 2000 mg group received 1000 mg. Our primary endpoint was the total number of gadolinium-enhancing lesions (GEL) and T1-weighted MRI at weeks 12, 16, 20, and 24. Analyses were done on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov , number NCT00676715. Findings 218 (99%) of the 220 randomised patients received at least one dose of ocrelizumab, 204 (93%) completed 24 weeks of the study and 196 (89%) completed 48 weeks. In the intention-to-treat population of 218 patients, at week 24, the number of gadolinium-enhancing lesions was 89% (95% CI 68–97; p<0·0001) lower in the 600 mg ocrelizumab group than in the placebo group, and 96% (89–99; p<0·0001) lower in the 2000 mg group. In exploratory analyses, both 600 mg and 2000 mg ocrelizumab groups were better than interferon beta-1a for GEL reduction. We noted serious adverse events in two of 54 (4%; 95% CI 3·0–4·4) patients in the placebo group, one of 55 (2%; 1·3–2·3) in the 600 mg ocrelizumab group, three of 55 (5%; 4·6–6·3) in the 2000 mg group, and two of 54 (4%; 3·0–4·4) in the interferon beta-1a group. Interpretation The similarly pronounced effects of B-cell depletion with both ocrelizumab doses on MRI and relapse-related outcomes support a role for B-cells in disease pathogenesis and warrant further assessment in large, long-term trials. Funding F Hoffmann-La Roche Ltd, Biogen Idec Inc.
Summary Natalizumab is a new treatment option for patients with active relapsing-remitting multiple sclerosis. In phase III studies, natalizumab was highly effective and well tolerated; however, ...three cases of progressive multifocal leucoencephalopathy (PML) were identified (estimated incidence of one per 1000; 95% CI 0·2–2·8; mean treatment period 17·9 months). In this Review we summarise the current information on PML, the three confirmed cases of PML, and the results of an extensive safety assessment of all patients treated with natalizumab. On the basis of these reviews, we make recommendations for appropriate selection of candidates for natalizumab and pretreatment assessments. In addition, a three-step diagnostic and management algorithm was developed to monitor natalizumab-treated patients with multiple sclerosis for PML and other opportunistic infections. The algorithm includes strategies for clinical, MRI, and laboratory assessments. Maintaining clinical vigilance allows for early suspension of natalizumab in potential cases of PML, thereby increasing the opportunity for immune reconstitution, which may improve prognosis if PML is confirmed.
Current guidelines recommend an implantable cardioverter-defibrillator (ICD) according to the left ventricular ejection fraction (LVEF). However, they do not mandate volumetric LVEF assessment. We ...sought to determine whether volumetric LVEF measurement using cardiovascular magnetic resonance imaging (CMR-LVEF) is superior to conventional LVEF measurement using 2-dimensional transthoracic echocardiography (Echo-LVEF) for risk stratifying patients referred for primary prevention ICD. Patients who underwent primary prevention ICD implantation at our institution and had undergone preimplantation CMR-LVEF from November 2001 to February 2011 were identified. Volumetric CMR-LVEF was determined from cine short-axis data sets. CMR-LVEF and Echo-LVEF were extracted from the clinical reports. The end point was appropriate ICD discharge (shock and/or antitachycardia pacing). Of 48 patients, appropriate ICD discharge occurred in 9 (19%) within 29 ± 25 months (range 1 to 99, median 20). All patients met the Echo-LVEF criteria for ICD implantation; however 25% (95% confidence interval 13% to 37%) did not meet the CMR-LVEF criteria. None (0%) of these latter patients had received an appropriate ICD discharge. Using CMR-LVEF ≤30% as a threshold for ICD eligibility, 19 patients (40%) with a qualifying Echo-LVEF would not have been referred for ICD, and none (0%) received an ICD discharge.For primary prevention ICD implantation, volumetric CMR-LVEF might be superior to clinical Echo-LVEF for risk stratification and can identify a large minority of subjects in whom ICD implantation can be safely avoided. In conclusion, if confirmed by larger prospective series, volumetric methods such as CMR should be considered a superior “gatekeeper” for the identification of patients likely to benefit from primary prevention ICD implantation.
The purpose of this study was to assess regional cerebral perfusion distribution in patients with Alzheimer disease (AD) or mild cognitive impairment (MCI) using dynamic susceptibility contrast ...magnetic resonance imaging.
Regional changes of perfusion were evaluated in 34 patients with AD, 51 patients with MCI, and 23 healthy controls (HCs). Using region of interest analyses, regional cerebral blood flow (CBF), cerebral blood volume, and mean transit time were measured bilaterally in the hippocampus; the temporal, temporoparietal, frontal, and sensomotoric cortices; the anterior and posterior cingulate gyri; the lentiform nucleus; and the cerebellum.
A significant reduction of CBF in patients with AD compared to HCs was shown in the frontal and temporoparietal cortices bilaterally, the lentiform nuclei bilaterally, the left posterior cingulate gyrus, and the cerebellum. Compared with patients with MCI, patients with AD presented a reduction of CBF in the frontal cortices bilaterally, the left temporoparietal cortex, and the left anterior and posterior cingulate gyrus. In both hippocampi and the posterior cingulate gyrus, a trend to a slight increase of CBF in patients with MCI was noticed with a decrease in patients with AD.
Using dynamic susceptibility contrast magnetic resonance imaging, pathologic alterations of regional brain perfusion can be demonstrated in patients with AD compared to patients with MCI or HCs.
Radiation therapy (RT) is an integral part of Ewing sarcoma (EwS) therapy. The Ewing 2008 protocol recommended RT doses ranging from 45 to 54 Gy. However, some patients received other doses of RT. We ...analyzed the effect of different RT doses on event-free survival (EFS) and overall survival (OS) in patients with EwS.
The Ewing 2008 database included 528 RT-admitted patients with nonmetastatic EwS. Recommended multimodal therapy consisted of multiagent chemotherapy and local treatment consisting of surgery (S&RT group) and/or RT (RT group). EFS and OS were analyzed with uni- and multivariable Cox regression models including known prognostic factors such as age, sex, tumor volume, surgical margins, and histologic response.
S&RT was performed in 332 patients (62.9%), and 145 patients (27.5%) received definitive RT. Standard dose ≤ 53 Gy (d1) was admitted in 57.8%, high dose of 54 to 58 Gy (d2) in 35.5%, and very high dose ≥ 59 Gy (d3) in 6.6% of patients. In the RT group, RT dose was d1 in 11.7%, d2 in 44.1%, and d3 in 44.1% of patients. Three-year EFS in the S&RT group was 76.6% for d1, 73.7% for d2, and 68.2% for d3 (P = .42) and in the RT group 52.9%, 62.5%, and 70.3% (P = .63), respectively. Multivariable Cox regression revealed age ≥ 15 years (hazard ratio HR, 2.68; 95% confidence interval CI, 1.63-4.38) and nonradical margins (HR, 1.76; 95% CI, 1.05-2.93) for the S&RT group (sex, P = .96; histologic response, P = .07; tumor volume, P = .50; dose, P = .10) and large tumor volume (HR, 2.20; 95% CI, 1.21-4.0) for the RT group as independent factors (dose, P = .15; age, P = .08; sex, P = .40).
In the combined local therapy modality group, treatment with higher RT dose had an effect on EFS, whereas higher dose of radiation when treated with definitive RT was associated with an increased OS. Indications for selection biases for dosage were found. Upcoming trials will assess the value of different RT doses in a randomized manner to control for potential selection bias.
Background Sensitive troponin (Tn) assays have been developed for the evaluation of patients with suspected acute coronary syndrome (ACS). We sought to compare the performance of a commercially ...available sensitive Tn I (sTnI) and precommercial highly sTnI (hsTnI) method to conventional Tn (cTn) assays. Methods Among patients with acute chest pain but normal cTn in the emergency department of 6 centers, sTnI and hsTnI were measured at baseline, 2 and 4 hours after presentation. Diagnostic accuracy of sTnI and hsTnI relative to cTn for diagnosis during index hospitalization as well as their associations with coronary artery disease in patients randomized to coronary computed tomographic angiography (CTA) was assessed. Results Overall, 322 patients were enrolled, of whom 161 had a CTA; 28 had ACS (8.7%), including 21 with unstable angina pectoris (UAP). Both sTnI and hsTnI values at baseline and second draw had significantly higher sensitivity for ACS and UAP than cTn and had significantly greater area under the receiver operator characteristic curve than cTn at first and second draws. Compared with cTn, 29% of ACS cases previously categorized as UAP were reclassified to acute myocardial infarction with sTnI or hsTnI. An hsTnI below limit of detection had 100% negative predictive value for ACS or significant coronary artery stenosis in those randomized to CTA. Conclusions In patients with acute chest discomfort, use of sTnI and hsTnI methods led to significant improvement in the early diagnostic accuracy for ACS, reclassifying one-third of UAP to myocardial infarction. Very low values for hsTnI excluded underlying coronary artery disease.
The objective was to study the incidence of febrile seizures prospectively determined through age 4 years. A standardized randomized cluster sample of nulliparous pregnant women from a geographically ...defined area were prospectively followed from the beginning of pregnancy through the child's age 4. Data on children eligible for the study ( n = 1287), including febrile seizures, sociodemographic data, developmental milestones, and chronic diseases, were prospectively collected from families and health care staff. Data were available for 1033 children. Through age 4, the average annual incidence of febrile seizures was 14 per 1000 person-years (15 for girls and 13.5 for boys). The incidence rate through age 4 was 6.9% (7.3% for girls and 6.5% for boys). The incidence rate of febrile seizures in Finnish children is comparable to that reported previously. The higher figure, based on prospective rather than retrospective data, may give a more accurate picture of the clinical importance of febrile seizures.
Abstract To examine the prevalence of pain, substance use disorder (SUD) diagnoses, and opioid analgesic prescription patterns among veterans infected with the hepatitis C virus (HCV), a ...retrospective review of the medical records of 8,224 HCV-positive (HCV+) veterans was performed. Twenty-nine percent and 46% of HCV+ patients were prescribed opioids in the prior one and three years, respectively. Sixty-seven percent of HCV+ patients had documented pain diagnoses and 56% had SUD diagnoses. Patients with co-occurring pain and SUD were less likely to be prescribed opioids than patients with pain only (prior year: 36% vs. 43%, P < 0.001; three years: 56% vs. 60%, P < 0.01). There were no differences in numbers of early opioid prescription fills or numbers of opioid prescribers when comparing patients with co-occurring pain and SUD to patients with pain only. Veterans with co-occurring pain and opioid use disorder had fewer early opioid fills than veterans with pain only (prior year: 2.6 vs. 5.3 days, P < 0.01; three years: 6.1 vs. 13.4 days, P < 0.001). These data demonstrate that pain and SUD diagnoses were common among HCV+ patients, and that opioids were frequently prescribed. Co-occurring SUD was not associated with indicators of prescription opioid misuse.
Objectives We sought to determine the prevalence of noncardiac pathology in a large consecutive series of patients referred for clinical cardiac magnetic resonance (CMR) studies. Background The ...imaging field for many CMR sequences extends outside of the heart border. As a result, noncardiac pathology may be identified. These noncardiac findings have clinical significance because they often lead to subsequent imaging/testing and intervention. The prevalence of noncardiac findings on clinical CMR studies has not been well described. Methods The reports of all 1,534 (62% male, age 50 ± 15 years) clinical CMR studies performed at an academic medical center during calendar years 2002 to 2006 were reviewed. All studies had been interpreted by both a staff cardiologist (level III trained in CMR) and a board-certified radiologist (with fellowship training in CMR). For each study, sex, age, indication for CMR study, and reported noncardiac pathology were extracted. Follow-up for each major noncardiac pathology was evaluated by reviewing the patient's medical center electronic medical record. These noncardiac pathologies were then categorized as significant if an intervention or change in the patient's management ensued. Results A total of 116 (7.6%) studies had at least one noncardiac finding. These findings included 55 major findings (e.g., lymphadenopathy, lung abnormalities, mediastinal masses) in 48 distinct reports (prevalence of 3.1%) and 74 minor findings (e.g., small pleural effusions, liver cysts, renal cysts) in 70 distinct reports (prevalence of 4.6%). The majority (62%) of major findings were previously known, with only 8 findings in 6 (0.4%) of 1,534 reports ultimately deemed to be new and clinically important/significant. The age of those with noncardiac pathology was greater (54 ± 16 years vs. 49 ± 16 years, p < 0.001). Conclusions In this large series of consecutive clinical CMR studies interpreted by both staff cardiologists and radiologists, noncardiac pathology is uncommonly reported. When reported, the majority of major findings are previously known. New major findings were detected in <0.5% of reports.
The "frozen elephant trunk" procedure (FET) represents the therapy of choice for extended aortic diseases. The aim of our study was to analyze whether 90 minutes of selective cerebral perfusion (SCP) ...at 28 °C followed by permanent occlusion of the thoracic segmental arteries (TSA) would cause spinal cord ischemia in a porcine model.
14 pigs (41 ± 3 kg) were cooled on CPB to 28 °C. After aortic clamping, SCP was established for 90 minutes. Randomly, in 7 animals the TSA were clipped (T4-T13); the TSA of 7 animals remained untouched. After the animals were weaned from CPB, hemodynamic data were registered for 120 minutes. Regional spinal cord blood flow (SCBF) was calculated, and motor-evoked potentials (MEP) were assessed at 6 time points. After sacrifice of the animals, the spinal cord was analyzed histologically by use of a schematic grading system (0 = normal; 8 = total necrosis).
During SCP the SCBF was maintained at baseline (5.9 ± 2.4 mL/min/100 g) in the T4-T13 region but showed a decrease (from 8.4 ± 4.3 to 1.3 ± 1.5 mL/min/100 g) in the L1-L5 region. During reperfusion it increased, with two to three times higher values in the nonclipped animals. After 90 minutes of SCP, the MEP reached lower levels in the L1-L5 region of the TSA-clipped animals: 59% ± 7% vs 84 ± 15% (vastus medialis muscle) and 48% ± 6% vs 82% ± 26% (tibialis anterior muscle). The MEP recovered only in the nonclipped group. Higher ischemia rates were seen in the L1-L5 region of the TSA-clipped animals (score: 6.0 ± 0.6 vs 2.5 ± 2.3).
90 minutes of SCP provided sufficient spinal cord protection during arch replacement at 28 °C. In combination with permanent TSA occlusion, the lumbar spinal cord perfusion may be altered, which causes functional and structural damage.
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