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BACKGROUND: Alzheimer's disease is a progressive, irreversible, and fatal disease for which accumulation of amyloid beta is thought to play a key role in pathogenesis. Aducanumab is a human monoclonal antibody directed against aggregated soluble and insoluble forms of amyloid beta. OBJECTIVES: We evaluated the efficacy and safety of aducanumab in early Alzheimer's disease. DESIGN: EMERGE and ENGAGE were two randomized, double-blind, placebo-controlled, global, phase 3 studies of aducanumab in patients with early Alzheimer's disease. SETTING: These studies involved 348 sites in 20 countries. PARTICIPANTS: Participants included 1638 (EMERGE) and 1647 (ENGAGE) patients (aged 50-85 years, confirmed amyloid pathology) who met clinical criteria for mild cognitive impairment due to Alzheimer's disease or mild Alzheimer's disease dementia, of which 1812 (55.2%) completed the study. INTERVENTION: Participants were randomly assigned 1:1:1 to receive aducanumab low dose (3 or 6 mg/kg target dose), high dose (10 mg/kg target dose), or placebo via IV infusion once every 4 weeks over 76 weeks. MEASUREMENTS: The primary outcome measure was change from baseline to week 78 on the Clinical Dementia Rating Sum of Boxes (CDR-SB), an integrated scale that assesses both function and cognition. Other measures included safety assessments; secondary and tertiary clinical outcomes that assessed cognition, function, and behavior; and biomarker endpoints. RESULTS: EMERGE and ENGAGE were halted based on futility analysis of data pooled from the first approximately 50% of enrolled patients; subsequent efficacy analyses included data from a larger data set collected up to futility declaration and followed prespecified statistical analyses. The primary endpoint was met in EMERGE (difference of -0.39 for high-dose aducanumab vs placebo [95% CI, -0.69 to -0.09; P=.012; 22% decrease]) but not in ENGAGE (difference of 0.03, [95% CI, -0.26 to 0.33; P=.833; 2% increase]). Results of biomarker substudies confirmed target engagement and dose-dependent reduction in markers of Alzheimer's disease pathophysiology. The most common adverse event was amyloid-related imaging abnormalities-edema. CONCLUSIONS: Data from EMERGE demonstrated a statistically significant change across all four primary and secondary clinical endpoints. ENGAGE did not meet its primary or secondary endpoints. A dose- and time-dependent reduction in pathophysiological markers of Alzheimer's disease was observed in both trials.
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Enfermedad de Alzheimer , Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides , Anticuerpos Monoclonales Humanizados/uso terapéutico , Biomarcadores , HumanosRESUMEN
Amyloid-related imaging abnormalities (ARIA) are adverse events reported in Alzheimer's disease trials of anti-amyloid beta (Aß) therapies. This review summarizes the existing literature on ARIA, including bapineuzumab, gantenerumab, donanemab, lecanemab, and aducanumab studies, with regard to potential risk factors, detection, and management. The pathophysiology of ARIA is unclear, but it may be related to binding of antibodies to accumulated Aß in both the cerebral parenchyma and vasculature, resulting in loss of vessel wall integrity and increased leakage into surrounding tissues. Radiographically, ARIA-E is identified as vasogenic edema in the brain parenchyma or sulcal effusions in the leptomeninges/sulci, while ARIA-H is hemosiderin deposits presenting as microhemorrhages or superficial siderosis. ARIA tends to be transient and asymptomatic in most cases, typically occurring early in the course of treatment, with the risk decreasing later in treatment. Limited data are available on continued dosing following radiographic findings of ARIA; hence, in the event of ARIA, treatment should be continued with caution and regular monitoring. Clinical trials have implemented management approaches such as temporary suspension of treatment until symptoms or radiographic signs of ARIA have resolved or permanent discontinuation of treatment. ARIA largely resolves without concomitant treatment, and there are no systematic data on potential treatments for ARIA. Given the availability of an anti-Aß therapy, ARIA monitoring will now be implemented in routine clinical practice. The simple magnetic resonance imaging sequences used in clinical trials are likely sufficient for effective detection of cases. Increased awareness and education of ARIA among clinicians and radiologists is vital.
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Enfermedad de Alzheimer , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/tratamiento farmacológico , Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Anticuerpos Monoclonales/uso terapéutico , Encéfalo/metabolismo , Humanos , Imagen por Resonancia MagnéticaRESUMEN
Infection with the dematiaceous environmental fungus Exophiala, an emerging pathogen in immunocompromised individuals, poses a diagnostic and therapeutic challenge. Herein, we report the first Exophiala dermatitidis fungemia case, to our knowledge, in an allogeneic hematopoietic stem cell transplant patient with graft-versus-host disease, expanding the clinical setting where Exophiala species mycosis should be suspected.
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Enfermedades Transmisibles Emergentes/microbiología , Exophiala/aislamiento & purificación , Enfermedad Injerto contra Huésped/complicaciones , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Feohifomicosis/tratamiento farmacológico , Feohifomicosis/microbiología , Antifúngicos/administración & dosificación , Antifúngicos/uso terapéutico , Farmacorresistencia Fúngica , Exophiala/efectos de los fármacos , Humanos , Linfoma de Células del Manto/terapia , Masculino , Persona de Mediana Edad , Infecciones OportunistasRESUMEN
Parainfluenza infection is a cause of significant morbidity and mortality in allogeneic hematopoietic stem cell transplant (HSCT) patients. DAS181 is a novel antiviral agent with activity against influenza and parainfluenza. We report the first 2 cases, to our knowledge, of successful DAS181 use in ventilated HSCT patients with severe parainfluenza lung disease.
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Antivirales/uso terapéutico , Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas , Huésped Inmunocomprometido , Inmunosupresores/uso terapéutico , Infecciones por Paramyxoviridae/tratamiento farmacológico , Neumonía Viral/tratamiento farmacológico , Proteínas Recombinantes de Fusión/uso terapéutico , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Infecciones por Paramyxoviridae/complicaciones , Infecciones por Paramyxoviridae/inmunología , Neumonía Viral/complicaciones , Neumonía Viral/inmunología , Prednisona/uso terapéutico , Respiración Artificial , Insuficiencia Respiratoria/etiología , Insuficiencia Respiratoria/terapia , Sirolimus/uso terapéutico , Resultado del TratamientoRESUMEN
The purpose of this project was to calculate the ROI of the middle cerebral artery (MCA) in patients with acute stroke to establish if this measurement could be used as another primary sign of infarction even if other established primary signs of infarction are absent. CT brain scans of 465 patients, who presented in the emergency room in the first six hours after the onset of symptoms, were studied retrospectively. Two polygonal ROIs were drawn on the M1 segments of both middle cerebral arteries and three parameters were calculated automatically: HU density, volume and surface of the corresponding artery segment. The age and gender of each patient were also recorded, as well as the CT findings (including the hyperdense appearance of MCA and the insular ribbon sign) and the neurological findings. The range of calculated ROIs was between 9 HU and 134 HU. A statistically significant difference was reported in ROI measurement between the right and left MCA in patients with left (or right) hemiparesis respectively. A significant difference was also reported between the ROIs of the right and left MCA in patients with acute ischemic stroke in the region of the brain supplied by the left (or right) MCA respectively. ROI measurement of MCA is easy to apply and interpret during the CT scan and might serve as an additional primary sign of infarction.
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PURPOSE: To evaluate the effectiveness of 6-month therapy with leucovorin (LV)+5-fluorouracil (5-FU) versus 12-month therapy with levamisole (LVS)+5-FU, as adjuvant chemotherapy in patients with completely resected Aster-Coller stage B(2) or C(1)/C(2) rectal cancer (RC). PATIENTS AND METHODS: One hundred and fifty patients with surgically resected RC were enrolled. Seventy patients with stage B(2) and 80 with stage C were randomly assigned to adjuvant chemotherapy with 5-FU+LXx6 months or 5-FU+LVSx12 months. Patient characteristics were equally balanced between the examined groups. Adjuvant chemotherapy consisted of LV 20 mg/m(2) intravenously (i.v.) plus 5-FU 450 mg/m(2) i.v. bolus every week plus LVS tablets 50 mg t.i.dx3 days every 2 weeks for 1 year. RESULTS: After a median follow up for survivors of 8.7 years (range 1.8-10.5), all of the patients were evaluable. There were no significant differences between the two treatment groups with respect to the recurrence rates (p=0.821). Moreover, there were no significant differences between the two tratment groups in disease-free survival (DFS) (p=0.84) [B(2)(p=0.805) and C (p=0.978)] and overall survival (OS) rates for patients of either stage B(2) or C (p=0.78). Toxicities were more frequent in the 5-FU+LVS versus 5-FU+LV group: myelosuppression (grade 3 leucopenia, 12 versus 4%, p<0.04), diarrhea (grade 0, 60 versus 76%, p<0.02), and liver toxicity (increase of transaminases >3-fold, 12 patients versus 2, p<0.03.). No patient stopped chemotherapy because of toxicity, and there were no treatment-related deaths. CONCLUSION: Adjuvant chemotherapy in RC with LV+5-FU for 6 months is equally effective and less toxic than LVS+5-FU for 12 months.
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MRI of the articular cartilage requires a careful technical approach since this structure is very thin, with a peculiar internal architecture between the supporting matrix and the cell component. On MR images the normal articular cartilage has a zonal appearance. To optimize the variables for best visualization of the internal architecture of the hyaline articular cartilage, an ex vivo and in vivo study was carried out. Accurate T1 and T2 relaxation times of the articular cartilage were obtained with a particular mixed sequence and then used to create isocontrast intensity graphs. The latter allowed, in all pulse sequences (SE and GRE), the best combination of TR, TE and FA to optimize signal differences between cartilage areas. A trilaminar pattern was demonstrated, with a superficial and a deep hypointense areas, in all sequences, together with an intermediate area which was moderately hyperintense on SE images and markedly hyperintense on GRE images. In the current literature, MRI appears to have been widely used to investigate hyaline cartilage conditions. In many series, the technique proved its efficacy in assessing both acute (traumatic cartilage fractures, osteochondritis dissecans, arthritis) and chronic (arthrosis, chondromalacia patellae, Hoffa's disease, synovial plica syndrome) conditions of the articular cartilage. T2-weighted sequences (both SE and GRE) are widely known as the most accurate in assessing cartilage conditions, which depends mainly on the arthrographic effect of synovial fluid on T2-weighted images. Of late, also MR arthrography, especially MR arthrography after the i.v. administration of Gadolinium, has emerged as an outstanding technique to investigate articular cartilage conditions. On the basis of MR arthrography findings, some authors suggested a classification of osteochondritis dissecans, arthrosis and chondromalacia patellae on MR images. MR stages seem to be closely correlated with the histologic classification suggested for these conditions.
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Cartílago Articular/patología , Imagen por Resonancia Magnética/métodos , Enfermedades de los Cartílagos/diagnóstico , Cartílago Articular/anatomía & histología , Cartílago Articular/diagnóstico por imagen , Enfermedad Crónica , Humanos , RadiografíaRESUMEN
In order to assess the value of the SPIR (Spectral Presaturation with Inversion Recovery) sequence (a fat-suppression technique) with Gd-DTPA in the investigation of skeletal diseases, 50 patients were examined with conventional SE T1- and T2-weighted sequences, as well as with SE T1 and SPIR sequences after the i.v. injection of Gd-DTPA. Twenty patients were affected with a skeletal infection (11 spondylodiscites and 9 osteomyelitis) and 5 with a primary tumor; 15 had metastases and 10 a hemolymphopoietic disorder (6 myelomas and 4 non-Hodgkin's lymphomas). In the four groups of patients, the mean visibility of skeletal lesions was higher on SPIR images with Gd-DTPA than on the other images, even though a statistically significant difference was observed only in the group of infections (p < 0.002) and in myelomas and lymphomas (p < 0.001). In 13 cases with extraosseous spread, visibility was higher on contrast-SPIR images than on the other sequences, even though high sensitivity was also exhibited by SE T2-weighted sequences. Even though the SPIR sequence still exhibits some technical limitations, our study assesses the value of this sequences with Gd-DTPA in the investigation of skeletal lesions. The major advantages of contrast-SPIR imaging follow: 1) it shows skeletal lesions, which are isointense on enhanced SE T1-weighted images, 2) it provides better visibility of the lesion than the other sequences, more accurately defining their borders, 3) it provides better anatomical detailing than SE T2-weighted images and 4) its sensitivity is higher.