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PurposeSix-19% of critically ill COVID-19 patients display circulating auto-antibodies against type I interferons (IFN-AABs). Here, we establish a clinically applicable strategy for early identification of IFN-AAB-positive patients for potential subsequent clinical interventions. MethodsWe analysed sera of 430 COVID-19 patients with severe and critical disease from four hospitals for presence of IFN-AABs by ELISA. Binding specificity and neutralizing activity were evaluated via competition assay and virus-infection-based neutralization assay. We defined clinical parameters associated with IFN-AAB positivity. In a subgroup of critically ill patients, we analyzed effects of therapeutic plasma exchange (TPE) on the levels of IFN-AABs, SARS-CoV-2 antibodies and clinical outcome. ResultsThe prevalence of neutralizing AABs to IFN- and IFN-{omega} in COVID-19 patients was 4.2% (18/430), while being undetectable in an uninfected control cohort. Neutralizing IFN-AABs were detectable exclusively in critically affected, predominantly male (83%) patients (7.6% IFN- and 4.6% IFN-{omega} in 207 patients with critical COVID-19). IFN-AABs were present early post-symptom onset and at the peak of disease. Fever and oxygen requirement at hospital admission co-presented with neutralizing IFN-AAB positivity. IFN-AABs were associated with higher mortality (92.3% versus 19.1 % in patients without IFN-AABs). TPE reduced levels of IFN-AABs in three of five patients and may increase survival of IFN-AAB-positive patients compared to those not undergoing TPE. ConclusionIFN-AABs may serve as early biomarker for development of severe COVID-19. We propose to implement routine screening of hospitalized COVID-19 patients according to our algorithm for rapid identification of patients with IFN-AABs who most likely benefit from specific therapies.
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Large alternative donor pools provide the potential for selecting a different donor for a second allogeneic (allo) bone or marrow transplant (BMT). As HLA disparity may contribute to the graft-versus-tumor effect, utilizing new mismatched haplotype donors may potentially improve the antitumor activity for relapsed hematologic malignancies despite a previous alloBMT. Data from patients who received a second alloBMT for relapsed hematologic malignancies at Johns Hopkins were analyzed. Outcomes were compared between patients who received a second allograft with the same MHC composition and those who received an allograft with a new mismatched haplotype. Loss of heterozygosity analysis was performed for patients with acute myeloid leukemia (AML) whose first allograft was haploidentical. Between 2005 and 2015, 40 patients received a second BMT for a relapsed hematologic malignancy. The median follow-up is 750 (range, 26 to 2950) days. The median overall survival (OS) in the cohort is 928 days (95% confidence interval [CI], 602 to not reached [NR]); median event-free survival (EFS) for the cohort is 500 days (95% CI, 355 to NR). The 4-year OS is 40% (95% CI, 25% to 64%), and the 4-year EFS is 36% (95% CI, 24% to 55%). The cumulative incidence of nonrelapsed mortality by 2 years was 27% (95% CI, 13% to 42%). The cumulative incidence of grade 3 to 4 acute graft-versus-host disease (GVHD) at 100 days was 15% (95% CI, 4% to 26%); the cumulative incidence of extensive chronic GVHD at 2 years was 22% (95% CI, 9% to 36%). The median survival was 552 days (95% CI, 376 to 2950+) in the group who underwent transplantation with a second allograft that did not harbor a new mismatched haplotype, while it was not reached in the group whose allograft contained a new mismatched haplotype (hazard ratio [HR], .36; 95% CI, .14 to .9; P = .02). EFS was also longer in the group who received an allograft containing a new mismatched haplotype, (NR versus 401 days; HR, .50; 95% CI, .22 to 1.14; P = .09). Although the allograft for this patient's second BMT contained a new mismatched haplotype, AML nevertheless relapsed a second time. Second BMTs are feasible and provide a reasonable chance of long-term survival. An allograft with a new mismatched haplotype may improve outcomes after second BMTs for relapsed hematologic malignancies.
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Trasplante de Médula Ósea/métodos , Complejo Mayor de Histocompatibilidad/inmunología , Trasplante Homólogo/métodos , Adolescente , Adulto , Anciano , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Donantes de Tejidos , Adulto JovenAsunto(s)
Reaginas , Sífilis , Infecciones por VIH , Humanos , Masculino , Panuveítis , Serodiagnóstico de la Sífilis , Trastornos de la VisiónRESUMEN
OBJECTIVE: Several criteria for time-consuming volumetric measurements of progressive supranuclear palsy Richardson syndrome subtype (PSP-RS) have been proposed. These often require image reconstruction in different planes for proper assessment. The purpose of this study was to evaluate the cerebral peduncle angle as a simple and reproducible measure of midbrain atrophy in patients with PSP-RS. MATERIALS AND METHODS: The records of 15 patients with PSP-RS were retrospectively identified. The records of 31 age-matched healthy control subjects, 15 patients with multiple-system atrophy, and 22 patients with Parkinson disease were included for comparison. Two neuroradiologists individually assessed these studies for midbrain atrophy by evaluating the cerebral peduncle angle, that is, the angle between the two cerebral peduncles. RESULTS: The cerebral peduncle angle measurements were 62.1° (SD, 6.8°) in PSP-RS patients, 51.2° (SD, 10.1°) in healthy control subjects, 55.7° (SD, 11.6°) in patients with multiple-system atrophy, and 53.7° (SD, 8.5°) in patients with Parkinson disease. A statistically significant difference was found in the cerebral peduncle angle measurements (observer 1, p = 0.015; observer 2, p = 0.004) between the PSP-RS patients and the other subgroups. Bland-Altman analysis showed a bias of 0.6° (95% limits of agreement, 6.9°, -5.8°), and intraobserver variability analysis showed a bias of 0.5° (4.1°, -3°). CONCLUSION: The cerebral peduncle angle is a simple, easy-to-calculate, and reproducible measure of midbrain atrophy. It is a useful criterion for differentiating patients with PSP-RS from healthy persons and from patients with multiple-system atrophy or Parkinson disease.
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Pedúnculo Cerebral/patología , Imagen por Resonancia Magnética/métodos , Parálisis Supranuclear Progresiva/patología , Anciano , Estudios de Casos y Controles , Femenino , Humanos , Interpretación de Imagen Asistida por Computador , Masculino , Persona de Mediana Edad , Atrofia de Múltiples Sistemas , Fenotipo , Reproducibilidad de los Resultados , Estudios RetrospectivosRESUMEN
Glioblastoma multiforme (GBM) is a deadly primary brain malignancy. Glioblastoma stem cells (GSC), which have the ability to self-renew and differentiate into tumor lineages, are believed to cause tumor recurrence due to their resistance to current therapies. A subset of GSCs is marked by cell surface expression of CD133, a glycosylated pentaspan transmembrane protein. The study of CD133-expressing GSCs has been limited by the relative paucity of genetic tools that specifically target them. Here, we present CD133-LV, a lentiviral vector presenting a single chain antibody against CD133 on its envelope, as a vehicle for the selective transduction of CD133-expressing GSCs. We show that CD133-LV selectively transduces CD133+ human GSCs in dose-dependent manner and that transduced cells maintain their stem-like properties. The transduction efficiency of CD133-LV is reduced by an antibody that recognizes the same epitope on CD133 as the viral envelope and by shRNA-mediated knockdown of CD133. Conversely, the rate of transduction by CD133-LV is augmented by overexpression of CD133 in primary human GBM cultures. CD133-LV selectively transduces CD133-expressing cells in intracranial human GBM xenografts in NOD.SCID mice, but spares normal mouse brain tissue, neurons derived from human embryonic stem cells and primary human astrocytes. Our findings indicate that CD133-LV represents a novel tool for the selective genetic manipulation of CD133-expressing GSCs, and can be used to answer important questions about how these cells contribute to tumor biology and therapy resistance.
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Antígenos CD/inmunología , Neoplasias Encefálicas/patología , Técnicas de Transferencia de Gen , Vectores Genéticos/administración & dosificación , Glioblastoma/patología , Glicoproteínas/inmunología , Células Madre Neoplásicas/patología , Péptidos/inmunología , Transducción Genética , Antígeno AC133 , Animales , Antígenos CD/análisis , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/inmunología , Vectores Genéticos/genética , Vectores Genéticos/inmunología , Glioblastoma/genética , Glioblastoma/inmunología , Glicoproteínas/análisis , Humanos , Lentivirus/genética , Lentivirus/inmunología , Ratones Endogámicos NOD , Ratones SCID , Células Madre Neoplásicas/inmunología , Células Madre Neoplásicas/metabolismo , Péptidos/análisis , Células Tumorales CultivadasRESUMEN
Endoscopic endonasal surgery has been established as the safest approach to pituitary tumors, yet its role in other common skull base lesions has not been established. To answer this question, we carried out a systematic review of reported series of open and endoscopic endonasal approaches to four major skull base tumors: olfactory groove meningiomas (OGM), tuberculum sellae meningiomas (TSM), craniopharyngiomas (CRA), and clival chordomas (CHO). Data from 162 studies containing 5,701 patients were combined and compared for differences in perioperative mortality, gross total resection (GTR), cerebrospinal fluid (CSF) leak, neurological morbidity, post-operative visual function, post-operative anosmia, post-operative diabetes insipidus (DI), and post-operative obesity/hyperphagia. Weighted average rates for each outcome were calculated using relative study size. Our findings indicate similar rates of GTR and perioperative mortality between open and endoscopic approaches for all tumor types. CSF leak was increased after endoscopic surgery. Visual function symptoms were more likely to improve after endoscopic surgery for TSM, CRA, and CHO. Post-operative DI and obesity/hyperphagia were significantly increased after open resection in CRA. Recurrence rates per 1,000 patient-years of follow-up were higher in endoscopy for OGM, TSM, and CHO. Trends for open and endoscopic surgery suggested modest improvement in all outcomes over time. Our observations suggest that endonasal endoscopy is a safe alternative to craniotomy and may be preferred for certain tumor types. However, endoscopic surgery is associated with higher rates of CSF leak, and possibly increased recurrence rates. Prospective study with long-term follow-up is required to verify these preliminary observations.