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ABSTRACT: Patients who undergo human leukocyte antigen-matched unrelated donor (MUD) allogeneic hematopoietic stem cell transplantation (HSCT) with myeloablative conditioning for hematologic malignancies often develop acute graft-versus-host disease (GVHD) despite standard calcineurin inhibitor-based prophylaxis in combination with methotrexate. This trial evaluated a novel human CD24 fusion protein (CD24Fc/MK-7110) that selectively targets and mitigates inflammation due to damage-associated molecular patterns underlying acute GVHD while preserving protective immunity after myeloablative conditioning. This phase 2a, multicenter study evaluated the pharmacokinetics, safety, and efficacy of CD24Fc in combination with tacrolimus and methotrexate in preventing acute GVHD in adults undergoing MUD HSCT for hematologic malignancies. A double-blind, placebo-controlled, dose-escalation phase to identify a recommended dose was followed by an open-label expansion phase with matched controls to further evaluate the efficacy and safety of CD24Fc in preventing acute GVHD. A multidose regimen of CD24Fc produced sustained drug exposure with similar safety outcomes when compared with single-dose regimens. Grade 3 to 4 acute GVHD-free survival at day 180 was 96.2% (95% confidence interval [CI], 75.7-99.4) in the CD24Fc expansion cohort (CD24Fc multidose), compared with 73.6% (95% CI, 63.2-81.4) in matched controls (hazard ratio, 0.1 [95% CI, 0.0-0.6]; log-rank test, P = .03). No participants in the CD24Fc escalation or expansion phases experienced dose-limiting toxicities (DLTs). The multidose regimen of CD24Fc was well tolerated with no DLTs and was associated with high rates of severe acute GVHD-free survival after myeloablative MUD HSCT. This trial was registered at ClinicalTrials.gov as #NCT02663622.
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Enfermedad Injerto contra Huésped , Neoplasias Hematológicas , Trasplante de Células Madre Hematopoyéticas , Adulto , Humanos , Metotrexato/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante Homólogo , Recurrencia Local de Neoplasia/tratamiento farmacológico , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Acondicionamiento Pretrasplante/efectos adversosRESUMEN
Abatacept plus calcineurin inhibitors/methotrexate (CNI/MTX) is the first FDA-approved regimen for acute graft-versus-host disease (aGVHD) prophylaxis during unrelated-donor hematopoietic cell transplantation (URD-HCT). We investigated its impact in URD-HCT patients using Center for International Blood and Marrow Transplant Research data for 7/8-human leukocyte antigen (HLA)-mismatched (MMUD) or 8/8-HLA-matched (MUD) URD-HCT recipients between 2011-2018. Primary outcomes included day-180, 1-year, and 2-year overall survival (OS) and relapse-free survival (RFS) for abatacept+CNI/MTX vs CNI/MTX, CNI/MTX+antithymocyte globulin (ATG), and post-transplant cyclophosphamide-based prophylaxis (PT-Cy); other outcomes included aGVHD, chronic GVHD, non-relapse mortality, and relapse. For 7/8-MMUDs, day-180 OS (primary endpoint supporting FDA approval) was significantly higher for abatacept+CNI/MTX vs CNI/MTX (98%vs75%; p=0.0028). Two-year OS was significantly higher for abatacept+CNI/MTX vs CNI/MTX (83%vs55%; p=0.0036), CNI/MTX+ATG (83%vs46%; p=0.0005) and similar to PT-Cy (80%vs68%; p=0.2325). Two-year RFS was significantly higher for abatacept+CNI/MTX vs CNI/MTX (74%vs49%; p=0.0098) and CNI/MTX+ATG (77%vs35%; p=0.0002), and similar vs PT-Cy (72%vs56%; p=0.1058). For 8/8-MUDs, 2-year OS was similar with abatacept+CNI/MTX vs CNI/MTX (70%vs62%; p=0.2569), CNI/MTX+ATG (75%vs64%; p=0.1048), and PT-Cy (74%vs69%; p=0.5543). Two-year RFS for abatacept+CNI/MTX was numerically higher vs CNI/MTX (63%vs52%; p=0.1497) with an improved hazard ratio (HR: 0.46 [0.25-0.86]), and vs CNI/MTX+ATG (66%vs55%; p=0.1193; HR: 0.39 [0.21-0.73]). Two-year RFS was similar vs PT-Cy (68%vs57%; p=0.2356; HR: 0.54 [0.26-1.11]). For both 7/8-MMUD and 8/8-MUD recipients, abatacept+CNI/MTX prophylaxis improved survival outcomes vs CNI/MTX and CNI/MTX+ATG; outcomes were similar to PT-Cy-based regimens. Abatacept+CNI/MTX has potential to facilitate unrelated donor pool expansion for HCT.
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BACKGROUND: The application of evoked potentials (EPs) to the diagnosis of acute disseminated encephalomyelitis (ADEM ) has not been investigated in detail. The aim of this study, therefore, was to analyze the value of multimodal EPs in the early diagnosis of pediatric ADEM. METHODS: This was a retrospective study in which we enrolled pediatric ADEM patients and controls (Cs) from neurology units between 2017 and 2021. We measured indices in patients using brainstem auditory evoked potentials (BAEPs), visual evoked potentials (VEPs) and somatosensory evoked potentials (SEPs), and then we analyzed their early diagnostic value in ADEM patients. RESULTS: The mean age of the ADEM group was 6.15 ± 3.28 years (range,1-12 years) and the male/female ratio was 2.1:1 The mean age of the Cs was 5.97 ± 3.40 years (range,1-12 years) and the male/female ratio was 1.3:1. As we used magnetic resonance imaging (MRI) as the diagnostic criterion, the sensitivity, specificity, and accuracy (κ was 0.88) of multimodal EPs were highly consistent with those of MRI; and the validity could be ranked in the following order with respect to the diagnosis of ADEM: multimodal Eps > single SEP > single VEP > single BAEP. Of 34 patients with ADEM, abnormalities in multimodal EPs were 94.12%, while abnormalities in single VEPs, BAEPs and SEPs were 70.59%,64.71%and 85.3%, respectively. We noted significant differences between single VEP/BAEPs and multimodal EPs (χ2 = 6.476/8.995,P = 0.011/0.003). CONCLUSIONS: The combined application of multimodal EPs was superior to BAEPs, VEPs, or SEPs alone in detecting the existence of central nerve demyelination, and we hypothesize that these modalities will be applicable in the early diagnosis of ADEM.
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Encefalomielitis Aguda Diseminada , Potenciales Evocados Visuales , Humanos , Niño , Femenino , Masculino , Lactante , Preescolar , Encefalomielitis Aguda Diseminada/diagnóstico , Estudios Retrospectivos , Potenciales Evocados Auditivos del Tronco Encefálico/fisiología , Potenciales Evocados Somatosensoriales/fisiologíaRESUMEN
Mucoralean fungi could cause mucormycosis in humans, particularly in immunodeficient individuals and those with diabetes mellitus or trauma. With plenty of species and genera, their molecular identification and pathogenicity have a large deviation. Reported cases of mucormycosis showed frequent occurrence in Rhizopus species, Mucor species, and Lichtheimia species. We analyzed the whole genome sequences of 25 species of the top 10 Mucorales genera, along with another 22 important pathogenic non-Mucorales species, to dig the target genes for monitoring Mucorales species and identify potential genomic imprints of virulence in them. Mucorales-specific genes have been found in various orthogroups extracted by Python script, while genus-specific genes were annotated covering cellular structure, biochemistry metabolism, molecular processing, and signal transduction. Proteins related to the virulence of Mucorales species varied with distinct significance in copy numbers, in which Orthofinder was conducted. Based on our fresh retrospective analysis of mucormycosis, a comparative genomic analysis of pathogenic Mucorales was conducted in more frequent pathogens. Specific orthologs between Mucorales and non-Mucoralean pathogenic fungi were discussed in detail. Referring to the previously reported virulence proteins, we included more frequent pathogenic Mucorales and compared them in Mucorales species and non-Mucorales species. Besides, more samples are needed to further verify the potential target genes.
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Mucorales , Mucormicosis , Humanos , Mucorales/genética , Estudios Retrospectivos , Genómica , Rhizopus/genéticaRESUMEN
Radiation-induced bystander effects (RIBEs) refer to a series of reactions displaying in nonirradiated cells triggered by signals from irradiated cells. Though bystander effects induced by ionizing radiation have been well studied, there are still limited data on ultraviolet(UV) induced bystander effects(UV-RIBEs). Studies have verified that exosomes, acting as a new tool of intercellular communication, participate in ionizing radiation-induced bystander effect. The purpose of what we studied was to explore the function of exosomes in UV-RIBEs, and seeking the relevant mechanism. Human skin fibroblasts (HSFs) were exposed to a single dose of ultraviolet A (UVA) radiation (20 J/cm2) or ultraviolet B (UVB) radiation (60 mJ/cm2), respectively. Exosomes were isolated from the culture medium of HSFs by differential ultracentrifugation. Three endpoints relevant to potodamage were used in the evaluation of UV-RIBEs, which including the cell proliferation, oxidative damage, and apoptosis. Our results showed that exosomes from UV-irradiated cells contributed to UV-RIBEs. The expression of miR-4655-3p in exosomes increased after UV radiation and exosomes assisted in the transportation of miR-4655-3p between cells. The upregulation of miR-4655-3p enhanced the UV-RIBEs in the bystander cells. MiR-4655-3p restrained the expression of E2F2 through direct binding to its 3'-UTR. In addition, E2F2 contributed to the cell proliferation and decreased oxidative damage of HSFs. To sum up that exosomal miR-4655-3p plays a crucial role in UV-RIBEs and this function mentioned partially related to the inhibition of E2F2.
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Exosomas , MicroARNs , Regiones no Traducidas 3' , Efecto Espectador/efectos de la radiación , Proliferación Celular/genética , Proliferación Celular/efectos de la radiación , Exosomas/metabolismo , Exosomas/efectos de la radiación , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Rayos UltravioletaRESUMEN
BACKGROUND: Onychomycosis was an ignored disease in children, and the prevalence was still unknown worldwide. OBJECTIVES: This study was conducted to investigate the prevalence and treatment regimens of onychomycosis in children younger than 18 years old. METHODS: We systemically reviewed all publications by searching the key terms to reveal the onychomycosis in children from 1990 to 2022. RESULTS: A total of 44 articles including 2,382 children with onychomycosis were enrolled in this study. The male to female ratio was 1.29:1. The youngest child was 35 days old and the average age was 9.8 years old. The duration of disease usually ranged from 7 days to 4 years. Onychomycosis in children was more prevalent in toenails compared to fingernails (77.6% vs. 18.4%), and 4% patients had both. A total of 527 children (22.12%) had concomitant tinea pedis infection, and in 267 patients (11.21%), their family members had onychomycosis or tinea pedis. The most common clinical type of onychomycosis was DLSO (67.74%) and the predominant isolates were T. rubrum (66.13%), followed by C. albicans (9.08%) and T. mentagrophytes complex (5.34%). There were 419 children (74.03%) receiving systematic treatment only, 74 patients (13.07%) receiving topical treatment only, and 73 patients (12.90%) receiving both systematic and topical treatment. Twelve patients (2.12%) had mild drug-related side effects. During the follow-up, 71.25% children were cured, 17.50% symptoms improved and 4.17% failed. CONCLUSIONS: Onychomycosis was underestimated in children and the diagnosis of onychomycosis should be properly considered in children with nail disorders. For mild patients, topical treatment can be a good choice, and oral antifungal drugs could be added to severe individuals under monitoring.
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Onicomicosis , Niño , Humanos , Masculino , Femenino , Adolescente , Onicomicosis/tratamiento farmacológico , Onicomicosis/epidemiología , Onicomicosis/diagnóstico , Tiña del Pie/microbiología , Estudios Retrospectivos , Antifúngicos , Uñas/microbiología , Candida albicansRESUMEN
BACKGROUND: Tinea capitis (TC) is a dermatophytosis of the scalp and hair, which occurs less common in children younger than two years of age, and the data of TC in this age group are still unknown. OBJECTIVES: We aimed to reveal the epidemiological, clinical and mycological characteristics of TC in children under two years old. METHODS: We retrospectively analyzed all reported cases of TC in children in their first two years of life from 1991 to 2022, by searching PubMed, Embase, Web of Science, CNKI, Wanfang and Weipu databases. RESULTS: A total of 47 articles involving 126 cases of pediatric TC were enrolled in this study. The sex ratio (M/F) was 1.28:1. The age of the children ranged from ten days old to two years old with a median age of three months. The main clinical manifestations were alopecic patches (40 cases, 31.7%) and scaling (39 cases, 31.0%) on the scalp, and 29 infants (23.0%) appeared kerion. The most common sources of contagion were animals (35 cases, 27.78%) and humans (31 cases, 24.60%). The leading pathogens were Microsporidium canis (64 cases, 50.79%), followed by Trichophyton violaceum (13 cases, 10.32%), T. mentagrophytes complex (12 cases, 9.52%) and T. tonsurans (10 cases, 7.94%). Ninety-five children (75.40%) were treated with systemic antifungal drugs and 22 patients (17.46%) were only treated with topical therapy. Except for 10 patients with unknown final prognosis, all the other cases were cured after treatment. There was one child (0.79%) relapsed after treatment with griseofulvin and one case (0.79%) presented with gastrointestinal symptoms from griseofulvin. CONCLUSION: The principal clinical symptoms of TC in children less than two years old were alopecic patches and scaling. The top four pathogens were M. canis, T. violaceum, T. mentagrophytes complex and T. tonsurans. Oral treatment for pediatric TC had achieved good therapeutic effects, and topical therapy can be an alternative choice.
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Griseofulvina , Tiña del Cuero Cabelludo , Lactante , Animales , Humanos , Niño , Recién Nacido , Preescolar , Griseofulvina/uso terapéutico , Estudios Retrospectivos , Tiña del Cuero Cabelludo/diagnóstico , Tiña del Cuero Cabelludo/tratamiento farmacológico , Tiña del Cuero Cabelludo/epidemiología , Antifúngicos/uso terapéutico , Alopecia , TrichophytonRESUMEN
BACKGROUND: Dermatophytoses are the most common infectious skin disease. Its epidemiology varies in different countries and regions, and its prevalence in China is still unknown. OBJECTIVES: We aimed to reveal the epidemiological features of dermatophytoses in Chinese mainland in the past thirty years. METHODS: From 1991 to 2020, a 30-year retrospective epidemiological study was carried out. All published literatures containing dermatophytoses and dermatophytes were collected and analysed. RESULTS: A total of more than 180,000 cases in 124 articles from more than 100 hospitals were included and analysed. Among dermatophytoses, tinea cruris (24.92%) was the predominant clinical type, followed by tinea pedis (22.97%) and tinea corporis (18.12%). In recent 10 years, tinea pedis (25.40%) was more common than tinea cruris (22.39%) and became the most common infection. Among dermatophytes, T rubrum (69.48%) has always been the most common isolates, followed by T mentagrophytes (16.45%) and M canis (8.09%). Other species were found below 3%. In superficial mycoses, dermatophytes accounted for 75.52%, higher than that of yeasts/yeast-like (21.83%) and moulds (2.65%). The prevalence of tinea capitis was lower in economically developed eastern region than that in central and western regions. Tinea cruris was more common in warm zones than cold zones. CONCLUSIONS: The top three dermatophytoses are tinea cruris, tinea pedis and tinea corporis, while the top three dermatophytes are T rubrum, T mentagrophytes and M canis. The distribution of dermatophytoses may be influenced by socioeconomic status and geographical-meteorological conditions.
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Dermatomicosis , China/epidemiología , Dermatomicosis/epidemiología , Dermatomicosis/microbiología , Hongos/aislamiento & purificación , Humanos , Estudios Retrospectivos , Tiña/epidemiologíaRESUMEN
OBJECTIVES: Our study aimed to better understand the different thermal adaptation in Mucor irregularis (M. irregularis) strains under high temperature and the involved virulence-related genes, and to offer more appropriate explanation for the diverse pathogenicity of M. irregularis in human infections. METHODS: M. irregularis isolates were incubated at 30 and 35°C for Illumina HiSeq technology (RNA-seq), as well as the virulence difference detected through Galleria mellonella infection models. We verified their transcriptional profile with RT-PCR and analysed differentially expressed genes with GO and KEGG annotations. RESULTS: All 25 isolates formed the biggest colonies at 28°C and did not grow at 37°C, while were differently inhibited at 22 and 35°C. Six selected M. irregularis displayed virulence in sync with their growth condition at high temperature. From the outcomes of RNA-seq, a total of 1559 differentially expressed genes (FC ≥ 2, FDR < 0.05) were obtained, of which 1021 genes were upregulated, and 538 genes were downregulated. Cell wall structure genes related to Ras-like and GH16 proteins, influx-efflux pumps consist of transmembrane proteins as ABC and MFS proteins, and metabolic genes as DGKÉ and Hsfs, seem to be essential in thermal adaptation and virulence of M. irregularis. CONCLUSION: We found some common genes expressed at high temperature, while some others specifically related to M. irregularis isolates with different virulence and thermal adaptation. Further research of genes involved in the pathogenic process is needed for the development of potential targeted antifungal.
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Antifúngicos , Mucor , Antifúngicos/uso terapéutico , Humanos , Mucor/genética , Virulencia/genéticaRESUMEN
BACKGROUND: Mucorales, as one major order of Zygomycetes fungi, can infect human beings and cause serious consequence. We have noticed the pathogenicity of Mucorales is closely related to energy metabolism, while mitochondria play the role of energy factories in almost all biological activities. METHODS: Virulence of M irregularis, M hiemalis, L corymbifera and R arrhizus were verified in Galleria mellonella larvae, as well as mitochondrial gene copies analysed with RT-qPCR. Mitogenomes of the four Mucorales species were sequenced based on illumina NovaSeq technology to study their characteristic features and functional regions. RESULTS: Variant virulence of M irregularis, M hiemalis, L corymbifera and R arrhizu were verified by clinical retrospective data and our G mellonella infection models, also copies of mitochondrial genes indicated the significant associations with pathogenicity. A total of 274.18 clean reads were generated to be assembled; the complete mitogenomes of the four Mucorales species were obtained with totally different length. After the genomes annotated and compared, M irregularis was found more similar with M hiemalis than those of L corymbifera and R arrhizus, especially the small (rrns) and large (rrnl) subunits of mitochondrial ribosomal RNA (rRNA) genes. The GC content, ncRNAs and the distribution of the SNPs and InDels were also compared, and the GC content rate of fungi seems to be related to the fungal thermal adaptability. In addition, linear mitogenomes of these four Mucorales showed diverse arrangements of orf genes and directionality of some conserved gene elements. CONCLUSION: This study uncovered the pathogenicity variances among the four Mucorales species and the relationship between their mitogenomic features and clinical pathogenicity. Further studies like spatial structure of mitochondrial genomes and the comprehensive analysis of transcription regulation are needed.
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Genoma Fúngico , Genoma Mitocondrial , Mucorales , Humanos , Mucorales/genética , Mucorales/patogenicidad , Mucormicosis , Virulencia/genéticaRESUMEN
BACKGROUND: Onychomycosis was a common nail disease caused by dermatophytes, yeasts or molds. The prevalence of onychomycosis varied in different counties and it was necessary to understand the epidemiology in China. OBJECTIVES: This study was conducted to investigate the epidemiology of onychomycosis in Chinese mainland in the past 30 years. METHODS: A 30-year systemic review was carried out by searching publications investigating the prevalence of onychomycosis in Chinese mainland from 1991 to 2020. RESULTS: A total of 90 articles involving more than 40,000 onychomycosis patients were enrolled in this study. The ratio of males to females was 1:1.32. Fingernail onychomycosis was found in 36.12% cases, toenail onychomycosis in 48.31%, and both fingernail and toenail onychomycosis in 15.57%. The most common clinical type of onychomycosis was distal lateral subungual onychomycosis (60.99%), followed by total dystrophic onychomycosis (18.91%), proximal subungual onychomycosis (10.19%) and superficial white onychomycosis (9.92%). Dermatophytes (60.59%) were the most frequently isolated pathogens, followed by yeasts (30.09%), molds (7.91%) and mixed infection (1.41%). The primary pathogens in dermatophytes, yeasts and molds were Trichophyton rubrum (49.93%), Candida albicans (10.99%) and Aspergillus (3.11%), respectively. Additionally, dermatophytes were more commonly affected males than females (63.69% vs. 51.57%), and mostly involved in toenail onychomycosis (75.63%). The infection of yeasts was higher in females than males (40.97% vs. 29.52%), often causing onychomycosis in fingernail than toenail (41.03% vs. 17.08%), and it was more common in warm and humid southern regions than northern area (34.07% vs. 24.41%). CONCLUSION: The proportion of the causative agents changed over time, dermatophytes, especially T. rubrum had always been the predominant pathogen, followed by yeasts and molds. The distribution of fungal pathogens varied among clinical types, gender, infection sites and geography gender.
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Enfermedades de la Uña , Onicomicosis , Femenino , Humanos , Masculino , Enfermedades de la Uña/complicaciones , Uñas/microbiología , Onicomicosis/epidemiología , Onicomicosis/microbiología , Estudios Retrospectivos , LevadurasRESUMEN
A generalized case-cohort design has been used when measuring exposures is expensive and events are not rare in the full cohort. This design collects expensive exposure information from a (stratified) randomly selected subset from the full cohort, called the subcohort, and a fraction of cases outside the subcohort. For the full cohort study with competing risks, He et al. (Scand J Stat 43:103-122, 2016) studied the non-stratified proportional subdistribution hazards model with covariate-dependent censoring to directly evaluate covariate effects on the cumulative incidence function. In this paper, we propose a stratified proportional subdistribution hazards model with covariate-adjusted censoring weights for competing risks data under the generalized case-cohort design. We consider a general class of weight functions to account for the generalized case-cohort design. Then, we derive the optimal weight function which minimizes the asymptotic variance of parameter estimates within the general class of weight functions. The proposed estimator is shown to be consistent and asymptotically normally distributed. The simulation studies show (i) the proposed estimator with covariate-adjusted weight is unbiased when the censoring distribution depends on covariates; and (ii) the proposed estimator with the optimal weight function gains parameter estimation efficiency. We apply the proposed method to stem cell transplantation and diabetes data sets.
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Proyectos de Investigación , Estudios de Cohortes , Simulación por Computador , Humanos , Incidencia , Modelos de Riesgos ProporcionalesRESUMEN
BACKGROUND: Gemtuzumab ozogamicin (GO) administered before allogeneic hematopoietic cell transplantation (alloHCT) has been linked to an increased risk of hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS). PROCEDURE: This retrospective analysis examined VOD/SOS risk and clinical outcomes in pediatric patients with acute myeloid leukemia who received myeloablative alloHCT in 2008-2011 with (n = 148) and without (n = 348; controls) prior GO exposure and were reported to the Center for International Blood and Marrow Transplant Research. RESULTS: Cumulative incidences (95% confidence interval [CI]) of VOD/SOS and severe VOD/SOS, respectively, at 100 days were 16% (11-23%) and 8% (4-13%) for GO-exposed patients and 10% (7-13%) and 3% (2-5%) for controls. With a median follow-up of approximately 7 years, the 5-year adjusted overall survival probability (95% CI) after alloHCT was 51% (43-58%) and 55% (50-60%) for GO-exposed patients and controls, respectively; three (4%) and one (<1%) deaths were attributed to VOD/SOS. In multivariate analyses, GO exposure was observed to be associated with an increased risk of VOD/SOS at 100 days, but was not associated with overall survival, disease-free survival, relapse, or nonrelapse mortality. CONCLUSIONS: Results suggest that GO treatment prior to alloHCT in pediatric patients may increase the risk of VOD/SOS but not death.
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Gemtuzumab/uso terapéutico , Trasplante de Células Madre Hematopoyéticas , Enfermedad Veno-Oclusiva Hepática , Leucemia Mieloide Aguda , Niño , Gemtuzumab/efectos adversos , Enfermedad Veno-Oclusiva Hepática/inducido químicamente , Humanos , Leucemia Mieloide Aguda/terapia , Estudios RetrospectivosRESUMEN
BACKGROUND: Ravuconazole is an extended-spectrum triazole agent that is efficient in vitro against Candida spp. and has been approved to work as an oral formulae for onychomycosis in Japan in 2018. However, nobody had determined the MIC of ravuconazole against the Candida auris, which is known as an emerging multidrug-resistant yeast. Meanwhile, rare is known of the in vitro activity of ravuconazole against vaginal Candida isolates. OBJECTIVES: To investigate the activity of ravuconazole against C. auris and vaginal Candida isolates of China and assess the feasibility of ravuconazole in the treatment of candidiasis caused by C. auris and other Candida spp. METHODS: We determined the in vitro activity of ravuconazole and 9 comparators against 15 C. auris isolates and determined the MIC of ravuconazole on 525 vaginal Candida isolates (Candida albicans, Candida tropicalis, Candida glabrata and Candida parapsilosis) from 9 provinces of China by Clinical and Laboratory Standards Institute (CLSI) methodology. RESULTS: The MICs of fluconazole and amphotericin B on C. auris were much higher than second-generation azoles and echinocandins. Ravuconazole was active against all the C. auris isolates and as effective as isavuconazole, posaconazole and echinocandins while showed a better antifungal activity than itraconazole, voriconazole to C. auris. For vaginal Candida isolates, the proportion of ravuconazole-resistant isolates is 0.19% (1/525). CONCLUSIONS: Ravuconazole was in good active against C. auris and vaginal Candida isolates, which suggested ravuconazole could be used in the treatment of drug-resistant candidiasis.
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Candida/efectos de los fármacos , Tiazoles/farmacología , Triazoles/farmacología , Anfotericina B/farmacología , Antifúngicos/farmacología , Candida/aislamiento & purificación , Candidiasis/tratamiento farmacológico , Farmacorresistencia Fúngica , Femenino , Humanos , Técnicas In Vitro , Pruebas de Sensibilidad Microbiana , Vagina/microbiologíaRESUMEN
Gemtuzumab ozogamicin (GO) therapy before allogeneic hematopoietic cell transplantation (alloHCT) has been historically associated with an increased risk of hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) in patients with acute myeloid leukemia (AML). The current analysis examined VOD/SOS risk and outcomes in a cohort of patients who in recent years were reported to the Center for International Blood and Marrow Transplant Research. Adults with AML who had GO exposure before myeloablative alloHCT were matched 1:4 by age and disease status at transplant to recipients without GO exposure (control subjects). One hundred thirty-seven patients with GO exposure and 548 matched control subjects who underwent alloHCT between 2008 and 2011 were included in this analysis. With a median â¼8-year follow-up of survivors, the 5-year overall survival probability was similar in the 2 cohorts: 38% and 38% in the GO-exposed versus control groups (P = .97). Incidence of VOD/SOS and severe VOD/SOS, respectively, at 100 days was 4% (95% confidence interval [CI], 1% to 7%) and 3% (95% CI, 1% to 6%) in GO-exposed patients and 3% (95% CI, 2% to 5%) and 1% (95% CI, 0% to 2%) in control subjects. Correspondingly, among patients who developed VOD/SOS, 1-year survival probability after VOD/SOS diagnosis was 33% (95% CI, 5% to 72%) and 27% (95% CI, 11% to 47%; P = .78). In multivariate analyses, GO exposure before alloHCT was not associated with an increased risk of VOD/SOS (odds ratio, 1.10; P = .85) or death (hazard ratio, 1.08; P = .57). Three deaths (3%) in the GO group and 3 deaths (<1%) in the control group were attributed to VOD/SOS. Our results suggest that GO treatment before myeloablative alloHCT in the recent era is not associated with an increased risk of post-transplant VOD/SOS or death.
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Trasplante de Células Madre Hematopoyéticas , Enfermedad Veno-Oclusiva Hepática , Leucemia Mieloide Aguda , Trasplantes , Adulto , Gemtuzumab , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Enfermedad Veno-Oclusiva Hepática/inducido químicamente , Humanos , Leucemia Mieloide Aguda/terapiaRESUMEN
The COVID-19 pandemic has created significant barriers to timely donor evaluation, cell collection, and graft transport for allogeneic hematopoietic stem cell transplantation (allo-HCT). To ensure availability of donor cells on the scheduled date of infusion, many sites now collect cryopreserved grafts before the start of pretransplantation conditioning. Post-transplantation cyclophosphamide (ptCY) is an increasingly used approach for graft-versus-host disease (GVHD) prophylaxis, but the impact of graft cryopreservation on the outcomes of allo-HCT using ptCY is not known. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we compared the outcomes of HCT using cryopreserved versus fresh grafts in patients undergoing HCT for hematologic malignancy with ptCY. We analyzed 274 patients with hematologic malignancy undergoing allo-HCT between 2013 and 2018 with cryopreserved grafts and ptCY. Eighteen patients received bone marrow grafts and 256 received peripheral blood stem cell grafts. These patients were matched for age, graft type, disease risk index (DRI), and propensity score with 1080 patients who underwent allo-HCT with fresh grafts. The propensity score, which is an assessment of the likelihood of receiving a fresh graft versus a cryopreserved graft, was calculated using logistic regression to account for the following: disease histology, Karnofsky Performance Score (KPS), HCT Comorbidity Index, conditioning regimen intensity, donor type, and recipient race. The primary endpoint was overall survival (OS). Secondary endpoints included acute and chronic graft-versus-host disease (GVHD), non-relapse mortality (NRM), relapse/progression and disease-free survival (DFS). Because of multiple comparisons, only P values <.01 were considered statistically significant. The 2 cohorts (cryopreserved and fresh) were similar in terms of patient age, KPS, diagnosis, DRI, HCT-CI, donor/graft source, and conditioning intensity. One-year probabilities of OS were 71.1% (95% confidence interval [CI], 68.3% to 73.8%) with fresh grafts and 70.3% (95% CI, 64.6% to 75.7%) with cryopreserved grafts (P = .81). Corresponding probabilities of OS at 2 years were 60.6% (95% CI, 57.3% to 63.8%) and 58.7% (95% CI, 51.9% to 65.4%) (P = .62). In matched-pair regression analysis, graft cryopreservation was not associated with a significantly higher risk of mortality (hazard ratio [HR] for cryopreserved versus fresh, 1.05; 95% CI, .86 to 1.29; P = .60). Similarly, rates of neutrophil recovery (HR, .91; 95% CI, .80 to 1.02; P = .12), platelet recovery (HR, .88; 95% CI, .78 to 1.00; P = .05), grade III-IV acute GVHD (HR, .78; 95% CI, .50 to 1.22; P = .27), NRM (HR, 1.16; 95% CI, .86 to 1.55; P = .32) and relapse/progression (HR, 1.21; 95% CI, .97 to 1.50; P = .09) were similar with cryopreserved grafts versus fresh grafts. There were somewhat lower rates of chronic GVHD (HR, 78; 95% CI, .61 to .99; P = .04) and DFS (HR for treatment failure, 1.19; 95% CI, 1.01 to 1.29; P = .04) with graft cryopreservation that were of marginal statistical significance after adjusting for multiple comparisons. Overall, our data indicate that graft cryopreservation does not significantly delay hematopoietic recovery, increase the risk of acute GVHD or NRM, or decrease OS after allo-HCT using ptCY.
Asunto(s)
Trasplante de Médula Ósea/métodos , Infecciones por Coronavirus/epidemiología , Criopreservación/métodos , Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia/terapia , Linfoma/terapia , Síndromes Mielodisplásicos/terapia , Neumonía Viral/epidemiología , Adulto , Anciano , Anciano de 80 o más Años , COVID-19 , Estudios de Cohortes , Ciclofosfamida/uso terapéutico , Femenino , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/mortalidad , Enfermedad Injerto contra Huésped/patología , Prueba de Histocompatibilidad , Humanos , Leucemia/inmunología , Leucemia/mortalidad , Leucemia/patología , Linfoma/inmunología , Linfoma/mortalidad , Linfoma/patología , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/inmunología , Síndromes Mielodisplásicos/mortalidad , Síndromes Mielodisplásicos/patología , Pandemias , Hermanos , Análisis de Supervivencia , Acondicionamiento Pretrasplante/métodos , Trasplante Homólogo , Estados Unidos/epidemiología , Donante no Emparentado/provisión & distribuciónRESUMEN
Although hematopoietic cell transplantation from an HLA-matched unrelated donor is potentially curative for hematologic malignancies, survival is lower for African Americans compared with Caucasians. Because only approximately 20% of African Americans will have an HLA-matched unrelated donor, many of these patients undergo HLA-haploidentical relative or umbilical cord blood transplantation. In this study, we analyzed outcomes after HLA-haploidentical related donor (n = 249) and umbilical cord blood (n = 118) transplantations in African American patients with hematologic malignancy between 2008 and 2016. The predominant disease was acute myelogenous leukemia for recipients of both types of donor grafts. The incidences of grade II-IV and III-IV acute graft-versus-host disease were higher after umbilical cord blood transplantation compared with HLA-haploidentical relative transplantation (56% and 29%, respectively, versus 33% and 11%, respectively; P < .0001). The 2-year incidence of transplantation-related mortality adjusted for age and conditioning regimen intensity was higher after umbilical cord blood transplantation compared with HLA-haploidentical related donor transplantation (31% versus 18%; P = .008); however, there were no between-group differences in the 2-year adjusted incidence of relapse (30% versus 34%; P = .51), overall survival (54% versus 57%; P = .66), or disease-free survival (43% versus 47%; P = .46). Our findings show that the use of HLA-haploidentical and umbilical cord blood transplants expands the access to transplantation with comparable leukemia-free and overall survival for African Americans with hematologic malignancies.
Asunto(s)
Trasplante de Células Madre de Sangre del Cordón Umbilical , Enfermedad Injerto contra Huésped , Neoplasias Hematológicas , Trasplante de Células Madre Hematopoyéticas , Negro o Afroamericano , Sangre Fetal , Neoplasias Hematológicas/terapia , Prueba de Histocompatibilidad , HumanosRESUMEN
With the COVID-19 pandemic and the ensuing barriers to the collection and transport of donor cells, it is often necessary to collect and cryopreserve grafts before initiation of transplantation conditioning. The effect on transplantation outcomes in nonmalignant disease is unknown. This analysis examined the effect of cryopreservation of related and unrelated donor grafts for transplantation for severe aplastic anemia in the United States during 2013 to 2019. Included are 52 recipients of cryopreserved grafts who were matched for age, donor type, and graft type to 194 recipients who received noncryopreserved grafts. Marginal Cox regression models were built to study the effect of cryopreservation and other risk factors associated with outcomes. We recorded higher 1-year rates of graft failure (hazard ratio [HR], 2.26; 95% confidence interval, 1.17 to 4.35; P = .01) and of 1-year overall mortality (HR, 3.13; 95% CI, 1.60 to 6.11; P = .0008) after transplantation of cryopreserved compared with noncryopreserved grafts, with adjustment for sex, performance score, comorbidity, cytomegalovirus serostatus, and ABO blood group match. The incidence of acute and chronic graft-versus-host disease did not differ between the 2 groups. Adjusted probabilities of 1-year survival were 73% (95% CI, 60% to 84%) in the cryopreserved graft group and 91% (95% CI, 86% to 94%) in the noncryopreserved graft group. These data support the use of noncryopreserved grafts whenever possible in patients with severe aplastic anemia.
Asunto(s)
Anemia Aplásica/terapia , Trasplante de Médula Ósea/métodos , Infecciones por Coronavirus/epidemiología , Criopreservación/métodos , Rechazo de Injerto/patología , Enfermedad Injerto contra Huésped/patología , Trasplante de Células Madre de Sangre Periférica/métodos , Neumonía Viral/epidemiología , Enfermedad Aguda , Adolescente , Adulto , Anciano , Anemia Aplásica/inmunología , Anemia Aplásica/mortalidad , Anemia Aplásica/patología , COVID-19 , Niño , Preescolar , Femenino , Rechazo de Injerto/inmunología , Rechazo de Injerto/mortalidad , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/mortalidad , Prueba de Histocompatibilidad , Humanos , Masculino , Persona de Mediana Edad , Pandemias , Estudios Retrospectivos , Hermanos , Análisis de Supervivencia , Acondicionamiento Pretrasplante/métodos , Estados Unidos/epidemiología , Donante no EmparentadoRESUMEN
Chronic graft-versus-host disease (cGVHD) is major cause of morbidity and mortality following allogeneic hematopoietic cell transplantation (HCT). Ixazomib is an oral, second-generation, proteasome inhibitor that has been shown in preclinical models to prevent GVHD. We conducted a phase I/II trial in 57 patients to evaluate the safety and efficacy of ixazomib administration for cGVHD prophylaxis in patients undergoing allogeneic HCT. Oral ixazomib was administered on a weekly basis for a total of 4 doses, beginning days +60 through +90, to recipients of matched related donor (MRD, n = 25) or matched unrelated donor (MUD, n = 26) allogeneic HCT in phase II portion of the study, once the recommended phase II dose of 4 mg was identified in phase I (n = 6). All patients received peripheral blood graft and standard GVHD prophylaxis of tacrolimus and methotrexate. Ixazomib administration was safe and well tolerated, with thrombocytopenia, leukopenia, gastrointestinal complaints, and fatigue the most common adverse events (>10%). In phase II (n = 51), the cumulative incidence of cGVHD at 1 year was 36% (95% confidence interval [CI], 19% to 54%) in the MRD cohort and 39% (95% CI, 21% to 56%) in the MUD cohort. One-year cumulative incidence of nonrelapse mortality (NRM) and relapse was 0% and 20% (95% CI, 8% to 36%) in the MRD cohort, respectively. In the MUD cohort, the respective NRM and relapse rates were 4% (0% to 16%) and 34% (17% to 52%). The outcomes on the study were compared post hoc with contemporaneous matched Center for International Blood and Marrow Transplant Research (CIBMTR) controls. This post hoc analysis showed no significant improvement in cGVHD rates in both the MRD (hazard ratio [HR] = 0.85, P = .64) or MUD cohorts (HR = 0.68, P = .26) on the study compared with CIBMTR controls. B cell activating factor plasma levels were significantly higher after ixazomib dosing in those who remained cGVHD free compared with those developed cGVHD. This study shows that the novel strategy of short-course oral ixazomib following allogeneic HCT is safe but did not demonstrate significant improvement in cGVHD incidence in recipients of MRD and MUD transplantation compared with matched CIBMTR controls. This study is registered at www.clinicaltrials.gov as NCT02250300.
Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Compuestos de Boro , Enfermedad Crónica , Glicina/análogos & derivados , Glicina/uso terapéutico , Enfermedad Injerto contra Huésped/prevención & control , Humanos , Tacrolimus , Acondicionamiento PretrasplanteRESUMEN
We sought to study whether survival after haploidentical transplantation is comparable to that after matched unrelated donor transplantation for 822 patients aged 50-75 years with acute myeloid leukemia in first or second complete remission. One hundred and ninety-two patients received grafts from haploidentical donors (sibling 25%; offspring 75%) and 631 patients from matched unrelated donors aged 18-40 years. Patients' and disease characteristics of the two groups were similar except that recipients of matched unrelated donor transplantation were more likely to have poor risk cytogenetics and more likely to receive myeloablative conditioning regimens. Time from documented remission to transplant did not differ by donor type. Five-year overall survival was 32% and 42% after haploidentical and matched unrelated donor transplant, respectively (P=0.04). Multivariable analysis showed higher mortality (hazard ratio 1.27, P=0.04) and relapse (hazard ratio 1.32, P=0.04) after haploidentical transplantation, with similar non-relapse mortality risks. Chronic graft-versus-host disease was higher after matched unrelated donor compared to haploidentical transplantation when bone marrow was the graft (hazard ratio 3.12, P<0.001), but when the graft was peripheral blood, there was no difference in the risk of chronic graft-versus-host disease between donor types. These data support the view that matched unrelated donor transplant with donors younger than 40 years is to be preferred.