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Failure-free survival (FFS), defined as the absence of new systemic treatment, recurrence of original malignancy and mortality not associated with recurrence after allogeneic hematopoietic stem cell transplantation (HCT), is a robust clinical measure to interpret results of initial systemic treatment of chronic graft-versus-host disease (cGVHD). We evaluate FFS after initial treatment of cGVHD in a mixed-race cohort from a resource-constrained country. This retrospective study included 354 consecutive patients after their first HCT between January 2014 and August 2020, who received initial systemic treatment for moderate or severe cGVHD at 13 Brazilian centers. Cox regression models were used to identify risk factors for treatment failure. The overall median follow-up among survivors was 28 months (range 1-71) after initial treatment. FFS was 89% at 6 months, 71% at 1 year and 52% at 2 years. New systemic treatment was the major cause of failure. In multivariable models, prior grades II-IV acute GVHD, a National Institutes of Health severity score of 3 in liver, gastrointestinal tract or lung involvement, and onset of initial treatment of cGVHD within 12 months after transplantation were all associated with an increased risk of treatment failure. Our results could serve as a benchmark for the design of future clinical trials evaluating initial treatment of cGVHD in resource-constrained locations.
Assuntos
Síndrome de Bronquiolite Obliterante , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Estados Unidos , Humanos , Brasil/epidemiologia , Estudos Retrospectivos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Doença Enxerto-Hospedeiro/tratamento farmacológicoRESUMO
Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.In the primary analysis of the global phase II ELIANA trial (ClinicalTrials.gov identifier: NCT02435849), tisagenlecleucel provided an overall remission rate of 81% in pediatric and young adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL), with 59% of responders remaining relapse-free at 12 months. Here, we report an update on efficacy, safety, and patient-reported quality of life in 79 pediatric and young adult patients with R/R B-ALL following a median follow-up of 38.8 months. The overall remission rate was 82%. The median event-free survival was 24 months, and the median overall survival was not reached. Event-free survival was 44% (95% CI, 31 to 57) and overall survival was 63% (95% CI, 51 to 73) at 3 years overall (most events occur within the first 2 years). The estimated 3-year relapse-free survival with and without censoring for subsequent therapy was 52% (95% CI, 37 to 66) and 48% (95% CI, 34 to 60), respectively. No new or unexpected long-term adverse events were reported. Grade 3/4 adverse events were reported in 29% of patients > 1 year after infusion; grade 3/4 infection rate did not increase > 1 year after infusion. Patients reported improvements in quality of life up to 36 months after infusion. These findings demonstrate favorable long-term safety and suggest tisagenlecleucel as a curative treatment option for heavily pretreated pediatric and young adult patients with R/R B-ALL.
Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras , Qualidade de Vida , Criança , Humanos , Adulto Jovem , Doença Crônica , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Receptores de Antígenos de Linfócitos T/uso terapêutico , RecidivaRESUMO
Given its biocompatibility, rheological, and physiological properties, hyaluronic acid (HA) has become a biomaterial of increasing interest with multiple applications in medicine and cosmetics. In recent decades, microbial fermentations have become an important source for the industrial production of HA. However, due to its final applications, microbial HA must undergo critical and long purification processes to ensure clinical and cosmetic grade purity. Aqueous two-phase systems (ATPS) have proven to be an efficient technique for the primary recovery of high-value biomolecules. Nevertheless, their implementation in HA downstream processing has been practically unexplored. In this work, polyethylene glycol (PEG)-citrate ATPS were used for the first time for the primary recovery of HA produced with an engineered strain of Streptococcus equi subsp. zooepidemicus. The effects of PEG molecular weight (MW), tie-line length (TLL), volume ratio (VR), and sample load on HA recovery and purity were studied with a clarified fermentation broth as feed material. HA was recovered in the salt-rich bottom phase, and its recovery increased when a PEG MW of 8000 g mol-1 was used. Lower VR values (0.38) favoured HA recovery, whereas purity was enhanced by a high VR (3.50). Meanwhile, sample load had a negative impact on both recovery and purity. The ATPS with the best performance was PEG 8000 g mol-1, TLL 43% (w/w), and VR 3.50, showing 79.4% HA recovery and 74.5% purity. This study demonstrated for the first time the potential of PEG-citrate ATPS as an effective primary recovery strategy for the downstream process of microbial HA.
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Hepatitis B (HBV) is endemic in Haiti, therefore Haitian immigrants should be screened to identify and link affected individuals to care. Current screening approaches are ineffective. We assessed the acceptability and feasibility of home-based screening among Haitian immigrants using community health workers (CHWs). We recruited participants exiting a pragmatic trial evaluating strategies to improve care delivery (NCT02970136). Participants completed an acceptability questionnaire. Blood drawn by CHWs at participants' homes or community sites was tested for hepatitis B surface antigen, hepatitis B surface antibody and hepatitis B core antibody. Of 60 participants, 59 found screening acceptable; 53 had blood drawn. Of those, 45.3% had HBV previously, 49.1% remained susceptible and 5.7% were vaccinated. Respondents cited various reasons community members might find screening unacceptable. The high prior HBV rate highlights the need for effective outreach programs. Home-based HBV screening was both acceptable and feasible among Haitian immigrants.
Assuntos
Emigrantes e Imigrantes , Hepatite B , Estudos de Viabilidade , Haiti , Hepatite B/diagnóstico , Hepatite B/prevenção & controle , Humanos , Programas de RastreamentoRESUMO
Human bone histological analysis is a useful tool to assess post mortem diagenesis and to predict successful nuclear DNA typing of forensic material. This study is part of a series of studies developed by the authors intended to improve the understanding of post mortem diagenesis and to develop applications for DNA analysis of skeletal species from tropical soils, in order to optimize genetic and anthropological protocols. The aim of this study was to analyze the impact of burial period on the integrity of exhumed compact bone microstructure from tropical climate. In fragments of exhumed human femora from 39 individuals from the same cemetery (exhumed group) and 5 fresh femora from routine autopsies (control group), sections stained by hematoxylin-eosin were analyzed in order to measure bone microstructural integrity. We found that bone integrity index in exhumed group was negatively influenced by the period of burial (r = -0.37, p < 0.05) and highly significantly decreased (p < 0.0001) in comparison to control group. The period of burial and nitric acid decalcification time was positively correlated (r = 0.51; p < 0.01), leading to imply a bone petrification process during inhumation. Exhumed group showed higher level of matrix bone loss (p < 0.001), as expected, and 87% of cases analyzed were "tunneled" as described by Hackett. Bone integrity index and bone matrix tend to decrease in bones buried in tropical soil between 8-14 years of inhumation. This period is short if we consider cases in which there are preserved bones interred for longer periods in other environments. These data must be considered in cases where genetic identification of exhumed skeletons from tropical environment is required. The diagenesis in these bones and the variations of results found are discussed, clarifying some challenges for forensic laboratories, especially in DNA analysis.
Assuntos
Sepultamento , Fêmur/patologia , Mudanças Depois da Morte , Solo , Clima Tropical , Adulto , Idoso , Idoso de 80 Anos ou mais , Matriz Óssea/patologia , Brasil , Estudos de Casos e Controles , Contagem de Células , Núcleo Celular/patologia , Osso Cortical/patologia , Descalcificação Patológica/patologia , Exumação , Antropologia Forense , Patologia Legal , Ósteon/patologia , Humanos , Masculino , Microscopia , Pessoa de Meia-Idade , Osteócitos/patologia , Fatores de Tempo , Adulto JovemRESUMO
The study of facial growth is explored in many fields of science, including anatomy, genetics, and forensics. In the field of forensics, it acts as a valuable tool for combating child pornography. The present research proposes a new method, based on relative measurements and fixed references of the human face-specifically considering measurements of the diameter of the iris (iris ratio)-for the analysis of facial growth in association with age in children and sub-adults. The experimental sample consisted of digital photographs of 1000 Brazilian subjects, aged between 6 and 22 years, distributed equally by sex and divided into five specific age groups (6, 10, 14, 18, and 22 year olds ± one month). The software package SAFF-2D® (Forensic Facial Analysis System, Brazilian Federal Police, Brazil) was used for positioning 11 landmarks on the images. Ten measurements were calculated and used as fixed references to evaluate the growth of the other measurements for each age group, as well the accumulated growth (6-22 years old). The Intraclass Correlation Coefficient (ICC) was applied for the evaluation of intra-examiner and inter-examiner reliability within a specific set of images. Pearson's Correlation Coefficient was used to assess the association between each measurement taken and the respective age groups. ANOVA and Post-hoc Tukey tests were used to search for statistical differences between the age groups. The outcomes indicated that facial structures grow with different timing in children and adolescents. Moreover, the growth allometry expressed in this study may be used to understand what structures have more or less proportional variation in function for the age ranges studied. The diameter of the iris was found to be the most stable measurement compared to the others and represented the best cephalometric measurement as a fixed reference for facial growth ratios (or indices). The method described shows promising potential for forensic applications, especially as part of the armamentarium against crimes involving child pornography and child abuse.
Assuntos
Cefalometria/métodos , Face/anatomia & histologia , Processamento de Imagem Assistida por Computador , Iris/anatomia & histologia , Software , Adolescente , Brasil , Criança , Abuso Sexual na Infância/prevenção & controle , Literatura Erótica , Feminino , Humanos , Masculino , Fotografação , Adulto JovemRESUMO
Taphonomic processes affecting bone post mortem are important in forensic, archaeological and palaeontological investigations. In this study, the application of tissue microarray (TMA) analysis to a sample of femoral bone specimens from 20 exhumed individuals of known period of burial and age at death is described. TMA allows multiplexing of subsamples, permitting standardized comparative analysis of adjacent sections in 3-D and of representative cross-sections of a large number of specimens. Standard hematoxylin and eosin, periodic acid-Schiff and silver methenamine, and picrosirius red staining, and CD31 and CD34 immunohistochemistry were applied to TMA sections. Osteocyte and osteocyte lacuna counts, percent bone matrix loss, and fungal spheroid element counts could be measured and collagen fibre bundles observed in all specimens. Decalcification with 7% nitric acid proceeded more rapidly than with 0.5 M EDTA and may offer better preservation of histological and cellular structure. No endothelial cells could be detected using CD31 and CD34 immunohistochemistry. Correlation between osteocytes per lacuna and age at death may reflect reported age-related responses to microdamage. Methodological limitations and caveats, and results of the TMA analysis of post mortem diagenesis in bone are discussed, and implications for DNA survival and recovery considered.
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Osso e Ossos/química , Osso e Ossos/metabolismo , Antropologia Forense/métodos , Análise Serial de Tecidos , Adulto , Idoso , Matriz Óssea/metabolismo , Calcificação Fisiológica , Células Endoteliais/metabolismo , Humanos , Pessoa de Meia-Idade , Osteócitos/metabolismoRESUMO
Oxidative stress is involved in activating photoreceptor death in several retinal degenerations. Docosahexaenoic acid (DHA), the major polyunsaturated fatty acid in the retina, protects cultured retina photoreceptors from apoptosis induced by oxidative stress and promotes photoreceptor differentiation. Here, we investigated whether eicosapentaenoic acid (EPA), a metabolic precursor to DHA, had similar effects and whether retinal neurons could metabolize EPA to DHA. Adding EPA to rat retina neuronal cultures increased opsin expression and protected photoreceptors from apoptosis induced by the oxidants paraquat and hydrogen peroxide (H2 O2 ). Palmitic, oleic, and arachidonic acids had no protective effect, showing the specificity for DHA. We found that EPA supplementation significantly increased DHA percentage in retinal neurons, but not EPA percentage. Photoreceptors and glial cells expressed Δ6 desaturase (FADS2), which introduces the last double bond in DHA biosynthetic pathway. Pre-treatment of neuronal cultures with CP-24879 hydrochloride, a Δ5/Δ6 desaturase inhibitor, prevented EPA-induced increase in DHA percentage and completely blocked EPA protection and its effect on photoreceptor differentiation. These results suggest that EPA promoted photoreceptor differentiation and rescued photoreceptors from oxidative stress-induced apoptosis through its elongation and desaturation to DHA. Our data show, for the first time, that isolated retinal neurons can synthesize DHA in culture. Docosahexaenoic acid (DHA), the major polyunsaturated fatty acid in retina photoreceptors, and its precursor, eicosapentaenoic acid (EPA) have multiple beneficial effects. Here, we show that retina neurons in vitro express the desaturase FADS2 and can synthesize DHA from EPA. Moreover, addition of EPA to these cultures protects photoreceptors from oxidative stress and promotes their differentiation through its metabolization to DHA.
Assuntos
Ácidos Docosa-Hexaenoicos/farmacologia , Ácido Eicosapentaenoico/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Células Fotorreceptoras de Vertebrados/metabolismo , Retina/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Sobrevivência Celular/efeitos dos fármacos , Mitocôndrias/metabolismo , Paraquat/farmacologia , Substâncias Protetoras/farmacologia , Ratos Wistar , Retina/metabolismoRESUMO
R788 (fostamatinib) is an oral prodrug that is rapidly converted into a relatively selective spleen tyrosine kinase (SYK) inhibitor R406, evaluated for the treatment of rheumatoid arthritis (RA). This analysis aimed at developing a pharmacodynamic model for efficacy using pooled ACR20 data from two phase II studies in patients with rheumatoid arthritis (TASKi1 and TASKi2), describing the effect of fostamatinib as a function of fostamatinib exposure (dose, R406 plasma concentration) and other explanatory variables. The exposure-response relationship of fostamatinib was implemented into a continuous time Markov model describing the time course of transition probabilities between the three possible states of ACR20 non-responder, responder, and dropout at each visit. The probability of transition to the ACR20 response state was linearly (at the rate constant level) related to average R406 plasma concentrations and the onset of this drug effect was fast. Further, increases of fostamatinib dose resulted in increased dropout and subsequent loss of efficacy. This analysis provided an increased understanding of the exposure-response relationship, and provided support for fostamatinib 100 mg BID an appropriate dose regimen for further clinical evaluation.