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Depressive symptoms are prevalent in individuals living with sickle cell disease (SCD) and may exacerbate pain. This study examines whether higher depressive symptoms are associated with pain outcomes, pain catastrophizing, interference and potential opioid misuse in a large cohort of adults with SCD. The study utilized baseline data from the 'CaRISMA' trial, which involved 357 SCD adults with chronic pain. Baseline assessments included pain intensity, daily mood, the Patient Health Questionnaire (PHQ), the Generalized Anxiety Disorders scale, PROMIS Pain Interference, Pain Catastrophizing Scale, the Adult Sickle Cell Quality of Life Measurement Information System and the Current Opioid Misuse Measure. Participants were categorized into 'high' or 'low' depression groups based on PHQ scores. Higher depressive symptoms were significantly associated with increased daily pain intensity, negative daily mood, higher pain interference and catastrophizing, poorer quality of life and a higher likelihood of opioid misuse (all p < 0.01). SCD patients with more severe depressive symptoms experienced poorer pain outcomes, lower quality of life and increased risk of opioid misuse. Longitudinal data from this trial will determine whether addressing depressive symptoms may potentially reduce pain frequency and severity in SCD.
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Anemia Falciforme , Dor Crônica , Transtornos Relacionados ao Uso de Opioides , Adulto , Humanos , Anemia Falciforme/complicações , Saúde Mental , Transtornos Relacionados ao Uso de Opioides/complicações , Transtornos Relacionados ao Uso de Opioides/psicologia , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is characterized by recurring episodes of thrombotic microangiopathy, causing ischemic organ impairment. Black patients are overrepresented in iTTP cohorts in the United States, but racial disparities in iTTP outcome and response to therapy have not been studied. Using the United States Thrombotic Microangiopathies Consortium iTTP Registry, we evaluated the impact of race on mortality and relapse-free survival (RFS) in confirmed iTTP in the United States from 1995 to 2020. We separately examined the impact of rituximab therapy and presentation with newly diagnosed (de novo) or relapsed iTTP on RFS by race. A total of 645 participants with 1308 iTTP episodes were available for analysis. Acute iTTP mortality did not differ by race. When all episodes of iTTP were included, Black race was associated with shorter RFS (hazard ratio [HR], 1.60; 95% CI, 1.16-2.21); the addition of rituximab to corticosteroids improved RFS in White (HR, 0.37; 95% CI, 0.18-0.73) but not Black patients (HR, 0.96; 95% CI, 0.71-1.31). In de novo iTTP, rituximab delayed relapse, but Black patients had shorter RFS than White patients, regardless of treatment. In relapsed iTTP, rituximab significantly improved RFS in White but not Black patients. Race affects overall relapse risk and response to rituximab in iTTP. Black patients may require closer monitoring, earlier retreatment, and alternative immunosuppression after rituximab treatment. How race, racism, and social determinants of health contribute to the disparity in relapse risk in iTTP deserves further study.
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Púrpura Trombocitopênica Trombótica , Proteína ADAMTS13 , Corticosteroides , Humanos , Púrpura Trombocitopênica Trombótica/terapia , Recidiva , Rituximab/uso terapêuticoRESUMO
This is a celebratory reprint of a historical paper published in STH in 1998. The original Abstract follows.The PFA-100 system is a platelet function analyzer designed to measure platelet-related primary hemostasis. The instrument uses two disposable cartridges: a collagen/epinephrine (CEPI) and a collagen/ADP (CADP) cartridge. Previous experience has shown that CEPI cartridges detect qualitative platelet defects, including acetylsalicylic acid (ASA)-induced abnormalities, while CADP cartridges detect only thrombocytopathies and not ASA use. In this seven-center trial, 206 healthy subjects and 176 persons with various platelet-related defects, including 127 ASA users, were studied. The platelet function status was determined by a platelet function test panel. Comparisons were made as to how well the defects were identified by the PFA-100 system and by platelet aggregometry. The reference intervals for both cartridges, testing the 206 healthy subjects, were similar to values described in smaller studies in the literature (mean closure time [CT] of 132 seconds for CEPI and 93 seconds for CADP). The use of different lot numbers of cartridges or duplicate versus singleton testing revealed no differences. Compared with the platelet function status, the PFA-100 system had a clinical sensitivity of 94.9% and a specificity of 88.8%. For aggregometry, a sensitivity of 94.3% and a specificity of 88.3% were obtained. These values are based on all 382 specimens. A separate analysis of sensitivity by type of platelet defect, ASA use versus congenital thrombocytopathies, revealed for the PFA-100 system a 94.5% sensitivity in identifying ASA users and a 95.9% sensitivity in identifying the other defects. For aggregometry, the values were 100% for ASA users and 79.6% for congenital defects. Analysis of concordance between the PFA-100 system and aggregometry revealed no difference in clinical sensitivity and specificity between the systems (p > 0.9999). The overall agreement was 87.5%, with a Kappa index of 0.751. The two tests are thus equivalent in their ability to identify normal and abnormal platelet defects. Testing 126 subjects who took 325 mg ASA revealed that the PFA-100 system (CEPI) was able to detect 71.7% of ASA-induced defects with a positive predictive value of 97.8%. The overall clinical accuracy of the system, calculated from the area under the receiver operating characteristic curve, was 0.977. The data suggest that the PFA-100 system is highly accurate in discriminating normal from abnormal platelet function. The ease of operation of the instrument makes it a useful tool to use in screening patients for platelet-related hemostasis defects.
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Hydroxyurea (hydroxycarbamide) (HU) for sickle cell anaemia (SCA) is underutilised. Case management is an evidence-based health management strategy and in this regard patient navigators (PNs) may provide case management for SCA. We hypothesised that HU-eligible patients exposed to PNs would have improved indicators of starting HU and HU adherence. We randomised 224 HU-eligible SCA adults into the Start Healing in Patients with Hydroxyurea (SHIP-HU) Trial. All patients received care from trained physicians using standardised HU prescribing protocols. Patients in the Experimental arm received case management and education from PNs through multiple contacts. All other patients were regarded as the Control arm and received specialty care alone. Study physicians were blinded to the study arms and did not interact with PNs. At baseline, 6 and 12 months we assessed and compared laboratory parameters and HU adherence indicators. Experimental patients had higher 6-month mean fetal haemoglobin (HbF) levels than controls. But at 12 months, mean HbF was similar, as were white blood cell count, absolute neutrophil count, total haemoglobin, platelet count and mean corpuscular volume. At 12 months there were fewer experimental patients missing HU doses than controls (mean 1·8 vs. 4·5, P = 0·0098), and more recent HU prescriptions filled than for controls (mean 53·8 vs. 92 days, median 27·5 vs. 62 days, P = 0·0082). Mean HU doses were largely similar. We detected behavioural improvements in HU adherence but no haematological improvements by adding PNs to specialty care.
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Anemia Falciforme/epidemiologia , Agentes Comunitários de Saúde , Adesão à Medicação , Adulto , Anemia Falciforme/sangue , Anemia Falciforme/diagnóstico , Anemia Falciforme/terapia , Índices de Eritrócitos , Feminino , Humanos , Hidroxiureia/administração & dosagem , Hidroxiureia/efeitos adversos , Hidroxiureia/uso terapêutico , Análise de Intenção de Tratamento , Masculino , Pessoa de Meia-Idade , Assistência ao Paciente , Melhoria de Qualidade , Qualidade de Vida , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Platelet transfusion carries risk of transfusion-transmitted infection (TTI). Pathogen reduction of platelet components (PRPC) is designed to reduce TTI. Pulmonary adverse events (AEs), including transfusion-related acute lung injury and acute respiratory distress syndrome (ARDS) occur with platelet transfusion. STUDY DESIGN: An open label, sequential cohort study of transfusion-dependent hematology-oncology patients was conducted to compare pulmonary safety of PRPC with conventional PC (CPC). The primary outcome was the incidence of treatment-emergent assisted mechanical ventilation (TEAMV) by non-inferiority. Secondary outcomes included: time to TEAMV, ARDS, pulmonary AEs, peri-transfusion AE, hemorrhagic AE, transfusion reactions (TRs), PC and red blood cell (RBC) use, and mortality. RESULTS: By modified intent-to-treat (mITT), 1068 patients received 5277 PRPC and 1223 patients received 5487 CPC. The cohorts had similar demographics, primary disease, and primary therapy. PRPC were non-inferior to CPC for TEAMV (treatment difference -1.7%, 95% CI: (-3.3% to -0.1%); odds ratio = 0.53, 95% CI: (0.30, 0.94). The cumulative incidence of TEAMV for PRPC (2.9%) was significantly less than CPC (4.6%, p = .039). The incidence of ARDS was less, but not significantly different, for PRPC (1.0% vs. 1.8%, p = .151; odds ratio = 0.57, 95% CI: (0.27, 1.18). AE, pulmonary AE, and mortality were not different between cohorts. TRs were similar for PRPC and CPC (8.3% vs. 9.7%, p = .256); and allergic TR were significantly less with PRPC (p = .006). PC and RBC use were not increased with PRPC. DISCUSSION: PRPC demonstrated reduced TEAMV with no excess treatment-related pulmonary morbidity.
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Síndrome do Desconforto Respiratório , Reação Transfusional , Plaquetas , Transfusão de Sangue , Estudos de Coortes , Humanos , Fármacos Fotossensibilizantes , Transfusão de Plaquetas/efeitos adversos , Síndrome do Desconforto Respiratório/etiologia , Síndrome do Desconforto Respiratório/terapia , Reação Transfusional/epidemiologia , Reação Transfusional/etiologiaRESUMO
BACKGROUND: The up-regulation of P-selectin in endothelial cells and platelets contributes to the cell-cell interactions that are involved in the pathogenesis of vaso-occlusion and sickle cell-related pain crises. The safety and efficacy of crizanlizumab, an antibody against the adhesion molecule P-selectin, were evaluated in patients with sickle cell disease. METHODS: In this double-blind, randomized, placebo-controlled, phase 2 trial, we assigned patients to receive low-dose crizanlizumab (2.5 mg per kilogram of body weight), high-dose crizanlizumab (5.0 mg per kilogram), or placebo, administered intravenously 14 times over a period of 52 weeks. Patients who were receiving concomitant hydroxyurea as well as those not receiving hydroxyurea were included in the study. The primary end point was the annual rate of sickle cell-related pain crises with high-dose crizanlizumab versus placebo. The annual rate of days hospitalized, the times to first and second crises, annual rates of uncomplicated crises (defined as crises other than the acute chest syndrome, hepatic sequestration, splenic sequestration, or priapism) and the acute chest syndrome, and patient-reported outcomes were also assessed. RESULTS: A total of 198 patients underwent randomization at 60 sites. The median rate of crises per year was 1.63 with high-dose crizanlizumab versus 2.98 with placebo (indicating a 45.3% lower rate with high-dose crizanlizumab, P=0.01). The median time to the first crisis was significantly longer with high-dose crizanlizumab than with placebo (4.07 vs. 1.38 months, P=0.001), as was the median time to the second crisis (10.32 vs. 5.09 months, P=0.02). The median rate of uncomplicated crises per year was 1.08 with high-dose crizanlizumab, as compared with 2.91 with placebo (indicating a 62.9% lower rate with high-dose crizanlizumab, P=0.02). Adverse events that occurred in 10% or more of the patients in either active-treatment group and at a frequency that was at least twice as high as that in the placebo group were arthralgia, diarrhea, pruritus, vomiting, and chest pain. CONCLUSIONS: In patients with sickle cell disease, crizanlizumab therapy resulted in a significantly lower rate of sickle cell-related pain crises than placebo and was associated with a low incidence of adverse events. (Funded by Selexys Pharmaceuticals and others; SUSTAIN ClinicalTrials.gov number, NCT01895361 .).
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Anemia Falciforme/tratamento farmacológico , Anticorpos Monoclonais/uso terapêutico , Selectina-P/antagonistas & inibidores , Dor/prevenção & controle , Adolescente , Adulto , Anemia Falciforme/complicações , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Hidroxiureia/uso terapêutico , Masculino , Pessoa de Meia-Idade , Selectina-P/imunologia , Dor/etiologia , Qualidade de Vida , Adulto JovemRESUMO
The cell adhesion molecule P-selectin plays a key role in the pathogenesis of a vaso-occlusive crisis (VOC) in patients with sickle cell disease (SCD). In the double-blind, placebo-controlled phase 2 SUSTAIN study, crizanlizumab (humanized, anti-P-selectin monoclonal antibody) 5 mg/kg significantly lowered the rate of VOC in patients with SCD by 45% vs placebo. In SUSTAIN, patients with SCD were randomized to crizanlizumab 2.5 mg/kg, crizanlizumab 5 mg/kg, or placebo intravenously 14 times over 52 weeks. The primary endpoint was the annual rate of VOC with crizanlizumab vs placebo. This post hoc descriptive analysis evaluated the proportion of patients who did not experience a VOC during the study in the following subgroups: VOCs in the year prior to study entry (2-4/5-10), SCD genotype (HbSS/non-HbSS), and concomitant hydroxyurea use (yes/no). More patients were VOC event-free in the crizanlizumab 5 mg/kg arm than in the placebo arm, including those with more frequent prior VOCs (ie, 5-10; 28.0% vs 4.2%), the HbSS genotype (31.9% vs 17.0%) and/or using concomitant hydroxyurea (33.3% vs 17.5%). Further analyses of secondary endpoints demonstrated that crizanlizumab treatment significantly increased time-to-first VOC vs placebo in these subgroups. The rates of treatment-emergent adverse events were similar between treatment arms across all subgroups. This post hoc analysis of SUSTAIN shows that in patients with a high number of prior VOCs, on concomitant hydroxyurea and/or with the HbSS genotype, crizanlizumab treatment increases the likelihood of patients being VOC event-free and delays time-to-first VOC.
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Anemia Falciforme/complicações , Anticorpos Monoclonais/uso terapêutico , Selectina-P/antagonistas & inibidores , Dor/tratamento farmacológico , Adolescente , Adulto , Idoso , Anemia Falciforme/tratamento farmacológico , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados , Antidrepanocíticos/uso terapêutico , Método Duplo-Cego , Feminino , Humanos , Hidroxiureia/administração & dosagem , Hidroxiureia/uso terapêutico , Masculino , Pessoa de Meia-Idade , Dor/etiologia , Intervalo Livre de Progressão , Adulto JovemRESUMO
INTRODUCTION: Vitamin D levels in adult black Americans with sickle cell disease (SCD) are comparatively lower than those found in the general population of black Americans. The objectives of this study were to examine the prevalence of Vitamin D deficiency (VDD) in adults with various subtypes of sickle cell disease and identify risk factors for vitamin D deficiency. METHODS: In a retrospective study serum Vitamin D25(OH)D and/or VitaminD1,25(OH)2D levels were obtained in 120 subjects with sickle cell disease. Baseline studies also included LFTs, total protein, albumin, total bilirubin, and creatinine levels. In a portion of subjects that were treated with oral ergocalciferol vitamin D levels and chemistries were obtained within 6 months of treatment. Data was statistically analyzed with Welch two sample t-tests and individual simple linear regressions (including logarithmic values) for each variable. RESULTS: Vitamin D25(OH)D levels were found to be significantly lower in a group of subjects with Hgb SS disease, than in a group with other subtypes of sickle cell disease. In both groups combined, significant (p = 0.05) and clinically suggestive negative correlations with Vitamin D25(OH)D were seen for total bilirubin and total protein, respectively. When total bilirubin and total protein levels were compared between the Hgb SS and HgbS/other groups, t-test revealed these levels were significantly higher in the Hgb SS group levels at p < 0.001 and p = 0.005, respectively. IMPLICATIONS: Low total Vitamin D25(OH)D levels in adults with sickle cell disease may be a reflection of chronic inflammation and overall disease severity.
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Anemia Falciforme , Deficiência de Vitamina D , Vitamina D/sangue , Negro ou Afro-Americano , Anemia Falciforme/sangue , Anemia Falciforme/diagnóstico , Anemia Falciforme/etnologia , Correlação de Dados , Eritrócitos Anormais , Feminino , Humanos , Inflamação/sangue , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/diagnósticoAssuntos
Dor Aguda/etiologia , Anemia Falciforme/complicações , Anticorpos Monoclonais Humanizados/uso terapêutico , Arteriopatias Oclusivas/etiologia , Dor Aguda/epidemiologia , Dor Aguda/prevenção & controle , Anemia Falciforme/tratamento farmacológico , Arteriopatias Oclusivas/epidemiologia , Arteriopatias Oclusivas/prevenção & controle , Ensaios Clínicos como Assunto/estatística & dados numéricos , Seguimentos , Humanos , Incidência , Selectina-P/antagonistas & inibidores , Selectina-P/imunologiaRESUMO
Ado-trastuzumab emtansine (T-DM1) is a novel antibody-drug conjugate with current FDA recommendation for second-line treatment of HER-2-positive metastatic breast cancer. It is a human epidermal growth factor receptor (HER-2)-targeted antibody-drug conjugate composed of trastuzumab, a stable thioether linker, and the potent cytotoxic agent DM1 (derivative of maytansine). Ado-trastuzumab emtansine improved both progression-free and overall survival as reported in EMILIA trial. With ongoing clinical trials in adjuvant and first-line setting for HER-2-positive early and metastatic breast cancer, it is prudent to recognize, report, and treat any adverse events related to T-DM1. We report a case of acute pancreatitis in a 54-year-old woman with metastatic breast cancer after she received her first dose of ado-trastuzumab emtansine. To the best of our knowledge, this is the first reported case of acute pancreatitis with probable association with ado-trastuzumab emtansine.
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Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Maitansina/análogos & derivados , Pancreatite/induzido quimicamente , Doença Aguda , Ado-Trastuzumab Emtansina , Feminino , Humanos , Maitansina/efeitos adversos , Pessoa de Meia-Idade , TrastuzumabRESUMO
OBJECTIVES: Although the extension of palliative care methodology to sickle cell disease (SCD) care has been proposed, there is no current standard for symptom assessment. Our goal was to assess the feasibility of integrating the Edmonton Symptom Assessment System (ESAS) into the outpatient management of SCD. METHODS: Seventy-five adult patients presenting for outpatient visits at a comprehensive SCD center were enrolled. Patients completed the ESAS (self-report of 10 symptoms during the last 24 hours) and a survey regarding their opinion of the ESAS at enrollment and follow-up. RESULTS: Pain (P = 0.0272) was the only symptom score that changed significantly between the initial and follow-up visits. In patients with a self-reported pain crisis, pain (P < 0.0001), fatigue (P = 0.0025), depression (P = 0.0458), nausea (P = 0.0384), and symptom distress scores (P = 0.0019) were significantly higher than for patients without a pain crisis. On the initial visit, 92% of all patients agreed or strongly agreed that the ESAS was easy to complete; 83% were satisfied or very satisfied with the ESAS as a way to report symptoms. CONCLUSIONS: Our data suggest that the ESAS is well received and can be successfully included as part of the longitudinal symptom management strategy for SCD.
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Assistência Ambulatorial/métodos , Anemia Falciforme/diagnóstico , Cuidados Paliativos/métodos , Índice de Gravidade de Doença , Avaliação de Sintomas , Adulto , Anemia Falciforme/complicações , Estudos de Viabilidade , Feminino , Seguimentos , Humanos , Masculino , Estudos Prospectivos , AutorrelatoRESUMO
Despite early optimism, therapeutics targeting oxidative phosphorylation (OxPhos) have faced clinical setbacks, stemming from their inability to distinguish healthy from cancerous mitochondria. Herein, we describe an actionable bioenergetic mechanism unique to cancerous mitochondria inside acute myeloid leukemia (AML) cells. Unlike healthy cells which couple respiration to the synthesis of ATP, AML mitochondria were discovered to support inner membrane polarization by consuming ATP. Because matrix ATP consumption allows cells to survive bioenergetic stress, we hypothesized that AML cells may resist cell death induced by OxPhos damaging chemotherapy by reversing the ATP synthase reaction. In support of this, targeted inhibition of BCL-2 with venetoclax abolished OxPhos flux without impacting mitochondrial membrane potential. In surviving AML cells, sustained polarization of the mitochondrial inner membrane was dependent on matrix ATP consumption. Mitochondrial ATP consumption was further enhanced in AML cells made refractory to venetoclax, consequential to downregulations in both the proton-pumping respiratory complexes, as well as the endogenous F1-ATPase inhibitor ATP5IF1. In treatment-naive AML, ATP5IF1 knockdown was sufficient to drive venetoclax resistance, while ATP5IF1 overexpression impaired F1-ATPase activity and heightened sensitivity to venetoclax. Collectively, our data identify matrix ATP consumption as a cancer-cell intrinsic bioenergetic vulnerability actionable in the context of mitochondrial damaging chemotherapy.
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Background: Mortality due to immune-mediated thrombotic thrombocytopenic purpura (iTTP) remains significant. Predicting mortality risk may potentially help individualize treatment. The French Thrombotic Microangiopathy (TMA) Reference Score has not been externally validated in the United States. Recent advances in machine learning technology can help analyze large numbers of variables with complex interactions for the development of prediction models. Objectives: To validate the French TMA Reference Score in the United States Thrombotic Microangiopathy (USTMA) iTTP database and subsequently develop a novel mortality prediction tool, the USTMA TTP Mortality Index. Methods: We analyzed variables available at the time of initial presentation, including demographics, symptoms, and laboratory findings. We developed our model using gradient boosting machine, a machine learning ensemble method based on classification trees, implemented in the R package gbm. Results: In our cohort (n = 419), the French score predicted mortality with an area under the receiver operating characteristic curve of 0.63 (95% CI: 0.50-0.77), sensitivity of 0.35, and specificity of 0.84. Our gradient boosting machine model selected 8 variables to predict acute mortality with a cross-validated area under the receiver operating characteristic curve of 0.77 (95% CI: 0.71-0.82). The 2 cutoffs corresponded to sensitivities of 0.64 and 0.50 and specificities of 0.76 and 0.87, respectively. Conclusion: The USTMA Mortality Index was acceptable for predicting mortality due to acute iTTP in the USTMA registry, but not sensitive enough to rule out death. Identifying patients at high risk of iTTP-related mortality may help individualize care and ultimately improve iTTP survival outcomes. Further studies are needed to provide external validation. Our model is one of many recent examples where machine learning models may show promise in clinical prediction tools in healthcare.
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ABSTRACT: Patients treated with antineoplastic therapy often develop thrombocytopenia requiring platelet transfusion, which has potential to exacerbate pulmonary injury. This study tested the hypothesis that amotosalen-UVA pathogen-reduced platelet components (PRPCs) do not potentiate pulmonary dysfunction compared with conventional platelet components (CPCs). A prospective, multicenter, open-label, sequential cohort study evaluated the incidence of treatment-emergent assisted mechanical ventilation initiated for pulmonary dysfunction (TEAMV-PD). The first cohort received CPC. After the CPC cohort, each site enrolled a second cohort transfused with PRPC. Other outcomes included clinically significant pulmonary adverse events (CSPAE) and the incidence of treatment-emergent acute respiratory distress syndrome (TEARDS) diagnosed by blinded expert adjudication. The incidence of TEAMV-PD in all patients (1068 PRPC and 1223 CPC) was less for PRPC (1.7 %) than CPC (3.1%) with a treatment difference of -1.5% (95% confidence interval [CI], -2.7 to -0.2). In patients requiring ≥2 PCs, the incidence of TEAMV-PD was reduced for PRPC recipients compared with CPC recipients (treatment difference, -2.4%; 95% CI, -4.2 to -0.6). CSPAE increased with increasing PC exposure but were not significantly different between the cohorts. For patients receiving ≥2 platelet transfusions, TEARDS occurred in 1.3% PRPC and 2.6% CPC recipients (P = .086). Bayesian analysis demonstrated PRPC may be superior in reducing TEAMV-PD and TEARDS for platelet transfusion recipients compared with CPC recipients, with 99.2% and 88.8% probability, respectively. In this study, PRPC compared with CPC demonstrated high probability of reduced severe pulmonary injury requiring assisted mechanical ventilation in patients with hematology disorders dependent on platelet transfusion. This trial was registered at www.ClinicalTrials.gov as #NCT02549222.
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Transfusão de Plaquetas , Humanos , Transfusão de Plaquetas/efeitos adversos , Feminino , Pessoa de Meia-Idade , Masculino , Idoso , Lesão Pulmonar Aguda/etiologia , Plaquetas , Estudos Prospectivos , Adulto , Trombocitopenia/etiologia , Doenças Hematológicas/terapiaRESUMO
BACKGROUND: Although nitric oxide based therapeutics have been shown in preclinical models to reduce vaso-occlusive events and improve cardiovascular function, a clinical trial of a phosphodiesterase 5 inhibitor increased rates of admission to hospital for pain. We aimed to examine if riociguat, a direct stimulator of the nitric oxide receptor soluble guanylate cyclase, causes similar increases in vaso-occlusive events. METHODS: This was a phase 1-2, randomised, double blind, placebo-controlled trial. Eligible patients were 18 years or older, had confirmed sickle cell disease documented by haemoglobin electrophoresis or HPLC fractionation (haemoglobin SS, SC, Sß-thalassemia, SD, or SO-Arab), and stage 1 hypertension or proteinuria. Participants were randomly assigned 1:1 to receive either riociguat or matching placebo via a web-based system to maintain allocation concealment. Both treatments were administered orally starting at 1·0 mg three times a day up to 2·5 mg three times a day (highest tolerated dose) for 12 weeks. Dose escalation by 0·5 mg was considered every 2 weeks if systolic blood pressure was greater than 95 mm Hg and the participant had no signs of hypotension; otherwise, the last dose was maintained. The primary outcome was the proportion of participants who had at least one adjudicated treatment-emergent serious adverse event. The analysis was performed by the intention-to-treat. This trial is registered with ClinicalTrials.gov (NCT02633397) and was completed. FINDINGS: Between April 11, 2017, and Dec 31, 2021, 165 participants were screened and consented to be enrolled into the study. Of these, 130 participants were randomly assigned to either riociguat (n=66) or placebo (n=64). The proportion of participants with at least one treatment-emergent serious adverse event was 22·7% (n=15) in the riociguat group and 31·3% (n=20) in the placebo group (difference -8·5% [90% CI -21·4 to 4·5]; p=0·19). A similar pattern emerged in other key safety outcomes, sickle cell related vaso-occlusive events (16·7 [n=11] vs 21·9% [n=14]; difference -5·2% [-17·2 to 6·5]; p=0·42), mean pain severity (3·18 vs 3·32; adjusted mean difference -0·14 [-0·70 to 0·42]; p=0·69), and pain interference (3·15 vs 3·12; 0·04 [-0·62 to 0·69]; p=0·93) at 12 weeks were similar between groups. Regarding the key clinical efficacy endpoints, participants taking riociguat had a blood pressure of -8·20 mm Hg (-10·48 to -5·91) compared with -1·24 (-3·58 to 1·10) in those taking placebo (-6·96 mm Hg (90% CI -10·22 to -3·69; p<0·001). INTERPRETATION: Riociguat was safe and had a significant haemodynamic effect on systemic blood pressure. The results of this study provide measures of effect and variability that will inform power calculations for future trials. FUNDING: Bayer Pharmaceuticals.
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Anemia Falciforme , Hipertensão , Proteinúria , Pirazóis , Pirimidinas , Humanos , Anemia Falciforme/tratamento farmacológico , Anemia Falciforme/complicações , Masculino , Feminino , Método Duplo-Cego , Pirazóis/uso terapêutico , Pirazóis/efeitos adversos , Adulto , Pirimidinas/uso terapêutico , Pirimidinas/efeitos adversos , Pirimidinas/administração & dosagem , Hipertensão/tratamento farmacológico , Proteinúria/tratamento farmacológico , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Multiple myeloma is a treatable, but currently incurable, hematological malignancy of plasma cells characterized by diverse and complex tumor genetics for which precision medicine approaches to treatment are lacking. The Multiple Myeloma Research Foundation's Relating Clinical Outcomes in Multiple Myeloma to Personal Assessment of Genetic Profile study ( NCT01454297 ) is a longitudinal, observational clinical study of newly diagnosed patients with multiple myeloma (n = 1,143) where tumor samples are characterized using whole-genome sequencing, whole-exome sequencing and RNA sequencing at diagnosis and progression, and clinical data are collected every 3 months. Analyses of the baseline cohort identified genes that are the target of recurrent gain-of-function and loss-of-function events. Consensus clustering identified 8 and 12 unique copy number and expression subtypes of myeloma, respectively, identifying high-risk genetic subtypes and elucidating many of the molecular underpinnings of these unique biological groups. Analysis of serial samples showed that 25.5% of patients transition to a high-risk expression subtype at progression. We observed robust expression of immunotherapy targets in this subtype, suggesting a potential therapeutic option.
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Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias do Colo/terapia , Síndrome de Guillain-Barré/induzido quimicamente , Ifosfamida/efeitos adversos , Lipossarcoma/tratamento farmacológico , Neoplasias Retroperitoneais/tratamento farmacológico , Idoso , Quimioterapia Adjuvante/efeitos adversos , Quimioterapia Adjuvante/métodos , Colectomia , Eletromiografia , Síndrome de Guillain-Barré/diagnóstico , Síndrome de Guillain-Barré/tratamento farmacológico , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Lipossarcoma/diagnóstico , Masculino , Neoplasias Retroperitoneais/diagnósticoRESUMO
Vaso-occlusion in sickle cell disease (SCD) leads to a myriad of manifestations driving morbidity and mortality in patients with SCD. Increased leucocyte adhesion and P-selectin expression on platelets and endothelial cells is an inciting event that leads to obstruction of microcirculation by adhesion with rigid sickled red blood cells. Crizanlizumab is a first-in-class monoclonal antibody that inhibits P-selectin and has been shown to decrease the frequency of vaso-occlusive pain crises in patients with SCD in clinical trials. The role of crizanlizumab in other manifestations of SCD still needs further investigation.
There are more than 100,000 people in the USA living with sickle cell anemia, which is a form of the inherited blood disorder, sickle cell disease. Patients with sickle cell anemia are typically diagnosed through newborn screening programs. They are also diagnosed during times of vaso-occlusive pain crisis, where patients present with severe pain without an obvious cause, and also through hemolytic anemia, a disorder in which red blood cells are destroyed faster than they can be made. While children typically survive into adulthood, the life expectancy of those with sickle cell remains shorter secondary to the after-effects of chronic sickling, where the hemoglobin inside red blood cells sticks or clumps together, causing the cell to become fragile. The associated complications of chronic sickling include pulmonary hypertension (high blood pressure in the arteries of the lung and the right side of the heart), heart failure, stroke, liver dysfunction and splenic infarction, where the blood flow to the spleen is compromised. Crizanlizumab is a new therapy targeting P-selectin, a protein that blocks interaction with p-selectin glycoprotein ligand, and has shown promise in reducing vaso-occlusive crises.
RESUMO
Key Clinical Message: Acquired factor VIII inhibitors can be a rare cause of extensive intramuscular bleeding requiring fasciotomy. The subsequent postoperative period requires close monitoring due to high risk of fatal blood loss. Abstract: Acquired factor VIII inhibitors are a rare cause of often extensive bleeding and subsequently large hematomas. This disorder's overall mortality can reach 38%, largely due to immunosuppression and subsequent infections or an underlying cause such as malignancy. The patient in this case study presented with a hematoma and extensive ecchymosis of the hand and forearm, which continued to progress, precipitating compartment syndrome of the hand and forearm and ultimately requiring fasciotomy. The combination of factors led to significant blood loss in the postoperative period requiring major fluid resuscitation and intensive care unit (ICU) level care. Due to this disorder's rarity and overall mortality, we present this case report with a literature review for management of acquired hemophilia in the setting of urgent fasciotomy.