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1.
Cancers (Basel) ; 14(9)2022 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-35565461

RESUMO

The comorbidity burden is an important risk factor for overall survival (OS) in several hematological malignancies. This observational prospective study was conducted to evaluate the impact of individual comorbidities on survival in a multicenter series of 668 patients with primary myelofibrosis (PMF) or MF secondary to polycythemia vera (PPV-MF) or essential thrombocythemia (PET-MF). Hypertension (hazard ratio (HR) = 4.96, p < 0.001), smoking (HR = 5.08, p < 0.001), dyslipidemia (HR = 4.65, p < 0.001) and hepatitis C virus (HCV) (HR = 4.26, p = 0.015) were most adversely associated with OS. Diabetes (HR = 3.01, p < 0.001), pulmonary disease (HR = 3.13, p < 0.001) and renal dysfunction (HR = 1.82, p = 0.037) were also associated with an increased risk of death. Multivariate analysis showed that pulmonary disease (HR = 2.69, p = 0.001), smoking (HR = 3.34, p < 0.001), renal dysfunction (HR = 2.08, p = 0.043) and HCV (HR = 11.49, p = 0.001) had a negative impact on OS. When ruxolitinib exposure was included in the model, the effect of each comorbidity on survival was modified. Therefore, individual comorbidities should be taken into account in determining the survival prognosis for patients with MF.

2.
J Natl Cancer Inst ; 2022 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-35417006

RESUMO

BACKGROUND: 15% of patients with cancer experience symptomatic sequelae, which impair post COVID-19 outcomes. In this study we investigated whether a pro-inflammatory status is associated with the development of COVID-19 sequelae. METHODS: OnCovid recruited 2795 consecutive patients, diagnosed with SARS-CoV-2 infection between 27/02/2020-14/02/2021. This analysis focused on COVID-19 survivors who underwent a clinical re-assessment after the exclusion of patients with haematological malignancies. We evaluated the association of inflammatory markers collected at COVID-19 diagnosis with sequelae, considering the impact of prior systemic anticancer therapy (SACT). RESULTS: Out of 1339 patients eligible, 203 experienced at least one sequela (15.2%). Median baseline C-reactive protein (CRP, 77.5 mg/L vs 22.2 mg/L, p<.001), lactate dehydrogenase (LDH, 310 UI/L vs 274 UI/L, p=.028) and neutrophil-to-lymphocyte ratio (NLR, 6.0 vs 4.3, p=.001) were statistically significantly higher among patients who experienced sequelae, while no association were reported for platelet-to-lymphocyte ratio (PLR) and the OnCovid Inflammatory Score (OIS), which includes albumin and lymphocytes. The widest Area under the ROC curve was reported for baseline CRP (AUC 0.66,95%CI:0.63-0.69), followed by the NLR (AUC0.58,95%CI:0.55-0.61) and LDH (AUC=0.57,95%CI:0.52-0.61). Using a fixed categorical multivariable analysis high CRP (OR 2.56,95%CI:1.67-3.91) and NLR (OR 1.45,95%CI:1.01-2.10) were confirmed to be statistically significantly associated with an increased risk of sequelae. Exposure to chemotherapy was associated with a decreased risk of sequelae (OR 0.57,95%CI:0.36-0.91), while no associations with immune checkpoint inhibitors, endocrine therapy, and other types of SACT were found. CONCLUSIONS: Although the association between inflammatory status, recent chemotherapy and sequelae warrants further investigations, our findings suggest that a deranged pro-inflammatory reaction at COVID-19 diagnosis may predict for sequelae development.

3.
J Ind Microbiol Biotechnol ; 49(1)2022 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-34718634

RESUMO

The control of microorganisms is a key objective in disease prevention and in medical, industrial, domestic, and food-production environments. Whilst the effectiveness of biocides in these contexts is well-evidenced, debate continues about the resistance risks associated with their use. This has driven an increased regulatory burden, which in turn could result in a reduction of both the deployment of current biocides and the development of new compounds and formulas. Efforts to balance risk and benefit are therefore of critical importance and should be underpinned by realistic methods and a multi-disciplinary approach, and through objective and critical analyses of the literature. The current literature on this topic can be difficult to navigate. Much of the evidence for potential issues of resistance generation by biocides is based on either correlation analysis of isolated bacteria, where reports of treatment failure are generally uncommon, or laboratory studies that do not necessarily represent real biocide applications. This is complicated by inconsistencies in the definition of the term resistance. Similar uncertainties also apply to cross-resistance between biocides and antibiotics. Risk assessment studies that can better inform practice are required. The resulting knowledge can be utilised by multiple stakeholders including those tasked with new product development, regulatory authorities, clinical practitioners, and the public. This review considers current evidence for resistance and cross-resistance and outlines efforts to increase realism in risk assessment. This is done in the background of the discussion of the mode of application of biocides and the demonstrable benefits as well as the potential risks.


Assuntos
Desinfetantes , Antibacterianos/farmacologia , Bactérias/genética , Biofísica , Desinfetantes/farmacologia , Farmacorresistência Bacteriana , Testes de Sensibilidade Microbiana
4.
Blood Adv ; 6(3): 774-784, 2022 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-34844263

RESUMO

Recent studies have shown a suboptimal humoral response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) messenger RNA (mRNA) vaccines in patients diagnosed with hematologic malignancies; however, data about cellular immunogenicity are scarce. The aim of this study was to evaluate both the humoral and cellular immunogenicity 1 month after the second dose of the mRNA-1273 vaccine. Antibody titers were measured by using the Elecsys and LIAISON anti-SARS-CoV-2 S assays, and T-cell response was assessed by using interferon-γ release immunoassay technology. Overall, 76.3% (184 of 241) of patients developed humoral immunity, and the cellular response rate was 79% (184 of 233). Hypogammaglobulinemia, lymphopenia, active hematologic treatment, and anti-CD20 therapy during the previous 6 months were associated with an inferior humoral response. Conversely, age >65 years, active disease, lymphopenia, and immunosuppressive treatment of graft-versus-host disease (GVHD) were associated with an impaired cellular response. A significant dissociation between the humoral and cellular responses was observed in patients treated with anti-CD20 therapy (the humoral response was 17.5%, whereas the cellular response was 71.1%). In these patients, B-cell aplasia was confirmed while T-cell counts were preserved. In contrast, humoral response was observed in 77.3% of patients undergoing immunosuppressive treatment of GVHD, whereas only 52.4% had a cellular response. The cellular and humoral responses to the SARS-CoV-2 mRNA-1273 vaccine in patients with hematologic malignancies are highly influenced by the presence of treatments such as anti-CD20 therapy and immunosuppressive agents. This observation has implications for the further management of these patients.


Assuntos
COVID-19 , Neoplasias Hematológicas , Idoso , Anticorpos Neutralizantes , Anticorpos Antivirais , Vacinas contra COVID-19 , Neoplasias Hematológicas/terapia , Humanos , Imunogenicidade da Vacina , RNA Mensageiro/genética , SARS-CoV-2
5.
JAMA Oncol ; 8(1): 114-122, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34817562

RESUMO

Importance: Whether the severity and mortality of COVID-19 in patients with cancer have improved in terms of disease management and capacity is yet to be defined. Objective: To test whether severity and mortality from COVID-19 among patients with cancer have improved during the course of the pandemic. Design, Setting, and Participants: OnCovid is a European registry that collects data on consecutive patients with solid or hematologic cancer and COVID-19. This multicenter case series study included real-world data from 35 institutions across 6 countries (UK, Italy, Spain, France, Belgium, and Germany). This update included patients diagnosed between February 27, 2020, and February, 14, 2021. Inclusion criteria were confirmed diagnosis of SARS-CoV-2 infection and a history of solid or hematologic cancer. Exposures: SARS-CoV-2 infection. Main Outcomes and Measures: Deaths were differentiated at 14 days and 3 months as the 2 landmark end points. Patient characteristics and outcomes were compared by stratifying patients across 5 phases (February to March 2020, April to June 2020, July to September 2020, October to December 2020, and January to February 2021) and across 2 major outbreaks (February to June 2020 and July 2020 to February 2021). Results: At data cutoff, 2795 consecutive patients were included, with 2634 patients eligible for analysis (median [IQR] age, 68 [18-77] years ; 52.8% men). Eligible patients demonstrated significant time-dependent improvement in 14-day case-fatality rate (CFR) with estimates of 29.8% (95% CI, 0.26-0.33) for February to March 2020; 20.3% (95% CI, 0.17-0.23) for April to June 2020; 12.5% (95% CI, 0.06-22.90) for July to September 2020; 17.2% (95% CI, 0.15-0.21) for October to December 2020; and 14.5% (95% CI, 0.09-0.21) for January to February 2021 (all P < .001) across the predefined phases. Compared with the second major outbreak, patients diagnosed in the first outbreak were more likely to be 65 years or older (974 of 1626 [60.3%] vs 564 of 1008 [56.1%]; P = .03), have at least 2 comorbidities (793 of 1626 [48.8%] vs 427 of 1008 [42.4%]; P = .001), and have advanced tumors (708 of 1626 [46.4%] vs 536 of 1008 [56.1%]; P < .001). Complications of COVID-19 were more likely to be seen (738 of 1626 [45.4%] vs 342 of 1008 [33.9%]; P < .001) and require hospitalization (969 of 1626 [59.8%] vs 418 of 1008 [42.1%]; P < .001) and anti-COVID-19 therapy (1004 of 1626 [61.7%] vs 501 of 1008 [49.7%]; P < .001) during the first major outbreak. The 14-day CFRs for the first and second major outbreaks were 25.6% (95% CI, 0.23-0.28) vs 16.2% (95% CI, 0.13-0.19; P < .001), respectively. After adjusting for country, sex, age, comorbidities, tumor stage and status, anti-COVID-19 and anticancer therapy, and COVID-19 complications, patients diagnosed in the first outbreak had an increased risk of death at 14 days (hazard ratio [HR], 1.85; 95% CI, 1.47-2.32) and 3 months (HR, 1.28; 95% CI, 1.08-1.51) compared with those diagnosed in the second outbreak. Conclusions and Relevance: The findings of this registry-based study suggest that mortality in patients with cancer diagnosed with COVID-19 has improved in Europe; this improvement may be associated with earlier diagnosis, improved management, and dynamic changes in community transmission over time.


Assuntos
COVID-19 , Neoplasias , Idoso , Feminino , Humanos , Lactente , Masculino , Neoplasias/epidemiologia , Pandemias , Sistema de Registros , SARS-CoV-2
6.
Lancet Oncol ; 22(12): 1669-1680, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34741822

RESUMO

BACKGROUND: The medium-term and long-term impact of COVID-19 in patients with cancer is not yet known. In this study, we aimed to describe the prevalence of COVID-19 sequelae and their impact on the survival of patients with cancer. We also aimed to describe patterns of resumption and modifications of systemic anti-cancer therapy following recovery from SARS-CoV-2 infection. METHODS: OnCovid is an active European registry study enrolling consecutive patients aged 18 years or older with a history of solid or haematological malignancy and who had a diagnosis of RT-PCR confirmed SARS-CoV-2 infection. For this retrospective study, patients were enrolled from 35 institutions across Belgium, France, Germany, Italy, Spain, and the UK. Patients who were diagnosed with SARS-CoV-2 infection between Feb 27, 2020, and Feb 14, 2021, and entered into the registry at the point of data lock (March 1, 2021), were eligible for analysis. The present analysis was focused on COVID-19 survivors who underwent clinical reassessment at each participating institution. We documented prevalence of COVID-19 sequelae and described factors associated with their development and their association with post-COVID-19 survival, which was defined as the interval from post-COVID-19 reassessment to the patients' death or last follow-up. We also evaluated resumption of systemic anti-cancer therapy in patients treated within 4 weeks of COVID-19 diagnosis. The OnCovid study is registered in ClinicalTrials.gov, NCT04393974. FINDINGS: 2795 patients diagnosed with SARS-CoV-2 infection between Feb 27, 2020, and Feb 14, 2021, were entered into the study by the time of the data lock on March 1, 2021. After the exclusion of ineligible patients, the final study population consisted of 2634 patients. 1557 COVID-19 survivors underwent a formal clinical reassessment after a median of 22·1 months (IQR 8·4-57·8) from cancer diagnosis and 44 days (28-329) from COVID-19 diagnosis. 234 (15·0%) patients reported COVID-19 sequelae, including respiratory symptoms (116 [49·6%]) and residual fatigue (96 [41·0%]). Sequelae were more common in men (vs women; p=0·041), patients aged 65 years or older (vs other age groups; p=0·048), patients with two or more comorbidities (vs one or none; p=0·0006), and patients with a history of smoking (vs no smoking history; p=0·0004). Sequelae were associated with hospitalisation for COVID-19 (p<0·0001), complicated COVID-19 (p<0·0001), and COVID-19 therapy (p=0·0002). With a median post-COVID-19 follow-up of 128 days (95% CI 113-148), COVID-19 sequelae were associated with an increased risk of death (hazard ratio [HR] 1·80 [95% CI 1·18-2·75]) after adjusting for time to post-COVID-19 reassessment, sex, age, comorbidity burden, tumour characteristics, anticancer therapy, and COVID-19 severity. Among 466 patients on systemic anti-cancer therapy, 70 (15·0%) permanently discontinued therapy, and 178 (38·2%) resumed treatment with a dose or regimen adjustment. Permanent treatment discontinuations were independently associated with an increased risk of death (HR 3·53 [95% CI 1·45-8·59]), but dose or regimen adjustments were not (0·84 [0·35-2·02]). INTERPRETATION: Sequelae post-COVID-19 affect up to 15% of patients with cancer and adversely affect survival and oncological outcomes after recovery. Adjustments to systemic anti-cancer therapy can be safely pursued in treatment-eligible patients. FUNDING: National Institute for Health Research Imperial Biomedical Research Centre and the Cancer Treatment and Research Trust.


Assuntos
COVID-19/complicações , Neoplasias/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Bélgica , COVID-19/epidemiologia , COVID-19/mortalidade , Progressão da Doença , Feminino , França , Alemanha , Hospitalização , Humanos , Itália , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Prevalência , Sistema de Registros , Estudos Retrospectivos , Espanha , Reino Unido
8.
Transplant Cell Ther ; 27(10): 865.e1-865.e7, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34217846

RESUMO

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective therapy resulting in increased definitive cure rates or extended disease-free survival in various malignant and nonmalignant hematologic diseases. However, because of the high risk of severe complications of this therapy, up to 50% of patients may require being admitted to the intensive care unit (ICU) to manage life-threatening conditions. We aimed to evaluate the in-hospital mortality of allo-HSCT recipients admitted to the ICU and to identify those variables associated with in-hospital mortality. A 10-year (January 2010 to December 2019), single-center, retrospective study was conducted in Vall d´Hebron University Hospital, Barcelona. We included all consecutive allo-HSCT patients who required admission to the ICU. Baseline and disease-related characteristics were registered. Severity scores and the need for organ support were also assessed on days 1, 3, and 5 of ICU admission. In-hospital mortality-associated independent variables were identified using the Cox proportional hazards regression model. Three hundred twenty-three patients underwent allo-HSCT during the study period, of whom 82 (25%) were admitted to the ICU; 53 (65%) male, with a median age of 51 (38-59) years. Most patients received allo-HSCT for the treatment of lymphoma (20 patients [24%]) or acute leukemia (44 patients [54%]). The median Acute Physiology And Chronic Health Evaluation II score was 23 (17-28), and the median Sequential Organ Failure Assessment (SOFA) score on admission was 9 (7-11). Forty-nine (60%) patients died in the ICU, and 11 (13%) died in the hospital after being discharged from the ICU. Disease-related characteristics were not associated with mortality. Yet, SOFA score on day 1 (hazard ratio [HR]: 1.11 [95% confidence interval {CI}: 1.04-1.02]; P = .002), the need for vasopressors on day 3 (HR: 2.35 [95% CI: 1.27-4.36]; P = .007), and a nondecreasing SOFA score on day 5 (HR: 2.13 [95% CI: 1.03-4.39]; P = .04), were independently associated with in-hospital mortality. Mortality in allo-HSCT patients who require ICU admission remains high. In the present study, SOFA score, the need for vasopressors on day 3, and a nondecreasing SOFA score on day 5 predicted in-hospital mortality.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Escores de Disfunção Orgânica , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos
9.
J Colloid Interface Sci ; 590: 506-517, 2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-33567375

RESUMO

HYPOTHESIS: Despite the widespread industrial usage of erucamide as a slip additive to modify polymer surface properties, a controversy appears to have persisted regarding the nanostructure of erucamide surface layers, particularly the molecular orientation at the outermost layer. The erucamide nanostructure and molecular orientation, along with its surface coverage, hydrophobicity, and adhesive response, can be tuned by simply varying the erucamide concentration in the solution from which the spin coated layer is prepared. EXPERIMENTS: Synchrotron X-ray reflectivity (XRR) allowed a comprehensive characterisation of the out-of-plane structural parameters (e.g. molecular packing and thickness) of the erucamide layers prepared via spin coating from nonaqueous solution on silica. Complementary Atomic Force Microscopy (AFM) imaging with high lateral resolution revealed localised in-plane structures. Contact angle measurements provided information on the wettability of erucamide-coated surfaces. Peak Force Quantitative Nanomechanical Mapping (QNM) allowed a correlation between the erucamide nanostructure with the surface nanomechanical properties (i.e. adhesive response). FINDINGS: Our results reveal erucamide surface nanostructures on silica as patchy monolayers, isolated circular bilayers/rounded rectangle-like aggregates and overlapping plate-like multilayers as the erucamide concentration in the spin coating solution was varied. In all the cases, XRR and AFM results were consistent with the picture that the erucamide tails were oriented outwards. The QNM adhesion force mapping of all the observed morphologies also supported this molecular orientation at the outermost erucamide monolayer. The wettability study further confirmed this conclusion with the observed increase in the surface hydrophobicity and coverage upon increasing erucamide concentration, with the macroscopic water contact angle θ = 92.9° ± 2.9° at the highest erucamide concentration of 2 wt%.

10.
Future Oncol ; 17(12): 1449-1458, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33423550

RESUMO

Hallmark features of myelofibrosis (MF) are cytopenias, constitutional symptoms and splenomegaly. Anemia and transfusion dependency are among the most important negative prognostic factors and are exacerbated by many JAK inhibitors (JAKi). Momelotinib (MMB) has been investigated in over 820 patients with MF and possesses a pharmacological and clinical profile differentiated from other JAKi by inhibition of JAK1, JAK2 and ACVR1. MMB is designed to address the complex drivers of iron-restricted anemia and chronic inflammation in MF and should improve constitutional symptoms and splenomegaly while maintaining or improving hemoglobin in JAKi-naive and previously JAKi-treated patients. The MOMENTUM Phase III study is designed to confirm and extend observations of safety and clinical activity of MMB.


Lay abstract The most important features of myelofibrosis (MF) are low blood cell counts and symptoms including tiredness, night sweats and itching, along with increased size of the spleen, which may cause a feeling of fullness and pain. Low red blood cell counts (anemia) may mean regular blood transfusions are needed and this is one of the signs MF is getting worse. Drugs called JAK inhibitors (JAKi) are available to treat MF, but can have a side effect of making blood cell counts lower. Momelotinib (MMB) is a different type of JAKi to the ones currently available, and is an experimental drug for MF. MMB is designed to treat symptoms and spleen like other JAKi, but also to improve blood cell counts. MMB has already been given to more than 820 patients with MF in other clinical studies. Some of the patients in these studies had been treated with different JAKi before, and others got MMB as their first JAKi treatment. The MOMENTUM Phase III study is designed to collect more information on the safety and effectiveness of MMB in MF.


Assuntos
Benzamidas/administração & dosagem , Danazol/administração & dosagem , Inibidores de Janus Quinases/administração & dosagem , Mielofibrose Primária/tratamento farmacológico , Pirimidinas/administração & dosagem , Receptores de Ativinas Tipo I/antagonistas & inibidores , Administração Oral , Adulto , Benzamidas/efeitos adversos , Ensaios Clínicos Fase III como Assunto , Danazol/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 2/antagonistas & inibidores , Inibidores de Janus Quinases/efeitos adversos , Masculino , Pessoa de Meia-Idade , Pirimidinas/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Autoadministração , Resultado do Tratamento
11.
Eur J Haematol ; 106(1): 114-125, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33025625

RESUMO

OBJECTIVE: To compare the efficacy and safety of CD34+ selected ex vivo T-cell depletion (TCD) vs post-transplant cyclophosphamide, sirolimus, and mycophenolate mofetil (PTCy-Sir-MMF) as graft-vs-host disease (GVHD) prophylaxis. METHODS: We retrospectively included patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) with either TCD (n = 38) or PTCy-Sir-MMF (n = 91). RESULTS: Cumulative incidence of neutrophil and platelet recovery was 92% vs 99% (P = .06) and 89% vs 97% (P = .3) in TCD and PTCy-Sir-MMF, respectively. Cumulative incidences of aGHVD grade II-IV, III-IV, and moderate to severe cGVHD were 11% vs 19% (P = .2), 3% vs 2% (P = .9), and 3% vs 36% (P < .001) in TCD and PTCy-Sir-MMF, respectively. The 2-year non-relapse mortality, relapse, disease-free and overall survival were 25% vs 8% (P = .01), 20% vs 16% (P = .2), 55% vs 76% (P = .004), 57% vs 83% (P = .004) for TCD and PTCy-Sir-MMF, respectively. Cumulative incidence of cytomegalovirus and Epstein-Barr infection requiring therapy was 76% vs 40% (P < .001) and 32% vs 0% (P < .001) in TCD and PTCy-Sir-MMF, respectively. PTCy-Sir-MMF platform showed faster T-cell reconstitution. CONCLUSIONS: PTCy-Sir-MMF provides better survival outcomes but is associated with higher risk of cGVHD compared to TCD.


Assuntos
Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas , Depleção Linfocítica/efeitos adversos , Depleção Linfocítica/métodos , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores , Ciclofosfamida/administração & dosagem , Feminino , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/mortalidade , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Reconstituição Imune , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/terapia , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/administração & dosagem , Cuidados Pós-Operatórios , Complicações Pós-Operatórias , Prognóstico , Recidiva , Índice de Gravidade de Doença , Sirolimo/administração & dosagem , Transplante Homólogo , Resultado do Tratamento , Adulto Jovem
12.
Br J Haematol ; 192(6): 988-996, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32745264

RESUMO

The present study assessed the criteria for initiating cytoreduction and response to conventional therapies in 1446 patients with essential thrombocythemia (ET), 267 (17%) of which were CALR-mutated. In low risk patients, time from diagnosis to cytoreduction was shorter in CALR-positive than in the other genotypes (2·8, 3·2, 7·4 and 12·5 years for CALR, MPL, JAK2V617F and TN, respectively, P < 0·0001). A total of 1104 (76%) patients received cytoreductive treatment with hydroxycarbamide (HC) (n = 977), anagrelide (n = 113), or others (n = 14). The estimated cumulative rates of complete haematological response (CR) at 12 months were 40 % and 67% in CALR and JAK2V617F genotypes, respectively. Median time to CR was 192 days for JAK2V617F, 343 for TN, 433 for MPL, and 705 for CALR genotypes (P < 0·0001). Duration of CR was shorter in CALR-mutated ET than in the remaining patients (P = 0·003). In CALR-positive patients, HC and anagrelide had similar efficacy in terms of response rates and duration. CALR-mutated patients developed resistance/intolerance to HC more frequently (5%, 23%, 27% and 15% for JAK2V617F, CALR, MPL and TN, respectively; P < 0·0001). In conclusion, conventional cytoreductive agents are less effective in CALR-mutated ET, highlighting the need for new treatment modalities and redefinition of haematologic targets for patients with this genotype.


Assuntos
Calreticulina/genética , Genótipo , Hidroxiureia/administração & dosagem , Mutação de Sentido Incorreto , Quinazolinas/administração & dosagem , Sistema de Registros , Trombocitemia Essencial , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Substituição de Aminoácidos , Criança , Feminino , Seguimentos , Humanos , Janus Quinase 2/genética , Masculino , Pessoa de Meia-Idade , Espanha , Trombocitemia Essencial/tratamento farmacológico , Trombocitemia Essencial/genética
13.
J Autism Dev Disord ; 51(5): 1772-1780, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-32737668

RESUMO

Parents of children with Special Educational Needs and Disabilities in the UK (n = 241) were asked to describe the impact of COVID-19 on their own mental health and that of their child. An inductive content analysis of the data was undertaken. Both parents and children appear to be experiencing loss, worry and changes in mood and behaviour as a result of the rapid social changes that have occurred. Some parents reported feeling overwhelmed and described the impact of child understanding and awareness. Finally, a minority of parents reported that COVID-19 has had little impact on mental health in their family, or has even led to improvements. Implications for how to support these families in the immediate future are discussed.


Assuntos
COVID-19/psicologia , Pessoas com Deficiência/psicologia , Educação Especial/tendências , Família/psicologia , Saúde Mental/tendências , Adolescente , Ansiedade/epidemiologia , Ansiedade/psicologia , Transtorno do Espectro Autista/epidemiologia , Transtorno do Espectro Autista/psicologia , COVID-19/epidemiologia , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pais/psicologia , Reino Unido/epidemiologia
14.
Biochim Biophys Acta Gen Subj ; 1865(4): 129542, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-31987955

RESUMO

BACKGROUND: Understanding the structure of hybrid nanoparticle-lipid multilayers is of fundamental importance to their bioanalytical applications and nanotoxicity, where nanoparticle-membrane interactions play an important role. Poly(amidoamine) (PAMAM) dendrimers are branched polymeric nanoparticles with potential biomedical applications due to precise tunability of their physicochemical properties. Here, the effect of PAMAM dendrimers (2.9-4.5 nm) with either a hydrophilic amine (NH2) or a hydrophobic C12 chain surface termination on the 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) multilayers has been studied for the first time. METHODS: DOPC multilayers were created by the liposome-rupture method via drop-casting dendrimer-liposome dispersions with the dendrimers added at different concentrations and at three different stages. The multilayer structure was evaluated via the analysis of the synchrotron X-ray reflectivity (XRR) curves, obtaining the bilayer d-spacing, the coherence length from the Scherrer (Ls) analysis of the Bragg peaks, and the paracrystalline disorder parameter (g). RESULTS: Dendrimer addition led to lipid bilayer thinning and more disordered multilayer structures. Larger hydrophobic dendrimers caused greater structural disruption to the multilayers compared to the smaller dendrimers. The smallest, positively charged dendrimers at their highest concentration caused the most pronounced bilayer thinning. The dendrimer-liposome mixing method also affected the multilayer structure due to different dendrimer aggregation involved. CONCLUSIONS: These results show the complexity of the effect of dendrimer physicochemical properties and the addition method of dendrimers on the structure of mixed dendrimer-DOPC multilayers. GENERAL SIGNIFICANCE: These insights are useful for fundamental understanding of nanotoxicity and future biomedical application of nanocomposite multilayer materials in which nanoparticles are added for enhanced properties and functionality.


Assuntos
Dendrímeros/química , Bicamadas Lipídicas/química , Lipossomos/química , Fosfatidilcolinas/química , Interações Hidrofóbicas e Hidrofílicas
15.
Exp Hematol Oncol ; 9: 21, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32864192

RESUMO

BACKGROUND: Prognostic factors of poor outcome in patients with hematological malignancies and COVID-19 are poorly defined. PATIENTS AND METHODS: This was a Spanish transplant group and cell therapy (GETH) multicenter retrospective observational study, which included a large cohort of blood cancer patients with laboratory-confirmed SARS-CoV-2 infection through PCR assays from March 1st 2020 to May 15th 2020. RESULTS: We included 367 pediatric and adult patients with hematological malignancies, including recipients of autologous (ASCT) (n = 58) or allogeneic stem cell transplantation (allo-SCT) (n = 65) from 41 hospitals in Spain. Median age of patients was 64 years (range 1-93.8). Recipients of ASCT and allo-SCT showed lower mortality rates (17% and 18%, respectively) compared to non-SCT patients (31%) (p = 0.02). Prognostic factors identified for day 45 overall mortality (OM) by logistic regression multivariate analysis included age > 70 years [odds ratio (OR) 2.1, 95% confidence interval (CI) 1.2-3.8, p = 0.011]; uncontrolled hematological malignancy (OR 2.9, 95% CI 1.6-5.2, p < 0.0001); ECOG 3-4 (OR, 2.56, 95% CI 1.4-4.7, p = 0.003); neutropenia (< 0.5 × 109/L) (OR 2.8, 95% CI 1.3-6.1, p = 0.01); and a C-reactive protein (CRP) > 20 mg/dL (OR 3.3, 95% CI 1.7-6.4, p < 0.0001). In multivariate analysis of 216 patients with very severe COVID-19, treatment with azithromycin or low dose corticosteroids was associated with lower OM (OR 0.42, 95% CI 0.2-0.89 and OR 0.31, 95% CI 0.11-0.87, respectively, p = 0.02) whereas the use of hidroxycloroquine did not show significant improvement in OM (OR 0.64, 95% CI 0.37-1.1, P = 0.1). CONCLUSIONS: In most patients with hematological malignancies COVID-19 mortality was directly driven by older age, disease status, performance status, as well as by immune (neutropenia) parameters and level of inflammation (high CRP). Use of azithromycin and low dose corticosteroids may be of value in very severe COVID-19.

16.
Am J Health Syst Pharm ; 77(14): 1144-1148, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32537625

RESUMO

PURPOSE: Critically ill patients with septic shock often receive multiple intravenous medications, necessitating either the placement of separate lines for medication administration or administration of medications concurrently through a Y-site connector only where compatibility has been demonstrated. The purpose of this study was to examine the physical compatibility of hydrocortisone infusions and select intravenous medications through a simulated Y site. METHODS: The medications tested for simulated Y-site physical compatibility with hydrocortisone included acetaminophen, albumin, cefepime, ciprofloxacin, cisatracurium, doripenem, epinephrine, esomeprazole, ibuprofen, levofloxacin, levothyroxine, meropenem, and norepinephrine. Hydrocortisone in solution with 0.9% sodium chloride injection was combined with an equivalent volume of solutions of each test drug at maximum or commercially available concentrations used clinically in intensive care units, as appropriate. The samples were evaluated using turbidimetric measurements and examined visually against light and dark backgrounds to determine physical compatibility. Observations and analyses were completed over a one-hour period at 15-minute intervals beginning immediately after mixing. Each test was performed in triplicate. RESULTS: All study medications demonstrated visual and/or turbidimetric physical compatibility when combined with hydrocortisone in a simulated Y-site infusion. No medications demonstrated a visual physical incompatibility when combined with hydrocortisone. CONCLUSION: Acetaminophen, albumin, cefepime, ciprofloxacin, cisatracurium, doripenem, epinephrine, esomeprazole, ibuprofen, levofloxacin, levothyroxine, meropenem, and norepinephrine exhibited physical compatibility with hydrocortisone via Y-site infusion.


Assuntos
Incompatibilidade de Medicamentos , Hidrocortisona/química , Preparações Farmacêuticas/química , Estado Terminal , Humanos , Hidrocortisona/administração & dosagem , Infusões Intravenosas , Unidades de Terapia Intensiva , Nefelometria e Turbidimetria , Preparações Farmacêuticas/administração & dosagem , Choque Séptico/tratamento farmacológico
17.
Int J Pharm Compd ; 24(3): 238-241, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32401743

RESUMO

Using balanced fluids for resuscitation in patients with septic shock may lead to improved patient outcomes. However, compatibility data on co-administering balanced fluids via y-site connector with other intravenous medications is lacking. The purpose of this study was to examine the physical compatibility of frequently used intravenous medications for patients with septic shock with balanced fluids, Plasma-Lyte A, and Lactated Ringers, using a simulated y-site. Medications studied were acyclovir, amiodarone, ampicillin, aztreonam, cefepime, ceftriaxone, ciprofloxacin, heparin, hydrocortisone, gentamicin, levofloxacin, meropenem, piperacillin-tazobactam, tobramycin, and vancomycin. All medications were assessed with Plasma-Lyte A; amiodarone, ampicillin, cefepime, hydrocortisone, and levofloxacin were also assessed for compatibility with Lactated Ringers, based on missing or conflicting compatibility data. The medications were diluted to maximum concentrations used for patient administration and mixed with the balanced fluid solution in equal volumes. Physical compatibility was determined by assessing samples visually against light and dark backgrounds and using a laboratory turbidimeter. Assessments occurred at time of mixing and at 15-minute intervals up to one hour. Amiodarone demonstrated turbidimetric incompatibility when combined with Plasma- Lyte A or Lactated Ringers and should not be co-administered with either of these fluids via y-site connector. Each remaining study drug displayed visible and turbidimetric compatibility with the assessed balanced fluid. Acyclovir, ampicillin, aztreonam, cefepime, ceftriaxone, ciprofloxacin, gentamicin, heparin, hydrocortisone, levofloxacin, meropenem, piperacillin-tazobactam, tobramycin, and vancomycin exhibited physical compatibility with Plasma- Lyte A in a simulated y-site for up to one hour. Ampicillin, cefepime, hydrocortisone, and levofloxacin were also physically compatible with Lactated Ringers.


Assuntos
Antibacterianos/farmacologia , Estado Terminal , Vancomicina , Antibacterianos/química , Humanos , Infusões Intravenosas/métodos , Soluções , Vancomicina/química , Vancomicina/farmacologia
18.
Leukemia ; 34(12): 3420-3425, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32393842

RESUMO

Patients receiving an allogeneic hematopoietic cell transplantation (allo-HCT) after the use of PD-1 inhibitors seem to be at a higher risk of developing acute graft-versus-host disease (aGHVD) through etiopathogenetic mechanisms not fully elucidated. Herein, we investigated the effect of nivolumab administered prior to allo-HCT on the following early T-cell reconstitution and its modulation by the GVHD prophylaxis (tacrolimus/sirolimus vs. posttransplant cyclophosphamide [PTCY]). In all nivolumab-exposed patients we detected circulating nivolumab in plasma for up to 56 days after allo-HCT. This residual nivolumab was able to bind and block PD-1 on T-cells at day 21 after allo-HCT, inducing a T cell activation that was differentially modulated depending on the GVHD prophylactic regimen. Among patients receiving tacrolimus/sirolimus, nivolumab-exposed patients had a higher incidence of severe aGVHD and a more effector T-cell profile compared with anti-PD-1-naïve patients. Conversely, patients receiving PTCY-based prophylaxis showed a similar risk of aGVHD and T-cell profile irrespective of the previous nivolumab exposure. In conclusion, nivolumab persists in plasma after transplantation, binds to allogeneic T cells and generates an increased T-cell activation. This T-cell activation status can be mitigated with the use of PTCY, thus reducing the risk of aGVHD.


Assuntos
Ciclofosfamida/uso terapêutico , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/prevenção & controle , Imunossupressores/uso terapêutico , Nivolumabe/uso terapêutico , Células Cultivadas , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Masculino , Sirolimo/uso terapêutico , Linfócitos T/efeitos dos fármacos , Transplante Homólogo/métodos
19.
Acta Biomater ; 104: 198-209, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31904557

RESUMO

Understanding interactions between nanoparticles and model membranes is relevant to functional nano-composites and the fundamentals of nanotoxicity. In this study, the effect of polyamidoamine (PAMAM) dendrimers as model nanoparticles (NP) on the mesophase behaviour of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE) has been investigated using high-pressure small-angle X-ray scattering (HP-SAXS). The pressure-temperature (p-T) diagrams for POPE mesophases in excess water were obtained in the absence and presence of G2 and G4 polyamidoamine (PAMAM) dendrimers (29 Å and 45 Å in diameter, respectively) at varying NP-lipid number ratio (ν = 0.0002-0.02) over the pressure range p = 1-3000 bar and temperature range T = 20-80 °C. The p-T phase diagram of POPE exhibited the Lß, Lα and HII phases. Complete analysis of the phase diagrams, including the relative area pervaded by different phases, phase transition temperatures (Tt) and pressures (pt), the lattice parameters (d-spacing), the pressure-dependence of d-spacing (Δd/Δp), and the structural ordering in the mesophase as gauged by the Scherrer coherence length (L) permitted insights into the size- and concentration-dependent interactions between the dendrimers and the model membrane system. The addition of dendrimers changed the phase transition pressure and temperature and resulted in the emergence of highly swollen lamellar phases, dubbed Lß-den and Lα-den. G4 PAMAM dendrimers at the highest concentration ν = 0.02 suppressed the formation of the HII phase within the temperature range studied, whereas the addition of G2 PAMAM dendrimers at the same concentration promoted an extended mixed lamellar region in which Lα and Lß phases coexisted. STATEMENT OF SIGNIFICANCE: Using high pressure small angle X-ray scattering in the pressure range 1-3000 bar and temperature range 20-60 °C, we have studied interactions between PAMAM dendrimers (as model nanoparticles) and POPE lipid mesophases (as model membranes). We report the pressure-temperature phase diagrams for the dendrimer-lipid mesophases for the first time. We find that the dendrimers alter the phase transition temperatures (Tt) and pressures (pt), the lattice parameters (d-spacing), and the structural order in the mesophase. We interpret these unprecedented results in terms of the fluidity of the lipid membranes and the interactions between the dendrimers and the membranes. Our findings are of fundamental relevance to the field of nanotoxicity and functional nanomaterials that integrate nanoparticles and organized lipid structures.


Assuntos
Dendrímeros/química , Lipídeos/química , Nanopartículas/química , Polímeros/química , Transição de Fase , Fosfatidiletanolaminas/química , Pressão , Temperatura de Transição
20.
J Colloid Interface Sci ; 562: 409-417, 2020 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-31806357

RESUMO

HYPOTHESIS: Supported lipid bilayers (SLBs) embedded with hydrophobic quantum dots (QDs) undergo temporal structural rearrangement. EXPERIMENTS: Synchrotron X-ray reflectivity (XRR) was applied to monitor the temporal structural changes over a period of 24 h of mixed SLBs of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) / 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-ethanolamine (POPE) intercalated with 4.9 nm hydrophobic cadmium sulphide quantum dots (CdS QDs). The QD-embedded SLBs (QD-SLBs) were formed via rupture of the mixed liposomes on a positively charged polyethylene imine (PEI) monolayer. Atomic force microscopy (AFM) imaging provided complementary characterization of the bilayer morphology. FINDINGS: Our results show time-dependent perturbations in the SLB structure due to the interaction upon QD incorporation. Compared to the SLB without QDs, at 3 h incubation time, there was a measurable decrease in the bilayer thickness and a concurrent increase in the scattering length density (SLD) of the QD-SLB. The QD-SLB then became progressively thicker with increasing incubation time, which - along with the fitted SLD profile - was attributed to the structural rearrangement due to the QDs being expelled from the inner leaflet to the outer leaflet of the bilayer. Our results give unprecedented mechanistic insights into the structural evolution of QD-SLBs on a polymer cushion, important to their potential biomedical and biosensing applications.


Assuntos
Bicamadas Lipídicas/química , Modelos Químicos , Fosfatidilcolinas/química , Fosfatidiletanolaminas/química , Pontos Quânticos/química
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