RESUMO
Despite recent advances in prophylactic vaccination, SARS-CoV-2 infections continue to cause significant morbidity. A better understanding of immune response differences between vaccinated individuals with and without later SARS-CoV-2 breakthrough infection is urgently needed. CoV-ADAPT is a prospective long-term study comparing humoral (anti-spike-RBD-IgG, neutralization capacity, avidity) and cellular (spike-induced T-cell interferon-γ [IFN-γ] release) immune responses in individuals vaccinated against SARS-CoV-2 at four different time points (three before and one after third vaccination). In this cohort study, 62 fully vaccinated individuals presented with SARS-CoV-2 breakthrough infections vs 151 without infection 3-7 months following third vaccination. Breakthrough infections significantly increased anti-spike-RBD-IgG (p < 0.01), but not spike-directed T-cell IFN-γ release (TC) or antibody avidity. Despite comparable surrogate neutralization indices, the functional neutralization capacity against SARS-CoV-2-assessed via a tissue culture-based assay-was significantly higher following breakthrough vs no breakthrough infection. Anti-spike-RBD-IgG and antibody avidity decreased with age (p < 0.01) and females showed higher anti-spike-RBD-IgG (p < 0.01), and a tendency towards higher antibody avidity (p = 0.051). The association between humoral and cellular immune responses previously reported at various time points was lost in subjects after breakthrough infections (p = 0.807). Finally, a machine-learning approach based on our large immunological dataset (a total of 49 variables) from different time points was unable to predict breakthrough infections (area under the curve: 0.55). In conclusion, distinct differences in humoral vs cellular immune responses in fully vaccinated individuals with or without breakthrough infection could be demonstrated. Breakthrough infections predominantly drive the humoral response without boosting the cellular component. Breakthrough infections could not be predicted based on immunological data, which indicates a superior role of environmental factors (e.g., virus exposure) in individualized risk assessment.
Assuntos
COVID-19 , Feminino , Humanos , SARS-CoV-2 , Infecções Irruptivas , Estudos de Coortes , Estudos Prospectivos , Interferon gama , Imunidade Celular , Imunoglobulina G , Anticorpos Antivirais , Vacinação , Imunidade HumoralRESUMO
BACKGROUND: Intravenous high-dose methotrexate (MTX ≥ 1 g/m 2 ) is frequently used in patients with cerebral lymphoma or other malignancies. In addition to its potent efficacy, it is known to have pronounced toxicity and life-threatening side effects. Regular-level monitoring at short and defined intervals is mandatory. This study aimed to evaluate the possibility of replacing peripheral blood sampling with blood samples from central venous catheters for therapeutic monitoring of MTX in adults. METHODS: A total of 6 patients and 7 cycles of chemotherapy (6 females; 5 with cerebral non-Hodgkin lymphoma and 1 with osteosarcoma, median age 51 years; range 33-62 years) were included. An immunoassay was used for quantitative analysis of MTX levels. The measurement points were obtained in the time intervals of 24, 42, 48, and 72 hours, and afterward, every 24 hours until the level was below <0.1 µmol/L. After flushing with 10 mL of saline solution and discarding 10 mL of venous blood, blood was drawn from the central venous access through which MTX had previously been administered. Simultaneously, MTX levels were obtained from peripheral venipuncture. RESULTS: Methotrexate levels from central venous access and MTX levels from peripheral venipuncture showed a significant correlation (r = 0.998; P < 0.01; n = 35). During withdrawal from the central access group, 17 values showed a lower MTX level, 10 showed a higher level, and 8 showed no difference. However, the MTX level difference was not significant ( P = 0.997, linear mixed model). No increase in the dose of calcium folinate was necessary based on the collected MTX levels. CONCLUSIONS: In adults, MTX monitoring from central venous access is not inferior to monitoring from peripheral venipuncture. Repeated venipuncture to measure MTX levels can be replaced after establishing standardized instructions for proper sampling by a central venous catheter.
Assuntos
Neoplasias Ósseas , Flebotomia , Feminino , Humanos , Adulto , Pessoa de Meia-Idade , Metotrexato/uso terapêutico , Monitoramento de Medicamentos , Coleta de Amostras SanguíneasRESUMO
BACKGROUND: Homologous and heterologous SARS-CoV-2 vaccinations yield different spike protein-directed humoral and cellular immune responses. This study aimed to explore their currently unknown interdependencies. METHODS: COV-ADAPT is a prospective, observational cohort study of 417 healthcare workers who received vaccination with homologous ChAdOx1 nCoV-19, homologous BNT162b2 or with heterologous ChAdOx1 nCoV-19/BNT162b2. We assessed humoral (anti-spike-RBD-IgG, neutralizing antibodies, and avidity) and cellular (spike-induced T-cell interferon-γ release) immune responses in blood samples up to 2 weeks before (T1) and 2-12 weeks following secondary immunization (T2). RESULTS: Initial vaccination with ChAdOx1 nCoV-19 resulted in lower anti-spike-RBD-IgG compared with BNT162b2 (70 ± 114 vs. 226 ± 279 BAU/ml, p < .01) at T1. Booster vaccination with BNT162b2 proved superior to ChAdOx1 nCoV-19 at T2 (anti-spike-RBD-IgG: ChAdOx1 nCoV-19/BNT162b2 2387 ± 1627 and homologous BNT162b2 3202 ± 2184 vs. homologous ChAdOx1 nCoV-19 413 ± 461 BAU/ml, both p < .001; spike-induced T-cell interferon-γ release: ChAdOx1 nCoV-19/BNT162b2 5069 ± 6733 and homologous BNT162b2 4880 ± 7570 vs. homologous ChAdOx1 nCoV-19 1152 ± 2243 mIU/ml, both p < .001). No significant differences were detected between BNT162b2-boostered groups at T2. For ChAdOx1 nCoV-19, no booster effect on T-cell activation could be observed. We found associations between anti-spike-RBD-IgG levels (ChAdOx1 nCoV-19/BNT162b2 and homologous BNT162b2) and T-cell responses (homologous ChAdOx1 nCoV-19 and ChAdOx1 nCoV-19/BNT162b2) from T1 to T2. Additionally, anti-spike-RBD-IgG and T-cell response were linked at both time points (all groups combined). All regimes yielded neutralizing antibodies and increased antibody avidity at T2. CONCLUSIONS: Interdependencies between humoral and cellular immune responses differ between common SARS-CoV-2 vaccination regimes. T-cell activation is unlikely to compensate for poor humoral responses.
Assuntos
Vacinas contra COVID-19 , COVID-19 , Imunidade Celular , Imunidade Humoral , Anticorpos Neutralizantes , Vacina BNT162 , COVID-19/prevenção & controle , Vacinas contra COVID-19/imunologia , ChAdOx1 nCoV-19 , Humanos , Imunoglobulina G , Interferon gama , Estudos Prospectivos , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , VacinaçãoRESUMO
OBJECTIVES: Thyroid-stimulating hormone (TSH) is the routine primary screening test to assess thyroid function and rapid measurement of TSH levels is highly desirable especially in emergency situations. In the present study, we compared the analytical performance of a commercially available point-of-care test (AFIAS-1) and five laboratory-based systems. METHODS: Left over material of 60 patient plasma samples was collected from patient care and used in the respective assay. For statistical analysis of the produced data Bland-Altman and Passing-Bablok regression analysis were applied. RESULTS: Good correlation (r=0.982 or higher) was found between all devices. Slopes from regression analysis ranged from 0.972 (95% CI: 0.927-1.013) to 1.276 (95% CI: 1.210-1.315). Among the compared devices, imprecision was high in terms of coefficient of variation (CV=10.3%) for low TSH concentrations and lower (CV=7.3%) for high TSH concentrations. Independent of the method used, we demonstrated a poor standardization of TSH assays, which might impact clinical diagnosis e.g. of hyperthyreosis. CONCLUSIONS: This study shows that the point-of-care (POC) test AFIAS-1 can serve as an alternative to laboratory-based assays. In addition the data imply that better standardization of TSH measurements is needed.
Assuntos
Testes Imediatos , Tireotropina , Humanos , Padrões de ReferênciaRESUMO
The karyotype is a strong independent prognostic factor in myelodysplastic syndromes (MDS). Since the implementation of the new comprehensive cytogenetic scoring system for MDS, chromosome 7 anomalies are no longer generally assigned to poor risk features but are thoroughly separated. However, der(1;7)(q10;p10), hereinafter der(1;7), is merged into the group labeled "any other single" and belongs to the intermediate risk group, just by definition due to lack of adequate clinical data. The aim of our international collaborative was to clarify the "real" prognostic impact of der(1;7) on a homogenous and well-documented data base. We performed detailed analysis of 63 MDS patients with isolated der(1;7) constituting the largest cohort hitherto reported. Furthermore, clinical data are compared with those of patients with isolated del(7q) and isolated monosomy 7. Median overall survival (OS) of patients with der(1;7) is 26 months (hazard ratio (HR) 0.91 for del(7q) vs der(1;7) and 2.53 for monosomy 7 vs der(1;7)). The der(1;7) is associated with profound thrombocytopenia most probably causing the reduced OS which is in striking contrast to the low risk for AML transformation (HR 3.89 for del(7q) vs der(1;7) and 5.88 for monosomy 7 vs der(1;7)). Molecular karyotyping indicates that der(1;7) is generated in a single step during mitosis and that a chromosomal imbalance rather than a single disrupted gene accounts for malignancy. Thus, the current cytogenetic scoring system assigning isolated der(1;7) to the intermediate risk group is now confirmed by a sufficient data set.
Assuntos
Biomarcadores Tumorais/genética , Deleção Cromossômica , Duplicação Cromossômica , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 7/genética , Síndromes Mielodisplásicas/genética , Cariótipo Anormal , Adulto , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/patologia , Análise de SobrevidaRESUMO
Chronic myelomonocytic leukemia (CMML) is a myeloid neoplasm characterized by dysplasia, abnormal production and accumulation of monocytic cells and an elevated risk of transforming into acute leukemia. Over the past two decades, our knowledge about the pathogenesis and molecular mechanisms in CMML has increased substantially. In parallel, better diagnostic criteria and therapeutic strategies have been developed. However, many questions remain regarding prognostication and optimal therapy. In addition, there is a need to define potential pre-phases of CMML and special CMML variants, and to separate these entities from each other and from conditions mimicking CMML. To address these unmet needs, an international consensus group met in a Working Conference in August 2018 and discussed open questions and issues around CMML, its variants, and pre-CMML conditions. The outcomes of this meeting are summarized herein and include diag nostic criteria and a proposed classification of pre-CMML conditions as well as refined minimal diagnostic criteria for classical CMML and special CMML variants, including oligomonocytic CMML and CMML associated with systemic mastocytosis. Moreover, we propose diagnostic standards and tools to distinguish between 'normal', pre-CMML and CMML entities. These criteria and standards should facilitate diagnostic and prognostic evaluations in daily practice and clinical studies in applied hematology.
Assuntos
Leucemia Mielomonocítica Crônica/diagnóstico , Lesões Pré-Cancerosas/diagnóstico , Idoso , Congressos como Assunto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Guias de Prática Clínica como AssuntoRESUMO
The study analyzes the clonal architecture and the abnormalities involved in a series of 191 patients with myelodysplastic syndromes (MDS) and 2-3 clonal abnormalities. All patients were extracted from an international database. The patients were classified into six clonal subtypes (2A-3C) based on the number of abnormalities and the presentation of unrelated clones (UC) and/or a clonal evolution. UC were detected in 23/191 patients (12%). The composition of UC showed great variability. The only recurrent combination of abnormalities was del(5q) and + 8 in 8 of 23 patients (35%). In patients with clonal evolution, the clone size of the primary and secondary clone varied: Patients with -7 and + 8 in the primary clone showed a larger primary and a smaller secondary clone (-7: median 74% vs 10%; +8 73% vs 18%) while patients with del(5q) in the primary clone showed a smaller primary and a larger secondary clone (33% vs 61%). Univariate and multivariate analyses showed no significant differences regarding overall or AML-free survival between the clonal subtypes. Only the subtype 3C (3 abnormalities and clonal evolution) was an independent risk factor for developing AML (Hazard Ratio 5.5 as compared to subtype 2A, P < .05). Finally, our study confirms that the number of abnormalities clearly defines a significant risk factor for overall- as well as AML-free survival. Importantly, in patients with more than one clone, the calculation of the number of abnormalities in the entire sample instead of the number of abnormalities per clone allows a higher prognostic accuracy.
Assuntos
Aberrações Cromossômicas , Síndromes Mielodisplásicas , Idoso , Análise Citogenética , Feminino , Humanos , Masculino , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/epidemiologia , Síndromes Mielodisplásicas/genética , Prognóstico , Estudos RetrospectivosRESUMO
In myelodysplastic syndromes (MDSs), the evolution of risk for disease progression or death has not been systematically investigated despite being crucial for correct interpretation of prognostic risk scores. In a multicenter retrospective study, we described changes in risk over time, the consequences for basal prognostic scores, and their potential clinical implications. Major MDS prognostic risk scoring systems and their constituent individual predictors were analyzed in 7212 primary untreated MDS patients from the International Working Group for Prognosis in MDS database. Changes in risk of mortality and of leukemic transformation over time from diagnosis were described. Hazards regarding mortality and acute myeloid leukemia transformation diminished over time from diagnosis in higher-risk MDS patients, whereas they remained stable in lower-risk patients. After approximately 3.5 years, hazards in the separate risk groups became similar and were essentially equivalent after 5 years. This fact led to loss of prognostic power of different scoring systems considered, which was more pronounced for survival. Inclusion of age resulted in increased initial prognostic power for survival and less attenuation in hazards. If needed for practicability in clinical management, the differing development of risks suggested a reasonable division into lower- and higher-risk MDS based on the IPSS-R at a cutoff of 3.5 points. Our data regarding time-dependent performance of prognostic scores reflect the disparate change of risks in MDS subpopulations. Lower-risk patients at diagnosis remain lower risk whereas initially high-risk patients demonstrate decreasing risk over time. This change of risk should be considered in clinical decision making.
Assuntos
Transformação Celular Neoplásica/patologia , Síndromes Mielodisplásicas/mortalidade , Idoso , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Fatores de Risco , Fatores de Tempo , Organização Mundial da SaúdeAssuntos
Dioxigenases , Linfoma , Síndromes Mielodisplásicas , Humanos , Hematopoiese Clonal , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/patologia , Mutação , Sistema Nervoso Central/patologia , Hematopoese/genética , Proteínas de Ligação a DNA/genética , Dioxigenases/genéticaAssuntos
COVID-19 , SARS-CoV-2 , COVID-19/prevenção & controle , Vacinas contra COVID-19 , Humanos , Imunidade Celular , Imunidade Humoral , VacinaçãoRESUMO
Transfusion-dependent patients with low- or intermediate-1-risk myelodysplastic syndrome, <5% bone marrow (BM) blasts and isolated 5q-deletion received lenalidomide within the German MDS study group phase-II clinical trial LE-MON-5 (EudraCT:2008-001866-10) of the University of Duesseldorf, Germany. Cytogenetic monitoring was performed by chromosome banding analyses (CBA) of BM cells and fluorescence in situ hybridization (FISH) analyses of peripheral blood (PB) mononuclear CD34+ cells using extended probe panels. Out of 144 patients screened for study enrollment, 24% failed to meet inclusion criteria due to cytogenetic findings. Eighty-seven patients were followed with a median observation time of 30 months. Cytogenetic response detected by FISH and CBA in 74 and 66% of patients, respectively, was predictive for hematologic response as well as of high prognostic relevance. After 2 years, AML rate was 8% for all patients. Karyotype evolution was detected in 21 (FISH)-34% (CBA) of patients associated with significantly shorter AML-free survival. Disease progression was first detectable on the cytogenetic level on average 5-6 months before recurrence of transfusion dependence. Our data show for the first time in a prospective setting that a cytogenetic monitoring from the PB helps to early identify treatment failure and progressive disease in lenalidomide-treated patients to improve clinical management. TRIAL REGISTRATION: EudraCT:2008-001866-10.
Assuntos
Síndromes Mielodisplásicas/tratamento farmacológico , Talidomida/análogos & derivados , Doença Aguda , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/uso terapêutico , Antígenos CD34/sangue , Bandeamento Cromossômico , Deleção Cromossômica , Cromossomos Humanos Par 5/genética , Intervalo Livre de Doença , Feminino , Alemanha , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Lenalidomida , Leucemia Mieloide/diagnóstico , Leucemia Mieloide/genética , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/genética , Prognóstico , Talidomida/uso terapêutico , Falha de TratamentoRESUMO
Loss of the Y-chromosome (LOY) is described as both a normal age-related event and a marker of a neoplastic clone in hematologic diseases. To assess the significance of LOY in myelodysplastic syndromes (MDS), we determined the percentage of LOY in clonal CD34+ peripheral blood cells in comparison to normal CD3+ T-cells of 27 MDS patients using fluorescence in situ hybridization (FISH) analysis. Results were compared with the percentage of LOY in CD34+ and CD3+ cells of 32 elderly men without hematologic diseases and in 25 young blood donors. While LOY could not be detected in CD3+ cells of young men, it was observed in CD3+ cells of elderly men without hematologic diseases (2.5% LOY) as well as in CD3+ cells of elderly MDS patients (5.8% LOY). The percentage of CD34+ cells affected by LOY was significantly higher in MDS patients compared to elderly men without hematologic diseases (43.3% vs. 13.2%, P = 0.005), indicating that LOY has an age-related basis but is also associated with MDS. Furthermore, we aimed to define a threshold between age- and disease-associated LOY in MDS. Statistical analysis revealed that a value of 21.5% LOY in CD34+ peripheral blood cells provided the best threshold to discriminate between these two conditions in MDS. We conclude that LOY is clonal in a substantial number of MDS based on an age-related predisposition.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Y/genética , Síndromes Mielodisplásicas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD34/metabolismo , Doadores de Sangue , Complexo CD3/metabolismo , Células Cultivadas , Seleção Clonal Mediada por Antígeno , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Linfócitos T/imunologia , Linfócitos T/metabolismo , Adulto JovemRESUMO
In myelodysplastic syndromes (MDS), deletion of the short arm of chromosome 12 (del(12p)) is usually a small abnormality, rarely detected as a single aberration by chromosome banding analysis (CBA) of bone marrow metaphases. Del(12p) has been described in 0.6 to 5% of MDS patients at initial diagnosis and is associated with a good to intermediate prognosis as a sole anomaly according to current scoring systems. Here, we present the results of a systematic del(12p) testing in a German prospective diagnostic study (clinicaltrials.gov: NCT01355913) on 367 MDS patients in whom CD34+ peripheral blood cells were analysed for the presence of del(12p) by sequential fluorescence in situ hybridization (FISH) analyses. A cohort of 2,902 previously published MDS patients diagnosed by CBA served as control. We demonstrate that, using a sensitive FISH technique, 12p deletion occurs significantly more frequently in MDS than previously described (7.6% by CD34+ PB-FISH vs. 1.6% by CBA, P < 0.001) and is often associated with other aberrations (93% by CD34+ PB-FISH vs. 60% by CBA). Additionally, the detection rate can be increased by repeated analyses in a patient over time which is important for the patient´s prognosis to distinguish a sole anomaly from double or complex aberrations. To our knowledge, this is the first study to screen for 12p deletions with a suitable probe for ETV6/TEL in 12p13. Our data suggest that the supplement of a probe for the detection of a 12p deletion to common FISH probe panels helps to avoid missing a del(12p), especially as part of more complex aberrations.
Assuntos
Hibridização in Situ Fluorescente/métodos , Síndromes Mielodisplásicas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD34/genética , Bandeamento Cromossômico , Deleção Cromossômica , Cromossomos Humanos Par 12/genética , Grupos Controle , Feminino , Alemanha , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Repressoras/genética , Adulto Jovem , Variante 6 da Proteína do Fator de Translocação ETSRESUMO
International Prognostic Scoring Systems are used to determine the individual risk profile of myelodysplastic syndrome patients. For the assessment of International Prognostic Scoring Systems, an adequate chromosome banding analysis of the bone marrow is essential. Cytogenetic information is not available for a substantial number of patients (5%-20%) with dry marrow or an insufficient number of metaphase cells. For these patients, a valid risk classification is impossible. In the study presented here, the International Prognostic Scoring Systems were validated based on fluorescence in situ hybridization analyses using extended probe panels applied to cluster of differentiation 34 positive (CD34(+)) peripheral blood cells of 328 MDS patients of our prospective multicenter German diagnostic study and compared to chromosome banding results of 2902 previously published patients with myelodysplastic syndromes. For cytogenetic risk classification by fluorescence in situ hybridization analyses of CD34(+) peripheral blood cells, the groups differed significantly for overall and leukemia-free survival by uni- and multivariate analyses without discrepancies between treated and untreated patients. Including cytogenetic data of fluorescence in situ hybridization analyses of peripheral CD34(+) blood cells (instead of bone marrow banding analysis) into the complete International Prognostic Scoring System assessment, the prognostic risk groups separated significantly for overall and leukemia-free survival. Our data show that a reliable stratification to the risk groups of the International Prognostic Scoring Systems is possible from peripheral blood in patients with missing chromosome banding analysis by using a comprehensive probe panel (clinicaltrials.gov identifier:01355913).
Assuntos
Antígenos CD34/sangue , Aberrações Cromossômicas , Análise Citogenética/métodos , Hibridização in Situ Fluorescente/métodos , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Agências Internacionais , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/mortalidade , Estadiamento de Neoplasias , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida , Adulto JovemRESUMO
A 62-yr-old man with two healthy daughters was diagnosed with osteomyelofibrosis. To our surprise, a female XX-karyotype was observed in bone marrow and confirmed in PHA-stimulated T-lymphocytes from peripheral blood. Further molecular genetic investigation revealed a submicroscopic translocation between the short arm of X and Y, which leads to an XX-male genotype based on an unbalanced translocation X;Y. This rare coincidence was further accentuated as the USP9Y gene, suspected to be to be involved in sperm cell production, was absent, but no azoospermia was present. In general, routine cytogenetics may result in findings that need to be further delineated and, as here, lead to a rare observation.
Assuntos
Genótipo , Cariótipo , Mielofibrose Primária/diagnóstico , Mielofibrose Primária/genética , Feminino , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Masculino , Pessoa de Meia-Idade , Fenótipo , Análise para Determinação do Sexo , Linfócitos T/metabolismoRESUMO
The International Prognostic Scoring System (IPSS) is an important standard for assessing prognosis of primary untreated adult patients with myelodysplastic syndromes (MDS). To refine the IPSS, MDS patient databases from international institutions were coalesced to assemble a much larger combined database (Revised-IPSS [IPSS-R], n = 7012, IPSS, n = 816) for analysis. Multiple statistically weighted clinical features were used to generate a prognostic categorization model. Bone marrow cytogenetics, marrow blast percentage, and cytopenias remained the basis of the new system. Novel components of the current analysis included: 5 rather than 3 cytogenetic prognostic subgroups with specific and new classifications of a number of less common cytogenetic subsets, splitting the low marrow blast percentage value, and depth of cytopenias. This model defined 5 rather than the 4 major prognostic categories that are present in the IPSS. Patient age, performance status, serum ferritin, and lactate dehydrogenase were significant additive features for survival but not for acute myeloid leukemia transformation. This system comprehensively integrated the numerous known clinical features into a method analyzing MDS patient prognosis more precisely than the initial IPSS. As such, this IPSS-R should prove beneficial for predicting the clinical outcomes of untreated MDS patients and aiding design and analysis of clinical trials in this disease.
Assuntos
Medula Óssea/patologia , Análise Citogenética , Síndromes Mielodisplásicas/classificação , Síndromes Mielodisplásicas/mortalidade , Pancitopenia/diagnóstico , Pancitopenia/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Aberrações Cromossômicas , Feminino , Humanos , Agências Internacionais , Cariotipagem , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/patologia , Prognóstico , Medição de Risco , Fatores de Risco , Taxa de SobrevidaRESUMO
BACKGROUND AND OBJECTIVE: Resistance to antibacterial substances is a huge and still emerging issue, especially with regard to Gram-negative bacteria and in critically ill patients. We report a study in six patients infected with extensively drug-resistant Gram-negative bacteria in a limited outbreak who were successfully managed with a quasi-continuous infusion of cefiderocol. METHODS: Patients were initially treated with prolonged infusions of cefiderocol over 3 h every 8 h, and the application mode was then switched to a quasi-continuous infusion of 2 g over 8 h, i.e. 6 g in 24 h. Therapeutic drug monitoring (TDM) was established using an in-house liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. RESULTS: Determined trough plasma concentrations were a median of 50.00 mg/L [95% confidence interval (CI) 27.20, 74.60] and steady-state plasma concentrations were a median of 90.96 mg/L [95% CI 37.80, 124]. No significant differences were detected with respect to acute kidney injury/continuous renal replacement therapy. Plasma concentrations determined from different modes of storage were almost equal when frozen or cooled, but markedly reduced when stored at room temperature. CONCLUSIONS: (Quasi) continuous application of cefiderocol 6 g/24 h in conjunction with TDM is a feasible mode of application; the sample for TDM should either be immediately analyzed, cooled, or frozen prior to analysis.