RESUMO
Measurable residual disease (MRD) is a powerful predictor of outcome in acute myeloid leukemia. In the early phases of treatment, MRD refines initial disease risk stratification and is used for the allocation to allogeneic transplant. Despite its well-established role, a relatively high fraction of patients eventually relapses albeit achieving MRDneg status. The aim of this work was to assess specifically the influence of baseline features and treatment intensity on the predictive value of an MRDneg status, particularly focusing on MRD2, measured after two consecutive chemotherapy cycles. Among baseline features, younger MRD2neg patients (<55 years) had a significantly longer disease-free survival (median not reached) compared to their older counterparts (median 25.0 months, P=0.013, hazard ratio=2.08). Treatment intensity, specifically the delivery of a high dose of cytarabine in induction or first consolidation, apparently had a pejorative effect on the outcome of MRD2neg patients compared to standard dose (P=0.048, hazard ratio=1.80), a finding also confirmed by the analysis of data extracted from the literature. The combination of age and treatment intensity allowed us to identify categories of patients, among those who reached a MRD2neg status, characterized by significantly different disease-free survival rate. Our data showed that variables such as age and intensity of treatment administered can influence the predictive value of MRD in patients with acute myeloid leukemia. In addition to underscoring the need for further improvement of MRD analysis, these findings call for a reasoned application of MRD data, as currently available, to modulate consolidation therapy on adequately estimated relapse rates.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Adulto , Humanos , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/tratamento farmacológico , Recidiva , Transplante Homólogo , Intervalo Livre de Doença , Doença Crônica , Neoplasia Residual/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , PrognósticoRESUMO
Contemporary risk models in primary myelofibrosis (PMF) include the mutation (MIPSS70) and mutation/karyotype enhanced (MIPSS70 plus/v2.0) international prognostic scoring systems. High molecular risk (HMR) mutations incorporated in one or both of these models include ASXL1, SRSF2, EZH2, IDH1/2, and U2AF1Q157; the current study examines additional prognostic contribution from more recently described HMR mutations, including CBL, NRAS, KRAS, RUNX1, and TP53. In a cohort of 363 informative cases (median age 58 years; 60% males), mutations included JAK2 61%, CALR 24%, MPL 6%, ASXL1 29%, SRSF2 10%, U2AF1Q157 5%, EZH2 10%, IDH1/2 4%, TP53 5%, CBL 5%, NRAS 7%, KRAS 4%, and RUNX1 4%. At a median follow-up of 4.6 years, 135 (37%) deaths and 42 (11.6%) leukemic transformations were recorded. Univariate analysis confirmed significant survival impact from the original MIPSS70/plus/v2.0 HMR mutations as well as CBL (HR 2.8; p < .001), NRAS (HR 2.4; p < .001), KRAS (HR 2.1; p = .01), and TP53 (HR 2.4; p = .004), but not RUNX1 mutations (HR 1.8; p = .08). Multivariate analysis (MVA) that included both the original and more recently described HMR mutations confirmed independent prognostic contribution from ASXL1 (HR 1.8; p = .007), SRSF2 (HR 4.3; p < .001), U2AF1Q157 (HR 2.9, p = .004), and EZH2 (HR 2.4; p < .001), but not from IDH1/2 (p = .3), TP53 (p = .2), CBL (p = .3), NRAS (p = .8) or KRAS (p = .2) mutations. The lack of additional prognostic value from CBL, NRAS, KRAS, RUNX1, and TP53 was further demonstrated in the setting of (i) MVA of mutations and karyotype, (ii) MVA of MIPSS70/plus/v2.0 composite scores and each one of the recently described HMR mutations, except TP53, and iii) modified MIPSS70/plus/plus v2.0 that included CBL, NRAS, KRAS, and TP53 as part of the HMR constituency, operationally referred to as "HMR+" category. Furthermore, "HMR+" enhancement of MIPSS70/plus/plus v2.0 did not result in improved model performance, as measured by C-statistics. We conclude that prognostic integrity of MIPSS70/plus/plus v2.0, as well as their genetic components, was sustained and their value not significantly upgraded by the inclusion of more recently described HMR mutations, including CBL, NRAS, KRAS, and RUNX1. Additional studies are needed to clarify the apparent additional prognostic value of TP53 mutation and its allelic state.
Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core , Mielofibrose Primária , Masculino , Humanos , Pessoa de Meia-Idade , Feminino , Prognóstico , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Mielofibrose Primária/diagnóstico , Mielofibrose Primária/genética , Mutação , Proteína Supressora de Tumor p53/genética , Proteínas de Membrana/genética , GTP Fosfo-Hidrolases/genéticaRESUMO
The variant allele frequency (VAF) of driver mutations (JAK2, CALR) in myeloproliferative neoplasms is associated with features of advanced disease and complications. Ruxolitinib and interferon were reported to variably reduce the mutant VAF, but the long-term impact of molecular responses (MR) remains debated. We prospectively measured changes in JAK2 and CALR VAF in 77 patients with polycythemia vera and essential thrombocythemia, treated with ruxolitinib for a median of 8 years, and assessed correlation with complete clinical and hematological response (CCHR) and outcomes. At last observation time, JAK2 VAF reduced overall from a median of 68% (range, 20%-99%) to 3.5% (0%-98%). A profound and durable MR (DMR; defined as a VAF stably ≤2%), including complete MR in 8%, was achieved in 20% of the patients, a partial MR (PMR; VAF reduction >50% of the baseline level) in 25%, and 56% had no molecular response (NMR). A CCHR was reached by 69% overall, independently of any degree of MR achieved; conversely, a DMR correlated with longer duration of CCHR and, most importantly, with reduced rate of progression to myelofibrosis and with longer myelofibrosis-free, event-free and progression-free survival. Achievement of PMR also had some favorable impact on outcomes, compared to NMR. A baseline JAK2 VAF <50%, and a VAF reduction of ≥35% after 2 years of treatment, predicted for the achievement of DMR and reduced progression to myelofibrosis. Overall, these findings support the clinical value of achieving profound, durable MR and its consideration as surrogate endpoint in future clinical trials.
Assuntos
Janus Quinase 2 , Mutação , Policitemia Vera , Pirazóis , Trombocitemia Essencial , Humanos , Janus Quinase 2/genética , Policitemia Vera/genética , Policitemia Vera/tratamento farmacológico , Trombocitemia Essencial/genética , Trombocitemia Essencial/tratamento farmacológico , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Adulto , Pirazóis/uso terapêutico , Idoso de 80 Anos ou mais , Pirimidinas/uso terapêutico , Nitrilas/uso terapêutico , Frequência do Gene , Alelos , Calreticulina/genética , Estudos Prospectivos , Resultado do TratamentoRESUMO
Relapsed/refractory (R/R) acute myeloid leukemia (AML) is a largely unmet medical need, owing to the lack of standardized, effective treatment approaches, resulting in an overall dismal outcome. The only curative option for R/R AML patients is allogeneic hematopoietic stem cell transplantation (HSCT) which is only applicable in a fraction of patients due to the scarce efficacy and high toxicity of salvage regimens. Recently, a number of targeted agents with relatively favorable toxicity profiles have been explored in clinical trials for R/R AML patients. The Bcl-2 inhibitor venetoclax, in combination with hypomethylating agents or low dose cytarabine, has produced impressive results for newly diagnosed AML, while its role in R/R disease is not well defined yet. We retrospectively analyzed the clinical outcomes of 47 R/R AML patients treated with venetoclax-based regimens between March 2018 and December 2020 at our institution. Overall, we report a composite complete response rate of 55% with an overall acceptable toxicity profile. Outcomes were particularly favorable for NPM1 mutated patients, unlike for FLT3-ITD positive patients irrespective of NPM1 status. For patients treated with intention to transplant, the procedure could be finally performed in 54%. These findings suggest a role for venetoclax-based regimens in R/R AML patients and support the design of prospective studies.
RESUMO
Acute myeloid leukemia (AML) "with myelodysplasia-related changes (MRC)" is considered a separate entity by the World Health Organization (WHO) classification of myeloid neoplasms. While anamnestic and cytogenetic criteria provide objective attribution to this subset, with clear unfavorable prognostic significance, the actual role of multi-lineage dysplasia (MLD) as assessed by morphology is debated. The aim of our work was to study MLD by a technique alternative to morphology, which is multiparameter flow cytometry (MFC), in a large series of 302 AML patients intensively treated at our Center. The correlation with morphology we observed in the unselected analysis reiterated the capability of the MFC-based approach at highlighting dysplasia. MLD data, estimated through an immune-phenotypic score (IPS), provided no insight into prognosis when considered overall nor within well-defined genetic categories. Of interest, IPS-related dysplasia conveyed significant prognostic information when we focused on genetically undefined patients, triple-negative for NPM1, FLT3 and CEBPA (TN-AML). In this context, the lack of dysplastic features (IPS_0) correlated with a significantly higher CR rate and longer survival compared to patients showing dysplasia in one or both (neutrophil and erythroid) cell lineages. The impact of IPS category maintained its validity after censoring at allogeneic HSCT and in a multivariate analysis including baseline and treatment-related covariates. In a subgroup featured by the lack of genetic determinants, our data could help address the relative unmet needs in terms of risk assessment and treatment strategy, and provide insight into prediction of response in the rapidly evolving therapeutic scenario of AML.
RESUMO
BACKGROUND: Bronchial carcinoid is an infrequent neoplasm with a neuroendocrine differentiation. Surgical treatment is the gold standard therapy, with procedures varying from sublobar resections to complex lung sparing broncoplastic procedures. This study evaluates the results of surgical treatment of bronchial carcinoids and its prognostic factors. PATIENTS AND METHODS: Retrospective review of 126 consecutive patients who underwent surgical treatment for bronchial carcinoid tumors between December 1974 and July 2007. RESULTS: There were 70 females (55%) and the mean age was 46 years, ranging from 17 to 81 years. Upon clinical presentation, 38 patients (30%) have had recurrent respiratory tract infection, 31 (24%) cough, 16 (12%) chest pain and 25 (20%) were asymptomatic. Preoperative bronchoscopic diagnosis was obtained in 74 cases (58.7%). The procedures performed were: 19 sublobar resections (14,9%), 58 lobectomies (46%), 8 bilobectomies (6.3%), 6 pneumonectomies (4.7%), 2 sleeve segmentectomies (1.5%), 26 sleeve lobectomies (20.6%) and 9 bronchoplastic procedures without lung resection (7.1%). Operative mortality was 1.5% (n = 2) and morbidity was 25.8% (n=32), including 12 respiratory tract infections and 4 reinterventions due to bleeding (3) and pleural empyema (1). Among the 112 patients available for follow-up, the overall survival at 3, 5 and 10 years was 89.2%, 85.5% and 79.8%, respectively. Five and 10-year survival for typical and atypical carcinoids were 91, 89% and 56, 47%, respectively. Overall disease-free survival at 5 years was 91.9% Statistical analysis showed that overall disease-free survival correlated with histology--typical vs. atypical--(p = 0.04) and stage (p = 0.02). CONCLUSION: Surgery provides safe and adequate treatment to bronchial carcinoid tumors. Histology and stage were the main prognostic factors.
Assuntos
Neoplasias Brônquicas/diagnóstico , Neoplasias Brônquicas/cirurgia , Broncoscopia , Tumor Carcinoide/diagnóstico , Tumor Carcinoide/cirurgia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Brônquicas/patologia , Neoplasias Brônquicas/fisiopatologia , Broncoscopia/métodos , Broncoscopia/mortalidade , Tumor Carcinoide/patologia , Tumor Carcinoide/fisiopatologia , Feminino , Tecnologia de Fibra Óptica/tendências , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Fatores de Risco , Análise de Sobrevida , Resultado do TratamentoRESUMO
OBJECTIVE: Simple diagnostic methods can facilitate the diagnosis of COPD, which is a major public health problem. The objective of this study was to investigate the accuracy of clinical variables in the diagnosis of COPD. METHODS: Patients with COPD and control subjects were prospectively evaluated by two investigators regarding nine clinical variables. The likelihood ratio for the diagnosis of COPD was determined using a logistic regression model. RESULTS: The study comprised 98 patients with COPD (mean age, 62.3+/- 12.3 years; mean FEV1, 48.3 +/- 21.6%) and 102 controls. The likelihood ratios (95% CIs) for the diagnosis of COPD were as follows: 4.75 (2.29-9.82; p < 0.0001) for accessory muscle recruitment; 5.05 (2.72-9.39; p < 0.0001) for pursed-lip breathing; 2.58 (1.45-4.57; p < 0.001) for barrel chest; 3.65 (2.01-6.62; p < 0.0001) for decreased chest expansion; 7.17 (3.75-13.73; p < 0.0001) for reduced breath sounds; 2.17 (1.01-4.67; p < 0.05) for a thoracic index > or = 0.9; 2.36 (1.22-4.58; p < 0.05) for laryngeal height < or = 5.5 cm; 3.44 (1.92-6.16; p < 0.0001) for forced expiratory time > or = 4 s; and 4.78 (2.13-10.70; p < 0.0001) for lower liver edge > or = 4 cm from lower costal edge. Inter-rater reliability for those same variables was, respectively, 0.57, 0.45, 0.62, 0.32, 0.53, 0.32, 0.59, 0.52 and 0.44 (p < 0.0001 for all). CONCLUSIONS: Various clinical examination findings could be used as diagnostic tests for COPD.
Assuntos
Exame Físico , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Métodos Epidemiológicos , Feminino , Humanos , Lábio/fisiopatologia , Masculino , Pessoa de Meia-Idade , Exame Físico/classificação , Mecânica Respiratória/fisiologia , Músculos Respiratórios/fisiologiaRESUMO
OBJECTIVE: To evaluate the frequency of the use of sputum examination in the clinical management of community-acquired pneumonia (CAP) in a general hospital and to determine whether its use has an impact on mortality. METHODS: The medical records of CAP patients treated as inpatients between May and November of 2004 at the Nossa Senhora da Conceição Hospital, located in Porto Alegre, Brazil, were reviewed regarding the following aspects: age; gender; severity of pneumonia (Fine score); presence of sputum; sputum bacteriology; treatment history; change in treatment; and mortality. RESULTS: A total of 274 CAP patients (134 males and 140 females) were evaluated. Using the Fine score to quantify severity, we classified 79 (28.8%) of those 274 patients as class II, 45 (16.4%) as class III, 97 (35.4%) as class IV, and 53 (19.3%) as class V. Sputum examination was carried out in 92 patients (33.6%). A valid sample was obtained in 37 cases (13.5%), and an etiological diagnosis was obtained in 26 (9.5%), resulting in a change of treatment in only 9 cases (3.3%). Overall mortality was 18.6%. Advanced age (above 65), CAP severity, and dry cough were associated with an increase in the mortality rate. Sputum examination did not alter any clinical outcome or have any influence on mortality. CONCLUSION: Sputum examination was used in a minority of patients and was not associated with any noticeable benefit in the clinical management of patients with CAP treated in a hospital setting.
Assuntos
Pneumonia Bacteriana/diagnóstico , Avaliação de Processos em Cuidados de Saúde , Escarro/microbiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/uso terapêutico , Brasil/epidemiologia , Infecções Comunitárias Adquiridas/diagnóstico , Infecções Comunitárias Adquiridas/tratamento farmacológico , Infecções Comunitárias Adquiridas/mortalidade , Feminino , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Pneumonia Bacteriana/tratamento farmacológico , Pneumonia Bacteriana/mortalidade , Estudos Retrospectivos , Índice de Gravidade de Doença , Fatores Sexuais , Taxa de SobrevidaRESUMO
Objetivo: A DPOC é um problema de saúde pública, e métodos diagnósticos simples podem ser úteis para facilitar o diagnóstico desta doença. O objetivo deste estudo foi avaliar a acurácia de variáveis clínicas para o diagnóstico de DPOC. Métodos: Pacientes com DPOC e controles foram prospectivamente avaliados por dois examinadores quanto a nove variáveis clínicas. A razão de verossimilhança para o diagnóstico de DPOC foi determinada utilizando-se o modelo de regressão logística. Resultados: Foram incluídos 98 pacientes com DPOC (idade média, 62,3 ± 12,3 anos; VEF1 médio, 48,3 ± 21,6%) e 102 controles. A razão de verossimilhança e IC95% para o diagnóstico de DPOC foram: 4,75 (2,29-9,82; p < 0,0001) para uso da musculatura acessória; 5,05 (2,72-9,39; p < 0,0001) para respiração com os lábios semicerrados; 2,58 (1,45-4,57; p < 0,001) para tórax em barril; 3,65 (2,01-6,62; p < 0,0001) para redução da expansibilidade torácica; 7,17 (3,75-13,73; p < 0,0001) para redução do murmúrio vesicular; 2,17 (1,01‑4,67; p < 0,05) para índice torácico ≥ 0,9; 2,36 (1,22-4,58; p < 0,05) para comprimento laríngeo ≤ 5,5 cm; 3,44 (1,92‑6,16; p < 0,0001) para tempo expiratório forçado ≥ 4 s; e 4,78 (2,13-10,70; p < 0.0001) para limite inferior do fígado ≥ 4 cm abaixo do rebordo costal. A concordância entre observadores para as mesmas variáveis foi, respectivamente, 0,57, 0,45, 0,62, 0,32, 0,53, 0,32, 0,59, 0,52 e 0,44 (p < 0,0001 para todas). Conclusões: Vários achados do exame clínico podem ser utilizados como testes diagnósticos para DPOC.
Objective: Simple diagnostic methods can facilitate the diagnosis of COPD, which is a major public health problem. The objective of this study was to investigate the accuracy of clinical variables in the diagnosis of COPD. Methods: Patients with COPD and control subjects were prospectively evaluated by two investigators regarding nine clinical variables. The likelihood ratio for the diagnosis of COPD was determined using a logisticregression model. Results: The study comprised 98 patients with COPD (mean age, 62.3± 12.3 years; mean FEV1, 48.3 ± 21.6%) and 102 controls. The likelihood ratios (95% CIs) for the diagnosis of COPD were as follows: 4.75 (2.29-9.82; p < 0.0001) for accessory muscle recruitment; 5.05 (2.72-9.39; p < 0.0001) for pursed-lipbreathing; 2.58 (1.45‑4.57; p < 0.001) for barrel chest; 3.65 (2.01-6.62; p < 0.0001) for decreased chest expansion;7.17 (3.75-13.73; p < 0.0001) for reduced breath sounds; 2.17 (1.01- .67; p < 0.05) for a thoracic index ≥ 0.9; 2.36 (1.22-4.58; p < 0.05) for laryngeal height ≤ 5.5 cm; 3.44 (1.92-6.16; p < 0.0001) for forced expiratory time ≥ 4 s; and 4.78 (2.13-10.70; p < 0.0001) for lower liver edge ≥ 4 cm from lower costal edge. Inter-rater reliability for those same variables was, respectively, 0.57, 0.45, 0.62, 0.32, 0.53, 0.32, 0.59, 0.52 and 0.44 (p < 0.0001 for all). Conclusions: Various clinical examination findings could be used as diagnostic tests for COPD.
Assuntos
Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Exame Físico , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Métodos Epidemiológicos , Lábio/fisiopatologia , Exame Físico/classificação , Mecânica Respiratória/fisiologia , Músculos Respiratórios/fisiologiaRESUMO
OBJETIVO: Este estudo retrospectivo avaliou a freqüência do uso da bacteriologia do escarro no manejo clínico de pacientes com pneumonia adquirida na comunidade (PAC) em um hospital geral, e se a utilização deste método modificou a mortalidade. MÉTODOS: Os prontuários de pacientes internados no Hospital Nossa Senhora da Conceição, em Porto Alegre (RS) Brasil, para tratamento de PAC entre maio e novembro de 2004 foram revisados quanto aos seguintes aspectos: idade; sexo; gravidade da pneumonia (escore de Fine); presença de expectoração; bacteriologia do escarro; história de tratamento; resposta clínica; troca de tratamento; e mortalidade. RESULTADOS: Foram avaliados 274 pacientes com PAC, sendo 134 do sexo masculino. Dentre os 274 pacientes, 79 (28,8 por cento) apresentavam, de acordo com o escore de Fine, classe II; 45 (16,4 por cento), classe III; 97 (35,4 por cento), classe IV; e 53 (19,3 por cento), classe V. Em 92 pacientes (33,6 por cento), uma amostra de escarro foi colhida para exame bacteriológico. Obtivemos amostra válida em 37 casos (13,5 por cento) e diagnóstico etiológico em 26 (9,5 por cento), o que resultou em modificação do tratamento em apenas 9 casos (3,3 por cento). A mortalidade geral foi 18,6 por cento. Idade acima de 65 anos, a gravidade da PAC e a ausência de escarro associaram-se à maior mortalidade. A bacteriologia do escarro não influenciou o desfecho clínico, nem a taxa de mortalidade. CONCLUSÃO: O exame do escarro foi uma ferramenta diagnóstica utilizada na minoria dos pacientes, e não trouxe benefício detectável no manejo clínico dos pacientes com PAC tratados em ambiente hospitalar.
OBJECTIVE: To evaluate the frequency of the use of sputum examination in the clinical management of community-acquired pneumonia (CAP) in a general hospital and to determine whether its use has an impact on mortality. METHODS: The medical records of CAP patients treated as inpatients between May and November of 2004 at the Nossa Senhora da Conceição Hospital, located in Porto Alegre, Brazil, were reviewed regarding the following aspects: age; gender; severity of pneumonia (Fine score); presence of sputum; sputum bacteriology; treatment history; change in treatment; and mortality. RESULTS: A total of 274 CAP patients (134 males and 140 females) were evaluated. Using the Fine score to quantify severity, we classified 79 (28.8 percent) of those 274 patients as class II, 45 (16.4 percent) as class III, 97 (35.4 percent) as class IV, and 53 (19.3 percent) as class V. Sputum examination was carried out in 92 patients (33.6 percent). A valid sample was obtained in 37 cases (13.5 percent), and an etiological diagnosis was obtained in 26 (9.5 percent), resulting in a change of treatment in only 9 cases (3.3 percent). Overall mortality was 18.6 percent. Advanced age (above 65), CAP severity, and dry cough were associated with an increase in the mortality rate. Sputum examination did not alter any clinical outcome or have any influence on mortality. CONCLUSION: Sputum examination was used in a minority of patients and was not associated with any noticeable benefit in the clinical management of patients with CAP treated in a hospital setting.