RESUMO
Resistance remains the major clinical challenge for the therapy of Philadelphia chromosome-positive (Ph+) leukemia. With the exception of ponatinib, all approved tyrosine kinase inhibitors (TKIs) are unable to inhibit the common "gatekeeper" mutation T315I. Here we investigated the therapeutic potential of crizotinib, a TKI approved for targeting ALK and ROS1 in non-small cell lung cancer patients, which inhibited also the ABL1 kinase in cell-free systems, for the treatment of advanced and therapy-resistant Ph+ leukemia. By inhibiting the BCR-ABL1 kinase, crizotinib efficiently suppressed growth of Ph+ cells without affecting growth of Ph- cells. It was also active in Ph+ patient-derived long-term cultures (PD-LTCs) independently of the responsiveness/resistance to other TKIs. The efficacy of crizotinib was confirmed in vivo in syngeneic mouse models of BCR-ABL1- or BCR-ABL1T315I-driven chronic myeloid leukemia-like disease and in BCR-ABL1-driven acute lymphoblastic leukemia (ALL). Although crizotinib binds to the ATP-binding site, it also allosterically affected the myristol binding pocket, the binding site of GNF2 and asciminib (former ABL001). Therefore, crizotinib has a seemingly unique double mechanism of action, on the ATP-binding site and on the myristoylation binding pocket. These findings strongly suggest the clinical evaluation of crizotinib for the treatment of advanced and therapy-resistant Ph+ leukemia.
Assuntos
Antineoplásicos/farmacologia , Crizotinibe/farmacologia , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Proteínas Proto-Oncogênicas c-abl/antagonistas & inibidores , Trifosfato de Adenosina/metabolismo , Regulação Alostérica/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Proteínas de Fusão bcr-abl/genética , Proteínas de Fusão bcr-abl/metabolismo , Humanos , Células Jurkat , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Camundongos , Mutação/efeitos dos fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-abl/metabolismoRESUMO
BACKGROUND: Chronic lymphocytic leukemia (CLL) is frequently accompanied by immune dysregulation. AIMS: In this multicenter prospective study, we investigated whether heavy + light chains (HLC: IgGκ, IgGλ, IgAκ, IgAκ, IgMκ, IgMλ) and IgG subclasses (IgG1, IgG2, IgG3, and IgG4) could be used as novel prognostic markers of immunoparesis in 105 treatment-naïve patients with CLL. RESULTS: Heavy + light chains immunoparesis of ≥1, ≥2, and ≥3 isotypes was evident in 74 (70%), 58 (55%), and 36 (34%) patients, respectively. Severe HLC immunoparesis was identified in 40 (38%) patients. Of the IgG subclasses, IgG1 and IgG2 were most frequently suppressed, affecting 46 (44%) and 36 (34%) patients, respectively; 63 (60%) patients had low levels of at least one IgG subclass. In multivariate analysis, severe HLC immunoparesis (hazard ratio [HR]: 36.5; P = .010) and ΣFLC ≥ 70 mg/L (HR: 13.2; P = .004) were the only factors independently associated with time to first treatment (TTFT). A risk model including these variables identified patients with 0, 1, and 2 risk factors and significantly different TTFT (P < .001). Patients with two factors represented an ultra-high-risk group with a median TTFT of only 1.3 months. CONCLUSION: The above findings demonstrate the potential for the use of HLC immunoparesis, together with sFLC measurements, as future prognostic biomarkers in CLL.
Assuntos
Cadeias Pesadas de Imunoglobulinas/sangue , Cadeias Leves de Imunoglobulina/sangue , Leucemia Linfocítica Crônica de Células B/sangue , Leucemia Linfocítica Crônica de Células B/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/imunologia , Leucemia Linfocítica Crônica de Células B/terapia , Masculino , Pessoa de Meia-Idade , Modelos Teóricos , Prognóstico , Modelos de Riscos Proporcionais , Tempo para o TratamentoRESUMO
INTRODUCTION: Acute appendicitis (AA) requires a prompt diagnosis. According to postoperative pathological results, a significant number of appendectomies are performed on a normal appendix (NA). The aim of this study is to evaluate the role of preoperative inflammatory markers in supporting and improving the clinical diagnosis of AA, extracting more information from CBC parameters. METHODS: The study is a retrospective one. The histopathological results of operated appendix from 102 patients, who underwent appendectomy for clinically suspected AA, were extracted from the Galilee Medical Center systems. Two patient groups (NA and true AA) were compared for neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), monocyte to lymphocyte ratio (MLR) and mean platelet volume (MPV). The obtained data were statistically analyzed, using the independent sample t test and Mann-Whitney test. Category data have been compared among groups with the chi-squared test. The primary endpoint of our research was to assess the predictive power of blood biomarkers. RESULTS: Patients with suspected AA, based on clinical picture and contrast enhanced computed tomography (CECT), and with MLR-value ≥0.3357 were 5.25 times more likely than normal to have AA. Patients with NLR-value ≥3.2223 were 7 times more likely than normal to have AA. The differences in PLR and MPV values were not statistically significant. CONCLUSIONS: The NLR and MLR biomarkers can assist in diagnosis of AA. This can be particularly helpful in cases where CECT is contraindicated, as in pregnant women or children.
Assuntos
Apendicite , Criança , Humanos , Feminino , Gravidez , Apendicite/diagnóstico , Apendicite/cirurgia , Estudos Retrospectivos , Volume Plaquetário Médio , Linfócitos , Neutrófilos , Biomarcadores , Doença AgudaRESUMO
The clinical significance and optimal therapy of patients with subsegmental pulmonary embolism (SSPE) remain controversial. We used the data in the RIETE Registry to compare the baseline characteristics, treatment, and outcomes during anticoagulation and after its discontinuation in patients with asymptomatic vs. symptomatic SSPE. From January 2009 to September 2022, there were 2135 patients with a first episode of SSPE, of whom 160 (7.5%) were asymptomatic. Most patients in both subgroups received anticoagulant therapy (97% vs. 99.4%, respectively). During anticoagulation, 14 patients developed symptomatic pulmonary embolism (PE) recurrences, 28 lower-limb deep vein thrombosis (DVT), 54 bled, and 242 died. The patients with asymptomatic SSPE had similar rates of symptomatic PE recurrences (hazard ratio (HR): 2.46; 95% CI: 0.37-9.74), DVT (HR: 0.53; 95% CI: 0.03-2.80), or major bleeding (HR: 0.85; 95% CI: 0.21-2.42) to those with symptomatic SSPE, but had a higher mortality rate (HR: 1.59; 95% CI: 1.25-2.94). The rate of major bleeding outweighed the rate of PE recurrences (54 major bleeds vs. 14 PE recurrences), and the rate of fatal bleeds outweighed the rate of fatal PE recurrences (12 vs. 6 deaths). After discontinuing anticoagulation, the patients with asymptomatic SSPE had a similar rate of PE recurrences (HR: 1.27; 95% CI: 0.20-4.55) and a non-significantly higher mortality rate (HR: 2.06; 95% CI: 0.92-4.10). The patients with asymptomatic SSPE had similar rates of PE recurrences to those with symptomatic SSPE, during and after discontinuing anticoagulation. The unexpectedly higher rate of major bleeding than recurrences highlights the need for randomized trials to find the best management.
RESUMO
BACKGROUND/AIM: In this retrospective study, we summarized the national Israeli experience with hairy cell leukemia (HCL) in a large cohort of patients with a long follow-up. PATIENTS AND METHODS: Demographic data, and relevant laboratory and clinical parameters were analyzed, emphasizing the outcome after first-line treatment with cladribine. RESULTS: Data on 203 patients was collected from 12 medical centers during 1985-2015. Mean and median follow-up were 7.5 years and 5.18 years (interquartile range=0.1-40 years), and 5- and 10-year survival were 96% and 90.62%, respectively. The median age of diagnosis was 55.5 years for Jews and 49 years for Arabs (p=0.021), and most patients were males (81.77%); 52.2% were Ashkenazi Jews, 36.1% Sephardic Jews and 11.7% were Arab, Druze or other ethnicity. Cladribine was given to 159 patients (80.7%%) and most (62%) received intravenous (i.v.) and 38% received subcutaneous (s.c.) therapy. Overall survival and time to next treatment were not significantly different between the two schedules (i.v., s.c.). In univariate analysis of a variety of factors, only age >65 years had a negative impact on outcome, with shorter overall survival. It is of interest that Arab patients with HCL were diagnosed at an earlier age, but had a similar clinical course and outcome to both Ashkenazi and Sephardic Jews.
Assuntos
Antineoplásicos/administração & dosagem , Cladribina/administração & dosagem , Leucemia de Células Pilosas/tratamento farmacológico , Leucemia de Células Pilosas/etnologia , Administração Intravenosa , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Cladribina/uso terapêutico , Detecção Precoce de Câncer , Feminino , Humanos , Injeções Subcutâneas , Israel/etnologia , Leucemia de Células Pilosas/diagnóstico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Análise de Sobrevida , Tempo para o Tratamento , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: This study investigated the importance of neutrophil/lymphocyte ratio (NLR) and other new inflammatory markers including CD64 expression in patients with chronic obstructive pulmonary disease (COPD) for identifying the severity of inflammation and recognition of acute exacerbation and infection. METHODS: Seventy-two patients with a diagnosis of COPD exacerbation who were admitted to the Department of Internal Medicine B, 13 with stable COPD, and control group of 15 healthy people were enrolled in the study. Complete blood count (CBC), measurement of C-reactive protein (CRP), mean platelet volume (MPV), red blood cell distribution width (RDW) and CD64 expression were determined within 2 hours of hospital admission. RESULTS: NLR and other inflammatory markers, such as RDW, CRP, and CD64 were found to be significantly elevated in exacerbated COPD compared to stable COPD and control participants. There was a significant correlation of NLR with CRP (r=0.309, P<0.001), For an NLR cutoff of 7.3, sensitivity for detecting exacerbation of COPD was 0.768 and specificity was 1-0.269 (AUC=0.793, P=0.001) RDW was significant as NLR. CD64 is statistically significant (P=0.002) the lack of significance was between acute exacerbation of COPD and stable COPD, but indexes were higher in the group of COPD patients with complications. CONCLUSIONS: Elevated NLR can be used as a marker similar to CRP, and RDW, in the determination of increased inflammation in acutely exacerbated COPD. NLR could be beneficial for the early detection of potential acute exacerbations in patients with COPD who have normal levels of traditional markers; CD64 was higher but did not reach statistical significance. MPV was not helpful.