RESUMO
BACKGROUND: Alectinib is a second-generation anaplastic lymphoma kinase (ALK) inhibitor indicated for ALK-mutated non-small-cell lung cancer. Recently, the association between alectinib and red cell morphological abnormalities has been reported in a few case series. This retrospective observational study aims to determine the frequency of occurrence of acanthocytosis in patients taking alectinib and to evaluate the red cell indices, biochemical markers of haemolysis and eosin-5-maleimide (EMA) binding assay results in patients receiving alectinib. METHODS: Patients who were on alectinib and had a complete blood count test performed in Queen Elizabeth Hospital Haematology Laboratory between 1 May 2021 and 31 August 2021 were included in the study. Haematological investigations that had been performed before and after the commencement of alectinib were reviewed. RESULTS: Fifty patients receiving alectinib were evaluated in this analysis. One hundred per cent of patients showed 3+ acanthocytes on the peripheral blood smears. Compared with the test results before starting alectinib, the post-alectinib blood tests showed a significantly lower haemoglobin concentration, red blood cell count and haematocrit; and a significantly higher mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration and red cell distribution width. All the tested patients showed a marked reduction in EMA mean channel fluorescence compared with normal control. CONCLUSION: Our cohort revealed that alectinib caused significant acanthocytosis in all patients. Alectinib was also associated with changes in red cell indices and biochemical markers of haemolysis, compatible with a spherocytic and anisopoikilocytic morphology with haemolysis. Patients on alectinib had reduced EMA binding.
Assuntos
Carbazóis , Eritrócitos , Piperidinas , Humanos , Piperidinas/uso terapêutico , Piperidinas/farmacologia , Carbazóis/farmacologia , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Retrospectivos , Idoso , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Índices de Eritrócitos/efeitos dos fármacos , Adulto , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/patologia , Idoso de 80 Anos ou mais , Testes HematológicosRESUMO
There is an urgent need for the identification as well as clinicopathological and functional characterization of potent prognostic biomarkers and therapeutic targets in acute myeloid leukemia (AML). Using immunohistochemistry and next-generation sequencing, we investigated the protein expression as well as clinicopathological and prognostic associations of serine protease inhibitor Kazal type 2 (SPINK2) in AML and examined its potential biological functions. High SPINK2 protein expression was an independent adverse biomarker for survival and an indicator of elevated therapy resistance and relapse risk. SPINK2 expression was associated with AML with an NPM1 mutation and an intermediate risk by cytogenetics and European LeukemiaNet (ELN) 2022 criteria. Furthermore, SPINK2 expression could refine the ELN2022prognostic stratification. Functionally, an RNA sequencing analysis uncovered a potential link of SPINK2 with ferroptosis and immune response. SPINK2 regulated the expression of certain P53 targets and ferroptosis-related genes, including SLC7A11 and STEAP3, and affected cystine uptake, intracellular iron levels and sensitivity to erastin, a specific ferroptosis inducer. Furthermore, SPINK2 inhibition consistently increased the expression of ALCAM, an immune response enhancer and promoter of T-cell activity. Additionally, we identified a potential small-molecule inhibitor of SPINK2, which requires further characterization. In summary, high SPINK2 protein expression was a potent adverse prognostic marker in AML and might represent a druggable target.
Assuntos
Ferroptose , Leucemia Mieloide Aguda , Humanos , Ferroptose/genética , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Prognóstico , Inibidores de Serina Proteinase/sangue , Inibidores de Serina Proteinase/metabolismo , Serpinas/sangue , Serpinas/metabolismoAssuntos
Adenocarcinoma de Pulmão , Carbazóis , Eritrócitos Anormais , Neoplasias Pulmonares , Piperidinas , Talassemia alfa , Adenocarcinoma de Pulmão/sangue , Adenocarcinoma de Pulmão/tratamento farmacológico , Carbazóis/administração & dosagem , Carbazóis/efeitos adversos , Eritrócitos Anormais/metabolismo , Eritrócitos Anormais/patologia , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Talassemia alfa/sangue , Talassemia alfa/tratamento farmacológico , Talassemia alfa/patologiaRESUMO
Amyloid light-chain (AL) amyloidosis is the most common form of systemic amyloidosis. It can cause progressive organ dysfunction and eventually death, mainly due to cardiac involvement. Amyloidosis may rarely present as extensive amorphous, purplish-blue deposits in marrow aspirate smears. Demonstration of congophilic property and apple-green birefringence under polarized light in aspirate smears can allow a rapid diagnosis of amyloidosis.
RESUMO
This study examined the treatment efficacy of PEERS® (Program for the Education and Enrichment of Relational Skills) among Chinese adolescents with autism spectrum disorder (ASD) in Hong Kong. The original PEERS® manual was translated into Chinese, and cultural adjustments were made according to a survey among 209 local adolescents in the general population. 72 high-functioning adolescents with ASD were randomly assigned to a treatment or waitlist control group. The 14-week parent-assisted training significantly improved social skills knowledge and social functioning, and also reduced autistic mannerisms. Treatment outcomes were maintained for 3 months after training and replicated in the control group after delayed treatment. The present study represents one of the few randomized controlled trials on PEERS® conducted outside North America.
Assuntos
Transtorno do Espectro Autista/psicologia , Transtorno do Espectro Autista/terapia , Amigos/psicologia , Aprendizagem/fisiologia , Habilidades Sociais , Tradução , Adolescente , Transtorno do Espectro Autista/epidemiologia , Criança , Feminino , Hong Kong/epidemiologia , Humanos , Masculino , Ajustamento Social , Inquéritos e Questionários , Resultado do TratamentoAssuntos
Anemia Sideroblástica/genética , Mutação da Fase de Leitura , Doenças Genéticas Ligadas ao Cromossomo X/genética , Proteínas de Transporte da Membrana Mitocondrial/genética , Anemia Sideroblástica/sangue , Anemia Sideroblástica/diagnóstico , Anemia Sideroblástica/terapia , Biomarcadores/sangue , Transfusão de Sangue , Exame de Medula Óssea , Análise Mutacional de DNA , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/sangue , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Predisposição Genética para Doença , Humanos , Lactente , FenótipoRESUMO
The BRAFV600E mutation is a highly sensitive and specific marker for the diagnosis of hairy cell leukaemia (HCL) and a potential therapeutic target. We assessed the performance of high resolution melting (HRM), allele-specific priming (ASP) and Sanger sequencing (SS) for BRAFV600E detection in 17 unenriched samples from 15 HCL patients: blood (nâ=â7), marrow aspirate (nâ=â3), ethylenediaminetetraacetic acid (EDTA)-decalcified trephine biopsy (nâ=â2), formic acid (FA)-decalcified trephine biopsy (nâ=â5). Our results showed that for blood and marrow aspirate samples, both HRM and ASP had a very high analytical sensitivity (1%) in clinical specimens and excellent diagnostic sensitivity (100%) and specificity (100%) in analysable samples. Sanger sequencing had a lower analytical sensitivity (4%), resulting in false-negative analysis in samples with a low tumour cell percentage. High resolution melting was technically the simplest and had the shortest turn-around time (2âhours). Analysis of decalcified trephine biopsies was more difficult because of suboptimal DNA preservation. Although Sanger sequencing was least demanding on sample DNA quality for a successful analysis, none of the three techniques showed satisfactory diagnostic performance on trephine biopsies. Therefore, careful selection of a suitable sample type and testing platform is important to optimise the detection of this important mutation in HCL.
Assuntos
Biomarcadores Tumorais/genética , Análise Mutacional de DNA/métodos , Leucemia de Células Pilosas/genética , Técnicas de Diagnóstico Molecular/métodos , Proteínas Proto-Oncogênicas B-raf/genética , Alelos , Biópsia por Agulha , Medula Óssea/patologia , DNA de Neoplasias/sangue , DNA de Neoplasias/genética , Humanos , Leucemia de Células Pilosas/diagnóstico , Mutação , Desnaturação de Ácido Nucleico , Inclusão em Parafina , Reação em Cadeia da Polimerase , Sensibilidade e Especificidade , Análise de Sequência de DNAAssuntos
Hepatopatias/patologia , Febre Q/patologia , Antibacterianos/uso terapêutico , Anticorpos Antibacterianos , Doxiciclina/uso terapêutico , Granuloma/diagnóstico , Granuloma/microbiologia , Granuloma/patologia , Humanos , Hepatopatias/diagnóstico , Hepatopatias/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Febre Q/diagnóstico , Febre Q/tratamento farmacológicoRESUMO
A 66-year-old man who presented with progressive and marked thrombocytosis but normal hemoglobin was diagnosed to have essential thrombocythemia upon the demonstration of JAK2 V617F mutation. Bone marrow examination, however, showed the presence of monolobulated megakaryocytes and conventional cytogenetic analysis revealed an isolated interstitial deletion of the long arm of chromosome 5, characteristic of 5q- syndrome. A literature review indicated that isolated deletion of 5q is uncommon in essential thrombocythemia but that, when this isolated deletion is present, the disease often shows mixed features of both essential thrombocythemia and 5q- syndrome.
Assuntos
Cromossomos Humanos Par 5 , Trombocitemia Essencial/genética , Idoso , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Masculino , Mutação , Deleção de SequênciaRESUMO
Recent linkage analyses of nondiabetic African-American patients with focal segmental glomerulosclerosis (FSGS) have identified MYH9, encoding nonmuscle myosin heavy chain IIA (NMMHC-IIA), as a gene having a critical role in this disease. Abnormalities of the MYH9 locus also underlie rare autosomal dominant diseases such as May-Hegglin anomaly, and Sebastian, Epstein (EPS), and Fechtner (FTNS) syndromes that are characterized by macrothrombocytopenia and cytoplasmic inclusion bodies in granulocytes. Among these diseases, patients with EPS or FTNS develop progressive nephritis and hearing disability. We analyzed clinical features and pathophysiological findings of nine EPS-FTNS patients with MYH9 mutations at the R702 codon hot spot. Most developed proteinuria and/or hematuria in early infancy and had a rapid progression of renal impairment during adolescence. Renal histopathological findings in one patient showed changes compatible with FSGS. The intensity of immunostaining for NMMHC-IIA in podocytes was decreased in this patient compared with control patients. Thus, MYH9 R702 mutations display a strict genotype-phenotype correlation, and lead to the rapid deterioration of podocyte structure. Our results highlight the critical role of NMMHC-IIA in the development of FSGS.
Assuntos
Nefropatias/etiologia , Proteínas Motores Moleculares/genética , Mutação , Cadeias Pesadas de Miosina/genética , Proteinúria/etiologia , Adolescente , Adulto , Criança , Pré-Escolar , Progressão da Doença , Feminino , Perda Auditiva Neurossensorial/genética , Humanos , Masculino , Nefrite Hereditária/genética , Trombocitopenia/genética , Adulto JovemRESUMO
BACKGROUND: We studied the application of the BCR-ABL1 + 9q34 tri-colour dual fusion fluorescence in situ hybridization (FISH) system in the characterization of fusion signal pattern and the monitoring of residual disease in chronic myelogenous leukaemia (CML). The signal constellation on metaphases with the tri-colour dual fusion system was defined. The knowledge of various signal patterns obtained from the different genetic rearrangements was further applied to the analysis of hybridization signals on interphase nuclei. METHODS: BCR-ABL1 dual colour, dual fusion FISH (D-FISH) was performed on diagnostic samples of 22 CML patients. The tri-colour FISH system was performed on cases that showed aberrant signal patterns other than the classical 1 green (G) 1 orange (O) 2 fusions (F). Using the aqua band-pass filter, random signal overlap in interphase nuclei would be indicated by the presence of an aqua signal (ASS1), while genuine fusion was represented by the absence of the ASS1 signal. RESULTS: Using the D-FISH system, the signal patterns could be categorized into 4 groups: group 1 (n = 17) showed the classical 1G1O2F; group 2 (n = 2) showed 2G1O1F indicating ABL1 deletion; group 3 (n = 1) showed 1G2O1F indicating BCR deletion; group 4 (n = 2) with 1G1O1F indicating reciprocal ABL1-BCR deletion. The tri-colour dual fusion system correlated with the D-FISH system for cases with der(9) deletion. The added aqua-labelled ASS1 probe was useful in differentiating random signal overlap from genuine BCR-ABL1 fusion in the interphase cells (group 4). CONCLUSION: Although the D-FISH probe was valuable in establishing the different patterns of aberrant signals and monitoring patients with the classic 2-fusion signals in CML, the tri-colour dual fusion probe should be used for patients with der(9) deletion to monitor response to treatment.
Assuntos
Síndrome da Imunodeficiência Adquirida/complicações , Febre/etiologia , Infecção por Mycobacterium avium-intracellulare/diagnóstico , Pancitopenia/etiologia , Tuberculose/diagnóstico , Adulto , Humanos , Masculino , Complexo Mycobacterium avium/isolamento & purificação , Infecção por Mycobacterium avium-intracellulare/microbiologia , Tuberculose/microbiologiaRESUMO
We describe a case of coexisting BCR-ABL negative myeloproliferative disorder and precursor T-cell lymphoblastic lymphoma associated with t(8;13) involving FGFR1 at 8p11 in a 14-year-old boy who presented with generalized lymphadenopathy and an abdominal mass. JAK2 mutation and FIP1L1-PDGFRalpha were not detected. RT-PCR revealed the ZNF198-FGFR1 fusion transcript in both the bone marrow (BM) and lymph node (LN) of the patient at diagnosis. Of interest, reciprocal FGFR1-ZNF198 fusion transcript was demonstrated in the BM but not LN. Also differential clonal TcRgamma gene rearrangements in the BM and LN samples were observed. These findings provide novel insights into the genetic pathogenesis.