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1.
Orv Hetil ; 161(38): 1623-1628, 2020 09.
Artigo em Húngaro | MEDLINE | ID: mdl-32924966

RESUMO

Maintenance therapy has been the strong and standard element of many acute lymphoblastic leukaemia protocols, used much less frequently and systematically in adult oncohematological disorders. The first adult maintenance efforts appeared in follicular and mantle cell lymphoma (mostly monoclonal antibody based), along with an early maintenance effort to prolong the plateau phase of myeloma. For the time being, after a long debate, the prognosis-dependent type of consolidation and maintenance became - sometimes until relapse - the standard approach in myeloma patients. The so-called small molecules, which turned out to be effective as induction and relapse agents, are continuously moving toward maintenance settings. Moreover, maintenance efforts seem to be more and more considered and used in transplanted or some non-transplanted acute myeloid leukaemia patients as well. Nevertheless, maintenance should be patient-friendly, easy to use (e.g., tablets) by enabling short outpatient office time, done not very frequently, and as much quality-of-life-based as possible. Orv Hetil. 2020; 161(38): 1623-1628.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Mieloma Múltiplo/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adulto , Humanos , Leucemia Mieloide Aguda/patologia , Mieloma Múltiplo/patologia , Recidiva Local de Neoplasia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia
2.
Anticancer Res ; 40(10): 5751-5756, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988902

RESUMO

BACKGROUND/AIM: A single study has shown positive association and genotype-phenotype correlation between metalloproteinase-9 (MMP-9) promoter genotypes and adult acute lymphocytic leukemia (ALL). However, there is no report about childhood ALL. Thus, this study aimed at examining the role of MMP-9 rs3918242 genotypes in childhood ALL risk. PATIENTS AND METHODS: A total of 266 childhood ALL cases and 266 healthy controls in Taiwan were examined for their MMP-9 rs3918242 genotypes via polymerase chain reaction-restriction fragment length polymorphism methodology. RESULTS: The MMP-9 rs3918242 CT or TT genotype carriers only had a slightly increased risk compared with CC carriers (p=0.6386 and 0.6005, respectively). The allelic frequency analysis also supported the idea that the variant T allele at MMP-9 rs3918242 is not differentially distributed between the case and control groups (p=0.4834). CONCLUSION: MMP-9 rs3918242 genotypes may indirectly influence the risk of childhood ALL. Further validations in other populations and analysis of the detail mechanisms are needed.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Metaloproteinase 9 da Matriz/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adulto , Alelos , Criança , Feminino , Genótipo , Heterozigoto , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Regiões Promotoras Genéticas/genética
3.
Mol Cell Biol ; 40(18)2020 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-32631903

RESUMO

Precursor B cell acute lymphoblastic leukemia (B-ALL) is caused by genetic lesions in developing B cells that function as drivers for the accumulation of additional mutations in an evolutionary selection process. We investigated secondary drivers of leukemogenesis in a mouse model of B-ALL driven by PU.1/Spi-B deletion (Mb1-CreΔPB). Whole-exome-sequencing analysis revealed recurrent mutations in Jak3 (encoding Janus kinase 3), Jak1, and Ikzf3 (encoding Aiolos). Mutations with a high variant-allele frequency (VAF) were dominated by C→T transition mutations that were compatible with activation-induced cytidine deaminase, whereas the majority of mutations, with a low VAF, were dominated by C→A transversions associated with 8-oxoguanine DNA damage caused by reactive oxygen species (ROS). The Janus kinase (JAK) inhibitor ruxolitinib delayed leukemia onset, reduced ROS and ROS-induced gene expression signatures, and altered ROS-induced mutational signatures. These results reveal that JAK mutations can alter the course of leukemia clonal evolution through ROS-induced DNA damage.


Assuntos
Dano ao DNA , Janus Quinase 1/genética , Janus Quinase 1/metabolismo , Leucemia de Células B/metabolismo , Animais , Linfócitos B/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Janus Quinase 3/metabolismo , Leucemia de Células B/genética , Leucemia de Células B/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Proto-Oncogênicas c-ets/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transativadores/genética , Transativadores/metabolismo
4.
Nat Commun ; 11(1): 3194, 2020 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-32581241

RESUMO

Ph+ acute lymphoblastic leukemia (ALL) is characterized by the expression of an oncogenic fusion kinase termed BCR-ABL1. Here, we show that interleukin 7 receptor (IL7R) interacts with the chemokine receptor CXCR4 to recruit BCR-ABL1 and JAK kinases in close proximity. Treatment with BCR-ABL1 kinase inhibitors results in elevated expression of IL7R which enables the survival of transformed cells when IL7 was added together with the kinase inhibitors. Importantly, treatment with anti-IL7R antibodies prevents leukemia development in xenotransplantation models using patient-derived Ph+ ALL cells. Our results suggest that the association between IL7R and CXCR4 serves as molecular platform for BCR-ABL1-induced transformation and development of Ph+ ALL. Targeting this platform with anti-IL7R antibody eliminates Ph+ ALL cells including those with resistance to commonly used ABL1 kinase inhibitors. Thus, anti-IL7R antibodies may provide alternative treatment options for ALL in general and may suppress incurable drug-resistant leukemia forms.


Assuntos
Proteínas de Fusão bcr-abl/metabolismo , Subunidade alfa de Receptor de Interleucina-7/metabolismo , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Receptores CXCR4/metabolismo , Animais , Linhagem Celular Tumoral , Transformação Celular Neoplásica/efeitos dos fármacos , Feminino , Proteína Forkhead Box O1/metabolismo , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Proteínas de Fusão bcr-abl/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Interleucina-7/farmacologia , Subunidade alfa de Receptor de Interleucina-7/antagonistas & inibidores , Subunidade alfa de Receptor de Interleucina-7/genética , Camundongos , Camundongos Mutantes , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Receptores CXCR4/genética , Transdução de Sinais/efeitos dos fármacos
5.
PLoS One ; 15(5): e0231588, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32421698

RESUMO

We have recently established a protocol to grow wildtype human oral mucosa organoids. These three-dimensional structures can be maintained in culture long-term, do not require immortalization, and recapitulate the multilayered composition of the epithelial lining of the oral mucosa. Here, we validate the use of this model to study the effect of Leucovorin (LV) on Methotrexate (MTX)-induced toxicity. MTX is a chemotherapeutic agent used in the treatment of pediatric acute lymphoblastic leukemia. Although effective, the use of MTX often results in severe side-effects, including oral mucositis, which is characterized by epithelial cell death. Here, we show that organoids are sensitive to MTX, and that the addition of LV reduces MTX toxicity, in both a concentration- and timing-dependent manner. Additionally, we show that a 24 hour 'pretreatment' with LV reduces MTX-induced cell death, suggesting that such a pretreatment could decrease mucositis in patients. Taken together, we provide the first in vitro model to study the effect of MTX on wildtype oral mucosa cells. Our findings underscore the relevance of the clinically applied LV regimen and highlight the potential of this model to further optimize modifications in dosing and timing of Leucovorin on oral mucosa cells.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Apoptose/efeitos dos fármacos , Mucosa Bucal/efeitos dos fármacos , Organoides/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Estomatite/patologia , Adolescente , Criança , Humanos , Técnicas In Vitro , Leucovorina/administração & dosagem , Metotrexato/administração & dosagem , Mucosa Bucal/patologia , Técnicas de Cultura de Órgãos , Organoides/efeitos dos fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Estomatite/induzido quimicamente
6.
Medicine (Baltimore) ; 99(18): e20082, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32358392

RESUMO

BACKGROUND: To systematic review the efficacy and safety of 6-thioguanine (6-TG) in the substitute of 6-mercaptopurine (6-MP) in the treatment for patients with childhood acute lymphoblastic leukemia (ALL) in the maintenance phase, and to explore its clinical application value. It provides theoretical guidance for the maintenance treatment of ALL in children from the perspective of evidence-based medicine. METHODS: By means of computer retrieval, Chinese databases were searched: Chinese Biomedical Database (CBM), China national knowledge internet (CNKI), Chongqing Weipu Database (VIP), and Wanfang Database; Foreign databases: PubMed, The Cochrane Library, Embase, and Web of Science were applied to find out randomized controlled trial (RCT) for 6-TG in childhood acute lymphoblastic leukemia. By manual retrieval, documents without electronic edition and related conference papers were retrieved. The retrieval time ranges from the beginning of the establishment of the databases to September 1st, 2019. According to the inclusion, and exclusion criteria by 3 researchers, the literature screening, data extraction, and research methodological quality evaluation were completed. RevMan 5.3 software was applied to evaluate the quality of the included literature, and Stata 12.0 software was used to conduct meta-analysis of the outcome indicators of the included literature. RESULTS: This study systematically evaluated the efficacy and safety of 6-TG in the substitute of 6-MP as a maintenance drug for childhood acute lymphoblastic leukemia. Through the key outcome indicators, this study is expected to draw a scientific, practical conclusion for 6-TG in the treatment of childhood acute lymphoblastic leukemia. This conclusion will provide evidence-based medical direction for clinical treatment. CONCLUSION: The efficacy and safety of 6-TG in the substitute of 6-MP in the maintenance treatment of childhood acute lymphoblastic leukemia will be confirmed through this study. The conclusions will be published in relevant academic journals. REGISTRATION: PROSPERO (registration number is CRD42020150466).


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Tioguanina/uso terapêutico , Adolescente , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/efeitos adversos , Criança , Pré-Escolar , Substituição de Medicamentos , Humanos , Lactente , Mercaptopurina/uso terapêutico , Metástase Neoplásica , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Recidiva , Projetos de Pesquisa , Tioguanina/administração & dosagem , Tioguanina/efeitos adversos
7.
Pediatr Blood Cancer ; 67(7): e28388, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32383821

RESUMO

BACKGROUND: Cardiac autonomic dysfunction (CAD) is possible following treatment for childhood cancer. The aims of our analyses were to compare the prevalence of CAD between adult survivors of childhood acute lymphoblastic leukemia and controls, compare exercise response among survivors with and without CAD, and identify treatment-related risk factors for CAD. PROCEDURE: Participants were treated for childhood acute lymphoblastic leukemia at St. Jude Children's Research Hospital between 1980 and 2003 (N = 338). A comparison group matched for race/ethnicity, age, and sex was also recruited (N = 325). Resting heart rate (HR) was assessed via electrocardiogram, and heart rate recovery (HRR) and exercise capacity were evaluated with submaximal cardiopulmonary exercise testing. RESULTS: CAD was present in 33.7% of survivors and 27.6% of controls (P = 0.09). Although mean resting HR did not differ between survivors and controls (74 ± 12 vs 72 ± 12 beats per minute (bpm), P = 0.07), survivors had lower mean HRR than controls (22 ± 9 vs 25 ± 10 bpm; P < 0.001). Survivors with CAD had lower peak exercise tolerance (25.7 ± 6.5 vs 21.2 ± 4.9 mL/kg/min, P < 0.001) than those without. Survivors treated with cyclophosphamide in combination with vincristine ≥38 mg/m2 and/or glucocorticoids ≥10 000 mg/m2 were 1.56 (95% CI 1.09-2.24) times more likely to have CAD than those without this treatment. Obese survivors were 1.78 (95% CI: 1.31-2.40) times more likely to have CAD than nonobese survivors (P < 0.001). CONCLUSION: CAD was present in over one third of survivors and was associated with lower exercise capacity. Obese survivors and those exposed to cyclophosphamide with high doses of vincristine and/or corticosteroids were at greatest risk.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doenças do Sistema Nervoso Autônomo/diagnóstico , Sobreviventes de Câncer/estatística & dados numéricos , Cardiopatias/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Adulto , Doenças do Sistema Nervoso Autônomo/etiologia , Doenças do Sistema Nervoso Autônomo/terapia , Criança , Estudos de Coortes , Exercício Físico , Feminino , Seguimentos , Cardiopatias/etiologia , Cardiopatias/terapia , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Prevalência , Prognóstico , Fatores de Risco , Taxa de Sobrevida
8.
Pediatr Blood Cancer ; 67(7): e28306, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32391957

RESUMO

Relapse-enriched somatic variants drive drug resistance in childhood acute lymphoblastic leukemia. We used digital droplet-based polymerase chain reaction to establish whether relapse-enriched mutations in emerging subclones could be detected in peripheral blood samples before frank relapse. Although limitations in sensitivity for some probes hindered detection of certain variants, we successfully detected variants in NT5C2 and PRPS1 at a fractional abundance of 0.005% to 0.3%, 41 to 116 days before relapse. As mutations in both these genes confer resistance to thiopurines, early detection protocols using peripheral blood could be implemented to preemptively alter maintenance therapy to extinguish resistant clones before overt relapse.


Assuntos
Biomarcadores Tumorais/sangue , Células Clonais/patologia , Mutação , Recidiva Local de Neoplasia/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Criança , Células Clonais/metabolismo , Terapia Combinada , Estudos de Viabilidade , Feminino , Seguimentos , Humanos , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/terapia , Reação em Cadeia da Polimerase , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Prognóstico
9.
Ann Hematol ; 99(7): 1643-1653, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32458063

RESUMO

To explore the incidence, risk factors, and outcomes of central nervous system (CNS) relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for acute lymphoblastic leukemia (ALL) and to compare the differences in CNS relapse between haploidentical donor HSCT (HID-HSCT) and HLA-identical sibling donor HSCT (ISD-HSCT). We performed a retrospective nested case-control study on patients with CNS relapse after allo-HSCT. The cumulative incidence of CNS relapse was 4.06% after allo-HSCT in ALL, with a significantly poor prognosis. The incidence was 3.91% and 5.36% in HID-HSCT and ISD-HSCT, respectively (p = .227). Among the patients with CNS relapse, the overall survival (OS) at 3 years was 56.2 ± 6.8% in the HID-HSCT subgroup and 76.9 ± 10.2% in the ISD-HSCT subgroup (p = .176). The 3-year cumulative incidence of systemic relapse was also comparable between the two subgroups (HID-HSCT, 40.6 ± 7.4%; ISD-HSCT, 13.3 ± 8.7%, respectively, p = .085). Younger age (p = .045), T-ALL (p = .035), hyperleukocytosis at diagnosis (p < .001), advanced disease stage at transplant (p < .001), pre-HSCT CNS involvement (p < .001), and absence of chronic graft vs host disease (cGVHD) (p < .001) were independent risk factors for CNS relapse after allo-HSCT. In conclusion, CNS relapse was a significant complication after allo-HSCT in ALL and was associated with poor prognosis. The incidences and outcomes were comparable between HID-HSCT and ISD-HSCT.


Assuntos
Neoplasias do Sistema Nervoso Central/epidemiologia , Neoplasias do Sistema Nervoso Central/secundário , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Irmãos , Transplante Haploidêntico , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Pré-Escolar , Doenças em Gêmeos/epidemiologia , Doenças em Gêmeos/terapia , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/estatística & dados numéricos , Teste de Histocompatibilidade/métodos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Recidiva , Estudos Retrospectivos , Doadores de Tecidos/estatística & dados numéricos , Transplante Haploidêntico/efeitos adversos , Transplante Haploidêntico/estatística & dados numéricos , Transplante Homólogo/efeitos adversos , Transplante Homólogo/estatística & dados numéricos , Resultado do Tratamento , Gêmeos Monozigóticos/estatística & dados numéricos , Adulto Jovem
10.
Cancer Immunol Immunother ; 69(10): 2139-2145, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32451682

RESUMO

B-cell malignancies can potentially be cured by CD19 chimeric antigen receptor (CAR) T-cell therapy. Although clinical response rates can be up to 93% in acute lymphoblastic leukemia, treatment-related antigen loss and lack of therapeutic persistence contribute to disease relapse. These shortcomings of current CAR T-cell therapy indicate the need for biologically relevant target selection and for improving the efficacy and persistence of the CAR T cells, which we have addressed by developing a novel B-cell activating factor receptor (BAFF-R) CAR T-cell therapy with improved therapeutic persistence. BAFF-R is a B-cell survival receptor and highly expressed in B-cell malignancies. We developed a prototype CAR T cell that efficiently and specifically eliminated BAFF-R expressing human B-cell tumors in several xenogeneic mouse models, including models of CD19 antigen loss. We proceeded with translational development and validation of BAFF-R CAR T cells produced under current good manufacturing practices (cGMP). cGMP-grade BAFF-R CAR T cells underwent in vitro and in vivo validation in established models to confirm that the potency and efficacy of our original research modeling was replicated. Food and Drug Administration required release testing was performed to ensure our BAFF-R CAR T cells meet specifications for new drug products. Completing and exceeding these requirements, the data fully support the initiation of a first-in-human Phase 1 trial for BAFF-R-positive relapsed/refractory (r/r) B-ALL.


Assuntos
Antígenos CD19/imunologia , Receptor do Fator Ativador de Células B/antagonistas & inibidores , Receptor do Fator Ativador de Células B/imunologia , Linfócitos B/imunologia , Imunoterapia Adotiva/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Animais , Ensaios Clínicos Fase I como Assunto , Humanos , Camundongos , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia
11.
J Cancer Res Ther ; 16(1): 30-33, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32362606

RESUMO

Background: Interleukin 6 (IL6) has been suggested to be a valuable prognostic marker in chronic myeloid leukemia (CML). IL6 is a pleiotropic cytokine and plays an important role in immune response, hematopoiesis, and acute phase response. IL6 is regarded as a prominent target for clinical interventions. Objective: The aim of the present study was to investigate the serum levels of IL6 in CML to provide greater insight to their role in disease transformation in Indian patients. Materials and Methods: A total of 50 CML cases and 10 acute lymphocytic leukemia (ALL) cases along with 20 healthy controls were included in the study between 2015 and 2016. About 4 mL blood samples were collected from all cases in plain vial and serum was separated. Levels of IL6 were determined in all cases by enzyme-linked immunosorbent assay. Results: The study suggests that both ALL and CML are associated with significantly elevated serum IL6 level than the healthy control group. Mean levels of serum IL6 are 223.4 ± 53.403 pg/mL in CML, 71.020 ± 29.549 pg/mL in ALL, and 5.360 ± 0.467 pg/mL in healthy control group. Serum IL6 correlated with different phases of CML. Mean IL6 levels are 50.93 ± 29.37 pg/mL in chronic phase (CP), 69.02 ± 22.60 pg/mL in accelerated phase (AP), and 652.77 ± 124.62 pg/mL in blast crisis (BC) phase of CML. In compared to CP and AP, in BC, IL-6 is significantly elevated ( P = 0.00 and 0.00, respectively); however, we did not find a significant difference in IL-6 serum levels between CP and AP ( P = 0.703). Conclusion: Study suggests that the detection of IL6 level in newly diagnosed patient can predict the severity of the disease. There might be association of level of IL6 with the disease transformation.


Assuntos
Crise Blástica/patologia , Interleucina-6/sangue , Leucemia Mielogênica Crônica BCR-ABL Positiva/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Adolescente , Adulto , Idoso , Crise Blástica/metabolismo , Criança , Pré-Escolar , Citocinas/sangue , Progressão da Doença , Feminino , Humanos , Índia , Lactente , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Prognóstico , Adulto Jovem
12.
J Cancer Res Ther ; 16(1): 105-109, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32362618

RESUMO

Background: Aberrant phenotypes in acute leukemia have been reported with varying frequencies in independent studies and their association with prognostic factors is still a matter of debate. Aim: This study aims to identify the frequency of aberrant immunophenotypes in de novo acute myeloid leukemia (AML) and to evaluate their association with initial clinical and hematological features. Materials and Methods: A total of 181 patients of de novo AML were included during the time (July 2010-June 2012). The immunophenotype of all cases of AML was studied by using flow cytometry. Results: Aberrant lymphoid antigen expression was seen in 43.1% cases. Most frequent aberrant lymphoid antigen was CD7, seen in 26.5% cases. All French-American-British (FAB) subtypes except AML-M3 expressed aberrant lymphoid antigens. The expression was most common in AML-M4 in the current study. CD34 expression in AMLs was significantly associated with the expression of aberrant lymphoid antigens. Lymphoid antigen expression in adult AML was significantly associated with higher white blood cell (WBC) count (>50,000/mm3) and higher number of peripheral blasts (>70%). Conclusion: In summary, CD7 is the most common aberrant lymphoid antigen expressed in AML. FAB subtype AML-M3 is usually not associated with aberrant lymphoid antigen expression. AML cases with CD34 positivity are more likely to express aberrant lymphoid markers. The current study also supports that aberrant lymphoid antigen expression in adult AML is associated with adverse presenting hematological features (WBC count >50,000/mm3, peripheral blasts >70%). Pediatric Ly + AML cases are not associated with adverse presenting clinical and biological features.


Assuntos
Antígenos de Neoplasias/imunologia , Biomarcadores Tumorais/imunologia , Imunofenotipagem/métodos , Leucemia Mieloide Aguda/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD34/imunologia , Antígenos CD34/metabolismo , Antígenos CD7/imunologia , Antígenos CD7/metabolismo , Antígenos de Neoplasias/metabolismo , Biomarcadores Tumorais/metabolismo , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/metabolismo , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Prognóstico , Estudos Prospectivos , Centros de Atenção Terciária , Adulto Jovem
13.
J Cancer Res Clin Oncol ; 146(8): 2143-2152, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32346759

RESUMO

PURPOSE: We aimed at describing for the first time peripheral small-fiber neurotoxicity and pain sensitization in survivors of pediatric acute lymphoblastic leukemia after stem cell transplantation (SCT). METHODS: In a cross-sectional, retrospective, single-center study, we assessed 25 relapse-free long-term survivors (median age at SCT: 11 ± 4.9 years; median time between SCT and testing: 8.25 years, 19 males) using a reduced version of the pediatric-modified total neuropathy score for clinical assessment and Quantitative Sensory Testing (QST). INCLUSION CRITERIA: [Formula: see text] 6 years old at testing, [Formula: see text] 18 years old at time of SCT, [Formula: see text] 1 year between SCT and testing. RESULTS: Nine patients (36%) had peripheral neuropathy as defined by the clinical red-pmTNS (≥ 4). The QST parameters mechanical pain sensitivity, mechanical detection threshold, thermal sensory limen, vibration detection threshold and pressure pain threshold were significantly abnormal in the survivor cohort (p < 0.0038). Except for one, all survivors showed at least one abnormal QST parameter. When using QST, signs of small and large fiber dysfunction were present in 22 (88%) and 17 (68%) survivors, respectively. More than half of all survivors were found to experience pathologic sensitization to pain. CONCLUSIONS AND IMPLICATIONS FOR CANCER SURVIVORS: Survivors of pediatric acute lymphoblastic leukemia after SCT are at high risk for long-term peripheral neuropathy with a dominating small-fiber and pain sensitization pattern.


Assuntos
Dor do Câncer/etiologia , Sobreviventes de Câncer , Sensibilização do Sistema Nervoso Central , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Neuropatia de Pequenas Fibras/etiologia , Adolescente , Adulto , Dor do Câncer/diagnóstico , Criança , Pré-Escolar , Estudos de Coortes , Estudos Transversais , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Masculino , Estudos Retrospectivos , Neuropatia de Pequenas Fibras/diagnóstico , Adulto Jovem
14.
Georgian Med News ; (299): 39-43, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32242842

RESUMO

Cancer in children, and mainly the acute lymphoblastic leukemia (ALL), is considered as one of the leading public health problems in Mexico. Glucocorticoids used to treat ALL may cause suppression of the hypothalamic-pituitary-adrenal axis. The aim of the present study was to determine whether cortisol levels in saliva of the patients with ALL are related to the response to the remission induction therapy. The authors have conducted a clinical, prospective and comparative study. The Mann-Whitney U test was used to compare the variables values by gender or type of evolution. According to the patients' evolution, ROC curves were made for salivary cortisol levels and uric acid. An absolute value of 1000 blasts in peripheral blood count after a week of prednisone regimen was defined as a satisfactory response to the treatment. Review of the data has shown that area under the salivary cortisol levels' curve (AUC) was greater than that under the uric acid levels', as a predictor of a poor response to the remission induction. There were no statistically significant gender-associated differences in any variables except in erythrocytes. High levels of cortisol in saliva at the time of diagnosis of ALL seem to be of bad prognosis of the response to the remission induction therapy.


Assuntos
Hidrocortisona/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Saliva/química , Criança , Humanos , Hidrocortisona/análise , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Estudos Prospectivos , Indução de Remissão , Saliva/metabolismo
15.
Pediatr Blood Cancer ; 67(6): e28280, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32277801

RESUMO

Acute lymphoblastic leukemia (ALL) is often composed of numerous subclones. Here we test whether the clonal composition of the blood is representative of the bone marrow at leukemia onset. Using ultra-deep IGH sequencing, we detected 28 clones across 16 patients; 5/28 were only in the marrow. In four patients, the most abundant clones differed between sites, including three in which the dominant medullary clones were minimally detectable in the blood. These findings demonstrate that the peripheral blood often underrepresents the genetic heterogeneity in a B-ALL and highlight the potential impact of tissue site selection on the detection of minor subclones.


Assuntos
Biomarcadores Tumorais/genética , Medula Óssea/patologia , Evolução Clonal , Células Clonais/patologia , Cadeias Pesadas de Imunoglobulinas/genética , Leucócitos Mononucleares/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Adolescente , Adulto , Medula Óssea/metabolismo , Criança , Pré-Escolar , Células Clonais/metabolismo , Feminino , Seguimentos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Prognóstico
16.
Pediatr Blood Cancer ; 67(7): e28244, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32323890

RESUMO

It is unclear if dosing intervals for Erwinase can be extended with intramuscular (i.m.) versus intravenous (i.v.) dosing. Children with acute lymphoblastic leukemia received Erwinase at 30 000-42 000 IU/m2 i.v. or i.m. I.m. Erwinase (n = 22) achieved activity above 0.1 IU/mL for longer than i.v. Erwinase (n = 33) (3.4 vs 2.9 days, P = 0.0007). With 30 000 IU/m2 Monday, Wednesday, Friday, more patients achieved adequate concentrations over the weekend with i.m. vs i.v. dosing (P = 5 × 10-36 ). A schedule with i.v. doses on Monday and Wednesday and i.m. doses on Friday of 30 000 IU/m2 maintained activity > 0.1 IU/mL over the weekend in 80% of patients.


Assuntos
Asparaginase/administração & dosagem , Asparaginase/sangue , Erwinia/enzimologia , Injeções Intramusculares/métodos , Injeções Intravenosas/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Antineoplásicos/administração & dosagem , Antineoplásicos/sangue , Criança , Seguimentos , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/enzimologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia
18.
Life Sci ; 249: 117532, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32151689

RESUMO

AIMS: B-lineage acute lymphoblastic leukemia (B-ALL) is most common in children. We had reported heat shock protein 90 (Hsp90) over-expressed in high risk B-ALL children. 17-DMAG is a water soluble Hsp90 inhibitor, which was proved to be effective for advanced solid tumors and hematological malignancy. However, there is little research on its application in newly diagnosed B-ALL. And the detailed mechanism is seldom discussed. MAIN METHODS: Primary blast cells from 24 newly diagnosed B-ALL pediatric patients and two B-ALL cell lines were used in this study. Cell viability was measured by MTS assay. Apoptosis was evaluated by flow cytometry after annexin V-PI double staining. Protein expression was detected by immunoblotting analysis and immunofluorescence imaging. Cyto-ID autophagy detection assay was performed to show the autophagosomes and LysoTracker labeling to show the lysosomes. Gene knockdown was performed by RNA interference, and mRNA expression was measured by RT-qPCR. KEY FINDINGS: We showed 17-DMAG induced apoptosis in newly diagnosed B-ALL blasts and cell lines effectively. 17-DMAG induced heat shock cognate protein 70 (Hsc70) expression significantly. High expressed Hsc70 inhibited cathepsin D post-transcriptionally to impede the autophagic flux, which lead to the cell death. SIGNIFICANCE: Our work added new information towards understanding the molecular pharmacology of 17-DMAG, and suggested the newly diagnosed B-ALL pediatric patients might be benefited from 17-DMAG. Furthermore, we proved Hsc70 participated in the mechanism of cell death 17-DMAG leading in B-ALL.


Assuntos
Autofagia/efeitos dos fármacos , Benzoquinonas/farmacologia , Proteínas de Choque Térmico HSC70/biossíntese , Lactamas Macrocíclicas/farmacologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Apoptose/efeitos dos fármacos , Catepsina D/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Processamento Pós-Transcricional do RNA
19.
Pediatr Blood Cancer ; 67(6): e28224, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32196935

RESUMO

AIM: The aim of the study was to assess long-term consequences of central nervous system (CNS) prophylaxis in patients with high-risk ALL (HR-ALL) treated according to ALL IC-BFM 2002 and to compare observed abnormalities in patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) with those who received only prophylactic CNS irradiation (12 Gy) and with control group. PATIENTS AND METHODS: We studied 29 patients with HR-ALL in CR1 after treatment according to protocol ALL IC-BFM 2002 (14 with allo-HSCT conditioned with fractionated total body irradiation [FTBI] and 15 without HSCT) and 16 children with newly diagnosed ALL (control group). The median time from therapy completion to evaluation was 5 years. To assess brain status, volumetric T1-weighted sequences of magnetic resonance imaging were used. Neuropsychological assessment based on battery neuropsychological tests. RESULTS: Transplanted patients had significantly lower volumes of white and gray matter (P = .048 and P < .001) and also of subcortical structures, including the thalamus (P < .001), the hippocampus (P = .007), the putamen (P = .011), the globus pallidus (P = .001), and the accumbens (P < .001). In addition, these patients had generally lower cognitive performance, especially in vocabulary (P = .011), visuospatial ability (P = .047), executive functions and attention (P = .034; P = .002; P = .048), and processing speed (P = .049 and P = .037). The thalamus volume is correlated with neuropsychological performance in verbal functions (P < .001), executive functions (P < .001 and P = .024), and processing speed (P < .001). CONCLUSIONS: In pediatric patients treated for ALL, FTBI-based preparative regimen preceding allo-HSCT causes reduction of subcortical structure volumes and decline in cognitive performance. The observed long-term structural and functional CNS sequelae are significantly more pronounced in transplanted HR-ALL patients than in those treated with prophylactic CNS- radiotherapy only.


Assuntos
Encéfalo/patologia , Disfunção Cognitiva/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Irradiação Corporal Total/efeitos adversos , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Disfunção Cognitiva/patologia , Terapia Combinada , Feminino , Seguimentos , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Prognóstico , Transplante Homólogo
20.
Pediatr Blood Cancer ; 67(6): e28197, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32207557

RESUMO

Fibrin sheath formation around long-term indwelling central venous catheters is common and usually benign. Fibrin sheath can persist after catheter removal and rarely leads to complications. This is a report of three pediatric oncology patients that required cardiac surgery for cardiac embolization of a "ghost" catheter several years after catheter removal. One case required tricuspid valve replacement for complete tricuspid valve destruction and two had erosion through the atrial wall. The severity of these rare complications mandates follow-up of "ghost" catheters in pediatric oncology patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Procedimentos Cirúrgicos Cardíacos/métodos , Cateteres de Demora/efeitos adversos , Embolia/cirurgia , Átrios do Coração/cirurgia , Linfoma não Hodgkin/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Criança , Embolia/etiologia , Embolia/patologia , Átrios do Coração/patologia , Humanos , Linfoma não Hodgkin/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Prognóstico
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