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1.
Medicine (Baltimore) ; 98(23): e15685, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31169671

RESUMO

RATIONALE: Acute lymphoblastic leukemia (ALL) is a malignant disease originating from abnormal proliferation of B or T lymphocytes in bone marrow (BM). Invasion of the pancreas is extremely rare in adults. PATIENT CONCERNS: In this article, we report a case presenting that ALL invades the pancreas, as well as liver, kidney, and duodenum detected by magnetic resonance image. The patient was misdiagnosed as pancreatic tumor at initial since hemogram was unremarkable. DIAGNOSES: The diagnosis of ALL was established based on the endoscopic ultrasonography-guided fine-needle aspiration and bone marrow examination, showing BCR/ABL gene positive. INTERVENTIONS: The patient was actively treated with chemotherapy. Hematological remission was obtained and the lesions in the pancreas disappeared. OUTCOMES: The patient finally died of complication from fungal pneumonia and central nervous system involvement 12 months after diagnosis. LESSONS: Under the context of infection, persistent or intermittent fever and complete blood count are not significant prognoses of pancreatic involvement for adult with ALL. We hope that this case will help hepatobiliary and pancreatic surgeon to be aware of this kind of disease as pancreatic carcinoma and pancreas involvement by ALL have totally different treatment strategy.


Assuntos
Neoplasias Pancreáticas/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Adulto , Diagnóstico Diferencial , Feminino , Humanos , Pâncreas/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia
2.
J Cancer Res Clin Oncol ; 145(8): 1987-1998, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31214760

RESUMO

PURPOSE: Based on the poor prognosis of drug resistance in pediatric acute lymphoblastic leukemia (ALL) and adverse effects of chemotherapy, this study was aimed to evaluate the effect of several herbal extracts on leukemic cells. METHODS: Two subtypes of T- and B-ALL cell lines, followed by ALL primary cells were treated with cinnamon, ginger, and green tea extracts, alone or in combination with methotrexate (MTX). Possible apoptosis was investigated using Annexin-V/PI double staining. Real-time PCR was applied to evaluate the expression levels of related ABC transporters upon combination therapy. RESULTS: The IC50s for cinnamon, ginger and green tea extracts on ALL cell lines were 300 µg/ml, 167 µg/ml and 70 µg/ml, respectively. Surprisingly, the methotrexate (MTX)-resistant sub-line showed more sensitivity to ginger. Combined treatment with ginger and MTX showed synergistic effects on CCRF-CEM, Nalm-6 and ALL primary cells. It was shown that ginger does not impair the high expression levels of ABCA2 or ABCA3 transporter genes in the ALL malignant cells, suggesting other molecular pathways involved in its anticancer potential. CONCLUSION: To the best of our knowledge, this is the first study that reveals the antileukemic effect of ginger extract on both, pediatric ALL cell lines and primary cells.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Gengibre/química , Extratos Vegetais/farmacologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Antineoplásicos Fitogênicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Pré-Escolar , Cinnamomum zeylanicum/química , Terapia Combinada , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Masculino , Metotrexato/administração & dosagem , Fitoterapia , Extratos Vegetais/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Chá/química , Células Tumorais Cultivadas , Adulto Jovem
3.
Indian J Cancer ; 56(2): 180-181, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31062741

RESUMO

Severe hyperlipidemia (>1000 mg/dL) at initial presentation of acute lymphoblastic leukemia (ALL) is rare. Cases of hyperlipidemia during therapy for childhood ALL where they were secondary to L-asparaginase or steroids have been described. This is a case report of a one-and-half-year-old boy who presented to us with fever, abdominal distension, severe pallor, and hepatosplenomegaly. Although his investigations were suggestive of ALL, the initial blood samples were found to be grossly lipemic. The lipid profile was abnormal, showing severe hypertriglyceridemia (serum triglycerides 1552 mg/dL). High-density lipoprotein and low-density lipoprotein levels were low, but there were raised very low-density lipoprotein level and serum lactate dehydrogenase (18117 U/L). The patient was started on induction of remission with careful monitoring of biochemical parameters. Abnormal lipid levels declined gradually with normalization of the levels at the end of one week of chemotherapy. No further complications were encountered during the course of induction of remission.


Assuntos
Hiperlipidemias/sangue , Lipídeos/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Humanos , Hiperlipidemias/complicações , Hiperlipidemias/patologia , Lactente , L-Lactato Desidrogenase/sangue , Lipoproteínas HDL/sangue , Lipoproteínas LDL/sangue , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Indução de Remissão , Triglicerídeos/sangue
4.
J Pediatr Endocrinol Metab ; 32(5): 537-541, 2019 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-31075084

RESUMO

Hematopoietic stem cell transplantation (HSCT) has been newly identified as an etiology underlying acquired lipodystrophy (ALD). We report about two children with leukemia who underwent HSCT and later manifested aberrant fat distributions consistent with acquired partial lipodystrophy (APL). Both patients manifested graft-versus-host disease (GVHD), suggesting that GVHD may trigger lipodystrophy. The patients exhibited diabetic blood glucose patterns in the oral glucose tolerance test (OGTT) with high homeostasis model assessment ratios (HOMA-Rs), hypertriglyceridemia, fatty liver, and decreased serum leptin and adiponectin levels. Both patients were diagnosed with APL with metabolic disease. A review of the data of patients with ALD after HSCT revealed common clinical features, including aberrant fat distribution, impaired glucose tolerance (IGT) or diabetes and dyslipidemia. Based on previous reports and our two cases, we speculate that GVHD in the adipose tissue supports the development of ALD after HSCT. In conclusion, children may develop APL after HSCT. Therefore, evaluations of fat distribution and metabolic disease may be important during the long-term follow-up of these patients.


Assuntos
Fígado Gorduroso/etiologia , Intolerância à Glucose/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hipertrigliceridemia/etiologia , Leucemia Mieloide Aguda/terapia , Lipodistrofia/etiologia , Doenças Metabólicas/etiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Criança , Fígado Gorduroso/patologia , Feminino , Intolerância à Glucose/patologia , Humanos , Hipertrigliceridemia/patologia , Lactente , Leucemia Mieloide Aguda/patologia , Lipodistrofia/patologia , Doenças Metabólicas/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Prognóstico
5.
J Coll Physicians Surg Pak ; 29(6): 549-552, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31133155

RESUMO

OBJECTIVE: To determine the frequency of cytogenetic type and its significance in the prognostic outcome of the pediatric patients in acute lymphoblastic leukemia (ALL), aged 1 to 15 years, and also determine the importance of minimal residual disease (MRD) in the management of the condition. STUDY DESIGN: An observational study. PLACE AND DURATION OF STUDY: Pediatric Oncology Ward, Shaukat Khanum Cancer Hospital, Lahore, from January 2015 to July 2017. METHODOLOGY: Patients aged 1-15 years, diagnosed with ALL, were included. Studied variables were cytogenetic type and MRD outcome in patients with ALL. Patients under one year of age and more than 15 years, or those having comorbidities, were excluded. RESULTS: Total 150 patients' data were retrieved from the Hospital database. One hundred and thirty-three belonged to age 1 to 5 years group (89%) and 17 (11%) were in 5 to 10 years group. The mean age of the patient was 4.3 +3.1 years. One hundred and two (68%) were males; whereas, 48 (32%) were females. Pre B acute lymphoblastic leukemia was diagnosed in 139 (93%) patients and 11(7%) were diagnosed with Pre T acute lymphoblastic leukemia. Standard risk was observed in 120 (80%) patients and 30 (20%) patients were on high risk as per National Cancer Institute (NCI) Guidelines. Regimen A was used in 125 (83.3%), Regimen B in 16 (10.7%), and Regimen C in 9 (6%) patients. BCR-ABL was positive in 2 (1.30%), TEL-AML in 68 (45%), MLL in 5 (3.30%), and normal in 54 (36%). MRD at day 29 was negative in 40 (93%) and positive in 3 (7%). The karyotyping was done in 128 (85%) patients, out of which 68 (53%) were hyperploids, 41 (32%) euploid, and 19 (15%) were hypoploid. Death was observed in 22 (15%) patients. Nineteen (86%) deaths were due to fungal and bacterial sepsis; and disease-related deaths were noted in 3 (14%) patients. CONCLUSION: The role of MRD and cytogenetics in risk assessment has improved in the early prognosis determination.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasia Residual/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Criança , Pré-Escolar , Citogenética , Intervalo Livre de Doença , Feminino , Humanos , Incidência , Lactente , Masculino , Neoplasia Residual/mortalidade , Neoplasia Residual/patologia , Paquistão/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do Tratamento
6.
Blood Coagul Fibrinolysis ; 30(4): 149-155, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31090597

RESUMO

OBJECTIVES: Thromboembolism is one of the most common complications during induction therapy of pediatric acute lymphoblastic leukemia (ALL). Procoagulant microparticles in the circulation may cause thromboembolic events. The aim of our study was to determine the levels of apoptotic, platelet-derived, endothelial-derived, and tissue factor-positive microparticles of children with ALL at diagnosis and during induction therapy. METHODS: Sixteen precursor B-cell ALL cases and 30 healthy children between 1 and 18 years of age were included. Microparticle levels were analyzed from peripheral blood samples at initial diagnosis, on days 12 and 13 (before and after the first L-asparaginase administration), and on day 33 of ALL-BFM 2000 treatment protocol. Microparticle levels were analyzed by using flow cytometry. RESULTS: At initial diagnosis, platelet, endothelial-derived, and tissue factor-positive microparticle levels were significantly high in children with ALL. They increased significantly after prednisone and L-asparaginase administration. Apoptotic microparticle levels were not elevated at diagnosis, but remained high during all induction therapy period. None of the patients had evidence of thromboembolism during induction therapy. CONCLUSION: Our study demonstrated that children with ALL have increased levels of apoptotic, platelet-derived, endothelial-derived, and tissue factor-positive microprticles during induction therapy. Further studies are needed in larger groups of patients in order to evaluate the risk of elevated microprticles for development of thromboembolism during induction therapy period in children with ALL.


Assuntos
Micropartículas Derivadas de Células/química , Micropartículas Derivadas de Células/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Indução de Remissão/métodos , Adolescente , Apoptose , Asparaginase/administração & dosagem , Plaquetas , Criança , Pré-Escolar , Células Endoteliais , Feminino , Humanos , Lactente , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Prednisona/administração & dosagem , Tromboembolia/etiologia , Tromboplastina
7.
Lancet Haematol ; 6(6): e306-e316, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31078468

RESUMO

BACKGROUND: Treatment for childhood acute lymphoblastic leukemia has evolved over the past five decades, with moderation of traditional chemotherapy and radiotherapy and the introduction of targeted immune-based and cellular-based therapies. The affect of these changes on late health outcomes has not been assessed. Using data from the The St Jude Lifetime (SJLIFE) Cohort, we aimed to characterise the magnitude of morbidity and patterns of late health outcomes among survivors of childhood acute lymphoblastic leukaemia treated over time. METHODS: The St Jude Lifetime (SJLIFE) Cohort is a retrospective cohort study with prospective follow-up and ongoing data accrual designed to facilitate longitudinal, clinically-based assessment of health outcomes among survivors of paediatric malignancies. 980 survivors included in this analysis were diagnosed with paediatric acute lymphoblastic leukaemia at St Jude Children's Research Hospital (SJCRH) between Aug 28, 1963, and July 19, 2003, were aged 18 years old and older at enrolment, had a minimum follow-up of 10 years after diagnosis, and completed an initial on-campus SJLIFE assessment as of data cutoff (June 30, 2015). 272 community control participants, matched to survivors on 5-year age blocks in each sex, were recruited for comparison. Cumulative chemotherapy and radiation dose exposures and major medical events during and after therapy were retrieved from the medical records of the survivors. History or physical examination, laboratory analysis, physical fitness, and neurocognitive testing were done. Health conditions were graded according to a modified version of the Common Terminology Criteria for Adverse Events. Neurocognitive domains of attention (Trial Making Test Part A and Conner's Continuous Performance Test-II) and executive function (Trail Making Test Part B, Controlled Oral Word Association Test, and Wechsler Adult Intelligence Scale-III Digit Span Test Backward) were measured and age-adjusted Z scores were calculated. Mean cumulative count was used to calculate the age-standardised cumulative burden of health conditions over time. This cohort study is registered at ClinicalTrials.gov, number NCT00760656. FINDINGS: 980 survivors of acute lymphoblastic leukaemia (50% women, median age at diagnosis 5 years [IQR 3·1-9·1 years], and median time from diagnosis of 30·0 years [22·7-36·3]) had a median age of 35·8 years (29·4-42·9) at assessment compared with 35·1 years (28·7-42·6) for 272 controls. Survivors had significantly more growth hormone deficiency, hypogonadism, and neuropathy than controls. By age 30 years, survivors of acute lymphoblastic leukaemia had, on average, 5·4 (95% CI 5·1-5·8) grade 1-4 health conditions, including 3·2 (2·9-3·4) grade 2-4 health conditions, compared with 2·0 (CI 1·7-2·2) grade 1-4 and 1·2 (1·03-1·4) grade 2-4 health conditions among controls. The cumulative burden of grade 2-4 health conditions involved multiple organ systems for survivors treated on protocols between 1962-91, but after elimination of cranial radiotherapy for children with acute lymphoblastic leukaemia, conditions now predominately include musculoskeletal and endocrine disorders for survivors on protocols between 1991-2007. INTERPRETATION: Although changes in paediatric acute lymphoblastic leukaemia treatment protocols have improved overall survival, the burden of late morbidity remains high for these patients. We show that the pattern of late toxic effects has markedly changed over time, with survivors having a reduction in health conditions that are immediately life-threatening, however, maintaining health status and quality of life for survivors of paediatric acute lymphoblastic leukaemia requires continued medical surveillance, counselling, and lifestyle modifications. FUNDING: US National Cancer Institute and the American Lebanese Syrian Associated Charities.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Adolescente , Adulto , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Seguimentos , Humanos , Hipogonadismo/diagnóstico , Hipogonadismo/epidemiologia , Doenças Hipotalâmicas/diagnóstico , Doenças Hipotalâmicas/epidemiologia , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/psicologia , Estudos Retrospectivos , Fatores de Risco , Sobreviventes/estatística & dados numéricos , Adulto Jovem
8.
Oncol Rep ; 41(6): 3455-3463, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30942469

RESUMO

CD19 chimeric antigen receptor (CAR) T cell therapy has changed the outcomes of relapsed/refractory B­cell leukemia and lymphoma. However, its efficacy in patients with relapsed/refractory non­Hodgkin lymphoma (NHL) has been less impressive compared with that in patients with acute lymphoid leukemia. Furthermore, immune checkpoints have a critical role in the immune system. Several clinical trials have confirmed the dramatic effects of programmed death­1/programmed death­ligand 1 (PD­1/PD­L1) inhibitors in numerous malignancies, but the immune­associated adverse events of PD­1/PD­L1 inhibitors may occur in a number of systems. The aim of the present study was to investigate the combination of CD19 CAR­T cells with a reduced dose of PD­1 inhibitor. This method is expected to overcome the side-effects of PD­1 inhibitors, while maintaining therapeutic efficacy. The findings demonstrated that a reduced dose of PD­1 inhibitor did not affect the transfection rate, proliferation rate or cytokine secretion of CD19 CAR­T cells. An interesting finding of the present study was that the number of PD­1­positive cells CAR­T cells, measured by flow cytometry, declined when they were cultured in vitro, but returned to high levels with gradual prolongation of the co­culture time of CD19 CAR­T cells with lymphoma cells; however, there was no change in the mRNA expression of T cells and CAR­T cells during this process. This phenomenon may be one of the reasons why the curative effect of CAR­T cells on B­cell lymphoma is unsatisfactory compared with B­cell leukemia. The synergistic effect of a reduced­dose PD­1 inhibitor combined with CD19 CAR­T cells from T cells highly expressing PD­1 was confirmed in a mouse trial. Mice in the combined treatment group achieved the longest survival time. In this group, the proportion of CAR­T cells and the level of interleukin­6 were higher compared with those in the CAR­T cell group. In conclusion, a reduced dose of a PD­1 inhibitor combined with CD19 CAR­T cells appears to be a promising treatment option for relapsed/refractory B­NHL exhibiting high PD­1 expression by T cells. This method may achieve good clinical efficacy while reducing the side-effects of PD­1 inhibitors.


Assuntos
Linfoma/terapia , Nivolumabe/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Adulto , Antígenos CD19/genética , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Proliferação de Células/efeitos dos fármacos , Feminino , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Imunoterapia Adotiva/métodos , Linfoma/genética , Linfoma/imunologia , Linfoma/patologia , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Receptor de Morte Celular Programada 1/genética , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Oncol Rep ; 41(6): 3488-3498, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31002356

RESUMO

Epigenetic analysis of the association between the methylation status of the promoter region of the MTRR (5­methyltetrahydrofolate­homocysteine methyltransferase reductase) gene and the risk of acute lymphoblastic leukemia (ALL) in children plays an important role in the early diagnosis, assessment of the malignant degree, treatment and evaluation of the risk of relapse and prognosis of the disease. In the present study, RT­qPCR was used to detect the mRNA levels of the MTRR and MTHFR (methylenetetrahydrofolate reductase) genes in the bone marrow of 20 ALL patients and 20 age­ and sex­matched controls with normal bone marrow. The methylation pattern of the MTRR promoter region in eligible DNA samples was quantitatively analyzed using MALDI­TOF MS. The results indicated that the mRNA expression level of MTRR in the bone marrow from children with ALL was lower than that in the control samples (P<0.05), but no significant difference was detected in the MTHFR gene between the two groups (P>0.05). According to the risk classification of ALL in children with high, medium and low risk, the low­risk group had a higher methylation rate of CpG_6 compared to the medium­risk group. However, the medium­risk group had a higher CpG_46.47 methylation rate compared to the low­risk group. The methylation rates of CpG_26 and CpG_46.47 in the high­risk group were higher than these rates in the low­risk group, while the CpG_42.23.44 methylation rate was lower in the high­risk group than in the low­risk group (P<0.05). The methylation rates at CpG_1, CpG_10, CpG_48 sites, score and the average methylation rate in the ALL­H (high) group (≥50x109/l) were lower than these in the ALL­NH (not high) group (<50x109/l) and the control group (P<0.05). We conclude that abnormal MTRR mRNA expression and the methylation of the MTRR promoter can be used to classify the risk of ALL in children.


Assuntos
Metilação de DNA/genética , Ferredoxina-NADP Redutase/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Prognóstico , Adolescente , Criança , Pré-Escolar , Ilhas de CpG/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Lactente , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Regiões Promotoras Genéticas , Fatores de Risco
10.
Clin Adv Hematol Oncol ; 17(3): 166-175, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30969955

RESUMO

Patients with relapsed or refractory acute lymphoblastic leukemia (R/R ALL) have dismal outcomes, with survival of less than 6 months, and treatment options in the salvage setting have been limited to conventional cytotoxic chemotherapy with minimal activity. Advances in the development of novel targeted therapies have significantly improved outcomes in R/R ALL. Blinatumomab, inotuzumab ozogamicin, and chimeric antigen receptor (CAR) T-cell therapy constitute new treatment modalities that are challenging the historical regimens and paving a new path for treating patients with R/R ALL.


Assuntos
Anticorpos Biespecíficos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Imunoterapia Adotiva/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Feminino , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia
11.
Medicine (Baltimore) ; 98(15): e15204, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30985716

RESUMO

RATIONALE: Second diffuse large B-cell lymphoma (DLBCL) after treatment of acute lymphoblastic leukemia (ALL) is uncommon. To our knowledge, primary middle ear DLBCL which presents CD20-negative and coexpression of MYC and BCL-2 has not been reported yet. PATIENT CONCERNS: A 20-year-old Chinese man complained fever and weakness for 2 months. Subsequently bone marrow morphology and flow cytometry immunophenotype suggested ALL. Administrated with 9 cycles of multiagent combined chemotherapy, he felt right ear progressive hearing loss, otalgia, aural fullness. Otoendoscopic examination revealed a pitchy mass obstructing the right external auditory canal. Then the mass resection was performed for biopsy and immunohistochemistry examination. DIAGNOSIS: The mass was diagnosed as DLBCL which was negative for CD20 and double expression of MYC and BCL-2. INTERVENTIONS: Chemotherapy. OUTCOMES: The patient eventually gave up and died of severe infection. LESSONS: Although intensive chemotherapy has markedly improved the survival of ALL, more and more secondary cancers have been reported. In addition, primary middle ear lymphoma is much rare; hence, it is easy to be misdiagnosed. Furthermore, DLBCL with negative CD20 and double expression of MYC and BCL-2 is aggressive, which is characterized by chemotherapy resistance and inferior survival rates. We discuss this case aiming at raising awareness of tumors secondary to ALL and exploring the appropriate treatment options for the rare DLBCL.


Assuntos
Neoplasias da Orelha/diagnóstico , Orelha Média , Linfoma Difuso de Grandes Células B/diagnóstico , Segunda Neoplasia Primária/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Proteínas Proto-Oncogênicas c-bcl-2/análise , Proteínas Proto-Oncogênicas c-myc/análise , Antígenos CD20/análise , Biomarcadores Tumorais/análise , Diagnóstico Diferencial , Neoplasias da Orelha/química , Neoplasias da Orelha/tratamento farmacológico , Neoplasias da Orelha/patologia , Evolução Fatal , Humanos , Linfoma Difuso de Grandes Células B/química , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/patologia , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adulto Jovem
12.
Asian Pac J Cancer Prev ; 20(4): 1171-1176, 2019 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-31030491

RESUMO

Objective: Chemotherapy is the most widely recognized technique to regard leukemia and also different sorts of human tumors. In any case, tranquilize protection has stayed as the primary test against the adequacy of medications. Besides, having different unfriendly impacts, chemotherapy drugs are getting to be traded by characteristic modalities for growth treatment. In such manner, natural segments, for example, resveratrol and prednisolone have been recognized to sharpen the leukemic cells to modified cell demise through an arrangement of complex procedures. In this investigation, we have analyzed effect of 15, 50 and 100µM of resveratrol and 700µM of prednisolone on the human multidrug protection quality 1 (MDR1) as a notable marker for cell sedate protection. We assessed the impact of resveratrol and prednisolone on MDR1 protein expression in the CCRF-CEM cell line as an agent for intense lymphoblastic leukemia. The investigation was planned to clear up whether. Materials and methods: CCRF-CEM cells linage get under drug treatment with use of resveratrol and prednisolone. Western blot use at 24 and 48 hours with different doses of resveratrol and prednisolone to analysis of MDR1 expression changes. Results: Effect of 15, 50, and 100 micro molar of resveratrol and 700 micro molars of prednisolone on CCRF-CEM cells led to the MDR1 decrease. Western blot use for evaluation of MDR1 protein expression changes. Conclusion: In the present study, we observed that resveratrol and prednisolone, with a dose-dependent effect, can reduce the expression of the MDR1 protein. This reduction of expression demonstrates that resveratrol and prednisolone can overcome to drug resistance created by MDR1.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Apoptose , Proliferação de Células , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Prednisolona/administração & dosagem , Resveratrol/administração & dosagem , Células Tumorais Cultivadas
13.
Mol Cell ; 74(3): 584-597.e9, 2019 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-30905508

RESUMO

V(D)J recombination is essential to generate antigen receptor diversity but is also a potent cause of genome instability. Many chromosome alterations that result from aberrant V(D)J recombination involve breaks at single recombination signal sequences (RSSs). A long-standing question, however, is how such breaks occur. Here, we show that the genomic DNA that is excised during recombination, the excised signal circle (ESC), forms a complex with the recombinase proteins to efficiently catalyze breaks at single RSSs both in vitro and in vivo. Following cutting, the RSS is released while the ESC-recombinase complex remains intact to potentially trigger breaks at further RSSs. Consistent with this, chromosome breaks at RSSs increase markedly in the presence of the ESC. Notably, these breaks co-localize with those found in acute lymphoblastic leukemia patients and occur at key cancer driver genes. We have named this reaction "cut-and-run" and suggest that it could be a significant cause of lymphocyte genome instability.


Assuntos
Instabilidade Genômica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Translocação Genética/genética , Recombinação V(D)J/genética , Animais , Sequência de Bases/genética , Células COS , Cercopithecus aethiops , Cromossomos/genética , DNA/genética , Quebras de DNA de Cadeia Dupla , Células HEK293 , Proteínas de Homeodomínio/genética , Humanos , Camundongos , Células NIH 3T3 , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Recombinases/genética
14.
Mol Med Rep ; 19(5): 4195-4204, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30896872

RESUMO

Regulatory T cells (Tregs) maintain immune homeostasis and modulate tumor­induced neovascularization. However, the mechanisms underlying the role of Tregs in acute lymphoblastic leukemia (ALL) remain to be elucidated. Helios, combined with forkhead box P3, is considered a suitable marker for discriminating functional Tregs. In the present study, a microenvironment was created with a high proportion of Helios+ Tregs in T cell­deficient nude mice to determine the mechanism underlying Tregs expressing Helios in ALL. It was revealed that umbilical cord blood­derived Helios+ Tregs had proliferation and immunosuppression abilities similar to those of normal pediatric Tregs. The accumulation of Helios+ Tregs accelerated leukemogenesis and the infiltration of leukemic cells into the bone marrow. Importantly, a high expression of Helios in Tregs promoted angiogenesis in the bone marrow via the vascular endothelial growth factor (VEGF)A/VEGF receptor 2 (VEGFR2) pathway. Furthermore, the expression of chemokine CC­chemokine ligand 22 (CCL22) in the bone marrow and serum of ALL mice infused with Helioshigh Treg cells was increased. The results demonstrated that Helios promotes the secretion of chemokine CCL22, which may recruit more Tregs into the bone marrow. Increased Helios+ Treg cells promoted angiogenesis in the bone marrow of ALL mice via the VEGFA/VEGFR2 pathway. Therefore, Helios may be a target to manipulate Treg activity in clinical settings.


Assuntos
Quimiocina CCL22/metabolismo , Sangue Fetal/citologia , Neovascularização Patológica/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Linfócitos T Reguladores/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Animais , Medula Óssea/patologia , Humanos , Camundongos , Neovascularização Patológica/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Transdução de Sinais , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/imunologia
15.
Rinsho Ketsueki ; 60(2): 134-136, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-30842381

RESUMO

A 48-year-old Filipino woman underwent umbilical cord blood stem cell transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia under non-remission status. Left aqueous humor puncture was performed owing to the development of left eye pain and exacerbation of anterior eye chamber inflammation 72 days after the transplantation; this revealed the relapse of leukemia in the anterior chamber. Subsequently, the patient tested positive for peripheral blood minimal residual disease. Therefore, doctors should take note that anterior chamber disease may appear as a non-typical relapse of leukemia.


Assuntos
Câmara Anterior/patologia , Neoplasias Oculares/secundário , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Feminino , Humanos , Pessoa de Meia-Idade , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Recidiva
16.
BMC Cancer ; 19(1): 202, 2019 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-30841886

RESUMO

BACKGROUND: The tumor suppressor protein phosphatase and tensin homolog (PTEN) is a key regulator of the PI3K/AKT pathway which is frequently altered in a variety of tumors including a subset of acute B-lymphoblastic leukemias (B-ALL). While PTEN mutations and deletions are rare in B-ALL, promoter hypermethylation and posttranslational modifications are the main pathways of PTEN inactivation. Casein Kinase II (CK2) is often upregulated in B-ALL and phosphorylates both PTEN and DNA methyltransferase 3A, resulting in increased PI3K/AKT signaling and offering a potential mechanism for further regulation of tumor-related pathways. METHODS: Here, we evaluated the effects of CK2 inhibitor CX-4945 alone and in combination with hypomethylating agent decitabine on B-ALL proliferation and PI3K/AKT pathway activation. We further investigated if CX-4945 intensified decitabine-induced hypomethylation and identified aberrantly methylated biological processes after CK2 inhibition. In vivo tumor cell proliferation in cell line and patient derived xenografts was assessed by longitudinal full body bioluminescence imaging and peripheral blood flow cytometry of NSG mice. RESULTS: CX-4945 incubation resulted in CK2 inhibition and PI3K pathway downregulation thereby inducing apoptosis and anti-proliferative effects. CX-4945 further affected methylation patterns of tumor-related transcription factors and regulators of cellular metabolism. No overlap with decitabine-affected genes or processes was detected. Decitabine alone revealed only modest anti-proliferative effects on B-ALL cell lines, however, if combined with CX-4945 a synergistic inhibition was observed. In vivo assessment of CX-4945 in B-ALL cell line xenografts resulted in delayed proliferation of B-ALL cells. Combination with DEC further decelerated B-ALL expansion significantly and decreased infiltration in bone marrow and spleen. Effects in patient-derived xenografts all harboring a t(4;11) translocation were heterogeneous. CONCLUSIONS: We herein demonstrate the anti-leukemic potential of CX-4945 in synergy with decitabine in vitro as well as in vivo identifying CK2 as a potentially targetable kinase in B-ALL.


Assuntos
Antineoplásicos/farmacologia , Caseína Quinase II/antagonistas & inibidores , Epigênese Genética/efeitos dos fármacos , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Biologia Computacional , DNA (Citosina-5-)-Metiltransferases/antagonistas & inibidores , Metilação de DNA , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Humanos , Camundongos , Naftiridinas/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
17.
J Cancer Res Clin Oncol ; 145(5): 1331-1339, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30840196

RESUMO

BACKGROUND: Usually, central nervous system (CNS) involvement in acute lymphoblastic leukemia (ALL) is diagnosed by cytomorphology (CM) of cerebrospinal fluid (CSF) on cytospin slides. Multicolor flow cytometry (MFC) provides the opportunity to detect low numbers of leukemia cells undetectable by CM. The present study aimed at evaluating the clinical significance of MFC for the diagnosis of CNS involvement at initial manifestation of childhood ALL. METHODS: In 155 children with ALL, CSF samples were studied in parallel by CM and MFC. Patients were treated according to protocol ALL-MB-2008 for childhood ALL. The prognostic impact of the leukemia burden in CSF was determined categorizing the findings as positive/negative. In addition, the absolute blast cell count per 1 ml of CSF was studied as a continuous variable. RESULTS: CSF positivity was significantly more frequent using MFC compared with CM (35.3% vs. 15.3% of patients). The outcome of MFC-positive and MFC-negative patients was not different in clinically relevant patient risk groups-CNS1, standard and intermediate-risk groups. Using the quantitative approach, at the threshold level of 20 blasts per ml of CSF, patients could be divided into two groups with a significantly different outcome, irrespective of the clinical risk group, the type of CNS-directed therapy, and the CNS status determined by CM. CONCLUSIONS: Our data do not support the concept of re-stratification and modification of therapy based on qualitative CSF investigation by MFC. However, MFC is a highly sensitive technique of CSF investigation improving the definition of CNS involvement in childhood ALL, and quantitative measurement of blast cells in CSF, if well-organized, can be a useful additional tool for stratification of patients in clinical trials.


Assuntos
Biomarcadores Tumorais , Líquido Cefalorraquidiano , Contagem de Leucócitos , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Adolescente , Criança , Pré-Escolar , Feminino , Citometria de Fluxo , Humanos , Imunofenotipagem , Lactente , Masculino , Metástase Neoplásica , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Prognóstico , Curva ROC , Recidiva , Resultado do Tratamento
18.
Expert Opin Investig Drugs ; 28(5): 411-420, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30916583

RESUMO

INTRODUCTION: Acute lymphoblastic leukemia (ALL) with BCR-ABL1 translocation is an aggressive malignancy that is usually treated with intensive chemotherapy with the possibility of allogeneic stem cell transplantation. The encoded fusion protein may be important for leukemogenesis; clinical studies show that dasatinib has an antileukemic effect in combination with steroids alone or intensive chemotherapy. Areas covered: Relevant publications were identified through literature searches (the used terms being acute lymphoblastic leukemia plus dasatinib) in the PubMed database. We searched for original articles and reviews describing the pharmacology and clinical use of dasatinib in ALL with BCR-ABL1. The mechanism of action, pharmacology and clinical study findings are examined. Expert opinion: Dasatinib is associated with a high complete remission rate in ALL when used alone and in combination with steroids or intensive chemotherapy. However, mutations at T315 and F317 are associated with dasatinib resistance. Overall toxicity has been acceptable in these studies and no unexpected toxicity was observed. It is not known whether the antileukemic effect of dasatinib differs between subsets of BCR-ABL1+ patients or is attributed to inhibition of the fusion protein alone, or a combined effect on several kinases, and whether dasatinib-containing combination treatment should be preferred in these patients instead of other emerging strategies, e.g. monoclonal antibodies.


Assuntos
Dasatinibe/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Adulto , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Dasatinibe/efeitos adversos , Dasatinibe/farmacologia , Resistencia a Medicamentos Antineoplásicos , Drogas em Investigação/efeitos adversos , Drogas em Investigação/farmacologia , Drogas em Investigação/uso terapêutico , Humanos , Mutação , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacologia , Indução de Remissão
19.
Wiad Lek ; 72(1): 133-136, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30796878

RESUMO

The article presents data on classification, diagnostic problems, treatment of acute lymphoblastic leukemia in children. Remaining unresolved problems of protocol chemotherapy complications of acute lymphoblastic leukemia. The presented clinical case of successful treatment of thrombosis of mesenteric vessels in a child with acute lymphoblastic leukemia, which included the stages of thrombolytic therapy and surgical treatment for resection of necrotized part of the ileum.


Assuntos
Mesentério/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Trombose/patologia , Criança , Humanos , Terapia Trombolítica
20.
Ann Hematol ; 98(3): 647-656, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30613837

RESUMO

The 2016 revised World Health Organization (WHO) classification of lymphoid neoplasms included the category of high-grade B cell lymphomas (HGBLs) with combined MYC and BCL2 and/or BCL6 rearrangements (double-hit, DH). However, the clinical features of B cell precursor leukemia (BCP-ALL) that harbor DH genetics remain widely unknown. We performed a retrospective analysis of the German Multicenter Study Group for Adult ALL registry and a literature search for de novo DH-BCP-ALLs. We identified 6 patients in the GMALL registry and 11 patients published in the literature between 1983 and June 2018. Patients of all ages (range, 15-86 years) are affected. There is a high incidence of meningeal disease and other extramedullary disease manifestations. Current treatment approaches are mainly ALL-based and are sufficient to induce first complete remissions, but progression-free survival is only 4.0 months (95% CI, 1.5-6.5 months) and all patients succumb to their disease, once relapsed, with a median survival of 5.0 months (95% CI, 3.1-6.9 months), despite intensive salvage and targeted therapy approaches. Of all patients, only two that attained an initial complete remission were alive at data cutoff. In all cases, the BCL2 gene was rearranged to be in proximity to the IGH locus, whereas MYC had various translocation partners juxtaposed. There was no significant survival difference between IG and non-IG translocation partners (HR, 1.03; 95% CI, 0.33-3.2; p = 0.89). In conclusion, de novo DH-BCP-ALL is an aggressive B cell malignancy with deleterious outcome. Physicians have to be aware of this rare disease subset due to the atypical clinical behavior and especially because latest classification systems do not cover this sub-entity.


Assuntos
Genes bcl-2 , Genes myc , Leucemia-Linfoma Linfoblástico de Células Precursoras/classificação , Proteínas Proto-Oncogênicas c-bcl-6/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Rearranjo Gênico do Linfócito B , Humanos , Infiltração Leucêmica , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Prognóstico , Intervalo Livre de Progressão , Recidiva , Terapia de Salvação , Translocação Genética , Adulto Jovem
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