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1.
JAMA Oncol ; 2020 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-31944221

RESUMO

Importance: A randomized clinical trial is needed to determine whether the second-generation Abl-tyrosine kinase inhibitor dasatinib is more effective than the first-generation inhibitor imatinib mesylate for childhood Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL). Objective: To determine whether dasatinib given at a daily dosage of 80 mg/m2 is more effective than imatinib mesylate at a daily dosage of 300 mg/m2 to improve event-free survival of children with Philadelphia chromosome-positive ALL in the context of intensive chemotherapy without prophylactic cranial irradiation. Design, Setting, and Participants: This open-label, phase 3 randomized clinical trial was conducted at 20 hospitals in China. Enrollment occurred from January 1, 2015, through September 18, 2018, and randomization was stopped on October 4, 2018, when the early stopping criterion of the trial was met. Patients aged 0 to 18 years were recruited. Of the 225 patients with the diagnosis, 35 declined participation and 1 died before treatment, leaving 189 patients available for analysis. Data were analyzed from January 1 through August 4, 2019. Interventions: Patients were randomized to receive daily dasatinib (n = 92) or imatinib (n = 97) continuously for the entire duration of ALL therapy from the time of diagnosis made during remission induction to the end of continuation therapy. Main Outcomes and Measures: The primary outcome was event-free survival, analyzed based on intention to treat. The secondary outcomes were relapse, death due to toxic effects, and overall survival. Results: Among the 189 participants (136 male [72.0%]; median age, 7.8 [interquartile range (IQR), 5.2-11.3] years) and a median follow-up of 26.4 (IQR, 16.3-34.1) months, the 4-year event-free survival and overall survival rates were 71.0% (95% CI, 56.2%-89.6%) and 88.4% (95% CI, 81.3%-96.1%), respectively, in the dasatinib group and 48.9% (95% CI, 32.0%-74.5%; P = .005, log-rank test) and 69.2% (95% CI, 55.6%-86.2%; P = .04, log-rank test), respectively, in the imatinib group. The 4-year cumulative risk of any relapse was 19.8% (95% CI, 4.2%-35.4%) in the dasatinib group and 34.4% (95% CI, 15.6%-53.2%) in the imatinib group (P = .01, Gray test), whereas the 4-year cumulative risk of an isolated central nervous system relapse was 2.7% (95% CI, 0.0%-8.1%) in the dasatinib group and 8.4% (95% CI, 1.2%-15.6%) in the imatinib group (P = .06, Gray test). There were no significant differences in the frequency of severe toxic effects between the 2 treatment groups. Conclusions and Relevance: Intensive chemotherapy including dasatinib at a dosage of 80 mg/m2 per day yielded superior results in the treatment of Philadelphia chromosome-positive ALL compared with imatinib mesylate at a dosage of 300 mg/m2 per day and provided excellent control of central nervous system leukemia without the use of prophylactic cranial irradiation. Trial Registration: Chinese Clinical Trial Registry: ChiCTR-IPR-14005706.

2.
Blood ; 135(1): 41-55, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31697823

RESUMO

To study the mechanisms of relapse in acute lymphoblastic leukemia (ALL), we performed whole-genome sequencing of 103 diagnosis-relapse-germline trios and ultra-deep sequencing of 208 serial samples in 16 patients. Relapse-specific somatic alterations were enriched in 12 genes (NR3C1, NR3C2, TP53, NT5C2, FPGS, CREBBP, MSH2, MSH6, PMS2, WHSC1, PRPS1, and PRPS2) involved in drug response. Their prevalence was 17% in very early relapse (<9 months from diagnosis), 65% in early relapse (9-36 months), and 32% in late relapse (>36 months) groups. Convergent evolution, in which multiple subclones harbor mutations in the same drug resistance gene, was observed in 6 relapses and confirmed by single-cell sequencing in 1 case. Mathematical modeling and mutational signature analysis indicated that early relapse resistance acquisition was frequently a 2-step process in which a persistent clone survived initial therapy and later acquired bona fide resistance mutations during therapy. In contrast, very early relapses arose from preexisting resistant clone(s). Two novel relapse-specific mutational signatures, one of which was caused by thiopurine treatment based on in vitro drug exposure experiments, were identified in early and late relapses but were absent from 2540 pan-cancer diagnosis samples and 129 non-ALL relapses. The novel signatures were detected in 27% of relapsed ALLs and were responsible for 46% of acquired resistance mutations in NT5C2, PRPS1, NR3C1, and TP53. These results suggest that chemotherapy-induced drug resistance mutations facilitate a subset of pediatric ALL relapses.

3.
Zhongguo Dang Dai Er Ke Za Zhi ; 21(11): 1073-1078, 2019 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-31753087

RESUMO

OBJECTIVE: To study the clinical effect of the SCMC APL-2010 regimen in the treatment of acute promyelocytic leukemia (APL) in children. METHODS: A retrospective analysis was performed for the clinical data of 44 children with APL who received treatment with the SCMC APL-2010 regimen between April 2010 and July 2016. The Kaplan-Meier survival analysis was used to evaluate event-free survival (EFS) rate and overall survival (OS) rate. RESULTS: Of the 44 children with APL, 42 (95%) achieved a complete remission (CR) after one course of treatment and 1 achieved CR after two courses of treatment, with an overall CR rate of 98%. The 9-year EFS and OS rates were 96%±3% and 97.7%±2.2% respectively. As for adverse events, 41 (93%) had infection, 29 (66%) had granulocyte reduction, 12 (27%, 1 died) had differentiation syndrome, 16 (36%) had liver dysfunction, 12 (27%) had adverse gastrointestinal reactions, and 7 (16%) had QT prolongation, 1 (2%) had orchitis, and no secondary neoplasm was observed. CONCLUSIONS: Children with APL receiving the SCMC APL-2010 regimen have a good prognosis and can achieve a long-term survival, while treatment-related infection is commonly seen.


Assuntos
Leucemia Promielocítica Aguda , Protocolos de Quimioterapia Combinada Antineoplásica , Criança , Intervalo Livre de Doença , Humanos , Masculino , Indução de Remissão , Estudos Retrospectivos , Resultado do Tratamento , Tretinoína
4.
Haematologica ; 2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31467124

RESUMO

Hematopoiesis is a finely regulated process in vertebrates under both homeostatic and stress conditions. By whole exome sequencing we have studied the genomics of acute lymphoid leukemia patients who needed multiple red blood cell transfusions after intensive chemotherapies. ARHGEF12, encoding a RhoA guanine nucleotide exchange factor, was found associated with chemotherapy-induced anemia by genome-wide association study analyses. A single nucleotide polymorphism (SNP) of ARHGEF12 located in an intron predicted to be a GATA1 binding site, rs10892563, is significantly associated with patients who need red blood cell transfusion (P=3.469E-03, odds ratio 5.864). A luciferase reporter assay revealed that this SNP impairs GATA1 mediated trans-regulation of ARHGEF12, and quantitative PCR studies confirmed that the homozygotes status is associated with ~61% reduction of ARHGEF12 expression (P=0.0088). Consequently, erythropoiesis was affected at the pro-erythroblast phase in the patients. A role of ARHGEF12 and its homologs in erythroid differentiation was confirmed in human K562 cells, mouse 32D cells and primary murine bone marrow cells. We further demonstrated in zebrafish by morpholino-mediated knockdown and CRISPR/Cas9-mediated knockout of arhgef12 that its reduction resulted in erythropoiesis defects. The p38 kinase pathway was affected by the ARHGEF12-RhoA signaling in K562 cells, and consistently, the arhgef12-rhoA-p38 pathway was also shown to be important for erythroid differentiation in zebrafish as active rhoA or p38 readily rescued the impaired erythropoiesis caused by arhgef12 knocking down. Finally, ARHGEF12 mediated p38 activity also appeared to be involved in phenotypes of patients of the rs10892563 homozygous genotype. Our findings present a novel SNP of ARHGEF12 that may involve ARHGEF12-RhoA-p38 signaling in erythroid regeneration in acute lymphoblastic leukemia patients after chemotherapy.

5.
Cancer Res Treat ; 2019 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-31352772

RESUMO

Purpose: The presentations and geographic incidence of pediatric non-Hodgkin lymphoma differ from those of adults. This study delineated the characteristics and outcomes of pediatric NHL in East Asia. Material and Methods: Medical records of 749 pediatric patients with NHL treated at participating institutions in mainland China, Japan, Korea, and Taiwan from January 2008 to December 2013 were reviewed. Demographic and clinical features, survival outcomes, and putative prognostic factors were analyzed. Results: Five hundred thirty patients (71%) were male. The most common pathologic subtypes were Burkitt lymphoma (BL) (36%). Six hundred seven (81%) patients had advanced diseases at diagnosis. The 5-year overall survival (OS) and event-free survival (EFS) rates were 89% and 84%. The 5-year EFS rates of BL, LL and DLBCL were 88%, 88%, and 89%, and those of ALCL and peripheral T-cell lymphoma (PTCL) were 71% and 56% (P<0.001). CNS involvement, high lactate dehydrogenase level (>250 IU/mL), and advanced disease at diagnosis (≥ stage III) were associated with poor outcomes (P<0.05). ALCL and PTCL relapsed more frequently than other pathologic subtypes (P<0.001). Conclusion: In East Asia, PTCL was more frequent than in Western countries, and BM involvement did not affect treatment outcome. This international study should motivate future collaborative study on NHL in East Asia.

6.
World J Pediatr ; 15(6): 572-579, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31342464

RESUMO

BACKGROUND: Although localized neuroblastoma has a good prognosis, some cases have undergone treatment failure or recurrence. Apart from biologic features such as MYCN status, we wondered whether some characteristics of growing tumors are prognostic, such as a well-encapsulated mass without infiltration of vital organs. We analyzed the diagnostic utility of image-defined risk factors (IDRFs) to predict successful treatment and prognosis. The overall goal was to achieve maximum cure rates for patients with localized neuroblastoma through a better understanding of clinical characteristics. METHODS: We retrospectively reviewed the images of patients with localized neuroblastoma who were enrolled between June 1998 and December 2012 at a single institution in Shanghai, China. Unequivocal categorization regarding IDRFs was available in 67 patients. IDRF was assessed at diagnosis and after four cycles of neoadjuvant chemotherapy, on average. The median follow-up period was 84 months (range: 48-132 months) after diagnosis. RESULTS: MRI and CT indicated a total of 177 IDRFs in these 67 patients. Logistic regression analysis revealed a highly significant negative correlation between the numbers of IDRFs and the possibility of complete removal of neuroblastoma. Intraspinal extension of the tumor, compression of the trachea, and encasement of the main artery in localized neuroblastoma were predictors for incomplete tumor resection. According to univariate analysis, ≥ 4 IDRFs and intraspinal extension of the tumor were significant indicators of poor prognosis. CONCLUSIONS: The number of IDRFs was useful in predicting surgical outcome and event-free survival. The number of IDRFs should be considered in protocol planning, instead of IDRF presence or absence.

8.
Acta Haematol ; 142(3): 162-170, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31091521

RESUMO

Aplastic anemia (AA) is a hematologic disease characterized by pancytopenia and hypocellular bone marrow, potentially leading to chronic anemia, hemorrhage, and infection. The China Aplastic Anemia Committee and British Committee for Standards in Haematology guidelines recommend hematopoietic stem-cell transplantation (HSCT) or immunosuppressive therapy (IST) comprising antithymocyte globulin (ATG) with cyclosporine (CsA) as initial treatment for AA patients. With limited epidemiological data on the clinical management of AA in Asia, a prospective cohort registry study involving 22 AA treatment centers in China was conducted to describe the disease characteristics of newly diagnosed AA patients and investigate real-world treatment patterns and patient outcomes. Of 340 AA patients, 72.9, 12.6, and 3.5% were receiving IST, traditional Chinese medicine, and HSCT, respectively, at baseline; only 22.2% of IST-treated patients received guideline-recommended ATG with CsA initially. Almost all patients received supportive care (95.6%) as blood transfusion (97.8%), antibiotics (63.7%), and/or hematopoietic growth factors (58.2%). Overall, 64.8% achieved a partial or complete response, and 0.9% experienced relapse. No new safety concerns were identified; serious adverse events were largely unrelated to the treatment regimen. These results demonstrate the need to identify and minimize treatment barriers to standardize and align AA management in China with treatment guideline recommendations and further improve patient outcomes.

9.
Pediatr Hematol Oncol ; 36(2): 113-121, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31002269

RESUMO

OBJECTIVES: To assess the impact of second-look biopsy of residual mass during or after chemotherapy in pediatric mature B-cell NHL. METHODS: Patients with mature B-cell non-Hodgkin lymphoma (NHL) who were suspicious of radiological residual mass at mid or end of treatment and subjected to second biopsy were treated at our center between January 2001 and December 2015. Their clinical characteristics, imaging findings, pathological changes, management, and prognosis were reviewed retrospectively. RESULTS: A total of 31 children were included (13 boys and 18 girls, median age at diagnosis 6.1 years). The median time from diagnosis to second biopsy was 3.15 months (range 2.3-18 months). Biopsy confirmed the presence of viable tumor in eight patients. The specificity and positive predictive value of conventional imaging in detecting residual detectable by biopsy were at 9 and 28.6%, while sensitivity and negative predictive value of this approach were both 100%. Three of the histologic positive patients experienced progressive disease or relapse while the others achieved complete remission (CR) and 21 patients achieved long-time CR at median follow-up of 3.2 years. The median progression-free survival (PFS) time of all 31 was 28 months and 5-year PFS rate was 90.0%. Five-year PFS rate of negative-biopsy and positive-biopsy group were 100 and 62.5%, respectively (p = 0.002). CONCLUSION: Conventional imaging has very high sensitivity but very low specificity for the accurate determination of residual disease in pediatric NHL. Second-look biopsy is necessary to differentiate viable tumor from necrosis or fibrosis and is solid evidence-based foundation of subsequent treatment.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biópsia , Linfoma de Células B/patologia , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Estimativa de Kaplan-Meier , Linfoma de Células B/diagnóstico por imagem , Linfoma de Células B/tratamento farmacológico , Imagem por Ressonância Magnética , Masculino , Neoplasia Residual , Valor Preditivo dos Testes , Prognóstico , Intervalo Livre de Progressão , Indução de Remissão , Estudos Retrospectivos , Sensibilidade e Especificidade , Tomografia Computadorizada por Raios X
10.
Medicine (Baltimore) ; 98(5): e14280, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30702592

RESUMO

The forearm deformity classified by Masada is a characteristic trait of patients with hereditary multiple exostoses (HME). Ulnar gradual lengthening, which was considered to be a safe and reliable procedure, was popular in treating these difficult deformities, however, delayed consolidation of the callus is uncommon but not rare in literature review. The purpose of this study was to try to identify the risk factors influencing bone healing in gradual ulnar lengthening in HME.We retrospectively reviewed patients with HME-induced forearm deformity who underwent gradual ulnar lengthening at our hospital from 2010 to 2016. Patients' demographic data, forearm deformity of Masada type, surgical procedure, ulnar diameter of osteotomy site, and external fixator type were recorded. We also reviewed radiographical data included gained length, axis deviation, callus form. Clinical outcome was assessed by the bone healing index (HI). Multiple linear regression was used to analyze the relationships between diffident parameters and the HI, the level of significance was set P <.05.Thirty-three patients were included in this study. The mean follow-up period was 1.5 (range 0.5-8) years. Circular external fixators were used in 5 patients and monolateral external fixators were used in 28 patients. The mean achieved length was 4.24 cm. The mean HI was 50.3 (range 26.6-99.3) days/cm. In patient with monolateral external fixator, patient's age was positively correlated with the bone HI (P = .001), while diameter and body mass index (BMI) were negatively correlated with the HI (P = .040, .018, respectively). Patient's sex, removal of distal ulnar exostoses, lengthening percentage, and axis deviation were non-significant in the regression model.When using monolateral external fixator for ulnar lengthening, patient's age, diameter of osteotomy site, and BMI are the most important risk factors related to bone formation. Pediatric orthopedic surgeons should consider these variables in order to avoid delayed union.


Assuntos
Alongamento Ósseo , Exostose Múltipla Hereditária/cirurgia , Osteogênese , Ulna/cirurgia , Adolescente , Criança , Pré-Escolar , Exostose Múltipla Hereditária/diagnóstico , Fixadores Externos , Feminino , Humanos , Masculino , Radiografia , Estudos Retrospectivos , Fatores de Risco
11.
Arch Dis Child ; 104(6): 522-529, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30705079

RESUMO

OBJECTIVES: Before 2003, most children with acute lymphoblastic leukaemia (ALL) abandoned treatment, with only approximately 30% treated in China. With the development of national insurance for underprivileged patients, we assessed the current frequency and causes of treatment abandonment among patients with ALL who were enrolled in the Chinese Children's Cancer Group ALL protocol between 2015 and 2016. METHODS: Demographic, clinical and laboratory data on patients who abandoned treatment, as well as economic and sociocultural data of their families were collected and analysed. General health-related statistics were retrieved from publicly accessible databanks maintained by the Chinese government. RESULTS: At a median follow-up of 119 weeks, 83 (3.1%, 95% CI 2.5% to 3.8%) of the 2641 patients abandoned treatment. Factors independently associated with abandonment included standard/high-risk ALL (OR 2.62, 95% CI 1.43 to 4.77), presence of minimal residual disease at the end of remission induction (OR 3.57, 95% CI 1.90 to 6.74) and low-income economic region (OR 3.7, 95% CI 1.89 to 7.05). According to the family members, economic constraints (50.6%, p=0.0001) were the main reason for treatment abandonment, followed by the belief of incurability, severe side effects and concern over late complications. CONCLUSIONS: The rate of ALL treatment abandonment has been greatly reduced in China. Standard/high-risk ALL, residence in a low-income region and economic difficulties were associated with treatment abandonment. CLINICAL TRIAL REGISTRATION NUMBER: ChiCTR-IPR-14005706, pre-results.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Recusa do Paciente ao Tratamento/estatística & dados numéricos , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Criança , Pré-Escolar , China , Feminino , Seguimentos , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Lactente , Recém-Nascido , Masculino , Neoplasia Residual , Pacientes Desistentes do Tratamento/estatística & dados numéricos , Indução de Remissão , Estudos Retrospectivos , Fatores Socioeconômicos
12.
Front Med ; 13(3): 378-387, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30635781

RESUMO

Homoharringtonine (HHT), a plant alkaloid from Cephalotaxus harringtonia, exhibits a unique anticancer mechanism and has been widely used in China to treat patients with acute myeloid leukemia (AML) since the 1970s. Trial SCMC-AML-2009 presented herein was a randomized clinical study designed based on our previous findings that pediatric AML patients younger than two years old may benefit from HHT-containing chemotherapy regimens. Patients randomized to arm A were treated with a standard chemotherapy regimen comprising mainly of anthracyclines and cytarabine (Ara-C), whereas patients in arm B were treated with HHT-containing regimens in which anthracyclines in all but the initial induction therapy were replaced by HHT. From February 2009 to November 2015, 59 patients less than 2 years old with de novo AML (other than acute promyelocytic leukemia) were recruited. A total of 42 patients achieved a morphologic complete remission (CR) after the first course, with similar rates in both arms (70.6% vs.72.0%). At the end of the follow-up period, 40 patients remained in CR and 5 patients underwent hematopoietic stem cell transplantation in CR, which could not be considered as events but censors. The 5-year event-free survival (EFS) was 60.2%±9.6% for arm A and 88.0%±6.5% for arm B (P= 0.024). Patients in arm B experienced shorter durations of leukopenia, neutropenia, and thrombocytopenia and had a lower risk of infection during consolidation chemotherapy with high-dosage Ara-C. Consequently, the homoharringtonine-based regimen achieved excellent EFS and alleviated hematologic toxicity for children aged younger than 2 years with de novo AML compared with the anthracycline-based regimen.


Assuntos
Antraciclinas/uso terapêutico , Citarabina/uso terapêutico , Mepesuccinato de Omacetaxina/uso terapêutico , Leucemia Mieloide Aguda/terapia , Terapia Neoadjuvante , China , Intervalo Livre de Doença , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Lactente , Leucemia Mieloide Aguda/mortalidade , Masculino , Indução de Remissão
13.
Int J Cancer ; 144(1): 117-124, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30098202

RESUMO

Langerhans cell histiocytosis (LCH) is the most common histiocytosis with constitutive activation of the RAS-RAF-MEK-ERK (MAPKinase) cell signaling pathway. We analyzed 89 cases of BRAF and MAP2K1 mutations by Sanger sequencing, of which 18 cases showed that these two gene mutations are negative. Whole genome sequencing of suitable specimens in these negative cases revealed a translocation from the 3 intron of PLEKHA6 to the 13 intron of NTRK3 in one case. We identified that this translocation could cause a novel fusion mutation, PLEKHA6-NTRK3. Overexpression of the PLEKHA6-NTRK3 mutant in NIH 3T3 cells enhanced MAPKinase pathway activation, promote cell growth. Our result suggested that a new mutation need be included in LCH molecular screening panel to better define its prevalence in LCH.


Assuntos
Histiocitose de Células de Langerhans/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Receptor trkC/genética , Proteínas Recombinantes de Fusão/genética , Adolescente , Animais , Proliferação de Células/genética , Criança , Pré-Escolar , Feminino , Histiocitose de Células de Langerhans/patologia , Humanos , Lactente , Masculino , Camundongos , Mutação , Células NIH 3T3
14.
Leukemia ; 33(6): 1387-1399, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30575821

RESUMO

Acute promyelocytic leukemia (APL) is characterized by t(15;17)(q22;q21), resulting in a PML-RARA fusion that is the master driver of APL. A few cases that cannot be identified with PML-RARA by using conventional methods (karyotype analysis, FISH, and RT-PCR) involve abnormal promyelocytes that are fully in accordance with APL in morphology, cytochemistry, and immunophenotype. To explore the mechanisms involved in pathogenesis and recurrence of morphologically diagnosed APL, we performed comprehensive variant analysis by next-generation sequencing in 111 pediatric patients morphologically diagnosed as APL. Structural variant (SV) analysis in 120 DNA samples from both diagnosis and relapse stage identified 95 samples with RARA rearrangement (including 94 with PML-RARA and one with NPM-RARA) and two samples with KMT2A rearrangement. In the eligible 13 RNA samples without any RARA rearrangement at diagnosis, one case each with CPSF6-RARG, NPM1-CCDC28A, and TBC1D15-RAB21 and two cases with a TBL1XR1-RARB fusion were discovered. These uncovered fusion genes strongly suggested their contributions to leukemogenesis as driver alternations and APL phenotype may arise by abnormalities of other members of the nuclear receptor superfamily involved in retinoid signaling (RARB or RARG) or even by mechanisms distinct from the formation of aberrant retinoid receptors. Single-nucleotide variant (SNV) analysis in 77 children (80 samples) with RARA rearrangement showed recurrent alternations of primary APL in FLT3, WT1, USP9X, NRAS, and ARID1A, with a strong potential for involvement in pathogenesis, and WT1 as the only recurrently mutated gene in relapsed APL. WT1, NPM1, NRAS, FLT3, and NSD1 were identified as recurrently mutated in 17 primary samples without RARA rearrangement and WT1, NPM1, TP53, and RARA as recurrently mutated in 9 relapsed samples. The survival of APL with RARA rearrangement is much better than without RARA rearrangement. Thus, patients morphologically diagnosed as APL that cannot be identified as having a RARA rearrangement are more reasonably classified as a subclass of AML other than APL, and individualized treatment should be considered according to the genetic abnormalities.


Assuntos
Biomarcadores Tumorais/genética , Células Precursoras de Granulócitos/patologia , Leucemia Promielocítica Aguda/genética , Mutação , Recidiva Local de Neoplasia/genética , Proteínas de Fusão Oncogênica/genética , Translocação Genética , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Seguimentos , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Células Precursoras de Granulócitos/metabolismo , Humanos , Lactente , Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/tratamento farmacológico , Masculino , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/tratamento farmacológico , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
15.
Medicine (Baltimore) ; 97(42): e12855, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30334991

RESUMO

Hereditary multiple osteochondroma (HMO) is one of the most common genetic skeletal disorders. It is caused by mutations in either EXT1 or EXT2 resulting in abnormal skeletal growth and morphogenesis. However, the spectrum and frequency of EXT1 and EXT2 mutations in Chinese patients with HMO was not previously investigated.Mutations were identified by performing Sanger sequencing analysis of the complete coding regions and flanking intronic sequences of EXT1 and EXT2, followed by multiplex ligation-dependent probe amplification (MLPA) analysis to detect gene deletions or duplications that could not be identified by the Sanger sequencing method.The present study identified pathogenic mutations in 93% (68/73) of unrelated HMO probands from 73 pedigrees. Mutations in EXT1 and EXT2 were identified in 53% (39/73) and 40% (29/73) of families. We identified 58 distinct mutations in EXT1 and EXT2, including 20 frameshift mutations, 16 nonsense mutations, 7 missense mutations, 9 splice site mutations, 5 large deletions, and 1 in-frame deletion mutation. Twenty-six of these mutations were novel and 32 were previously reported. Most of the mutations in EXT1 were base deletions or insertions (21/33), whereas the majority of those in EXT2 were single base substitution (18/25).Complete sequencing of both the EXT1 and EXT2 followed by MLPA analysis is recommended for genetic analysis of Chinese patients with HMO. This study provides a comprehensive characterization of the genetic aberrations found in Chinese patients with HMO and highlights the diagnostic value of molecular genetic analysis in this particular disease.


Assuntos
Exostose Múltipla Hereditária/genética , N-Acetilglucosaminiltransferases/genética , Adolescente , Grupo com Ancestrais do Continente Asiático/genética , Criança , Pré-Escolar , Feminino , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Reação em Cadeia da Polimerase Multiplex , Mutação
16.
Hematol Oncol ; 36(4): 679-688, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30133806

RESUMO

Long-term follow-up data for childhood acute lymphoblastic leukemia (ALL) are scarce in China because of lacking population-based and hospitalized registry system. This retrospective study, conducted at Shanghai's Children's Medical Center in China (SCMC), aimed to investigate the long-term results of childhood ALL and to identify prognostic factors. The Pediatric Oncology Network Database, designed by St. Jude Children's Research Hospital, USA, were used to collect data for the enrolled patients starting in 2005. From 2005 to 2014, 1085 evaluable patients with ALL aged 1 to 18 years old were enrolled and treated using SCMC-ALL-2005 risk-stratified protocol. Complete remission was achieved in 95.6% of patients. At 5 and 10 years, the event-free survival rate was 68.3 ± 1.4% and 64.6 ± 1.6%, and the overall survival rate was 80.0 ± 1.2% and 76.3 ± 1.6%, respectively. The 5-year event-free survival rates were 81.8 ± 2.0%, 67.0 ± 1.9%, and 14.3 ± 4.0% for patients in low-risk, intermediate-risk, and high-risk groups, respectively. The cumulative risk of relapse was 24.5% at 10 years. Induction failure conferred worse prognosis. Patients younger than 1 year of age at diagnosis, intermediate-risk/high-risk group, male gender, and positive minimal residual disease (MRD) results at day 55, both in the univariate and multivariate analysis, were associated with significantly worse prognosis (P < .05). Patients with positive MRD at both day 35 and day 55 were related to a significantly poor outcome (P < .0001), but not for patients with negitive MRD at day 35. The overall outcomes for ALL patients treated with protocol SCMC-ALL-2005 in SCMC are lower than in developed countries. Factors including age, gender, risk group and MRD results at day 55 were associated with treatment outcomes in childhood ALL.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Pré-Escolar , China/epidemiologia , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Lactente , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Sistema de Registros , Estudos Retrospectivos , Resultado do Tratamento
17.
Pediatr Blood Cancer ; 65(2)2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28921877

RESUMO

BACKGROUND: Infantile fibrosarcoma (IFS) is a rare pediatric malignancy with relatively good prognosis, but the risk of progression or recurrence after therapy exists. To understand the immune microenvironment of IFS and determine if immunotherapy is a potential treatment, we analyzed T-cell responses in IFS tumors. PROCEDURE: IFS tumors were analyzed by immunohistochemistry and multicolor flow cytometry to characterize immune cell infiltration and function. Tumor infiltrating lymphocytes (TILs) were expanded in vitro and evaluated for recognition of autologous tumor cells. Real-time PCR was applied to evaluate tumor expression of chemokines/cytokines and tumor antigens. RESULTS: Significant infiltration of both CD4+ and CD8+ T cells was found in seven of 10 IFS but rarely found in age- and sex-matched rhabdomyosarcoma tumors. The TILs from recurrent IFS tumors expressed high levels of costimulatory molecules such as CD28, 4-1BB, and OX40, but little or no coinhibitory molecules such as PD-1 and CTLA4, Tim3, Lag3, and CD39. Upon activation, large portions of TILs produced IFN-γ and TNF-α. Eighteen out of 40 T cell lines generated from surgically removed tumors could recognize autologous tumor cells. Moreover, we found that IFS tumors expressed high levels of T-cell chemokines such as CXCL10 and CXCL16, and also classic tumor antigens such as CTAG2, GAGE, and NY-ESO-1, whose expression could be further enhanced by treatment with epigenetic modulator decitabine. CONCLUSIONS: IFS tumors are highly immunogenic and expansion of TILs followed by adoptive cell transfer could be a potential immunotherapy for IFS patients undergoing tumor recurrence.


Assuntos
Antígenos de Diferenciação/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Citocinas/imunologia , Fibrossarcoma/imunologia , Proteínas de Neoplasias/imunologia , Adolescente , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/patologia , Criança , Pré-Escolar , Feminino , Fibrossarcoma/patologia , Fibrossarcoma/terapia , Humanos , Imunoterapia , Lactente , Masculino
18.
Proc Natl Acad Sci U S A ; 115(2): 373-378, 2018 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-29279377

RESUMO

T-cell acute lymphoblastic leukemia (T-ALL) is a clonal malignancy of immature T cells. Recently, the next-generation sequencing approach has allowed systematic identification of molecular features in pediatric T-ALL. Here, by performing RNA-sequencing and other genomewide analysis, we investigated the genomic landscape in 61 adult and 69 pediatric T-ALL cases. Thirty-six distinct gene fusion transcripts were identified, with SET-NUP214 being highly related to adult cases. Among 18 previously unknown fusions, ZBTB16-ABL1, TRA-SALL2, and involvement of NKX2-1 were recurrent events. ZBTB16-ABL1 functioned as a leukemogenic driver and responded to the effect of tyrosine kinase inhibitors. Among 48 genes with mutation rates >3%, 6 were newly found in T-ALL. An aberrantly overexpressed short mRNA transcript of the SLC17A9 gene was revealed in most cases with overexpressed TAL1, which predicted a poor prognosis in the adult group. Up-regulation of HOXA, MEF2C, and LYL1 was often present in adult cases, while TAL1 overexpression was detected mainly in the pediatric group. Although most gene fusions were mutually exclusive, they coexisted with gene mutations. These genetic abnormalities were correlated with deregulated gene expression markers in three subgroups. This study may further enrich the current knowledge of T-ALL molecular pathogenesis.


Assuntos
Regulação Leucêmica da Expressão Gênica , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Transcriptoma , Adulto , Criança , Estudos de Coortes , Perfilação da Expressão Gênica/métodos , Ontologia Genética , Células HEK293 , Humanos , Células Jurkat , Estimativa de Kaplan-Meier , Mutação
19.
J Pediatr Hematol Oncol ; 40(1): e9-e12, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29200145

RESUMO

We reported the outcome of 150 children newly diagnosed with multisystem langerhans cell histiocytosis following a langerhans cell histiocytosis-II-based protocol (arm B). However, the continuation treatment was extended to 56 weeks and etoposide was omitted from the continuation treatment. Risk organ (RO) involvement was defined as: liver (≥3 cm with or without functional impairment); spleen (≥2 cm below the costal margin in the midclavicular line); hematopoietic system (hemoglobin <100 g/L, and/or white blood cell count <4.0×10/L, and/or platelets <100×10/L). The lungs are not considered a RO in the current study. For the 59 patients with RO involvement (RO+), the rapid response rate (week 6) was 61.0% and the 3-year overall survival 73.4%±5.9%. Rapid responders had a better 3-year survival rate than poor responders (90.9%±5.0% vs. 45.7%±11.0%, P<0.001). Ninety-one patients without RO involvement (RO-) had a relatively low 3-year cumulative reactivation rate (10.7%). No deaths occurred in this subgroup and the 3-year overall survival of RO- patients was 100%. Poor responders of RO+ patients had an extremely poor prognosis. An effective salvage therapy is essential for this high-risk group. The initial treatment intensity and duration of continuation therapy both impact disease reactivation in RO- patients.


Assuntos
Histiocitose de Células de Langerhans/diagnóstico , Histiocitose de Células de Langerhans/terapia , Medição de Risco , Adolescente , Criança , Pré-Escolar , China , Feminino , Sistema Hematopoético/patologia , Histiocitose de Células de Langerhans/mortalidade , Histiocitose de Células de Langerhans/patologia , Hospitais Pediátricos , Humanos , Lactente , Hepatopatias , Masculino , Terapia de Salvação , Esplenopatias , Taxa de Sobrevida , Resultado do Tratamento
20.
Pediatr Hematol Oncol ; 35(7-8): 385-392, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30693828

RESUMO

BACKGROUND: This is a descriptive review of the clinical patterns and outcomes of children with Langerhans cell histiocytosis and single-system involvement (SS-LCH) treated at Shanghai Children's Medical Center. PROCEDURE: 60 evaluable newly diagnosed patients (37 boys, 23 girls) with a median age of 3.9 years (range: 0.3-15.3 years) and histiopathology-confirmed SS-LCH were enrolled from 2010 to 2014. All patients received systemic chemotherapy using either the DAL HX-83 or LCH-II protocol as determined by the physician. RESULTS: Bone was the most frequently affected organ (56/60, 93.3%). Of the 56 patients suffering from SS-bone disease, 35 (62.5%) had unifocal disease and 21 (37.5%) had multifocal disease. CNS-risk lesions were seen in nine patients (16.1%, 9/56) at diagnosis. Thirty-two patients were treated with the LCH-II protocol and 28 received the DAL HX-83 protocol. No patient received intralesional steroid injection at the time of surgery. CNS-risk lesion correlated with an inferior event-free survival (EFS) for patients with bone disease (62.5 ± 17.1% vs. 90.7 ± 4.5%; p = 0.039). The difference in the 5-year EFS between patients with unifocal and multifocal SS-bone LCH did not reach the statistical significance (93.8 ± 4.3% vs. 75.0 ± 9.7%; p = 0.074). No deaths were observed, leading to a 5-year OS of 100% in the present cohort of patients. Permanent consequences and secondary malignancies were not observed but were also limited by short follow-up. CONCLUSIONS: Optimal therapy for patients with SS-bone LCH has not been established. Less toxic therapeutic approaches should be considered for these patients and tested in prospective trials.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Ósseas , Neoplasias do Sistema Nervoso Central , Histiocitose de Células de Langerhans , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/mortalidade , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/mortalidade , Criança , Pré-Escolar , China/epidemiologia , Intervalo Livre de Doença , Feminino , Histiocitose de Células de Langerhans/tratamento farmacológico , Histiocitose de Células de Langerhans/mortalidade , Humanos , Lactente , Masculino , Estudos Retrospectivos , Taxa de Sobrevida
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