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2.
Hematology ; 24(1): 577-582, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31389303

RESUMO

Objective: To investigate clinical features, diagnosis, treatment strategies and prognosis of juvenile myelomonocytic leukemia (JMML). Methods: The clinical data of 21 patients with JMML who were diagnosed in our hospital from January 2013 to May 2018 were retrospectively analyzed. Results: Among the 21 children with JMML, 16 were male and 5 were female. Out of the 21 children who were diagnosed with JMML, 7 were lost after treatment while the remaining 14 received A-3V chemotherapy regimen of South Korea. The effective response rate was 78.5%. The three-year overall survival (OS) rate and three-year disease-free survival (DFS) rate were (76.2 ± 14.8)% and (66.2 ± 14)%, respectively. Single factor analysis showed that PLT count ≤33×109/L, LDH level >500 U/L and HbF level >10% and chemotherapy only were the significant factors that lead to poor prognosis in children. Cox multivariate analysis showed that the choice of treatment options affected the prognosis of JMML children. By taking prognostic factors for long-term efficacy into account, patients with treatment strategy of chemotherapy alongside hematopoietic stem cell transplantation (HSCT) have a better prognosis. Conclusion: The PLT count, LDH level, HbF level and choice of treatment plan are important for the evaluation of prognosis for children with JMML. Although there is a lack of consistency in terms of donors but the A-3V scheme is relatively stable, so HSCT should be preferred for children with poor prognostic factors.


Assuntos
Leucemia Mielomonocítica Juvenil/diagnóstico , Leucemia Mielomonocítica Juvenil/terapia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Leucemia Mielomonocítica Juvenil/patologia , Masculino
3.
Pediatr Blood Cancer ; 66(11): e27948, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31347788

RESUMO

BACKGROUND: Despite the intensity of hematopoietic stem cell transplantation (HCT), relapse remains the most common cause of death in juvenile myelomonocytic leukemia (JMML). In contrast to other leukemias where therapy is used to reduce leukemic burden prior to transplant, many patients with JMML proceed directly to HCT with active disease. The objective of this study was to elucidate whether pre-HCT therapy has an effect on the molecular burden of disease and how this affects outcome post-HCT. PROCEDURE: Twenty-one patients with JMML who received pre-HCT therapy and were transplanted at UCSF were analyzed in this study. The mutant allele frequency of the driver mutation was assessed before and after pre-HCT therapy, using custom amplicon next-generation sequencing. RESULTS: Of the 21 patients, seven patients (33%) responded to therapy with a significant reduction in their mutant allele frequency and were classified as molecular responders. Six of these patients received moderate-intensity chemotherapy, one patient received only azacitidine. The 5-year progression-free survival after HCT of molecular responders was 100% versus 61% for nonresponders (P = .12). Survival of molecular nonresponders was not improved by use of high-intensity conditioning, but patients were salvaged if they experienced severe graft versus host disease. There were no baseline clinical characteristics that were associated with response to pre-HCT therapy. CONCLUSIONS: Despite the myelodysplastic nature of JMML, patients treated with pre-HCT therapy can achieve molecular remissions. These patients experienced a trend toward improved outcomes post-HCT. Importantly, molecular testing can be helpful to distinguish between responders and nonresponders and should become an integral part of clinical care.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Genes Neoplásicos , Transplante de Células-Tronco Hematopoéticas , Leucemia Mielomonocítica Juvenil/tratamento farmacológico , Terapia Neoadjuvante , Análise de Sequência de DNA , Carga Tumoral/efeitos dos fármacos , Antimetabólitos Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Pré-Escolar , Terapia Combinada , DNA de Neoplasias/sangue , Avaliação de Medicamentos , Monitoramento de Medicamentos , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/terapia , Humanos , Lactente , Leucemia Mielomonocítica Juvenil/sangue , Leucemia Mielomonocítica Juvenil/genética , Leucemia Mielomonocítica Juvenil/terapia , Masculino , Proteínas de Neoplasias/genética , Intervalo Livre de Progressão , Recidiva , Estudos Retrospectivos , Esplenectomia , Condicionamento Pré-Transplante
4.
Neoplasma ; 20192019 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-31088105

RESUMO

Juvenile myelomonocytic leukemia (JMML) is a rare, aggressive clonal myeloproliferative disorder of infancy and early childhood caused by oncogenic mutations in genes involved in the Ras pathway. Long-term survival has only been achieved with hematopoietic stem cell transplantation (HSCT), being able to cure more than 50% patients. To manage the disease before HSCT remains an important issue with constant searching for optimal treatment modalities. According to several retrospective analyses, azacytidine (AZA) induced clinical and molecular responses in patients with relapsed JMML pre-transplant and post-transplant, suggesting its use as a promising "bridging" therapy before HSCT. In this paper we report our first consecutive cohort of patients with JMML treated at our institution as well as our experience with the diagnosis, novel treatment and management of these patients before the HSCT. We present 6 patients with JMML, harboring different somatic mutations (PTPN11 and NRAS), with distinct clinical features; 3 of them had been treated with AZA 75mg/m2 i.v. on days 1 to 7 of a 28-day cycle before the HSCT. Response to therapy was evaluated after each cycle in accordance with the International response criteria. One patient had a progression of splenomegaly during the treatment and after three cycles he was urgently transplanted. At present, he is remaining in complete remission 3 years after HSCT. Two patients showed impressive response following the first cycle of the therapy with a regression of splenomegaly and monocyte count, normalized leukocytes, platelets, and absent blasts in peripheral blood. The treatment was well-tolerated with no adverse effect recorded. The clinical activity and favorable toxicity of AZA in JMML provide a rationale for its use as a "bridging" therapy before HSCT. Prospective trials with accompanying translational studies are required to provide further information regarding individual factors that may direct the most appropriate choice of pretransplantation therapy.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mielomonocítica Juvenil/diagnóstico , Leucemia Mielomonocítica Juvenil/terapia , Criança , Pré-Escolar , Humanos , Masculino , Estudos Retrospectivos , Eslováquia
5.
Neoplasma ; 66(5): 818-824, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31129971

RESUMO

Juvenile myelomonocytic leukemia (JMML) is a rare, aggressive clonal myeloproliferative disorder of infancy and early childhood caused by oncogenic mutations in genes involved in the Ras pathway. Long-term survival has only been achieved with hematopoietic stem cell transplantation (HSCT), being able to cure more than 50% patients. To manage the disease before HSCT remains an important issue with constant searching for optimal treatment modalities. According to several retrospective analyses, azacitidine (AZA) induced clinical and molecular responses in patients with relapsed JMML pre-transplant and post-transplant, suggesting its use as a promising "bridging" therapy before HSCT. In this paper we report our first consecutive cohort of patients with JMML treated at our institution as well as our experience with the diagnosis, novel treatment and management of these patients before the HSCT. We present 6 patients with JMML, harboring different somatic mutations (PTPN11 and NRAS), with distinct clinical features; 3 of them had been treated with AZA 75 mg/m2 i.v. on days 1 to 7 of a 28-day cycle before the HSCT. Response to therapy was evaluated after each cycle in accordance with the International response criteria. One patient had a progression of splenomegaly during the treatment and after three cycles he was urgently transplanted. At the present, he is remaining in complete remission 3 years after HSCT. Two patients showed impressive response following the first cycle of the therapy with a regression of splenomegaly and monocyte count, normalized leukocytes, platelets and absent blasts in peripheral blood. The treatment was well tolerated with no adverse effect recorded. The clinical activity and favorable toxicity of AZA in JMML provide a rationale for its use as a "bridging" therapy before HSCT. Prospective trials with accompanying translational studies are required to provide further information regarding individual factors that may direct the most appropriate choice of pretransplantation therapy.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mielomonocítica Juvenil/diagnóstico , Leucemia Mielomonocítica Juvenil/terapia , Azacitidina/uso terapêutico , Criança , Humanos , Masculino , Estudos Retrospectivos , Eslováquia
6.
Hematology Am Soc Hematol Educ Program ; 2018(1): 307-312, 2018 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-30504325

RESUMO

Juvenile myelomonocytic leukemia (JMML) is a unique clonal hematopoietic disorder of early childhood characterized by hyperactivation of the RAS signal transduction pathway. Approximately 90% of patients harbor molecular alteration in 1 of 5 genes (PTPN11, NRAS, KRAS, NF1, CBL), which define genetically and clinically distinct JMML subtypes. Three subtypes, PTPN11- , NRAS-, and KRAS-mutated JMML, are characterized by heterozygous somatic gain-of-function mutations in non syndromic children, while two subtypes, JMML in neurofibromatosis type 1 and in JMML in children with CBL syndrome, are characterized by germ line RAS disease and acquired biallelic inactivation of the respective tumor suppressor genes in hematopoietic cells. In addition to the initiating RAS pathway lesion, secondary genetic alterations within and outside of the RAS pathway are detected in about half the patients. Most recently, genome-wide DNA methylation profiles identified distinct methylation signatures correlating with clinical and genetic features and highly predictive of outcome. JMML is a stem cell disorder, and most JMML patients require allogeneic stem cell transplantation for long-term survival. However, spontaneous disease regression is noted in the majority of children with CBL-mutated JMML and in some NRAS-mutated cases. In the absence of 1 of the 5 canonical RAS pathway alteration, rare mutations in other RAS genes and non-JMML myeloproliferative disorders need to be excluded. Understanding the genetic basis of myeloproliferative disorders in early childhood will greatly improve clinical decision making.


Assuntos
Tomada de Decisões , Leucemia Mielomonocítica Juvenil , Transplante de Células-Tronco , Aloenxertos , Criança , Metilação de DNA , DNA de Neoplasias/genética , DNA de Neoplasias/metabolismo , Estudo de Associação Genômica Ampla , Humanos , Leucemia Mielomonocítica Juvenil/genética , Leucemia Mielomonocítica Juvenil/metabolismo , Leucemia Mielomonocítica Juvenil/patologia , Leucemia Mielomonocítica Juvenil/terapia , Mutação , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Transdução de Sinais
7.
Pediatr Blood Cancer ; 65(7): e27034, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29528181

RESUMO

BACKGROUND: Most patients with juvenile myelomonocytic leukemia (JMML) are curable only with allogeneic hematopoietic cell transplantation (HCT). However, the current standard conditioning regimen, busulfan-cyclophosphamide-melphalan (Bu-Cy-Mel), may be associated with higher risks of morbidity and mortality. ASCT1221 was designed to test whether the potentially less-toxic myeloablative conditioning regimen containing busulfan-fludarabine (Bu-Flu) would be associated with equivalent outcomes. PROCEDURE: Twenty-seven patients were enrolled on ASCT1221 from 2013 to 2015. Pre- and post-HCT (starting Day +30) mutant allele burden was measured in all and pre-HCT therapy was administered according to physician discretion. RESULTS: Fifteen patients were randomized (six to Bu-Cy-Mel and nine to Bu-Flu) after meeting diagnostic criteria for JMML. Pre-HCT low-dose chemotherapy did not appear to reduce pre-HCT disease burden. Two patients, however, received aggressive chemotherapy pre-HCT and achieved low disease-burden state; both are long-term survivors. All four patients with detectable mutant allele burden at Day +30 post-HCT eventually progressed compared to two of nine patients with unmeasurable allele burden (P = 0.04). The 18-month event-free survival of the entire cohort was 47% (95% CI, 21-69%), and was 83% (95% CI, 27-97%) and 22% (95% CI, 03-51%) for Bu-Cy-Mel and Bu-Flu, respectively (P = 0.04). ASCT1221 was terminated early due to concerns that the Bu-Flu arm had inferior outcomes. CONCLUSIONS: The regimen of Bu-Flu is inadequate to provide disease control in patients with JMML who present to HCT with large burdens of disease. Advances in molecular testing may allow better characterization of biologic risk, pre-HCT responses to chemotherapy, and post-HCT management.


Assuntos
Rejeição de Enxerto/tratamento farmacológico , Doença Enxerto-Hospedeiro/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Leucemia Mielomonocítica Juvenil/terapia , Agonistas Mieloablativos/administração & dosagem , Condicionamento Pré-Transplante , Bussulfano/administração & dosagem , Criança , Pré-Escolar , Feminino , Seguimentos , Rejeição de Enxerto/etiologia , Doença Enxerto-Hospedeiro/etiologia , Humanos , Lactente , Recém-Nascido , Leucemia Mielomonocítica Juvenil/complicações , Masculino , Prognóstico , Vidarabina/administração & dosagem , Vidarabina/análogos & derivados
8.
Semin Cancer Biol ; 51: 68-79, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29129488

RESUMO

Myelodysplastic syndrome (MDS) is a clonal bone marrow disorder, typically of older adults, which is characterized by ineffective hematopoiesis, peripheral blood cytopenias and risk of progression to acute myeloid leukemia. Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative neoplasm occurring in young children. The common denominator of these malignant myeloid disorders is the limited benefit of conventional chemotherapy and a particular responsiveness to epigenetic therapy with the DNA-hypomethylating agents 5-azacytidine (azacitidine) or decitabine. However, hypomethylating therapy does not eradicate the malignant clone in MDS or JMML and allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative treatment option. An emerging concept with intriguing potential is the combination of hypomethylating therapy and HSCT. Possible advantages include disease control with good tolerability during donor search and HSCT preparation, improved antitumoral alloimmunity, and reduced risk of relapse even with non-myeloablative regimens. Herein we review the current role of pre- and post-transplant therapy with hypomethylating agents in MDS and JMML.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Metilação de DNA , Epigênese Genética , Transplante de Células-Tronco Hematopoéticas , Leucemia Mielomonocítica Juvenil/terapia , Síndromes Mielodisplásicas/terapia , Azacitidina/análogos & derivados , Azacitidina/uso terapêutico , Terapia Combinada , Decitabina , Humanos , Leucemia Mielomonocítica Juvenil/genética , Leucemia Mielomonocítica Juvenil/patologia , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/patologia
9.
Turk J Haematol ; 35(1): 27-34, 2018 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-28179213

RESUMO

OBJECTIVE: This study aimed to define the status of juvenile myelomonocytic leukemia (JMML) patients in Turkey in terms of time of diagnosis, clinical characteristics, mutational studies, clinical course, and treatment strategies. MATERIALS AND METHODS: Data including clinical and laboratory characteristics and treatment strategies of JMML patients were collected retrospectively from pediatric hematology-oncology centers in Turkey. RESULTS: Sixty-five children with JMML diagnosed between 2002 and 2016 in 18 institutions throughout Turkey were enrolled in the study. The median age at diagnosis was 17 months (min-max: 2-117 months). Splenomegaly was present in 92% of patients at the time of diagnosis. The median white blood cell, monocyte, and platelet counts were 32.9x109/L, 5.4x109/L, and 58.3x109/L, respectively. Monosomy 7 was present in 18% of patients. JMML mutational analysis was performed in 32 of 65 patients (49%) and PTPN11 was the most common mutation. Hematopoietic stem cell transplantation (HSCT) could only be performed in 28 patients (44%), the majority being after the year 2012. The most frequent reason for not performing HSCT was the inability to find a suitable donor. The median time from diagnosis to HSCT was 9 months (min-max: 2-63 months). The 5-year cumulative survival rate was 33% and median estimated survival time was 30±17.4 months (95% CI: 0-64.1) for all patients. Survival time was significantly better in the HSCT group (log-rank p=0.019). Older age at diagnosis (>2 years), platelet count of less than 40x109/L, and PTPN11 mutation were the factors significantly associated with shorter survival time. CONCLUSION: Although there has recently been improvement in terms of definitive diagnosis and HSCT in JMML patients, the overall results are not satisfactory and it is necessary to put more effort into this issue in Turkey.


Assuntos
Leucemia Mielomonocítica Juvenil/epidemiologia , Biópsia , Pré-Escolar , Terapia Combinada , Feminino , Testes Genéticos , Humanos , Lactente , Leucemia Mielomonocítica Juvenil/diagnóstico , Leucemia Mielomonocítica Juvenil/etiologia , Leucemia Mielomonocítica Juvenil/terapia , Masculino , Vigilância em Saúde Pública , Estudos Retrospectivos , Análise de Sobrevida , Avaliação de Sintomas , Turquia/epidemiologia
10.
J Pediatr Hematol Oncol ; 40(5): e315-e318, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29023302

RESUMO

Lymphoid interstitial pneumonia (LIP) is a rare disease characterized by benign reactive polyclonal proliferation of bronchus-associated lymphoid tissue after exposure to inhaled or circulating antigen(s), leading to a disease symptomatology similar to idiopathic interstitial pneumonia. Its association with diseases that are caused due to immune dysregulation (autoimmune diseases, congenital/acquired immunodeficiency, and allogeneic bone marrow transplant) and response to immunomodulatory/suppressive medications suggests an immunologic pathophysiology. Although LIP has been reported in association with lymphoproliferative diseases like Castleman disease, it has never been described in patients with leukemia. We report the first case of LIP in a patient with juvenile myelomonocytic leukemia (JMML) who was found to have a novel germline mutation of unknown significance in additional sex combs-like-1 (ASXL1) gene and a pathogenic somatic mutation of protein tyrosine phosphatase, nonreceptor type 11 (PTPN11) gene at diagnosis. The patient underwent a matched unrelated bone marrow transplant for JMML with complete resolution of JMML and LIP with no recurrence to date. We also emphasize the importance of considering LIP in differential diagnosis of pulmonary lesions seen in conjunction with hematologic malignancies and distinguishing it from malignant infiltration of the lung.


Assuntos
Transplante de Medula Óssea , Leucemia Mielomonocítica Juvenil/terapia , Doenças Pulmonares Intersticiais/terapia , Aloenxertos , Mutação em Linhagem Germinativa , Humanos , Lactente , Leucemia Mielomonocítica Juvenil/diagnóstico , Leucemia Mielomonocítica Juvenil/genética , Leucemia Mielomonocítica Juvenil/patologia , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/genética , Doenças Pulmonares Intersticiais/patologia , Masculino , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Proteínas Repressoras/genética
14.
Nat Commun ; 8(1): 2127, 2017 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-29259179

RESUMO

Juvenile myelomonocytic leukemia (JMML) is a myeloproliferative disorder of childhood caused by mutations in the Ras pathway. Outcomes in JMML vary markedly from spontaneous resolution to rapid relapse after hematopoietic stem cell transplantation. Here, we hypothesized that DNA methylation patterns would help predict disease outcome and therefore performed genome-wide DNA methylation profiling in a cohort of 39 patients. Unsupervised hierarchical clustering identifies three clusters of patients. Importantly, these clusters differ significantly in terms of 4-year event-free survival, with the lowest methylation cluster having the highest rates of survival. These findings were validated in an independent cohort of 40 patients. Notably, all but one of 14 patients experiencing spontaneous resolution cluster together and closer to 22 healthy controls than to other JMML cases. Thus, we show that DNA methylation patterns in JMML are predictive of outcome and can identify the patients most likely to experience spontaneous resolution.


Assuntos
Metilação de DNA , Genoma Humano/genética , Leucemia Mielomonocítica Juvenil/genética , Regressão Neoplásica Espontânea/genética , Antineoplásicos/uso terapêutico , Biópsia , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Lactente , Estimativa de Kaplan-Meier , Leucemia Mielomonocítica Juvenil/sangue , Leucemia Mielomonocítica Juvenil/mortalidade , Leucemia Mielomonocítica Juvenil/terapia , Masculino , Monócitos , Mutação , Prognóstico , Estudos Prospectivos
15.
Nat Commun ; 8(1): 2126, 2017 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-29259247

RESUMO

Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative disorder of early childhood characterized by mutations activating RAS signaling. Established clinical and genetic markers fail to fully recapitulate the clinical and biological heterogeneity of this disease. Here we report DNA methylome analysis and mutation profiling of 167 JMML samples. We identify three JMML subgroups with unique molecular and clinical characteristics. The high methylation group (HM) is characterized by somatic PTPN11 mutations and poor clinical outcome. The low methylation group is enriched for somatic NRAS and CBL mutations, as well as for Noonan patients, and has a good prognosis. The intermediate methylation group (IM) shows enrichment for monosomy 7 and somatic KRAS mutations. Hypermethylation is associated with repressed chromatin, genes regulated by RAS signaling, frequent co-occurrence of RAS pathway mutations and upregulation of DNMT1 and DNMT3B, suggesting a link between activation of the DNA methylation machinery and mutational patterns in JMML.


Assuntos
Metilação de DNA , Leucemia Mielomonocítica Juvenil/genética , Síndrome de Noonan/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Transdução de Sinais/genética , Antineoplásicos/uso terapêutico , Biópsia , Criança , Pré-Escolar , Cromatina/genética , Cromatina/metabolismo , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , DNA (Citosina-5-)-Metiltransferases/metabolismo , Análise Mutacional de DNA , Epigenômica , Feminino , Regulação Leucêmica da Expressão Gênica , Transplante de Células-Tronco Hematopoéticas , Humanos , Lactente , Leucemia Mielomonocítica Juvenil/mortalidade , Leucemia Mielomonocítica Juvenil/patologia , Leucemia Mielomonocítica Juvenil/terapia , Masculino , Mutação , Síndrome de Noonan/patologia , Prognóstico , Estudos Prospectivos , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Proteínas Proto-Oncogênicas c-cbl , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Regulação para Cima
16.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 25(5): 1524-1527, 2017 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-29070137

RESUMO

OBJECTIVE: To analyze the therapeutic efficacy of haploidentical-hematopoietic stem cell transplantation (hi-HSCT) for patients with juvenile myelomonocytic leukemia (JMML). METHODS: The engraftment of hematopoietic stem cells, incidence of graft versus host disease (GVHD), infection, relapse, and survival of 6 JMML patients received hi-HSCT were retrospectively analyzed. RESULTS: Six (6 males) JMML patients received hi-HSCT from haplo-HLA-matched related donors. The results showed that the hematopoictic stem cells in all 6 patients were grafted successfully. Two cases of JMML died of pulmenary infections, other 4 cases survive without disease. Acute GVHD occurred in 3 patients and chronic GVHD occurred in 1 patients. The overall survival, disease free survival and relapse rates were 66.7%, 66.7%, 0%, respectively. CONCLUSION: The hi-HSCT is an effective method for treatment of patients with JMML, but there also is a serial problems to be resolved.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mielomonocítica Juvenil/terapia , Criança , Intervalo Livre de Doença , Doença Enxerto-Hospedeiro , Humanos , Masculino , Transplante Homólogo
18.
Ann Dermatol Venereol ; 144(11): 705-711, 2017 Nov.
Artigo em Francês | MEDLINE | ID: mdl-28728859

RESUMO

BACKGROUND: Granular cell tumour (GCT) is a rare form of tumour comprising Schwann cells. Herein, we report a case of a child presenting Noonan syndrome complicated by juvenile myelomonocytic leukaemia (JMML) and who also developed a multiple form of GCT. We discussed the molecular mechanisms that might account for this association. PATIENTS AND METHODS: A six-year-old boy with Noonan syndrome complicated by JMML presented three asymptomatic subcutaneous nodules on his back, forearm and neck. Histological analysis revealed GCT. A literature review revealed seven cases of Noonan syndrome presenting GCT, none of which were associated with JMML. Mutation of gene PTPN11, via hyperactivation of intracellular Ras signalling may cause the development of GCT and JMML in children presenting Noonan syndrome. DISCUSSION: Detailed clinical examination is recommended in children presenting GCT to screen for multiple forms and for signs of malformation suggestive of a genetic syndrome. Ours is the first case to be described of Noonan syndrome complicated by JMML associated with multiple GCT. This association once again raises the important question of the role of the Ras-MAPK signalling pathway in the development of benign and malignant tumours of solid organs or blood, associated with genetic syndromes.


Assuntos
Tumor de Células Granulares/diagnóstico , Leucemia Mielomonocítica Juvenil , Neoplasias Primárias Múltiplas/diagnóstico , Síndrome de Noonan , Neoplasias Cutâneas/diagnóstico , Anormalidades Múltiplas/genética , Dorso , Transplante de Medula Óssea , Criança , Quilotórax/congênito , Antebraço , Predisposição Genética para Doença , Tumor de Células Granulares/genética , Tumor de Células Granulares/patologia , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Leucemia Mielomonocítica Juvenil/genética , Leucemia Mielomonocítica Juvenil/terapia , Sistema de Sinalização das MAP Quinases/genética , Masculino , Mutação , Pescoço , Neoplasias Primárias Múltiplas/genética , Neoplasias Primárias Múltiplas/patologia , Síndrome de Noonan/genética , Fenótipo , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Trombocitopenia Neonatal Aloimune
19.
Hum Pathol ; 68: 147-153, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28414089

RESUMO

Myeloid malignancies showing CD141+ myeloid dendritic cell (MDC) differentiation have not been documented. Here, we describe a patient with juvenile myelomonocytic leukemia in which a prominent CD141+ cell population was identified most consistent with CD141+ MDCs based on phenotypic similarity with normal CD141+ MDCs. Molecular studies demonstrated a KRAS mutation. The findings from the spleen and bone marrow are described. This is the first well-documented demonstration of CD141+ MDC differentiation of a hematopoietic neoplasm.


Assuntos
Antígenos de Superfície/análise , Biomarcadores Tumorais/análise , Diferenciação Celular , Células Dendríticas/imunologia , Leucemia Mielomonocítica Juvenil/imunologia , Antígenos CD1/análise , Biomarcadores Tumorais/genética , Biópsia , Antígenos CD13/análise , Criança , Células Dendríticas/patologia , Citometria de Fluxo , Predisposição Genética para Doença , Glicoproteínas/análise , Humanos , Imuno-Histoquímica , Leucemia Mielomonocítica Juvenil/genética , Leucemia Mielomonocítica Juvenil/patologia , Leucemia Mielomonocítica Juvenil/terapia , Masculino , Mutação , Fenótipo , Proteínas Proto-Oncogênicas p21(ras)/genética
20.
Pediatr Blood Cancer ; 64(9)2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28244637

RESUMO

Previous studies have reported several cases of juvenile myelomonocytic leukemia (JMML) developing blastic transformation during an indolent clinical course, but the underlying mechanism of transformation is still not well understood. In this report, we describe a case of JMML with blastic transformation possibly caused by additional copy number gains of the KRAS mutant allele. We have discovered that the copy number gain of the mutant allele is an additional possible cause of blastic transformation in JMML.


Assuntos
Dosagem de Genes , Leucemia Mielomonocítica Juvenil/genética , Ativação Linfocitária/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Transplante de Medula Óssea , Feminino , Humanos , Lactente , Leucemia Mielomonocítica Juvenil/terapia
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