RESUMO
ABSTRACT: Transient abnormal myelopoiesis (TAM) is a common complication in newborns with Down syndrome (DS). It commonly progresses to myeloid leukemia (ML-DS) after spontaneous regression. In contrast to the favorable prognosis of primary ML-DS, patients with refractory/relapsed ML-DS have poor outcomes. However, the molecular basis for refractoriness and relapse and the full spectrum of driver mutations in ML-DS remain largely unknown. We conducted a genomic profiling study of 143 TAM, 204 ML-DS, and 34 non-DS acute megakaryoblastic leukemia cases, including 39 ML-DS cases analyzed by exome sequencing. Sixteen novel mutational targets were identified in ML-DS samples. Of these, inactivations of IRX1 (16.2%) and ZBTB7A (13.2%) were commonly implicated in the upregulation of the MYC pathway and were potential targets for ML-DS treatment with bromodomain-containing protein 4 inhibitors. Partial tandem duplications of RUNX1 on chromosome 21 were also found, specifically in ML-DS samples (13.7%), presenting its essential role in DS leukemia progression. Finally, in 177 patients with ML-DS treated following the same ML-DS protocol (the Japanese Pediatric Leukemia and Lymphoma Study Group acute myeloid leukemia -D05/D11), CDKN2A, TP53, ZBTB7A, and JAK2 alterations were associated with a poor prognosis. Patients with CDKN2A deletions (n = 7) or TP53 mutations (n = 4) had substantially lower 3-year event-free survival (28.6% vs 90.5%; P < .001; 25.0% vs 89.5%; P < .001) than those without these mutations. These findings considerably change the mutational landscape of ML-DS, provide new insights into the mechanisms of progression from TAM to ML-DS, and help identify new therapeutic targets and strategies for ML-DS.
Assuntos
Síndrome de Down , Mutação , Humanos , Síndrome de Down/genética , Síndrome de Down/complicações , Masculino , Feminino , Reação Leucemoide/genética , Lactente , Pré-Escolar , Sequenciamento do Exoma , Prognóstico , Leucemia Mieloide/genética , Recém-Nascido , Criança , Subunidade alfa 2 de Fator de Ligação ao Core/genéticaRESUMO
The prognosis of patients with osteosarcoma who experience recurrence or progression (R/P) is extremely poor, and more effective and less toxic therapies are needed. In the current study, the clinical data of osteosarcoma patients who experienced R/P were retrospectively analyzed to verify the reliability of O-6-methylguanine-DNA methyltransferase (MGMT) protein expression or MGMT promoter methylation for predicting the response to off-label temozolomide (TMZ)-containing chemotherapy. Of the 30 evaluable patients, 9 (30%) showed no/low MGMT protein expression, whereas all 16 evaluable patients had unmethylated MGMT promoter irrespective of MGMT protein expression levels. Twenty-three patients received TMZ-containing chemotherapy for measurable lesions (n = 14) or as adjuvant therapy following resection of recurrent lesions (n = 9). Among 14 patients with radiologically measurable lesions, the objective response rate was higher in the MGMT no/low-expression group (50.0%) than in the MGMT intermediate/high-expression group with borderline significance (0%, p = 0.066). The 6-month progression-free survival (PFS) rate in patients with radiologically measurable lesions was significantly higher in the MGMT no/low-expression group (50.0%) than in the MGMT intermediate/high-expression group (0%, p = 0.036). In the multivariate analysis of the 23 patients receiving TMZ-containing chemotherapy, MGMT expression and disease status before TMZ-containing chemotherapy were significantly associated with PFS. No severe adverse effects were observed during TMZ-containing chemotherapy. MGMT protein expression, but not MGMT promoter methylation, could predict a favorable outcome in patients receiving TMZ-containing chemotherapy.
RESUMO
Here, we describe two patients with juvenile xanthogranuloma (JXG) manifesting with Langerhans cell histiocytosis (LCH)-associated neurodegenerative disease (ND)-like radiological findings. One patient showed typical radiological abnormalities at onset, which worsened with progressing central nervous system symptoms 7 years after LCH-oriented chemotherapy. Another showed spontaneous regression of clinical symptoms, with a transient radiological change 1 year after salvage chemotherapy for recurrence of JXG. These data regarding JXG-associated ND will facilitate future investigation of the disease, as well as development of therapeutic interventions.
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Histiocitose de Células de Langerhans , Doenças Neurodegenerativas , Xantogranuloma Juvenil , Criança , Humanos , Lactente , Masculino , Histiocitose de Células de Langerhans/diagnóstico por imagem , Histiocitose de Células de Langerhans/patologia , Histiocitose de Células de Langerhans/complicações , Histiocitose de Células de Langerhans/tratamento farmacológico , Imageamento por Ressonância Magnética , Doenças Neurodegenerativas/diagnóstico por imagem , Doenças Neurodegenerativas/patologia , Doenças Neurodegenerativas/complicações , Xantogranuloma Juvenil/diagnóstico por imagem , Xantogranuloma Juvenil/patologiaRESUMO
There is no clear consensus on the most effective treatment for relapsed/refractory high-risk neuroblastoma (NB). We retrospectively assessed seven NB patients with relapsed/refractory disease who received high-dose carboplatin-irinotecan-temozolomide (HD-CIT). Five of seven patients showed favorable therapeutic response (complete remission or partial remission). Regarding toxicity, the cytopenia period tended to prolong when more than three cycles were repeated, but nonhematological toxicities were controllable with general supportive care. Due to its antitumor efficacy and well-tolerated nonhematologic toxicity, HD-CIT is a promising salvage chemotherapy for relapsed/refractory NB. However, it is important to pay attention to the exacerbation of hematological toxicity when repeating the regimen.
Assuntos
Neuroblastoma , Humanos , Carboplatina , Irinotecano , Temozolomida , Estudos Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica , Terapia de Salvação , Recidiva Local de NeoplasiaRESUMO
Detailed case reports of autologous recovery of hematopoiesis after hematopoietic stem cell transplantation with myeloablative conditioning are scarce. We present a rare case of a 3-year-old male with relapsed KMT2A -rearranged acute lymphoblastic leukemia who experienced autologous recovery following secondary engraftment failure after cord blood transplantation with myeloablative conditioning. Similar to prior reports, we detected unusual chromosomal abnormalities, which differed at each bone marrow examination. He remains alive without relapse of acute lymphoblastic leukemia 8 months after cord blood transplantation. As the rate of recurrence or late occurrence of secondary malignant neoplasm remains unclear, careful follow-up is required, especially in pediatric patients.
Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Masculino , Humanos , Criança , Pré-Escolar , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Doença Crônica , Condicionamento Pré-Transplante/efeitos adversos , RecidivaRESUMO
Pediatric colorectal cancer (CRC) is extremely rare, with little information about genetic profiles compared with adult CRC. Here, a 13-year-old male with advanced CRC underwent cancer gene panel testing, which detected 4 genetic abnormalities ( MET amplification in addition to TP53 , SMAD4 , and CTNNA1 mutations) that might be associated with a poor prognosis. Based on high-level MET amplification, he received a multikinase inhibitor, cabozantinib, after failure of first-line and second-line chemotherapy, resulting in transient disease stabilization. Tailored targeted therapy based on molecular profiling can be an effective treatment strategy for rare cancers such as pediatric CRC.
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Neoplasias Colorretais , Piridinas , Adulto , Masculino , Humanos , Criança , Adolescente , Piridinas/uso terapêutico , Anilidas/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , MutaçãoRESUMO
BACKGROUND: Patients with osteosarcoma who experience relapse or progression [R/P] have a poor prognosis. METHODS: Data from 30 patients who experienced R/P among 59 with a diagnosis of high-grade osteosarcoma, who were younger than 40 years old between 2000 and 2019, were retrospectively analyzed to identify prognostic and therapeutic factors influencing their outcomes. RESULTS: The 5-year overall survival [OS] rates after the last R/P of patients experiencing first [n=30], second [n=14], and third [n=9] R/P were 50.3%, 51.3%, and 46.7%, respectively. Multivariate analysis did not identify any independent risk factors affecting OS. The 5-year PFS rate of the 30 patients after first R/P was 22.4%, and multivariate analysis identified histologic subtype and curative local surgery as independent risk factors influencing PFS. Long [>6 mo] partial response was observed in three patients treated using temozolomide+etoposide, irinotecan+carboplatin, or regorafenib. CONCLUSIONS: OS rate in the patients with osteosarcoma experiencing R/P included in this study was markedly higher than that reported previously, mainly due to the surgical total removal of tumors, even after subsequent R/P. The recent establishment of salvage chemotherapy or molecular targeted therapy may also increase survival rates in a subgroup of patients.
Assuntos
Neoplasias Ósseas , Osteossarcoma , Humanos , Adulto , Estudos Retrospectivos , Recidiva Local de Neoplasia/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Osteossarcoma/tratamento farmacológico , Osteossarcoma/patologia , Prognóstico , Neoplasias Ósseas/patologiaRESUMO
Lineage switch is a rare event at leukemic relapse. While mostly known to occur in KMT2A-rearranged infant leukemia, the underlying mechanism is yet to be depicted. This case report describes a female infant who achieved remission of KMT2A-MLLT3-rearranged acute monocytic leukemia, but 6 months thereafter, relapsed as KMT2A-MLLT3-rearranged acute lymphocytic leukemia. Whole exome sequencing of the bone marrow obtained pre-post lineage switch revealed two somatic mutations of PAX5 in the relapse sample. These two PAX5 alterations were suggested to be loss of function, thus to have played the driver role in the lineage switch from acute monocytic leukemia to acute lymphocytic leukemia.
Assuntos
Leucemia Monocítica Aguda , Leucemia Mieloide Aguda , Leucemia-Linfoma Linfoblástico de Células Precursoras , Medula Óssea , Criança , Feminino , Histona-Lisina N-Metiltransferase , Humanos , Lactente , Leucemia Monocítica Aguda/genética , Leucemia Mieloide Aguda/genética , Proteína de Leucina Linfoide-Mieloide/genética , Fator de Transcrição PAX5 , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , RecidivaRESUMO
Due to the considerable success of cancer immunotherapy for leukemia, the tumor immune environment has become a focus of intense research; however, there are few reports on the dynamics of the tumor immune environment in leukemia. Here, we analyzed the tumor immune environment in pediatric B cell precursor acute lymphoblastic leukemia by analyzing serial bone marrow samples from nine patients with primary and recurrent disease by mass cytometry using 39 immunophenotype markers, and transcriptome analysis. High-dimensional single-cell mass cytometry analysis elucidated a dynamic shift of T cells from naïve to effector subsets, and clarified that, during relapse, the tumor immune environment comprised a T helper 1-polarized immune profile, together with an increased number of effector regulatory T cells. These results were confirmed in a validation cohort using conventional flow cytometry. Furthermore, RNA transcriptome analysis identified the upregulation of immune-related pathways in B cell precursor acute lymphoblastic leukemia cells during relapse, suggesting interaction with the surrounding environment. In conclusion, a tumor immune environment characterized by a T helper 1-polarized immune profile, with an increased number of effector regulatory T cells, could contribute to the pathophysiology of recurrent B cell precursor acute lymphoblastic leukemia. This information could contribute to the development of effective immunotherapeutic approaches against B cell precursor acute lymphoblastic leukemia relapse.
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Biomarcadores Tumorais/genética , Medula Óssea/imunologia , Perfilação da Expressão Gênica/métodos , Recidiva Local de Neoplasia/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Adolescente , Medula Óssea/química , Criança , Pré-Escolar , Feminino , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica , Humanos , Lactente , Masculino , Recidiva Local de Neoplasia/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Análise de Sequência de RNA , Análise de Célula Única , Microambiente Tumoral , Regulação para Cima , Adulto JovemRESUMO
The prognosis of patients with osteosarcoma recurring at extrapulmonary/extraosseous sites, especially those with unresectable tumors, is generally dismal due to high resistance to chemotherapy. The present study describes a pediatric patient with osteosarcoma recurring to the liver and stomach. Complete remission was achieved by long-term systemic chemotherapy with temozolomide+etoposide, local irradiation of the stomach, and radical surgical removal of multiple liver metastases following percutaneous transhepatic portal embolization. Second-line multimodal therapy, consisting of salvage chemotherapy and curative local treatment of metastases, may enhance disease-free survival of patients with osteosarcoma experiencing relapse to uncommon sites.
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Neoplasias Ósseas , Osteossarcoma , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/patologia , Criança , Terapia Combinada , Etoposídeo/uso terapêutico , Humanos , Fígado/patologia , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/etiologia , Osteossarcoma/tratamento farmacológico , Osteossarcoma/patologia , Estômago , TemozolomidaRESUMO
Neuroblastoma, the most common extracranial solid tumor of childhood, is thought to arise from neural crest-derived immature cells. The prognosis of patients with high-risk or recurrent/refractory neuroblastoma remains quite poor despite intensive multimodality therapy; therefore, novel therapeutic interventions are required. We examined the expression of a cell adhesion molecule CD146 (melanoma cell adhesion molecule [MCAM]) by neuroblastoma cell lines and in clinical samples and investigated the anti-tumor effects of CD146-targeting treatment for neuroblastoma cells both in vitro and in vivo. CD146 is expressed by 4 cell lines and by most of primary tumors at any stage. Short hairpin RNA-mediated knockdown of CD146, or treatment with an anti-CD146 polyclonal antibody, effectively inhibited growth of neuroblastoma cells both in vitro and in vivo, principally due to increased apoptosis via the focal adhesion kinase and/or nuclear factor-kappa B signaling pathway. Furthermore, the anti-CD146 polyclonal antibody markedly inhibited tumor growth in immunodeficient mice inoculated with primary neuroblastoma cells. In conclusion, CD146 represents a promising therapeutic target for neuroblastoma.
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Anticorpos/uso terapêutico , Antígeno CD146/antagonistas & inibidores , Terapia de Alvo Molecular/métodos , Neuroblastoma/terapia , RNA Interferente Pequeno/uso terapêutico , Animais , Apoptose , Antígeno CD146/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular , Quinase 1 de Adesão Focal/metabolismo , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Técnicas de Silenciamento de Genes , Xenoenxertos , Humanos , Camundongos , NF-kappa B/metabolismo , Recidiva Local de Neoplasia , Transplante de Neoplasias , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Prognóstico , Transdução de Sinais , Esferoides Celulares , Transdução Genética/métodosRESUMO
Growing teratoma syndrome is a well-recognized condition associated with both intracranial and extracranial nongerminomatous germ cell tumors (NGGCTs), which mostly manifest as rapid growth of cystic and solid components during or within several months after treatment. Here, we report a patient with NGGCT who experienced slow growth of intracranial growing teratoma syndrome with intraventricular lipid accumulation over 10 years without any clinical symptoms. Considering the clinicopathologic heterogeneity of this syndrome, long-term clinical and radiologic follow-up is required for all patients with intracranial NGGCT.
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Neoplasias Encefálicas/patologia , Lipídeos/análise , Teratoma/patologia , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/metabolismo , Pré-Escolar , Humanos , Metabolismo dos Lipídeos , Masculino , Pinealoma/diagnóstico , Pinealoma/metabolismo , Pinealoma/patologia , Teratoma/diagnóstico , Teratoma/metabolismoRESUMO
Cryotherapy is a conventional method for preventing melphalan-induced oral mucositis (OM) in adult patients. We retrospectively examined the clinical benefits of cryotherapy in 41 pediatric patients undergoing autologous stem cell transplantation using a melphalan-etoposide-carboplatin regimen. Twenty-two patients received cryotherapy. The cumulative incidence of grade 3-4 OM was significantly lower in the cryotherapy group (57.1%) than in the noncryotherapy group (89.5%; P = .041). Multivariate analyses identified cryotherapy and the melphalan dose as independent factors for the lower occurrence of OM. The present study demonstrates the clinically significant efficacy of cryotherapy for preventing melphalan-induced OM in pediatric patients.
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Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Crioterapia/métodos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Melfalan/efeitos adversos , Neoplasias/terapia , Estomatite/terapia , Adolescente , Adulto , Carboplatina/administração & dosagem , Criança , Pré-Escolar , Terapia Combinada , Relação Dose-Resposta a Droga , Etoposídeo/administração & dosagem , Feminino , Seguimentos , Humanos , Lactente , Masculino , Melfalan/administração & dosagem , Neoplasias/patologia , Prognóstico , Estudos Retrospectivos , Estomatite/induzido quimicamente , Estomatite/patologia , Transplante Autólogo , Adulto JovemRESUMO
The prognosis of patients with relapsed osteosarcoma is extremely poor and the optimal treatment remains to be identified. Here, we retrospectively analysed the clinical outcomes of nine patients with relapsed osteosarcoma treated with temozolomide/etoposide. Of the two patients who received temozolomide/etoposide as palliative therapy for unresectable tumours, one remained alive with stable disease for >4 years. The remaining seven patients received temozolomide/etoposide as adjuvant therapy following resection of relapsed metastatic disease; of these, one was free from disease for 41 months. Potentially beneficial effects were observed in two of three O6-methylguanine-DNA methyltransferase protein-negative patients, whereas all five O6-methylguanine-DNA methyltransferase-positive patients experienced subsequent relapse. None of the patients experienced severe adverse effects requiring hospitalization. Temozolomide/etoposide is a feasible candidate as salvage therapy for relapsed osteosarcoma. Further studies are needed to verify the utility of O6-methylguanine-DNA methyltransferase protein expression as a biomarker for predicting the response to this treatment.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Etoposídeo/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Osteossarcoma/tratamento farmacológico , Temozolomida/uso terapêutico , Adolescente , Adulto , Antineoplásicos Alquilantes/uso terapêutico , Criança , Feminino , Humanos , Masculino , Prognóstico , Estudos Retrospectivos , Adulto JovemRESUMO
No studies have examined CMV infection in pediatric patients with HB receiving LT. Here, we retrospectively analyzed the incidence of and risk factors for CMV infection in 24 pediatric patients with HB who underwent LT between 1997 and 2015. CMV infection was monitored by measuring expression of pp65 CMV antigen for up to 4 months post-LT. CMV infection, defined as detection of at least one pp65-positive leukocyte, was detected in nine (37.5%) patients who did not develop CMV disease. Nine (47.4%) of nineteen patients who received post-LT chemotherapy experienced CMV infection; however, no CMV infection was observed in the five patients who did not receive post-LT chemotherapy (P = 0.012). There were no significant differences in the incidence of CMV infection between patients with ACR (60.0%) and those without (21.4%, P = 0.092), or between CMV seropositive (55.6%) and seronegative patients (33.3%, P = 0.675). All nine patients with CMV infection did not experience CMV disease due to the use of preemptive antiviral therapy. Close monitoring of CMV infection is recommended for patients with HB, particularly those receiving post-LT chemotherapy. Preemptive antiviral therapy is feasible for prophylaxis of CMV disease.
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Infecções por Citomegalovirus/etiologia , Hepatoblastoma/cirurgia , Neoplasias Hepáticas/cirurgia , Transplante de Fígado , Complicações Pós-Operatórias/etiologia , Adolescente , Antivirais/uso terapêutico , Criança , Pré-Escolar , Infecções por Citomegalovirus/diagnóstico , Infecções por Citomegalovirus/epidemiologia , Infecções por Citomegalovirus/prevenção & controle , Feminino , Seguimentos , Humanos , Incidência , Lactente , Masculino , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/prevenção & controle , Estudos Retrospectivos , Fatores de RiscoRESUMO
LT has contributed to an elevation in cure rates for patients with unresectable HB; however, patients with recurrent HB after LT have poor prognosis. To analyze the prognostic and therapeutic factors that influence the clinical outcome of patients with HB receiving LT, we retrospectively analyzed 24 patients with HB who underwent LT between 1997 and 2015. The 5-year OS rate of all patients was 69.6±9.7%. The 5-year OS rate of 11 patients receiving salvage LT for recurrent tumor after a primary resection was comparable to that of 13 patients receiving primary LT. Among 12 evaluable patients receiving primary LT, six of 10 patients with a decline of serum AFP >95% at LT are currently alive and in remission, whereas two patients with a decline of AFP ≤95% experienced post-LT relapse. Among 9 evaluable patients receiving salvage LT, all three patients with any decline of AFP at LT are currently alive in remission, and three of six patients with no response to pre-LT salvage chemotherapy are also alive and in remission. Response to chemotherapy may be a reliable marker for prediction of post-LT relapse, even for patients receiving salvage LT.
Assuntos
Hepatoblastoma/cirurgia , Neoplasias Hepáticas/cirurgia , Transplante de Fígado , Recidiva Local de Neoplasia/etiologia , Antineoplásicos/uso terapêutico , Quimioterapia Adjuvante , Criança , Pré-Escolar , Feminino , Seguimentos , Hepatoblastoma/diagnóstico , Hepatoblastoma/tratamento farmacológico , Hepatoblastoma/mortalidade , Humanos , Lactente , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/mortalidade , Masculino , Terapia Neoadjuvante , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/cirurgia , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Terapia de Salvação , Análise de Sobrevida , Resultado do TratamentoRESUMO
A 16-year-old boy was incidentally found to have hyperleukocytosis during a school physical examination. He was diagnosed with atypical chronic myeloid leukemia in chronic phase. Although treatment with hydoxyurea was started, his white blood cell count increased and he eventually developed lethal intracranial hemorrhage. Although very rare, intracranial hemorrhage should be considered as a possible complication in patients with atypical chronic myeloid leukemia, even in chronic phase, if they have hyperleukocytosis and thrombocytopenia.