RESUMO
ABSTRACT: Acute leukemia cells require bone marrow microenvironments, known as niches, which provide leukemic cells with niche factors that are essential for leukemic cell survival and/or proliferation. However, it remains unclear how the dynamics of the leukemic cell-niche interaction are regulated. Using a genome-wide CRISPR screen, we discovered that canonical BRG1/BRM-associated factor (cBAF), a variant of the switch/sucrose nonfermenting chromatin remodeling complex, regulates the migratory response of human T-cell acute lymphoblastic leukemia (T-ALL) cells to a niche factor CXCL12. Mechanistically, cBAF maintains chromatin accessibility and allows RUNX1 to bind to CXCR4 enhancer regions. cBAF inhibition evicts RUNX1 from the genome, resulting in CXCR4 downregulation and impaired migration activity. In addition, cBAF maintains chromatin accessibility preferentially at RUNX1 binding sites, ensuring RUNX1 binding at these sites, and is required for expression of RUNX1-regulated genes, such as CDK6; therefore, cBAF inhibition negatively impacts cell proliferation and profoundly induces apoptosis. This anticancer effect was also confirmed using T-ALL xenograft models, suggesting cBAF as a promising therapeutic target. Thus, we provide novel evidence that cBAF regulates the RUNX1-driven leukemic program and governs migration activity toward CXCL12 and cell-autonomous growth in human T-ALL.
Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Humanos , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Medula Óssea/metabolismo , Cromatina , Linfócitos T/metabolismo , Linhagem Celular Tumoral , Microambiente TumoralRESUMO
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.
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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
Chimeric antigen receptor T-cell therapy (CAR-T-cell therapy) has revolutionized the treatment of relapsed and refractory hematological malignancies. Targeting of the CD19 antigen on B cells has yielded high rates of remission induction and sustained remission in patients with acute lymphoblastic leukemia and B-cell lymphomas. Despite these remarkable responses, many escape mechanisms from CAR-T cell therapy have been identified, with the most common being target antigen deficiency. This paper focuses on CD19 CAR-T cell therapies, which are currently the most clinically used, and describes new strategies to overcome resistance using multi-targeted CAR-T cells, such as CD19-CD20 CAR-T cells and CD19-CD22 CAR-T cells, which are being developed in preclinical and clinical trials.
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Antígenos CD19 , Humanos , Antígenos CD19/imunologia , Imunoterapia Adotiva/métodos , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/imunologiaRESUMO
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.
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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.
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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.
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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
A lack of practical resources in Japan has limited preclinical discovery and testing of therapies for pediatric relapsed and refractory acute lymphoblastic leukemia (ALL), which has poor outcomes. Here, we established 57 patient-derived xenografts (PDXs) in NOD.Cg-Prkdcscid ll2rgtm1Sug /ShiJic (NOG) mice and created a biobank by preserving PDX cells including three extramedullary relapsed ALL PDXs. We demonstrated that our PDX mice and PDX cells mimicked the biological features of relapsed ALL and that PDX models reproduced treatment-mediated clonal selection. Our PDX biobank is a useful scientific resource for capturing drug sensitivity features of pediatric patients with ALL, providing an essential tool for the development of targeted therapies.
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Bancos de Espécimes Biológicos , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Camundongos , Animais , Ensaios Antitumorais Modelo de Xenoenxerto , Camundongos Endogâmicos NOD , Japão , Xenoenxertos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Camundongos SCID , Modelos Animais de DoençasRESUMO
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
The emergence of tyrosine kinase inhibitors as part of a front-line treatment has greatly improved the clinical outcome of the patients with Ph+ acute lymphoblastic leukemia (ALL). However, a portion of them still become refractory to the therapy mainly through acquiring mutations in the BCR-ABL1 gene, necessitating a novel strategy to treat tyrosine kinase inhibitor (TKI)-resistant Ph+ ALL cases. In this report, we show evidence that RUNX1 transcription factor stringently controls the expression of BCR-ABL1, which can strategically be targeted by our novel RUNX inhibitor, Chb-M'. Through a series of in vitro experiments, we identified that RUNX1 binds to the promoter of BCR and directly transactivates BCR-ABL1 expression in Ph+ ALL cell lines. These cells showed significantly reduced expression of BCR-ABL1 with suppressed proliferation upon RUNX1 knockdown. Moreover, treatment with Chb-M' consistently downregulated the expression of BCR-ABL1 in these cells and this drug was highly effective even in an imatinib-resistant Ph+ ALL cell line. In good agreement with these findings, forced expression of BCR-ABL1 in these cells conferred relative resistance to Chb-M'. In addition, in vivo experiments with the Ph+ ALL patient-derived xenograft cells showed similar results. In summary, targeting RUNX1 therapeutically in Ph+ ALL cells may lead to overcoming TKI resistance through the transcriptional regulation of BCR-ABL1. Chb-M' could be a novel drug for patients with TKI-resistant refractory Ph+ ALL.
Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Proteínas de Fusão bcr-abl/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Animais , Antineoplásicos/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/genética , Subunidade alfa 2 de Fator de Ligação ao Core/antagonistas & inibidores , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Mesilato de Imatinib/farmacologia , Camundongos , Mutação , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Inibidores de Proteínas Quinases/farmacologiaRESUMO
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.
Assuntos
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 impact of human leukocyte antigen (HLA) mismatching at the HLA-A, -B, -C, and -DRB1 loci after unrelated bone marrow transplantation in paediatric patients with haematological malignancies has not been fully examined. Here, we analysed patients with haematological malignancies (all aged ≤15 years; n = 1330) who underwent a first unrelated bone marrow transplantation between 1993 and 2017 in Japan. The results show that although an HLA mismatch was significantly associated with a low relapse rate, it was also associated with higher non-relapse mortality. There was a significant association between HLA mismatch and low overall survival. Locus mismatch analysis revealed that, as in adults, an HLA-C mismatch had a significant negative impact on survival; however, in paediatric patients, an HLA-DRB1 mismatch did not have a negative impact, although these HLA mismatch effects are weakened in recent cases. Taken together, the results suggest that an HLA-matched donor should be the first candidate for paediatric patients; however, for patients without a matched sibling or matched unrelated donor, we can select an unrelated donor with a mismatch at HLA-DRB1 if available.
Assuntos
Doença Enxerto-Hospedeiro , Neoplasias Hematológicas , Criança , Humanos , Transplante de Medula Óssea/métodos , Neoplasias Hematológicas/terapia , Teste de Histocompatibilidade , Antígenos HLA , Antígenos HLA-A , Antígenos HLA-C , Cadeias HLA-DRB1/genética , Recidiva Local de Neoplasia , Estudos Retrospectivos , Doadores não RelacionadosRESUMO
Acute lymphoblastic leukemia with chromosomal rearrangements involving the mixed-lineage leukemia (MLL) gene (MLL-r ALL) remains an incurable disease. Thus, development of a safe and effective therapeutic agent to treat this disease is crucial to address this unmet medical need. BRD4, a member of the bromodomain and extra-terminal domain (BET) protein family, and cyclic AMP response element binding protein binding protein (CBP) and p300, two paralogous histone acetyltransferases, are all considered cancer drug targets and simultaneous targeting of these proteins may have therapeutic advantages. Here, we demonstrate that a BET/CBP/p300 multi-bromodomain inhibitor, CN470, has anti-tumor activity against MLL-r ALL in vitro and in vivo. CN470, potently inhibited ligand binding to the bromodomains of BRD4, CBP, and p300 and suppressed the growth of MLL-r ALL cell lines and patient-derived cells with MLL rearrangements. CN470 suppressed mRNA and protein expression of MYC and induced apoptosis in MLL-r ALL cells, following a cell cycle arrest in the G1 phase. Moreover, CN470 reduced BRD4 binding to acetylated histone H3. The in vivo effects of CN470 were investigated using SEMLuc/GFP cells expressing luminescent markers in an orthotopic mouse model. Mice administered CN470 daily had prolonged survival compared to the vehicle group. Further, CN470 also showed anti-tumor effects against an MLL-r ALL patient-derived xenograft model. These findings suggest that inhibition of BET/CBP/p300 by the multi-bromodomain inhibitor, CN470, represents a promising therapeutic approach against MLL-r ALL.
Assuntos
Antineoplásicos/farmacologia , Proteína p300 Associada a E1A/antagonistas & inibidores , Rearranjo Gênico , Histona-Lisina N-Metiltransferase/genética , Proteína de Leucina Linfoide-Mieloide/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Proteína p300 Associada a E1A/metabolismo , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Rearranjo Gênico/efeitos dos fármacos , Humanos , Camundongos , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Análise de Sobrevida , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
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.
Assuntos
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
Bone marrow necrosis (BMN) describes necrosis of the myeloid tissues without cortical bone involvement. Imatinib, a tyrosine kinase inhibitor, can trigger BMN during the treatment of malignant disease. In such cases, it is necessary to reduce imatinib dose or discontinue its administration, which could influence treatment outcomes. Here, we report a 6-year-old boy with Philadelphia chromosome-positive acute lymphoblastic leukemia, who developed BMN in response to imatinib. We replaced imatinib with dasatinib, and necrotic lesions gradually disappeared and were never exacerbated. In Philadelphia chromosome-positive acute lymphoblastic leukemia with BMN, tyrosine kinase inhibitor replacement may allow continued chemotherapy without intensity reduction.
Assuntos
Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras , Medula Óssea , Criança , Humanos , Mesilato de Imatinib/uso terapêutico , Masculino , Necrose , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
Patient-derived xenograft (PDX) models have gained attention due to their wide applications in basic research and drug development, and due to the increase in requirements for pathological analysis and anticancer drug evaluation. The development of immunodeficient mouse strains with high-level engraftment of normal and diseased cells has contributed to the considerable progress in understanding the human pathophysiology. The PDX model is one of the most important tools to bridge the gap between traditional animal models and the clinical trials. PDX not only recapitulates human disease in vivo, but also multiplies the tumor cells. Therefore, efforts were made internationally to develop a PDX bank for leukemias and solid tumors for future research and experimentation. PDX might be an ideal model to simulate actual human diseases for cancer research; however, some challenges still persist. Thus, this review aimed to summarize the developmental history of immune-deficient mice, the efforts of overcoming PDX limitations, PDX model applications for preclinical research, and the current attempts to establish domestic leukemia PDX bank in Japan.
Assuntos
Leucemia , Neoplasias , Animais , Modelos Animais de Doenças , Xenoenxertos , Humanos , Leucemia/terapia , Camundongos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
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.
Assuntos
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.
Assuntos
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
This is a case report of a successful single-lobe lung transplantation for pulmonary hypertension secondary to alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV). A 6-year-old boy underwent living-donor single-lobe transplantation with the right lower lobe from his 31-year-old mother. The pretransplantation graft size matching was acceptable: the estimated graft forced vital capacity (FVC) was 96.5% of the recipient's predicted FVC, and the graft size measured by computed tomography (CT) volumetry was 166% of the recipient's chest cavity volume. Right pneumonectomy followed by implantation was performed under cardiopulmonary bypass (CPB). The pulmonary arterial pressure was significantly decreased to 31/12 mm Hg immediately after transplantation, and the first PaO2 /FiO2 in the intensive-care unit (ICU) was 422 mm Hg. Lung perfusion scintigraphy showed 97.5% perfusion to the right implanted lung 3 months after transplantation. Chest CT showed a mass rapidly growing in the native left upper lobe 6 months after transplantation, which was diagnosed as posttransplant lymphoproliferative disorder (PTLD) by a CT-guided biopsy. After immunosuppressant reduction and six courses of chemotherapy with rituximab, he underwent native left upper lobectomy for salvage lung resection 13 months after transplantation. Seven months after lobectomy, he has returned to normal school life without any sign of tumor recurrence.