RESUMO
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.
Assuntos
Neoplasias Colorretais , Piridinas , Adulto , Masculino , Humanos , Criança , Adolescente , Piridinas/uso terapêutico , Anilidas/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , MutaçãoRESUMO
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
Shwachman-Diamond syndrome (SDS), an autosomal recessive disorder characterized by bone marrow failure, exocrine pancreatic insufficiency, and skeletal abnormalities, is caused by mutations in the Shwachman-Bodian-Diamond syndrome (SBDS) gene, which plays a role in ribosome biogenesis. Although the causative genes of congenital disorders frequently involve regulation of embryogenesis, the role of the SBDS gene in early hematopoiesis remains unclear, primarily due to the lack of a suitable experimental model for this syndrome. In this study, we established induced pluripotent stem cells (iPSCs) from patients with SDS (SDS-iPSCs) and analyzed their in vitro hematopoietic and endothelial differentiation potentials. SDS-iPSCs generated hematopoietic and endothelial cells less efficiently than iPSCs derived from healthy donors, principally due to the apoptotic predisposition of KDR+CD34+ common hemoangiogenic progenitors. By contrast, forced expression of SBDS gene in SDS-iPSCs or treatment with a caspase inhibitor reversed the deficiency in hematopoietic and endothelial development, and decreased apoptosis of their progenitors, mainly via p53-independent mechanisms. Patient-derived iPSCs exhibited the hematological abnormalities associated with SDS even at the earliest hematopoietic stages. These findings will enable us to dissect the pathogenesis of multiple disorders associated with ribosomal dysfunction.
Assuntos
Diferenciação Celular , Células Endoteliais , Hematopoese , Células-Tronco Hematopoéticas , Células-Tronco Pluripotentes Induzidas , Síndrome de Shwachman-Diamond , Apoptose/genética , Células Cultivadas , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/patologia , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/patologia , Japão , Masculino , Mutação , Proteínas/genética , Síndrome de Shwachman-Diamond/metabolismo , Síndrome de Shwachman-Diamond/patologiaRESUMO
We report on three cases of pediatric acute lymphoblastic leukemia presenting with bone pain and arthralgia as initial symptoms. At the first visit, their primary signs were recurrent bone pain and arthralgia, without significant peripheral blood abnormalities. It took 2-4 months to confirm the diagnosis from the onset of arthralgia due to this atypical presentation of the disease. Definitive diagnosis was obtained by bone marrow examination, and in all cases, complete remission was achieved by chemotherapy. As a feature of imaging, MRI exhibited diffuse bone marrow signal changes in T1-weighted images, and FDG-PET showed extensive abnormal bone marrow uptakes. In cases 2 and 3, it was difficult to diagnose by bone marrow aspiration from the iliac bone, but definitive diagnosis was obtained by bone marrow aspiration from the tibia, in which FDG-PET showed increased uptake. FDG-PET was therefore considered useful for the selection of bone marrow aspiration sites. In cases presenting with recurrent migratory bone pain and arthralgia, we need to consider performing bone marrow aspiration and imaging, such as MRI and FDG-PET, for early diagnosis and treatment of leukemia.
Assuntos
Doenças Ósseas/etiologia , Dor/etiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Artralgia/etiologia , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Indução de RemissãoRESUMO
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.
Assuntos
Hidroxiureia , Hemorragias Intracranianas , Leucemia Mielogênica Crônica BCR-ABL Positiva , Adolescente , Humanos , Hidroxiureia/administração & dosagem , Hidroxiureia/efeitos adversos , Hemorragias Intracranianas/sangue , Hemorragias Intracranianas/induzido quimicamente , Hemorragias Intracranianas/patologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/sangue , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Contagem de Leucócitos , MasculinoAssuntos
Subunidade gama Comum de Receptores de Interleucina/deficiência , Linfoma Anaplásico de Células Grandes/genética , Linfoma Anaplásico de Células Grandes/patologia , Bexiga Urinária/patologia , Animais , Criança , Modelos Animais de Doenças , Feminino , Xenoenxertos , Humanos , Linfoma Anaplásico de Células Grandes/diagnóstico , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Invasividade Neoplásica , Tomografia por Emissão de Pósitrons , Tomografia Computadorizada por Raios XRESUMO
The incidence of HHV-6 encephalitis during hematopoietic stem cell transplantation (HSCT) in children is thought to be less than that in adults and risk factors, prognosis and complications are virtually unknown. Herein, we report a pediatric case developing epileptic encephalopathy following HHV-6 encephalitis after a second cord blood transplantation (CBT). A 7-year-old boy with relapsed B-precursor acute lymphoblastic leukemia in second remission underwent CBT. However, he received a second CBT due to graft failure. On day 25 after the second CBT, he developed short-term memory defects and seizures. He was diagnosed with HHV-6 encephalitis because HHV-6 DNA was detected in his blood and cerebrospinal fluid and abnormal hippocampal signals were seen on cranial magnetic resonance imaging (MRI). After treatment with foscarnet, HHV-6 DNA levels and MRI findings improved; however, he developed epileptic encephalopathy five months after the onset of encephalitis. There are very few reports on pediatric epileptic encephalopathy associated with HHV-6 encephalitis after HSCT. Detailed studies are needed to analyze risk factors, prognosis, and complications.