RESUMO
The purpose of this study is to establish a treatment with appropriate intensity for children (<16 years old at diagnosis) with de novo acute myeloid leukemia (excluding acute promyelocytic leukemia and myeloid leukemia associated with Down syndrome) according to a risk stratification based on recurrent leukemic cytogenetic abnormalities and flow-cytometric minimal residual disease at end of initial induction chemotherapy and to validate the safety and efficacy of gemtuzumab ozogamicin (GO)-combined post-induction chemotherapy for the non-low-risk (non-LR) patients. The primary endpoint of this phase III study is three-year disease-free survival rate, which will be compared between the GO and non-GO arms of the non-LR (intermediate-risk and high-risk [HR]) patients. All HR patients will be allocated to allogeneic hematopoietic stem cell transplantation in first remission. This trial has been registered at the Japan Registry of Clinical Trials (jRCTs041210015).
Assuntos
Quimioterapia de Indução , Leucemia Mieloide Aguda , Adolescente , Aminoglicosídeos/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Criança , Gemtuzumab , Humanos , Neoplasia Residual/tratamento farmacológico , Medição de RiscoRESUMO
Cell-free DNA (cfDNA), which are small DNA fragments in blood derived from dead cells including tumor cells, could serve as useful biomarkers and provide valuable genetic information about the tumors. cfDNA is now used for the genetic analysis of several types of cancers, as a surrogate for tumor biopsy, designated as "liquid biopsy." Rhabdomyosarcoma (RMS), the most frequent soft tissue tumor in childhood, can arise in any part of the body, and radiological imaging is the only available method for estimating the tumor burden, because no useful specific biological markers are present in the blood. Because tumor volume is one of the determinants of treatment response and outcome, early detection at diagnosis as well as relapse is essential for improving the treatment outcome. A 15-year-old male patient was diagnosed with alveolar RMS of prostate origin with bone marrow invasion. The PAX3-FOXO1 fusion was identified in the tumor cells in the bone marrow. After the diagnosis, cfDNA was serially collected to detect the PAX3-FOXO1 fusion sequence as a tumor marker. cfDNA could be an appropriate source for detecting the fusion gene; assays using cfDNA have proved to be useful for the early detection of tumor progression/recurrence. Additionally, the fusion gene dosage estimated by quantitative polymerase chain reaction reflected the tumor volume during the course of the treatment. We suggest that for fusion gene-positive RMSs, and other soft tissue tumors, the fusion sequence should be used for monitoring the tumor burden in the body to determine the diagnosis and treatment options for the patients.
Assuntos
Biomarcadores Tumorais , DNA Tumoral Circulante , Proteínas de Fusão Oncogênica/genética , Fatores de Transcrição Box Pareados/genética , Rabdomiossarcoma Alveolar/diagnóstico , Rabdomiossarcoma Alveolar/genética , Adolescente , Biópsia , Detecção Precoce de Câncer , Humanos , Masculino , Reação em Cadeia da Polimerase , Tomografia por Emissão de Pósitrons , Prognóstico , Recidiva , Rabdomiossarcoma Alveolar/terapia , Análise de Sequência de DNARESUMO
Primary bone marrow lymphoma (PBML) is hard to diagnose in children, due to the difficult identification of malignant cells in bone marrow. The first case, a 5-year-old boy, showed knee swelling with an intermittent fever. The second case, a 12-year-old girl, showed fever of unknown origin without lymphadenopathy or hepatosplenomegaly. In both cases, the diagnosis was not confirmed despite the repeated bone marrow aspirations. Finally, bone marrow aspiration and biopsy at the positive site by positron emission tomography (PET)-CT contributed to definitive diagnosis of PBML. The PET-CT is useful for the accurate diagnosis of PBML in children with non-specific symptoms.
Assuntos
Neoplasias da Medula Óssea/diagnóstico por imagem , Linfoma/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Tomografia Computadorizada por Raios X , Criança , Pré-Escolar , Feminino , Humanos , MasculinoRESUMO
Although outcomes for infant leukemia have improved recently, transient adrenal insufficiency is commonly observed during treatment, especially after glucocorticoid administration. We identified three infants with acute leukemia who suffered from prolonged adrenal insufficiency requiring long-term (from 15 to 66 months) hydrocortisone replacement. All infants showed life-threatening symptoms associated with adrenal crisis after viral infections or other stress. Severe and prolonged damage of hypothalamo-pituitary-adrenal (HPA) axis is likely to occur in early infants with leukemia, therefore routine tolerance testing to evaluate HPA axis and hydrocortisone replacement therapy are recommended for infants with leukemia to avoid life-threatening complications caused by adrenal crisis.
Assuntos
Insuficiência Adrenal , Glucocorticoides/efeitos adversos , Leucemia/tratamento farmacológico , Doença Aguda , Insuficiência Adrenal/induzido quimicamente , Insuficiência Adrenal/metabolismo , Insuficiência Adrenal/patologia , Insuficiência Adrenal/terapia , Pré-Escolar , Feminino , Glucocorticoides/administração & dosagem , Humanos , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipotálamo-Hipofisário/patologia , Recém-Nascido , Leucemia/metabolismo , Leucemia/patologia , Masculino , Sistema Hipófise-Suprarrenal/metabolismo , Sistema Hipófise-Suprarrenal/patologia , Fatores de TempoRESUMO
We report the long-term morbidity and mortality of 105 pediatric patients who developed chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). According to the consensus criteria of the National Institutes of Health, the global severity of cGVHD was mild in 26 patients (25%), moderate in 30 patients (29%), and severe in 49 patients (47%). Patients with severe cGVHD had a significantly lower cumulative incidence of cGVHD remission and higher probability of continuing cGVHD at 8 years from cGVHD diagnosis compared with those with mild or moderate cGVHD. The 10-year cumulative incidence of nonrelapse mortality in severe cGVHD patients was significantly higher and the probability of disease-free survival was significantly lower than those among patients with mild and moderate cGVHD. Of the 59 patients who survived for more than 5 years, 20 (34%) (4 with moderate and 16 with severe cGVHD) had persistent functional impairment caused by cGVHD with a Karnofsky/Lansky performance score of 90% in 3 patients, 80% in 4 patients, and below 70% in 13 patients at the time of relapse, death, or last follow-up. Better therapeutic strategies are needed to lower the incidence of severe cGVHD, considering the longer life expectancy of pediatric HSCT survivors.
Assuntos
Doença Enxerto-Hospedeiro/patologia , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas , Imunossupressores/uso terapêutico , Agonistas Mieloablativos/uso terapêutico , Condicionamento Pré-Transplante/métodos , Adolescente , Criança , Pré-Escolar , Doença Crônica , Consenso , Feminino , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/terapia , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/patologia , Teste de Histocompatibilidade , Humanos , Lactente , Recém-Nascido , Masculino , National Institutes of Health (U.S.) , Estudos Retrospectivos , Índice de Gravidade de Doença , Análise de Sobrevida , Terminologia como Assunto , Doadores de Tecidos , Transplante Homólogo , Estados UnidosRESUMO
Aurora kinase A (AURKA) is overexpressed in leukemias. Previously, we demonstrated that AURKA-specific CD8(+) T cells specifically and selectively lysed leukemia cells, indicating that AURKA is an excellent target for immunotherapy. In this study, we examined the feasibility of adoptive therapy using redirected T cells expressing an HLA-A*0201-restricted AURKA(207-215)-specific T-cell receptor (TCR). Retrovirally transduced T cells recognized relevant peptide-pulsed but not control target cells. Furthermore, TCR-redirected CD8(+) T cells lysed AURKA-overexpressing human leukemic cells in an HLA-A*0201-restricted manner, but did not kill HLA-A*0201(+) normal cells, including hematopoietic progenitors. In addition, AURKA(207-215)-specific TCR-transduced CD4(+) T cells displayed target-responsive Th1 cytokine production. Finally, AURKA(207-215)-specific TCR-transduced CD8(+) T cells displayed antileukemia efficacy in a xenograft mouse model. Collectively, these data demonstrate the feasibility of redirected T cell-based AURKA-specific immunotherapy for the treatment of human leukemia.
Assuntos
Genes Codificadores dos Receptores de Linfócitos T/genética , Terapia Genética , Imunoterapia , Leucemia/terapia , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/imunologia , Linfócitos T/imunologia , Animais , Aurora Quinase A , Aurora Quinases , Western Blotting , Estudos de Casos e Controles , Estudos de Viabilidade , Citometria de Fluxo , Antígeno HLA-A2/imunologia , Humanos , Leucemia/genética , Leucemia/imunologia , Luciferases/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Interleucina-2/fisiologia , Especificidade do Receptor de Antígeno de Linfócitos T , Linfócitos T Citotóxicos/imunologia , Transdução Genética , Células Tumorais CultivadasRESUMO
Subcutaneous panniculitis-like T-cell lymphoma (SPTL) is a rare type of skin lymphoma. Histopathology mimicking a lobular panniculitis makes it difficult to distinguish SPTL from benign autoimmune disease. We present cases of a 10-year-old female and an 11-year-old male with SPTL showing recurrent panniculitis and systemic manifestations. Initially, antibiotics and steroids were administered to treat infectious disease and benign panniculitis. However, they experienced recurrent fever and erythema nodosum. Additional immunohistochemistry and T-cell receptor (TCR) gene rearrangement analyses were performed, enabling the establishment of an SPTL diagnosis. The affected patients were given immunosuppressive therapy with favorable results.
Assuntos
Imunossupressores/administração & dosagem , Linfoma de Células T/diagnóstico , Linfoma de Células T/tratamento farmacológico , Paniculite/diagnóstico , Paniculite/tratamento farmacológico , Criança , Estudos de Coortes , Feminino , Humanos , Linfoma de Células T/imunologia , Linfoma de Células T/cirurgia , Masculino , Paniculite/imunologia , Paniculite/cirurgia , Fatores de RiscoRESUMO
Adoptive T-cell therapy for malignancies using redirected T cells genetically engineered by tumor antigen-specific T-cell receptor (TCR) gene transfer is associated with mispairing between introduced and endogenous TCR chains with unknown specificity. Therefore, deterioration of antitumor reactivity and serious autoimmune reactivity are major concerns. To address this problem, we have recently established a novel retroviral vector system encoding siRNAs for endogenous TCR genes (siTCR vector). In this study, to test the clinical application of siTCR gene therapy for human leukemia, we examined in detail the efficacy and safety of WT1-siTCR-transduced T cells. Compared with conventional WT1-TCR (WT1-coTCR) gene-transduced T cells, these cells showed significant enhancement of antileukemia reactivity resulting from stronger expression of the introduced WT1-specific TCR with inhibition of endogenous TCRs. Notably, WT1-siTCR gene-transduced T cells were remarkably expandable after repetitive stimulation with WT1 peptide in vitro, without any deterioration of antigen specificity. WT1-siTCR gene-transduced T cells from leukemia patients successfully lysed autologous leukemia cells, but not normal hematopoietic progenitor cells. In a mouse xenograft model, adoptively transferred WT1-siTCR gene-transduced T cells exerted distinct antileukemia efficacy but did not inhibit human hematopoiesis. Our results suggest that gene-immunotherapy for leukemia using this WT1-siTCR system holds considerable promise.
Assuntos
Imunoterapia Adotiva/métodos , Leucemia/terapia , RNA Interferente Pequeno/genética , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Proteínas WT1/genética , Animais , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Células Cultivadas , Citotoxicidade Imunológica/imunologia , Feminino , Terapia Genética/métodos , Humanos , Subunidade gama Comum de Receptores de Interleucina/deficiência , Subunidade gama Comum de Receptores de Interleucina/genética , Células Jurkat , Células K562 , Leucemia/genética , Leucemia/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/metabolismo , RNA Interferente Pequeno/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo , Transfecção , Células Tumorais Cultivadas , Proteínas WT1/química , Proteínas WT1/imunologia , Proteínas WT1/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Chédiak-Higashi syndrome (CHS) is a rare autosomal recessive disorder characterized by immunodeficiency, neurological dysfunction, and oculocutaneous albinism. Recently, several clinical CHS phenotypes have been reported. Here, we report results of a nationwide survey performed to clarify clinical characteristics and outcomes of CHS patients in Japan. METHODS: Questionnaires were sent to 287 institutions to collect data regarding CHS patients diagnosed between 2000 and 2010, including results of lysosomal trafficking regulator (LYST) gene analysis. Cytotoxicity and degranulation activity of cytotoxic T lymphocytes were analyzed in available patient samples. RESULTS: A total of 15 patients diagnosed with CHS were eligible for enrollment in this study. Of these, 10 (67%) had recurrent bacterial infections, five (33%) developed life-threatening hemophagocytic lymphohistiocytosis (HLH), and one patient had complicated malignant lymphoma. Hematopoietic stem cell transplantation (HSCT) was performed for six patients including three with HLH, and 10 of the enrolled patients have survived at the time of this writing. LYST analysis was performed for 10 patients; seven different mutations were detected in seven patients, whereas no mutation was identified in three patients. Cytotoxicity and degranulation activity were impaired in patients with and without LYST mutation. DISCUSSION: Results of this survey indicate that one or two patients with CHS were newly diagnosed each year in Japan. The incidence of HLH was not as high as expected. Mutations of genes other than LYST were suspected in some cases. We conclude that determining indication for HSCT for CHS patients should be based on genetic and cytotoxic analysis.
Assuntos
Síndrome de Chediak-Higashi , Transplante de Células-Tronco Hematopoéticas , Linfo-Histiocitose Hemofagocítica , Linfoma , Proteínas de Transporte Vesicular/genética , Adolescente , Adulto , Síndrome de Chediak-Higashi/complicações , Síndrome de Chediak-Higashi/diagnóstico , Síndrome de Chediak-Higashi/genética , Síndrome de Chediak-Higashi/mortalidade , Síndrome de Chediak-Higashi/patologia , Síndrome de Chediak-Higashi/terapia , Criança , Pré-Escolar , Coleta de Dados , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Japão/epidemiologia , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/etiologia , Linfo-Histiocitose Hemofagocítica/genética , Linfo-Histiocitose Hemofagocítica/mortalidade , Linfo-Histiocitose Hemofagocítica/patologia , Linfo-Histiocitose Hemofagocítica/terapia , Linfoma/diagnóstico , Linfoma/etiologia , Linfoma/genética , Linfoma/mortalidade , Linfoma/patologia , Masculino , Estudos Retrospectivos , Taxa de Sobrevida , Transplante HomólogoAssuntos
Bacteriemia/diagnóstico , Transplante de Medula Óssea , Infecções Relacionadas a Cateter/diagnóstico , Infecção Hospitalar/diagnóstico , Linfoma de Células T Periférico/terapia , Infecções por Pseudomonas/diagnóstico , Bacteriemia/etiologia , Criança , Feminino , Humanos , Infecções por Pseudomonas/etiologiaRESUMO
Deficiency of X-linked inhibitor of apoptosis (XIAP) caused by XIAP/BIRC4 gene mutations is an inherited immune defect recognized as X-linked lymphoproliferative syndrome type 2. This disease is mainly observed in patients with hemophagocytic lymphohistiocytosis (HLH) often associated with Epstein-Barr virus infection. We described nine Japanese patients from six unrelated families with XIAP deficiency and studied XIAP protein expression, XIAP gene analysis, invariant natural killer T (iNKT) cell counts, and the cytotoxic activity of CD8(+) alloantigen-specific cytotoxic T lymphocytes. Of the nine patients, eight patients presented with symptoms in infancy or early childhood. Five patients presented with recurrent HLH, one of whom had severe HLH and died after cord blood transplantation. One patient presented with colitis, as did another patient's maternal uncle, who died of colitis at 4 years of age prior to diagnosis with XIAP deficiency. Interestingly, a 17-year-old patient was asymptomatic, while his younger brother suffered from recurrent HLH and EBV infection. Seven out of eight patients showed decreased XIAP protein expression. iNKT cells from patients with XIAP deficiency were significantly decreased as compared with age-matched healthy controls. These results in our Japanese cohort are compatible with previous studies, confirming the clinical characteristics of XIAP deficiency.
Assuntos
Linfo-Histiocitose Hemofagocítica/diagnóstico , Transtornos Linfoproliferativos/diagnóstico , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/deficiência , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genética , Adolescente , Criança , Pré-Escolar , Humanos , Lactente , Japão , Leucócitos Mononucleares/imunologia , Contagem de Linfócitos , Linfo-Histiocitose Hemofagocítica/genética , Linfo-Histiocitose Hemofagocítica/imunologia , Transtornos Linfoproliferativos/genética , Transtornos Linfoproliferativos/imunologia , Masculino , Mutação , Células T Matadoras Naturais/imunologia , Linfócitos T Citotóxicos/imunologia , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/imunologiaRESUMO
Hemophagocytic syndrome is a rare disorder with dysfunction of cytotoxic T lymphocyte (CTL) or NK cell activity, leading to excessive production of inflammatory cytokines and various clinical symptoms. HLH can be classified as either primary or secondary form; primary HLH includes familial hemophagocytic lymphohistiocytosis (FHL) and several immune deficiencies. All affected genes are involved in the transport and membrane fusion, or exocytosis of perforin/granzyme in lytic granules. Making a rapid screening of FHL with flow cytometry followed by genetic analysis is mandatory for the appropriate treatment of this fatal disease. Whereas, pathogenesis of secondary HLH is still unknown; several genetic backgrounds to affect on the pathway of T-cell activity will be associated with secondary HLH. With perforin- or Munc-deficient mouse model that develop HLH-like symptoms after virus infection, CD8+ T cells and interferon-gamma have been proven to be necessary for the HLH development. These data will provide new targets for specific therapeutic intervention of HLH in the future.
Assuntos
Linfo-Histiocitose Hemofagocítica , Animais , Modelos Animais de Doenças , Infecções por Vírus Epstein-Barr/complicações , Humanos , Linfo-Histiocitose Hemofagocítica/etiologia , Linfo-Histiocitose Hemofagocítica/fisiopatologia , CamundongosRESUMO
The most common organisms isolated from pediatric catheter-related bloodstream infections (CRBSIs) are Gram-positive cocci, such as coagulase-negative staphylococci and Staphylococcus aureus. There are few formal reports of Brevibacterium casei infection and even fewer reports of CRBSI due to this Gram-positive rod. Here we report the first case of CRBSI due to B. casei in an 8-year-old girl with acute myeloid leukemia in Japan. The isolate exhibited decreased susceptibility to ß-lactam antibiotics. Antimicrobial therapy with meropenem and vancomycin, in addition to the removal of central venous catheter line, consequently led to a significant clinical improvement of the patient's symptoms. A literature review found available clinical courses in 16 cases (4 pediatric cases including our case) of B. casei infection. Our case and those in literature suggested that B. casei infection often occurs in patients with indwelling central venous catheters; the literature review further suggested that removal of central venous catheters is required in most cases. Special attention should be paid to the detection of opportunistic infections due to Brevibacterium spp. in immunocompromized children who are using a central venous catheter.
RESUMO
Brain abscesses, infections within the brain parenchyma, can arise as complications of various conditions including infections, trauma, and surgery. However, brain abscesses due to polymicrobial organisms have rarely been reported in children. We herein report a case of a 9-year-old girl with unresolved congenital cyanotic heart disease (CCHD) presenting with right hemiplegia who was diagnosed with brain abscess caused by Streptococcus intermedius, Parvimonas micra, and Fusobacterium nucleatum after oropharyngeal injury. She was treated with intravenous antimicrobial therapy, drainage under craniotomy, and antiedema therapy with glycerol and goreisan, which led to the improvement of right hemiplegia to baseline; she was discharged following eight weeks of intravenous antimicrobial therapy. The clinical diagnosis of the brain abscess was difficult due to the nonspecific presentation, highlighting the importance of cranial imaging without haste in patients at increased risk for brain abscesses such as those with CCHD, presenting with fever in the absence of localizing symptoms or fever, accompanied with abnormal neurological findings.
RESUMO
We report a case of a 4-year-old girl with an ovarian steroid cell tumor, not otherwise specified (SCT-NOS). She was admitted to the hospital with progressing virilization and Cushing's syndrome, which included abnormality of the perineum, hirsutism, hypertrichosis, flushing of face, hoarseness, and weight gain. Blood testing showed a significantly increased testosterone level and slightly increased cortisol level. Computed tomography scan revealed an 8.0 × 5.0 × 5.0 cm tumor of the right ovary. The patient underwent right salpingo-oophorectomy, and pathological examination showed malignant potential. Three courses of bleomycin, etoposide, and cisplatin were administered as postoperative chemotherapy. After tumor resection, her testosterone decreased to undetectable levels. However, during the course of the treatment, the patient suffered from adrenal insufficiency resulting in the need for hydrocortisone replacement therapy. Although SCT-NOS in childhood are typically benign, pathological findings should be carefully observed for potential malignancy. In cases of cortisol-producing SCT-NOS, serum levels should be monitored, and hydrocortisone replacement therapy should be considered before resection.
RESUMO
The authors describe the high effectiveness of human mesenchymal stem cell (hMSC) therapy to treat steroid-refractory gastrointestinal acute graft-versus-host Disease (aGVHD) in a 15-year-old boy with acute lymphoblastic leukemia (ALL). He received allogeneic hematopoietic stem cell transplantation due to high-risk hypodiploid ALL. Around the time of engraftment, he developed severe diarrhea following high-grade fever and erythema. Although methylprednisolone pulse therapy was added to tacrolimus and mycophenolate mofetil, diarrhea progressed up to 5000~6000 ml/day and brought about hypocalcemia, hypoalbuminemia, and edema. Daily fresh frozen plasma (FFP), albumin, and calcium replacements were required to maintain blood circulation. After aGVHD was confirmed by colonoscopic biopsy, MSC therapy was administered. The patient received 8 biweekly intravenous infusions of 2×106 hMSCs/kg for 4 weeks, after which additional 4 weekly infusions were performed. A few weeks after initiation, diarrhea gradually resolved, and at the eighth dose of hMSC, lab data improved without replacements. MSC therapy successfully treated steroid-refractory gastrointestinal GVHD without complications. Despite life-threatening diarrhea, the regeneration potential of children and adolescents undergoing SMC therapy successfully supports restoration of gastrointestinal damage. Even with its high treatment costs, SMC therapy should be proactively considered in cases where young patients suffer from severe gastrointestinal GVHD.
RESUMO
Streptococcus pyogenes (also referred to as group A streptococci, GAS) causes severe invasive diseases such as bacteremia, necrotizing fasciitis, pneumonia, osteomyelitis, septic arthritis, and toxic shock syndrome in children. However, there are only a few reports on pleural empyema caused by GAS in children. Here, we report the case of a 4-year-old boy who presented with pleural empyema due to GAS after influenza A virus infection. With intravenous antibiotic administration and continuous chest-tube drainage, followed by video-assisted thoracoscopic surgery, his condition improved. During the clinical course, cytokines induced in response to the influenza virus, especially IL-1ß and IL-10, were elevated 1 week after influenza A infection, but these decreased as the symptoms improved. Reportedly, the IL-10 production increases during influenza virus-bacteria superinfection. These observations suggest that the immunological mechanisms induced by the influenza virus can play an important role in influencing the susceptibility to secondary bacterial infections, such as GAS, in children.
RESUMO
We evaluated the efficacy of linezolid treatment in 6 children with health care-associated meningitis or ventriculitis (HCAMV) caused by gram-positive cocci. All children were diagnosed and treated at the Ehime University Hospital between January 2010 and December 2017. Of these, 5 were treated with linezolid as an empirical therapy. In these 5 patients, vancomycin was initially used but was changed to linezolid because of cerebrospinal fluid (CSF) culture positivity (n = 3) and a high minimum inhibitory concentration of vancomycin (n = 2). The most common HCAMV pathogens were methicillin-resistant coagulase-negative staphylococci (n = 3). In 3 patients, vancomycin concentration was low in CSF but reached the target concentration in serum, while linezolid concentration was high in both CSF and serum. HCAMV treatment using antimicrobial agents with poor CSF penetration may increase the likelihood of therapy failure. Linezolid is more susceptible as the first-line treatment for HCAMV compared with vancomycin.
Assuntos
Antibacterianos/uso terapêutico , Ventriculite Cerebral/tratamento farmacológico , Infecção Hospitalar/tratamento farmacológico , Linezolida/uso terapêutico , Meningite/tratamento farmacológico , Adolescente , Ventriculite Cerebral/etiologia , Estudos de Coortes , Infecção Hospitalar/microbiologia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Meningite/etiologia , Resultado do TratamentoRESUMO
Acute myeloid leukemia (AML) patients with FLT3/ITD mutations have a poor prognosis. Monotherapy with selective FLT3 tyrosine kinase inhibitors (TKIs) have shown transient and limited efficacy due to the development of resistance. Arsenic trioxide (ATO, As2O3) has been proven effective in treating acute promyelocytic leukemia (APL) and has shown activity in some cases of refractory and relapsed AML and other hematologic malignances. We explored the feasibility of combining FLT3 TKIs with ATO in the treatment of FLT3/ITD+ leukemias. The combination of FLT3 TKIs with ATO showed synergistic effects in reducing proliferation, viability and colony forming ability, and increased apoptosis in FLT3/ITD+ cells and primary patient samples. In contrast, no cooperativity was observed against wild-type FLT3 leukemia cells. ATO reduced expression of FLT3 RNA and its upstream transcriptional regulators (HOXA9, MEIS1), and induced poly-ubiquitination and degradation of the FLT3 protein, partly through reducing its binding with USP10. ATO also synergizes with FLT3 TKIs to inactivate FLT3 autophosphorylation and phosphorylation of its downstream signaling targets, including STAT5, AKT and ERK. Furthermore, ATO combined with sorafenib, a FLT3 TKI, in vivo reduced growth of FLT3/ITD+ leukemia cells in NSG recipients. In conclusion, these results suggest that ATO is a potential candidate to study in clinical trials in combination with FLT3 TKIs to improve the treatment of FLT3/ITD+ leukemia.