RESUMO
The dosage of chemotherapy drugs for overweight/obese children with acute myeloid leukemia (AML) has been empirically reduced based on ideal body weight (BW) in Japan to reduce the risk of adverse events. We investigated the associations between pre-therapeutic body mass index (BMI) and clinical outcomes among children with AML. A total of 280 children were divided into two groups based on the World Health Organization Child Growth Standards: a healthy-weight group (n = 254), and an overweight/obese group (n = 26). If BW exceeded 1.2 times the standard BW of Japanese children, the dosage of chemotherapy drugs was calculated using 1.2 times the standard BW. The dosage of chemotherapy drugs was reduced during at least one chemotherapy cycle in 24 of 26 patients (92.3%) in the overweight/obese group, compared with zero patients in the healthy-weight group. Overall/event-free survival, cumulative incidence of relapse, and treatment-related mortality (TRM) did not differ between the overweight/obese and healthy weight groups. However, the frequency of bacteremia was higher in the overweight/obese group (80.8 vs. 52.4%, P = 0.006). This indicates that TRM may increase when chemotherapy drug dosage is not corrected in overweight/obese patients. Drug reduction is a potential treatment strategy.
Assuntos
Índice de Massa Corporal , Leucemia Mieloide Aguda , Sobrepeso , Humanos , Criança , Masculino , Feminino , Leucemia Mieloide Aguda/tratamento farmacológico , Japão/epidemiologia , Pré-Escolar , Adolescente , Sobrepeso/complicações , Obesidade/complicações , Lactente , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , População do Leste AsiáticoRESUMO
BACKGROUND: The etiological significance of the RAS and PI3K pathways has been reported in systemic embryonal rhabdomyosarcoma (ERMS) but not in primary intracranial ERMS (PIERMS). Herein, the authors present a unique case of PIERMS with a BRAF mutation. OBSERVATIONS: A 12-year-old girl with progressive headache and nausea was diagnosed with a tumor in the right parietal lobe. Semi-emergency surgery revealed an intra-axial lesion that was histopathologically identical to an ERMS. Next-generation sequencing indicated a BRAF mutation as a pathogenic variation, but the RAS and PI3K pathways showed no alteration. Although there is no established reference class for PIERMS, the DNA methylation prediction was closest to that of ERMS, indicating the possibility of PIERMS. The final diagnosis was PIERMS. The patient underwent local radiotherapy (50.4 Gy) and multiagent chemotherapy, with no recurrence for 12 months after surgery. LESSONS: This may be the first case demonstrating the molecular features of PIERMS, especially the intra-axial type. The results showed a mutation in BRAF but not in the RAS and PI3K pathways, which is different from the existing ERMS features. This molecular difference may cause differences in DNA methylation profiles. Accumulation of the molecular features of PIERMS is necessary before any conclusions can be drawn.
RESUMO
BACKGROUND: Preventing infection and managing febrile neutropenia (FN) is mandatory for children with cancer undergoing chemotherapy. However, the current situation in Japan is unknown. METHODS: We conducted a nationwide web-based questionnaire survey in 153 institutions treating childhood cancer in Japan. We asked about the type prophylaxis used to prevent infectious disease and manage FN. If patients with childhood cancer were managed by both pediatricians and surgeons at the same institution, we asked both to reply. RESULTS: We received replies from 117 departments at 111 centers: of these, 108 were from pediatricians. Laminar air flow for neutropenic patients, and frequent hand sanitization with ethanol, were widespread. Twenty-eight percent and forty percent of departments performed active surveillance by taking cultures from patients and the environment, respectively, before initiation of chemotherapy. Forty-four percent of departments administered prophylactic intravenous antibiotics according to patient status. Many departments measured serum (1,3)-ß-D glucan, procalcitonin, and aspergillus galactomannan at the onset of FN. Twenty-eight percent of departments used carbapenem as empirical therapy for FN. Some departments used prophylactic granulocyte-colony stimulating factor for acute leukemia. Seventy-two percent of departments used prophylactic immunoglobulin for hypogammaglobinemia caused by chemotherapy. Palivizumab was administered widely for respiratory syncytial virus prophylaxis in immunocompromised infants. CONCLUSION: As a whole, intensive care for infectious prophylaxis or FN is applied in Japan; however, the methods vary among centers, and some are excessive or inadequate. Therefore, it is desirable to conduct clinical trials and establish adequate care protocols for infection in children with cancer in Japan.
Assuntos
Antineoplásicos , Neutropenia Febril , Controle de Infecções , Infecções , Neoplasias , Criança , Humanos , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Doenças Transmissíveis/complicações , Neutropenia Febril/induzido quimicamente , Neutropenia Febril/etiologia , Neutropenia Febril/prevenção & controle , Febre/induzido quimicamente , Febre/etiologia , Febre/prevenção & controle , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Controle de Infecções/métodos , Infecções/etiologia , Internet , Japão , Leucemia Mieloide Aguda/tratamento farmacológico , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Inquéritos e QuestionáriosRESUMO
This study aims to elucidate how self-efficacy influences cancer-related fatigue and health-related quality of life (HRQoL) in young survivors of childhood cancer. Forty-six young survivors (age range, 8-18 years) of childhood cancer who were currently in complete remission completed measures for self-efficacy (Pediatric General Self-Efficacy Scale (PedsSE)), cancer-related fatigue (Cancer-related Fatigue Score (CRFS)), and HRQoL (Pediatric Quality of Life Inventory 4.0 Generic Core Scale, Pediatric Quality of Life Inventory (PedsQL)). Structural relationships between the PedsSE and CRFS or PedsQL, including the effects of potential demographic or clinical confounders, were examined by machine learning random forest algorithms and structural equation modeling. According to the distribution of the PedsQL, six survivors with PedsQL < 70 were determined to have compromised HRQoL (referred to as "low-PedsQL survivors"). The random forest model identified six variables for the prediction of the CRFS, with the PedsSE being the most important, and eight variables for the distinction of low-PedsQL survivors, with the CRFS being the most and the PedsSE the third most important variable. The structural equation model indicated that a direct influence of the PedsSE on the PedsQL was less detectable (ß = -0.049), whereas an indirect influence of the PedsSE on the PedsQL via the CRFS was evident (ß = 0.333). The model explained 51% of the variation of the CRFS and 28% of the variation of the PedsQL. The PedsSE was strongly correlated with "altered mood" in the subclass of the CRFS (r = -0.470), and "altered mood" was strongly correlated with the PedsQL (r = 0.737). In conclusion, self-efficacy is a major determinant of cancer-related fatigue and influences HRQoL via cancer-related fatigue in survivors of childhood cancer. The main pathway from self-efficacy to HRQoL is thought to be via the emotional aspect of cancer-related fatigue. However, unlike adult survivors of cancer, self-efficacy for young survivors may not contribute much to self-management behaviors that maintain HRQoL.
Assuntos
Sobreviventes de Câncer , Neoplasias , Adolescente , Adulto , Criança , Fadiga/epidemiologia , Fadiga/etiologia , Fadiga/psicologia , Humanos , Neoplasias/complicações , Neoplasias/psicologia , Qualidade de Vida , Autoeficácia , Sobreviventes/psicologiaRESUMO
CONTEXT: Few instruments in Japanese assess health-related quality of life in pediatric cancer patients. OBJECTIVES: To translate the Memorial Symptom Assessment Scale (MSAS) into Japanese pediatric and proxy versions (MSAS-J 7-12, MSAS-J 13-18, and MSAS-J-Proxy) and assess validity and reliability. METHODS: Phase I comprised forward-backward translation and pilot testing in 13 children and 16 guardians. Phase II consisted of psychometric testing of the three MSAS-J versions in 162 children and 238 guardians. Internal consistency, test-retest reliability, and construct and known-group validity of the MSAS-J were assessed. RESULTS: Cronbach's alpha coefficients for the total and subscale scores were over 0.70, excluding the psychological symptom (PSYCH) subscale score of the MSAS-J 7-12. Most MSAS-J scores significantly inversely correlated with two versions of the Pediatric Quality of Life Inventory. A strong child-guardian correlation was shown in the total and subscale scores (ICC range 0.66-0.83). Kappa estimates showed acceptable child-guardian symptom agreement. MSAS-J 7-12 and proxy differentiated patients according to clinical status. CONCLUSION: MSAS-J is a reliable and valid instrument to assess symptoms among Japanese children with cancer.
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Neoplasias , Qualidade de Vida , Criança , Humanos , Japão , Neoplasias/diagnóstico , Neoplasias/psicologia , Psicometria , Reprodutibilidade dos Testes , Inquéritos e Questionários , Avaliação de SintomasRESUMO
BACKGROUND: The SIOPEL-4 study has demonstrated that dose-dense cisplatin-based chemotherapy dramatically improves outcome in children with high-risk hepatoblastoma in western countries. However, the feasibility and safety of this regimen have not been clarified in Japanese patients. METHODS: A pilot study, JPLT3-H, was designed to evaluate the safety profile of the SIOPEL-4 regimen in Japanese children with newly diagnosed hepatoblastoma with either metastatic disease or low alpha-fetoprotein. RESULTS: A total of 15 patients (three female) were enrolled. Median age was 2 years (range, 0-14). Three patients were PRETEXT II (where PRETEXT is PRETreatment EXTent of disease), six PRETEXT III, and six PRETEXT IV. All patients had lung metastasis, none had low alpha-fetoprotein. Eight patients completed the prescribed treatment, and seven patients discontinued therapy prematurely, four due to progressive disease and three due to causes other than severe toxicity. Grade 4 neutropenia was documented in most patients in preoperative cycles A1-3 (11/15 in A1, 9/11 in A2, and 7/11 in A3) and in all considering all cycles. Grade 3-4 thrombocytopenia and grade 3 anemia were also frequently observed. Patients experienced several episodes of grade 3 febrile neutropenia, but none had grade 4 febrile neutropenia or severe infections. One patient had grade 3 heart failure only in the first cycle. Other grade 3 or 4 toxicities were hypomagnesemia, anorexia, nausea, mucositis, liver enzyme elevation, fever, infection, and fatigue. There were no unexpected severe toxicities. CONCLUSION: The toxicity profile of JPLT3-H was comparable to that of SIOPEL-4. Dose-dense cisplatin-based chemotherapy may be feasible among Japanese patients with high-risk hepatoblastoma.
Assuntos
Neutropenia Febril , Hepatoblastoma , Neoplasias Hepáticas , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Criança , Pré-Escolar , Cisplatino , Estudos de Viabilidade , Neutropenia Febril/tratamento farmacológico , Feminino , Hepatoblastoma/patologia , Humanos , Lactente , Recém-Nascido , Japão , Neoplasias Hepáticas/patologia , Projetos Piloto , alfa-FetoproteínasRESUMO
Hepatoblastoma (HB) is the most common pediatric liver malignancy; however, hereditary predisposition and acquired molecular aberrations related to HB clinicopathological diversity are not well understood. Here, we perform an integrative genomic profiling of 163 pediatric liver tumors (154 HBs and nine hepatocellular carcinomas) based on the data acquired from a cohort study (JPLT-2). The total number of somatic mutations is precious low (0.52/Mb on exonic regions) but correlated with age at diagnosis. Telomerase reverse transcriptase (TERT) promoter mutations are prevalent in the tween HBs, selective in the transitional liver cell tumor (TLCT, > 8 years old). DNA methylation profiling reveals that classical HBs are characterized by the specific hypomethylated enhancers, which are enriched with binding sites for ASCL2, a regulatory transcription factor for definitive endoderm in Wnt-pathway. Prolonged upregulation of ASCL2, as well as fetal-liver-like methylation patterns of IGF2 promoters, suggests their "cell of origin" derived from the premature hepatoblast, similar to intestinal epithelial cells, which are highly proliferative. Systematic molecular profiling of HB is a promising approach for understanding the epigenetic drivers of hepatoblast carcinogenesis and deriving clues for risk stratification.
Assuntos
Metilação de DNA , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Hepatoblastoma/genética , Neoplasias Hepáticas/genética , Pré-Escolar , Sequenciamento de Cromatina por Imunoprecipitação/métodos , Estudos de Coortes , Variações do Número de Cópias de DNA , Feminino , Humanos , Lactente , Estimativa de Kaplan-Meier , Masculino , Mutação , Regiões Promotoras Genéticas/genética , Telomerase/genética , Sequenciamento do Exoma/métodos , beta Catenina/genéticaRESUMO
Although approximately 70% of pediatric hematological malignancies are curable, approximately 30% remain fatal. No standard treatment is available in patients showing relapse and those with refractory disease. Although different methods are adopted in different hospitals, its efficacy is extremely limited. In recent years, haploidentical stem cell transplantation, involving high-dose cyclophosphamide administration post-transplanta tion, has been used, mainly in adults; however, its application is limited to removal of alloreactive T cells. Multicenter single-arm clinical trials of T-cell replete haploidentical stem cell transplantation (TCR-haplo-SCT) will be conducted in children with relapsed and refractory acute leukemia. After myeloablative conditioning using total body irradiation or busulfan, intensive graft versus host disease prophylaxis is administered, consisting of low-dose rabbit anti-human thymocyte globulin, tacrolimus, methotrexate, and prednisolone. An external control group is set up for the study. The treatment period is around 3 months, and the follow-up period is 2 years from transplantation completion.The aim of this study is to verify the efficacy and safety of TCR-haplo-SCT and present it as a new immune cell therapy for improving survival rate in children with relapsed and refractory acute leukemia.
Assuntos
Soro Antilinfocitário/administração & dosagem , Leucemia/terapia , Transplante de Células-Tronco , Linfócitos T/transplante , Condicionamento Pré-Transplante/métodos , Transplante Homólogo/métodos , Adolescente , Soro Antilinfocitário/uso terapêutico , Criança , Feminino , Haplótipos , Humanos , Fatores Imunológicos , Imunossupressores/uso terapêutico , Leucemia/mortalidade , Masculino , Receptores de Antígenos de Linfócitos T , Taxa de Sobrevida , Resultado do TratamentoRESUMO
PURPOSE: We report here the outcomes and late effects of the Japanese Study Group for Pediatric Liver Tumors (JPLT)-2 protocol, on the basis of cisplatin-tetrahydropyranyl-adriamycin (CITA) with risk stratification according to the pretreatment extent of disease (PRETEXT) classification for hepatoblastoma (HB). PATIENTS AND METHODS: From 1999 to 2012, 361 patients with untreated HB were enrolled. PRETEXT I/II patients were treated with up-front resection, followed by low-dose CITA (stratum 1) or received low-dose CITA, followed by surgery and postoperative chemotherapy (stratum 2). In the remaining patients, after 2 cycles of CITA, responders received the CITA regimen before resection (stratum 3), and nonresponders were switched to ifosfamide, pirarubicin, etoposide, and carboplatin (ITEC; stratum 4). Intensified chemotherapeutic regimens with autologous hematopoietic stem-cell transplantation (SCT) after resection were an optional treatment for patients with refractory/metastatic disease. RESULTS: The 5-year event-free and overall survival rates of HB patients were 74.2% and 89.9%, respectively, for stratum 1, 84.8% and 90.8%%, respectively, for stratum 2, 71.6% and 85.9%%, respectively, for stratum 3, and 59.1% and 67.3%%, respectively, for stratum 4. The outcomes for CITA responders were significantly better than those for nonresponders, whose outcomes remained poor despite salvage therapy with a second-line ITEC regimen or SCT. The late effects, ototoxicity, cardiotoxicity, and delayed growth, occurred in 61, 18, and 47 patients, respectively. Thirteen secondary malignant neoplasms (SMNs), including 10 leukemia, occurred, correlating with higher exposure to pirarubicin and younger age at diagnosis. CONCLUSION: The JPLT-2 protocol achieved up-front resectability in PRETEXT I/II patients with no annotation factors, and satisfactory survival in patients who were CITA responders in the remaining patients. However, outcomes for CITA nonresponders were unsatisfactory, despite therapy intensification with ITEC regimens and SCT. JPLT-2 had a relatively low incidence of cardiotoxicity but high rates of SMNs.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/mortalidade , Hepatectomia/mortalidade , Hepatoblastoma/mortalidade , Neoplasias Hepáticas/mortalidade , Complicações Pós-Operatórias/mortalidade , Pré-Escolar , Terapia Combinada , Feminino , Seguimentos , Hepatoblastoma/patologia , Hepatoblastoma/terapia , Humanos , Lactente , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Masculino , Ensaios Clínicos Controlados não Aleatórios como Assunto , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/patologia , Prognóstico , Estudos Prospectivos , Taxa de SobrevidaRESUMO
Optimal supportive care for disseminated intravascular coagulation (DIC) and hemostatic complications by asparaginase is indispensable for the successful treatment of pediatric leukemia. However, the situation regarding this type of care in Japan is unclear. We conducted a questionnaire-based survey at 155 institutions treating childhood leukemia in Japan. The questionnaire asked about the supportive care provided by each institution to acute leukemia patients with DIC and asparaginase-induced hemostatic alterations. Ninety-eight institutions responded. The most common diagnostic criteria for DIC were those established by the Japanese Ministry of Health and Welfare. Regardless of the etiology underlying DIC, recombinant human thrombomodulin and synthetic protease inhibitors were used as anticoagulation therapy by around 70% and 40% of institutions, respectively. Additionally, 92%, 93%, and 73% of institutions measured plasma antithrombin, fibrinogen, and D-dimer/fibrin degradation products, respectively, more than twice per week during induction therapy for acute lymphoblastic leukemia. Survey responses indicate that 95% and 24% of the institutions used antithrombin replacement and fresh-frozen plasma, respectively. Supportive care for DIC and/or asparaginase-induced hemostatic alterations at Japanese pediatric centers was intensive and differs markedly from protocols in other countries. The efficacy of supportive care should be evaluated prospectively in the setting of pediatric leukemia.
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Hemostáticos/efeitos adversos , Leucemia/complicações , Cuidados Paliativos/métodos , Anticoagulantes , Asparaginase/efeitos adversos , Criança , Coagulação Intravascular Disseminada/etiologia , Coagulação Intravascular Disseminada/terapia , Humanos , Japão , Leucemia/tratamento farmacológico , Pediatria , Inibidores de Proteases/uso terapêutico , Inquéritos e Questionários , Trombomodulina/uso terapêuticoRESUMO
In the AML-05 clinical trial conducted by the Japanese Pediatric Leukemia/Lymphoma Group from 2006 to 2010, children with high-risk acute myeloid leukemia (HR AML) received allogeneic hematopoietic stem cell transplantation (allo-HSCT) at first complete remission (CR1). The aim of this study was to investigate the impact of allo-HSCT on the outcome of HR AML. Patients with either monosomy 7, 5q-, t(16;21), Ph1, FLT3-ITD, or induction failure after the first course of chemotherapy were eligible for transplant. Of 53 children with HR AML, 51 received allo-HSCT-45 in CR1, five in CR2, and one with non-CR. t(8;21), t(9;11), and t(16;21) abnormalities were identified in eight, five, and four patients, respectively. The stem cell sources varied-bone marrow in 30 patients, peripheral blood in three, and cord blood in 18. The median follow-up was 62 months. The overall survival (OS) rates at 3 years were 73% and 25% for patients who received transplant at CR1 and ≥CR2, respectively. Multivariable analysis showed that patients with chronic graft-versus-host disease (cGVHD) had better OS. This study supports that allo-HSCT is a suitable treatment for HR AML in CR1. The favorable outcome associated with cGVHD indicates that a graft-versus-leukemia effect might be occurring.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Combinada/métodos , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Mieloide Aguda/terapia , Adolescente , Criança , Pré-Escolar , Ensaios Clínicos como Assunto , Terapia Combinada/mortalidade , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Quimioterapia de Indução/métodos , Quimioterapia de Indução/mortalidade , Lactente , Recém-Nascido , Leucemia Mieloide Aguda/mortalidade , Masculino , Estudos Retrospectivos , Transplante Homólogo , Resultado do TratamentoRESUMO
BACKGROUND/PURPOSE: The purpose of this study was to clarify the role of pulmonary metastasectomy in hepatoblastomas with lung metastasis at diagnosis. We reviewed cases enrolled in the JPLT-2 study. METHODS: A total of 360 cases with hepatoblastoma were enrolled. The clinical courses and outcome of 60 cases with pulmonary metastasis at diagnosis were reviewed, focusing on metastasectomy. RESULTS: Induction chemotherapy resulted in eradication of nodules in 26, residual nodules in 33, and early treatment-related death in one. Of the 33 cases with residual nodules, 11 underwent complete resection of the lung lesions, and among these, progression was reported in five. Complete resection of the liver tumor was not achieved in two of these. Three underwent incomplete resection of lung nodules, eventually leading to progression. Twelve cases with incomplete or no liver tumor resection progressed regardless of the status of lung lesions. Contrarily, among patients who underwent complete resection of the liver tumor, half were cured without metastasectomy. CONCLUSIONS: Metastasectomy for residual pulmonary nodules after induction chemotherapy is effective provided that the liver tumor could be completely resected. TYPE OF STUDY: Prospective Cohort Study. LEVEL OF EVIDENCE: Level II.
Assuntos
Hepatoblastoma/secundário , Neoplasias Hepáticas/patologia , Neoplasias Pulmonares/secundário , Metastasectomia , Criança , Intervalo Livre de Doença , Hepatectomia , Hepatoblastoma/tratamento farmacológico , Hepatoblastoma/cirurgia , Humanos , Quimioterapia de Indução , Neoplasias Hepáticas/cirurgia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/cirurgia , Estudos Prospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Survival for childhood acute lymphoblastic leukaemia surpasses 90% with contemporary therapy; however, patients remain burdened by the severe toxic effects of treatment, including asparaginase-associated pancreatitis. To investigate the risk of complications and risk of re-exposing patients with asparaginase-associated pancreatitis to asparaginase, 18 acute lymphoblastic leukaemia trial groups merged data for this observational study. METHODS: Patient files from 26 trials run by 18 trial groups were reviewed on children (aged 1·0-17·9 years) diagnosed with t(9;22)-negative acute lymphoblastic leukaemia between June 1, 1996, and Jan 1, 2016, who within 50 days of asparaginase exposure developed asparaginase-associated pancreatitis. Asparaginase-associated pancreatitis was defined by at least two criteria: abdominal pain, pancreatic enzymes at least three times the upper limit of normal (ULN), and imaging compatible with pancreatitis. Patients without sufficient data for diagnostic criteria were excluded. Primary outcomes were defined as acute and persisting complications of asparaginase-associated pancreatitis and risk of re-exposing patients who suffered an episode of asparaginase-associated pancreatitis to asparaginase. Data were collected from Feb 2, 2015, to June 30, 2016, and analysed and stored in a common database at Rigshospitalet, Copenhagen, Denmark. FINDINGS: Of 465 patients with asparaginase-associated pancreatitis, 33 (8%) of 424 with available data needed mechanical ventilation, 109 (26%) of 422 developed pseudocysts, acute insulin therapy was needed in 81 (21%) of 393, and seven (2%) of 458 patients died. Risk of assisted mechanical ventilation, need for insulin, pseudocysts, or death was associated with older age (median age for patients with complications 10·5 years [IQR 6·4-13·8] vs without complications 6·1 years [IQR 3·6-12·2], p<0·0001), and having one or more affected vital signs (fever, hypotension, tachycardia, or tachypnoea; 96 [44%] of 217 patients with affected vital signs vs 11 [24%] of 46 patients without affected vital signs, p=0·02). 1 year after diagnosis of asparaginase-associated pancreatitis, 31 (11%) of 275 patients still needed insulin or had recurrent abdominal pain or both. Both the risk of persisting need for insulin therapy and recurrent abdominal pain were associated with having had pseudocysts (odds ratio [OR] 9·48 [95% CI 3·01-35·49], p=0·0002 for insulin therapy; OR 11·79 [4·30-37·98], p<0·0001 for recurrent abdominal pain). Within 8 years of asparaginase-associated pancreatitis, risk of abdominal symptoms dropped from 8% (26 of 312) to 0% (0 of 35) but the need for insulin therapy remained constant (9%, three of 35). 96 patients were re-exposed to asparaginase, including 59 after a severe asparaginase-associated pancreatitis (abdominal pain or pancreatic enzymes at least three times the ULN or both lasting longer than 72 h). 44 (46%) patients developed a second asparaginase-associated pancreatitis, 22 (52%) of 43 being severe. Risk of persisting need for insulin or abdominal pain after having had two versus one asparaginase-associated pancreatitis did not differ (three [7%] of 42 vs 28 [12%] of 233, p=0·51). Risk of a second asparaginase-associated pancreatitis was not associated with any baseline patient characteristics. INTERPRETATION: Since the risk of a second asparaginase-associated pancreatitis was not associated with severity of the first asparaginase-associated pancreatitis and a second asparaginase-associated pancreatitis did not involve an increased risk of complications, asparaginase re-exposure should be determined mainly by the anticipated need for asparaginase for antileukaemic efficacy. A study of the genetic risk factors identifying patients in whom asparaginase exposure should be restricted is needed. FUNDING: The Danish Childhood Cancer Foundation and The Danish Cancer Society (R150-A10181).
Assuntos
Antineoplásicos/efeitos adversos , Asparaginase/efeitos adversos , Pancreatite/induzido quimicamente , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Masculino , Pancreatite/epidemiologia , Pancreatite/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaçõesRESUMO
Epidermal γδ T cells that reside in the front line of the skin play a pivotal role in stress immune surveillance. However, it is not clear whether these cells are involved in further induction of immune responses after they are activated in dysregulated epidermis. In this study, we found that activated γδ T cells expressed occludin and migrated into draining lymph nodes in an occludin-dependent manner. Epidermal γδ T cells in occludin-deficient mice exhibited impairments in morphology changes and motility, although they expressed activation markers at levels comparable to those in wild-type cells. Occludin deficiency weakened the induction of allergen-induced contact hypersensitivity, primarily as the result of the impaired migration of epidermal γδ T cells. Thus, occludin expression by epidermal γδ T cells upon activation in response to epidermal stress allows them to move, which could be important for augmentation of immune responses via collaboration with other cells.
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Movimento Celular , Epiderme/imunologia , Linfonodos/imunologia , Ocludina/genética , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Estresse Fisiológico , Subpopulações de Linfócitos T/imunologia , Animais , Dermatite de Contato/imunologia , Células Epidérmicas , Epiderme/efeitos da radiação , Vigilância Imunológica , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pele/imunologia , Subpopulações de Linfócitos T/fisiologiaRESUMO
BACKGROUND/PURPOSE: We aimed to clarify whether surgical resectability and tumor response after preoperative chemotherapy (preCTx) represented prognostic factors for patients with hepatoblastoma (HBL) in the JPLT-2 study (1999-2012). METHODS: Patients (N=342) with HBL who underwent preCTx were eligible. PRETEXT, CHIC risk stratification (standard [SR], intermediate [IR] and high risk [HR]) at diagnosis, POST-TEXT, and tumor resectability were evaluated by imaging. Tumor response was classified into responders (CR or PR) and nonresponders (NC or PD) according to RECIST criteria. RESULTS: There were 7 PRETEXT I, 106 II, 143 III, and 86 IV, including 71 metastatic HBLs. In POST-TEXT, 12 PRETEXT II, 42 III, and 58 IV were down-staged. The 5-year EFS/OS rates of 198 SR, 73 IR, and 71 HR-HBLs were 82/94%, 49/64%, and 28/34%, respectively. In 198 SR, 154 of 160 responders and 24 of 38 nonresponders survived event-free (P<0.01). In 73 IR, 12 of 24 whose tumors remained unresectable experienced recurrence, 9 of whom were nonresponders (P<0.01). In 71 HR, chemoresponders and tumor resectability after preCTx correlated with favorable outcomes (P<0.05). CONCLUSIONS: Evaluation of response and tumor resectability after preCTx is useful for predicting prognosis in HBLs. To improve outcomes, we should reconsider surgical procedures according to resectability and chemoresponsiveness. LEVEL OF EVIDENCE: Level II.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Hepatoblastoma/tratamento farmacológico , Hepatoblastoma/cirurgia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/cirurgia , Adolescente , Carboplatina/administração & dosagem , Criança , Pré-Escolar , Cisplatino/administração & dosagem , Protocolos Clínicos , Terapia Combinada , Doxorrubicina/administração & dosagem , Doxorrubicina/análogos & derivados , Etoposídeo/administração & dosagem , Feminino , Hepatoblastoma/diagnóstico por imagem , Humanos , Ifosfamida/administração & dosagem , Lactente , Neoplasias Hepáticas/diagnóstico por imagem , Masculino , Terapia Neoadjuvante , Prognóstico , Resultado do TratamentoRESUMO
BACKGROUND: In the Japanese Study Group for Pediatric Liver Tumor (JPLT) protocols (JPLT-1 and 2) for evaluating the cure rate of risk-stratified hepatoblastoma, primary resection was permitted in PRETEXT I and II cases, followed by postoperative chemotherapy. METHODS: In approximately 500 enrolled cases, resection was performed as the initial treatment in 60 cases, including all 18 PRETEXT I, 30 PRETEXT II, and 12 ruptured cases. The clinical features, surgical procedures, complications, and survival rates were compared in these three groups. RESULTS: All 18 PRETEXT I cases underwent complete resection by lobectomy or segmentectomy (n=14) or nonanatomical partial hepatectomy (NPH) (n=4). The 30 PRETEXT II cases underwent primary resection by right or left lobectomy (n=16), NPH (n=10), or other procedures (n=4). Of these 30 cases, operational death occurred in 1 newborn, and recurrence occurred in 7 cases (14.6%), including 6 NPH cases and 4 older cases (aged >3years). Of the 12 ruptured cases, 7 (58.3%) showed recurrence. Event-free survival rates at 5years in the 3 groups were 88%, 70%, and 32%, respectively. CONCLUSIONS: Primary resection for PRETEXT I or II HB cases should be performed by anatomical resection according to strict surgical guidelines. More intensified chemotherapy is required for primary resected cases whose tumors have ruptured.
Assuntos
Hepatoblastoma/mortalidade , Hepatoblastoma/cirurgia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/cirurgia , Adolescente , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Hepatectomia/mortalidade , Humanos , Lactente , Recém-Nascido , Japão/epidemiologia , Masculino , Recidiva Local de Neoplasia , Taxa de Sobrevida , Resultado do TratamentoRESUMO
Iron-refractory iron deficiency anemia (IRIDA) is a rare autosomal recessive disease characterized by congenital hypochromic microcytic anemia, low transferrin saturation, low serum iron, normal-high serum ferritin, and increased hepcidin. This disease is caused by loss-of-function mutations in TMPRSS6 that lead to high hepcidin and result in severe anemia. We report our experience with an 11-year-old Japanese girl with hypochromic microcytic anemia, low serum iron, and high serum ferritin, with anemia that was refractory to the oral iron that was prescribed frequently from early childhood. Presence of high hepcidin suggested a diagnosis of IRIDA, which was eventually confirmed by identification of a novel homozygous mutation, p.Pro354Leu, in the TMPRSS6 gene. This case suggests that serum hepcidin should be routinely measured for differential diagnosis when patients with IDA are unresponsive to oral iron or have unusual clinical features.
Assuntos
Anemia Ferropriva/genética , Proteínas de Membrana/genética , Mutação , Serina Endopeptidases/genética , Criança , Feminino , HumanosRESUMO
INTRODUCTION: The Japanese Study Group for Pediatric Liver Tumor (JPLT) has conducted cooperative treatment studies on hepatoblastoma (HBL) since 1991. The JPLT2 protocol was launched in 1999 to evaluate the efficacy of cisplatin/pirarubicin (CITA) under risk stratification. European and North American groups showed the improvement of HBL patients by pre- and postoperative chemotherapeutic regimens. Therefore, we evaluated the results of JPLT study and considered the future aspect of JPLT. METHODS: A total of 389 children with malignant hepatic tumors were enrolled in JPLT-2 until 2010. Data from 331 HBL cases were analyzed. RESULTS AND DICUSSION: Of the 331 patients enrolled, their 5-year overall survival and event-free survival rates were 83.3 and 68.0%, respectively. While outcomes of standard-risk cases (tumors involving 3 or fewer sectors of the liver) were excellent, those of high-risk cases (tumors involving 4 sectors of the liver or with distant metastases) remained poor. For 26 high-risk or relapse/refractory HBL cases, high-dose chemotherapy (HDC) with stem cell transplantation (SCT) was carried out. Among them, 6 of 12 relapse or refractory cases died. Compared with other regimens, the CITA regimen achieved similar or superior rates of survival among children with standard-risk HBL, while HDC with SCT was not effective in patients with high-risk HBL. Presently, a global Children's Hepatic Tumor International Consortium (CHIC) project is ongoing, with a focus on international cooperation and risk stratification in the field of rare liver cancers in children. More promising strategies, including liver transplantation and new targeting drugs under global risk stratification, are being proposed.