RESUMO
Sarcopenia, the age-related loss of skeletal muscle mass and function, can dramatically impinge on quality of life and mortality. While mitochondrial dysfunction and imbalanced proteostasis are recognized as hallmarks of sarcopenia, the regulatory and functional link between these processes is underappreciated and unresolved. We therefore investigated how mitochondrial proteostasis, a crucial process that coordinates the expression of nuclear- and mitochondrial-encoded mitochondrial proteins with supercomplex formation and respiratory activity, is affected in skeletal muscle aging. Intriguingly, a robust mitochondrial translation impairment was observed in sarcopenic muscle, which is regulated by the peroxisome proliferator-activated receptor γ coactivator 1 α (PGC-1α) with the estrogen-related receptor α (ERRα). Exercise, a potent inducer of PGC-1α activity, rectifies age-related reduction in mitochondrial translation, in conjunction with quality control pathways. These results highlight the importance of mitochondrial proteostasis in muscle aging, and elucidate regulatory interactions that underlie the powerful benefits of physical activity in this context.
Assuntos
Qualidade de Vida , Sarcopenia , Humanos , Exercício Físico , Proteínas Mitocondriais/genética , Músculo EsqueléticoRESUMO
OBJECTIVES: To describe the health-related quality of life (HRQoL) of patients in a prospective 12-month observational cohort study of new bladder cancer diagnoses and compare with national cancer and general population surveys. PATIENTS AND METHODS: A prospective UK study in patients with new bladder cancer diagnoses at 13 NHS Trusts. The HRQoL data were collected at 3, 6, 9 and 12 months. Questionnaires used included: the EuroQoL five Dimensions (EQ-5D), European Organisation for Research and Treatment of Cancer quality of life questionnaire (EORTC QLQ)-30-item core, EORTC QLQ-24-item non-muscle-invasive bladder cancer, and EORTC QLQ-30-item muscle-invasive bladder cancer. Results were compared with the Cancer Quality of Life Survey and Health Survey for England. RESULTS: A total of 349 patients were recruited, 296 (85%) completed the first (baseline) and 233 (67%) the final survey. The patients underwent transurethral resection of bladder tumour (TURBT) ± intravesical therapy (238 patients, 80%), radical cystectomy/radiotherapy (51, 17%) or palliation (seven, 2%). At baseline, patients needing radical treatment reported worse HRQoL including lower social function (74.2 vs 83.8, P = 0.002), increased fatigue (31.5 vs 26.1, P = 0.03) and more future worries (39.2 vs 29.4, P = 0.005) than patients who underwent TURBT. Post-treatment surveys showed no change/improvements for patients who underwent TURBT but deterioration for the radically treated cohort. At final survey, reports were similar to baseline, regardless of treatment. Radically treated patients continued to report poorer HRQoL including issues with body image (23.4 vs 12.5, P = 0.007) and male sexual function (75.8 vs 40.4, P < 0.001) compared to those who underwent TURBT. Radically treated patients reported lower EQ-5D utility scores and more problems with usual activities than the general population. DISCUSSION: Patients undergoing TURBT can be reassured regarding HRQoL following treatment. However, those requiring radical treatment report greater changes in HRQoL with the need for appropriate clinical and supportive care to minimise the impact of treatments.
Assuntos
Qualidade de Vida , Neoplasias da Bexiga Urinária , Humanos , Masculino , Estudos Prospectivos , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/terapia , Neoplasias da Bexiga Urinária/patologia , Inquéritos e Questionários , Estudos LongitudinaisRESUMO
Access to genomic sequencing (GS) and resulting recommendations have not been well described in pediatric oncology. GS results may provide a cancer predisposition syndrome (CPS) diagnosis that warrants screening and specialist visits beyond cancer treatment, including testing or surveillance for family members. The Texas KidsCanSeq (KCS) Study evaluated implementation of GS in a diverse pediatric oncology population. We conducted semi-structured interviews (n = 20) to explore experiences of KCS patients' families around learning about a CPS diagnosis and following up on recommended care. We used qualitative content analysis to develop themes and subthemes across families' descriptions of their experiences accessing care and to understand which factors presented barriers and/or facilitators. We found participants had difficulty differentiating which follow-up care recommendations were made for their child's current cancer treatment versus the CPS. In families' access to follow-up care for CPS, organizational factors were crucial: travel time and distance were common hardships, while coordination of care to streamline multiple appointments with different providers helped facilitate CPS care. Financial factors also impacted families' access to CPS-related follow-up care: having financial assistance and insurance were facilitators for families, while costs and lack of insurance posed as barriers for patients who lost coverage during transitions from pediatric to adult care, and for adult family members who had no coverage. Factors related to beliefs and perceptions, specifically perceiving the risk as less salient to them and feeling overwhelmed with the patient's cancer care, presented barriers to follow-up care primarily for family members. Regarding social factors, competing life priorities made it difficult for families to access follow-up care, though having community support alleviated these barriers. We suggest interventions to improve coordination of cancer treatment and CPS-related care and adherence to surveillance protocols for families as children age, such as care navigators and integrating longitudinal genetic counseling into hereditary cancer centers.
RESUMO
Copanlisib is a pan-class I phosphoinositide 3-kinase (PI3K) inhibitor, with activity against all four PI3K class I isoforms (PI3Kα, PI3Kß, PI3Kγ, and PI3Kδ). Whole-genome and RNA sequencing data have revealed several PI3K aberrations in osteosarcoma tumor samples. The in vivo anticancer effects of copanlisib were assessed in a panel of six osteosarcoma models. Copanlisib induced prolonged event-free survival in five of six osteosarcoma models; however, all models demonstrated progressive disease suggesting minimal activity. While copanlisib did not result in tumor regression, more data are needed to fully explore the role of the PI3K pathway in the pathogenesis of osteosarcoma.
Assuntos
Osteossarcoma , Fosfatidilinositol 3-Quinases , Humanos , Criança , Inibidores de Fosfoinositídeo-3 Quinase , Quinazolinas/farmacologia , Quinazolinas/uso terapêutico , Osteossarcoma/tratamento farmacológicoRESUMO
The potential of circulating tumor DNA (ctDNA) analysis to serve as a real-time "liquid biopsy" for children with central nervous system (CNS) and non-CNS solid tumors remains to be fully elucidated. We conducted a study to investigate the feasibility and potential clinical utility of ctDNA sequencing in pediatric patients enrolled on an institutional clinical genomics trial. A total of 240 patients had tumor DNA profiling performed during the study period. Plasma samples were collected at study enrollment from 217 patients and then longitudinally from a subset of patients. Successful cell-free DNA extraction and quantification occurred in 216 of 217 (99.5%) of these initial samples. Twenty-four patients were identified whose tumors harbored 30 unique variants that were potentially detectable on a commercially-available ctDNA panel. Twenty of these 30 mutations (67%) were successfully detected by next-generation sequencing in the ctDNA from at least one plasma sample. The rate of ctDNA mutation detection was higher in patients with non-CNS solid tumors (7/9, 78%) compared to those with CNS tumors (9/15, 60%). A higher ctDNA mutation detection rate was also observed in patients with metastatic disease (9/10, 90%) compared to non-metastatic disease (7/14, 50%), although tumor-specific variants were detected in a few patients in the absence of radiographic evidence of disease. This study illustrates the feasibility of incorporating longitudinal ctDNA analysis into the management of relapsed or refractory patients with childhood CNS or non-CNS solid tumors.
Assuntos
Neoplasias Encefálicas , DNA Tumoral Circulante , Humanos , Criança , DNA Tumoral Circulante/genética , Estudos de Viabilidade , Biomarcadores Tumorais , Sequenciamento de Nucleotídeos em Larga Escala , Neoplasias Encefálicas/genética , MutaçãoRESUMO
Brain-derived neurotrophic factor (BDNF) influences the differentiation, plasticity, and survival of central neurons and likewise, affects the development of the neuromuscular system. Besides its neuronal origin, BDNF is also a member of the myokine family. However, the role of skeletal muscle-derived BDNF in regulating neuromuscular physiology in vivo remains unclear. Using gain- and loss-of-function animal models, we show that muscle-specific ablation of BDNF shifts the proportion of muscle fibers from type IIB to IIX, concomitant with elevated slow muscle-type gene expression. Furthermore, BDNF deletion reduces motor end plate volume without affecting neuromuscular junction (NMJ) integrity. These morphological changes are associated with slow muscle function and a greater resistance to contraction-induced fatigue. Conversely, BDNF overexpression promotes a fast muscle-type gene program and elevates glycolytic fiber number. These findings indicate that BDNF is required for fiber-type specification and provide insights into its potential modulation as a therapeutic target in muscle diseases.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Glicólise , Fibras Musculares Esqueléticas/metabolismo , Animais , Marcha , Regulação da Expressão Gênica , Locomoção , Camundongos Knockout , Modelos Biológicos , Placa Motora/metabolismo , Contração Muscular , Fadiga Muscular , Especificidade de Órgãos , Oxirredução , Condicionamento Físico Animal , Transdução de SinaisRESUMO
Eltrombopag is a small molecule, thrombopoietin receptor agonist approved for the treatment of patients with aplastic anemia and chronic immune thrombocytopenia. It is also a polyvalent cation chelator and inhibits leukemia cell proliferation via reduction of intracellular iron. The in vivo efficacy of eltrombopag was tested against a panel of six Pediatric Preclinical Testing Consortium osteosarcoma xenografts at doses of 5 mg/kg/day (moderate dose) and 50 mg/kg/day (high dose). Eltrombopag, at moderate doses, failed to significantly improve event-free survival (EFS) in 6/6 models. At high doses, eltrombopag significantly prolonged EFS in 2/2 models, though the effect size was small. All models tested demonstrated progressive disease. While eltrombopag did not meaningfully inhibit osteosarcoma growth, it also did not stimulate tumor growth, suggesting it may be safely investigated as a supportive care agent to enhance platelet recovery post chemotherapy.
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Proteínas da Membrana Bacteriana Externa/metabolismo , Benzoatos/uso terapêutico , Proteínas de Escherichia coli/metabolismo , Hidrazinas/uso terapêutico , Complexos Multienzimáticos/metabolismo , Osteossarcoma/tratamento farmacológico , Pirazóis/uso terapêutico , Animais , Benzoatos/farmacologia , Modelos Animais de Doenças , Feminino , Humanos , Hidrazinas/farmacologia , Masculino , Camundongos , Pirazóis/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Neuroblastoma (NB) is a deadly childhood disease that carries a 50% chance of relapse for anyone in remission and similar level of 5-year survival. We investigated the value of our proprietary approach-cell surface vimentin (CSV) positive circulating tumor cells (CTC) to monitor treatment response and predict relapse in NB patients under remission in a Phase II long-term preventative clinical trial. We longitudinally analyzed peripheral blood samples from 93 patients for 27 cycles (~25 months) and discovered that the presence of CSV+ CTCs in the first two sequential samples (baseline, cycle 4 [month 3-4]) was a significant indicator of earlier relapse. We observed strong correlation between relapse-free survival (RFS) and lack of CSV+ CTCs in first 4 cycles of therapy (95%). There was sensitivity reaching 100% in predicting RFS in patients who had neither CSV+ CTCs nor MycN amplification. Of note, the low number of CSV+ CTCs seems equivalent to low tumor load because the prevention therapy difluoromethylornithine yields faster reduction of relapse risk when none or only 1-2 CSV+ CTCs (every 6 mL) are present in the blood samples compared to >3 CSV+ CTCs. To the best of our knowledge, this is the first study that directly observes CTCs in under remission NB patients for relapse prediction and the first to gather sequential CSV+ CTC data in any study in a long-term longitudinal manner.
Assuntos
Recidiva Local de Neoplasia/diagnóstico , Células Neoplásicas Circulantes/metabolismo , Neuroblastoma/diagnóstico , Vimentina/metabolismo , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Ensaios Clínicos Fase II como Assunto , Detecção Precoce de Câncer , Eflornitina/uso terapêutico , Transição Epitelial-Mesenquimal , Feminino , Humanos , Estudos Longitudinais , Masculino , Recidiva Local de Neoplasia/metabolismo , Neuroblastoma/metabolismo , Sensibilidade e Especificidade , Análise de SobrevidaRESUMO
BACKGROUND: Regorafenib is a small molecule multikinase inhibitor that inhibits multiple kinases including BRAF, KIT, PDGFRB, RAF, RET, and VEGFR1-3. PROCEDURES: The in vivo anticancer effects of regorafenib were assessed in a panel of six osteosarcoma models, three rhabdomyosarcoma models, and one Ewing sarcoma model. RESULTS: Regorafenib induced modest inhibition of tumor growth in the models evaluated. CONCLUSION: The overall pattern of response to regorafenib appears similar to that of the kinase inhibitor sorafenib, with pronounced slowing of tumor growth in some models, limited to the period of agent administration, being the primary treatment effect.
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Neoplasias Ósseas/tratamento farmacológico , Osteossarcoma/tratamento farmacológico , Compostos de Fenilureia/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Rabdomiossarcoma/tratamento farmacológico , Sarcoma de Ewing/tratamento farmacológico , Animais , Apoptose , Neoplasias Ósseas/enzimologia , Neoplasias Ósseas/patologia , Proliferação de Células , Criança , Feminino , Humanos , Camundongos , Camundongos SCID , Osteossarcoma/enzimologia , Osteossarcoma/patologia , Rabdomiossarcoma/enzimologia , Rabdomiossarcoma/patologia , Sarcoma de Ewing/enzimologia , Sarcoma de Ewing/patologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The pediatric preclinical testing program previously demonstrated activity of eribulin in osteosarcoma patient-derived xenograft (PDX) models. The phase 2 trial in patients with relapsed osteosarcoma failed to meet response endpoints. Eribulin was evaluated in the original and an expanded set of PDX models and tested at multiple dose levels and schedules to evaluate dose-response. Maximal response was observed at the highest dose, consistent with prior results. The alternative schedule generated similar responses. We demonstrate steep dose-response for eribulin in osteosarcoma PDX models, implying that any deviation from achievement of effective concentrations may have a significant impact on activity.
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Neoplasias Ósseas/tratamento farmacológico , Avaliação Pré-Clínica de Medicamentos/métodos , Furanos/farmacologia , Cetonas/farmacologia , Osteossarcoma/tratamento farmacológico , Animais , Apoptose , Neoplasias Ósseas/patologia , Proliferação de Células , Criança , Humanos , Camundongos , Osteossarcoma/patologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
In this chapter, we will review studies of HER2 in osteosarcoma and discuss the controversies that have existed in this field. Our present understanding of HER2 in the context of osteosarcoma is that it is expressed on a subset of patient samples, but that expression is not prognostic. We will review the two trials that have been conducted in osteosarcoma which have targeted HER2. Use of an antibody, trastuzumab, did not suggest activity, but a smaller study using HER2-targeted CAR T cells suggested activity may be present. A trial of an antibody-drug conjugate targeting HER2 for recurrent osteosarcoma is under consideration. Trials targeting other surface proteins for the treatment of osteosarcoma have occurred or are in development. Indeed, this leads us to discuss in a broader fashion therapeutic approaches to targeting surface proteins. It is hoped that some of these approaches will lead to new effective therapies for patients with osteosarcoma.
Assuntos
Neoplasias Ósseas , Osteossarcoma , Receptor ErbB-2 , Antineoplásicos/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Humanos , Recidiva Local de Neoplasia , Osteossarcoma/tratamento farmacológico , Receptor ErbB-2/metabolismo , Trastuzumab/uso terapêuticoRESUMO
BACKGROUND: Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome caused by mutations in the tumor-suppressor gene TP53. Osteosarcoma is a sentinel cancer in LFS. Prior studies using Sanger sequencing platforms have demonstrated that 3% of individuals with osteosarcoma harbor a mutation in TP53. New data from next-generation sequencing have demonstrated that 3.8% of patients with osteosarcoma have a known pathogenic variant, and an additional 5.7% carry exonic variants of unknown significance in TP53. METHODS: Pediatric oncologists were e-mailed an anonymous 18-question survey assessing their willingness to offer TP53 germline testing to a child with osteosarcoma with or without a family history, and they were evaluated for changes in their choices with the prior data and the new data. RESULTS: One hundred seventy-seven pediatric oncologists (22%) responded to the survey. Respondents were more likely to offer TP53 testing to a patient with a positive family history (77.4% vs 12.4%; P < .0001). Significantly more providers responded that they would offer TP53 testing once they were provided with the new data (25.4% vs 12.4%; P = .0038). The proportion of providers who responded that they were unsure increased significantly when they were presented with the new data (25.4% vs 10.2%; P = .0002). Potential implications for other family members and the possibility that surveillance imaging would detect new malignancies at an earlier stage were important factors influencing a provider's decision to offer TP53 testing. CONCLUSIONS: Recent data increase the proportion of providers willing to offer testing, and this suggests concern on the part of pediatric oncologists that variants of unknown significance may be disease-defining in rare cancers. Cancer 2018;124:1242-50. © 2018 American Cancer Society.
Assuntos
Testes Genéticos/estatística & dados numéricos , Síndrome de Li-Fraumeni/diagnóstico , Osteossarcoma/genética , Padrões de Prática Médica/estatística & dados numéricos , Proteína Supressora de Tumor p53/genética , Adolescente , Criança , Feminino , Predisposição Genética para Doença , Testes Genéticos/métodos , Mutação em Linhagem Germinativa/genética , Humanos , Síndrome de Li-Fraumeni/genética , Masculino , Oncologistas/estatística & dados numéricos , Osteossarcoma/diagnóstico , Pediatras/estatística & dados numéricos , Inquéritos e Questionários/estatística & dados numéricosRESUMO
BACKGROUND: Curative therapy for ES requires both chemotherapy and local control of primary tumor. There is no universally accepted standard approach to local control modalities. This survey was conducted to determine practice patterns and factors influencing the choice to offer various local control modalities to patients with ES of the spine and pelvis. METHODS: The survey consisted of four scenarios involving a 15-year-old girl who presented with Ewing sarcoma of thoracic vertebra, sacrum, iliac wing, and acetabulum with or without neurologic compromise. The questionnaire was sent to oncologists, orthopedic surgeons, and radiation oncologists, asking their recommendations for local control modality. RESULTS: Among 94 respondents, radiotherapy was most frequently chosen for sacral tumors (68.1%) and T10 vertebral tumors (46.2%) whereas surgery was preferred for iliac wing pelvic tumors (45.7%) and acetabular tumors (43.6%). Orthopedic surgeons were significantly more likely to offer surgery than radiation oncologists (OR 3.07, 95%CI 1.37-6.88, P = 0.007). Providers outside North America were more likely to offer combined surgery plus radiotherapy (OR 10.58, 95%CI 5.41-20.70, P < 0.001). CONCLUSION: Considerable heterogeneity exists in local control modalities for Ewing sarcoma of the spine and pelvis. Specialty and location of practice may influence treatment recommendations.
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Neoplasias Ósseas/radioterapia , Neoplasias Ósseas/cirurgia , Padrões de Prática Médica , Sarcoma de Ewing/radioterapia , Sarcoma de Ewing/cirurgia , Neoplasias da Coluna Vertebral/radioterapia , Neoplasias da Coluna Vertebral/cirurgia , Adolescente , Neoplasias Ósseas/patologia , Estudos Transversais , Feminino , Humanos , Oncologistas , Cirurgiões Ortopédicos , Ossos Pélvicos/patologia , Radioterapia (Especialidade) , Sarcoma de Ewing/patologia , Neoplasias da Coluna Vertebral/patologia , Inquéritos e Questionários , Vértebras Torácicas/patologiaRESUMO
BACKGROUND: The neutropenic diet (ND) is prescribed to avoid introduction of bacteria into a host's gastrointestinal tract and reduce infection. Due to a lack of evidence to support the ND, there continues to be debate among pediatric oncologists regarding its usefulness. This prospective randomized controlled trial evaluated the difference in neutropenic infection rates in pediatric oncology patients randomized to Food and Drug Administration approved food safety guidelines (FSGs) versus the ND plus FSGs during one cycle of chemotherapy. PROCEDURE: Pediatric patients receiving cancer treatment with myelosuppressive chemotherapy were eligible. Neutropenic infection was the primary outcome and defined as (i) fever with neutropenia or (ii) hospital admission and treatment for clinical infection and neutropenia. The rate of neutropenic infection was compared with Student's t-test for independent samples. Documented infections were identified by comprehensive chart review and compared between groups using a χ2 test. RESULTS: One hundred fifty patients were randomly assigned to FSGs (n = 73) or ND + FSGs (n = 77). The most common diagnoses were acute lymphoblastic leukemia (32%) and sarcoma (32%). There was no significant difference between the groups in the percentage of patients who developed neutropenic infection: FSGs 33% versus ND + FSGs 35% (P = 0.78). Patients randomized to ND + FSGs reported that following the diet required more effort than those on FSGs alone. CONCLUSION: The ND offers no benefit over FSGs in the prevention of infection in pediatric oncology patients undergoing myelosuppressive chemotherapy and adherence requires more effort for patients and families. Institutions caring for children with cancer should consider replacing ND guidelines with FSGs.
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Inocuidade dos Alimentos , Neoplasias/tratamento farmacológico , Neutropenia , Adolescente , Adulto , Criança , Pré-Escolar , Método Duplo-Cego , Feminino , Humanos , Lactente , Infecções/induzido quimicamente , Infecções/terapia , Masculino , Neutropenia/induzido quimicamente , Neutropenia/dietoterapia , Guias de Prática Clínica como Assunto , Estudos ProspectivosRESUMO
BACKGROUND: Acute lymphoblastic leukemia (ALL) remains a major cause of death in children. AMP-activated protein kinase (AMPK) affects the unfolded protein response (UPR), leading to increased vulnerability to endoplasmic reticulum (ER) stress in ALL cells. In vitro, metformin causes ALL cell death via AMPK-mediated inhibition of the UPR. It was evaluated whether ER stress could be induced in relapsed ALL through a phase I study investigating the safety and feasibility of metformin in combination with relapse induction chemotherapy. PROCEDURE: Metformin was administered twice daily for 28 days in addition to vincristine, dexamethasone, PEG-asparaginase and doxorubicin (VXLD). Dose escalation of metformin was evaluated using a 3+3 design. Pharmacokinetics (PK), pharmacodynamic (PD) evaluation of the AMPK and ER stress/UPR pathways, and treatment response were assessed. RESULTS: Fourteen patients were enrolled; all were evaluable for toxicity. The recommended phase 2 dose (RP2D) was Dose level 2, 1,000 mg/m2 /day. A single dose-limiting toxicity (DLT), hypoglycemia with acidosis, was observed at the RP2D and two DLTs, diarrhea and acidosis, were observed at Dose Level 3. Nine patients were evaluable for response as defined by the protocol, receiving at least 85% of planned metformin doses. Five complete remissions, one partial response, and one stable disease were observed. PD evaluation showed induction of ER stress, activation of AMPK, and inhibition of the UPR. CONCLUSIONS: The VXLD with metformin was tolerable with a RP2D for metformin of 1,000 mg/m2 /day and yielded responses in a heavily pretreated population. ER stress was induced and toxicities attributable to metformin occurred in all dose levels.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Terapia de Salvação , Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Asparaginase/administração & dosagem , Asparaginase/efeitos adversos , Criança , Pré-Escolar , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Relação Dose-Resposta a Droga , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Feminino , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Dose Máxima Tolerável , Metformina/administração & dosagem , Metformina/efeitos adversos , Metformina/farmacologia , Proteínas de Neoplasias/antagonistas & inibidores , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/efeitos adversos , Recidiva , Resultado do Tratamento , Resposta a Proteínas não Dobradas/efeitos dos fármacos , Vincristina/administração & dosagem , Vincristina/efeitos adversos , Adulto JovemRESUMO
Primary isolated CNS presentation of HLH is exceedingly rare and typically associated with significant morbidity and mortality. We describe an adolescent patient with late-onset, primary isolated CNS HLH and a compound heterozygous PRF1 mutation (c50delT (p.L17 fs); c.1229G>C (p.R410P)), not previously reported with this phenotype. He was successfully treated with allogeneic HSCT following a reduced-intensity conditioning regimen, despite a high pre-HSCT comorbidity index. Two years after transplant, he is alive and in disease remission. While patients with systemic HLH and active CNS disease have relatively poorer outcomes, a high index of suspicion may aid with early diagnosis of primary isolated CNS HLH; prompt treatment with HSCT may be associated with improved cure and durable remission of this rare disease.
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Doenças do Sistema Nervoso Central/terapia , Transplante de Células-Tronco Hematopoéticas , Linfo-Histiocitose Hemofagocítica/terapia , Adolescente , Humanos , Masculino , Condicionamento Pré-Transplante/métodos , Transplante HomólogoRESUMO
OBJECTIVE: The main objective of this study was to determine if family history of malignant peripheral nerve sheath tumor (MPNST) increases risk of developing an MPNST in patients with neurofibromatosis-1 (NF-1). MATERIALS AND METHODS: Individuals with NF-1 registered with the Children's Tumor Foundation's Neurofibromatosis Registry were emailed an anonymous 15-minute survey with regard to personal and family history of NF-1, MPNST, ages of onset, and symptomatology. Participation was voluntary and information was self-reported. RESULTS: The survey was sent to 4801 registrants, 878 responded. Presence of a family history of MPNST was found to be a risk factor for the development of MPNST; 19.4% of respondents confirming a family history of MPNST developed MPNST compared with 7.5% of respondents with no family history (odds ratio, 2.975; 95% confidence interval, 1.232-7.187; P=0.021). NF-1 patients with a positive family history developed MPNST at a younger age than those with no family history (8.3% vs. 0.5% P=0.003 and 13.9% vs. 2.4% P=0.003, for onset before 10 and 20, respectively). In the MPNST population with a known family history, onset prior to age 10 was significantly more prevalent (42.9% vs. 7% P=0.029). CONCLUSIONS: These results suggest a positive family history of MPNST represents a risk factor for the development and early onset of MPNST in individuals with NF-1.
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Família , Neurofibromatose 1 , Neurofibrossarcoma , Sistema de Registros , Adolescente , Adulto , Idade de Início , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Anamnese , Pessoa de Meia-Idade , Neurofibromatose 1/epidemiologia , Neurofibromatose 1/genética , Neurofibromatose 1/patologia , Neurofibrossarcoma/epidemiologia , Neurofibrossarcoma/genética , Neurofibrossarcoma/patologia , Fatores de RiscoRESUMO
INTRODUCTION: The vascularized fibular graft prosthetic composite (VFGPC) is used for reconstruction after internal hemipelvectomy. The purpose of this study was to create a mathematical model that calculates the mechanical effects of the vascularized fibular graft on the VFGPC. METHODS: The effects of the VFG positioning were calculated based on three-dimensional static analyzes to determine the direction, magnitude, and distribution of the forces through the prosthesis and VFG. The shear stress (SS) and cyclic loads to failure (CLF) were calculated. By varying the location of the VFG on the sacrum the zone of acceptable placement was calculated. RESULTS: Utilization of the VFG decreased the forces through the implant by 15-35% and decreased SS 20-54%, depending on stance. The CLF improved by 94%. The zone of acceptable placement for the VFG was found to be between 0° and 15° of the vertical axis in the sagittal plane and 0° and 30° of the posterior axis in coronal plane. CONCLUSION: Determining the position of the VFG pre-operatively allows for the creation of a customized cutting jig can be utilized to create graft allowing for accurate fibular osteotomies, minimization of ischemia time, and decreased intra-operative handling of the graft.
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Neoplasias Ósseas/cirurgia , Fíbula/transplante , Hemipelvectomia , Prótese de Quadril , Teste de Materiais , Artroplastia de Quadril , Interface Osso-Implante , Humanos , Desenho de Prótese , Estresse MecânicoRESUMO
BACKGROUND: Chemotherapy-induced febrile neutropenia (FN) is traditionally managed with hospital admission for parenteral antibiotics until neutropenia resolves. Recent studies have explored risk stratification and the safety of managing "low-risk" patients as outpatients. Few studies have directly assessed pediatric provider preferences for managing FN. PROCEDURE: We conducted a survey of practicing US and Canadian pediatric hematology/oncology (PHO) and pediatric infectious disease (PID) physicians to assess their FN management preferences using case scenarios with varying risk profiles. RESULTS: Twenty-one percent (n = 186) of PHO and 32% (n = 123) of PID physicians completed the survey. Overall, both groups of providers agreed regarding which patients with FN could be managed outpatient. For a child with acute lymphoblastic leukemia receiving maintenance chemotherapy with an absolute neutrophil count (ANC) of 400 cells/µl, 35% (n = 66) of PHO and 49% (n = 60) of PID physicians would consider outpatient management (P = 0.02). Of those physicians selecting inpatient management, 41% (n = 49) of PHO and 52% (n = 33) of PID physicians would be willing to discharge the patient without an increase in ANC, if afebrile with a negative blood culture (P = 0.16). For a similar patient with an ANC of 100 cells/µl, only 23% (n = 35) of PHO and 42% (n = 39) of PID physicians would consider discharge without an increase in ANC (P = 0.002). CONCLUSIONS: Despite the lack of established guidelines for low-risk pediatric FN, a significant proportion of North American physicians report willingness to modify traditional management. This reinforces the need for evidence-based low-risk criteria and outpatient management guidelines to optimize consistency of care for these patients.
Assuntos
Neutropenia Febril Induzida por Quimioterapia/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Estudos Transversais , Feminino , Hematologia , Humanos , Masculino , Pediatria , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Patients with relapsed and refractory solid tumors have a poor prognosis. Recent advances in genomic technology have made it feasible to screen tumors for actionable mutations, with the anticipation that this may provide benefit to patients. METHODS: Pediatric oncologists were emailed an anonymous 34-question survey assessing their willingness to offer a rebiopsy to patients with relapsed disease for the purpose of tumor genomic profiling. They were presented with two scenarios evaluating morbidity and invasiveness of the procedures using the clinical examples of medulloblastoma and Ewing sarcoma. RESULTS: A total of 195 pediatric oncologists responded to the questionnaire. Morbidity and invasiveness of the procedure demonstrated significant differences in provider willingness to refer their patients for rebiopsy. The pretest probability was a major variable influencing provider willingness to offer a rebiopsy. Respondents were more likely to offer a rebiopsy if the likelihood was high that the results would have an impact on clinical management than if the biopsy was for histologic confirmation alone (mean 89 vs. 56 %; p = 0.017). Compared with the rate of a rebiopsy for histologic confirmation, significantly fewer providers were willing to offer a rebiopsy if they were led to believe the likelihood of finding an actionable mutation was low (mean 45 vs. 56 %; p = 0.021). CONCLUSION: The scenario showed that the pretest probability of finding an actionable mutation was influential in determining provider willingness to offer a rebiopsy for the purpose of tumor genomic profiling. Further research is warranted to evaluate the benefit of tumor genomic profiling in terms of patient outcomes.