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Ewing sarcoma (ES) is a malignant tumor of bone and soft tissue that most often occurs in children, adolescents, and young adults. Debate and controversy remain in the management of relapsed/refractory ES (RR-ES). The authors leveraged the expertise assembled by the National Ewing Sarcoma Tumor Board, a multidisciplinary virtual tumor board that meets monthly to discuss challenging cases of ES. In this review, they focus on select topics that apply to the management of patients with RR-ES. The specific topics covered include the initial approach of such patients and discussion of the goals of care, the role of molecular testing, chemotherapy regimens and novel agents to consider, the role of maintenance therapy, and the use of high-dose chemotherapy with autologous stem cell rescue. The data referenced are often limited to subgroup analyses and/or compiled from multiple sources. Although not intended to replace the clinical judgement of treating physicians, these guidelines are intended to support clinicians and provide some clarity and recommendations for the management of patients with RR-ES. PLAIN LANGUAGE SUMMARY: Ewing sarcoma (ES) is a bone and soft tissue cancer that most often occurs in teenagers and young adults. This article uses the experience of the National Ewing Sarcoma Tumor Board, a multi-institution, multidisciplinary virtual tumor board that meets monthly to discuss challenging cases of ES and to address questions related to the treatment of patients with relapsed ES. Although not intended to replace the clinical judgement of treating physicians and limited by available data, these consensus recommendations will support clinicians who treat patients with this challenging malignancy, made even more difficult when it recurs.
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INTRODUCTION: Treatment for pediatric solid tumors is often intense and multidisciplinary and can create a substantial financial burden for families. Assessing these burdens, termed the financial toxicity of treatment, can be difficult. Using Wilms tumor as an example, we evaluated crowdfunding campaigns in an attempt to better understand the impact of economic and logistic challenges associated with pediatric solid tumor care and identify features associated with successful fundraising with this method. METHODS: We used a webscraping algorithm to identify crowdfunding campaigns on GoFundMe.com for pediatric patients with Wilms tumor in the United States. We conducted a cross-sectional analysis to describe the patients and families seeking crowdfunding support for cancer care. After fundraizing information was extracted using the webscraping algorithm, each fundraiser was verified and examined by two independent reviewers to assess demographic, qualitative, disease, and treatment variables. Successful fundraisers, defined as those meeting stated financial goals, were compared to unsuccessful campaigns to identify variables associated with successful crowdfunding campaigns. RESULTS: We identified 603 children with Wilms tumor and an associated crowdfunding campaign. The median age was 4 y. The majority lived in two-parent households (68.5%). Patients mentioned siblings in 35.5% of fundraisers. While motivations for crowdfunding varied, hardships endured by families included loss of employment (52.2%), need for childcare for other children (9.8%), direct costs of care [co-payments, insurance, pharmaceuticals, out-of-pocket care costs, etc.] (80.9%), indirect costs associated with seeking care [transportation, parking, lodging, lost opportunity cost, etc.] (56.2%), and need for relocation to pursue complex cancer care (6.8%). Disease characteristics in this cohort were limited to self-reports by families. However, fundraisers mentioned disease characteristics, including tumor stage (47.6%), size (11.4%), positive nodal status (9.6%), metastatic disease (3.6%), pathology (11.8%), upstaging (4.6%), and disease recurrence (8.6%). No individually examined demographic, support, disease, or hardship-related factors varied significantly between successful and unsuccessful crowdfunding campaigns (all P > 0.05). However, successful campaigns requested less money ($11,783.25 successful versus $22,442.2 unsuccessful, <0.001), received more money ($16,409.5 successful vs 7427.4 unsuccessful, P < 0.001), and solicited larger donor numbers (170.3 successful versus 86.3 unsuccessful, P < 0.001). CONCLUSIONS: Families whose children undergo multimodal cancer care have significant expenses and burdens and can use crowdfunding to support their costs. Careful consideration of the financial and logistic strains associated with pediatric solid tumor treatment, including thorough analysis of crowdfunding sites, may support better understanding of nonclinical burdens, supporting therapeutic relationships and patient outcomes.
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Crowdsourcing , Neoplasias Renais , Tumor de Wilms , Humanos , Criança , Estados Unidos , Pré-Escolar , Estresse Financeiro , Estudos Transversais , Recidiva Local de Neoplasia , Tumor de Wilms/terapia , Neoplasias Renais/terapiaRESUMO
BACKGROUND AND OBJECTIVES: New childhood cancer diagnoses require timely, complex care coordination and cause considerable logistic burden for families. We used renal tumors as a model to examine healthcare utilization and cost following new solid tumor diagnosis. METHODS: Children (ages 0-21) with International Classification of Disease (ICD) codes for renal malignancy and subsequent nephrectomy were identified from North Carolina Medicaid claims data (2014-2020). We stratified patients by duration of follow-up, then quantified healthcare utilization and billing totals. RESULTS: Eighty-one children met study criteria. Median age at diagnosis was 3 years (interquartile range [IQR]: 1-5). Median family monthly earned income was $0. One month following diagnosis, children cumulatively spent a median of 16 days receiving medical care (IQR: 10-20), 28 days at 3 months (IQR: 21-43), and 50.5 days at 1 year (IQR: 35-94.5). Children cumulatively spent a median 12 days as inpatients during the first 3 months (IQR: 7-17) and 13.5 days at 1 year (IQR: 8.5-37). Children cumulatively completed a median 12 outpatient encounters at 3 months (IQR: 7-17) and 26 at 1 year (IQR: 12-36). At 1 year, median Medicaid claim reimbursements for children with renal malignancy was $50,041 (IQR: $36,670-$80,734). CONCLUSION: In examining healthcare utilization in children with renal tumor diagnoses, the substantial number of days spent in medical facilities greatly impacts the burden of care on families, especially for those with limited financial resources. Awareness of this logistic strain on families and careful planning to consolidate patient visits may improve the navigability of pediatric cancer regimens for families, particularly those with limited resources.
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BACKGROUND. In current clinical practice, thyroid nodules in children are generally evaluated on the basis of radiologists' overall impressions of ultrasound images. OBJECTIVE. The purpose of this article is to compare the diagnostic performance of radiologists' overall impression, the American College of Radiology Thyroid Imaging Reporting and Data System (ACR TI-RADS), and a deep learning algorithm in differentiating benign and malignant thyroid nodules on ultrasound in children and young adults. METHODS. This retrospective study included 139 patients (median age 17.5 years; 119 female patients, 20 male patients) evaluated from January 1, 2004, to September 18, 2020, who were 21 years old and younger with a thyroid nodule on ultrasound with definitive pathologic results from fine-needle aspiration and/or surgical excision to serve as the reference standard. A single nodule per patient was selected, and one transverse and one longitudinal image each of the nodules were extracted for further evaluation. Three radiologists independently characterized nodules on the basis of their overall impression (benign vs malignant) and ACR TI-RADS. A previously developed deep learning algorithm determined for each nodule a likelihood of malignancy, which was used to derive a risk level. Sensitivities and specificities for malignancy were calculated. Agreement was assessed using Cohen kappa coefficients. RESULTS. For radiologists' overall impression, sensitivity ranged from 32.1% to 75.0% (mean, 58.3%; 95% CI, 49.2-67.3%), and specificity ranged from 63.8% to 93.9% (mean, 79.9%; 95% CI, 73.8-85.7%). For ACR TI-RADS, sensitivity ranged from 82.1% to 87.5% (mean, 85.1%; 95% CI, 77.3-92.1%), and specificity ranged from 47.0% to 54.2% (mean, 50.6%; 95% CI, 41.4-59.8%). The deep learning algorithm had a sensitivity of 87.5% (95% CI, 78.3-95.5%) and specificity of 36.1% (95% CI, 25.6-46.8%). Interobserver agreement among pairwise combinations of readers, expressed as kappa, for overall impression was 0.227-0.472 and for ACR TI-RADS was 0.597-0.643. CONCLUSION. Both ACR TI-RADS and the deep learning algorithm had higher sensitivity albeit lower specificity compared with overall impressions. The deep learning algorithm had similar sensitivity but lower specificity than ACR TI-RADS. Interobserver agreement was higher for ACR TI-RADS than for overall impressions. CLINICAL IMPACT. ACR TI-RADS and the deep learning algorithm may serve as potential alternative strategies for guiding decisions to perform fine-needle aspiration of thyroid nodules in children.
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Aprendizado Profundo , Nódulo da Glândula Tireoide , Humanos , Masculino , Criança , Feminino , Adulto Jovem , Adolescente , Adulto , Nódulo da Glândula Tireoide/patologia , Estudos Retrospectivos , Ultrassonografia/métodos , RadiologistasRESUMO
Adjuvant chemotherapy for osteosarcoma and Ewing sarcoma consists of conventional cytotoxic regimens that have changed little over the past decades. There is an urgent need for agents that are more effective and have less long-term toxicity. Receptor tyrosine kinases regulate cell growth and proliferation of these tumors, and small-molecule inhibitors for many of these kinases are now available. In this article, we review published phase II trials for patients with recurrent disease and highlight the pathways targeted by available agents, as well as the toxicity and efficacy results seen to date. We also discuss the difficulties in identifying biomarkers to facilitate rational patient selection, as well as published and proposed strategies for how these inhibitors can be combined with conventional chemotherapy or other targeted agents. It is hoped future trials can capitalize on this growing experience to optimize the use of this exciting class of agents.
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Antineoplásicos , Neoplasias Ósseas , Osteossarcoma , Inibidores de Proteínas Quinases , Sarcoma de Ewing , Antineoplásicos/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Ensaios Clínicos Fase II como Assunto , Humanos , Osteossarcoma/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Sarcoma de Ewing/tratamento farmacológicoRESUMO
BACKGROUND: The combination of gemcitabine and docetaxel is often used to treat patients with recurrent sarcoma. Nab-paclitaxel is a taxane modified to improve drug exposure and increase intratumoral accumulation and, in combination with gemcitabine, is standard therapy for pancreatic cancer. Applying the dosages and schedule used for pancreatic cancer, we performed a phase II trial to assess the response rate of gemcitabine and nab-paclitaxel in patients with relapsed Ewing sarcoma. PROCEDURE: Using a Simon's two-stage design to identify a response rate of ≥ 35%, patients received nab-paclitaxel 125 mg/m2 followed by gemcitabine 1000 mg/m2 i.v. on days 1, 8, and 15 of four-week cycles. Immunohistochemical analysis of archival tissue was performed to identify possible biomarkers of response. RESULTS: Eleven patients from four institutions enrolled, with a median age of 22 years (range, 14-27). Patients were heavily pretreated (median 3 prior regimens, range, 1-7). Thirty-five cycles were administered (median 2, range, 1-8). Accrual was stopped after 11 patients, due to only one confirmed partial response. Two other patients had partial responses after two cycles, but withdrew because of adverse effects or progression before confirmation of continued response. The predominant toxicity was myelosuppression, and four (36%) patients were removed due to hematologic toxicity despite pegfilgrastim and dose reductions. Expression of secreted protein, acidic and rich in cysteine (SPARC) and CAV-1 in archival tumors was not predictive of clinical benefit in this small cohort of patients. CONCLUSIONS: In patients with heavily pretreated Ewing sarcoma, the confirmed response rate of 9% was similar to multi-institutional studies of gemcitabine and docetaxel.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Sarcoma de Ewing/tratamento farmacológico , Adolescente , Adulto , Albuminas/administração & dosagem , Neoplasias Ósseas/patologia , Criança , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Feminino , Seguimentos , Humanos , Masculino , Recidiva Local de Neoplasia/patologia , Paclitaxel/administração & dosagem , Prognóstico , Sarcoma de Ewing/patologia , Adulto Jovem , GencitabinaRESUMO
Osteosarcoma is the most common bone tumor in children and young adults, with few advances in survival and treatment, especially for metastatic disease, in the last 30 years. Recently, immunotherapy has begun to show promise in various adult cancers, but the utility of this approach for osteosarcoma remains relatively unexplored. In this review, we outline the mechanisms and status of immunotherapies currently in clinical trials as well as future therapies on the horizon, and discuss their potential application for osteosarcoma.
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Neoplasias Ósseas/terapia , Imunoterapia/métodos , Osteossarcoma/terapia , Adolescente , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Biomarcadores Tumorais , Antígeno CTLA-4/antagonistas & inibidores , Vacinas Anticâncer/uso terapêutico , Criança , Ensaios Clínicos como Assunto , Terapia Combinada , Células Dendríticas/transplante , Previsões , Humanos , Imunoterapia Adotiva , Terapia de Alvo Molecular/métodos , Terapia Viral Oncolítica , Osteossarcoma/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Resultado do Tratamento , Microambiente TumoralRESUMO
Young children with emaciation caused by a hypothalamic glioma are considered to have diencephalic syndrome (DS), which is often poorly controlled with conventional treatment. We describe an infant with DS whose tumor progressed following chemotherapy. Biopsy was performed for molecular testing and demonstrated a BRAF fusion. Treatment with the MEK inhibitor trametinib for 18 months resulted in reduction of tumor size, normalization of his weight curve, and marked neurodevelopmental improvement. Our results build on earlier reports of using targeted agents for low-grade glioma, and we review the evolving management strategy for such patients in the era of precision medicine.
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Doenças Hipotalâmicas/tratamento farmacológico , Terapia de Alvo Molecular , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Piridonas/uso terapêutico , Pirimidinonas/uso terapêutico , Gerenciamento Clínico , Humanos , Doenças Hipotalâmicas/metabolismo , Doenças Hipotalâmicas/patologia , Lactente , Masculino , PrognósticoRESUMO
Optimal treatment of rhabdomyosarcoma (RMS) requires multidisciplinary approach, incorporating chemotherapy with local control. Although current therapies are built on cooperative group trials, a comprehensive standard of care to guide clinical decision making has been lacking, especially for relapsed patients. Therefore, we assembled a panel of pediatric and adolescent and young adult sarcoma experts to develop treatment guidelines for managing RMS and to identify areas in which further research is needed. We created algorithms incorporating evidence-based care for patients with RMS, emphasizing the importance of clinical trials and close integration of all specialties involved in the care of these patients.
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Algoritmos , Medicina Baseada em Evidências/métodos , Rabdomiossarcoma/terapia , Ensaios Clínicos como Assunto , Humanos , Guias de Prática Clínica como AssuntoRESUMO
BACKGROUND: Lymph node metastases are an important cause of treatment failure for pediatric and adolescent/young adult (AYA) sarcoma patients. Nodal sampling is recommended for certain sarcoma subtypes that have a predilection for lymphatic spread. Sentinel lymph node biopsy (SLNB) may improve the diagnostic yield of nodal sampling, particularly when single-photon emission computed tomography/computed tomography (SPECT-CT) is used to facilitate anatomic localization. Functional imaging with positron emission tomography/computed tomography (PET-CT) is increasingly used for sarcoma staging and is a less invasive alternative to SLNB. To assess the utility of these 2 staging methods, this study prospectively compared SLNB plus SPECT-CT with PET-CT for the identification of nodal metastases in pediatric and AYA patients. METHODS: Twenty-eight pediatric and AYA sarcoma patients underwent SLNB with SPECT-CT. The histological findings of the excised lymph nodes were then correlated with preoperative PET-CT imaging. RESULTS: A median of 2.4 sentinel nodes were sampled per patient. No wound infections or chronic lymphedema occurred. SLNB identified tumors in 7 of the 28 patients (25%), including 3 patients who had normal PET-CT imaging of the nodal basin. In contrast, PET-CT demonstrated hypermetabolic regional nodes in 14 patients, and this resulted in a positive predictive value of only 29%. The sensitivity and specificity of PET-CT for detecting histologically confirmed nodal metastases were only 57% and 52%, respectively. CONCLUSIONS: SLNB can safely guide the rational selection of nodes for biopsy in pediatric and AYA sarcoma patients and can identify therapy-changing nodal disease not appreciated with PET-CT. Cancer 2017;155-160. © 2016 American Cancer Society.
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Fluordesoxiglucose F18/metabolismo , Metástase Linfática/diagnóstico , Metástase Linfática/patologia , Sarcoma/patologia , Linfonodo Sentinela/patologia , Linfonodo Sentinela/cirurgia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Excisão de Linfonodo/métodos , Linfocintigrafia/métodos , Masculino , Estadiamento de Neoplasias/métodos , Tomografia por Emissão de Pósitrons/métodos , Estudos Prospectivos , Sarcoma/metabolismo , Sarcoma/cirurgia , Sensibilidade e Especificidade , Linfonodo Sentinela/metabolismo , Biópsia de Linfonodo Sentinela/métodos , Tomografia Computadorizada por Raios X/métodos , Adulto JovemRESUMO
When pediatric, adolescent, and young adult patients present with a bone sarcoma, treatment decisions, especially after relapse, are complex and require a multidisciplinary approach. This review presents scenarios commonly encountered in the therapy of bone sarcomas with the goal of objectively presenting a consensus, multidisciplinary management approach. Little variation was found in the authors' group with respect to local control or systemic therapy. Clinical trials were universally prioritized in all settings. Decisions regarding relapse therapies in the absence of a clinical trial had very minor variations initially, but a consensus was reached after a literature review and discussion. This review presents a concise document and figures as a starting point for evidence-based care for patients with these rare diseases. This framework allows prospective decision making and prioritization of clinical trials. It is hoped that this framework will inspire and focus future clinical research and thus lead to new trials to improve efficacy and reduce toxicity. Cancer 2017;123:2206-2218. © 2017 American Cancer Society.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/terapia , Tomada de Decisão Clínica , Recidiva Local de Neoplasia/terapia , Procedimentos Ortopédicos , Osteossarcoma/terapia , Radioterapia , Sarcoma de Ewing/terapia , Adolescente , Neoplasias Ósseas/diagnóstico por imagem , Neoplasias Ósseas/patologia , Criança , Ensaios Clínicos como Assunto , Terapia Combinada , Humanos , Osteossarcoma/diagnóstico por imagem , Osteossarcoma/patologia , Equipe de Assistência ao Paciente , Sarcoma/diagnóstico por imagem , Sarcoma/patologia , Sarcoma/terapia , Sarcoma de Ewing/diagnóstico por imagem , Sarcoma de Ewing/patologia , Adulto JovemRESUMO
BACKGROUND: Describe a single-center real-world experience with comprehensive genomic profiling (CGP) to identify genotype directed therapy (GDT) options for patients with malignancies refractory to standard treatment options. METHODS: Patients who had CGP by a CLIA-certified laboratory between November 2012 and December 2015 were included. The medical records were analyzed retrospectively after Institutional Review Board (IRB) approval. The treating oncologist made the decision to obtain the assay to provide potential therapeutic options. The objectives of this study were to determine the proportion of patients who benefited from GDT, and to identify barriers to receiving GDT. RESULTS: A total of 125 pediatric and adult patients with a histologically confirmed diagnosis of malignancy were included. Among these, 106 samples were from adult patients, and 19 samples were from pediatric patients. The median age was 54 years for adults. The majority had stage IV malignancy (53%) and were pretreated with 2-3 lines of therapy (45%). The median age was 8 years for pediatric patients. The majority had brain tumors (47%) and had received none or 1 line of therapy (58%) when the profiling was requested. A total of 111 (92%) patients had genomic alterations and were candidates for GDT either via on/off-label use or a clinical trial (phase 1 through 3). Fifteen patients (12%) received GDT based on these results including two patients who were referred for genomically matched phase 1 clinical trials. Three patients (2%) derived benefit from their GDT that ranged from 2 to 6 months of stable disease. CONCLUSIONS: CGP revealed potential treatment options in the majority of patients profiled. However, multiple barriers to therapy were identified, and only a small minority of the patients derived benefit from GDT.
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Neoplasias/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Ensaios Clínicos como Assunto , Feminino , Genômica/métodos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
BACKGROUND: Early lymphocyte recovery following chemotherapy has been associated with improved outcome in many cancers, including in one small study of osteosarcoma patients. MATERIALS AND METHODS: To confirm this finding, we retrospectively reviewed data from 53 patients with newly diagnosed osteosarcoma who had blood counts on day 14 (±1 d) following the first cycle of cisplatin and doxorubicin. RESULTS: The median absolute lymphocyte count (ALC) 14 days after starting the first cycle of chemotherapy (ALC-14) was 1990 cells/µL (range: 600 to 6470). For 32 patients with an ALC-14≥1800 cells/µL, the 5-year progression-free survival (PFS) was 69%, compared with 33% for patients with an ALC-14 of <1800 cell/µL (P=0.036). In multivariable analysis of factors including age, sex, metastatic disease, and favorable histologic response to induction chemotherapy, ALC-14 was significantly associated with PFS (P=0.0081) and overall survival (P=0.0131). The use of ALC-14 appears to further stratify PFS and overall survival among patients when grouped by histologic response. CONCLUSIONS: We confirmed that early lymphocyte recovery was associated with outcome in pediatric osteosarcoma. Although presumably reflecting immune-mediated tumor control, the precise mechanism for this is unclear. Further study of peripheral blood lymphocyte subpopulations in prospectively treated patients is underway.
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Contagem de Linfócitos , Osteossarcoma/tratamento farmacológico , Adolescente , Adulto , Criança , Cisplatino/uso terapêutico , Intervalo Livre de Doença , Doxorrubicina/uso terapêutico , Feminino , Humanos , Masculino , Osteossarcoma/sangue , Osteossarcoma/mortalidade , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVE: Physiologic uptake of 18F-fluorodeoxyglucose (FDG) in brown adipose tissue (adipose tissue) of cancer patients may confound interpretation of positron emission tomography (PET) scans. Uptake in adipose tissue occurs in up to half of pediatric oncology patients undergoing PET scans, and is especially common in adolescents. adipose tissue is innervated by the sympathetic nervous system, and beta blockers such as propranolol have shown efficacy in reducing adipose tissue uptake on PET scans done in older adult oncology patients. PARTICIPANTS: Because propranolol may cause hypoglycemia or other side effects in fasting patients, we prospectively assessed the safety of a single dose of 20 mg propranolol in adolescent and young adult oncology patients undergoing FDG-PET imaging. METHODS: Ten patients (median age 18 years, range 14-24) received propranolol premedication prior to FDG-PET. RESULTS: No adverse effects or clinically significant changes in serum glucose, heart rate, or blood pressure were observed. Five of the 10 patients had adipose tissue identified on previous PET scans. However, following propranolol administration only, one patient had persistent uptake in adipose tissue. CONCLUSIONS: Propranolol was convenient and safe in fasting adolescent and young adult oncology patients undergoing PET scans. Larger studies are warranted to better define the effectiveness of this approach.
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Tecido Adiposo Marrom/metabolismo , Fluordesoxiglucose F18 , Neoplasias/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Propranolol/administração & dosagem , Tecido Adiposo Marrom/diagnóstico por imagem , Tecido Adiposo Marrom/fisiopatologia , Adolescente , Adulto , Glicemia/metabolismo , Pressão Sanguínea , Feminino , Fluordesoxiglucose F18/administração & dosagem , Fluordesoxiglucose F18/farmacocinética , Frequência Cardíaca , Humanos , Masculino , Neoplasias/sangue , Neoplasias/fisiopatologia , Projetos Piloto , Propranolol/efeitos adversos , Estudos Prospectivos , Adulto JovemRESUMO
BACKGROUND: The combined inhibition of insulin-growth factor type 1 receptor (IGF-1R) and the mammalian target of rapamycin (mTOR) has shown activity in preclinical models of pediatric sarcoma and in adult sarcoma patients. We evaluated the activity of the anti-IGF-1R antibody cixutumumab with the mTOR inhibitor temsirolimus in patients with relapsed or refractory Ewing sarcoma, osteosarcoma, rhabdomyosarcoma, and other soft tissue sarcoma, using the recommended dosages from a pediatric phase I trial. METHODS: Cixutumumab 6 mg/kg and temsirolimus 8 mg/m(2) were administered intravenously once weekly in 4-week cycles to patients <30 years. Temsirolimus was escalated to 10 mg/m(2) for subsequent cycles in patients who did not experience unacceptable first-cycle toxicity. A two-stage design was used to identify a response rate <10 or >35% for each tumor-specific cohort. Tumor tissue was analyzed by immunohistochemistry for potential biomarkers of response. RESULTS: Forty-three evaluable patients received a median of 2 cycles (range 1-7). No objective responses were observed, and 16% of patients were progression-free at 12 weeks. Dose-limiting toxicity was observed in 15 (16%) of 92 cycles. The most common toxicities were mucositis, electrolyte disturbances, and myelosuppression. The majority of patients receiving a second cycle were not eligible for temsirolimus escalation due to first-cycle toxicity. The lack of objective responses precluded correlation with tissue biomarkers. CONCLUSIONS: Despite encouraging preclinical data, the combination of cixutumumab and temsirolimus did not result in objective responses in this phase II trial of pediatric and young adults with recurrent or refractory sarcoma.
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Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Biomarcadores Tumorais/metabolismo , Sarcoma , Sirolimo/análogos & derivados , Adolescente , Adulto , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Sarcoma/tratamento farmacológico , Sarcoma/metabolismo , Sarcoma/patologia , Sirolimo/administração & dosagem , Sirolimo/efeitos adversos , Adulto JovemRESUMO
PURPOSE: Amplification and high levels of NOTCH ligand expression have been identified in several types of pediatric brain tumors. A phase I trial of weekly MK-0752, an oral inhibitor of gamma-secretase, was conducted in children with recurrent central nervous system (CNS) malignancies to estimate the maximum tolerated dose, dose-limiting toxicities (DLT), pharmacokinetics (PK), and pharmacodynamics of weekly MK-0752. METHODS: MK-0752 was administered once weekly at 1000 and 1400 mg/m(2) using a rolling-6 design. PK analysis was performed during the first course. NOTCH and HES expression was assessed by immunohistochemistry and Western blot. RESULTS: Ten eligible patients were enrolled (median age 8.8 years; range 3.1-19.2) with diagnoses of brain stem glioma (n = 3), ependymoma (n = 2), anaplastic astrocytoma (n = 1), choroid plexus carcinoma (n = 2), medulloblastoma (n = 1), and primitive neuroectodermal tumor (n = 1). Nine were evaluable for toxicity. One DLT of fatigue occurred in the six evaluable patients enrolled at 1000 mg/m(2)/dose. No DLTs were experienced by three patients treated at 1400 mg/m(2)/dose. Non-dose-limiting grade 3 toxicities included lymphopenia, neutropenia, and anemia. Median number of treatment courses was 2 (range 1-10). Two patients continued on therapy for at least 6 months. The median (range) C(max) of MK-0752 was 88.2 µg/mL (40.6 to 109 µg/mL) and 60.3 µg/mL (59.2 to 91.9 µg/mL) in patients receiving 1000 and 1400 mg/m(2)/week, respectively. NOTCH expression was decreased in six of seven patients for whom tissue was available at 24 h post-MK-0752. CONCLUSION: MK-0752 is well tolerated and exhibits target inhibition at 1000 and 1400 mg/m(2)/week in children with recurrent CNS malignancies.
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Derivados de Benzeno/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Doenças do Sistema Nervoso Central/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Propionatos/uso terapêutico , Sulfonas/uso terapêutico , Administração Oral , Adolescente , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Área Sob a Curva , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Derivados de Benzeno/sangue , Doenças do Sistema Nervoso Central/sangue , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/sangue , Feminino , Seguimentos , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas de Homeodomínio/metabolismo , Humanos , Masculino , Propionatos/sangue , Receptor Notch1/metabolismo , Proteínas Repressoras/metabolismo , Sulfonas/sangue , Fatores de Tempo , Fatores de Transcrição HES-1 , Adulto JovemRESUMO
The combination of docetaxel and gemcitabine is frequently used to treat recurrent bone sarcoma. Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is less toxic and more active than docetaxel or paclitaxel for breast cancer patients. The combination of nab-paclitaxel and gemcitabine has preclinical synergy and is approved to treat pancreatic cancer. We observed growth inhibition and improved survival with nab-paclitaxel in a Ewing sarcoma xenograft, and activity was additive with gemcitabine in an osteosarcoma model. Primary Ewing sarcoma tumors expressed the transport protein SPARC, previously associated with nab-paclitaxel activity. These findings provide rationale for further evaluation of nab-paclitaxel with gemcitabine for bone sarcoma.
Assuntos
Neoplasias Ósseas/tratamento farmacológico , Osteossarcoma/tratamento farmacológico , Paclitaxel/uso terapêutico , Paclitaxel Ligado a Albumina , Albuminas/uso terapêutico , Animais , Linhagem Celular Tumoral , Criança , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Camundongos , Nanopartículas , Osteonectina/análise , Sarcoma de Ewing/tratamento farmacológicoRESUMO
PURPOSE: Video-based intra-abdominal instrument tracking for laparoscopic surgeries is a common research area. However, the tracking can only be done with instruments that are actually visible in the laparoscopic image. By using extra-abdominal cameras to detect trocars and classify their occupancy state, additional information about the instrument location, whether an instrument is still in the abdomen or not, can be obtained. This can enhance laparoscopic workflow understanding and enrich already existing intra-abdominal solutions. METHODS: A data set of four laparoscopic surgeries recorded with two time-synchronized extra-abdominal 2D cameras was generated. The preprocessed and annotated data were used to train a deep learning-based network architecture consisting of a trocar detection, a centroid tracker and a temporal model to provide the occupancy state of all trocars during the surgery. RESULTS: The trocar detection model achieves an F1 score of 95.06 ± 0.88 % . The prediction of the occupancy state yields an F1 score of 89.29 ± 5.29 % , providing a first step towards enhanced surgical workflow understanding. CONCLUSION: The current method shows promising results for the extra-abdominal tracking of trocars and their occupancy state. Future advancements include the enlargement of the data set and incorporation of intra-abdominal imaging to facilitate accurate assignment of instruments to trocars.