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The authors have noticed that the final paragraph of the Results section contains errors in the number of patients involved. The correct number of patients is included in the text below. These errors do not affect the Figure referenced.In osteosarcoma, we focused on 8q gain as a specific biological feature of interest. Among the 41 patients with detectable ctDNA in the osteosarcoma cohort, 8q gain was detected in 73.2% (30/41). The 3-year EFS for patients with 8q gain (n = 30) in ctDNA was 60.0% (95% CI 40.5-75.0) compared to 80.8 (95% CI 42.4-94.9) in patients without 8q gain (n = 11) in ctDNA (p = 0.18; Fig. 3).
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Outcome for patients with metastatic or recurrent/refractory osteosarcoma remains poor. Responses to sorafenib, a multikinase inhibitor, have been seen in recurrent/refractory osteosarcoma, although specific biomarkers of response have not been described. We report a partial response in a 7-year-old with refractory osteosarcoma treated with sorafenib 200 mg twice daily. Toxicities included Common Terminology Criteria for Adverse Events Grade 2 skin toxicities and growth suppression. After 51 months of therapy, he suffered a recurrence. Tumor sequencing later revealed a PDGFRA D846V mutation that was not identified in the relapse specimen. This case demonstrates prolonged partial response to sorafenib and provides a potential biomarker for response.
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Biomarcadores de Tumor/genética , Neoplasias Óseas/tratamiento farmacológico , Resistencia a Antineoplásicos , Mutación , Osteosarcoma/tratamiento farmacológico , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética , Sorafenib/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias Óseas/genética , Neoplasias Óseas/secundario , Niño , Humanos , Masculino , Osteosarcoma/genética , Osteosarcoma/patología , Pronóstico , Terapia RecuperativaRESUMEN
BACKGROUND: New prognostic markers are needed to identify patients with Ewing sarcoma (EWS) and osteosarcoma unlikely to benefit from standard therapy. We describe the incidence and association with outcome of circulating tumour DNA (ctDNA) using next-generation sequencing (NGS) assays. METHODS: A NGS hybrid capture assay and an ultra-low-pass whole-genome sequencing assay were used to detect ctDNA in banked plasma from patients with EWS and osteosarcoma, respectively. Patients were coded as positive or negative for ctDNA and tested for association with clinical features and outcome. RESULTS: The analytic cohort included 94 patients with EWS (82% from initial diagnosis) and 72 patients with primary localised osteosarcoma (100% from initial diagnosis). ctDNA was detectable in 53% and 57% of newly diagnosed patients with EWS and osteosarcoma, respectively. Among patients with newly diagnosed localised EWS, detectable ctDNA was associated with inferior 3-year event-free survival (48.6% vs. 82.1%; p = 0.006) and overall survival (79.8% vs. 92.6%; p = 0.01). In both EWS and osteosarcoma, risk of event and death increased with ctDNA levels. CONCLUSIONS: NGS assays agnostic of primary tumour sequencing results detect ctDNA in half of the plasma samples from patients with newly diagnosed EWS and osteosarcoma. Detectable ctDNA is associated with inferior outcomes.
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Biomarcadores de Tumor/genética , Neoplasias Óseas/genética , ADN Tumoral Circulante/análisis , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Osteosarcoma/genética , Adolescente , Biomarcadores de Tumor/sangre , Neoplasias Óseas/sangre , Niño , Preescolar , Estudios de Cohortes , Femenino , Humanos , Masculino , Osteosarcoma/sangre , Pronóstico , Estudios Retrospectivos , Sarcoma de Ewing/sangre , Sarcoma de Ewing/genética , Análisis de Secuencia de ADN/métodos , Análisis de SupervivenciaRESUMEN
Objective: To examine hope and its components of agency and pathways as predictors of anxiety and depressive symptoms in children receiving cancer treatment. Methods: Sixty patients (mean standard deviation age = 13.3 (2.7); 57% male) completed Snyder's Hope Scales, the Children's Depression Inventory, and the State-Trait Anxiety Inventory at diagnosis and 3 month intervals for 1 year following pediatric cancer diagnosis. Parents also completed Snyder's Hope Scales. Linear mixed-effect regression was used to assess hope's role in longitudinal models of symptoms of depression and anxiety. Results: Agency was a significant predictor of between-patient differences and within-patient changes in symptoms of depression and anxiety. Neither patient pathways nor either component of parent hope was predictive of symptoms of depression or anxiety. Patients who were more likely to have depressive symptoms at baseline were older, diagnosed with leukemia, and non-Hispanic White as opposed to Hispanic. Patient demographics were not predictive of anxiety. Conclusions: Patient agency is a potential target for intervention to prevent or reduce anxiety and depressive symptoms following pediatric cancer diagnosis.
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Ansiedad/psicología , Depresión/psicología , Esperanza , Neoplasias/psicología , Adolescente , Niño , Femenino , Humanos , Estudios Longitudinales , Masculino , Neoplasias/diagnósticoRESUMEN
BACKGROUND: We designed the EURAMOS-1 trial to investigate whether intensified postoperative chemotherapy for patients whose tumour showed a poor response to preoperative chemotherapy (≥10% viable tumour) improved event-free survival in patients with high-grade osteosarcoma. METHODS: EURAMOS-1 was an open-label, international, phase 3 randomised, controlled trial. Consenting patients with newly diagnosed, resectable, high-grade osteosarcoma aged 40 years or younger were eligible for randomisation. Patients were randomly assigned (1:1) to receive either postoperative cisplatin, doxorubicin, and methotrexate (MAP) or MAP plus ifosfamide and etoposide (MAPIE) using concealed permuted blocks with three stratification factors: trial group; location of tumour (proximal femur or proximal humerus vs other limb vs axial skeleton); and presence of metastases (no vs yes or possible). The MAP regimen consisted of cisplatin 120 mg/m2, doxorubicin 37·5 mg/m2 per day on days 1 and 2 (on weeks 1 and 6) followed 3 weeks later by high-dose methotrexate 12 g/m2 over 4 h. The MAPIE regimen consisted of MAP as a base regimen, with the addition of high-dose ifosfamide (14 g/m2) at 2·8 g/m2 per day with equidose mesna uroprotection, followed by etoposide 100 mg/m2 per day over 1 h on days 1-5. The primary outcome measure was event-free survival measured in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00134030. FINDINGS: Between April 14, 2005, and June 30, 2011, 2260 patients were registered from 325 sites in 17 countries. 618 patients with poor response were randomly assigned; 310 to receive MAP and 308 to receive MAPIE. Median follow-up was 62·1 months (IQR 46·6-76·6); 62·3 months (IQR 46·9-77·1) for the MAP group and 61·1 months (IQR 46·5-75·3) for the MAPIE group. 307 event-free survival events were reported (153 in the MAP group vs 154 in the MAPIE group). 193 deaths were reported (101 in the MAP group vs 92 in the MAPIE group). Event-free survival did not differ between treatment groups (hazard ratio [HR] 0·98 [95% CI 0·78-1·23]); hazards were non-proportional (p=0·0003). The most common grade 3-4 adverse events were neutropenia (268 [89%] patients in MAP vs 268 [90%] in MAPIE), thrombocytopenia (231 [78% in MAP vs 248 [83%] in MAPIE), and febrile neutropenia without documented infection (149 [50%] in MAP vs 217 [73%] in MAPIE). MAPIE was associated with more frequent grade 4 non-haematological toxicity than MAP (35 [12%] of 301 in the MAP group vs 71 [24%] of 298 in the MAPIE group). Two patients died during postoperative therapy, one from infection (although their absolute neutrophil count was normal), which was definitely related to their MAP treatment (specifically doxorubicin and cisplatin), and one from left ventricular systolic dysfunction, which was probably related to MAPIE treatment (specifically doxorubicin). One suspected unexpected serious adverse reaction was reported in the MAP group: bone marrow infarction due to methotrexate. INTERPRETATION: EURAMOS-1 results do not support the addition of ifosfamide and etoposide to postoperative chemotherapy in patients with poorly responding osteosarcoma because its administration was associated with increased toxicity without improving event-free survival. The results define standard of care for this population. New strategies are required to improve outcomes in this setting. FUNDING: UK Medical Research Council, National Cancer Institute, European Science Foundation, St Anna Kinderkrebsforschung, Fonds National de la Recherche Scientifique, Fonds voor Wetenschappelijk Onderzoek-Vlaanderen, Parents Organization, Danish Medical Research Council, Academy of Finland, Deutsche Forschungsgemeinschaft, Deutsche Krebshilfe, Federal Ministry of Education and Research, Semmelweis Foundation, ZonMw (Council for Medical Research), Research Council of Norway, Scandinavian Sarcoma Group, Swiss Paediatric Oncology Group, Cancer Research UK, National Institute for Health Research, University College London Hospitals, and Biomedical Research Centre.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Osteosarcoma/tratamiento farmacológico , Adolescente , Adulto , Anciano , Neoplasias Óseas/mortalidad , Niño , Preescolar , Terapia Combinada , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Osteosarcoma/mortalidadRESUMEN
Infantile myofibromatosis (IM) is most commonly limited to cutaneous lesions that resolve spontaneously. However, generalized IM with visceral involvement, which has a reported mortality rate as high as 73%, has been successfully treated with a combination of methotrexate and vinblastine. Here we report the further efficacy of low-dose methotrexate and vinblastine in 2 pediatric patients with IM and visceral involvement and review the literature describing chemotherapy for these patients.
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Antineoplásicos/uso terapéutico , Metotrexato/uso terapéutico , Miofibromatosis/congénito , Vincristina/uso terapéutico , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Miofibromatosis/tratamiento farmacológico , Miofibromatosis/patología , Vísceras/patologíaRESUMEN
OBJECTIVE: To determine the pattern of resilience and adjustment following pediatric cancer diagnosis and to evaluate hope as a mediator of adjustment. METHODS: 61 participants with pediatric cancer completed measures of hope, depression, anxiety, and quality of life (QoL) within 4 weeks of cancer diagnosis and every 3 months for 1 year. RESULTS: Participants showed high and increasing levels of hope and QoL, as well as low and decreasing levels of depression and anxiety. Linear mixed-effects regression analyses revealed changes in depression, anxiety, and hope to be significant predictors of changes in QoL. Changes in hope were found to partially mediate the effects of depression and anxiety on QoL. CONCLUSIONS: While a variety of interventions are efficacious for treating anxiety and depression, hope theory provides a framework for choosing interventions that may more globally promote children's ability to maintain good functioning, adjustment, well-being, and QoL following cancer diagnosis.
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Adaptación Psicológica , Ansiedad/psicología , Depresión/psicología , Esperanza , Neoplasias/psicología , Calidad de Vida/psicología , Adolescente , Niño , Femenino , Humanos , MasculinoRESUMEN
Bone scintigraphy is a well-established method to evaluate for metastatic disease in osteosarcoma. We identified a patient who had a negative (cold) bone scan at skeletal relapse and consequently reviewed the frequency of cold scans in osteosarcoma at our institution. No cold scans were identified at diagnosis, and only 1 patient had a cold scan at skeletal recurrence. No correlation was identified between clinical outcomes and bone scan features, other than identification of metastatic disease. Patients with skeletal recurrence were all symptomatic, thus we suggest that bone scintigraphy is not indicated in routine postchemotherapy surveillance for patients with osteosarcoma.
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Neoplasias Óseas/diagnóstico por imagen , Neoplasias Óseas/patología , Osteosarcoma/diagnóstico por imagen , Osteosarcoma/secundario , Adolescente , Neoplasias Óseas/tratamiento farmacológico , Niño , Preescolar , Monitoreo de Drogas/métodos , Femenino , Humanos , Masculino , Recurrencia Local de Neoplasia/diagnóstico por imagen , Recurrencia Local de Neoplasia/patología , Osteosarcoma/tratamiento farmacológico , Cintigrafía , Estudios RetrospectivosRESUMEN
ABSTRACT: Children and adults with sickle cell disease (SCD) have increases in morbidity and mortality with COVID-19 infections. The American Society of Hematology Research Collaborative Sickle Cell Disease Research Network performed a prospective COVID-19 vaccine study to assess antibody responses and analyze whether messenger RNA (mRNA) vaccination precipitated any adverse effects unique to individuals with SCD. Forty-one participants received 2 doses of the Pfizer-BioNTech vaccine and provided baseline blood samples before vaccination and 2 months after the initial vaccination for analysis of immunoglobulin G (IgG) reactivity against the receptor binding domain (RBD) of the severe acute respiratory syndrome coronavirus 2 spike protein. Six-month IgG reactivity against the viral RBD was also available in 37 patients. Postvaccination reactogenicity was common and similar to the general population. There were no fevers that required inpatient admission. Vaso-occlusive pain within 2 to 3 days of first or second vaccination was reported by 5 participants (12%) including 4 (10%) who sought medical care. Twenty-seven participants (66%) were seropositive at baseline, and all 14 initially seronegative participants (34%) converted to seropositive after vaccination. Overall, mRNA vaccination had a good risk-benefit profile in individuals with SCD. This mRNA vaccine study also marks the first evaluation of vaccine safety and antibody response in very young children with SCD. This trial was registered at www.ClinicalTrials.gov as #NCT05139992.
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Anemia de Células Falciformes , Vacunas contra la COVID-19 , COVID-19 , SARS-CoV-2 , Vacunación , Humanos , Anemia de Células Falciformes/inmunología , Anemia de Células Falciformes/terapia , Masculino , Femenino , Adulto , COVID-19/prevención & control , COVID-19/inmunología , Vacunas contra la COVID-19/efectos adversos , Vacunas contra la COVID-19/inmunología , Vacunas contra la COVID-19/administración & dosificación , SARS-CoV-2/inmunología , Adolescente , Vacuna BNT162 , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Adulto Joven , Niño , Glicoproteína de la Espiga del Coronavirus/inmunología , Persona de Mediana Edad , Estudios Prospectivos , Vacunas de ARNmRESUMEN
PURPOSE: Osteosarcoma research advancement requires enhanced data integration across different modalities and sources. Current osteosarcoma research, encompassing clinical, genomic, protein, and tissue imaging data, is hindered by the siloed landscape of data generation and storage. MATERIALS AND METHODS: Clinical, molecular profiling, and tissue imaging data for 573 patients with pediatric osteosarcoma were collected from four public and institutional sources. A common data model incorporating standardized terminology was created to facilitate the transformation, integration, and load of source data into a relational database. On the basis of this database, a data commons accompanied by a user-friendly web portal was developed, enabling various data exploration and analytics functions. RESULTS: The Osteosarcoma Explorer (OSE) was released to the public in 2021. Leveraging a comprehensive and harmonized data set on the backend, the OSE offers a wide range of functions, including Cohort Discovery, Patient Dashboard, Image Visualization, and Online Analysis. Since its initial release, the OSE has experienced an increasing utilization by the osteosarcoma research community and provided solid, continuous user support. To our knowledge, the OSE is the largest (N = 573) and most comprehensive research data commons for pediatric osteosarcoma, a rare disease. This project demonstrates an effective framework for data integration and data commons development that can be readily applied to other projects sharing similar goals. CONCLUSION: The OSE offers an online exploration and analysis platform for integrated clinical, molecular profiling, and tissue imaging data of osteosarcoma. Its underlying data model, database, and web framework support continuous expansion onto new data modalities and sources.
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Manejo de Datos , Osteosarcoma , Niño , Humanos , Bases de Datos Factuales , Genómica , Osteosarcoma/diagnóstico por imagen , Osteosarcoma/genéticaRESUMEN
The Accreditation Council for Graduate Medical Education (ACGME) established new duty hour recommendations for pediatric subspecialty trainees in July 2011. Short-term and long-term implications to Pediatric Hematology/Oncology (PHO) are reviewed. Other modifications have been introduced by the ACGME and the American Board of Pediatrics (ABP) in the last decade, including the introduction of the six core competencies and an expansion in the definition of scholarship for fellows. The effect of these on fellows are discussed with suggested strategies for PHO to prepare for further change likely to result from a new ABP initiative to evaluate subspecialty training and certification over the next 3 years. Pediatr Blood Cancer 2012; 59: 1168-1172. © 2012 Wiley Periodicals, Inc.
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Educación de Postgrado en Medicina , Internado y Residencia , Pediatría/educación , Acreditación/normas , Hematología/educación , Humanos , Oncología Médica/educación , MedicinaRESUMEN
A variety of clinical and laboratory parameters have been used to predict bacteremia. We hypothesize that the generation of a cytokine profile could be used to identify patients at higher risk of bacteremia at the time of presentation with febrile neutropenia. We prospectively evaluated children with cancer who presented with an episode of febrile neutropenia. A multiplexed flow cytometric assay was performed which measured 15 cytokines and chemokines obtained before the initiation of antibiotics. Fifty-eight episodes of chemotherapy-induced febrile neutropenia were included in this study during which 4 patients (7%) had bacteremia. An interleukin-5 level of >8 pg/dL had a sensitivity of 67% and a specificity of 96% to predict bacteremia. An monocyte chemotactic protein-1 level >1650 pg/dL had a sensitivity of 80% and a specificity of 82% to predict bacteremia. Erythrocyte sedimentation rate, C-reactive protein, protein C, and other cytokines/chemokines were not predictive of bacteremia. Elevations of interleukin-5 and monocyte chemotactic protein-1 are predictive of bacteremia in children with cancer who have febrile neutropenia. Prospective studies should be undertaken to determine whether these parameters retain predictive value in a larger series of patients and can select children for outpatient management or early discharge.
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Bacteriemia/diagnóstico , Biomarcadores/sangre , Quimiocina CCL2/sangre , Interleucina-5/sangre , Neoplasias/tratamiento farmacológico , Neutropenia/diagnóstico , Antineoplásicos/efectos adversos , Bacteriemia/sangre , Bacteriemia/inducido químicamente , Niño , Femenino , Humanos , Masculino , Neutropenia/sangre , Neutropenia/inducido químicamente , Valor Predictivo de las Pruebas , Pronóstico , Estudios Prospectivos , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: Osteosarcoma, which is the most common malignant pediatric bone cancer, remains dependent on an imprecise systemic treatment largely unchanged in 30 years. In this study, we correlated histopathology with magnetic resonance imaging (MRI), used the correlation to extract MRI-specific features representative of tumor necrosis, and subsequently developed a novel classification model for predicting tumor response to neoadjuvant chemotherapy in pediatric patients with osteosarcoma using multi-modal MRI. The model could ultimately serve as a testable biomarker for a high-risk malignancy without successful precision treatments. METHODS: Patients with newly diagnosed high-grade appendicular osteosarcoma were enrolled in a single-center observational study, wherein patients underwent pre-surgical evaluation using both conventional MRI (post-contrast T1-weighted with fat saturation, pre-contrast T1-weighted, and short inversion-time inversion recovery (STIR)) and advanced MRI (diffusion weighted (DW) and dynamic contrast enhanced (DCE)). A classification model was established based on a direct correlation between histopathology and MRI, which was achieved through histologic-MR image co-registration and subsequent extraction of MR image features for identifying histologic tumor necrosis. By operating on the MR image features, tumor necrosis was estimated from different combinations of MR images using a multi-feature fuzzy clustering technique together with a weighted majority ruling. Tumor necrosis calculated from MR images, for either an MRI plane of interest or whole tumor volume, was compared to pathologist-estimated necrosis and necrosis quantified from digitized histologic section images using a previously described deep learning classification method. RESULTS: 15 patients were enrolled, of whom two withdrew, one became ineligible, and two were subjected to inadequate pre-surgical imaging. MRI sequences of n = 10 patients were subsequently used for classification model development. Different MR image features, depending on the modality of MRI, were shown to be significant in distinguishing necrosis from viable tumor. The scales at which MR image features optimally signified tumor necrosis were different as well depending on the MR image type. Conventional MRI was shown capable of differentiating necrosis from viable tumor with an accuracy averaging above 90%. Conventional MRI was equally effective as DWI in distinguishing necrotic from viable tumor regions. The accuracy of tumor necrosis prediction by conventional MRI improved to above 95% when DCE-MRI was added into consideration. Volume-based tumor necrosis estimations tended to be lower than those evaluated on an MRI plane of interest. CONCLUSIONS: The study has shown a proof-of-principle model for interpreting chemotherapeutic response using multi-modal MRI for patients with high-grade osteosarcoma. The model will continue to be evaluated as MR image features indicative of tumor response are now computable for the disease prior to surgery.
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Neoplasias Óseas/patología , Imagen por Resonancia Magnética , Osteosarcoma/patología , Adolescente , Antineoplásicos/uso terapéutico , Neoplasias Óseas/diagnóstico por imagen , Neoplasias Óseas/tratamiento farmacológico , Niño , Aprendizaje Profundo , Femenino , Humanos , Masculino , Necrosis , Clasificación del Tumor , Osteosarcoma/diagnóstico por imagen , Osteosarcoma/tratamiento farmacológico , Estudios Prospectivos , Adulto JovenRESUMEN
As clinical trials have become more complex, with increasing numbers of required procedures and clinic visits, gaining access to promising new treatments has become even more challenging for many individuals. To address these barriers, we implemented a financial reimbursement and outreach program designed to increase the number and diversity of participants in cancer clinical trials at centers in Dallas, Houston, and Philadelphia. As endorsed by U.S. Food and Drug Administration (FDA) and the Texas and Pennsylvania State Legislatures, the program provides financial reimbursement for non-clinical costs (e.g., travel, lodging) to patients on cancer clinical trials with household income up to 700% the Federal poverty rate. The research study described here, centered at the Dallas site, evaluates program impact by assessing (1) numbers and diversity of patients enrolled to cancer clinical trials before and after program implementation; (2) characteristics of patients offered participation in the program who do versus do not enroll; (3) characteristics of patients enrolled in the program who do versus do not complete the reimbursement process. To evaluate perceived barriers and facilitators of program participation, we will conduct semi-structured interviews and administer the Comprehensive Score for Financial Toxicity Patient Reported Outcome Measure (COST PROM) and the Short Assessment of Health Literacy (SAHL). This program will examine how reimbursement of non-clinical costs can improve access to cancer clinical trials, with the eventual goal of increasing trial enrollment, diversity, representativeness, and generalizability.
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Neoplasias , Ensayos Clínicos como Asunto , Humanos , Neoplasias/terapia , Philadelphia , Pobreza , Texas , ViajeRESUMEN
Precise and reliable cell-specific gene delivery remains technically challenging. Here we report a splicing-based approach for controlling gene expression whereby separate translational reading frames are coupled to the inclusion or exclusion of mutated, frameshifting cell-specific alternative exons. Candidate exons are identified by analyzing thousands of publicly available RNA sequencing datasets and filtering by cell specificity, conservation, and local intron length. This method, which we denote splicing-linked expression design (SLED), can be combined in a Boolean manner with existing techniques such as minipromoters and viral capsids. SLED can use strong constitutive promoters, without sacrificing precision, by decoupling the tradeoff between promoter strength and selectivity. AAV-packaged SLED vectors can selectively deliver fluorescent reporters and calcium indicators to various neuronal subtypes in vivo. We also demonstrate gene therapy utility by creating SLED vectors that can target PRPH2 and SF3B1 mutations. The flexibility of SLED technology enables creative avenues for basic and translational research.
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Calcio , Empalme del ARN , Empalme Alternativo/genética , Secuencia de Bases , Exones/genética , Regulación de la Expresión Génica , Intrones/genéticaRESUMEN
The advent of dose intensified interval compressed therapy has improved event-free survival for patients with localized Ewing sarcoma (EwS) to 78% at 5 years. However, nearly a quarter of patients with localized tumors and 60-80% of patients with metastatic tumors suffer relapse and die of disease. In addition, those who survive are often left with debilitating late effects. Clinical features aside from stage have proven inadequate to meaningfully classify patients for risk-stratified therapy. Therefore, there is a critical need to develop approaches to risk stratify patients with EwS based on molecular features. Over the past decade, new technology has enabled the study of multiple molecular biomarkers in EwS. Preliminary evidence requiring validation supports copy number changes, and loss of function mutations in tumor suppressor genes as biomarkers of outcome in EwS. Initial studies of circulating tumor DNA demonstrated that diagnostic ctDNA burden and ctDNA clearance during induction are also associated with outcome. In addition, fusion partner should be a pre-requisite for enrollment on EwS clinical trials, and the fusion type and structure require further study to determine prognostic impact. These emerging biomarkers represent a new horizon in our understanding of disease risk and will enable future efforts to develop risk-adapted treatment.
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PTEN promoter hypermethylation is nearly universal and PTEN copy number loss occurs in ~25% of fusion-negative rhabdomyosarcoma (FN-RMS). Here we show Pten deletion in a mouse model of FN-RMS results in less differentiated tumors more closely resembling human embryonal RMS. PTEN loss activated the PI3K pathway but did not increase mTOR activity. In wild-type tumors, PTEN was expressed in the nucleus suggesting loss of nuclear PTEN functions could account for these phenotypes. Pten deleted tumors had increased expression of transcription factors important in neural and skeletal muscle development including Dbx1 and Pax7. Pax7 deletion completely rescued the effects of Pten loss. Strikingly, these Pten;Pax7 deleted tumors were no longer FN-RMS but displayed smooth muscle differentiation similar to leiomyosarcoma. These data highlight how Pten loss in FN-RMS is connected to a PAX7 lineage-specific transcriptional output that creates a dependency or synthetic essentiality on the transcription factor PAX7 to maintain tumor identity.
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Factor de Transcripción PAX7/metabolismo , Fosfohidrolasa PTEN/metabolismo , Rabdomiosarcoma/metabolismo , Rabdomiosarcoma/patología , Animales , Cruzamiento , Diferenciación Celular , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Proteínas de Homeodominio/metabolismo , Humanos , Integrasas/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Ratones Noqueados , Desarrollo de Músculos , Fosfohidrolasa PTEN/deficiencia , Fosfoproteínas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Rabdomiosarcoma/genéticaRESUMEN
PURPOSE: The primary aim of this phase III randomized trial was to test whether the addition of vincristine, topotecan, and cyclophosphamide (VTC) to interval compressed chemotherapy improved survival outcomes for patients with previously untreated nonmetastatic Ewing sarcoma. METHODS: Patients were randomly assigned to receive standard five-drug interval compressed chemotherapy (regimen A) for 17 cycles or experimental therapy with five cycles of VTC within the 17 cycles (regimen B). Patients were stratified by age at diagnosis (< 18 years and ≥18 years) and tumor site (pelvic bone, nonpelvic bone, and extraosseous). Tumor volume at diagnosis was categorized as < 200 mL or ≥ 200 mL. Local control occurred following six cycles. Histologic response was categorized as no viable or any viable tumor. Event-free survival (EFS) and overall survival (OS) were compared between randomized groups with stratified log-rank tests. RESULTS: Of 642 enrolled patients, 309 eligible patients received standard and 320 received experimental therapy. The 5-year EFS and OS were 78% and 87%, respectively. There was no difference in survival outcomes between randomized groups (5-year EFS regimen A v regimen B, 78% v 79%; P = .192; 5-year OS 86% v 88%; P = .159). Age and primary site did not affect the risk of an EFS event. However, age ≥ 18 years was associated with an increased risk of death at 5 years (hazard ratio 1.84; 95% CI, 1.15 to 2.96; P = .009). The 5-year EFS rates for patients with pelvic, nonpelvic bone, and extraosseous primary tumors were 75%, 78%, and 85%, respectively. Tumor volume ≥ 200 mL was significantly associated with lower EFS. CONCLUSION: While VTC added to five-drug interval compressed chemotherapy did not improve survival, these outcomes represent the best survival estimates to date for patients with previously untreated nonmetastatic Ewing sarcoma.