RESUMO
OBJECTIVES: Clinical practice is shifting toward an era of precision medicine. The use of comprehensive genomic profiling (CGP) in oncology has broad potential as a universal companion diagnostic for targeted therapies which may significantly improve health outcomes while using healthcare resources more efficiently. Given the nature of this technology, assessing the value of CGP presents unique challenges. METHODS: This paper draws on evidence from the academic and policy literature in oncology, as well as stakeholder interviews (health economists, payers, clinicians, and public policy officials) in countries using incremental cost-effectiveness ratios (ICER) as part of health technology assessment (HTA). RESULTS: The degree to which CGP is subject to a value assessment varies significantly across healthcare systems. Current HTA processes focus on evaluating diagnostic testing through co-dependent assessment of diagnostic testing and associated therapeutic interventions. Diagnostic tests with multiple associated therapeutic interventions are rapidly evolving and poorly unsuited to current HTA approaches. Moreover, HTA approaches are limited in their ability to consider broader systemic benefits of the expanded diagnostic capabilities and enhanced opportunities for clinical trial participation offered by CGP. CONCLUSIONS: The assessment of the overall value of CGP is limited by the current models of HTA. This paper suggests policy proposals for value assessment and funding reforms to help broaden patient access to CGP. These include investing in genomic testing infrastructure; decoupling the assessment of the value of CGP testing to identifying predetermined therapeutic interventions; tailoring evaluation methodology; and developing approaches to collecting evidence of clinical, healthcare system and societal benefit.
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Medicina de Precisão , Avaliação da Tecnologia Biomédica , Análise Custo-Benefício , Genômica , Humanos , OncologiaRESUMO
PURPOSE: High-grade glioma (HGG) treatment is limited by the inability of otherwise potentially efficacious drugs to penetrate the blood-brain barrier. We evaluate the unique intracavity delivery mode and translational potential of a blend of poly(DL-lactic acid-co-glycolic acid; PLGA) and poly(ethylene glycol; PEG) paste combining temozolomide and etoposide to treat surgically resected HGG. EXPERIMENTAL DESIGN: To prolong stability of temozolomide prodrug, combined in vitro drug release was quantitatively assessed from low pH-based PLGA/PEG using advanced analytic methods. In vitro cytotoxicity was measured against a panel of HGG cell lines and patient-derived cultures using metabolic assays. In vivo safety and efficacy was evaluated using orthotopic 9L gliosarcoma allografts, previously utilized preclinically to develop Gliadel. RESULTS: Combined etoposide and temozolomide in vitro release (22 and 7 days, respectively) was achieved from a lactic acid-based PLGA/PEG paste, used to enhance stability of temozolomide prodrug. HGG cells from central-enhanced regions were more sensitive to each compound relative to primary lines derived from the HGG-invasive margin. Both drugs retained cytotoxic capability upon release from PLGA/PEG. In vivo studies revealed a significant overall survival benefit in postsurgery 9L orthotopic gliosarcomas, treated with intracavity delivered PLGA/PEG/temozolomide/etoposide and enhanced with adjuvant radiotherapy. Long-term survivorship was observed in over half the animals with histologic confirmation of disease-free brain. CONCLUSIONS: The significant survival benefit of intracavity chemotherapy demonstrates clinical applicability of PLGA/PEG paste-mediated delivery of temozolomide and etoposide adjuvant to radiotherapy. PLGA/PEG paste offers a future platform for combination delivery of molecular targeted compounds.
Assuntos
Portadores de Fármacos , Etoposídeo/administração & dosagem , Glioma/mortalidade , Glioma/terapia , Temozolomida/administração & dosagem , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linhagem Celular Tumoral , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Etoposídeo/farmacocinética , Glioma/diagnóstico , Glioma/patologia , Humanos , Nanopartículas , Poliésteres , Polietilenoglicóis , Temozolomida/farmacocinética , Resultado do Tratamento , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A dual thermoresponsive and magnetic colloidal gel matrix is described for enhanced stem-cell culture. The combined properties of the material allow enzyme-free passaging and expansion of mesenchymal stem cells, as well as isolation of cells postculture by the simple process of lowering the temperature and applying an external magnetic field. The colloidal gel can be reconfigured with thermal and magnetic stimuli to allow patterning of cells in discrete zones and to control movement of cells within the porous matrix during culture.
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Técnicas de Cultura de Células/métodos , Fenômenos Magnéticos , Temperatura , Proliferação de Células , Coloides , Humanos , Células-Tronco Mesenquimais/citologiaRESUMO
Sustained and controlled delivery of growth factors, such as bone morphogenetic protein 2 (BMP-2), from polymer scaffolds has excellent potential for enhancing bone regeneration. The present study investigated the use of novel sintered polymer scaffolds prepared using temperature-sensitive PLGA/PEG particles. Growth factors can be incorporated into these scaffolds by mixing the reconstituted growth factor with the particles prior to sintering. The ability of the PLGA/PEG scaffolds to deliver BMP-2 in a controlled and sustained manner was assessed and the osteogenic potential of these scaffolds was determined in a mouse calvarial defect model. BMP-2 was released from the scaffolds in vitro over 3 weeks. On average, ca. 70% of the BMP-2 loaded into the scaffolds was released by the end of this time period. The released BMP-2 was shown to be active and to induce osteogenesis when used in a cell culture assay. A substantial increase in new bone volume of 55% was observed in a mouse calvarial defect model for BMP-2-loaded PLGA/PEG scaffolds compared to empty defect controls. An increase in new bone volume of 31% was observed for PLGA/PEG scaffolds without BMP-2, compared to empty defect controls. These results demonstrate the potential of novel PLGA/PEG scaffolds for sustained BMP-2 delivery for bone-regeneration applications.
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Proteína Morfogenética Óssea 2/metabolismo , Animais , Linhagem Celular , Camundongos , Microscopia Eletrônica de Varredura , Alicerces TeciduaisRESUMO
Electrospinning is a common technique used to fabricate fibrous scaffolds for tissue engineering applications. There is now growing interest in assessing the ability of collector plate design to influence the patterning of the fibres during the electrospinning process. In this study, we investigate a novel method to generate hybrid electrospun scaffolds consisting of both random fibres and a defined three-dimensional (3D) micro-topography at the surface, using patterned resin formers produced by rapid prototyping (RP). Poly(D,L-lactide-co-glycolide) was electrospun onto the engineered RP surfaces and the ability of these formers to influence microfibre patterning in the resulting scaffolds visualized by scanning electron microscopy. Electrospun scaffolds with patterns mirroring the microstructures of the formers were successfully fabricated. The effect of the resulting fibre patterns and 3D geometries on mammalian cell adhesion and proliferation was investigated by seeding enhanced green fluorescent protein labelled 3T3 fibroblasts onto the scaffolds. Following 24 h and four days of culture, the seeded scaffolds were visually assessed by confocal macro- and microscopy. The patterning of the fibres guided initial cell adhesion to the scaffold with subsequent proliferation over the geometry resulting in the cells being held in a 3D micro-topography. Such patterning could be designed to replicate a specific in vivo structure; we use the dermal papillae as an exemplar here. In conclusion, a novel, versatile and scalable method to produce hybrid electrospun scaffolds has been developed. The 3D directional cues of the patterned fibres have been shown to influence cell behaviour and could be used to culture cells within a similar 3D micro-topography as experienced in vivo.
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Técnicas Eletroquímicas/métodos , Ácido Láctico/síntese química , Ácido Poliglicólico/síntese química , Engenharia Tecidual/instrumentação , Alicerces Teciduais/química , Animais , Adesão Celular , Proliferação de Células , Sobrevivência Celular , Fibroblastos/citologia , Ácido Láctico/química , Camundongos , Células NIH 3T3 , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido PoliglicólicoRESUMO
OBJECTIVES/HYPOTHESIS: To develop a porous, biodegradable scaffold for mastoid air-cell regeneration. STUDY DESIGN: In vitro development of a temperature-sensitive poly(DL-lactic acid-co-glycolic acid)/poly(ethylene glycol) (PLGA/PEG) scaffold tailored for this application. METHODS: Human mastoid bone microstructure and porosity were investigated using micro-computed tomography. PLGA/PEG-alginate scaffolds were developed, and scaffold porosity was assessed. Human bone marrow mesenchymal stem cells (hBM-MSCs) were cultured on the scaffolds in vitro. Scaffolds were loaded with ciprofloxacin, and release of ciprofloxacin over time in vitro was assessed. RESULTS: Porosity of human mastoid bone was measured at 83% with an average pore size of 1.3 mm. PLGA/PEG-alginate scaffold porosity ranged from 43% to 78% depending on the alginate bead content. The hBM-MSCs proliferate on the scaffolds in vitro, and release of ciprofloxacin from the scaffolds was demonstrated over 7 to 10 weeks. CONCLUSIONS: The PLGA/PEG-alginate scaffolds developed in this study demonstrate similar structural features to human mastoid bone, support cell growth, and display sustained antibiotic release. These scaffolds may be of potential clinical use in mastoid air-cell regeneration. Further in vivo studies to assess the suitability of PLGA/PEG-alginate scaffolds for this application are required.