Citations

Abstract Purpose: Glioblastoma is the most frequent and lethal primary brain tumor. Development of novel therapies relies on the availability of relevant preclinical models. We have established a panel of 96 glioblastoma patient-derived xenografts (PDX) and undertaken its genomic and phenotypic characterization. Experimental Design: PDXs were established from glioblastoma, IDH-wildtype (n = 93), glioblastoma, IDH-mutant (n = 2), diffuse midline glioma, H3 K27M-mutant (n = 1), and both primary (n = 60) and recurrent (n = 34) tumors. Tumor growth rates, histopathology, and treatment response were characterized. Integrated molecular profiling was performed by whole-exome sequencing (WES, n = 83), RNA-sequencing (n = 68), and genome-wide methylation profiling (n = 76). WES data from 24 patient tumors was compared with derivative models. Results: PDXs recapitulate many key phenotypic and molecular features of patient tumors. Orthotopic PDXs show characteristic tumor morphology and invasion patterns, but largely lack microvascular proliferation and necrosis. PDXs capture common and rare molecular drivers, including alterations of TERT, EGFR, PTEN, TP53, BRAF, and IDH1, most at frequencies comparable with human glioblastoma. However, PDGFRA amplification was absent. RNA-sequencing and genome-wide methylation profiling demonstrated broad representation of glioblastoma molecular subtypes. MGMT promoter methylation correlated with increased survival in response to temozolomide. WES of 24 matched patient tumors showed preservation of most genetic driver alterations, including EGFR amplification. However, in four patient–PDX pairs, driver alterations were gained or lost on engraftment, consistent with clonal selection. Conclusions: Our PDX panel captures the molecular heterogeneity of glioblastoma and recapitulates many salient genetic and phenotypic features. All models and genomic data are openly available to investigators.

OBJECTIVEDischarge to an inpatient rehabilitation facility or another acute-care facility not only constitutes a postoperative challenge for patients and their care team but also contributes significantly to healthcare costs. In this era of changing dynamics of healthcare payment models in which cost overruns are being increasingly shifted to surgeons and hospitals, it is important to better understand outcomes such as discharge disposition. In the current article, the authors sought to develop a predictive model for factors associated with nonroutine discharge after surgery for grade I spondylolisthesis.METHODSThe authors queried the Quality Outcomes Database for patients with grade I lumbar degenerative spondylolisthesis who underwent a surgical intervention between July 2014 and June 2016. Only those patients enrolled in a multisite study investigating the impact of fusion on clinical and patient-reported outcomes among patients with grade I spondylolisthesis were evaluated. Nonroutine discharge was defined as those who were discharged to a postacute or nonacute-care setting in the same hospital or transferred to another acute-care facility.RESULTSOf the 608 patients eligible for inclusion, 9.4% (n = 57) had a nonroutine discharge (8.7%, n = 53 discharged to inpatient postacute or nonacute care in the same hospital and 0.7%, n = 4 transferred to another acute-care facility). Compared to patients who were discharged to home, patients who had a nonroutine discharge were more likely to have diabetes (26.3%, n = 15 vs 15.7%, n = 86, p = 0.039); impaired ambulation (26.3%, n = 15 vs 10.2%, n = 56, p < 0.001); higher Oswestry Disability Index at baseline (51 [IQR 42–62.12] vs 46 [IQR 34.4–58], p = 0.014); lower EuroQol-5D scores (0.437 [IQR 0.308–0.708] vs 0.597 [IQR 0.358–0.708], p = 0.010); higher American Society of Anesthesiologists score (3 or 4: 63.2%, n = 36 vs 36.7%, n = 201, p = 0.002); and longer length of stay (4 days [IQR 3–5] vs 2 days [IQR 1–3], p < 0.001); and were more likely to suffer a complication (14%, n = 8 vs 5.6%, n = 31, p = 0.014). On multivariable logistic regression, factors found to be independently associated with higher odds of nonroutine discharge included older age (interquartile OR 9.14, 95% CI 3.79–22.1, p < 0.001), higher body mass index (interquartile OR 2.04, 95% CI 1.31–3.25, p < 0.001), presence of depression (OR 4.28, 95% CI 1.96–9.35, p < 0.001), fusion surgery compared with decompression alone (OR 1.3, 95% CI 1.1–1.6, p < 0.001), and any complication (OR 3.9, 95% CI 1.4–10.9, p < 0.001).CONCLUSIONSIn this multisite study of a defined cohort of patients undergoing surgery for grade I spondylolisthesis, factors associated with higher odds of nonroutine discharge included older age, higher body mass index, presence of depression, and occurrence of any complication.

Catheter ablation has brought major advances in the management of patients with atrial fibrillation (AF). As evidenced by multiple randomized trials, AF catheter ablation can reduce the risk of recurrent AF and improve quality of life. In some studies, AF ablation significantly reduced cardiovascular hospitalizations. Despite the existing data on AF catheter ablation, numerous knowledge gaps remain concerning this intervention. This report is based on a recent virtual workshop convened by the National Heart, Lung, and Blood Institute to identify key research opportunities in AF ablation. We outline knowledge gaps related to emerging technologies, the relationship between cardiac structure and function and the success of AF ablation in patient subgroups in whom clinical benefit from ablation varies, and potential platforms to advance clinical research in this area. This report also considers the potential value and challenges of a sham ablation randomized trial. Prioritized research opportunities are identified and highlighted to empower relevant stakeholders to collaborate in designing and conducting effective, cost-efficient, and transformative research to optimize the use and outcomes of AF ablation.