TGF-ß and BMP signaling are associated with the transformation of glioblastoma to gliosarcoma and then osteosarcoma.

Background: Gliosarcoma, an isocitrate dehydrogenase wildtype (IDH-WT) variant of glioblastoma, is defined by clonal biphasic differentiation into gliomatous and sarcomatous components. While the transformation from a glioblastoma to gliosarcoma is uncommon, the subsequent transformation to osteosarcoma is rare but may provide additional insights into the biology of these typically distinct cancers. We observed a patient initially diagnosed with glioblastoma, that differentiated into gliosarcoma at recurrence, and further evolved to osteosarcoma at the second relapse. Our objective was to characterize the molecular mechanisms of tumor progression associated with this phenotypic transformation. Methods: Tumor samples were collected at all 3 stages of disease and RNA sequencing was performed to capture their transcriptomic profiles. Sequential clonal evolution was confirmed by the maintenance of an identical PTEN mutation throughout the tumor differentiation using the TSO500 gene panel. Publicly available datasets and the Nanostring nCounter technology were used to validate the results. Results: The glioblastoma tumor from this patient possessed mixed features of all 3 TCGA-defined transcriptomic subtypes of an IDH-WT glioblastoma and a proportion of osteosarcoma signatures were upregulated in the original tumor. Analysis showed that enhanced transforming growth factor-ß (TGF-ß) and bone morphogenic protein signaling was associated with tumor transformation. Regulatory network analysis revealed that TGF-ß family signaling committed the lineage tumor to osteogenesis by stimulating the expression of runt-related transcription factor 2 (RUNX2), a master regulator of bone formation. Conclusions: This unusual clinical case provided an opportunity to explore the modulators of longitudinal sarcomatous transformation, potentially uncovering markers indicating predisposition to this change and identification of novel therapeutic targets.

Underutilization of advanced presurgical studies and high rates of vagus nerve stimulation for drug-resistant epilepsy: a single-center experience and recommendations.

INTRODUCTION: Epilepsy surgery continues to be profoundly underutilized despite its safety and effectiveness. We sought to investigate factors that may contribute to this phenomenon, with a particular focus on the antecedent underutilization of appropriate preoperative studies. METHODS: We reviewed patient data from a pediatric epilepsy clinic over an 18-month period. Patients with drug-resistant epilepsy (DRE) were categorized according to brain magnetic resonance imaging (MRI) findings (lesional, MRI-negative, or multifocal abnormalities) and type of epilepsy diagnosis based on semiology and electroencephalography (EEG) (focal or generalized). We then analyzed the rates of diagnostic test utilization, surgical referral, and subsequent epilepsy surgery as well as vagus nerve stimulation (VNS). RESULTS: Of the 249 patients with a diagnosis of epilepsy, 138 (55.4%) were found to have DRE. Excluding the 10 patients with DRE who did not undergo MRI, 76 patients (59.4%) were found to be MRI-negative (non-lesional epilepsy), 37 patients (28.9%) were found to have multifocal abnormalities, and 15 patients (11.7%) were found to have a single epileptogenic lesion on MRI (lesional epilepsy). Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) were each completed in nine patients (7.0%) and magnetoencephalography (MEG) in four patients (3.1%). Despite the low utilization rate of adjunctive studies, over half (56.3%) ultimately underwent VNS alone, and 8.6% ultimately underwent definitive intracranial resection or disconnection surgery. CONCLUSIONS: The underutilization of appropriate non-invasive, presurgical testing in patients with focal DRE may in part explain the continued underutilization of definitive, resective/disconnective surgery. For patients without access to a high-volume, multidisciplinary surgical epilepsy center, adjunctive presurgical studies [e.g., PET, SPECT, MEG, electrical source imaging (ESI), EEG-functional magnetic resonance imaging (fMRI)], even when available, are rarely ordered, and this may contribute to excessive rates of VNS in lieu of definitive intracranial surgery.

Role of Structural, Metabolic, and Functional MRI in Monitoring Visual System Impairment and Recovery.

The visual system, consisting of the eyes and the visual pathways of the brain, receives and interprets light from the environment so that we can perceive the world around us. A wide variety of disorders can affect human vision, ranging from ocular to neurologic to systemic in nature. While other noninvasive imaging techniques such as optical coherence tomography and ultrasound can image particular sections of the visual system, magnetic resonance imaging (MRI) offers high resolution without depth limitations. MRI also gives superior soft-tissue contrast throughout the entire pathway compared to computed tomography. By leveraging different imaging sequences, MRI is uniquely capable of unveiling the intricate processes of ocular anatomy, tissue physiology, and neurological function in the human visual system from the microscopic to macroscopic levels. In this review we discuss how structural, metabolic, and functional MRI can be used in the clinical assessment of normal and pathologic states in the anatomic structures of the visual system, including the eyes, optic nerves, optic chiasm, optic tracts, visual brain nuclei, optic radiations, and visual cortical areas. We detail a selection of recent clinical applications of MRI at each position along the visual pathways, including the evaluation of pathology, plasticity, and the potential for restoration, as well as its limitations and key areas of ongoing exploration. Our discussion of the current and future developments in MR ocular and neuroimaging highlights its potential impact on our ability to understand visual function in new detail and to improve our protection and treatment of anatomic structures that are integral to this fundamental sensory system. LEVEL OF EVIDENCE 3: TECHNICAL EFFICACY STAGE 3: .

Deciphering the surgical treatment gap for drug-resistant epilepsy (DRE): A literature review.

Patients with drug-resistant epilepsy (DRE) rarely achieve seizure freedom with medical therapy alone. Despite being safe and effective for select patients with DRE, epilepsy surgery remains heavily underutilized. Multiple studies have indicated that the overall rates of surgery in patients with DRE have stagnated in recent years and may be decreasing, even when hospitalizations for epilepsy-related problems are on the rise. Ultimately, many patients with DRE who might otherwise benefit from surgery continue to have intractable seizures, lacking access to the full spectrum of available treatment options. In this article, we review the various factors accounting for the persistent underutilization of epilepsy surgery and uncover several key themes, including the persistent knowledge gap among physicians in identifying potential surgical candidates, lack of coordinated patient care, patient misconceptions of surgery, and socioeconomic disparities impeding access to care. Moreover, factors such as the cost and complexity of the preoperative evaluation, a lack of federal resource allocation for the research of surgical therapies for epilepsy, and difficulties recruiting patients to clinical trials all contribute to this multifaceted dilemma.

Low preoperative serum prealbumin levels and the postoperative surgical site infection risk in elective spine surgery: a consecutive series.

OBJECTIVENutritional deficiency negatively affects outcomes in many health conditions. In spine surgery, evidence linking preoperative nutritional deficiency to postoperative surgical site infection (SSI) has been limited to small retrospective studies. Authors of the current study analyzed a large consecutive cohort of patients who had undergone elective spine surgery to determine the relationship between a serum biomarker of nutritional status (preoperative prealbumin levels) and SSI.METHODSThe authors conducted a retrospective review of the electronic medical charts of patients who had undergone posterior spinal surgeries and whose preoperative prealbumin level was available. Additional data pertinent to the risk of SSI were also collected. Patients who developed a postoperative SSI were identified, and risk factors for postoperative SSI were analyzed. Nutritional deficiency was defined as a preoperative serum prealbumin level ≤ 20 mg/dl.RESULTSAmong a consecutive series of 387 patients who met the study criteria for inclusion, the infection rate for those with preoperative prealbumin ≤ 20 mg/dl was 17.8% (13/73), versus 4.8% (15/314) for those with preoperative prealbumin > 20 mg/dl. On univariate and multivariate analysis a low preoperative prealbumin level was a risk factor for postoperative SSI with a crude OR of 4.29 (p < 0.01) and an adjusted OR of 3.28 (p = 0.02). In addition, several previously known risk factors for infection, including diabetes, spinal fusion, and number of operative levels, were significant for the development of an SSI.CONCLUSIONSIn this consecutive series, preoperative prealbumin levels, a serum biomarker of nutritional status, correlated with the risk of SSI in elective spine surgery. Prehabilitation before spine surgery, including strategies to improve nutritional status in patients with nutritional deficiencies, may increase value and improve spine care.

Protein phosphatase 2A inhibition enhances radiation sensitivity and reduces tumor growth in chordoma.

Background: Standard therapy for chordoma consists of surgical resection followed by high-dose irradiation. Protein phosphatase 2A (PP2A) is a ubiquitously expressed serine/threonine phosphatase involved in signal transduction, cell cycle progression, cell differentiation, and DNA repair. LB100 is a small-molecule inhibitor of PP2A designed to sensitize cancer cells to DNA damage from irradiation and chemotherapy. A recently completed phase I trial of LB100 in solid tumors demonstrated its safety. Here, we show the therapeutic potential of LB100 in chordoma. Methods: Three patient-derived chordoma cell lines were used: U-CH1, JHC7, and UM-Chor1. Cell proliferation was determined with LB100 alone and in combination with irradiation. Cell cycle progression was assessed by flow cytometry. Quantitative γ-H2AX immunofluorescence and immunoblot evaluated the effect of LB100 on radiation-induced DNA damage. Ultrastructural evidence for nuclear damage was investigated using Raman imaging and transmission electron microscopy. A xenograft model was established to determine potential clinical utility of adding LB100 to irradiation. Results: PP2A inhibition in concert with irradiation demonstrated in vitro growth inhibition. The combination of LB100 and radiation also induced accumulation at the G2/M phase of the cell cycle, the stage most sensitive to radiation-induced damage. LB100 enhanced radiation-induced DNA double-strand breaks. Animals implanted with chordoma cells and treated with the combination of LB100 and radiation demonstrated tumor growth delay. Conclusions: Combining LB100 and radiation enhanced DNA damage-induced cell death and delayed tumor growth in an animal model of chordoma. PP2A inhibition by LB100 treatment may improve the effectiveness of radiation therapy for chordoma.

Hypoxia in the glioblastoma microenvironment: shaping the phenotype of cancer stem-like cells.

Glioblastoma is the most common and aggressive malignant primary brain tumor. Cellular heterogeneity is a characteristic feature of the disease and contributes to the difficulty in formulating effective therapies. Glioma stem-like cells (GSCs) have been identified as a subpopulation of tumor cells that are thought to be largely responsible for resistance to treatment. Intratumoral hypoxia contributes to maintenance of the GSCs by supporting the critical stem cell traits of multipotency, self-renewal, and tumorigenicity. This review highlights the interaction of GSCs with the hypoxic tumor microenvironment, exploring the mechanisms underlying the contribution of GSCs to tumor vessel dynamics, immune modulation, and metabolic alteration.

New evidence on the validity of the Arnett Caregiver Interaction Scale: Results from the Early Childhood Longitudinal Study-Birth Cohort.

The Arnett Caregiver Interaction Scale (CIS) has been widely used in research studies to measure the quality of caregiver-child interactions. The scale was modeled on a well-established theory of parenting, but there are few psychometric studies of its validity. We applied factor analyses and item response theory methods to assess the psychometric properties of the Arnett CIS in a national sample of toddlers in home-based care and preschoolers in center-based care from the Early Childhood Longitudinal Study-Birth Cohort. We found that a bifactor structure (one common factor and a second set of specific factors) best fits the data. In the Arnett CIS, the bifactor model distinguishes a common substantive dimension from two methodological dimensions (for positively and negatively oriented items). Despite the good fit of this model, the items are skewed (most teachers/caregivers display positive interactions with children) and, as a result, the Arnett CIS is not well suited to distinguish between caregivers who are "highly" versus "moderately" positive in their interactions with children, according to the items on the scale. Regression-adjusted associations between the Arnett CIS and child outcomes are small, especially for preschoolers in centers. We encourage future scale development work on measures of child care quality by early childhood scholars.