The chemokine CXCL12 regulates multiple cell functions through its receptor, CXCR4. However, recent studies have shown that CXCL12 also binds a second receptor, CXCR7, to potentiate signal ...transduction and cell activity. In contrast to CXCL12/CXCR4, few studies have focused on the role of CXCR7 in vascular biology and its role in human brain microvascular endothelial cells (HBMECs) remains unclear. In this report, we used complementary methods, including immunocytofluorescence, Western blot, and flow cytometry analyses, to demonstrate that CXCR7 was expressed on HBMECs. We then employed short hairpin RNA (shRNA) technology to knockdown CXCR7 in HBMECs. Knockdown of CXCR7 in HBMECs resulted in significantly reduced HBMEC proliferation, tube formation, and migration, as well as adhesion to matrigel and tumor cells. Blocking CXCR7 with a specific antibody or small molecule antagonist similarly disrupted HBMEC binding to matrigel or tumor cells. We found that tumor necrosis factor (TNF)-α induced CXCR7 in a time and dose-response manner and that this increase preceded an increase in vascular cell adhesion molecule-1 (VCAM-1). Knockdown of CXCR7 resulted in suppression of VCAM-1, suggesting that the reduced binding of CXCR7-knockdown HBMECs may result from suppression of VCAM-1. Collectively, CXCR7 acted as a functional receptor for CXCL12 in brain endothelial cells. Targeting CXCR7 in tumor vasculature may provide novel opportunities for improving brain tumor therapy.
Sport-related concussion is an important topic in nearly all sports and at all levels of sport for children and adolescents. Concussion knowledge and approaches to management have progressed since ...the American Academy of Pediatrics published its first clinical report on the subject in 2010. Concussion's definition, signs, and symptoms must be understood to diagnose it and rule out more severe intracranial injury. Pediatric health care providers should have a good understanding of diagnostic evaluation and initial management strategies. Effective management can aid recovery and potentially reduce the risk of long-term symptoms and complications. Because concussion symptoms often interfere with school, social life, family relationships, and athletics, a concussion may affect the emotional well-being of the injured athlete. Because every concussion has its own unique spectrum and severity of symptoms, individualized management is appropriate. The reduction, not necessarily elimination, of physical and cognitive activity is the mainstay of treatment. A full return to activity and/or sport is accomplished by using a stepwise program while evaluating for a return of symptoms. An understanding of prolonged symptoms and complications will help the pediatric health care provider know when to refer to a specialist. Additional research is needed in nearly all aspects of concussion in the young athlete. This report provides education on the current state of sport-related concussion knowledge, diagnosis, and management in children and adolescents.
This retrospective study was done to better understand the conditions for which stereotactic radiosurgery (SRS) for glioblastoma may be efficacious.
Between 2000 and 2007, 33 patients with a ...pathological diagnosis of glioblastoma received SRS with the Novalis Shaped Beam Radiosurgery system. Eighteen patients (54%) underwent salvage SRS for recurrence while 15 (45%) patients received upfront SRS following standard fractionated RT for newly diagnosed glioblastoma.
There were no RTOG grade >2 acute side effects. The median survival after SRS was 6.7 months (range 1.4 - 74.7). There was no significant difference in overall survival (from the time of initial diagnosis) with respect to the timing of SRS (p = 0.2). There was significantly better progression free survival in patients treated with SRS as consolidation versus at the time of recurrence (p = 0.04). The majority of patients failed within or at the margin of the SRS treatment volume (21/26 evaluable for recurrence).
SRS is well tolerated in the treatment of glioblastoma. As there was no difference in survival whether SRS is delivered upfront or at recurrence, the treatment for each patient should be individualized. Future studies are needed to identify patients most likely to respond to SRS.
To investigate concussion rates and reporting frequencies in high school and collegiate athletes in 2013, compare results to those obtained from 1999 to 2002, and examine to what extent the 2012 ...Wisconsin state concussion law affected reporting in 2013.
Retrospective 2013 survey compared with prior survey.
High schools and colleges in the Milwaukee, Wisconsin, area.
Athletes (N = 784) from multiple sports were surveyed in 2013. Football players (N = 1532) from 1999 to 2002 completed the same measure.
Both surveys assessed concussion history, concussion incidence during the current season, whether incident concussions were reported, who concussions were reported to, and reasons for not reporting. The 2013 survey also assessed awareness of the Wisconsin state law and its effect on reporting.
Rates of concussion in the surveyed season were comparable to previous findings from 1999 to 2002 (16.6% vs 15.3%, P = 0.558). Notably, athletes were significantly more likely to report their concussions in 2013 (70.6% vs 47.3% previously, P = 0.011). Among high school athletes surveyed, 59.5% were aware of the Wisconsin state law, with 55.1% stating it would make them more likely to report a concussion.
Rates of concussion for 1 sport season have not changed significantly over the past 14 years. The percentage of concussions that are reported to someone has increased significantly. Awareness of the Wisconsin state law does not fully account for the increase in concussion reporting.
Given the finite amount of knowledge regarding the influence of concussion-related cultural and legal changes, these findings will help to inform clinicians of the current concussion milieu from the perspective of athletes. It will inform practitioners involved in concussion management to what extent athletes are aware of and report concussions.
To determine recurrence patterns of glioblastoma treated with temozolomide-based chemoradiation.
Pretreatment and serial posttreatment magnetic resonance imaging scans of 54 patients were ...retrospectively evaluated. Central recurrence (i.e., local progression) and the development of new (i.e., interval appearance of discrete enhancing lesion) in-field, marginal, and distant recurrences were assessed, with the pattern of recurrence of individual lesions defined relative to the 95% isodose line (D(95)). Distant recurrences were defined as lesions completely outside D(95), marginal recurrences crossed D(95), and in-field recurrences were completely inside D(95).
At a median follow-up of 17 months, 39 of 54 (72%) patients developed recurrent glioblastoma. Among these 39 patients, central recurrence occurred in 80% (at a median of 7 months from diagnosis); new in-field recurrence developed in 33% (at a median of 14 months); marginal recurrences developed in 15% (at a median of 18 months); and distant recurrences developed in 20% (at a median of 11 months). The actuarial rates of central, new in-field, marginal, distant, and any new recurrences at 1-year were 46%, 15%, 3%, 14%, and 25% respectively, whereas at 2 years, the rates were 68%, 60%, 32%, 28%, and 66%, reflecting an increasing probability of new lesions developing at later time points. Ten patients developed subependymal recurrences, of whom 7 developed multiple subependymal lesions.
Whereas central recurrence of glioblastoma treated with radiation and temozolomide predominates and persists over time, new in-field, marginal, and distant recurrences commonly develop, particularly at later time points in patients with longer survival.
Patients undergoing neurosurgical procedures for neoplasia have historically been considered at higher risk for developing venous thromboembolism (VTE). We sought to identify risk factors associated ...with VTE in patients undergoing craniotomy for tumor resection. We reviewed a national surgical quality database (American College of Surgeons National Surgical Quality Improvement Project, ACS-NSQIP,
http://site.acsnsqip.org/
). Patients undergoing non-emergent craniotomy for neoplastic indications were identified based on current procedural terminology codes. Clinical factors were identified that were associated with VTE events. 3,098 patients who underwent non-emergent craniotomy were identified. 1,741 patients underwent procedures for neoplastic disease (56.2 %). The rate of DVT in these patients was 3.2 % compared to 1.4 % in other neurosurgical patients (OR 2.30, CI 2.29–2.30). The rate of pulmonary embolism was 1.8 % compared to 0.5 % (OR 3.61, CI 3.60–3.62). Univariate analysis identified several factors correlated with VTE. Pre-operative characteristics associated with VTE were the presence of impaired sensorium, dependent functional status, and age > 60 years. Total operative time > 4 h was associated with VTE. Post-operative events associated with VTE included pneumonia, unplanned intubation, fail to wean from ventilator, UTI, stroke, sepsis and septic shock. Age > 60, OR time > 4 h, UTI, and septic shock were significantly associated with VTE in multivariate analysis. Patients undergoing craniotomy for neoplasm are at increased risk of VTE. This risk appears to be modified by pre-operative medical comorbidities, longer operative time, and post-operative complications.
Data on verified healthcare costs for high-grade gliomas (HGGs) are limited. This study aimed to determine the healthcare costs for HGGs.
A total of 88 primary HGGs patients diagnosed and treated at ...our Institution between 2011 and 2017 who had insurance plans administered with Excellus BCBS were retrospectively identified. Patient clinical information was linked with all verified insurance payment data.
Median insurance payments for clinical management of HGGs were $184,159.83. The leading cost was therapeutic radiation oncology. Patients under commercial insurance had a longer survival time, and higher healthcare expenditures in total and in each phase of clinical care. Healthcare costs were higher during therapy initiation and at disease recurrence and lower during the interim. A generalized linear model showed that patients with commercial insurance, better Karnofsky Performance Status, and longer survival time had higher healthcare expenditures.
Healthcare payments for HGGs patients were substantial and such high healthcare expenditures were positively associated with patient survival and commercial insurance.
The functional contribution of chemokine receptor CXCR7 to malignant brain tumor biology remains controversial.
Complementary methods were used to confirm CXCR7 expression in clinical glioblastoma ...multiforme (GBM) specimens and multiple GBM cell lines. Loss-of-function studies were performed using small interfering RNA (siRNA) technology.
Elevated CXCR7 levels correlated with reduced survival in glioma patients. CXCR7 was expressed by GBM cell lines and stem-like progenitor cells. Knockdown of CXCR7 by siRNA attenuated phosphorylation of the extracellular signal-regulated kinase (ERK1/2) signaling pathway in response to CXCL12 and resulted in significantly reduced cell proliferation, invasion and migration. Similarly, treatment of glioma cells with a small molecule antagonist of CXCR7, CCX771, significantly inhibited cell proliferation and invasion.
CXCR7 actively promotes the proliferation and invasive behavior of glioma tumor cells and stem-like progenitor cells and may be a potential target for glioma therapy.
Plasmalemmal vesicle associated protein-1 (PV-1) is selectively expressed in human brain microvascular endothelial cells derived from clinical specimens of primary and secondary malignant brain ...tumors, cerebral ischemia, and other central nervous system (CNS) diseases associated with blood-brain barrier breakdown. In this study, we characterize the murine CNS expression pattern of PV-1 to determine whether localized PV-1 induction is conserved across species and disease state.
We demonstrate that PV-1 is selectively upregulated in mouse blood vessels recruited by brain tumor xenografts at the RNA and protein levels, but is not detected in non-neoplastic brain. Additionally, PV-1 is induced in a mouse model of acute ischemia. Expression is confined to the cerebovasculature within the region of infarct and is temporally regulated.
Our results confirm that PV-1 is preferentially induced in the endothelium of mouse brain tumors and acute ischemic brain tissue and corresponds to blood-brain barrier disruption in a fashion analogous to human patients. Characterization of PV-1 expression in mouse brain is the first step towards development of rodent models for testing anti-edema and anti-angiogenesis therapeutic strategies based on this molecule.
The radiogenomics association of neovascularization is important for overall survival (OS) in glioblastoma patients and remains unclear. The purpose of this study is to assess the association between ...MR perfusion imaging derived parameters and genomic biomarkers of glioblastoma, and to evaluate their prognostic value. This retrospective study enrolled 41 patients with newly diagnosed glioblastoma. The mean and maximal relative cerebral blood volume (rCBV) ratio (rCBV
mean
and rCBV
max
), derived from MR perfusion weighted imaging, of the enhancing tumor, as well as maximal rCBV ratio of peri-enhancing tumor area (rCBV
peri-tumor
) were measured. The ki-67 labeling index, mammalian target of rapamycin (mTOR) activation, epidermal growth factor receptor (EGFR) amplification, isocitrate dehydrogenase (IDH) mutation and TP53 were assessed. There was a significant correlation between rCBV
max
and mTOR based on Pearson’s correlations with Benjamini–Hochberg adjustment for controlling false discovery rate,
p
= 0.047. The rCBV
peri-tumor
showed significant correlation with mTOR (
p
= 0.0183) after adjustment of gender and EGFR status. The mean rCBV
peri-tumor
value of the patients with OS shorter than 14 months was significantly higher than patients with OS longer than 14 months,
p
= 0.002. The rCBV
peri-tumor
and age were the two strongest predictors of OS (hazard ratio = 1.29 and 1.063 respectively) by Cox regression analysis. This study showed that hemodynamic abnormalities of glioblastoma were associated with genomics activation status of mTOR-EGFR pathway, however, the radiogenomics associations are different in enhancing and peri-enhancing area of glioblastoma. The rCBV
peri-tumor
has better prognostic value than genomic biomarkers alone.
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