Accumulating evidence suggests cancer cells exhibit a dependency on metabolic pathways regulated by nicotinamide adenine dinucleotide (NAD⁺). Nevertheless, how the regulation of this metabolic ...cofactor interfaces with signal transduction networks remains poorly understood in glioblastoma. Here, we report nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting step in NAD⁺ synthesis, is highly expressed in glioblastoma tumors and patient-derived glioblastoma stem-like cells (GSCs). High NAMPT expression in tumors correlates with decreased patient survival. Pharmacological and genetic inhibition of NAMPT decreased NAD⁺ levels and GSC self-renewal capacity, and NAMPT knockdown inhibited the in vivo tumorigenicity of GSCs. Regulatory network analysis of RNA sequencing data using GSCs treated with NAMPT inhibitor identified transcription factor E2F2 as the center of a transcriptional hub in the NAD⁺-dependent network. Accordingly, we demonstrate E2F2 is required for GSC selfrenewal. Downstream, E2F2 drives the transcription of members of the inhibitor of differentiation (ID) helix–loop–helix gene family. Finally, we find NAMPT mediates GSC radiation resistance. The identification of a NAMPT-E2F2-ID axis establishes a link between NAD+ metabolism and a self-renewal transcriptional program in glioblastoma, with therapeutic implications for this formidable cancer.
To review clinical outcomes of moderate dose escalation using high-dose radiation therapy (HDRT) in the setting of concurrent temozolomide (TMZ) in patients with newly diagnosed glioblastoma ...multiforme (GBM), compared with standard-dose radiation therapy (SDRT).
Adult patients aged <70 years with biopsy-proven GBM were treated with SDRT (60 Gy at 2 Gy per fraction) or with HDRT (>60 Gy) and TMZ from 2000 to 2012. Biological equivalent dose at 2-Gy fractions was calculated for the HDRT assuming an α/β ratio of 5.6 for GBM.
Eighty-one patients received SDRT, and 128 patients received HDRT with a median (range) biological equivalent dose at 2-Gy fractions of 64 Gy (61-76 Gy). Overall median follow-up time was 1.10 years, and for living patients it was 2.97 years. Actuarial 5-year overall survival (OS) and progression-free survival (PFS) rates for patients that received HDRT versus SDRT were 12.4% versus 13.2% (P=.71), and 5.6% versus 4.1% (P=.54), respectively. Age (P=.001) and gross total/near-total resection (GTR/NTR) (P=.001) were significantly associated with PFS on multivariate analysis. Younger age (P<.0001), GTR/NTR (P<.0001), and Karnofsky performance status ≥80 (P=.001) were associated with improved OS. On subset analyses, HDRT failed to improve PFS or OS for those aged <50 years or those who had GTR/NTR.
Moderate radiation therapy dose escalation above 60 Gy with concurrent TMZ does not seem to improve clinical outcomes for patients with GBM.
Cilengitide, an inhibitor of alphavbeta3 and alphavbeta5 integrin receptors, demonstrated minimal toxicity and durable activity across a wide range of doses administered to adults with recurrent ...glioblastoma multiforme (GBM) in a prior phase I study. The current multicenter phase II study was conducted to evaluate the activity and safety of cilengitide in GBM patients at first recurrence.
Eligible patients were randomly assigned to receive either 500 or 2,000 mg of cilengitide twice weekly on a continuous basis. Patients were assessed every 4 weeks. The primary end point was 6-month progression-free survival (PFS) rate. Secondary end points included PFS, overall survival (OS), and radiographic response, as well as quality-of-life and pharmacokinetic assessments.
Eighty-one patients were enrolled, including 41 on the 500-mg arm and 40 on the 2,000-mg arm. The safety profile of cilengitide was excellent, with no significant reproducible toxicities observed on either arm. Antitumor activity was observed in both treatment cohorts but trended more favorably among patients treated with 2,000 mg, including a 6-month PFS of 15% and a median OS of 9.9 months.
Cilengitide monotherapy is well tolerated and exhibits modest antitumor activity among recurrent GBM patients. Additional studies integrating cilengitide into combinatorial regimens for GBM are warranted.
Glioblastoma (GBM) remains incurable, despite state-of-the-art treatment involving surgical resection, chemotherapy, and radiation. GBM invariably recurs as a highly invasive and aggressive ...phenotype, with the majority of recurrences within the radiation therapy treatment field. Although a large body of literature reporting on primary GBM exists, comprehensive studies of how prior irradiation alters recurrent tumor growth are lacking. An animal model that replicates the delayed effects of radiation therapy on the brain microenvironment, and its impact on the development of recurrent GBM, would be a significant advance.
Cohorts of mice received a single fraction of 0, 20, 30, or 40 Gy Gamma Knife irradiation. Naïve, nonirradiated mouse GBM tumor cells were implanted into the ipsilateral hemisphere 6 weeks postirradiation. Tumor growth was measured by magnetic resonance imaging, and animal survival was assessed by monitoring weight loss. Magnetic resonance imaging results were supported by hemotoxylin and eosin histology.
Tumorous lesions generated from orthotopic implantation of nonirradiated mouse GBM tumor cells into irradiated mouse brain grew far more aggressively and invasively than implantation of these same cells into nonirradiated brain. Lesions in irradiated brain tissue were significantly larger, more necrotic, and more vascular than those in control animals with increased invasiveness of tumor cells in the periphery, consistent with the histologic features commonly observed in recurrent high-grade tumors in patients.
Irradiation of normal brain primes the targeted cellular microenvironment for aggressive tumor growth when naïve (not previously irradiated) cancer cells are subsequently introduced. The resultant growth pattern is similar to the highly aggressive pattern of tumor regrowth observed clinically after therapeutic radiation therapy. The mouse model offers an avenue for determining the cellular and molecular basis for the aggressiveness of recurrent GBM.
OBJECTIVE Internal carotid artery (ICA) injury is a rare but severe complication of endonasal surgery. The authors describe their endovascular experience managing ICA injuries after transsphenoidal ...surgery; they review and summarize the current literature regarding endovascular techniques; and they propose a treatment algorithm based on the available evidence. METHODS A retrospective review of 576 transsphenoidal pituitary adenoma resections was performed. Cases of ICA injury occurring at our institution and transfers from other hospitals were evaluated. Endovascular treatments for ICA injury reported in the literature were also reviewed and summarized. RESULTS Seven cases were identified from the institutional cohort (mean age 46.3 years, mean follow-up 43.4 months 1-107 months) that received endovascular treatment for ICA injury. Five injuries occurred at our institution (5 0.9% of 576), and 2 injuries occurred at outside hospitals. Three patients underwent ICA sacrifice by coil placement, 2 underwent lesion embolization (coil or stent-assisted coil placement), and 2 underwent endoluminal reconstruction (both with flow diversion devices). Review of the literature identified 98 cases of ICA injury treated with endovascular methods. Of the 105 total cases, 46 patients underwent ICA sacrifice, 28 underwent lesion embolization, and 31 underwent endoluminal reconstruction. Sacrifice of the ICA proved a durable solution in all cases; however, the rate of persistent neurological complications was relatively high (10 21.7% of 46). Lesion embolization was primarily performed by coil embolization without stenting (16 cases) and stent-assisted coiling (9 cases). Both techniques had a relatively high rate of at least some technical complication (6 37.5% of 16 and 5 55.6% of 9, respectively) and major technical complications (i.e., injury, new neurological deficit, or ICA sacrifice) (5 31.3% of 16 and 2 22.2% of 9, respectively). Endoluminal reconstruction was performed by covered stent (24 cases) and flow diverter (5 cases) placement. Covered stents showed a reasonably high rate of technical complications (10 41.7% of 24); however, 8 of these problems were resolved, leaving a small percentage with major technical complications (2 8.3% of 24). Flow diverter placement was also well tolerated, with only 1 minor technical complication. CONCLUSIONS Endovascular treatments including vessel sacrifice, coil embolization (with or without stent assistance), and endoluminal reconstruction offer a tailored approach to ICA injury management after endonasal surgery. Vessel sacrifice remains the definitive treatment for acute, uncontrolled bleeding; however, vessel preservation techniques should be considered carefully in select patients. Multiple factors including vascular anatomy, injury characteristics, and risk of dual antiplatelet therapy should guide best treatment, but more study is needed (particularly with flow diverters) to refine this decision-making process. Ideally, all endovascular treatment options should be available at institutions performing endonasal surgery.
Glioblastoma harbors a dynamic subpopulation of glioblastoma stem-like cells (GSCs) that can propagate tumors in vivo and is resistant to standard chemoradiation. Identification of the cell-intrinsic ...mechanisms governing this clinically important cell state may lead to the discovery of therapeutic strategies for this challenging malignancy. Here, we demonstrate that the mitotic E3 ubiquitin ligase CDC20-anaphase-promoting complex (CDC20-APC) drives invasiveness and self-renewal in patient tumor-derived GSCs. Moreover, CDC20 knockdown inhibited and CDC20 overexpression increased the ability of human GSCs to generate brain tumors in an orthotopic xenograft model in vivo. CDC20-APC control of GSC invasion and self-renewal operates through pluripotency-related transcription factor SOX2. Our results identify a CDC20-APC/SOX2 signaling axis that controls key biological properties of GSCs, with implications for CDC20-APC-targeted strategies in the treatment of glioblastoma.
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•CDC20-APC drives the invasiveness and self-renewal of glioblastoma stem-like cells•CDC20 is essential for the in vivo tumorigenicity of glioblastoma stem-like cells•CDC20-APC operates through SOX2 to control glioblastoma stem-like cell function•CDC20 is prognostic of overall survival in Proneural subtype glioblastoma patients
Mao et al. report that E3 ubiquitin ligase CDC20-APC is required for invasiveness, self-renewal, and in vivo tumorigenicity of human glioblastoma stem-like cells (GSCs). CDC20-APC interacts with and regulates SOX2 protein to promote SOX2-dependent transcription and drive GSC invasiveness and self-renewal. Using the Cancer Genome Atlas dataset, the authors find that high CDC20 expression in proneural glioblastomas is associated with shorter overall survival.
To explore if early perfusion-weighted magnetic resonance imaging (PWI) may be a promising imaging biomarker to predict local recurrence (LR) of brain metastases after stereotactic radiosurgery ...(SRS).
This is a prospective pilot study of adult brain metastasis patients who were treated with SRS and imaged with PWI before and 1 week later. Relative cerebral blood volume (rCBV) parameter maps were calculated by normalizing to the mean value of the contralateral white matter on PWI. Cox regression was conducted to explore factors associated with time to LR, with Bonferroni adjusted p<0.0006 for multiple testing correction. LR rates were estimated with the Kaplan-Meier method and compared using the log-rank test.
Twenty-three patients were enrolled from 2013 through 2016, with 22 evaluable lesions from 16 patients. After a median follow-up of 13.1 months (range: 3.0-53.7), 5 lesions (21%) developed LR after a median of 3.4 months (range: 2.3-5.7). On univariable analysis, larger tumor volume (HR 1.48, 95% CI 1.02-2.15, p = 0.04), lower SRS dose (HR 0.45, 95% CI 0.21-0.97, p = 0.04), and higher rCBV at week 1 (HR 1.07, 95% CI 1.003-1.14, p = 0.04) had borderline association with shorter time to LR. Tumors >2.0cm3 had significantly higher LR than if ≤2.0cm3: 54% vs 0% at 1 year, respectively, p = 0.008. A future study to confirm the association of early PWI and LR of the high-risk cohort of lesions >2.0cm3 is estimated to require 258 patients.
PWI at week 1 after SRS may have borderline association with LR. Tumors <2.0cm3 have low risk of LR after SRS and may be low-yield for predictive biomarker studies. Information regarding sample size and potential challenges for future imaging biomarker studies may be gleaned from this pilot study.
The purpose of aneurysm surgery is complete aneurysm obliteration while sparing associated arteries. Indocyanine green (ICG) videoangiography is a new technique that allows for real-time evaluation ...of blood flow in the aneurysm and vessels. The authors performed a retrospective study to compare the accuracy of ICG videoangiography with intraoperative angiography (IA), and determine if ICG videoangiography can be used without follow-up IA.
From June 2007 through September 2009, 155 patients underwent craniotomies for clipping of aneurysms. Operative summaries, angiograms, and operative and ICG videoangiography videos were reviewed. The number, size, and location of aneurysms, the ICG videoangiography and IA findings, and the need for clip adjustment after ICG videoangiography and IA were recorded. Discordance between ICG videoangiography and IA was defined as ICG videoangiography demonstrating aneurysm obliteration and normal vessel flow, but post-IA showing either an aneurysmal remnant and/or vessel occlusion requiring clip adjustment.
Thirty-two percent of patients (49 of 155) underwent both ICG videoangiography and IA. The post-ICG videoangiography clip adjustment rate was 4.1% (2 of 49). The overall rate of ICG videoangiography-IA agreement was 75.5% (37 of 49) and the ICG videoangiography-IA discordance rate requiring post-IA clip adjustment was 14.3% (7 of 49). Adjustments were due to 3 aneurysmal remnants and 4 vessel occlusions. These adjustments were attributed to obscuration of the residual aneurysm or the affected vessel from the field of view and the presence of dye in the affected vessel via collateral flow. Although not statistically significant, there was a trend for ICG videoangiography-IA discordance requiring clip adjustment to occur in cases involving the anterior communicating artery complex, with an odds ratio of 3.3 for ICG videoangiography-IA discordance in these cases.
These results suggest that care should be taken when considering ICG videoangiography as the sole means for intraoperative evaluation of aneurysm clip application. The authors further conclude that IA should remain the gold standard for evaluation during aneurysm surgery. However, a combination of ICG videoangiography and IA may ultimately prove to be the most effective strategy for maximizing the safety and efficacy of aneurysm surgery.
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