Validation of postoperative residual contrast-enhancing tumor volume as an independent prognostic factor for overall survival in newly diagnosed glioblastoma

Ellingson, Benjamin M.; Abrey, Lauren E.; Nelson, Sarah J.; Kaufmann, Timothy J.; Garcia, Josep; Chinot, Olivier; Saran, Frank; Nishikawa, Ryo; Henriksson, Roger; Mason, Warren P.; Wick, Wolfgang; Butowski, Nicholas; Ligon, Keith L.; Gerstner, Elizabeth R.; Colman, Howard; Groot, John de; Chang, Susan M.; Mellinghoff, Ingo K.; Young, Robert J.; Alexander, Brian M.; Colen, Rivka R.; Taylor, Jennie; Arrillaga‐Romany, Isabel; Mehta, Arnav; Huang, Raymond Y.; Pope, Whitney; Reardon, David A.; Batchelor, Tracy T.; Prados, Michael D.; Galanis, Evanthia; Wen, Patrick Y.; Cloughesy, Timothy F.

doi:10.1093/neuonc/noy053

Cited by 66 publications

(50 citation statements)

References 26 publications

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“…Another possible explanation regards the secretion rate by different subpopulations of GBM cells. It is possible to speculate that the global concentration in plasma is consequence of nonhomogeneous release of extracellular vesicles by different subpopulations, thus making the global concentration not related to markers or tumor/necrosis size (43)(44)(45).…”

Section: Discussionmentioning

confidence: 99%

Clinical Significance of Extracellular Vesicles in Plasma from Glioblastoma Patients

Osti

Bene

Rappa

et al. 2019

Clinical Cancer Research

194

139

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Purpose: Glioblastoma (GBM) is the most common primary brain tumor. The identification of blood biomarkers reflecting the tumor status represents a major unmet need for optimal clinical management of patients with GBM. Their high number in body fluids, their stability, and the presence of many tumor-associated proteins and RNAs make extracellular vesicles potentially optimal biomarkers. Here, we investigated the potential role of plasma extracellular vesicles from patients with GBM for diagnosis and follow-up after treatment and as a prognostic tool. Experimental Design: Plasma from healthy controls (n ¼ 33), patients with GBM (n ¼ 43), and patients with different central nervous system malignancies (n ¼ 25) were collected. Extracellular vesicles were isolated by ultracentrifugation and characterized in terms of morphology by transmission electron microscopy, concentration, and size by nanoparticle tracking analysis, and protein composition by mass spectrometry. An orthotopic mouse model of human GBM confirmed human plasma extracellular vesicle quantifications. Associations between plasma extracellular vesicle concentration and clinicopathologic features of patients with GBM were analyzed. All statistical tests were two-sided. Results: GBM releases heterogeneous extracellular vesicles detectable in plasma. Plasma extracellular vesicle concentration was higher in GBM compared with healthy controls (P < 0.001), brain metastases (P < 0.001), and extra-axial brain tumors (P < 0.001). After surgery, a significant drop in plasma extracellular vesicle concentration was measured (P < 0.001). Plasma extracellular vesicle concentration was also increased in GBM-bearing mice (P < 0.001). Proteomic profiling revealed a GBM-distinctive signature. Conclusions: Higher extracellular vesicle plasma levels may assist in GBM clinical diagnosis: their reduction after GBM resection, their rise at recurrence, and their protein cargo might provide indications about tumor, therapy response, and monitoring.

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Section: Discussionmentioning

confidence: 99%

Clinical Significance of Extracellular Vesicles in Plasma from Glioblastoma Patients

Osti

Bene

Rappa

et al. 2019

Clinical Cancer Research

194

139

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“…A recent study investigated the impact of maximal CE resection and MGMT promoter methylation status in a homogenous IDH-wildtype glioblastoma population ( n = 175) and showed that both were significantly associated with longer overall survival ( 2 ). Ellingson et al showed in 1,054 glioblastoma patients (with partially available data on IDH mutation and MGMT methylation) that smaller residual CE tumor volumes (<12 cm 3 ) and MGMT methylation were significantly associated with longer overall survival in patients receiving chemoradiation ( 18 ). A recent study published by Molinaro et al confirmed the association between maximal CE resection and overall survival across all molecular subgroups of glioblastoma ( 19 ).…”

Section: Discussionmentioning

confidence: 99%

The Association Between the Extent of Glioblastoma Resection and Survival in Light of MGMT Promoter Methylation in 326 Patients With Newly Diagnosed IDH-Wildtype Glioblastoma

et al. 2020

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Background: The association between contrast enhanced (CE) and non-contrast enhanced (NCE) tumor resection and survival in patients with glioblastoma in relation to molecular subtypes is poorly understood. The aim of this study was to assess the association between CE and NCE tumor resection and survival in light of MGMT promoter methylation in newly diagnosed IDH-wildtype glioblastoma. Materials and methods: Patients with newly diagnosed IDH-wildtype glioblastoma who underwent surgery were eligible. CE and NCE tumor volumes were assessed on pre-and post-operative MRI scans and extent of resection was calculated. The association between CE and NCE tumor resection and survival was evaluated using multivariable Cox proportional hazards models and Kaplan Meier estimates. Results: Three hundred and twenty-six patients were included: 177 (54.3%) with and 149 (45.7%) without MGMT methylation. Multivariable Cox proportional hazards models stratified for MGMT methylation identified age ≤ 65y (HR 0.63; 95% CI, 0.49-0.81; p < 0.0001), chemoradiation (HR 0.13; 95% CI, 0.09-0.19; p < 0.0001), maximal CE tumor resection (HR 0.58; 95% CI, 0.39-0.87; p = 0.009), ≥ 30% NCE tumor resection (HR 0.71; 95% CI, 0.53-0.93; p = 0.014), and minimal residual CE tumor volume (HR 0.64; 95% CI, 0.46-0.88 p = 0.007) as being associated with longer overall survival. Kaplan Meier estimates showed that extensive surgery was more beneficial for patients with MGMT methylated glioblastoma. Conclusions: This study shows an association between maximal CE tumor resection, ≥30% NCE tumor resection, minimal residual CE tumor volume, and longer overall survival in patients with newly diagnosed IDH wildtype glioblastoma. Intraoperative imaging and stimulation mapping may be used to pursue safe and maximal resection. In future research, the safety aspect of maximizing tumor resection needs to be addressed.

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“…Contrast enhanced T1-weighted digital subtraction maps were created in order to isolate the areas of contrast enhancement and negate blood products within tumor regions of interest. The process of generating T1 subtraction maps has been detailed previously 123 – 125 . Briefly, T1 weighted images with and without contrast were co-registered using affine registration (12 degrees-of-freedom; correlation coefficient cost function, FSL (FLIRT;FMRIB Software Library, Oxford, England).…”

Section: Methodsmentioning

confidence: 99%

Decorin expression is associated with predictive diffusion MR phenotypes of anti-VEGF efficacy in glioblastoma

Patel

Yao

Raymond

et al. 2020

Sci Rep

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Previous data suggest that apparent diffusion coefficient (ADC) imaging phenotypes predict survival response to anti-VEGF monotherapy in glioblastoma. However, the mechanism by which imaging may predict clinical response is unknown. We hypothesize that decorin (DCN), a proteoglycan implicated in the modulation of the extracellular microenvironment and sequestration of pro-angiogenic signaling, may connect ADC phenotypes to survival benefit to anti-VEGF therapy. Patients undergoing resection for glioblastoma as well as patients included in The Cancer Genome Atlas (TCGA) and IVY Glioblastoma Atlas Project (IVY GAP) databases had pre-operative imaging analyzed to calculate pre-operative ADCL values, the average ADC in the lower distribution using a double Gaussian mixed model. ADCL values were correlated to available RNA expression from these databases as well as from RNA sequencing from patient derived mouse orthotopic xenograft samples. Targeted biopsies were selected based on ADC values and prospectively collected during resection. Surgical specimens were used to evaluate for DCN RNA and protein expression by ADC value. The IVY Glioblastoma Atlas Project Database was used to evaluate DCN localization and relationship with VEGF pathway via in situ hybridization maps and RNA sequencing data. In a cohort of 35 patients with pre-operative ADC imaging and surgical specimens, DCN RNA expression levels were significantly larger in high ADCL tumors (41.6 vs. 1.5; P = 0.0081). In a cohort of 17 patients with prospectively targeted biopsies there was a positive linear correlation between ADCL levels and DCN protein expression between tumors (Pearson R2 = 0.3977; P = 0.0066) and when evaluating different targets within the same tumor (Pearson R2 = 0.3068; P = 0.0139). In situ hybridization data localized DCN expression to areas of microvascular proliferation and immunohistochemical studies localized DCN protein expression to the tunica adventitia of blood vessels within the tumor. DCN expression positively correlated with VEGFR1 & 2 expression and localized to similar areas of tumor. Increased ADCL on diffusion MR imaging is associated with high DCN expression as well as increased survival with anti-VEGF therapy in glioblastoma. DCN may play an important role linking the imaging features on diffusion MR and anti-VEGF treatment efficacy. DCN may serve as a target for further investigation and modulation of anti-angiogenic therapy in GBM.

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Validation of postoperative residual contrast-enhancing tumor volume as an independent prognostic factor for overall survival in newly diagnosed glioblastoma

Abstract: Postsurgical, residual contrast-enhancing disease significantly negatively influences survival in patients with newly diagnosed GBM treated with chemoradiation with or without concomitant experimental therapy.

Cited by 66 publications

References 26 publications

Clinical Significance of Extracellular Vesicles in Plasma from Glioblastoma Patients

Clinical Significance of Extracellular Vesicles in Plasma from Glioblastoma Patients

The Association Between the Extent of Glioblastoma Resection and Survival in Light of MGMT Promoter Methylation in 326 Patients With Newly Diagnosed IDH-Wildtype Glioblastoma

Decorin expression is associated with predictive diffusion MR phenotypes of anti-VEGF efficacy in glioblastoma

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