Association of Maximal Extent of Resection of Contrast-Enhanced and Non–Contrast-Enhanced Tumor With Survival Within Molecular Subgroups of Patients With Newly Diagnosed Glioblastoma

Molinaro, Annette M.; Hervey-Jumper, Shawn L.; Morshed, Ramin A.; Young, Jacob S; Han, Seunggu J.; Chunduru, Pranathi; Zhang, Yalan; Phillips, Joanna J.; Shai, Anny; Lafontaine, Marisa; Crane, Jason C.; Chandra, Ankush; Flanigan, Patrick M.; Jahangiri, Arman; Cioffi, Gino; Ostrom, Quinn T.; Anderson, John E.; Badve, Chaitra; Barnholtz‐Sloan, Jill S.; Sloan, Andrew E.; Erickson, Bradley J.; Decker, Paul A.; Kosel, Matthew L.; Lachance, Daniel H.; Eckel‐Passow, Jeanette E.; Jenkins, Robert B.; Villanueva‐Meyer, Javier; Rice, Terri; Wrensch, Margaret; Wiencke, John K.; Bush, Nancy Ann Oberheim; Taylor, Jennie; Butowski, Nicholas; Prados, Michael D.; Clarke, Jennifer; Chang, Susan M.; Chang, Edward F.; Aghi, Manish K.; Theodosopoulos, Philip V.; McDermott, Michael W.; Berger, Mitchel S.

doi:10.1001/jamaoncol.2019.6143

Cited by 342 publications

(271 citation statements)

References 27 publications

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“…The larger the FLAIR-T 2 hyper-intensity volume, the shorter OS and PFS predictions. On these basis, surgical resection of the largest part of the FLAIR-T 2 hyperintensity tissue might determine a better prognosis, in agreement with previous studies ( 40 , 51 , 52 ). Additionally we show, that the 3D semi-automatic method, more complex and time consuming than the other alternatives ( 22 , 53 ), ends up providing similar pre-operative tumor volumetry results, without any preponderance in terms of survival.…”

Section: Discussionsupporting

confidence: 91%

Assessment of Pre-operative Measurements of Tumor Size by MRI Methods as Survival Predictors in Wild Type IDH Glioblastoma

et al. 2020

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Objective: We evaluate the performance of three MRI methods to determine non-invasively tumor size, as overall survival (OS) and Progression Free Survival (PFS) predictors, in a cohort of wild type, IDH negative, glioblastoma patients. Investigated protocols included bidimensional (2D) diameter measurements, and three-dimensional (3D) estimations by the ellipsoid or semi-automatic segmentation methods. Methods: We investigated OS in a cohort of 44 patients diagnosed with wild type IDH glioblastoma (58.2 ± 11.4 years, 1.9/1 male/female) treated with neurosurgical resection followed by adjuvant chemo and radiotherapy. Pre-operative MRI images were evaluated to determine tumor mass area and volume, gadolinium enhancement volume, necrosis volume, and FLAIR-T 2 hyper-intensity area and volume. We implemented then multivariate Cox statistical analysis to select optimal predictors for OS and PFS. Results: Median OS was 16 months (1–42 months), ranging from 9 ± 2.4 months in patients over 65 years, to 18 ± 1.6 months in younger ones. Patients with tumors carrying O 6 -methylguanin-DNA-methyltransferase (MGMT) methylation survived 30 ± 5.2 vs. 13 ± 2.5 months in non-methylated. Our study evidenced high and positive correlations among the results of the three methods to determine tumor size. FLAIR-T 2 hyper-intensity areas (2D) and volumes (3D) were also similar as determined by the three methods. Cox proportional hazards analysis with the 2D and 3D methods indicated that OS was associated to age ≥ 65 years (HR 2.70, 2.94, and 3.16), MGMT methylation (HR 2.98, 3.07, and 2.90), and FLAIR-T 2 ≥ 2,000 mm 2 or ≥60 cm 3 (HR 4.16, 3.93, and 3.72), respectively. Other variables including necrosis, tumor mass, necrosis/tumor ratio, and FLAIR/tumor ratio were not significantly correlated with OS. Conclusion: Our results reveal a high correlation among measurements of tumor size performed with the three methods. Pre-operative FLAIR-T 2 hyperintensity area and volumes provided, independently of the measurement method, the optimal neuroimaging features predicting OS in primary glioblastoma patients, followed by age ≥ 65 years and MGMT methylation.

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Section: Discussionsupporting

confidence: 91%

Assessment of Pre-operative Measurements of Tumor Size by MRI Methods as Survival Predictors in Wild Type IDH Glioblastoma

et al. 2020

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“…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: 93%

“…Secondly, the association between glioblastoma resection and overall survival is also being reassessed by evaluating the value of NCE tumor resection, because it is known that glioblastoma infiltrates beyond the margins of CE into the NCE area (4). This aspect of glioblastoma surgery is also recently investigated by Molinaro et al (19). The authors found that maximal resection of CE and NCE tumor was associated with longer overall survival in younger patients with IDH wildtype glioblastoma regardless of MGMT methylation status (subset of 190 patients with known IDH mutation and MGMT methylation status).…”

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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“…The IMPDH1 high and low groups were similar with respect to known clinical and pathologic determinants of survival including age (median 60 vs. 59 years) and MGMT promoter methlation (39 vs. 40%). We could not quantify the extent of resection in IMPDH1 high and low groups and therefore do not know if this key variable is partially responsible for the apparent decreased survival in patients with low IMPDH1 expression 46 . Increased expression of the rate limiting enzymes in de novo ATP synthesis (ADSS: adenylosuccinate synthase and ADSL: adenylosuccinate lyase) or de novo pyrimidine synthesis (DHODH: dihydroorotate dehydrogenase and CAD: carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase) were not associated with decreased survival in patients with newly diagnosed IDH wild type glioma (Fig.…”

Section: Resultsmentioning

confidence: 99%

Purine metabolism regulates DNA repair and therapy resistance in glioblastoma

et al. 2020

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Intratumoral genomic heterogeneity in glioblastoma (GBM) is a barrier to overcoming therapy resistance. Treatments that are effective independent of genotype are urgently needed. By correlating intracellular metabolite levels with radiation resistance across dozens of genomically-distinct models of GBM, we find that purine metabolites, especially guanylates, strongly correlate with radiation resistance. Inhibiting GTP synthesis radiosensitizes GBM cells and patient-derived neurospheres by impairing DNA repair. Likewise, administration of exogenous purine nucleosides protects sensitive GBM models from radiation by promoting DNA repair. Neither modulating pyrimidine metabolism nor purine salvage has similar effects. An FDA-approved inhibitor of GTP synthesis potentiates the effects of radiation in flank and orthotopic patient-derived xenograft models of GBM. High expression of the rate-limiting enzyme of de novo GTP synthesis is associated with shorter survival in GBM patients. These findings indicate that inhibiting purine synthesis may be a promising strategy to overcome therapy resistance in this genomically heterogeneous disease.

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Association of Maximal Extent of Resection of Contrast-Enhanced and Non–Contrast-Enhanced Tumor With Survival Within Molecular Subgroups of Patients With Newly Diagnosed Glioblastoma

Cited by 342 publications

References 27 publications

Assessment of Pre-operative Measurements of Tumor Size by MRI Methods as Survival Predictors in Wild Type IDH Glioblastoma

Assessment of Pre-operative Measurements of Tumor Size by MRI Methods as Survival Predictors in Wild Type IDH Glioblastoma

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

Purine metabolism regulates DNA repair and therapy resistance in glioblastoma

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