Association Between the Extent of Resection and Prognosis in Adult Patients With WHO Grade III Gliomas: a Population-based Study

PurposeThe role of surgical resection in the treatment of anaplastic glioma is poorly understood. The aim of the present retrospective study was to clarify the survival of patients with anaplastic gliomas.MethodsWe utilized the SEER database to assess the association between prognostic and demographic data, tumor characteristics, and treatment factors in adult patients with anaplastic glioma. Overall survival and cause-specific survival were analyzed using multivariable Cox regression and competing risk regression, respectively.ResultsA total of 3979 patients with anaplastic glioma who had undergone surgical intervention were included in the analysis. Patients who underwent gross total resection (GTR) had significantly better 5-year and 10-year overall survival (OS) (59.9% vs. 44.0%, 45.0% vs. 29.4%, p < 0.001) than those who did not. The 5-year and 10-year cumulative incidence rates of cancer-specific death in the GTR group were lower than those in the corresponding N-GTR group (36.6% vs.51.9%, 49.9% vs. 65.5%, p < 0.001). Multivariable analysis identified GTR as an independent significant predictor for prolonged OS (HR:0.72; 95% confidence interval [CI] 0.65-0.79, P<0.05) and cause-specific survival (CSS) (HR:0.72, 95% CI 0.65-0.80, P<0.05).Further subgroup analysis revealed a stable association between the extent of resection and OS (P values for interaction >0.05), except for tumor location and histologic type groups.ConclusionsWhile the survival of patients with anaplastic glioma remains poor, GTR is associated with increased OS and CSS compared to N-GTR.

NIMG-29. ELEVATION OF GLUTAMINE AND CITRATE BY MR SPECTROSCOPY IS AN IMAGING BIOMARKER OF RAPID CELL PROLIFERATION IN GLIOMAS

Prior studies suggested glutamine metabolism in cancers may be altered to meet the high demands of nucleotide biosynthesis in cancers. We conducted 1H MR spectroscopy in 18 glioma patients and analyzed the metabolic data together with post-gadolinium MRI and cell proliferation rate (MIB-1 label index). The optimized MRS (TE 97 ms PRESS) provided well discernible signal of glutamine at 2.45 ppm and a negative-polarity signal of citrate at 2.6 ppm, without considerable overlaps with neighboring signals. The 18 patients had biopsy-proven anaplastic gliomas or glioblastomas. Concurrent elevation of glutamine and citrate was identified in 15 gliomas. These gliomas presented with enhancement in post-gadolinium MRI, indicative of broken blood-brain barrier (BBB). The 15 gliomas were grouped as subset-1 while the other 3 gliomas that had elevated citrate without elevation of glutamine were grouped as subset-2. Citrate level was significantly different between the two subsets of gliomas (1.4+/-0.5 vs. 1.6+/-0.4 mM). However, subst-1 had significantly higher choline (4.7+/-1.8 vs. 1.6+/-0.3 mM, p&lt; 0.01) and higher MIB-1 compared with subset-2. Given that choline is a cellularity marker, a finding of high choline and high MIB-1 with elevation of glutamine and citrate suggests that the tumors have high tumor cellularity and cell multiplication competence. Of the 18 gliomas, 13 were IDH mutated with elevated 2HG. The glutamine and citrate levels in IDH-mutant gliomas were not significantly different from those in IDH wildtype gliomas. In conclusion, high-grade gliomas undergo a metabolic rearrangement of concurrent elevation of glutamine and citrate to attain malignant characters such as high cellularity, rapid cell proliferation, and BBB breakdown. IDH mutant and IDH wildtype gliomas may share a common metabolic rearrangement of glutamine-mediated citrate elevation to attain malignancy. Measurements of glutamine and citrate may serve a potential imaging biomarker for aggressive gliomas.

KS02.4.A Olaparib in Recurrent IDH-mutant High-Grade Glioma (OLAGLI)

BACKGROUND There is a need to develop new treatments in IDH-mutant high-grade gliomas recurring after radiotherapy and chemotherapy. Based on preclinical studies showing that IDH-mutant tumors could be vulnerable to PARP inhibition we launched a phase II study to test the efficacy of olaparib (Lynparza) monotherapy in this population. METHODS Adults with recurrent high-grade IDH-mutant gliomas after radiotherapy and at least one line of alkylating chemotherapy (PCV or TMZ), KPS &gt; 60, normal organ function were enrolled. The primary endpoint was 6 months PFS according to RANO criteria. Patients were treated with olaparib 300 mg twice daily. We used a single-stage Fleming design with p0 = 30%, p1 = 50%, a type I unilateral error rate of 5% and a power of 80%. RESULTS 35 patients with recurrent IDH-mutant gliomas (IDH1R132H-mutant n = 32, other IDH mutation n = 3, 1p/19 codeleted n = 16, 1p/19q non-codeleted n = 14) were enrolled (malignantly transformed low-grade gliomas n = 21, anaplastic gliomas n = 8, glioblastomas n = 6). Median time since diagnosis was 7.4 years (1–22 years), median time since radiotherapy was 2.8 years (0.6–18 years), median number of previous chemotherapy lines was 2 (1–5). With a median follow-up of 11 months, 30 patients had stopped treatment due to tumor progression and 2 patients were still on treatment 16 to 18 months after treatment start. At 6 months, 11/35 patients were progression-free (31 %). According to RANO criteria, based on local investigator analysis, 2 patients (5%) had a partial response and 14 patients a stable disease (37%) with a median duration of response of 9 months (4–18+). Median PFS and OS were 2.3 and 15.9 months and were similar in 1p/19q codeleted and non-codeleted patients. A grade 3 olaparib-related adverse event was observed in 5 patients (14%, lymphopenia n = 3, fatigue n = 2, diarrhea n = 1) and a grade 2 in 15 patients (43%), most frequently consisting in fatigue (23%), gastrointestinal disorders (20%) and lymphopenia (20%). No patient definitively stopped olaparib due to side effects. CONCLUSIONS In this heavily pre-treated population of recurrent IDH-mutant gliomas, olaparib monotherapy was well tolerated and resulted in some activity supporting its evaluation in association with alkylating chemotherapy in recurrent IDH-mutant gliomas in future studies.

CALD1 Modulates Gliomas Progression via Facilitating Tumor Angiogenesis

Angiogenesis is more prominent in anaplastic gliomas and glioblastoma (GBM) than that in pilocytic and diffuse gliomas. Caldesmon (CALD1) plays roles in cell adhesion, cytoskeletal organization, and vascularization. However, limited information is available on mechanisms underlying the effect of CALD1 on the microvascular facilitation and architecture in glioma. In this study, we explored the role of CALD1 in gliomas by integrating bulk RNA-seq analysis and single cell RNA-seq analysis. A positive correlation between CALD1 expression and the gliomas’ pathological grade was noticed, according to the samples from the TCGA and CGGA database. Moreover, higher CALD1 expression samples showed worse clinical outcomes than lower CALD1 expression samples. Biofunction prediction suggested that CALD1 may affect glioma progression through modulating tumor angiogenesis. The map of the tumor microenvironment also depicted that more stromal cells, such as endothelial cells and pericytes, infiltrated in high CALD1 expression samples. CALD1 was found to be remarkably upregulated in neoplastic cells and was involved in tumorigenic processes of gliomas in single cell sequencing analysis. Histology and immunofluorescence analysis also indicated that CALD1 associates with vessel architecture, resulting in glioma grade progression. In conclusion, the present study implies that CALD1 may serve as putative marker monitoring the progress of glioma.

Olaparib in recurrent IDH-mutant high-grade glioma (OLAGLI).

2007 Background: There is a need to develop new treatments in IDH-mutant high-grade gliomas recurring after radiotherapy and chemotherapy. Based on preclinical studies showing that IDH-mutant tumors could be vulnerable to PARP inhibition we launched a phase II study to test the efficacy of olaparib (Lynparza) monotherapy in this population. Methods: Adults with recurrent high-grade IDH-mutant gliomas after radiotherapy and at least one line of alkylating chemotherapy (PCV or TMZ), KPS > 60, normal organ function were enrolled. The primary endpoint was 6 months PFS according to RANO criteria. Patients were treated with olaparib 300 mg twice daily. We used a single-stage Fleming design with p0 = 30%, p1 = 50%, a type I unilateral error rate of 5% and a power of 80%. Results: 35 patients with recurrent IDH-mutant gliomas (IDH1R132H-mutant n = 32, other IDH mutation n = 3, 1p/19 codeleted n = 16, 1p/19q non-codeleted n = 14) were enrolled (malignantly transformed low-grade gliomas n = 21, anaplastic gliomas n = 8, glioblastomas n = 6). Median time since diagnosis was 7.4 years (1-22 years), median time since radiotherapy was 2.8 years (0.6-18 years), median number of previous chemotherapy lines was 2 (1-5). With a median follow-up of 11 months, 30 patients had stopped treatment due to tumor progression and 2 patients were still on treatment 16 to 18 months after treatment start. At 6 months, 11/35 patients were progression-free (31 %). According to RANO criteria, based on local investigator analysis, 2 patients (5%) had a partial response and 14 patients a stable disease (37%) with a median duration of response of 9 months (4-18 months+). Median PFS and OS were 2.3 and 15.9 months and were similar in 1p/19q codeleted and non-codeleted patients. A grade 3 olaparib-related adverse event was observed in 5 patients (14%, lymphopenia n = 3, fatigue n = 2, diarrhea n = 1) and a grade 2 in 15 patients (43%), most frequently consisting in fatigue (23%), gastrointestinal disorders (20%) and lymphopenia (20%). No patient definitively stopped olaparib due to side effects. Conclusions: In this heavily pre-treated population of recurrent IDH-mutant gliomas, olaparib monotherapy was well tolerated and resulted in some activity supporting its evaluation in association with alkylating chemotherapy in recurrent IDH-mutant gliomas in future studies. Clinical trial information: NCT03561870.

Hypoxia and Microvascular Alterations Are Early Predictors of IDH-Mutated Anaplastic Glioma Recurrence

Anaplastic gliomas (AG) represents aggressive brain tumors that often affect young adults. Although isocitrate-dehydrogenase (IDH) gene mutation has been identified as a more favorable prognostic factor, most IDH-mutated AG patients are confronted with tumor recurrence. Hence, increased knowledge about pathophysiological precursors of AG recurrence is urgently needed in order to develop precise diagnostic monitoring and tailored therapeutic approaches. In this study, 142 physiological magnetic resonance imaging (phyMRI) follow-up examinations in 60 AG patients after standard therapy were evaluated and magnetic resonance imaging (MRI) biomarker maps for microvascular architecture and perfusion, neovascularization activity, oxygen metabolism, and hypoxia calculated. From these 60 patients, 34 patients developed recurrence of the AG, and 26 patients showed no signs for AG recurrence during the study period. The time courses of MRI biomarker changes were analyzed regarding early pathophysiological alterations over a one-year period before radiological AG recurrence or a one-year period of stable disease for patients without recurrence, respectively. We detected intensifying local tissue hypoxia 250 days prior to radiological recurrence which initiated upregulation of neovascularization activity 50 to 70 days later. These changes were associated with a switch from an avascular infiltrative to a vascularized proliferative phenotype of the tumor cells another 30 days later. The dynamic changes of blood perfusion, microvessel density, neovascularization activity, and oxygen metabolism showed a close physiological interplay in the one-year period prior to radiological recurrence of IDH-mutated AG. These findings may path the wave for implementing both new MR-based imaging modalities for routine follow-up monitoring of AG patients after standard therapy and furthermore may support the development of novel, tailored therapy options in recurrent AG.