Subventricular Zone Involvement Research Articles

Validation of a methylation-based signature for subventricular zone involvement in glioblastoma

PurposeGlioblastomas (GBM) with subventricular zone (SVZ) contact have previously been associated with a specific epigenetic fingerprint. We aim to validate a reported bulk methylation signature to determine SVZ contact.MethodsMethylation array analysis was performed on IDHwt GBM patients treated at our institution. The v11b4 classifier was used to ensure the inclusion of only receptor tyrosine kinase (RTK) I, II, and mesenchymal (MES) subtypes. Methylation-based assignment (SVZM ±) was performed using hierarchical cluster analysis. Magnetic resonance imaging (MRI) (T1ce) was independently reviewed for SVZ contact by three experienced readers.ResultsSixty-five of 70 samples were classified as RTK I, II, and MES. Full T1ce MRI-based rater consensus was observed in 54 cases, which were retained for further analysis. Epigenetic SVZM classification and SVZ were strongly associated (OR: 15.0, p = 0.003). Thirteen of fourteen differential CpGs were located in the previously described differentially methylated LRBA/MAB21L2 locus. SVZ + tumors were linked to shorter OS (hazard ratio (HR): 3.80, p = 0.02) than SVZM + at earlier time points (time-dependency of SVZM, p < 0.05). Considering the SVZ consensus as the ground truth, SVZM classification yields a sensitivity of 96.6%, specificity of 36.0%, positive predictive value (PPV) of 63.6%, and negative predictive value (NPV) of 90.0%.ConclusionHerein, we validated the specific epigenetic signature in GBM in the vicinity of the SVZ and highlighted the importance of methylation of a part of the LRBA/MAB21L2 gene locus. Whether SVZM can replace MRI-based SVZ assignment as a prognostic and diagnostic tool will require prospective studies of large, homogeneous cohorts.

Histopathologically confirmed radiation-induced damage of the brain – an in-depth analysis of radiation parameters and spatio-temporal occurrence

BackgroundRadiation-induced damage (RID) after radiotherapy (RT) of primary brain tumors and metastases can be challenging to clinico-radiographically distinguish from tumor progression. RID includes pseudoprogression and radiation necrosis; the latter being irreversible and often associated with severe symptoms. While histopathology constitutes the diagnostic gold standard, biopsy-controlled clinical studies investigating RID remain limited. Whether certain brain areas are potentially more vulnerable to RID remains an area of active investigation. Here, we analyze histopathologically confirmed cases of RID in relation to the temporal and spatial dose distribution.MethodsHistopathologically confirmed cases of RID after photon-based RT for primary or secondary central nervous system malignancies were included. Demographic, clinical, and dosimetric data were collected from patient records and treatment planning systems. We calculated the equivalent dose in 2 Gy fractions (EQD22) and the biologically effective dose (BED2) for normal brain tissue (α/β ratio of 2 Gy) and analyzed the spatial and temporal distribution using frequency maps.ResultsThirty-three patients were identified. High-grade glioma patients (n = 18) mostly received one normofractionated RT series (median cumulative EQD22 60 Gy) to a large planning target volume (PTV) (median 203.9 ccm) before diagnosis of RID. Despite the low EQD22 and BED2, three patients with an accelerated hyperfractionated RT developed RID. In contrast, brain metastases patients (n = 15; 16 RID lesions) were often treated with two or more RT courses and with radiosurgery or fractionated stereotactic RT, resulting in a higher cumulative EQD22 (median 162.4 Gy), to a small PTV (median 6.7 ccm). All (n = 34) RID lesions occurred within the PTV of at least one of the preceding RT courses. RID in the high-grade glioma group showed a frontotemporal distribution pattern, whereas, in metastatic patients, RID was observed throughout the brain with highest density in the parietal lobe. The cumulative EQD22 was significantly lower in RID lesions that involved the subventricular zone (SVZ) than in lesions without SVZ involvement (median 60 Gy vs. 141 Gy, p = 0.01).ConclusionsAccelerated hyperfractionated RT can lead to RID despite computationally low EQD22 and BED2 in high-grade glioma patients. The anatomical location of RID corresponded to the general tumor distribution of gliomas and metastases. The SVZ might be a particularly vulnerable area.

MR Imaging, MGMT Promoter Methylation Features and Prognostic Analysis of Subventricular Zone Contacting IDH Wild-type Glioblastoma.

As the largest concentration of neural stem cells in adult brain, the subventricular zone (SVZ) is considered to be a potential source of glioblastoma (GBM) occurrence in recent years. In this study, 116 patients with glioblastoma treated at PLA General Hospital were retrospectively reviewed. The features of SVZ contacting glioblastoma were analyzed in terms of MR imaging and MGMT promoter methylation. We also evaluated the prognostic value of SVZ contacting in GBM patients. GBM with SVZ involvement on MRI is more likely to grow across the midline (36.8% vs. 6.9%, P=0.002), more often multifocal lesion (35.6% vs. 6.9%, P=0.003) and have a lower proportion of MGMT promoter methylation (36.8% vs. 69.0%, P=0.003). The median overall survival and progression- free survival of patients in the SVZ contacting group were 12 months and 7 months, while 25 months and 17 months in the non-contacting group (P<0.001, respectively). There was no significant difference in overall survival (P=0.229) and progression-free survival (P=0.808) between patients with different SVZ contacting regions. Multivariate survival analysis indicated that patients with MRI SVZ involvement showed worse overall survival (HR=2.060, 95%CI 1.195-3.550，P=0.009) and progression- free survival (HR=3.021, 95%CI 1.788-5.104，P＜0.001). This study suggested that MRI SVZ involvement at diagnosis is an independent risk factor for overall survival and progression-free survival in IDH wild-type glioblastoma patients. Based on MR imaging, we also found that SVZ contacting glioblastomas had a larger proportion of crossing midline tumors and multifocal lesions. In addition, patients with SVZ contact in our research presented a lower proportion of MGMT promoter methylation.

Choosing Wisely between Radiotherapy Dose-Fractionation Schedules: The Molecular Graded Prognostic Assessment (molGPA) for Elderly Glioblastoma (eGBM-molGPA)

This study aimed to develop a graded prognostic assessment (GPA) model integrating genomic characteristics in patients with elderly glioblastoma (eGBM), and compare the efficacy between conventionally fractionated radiotherapy (CFRT) vs. hypofractionated radiotherapy (HFRT) in each risk group. Patients aged ≥65 years who underwent surgical resection followed by radiotherapy (RT) with or without temozolomide (TMZ) for newly diagnosed IDH-wildtype eGBM between 2006 and 2021 were included in this multicenter cohort study. Patients who were planned for a ≥6-week or ≤4-week radiotherapy were regarded as being treated with CFRT or HFRT, respectively. Based on the prognostic factors significantly identified through multivariate analysis for overall survival (OS), we developed the molecular GPA for eGBM (eGBM-molGPA) and assigned 0.0, 0.5, and 1.0 points in proportion to the corresponding hazard ratio (HR) of each factor. Then, the survival outcomes by treatment groups were evaluated according to the eGBM-molGPA scores. A total of 334 and 239 patients who underwent CFRT and HFRT were included, respectively, and 86% of patients were treated with TMZ-based chemoradiation. With a median follow-up of 17.4 months for survivors, the median OS was 18.7 months for CFRT plus TMZ group, 15.1 months for HFRT plus TMZ group, and 10.4 months for RT alone group, respectively (all p<0.001). In the multivariate analysis, Karnofsky performance scale, surgical extent, TMZ, and the methylation status of the MGMT promoter were identified as strong prognostic factors for OS, with an estimated HR of greater than 1.5 (all p<0.001). Additionally, subventricular zone involvement, temporalis muscle thickness, RT regimen, and the mutation status of TERT promoter and TP53 gene were found to be significant prognostic factors for OS, with an estimated HR of less than 1.5. The eGBM-molGPA was established based on these prognostic factors (Table 1) and patients were allocated to three risk groups, which included high risk (total score of 3.0-4.5), intermediate risk (1.5-2.5), and low risk (0.0-1.0). Patients treated with CFRT plus TMZ had significantly improved OS compared to those treated with HFRT plus TMZ or RT alone in the low and intermediate risk groups (p<0.001). However, in the high-risk group, there was no significant difference in OS between treatment options (p = 0.770). CFRT plus TMZ can be a more effective strategy for selected eGBM patients compared to HFRT. For high-risk patients, a protracted treatment schedule might not be beneficial. The novel eGBM-molGPA can be used as a clinical tool for choosing wisely among treatment options. Further prospective studies are warranted to establish optimal RT guidelines for eGBM patients.

LMAP-04 CHOOSING WISELY BETWEEN RADIOTHERAPY DOSE-FRACTIONATION SCHEDULES: THE MOLECULAR GRADED PROGNOSTIC ASSESSMENT (MOLGPA) FOR ELDERLY GLIOBLASTOMA (EGBM-MOLGPA)

Abstract This study aimed develop a prognostic model integrating genomic characteristics in patients with elderly glioblastoma (eGBM), and compare the efficacy between conventionally fractionated radiotherapy (CFRT) vs. hypofractionated radiotherapy (HFRT). Patients aged ≥65 years who underwent radiotherapy for IDH-wildtype eGBM between 2006 and 2021 were included. Patients planned for a ≥6-week or ≤4-week radiotherapy were regarded as being treated with CFRT (334 patients; median, 60 Gy in 30 fractions) or HFRT (239 patients; median, 45 Gy in 15 fractions), respectively. We developed the molecular graded prognostic assessment score for eGBM (eGBM-molGPA) and assigned 0.0, 0.5, and 1.0 points in proportion to the corresponding hazard ratio (HR) of each prognostic factor for overall survival (OS). Temozolomide-based chemoradiation was applied for 86% of patients. With a median follow-up of 17.4 months, the median OS was 18.7 months for CFRT plus temozolomide group, 15.1 months for HFRT plus temozolomide group, and 10.4 months for RT alone group. The eGBM-molGPAwas established based on prognostic factors from multivariate analysis (performance, extent of resection, temozolomide, methylation of the MGMT promoter, subventricular zone involvement, temporalis muscle thickness, and the mutation status of TERT promoter and TP53 gene) and patients were allocated to three risk groups (high risk, total score 3.0–4.5; intermediate risk, 1.5–2.5; low risk, 0.0–1.0). Patients treated with CFRT plus temozolomide had significantly improved OS compared to those treated with HFRT plus temozolomide or radiotherapy alone in the low and intermediate risk groups (p&amp;lt;0.001). However, in the high-risk group, there was no significant difference in OS between treatment options. CFRT plus temozolomide can be a more effective strategy for selected eGBM patients compared to HFRT. For high-risk patients, a protracted treatment schedule might not be beneficial. The novel eGBM-molGPA can be used as a clinical tool for choosing wisely among radiotherapy options.

Clinicogenetic characteristics and the effect of radiation on the neural stem cell niche in subventricular zone-contacting glioblastoma

Background and purposeNeural stem cells (NSCs) in the subventricular zone (SVZ) are recognized as the cellular origin of glioblastoma (GBM) and a potential therapeutic target. However, the characteristics of SVZ contacting GBM (SVZ + GBM) and radiotherapeutic strategies for NSCs are still controversial. Here, we investigated the clinicogenetic features of SVZ + GBM and evaluated the dose effect of NSC irradiation depending on SVZ involvement. Materials and methodsWe identified 125 patients with GBM treated with surgery followed by chemoradiotherapy. The genomic profiles were obtained by next-generation sequencing targeting 82 genes. NSCs in the SVZ and hippocampus were contoured using standardized methods, and dosimetric factors were analyzed. SVZ + GBM was defined as GBM with SVZ involvement in a T1 contrast-enhanced image. Progression-free survival (PFS) and overall survival (OS) were used as endpoints. ResultsThe number of patients with SVZ + GBM was 95 (76%). SVZ + GBM showed lower PFS than GBM without SVZ involvement (SVZ-GBM) (median 8.6 vs. 11.5 months, p = 0.034). SVZ contact was not associated with any specific genetic profile but was an independent prognostic factor in multivariate analysis. In SVZ + GBM, patients receiving high doses to the ipsilateral NSC region showed significantly better OS (HR = 1.89, p = 0.011) and PFS (HR = 1.77, p = 0.013). However, in SVZ-GBM, high doses to the ipsilateral NSC region were associated with worse OS (HR = 0.27, p = 0.013) and PFS (HR = 0.37, p = 0.035) in both univariate and multivariate analyses. ConclusionSVZ involvement in GBM was not associated with distinct genetic features. However, irradiation of NSCs was associated with better prognosis in patients with tumors contacting the SVZ.

Prognostic analysis and nomogram construction for older patients with IDH-wild-type glioblastoma

As many countries face an ageing population, the number of older patients with glioblastoma (GB) is increasing. Thus, there is an urgent need for prognostic models to aid in treatment decision-making and life planning. A total of 98 patients with isocitrate dehydrogenase (IDH)-wild-type GB aged ≥65 years were analysed from January 2012 to January 2020. Independent prognostic factors were identified by prognostic analysis. Using the independent prognostic factors for overall survival (OS), a nomogram was constructed by R software to predict the prognosis of older patients with IDH-wild-type GB. The concordance index (C-index) and receiver operating characteristic (ROC) curve were used to assess model discrimination, and the calibration curve was used to assess model calibration. Prognostic analysis showed that the extent of resection (EOR), adjusted Charlson comorbidity index (ACCI), O6-methylguanine-DNA methyltransferase (MGMT) methylation status, postoperative radiotherapy, and postoperative temozolomide (TMZ) chemotherapy were independent prognostic factors for OS. MGMT methylation status and subventricular zone (SVZ) involvement were independent prognostic factors for progression-free survival (PFS). A nomogram was constructed based on EOR, ACCI, MGMT methylation status, postoperative radiotherapy and postoperative TMZ chemotherapy to predict the 6-month, 12-month and 18-month OS of older patients with IDH-wild-type GB. The C-index of the nomogram was 0.72, and the ROC curves showed that the areas under the curve (AUCs) at 6, 12 and 18 months were 0.874, 0.739 and 0.779, respectively. The calibration plots showed that the nomogram was in good agreement with the actual observations in predicting the OS of older patients with IDH-wild-type GB. Older patients with IDH-wild-type GB can benefit from gross total resection (GTR), postoperative radiotherapy and postoperative TMZ chemotherapy. A high ACCI score and MGMT nonmethylation are poor prognostic factors. We constructed a nomogram including the ACCI to facilitate clinical decision-making and follow-up interval selection.

Risk Estimation in Non-Enhancing Glioma: Introducing a Clinical Score.

The preoperative grading of non-enhancing glioma (NEG) remains challenging. Herein, we analyzed clinical and magnetic resonance imaging (MRI) features to predict malignancy in NEG according to the 2021 WHO classification and developed a clinical score, facilitating risk estimation. A discovery cohort (2012-2017, n = 72) was analyzed for MRI and clinical features (T2/FLAIR mismatch sign, subventricular zone (SVZ) involvement, tumor volume, growth rate, age, Pignatti score, and symptoms). Despite a "low-grade" appearance on MRI, 81% of patients were classified as WHO grade 3 or 4. Malignancy was then stratified by: (1) WHO grade (WHO grade 2 vs. WHO grade 3 + 4) and (2) molecular criteria (IDHmut WHO grade 2 + 3 vs. IDHwt glioblastoma + IDHmut astrocytoma WHO grade 4). Age, Pignatti score, SVZ involvement, and T2/FLAIR mismatch sign predicted malignancy only when considering molecular criteria, including IDH mutation and CDKN2A/B deletion status. A multivariate regression confirmed age and T2/FLAIR mismatch sign as independent predictors (p = 0.0009; p = 0.011). A "risk estimation in non-enhancing glioma" (RENEG) score was derived and tested in a validation cohort (2018-2019, n = 40), yielding a higher predictive value than the Pignatti score or the T2/FLAIR mismatch sign (AUC of receiver operating characteristics = 0.89). The prevalence of malignant glioma was high in this series of NEGs, supporting an upfront diagnosis and treatment approach. A clinical score with robust test performance was developed that identifies patients at risk for malignancy.

Defining subventricular zone involvement to predict the survival of patients in isocitrate dehydrogenase-wild type glioblastoma: validation in a prospective registry.

The prognostic value of subventricular zone distance (SVD) is unclear because of different definitions and lack of evaluation of clinical survival models. The aim of this study was to define SVD and evaluate its prognostic value in a survival nomogram for glioblastoma. This retrospective study included 158 (SVD biomarker) from historical glioblastoma patients and 187 (survival modeling) with IDH-wild type glioblastoma from a prospective registry (NCT02619890). SVD was assessed by two radiologists: definition 1, the distance between the tumor edge to subventricular zone (SVZ); definition 2, the distance between the tumor centroid to SVZ; definition 3, enhancement at the ventricular wall. The associations between SVD and overall survival (OS) were evaluated using multivariable Cox proportional hazards regression analysis. Performance of an updated SVD survival model was compared with that of the Radiation Therapy Oncology Group (RTOG) 0525 nomogram. SVD according to both definition 1 (hazard ratio [HR]: 0.97, 95% CI: 0.94-0.99; p = .011) and definition 2 (HR: 0.96, 0.94-0.98, p < .001) was adversely associated with OS. Definition 1 was adversely associated with PFS (HR: 0.96, 0.94-0.99, p = .008) and showed the highest reproducibility (intraclass correlation coefficient, 0.90). The SVD-updated model showed similar to better performance than the RTOG model for predicting OS of up to 3years (AUC: 0.735-0.738 vs. 0.687-0.708), with higher time-dependent specificity for 1-year (89.9% vs. 70.6%) and 3-year OS (93.3% vs. 80.0%). SVZ distance is an independent adverse prognostic factor in patients with IDH-wild type glioblastoma. Updating the survival model with SVZ provides better time-dependent specificity and reproducibility. •Subventricular zone distance (SVD) measurement from tumor edge showed high reproducibility. •Longer SVD was independently associated with longer overall survival. •Adding SVD improved time-dependent specificity for survival model in a prospective registry.

Prognosis prediction for glioblastoma multiforme patients using machine learning approaches: Development of the clinically applicable model

Background and purposeWe aimed to develop a clinically applicable prognosis prediction model predicting overall survival (OS) and progression-free survival (PFS) for glioblastoma multiforme (GBM) patients. Materials and methodsAll 467 patients treated with concurrent chemoradiotherapy at Yonsei Cancer Center from 2016 to 2020 were included in this study. We developed a conventional linear regression, Cox proportional hazards (COX), and non-linear machine learning algorithms, random survival forest (RSF) and survival support vector machine (SVM) based on 16 clinical variables. After backward feature selection and hyperparameter tuning using grid search, we repeated 100 times of cross-validations to combat overfitting and enhance the model performance. Harrell's concordance index (C-index) and integrated brier score (IBS) were employed as quantitative performance metrics. ResultsIn both predictions, RSF performed much better than COX and SVM. (For OS prediction: RSF C-index = 0.72 90%CI [0.71–0.72] and IBS = 0.12 90%CI [0.10–0.13]; For PFS prediction: RSF C-index = 0.70 90%CI [0.70–0.71] and IBS = 0.12 90%CI [0.10–0.14]). Permutation feature importance confirmed that MGMT promoter methylation, extent of resection, age, cone down planning target volume, and subventricular zone involvement are significant prognostic factors for OS. The importance of the extent of resection and MGMT promoter methylation was much higher than other selected input factors in PFS. Our final models accurately stratified two risk groups with root mean square errors less than 0.07. The sensitivity analysis revealed that our final models are highly applicable to newly diagnosed GBM patients. ConclusionOur final models can provide a reliable outcome prediction for individual GBM. The final OS and PFS predicting models we developed accurately stratify high-risk groups up to 5-years, and the sensitivity analysis confirmed that both final models are clinically applicable.

Observation of the delineation of the target volume of radiotherapy in adult-type diffuse gliomas after temozolomide-based chemoradiotherapy: analysis of recurrence patterns and predictive factors

BackgroundRadiation therapy is the cornerstone of treatment for adult-type diffuse gliomas, but recurrences are inevitable. Our study assessed the prognosis and recurrence pattern of different radiotherapy volumes after temozolomide-based chemoradiation in our institution.MethodsThe treatment plans were classified into two groups, the plan 1 intentionally involved the entire edema area while plan 2 did not. Retrospectively investigate the differences in outcomes of 118 adult-type diffuse gliomas patients between these two treatment plans. Then, patients who underwent relapse were selected to analyze their recurrence patterns. Continuous dynamic magnetic resonance images (MRI) were collected to categorized the recurrence patterns into central, in-field, marginal, distant, and cerebrospinal fluid dissemination (CSF-d) recurrence. Finally, the clinical and molecular characteristics which influenced progression were analyzed.ResultsPlan 1 (n = 63) showed a median progression-free survival (PFS) and overall survival (OS) of 9.5 and 26.4 months while plan 2 (n = 55) showed a median PFS and OS of 9.4 and 36.5 months (p = 0.418; p = 0.388). Treatment target volume had no effect on the outcome in patients with adult-type diffuse gliomas. And there was no difference in radiation toxicity (p = 0.388). Among the 90 relapsed patients, a total of 58 (64.4%) patients had central recurrence, 10 (11.1%) patients had in-field recurrence, 3 (3.3%) patients had marginal recurrence, 11 (12.2.%) patients had distant recurrence, and 8 (8.9%) patients had CSF-d recurrence. By treatment plans, the recurrence patterns were similar and there was no significant difference in survival. Reclassifying the progression pattern into local and non-local groups, we observed that oligodendroglioma (n = 10) all relapsed in local and no difference in PFS and OS between the two groups (p > 0.05). Multivariable analysis showed that subventricular zone (SVZ) involvement was the independent risk factor for non-local recurrence in patients with GBM (p < 0.05).ConclusionIn our study, deliberately including or not the entire edema had no impact on prognosis and recurrence. Patients with varied recurrence patterns had diverse clinical and genetic features.

Subventricular Zone Involvement in IDH Mutant Lower-Grade Glioma: Impact on Treatment and Patient Outcome

Subventricular Zone Involvement in IDH Mutant Lower-Grade Glioma: Impact on Treatment and Patient Outcome

The imaging features and prognosis of gliomas involving the subventricular zone: An MRI study

Rationale and objectivesAs the largest concentrated region of neural stem cells in the adult brain, the subventricular zone (SVZ) is considered to have a close relationship with the origin of gliomas. An in-depth study of the characteristic manifestations associated with SVZ involvement in glioma may provide new ideas for individualized diagnosis and treatment of this fatal disease. Materials and methodsAll 279 patients with glioma who underwent surgical treatment in our department from January 2016 to December 2021 were included. Clinical and imaging data were collected, and telephonic follow-up was conducted to analyze the overall survival and progression-free survival. Prognostic factors including SVZ involvement on glioblastoma patients’ survival were analyzed. Next, the relationship between SVZ involvement, a set of unique imaging features and gene status were determined respectively. The chi-squared test, logistics regression, and Cox regression were used for statistical analysis. ResultsThe patients were divided into the SVZ involvement group (n = 198, 70.97 %) and SVZ non-involvement group (n = 81, 29.03 %). The median overall survival and progression-free survival were 13 months and 7 months for the SVZ involvement group, but 25 months and 17 months for the SVZ non-involvement group, respectively. In multivariate Cox survival analysis, MRI SVZ involvement proved an independent risk factor for the survival of patients with glioblastoma. The patients with SVZ involvement sign had a lower rate of cystic lesion (32.32 % vs. 48.48 %, p = 0.029), and a larger mean maximum diameter (5.88 ± 1.28 vs. 3.28 ± 1.65 cm). Compared with high grade gliomas (HGG), T1 enhancement (25.25 % vs. 10.42 %, p = 0.041) and homogeneous signal on T2WI (14.14 % vs. 43.75 %, p = 0.025) were independently associated with SVZ involvement in WHO grade 2 gliomas(LGG). In the gene status analysis, the SVZ involvement group showed the lower rate of MGMT promoter methylation (57.58 % vs. 79.17 %, p = 0.017). ConclusionSVZ involvement in MRI at diagnosis is an independent negative prognostic indicator for the survival of glioblastoma patients. Some image signs are associated with SVZ involvement in HGG and LGG respectively. The unique imaging and gene features of gliomas with SVZ involvement indicate that this kind of tumor maybe a unique subgroup of gliomas.

Clinical features and prognostic significance of tumor involved with subventricular zone in pediatric glioblastoma: a 10-year experience in a single hospital.

Tumors involved with subventricular zone (SVZ) predicted an adverse prognosis had been well proved in adult glioblastoma (GBM). However, we still know less about its impact on children due to the rarity of pediatric glioblastoma (pGBM). We performed this retrospective study to better understand the clinical and prognostic features of pGBM involved with SVZ. Fifty-two patients diagnosed with pGBM at our center between January 2011 and January 2021 were selected for review to demonstrate the characteristics of tumor contacting SVZ. Thirty patients who underwent concurrent chemoradiotherapy and adjuvant chemotherapy postoperatively were selected for survival analysis. Of all the 52 patients, 21 were found to contact SVZ and 31 were not. The median PFS and OS in SVZ + patients were 5.2 and 8.9months, respectively, whereas median PFS and OS were 11.9 and 17.9months, respectively, in SVZ - patients. Multivariate analysis showed that involvement of SVZ was an independent prognostic factor for OS while focality at diagnosis was an independent prognostic factor for PFS. Tumors contacted with SVZ tend to have larger volumes, lower incidence of epilepsy, and lower total resect rate and they were more likely to originate from midline location. Age at diagnosis; gender; adjuvant therapy; focality at diagnosis; focality at relapse; mutational status of H3K27M, MGMT, IDH1, and IDH2; and expression of P53 and ATRX protein failed to characterize SVZ + patients. Involvement of SVZ predicted worse OS in pGBM and it had some distinct clinical features in comparison with those that did not contact with SVZ. Multifocal tumor at diagnosis was related to a shorter PFS. We should make a further step to clarify its molecular features.

Glioblastoma radiotherapy using Intensity modulated Radiotherapy (IMRT) or proton Radiotherapy\u2014GRIPS Trial (Glioblastoma Radiotherapy via IMRT or Proton BeamS): a study protocol for a multicenter, prospective, open-label, randomized, two-arm, phase III study

BackgroundRadiation therapy is an integral part of the multimodal primary therapy of glioblastomas. As the overall prognosis in this tumor entity remains unfavorable, current research is focused on additional drug therapies, which are often accompanied by increases in toxicity. By using proton beams instead of photon beams, it is possible to protect large parts of the brain which are not affected by the tumor more effectively. An initial retrospective matched-pair analysis showed that this theoretical physical benefit is also clinically associated with a reduction in toxicity during therapy and in the first few months thereafter.Methods/designThe GRIPS trial is a multicenter, prospective, open-label, randomized, two-arm, phase III study using either intensity modulated photon radiation techniques (standard arm) or proton beam radiotherapy (experimental arm). Additionally, patients are stratified according to "fractionation scheme" (normofractionated/hypofractionated), "subventricular zone involvement" (yes/no) and concurrent chemotherapy (yes/no) and the planned case number is 326 patients.Radiation therapy is performed with a dose of 30 × 2 Gy(RBE) or 33 × 1.8 Gy(RBE), or for patients treated according to the hypofractionation protocol with 15 × 2.67 Gy(RBE). A possible administration of additional chemotherapy (concurrent or adjuvant) or tumor treating fields is applied in dosage and frequency according to the therapy standard outside of this study. The primary endpoint is the cumulative rate of toxicity CTC grade 2 and higher in the first 4 months. Secondary endpoints include overall survival, progression-free survival, quality of life, and neurocognition.DiscussionAim of the GRIPS study is to prospectively assess whether the theoretical physical advantage of proton beam radiotherapy will translate into a clinical reduction of toxicity during and in the first months after therapy.Trial registrationClinicalTrials (NCT): NCT04752280.

Subventricular zone involvement is associated with worse outcome in glioma WHO grade 2 depending on molecular markers

Neural stem cells within the subventricular zone were identified as cells of origin driving growth of high-grade gliomas, and anatomical involvement of the subventricular zone has been associated with an inferior clinical outcome. Whether the association between poor outcome and subventricular zone involvement also applies to glioma of lower grades is unclear. We therefore analysed a retrospective cohort of 182 patients with glioma grade 2 (according to the WHO 2016 classification) including 78 individuals (43%) with subventricular zone involvement. Patients with and without subventricular zone involvement did not differ in regard to demographics, histopathology, and molecular markers. Notably, subventricular zone involvement was a negative prognostic marker for malignant progression and overall survival on uni- and multivariate analysis. When patients were stratified according to the cIMPACT-NOW update 6, subventricular zone involvement was negatively associated with outcome in IDH-wildtype astrocytomas and 1p19q-codeleted oligodendrogliomas but not in IDH-mutant astrocytomas. Collectively, subventricular zone involvement may represent a risk factor for worse outcome in glioma WHO grade 2 depending on the molecular tumor signature. The present data confirm the relevance of molecular glioma classifications as proposed by the cIMPACT-NOW update 6. These findings warrant evaluation in prospective cohorts.

Combination of the Distance From Tumor Edge to Subventricular Zone and IDH Mutation Predicts Prognosis of Patients With Glioma.

Both subventricular zone (SVZ) contact and isocitrate dehydrogenase 1 (IDH1) mutation have been reported to be related to the outcome of glioma, respectively. However, far too little attention has been paid to the role of tumor edge-SVZ distance in the outcome of glioma. We aim to assess the value of tumor-SVZ distance, as well as combined tumor-SVZ distance and IDH status, in predicting the outcome of gliomas (WHO grade II–IV). Here, the MR images and clinical data from 146 patients were included in the current study. The relationship between survival and the tumor-SVZ distance as well as survival and combination of tumor-SVZ distance and IDH status were determined via univariate and multivariate analyses. In univariate analysis of tumor-SVZ distance, the patients were divided into three types (SVZ involvement, tumor-SVZ distance from 0 to 10 mm, and tumor-SVZ distance >10 mm). The results showed that the OS (p = 0.02) and PFS (p = 0.002) for the patients had a positive correlation with the tumor-SVZ distance. In addition, simple linear correlation found a significant relationship between the two parameters (OS and PFS) and tumor-SVZ distance in patients with non-SVZ-contacting glioma. Combination analysis of the tumor-SVZ distance and IDH status showed that IDH1 mutation and SVZ non-involvement enable favorable outcomes, whereas IDH1 wild type with SVZ involvement indicates a significantly worse prognosis in all patients. Moreover, in patients with non-SVZ-contacting glioma, IDH1 mutation concurrent with tumor-SVZ distance >10 mm has better OS and PFS. IDH1 wild type and tumor-SVZ distance from 0 to 10 mm suggest poorer OS and PFS. Multivariate analysis showed WHO grade IV, SVZ involvement, tumor-SVZ distance from 0 to 10 mm, IDH1 mutation, gross total resection, and chemotherapy serve as independent predictors of OS. WHO grade IV, SVZ involvement, tumor-SVZ distance from 0 to 10 mm, IDH1 mutation, and chemotherapy serve as independent predictors of PFS of patients with glioma. In conclusion, tumor-SVZ distance and IDH1 mutation status are the determinants affecting patient outcome.

Glioblastomas within the Subventricular Zone Are Region-Specific Enriched for Mesenchymal Transition Markers: An Intratumoral Gene Expression Analysis.

Simple SummaryInvolvement of the subventricular zone (SVZ) in glioblastoma is associated with poor prognosis and is associated with specific tumor-biological characteristics. In this study, we demonstrate that patient-derived glioblastoma samples from within the SVZ region show increased (epithelial-)mesenchymal transition and angiogenesis/hypoxia signaling as compared to glioblastoma samples from the same patient from outside the SVZ. These results suggest that intratumoral alterations in oncogenic signaling could be mediated by the SVZ microenvironment. Our findings offer rationale for specific targeting of the SVZ in the development of glioblastoma therapy.Background: Involvement of the subventricular zone (SVZ) in glioblastoma is associated with poor prognosis and is associated with specific tumor-biological characteristics. The SVZ microenvironment can influence gene expression in glioblastoma cells in preclinical models. We aimed to investigate whether the SVZ microenvironment has any influence on intratumoral gene expression patterns in glioblastoma patients. Methods: The publicly available Ivy Glioblastoma database contains clinical, radiological and whole exome sequencing data from multiple regions from resected glioblastomas. SVZ involvement of the various tissue samples was evaluated on MRI scans. In tumors that contacted the SVZ, we performed gene expression analyses and gene set enrichment analyses to compare gene (set) expression in tumor regions within the SVZ to tumor regions outside the SVZ. We also compared these samples to glioblastomas that did not contact the SVZ. Results: Within glioblastomas that contacted the SVZ, tissue samples within the SVZ showed enrichment of gene sets involved in (epithelial-)mesenchymal transition, NF-κB and STAT3 signaling, angiogenesis and hypoxia, compared to the samples outside of the SVZ region from the same tumors (p < 0.05, FDR < 0.25). Comparison of glioblastoma samples within the SVZ region to samples from tumors that did not contact the SVZ yielded similar results. In contrast, we observed no differences when comparing the samples outside of the SVZ from SVZ-contacting glioblastomas with samples from glioblastomas that did not contact the SVZ at all. Conclusion: Glioblastoma samples in the SVZ region are enriched for increased (epithelial-)mesenchymal transition and angiogenesis/hypoxia signaling, possibly mediated by the SVZ microenvironment.

Magnetic Resonance Features of Lower-grade Gliomas in Prediction of the Reverse Phase Protein A.

The Cancer Genome Atlas Research Network identified 4 novel protein expression-defined subgroups in patients with lower-grade gliomas (LGGs). The RPPA3 subtype had high levels of Epidermal Growth Factor Receptor and Human epidermal growth factor receptor-2, further increasing the chances for targeted therapy. In this study, we aimed to explore the relationships between magnetic resonance features and reverse phase protein array (RPPA) subtypes (R1-R4). Survival estimates for the Cancer Genome Atlas cohort were generated using the Kaplan-Meier method and time-dependent receiver operating characteristic curves. A total of 153 patients with LGG with brain magnetic resonance imaging from The Cancer Imaging Archive were retrospectively analyzed. Least absolute shrinkage and selection operator algorithm was used to reduce the feature dimensions of the RPPA3 subtype. A total of 51 (33.3%) RPPA1 subtype, 42 (27.4) RPPA2 subtype, 19 (12.4%) RPPA3 subtype, and 38 (24.8%) RPPA4 subtype were identified. On multivariate logistic regression analysis, subventricular zone involvement [odds ratio (OR), 0.370; P = 0.006; 95% confidence interval (CI), 0.181-0.757) was associated with RPPA1 subtype [area under the curve (AUC), 0.598]. Volume of 60 cm3 or greater (OR, 5.174; P < 0.001; 95% CI, 2.182-12.267) was associated with RPPA2 subtype (AUC, 0.684). Proportion contrast-enhanced tumor greater than 5% (OR, 4.722; P = 0.010; 95% CI, 1.456-15.317), extranodular growth (OR, 5.524; P = 0.010; 95% CI, 1.509-20.215), and L/CS ratio equal to or greater than median (OR, 0.132; P = 0.003; 95% CI, 0.035-0.500) were associated with RPPA3 subtype (AUC, 0.825). Proportion contrast-enhanced tumor greater than 5% (OR, 0.206; P = 0.005; 95% CI, 0.068-0.625) was associated with RPPA4 subtype (AUC, 0.638). For the prediction of RPPA3 subtype, the nomogram showed good discrimination, with an AUC of 0.825 (95% CI, 0.711-0.939) and was well calibrated. The RPPA3 subtype was associated with shortest mean overall survival (RPPA3 subtype vs other: 613 vs 873 days; P < 0.05). The time-dependent receiver operating characteristic curves for the RPPA3 subtype was 0.72 (95% CI, 0.60-0.84) for survival at 1 year. Decision curve analysis indicated that prediction for the RPPA3 model was clinically useful. The RPPA3 subtype is an unfavorable prognostic biomarker for overall survival in patients with LGG. Radiogenomics analysis of magnetic resonance features can predict the RPPA subtype preoperatively and may be of clinical value in tailoring the management strategies in patients with LGG.

BIOM-15. SUBVENTRICULAR ZONE INVOLVEMENT IS ASSOCIATED WITH WORSE OUTCOME IN GLIOMA WHO GRADE II INDEPENDENT OF MOLECULAR MARKERS

Abstract BACKGROUND The subventricular zone represents a niche of adult neural stem cells. Involvement of the subventricular zone is associated with decreased survival in malignant glioma. We aimed to determine whether a similar association applies to low-grade gliomas. METHODS A retrospective institutional database search was performed for patients with glioma WHO grade II according to the 2016 classification. Demographic data, histology and molecular signature, imaging, and therapy were recorded and outcome was analysed for tumors with and without infiltration of the subventricular zone. RESULTS 182 patients with glioma WHO grade II were identified, including 97 oligodendrogliomas and 85 astrocytomas. 78 of 182 patients (43%) presented with subventricular zone involvement. Demographics, histopathology, and molecular signature did not differ between patients with and without subventricular zone involvement. First-line management included surgery, chemotherapy, radiotherapy, brachytherapy, and wait-and-scan approaches. Median follow-up was 43 months. Median time to malignant progression was 122 months; median overall survival was not reached. Subventricular zone involvement was a negative prognostic marker for time to malignant progression (p = 0.002) and overall survival (p = 0.023) in the entire cohort as well as in the subgroup of patients who were managed with wait-and-scan approaches. Among patients in which early therapy was provided, subventricular zone involvement was not prognostic for overall survival but for time to malignant progression. In multivariate analysis, subventricular zone involvement was associated with worse prognosis independent of molecular markers or treatment approaches including use of resection. CONCLUSION Subventricular zone involvement represents a key risk factor for worse outcome in glioma WHO grade II. Early first-line therapy may improve outcome in such patients.