MRI Scoring Systems for Predicting Isocitrate Dehydrogenase Mutation and Chromosome 1p/19q Codeletion in Adult-type Diffuse Glioma Lacking Contrast Enhancement.

Background According to 2021 World Health Organization criteria, adult-type diffuse gliomas include glioblastoma, isocitrate dehydrogenase (IDH)-wildtype; oligodendroglioma, IDH-mutant and 1p/19q-codeleted; and astrocytoma, IDH-mutant, even when contrast enhancement is lacking. Purpose To develop and validate simple scoring systems for predicting IDH and subsequent 1p/19q codeletion status in gliomas without contrast enhancement using standard clinical MRI sequences. Materials and Methods This retrospective study included adult-type diffuse gliomas lacking contrast at contrast-enhanced MRI from two tertiary referral hospitals between January 2012 and April 2022 with diagnoses confirmed at pathology. IDH status was predicted primarily by using T2-fluid-attenuated inversion recovery (FLAIR) mismatch sign, followed by 1p/19q codeletion prediction. A visual rating of MRI features, apparent diffusion coefficient (ADC) ratio, and relative cerebral blood volume was measured. Scoring systems were developed through univariable and multivariable logistic regressions and underwent calibration and discrimination, including internal and external validation. Results For the internal validation cohort, 237 patients were included (mean age, 44.4 years ± 14.4 [SD]; 136 male patients; 193 patients in IDH prediction and 163 patients in 1p/19q prediction). For the external validation cohort, 35 patients were included (46.1 years ± 15.3; 20 male patients; 28 patients in IDH prediction and 24 patients in 1p/19q prediction). The T2-FLAIR mismatch sign demonstrated 100% specificity and 100% positive predictive value for IDH mutation. IDH status prediction scoring system for tumors without mismatch sign included age, ADC ratio, and morphologic characteristics, whereas 1p/19q codeletion prediction for IDH-mutant gliomas included ADC ratio, cortical involvement, and mismatch sign. For IDH status and 1p/19q codeletion prediction, bootstrap-corrected areas under the receiver operating characteristic curve were 0.86 (95% CI: 0.81, 0.90) and 0.73 (95% CI: 0.65, 0.81), respectively, whereas at external validation they were 0.99 (95% CI: 0.98, 1.0) and 0.88 (95% CI: 0.63, 1.0). Conclusion The T2-FLAIR mismatch sign and scoring systems using standard clinical MRI predicted IDH and 1p/19q codeletion status in gliomas lacking contrast enhancement. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Badve and Hodges in this issue.

Epigenetic Alteration of H3K27me3 as a Possible Oncogenic Mechanism of Central Neurocytoma.

Central neurocytoma (CN) is a low-grade neuronal tumor that mainly arises from the lateral ventricle (LV). This tumor remains poorly understood in the sense that no driver gene aberrations have been identified thus far. We investigated immunomarkers in fetal and adult brains and 45 supratentorial periventricular tumors to characterize the biomarkers, cell of origin, and tumorigenesis of CN. All CNs occurred in the LV. A minority involved the third ventricle, but none involved the fourth ventricle. As expected, next-generation sequencing performed using a brain-tumor-targeted gene panel in 7 CNs and whole exome sequencing in 5 CNs showed no driver mutations. Immunohistochemically, CNs were robustly positive for FGFR3 (100%), SSTR2 (92%), TTF-1 (Nkx2.1) (88%), GLUT-1 (84%), and L1CAM (76%), in addition to the well-known markers of CN, synaptophysin (100%) and NeuN (96%). TTF-1 was also positive in subependymal giant cell astrocytomas (100%, 5/5) and the pituicyte tumor family, including pituicytoma and spindle cell oncocytoma (100%, 5/5). Interestingly, 1 case of LV subependymoma (20%, 1/5) was positive for TTF-1, but all LV ependymomas were negative (0/5 positive). Because TTF-1-positive cells were detected in the medial ganglionic eminence around the foramen of Monro of the fetal brain and in the subventricular zone of the LV of the adult brain, CN may arise from subventricular TTF-1-positive cells undergoing neuronal differentiation. H3K27me3 loss was observed in all CNs and one case (20%) of LV subependymoma, suggesting that chromatin remodeling complexes or epigenetic alterations may be involved in the tumorigenesis of all CNs and some ST-subependymomas. Further studies are required to determine the exact tumorigenic mechanism of CN.

Fully Automated MRI Segmentation and Volumetric Measurement of Intracranial Meningioma Using Deep Learning.

BACKGROUND: Accurate and rapid measurement of the MRI volume of meningiomas is essential in clinical practice to determine the growth rate of the tumor. Imperfect automation and disappointing performance for small meningiomas of previous automated volumetric tools limit their use in routine clinical practice. PURPOSE: To develop and validate a computational model for fully automated meningioma segmentation and volume measurement on contrast-enhanced MRI scans using deep learning. STUDY TYPE: Retrospective. POPULATION: A total of 659 intracranial meningioma patients (median age, 59.0 years; interquartile range: 53.0-66.0 years) including 554 women and 105 men. FIELD STRENGTH/SEQUENCE: The 1.0 T, 1.5 T, and 3.0 T; three-dimensional, T1 -weighted gradient-echo imaging with contrast enhancement. ASSESSMENT: The tumors were manually segmented by two neurosurgeons, H.K. and C.-K.P., with 10 and 26 years of clinical experience, respectively, for use as the ground truth. Deep learning models based on U-Net and nnU-Net were trained using 459 subjects and tested for 100 patients from a single institution (internal validation set [IVS]) and 100 patients from other 24 institutions (external validation set [EVS]), respectively. The performance of each model was evaluated with the Sørensen-Dice similarity coefficient (DSC) compared with the ground truth. STATISTICAL TESTS: According to the normality of the data distribution verified by the Shapiro-Wilk test, variables with three or more categories were compared by the Kruskal-Wallis test with Dunn's post hoc analysis. RESULTS: A two-dimensional (2D) nnU-Net showed the highest median DSCs of 0.922 and 0.893 for the IVS and EVS, respectively. The nnU-Nets achieved superior performance in meningioma segmentation than the U-Nets. The DSCs of the 2D nnU-Net for small meningiomas less than 1 cm3 were 0.769 and 0.780 with the IVS and EVS, respectively. DATA CONCLUSION: A fully automated and accurate volumetric measurement tool for meningioma with clinically applicable performance for small meningioma using nnU-Net was developed. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 2.

The Warburg effect in patients with brain tumors: a comprehensive analysis of clinical significance.

PURPOSE: The Warburg Effect, referring to an elevation in serum lactate level attributable to increased tumor metabolism, is present in patients with brain tumors. This study comprehensively analyzes the Warburg effect in patients undergoing brain tumor resection. METHODS: We retrospectively analyzed the baseline intraoperative serum lactate levels of 2,053 patients who underwent craniotomies, including 415 with cerebral aneurysms and 1,638 with brain tumors. The brain tumor group was divided into subgroups based on the tumor pathology (extra-axial and intra-axial tumor) and the WHO tumor grade (high-grade and low-grade). RESULTS: Serum lactate level was significantly higher in the tumor group than in the aneurysm group (1.98 ± 0.97 vs. 1.09 ± 0.57 mmol/L, p < 0.001). The hyperlactatemia incidence (serum lactate level > 2.2 mmol/L) was higher in the tumor group (33.5 vs. 3.1%, p < 0.001). Severe hyperlactatemia (serum lactate level > 4.4 mmol/L) was found in 34 patients (2.1%) of only the tumor group. In patients with intra-axial tumors, serum lactate level was greater in high- than low-grade tumors (2.10 ± 1.05 vs. 1.88 ± 0.92 mmol/L, p = 0.006). Factors predictive of hyperlactatemia included supratentorial tumor location (odds ratio[95%CI] 2.926[2.127-4.025], p < 0.001) and a long tumor diameter (1.071[1.007-1.139], p = 0.028). In high-grade intra-axial brain tumor patients, there was a significant difference in overall survival between patients with hyperlactatemia than those without (p = 0.048). CONCLUSION: Our results show that brain tumor patients exhibit the Warburg effect and serum lactate may be a useful diagnostic and prognostic biomarker in patients with high-grade intra-axial brain tumors.

Involvement of cell shape and lipid metabolism in glioblastoma resistance to temozolomide.

Temozolomide (TMZ) has been used as standard-of-care for glioblastoma multiforme (GBM), but the resistance to TMZ develops quickly and frequently. Thus, more studies are needed to elucidate the resistance mechanisms. In the current study, we investigated the relationship among the three important phenotypes, namely TMZ-resistance, cell shape and lipid metabolism, in GBM cells. We first observed the distinct difference in cell shapes between TMZ-sensitive (U87) and resistant (U87R) GBM cells. We then conducted NMR-based lipid metabolomics, which revealed a significant increase in cholesterol and fatty acid synthesis as well as lower lipid unsaturation in U87R cells. Consistent with the lipid changes, U87R cells exhibited significantly lower membrane fluidity. The transcriptomic analysis demonstrated that lipid synthesis pathways through SREBP were upregulated in U87R cells, which was confirmed at the protein level. Fatostatin, an SREBP inhibitor, and other lipid pathway inhibitors (C75, TOFA) exhibited similar or more potent inhibition on U87R cells compared to sensitive U87 cells. The lower lipid unsaturation ratio, membrane fluidity and higher fatostatin sensitivity were all recapitulated in patient-derived TMZ-resistant primary cells. The observed ternary relationship among cell shape, lipid composition, and TMZ-resistance may be applicable to other drug-resistance cases. SREBP and fatostatin are suggested as a promising target-therapeutic agent pair for drug-resistant glioblastoma.

Subcellular progression of mesenchymal transition identified by two discrete synchronous cell lines derived from the same glioblastoma.

Glioblastomas (GBM) exhibit intratumoral heterogeneity of various oncogenic evolutional processes. We have successfully isolated and established two distinct cancer cell lines with different morphological and biological characteristics that were derived from the same tissue sample of a GBM. When we compared their genomic and transcriptomic characteristics, each cell line harbored distinct mutation clusters while sharing core driver mutations. Transcriptomic analysis revealed that one cell line was undergoing a mesenchymal transition process, unlike the other cell line. Furthermore, we could identify four tumor samples containing our cell line-like clusters from the publicly available single-cell RNA-seq data, and in a set of paired longitudinal GBM samples, we could confirm three pairs where the recurrent sample was enriched in the genes specific to our cell line undergoing mesenchymal transition. The present study provides direct evidence and a valuable source for investigating the ongoing process of subcellular mesenchymal transition in GBM, which has prognostic and therapeutic implications.

Comparison of the clinical features and treatment outcomes of pilocytic astrocytoma in pediatric and adult patients.

PURPOSE: Pilocytic astrocytoma is a slow-growing tumor that predominantly develops in children, but has a broad age spectrum. A notable characteristic of pilocytic astrocytoma is that the tumor arises in diverse locations and the clinical course is not always benign. Therefore, it is necessary to elucidate the clinical spectrum of the disease and analyze the relevant prognostic factors. METHODS: Demographic and treatment-related factors were retrospectively reviewed in a cohort of 254 patients with histologically confirmed pilocytic astrocytoma. Clinical features were compared between the pediatric group (N = 208; age < 18 years) and the adult group (N = 46; age ≥ 18 years). Cox regression analysis was performed to identify relevant prognostic factors. RESULTS: There was no difference in progression-free survival (PFS) between the pediatric and adult groups (p = 0.36); however, patients under 8 years of age exhibited worse PFS (p < 0.01). Leptomeningeal seeding at diagnosis and pilomyxoid histology was observed only in pediatric patients. In the pediatric group, nine patients experienced recurrence after complete resection. Increasing age (hazard ratio (HR) = 0.89, p < 0.01) and adjuvant therapy (HR = 0.32, p < 0.01) were protective factors against tumor progression. In the adult group, no progression occurred after complete resection. Age and adjuvant therapy were not significant factors in the adult group. CONCLUSION: Pilocytic astrocytoma presents with a diverse clinical spectrum. Complete resection is of utmost importance, and appropriate adjuvant treatment is recommended if complete resection cannot be achieved. Children with younger age are associated with more aggressive tumors, and recurrence may occur even after complete resection.

Sporadic and Lynch syndrome-associated mismatch repair-deficient brain tumors.

Mismatch repair-deficient (MMRD) brain tumors are rare among primary brain tumors and can be induced by germline or sporadic mutations. Here, we report 13 MMRD-associated (9 sporadic and 4 Lynch syndrome) primary brain tumors to determine clinicopathological and molecular characteristics and biological behavior. Our 13 MMRD brain tumors included glioblastoma (GBM) IDH-wildtype (n = 9) including 1 gliosarcoma, astrocytoma IDH-mutant WHO grade 4 (n = 2), diffuse midline glioma (DMG) H3 K27M-mutant (n = 1), and pleomorphic xanthoastrocytoma (PXA) (n = 1). Next-generation sequencing using a brain tumor-targeted gene panel, microsatellite instability (MSI) testing, Sanger sequencing for germline MMR gene mutation, immunohistochemistry of MMR proteins, and clinicopathological and survival analysis were performed. There were many accompanying mutations, suggesting a high tumor mutational burden (TMB) in 77%, but TMB was absent in one case of GBM, IDH-wildtype, DMG, and PXA, respectively. MSH2, MLH1, MSH6, and PMS2 mutations were found in 31%, 31%, 31% and 7% of patients, respectively. MSI-high and MSI-low were found in 50% and 8% of these gliomas, respectively and 34% was MSI-stable. All Lynch syndrome-associated GBMs had MSI-high. In addition, 77% (10/13) had histopathologically multinucleated giant cells. The progression-free survival tended to be poorer than the patients with no MMRD gliomas, but the number and follow-up duration of our patients were insufficient to get statistical significance. In the present study, we found that the most common MMRD primary brain tumor was GBM IDH-wildtype. The genetic profile of MMRD GBM was different from that of conventional GBM. MMRD gliomas with TMB and MSI-H may be sensitive to immunotherapy but resistant to temozolomide. Our findings can help develop better treatment options.

Modulation of Nogo receptor 1 expression orchestrates myelin-associated infiltration of glioblastoma.

As the clinical failure of glioblastoma treatment is attributed by multiple components, including myelin-associated infiltration, assessment of the molecular mechanisms underlying such process and identification of the infiltrating cells have been the primary objectives in glioblastoma research. Here, we adopted radiogenomic analysis to screen for functionally relevant genes that orchestrate the process of glioma cell infiltration through myelin and promote glioblastoma aggressiveness. The receptor of the Nogo ligand (NgR1) was selected as the top candidate through Differentially Expressed Genes (DEG) and Gene Ontology (GO) enrichment analysis. Gain and loss of function studies on NgR1 elucidated its underlying molecular importance in suppressing myelin-associated infiltration in vitro and in vivo. The migratory ability of glioblastoma cells on myelin is reversibly modulated by NgR1 during differentiation and dedifferentiation process through deubiquitinating activity of USP1, which inhibits the degradation of ID1 to downregulate NgR1 expression. Furthermore, pimozide, a well-known antipsychotic drug, upregulates NgR1 by post-translational targeting of USP1, which sensitizes glioma stem cells to myelin inhibition and suppresses myelin-associated infiltration in vivo. In primary human glioblastoma, downregulation of NgR1 expression is associated with highly infiltrative characteristics and poor survival. Together, our findings reveal that loss of NgR1 drives myelin-associated infiltration of glioblastoma and suggest that novel therapeutic strategies aimed at reactivating expression of NgR1 will improve the clinical outcome of glioblastoma patients.

Safety of endoscopic endonasal biopsy for the pituitary stalk-hypothalamic lesions.

PURPOSE: The indications for and the optimal biopsy approach in pituitary stalk-hypothalamic (PsH) lesions are controversial. Biopsies through an endoscopic endonasal approach (EEA) for PsH lesions have often been considered to cause the infundibulo-tuberal syndrome. The purpose of this study was to analyze the surgical and endocrinological safety of EEA biopsies for PsH lesions. METHODS: A total of 39 consecutive patients who underwent an EEA biopsy between June 2011 and August 2020 in a single institute were retrospectively analyzed. The ophthalmological and endocrinological outcomes were assessed before and after surgery. RESULTS: PsH lesions were confirmed to be diverse pathological diagnoses, ranging from lymphocytic hypophysitis to diffuse midline glioma, and the most common pathologic diagnosis was a germinoma (18 patients, 46.2%). No patients developed visual deterioration after the biopsy. In patients without preoperative panhypopituitarism, 13 out of 28 patients (46.4%) developed new anterior pituitary hormonal deficiencies after the biopsy. When the tissue was collected from the stalk, the endocrinological deterioration rate was 100% (6 of 6 patients), while the rate was 31.8% (7 of 22 patients) when tissue could be harvested from an extra-stalk lesion. The rate of newly developed permanent diabetes insipidus after surgery was 40.9% (9 of 22 patients). The median surgery time was 125 min, and there was no postoperative CSF leakage or infections noted. CONCLUSIONS: An EEA biopsy for PsH lesions is a safe and efficient surgical method unless the tissue is collected from the stalk.

Brain parenchymal angiomatoid fibrous histiocytoma and spinal myxoid mesenchymal tumor with FET: CREB fusion, a spectrum of the same tumor type.

Angiomatoid fibrous histiocytomas (AFH) is a rare soft tissue tumor of intermediate malignant potential, and its histology is diverse. It can occur in several organs including intracranial and soft tissues. Here, we report two cases of brain parenchymal classic AFH and spinal extramedullary myxoid mesenchymal tumor with clinicopathological and molecular investigations by next-generation sequencing and a comprehensive review. The current brain parenchymal AFH occurred in a 79-year-old woman, and the spinal myxoid mesenchymal tumor arose in the thoracic spine of a 28-year-old woman; both harbored FET:CREB fusion. The current brain parenchymal AFH has not recurred for 15-months follow-up period, but the spinal myxoid mesenchymal tumor recurred three times and metastasized to T8 spine level for 30-months follow-up period. We reviewed 40 reported cases of central nervous system (CNS) AFHs/myxoid mesenchymal tumors including our two cases to identify clinicopathological features and biological behaviors. They occur with a slight female predominance (M:F = 1:1.7) in children and young adults (median age: 17 years; range: 4-79 years old). Approximately 80% of CNS AFHs were younger than 30 year. Most of them were dura-based and were not just intracranial tumors as they occurred anywhere in the CNS including spinal dura. EWSR1 rearrangement was the most common driver (98%), including FET:CREB (33%), EWSR1:ATF1 (30%), and EWSR1:CREM (27%) fusions, but FUS:CREM fusion (2%) was also present. During the follow-up period (median: 27 months), 43% (17/40) of CNS AFHs recurred between two months and 11 years, and multiple recurrences were also observed. One case showed metastases to the lymph nodes and vertebrae, and among 11 cases that resulted in death, four cases provided available clinical data. Because these tumors are identical to soft tissue AFH or primary pulmonary myxoid sarcoma with an FET:CREB fusion in morphological and immunohistochemical spectra, the authors propose incorporating the two tumor terms into one.

Absolute quantification of tumor-infiltrating immune cells in high-grade glioma identifies prognostic and radiomics values.

PURPOSE: To understand the tumor immune microenvironment precisely, it is important to secure the quantified data of tumor-infiltrating immune cells, since the immune cells are true working unit. We analyzed unit immune cell number per unit volume of core tumor tissue of high-grade gliomas (HGG) to correlate their immune microenvironment characteristics with clinical prognosis and radiomic signatures. METHODS: The number of tumor-infiltrating immune cells from 64 HGG core tissue were analyzed using flow cytometry and standardized. After sorting out patient groups according to diverse immune characteristics, the groups were tested if they have any clinical prognostic relevance and specific radiomic signature relationships. Sparse partial least square with discriminant analysis using multimodal magnetic resonance images was employed for all radiomic classifications. RESULTS: The median number of CD45 + cells per one gram of HGG core tissue counted 865,770 cells which was equivalent to 8.0% of total cells including tumor cells. There was heterogeneity in the distribution of immune cell subpopulations among patients. Overall survival was significantly better in T cell-deficient group than T cell-enriched group (p = 0.019), and T8 dominant group than T4 dominant group (p = 0.023). The number of tumor-associated macrophages (TAM) and M2-TAM was significantly decreased in isocitrate dehydrogenase mutated HGG. Radiomic signature classification showed good performance in predicting immune phenotypes especially with features extracted from apparent diffusion coefficient maps. CONCLUSIONS: Absolute quantification of tumor-infiltrating immune cells confirmed the heterogeneity of immune microenvironment in HGG which harbors prognostic impact. This immune microenvironment could be predicted by radiomic signatures non-invasively.

Prognostic significance of the postoperative prognostic nutritional index in patients with glioblastoma: a retrospective study.

BACKGROUND: The prognostic nutritional index (PNI) reflects immunonutritional status. We evaluated the effects of postoperative PNI and perioperative changes in the PNI on overall survival (OS) in glioblastoma (GBM) patients. METHODS: Demographic, laboratory, and clinical data were retrospectively collected from 335 GBM patients. Preoperative and postoperative PNIs were calculated from serum albumin concentration and lymphocyte count, which were measured within 3 weeks before surgery and 1 month after surgery. Patients were classified into high (n = 206) or low (n = 129) postoperative PNI groups according to the postoperative PNI cutoff value and further classified into four groups according to the cutoff values of the preoperative and postoperative PNIs, as follows: Group HH (both high PNIs, n = 92), Group HL (high preoperative and low postoperative PNI, n = 70), Group LH (low preoperative and high postoperative PNI, n = 37), and Group LL (both low PNIs, n = 136). RESULTS: The median OS was significantly longer in the high postoperative PNI (PNI ≥ 50.2) group than the low postoperative PNI (PNI < 50.2) group (24.0 vs. 15.0 months, p <  0.001). In multivariate analysis, high postoperative PNI was a significant predictor of OS. OS was significantly longer in Group HH than in Group LL and seemed longer in Group HH than in Group HL and in Group LH than in Group LL. OS was not different between Groups HH and LH or between Groups HL and LL. CONCLUSIONS: High postoperative PNI was associated with improved OS and perioperative changes in PNI may provide additional important information for prognostic prediction in GBM patients.

Development of an inside-out augmented reality technique for neurosurgical navigation.

OBJECTIVE: With the advancement of 3D modeling techniques and visualization devices, augmented reality (AR)-based navigation (AR navigation) is being developed actively. The authors developed a pilot model of their newly developed inside-out tracking AR navigation system. METHODS: The inside-out AR navigation technique was developed based on the visual inertial odometry (VIO) algorithm. The Quick Response (QR) marker was created and used for the image feature-detection algorithm. Inside-out AR navigation works through the steps of visualization device recognition, marker recognition, AR implementation, and registration within the running environment. A virtual 3D patient model for AR rendering and a 3D-printed patient model for validating registration accuracy were created. Inside-out tracking was used for the registration. The registration accuracy was validated by using intuitive, visualization, and quantitative methods for identifying coordinates by matching errors. Fine-tuning and opacity-adjustment functions were developed. RESULTS: ARKit-based inside-out AR navigation was developed. The fiducial marker of the AR model and those of the 3D-printed patient model were correctly overlapped at all locations without errors. The tumor and anatomical structures of AR navigation and the tumors and structures placed in the intracranial space of the 3D-printed patient model precisely overlapped. The registration accuracy was quantified using coordinates, and the average moving errors of the x-axis and y-axis were 0.52 ± 0.35 and 0.05 ± 0.16 mm, respectively. The gradients from the x-axis and y-axis were 0.35° and 1.02°, respectively. Application of the fine-tuning and opacity-adjustment functions was proven by the videos. CONCLUSIONS: The authors developed a novel inside-out tracking-based AR navigation system and validated its registration accuracy. This technical system could be applied in the novel navigation system for patient-specific neurosurgery.

Validation and optimization of a web-based nomogram for predicting survival of patients with newly diagnosed glioblastoma.

PURPOSE: To optimize and validate a current (NRG [a newly constituted National Clinical Trials Network group through National Surgical Adjuvant Breast and Bowel Project [NSABP], the Radiation Therapy Oncology Group [RTOG] and the Gynecologic Oncology Group (GOG)]) nomogram for glioblastoma patients as part of continuous validation. METHODS: We identified patients newly diagnosed with glioblastoma who were treated with temozolomide-based chemoradiotherapy between 2006 and 2016 at three large-volume hospitals. The extent of resection was determined via postoperative MRI. The discrimination and calibration abilities of the prediction algorithm were assessed; if additional factors were identified as independent prognostic factors, updated models were developed using the data from two hospitals and were externally validated using the third hospital. Models were internally validated using cross-validation and bootstrapping. RESULTS: A total of 837 patients met the eligibility criteria. The median overall survival (OS) was 20.0 (95% CI 18.5-21.5) months. The original nomogram was able to estimate the 6­, 12-, and 24-month OS probabilities, but it slightly underestimated the OS values. In multivariable Cox regression analysis, MRI-defined total resection had a greater impact on OS than that shown by the original nomogram, and two additional factors-IDH1 mutation and tumor contacting subventricular zone-were newly identified as independent prognostic values. An updated nomogram incorporating these new variables outperformed the original nomogram (C-index at 6, 12, 24, and 36 months: 0.728, 0.688, 0.688, and 0.685, respectively) and was well calibrated. External validation using an independent cohort showed C­indices of 0.787, 0.751, 0.719, and 0.702 at 6, 12, 24, and 36 months, respectively, and was well calibrated. CONCLUSION: An updated and validated nomogram incorporating the contemporary parameters can estimate individual survival outcomes in patients with glioblastoma with better accuracy.

Chemoradiation in elderly patients with glioblastoma from the multi-institutional GBM-molRPA cohort: is short-course radiotherapy enough or is it a matter of selection?

BACKGROUND: The optimal radiotherapy regimen in elderly patients with glioblastoma treated by chemoradiation needs to be addressed. We provide the results of a comparison between conventionally fractionated standard radiotherapy (CRT) and short-course radiotherapy (SRT) in those patients treated by temozolomide-based chemoradiation. METHODS: Patients aged 65 years or older from the GBM-molRPA cohort were included. Patients who were planned for a ≥ 6-week or ≤ 4-week radiotherapy were regarded as being treated by CRT or SRT, respectively. The median RT dose in the CRT and SRT group was 60 Gy in 30 fractions and 45 Gy in 15 fractions, respectively. RESULTS: A total of 260 and 134 patients aged older than 65 and 70 years were identified, respectively. CRT- and SRT-based chemoradiation was applied for 192 (73.8%) and 68 (26.2%) patients, respectively. Compared to SRT, CRT significantly improved MS from 13.2 to 17.6 months and 13.3 to 16.4 months in patients older than 65 years (P < 0.001) and 70 years (P = 0.002), respectively. Statistical significance remained after adjusting for age, performance status, surgical extent, and MGMT promoter methylation in both age groups. The benefit was clear in all subgroup analyses for patients with Karnofsky performance score 70-100, Karnofsky performance score ≤ 60, gross total resection, biopsy, methylated MGMT promoter, and unmethylated MGMT promoter (all P < 0.05). CONCLUSION: CRT significantly improved survival compared to SRT in elderly glioblastoma patients treated with chemoradiation in selected patients amenable for chemoradiation. This study is hypothesis-generating and a prospective randomized trial is urgently warranted.

Correction to: Chemoradiation in elderly patients with glioblastoma from the multi­institutional GBM­molRPA cohort: is short­course radiotherapy enough or is it a matter of selection?

The name of author Do Hoon Lim was incorrect in the initial online publication. The original article has been corrected.

Prognostication of anaplastic astrocytoma patients: application of contrast leakage information of dynamic susceptibility contrast-enhanced MRI and dynamic contrast-enhanced MRI.

PURPOSE: To examine the applicability of contrast leakage information from dynamic susceptibility contrast-enhanced (DSC) MRI and dynamic contrast-enhanced (DCE) MRI to determine which one is the most valuable surrogate imaging biomarker for predicting disease progression in anaplastic astrocytoma (AA) patients. MATERIALS AND METHODS: This study was approved by the institutional review board (IRB), which waived informed consent. A total of seventy-three AA patients who had undergone preoperative DCE and DSC MRI and received standard treatment, including partial resection or biopsy followed by radiation therapy, were included in this retrospective study. Based on Response Assessment in Neuro-Oncology (RANO), patients were sorted into progression (n = 21) and non-progression (n = 52) groups. Tumor boundaries were defined as high-signal intensity (SI) lesions on fluid-attenuated inversion recovery (FLAIR) imaging, where we analyzed mean pharmacokinetic parameters (Ktrans, Vp, and Ve) from DCE MRI and contrast leakage information (mean extraction fraction (EF)) from DSC MRI. RESULTS: Mean Ve and mean EF were significantly higher in patients with progression-free survival (PFS) < 18 months than in those with PFS ≥ 18 months. For distinguishing the group with PFS < 18 months, AUC values were calculated using the mean Ve value (AUC = 0.716). The Kaplan-Meier survival analysis revealed that mean Ve value was significantly correlated with PFS. In Cox proportional-hazards regression, only the mean Ve value was found to be significantly associated with PFS. CONCLUSION: We found that the mean Ve value based on high-SI tumor lesions on FLAIR imaging was capable of predicting outcomes of AA patients as a potential surrogate imaging biomarker. KEY POINTS: • Mean Ve(2.152 ± 1.857 vs. 1.173 ± 1.408) was significantly higher in anaplastic astrocytoma patients with PFS < 18 months that in those with PFS ≥ 18 months (p = 0.02). • Cox proportional-hazards regression showed that only mean Ve(p = 0.034) was significantly associated with PFS, regardless of IDH mutation status, in anaplastic astrocytoma patients.

Arterial spin labeling perfusion-weighted imaging aids in prediction of molecular biomarkers and survival in glioblastomas.

OBJECTIVES: Prediction of progression-free survival (PFS) and overall survival (OS) and early identification of molecular biomarkers with prognostic information are clinically important in glioblastoma (GBM) patients. We aimed to explore the utility of arterial spin labeling perfusion-weighted imaging (ASL-PWI) in the prediction of molecular biomarkers and survival in GBM patients. METHODS: We retrospectively analyzed 149 consecutive GBM patients, who had undergone maximal surgical resection or biopsy followed by concurrent chemoradiotherapy and adjuvant chemotherapy using temozolomide between November 2010 and June 2016. On preoperative ASL-PWI, cerebral blood flow (CBF) within contrast-enhancing (CE) and nonenhancing (NE) portions were evaluated both qualitatively (perfusion pattern[CE] and perfusion pattern[NE]) and quantitatively (nCBFCE and nCBFNE). ASL-PWI findings were correlated with molecular biomarkers, including isocitrate dehydrogenase (IDH) and O6-methylguanine-DNA methyltransferase (MGMT) methylation statuses, and survival, using the Mann-Whitney U-test, Spearman rank correlation, Kaplan-Meier analysis, and receiver operating characteristics analysis. RESULTS: nCBFCE was significantly higher in the IDH wild-type group than in the IDH mutant group (p = .013) and in the MGMT unmethylated group than in the methylated group (p = .047). Areas under the receiver operating characteristic curve were 0.678 for IDH mutation (p = .022) and 0.601 for MGMT promoter methylation (p = .043). Hyperperfusion was associated with the shortest median PFS for both perfusion pattern[CE] (7.6 months) and perfusion pattern[NE] (4.0 months). The perfusion pattern[NE] remained an independent predictor for PFS and OS even after adjusting for clinical and molecular predictors, unlike perfusion pattern[CE]. CONCLUSIONS: ASL-PWI can aid to predict survival and molecular biomarkers including IDH mutation and MGMT promoter methylation statuses in GBM patients. KEY POINTS: • ASL-PWI can aid to predict survival in GBM patients. • ASL-PWI can aid to predict IDH and MGMT promoter methylation statuses in GBM.

Genome-wide investigation of intragenic DNA methylation identifies ZMIZ1 gene as a prognostic marker in glioblastoma and multiple cancer types.

DNA methylation has long been recognized as a tumor-promoting factor when aberrantly regulated in the promoter region of genes. However, the effect of intragenic DNA methylation remains poorly understood on the clinical aspects of cancer. Here, we first evaluated the significance of intragenic DNA methylation for survival outcomes of cancer patients in a genome-wide manner. Glioblastoma patients with hypermethylated intragenic regions exhibited better survival than hypomethylated patients. Enrichment analyses of intragenic DNA methylation profiles with epigenetic signatures prioritized the intragenic DNA methylation of ZMIZ1 as a possible glioblastoma prognostic marker that is independent of MGMT methylation in IDH1 wild-type patients. This intragenic region harbored molecular signatures of alternative transcription across many cell types. Furthermore, we found that the intragenic region of ZMIZ1 can serve as a molecular marker in multiple cancers including astrocytomas, bladder cancer and renal cell carcinoma according to DNA methylation status. Finally, in vitro and in vivo experiments uncovered the role of ZMIZ1 as a driver of tumor cell migration. Altogether, our results identify ZMIZ1 as a prognostic marker in cancer and highlight the clinical significance of intragenic methylation in cancer.