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Necrosis is a hallmark of glioblastoma (GBM) and is responsible for poor prognosis and resistance to conventional therapies. However, the molecular mechanisms underlying necrotic microenvironment-induced malignancy of GBM have not been elucidated. Here, we report that transglutaminase 2 (TGM2) is upregulated in the perinecrotic region of GBM and triggered mesenchymal (MES) transdifferentiation of glioma stem cells (GSC) by regulating master transcription factors (TF), such as C/EBPβ, TAZ, and STAT3. TGM2 expression was induced by macrophages/microglia-derived cytokines via NF-κB activation and further degraded DNA damage–inducible transcript 3 (GADD153) to induce C/EBPβ expression, resulting in expression of the MES transcriptome. Downregulation of TGM2 decreased sphere-forming ability, tumor size, and radioresistance and survival in a xenograft mouse model through a loss of the MES signature. A TGM2-specific inhibitor GK921 blocked MES transdifferentiation and showed significant therapeutic efficacy in mouse models of GSC. Moreover, TGM2 expression was significantly increased in recurrent MES patients and inversely correlated with patient prognosis. Collectively, our results indicate that TGM2 is a key molecular switch of necrosis-induced MES transdifferentiation and an important therapeutic target for MES GBM. Cancer Res; 77(18); 4973–84. ©2017 AACR.

Supplementary Figure 1 related to Figure 1. TGM2 is highly expressed in the necrotic region of MES GBM. Supplementary Figure 2 related to Figure 2. TGM2 regulates stemness of MES, PN, and CL GSCs. Supplementary Figure 3 related to Figure 4. A negative correlation between C/EBPβ and GADD153.

The present study aimed to evaluate whether the cerebrospinal fluid (CSF) neurofilament light chain (NfL) is a potential prognostic marker for patients with leptomeningeal metastasis (LM). NfL levels were measured in CSF using a single-molecule array assay. A total of 42 patients with LM who were treated with ventriculo-lumbar perfusion (VLP) chemotherapy and had available stored CSF samples from the lumbar subarachnoid space before VLP chemotherapy were included in the present study, in order to investigate the prognostic value of CSF NfL. The median CSF NfL level in patients with LM was 8.15 ng/ml; 30% of patients who had died at the time of analysis had CSF NfL levels higher than the calculated overall prognostic cut-off value (11 ng/ml). The median overall survival after initiation of VLP chemotherapy was significantly longer in patients with LM and low CSF NfL levels compared with in patients with LM and high CSF NfL levels (P

Our objective is to analyze the occurrence, clinical course and risk factors for glioma patients with leptomeningeal metastasis (LM) according to different metastasis patterns and clinical variables.We retrospectively reviewed data from 376 WHO grade II-IV adult glioma patients who were treated in the National Cancer Center from 2001 to 2020. Patients who underwent surgery at other institutions, those without initial images or those with pathologically unconfirmed cases were excluded. LM was diagnosed based on MRI findings or cerebrospinal fluid (CSF) cytology. The metastasis pattern was categorized as nodular or linear according to the enhancement pattern. Tumor proximity to the CSF space was classified as involved or separated, whereas location of the tumor was dichotomized as midline, for tumors residing in the thalamus, basal ganglia and brainstem, or lateral, for tumors residing in the cerebral and cerebellar hemispheres.A total of 138 patients were enrolled in the study. A total of 44 patients (38%) were diagnosed with LM during a median follow-up of 9 months (range, 0-60 months). Among the clinical variables, tumor proximity to CSF space, the location of the tumor and the WHO grade were significant factors for LM development in univariate analysis. In multivariate analysis, the midline location of the tumor and WHO grade IV gliomas were the most significant factor for LM development. The hazard ratio (HR) was 2.624 for midline located gliomas (95% confidence interval 1.384-4.974,Midline location and histological grading are an important factor for LM in glioma patients. The proximity to the CSF circulation pathway is also an important factor for WHO grade IV glioma LM. Patients carrying high risks should be followed up more thoroughly.

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.

Glioma shows progression presenting as malignant transformation or leptomeningeal metastasis (LM). However, longitudinal biopsy of brain parenchyma is difficult due to its critical location, whereas cerebrospinal fluid (CSF) can be obtained serially with a little invasiveness of puncture. Thus, if we could find a biomarker for glioma progression, we could predict such event and determine therapeutic interventions as early as possible. In this study, we examined whether cerebrospinal fluid (CSF) metabolome profiles can reflect glioma grade, difference with non-glial tumor, and LM status. We selected 32 CSF samples from glioma patients, and compared them with 10 non-tumor control and seven non-glial brain tumor (medulloblastoma) samples. A total of 10,408 low-mass ions (LMIs) were detected as a candidate of metabolites using mass spectrometry, and representative LMIs were identified via the Human Metabolome Database. Grade IV gliomas showed eight LMIs, including acetic acid, of higher levels (summed sensitivity and specificity > 180%) than grade III gliomas. Grade IV gliomas demonstrated more abundant 30 LMIs, including glycerophosphate, compared with medulloblastoma, but none was mutually exclusive. Phospholipid derivatives were significantly more abundant in LM (−) than LM (+) gliomas regardless of glioma grade. LMIs representative of LM (+) gliomas were derivatives of glycolysis. We also verified discriminative LMIs based on mean expression level of each LMI (Student t test, p < 0.05) and evaluated the differences of the above analyses. Over 90% of metabolite pathways indicated from two analytical models were common to each other. Non-targeted mass spectrometry of CSF metabolites revealed significantly different profiles across gliomas that possibly permitted differentiation between glioma grades, LM, and non-glial brain tumors. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13167-020-00211-4) contains supplementary material, which is available to authorized users.

The interplay between glioblastoma stem cells (GSCs) and tumor-associated macrophages (TAMs) promotes progression of glioblastoma multiforme (GBM). However, the detailed molecular mechanisms underlying the relationship between these two cell types remain unclear. Here, we demonstrate that ARS2 (arsenite-resistance protein 2), a zinc finger protein that is essential for early mammalian development, plays critical roles in GSC maintenance and M2-like TAM polarization. ARS2 directly activates its novel transcriptional target MGLL, encoding monoacylglycerol lipase (MAGL), to regulate the self-renewal and tumorigenicity of GSCs through production of prostaglandin E2 (PGE2), which stimulates β-catenin activation of GSC and M2-like TAM polarization. We identify M2-like signature downregulated by which MAGL-specific inhibitor, JZL184, increased survival rate significantly in the mouse xenograft model by blocking PGE2 production. Taken together, our results suggest that blocking the interplay between GSCs and TAMs by targeting ARS2/MAGL signaling offers a potentially novel therapeutic option for GBM patients., How glioblastoma stem cells (GSCs) and tumor-associated macrophages (TAMs) interact to promote progression of glioblastoma multiforme (GBM) is currently unclear. Here, the authors demonstrate a role for the ARS2/MAGL signalling in regulating self-renewal and tumorigenicity of GSCs and M2-like TAM polarization.

Background To investigate the feasibility of cerebrospinal fluid (CSF) CYFRA 21-1 levels as a therapeutic monitoring biomarker in leptomeningeal carcinomatosis (LMC) patients undergoing ventriculo-lumbar perfusion (VLP) chemotherapy. Methods The levels of CYFRA 21-1 in 42 CSF samples from 15 LMC patients were analyzed using an electrochemiluminescence immunoassay. Samples were collected at individual time points during VLP chemotherapy. Therapeutic outcomes were measured as improvements in the Karnofsky Performance Status (KPS) score and decreasing intracranial pressure (ICP) as the main endpoint of VLP chemotherapy. Changes in CSF CYFRA 21-1 levels, protein levels, and cytology results were also investigated. We subsequently evaluated whether these changes were correlated with KPS score and ICP. Results The CSF CYFRA 21-1 levels at individual time points were associated with KPS score and ICP. The KPS scores (p= 0.007) and ICP (p= 0.018) of patients with high CSF CYFRA 21-1 levels were significantly different from those of patients with low CSF CYFRA 21-1 levels. By contrast, CSF protein levels and cytological responses were not significantly associated with KPS scores and ICP. Conclusions CSF CYFRA 21-1 may have utility as a therapeutic monitoring biomarker to design personalized therapeutic strategies in LMC patients undergoing VLP chemotherapy.

A 74-year-old woman presented with a month-long nausea and vomiting, then she could not take a meal. She had found an asymptomatic 4th ventricular mass 6 year ago as a preoperative work-up for ovarian cancer. And during the yearly follow-up, the mass had grown continuously over 6 years, and caused symptoms in the seventh year. MRI revealed a large ovoid extra-axial mass in the fourth ventricle compressing adjacent medulla and cerebellum. Surgery achieved near total resection since the tumor tightly adhered to the brain stem of 4th ventricle floor. The histological diagnosis was ependymoma (WHO grade II). She transferred rehabilitation facility for mild gait disturbance, hoarseness and swallowing difficulty. Fourth ventricle ependymoma in the elderly is extremely rare and the growth rate has not been reported. Here, we present a rare care of 4th ventricle ependymoma found asymptomatic at elderly but continuously grow to cause local pressure symptoms.

Magnetic resonance imagining (MRI) is helpful for diagnosis of leptomeningeal carcinomatosis (LMC) and localizing LMC symptoms. Goal of this study is how MRI findings of LMC are associated with clinical characteristics or prognosis in patients with non-small cell lung cancer (NSCLC). We retrospectively collected data on 283 patients with LMC from NSCLC, adenocarcinoma based on cerebrospinal fluid cytology. All patients had brain MRI with gadolinium enhancement at LMC diagnosis, and spinal MRI was performed at the physician’s discretion. We evaluated the prognostic factors for overall survival (OS) of all patients and subgroup of patients with central nervous system cause of death. Two-hundred sixteen patients (76%) had definite or suggestive LMC findings and 67 had negative findings on brain MRI. Of the 37 patients who presented with cauda equina syndrome, 35 (95%) exhibited typical spinal MRI findings. Median OS of all patients was 3.65 months (95% confidence interval, 3.06–4.18). There was no significant difference in median OS between MRI-negative and MRI-positive groups (4.31 vs. 3.48 months, p = 0.711), whereas negative MRI finding showed longer median OS significantly in a subgroup of 77 patients with a central nervous system cause of death (p = 0.035). Considering clinical characteristics, progressive systemic disease, and altered mentality were significant prognostic factors associated with poor OS, whereas presenting symptom of headache with nausea/vomiting, intra-CSF chemotherapy, WBRT after LMC diagnosis, and concurrent RTKi treatment were significant for favorable OS in multivariable analysis. Positive MRI findings suggests heavier disease burden than negative MRI findings in patients with LMC who died of a central nervous system cause. Spinal MRI findings in patients with LMC correlate with cauda equina symptoms.

BackgroundInterleukin-13 receptor α 2 (IL13Rα2) is a promising tumor-directed antigen of malignant glioma (MG). Here, we examine the efficacy and safety of T cells containing a YYB-103 chimeric antigen receptor (CAR) that can preferentially bind to IL13Rα2 on MG cells.MethodsIL13 was modified on the extracellular domain by substitution of amino acids with E13K, R66D, S69D, and R109K and stably transfected into human T cells using a retroviral vector. The in vitro efficacy of YYB-103 CAR T cells was tested in cell lines with differing IL13Rα1 and IL13Rα2 expression. The in vivo efficacy of intracerebroventricular (i.c.v.) and intravenous (i.v.) routes of YYB-103 CAR T-cell administration were tested in orthotopic MG mouse models. Immunohistochemical staining of MG was performed using WHO grade 3/4 surgical specimens from 53 patients. IL13Rα2 expression was quantified by H-score calculated from staining intensity and percentage of positive cells.ResultsBinding affinity assay of YYB-103 verified apparently nil binding to IL13Rα1, which was more selective than previously reported IL13 modification (E13Y). YYB-103 CAR T cells showed selective toxicity toward co-cultured U87MG (IL13Rα1+/IL13Rα2+) cells but not A431 (IL13Rα1+/IL13Rα2−) cells. Consistently, YYB-103 CAR T cells suppressed tumor growth in nude mice receiving orthotopic injection of U87 MG cells. Both i.c.v. and i.v. injections of YYB-103 CAR T cells reduced tumor volume and prolonged overall survival of tumor-bearing mice. The median H-score for IL13Rα2 in patient-derived MG tissue was 5 (mean, 57.5; SD, 87.2; range, 0 to 300).ConclusionThis preclinical study demonstrates the efficacy of IL13Rα2-targeted YYB-103 CAR T cells against MG cells. The use of modified IL13 to construct a CAR facilitated the selective targeting of IL13Rα2-expressing MG cells while sparing IL13Rα1-expressing cells. Notably, YYB-103 CAR T cells exhibited effective blood–brain barrier crossing, suggesting compatibility with i.v. administration rather than intracranial injection. Additionally, the high H-score for IL13Rα2 in glioblastoma, especially in conjunction with the poor prognostic markers of wild-type isocitrate dehydrogenase-1 (IDH-1) and unmethylated O6-methyl guanine methyl-transferase (MGMT), could be used to determine the eligibility of patients with recurrent glioblastoma for a future clinical trial of YYB-103 CAR T cells.

We evaluated the potential serum neurofilament light chain (sNfL) and serum glial fibrillary acidic protein (sGFAP) roles in diagnosing and monitoring brain metastases (BMs). We included 70 patients with newly diagnosed BMs, 71 age- and cancer type-matched patients without BMs, and 67 healthy controls (HCs). We compared sNfL and sGFAP levels among the groups using a single-molecule array immunoassay. We prospectively followed 26 patients with BMs every 2–3 months by measuring sNfL and sGFAP levels and performing magnetic resonance imaging (MRI) scans. The sNfL and the sGFAP levels were higher in patients with BMs (medians: sNfL, 63.7 µL, sGFAP, 819.5 pg/µL) than in those without BMs (sNfL, 13.3 µL, sGFAP, 154 pg/µL, p &lt, 0.001) and HCs (sNfL, 12.5 µL, sGFAP, 135 pg/µL, 0.001). The sNfL and the sGFAP cutoff levels had a sensitivity and a specificity of 91%. The sGFAP cutoff level had a sensitivity of 91% and a specificity of 97%. The sNfL and the sGFAP levels were related to the BM size but not to the primary cancer type. After BM treatment, sNfL and sGFAP levels decreased with reduced BM lesions on MRI, however, they increased when BMs progressed. sNfL and sGFAP are potential biomarkers for BM screening in cancer patients.

BACKGROUND To date, there has been no practical guidelines for the prescription of antiepileptic drugs (AEDs) in brain tumor patients in Korea. Thus, the Korean Society for Neuro-Oncology (KSNO), a multidisciplinary academic society, had begun preparing guidelines for AED usage in brain tumors since 2019. METHODS The Working Group was composed of 27 multidisciplinary medical experts in Korea. References were identified through searches of PubMed, MEDLINE, EMBASE, and Cochrane CENTRAL using specific and sensitive keywords as well as combinations of the keywords. RESULTS The core contents are as follows. Prophylactic AED administration is not recommended in newly diagnosed brain tumor patients without previous seizure history. When AEDs are administered during peri/postoperative period, it may be tapered off according to the following recommendations. In seizure-naive patients with no postoperative seizure, it is recommended to stop or reduce AED 1 week after surgery. In seizure-naive patients with one early postoperative seizure (

Simple Summary Leptomeningeal metastasis (LM) is a lethal complication in which cancer metastasizes to the meninges. Currently, there are neither definitive treatments nor diagnosis methods for LM patients. In this study, we suggest the examination of small non-coding RNA (smRNA) populations of extracellular vesicles (EVs) derived from the cerebrospinal fluid (CSF) as a potential vehicle for diagnosis and treatment strategies. Systemic and quantitative analysis of smRNA subpopulations from LM CSF EVs showed unique expression patterns between LM patients and healthy donors. In addition, LM CSF EVs smRNAs appeared to be associated with LM pathogenesis suggesting they may be viable targets for novel diagnostic and treatment strategies. Abstract Leptomeningeal metastasis (LM) is a fatal and rare complication of cancer in which the cancer spreads via the cerebrospinal fluid (CSF). At present, there is no definitive treatment or diagnosis for this deleterious disease. In this study, we systemically and quantitatively investigated biased expression of key small non-coding RNA (smRNA) subpopulations from LM CSF extracellular vesicles (EVs) via a unique smRNA sequencing method. The analyzed subpopulations included microRNA (miRNA), Piwi-interacting RNA (piRNA), Y RNA, small nuclear RNA (snRNA), small nucleolar RNAs (snoRNA), vault RNA (vtRNA), novel miRNA, etc. Here, among identified miRNAs, miR-21, which was already known to play an essential oncogenic role in tumorigenesis, was thoroughly investigated via systemic biochemical, miR-21 sensor, and physiological cell-based approaches, with the goal of confirming its functionality and potential as a biomarker for the pathogenesis and diagnosis of LM. We herein uncovered LM CSF extravesicular smRNAs that may be associated with LM-related complications and elucidated plausible pathways that may mechanistically contribute to LM progression. In sum, the analyzed smRNA subpopulations will be useful as targets for the development of therapeutic and diagnostic strategies for LM and LM-related complications.

BACKGROUND To evaluate the impact of adjuvant postoperative radiotherapy (PORT) in adult WHO grade II–III intracranial ependymoma (IEPN). METHODS A total of 172 pathologically confirmed adult grade II–III IEPN patients from 12 institutions were eligible. Of them, 106 (61.6%) and 66 (38.4%) patients were grade II and III, respectively. For grade II and III IEPNs, 51 (48.1%) and 59 (89.4%) patients received PORT, respectively. The median dose to the primary tumor bed was 54.0 Gy and 59.4 Gy for grade II and III patients, respectively. The prognostic impact of sex, age, performance, WHO grade, location, size, surgical extent, and PORT on local control (LC), progression-free survival (PFS), and overall survival (OS) were evaluated by univariate and multivariate analysis. RESULTS The median follow-up period for survivors was 88.1 months. The 5-/10-year LC, PFS, and OS rates were 64.8%/54.0%, 56.4%/44.8%, and 76.6%/71.0%, respectively. On multivariate analysis, adjuvant PORT significantly improved LC (P=0.002), PFS (P=0.002), and OS (P=0.043). Older age (P< 0.001), WHO grade III (P< 0.001), larger tumor size (P=0.004), and lesser surgical extent (P< 0.001) were also negative factors for OS. Adjuvant PORT also improved LC (P=0.010), PFS (P=0.007), and OS (P=0.069) on multivariate analysis for grade II IEPNs. CONCLUSION This multicenter retrospective study supports the role of adjuvant PORT in terms of disease control and survival in adult grade II–III IEPNs. Prospective randomized trials focused on individualized treatment based on molecular subtypes is warranted.

Leptomeningeal metastasis (LM) has a poor prognosis and is difficult to diagnose and predict the response of treatment. In this study, we suggested that the monitoring of changes in the concentration of extracellular vesicles in cerebrospinal fluid could help diagnose or predict outcomes for LM. We measured nanoparticles in 472 human cerebrospinal fluid (CSF) from patients including LM with both Dynamic Light Scattering (DLS) and Nanoparticle Tracking Analysis (NTA) after two-step centrifugations. NTA revealed that the concentration of CSF nanoparticles was significantly increased in LM compared to other groups (2.80 &times, 108 /mL vs. 1.49 &times, 108 /mL, p &lt, 0.01). Changes in NTA-measured nanoparticles concentration after intra-CSF chemotherapy were further examined in 33 non-small cell lung cancer patients with LM. Overall survival was longer for patients with increased EV than the others (442 vs. 165 days, p &lt, 0.001). Markers of extracellular vesicles (CD9/CD63/CD81) significantly decreased in the EV-decreased group. MicroRNA-21 expression decreased in this favorable prognostic group, whereas it increased in the EV-decreased group. In conclusion, the elevated concentration of extracellular vesicles in cerebrospinal fluid in patients with LM may be a predictive marker for survival duration. Moreover, EV changes combined with microRNA-21 might be a biomarker for monitoring the efficacy of intracranial chemotherapy of LM in non-small cell lung cancer patients.

Brain metastasis is a common complication in cancer patients. Local recurrence after total resection of metastatic brain tumor has been frequently reported. In this study, we developed a new hyperthermia device and applied it to metastatic brain tumor patients intra-operatively to study if hyperthermia treatment could reduce local tumor recurrence.A total of 63 metastatic brain patients were enrolled in the study with an informed consent obtained from every patient. After total resection of the tumor, the hyperthermia device was applied intra-operatively to the resection cavity. The surrounding brain tissue at 5 mm in depth from the tumor resection margin was raised to 42.5 °C for a total of 60 minutes (Clinical Research Information Service Registration Number: KCT0001308).A total of 10 local recurrences were observed in 63 patients who received hyperthermia treatment showing a local recurrence rate of 15.8%. It was significantly lower than the local recurrence rate of those who received conventional treatment (34%) when analyzed with one tailed z-test (p value: .001). Kaplan-Meier analysis also showed a significantly lower recurrence rate in the hyperthermia treatment group (p value: .0003). Complications included two cases of seizures and two cases of wound infection.Results of this study suggest that intra-operative hyperthermia treatment after total resection of metastatic brain tumor could reduce local recurrence of tumor. We believe that intra-operative hyperthermia treatment could be used as an adjuvant therapy to surgery and post-operative radiotherapy, or as a salvage treatment in patients who cannot receive further radiotherapy.

Objective The purpose of this pilot study was to examine the safety and function of the newly developed cerebrospinal fluid (CSF) reservoir called the V-Port. Methods The newly developed V-Port consists of a non-collapsible reservoir outlined with a titanium cage and a connector for the ventricular catheter to be assembled. It is designed to be better palpated and more durable to multiple punctures than the Ommaya reservoir. A total of nine patients diagnosed with leptomeningeal carcinomatosis were selected for V-Port insertion. Each patient was followed up for evaluation for a month after the operation. Results The average operation time for V-Port insertion was 42 minutes and the average incision size was 6.6 cm. The surgical technique of V-Port insertion was found to be intuitive by all neurosurgeons who participated in the pilot study. There was no obstruction or leakage of the V-Port during intrathecal chemotherapy or CSF drainage. Also, there were no complications including post-operative intracerebral hemorrhage, infection and skin problems related to the V-Port. Conclusion V-Port is a safe and an easy to use implantable CSF reservoir that addresses problems of other implantable CSF reservoirs. Further multicenter clinical trial is needed to prove the safety and the function of the V-Port.

We performed this study to identify the treatment patterns of patients with low-grade gliomas (LGG) in Korea. A total of 555 patients diagnosed as WHO grade II gliomas between 2000 and 2010 at 14 Korean institutions were included. The patients were divided into four adjuvant treatment groups: adjuvant fractionated radiotherapy (RT, N = 204), adjuvant chemotherapy (N = 20), adjuvant fractionated RT and chemotherapy (N = 65), and non-adjuvant treatment (N = 266) groups. We examined differences among the groups and validated patient/tumor characteristics associated with the adjuvant treatments. Astrocytoma was diagnosed in 210 patients (38%), oligoastrocytoma in 85 patients (15%), and oligodendroglioma in 260 patients (47%). Gross total resection was performed in 200 patients (36%), subtotal resection in 153 (28%), partial resection in 71 patients (13%), and biopsy in 131 patients (24%). RT was most commonly applied as an adjuvant treatment. The use of chemotherapy with or without RT decreased after 2008 (from 38 to 4%). The major chemotherapeutic regimen was procarbazine, lomustine, and vincristine (PCV); however, the proportion of temozolomide increased since 2005 (up to 69%). Patient/tumor characteristics related with RT were male gender, non-seizure, multiple lobes involvement, and non-gross total resection. Chemotherapy was associated with non-gross total resection and non-astrocytoma. A preference for RT and increased use of temozolomide was evident in the treatment pattern of LGG. The extent of resection was associated with a decision to perform RT and chemotherapy. To establish a robust guideline for LGG, further studies including molecular information are needed.

The diagnosis of leptomeningeal metastasis (LM) is often difficult due to the paucity of cancer cells in cerebrospinal fluid (CSF) and nonspecific findings on neuroimaging. Investigations of extracellular microRNAs (miRNAs) in CSF could be used for both the diagnosis and study of LM pathogenesis because they reflect the activity of disseminating cancer cells. We isolated CSF extracellular miRNAs from patients (n = 65) of different central nervous system tumor statuses, including cancer control, healthy control, LM, brain metastasis (BM), and primary brain tumor (BT) groups, and performed miRNA microarrays. In unsupervised clustering analyses, all LM and two BM samples showed unique profiles. Among 30 miRNAs identified for LM-specific biomarkers via a Prediction Analysis of Microarrays, miR-335-5p and miR-34b-3p were confirmed in both the discovery and validation samples (n = 23). Next, we performed a significance analysis of the microarray (SAM) to extract discriminative miRNA profiles of two selected CSF groups, with LM samples revealing a greater number of discriminative miRNAs than BM and BT samples compared to controls. Using SAM comparisons between LM and BM samples, we identified 30 upregulated and 6 downregulated LM miRNAs. To reduce bias from different primary cancers, we performed a subset analysis with primary non-small cell lung cancer, and 12 of 13 upregulated miRNAs in LM vs. BM belonged to the upregulated miRNAs in LM. We identified possible target genes and their biological processes that could be affected by LM discriminative miRNAs in NSCLC using the gene ontology database. In conclusion, we identified a unique extracellular miRNA profile in LM CSF that was different from BM, suggesting the use of miRNAs as LM biomarkers in studies of LM pathogenesis.

When distant metastases are discovered, it is important to determine receptor profiles of these lesions through histologic examination. However, brain metastasis sites are difficult to reach to be routinely biopsied. The purpose of this study was to determine expression profiles of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) in breast cancer brain metastasis (BCBM) and the existence of discordance between primary breast cancer and brain metastasis. A total of 37 patients who underwent craniotomies for metastatic brain tumors arising from breast cancer at National Cancer Center (NCC) of Korea between 2002 and 2014 were retrospectively reviewed. Clinicopathologic data were collected from electronic medical records. Receptor profiles of primary breast cancer and brain metastasis in each patient were identified. Data of ER, PR, and HER2 expression in brain metastasis were available in electronic medical records for 21 (56.8%) of 37 cases. Results of ER, PR, and HER2 expression were positive in 47.6, 42.9, and 38.1% of patients with brain metastasis, respectively. Receptor conversion occurred in 11 (52.4%) of 21 patients (for ER, 9.5%; for PR, 38.1%; for HER2, 23.8%). Overall survival was longer in patients with concordant receptor expression patterns between primary breast cancer and brain lesion compared to that in patients with discordant patterns. However, such difference was not statistically significant (discordant vs. concordant median survival: 19.2 versus 31.1 months, p = 0.181). Receptor conversion in BCBMs was observed in over 50% of Korean patients used in this study. HER2 conversion was observed in 23.8% of patients in this study. Therefore, if resistance to anti-HER2 treatment is suspected in patients with BCBM, biopsy is needed to determine receptor profiles of brain lesion.

The incidence of leptomeningeal dissemination (LMD) of anaplastic glioma has been increasing. LMD can be observed at the time of initial presentation or the time of recurrence. As a result of both rarity and unusual presentation, a standard therapy has not yet been suggested. In contrast to leptomeningeal carcinomatosis for systemic solid cancers, a relatively prolonged survival is observed in some patients with LMD of anaplastic gliomas. Treatment modalities include whole craniospinal irradiation, intra-cerebrospinal fluid (CSF) chemotherapy, and systemic chemotherapy. In some cases, response to temozolomide (TMZ), with or without combined radiation has been reported. Here, we report two cases of LMD of an anaplastic glioma. In one case LMD presented at the time of diagnosis, and in the other at the time of recurrence after radiation. CSF cytology was positive in both cases, and persisted in spite of intrathecal methotrexate chemotherapy. Later, TMZ was prescribed for progressing brain parenchymal lesions, and both radiological and cytological responses were obtained after oral TMZ treatment.

// Byong Chul Yoo 1 , Jun Hwa Lee 1 , Kyung-Hee Kim 1 , Weiwei Lin 2 , Jong Heon Kim 2 , Jong Bae Park 2 , Hyun Jin Park 3 , Sang Hoon Shin 4 , Heon Yoo 4 , Ji Woong Kwon 4 and Ho-Shin Gwak 2, 4 1 Biomarker Branch, Research Institute, National Cancer Center, Goyang, Republic of Korea 2 Department of Cancer Biomedical Science, National Cancer Center, Graduate School of Cancer Science and Policy, Goyang, Republic of Korea 3 Center for Pediatric Cancer, National Cancer Center, Goyang, Republic of Korea 4 Neuro-oncology Clinic, National Cancer Center, Goyang, Republic of Korea Correspondence to: Ho-Shin Gwak, email: nsghs@ncc.re.kr Keywords: cerebrospinal fluid, metabolome, leptomeningeal carcinomatosis, profile, diagnosis Received: July 28, 2017 Accepted: August 28, 2017 Published: September 18, 2017 ABSTRACT Purpose: Early diagnosis of leptomeningeal carcinomatosis (LMC) is necessary to improve outcomes of this formidable disease. However, cerebrospinal fluid (CSF) cytology is frequently false negative. We examined whether CSF metabolome profiles can be used to differentiate patients with LMC from patients having a risk for development of LMC. Results: A total of 10,905 LMIs were evaluated using PCA-DA. The LMIs defined Group 2 with a sensitivity of 85% and a specificity of 91%. After selecting 33 LMIs, including diacetylspermine and fibrinogen fragments, the CSF metabolomics profile had a sensitivity of 100% and a specificity of 93% for discriminating Group 1b from the other groups. After selecting 21 LMIs, including phosphatidylcholine, the CSF metabolomics profile differentiated LMC (Group 2) patients from the high-risk groups of Group 3 and Group 4 with 100% sensitivity and 100% specificity. Materials and Methods: We prospectively collected CSF from five groups of patients: Group 1a, systemic cancer; Group 1b, no tumor; Group 2, LMC; Group 3, brain metastasis; Group 4, brain tumor other than brain metastasis. All metabolites in the CSF samples were detected as low-mass ions (LMIs) using mass spectrometry. Principal component analysis-based discriminant analysis (PCA-DA) and two search algorithms were used to select the LMIs that differentiated the patient groups of interest from controls. Conclusions: Analysis of CSF metabolite profiles could be used to diagnose LMC and exclude patients at high-risk of LMC with a 100% accuracy. We expect a future validation trial to evaluate CSF metabolic profiles supporting CSF cytology.

Purpose In this retrospective study, we compared the incidence of leptomeningeal carcinomatosis or dural metastasis (LMCDM) in patients who received whole brain radiotherapy (WBRT), partial radiotherapy (PRT), or no radiotherapy (RT) following resection of brain metastases from breast cancer. Materials and Methods Fifty-one patients with breast cancer underwent surgical resection for newly diagnosed brain metastases in two institutions between March 2001 and March 2015. Among these, 34 received postoperative WBRT (n=24) or PRT (n=10) and 17 did not. Results With a median follow-up of 12.4 months (range, 2.3 to 83.6 months), 22/51 patients developed LMCDM at a median of 8.6 months (range, 4.8 to 51.2 months) after surgery. The 18-months LMCDM-free survival (LMCDM-FS) rates were 77.5%, 30.0%, and 13.6%, in the WBRT, PRT, and no RT groups, respectively (p=0.013). The presence of a tumor adjacent to cerebrospinal fluid flow and no systemic treatment after treatment for brain metastases were also associated with poor LMCDM-FS rate. Multivariate analysis showed that WBRT compared to PRT (p=0.009) and systemic treatment (p < 0.001) were independently associated with reduced incidence of LMCDM. Conclusion WBRT improved LMCDM-FS rate after resection of brain metastases compared to PRT in breast cancer patients.

// Jae-Won Hyun 1, 6 , Ji Hyun Park 2 , Boo Gil Kang 3 , Eun Young Park 4 , Boram Park 4 , Jungnam Joo 4 , Jong Kuk Kim 5 , Su-Hyun Kim 1 , Jee Hyang Jeong 6 , Hyang Woon Lee 6 , Kee Duk Park 6 , Kyung Gyu Choi 6 , Sang-Hyun Hwang 3, 7 , Ho-Shin Gwak 7 and Ho Jin Kim 1, 7 1 Department of Neurology, National Cancer Center, Goyang, Korea 2 Department of Oncology, Konkuk University of Medical College, Seoul, Korea 3 Department of Laboratory Medicine, National Cancer Center, Goyang, Korea 4 Biometric Research Branch, National Cancer Center, Goyang, Korea 5 Department of Neurology, Dong-A University College of Medicine, Busan, Korea 6 Department of Neurology, Ewha Womans University School of Medicine and Ewha Medical Research Institute, Seoul, Korea 7 Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Korea Correspondence to: Ho Jin Kim, email: hojinkim@ncc.re.kr Keywords: leptomeningeal carcinomatosis, diagnosis, prognosis, CSF, CYFRA 21-1 Received: November 30, 2016 Accepted: May 18, 2017 Published: June 08, 2017 ABSTRACT Objectives: To investigate the diagnostic and prognostic values of cerebrospinal fluid (CSF) CYFRA 21-1 in patients with leptomeningeal carcinomatosis (LMC). Methods: Concentration of CSF CYFRA 21-1 was detected using electro-chemiluminescent immunoassay. The difference in level of CYFRA 21-1 between 61 patients with LMC and 200 patients with other neurological disease was evaluated, and diagnostic performance of CSF CYFRA 21-1 was investigated. In LMC patients treated with ventriculo-lumbar perfusion (VLP) chemotherapy, prognostic performance of CSF CYFRA 21-1 was evaluated. Results: The CSF CYFRA 21-1 was significantly higher in LMC patients than that in patients with other neurological diseases (p

To evaluate the impact of adjuvant postoperative radiotherapy (PORT) in adult WHO grade II-III intracranial ependymoma (IEPN).A total of 172 pathologically confirmed adult grade II-III IEPN patients from 12 institutions were eligible. Of them, 106 (61.6%) and 66 (38.4%) patients were grade II and III, respectively. For grade II and III IEPNs, 51 (48.1%) and 59 (89.4%) patients received PORT, respectively. The median dose to the primary tumor bed was 54.0 Gy and 59.4 Gy for grade II and III patients, respectively. The prognostic impact of sex, age, performance, WHO grade, location, size, surgical extent, and PORT on local control (LC), progression-free survival (PFS), and overall survival (OS) were evaluated by univariate and multivariate analysis.The median follow-up period for survivors was 88.1 months. The 5-/10-year LC, PFS, and OS rates were 64.8%/54.0%, 56.4%/44.8%, and 76.6%/71.0%, respectively. On multivariate analysis, adjuvant PORT significantly improved LC (P = 0.002), PFS (P = 0.002), and OS (P = 0.043). Older age (P 0.001), WHO grade III (P 0.001), larger tumor size (P = 0.004), and lesser surgical extent (P 0.001) were also negative factors for OS. Adjuvant PORT also improved LC (P = 0.010), PFS (P = 0.007), and OS (P = 0.069) on multivariate analysis for grade II IEPNs.This multicenter retrospective study supports the role of adjuvant PORT in terms of disease control and survival in adult grade II-III IEPNs. Prospective randomized trials focused on individualized treatment based on molecular subtypes is warranted.

Objective Radiation is known to induce autophagy in malignant glioma cells whether it is cytocidal or cytoprotective. Dexamethasone is frequently used to reduce tumor-associated brain edema, especially during radiation therapy. The purpose of the study was to determine whether and how dexamethasone affects autophagy in irradiated malignant glioma cells and to identify possible intervening molecular pathways. Methods We prepared p53 mutant U373 and LN229 glioma cell lines, which varied by phosphatase and tensin homolog (PTEN) mutational status and were used to make U373 stable transfected cells expressing GFP-LC3 protein. After performing cell survival assay after irradiation, the IC50 radiation dose was determined. Dexamethasone dose (10 μM) was determined from the literature and added to the glioma cells 24 hours before the irradiation. The effect of adding dexamethasone was evaluated by cell survival assay or clonogenic assay and cell cycle analysis. Measurement of autophagy was visualized by western blot of LC3-I/LC3-II and quantified by the GFP-LC3 punctuated pattern under fluorescence microscopy and acridine orange staining for acidic vesicle organelles by flow cytometry. Results Dexamethasone increased cell survival in both U373 and LN229 cells after irradiation. It interfered with autophagy after irradiation differently depending on the PTEN mutational status : the autophagy decreased in U373 (PTEN-mutated) cells but increased in LN229 (PTEN wild-type) cells. Inhibition of protein kinase B (AKT) phosphorylation after irradiation by LY294002 reversed the dexamethasone-induced decrease of autophagy and cell death in U373 cells but provoked no effect on both autophagy and cell survival in LN229 cells. After ATG5 knockdown, radiation-induced autophagy decreased and the effect of dexamethasone also diminished in both cell lines. The diminished autophagy resulted in a partial reversal of dexamethasone protection from cell death after irradiation in U373 cells; however, no significant change was observed in surviving fraction LN229 cells. Conclusion Dexamethasone increased cell survival in p53 mutated malignant glioma cells and increased autophagy in PTEN-mutant malignant glioma cell but not in PTEN-wildtype cell. The difference of autophagy response could be mediated though the phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin signaling pathway.

OBJECTIVE Elevated cell counts and protein levels in cerebrospinal fluid (CSF) result from disease activity in patients with leptomeningeal carcinomatosis (LMC). Previous studies evaluated the use of CSF profiles to monitor a treatment response or predict prognosis. CSF profiles vary, however, according to the sampling site and the patient's systemic condition. We compared lumbar and ventricular CSF profiles collected before intraventricular chemotherapy for LMC and evaluated the association of these profiles with patients' systemic factors and LMC disease activity. METHODS CSF profiles were retrospectively collected from 228 patients who underwent Ommaya reservoir insertion for intraventricular chemotherapy after a diagnosis of LMC. Lumbar samples taken via lumbar puncture were used for the diagnosis, and ventricular samples were obtained later at the time of Ommaya reservoir insertion. LMC disease activity was defined as the presence of LMC-related symptoms such as increased intracranial pressure, hydrocephalus, cranial neuropathy, and cauda equina syndrome. RESULTS Cell counts (median : 8 vs. 1 cells/mL) and protein levels (median : 68 vs. 17 mg/dL) significantly higher in lumbar CSF than in ventricular CSF (p

PURPOSE The purpose of this study was to investigate the feasibility and survival benefits of combined treatment with radiotherapy and adjuvant temozolomide (TMZ) in a Korean sample. MATERIALS AND METHODS A total of 750 Korean patients with histologically confirmed glioblastoma multiforme, who received concurrent chemoradiotherapy with TMZ (CCRT) and adjuvant TMZ from January 2006 until June 2011, were analyzed retrospectively. RESULTS After the first operation, a gross total resection (GTR), subtotal resection (STR), partial resection (PR), biopsy alone were achieved in 388 (51.7%), 159 (21.2%), 96 (12.8%), and 107 (14.3%) patients, respectively. The methylation status of O6-methylguanine-DNA methyltransferase (MGMT) was reviewed retrospectively in 217 patients. The median follow-up period was 16.3 months and the median overall survival (OS) was 17.5 months. The actuarial survival rates at the 1-, 3-, and 5-year OS were 72.1%, 21.0%, and 9.0%, respectively. The median progression-free survival (PFS) was 10.1 months, and the actuarial PFS at 1-, 3-, and 5-year PFS were 42.2%, 13.0%, and 7.8%, respectively. The patients who received GTR showed a significantly longer OS and PFS than those who received STR, PR, or biopsy alone, regardless of the methylation status of the MGMT promoter. Patients with a methylated MGMT promoter also showed a significantly longer OS and PFS than those with an unmethylated MGMT promoter. Patients who received more than six cycles of adjuvant TMZ had a longer OS and PFS than those who received six or fewer cycles. Hematologic toxicity of grade 3 or 4 was observed in 8.4% of patients during the CCRT period and in 10.2% during the adjuvant TMZ period. CONCLUSION Patients treated with CCRT followed by adjuvant TMZ had more favorable survival rates and tolerable toxicity than those who did not undergo this treatment.

Background There have been no guidelines for the management of adult patients with diffuse midline glioma (DMG), H3K27M-mutant in Korea since the 2016 revised WHO classification newly defined this disease entity. Thus, the Korean Society for Neuro-Oncology (KSNO), a multidisciplinary academic society, had begun preparing guidelines for DMG since 2019. Methods The Working Group was composed of 27 multidisciplinary medical experts in Korea. References were identified through searches of PubMed, MEDLINE, EMBASE, and Cochrane CENTRAL using specific and sensitive keywords as well as combinations of keywords. As 'diffuse midline glioma' was recently defined, and there was no international guideline, trials and guidelines of 'diffuse intrinsic pontine glioma' or 'brain stem glioma' were thoroughly reviewed first. Results The core contents are as follows. The DMG can be diagnosed when all of the following three criteria are satisfied: the presence of the H3K27M mutation, midline location, and infiltrating feature. Without identification of H3K27M mutation by diagnostic biopsy, DMG cannot be diagnosed. For the primary treatment, maximal safe resection should be considered for tumors when feasible. Radiotherapy is the primary option for tumors in case the total resection is not possible. A total dose of 54 Gy to 60 Gy with conventional fractionation prescribed at 1-2 cm plus gross tumor volume is recommended. Although no chemotherapy has proven to be effective in DMG, concurrent chemoradiotherapy (± maintenance chemotherapy) with temozolomide following WHO grade IV glioblastoma's protocol is recommended. Conclusion The detection of H3K27M mutation is the most important diagnostic criteria for DMG. Combination of surgery (if amenable to surgery), radiotherapy, and chemotherapy based on comprehensive multidisciplinary discussion can be considered as the treatment options for DMG.