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Purpose To comprehensively investigate prognostic factors, including clinical and molecular factors and treatment modalities, in adult glioma patients with leptomeningeal metastases (LM). Methods Total 226 patients with LM (from 2001 to 2021 among 1495 grade 2 to 4 glioma patients, 88.5% of LM patients being IDH-wildtype) with complete information on IDH mutation, 1p/19q codeletion, and MGMT promoter methylation status were enrolled. Predictors of overall survival (OS) of entire patients were determined by time-dependent Cox analysis, including clinical, molecular, and treatment data. Subgroup analyses were performed for patients with LM at initial diagnosis and LM diagnosed at recurrence (herein, initial and recurrent LM). Identical analyses were performed in IDH-wildtype glioblastoma patients. Results Median OS was 17.0 (IQR 9.7–67.1) months, with shorter median OS in initial LM than recurrent LM patients (12.2 vs 20.6 months, P Conclusion Active chemotherapy and antiangiogenic therapy demonstrated survival benefit in glioma patients with LM. There is consistent female survival advantage, whereas longer interval between initial glioma diagnosis and LM development suggests longer OS in recurrent LM.

Previous genomewide association studies (GWASs), single nucleotide polymorphisms (SNPs) on cyclin-dependent kinase inhibitor 2 A (CDKN2A), cyclin-dependent kinase inhibitor 2B (CDKN2B), and cyclin-dependent kinase inhibitor 2B antisense RNA1 (CDKN2B-AS1) were reported as risk loci for glioma, a subgroup of the brain tumor. To further characterize this association with the risk of brain tumors in a Korean population, we performed a fine-mapping association study of CDKN2A, CDKN2B, and CDKN2B-AS1.A total of 17 SNPs were selected and genotyped in 1,439 subjects which were comprised of 959 patients (pituitary adenoma 335; glioma 324; meningioma 300) and 480 population controls (PCs). We discovered that a 3'untranslated region (3'UTR) variant, rs181031884 of CDKN2B (Asian-specific variant), had significant association with the risk of pituitary adenoma (PA) (Odds ratio = 0.58, P = 0.00003). Also, rs181031884 appeared as an independent causal variant among the significant variants in CDKN2A and CDKN2B, and showed dose-dependent effects on PA.Although further studies are needed to verify the impact of this variant on PA susceptibility, our results may help to understand CDKN2B polymorphism and the risk of PA.

Objective : Pituitary adenomas frequently extend into the suprasellar space. After a suprasellar tumor is removed, the superiorly extended arachnoid becomes redundant and sinks down into the intrasellar space which often hiders visualization and accessibility to the hidden space behind the evaginated arachnoid. We introduced arachnoid remodeling by clipping technique, and evaluated its usefulness and safety during TSS.Methods : Total 223 patients who underwent arachnoid remodeling with our new clipping technique were included. Redundant arachnoid was clipped along the dural edge with multiple 2.6-mm titanium clips until the redundant arachnoid membrane no longer blocked the surgical route. To check for possible deterioration of hormonal function by this technique, we assessed anterior pituitary function of 166 patients who underwent arachnoid remodeling by clipping and compared this with those of other 429 control patients.Results : Our technique greatly enhanced the accessibility and visualization of intrasellar and parasellar spaces, both of which are generally hindered by redundant arachnoid during transsphenoidal surgery (TSS). We found no difference in anterior pituitary function between a clip-assisted arachnoid remodeling group and the control group, implying that this technique does not result in hypopituitarism.Conclusion : During TSS for pituitary adenomas with suprasellar extension, arachnoid remodeling by clipping technique is very useful and convenient for the management of the redundant arachnoid membrane to enhance visualization and surgical accessibility.

To develop a fully automatic radiomics model to differentiate adult pilocytic astrocytomas (PA) from high-grade gliomas (HGGs).This retrospective study included 302 adult patients with PA (n = 62) or HGG (n = 240). The patients were randomly divided into training (n = 211) and test (n = 91) sets. Clinical data were obtained, and radiomic features (n = 372) were extracted from multiparametric MRI with automatic tumour segmentation. After feature selection with F-score, a Light Gradient Boosting Machine classifier with subsampling was trained to develop three models: (1) clinical model, (2) radiomics model, and (3) combined clinical and radiomics model. Human performance was also assessed. The performance of the classifier was validated in the test set. SHapley Additive exPlanations (SHAP) was applied to explore the interpretability of the model.A total of 15 radiomic features were selected. In the test set, the combined clinical and radiomics model (area under the curve [AUC], 0.93) showed a significantly higher performance than the clinical model (AUC, 0.79, p = 0.037) and had a similar performance to the radiomics model (AUC, 0.92, p = 0.828). The combined clinical and radiomics model also showed a significantly higher performance than humans (AUC, 0.76-0.81, p0.05). The model explanation by SHAP suggested that lower intratumoural heterogeneity from T2-weighted images was highly associated with PA diagnosis.The fully automatic combined clinical and radiomics model may be helpful for differentiating adult PAs from HGGs.• Differentiating adult PAs from HGGs is challenging because PAs may manifest a large spectrum of imaging presentations, often including aggressive imaging features. • The fully automatic combined clinical and radiomics model showed a significantly higher performance than the clinical model or humans. • The model explanation by SHAP suggested that second-order features from T2-weighted imaging were important in diagnosis and might reflect the underlying pathophysiology that PAs have lesser tissue heterogeneity than HGGs.

Purpose: The Cancer Genome Atlas (TCGA) project recently uncovered four molecular subtypes of gastric cancer: Epstein–Barr virus (EBV), microsatellite instability (MSI), genomically stable (GS), and chromosomal instability (CIN). However, their clinical significances are currently unknown. We aimed to investigate the relationship between subtypes and prognosis of patients with gastric cancer.Experimental Design: Gene expression data from a TCGA cohort (n = 262) were used to develop a subtype prediction model, and the association of each subtype with survival and benefit from adjuvant chemotherapy was tested in 2 other cohorts (n = 267 and 432). An integrated risk assessment model (TCGA risk score) was also developed.Results: EBV subtype was associated with the best prognosis, and GS subtype was associated with the worst prognosis. Patients with MSI and CIN subtypes had poorer overall survival than those with EBV subtype but better overall survival than those with GS subtype (P = 0.004 and 0.03 in two cohorts, respectively). In multivariate Cox regression analyses, TCGA risk score was an independent prognostic factor [HR, 1.5; 95% confidence interval (CI), 1.2–1.9; P = 0.001]. Patients with the CIN subtype experienced the greatest benefit from adjuvant chemotherapy (HR, 0.39; 95% CI, 0.16–0.94; P = 0.03) and those with the GS subtype had the least benefit from adjuvant chemotherapy (HR, 0.83; 95% CI, 0.36–1.89; P = 0.65).Conclusions: Our prediction model successfully stratified patients by survival and adjuvant chemotherapy outcomes. Further development of the prediction model is warranted. Clin Cancer Res; 23(15); 4441–9. ©2017 AACR.

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Objective: To evaluate the quality of radiomics studies on pituitary adenoma according to the radiomics quality score (RQS) and Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD). Methods: PubMed MEDLINE and EMBASE were searched to identify radiomics studies on pituitary adenomas. From 138 articles, 20 relevant original research articles were included. Studies were scored based on RQS and TRIPOD guidelines. Results: Most included studies did not perform pre-processing; isovoxel resampling, signal intensity normalization, and N4 bias field correction were performed in only five (25%), eight (40%), and four (20%) studies, respectively. Only two (10%) studies performed external validation. The mean RQS and basic adherence rate were 2.8 (7.6%) and 26.6%, respectively. There was a low adherence rate for conducting comparison to “gold-standard” (20%), multiple segmentation (25%), and stating potential clinical utility (25%). No study stated the biological correlation, conducted a test–retest or phantom study, was a prospective study, conducted cost-effectiveness analysis, or provided open-source code and data, which resulted in low-level evidence. The overall adherence rate for TRIPOD was 54.6%, and it was low for reporting the title (5%), abstract (0%), explaining the sample size (10%), and suggesting a full prediction model (5%). Conclusion: The radiomics reporting quality for pituitary adenoma is insufficient. Pre-processing is required for feature reproducibility and external validation is necessary. Feature reproducibility, clinical utility demonstration, higher evidence levels, and open science are required. Titles, abstracts, and full prediction model suggestions should be improved for transparent reporting. Advances in knowledge: Despite the rapidly increasing number of radiomics researches on pituitary adenoma, the quality of science in these researches is unknown. Our study indicates that the overall quality needs to be significantly improved in radiomics studies on pituitary adenoma, and since the concept of RQS and IBSI is still unfamiliar to clinicians and radiologist researchers, our study may help to reach higher technical and clinical impact in the future study.

Introduction The importance of fatty acid oxidation (FAO) in the bioenergetics of glioblastoma (GBM) is being realized. Etomoxir (ETO), a carnitine palmitoyltransferase 1 (CPT1) inhibitor exerts cytotoxic effects in GBM, which involve interrupting the FAO pathway. We hypothesized that FAO inhibition could affect the outcomes of current standard temozolomide (TMZ) chemotherapy against GBM. Methods The FAO-related gene expression was compared between GBM and the tumor-free cortex. Using four different GBM tumorspheres (TSs), the effects of ETO and/or TMZ was analyzed on cell viability, tricarboxylate (TCA) cycle intermediates and adenosine triphosphate (ATP) production to assess metabolic changes. Alterations in tumor stemness, invasiveness, and associated transcriptional changes were also measured. Mouse orthotopic xenograft model was used to elucidate the combinatory effect of TMZ and ETO. Results GBM tissues exhibited overexpression of FAO-related genes, especially CPT1A, compared to the tumor-free cortex. The combined use of ETO and TMZ further inhibited TCA cycle and ATP production than single uses. This combination treatment showed superior suppression effects compared to treatment with individual agents on the viability, stemness, and invasiveness of GBM TSs, as well as better downregulation of FAO-related gene expression. The results of in vivo study showed prolonged survival outcomes in the combination treatment group. Conclusion ETO, an FAO inhibitor, causes a lethal energy reduction in the GBM TSs. When used in combination with TMZ, ETO effectively reduces GBM cell stemness and invasiveness and further improves survival. These results suggest a potential novel treatment option for GBM.

Background The brainstem has the critical role of regulating cardiac and respiratory function and it also provides motor and sensory function to the face via the cranial nerves. Despite the observation of a brainstem lesion in a radiological examination, it is difficult to obtain tissues for a pathological diagnosis because of the location and small volume of the brainstem. Thus, we aimed to share our 6‐year experience with stereotactic biopsies from brainstem lesions and confirm the value and safety of stereotactic biopsy on this highly eloquent area in this study. Methods We retrospectively reviewed the medical records of 42 adult patients who underwent stereotactic biopsy on brainstem lesions from 2015 to 2020. The radiological findings, surgical records, pathological diagnosis, and postoperative complications of all patients were analyzed. Results Histopathological diagnoses were made in 40 (95.2%) patients. Astrocytic tumors were diagnosed in 29 (69.0%) patients, diffuse large B cell lymphoma in 5 (11.9%) patients, demyelinating disease in 4 (9.5%) patients, germinoma in 1 (2.4%) patient, and radiation necrosis in 1 (2.4%) patient. In the 40 patients with successful stereotactic biopsy, 10 (25.0%) patients had inconsistent preoperative radiological diagnosis and postoperative pathological diagnosis. In addition, there was a difference between the treatments prescribed by the radiological and pathological diagnoses in 8 out of 10 patients whose diagnoses changed after biopsy. There was no operative mortality among the 42 patients. Conclusions A pathological diagnosis can be made safely and efficiently in brainstem lesions using stereotactic biopsy. This pathological diagnosis will enable patients to receive appropriate treatment., Three approaches to stereotactic biopsy for brainstem and a Venn diagram showing the location of 42 brainstem lesion that performed stereotactic biopsy.

Limited treatment options are currently available for glioblastoma (GBM), an extremely lethal type of brain cancer. For a variety of tumor types, bioenergetic deprivation through inhibition of cancer-specific metabolic pathways has proven to be an effective therapeutic strategy. Here, we evaluated the therapeutic effects and underlying mechanisms of dual inhibition of carnitine palmitoyltransferase 1A (CPT1A) and glucose-6-phosphate dehydrogenase (G6PD) critical for fatty acid oxidation (FAO) and the pentose phosphate pathway (PPP), respectively, against GBM tumorspheres (TSs).Therapeutic efficacy against GBM TSs was determined by assessing cell viability, neurosphere formation, and 3D invasion. Liquid chromatography-mass spectrometry (LC-MS) and RNA sequencing were employed for metabolite and gene expression profiling, respectively. Anticancer efficacy in vivo was examined using an orthotopic xenograft model.CPT1A and G6PD were highly expressed in GBM tumor tissues. Notably, siRNA-mediated knockdown of both genes led to reduced viability, ATP levels, and expression of genes associated with stemness and invasiveness. Similar results were obtained upon combined treatment with etomoxir and dehydroepiandrosterone (DHEA). Transcriptome analyses further confirmed these results. Data from LC-MS analysis showed that this treatment regimen induced a considerable reduction in the levels of metabolites associated with the TCA cycle and PPP. Additionally, the combination of etomoxir and DHEA inhibited tumor growth and extended survival in orthotopic xenograft model mice.Our collective findings support the utility of dual suppression of CPT1A and G6PD with selective inhibitors, etomoxir and DHEA, as an efficacious therapeutic approach for GBM.

Advancements in photodynamic diagnosis (PDD) and photodynamic therapy (PDT) as a standard care in cancer therapy have been limited. This study is aimed to investigate the clinical availability of 5-aminolevulinic acid (5-ALA)-based PDD and PDT in glioblastoma (GBM) patient-derived tumorspheres (TSs) and mouse orthotopic xenograft model.PDT was performed using a 635 nm light-emitting diode (LED). Transcriptome profiles were obtained from microarray data. For knockdown of C5α, siRNA was transfected into tumor mesenchymal stem-like cells (tMSLCs). The invasiveness of TSs was quantified using collagen-based 3D invasion assays.Treatment with 1 mM 5 ALA induced distinct protoporphyrin IX (PpIX) fluorescence in GBM TSs, but not in non-tumor cells or tissues, including tMSLCs. These observations were negatively correlated with the expression levels of FECH, which catalyzes the conversion of accumulated PpIX to heme. Furthermore, the 5-ALA-treated GBM TSs were sensitive to PDT, thereby significantly decreasing cell viability and invasiveness. Notably, the effects of PDT were abolished by culturing TSs with tMSLC-conditioned media. Transcriptome analysis revealed diverse tMSLC-secreted chemokines, including C5α, and their correlations with the expression of stemness- or mesenchymal transition-associated genes. By adding or inhibiting C5α, we confirmed that acquired resistance to PDT was induced via tMSLC-secreted C5α.Our results show substantial therapeutic effects of 5-ALA-based PDT on GBM TSs, suggesting C5α as a key molecule responsible for PDT resistance. These findings could trigger PDT as a standard clinical modality for the treatment of GBM.

ObjectiveCavernous sinus (CS) invasion is frequently encountered in the management of skull base tumors. Surgical treatment of tumors in the CS is technically demanding, and selection of an optimal surgical approach is critical for maximal tumor removal and patient safety. We aimed to evaluate the feasibility of an endoscopic transorbital approach (ETOA) to the CS based on a cadaveric study.MethodsFive cadaveric heads were used for dissection under the ETOA in the comparison with the endoscopic endonasal approach (EEA) and the microscopic transcranial approach (TCA). The CS was exposed, accessed, and explored, first using the ETOA, followed by the EEA and TCA. A dedicated endoscopic system aided by neuronavigation guidance was used for the procedures. During the ETOA, neurovascular structures inside the CS were approached through different surgical triangles.ResultsAfter completing the ETOA with interdural dissection, the lateral wall of the CS was fully exposed. The lateral and posterior compartments of the CS, of which accessibility is greatly limited under the EEA, were effectively approached and explored under the ETOA. The anteromedial triangle was the largest window via which most of the lateral compartment was freely approached. The internal carotid artery and abducens nerve were also observed through the anteromedial triangle and just behind V1. During the ETOA, the approaching view through the supratrochlear and infratrochlear triangles was more directed towards the posterior compartment. After validation of the feasibility and safety based on the cadaveric study, ETOA was successfully performed in a patient with a pituitary adenoma with extensive CS invasion.ConclusionsBased on the cadaveric study, we demonstrated that the lateral CS wall was reliably accessed under the ETOA. The lateral and posterior compartments of the CS were effectively explored via surgical triangles under the ETOA. ETOA provides a unique and valuable surgical route to the CS with a promising synergy when used with EEA and TCA. Our experience with a clinical case convinces us of the efficacy of the ETOA during surgical management of skull base tumors with CS-invasion.

Forkhead Box M1 (FOXM1) is known to regulate cell proliferation, apoptosis and tumorigenesis. The lignan, (−)-(2R,3R)-1,4-O-diferuloylsecoisolariciresinol (DFS), from Alnus japonica has shown anti-cancer effects against colon cancer cells by suppressing FOXM1. The present study hypothesized that DFS can have anti-cancer effects against glioblastoma (GBM) tumorspheres (TSs). Immunoprecipitation and luciferase reporter assays were performed to evaluate the ability of DFS to suppress nuclear translocation of β-catenin through β-catenin/FOXM1 binding. DFS-pretreated GBM TSs were evaluated to assess the ability of DFS to inhibit GBM TSs and their transcriptional profiles. The in vivo efficacy was examined in orthotopic xenograft models of GBM. Expression of FOXM1 was higher in GBM than in normal tissues. DFS-induced FOXM1 protein degradation blocked β-catenin translocation into the nucleus and consequently suppressed downstream target genes of FOXM1 pathways. DFS inhibited cell viability and ATP levels, while increasing apoptosis, and it reduced tumorsphere formation and the invasiveness of GBM TSs. And DFS reduced the activities of transcription factors related to tumorigenesis, stemness, and invasiveness. DFS significantly inhibited tumor growth and prolonged the survival rate of mice in orthotopic xenograft models of GBM. It suggests that DFS inhibits the proliferation of GBM TSs by suppressing FOXM1. DFS may be a potential therapeutic agent to treat GBM.

This study aimed to evaluate the efficacy of radiation therapy (RT) for recurrent or residual pituitary macroadenoma (PMA) invading extrasellar regions.Patients from 2000 to 2020 who received RT with conventional fractionation for recurrent or residual PMA were included. The patients were divided according to the type of tumor [functioning (fx) or non-fx] and the aim of RT (salvage RT alone, immediate postoperative RT, delayed postoperative RT). Local and biochemical failure-free rates (FFR) were calculated using the Kaplan-Meier method.With a median follow up of 82 months (IQR; 42-132 months), 36 patients treated with conventional RT (total 45-54 Gy in 1.8 or 2 Gy per fraction) for recurrent or residual PMA were analyzed. The 10-year local FFRs after RT for non-fx and fx tumor were 100% and 74.4%, respectively (Conventional RT is safe and effective for the local control of recurrent or residual PMA. Our data suggest that immediate postoperative RT can be beneficial in recurrent or residual PMA, although further studies to evaluate risk factors of treatment failure in terms of treatment and disease characteristics are required.

To investigate whether type-specific sex differences in survival exist independently of clinical and molecular factors in adult-type diffuse gliomas according to the 2021 World Health Organization (WHO) classification.A retrospective chart and imaging review of 1325 patients (mean age, 54 ± 15 years; 569 females) with adult-type diffuse gliomas (oligodendroglioma, IDH-mutant, and 1p/19q-codeleted, n = 183; astrocytoma, IDH-mutant, n = 211; glioblastoma, IDH-wildtype, n = 800; IDH-wildtype diffuse glioma, NOS, n = 131) was performed. The demographic information, extent of resection, imaging data, and molecular data including OIn patients with glioblastoma, IDH-wildtype, female sex remained as an independent predictor of better overall survival (hazard ratio = 0.91, P = 0.031), along with age, histological grade 4, MGMT promoter methylation status, and gross total resection. Female sex showed a higher prevalence of MGMT promoter methylation (40.2% vs 32.0%, P = 0.017) but there was no interaction effect between female sex and MGMT promoter methylation status (P-interaction = 0.194), indicating independent role of female sex. The median OS for females were 19.2 months (12.3-35.0) and 16.2 months (10.5-30.6) for males. No sex difference in survival was seen in other types of adult-type diffuse gliomas.There was a female survival advantage in glioblastoma, IDH-wildtype, independently of clinical data or MGMT promoter methylation status. There was no sex difference in survival in other types of adult-type diffuse gliomas, suggesting type-specific sex effects solely in glioblastoma, IDH-wildtype.

OBJECTIVE Leptomeningeal metastases (LMs) in glioma have been underestimated given their low incidence and the lack of reliable imaging. Authors of this study aimed to investigate the real-world incidence of LMs using cerebrospinal fluid (CSF)–sensitive imaging, namely postcontrast fluid-attenuated inversion recovery (FLAIR) imaging, and to analyze molecular predictors for LMs in the molecular era. METHODS A total of 1405 adult glioma (World Health Organization [WHO] grade 2–4) patients underwent postcontrast FLAIR imaging at initial diagnosis and during treatment monitoring between 2001 and 2021. Collected molecular data included isocitrate dehydrogenase (IDH) mutation, 1p/19q codeletion, H3 K27 alteration, and O6-methylguanine–DNA methyltransferase (MGMT) promoter methylation status. LM diagnosis was performed with MRI including postcontrast FLAIR sequences. Logistic regression analysis for LM development was performed with molecular, clinical, and imaging data. Overall survival (OS) was compared between patients with and those without LM. RESULTS LM was identified in 228 patients (16.2%), 110 (7.8%) at the initial diagnosis and 118 (8.4%) at recurrence. Among the molecular diagnostics, IDH-wildtype (OR 3.14, p = 0.001) and MGMT promoter unmethylation (OR 1.43, p = 0.034) were independent predictors of LM. WHO grade 4 (OR 10.52, p < 0.001) and nonlobar location (OR 1.56, p = 0.048) were associated with LM at initial diagnosis, whereas IDH-wildtype (OR 5.04, p < 0.001) and H3 K27 alteration (OR 3.39, p = 0.003) were associated with LM at recurrence. Patients with LM had a worse median OS than those without LM (16.7 vs 32.0 months, p < 0.001, log-rank test), which was confirmed as an independent factor on multivariable Cox analysis (p = 0.004). CONCLUSIONS CSF-sensitive imaging aids the diagnosis of LM, demonstrating a high incidence of LM in adult gliomas. Furthermore, molecular markers are associated with LM development in glioma, and patients with aggressive molecular markers warrant imaging surveillance for LM.

Background: Leptomeningeal metastases (LM) in glioma have been underestimated due to low incidence and lack of reliable imaging. This study aimed to investigate a real-world incidence of LM using a CSF-sensitive imaging, namely post-contrast FLAIR, and analyze molecular predictors for LM in the molecular era. Patients and Methods: Total 1,405 adult glioma patients underwent post-contrast FLAIR imaging at initial diagnosis and during treatment monitoring between 2001 and 2021. Molecular data included isocitrate dehydrogenase (IDH) mutation, 1p/19q co-deletion, H3 K27M alteration, and O6-methylguanine-methyltransferase (MGMT) promoter methylation status. LM diagnosis was performed with MRI including post-contrast FLAIR. Logistic regression analysis for LM development was performed with molecular, clinical, and imaging data. Overall survival (OS) was compared between patients with and without LM. Results: LM was identified in 228 patients (16.2%), with 110 patients (7.8%) at initial diagnosis, and 118 patients (8.4%) at recurrence. Among molecular diagnostics, IDH-wildtype (odds ratio [OR] 3.14, P = .001) and MGMT promoter unmethylation (OR=1.43, P=.034) were independent predictors of LM. WHO grade 4 (OR=10.52, P

Objective Electrooculography (EOG) records eyeball movements as changes in the potential difference between the negatively charged retina and the positively charged cornea. We aimed to investigate whether reliable EOG waveforms can be evoked by electrical stimulation of the oculomotor and abducens nerves during skull base surgery. Methods We retrospectively reviewed the records of 18 patients who had undergone a skull base tumor surgery using EOG (11 craniotomies and seven endonasal endoscopic surgeries). Stimulation was performed at 5 Hz with a stimulus duration of 200 μs and an intensity of 0.1-5 mA using a concentric bipolar probe. Recording electrodes were placed on the upper (active) and lower (reference) eyelids, and on the outer corners of both eyes; the active electrode was placed on the contralateral side. Results Reproducibly triggered EOG waveforms were observed in all cases. Electrical stimulation of cranial nerves (CNs) III and VI elicited positive waveforms and negative waveforms, respectively, in the horizontal recording. The median latencies were 3.1 and 0.5 ms for craniotomies and endonasal endoscopic surgeries, respectively (p=0.007). Additionally, the median amplitudes were 33.7 and 46.4 μV for craniotomies and endonasal endoscopic surgeries, respectively (p=0.40). Conclusion This study showed reliably triggered EOG waveforms with stimulation of CNs III and VI during skull base surgery. The latency was different according to the point of stimulation and thus predictable. As EOG is noninvasive and relatively easy to perform, it can be used to identify the ocular motor nerves during surgeries as an alternative of electromyography.

Klotho protein is well-known as an anti-aging agent, however, several studies have suggested that Klotho protein also increases antioxidant activity and the reproductive system, as Klotho protein is closely associated with Wnt signaling. The objective of our study was to investigate the enhancement of porcine oocyte in vitro maturation via the Klotho protein-Wnt signaling pathway. Following immunohistochemistry and ELISA, we treated cells with Klotho protein during in vitro maturation. Lithium Chloride, a specific activator of Wnt signaling, was subsequently co-administered with Klotho protein. Mature oocytes subjected to treatments were used for the analysis of embryonic development, qRT-PCR, and immunocytochemistry. Treatment with 5pg/ml Klotho protein significantly increased cumulus cell expansion, blastocyst formation rates, and the total cell number of blastocysts. During cotreatment with 5mM Lithium Chloride and 5pg/ml Klotho protein, blastocyst formation rates were the highest in Klotho protein-treated oocytes and the lowest in Lithium Chloride-treated oocytes. Expression levels of Wnt signaling-related transcripts and proteins were significantly impacted by Klotho protein and Lithium Chloride. Moreover, cellular ATP levels and antioxidant activities were enhanced by Klotho protein treatment. These findings suggest a significant involvement of the Klotho protein-Wnt signaling mechanism in porcine oocyte maturation.

An increasing number of studies indicate air pollutants infiltrate into the brain. We aimed to find the association of cumulative air pollution exposure in the main body of primary brain tumor: glioblastoma (GBM). In this double‐cohort, retrospective analysis study with a protocol, we compared the health effect of air pollution on the GBM patients from the SEER (Surveillance, Epidemiology, and End Results Program) in 27 U.S. counties from 10 states and GBM patients of Severance cohort of Korea. From 2000 to 2015, 10621 GBM patients of the SEER were individually evaluated for the cumulative average exposure for each pollutant, and 9444 (88.9%) mortality events were reported. From 2011 to 2018, 398 GBM patients of the Severance with the same protocol showed 259 (65.1%) mortality events. The multi‐pollutant models show that the association level of risk with CO is increased in the SEER (HR 1.252; 95% CI 1.141‐1.373) with an increasing linear trend of relative death rate in the spline curve. The Severance GBM data showed such a statistically significant result of the health impact of CO on GBM patients. The overall survival gain of the less exposure group against CO was 2 and 3 months in the two cohorts. Perioperative exposure to CO may increase the risk of shorter survival of GBM patients of the SEER and the Severance cohort., This retrospective observational study found that chronic exposure to ambient level of carbon monoxide is associated with a shorter survival of glioblastoma patients (2‐3 months). Such association was validated in the cohorts of the United states (N=10621, HR 1.252, 95% CI 1.141‐1.373) and Korea (N=398, HR 2.874, 95% CI 1.040‐7.944).

Context Dopamine agonists (DAs) are the first-line therapy for prolactinomas. Although pituitary tumors often do not completely disappear, discontinuing DAs in patients with no visible tumor on magnetic resonance imaging is advised. Objective To analyze biochemical remission after cabergoline (CAB) withdrawal in patients with visible remnant pituitary tumors. Design Retrospective cohort study. Setting Severance Hospital. Subjects We identified 734 patients with prolactinomas undergoing CAB therapy for at least 12 months from 2005 to 2018. We selected 44 patients with prolactinomas who discontinued CAB with normal prolactin levels; they were receiving a minimal CAB dose but had visible remnant tumors. Results Median age at diagnosis was 32 (18-58) years, and most patients were women (95.45%). Median treatment duration was 32 (12-120) months. Of 44 patients, 33 continued to have normoprolactinemia, but 11 patients developed hyperprolactinemia after drug withdrawal within 26 (12-97) months. Age, sex, maximal and remnant tumor size, and treatment duration were similar between the groups. The initial prolactin level and chances of cavernous sinus (CS) invasion were higher in the recurrence group. CS invasion at diagnosis was associated with an increased recurrence rate. Although treatment response did not correlate with the initial and final signal intensity assessments, a significant decrease in T2 intensity ratio after 6 months of CAB therapy was observed in the remission group (P = .043). Conclusion In patients with visible tumors, the presence of CS invasion at diagnosis may be an unfavorable predictor for biochemical remission after CAB discontinuation.

Objective To investigate the molecular characteristics of AGEJ compared with EAC and gastric adenocarcinoma. Summary of background data Classification of AGEJ based on differential molecular characteristics between EAC and gastric adenocarcinoma has been long-standing controversy but rarely conducted due to anatomical ambiguity and epidemiologic difference. Methods The molecular classification model with Bayesian compound covariate predictor was developed based on differential mRNA expression of EAC (N = 78) and GCFB (N = 102) from the Cancer Genome Atlas (TCGA) cohort. AGEJ/cardia (N = 48) in TCGA cohort and AGEJ/upper third GC (N = 46 pairs) in Seoul National University cohort were classified into the EAC-like or GCFB-like groups whose genomic, transcriptomic, and proteomic characteristics were compared. Results AGEJ in both cohorts was similarly classified as EAC-like (31.2%) or GCFB-like (68.8%) based on the 400-gene classifier. The GCFB-like group showed significantly activated phosphoinositide 3-kinase-AKT signaling with decreased expression of ERBB2. The EAC-like group presented significantly different alternative splicing including the skipped exon of RPS24, a significantly higher copy number amplification including ERBB2 amplification, and increased protein expression of ERBB2 and EGFR compared with GCFB-like group. High-throughput 3D drug test using independent cell lines revealed that the EAC-like group showed a significantly better response to lapatinib than the GCFB-like group (P = 0.015). Conclusions AGEJ was the combined entity of the EAC-like and GCFB-like groups with consistently different molecular characteristics in both Seoul National University and TCGA cohorts. The EAC-like group with a high Bayesian compound covariate predictor score could be effectively targeted by dual inhibition of ERBB2 and EGFR.

To investigate whether radiomic features from magnetic resonance image (MRI) can predict the granulation pattern of growth hormone (GH)-secreting pituitary adenoma patients. Sixty-nine pathologically proven acromegaly patients (densely granulated [DG] = 50, sparsely granulated [SG] = 19) were included. Radiomic features (n = 214) were extracted from contrast-enhancing and total tumor portions from T2-weighted (T2) MRIs. Imaging features were selected using a least absolute shrinkage and selection operator (LASSO) logistic regression model with fivefold cross-validation. Diagnostic performance for predicting granulation pattern was compared with that for qualitative T2 signal intensity assessment and T2 relative signal intensity (rSI) using the area under the receiver operating characteristics curve (AUC). Four significant radiomic features from the contrast-enhancing tumor (1 from shape, 1 from first order feature, and 2 from second order features) were selected by LASSO for model construction. The radiomics model showed an AUC, accuracy, sensitivity, and specificity of 0.834 (95% confidence interval [CI] 0.738–0.930), 73.7%, 74.0%, and 73.9%, respectively. The radiomics model showed significantly better performance than the model using qualitative T2 signal intensity assessment (AUC 0.597 [95% CI 0.447–0.747], P = 0.009) and T2 rSI (AUC 0.647 [95% CI 0.523–0.759], P = 0.037). Radiomic features may be useful biomarkers to differentiate granulation pattern of GH-secreting pituitary adenoma patients, and showed better performance than qualitative assessment or rSI evaluation.

Purpose Glioblastoma (GBM) is the most aggressive type of brain tumor and has poor survival outcomes, even after a combination of surgery, radiotherapy, and chemotherapy. Temozolomide is the only agent that has been shown to be effective against GBM, suggesting that combination of temozolomide with other agents may be more effective. Niclosamide, an FDA approved anthelmintic agent, has shown anti-cancer effects against human colon, breast, prostate cancers as well as GBM. However, the efficacy of the combination of niclosamide with temozolomide against GBM tumorspheres (TSs) has not been determined. We hypothesized that the combined treatment could effectively suppress GBM TSs. Methods GBM TSs (TS15-88, GSC11) were treated with niclosamide and/or temozolomide. Combined effects of two drugs were evaluated by measuring viability, neurosphere formation, and 3D-invasion in collagen matrix. Transcriptional profiles of GBM TS were analyzed using RNA sequencing. In vivo anticancer efficacy of combined drugs was tested in a mouse orthotopic xenograft model. Results Combination treatment of niclosamide and temozolomide significantly inhibited the cell viability, stemness, and invasive properties of GBM TSs. This combined treatment significantly down-regulated the expression of epithelial mesenchymal transition-related markers, Zeb1, N-cadherin, and β-catenin. The combined treatment also significantly decreased tumor growth in orthotopic xenograft models. Conclusion The combination of niclosamide and temozolomide effectively decreased the stemness and invasive properties of GBM TSs, suggesting that this regimen may be therapeutically effective in treating patients with GBM.

We devised a biportal endoscopic transorbital approach (BiETOA) to gain surgical freedom by making a port for the endoscope and investigated the benefits and limitations of BiETOA. A cylindrical port was designed and 3-D printed using biocompatible material. The port was inserted through a keyhole between the superolateral side of the orbital rim and the temporal muscle. An endoscope was inserted through the port, and other instruments were inserted through the conventional transorbital route. BiETOA was used to dissect eight cadaveric heads, and the angle of attack and surgical freedom were assessed. The mean maximal angle of attack was significantly different in BiETOA and endoscopic transorbital approach (ETOA) (P

Hemangioblastomas (HBMs) are known to exhibit very typical radiological features and thus classified by well-established radiological classification scheme. We reviewed our series of posterior fossa HBMs in order not only to evaluate the relevance of current classification scheme, but also to possibly refine it. Also, we added descriptions on several cases with unusual radiological magnetic resonance imaging (MRI) findings in which differential diagnosis was challenging. We retrospectively reviewed preoperative MRI of 118 patients with pathologically diagnosed posterior fossa HBMs at our institution between 2002 and 2015. Total 128 tumors were included to this study and classified into four categories based on the presence and nature of cystic components: extratumoral cystic (Type Ce, classical cystic with a mural nodule), intratumoral cystic (Type Ci), mixed cystic (Type Cm), and solid (Type S). The association with von Hippel-Lindau (VHL) disease was also investigated. In 118 patients (65 male and 53 female), 79 (66.9%) had solitary HBMs and 39 (33.1%) were diagnosed with VHL disease. Type Ce with typical radiological findings was the most prevalent type of HBM (63.3%), followed by Type S (21.1%). HBMs with intratumoral cysts were uncommon (Type Ci, 11.7%) and mixed extratumoral and intratumoral cysts (Type Cm) accounted for only 3.9%. No intergroup differences were observed in the proportions of each subtype between the solitary and VHL disease-associated HBMs. The blood loss was much lower in Type Ce than in other subtypes. In Type Cm, radical resection was often challenging as the differentiation between intratumoral and extratumoral cysts was difficult resulting in incomplete resection. Refined radiological classification scheme is more practical because it does not only help surgeons determine whether the cystic wall should be removed or not, but also covers cases with atypical radiological presentations. For solid and extraparenchymal HBMs, differential diagnosis is more difficult as well as very critical as surgical removal is often very challenging.

Cavernous sinus (CS) invasion is frequently encountered in the management of skull base tumors. Surgical treatment of tumors in the CS is technically demanding, and selection of an optimal surgical approach is critical for maximal tumor removal and patient safety. We aimed to evaluate the feasibility of an endoscopic transorbital approach (ETOA) to the CS based on a cadaveric study.Five cadaveric heads were used for dissection under the ETOA in the comparison with the endoscopic endonasal approach (EEA) and the microscopic transcranial approach (TCA). The CS was exposed, accessed, and explored, first using the ETOA, followed by the EEA and TCA. A dedicated endoscopic system aided by neuronavigation guidance was used for the procedures. During the ETOA, neurovascular structures inside the CS were approached through different surgical triangles.After completing the ETOA with interdural dissection, the lateral wall of the CS was fully exposed. The lateral and posterior compartments of the CS, of which accessibility is greatly limited under the EEA, were effectively approached and explored under the ETOA. The anteromedial triangle was the largest windowBased on the cadaveric study, we demonstrated that the lateral CS wall was reliably accessed under the ETOA. The lateral and posterior compartments of the CS were effectively explored

Background: Gastric adenocarcinoma (GAC) is heterogeneous lethal disease in genomic and clinical level. Although the clinical relevance of genomic and molecular subtypes of GAC has been demonstrated, their translation to the clinic has been hindered by discrepancies in classification methods. We aim to examine a consensus of genomic subtypes and correlate them with clinical outcomes. Method: We collected genomic data from 2527 GAC tumors and divided the data into discovery (n = 1427) and validation sets (n = 1100). By integrating 8 previously established genomic subtype algorithms, we identified 6 clinically and molecularly distinct genomic consensus subtypes (CGSs) in discovery set. For validation of clinical significance of new subtypes, we constructed GAC predictor of integrated consensus subtype with 120 genes (GPICS120) and applied it to validation data set. In systematic analysis of genomic and proteomic data, we estimated potential response rate of each subtype to standard and experimental treatments such as radiation therapy, target therapy, and immunotherapy and further validated their functional significance in cell line models. Results: Among identified 6 subtypes. CGS1 is characterized by poorest prognosis, very high stem cell characteristics, and high IGF1 expression, but low genomic alterations. CGS2 showed canonical epithelial gene expression patterns. CGS3 and CGS4 are characterized by high copy number alterations and low immune activity. However, CGS3 and CGS4 are different in high HER2 activation (CGS3) and SALL4 and KRAS activation (CSG4). CGS5 has highest mutation burden and moderately high immune activity that is characteristics of MSI-high tumors. Most of CGS6 tumors are EBV-positive and shows extremely high methylation and high immune activity. Most interestingly, CSG1 is most responsive to immunotherapy while CGS3 is significantly associated with benefit of chemoradiation therapy due to high basal level ferroptosis. In addition, we also identified potential therapeutic targets for each subtype. Conclusion: Consensus subtype is robust classification system and can be the basis for pre-clinical investigation of subtype-based targeted interventions and future clinical trials. Citation Format: Yun Seong Jeong, Young-Gyu Eun, Sung Hwan Lee, Sang-Hee Kang, Sun Young Yim, Eui Hyun Kim, Joo Kyung Noh, Bo Hwa Sohn, Ju-Seog Lee. Consensus genomic subtypes of gastric adenocarcinoma and their therapeutic implication. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4344.

PURPOSE Since it is known that midline located glioma with H3K27 mutation in children has a disastrous prognosis, in 2016 WHO classification, these tumors were defined as diffuse midline glioma (DMG) and classified as grade IV. A lot of papers about pediatric DMG have been published, but there are not many papers about adult DMG. In this study, we aimed to identify factors affecting the prognosis of adult midline glioma. This is the first paper to study the prognosis of adult DMG according to histological grade and is the largest study to investigate the survival of adult DMG. METHODS We reviewed the chart of adult patients diagnosed with midline glioma with H3K27M mutation after undergoing resection or biopsy among patients who visited our institution between January 2010 and December 2020. Survival analysis was performed according to tumor location, histological grading, Karnofsky Performance Scale (KPS), and age. RESULTS Among the 125 adult midline gliomas we identified, 45 (36.0%) had the H3K27M mutation. As a result of survival analysis performed on 125 adult midline gliomas, low histological grade, KPS ≥ 80, and age ≤ 60 showed significantly better survival. After adjusting for age, the difference in survival between H3K27M mutation and wildtype group was not significant. As a result of survival analysis performed on 45 DMG, low histological grade, KPS ≥ 80, total resection, and concurrent chemoradiation therapy group showed significantly better survival. CONCLUSION In adult midline glioma, disastrous prognosis due to H3K27M mutation was not observed as in children. The prognosis of adult midline gliomas is determined by histological grade, age, KPS, and extent of tumor resection. Therefore, the current WHO classification, which classifies all H3K27M mutant midline gliomas as grade IV regardless of histological diagnoses, is not suitable for adults.

PurposeWe aimed to compare the outcomes of adjuvant radiotherapy (ART) and surveillance in patients with grade 2 meningiomas (MNG2) who underwent surgical resection.Materials and MethodsData from four hospitals, in which patients aged ≥18 years underwent Simpson grade 1−4 surgical resection for newly diagnosed MNG2 between 1998 and 2018, were examined in this multicenter retrospective cohort study. Patients receiving ART with conventional fractionation were compared with those undergoing surveillance. Progression-free survival (PFS), progression/recurrence (P/R) were evaluated.ResultsThis study included 518 patients, 158 of whom received ART. The median follow-up duration was 64.9 months. In the total cohort, ART was independently associated with significantly improved PFS (HR, 0.35; 95% CI, 0.23–0.55; PConclusionsART significantly improved PFS and P/R in patients with MNG2, irrespective of the surgical extent, and can be recommended after gross total resection. A prognostic model may guide decision-making for the use of ART.