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Mebendazole (MBZ), a microtubule depolymerizing drug commonly used for the treatment of helminthic infections, has been suggested as a repositioning candidate for the treatment of brain tumors. However, the efficacy of MBZ needs further study to improve the beneficial effect on the survival of those patients. In this study, we explored a novel strategy to improve MBZ efficacy using a drug combination. When glioblastoma cells were treated with MBZ, cell proliferation was dose-dependently inhibited with an IC

Osteoporosis is a well-known risk factor of screw loosening. Classically, dual-energy x-ray absorptiometry (DEXA) scan is an easy and cost-effective method of detecting bone mineral density (BMD). However, T-score on DEXA scan can be overestimated in patients with degenerative changes of the spine. Our objective was to identify correlation between Hounsfield unit (HU) measured by 3-dimensional computed tomography (3D-CT) and screw loosening.A total of 113 patients treated with lumbosacral spinal fusion were reviewed and categorized into a screw loosening group and a normal group to compare their average values of preoperative CT HU. Screw loosening was defined as radiolucent area around screw that was thicker than 1 mm with a "double halo sign".There were statistically significant differences in patient age and steroid use between screw loosening and non-loosening groups. There was no significant difference in BMD or T-score between the 2 groups. However, HU values measured in axial, coronal, and sagittal images were significantly different between the 2 groups. In the receiver operating characteristic for HU values measured in CT images, the greatest area under the curve was 0.774 and that was in case of Hounsfield unit measured by axial CT images from L1 to L4.Preoperative CT HU is associated with screw loosening. It can be a better predictor of screw loosening than DEXA scan. The best predictor of screw loosening in this study is the average value of HU from L1 to L4 in axial cut.

PurposeThe KNOG-1101 study showed improved 2-year PFS with temozolomide during and after radiotherapy compared to radiotherapy alone for patients with anaplastic gliomas. This trial investigates the effect of concurrent and adjuvant temozolomide on health-related quality of life (HRQoL).Materials and MethodsIn this randomized, open-label, phase II trial, 90 patients with World Health Organization grade III glioma were enrolled across multiple centers in South Korea between March 2012 to February 2015 and followed up through 2017. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire 30 (EORTC QLQ-C30) and 20-item EORTC QLQ-Brain Neoplasm (QLQ-BN20) were used to compare HRQoL between patients assigned to concurrent chemoradiotherapy with temozolomide followed by 6 cycles of adjuvant temozolomide (arm A) and radiotherapy (RT) alone (arm B).ResultsOf the 90 patients in the study, 84 patients (93.3%) completed the baseline HRQoL questionnaire. Emotional functioning, fatigue, nausea and vomiting, dyspnea, constipation, appetite loss, diarrhea, seizures, itchy skin, drowsiness, hair loss, and bladder control were not affected by the addition of temozolomide. All other items did not differ significantly between arm A and arm B throughout treatment. Global health status particularly stayed consistent at the end of adjuvant temozolomide (p=0.47) and at the end of RT (p=0.33).ConclusionThe addition of concurrent and adjuvant temozolomide did not show negative influence on HRQoL with improvement of progression-free survival for patients with anaplastic gliomas. The absence of systematic and clinically relevant changes in HRQoL suggests that an overall long-term net clinical benefit exists for concurrent and adjuvant temozolomide.

We estimated volume changes in the posterior bony wall of the sphenoid sinus, as well as alterations in nasal function (including olfactory function and subjective symptoms), after sphenoid mucosal repositioning using the endoscopic endonasal transsphenoidal approach (EETSA).During 2010 and 2021, 13 patients underwent sphenoid mucosal repositioning during EETSA, while 24 patients (the control group) did not. Pre- and postoperative paranasal sinus computed tomography and the Mimics program were used to evaluate three-dimensional changes in the posterior wall of the sphenoid sinus. All patients underwent the Connecticut Chemosensory Clinical Research Center (CCCRC) test, the Cross-Cultural Smell Identification Test (CCSIT), Nasal Obstruction Symptoms Evaluation (NOSE), the Sino-Nasal Outcome Test-20 (SNOT-20), and visual analog scale (VAS) evaluation.The increase in the volume of the posterior wall of the sphenoid sinus after surgery was objectively smaller in the sphenoid mucosal repositioning group than in the control group (P = .046). However, this did not affect olfactory function (as revealed by the CCCRC test or the CCSIT) or subjective symptoms (as revealed by the NOSE, SNOT-20, and VAS scores) (all P .05).Surgical closure via sphenoid mucosal repositioning during EETSA reduces the volume of the posterior wall of the sphenoid sinus and facilitates re-operation. We suggest that sphenoid mucosal repositioning is appropriate during EETSA.4 Laryngoscope, 132:965-972, 2022.

Supplementary Materials and Figures 1-4 from Tumor Angiogenesis Promoted by Ex vivo Differentiated Endothelial Progenitor Cells Is Effectively Inhibited by an Angiogenesis Inhibitor, TK1-2

Neovascularization plays a critical role in the growth and metastatic spread of tumors and involves recruitment of circulating endothelial progenitor cells (EPC) from bone marrow as well as sprouting of preexisting endothelial cells. In this study, we examined if EPCs could promote tumor angiogenesis and would be an effective cellular target for an angiogenesis inhibitor, the recombinant kringle domain of tissue-type plasminogen activator (TK1-2). When TK1-2 was applied in the ex vivo culture of EPCs isolated from human cord blood, TK1-2 inhibited adhesive differentiation of mononuclear EPCs into endothelial-like cells. In addition, it inhibited the migration of ex vivo cultivated EPCs and also inhibited their adhesion to fibronectin matrix or endothelial cell monolayer. When A549 cancer cells were coimplanted along with ex vivo cultivated EPCs s.c. in nude mice, the tumor growth was increased. However, the tumor growth and the vascular density of tumor tissues increased by coimplanted EPCs were decreased upon TK1-2 treatment. Accordingly, TK1-2 treatment reduced the remaining number of EPCs in tumor tissues and their incorporation into the host vascular channels. In addition, overall expression levels of vascular endothelial growth factor (VEGF) and von Willebrand factor in tumor tissues were decreased upon TK1-2 treatment. Interestingly, strong VEGF expression by implanted EPCs was decreased by TK1-2. Finally, we confirmed in vitro that TK1-2 inhibited VEGF secretion of EPCs. TK1-2 also inhibited endothelial cell proliferation and migration induced by the conditioned medium of EPCs. Therefore, we concluded that EPCs, as well as mature endothelial cells, could be an important target of TK1-2. [Cancer Res 2007;67(10):4851–9]

Central nervous system (CNS) tumor patients commonly undergo multimodality treatment in the course of their disease. Adverse effects and complications from these interventions have not been systematically studied, but pose significant challenges in clinical practice and impact function and quality of life, especially in the management of long-term brain tumor survivors. Here, the European Association of Neuro-Oncology (EANO) has developed recommendations to prevent, diagnose, and manage adverse effects and complications in the adult primary brain CNS tumor (except lymphomas) patient population with a specific focus on surgery, radiotherapy, and pharmacotherapy. Specifically, we also provide recommendations for dose adaptations, interruptions, and reexposure for pharmacotherapy that may serve as a reference for the management of standard of care in clinical trials. We also summarize which interventions are unnecessary, inactive or contraindicated. This consensus paper should serve as a reference for the conduct of standard therapy within and outside of clinical trials.

Background An open‐label single‐arm phase 2 study was conducted to evaluate the role of levetiracetam as a sensitizer of concurrent chemoradiotherapy (CCRT) for patients with newly diagnosed glioblastoma. This study aimed to determine the survival benefit of levetiracetam in conjunction with the standard treatment for glioblastoma. Methods Major eligibility requirements included histologically proven glioblastoma in the supratentorial region, patients 18 years or older, and Eastern Cooperative Oncology Group (ECOG) performance status of 0–2. Levetiracetam was given at 1,000–2,000 mg daily in two divided doses during CCRT and adjuvant chemotherapy thereafter. The primary and the secondary endpoints were 6‐month progression‐free survival (6mo‐PFS) and 24‐month overall survival (24mo‐OS), respectively. Outcomes of the study group were compared to those of an external control group. Results Between July 2016 and January 2019, 76 patients were enrolled, and 73 patients were included in the final analysis. The primary and secondary outcomes were improved in the study population compared to the external control (6mo‐PFS, 84.9% vs. 72.3%, p = 0.038; 24mo‐OS, 58.0% vs. 39.9%, p = 0.018), but the differences were less prominent in a propensity score‐matched analysis (6mo‐PFS, 88.0% vs. 76.9%, p = 0.071; 24mo‐OS, 57.1% vs. 38.8%, p = 0.054). In exploratory subgroup analyses, some results suggested that patients with ages under 65 years or unmethylated MGMT promoter might have a greater survival benefit from the use of levetiracetam. Conclusions The use of levetiracetam during CCRT in patients with newly diagnosed glioblastoma may result in improved outcomes, but further investigations are warranted., Patients aged less than 65 years exhibited better outcomes with levetiracetam. Patients with unmethylated MGMT promoter possibly have greater benefits from levetiracetam.

AIM Primary central nervous system lymphoma (PCNSL) is rare disease and shows poor prognosis although methotrexate-based chemotherapy is used. Here, we present our experiences with high-dose methotrexate (HD-MTX) monotherapy for immunocompetent patients with PCNSL at three institutions and investigate factors related to survival. METHODS PCNSL patients, who were histologically confirmed with diffuse large B cells and treated with HD-MTX monotherapy from 2001 to 2016, were retrospectively reviewed. Patients underwent induction chemotherapy with 8 g/m2 of MTX every 10 days (maximum three cycles). Maintenance chemotherapy of 3.5 g/m2 of MTX (maximum six cycles) was selectively performed depending on the response to induction chemotherapy. RESULTS A total of 67 patients were included. Although seven patients discontinued induction chemotherapy because of MTX toxicity, 40 (59.7%) patients showed a complete response (CR) to induction chemotherapy. Twenty-six (38.8%) and three (4.5%) patients showed a CR and partial response, respectively, after maintenance chemotherapy. Forty-one patients with recurrence or progression following HD-MTX underwent second-line treatment. Progression-free survival rates were 43% and 24% at 1 and 2 years, respectively. The median overall survival was 40.3 months. In a multivariate analysis, a radiological CR to induction chemotherapy was a significant factor related to prolonged progression-free survival and overall survival (P

PurposeWe investigated the efficacy of temozolomide during and after radiotherapy in Korean adults with anaplastic gliomas without 1p/19q co-deletion.Materials and MethodsThis was a randomized, open-label, phase 2 study and notably the first multicenter trial for Korean grade III glioma patients. Eligible patients were aged 18 years or older and had newly diagnosed non-co-deleted anaplastic glioma with an Eastern Cooperative Oncology Group performance status of 0-2. Patients were randomized 1:1 to receive radiotherapy alone (60 Gy in 30 fractions of 2 Gy) (control group, n=44) or to receive radiotherapy with concurrent temozolomide (75 mg/m2/day) followed by adjuvant temozolomide (150-200 mg/m2/day for 5 days during six 28-day cycles) (treatment group, n=40). The primary end-point was 2-year progression-free survival (PFS). Seventy patients (83.3%) were available for the analysis of the isocitrate dehydrogenase 1 gene (IDH1) mutation status.ResultsThe two-year PFS was 42.2% in the treatment group and 37.2% in the control group. Overall survival (OS) did not reach to significant difference between the groups. In multivariable analysis, age was a significant risk factor for PFS (hazard ratio [HR], 2.08; 95% confidence interval [CI], 1.04 to 4.16). The IDH1 mutation was the only significant prognostic factor for PFS (HR, 0.28; 95% CI, 0.13 to 0.59) and OS (HR, 0.19; 95% CI, 0.07 to 0.50). Adverse events over grade 3 were seen in 16 patients (40.0%) in the treatment group and were reversible.ConclusionConcurrent and adjuvant temozolomide in Korean adults with newly diagnosed non-co- deleted anaplastic gliomas showed improved 2-year PFS. The survival benefit of this regimen needs further analysis with long-term follow-up at least more than 10 years.

Background Mesenchymal stemlike cells (MSLCs) have been detected in many types of cancer including brain tumors and have received attention as stromal cells in the tumor microenvironment. However, the cellular mechanisms underlying their participation in cancer progression remain largely unexplored. The aim of this study was to determine whether MSLCs have a tumorigenic role in brain tumors. Methods To figure out molecular and cellular mechanisms in glioma invasion, we have cultured glioma with MSLCs in a co-culture system. Results Here, we show that MSLCs in human glioblastoma (GBM) secrete complement component C5a, which is known for its role as a complement factor. MSLC-secreted C5a increases expression of zinc finger E-box-binding homeobox 1 (ZEB1) via activation of p38 mitogen-activated protein kinase (MAPK) in GBM cells, thereby enhancing the invasion of GBM cells into parenchymal brain tissue. Conclusion Our results reveal a mechanism by which MSLCs undergo crosstalk with GBM cells through the C5a/p38 MAPK/ZEB1 signaling loop and act as a booster in GBM progression. Key Points 1. MSLCs activate p38 MAPK-ZEB1 signaling in GBM cells through C5a in a paracrine manner, thereby boosting the invasiveness of GBM cells in the tumor microenvironment. 2. Neutralizing of C5a could be a potential therapeutic target for GBM by inhibition of mesenchymal phenotype.

Tumor treating fields (TTFields) are anti-mitotic, non-invasive loco-regional cancer therapy comprising low intensity, intermediate frequency alternating electric fields. TTFields plus Temozolomide (TTFields/TMZ) extended survival versus TMZ alone in newly diagnosed glioblastoma (GBM) patients in the EF-14 trial. We report on Korean newly diagnosed GBM patients who participated in the EF-14 trial. Thirty-nine participants of the EF-14 trial were enrolled at 8 sites in South Korea. Patients (24 TTFields/TMZ; 14 TMZ alone) received: TTFields (200 kHz) for > 18 h/day; TMZ at 120–150 mg for 5 days per a 28 day cycle. Safety and efficacy were assessed. Patient baseline characteristics were balanced in the 2 arms and the mean age was 52.1 years, 66.7% were male with a mean KPS of 90. Safety incidence was comparable between the 2 arms. In the TTFields/TMZ arm, 30% suffered from skin irritation versus 52% in the entire study population. No TTFields-related serious adverse events were reported. The median progression-free survival (PFS) in the TTFields/TMZ arm was 6.2 months (95% CI 4.2–12.2) versus 4.2 (95% CI 1.9–11.2) with TMZ alone (p = 0.67). Median overall survival was 27.2 months (95% CI 21-NA) with TTFields/TMZ versus 15.2 months (95% CI 7.5–24.1; HR 0.27, p = 0.01) with TMZ alone. Median OS and 1- and 2-year survival rates were higher with TTFields/TMZ and similar to the entire EF-14 population. About 30% of patients reported skin irritation, a lower rate than seen in the entire EF-14 population. These results demonstrate the efficacy and safety of TTFields in Korean newly diagnosed glioblastoma patients. Clinicaltrials.gov Identifier: NCT00916409.

Stereotactic radiosurgery(SRS) is one of primary treatment modalities for brain metastases(BM), however local control and radiation necrosis of large BM remain challenging. To overcome these limitations, biweekly 3-stage SRS for LBM was performed in this study. Total 53 patients were treated for 62 LBM. Female was 27(50.9%), and mean age was 63.7±11.8years. The mean KPS was 79.2±9.0 and GPA score was 1.9±0.7. Non-small cell lung cancer(NSCLC) was the most common primary cancer in 31 patients, others include 6 small cell lung cancer(SCLC), 9 gastro-intestinal tract cancer, 5 gynecological cancer, and etc. Epidermal growth factor receptor(EGFR) mutation was identified in 13 patients, and EGFR tyrosine-kinase inhibitor(TKI) was used in 10 patients during and after staged SRS. The mean tumor volume was 19.1cm3. The mean marginal dose of 11.7Gy was delivered to the 50% isodose line based on new treatment planning every two weeks. The mean tumor volume at the second and third stage was 14.8cm3 and 11.0cm3, respectively. The lesions from squamous cell carcinoma of NSCLC decreased most rapidly, and followed by gynecological cancer, SCLC and adenocarcinoma of NSCLC(volume ratio at 3rd stage was 0.39, 0.53, 0.56, and 0.64, respectively). The most significant factor related with tumor volume reduction at 3rd stage was usage of EGFR-TKI(p=0.016; LR analysis). The mean overall survival(OS) was 15.3months, and estimated OS were 62% and 46% at 6 and 12months. In the multivariate analysis, KPS(OR=0.918; 95% CI,0.871-0.968; p=0.002) and usage of EGFR-TKI(OR=0.216; 95% CI,0.059-0.790; p=0.021) were significantly associated with OS. The mean OS of the group of usage of EGFR-TKI was significantly longer than that of the others(20.7months, and 13.1months; p=0.029; log-rank test). The biweekly 3-stage SRS seems to be effective treatment for patients with LBM, especially in patients who were treated with EGFR-TKI during and/or after SRS, also cautiously considering the primary tumor origin.

BACKGROUND Glioblastoma is the most common primary intracranial malignancy in adults. In cases where biopsy is not feasible due to tumors in inoperable locations including the brainstem, biomarkers such as micro RNA-21 (miR-21) extracted from blood samples could be utilized for diagnostic or prognostic purposes. In this study, we examined the role of miR-21 as a diagnostic factor in patients with glioblastoma. METHODS Inclusion criteria included patients with age greater than 20 years and with histologic confirmation of diagnosis. The blood samples were collected prior to surgery, after surgical resection, after concurrent chemoradiotherapy, and after 3 cycles of adjuvant temozolomide therapy. Using TaqMan assay, we extracted miR-21 from blood samples and compared its level with tumor volume on brain magnetic resonance imaging (MRI) scans. miR-21 levels before and after treatments were compared within each subject. RESULTS Eleven newly diagnosed glioblastoma patients were enrolled in this study, and final analyses were performed for eight patients with complete follow up serum samples. Two patients with stable disease after treatment displayed a decrease in miR-21 levels. Three out of four subjects with increase in miR-21 showed progressive disease on MRI scans. One patient with stable disease and an increased miR-21 level experienced postoperative intracranial hemorrhage and ischemic event. The two patients with unchanged miR-21 levels showed stable disease. CONCLUSION miR-21 levels were associated with progressive disease in glioblastoma patients. miR-21 has potential be utilized as a diagnostic marker in patients with glioblastoma, and further studies are needed to elucidate its role as a prognostic marker.

PurposeWhile procarbazine, lomustine, and vincristine (PCV) chemotherapy is considered a salvage option for adult glioma, whether vincristine included in this regimen is beneficial is uncertain due to its potential toxicity and uncertain efficacy. In this study, we evaluated the safety and efficacy of PC chemotherapy in contrast with those of PCV chemotherapy. MethodsUsing electronic medical records, all patient with adult recurrent glioma who received PC or PCV chemotherapy between 2009 and 2020 at Seoul St. Mary’s Hospital or St. Vincent’s Hospital were examined retrospectively. A total of 59 patients met our eligibility criteria. Among them, 15 patients received PC chemotherapy (PC group) and 44 patients received PCV chemotherapy (PCV group). ResultsThe PC group presented a significantly lower hematology toxicity (anemia: 6.7% vs. 45.5%; p = 0.02 and thrombocytopenia: 20.0% vs. 70.4%; p < 0.001). Also, the clinical impacts of PC chemotherapy, including delay of a cycle, dose reduction, discontinuation of drug(s), or total cessation of chemotherapy, were significantly less frequent (26.7% vs. 68.2%; p = 0.012). The overall survival of PC group was significantly longer than that of PCV group (396 vs. 232 days; p = 0.042), while there was no significant difference in progression-free survival between two groups (284.5 vs. 131 days; p = 0.077). ConclusionThis is the first comparative study to suggest that PC chemotherapy leads to less toxicity than PCV chemotherapy without loss of clinical efficacy in patients with recurrent adult glioma. Further prospective and larger studies are needed to validate our findings.

Brain metastasis is a rare event in patients with hepatocellular carcinoma (HCC). This retrospective study aimed to identify the prognostic factors and determine the outcomes of patients with brain metastases from HCC. About 86 patients with brain metastases (0.6%) from HCC were identified from two institutions; of them, 32 underwent tumor-removing surgery or stereotactic radiosurgery (SRS) with or without adjuvant whole brain radiotherapy (WBRT) (group 1), 30 had WBRT alone (group 2), and 24 received conservative treatment (group 3). Estimates for overall survival (OS) after brain metastases were determined, and clinical prognostic factors were identified. The median OS after development of brain metastases was 50 days. About 75 (87.2%) patients had lung metastases at the time of brain metastasis diagnosis. Group 1 showed better OS, followed by group 2 and group 3, sequentially (p

Mebendazole (MBZ), a microtubule depolymerizing drug commonly used for the treatment of helminthic infections, has recently been noted as a repositioning candidate for angiogenesis inhibition and cancer therapy. However, the definite anti-angiogenic mechanism of MBZ remains unclear. In this study, we explored the inhibitory mechanism of MBZ in endothelial cells (ECs) and developed a novel strategy to improve its anti-angiogenic therapy. Treatment of ECs with MBZ led to inhibition of EC proliferation in a dose-dependent manner in several culture conditions in the presence of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) or FBS, without selectivity of growth factors, although MBZ is known to inhibit VEGF receptor 2 kinase. Furthermore, MBZ inhibited EC migration and tube formation induced by either VEGF or bFGF. However, unexpectedly, treatment of MBZ did not affect FAK and ERK1/2 phosphorylation induced by these factors. Treatment with MBZ induced shrinking of ECs and caused G2-M arrest and apoptosis with an increased Sub-G1 fraction. In addition, increased levels of nuclear fragmentation, p53 expression, and active form of caspase 3 were observed. The marked induction of autophagy by MBZ was also noted. Interestingly, inhibition of autophagy through knocking down of Beclin1 or ATG5/7, or treatment with autophagy inhibitors such as 3-methyladenine and chloroquine resulted in marked enhancement of anti-proliferative and pro-apoptotic effects of MBZ in ECs. Consequently, we suggest that MBZ induces autophagy in ECs and that protective autophagy can be a novel target for enhancing the anti-angiogenic efficacy of MBZ in cancer treatment.

Introduction: The impact of obesity on survival outcomes in patients with glioblastoma (GBM) has not been well reported and the results for patients are currently unclear. We investigated the effect of obesity on survival outcomes in patients with newly diagnosed GBM. Methods: Using electronic medical records, all GBM patients that visited the Seoul St. Mary’s Hospital between 2008 and 2018 were reviewed. A total of 177 patients met our eligibility criteria. The cut-off point for BMI was 23.0 kg/m2 based on previous studies which focused on Asian populations. Results: A total of 177 patients met our eligibility criteria. The overall median BMI of patients was 24.5 kg/m2 (range 15.82-39.26). About 62 patients who had a BMI less than the cut-off value were assigned to the “lower BMI” group, while 115 patients who had a BMI greater than the cut-off value were assigned to the “higher BMI” group. In Kaplan-Meier survival analysis, the median OS of the higher BMI group was longer than that of the lower BMI group (21.3 months vs 15.3 months, P = .002). In multivariate Cox regression analysis for OS, lower BMI was associated with inferior OS (HR 1.48 CI 1.06-2.08, P = .002). Conclusion: Our findings suggest that elevated BMI may be associated with better survival in patients with newly diagnosed GBM. Additional larger prospective studies could help validate our findings to confirm the effect of body composition and survival outcomes in GBM patients.

Objectives We describe the strategy used to repair intraoperative leaks of various grades and define factors for preventing postoperative cerebrospinal fluid leakage (CSF) after surgery via the endoscopic endonasal transsphenoidal approach (EETA). Study design Retrospective chart review at a tertiary referral center. Methods Patients who underwent surgery via EETA from January 2009 to May 2020 were retrospectively reviewed. Intraoperative CSF leakage was graded 0–3 in terms of the dural defect size; various repairs were used depending on the grade. Results A total of 777 patients underwent 869 operations via EETA; 609 (70.1%) experienced no intraoperative CSF leakage (grade 0) but 260 (29.9%) did. Leakage was of grade 1 in 135 cases (15.5%), grade 2 in 83 (9.6%), and grade 3 in 42 (4.8%). In 260 patients with intraoperative CSF leakage, a buttress was wedged into the sellar defect site in 178 cases (68.5%) and a pedicled flap was placed in 105 cases (40.4%). Autologous fat (108 cases, 41.5%) and a synthetic dural substitute (91 cases, 35%) were used to fill the dead space of the sellar resection cavity. Postoperative CSF leakage developed in 21 patients: 6 of grade 1, 7 of grade 2, and 8 of grade 3. Buttress placement significantly decreased postoperative leakage in grade 1 patients (p = 0.041). In patients of perioperative leakage grades 2 and 3, postoperative CSF leakage was significantly reduced only when both fat and a buttress were applied (p = 0.042 and p = 0.043, respectively). Conclusion A buttress prevented postoperative CSF leakage in grade 1 patients; both fat and buttress were required by patients with intraoperative leakage of grades 2 and 3.

BACKGROUND The authors investigated the incidence of ischemic lesions on immediate postoperative diffusion-weighted imaging (DWI) according to the findings of intraoperative motor evoked potential (MEP) and the correlation with postoperative motor function deficits. METHODS From January 2016 to June 2018, total 127 supratentorial brain tumor patients were enrolled in this study. The intraoperative MEP results were analyzed in the following three groups: no decline below 50 % of baseline (A), transient decline below 50 % of baseline (B), no recovery until end stage of surgery (C). Postoperative magnetic resonance imaging was performed within 48 hours after surgery. RESULTS Of the total 127 patients, MEP changes (group B&C) were observed in 25 patients (25/127, 19.7%), DWI positive findings were identified in 31 patients (31/127, 24.4%) and motor function deficits were observed in 19 patients (19/127, 15%), respectively. DWI positive finding rate was higher in gliomas (14/43, 32.6%) than meningiomas (8/51, 15.7%) or other tumors including metastasis (6/32, 18.8%), however, there was no statistical significance. In MEP changes, group B&C (16/25, 64%) showed higher DWI positive rate than group A (13/102, 12.7%). In DWI findings, the DWI positive cases (16/31, 51.6%) showed a higher motor function deficit rates than the DWI negative cases (3/96, 3%). These two results were all statistically significant (P CONCLUSIONS Both intraoperative MEP changes and postoperative DWI positive findings in supratentorial brain tumor surgery were significant related with postoperative motor function deficits. Even if intraoperative MEP changes occur during supratentorial brain tumor surgery, active and appropriate efforts to prevent irreversible MEP changes may reduce the occurrence of permanent postoperative motor function deficits.

PurposeTemporal muscle thickness (TMT) has been suggested as a novel biomarker that can represent sarcopenia in head and neck malignancies. This study investigated the association of TMT with clinical outcomes in patients with newly diagnosed glioblastoma (GBM).Materials and MethodsUsing electronic medical records, all GBM patients between 2008 and 2018 at Seoul St. Mary’s Hospital were reviewed. Total 177 patients met our eligibility criteria.ResultsThe thinner group who had TMT less than the median showed shorter overall survival (OS) and progression-free survival (PFS) than the thicker group who had TMT more than median (OS; 11.0 versus 18.0 months, p < 0.001, and PFS; 6.0 versus 11.0 months, p < 0.001). In the multivariate analysis, the thinner group had negative associations with OS and PFS (OS; HR 2.63 (1.34-2.63), p < 0.001, and PFS; HR 2.21 (1.34-2.50), p = 0.002). We also performed propensity score matching between the thinner and thicker groups to minimize the potential bias. The thinner group showed shorter OS and PFS (OS; 13.5 versus 19.0 months, p = 0.006, and PFS; 6.5 versus 9.0 months, p = 0.028) and had negative associations with OS and PFS than the thicker group (OS; HR 1.90 (1.19-3.03), p = 0.008, and PFS; HR 1.70 (1.07-2.70), p = 0.026) in matched patients.ConclusionOur findings suggest that TMT can be a useful prognostic biomarker for clinical outcomes in GBM patients. Further preclinical and clinical studies could help elucidate this association of sarcopenia with clinical outcomes in GBM patients.

Background Lymphopenia frequently occurs after concomitant chemoradiation (CCRT) in patients with glioblastoma (GBM) and is associated with worse overall survival (OS). A few studies have tried to identify risk factors for lymphopenia; however, the results were not clear. We aimed to identify potential risk factors for lymphopenia, focusing on the use of dexamethasone to control cerebral edema in patients with GBM. Methods The electronic medical records of 186 patients with newly diagnosed GBM treated at our institution between 2009 and 2017 were retrospectively examined. Acute lymphopenia was defined as total lymphocyte count less than 1,000 cells/μL at 4 weeks after completion of CCRT. Multivariate logistic regression analysis was used to identify independent risk factors for lymphopenia, and Cox regression analysis was used to identify independent risk factors for OS. Results Of the 125 eligible patients, 40 patients (32.0%) developed acute lymphopenia. Female sex and median daily dexamethasone dose ≥2 mg after initiation of CCRT were independent risk factors for acute lymphopenia on multivariate analysis. Acute lymphopenia, extent of surgical resection, and performance status were associated with OS; however, dexamethasone use itself was not an independent risk factor for poor OS. Conclusion Female sex, median daily dexamethasone dose ≥2 mg after initiation of CCRT until 4 weeks after completion of CCRT may be associated with acute lymphopenia. However, dexamethasone use itself did not affect OS in patients newly diagnosed with GBM. These results should be validated by further prospective studies controlling for other confounding factors.

Purpose The purpose of the study is to investigate the efficacy of combined treatment with temozolomide (TMZ) and metformin for glioblastoma (GBM) in vitro and in vivo. Materials and methods We investigated the efficacy of combined treatment with TMZ and metformin using cell viability and apoptosis assays. A GBM orthotopic mice model was established by inoculation of 5×105 U87 cells and treatedwith metformin, TMZ, and the combination for 4weeks. Western blotting and immunofluorescence of tumor specimens were analyzed to investigate AMP-activated protein kinase (AMPK) and AKT pathway. Results The combination of TMZ and metformin showed higher cytotoxicity than single agents in U87, U251, and A172 cell lines. A combination of high-dose metformin and TMZ showed the highest apoptotic activity. The combination of TMZ and metformin enhanced AMPK phosphorylation and inhibited mammalian target of rapamycin phosphorylation, AKT phosphorylation, and p53 expression. The median survival of each group was 43.6, 55.2, 53.2, 65.2, and 71.3 days for control, metformin treatment (2 mg/25 g/day or 10 mg/25 g/day), TMZ treatment (15 mg/kg/day), combination treatment with low-dose metformin and TMZ, and combination treatment with high-dose metformin and TMZ, respectively. Expression of fatty acid synthase (FASN) was significantly decreased in tumor specimens treated with metformin and TMZ. Conclusion The combination of metformin and TMZ was superior to monotherapy using metformin or TMZ in terms of cell viability in vitro and survival in vivo. The combination of high-dose metformin and TMZ inhibited FASN expression in an orthotopic model. Inhibition of FASN might be a potential therapeutic target of GBM.

BACKGROUND AND OBJECTIVE The aim of this study is to investigate the relationships between tumor size, nasal symptoms including olfactory function, and posoperative atrophic mucosal changes after the endoscopic endonasal transsphenoidal approach (EETSA). METHODS This was a retrospective review of the medical records of 112 patients who underwent the 2 nostrils/4 hands EETSA with bilateral modified nasoseptal rescue flaps between February 2009 and January 2016. Pre- and postoperative paranasal sinus computed tomography, nasal cavity endoscopic images, the Connecticut Chemosensory Clinical Research Center (CCCRC) test, Cross-Cultural Smell Identification Test (CCSIT), the Nasal Obstruction Symptoms Evaluation, and the Sino-Nasal Outcome Test-20 were conducted. Nasal mucosal changes as determined by endoscopy were divided into 4 groups: normal to normal, Group A; atrophy to atrophy, Group B; normal to atrophy, Group C; and atrophy to more atrophy, Group D. The Mimics program was used to calculate nasal cavity volume changes after surgery. RESULTS There were significant differences between pre- and postoperative olfactory function as reflected by the CCCRC (P

Background To investigate the effect of rhinosinusitis in patients who undergo surgery via the endoscopic endonasal transsphenoidal approach (EETSA). Methods The authors retrospectively reviewed the medical records of patients who underwent surgery via the EETSA between February 2009 and November 2016. In total, 505 patients were included in the study. Preoperative paranasal sinus computed tomography, sellar magnetic resonance imaging, and nasal endoscopy were performed for all the patients. Results Fifteen patients without sphenoid sinusitis underwent surgery with the concomitant transsphenoidal approach and functional endoscopic sinus surgery, and showed no central nervous system (CNS) complication. During surgery via the EETSA, the presence of rhinosinusitis did not significantly affect the incidence of postoperative CNS infection (P = 0.051), except for sphenoid sinusitis (P = 0.003). Conversely, the incidence of postoperative CNS infection was not related significantly to the Lund-Mackay score or tumor size. The risk of CNS infection was 12.151-fold higher in patients with sphenoid sinusitis (95% confidence interval, 3.153-46.827; P ≤ 0.001). Conclusion Surgery via the EETSA and functional endoscopic sinus surgery can be safely performed together in most patients with rhinosinusitis. However, sphenoid sinus infection appears to be a predisposing factor for postoperative CNS infection. Therefore, a separate surgical procedure for sphenoid lesions should be considered in these patients before the use of the EETSA.

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 recombinant kringle domain of urokinase (UK1) has been shown to inhibit angiogenesis and brain tumor growth in vivo. To avoid limitations in application due to mass production of recombinant protein, we attempted to develop a novel peptide inhibitor from UK1 sequence consisting of 83 amino acids that contains α-helices, loops and β-sheets. We dissected UK1 sequence to seven peptides based on structure and amino acid characteristics, and examined the anti-angiogenic activities for the constructed peptides. Among the tested peptides, UP-7 most potently inhibited the proliferation and migration of endothelial cells (ECs) in vitro, and also potently inhibited in vivo angiogenesis in the mouse matrigel plug assay. Such anti-angiogenic activities were not exerted by the scrambled peptide. At molecular level, UP-7 inhibited growth factor-induced phosphorylation of FAK and ERK1/2. It also suppressed formation of stress fibers and focal adhesions and also inhibited the attachment and spreading of ECs onto immobilized fibronectin. In a lung cancer animal model xenografted with non-UP-7-sensitive NCI-H460 cells, systemic treatment of UP-7 effectively suppressed tumor growth through inhibition of angiogenesis. Interestingly, breast cancer cells such as LM-MDA-MB-231 cells were moderately sensitive to UP-7 in proliferation differently from other cancer cells. UP-7 also inhibited migration, invasion and FAK phosphorylation of LM-MDA-MB-231 cells. Accordingly, UP-7 potently inhibited lung metastatic growth of LM-MDA-MB-231 cells in an experimental metastasis model. Taken together, these results suggest that novel peptide UP-7 can be effectively used for treatment of breast cancer metastatic growth through inhibition of angiogenesis and invasion.

OBJECTIVE In February 2009, the authors' center formed a team of neurosurgeons, otolaryngologists, endocrinologists, and radiologists to perform pituitary surgery using the endoscopic endonasal transsphenoidal approach (EETSA). This paper reviews the authors' experience with the technique, pathological outcomes, hormone profiles, and postoperative complications. METHODS Between February 2009 and December 2015, 535 patients underwent the EETSA with 2-nostrils/4-hands surgery. All of the patients had preoperative neurophthalmological and endocrinological assessments and neuroimaging. Patients were followed for at least 6 months with otolaryngological evaluations. RESULTS The most common pathology treated was pituitary adenomas, with 390 (72.9%) patients. Of these, 287 (73.6%) were nonfunctioning adenomas. As the surgical method, the conventional 2-nostrils/4-hands technique was performed in 77 patients (14.4%), a right conventional nasoseptal flap and left modified nasoseptal rescue flap technique was used in 135 patients (25.2%), and bilateral modified nasoseptal rescue flaps were used in 323 patients (60.4%). Postoperative complications occurred in 46 patients (8.6%). The most common complications were vascular injury or hematoma (10 patients, 1.9%), and the most common postoperative sinonasal complaints were hyposmia or anosmia. Olfactory function was significantly decreased according to the Connecticut Chemosensory Clinical Research Center test (P

The purposes of the present study are to assess whether different characteristics of oligodendrogliomas and astrocytic tumors are visible on MR imaging and to determine the added value of perfusion imaging in conventional MR imaging when differentiating oligodendrogliomas from astrocytic tumors. We retrospectively studied 22 oligodendroglioma and 54 astrocytic tumor patients, including glioblastoma multiforme (GBM). The morphological tumor characteristics were evaluated using MR imaging. The rCBV, K trans, and V e values were recorded. All imaging and clinical values were compared. The ability to discriminate between the two entities was evaluated using receiver operating characteristic curve analyses. Separate comparison analysis between oligodendroglioma and astrocytic tumors excluding GBM was also performed. The presence of calcification, higher cortex involvement ratio, and lower V e value were more representative of oligodendrogliomas than astrocytic tumors (P =

Objective Reconstruction of the skull base using a pedicled nasoseptal flap (NSF) seems to be advantageous after the endoscopic endonasal transsphenoidal approach (EETSA). A few reports have evaluated the cause of flap failure in EETSA using NSFs. The aim of this study was to evaluate the perioperative risk factors for NSF failure. Study design Patient series. Setting Retrospective review of medical records at a tertiary referral center. Methods The study population comprised patients who underwent EETSA with NSF elevation between February 2009 and March 2014. The authors retrospectively reviewed the all patients' medical records, including operative findings. Results Four hundred thirteen patients (203 males and 210 females) underwent EETSA, and 315 patients underwent EETSA with NSF elevation. The mean patient age was 48.0 years. The total number of patients of NSF failure was 6 (overall rate: 1.61%, 6/315; flap elevation: 0.31%, 1/315; flap reconstruction: 15.1%, 5/33). Two patients had diabetes mellitus. One patient had cardiovascular problems. Five patients were elderly (>60 years; mean age: 70 years). Five patients had postoperative nasal infection. One patient underwent preoperative radiation therapy. Conclusion Nasoseptal flap is a usually safe and effective technique for skull base reconstruction. However, the management of patients with diabetes mellitus, cardiovascular problems, advanced age, postoperative nasal infection, and radiation therapy may require more attention to improve NSF survival.

Background Programmed death ligand 1 (PD-L1) in tumor cells is known to promote immune escape of cancer by interacting with programmed cell death 1 (PD-1) in tumor infiltrating immune cells. Immunotherapy targeting these molecules is emerging as a new strategy for the treatment of glioblastoma (GBM). Understanding the relationship between the PD-L1/PD-1 axis and prognosis in GBM patients may be helpful to predict the effects of immunotherapy. Methods PD-L1 expression and PD-1-positive tumor infiltrating mononuclear cell (PD-1+tumor infiltrating mononuclear cell [TIMC]) density were evaluated using tissue microarray containing 54 GBM cases by immunohistochemical analysis; the associations with patient clinical outcomes were evaluated. Results PD-L1 expression and high PD-1+TIMC density were observed in 31.5% and 50% of GBM cases, respectively. High expression of PD-L1 in tumor cells was an independent and significant predictive factor for worse overall survival (OS; hazard ratio, 4.958; p = .007) but was not a significant factor in disease-free survival (DFS). PD-1+TIMC density was not correlated with OS or DFS. When patients were classified based on PD-1 expression and PD-1+TIMC density, patients with PD-L1+/PD-1+TIMC low status had the shortest OS (13 months, p = .009) and DFS (7 months, p = .053). Conclusions PD-L1 expression in GBM was an independent prognostic factor for poor OS. In addition, combined status of PD-L1 expression and PD-1+TIMC density also predicted patient outcomes, suggesting that the therapeutic role of the PD-1/PD-L1 axis should be considered in the context of GBM immunity.

Several studies have been conducted to determine the relationship between post-treatment total lymphocyte count (TLC) and overall survival (OS) in patients with malignant tumors including glioblastomas (GBMs). In this retrospective study, whether patients with newly diagnosed GBM experience significant lymphopenia after concomitant chemoradiation (CCRT) was evaluated, and whether TLC after this treatment is associated with OS in the treated population was examined. Using electronic medical records, all patients newly diagnosed with GBM between 2008 and 2016 at Seoul St. Mary’s Hospital were retrospectively examined. The eligible criteria included the following: 1) craniotomy with surgical resection or biopsy, 2) completion of CCRT, 3) accessible baseline and/or follow-up complete blood count (CBC). Median TLC significantly decreased after completion of CCRT, compared to TLC at baseline (1,742 versus 1,319 cells/mm3, P-value < 0.001). Patients with TLC < 1,200 cells/mm3 at 4 weeks after the completion of CCRT showed shorter survival than those with TLC ≥ 1,200 cells/mm3 with median OS of 14.5 versus 21.0 months (P-value = 0.017). Also, in multivariate analysis for OS, TLC < 1,200 cells/mm3 at 4 weeks after the completion of CCRT (HR 1.97, 95% CI 1.61 – 2.25, P-value = 0.004) were significantly associated with shorter survival. The results from the present study indicate that treatment-related total lymphocyte counts after CCRT is associated with worse survival in patients with newly diagnosed GBM.

Objective Concomitant chemoradiation (CCRT) after surgical resection was established as standard care for patients with newly diagnosed GBM. However, the optimal time interval from surgery to starting CCRT (IST) is still controversial. Methods The electronic medical records of 160 patients with newly diagnosed GBM treated at our institution between 2009 and 2016 were retrospectively examined. The eligibility criteria were as follows: 1) newly diagnosed GBM, 2) pathology confirmed by craniotomy or stereotactic biopsy, and 3) CCRT treated in our institution. Patients who received CCRT within 28 days after surgery were defined as the early group, while patients who received CCRT more than 28 days after surgery were defined as the delayed group. Results We included 138 patients who met our eligibility criteria. The median IST was 26 (range 10-55) days. In a Kaplan-Meier analysis, overall survival did not differ between groups (15.5 versus 14.5 months for early and delayed groups, respectively; p = 0.707). In the GTR (gross total resection) subgroup, the two groups did not differ (20.0 versus 21.0 months for early and delayed groups, respectively; p = 0.854). In the non-GTR subgroup, however, the early group had better overall survival than the delayed group (11.0 versus 5.0 months, respectively; p = 0.029). Conclusions Performing CCRT within versus after 28 days after surgery did not result in a statistically significant difference in OS. However, a subgroup analysis showed that delayed CCRT may be associated with worse OS in the non-GTR group.

Several studies have been conducted to determine the relationship between post-treatment total lymphocyte count (TLC) and overall survival (OS) in patients with malignant tumors including glioblastomas (GBMs). In this retrospective study, whether patients with newly diagnosed GBM experience significant lymphopenia after concomitant chemoradiation (CCRT) was evaluated, and whether TLC after this treatment is associated with OS in the treated population was examined. Using electronic medical records, all patients newly diagnosed with GBM between 2008 and 2016 at Seoul St. Mary’s Hospital were retrospectively examined. The eligible criteria included the following: 1) craniotomy with surgical resection or biopsy, 2) completion of CCRT, 3) accessible baseline and/or follow-up complete blood count (CBC). Median TLC significantly decreased after completion of CCRT, compared to TLC at baseline (1742 versus 1319 cells/mm3, P-value

BACKGROUND The 2004 World Health Organization classification introduced atypical pituitary adenoma (aPA), which was equivocally defined as invasion with increased mitotic activity that had a Ki-67 labeling index (LI) greater than 3%, and extensive p53 immunoreactivity. However, aPAs that exhibit all of these features are rare and the predictive value for recurrence in pituitary adenomas (PAs) remains uncertain. Thus, we sought to characterize pathological features of PAs that correlated with recurrence. METHODS One hundred and sixty-seven cases of surgically resected PA or aPA were retrieved from 2011 to 2013 in Seoul St. Mary's Hospital. Among them, 28 cases were confirmed to be recurrent, based on pathologic or radiologic examination. The pathologic characteristics including mitosis, invasion, Ki-67 LI and p53 immunoreactivity were analyzed in relation to recurrence. RESULTS Analysis of the pathologic features indicated that only Ki-67 LI over 3% was significantly associated with tumor recurrence (p = .02). The cases with at least one pathologic feature showed significantly higher recurrence rates (p < .01). Analysis indicated that cases with two pathologic features, Ki-67 LI over 3% and extensive p53 immunoreactivity 20% or more, were significantly associated with tumor recurrence (p < .01). CONCLUSIONS Based on these results, PA tumor recurrence can be predicted by using mitosis, invasion, Ki-67 LI (3%), or extensive p53 immunoreactivity (≥ 20%). Assessment of these features is recommended for PA diagnosis for more accurate prediction of recurrence.