Delineation of three-dimensional tumor margins based on normalized absolute difference mapping via volumetric optical coherence tomography.

The extent of surgical resection is an important prognostic factor in the treatment of patients with glioblastoma. Optical coherence tomography (OCT) imaging is one of the adjunctive methods available to achieve the maximal surgical resection. In this study, the tumor margins were visualized with the OCT image obtained from a murine glioma model. A commercialized human glioblastoma cell line (U-87) was employed to develop the orthotopic murine glioma model. A swept-source OCT (SS-OCT) system of 1300 nm was used for three-dimensional imaging. Based on the OCT intensity signal, which was obtained via accumulation of each A-scan data, an en-face optical attenuation coefficient (OAC) map was drawn. Due to the limited working distance of the focused beam, OAC values decrease with depth, and using the OAC difference in the superficial area was chosen to outline the tumor boundary, presenting a challenge in analyzing the tumor margin along the depth direction. To overcome this and enable three-dimensional tumor margin detection, we converted the en-face OAC map into an en-face difference map with x- and y-directions and computed the normalized absolute difference (NAD) at each depth to construct a volumetric NAD map, which was compared with the corresponding H&E-stained image. The proposed method successfully revealed the tumor margin along the peripheral boundaries as well as the margin depth. We believe this method can serve as a useful adjunct in glioma surgery, with further studies necessary for real-world practical applications.

Transepithelial Electrical Impedance Increase Following Porous Substrate Electroporation Enables Label-Free Delivery.

Porous substrate electroporation (PSEP) is a promising new method for intracellular delivery, yet fundamentals of PSEP are not well understood, especially the intermediate processes leading to delivery. PSEP is an electrical method, yet the relationship between PSEP and electrical impedance remains underexplored. In this study, a device capable of measuring impedance and performing PSEP is developed and the changes in transepithelial electrical impedance (TEEI) are monitored. These measurements show TEEI increases following PSEP, unlike other electroporation methods. The authors then demonstrate how cell culture conditions and electrical waveforms influence this response. More importantly, TEEI response features are correlated with viability and delivery efficiency, allowing prediction of outcomes without fluorescent cargo, imaging, or image processing. This label-free delivery also allows improved temporal resolution of transient processes following PSEP, which the authors expect will aid PSEP optimization for new cell types and cargos.

Sinonasal Outcomes of the Combined Transseptal/Transnasal Approach with Unilateral Nasoseptal Rescue Flap in Endoscopic Endonasal Transsphenoidal Surgery: A Propensity Score Matching Analysis.

Objectives The authors applied surgical techniques acquired during the use of endoscopic combined transseptal/transnasal approach to reduce approach-related morbidity and improve sinonasal outcomes. Study Design This is a retrospective cohort study of a prospectively collected database. Setting The study setting involves a tertiary referral center. Participants A total of 86 patients who underwent endoscopic endonasal transsphenoidal surgery for newly diagnosed pituitary adenomas from April 2018 to March 2021 were included. Patients treated via the combined transseptal/transnasal approach served as the study group ( n = 18); those treated via the bilateral transnasal approach comprised the control group ( n = 68). From the control group, propensity score matching (PSM) analysis was further performed to account for potential confounders and selection bias. Main Outcome Measures Paired analysis was performed for pre- and 6-month-postoperative time points in study group, control group, and PSM control group. Olfactory function was evaluated by Connecticut Chemosensory Clinical Research Center (CCCRC) test, Cross-Cultural Smell Identification Test (CCSIT), and sinonasal outcomes were assessed by Sino-Nasal Outcome Test-22 (SNOT-22). Results In the study group, CCCRC ( p = 0.517) and CCSIT ( p = 0.497) did not show any significant difference before and after surgery. There was some improvement in the symptom score of SNOT-22, but it was not statistically significant ( p = 0.115). In the control group adjusted with PSM, a significant decrease in olfaction ( p = 0.047) was observed using CCCRC. The CCSIT score was also decreased but not significant ( p = 0.163). Also, there was no difference in the improvement of SNOT-22 ( p = 0.781). Conclusion Our new surgical method preserves olfactory function without compromising surgical outcomes.

Comprehensive Molecular Genetic Analysis in Glioma Patients by Next Generation Sequencing.

BACKGROUND: Glioma is caused by multiple genomic alterations. The evolving classification of gliomas emphasizes the significance of molecular testing. Next generation sequencing (NGS) offers the assessment of parallel combinations of multiple genetic alterations and identifying actionable mutations that guide treatment. This study comprehensively analyzed glioma patients using multi-gene NGS panels, providing powerful insights to inform diagnostic classification and targeted therapies. METHODS: We conducted a targeted panel-based NGS analysis on formalin-fixed and paraffin-embedded nucleic acids extracted from a total of 147 glioma patients. These samples underwent amplicon capture-based library preparation and sequenced using the Oncomine Comprehensive Assay platform. The resulting sequencing data were then analyzed using the bioinformatics tools. RESULTS: A total of 301 mutations, were found in 132 out of 147 tumors (89.8%). These mutations were in 68 different genes. In 62 tumor samples (42.2%), copy number variations (CNVs) with gene amplifications occurred in 25 genes. Moreover, 25 tumor samples (17.0%) showed gene fusions in 6 genes and intragenic deletion in a gene. Our analysis identified actionable targets in several genes, including 11 with mutations, 8 with CNVs, and 3 with gene fusions and intragenic deletion. These findings could impact FDA-approved therapies, NCCN guideline-based treatments, and clinical trials. CONCLUSION: We analyzed precisely diagnosing the classification of gliomas, detailing the frequency and co-occurrence of genetic alterations and identifying genetic alterations with potential therapeutic targets by NGS-based molecular analysis. The high-throughput NGS analysis is an efficient and powerful tool to comprehensively support molecular testing in neurooncology.

Establishment of tumor microenvironment-preserving organoid model from patients with intracranial meningioma.

BACKGROUND: Although meningioma is the most common primary brain tumor, treatments rely on surgery and radiotherapy, and recurrent meningiomas have no standard therapeutic options due to a lack of clinically relevant research models. Current meningioma cell lines or organoids cannot reflect biological features of patient tumors since they undergo transformation along culture and consist of only tumor cells without microenvironment. We aim to establish patient-derived meningioma organoids (MNOs) preserving diverse cell types representative of the tumor microenvironment. METHODS: The biological features of MNOs were evaluated using WST, LDH, and collagen-based 3D invasion assays. Cellular identities in MNOs were confirmed by immunohistochemistry (IHC). Genetic alteration profiles of MNOs and their corresponding parental tumors were obtained by whole-exome sequencing. RESULTS: MNOs were established from four patients with meningioma (two grade 1 and two grade 2) at a 100% succession rate. Exclusion of enzymatic dissociation-reaggregation steps endowed MNOs with original histology and tumor microenvironment. In addition, we used a liquid media culture system instead of embedding samples into Matrigel, resulting in an easy-to-handle, cost-efficient, and time-saving system. MNOs maintained their functionality and morphology after long-term culture (> 9 wk) and repeated cryopreserving-recovery cycles. The similarities between MNOs and their corresponding parental tumors were confirmed by both IHC and whole-exome sequencing. As a representative application, we utilized MNOs in drug screening, and mifepristone, an antagonist of progesterone receptor, showed prominent antitumor efficacy with respect to viability, invasiveness, and protein expression. CONCLUSION: Taken together, our MNO model overcame limitations of previous meningioma models and showed superior resemblance to parental tumors. Thus, our model could facilitate translational research identifying and selecting drugs for meningioma in the era of precision medicine.

Is reduced-dose whole-brain radiotherapy also feasible in primary CNS lymphoma for curative or salvage purpose?

PURPOSE: Recently, reduced-dose whole-brain radiotherapy (WBRT) has been used to treat primary central nervous system lymphoma (PCNSL). However, whether reduced-dose WBRT is also an acceptable option for curative or salvage purposes has not yet been reported. We analyzed the clinical outcomes of patients with PCNSL who received radiotherapy for curative or salvage purposes and compared the clinical outcomes according to the WBRT dose. METHODS: A total of 66 patients were divided into two groups: those treated with 30 Gy (2 Gy per fraction) or less WBRT (low-dose WBRT, n = 34) and those treated with more than 30 Gy WBRT (high-dose WBRT, n = 32). The median WBRT dose was 25.2 and 49.6 Gy in low-dose and high-dose WBRT groups, respectively. The median total radiotherapy dose, including the boost dose, was 50 Gy (range, 36.0-55.8 Gy). RESULTS: The 3-year overall survival and progression-free survival were 77.8% and 29.8%, respectively. Intracranial relapse occurred in 31 patients (47.0%) at a median of 27 months after RT. Overall survival and progression-free survival did not differ between the two groups. The 3-year intracranial disease control rate did not differ between the two groups (35.2% vs. 41.6%, p = 0.300). Grade 3 or higher neurological toxicities were observed in six patients, of whom five were in the high-dose WBRT group. CONCLUSION: Reduced-dose WBRT in curative and salvage treatments for PCNSL had no significant negative effect on the intracranial disease control rate or survival. Therefore, without impaired efficacy, use of reduced-dose WBRT appears promising for reduction of neurotoxicity.

Potential impact of high-density lipoprotein cholesterol in the postoperative outcomes of chronic subdural hematoma patients: multi-institutional study in Korea.

BACKGROUND: Chronic subdural hematoma (CSDH) is a common clinical situation in neurosurgical practice, but the optimal treatment option is controversial. This study aimed to evaluate the effect of cholesterol-lowering medications on and how they affected the prognoses of CSDH patients. METHODS: In this multi-institutional observational study performed in Korea, data from recently treated CSDH patients were gathered from 5 hospitals. A total of 462 patients were collected from March 2010 to June 2021. Patient clinical characteristics, history of underlying diseases and their treatments, radiologic features, and surgical outcomes were analyzed. RESULTS: Seventy-five patients experienced recurrences, and 62 had reoperations after the initial burr hole surgery. Among these, 15 patients with recurrences and 12 with reoperations were taking cholesterol-lowering medications. However, the use of medications did not significantly affect recurrence or reoperation rates (P = 0.350, P = 0.336, respectively). When analyzed by type of medication, no clinically relevant differences in total cholesterol (TC), triglyceride (TG), or low-density lipoprotein cholesterol (LDL-C) levels were identified. The combination of a statin drug and ezetimibe significantly elevated high-density lipoprotein cholesterol (HDL-C) levels (P = 0.004). TC, LDL-C, and TG levels did not significantly affect patient prognoses. However, HDL-C levels and recurrence (odds ratio (OR) = 0.96; 95% confidence interval (CI): 0.94-0.99; p = 0.010) were negatively correlated. An HDL-C level of 42.50 mg/dL was identified as the threshold for recurrence and reoperation. CONCLUSIONS: In this study, using cholesterol-lowering medications did not significantly impact the prognosis of patients who underwent surgical management for a chronic subdural hematoma. However, the findings showed that the higher the HDL-C level, the lower the probability of recurrence and reoperation.

Transepithelial Electrical Impedance Increase Following Porous Substrate Electroporation Enables Label-Free Delivery.

Porous substrate electroporation (PSEP) is a promising new method for intracellular delivery, yet fundamentals of the PSEP delivery process are not well understood, partly because most PSEP studies rely solely on imaging for evaluating delivery. Although effective, imaging alone limits understanding of intermediate processes leading to delivery. PSEP is an electrical process, so electrical impedance measurements naturally complement imaging for PSEP characterization. In this study, we developed a device capable of measuring impedance and performing PSEP and we monitored changes in transepithelial electrical impedance (TEEI). Our measurements show TEEI increases following PSEP, unlike other electroporation methods. We then demonstrated how cell culture conditions and electrical waveforms influence this response. More importantly, we correlated TEEI response features with viability and delivery efficiency, allowing prediction of outcomes without fluorescent cargo, imaging, or image processing. This label-free delivery also allows improved temporal resolution of transient processes following PSEP, which we expect will aid PSEP optimization for new cell types and cargos.

Operative Findings of over 5000 Microvascular Decompression Surgeries for Hemifacial Spasm: Our Perspective and Current Updates.

Hemifacial spasm (HFS) is a hyperactive cranial neuropathy, and it has been well established that the cause of primary HFS is compression on the root exit zone (REZ) of the facial-vestibulocochlear nerve complex (CN VII-VIII) by a vessel or vessels. MVD is the only curative treatment option for HFS with a high success rate and low incidence of recurrence and complications. We categorize six classical compressive patterns on the REZ as well as five challenging types. Knowledge of these patterns may help in achieving a better surgical outcome.

Genomic surveillance of genes encoding the SARS-CoV-2 spike protein to monitor for emerging variants on Jeju Island, Republic of Korea.

Introduction: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has been fueled by new variants emerging from circulating strains. Here, we report results from a genomic surveillance study of SARS-CoV-2 on Jeju Island, Republic of Korea, from February 2021 to September 2022. Methods: A total of 3,585 SARS-CoV-2 positive samples were analyzed by Sanger sequencing of the gene encoding the spike protein before performing phylogenetic analyses. Results: We found that the Alpha variant (B.1.1.7) was dominant in May 2021 before being replaced by the Delta variant (B.1.617.2) in July 2021, which was dominant until December 2021 before being replaced by the Omicron variant. Mutations in the spike protein, including N440K and G446S, have been proposed to contribute to immune evasion, accelerating the spread of Omicron variants. Discussion: Our results from Juju Island, Republic of Korea, are consistent with and contribute to global surveillance efforts crucial for identifying new variants of concern of SARS-CoV-2 and for monitoring the transmission dynamics and characteristics of known strains.

Balancing Bleeding Risk and Thromboembolic Complications in Elderly Chronic Subdural Hematoma Patients Undergoing Burr Hole Trephination : A Multicenter Retrospective Cohort Study and Literature Review.

OBJECTIVE: Chronic subdural hematoma (CSDH) patients using antithrombotic agents (AT) at high risk for cardiovascular disease are increasing. The authors aimed to analyze the factors influencing outcome by targeting patients using AT and to establish a desirable treatment strategy. METHODS: A retrospective analysis was performed on data from 462 patients who underwent burr hole trephination (BHT) surgery for CSDH at five hospitals from March 2010 to June 2021. Outcomes included incidence of postoperative acute bleeding, recurrence rate, and morbidity or mortality rate. Patients were divided into the following four groups based on their history of AT use : no AT. Only antiplatelet agents (AP), only anticoagulants (AC), both of AP and AC. In addition, a concurrent literature review was conducted alongside our cohort study. RESULTS: Of 462 patients, 119 (119/462, 25.76%) were using AT. AP prescription did not significantly delay surgery (p=0.318), but AC prescription led to a significant increase in the time interval from admission to operation (p=0.048). After BHT, AP or AC intake significantly increased the period required for an in-dwelling drain (p=0.026 and p=0.037). The use of AC was significantly related to acute bleeding (p=0.044), while the use of AP was not (p=0.808). Use of AP or AC had no significant effect on CSDH recurrence (p=0.517 and p=1.000) or reoperation (p=0.924 and p=1.000). Morbidity was not statistically correlated with use of either AP or AC (p=0.795 and p=0.557, respectively), and there was no significant correlation with mortality for use of these medications (p=0.470 and p=1.000). CONCLUSION: Elderly CSDH patients may benefit from maintenance of AT therapy during BHT due to reduced thromboembolic risk. However, the use of AC necessitates individualized due to potential postoperative bleeding. Careful post-operative monitoring could mitigate prognosis and recurrence impacts.

Polymorphisms of Killer Ig-like Receptors and the Risk of Glioblastoma.

PURPOSE: The immune responses of natural killer (NK) cells against cancer cells vary by patient. Killer Ig-like receptors (KIRs), which are some of the major receptors involved in regulating NK cell activity for killing cancer cells, have significant genetic variation. Numerous studies have suggested a potential association between the genetic variation of KIR genes and the risk of development or prognosis of various cancer types. However, an association between genetic variations of KIR genes and glioblastoma (GB) remains uncertain. We sought to evaluate the association of genetic variations of KIRs and their ligand genes with the risk of GB development in Koreans. METHODS: A case-control study was performed to identify the odds ratios (ORs) of KIR genes and Classes A, B, and, C of the human leukocyte antigen (HLA) for GB. The GB group was comprised of 77 patients with newly diagnosed IDH-wildtype GB at our institution, and the control group consisted of 200 healthy Korean volunteers. RESULTS: There was no significant difference in the frequency of KIR genes and KIR haplotypes between the GB and control groups. Genetic variations of KIR-2DL1, 3DL1, and 3DS1 with their ligand genes (HLA-C2, HLA-Bw4/6, and Bw4, respectively) had effects on the risk of GB in Korean patients. The frequency of KIR-2DL1 with HLA-C2 (OR 2.05, CI 1.19-3.52, p = 0.009), the frequency of KIR-3DL1 without HLA-Bw4 (80I) (OR 8.36, CI 4.06-17.18, p < 0.001), and the frequency of KIR-3DL1 with Bw6 (OR 4.54, CI 2.55-8.09, p < 0.001) in the GB group were higher than in the control group. In addition, the frequency of KIR-2DL1 without HLA-C2 (OR 0.44, CI 0.26-0.75, p = 0.003), the frequency of KIR-3DL1 with HLA-Bw4 (80T) (OR 0.13, CI 0.06-0.27, p < 0.001), the frequency of KIR-3DL1 without Bw6 (OR 0.27, CI 0.15-0.49, p < 0.001), and the frequency of KIR-3DS1 with Bw4 (80I) (OR 0.03, CI 0.00-0.50, p < 0.001) in the GB group were lower than in the control group. CONCLUSIONS: This study suggests that genetic variations of KIRs and their ligand genes may affect GB development in the Korean population. Further investigations are needed to demonstrate the different immune responses for GB cells according to genetic variations of KIR genes and their ligand genes.

Single-center study on clinicopathological and typical molecular pathologic features of metastatic brain tumor.

BACKGROUND: The metastatic brain tumor is the most common brain tumor. The aim of this study was to demonstrate the clinicopathological and molecular pathologic features of brain metastases (BM). METHODS: A total of 269 patients were diagnosed with BM through surgical resection at Seoul St. Mary's Hospital from January 2010 to March 2020. We reviewed the clinicopathological features and molecular status of primary and metastatic brain tissues using immunohistochemistry and molecular pathology results. RESULTS: Among 269 patients, 139 males and 130 females were included. The median age of primary tumor was 58 years (range, 13 to 87 years) and 86 patients (32.0%) had BM at initial presentation. Median BM free interval was 28.0 months (range, 1 to 286 months). The most frequent primary site was lung 46.5% (125/269), and followed by breast 15.6% (42/269), colorectum 10.0% (27/269). Epidermal growth factor receptor (EGFR) mutation was found in 50.8% (32/63) and 58.0% (40/69) of lung primary and BM, respectively. In both breast primary and breast cancer with BM, luminal B was the most frequent subtype at 37.9% (11/29) and 42.9% (18/42), respectively, followed by human epidermal growth factor receptor 2 with 31.0% (9/29) and 33.3% (14/42). Triple-negative was 20.7% (6/29) and 16.7% (7/42), and luminal A was 10.3% (3/29) and 7.1% (3/42) of breast primary and BM, respectively. In colorectal primary and colorectal cancer with BM, KRAS mutation was found in 76.9% (10/13) and 66.7% (2/3), respectively. CONCLUSIONS: We report the clinicopathological and molecular pathologic features of BM that can provide useful information for understanding the pathogenesis of metastasis and for clinical trials based on the tumor's molecular pathology.

Glioma grading using multiparametric MRI: head-to-head comparison among dynamic susceptibility contrast, dynamic contrast-enhancement, diffusion-weighted images, and MR spectroscopy.

PURPOSE: To assess the diagnostic accuracy of dynamic susceptibility contrast, dynamic contrast-enhancement, MR spectroscopy (MRS), and diffusion-weighted imaging for differentiating high-grade (HGGs) from low-grade gliomas (LGGs). METHODS: Seventy-two patients (16 LGGs, 56 HGGs) with pathologically confirmed gliomas were retrospectively included. From three-dimensionally segmented tumor, histogram analyses of relative cerebral blood volume (rCBV), volume transfer constant (Ktrans), and apparent diffusion coefficient (ADC) were performed. Choline-to-creatinine ratio (Cho/Cr) was calculated using MRS. Logistic regression analyses were performed to differentiate HGGs (grade ≥ 3) from LGGs (grade ≤ 2). Areas under the receiver operating characteristics curves (AUC) were plotted. Subgroup analysis was performed between IDH-wildtype glioblastomas and IDH-mutant astrocytomas. Pairwise Spearman's correlation coefficients (ρ) were computed. RESULTS: HGGs had higher 95th percentile rCBV, Ktrans and Cho/Cr (P < 0.01) than LGGs. AUC of 95th percentiles of rCBV and Ktrans were 0.79 (95% CI, 0.67-0.91) and 0.74 (95% CI, 0.59-0.88), respectively. AUC of 5th percentile of ADC was 0.63 (95% CI, 0.48-0.79), and that of Cho/Cr was 0.67 (95% CI, 0.52-0.81). IDH-wildtype glioblastomas and IDH-mutant astrocytomas showed significantly different 95th percentile rCBV (P = 0.04) and Ktrans (P < 0.01), with Ktrans showing the highest AUC (0.73, 95% CI 0.57-0.89) in IDH status prediction. Moderate correlations were observed between 95th percentile rCBV and Ktrans (ρ = 0.47), Cho/Cr (ρ = 0.40), and 5th percentile ADC (ρ = -0.36) (all P < 0.01). CONCLUSIONS: The 95th percentile rCBV may be most helpful in discriminating HGGs from LGGs. The 95th percentile Ktrans may aid predicting IDH status of diffuse gliomas.

A clinical evaluation of cystic features in patients with newly diagnosed glioblastoma with IDH-wildtype.

BACKGROUND: The prognostic significance of the presence of cystic features in patients with newly diagnosed glioblastoma (GB) is highly controversial. The purpose of this study was to determine whether cystic GB patients have a more favorable prognosis compared to non-cystic GB patients. METHODS: The records of all GB patients diagnosed between August 2008 and December 2020 at Seoul St. Mary's Hospital were reviewed retrospectively. Out of 254 GB patients, we excluded patients with a confirmed isocitrate dehydrogenase (IDH) mutation or an unknown IDH mutation status. A total of 145 patients met our eligibility criteria. RESULTS: Of the 145 patients we analyzed, 16 patients were classified as the cystic group, and 129 patients were classified into the non-cystic group. As there was a significant difference in the extent of resection between the two groups, 32 patients were matched according to propensity score matching. A Kaplan-Meier survival curve of the two groups indicated that the cystic group had better survival than the non-cystic group (28.6 months versus 18.8 months, respectively; p = 0.055). On multivariate analysis, the presence of cystic features (hazard ratio [HR]: 0.40, 95% confidence interval [CI]: 0.17-0.91, p = 0.029) was significantly related with a longer OS. Longer OS was also related with well-known prognostic factors, such as grossly total resection (HR: 0.05, CI: 0.01-0.31, respectively; p = 0.001) and lower European Cooperative Oncology Group (ECOG) score (HR: 3.67, CI: 1.56-9.02, respectively; p = 0.003). CONCLUSION: Our results suggest that the presence of cystic features could be an independent prognostic factor suggesting better survival in GB patients. Further larger and prospective studies to validate our findings are needed.

Differences in the predicted nasoseptal flap length among races: A propensity score matching analysis.

OBJECTIVES: We compared the lengths of a nasoseptal flap (NSF) and skull base according to race, age, and sex. METHODS: We performed paranasal sinus computed tomography in 19,961 adult patients between 2003 and 2022. The race of the patients was East Asian (n = 71), Caucasian (n = 71), or Middle Eastern (n = 71). The expected lengths of the NSF and anterior skull base defect were measured and analyzed according to race, age, and sex. RESULTS: Compared with Caucasians and Middle Easterners, East Asians had a shorter NSF length (p < 0.001) and lower ratio of the expected NSF length to the expected defect length (p < 0.001). There was no difference in the values among age groups. The expected NSF length was longer, and the ratio of the expected NSF length to the expected defect length was higher, in males than females (p < 0.001 for both). CONCLUSIONS: East Asians and females had a shorter NSF length and lower ratio of expected NSF to surgical defect lengths after anterior skull base reconstruction compared with the other races and with males, respectively. Anatomical differences should be considered when long NSF lengths are required, such as for anterior skull base reconstruction.

Glossopharyngeal Neuralgia.

Glossopharyngeal neuralgia (GPN) is a rare disease that must be differentiated from trigeminal neuralgia. The purpose of this article is to provide a comprehensive review of anatomy, pathophysiology, diagnostic criteria, and several options of treatment for GPN. Lessons learned through our experience of treating GPN are presented in detail, as well as cases of misdiagnosis and diagnostic pitfalls. Microvascular decompression (MVD) should be primarily considered for medically intractable GPN. Techniques employed in MVD for GPN are categorized and described. Especially, we underscore the advantages of the 'transposition' technique where insulating material is positioned 'off' the root entry zone (REZ), instead of 'on' it. We believe this 'off-the-REZ' technique can fundamentally prevent recurrence, if applicable. In addition, Gamma Knife radiosurgery can be an alternative option when a patient is ineligible for MVD, though it is categorized as a destructive procedure.

Compassionate use of recombinant human IL-7-hyFc as a salvage treatment for restoring lymphopenia in patients with recurrent glioblastoma.

PURPOSE: Addressing lymphopenia in cancer patients has been suggested as a novel immunotherapeutic strategy. As interleukin-7 (IL-7) is necessary for proliferation of lymphocytes and to increase total lymphocyte count (TLC), IL-7 therapy has been attempted in various cancers. Here, we describe the clinical results of treatment of recurrent glioblastoma (GBM) with a long-acting engineered version of recombinant human IL-7 (rhIL-7-hyFc). METHODS: This prospective case series based on compassionate use was approved by the Ministry of Food and Drug Safety in South Korea. Primary outcomes were safety profile and TLC. Secondary outcomes were overall survival (OS) and progression-free survival (PFS). RESULTS: Among the 18 patients enrolled, 10 received rhIL-7-hyFc with temozolomide, 5 received rhIL-7-hyFc with bevacizumab, 1 received rhIL-7-hyFc with PCV chemotherapy, and 2 received rhIL-7-hyFc alone. Mean TLC of the enrolled patients after the first rhIL-7-hyFc treatment increased significantly from 1131 cells/mm3 (330-2989) at baseline to 4356 cells/mm3 (661-22,661). Higher TLCs were maintained while rhIL-7-hyFc was repeatedly administered. Median OS and PFS were 378 days (107-864 days) and 231 days (55-726 days), respectively. CONCLUSION: Our study reports that IL-7 immunotherapy can restore and maintain TLC during treatment with various salvage chemotherapies in recurrent GBM patients without serious toxicity.

Enhancing Anti-Cancer Therapy with Selective Autophagy Inhibitors by Targeting Protective Autophagy.

Autophagy is a process of eliminating damaged or unnecessary proteins and organelles, thereby maintaining intracellular homeostasis. Deregulation of autophagy is associated with several diseases including cancer. Contradictory dual roles of autophagy have been well established in cancer. Cytoprotective mechanism of autophagy has been extensively investigated for overcoming resistance to cancer therapies including radiotherapy, targeted therapy, immunotherapy, and chemotherapy. Selective autophagy inhibitors that directly target autophagic process have been developed for cancer treatment. Efficacies of autophagy inhibitors have been tested in various pre-clinical cancer animal models. Combination therapies of autophagy inhibitors with chemotherapeutics are being evaluated in clinal trials. In this review, we will focus on genetical and pharmacological perturbations of autophagy-related proteins in different steps of autophagic process and their therapeutic benefits. We will also summarize combination therapies of autophagy inhibitors with chemotherapies and their outcomes in pre-clinical and clinical studies. Understanding of current knowledge of development, progress, and application of cytoprotective autophagy inhibitors in combination therapies will open new possibilities for overcoming drug resistance and improving clinical outcomes.

Modulation of Autophagy is a Potential Strategy for Enhancing the Anti-Tumor Effect of Mebendazole in Glioblastoma Cells.

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 IC50 of less than 1 µM. MBZ treatment also inhibited glioblastoma cell migration with an IC50 of less than 3 µM in the Boyden chamber migration assay. MBZ induced G2-M cell cycle arrest in U87 and U373 cells within 24 h. Then, at 72 h of treatment, it mainly caused cell death in U87 cells with an increased sub-G1 fraction, whereas polyploidy was seen in U373 cells. However, MBZ treatment did not affect ERK1/2 activation stimulated by growth factors. The marked induction of autophagy by MBZ was observed, without any increased expression of autophagy-related genes ATG5/7 and Beclin 1. Co-treatment with MBZ and the autophagy inhibitor chloroquine (CQ) markedly enhanced the anti-proliferative effects of MBZ in the cells. Triple combination treatment with temozolomide (TMZ) (another autophagy inducer) further enhanced the anti-proliferative effect of MBZ and CQ. The combination of MBZ and CQ also showed an enhanced effect in TMZ-resistant glioblastoma cells. Therefore, we suggest that the modulation of protective autophagy could be an efficient strategy for enhancing the anti-tumor efficacy of MBZ in glioblastoma cells.