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Yeon Seong Kim,1,* Young-Il Jeong,2,* Shu-Guang Jin,2 Jian Pei,2 Min Wen,2 In-Young Kim,1 Kyung-Sub Moon,1 Tae-Young Jung,1 Hyang-Hwa Ryu2, Shin Jung1–3 1Department of Neurosurgery, 2Brain Tumor Research Laboratory, 3Chonnam National University Research Institute of Medical Sciences, Chonnam National University Hwasun Hospital and Medical School, Jeollanam-do, Korea *These authors contributed equally to this work Background: In this study, 293T cells were genetically engineered to secrete tissue inhibitor of metalloproteinase-2 (TIMP2) and encapsulated into alginate microcapsules to continuously release TIMP2 protein. Methods: The anti-invasive potential of the microcapsules was studied in vitro using brain tumor cells. The TIMP2 gene was transfected to 293T cells, and genetically engineered 293TIMP2 cells were encapsulated into alginate microcapsules. Release of TIMP2 protein was detected with Western blot analysis and the anti-invasive potential against U87MG cells was tested using gelatin zymography and a Matrigel assay. Results: Cell viability within the alginate microcapsules was maintained at a cell density of 5 × 106. Because polycationic polymers are helpful for maintaining the mechanical strength of microcapsules with good cell viability, the alginate microcapsules were reinforced with chitosan (0.1% w/v). Expression of TIMP2 protein in cell lysates and secretion of TIMP2 into the conditioned medium was confirmed by Western blot analysis. Alginate microcapsules encapsulating 293TIMP2 cells released TIMP2 protein into the medium efficiently, where the TIMP2 protein participated in degradation of the matrix metalloproteinase-2 enzyme and inhibited invasion of U87MG cells. Conclusion: Alginate microcapsules encapsulating 293TIMP2 cells are promising candidates for anti-invasive treatment of glioma. Keywords: 293T cells, tissue inhibitor of metalloproteinase-2, alginate microcapsule, therapeutic protein

Tae-Ho Kim1*, Young-Il Jeong2*, Shu-Guang Jin2, Jian Pei2, Tae-Young Jung1, Kyung-Sub Moon1, In-Young Kim1, Sam-Suk Kang1, Shin Jung1,21Department of Neurosurgery, 2Brain Tumor Research Laboratory, Chonnam National University Research Institute of Medical Science, Chonnam National University Hwasun Hospital and Medical School, Gwangju, Republic of Korea *These authors contributed equally to this work. Background: Celecoxib, a cyclo-oxygenase (COX)-2 inhibitor, has been reported to mediate growth inhibitory effects and to induce apoptosis in various cancer cell lines. In this study, we examined the potential effects of celecoxib on glioma cell proliferation, migration, and inhibition of COX-2 expression in vitro. Methods: Celecoxib was incorporated into poly DL-lactide-co-glycolide (PLGA) nanoparticles for antitumor drug delivery. Results: PLGA nanoparticles incorporating celecoxib had spherical shapes and their particle sizes were in the range of 50–200 nm. Drug-loading efficiency was not significantly changed according to the solvent used, except for acetone. Celecoxib was released from the PLGA nanoparticles for more than 2 days, and the higher the drug content, the longer the duration of drug release. PLGA nanoparticles incorporating celecoxib showed cytotoxicity against U87MG tumor cells similar to that of celecoxib administered alone. Furthermore, celecoxib did not affect the degree of migration of U87MG cells. PLGA nanoparticles incorporating celecoxib showed dose-dependent cytotoxicity similar to that of celecoxib alone in C6 rat glioma cells. Western blot assay of the C6 cells showed that neither celecoxib alone nor PLGA nanoparticles incorporating celecoxib affected COX-2 expression. Conclusion: PLGA nanoparticles incorporating celecoxib had antitumor activity similar to that of celecoxib alone, even though these particles did not affect the degree of migration or COX-2 expression in the tumor cells. Keywords: celecoxib, cyclo-oxygenase-2, PLGA nanoparticles, glioma, antitumor activity

This paper presents the results of study on titanium dioxide thin films prepared by atomic layer deposition method on a silicon substrate. The changes of surface morphology have been observed in topographic images performed with the atomic force microscope (AFM) and scanning electron microscope (SEM). Obtained roughness parameters have been calculated with XEI Park Systems software. Qualitative studies of chemical composition were also performed using the energy dispersive spectrometer (EDS). The structure of titanium dioxide was investigated by X-ray crystallography. A variety of crystalline TiO2 was also confirmed by using the Raman spectrometer. The optical reflection spectra have been measured with UV-Vis spectrophotometry.

Background: In endoscopic transsphenoidal surgery for pituitary adenoma with suprasellar extension, the prolapse of the stretched floppy diaphragma sellae can obstruct the surgical corridor, posing challenges during pituitary surgery. We have introduced a simple postural change technique to mitigate this issue and are sharing our clinical experience., Methods: Pituitary surgery is performed on an operating bed where the patient's position can be adjusted. During transsphenoidal pituitary surgery, raising the patient's head to a Fowler's position causes the diaphragma sellae to move upward, while lowering the head to a supine position causes it to descend. This simple adjustment minimizes hindrance from the floppy diaphragm sellae during surgery., Results: We illustrate this technique in pituitary surgery, where diaphragm sellae relocation is necessary., Conclusion: A simple postural change technique effectively manages prolapsed floppy diaphragma sellae, enhancing visualization and surgical accessibility during endoscopic transsphenoidal pituitary surgery., (Copyright © 2024. Published by Elsevier Inc.)

Objective: We investigated how treating large brain metastasis (LBM) using 2-day fraction Gamma Knife radiosurgery (GKRS) affects tumor control and patient survival. A prescription dose of 10.3 Gy was applied for 2 consecutive days, with a biologically effective dose equivalent to a tumor single-fraction dose of 16.05 Gy and a brain single-fraction dose of 15.12 Gy., Methods: Between November 2017 and December 2021, 42 patients (mean age, 68.3 years; range, 50-84 years; male, 29 [69.1%]; female, 13 [30.9%]) with 44 tumors underwent 2-day fraction GKRS to treat large volume brain metastasis. The main cancer types were non-small cell lung cancer (n=16), small cell lung cancer (n=7), colorectal cancer (n=7), breast cancer (n=3), gastric cancer (n=2), and other cancers (n=7). Twenty-one patients (50.0%) had a single LBM, 19 (46.3%) had a single LBM and other metastases, and two had two (4.7%) large brain metastases. At the time of the 2-day fraction GKRS, the tumors had a mean volume of 23.1 mL (range, 12.5-67.4). On each day, radiation was administered at a dose of 10.3 Gy, mainly using a 50% isodose-line., Results: We obtained clinical and magnetic resonance imaging follow-up data for 34 patients (81%) with 35 tumors, who had undergone 2-day fraction GKRS. These patients did not experience acute or late radiation-induced complications during follow-up. The median and mean progression-free survival (PFS) periods were 188 and 194 days, respectively. The local control rates at 6, 9, and 12 months were 77%, 40%, and 34%, respectively. The prognostic factors related to PFS were prior radiotherapy (p=0.019) and lung cancer origin (p=0.041). Other factors such as tumor volumes, each isodose volumes, and peri-GKRS systemic treatment were not significantly related to PFS. The overall survival period of the 44 patients following repeat stereotactic radiosurgery (SRS) ranged from 15-878 days (median, 263±38 days; mean, 174±43 days) after the 2-day fraction GKRS. Eight patients (18.2%) were still alive., Conclusion: Considering the unsatisfactory tumor control, a higher prescription dose should be needed in this procedure as a salvage management. Moreover, in the treatment for LBM with fractionated SRS, using different isodoses and prescription doses at the treatment planning for LBMs should be important. However, this report might be a basic reference with the same fraction number and prescription dose in the treatment for LBMs with frame-based SRS.

Background: Meningioma in the cerebellopontine angle (CPA) without dural attachment is extremely rare. We report a unique case of meningioma derived from the superior petrosal vein without dural attachment., Case Summary: A 44-year-old right-handed woman presented with a two-month history of headache and tinnitus. Brain magnetic resonance imaging showed a well-defined contrast-enhancing lesion in the right CPA without a dural tail sign. Tumor resection was performed using a right retro sigmoid approach. A dural attachment was not seen at the tentorium or posterior surface of the petrous pyramid. The tumor was firmly adherent to the superior petrosal vein. The origin site was cauterized and resected with the preservation of the superior petrosal vein. A diagnosis of meningothelial meningioma was made. The patient's headache and tinnitus gradually disappeared, and a recurrence was not observed five years after the surgery., Conclusion: The rare occurrence of meningioma without dural attachment makes it difficult to determine dural attachment before surgery. The absence of dural attachment makes it easy to completely resect such tumors. Vessels related to tumors should be removed carefully, considering the possible presence of tumor stem cells in the microvessels., Competing Interests: Conflict-of-interest statement: The authors declare that they have no potential or actual conflicts of interest with regard to this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Choroid plexus tumors (CPTs) are intraventricular tumors derived from the choroid plexus epithelium and occur frequently in children. The aim of this study was to investigate the genomic and epigenomic characteristics of CPT and identify the differences between choroid plexus papilloma (CPP) and choroid plexus carcinoma (CPC). We conducted multiomics analyses of 20 CPT patients including CPP and CPC. Multiomics analysis included whole-genome sequencing, whole-transcriptome sequencing, and methylation sequencing. Mutually exclusive TP53 and EPHA7 point mutations, coupled with the amplification of chromosome 1, were exclusively identified in CPC. In contrast, amplification of chromosome 9 was specific to CPP. Differential gene expression analysis uncovered a significant overexpression of genes related to cell cycle regulation and epithelial-mesenchymal transition pathways in CPC compared to CPP. Overexpression of genes associated with tumor metastasis and progression was observed in the CPC subgroup with leptomeningeal dissemination. Furthermore, methylation profiling unveiled hypomethylation in major repeat regions, including long interspersed nuclear elements, short interspersed nuclear elements, long terminal repeats, and retrotransposons in CPC compared to CPP, implying that the loss of epigenetic silencing of transposable elements may play a role in tumorigenesis of CPC. Finally, the differential expression of AK1, regulated by both genomic and epigenomic factors, emerged as a potential contributing factor to the histological difference of CPP against CPC. Our results suggest pronounced genomic and epigenomic disparities between CPP and CPC, providing insights into the pathogenesis of CPT at the molecular level., (© 2024. The Author(s).)

Background. The aim of the study was to synthesize liposomal nanoparticles loaded with temozolomide and ferucarbotran (LTF) and to evaluate the theranostic effect of LTF in the glioma model. Methods. We synthesized an LTF that could pass through the Blood Brain Barrier (BBB) and localize in brain tumor tissue with the help of magnet guidance. We examined the chemical characteristics. Cellular uptake and cytotoxicity studies were conducted in vitro. A biodistribution and tumor inhibition study was conduted using an in vivo glioma model. Results. The particle size and surface charge of LTF show 108 nm and -38 mV, respectively. Additionally, the presence of ferucarbotran significantly increased the contrast agent effect of glioma compared to the control group in MR imaging. Magnet-guided LTF significantly reduced the tumor size compared to control and other groups. Furthermore, compared to the control group, our results demonstrate a significant inhibition in brain tumor size and an increase in lifespan. Conclusions. These findings suggest that the LTF with magnetic guidance represents a novel approach to address current obstacles, such as BBB penetration of nanoparticles and drug resistance. Magnet-guided LTF is able to enhance therapeutic efficacy in mouse brain glioma.

Purpose: In men with metastatic castration-resistant prostate cancer (mCRPC), new bone lesions are sometimes not properly categorized through a confirmatory bone scan, and clinical significance of the test itself remains unclear. This study aimed to demonstrate the performance rate of confirmatory bone scans in a real-world setting and their prognostic impact in enzalutamide-treated mCRPC., Materials and Methods: Patients who received oral enzalutamide for mCRPC during 2014-2017 at 14 tertiary centers in Korea were included. Patients lacking imaging assessment data or insufficient drug exposure were excluded. The primary outcome was overall survival (OS). Secondary outcomes included performance rate of confirmatory bone scans in a real-world setting. Kaplan-Meier analysis and multivariate Cox regression analysis were performed., Results: Overall, 520 patients with mCRPC were enrolled (240 [26.2%] chemotherapy-naïve and 280 [53.2%] after chemotherapy). Among 352 responders, 92 patients (26.1%) showed new bone lesions in their early bone scan. Confirmatory bone scan was performed in 41 patients (44.6%), and it was associated with prolonged OS in the entire population (median, 30.9 vs. 19.7 months; p < 0.001), as well as in the chemotherapy-naïve (median, 47.2 vs. 20.5 months; p=0.011) and post-chemotherapy sub-groups (median, 25.5 vs. 18.0 months; p=0.006). Multivariate Cox regression showed that confirmatory bone scan performance was an independent prognostic factor for OS (hazard ratio 0.35, 95% confidence interval, 0.18 to 0.69; p=0.002)., Conclusion: Confirmatory bone scan performance was associated with prolonged OS. Thus, the premature discontinuation of enzalutamide without confirmatory bone scans should be discouraged.

The Leksell frame-based transcerebellar approach was proposed with the arc support frame attached upside down to the Z coordinate. This study presented practical tips and considerations for obtaining adequate tissue samples for deep-seated cerebellar lesions or lower brainstem lesions specifically those accessible via the cerebellar peduncle. For practical insights, the Leksell coordinate frame G was fixed to prevent the anterior screw implantation within the temporalis muscle, to avoid interference with the magnetic resonance (MR)-adapter, and taking into account the magnetic field of MR in close proximity to the tentorium. After mounting of indicator box, the MR imaging evaluation should cover both the indicator box and the infratentorial region that deviated from it. The coordinates [X, Y, Za, Arc0, Ringa0] obtained from Leksell SurgiPlan® software (Elekta, Stockholm, Sweden) with arc 00 located on the patient's right side were converted to [X, Y, Zb=360-Za, Arc0, Ringb0=Ringa0-1800]. The operation was performed in the prone position under general anesthesia in four patients with deep cerebellar (n=3) and brainstem (n=1) tumors. The biopsy results showed two cases of diffuse large B-cell lymphoma, one metastatic braintumor and one glioblastoma. One patient required frame repositioning as a complication. Drawing upon the methodology outlined in existing literature, we anticipate that imparting supplementary expertise could render the stereotactic biopsy of infratentorial tumors more consistent and manageable for the practitioner, thereby facilitating adequate tissue samples and minimizing patient complications.

Gamma knife radiosurgery (GKRS) has emerged as a highly effective therapeutic modality for the management of intracranial meningiomas. However, the role of GKRS in treating growing meningiomas detected during active surveillance remains unclear. This study seeks to investigate the long-term outcomes of GKRS treatment for growing meningiomas. A retrospective analysis was conducted on patients who underwent GKRS as the primary treatment for growing meningiomas between 2004 and 2021. Growing meningiomas were defined as those exhibiting a > 10% increase in tumor volume (TV) compared to the previous imaging. Fifty-nine patients who received GKRS as their initial treatment were included, with a minimum follow-up period of 12 months. Comprehensive clinical, radiological, and procedural data were analyzed. Serial TV assessments were performed for all tumors before and after GKRS. Tumor progression and regression were defined as a > 10% increase or decrease in TV, respectively, compared to the pretreatment image. At a median follow-up of 41 months (range 15-197 months), TV was unchanged in 16 patients (27.1%), decreased in 41 patients (69.5%), and increased in 2 patients (3.4%). Multivariate analysis revealed that both TV (cm3) (hazard ratio [HR], 1.107; 95% confidence interval [CI], 1.002-1.222; P = .045) and volume growing rate (%/yr) (HR, 1.013; 95% CI, 1.000-1.025; P = .04) significantly correlated with tumor progression. Eleven patients (18.6%) experienced new or worsening symptoms. In multivariate analysis, factor predicting new or worsening neurological function was preexisting calcification (HR, 5.297; 95% CI, 1.328-21.124; P = .018). GKRS demonstrates a promising level of tumor control with minimal risk of neurological deterioration when applied to growing meningiomas. These findings provide compelling support for considering GKRS as a valuable therapeutic option following an initial period of active surveillance for these tumors., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: To analyze the degree of psychological distress experienced pre- and postoperatively in patients who underwent radical prostatectomy after being diagnosed with prostate cancer., Materials and Methods: Patients diagnosed with prostate cancer who underwent radical prostatectomy without history of psychiatric disorders were included in this study. The degree of psychological distress was evaluated using hospital anxiety and depression scale (HADS) and distress thermometer (DT) questionnaires preoperatively and at 1, 3, 6, and 12 months postoperatively., Results: Distress was high preoperatively and decreased over the entire period. In addition, HADS-anxiety and HADS-depression scores showed an improved severity, shifting from an abnormal state to a borderline state in some patients. However, the DT score, including emotional problems, spiritual concerns, physical problems, family problems, and practical problems, was slightly higher at 1 month postoperatively compared to preoperatively. Furthermore, even at 12 months postoperatively, about one fifth of patients surveyed had a DT score of 4 or higher, requiring psychiatric intervention., Conclusions: Before and after radical prostatectomy, a significant number of patients complained of distress such as anxiety, depression, and insomnia, and they needed help from a specialist because of psychological distress even 12 months postoperatively. Therefore, a close evaluation of the patient's psychological distress and supportive treatment are needed during the entire pre- and postoperative period., Competing Interests: The authors have nothing to disclose., (© The Korean Urological Association.)

Obstructive sleep apnea syndrome (OSAS) is associated with cerebrovascular disease, which can lead to life-threatening outcomes. The purpose of the study was to investigate the relationship between OSAS and comorbid intracranial aneurysms. We retrospectively reviewed 564 patients who underwent a polysomnography and brain magnetic resonance angiography as part of their health checkup. We calculated the prevalence of an intracranial aneurysm and OSAS in patients and measured the size of the intracranial aneurysm if present. The mean patient age was 55.6 ± 8.5 years, and 82.3% of them were men. The prevalence of an intracranial aneurysm in patients with OSAS was 12.1%, which is significantly higher than patients with non-OSAS (5.9%, p = 0.031). Patients with OSAS had a much higher prevalence of intracranial aneurysms, after adjusting all possible confounding factors such as age, sex, smoking status, alcohol drinking, and body mass index (odds ratio: 2.32; 95% confidence interval: 1.07-5.04). Additionally, the OSAS group had noticeably larger aneurysms compared with those of the non-OSAS group (3.2 ± 2.0 mm vs. 2.0 ± 0.4 mm, p = 0.013). We found a significant association between OSAS and intracranial aneurysms. OSAS could be another risk factor for the development of intracranial aneurysms.

Rationale: A persistent primitive trigeminal artery (PPTA) is a rare embryonic cerebrovascular anomaly. Hemifacial spasm (HFS) refers to involuntary contractions of facial muscles caused by the compression of blood vessels against the root exit zone of the facial nerve. There have been no reported cases of PPTA causing neurovascular contact and HFS. Microvascular decompression surgery effectively treats HFS, but operating on strong PPTA vessels poses challenges. We aim to introduce a more efficient approach for overcomes these difficulties and facilitates surgery., Patient Concerns: A 44-year-old male patient without any underlying medical conditions presented to our hospital with involuntary movements of the left side of his face accompanied by numbness in the left maxilla (V2 area)., Diagnosis: Brain magnetic resonance imaging and magnetic resonance angiography showed that PPTA was in contact with the left facial nerve., Interventions and Outcomes: Following a retro-sigmoid craniotomy, we attempted to interpose the facial nerve and the PPTA as an offender vessel, but the decompression was not sufficient. However, after transposing the vessel using the proximal Teflon transposition with interposition technique, the strength of the involuntary movements was reduced. Following surgery, there was no more lateral spreading response, and the patient symptoms improved., Lessions: In cases where the vessel causing HFS is particularly strong and thick, the proximal Teflon transposition with interposition technique for transposition may be advantageous. This method could simplify and enhance the efficacy of microvascular decompression, without compromising the quality of surgical outcomes., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: Despite advances in technology, such as advent of laser enucleation and minimally invasive surgical therapies, transurethral resection of the prostate (TURP) remains the most widely performed surgical technique for benign prostatic hyperplasia (BPH). We evaluated resection volume (RV)-derived parameters and analyzed the effect of RV on post-TURP outcomes., Methods: This observational study used data from patients who underwent TURP at two institutions between January 2011 and December 2021 Data from patients with previous BPH surgical treatment, incomplete data, and underlying disease affecting voiding function were excluded. The collected data included age, prostate-specific antigen, transrectal ultrasound (TRUS)- and uroflowmetry-derived parameters, RV, perioperative laboratory values, perioperative International Prostatic Symptom Score (IPSS), follow-up period, retreatment requirements and interval between the first TURP and retreatment., Results: In 268 patients without prior BPH medication, there were no differences in prostate volume (PV), transitional zone volume (TZV), or RV according to IPSS. A total of 60 patients started retreatment, including medical or surgical treatment, within the follow-up period. There was a significant difference in RV/PV between the groups without and with retreatment respectively (0.56 and 0.37; p = 0.008). However, preoperative TRUS- and uroflowmetry-derived parameters did not differ between the two groups. Multiple linear regression analysis showed that RV (p = 0.003) and RV/TZV (p = 0.006) were significantly associated with differences in perioperative IPSS. In the multivariate logistic regression analysis, only RV/PV was correlated with retreatment (p = 0.010)., Conclusion: Maximal TURP leads to improved postoperative outcomes and reduced retreatment rate, it may gradually become a requirement rather than an option., (© 2023. The Author(s).)

Gamma knife radiosurgery (GKRS) has been accepted as a safe and effective treatment for vestibular schwannoma (VS). However, during follow-up, tumor expansion induced by irradiation can occur, and diagnosis of failure in radiosurgery for VS is still controversial. Tumor expansion with cystic enlargement causes some confusion regarding whether further treatment should be performed. We analyzed more than 10 years of clinical findings and imaging of patients with VS with cystic enlargement after GKRS. A 49-year-old male with hearing impairment was treated with GKRS (12 Gy; isodose, 50%) for a left VS with a preoperative tumor volume of 0.8 cc. The tumor size increased with cystic changes from the third year after GKRS, reaching a volume of 10.8 cc at 5 years after GKRS. At the 6th year of follow-up, the tumor volume started to decrease, up to 0.3 cc by the 14th year of follow-up. A 52-year-old female with hearing impairment and left facial numbness was treated with GKRS for a left VS (13 Gy; isodose, 50%). The preoperative tumor volume was 6.3 cc, which started to increase with cystic enlargement from the first year after GKRS, and reaching 18.2 cc by 5 years after GKRS. The tumor maintained a cystic pattern with slight changes in size, but no other neurologic symptoms developed during the follow-up period. After 6 years of GKRS, tumor regression was observed, eventually reaching a volume of 3.2 cc by the 13th year of follow-up. In both cases, persistent cystic enlargement in VS was observed at 5 years after GKRS, after which the tumors began to stabilize. After more than 10 years of GKRS, the tumor volume was less than that before GKRS. Enlargement with large cystic formation in the first 3-5 years after GKRS has been considered as treatment failure. However, our cases show that further treatment for cystic enlargement should be deferred for at least 10 years, especially in patients without neurological deterioration, as inadequate surgery can be prevented within that period., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

There has been controversy over whether to radiologically follow up or use local treatment for asymptomatic small-sized brain metastases from primary lung cancer. For brain tumors without local treatment, we evaluated potential factors related to the brain progression and whether systemic therapy controlled the tumor. We analyzed 96 patients with asymptomatic small-sized metastatic brain tumors from lung cancer. These underwent a radiologic follow-up every 2 or 3 months without local treatment of brain metastases. The pathologies of the tumors were adenocarcinoma ( n = 74), squamous cell carcinoma ( n = 11), and small cell carcinoma ( n = 11). The primary lung cancer was treated with cytotoxic chemotherapy ( n = 57) and targeted therapy ( n = 39). Patients who received targeted therapy were divided into first generation ( n = 23) and second or third generation ( n = 16). The progression-free survival (PFS) of brain metastases and the overall survival (OS) of patients were analyzed depending on the age, tumor pathology, number, and location of brain metastases, the extent of other organ metastases, and chemotherapy regimens. The median PFS of brain metastases was 7.4 months (range, 1.1-48.3). Targeted therapy showed statistically significant PFS improvement compared to cytotoxic chemotherapy ( p = 0.020). Especially, on univariate and multivariate analyses, the PFS in the second or third generation targeted therapy was more significantly improved compared to cytotoxic chemotherapy (hazard ratio 0.229; 95% confidence interval, 0.082-0.640; p = 0.005). The median OS of patients was 13.7 months (range, 2.0-65.0). Univariate and multivariate analyses revealed that the OS of patients was related to other organ metastases except for the brain ( p = 0.010 and 0.020, respectively). Three out of 52 patients with brain recurrence showed leptomeningeal dissemination, while the recurrence patterns of brain metastases were mostly local and/or distant metastases (94.2%). Of the 52 patients who relapsed, 25 patients received local brain treatment. There was brain-related mortality in two patients (2.0%). The intracranial anti-tumor effect was superior to cytotoxic chemotherapy in the treatment of asymptomatic small-sized brain metastases with targeted therapy. Consequently, it becomes possible to determine the optimal timing for local brain treatment while conducting radiological follow-up for these tumors, which do not appear to increase brain-related mortality. Furthermore, this approach has the potential to reduce the number of cases requiring brain local treatment.

Purpose: Glioblastoma (GBM) has a poor prognosis after standard treatment. Recently, metformin has been shown to have an antitumor effect on glioma cells. We performed the first randomized prospective phase II clinical trial to investigate the clinical efficacy and safety of metformin in patients with recurrent or refractory GBM treated with low-dose temozolomide., Methods: Included patients were randomly assigned to a control group [placebo plus low-dose temozolomide (50 mg/m 2 , daily)] or an experimental group [metformin (1000 mg, 1500 mg, and 2000 mg per day during the 1st, 2nd, and 3rd week until disease progression, respectively) plus low-dose temozolomide]. The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), disease control rate, overall response rate, health-related quality of life, and safety., Results: Among the 92 patients screened, 81 were randomly assigned to the control group (43 patients) or the experimental group (38 patients). Although the control group showed a longer median PFS, the difference between the two groups was not statistically significant (2.66 versus 2.3 months, p = 0.679). The median OS was 17.22 months (95% CI 12.19-21.68 months) in the experimental group and 7.69 months (95% CI 5.16-22.67 months) in the control group, showing no significant difference by the log-rank test (HR: 0.78; 95% CI 0.39-1.58; p = 0.473). The overall response rate and disease control rate were 9.3% and 46.5% in the control group and 5.3% and 47.4% in the experimental group, respectively., Conclusions: Although the metformin plus temozolomide regimen was well tolerated, it did not confer a clinical benefit in patients with recurrent or refractory GBM. Trial registration NCT03243851, registered August 4, 2017., (© 2023. The Author(s).)

Purpose: We investigated the efficacy and optimal dosage of recombinant Bacillus Calmette-Guérin-dltA (rBCG-dltA) in a high-throughput 3D bio-printed bladder cancer-on-a-chip (BCOC) and orthotopic bladder cancer mouse model., Materials and Methods: We fabricated high-throughput BCOC with microfluidic systems, enabling efficient drug screening. The efficacy of rBCG-dltA was evaluated using BCOC by the cell viability assay, monocyte migration assay, and measuring cytokine levels. The anti-tumor effect was compared using the orthotopic bladder cancer mouse model., Results: The cell proliferation rates of T24 and 253J bladder cancer cell lines (mean±standard error) were measured at three days after treatment. In T24 cell line, there was significantly decreased T24 cells compared to control at rBCG 1 multiplicity of infection (MOI) and 10 MOI (30 MOI: 63.1±6.4, 10 MOI: 47.4±5.2, 1 MOI: 50.5±7.5, control: 100.0±14.5, p<0.05). In 253J cell line, a statistically significant decrease in 253J cell count compared to control and mock BCG 30 MOI (30 MOI: 11.2±1.3, 10 MOI: 22.5±2.3, 1 MOI: 39.4±4.7, Mock: 54.9±10.8, control: 100.0±5.6, p<0.05). The migration rates of THP-1 cells showed increased patterns after rBCG-dltA treatment in BCOC. The concentration of tumor necrosis factor-α and interleukin-6 after rBCG-dltA 30 MOI treatment was higher than control in T24 and 253J cell line., Conclusions: In conclusion, rBCG-dltA has the potential to have better anti-tumor activity and immunomodulatory effects than BCG. Furthermore, high-throughput BCOCs have potential to reflect the bladder cancer microenvironment., Competing Interests: The authors have nothing to disclose., (© The Korean Urological Association.)

The paper provides a comprehensive overview of the growth and development of Hwasun Neurosurgery at Chonnam National University Hwasun Hospital over the past 18 years. As the first brain tumor center in Korea when it was established in April 2004, Hwasun Neurosurgery has since become one of the leading institutions in brain tumor education and research in the country. Its impressive clinical and basic research capabilities, dedication to professional education, and numerous academic achievements have all contributed to its reputation as a top-tier institution. We hope this will become a useful guide for other brain tumor centers or educational institutions by sharing the story of Hwasun Neurosurgery., Competing Interests: The authors have no potential conflicts of interest to disclose., (Copyright © 2023 The Korean Brain Tumor Society, The Korean Society for Neuro-Oncology, and The Korean Society for Pediatric Neuro-Oncology.)

Aims: This study assessed the expression and clinical relevance of cancer-asssociated fibroblast (CAF)-related biomarkers in brain metastasis (BM). Moreover, molecular characterization of patient-derived primary CAFs and normal fibroblasts (NFs) was performed. Methods: Sixty-eight patients with BM from various primary cancer types were selected. Immunohistochemistry (IHC) and immunofluorescence (IF) staining were performed to evaluate the expression of various CAF-related biomarkers. CAFs and NFs were isolated from fresh tissues. Results: Various CAF-related biomarkers were expressed in CAFs in BMs of different primary cancers. However, only PDGFR-β, α-SMA, and collagen type I were associated with BM size. PDGFR-β and α-SMA were associated with BM recurrence after resection. PDGFR-β was associated with recurrence-free survival (RFS). Interestingly, high expression of PDGFR-β and α-SMA was found in the patients with previous chemotherapy or radiotherapy for primary cancer. In primary cell culture, PDGFR-β and α-SMA were expressed at higher levels in patient-derived CAFs than in NFs or cancer cells. The origins of CAF in BM were presumed to be pericytes of blood vessels, circulating endothelial progenitor cells, or transformed astrocytes of the peritumoral glial stroma. Conclusion: Our results suggest that high expression of CAF-related biomarkers, particularly PDGFR-β and α-SMA, is associated with poor prognosis and recurrence in patients with BM. With the elucidation of the role and origins of CAF in the tumor microenvironment, CAF can be a new imperative target for BM immunotherapy., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Various combination treatments have been considered to attain the effective therapy threshold by combining independent antitumor mechanisms against the heterogeneous characteristics of tumor cells in malignant brain tumors. In this study, the natural killer (NK) cells associated with bevacizumab (Bev) plus irinotecan (Iri) against glioblastoma multiforme (GBM) were investigated. For the experimental design, NK cells were expanded and activated by K562 cells expressing the OX40 ligand and membrane-bound IL-18 and IL-21. The effects of Bev and Iri on the proliferation and NK ligand expression of GBM cells were evaluated through MTT assay and flow cytometry. The cytotoxic effects of NK cells against Bev plus Iri-treated GBM cells were also predicted via the LDH assay in vitro . The therapeutic effect of different injected NK cell routes and numbers combined with the different doses of Bev and Iri was confirmed according to tumor size and survival in the subcutaneous (s.c) and intracranial (i.c) U87 xenograft NOD/SCID IL-12Rγ null mouse model. The presence of injected-NK cells in tumors was detected using flow cytometry and immunohistochemistry ex vivo . As a result, Iri was found to affect the proliferation and NK ligand expression of GBM cells, while Bev did not cause differences in these cellular processes. However, the administration of Bev modulated Iri efficacy in the i.c U87 mouse model. NK cells significantly enhanced the cytotoxic effects against Bev plus Iri-treated GBM cells in vitro. Although the intravenous (IV) injection of NK cells in combination with Bev plus Iri significantly reduced the tumor volume in the s.c U87 mouse model, only the direct intratumorally (IT) injection of NK cells in combination with Bev plus Iri elicited delayed tumor growth in the i.c U87 mouse model. Tumor-infiltrating NK cells were detected after IV injection of NK cells in both s.c and i.c U87 mouse models. In conclusion, the potential therapeutic effect of NK cells combined with Bev plus Iri against GBM cells was limited in this study. Accordingly, further research is required to improve the accessibility and strength of NK cell function in this combination treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Tran, Kim, Duong, Thangaraj, Chu, Jung, Kim, Moon, Kim, Lee, Lee, Yun, Lee, Lee, Lee and Jung.)

Emerging data have suggested that single short peptides have limited success as a cancer vaccine; however, extending the short peptides into longer multi-epitope peptides overcame the immune tolerance and induced an immune response. Moreover, the combination of adjuvants such as lenalidomide and anti-programmed cell death protein 1 (PD1) with a peptide vaccine showed potential vaccine effects in previous studies. Therefore, the effects of a long multi-epitope peptide vaccine in combination with lenalidomide and anti-PD1 were analyzed in this study. Long multi-epitope peptides from two MHCI peptides (BIRC5 97-104 and EphA2 682-689 ) and the pan-human leukocyte antigen-DR isotype (HLA-DR) binding epitope (PADRE) were synthesized. The therapeutic effects of long multi-epitope peptides in combination with lenalidomide and anti-PD1 were confirmed in the murine GL261 intracranial glioma model. Immune cells' distribution and responses to the long multi-epitope peptides in combination with these adjuvants were also estimated in the spleens, lymph nodes, and tumor tissues. The difference between long multi-epitope peptides and a cocktail of multi-epitope peptides combined with lenalidomide and anti-PD1 was also clarified. As a result, long multi-epitope peptides combined with lenalidomide and anti-PD1 prolonged the survival of mice according to the suppression of tumor growth in an intracranial mouse model. While long multi-epitope peptides combined with these adjuvants enhanced the percentages of activated and memory effector CD8 + T cells, the increase in percentages of regulatory T cells (Tregs) was observed in a cocktail of multi-epitope peptides combined with lenalidomide and anti-PD1 group in the tumors. Long multi-epitope peptides combined with these adjuvants also enhanced the function of immune cells according to the enhanced pro-inflammatory cytokines and cytotoxicity against GL261 cells in ex vivo . In conclusion, long multi-epitope peptides composed of MHCI peptides, BIRC5 and EphA2, and the MHCII peptide, PADRE, in combination with lenalidomide and anti-PD1 has the potential to improve the therapeutic effects of a vaccine against GBM., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tran, Kim, Kim, Jung, Kim, Moon, Kim, Lee, Yun, Lee, Lee, Lee and Jung.)

Introduction: Neurofibromatosis type 2 (NF-2) is an inherited disease, linked with abnormalities in the NF-2 gene, which is located on chromosome 22 and involved in merlin production. Many craniospinal tumors are common in individuals with NF-2. We present a case of NF-2 with the rapid symptomatic progression of multiple craniospinal tumors., Case Report: A 12-year-old male complained of headache and hearing impairment in the right ear for 7 months. Brain magnetic resonance imaging (MRI) revealed a right frontal meningioma, bilateral vestibular and trigeminal schwannomas, and a brainstem tumor. He was diagnosed with NF-2 and underwent brain surgery and radiotherapy for chordoid meningioma. He complained of right leg motor weakness 5 months post-surgery. The spine MRI showed multiple heterogeneously enhanced masses spreading over the entire spinal cord. The symptomatic intradural extramedullary mass at the cervicothoracic area was removed and the histological finding was schwannoma. His leg motor weakness was relieved after surgery. At the 6-month follow-up, brain MRI revealed the progression of the vestibular schwannoma, trigeminal schwannoma, and brainstem tumor. The patient was treated with bevacizumab (5 mg/kg) every 2 weeks for 6 months. For 2 years, all of the craniospinal tumors were stable without neurological deterioration after the completion of chemotherapy., Conclusion: Meningiomas and schwannomas grow slowly in most patients with NF-2, but these multiple craniospinal tumors can show sudden rapid growth and manifest as neurological symptoms in a pediatric patient. These tumors could be controlled with local symptomatic and systemic bevacizumab treatments., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Cognitive impairment often occurs in glioblastoma (GBM) patients due to the tumor itself and treatment side effects. Choline alphoscerate (L-alpha-glycerylphosphorylcholine, GPC) is frequently used to compensate for cognitive impairment in GBM patients. This study was conducted to determine whether GPC affects the overall survival (OS) and progression-free survival (PFS) of GBM patients. From 2011 to 2020, 187 isocitrate dehydrongenase (IDH)-wild-type GBM patients were analyzed. The patients were classified based on whether GPC was continuously used for at least 3 or 12 months (mos) after GBM diagnosis. Although GPC usage (≥3 mos) did not make significant differences in survival extension, median OS in the long-term GPC group (≥12 mos) was longer with statistical significance, compared to the control group (<12 mos) (38.3 vs. 24.0 mos, p = 0.004). In addition to younger age, supratentorial location, complete resection, and MGMT promoter methylation, long-term use of GPC (≥12 mos) was significantly associated with longer OS in multivariate analysis (p = 0.019, hazard ratio [HR] 0.532, 95% confidence interval [CI] 0.314−0.900). Despite the limitations of this study, long-term GPC use was possibly associated with prolonged survival in GBM patients. Multi-center prospective randomized studies with a large number of patients are needed to validate these findings.

The non-POU domain-containing octamer-binding protein (NONO, also referred to as p54nrb) is a multifunctional nuclear protein engaging in transcriptional regulation, mRNA splicing, nuclear retention of defective RNA, and DNA repair. Emerging evidence has demonstrated that p54nrb is subjected to various posttranslational modifications, including phosphorylation and methylation, which may be important regulators of its multifunction. However, among these modifications, direct evidence of p54nrb acetylation and its underlying mechanism remains unclear. In this study, we reported that lysine 371 of p54nrb was reversibly acetylated by the acetyltransferase general control non-depressible 5 (GCN5) and deacetylase sirtuin 1 (SIRT1), which was crucial for activity of p54nrb to inhibit interleukin-8 (IL-8) expression. Mechanistically, GCN5-mediated acetylation attenuates the recruitment of p54nrb on its core binding motif within the IL-8 gene promoter, preferentially increasing the expression of the IL-8 gene. In contrast, deacetylation by SIRT1 reverses this process. Altogether, our data suggest that reversible acetylation is an important switch for the multiple nuclear functions of p54nrb/NONO., Competing Interests: Declaration of competing interest The authors declare that no competing interest exists., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Tuberculum sellae meningiomas (TSMs) present a burdensome surgical challenge because of their adjacency to vital neurovascular structures. The contralateral subfrontal approach provides an outstanding corridor for removing a TSM with an excellent visual outcome and limited complications. The authors present their long-term surgical experience in treating TSMs via the contralateral subfrontal approach and discuss patient selection, surgical techniques, and clinical outcomes., Methods: Between 2005 and 2021, the authors used the contralateral subfrontal approach in 74 consecutive patients presenting with TSMs. The surgical decision-making process and surgical techniques are described, and the clinical outcomes were retrospectively analyzed., Results: The mean patient age was 54.4 years, with a female predominance (n = 61, 82%). Preoperatively, 61 patients (82%) had vision symptoms and 73 (99%) had optic canal invasion by tumor. Gross-total resection was achieved in almost all patients (n = 70, 95%). The visual function improvement and stabilization rate was 91% (67/74). Eight patients (11%) showed a worsening of visual function on the less-compromised (approach-side) optic nerve. There was no occurrence of cerebrospinal fluid leakage. Four patients (5%) experienced recurrences after the initial operation (mean follow-up duration 63 months). There were no deaths in this study., Conclusions: The contralateral subfrontal approach provides a high chance of complete tumor removal and visual improvement with limited complications and recurrences, especially when the tumor is in a unilateral or midline location causing unilateral visual symptoms or bilateral asymmetrical visual symptoms, regardless of tumor size or encasement of major vessels. With the appropriate patient selection, surgical technique, and familiarity with surrounding neurovascular structures, this approach is reliable for TSM surgery.

Background: Oral squamous cell carcinoma causes a significant proportion of global cancer morbidity and mortality. The aim of this study is to investigate whether the exhaled breath test can be a new, non-invasive, and effective method for diagnosing oral squamous cell carcinoma., Methods: A comparative analysis of exhaled breath between patients with oral squamous cell carcinoma (OSCC) and healthy controls (HC) was performed with the Twin Breasor II™, a simple gas chromatography system., Results: Both hydrogen sulfide (H 2 S) and methyl mercaptan (Ch 3 SH) were significantly higher in the OSCC group than in the HC group. The total sulfur concentration was also higher in the OSCC group, but there was no significant difference in the ratio of Ch 3 SH to H 2 S between the two groups. Using logistic regression, we constructed a new variable with an area under the curve (AUC) of 0.740, 68.0% sensitivity, and 72.0% specificity., Conclusions: Exhaled gas analysis via simple gas chromatography can potentially serve as an accessory non-invasive method for OSCC diagnosis., (© 2022. The Author(s).)

Adeno-associated virus (AAV)-mediated gene delivery holds great promise for gene therapy. However, the non-invasive delivery of AAV for lung tissues has not been adequately established. Here, we revealed that the intratracheal administration of an appropriate amount of AAV2/8 predominantly targets lung tissue. AAV-mediated gene delivery that we used in this study induced the expression of the desired protein in lung parenchymal cells, including alveolar type II cells. We harnessed the technique to develop severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-susceptible mice. Three kinds of immune function-relevant gene knockout (KO) mice were transduced with AAV encoding human angiotensin-converting enzyme 2 (hACE2) and then injected with SARS-CoV-2. Among these mice, type I interferon receptor (IFNAR) KO mice showed increased viral titer in the lungs compared to that in the other KO mice. Moreover, nucleocapsid protein of SARS-CoV-2 and multiple lesions in the trachea and lung were observed in AAV-hACE2-transduced, SARS-CoV-2-infected IFNAR KO mice, indicating the involvement of type I interferon signaling in the protection of SARS-CoV-2. In this study, we demonstrate the ease and rapidness of the intratracheal administration of AAV for targeting lung tissue in mice, and this can be used to study diverse pulmonary diseases., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

The present study investigated the potential adverse effects of aluminum chloride (AlCl 3 ) following a 4-week repeated oral administration in Sprague-Dawley rats. The test article was administered once daily by gavage to male and female rats at dose levels of 0, 100, 300, and 900 mg/kg/day for 4 weeks. After administration of AlCl 3 at 900 mg/kg/day, treatment-related systemic toxicity manifested as significant increases in salivation incidence, neutrophil percentage, reticulocytes, serum triglyceride, adrenal gland and liver weights, and single-hepatocyte necrosis, as well as significant decreases in body weight gain, food intake, hemoglobin, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration (MCHC), lymphocyte percentage, serum total protein and albumin, and thymus weight in male rats; and significant increases in salivation incidence, serum triglyceride, and liver weight, as well as a significant decrease in lymphocyte percentage in female rats. At 300 mg/kg/day, a significant decrease in MCHC was found in male rats, but not in female rats. However, this finding was not toxicologically significant because the reduction was minimal and was not accompanied by changes in any other parameters. No treatment-related effects were observed in the 100 mg/kg/day group of both genders. Under the experimental conditions of this study, the target organs of AlCl 3 were determined to be the blood, liver, and thymus in rats. The no-observed-adverse-effect level was found to be 300 mg/kg/day in rats of both genders.

Purpose: The 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 Methods: In 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)., Results: Of 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)., Conclusion: The 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.

This study investigated how three Asian countries-Republic of Korea (ROK), Republic of China (Taiwan), and Singapore-considered as standouts, responded to the coronavirus disease 2019 (COVID-19) in terms of governance system, health sector innovation, and social distancing to draw lessons that other countries can learn from. The countries were commonly in success of the response in early stage of the pandemic thanks to their effective and efficient strategies paired with advanced information and communications technology (ICT). Consequently, the three jurisdictions reported lower confirmed cases as well as fatality rate of the infectious disease compared to other high-income countries. In addition, the countries' previous experiences with other pandemics, including influenza A, Middle East respiratory syndrome, and severe acute respiratory syndrome, enabled them to establish resilient public health systems and gain public acceptance to governmental control or surveillance during national infectious disease-related crises outbreaks. Advanced ICT infrastructure and digital technology were used as effective tools for testing, tracing, and treatment of the pandemic in collaboration with the private sector as a crucial player. The ROK, Taiwan, and Singapore adopted different strategies between containment and mitigation policy to flatten the epidemic curves effectively according to their own situation and judgement. Despite the exemplary aspect of the three nations in coping with the COVID-19 pandemic, a few limitations were also observed in terms of vaccination and unequal consequences of the pandemic among people. These should be further discussed in order to be prepared for future pandemics., Competing Interests: The authors have no potential conflicts of interest to disclose., (© Copyright: Yonsei University College of Medicine 2022.)

Introduction: A mixed germ cell tumor with a teratoma component can become enlarged following chemotherapy, and such an event is diagnosed as growing teratoma syndrome. Removing large, hypervascular tumors including a tumor encased by developed vasculatures from the pineal region is challenging during a single operation., Case Report: A 15-year-old male underwent chemotherapy for mixed germ cell tumors according to the KSPNO G082 protocol. This case of a mixed germ cell tumor with growing teratoma syndrome was recognized very early during chemotherapy. The tumor was completely removed during the staged operations. First, the anteriorly located tumor on the third ventricle was removed via the transcallosal interforniceal approach, and 1 month later, the occipital transtentorial approach was used for the pineal tumor with decreased vascularity., Conclusion: Performing staged operations could be recommended for large hypervascular pineal tumors, which can be safely removed during the second operation once vascularity has decreased., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Nicotinamide adenine dinucleotide (NAD + ) is an important cofactor in many redox and non-redox NAD + -consuming enzyme reactions. Intracellular NAD + level steadily declines with age, but its role in the innate immune potential of myeloid cells remains elusive. In this study, we explored whether NAD + depletion by FK866, a highly specific inhibitor of the NAD salvage pathway, can affect pattern recognition receptor-mediated responses in macrophages. NAD + -depleted mouse bone marrow-derived macrophages (BMDMs) exhibited similar levels of proinflammatory cytokine production in response to LPS or poly (I:C) stimulation compared with untreated cells. Instead, FK866 facilitated robust caspase-1 activation in BMDMs in the presence of NLRP3-activating signals such as ATP and nigericin, a potassium ionophore. However, this FK866-mediated caspase-1 activation was completely abolished in Nlrp3 -deficient macrophages. FK866 plus nigericin stimulation caused an NLRP3-dependent assembly of inflammasome complex. In contrast, restoration of NAD + level by supplementation with nicotinamide mononucleotide abrogated the FK866-mediated caspase-1 cleavage. FK866 did not induce or increase the expression levels of NLRP3 and interleukin (IL)-1β but drove mitochondrial retrograde transport into the perinuclear region. FK866-nigericin-induced mitochondrial transport is critical for caspase-1 cleavage in macrophages. Consistent with the in vitro experiments, intradermal coinjection of FK866 and ATP resulted in robust IL-1β expression and caspase-1 activation in the skin of wild-type, but not Nlrp3 -deficient mice. Collectively, our data suggest that NAD + depletion provides a non-transcriptional priming signal for NLRP3 activation via mitochondrial perinuclear clustering, and aging-associated NAD + decline can trigger NLRP3 inflammasome activation in ATP-rich environments., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Shim, Cho, Hwang, Jung, Kim, Ryu and Yu.)

Objective: The effectiveness of gamma knife radiosurgery (GKR) in the treatment of brain metastases is well established. The aim of this study was to evaluate the efficacy and safety of maximizing the radiation dose in GKR and the factors influencing tumor control in cases of small and medium-sized brain metastases from non-small cell lung cancer (NSCLC)., Methods: We analyzed 230 metastatic brain tumors less than 5 mL in volume in 146 patients with NSCLC who underwent GKR. The patients had no previous radiation therapy for brain metastases. The pathologies of the tumors were adenocarcinoma (n=207), squamous cell carcinoma (n=18), and others (n=5). The radiation doses were classified as 18, 20, 22, and 24 Gy, and based on the tumor volume, the tumors were categorized as follows : small-sized (less than 1 mL) and medium-sized (1-3 and 3-5 mL). The progression-free survival (PFS) of the individual 230 tumors and 146 brain metastases was evaluated after GKR depending on the pathology, Eastern Cooperative Oncology Group (ECOG) performance score (PS), tumor volume, radiation dose, and anti-cancer regimens. The radiotoxicity after GKR was also evaluated., Results: After GKR, the restricted mean PFS of individual 230 tumors at 24 months was 15.6 months (14.0-17.1). In small-sized tumors, as the dose of radiation increased, the tumor control rates tended to increase (p=0.072). In medium-sized tumors, there was no statistically difference in PFS with an increase of radiation dose (p=0.783). On univariate analyses, a statistically significant increase in PFS was associated with adenocarcinomas (p=0.001), tumors with ECOG PS 0 (p=0.005), small-sized tumors (p=0.003), radiation dose of 24 Gy (p=0.014), synchronous lesions (p=0.002), and targeted therapy (p=0.004). On multivariate analyses, an improved PFS was seen with targeted therapy (hazard ratio, 0.356; 95% confidence interval, 0.150-0.842; p=0.019). After GKR, the restricted mean PFS of brain at 24 months was 9.8 months (8.5-11.1) in 146 patients, and the pattern of recurrence was mostly distant within the brain (66.4%). The small and medium-sized tumors treated with GKR showed radiotoxicitiy in five out of 230 tumors (2.2%), which were controlled with medical treatment., Conclusion: The small-sized tumors were effectively controlled without symptomatic radiation necrosis as the radiation dose was increased up to 24 Gy. The medium-sized tumors showed potential for symptomatic radiation necrosis without signifcant tumor control rate, when greater than 18 Gy. GKR combined targeted therapy improved the tumor control of GKR-treated tumors.

Background: There is no clear consensus on the optimal treatment with curative intent for patients with positive surgical margins (PSMs) following radical prostatectomy (RP). The aim of this study was to investigate the perceptions and treatment patterns of Korean urologists regarding the resection margin after RP., Methods: A preliminary questionnaire was prepared by analyzing various studies on resection margins after RP. Eight experienced urologists finalized the 10-item questionnaire. In July 2019, the final questionnaire was delivered via e-mail to 105 urologists in Korea who specialize in urinary cancers., Results: We received replies from 91 of the 105 urologists (86.7%) in our sample population. Among them, 41 respondents (45.1%) had performed more than 300 RPs and 22 (24.2%) had completed 500 or more RPs. In the question about whether they usually performed an additional biopsy beyond the main specimen, to get information about surgical margin invasion during surgery, the main opinion was that if no residual cancer was suspected, it was not performed (74.7%). For PSMs, the Gleason score of the positive site (49.5%) was judged to be a more important prognostic factor than the margin location (18.7%), multifocality (14.3%), or margin length (17.6%). In cases with PSMs after surgery, the prevailing opinion on follow-up was to measure and monitor prostate-specific antigen (PSA) levels rather than to begin immediate treatment (68.1%). Many respondents said that they considered postoperative radiologic examinations when PSA was elevated (72.2%), rather than regularly (24.4%). When patients had PSMs without extracapsular extension (pT2R1) or a negative surgical margin with extracapsular extension (pT3aR0), the response 'does not make a difference in treatment policy' prevailed at 65.9%. Even in patients at high risk of PSMs on preoperative radiologic screening, 84.6% of the respondents said that they did not perform neoadjuvant androgen deprivation therapy. Most respondents (75.8%) indicated that they avoided nerve-sparing RP in cases with a high risk of PSMs, but 25.7% said that they had tried nerve-sparing surgery. Additional analyses showed that urologists who had performed 300 or more prostatectomies tended to attempt more nerve-sparing procedures in patients with a high risk of PSMs than less experienced surgeons (36.6% vs. 14.0%; P = 0.012)., Conclusion: The most common response was to monitor PSA levels without recommending any additional treatment when PSMs were found after RP. Through this questionnaire, we found that the perceptions and treatment patterns of Korean urologists differed considerably according to RP resection margin status. Refined research and standard practice guidelines are needed., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2021 The Korean Academy of Medical Sciences.)

Breast cancer (BC) is the second most common solid malignant tumor that metastasizes to the brain. Despite emerging therapies such as immunotherapy, whether the tumor microenvironment (TME) in breast cancer brain metastasis (BCBM) has potential as a target of new treatments is unclear. Expression profiling of 770 genes in 12 pairs of primary BC and matched brain metastasis (BM) samples was performed using the NanoString nCounter PanCancer IO360 TM Panel. Immune cell profiles were validated by immunohistochemistry (IHC) in samples from 50 patients with BCBM. Pathway analysis revealed that immune-related pathways were downregulated. Immune cell profiling showed that CD8+ T cells and M1 macrophages were significantly decreased, and M2 macrophages were significantly increased, in BM compared to primary BC samples ( p = 0.001, p = 0.021 and p = 0.007, respectively). CCL19 and CCL21 , the top differentially expressed genes, were decreased significantly in BM compared to primary BC ( p < 0.001, both). IHC showed that the CD8+ count was significantly lower ( p = 0.027), and the CD163+ and CD206+ counts were higher, in BM than primary BC ( p < 0.001, both). A low CD8+ T cell count, low CD86+ M1 macrophage count, and high M2/M1 macrophage ratio were related to unfavorable clinical outcomes. BC exhibits an immunosuppressive characteristic after metastasis to the brain. These findings will facilitate establishment of a treatment strategy for BCBM based on the TME of metastatic cancer.

The government of the Republic of Korea (ROK) has established relevant laws and a master plan for infectious disease control and prevention based on their experiences with past epidemics. In addition, the Ministry of Health and Welfare has designed a standard manual for risk management that involves pan-governmental crisis management systems. This national infectious disease management system is constantly being supplemented and developed in face of infectious disease-related crises. In this study, we set out to present directions for infectious disease prevention and flow of management and governance between central and local governments to ensure systematic quarantine activities in the ROK. During the coronavirus disease 2019 (COVID-19) pandemic, public-private partnerships have been established to collect, provide, process, and disseminate information for effective quarantine. This has enabled the development and rapid approval of test kits, the tracking of cases, and the allocation of appropriate resources for patient treatment. Additionally, the Infectious Disease Control Agency has actively utilized information and communication technology platforms to disclose information necessary in real-time for COVID-19 quarantine and management. Overall, these efforts have played an important role in epidemiological investigations, patient management, and quarantine in the early stages of the COVID-19 pandemic., Competing Interests: The authors have no potential conflicts of interest to disclose., (© Copyright: Asian Development Bank and Yonsei University College of Medicine 2021.)

Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide-dependent histone deacetylase that plays diverse physiological roles. However, little is known about the regulation of SIRT1 activity. Here, we show that phospholipase D2 (PLD2), but not PLD1, selectively interacts with SIRT1 and increases the deacetylase activity of SIRT1. PLD2 does not interact with the other isozymes of SIRT (SIRT2-7). Two leucine residues in the LXXLL motif (L173 and L174) in the phox domain of PLD2 interact with the region essential for SIRT1 activity. PLD2 stimulates the SIRT1-mediated deacetylation of p53 independent of its lipase activity. In our study, mutagenesis of the LXXLL motif suppressed the interaction of PLD2 with SIRT1 and inhibited SIRT1-mediated p53 deacetylation and p53-induced transactivation of proapoptotic genes. Ultimately, overexpression of wild-type PLD2 but not that of LXXLL-mutant PLD2 protected cells against etoposide-induced apoptosis. Moreover, PLD2 did not protect against apoptosis induced by SIRT1 depletion under genotoxic stress. Collectively, our results suggest that PLD2 is a positive regulator of SIRT1 and modulates p53-mediated apoptosis via SIRT1., (© 2021. The Author(s).)

Yijin-tang is an oriental traditional herb used to treat inflammatory diseases. In the present study, we investigated the protective effects of Yijin-tang water extract (YTE) using an ovalbumin- (OVA-) induced asthma model, focusing on the antioxidant and anti-inflammatory properties of the herb. BALB/c mice were intraperitoneally injected with OVA on days 0 and 14 and then challenged with OVA on days 21, 22, and 23. The animals were orally administered YTE (200 and 400 mg/kg) from days 18 to 23, and this was found to significantly decrease airway hyperresponsiveness and release of inflammatory cells, cytokines, and OVA-specific immunoglobulin E in mice with asthma. In addition, YTE was associated with a marked reduction in airway inflammation and mucus production in lung tissue of mice with asthma. Furthermore, YTE suppressed the expression of matrix metalloproteinase-9 and phosphorylation of ERK in the lungs, which in turn led to a reduction in inducible nitric oxide synthases and an elevation in reduced glutathione and heme oxygenase-1. In conclusion, YTE effectively suppressed allergic responses in mice with asthma and the effect was closely related to antioxidant and anti-inflammatory properties of the herb. Our results indicate that YTE may be a potential agent for the treatment of allergic asthma., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Se-Jin Lee et al.)