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INTRODUCTION Patterns of failure in patients with olfactory neuroblastoma (ONB) according to two surgical approaches, craniofacial resection (CFR) and endoscopic surgery (ENDO), have yet to be analyzed. METHODS We retrospectively reviewed 30 patients with surgically treated ONB between January 1995 and October 2018. Sixteen (53.3%) patients underwent CFR (9 CFR alone, 7 ENDO-assisted CFR) and 14 (46.7%) underwent ENDO. Twenty-one (70.0%) patients underwent post-operative radiotherapy (RT). RESULTS At a median follow-up of 53.8 months (range 10.4–195.3), the 5-year progression-free survival (PFS) and 10-year overall survival were 37.3% and 57.5%, respectively. Patients with adjuvant RT had a 5-year PFS of 46.7%, whereas those treated with surgery alone had a 5-year PFS of 19.4% (p = 0.01). Locoregional failure (LRF) occurred in ten patients (median 59.6 months after initial diagnosis; range 12.7–59.7). Neck node metastasis occurred in 23.3% (7 of 30). Five patients with ENDO showed LRF and underwent proper subsequent treatments with either surgery or adjuvant RT. Approximately 31.3% patients (five patients) in the CFR group experienced distant metastasis in the intracranial dura region (median 116.4 months after initial diagnosis; range 2.6–142.4). Three of four patients who developed LRF after CFR developed dura-based metastasis. CONCLUSIONS Both dura-based and neck node metastasis in the delayed phase were distinct patterns of failure in ONB. Patterns of recurrence differed based on surgical approach; dura-based metastases were common after CFR. LRF was the distinct failure pattern in ENDO, but could be successfully salvaged. Treatment outcome was improved considerably with RT following surgical resection.

Recent studies have highlighted the importance of isocitrate dehydrogenase (IDH) mutational status in stratifying biologically distinct subgroups of gliomas. This study aimed to evaluate whether MRI-based radiomic features could improve the accuracy of survival predictions for lower grade gliomas over clinical and IDH status. Radiomic features (n = 250) were extracted from preoperative MRI data of 296 lower grade glioma patients from databases at our institutional (n = 205) and The Cancer Genome Atlas (TCGA)/The Cancer Imaging Archive (TCIA) (n = 91) datasets. For predicting overall survival, random survival forest models were trained with radiomic features; non-imaging prognostic factors including age, resection extent, WHO grade, and IDH status on the institutional dataset, and validated on the TCGA/TCIA dataset. The performance of the random survival forest (RSF) model and incremental value of radiomic features were assessed by time-dependent receiver operating characteristics. The radiomics RSF model identified 71 radiomic features to predict overall survival, which were successfully validated on TCGA/TCIA dataset (iAUC, 0.620; 95% CI, 0.501–0.756). Relative to the RSF model from the non-imaging prognostic parameters, the addition of radiomic features significantly improved the overall survival prediction accuracy of the random survival forest model (iAUC, 0.627 vs. 0.709; difference, 0.097; 95% CI, 0.003–0.209). Radiomic phenotyping with machine learning can improve survival prediction over clinical profile and genomic data for lower grade gliomas. • Radiomics analysis with machine learning can improve survival prediction over the non-imaging factors (clinical and molecular profiles) for lower grade gliomas, across different institutions.

OBJECTIVEThyroid-stimulating hormone (TSH)–secreting pituitary adenoma (TSHoma) is a rare type of pituitary adenoma; thus, little is known about TSHomas. The purpose of this study was to analyze clinical characteristics and therapeutic outcomes of TSHomas based on a single-center experience. The authors also searched for reliable preoperative and early postoperative factors that could predict long-term endocrinological remission.METHODSThe clinical, radiological, and pathological characteristics and surgical and endocrinological outcomes of 31 consecutive cases of TSHomas that were surgically treated between 2005 and 2017 were reviewed retrospectively. Preoperative factors were evaluated for their ability to predict long-term remission by comparing remission and nonremission groups. TSH and free thyroxine levels were measured at 2, 6, 12, 18, and 24 hours after surgery to determine whether they could predict long-term remission.RESULTSGross-total removal of tumor was achieved in 28 patients (90.3%), and 26 patients (83.9%) achieved endocrinological remission by surgery alone based on long-term endocrinological follow-up (median 50 months, range 32–81 months). The majority of the tumors were solid (21/31, 67.7%), and en bloc resection was possible in 16 patients (51.6%). Larger tumor size and tumor invasion into cavernous sinus and sphenoid sinus were strong predictors of lower rates of endocrinological remission. Immediate postoperative TSH level at 12 hours after surgery was the strongest predictor, with a 0.62 μIU/mL cutoff. Postoperative complications included CSF rhinorrhea in one patient and epistaxis in another patient, who underwent additional surgical treatment for the complications.CONCLUSIONSTumor size and extent are major prognostic factors for both extent of resection and endocrinological remission. The consistency of TSHomas was more likely to be solid, which makes extracapsular dissection more feasible. Long-term remission of TSHomas could be predicted even during the early postoperative period.

Background There was no practical guideline for the management of patients with central nervous system tumor in Korea in the past. Thus, the Korean Society for Neuro-Oncology (KSNO), a multidisciplinary academic society, developed the guideline for glioblastoma successfully and published it in Brain Tumor Research and Treatment, the official journal of KSNO, in April 2019. Recently, the KSNO guideline for World Health Organization (WHO) grade III cerebral glioma in adults has been established. Methods The Working Group was composed of 35 multidisciplinary medical experts in Korea. References were identified by searches in PubMed, MEDLINE, EMBASE, and Cochrane CENTRAL databases using specific and sensitive keywords as well as combinations of keywords. Scope of the disease was confined to cerebral anaplastic astrocytoma and oligodendroglioma in adults. Results Whenever radiological feature suggests high grade glioma, maximal safe resection if feasible is globally recommended. After molecular and histological examinations, patients with anaplastic astrocytoma, isocitrate dehydrogenase (IDH)-mutant should be primary treated by standard brain radiotherapy and adjuvant temozolomide chemotherapy whereas those with anaplastic astrocytoma, NOS, and anaplastic astrocytoma, IDH-wildtype should be treated following the protocol for glioblastomas. In terms of anaplastic oligodendroglioma, IDH-mutant and 1p19q-codeletion, and anaplastic oligodendroglioma, NOS should be primary treated by standard brain radiotherapy and neoadjuvant or adjuvant PCV (procarbazine, lomustine, and vincristine) combination chemotherapy. Conclusion The KSNO's guideline recommends that WHO grade III cerebral glioma of adults should be treated by maximal safe resection if feasible, followed by radiotherapy and/or chemotherapy according to molecular and histological features of tumors.

Oxidative stress (OS) is a major problem during in vitro culture of embryos. Numerous studies have shown that melatonin, which is known to have antioxidant properties, prevents the occurrence of OS in embryos. However, the molecular mechanisms by which melatonin prevents OS in embryos are still unclear. The present study suggests a possible involvement of the nuclear factor erythroid 2-related factor 2/antioxidant-responsive element (Nrf2/ARE) signaling pathway, which is one of the prominent signals for OS prevention through Nrf2 activation, connecting melatonin, OS prevention and porcine embryonic development. The aim of this study was to investigate the effects of melatonin (10−7 M) on porcine embryonic development via the Nrf2/ARE signaling pathway; brusatol (50 nM; Nrf2 specific inhibitor) was used to validate the mechanism. Treatment of porcine embryo with melatonin significantly increased formation rates of blastocysts and their total cell numbers and also upregulated the expression of Nrf2/ARE signaling and apoptosis-related genes (MT2, NRF2, UCHL, HO-1, SOD1 and BCL-2). Furthermore, the expression of proteins (NRF2 and MT2) was also upregulated in the melatonin-treated group. Concomitantly, brusatol significantly inhibited these effects, upregulating the expression of KEAP1 and BAX, including the expression level of KEAP1 protein. These results provide evidences that melatonin prevents OS through Nrf2/ARE signaling pathway in porcine in vitro fertilization -derived embryos.

Patients with nonfunctioning pituitary macroadenomas commonly experience headaches before and after surgery, and headaches have been reported to significantly detract from the quality of life. Despite this adverse impact, few studies have examined the prevalence and pattern of headaches on a long-term basis. Thus, this study employed a longitudinal cohort design to identify headache prevalence and severity during a 6-month postoperative period and its predictors.Forty patients with nonfunctioning pituitary macroadenomas who underwent transsphenoidal surgery were enrolled as subjects, and Headache Impact Test-6 (HIT-6) was performed at 4 time points: before and 1, 3, and 6 months after surgery.This study revealed that patients with nonfunctioning pituitary macroadenoma suffered from headaches at each of the 4 time points and that 37.5%, 27.8%, 17.9%, and 12.8% of the patients experienced "substantial and severe impact headaches" before and 1, 3, and 6 months after surgery, respectively. In addition, total HIT-6 scores 1 month after surgery were a significant predictor (B = 0.41, P0.001) of headaches 3 and 6 months after surgery. Among the HIT-6 items, pain (B = 0.09, P0.001), cognitive function (B = 0.07, P0.001), and psychological distress (B = 0.07, P0.001) showed the greatest impact on long-term headaches.Headaches adversely affected patients even 6 months after surgery. In addition, headaches 1 month after surgery predicted the prevalence of long-term headaches at 3 and 6 months, demonstrating the importance of timely postsurgical measurement of headaches to anticipate patients' long-term headache patterns.

Glioblastoma (GBM) is a disease without any definite cure. Numerous approaches have been tested in efforts to conquer this brain disease, but patients invariably experience recurrence or develop resistance to treatment. New surgical tools, carefully chosen samples, and experimental methods are enabling discoveries at single-cell resolution. The present article reviews the cell-of-origin of isocitrate dehydrogenase (IDH)-wildtype GBM, beginning with the historical background for focusing on cellular origin and introducing the cancer genesis patterned on firework. The authors also review mutations associated with the senescence process in cells of the subventricular zone (SVZ), and biological validation of somatic mutations in a mouse SVZ model. Understanding GBM would facilitate research on the origin of other cancers and may catalyze the development of new management approaches or treatments against IDH-wildtype GBM.

Background Although surgical resection is the first line therapy for acromegaly, many patients do not achieve biochemical remission after surgery and require the adjuvant therapy including medical treatment (somatostatin analogues; SSA, GH antagonist, and dopamine agonist), conventional radiotherapy, and gamma-knife surgery (GKS). Due to the limitations of rare disease, there are few studies evaluating the efficacy of each adjuvant treatment. In this study, we investigated clinical course and disease control after initiation of adjuvant treatment. Method We performed a single-center retrospective study including acromegalic patients treated with SSA at least for 6 months from January 1, 2005 to June 30, 2018. Age, gender, fasting GH, IGF-1 levels, 75 g oral glucose tolerance tests and tumor size were measured before/after operation, medical treatments, or radiotherapy. The patients were considered biochemically controlled/cured if fasting mean GH levels were less than 2.5ng/ml or nadir GH after oral glucose loading was less than 1 ng/ml together with age- and sex-matched normalized IGF-1. Result We analyzed 72 patients for median 62.9 months (40.0-111.5). The median age was 46 (37-53) years. The median duration of SSA use was 31.5 months (12.6-53.0). The median GH level was 30.5 (17.6-47.3) ng/ml, IGF-1 was 694.7 (600.0-862.8) ng/ml, initial tumor size was 24 (17.2-32.2) mm. Of 72 patients, 59 patients (81%) underwent surgical resection and 40 patients (55.6%) underwent GKS. Of the 40 patients who underwent GKS, 16 (40%) discontinued the medication after 26 (10.3-35.2) months. After treatment, 54 patients (75%) were biochemically controlled. Before initiation of SSA treatment, biochemically controlled group had significantly lower GH (3.63 vs 15.35ng/ml, p

To optimize and validate a current (NRG [a newly constituted National Clinical Trials Network group through National Surgical Adjuvant Breast and Bowel Project [NSABP], the Radiation Therapy Oncology Group [RTOG] and the Gynecologic Oncology Group (GOG)]) nomogram for glioblastoma patients as part of continuous validation. We identified patients newly diagnosed with glioblastoma who were treated with temozolomide-based chemoradiotherapy between 2006 and 2016 at three large-volume hospitals. The extent of resection was determined via postoperative MRI. The discrimination and calibration abilities of the prediction algorithm were assessed; if additional factors were identified as independent prognostic factors, updated models were developed using the data from two hospitals and were externally validated using the third hospital. Models were internally validated using cross-validation and bootstrapping. A total of 837 patients met the eligibility criteria. The median overall survival (OS) was 20.0 (95% CI 18.5–21.5) months. The original nomogram was able to estimate the 6‑, 12-, and 24-month OS probabilities, but it slightly underestimated the OS values. In multivariable Cox regression analysis, MRI-defined total resection had a greater impact on OS than that shown by the original nomogram, and two additional factors—IDH1 mutation and tumor contacting subventricular zone—were newly identified as independent prognostic values. An updated nomogram incorporating these new variables outperformed the original nomogram (C-index at 6, 12, 24, and 36 months: 0.728, 0.688, 0.688, and 0.685, respectively) and was well calibrated. External validation using an independent cohort showed C‑indices of 0.787, 0.751, 0.719, and 0.702 at 6, 12, 24, and 36 months, respectively, and was well calibrated. An updated and validated nomogram incorporating the contemporary parameters can estimate individual survival outcomes in patients with glioblastoma with better accuracy.

BACKGROUND There has been no practical guidelines for the management of patients with central nervous system (CNS) tumors in Korea for many years. Thus, the Korean Society for Neuro-Oncology (KSNO), a multidisciplinary academic society, started to prepare guidelines for CNS tumors from February 2018. METHODS The Working Group was composed of 35 multidisciplinary medical experts in Korea. References were identified through searches of PubMed, MEDLINE, EMBASE, and Cochrane CENTRAL using specific and sensitive keywords as well as combinations of keywords. RESULTS First, the maximal safe resection if feasible is recommended. After the diagnosis of a glioblastoma with neurosurgical intervention, patients aged ≤70 years with good performance should be treated by concurrent chemoradiotherapy with temozolomide followed by adjuvant temozolomide chemotherapy (Stupp's protocol) or standard brain radiotherapy alone. However, those with poor performance should be treated by hypofractionated brain radiotherapy (preferred)±concurrent or adjuvant temozolomide, temozolomide alone (Level III), or supportive treatment. Alternatively, patients aged >70 years with good performance should be treated by hypofractionated brain radiotherapy+concurrent and adjuvant temozolomide or Stupp's protocol or hypofractionated brain radiotherapy alone, while those with poor performance should be treated by hypofractionated brain radiotherapy alone or temozolomide chemotherapy if the patient has methylated MGMT gene promoter (Level III), or supportive treatment. CONCLUSION The KSNO's guideline recommends that glioblastomas should be treated by maximal safe resection, if feasible, followed by radiotherapy and/or chemotherapy according to the individual comprehensive condition of the patient.

Aberrant epigenetic reprogramming is known to be a major cause of inefficient somatic cell nuclear transfer (SCNT) in pigs, and use of epigenetic modification agents, such as DNA methyltransferase inhibitors (DNMTis), is a promising approach for enhancing SCNT efficacy. Here, we attempted to find the optimal condition of zebularine (Zb), a DNMTi, treatment on porcine SCNT embryos during in vitro culture (IVC). As results, treatment with 5 nM Zb for 24 hr showed the highest rate of embryo development to blastocyst compared to other groups (p < .05). Also, the relative intensities of global DNA methylation levels of anti-5-methylcytosine in pseudo-pronuclear (PNC), 2-cell and 4-cell stages were significantly lower in the Zb-treated group (p < .05), however, changes in methylation levels of centromeric satellite repeat were noted only in PNC and blastocyst stages. In addition, significant positive alterations in the relative expression of genes related to pluripotency (OCT4 and SOX2), histone acetylation (HAT1, HDAC1, HDAC2, and HDAC3) and DNA methylation (DNMT1 and DNMT3a) were observed compared to the control (p < .05). In conclusion, we found that Zb could modify DNA methylation levels in the early stages of porcine SCNT embryos and promote their developmental competence.

High metabolic activity, reflected in increased glucose uptake, is one of the hallmarks of many cancers including breast cancer. However, not all cancers avidly take up glucose, suggesting heterogeneity in their metabolic demand. Thus, we aim to generate a genomic signature of glucose hypermetabolism in breast cancer and examine its clinical relevance. To identify genes significantly associated with glucose uptake, gene expression data were analyzed together with the standardized uptake values (SUVmax) of (18)F-fluorodeoxy-glucose on positron emission tomography (PET) for 11 breast cancers. The resulting PET signature was evaluated for prognostic significance in four large independent patient cohorts (n = 5417). Potential upstream regulators accountable for the high glucose uptake were identified by gene network analysis. A PET signature of 242 genes was significantly correlated with SUVmax in breast cancer. In all four cohorts, high PET signature was significantly associated with poorer prognosis. The prognostic value of this PET signature was further supported by Cox regression analyses (hazard ratio 1.7, confidential interval 1.48–2.02; P

Melatonin and phytanic acid (PA) are known to be involved in lipid metabolism and β-oxidation, in which peroxisomal activities also significantly participate. In addition, other studies have reported that the nuclear factor-erythroid-derived 2-like 2 (Nrf2 or NFE2L2) signaling pathway mediates lipid metabolism and its subsequent cascades. As these mechanisms are partially involved in porcine oocytes or embryonic development, we hypothesized that the factors governing these mechanisms could be interconnected. Therefore, we aimed to investigate possible crosstalk between peroxisomal activities and Nrf2 signaling in porcine embryos following melatonin and PA treatment. Porcine embryos were cultured for seven days after parthenogenetic activation, and subsequently treated with melatonin and PA, or injected with Pex19-targeted siRNAs. Real-time PCR, immunocytochemistry, and BODIPY staining were used to evaluate peroxisomal activities, Nrf2 signaling, and subsequent lipid metabolism. We found that melatonin/PA treatment enhanced embryonic development, whereas injection with Pex19-targeted siRNAs had the opposite effect. Moreover, melatonin/PA treatment upregulated peroxisomal activities, Nrf2 signaling, lipid metabolism, and mitochondrial membrane potentials, whereas most of these mechanisms were downregulated by Pex19-targeted siRNAs. Therefore, we suggest that there is a connection between the action of melatonin and PA and the Nrf2 signaling pathway and peroxisomal activities, which positively influences porcine embryonic development.

Purpose To investigate the incremental prognostic value of apparent diffusion coefficient (ADC) histogram analysis over oxygen 6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status in patients with glioblastoma and the correlation between ADC parameters and MGMT status. Materials and Methods This retrospective study was approved by institutional review board, and informed consent was waived. A total of 112 patients with glioblastoma were divided into training (74 patients) and test (38 patients) sets. Overall survival (OS) and progression-free survival (PFS) was analyzed with ADC parameters, MGMT status, and other clinical factors. Multivariate Cox regression models with and without ADC parameters were constructed. Model performance was assessed with c index and receiver operating characteristic curve analyses for 12- and 16-month OS and 12-month PFS in the training set and validated in the test set. ADC parameters were compared according to MGMT status for the entire cohort. Results By using ADC parameters, the c indices and diagnostic accuracies for 12- and 16-month OS and 12-month PFS in the models showed significant improvement, with the exception of c indices in the models for PFS (P.05 for all) in the training set. In the test set, the diagnostic accuracy was improved by using ADC parameters and was significant, with the 25th and 50th percentiles of ADC for 16-month OS (P = .040 and P = .047) and the 25th percentile of ADC for 12-month PFS (P = .026). No significant correlation was found between ADC parameters and MGMT status. Conclusion ADC histogram analysis had incremental prognostic value over MGMT promoter methylation status in patients with glioblastoma. (©) RSNA, 2016 Online supplemental material is available for this article.

During 5-aminolevulinic acid (ALA)-guided glioblastoma multiforme (GBM) surgery, we encountered fluorescence in ventricular walls that lacked enhancement on magnetic resonance (MR) images and were free of macroscopic invasion of tumor cells. However, the meaning of ventricular wall fluorescence during 5-ALA-guided surgery is still unknown. The aim of this study was to investigate the relationship between intraoperative 5-ALA fluorescence and histopathological findings of ventricular walls free of enhancement on MR images. Nineteen patients with newly diagnosed GBM located near the lateral ventricle underwent 5‑ALA fluorescence‑guided surgery. During the surgery, the ventricle wall was opened and investigated with the aid of a surgical microscope equipped with optical filters to examine 5‑ALA fluorescence of the ventricular wall. Twenty‑five ventricular wall tissues that were apparently free of tumor involvement by MR imaging and macroscopic observation were obtained during surgery. Among the 19 cases with brightly fluorescing tumor masses, 11 patients (57.9%) exhibited 5‑ALA‑induced fluorescence in the ventricular wall. Of the 25 ventricular wall samples, 11 exhibited 5‑ALA‑induced fluorescence; upon pathologic examination, tumors were present in 5 samples (45.5%), but the remaining 6 (54.5%) were free of tumor cells. A pathologic examination revealed no tumor cells in the 14 samples that lacked 5‑ALA‑induced fluorescence. Our data suggest the possibility that glioma cells exhibiting 5‑ALA fluorescence are present in the ventricle wall, despite no signs of tumor involvement in MR images. Further investigation of non‑tumor cells from tissues with 5‑ALA fluorescence is needed to understand the nature of this unexpected ventricular wall fluorescence.

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

Endoplasmic reticulum (ER) stress can be triggered during in vitro embryo production and is a major obstacle to embryo survival. MicroRNA (miR)-210 is associated with cellular adaptation to cellular stress and inflammation. An experiment was conducted to understand the effects of miR-210 on in vitro embryo development, ER stress, and apoptosis, to achieve this, miR-210 was microinjected into parthenogenetically activated embryos. Our results revealed that miR-210 inhibition significantly enhanced the cleavage rate, blastocyst formation rate, and total cell number (TCN) of blastocysts, and reduced expression levels of XBP1 (p &lt, 0.05). miR-210 inhibition greatly reduced the expression of ER stress-related genes (uXBP1, sXBP1, ATF4, and PTPN1) and Caspase 3 and increased the levels of NANOG and SOX2 (p &lt, 0.05). A miR-210-mimic significantly decreased the cleavage, blastocyst rate, TCN, and expression levels of XBP1 compared with other groups (p &lt, 0.05). The miR-210-mimic impaired the expression levels of uXBP1, sXBP1, ATF4, PTPN1, and Caspase 3 and decreased the expression of NANOG and SOX2 (p &lt, 0.05). In conclusion, miR-210 plays an essential role in porcine in vitro embryo development. Therefore, we suggest that miR-210 inhibition could alleviate ER stress and reduce apoptosis to support the enhancement of in vitro embryo production.

Background Hyponatremia is a common complication after transsphenoidal surgery (TSS) for pituitary adenomas. This study retrospectively reviewed various clinical factors of pituitary adenoma patients who underwent TSS and aimed to identify possible risk factors of postoperative hyponatremia. Methods Total 1,343 patients who underwent TSS for their pituitary adenomas in a single institution were enrolled to this study. We identified and analyzed 93 patients (6.9%) with postoperative hyponatremia and compared them with other 1,250 patients in a control group. Patients' age, sex, tumor extent based on the modified Hardy classification, tumor size and hormonal type of the tumors were analyzed in comparison between two groups. The results of pre- and post-operative combined pituitary function test and their comparison were analyzed to elucidate a possible association between postoperative hyponatremia and hypopituitarism. Results The onset of postoperative hyponatremia was 7.8 days after surgery (range: postoperative day 3-13). The initial level of serum sodium (Na) level at the start of treatment was 123.5 mmol/L (range: 114-131 mmol/L) and the duration of treatment was 2.7 days (range: 1-9 days). Female predominance was evident in the hyponatremia group (77.4% vs. 61.4%, p=0.02). Preoperative hypopituitarism (58.5% vs. 71.5%, p=0.007) and postoperative hypocortisolism (33.7% vs. 23.4%, p=0.029) were related to postoperative hyponatremia. Other pre- and post-operative clinical factors were not associated with postoperative hyponatremia. Conclusion Postoperative hyponatremia is a common complication after TSS and is potentially fatal. Female patients were more likely to develop delayed hyponatremia. We demonstrated possible associations of delayed postoperative hyponatremia with preoperative and postoperative pituitary functions, but the mechanism behind it should be further investigated.

Purpose A critical indicator of the overall survival of patients with high-grade glioma is the successful isolation of tumor mesenchymal stem-like cells (tMSLCs), which play important roles in glioma progression. However, attempts to isolate tMSLCs from surgical specimens have not always been successful, and the reasons for this remain unclear. Considering that the amount of surgical high-grade glioma specimens varies, we hypothesized that larger surgical specimens would be better for tMSLC isolation. Materials and methods We assessed 51 fresh, high-grade glioma specimens and divided them into two groups according to the success or failure of tMSLC isolation. The success of tMSLC isolation was confirmed by plastic adherence, presenting antigens, tri-lineage differentiation, and non-tumorigenicity. Differences in characteristics between the two groups were tested using independent two sample t-tests, chi-square tests, or Kaplan-Meier survival analysis. Results The mean specimen weights of the groups differed from each other (tMSLC-negative group: 469.9±341.9 mg, tMSLC positive group: 546.7±618.9 mg), but the difference was not statistically significant. The optimal cut-off value of specimen weight was 180 mg, and the area under the curve value was 0.599. Conclusion Our results suggested a minimum criterion for specimen collection, and found that the specimen amount was not deeply related to tMSLC detection. Collectively, our findings imply that the ability to isolate tMSLCs is determined by factors other than the specimen amount.

IgG4-related disease (IgG4-RD) is an immune-mediated inflammatory condition which is characterized by dense lymphoplasmacytic infiltrations with a predominance of IgG4 plasma cells in the affected tissue. Although pachymeninx and pituitary gland are the most common sites where IgG4-RD infiltrates, the associations with IgG4-RD and a true intracranial tumor have not been yet reported in literature. Herein, we report two cases with intracranial tumors associated with IgG4-RD; a 36-year-old male patient with a huge meningioma and another 54-year old woman with a pituitary macroadenoma. Pathological examination revealed their tumors were substantially infiltrated by IgG4 plasma cells indicating its possible relation with IgG4-RD.

Sleep disturbance is a common comorbidity among patients with acromegaly [patients with growth hormone (GH)-secreting tumor] due to somatotropic axis change and sleep apnea. However, no previous studies exist concerning sleep disturbance and delirium in the early postoperative period in patients with acromegaly undergoing transsphenoidal tumor surgery. Herein, we aimed to compare the incidence of postoperative sleep disturbance and delirium in the early postoperative period between patients with GH-secreting and nonfunctioning pituitary tumors. We retrospectively reviewed the medical records of 1286 patients (969 with nonfunctioning and 317 with GH-secreting tumors) without history of psychological disease and sedative or antipsychotic use. We examined the use of antipsychotics/sedatives and findings of psychology consultation within the first postoperative week. Only patients with sleep disturbance noted in medical records were considered to have postoperative sleep disturbance. Patients with an Intensive Care Delirium Screening Checklist score of 4 or more were considered to have postoperative delirium. The incidence of postoperative sleep disturbance was higher in the GH-secreting group than in the nonfunctioning tumor group (2/969 [0.2%] vs 6/317 [1.9%]; P = .004; odds ratio = 9.328 [95% confidence interval, 1.873–46.452]). Univariable regression analysis showed that only diagnosis (GH-secreting tumor or nonfunctioning tumor) was a risk factor for sleep disturbance, and not sex, age, body mass index, American Society of Anesthesiologists physical status score, surgery duration, anesthesia duration, anesthesia type, tumor size, cavernous sinus invasion, or bleeding. The incidence of postoperative delirium was comparable between the 2 groups (6/969 [0.6%] vs 0/317 [0%]; P = .346). Patients with acromegaly showed increased incidence of sleep disturbance than those with nonfunctioning tumors in the early postoperative period after transsphenoidal tumor surgery. A prospective study evaluating sleep quality in patients with GH-secreting tumors in the early postoperative period could be conducted based on our findings.

OBJECTIVE The concept for maximal resection of glioblastoma(GBM) is changing to resect not only contrast-enhanced (CE) tumor but non-contrast-enhanced (NCE) tumor. Although maximal resection is associated with longer survival, the pattern of recurrence in glioblastoma, isocitrate dehydrogenase (IDH)-wildtype patient is poorly understood. METHODS This retrospective, single-center study included 358 eligible patients through November 1, 2005 to December 31, 2018. Those patients were grouped along extent of resection (subtotal resection (STR, n=123), gross-total resection (GTR, n=194), and supratotal resection (SupTR, n=41)). The pattern of recurrence was classified based on the range of radiation treatment, into infield gross target volume (GTV), infield clinical target volume (CTV), marginal, outfield and CSF seeding. RESULTS Tumor recurrence was observed for each group as follows: STR group, 80.5%, GTR group, 75.3%, and SupTR group, 63.4%. Statistical differences in pattern of recurrence among each group were observed in infield GTV (STR group:75.8%, GTR group: 71.9%, and SupTR group: 42.3%, p=0.003) and Outfield (STR group:11.0%, GTR group: 21.2%, SupTR group: 34.6%, p=0.012) recurrence. The survival for SupTR group was significantly longer than that for the STR and GTR in terms of both overall survival (OS) and progression free survival (PFS) (OS, STR: 15.7m, GTR: 21.6m, SupTR: 44.7m, PFS, STR: 10.4m, GTR: 14.3m, SupTR: 35.5m) CONCLUSIONS As the extent of resection increased, local recurrence decreased and distant recurrence increased. During treatment of glioblastoma, expectation

The quality of embryos produced by assisted reproductive techniques should be advanced by the improvement of in vitro culture conditions for successful implantation and pregnancy maintenance. We investigated the anti-oxidative effect of human adipose stem cell (ASC) conditioned medium with its optimal basal medium, Dulbecco&prime, s modified Eagle&prime, s medium (DMEM-CM), or keratinocyte serum-free medium (KSFM-CM) as supplements during in vitro culture (IVC) of in vitro fertilized mouse embryo. At first, preimplantation embryo development was evaluated in KSFM-CM and DMEM-CM supplemented cultures at various concentrations. The blastocyst (BL) and hatched BL formation rates were significantly increased in 5% DMEM-CM, while no difference was observed from KSFM-CM. Next, comparing the efficacy of KSFM-CM and DMEM-CM at the same concentration, DMEM-CM enhanced the developmental rate of 16 cells, morula, BL, and hatched BL. The expression level of reactive oxygen species decreased and that of glutathione increased in BL cultured with DMEM-CM, which confirms its anti-oxidative effect. Furthermore, apoptosis in BL cultured with DMEM-CM was reduced compared with that in KSFM-CM. This study demonstrated that the comparative effect of human ASC-CM made of two different basal media during mouse embryo IVC and anti-oxidative effect of 5% DMEM-CM was optimal to improve preimplantation embryo development.

Background: Although glioblastoma (GBM) is the most common primary brain tumor, the best available treatment options are still associated with poor prognosis. Recently, the Hippo/YAP signaling pathway has emerged as an important driver of GBM. Nevertheless, extensive studies have not yet been focused on the importance of phosphorylation event in regulating endogenous YAP activity in GBM. Here, we sought to elucidate that the modulation and stabilization of YAP/TAZ in Hippo pathway promote GBM progression. Methods: A core gene expression signature reflecting Silence of Hippo pathway (SOH) was developed in GBM patient samples to determine whether SOH enhances the tumor progression. In GBM tumorsphere (TS), mRNA levels of YAP1 were determined by microarray, and nuclear YAP1 expression level and its correlation with tumor aggressiveness were assessed through nucleus cytosolic fractionation, quantitative confocal microscopy, Western blot, and TEAD4 reporter assay. Cell proliferation, stemness, and invasive properties were also measured after treatment of YAP siRNA or its inhibitor verteporfin (VP). Results: GBM patients with SOH signature associated with poor prognosis and shorter survival. GBM TSs exhibited various phosphorylation states of YAP and could be distinguished by its phosphorylation status. GBM TSs with reduced YAP phosphorylation, including TS15-88, and other GBM TSs with higher YAP phosphorylation, which includes TS13-64, showed aggressive or less-aggressive cancer phenotypes, respectively. The siRNA-mediated knockdown of YAP1 significantly suppressed proliferation of TSs, and the results were confirmed using VP. Knockdown of YAP1 not only attenuated the invasiveness and stemness of TSs. Conclusion: We showed that reduced phosphorylation of endogenous YAP contributes to GBM progression. Moreover, we found that GBM TSs can be classified into two groups based on their YAP phosphorylation. These associations emphasize the YAP signaling network as new therapeutic opportunities in diagnosing and treating GBM. Citation Format: Yoojung Oh, Eui Hyun Kim, Dongkyu Lee, Junseong Park, Ju Hyung Moon, Hyun Woo Park, Jong Hee Chang, Seok-Gu Kang. Classification of glioblastoma tumorsphere depending on the regulatory mechanisms of the Hippo pathway [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr A26.

The Hippo pathway plays a critical role in various cancers, but its role in glioblastoma (GBM) has not been properly addressed. To assess the clinical relevance of the Hippo pathway in GBM, we generated a core gene expression signature reflecting silence of the Hippo pathway (SOH), and validated it in GBM patient samples from The Cancer Genome Atlas (TCGA) and in a separate cohort, revealing that SOH signature was associated with poor prognosis in GBM in both cohorts. Expression levels of CTGF and CYR61, the most reliable and well-known downstream targets of YAP1 (a target of the Hippo pathway), were markedly increased in GBM with the SOH signature. GBM showing the SOH signature was associated with an increased Immune signature score (ISS), suggesting that these patients might be good potential candidates for immunotherapy. Genes differentially expressed between samples with the SOH signature and samples with an active Hippo signature showed that many inhibitory immune checkpoint genes, such as CTLA4, PD-1, and PD-L2, were upregulated in the SOH subgroup, suggesting that YAP1/TAZ may induce resistance of cancer cells to host immune response in GBM. Also, many M2-polarized microglial markers and innate immune pathways were activated in the SOH subgroup. The SOH signature was strongly correlated with the TGF-β signature, which was also associated with a high ISS and mesenchymal features. In summary, SOH induces protumoral immunity in various ways, which may be new immunotherapeutic targets of GBM. Note: This abstract was not presented at the conference. Citation Format: Eui Hyun Kim, Seok-Gu Kang, Ju-Seog Lee. Silence of Hippo pathway induces protumoral immunity: New therapeutic target of glioblastomas [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr B16.

BACKGROUND: Grade II glioma is a heterogeneous group of various pathologies. 2016 WHO classification defined subgroups of Grade II gliomas based on isocitrate dehydrogenase (IDH) mutation and 1p/19q codeletion status. However, implications of telomerase reverse transcriptase promoter (TERTp) mutation and alpha-thalassemia/mental retardation syndrome X-linked (ATRX) loss are not considered in the classification. METHODS: Patients (n = 191) who underwent surgery and pathologically proven for supratentorial newly diagnosed low-grade glioma (WHO grade II) were included this study. Molecular diagnoses including IDH1/2 mutation, 1p/19q codeletion, TERTp mutation, ATRX expression, O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation status was evaluated. The overall survival according to TERTp mutation and ATRX loss in each 2016 WHO class were compared. RESULTS: There were 34 (17.8%) IDH-wildtype astrocytomas, 81 (42.4%) IDH-mutant astrocytomas, and 76 (39.8%) IDH-mutant and 1p/19q-codeleted oligodendrogliomas. The median overall survival (OS) of each group were 3.9, 10.4, and 18.7 years, respectively. TERTp mutation had negative impact for survival in IDH-wildtype astrocytomas (HR = 5.458, 95% confidence interval [CI] 1.771–16.826), while no significant differences were observed regarding TERTp mutation in IDH-mutant astrocytomas and oligodendrogliomas. Among IDH-wildtype/TERTp-mutant astrocytomas, ATRX loss was significantly correlated with poor outcome (2.1 vs 3.0 years, p=0.033). CONCLUSIONS: Molecular status of TERTp mutation and ATRX expression can help stratifying IDH-wildtype astrocytomas. IDH-wildtype astrocytomas which harbor TERTp mutation only without ATRX loss showed the worst outcome. Further study is needed to verify the role of TERTp mutation and ATRX in gliomas.

Two hypotheses about the origin of human glioblastoma (GBM) genesis are known to be dedifferentiation of cancer cells and orthodox differentiation of cancer stem cells. However, little is known about whether the direction of the human GBM genesis begins at the site of the tumor or at the subventricular zone (SVZ) where normal neural stem cells (NSCs) are present. Here, we describe direct molecular genetic evidence from patient brain tissue and genome-edited mouse models that show astrocyte-like NSCs in the SVZ to be the cell of origin that harbors the driver mutations of human GBM. First, we performed deep sequencing of triple-matched tissues, consisting of i) normal SVZ tissue away from the tumor mass, ii) tumor tissue, and iii) normal cortical tissue (or blood), from 28 patients with GBM, isocitrate dehydrogenase-wild type (IDH-wildtype) or other types of brain tumors. In doing so, we found that normal SVZ tissue away from the tumor in 56.3% of GBM IDH-wildtype patients contained low-level GBM driver mutations (down to ~1% of the mutational burden) that were observed at high levels in their matching tumors. Moreover, via single cell sequencing and laser microdissection analysis of patient brain tissue and genome editing of a mouse model, we discovered that astrocyte-like NSCs carrying driver mutations migrate from the SVZ and lead to the development of high-grade malignant gliomas in distant brain regions. Altogether, our results highlight NSCs in human SVZ tissue as the cell of origin that harbors the driver mutations of GBM. In addition, the origin of human glioblastoma is not the location of the tumor but the subventricular zone.

Although programmed death-1 (PD-1) blockade is effective in treating several types of cancer, the efficacy of this agent in glioblastoma (GBM) is largely unknown. We evaluated therapeutic effects of anti-PD-1, temozolomide (TMZ), and their combination in an orthotopic murine GBM model. The phenotype, number, and composition of lymphocytes were evaluated using flow cytometry. Transcriptional profiles of tumor tissues were analyzed using microarrays. Generation of antitumor immunological memory was investigated upon rechallenge. Combined treatment with anti-PD-1 and TMZ yielded synergistic antitumor efficacy in the presence of donor-originated PD-1(+)CD8(+) T cells in vitro, necessitating in vivo validation. Whereas TMZ did not rescue GBM-implanted mice, anti-PD-1 completely eradicated GBM in 44.4% of mice, and combination of anti-PD-1 and TMZ in all mice. Anti-PD-1 significantly increased the number of tumor-infiltrating lymhpocytes (TILs), and reduced frequencies of exhausted T cells and regulatory T cells. However, combining TMZ with anti-PD-1 significantly decreased the number of TILs, which was also observed with TMZ treatment alone. A transcriptome analysis of tumor tissues revealed that anti-PD-1 monotherapy perturbed immune-related genes, distinctly with combined therapy. Upon rechallenge, tumor growth was not observed in mice cured by anti-PD-1 monotherapy, whereas tumors regrew in the combination group. Furthermore, an analysis of peripheral blood revealed that antitumor memory T cells were generated in mice cured by anti-PD-1 monotherapy, not in the combination group. PD-1 blockade induces long-term therapeutic response, and combination with TMZ further enhances antitumor efficacy. However, immunological memory is provoked by anti-PD-1 monotherapy, not by combined therapy.

The Hippo pathway plays a critical role in various cancers, but its role in glioblastoma (GBM) has not been properly addressed. To assess the clinical relevance of the Hippo pathway in GBM, we generated a core gene expression signature reflecting silence of the Hippo pathway (SOH), and validate it in GBM patient samples from The Cancer Genome Atlas (TCGA) and in a separate cohort revealing that SOH signature was associated with poor prognosis in GBM in both cohorts. Expression levels of CTGF and CYR61, the most reliable and well-known downstream targets of YAP1 (a target of the Hippo pathway), were markedly increased in GBM with the SOH signature. GBM showing the SOH signature was associated with an increased Immune signature score (ISS), suggesting that these patients might be good potential candidates for immunotherapy. Genes differentially expressed between samples with the SOH signature and samples with an active Hippo signature showed that many inhibitory immune checkpoint genes, such as CTLA4, PD-1, and PD-L2, were upregulated in the SOH subgroup, suggesting that YAP1/TAZ may induce resistance of cancer cells to host immune response in GBM. Also, many M2-polarized microglial markers and innate immune pathways were activated in the SOH subgroup. The SOH signature was strongly correlated with the TGF-β signature, which was also associated with a high ISS and mesenchymal features. In summary, SOH induces pro-tumoral immunity in various ways, which may be new immunotherapeutic targets of GBM.

OBJECTIVE: This single center retrospective study aims to assess survival benefit of lobectomy compared to gross-total resection without lobectomy for primary glioblastomas (pGBM) in non-eloquent region. BACKGROUND: The only prognostic factor of glioblastoma that can be determined by the surgeon is the extent of resection. However, glioblastomas are known to infiltrate to a wider extent and are eventually recurred by remaining microscopic tumors. In surgical oncology field, the classic concept of radical resection was wide resection including normal surrounding tissue. Nevertheless, it is not yet known whether further removal of tumor-surrounding tissue may be helpful for survival in pGBM patients. METHODS: Among the patients who had undergone surgical resection and were diagnosed as glioblastoma by histopathologic examination, we selected patients who had complete resection with the lesion localized on the non-dominant frontal or temporal lobe. Patients were divided into two groups: those who underwent gross-total resection of the tumor without additional tissue resection (GTR group) and those who underwent gross-total resection of the tumor with additional lobectomy (SupTR group). Progression-free survival (PFS), overall survival (OS) and postoperative Karnofsky performance scale (KPS) score were compared between groups. RESULTS: Thirteen of 28 patients underwent complete resection only, and 15 patients underwent complete resection with additional frontal or temporal lobectomy. The median PFS time after surgery was 13.1 months (95% CI 6.4–19.8) in GTR group and 38.3 months (95% CI 11.9–64.7) in SupTR group (p=0.098), respectively. The median OS time after surgery was 14.4 months (95% CI 12.1–16.7) in GTR group and 35.0 months (95% CI 17.4–52.6) in SupTR group (p=0.018), respectively. The mean postoperative KPS score was 73.4 in GTR group and 71.33 in SupTR group (p=0.586), respectively. CONCLUSIONS: In the non-dominant frontal or temporal glioblastomas which were completely resectable, additional lobectomy improved overall survival, without deteriorating performance of the patients.

In malignant gliomas, invasive phenotype and cancer stemness promoting resurgence of residual tumor cells render treatment very difficult. Hence, identification of epithelial–mesenchymal transition (EMT) factors associated with invasion and stemness of glioma cells is critical. To address the issue, we investigated several EMT factors in hypermotile U87MG and U251 cells, orthotopic mouse glioma model, and human glioma samples. Of several EMT markers, SLUG expression was notably increased at the invasive fronts of gliomas, both in mouse tumor grafts and human glioma samples. The biological role played by SLUG was investigated using a colony-forming assay after chemotherapy and irradiation, and by employing a neurosphere culture assay. The effect of SLUG on glioma progression was examined in our patient cohort and samples, and compared to large public data from the REMBRANDT and TCGA. Genetic upregulation of SLUG was associated with increased levels of stemness factors and enhanced resistance to radiation and temozolomide. In our cohort, patients exhibiting lower-level SLUG expression evidenced longer progression-free survival (P = 0.042). Also, in the REMBRANDT dataset, a group in which SLUG was downregulated exhibited a significant survival benefit (P

Patterns of failure in patients with olfactory neuroblastoma (ONB) according to two surgical approaches, craniofacial resection (CFR) and endoscopic surgery (ENDO), have yet to be analyzed. We retrospectively reviewed 28 patients with surgically treated ONB between January 1995 and October 2017. Fourteen (50.0%) patients underwent CFR (9 CFR alone, 5 ENDO-assisted CFR) and 14 (50.0%) underwent ENDO. Nineteen (67.9%) patients underwent post-operative radiotherapy (RT). At a median follow-up of 53.8 months (range 10.4–195.3), the 5-year progression-free survival (PFS) and 10-year overall survival were 37.3% and 57.5%, respectively. Patients with adjuvant RT had a 5-year PFS of 46.7%, whereas those treated with surgery alone had a 5-year PFS of 19.4% (p = 0.01). Locoregional failure (LRF) occurred in ten patients (median 59.6 months after initial diagnosis; range 12.7–59.7). Neck node metastasis occurred in 25.0% (7 of 28). Five patients with ENDO showed LRF and underwent proper subsequent treatments with either surgery or adjuvant RT. Approximately 35.7% patients (five patients) in the CFR group experienced distant metastasis in the intracranial dura region (median 116.4 months after initial diagnosis; range 2.6–142.4). Three of four patients who developed LRF after CFR developed dura-based metastasis. Both dura-based and neck node metastasis in the delayed phase were distinct patterns of failure in ONB. Patterns of recurrence differed based on surgical approach; dura-based metastases were common after CFR. LRF was the distinct failure pattern in ENDO, but could be successfully salvaged. Treatment outcome was improved considerably with RT following surgical resection.

Immune checkpoint inhibitors (ICI) are used for the treatment of various cancers, but clinical trials of anti-programmed cell death protein 1 (PD-1) with patients with recurrent glioblastoma (GBM) have failed to show clinical benefits. In this study, we examined the differentiation status of CD8We isolated TILs from 98 patients with newly diagnosed GBM and examined the expression of immune checkpoint receptors and T-cell transcription factors using flow cytometry. TILs wereCD8In primary GBM, the differentiation status of CD8

OBJECTIVEEndonasal surgery of the skull base requires watertight reconstruction of the skull base that can seal the dural defect to prevent postoperative CSF rhinorrhea and consequent intracranial complications. Although the incidence of CSF leakage has decreased significantly since the introduction in 2006 of the vascularized nasoseptal flap (the Hadad-Bassagasteguy flap), reconstruction of extensive skull base dural defects remains challenging. The authors describe a new, modified vascularized nasoseptal flap for reconstruction of extensive skull base dural defects.METHODSA retrospective review was conducted on 39 cases from 2010 to 2017 that involved reconstruction of the skull base with an endonasal vascularized flap. Extended nasoseptal flaps were generated by adding the nasal floor and inferior meatus mucosa, inferior turbinate mucosa, or entire lateral nasal wall mucosa. The authors specifically highlight the surgical techniques for flap design and harvesting of these various modifications of the vascularized nasoseptal flap.RESULTSThirty-nine endonasal vascularized flaps were used to reconstruct skull base defects in 37 patients with nonsurgical or postoperative CSF rhinorrhea. Of the 39 procedures, extended nasoseptal flaps were used in 5 cases (13%). These included 2 extended nasoseptal flaps including the inferior turbinate mucosa and 3 extended nasoseptal flaps including the entire lateral nasal wall mucosa. These 5 extended nasoseptal flaps were used in patients who had nonsurgical CSF rhinorrhea due to extensive skull base destruction by invasive pituitary tumors. All flaps healed completely and sealed off the CSF leaks. Olfactory function slightly decreased in the 3 patients with extended nasoseptal flaps including the entire lateral nasal wall mucosa. One patient experienced nasolacrimal duct obstruction, which was treated by dacryocystorhinostomy. The authors encountered no wound complication in this series, while crusting at the donor site required daily nasal toilette and frequent debridement until the completion of mucosalization, which usually takes 8 to 12 weeks after surgery.CONCLUSIONSExtended nasoseptal flaps are a reliable and versatile option that can be used to reconstruct extensive skull base dural defects resulting from destruction by large invasive tumors or complex endoscopic endonasal surgery. An extended nasoseptal flap that includes the entire lateral nasal wall mucosa (360° flap) is the largest endonasal vascularized flap reported to date and may be an alternative for the reconstruction of extensive skull base defects while avoiding the need for additional external approaches.

OBJECT The authors investigated the value of retinal nerve fiber layer (RNFL) thickness in predicting visual outcome after surgery for parachiasmal meningioma. METHODS Forty-nine eyes of 25 patients who underwent craniotomy and resection of a parachiasmal meningioma were analyzed retrospectively. Visual parameters including visual field (VF) (recorded as the mean deviation [MD]), visual acuity (VA), and RNFL thickness (via optical coherence tomography) were measured before and 1 week, 6 months, and 1 year after surgery. Postoperative visual outcome was compared among the patients with a thin or normal RNFL. A separate analysis of data pertaining to 22 eyes of 13 patients with severe VF defects (MD ≤ −10 dB) was performed to compare visual outcome for those with a thin or normal RNFL. RESULTS Of the 23 eyes that showed VF improvement, 22 (95.7%) had normal RNFL thickness. The positive predictive value of normal RNFL thickness for VF improvement was 78.6%. The VF of patients with normal RNFL thickness improved in 6 months and continued improving 1 year after surgery (MD −5.9 dB before surgery, −5.5 dB 1 week after surgery, −2.8 dB 6 months after surgery [p < 0.01], and −1.1 dB 1 year after surgery [p < 0.01]). In contrast, those with a thin preoperative RNFL showed deterioration at first and then slower, worse visual recovery after surgery (MD −18.1 dB before surgery, −22.4 dB 1 week after surgery, −21.2 dB 6 months after surgery, and −19.1 dB 1 year after surgery). VA also showed significant progress 6 months after surgery in patients with normal RNFL thickness (0.6 before surgery, 0.7 one week after surgery, 0.9 six months after surgery [p = 0.025], and 0.9 one year after surgery [p = 0.050]) compared to those with a thin RNFL (0.3 before surgery, 0.2 one week after surgery, 0.3 six months after surgery, and 0.4 one year after surgery). Preoperative differences in VF MD and VA were noted between the 2 groups (p < 0.01). Even patients with severe VF defects and normal RNFL thickness improved by 11.1 dB by 1 year after surgery compared with patients with a thin RNFL (−0.01 dB) (p < 0.01). Patients with normal RNFL thickness also did better in VA improvement (from 0.7 to 1.1) than those with a thin RNFL (from 0.2 to 0.3), but these results were not statistically significant. CONCLUSIONS RNFL thickness measured by optical coherence tomography has significant value as a prognostic factor of postoperative visual recovery for parachiasmal meningioma. Patients with normal RNFL thickness before surgery are more likely to have visual improvement after surgery than patients with a thin RNFL.

Metal-supported solid oxide electrolysis cell integrated with metal interconnect by joining process (so-called, with fuel electrode(cathode)-supported electrolysis cell) was fabricated and its electrical performance are investigated under both operation mode of fuel cell(hydrogen) and co-electrolysis(steam and CO2) mode at the intermediate temperature of 750 oC~850 oC. The fuel(or steam) electrode layers are prepared using NiO and YSZ(8 mol% Y2O3-doped ZrO2) at the ratio of 1:1. In order to obtain pores in the cathode, graphite powders of 24 volume % with average particle size of 44 mm are added. In the case of a metal-supported solid oxide electrolysis cell(SOEC) with heat-treated cathode support, 10 mol % Sm2O3-doped CeO2 (SDC) paste is screen-printed on the surface of YSZ and subsequently (La0.6Sr0.4) (Co0.2Fe0.8)O3 (LSCF) paste mixed with SDC at 1:1 weight ratio as anode(air electrode) is screen-printed on the SDC layer and heat-treated for desirable adhesion. The single electrolysis cell performances are compared by analyzing AC impedance spectra and product gas composition by GC(gas chromatography)of metal-supported electrolysis cell integrated with metal interconnect and cathode-supported electrolysis cell, and the current-voltage characteristics and cross-sectional microstructure of cathode-supported cell integrated with metal interconnect are tested. The stable long-term performance with co-electrolysis of carbon dioxide (CO2)and steam(H2O) is shown for about 800 h at 800 oC under the constant current density of 300 mA/cm2, 600 mA/cm2, 800 mA/cm2, and 1000 mA/cm2. In the fuel cell mode operation of metal-supported SOEC cell, the maximum power density of 0.8W/cm2 is indicated with hydrogen fuel. The microstructures are analyzed using optical microscope for observing a diffusion of metal ions at the cathode, adhesion layer and metal support(ferritic stainless steel, STS430) with EDAX analysis. In the present work, we have investigated the performance and microstructures of metal-supported SOEC for the co-electrolysis of CO2 and H2O steam. The exemplary works with AC impedance and the composition of product gas are analyzed in the operation of metal-supported co-electrolysis cell.

A decade ago, cancer stem cells (CSCs) were introduced as target cells for an innovative cancer treatment. Particularly, there have been a lot of biological researches on glioblastoma (GBM) CSCs. However, as there is a comprehensive change in the concept of CSCs, it is required to review how the different CSCs for patients can be clinically used, or clinical credentialing, and summarize the possibilities of clinical credentialing. In this regard, this review aims to introduce the tumorsphere obtained from GBM specimen and summarize the clinical dilemma and clinically applicable areas.

Glioblastoma (GBM) is an incurable brain tumor, with a median overall survival of 15 months. Identifying the cell of origin that harbors mutations driving GBM could provide a fundamental basis for understanding disease developing novel treatments. Given that the accumulation of somatic mutations is implicated in gliomagenesis, studies have suggested that neural stem cells (NSCs), with their self-renewal and proliferative capacities, in the subventricular zone (SVZ) of the adult human brain may be the cells from which GBM originates. However, there is a lack of direct genetic evidence thereof in human GBM patients. Here, we describe direct molecular genetic evidence from patient brain tissue and genome edited mouse models that show astrocyte-like NSCs in the SVZ to be the cell of origin that harbors the driver mutations of human GBM. First, we performed deep sequencing of triple-matched tissues, consisting of i) radiologically and pathologically normal SVZs away from the tumor mass, ii) the tumor, and iii) normal cortical tissue (or blood), from 17 patients with primary GBM (isocitrate dehydrogenase-wild type) or other types of brain tumors. In doing so, we found that normal SVZ tissue away from the tumor in 46.2% of primary GBM patients contained low-level GBM driver mutations (down to ~1% of the mutational burden; TP53, PTEN, EGFR, PDGRF or TERT variations) that were observed at high levels in their matching tumors. Moreover, via single cell sequencing and laser microdissection analysis of patient’s brain tissues and genome editing of a mouse model (CRISPR-Cas9 system), we discovered that astrocyte-like NSCs (the astrocyte ribbon area) carrying driver mutations (TP53, PTEN, EGFR) migrate from the SVZ and lead to the development of high-grade gliomas in distant brain regions through aberrant growth. Altogether, our results highlight NSCs in human SVZ as the cell of origin that harbors the driver mutations of GBM.