Long-Term Outcome of Unilateral Acoustic Neuromas With or Without Hearing Loss: Over 10 Years and Beyond After Gamma Knife Radiosurgery

Background@#Since the long-term outcomes of 162 patients who underwent gamma knife radiosurgery (GKS) as an initial or adjuvant treatment for acoustic neuromas (ANs) with unilateral hearing loss were first reported in 1998, there has been no report of a comprehensive analysis of what has changed in GKS practice. @*Methods@#We performed a retrospective study of the long-term outcomes of 106 patients with unilateral sporadic ANs who underwent GKS as an initial treatment. The mean patient age was 50 years, and the mean initial tumor volume was 3.68 cm 3 (range, 0.10–23.30 cm 3 ).The median marginal tumor dose was 12.5 Gy (range, 8.0–15.0 Gy) and the median follow-up duration was 153 months (range, 120–216 months). @*Results@#The tumor volume increased in 11 patients (10.4%), remained stationary in 27 (25.5%), and decreased in 68 patients (64.2%). The actuarial 3, 5, 10, and 15-year tumor control rates were 95.3 ± 2.1%, 94.3 ± 2.2%, 87.7 ± 3.2%, and 86.6 ± 3.3%, respectively.The 10-year actuarial tumor control rate was significantly lower in the patients with tumor volumes of ≥ 8 cm 3 (P = 0.010). The rate of maintaining the same Gardner-Robertson scale grade was 28.6%, and that of serviceable hearing was 46.4%. The rates of newly developed facial and trigeminal neuropathy were 2.8% and 4.7%, respectively. The patients who received marginal doses of less than 12 Gy revealed higher tumor control failure rates (P = 0.129) and newly occurred facial or trigeminal neuropathy rates (P = 0.040 and 0.313, respectively). @*Conclusion@#GKS as an initial treatment for ANs could be helpful in terms of tumor control, the preservation of serviceable hearing, and the prevention of cranial neuropathy. It is recommended to perform GKS as soon as possible not only for tumor control in unilateral ANs with hearing loss but also for hearing preservation in those without hearing loss.

A Case of Sensorineural Hearing Loss Caused by Neurosyphilis in Patient Who Is Treated by Anti-Interleukin 17A Monoclonal Antibody / 대한이비인후과학회지

Syphilis is a sexually transmitted disease caused by Treponema pallidum, which can invade various organs. Syphilis can also cause otologic symptoms such as hearing impairment, tinnitus or dizziness and these otologic symptoms can occur at any stage of syphilis and can be associated with neurosyphilis. We report here a case of rapid progressive neurosyphilis showing hearing impairment in a patient with ankylosing spondylitis. He was treated with anti-interleukin 17A monoclonal antibody. Since syphilis is one of the causes of reversible sensorineural hearing loss and syphilis infection with immunosuppression can cause progressive hearing loss if patients in immunomodulatory therapy have sensorineural hearing loss, the possibility of syphilis should be considered.

Revised Korean Cough Guidelines, 2020: Recommendations and Summary Statements / 결핵및호흡기질환

Cough is the most common respiratory symptom that can have various causes. It is a major clinical problem that can reduce a patient’s quality of life. Thus, clinical guidelines for the treatment of cough were established in 2014 by the cough guideline committee under the Korean Academy of Tuberculosis and Respiratory Diseases. From October 2018 to July 2020, cough guidelines were revised by members of the committee based on the first guidelines. The purpose of these guidelines is to help clinicians efficiently diagnose and treat patients with cough. This article highlights the recommendations and summary of the revised Korean cough guidelines. It includes a revised algorithm for the evaluation of acute, subacute, and chronic cough. For a chronic cough, upper airway cough syndrome (UACS), cough variant asthma (CVA), and gastroesophageal reflux disease (GERD) should be considered in differential diagnoses. If UACS is suspected, first-generation antihistamines and nasal decongestants can be used empirically. In cases with CVA, inhaled corticosteroids are recommended to improve cough. In patients with suspected chronic cough due to symptomatic GERD, proton pump inhibitors are recommended. Chronic bronchitis, bronchiectasis, bronchiolitis, lung cancer, aspiration, intake of angiotensin-converting enzyme inhibitor, intake of dipeptidyl peptidase-4 inhibitor, habitual cough, psychogenic cough, interstitial lung disease, environmental and occupational factors, tuberculosis, obstructive sleep apnea, peritoneal dialysis, and unexplained cough can also be considered as causes of a chronic cough. Chronic cough due to laryngeal dysfunction syndrome has been newly added to the guidelines.

Analysis for Risk Factors and Effect of Vocal Hygiene Education in Patients of Vocal Polyp

Background and Objectives@#Vocal polyp is one of the most common benign diseases of vocal fold caused by overuse of voice. Laryngeal microsurgery is the first treatment of choice for vocal polyp. However, surgery has many risks such as side effects of general anesthesia, injury of tooth and psychological burden. And we often experience reduction of vocal polyps without surgical procedure. The purpose of study is to evaluate the effect of non-surgical treatment such as vocal hygiene education and proton pump inhibitor (PPI) in patients with vocal polyp.Materials and Method We performed retrospective study for seventy-three patients of vocal polyp who treated with non-surgical modalities such as vocal hygiene education and PPI over three months. Treatment outcomes and risk factors such as age, sex, polyp size, position, symptom duration, presence of laryngopharyngeal reflux (LPR) symptoms, smoking history, voice abuse history and vocal hygiene education were evaluated by comparison between polyp size improved group and non-improved group. @*Results@#5.5% of enrolled patients showed complete response and 23.3% showed partial response without surgery. Polyp size improved group significantly carried out more practice of vocal hygiene education treatment than the non-improved group (p=0.040). And the presence of LPR symptoms [hazard ratio (HR) 3.368, confidence interval (CI) 1.055–10.754, p=0.040] and not performing of vocal hygiene education (HR 3.664, 95% CI 1.078–12.468, p=0.038). @*Conclusion@#Vocal hygiene education can be a useful treatment option when making a decision to treat with vocal polyp.

Tumor Spheroids of an Aggressive Form of Central Neurocytoma Have Transit-Amplifying Progenitor Characteristics with Enhanced EGFR and Tumor Stem Cell Signaling

Central neurocytoma (CN) has been known as a benign neuronal tumor. In rare cases, CN undergoes malignant transformation to glioblastomas (GBM). Here we examined its cellular origin by characterizing differentiation potential and gene expression of CN-spheroids. First, we demonstrate that both CN tissue and cultured primary cells recapitulate the hierarchal cellular composition of subventricular zone (SVZ), which is comprised of neural stem cells (NSCs), transit amplifying progenitors (TAPs), and neuroblasts. We then derived spheroids from CN which displayed EGFR+/ MASH+ TAP and BLBP+ radial glial cell (RGC) characteristic, and mitotic neurogenesis and gliogenesis by single spheroids were observed with cycling multipotential cells. CN-spheroids expressed increased levels of pluripotency and tumor stem cell genes such as KLF4 and TPD5L1, when compared to their differentiated cells and human NSCs. Importantly, Gene Set Enrichment Analysis showed that gene sets of GBM-Spheroids, EGFR Signaling, and Packaging of Telomere Ends are enriched in CN-spheroids in comparison with their differentiated cells. We speculate that CN tumor stem cells have TAP and RGC characteristics, and upregulation of EGFR signaling as well as downregulation of eph-ephrin signaling have critical roles in tumorigenesis of CN. And their ephemeral nature of TAPs destined to neuroblasts, might reflect benign nature of CN.

Revised Korean Cough Guidelines, 2020: Recommendations and Summary Statements / 결핵및호흡기질환

Cough is the most common respiratory symptom that can have various causes. It is a major clinical problem that can reduce a patient’s quality of life. Thus, clinical guidelines for the treatment of cough were established in 2014 by the cough guideline committee under the Korean Academy of Tuberculosis and Respiratory Diseases. From October 2018 to July 2020, cough guidelines were revised by members of the committee based on the first guidelines. The purpose of these guidelines is to help clinicians efficiently diagnose and treat patients with cough. This article highlights the recommendations and summary of the revised Korean cough guidelines. It includes a revised algorithm for the evaluation of acute, subacute, and chronic cough. For a chronic cough, upper airway cough syndrome (UACS), cough variant asthma (CVA), and gastroesophageal reflux disease (GERD) should be considered in differential diagnoses. If UACS is suspected, first-generation antihistamines and nasal decongestants can be used empirically. In cases with CVA, inhaled corticosteroids are recommended to improve cough. In patients with suspected chronic cough due to symptomatic GERD, proton pump inhibitors are recommended. Chronic bronchitis, bronchiectasis, bronchiolitis, lung cancer, aspiration, intake of angiotensin-converting enzyme inhibitor, intake of dipeptidyl peptidase-4 inhibitor, habitual cough, psychogenic cough, interstitial lung disease, environmental and occupational factors, tuberculosis, obstructive sleep apnea, peritoneal dialysis, and unexplained cough can also be considered as causes of a chronic cough. Chronic cough due to laryngeal dysfunction syndrome has been newly added to the guidelines.

Analysis for Risk Factors and Effect of Vocal Hygiene Education in Patients of Vocal Polyp

Background and Objectives@#Vocal polyp is one of the most common benign diseases of vocal fold caused by overuse of voice. Laryngeal microsurgery is the first treatment of choice for vocal polyp. However, surgery has many risks such as side effects of general anesthesia, injury of tooth and psychological burden. And we often experience reduction of vocal polyps without surgical procedure. The purpose of study is to evaluate the effect of non-surgical treatment such as vocal hygiene education and proton pump inhibitor (PPI) in patients with vocal polyp.Materials and Method We performed retrospective study for seventy-three patients of vocal polyp who treated with non-surgical modalities such as vocal hygiene education and PPI over three months. Treatment outcomes and risk factors such as age, sex, polyp size, position, symptom duration, presence of laryngopharyngeal reflux (LPR) symptoms, smoking history, voice abuse history and vocal hygiene education were evaluated by comparison between polyp size improved group and non-improved group. @*Results@#5.5% of enrolled patients showed complete response and 23.3% showed partial response without surgery. Polyp size improved group significantly carried out more practice of vocal hygiene education treatment than the non-improved group (p=0.040). And the presence of LPR symptoms [hazard ratio (HR) 3.368, confidence interval (CI) 1.055–10.754, p=0.040] and not performing of vocal hygiene education (HR 3.664, 95% CI 1.078–12.468, p=0.038). @*Conclusion@#Vocal hygiene education can be a useful treatment option when making a decision to treat with vocal polyp.

Tumor Spheroids of an Aggressive Form of Central Neurocytoma Have Transit-Amplifying Progenitor Characteristics with Enhanced EGFR and Tumor Stem Cell Signaling

Central neurocytoma (CN) has been known as a benign neuronal tumor. In rare cases, CN undergoes malignant transformation to glioblastomas (GBM). Here we examined its cellular origin by characterizing differentiation potential and gene expression of CN-spheroids. First, we demonstrate that both CN tissue and cultured primary cells recapitulate the hierarchal cellular composition of subventricular zone (SVZ), which is comprised of neural stem cells (NSCs), transit amplifying progenitors (TAPs), and neuroblasts. We then derived spheroids from CN which displayed EGFR+/ MASH+ TAP and BLBP+ radial glial cell (RGC) characteristic, and mitotic neurogenesis and gliogenesis by single spheroids were observed with cycling multipotential cells. CN-spheroids expressed increased levels of pluripotency and tumor stem cell genes such as KLF4 and TPD5L1, when compared to their differentiated cells and human NSCs. Importantly, Gene Set Enrichment Analysis showed that gene sets of GBM-Spheroids, EGFR Signaling, and Packaging of Telomere Ends are enriched in CN-spheroids in comparison with their differentiated cells. We speculate that CN tumor stem cells have TAP and RGC characteristics, and upregulation of EGFR signaling as well as downregulation of eph-ephrin signaling have critical roles in tumorigenesis of CN. And their ephemeral nature of TAPs destined to neuroblasts, might reflect benign nature of CN.

Clinical Characteristics of Chronic Cough in Korea / 결핵및호흡기질환

BACKGROUND@#Chronic cough is defined as a cough lasting more than 8 weeks and socio-economic burden of chronic cough is enormous. The characteristics of chronic cough in Korea are not well understood. The Korean Academy of Tuberculosis and Respiratory Diseases (KATRD) published guidelines on cough management in 2014. The current study evaluated the clinical characteristics of chronic cough in Korea and the efficacy of the KATRD guidelines.@*METHODS@#This was a multi-center, retrospective observational study conducted in Korea. The participants were over 18 years of age. They had coughs lasting more than 8 weeks. Subjects with current pulmonary diseases, smokers, ex-smokers with more than 10 pack-years or who quit within the past 1 year, pregnant women, and users of cough-inducing medications were excluded. Evaluation and management of cough followed the KATRD cough-management guidelines.@*RESULTS@#Participants with chronic cough in Korea showed age in the late forties and cough duration of more than 1 year. Upper airway cough syndrome was the most common cause of cough, followed by cough-variant asthma (CVA). Gastro-esophageal reflux diseases and eosinophilic bronchitis were less frequently observed. Following the KATRD cough-management guidelines, 91.2% of the subjects improved after 4 weeks of treatment. Responders were younger, had a longer duration of cough, and an initial impression of CVA. In univariate and multivariate analyses, an initial impression of CVA was the only factor related to better treatment response.@*CONCLUSION@#The causes of chronic cough in Korea differed from those reported in other countries. The current Korean guidelines proved efficient for treating Korean patients with chronic cough.

Clinical Characteristics of Chronic Cough in Korea / 결핵및호흡기질환

BACKGROUND@#Chronic cough is defined as a cough lasting more than 8 weeks and socio-economic burden of chronic cough is enormous. The characteristics of chronic cough in Korea are not well understood. The Korean Academy of Tuberculosis and Respiratory Diseases (KATRD) published guidelines on cough management in 2014. The current study evaluated the clinical characteristics of chronic cough in Korea and the efficacy of the KATRD guidelines.@*METHODS@#This was a multi-center, retrospective observational study conducted in Korea. The participants were over 18 years of age. They had coughs lasting more than 8 weeks. Subjects with current pulmonary diseases, smokers, ex-smokers with more than 10 pack-years or who quit within the past 1 year, pregnant women, and users of cough-inducing medications were excluded. Evaluation and management of cough followed the KATRD cough-management guidelines.@*RESULTS@#Participants with chronic cough in Korea showed age in the late forties and cough duration of more than 1 year. Upper airway cough syndrome was the most common cause of cough, followed by cough-variant asthma (CVA). Gastro-esophageal reflux diseases and eosinophilic bronchitis were less frequently observed. Following the KATRD cough-management guidelines, 91.2% of the subjects improved after 4 weeks of treatment. Responders were younger, had a longer duration of cough, and an initial impression of CVA. In univariate and multivariate analyses, an initial impression of CVA was the only factor related to better treatment response.@*CONCLUSION@#The causes of chronic cough in Korea differed from those reported in other countries. The current Korean guidelines proved efficient for treating Korean patients with chronic cough.

HL301 in the treatment of acute bronchitis: a phase 2b, randomized, double-blind, placebocontrolled, multicenter study

There is insufficient quality data to recommend the use of herbs for the treatment of acute bronchitis. Small number of randomized trials of plant extracts for this purpose were determined to be low quality and there are concerns for the safety. HL301 is a combined product of seven medicinal plants. In the present study, we tried to evaluate the efficacy and safety of HL301 for the treatment of acute bronchitis with a randomized, double-blind, placebo-controlled, multicenter trial design. Methods: A total of 166 patients with acute bronchitis were randomized to receive placebo or HL301 (600 mg/day) for 7 days. The primary endpoint was change in bronchitis severity score (BSS) from baseline visit (visit 2) to the end of treatment (visit 3). Other efficacy variables were the change of each component of the BSS (cough, sputum, dyspnea, chest pain, and crackle) with treatment, response rate, improvement rate, satisfaction rate and number of rescue medications taken. Results: Changes in the BSS from visit 2 to visit 3 were higher in the HL301 group than in the placebo group both in the full analysis set (4.57 ± 1.82 vs. 3.15 ± 3.08, p < 0.01) and in the per protocol set (4.62 ± 1.81 vs. 3.30 ± 3.03, p < 0.01). Four BSS components (cough, sputum, dyspnea, and chest pain) improved more with HL301 treatment than with placebo treatment. Participants treated with HL301 showed higher response, improvement, and satisfaction rates and less use of rescue medication than the placebo group. Conclusions: HL301 (600 mg/day) was effective and safe for symptomatic treatment of acute bronchitis.

How to approach orthognathic surgery in patients who refuse blood transfusion

Background@#Some patients who need surgery refuse a blood transfusion because of their religious beliefs or concerns about blood-borne infections. In recent years, bloodless surgery has been performed successfully in many procedures, and is therefore of increasing interest in orthognathic surgery. @*Methods@#Ten Jehovah’s Witnesses who visited our bloodless surgery center for orthognathic surgery participated in this study. To maintain hemoglobin (Hb) levels above 10 g/dL before surgery, recombinant erythropoietin (rEPO) was subcutaneously administered and iron supplements were intravenously administered. During surgery, acute normovolemic hemodilution (ANH) and induced hypotensive anesthesia were used. To elevate the Hb levels to >10 g/dL after surgery, a similar method to the preoperative approach was used. @*Results@#The 10 patients comprised three men and seven women. Their average Hb level at the first visit was 11.1 g/dL. With treatment according to our protocol, the average preoperative Hb level rose to 12.01 g/dL, and the average Hb level on postoperative day 1 was 10.01 g/dL. No patients needed a blood transfusion, and all patients were discharged without any complications. @*Conclusions@#This study presents a way to manage patients who refuse blood transfusions while undergoing orthognathic surgery. rEPO and iron supplementation were used to maintain Hb levels above 10 g/dL. During surgery, blood loss was minimized by a meticulous procedure and induced hypotensive anesthesia, and intravascular volume was maintained by ANH. Our practical approach to orthognathic surgery for Jehovah’s Witnesses can be applied to the management of all patients who refuse blood transfusions.

Clinical Characteristics of Chronic Cough in Korea / 결핵

Frameless Fractionated Gamma Knife Radiosurgery with ICON™ for Large Metastatic Brain Tumors

BACKGROUND: Recently, a new generation of gamma knife radiosurgery (GKRS) equipped with a frameless immobilization system has encouraged the use of fractionated GKRS as an increasingly favorable treatment option. We investigated the preliminary outcome of efficacy and toxicity associated with frameless fractionated gamma knife radiosurgery (FF GKRS) for the treatment of large metastatic brain tumors. METHODS: Fifteen patients with 17 lesions were treated using FF GKRS and included in this study, because of the large tumor size of more than 10 cm3. FF GKRS was performed based on a thermoplastic mask system for 3 to 5 consecutive days. RESULTS: The mean duration of clinical follow-up was 12 months (range, 4–24), and the local control rate was 100%. Tumor volume decreased in 13 lesions (76.5%), and remained stable in 4 lesions (23.5%). One patient was classified as new lesion development because of the occurrence of leptomeningeal seeding regardless of the tumor volume change. Compared with the initial volume at the time of FF GKRS, tumor volume change at the last follow-up was 62.32% ± 29.80%. Cumulative survival rate at 12 months was 93.3% ± 6.4%. One patient died during the follow-up period because of the progression of the primary disease. No patient showed radiation necrosis on the follow-up images. CONCLUSION: Daily FF GKRS by gamma knife ICON™ revealed satisfactory tumor control rate and low morbidity, despite the short follow-up period. Further prospective studies and a longer follow-up of a large cohort of patients diagnosed with brain metastases are required to elucidate the effect of FF GKRS in brain metastases.

Clinical Implications of Microsatellite Instability in Early Gastric Cancer

PURPOSE: We aimed to evaluate the clinical characteristics of microsatellite instability in early gastric cancer.MATERIALS AND METHODS: The microsatellite instability status of resected early gastric tumors was evaluated using two mononucleotide repeat markers (BAT25 and BAT26) and three dinucleotide repeat markers (D5S346, D2S123, and D17S250). Tumors with instability in two or more markers were defined as microsatellite instability-high (MSI-H) and others were classified as microsatellite stable (MSS).RESULTS: Overall, 1,156 tumors were included in the analysis, with 85 (7.4%) classified as MSI-H compared with MSS tumors. For MSI-H tumors, there was a significant correlation with the female sex, older age, tumor location in the lower gastric body, intestinal histology, lymphovascular invasion (LVI), and submucosal invasion (P<0.05). There was also a trend toward an association with lymph node (LN) metastasis (P=0.056). In mucosal gastric cancer, there was no significant difference in MSI status in tumors with LN metastasis or tumors with LVI. In submucosal gastric cancer, LVI was more frequently observed in MSI-H than in MSS tumors (38.9% vs. 25.0%, P=0.027), but there was no difference in the presence of LN metastases. The prognosis of MSI-H tumors was similar to that of MSS tumors (log-rank test, P=0.797, the hazard ratio for MSI-H was adjusted by age, sex, pT stage, and the number of metastatic LNs, 0.932; 95% confidence interval, 0.423–2.054; P=0.861).CONCLUSIONS: MSI status was not useful in predicting prognosis in early gastric cancer. However, the frequent presence of LVI in early MSI-H gastric cancer may help guide the appropriate treatment for patients, such as endoscopic treatment or limited LN surgical dissection.

Analysis of lawsuit cases in the Department of Surgery in Korea

PURPOSE: The aim of this study is to prepare medical staff in order to prevent medical malpractice litigation through analysis of litigation cases related to the department of surgery in Korea. METHODS: A total of 94 litigation cases related to the department of surgery, where a certain amount of payment was ordered to the defendant between 2005 through 2010, were analyzed. We examined time of occurrence, amount claimed and awarded in damages, plaintiff claims, and court opinion. RESULTS: An average of 3.2 years was spent from the date of the incident occurring to the end of the litigation procedures. The average amount awarded in judgments for damages was 59,708,983 ± 67,307,264 (range, 1,700,000–365,201,482) Korean won. Cases were found involving the following opinion of the court: violation of duty of care (49 cases), violation of informed consent (7 cases), violation of duty of care and informed consent (5 cases), and settlement, reconciliation, and others (32 cases). By analyzing defendants' negligence in court opinions, diagnosis (30.8%) was the most common, followed by post-operation management (27.7%). CONCLUSION: Physicians have to conduct treatment and surgery based on exact diagnosis and be careful to observe patients' conditions and symptoms after surgery. It is essential to identify the current status and characteristics of medical litigation for reducing further litigation and improving patient safety. In order to create a safe medical environment, national efforts should be made not only by individuals but also at the national level.

Fractionated Gamma Knife Radiosurgery as Initial Treatment for Large Skull Base Meningioma

We present our experience on the hypofractionated Gamma Knife radiosurgery (FGKS) for large skull base meningioma as an initial treatment. We retrospectively reviewed 23 patients with large skull base meningioma ≥10 cm³ who underwent FGKS as the initial treatment option. The mean volume of tumors prior to radiosurgery was 21.2±15.63 cm³ (range, 10.09~71.42). The median total margin dose and marginal dose per fraction were 18 Gy (range, 15~20) and 6 Gy (range, 5~6), respectively. Patients underwent three or four fractionations in consecutive days with the same Leksell® frame. The mean follow-up duration was 38 months (range, 17~78). There was no mortality. At the last follow-up, the tumor volume was stationary in 15 patients (65.2%) and had decreased in 8 patients (34.8%). Six patients who had cranial neuropathy at the time of FGKS showed improvement at the last clinical follow-up. Following FGKS, 4 patients (17%) had new cranial neuropathy. The trigeminal neuropathy was the most common and all were transient. The mean Karnofsky Performance Status score at pre-FGKS and the last clinical follow-up was 97.0±10.4 points (median, 100) and 98.6±6.9 (median, 100) points, respectively. FGKS has showed satisfactory tumor control with functional preservation for large skull base meningiomas. Further prospective studies of large cohorts with long term follow-up are required to clarify the efficacy in the tumor control and functional outcome as well as radiation toxicity.

Underexpression of HOXA11 Is Associated with Treatment Resistance and Poor Prognosis in Glioblastoma / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Homeobox (HOX) genes are essential developmental regulators that should normally be in the silenced state in an adult brain. The aberrant expression of HOX genes has been associated with the prognosis of many cancer types, including glioblastoma (GBM). This study examined the identity and role of HOX genes affecting GBM prognosis and treatment resistance. MATERIALS AND METHODS: The full series of HOX genes of five pairs of initial and recurrent human GBM samples were screened by microarray analysis to determine the most plausible candidate responsible for GBM prognosis. Another 20 newly diagnosed GBM samples were used for prognostic validation. In vitro experiments were performed to confirm the role of HOX in treatment resistance. Mediators involved in HOX gene regulation were searched using differentially expressed gene analysis, gene set enrichment tests, and network analysis. RESULTS: The underexpression of HOXA11 was identified as a consistent signature for a poor prognosis among the HOX genes. The overall survival of the GBM patients indicated a significantly favorable prognosis in patients with high HOXA11 expression (31±15.3 months) compared to the prognoses in thosewith low HOXA11 expression (18±7.3 months, p=0.03). When HOXA11 was suppressed in the GBM cell lines, the anticancer effect of radiotherapy and/or temozolomide declined. In addition, five candidate mediators (TGFBR2, CRIM1, TXNIP, DPYSL2, and CRMP1) that may confer an oncologic effect after HOXA11 suppression were identified. CONCLUSION: The treatment resistance induced by the underexpression of HOXA11 can contribute to a poor prognosis in GBM. Further investigation will be needed to confirm the value of HOXA11 as a potential target for overcoming the treatment resistance by developing chemo- or radiosensitizers.

Effect of Single and Double Administration of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells Following Focal Cerebral Ischemia in Rats

Stem cell therapies are administered during the acute phase of stroke to preserve the penumbral tissues from ischemic injury. However, the effect of repeated cell therapy during the acute phase remains unclear. In this study, we investigated and compared the functional outcome of single (two days post-injury) and repeated (two and nine days post-injury) treatment with human umbilical cord derived mesenchymal stem cells (hUCB-MSCs) after middle cerebral artery occlusion (MCAO). The rotarod and limb placement tests were utilized to investigate functional outcomes, while infarct volume and tissue damage were measured by immunofluorescent staining for neovascularization, neurogenesis, apoptosis, and inflammation in the penumbral zones. We observed notable motor dysfunction and a significant decrease in infarcted brain volume, as well as increases in neurons and vessels in both single and repeated hUCB-MSC treatments compared to the control group. Interestingly, repeated administration of hUCB-MSCs was not found to elicit additional or synergistic improvements over monotherapy. This study suggests that a clearer understanding of the therapeutic window after stroke will facilitate the development of more efficient treatment protocols in the clinical application of stem cell therapy.

Inhibition of HIF1α and PDK Induces Cell Death of Glioblastoma Multiforme

Glioblastoma multiforme (GBM) is the most common and aggressive form of brain tumors. GBMs, like other tumors, rely relatively less on mitochondrial oxidative phosphorylation (OXPHOS) and utilize more aerobic glycolysis, and this metabolic shift becomes augmented under hypoxia. In the present study, we investigated the physiological significance of altered glucose metabolism and hypoxic adaptation in the GBM cell line U251 and two newly established primary GBMs (GBM28 and GBM37). We found that these three GBMs exhibited differential growth rates under hypoxia compared to those under normoxia. Under normoxia, the basal expressions of HIF1α and the glycolysis-associated genes, PDK1, PDK3, and GLUT1, were relatively low in U251 and GBM28, while their basal expressions were high in GBM37. Under hypoxia, the expressions of these genes were enhanced further in all three GBMs. Treatment with dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase (PDK), induced cell death in GBM28 and GBM37 maintained under normoxia, whereas DCA effects disappeared under hypoxia, suggesting that hypoxic adaptation dominated DCA effects in these GBMs. In contrast, the inhibition of HIF1α with chrysin suppressed the expression of PDK1, PDK3, and GLUT1 and markedly promoted cell death of all GBMs under both normoxia and hypoxia. Interestingly, however, GBMs treated with chrysin under hypoxia still sustained higher viability than those under normoxia, and chrysin and DCA co-treatment was unable to eliminate this hypoxia-dependent resistance. Together, these results suggest that hypoxic adaptation is critical for maintaining viability of GBMs, and targeting hypoxic adaptation can be an important treatment option for GBMs.