Current status of advance care planning, palliative care consultation, and end-of-life care in patients with glioblastoma in South Korea.

BACKGROUND: Given the typical trajectory of glioblastoma, many patients lose decision-making capacity over time, which can lead to inadequate advance care planning (ACP) and end-of-life (EOL) care. We aimed to evaluate patients' current ACP and EOL care status. PATIENTS AND METHODS: We conducted a cohort study on 205 patients referred to oncologists at a Korean tertiary hospital between 2017 and 2022. We collected information on sociodemographic factors, cancer treatment, palliative care consultation, ACP, legal documents on life-sustaining treatment (LST) decisions, and aggressiveness of EOL care. RESULTS: With a median follow-up time of 18.3 months: 159 patients died; median overall survival: 20.3 months. Of the 159 patients, 11 (6.9%) and 63 (39.6%) had advance directive (AD) and LST plans, respectively, whereas 85 (53.5%) had neither. Among the 63 with LST plans, 10 (15.9%) and 53 (84.1%) completed their forms through self-determination and family determination, respectively. Of the 159 patients who died, 102 (64.2%) received palliative care consultation (median time: 44 days from the first consultation to death) and 78 (49.1%) received aggressive EOL care. Those receiving palliative care consultations were less likely to receive aggressive EOL care (83.3% vs 32.4%, P < .001), and more likely to use more than 3 days of hospice care at EOL (19.6% vs 68.0%, P < .001). CONCLUSIONS: The right to self-determination remains poorly protected among patients with glioblastoma, with nearly 90% not self-completing AD or LST plan. As palliative care consultation is associated with less aggressive EOL care and longer use of hospice care, physicians should promptly introduce patients to ACP conversations and palliative care consultations.

Natural Product-Based Glycolysis Inhibitors as a Therapeutic Strategy for Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor-Resistant Non-Small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths worldwide. Targeted therapy against the epidermal growth factor receptor (EGFR) is a promising treatment approach for NSCLC. However, resistance to EGFR tyrosine kinase inhibitors (TKIs) remains a major challenge in its clinical management. EGFR mutation elevates the expression of hypoxia-inducible factor-1 alpha to upregulate the production of glycolytic enzymes, increasing glycolysis and tumor resistance. The inhibition of glycolysis can be a potential strategy for overcoming EGFR-TKI resistance and enhancing the effectiveness of EGFR-TKIs. In this review, we specifically explored the effectiveness of pyruvate dehydrogenase kinase inhibitors and lactate dehydrogenase A inhibitors in combating EGFR-TKI resistance. The aim was to summarize the effects of these natural products in preclinical NSCLC models to provide a comprehensive understanding of the potential therapeutic effects. The study findings suggest that natural products can be promising inhibitors of glycolytic enzymes for the treatment of EGFR-TKI-resistant NSCLC. Further investigations through preclinical and clinical studies are required to validate the efficacy of natural product-based glycolytic inhibitors as innovative therapeutic modalities for NSCLC.

Single-Cell RNA Sequencing Reveals Immuno-Oncology Characteristics of Tumor-Infiltrating T Lymphocytes in Photodynamic Therapy-Treated Colorectal Cancer Mouse Model.

Photodynamic therapy (PDT) has shown promise in reducing metastatic colorectal cancer (CRC); however, the underlying mechanisms remain unclear. Modulating tumor-infiltrating immune cells by PDT may be achieved, which requires the characterization of immune cell populations in the tumor microenvironment by single-cell RNA sequencing (scRNA-seq). Here, we determined the effect of Chlorin e6 (Ce6)-mediated PDT on tumor-infiltrating T cells using scRNA-seq analysis. We used a humanized programmed death-1/programmed death ligand 1 (PD-1/PD-L1) MC38 cell allograft mouse model, considering its potential as an immunogenic cancer model and in combination with PD-1/PD-L1 immune checkpoint blockade. PDT treatment significantly reduced tumor growth in mice containing hPD-1/PD-L1 MC38 tumors. scRNA-seq analysis revealed that the PDT group had increased levels of CD8+ activated T cells and CD8+ cytotoxic T cells, but decreased levels of exhausted CD8+ T cells. PDT treatment also enhanced the infiltration of CD8+ T cells into tumors and increased the production of key effector molecules, including granzyme B and perforin 1. These findings provide insight into immune-therapeutic modulation for CRC patients and highlight the potential of PDT in overcoming immune evasion and enhancing antitumor immunity.

The impact of neonatal morbidities on child growth and developmental outcomes in very low birth weight infants: a nationwide cohort study.

Growth in preterm infants has long-term implications for neurodevelopmental outcomes. We aimed to estimate the nationwide growth outcomes from birth to 5 years in infants born under 1500 g and to analyze the effects of major morbidities in preterm infants on growth. In total, 2961 children born in 2013 with a birth weight under 1500 g who underwent an infant health checkup between 2013 and 2018 according to the National Health Insurance Service database were included. Checkups were conducted at 4-6, 9-12, 18-24, 30-36, 42-48, and 54-60 months of age. Information was obtained from the International Classification of Diseases-10 codes or a questionnaire administered during the check-up. At 60 months of age, the mean percentiles of weight, height, and head circumference fell within only the 30-40th percentile of normal growth values. About 30% of infants had growth parameters below the 10th percentile and showed worse neurodevelopmental outcomes. Using multiple logistic regression, infants with bronchopulmonary dysplasia showed a significantly higher incidence of growth restriction in all three categories of weight (odds ratio [OR] 1.50), height (OR 1.33), and head circumference (OR 1.36) at 60 months. Sepsis was associated with growth restriction in weight (OR 1.43) and head circumference (OR 1.33). Periventricular leukomalacia infants had relatively small head circumferences (OR 1.91) and poor developmental screening results (OR 2.89).Conclusion: Catch-up growth remains a major issue in infants born under 1500 g, especially those with some morbidities from preterm birth. Regular checkups to monitor and early intervention to achieve normal growth are essential. What is Known: • Growth in preterm infants has long-term implications for neurodevelopmental and cardiometabolic outcomes. • Data are lacking on the time-serial effects of many preterm morbidities simultaneously on long-term growth outcomes. What is New: • All growth parameters of VLBW infants, including weight, height, and head circumference, fell within the 30-40th percentile of normal growth for infants at 60 months of age, indicating that catch-up growth for VLBW infants remains an issue. • VLBW infants with major preterm morbidities, including BPD, PVL, and sepsis, showed difficulties in achieving normal catch-up growth and neurodevelopment at 60 months of age.

Tools for assessing lung fluid in neonates with respiratory distress.

BACKGROUND: Transient tachypnea of the newborn (TTN), as a common cause of neonatal respiratory distress, needs to be distinguished from respiratory distress syndrome (RDS). Various modalities such as lung ultrasonography, cytokine analysis, and electrical cardiometry for the evaluation of lung fluid can be helpful for the exact diagnosis, however, clinical diagnosis has been applied mainly. This study aimed to evaluate the usefulness of the various tools for the diagnosis of TTN and RDS in neonates. METHODS: This study evaluated 22 late-preterm and term infants admitted to the neonatal intensive care unit of Gangnam Severance Hospital because of respiratory distress. Total 9 neonates were diagnosed with TTN and 13 had RDS. In addition to chest radiography, the LUS score was calculated by a neonatologist using the portable ultrasound device. Cytokines in the bronchoalveolar lavage fluid supernatant were measured. Thoracic fluid content was measured using an electrical cardiometry device. RESULTS: We enrolled 22 patients with median gestational age, 37.1 weeks, and birth weight 3100 g. There is no difference in patient characteristics between RDS and TTN group. Lung ultrasound score was significantly higher in RDS than TTN (11 vs 6, p = 0.001). Score 0 is shown in all infants with TTN. Score 1 is shown as significantly more in RDS than TTN. Between the TTN and RDS groups, there were significant differences in the changes of thoracic fluid content (2 vs - 1.5, p < 0.001), IL-1ß levels (2.5 vs 11.3, p = 0.02), and TNF-α levels (20.1 vs 11.2, p = 0.04). CONCLUSION: We found lung ultrasound and electrical cardiometry to be reliable diagnostic tools for assessing infants with respiratory distress among late-preterm and term infants. Further studies with a large number of patients are needed to confirm their clinical usefulness.

Growth Pattern With Morbidities From Birth to 5 Years of Age in Very Low Birth Weight Infants: Comparison of the Korean National Network and National Health Insurance Service.

BACKGROUND: Long-term growth data of very low birth weight (VLBW) infants are currently collected in the Korean Neonatal Network (KNN) and National Health Insurance Service (NHIS) database. However, variance in the number of infants, check-up time, and check-up parameters led to decreased credibility of cumulated data. We aimed to compare the data on serial growth outcomes by major morbidities from birth to 5 years in VLBW infants between the KNN and NHIS databases. METHODS: We combined the NHIS and KNN data of VLBW infants born between 2013 and 2015. The check-up times in the NHIS database were at 4-6, 9-12, 18-24, 30-36, 42-48, and 54-60 months of age, whereas in the KNN were at 18-24 months of corrected age and at 36 months of age. RESULT: Among 8,864 VLBW infants enrolled based on the birth certificates from the Statistics Korea, 6,086 infants (69%) were enrolled in the KNN, and 5,086 infants (57%) participated in the NHIS health check-up. Among 6,068 infants, 3,428 infants (56%) were enrolled at a corrected age of 18-24 months and 2,572 infants (42%) were enrolled at a chronological age of 33-36 months according to the KNN follow-up registry. However, based on the national birth statistics data, the overall follow-up rate of the KNN at 36 months of age was as low as 29%. The NHIS screening rate was lower at first (23%); however, it increased over time to exceed the KNN follow-up rate. Growth failure (weight under 10th percentile) at corrected ages of 18-24 months and 36 months were more common in the NHIS than KNN (42% vs. 20%, 37% vs. 34.5%). Infants with bronchopulmonary dysplasia and periventricular leukomalacia showed similar rates of growth failure at 2 years but varying rates at 3 years between the KNN and NHIS. CONCLUSION: By integrating the KNN and NHIS data indirectly at continuous time points according to morbidities, we found that there are discontinuities and discrepancies between the two databases among VLBW infants. Establishing an integrated system by patient level linking the KNN and NHIS databases can lead to better understanding and improved neonatal outcomes in VLBW infants in Korea.

Outcomes of infants born to pregnant women with syphilis: a nationwide study in Korea.

BACKGROUND: Despite the expansion of antenatal syphilis screening programs, congenital syphilis (CS) remains a concern. PURPOSE: This study aimed to analyze the manifestation and progress of CS, including treatment and follow-up, based on a nationwide study. METHODS: From the Korean National Health Insurance Service database, a total of 548 infants were examined for CS during their first year of life from 2013 to 2018. Neurosyphilis and complications were investigated using the International Classification of Diseases-10 codes. RESULTS: The birth rate of infants from mothers with syphilis was 2.8 per 10,000 live births for 5 years, which is not indicative of a decreasing trend. Overall, 148 infants were proven or highly probable or possible of having CS with treatment for 10 days; 66 infants were possible or less likely of having CS with only 1-day treatment. Jaundice (56 %) was common, followed by hearing impairment (14 %), renal disease (8 %), and mental retardation (8 %). Fourteen cases of neurosyphilis occurred. Infants with complications, including mental retardation, eye involvement, hearing impairment, or renal disease, were significantly associated with neurosyphilis (OR 8.49, P < 0.0001). Of 250 patients who received treatment, 92.8 % were treated with one medication: benzathine penicillin was used in 73 % of patients. Only four patients were re-treated due to treatment failure. In addition to the treponemal test, fluorescent treponemal antibody-absorption was the most utilized tool for diagnosis and follow-up. CONCLUSIONS: Establishing standardized guidelines for the evaluation of CS, as well as the establishment of treatment regimens and follow up-plans for the disease, at a national level would help improve maternal and neonatal care and facilitate the eradication of CS in Korea.

Targeting Lactate Dehydrogenase A with Catechin Resensitizes SNU620/5FU Gastric Cancer Cells to 5-Fluorouracil.

Resistance to anticancer therapeutics occurs in virtually every type of cancer and becomes a major difficulty in cancer treatment. Although 5-fluorouracil (5FU) is the first-line choice of anticancer therapy for gastric cancer, its effectiveness is limited owing to drug resistance. Recently, altered cancer metabolism, including the Warburg effect, a preference for glycolysis rather than oxidative phosphorylation for energy production, has been accepted as a pivotal mechanism regulating resistance to chemotherapy. Thus, we investigated the detailed mechanism and possible usefulness of antiglycolytic agents in ameliorating 5FU resistance using established gastric cancer cell lines, SNU620 and SNU620/5FU. SNU620/5FU, a gastric cancer cell harboring resistance to 5FU, showed much higher lactate production and expression of glycolysis-related enzymes, such as lactate dehydrogenase A (LDHA), than those of the parent SNU620 cells. To limit glycolysis, we examined catechin and its derivatives, which are known anti-inflammatory and anticancer natural products because epigallocatechin gallate has been previously reported as a suppressor of LDHA expression. Catechin, the simplest compound among them, had the highest inhibitory effect on lactate production and LDHA activity. In addition, the combination of 5FU and catechin showed additional cytotoxicity and induced reactive oxygen species (ROS)-mediated apoptosis in SNU620/5FU cells. Thus, based on these results, we suggest catechin as a candidate for the development of a novel adjuvant drug that reduces chemoresistance to 5FU by restricting LDHA.

The Oral Administration of Sanguisorba officinalis Extract Improves Physical Performance through LDHA Modulation.

Muscle fatigue is induced by an acute or chronic physical performance inability after excessive physical activity often associated with lactate accumulation, the end-product of glycolysis. In this study, the water-extracted roots of Sanguisorba officinalis L., a herbal medicine traditionally used for inflammation and diarrhea, reduced the activities of lactate dehydrogenase A (LDHA) in in vitro enzyme assay myoblast C2C12 cells and murine muscle tissue. Physical performance measured by a treadmill test was improved in the S. officinalis-administrated group. The analysis of mouse serum and tissues showed significant changes in lactate levels. Among the proteins related to energy metabolism-related physical performance, phosphorylated-AMP-activated protein kinase alpha (AMPKα) and peroxisome proliferator-activated receptor-coactivator-1 alpha (PGC-1α) levels were enhanced, whereas the amount of LDHA was suppressed. Therefore, S. officinalis might be a candidate for improving physical performance via inhibiting LDHA and glycolysis.

Predictors of pre-operative cognitive impairment in meningioma patients over 60 years old.

BACKGROUND: The aim of this study was to assess the cognitive function of patients over 60 years old with meningioma using a domain-specific neuropsychological test and to investigate the relevant factors affecting pre-operative cognitive decline in different subdomains. METHODS: We retrospectively investigated 46 intracranial meningioma patients between the ages of 60 and 85 years. All patients underwent brain MRI and neuropsychological test. Tumor size, location, peritumoral edema, and medial temporal atrophy (MTA) were examined to determine the association with cognitive impairment. We performed a logistic regression analysis to examine the odds ratios (ORs) for cognitive decline of four subdomains: verbal memory, language, visuospatial, and executive functions. RESULTS: Tumor size and age were associated with executive dysfunction (OR 1.083, 95% confidence interval (CI) 1.006-1.166, and OR 1.209, 95% CI 1.018-1.436, respectively). There was no statistically significant association in other cognitive domains (language, verbal memory, and visuospatial function) with variables in regression analysis. CONCLUSIONS: We conclude that tumor size and age are positively related with executive function in pre-operative meningioma patients over 60 years old.

Ilimaquinone Induces the Apoptotic Cell Death of Cancer Cells by Reducing Pyruvate Dehydrogenase Kinase 1 Activity.

In cancer cells, aerobic glycolysis rather than oxidative phosphorylation (OxPhos) is generally preferred for the production of ATP. In many cancers, highly expressed pyruvate dehydrogenase kinase 1 (PDK1) reduces the activity of pyruvate dehydrogenase (PDH) by inducing the phosphorylation of its E1α subunit (PDHA1) and subsequently, shifts the energy metabolism from OxPhos to aerobic glycolysis. Thus, PDK1 has been regarded as a target for anticancer treatment. Here, we report that ilimaquinone (IQ), a sesquiterpene quinone isolated from the marine sponge Smenospongia cerebriformis, might be a novel PDK1 inhibitor. IQ decreased the cell viability of human and murine cancer cells, such as A549, DLD-1, RKO, and LLC cells. The phosphorylation of PDHA1, the substrate of PDK1, was reduced by IQ in the A549 cells. IQ decreased the levels of secretory lactate and increased oxygen consumption. The anticancer effect of IQ was markedly reduced in PDHA1-knockout cells. Computational simulation and biochemical assay revealed that IQ interfered with the ATP binding pocket of PDK1 without affecting the interaction of PDK1 and the E2 subunit of the PDH complex. In addition, similar to other pyruvate dehydrogenase kinase inhibitors, IQ induced the generation of mitochondrial reactive oxygen species (ROS) and depolarized the mitochondrial membrane potential in the A549 cells. The apoptotic cell death induced by IQ treatment was rescued in the presence of MitoTEMPO, a mitochondrial ROS inhibitor. In conclusion, we suggest that IQ might be a novel candidate for anticancer therapeutics that act via the inhibition of PDK1 activity.

Middle Meningeal Artery Embolization for Chronic Subdural Hematoma.

Purpose To evaluate the effect of middle meningeal artery (MMA) embolization on chronic subdural hematoma (CSDH) and compare the treatment outcomes of MMA embolization and conventional treatment. Materials and Methods All consecutive patients 20 years or older with CSDH were assessed for eligibility. CSDHs with a focal location, a thickness of 10 mm or less, no mass effect, or underlying conditions were excluded. Seventy-two prospectively enrolled patients with CSDH underwent MMA embolization (embolization group; as the sole treatment in 27 [37.5%] asymptomatic patients and with additional hematoma removal for symptom relief in 45 [62.5%] symptomatic patients). For comparison, 469 patients who underwent conventional treatment were included as a historical control group (conventional treatment group; close, nonsurgical follow-up in 67 [14.3%] and hematoma removal in 402 [85.7%] patients). Primary outcome was treatment failure defined as a composite of incomplete hematoma resolution (remaining or reaccumulated hematoma with thickness > 10 mm) or surgical rescue (hematoma removal for relief of symptoms that developed with continuous growth of initial or reaccumulated hematoma). Secondary outcomes included surgical rescue as a component of the primary outcome and treatment-related complication for safety measure. Six-month outcomes were compared between the study groups with logistic regression analysis. Results Spontaneous hematoma resolution was achieved in all of 27 asymptomatic patients undergoing embolization without direct hematoma removal. Hematoma reaccumulation occurred in one (2.2%) of 45 symptomatic patients receiving embolization with additional hematoma removal. Treatment failure rate in the embolization group was lower than in the conventional treatment group (one of 72 patients [1.4%] vs 129 of 469 patients [27.5%], respectively; adjusted odds ratio [OR], 0.056; 95% confidence interval [CI]: 0.011, 0.286; P = .001). Surgical rescue was less frequent in the embolization group (one of 72 patients [1.4%] vs 88 of 469 patients [18.8%]; adjusted OR, 0.094; 95% CI: 0.018, 0.488; P = .005). Treatment-related complication rate was not different between the two groups (0 of 72 patients vs 20 of 469 patients [4.3%]; adjusted OR, 0.145; 95% CI: 0.009, 2.469; P = .182). Conclusion MMA embolization has a positive therapeutic effect on CSDH and is more effective than conventional treatment. © RSNA, 2017.

Prognostic relevance of programmed cell death ligand 1 expression in glioblastoma.

The aim of this study was to determine the clinicopathological significance of programmed cell death ligand 1 (PD-L1) expression in glioblastoma (GBM). In a retrospective cohort of 115 consecutive patients with GBM, PD-L1 expression was determined using immunohistochemistry (IHC). Membranous and fibrillary PD-L1 staining of any intensity in > 5% neoplastic cells and tumour infiltrating immune cells (TIIs) was considered positive staining. In addition, isocitrate dehydrogenase-1 (IDH-1) (R132H) expression and cluster of differentiation 3 (CD3)-positive T-cell infiltration were investigated using IHC. O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation assay and fluorescence in situ hybridization (FISH) for the assessment of 1p/19q deletion were performed. Expression of PD-L1 in tumour cells and TIIs was found in 37 (32.2%) and 6 (5.2%) patients, respectively. Kaplan-Meier analysis indicated that PD-L1 expression in tumour cells was significantly associated with poor overall survival (OS) (P = 0.017), though multivariate Cox analysis did not confirm this association (hazard ratio 1.204; P = 0.615). PD-L1 expression in TIIs did not correlate with the patient prognosis (P = 0.545). In addition, MGMT methylation and IDH-1 (R132H) expression were associated with a better prognosis (P < 0.001 and P = 0.024, respectively). The expression of PD-L1 was associated with CD3-positive T-cell infiltration (P < 0.001), and IDH-1 wild type status (P = 0.008). A deeper insight into PD-L1 expression could help to ensure the success of future immunotherapy in GBM. Our study suggested that PD-L1 target therapy might be beneficial for PD-L1-expressing GBM patients with a poor prognosis.

PD-1/PD-L1 and immune-related gene expression pattern in pediatric malignant brain tumors: clinical correlation with survival data in Korean population.

BACKGROUND: PD-L1 expression has been evaluated as a predictive biomarker for immunotherapy in numerous tumor types. However, very limited data are available in pediatric brain tumors. The aim of this study was to characterize PD-1 and PD-L1 expressions of four pediatric malignant brain tumors and gene expression profile. METHODS: This study included 89 pediatric patients receiving standard treatment at Seoul National University Children's Hospital and Seoul National University Bundang Hospital between 1990 and 2014: atypical teratoid/rhabdoid tumor (AT/RT) 20; ependymoma (EPN) 20; high grade glioma (HGG) 21; and medulloblastoma (MBL) 28. We performed immunohistochemistry assays for PD-1 and PD-L1. To characterize the gene expression, a custom immune-response focused gene panel was used. RESULTS: PD-1 expression was positive in 7 (35%) AT/RT, 7 (35%) EPN, 4 (19%) HGG, and 3 (11%) MBL patients. PD-L1 expression was positive in 8 (40%) AT/RT, 4 (20%) EPN, and 4 (19%) HGG; negative in all MBL patients. There was no statistically significant difference in the overall survival of PD-L1 positive patients. The gene expression analysis demonstrated differences in two clustering functional categories: cell-cell signaling and antigen presentation pathway. CONCLUSIONS: AT/RT, EPN, and HGG showed a relatively higher expression rate of PD-L1 (19-40%). This suggests these tumor types might be good candidates for PD-1 checkpoint blockade. We determined that gene expression may potentially serve as a molecular tool in predicting which patients will respond to immunotherapy. Further investigation is required to better understand the predictive and prognostic role of PD-L1 in pediatric brain tumors.

Analysis of survival outcomes based on molecular subtypes in breast cancer brain metastases: A single institutional cohort.

PURPOSE: To evaluate the survival outcomes based on molecular subtypes of breast cancer in patients with brain metastasis. MATERIALS AND METHODS: We retrospectively reviewed 106 breast cancer patients treated for brain metastases, from January 2005 to May 2016. Patients were divided into four groups based on the tumor molecular subtype: luminal A (Estrogen Receptor [ER]/Progesterone Receptor [PR] positive, human epithelial growth factor receptor-2 [HER2] negative), luminal B (ER/PR positive, HER2 Positive), HER2 (HER2 positive and ER/PR negative), and Triple negative (TNBC). RESULTS: The median follow-up time for surviving patients was 22 months (range: 11.2-51.1 months). The median survival of all patients was 14 months, with a 1-year overall survival (OS) rate of 57.5% and a 2-year OS rate of 32.1%. Thirty patients (28.3%) had a solitary brain metastasis while 62 (58.5%) patients had multiple metastases. A significant difference was observed in the survival rates of the two groups. Based on the Karnofsky performance score, the performance status of the patients at the time of brain metastasis was also found to affect survival. Patients with different molecular subtypes had different survival rates; the luminal A group showed the highest median survival (luminal A: 23.1, luminal B: 15.0, HER2: 12.5 and TNBC: 6.4 months, respectively), which was statistically significant. CONCLUSION: In breast cancer patients with brain metastasis, survival rates were different based on the molecular subtype of the tumor, despite various local and systemic treatments. Appropriate and tailored treatment approaches should, therefore, be considered for the different molecular subtypes.

Hearing Outcomes After Stereotactic Radiosurgery for Vestibular Schwannomas : Mechanism of Hearing Loss and How to Preserve Hearing.

The use of stereotactic radiosurgery (SRS) expanded to include the treatment of vestibular schwannomas (VSs) in 1969; since then, efforts to increase tumour control and to reduce cranial neuropathy have continued. Using the currently recommended marginal dose of 12-13 Gy, long-term reported outcomes after SRS include not only excellent tumour control rates of 92-100 % but also outstanding functional preservation of the trigeminal and facial nerves, with values of 92-100 % and 94-100 %, respectively. Nonetheless, hearing preservation remains in the range of 32-81 %. Previous studies have suggested possible prognostic factors of hearing preservation such as the Gardner-Robertson grade, radiation dose to the cochlea, transient volume expansion (TVE) after SRS, length of irradiated cochlear nerve, marginal dose to the tumour, and age. However, we still do not clearly understand why patients lose their hearing after SRS for VS.Relevant to these considerations, one study recently reported that the auditory brainstem response (ABR) wave V latency and waves I and V interval (IL_I-V) correlated well with intracanalicular pressure values and even with hearing level. The demonstration that ABR values, especially wave V latency and IL_I-V, correlate well with intracanalicular pressure suggests that patients with previously elevated intracanalicular pressure might have an increased chance of hearing loss on development of TVE, which has been recognised as a common phenomenon after SRS or stereotactic radiotherapy (SRT) for intracranial schwannomas.In our experience, the ABR IL_I-V increased during the first 12 months after SRS for VSs in patients who lost their serviceable hearing. The effect of increased ABR IL_I-V on hearing outcome also became significant over time, especially at 12 months after SRS, and was more prominent in patients with poor initial pure-tone average (PTA) and/or ABR values. We hypothesise that patients with considerable intracanalicular pressure at the time of SRS are prone to lose their serviceable hearing due to the added intracanalicular pressure induced by TVE, which usually occurs within the first 12 months after SRS for VSs. Using these findings, we suggested a classification system for the prediction of hearing outcomes after SRS for VSs. This classification system could be useful in the proper selection of management modalities for hearing preservation, especially in patients with only hearing ear schwannoma or neurofibromatosis type 2.Advances in diagnostic tools, treatment modalities, and optimisation of radiosurgical dose have improved clinical outcomes, including tumour control and cranial neuropathies, in patients with VSs. However, the preservation of hearing function still falls short of our expectation. A prediction model for hearing preservation after each treatment modality will guide the proper selection of treatment modalities and permit the appropriate timing of active treatment, which will lead to the preservation of hearing function in patients with VSs.

Survival benefit of levetiracetam in patients treated with concomitant chemoradiotherapy and adjuvant chemotherapy with temozolomide for glioblastoma multiforme.

BACKGROUND: A chemosensitizing effect of levetiracetam (LEV) has been suggested because LEV inhibits O-6 methylguanine-DNA methyltransferase (MGMT). However, the survival benefit of LEV has not been clinically documented. The objective of this study was to assess the survival benefit of LEV compared with other antiepileptic drugs as a chemosensitizer to temozolomide for patients with glioblastoma. METHODS: In total, 103 consecutive patients with primary glioblastoma who received concomitant chemoradiotherapy and adjuvant chemotherapy with temozolomide were retrospectively reviewed, and 58 patients (56%) received LEV during temozolomide chemotherapy for at least 3 months. A Cox regression survival analysis was performed to adjust for confounding factors, including age, extent of lesion, Karnofsky performance scale score, extent of removal, and MGMT promoter methylation status. RESULTS: The median progression-free survival (PFS) and overall survival (OS) for patients who received LEV in combination with temozolomide (PFS: median, 9.4 months; 95% confidence interval [CI], 7.5-11.3 months; OS: median, 25.7 months; 95% CI, 21.7-29.7 months) were significantly longer than those for patients who did not receive LEV (PFS: median, 6.7 months; 95% CI, 5.8-7.6 months; OS: median, 16.7 months; 95% CI, 12.1-21.3 months; P = .010 and P = .027, respectively). In multivariate analysis, the variables that were identified as significant prognostic factors for OS were preoperative Karnofsky performance scale score (hazard ratio [HR], 0.37; P = .016), MGMT promoter methylation (HR, 0.30; P = .002), and receipt of LEV (HR, 0.31; P < .001. CONCLUSIONS: LEV may provide a survival benefit in patients with glioblastoma who receive temozolomide-based chemotherapy. A prospective randomized study may be indicated.

Validation of the Effectiveness and Safety of Temozolomide during and after Radiotherapy for Newly Diagnosed Glioblastomas: 10-year Experience of a Single Institution.

This study was performed to validate the effectiveness and safety of concurrent chemoradiotherapy and adjuvant therapy with temozolomide for newly diagnosed glioblastoma multiforme as a standard treatment protocol. Between 2004 and 2011, patients newly diagnosed with glioblastoma who were treated with temozolomide during concurrent chemoradiotherapy and adjuvant chemotherapy were included from a single institution and analyzed retrospectively. The primary endpoint was overall survival, and the secondary endpoints were progression-free survival, response, and safety. A total of 71 patients were enrolled in this study. The response rate was 41% (29/71), and the tumor control rate was 80% (57/71). In the 67 patients who completed the concurrent chemoradiotherapy with temozolomide, the median overall survival was 19 months and the 1- and 2-yr overall survival rates were 78.3% and 41.7%, respectively. The median progression free survival was 9 months, and the 1- and 2-yr progression free survival rates were 33.8% and 14.3%, respectively. The mean duration of survival after progression of disease in salvage treatment group was 11.9 (1.3-53.2) months. Concurrent chemoradiotherapy with temozolomide resulted in grade 3 or 4 hematologic toxic effects in 2.8% of the patients. The current protocol of temozolomide during and after radiation therapy is both effective and safe and is still appropriate as the standard protocol for treatment of glioblastoma. An active salvage treatment might be required for a better prognosis.

Stereotactic radiosurgery for cavernous sinus hemangiomas.

We performed this retrospective study to analyze the outcome of patients with cavernous sinus hemangioma (CSH) after stereotactic radiosurgery (SRS). We analyzed 19 patients with CSHs who were treated with SRS between 1998 and 2011. The median age of the patients was 50 years (range, 35-73 years), and 16 (84.2%) of the patients were female. SRS was performed as a primary treatment for 18 patients and to treat a residual lesion after surgical resection in one patient. Nine (47.4%) patients had cranial neuropathies in 14 cranial nerves before SRS, whereas five (26.3%) patients were initially asymptomatic. The mean volume of the CSHs was 6.1 ± 7.2 cm(3) (range, 0.3-32.3 cm(3)), and the median marginal dose at the 50% isodose line was 14.5 Gy (range, 11.5-16.0 Gy). The mean follow-up period was 37 months (range, 12-85 months). At the last follow-up, the lesion volume had decreased in all patients. The average tumor volume had decreased to 26% (range, 0-70%) of the initial volume at the last follow-up MRI. The first follow-up MRI, performed 6.1 ± 1.0 months after the SRS, showed that the tumor volume had decreased to 41% (range, 0-88%) of the initial volume. All 14 of the cranial neuropathies observed before SRS had improved, with complete remission in 12 (85.7%) cranial nerves and partial remission in two (14.3%). There were no radiation-induced neuropathies or complications during the follow-up period. SRS appears to be an effective and safe treatment modality for the management of CSHs.

Lower Plasma Amyloid Beta - 42 Levels Associated With Worse Survival in Patients With Glioma.

BACKGROUND/AIM: Glioma is often refractory. The accumulation of amyloid beta (Aß) in the brain is commonly associated with Alzheimer's disease (AD), but there are studies suggesting that Aß has tumor suppressor potential. The aim of this study was to identify a novel, non-invasive candidate biomarker for histological prediction and prognostic assessment of glioma. PATIENTS AND METHODS: Serum was prepared from blood samples collected preoperatively from 48 patients with WHO grade II-IV glioma between October 2004 and December 2017 at a single tertiary institution. The concentration of Aß42 was measured using the SMCxPRO immunoassay (Merck). The clinical and histological characteristics of the patients, including molecular subtypes, were reviewed. RESULTS: The mean age of the patients was 52.2±12.5 years. The mean value of serum Aß42 concentration was 7.6±7.8 pg/ml in the anaplastic astrocytoma (WHO grade III) group and 6.4±6.5 pg/ml in the glioblastoma multiforme (WHO grade IV) group. The Negative epidermal growth factor receptor (EGFR) expression was associated with higher serum Aß42 levels (p=0.020). Kaplan-Meier analysis demonstrated that patients with high serum Aß42 (>11.78 pg/ml) had significantly longer progression-free survival (PFS) (p=0.038) and overall survival (OS) (p=0.018). CONCLUSION: This study investigated serum Aß42 levels as a potential biomarker for glioma. The results showed that low serum Aß42 levels were associated with EGFR expression and poor PFS and OS. Overall, these findings suggest a potential role of Aß42 as a prognostic marker in astrocytomas.