Nucleolin-Targeting AS1411 Aptamer-Conjugated Nanospheres for Targeted Treatment of Glioblastoma.

Post-operative chemotherapy is still required for the treatment of glioblastoma (GBM), for which nanocarrier-based drug delivery has been identified as one of the most effective methods. However, the blood-brain barrier (BBB) and non-specific delivery to non-tumor tissues can significantly limit drug accumulation in tumor tissues and cause damage to nearby normal tissues. This study describes a targeted cancer therapy approach that uses AS1411 aptamer-conjugated nanospheres (100-300 nm in size) loaded with doxorubicin (Dox) to selectively identify tumor cells overexpressing nucleolin (NCL) proteins. The study demonstrates that the active target model, which employs aptamer-mediated drug delivery, is more effective than non-specific enhanced permeability and maintenance (EPR)-mediated delivery and passive drug delivery in improving drug penetration and maintenance in tumor cells. Additionally, the study reveals the potential for anti-cancer effects through 3D spheroidal and in vivo GBM xenograft models. The DNA-protein hybrid nanospheres utilized in this study offer numerous benefits, such as efficient synthesis, structural stability, high drug loading, dye labeling, biocompatibility, and biodegradability. When combined with nanospheres, the 1411 aptamer has been shown to be an effective drug delivery carrier allowing for the precise targeting of tumors. This combination has the potential to produce anti-tumor effects in the active targeted therapy of GBM.

Central neurocytoma exhibits radial glial cell signatures with FGFR3 hypomethylation and overexpression.

We explored the genomic events underlying central neurocytoma (CN), a rare neoplasm of the central nervous system, via multiomics approaches, including whole-exome sequencing, bulk and single-nuclei RNA sequencing, and methylation sequencing. We identified FGFR3 hypomethylation leading to FGFR3 overexpression as a major event in the ontogeny of CN that affects crucial downstream events, such as aberrant PI3K-AKT activity and neuronal development pathways. Furthermore, we found similarities between CN and radial glial cells based on analyses of gene markers and CN tumor cells and postulate that CN tumorigenesis is due to dysregulation of radial glial cell differentiation into neurons. Our data demonstrate the potential role of FGFR3 as one of the leading drivers of tumorigenesis in CN.

Intraoperative Brainstem Auditory Evoked Potentials and Postoperative Nausea and Vomiting After Microvascular Decompression.

BACKGROUND: We performed this study to investigate the effect of intraoperative brainstem auditory evoked potential (IBAEP) changes on the development of postoperative nausea and vomiting (PONV) after microvascular decompression (MVD) for neurovascular cross compression. METHODS: A total of 373 consecutive cases were treated with MVD. The use of rescue antiemetics after surgery was used as an objective indicator of PONV. IBAEP monitoring was routinely performed in all. RESULTS: The use of rescue antiemetics was significantly associated with female sex (OR = 3.427; 95% CI, 2.077-5.654; P < 0.001), PCA use (OR = 3.333; 95% CI, 1.861-5.104; P < 0.001), and operation time (OR = 1.017; 95% CI, 1.008-1.026; P < 0.001). A Wave V peak delay of more than 1.0 milliseconds showed a significant relation with the use of rescue antiemetics (OR = 1.787; 95% CI, 1.114-2.867; P = 0.016) and a strong significant relation with the use of rescue antiemetics more than 5 times (OR = 2.426; 95% CI, 1.372-4.290; P = 0.002). CONCLUSIONS: A wave V peak delay of more than 1.0 milliseconds might have value as a predictor of PONV after MVD. More detailed neurophysiological studies will identify the exact pathophysiology underlying PONV after MVD.

Validation of Korean Olfactory Questionnaire for Perioperative Olfactory Assessment in Endoscopic Endonasal Skull Base Surgery.

Objective: To analyze changes in olfactory function after endoscopic endonasal skull base surgery and compare performance of the olfactory questionnaire with those of conventional psychophysical tests. Methods: Patients were classified into 5 categories for olfactory function evaluation (normal, mild hyposmia, moderate hyposmia, severe hyposmia, and anosmia) based on a self-assessment. Patients also underwent the butanol threshold test (BTT), Cross-Cultural Smell Identification Test (CCSIT), and 11-item olfactory questionnaire. Subjects with normosmia preoperatively and who were followed up at least 6 months after surgery were analyzed. Receiver operating characteristic curves and confusion matrix analysis were performed for BTT, CCSIT, and olfactory questionnaire to compare their diagnostic abilities. The effects of age, preoperative olfaction, septal flap, tumor pathology, and tumor size on postoperative olfaction were evaluated using multivariate linear regression analysis. Results: Data from 108 patients were analyzed. Postoperative changes in the olfactory questionnaire were significantly associated with changes in the BTT and CCSIT. The area under the curve for postoperative self-olfactory function classification was highest for olfactory questionnaire (0.894), followed by BTT (0.767) and CCSIT (0.688). Patient age at the time of surgery and preoperative BTT score were significantly related to postoperative olfactory outcomes. Conclusion: The olfactory questionnaire correlated well with conventional psychosomatic olfactory function tests. In combination with clinical parameters and preoperative psychosomatic olfactory function tests, the olfactory questionnaire is suitable for assessing subjective olfactory function after endoscopic endonasal skull base surgery.

Hearing preservation after stereotactic radiosurgery for sporadic intracanalicular vestibular schwannomas classified as Koos grade 1.

INTRODUCTION: The mechanism of hearing loss following stereotactic radiosurgery (SRS) for vestibular schwannomas (VSs) remains unclear. There is conflicting evidence regarding cochlear nerve damage by transient volume expansion of VSs after radiosurgery and radiation-induced cochlear damage. This study aimed to investigate whether there is a specific patient population that can achieve definite hearing preservation after SRS for VSs. METHODS: A total of 37 consecutive patients with sporadic unilateral intracanalicular VSs and serviceable hearing (Gardner-Roberson [G-R] class I or II) were treated with SRS from 2009 to 2023. This is a retrospective study. Survival analysis with Cox regression for hearing deterioration was performed. RESULTS: The median age was 55 years old. The median tumor volume was 0.089 cm3 , and the median marginal dose was 12.0 Gy. Nonserviceable hearing deterioration occurred in 9 patients (24.3%), with a median onset of 11.9 months after SRS. The actuarial rates of serviceable hearing preservation were 86%, 82%, and 70% at 1, 2, and 3 years after SRS, respectively. In a multivariate analysis, only baseline pure tone average > 30 dB increased the risk of nonserviceable hearing deterioration with significant hazard ratio. There were 13 patients with petit VSs whose tumor volume was smaller than 0.05 cm3 , and 11 of them were treated by a 4-mm single shot with a marginal dose of 12 Gy. None of the 13 patients had nonserviceable hearing deterioration. CONCLUSIONS: Petit VSs that can be treated with 4-mm single or double shots with a marginal dose of 12 Gy may achieve hearing preservation after SRS.

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.

Diffuse Leptomeningeal Glioneuronal Tumor with FGFR1 Mutation in a 29-Year-Old Male.

This study reports on diffuse leptomeningeal glioneuronal tumor (DL-GNT) in a 29-year-old male. DL-GNT is a rare central nervous system (CNS) tumor mostly seen in children and only few cases have been reported in adult patients. Our patient presented with a chronic headache that lasted for five months. MR imaging showed mild hydrocephalus, multiple rim-enhancing nodular lesions in the suprasellar cistern, diffuse leptomeningeal enhancement in the lumbosacral area, and multiple small non-enhancing cyst-appearing lesions not suppressed on fluid attenuated inversion recovery (FLAIR) images in the bilateral basal ganglia, thalami, and cerebral hemispheres. Under the impression of germ cell tumor with leptomeningeal seeding, the patient underwent trans-sphenoidal tumor removal. DL-GNT was pathologically confirmed and FGFR1 mutation was detected through a next-generation sequencing test. In conclusion, a combination of leptomeningeal enhancement and multiple parenchymal non-enhancing cyst-appearing lesions not suppressed on FLAIR images may be helpful for differential diagnosis despite overlapping imaging features with many other CNS diseases that have leptomeningeal enhancement.

The Korean Society for Neuro-Oncology (KSNO) Guideline for the Management of Brain Tumor Patients During the Crisis Period: A Consensus Recommendation Using the Delphi Method (Version 2023.1).

BACKGROUND: During the coronavirus disease 2019 (COVID-19) pandemic, the need for appropriate treatment guidelines for patients with brain tumors was indispensable due to the lack and limitations of medical resources. Thus, the Korean Society for Neuro-Oncology (KSNO), a multidisciplinary academic society, has undertaken efforts to develop a guideline that is tailored to the domestic situation and that can be used in similar crisis situations in the future. METHODS: The KSNO Guideline Working Group was composed of 22 multidisciplinary experts on neuro-oncology in Korea. In order to reach consensus among the experts, the Delphi method was used to build up the final recommendations. RESULTS: All participating experts completed the series of surveys, and the results of final survey were used to draft the current consensus recommendations. Priority levels of surgery and radiotherapy during crises were proposed using appropriate time window-based criteria for management outcome. The highest priority for surgery is assigned to patients who are life-threatening or have a risk of significant impact on a patient's prognosis unless immediate intervention is given within 24-48 hours. As for the radiotherapy, patients who are at risk of compromising their overall survival or neurological status within 4-6 weeks are assigned to the highest priority. Curative-intent chemotherapy has the highest priority, followed by neoadjuvant/adjuvant and palliative chemotherapy during a crisis period. Telemedicine should be actively considered as a management tool for brain tumor patients during the mass infection crises such as the COVID-19 pandemic. CONCLUSION: It is crucial that adequate medical care for patients with brain tumors is maintained and provided, even during times of crisis. This guideline will serve as a valuable resource, assisting in the delivery of treatment to brain tumor patients in the event of any future crisis.

The Korean Society for Neuro-Oncology (KSNO) Guideline for the Management of Brain Tumor Patients During the Crisis Period: A Consensus Survey About Specific Clinical Scenarios (Version 2023.1).

BACKGROUND: During the coronavirus disease 2019 (COVID-19) pandemic, there was a shortage of medical resources and the need for proper treatment guidelines for brain tumor patients became more pressing. Thus, the Korean Society for Neuro-Oncology (KSNO), a multidisciplinary academic society, has undertaken efforts to develop a guideline that is tailored to the domestic situation and that can be used in similar crisis situations in the future. As part II of the guideline, this consensus survey is to suggest management options in specific clinical scenarios during the crisis period. METHODS: The KSNO Guideline Working Group consisted of 22 multidisciplinary experts on neuro-oncology in Korea. In order to confirm a consensus reached by the experts, opinions on 5 specific clinical scenarios about the management of brain tumor patients during the crisis period were devised and asked. To build-up the consensus process, Delphi method was employed. RESULTS: The summary of the final consensus from each scenario are as follows. For patients with newly diagnosed astrocytoma with isocitrate dehydrogenase (IDH)-mutant and oligodendroglioma with IDH-mutant/1p19q codeleted, observation was preferred for patients with low-risk, World Health Organization (WHO) grade 2, and Karnofsky Performance Scale (KPS) ≥60, while adjuvant radiotherapy alone was preferred for patients with high-risk, WHO grade 2, and KPS ≥60. For newly diagnosed patients with glioblastoma, the most preferred adjuvant treatment strategy after surgery was radiotherapy plus temozolomide except for patients aged ≥70 years with KPS of 60 and unmethylated MGMT promoters. In patients with symptomatic brain metastasis, the preferred treatment differed according to the number of brain metastasis and performance status. For patients with newly diagnosed atypical meningioma, adjuvant radiation was deferred in patients with older age, poor performance status, complete resection, or low mitotic count. CONCLUSION: It is imperative that proper medical care for brain tumor patients be sustained and provided, even during the crisis period. The findings of this consensus survey will be a useful reference in determining appropriate treatment options for brain tumor patients in the specific clinical scenarios covered by the survey during the future crisis.

Elucidating the cellular uptake mechanisms of heptamethine cyanine dye analogues for their use as an anticancer drug-carrier molecule for the treatment of glioblastoma.

The development of chemotherapies for glioblastoma is hindered by their limited bioavailability and toxicity on normal brain function. To overcome these limitations, we investigated the structure-dependent activity of heptamethine cyanine dyes (HMCD), a group of tumour-specific and BBB permeable near-infrared fluorescent dyes, in both commercial (U87MG) and patient-derived GBM cell lines. HMCD analogues with strongly ionisable sulphonic acid groups were not taken up by patient-derived GBM cells, but were taken up by the U87MG cell line. HMCD uptake relies on a combination of transporter uptake through organic anion-transporting polypeptides (OATPs) and endocytosis into GBM cells. The uptake of HMCDs was not affected by p-glycoprotein efflux in GBM cells. Finally, we demonstrate structure-dependent cytotoxic activity at high concentrations (EC50 : 1-100 µM), likely due to mitochondrial damage-induced apoptosis. An in vivo orthotopic glioblastoma model highlights tumour-specific accumulation of our lead HMCD, MHI-148, for up to 7 days following a single intraperitoneal injection. These studies suggest that strongly ionisable groups like sulphonic acids hamper the cellular uptake of HMCDs in patient-derived GBM cell lines, highlighting cell line-specific differences in HMCD uptake. We envisage these findings will help in the design and structural modifications of HMCDs for drug-delivery applications for glioblastoma.

Surgical Management and Long-Term Results of Rathke's Cleft Cyst.

OBJECTIVE: Rathke's cleft cysts (RCCs) are nonneoplastic cysts. Most of them are asymptomatic and stable; when symptomatic, RCCs are surgically fenestrated and drained. However, the outcomes remain unclear. The authors evaluated the outcomes of RCC decompression. METHODS: Between 2004 and 2019, 32 RCCs were decompressed in a single tertiary institution. The clinical characteristics, intraoperative findings, postoperative complications, and endocrinological and surgical outcomes were retrospectively reviewed. Patients who underwent sequential imaging at least twice and at least 12 months after surgery were included in the analysis. RESULTS: Patients' mean age was 40.8±14.9 years, and 62.5% were women. The mean follow-up duration was 62.3±48.6 months. In 21 patients (65.6%), no residual cysts were identified on postoperative magnetic resonance imaging. Of the 18 patients with preoperative visual field defects, 17 (94.4%) experienced postoperative visual improvement. Postoperative complications included endocrinological deterioration in 11 patients (34.4%), permanent diabetes insipidus in 11 (34.4%), infection in four (12.5%), intrasellar hemorrhage in three (9.4%), and cerebrospinal fluid leak in two (6.3%). Follow-up images revealed cyst recurrence in nine patients (28.1%), an average of 20.4 months after surgery; in three patients, the cysts were symptomatic, and resection was repeated. Multivariable analysis revealed that postoperative endocrinological deterioration was the only independent factor associated with cyst recurrence (p=0.028; hazard ratio, 6.800). CONCLUSION: Our findings showed that although only cyst fenestration for decompression was performed to preserve pituitary function, more pituitary dysfunction occurred than expected. Besides, the postoperative hormonal deterioration itself acted as a risk factor for cyst recurrence. In conclusion, surgery for RCC should be more careful.

Fully Automated Segmentation Models of Supratentorial Meningiomas Assisted by Inclusion of Normal Brain Images.

To train an automatic brain tumor segmentation model, a large amount of data is required. In this paper, we proposed a strategy to overcome the limited amount of clinically collected magnetic resonance image (MRI) data regarding meningiomas by pre-training a model using a larger public dataset of MRIs of gliomas and augmenting our meningioma training set with normal brain MRIs. Pre-operative MRIs of 91 meningioma patients (171 MRIs) and 10 non-meningioma patients (normal brains) were collected between 2016 and 2019. Three-dimensional (3D) U-Net was used as the base architecture. The model was pre-trained with BraTS 2019 data, then fine-tuned with our datasets consisting of 154 meningioma MRIs and 10 normal brain MRIs. To increase the utility of the normal brain MRIs, a novel balanced Dice loss (BDL) function was used instead of the conventional soft Dice loss function. The model performance was evaluated using the Dice scores across the remaining 17 meningioma MRIs. The segmentation performance of the model was sequentially improved via the pre-training and inclusion of normal brain images. The Dice scores improved from 0.72 to 0.76 when the model was pre-trained. The inclusion of normal brain MRIs to fine-tune the model improved the Dice score; it increased to 0.79. When employing BDL as the loss function, the Dice score reached 0.84. The proposed learning strategy for U-net showed potential for use in segmenting meningioma lesions.

Volumetric changes in gray matter after radiotherapy detected with longitudinal magnetic resonance imaging in glioma patients.

BACKGROUND AND PURPOSE: We evaluated volumetric changes in the gray matter (GM) after radiotherapy (RT) and identified factors that were strongly associated with GM volume reduction. MATERIALS AND METHODS: A total of 461 magnetic resonance imagings (MRI) from 105 glioma patients treated with postoperative RT was retrospectively analyzed. Study patients' MRIs were collected at five time points: before RT and 1 month, 6 months, 1 year, and 2 years after RT. Using the 'FastSurfer' platform, a deep learning-based neuroimaging pipeline, 73 regions were automatically segmented from longitudinal MRIs and their volumetric changes were calculated. Regions were grouped into 10 functional fields. A multivariable linear mixed-effects model was established to identify the potential predictors of significant volume reduction. RESULTS: The median age was 50 years (range, 16-86 years). Forty-seven (44.8 %) patients were female and 68 (64.8 %) had glioblastoma. Postoperative RT was delivered at 54-60 Gy with or without concurrent chemotherapy. At 2 years after RT, the median volumetric changes in the overall, ipsilateral, and contralateral GM were -3.5%, -4.5%, and -2.4%, respectively. The functional fields of cognition and execution of movement showed the greatest volume reductions. In the multivariable linear mixed model, female sex (normalized coefficient = -0.14, P < 0.001) and the interaction between age at RT and days after RT (normalized coefficient = -6.48e-6, P < 0.001) were significantly associated with GM reduction. The older patients received RT, the greater volume reduction was seen over time. However, in patients with relatively younger age (e.g., 45, 50, and 60 years for hippocampus, Broca area, and Wernicke area, respectively), the volume was not significantly reduced. CONCLUSIONS: GM volume reduction was identified after RT that could lead to long-term treatment sequelae. Particularly for susceptible patients, individualized treatment and prevention strategies are needed.

Enhanced delivery to brain using sonosensitive liposome and microbubble with focused ultrasound.

Glioblastoma is considered one of the most aggressive and dangerous brain tumors. However, treatment of GBM has been still challenged due to blood-brain barrier (BBB). BBB prevents that the chemotherapeutic molecules are extravasated to brain. In this study, sonosensitive liposome encapsulating doxorubicin (DOX) was developed for enhancement of GBM penetration in combination with focused ultrasound (FUS) and microbubbles. Upon ultrasound (US) irradiation, microbubbles induce cavitation resulting in the tight junction of BBB endothelium to temporarily open. In addition, the composition of sonosensitive liposome was optimized by comparison of sonosensitivity and intracellular uptake to U87MG cells. The optimal sonosensitive liposome, IMP301-DC, resulted 123.9 ± 38.2 nm in size distribution and 98.2 % in loading efficiency. Related to sonosensitivity of IMP301-DC, US-triggered release ratio of doxorubicin was 69.2 ± 12.3 % at 92 W/cm2 of US intensity for 1 min. In the in vivo experiments, the accumulation of DiD fluorescence probe labeled IMP301-DC-shell in the brain through the BBB opening was increased more than two-fold compared to that of Doxil-shell, non-sonosensitive liposome. US exposure significantly increased GBM cytotoxicity of IMP301-DC. In conclusion, this study demonstrated that IMP301-DC could serve as an alternative solution to enhance the penetration to GBM treatment via BBB opening by non-invasive FUS combined with microbubbles.

Clinicopathologic Characteristics of Grade 2/3 Meningiomas: A Perspective on the Role of Next-Generation Sequencing.

Background: Grade 2/3 meningiomas have locally aggressive behaviors often requiring additional treatment plans after surgical resection. Herein, we explored the clinical significance of next-generation sequencing (NGS) in characterizing the molecular profiles of high-grade meningiomas. Methods: Patients with intracranial meningioma who underwent surgical resection in a single institution were retrospectively reviewed. Clinicopathologic relevance was evaluated using recurrence-free survival (RFS) as an outcome measure. NGS for the targeted gene regions was performed in 40 participants. Results: Among the 713 individuals in the study population, 143 cases (20.1%) were identified as having grade 2 or 3 meningiomas with a significantly lower female predominance. While the difference in RFS between grade 2 and 3 meningiomas was insignificant, a few conventional grade 2 cases, but with TERT promoter hotspot mutation, were highly progressive and refractory to the treatment. From the NGS study, recurrent mutations in TRAF and AKT1 were identified with a higher prevalence (17.5% and 12.5%, respectively) compared with grade 2/3 meningiomas reported in previous literature. However, their relations to other histopathologic properties or clinical factors were rarely observed. Conclusions: Grade 2/3 meningiomas show a broad spectrum of molecular profiles, as they have heterogeneous histologic characteristics.

Communicating Hydrocephalus Following Treatment of Cerebellopontine Angle Tumors.

OBJECTIVE: This study aimed to clarify the risk of communicating hydrocephalus in cerebellopontine angle tumors, focusing on distinct tumor types and treatment modalities, i.e., tumor resection and stereotactic radiosurgery (SRS). METHODS: This study was a retrospective single-center cohort study. The cumulative incidences of symptomatic communicating hydrocephalus in schwannoma and meningioma patients were evaluated. A multivariate Cox model was used to assess the hazard ratios for the risk factors and odds ratios of distinct treatment subgroups. RESULTS: A total of 405 cases, including 286 schwannomas and 119 meningiomas, were retrospectively reviewed. The risk of hydrocephalus was significantly higher in schwannomas than that in meningiomas (hazard ratio, 4.70 [95% confidence interval, 1.78-12.4, P = 0.002]). Patients with schwannomas who received SRS without tumor resection showed a significantly higher incidence than meningioma cases: 10.6% versus 1.4% (P = 0.037). We identified specific subgroups that were prone to increase the risk of hydrocephalus when treated with SRS alone. The result showed that patients with vestibular schwannoma of Koos grade III had a greater benefit from tumor resection than from SRS in preventing hydrocephalus (odds ratio, 0.089 [95% confidence interval, 0.011-0.743, P = 0.025]). CONCLUSIONS: Symptomatic communicating hydrocephalus is more frequent in schwannoma than that in meningiomas. Primary treatment with tumor resection lowers the risk of hydrocephalus in specific subgroups of vestibular schwannoma.

Influence of Concurrent and Adjuvant Temozolomide on Health-Related Quality of Life of Patients with Grade III Gliomas: A Secondary Analysis of a Randomized Clinical Trial (KNOG-1101 Study).

PURPOSE: The KNOG-1101 study showed improved 2-year PFS with temozolomide during and after radiotherapy compared to radiotherapy alone for patients with anaplastic gliomas. This trial investigates the effect of concurrent and adjuvant temozolomide on health-related quality of life (HRQoL). MATERIALS AND METHODS: In this randomized, open-label, phase II trial, 90 patients with World Health Organization grade III glioma were enrolled across multiple centers in South Korea between March 2012 to February 2015 and followed up through 2017. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire 30 (EORTC QLQ-C30) and 20-item EORTC QLQ-Brain Neoplasm (QLQ-BN20) were used to compare HRQoL between patients assigned to concurrent chemoradiotherapy with temozolomide followed by 6 cycles of adjuvant temozolomide (arm A) and radiotherapy (RT) alone (arm B). RESULTS: Of the 90 patients in the study, 84 patients (93.3%) completed the baseline HRQoL questionnaire. Emotional functioning, fatigue, nausea and vomiting, dyspnea, constipation, appetite loss, diarrhea, seizures, itchy skin, drowsiness, hair loss, and bladder control were not affected by the addition of temozolomide. All other items did not differ significantly between arm A and arm B throughout treatment. Global health status particularly stayed consistent at the end of adjuvant temozolomide (p=0.47) and at the end of RT (p=0.33). CONCLUSION: The addition of concurrent and adjuvant temozolomide did not show negative influence on HRQoL with improvement of progression-free survival for patients with anaplastic gliomas. The absence of systematic and clinically relevant changes in HRQoL suggests that an overall long-term net clinical benefit exists for concurrent and adjuvant temozolomide.

Levetiracetam as a sensitizer of concurrent chemoradiotherapy in newly diagnosed glioblastoma: An open-label phase 2 study.

BACKGROUND: An open-label single-arm phase 2 study was conducted to evaluate the role of levetiracetam as a sensitizer of concurrent chemoradiotherapy (CCRT) for patients with newly diagnosed glioblastoma. This study aimed to determine the survival benefit of levetiracetam in conjunction with the standard treatment for glioblastoma. METHODS: Major eligibility requirements included histologically proven glioblastoma in the supratentorial region, patients 18 years or older, and Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. Levetiracetam was given at 1,000-2,000 mg daily in two divided doses during CCRT and adjuvant chemotherapy thereafter. The primary and the secondary endpoints were 6-month progression-free survival (6mo-PFS) and 24-month overall survival (24mo-OS), respectively. Outcomes of the study group were compared to those of an external control group. RESULTS: Between July 2016 and January 2019, 76 patients were enrolled, and 73 patients were included in the final analysis. The primary and secondary outcomes were improved in the study population compared to the external control (6mo-PFS, 84.9% vs. 72.3%, p = 0.038; 24mo-OS, 58.0% vs. 39.9%, p = 0.018), but the differences were less prominent in a propensity score-matched analysis (6mo-PFS, 88.0% vs. 76.9%, p = 0.071; 24mo-OS, 57.1% vs. 38.8%, p = 0.054). In exploratory subgroup analyses, some results suggested that patients with ages under 65 years or unmethylated MGMT promoter might have a greater survival benefit from the use of levetiracetam. CONCLUSIONS: The use of levetiracetam during CCRT in patients with newly diagnosed glioblastoma may result in improved outcomes, but further investigations are warranted.

Bioconcentration and Metabolism of the New Herbicide Methiozolin in Ricefish (Oryzias latipes).

Methiozolin is a novel herbicide used to control annual bluegrass. It has low vapor pressure and high hydrophobicity, which could result in persistence in water and bioaccumulation. We measured the bioconcentration factors (BCFs) of methiozolin in ricefish (Oryzias latipes). Two radiolabels were used to quantify the parent compound and identify its metabolites. Ricefish were exposed to 2.0 and 20.0 ng/L methiozolin for 28 days in the uptake phase with a 96-h LC50 of 2.2 mg/L(95% confidence limit: 2.1-2.5 mg/L) and water solubility of 4.2 mg/L after 48 h was observed. On the basis of total radioactivity residues (TRRs), BCFss and BCFk values of 797.0-851.9 and 992.9-1077.4 were observed, respectively, while BCFss values for methiozolin were 251.9-257.5. Several minor metabolites with TRR < 3.4% were detected. Among them, 4-(2,6-difluorobenzyloxy-methyl)-3-hydroxy-3-methyl-1-(3-methylthiophen-2-yl)butan-1-one, 2,6-difluorobenzyl alcohol, and 4,5-dihydro-5-methyl-3-(3-methylthiophen-2-yl)isoxazol-5-yl)methanol were identified. Methiozolin is metabolized into numerous minor metabolites with potentially low bioaccumulation capacity in ricefish. These findings can facilitate risk assessments regarding methiozolin use, particularly its movements and final stages in aquatic environments.

The Combination PARP Inhibitor Olaparib With Temozolomide in an Experimental Glioblastoma Model.

BACKGROUND/AIM: Poly (ADP-ribose) polymerase (PARP) inhibition could enhance the efficacy of temozolomide and prolong survival in patients with glioblastoma. The aim of this study was to evaluate the combination of the PARP inhibitor olaparib with temozolomide in the treatment of glioblastoma. MATERIALS AND METHODS: The in vitro and in vivo antitumor effects of the PARP inhibitor olaparib together with temozolomide were evaluated. The in vitro experimental glioblastoma model involved O6-methylguanine methyltransferase (MGMT) promoter-methylated (U87MG, U251MG) and MGMT promoter-unmethylated (T98G) glioblastoma cell lines using In this model cell viability and apoptosis were assessed. For the in vivo studies, nude mice bearing orthotopically xenografted glioblastoma cell lines (U87MG) were randomized to four experimental groups: i) the untreated, ii) temozolomide alone, iii) olaparib alone and iv) olaparib and temozolomide combination groups. Mice were treated daily for 4 weeks and monitored for tumor growth and survival. RESULTS: In vitro we found that the combination of olaparib with temozolomide enhanced temozolomide-induced cytotoxicity in all glioblastoma cell lines regardless of the status of MGMT promoter methylation. In vivo, mice treated with temozolomide alone or in combination with olaparib showed greater survival than those untreated or with the olaparib monotherapy, as well as significantly decreased tumor volume. There was no significant difference in survival and tumor volume between temozolomide alone and the combination treatment. CONCLUSION: The combination of the PARP inhibitor olaparib with temozolomide could be promising candidates for combination therapy of glioblastoma regardless of the MGMT promoter methylation status.