Evaluation the Effect of Sonodynamic Therapy with 5-Aminolevulinic Acid and Sodium Fluorescein by Preclinical Animal Study.

Sonodynamic therapy (SDT) is a novel tumor treatment that combines biosafe sonosensitizers and noninvasive focused ultrasound to eradicate solid tumors. Sonosensitizers such as 5-aminolevulinic acid and fluorescein have great potential in tumor treatment. Here, rodent subcutaneous and brain tumor models were used to evaluate the treatment effect of both 5-ALA- and fluorescein-mediated SDT. The subcutaneous tumor growth rates of both SDT groups were significantly inhibited compared with that of the control groups. For intracranial tumors, 5-ALA-SDT treatment significantly inhibited brain tumor growth, while fluorescein-SDT exerted no therapeutic effect in animals. The distribution of fluorescein in the brain tumor region underwent further assessment. Seven days post tumor implantation, experimental animals received fluorescein and were sacrificed for brain specimen collection. Analysis of the dissected brains revealed no fluorescence signals, indicating an absence of fluorescein accumulation in the early-stage glioma tissue. These data suggest that the fluorescein-SDT treatment response is closely related to the amount of accumulated fluorescein. This study reports the equivalent effects of 5-ALA and fluorescein on the treatment of somatic tumors. For orthotopic brain tumor models, tumor vascular permeability should be considered when choosing fluorescein as a sonosensitizer. In conclusion, both fluorescein and 5-ALA are safe and effective SDT sonosensitizers, and the tumor microenvironment and pathologic type should be considered in the selection of adequate sonosensitizers.

Minimally invasive endoscopic evacuation with the novel, portable Axonpen neuroendoscopic system for spontaneous intracerebral hemorrhage.

Minimally invasive surgeries have shown potential to improve mortality and clinical outcomes of spontaneous intracerebral hemorrhage (ICH). The present study assessed the first-in-human outcomes of a novel, portable neuroendoscopic system for ICH evacuation at our single center. This neuroendoscopic system integrates real-time visualization into a handpiece which has controllable suction, irrigation, and coagulation to allow a neurosurgeon to conduct minimally invasive ICH evacuation independently with bimanual dexterity. Pre- and postoperative data of ten patients who had spontaneous basal ganglia hemorrhage (mean: 46.5 ± 12.2 mL) and underwent evacuation with the specified neuroendoscopic system were collected prospectively. The mean time to receive surgery was 12.1 ± 7.6 h. Mean operative time was 3.4 ± 0.9 h. The mean hematoma volume decreased to 6.0 ± 3.9 mL at postoperative 6 h, resulting in a mean volume reduction of 86.0 ± 11.2% (P = 0.005). The median length of intensive care unit stay was 3 days (IQR, 3-4 days). At discharge, the median Glasgow Coma Scale (GCS) score significantly improved to 11.5 (IQR, 11-15; P = 0.016), and the median modified Rankin Scale (mRS) score was 4 (IQR, 4-5). Six patients (60%) showed a favorable mRS score of ≤ 3 on their last return visit. Neither death nor rebleeding occurred during the follow-up periods. Integrated design of the innovative device is valuable to optimize minimally invasive endoscopic ICH evacuation procedure. Further studies are needed to clarify long-term benefits from such type of the innovative device to early intervention of ICH.

Focused ultrasound combined with radiotherapy for malignant brain tumor: a preclinical and clinical study.

INTRODUCTION: Blood-brain barrier (BBB) remains to be the major obstacle to conquer in treating patients with malignant brain tumors. Radiation therapy (RT), despite being the mainstay adjuvant modality regardless of BBB, the effect of radiation induced cell death is hindered by the hypoxic microenvironment. Focused ultrasound (FUS) combined with systemic microbubbles has been shown not only to open BBB but also potentially increased regional perfusion. However, no clinical study has investigated the combination of RT with FUS-BBB opening (RT-FUS). METHODS: We aimed to provide preclinical evidence of RT-FUS combination in GBM animal model, and to report an interim analysis of an ongoing single arm, prospective, pilot study (NCT01628406) of combining RT-FUS for recurrent malignant high grade glioma patients, of whom re-RT was considered for disease control. In both preclinical and clinical studies, FUS-BBB opening was conducted within 2 h before RT. Treatment responses were evaluated by objective response rate (ORR) using magnetic resonance imaging, progression free survival, and overall survival, and adverse events (AE) in clinical study. Survival analysis was performed in preclinical study and descriptive analysis was performed in clinical study. RESULTS: In mouse GBM model, the survival analysis showed RT-FUS (2 Gy) group was significantly longer than RT (2 Gy) group and control, but not RT (5 Gy) group. In the pilot clinical trial, an interim analysis of six recurrent malignant high grade glioma patients underwent a total of 24 RT-FUS treatments was presented. Three patients had rapid disease progression at a mean of 33 days after RT-FUS, while another three patients had at least stable disease (mean 323 days) after RT-FUS with or without salvage chemotherapy or target therapy. One patient had partial response after RT-FUS, making the ORR of 16.7%. There was no FUS-related AEs, but one (16.7%) re-RT-related grade three radiation necrosis. CONCLUSION: Reirradiation is becoming an option after disease recurrence for both primary and secondary malignant brain tumors since systemic therapy significantly prolongs survival in cancer patients. The mechanism behind the synergistic effect of RT-FUS in preclinical model needs further study. The clinical evidence from the interim analysis of an ongoing clinical trial (NCT01628406) showed a combination of RT-FUS was safe (no FUS-related adverse effect). A comprehensive analysis of radiation dosimetry and FUS energy distribution is expected after completing the final recruitment.

Predictors for delayed awakening in adult glioma patients receiving awake craniotomy under monitored anesthesia care.

PURPOSE: Delayed awakening after anesthetic discontinuation during awake craniotomy is associated with somnolence during functional brain mapping. However, predictors of delayed awakening in patients receiving monitored anesthesia care for awake craniotomy are unknown. METHODS: This retrospective cohort study analyzed 117 adult patients with supratentorial glioma in or near eloquent areas who received monitored anesthesia care for awake craniotomy between July 2020 and January 2023 at Linkou Chang Gung Memorial Hospital. These patients were divided into two groups according to their time to awakening (ability to speak their names) after propofol cessation: longer or shorter than 20 min (median duration). Because propofol was solely used anesthetic from skin incision to dural opening, parameters in Schnider model for propofol target-controlled infusion, such as age, sex, and BMI, were adjusted or propensity-matched to compare their anesthetic, surgical, and histopathological profiles. RESULTS: After propensity-matched comparisons of age and BMI, significant predictors of delayed awakening included IDH1 wild-type tumors and repeated craniotomies. Subgroup analysis revealed that older age and larger T2 volume were predictors in patients undergoing the first craniotomy, while lower preoperative Karnofsky performance scale scores and depression were predictors in repeated craniotomy cases. Delayed awakening was also associated with somnolence and a lower gross total resection rate. CONCLUSION: Our retrospective analysis of patients receiving monitored anesthesia care for awake craniotomy revealed that delayed awakening after propofol discontinuation occurred more often in patients with IDH1 wild-type tumors and repeated craniotomies. Also, delayed awakening was associated with somnolence during functional mapping and a lower gross total resection rate.

Primary Graviceptive System and Astasia: A Case Report and Literature Review.

Astasia refers to the inability to maintain upright posture during standing, despite having full motor strength. Impairment of the vestibulocerebellar pathway, graviceptive system, and cingulate motor area have been proposed to be related to astasia. However, the responsible neural pathways remain unclear. We hypothesize that there is a common neural network behind astasia. To test the hypothesis, we reviewed all reported cases with astasia, including ours, and focused on the correlation between anatomical destruction and symptom presentation. A total of 26, including ours, non-psychogenic astasia patients were identified in the English literature. Seventy-three percent of them were associated with other neurologic symptoms and sixty-two percent of reported lesions were on the right side. Contralateral lateropulsion was very common, followed by retropulsion, when describing astasia. Infarction (54%) was the most reported cause. The thalamus (65%) was the most reported location. Infarctions were the fastest to recover (mean: 10.6 days), while lesions at the brainstem needed a longer time (mean: 61.6 days). By combining the character of lateropulsion in astasia and the presentation of an interrupted graviceptive system, we concluded that the primary graviceptive system may be the common neural network behind astasia. Future studies on astasia should focus on the pathological changes in the perception of verticality in the visual world and the body.

Neuropsychological impairment in primary malignant brain tumor patients with awake craniotomy: a hospital-based registration study.

PURPOSE: Neuroplasticity is an ability to maintain neural circuit function when facing damages. It is one of the reasons that making brain tumors notorious. Therefore, we evaluated the characteristics of patients with primary brain tumors, compared neuropsychological deficits between patients who had awake craniotomy with left- or right-sided tumors, and analyzed the association between white matter tracts and neuropsychological deficits in patients with right-sided tumors. METHODS: Using the registration dataset of Chang Gung Memory Hospital between 2014 and 2020, this study included a total of 698 adult patients who received craniotomy for primary brain tumors (538 of conventional craniotomy; 160 of awake craniotomy). Neuropsychological assessments were arranged in patients as preoperative evaluation for awake craniotomies. RESULTS: A lower proportion of right-sided tumors was noted in patient who had awake craniotomy than those who had conventional craniotomy (33.8% and 51.5%, p < 0.001). In awake craniotomy, 88.7% of patients with left-sided tumors and 77.8% of patients with right-sided tumors had neuropsychological impairment. Patients with left-sided tumors had worse preoperative performance compared to those with right-sided tumors in global function (36.2% and 8.0%, p < 0.001), language domain (57.6% and 22.2%, p < 0.001), and attention (36.0% and 18.5%, p = 0.02). Furthermore, in those with right-sided low-grade gliomas, patients involving pathway of superior longitudinal fasciculus (SLF) I had a higher risk of deficits than those without involvement in verbal memory (p = 0.001, Odd ratio = 11.2, 95% CI = 1.8 ~ 71.4) and visual memory (p = 0.048, Odd ratio = 10.5, 95% CI = 1.0 ~ 111). CONCLUSION: In awake craniotomy, patients with left-sided brain tumors had worse cognitive function than those with right-sided tumors in terms of global function, language, and attention. 77% of patients with right-sided tumors had neuropsychological impairment. Therefore, a comprehensive neuropsychological evaluation and awake craniotomy are necessary for patients with brain tumors.

Clinical outcome analysis of non-small cell lung cancer patients with brain metastasis receiving metastatic brain tumor resection surgery: a multicenter observational study.

Brain metastasis is most common in primary non-small cell lung cancer (NSCLC), and some patients require neurosurgical resection for intracranial disease control. Because advances in systemic therapies for metastatic NSCLC have been developed in the past decade, we aimed to analyze and determine clinical factors associated with the postresection survival of NSCLC patients with brain metastasis who underwent neurosurgery followed by systemic therapy. Between January 2017 and December 2021, data for 93 NSCLC patients with brain metastasis treated with neurosurgery followed by systemic therapy at Linkou, Kaohsiung and Chiayi Chang Gung Memorial Hospitals were retrospectively retrieved for analysis. For all study patients, median postresection survival was 34.36 months (95% confidence interval (CI), 28.97-39.76), median brain metastasis (BM)-free survival was 26.90 months (95% CI, 22.71-31.09), and overall survival (OS) was 41.13 months (95% CI, 34.47-47.52). In multivariate analysis, poor performance status (Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2) and concurrent liver metastasis were identified as independent unfavorable factors associated with significantly shortened postresection survival (P<0.001). The histological type adenocarcinoma was associated with significantly longer postresection survival (P = 0.001). The median postresection survival for adenocarcinoma and nonadenocarcinoma patients was 36.23 and 10.30 months, respectively (hazard ratio (HR) = 0.122; 95% CI, 0.035-0.418; P<0.001); that for patients with and without concurrent liver metastasis was 11.43 and 36.23 months, respectively (HR = 22.18; 95% CI, 5.827-84.459; P<0.001). Patients with preserved ECOG PS, adenocarcinoma histology type and no concurrent liver metastasis appeared to have better postresection survival than nonadenocarcinoma patients. Our results provide counseling and decision-making references for neurosurgery feasibility in NSCLC patients with brain metastasis.

CAN008 prolongs overall survival in patients with newly diagnosed GBM characterized by high tumor mutational burden.

BACKGROUND: A previous phase 1 dose-escalation study in Taiwan indicated CAN008 (asunercept) with standard concurrent chemoradiotherapy (CCRT) improved progression-free survival (PFS) in newly diagnosed glioblastoma (GBM) patients. This study evaluates the efficacy of CAN008 in promoting overall survival (OS) and identifies genetic alterations associated with treatment responses. METHODS: We compared OS of 5-year follow-ups from 9 evaluable CAN008 cohort patients (6 received high-dose and 3 received low-dose) to a historical Taiwanese GBM cohort with 164 newly diagnosed patients. CAN008 treatment response-associated genetic alterations were identified by whole-exome sequencing and comparing variant differences between response groups. Associations among patient survival, tumor mutational burden (TMB), and genetic alterations were analyzed using CAN008 cohort and TCGA-GBM dataset. RESULTS: OS for high-dose CAN008 patients at 2 and 5 years was 83% and 67%, respectively, and 40.1% and 8.8% for the historical GBM cohort, respectively. Better OS was observed in the high-dose CAN008 cohort (without reaching the median survival) than the historical GBM cohort (median OS: 20 months; p=0.0103). Five high-dose CAN008 patients were divided into good and poor response groups based on their PFS. A higher variant count and TMB were observed in good response patients, whereas no significant association was observed between TMB and patient survival in the newly diagnosed TCGA-GBM dataset, suggesting TMB may modulate patient CAN008 response. CONCLUSION: CAN008 combined with standard CCRT treatment prolonged the PFS and OS of newly diagnosed GBM patients compared to standard therapy alone. Higher treatment efficacy was associated with higher TMB.

Acrolein produced by glioma cells under hypoxia inhibits neutrophil AKT activity and suppresses anti-tumoral activities.

Acrolein, which is the most reactive aldehyde, is a byproduct of lipid peroxidation in a hypoxic environment. Acrolein has been shown to form acrolein-cysteine bonds, resulting in functional changes in proteins and immune effector cell suppression. Neutrophils are the most abundant immune effector cells in circulation in humans. In the tumor microenvironment, proinflammatory tumor-associated neutrophils (TANs), which are termed N1 neutrophils, exert antitumor effects via the secretion of cytokines, while anti-inflammatory neutrophils (N2 neutrophils) support tumor growth. Glioma is characterized by significant tissue hypoxia, immune cell infiltration, and a highly immunosuppressive microenvironment. In glioma, neutrophils exert antitumor effects early in tumor development but gradually shift to a tumor-supporting role as the tumor develops. However, the mechanism of this anti-to protumoral switch in TANs remains unclear. In this study, we found that the production of acrolein in glioma cells under hypoxic conditions inhibited neutrophil activation and induced an anti-inflammatory phenotype by directly reacting with Cys310 of AKT and inhibiting AKT activity. A higher percentage of cells expressing acrolein adducts in tumor tissue are associated with poorer prognosis in glioblastoma patients. Furthermore, high-grade glioma patients have increased serum acrolein levels and impaired neutrophil functions. These results suggest that acrolein suppresses neutrophil function and contributes to the switch in the neutrophil phenotype in glioma.

The impact of patient factors and tumor characteristics on language neuroplasticity in left hemispheric diffuse gliomas prior to surgical resection.

PURPOSE: Language networks are reorganized during glioma growth, leading to varying language performance in patients with gliomas located in or around language-eloquent areas. Therefore, pre-treated language performance reflects the neuroplasticity potential. Different domains of language processing, such as speech expression, repetition, and comprehension, involving different neural networks. We analyzed the effects of patient factors and tumor characteristics on the pre-treated performance to investigate neuroplastic potential of different language domains. METHODS: Patient age, sex, education level, tumor grade, language pathway involvement, T1 contrast enhanced (C+), and FLAIR (T2) volume were selected as variables. The correlation with abnormal language performance was verified using univariate and multivariate logistic regression. RESULTS: In total, 104 left hemispheric glioma patients were enrolled in this study. 44% of patients had repetitive abnormalities, 34.9% had comprehensive abnormalities, and 32.1% had expressive abnormalities. The proportion of normal language performance was 60% in grade 2 and 3 gliomas and 16% in grade 4 gliomas. Tumor grade (p = 0.006) and T2 volume (p = 0.008) were associated with abnormal performance in the expressive domain, education level (p = 0.004) and T1 C+ volume (p = 0.049) in the repetitive domain, and education level (p = 0.013), T2 volume (p = 0.011), and tumor grade (p = 0.089) in the comprehensive domain. CONCLUSION: Different clinical and radiological factors affected the abnormal performance of the three language domains, indicating their functional connectivity and neuroplastic potential are inherently varied. The dynamic interactions between patient factors, tumor characteristics, and language processing should be considered when resecting left hemispheric gliomas.

Weak Ultrasound Contributes to Neuromodulatory Effects in the Rat Motor Cortex.

Transcranial focused ultrasound (tFUS) is a novel neuromodulating technique. It has been demonstrated that the neuromodulatory effects can be induced by weak ultrasound exposure levels (spatial-peak temporal average intensity, ISPTA < 10 mW/cm2) in vitro. However, fewer studies have examined the use of weak tFUS to potentially induce long-lasting neuromodulatory responses in vivo. The purpose of this study was to determine the lower-bound threshold of tFUS stimulation for inducing neuromodulation in the motor cortex of rats. A total of 94 Sprague-Dawley rats were used. The sonication region aimed at the motor cortex under weak tFUS exposure (ISPTA of 0.338-12.15 mW/cm2). The neuromodulatory effects of tFUS on the motor cortex were evaluated by the changes in motor-evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS). In addition to histology analysis, the in vitro cell culture was used to confirm the neuromodulatory mechanisms following tFUS stimulation. In the results, the dose-dependent inhibitory effects of tFUS were found, showing increased intensities of tFUS suppressed MEPs and lasted for 30 min. Weak tFUS significantly decreased the expression of excitatory neurons and increased the expression of inhibitory GABAergic neurons. The PIEZO-1 proteins of GABAergic neurons were found to involve in the inhibitory neuromodulation. In conclusion, we show the use of weak ultrasound to induce long-lasting neuromodulatory effects and explore the potential use of weak ultrasound for future clinical neuromodulatory applications.

Prognostic value of an APOBEC3 deletion polymorphism for glioma patients in Taiwan.

OBJECTIVE: The molecular pathogenesis of malignant gliomas, characterized by diverse tumor histology with differential prognosis, remains largely unelucidated. An APOBEC3 deletion polymorphism, with a deletion in APOBEC3B, has been correlated to risk and prognosis in several cancers, but its role in glioma is unclear. The authors aimed to examine the clinical relevance of the APOBEC3 deletion polymorphism to glioma risk and survival in a glioma patient cohort in Taiwan. METHODS: The authors detected deletion genotypes in 403 glioma patients and 1365 healthy individuals in Taiwan and correlated the genotypes with glioma risk, clinicopathological factors, patient survival, and patient sex. APOBEC3 gene family expression was measured and correlated to the germline deletion. A nomogram model was constructed to predict patient survival in glioma. RESULTS: The proportion of APOBEC3B-/- and APOBEC3B+/- genotypes was higher in glioblastoma (GBM) patients than healthy individuals and correlated with higher GBM risk in males. A higher percentage of cases with APOBEC3B- was observed in male than female glioma patients. The presence of APOBEC3B-/- was correlated with better overall survival (OS) in male astrocytic glioma patients. No significant correlation of the genotypes to glioma risk and survival was observed in the female patient cohort. Lower APOBEC3B expression was observed in astrocytic glioma patients with APOBEC3B-/- and was positively correlated with better OS. A 5-factor nomogram model was constructed based on male patients with astrocytic gliomas in the study cohort and worked efficiently for predicting patient OS. CONCLUSIONS: The germline APOBEC3 deletion was associated with increased GBM risk and better OS in astrocytic glioma patients in the Taiwan male population. The APOBEC3B deletion homozygote was a potential independent prognostic factor predicting better survival in male astrocytic glioma patients.

Gross Total Resection Promotes Subsequent Recovery and Further Enhancement of Impaired Natural Killer Cell Activity in Glioblastoma Patients.

Glioblastoma is the most common primary malignant brain tumor, and median survival is relatively short despite aggressive standard treatment. Natural killer (NK) cell dysfunction is strongly associated with tumor recurrence and metastasis but is unclear in glioblastoma. NK activity (NKA) represents NK cell-secreted interferon-γ (IFN-γ), which modulates immunity and inhibits cancer progression. This study aimed to analyze NKA in glioblastoma patients to obtain a clearer overview of immunity surveillance. From 2020 to 2021, a total of 20 patients and six healthy controls were recruited. Peripheral blood samples were collected preoperatively and on postoperative days (POD) 3 and 30. Then, NKA was measured using the NK VUE kit. Although NKA decreased on POD3, it recovered and further significantly enhanced on POD30, with a nearly five-fold increase compared to baseline (p = 0.004). Furthermore, the percentage of CD56brightCD16- NK cells decreased significantly on POD3 (p = 0.022) and further recovered on PO30. Subgroup analysis of extent surgical resection further revealed that the recovery of impaired NKA was attributable to gross total resection (GTR) rather than subtotal resection (STR). In conclusion, NKA is significantly impaired in glioblastoma, and GTR has demonstrated superior benefit in improving the suppressed NKA and increased CD56brightCD16- NK subset in glioblastoma patients, which may be associated with subsequent patients' prognosis. Therefore, the goal of performing GTR for glioblastoma should be achieved when possible since it appears to increase NKA cell immunity.

The Prognostic Impacts of Body Mass Index and Distance to the Peritoneal Bottom on Laparoscopic Ventriculoperitoneal Shunt Placement.

OBJECTIVE: Laparoscopic ventriculoperitoneal shunt surgery has been reported to have several advantages in selected patients. However, the prognostic factors have been understudied specifically for this surgery. We sought to investigate the factors influencing the complications after the laparoscopic ventriculoperitoneal shunt placement. METHODS: All surgeries in this prospective study were performed by the same team of neurosurgeons and general surgeons. Clinical parameters as well as potential risk factors for postoperative complications were analyzed. The endpoint was overall complications requiring surgical revision within the follow-up period after surgery. RESULTS: Ninety-nine patients (51 male and 48 female) scheduled for laparoscopic-assisted ventriculoperitoneal shunt surgery between 2019 and 2021 were included. Overall shunt complication rate was 9% (9 of 99 cases), and there was 1 patient (1%) who had distal dysfunction among them. Body mass index ≥27 kg/m2 (hazard ratio 4.87; 95% confidence interval 1.05-22.57; P = 0.043), and nonprogrammable shunts (hazard ratio 7.91; 95% confidence interval 1.51-41.50; P = 0.014) were significantly associated with an increased risk of complications. Among 75 patients who received programmable shunts, the vertical distance from the distal tip to the presumed bottom of peritoneal cavity was significant positively associated with the number of pressure adjustments (R2 0.511, adjusted R2 0.504, and P < 0.001). CONCLUSIONS: Ventriculoperitoneal shunt surgery provided benefits with little complication rate, whereas patients treated with nonprogrammable shunts and obese patients had less favorable outcome. A positive correlation between the vertical distance from the distal tip to the bottom of peritoneal cavity and pressure adjustments inferred to the advantage of the laparoscopic method.

Individual cerebrocerebellar functional network analysis decoding symptomatologic dynamics of postoperative cerebellar mutism syndrome.

Introduction: Postoperative cerebellar mutism syndrome (pCMS) consists of three types of symptoms (motoric, linguistic, and neurobehavioral) in patients with posterior fossa pathologies. The evolutional mechanism of this high cognitive syndromic complex from cerebellar origin remains unconfirmed. Previous studies analyzing CMS patients mostly focused on the association between structural abnormalities that occur during CMS, of which proximal efferent cerebellar pathway (pECP) injury appears to be the most common pathogenesis. However, structural imaging may not be sensitive enough to determine the dynamic course of CMS, since the symptomatology is primarily an output of cerebral operation. Method: We took a network approach in a child during her course of development and recovery of the pCMS. On the other hand, a network neuroscience approach using a mathematical model to extract information from functional imaging to generate interregional connectivity provides abundant evidence that the cerebellum is influential in modulating cerebral functions. Result: This study applied a network approach to children with pCMS. An individual cerebrocerebellar functional network analysis using graph theory was then performed to determine the network dynamics during CMS. Cross-validation of clinical neurophysiology and functional neuroscience suggested the critical role of the pECP within CMS from the network analysis. Conclusion: The employed approach was therefore useful in determining the complex clinical symptoms using individual functional network analysis, which bridges the gap between structural neuroimaging and clinical neurophysiology.

Receptor-Interacting Protein 140 Enhanced Temozolomide-Induced Cellular Apoptosis Through Regulation of E2F1 in Human Glioma Cell Lines.

Glioblastoma (GBM), a grade IV glioma, is responsible for the highest years of potential life lost among cancers. The poor prognosis is attributable to its high recurrence rate, caused in part by the development of resistance to chemotherapy. Receptor-interacting protein 140 (RIP140) is a very versatile coregulator of nuclear receptors and transcription factors. Although many of the pathways regulated by RIP140 contribute significantly to cancer progression, the function of RIP140 in GBM remains to be determined. In this study, we found that higher RIP140 expression was associated with prolonged survival in patients with newly diagnosed GBM. Intracellular RIP140 levels were increased after E2F1 activation following temozolomide (TMZ) treatment, which in turn modulated the expression of E2F1-targeted apoptosis-related genes. Overexpression of RIP140 reduced glioma cell proliferation and migration, induced cellular apoptosis, and sensitized GBM cells to TMZ. Conversely, knockdown of RIP140 increased TMZ resistance. Taken together, our results suggest that RIP140 prolongs the survival of patients with GBM both by inhibiting tumor cell proliferation and migration and by increasing cellular sensitivity to chemotherapy. This study helps improve our understanding of glioma recurrence and may facilitate the development of more effective treatments.

Safety and tolerability of asunercept plus standard radiotherapy/temozolomide in Asian patients with newly-diagnosed glioblastoma: a phase I study.

Asunercept (company code APG101 [Apogenix AG]; company code CAN008 [CANbridge Pharmaceuticals]) is a novel glycosylated fusion protein that has shown promising effectiveness in glioblastoma. This Phase I study was initiated to evaluate the tolerability and safety of asunercept in combination with standard radiotherapy and temozolomide (RT/TMZ) in Asian patients with newly diagnosed glioblastoma. This was the Phase I portion of a Phase I/II open label, multicenter trial of asunercept plus standard RT/TMZ. Adults with newly-diagnosed glioblastoma received surgical resection followed by standard RT/TMZ plus asunercept 200 mg/week (Cohort 1) or 400 mg/week (Cohort 2) by 30-min IV infusion. The primary endpoint was the safety and tolerability of asunercept during concurrent asunercept and RT/TMZ; dose-limiting toxicities were observed for each dose. Secondary endpoints included pharmacokinetics (PK) and 6-month progression-free survival (PFS6). All patients (Cohort 1, n = 3; Cohort 2, n = 7) completed ≥ 7 weeks of asunercept treatment. No DLTs were experienced. Only one possibly treatment-related treatment emergent adverse event (TEAE), Grade 1 gingival swelling, was observed. No Grade > 3 TEAEs were reported and no TEAE led to treatment discontinuation. Systemic asunercept exposure increased proportionally with dose and showed low inter-patient variability. The PFS6 rate was 33.3% and 57.1% for patients in Cohort 1 and 2, respectively. Patients in Cohort 2 maintained a PFS rate of 57.1% at Month 12. Adding asunercept to standard RT/TMZ was safe and well tolerated in patients with newly-diagnosed glioblastoma and 400 mg/week resulted in encouraging efficacy.Trial registration NCT02853565, August 3, 2016.