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.

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.

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.

Valproic Acid Enhanced Temozolomide-Induced Anticancer Activity in Human Glioma Through the p53-PUMA Apoptosis Pathway.

Glioblastoma (GBM), the most lethal type of brain tumor in adults, has considerable cellular heterogeneity. The standard adjuvant chemotherapeutic agent for GBM, temozolomide (TMZ), has a modest response rate due to the development of drug resistance. Multiple studies have shown that valproic acid (VPA) can enhance GBM tumor control and prolong survival when given in conjunction with TMZ. However, the beneficial effect is variable. In this study, we analyzed the impact of VPA on GBM patient survival and its possible correlation with TMZ treatment and p53 gene mutation. In addition, the molecular mechanisms of TMZ in combination with VPA were examined using both p53 wild-type and p53 mutant human GBM cell lines. Our analysis of clinical data indicates that the survival benefit of a combined TMZ and VPA treatment in GBM patients is dependent on their p53 gene status. In cellular experiments, our results show that VPA enhanced the antineoplastic effect of TMZ by enhancing p53 activation and promoting the expression of its downstream pro-apoptotic protein, PUMA. Our study indicates that GBM patients with wild-type p53 may benefit from a combined TMZ+VPA treatment.

Cigarette Smoke Containing Acrolein Upregulates EGFR Signaling Contributing to Oral Tumorigenesis In Vitro and In Vivo.

Oral squamous cell carcinoma (OSCC) accounts for 80-90% of all intraoral malignant neoplasms. The single greatest risk factor for oral cancer is tobacco use, including cigarettes, cigars, chewing tobacco, and snuff. Aberrations of the epidermal growth factor receptor (EGFR) pathway features prominently in oral tumorigenesis and progression. It was shown that cigarette smoking (CS) is associated with worse prognosis in OSCC patients and overexpression of EGFR in tumor tissue. However, the mechanism by which cigarette smoking induced EGFR pathway activation remains to be fully elucidated. Acrolein, an IARC group 2A carcinogen, is a highly reactive aldehyde found in CS. Here we report that acrolein is capable of inducing tumorigenic transformation in normal human oral keratinocytes (NOK). The acrolein-transformed NOK cells showed EGFR copy number amplification, increased EGFR expression, and activation of downstream ERK and AKT signaling pathway. No p53 mutations were observed in acrolein-transformed NOK cells. Inhibiting EGFR pathway using an anti-EGFR antibody, cetuximab, inhibits tumor growth. Furthermore, by examining tissue sample from patients, we found an increased EGFR copy number was positively associated with acrolein-induced DNA damages in OSCC patients. Taken together, our results indicate that acrolein is important in tumorigenic transformation through amplification of EGFR and activating the downstream signaling pathway, contributing to oral carcinogenesis. This is the first study to provide molecular evidence showing that CS containing acrolein contributes to EGFR amplification in OSCC.

Acrolein contributes to human colorectal tumorigenesis through the activation of RAS-MAPK pathway.

Colorectal cancer (CRC) is one of the most well-known malignancies with high prevalence and poor 5-year survival. Previous studies have demonstrated that a high-fat diet (HFD) is capable of increasing the odds of developing CRC. Acrolein, an IARC group 2A carcinogen, can be formed from carbohydrates, vegetable oils, animal fats, and amino acids through the Maillard reaction during the preparation of foods. Consequently, humans are at risk of acrolein exposure through the consumption of foods rich in fat. However, whether acrolein contributes to HFD-induced CRC has not been determined. In this study, we found that acrolein induced oncogenic transformation, including faster cell cycling, proliferation, soft agar formation, sphere formation and cell migration, in NIH/3T3 cells. Using xenograft tumorigenicity assays, the acrolein-transformed NIH/3T3 clone formed tumors. In addition, cDNA microarray and bioinformatics studies by Ingenuity Pathway Analysis pointed to the fact that RAS/MAPK pathway was activated in acrolein-transformed clones that contributed to colon tumorigenesis. Furthermore, acrolein-induced DNA damages (Acr-dG adducts) were higher in CRC tumor tissues than in normal epithelial cells in CRC patients. Notably, CRC patients with higher levels of Acr-dG adducts appeared to have better prognosis. The results of this study demonstrate for the first time that acrolein is important in oncogenic transformation through activation of the RAS/MAPK signaling pathway, contributing to colon tumorigenesis.

Neuronavigation-guided focused ultrasound for transcranial blood-brain barrier opening and immunostimulation in brain tumors.

Focused ultrasound (FUS) in the presence of microbubbles can transiently open the blood-brain barrier (BBB) to increase therapeutic agent penetration at the targeted brain site to benefit recurrent glioblastoma (rGBM) treatment. This study is a dose-escalating pilot trial using a device combining neuronavigation and a manually operated frameless FUS system to treat rGBM patients. The safety and feasibility were established, while a dose-dependent BBB-opening effect was observed, which reverted to baseline within 24 hours after treatment. No immunological response was observed clinically under the applied FUS level in humans; however, selecting a higher level in animals resulted in prolonged immunostimulation, as confirmed preclinically by the recruitment of lymphocytes into the tumor microenvironment (TME) in a rat glioma model. Our findings provide preliminary evidence of FUS-induced immune modulation as an additional therapeutic benefit by converting the immunosuppressive TME into an immunostimulatory TME via a higher but safe FUS dosage.

Acrolein is involved in ischemic stroke-induced neurotoxicity through spermidine/spermine-N1-acetyltransferase activation.

BACKGROUND AND PURPOSE: Ischemic stroke is the most common type of cerebrovascular event and is responsible for approximately 85% of all strokes in Taiwan. Neurons contain high concentrations of polyamines, which are prone to various pathological states in the brain and are perturbed after cerebral ischemia. Acrolein, an α,ß-unsaturated aldehyde, has been suggested as the primary culprit of neuronal damage in stroke patients. However, the mechanism by which acrolein induces neuronal damage during ischemic stroke is not clear. METHODS: Urinary 3-hydroxypropyl mercapturic acid (3-HPMA), an acrolein-glutathione (GSH) metabolite, plasma acrolein-protein conjugates (Acr-PC) and plasma GSH levels were analyzed to correlate disease severity and prognosis of stroke patients compared with control subjects. In vivo middle cerebral artery occlusion (MCAO) animal models and an in vitro oxygen glucose deprivation (OGD) stroke model were used to investigate the mechanisms of acrolein-induced neuronal damage. RESULTS: A deregulated acrolein metabolism, including significantly increased plasma Acr-PC levels, decreased urinary 3-HPMA levels and decreased plasma GSH levels, was found in stroke patients compared to control subjects. We further observed that acrolein was produced during ischemia resulting in brain damage in in vivo MCAO animal model. The induction of acrolein in neuronal cells during OGD occurred due to the increased expression of spermidine/spermine N1-acetyltransferase (SSAT) by NF-kB pathway activation. In addition, acrolein elicited a vicious cycling of oxidative stress resulting in neurotoxicity. Finally, N-acetylcysteine effectively prevented OGD-induced neurotoxicity by scavenging acrolein. CONCLUSION: Overall, our current results demonstrate that acrolein is a culprit of neuronal damage through GSH depletion in stroke patients. The mechanism underlying the role of acrolein in stroke-related neuronal damage occurs through SSAT-induced polyamine oxidation by NF-kB pathway activation. These results provide a novel mechanism of neurotoxicity in stroke patients, aid in the development of neutralizing or preventive measures, and further our understanding of neural protection.

The Outcome Predictors of Malignant Large Infarction and the Functional Outcome of Survivors Following Decompressive Craniectomy.

OBJECTIVE: Cerebral infarction is a common cause of disability. Malignant large infarction (MLI) is a catastrophic event, and there is no effective medical treatment. This study aimed to assess the outcome predictors of MLI and to analyze the impact of decompressive craniectomy (DC) on the functional outcome of survivors. METHODS: This study comprised 213 MLI cases. Outcome was evaluated with modified Rankin Scale (mRS) at 1-year follow-up, and various parameters were tested for MLI outcome predictors. The impact of DC on functional outcome was examined after being further stratified into good survival (mRS score = 0, 1, 2, 3), poor survival (mRS score = 4, 5), and mortality (mRS score = 6) groups. RESULTS: Standard medical treatment only was used in 106 cases, and both medical treatment and DC were used in 107 cases. With multiple logistic regression analysis, age, motor response at deterioration/operation, and DC were identified as independent outcome predictors of MLI (P = 0.027, P < 0.001, P < 0.001). Compared with the sole standard medical treatment, additional DC resulted in a better outcome (odds ratio [OR] =19.95; 95% confidence interval [CI], 7.61-52.27; P < 0.001). Further analysis of functional outcome revealed that DC significantly increased the chance of good survival as opposed to poor survival (OR = 20.04; 95% CI, 6.05-66.32; P < 0.001) and death (OR = 43.72; 95% CI, 13.21-144.72; P < 0.001). CONCLUSIONS: In this study, DC performed on a young patient with motor response of localizing pain or better was linked with a better outcome. DC not only reduced mortality and increased the number of good survivals but also, most importantly, decreased the number of poor functional outcome survivals.

A closer examination of the interaction among risk factors for low back pain.

PURPOSE: To evaluate the interactions of risk factors and identify their most powerful discrimination pathway for the occurrence of low back pain (LBP). DESIGN: A cross-sectional study. SETTING: Taiwan. SUBJECTS: Taiwanese population of 30 to 64 years old. MEASURES: A self-reported question, "Have you experienced LBP within the last 3 months?" was used to evaluate LBP. The study variables included demographics (age, gender, occupation, education level, marital status, and household income), biometric health measures (bone mineral density and body mass index), dietary habits (weekly milk, coffee, tea, and soybean consumption), and other lifestyle factors (smoking habits, alcohol consumption, betel nut chewing, body weight control, exercise regularity, and stress management). ANALYSIS: Logistic regression and classification tree analyses. RESULTS: A total of 969 Taiwanese participants were analyzed. Primary logistic regression analysis identified three critical risk factors (gender, bone mineral density, and exercise regularity) for the occurrence of LBP. By classification tree analysis, demographic factors, dietary habits, and lifestyle factors had modifying effects on LBP. CONCLUSIONS: Various factors contribute to the risk of LBP. Interactions between risk factors should be considered when developing future strategies for the prevention and management of LBP.

Factors associated with poor outcome in patients with major intraoperative rupture of intracranial aneurysm.

PURPOSE: This clinical study was conducted to evaluate factors affecting outcome in the cases following major intraoperative rupture (MIOR) of the intracranial aneurysms. METHODS: Thirty cases with MIOR in a series of 467 surgeries for ruptured aneurysms were enrolled in this study. Clinical parameters, including: age, Hunt-Hess grading, Fisher grading, aneurysm size, aneurysm contour, operative timing, aneurysm location, and rupture timing were studied and compared with the prognosis in this particular cohort. The outcome was evaluated using the Glasgow Outcome Scale at least 3 months after surgery. Severe disability, vegetative survival, and death were classified as poor outcome. RESULTS: Among the 30 cases with MIOR, 11 resulted in poor outcomes (36.7%). Age was an important prognostic factor in this cohort. Those patients with poor outcome after MIOR were significantly older than those with good outcome (mean age: 64.6 vs 51.4 years, P=0.006). In this study, a trend toward poor outcome was observed in cases with MIOR on internal carotid artery aneurysms (8/14, 57.1% vs 2/9, 22.2% and 1/6, 16.7% on middle cerebral artery and anterior communicating artery aneurysms, P=0.197, after adjustment for age factor). There was a higher incidence of a poor outcome when MIOR occurred during clip application (5/6, 83.3% vs 1/5, 20.0% and 5/19, 26.3% when MIOR happened during brain retraction and aneurysm dissection, P=0.041 after adjustment with the factor of age). CONCLUSION: Although a larger sample population is required for a more conclusive result, MIOR occuring in older age, during clip application, or on an internal carotid artery aneurysm possibly has the trend to bear a worse outcome in the cohort of patients with MIOR during aneurysm surgery.

MicroRNA-495 inhibits proliferation of glioblastoma multiforme cells by downregulating cyclin-dependent kinase 6.

BACKGROUND: Glioblastoma multiforme (GBM) is the most aggressive type of glioma and carries the poorest chances of survival. There is therefore an urgent need to understand the mechanisms of glioma tumorigenesis and develop or improve therapeutics. The aim of this study was to assess the possible prognostic value of cyclin-dependent kinase 6 (CDK6) and the effects of microRNA-495 (miR-495) manipulation on CDK6 expression and cell survival in glioma cells. METHODS: Analyses of clinical specimens from GBM patients were used. Expression of CDK6 was analyzed by real-time polymerase chain reaction (RT-PCR), Western blotting, and immunohistochemistry. Expression of CDK6 was also analyzed after over-expression of miR-495 in T98 cells; both cell proliferation and RB phosphorylation were examined. Cell proliferation, cell cycle distribution, and RB phosphorylation were also examined after knockdown of CDK6 in U87-MG and T98 cells. RESULTS: Analyses of clinical specimens from GBM patients identified that CDK6 is significantly expressed in gliomas. CDK6 antigen expression was higher in tumor cores and margins than in adjacent normal brain tissues, and higher levels of CDK6 expression in the tumor margin correlated with decreased survival. Over-expression of miR-495 in T98 cells downregulated the expression of CDK6 and inhibited retinoblastoma phosphorylation, and knockdown of CDK6 in U87-MG and T98 cells by siRNAs resulted in cell cycle arrest at the G1/S transition and inhibition of cell proliferation. CONCLUSIONS: This study revealed miR-495 is down-regulated in glioma tissues. Furthermore, miR-495 regulated CDK6 expression and involved in glioma cell growth inhibition, which indicated the possible role of miR-495 in tumor progression.

Focused ultrasound-induced blood-brain barrier opening to enhance temozolomide delivery for glioblastoma treatment: a preclinical study.

The purpose of this study is to assess the preclinical therapeutic efficacy of magnetic resonance imaging (MRI)-monitored focused ultrasound (FUS)-induced blood-brain barrier (BBB) disruption to enhance Temozolomide (TMZ) delivery for improving Glioblastoma Multiforme (GBM) treatment. MRI-monitored FUS with microbubbles was used to transcranially disrupt the BBB in brains of Fisher rats implanted with 9L glioma cells. FUS-BBB opening was spectrophotometrically determined by leakage of dyes into the brain, and TMZ was quantitated in cerebrospinal fluid (CSF) and plasma by LC-MS\MS. The effects of treatment on tumor progression (by MRI), animal survival and brain tissue histology were investigated. Results demonstrated that FUS-BBB opening increased the local accumulation of dyes in brain parenchyma by 3.8-/2.1-fold in normal/tumor tissues. Compared to TMZ alone, combined FUS treatment increased the TMZ CSF/plasma ratio from 22.7% to 38.6%, reduced the 7-day tumor progression ratio from 24.03 to 5.06, and extended the median survival from 20 to 23 days. In conclusion, this study provided preclinical evidence that FUS BBB-opening increased the local concentration of TMZ to improve the control of tumor progression and animal survival, suggesting its clinical potential for improving current brain tumor treatment.

The impact of traumatic subarachnoid hemorrhage on outcome: a study with grouping of traumatic subarachnoid hemorrhage and transcranial Doppler sonography.

BACKGROUND: To clarify the clinical role of traumatic subarachnoid hemorrhage (tSAH), stratified analysis with grouping of tSAH was performed. Their blood flow changes and correlations with outcome were assayed. METHODS: One hundred seventeen tSAH patients were classified into several groups according to their initial computerized tomography scans. Group I included patients with tSAH only in the posterior interhemispheric fissure, whereas Group II contained patients with tSAH located elsewhere. Group II was further subdivided into IIa, little SAH; IIb, extensive SAH; IIc, little SAH with intraventricular hemorrhage (IVH); and IId, extensive SAH with IVH. The cerebral blood flow velocity was monitored using transcranial Doppler sonography (TCD). RESULTS: Both age and initial coma scale were independent predictors of poor outcome. The poor outcome rates in various subgroups of tSAH increased stepwise from group I to group IId (I, 7.4%; IIa, 18.4%; IIb, 33.3%; IIc, 62.5%; and IId, 90.9%) (p = 0.0010). Stratified analyses revealed that patients with extensive tSAH (group IIb + IId) were more likely to have unfavorable outcomes (47.7%) than patients with little tSAH (group IIa + IIc) (26.1%) (p = 0.0185); patients with IVH (group IIc + IId) also displayed a higher incidence (78.9%) of poor outcomes than patients without IVH (group IIa + IIb) (25.4%) (p = 0.0030). TCD study demonstrated that patients with extensive tSAH (group IIb + IId) were more likely to have the vasospasm based on TCD criteria than did patients in group I and group IIa + IIc (37.5% vs. 5.9% and 7.7%, p = 0.0105). Notably, there was a tendency of worse outcome in patients with vasospasm on the basis of TCD-derived criteria than those without, with the unfavorable outcome rates being 47.4% and 24.7% (p = 0.0799). CONCLUSIONS: Age, initial coma scale, extensive tSAH, and IVH are independent predictors of poor outcome in the cohort of tSAH patients. Statistically, patients with extensive tSAH are significantly more likely to have vasospasm.