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.

Oxygen-loaded microbubble-mediated sonoperfusion and oxygenation for neuroprotection after ischemic stroke reperfusion.

BACKGROUND: Ischemic stroke-reperfusion (S/R) injury is a crucial issue in the protection of brain function after thrombolysis. The vasodilation induced by ultrasound (US)-stimulated microbubble cavitation has been applied to reduce S/R injury through sonoperfusion. The present study uses oxygen-loaded microbubbles (OMBs) with US stimulation to provide sonoperfusion and local oxygen therapy for the reduction of brain infarct size and neuroprotection after S/R. METHODS: The murine S/R model was established by photodynamic thrombosis and thrombolysis at the remote branch of the anterior cerebral artery. In vivo blood flow, partial oxygen pressure (pO2), and brain infarct staining were examined to analyze the validity of the animal model and OMB treatment results. The animal behaviors and measurement of the brain infarct area were used to evaluate long-term recovery of brain function. RESULTS: The percentage of blood flow was 45 ± 3%, 70 ± 3%, and 86 ± 2% after 60 min stroke, 20 min reperfusion, and 10 min OMB treatment, respectively, demonstrating sonoperfusion, and the corresponding pO2 level was 60 ± 1%, 76 ± 2%, and 79 ± 4%, showing reoxygenation. After 14 days of treatment, a 87 ± 3% reduction in brain infarction and recovery of limb coordination were observed in S/R mice. The expression of NF-κB, HIF-1α, IL-1ß, and MMP-9 was inhibited and that of eNOS, BDNF, Bcl2, and IL-10 was enhanced, indicating activation of anti-inflammatory and anti-apoptosis responses and neuroprotection. Our study demonstrated that OMB treatment combines the beneficial effects of sonoperfusion and local oxygen therapy to reduce brain infarction and activate neuroprotection to prevent S/R injury.

Selective Activation of Cells by Piezoelectric Molybdenum Disulfide Nanosheets with Focused Ultrasound.

An accurate method for neural stimulation within the brain could be very useful for treating brain circuit dysfunctions and neurological disorders. With the aim of developing such a method, this study investigated the use of piezoelectric molybdenum disulfide nanosheets (MoS2 NS) to remotely convert ultrasound energy into localized electrical stimulation in vitro and in vivo. The application of ultrasound to cells surrounding MoS2 NS required only a single pulse of 2 MHz ultrasound (400 kPa, 1,000,000 cycles, and 500 ms pulse duration) to elicit significant responses in 37.9 ± 7.4% of cells in terms of fluxes of calcium ions without detectable cellular damage. The proportion of responsive cells was mainly influenced by the acoustic pressure, number of ultrasound cycles, and concentration of MoS2 NS. Tests using appropriate blockers revealed that voltage-gated membrane channels were activated. In vivo data suggested that, with ultrasound stimulation, neurons closest to the MoS2 NS were 3-fold more likely to present c-Fos expression than cells far from the NS. The successful activation of neurons surrounding MoS2 NS suggests that this represents a method with high spatial precision for selectively modulating one or several targeted brain circuits.

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.

Safety evaluation of frequent application of microbubble-enhanced focused ultrasound blood-brain-barrier opening.

Focused ultrasound (FUS) with the presence of microbubbles induces blood brain barrier (BBB) opening in targeted areas and facilitates drug delivery. However, recent studies have indicated that FUS-BBB opening with excessive exposure levels may be associated with inflammatory response and cellular/tissue damage. Multiple weekly FUS exposures have been shown to be safe for human subjects. However the effect of more frequent FUS exposures is still unknown. This study examines whether frequent focused ultrasound blood brain barrier opening is associated with aggravated behavioral, histopathologic change or brain tissue damage. Two protocols of focused ultrasound blood brain barrier opening were devised using different microbubble doses (0.15 µl/kg and 0.4 µl/kg). Focused ultrasound exposure at a threshold level of BBB-opening, below-threshold level, or above level for intracerebral hemorrhage were delivered every 2 days. Animal behavioral and physiological changes were examined and recorded. Brain tissue was examined for hemorrhage and apoptosis. Results indicate that frequent exposure of excessive focused ultrasound (1.4 mechanical index) produced minor and short-term behavioral changes despite significant tissue damage, while frequent BBB opening with threshold or below-threshold FUS exposure (0.33-0.8 mechanical index) did not cause behavioral or histological change. Immunofluorescent examination of rat brain tissue indicated that excessive doses of microbubble administration induce an apparent cellular apoptotic response, which may be exacerbated by intracerebral hemorrhage. Experimental results suggest that frequent focused ultrasound blood brain barrier opening with sufficient ultrasound exposure level and a microbubble dose can be safe and pose minimal risk to brain tissue.

Receptor-interacting protein 140 as a co-repressor of Heat Shock Factor 1 regulates neuronal stress response.

Heat shock response (HSR) is a highly conserved transcriptional program that protects organisms against various stressful conditions. However, the molecular mechanisms modulating HSR, especially the suppression of HSR, is poorly understood. Here, we found that RIP140, a wide-spectrum cofactor of nuclear hormone receptors, acts as a co-repressor of heat shock factor 1 (HSF1) to suppress HSR in healthy neurons. When neurons are stressed such as by heat shock or sodium arsenite (As), cells engage specific proteosome-mediated degradation to reduce RIP140 level, thereby relieving the suppression and activating HSR. RIP140 degradation requires specific Tyr-phosphorylation by Syk that is activated in stressful conditions. Lowering RIP140 level protects hippocampal neurons from As stress, significantly it increases neuron survival and improves spine density. Reducing hippocampal RIP140 in the mouse rescues chronic As-induced spatial learning deficits. This is the first study elucidating RIP140-mediated suppression of HSF1-activated HSR in neurons and brain. Importantly, degradation of RIP140 in stressed neurons relieves this suppression, allowing neurons to efficiently and timely engage HSR programs and recover. Therefore, stimulating RIP140 degradation to activate anti-stress program provides a potential preventive or therapeutic strategy for neurodegeneration diseases.

Sterols from the Octocoral Nephthea columnaris.

Two new sterols, columnaristerols B (1) and C (2), along with two known analogues, 5,6-epoxylitosterol (3) and litosterol (4), were obtained from the octocoral Nephthea columnaris. The structures of new sterols 1 and 2 were elucidated by using spectroscopic methods and comparing the spectroscopic data with those of known related metabolites. Sterol 3 was found to suppress superoxide anion production and elastase secretion by human neutrophils.

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.