Repeat resection for recurrent glioblastoma in the temozolomide era: a real-world multi-centre study.

INTRODUCTION: In contrast to standard-of-care treatment of newly diagnosed glioblastoma, there is limited consensus on therapy upon disease progression. The role of resection for recurrent glioblastoma remains unclear. This study aimed to identify factors for overall survival (OS) and post-progression survival (PPS) as well as to validate an existing prediction model. METHODS: This was a multi-centre retrospective study that reviewed consecutive adult patients from 2006 to 2019 that received a repeat resection for recurrent glioblastoma. The primary endpoint was PPS defined as from the date of second surgery until death. RESULTS: 1032 glioblastoma patients were identified and 190 (18%) underwent resection for recurrence. Patients that had second surgery were more likely to be younger (<70 years) (adjusted OR: 0.3; 95% CI: 0.1-0.6), to have non-eloquent region tumours (aOR: 1.7; 95% CI: 1.1-2.6) and received temozolomide chemoradiotherapy (aOR: 0.2; 95% CI: 0.1-0.4). Resection for recurrent tumour was an independent predictor for OS (aOR: 1.5; 95% CI: 1.3-1.7) (mOS: 16.9 months versus 9.8 months). For patients that previously received temozolomide chemoradiotherapy and subsequent repeat resection (137, 13%), the median PPS was 9.0 months (IQR: 5.0-17.5). Independent PPS predictors for this group were a recurrent tumour volume of >50cc (aOR: 0.6; 95% CI: 0.4-0.9), local recurrence (aOR: 1.7; 95% CI: 1.1-3.3) and 5-ALA fluorescence-guided resection during second surgery (aOR: 1.7; 95% CI: 1.1-2.8). A National Institutes of Health Recurrent Glioblastoma Multiforme Scale score of 0 conferred an mPPS of 10.0 months, a score of 1-2, 9.0 months and a score of 3, 4.0 months (log-rank test, p-value < 0.05). CONCLUSION: Surgery for recurrent glioblastoma can be beneficial in selected patients and carries an acceptable morbidity rate. The pattern of recurrence influenced PPS and the NIH Recurrent GBM Scale was a reliable prognostication tool.

Home-based self-help telerehabilitation of the upper limb assisted by an electromyography-driven wrist/hand exoneuromusculoskeleton after stroke.

BACKGROUND: Most stroke survivors have sustained upper limb impairment in their distal joints. An electromyography (EMG)-driven wrist/hand exoneuromusculoskeleton (WH-ENMS) was developed previously. The present study investigated the feasibility of a home-based self-help telerehabilitation program assisted by the aforementioned EMG-driven WH-ENMS and its rehabilitation effects after stroke. METHODS: Persons with chronic stroke (n = 11) were recruited in a single-group trial. The training progress, including the training frequency and duration, was telemonitored. The clinical outcomes were evaluated using the Fugl-Meyer Assessment (FMA), Action Research Arm Test (ARAT), Wolf Motor Function Test (WMFT), Motor Functional Independence Measure (FIM), and Modified Ashworth Scale (MAS). Improvement in muscle coordination was investigated in terms of the EMG activation level and the Co-contraction Index (CI) of the target muscles, including the abductor pollicis brevis (APB), flexor carpi radialis-flexor digitorum (FCR-FD), extensor carpi ulnaris-extensor digitorum (ECU-ED), biceps brachii (BIC), and triceps brachii (TRI). The movement smoothness and compensatory trunk movement were evaluated in terms of the following two kinematic parameters: number of movement units (NMUs) and maximal trunk displacement (MTD). The above evaluations were conducted before and after the training. RESULTS: All of the participants completed the home-based program with an intensity of 63.0 ± 1.90 (mean ± SD) min/session and 3.73 ± 0.75 (mean ± SD) sessions/week. After the training, motor improvements in the entire upper limb were found, as indicated by the significant improvements (P < 0.05) in the FMA, ARAT, WMFT, and MAS; significant decreases (P < 0.05) in the EMG activation levels of the APB and FCR-FD; significant decreases (P < 0.05) in the CI of the ECU-ED/FCR-FD, ECU-ED/BIC, FCR-FD/APB, FCR-FD/BIC, FCR-FD/TRI, APB/BIC and BIC/TRI muscle pairs; and significant reductions (P < 0.05) in the NMUs and MTD. CONCLUSIONS: The results suggested that the home-based self-help telerehabilitation program assisted by EMG-driven WH-ENMS is feasible and effective for improving the motor function of the paretic upper limb after stroke. Trial registration ClinicalTrials.gov. NCT03752775; Date of registration: November 20, 2018.

Radiotherapy-induced glioblastoma: distinct differences in overall survival, tumor location, pMGMT methylation and primary tumor epidemiology in Hong Kong chinese patients.

INTRODUCTION: Radiotherapy-induced glioblastomas (RIGB) are a well-known late and rare complication of brain irradiation. Yet the clinical, radiological and molecular characteristics of these tumors are not well characterized. METHODS: This was a retrospective multicentre study that analysed adult patients with newly diagnosed glioblastoma over a 10-year period. Patients with RIGB were identified according to Cahan's criteria for radiation-induced tumors. A case-control analysis was performed to compare known prognostic factors for overall survival (OS) with an independent cohort of IDH-1 wildtype de novo glioblastomas treated with standard temozolomide chemoradiotherapy. Survival analysis was performed by Cox proportional hazards regression. RESULTS: A total of 590 adult patients were diagnosed with glioblastoma. 19 patients (3%) had RIGB. The mean age of patients upon diagnosis was 48 years ± 15. The mean latency duration from radiotherapy to RIGB was 14 years ± 8. The mean total dose was 58Gy ± 10. One-third of patients (37%, 7/19) had nasopharyngeal cancer and a fifth (21%, 4/19) had primary intracranial germinoma. Compared to a cohort of 146 de novo glioblastoma patients, RIGB patients had a shorter median OS of 4.8 months versus 19.2 months (p-value: <.001). Over a third of RIGBs involved the cerebellum (37%, 7/19) and was higher than the control group (4%, 6/146; p-value: <.001). A fifth of RIGBs (21%, 3/19) were pMGMT methylated which was significantly fewer than the control group (49%, 71/146; p-value: .01). For RIGB patients (32%, 6/19) treated with re-irradiation, the one-year survival rate was 67% and only 8% for those without such treatment (p-value: .007). CONCLUSION: The propensity for RIGBs to develop in the cerebellum and to be pMGMT unmethylated may contribute to their poorer prognosis. When possible re-irradiation may offer a survival benefit. Nasopharyngeal cancer and germinomas accounted for the majority of original malignancies reflecting their prevalence among Southern Chinese.

Forward and reverse mutations in stages of cancer development.

BACKGROUND: Massive occurrences of interstitial loss of heterozygosity (LOH) likely resulting from gene conversions were found by us in different cancers as a type of single-nucleotide variations (SNVs), comparable in abundance to the commonly investigated gain of heterozygosity (GOH) type of SNVs, raising the question of the relationships between these two opposing types of cancer mutations. METHODS: In the present study, SNVs in 12 tetra sample and 17 trio sample sets from four cancer types along with copy number variations (CNVs) were analyzed by AluScan sequencing, comparing tumor with white blood cells as well as tissues vicinal to the tumor. Four published "nontumor"-tumor metastasis trios and 246 pan-cancer pairs analyzed by whole-genome sequencing (WGS) and 67 trios by whole-exome sequencing (WES) were also examined. RESULTS: Widespread GOHs enriched with CG-to-TG changes and associated with nearby CNVs and LOHs enriched with TG-to-CG changes were observed. Occurrences of GOH were 1.9-fold higher than LOH in "nontumor" tissues more than 2 cm away from the tumors, and a majority of these GOHs and LOHs were reversed in "paratumor" tissues within 2 cm of the tumors, forming forward-reverse mutation cycles where the revertant LOHs displayed strong lineage effects that pointed to a sequential instead of parallel development from "nontumor" to "paratumor" and onto tumor cells, which was also supported by the relative frequencies of 26 distinct classes of CNVs between these three types of cell populations. CONCLUSIONS: These findings suggest that developing cancer cells undergo sequential changes that enable the "nontumor" cells to acquire a wide range of forward mutations including ones that are essential for oncogenicity, followed by revertant mutations in the "paratumor" cells to avoid growth retardation by excessive mutation load. Such utilization of forward-reverse mutation cycles as an adaptive mechanism was also observed in cultured HeLa cells upon successive replatings. An understanding of forward-reverse mutation cycles in cancer development could provide a genomic basis for improved early diagnosis, staging, and treatment of cancers.

The importance of aspirin, catheterization accuracy, and catheter design in external ventricular drainage-related hemorrhage: a multicenter study of 1002 procedures.

BACKGROUND: External ventricular drainage (EVD) is the commonest neurosurgical procedure performed in daily neurosurgical practice, but relatively few studies have investigated the incidence and risk factors of its related hemorrhagic complications. METHODS: This was a multicenter retrospective review of consecutive EVD procedures. Patients 18 years or older who underwent EVD and had a routine postoperative computed tomography (CT) scan performed within 24 hours were included. EVD-related hemorrhage was defined as new intracranial hemorrhage immediately adjacent or within the ventricular catheter trajectory. The volume of hemorrhage and the position of the catheter tip were assessed. A review of patient-, disease-, and surgery-related factors including the ventricular catheter design utilized was conducted. The Bonferroni correction was applied to the alpha level of significance (0.05) for multivariable analysis. RESULTS: Nine hundred sixty-two patients underwent 1002 EVD performed by neurosurgeons in the operating theater. Sixteen percent (154) of patients were on aspirin before the procedure. Thirty-four percent (333) of patients had intracerebral hemorrhage, 25% (251) had aneurysmal subarachnoid hemorrhage and 16% (158) had traumatic brain injury. The mean duration from EVD to the first postoperative CT scan was 20 ± 4 h. EVD-related hematomas were detected after 81 procedures with a per-catheter risk of 8.1%. Mean hematoma volume was 1.2 ± 3.3 ml. Most were less than 1 ml (grade I, 79%, 64), 1 to 15 ml (grade II) in 20% (16) and a single clot larger than 15 ml (grade III, 1%) were detected. Clinically significant hemorrhage that resulted in catheter occlusion occurred in 1.7% (17) of procedures. Most catheters (62%, 625) were optimally placed, i.e., its tip being within the ipsilateral frontal horn or third ventricle. Three non-antibiotic-impregnated ventricular catheter designs were used with 55% (550) being the 2.2-mm Integra™ catheter, 14% (137) being the 2.8-mm Medtronic™ catheter, and 31% (315) being the 3.1-mm Codman™ catheter. Independent significant predictors for EVD-related hemorrhage were the preoperative prescription of aspirin (adjusted OR 1.94; 95% CI 1.10-3.44), catheter malposition (aOR 1.99; 95% CI 1.22-3.23), and use of the 2.8-mm Medtronic™ catheter (aOR 4.22; 95% CI 2.39-7.41). CONCLUSIONS: The per-catheter risk of hemorrhage was 8.1%, but the incidence of symptomatic hemorrhage was low. The only patient risk factor was aspirin intake. This is the first study to evaluate and establish an association between catheter malposition and catheter design with EVD-related hemorrhage.

Distal versus proximal - an investigation on different supportive strategies by robots for upper limb rehabilitation after stroke: a randomized controlled trial.

BACKGROUND: Different mechanical supporting strategies to the joints in the upper extremity (UE) may lead to varied rehabilitative effects after stroke. This study compared the rehabilitation effectiveness achieved by electromyography (EMG)-driven neuromuscular electrical stimulation (NMES)-robotic systems when supporting to the distal fingers and to the proximal (wrist-elbow) joints. METHODS: Thirty subjects with chronic stroke were randomly assigned to receive motor trainings with NMES-robotic support to the finger joints (hand group, n = 15) and with support to the wrist-elbow joints (sleeve group, n = 15). The training effects were evaluated by the clinical scores of Fugl-Meyer Assessment (FMA), Action Research Arm Test (ARAT), and Modified Ashworth Scale (MAS) before and after the trainings, as well as 3 months later. The cross-session EMG monitoring of EMG activation level and co-contraction index (CI) were also applied to investigate the recovery progress of muscle activations and muscle coordination patterns through the training sessions. RESULTS: Significant improvements (P < 0.05) in FMA full score, FMA shoulder/elbow (FMA-SE) and ARAT scores were found in both groups, whereas significant improvements (P < 0.05) in FMA wrist/hand (FMA-WH) and MAS scores were only observed in the hand group. Significant decrease of EMG activation levels (P < 0.05) of UE flexors was observed in both groups. Significant decrease in CI values (P < 0.05) was observed in both groups in the muscle pairs of biceps brachii and triceps brachii (BIC&TRI) and the wrist-finger flexors (flexor carpi radialis-flexor digitorum) and TRI (FCR-FD&TRI). The EMG activation levels and CIs of the hand group exhibited faster reductions across the training sessions than the sleeve group (P < 0.05). CONCLUSIONS: Robotic supports to either the distal fingers or the proximal elbow-wrist could achieve motor improvements in UE. The robotic support directly to the distal fingers was more effective than to the proximal parts in improving finger motor functions and in releasing muscle spasticity in the whole UE. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov , identifier NCT02117089; date of registration: April 10, 2014. https://clinicaltrials.gov/ct2/show/NCT02117089.

Intra-arterial revascularization therapy for basilar artery occlusion-a systematic review and analysis.

Acute basilar artery occlusion has been managed aggressively with various modalities due to its potentially debilitating outcome. While intra-arterial mechanical thrombectomy with stentriever has established clear evidence for anterior circulation stroke with large vessel occlusion as an adjunct to intravenous thrombolysis or the sole modality in intravenous thrombolysis ineligible patients, similar high-level evidence was not available for intra-arterial mechanical thrombectomy of posterior circulation stroke with acute basilar artery occlusion. We hence perform a systematic review of current literature to compare intra-arterial pharmacological thrombolysis (IA-P) and intra-arterial mechanical thrombectomy (IA-MT) for acute basilar artery occlusion. Forty-one studies published between 1996 and 2015 were compared and studied by odds ratio analysis using Mantel-Haenszel risk ratio estimation, and time trend analysis using meta-regression. Patients in the IA-MT group were older, presented with more severe stroke, and more likely received treatment more than 12 h since onset of stroke. At 3 months, survival and clinical outcome were superior in the IA-MT group than the IA-P group, associated with higher recanalization rate. There were no difference between proportion of dependent survivors, and rate of symptomatic intracerebral hemorrhage across groups. Intra-arterial thrombolysis with mechanical devices led to improved survival, better short-term clinical outcome and higher recanalization rate than intra-arterial pharmacological thrombolysis.

A novel compound 6D-offset simulating phantom and quality assurance program for stereotactic image-guided radiation therapy system.

A comprehensive quality assurance (QA) device cum program was developed for the commissioning and routine testing of the 6D IGRT systems. In this article, both the new QA system and the BrainLAB IGRT system which was added onto a Varian Clinac were evaluated. A novel compound 6D-offset simulating phantom was designed and fabricated in the Prince of Wales Hospital (PWH), Hong Kong. The QA program generated random compound 6D-offset values. The 6D phantom was simply set up and shifted accordingly. The BrainLAB ExacTrac X-ray IGRT system detected the offsets and then corrected the phantom position automatically through the robotic couch. Routine QA works facilitated data analyses of the detection errors, the correction errors, and the correlations. Fifty sets of data acquired in 2011 in PWH were thoroughly analyzed. The 6D component detection errors and correction errors of the IGRT system were all within ± 1 mm and ± 1° individually. Translational and rotational scalar resultant errors were found to be 0.50 ± 0.27 mm and 0.54 ± 0.23°, respectively. Most individual component errors were shown to be independent of their original offset values. The system characteristics were locally established. The BrainLAB 6D IGRT system added onto a regular linac is sufficiently precise for stereotactic RT. This new QA methodology is competent to assure the IGRT system overall integrity. Annual grand analyses are recommended to check local system consistency and for external cross comparison. The target expansion policy of 1.5 mm 3D margin from CTV to PTV is confirmed for this IGRT system currently in PWH.

Interactive Multi-Stage Robotic Positioner for Intra-Operative MRI-Guided Stereotactic Neurosurgery.

Magnetic resonance imaging (MRI) demonstrates clear advantages over other imaging modalities in neurosurgery with its ability to delineate critical neurovascular structures and cancerous tissue in high-resolution 3D anatomical roadmaps. However, its application has been limited to interventions performed based on static pre/post-operative imaging, where errors accrue from stereotactic frame setup, image registration, and brain shift. To leverage the powerful intra-operative functions of MRI, e.g., instrument tracking, monitoring of physiological changes and tissue temperature in MRI-guided bilateral stereotactic neurosurgery, a multi-stage robotic positioner is proposed. The system positions cannula/needle instruments using a lightweight (203 g) and compact (Ø97 × 81 mm) skull-mounted structure that fits within most standard imaging head coils. With optimized design in soft robotics, the system operates in two stages: i) manual coarse adjustment performed interactively by the surgeon (workspace of ±30°), ii) automatic fine adjustment with precise (<0.2° orientation error), responsive (1.4 Hz bandwidth), and high-resolution (0.058°) soft robotic positioning. Orientation locking provides sufficient transmission stiffness (4.07 N/mm) for instrument advancement. The system's clinical workflow and accuracy is validated with lab-based (<0.8 mm) and MRI-based testing on skull phantoms (<1.7 mm) and a cadaver subject (<2.2 mm). Custom-made wireless omni-directional tracking markers facilitated robot registration under MRI.

Molecular landscapes of longitudinal NF2/22q and non-NF2/22q meningiomas show different life histories.

Recurrence is a major complication of some meningiomas. Although there were many studies on biomarkers associated with higher grades or increased aggressiveness, few studies specifically examined longitudinal samples of primary meningiomas and recurrences from the same patients for molecular life history. We studied 99 primary and recurrent meningiomas from 42 patients by FISH for 22q, 1q, 1p, 3p, 5q, 6q, 10p, 10q, 14q, 18q, CDKN2A/B homozygous deletion, ALT (Alternative Lengthening of Telomere), TERT re-arrangement, targeted sequencing and TERTp sequencing. Although NF2 mutation and 22q were well known to be aetiological events in meningiomas, we found that in these paired meningiomas, combining the two events resulted in an NF2/22q group (57 tumors from 25 patients) which were almost mutually exclusive with those cases without these two changes (42 tumors from 17 patients) for NF2/22q. No other molecular changes were totally unique to NF2/22q or non-NF2/22q tumors. For molecular evolution, NF2/22q meningiomas had higher cytogenetic abnormalities than non-NF2/22q meningiomas (p = 0.003). Most of the cytogenetic changes in NF2/22q meningiomas were present from the outset whereas for non-NF2/22q meningiomas, cytogenetic events were uncommon in the primary tumors and most were acquired in recurrences. For non-NF2/22q tumors, CDKN2A/B homozygous deletion, 1q gain, 18p loss, 3p loss, and ALT were preferentially found in recurrences. Mutations were largely conserved between primary and recurrent tumors. Phylogenetic trees showed 11/11 patients with multiple recurrent tumors had a conserved evolutionary pattern. We conclude that for molecular life history, NF2 and 22q should be regarded as a group. NF2/22q recurring meningiomas showed more cytogenetic abnormalities in the primary tumors, whereas non-NF2/22q meningiomas showed CDKN2A/B deletion and other cytogenetic abnormalities and ALT at recurrences. Although chromosome 1p loss is a known poor prognostic marker in meningiomas, it was also associated with a shorter TBR (time between resection) in this cohort (p = 0.002).

Patterns of care and survival of Chinese glioblastoma patients in the temozolomide era: a Hong Kong population-level analysis over a 14-year period.

Background: The aim of this study is to address the paucity of epidemiological data regarding the characteristics, treatment patterns and survival outcomes of Chinese glioblastoma patients. Methods: This was a population-level study of Hong Kong adult (>18 years) Chinese patients with newly diagnosed histologically confirmed glioblastoma between 2006 and 2019. The age standardized incidence rate (ASIR), patient-, tumor- treatment-related characteristics, overall survival (OS) as well as its predictors were determined. Results: One thousand and ten patients with a median follow-up of 10.0 months were reviewed. The ASIR of glioblastoma was 1.0 per 100 000 population with no significant change during the study period. The mean age was 57 + 14 years. The median OS was 10.6 months (IQR: 5.2-18.4). Independent predictors for survival were: Karnofsky performance score >80 (adjusted OR: 0.8; 95% CI: 0.6-0.9), IDH-1 mutant (aOR: 0.7; 95% CI: 0.5-0.9) or MGMT methylated (aOR: 0.7; 95% CI: 0.5-0.8) glioblastomas, gross total resection (aOR: 0.8; 95% CI: 0.5-0.8) and temozolomide chemoradiotherapy (aOR 0.4; 95% CI: 0.3-0.6). Despite the significant increased administration of temozolomide chemoradiotherapy from 39% (127/326) of patients in 2006-2010 to 63% (227/356) in 2015-2019 (P-value < .001), median OS did not improve (2006-2010: 10.3 months vs 2015-2019: 11.8 months) (OR: 1.1; 95% CI: 0.9-1.3). Conclusions: The incidence of glioblastoma in the Chinese general population is low. We charted the development of neuro-oncological care of glioblastoma patients in Hong Kong during the temozolomide era. Although there was an increased adoption of temozolomide chemoradiotherapy, a corresponding improvement in survival was not observed.

Protective effect of Homer 1a on tumor necrosis factor-α with cycloheximide-induced apoptosis is mediated by mitogen-activated protein kinase pathways.

Although Homer 1, of the postsynaptic density, regulates apoptosis, the signaling mechanisms are not fully elucidated. In this study, we found that tumor necrosis factor-α (TNF-α)/cycloheximide (CHX) treatment transiently increased Homer 1a (the short variant of Homer 1), but did not affect Homer 1b/c (the long variant of Homer 1). Overexpression of Homer 1a blocked TNF-α/CHX-induced apoptotic cell death, whereas inhibition of Homer 1a induction enhanced the pro-apoptotic effect of TNF-α/CHX treatment. Moreover, brain-derived neurotrophic factor, as a potential activator of endogenous Homer 1a, inhibited apoptotic cell death after TNF-α/CHX treatment through induction of Homer 1a. Since three major mitogen-activated protein kinase (MAPK) pathways have important roles in apoptosis, we examined if Homer 1a is involved in the effects of MAPK pathways on apoptosis. It was shown that inhibition of the ERK1/2 pathway increased the expression and the protective effect of Homer 1a, but inhibition of the p38 pathway produced the opposite effect. Cross-talk among MAPK pathways was also associated with the regulation of Homer 1a during apoptotic cell death. Blocking the p38 pathway increased the activity in the ERK1/2 pathway, while inhibition of ERK1/2 pathway abolished the effect of p38 inhibitor on Homer 1a. Furthermore, Homer 1a reversely affected the activation of MAPK pathways. These findings suggest that Homer 1a plays an important role in the prevention of apoptotic cell death and contributes to distinct regulatory effects of MAPK pathways on apoptotic cell death.

Rhythmic auditory stimulation promotes gait recovery in Parkinson's patients: A systematic review and meta-analysis.

Objective: Using rhythmic auditory stimulation (RAS) to improve gait disturbance in Parkinson's disease (PD) is an available treatment option, yet a consensus on its effectiveness remains controversial. We summarized the effects of RAS on gait, functional activity and quality of life in PD patients through a systematic review and meta-analysis. Methods: PubMed, Embase, Web of Science, Medline, and Cochrane Library databases were initially searched to identify relevant literature up to August 2021. Next, the methodological quality of eligible comparative studies was assessed by the Physiotherapy Evidence Database Scale. The treatment effects to clinical outcome in relation to gait, motor activities, and quality of life were analyzed. Results: A total of 18 studies consisted of 774 subjects were included in this meta-analysis. Comparing with the control group, RAS had significantly increased stride length (p < 0.001), accelerated gait speed (p < 0.001), reduced the occurrence of freezing events during walking (P = 0.009), achieved an improvement in Unified Parkinson's Disease Rating Scale (UPDRS) II (P = 0.030), UPDRS-III (P < 0.001) and Parkinson's Disease Quality of Life Questionnaire (PDQL) (p = 0.009) scores over an interval of 1-26 months. Conclusion: In this meta-analysis of 18 randomized controlled trials, we have demonstrated that RAS improves the general motor functions (UPDRS-III), particularly in gait, mobility and quality of life, in patients with Parkinson's disease.

Immune related biomarkers for cancer metastasis to the brain.

Brain metastasis accounts for a large number of cancer-related deaths. The host immune system, involved at each step of the metastatic cascade, plays an important role in both the initiation of the brain metastasis and their treatment responses to various modalities, through either local and or systemic effect. However, few reliable immune biomarkers have been identified in predicting the development and the treatment outcome in patients with cancer brain metastasis. Here, we provide a focused perspective of immune related biomarkers for cancer metastasis to the brain and a thorough discussion of the potential utilization of specific biomarkers such as tumor mutation burden (TMB), genetic markers, circulating and tumor-infiltrating immune cells, cytokines, in predicting the brain disease progression and regression after therapeutic intervention. We hope to inspire the field to extend the research and establish practical guidelines for developing and validating immune related biomarkers to provide personalized treatment and improve treatment outcomes in patients with metastatic brain cancers.

Deep brain stimulation in a young child with GNAO1 mutation - Feasible and helpful.

Background: GNAO1 is an emerging disorder characterized with hypotonia, developmental delay, epilepsy, and movement disorder, which can be potentially life threatening during acute exacerbation. In the USA, deep brain stimulation (DBS) has been licensed for treating children with chronic, treatment-resistant primary dystonia, who are 7 years old or older. Case Description: A 4-year-old girl diagnosed to have GNAO1-related dyskinesia and severe global developmental delay. She had severe dyskinesia precipitated by intercurrent infection, requiring prolonged intensive care for heavy sedation and related complications. Her dyskinesia improved dramatically after DBS implantation. Technical difficulties and precautions of DBS in preschool children were discussed. Conclusion: DBS should be considered early in the treatment of drug-resistant movement disorders in young children with GNAO1, especially after dyskinetic crisis, as they tend to recur. Presurgical counseling to parents and close monitoring of complications is also important in the process.

Combinations of Single-Gene Biomarkers Can Precisely Stratify 1,028 Adult Gliomas for Prognostication.

Advanced genomic techniques have now been incorporated into diagnostic practice in neuro-oncology in the literature. However, these assays are expensive and time-consuming and demand bioinformatics expertise for data interpretation. In contrast, single-gene tests can be run much more cheaply, with a short turnaround time, and are available in general pathology laboratories. The objective of this study was to establish a molecular grading scheme for adult gliomas using combinations of commonly available single-gene tests. We retrospectively evaluated molecular diagnostic data of 1,275 cases of adult diffuse gliomas from three institutions where we were testing for IDH1/2 mutation, TERTp mutation, 1p19q codeletion, EGFR amplification, 10q deletion, BRAF V600E, and H3 mutations liberally in our regular diagnostic workup. We found that a molecular grading scheme of Group 1 (1p19q codeleted, IDH mutant), Group 2 (IDH mutant, 1p19q non-deleted, TERT mutant), Group 3 (IDH mutant, 1p19q non-deleted, TERT wild type), Group 4 (IDH wild type, BRAF mutant), Group 5 (IDH wild type, BRAF wild type and not possessing the criteria of Group 6), and Group 6 (IDH wild type, and any one of TERT mutant, EGFR amplification, 10q deletion, or H3 mutant) could significantly stratify this large cohort of gliomas for risk. A total of 1,028 (80.6%) cases were thus classifiable with sufficient molecular data. There were 270 cases of molecular Group 1, 59 cases of molecular Group 2, 248 cases of molecular Group 3, 27 cases of molecular Group 4, 117 cases of molecular Group 5, and 307 cases of molecular Group 6. The molecular groups were independent prognosticators by multivariate analyses and in specific instances, superseded conventional histological grades. We were also able to validate the usefulness of the Groups with a cohort retrieved from The Cancer Genome Atlas (TCGA) where similar molecular tests were liberally available. We conclude that a single-gene molecular stratification system, useful for fine prognostication, is feasible and can be adopted by a general pathology laboratory.

AluScan: a method for genome-wide scanning of sequence and structure variations in the human genome.

BACKGROUND: To complement next-generation sequencing technologies, there is a pressing need for efficient pre-sequencing capture methods with reduced costs and DNA requirement. The Alu family of short interspersed nucleotide elements is the most abundant type of transposable elements in the human genome and a recognized source of genome instability. With over one million Alu elements distributed throughout the genome, they are well positioned to facilitate genome-wide sequence amplification and capture of regions likely to harbor genetic variation hotspots of biological relevance. RESULTS: Here we report on the use of inter-Alu PCR with an enhanced range of amplicons in conjunction with next-generation sequencing to generate an Alu-anchored scan, or 'AluScan', of DNA sequences between Alu transposons, where Alu consensus sequence-based 'H-type' PCR primers that elongate outward from the head of an Alu element are combined with 'T-type' primers elongating from the poly-A containing tail to achieve huge amplicon range. To illustrate the method, glioma DNA was compared with white blood cell control DNA of the same patient by means of AluScan. The over 10 Mb sequences obtained, derived from more than 8,000 genes spread over all the chromosomes, revealed a highly reproducible capture of genomic sequences enriched in genic sequences and cancer candidate gene regions. Requiring only sub-micrograms of sample DNA, the power of AluScan as a discovery tool for genetic variations was demonstrated by the identification of 357 instances of loss of heterozygosity, 341 somatic indels, 274 somatic SNVs, and seven potential somatic SNV hotspots between control and glioma DNA. CONCLUSIONS: AluScan, implemented with just a small number of H-type and T-type inter-Alu PCR primers, provides an effective capture of a diversity of genome-wide sequences for analysis. The method, by enabling an examination of gene-enriched regions containing exons, introns, and intergenic sequences with modest capture and sequencing costs, computation workload and DNA sample requirement is particularly well suited for accelerating the discovery of somatic mutations, as well as analysis of disease-predisposing germline polymorphisms, by making possible the comparative genome-wide scanning of DNA sequences from large human cohorts.

Clinical practice guidelines for the management of adult diffuse gliomas.

To follow the revision of the fourth edition of WHO classification and the recent progress on the management of diffuse gliomas, the joint guideline committee of Chinese Glioma Cooperative Group (CGCG), Society for Neuro-Oncology of China (SNO-China) and Chinese Brain Cancer Association (CBCA) updated the clinical practice guideline. It provides recommendations for diagnostic and management decisions, and for limiting unnecessary treatments and cost. The recommendations focus on molecular and pathological diagnostics, and the main treatment modalities of surgery, radiotherapy, and chemotherapy. In this guideline, we also integrated the results of some clinical trials of immune therapies and target therapies, which we think are ongoing future directions. The guideline should serve as an application for all professionals involved in the management of patients with adult diffuse glioma and also a source of knowledge for insurance companies and other institutions involved in the cost regulation of cancer care in China and other countries.

Effects of magnesium sulfate infusion on cerebral perfusion in patients after aneurysmal SAH.

BACKGROUND: A meta-analysis of current data suggests that magnesium sulfate infusion improves the outcome after aneurysmal subarachnoid hemorrhage through a reduction in delayed ischemic neurological deficit. Two multi-center randomized controlled trials are currently underway to investigate this hypothesis. The possible pharmacological basis of this hypothesis includes neuroprotection and vasodilatation. We aim to investigate the cerebral hemodynamic effects of magnesium sulfate infusion in aneurysmal subarachnoid hemorrhage patients. METHOD: A total of 12 patients who had experienced aneurysmal subarachnoid hemorrhage were randomized to magnesium sulfate infusion (n = 6) or placebo infusion (n = 6) for 14 days. Each patient had two perfusion MRIs performed, one in the first week after subarachnoid hemorrhage and one in the second week after subarachnoid hemorrhage. FINDINGS: Age, sex, and Fisher CT grade were not different between the two groups. All but one patient were of WFNS Grade I to II on presentation. There was no increase in rCBV, rCBF and MTT between the two perfusion scans within the same group or between the two groups. CONCLUSION: Magnesium sulfate infusion, in the dosage of current clinical trials, did not increase cerebral blood volume and cerebral blood flow, as postulated by dilation of small vessels and/or collateral pathways.

Assessing the neurological outcome of traumatic acute subdural hematoma patients with and without primary decompressive craniectomies.

BACKGROUND: We have investigated the impact of primary decompressive craniectomies on neurological outcomes after adjusting for other predictive variables. METHOD: We have collected data from trauma patients with acute subdural hematomas in a regional trauma center in Hong Kong over a 4-year period. Patient risk factors were investigated using logistic regression. RESULTS: Out of 464 patients with significant head injuries, 100 patients had acute subdural hematomas and were recruited for analysis. Forty-four percent of the patients achieved favorable neurological outcomes after 6 months. Favorable neurological outcomes at 1 year were related to age, pupil dilatation, and motor GCS scores at the time of admission. In the 34 patients who underwent evacuation of acute subdural hematomas, primary decompressive craniectomy was not associated with favorable neurological outcomes. CONCLUSION: Primary decompressive craniectomy failed to show benefit in terms of neurological outcomes and should be reserved for cases with uncontrolled intra-operative brain swelling.