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Meningiomas are the most common primary intracranial tumors. There are no effective medical therapies for meningioma patients, and new treatments have been encumbered by limited understanding of meningioma biology. Here, we use DNA methylation profiling on 565 meningiomas integrated with genetic, transcriptomic, biochemical, proteomic and single-cell approaches to show meningiomas are composed of three DNA methylation groups with distinct clinical outcomes, biological drivers and therapeutic vulnerabilities. Merlin-intact meningiomas (34%) have the best outcomes and are distinguished by NF2/Merlin regulation of susceptibility to cytotoxic therapy. Immune-enriched meningiomas (38%) have intermediate outcomes and are distinguished by immune infiltration, HLA expression and lymphatic vessels. Hypermitotic meningiomas (28%) have the worst outcomes and are distinguished by convergent genetic and epigenetic mechanisms driving the cell cycle and resistance to cytotoxic therapy. To translate these findings into clinical practice, we show cytostatic cell cycle inhibitors attenuate meningioma growth in cell culture, organoids, xenografts and patients.

Background Facial paresis is one of the complications after treatment for vestibular schwannoma (VS). Acupuncture has been used for Bell palsy but not in iatrogenic facial paresis. The objective of this study is to measure the efficacy of using acupuncture for iatrogenic facial nerve palsy and patients' satisfaction. Methods This is a single-center retrospective study with patients from 2007–2019 received treatment for newly diagnosed or recurrent VS. Some patients who suffered facial paresis after surgery had self-initiated acupuncture. All patients who had facial paresis were included. Their facial nerve status before and immediately after surgery, postoperative 6 months and 12 months, were recorded. Those who received acupuncture also answered 6- and 12-month patient satisfaction surveys over the phone. Adverse effects were also assessed. Results There were 123 patients in this period. Of these, 29 patients had iatrogenic facial paresis and 23 of them received acupuncture. There was significant improvement of facial paresis for the acupuncture group compared with the nonacupuncture group at 6 and 12 months. More than 80% of patients who received acupuncture were satisfied. They had motor improvement and experienced less pain and tightness. No adverse effects were reported. Conclusions Acupuncture for postresection VS facial paresis seemed to speed up its recovery. Both patients' recovery and satisfaction were good after acupuncture, and it seemed to be a safe procedure in trained hands.

Background Fall with head injury is a pervasive challenge, especially in the aging population. Contributing factors for mortality include the development of cerebral contusions and delayed traumatic intracerebral hematoma. Currently, there is no established specific treatment for these conditions. Object This study aimed to investigate the impact of independent factors on the mortality rate of traumatic brain injury with contusions or traumatic subarachnoid hemorrhage. Methods Data were collected from consecutive patients admitted for cerebral contusions or traumatic subarachnoid hemorrhage at an academic trauma center from 2010 to 2016. The primary outcome was the 30-day mortality rate. Independent factors for analysis included patient factors and treatment modalities. Univariate and multivariate analyses were conducted to identify independent factors related to mortality. Secondary outcomes included thromboembolic complication rates associated with the use of tranexamic acid. Results In total, 651 consecutive patients were identified. For the patient factors, low Glasgow Coma Scale on admission, history of renal impairment, and use of warfarin were identified as independent factors associated with higher mortality from univariate and multivariate analyses. For the treatment modalities, univariate analysis identified tranexamic acid as an independent factor associated with lower mortality (P = 0.021). Thromboembolic events were comparable in patients with or without tranexamic acid. Conclusion Tranexamic acid was identified by univariate analysis as an independent factor associated with lower mortality in cerebral contusions or traumatic subarachnoid hemorrhage. Further prospective studies are needed to validate this finding.

Introduction Normal skull base structures are destroyed either by the skull base pathology itself or during surgery that results in cerebrospinal fluid (CSF) leak. Skull base repair is usually performed transnasally by using a nasal septal flap. But when NSF is not available and failed repeated transnasal repair, a cranionasal repair with frontal pericranial flap (PF) can be attempted to achieve the highest successful chance. We performed a dual layer/split PF repair of a skull base defect using cranionasal approach and here we describe the technique. Case Description A 74-year-old man suffered from CSF leak and ventriculitis after multiple transnasal surgeries for pituitary macroadenoma despite multiple repairs with intranasal vascularized flaps. We performed repair by cranionasal approach and using frontal PF. The frontal PF was divided into left and right halves. The left half went intradural, through the chiasmatic window to reach the sella and cover the tubercular and sellar defect from above. The right half went through the nasion into the nose to cover the defect from below. So the defect was covered by two vascularized flap from a single frontal PF. The repair was successful with no CSF leak and infection successfully treated by antibiotics. Conclusion We introduced the cranionasal dual layer/split PF technique to repair anterior skull base and successfully stopped the CSF leak in a patient after multiple EEA surgeries. This technique should only be considered in specific difficult situation where usual repair by EEA is impossible.

BACKGROUND Surgery is the mainstay of meningioma treatment, but improvements in meningioma risk stratification are needed and indications for postoperative radiotherapy are controversial. DNA methylation profiling, copy number variants (CNVs), exome sequencing, and RNA sequencing have improved understanding of meningioma biology, but have not superseded histologic grading, or revealed biomarkers for radiotherapy responses. To address these unmet needs, we optimized and validated a targeted gene expression biomarker predicting meningioma outcomes and responses to radiotherapy. METHODS Targeted gene expression profiling was performed on a discovery cohort of 173 meningiomas (median follow-up 8.1 years) and a validation cohort of 331 meningiomas (median follow-up 6.1 years) treated with surgery (n=504) and postoperative radiotherapy (n=73) at independent, international institutions (70% WHO grade 1, 24% WHO grade 2, 6% WHO grade 3). Optimized targeted gene expression models predicting clinical outcomes (34 genes) or radiotherapy responses (12 genes) were developed from the discovery cohort, and compared to histologic and molecular classification systems by performing DNA methylation profiling, CNV analysis, exome sequencing, and RNA sequencing on the same meningiomas. RESULTS Targeted gene expression profiling achieved a concordance-index of 0.75 ± 0.03 (SEM) for local freedom from recurrence (LFFR) and 0.72 ± 0.03 for overall survival (OS) in the validation cohort, outperforming WHO grade (5-year LFFR delta-AUC 0.15, 95% CI 0.076-0.229, p=0.001) and DNA methylation grouping (delta-AUC 0.075, 95% CI 0.006-0.130, p=0.01) for LFFR, disease-specific survival, and OS. The biomarker was independently prognostic after accounting for WHO grade, extent of resection, primary versus recurrent presentation, CNV status, DNA methylation group, and Ki67 labeling index, and identified meningiomas benefiting from radiotherapy (interaction p-value=0.0008), suggesting postoperative radiotherapy could be refined in 30.2% of cases. CONCLUSIONS Targeted gene expression profiling of 504 meningiomas improves discrimination of meningioma local recurrence, disease-specific survival, and overall survival, and predicts radiotherapy responses.

Purpose/Objective(s) Indications for postoperative radiotherapy after meningioma resection are controversial. DNA methylation profiling identifies meningiomas at risk for recurrence, but logistic and technical barriers have encumbered clinical translation of this approach. The aim of this study was to optimize and validate a clinically-tractable targeted gene expression biomarker to predict meningioma outcomes and responses to postoperative radiotherapy. Materials/Methods Targeted gene expression and Illumina 850k DNA methylation profiling were performed on a discovery cohort of 173 meningiomas (median follow-up 7.8 years) and an external validation cohort of 331 meningiomas (median follow-up 5.8 years) from patients treated with surgery (n = 504) and postoperative radiotherapy (n = 73) at independent, international institutions (70% WHO grade 1, 24% WHO grade 2, 6% WHO grade 3). RNA sequencing was performed on the discovery cohort, and 125 genes were selected for targeted gene expression profiling based on associations with meningioma recurrence. Regularized Cox regression was used to develop continuous gene expression risk score for local freedom from recurrence (LFFR). The model (34 meningioma genes and 7 housekeeping genes) and risk quartiles (low, low-intermediate, high-intermediate, and high) were locked and validated on the external cohort. Multivariate regressions (MVR) incorporating WHO grade, DNA methylation grouping, extent of resection, primary versus recurrent presentation, and postoperative radiotherapy were used to assess the risk score across clinical contexts. Results The gene expression risk score (concordance-index 0.78 ± 0.03) outperformed DNA methylation grouping (0.71 ± 0.03) and WHO grade (0.65 ± 0.03) in stratifying meningioma LFFR in the validation cohort (n = 331). The risk score classified 43% of WHO grade 1 meningiomas as high-intermediate (n = 82) or high risk (n = 34), with 5-year LFFR and overall survival (OS) of 83% and 89% for high-intermediate risk WHO grade 1 meningiomas, and 41% and 73% for high risk WHO grade 1 meningiomas, respectively. Low risk WHO grade 1 meningiomas (n = 50) had 5-year LFFR and OS of 92% and 88%, respectively. High and high-intermediate risk scores were independently prognostic for LFFR (HR 2.9, 95% CI 1.2-4.4) and OS (HR 2.7, 95% CI 1.3-5.6) on MVR. An interaction term between postoperative radiotherapy and risk score was predictive for LFFR (P = 0.046) and OS (P = 0.001) on MVR in the validation cohort, suggesting meningiomas with higher risk scores derived greater benefit from postoperative radiotherapy. Conclusion Here we use targeted gene expression profiling to develop a risk score predicting meningioma outcomes and responses to postoperative radiotherapy. This cost-effective assay outperforms DNA methylation grouping and WHO grade in discriminating meningioma outcomes, and may be useful for guiding clinical trial design.

Meningiomas arising from the meningothelial central nervous system lining are the most common primary intracranial tumors, and a significant cause of neurologic morbidity and mortality1. There are no effective medical therapies for meningioma patients2,3, and new treatments have been encumbered by limited understanding of meningioma biology. DNA methylation profiling provides robust classification of central nervous system tumors4, and can elucidate targets for molecular therapy5. Here we use DNA methylation profiling on 565 meningiomas integrated with genetic, transcriptomic, biochemical, and single-cell approaches to show meningiomas are comprised of 3 epigenetic groups with distinct clinical outcomes and biological features informing new treatments for meningioma patients. Merlin-intact meningiomas (group A, 34%) have the best outcomes and are distinguished by a novel apoptotic tumor suppressor function of NF2/Merlin. Immune-enriched meningiomas (group B, 38%) have intermediate outcomes and are distinguished by immune cell infiltration, HLA expression, and lymphatic vessels. Hypermitotic meningiomas (group C, 28%) have the worst outcomes and are distinguished by convergent genetic mechanisms misactivating the cell cycle. Consistently, we find cell cycle inhibitors block meningioma growth in cell culture, organoids, xenografts, and patients. Our results establish a framework for understanding meningioma biology, and provide preclinical rationale for new therapies to treat meningioma patients.

SUMMARYMeningiomas arising from the meningothelial central nervous system lining are the most common primary intracranial tumors, and a significant cause of neurologic morbidity and mortality1. There are no effective medical therapies for meningioma patients2,3, and new treatments have been encumbered by limited understanding of meningioma biology. DNA methylation profiling provides robust classification of central nervous system tumors4, and can elucidate targets for molecular therapy5. Here we use DNA methylation profiling on 565 meningiomas integrated with genetic, transcriptomic, biochemical, and single-cell approaches to show meningiomas are comprised of 3 epigenetic groups with distinct clinical outcomes and biological features informing new treatments for meningioma patients. Merlin-intact meningiomas (group A, 34%) have the best outcomes and are distinguished by a novel apoptotic tumor suppressor function ofNF2/Merlin. Immune-enriched meningiomas (group B, 38%) have intermediate outcomes and are distinguished by immune cell infiltration,HLAexpression, and lymphatic vessels. Hypermitotic meningiomas (group C, 28%) have the worst outcomes and are distinguished by convergent genetic mechanisms misactivating the cell cycle. Consistently, we find cell cycle inhibitors block meningioma growth in cell culture, organoids, xenografts, and patients. Our results establish a framework for understanding meningioma biology, and provide preclinical rationale for new therapies to treat meningioma patients.

BACKGROUND Meningioma treatments are limited due to incomplete understanding of meningioma biology. To address this, we performed multiplatform molecular profiling on 565 meningiomas with comprehensive clinical data to define genomic drivers and identify therapeutic vulnerabilities. METHODS DNA methylation profiling was performed on meningiomas from UCSF (n=200, discovery) and Hong Kong University (n=365, validation). Median follow-up was 5.6 years, and there were 388/142/35 WHO grade I/II/III meningiomas. Copy number variants (CNVs) were calculated for all meningiomas, and RNA sequencing was performed on UCSF meningiomas. Cell type deconvolution, metagenomics, CRISPR, and pharmacology were used for mechanistic and functional validation. RESULTS Unsupervised hierarchical clustering of differentially methylated DNA probes revealed that meningiomas were comprised of 3 epigenetic subgroups associated with good, intermediate, and poor outcomes, with representation from all WHO grades in each subgroup. Meningiomas from the subgroup with the best outcomes (52% WHO grade I) were distinguished by recurrent gain of Chr5. Meningiomas from the subgroup with intermediate outcomes (31% WHO grade II) were distinguished by genomic stability, enrichment of innate immune genes, and immune infiltration in the setting of endogenous retroviral gene re-expression, a mechanism of immune recruitment. The most aggressive subgroup of meningiomas (57% WHO grade III) was distinguished by genomic instability, including recurrent loss of Chr22q harboring NF2, and decreased immune infiltration. Consistently, NF2 suppression in primary meningioma cells derived from immunogenic meningiomas decreased expression of innate immune genes critical for immune recruitment, suggesting a novel immunostimulatory function of NF2. The most aggressive subgroup of meningiomas were further distinguished by activation of the mitogenic FOXM1 transcriptional program, and recurrent loss of Chr9p harboring CDKN2A/B, which rendered primary meningioma cells from this subgroup susceptible to CDK4/6 inhibitors. CONCLUSIONS Meningiomas are comprised of 3 epigenetic subgroups defined by genetic mechanisms driving immune infiltration in the tumor microenvironment and meningioma cell proliferation.

The chemotherapeutic agent temozolomide (TMZ) is widely used in the treatment of glioblastoma multiforme (GBM). Rutin, a citrus flavonoid ecglycoside found in edible plants, has neuroprotective and anticancer activities. This study aimed to investigate the efficacy and the underlying mechanisms of rutin used in combination with TMZ in GBM. In vitro cell viability assay demonstrated that rutin alone had generally low cytotoxic effect, but it enhanced the efficacy of TMZ in a dose-dependent manner. Subcutaneous and orthotopic xenograft studies also showed that tumor volumes were significantly lower in mice receiving combined TMZ/Rutin treatment as compared to TMZ or rutin alone treatment. Moreover, immunoblotting analysis showed that TMZ activated JNK activity to induce protective response autophagy, which was blocked by rutin, resulting in decreased autophagy and increased apoptosis, suggesting that rutin enhances TMZ efficacy both in vitro and in vivo via inhibiting JNK-mediated autophagy in GBM. The combination rutin with TMZ may be a potentially useful therapeutic approach for GBM patient.

BACKGROUND The development of next generation sequencing (NGS) based comprehensive genomic profiling (CGP) has enabled identification of druggable somatic mutations in brain tumours. This cohort reviewed the efficacy of CGP-guided precision treatment in a tertiary neuro-oncology centre. METHODOLOGY From May 2017 to May 2020, CGP were arranged for 43 patients. All patients had exhausted conventional treatments or received CGP for clinical trial screening. Targeted deep NGS was used to assess the mutational status, single nucleotide variant, small insertions and deletions and copy number variant of 440 cancer-related genes. RESULTS The diagnoses of the 43 patients were GBM (n=23), high grade glioma (n=11), brain metastases (n=4), chordoma (n=3), atypical choroid plexus papilloma (n=1) and meningioma (n=1). In most of the patients (42/43, 97.7%), CGP identified at least one druggable targets with a median of 3. Based on the CGP, 27 patients received precision treatment (62.7%). Among these, 14 were GBM and 6 were other high grade glioma. Treatment given included PARP inhibitors, immunotherapy, multi-kinase inhibitor, selective CDK4/6 inhibitor and mTOR inhibitor. Clinical benefit was achieved in 20 patients out of 27 (74%), including 2 complete response (7.4%), 9 partial response (33.3%) and 9 stable disease (33.3%). The median progression free survival (PFS) were 183 days [95% confident intervals (CI): 81–302 days]. For GBM/high grade glioma patients, median PFS was 125 days [95% CI: 52–215] and six-month PFS was 32.7%. Treatment toxicity was mild except two patients developed grade 3 complications and one grade 5 complication (fatal neutropenic fever). For the 16 patients who did not receive precision treatment, one had no druggable target identified, nine were still stable on standard therapies, 6 were too weak when CGP was available. CONCLUSION CGP guided precision treatment for selected, advanced neuro-oncological patients yielded modest clinical efficacy and satisfactory safety profile in real world setting.

OBJECTIVEHydrocephalus with a blocked ventriculoperitoneal (VP) shunt is a life-threatening condition. Emergency endoscopic third ventriculostomy (ETV) is a potential treatment option. The aim of the study was to identify independent risk factors associated with failure of ETV in treating patients with blocked shunts.METHODSThe authors retrospectively reviewed data from consecutive patients admitted for blocked shunt treated by ETV during the study period from 2000 to 2016. Univariate and multivariate analyses were performed to identify independent factors associated with failed ETV for blocked shunts, such as age, sex, history of CNS infection, number of previous shunt revisions, operations performed as an emergency or elective, number of specialists, and other factors.RESULTSIn total, 121 patients underwent ETV during the study period. Of these, 31 patients (25.6%) had ETV for treatment of a blocked shunt. In 25 (80.6%) of 31 ETV was performed as an emergency procedure. There was no significant difference in the success rate of ETV depending on whether it was performed as an emergency procedure (64% [16/25]) or an elective procedure (66.7% [4/6]; OR 0.062, 95% CI 0.001–2.708; p = 0.149). Univariate and multivariate analyses identified that history of a CNS infection was an independent risk factor for failure of ETV in treating patients with a blocked shunt (OR 0.030, 95% CI 0.001–0.888; p = 0.043).CONCLUSIONSEmergency ETV had a comparable success rate as elective ETV. A history of CNS infection is an independent predictor of ETV failure in treating patients with blocked shunts.

The long non-coding RNA CRNDE has emerged as an important regulator in carcinogenesis and cancer progression. While CRNDE has previously been found to be the most highly upregulated lncRNA in glioma, detailed information on its roles in regulating cancer cell growth remains limited. In the present study, we aimed at exploring the functional roles and underlying mechanisms of CRNDE in glioma. We applied microarray data analysis to determine the prognostic significance of CRNDE in glioma patients and its correlation with epidermal growth factor receptor (EGFR) activation. EGFR inhibition was used to confirm the role of EGFR in regulating CRNDE expression. Functional studies were performed upon CRNDE silencing to explore its role in gliomagenesis. We confirm that CRNDE acts as an oncogene that is highly up-regulated in glioma, and high CRNDE expression correlates with poor prognosis in glioma patients. We further demonstrate that the expression of CRNDE correlates with EGFR activation. EGF and EGFR tyrosine kinase inhibitor (TKI) enhance and block the up-regulation of CRNDE expression, respectively, suggesting that EGFR signaling may positively regulate CRNDE expression. Functional assays show that CRNDE depletion inhibits glioma cell growth both in vitro and in vivo, and is associated with induced cellular apoptosis with decreased Bcl2/Bax ratio. Our findings suggest that the aberrant expression of CRNDE may be mediated by activated EGFR signaling and play significant roles in gliomagenesis.

// Stella Sun 1 , Karrie M.Y. Kiang 1 , Amy S.W. Ho 1 , Derek Lee 1 , Ming-Wai Poon 1 , Fei-Fan Xu 1 , Jenny K.S. Pu 1 , Amanda N.C. Kan 2 , Nikki P.Y. Lee 1 , Xiao-Bing Liu 1 , Kwan Man 1 , Philip J.R. Day 3 , Wai-Man Lui 1 , Ching-Fai Fung 1 and Gilberto K.K. Leung 1 1 Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong 2 Department of Pathology and Clinical Biochemistry, Queen Mary Hospital, Pokfulam, Hong Kong 3 The Manchester Institute of Biotechnology, Faculty of Biology, Medicine and Health Sciences, University of Manchester, Manchester, United Kingdom Correspondence to: Gilberto K.K. Leung, email: gilberto@hku.hk Keywords: P4HB, angiogenesis, glioma, invasion, MAPK signaling Received: April 19, 2017 Accepted: May 08, 2017 Published: May 19, 2017 ABSTRACT Endoplasmic reticulum (ER) chaperone Prolyl 4-hydroxylase, beta polypeptide (P4HB) has previously been identified as a novel target for chemoresistance in glioblastoma multiforme (GBM). Yet its functional roles in glioma carcinogenesis remain elusive. In clinical analysis using human glioma specimens and Gene Expression Omnibus (GEO) profiles, we found that aberrant expression of P4HB was correlated with high-grade malignancy and an angiogenic phenotype in glioma. Furthermore, P4HB upregulation conferred malignant characteristics including proliferation, invasion, migration and angiogenesis in vitro , and increased tumor growth in vivo via the mitogen-activated protein kinase (MAPK) signaling pathway. Pathway analysis suggested genetic and pharmacologic inhibition of P4HB suppressed MAPK expression and its downstream targets were involved in angiogenesis and invasion. This is the first study that demonstrates the oncogenic roles of P4HB and its underlying mechanism in glioma. Since tumor invasion and Vascularisation are typical hallmarks in malignant glioma, our findings uncover a promising anti-glioma mechanism through P4HB-mediated retardation of MAPK signal transduction.

Background Iatrogenic cerebral venous sinus injury and occlusion may occur during resection of parasagittal meningioma and lateral skull base surgery. The former involves the superior sagittal sinus, and direct surgical repair is associated with good results. Outcome of direct repair of transverse–sigmoid sinus injury is less clear. We present a patient with iatrogenic sigmoid sinus injury in whom direct repair was complicated by subsequent thrombosis that was successfully salvaged by combined endovascular mechanical and chemical thrombolysis. Case Description A 60-year-old man with left tentorial atypical meningioma had disease recurrence after 3 excisions. Angiography revealed that the straight sinus and torcular and bilateral transverse sinuses were occluded. He underwent a fourth craniotomy with inadvertent occlusion of the transverse–sigmoid sinus junction. Direct surgical repair was done but was complicated by thrombosis. Mechanical endovenous thrombectomy was done followed by continuous urokinase infusion for 1 week. Digital subtraction angiography performed 7 days after endovascular treatment showed improved venous drainage through the left transverse–sigmoid sinus junction. The patient was ambulatory and fully independent, with no new neurologic deficit. Conclusions This case emphasizes the need to preserve every vein, especially when major venous sinuses have been obliterated. Detailed study of high-quality preoperative digital subtraction angiography is extremely important. Venous injury should be repaired immediately whenever possible. Postrepair venous sinus thrombosis may be effectively salvaged by endovascular thrombectomy for rapid recannulation, with or without combined use of continuous in situ thrombolytic therapy.

Studies directly comparing the outcomes of intracranial meningioma resection between elderly and younger patients are currently limited. This study aimed to assess the perioperative complications, mortalities and functional outcomes in these two groups. Consecutive elderly patients (aged ≥ 65) and tumor-location-matched younger patients who underwent intracranial meningioma resections were retrospectively reviewed. Outcomes were assessed at 30-day, 90-day, 6-month and 1-year. We used a standardized classification of operative complications, and conducted subgroup analyses based on tumor location [convexity, parasagittal and falcine (CPF) as one group; skull base (SB) as another]. There were 92 patients in each group. The mean age was 74.6 ± 6.4 years in the elderly and 49.3 ± 10.1 years in the younger groups. The cumulative 30-day, 90-day and 1-year mortality rates were 0, 2.2 and 4.3 % for the elderly, respectively, and 1.1 % for all time points in the young. These differences were not statistically significant. Overall, the elderly suffered from more perioperative complications (P = 0.010), and these were mostly minor complications according to the classification of operative complications. However, these differences were observed only in the SB but not in the CPF subgroup. More elderly patients had impaired functional outcome 1-year after surgery. Significantly more elderly patients had new neurological deficits 1-year after surgery (26.1 vs. 6.6 %; P = 0.001). Comparable mortality rates were observed in elderly and younger patients. However, the elderly had more minor complications and poorer functional outcomes. Patient selection remains key to good clinical outcome.

Aim There is a lack of recent data regarding the incidence of central nervous system (CNS) tumours in Hong Kong patients of Chinese origin. The aim of this study was to provide a current registry of brain and CNS tumour incidence in Hong Kong, which would contribute to the current knowledge of brain tumour epidemiology. Patients and Methods Prospective data were collected from neurosurgical centres in Hong Kong between July 2008 and June 2009. Demographic and diagnostic data were collected for each patient diagnosed with a brain tumour, and collated at a central coordination centre. Diagnosis was confirmed either histologically or radiologically. Results There were 1031 newly-diagnosed cases of spinal/intracranial tumours, 759 of which were primary tumours. The estimated annual incidence of spinal/intracranial tumours was 14.7 per 100 000. The annual incidence of primary CNS tumours was 10.8 per 100 000, and 3.5 per 100 000 for meningiomas. A total of 70 high-grade gliomas (incidence rate of 1/100 000) and 171 pituitary tumours were diagnosed, both of which were more prevalent in the 45–64-year age group. Meningiomas and pituitary tumours were more common in females. In paediatric patients, there were 36 cases of newly-diagnosed brain tumours, glioma being the most common. Conclusion The annual incidence rate of malignant gliomas was one per 100 000 in the Hong Kong population of Chinese origin. From comparisons with other studies, this suggests geographical and racial differences in the incidence of brain tumours, and warrants further collaboration and research regarding brain tumour epidemiology.

Glioma is the commonest form of primary brain tumor in adults with varying malignancy grades and histological subtypes. Long non-coding RNAs (lncRNAs) are a novel class of non-protein-coding transcripts that have been shown to play important roles in cancer development. To discover novel tumor-related lncRNAs and determine their associations with glioma subtypes, we first applied a lncRNA classification pipeline to identify 1970 lncRNAs that were represented on Affymetrix HG-U133 Plus 2.0 array. We then analyzed the lncRNA expression patterns in a set of previously published glioma gene expression profiles of 268 clinical specimens, and identified sets of lncRNAs that were unique to different histological subtypes (astrocytic versus oligodendroglial tumors) and malignancy grades. These lncRNAs signatures were then subject to validation in another non-overlapping, independent data set that contained 157 glioma samples. This is the first reported study that correlates lncRNA expression profiles with malignancy grade and histological differentiation in human gliomas. Our findings indicate the potential roles of lncRNAs in the biogenesis, development and differentiation of gliomas, and provide an important platform for future studies.

SummaryIntracranial haemorrhage (ICH) accounts for ~35% of all strokes in Chinese. Anti-platelet agent is often avoided after an index event due to the possibility of recurrent ICH. This single-centered observational study included 440 consecutive Chinese patients with a first spontaneous ICH surviving the first month performed during 1996–2010. The subjects were identified, and their clinical characteristics, anti-platelet therapy after ICH, and outcomes including recurrent ICH, ischaemic stroke, and acute coronary syndrome were checked from hospital records. Of these 440 patients, 56 patients (12.7%) were prescribed aspirin (312 patient-aspirin years). After a follow-up of 62.2 ± 1.8 months, 47 patients had recurrent ICH (10.7%, 20.6 per 1,000 patient years). Patients prescribed aspirin did not have a higher risk of recurrent ICH compared with those not prescribed aspirin (22.7 per 1,000 patient-aspirin years vs. 22.4 per 1,000 patient years, p=0.70). Multivariate analysis identified age > 60 years (hazard ratio [HR]: 2.0, 95% confidence interval [CI]: 1.07–3.85, p=0.03) and hypertension (HR: 2.0, 95% CI: 1.06–3.75, p=0.03) as independent predictors for recurrent ICH. In a subgroup analysis including 127 patients with standard indications for aspirin of whom 56 were prescribed aspirin, the incidence of combined vascular events including recurrent ICH, ischaemic stroke, and acute coronary syndrome was statistically lower in patients prescribed aspirin than those not prescribed aspirin (52.4 per 1,000 patient-aspirin years, vs. 112.8 per 1,000 patient-years, p=0.04). In conclusion, we observed in a cohort of Chinese post-ICH patients that aspirin use was not associated with an increased risk for a recurrent ICH.

A functional magnetic resonance imaging (fMRI) study was conducted to integrate the clinical observations of the impaired judgment of spatial orientation of cerebellar patients with recent theoretical discoveries about the role of the cerebellum in cognitive functions. Ten normal healthy male right-handed Chinese postgraduates consented to participate in this study. The experimental task employed was a modified version of Benton's Judgment of Line Orientation Test, administered in a blocked fMRI study. The findings indicated activation of the cerebellar regions, the Hemisphere Lobules IV, VI and Crus I, while the subjects were performing the experimental task of the judgment of the orientation of lines. Furthermore, cortical regions were activated, including the bilateral precuneus (BA 7), the extrastriate regions (BA 19), and the bilateral prefrontal regions (BA 9, 10, 44, 46). The imaging data confirmed that the activity of the cerebellum is associated with judging spatial orientation. The theoretical and clinical implications of the findings are discussed.

BACKGROUND: Tumor invasion and vascularization are typical hallmarks in malignant glioma with the majority showing elevated expression and activation of the epidermal growth factor receptor (EGFR). Our group has previously shown that prolyl 4-hydroxylase, beta polypeptide (P4HB), an endoplasmic reticulum (ER) chaperone, was intimately related to chemoresistance in malignant glioma. The role of P4HB in determining other glioblastoma malignant phenotypes, however, remains unknown. METHODS: We studied both the in vitro and in vivo behaviors of globlastoma cells with established P4HB-overexpression. We also studied P4HB expression profiles in clinical specimens and publicly available microarray database. Hierarchical clustering graphically was performed to detect differential gene expression patterns between low and high P4HB tumors. The effect of P4HB in determining EGFR signaling and functioning were also studied. RESULTS: We found that inhibition of P4HB would dyregulate EGFR/MAPK-mediated angiogenic and invasive phenotypes of malignant glioma. Clinical analysis on human glioma specimens and Gene Expression Omnibus (GEO) expression profiles showed that excessive P4HB were correlated with high-grade malignancy, angiogenesis and invasion. Functionally, upregulation of P4HB conferred glioma cells with malignant characteristics including proliferation, invasion and angiogenesis in vitro, and tumor growth in orthotopic mouse model. Genetic and pharmacologic inhibitions of oncogenic P4HB were found to suppress EGFR/MAPK signaling. CONCLUSION: Our study is the first to describe a mechanistic link between P4HB-EGFR-mediated MAPK activation and glioma progression, invasion and angiogenesis. The findings uncovered a novel and promising anti-glioma mechanism related to P4HB-mediated retardation of EGFR/MAPK signal transduction. Targeting P4HB with small molecular agents may provide an alternative therapeutic approach by deactivating several critical downstream events that mediate the aggressive and resistant behaviors of glioblastoma.

BACKGROUND: Glioblastoma multiforme (GBM), the most aggressive malignant primary brain tumor of the central nervous system, is characterized by a relentless disease recurrence despite continued advancement in surgery, radiotherapy, and chemotherapy. Resistance to temozolomide (TMZ), a standard chemotherapeutic agent for GBM, remains a major challenge. Understanding the mechanisms behind TMZ resistance can direct the development of novel strategies for the prevention, monitoring, and treatment of tumor relapse. METHODS AND RESULTS: Our research platform, based on the establishment of 2 pairs of TMZ-sensitive/resistant GBM cells (D54-S and D54-R; U87-S and U87-R), has successfully identified prolyl 4-hydroxylase, beta polypeptide (P4HB) over-expression to be associated with an increased IC50 of TMZ. Elevated P4HB expression was verified using in vivo xenografts developed from U87-R cells. Clinically, we found that P4HB was relatively up-regulated in the recurrent GBM specimens that were initially responsive to TMZ but later developed acquired resistance, when compared with treatment-naive tumors. Functionally, P4HB inhibition by RNAi knockdown and bacitracin inhibition could sensitize D54-R and U87-R cells to TMZ in vitro and in vivo, whereas over-expression of P4HB in vitro conferred resistance to TMZ in both D54-S and U87-S cells. Moreover, targeting P4HB blocked its protective function and sensitized glioma cells to TMZ through the PERK arm of the endoplasmic reticulum stress response. CONCLUSIONS: Our study identified a novel target together with its functional pathway in the development of TMZ resistance. P4HB inhibition may be used alone or in combination with TMZ for the treatment of TMZ-resistant GBM., link_to_OA_fulltext, Neuro-oncology, 2013, v. 15 n. 5, p. 562-577

Background Patients who survive intracranial hemorrhage (ICH) are at high risk of recurrence. The Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly (Age >65 years), Drugs/Alcohol Concomitantly (HAS-BLED) score has recently been developed to assess bleeding risk. Methods This observational study was aimed to investigate the prognostic performance of the HAS-BLED score in predicting recurrent ICH. Consecutive patients (434) with a first spontaneous ICH who were not prescribed antiplatelet or anticoagulation therapy (59.8 ± 15.3 years; men, 62.3%) were recruited. Results Most patients (71.6%) had a HAS-BLED score of >1. After a follow-up of 52.7 months, there were 42 ICH recurrences (2.25 per 100 patient-years). The risk of ICH recurrence increased with HAS-BLED score. Specifically, the risk of ICH recurrence with HAS-BLED score of 1, 2, 3, and 4 were 1.37, 2.38, 3.39, and 2.90 per 100 patient-years, respectively. The sensitivity and specificity of HAS-BLED was 79.1% and 29.2%, respectively, with C-statistic of 0.54 (0.50–0.59). Conclusion This study provided data on the risk of ICH recurrence stratified using the HAS-BLED score in patients after an ICH.

Temozolomide (TMZ) is standard chemotherapy for glioblastoma multiforme (GBM). Intratumoral hypoxia is common in GBM and may be associated with the development of TMZ resistance. Oxygen therapy has previously been reported to potentiate the effect of chemotherapy in cancer. In this study, we investigated whether hyperoxia can enhance the TMZ-induced cytotoxicity of human GBM cells, and whether and how it would resensitize TMZ-resistant GBM cells to TMZ. TMZ-sensitive human GBM cells (D54-S and U87-S) were treated with TMZ to develop isogenic subclones of TMZ-resistant cells (D54-R and U87-R). All cell lines were then exposed to different oxygen levels (1, 21, 40, or 80 %), with or without concomitant TMZ treatment, before assessment of cell cytotoxicity and morphology. Cell death and survival pathways elicited by TMZ and/or hyperoxia were elucidated by western blotting. Our results showed that TMZ sensitivity of both chemo-sensitive and resistant cells was enhanced significantly under hyperoxia. At the cell line-specific optimum oxygen concentration (D54-R, 80 %; U87-R, 40 %), resistant cells had the same response to TMZ as the parent chemosensitive cells under normoxia via the caspase-dependent pathway. Both TMZ and hyperoxia were associated with increased phosphorylation of ERK p44/42 MAPK (Erk1/2), but to a lesser extent in D54-R cells, suggesting that Erk1/2 activity may be involved in regulation of hyperoxia and TMZ-mediated cell death. Overall, hyperoxia enhanced TMZ toxicity in GBM cells by induction of apoptosis, possibly via MAPK-related pathways. Induced hyperoxia is a potentially promising approach for treatment of TMZ-resistant GBM., published_or_final_version

Cerebellar hemorrhage is the least common type of intracranial hemorrhage (ICH) encountered in clinical practice, and clinical data concerning the long-term outcomes are limited. This study aimed to investigate the long-term outcomes following spontaneous cerebellar hemorrhage in a cohort of Chinese patients. This single-center observational study was carried out between 1996 and 2010 and included 72 consecutive Chinese patients with a first spontaneous cerebellar hemorrhage. Of 440 patients with primary ICH, 72 (16.4%) had primary cerebellar hemorrhage. The mean age was 67.5 ± 12.3 years and patients were predominantly male (54%). The 30-day mortality was 16.7% with Glasgow coma scale ≤ 8 as the only predictor. At 6 months, 56.7% of patients who survived the first 30 days had a persistently poor functional status with modified Rankin scale score >2. After a mean follow-up of 4.7 years, 3.3% of patients had recurrent ICH, a recurrence rate of 7.3 per 1,000 patient-years. Ischemic stroke occurred in 12% of patients, an incidence of 25.5 per 1,000 patient-years. This study provided data on the long-term outcome of post-cerebellar hemorrhage in Chinese patients.

Glioblastoma is a type of highly malignant primary brain tumour. By means of ion excretion and the associated obligatory water loss, glioma cells can change shapes and undergo extensive migration and invasion. This study investigated the effects of inhibition of ion excretion in glioma cells.The expression of chloride channels (ClCs) and metalloproteinase-2 (MMP-2) was studied in two human glioma cell lines (STTG1 and U251-MG). The effects of ClC inhibition with chlorotoxin (a ClC-3 inhibitor), 5-nitro-2-3-phenylpropylamino benzoic acid (NPPB) (a non-specific ClC inhibitor), and ClC-3 siRNA knockdown were studied.Both STTG1 and U251-MG cells expressed ClC family members ClC-2, -3, -4, -5, -6 and -7, as well as MMP-2. Glioma cell invasion was markedly but not completely inhibited by ClC-3 and MMP-2 siRNA knockdown, and by chlorotoxin treatment. Addition of chlorotoxin to siRNA-treated glioma cells only slightly increased the suppression of invasion. In contrast, invasion was completely blocked by the non-specific ClC blocker NPPB.ClCs are crucial in glioma cell migration and invasion. Blockade of a single ClC, however, is not sufficient to achieve complete inhibition of glioma cell invasion, suggesting that any future therapy should be targeted at pharmacological blockade of multiple ClCs.

Traumatic brain injury (TBI) or brain surgery may cause extensive loss of cerebral parenchyma. However, no strategy for reconstruction has been clinically effective. Our previous study had shown that self-assembling peptide nanofiber scaffold (SAPNS) can bridge the injured spinal cord, elicit axon regeneration, and eventually promote locomotor functional recovery. In the present study we investigated the effect of SAPNS for the reconstruction of acutely injured brain. The lesion cavity of the injured cortex was filled with SAPNS or saline immediately after surgically induced TBI, and the rats were killed 2 days, 2 weeks, or 6 weeks after the surgery for histology, immunohistochemistry, and TUNEL studies. Saline treatment in the control animals resulted in a large cavity in the injured brain, whereas no cavity of any significant size was found in the SAPNS-treated animals. Around the lesion site in control animals were many macrophages (ED1 positive) but few TUNEL-positive cells, indicating that the TBI caused secondary tissue loss mainly by means of necrosis, not apoptosis. In the SAPNS-treated animals the graft of SAPNS integrated well with the host tissue with no obvious gaps. Moreover, there were fewer astrocytes (GFAP positive) and macrophages (ED1 positive) around the lesion site in the SAPNS-treated animals than were found in the controls. Thus, SAPNS may help to reconstruct the acutely injured brain and reduce the glial reaction and inflammation in the surrounding brain tissue. From the Clinical Editor Self-assembling peptide nanofiber scaffold (SAPNS) was reported earlier to bridge the injured spinal cord, elicit axon regeneration, and promote locomotor recovery. In this study the effect of SAPNS for the reconstruction of acutely injured brain was investigated. In SAPNS-treated animals the graft integrated well with the host tissue with no obvious gaps. SAPNS may help to reconstruct the acutely injured brain and reduced the glial reaction and inflammation in the surrounding brain tissue.

Background Primary central nervous system (CNS) natural killer (NK)-cell lymphoma is rare with only 7 cases reported previously. Magnetic resonance spectroscopy (MRS) and [ 18 F]fluorodeoxyglucose (FDG) positron emission tomography (PET) are frequently used for disease diagnosis and monitoring. Choline (CHO) PET is gaining popularity for identifying CNS lesions because of its high disease to background radioactivity ratio compared with FDG. Normally, CNS lymphoma shows high choline uptake on CHO-PET and a high choline peak on MRS. We present an unusual case of primary CNS NK-cell lymphoma with high choline uptake but absence of a high choline peak on MRS. Case Description A 39-year-old woman presented with subacute onset of cognitive deterioration. Magnetic resonance imaging of the brain showed a gadolinium-enhancing lesion in the left temporal lobe. MRS showed suppressed N -acetyl-aspartate and the absence of a high choline peak. CHO-PET confirmed that it was the only hypermetabolic lesion in the body with moderate uptake of choline. The differential diagnoses included encephalitis and neoplasm. She was initially treated for the former but did not respond to steroids, intravenous immunoglobulin, and plasmapheresis. A surgical biopsy later confirmed NK-cell lymphoma. She was then treated as primary CNS NK-cell lymphoma with intravenous and intrathecal chemotherapy. Conclusions We presented a unique case of primary CNS NK-cell lymphoma with atypical imaging findings characterized by moderately increased uptake of choline without a corresponding high choline peak on MRS. Although CHO-PET was suggestive of malignancy, surgical biopsy was required to confirm the diagnosis.

Temozolomide (TMZ) is the standard chemotherapeutic agent for human malignant glioma, but intrinsic or acquired chemoresistance represents a major obstacle to successful treatment of this highly lethal group of tumours. Obtaining better understanding of the molecular mechanisms underlying TMZ resistance in malignant glioma is important for the development of better treatment strategies. We have successfully established a passage control line (D54-C10) and resistant variants (D54-P5 and D54-P10) from the parental TMZ-sensitive malignant glioma cell line D54-C0. The resistant sub-cell lines showed alterations in cell morphology, enhanced cell adhesion, increased migration capacities, and cell cycle arrests. Proteomic analysis identified a set of proteins that showed gradual changes in expression according to their 50% inhibitory concentration (IC(50)). Successful validation was provided by transcript profiling in another malignant glioma cell line U87-MG and its resistant counterparts. Moreover, three of the identified proteins (vimentin, cathepsin D and prolyl 4-hydroxylase, beta polypeptide) were confirmed to be upregulated in high-grade glioma. Our data suggest that acquired TMZ resistance in human malignant glioma is associated with promotion of malignant phenotypes, and our reported molecular candidates may serve not only as markers of chemoresistance but also as potential therapeutic targets in the treatment of TMZ-resistant human malignant glioma, providing a platform for future investigations., published_or_final_version, Springer Open Choice, 21 Feb 2012

Intracranial meningioma is a common condition in the elderly population. Surgical resection in this group of patients may be rendered more hazardous due to the patients' ageing physiology and to multiple comorbidities. This systematic review and meta-analysis aimed to summarise outcome data of elderly patients undergoing intracranial meningioma resection.Using Ovid Medline, longitudinal studies published from 2002 to October 2012 with patients aged ≥ 65 years that described outcomes after intracranial meningioma resection were reviewed. Outcome data included mortality, recurrence, complication rate and length of hospital stay (LoS). Grading score systems and covariates for predicting outcome were collected. Pooled estimates of mortality data were calculated in StatsDirect using a random effects method. I(2) statistic was used to assess heterogeneity.Thirteen eligible studies with a total of 7010 patients (mean age, 73.6 years) were included, in which 82% patients came from one study. The pooled estimates of 90-day and 1-year mortality from available data were 6.6% (95% confidence interval [CI], 4.6-9.1%; n = 735; I(2) = 32.1) and 9.6% (95% CI, 7.0-12.6%; n = 564; I(2) = 24.3), respectively. The overall complication rates ranged from 2.7% to 29.8%, and the overall incidence of complications was 20% per patient (range, 3-61%). Other outcome data were heterogeneous mainly due to incomparable study designs.Current evidence indicates satisfactory surgical outcomes in the elderly with intracranial meningiomas, though the risks of complications necessitate careful consideration when deciding to operate. Risk factor analysis emphasised the importance of considering pre-operative status and comorbidities during patient selection. Future research should address the causes and prevention of complications, and compare outcomes between younger and older patients using detailed stratifications of tumour characteristics.