METTL8 links mt-tRNA m3C modification to the HIF1α/RTK/Akt axis to sustain GBM stemness and tumorigenicity.

Epitranscriptomic RNA modifications are crucial for the maintenance of glioma stem cells (GSCs), the most malignant cells in glioblastoma (GBM). 3-methylcytosine (m3C) is a new epitranscriptomic mark on RNAs and METTL8 represents an m3C writer that is dysregulated in cancer. Although METTL8 has an established function in mitochondrial tRNA (mt-tRNA) m3C modification, alternative splicing of METTL8 can also generate isoforms that localize to the nucleolus where they may regulate R-loop formation. The molecular basis for METTL8 dysregulation in GBM, and which METTL8 isoform(s) may influence GBM cell fate and malignancy remain elusive. Here, we investigated the role of METTL8 in regulating GBM stemness and tumorigenicity. In GSC, METTL8 is exclusively localized to the mitochondrial matrix where it installs m3C on mt-tRNAThr/Ser(UCN) for mitochondrial translation and respiration. High expression of METTL8 in GBM is attributed to histone variant H2AZ-mediated chromatin accessibility of HIF1α and portends inferior glioma patient outcome. METTL8 depletion impairs the ability of GSC to self-renew and differentiate, thus retarding tumor growth in an intracranial GBM xenograft model. Interestingly, METTL8 depletion decreases protein levels of HIF1α, which serves as a transcription factor for several receptor tyrosine kinase (RTK) genes, in GSC. Accordingly, METTL8 loss inactivates the RTK/Akt axis leading to heightened sensitivity to Akt inhibitor treatment. These mechanistic findings, along with the intimate link between METTL8 levels and the HIF1α/RTK/Akt axis in glioma patients, guided us to propose a HIF1α/Akt inhibitor combination which potently compromises GSC proliferation/self-renewal in vitro. Thus, METTL8 represents a new GBM dependency that is therapeutically targetable.

Adjuvant radiotherapy versus observation after gross total resection of WHO grade II ependymoma: a systematic review and individual-participant data meta-analysis.

BACKGROUND: The role of adjuvant radiotherapy (RT) after gross total resection (GTR) of the World Health Organization (WHO) grade II ependymoma is controversial. Therefore, we aimed to compare the outcomes of adjuvant RT against observation after GTR of WHO grade II ependymoma. We also compared the outcomes of adjuvant RT against observation after subtotal resection (STR) of WHO grade II ependymoma and performed further subgroup analysis by age and tumor location. METHODS: PubMed and Embase were systematically reviewed for studies published up till 25 November 2022. Studies that reported individual-participant data on patients who underwent surgery followed by adjuvant RT/observation for WHO grade II ependymoma were included. The exposure was whether adjuvant RT was administered, and the outcomes were recurrence and overall survival (OS). Subgroup analyses were performed by the extent of resection (GTR or STR), tumor location (supratentorial or infratentorial), and age at the first surgery (<18 or ≥18 years old). RESULTS: Of the 4,647 studies screened, three studies reporting a total of 37 patients were included in the analysis. Of these 37 patients, 67.6% (25 patients) underwent GTR, and 51.4% (19 patients) underwent adjuvant RT. Adjuvant RT after GTR was not significantly associated with both recurrence (odds ratio =5.50; 95% confidence interval: 0.64-60.80; P=0.12) and OS (P=0.16). Adjuvant RT was also not significantly associated with both recurrence and OS when the cohort was analyzed as a whole and on subgroup analysis by age and tumor location. However, adjuvant RT was associated with significantly longer OS after STR (P=0.03) with the median OS being 6.33 years, as compared to 0.40 years for patients who underwent STR followed by observation. CONCLUSIONS: Based on our meta-analysis of 37 patients, administration of adjuvant RT after GTR was not significantly associated with improvement in OS or recurrence in patients with WHO grade II ependymoma. However, due to the small number of patients included in the analysis, further prospective controlled studies are warranted.

Effect of sarcopenia and frailty on outcomes among patients with brain metastases.

PURPOSE: Sarcopenia and frailty have been associated with increased mortality and duration of hospitalization in cancer. However, data investigating these effects in patients with brain metastases remain limited. This study aimed to investigate the effects of sarcopenia and frailty on clinical outcomes in patients with surgically treated brain metastases. METHODS: Patients who underwent surgical resection of brain metastases from 2011 to 2019 were included. Psoas cross-sectional area and temporalis thickness were measured by two independent radiologists (Cronbach's alpha > 0.98). Frailty was assessed using the Clinical Frailty Scale (CFS) pre-operatively and post-operatively. Overall mortality, recurrence, and duration of hospitalization were collected. Cox regression was performed for mortality and recurrence, and multiple linear regression for duration of hospitalization. RESULTS: 145 patients were included, with median age 60.0 years and 52.4% female. Psoas cross-sectional area was an independent risk factor for overall mortality (HR = 2.68, 95% CI 1.64-4.38, p < 0.001) and recurrence (HR = 2.31, 95% CI 1.14-4.65, p = 0.020), while post-operative CFS was an independent risk factor for overall mortality (HR = 1.88, 95% CI 1.14-3.09, p = 0.013). Post-operative CFS (ß = 15.69, 95% CI 7.67-23.72, p < 0.001) and increase in CFS (ß = 11.71, 95% CI 3.91-19.51, p = 0.004) were independently associated with increased duration of hospitalization. CONCLUSION: In patients with surgically treated brain metastases, psoas cross-sectional area was an independent risk factor for mortality and recurrence, while post-operative CFS was an independent risk factor for mortality. Post-operative frailty and increase in CFS significantly increased duration of hospitalization. Measurement of psoas cross-sectional area and CFS may aid in risk stratification of surgical candidates for brain metastases.

Is two-staged gamma knife surgery a reasonable management option for very large cerebellar metastases? A case series of three patients.

OBJECTIVE: Two-staged gamma knife surgery (GKS) is a method that may extend the upper tumor volume limit for using GKS in the management of brain metastases. However, the safety of treating very large posterior fossa lesions with this technique has not been well demonstrated. Therefore, we analyzed our experience in treating cerebellar metastases larger than 12 cm3 with two-staged GKS. METHODS: Four consecutive patients harboring 12 to 30 cm3 cerebellar metastases scheduled two-staged GKS were included in the study, and all but one patient completed the treatment. The treatment doses were 10-13 Gy. All patients were followed with regular MR imaging and clinical assessments, and the tumor volumes were measured on all treatment and follow-up images. RESULTS: Tumor progression was not demonstrated in any of the patients. Tumor volumes decreased by, on average, more than half between the two stages. The median survival was 22 months, and no patient died due to intracranial tumor progression. Peritumoral edema at the first GKS resolved in all patients, replaced by asymptomatic mild T2 changes in two of them not requiring any treatment. No radiation-induced complication has developed thus far. CONCLUSION: Staged GKS seems to be a feasible management option for very large cerebellar metastases.

Outcomes after surgical revascularization for adult Moyamoya disease: A Southeast Asian tertiary centre experience.

There are numerous studies on the natural history and outcomes of adult Moyamoya disease (MMD) in the literature, but limited data from Southeast Asian cohorts. Hence, we aimed to retrospectively review the clinical characteristics and outcomes after surgical revascularization for adult MMD in our Southeast Asian cohort. Patients were included if they were above 18 years old at the first surgical revascularization for MMD, and underwent surgery between 2012 and 2022 at the National University Hospital, Singapore. The outcomes were transient ischemic attack (TIA), ischemic stroke, intracerebral hemorrhage, and all-cause mortality during the postoperative follow-up period. In total, 26 patients who underwent 27 revascularization procedures were included. Most patients were of Chinese ethnicity, and the mean (SD) age at the time of surgery was 47.7 (12.6) years. The commonest clinical presentation was intracerebral hemorrhage, followed by TIA and ischemic stroke. Direct revascularization with superficial temporal artery-middle cerebral artery (STA-MCA) bypass was the most common procedure (24/27 surgeries, 88.9 %). The mean (SD) follow-up duration was 4.2 (2.5) years, during which the overall incidence of postoperative TIA/stroke was 25.9 % (7/27 surgeries), with most cases occurring within 7 days postoperatively. There were no mortalities during the postoperative follow-up period. Risk factors for 30-day postoperative TIA/stroke included a higher number of TIAs/strokes preoperatively (p = 0.044) and indirect revascularization (p = 0.028). Diabetes mellitus demonstrated a trend towards an increased risk of 30-day postoperative TIA/stroke, but this was not statistically significant (p = 0.056). These high-risk patients may benefit from more aggressive perioperative antithrombotic and hydration regimens.

Prognostication of Outcomes in Spontaneous Intracerebral Hemorrhage: A Propensity Score-Matched Analysis with Support Vector Machine.

OBJECTIVE: The role of surgery in spontaneous intracerebral hemorrhage (SICH) remains controversial. We aimed to use explainable machine learning (ML) combined with propensity-score matching to investigate the effects of surgery and identify subgroups of patients with SICH who may benefit from surgery in an interpretable fashion. METHODS: We conducted a retrospective study of a cohort of 282 patients aged ≥21 years with SICH. ML models were developed to separately predict for surgery and surgical evacuation. SHapley Additive exPlanations (SHAP) values were calculated to interpret the predictions made by ML models. Propensity-score matching was performed to estimate the effect of surgery and surgical evacuation on 90-day poor functional outcomes (PFO). RESULTS: Ninety-two patients (32.6%) underwent surgery, and 57 patients (20.2%) underwent surgical evacuation. A total of 177 patients (62.8%) had 90-day PFO. The support vector machine achieved a c-statistic of 0.915 when predicting 90-day PFO for patients who underwent surgery and a c-statistic of 0.981 for patients who underwent surgical evacuation. The SHAP scores for the top 5 features were Glasgow Coma Scale score (0.367), age (0.214), volume of hematoma (0.258), location of hematoma (0.195), and ventricular extension (0.164). Surgery, but not surgical evacuation of the hematoma, was significantly associated with improved mortality at 90-day follow-up (odds ratio, 0.26; 95% confidence interval, 0.10-0.67; P = 0.006). CONCLUSIONS: Explainable ML approaches could elucidate how ML models predict outcomes in SICH and identify subgroups of patients who respond to surgery. Future research in SICH should focus on an explainable ML-based approach that can identify subgroups of patients who may benefit functionally from surgical intervention.

Management of first recurrence or progression of craniopharyngioma after resection alone: A systematic review and individual-participant data meta-analysis.

The initial management of craniopharyngioma is generally either gross total resection (GTR) or subtotal resection (STR) with adjuvant radiotherapy (RT). However, the optimal management strategy for recurrent/progressive craniopharyngioma remains unclear. In this systematic review and individual participant data meta-analysis, we aimed to compare the outcomes of surgery and/or RT for the first recurrence/progression of craniopharyngioma after resection alone. The exposure was the treatment that was administered for the first recurrence/progression, and the outcomes were tumor regrowth and overall survival (OS). Subgroup analyses were performed by age at the treatment for the first recurrence/progression (<18 or ≥ 18 years old), duration between the first treatment and the first recurrence/progression (<2 or ≥ 2 years), and the initial treatment that was administered (STR or GTR). Of the 2932 studies screened, 11 studies reporting a total of 80 patients were included. Across almost all subgroups, patients who received RT for the first recurrence/progression had a significantly lower risk of tumor regrowth than those who did not, regardless of whether surgery was performed and the extent of resection. There was no significant association between the treatment administered for the first recurrence/progression and OS, except for patients with a recurrence/progression < 2 years after the first treatment, where GTR was associated with a higher risk of mortality. For patients with the first recurrence/progression of craniopharyngioma after resection alone, RT should be considered for better local control. In cases where RT is not administered, GTR is preferred over STR provided it can be safely performed, for improved local control.

Intracranial Germ Cell Tumors.

Intracranial germ cell tumors are rare tumors occurring in adolescents and young adults, which include germinomas and non-germinomatous type germ cell tumors (NGGCT). In the past few decades, cooperative trial groups in Europe and North America have developed successful strategies to improve survival outcomes and decrease treatment-related toxicities. New approaches to establishing diagnosis have deferred the need for radical surgery. The 5-year event-free survival (EFS) is above 90% and even patients who present with metastatic germinoma can still be cured with chemotherapy and craniospinal irradiation. The combination of surgery, chemotherapy, and radiation therapy is tailored to patients based on grouping and staging. For NGGCT, neoadjuvant chemotherapy followed by delayed surgery for residual disease and radiotherapy can yield a 5-year EFS of 70%. Further strategies should focus on reducing long-term complications while preserving high cure rates.

Presenting characteristics, histological subtypes and outcomes of adult central nervous system tumours: retrospective review of a surgical cohort.

Introduction: The most recent local study on the incidence of histological subtypes of all brain and spinal tumours treated surgically was published in 2000. In view of the outdated data, we investigated the presenting characteristics, histological subtypes and outcomes of adult patients who underwent surgery for brain or spinal tumours at our institution. Methods: A single-centre retrospective review of 501 patients who underwent surgery for brain or spinal tumours from 2016 to 2020 was conducted. The inclusion criteria were (a) patients who had a brain or spinal tumour that was histologically verified and (b) patients who were aged 18 years and above at the time of surgery. Results: Four hundred and thirty-five patients (86.8%) had brain tumours and 66 patients (13.2%) had spinal tumours. Patients with brain tumours frequently presented with cranial nerve palsy, headache and weakness, while patients with spinal tumours frequently presented with weakness, numbness and back pain. Overall, the most common histological types of brain and spinal tumours were metastases, meningiomas and tumours of the sellar region. The most common complications after surgery were cerebrospinal fluid leak, diabetes insipidus and urinary tract infection. In addition, 15.2% of the brain tumours and 13.6% of the spinal tumours recurred, while 25.7% of patients with brain tumours and 18.2% of patients with spinal tumours died. High-grade gliomas and metastases had the poorest survival and highest recurrence rates. Conclusion: This study serves as a comprehensive update of the epidemiology of brain and spinal tumours and could help guide further studies on brain and spinal tumours.

Effect of blood type on mortality among patients with brain metastases.

OBJECTIVE: ABO blood type has been associated with mortality among patients with cancer, but this association has thus far not been investigated among patients with brain metastases. Hence, we aimed to investigate the association between ABO blood type and mortality among patients who underwent surgical resection of brain metastases. METHODS: A single-center retrospective study of patients who underwent surgical resection of brain metastases between 2011 and 2019 was conducted. Cox proportional hazards models were constructed, adjusting for potential confounders, to evaluate whether blood type was independently associated with overall mortality. RESULTS: A total of 158 patients were included in the analysis. The mean (SD) age of the cohort was 59.3 (12.0) years, and 67.7% of patients were female. The median overall survival of patients with blood type AB was 11.2 months, while the median overall survival of patients with blood types O, B, and A were 11.7, 13.5, and 14.4 months respectively. On univariate analysis, patients with blood type AB had a higher risk of overall mortality (p = 0.017). On multivariate analysis adjusting for potential confounders, blood type AB was again associated with a higher risk of overall mortality (HR: 2.29, 95% CI: 1.11-4.72, p = 0.025). CONCLUSION: Blood type AB was independently associated with a higher risk of overall mortality among patients who underwent surgical resection of brain metastases, indicating the potential prognostic value of ABO blood type in brain metastases.

Management and Outcomes of Pediatric Craniopharyngioma: A 15-Year Experience in Singapore.

BACKGROUND: Craniopharyngiomas arise from the Rathke pouch and account for 1.2%-18.4% of pediatric primary brain tumors. Despite relatively good survival outcomes, patients face long-term morbidity from recurrences, visual impairment, and endocrinopathies, which reduce quality of life. We examined the management of pediatric craniopharyngiomas, their recurrences, and subsequent neuroendocrine sequelae in a tertiary center in South-East Asia. METHODS: A retrospective cohort of 12 paediatric patients (aged ≤18 years) with histologically confirmed diagnosis of craniopharyngioma treated from January 2002 to June 2017 was conducted. Data collected included demographics, clinical presentation, imaging data, treatment details, postoperative sequelae, and outcomes on mortality and recurrence. Survival analysis was conducted using Cox-proportional hazards model. RESULTS: The median follow-up time was 6.60 years (1.9-11.5 years). The mean age was 7.6 years (standard deviation 4.8) and 7 patients (58.3%) were male. The most common presenting symptoms were raised intracranial pressure (7, 58.3%), visual deficits (6, 50.0%), and preoperative endocrine abnormalities (2, 16.7%). Five patients underwent gross total resection (41.7%), and 7 underwent subtotal resection (58.3%). Overall survival was 75.0% (9 patients), and recurrence was 58.0% (7 patients). Median time-to-recurrence was 5.87 months (0.23-33.7, interquartile range 15.8), and median progression-free survival was 4.16 years (0.18-10.1, interquartile range 5.29). CONCLUSIONS: Long-term management of pediatric craniopharyngioma remains difficult, with multiple recurrences and long-term neuroendocrine sequelae impairing quality of life for patients. Further research into management of recurrences and neuroendocrine sequelae, as well as novel therapies to improve outcomes in these patients, may be warranted.

Postsurgical outcomes of nonfunctioning pituitary adenomas: a patient-level meta-analysis.

BACKGROUND: Surgical resection is the main treatment for symptomatic nonfunctioning pituitary adenomas (NFPA). We aimed to analyze the impact of surgical approach, completeness of resection, and postoperative radiotherapy on long-term progression-free survival (PFS) of NFPA, using individual patient data (IPD) meta-analysis. METHODS: An electronic literature searched was conducted on PubMed, EMBASE, and Web of Science from database inception to 6 November 2022. Studies describing the natural history of surgically resected NFPA, with provision of Kaplan-Meier curves, were included. These were digitized to obtain IPD, which was pooled in one-stage and two-stage meta-analysis to determine hazard ratios (HRs) and 95%CIs of gross total resection (GTR) versus subtotal resection (STR), and postoperative radiotherapy versus none. An indirect analysis of single-arm data between endoscopic endonasal (EES) and microscopic transsphenoidal (MTS) surgical technique was also performed. RESULTS: Altogether, eleven studies (3941 patients) were retrieved. PFS was significantly lower in STR than GTR (shared-frailty HR 0.32, 95%CI 0.27-0.39, p < 0.001). Postoperative radiotherapy significantly improved PFS compared to no radiotherapy (shared-frailty HR 0.20, 95%CI 0.15-0.26, p < 0.001), including in the subgroup of patients with STR (shared-frailty HR 0.12, 95%CI 0.08-0.18, p < 0.001). Similar PFS was observed between EES and MTS (indirect HR 1.09, 95%CI 0.92-1.30, p = 0.301). CONCLUSIONS: This systematic review and patient-level meta-analysis provides a robust prognostication of surgically treated NFPA. We reinforce current guidelines stating that GTR should be the standard of surgical resection. Postoperative radiotherapy is of considerable benefit, especially for patients with STR. Surgical approach does not significantly affect long-term prognosis. REGISTRATION: PROSPERO CRD42022374034.

Functional and Mortality Outcomes with Medical and Surgical Therapy in Malignant Posterior Circulation Infarcts: A Systematic Review.

BACKGROUND: There remains uncertainty regarding optimal definitive management for malignant posterior circulation infarcts (MPCI). While guidelines recommend neurosurgery for malignant cerebellar infarcts that are refractory to medical therapy, concerns exist about the functional outcome and quality of life after decompressive surgery. OBJECTIVE: This study aims to evaluate the outcomes of surgical intervention compared to medical therapy in MPCI. METHODS: In this systematic review, MEDLINE, Embase and Cochrane databases were searched from inception until 2 April 2021. Studies were included if they involved posterior circulation strokes treated with neurosurgical intervention and reported mortality and functional outcome data. Data were collected according to PRISMA guidelines. RESULTS: The search yielded 6677 studies, of which 31 studies (comprising 723 patients) were included for analysis. From the included studies, we found that surgical therapy led to significant differences in mortality and functional outcomes in patients with severe disease. Neurological decline and radiological criteria were often used to decide the timing for surgical intervention, as there is currently limited evidence for preventative neurosurgery. There is also limited evidence for the superiority of one surgical modality over another. CONCLUSION: For patients with MPCI who are clinically stable at the time of presentation, in terms of mortality and functional outcome, surgical therapy appears to be equivocal to medical therapy. Reliable evidence is lacking, and further prospective studies are rendered.

Risk for Brain Arteriovenous Malformation Rupture During Pregnancy and Puerperium.

BACKGROUND: The hemorrhage risk of unruptured and untreated cerebral arteriovenous malformations (AVMs) has been shown to be higher for female patients than male patients in their child bearing ages. Although it has been neurosurgical practice to advise female patients in their childbearing ages to postpone pregnancy until proven AVM obliteration, there is no literature consensus regarding this potential hemorrhage risk increase. OBJECTIVE: To accurately quantify the risk increase for AVM hemorrhage during pregnancy. METHODS: This study is based on data from previous publications, consisting of known age at the first AVM hemorrhage in 3425 patients. The risk increase during pregnancy could be calculated from the difference in age distribution for the first AVM hemorrhage between male patients and female patients, taking the average pregnancy time per female into account. A comparison was also made with data for all hospital discharges (13 751) in Germany 2008 to 2018 with the diagnosis brain AVM. RESULTS: The average pregnancy and puerperium time was 1.54 years per female in the patient population, which was used to determine the annual AVM hemorrhage risk during pregnancy to be around 9%. The increased risk during pregnancy was further evidenced by analysis of a subgroup of 105 female patients, for which pregnancy status at the time of hemorrhage was known. CONCLUSION: The quantified annual risk for AVM hemorrhage during pregnancy is about 3 times higher than that of male patients at corresponding age. This provides an important basis for advising female patients with patent AVMs about the increased risk for hemorrhage that a pregnancy would entail.

Risk factors for 30-day postoperative surgical site hematoma requiring evacuation after resection of brain metastases.

OBJECTIVE: To identify the risk factors for a 30-day postoperative surgical site hematoma requiring evacuation (POH) after surgical resection of brain metastases. METHODS: Patients who underwent surgical resection of brain metastases between 2011 and 2019 at our institution were included. Risk factors for a 30-day POH were identified using a multivariate logistic regression model. RESULTS: A total of 158 patients were included in the analysis. The mean (SD) age of the study population was 59.3 (12.0) years, and 82 (53.2%) patients were female. The incidence of a 30-day POH was 8.2% (13 patients). There was no statistically significant association between the occurrence of a 30-day POH and overall mortality (p = 0.100). On multivariate analysis, there was a statistically significant association between a 30-day POH and younger age (OR=0.91; 95% CI=0.83, 0.99; p = 0.035), higher BMI (OR=1.61; 95% CI=1.16, 2.46; p = 0.010), and blood type AB (OR=21.7; 95% CI=1.66, 522; p = 0.031). On receiver operating characteristic analysis, a threshold BMI of 25.1 kg/m2 and threshold age of 57 gave the optimum balance of sensitivity and specificity in predicting the occurrence of a 30-day POH. CONCLUSIONS: Patients below 57 years old, who have a BMI of above 25, and/or have blood type AB were at higher risk of developing a 30-day POH after surgical resection of brain metastases. Additional care in intraoperative hemostasis and postoperative monitoring may be indicated among patients who have these risk factors.

Effect of perioperative seizures on mortality and recurrence in patients with brain metastases.

Objective: To identify the independent risk factors for 30-day perioperative seizures, as well as to evaluate the effect of perioperative seizures on overall mortality and tumor recurrence among patients who underwent surgical resection of brain metastases. Methods: Patients who underwent surgical resection of brain metastases at our institution between 2011 and 2019 were included. 30-day perioperative seizures were defined as the presence of any preoperative or postoperative seizures diagnosed by a neurosurgeon or neurologist within 30 days of metastases resection. Independent risk factors for 30-day perioperative seizures were evaluated using multivariate logistic regression models. Kaplan-Meier plots and Cox regression models were constructed to evaluate the effects of 30-day perioperative seizures on overall mortality and tumor recurrence. Subgroup analyses were conducted for 30-day preoperative and 30-day postoperative seizures. Results: A total of 158 patients were included in the analysis. The mean (SD) age was 59.3 (12.0) years, and 20 (12.7%) patients had 30-day perioperative seizures. The presence of 30-day preoperative seizures (OR=41.4; 95% CI=4.76, 924; p=0.002) was an independent risk factor for 30-day postoperative seizures. Multivariate Cox regression revealed that any 30-day perioperative seizure (HR=3.25; 95% CI=1.60, 6.62; p=0.001) was independently and significantly associated with overall mortality but not tumor recurrence (HR=1.95; 95% CI=0.78, 4.91; p=0.154). Conclusions: Among patients with resected brain metastases, the presence of any 30-day perioperative seizure was independently associated with overall mortality. This suggests that 30-day perioperative seizures may be a prognostic marker of poor outcome. Further research evaluating this association as well as the effect of perioperative antiepileptic drugs in patients with resected brain metastases may be warranted.

Paediatric brain tumours in Singapore: A 15-year epidemiological and outcome study.

Paediatric brain tumours (PBTs) are the most common solid tumours in children. Previous publications reflect variations in incidence rates and frequency of histological types in different global populations. However, there are limited studies on the epidemiology of PBTs in Singapore. This study aims to summarise the epidemiology of paediatric brain tumours managed in Singapore. This is an ethics-approved retrospective study of all patients below 19 years old diagnosed with PBTs managed by Singapore's 2 tertiary paediatric neurosurgical centres, KK Women's and Children's Hospital (KKH) and the National University Hospital (NUH) over a 15-year period from 01 January 2002 to 31 December 2017. Data collected was analysed for age, gender, tumour characteristics, presenting complaints, location, treatment modalities, 1-year and 5-year overall survival (OS). A total of 396 patients were included. The mean age of diagnosis was 7.05 years (0.25-18; ± 4.83) and male-to-female ratio was 1.41:1. Top histological groups were astrocytic (30.6%), embryonal (26.0%), germ cell (11.1%), ependymoma (30, 7.58%) and craniopharyngioma (27, 6.82%). Outcomes included recurrence rate (31.2%), 1-year OS (89.5%) and 5-year OS (72.2%). Poorer 5-year OS were noted in embryonal tumours (47.0%; p < 0.001) and ependymoma (50.0%; p = 0.0074) patients. Of note, the following cohorts also had poorer OS at 5 years: supratentorial tumours (76.2%; p = 0.0426), radiotherapy (67.4%; p = 0.0467) and surgery (74.9%, HR; p < 0.001). Overall, our data reflects patient demographics, presenting complaints, treatment modalities and survival outcomes, that are comparable to other international paediatric neurosurgical centres.

Tenets for the Proper Conduct and Use of Meta-Analyses: A Practical Guide for Neurosurgeons.

Neurosurgeons today are inundated with rapidly amassing neurosurgical research publications. Systematic reviews and meta-analyses have consequently surged in popularity because, when executed properly, they constitute a high level of evidence and may save busy neurosurgeons many hours of combing and reviewing the literature for relevant articles. Meta-analysis refers to the quantitative (and discretionary) component of systematic reviews. It involves applying statistical techniques to combine effect sizes from multiple studies, which might offer more actionable insights than a systematic review without meta-analysis. Well-executed meta-analyses may prove instructive for clinical practice, but poorly conducted ones sow confusion and have the potential to cause harm. Unfortunately, recent audits have found the conduct and reporting of meta-analyses in neurosurgery (but also other surgical disciplines) to be relatively lackluster in methodologic rigor and compliance to established guidelines. Some of these deficiencies can be easily remedied through better awareness and adherence to prescribed standards-which will be reviewed in this article-but others stem from inherent problems with the source data (e.g., poor reporting of original research) as well as unique constraints faced by surgery as a field (e.g., lack of equipoise for randomized trials, or existence of learning curves for novel surgical procedures, which can lead to temporal heterogeneity), which may require unconventional tools (e.g., cumulative meta-analysis) to address. Therefore, it is also our goal to take stock of the unique issues encountered by surgeons who do meta-analysis and to highlight various techniques-some of which less well-known-to address such challenges.

Is there any survival benefit from post-operative radiation in brain metastases? A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: The benefits of adding upfront post-operative radiation, either whole-brain (WBRT) or cavity, after resection of brain metastases have been debated, particularly due to the long-term sequalae post radiation. We sought to compare the efficacy and safety between post-operative radiation versus resection alone. METHODS: We searched various biomedical databases from 1983 to 2018, for eligible randomized controlled trials (RCT). Outcomes studied were local recurrence (LR), overall survival (OS) and serious (Grade 3 + ) adverse events. We used the random effects model to pool outcomes. Methodological quality of each study was assessed using the Cochrane Risk of Bias tool. We employed the GRADE approach to assess the certainty of evidence. RESULTS: We included 5 RCTs comprising of 673 patients. The pooled odds ratio (OR) for LR is 0.26 (95% confidence interval (CI) 0.19-0.37, P < 0.001, GRADE certainty high), strongly supporting the use of post-operative radiation. Meta-regression analysis done comparing cavity and WBRT, did not show any difference in LR. The pooled hazard ratio (HR) for overall survival (OS) is 1.1 (95% CI 0.90-1.34, P = 0.37, GRADE certainty high). The treatment-related toxicities could not be pooled; the 2 studies which reported this did not find differences between the approaches. The risk of bias across the included studies was low. CONCLUSION: Our analysis confirms that upfront post-operative radiation significantly reduces the risk of LR. However, the lack of improvement in OS suggests that local control alone may not impact survival. Balancing local control, and neuro-cognitive effects of WBRT, cavity radiation seems to be a safe and effective option.

A systematic review and meta-analysis of the association between cyproterone acetate and intracranial meningiomas.

The influence of exposure to hormonal treatments, particularly cyproterone acetate (CPA), has been posited to contribute to the growth of meningiomas. Given the widespread use of CPA, this systematic review and meta-analysis attempted to assess real-world evidence of the association between CPA and the occurrence of intracranial meningiomas. Systematic searches of Ovid MEDLINE, Embase and Cochrane Controlled Register of Controlled Trials, were performed from database inception to 18th December 2021. Four retrospective observational studies reporting 8,132,348 patients were included in the meta-analysis. There was a total of 165,988 subjects with usage of CPA. The age of patients at meningioma diagnosis was generally above 45 years in all studies. The dosage of CPA taken by the exposed group (n = 165,988) was specified in three of the four included studies. All studies that analyzed high versus low dose CPA found a significant association between high dose CPA usage and increased risk of meningioma. When high and low dose patients were grouped together, there was no statistically significant increase in risk of meningioma associated with use of CPA (RR = 3.78 [95% CI 0.31-46.39], p = 0.190). Usage of CPA is associated with increased risk of meningioma at high doses but not when low doses are also included. Routine screening and meningioma surveillance by brain MRI offered to patients prescribed with CPA is likely a reasonable clinical consideration if given at high doses for long periods of time. Our findings highlight the need for further research on this topic.