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.

Endovascular coiling versus neurosurgical clipping in the management of aneurysmal subarachnoid haemorrhage in the elderly: a multicenter cohort study.

The comparability of endovascular coiling over neurosurgical clipping has not been firmly established in elderly patients with aneurysmal subarachnoid haemorrhage (aSAH). Data were obtained from all patients with aSAH aged ≥60 across three tertiary hospitals in Singapore from 2014 to 2019. Outcome measures included modified Rankin Scale (mRS) score at 3 and at 6 months, and in-hospital mortality. Of the 134 patients analyzed, 84 (62.7%) underwent coiling and 50 (37.3%) underwent clipping. The endovascular group showed a higher incidence of good mRS score 0-2 at 3 months (OR = 2.45 [95%CI:1.16-5.20];p = 0.018), and a lower incidence of in-hospital mortality (OR = 0.31 [95%CI:0.10-0.91];p = 0.026). There were no significant difference between the two treatment groups in terms of good mRS score at 6 months (OR = 1.98 [95%CI:0.97-4.04];p = 0.060). There were no significant differences in the incidence of complications, such as aneurysm rebleed, delayed hydrocephalus, delayed ischemic neurological deficit and venous thromboembolism between the two treatment groups. However, fewer patients in the coiling group developed large infarcts requiring decompressive craniectomy (OR = 0.32 [95%CI:0.12-0.90];p = 0.025). Age, admission WFNS score I-III, and coiling were independent predictors of good functional outcomes at 3 months. Only age and admission WFNS score I-III remained significant predictors of good functional outcomes at 6 months. Endovascular coiling, compared with neurosurgical clipping, is associated with significantly better short term outcomes in carefully selected elderly patients with aSAH. Maximal intervention is recommended for aSAH in the young elderly age group and those with favorable WFNS scores.

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.

Trends in hemorrhagic stroke incidence and mortality in a National Stroke Registry of a multi-ethnic Asian population.

INTRODUCTION: High-quality epidemiological data on hemorrhagic stroke (HS) and its subtypes, intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH), remains limited in Asian ethnicities. We investigated the trends in HS incidence and 30-day mortality from 2005 to 2019 in a multi-ethnic Asian population from a national registry. PATIENTS AND METHODS: Data on all stroke cases from the Singapore Stroke Registry from 2005 to 2019 were collected. Cases were defined using centrally adjudicated review of diagnosis codes. Death outcomes were obtained by linkage with the national death registry. Incidence (per 100,000 people) and 30-day mortality (per 100 people) were measured as crude and age-standardized rates. Trends were analyzed using linear regression. RESULTS: We analyzed 19,017 cases of HS (83.9% ICH; 16.1% SAH). From 2005 to 2019, age-standardized incidence rates (ASIR) for HS remained stable from 34.4 to 34.5. However, age-standardized mortality rates (ASMR) decreased significantly from 29.5 to 21.4 (p < 0.001). For ICH, ASIR remained stable while ASMR decreased from 30.4 to 21.3 (p < 0.001); for SAH, ASIR increased from 2.7 to 6.0 (p = 0.006) while ASMR remained stable. In subgroup analyses, HS incidence increased significantly in persons <65 years (from 18.1 to 19.6) and Malays (from 39.5 to 49.7). DISCUSSION: From 2005 to 2019, ASIR of HS remained stable while ASMR decreased. Decreasing ASMR reflects improvements in the overall management of HS, consistent with global trends. CONCLUSION: Population health efforts to address modifiable risk factors for HS in specific demographic subgroups may be warranted to reduce incidence and mortality of HS.

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.

Ischemic and hemorrhagic strokes in young adults: Comparison of functional outcomes and return to work after stroke.

BACKGROUND: Functional recovery and return to work (RTW) after stroke are important rehabilitation goals that have significant impact on quality of life. Comparisons of functional outcomes and RTW between ischemic stroke (IS) and hemorrhagic stroke (HS), especially among young adults with stroke, have either been limited or yielded inconsistent results. We aimed to assess functional outcomes and ability to RTW in young adults with IS and HS, specifically primary spontaneous intracranial hemorrhage (SICH). METHODS: Young adults with IS or SICH aged 18-50-years-old were included. Outcome measures were modified Rankins score (mRS) on discharge and 3-months and RTW at 3-months after stroke. Good functional outcome was defined as an mRS of 0-2. RESULTS: We included 459 patients (71.5% male) with a mean age of 43.3 ± 5.7 years, comprising 49.2% IS and 50.8% SICH. Patients with SICH were more likely to have unfavourable shifts in ordinal mRS on discharge (OR 7.52, CI 5.18-10.87, p < 0.001) and at 3-months (OR 6.41, CI 4.17-9.80, p < 0.001). Patients with IS more likely achieved good functional outcomes (80.2% vs. 51.8%, p < 0.001) and were able to RTW at 3-months (54.4% vs. 36.3%, p = 0.004). Among all stroke patients with good functional outcomes, one-third did not RTW at 3-months. Patients with longer length of hospitalisation and higher National Institutes of Health Stroke Scale (NIHSS) score on admission, especially in the domain categories of level of consciousness, vision, motor function, language and neglect, were less likely to RTW at 3-months. CONCLUSION: Patients with IS were more likely to RTW when compared to SICH patients. Many young stroke patients did not RTW despite good functional outcomes. Further research should therefore address differences in prognosis and identify predictors that influence ability to RTW after stroke in the young adult population.

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.

Antiplatelet therapy in aneurysmal subarachnoid hemorrhage: an updated meta-analysis.

Antiplatelet therapy (AT) may serve to reduce the effects of aneurysmal subarachnoid hemorrhage (aSAH)-induced pro-coagulant state in the cerebral circulation. Several studies, however, have delivered conflicting conclusions on the efficacy of AT post aSAH. Systematic searches of Medline, Embase, and Cochrane Central were undertaken on 27th March 2023. The primary outcome was delayed cerebral ischaemia (DCI). Secondary outcomes were symptomatic and angiographic vasospasm, good functional outcome (modified Rankin Scale [mRS] with scores 0-2), hemorrhagic events, and in-hospital mortality. Twenty-two studies reporting 4378 patients with aSAH were included in the meta-analysis. AT was associated with lower rates of DCI (RR=0.62, 95% CI: 0.43; 0.89), symptomatic vasospasm (RR=0.63, 95% CI: 0.46; 0.86), and moderate/severe angiographic vasospasm (RR=0.74, 95% CI: 0.65; 0.84), with no effect on hemorrhagic complications (RR=1.36, 95% CI: 0.77; 2.41). When analyzing only post-ictal use of AT, AT additionally favored rates of good functional outcomes (RR=1.18, 95% CI: 1.10; 1.26) and in-hospital mortality (RR=0.56, 95% CI: 0.39; 0.80). In the subgroup treated with cilostazol, AT was associated with lower rates of DCI (RR=0.40, 95% CI: 0.32), symptomatic vasospasm (RR=0.47, 95% CI: 0.33; 0.65), moderate/severe angiographic vasospasm (RR=0.75, 95% CI: 0.57; 0.98) and good functional outcome (RR=1.24, 95% CI: 1.08; 1.43). In the surgically treated aSAH subgroup, AT favored rates of symptomatic vasospasm (RR=0.55, 95% CI: 0.30; 0.98), moderate/severe angiographic vasospasm (RR=0.70, 95% CI: 0.54; 0.90) and good functional outcome (RR=1.23, 95% CI: 1.09; 1.41). In the endovascularly treated aSAH subgroup, AT was associated with lower rates of in-hospital mortality (RR=0.60, 95% CI: 0.41; 0.88). In aSAH patients, post-ictal AT is associated with benefits in terms of rates of DCI, vasospasm, good functional outcomes, and in-hospital mortality without an increased risk of hemorrhagic events.

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.

The role of intracranial pressure variability as a predictor of intracranial hypertension and mortality in critically ill patients.

OBJECTIVE: Intracranial pressure (ICP) monitoring is a widely utilized and essential tool for tracking neurosurgical patients, but there are limitations to the use of a solely ICP-based paradigm for guiding management. It has been suggested that ICP variability (ICPV), in addition to mean ICP, may be a useful predictor of neurological outcomes, as it represents an indirect measure of intact cerebral pressure autoregulation. However, the current literature regarding the applicability of ICPV shows conflicting associations between ICPV and mortality. Thus, the authors aimed to investigate the effect of ICPV on intracranial hypertensive episodes and mortality using the eICU Collaborative Research Database version 2.0. METHODS: The authors extracted from the eICU database 1,815,676 ICP readings from 868 patients with neurosurgical conditions. ICPV was computed using two methods: the rolling standard deviation (RSD) and the absolute deviation from the rolling mean (DRM). An episode of intracranial hypertension was defined as at least 25 minutes of ICP > 22 mm Hg in any 30-minute window. The effects of mean ICPV on intracranial hypertension and mortality were computed using multivariate logistic regression. A recurrent neural network with long short-term memory was used for time-series predictions of ICP and ICPV to prognosticate future episodes of intracranial hypertension. RESULTS: A higher mean ICPV was significantly associated with intracranial hypertension using both ICPV definitions (RSD: aOR 2.82, 95% CI 2.07-3.90, p < 0.001; DRM: aOR 3.93, 95% CI 2.77-5.69, p < 0.001). ICPV was significantly associated with mortality in patients with intracranial hypertension (RSD: aOR 1.28, 95% CI 1.04-1.61, p = 0.026, DRM: aOR 1.39, 95% CI 1.10-1.79, p = 0.007). In the machine learning models, both definitions of ICPV achieved similarly good results, with the best F1 score of 0.685 ± 0.026 and an area under the curve of 0.980 ± 0.003 achieved with the DRM definition over 20 minutes. CONCLUSIONS: ICPV may be useful as an adjunct for the prognostication of intracranial hypertensive episodes and mortality in neurosurgical critical care as part of neuromonitoring. Further research on predicting future intracranial hypertensive episodes with ICPV may help clinicians react expediently to ICP changes in patients.

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.