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.

PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer.

The PI3K/AKT/mTOR (PAM) signaling pathway is a highly conserved signal transduction network in eukaryotic cells that promotes cell survival, cell growth, and cell cycle progression. Growth factor signalling to transcription factors in the PAM axis is highly regulated by multiple cross-interactions with several other signaling pathways, and dysregulation of signal transduction can predispose to cancer development. The PAM axis is the most frequently activated signaling pathway in human cancer and is often implicated in resistance to anticancer therapies. Dysfunction of components of this pathway such as hyperactivity of PI3K, loss of function of PTEN, and gain-of-function of AKT, are notorious drivers of treatment resistance and disease progression in cancer. In this review we highlight the major dysregulations in the PAM signaling pathway in cancer, and discuss the results of PI3K, AKT and mTOR inhibitors as monotherapy and in co-administation with other antineoplastic agents in clinical trials as a strategy for overcoming treatment resistance. Finally, the major mechanisms of resistance to PAM signaling targeted therapies, including PAM signaling in immunology and immunotherapies are also discussed.

Thoracic aortic dissection presenting with bilateral haemothoraces: a potentially missed diagnosis.

Thoracic aortic dissection is a life-threatening diagnosis, which should not be missed. We present a case in which a patient who presented to the emergency department with chest pain was assessed and referred for admission for treatment of pneumonia, due to misinterpretation of a chest radiograph finding. The patient was re-reviewed and subsequently underwent further investigation, which confirmed aortic dissection. She underwent emergency thoracic endovascular aortic graft repair with stent graft insertion. This case demonstrates haemothorax as an uncommon complication of aortic dissection.

SIRIUS, Ultra-Scintillating Upconversion Breast Implant for Remote Orthotopic Photodynamic Therapy.

Present day strategies for delivery of wireless photodynamic therapy (PDT) to deep-seated targets are limited by the inadequacy of irradiance and insufficient therapeutic depth. Here we report the design and preclinical validation of a flexible wireless upconversion nanoparticle (UCNP) implant (SIRIUS) that is capable of large field, high intensity illumination for PDT of deep-seated tumors. The implant achieves this by incorporating submicrometer core-shell-shell NaYF4 UCNPs into its design, which significantly enhances upconversion efficiency and mitigates light loss from surface quenching. We demonstrate the efficacy of SIRIUS UCNP implant mediated PDT in preclinical breast cancer disease models. In our in vitro experiments, SIRIUS directed 5-Aminolevulinic Acid (5-ALA) based wireless PDT leads to significant reactive oxygen species (ROS) generation and tumor apoptosis in hormonal receptor+/HER2+ (MCF7) and triple-negative (MDA-MB-231) breast cancer cell lines. In our in vivo rodent model, SIRIUS-driven PDT is shown to be significant in regressing tumors when applied to orthotopically inoculated breast tumors. Following successful preclinical validation, we also describe a clinical prototype of UCNP breast implant with potential dual cosmetic and onco-therapeutic functions. SIRIUS is an upconversion breast implant for wireless PDT that fulfils all the design prerequisites necessary for seamless clinical translation.

Biomimetic nanotherapeutics for targeted drug delivery to glioblastoma multiforme.

Glioblastoma multiforme (GBM) is an aggressive brain tumor with poor prognosis and high mortality, with no curative treatment to date as limited trafficking across the blood-brain barrier (BBB) combined with tumor heterogeneity often leads to therapeutic failure. Although modern medicine poses a wide range of drugs that are otherwise efficacious in treating other tumors, they often do not achieve therapeutic concentrations in the brain, hence driving the need for more effective drug delivery strategies. Nanotechnology, an interdisciplinary field, has been gaining immense popularity in recent years for remarkable advancements such as nanoparticle (NP) drug carriers, which possess extraordinary versatility in modifying surface coatings to home in on target cells, including those beyond the BBB. In this review, we will be highlighting recent developments in biomimetic NPs in GBM therapy and how these allowed us to overcome the physiological and anatomical challenges that have long plagued GBM treatment.

Clinical Outcomes of 3D-Printed Bioresorbable Scaffolds for Bone Tissue Engineering-A Pilot Study on 126 Patients for Burrhole Covers in Subdural Hematoma.

Burrhole craniostomy is commonly performed for subdural hematoma (SDH) evacuation, but residual scalp depressions are often cosmetically suboptimal for patients. OsteoplugTM, a bioresorbable polycaprolactone burrhole cover, was introduced by the National University Hospital, Singapore, in 2006 to cover these defects, allowing osseous integration and vascular ingrowth. However, the cosmetic and safety outcomes of OsteoplugTM-C-the latest (2017) iteration, with a chamfered hole for subdural drains-remain unexplored. Data were collected from a single institution from April 2017 to March 2021. Patient-reported aesthetic outcomes (Aesthetic Numeric Analog (ANA)) and quality of life (EQ-5D-3L including Visual Analog Scale (VAS)) were assessed via telephone interviews. Clinical outcomes included SDH recurrence, postoperative infections, and drain complications. OsteoplugTM-C patients had significantly higher satisfaction and quality of life compared to those without a burrhole cover (ANA: 9 [7, 9] vs. 7 [5, 8], p = 0.019; VAS: 85 [75, 90] vs. 70 [50, 80], p = 0.021), and the absence of a burrhole cover was associated with poorer aesthetic outcomes after multivariable adjustment (adjusted OR: 4.55, 95% CI: 1.09-22.68, p = 0.047). No significant differences in other clinical outcomes were observed between OsteoplugTM-C, OsteoplugTM, or no burrhole cover. Our pilot study supports OsteoplugTM-C and its material polycaprolactone as suitable adjuncts to burrhole craniostomy, improving cosmetic outcomes while achieving comparable safety outcomes.

Computed tomography scan measurements of the globe and orbit to assess the risks of traumatic complications from medial peribulbar anaesthesia.

Complications of peribulbar anaesthesia include retrobulbar haemorrhage, globe perforation and brainstem anaesthesia. Therefore, this study took measurements relating the proximity of medial canthus to the optic nerve and also the safe angle between orbit and globe using 200 multiplanar reconstructed computed tomography (CT) images of the orbit. The principal results show that in 1.5% of the sample, the optic nerve is within 20 mm of the medial canthus, with a minimum distance of 15 mm. One% have a safe angle of 10 degrees or less between bone and globe. None of the demographic data, nor axial length were predictive of these results. We have shown that there are a minority of patients with unusual orbital anatomy. This places them at a theoretical higher risk of complications. These cases are not currently predicted by measured data.

Conditional disruption of AMP kinase in dopaminergic neurons promotes Parkinson's disease-associated phenotypes in vivo.

Emerging studies implicate energy dysregulation as an underlying trigger for Parkinson's disease (PD), suggesting that a better understanding of the molecular pathways governing energy homeostasis could help elucidate therapeutic targets for the disease. A critical cellular energy regulator is AMP kinase (AMPK), which we have previously shown to be protective in PD models. However, precisely how AMPK function impacts on dopaminergic neuronal survival and disease pathogenesis remains elusive. Here, we showed that Drosophila deficient in AMPK function exhibits PD-like features, including dopaminergic neuronal loss and climbing impairment that progress with age. We also created a tissue-specific AMPK-knockout mouse model where the catalytic subunits of AMPK are ablated in nigral dopaminergic neurons. Using this model, we demonstrated that loss of AMPK function promotes dopaminergic neurodegeneration and associated locomotor aberrations. Accompanying this is an apparent reduction in the number of mitochondria in the surviving AMPK-deficient nigral dopaminergic neurons, suggesting that an impairment in mitochondrial biogenesis may underlie the observed PD-associated phenotypes. Importantly, the loss of AMPK function enhances the susceptibility of nigral dopaminergic neurons in these mice to 6-hydroxydopamine-induced toxicity. Notably, we also found that AMPK activation is reduced in post-mortem PD brain samples. Taken together, these findings highlight the importance of neuronal energy homeostasis by AMPK in PD and position AMPK pathway as an attractive target for future therapeutic exploitation.

Impact of time to resumption of antithrombotic therapy on outcomes after surgical evacuation of chronic subdural hematoma: A multicenter cohort study.

BACKGROUND: The decision to resume antithrombotic therapy after surgical evacuation of chronic subdural hematoma (CSDH) requires judicious weighing of the risk of bleeding against that of thromboembolism. This study aimed to investigate the impact of time to resumption of antithrombotic therapy on outcomes of patients after CSDH drainage. METHODS: Data were obtained retrospectively from three tertiary hospitals in Singapore from 2010 to 2017. Outcome measures analyzed were CSDH recurrence and any thromboembolic events. Logistic and Cox regression tests were used to identify associations between time to resumption and outcomes. RESULTS: A total of 621 patients underwent 761 CSDH surgeries. Preoperative antithrombotic therapy was used in 139 patients. 110 (79.1%) were on antiplatelets and 35 (25.2%) were on anticoagulants, with six patients (4.3%) being on both antiplatelet and anticoagulant therapy. Antithrombotic therapy was resumed in 84 patients (60.4%) after the surgery. Median time to resumption was 71 days (IQR 29 - 201). Recurrence requiring reoperation occurred in 15 patients (10.8%), of which 12 had recurrence before and three after resumption. Median time to recurrence was 35 days (IQR 27 - 47, range 4 - 82 days). Recurrence rates were similar between patients that were restarted on antithrombotic therapy before and after 14, 21, 28, 42, 56, 70 and 84 days, respectively. Thromboembolic events occurred in 12 patients (8.6%), of which five had the event prior to restarting antithrombosis. CONCLUSIONS: Time to antithrombotic resumption did not significantly affect CSDH recurrence. Early resumption of antithrombotic therapy can be safe for patients with a high thromboembolic risk.

Development of a prognostic scoring system to predict risk of reoperation for contralateral hematoma growth after unilateral evacuation of bilateral chronic subdural hematoma.

Bilateral chronic subdural hematoma (bCSDH) is frequently drained unilaterally when the contralateral CSDH is small and asymptomatic. However, reoperation rates for contralateral CSDH growth can be high. We aimed to develop a prognostic scoring system to guide the selection of suitable patients for unilateral drainage of bCSDH. Data were collected retrospectively across three tertiary hospitals from 2010 to 2017 on all consecutive bCSDH patients aged 21 or above. Predictors of reoperation were identified using multivariable logistic regression. A prognostic score was developed and internally validated. 240 bCSDH patients were analyzed. 98 (40.8%) underwent unilateral and 142 (59.2%) underwent bilateral evacuation. Clinical outcomes were comparable between the unilateral and bilateral evacuation groups. Within the unilateral evacuation group, 4 (4.1%) had a reoperation for contralateral CSDH growth. Reoperation for contralateral CSDH was predicted by preoperative use of anticoagulants (OR = 15.0, 95% CI: 1.49-169.15, p = 0.017). Complete resolution of contralateral CSDH was predicted by its preoperative maximum width, with a cut-off of 9 mm producing the highest sensitivity and specificity (OR = 4.17 for ≤9 mm, 95% CI: 1.54-11.11, p = 0.004). Using our prognostic score, reoperation rate for contralateral CSDH was 1.6%, 3.6%, 16.7%, and 50.0% in low-risk, moderate-risk, high-risk and very high-risk patients, respectively. With each increase of 1 in the prognostic score, patients were 4 times as likely to undergo reoperation for contralateral CSDH (OR = 3.98, 95% CI: 1.36-13.53, p = 0.013). Our proposed risk score may be used as an adjunct in clinical decision making for bCSDH patients undergoing unilateral evacuation.

Mitochondrial Dysfunction and Parkinson's Disease-Near-Infrared Photobiomodulation as a Potential Therapeutic Strategy.

As the main driver of energy production in eukaryotes, mitochondria are invariably implicated in disorders of cellular bioenergetics. Given that dopaminergic neurons affected in Parkinson's disease (PD) are particularly susceptible to energy fluctuations by their high basal energy demand, it is not surprising to note that mitochondrial dysfunction has emerged as a compelling candidate underlying PD. A recent approach towards forestalling dopaminergic neurodegeneration in PD involves near-infrared (NIR) photobiomodulation (PBM), which is thought to enhance mitochondrial function of stimulated cells through augmenting the activity of cytochrome C oxidase. Notwithstanding this, our understanding of the neuroprotective mechanism of PBM remains far from complete. For example, studies focusing on the effects of PBM on gene transcription are limited, and the mechanism through which PBM exerts its effects on distant sites (i.e., its "abscopal effect") remains unclear. Also, the clinical application of NIR in PD proves to be challenging. Efficacious delivery of NIR light to the substantia nigra pars compacta (SNpc), the primary site of disease pathology in PD, is fraught with technical challenges. Concerted efforts focused on understanding the biological effects of PBM and improving the efficiency of intracranial NIR delivery are therefore essential for its successful clinical translation. Nonetheless, PBM represents a potential novel therapy for PD. In this review, we provide an update on the role of mitochondrial dysfunction in PD and how PBM may help mitigate the neurodegenerative process. We also discussed clinical translation aspects of this treatment modality using intracranially implanted NIR delivery devices.

Outcomes of Subdural Versus Subperiosteal Drain After Burr-Hole Evacuation of Chronic Subdural Hematoma: A Multicenter Cohort Study.

BACKGROUND: Although the use of a postoperative drain after burr-hole evacuation of chronic subdural hematoma (CSDH) is known to improve surgical outcomes, the superiority of subdural over subperiosteal drains has not been firmly established. Evidence comparing these 2 drain types is largely restricted to single-center series with limited numbers. Using a multicenter cohort study, we aimed to show noninferiority of subperiosteal drains vis-à-vis subdural drains after burr-hole evacuation of CSDH. METHODS: We performed a retrospective analysis of all consecutive patients with CSDH aged 21 years and older who had undergone burr-hole craniostomy across 3 tertiary hospitals from 2010 to 2017. Primary outcome measures included CSDH recurrence and modified Rankin Scale (mRS) score at 6 months. Outcomes of patients in the subdural and subperiosteal drain groups were analyzed and confounders were adjusted for using multivariate logistic regression. RESULTS: Of the 570 cases analyzed, 329 (57.7%) received a subdural drain and 241 (42.3%) received a subperiosteal drain. There was no significant difference between the 2 drain groups in CSDH recurrence (13.1% in the subdural group vs. 11.2% in the subperiosteal group; P = 0.502) or 6-month mRS score (27.2% with mRS 4-6 in the subdural group vs. 20.4% in the subperiosteal group; P = 0.188). Independent predictors of CSDH recurrence identified on multivariate analysis included premorbid mRS score 0-3 (P = 0.021), separated CSDH type on preoperative computed tomography scan (P = 0.002), and postoperative pneumocephalus of ≥15 mm (P = 0.005). CONCLUSIONS: Outcomes of subdural and subperiosteal drains after burr-hole craniostomy for CSDH are largely equivalent based on our findings.

Spinal Extradural Cyst: Case Report and Review of Literature.

BACKGROUND: Spinal extradural cyst (SEDC) accounts for <1% of spinal epidural lesions. It is commonly asymptomatic but can give rise to back pain and compressive neurologic symptoms. CASE DESCRIPTION: We report the case of a 51-year-old male who presented with gait difficulties over 5 months associated with occasional urge incontinence. Clinical examination revealed signs suggestive of thoracic myelopathy with bilateral lower limbs spasticity, decreased proprioception, and pinprick sensation. Magnetic resonance imaging showed a thoracic (T) 7-T9 extradural cystic lesion with an area of flow void on the right side between T8 and T9. A right hemilaminotomy was initially performed, and the dural defect was identified and repaired primarily. Unfortunately, there was a recurrence of the SEDC 2 weeks post operation and a T7-T9 laminoplasty with a complete excision was performed. CONCLUSIONS: Computed tomography myelography or magnetic resonance imaging flow study best visualizes the communication between the epidural cyst and subarachnoid space. The ideal surgical management for SEDC remains controversial. Our case suggests that there may be higher recurrence associated with fenestration of the SEDC and closure of the dural defect, but perhaps higher complications associated with complete excision. We present a case report and literature review of the terminology, presentation, recommended investigations, management, and outcomes of patients with SEDC.

The "Blush" Sign on Computed Tomography Angiography is an Independent Predictor of Hematoma Progression in Primary Hypertensive Hemorrhage.

BACKGROUND AND PURPOSE: Hypertension is an important etiology of intracerebral hemorrhage (ICH) in neurosurgical practice. Contrast extravasation on computed tomography angiography, known as the "spot sign", has been described as an independent predictor of hematoma progression and clinical deterioration. However, its role in hypertensive ICH alone has not been determined and is the primary aim of this study. MATERIALS AND METHODS: A retrospective review was carried out of patients with hypertensive ICH admitted to our institution between May 2014 and December 2016. Evaluation of the neuroimaging studies of these patients revealed two distinct morphologies, "spot" and "blush" sign. These distinct signs and covariates were tested for association with hematoma expansion and mortality using multivariate logistic regression. The accuracy of the "spot" and "blush" signs as predictors of hematoma expansion and mortality was determined using receiver-operator characteristic (ROC) analysis. RESULTS: A total of 54 patients were identified as hypertensive ICH during the study period. "spot" sign was observed in 11 (20.4%) of the study population. Contrast extravasation (blush-sign) was seen in 7 (14.8%) patients. The "blush" was an independent predictor of hematoma expansion (odds ratio [OR] 6.052; confidence interval [CI] 1.036-15.945 [P = .012]) and mortality (OR 3.305; CI 1.240-25.414 [P = .032]). With ROC analysis, the "blush" sign was found to have a better predictive value for significant hematoma expansion (area under the curve [AUC]: .795) than the spot sign (AUC: .432). CONCLUSION: The "blush" sign has better accuracy for predicting hematoma expansion in hypertensive ICH and could be used to risk stratify these patients for early therapeutic interventions.

Report of a Novel Case of Anaplastic Olfactory Groove Meningioma and Its Methylation Subtype.

We report a novel case of a World Health Organization grade 3 anaplastic meningioma arising from the olfactory groove in an 83-year-old woman. Molecular and methylation profiling confirm this lesion to be an NF2 subtype, methylation class intermediate type B meningioma. As most meningiomas in this location are indolent SMO subtype lesions, our report suggests that even though rare, aggressive NF2 subtype meningiomas can also occur along the midline anterior skull base.

Spontaneous obliteration highlights the dynamic nature of cerebral arteriovenous malformations: A case report and review of the literature.

BACKGROUND: Cerebral arteriovenous malformations (AVMs) are dynamic lesions and have been documented to arise de novo, enlarge, regress, obliterate, and even recur. Spontaneous obliteration of AVM is a rare and poorly understood phenomenon. CASE DESCRIPTION: We present a case of spontaneous obliteration of AVM in a 60-year-old gentleman who presented with intraparenchymal hemorrhage from a ruptured right parieto-occipital AVM. Angiography performed before gamma knife surgery 4 months after his initial presentation demonstrated complete absence of AVM. CONCLUSION: In our center's 20-year experience of treatment of cerebral AVMs (approximately 600 cases), this is the only case that has been aborted due to spontaneous obliteration leading us to infer that the incidence of spontaneous AVM obliteration is <1%. Spontaneous obliteration of AVM is a rare but well-established phenomenon that bears testimony to the dynamics of this vascular disorder.

Primary intracranial germ cell tumours: experience of a single South-East Asian institution.

Primary intracranial germ cell tumours (ICGCT) are a rare group of brain tumours arising predominantly in the paediatric and pre-adult population, accounting for up to 9.5% of paediatric brain tumours in East Asia. The National Cancer Centre Singapore (NCCS) is a tertiary referral centre for patients from all over South-East Asia. Our study aims to describe the characteristics of ICGCT patients in South-East Asia. Data on all patients with ICGCT who were seen at the Therapeutic Radiology Department of NCCS from 2000 to 2013 were collected retrospectively. Patient demographics, disease characteristics and treatment outcomes were analysed. Characteristics and survival of our patients were similar to other centres. Pure germinomas demonstrated 5 year overall survival (OS) and disease-free survival (DFS) rates of 89.2% (95% confidence interval [CI] 60.2-97.5) and 85.2% (95%CI 60.8-95.0) respectively. Secreting germinomas, non-germinomatous germ cell tumours and mixed germ cell tumours were evaluated together and demonstrated 5 year OS of 70.6% (95%CI 41.0-87.3) and DFS of 61.4% (95%CI 31.9-81.3). Patients ⩽ 12 years had marginally better 5 year OS than their older counterparts (81.0% [95%CI 49.5-93.9] versus 77.9% [95%CI 47.3-92.0], respectively). Patients who underwent extended field radiotherapy had longer OS and DFS than those who received local field irradiation. Treatment outcomes of our ICGCT patients are comparable with those in other Asian and Western centres. Extended field radiotherapy is a pivotal component of ICGCT treatment. Adding chemotherapy confers no extra survival benefit in treating germinomas. Treatment of mixed germ cell tumours and non-germinomatous germ cell tumours involves a multidisciplinary approach that varies for each histological subtype.