Anatomical and surgical characteristics correlate with pachymeningeal failure in patients with brain metastases after neurosurgical resection and adjuvant stereotactic radiosurgery.

PURPOSE: Neurosurgery (NS) is an essential modality for large brain metastases (BM). Postoperative stereotactic radiosurgery (SRS) is the standard of care adjuvant treatment. Pachymeningeal failure (PMF) is a newly described entity, distinct from classical leptomeningeal failure (LMF), that is uniquely observed in postoperative patients treated with adjuvant SRS. We sought to identify risk factors for PMF in patients treated with NS + SRS. METHODS: From a prospective registry (2009 to 2021), we identified all patients treated with NS + SRS. Clinical, imaging, pathological, and treatment factors were analyzed. PMF incidence was evaluated using a competing risks model. RESULTS: 144 Patients were identified. The median age was 62 (23-90). PMF occurred in 21.5% (31/144). Female gender [Hazard Ratio (HR) 2.65, p = 0.013], higher Graded Prognostic Assessment (GPA) index (HR 2.4, p < 0.001), absence of prior radiation therapy (HR N/A, p = 0.018), controlled extracranial disease (CED) (HR 3.46, p = 0.0038), and pia/dura contact (PDC) (HR 3.30, p = 0.0053) were associated with increased risk for PMF on univariate analysis. In patients with PDC, wider target volumes correlated with reduced risk of PMF. Multivariate analysis indicated PDC (HR 3.51, p = 0.0053), piecemeal resection (HR 2.38, p = 0.027), and CED (HR 3.97, p = 0.0016) independently correlated with PMF risk. PMF correlated with reduced OS (HR 2.90, p < 0.001) at a lower rate compared to LMF (HR 10.15, p < 0.001). CONCLUSION: PMF correlates with tumor PDC and piecemeal resection in patients treated with NS + SRS. For unclear reasons, it is also associated with CED. In tumors with PDC, wider dural radiotherapy coverage was associated with a lower risk of PMF.

Comparative analysis of deeply phenotyped GBM cohorts of 'short-term' and 'long-term' survivors.

BACKGROUND: Glioblastoma (GBM) is an aggressive brain cancer that typically results in death in the first 15 months after diagnosis. There have been limited advances in finding new treatments for GBM. In this study, we investigated molecular differences between patients with extremely short (≤ 9 months, Short term survivors, STS) and long survival (≥ 36 months, Long term survivors, LTS). METHODS: Patients were selected from an in-house cohort (GLIOTRAIN-cohort), using defined inclusion criteria (Karnofsky score > 70; age < 70 years old; Stupp protocol as first line treatment, IDH wild type), and a multi-omic analysis of LTS and STS GBM samples was performed. RESULTS: Transcriptomic analysis of tumour samples identified cilium gene signatures as enriched in LTS. Moreover, Immunohistochemical analysis confirmed the presence of cilia in the tumours of LTS. Notably, reverse phase protein array analysis (RPPA) demonstrated increased phosphorylated GAB1 (Y627), SRC (Y527), BCL2 (S70) and RAF (S338) protein expression in STS compared to LTS. Next, we identified 25 unique master regulators (MR) and 13 transcription factors (TFs) belonging to ontologies of integrin signalling and cell cycle to be upregulated in STS. CONCLUSION: Overall, comparison of STS and LTS GBM patients, identifies novel biomarkers and potential actionable therapeutic targets for the management of GBM.

Endoscopic endonasal surgery for prolactinomas: prognostic factors for disease control and management of persistent disease.

Only a limited number of studies have focused on the results of the Endoscopic Endonasal Approach (EEA) for treatment of prolactinomas. We sought to assess the effectiveness of EEA for prolactinoma surgery, identify factors for disease remission, and present our approach for the management of persistent disease. Forty-seven prolactinomas operated over 10 years, with a mean follow-up of 59.9 months, were included. The primary endpoints were early disease remission and remission at last follow-up. Resistance/intolerance to DA were surgical indications in 76.7%. Disease remission was achieved in 80% of microprolactinomas and 100% of microprolactinomas enclosed by the pituitary. Early disease remission was correlated with female gender (p=0.03), lower preoperative PRL levels (p=0.014), microadenoma (p=0.001), lack of radiological hemorrhage (p=0.001), absence of cavernous sinus (CS) invasion (p<0.001), and extent of resection (EOR) (p<0.001). Persistent disease was reported in 48.9% of patients, with 47% of them achieving remission at last follow-up with DA therapy alone. Repeat EEA and/or radiotherapy were utilized in 6 patients, with 66.7% achieving remission. Last follow-up remission was achieved in 76.6%, with symptomatic improvement in 95.8%. Factors predicting last follow-up remission were no previous operation (p=0.001), absence of CS invasion (p=0.01), and EOR (p<0.001). Surgery is effective for disease control in microprolactinomas. In giant and invasive tumors, it may significantly reduce the tumor volume. A multidisciplinary approach may lead to long-term disease control in three-quarters of patients, with symptomatic improvement in an even greater proportion.

Clostridioides difficile infection in neurosurgical patients in a national centre over 10 years: less common but associated with longer hospital stays.

BACKGROUND: Clostridioides difficile infection (CDI) is a leading cause of healthcare-associated (HA) diarrhoea, contributing to patient morbidity and prolonged length-of-stay (LOS). We retrospectively assessed CDI over a decade in a national neurosurgical centre, with a multi-disciplinary approach to CDI surveillance and antimicrobial stewardship, by comparing CDI patients with other patient groups. METHODS: Data on CDI in neurosurgical inpatients between January 2012 and December 2021 were collated. Disease-specific variables were compared to other inpatients with CDI. Rates per 10,000 bed days used were calculated. Patient-specific differences were compared with neurosurgical patients without CDI. CDI rates by patient group were explored using odds ratio (OR) and χ2 analyses. Negative binomial regression was used to investigate CDI rates over time. RESULTS: Of 50 neurosurgical patients with CDI, all were HA; the average age was 53 years (standard deviation (SD) 16.3 years), 49 were first-episode CDI, and three had severe CDI. The majority (76.7%) had received recent antimicrobials. Compared with non-neurosurgical CDI patients, neurosurgical CDI rates differed significantly (1.9 versus 3.6 per 10,000 bed days used, p < 0.05), neurosurgical patients were younger (p ≤ 0.01), C. difficile testing was more likely to be requested by neurosurgeons (OR 2.4; p ≤ 0.01), and the proportion of severe CDI was higher (6% versus 2%, OR 3.0, p = 0.07, confidence interval (CI) 0.54 to 11.3). Within the neurosurgical cohort, CDI patients had an average LOS four times that of other patients (CI 15.2 to 35.1; p < 0.01) and were older (53.5 versus 47.8 years, CI 0.1 to 11 years; p < 0.05). Only one CDI outbreak was linked to neurosurgical patients. CONCLUSION: CDI in neurosurgery patients differed from the wider hospital, with greater awareness of CDI testing. Longer LOS impacted bed utilisation with limited capacity. Robust surveillance supports proactive antimicrobial stewardship programmes in this vulnerable population.

Subdural haematoma in the elderly: management and outcomes of a UK Major Trauma Centre.

BACKGROUND: An estimated 40% of all traumatic brain injury (TBI) occurs in ≥70-year-olds with a high prevalence of traumatic subdural haematoma (tSDH). It is anticipated that an expanding elderly population will lead to a proportional increase in the incidence of patients with tSDH presenting to UK trauma centres, but the long-term clinical outcomes and factors influencing functional outcomes in this patient group remain poorly understood. AIM: To examine the management and clinical outcomes for elderly (≥70 years) patients diagnosed with tSDH. METHODS: Patient data for this single-centre, retrospective cohort study were analysed from a Major Trauma Centre (MTC) electronic patient records between January 2013 and December 2019. RESULTS: Two hundred and eighty patients were included, 43% aged 70-79, 42% aged 80-89 and 15% >90. In total, 37% underwent a surgical intervention. The 6-month survival in the severe, moderate, and mild TBI groups was 14%, 43%, and 67%, respectively. The 6-month survival in the surgical group was 58%, vs. 60% in the conservatively managed group. Surgical intervention did not significantly impact Extended Glasgow Coma Score (GOS-E) at 6 months, regardless of injury severity. Advanced age (p = 0.04), mixed intracranial injuries (p < 0.0001), craniotomies (p = 0.03), and poor premorbid performance status (p = 0.02) were associated with worse survival and functional outcomes. CONCLUSIONS: Our study demonstrated that increasing age, increasing severity of TBI and poorer premorbid performance status were associated with significantly poorer 6-month survival and functional outcomes in elderly patients with tSDH. Burr hole evacuation was associated with better functional outcomes compared to craniotomy, but overall, there was no significant difference in the outcomes of the surgical and non-surgical groups. We identified strong risk factors for death and poor functional outcomes at 6-months which are important to consider when counselling patients and families about the long-term prognosis of elderly patients with tSDH and can help guide clinical decision-making.

S100B, GFAP, UCH-L1 and NSE as predictors of abnormalities on CT imaging following mild traumatic brain injury: a systematic review and meta-analysis of diagnostic test accuracy.

Biomarkers such as calcium channel binding protein S100 subunit beta (S100B), glial fibrillary acidic protein (GFAP), ubiquitin c-terminal hydrolase L1 (UCH-L1) and neuron-specific enolase (NSE) have been proposed to aid in screening patients presenting with mild traumatic brain injury (mTBI). As such, we aimed to characterise their accuracy at various thresholds. MEDLINE, SCOPUS and EMBASE were searched, and articles reporting the diagnostic performance of included biomarkers were eligible for inclusion. Risk of bias was assessed using the QUADAS-II criteria. A meta-analysis was performed to assess the predictive value of biomarkers for imaging abnormalities on CT. A total of 2939 citations were identified, and 38 studies were included. Thirty-two studies reported data for S100B. At its conventional threshold of 0.1 µg/L, S100B had a pooled sensitivity of 91% (95%CI 87-94) and a specificity of 30% (95%CI 26-34). The optimal threshold for S100B was 0.72 µg/L, with a sensitivity of 61% (95% CI 50-72) and a specificity of 69% (95% CI 64-74). Nine studies reported data for GFAP. The optimal threshold for GFAP was 626 pg/mL, at which the sensitivity was 71% (95%CI 41-91) and specificity was 71% (95%CI 43-90). Sensitivity of GFAP was maximised at a threshold of 22 pg/mL, which had a sensitivity of 93% (95%CI 73-99) and a specificity of 36% (95%CI 12-68%). Three studies reported data for NSE and two studies for UCH-L1, which precluded meta-analysis. There is evidence to support the use of S100B as a screening tool in mild TBI, and potential advantages to the use of GFAP, which requires further investigation.

Melanoma brain metastases in Ireland: surgical and systemic considerations.

BACKGROUND: Cerebral metastases is a common complication in patients with melanoma. There is a paucity of information in the Republic of Ireland regarding the factors associated with melanoma brain metastases (MBM). METHODS: Patients diagnosed with melanoma brain metastases in Ireland were retrospectively identified in Beaumont Hospital between 1999 and 2018. Patient demographics; age at diagnosis of primary melanoma, age at detection of MBM, year of detection of MBM, anatomical location of primary melanoma, BRAF mutation analysis and the number of metastases were investigated. Follow-up data were also derived, including overall survival. RESULTS: There has being a 158% increase in the incidence of primary melanoma from 1999 compared to 2016. Over the same time period 128 patients with melanoma brain metastases were diagnosed. There was a significant male predominance (n = 77/128; 60%; p < 0.0001). BRAF mutation and leptomeningeal disease were independent prognostic factors in our cohort with a median survival 8 months and 0.5 months, respectively. CONCLUSIONS: Male predominance, leptomeningeal disease and BRAF mutation represent important considerations in this population group. The results of this study add to our knowledge concerning outcomes in melanoma brain metastases and may be useful in clinical planning and future treatments.

The centrally restricted diffusion sign on MRI for assessment of radiation necrosis in metastases treated with stereotactic radiosurgery.

PURPOSE: Differentiation of radiation necrosis from tumor progression in brain metastases treated with stereotactic radiosurgery (SRS) is challenging. For this, we assessed the performance of the centrally restricted diffusion sign. METHODS: Patients with brain metastases treated with SRS who underwent a subsequent intervention (biopsy/resection) for a ring-enhancing lesion on preoperative MRI between 2000 and 2020 were included. Excluded were lesions containing increased susceptibility limiting assessment of DWI. Two neuroradiologists classified the location of the diffusion restriction with respect to the post-contrast T1 images as centrally within the ring-enhancement (the centrally restricted diffusion sign), peripherally correlating to the rim of contrast enhancement, both locations, or none. Measures of diagnostic accuracy and 95% CI were calculated for the centrally restricted diffusion sign. Cohen's kappa was calculated to identify the interobserver agreement. RESULTS: Fifty-nine patients (36 female; mean age 59, range 40 to 80) were included, 36 with tumor progression and 23 with radiation necrosis based on histopathology. Primary tumors included 34 lung, 12 breast, 5 melanoma, 3 colorectal, 2 esophagus, 1 head and neck, 1 endometrium, and 1 thyroid. The centrally restricted diffusion sign was seen in 19/23 radiation necrosis cases (sensitivity 83% (95% CI 63 to 93%), specificity 64% (95% CI 48 to 78%), PPV 59% (95% CI 42 to 74%), NPV 85% (95% CI 68 to 94%)) and 13/36 tumor progression cases (difference p < 0.001). Interobserver agreement was substantial, at 0.61 (95% CI 0.45 to 70.8). CONCLUSION: We found a low probability of radiation necrosis in the absence of the centrally restricted diffusion sign.

Brain Metastases: A Modern Multidisciplinary Approach.

Brain metastases (BM) are the most common intracranial neoplasm and represent a major clinical challenge across many medical disciplines. The incidence of BM is increasing, largely due to improvements in primary disease therapeutics conferring greater systemic control, and advancements in neuroimaging techniques and availability leading to earlier diagnosis. In recent years, the landscape of BM treatment has changed significantly with the advent of personalized targeted chemotherapies and immunotherapy, the adoption of focal radiotherapy (RT) for higher intracranial disease burden, and the implementation of new surgical strategies. The increasing permutations of options available for the treatment of patients diagnosed with BM necessitate coordinated care by a multidisciplinary team. This review discusses the current treatment regimens for BM as well as examines the salient features of a modern multidisciplinary approach.

Venous sinus thrombosis in traumatic brain injury: a major trauma centre experience.

BACKGROUND: This study explores the presentation, management and outcomes of traumatic venous sinus thrombosis (VST) and identifies risk factors associated with poor outcomes. METHODS: This study is a retrospective review of all patients with VST secondary to trauma who presented to a major trauma centre, between April 2015 and January 2020. VST was confirmed by CT venogram and a consultant neuroradiologist. RESULTS: Forty-six patients were identified (38 male), mean age of 43 (range 12-78) and median follow-up 10.2 months (range 0.7-39.1). Fifty-two percent presented as a severe traumatic brain injury, and all had an associated skull fractures overlying the sinus. Ninety-six percent had cerebral contusions, 96% had an intracranial haematoma, 91% had traumatic subarachnoid haemorrhage (tSAH) and 22% had acute cerebral infarction. Thirty-seven percent of the VSTs were occlusive. Fifty-eight percent had sustained, unprovoked intracranial pressure (ICP) spikes (> 20 mmHg). Fifty percent underwent surgical intervention-20% external ventricular drain and 46% craniotomy/craniectomy. Nine percent were treated with anticoagulation and 4% with antiplatelets, at a median of 13.5 days and 9.5 days post-injury, with no additional complications. Age > 60 was associated with poor outcome (GOS of 3-5) (p = 0.0098). On follow-up CT, 52% of the VSTs remained unchanged, 29% re-canalised, 14% improved and 5% worsened, independent of treatment. CONCLUSIONS: This study demonstrated a higher incidence of VST in severe TBI and strong associations with skull fractures, cerebral contusions, tSAH, raised ICP and surgical intervention. Management was inconsistent, with no difference in outcome with or without anticoagulation. Larger, prospective cohort studies are needed to better understand this condition and establish evidence-based guidelines.

ADAM22/LGI1 complex as a new actionable target for breast cancer brain metastasis.

BACKGROUND: Metastatic breast cancer is a major cause of cancer-related deaths in woman. Brain metastasis is a common and devastating site of relapse for several breast cancer molecular subtypes, including oestrogen receptor-positive disease, with life expectancy of less than a year. While efforts have been devoted to developing therapeutics for extra-cranial metastasis, drug penetration of blood-brain barrier (BBB) remains a major clinical challenge. Defining molecular alterations in breast cancer brain metastasis enables the identification of novel actionable targets. METHODS: Global transcriptomic analysis of matched primary and metastatic patient tumours (n = 35 patients, 70 tumour samples) identified a putative new actionable target for advanced breast cancer which was further validated in vivo and in breast cancer patient tumour tissue (n = 843 patients). A peptide mimetic of the target's natural ligand was designed in silico and its efficacy assessed in in vitro, ex vivo and in vivo models of breast cancer metastasis. RESULTS: Bioinformatic analysis of over-represented pathways in metastatic breast cancer identified ADAM22 as a top ranked member of the ECM-related druggable genome specific to brain metastases. ADAM22 was validated as an actionable target in in vitro, ex vivo and in patient tumour tissue (n = 843 patients). A peptide mimetic of the ADAM22 ligand LGI1, LGI1MIM, was designed in silico. The efficacy of LGI1MIM and its ability to penetrate the BBB were assessed in vitro, ex vivo and in brain metastasis BBB 3D biometric biohybrid models, respectively. Treatment with LGI1MIM in vivo inhibited disease progression, in particular the development of brain metastasis. CONCLUSION: ADAM22 expression in advanced breast cancer supports development of breast cancer brain metastasis. Targeting ADAM22 with a peptide mimetic LGI1MIM represents a new therapeutic option to treat metastatic brain disease.

Traumatic brain injury in the Republic of Ireland twenty-five years on: a comparison of two cohorts from a neurosurgical unit.

OBJECTIVE: We assessed for change in the number of admissions, demographics, mechanism, severity, operative management, length of stay, and in-hospital mortality of Traumatic Brain Injury (TBI) in patients admitted to a Neurosurgical Unit (NSU) in the Republic of Ireland in 2017 compared to 25 years previously. METHOD: We performed a retrospective cohort study of TBI admissions during 2017 and compared the results with a prospective cohort study covering a one-year period across 1992 and 1993. RESULTS: In 2017, 184 patients (5.78 per 100,000) were admitted, compared to 225 in 1992/1993 (7.31 per 100,000). Mean age increased by 8.5 years. The contribution of road traffic collisions (RTCs) decreased by 62% while sports injuries increased by 300%, led by soccer. Falls replaced RTCs as the leading mechanism of injury. We report a decrease in severe injuries (GCS≤8) of 52% while mild injuries (GCS≥13) increased by 58%. The number undergoing neurosurgery remained comparable (2017: 55%, 1992/1993: 48%), as did in-hospital mortality (13%, 16%). Mean length of stay decreased by four days. CONCLUSION: There has been a sizable change in the landscape of TBI as seen in the Republic of Ireland's national NSU including in demographics, mechanism of injury, and injury severity.

Metastasis of papillary thyroid carcinoma to the thoracic spine.

INTRODUCTION: Papillary thyroid carcinoma (PTC) is the most common form of well-differentiated thyroid carcinoma. Despite its well-differentiated microscopic features, PTC may be minimally or overtly invasive. We present the case of a patient in whom thoracic spinal cord compression was the first presentation of metastatic PTC. CASE REPORT: A 65-year-old woman presented with deteriorating mobility over a 2-month period. Her past history was significant for a right hemithyroidectomy 10 years prior. Examination revealed bilateral lower limb weakness, worse on the right side. Investigations showed a large extradural contrast-enhancing mass at the T7 spinal level. Laminectomy and debulking of this lesion was undertaken. Histopathological examination revealed PTC. The patient proceeded to further treatment with external beam radiotherapy. DISCUSSION: Spinal metastases are an unusual presentation of PTC. Further research into the outcomes for these patients is imperative to bettering our ability to care for these patients through a multi-modality approach.
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Predictors of early progression of surgically treated atypical meningiomas.

BACKGROUND: Clinical behaviour of atypical meningiomas is not uniform. While, as a group, they exhibit a high recurrence rate, some pursue a more benign course, whereas others progress early. We aim to investigate the imaging and pathological factors that predict risk of early tumour progression and to determine whether early progression is related to outcome. METHODS: Adult patients with WHO grade II meningioma treated in three regional referral centres between 2007 and 2014 were included. MRI and pathology characteristics were assessed. Gross total resection (GTR) was defined as Simpson 1-3. Recurrence was classified into early and late (≤ 24 vs. > 24 months). RESULTS: Among the 220 cases, 37 (16.8%) patients progressed within 24 months of operation. Independent predictors of early progression were subtotal resection (STR) (p = 0.005), parafalcine/parasagittal location (p = 0.015), peritumoural oedema (p = 0.027) and mitotic index (MI) > 7 (p = 0.007). Adjuvant radiotherapy was negatively associated with early recurrence (p = 0.046). Thirty-two per cent of patients with residual tumour and 26% after GTR received adjuvant radiotherapy. There was a significantly lower proportion of favourable outcomes at last follow-up (mRS 0-1) in patients with early recurrence (p = 0.001). CONCLUSIONS: Atypical meningiomas are a heterogeneous group of tumours with 16.8% patients having recurrence within 24 months of surgery. Residual tumour, parafalcine/parasagittal location, peritumoural oedema and a MI > 7 were all independently associated with early recurrence. As administration of adjuvant radiotherapy was not protocolised in this cohort, any conclusions about benefits of irradiation of WHO grade II meningiomas should be viewed with caution. Patients with early recurrence had worse neurological outcome. While histological and imaging characteristics provide some prognostic value, further molecular characterisation of atypical meningiomas is warranted to aid clinical decision making.

Outcomes of emergency neurosurgical intervention in neuro-critical care patients with traumatic brain injury at Cork University Hospital.

Traumatic Brain Injury (TBI) is a major cause of death and disability; the leading cause of mortality and morbidity in previously healthy people aged under 40 in the United Kingdom (UK). There are currently little official Irish statistics regarding TBI or outcome measures following TBI, although it is estimated that over 2000 people per year sustain TBI in Ireland. We performed a retrospective cohort study of TBI patients who were managed in the intensive care unit (ICU) at CUH between July 2012 and December 2015. Demographic data were compiled by patients' charts reviews. Using the validated Glasgow outcome scale extended (GOS-E) outcome measure tool, we interviewed patients and/or their carers to measure functional outcomes. Descriptive statistical analyses were performed. Spearman's correlation analysis was used to assess association between different variables using IBM's Statistical Package for the Social Sciences (SPSS) 20. In the 42-month period, 102 patients were identified, mainly males (81%). 49% had severe TBI and 56% were referred from other hospitals. The mean age was 44.7 and a most of the patients were previously healthy, with 65% of patients having ASA I or II. Falls accounted for the majority of the TBI, especially amongst those aged over 50. The 30-day mortality was 25.5% and the mean length of hospital stay (LOS-H) was 33 days. 9.8% of the study population had a good recovery (GOS-E 8), while 7.8% had a GOS-E score of 3 (lower sever disability). Patients with Extra-Dural haemorrhage had better outcomes compared with those with SDH or multi-compartmental haemorrhages (p = 0.007). Older patients had a higher mortality, with the highest mortality (37.5%) among those over 50 years old (p = 0.009). TBI is associated with significant morbidity and mortality. Despite the young mean age and low ASA the mortality, morbidity and average LOS-H were significant, highlighting the health and socioeconomic burden of TBI.

Gastrointestinal stromal tumor metastases to the pituitary: a rare entity.

Gastrointestinal stromal tumors (GISTs) are rare, but represent the most common mesenchymal tumor of the gastrointestinal tract. The paucity of intracranial metastasis makes treatment strategies difficult. This manuscript presents the first documented case report of a GIST that presented clinically with pituitary symptoms due to a pituitary metastasis.

Mechanistic interrogation of combination bevacizumab/dual PI3K/mTOR inhibitor response in glioblastoma implementing novel MR and PET imaging biomarkers.

PURPOSE: Resistance to bevacizumab (BEV) in glioblastoma is believed to occur via activation of molecular networks including the mTOR/PI3K pathway. Using an MR/PET molecular imaging biomarker approach, we investigated the response to combining BEV with the mTOR/PI3K inhibitor BEZ235. METHODS: Tumours were established by orthotopically implanting U87MG-luc2 cells in mice. Animals were treated with BEZ235 and/or BEV, and imaged using diffusion-weighted-MRI, T2-weighted and T2*-weighted before and after administration of superparamagnetic iron oxide contrast agent. Maps for changes in relaxation rates (ΔR2, ΔR2* and apparent diffusion coefficient) were calculated. Vessel size index and microvessel density index were derived. 3'-Deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT) PET and O-(2-[(18)F]fluoroethyl)-L-tyrosine ([(18)F]FET) PET were further performed and tumour endothelium/proliferation markers assessed by immunohistochemistry. RESULTS: Treatment with BEV resulted in a pronounced decrease in tumour volume (T2-weighted MRI). No additive effect on tumour volume was observed with the BEV/BEZ235 combination compared with BEV monotherapy. The Ki67 proliferation index and [(18)F]FLT uptake studies were used to support the observations. Using ΔR2* and ΔR2 values, respectively, the BEV/BEZ235 combination significantly reduced tumour microvessel volume in comparison to BEV alone. Decreased microvessel density index was further observed in animals treated with the combination, supported by von Willebrand factor (vWF) immunohistochemistry. [(18)F]FET uptake was decreased following treatment with BEV alone, but was not further reduced following treatment with the combination. vWF immunohistochemistry analysis showed that the mean tumour vessel size was increased in all cohorts. CONCLUSION: Assessing MR imaging biomarker parameters together with [(18)F]FET and [(18)F]FLT PET provided information on mechanism of action of the drug combination and clues as to potential clinical responses. Following translation to clinical use, treatment with a BEV/BEZ235 combination could reduce peritumoral oedema obviating the requirement for steroids. The use of hypothesis-driven molecular imaging studies facilitates the preclinical evaluation of drug response. Studies of this kind may more accurately predict the clinical potential of the BEV/BEZ235 combination regimen as a novel therapeutic approach in oncology.

Epilepsy surgery in pediatric epileptic encephalopathy: when interictal EEG counts the most.

PURPOSE: Traditionally, seizure onset localization in ictal electro-encephalography (EEG) is the main factor guiding resective epilepsy surgery. The situation is often different in infantile epileptic encephalopathy. We demonstrate the importance of the underrated interictal (rather than ictal) surface EEG in informing decision-making in epilepsy surgery for children with epileptic encephalopathy caused by subtle focal cortical dysplasia (FCD). METHODS: We present a small case series of three children who had an epileptic encephalopathy with either epileptic spasms or tonic seizures. All three were thought initially to have normal neuroimaging. RESULTS: Ictal EEG localizing features were seen in none and lateralizing features were seen only clinically in one of the three. However, the interictal EEG showed persistent and consistent focal irregular slowing in all, particularly after medically resolving the diffuse encephalopathy. Subtle FCDs were uncovered in all. Surgery was performed in all with excellent outcome. CONCLUSION: In infantile epileptic encephalopathy caused by subtle FCD, the often underrated interictal surface EEG (particularly persistent foal irregular slowing) informs the most; not only to the target area for surgical resection but also to its extent. This may negate the need for unnecessary and sometimes non-informative invasive monitoring in these cases. A matter of "zooming out" to define the extent of a resectable abnormality rather than "zooming in" to define a seemingly localized epileptic focus that may change with time.

A clinically relevant computed tomography (CT) radiomics strategy for intracranial rodent brain tumour monitoring.

Here, we establish a CT-radiomics based method for application in invasive, orthotopic rodent brain tumour models. Twenty four NOD/SCID mice were implanted with U87R-Luc2 GBM cells and longitudinally imaged via contrast enhanced (CE-CT) imaging. Pyradiomics was employed to extract CT-radiomic features from the tumour-implanted hemisphere and non-tumour-implanted hemisphere of acquired CT-scans. Inter-correlated features were removed (Spearman correlation > 0.85) and remaining features underwent predictive analysis (recursive feature elimination or Boruta algorithm). An area under the curve of the receiver operating characteristic curve was implemented to evaluate radiomic features for their capacity to predict defined outcomes. Firstly, we identified a subset of radiomic features which distinguish the tumour-implanted hemisphere and non- tumour-implanted hemisphere (i.e, tumour presence from normal tissue). Secondly, we successfully translate preclinical CT-radiomic pipelines to GBM patient CT scans (n = 10), identifying similar trends in tumour-specific feature intensities (E.g. 'glszm Zone Entropy'), thereby suggesting a mouse-to-human species conservation (a conservation of radiomic features across species). Thirdly, comparison of features across timepoints identify features which support preclinical tumour detection earlier than is possible by visual assessment of CT scans. This work establishes robust, preclinical CT-radiomic pipelines and describes the application of CE-CT for in-depth orthotopic brain tumour monitoring. Overall we provide evidence for the role of pre-clinical 'discovery' radiomics in the neuro-oncology space.

Paediatric spinal glioblastoma: case report and review of therapeutic strategies.

INTRODUCTION: Although uncommon, there is significant morbidity and mortality associated with paediatric spinal glioblastoma. The paucity of cases makes treatment options difficult. The current recommended standard of care is biopsy followed by adjuvant chemo-radiotherapy, with emerging data supporting the role of safe gross total resection. OBJECTIVE: The purpose of this paper is to provide a single-institution case study and to discuss current and future therapeutic treatment strategies. CASE PRESENTATION: A 14-year-old boy presented with a 2-year history of intermittent back pain with recent progressively worsening motor and sensory deficits of the right side. Pre-operative MRI revealed an enhancing intra-medullary tumour extending from C2 to C7. During the operative case, no tumour-cord margin could be identified, and the patient underwent a subtotal excision. Histopathology confirmed glioblastoma. In the subsequent weeks, the patient's clinical condition deteriorated. Adjuvant therapy was declined by the family, and the patient died 9 weeks after initial presentation. CONCLUSION: Despite major advances in surgical techniques, peri-operative neuro-imaging as well as chemo-radiotherapy, the prognosis of a paediatric intra-medullary high-grade spinal tumour remains poor. Detailed analysis of our understanding of tumour dynamics in this patient group is important in establishing future therapeutic strategies.