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.

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.

The identification of BCL-XL and MCL-1 as key anti-apoptotic proteins in medulloblastoma that mediate distinct roles in chemotherapy resistance.

Medulloblastoma is the most common malignant paediatric brain tumour, representing 20% of all paediatric intercranial tumours. Current aggressive treatment protocols and the use of radiation therapy in particular are associated with high levels of toxicity and significant adverse effects, and long-term sequelae can be severe. Therefore, improving chemotherapy efficacy could reduce the current reliance on radiation therapy. Here, we demonstrated that systems-level analysis of basal apoptosis protein expression and their signalling interactions can differentiate between medulloblastoma cell lines that undergo apoptosis in response to chemotherapy, and those that do not. Combining computational predictions with experimental BH3 profiling, we identified a therapeutically-exploitable dependence of medulloblastoma cells on BCL-XL, and experimentally validated that BCL-XL targeting, and not targeting of BCL-2 or MCL-1, can potentiate cisplatin-induced cytotoxicity in medulloblastoma cell lines with low sensitivity to cisplatin treatment. Finally, we identified MCL-1 as an anti-apoptotic mediator whose targeting is required for BCL-XL inhibitor-induced apoptosis. Collectively, our study identifies that BCL-XL and MCL-1 are the key anti-apoptotic proteins in medulloblastoma, which mediate distinct protective roles. While BCL-XL has a first-line role in protecting cells from apoptosis basally, MCL-1 represents a second line of defence that compensates for BCL-XL upon its inhibition. We provide rationale for the further evaluation of BCL-XL and MCL-1 inhibitors in the treatment of medulloblastoma, and together with current efforts to improve the cancer-specificity of BCL-2 family inhibitors, these novel treatment strategies have the potential to improve the future clinical management of medulloblastoma.

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.

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.

LITTing up Gliomas-Is the Future Bright?

Background: Laser interstitial thermal therapy (LITT) represents an attractive therapeutic strategy for several intracranial pathologies; however, there is a paucity of literature regarding its efficacy for the treatment of gliomas. Methods: MEDLINE, EMBASE, Scopus, and Web of Science were searched from inception until March 19, 2021. Studies specifically relating to the use of LITT in treatment of glioma were eligible for inclusion. A meta-analysis of means was performed to assess the progression-free survival (PFS) and overall survival (OS) following LITT and descriptive statistics relating to patients undergoing LITT were collated and a meta-analysis of proportions was also performed to assess the rate of complications. Results: In total, 17 studies were included for the meta-analysis, comprising 401 patients with 408 gliomas of which 88 of 306 (28.8%) were grade 1 or 2 and 218 of 306 (71.2%) were grade 3 or 4. Of these, 256 of 408 (62.8%) were primary presentation and 152 of 408 (37.2%) were recurrent. The pooled mean OS was 13.58 months (95% confidence interval [CI] 9.77-17.39) and the PFS was 4.96 months (95% CI 4.19-5.72). The OS and PFS of recurrent glioblastoma were 12.4 months (95% CI 9.61-16.18) and 4.84 months (95% CI 0.23-9.45), respectively. Complications occurred in 114 of 411 (24%; 95% CI 14-41), of which 44 (11%) were transient deficits. Conclusions: There is an increasing body of evidence demonstrating the use of LITT in the surgical management of deep-seated gliomas in patients of poor performance status. However, further studies are required to interrogate the clinical effectiveness of LITT in the setting of gliomas as well as assessing the survival benefit versus standard treatment alone.

Perceptions of Concussion and Associated Anxiety in Irish Collegiate Athletes.

BACKGROUND: Concussion nondisclosure and poor management after a concussion are a concern in Irish collegiate sports. How athletes perceive concussions and appraise their own concussion may affect their decisions and behaviors after a suspected concussion. However, this has yet to be examined in an Irish context. This study aimed to (1) establish concussion perceptions and associated anxiety in Irish collegiate athletes; (2) examine how sex, concussion, and mood disorder history influenced their perceptions; and (3) investigate factors associated with higher anxiety perceptions. HYPOTHESIS: Irish collegiate athletes will display negative concussion perceptions and anxiety related to concussion, especially in female athletes and those without a concussion history. STUDY DESIGN: Cross-sectional study. LEVEL OF EVIDENCE: Level 3. METHODS: Irish collegiate athletes [n = 268 (141 women,127 men), mean age = 21.5 ± 2.2 years] from high-risk sports completed a survey including the Perceptions of Concussion Inventory for Athletes (PCI-A), demographics, diagnosed concussion history, self-reported mood disorder history, and a concussion knowledge assessment. Differences in concussion perceptions by sex, concussion history, mood disorder history were examined using Mann-Whitney U tests, and factors associated with anxiety-related concussion perceptions were identified using multivariate logistic regression. RESULTS: Over half (53.0%, n = 142) of participants reported concerns regarding concussion. The thoughts of sustaining a concussion made participants feel upset (63.4%, n = 170), fearful (47.7%, n = 128), and anxious (35.1%, n = 94). Women reported significantly higher anxiety (P < 0.01, r = 0.23), effects (P = 0.04, r = 0.12), and clarity (P = 0.01, r = 0.16) perception scores. Participants with a diagnosed concussion history displayed greater symptom variability perception scores (P = 0.04, r = 0.12), but lower anxiety (P = 0.03, r = 0.13) and treatment (P < 0.01, r = 0.19) beliefs on the PCI-A. No differences were observed for those with a history of a mood disorder (P > 0.05). A significant multivariate model was established (χ2 = 55.44, P < 0.01), with female sex [odds ratio (OR) = 1.53], concussion history (OR = 0.63), effects (OR = 1.31), and treatment (OR = 1.15) subscales associated with greater anxiety. CONCLUSION: Concerns about sustaining a concussion are prevalent in Irish collegiate athletes. Women displayed more negative perceptions and those with a concussion history displayed fewer perceived benefits of treatment. CLINICAL RELEVANCE: The findings support the need for concussion awareness campaigns to provide accurate concussion information to mitigate anxiety-related concussion perceptions and injury belief misconceptions.

Targeting the apoptosis pathway to treat tumours of the paediatric nervous system.

New, more effective therapeutics are required for the treatment of paediatric cancers. Current treatment protocols of cytotoxic treatments including chemotherapy trigger cancer-cell death by engaging the apoptosis pathway, and chemotherapy efficacy is frequently impeded by apoptosis dysregulation. Apoptosis dysregulation, through genetic or epigenetic mechanisms, is a feature of many cancer types, and contributes to reduced treatment response, disease progression and ultimately treatment resistance. Novel approaches are required to overcome dysregulated apoptosis signalling, increase the efficacy of cancer treatment and improve patient outcomes. Here, we provide an insight into current knowledge of how the apoptosis pathway is dysregulated in paediatric nervous system tumours, with a focus on TRAIL receptors, the BCL-2 proteins and the IAP family, and highlight preclinical evidence demonstrating that pharmacological manipulation of the apoptosis pathway can restore apoptosis signalling and sensitise cancer cells to treatment. Finally, we discuss the potential clinical implications of these findings.

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.

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.

Permeability of the Blood-Brain Barrier after Traumatic Brain Injury: Radiological Considerations.

Traumatic brain injury (TBI) is a leading cause of death and disability, especially in young persons, and constitutes a major socioeconomic burden worldwide. It is regarded as the leading cause of mortality and morbidity in previously healthy young persons. Most of the mechanisms underpinning the development of secondary brain injury are consequences of disruption of the complex relationship between the cells and proteins constituting the neurovascular unit or a direct result of loss of integrity of the tight junctions (TJ) in the blood-brain barrier (BBB). A number of changes have been described in the BBB after TBI, including loss of TJ proteins, pericyte loss and migration, and altered expressions of water channel proteins at astrocyte end-feet processes. There is a growing research interest in identifying optimal biological and radiological biomarkers of severity of BBB dysfunction and its effects on outcomes after TBI. This review explores the microscopic changes occurring at the neurovascular unit, after TBI, and current radiological adjuncts for its evaluation in pre-clinical and clinical practice.

Prognostic factors influencing survival following re-resection for isocitrate dehydrogenase (IDH) -wildtype glioblastoma multiforme - Data from a national neuro-oncology registry.

The role of surgical resection in recurrent Glioblastoma Multiforme (GBM) remains unclear. We aimed to investigate survival outcomes and associated prognostic factors in patients undergoing surgical re-resection for recurrent IDH-wildtype GBM in a national neuro-oncology center. We evaluated all patients who underwent re-resection for recurrent GBM following adjuvant treatment between 2015 and 2018. 32 patients were eligible for inclusion. 19 (59%) were male,median age at re-resection was 53. Median time from initial surgery to re-resection was 13.5 months. Median overall survival (OS) was 28.6 months from initial surgery and 9.5 months from re-resection. MGMT methylation was significantly associated with improved OS from initial surgery, 40 months versus 19.1 months, (p = 0.004), and from re-resection, 9.47 months versus 6.93 months, (p = 0.028). A late re-resection was associated with improved OS compared to an early re-resection, 44.1 months versus 15.7 months, (p = 0.002). There was a trend for improved outcomes in younger patients, median OS from initial surgery 44.1 months for <53 years compared to 21.7 months for patients ≥53, (p = 0.099). Higher Karnofsky Performance Status (KPS) at re-resection was associated with improved median OS, 9.5 months versus 4.1 months for KPS ≥70 and <70 respectively, (p = 0.013). Furthermore, there was a trend for improved OS with greater extent of re-resection, however this did not reach statistical significance, possibly due to small sample size. Re-resection for recurrent GBM was associated with improved OS in those with good performance status and could be considered in carefully selected cases.

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.

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.

Comparative analysis of the AIB1 interactome in breast cancer reveals MTA2 as a repressive partner which silences E-Cadherin to promote EMT and associates with a pro-metastatic phenotype.

Steroid regulated cancer cells use nuclear receptors and associated regulatory proteins to orchestrate transcriptional networks to drive disease progression. In primary breast cancer, the coactivator AIB1 promotes estrogen receptor (ER) transcriptional activity to enhance cell proliferation. The function of the coactivator in ER+ metastasis however is not established. Here we describe AIB1 as a survival factor, regulator of pro-metastatic transcriptional pathways and a promising actionable target. Genomic alterations and functional expression of AIB1 associated with reduced disease-free survival in patients and enhanced metastatic capacity in novel CDX and PDX ex-vivo models of ER+ metastatic disease. Comparative analysis of the AIB1 interactome with complementary RNAseq characterized AIB1 as a transcriptional repressor. Specifically, we report that AIB1 interacts with MTA2 to form a repressive complex, inhibiting CDH1 (encoding E-cadherin) to promote EMT and drive progression. We further report that pharmacological and genetic inhibition of AIB1 demonstrates significant anti-proliferative activity in patient-derived models establishing AIB1 as a viable strategy to target endocrine resistant metastasis. This work defines a novel role for AIB1 in the regulation of EMT through transcriptional repression in advanced cancer cells with a considerable implication for prognosis and therapeutic interventions.

Adult isocitrate dehydrogenase-mutant brainstem glioma: illustrative case.

BACKGROUND: Adult brainstem gliomas are rare entities that demonstrate heterogeneous biology and appear to be distinct from both their pediatric counterparts and adult supratentorial gliomas. Although the role of histone 3 mutations is being increasingly understood in this disease, the effect of isocitrate dehydrogenase (IDH) mutations remains unclear, largely because of limited data. OBSERVATIONS: The authors present the case of a 29-year-old male with an IDH1-mutant, World Health Organization grade III anaplastic astrocytoma in the dorsal medulla, and they provide a review of the available literature on adult IDH-mutant brainstem glioma. The authors have amassed a cohort of 15 such patients, 7 of whom have survival data available. Median survival is 56 months in this small cohort, which is similar to that for IDH wild-type adult brainstem gliomas. LESSONS: The authors' work reenforces previous literature suggesting that the role of IDH mutation in glioma differs between brainstem and supratentorial lesions. Therefore, the authors advocate that adult brainstem gliomas be studied in terms of major molecular subgroups (including IDH mutant) because these gliomas may exhibit fundamental differences from each other, from pediatric brainstem gliomas, and from adult supratentorial gliomas.

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.