Search

High-grade gliomas (HGGs) continue to be some of the most devastating diseases in the USA. Despite extensive efforts, the survival of HGG patients has remained relatively stagnant. Chimeric antigen receptor (CAR) T-cell immunotherapy has recently been studied in the context of improving these tumors' clinical outcomes. HGG murine models treated with CAR T cells targeting tumor antigens have shown reduced tumor burden and longer overall survival than models without treatment. Subsequent clinical trials investigating the efficacy of CAR T cells have further shown that this therapy could be safe and might reduce tumor burden. However, there are still many challenges that need to be addressed to optimize the safety and efficacy of CAR T-cell therapy in treating HGG patients.

The efficacy of radiotherapy in many tumor types is limited by normal tissue toxicity and by intrinsic or acquired radioresistance. Therefore, it is essential to understand the molecular network responsible for regulating radiosensitivity/resistance. Here, an unbiased functional screen identified four microRNAs (miR1, miR125a, miR150, and miR425) that induce radioresistance. Considering the clinical importance of radiotherapy for patients with glioblastoma, the impact of these miRNAs on glioblastoma radioresistance was investigated. Overexpression of miR1, miR125a, miR150, and/or miR425 in glioblastoma promotes radioresistance through upregulation of the cell-cycle checkpoint response. Conversely, antagonizing with antagomiRs sensitizes glioblastoma cells to irradiation, suggesting their potential as targets for inhibiting therapeutic resistance. Analysis of glioblastoma datasets from The Cancer Genome Atlas (TCGA) revealed that these miRNAs are expressed in glioblastoma patient specimens and correlate with TGFβ signaling. Finally, it is demonstrated that expression of miR1 and miR125a can be induced by TGFβ and antagonized by a TGFβ receptor inhibitor. Together, these results identify and characterize a new role for miR425, miR1, miR125, and miR150 in promoting radioresistance in glioblastomas and provide insight into the therapeutic application of TGFβ inhibitors in radiotherapy.Implications: Systematic identification of miRs that cause radioresistance in gliomas is important for uncovering predictive markers for radiotherapy or targets for overcoming radioresistance. Mol Cancer Res; 12(12); 1767–78. ©2014 AACR.

S1A. List of miRNAs enriched independent of IR. S1B. Clonogenic survival assay was performed with 2 Gy IR in 12 different GBM lines. Bar graphs were generated with Mean {plus minus} S.D. of 3 independent experiments. S2A. IR sensitivity of LN229 with individual stable expression of miR-1, miR-125a, miR-150 and miR-425 was determined by clonogenic assay. Curves were generated with Mean {plus minus} S.D. of 3 independent experiments. For statistical analysis the areas under the curves were calculated by approximating them to trapezoids. Comparison was done with one-way ANOVA (p < 0.05) and Tukey's post hoc (p < 0.05) test. S2B. Expression of fused miR-1, miR-125a, miR-150 and miR-425 from pcDNA3.1 vector. S3. A) Illustration shows the construct of GFP-fused miRNA sponges. GFP is fused at the 3' end of 4 identical repeats of miRNA sponges in tandem. The sequence of each miRNA sponge is shown below. (B) Inhibition of GFP expression fused to miRNA sponges was tested by transfecting corresponding miRNA mimics. Comparison was done with one-way ANOVA (p < 0.05) and Tukey's post hoc (p < 0.05) test. S4A. Impact of individual miR-scr, miR-1, miR-125a, miR-150 and miR-425 and combined miR-4x' on apoptosis in LN229 cells. Cells were exposed to 10 Gy γ-IR and the activation of Caspase 3 and 7 was determined with Caspase-Glo 3/7 Assay System. Comparison was done with one-way ANOVA (p < 0.05) and Tukey's post hoc (p < 0.05) test. S4B. Phosphorylation of Chk1 S345 in LN229 cells transfected with indicated miRNA upon exposure to 10 Gy IR. The mean {plus minus} S.D. of 3 independent experiments is demonstrated. Comparison was done with one-way ANOVA (p < 0.05) and Tukey's post hoc (p

Supplementary Figure 3

Supplementary Figure 5

Supplementary Figure 6

Supplementary Figure 7

Supplementary Figure Legends and Methods

Supplementary Figure 4

Supplementary Figure 2

Supplementary Figure 1

Purpose:Radiomics is the extraction of multidimensional imaging features, which when correlated with genomics, is termed radiogenomics. However, radiogenomic biological validation is not sufficiently described in the literature. We seek to establish causality between differential gene expression status and MRI-extracted radiomic-features in glioblastoma.Experimental Design:Radiogenomic predictions and validation were done using the Cancer Genome Atlas and Repository of Molecular Brain Neoplasia Data glioblastoma patients (n = 93) and orthotopic xenografts (OX; n = 40). Tumor phenotypes were segmented, and radiomic-features extracted using the developed radiome-sequencing pipeline. Patients and animals were dichotomized on the basis of Periostin (POSTN) expression levels. RNA and protein levels confirmed RNAi-mediated POSTN knockdown in OX. Total RNA of tumor cells isolated from mouse brains (knockdown and control) was used for microarray-based expression profiling. Radiomic-features were utilized to predict POSTN expression status in patient, mouse, and interspecies.Results:Our robust pipeline consists of segmentation, radiomic-feature extraction, feature normalization/selection, and predictive modeling. The combination of skull stripping, brain-tissue focused normalization, and patient-specific normalization are unique to this study, providing comparable cross-platform, cross-institution radiomic features. POSTN expression status was not associated with qualitative or volumetric MRI parameters. Radiomic features significantly predicted POSTN expression status in patients (AUC: 76.56%; sensitivity/specificity: 73.91/78.26%) and OX (AUC: 92.26%; sensitivity/specificity: 92.86%/91.67%). Furthermore, radiomic features in OX were significantly associated with patients with similar POSTN expression levels (AUC: 93.36%; sensitivity/specificity: 82.61%/95.74%; P = 02.021E−15).Conclusions:We determined causality between radiomic texture features and POSTN expression levels in a preclinical model with clinical validation. Our biologically validated radiomic pipeline also showed the potential application for human–mouse matched coclinical trials.

Supplementary Tables

BACKGROUND Ganglioneuromas are rare peripheral nervous system tumors of neural crest origin. Most are often asymptomatic and incidentally found, but large tumors can cause mass effect. Herein, the authors report a case of a giant ganglioneuroma that arose from the lumbar foramina into the retroperitoneal and thoracic cavities. OBSERVATIONS A 62-year-old female presented with low back pain, left lower extremity swelling, and increased sensation of an abdominal mass. Surgical treatment options were reviewed with the patient and coordinated care was planned by surgical oncological specialists. The patient opted for multistage exploratory laparotomy for abdominal mobilization, diaphragm resection, and en bloc resection with neuromonitoring. After surgery, the patient experienced significant improvement in symptoms. LESSONS A combined surgical exposure involving gastrointestinal, thoracic, and neurological surgeons can be important in the safe resection of ganglioneuromas that span multiple body cavities. Hence, a thorough preoperative assessment could help plan surgery accordingly.

A history of atopy or allergy has been shown to be protective against the development of glioma, however the effect of atopy on patient outcomes, especially in conjunction with the survival benefit associated with IDH mutation, has not yet been investigated, and is the focus of the study we present here. Low grade glioma (LGG) data from the TCGA was downloaded, along with IDH, TERT, 1p/19q and ATRX mutational status and genetic alterations. History of asthma, eczema, hay fever, animal, or food allergies, as documented in TCGA, was used to determine patient atopy status. Patients with missing variables were excluded from the study. 374 LGG studies were included. Patients with a history of atopy demonstrated longer overall survival (OS) compared to those without (145.3 vs. 81.5 months, p = 00.0195). IDH mutant patients with atopy had longer OS compared those without atopy (158.8 vs. 85 months, p = 0.035). Multivariate cox regression analysis demonstrated that the effects of atopy on survival were independent of IDH and histological grade, (p = 0.002, HR 0.257, 95% 0.109–0.604), (p =

Limiting the spread of the disease is key to controlling the COVID-19 pandemic. This includes identifying people who have been exposed to COVID-19, minimizing patient contact, and enforcing strict hygiene measures. To prevent healthcare systems from becoming overburdened, elective and non-urgent medical procedures and treatments have been postponed, and primary health care has broadened to include virtual appointments via telemedicine. Although telemedicine precludes the physical examination of a patient, it allows collection of a range of information prior to a patient's admission, and may therefore be used in preoperative assessment. This new tool can be used to evaluate the severity and progression of the main disease, other comorbidities, and the urgency of the surgical treatment as well as preferencing anesthetic procedures. It can also be used for effective screening and triaging of patients with suspected or established COVID-19, thereby protecting other patients, clinicians and communities alike.

Background Fluorescein is an agent that accumulates in areas of blood-brain barrier breakdown and is commonly used in neurosurgical oncology to assist with lesion localization and visualizing the extent of resection. It is considered to be cost-effective and has a favorable safety profile. Studies on the utilization of fluorescein demonstrate an improved extent of tumor resection and increased overall survival. Currently, fluorescein detection systems are all microscope based, leading to limitations such as decreased maneuverability, limited visualization of the entire operative field, and significant cost associated with obtaining and maintaining a neurosurgical operating microscope. Methods Three consecutive craniotomy patients for tumor resection were included, and surgery was carried out under loupe fluorescence guidance using the ReVeal 450 System, and also a surgical microscope for comparison. Results Loupe-mounted fluorescence system enabled excellent visualization of fluorescence in all three cases. Conclusions In this manuscript, we describe our experience with a loupe-mounted fluorescein detection system in 3 patients with malignant gliomas. We found that the loupe-mounted system offered excellent ability to visualize fluorescein fluorescence. Although loupe-mounted systems are not an alternative to surgical microscopes, they could be a useful surgical adjunct for superficial lesions and in low-middle income counties.

Glioblastoma (GBM) is a malignant tumor with a median survival rate of 15-16 months with standard care; however, cases of successful treatment offer hope that an enhanced understanding of the pathology will improve the prognosis. The cell of origin in GBM remains controversial. Recent evidence has implicated stem cells as cells of origin in many cancers. Neural stem/precursor cells (NSCs) are being evaluated as potential initiators of GBM tumorigenesis. The NSCs in the subventricular zone (SVZ) have demonstrated similar molecular profiles and share several distinctive characteristics to proliferative glioblastoma stem cells (GSCs) in GBM. Genomic and proteomic studies comparing the SVZ and GBM support the hypothesis that the tumor cells and SVZ cells are related. Animal models corroborate this connection, demonstrating migratory patterns from the SVZ to the tumor. Along with laboratory and animal research, clinical studies have demonstrated improved progression-free survival in patients with GBM after radiation to the ipsilateral SVZ. Additionally, key genetic mutations in GBM for the most part carry regulatory roles in the SVZ as well. An exciting avenue towards SVZ modeling and determining its role in gliomagenesis in the human context is human brain organoids. Here we comprehensively discuss and review the role of the SVZ in GBM genesis, maintenance, and modeling.

BACKGROUND The occurrence of traumatic brain injury with spinal cord injury (SCI) in polytrauma patients is associated with significant morbidity. Clinicians face challenges from a decision-making and rehabilitative perspective. Management is complex and understudied. Treatment should be systematic beginning at the scene, focusing on airway resuscitation and hemodynamic stabilization, immobilization, and timely transport. Early operative interventions should be provided, followed by minimizing secondary pathophysiology. The authors present a case to delineate decision-making in the treatment of combined cranial and spinal trauma. OBSERVATIONS A 19-year-old man presented as a level I trauma patient after falling 30 feet as the result of scaffolding collapse. The patient was unresponsive and was intubated; he had an initial Glasgow Coma Scale score of 4. Computed tomography revealed multicompartmental bleeding and herniation, for which supra- and infratentorial decompressive craniectomies were performed. The patient also suffered from thoracic SCI that resulted in complete paraplegia. Multimodality monitoring was used. After stabilization and lengthy rehabilitation, the patient obtained significant functional improvement. LESSONS The approach to initial management of concomitant head and spine trauma is to establish intracranial stability followed by intraspinal stability. Patients can make considerable recovery, particularly younger patients, who are more likely to benefit from early aggressive interventions and medical treatment.

Toxoplasma gondii is one the most prevalent opportunist infections worldwide and can cause a severe and potentially fatal encephalitis. Toxoplasma encephalitis (TE) often presents in the setting of acquired immunodeficiency syndrome (AIDS), however, diagnosing TE can be challenging in patients with no signs of being immunocompromised. Here we report unusual presentations of TE in an immunocompetent patient, a patient four years post orthotopic liver transplantation, and two patients with undiagnosed AIDS that underwent prolonged workup for lesions that mimicked intracranial neoplasm. This report highlights the difficulties in diagnosing TE in patients with atypical presentations and unknown risk factors. A high clinical suspicion should be maintained to allow rapid treatment and to avoid significant morbidity and mortality.

Purpose:A history of atopy or allergy has been shown to be protective against the development of glioma, however the effect of atopy on patient outcomes, especially in conjunction with the survival benefit associated with IDH mutation, has not yet been investigated, and is the focus of the study we present here. Methods:Low grade glioma (LGG) data from the TCGA was downloaded, along with IDH, TERT, 1p/19q and ATRX mutational status and genetic alterations. History of asthma, eczema, hay fever, animal, or food allergies, as documented in TCGA, was used to determine patient atopy status. Patients with missing variables were excluded from the study. Results:374 LGG studies were included. Patients with a history of atopy demonstrated longer overall survival (OS) compared to those without (145.3 vs. 81.5 months, p=00.0195). IDH mutant patients with atopy had longer OS compared those without atopy (158.8 vs. 85 months, p=0.035). Multivariate cox regression analysis demonstrated that the effects of atopy on survival were independent of IDH and histological grade, (p=0.002, HR 0.257, 95% 0.109-0.604), (p=Conclusion:A history of atopy confers a survival benefit in patients with diffuse low-grade glioma. Activation of the BDNF pathway may drive the observed differences.

Over the past decade, the use of induced pluripotent stem cells (IPSCs), as both direct therapeutics and building blocks for 3D in vitro models, has exhibited exciting potential in both helping to elucidate pathogenic mechanisms and treating diseases relevant to neurosurgery. Transplantation of IPSCs is being studied in neurological injuries and diseases, such as spinal cord injury and Parkinson's disease, whose clinical manifestations stem from underlying neuronal and/or axonal degeneration. Both animal models and clinical trials have shown that IPSCs have the ability to regenerate damaged neural tissue. Such evidence makes IPSCs a potentially promising therapeutic modality for patients who suffer from these neurological injuries/diseases. In addition, the cerebral organoid, a 3D assembly of IPSC aggregates that develops heterogeneous brain regions, has become the first in vitro model to closely recapitulate the complexity of the brain extracellular matrix, a 3-dimensional network of molecules that structurally and biochemically support neighboring cells. Cerebral organoids have become an exciting prospect for modeling and testing drug susceptibility of brain tumors, such as glioblastoma and metastatic brain cancer. As patient-derived organoid models are becoming more faithful to the brain, they are becoming an increasingly accurate substitute for patient clinical trials; such patient-less trials would protect the patient from potentially ineffective drugs, and speed up trial results and optimize cost. In this review, we aim to describe the role of IPSCs and cerebral organoids in treating and modeling diseases that are relevant to neurosurgery.

The need to identify biomarkers to predict immunotherapy response for rare cancers has been long overdue. We aimed to study this in our paper, ‘Radiomics analysis for predicting pembrolizumab response in patients with advanced rare cancers’. In this response to the Letter to the Editor by Cunha et al, we explain and discuss the reasons behind choosing LASSO (Least Absolute Shrinkage and Selection Operator) and XGBoost (eXtreme Gradient Boosting) with LOOCV (Leave-One-Out Cross-Validation) as the feature selection and classifier method, respectively for our radiomics models. Also, we highlight what care was taken to avoid any overfitting on the models. Further, we checked for the multicollinearity of the features. Additionally, we performed 10-fold cross-validation instead of LOOCV to see the predictive performance of our radiomics models.

Background To date, there is limited data on evaluation of the cordotomy lesion and predicting clinical outcome. Objective To evaluate the utility of magnetic resonance (MR)-based radiomic analysis to quantify microstructural changes created by the cordotomy lesion and predict outcome in patients undergoing percutaneous cordotomy for medically refractory cancer pain. Methods This is a retrospective interpretation of prospectively acquired data in 10 patients (5 males, age range 43-76 yr) who underwent percutaneous computed tomography-guided high cervical cordotomy for medically refractory cancer pain between 2015 and 2016. All patients underwent magnetic resonance imaging (MRI) of the cordotomy lesion on postoperative day 1. After segmentation of T2-weighted images, 310 radiomic features were extracted. Pain outcomes were recorded on postoperative day 1 and day 7 using the visual analog scale. R software was used to build statistical models based on MRI radiomic features for prediction of pain outcomes. Results A total of 20 relevant radiomic features were identified using the maximum relevance minimum redundanc method. Radiomics predicted postoperative day 1 pain scores with an accuracy of 90% (P = .046), 100% sensitivity, 75% specificity, 85.7% positive predictive value, and 100% negative predictive value. The radiomics model also predicted if the postoperative day 1 pain score was sustained on postoperative day 7 with an accuracy of 100% (P = .028), 100% sensitivity, 100% specificity, and 100% positive and negative predictive value. Conclusion MR-based radiomic analysis of the cordotomy lesion was predictive of pain outcomes at 1 wk after percutaneous cordotomy for intractable cancer pain.

MRI-guided laser interstitial thermal therapy (LITT) is the selective ablation of a lesion or a tissue using heat emitted from a laser device. LITT is considered a less invasive technique compared to open surgery that provides a nonsurgical solution for patients who cannot tolerate surgery. Although laser ablation has been used to treat brain lesions for decades, recent advances in MRI have improved lesion targeting and enabled real-time accurate monitoring of the thermal ablation process. These advances have led to a plethora of research involving the technique, safety, and potential applications of LITT. LITT is a minimally invasive treatment modality that shows promising results and is associated with decreased morbidity. It has various applications, such as treatment of glioma, brain metastases, radiation necrosis, and epilepsy. It can provide a safer alternative treatment option for patients in whom the lesion is not accessible by surgery, who are not surgical candidates, or in whom other standard treatment options have failed. Our aim is to review the current literature on LITT and provide a descriptive review of the technique, imaging findings, and clinical applications for neurosurgery.