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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.

BackgroundSeveral studies have established Glioblastoma Multiforme (GBM) prognostic and predictive models based on age and Karnofsky Performance Status (KPS), while very few studies evaluated the prognostic and predictive significance of preoperative MR-imaging. However, to date, there is no simple preoperative GBM classification that also correlates with a highly prognostic genomic signature. Thus, we present for the first time a biologically relevant, and clinically applicable tumor Volume, patient Age, and KPS (VAK) GBM classification that can easily and non-invasively be determined upon patient admission.MethodsWe quantitatively analyzed the volumes of 78 GBM patient MRIs present in The Cancer Imaging Archive (TCIA) corresponding to patients in The Cancer Genome Atlas (TCGA) with VAK annotation. The variables were then combined using a simple 3-point scoring system to form the VAK classification. A validation set (N = 64) from both the TCGA and Rembrandt databases was used to confirm the classification. Transcription factor and genomic correlations were performed using the gene pattern suite and Ingenuity Pathway Analysis.ResultsVAK-A and VAK-B classes showed significant median survival differences in discovery (P = 0.007) and validation sets (P = 0.008). VAK-A is significantly associated with P53 activation, while VAK-B shows significant P53 inhibition. Furthermore, a molecular gene signature comprised of a total of 25 genes and microRNAs was significantly associated with the classes and predicted survival in an independent validation set (P = 0.001). A favorable MGMT promoter methylation status resulted in a 10.5 months additional survival benefit for VAK-A compared to VAK-B patients.ConclusionsThe non-invasively determined VAK classification with its implication of VAK-specific molecular regulatory networks, can serve as a very robust initial prognostic tool, clinical trial selection criteria, and important step toward the refinement of genomics-based personalized therapy for GBM patients.

BackgroundDespite recent discoveries of new molecular targets and pathways, the search for an effective therapy for Glioblastoma Multiforme (GBM) continues. A newly emerged field, radiogenomics, links gene expression profiles with MRI phenotypes. MRI-FLAIR is a noninvasive diagnostic modality and was previously found to correlate with cellular invasion in GBM. Thus, our radiogenomic screen has the potential to reveal novel molecular determinants of invasion. Here, we present the first comprehensive radiogenomic analysis using quantitative MRI volumetrics and large-scale gene- and microRNA expression profiling in GBM.MethodsBased on The Cancer Genome Atlas (TCGA), discovery and validation sets with gene, microRNA, and quantitative MR-imaging data were created. Top concordant genes and microRNAs correlated with high FLAIR volumes from both sets were further characterized by Kaplan Meier survival statistics, microRNA-gene correlation analyses, and GBM molecular subtype-specific distribution.ResultsThe top upregulated gene in both the discovery (4 fold) and validation (11 fold) sets was PERIOSTIN (POSTN). The top downregulated microRNA in both sets was miR-219, which is predicted to bind to POSTN. Kaplan Meier analysis demonstrated that above median expression of POSTN resulted in significantly decreased survival and shorter time to disease progression (PConclusionHere, we propose a novel diagnostic method to screen for molecular cancer subtypes and genomic correlates of cellular invasion. Our findings also have potential therapeutic significance since successful molecular inhibition of invasion will improve therapy and patient survival in GBM.

Despite the critical role of Epidermal Growth Factor Receptor (EGFR) in glioblastoma pathogenesis, EGFR targeted therapies have achieved limited clinical efficacy. Here we propose an alternate therapeutic strategy based on the conceptual framework of non-oncogene addiction. A directed RNAi screen revealed that glioblastoma cells over-expressing EGFRvIII, an oncogenic variant of EGFR, become hyper-dependent on a variety of DNA repair genes. Among these, there was an enrichment of Base Excision Repair (BER) genes required for the repair of Reactive Oxygen Species (ROS)-induced DNA damage, including poly-ADP ribose polymerase 1 (PARP1). Subsequent studies revealed that EGFRvIII over-expression in glioblastoma cells caused increased levels of ROS, DNA strand break accumulation, and genome instability. In a panel of primary glioblastoma lines, sensitivity to PARP1 inhibition correlated with the levels of EGFR activation and oxidative stress. Gene expression analysis indicated that reduced expression of BER genes in glioblastomas with high EGFR expression correlated with improved patient survival. These observations suggest that oxidative stress secondary to EGFR hyper-activation necessitates increased cellular reliance on PARP1 mediated BER, and offer critical insights into clinical trial design.

The insular cortex, a critical hub in the brain’s sensory, cognitive, and emotional networks, remains an intriguing subject of study. In this article, we discuss its intricate functional neuroanatomy, emphasizing its pivotal role in processing olfactory information. Through concise exploration, we delve into the insula’s diverse connectivity and its involvement in sensory integration, particularly in olfaction. Stimulation studies in humans reveal compelling insights into the insula’s contribution to the perception of smell, hinting at its broader implications for cognitive processing. Additionally, we explore an avenue of research in which studying olfactory processing via insular stimulation could unravel higher-level cognitive processes. This innovative approach could help give a fresh perspective on the interplay between sensory and cognitive domains, offering valuable insights into the neural mechanisms underlying cognition and emotion. In conclusion, future research efforts should emphasize a multidisciplinary approach, combining advanced imaging and surgical techniques to explore the intricate functions of the human insula. Moreover, awake craniotomies could offer a unique opportunity for real-time observation, shedding light on its neural circuitry and contributions to higher-order brain functions. Furthermore, olfaction’s direct cortical projection enables precise exploration of insular function, promising insights into cognitive and emotional processes. This multifaceted approach will deepen our understanding of the insular cortex and its significance in human cognition and emotion.

Abstract The ability to model physiological systems through 3D neural in-vitro systems may enable new treatments for various diseases while lowering the need for challenging animal and human testing. Creating such an environment, and even more impactful, one that mimics human brain tissue under mechanical stimulation, would be extremely useful to study a range of human-specific biological processes and conditions related to brain trauma. One approach is to use human cerebral organoids (hCOs) in-vitro models. hCOs recreate key cytoarchitectural features of the human brain, distinguishing themselves from more traditional 2D cultures and organ-on-a-chip models, as well as in-vivo animal models. Here, we propose a novel approach to emulate mild and moderate traumatic brain injury (TBI) using hCOs that undergo strain rates indicative of TBI. We subjected the hCOs to mild (2 s−1) and moderate (14 s−1) loading conditions, examined the mechanotransduction response, and investigated downstream genomic effects and regulatory pathways. The revealed pathways of note were cell death and metabolic and biosynthetic pathways implicating genes such as CARD9, ENO1, and FOXP3, respectively. Additionally, we show a steeper ascent in calcium signaling as we imposed higher loading conditions on the organoids. The elucidation of neural response to mechanical stimulation in reliable human cerebral organoid models gives insights into a better understanding of TBI in humans.

IntroductionGlioblastoma multiforme (GBM) is one of the most aggressive types of brain cancer, and despite rigorous research, patient prognosis remains poor. The characterization of sex-specific differences in incidence and overall survival (OS) of these patients has led to an investigation of the molecular mechanisms that may underlie this dimorphism.MethodsWe reviewed the published literature describing the gender specific differences in GBM Biology reported in the last ten years and summarized the available information that may point towards a patient-tailored GBM therapy.ResultsRadiomics analyses have revealed that imaging parameters predict OS and treatment response of GBM patients in a sex-specific manner. Moreover, gender-based analysis of the transcriptome GBM tumors has found differential expression of various genes, potentially impacting the OS survival of patients in a sex-dependent manner. In addition to gene expression differences, the timing (subclonal or clonal) of the acquisition of common GBM-driver mutations, metabolism requirements, and immune landscape of these tumors has also been shown to be sex-specific, leading to a differential therapeutic response by sex. In male patients, transformed astrocytes are more sensitive to glutaminase 1 (GLS1) inhibition due to increased requirements for glutamine uptake. In female patients, GBM is more sensitive to anti-IL1β due to an increased population of circulating granulocytic myeloid-derived suppressor cells (gMDSC).ConclusionMoving forward, continued elucidation of GBM sexual dimorphism will be critical in improving the OS of GBM patients by ensuring that treatment plans are structured to exploit these sex-specific, molecular vulnerabilities in GBM tumors.

Summary: Metabolic reprogramming in pediatric diffuse midline glioma is driven by gene expression changes induced by the hallmark histone mutation H3K27M, which results in aberrantly permissive activation of oncogenic signaling pathways. Previous studies of diffuse midline glioma with altered H3K27 (DMG-H3K27a) have shown that the RAS pathway, specifically through its downstream kinase, extracellular-signal-related kinase 5 (ERK5), is critical for tumor growth. Further downstream effectors of ERK5 and their role in DMG-H3K27a metabolic reprogramming have not been explored. We establish that ERK5 is a critical regulator of cell proliferation and glycolysis in DMG-H3K27a. We demonstrate that ERK5 mediates glycolysis through activation of transcription factor MEF2A, which subsequently modulates expression of glycolytic enzyme PFKFB3. We show that in vitro and mouse models of DMG-H3K27a are sensitive to the loss of PFKFB3. Multi-targeted drug therapy against the ERK5-PFKFB3 axis, such as with small-molecule inhibitors, may represent a promising therapeutic approach in patients with pediatric diffuse midline glioma.

Glioblastoma (GBM) is fatal and the study of therapeutic resistance, disease progression, and drug discovery in GBM or glioma stem cells is often hindered by limited resources. This limitation slows down progress in both drug discovery and patient survival. Here we present a genetically engineered human cerebral organoid model with a cancer-like phenotype that could provide a basis for GBM-like models. Specifically, we engineered a doxycycline-inducible vector encoding shRNAs enabling depletion of the TP53, PTEN, and NF1 tumor suppressors in human cerebral organoids. Designated as inducible short hairpin-TP53-PTEN-NF1 (ish-TPN), doxycycline treatment resulted in human cancer-like cerebral organoids that effaced the entire organoid cytoarchitecture, while uninduced ish-TPN cerebral organoids recapitulated the normal cytoarchitecture of the brain. Transcriptomic analysis revealed a proneural GBM subtype. This proof-of-concept study offers a valuable resource for directly investigating the emergence and progression of gliomas within the context of specific genetic alterations in normal cerebral organoids.

Human brain organoids are models derived from human embryonic or induced pluripotent stem cells that mimic basic cerebral microanatomy and demonstrate simple functional neuronal networks. Brain organoids have been a rapidly expanding avenue for biomedical research in general and specifically: neural development, regeneration, and central nervous system pathophysiology. However, technology replicating functional aspects of the human brain, including electrically active neural networks, requires a responsible code of conduct. In this review, we focus the discussion on intrinsic and extrinsic ethical factors associated with organoids: intrinsic considerations arise with the growing complexity of human brain organoids, including human-animal chimerism, consciousness development, and questions of where these human-like beings fall in a moral hierarchy. Extrinsic considerations explore ethics on obtainment, manufacturing, and production of sophisticated human products. In summary, a thoughtful code of conduct using human brain organoids towards the advancement of science and medicine is crucial. This article shall facilitate a structured thought process approaching the moral landscape of organoid technology.

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.

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.

Abstract 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.

MRI scans of glioblastoma patients can be misleading and some patients appear to show features of progressive disease although they respond to treatment. Here, the authors use MRI images of progressive disease or pseudoprogression and build a classifier using machine learning to distinguish the two.

Spinal epidermoid tumors are rare, benign tumors that are either acquired from trauma, surgery, or lumbar puncture or arise as congenital lesions, particularly spinal dysraphisms. We report a case of a massive spinal epidermoid tumor and review the literature with a focus on the surgical outcomes. A 71-year-old female patient presented after a fall with subsequent symptoms of severe back and hip pain, as well as loss of motor strength in the left leg. Her magnetic resonance imaging demonstrated a T2/short tau inversion recovery hyperintense mass extending from the level of the T10–11 disc caudally through S2. A biopsy was recommended to determine whether the tumor was radio- or chemo-sensitive. The patient underwent a L4 laminectomy and a pearly-white tumor was encountered, with a subsequent biopsy confirming it to be an epidermoid tumor. The following conclusions can be drawn from a review of the literature. Spinal epidermoid tumors are more common in women and tend to present in younger patients (median age of 23). The majority of patients had acquired lesions (46%). In terms of surgical outcomes for adherent tumors, gross total resection was found to provide optimal outcomes, with 90% of patients improving clinically after surgery.