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Objective: Immunotherapy has revolutionized cancer treatment in the past decade, but significant hurdles remain. Human studies with immune checkpoint inhibitors targeting programmed cell death protein have demonstrated suboptimal efficacy in the setting of low-grade gliomas (LGGs). Identification of mechanisms leading to inadequate anti-tumor immunity is paramount. The current study evaluates and validates barriers to immunotherapy using a novel machine learning algorithm., Methods: We utilized The Cancer Genome Atlas (TCGA) to generate expression levels of 28 immune genes related to known immunotherapeutic targets or lymphocyte cytolytic activity. We created training and testing groups and 3 machine learning models to determine the genes most highly correlated to cytolytic activity (CYT). The 3 models were run through multiple regression by exhaustive selection, LASSO, and random forest. We validated computational results by comparing expression of pertinent genes in patient-derived glioma samples., Results: Our models demonstrated linearity, a low mean-squared error, and consistent results with respect to the most important variables. Expression of ICOS, IDO1, and CD40 were the most important variables in all models and demonstrated positive correlation with CYT. Other variables included TIGIT and CD137. Genetic analysis from 3 IDH-mutants (IDHm) and 3 IDH-wild type (IDHwt) patient-derived glioma samples validated TCGA data and demonstrated lower levels of CYT in IDHm gliomas compared with IDHwt., Conclusions: This novel methodology has elucidated 3 potential targets for immunotherapy development in LGGs. We also demonstrated a novel method of analyzing data using advanced statistical techniques that can be further used in developing treatments for other diseases as well., (Copyright © 2022 Elsevier Inc. All rights reserved.)

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., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: Scheduled early postoperative computed tomography (EPOCT) after craniotomy for brain tumor resection is standard at many institutions. We analyzed utility of preplanned EPOCT after elective craniotomy for brain tumor resection., Methods: We retrospectively analyzed 755 brain tumor resections for which EPOCT was performed within 4 hours of surgery. Postoperative clinical neurologic examination results were classified into expected (baseline or predicted postoperative examination), changed (from baseline examination), and unreliable (sedated or baseline comatose patient). Scans were analyzed for unexpected and/or worrisome findings (e.g., hemorrhagic or ischemic stroke). In cases of unexpected findings, management changes were correlated to patient's neurologic examination. Demographic information, tumor histology, and tumor location were analyzed to determine risk factors for unexpected findings., Results: Rate of unexpected EPOCT findings was 4.1%. Patients with expected postoperative examinations were at significantly lower risk of abnormal findings (odds ratio [OR] = 0.074, P < 0.001). Patients with intraventricular tumors (OR = 5.7, P = 0.001) were at higher risk compared with patients with metastatic tumors (OR = 0.24, P = 0.06). No unexpected EPOCT findings led to management changes in patients with expected postoperative neurologic examinations. All unexpected EPOCT findings in patients with changed postoperative neurologic examinations led to management changes. Patients with nonreliable neurologic examinations were at significantly higher risk for unexpected findings on EPOCT (OR = 6.33, P < 0.001) and subsequent management changes., Conclusions: Routine EPOCT is not indicated for patients undergoing brain tumor resection if postoperative neurologic examination is unchanged, as imaging is unlikely to result in management changes. EPOCT should be obtained in all patients with worrisome changes in examination or nonreliable examinations, as both groups have high rates of unexpected findings on imaging that lead to management changes., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Cutaneous T-cell lymphoma (CTCL) is an incurable non-Hodgkin lymphoma of the skin-homing T cell. In early-stage disease, lesions are limited to the skin, but in later-stage disease, the tumor cells can escape into the blood, the lymph nodes, and at times the visceral organs. To clarify the genomic basis of CTCL, we performed genomic analysis of 220 CTCLs. Our analyses identify 55 putative driver genes, including 17 genes not previously implicated in CTCL. These novel mutations are predicted to affect chromatin ( BCOR , KDM6A , SMARCB1 , TRRAP ), immune surveillance ( CD58 , RFXAP ), MAPK signaling ( MAP2K1 , NF1 ), NF-κB signaling ( PRKCB , CSNK1A1 ), PI-3-kinase signaling ( PIK3R1 , VAV1 ), RHOA/cytoskeleton remodeling ( ARHGEF3 ), RNA splicing ( U2AF1 ), T-cell receptor signaling ( PTPRN2 , RLTPR ), and T-cell differentiation ( RARA ). Our analyses identify recurrent mutations in 4 genes not previously identified in cancer. These include CK1α (encoded by CSNK1A1 ) (p.S27F; p.S27C), PTPRN2 (p.G526E), RARA (p.G303S), and RLTPR (p.Q575E). Last, we functionally validate CSNK1A1 and RLTPR as putative oncogenes. RLTPR encodes a recently described scaffolding protein in the T-cell receptor signaling pathway. We show that RLTPR (p.Q575E) increases binding of RLTPR to downstream components of the NF-κB signaling pathway, selectively upregulates the NF-κB pathway in activated T cells, and ultimately augments T-cell-receptor-dependent production of interleukin 2 by 34-fold. Collectively, our analysis provides novel insights into CTCL pathogenesis and elucidates the landscape of potentially targetable gene mutations., (© 2017 by The American Society of Hematology.)

Background: Hyalinizing clear cell carcinoma (HCCC) is a rare epithelial malignant neoplasm typically arising from the minor salivary glands. Although it has been described as a benign neoplasm, there are increasing reports of malignant features and metastases to the lungs; we present the first case of biopsy-proven spinal metastases from HCCC and an overview of the literature., Case Description: This is a single-patient case report in which we used immunohistochemistry and fluorescence in situ hybridization for Ewing sarcoma breakpoint region 1 translocation to confirm the diagnosis of HCCC in a spinal metastasis. The diagnosis of metastatic HCCC was confirmed on the basis of histopathology, immunohistochemistry, and fluorescence in situ hybridization studies., Conclusions: We present the first pathologically confirmed case of a spinal metastasis in HCCC. As increasing of metastatic HCCC arise, a reconsideration of HCCC as a potentially high-grade disease seems increasingly necessary as it may impact the current treatment paradigm., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Accuracy in Ommaya reservoir catheter placement is critical to chemotherapy infusion. Most frameless image guidance is light emitting diode (LED) based, requiring a direct line of communication between instrument and tracker, limiting freedom of instrument movement within the surgical field. Electromagnetic neuronavigation may overcome this challenge., Objective: To compare Ommaya reservoir ventricular catheter placement using electromagnetic neuronavigation to LED-based optical navigation, with emphasis on placement accuracy, operative time and complication rate., Methods: Twenty-eight patients who underwent placement of Ommaya reservoirs at our institution between 2010 and 2014 with either electromagnetic (12 patients) or optical neuronavigation (16 patients) were retrospectively reviewed., Results: Half of the patients were male. Their mean age was 56 years (range 28-87 years). Accuracy and precision in catheter tip placement at the target site (foramen of Monro) were both higher (p=0.038 and p=0.043, respectively) with electromagnetic neuronavigation. Unintended placement of the distal catheter contralateral to the target site occurred more frequently with optical navigation, as did superior or inferior positioning by more than 5 mm. Mean operative times were shorter (p=0.027) with electromagnetic neuronavigation (43.2 min) than with optical navigation (51.0 min). There were three complications (10.7%)--one case each of cytotoxic edema, post-operative wound infection, and urinary tract infection. The rate of complication did not differ between groups., Conclusion: In contrast with optical neuronavigation, frameless and pinless electromagnetic image guidance allows the ability to track instrument depth in real-time. It may increase ventricular catheter placement accuracy and precision, and decrease operative times., (Copyright © 2015 Elsevier B.V. All rights reserved.)