PANCDR: precise medicine prediction using an adversarial network for cancer drug response.

Pharmacogenomics aims to provide personalized therapy to patients based on their genetic variability. However, accurate prediction of cancer drug response (CDR) is challenging due to genetic heterogeneity. Since clinical data are limited, most studies predicting drug response use preclinical data to train models. However, such models might not be generalizable to external clinical data due to differences between the preclinical and clinical datasets. In this study, a Precision Medicine Prediction using an Adversarial Network for Cancer Drug Response (PANCDR) model is proposed. PANCDR consists of two sub-models, an adversarial model and a CDR prediction model. The adversarial model reduces the gap between the preclinical and clinical datasets, while the CDR prediction model extracts features and predicts responses. PANCDR was trained using both preclinical data and unlabeled clinical data. Subsequently, it was tested on external clinical data, including The Cancer Genome Atlas and brain tumor patients. PANCDR outperformed other machine learning models in predicting external test data. Our results demonstrate the robustness of PANCDR and its potential in precision medicine by recommending patient-specific drug candidates. The PANCDR codes and data are available at https://github.com/DMCB-GIST/PANCDR.

MRI Scoring Systems for Predicting Isocitrate Dehydrogenase Mutation and Chromosome 1p/19q Codeletion in Adult-type Diffuse Glioma Lacking Contrast Enhancement.

Background According to 2021 World Health Organization criteria, adult-type diffuse gliomas include glioblastoma, isocitrate dehydrogenase (IDH)-wildtype; oligodendroglioma, IDH-mutant and 1p/19q-codeleted; and astrocytoma, IDH-mutant, even when contrast enhancement is lacking. Purpose To develop and validate simple scoring systems for predicting IDH and subsequent 1p/19q codeletion status in gliomas without contrast enhancement using standard clinical MRI sequences. Materials and Methods This retrospective study included adult-type diffuse gliomas lacking contrast at contrast-enhanced MRI from two tertiary referral hospitals between January 2012 and April 2022 with diagnoses confirmed at pathology. IDH status was predicted primarily by using T2-fluid-attenuated inversion recovery (FLAIR) mismatch sign, followed by 1p/19q codeletion prediction. A visual rating of MRI features, apparent diffusion coefficient (ADC) ratio, and relative cerebral blood volume was measured. Scoring systems were developed through univariable and multivariable logistic regressions and underwent calibration and discrimination, including internal and external validation. Results For the internal validation cohort, 237 patients were included (mean age, 44.4 years ± 14.4 [SD]; 136 male patients; 193 patients in IDH prediction and 163 patients in 1p/19q prediction). For the external validation cohort, 35 patients were included (46.1 years ± 15.3; 20 male patients; 28 patients in IDH prediction and 24 patients in 1p/19q prediction). The T2-FLAIR mismatch sign demonstrated 100% specificity and 100% positive predictive value for IDH mutation. IDH status prediction scoring system for tumors without mismatch sign included age, ADC ratio, and morphologic characteristics, whereas 1p/19q codeletion prediction for IDH-mutant gliomas included ADC ratio, cortical involvement, and mismatch sign. For IDH status and 1p/19q codeletion prediction, bootstrap-corrected areas under the receiver operating characteristic curve were 0.86 (95% CI: 0.81, 0.90) and 0.73 (95% CI: 0.65, 0.81), respectively, whereas at external validation they were 0.99 (95% CI: 0.98, 1.0) and 0.88 (95% CI: 0.63, 1.0). Conclusion The T2-FLAIR mismatch sign and scoring systems using standard clinical MRI predicted IDH and 1p/19q codeletion status in gliomas lacking contrast enhancement. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Badve and Hodges in this issue.

New Subependymal Enhancement After Radiation Therapy in High-Grade Glioma: Utilizing Morphological Features and DSC Perfusion MRI in Differentiate Progression and Post-Radiation Changes.

BACKGROUND: The specific patterns of subependymal enhancement (SE) that frequently occur as radiation-induced changes in high-grade gliomas following radiotherapy are often overlooked. Perfusion MRI may offer a diagnostic clue. PURPOSE: To distinguish between radiation-induced SE and progression in adult high-grade diffuse gliomas after standard treatment. STUDY TYPE: Retrospective. POPULATION: Ninety-four consecutive high-grade diffuse glioma patients (mean age, 55 ± 14 years; 54 [57.4%] males) with new SE identified in follow-up MRI after completion of surgery plus chemoradiation: progression (N = 74) vs. regression (N = 20). FIELD STRENGTH/SEQUENCE: 3 T, gradient-echo dynamic susceptibility contrast-enhanced MRI, 3D gradient-echo contrast-enhanced T1-weighted imaging. ASSESSMENT: To differentiate between radiation changes and progression in SE evaluation, multivariable logistic regression was performed using significant variables among SE appearance interval, IDH mutation, morphological features, and rCBV. Cox regression was performed to predict the tumor progression. For the added value of the rCBV, a log-rank test was conducted between the multivariable logistic regression models with and without the rCBV. STATISTICAL TESTS: Logistic regression, Cox regression, receiver operating characteristic analysis, log-rank test. RESULTS: 38.3% (36/94) patients had first specific SE (9.2 ± 9.5 months after surgery), which disappeared in 21.3% (20/94) after 5.8 ± 5.8 months after initial appearance on post-radiation MRI. IDH mutation, elongated, small lesions with lower rCBV tended to regress: IDH mutation, elongation, diameter, and rCBV_p95; odds ratio, 0.32, 1.92, 1.70, and 2.47, respectively. Qualitative evaluation of shape revealed that thin and curvilinear-shaped SE tended to regress, indicating a significant correlation with quantitative shape features (r = 0.31). In Cox regression, rCBV and lesion shape were significant (hazard ratio = 1.09 and 0.54, respectively). For sub-centimeter lesions, the rCBV showed added value in predicting outcomes (area under the curve, 0.873 vs. 0.836; log-rank test). DATA CONCLUSION: Smaller, elongated lesions with lower rCBV and IDH mutation are associated with regression when differentiating radiation changes from progression in high-grade glioma with post-radiotherapy SE. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 2.

Fibrous hamartoma of infancy of the spinal cord resembling conus and filum, with a coexisting sacral dimple.

Fibrous hamartoma of infancy (FHI) is a rare benign soft tissue lesion of infants and young children. It usually occurs within the first 2 years of life at the superficial layer of the axilla, trunk, upper arm, and external genitalia. FHI in the central nervous system (CNS) is extremely rare. So far, only two spinal cord FHI cases have been reported. We present a case of a 1-month-old girl who presented with a skin dimple in the coccygeal area. Her MRI showed a substantial intramedullary mass in the thoracolumbar area with a sacral soft tissue mass and a track between the skin lesion to the coccygeal tip. Her normal neurological status halted immediate surgical resection. A skin lesion biopsy was first performed, revealing limited information with no malignant cells. A short-term follow-up was performed until the intramedullary mass had enlarged on the 5-month follow-up MRI. Based on the frozen biopsy result of benign to low-grade spindle cell mesenchymal tumor, subtotal resection of the mass was done, minimizing damage to the functioning neural tissue. Both the skin lesion and the intramedullary mass were diagnosed as FHI. Postoperative 5.5-year follow-up MRI revealed minimal size change of the residual mass. Despite being diagnosed with a neurogenic bladder, the patient maintained her ability to void spontaneously, managed infrequent UTIs, and continued toilet training, all while demonstrating good mobility and no motor weakness. This case is unique because the lesion resembled the secondary neurulation structures, such as the conus and the filum, along with a related congenital anomaly of the dimple.

Intramedullary spinal capillary hemangioma with secondary neurulation defect in children.

Intramedullary spinal capillary hemangioma is a rare occurrence in pediatric patients, and only limited cases have been reported. This study presents the first two cases of spinal capillary hemangioma co-present with retained medullary cord and one case of spinal capillary hemangioma with lumbosacral lipomatous malformation. Previous literature on ten patients with this pathology was reviewed. We speculated pathogenesis, imaging features, and histopathologic findings of the disease.

Suprasellar teratoma to germinoma recurrence: implications for diagnosis and follow-up.

Mature teratoma is a subtype of intracranial germ cell tumors (GCTs), distinguished from malignant GCTs by its benign nature and excellent prognosis. Typically, no adjuvant therapy is recommended following gross total resection (GTR). We report a case of a prepubertal girl with a suprasellar mature teratoma that recurred as a germinoma 6 months post-GTR. A 7-year-old girl presented with headache and polydipsia. Imaging revealed a suprasellar mass. The patient underwent GTR, and pathological diagnosis confirmed a mature teratoma without other GCT components. Six months later, MRI identified a newly developed suprasellar mass adjacent to the optic chiasm. A second surgery confirmed the mass as a germinoma. The patient subsequently underwent adjuvant chemotherapy combined with proton therapy, resulting in complete remission. The diagnosis of mature teratoma must be approached with caution, and thorough follow-up is imperative, particularly in cases involving female patients, prepubertal age, or non-pineal locations.

Epigenetic Alteration of H3K27me3 as a Possible Oncogenic Mechanism of Central Neurocytoma.

Central neurocytoma (CN) is a low-grade neuronal tumor that mainly arises from the lateral ventricle (LV). This tumor remains poorly understood in the sense that no driver gene aberrations have been identified thus far. We investigated immunomarkers in fetal and adult brains and 45 supratentorial periventricular tumors to characterize the biomarkers, cell of origin, and tumorigenesis of CN. All CNs occurred in the LV. A minority involved the third ventricle, but none involved the fourth ventricle. As expected, next-generation sequencing performed using a brain-tumor-targeted gene panel in 7 CNs and whole exome sequencing in 5 CNs showed no driver mutations. Immunohistochemically, CNs were robustly positive for FGFR3 (100%), SSTR2 (92%), TTF-1 (Nkx2.1) (88%), GLUT-1 (84%), and L1CAM (76%), in addition to the well-known markers of CN, synaptophysin (100%) and NeuN (96%). TTF-1 was also positive in subependymal giant cell astrocytomas (100%, 5/5) and the pituicyte tumor family, including pituicytoma and spindle cell oncocytoma (100%, 5/5). Interestingly, 1 case of LV subependymoma (20%, 1/5) was positive for TTF-1, but all LV ependymomas were negative (0/5 positive). Because TTF-1-positive cells were detected in the medial ganglionic eminence around the foramen of Monro of the fetal brain and in the subventricular zone of the LV of the adult brain, CN may arise from subventricular TTF-1-positive cells undergoing neuronal differentiation. H3K27me3 loss was observed in all CNs and one case (20%) of LV subependymoma, suggesting that chromatin remodeling complexes or epigenetic alterations may be involved in the tumorigenesis of all CNs and some ST-subependymomas. Further studies are required to determine the exact tumorigenic mechanism of CN.

AXL+SIGLEC6+ dendritic cells in cerebrospinal fluid and brain tissues of patients with autoimmune inflammatory demyelinating disease of CNS.

Inflammatory demyelinating disease of the CNS (IDD) is a heterogeneous group of autoimmune diseases, and multiple sclerosis is the most common type. Dendritic cells (DCs), major antigen-presenting cells, have been proposed to play a central role in the pathogenesis of IDD. The AXL+SIGLEC6+ DC (ASDC) has been only recently identified in humans and has a high capability of T cell activation. Nevertheless, its contribution to CNS autoimmunity remains still obscure. Here, we aimed to identify the ASDC in diverse sample types from IDD patients and experimental autoimmune encephalomyelitis (EAE). A detailed analysis of DC subpopulations using single-cell transcriptomics for the paired cerebrospinal fluid (CSF) and blood samples of IDD patients (total n = 9) revealed that three subtypes of DCs (ASDCs, ACY3+ DCs, and LAMP3+ DCs) were overrepresented in CSF compared with their paired blood. Among these DCs, ASDCs were also more abundant in CSF of IDD patients than in controls, manifesting poly-adhesional and stimulatory characteristics. In the brain biopsied tissues of IDD patients, obtained at the acute attack of disease, ASDC were also frequently found in close contact with T cells. Lastly, the frequency of ASDC was found to be temporally more abundant in acute attack of disease both in CSF samples of IDD patients and in tissues of EAE, an animal model for CNS autoimmunity. Our analysis suggests that the ASDC might be involved in the pathogenesis of CNS autoimmunity.

Inhibition of CXXC5 function rescues Alzheimer's disease phenotypes by restoring Wnt/ß-catenin signaling pathway.

Alzheimer's disease (AD) is the most prevalent type of dementia and is characterized by cognitive deficits and accumulation of pathological plaques. Owing to the complexity of AD development, paradigms for AD research and drug discovery have shifted to target factors that mediate multiple pathogenesis in AD. Increasing evidence suggests that the suppression of the Wnt/ß-catenin signaling pathway plays substantial roles in AD progression. However, the underlying mechanism for the suppression of Wnt/ß-catenin pathway associated with AD pathogenesis remains unexplored. In this study, we identified that CXXC5, a negative feedback regulator of the Wnt/ß-catenin pathway, was overexpressed in the tissues of AD patients and 5xFAD transgenic mice paired with the suppression of Wnt/ß-catenin pathway and its target genes related to AD. The level of CXXC5 was upregulated, upon aging of 5xFAD mice. AD characteristics including cognitive deficits, amyloid-ß (Aß) plaques, neuronal inflammation, and age-dependent increment of AD-related markers were rescued in Cxxc5-/-/5xFAD mice. 5-methoxyindirubin-3'-oxime (KY19334), a small molecule that restores the suppressed Wnt/ß-catenin pathway via interference of the CXXC5-Dvl interaction, significantly improved the overall pathogenic phenotypes of 5xFAD mice. Collectively, our findings revealed that CXXC5 plays a key role in AD pathogenesis and suggest inhibition of CXXC5-Dvl interaction as a new therapeutic approach for AD.

Comparison of the clinical features and treatment outcomes of pilocytic astrocytoma in pediatric and adult patients.

PURPOSE: Pilocytic astrocytoma is a slow-growing tumor that predominantly develops in children, but has a broad age spectrum. A notable characteristic of pilocytic astrocytoma is that the tumor arises in diverse locations and the clinical course is not always benign. Therefore, it is necessary to elucidate the clinical spectrum of the disease and analyze the relevant prognostic factors. METHODS: Demographic and treatment-related factors were retrospectively reviewed in a cohort of 254 patients with histologically confirmed pilocytic astrocytoma. Clinical features were compared between the pediatric group (N = 208; age < 18 years) and the adult group (N = 46; age ≥ 18 years). Cox regression analysis was performed to identify relevant prognostic factors. RESULTS: There was no difference in progression-free survival (PFS) between the pediatric and adult groups (p = 0.36); however, patients under 8 years of age exhibited worse PFS (p < 0.01). Leptomeningeal seeding at diagnosis and pilomyxoid histology was observed only in pediatric patients. In the pediatric group, nine patients experienced recurrence after complete resection. Increasing age (hazard ratio (HR) = 0.89, p < 0.01) and adjuvant therapy (HR = 0.32, p < 0.01) were protective factors against tumor progression. In the adult group, no progression occurred after complete resection. Age and adjuvant therapy were not significant factors in the adult group. CONCLUSION: Pilocytic astrocytoma presents with a diverse clinical spectrum. Complete resection is of utmost importance, and appropriate adjuvant treatment is recommended if complete resection cannot be achieved. Children with younger age are associated with more aggressive tumors, and recurrence may occur even after complete resection.

The Role of Epigenetics in Brain and Spinal Cord Tumors.

Identification of distinct genetic and epigenetic profiles in various neuroepithelial tumors has improved the classification and uncovered novel diagnostic, prognostic, and predictive molecular biomarkers for improved prediction of treatment response and outcome. Especially, in pediatric high-grade brain tumors, such as diffuse midline glioma, H3K27M-altered and posterior fossa group A-ependymoma, epigenetic changes predominate, along with changes in expression of known oncogenes and tumor suppressor genes induced by histone modifications and DNA methylation. The precise role of epigenetic abnormalities is important for understanding tumorigenesis and the establishment of brain tumor treatment strategies. Using powerful epigenetic-based therapies for cancer cells, the aberrantly regulated epigenome can be restored to a more normal state through epigenetic reprogramming. Combinations of agents targeting DNA methylation and/or other epigenetic modifications may be a promising cancer treatment. Therefore, the integration of multi-omics data including epigenomics is now important for classifying primary brain tumors and predicting their biological behavior. Recent advances in molecular genetics and epigenetic integrated diagnostics of brain tumors influence new strategies for targeted therapy.

Brain Tumor Classification by Methylation Profile.

The goal of the methylation classifier in brain tumor classification is to accurately classify tumors based on their methylation profiles. Accurate brain tumor diagnosis is the first step for healthcare professionals to predict tumor prognosis and establish personalized treatment plans for patients. The methylation classifier can be used to perform classification on tumor samples with diagnostic difficulties due to ambiguous histology or mismatch between histopathology and molecular signatures, i.e., not otherwise specified (NOS) cases or not elsewhere classified (NEC) cases, aiding in pathological decision-making. Here, the authors elucidate upon the application of a methylation classifier as a tool to mitigate the inherent complexities associated with the pathological evaluation of brain tumors, even when pathologists are experts in histopathological diagnosis and have access to enough molecular genetic information. Also, it should be emphasized that methylome cannot classify all types of brain tumors, and it often produces erroneous matches even with high matching scores, so, excessive trust is prohibited. The primary issue is the considerable difficulty in obtaining reference data regarding the methylation profile of each type of brain tumor. This challenge is further amplified when dealing with recently identified novel types or subtypes of brain tumors, as such data are not readily accessible through open databases or authors of publications. An additional obstacle arises from the fact that methylation classifiers are primarily research-based, leading to the unavailability of charging patients. It is important to note that the application of methylation classifiers may require specialized laboratory techniques and expertise in DNA methylation analysis.

Sporadic and Lynch syndrome-associated mismatch repair-deficient brain tumors.

Mismatch repair-deficient (MMRD) brain tumors are rare among primary brain tumors and can be induced by germline or sporadic mutations. Here, we report 13 MMRD-associated (9 sporadic and 4 Lynch syndrome) primary brain tumors to determine clinicopathological and molecular characteristics and biological behavior. Our 13 MMRD brain tumors included glioblastoma (GBM) IDH-wildtype (n = 9) including 1 gliosarcoma, astrocytoma IDH-mutant WHO grade 4 (n = 2), diffuse midline glioma (DMG) H3 K27M-mutant (n = 1), and pleomorphic xanthoastrocytoma (PXA) (n = 1). Next-generation sequencing using a brain tumor-targeted gene panel, microsatellite instability (MSI) testing, Sanger sequencing for germline MMR gene mutation, immunohistochemistry of MMR proteins, and clinicopathological and survival analysis were performed. There were many accompanying mutations, suggesting a high tumor mutational burden (TMB) in 77%, but TMB was absent in one case of GBM, IDH-wildtype, DMG, and PXA, respectively. MSH2, MLH1, MSH6, and PMS2 mutations were found in 31%, 31%, 31% and 7% of patients, respectively. MSI-high and MSI-low were found in 50% and 8% of these gliomas, respectively and 34% was MSI-stable. All Lynch syndrome-associated GBMs had MSI-high. In addition, 77% (10/13) had histopathologically multinucleated giant cells. The progression-free survival tended to be poorer than the patients with no MMRD gliomas, but the number and follow-up duration of our patients were insufficient to get statistical significance. In the present study, we found that the most common MMRD primary brain tumor was GBM IDH-wildtype. The genetic profile of MMRD GBM was different from that of conventional GBM. MMRD gliomas with TMB and MSI-H may be sensitive to immunotherapy but resistant to temozolomide. Our findings can help develop better treatment options.

Molecular subgrouping of medulloblastoma in pediatric population using the NanoString assay and comparison with immunohistochemistry methods.

PURPOSE: Molecular subgrouping of medulloblastoma has become important due to its impact on risk group stratification. Immunohistochemistry (IHC) has been widely used but it has innate limitations. The NanoString assay has been proposed as an alternative method. This study aims to present the characteristics of medulloblastoma subgrouped by the NanoString assay and to compare the subgrouping results with the IHC method. METHODS: Pediatric patients with histological diagnosis of medulloblastoma who underwent surgery from 2007 to 2021 were included. Clinical characteristics, pathological findings were reviewed. Molecular subgrouping was performed by IHC and by NanoString nCounter Elements TagSets assay. Test for concordance between two methods was made. RESULTS: Among a total of 101 patients analyzed, subgrouping using the NanoString assay resulted in 14 (13.8%) WNT, 20 (19.8%) SHH, 18 (17.8%) Group 3, and 39 (38.6%) Group 4 subgroup cases. Survival analysis revealed the following from best to worse prognosis: WNT, Group 4, SHH, and Group 3. In SHH subgroup the large cell/anaplastic histology was present in 30% of cases. Seventy-one cases were analyzed for concordance between NanoString and IHC. Cohen's kappa value indicated moderate agreement but identification of Groups 3 and 4 with IHC using NPR3 and KCNA1 markers exhibited poor results. CONCLUSIONS: The NanoString assay of Korean medulloblastoma patients revealed a more aggressive clinical course in the SHH subgroup which may be explained by a higher proportion of large cell/anaplastic histology being present in this subgroup. IHC did not distinguish Group 3 or 4 accurately. The NanoString assay may represent a good alternative method for practical use in the clinical field.

Aberrant role of ALK in tau proteinopathy through autophagosomal dysregulation.

Proteinopathy in neurodegenerative diseases is typically characterized by deteriorating activity of specific protein aggregates. In tauopathies, including Alzheimer's disease (AD), tau protein abnormally accumulates and induces dysfunction of the affected neurons. Despite active identification of tau modifications responsible for tau aggregation, a critical modulator inducing tau proteinopathy by affecting its protein degradation flux is not known. Here, we report that anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase, is crucial for the tau-mediated AD pathology. ALK caused abnormal accumulation of highly phosphorylated tau in the somatodendritic region of neurons through its tyrosine kinase activity. ALK-induced LC3-positive axon swelling and loss of spine density, leading to tau-dependent neuronal degeneration. Notably, ALK activation in neurons impaired Stx17-dependent autophagosome maturation and this defect was reversed by a dominant-negative Grb2. In a Drosophila melanogaster model, transgenic flies neuronally expressing active Drosophila Alk exhibited the aggravated tau rough eye phenotype with retinal degeneration and shortened lifespan. In contrast, expression of kinase-dead Alk blocked these phenotypes. Consistent with the previous RNAseq analysis showing upregulation of ALK expression in AD [1], ALK levels were significantly elevated in the brains of AD patients showing autophagosomal defects. Injection of an ALK.Fc-lentivirus exacerbated memory impairment in 3xTg-AD mice. Conversely, pharmacologic inhibition of ALK activity with inhibitors reversed the memory impairment and tau accumulation in both 3xTg-AD and tauC3 (caspase-cleaved tau) transgenic mice. Together, we propose that aberrantly activated ALK is a bona fide mediator of tau proteinopathy that disrupts autophagosome maturation and causes tau accumulation and aggregation, leading to neuronal dysfunction in AD.

Toxic leukoencephalopathy with axonal spheroids caused by chemotherapeutic drugs other than methotrexate.

BACKGROUND: The objective of this report is to share the clinicopathological features of chemotherapy-induced toxic leukoencephalopathy, which is a rare and under-recognized disease, clinically characterized by rapidly progressive cognitive loss that often leads to sudden death. CASE PRESENTATION: A 64-year-old woman and a 63-year-old man, who had both suffered from a rapid deterioration of consciousness, were autopsied under the clinical impressions of either the central nervous system graft versus host disease (CNS-GVHD), infectious encephalitis, or autoimmune encephalitis. Both patients had been treated with multiple chemotherapy regimens, including adriamycin, cytarabine arabinoside, daunorubicin, fludarabine, azacitidine, and allogeneic peripheral blood stem cell transplantation to treat hematological malignancies (acute myelogenous leukemia and myelodysplastic syndrome). Neuropathological findings at autopsy revealed rarefaction and vacuolar changes of the white matter with axonal spheroids, reactive gliosis, and foamy macrophage infiltration, predominantly in the visual pathways of the occipital and temporal lobes. Damaged axons exhibited immunoreactivity to beta-amyloid, consistent with axonopathy. However, there was no lymphocyte infiltration that suggested CNS-GVHD or any type of encephalitis. CONCLUSION: The neuropathology found in the presented cases had the characteristic features of toxic leukoencephalopathy (chemobrain). Our cases showed that toxic leukoencephalopathy can also be caused by chemotherapy drugs other than methotrexate.

Modulation of Nogo receptor 1 expression orchestrates myelin-associated infiltration of glioblastoma.

As the clinical failure of glioblastoma treatment is attributed by multiple components, including myelin-associated infiltration, assessment of the molecular mechanisms underlying such process and identification of the infiltrating cells have been the primary objectives in glioblastoma research. Here, we adopted radiogenomic analysis to screen for functionally relevant genes that orchestrate the process of glioma cell infiltration through myelin and promote glioblastoma aggressiveness. The receptor of the Nogo ligand (NgR1) was selected as the top candidate through Differentially Expressed Genes (DEG) and Gene Ontology (GO) enrichment analysis. Gain and loss of function studies on NgR1 elucidated its underlying molecular importance in suppressing myelin-associated infiltration in vitro and in vivo. The migratory ability of glioblastoma cells on myelin is reversibly modulated by NgR1 during differentiation and dedifferentiation process through deubiquitinating activity of USP1, which inhibits the degradation of ID1 to downregulate NgR1 expression. Furthermore, pimozide, a well-known antipsychotic drug, upregulates NgR1 by post-translational targeting of USP1, which sensitizes glioma stem cells to myelin inhibition and suppresses myelin-associated infiltration in vivo. In primary human glioblastoma, downregulation of NgR1 expression is associated with highly infiltrative characteristics and poor survival. Together, our findings reveal that loss of NgR1 drives myelin-associated infiltration of glioblastoma and suggest that novel therapeutic strategies aimed at reactivating expression of NgR1 will improve the clinical outcome of glioblastoma patients.

Brain parenchymal angiomatoid fibrous histiocytoma and spinal myxoid mesenchymal tumor with FET: CREB fusion, a spectrum of the same tumor type.

Angiomatoid fibrous histiocytomas (AFH) is a rare soft tissue tumor of intermediate malignant potential, and its histology is diverse. It can occur in several organs including intracranial and soft tissues. Here, we report two cases of brain parenchymal classic AFH and spinal extramedullary myxoid mesenchymal tumor with clinicopathological and molecular investigations by next-generation sequencing and a comprehensive review. The current brain parenchymal AFH occurred in a 79-year-old woman, and the spinal myxoid mesenchymal tumor arose in the thoracic spine of a 28-year-old woman; both harbored FET:CREB fusion. The current brain parenchymal AFH has not recurred for 15-months follow-up period, but the spinal myxoid mesenchymal tumor recurred three times and metastasized to T8 spine level for 30-months follow-up period. We reviewed 40 reported cases of central nervous system (CNS) AFHs/myxoid mesenchymal tumors including our two cases to identify clinicopathological features and biological behaviors. They occur with a slight female predominance (M:F = 1:1.7) in children and young adults (median age: 17 years; range: 4-79 years old). Approximately 80% of CNS AFHs were younger than 30 year. Most of them were dura-based and were not just intracranial tumors as they occurred anywhere in the CNS including spinal dura. EWSR1 rearrangement was the most common driver (98%), including FET:CREB (33%), EWSR1:ATF1 (30%), and EWSR1:CREM (27%) fusions, but FUS:CREM fusion (2%) was also present. During the follow-up period (median: 27 months), 43% (17/40) of CNS AFHs recurred between two months and 11 years, and multiple recurrences were also observed. One case showed metastases to the lymph nodes and vertebrae, and among 11 cases that resulted in death, four cases provided available clinical data. Because these tumors are identical to soft tissue AFH or primary pulmonary myxoid sarcoma with an FET:CREB fusion in morphological and immunohistochemical spectra, the authors propose incorporating the two tumor terms into one.

Retained medullary cord and terminal myelocystocele as a spectrum: case report.

The caudal portion of the spinal cord, the medullary cord, is formed by secondary neurulation. One of the distinctive features of secondary neurulation compared to primary neurulation is that the medullary cord normally degenerates into a filum in humans. Various anomalies have been known to originate from degenerating process errors. One anomaly is terminal myelocystocele (TMCC), which is a closed spinal dysraphism with an elongated caudal spinal cord. The terminal part is filled with cerebrospinal fluid (CSF) and protrudes into the dorsal extradural space. Another anomaly is the retained medullary cord (RMC), which is a nonfunctioning cord-like structure extending to the cul-de-sac. In a 1-month-old boy, we identified an RMC with cystic dilatation of the caudal end extending to the epidural space at the very bottom of the cul-de-sac, resembling a degenerating terminal balloon, which is an essential feature of TMCC. Hence, this case may be considered an intermediate form between TMCC and RMC. This case provides clinical evidence that TMCC and RMC share the same pathoembryogenic origin, namely, failure of the regression phase of secondary neurulation.

Absolute quantification of tumor-infiltrating immune cells in high-grade glioma identifies prognostic and radiomics values.

PURPOSE: To understand the tumor immune microenvironment precisely, it is important to secure the quantified data of tumor-infiltrating immune cells, since the immune cells are true working unit. We analyzed unit immune cell number per unit volume of core tumor tissue of high-grade gliomas (HGG) to correlate their immune microenvironment characteristics with clinical prognosis and radiomic signatures. METHODS: The number of tumor-infiltrating immune cells from 64 HGG core tissue were analyzed using flow cytometry and standardized. After sorting out patient groups according to diverse immune characteristics, the groups were tested if they have any clinical prognostic relevance and specific radiomic signature relationships. Sparse partial least square with discriminant analysis using multimodal magnetic resonance images was employed for all radiomic classifications. RESULTS: The median number of CD45 + cells per one gram of HGG core tissue counted 865,770 cells which was equivalent to 8.0% of total cells including tumor cells. There was heterogeneity in the distribution of immune cell subpopulations among patients. Overall survival was significantly better in T cell-deficient group than T cell-enriched group (p = 0.019), and T8 dominant group than T4 dominant group (p = 0.023). The number of tumor-associated macrophages (TAM) and M2-TAM was significantly decreased in isocitrate dehydrogenase mutated HGG. Radiomic signature classification showed good performance in predicting immune phenotypes especially with features extracted from apparent diffusion coefficient maps. CONCLUSIONS: Absolute quantification of tumor-infiltrating immune cells confirmed the heterogeneity of immune microenvironment in HGG which harbors prognostic impact. This immune microenvironment could be predicted by radiomic signatures non-invasively.