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Quantifying intraventricular drug delivery utilizing programmable ventriculoperitoneal shunts as the intraventricular access device.

Programmable ventriculoperitoneal shunts (pVP shunts) are increasingly utilized for intraventricular chemotherapy, radioimmunotherapy, andor cellular therapy. Shunt adjustments allow optimization of drug concentrations in the thecal space with minimization in the peritoneum. This report assesses the success of the pVP shunt as an access device for intraventricular therapies. Quantifying intrathecal drug delivery using scintigraphy by pVP shunt model has not been previously reported. We performed a single-institution, retrospective analysis on patients with CNS tumors and pVP shunts from 2003 to 2020, noting shunt model. pVP flow was evaluated for consideration of compartmental radioimmunotherapy (cRIT) using In-111-DTPA scintigraphy. Scintigraphy studies at 2-4 h and at 24 h quantified ventricular-thecal and peritoneal drug activity. Twenty-two CSF flow studies were administered to 15 patients (N 15) with diagnoses including medulloblastoma, metastatic neuroblastoma, pineoblastoma, and choroid plexus carcinoma. Six different types of pVP models were noted. 100% of the studies demonstrated ventriculo-thecal drug activity. 27% (6 of 22) of the studies had no peritoneal uptake visible by imaging. 73% (16 of 22) of the studies had minimal relative peritoneal uptake (< 12%). 27% (6 of 22) of the studies demonstrated moderate relative peritoneal uptake (12-37%). No studies demonstrated peritoneal uptake above 37%. All patients had successful drug delivery of In-111-DTPA to the ventriculo-thecal space. 73% of the patients had minimal relative (< 12%) peritoneal drug uptake. Though efficacy varies by shunt model, low numbers preclude conclusions regarding model superiority. CSF flow scintigraphy studies assesses drug distribution of In-111-DTPA, informing CSF flow for delivery of intraventricular therapies.

Ultrasound and microbubble-mediated drug delivery and immunotherapy.

Ultrasound induces the oscillation and collapse of microbubbles such as those of an ultrasound contrast agent, where these behaviors generate mechanical and thermal effects on cells and tissues. These, in turn, induce biological responses in cells and tissues, such as cellular signaling, endocytosis, or cell death. These physiological effects have been used for therapeutic purposes. Most pharmaceutical agents need to pass through the blood vessel walls and reach the parenchyma cells to produce therapeutic effects in drug delivery. Therefore, the blood vessel walls act as an obstacle to drug delivery. The combination of ultrasound and microbubbles is a promising strategy to enhance vascular permeability, improving drug transport from blood to tissues. This combination has also been applied to gene and protein delivery, such as cytokines and antigens for immunotherapy. Immunotherapy, in particular, is an attractive technique for cancer treatment as it induces a cancer cell-specific response. However, sufficient anti-tumor effects have not been achieved with the conventional cancer immunotherapy. Recently, new therapies based on immunomodulation with immune checkpoint inhibitors have been reported. Immunomodulation can be regarded as a new strategy for cancer immunotherapy. It was also reported that mechanical and thermal effects induced by the combination of ultrasound and microbubbles could suppress tumor growth by promoting the cancer-immunity cycle via immunomodulation in the tumor microenvironment. In this review, we provide an overview of the application of ultrasound and microbubble combination for drug delivery and activation of the immune system in the microenvironment of tumor tissue.

ISL1 Promotes Human Glioblastoma-Derived Stem Cells Self-Renewal by Activation of Sonic HedgehogGLI1 Function.

Glioblastoma (GBM), the most aggressive primary heterogeneous primary brain tumor, is a glioma subtype that originates from the glial cells of the central nervous system. Glioblastoma stem cells (GSCs), situated at the top of the hierarchy, initiate and maintain the tumor and are largely accountable for GBM resistance to the mainstay treatment and recurrence. The LIM homeobox transcription factor islet 1 (ISL1) induces tumorigenicity in various tumors however, its function in GSCs has been less reported. We aimed to generate GSCs from surgical specimens of human GBM and investigate the effect of ISL1 knockdown on GSCs. We established patient-derived GSCs, determined cancer stem cell marker expression, and immunostained GSCs to assess cell viability and apoptosis. We demonstrated that ISL1 deletion decreased the GSC viability and proliferation, and upregulated apoptosis. Moreover, we performed enzyme-linked immunosorbent assay and western blotting and found that ISL1 knockdown affected the expression of sonic hedgehog (SHH) and its downstream regulator GLI1, and further validated these results by supplementing the cells with recombinant SHH. Our results suggested that ISL1 played a critical role in regulating GBM growth and that an ISL1SHHGLI1 pathway was required for the maintenance of GBM progression and malignancy. The regulation of GSC growth through ISL1 might be a mechanism of interest for future therapeutic studies.

PTPN14 Mutations and Cervical Cancer.

It was recently shown that rare germline loss-of-function variants in the tyrosine-protein phosphatase non-receptor type 14 (PTPN14) gene conferred substantial risk of basal cell carcinoma (BCC). A follow-up investigation of 24 cancers and three benign tumor types showed that PTPN14 loss-of-function variants were associated with high risk of cervical cancer and early age at diagnosis. We used the Cancer Genome Atlas (TCGA) to further evaluate the PTPN14 - cervical cancer association. We analyzed the Genomic Data Commons (GDC) TCGA Cervical Cancer (CESC) data set. We used cBioPortal for Cancer Genomics to access data in TCGA. cBioPortal provides visualization, analysis and download options for large-scale cancer genomic data sets. We also accessed TCGA data with the University of California Santa Cruz (UCSC) Xena Browser. UCSC Xena allows users to explore functional genomic data sets for assessing correlations between genomic andor phenotypic variables. Ten patients with PTPN14 mutations had significantly better survival than 266 patients without PTPN14 mutations (p0.05 log rank test). In the Human Protein Atlas, low expression of PTPN14 in 85 TCGA cervical cancer specimens was associated with better survival than high expression in 206 cervical cancer specimens. In general, factors that affect the risk of a cancer have the same effect on prognosis. For example, history of allergy reduces risk of malignant brain tumors and improves prognosis. However, this relationship is not the case for PTPN14. We conclude that in TCGA cervical cancer specimens, PTPN14 mutation is a favorable prognostic factor. However, germline variants of PTPN14 confer a worse prognosis. Further studies of the specific mutations would be worthwhile.

Cannabidiol Μay Prolong Survival in Patients With Glioblastoma Multiforme.

Glioblastoma multiforme (GBM) is a relatively rare type of brain tumour with an incidence rate around 6 per 100,000. Even with the widely practiced combination of radiotherapy with adjuvant temozolomide, the median overall survival remains low with just 13.5 to 16 months after diagnosis. We retrospectively reviewed the survival of a cohort of 15 consecutive, unselected patients with histopathologically confirmed glioblastoma multiforme (GBM) who received CBD (400 to 600 mg orally per day) in addition to standard therapy (maximum resection of the tumour followed by radio-chemotherapy). Of 15 patients, seven (46.7%) are now living for at least 24 months, and four (26.7%) for at least 36 months. This is more than twice as long as has been previously reported in the literature. The mean overall survival is currently 24.2 months (median 21 months). CBD is a well supported co-medication and seems to prolong the survival of patients with glioblastoma multiforme.

Psychosocial and behavioral factors affecting inflammation among pregnant African American women.

African American women are reported to have greater inflammation compared with women from other racial groups. Higher inflammation during pregnancy has been associated with increased risk of adverse perinatal outcomes. We hypothesized that maternal inflammation is related to depressive symptoms and social and behavioral risk factors among pregnant African American women. Pregnant African American women (n ​ ​187) were recruited at prenatal clinics in the Midwest. Women completed questionnaires and had blood drawn at a prenatal visit. Plasma levels of cytokines (interferon gamma IFN-γ, interleukin IL-6, IL-8, IL-10, tumor necrosis factor TNF-α) and C-reactive protein (CRP) were measured by multiplex assays. Women had a mean age of 26.58±5.42 years and a mean gestational age at data collection of 16.35±5.95 weeks. Twenty-six percent of women had Center for Epidemiological Studies-Depression (CES-D) scores ≥23 (scores that have been correlated with clinical diagnosis of depression), 15.5% smoked cigarettes, 16.6% used marijuana, and 5.3% reported experiencing intimate partner violence (IPV). Higher CES-D scores were correlated with higher plasma CRP levels (

Genetic Characteristics Associated With Drug Resistance in Lung Cancer and Colorectal Cancer Using Whole Exome Sequencing of Cell-Free DNA.

Circulating cell-free DNA (cfDNA) can be used to characterize tumor genomes through next-generation sequencing (NGS)-based approaches. We aim to identify novel genetic alterations associated with drug resistance in lung cancer and colorectal cancer patients who were treated with EGFR-targeted therapy and cytotoxic chemotherapy through whole exome sequencing (WES) of cfDNA. A cohort of 18 lung cancer patients was treated with EGFR TKI or cytotoxic chemotherapy, and a cohort of 37 colorectal cancer patients was treated with EGFR monoclonal antibody or cytotoxic chemotherapy alone. Serum samples were drawn before and after development of drug resistance, and the genetic mutational profile was analyzed with WES data. For 110 paired cfDNA and matched germline DNA WES samples, mean coverage of 138x (range, 52-208.4x) and 47x (range, 30.5-125.1x) was achieved, respectively. After excluding synonymous variants, mutants identified in more than two patients at the time of acquired resistance were selected. Seven genes in lung cancer and 16 genes in colorectal cancer were found, namely, APC, TP53, KRAS, SMAD4, and EGFR. In addition, the GPR155 I357S mutation in lung cancer and ADAMTS20 S1597P and TTN R7415H mutations in colorectal cancer were frequently detected at the time of acquired resistance, indicating that these mutations have an important function in acquired resistance to chemotherapy. Our data suggest that novel genetic variants associated with drug resistance can be identified using cfDNA WES. Further validation is necessary, but these candidate genes are promising therapeutic targets for overcoming drug resistance in lung cancer and colorectal cancer.

A Comprehensive Analysis of the Glutathione Peroxidase 8 (GPX8) in Human Cancer.

Nowadays, cancer is still a leading public health problem all over the world. Several studies have reported the GPX8 could be correlated with the poor prognostic of Gastric Cancer and Breast Cancer. However, the prognostic potential of GPX8 in pan-cancer remains unclear. In this work, we aimed to explore the prognostic and immunological role of GPX8 in human cancer and confirm the oncogenic value in GBM. The data of TCGA, CPTAC and GEO databases were adopted for the survival analysis. Based on the RNAseq and Methylation450 data of TCGA, the R language and package ggplot2 were used to analyze the DNA methylation at the region of the promoter of GPX8 in tumors. The genetic alteration of GPX8 from TCGA cancers was investigated in cBioPortal. The R package GSVA and ssGSEA were employed to evaluate the correlation of GPX8 expression with the immune infiltration. The KEGG website was used for pathway analysis. The STRING website and GEPIA were performed to predict GPX8-binding proteins. The R package ggplot2 and clusterprofile were used to analyze and visualize the GO and KEGG analysis. A normal human astrocyte cell line and three GBM cell lines were cultured under suitable conditions. The shRNA was transferred to cells by Lipofectamine 3000. The qRT-PCR and WB were adopted to detect the expression of GPX8. The wound-healing assay and transwell assay were taken to analyze the invasive and metastatic abilities. The tumor tissues and paracancerous ones were collected from patients with GBM. WB assay was employed to analyze the expression of GPX8 protein. GPX8 was a valuable diagnostic biomarker in multiple cancers, including GBMLGG (glioblastoma multiformeBrain lower grade glioma), KIRC (kidney renal clear cell carcinoma), KIRP (kidney renal papillary cell carcinoma) and STAD (stomach adenocarcinoma). Moreover, we observed a correlation between the expression of GPX8 and the reduced DNA methylation at the promoter region in several tumors, such as GBMLGG. Our results indicated a positive correlation between the GPX8 expression and immune infiltration. In addition, the enrichment analysis demonstrated that antioxidant activity was mainly involved in the functional mechanism of GPX8. In particular, we first confirmed the up-regulated of GPX8 in GBM cells and observed the suppression of migrative and invasive phenotypes by knockdown of GPX8. Furthermore, we confirmed the expression of GPX8 was higher in GBM tumor tissues than paracancerous ones. Our study showed a correlation of GPX8 expression with clinical prognosis, DNA methylation and immune infiltrates. Furthermore, we first confirmed GPX8 was highly expressed in GBM cells and contributed to migration and invasion. These results provided a predictive biomarker and an inclusive understanding of the GPX8 expression in multiple tumors types, especially in GBM.

Paclitaxel Chemotherapy Elicits Widespread Brain Anisotropy Changes in a Comprehensive Mouse Model of Breast Cancer Survivorship Evidence From

Breast cancer is one of the most common diseases in the United States with 1 in 8 women developing the disease in her lifetime. Women who develop breast cancer are often post-menopausal and undergo a complex sequence of treatments including surgery, chemotherapy, and aromatase inhibitor therapy. Both independently and through potential interactions, these factors and treatments are associated with behavioral comorbidities reported in patients (e.g., fatigue), although the underlying neurobiological mechanisms are poorly understood. Currently, brain imaging is the most feasible way to assess neurobiology in patients. Indeed, breast cancer patients display alterations in white matter connections and chemotherapy is associated with decreased white and gray matter in the corpus callosum and cortex as well as decreased hippocampal volume. However, imaging in breast cancer rodent models is lacking, impeding translation of the mechanistic neurobiological findings made possible through modeling. Furthermore, current rodent models of breast cancer often lack the complexity of typical multimodal breast cancer treatments, thereby limiting translational value. The present study aimed to develop a comprehensive model of post-menopausal breast cancer survival using immunocompetent ovariectomized mice, including an orthotopic syngeneic tumor, surgical tumor removal, chemotherapy, and aromatase inhibitor therapy. Using this model, we systematically investigated the cumulative effects of chemotherapy and hormone replacement therapy on neurostructure and behavior using diffusion weighted imaging, open field test, and spontaneous alternation test. Our previous findings, in a simplified chemotherapy-only model, indicate that this regimen of chemotherapy causes circulating and central inflammation concurrent with reduced locomotor activity. The current study, in the more comprehensive model, has recapitulated the peripheral inflammation coincident with reduced locomotor activity as well as demonstrated that chemotherapy also drives widespread changes in brain anisotropy. Validating the clinical relevance of this comprehensive rodent breast cancer model will allow for additional neurobiological investigations of the interactions among various cancer components associated with behavioral comorbidities, as well as the relationship between these mechanisms and neurostructural imaging changes that can be measured in cancer patients.

Identification and Management of Aggressive Meningiomas.

Meningiomas are common primary central nervous system tumors derived from the meninges, with management most frequently entailing serial monitoring or a combination of surgery andor radiation therapy. Although often considered benign lesions, meningiomas can not only be surgically inaccessible but also exhibit aggressive growth and recurrence. In such cases, adjuvant radiation and systemic therapy may be required for tumor control. In this review, we briefly describe the current WHO grading scale for meningioma and provide demonstrative cases of treatment-resistant meningiomas. We also summarize frequently observed molecular abnormalities and their correlation with intracranial location and recurrence rate. We then describe how genetic and epigenetic features might supplement or even replace histopathologic features for improved identification of aggressive lesions. Finally, we describe the role of surgery, radiotherapy, and ongoing systemic therapy as well as precision medicine clinical trials for the treatment of recurrent meningioma.

Chronic Stress Does Not Influence the Survival of Mouse Models of Glioblastoma.

The existence of a clear association between stress and cancer is still a matter of debate. Recent studies suggest that chronic stress is associated with some cancer types and may influence tumor initiation and patient prognosis, but its role in brain tumors is not known. Glioblastoma (GBM) is a highly malignant primary brain cancer, for which effective treatments do not exist. Understanding how chronic stress, or its effector hormones glucocorticoids (GCs), may modulate GBM aggressiveness is of great importance. To address this, we used both syngeneic and xenograft

Bone Metastasis From Gastric Adenocarcinoma-What Are the Risk Factors and Associated Survival A Large Comprehensive Population-Based Cohort Study.

While bone metastasis is not common in gastric adenocarcinoma (GaC), it can have important impacts on prognosis. This large cohort study aimed at exploring factors associated with bone metastasis in GaC and investigating the time-dependent cumulative mortalities and prognostic factors in GaC patients with bone metastasis at the population level. Data on patients with GaC diagnosed in 2010-2016 were retrieved from a large population-based database. We explored factors associated with bone metastasis using the multivariable-adjusted logistic model. We then calculated the time-dependent cancer-specific mortalities in GaC patients with bone metastasis using the cumulative incidence function and compared mortalities across subgroups using Grays test. We further assessed factors associated with mortality using the multivariable-adjusted Fine-Gray subdistribution hazard model. Together 11,072 eligible patients with metastatic GaC were enrolled, which comprised 1,511 (14%) people with bone metastasis and 9,561 (86%) with other metastasis, encompassing 6,999 person-years of follow-up. Bone metastasis was more frequently detected in 2014 or later, in younger patients, in patients with gastric cardia cancers, in people with signet-ring cell carcinoma, and in those with poorly differentiatedundifferentiated cancers it was less commonly observed in black patients. Bone metastasis was associated with more frequent brain and lung metastases. The median survival of patients with bone metastasis was 4 months the 6-month and 3-year cancer-specific cumulative mortalities were 56% and 85%, respectively. In patients receiving chemotherapy, American IndiansAlaskan Natives, patients with gastric antrumpylorus cancers, and those with positive lymph nodes had higher mortality risks, while those undergoing resection had lower mortality hazards. In GaC patients, bone metastasis was associated with various clinicopathologic factors including age, ethnicity, tumor location, histology, differentiation, and metastasis to other sites. Patients with bone metastasis had poor prognosis which was associated with ethnicity, tumor location, lymph node involvement, and treatment. Our findings provide important hints for tailed patient management and for further mechanistic investigations.

Immune suppressive microenvironment in brain metastatic non-small cell lung cancer comprehensive immune microenvironment profiling of brain metastases versus paired primary lung tumors (GASTO 1060).

Lung cancer is one of the most common causes of brain metastases and is always associated with poor prognosis. We investigated the immunophenotypes of primary lung tumors and paired brain metastases, as well as immunophenotypes in the synchronous group (patients with brain metastases upon initial diagnosis) and metachronous group (patients developed brain metastases during the course of their disease). RNA sequencing of eighty-six samples from primary lung tumors and paired brain metastases of 43 patients was conducted to analyze the tumor immune microenvironment. Our data revealed that matched brain metastases compared with primary lung tumors exhibited reduced tumor infiltrating lymphocytes (TILs), a higher fraction of neutrophils infiltration, decreased scores of immune-related signatures, and a lower proportion of tumor microenvironment immune type I (high PD-L1high CD8A) tumors. Additionally, we found a poor correlation of PD-L1 expression between paired brain metastases and primary lung tumors. In addition, gene set enrichment analysis (GSEA) showed that some gene sets associated with the immune response were enriched in the metachronous group, while other gene sets associated with differentiation and metastasis were enriched in the synchronous group in the primary lung tumors. Moreover, the tumor immune microenvironment between paired brain metastases and primary lung tumors displayed more differences in the metachronous group than in the synchronous group. Our work illustrates that brain metastatic tumors are more immunosuppressed than primary lung tumors, which may help guide immunotherapeutic strategies for NSCLC brain metastases.

Stereotactic radiotherapy for brain oligometastases.

Brain metastases, the most common metastases in adults, will develop in up to 40% of cancer patients, accounting for more than one-half of all intracranial tumors. They are most associated with breast and lung cancer, melanoma and, less frequently, colorectal and kidney carcinoma. Magnetic resonance imaging (MRI) is the gold standard for diagnosis. For the treatment plan, computed tomography (CT ) images are co-registered and fused with a gadolinium-enhanced T1-weighted MRI where tumor volume and organs at risk are contoured. Alternatively, plain and contrast-enhanced CT scans are co-registered. Single-fraction stereotactic radiotherapy (SRT ) is used to treat patients with good performance status and up to 4 lesions with a diameter of 30 mm or less that are distant from crucial brain function areas. Fractionated SRT (2-5 fractions) is used for larger lesions, in eloquent areas or in proximity to crucial or surgically inaccessible areas and to reduce treatment-related neurotoxicity. The single-fraction SRT dose, which depends on tumor diameter, impacts local control. Fractionated SRT may encompass different schedules. No randomized trial data compared the safety and efficacy of single and multiple fractions. Both single-fraction and fractionated SRT provide satisfactory local control rates, tolerance, a low risk of transient acute adverse events and of radiation necrosis the incidence of which correlated with the irradiated brain volume.

Painful Diabetic Neuropathy Is Associated with Compromised Microglial IGF-1 Signaling Which Can Be Rescued by Green Tea Polyphenol EGCG in Mice.

Painful diabetic neuropathy (PDN) is a frequent and troublesome complication of diabetes, with little effective treatment. PDN is characterized by specific spinal microglia-mediated neuroinflammation. Insulin-like growth factor 1 (IGF-1) primarily derives from microglia in the brain and serves a vital role in averting the microglial transition into the proinflammatory M1 phenotype. Given that epigallocatechin-3-gallate (EGCG) is a potent anti-inflammatory agent that can regulate IGF-1 signaling, we speculated that EGCG administration might reduce spinal microglia-related neuroinflammation and combat the development of PDN through IGF-1IGF1R signaling. Type 1 diabetes mellitus (T1DM) was established by a single intraperitoneal (i.p.) injection of streptozotocin (STZ) in mice. The protein expression level of IGF-1, its receptor IGF1R, interleukin 1 The spinal IGF-1 expression markedly decreased along with the presence of pain-like behaviors, the spinal genesis of neuroinflammation (increased IL-1 Our data highlighted the importance of maintaining spinal IGF-1 signaling in treating microglia-related neuroinflammation in PDN. This study also provides novel insights into the neuroprotective mechanisms of EGCG against neuropathic pain and neuroinflammation through IGF-1 signaling, indicating that this agent may be a promising treatment for PDN in the clinical setting.

Pyroptosis is a form of programmed cell death, playing a significant role in cancer. Glioblastoma multiforme (GBM) is the most common malignant brain tumor. The poor prognosis in GBM due to temozolomide (TMZ) resistance has been widely discussed. Such being the case, the correlation between TMZ resistance and pyroptosis is seldom investigated. On this basis, this paper aims to explore the potential prognostic value of genes related to TMZ resistance and pyroptosis as well as their relationship to the immune microenvironment in GBM. A total of 103 patients from TCGA were assigned to a training cohort 190 from CGGA were assigned to a validation cohort. The prognostic risk model reflecting pyroptosis and TMZ resistance was built from the training cohort using multivariate Cox regression and performed validation. RT-qPCR was used to examine the expression of 4 genes from the risk signature. A four genes-based risk signature was established and validated, separating GBM patients into high- and low-risk groups. Compared with the low-risk group, the high-risk group presented worse clinical survival outcomes. Its differential expressed genes were enriched in immune-related pathways and closely related to the immune microenvironment. Moreover, RT-qPCR results suggested that A novel gene signature relevant to pyroptosis and TMZ resistance was constructed and could be used for the prognosis of GBM. The four genes from the risk model might play a potential role in antitumor immunity and serve as therapeutic targets for GBM.

Monoallelic

Early T-cell development is precisely controlled by E proteins, that indistinguishably include HEBTCF12 and E2ATCF3 transcription factors, together with NOTCH1 and pre-T cell receptor (TCR) signalling. Importantly, perturbations of early T-cell regulatory networks are implicated in leukemogenesis. NOTCH1 gain of function mutations invariably lead to T-cell acute lymphoblastic leukemia (T-ALL), whereas inhibition of E proteins accelerates leukemogenesis. Thus, NOTCH1, pre-TCR, E2A and HEB functions are intertwined, but how these pathways contribute individually or synergistically to leukemogenesis remain to be documented. To directly address these questions, we leveraged

The Botanical Drug PBI-05204, a Supercritical CO

Glioblastoma multiforme (GBM) is the most common as well as one of the most malignant types of brain cancer. Despite progress in development of novel therapies for the treatment of GBM, it remains largely incurable with a poor prognosis and a very low life expectancy. Recent studies have shown that oleandrin, a unique cardiac glycoside from

Unique Finding of a Primary Central Nervous System Neuroendocrine Carcinoma in a 5-Year-Old Child A Case Report.

Neuroendocrine tumors (NETs) are rare neoplasms predominantly arising in the gastrointestinal-tract or the lungs of adults. To date, only ten cases of primary central nervous system (CNS) NETs have been reported, with just three of them describing a neuroendocrine carcinoma (NECA) and none occurring in a child. We report on a previously healthy 5-year-old boy, who presented with headaches, nausea and vomiting, and was diagnosed with a left cerebellar solid mass with a cystic component. After gross-total resection, histology revealed a neuroendocrine carcinoma. Molecular analysis of the tumor tissue showed a

Genetic Testing and Immunotherapy for Intracranial Inflammatory Myofibroblastic Tumor A Case Report.

Inflammatory myofibroblastic tumor (IMT) is a rare mesenchymal tumor that can develop in numerous organs, most commonly in the lungs and rarely in the brain. Here, we reported a 55-year-old patient with nasopharyngeal IMT and the recurrence in the skull base, slope and pterygoid sinus who underwent cranial base and slope tumor resection. Postoperative magnetic resonance imaging (MRI) and multiplex immunohistochemistry (mIHC) showed tumor recurrence and metastasis to the intracalvarium. While genetic testing revealed no significant related gene mutations, tertiary mutations in NSD1 and SOX9 genes were identified in the tumor tissues. The patient achieved partial remission after receiving 7 cycles of immunotherapy (toripalimab 240 mg for 1 cycle followed by 6 cycles of sintilimab 200 mg), and MRI examination indicated an almost complete remission of intracranial IMT after 16 cycles of immunotherapy. In summary, the novel class of immune-targeted agents may be effective in clinical management of rare intracranial IMT.

The sellar region as presenting theater for hematologic malignancies-A 17-year single-center experience.

Hematological neoplastic mass lesions of the sellar region are rare. We identified five cases of hematological malignancy with first presentation in the sellar region from our departmental database of 1,405 patients (0.36%) with sellar lesions diagnosed over the 17-year period (2005-2021). All patients were females (mean age 55.2 ± 3.4 years). One patient had multiple myeloma (MM), one patient had acute myeloid leukemia (AML), while three other patients had lymphoma (intravascular lymphoma (IVL, n 1) or non-Hodgkins lymphoma (NHL, n 2). Most patients presented with ophthalmoplegia, and one patient with diabetes insipidus (DI), with short duration of symptoms (median 30 days). All patients had an elevated erythrocyte sedimentation rate and altered blood count, while patients with lymphoma had elevated lactate dehydrogenase (LDH). Sellar mass was demonstrated in three patients while the patient with IVL had an empty sella and in the AML patient posterior lobe T1W hyperintensity was lost. Two patients (IVL and NHL) presented with multiple anterior pituitary deficiencies and one patient (AML) had DI. All patients were treated with chemotherapy. Two patients responded well to treatment (one had reversed hypopituitarism), while three patients died. Differential diagnosis of sellar-parasellar pathology should include suspicion of hematological malignancy, particularly in patients with short duration of nonspecific symptoms, neurological signs (ophthalmoplegia), blood count alterations and LDH elevation, pituitary dysfunction and imaging features atypical for pituitary adenoma. Early diagnosis is crucial for timely initiation of hematological treatment aimed at inducing disease remission and partial or full recovery of pituitary function.

Treatment for Hydrocephalus Caused by Intraventricular Tumors.

Intraventricular tumors often cause hydrocephalus because their location in the ventricles affect cerebrospinal fluid circulation. Even small tumors can lead to acute hydrocephalus when they block the cerebrospinal fluid flow. They may also be found as large tumors occurring in large spaces, such as in lateral ventricles. Since various histological tumors occur in ventricles, it is important to consider the treatment strategy according to the expected histological type before treating hydrocephalus in the early stage. In addition, it is beneficial to predict and evaluate the site and size of the tumor, the cause of hydrocephalus, and the effect of postoperative chemotherapy and radiation therapy. Some tumors are sensitive to chemotherapy and radiation therapy, so there is an advantage in performing a biopsy at the same time as hydrocephalus treatment. Ventricular drainage and ventricular peritoneal shunts for patients with high intracranial pressure are at risk of developing ascending hernias, so we should be careful with the procedure.

Antitumor Activities of tRNA-Derived Fragments and tRNA Halves from Non-pathogenic Escherichia coli Strains on Colorectal Cancer and Their Structure-Activity Relationship.

tRNAs purified from non-pathogenic Escherichia coli strains (NPECSs) possess cytotoxic properties on colorectal cancer cells. In the present study, the bioactivity of tRNA halves and tRNA fragments (tRFs) derived from NPECSs are investigated for their anticancer potential. Both the tRNA halves and tRF mimics studied exhibited significant cytotoxicity on colorectal cancer cells, with the latter being more effective, suggesting that tRFs may be important contributors to the bioactivities of tRNAs derived from the gut microbiota. Through high-throughput screening, the EC83 mimic, a double-strand RNA with a 22-nucleotide (nt) 5-tRF derived from tRNA-Leu(CAA) as an antisense chain, was identified as the one with the highest potency (50% inhibitory concentration IC

Literature review of management of brain metastases from germ cell tumors.

In this review article, we discuss the role of chemotherapy, surgery, and radiation therapy in the treatment of brain metastases from germ cell tumors (GCT). GCT rarely metastasize to the brain and there is limited data to guide management. Most instances of brain metastases occur in patients with non-seminomatous germ cell tumors (NSGCT). We searched PubMed using the terms central nervous system (CNS) metastases or brain metastases and germ cell from 2011 through August 2021. Review articles and prospective trials related to the treatment of brain metastases in GCT were included in addition to articles obtained by hand search of the references and clinical practice guidelines. We highlight the importance of using chemotherapy as first-line therapy in most situations. We discuss the very minimal data regarding surgery and its primary role when there is significant mass effect or brain shift. We also compare whole brain radiation therapy (WBRT) with the use of radiosurgery. We then provide overall recommendations based on the reviewed data and our experience as a referral center for GCT.

Risk-reduction strategies for late complications arising from brain metastases treated with radiotherapy a narrative review.

This review will focus on the late neurological complications from cranial irradiation and relevant mitigation strategies. Radiotherapy (RT) remains an important pillar in the management of brain metastases. Patients being treated in the modern era do experience longer survival, because of superior intra- and extra-cranial disease control. As a result, they can be more prone to developing and manifesting late complications post-brain radiotherapy. A search and narrative review of prospective clinical trials relating to neurological toxicity outcomes was conducted. Neurological toxicities can be challenging to diagnose and manage and should be considered during consideration of radiotherapy in brain metastasis, hence more emphasis should be placed on prevention and upfront mitigation of these complications, with novel strategies showing promising results in prospective trials being adopted into clinical practice.

Case Report Ventriculoperitoneal Shunting and Radiation Therapy Treatment in a Cat With a Suspected Choroid Plexus Tumor and Hypertensive Hydrocephalus.

A 14-year-old male neutered domestic short-hair cat was presented for a history of behavioral changes and episodes of urinary retention. Neurological examination was consistent with a multifocal intracranial neuroanatomical localization, with suspected right sided lateralisation and suspected raised intracranial pressure (ICP). Brain magnetic resonance imaging (MRI) revealed an intraventricular multilobulated well-defined T2W-hyperintense and T1W-isointense, markedly contrast enhancing mass lesion within the dorsal aspect of the III ventricle extending into the left lateral ventricle, causing hypertensive obstructive hydrocephalus. A ventriculoperitoneal shunt (VPS) was placed within the left lateral ventricle, followed by a radiation therapy (RT) course of 45 Gy total dose in 18 daily fractions. Six-months post-RT, computed tomography revealed mild reduction in mass size and resolution of the hydrocephalus. The patient was neurologically normal with no medical treatment. Raised ICP causes severe clinical signs, can lead to brain ischaemia and herniation, and significantly increases anesthetic risk during RT. Placement of a VPS in cats with hypertensive obstructive hydrocephalus may allow improvement of neurological signs due to raised ICP, and therefore making the patient a more stable candidate for anesthesia and radiation therapy.

Keyhole supraorbital eyebrow approach for the resection of a tuberculum sellae meningioma with intraoperative endoscopic assistance.

Tuberculum sellae meningiomas represent approximately 5-10% of intracranial meningiomas.2 Although benign, they are associated with substantial morbidity, especially visual disturbance. At present, there are three main treatment options for patients with tuberculum sellae meningiomas observational, with serial imaging follow microsurgical resection and stereotactic radiosurgery. The advantages of the supraorbital eyebrow craniotomy are the direct visualization of the anterior cranial fossa, anterior circulation, and the optical apparatus, reducing the extent of brain retraction, and the absence of risks of temporalis muscle hypotrophy and posterior chewing discomfort. Conversely, minor drawbacks are a steeper learning curve related to a narrower surgical corridor than a standard frontotemporal approach and the minimal risk of supraorbital nerve injury.1,3. The authors report the case of a 42-year-old female who presented with acute-onset vision loss and only finger counting in her left eye associated with headache. Magnetic resonance imaging (MRI) showed a suprasellar extra-axial T1 enhancing mass with encasement of the left optic nerve and paraclinoid internal carotid artery and mass effect on the optic chiasm. A keyhole supraorbital eyebrow approach assisted with a microinspection tool was performed for tumor resection and optic nerve decompression. A Simpson Grade 2 tumor resection was achieved, and histopathology revealed a WHO Grade-I tuberculum sellae meningioma. The patients presentation, rationale, key surgical steps, and outcome are discussed, and informed consent for surgery and video recording was obtained. This surgical video illustrates the use of a keyhole supraorbital eyebrow approach assisted with a microinspection endoscopic tool for the resection of a tuberculum sellae meningioma. The tumor size, extension, and preoperative clinical status determine the optimal surgical corridor in tuberculum sellae meningioma. The keyhole supraorbital eyebrow approach allows safe and direct access to anterior cranial fossa lesions.

Metastatic brain lesion as the initial presentation of follicular thyroid carcinoma.

Metastatic brain lesions, of thyroid origin, are rare manifestations of differentiated thyroid cancer, with papillary thyroid carcinoma being the most common subtype. Considering the rarity of metastatic follicular thyroid carcinoma to the brain, the present article outlines its clinical presentation, neuroradiological findings, pathological features, and outcome. A 52-year-old female presented with a 6-month history of progressive and holocephalic headache. Examination revealed a tracheal deviation to the left side due to an enlarged goiter. Brain CT scan showed a right occipital, slightly hyperdense lesion associated with a 0.4 cm midline shift to the left side. Brain MRI demonstrated a right occipital, avidly-enhancing, extra-axial lesion with disproportionate and extensive vasogenic edema. As the lesion was solitary, the patient underwent craniotomy and tumor resection. Histopathological examination revealed a tumor consistent of small follicles, composed of uniform round nuclei without papillary thyroid carcinoma nuclear features, suggestive of metastatic follicular thyroid carcinoma to the brain. Postoperatively, the patient was neurologically intact. She was discharged in a stable condition with laboratory radiological investigations and follow-up at neurosurgery, endocrine, radiotherapy, and thyroid surgery clinics. Follicular thyroid carcinoma may rarely metastasize to the central nervous system. A high index of suspicion is required to identify patients with thyroid cancer who initially present with neurological manifestations. Complete surgical resection of the metastatic brain lesion is safe, feasible and is associated with a prolonged overall survival.

Cholesterol metabolism and its implication in glioblastoma therapy.

Glioblastoma (GBM) is the most lethal malignant tumor in the central nervous system, with a median survival of only 14 months. Cholesterol, which is the main component of cell membrane and the precursor of many hormones, is one of the most important lipid components in human body. Since reprogramming of the cholesterol metabolic profile has been discovered in many cancers including GBM, cholesterol metabolism becomes a promising potential target for therapy. Since GBM cells rely on external cholesterol to survive and accumulate lipid droplets to meet their rapid growth needs, targeting the metabolism of cholesterol by different strategies including inhibition of cholesterol uptake and promotion of cholesterol efflux by activating LXRs and disruption of cellular cholesterol trafficking, inhibition of SREBP signaling, inhibition of cholesterol esterification, could potentially oppose the growth of glial tumors. In this review, we discussed the above findings and describe cholesterol synthesis and homeostatic feedback pathways in normal brain tissues and brain tumors, statin use in GBM and the role of lipid rafts and cholesterol precursors and oxysterols in the treatment and pathogenesis of GBM are also summarized.

Leptomeningeal Carcinomatosis Mimicking Reversible Cerebral Vasoconstriction Syndrome.

Leptomeningeal carcinomatosis is the result of metastatic infiltration of the leptomeninges by malignant cells originating from an extra-meningeal primary tumor site. We describe a patient with active breast cancer who presented with thunderclap headaches (THs) and imaging showing multi-segment irregular arterial narrowing of intracranial vasculature. A 58-year-old Caucasian woman with active stage IV estrogen receptor-positive breast adenocarcinoma and migraine presented with THs. Computed tomography and brain magnetic resonance imaging (MRI) without contrast were unremarkable. Over a period of one week, she had recurrent THs. Interval vessel imaging showed multi-segment irregular arterial narrowing. Treatment with verapamil was initiated for suspected reversible cerebral vasoconstriction syndrome (RCVS). She subsequently had two discrete episodes of confusion with aphasia and left upper extremity numbness. Repeat gadolinium-enhanced MRI showed nodular leptomeningeal enhancement. Lumbar puncture revealed malignant cells in the cerebrospinal fluid consistent with leptomeningeal carcinomatosis. She subsequently underwent whole brain radiation treatment and intrathecal chemotherapy and had no further episodes of TH. Our case emphasizes the importance of considering leptomeningeal carcinomatosis in the differential diagnosis of THs and reversible cerebral vasculopathy, especially in patients with known underlying active cancer. The illustration also proves the importance of a complete work-up in patients with known malignancy in the setting of suspected RCVS.

Distinct Slow-Wave Activity Patterns in Resting-State Electroencephalography and Their Relation to Language Functioning in Low-Grade Glioma and Meningioma Patients.

Brain tumours frequently cause language impairments and are also likely to co-occur with localised abnormal slow-wave brain activity. However, it is unclear whether this applies specifically to low-grade brain tumours. We investigate slow-wave activity in resting-state electroencephalography (EEG) in low-grade glioma and meningioma patients, and its relation to pre- and postoperative language functioning. Patients with a glioma ( Glioma patients had increased delta activity (affected area) and increased theta activity (all levels) before and after surgery. In these patients, increased preoperative theta activity was related to the presence of language impairment, especially to poor word retrieval and grammatical performance. Preoperative slow-wave activity was also related to postoperative language outcomes. Meningioma patients showed no significant increase in EEG slow-wave activity compared to healthy individuals, but they presented with word retrieval, grammatical, and writing problems preoperatively, as well as with writing impairments postoperatively. Although the brain-tumour pathology in low-grade gliomas and meningiomas has a different effect on resting-state brain activity, patients with low-grade gliomas and meningiomas both suffer from language impairments. Increased theta activity in glioma patients can be considered as a language-impairment marker, with prognostic value for language outcome after surgery.

A Case Report of Radiotherapy for Skull Lesions of Langerhans Cell Histiocytosis With Dural Invasion.

Langerhans cell histiocytosis (LCH) is a rare disease, especially in adults. It is often associated with non-fatal bone and skin lesions and has relatively good radiosensitivity. In contrast, brain and lymph node metastases from LCH lesions are considered to be less sensitive to radiotherapy. At our institution, 30 Gy radiotherapy was used to treat bone lesions with dural invasion in a patient with adult-onset LCH. The patient was treated with chemotherapy and radiotherapy for 21 years since the initial diagnosis. After radiotherapy, the tumor shrank rapidly, and a complete response was achieved 1 year after treatment. The patient survived without local recurrence. Here, we report the details of this case, along with a review of the literature. We suggest that even with invasion of the tissues around the bone lesions in LCH, local recurrence can be prevented by middle radiation doses.

Leiomyomatosis in an Infant With a SUFU Splice Site Variant Case Report.

Heterozygous loss-of-function variants in the suppressor of fused protein gene (SUFU) can result in Gorlin syndrome, which is characterized by an increased frequency of basal cell carcinoma, medulloblastoma, odontogenic keratocysts, as well as other tumors. We describe a case of a 5-month-old female who presented with multiple intra-abdominal leiomyomata and was found to have a likely pathogenic splice site variant in the SUFU gene. This is the first reported case of leiomyomatosis secondary to a pathogenic SUFU variant in an infant and may represent an early, atypical presentation of Gorlin syndrome.

Developing an International Classification of Functioning, Disability and Health Core Set for Pediatric Brain Tumor Survivors in Chinese Clinical Settings.

The International Classification of Functioning, Disability and Health (ICF) core set (CS) facilitates the standardization of functioning and impairment assessment for integration of holistic care. This study developed an ICF CS for interviewing pediatric brain tumor survivors in Taiwan to help healthcare professionals in implementing disability assessment and management measures. A group of 29 experts in 10 relevant fields with at least 5 years of experience working with children with brain tumors participated in this study. The first questionnaire contained 247 second-level ICF categories. The experts rated the significance of each category by using a 5-point Likert scale. Correlations between individual and group scores were calculated to determine consensus. Categories with an average rating of higher than 4 and for which greater than or equal to 80% (23) of the participants provided a rating of 4 or higher were included in the final CS. The final CS contained a total of 57 ICF categories 20 from the Body Functions and Structures component, 36 from the Activities and Participation component, and 1 from the Environmental Factors component. The ICF CS for pediatric brain tumor survivors provides a framework for relevant healthcare professionals to deliver patient-centered care, ensuring that services focus on all areas of development. Patient ratings for this ICF CS may serve as a new practical and effective patient-reported information tool for acquiring patient input and for the systematic monitoring of pediatric brain tumor survivors in clinical practice. Further research should be conducted on this CS to verify our findings.

Phenotypic and molecular states of IDH1 mutation-induced CD24-positive glioma stem-like cells.

Mutations in IDH1 and IDH2 drive the development of gliomas. These genetic alterations promote tumor cell renewal, disrupt differentiation states, and induce stem-like properties. Understanding how this phenotypic reprogramming occurs remains an area of high interest in glioma research. Previously, we showed that IDH mutation results in the development of a CD24-positive cell population in gliomas. Here, we demonstrate that this CD24-positive population possesses striking stem-like properties at the molecular and phenotypic levels. We found that CD24 expression is associated with stem-like features in IDH-mutant tumors, a patient-derived gliomasphere model, and a neural stem cell model of IDH1-mutant glioma. In orthotopic models, CD24-positive cells display enhanced tumor initiating potency compared to CD24-negative cells. Furthermore, CD24 knockdown results in changes in cell viability, proliferation rate, and gene expression that closely resemble a CD24-negative phenotype. Our data demonstrate that induction of a CD24-positive population is one mechanism by which IDH-mutant tumors acquire stem-like properties. These findings have significant implications for our understanding of the molecular underpinnings of IDH-mutant gliomas.

The BDNF-TrkB signaling pathway in the rostral anterior cingulate cortex is involved in the development of pain aversion in rats with bone cancer via NR2B and ERK-CREB signaling.

Patients with bone cancer pain (BCP) are more prone to aversion. which not only causes mental distress but also aggravates BCP. However, the mechanism of BCP-related aversion is still unclear. Previous studies have demonstrated that the brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase B (TrkB) signaling pathway of the rostral anterior cingulate cortex (rACC) plays an important role in the regulation of emotions related to chronic pain, such as neuropathic pain or inflammatory pain however, few studies have investigated the role of this pathway in cancer pain. This study explored the role of BDNF in cancer pain-related aversion in the rACC and to determine whether N-methyl D-aspartate receptor subtype 2B (NR2B) and extracellular signal-regulated kinase (ERK)-cAMP response element-binding (CREB) signaling are involved in cancer pain-related aversion. A Sprague-Dawley rat model of BCP (one of the classic BCP models) was established, and the changes in pain aversion were detected by mechanical stimulation-induced conditioned place avoidance. Our findings confirmed that rats with BCP exhibited intense pain aversion accompanied by the up-regulated BDNF expression in the rACC. Additionally, the pain aversion of BCP rats was reduced while blocking the BDNF-TrkB. Furthermore, the expression of NR2B and phosphorylated ERK (pERK)phosphorylated CREB (pCREB) were up-regulated with the development of pain aversion, whereas the use of NR2B blocker Ro25-6981, or ERK inhibitor U0126 could reduce the pain aversion. The expression of NR2B and pERKpCREB were up-regulated after exogenous BDNF was injected into the rACC, whereas the expression levels of NR2B and pERKpCREB were down-regulated after blocking the BDNF-TrkB signaling. In conclusion, the BDNF-TrkB signaling in the rACC mediates the generation of aversion in rats with BCP, which requires the involvement of NR2B and the ERK-CREB signaling pathway.

The Role of Chemotherapy in the Treatment of Adult Medulloblastoma.

The role of chemotherapy (CT) in the treatment of adult patients with medulloblastoma (MB) is unclear. The aim of this study is to compare the survival difference between adult patients with MB treated with and without chemotherapy. Data were derived from the SEER (Surveillance Epidemiology and End Results) database from 2010 to 2018. The Kaplan-Meier method with log-rank tests, univariate and multivariate Cox proportional hazard analyses, and propensity score matching (PSM) were used to investigate the association between chemotherapy and survival. We further conducted an exploratory subgroup analysis. The outcomes of interest were cancer-specific survival (CSS) and overall survival (OS). We included 333 patients in this study, with 227 patients in the CT cohort and 106 in the nonchemotherapy cohort. The median follow-up time and the median age of the study population were 61 months and 30 years, respectively. The 5-year CSS of the CT cohort was superior to the nonchemotherapy cohort, whereas the 5-year OS was not. Kaplan-Meier curves after PSM supported the survival benefit of CT on CSS but not on OS. In the multivariate analysis after PSM, CT was the only prognostic factor for CSS, whereas there were no independent prognostic factors for OS. The survival of patients receiving CT who were diagnosed between 2010 and 2018 was better than that of previous patients. The subgroup analysis showed that there were interaction effects between CT and sex. CT improved CSS for adult patients with MB. With therapeutic advances, adult patients with MB might benefit from the use of CT.

Ghost cells unveiled A comprehensive review.

Ghost cells (GCs) are cells with distinct intracytoplasmic keratinization, which leads to the preservation of the cellular outline with a clear area corresponding to the previous nucleus location. GCs may show various patterns, such as degeneration, tissue granulation, and calcification. Their true nature and the mechanism regulating the conversion of odontogenic epithelial cells into GCs remain unclear. GC keratinization is different from normal keratinization as they are larger than keratotic squames, are frequently vacuolated, and have prominent nuclear membrane remnants. Few cystic lesions, odontogenic tumors, and non-odontogenic tumors, such as calcifying odontogenic cyst, craniopharyngioma, pilomatrixoma, odontoma, dentinogenic ghost cell tumor, and ghost cell odontogenic carcinoma, exhibit GCs as a typical feature. The Wnt and Notch signaling pathways play a role in the histogenesis of the neoplasms. The review clarifies the various proposed hypotheses of the histogenesis of GCs, including molecular pathogenesis. Diagnostic workup for the identification of GCs, including special staining and immunohistochemistry, has been extensively discussed. A stepwise algorithm for identifying odontogenic and non-odontogenic lesions containing GCs has been proposed. Additionally, the prognostic role of GCs in the lesions has been elucidated. Among the various hypotheses of the origin of GCs, we suggest that aberrant keratinization is the most accepted based on various immunohistochemical studies and special staining characteristics. GCs are a distinct characteristic entity of many odontogenic and non-odontogenic lesions however, it remains controversial whether their presence has any pathognomonic role in the biological nature of these lesions.

Geriatric impairments were directly and indirectly associated with mortality in older patients with cancer a structural equation analysis.

We assessed the direct and indirect effects between six geriatric domains and 6- and 12-month mortality in older cancer patients. We included cancer patients aged ≥70 years from the Elderly Cancer Patients cohort, referred for geriatric assessment between 2007 and 2016. We used structural equation modelling to examine the interrelationships between six geriatric domains (function and mobility, nutrition, cognition, mood, comorbidities and polypharmacy, and social support) and the direct and indirect relationships between these domains, the cancer stage, site, and treatment on the one hand and mortality on the other. The analysis included 1,434 patients (mean age 80 ± 5.6 years women 48% main cancer sites digestive tract 36.2%, urinary tract and prostate 26.6%, and breast 16.5% metastatic cancer 48%). Direct relationships to 6- and 12-month mortality were identified for functional impairment (standardized coefficient SC 0.37 P < 0.001 and 0.32 P < 0.001, respectively), poor nutritional status (SC 0.11 P 0.005 and 0.14 P 0.001), poor social support (SC 0.07 P 0.08 and 0.09 P 0.02), cancer site, stage, and treatment. The effects of comorbidities, cognitive impairment, and depression on mortality were mediated by functional and nutritional status. In older cancer patients, functional and nutritional impairments were the strongest direct prognostic geriatric factors for mortality.

CircPOLR2A Promotes Proliferation and Impedes Apoptosis of Glioblastoma Multiforme Cells by Up-regulating POU3F2 to Facilitate SOX9 Transcription.

Glioblastoma multiforme (GBM) is the most common cancer in nervous system around the world. Little advancement has been achieved in promoting prognosis of GBM patients. Circular RNAs (circRNAs) are suggested as crucial effectors in modulating GBM development. HsacircRNA092437 (circPOLR2A), an up-regulated circRNA in GBM cells, has not been studied yet. In this study, RT-qPCR and western blot assays were applied to detect RNA and protein levels. Cell proliferation and apoptosis were analyzed via functional assays. Subcellular fractionation assay was carried out to determine circPOLR2A distribution in cells. Bioinformatics analysis and mechanism assays were done for detecting relationships among different factors. Rescue assays were performed to confirm validity of circPOLR2ASOX9 axis. According to experimental results, circPOLR2A was up-regulated in GBM cells and promoted GBM cell proliferation while inhibiting GBM cell apoptosis. CircPOLR2A mainly existed in cell cytoplasm and sponged miR-2113 to positively regulate POU3F2 expression. POU3F2 activated the transcription of SOX9 through interacting with SOX9 promoter (1-500). Rescue assays validated that circPOLR2A influenced GBM cell proliferation and apoptosis via SOX9. To conclude, circPOLR2A enhanced the transcription of SOX9 through miR-2113POU3F2 axis, thus exacerbating GBM cells growth.

Lacosamide in monotherapy in BTRE (brain tumor-related epilepsy) results from an Italian multicenter retrospective study.

Lacosamide (LCM) is a third-generation anti-seizure medication (ASM) approved for focal onset epilepsy in patients aged ≥ 4.378 Previous studies have reported an efficacy of LCM as add-on treatment in brain tumor-related epilepsy (BTRE). To date, there are no studies in the literature focusing on lacosamide used in monotherapy to treat BTRE. In our retrospective study we investigated efficacy and tolerability of LCM in monotherapy in a multicenter national cohort of primary brain tumor patients. We collected from 12 Italian Centers 132 patients with primary brain tumors who were treated with LCM in monotherapy. For each patient we evaluated seizure freedom at 3 and 6 months (primary endpoints), side effects and drop-out rate (secondary endpoints). Overall, LCM led to seizure freedom in 64.4% of patients at 3 months and 55% at 6 months. Patients who used two or more ASMs before LCM had a worse seizure control than patients in monotherapy with LCM as first choice. In 14 patients, we observed seizure control despite tumor progression on magnetic resonance (MRI). Multivariate analysis showed that gross-total resection at diagnosis was significantly associated with higher seizure freedom rate at 6 months. Side effects were mainly mild (grade 1-2 according to CTCAE classification) and drop-out rate was low (1.5%). Main side effects were dizziness and somnolence. This is the first study showing a good efficacy and tolerability of LCM when used in monotherapy in BTRE. Further prospective studies are needed to confirm these preliminary data, investigating also quality of life and neurocognitive functions.

MGMT gene promoter methylation by pyrosequencing method correlates volumetric response and neurological status in IDH wild-type glioblastomas.

Although the usefulness of O This retrospective study included newly diagnosed IDH wild-type glioblastoma patients with residual tumor after surgery, followed by local radiotherapy with temozolomide. TVR was defined as the tumor volume at 6 months after the initial chemoradiotherapy administration divided by the tumor volume before the start of therapy. The mean MGMTpm% of 16 CpG islands (74-89) was analyzed using pyrosequencing. We statistically analyzed the correlation between MGMTpm%, TVR, and change in Karnofsky performance status. The study included 44 patients with residual tumors. Thirteen (92.9%) of 14 patients with MGMTpm% ≥ 23.9% showed 50% or more volumetric response, leading to prolonged survival, and 17 (70.8%) of 24 patients with MGMTpm% < 8.2% had progressive disease after initial chemoradiotherapy administration. Three (50.0%) of six patients with MGMTpm% 8.2% to < 23.9% had stable disease or partial response. Evaluation of MGMTpm% by pyrosequencing is important in predicting the volumetric response and prognosis of glioblastoma patients with residual tumors.

An Evidence-Based Staging System for Mucosal Melanoma A Proposal.

There is no widely employed staging system for mucosal melanoma (MuM) that incorporates all anatomic sites. We hypothesized that MuM patients arising from different anatomical sites could be staged using a common approach. A prospective database contained 1814 MuM patients with a median follow-up of 5.14 years was employed. Overall survival (OS) was calculated from the time of pathological diagnosis to the date of death from any cause. Multivariate analyses of prognostic variables and OS were performed using the Cox proportional hazard model. For localized MuM, the most significant median OS differences were primary tumors invading submucosa (i.e., T1) versus deeper (i.e., T2T3T4) 4.3 versus 3.4, 3.1, and 2.9 years, respectively (p < 0.001). For patients only with regional node metastasis at presentation, the most significant were 1 versus ≥ 2 regional nodes (N1 vs. N2, 2.5 vs. 2.1 years, p < 0.001). For patients with distant metastasis at presentation, the median OS was 1.5, 1.2, 0.8, and 0.6 years respectively for skinsubcutaneous tissuedistant lymph nodes (M1a), lung metastasis (M1b), all other visceral sites except brain (M1c), and brain (M1d) (p < 0.001). Based on these results, the staging system for MuM is proposed (1) Stage I T1N0M0 (median OS, 4.3 years) (2) Stage II T2-4N0M0 (3.1 years) (3) Stage IIIA T1-4N1M0 (2.5 years), Stage IIIB T1-4N2M0 (2.1 years) (4) Stage IV T A single, unified, staging system for mucosal melanoma inclusive of all anatomical primary tumor sites can harmonize staging of MuM and the design of clinical trials.

Efficacy and safety of tumor-treating fields in recurrent glioblastoma a systematic review and meta-analysis.

Tumor-treating fields (TTF) is a novel cancer treatment that uses alternating electric fields to interfere with tumor cell mitosis. It has been approved by the U.S. food and drug administration for the treatment of recurrent glioblastoma (rGBM). We designed this meta-analysis to evaluate the efficacy and safety of TTF in the treatment of rGBM. The study was based on the PRISMA guideline. Systematic retrieval was performed in PubMed, Cochrane Library, and Embase databases. The outcomes were overall survival (OS) hazard ratio (HR), 1-year survival rate, and cutaneous toxicity. These studies included a total of 1048 rGBM patients who received TTF treatment. The overall survival time between the TTF group and the control group was HR 0.75 (95%CI 0.63 to 0.89 P 0.001). Pooled 1-year overall survival rate and incidence of cutaneous toxicity were 0.47 and 0.48, respectively. Data were insufficient to evaluate the effect of MGMT methylation status and tumor recurrence times on heterogeneity. TTF therapy is effective for recurrent glioblastoma. However, most relevant trials should assess rGBM patient baseline characteristics such as age, KPS, MGMT methylation status, and number of tumor recurrence,. In addition, the risk of rashes caused by long-term wearing of devices should also be considered.

Upfront molecular targeted therapy for the treatment of BRAF-mutant pediatric high-grade glioma.

The prognosis for patients with pediatric high-grade glioma (pHGG) is poor despite aggressive multimodal therapy. Objective responses to targeted therapy with BRAF inhibitors have been reported in some patients with recurrent BRAF-mutant pHGG but are rarely sustained. We performed a retrospective, multi-institutional review of patients with BRAF-mutant pHGG treated with off-label BRAF - MEK inhibitors as part of their initial therapy. Nineteen patients were identified, with a median age of 11.7 years (range, 2.3-21.4). Histologic diagnoses included HGG (n 6), glioblastoma (n 3), anaplastic ganglioglioma (n 4), diffuse midline glioma (n 3), high-grade neuroepithelial tumor (n 1), anaplastic astrocytoma (n 1), and anaplastic astroblastoma (n 1). Recurrent concomitant oncogenic alterations included CDKN2AB loss, H3 K27M, as well as mutations in ATRX, EGFR, and TERT. Eight patients received BRAF inhibitor monotherapy. Eleven patients received combination therapy with BRAF and MEK inhibitors. Most patients tolerated long-term treatment well with no grade 4-5 toxicities. Objective and durable imaging responses were seen in the majority of patients with measurable disease. At a median follow-up of 2.3 years (range, 0.3-6.5), three-year progression-free and overall survival for the cohort were 65% and 82%, respectively, and superior to a historical control cohort of BRAF-mutant pHGG patients treated with conventional therapies. Upfront targeted therapy for patients with BRAF-mutant pHGG is feasible and effective, with superior clinical outcomes compared to historical data. This promising treatment paradigm is currently being evaluated prospectively in the Childrens Oncology Group ACNS1723 clinical trial.

STAT3 is a biologically relevant therapeutic target in H3K27M-mutant diffuse midline glioma.

H3K27M-mutant diffuse midline glioma (DMG) is a lethal brain tumor that usually occurs in children. Despite advances in our understanding of its underlying biology, efficacious therapies are severely lacking. We screened a library of drugs either FDA-approved or in clinical trial using a library of patient-derived H3K27M-mutant DMG cell lines with cell viability as the outcome. Results were validated for clinical relevance and mechanistic importance using patient specimens from biopsy and autopsy, patient-derived cell lines, inhibition by gene knockdown and small molecule inhibitors, and patient-derived xenografts. Kinase inhibitors were highly toxic to H3K27M-mutant DMG cells. Within this class, STAT3 inhibitors demonstrated robust cytotoxic activity in vitro. Mechanistic analyses revealed one form of activated STAT3, phospho-tyrosine- 705 STAT3 (pSTAT3), was selectively upregulated in H3K27M-mutant cell lines and clinical specimens. STAT3 inhibition by CRISPRCas9 knockout, shRNA or small molecule inhibition reduced cell viability in vitro, and partially restored expression of the polycomb repressive mark H3K27me3, which is classically lost in H3K27M-mutant DMG. Putative STAT3-regulated genes were enriched in an H3K27M-knockout DMG cell line, indicating relative gain of STAT3 signaling in K27M-mutant cells. Treatment of patient-derived intracranial xenografts with WP1066, a STAT3 pathway inhibitor currently in clinical use for pediatric brain tumors, resulted in stasis of tumor growth, and increased overall survival. Finally, pSTAT3(Y705) was detected in circulating plasma extracellular vesicles of patients with H3K27M-mutant DMG. STAT3 is a biologically relevant therapeutic target in H3K27M-mutant DMG. STAT3 inhibition should be considered in future clinical trials.

Adult brain tumors in Sub-Saharan Africa A scoping review.

Sub-Saharan African (SSA) neuro-oncologists report high workloads and challenges in delivering evidence-based care however, these reports contrast with modeled estimates of adult neuro-oncology disease burden in the region. This scoping review aimed to better understand the reasons for this discrepancy by mapping out the SSA adult brain tumor landscape based on published literature. Systematic searches were conducted in OVID Medline, Global Index Medicus, African Journals Online, Google Scholar, and faculty of medicine libraries from database inception to May 31, 2021. The results were summarized quantitatively and narratively. English and French peer-reviewed articles were included (title, abstract, and full text). Of the 819 records identified, 119 articles by 24 SSA countries (42.9%) were included in the final review. Odeku published the first article in 1967, and nine of the ten most prolific years were in the 21st century. The greatest contributing region was Western Africa (n 58, 48.7%) led by Nigeria (n 37, 31.1%). Central Africa had fewer articles published later than the other SSA regions (P .61). Most studies were nonrandomized (n 75, 63.0%) and meningiomas (n 50, 42.0%) were the most common brain tumors reported. Less than 30 studies reported on adjuvant treatment or patient outcomes. Most publications were hospital-based, and there was significant heterogeneity in the quality of evidence and reporting. This study highlights the need for rapid and sustainable investments and brain tumor research capacity in SSA.

Supportive care of patients diagnosed with high grade glioma and their carers in Australia.

This study aimed to determine the supportive care available for Australian patients with High Grade Glioma (HGG) and their carers identify service gaps and inform changes needed to implement guidelines and Optimal Care Pathways. This cross-sectional online survey recruited multidisciplinary health professionals (HPs) who were members of the Cooperative Trials Group for Neuro-Oncology involved in management of patients diagnosed with HGG in Australian hospitals. Descriptive statistics were calculated. Fishers exact test was used to explore differences between groups. 42 complete responses were received. A majority of MDT meetings were attended by a neurosurgeon, radiation oncologist, medical oncologist, radiologist, and care coordinator. Less than 10% reported attendance by a palliative care nurse physiotherapist neuropsychologist or speech therapist. Most could access referral pathways to a cancer care coordinator (76%), neuropsychologist (78%), radiation oncology nurse (77%), or psycho-oncologist (73%), palliative care (93-100%) and mental health professionals (60-85%). However, few routinely referred to an exercise physiologist (10%), rehabilitation physician (22%), dietitian (22%) or speech therapist (28%). Similarly, routine referrals to specialist mental health services were not standard practice. Nearly all HPs (94%) reported HGG patients were advised to present to their GP for pre-existing conditionscomorbidities however, most HPs took responsibility (≤ 36% referred to GP) for social issues, mental health, symptoms, cancer complications, and treatment side-effects. While certain services are accessible to HGG patients nationally, improvements are needed. Psychosocial support, specialist allied health, and primary care providers are not yet routinely integrated into the care of HGG patients and their carers despite these services being considered essential in clinical practice guidelines and optimal care pathways.

Pharmacotherapeutic Treatment of Glioblastoma Where Are We to Date

The clinical management of glioblastoma (GBM) is still bereft of treatments able to significantly improve the poor prognosis of the disease. Despite the extreme clinical need for novel therapeutic drugs, only a small percentage of patients with GBM benefit from inclusion in a clinical trial. Moreover, often clinical studies do not lead to final interpretable conclusions. From the mistakes and negative results obtained in the last years, we are now able to plan a novel generation of clinical studies for patients with GBM, allowing the testing of multiple anticancer agents at the same time. This assumes critical importance, considering that, thanks to improved knowledge of altered molecular mechanisms related to the disease, we are now able to propose several potential effective compounds in patients with both newly diagnosed and recurrent GBM. Among the novel compounds assessed, the initially great enthusiasm toward trials employing immune checkpoint inhibitors (ICIs) was disappointing due to the negative results that emerged in three randomized phase III trials. However, novel biological insights into the disease suggest that immunotherapy can be a convincing and effective treatment in GBM even if ICIs failed to prolong the survival of these patients. In this regard, the most promising approach consists of engineered immune cells such as chimeric antigen receptor (CAR) T, CAR M, and CAR NK alone or in combination with other treatments. In this review, we discuss several issues related to systemic treatments in GBM patients. First, we assess critical issues toward the planning of clinical trials and the strategies employed to overcome these obstacles. We then move on to the most relevant interventional studies carried out on patients with previously untreated (newly diagnosed) GBM and those with recurrent and pretreated disease. Finally, we investigate novel immunotherapeutic approaches with special emphasis on preclinical and clinical data related to the administration of engineered immune cells in GBM.

COV-BT Ire study safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine in patients with brain tumors.

The BNT162b2 vaccine conferred 95% protection against COVID-19 in people aged 16 years or older. The aim of this observational study was to evaluate safety and efficacy of vaccine in patients affected by primary brain tumor (PBT). We proposed COVID-19 vaccine to all patients affected by PBT followed by Neuroncology Unit of National Cancer Institute Regina Elena. 102 patients received the first dose, 100 the second, and 73 patients received the booster dose. After first dose, we observed one patient with fever and severe fatigue, while after the second one, we recorded adverse events in ten patients. No correlation was observed between adverse events and comorbidities. The COVID-19 vaccine is safe and well tolerated in PBT patients.

Exploring the links among inflammation and gut microbiome with psychoneurological symptoms and gastrointestinal toxicities in gynecologic cancers a systematic review.

Emerging evidence highlights the roles the gut microbiome and the immune system, integral parts of the gut-brain axis, play in developing various symptoms in cancer patients. The purpose of this systematic review was to describe the roles of inflammatory markers and the gut microbiome, as well as to describe their associations with psychoneurological symptoms and gastrointestinal toxicities in women with gynecologic cancers. A comprehensive literature search was conducted in PubMed, Embase, and Web of Science from January 2000 to February 2021. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines were utilized to screen the found articles. The quality of the included studies was assessed using the Mixed Method Assessment Tool. In the included studies, various inflammatory markers and gut microbiome diversity and patterns were measured. Sixteen studies met the eligibility criteria and were included in this systematic review. While there were discrepancies in the associations between various inflammatory markers and symptoms, most of the studies showed positive correlations between interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) and cancer-related psychoneurological symptoms and gastrointestinal toxicities in gynecologic cancer patients. Although there was no consensus in alpha diversity, studies showed significant dissimilarity in the microbial communities (beta diversity) in patients with gastrointestinal toxicities compared with patients without symptoms or healthy controls. Studies also reported inconsistent findings in the abundance of bacteria at different taxonomic levels. Radiation enteritis-derived microbiota could stimulate TNF-α and interleukin 1 beta (IL-1β) secretion. Alteration of inflammatory markers, the gut microbiome, and their associations show emerging evidence in the development of psychoneurological symptoms and gastrointestinal toxicities in women with gynecologic cancers. More studies on the interactions between the immune system and the gut microbiome, two integral parts of the gut-brain axis, are required to shed light on the roles they play in symptom development.

Cerebrovascular Reactivity Mapping Using Resting-State Functional MRI in Patients With Gliomas.

Recently, a data-driven regression analysis method was developed to utilize the resting-state (rs) blood oxygenation level-dependent signal for cerebrovascular reactivity (CVR) mapping (rs-CVR), which was previously optimized by comparing with the CO To investigate the agreement of rs-CVR and the CVR mapping with breath-hold MRI (bh-CVR) in patients with gliomas. Retrospective. Twenty-five patients (12 males, 13 females mean age ± SD, 48 ± 13 years) with gliomas. Dynamic T2-weighted gradient-echo echo-planar imaging during a breath-hold paradigm and during the rs on a 3-T scanner. rs-CVR with various frequency ranges and resting-state fluctuation amplitude (RSFA) were assessed. The agreement between each rs-based CVR measurement and bh-CVR was determined by voxel-wise correlation and Dice coefficient in the whole brain, gray matter, and the lesion region of interest (ROI). Voxel-wise Pearson correlation, Dice coefficient, Fisher Z-transformation, repeated-measure analysis of variance and post hoc test with Bonferroni correction, and nonparametric repeated-measure Friedman test and post hoc test with Bonferroni correction were used. Significance was set at P < 0.05. Compared with bh-CVR, the highest correlations were found at the frequency bands of 0.04-0.08 Hz and 0.02-0.04 Hz for rs-CVR in both whole brain and the lesion ROI. RSFA had significantly lower correlations than did rs-CVR of 0.02-0.04 Hz and a wider frequency range (0-0.1164 Hz). Significantly higher correlations and Dice coefficient were found in normal tissues than in the lesion ROI for all three methods. The optimal frequency ranges for rs-CVR are determined by comparing with bh-CVR in patients with gliomas. The rs-CVR method outperformed the RSFA. Significantly higher correlation and Dice coefficient between rs- and bh-CVR were found in normal tissue than in the lesion. 3 TECHNICAL EFFICACY STAGE 2.

PDQ Cancer Information Summaries

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood astrocytomas. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions. This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Deep learning-based 3D MRI contrast-enhanced synthesis from a 2D noncontrast T2Flair sequence.

Gadolinium-based contrast agents (GBCAs) have been successfully applied in magnetic resonance (MR) imaging to facilitate better lesion visualization. However, gadolinium deposition in the human brain raised widespread concerns recently. On the other hand, although high-resolution three-dimensional (3D) MR images are more desired for most existing medical image processing algorithms, their long scan duration and high acquiring costs make 2D MR images still much more common clinically. Therefore, developing alternative solutions for 3D contrast-enhanced MR image synthesis to replace GBCAs injection becomes an urgent requirement. This study proposed a deep learning framework that produces 3D isotropic full-contrast T2Flair images from 2D anisotropic noncontrast T2Flair image stacks. The super-resolution (SR) and contrast-enhanced (CE) synthesis tasks are completed in sequence by using an identical generative adversarial network (GAN) with the same techniques. To solve the problem that intramodality datasets from different scanners have specific combinations of orientations, contrasts, and resolutions, we conducted a region-based data augmentation technique on the fly during training to simulate various imaging protocols in the clinic. We further improved our network by introducing atrous spatial pyramid pooling, enhanced residual blocks, and deep supervision for better quantitative and qualitative results. Our proposed method achieved superior CE-synthesized performance in quantitative metrics and perceptual evaluation. In detail, the PSNR, structural-similarity-index, and AUC are 32.25 dB, 0.932, and 0.991 in the whole brain and 24.93 dB, 0.851, and 0.929 in tumor regions. The radiologists evaluations confirmed that our proposed method has high confidence in the diagnosis. Analysis of the generalization ability showed that benefiting from the proposed data augmentation technique, our network can be applied to unseen datasets with slight drops in quantitative and qualitative results. Our work demonstrates the clinical potential of synthesizing diagnostic 3D isotropic CE brain MR images from a single 2D anisotropic noncontrast sequence.

Cryptotanshinone ameliorates MPP

Cryptotanshinone (CTN) has shown its neuroprotective and anti-inflammatory qualities in non-genetic mouse model of Alzheimers disease. According to bioinformatics analysis, CTN and Signal Transducer and Activator of Transcription 3 (STAT3) may interact to form a drug-target network. This study was conducted to identify the role of CTN-STAT3 interaction in Parkinsons disease (PD). PD model was established with MMP

Real-time molecular imaging of near-surface tissue using Raman spectroscopy.

The steady progress in medical diagnosis and treatment of diseases largely hinges on the steady development and improvement of modern imaging modalities. Raman spectroscopy has attracted increasing attention for clinical applications as it is label-free, non-invasive, and delivers molecular fingerprinting information of a sample. In combination with fiber optic probes, it also allows easy access to different body parts of a patient. However, image acquisition with fiber optic probes is currently not possible. Here, we introduce a fiber optic probe-based Raman imaging system for the real-time molecular virtual reality data visualization of chemical boundaries on a computer screen and the physical world. The approach is developed around a computer vision-based positional tracking system in conjunction with photometric stereo and augmented and mixed chemical reality, enabling molecular imaging and direct visualization of molecular boundaries of three-dimensional surfaces. The proposed approach achieves a spatial resolution of 0.5 mm in the transverse plane and a topology resolution of 0.6 mm, with a spectral sampling frequency of 10 Hz, and can be used to image large tissue areas in a few minutes, making it highly suitable for clinical tissue-boundary demarcation. A variety of applications on biological samples, i.e., distribution of pharmaceutical compounds, brain-tumor phantom, and various types of sarcoma have been characterized, showing that the system enables rapid and intuitive assessment of molecular boundaries.

Blocked metabotropic glutamate receptor 5 enhances chemosensitivity in hepatocellular carcinoma and attenuates chemotoxicity in the normal liver by regulating DNA damage.

DNA damaging agents are used as chemotherapeutics in many cancers, including hepatocellular carcinoma (HCC). However, they are associated with problems such as low sensitivity to chemotherapy and the induction of liver injury, underscoring the need to identify new therapies. Here, we investigated the differential regulatory effect of metabotropic glutamate receptor 5 (mGlu

Targeting NQO1GPX4-mediated ferroptosis by plumbagin suppresses in vitro and in vivo glioma growth.

Ferroptosis has attracted increasing interest in cancer therapy. Emerging evidences suggest that naturally occurring naphthoquinones exhibit potent anti-glioma effects via various mechanisms. The anti-glioma effects of plumbagin were evaluated by in vitro and in vivo experiments. Anti-glioma mechanism of plumbagin was studied by proteomics, flow cytometry, MDA assay, western blot, and RT-PCR. Gene knockdownoverexpression, molecular docking, PharmMappper database, and coimmunoprecipitation were used to study the targets of plumbagin. Plumbagin showed higher blood-brain barrier penetration ability than that of lapachol and shikonin and elicited significant growth inhibitory effects in vitro and in vivo. Ferroptosis was the main mechanism of plumbagin-induced cell death. Mechanistically, plumbagin significantly downregulated the protein and mRNA levels of xCT and decreased GPX4 protein levels. NAD(P)H quinone dehydrogenase 1 (NQO1) was revealed as a plumbagin predictive target using PharmMappper database and molecular docking. Plumbagin enhanced NQO1 activity and decreased xCT expression, resulting in NQO1-dependent cell death. It also induced GPX4 degradation via the lysosome pathway and caused GPX4-dependent cell death. Plumbagin inhibited in vitro and in vivo glioma growth via targeting NQO1GPX4-mediated ferroptosis, which might be developed as a novel ferroptosis inducer or anti-glioma candidate.

Ten-eleven translocation (TET) proteins are crucial epigenetic regulators highly conserved in multicellular organisms. TETs enzymatic function in demethylating 5-methyl cytosine in DNA is required for proper development and TETs are frequently mutated in cancer. Recently,

A tumor suppressor role for EZH2 in diffuse midline glioma pathogenesis.

Pediatric high-grade gliomas, specifically diffuse midline gliomas, account for only 20% of clinical cases but are 100% fatal. A majority of the DMG cases are characterized by the signature K27M mutation in histone H3. The H3K27M mutation opposes the function of enhancer of zeste homolog 2 (EZH2), the methyltransferase enzyme of the polycomb repressor complex 2. However, the role of EZH2 in DMG pathogenesis is unclear. In this study, we demonstrate a tumor suppressor function for EZH2 using Ezh2 loss- and gain-of-function studies in H3WT DMG mouse models. Genetic ablation of Ezh2 increased cell proliferation and tumor grade while expression of an Ezh2 gain-of-function mutation significantly reduced tumor incidence and increased tumor latency. Transcriptomic analysis revealed that Ezh2 deletion upregulates an inflammatory response with upregulation of immunoproteasome genes such as Psmb8, Psmb9, and Psmb10. Ezh2 gain-of-function resulted in enrichment of the oxidative phosphorylationmitochondrial metabolic pathway namely the isocitrate dehydrogenase Idh123 genes. Pharmacological inhibition of EZH2 augmented neural progenitor cell proliferation, supporting the tumor suppressive role of EZH2. In vivo 7-day treatment of H3K27M DMG tumor bearing mice with an EZH2 inhibitor, Tazemetostat, did not alter proliferation or significantly impact survival. Together our results suggest that EZH2 has a tumor suppressor function in DMG and warrants caution in clinical translation of EZH2 inhibitors to treat patients with DMG.

Prospective genomically guided identification of earlyevolving and undersampled IDH-wildtype glioblastoma leads to improved clinical outcomes.

Genomic profiling studies of diffuse gliomas have led to new improved classification schemes that better predict patient outcomes compared to conventional histomorphology alone. One example is the recognition that patients with IDH-wildtype diffuse astrocytic gliomas demonstrating lower-grade histologic features but genomic andor epigenomic profile characteristic of glioblastoma typically have poor outcomes similar to patients with histologically diagnosed glioblastoma. Here we sought to determine the clinical impact of prospective genomic profiling for these IDH-wildtype diffuse astrocytic gliomas lacking high-grade histologic features but with molecular profile of glioblastoma. Clinical management and outcomes were analyzed for 38 consecutive adult patients with IDH-wildtype diffuse astrocytic gliomas lacking necrosis or microvascular proliferation on histologic examination that were genomically profiled on a prospective clinical basis revealing criteria for an integrated diagnosis of diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV per cIMPACT-NOW criteria. We identified that this diagnosis consists of two divergent clinical scenarios based on integration of radiologic, histologic, and genomic features that we term earlyevolving and undersampled glioblastoma, IDH-wildtype. We found that prospective genomically guided identification of earlyevolving and undersampled IDH-wildtype glioblastoma resulted in more aggressive patient management and improved clinical outcomes compared to a biologically matched historical control patient cohort receiving standard-of-care therapy based on histomorphologic diagnosis alone. These results support routine use of genomic andor epigenomic profiling to accurately classify glial neoplasms, as these assays not only improve diagnostic classification but critically lead to more appropriate patient management that can improve clinical outcomes.

Association between socioeconomic status and presenting characteristics and extent of disease in patients with surgically resected nonfunctioning pituitary adenoma.

The aim of this study was to evaluate the association between zip code-level socioeconomic status (SES) and presenting characteristics and short-term clinical outcomes in patients with nonfunctioning pituitary adenoma (NFPA). A retrospective review of prospectively collected data from the University of Southern California Pituitary Center was conducted to identify all patients undergoing surgery for pituitary adenoma (PA) from 2000 to 2021 and included all patients with NFPA with recorded zip codes at the time of surgery. A normalized socioeconomic metric by zip code was then constructed using data from the American Community Survey estimates, which was categorized into tertiles. Multiple imputation was used for missing data, and multivariable linear and logistic regression models were constructed to estimate mean differences and multivariable-adjusted odds ratios for the association between zip code-level SES and presenting characteristics and outcomes. A total of 637 patients were included in the overall analysis. Compared with patients in the lowest SES tertile, those in the highest tertile were more likely to be treated at a private (rather than safety net) hospital, and were less likely to present with headache, vision loss, and apoplexy. After multivariable adjustment for age, sex, and prior surgery, SES in the highest compared with lowest tertile was inversely associated with tumor size at diagnosis (-4.9 mm, 95% CI -7.2 to -2.6 mm, p < 0.001) and was positively associated with incidental diagnosis (multivariable-adjusted OR 1.72, 95% CI 1.02-2.91). Adjustment for hospital (private vs safety net) attenuated the observed associations, but disparities by SES remained statistically significant for tumor size. Despite substantial differences at presentation, there were no significant differences in length of stay or odds of an uncomplicated procedure by zip code-level SES. Patients from lower-SES zip codes were more likely to require postoperative steroid replacement and less likely to achieve gross-total resection. In this series, lower zip code-level SES was associated with more severe disease at the time of diagnosis for NFPA patients, including larger tumor size and lower rates of incidental diagnosis. Despite these differences at presentation, no significant differences were observed in short-term postoperative complications, although patients with higher zip code-level SES had higher rates of gross-total resection.

Adult diffuse intrinsic pontine glioma clinical, radiological, pathological, molecular features, and treatments of 96 patients.

Unlike its pediatric counterpart, adult diffuse intrinsic pontine glioma (DIPG) remains largely unelucidated. In this study, the authors examined the clinical, radiological, pathological, molecular, and clinical aspects of 96 adult DIPGs. The National Brain Tumor Registry of China (April 2013-December 2019) was used to collect data on radiologically diagnosed adult DIPG patients. Survival analysis was conducted using Kaplan-Meier curves and univariate and multivariate Cox regression. The chi-square testWilcoxon rank-sum test and multivariable logistic regression were used to examine the clinical and radiological characteristics of patients with long-term survival (LTS). Interaction analyses between clinical factors were also conducted. The median age at symptom onset was 33.5 years, and the median duration of symptoms was 4.5 months. The frequencies of H3K27M and IDH1 mutations were 37.2% and 26.5%, respectively. All adult DIPG patients had a median overall survival (OS) of 19.5 months, with 1-, 2-, and 3-year survival rates of 67.0%, 42.8%, and 36.0%, respectively. The median OS of 40 patients who did not undergo treatment was 13.4 months. Patients with H3K27M-mutant tumors had a poorer prognosis than those with IDH-mutant tumors (p < 0.001) and H3K27M(-)IDH-wild-type tumors (p 0.002), with a median OS of 11.4 months. The median OSs of patients with H3K27M-mutant tumors who received treatment and those who did not were 13.8 months and 7.5 months, respectively (p 0.016). Among patients with and without a pathological diagnosis, H3K27M mutation (p < 0.001) and contrast enhancement on MRI (p 0.003), respectively, imparted a worse prognosis. Treatments were the predictive factor for patients with H3K27M-mutant tumors (p 0.038), whereas contrast enhancement on MRI was the prognostic factor for the H3K27M(-) group (p 0.038). In addition, H3K27M mutation and treatment were significant predictors for patients with symptom duration ≤ 4 months (H3K27M, p 0.020 treatment, p 0.014) and tumors with no contrast enhancement (H3K27M, p 0.003 treatment, p 0.042). Patients with LTS were less likely to have cranial nerve palsy (p 0.002) and contrast enhancement on MRI at diagnosis (p 0.022). It is recommended that all adult DIPG patients undergo genomic testing for H3K27M and IDH mutations. Despite the low prevalence, additional study is needed to better characterize the efficacy of various treatment modalities in adults with DIPG.

Augmented networks for faster brain metastases detection in T1-weighted contrast-enhanced 3D MRI.

Early detection of brain metastases (BM) is one of the determining factors for the successful treatment of patients with cancer however, the accurate detection of small BM lesions (< 15 mm) remains a challenging task. We previously described a framework for the detection of small BM in single-sequence gadolinium-enhanced T1-weighted 3D MRI datasets. It combined classical image processing (IP) with a dedicated convolutional neural network, taking approximately 30 s to process each dataset due to computation-intensive IP stages. To overcome the speed limitation, this study aims to reformulate the framework via an augmented pair of CNNs (eliminating the IP) to reduce the processing times while preserving the BM detection performance. Our previous implementation of the BM detection algorithm utilized Laplacian of Gaussians (LoG) for the candidate selection portion of the solution. In this study, we introduce a novel BM candidate detection CNN (cdCNN) to replace this classical IP stage. The network is formulated to have (1) a similar receptive field as the LoG method, and (2) a bias for the detection of BM lesion loci. The proposed CNN is later augmented with a classification CNN to perform the BM detection task. The cdCNN achieved 97.4% BM detection sensitivity when producing 60 K candidates per 3D MRI dataset, while the LoG achieved 96.5% detection sensitivity with 73 K candidates. The augmented BM detection framework generated on average 9.20 false-positive BM detections per patient for 90% sensitivity, which is comparable with our previous results. However, it processes each 3D data in 1.9 s, presenting a 93.5% reduction in the computation time.

The interleukin-1 axis and the tumor immune microenvironment in pancreatic ductal adenocarcinoma.

Interleukin-1 (IL-1) plays a key role in carcinogenesis and several IL-1-targeted therapeutics are under investigation for the treatment of pancreatic ductal adenocarcinoma (PDAC). We sought to broaden our understanding of how the family of IL-1 ligands and receptors impact the tumor immune landscape and patient survival in PDAC. Gene expression data and DNA methylation data for IL1A, IL1B, IL1RN, IL1R1, IL1R2, and IL1RAP was attained from The Cancer Genome Atlas (TCGA) database and cross validated using the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database. Immune cell-type abundance was estimated using CIBERSORTx. Further confirmatory soluble protein analysis and peripheral blood immunophenotyping were performed on available tissue samples from our institution. 169 PDAC patients and 50 benign pancreatic TCGA-based samples were analyzed. IL1A (p < 0.001), IL1RN (p < 0.001), IL1R2 (p < 0.001), and IL1RAP (p 0.006) were markedly increased in PDAC tumor tissue compared to benign pancreatic tissue. Furthermore, expression of IL1A, IL1B and IL1R1 were positively correlated with gene expression of immune checkpoints PVR, CD274, CD47, CD80, and HLA-ABC (p < 0.001). IL1B and IL1R1 were correlated to expression of PDCD1, CD86, CTLA4 and IDO1 (<0.001). Low expression of IL1RN (p 0.020), IL1R2 (p 0.015), and IL1RAP (p 0.003) and high expression of IL1B (p 0.031) were correlated with increased patient survival. At the protein level, IL-1β was correlated with increased peripheral central memory CD4 and CD8 T-cells as well as decreased Th2 cells. These findings suggest that the IL-1 axis plays a complex and pivotal role in the host immune response to PDAC.

Global variation in young adult central nervous system tumor incidence by region, age, and sex from 1988 to 2012.

Central nervous system (CNS) tumors result in tremendous morbidity and mortality. Incidence of CNS tumors in young adults is less studied. It is unknown how young adult CNS tumor incidence has changed globally in recent decades. We used Cancer Incidence in Five Continents (CI5) data (1988-2012) to estimate incidence rates (IR), average annual percent change in incidence (AAPC 95% confidence intervals 95% CI), and male-to-female incidence rate ratios (IRR 95% CI) by six histologies and age at diagnosis (20-29years, 30-39years). Tumors were classified as astrocytic, medulloblastoma, ependymal, oligodendroglial, meninges, and other embryonal. Geographic regions were defined using the United Nations Statistics Division geoscheme. There were 78,240 CNS tumor cases included. 20-29-year-old (yo) rates were lower than 30-39 yo in most regions for astrocytic, oligodendroglial and ependymal tumors. Globally, astrocytic tumor incidence decreased (20-29 yo AAPC - 0.70 95% CI - 1.32, - 0.08) while incidence increased for oligodendroglial (20-29 yo AAPC 3.03 95% CI 1.57-4.51 30-39 yo AAPC 2.67 95% CI 0.79-4.58), ependymal (20-29 yo AAPC 1.16 95% CI 0.31-2.03 30-39 yo AAPC 2.29 95% CI 1.14-3.46), medulloblastoma (30-39 yo AAPC 0.6 95% CI 0.04-1.24) and tumors of the meninges (20-29 yo AAPC 1.55 95% CI 0.04-3.07). There was a 20-40% male incidence excess in all histologies except for meninge tumors (30-39 yo IRR 0.71 95% CI 0.61, 0.84). Incidence of oligodendroglial and ependymal tumors increased globally in 20-39 yo suggesting better diagnoses or changes in risk factors. Males had a higher incidence of CNS tumors for most tumors studied and in most regions.

Topical instillation of cell-penetrating peptide-conjugated melphalan blocks metastases of retinoblastoma.

Retinoblastoma is the most common primary intraocular malignancy in infancy with a metastases-related death risk. However, a safe and convenient treatment without enucleation is still an unmet clinical need. In this work, a cell-penetrating peptide, 89WP, was conjugated with melphalan (89WP-Mel), which achieved high tumor inhibition effects as intravitreally injected melphalan via topical instillation for the first time. Notably, the outside-in diffusion of instilled 89WP-Mel created a protective shield surrounding the eye, efficiently preventing tumor metastases, while the mice treated with intravitreally injected melphalan suffered more brain metastases related death. The ocular absorption of 89WP-conjugated melphalan and other small molecules, both hydrophobic and hydrophilic, occurred via non-corneal pathway with high safety and a prolonged residence duration in retina up to 24 h. The present work paves a new avenue for simultaneous intraocular tumor inhibition and extraocular metastases prevention in a safe and convenient way via topical instillation.

The natural antisense transcript HAS2-AS1 regulates breast cancer cells aggressiveness independently from hyaluronan metabolism.

Hyaluronan (HA) is a ubiquitous extracellular matrix component playing a crucial role in the regulation of cell behaviors, including cancer. Aggressive breast cancer cells tend to proliferate, migrate and metastatize. Notably, triple-negative breast cancer cells lacking the expression of estrogen receptor (ER) as well as progesterone receptor and HER2 are more aggressive than ER-positive ones. As currently no targeted therapy is available for triple-negative breast cancer, the identification of novel therapeutic targets has a high clinical priority. In ER-negative cells, tumoral behavior can be reduced by inhibiting HA synthesis or silencing the enzymes involved in its metabolism, such as HA synthase 2 (HAS2). HAS2-AS1 is a long non-coding RNA belonging to the natural antisense transcript family which is known to favor HAS2 gene expression and HA synthesis, thus bolstering malignant progression in brain, ovary, and lung tumors. As the role of HAS2-AS1 has not yet been investigated in breast cancer, in this work we report that ER-positive breast cancers had lower HAS2-AS1 expression compared to ER-negative tumors. Moreover, the survival of patients with ER-negative tumors was higher when the expression of HAS2-AS1 was elevated. Experiments with ER-negative cell lines as MDA-MB-231 and Hs 578T revealed that the overexpression of either the full-length HAS2-AS1 or its exon 2 long or short isoforms alone, strongly reduced cell viability, migration, and invasion, whereas HAS2-AS1 silencing increased cell aggressiveness. Unexpectedly, in these ER-negative cell lines, HAS2-AS1 is involved neither in the regulation of HAS2 nor in HA deposition. Finally, transcriptome analysis revealed that HAS2-AS1 modulation affected several pathways, including apoptosis, proliferation, motility, adhesion, epithelial to mesenchymal transition, and signaling, describing this long non-coding RNA as an important regulator of breast cancer cells aggressiveness.

Pharmacological activities and pharmacokinetics of liquiritin A review.

Liquiritin is a flavonoid derived from Radix et Rhizoma Glycyrrhizae, which is a widely used traditional Chinese medicine with the effects of invigorating spleen qi, clearing heat, resolving toxins, and dispelling phlegm to stop coughs. In this review,the pharmacokinetics and pharmacological activities of liquiritin have been summarized. The information on liquiritin up to 2021 was collected from PubMed, Web of Science, Springer Link, and China National Knowledge Infrastructure databases. The key words were liquiritin, nerve, tumor, cardiac, etc. RESULTS The absorption mechanism of liquiritin conforms to the passive diffusion and first-order kinetics while with low bioavailability. Liquiritin can penetrate the blood-brain-barrier. Besides, liquiritin displays numerous pharmacological effects including anti-Alzheimers disease, antidepressant, antitumor, anti-inflammatory, cardiovascular protection, antitussive, hepatoprotection, and skin protective effects. In addition, the novel preparations, new pharmacological effects,and cdusafty of liquiritin are also discussed in this review. This review provides a comprehensive state of knowledge on the pharmacokinetics and pharmacological activities of liquiritin, and makes a forecast for its research directions and applications in clinic.

Recent Advances in the Therapeutic Strategies of Glioblastoma Multiforme.

Glioblastoma multiforme (GBM) is one of the most common, most formidable, and deadliest malignant types of primary astrocytoma with a poor prognosis. At present, the standard of care includes surgical tumor resection, followed by radiation therapy concomitant with chemotherapy and temozolomide. New developments and significant advances in the treatment of GBM have been achieved in recent decades. However, despite the advances, recurrence is often inevitable, and the survival of patients remains low. Various factors contribute to the difficulty in identifying an effective therapeutic option, among which are tumor complexity, the presence of the blood-brain barrier (BBB), and the presence of GBM cancer stem cells, prompting the need for improving existing treatment approaches and investigating new treatment alternatives for ameliorating the treatment strategies of GBM. In this review, we outline some of the most recent literature on the various available treatment options such as surgery, radiotherapy, cytotoxic chemotherapy, gene therapy, immunotherapy, phototherapy, nanotherapy, and tumor treating fields in the treatment of GBM, and we list some of the potential future directions of GBM. The reviewed studies confirm that GBM is a sophisticated disease with several challenges for scientists to address. Hence, more studies and a multimodal therapeutic approach are crucial to yield an effective cure and prolong the survival of GBM patients.

Effects of insulin and sitagliptin on early cardiac dysfunction in diabetic rats.

Cardiac affection is common in diabetic patients. Although insulin exerts a cardioprotective role, it may not be enough to totally prevent this affection. The current study aimed to compare the cardioprotective effect of insulin alone or combined with sitagliptin in a rat model of type 1 diabetes mellitus. Diabetes was induced by a single intraperitoneal injection of streptozotocin (STZ 60 mgkg). Diabetic rats were treated with insulin (3 IU), insulin (6 IU), or insulin (3 IU) sitagliptin (10 mgkg) for 42 days. Diabetic rats exhibited significant systolic and diastolic cardiac affection with significant elevation of tumor necrosis factor α (TNF-α), interleukin 6 (IL-6) and brain natriuretic peptide (BNP) levels. Treatment with insulin prevented the deterioration of diabetes-induced cardiac condition, an effect that was significantly potentiated by the combined use of sitagliptin. The combined use of sitagliptin and insulin significantly improved the cardioprotective effect of insulin and prevented the early cardiac dysfunction in STZ diabetic rats.

Eicosapentaenoic acid enhanced apoptotic and oxidant effects of cisplatin via activation of TRPM2 channel in brain tumor cells.

Cisplatin (CiSP) induced-overload Ca

Germline variants in tumor suppressor FBXW7 lead to impaired ubiquitination and a neurodevelopmental syndrome.

Neurodevelopmental disorders are highly heterogenous conditions resulting from abnormalities of brain architecture andor function. FBXW7 (F-box and WD-repeat-domain-containing 7), a recognized developmental regulator and tumor suppressor, has been shown to regulate cell-cycle progression and cell growth and survival by targeting substrates including CYCLIN E12 and NOTCH for degradation via the ubiquitin proteasome system. We used a genotype-first approach and global data-sharing platforms to identify 35 individuals harboring de novo and inherited FBXW7 germline monoallelic chromosomal deletions and nonsense, frameshift, splice-site, and missense variants associated with a neurodevelopmental syndrome. The FBXW7 neurodevelopmental syndrome is distinguished by global developmental delay, borderline to severe intellectual disability, hypotonia, and gastrointestinal issues. Brain imaging detailed variable underlying structural abnormalities affecting the cerebellum, corpus collosum, and white matter. A crystal-structure model of FBXW7 predicted that missense variants were clustered at the substrate-binding surface of the WD40 domain and that these might reduce FBXW7 substrate binding affinity. Expression of recombinant FBXW7 missense variants in cultured cells demonstrated impaired CYCLIN E1 and CYCLIN E2 turnover. Pan-neuronal knockdown of the Drosophila ortholog, archipelago, impaired learning and neuronal function. Collectively, the data presented herein provide compelling evidence of an F-Box protein-related, phenotypically variable neurodevelopmental disorder associated with monoallelic variants in FBXW7.

Restoration of cardiac metabolic flexibility by acetate in high-fat diet-induced obesity is independent of ANPBNP modulation.

The present study hypothesized that cardiac metabolic inflexibility is dependent on cardiac atrial natriuretic peptidebrain natriuretic peptide (ANPBNP) alteration and histone deacetylase (HDAC) activity. We further sought to investigate the therapeutic potential of short-chain amino acid (SCFA) acetate in high-fat diet (HFD)-induced obese rat model. Adult male Wistar rats were assigned into groups (

Histopathological and genetic features of mismatch repair-deficient high-grade prostate cancer.

Mismatch repair (MMR) deficiency is commonly caused by functional inactivation of MLH1, PMS2, MSH2 or MSH6. The morphological and molecular correlates of MMR deficiency have been extensively characterized in certain tumour types such as colorectal and endometrial adenocarcinoma. In contrast, the histological and molecular features of MMR-deficient prostate cancer remain incompletely described. In this study, we evaluated 19 MMR-deficient prostate cancers, including 11 cases without prior systemic treatment. All treatment-naive cases (11 of 11, 100%) were grade group 4-5 and had predominant cribriform andor solid growth patterns. Solid components (any amount) and tumour infiltrating lymphocytes were 7 cases each (7 of 11, 64%). In 68 MMR-proficient grade group 5 prostate cancers, predominant cribriform or solid growth patterns, solid components (any amount) and tumour infiltrating lymphocytes were seen at significantly lower frequencies (31 of 68, 46% 9 of 68, 13% and 6 of 62, 9%, respectively P < 0.001 for all comparisons). Molecular evaluation of 19 cases demonstrated that MMR-deficiency was secondary to functional loss of MSH2MSH6 and MLH1PMS2 in 15 (79%) and 4 cases (21%), respectively. Definite or probable germline mutations were present in 4 cases (4 of 19, 21%). TMPRSS2ERG rearrangements were identified in 2 cases (2 of 19, 11%). Recurrent cancer-relevant somatic mutations included (but were not limited to) ATM, TP53, FOXA1, RB1, BRCA2 and PTEN. MMR deficiency was most commonly secondary to inactivation of MSH2MSH6 in this study. Importantly, MMR-deficient high-grade prostatic adenocarcinomas had morphological features that might be useful to identify selected cases for MMR immunohistochemistry.

Clinical Biology of the Pituitary Adenoma.

All endocrine glands are susceptible to neoplastic growth, yet the health consequences of these neoplasms differ between endocrine tissues. Pituitary neoplasms are highly prevalent and overwhelmingly benign, exhibiting a spectrum of diverse behaviors and impact on health. To understand the clinical biology of these common yet often innocuous neoplasms, we review pituitary physiology and adenoma epidemiology, pathophysiology, behavior, and clinical consequences. The anterior pituitary develops in response to a range of complex brain signals integrating with intrinsic ectodermal cell transcriptional events that together determine gland growth, cell type differentiation, and hormonal production, in turn maintaining optimal endocrine health. Pituitary adenomas occur in 10% of the population however, the overwhelming majority remain harmless during life. Triggered by somatic or germline mutations, disease-causing adenomas manifest pathogenic mechanisms that disrupt intrapituitary signaling to promote benign cell proliferation associated with chromosomal instability. Cellular senescence acts as a mechanistic buffer protecting against malignant transformation, an extremely rare event. It is estimated that fewer than one-thousandth of all pituitary adenomas cause clinically significant disease. Adenomas variably and adversely affect morbidity and mortality depending on cell type, hormone secretory activity, and growth behavior. For most clinically apparent adenomas, multimodal therapy controlling hormone secretion and adenoma growth lead to improved quality of life and normalized mortality. The clinical biology of pituitary adenomas, and particularly their benign nature, stands in marked contrast to other tumors of the endocrine system, such as thyroid and neuroendocrine tumors.

The study of cognitive functions and the brain electrical activity in wakefulness and night sleep in patients with lobe tumors.

To study cognitive dysfunction and brain electrical activity in sleep-wakefulness cycle in patients with frontal lobe tumors. Twenty patients, aged 48.6±4.2 years, and ten healthy volunteers participated in the study. The first group included patients without cognitive impairment and tumors 8.9±5.1 cm Cognitive impairment in patients with lobe tumors is associated with increases in deltatheta, and areactivity of the cortex in wakefulness, increases in deltathetaalpha in REM and declining number of arousals in REM. The results of the study may be useful in early detection of biomarkers of the cognitive impairment in patients with frontal lobe tumors in order to increase the efficiency of rehabilitation of patients. Выполнена оценка нарушений когнитивных функций и исследование организации биоэлектрической активности мозга в цикле сон—бодрствование у пациентов с опухолями лобной доли. Обследованы 20 пациентов обоих полов в возрасте 48,6±6,4 года, а также 10 здоровых (контроль). В 1-ю группу были включены пациенты без неврологических нарушений с опухолями, средний объем которых составил 8,9±5,1 см Установлено, что ухудшение когнитивных функций у пациентов с опухолями лобной доли сопровождалось ростом мощности дельта- и тета-диапазонов и ареактивностью коры в бодрствовании, увеличением мощности в диапазоне частот дельта-, тета-, альфа-ритмов, уменьшением активаций в фазе быстрого сна. Полученные данные могут быть полезны в поиске маркеров ранних признаков ухудшения когнитивных функций у пациентов с опухолями лобной доли с целью своевременного осуществления коррекции функционального состояния пациентов.

The burden of a brain tumor guiding patient centric care in neuro-oncology.

Brain tumor patients report an overwhelming sense of uncertainty when navigating the course of their terminal disease. Historically, organizational experts andor treating physicians have established neuro-oncology programs. However, given the disease burden and incurable nature of current medical treatments, patient-centric care should be prioritized alongside institutional and academic objectives. Integrating patient perspectives into interdisciplinary programmatic development can improve comprehensive care and empower patients to advocate for their own quality healthcare needs. Data was derived from four focus groups with adult brain tumor patients (N 15 M Six distinct themes emerged, where the frequency of each theme ranged from 12.5 to 23.3%. Specifically, patients discussed relational concerns, navigation of interdisciplinary care, neurobehavioral impacts, emotional responses to stressors, existential concerns, and caregiver support. A discussion of themes follows. It is imperative that we include the patient perspective in the development of neuro-oncology programs considering the quality of survival in addition to quantity. Neuro-oncology quality care themes identified were relational concerns, navigating interdisciplinary care, neurobehavioral impact, emotional response to stressors, existential concerns, and caregiver support. A paramount concentration for comprehensive neuro-oncology programs must include patients quality needs.

ADC textural features in patients with single brain metastases improve clinical risk models.

In this retrospective study we performed a quantitative textural analysis of apparant diffusion coefficient (ADC) images derived from diffusion weighted MRI (DW-MRI) of single brain metastases (BM) patients from different primary tumors and tested whether these imaging parameters may improve established clinical risk models. We identified 87 patients with single BM who had a DW-MRI at initial diagnosis. Applying image segmentation, volumes of contrast-enhanced lesions in T1 sequences, hyperintense T2 lesions (peritumoral border zone (T2PZ)) and tumor-free gray and white matter compartment (GMWMC) were generated and registered to corresponding ADC maps. ADC textural parameters were generated and a linear backward regression model was applied selecting imaging features in association with survival. A cox proportional hazard model with backward regression was fitted for the clinical prognostic models (diagnosis-specific graded prognostic assessment score (DS-GPA) and the recursive partitioning analysis (RPA)) including these imaging features. Thirty ADC textural parameters were generated and linear backward regression identified eight independent imaging parameters which in combination predicted survival. Five ADC texture features derived from T2PZ, the volume of the T2PZ, the normalized mean ADC of the GMWMC as well as the mean ADC slope of T2PZ. A cox backward regression including the DS-GPA, RPA and these eight parameters identified two MRI features which improved the two risk scores (HR 1.14 1.051.24 for normalized mean ADC GMWMC and HR 0.87 0.770.97) for ADC 3D kurtosis of the T2PZ.) CONCLUSIONS Textural analysis of ADC maps in patients with single brain metastases improved established clinical risk models. These findings may aid to better understand the pathogenesis of BM and may allow selection of patients for new treatment options.

An Ascendant Challenge Central Nervous System Metastases in ALK Lung Cancers.

Central nervous system (CNS) metastases constitute a challenge for the design of anaplastic lymphoma kinase (ALK) fusion-positive lung cancer trials. The ASCEND-7 study of ceritinib demonstrates the feasibility of broadening CNS eligibility criteria to include symptomatic brain and leptomeningeal disease and highlights design features that contemporary trials will need to incorporate. See related article by Chow et al., p. 2506.

Tumor Immune Microenvironment of Brain Metastases Toward Unlocking Antitumor Immunity.

Brain metastasis (BrM) is a devastating complication of solid tumors associated with poor outcomes. Immune-checkpoint inhibitors (ICI) have revolutionized the treatment of cancer, but determinants of response are incompletely understood. Given the rising incidence of BrM, improved understanding of immunobiologic principles unique to the central nervous system (CNS) and dissection of those that govern the activity of ICIs are paramount toward unlocking BrM-specific antitumor immunity. In this review, we seek to discuss the current clinical landscape of ICI activity in the CNS and CNS immunobiology, and we focus, in particular, on the role of glial cells in the CNS immune response to BrM. There is an urgent need to improve patient selection for and clinical activity of ICIs in patients with cancer with concomitant BrM. Increased understanding of the unique immunobiologic principles that govern response to ICIs in the CNS is critical toward identifying targets in the tumor microenvironment that may potentiate antitumor immunity.

An Uncommon Presentation of Pheochromocytoma in Neurofibromatosis Type 1 and the Importance of Long-Term Follow-Up.

Neurofibromatosis type 1 (NFT1) is a disease caused by mutations in the tumor suppressor gene NF1. It is associated with a higher incidence of chromaffin cell tumors which are usually adrenal, unilateral and benign. The presence of these tumors during pregnancy is extremely rare and frequently associated with fatal outcomes. We report the case of a female patient with NFT1, who presented with paroxysmal spells of headache, palpitations, dizziness and pre-cordial discomfort, starting immediately after the delivery of her third child. Diagnostic work-up came to reveal a bilateral pheochromocytoma and the patient underwent bilateral adrenalectomy. Over 12 years after the initial surgery, metastatic disease was diagnosed, and a reintervention was performed. This is a rare presentation of bilateral malignant pheochromocytoma in a patient with NFT1, with postpartum occurrence of the first symptoms. This text focuses the important details and challenges found at each stage of diagnosis and follow-up. A neurofibromatose tipo 1 (NFT1) é uma doença causada por mutações no gene supressor de tumor NF1. Está associada a uma maior incidência de tumores de células cromafins que geralmente são adrenais, unilaterais e benignos. A presença destes tumores durante a gravidez é extremamente rara e com frequência associada a resultados fatais. Relatamos o caso de uma doente com NFT1, que apresentou crises paroxísticas de cefaleias, palpitações, tonturas e desconforto pré-cordial, com início imediatamente após o parto de seu terceiro filho. A investigação diagnóstica revelou feocromocitoma bilateral e a doente foi submetida a adrenalectomia bilateral. Mais de 12 anos após a cirurgia inicial, foi diagnosticada doença metastática e efetuada reintervenção. Esta é uma apresentação rara de feocromocitoma maligno bilateral numa doente com NFT1, com ocorrência pós-parto dos primeiros sintomas. Este texto foca detalhes e desafios importantes encontrados em cada fase do diagnóstico e acompanhamento.

Regulation of inflammation by VEGFBDNF signaling in mouse retinal Müller glial cells exposed to high glucose.

The inflammatory changes seem to play an important role in the development of diabetic retinopathy (DR). Anti-VEGF therapy has been testified to inhibit inflammation in animal models of diabetes, but the detailed mechanisms during this process are not yet clear. Müller glial cells (MGCs) in the mammalian retina are deeply involved in DR, while the BDNF overexpression reduces inflammation in diabetic mice. In this research, we aimed to explore the relationship between VEGF and BDNF in mouse retinal MGCs during inflammation of diabetes. We examined the expression of glutamine-synthetase (GS), glial fibrillary acidic protein (GFAP), vascular-endothelial growth factor (VEGF), interleukin-1beta (IL-1β), and tumor necrosis factor-alpha (TNF-α) at different time points after mouse retinal MGCs exposed to high glucose (25 mM). We also explored changes in the expression of brain-derived neurotrophic factor (BDNF), nuclear factor kappa B (NF-κB), IL-1β, and TNF-α in MGCs after treatments with anti-VEGF, VEGF siRNA, BDNF siRNA, BDNF recombination protein, and NF-κB inhibitor. In mouse retinal MGCs exposed to high glucose, BDNF was increased after treatments with anti-VEGF or VEGF siRNA. BDNF was decreased in MGCs from VEGF overexpressed mice. Moreover, the expressions of NF-κB, IL-1β, and TNF-α changed with BDNF NF-κB, IL-1β, and TNF-α were increased after treatments with BDNF siRNA NF-κB, IL-1β, and TNF-α were decreased after treatments with BDNF recombination protein. VEGF may regulate cytokines (IL-1β and TNF-α) by BDNFNF-κB signaling pathway. The regulation of the VEGFBDNFNF-κB signaling pathway may be a significant therapeutic strategy for DR.

Radiomics signature for the prediction of progression-free survival and radiotherapeutic benefits in pediatric medulloblastoma.

To develop and validate a radiomics signature for progression-free survival (PFS) and radiotherapeutic benefits in pediatric medulloblastoma. We retrospectively enrolled 253 consecutive children with medulloblastoma from two hospitals. A total of 1294 radiomic features were extracted from the region of tumor on the T1-weighted and contrast-enhanced T1-weighted (CE-T1w) MRI. Radiomic feature selection and machine learning modelling were performed to build radiomics signature for the prediction of PFS on the training set. Moreover, the prognostic performance of the clinical parameters was investigated for PFS. The Concordance index (a value of 0.5 indicates no predictive discrimination, and a value of 1 indicates perfect predictive discrimination) was used to measure and compare the prognostic performance of these models. The radiomics signature for the prediction of the PFS yielded Concordance indices of 0.711, 0.707, and 0.717 on the training and held-out test sets 1 and 2, respectively. The radiomics nomogram integrating the radiomics signature, age, and metastasis performed better than the nomogram incorporating only clinicopathological factors (C-index, 0.723 vs. 0.665 and 0.722 vs. 0.677 on the held-out test sets 1 and 2, respectively), which was also validated by the good calibration and decision curve analysis. Further analysis demonstrated that patients with lower value of radiomics signature were associated with better clinical outcomes after postoperative radiotherapy (p < 0.001). The radiomics signature and nomogram performed well for the prediction of PFS and could stratify patients underwent postoperative radiotherapy into the high- and low-risk groups with significantly different clinical outcomes.

The role and mechanism of TLR4-siRNA in the impairment of learning and memory in young mice induced by isoflurane.

Isoflurane can significantly induce inflammation in children without surgical stress. The toll-like receptor 4 (TLR4) is closely related to noninfectious inflammation in the brain. To investigate the role of TLR4-small interfering RNA (siRNA) in learning and memory impairment in young mice induced by isoflurane. The C57 newborn mice were randomly allocated into normal control (control), isoflurane anesthesia (isoflurane), TLR4 interference empty vectorisoflurane anesthesia (siRNA-NC), and TLR4 interferenceisoflurane anesthesia (TLR-siRNA) groups. Their behavior and pathological condition were detected using Morris water maze and hematoxylin and eosin (HE) staining, respectively. The TLR4, brain-derived neurotrophic factor (BDNF) and cyclic adenosine monophosphate response element-binding protein 1 (CREB1) mRNA expressions were detected using quantitative real-time polymerase chain reaction (qRT-PCR). Serum tumor necrosis factor alpha (TNF-α) and interleukin (IL)-6 were detected by means of the enzyme-linked immunosorbent assay (ELISA). Apoptosis rate was detected with terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). The TLR4, TNF-α, IL-6, BDNF, CREB1, extracellular signal-regulated kinase 12 (ERK12), and c-Jun N-terminal kinase (JNK) protein expressions were detected using western blot (WB). Compared with the control group, the number of times the mice crossed the platform, and the time spent at the circumjacent area I and II of the platform were significantly decreased in the isoflurane group the TLR4, TNF-α and IL-6 expressions were significantly increased in the isoflurane group, as compared to control the results were reversed after the TLR4 interference. The hippocampal neurons in the isoflurane and siRNA-NC groups showed arrangement disorder and a high number of inflammatory infiltrates, while in the TLR-siRNA group they were closely and orderly arranged. Compared with the control group, the apoptosis rate and JNK protein expression in the isoflurane group were significantly increased, CREB1 protein expression was significantly decreased, and BDNF and ERK12 protein expressions showed no significant changes. Compared with the isoflurane group, the apoptosis rate of the TLR-siRNA group was significantly decreased, BDNF and CREB1 protein expressions were significantly increased, and ERK12 and JNK did not change significantly. Isoflurane stimulates the overexpression of inflammatory response factors, playing an important role in the cognitive impairment process. As a mediator of the innate immune inflammatory response, TLR4 plays an important role in the process of cell injury, which may be delayed by blocking the TLR4 signal.

The optimal therapy strategy for epidermal growth factor receptor-mutated non-small cell lung cancer patients with brain metastasis A real-world study from Taiwan.

The treatment options for epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) with brain metastases (BMs) include EGFR-tyrosine kinase inhibitors (TKIs), stereotactic radiosurgery (SRS), whole-brain radiotherapy, brain surgery, and antiangiogenesis therapy. As treatment options evolve, redefining optimal treatment strategies to improve survival are crucial. A total of 150 EGFR-mutant NSCLC patients with BMs who received first- or second-generation EGFR-TKIs as first-line treatment between January 2012 and October 2019 were included in this analysis. After multivariate analysis, patients with the graded prognostic assessment for lung cancer using molecular markers (Lung-mol GPA) ≥3 (hazard ratio HR 0.538, 95% confidence interval CI 0.35-0.83), who received afatinib or erlotinib as first-line treatment (HR 0.521, 95% CI 0.33-0.82), underwent SRS therapy (HR 0.531, 95% CI 0.32-0.87), or were sequentially treated with osimertinib (HR 0.400, 95% CI 0.23-0.71) were associated with improved overall survival (OS). Furthermore, SRS plus EGFR-TKI provided more OS benefits in patients with Lung-mol GPA ≥3 compared with EGFR-TKI alone in our patient cohort (44.9 vs. 26.7 months, p 0.005). The OS in patients who received sequential osimertinib therapy was significantly longer than those without osimertinib treatment (43.5 vs. 24.3 months, p < 0.001), regardless of T790 mutation status (positive vs. negative vs. unknown 40.4 vs. 54.6 vs.43.4 months, p 0.227). The study demonstrated that EGFR-mutant NSCLC patients with BMs could be precisely treated with SRS according to Lung-mol GPA ≥3. Sequential osimertinib was associated with prolonged survival, regardless of T790M status.

Exploiting 4-1BB immune checkpoint to enhance the efficacy of oncolytic virotherapy for diffuse intrinsic pontine gliomas.

Diffuse intrinsic pontine gliomas (DIPGs) are aggressive pediatric brain tumors, and patient survival has not changed despite many therapeutic efforts, emphasizing the urgent need for effective treatments. Here, we evaluated the anti-DIPG effect of the oncolytic adenovirus Delta-24-ACT, which was engineered to express the costimulatory ligand 4-1BBL to potentiate the antitumor immune response of the virus. Delta-24-ACT induced the expression of functional 4-1BBL on the membranes of infected DIPG cells, which enhanced the costimulation of CD8 T lymphocytes. In vivo, Delta-24-ACT treatment of murine DIPG orthotopic tumors significantly improved the survival of treated mice, leading to long-term survivors that developed immunological memory against these tumors. In addition, Delta-24-ACT was safe and caused no local or systemic toxicity. Mechanistic studies showed that Delta-24-ACT modulated the tumor-immune content, not only increasing the number, but also improving the functionality of immune cells. All of these data highlight the safety and potential therapeutic benefit of Delta-24-ACT the treatment of patients with DIPG.

PDGF-R inhibition induces glioblastoma cell differentiation via DUSP1p38

Glioblastoma (GBM) is the most common and fatal primary brain tumour in adults. Considering that resistance to current therapies leads to limited response in patients, new therapeutic options are urgently needed. In recent years, differentiation therapy has been proposed as an alternative for GBM treatment, with the aim of bringing cancer cells into a post-mitoticdifferentiated state, ultimately limiting tumour growth. As an integral component of cancer development and regulation of differentiation processes, kinases are potential targets of differentiation therapies. The present study describes how the screening of a panel of kinase inhibitors (KIs) identified PDGF-Rαβ inhibitor CP-673451 as a potential differentiation agent in GBM. We show that targeting PDGF-Rαβ with CP-673451 in vitro triggers outgrowth of neurite-like processes in GBM cell lines and GBM stem cells (GSCs), suggesting differentiation into neural-like cells, while reducing proliferation and invasion in 3D hyaluronic acid hydrogels. In addition, we report that treatment with CP-673451 improves the anti-tumour effects of temozolomide in vivo using a subcutaneous xenograft mouse model. RNA sequencing and follow-up proteomic analysis revealed that upregulation of phosphatase DUSP1 and consecutive downregulation of phosphorylated-p38

Malignant peripheral nerve sheath tumor models, biology, and translation.

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive, invasive cancer that comprise around 10% of all soft tissue sarcomas and develop in about 8-13% of patients with Neurofibromatosis Type 1. They are associated with poor prognosis and are the leading cause of mortality in NF1 patients. MPNSTs can also develop sporadically or following exposure to radiation. There is currently no effective targeted therapy to treat MPNSTs and surgical removal remains the mainstay treatment. Unfortunately, surgery is not always possible due to the size and location of the tumor, thus, a better understanding of MPNST initiation and development is required to design novel therapeutics. Here, we provide an overview of MPNST biology and genetics, discuss findings regarding the developmental origin of MPNST, and summarize the various model systems employed to study MPNST. Finally, we discuss current management strategies for MPNST, as well as recent developments in translating basic research findings into potential therapies.

Incidence and impact of brain metastasis in patients with hereditary BRCA1 or BRCA2 mutated invasive breast cancer.

Patients with hereditary mutations in BRCA1 or BRCA2 (gBRCA12) and breast cancer have distinct tumor biology, and encompass a predilection for brain metastasis (BM). We looked into baseline risk of BMs among gBRCA12 patients. Patients with gBRCA12, stage I-III invasive breast cancer seen between 2000-2017 with parenchymal BMs. Among gBRCA1 with distant breast cancer recurrence, 34 of 76 (44.7%) were diagnosed with brain metastases compared to 7 of 42 (16.7%) patients with gBRCA2. In the comparator group, 65 of 182 (35.7%) noncarrier triple-negative breast cancer (TNBC) and a distant recurrence experienced BMs. In a competitive risk analysis using death as a competing factor, the cumulative incidence of BMs was similar between gBRCA1 and noncarrier TNBC patients. The time from primary breast cancer diagnosis to detection of BMs was similar between gBRCA1 and noncarrier TNBC patients (2.4 vs 2.2 years). Survival was poor after BMs (7.8 months for gBRCA1 patients vs. 6.2 months for TNBC noncarriers). Brain was a more common site of initial distant recurrence in gBRCA1 patients versus TNBC noncarriers (26.3% vs. 12.1%). Importantly, the presence of BMs, adversely impacted overall survival across groups (HR 1.68 (95% CI 1.12-2.53), hazard ratio for death if a patient had BMs at the time of initial breast cancer recurrence vs. not). In conclusion, breast cancer BMs is common and is similarly frequent among gBRCA1 and noncarrier patients with recurrent TNBC. Our study highlights the importance of improving the prevention and treatment of BMs in patients with TNBC, gBRCA1 carriers, and noncarriers.

N6-isopentenyladenosine induces cell death through necroptosis in human glioblastoma cells.

Targeting necroptosis is considered a promising therapeutic strategy in cancer, including Glioblastoma Multiforme (GBM), one of the most lethal brain tumors. Necroptosis is a mechanism of programmed cell death overcoming the apoptosis resistance mechanism underlying GBM tumorigenesis and malignant progression. N6-isopentenyladenosine (iPA), adenosine modified with isoprenoid derivative, displays antitumor activity in different cancer models. In previous studies, we demonstrated that iPA interferes with EGFR signaling reducing glioma cell viability. Here, we show that iPA induces necroptosis in glioblastoma cell lines and in primary cells established from tumor explants, without affecting the viability of non-cancerous brain cell lines, (Normal Human Astrocyte). The activation of RIP1, RIP3, and MLKL and the upregulation of necrosome formation were increased upon iPA treatment while caspase-3, caspase-8, and PARP were not activated in GBM cells. Co-treatment with specific necroptosis inhibitor necrostatin-1 (Nec-1) or Necrosulfonamide (NSA) prevented cell death caused by iPA treatment while the general caspase inhibitor Z-VAD-fluoromethylketone (z-VAD-fmk) did not elicit any effect, suggesting that this molecule induces caspase-independent necroptosis. These results suggest that iPA treatment can be able to bypass the apoptosis resistance mechanism in glioblastoma thereby offering higher therapeutic efficacy.

Inhibition of the CEBPβ-NFκB interaction by nanocarrier-packaged Carnosic acid ameliorates glia-mediated neuroinflammation and improves cognitive function in an Alzheimers disease model.

Neuroinflammation occurs early in Alzheimers disease (AD). The initial stage of AD is related to glial dysfunction, which contributes to impairment of Aβ clearance and disruption of synaptic connection. CEBPβ, a member of the CCAAT-enhancer-binding protein (CEBP) family, modulates the expression of inflammation-associated genes, and its expression is elevated in brains undergoing degeneration and injured brains. However, the mechanism underlying CEBPβ-mediated chronic inflammation in AD is unclear. In this study, we observed that increases in the levels of nuclear CEBPβ facilitated the interaction of CEBPβ with the NFκB p65 subunit, increasing the transcription of proinflammatory cytokines in the APPPS1 mouse brain. Oral administration of nanocarrier-packaged carnosic acid (CA) reduced the aberrant activation of microglia and astrocytes and diminished mature IL-1β, TNFα and IL-6 production in the APPPS1 mouse brain. CA administration reduced β-amyloid (Aβ) deposition and ameliorated cognitive impairment in APPPS1 mice. We observed that CA blocked the interaction of CEBPβ with NFκB p65, and chromatin immunoprecipitation revealed that CA reduced the transcription of the NFκB target genes TNFα and IL-6. We confirmed that CA alleviated inflammatory mediator-induced neuronal degeneration and reduced Aβ secretion by inhibiting the CEBPβ-NFκB signalling pathway in vitro. Sulfobutyl ether-beta-cyclodextrin (SBEβCD) was used as the encapsulation agent for the CA-loaded nanocarrier to overcome the poor water solubility and enhance the brain bioavailability of CA. The CA nanoparticles (NPs) had no obvious toxicity. We demonstrated a feasible SBEβCD-based nanodelivery system targeting the brain. Our data provide experimental evidence that CA-loaded NPs are potential therapeutic agents for AD treatment.

Correlation of EGFR mutation subtypes and survival in surgically treated brain metastasis from non-small-cell lung cancer.

Epidermal growth factor receptor (EGFR) mutation is a positive prognostic factor for survival in patients with non-small-cell lung cancer (NSCLC). In such patients, brain metastasis signifies negative outcomes. Patients with NSCLC brain metastasis that may benefit from neurosurgery is under investigation. We aim to investigate the impact of different mutation loci in surgically treated NSCLC brain metastasis patients. This retrospective cohort study included patients with NSCLC brain metastasis who underwent brain lesionectomy, followed by radiotherapy and chemotherapy or targeted therapy. Demographics and tumor characteristics were compared between the EGFR mutant type and wild type groups. Postoperative survival and risk factors were analyzed using log rank and Cox regression methods. Overall, 101 patients were included, with 57 belonging to the EGFR mutant type group and 44 to the EGFR wild type group. The median postoperative survival was 17 months for the entire cohort, with the duration being 19 and 14 months for EGFR mutant type and wild type patients (p 0.013), respectively. Multivariate analysis revealed that exon 19 del (p 0.02) and a high Karnofsky Performance Scale score (p < 0.01) were independent positive prognostic factors to predict survival. The timing of development of the brain metastasis or the location of the intracranial metastasis was not associated with EGFR mutations. EGFR mutations are associated with better survival outcomes in patients with NSCLC brain metastasis suitable for surgical treatment. This advantage was attributed to patients having a specific mutation of exon 19 deletion.

LncRNA WEE2-AS1 Knockdown Inhibits the Proliferation, Migration and 3 Invasion of Glioma Cells via Regulating miR-29b-2-5pTPM3 Axis.

Glioma is a general malignant tumor with a dismal prognosis. Long noncoding RNAs (lncRNAs) have been implicated in the initiation and processes of tumors. An investigation of the GEPIA database revealed that long noncoding RNA WEE2 antisense RNA 1 (WEE2-AS1) is upregulated in glioma tissues compared to normal brain tissues, and validation with quantitative real-time polymerase chain reaction (qRT-PCR) revealed that WEE2-AS1 expression was consistent with the database prediction. Fluorescence in situ hybridization (FISH) assays revealed that WEE2-AS1 was localized primarily in the cytoplasm. Clone formation experiment and EDU assay were used to detect cell proliferation ability, and Transwell assay was used to detect cell migration and invasion ability, Western-blot assay and immunofluorescence were used to determine TPM3 protein level. Functional experiments revealed that the downregulation of WEE2-AS1 impeded cell proliferation, migration, and invasion in glioma cell lines. Furthermore, downregulation of WEE2-AS1 suppressed tumor growth in vivo. Bioinformatics predictions and integrated experiments indicated that WEE2-AS1 promoted tropomyosin 3 (TPM3) expression by sponging miR-29b-2-5p. A dual-luciferase reporter assay was conducted to uncover the binding of WEE2-AS1 and miR-29b-2-5p and that of miR-29b-2-5p and TPM3. Additionally, a series of rescue assays showed that WEE2-AS1 promotes proliferation, migration, and invasion by targeting miR-29b-2-5p to regulate TPM3 expression. Ultimately, the results of this study indicate that WEE2-AS1 plays an oncogenic role in glioma and may promote further investigations of the diagnostic and prognostic value of WEE2-AS1 in glioma.

A functional role of S100A4non-muscle myosin IIA axis for pro-tumorigenic vascular functions in glioblastoma.

Glioblastoma (GBM) is the most aggressive form of brain tumor and has vascular-rich features. The S100A4non-muscle myosin IIA (NMIIA) axis contributes to aggressive phenotypes in a variety of human malignancies, but little is known about its involvement in GBM tumorigenesis. Herein, we examined the role of the S100A4NMIIA axis during tumor progression and vasculogenesis in GBM. We performed immunohistochemistry for S100A4, NMIIA, and two hypoxic markers, hypoxia-inducible factor-1α (HIF-1α) and carbonic anhydrase 9 (CA9), in samples from 94 GBM cases. The functional impact of S100A4 knockdown and hypoxia were also assessed using a GBM cell line. In clinical GBM samples, overexpression of S100A4 and NMIIA was observed in both non-pseudopalisading (Ps) and Ps (-associated) perinecrotic lesions, consistent with stabilization of HIF-1α and CA9. CD34() microvascular densities (MVDs) and the interaction of S100A4 and NMIIA were significantly higher in non-Ps perinecrotic lesions compared to those in Ps perinecrotic areas. In non-Ps perinecrotic lesions, S100A4()HIF-1α(-) GBM cells were recruited to the surface of preexisting host vessels in the vascular-rich areas. Elevated vascular endothelial growth factor A (VEGFA) mRNA expression was found in S100A4()HIF-1α() GBM cells adjacent to the vascular-rich areas. In addition, GBM patients with high S100A4 protein expression had significantly worse OS and PFS than did patients with low S100A4 expression. Knockdown of S100A4 in the GBM cell line KS-1 decreased migration capability, concomitant with decreased Slug expression the opposite effects were elicited by blebbistatin-dependent inhibition of NMIIA. S100A4()HIF-1α(-) GBM cells are recruited to (and migrate along) preexisting vessels through inhibition of NMIIA activity. This is likely stimulated by extracellular VEGF that is released by S100A4()HIF-1α() tumor cells in non-Ps perinecrotic lesions. In turn, these events engender tumor progression via acceleration of pro-tumorigenic vascular functions. Video abstract.

Concomitant Temozolomide plus radiotherapy for high-grade and recurrent meningioma a retrospective chart review.

High-grade and recurrent meningiomas are often treatment resistant and pose a therapeutic challenge after surgical and radiation therapy (RT) failure. Temozolomide (TMZ) is a DNA alkylating agent that appears to have a radiosensitizing effect when used in combination with RT and may be worthwhile in meningioma treatment. Thus, we investigated the potential efficacy of concomitant RT plus TMZ compared to historical controls of just RT used in the treatment of high-grade and recurrent meningiomas. We performed a retrospective analysis of patients with meningioma treated at the University of Colorado with TMZ chemoradiation. Progression free survival (PFS) and overall survival (OS) were calculated from the start of chemoradiation to local recurrence or death, respectively. Eleven patients (12 tumors) were treated with chemoradiation with a median follow-up of 41.5 months. There were two WHO grade 1, eight grade 2 and two grade 3 meningiomas. Three patients died during the follow-up period-one being disease related (11.1%). Two patients had meningioma recurrence-at 2.3 months (WHO grade 3), and 5.4 years (WHO grade 2). Three-year OS and PFS for grade 2 meningiomas were each 88%. Historical controls demonstrate a 3-year median OS and PFS of 83% and 75.8%, respectively. Treatment options are limited for meningiomas after local failure. In this study, TMZ chemoradiation demonstrated no significant difference in PFS and OS in the treatment of grade 2 meningiomas compared to historic controls. Further study is warranted to find novel methods for the treatment of malignant and recurrent meningiomas.

Therapeutic Effect of Repetitive Transcranial Magnetic Stimulation for Post-stroke Vascular Cognitive Impairment A Prospective Pilot Study.

Post-stroke cognitive impairment (PSCI) is resistant to treatment. Recent studies have widely applied repetitive transcranial magnetic stimulation (rTMS) to treat various brain dysfunctions, such as post-stroke syndromes. Nonetheless, a protocol for PSCI has not been established. Therefore, this study is aimed to evaluate the therapeutic effect of our high-frequency rTMS protocol for PSCI during the chronic phase of stroke. In this prospective study, ten patients with PSCI were enrolled and received high-frequency rTMS on the ipsilesional dorsolateral prefrontal cortex (DLPFC) for 10 sessions (5 days per week for 2 weeks). Cognitive and affective abilities were assessed at baseline and 2 and 14 weeks after rTMS initiation. To investigate the therapeutic mechanism of rTMS, the mRNA levels of pro-inflammatory cytokines (interleukin (IL)-6, IL-1β, transforming growth factor beta TGF-β, and tumor necrosis factor alpha TNF-α) in peripheral blood samples were quantified using reverse transcription polymerase chain reaction, and cognitive functional magnetic resonance imaging (fMRI) was conducted at baseline and 14 weeks in two randomly selected patients after rTMS treatment. The scores of several cognitive evaluations, i.e., the Intelligence Quotient (IQ) of Wechsler Adult Intelligence Scale, auditory verbal learning test (AVLT), and complex figure copy test (CFT), were increased after completion of the rTMS session. After 3 months, these improvements were sustained, and scores on the Mini-Mental Status Examination and Montreal Cognitive Assessment (MoCA) were also increased ( High-frequency rTMS on the ipsilesional DLPFC may exert immediate efficacy on cognition with the anti-inflammatory response and changes in brain network in PSCI, lasting at least 3 months.

Neuroinflammation, Sleep, and Circadian Rhythms.

Molecules involved in innate immunity affect sleep and circadian oscillators and vice versa. Sleep-inducing inflammatory molecules are activated by increased waking activity and pathogens. Pathologies that alter inflammatory molecules, such as traumatic brain injury, cancer, cardiovascular disease, and stroke often are associated with disturbed sleep and electroencephalogram power spectra. Moreover, sleep disorders, such as insomnia and sleep disordered breathing, are associated with increased dysregulation of inflammatory processes. Inflammatory molecules in both the central nervous system and periphery can alter sleep. Inflammation can also modulate cerebral vascular hemodynamics which is associated with alterations in electroencephalogram power spectra. However, further research is needed to determine the interactions of sleep regulatory inflammatory molecules and circadian clocks. The purpose of this review is to 1) describe the role of the inflammatory cytokines interleukin-1 beta and tumor necrosis factor-alpha and nucleotide-binding domain and leucine-rich repeat protein-3 inflammasomes in sleep regulation, 2) to discuss the relationship between the vagus nerve in translating inflammatory signals between the periphery and central nervous system to alter sleep, and 3) to present information about the relationship between cerebral vascular hemodynamics and the electroencephalogram during sleep.

Magnetic Resonance Imaging Correlates of Immune Microenvironment in Glioblastoma.

Glioblastoma (GBM) is the most commonly occurring primary malignant brain tumor, and it carries a dismal prognosis. Focusing on the tumor microenvironment may provide new insights into pathogenesis, but no clinical tools are available to do this. We hypothesized that the infiltration of different leukocyte populations in the tumoral and peritumoral brain tissues may be measured by magnetic resonance imaging (MRI). Pre-operative MRI was combined with immune phenotyping of intraoperative tumor tissue based on flow cytometry of myeloid cell populations that are associated with immune suppression, namely, microglia and bone marrow-derived macrophages (BMDM). These cell populations were measured from the central and marginal areas of the lesion identified intraoperatively with 5-aminolevulinic acid-guided surgery. MRI features (volume, mean and standard deviation of signal intensity, and fractality) were derived from all MR sequences (T1w, Gd T1w, T2w, FLAIR) and ADC MR maps and from different tumor areas (contrast- and non-contrast-enhancing tumor, necrosis, and edema). The principal components of MRI features were correlated with different myeloid cell populations by Pearsons correlation. We analyzed 126 samples from 62 GBM patients. The ratio between BMDM and microglia decreases significantly from the central core to the periphery. Several MRI-derived principal components were significantly correlated (p <0.05, r range -0.29, -0.41) with the BMDMmicroglia ratio collected in the central part of the tumor. We report a significant correlation between structural MRI clinical imaging and the ratio of recruited vs. resident macrophages with different immunomodulatory activities. MRI features may represent a novel tool for investigating the microenvironment of GBM.

PKM2 Interacts With the Cdk1-CyclinB Complex to Facilitate Cell Cycle Progression in Gliomas.

PKM2 is a phosphotyrosine-binding glycolytic enzyme upregulated in many cancers, including glioma, and contributes to tumor growth by regulating cell cycle progression. We noted, however, that in multiple glioma cell lines, PKM2 knock-down resulted in an accumulation of cells in G2-M phase. Moreover, PKM2 knock-down decreased Cdk1 activity while introducing a constitutively active Cdk1 reversed the effects of PKM2 knock-down on cell cycle progression. The means by which PKM2 increases Cdk1 activity have not been described. Transient interaction of T14Y15-phosphorylated Cdk1 with cyclin B allows Cdk7-mediated pT161 Cdk1 phosphorylation followed by cdc25C-mediated removal of pT14Y15 and activation of Cdk1 in cycling cells. In the present course of investigation, PKM2 modulation did not influence Cdk7 activity, but phosphotyrosine binding forms of PKM2 co-immunoprecipitated with pY15-containing Cdk1-cyclinB and enhanced formation of active pT161 Cdk1-cyclin B complexes. Moreover, exogenous expression of phosphotyrosine binding forms of PKM2 reversed the effects of PKM2 knock-down on G2-M arrest. We here show that PKM2 binds and stabilize otherwise transient pY15-containing Cdk1-cyclinB complexes that in turn facilitate Cdk1-cyclin B activation and entry of cells into mitosis. These results, therefore, establish metabolic enzyme PKM2 as a direct interactor and activator of Cdk1-cyclin B complex and thereby directly controls mitotic progression and the growth of brain tumor cells.