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The clinicopathological spectrum of sclerosing epithelioid fibrosarcoma report of an additional series with review of the literature.

We present a case series of sclerosing epithelioid fibrosarcoma (SEF) to further characterise its clinical and pathological features. Twenty-one patients with SEF were included in this study. There were 12 males and nine females (range 25-63 years median 38 years). Tumours were located in the kidney (n5), thigh (n3), chest wall (n3), head and neck (n2), bone (n2), abdominal wall (n1), psoas major (n1), retroperitoneum (n1), omentum (n1), popliteal space (n1) and lung (n1). Tumour sizes ranged from 2.5 to 16 cm (median 7 cm). Microscopically, epithelioid tumour cells were arranged in nests and cords and embedded in a dense sclerotic stroma. Some tumours showed myxoid areas, fibroma-like areas, acinar growth patterns and haemangiopericytoma-like appearance. A few tumour cells presented a rhabdomyoid shape. Calcification, ossification, cystic and necrosis were observed in some cases. The diagnosis was confirmed by immunoreactivity for MUC4, and by further fluorescence in situ hybridisation (FISH) or next generation sequencing (NGS) analysis. Clinical follow-up was available for 16 cases (median, 24 months range 6-62 months). Seven patients developed metastases to lung (n3), bone (n3), brain (n2) and back (n1). Four patients developed a local recurrence. Three patients died of disease. Overall survival (OS) of SEF was related to patient age (p0.001) and progression-free survival (PFS) was related to tumour size (p0.046). In addition to soft tissue, SEF is more likely to involve the viscera and the abdominal cavity and has morphological variants. Familiarity with its distinctive clinical and pathological features helps avoid misdiagnosis.

Comparison of intensity-modulated radiation therapy (IMRT), 3D conformal proton therapy and intensity-modulated proton therapy (IMPT) for the treatment of metastatic brain cancer.

The purpose of this study has been to compare photon intensity modulated radiation therapy (IMRT) against both conformal and intensity modulated proton therapy (IMPT) plans for metastatic brain cancer. Ten IMRT patients with brain cancer were chosen retrospectively, with prescription doses in the range of 20 to 40 Gy, delivered in 3 to 5 fractions using Varian TrueBeam STx machine. Three proton plans with proton double scattering, single collimation static-IMPT, and energy layer by layer collimation dynamic-IMPT were then generated for the same patients using the Mevion S250 system for conformal plans and the S250i system for IMPT plans. Each plan had respective treatment planning systems that include Brainlab iPlan for IMRT, Varian Eclipse for proton double scattering, and RaySearch Raystation for IMPT. Dosimetric and radiobiologic comparisons were made through dose-volume histogram (DVH) analysis of the target and the organs at risk (OAR) and with parameters of equivalent uniform dose (EUD), tumor control probability (TCP), and normal tissue complication probability (NTCP), respectively. A set of variables αβ ratio, survival fraction, and clonogenic cell density were selected and varied to observe their effect on the abovementioned parameters. Doses were observed to be more homogeneous for patients with brain malignancies with photon IMRT treatments, while dose conformity is improved with proton PBS treatments. Normal tissue is, on average, spared more through both proton treatment options. The minimum doses, closely approximated by dose to 98% of the target volume, are similar across treatment modalities with slight variations.

Natural Course and Prognosis of Primary Spinal Glioblastoma A Nationwide Study.

Primary spinal glioblastoma is extremely rare. The dramatic neurological deterioration and unresectability of primary spinal glioblastoma makes it a particularly disabling malignant neoplasm. Since it is a rare and heterogeneous disease, the assessment of prognostic factors remains limited. Primary spinal glioblastomas were identified from The French Brain Tumor Database and the Club de Neuro-Oncologie of the Société Française de Neurochirurgie retrospectively. Inclusion criteria were age ≥ 18 years at diagnosis, spinal location, histopathological diagnosis of newly glioblastoma according to the 2016 World Health Organization classification, and surgical management between 2004 and 2016. Diagnosis was confirmed by a centralized neuropathological review. The primary outcome was overall survival. Therapeutic interventions and neurological outcomes were also collected. Thirty-three patients with an histopathologically confirmed primary spinal glioblastoma (median age 50.9 years) were included (27 centers). The median overall survival (OS) was 13.1 months (range 2.5-23.7) and the median progression-free survival was 5.9 months (range 1.6-10.2). In multivariable analyses using Cox model, ECOG PS at 0-1 was the only independent predictor of longer OS Hazard Ratio 0.13, 95%CI 0.02-0.801 p0.02, whereas a Karnofsky PS score <60 Hazard Ratio 2.89, 95%CI 1.05-7.92 p0.03 and a cervical anatomical location Hazard Ratio 4.14, 95%CI 1.32-12.98 p0.01 were independent predictors of shorter OS. The ambulatory status (Frankel D-E) Hazard Ratio 0.38, 95%CI 0.07-1.985 p0.250 was not an independent prognostic factor while the concomitant standard radiochemotherapy with temozolomide (Stupp protocol) Hazard Ratio 0.35, 95%CI 0.118-1.05 p0.06 was at the limit of significance. Preoperative ECOG PS, Karnofsky PS score and the location are independent predictors of overall survival of primary spinal glioblastomas in adults. Further analyses are required to capture the survival benefit of concomitant standard radiochemotherapy with temozolomide.

What is the Best Preoperative Quantitative Indicator to Differentiate Primary Central Nervous System Lymphoma from Glioblastoma

The role of surgery in primary central nervous system lymphoma (PCNSL) is to allow pathological diagnosis from tumor biopsy. However, PCNSL is often difficult to distinguish from other tumors, particularly glioblastoma multiforme (GBM). Quantitative evaluations to facilitate differentiation between PCNSL and GBM would be useful. Here, we investigated the best examinations for exact differentiation of PCNSL from GBM among preoperative examinations, including imaging studies and tumor markers. Various examinations were performed for 68 patients with PCNSL , including serum soluble interleukin 2 receptor, β2-microglobulin (MG) in cerebrospinal fluid (CSF), diffusion-weighted imaging, CSF β2-MG ≥2.0 mgL was relatively specific for PCNSL, offering 95.0% sensitivity and 85.7% specificity. Tumor-to-contralateral normal brain tissue ratio ≥2.4 on Both β2-MG ≥2.0 mgdL in CSF and tumor-to-contralateral normal brain tissue ratio ≥2.4 from

Cancer-associated SMARCAL1 loss-of-function mutations promote alternative lengthening of telomeres and tumorigenesis in telomerase-negative glioblastoma cells.

Telomere maintenance mechanisms are required to enable the replicative immortality of malignant cells. While most cancers activate the enzyme telomerase, a subset of cancers use telomerase-independent mechanisms termed alternative lengthening of telomeres (ALT). ALT occurs via homology directed-repair mechanisms and is frequently associated with ATRX mutations. We previously showed that a subset of adult GBM patients with ATRX-expressing ALT-positive tumors harbored loss-of-function mutations in the SMARCAL1 gene, which encodes an annealing helicase involved in replication fork remodeling and the resolution of replication stress. However, the causative relationship between SMARCAL1 deficiency, tumorigenesis, and de novo telomere synthesis is not understood. We used a patient-derived ALT-positive GBM cell line with native SMARCAL1 deficiency to investigate the role of SMARCAL1 in ALT-mediated de novo telomere synthesis, replication stress, and gliomagenesis in vivo. Inducible rescue of SMARCAL1 expression suppresses ALT indicators and inhibits de novo telomere synthesis in GBM and osteosarcoma cells, suggesting that SMARCAL1 deficiency plays a functional role in ALT induction in cancers that natively lack SMARCAL1 function. SMARCAL1-deficient ALT-positive cells can be serially propagated in vivo in the absence of detectable telomerase activity, demonstrating that the SMARCAL1-deficient ALT phenotype maintains telomeres in a manner that promotes tumorigenesis. SMARCAL1 deficiency is permissive to ALT and promote gliomagenesis. Inducible rescue of SMARCAL1 in ALT-positive cell lines permits the dynamic modulation of ALT activity, which will be valuable for future studies aimed at understanding the mechanisms of ALT and identifying novel anti-cancer therapeutics that target the ALT phenotype.

Vitamin D3 improves spatial memory and modulates cytokine levels in aged rats.

Vitamin D3 deficiency is associated with an increased risk of dementia. An association between vitamin D3 deficiency and subjective cognitive complaints in geriatric patients has been previously reported. This study aimed to evaluate the effects of two doses of vitamin D3 on spatial memory (using the Radial Maze) and cytokine levels tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and interleukin-10 (IL-10) on 2-, 6-, 13-, 22-, and 31-month-old male Wistar rats. Animals were supplemented with vitamin D3 at doses of 42 IUkg and 420 IUkg for 21 days. A radial maze test was performed to evaluate spatial memory. After the behavioral test, the frontal cortex and hippocampus were dissected for enzyme immunoassay analyses to measure the cytokine levels (TNFα, IL-1β, IL-6, and IL-10). Our results showed that vitamin D3 supplementation reversed spatial memory impairment at the supplemented doses (42 and 420 IUkg) in 6-, 13-, and 22-month-old animals and at a dose of 420 IUkg in 31-month-old animals. The lower dose (42 IUkg) regulates both pro- and anti-inflammatory cytokines mainly in the frontal cortex. Our results suggest that vitamin D3 has a modulatory action on pro- and anti-inflammatory cytokines, since older animals showed increased cytokine levels compared to 2-month-old animals, and that vitamin D3 may exert an immunomodulatory effect on aging.

Imaging pathologies of the corpus callosum.

The corpus callosum is the largest fiber bundle in the cerebral white matter in the human brain. A multitude of disorders including congenital malformations, acute and chronic traumatic lesions, ischemia, neoplasms, secondary manifestations of metabolic, toxic or degenerative diseases as well as chronic inflammatory and demyelinating diseases can primarily or secondarily affect the corpus callosum. This article presents magnetic resonance imaging (MRI) characteristics of the most relevant diseases affecting the corpus callosum. Das Corpus callosum ist die größte gebündelte Struktur der weißen Substanz des menschlichen Gehirns. Eine Vielzahl Erkrankungen, darunter angeborene Malformationen, akute und chronische traumatische Läsionen, Ischämien, Neoplasien, sekundäre Manifestationen metabolischer, toxischer oder degenerativer Erkrankungen oder auch chronisch entzündliche und demyelinisierende Erkrankungen, betreffen unter anderem oder hauptsächlich das Corpus callosum. In diesem Beitrag werden die charakteristischen magnetresonanztomographisch-morphologischen Befunde von Erkrankungen, die sich typischerweise im Corpus callosum manifestieren, vorgestellt.

Tumor-Antigen Activated Dendritic Cell Membrane-Coated Biomimetic Nanoparticles with Orchestrating Immune Responses Promote Therapeutic Efficacy against Glioma.

Immunotherapy has had a profound positive effect on certain types of cancer but has not improved the outcomes of glioma because of the blood-brain barrier (BBB) and immunosuppressive tumor microenvironment. In this study, we developed an activated mature dendritic cell membrane (aDCM)-coated nanoplatform, rapamycin (RAPA)-loaded poly(lactic-

Imaging phenotypes from MRI for the prediction of glioma immune subtypes from RNA sequencing A multicenter study.

Tumor subtyping based on its immune landscape may guide precision immunotherapy. The aims of this study were to identify immune subtypes of adult diffuse gliomas with RNA sequencing data, and to noninvasively predict this subtype using a biologically interpretable radiomic signature from MRI. A subtype discovery dataset (n 210) from a public database and two radiogenomic datasets (n 130 and 55, respectively) from two local hospitals were included. Brain tumor microenvironment-specific signatures were constructed from RNA sequencing to identify the immune types. A radiomic signature was built from MRI to predict the identified immune subtypes. The pathways underlying the radiomic signature were identified to annotate their biological meanings. The reproducibility of the findings was verified externally in multicenter datasets. Three distinctive immune subtypes were identified, including an inflamed subtype marked by elevated hypoxia-induced immunosuppression, a cold subtype that exhibited scarce immune infiltration with downregulated antigen presentation, and an intermediate subtype that showed medium immune infiltration. A 10-feature radiomic signature was developed to predict immune subtypes, achieving an AUC of 0.924 in the validation dataset. The radiomic features correlated with biological functions underpinning immune suppression, which substantiated the hypothesis that molecular changes can be reflected by radiomic features. The immune subtypes, predictive radiomic signature, and radiomics-correlated biological pathways were validated externally. Our data suggest that adult-type diffuse gliomas harbor three distinctive immune subtypes that can be predicted by MRI radiomic features with clear biological significance. The immune subtypes, radiomic signature, and radiogenomic links can be replicated externally.

Efficacy and Safety of East Asian Herbal Medicine for Brain Metastases in Non-small Cell Lung Cancer A Systematic Review and Meta-analysis Protocol to Identify Specific Herbs.

Brain metastasis (BM) is a significant risk factor for survival and prognosis in non-small cell lung cancer (NSCLC). While surgical resection and radiotherapy are the primary treatment modalities, the overall prognosis in NSCLC patients with BM remains poor, and all therapies lead to adverse events. East Asian herbal medicine (EAHM) has broad prospects as an adjuvant treatment, but its efficacy and safety remain controversial. We propose to conduct a systematic review and meta-analysis to summarize the clinical efficacy and safety of EAHM for the treatment of NSCLC with BMs and to identify specific herbs that can improve the prognosis. The PubMed, EMBASE, CENTRAL, Web of Science, CBM, CNKI, Wanfang, VIP, Evidence Reports on Kampo Treatment, ICHUSHI, and Oriental Medicine Advanced Searching Integrated System databases will be searched from their inception to October 2022. Randomized controlled trials will be included. Two authors will evaluate the eligibility and quality of the included trials. The methodological quality will be assessed using the RoB 2 tool, and Stata 16 will be used for data synthesis. Publication bias will be assessed using funnel plots and Egger tests. The GRADE (Grading of Recommendations Assessment, Development, and Evaluation) system will evaluate the quality of the synthesized evidence. Further sensitivity analyses will be performed to determine the efficacies of specific herbs in EAHM. Given there are currently no systematic reviews and meta-analyses of the efficacy of EAHM as a treatment for NSCLC with BMs, a compilation and analysis of the available high-quality clinical research evidence are essential. The results will help establish guidelines for the application of specific herbs as a complementary alternative therapy for BMs in NSCLC. The findings will be published in a peer-reviewed journal. CRD42022300527.

Cancer stem cells, not bulk tumor cells, determine mechanisms of resistance to SMO inhibitors.

The emergence of treatment resistance significantly reduces the clinical utility of many effective targeted therapies. Although both genetic and epigenetic mechanisms of drug resistance have been reported, whether these mechanisms are stochastically selected in individual tumors or governed by a predictable underlying principle is unknown. Here, we report that the dependence of cancer stem cells (CSCs), not bulk tumor cells, on the targeted pathway determines the molecular mechanism of resistance in individual tumors. Using both spontaneous and transplantable mouse models of sonic hedgehog (SHH) medulloblastoma (MB) treated with an SHHSmoothened inhibitor, sonidegibLDE225, we show that genetic-based resistance occurs only in tumors that contain SHH-dependent CSCs (SD-CSCs). In contrast, SHH MBs containing SHH-dependent bulk tumor cells but SHH-independent CSCs (SI-CSCs) acquire resistance through epigenetic reprogramming. Mechanistically, elevated proteasome activity in SMOi-resistant SI-CSC MBs alters the tumor cell maturation trajectory through enhanced degradation of specific epigenetic regulators, including histone acetylation machinery components, resulting in global reductions in H3K9Ac, H3K14Ac, H3K56Ac, H4K5Ac, and H4K8Ac marks and gene expression changes. These results provide new insights into how selective pressure on distinct tumor cell populations contributes to different mechanisms of resistance to targeted therapies. This insight provides a new conceptual framework to understand responses and resistance to SMOis and other targeted therapies.

Genomic study and lipidomic bioassay of

The fraction of low-abundance microbiota in the marine environment is a promising target for discovering new bioactive molecules with pharmaceutical applications. Phenomena in the ocean such as diel vertical migration (DVM) and seasonal dynamic events influence the pattern of diversity of marine bacteria, conditioning the probability of isolation of uncultured bacteria. In this study, we report a new marine bacterium belonging to the rare biosphere,

Translational potential of synaptic alterations in Alzheimers disease patients and amyloid precursor protein knock-in mice.

Synaptic dysfunction is an early event in Alzheimers disease. Post-mortem studies suggest that alterations in synaptic proteins are associated with cognitive decline in Alzheimers disease. We measured the concentration of three synaptic proteins, zinc transporter protein 3, dynamin1 and AMPA glutamate receptor 3 in cerebrospinal fluid of subjects with mild cognitive impairment (

Lung cancer patients are at risk for brain metastases and often succumb to their intracranial disease. Chimeric Antigen Receptor (CAR) T-cells emerged as a powerful cell-based immunotherapy for hematological malignancies however, it remains unclear whether CAR T-cells represent a viable therapy for brain metastases. Here, we established a syngeneic orthotopic cerebral metastasis model in mice by combining a chronic cranial window with repetitive intracerebral two-photon laser scanning-microscopy. This approach enabled

MRI radiomic features of peritumoral edema may predict the recurrence sites of glioblastoma multiforme.

As one of the most aggressive malignant tumor in the central nervous system, the main cause of poor outcome of glioblastoma (GBM) is recurrence, a non-invasive method which can predict the area of recurrence pre-operation is necessary.To investigate whether there is radiological heterogeneity within peritumoral edema and identify the reproducible radiomic features predictive of the sites of recurrence of glioblastoma(GBM), which may be of value to optimize patients management. The clinical information and MR images (contrast-enhanced T1 weighted and FLAIR sequences) of 22 patients who have been histologically proven glioblastoma, were retrospectively evaluated. Kaplan-Meier methods was used for survival analysis. Oedematous regions were manually segmented by an expert into recurrence region, non-recurrence region. A set of 94 radiomic features were obtained from each region using the function of analyzing MR image of 3D slicer. Paired t test was performed to identify the features existing significant difference. Subsequently, the data of two patients from TCGA database was used to evaluate whether these features have clinical value. Ten features with significant differences between the recurrence and non-recurrence subregions were identified and verified on two individual patients from the TCGA database with pathologically confirmed diagnosis of GBM. Our results suggested that heterogeneity does exist in peritumoral edema, indicating that the radiomic features of peritumoral edema from routine MR images can be utilized to predict the sites of GBM recurrence. Our findings may further guide the surgical treatment strategy for GBM.

The impact of 1.5-T intraoperative magnetic resonance imaging in pediatric tumor surgery Safety, utility, and challenges.

In this study, we present our experience with 1.5-T high-field intraoperative magnetic resonance imaging (ioMRI) for different neuro-oncological procedures in a pediatric population, and we discuss the safety, utility, and challenges of this intraoperative imaging technology. A pediatric consecutive-case series of neuro-oncological surgeries performed between February 2020 and May 2022 was analyzed from a prospective ioMRI registry. Patients were divided into four groups according to the surgical procedure intracranial tumors (group 1), intraspinal tumors (group 2), stereotactic biopsy for unresectable tumors (group 3), and catheter placement for cystic tumors (group 4). The goal of surgery, the volume of residual tumor, preoperative and discharge neurological status, and postoperative complications related to ioMRI were evaluated. A total of 146 procedures with ioMRI were performed during this period. Of these, 62 were oncology surgeries 45 in group 1, two in group 2, 10 in group 3, and five in group 4. The mean age of our patients was 8.91 years, with the youngest being 12 months. ioMRI identified residual tumors and prompted further resection in 14% of the cases. The mean time for intraoperative image processing was 54 ± 6 min. There were no intra- or postoperative security incidents related to the use of ioMRI. The reoperation rate in the early postoperative period was 0%. ioMRI in pediatric neuro-oncology surgery is a safe and reliable tool. Its routine use maximized the extent of tumor resection and did not result in increased neurological deficits or complications in our series. The main limitations included the need for strict safety protocols in a highly complex surgical environment as well as the inherent limitations on certain patient positions with available MR-compatible headrests.

Peliminary exploration on the differential diagnosis between meningioma and schwannoma using contrast-enhanced T

Contrast-enhanced T To quantify the pre-operative imaging features of intratumoral microbleeds and intratumoral vessels using CE-T The ICC of intratumoral vessels count and intratumoral microbleeds count were 0.89 and 0.99, respectively. There were significant differences in the number of intratumoral microbleeds ( CE-T

Case Report Pituitary metastasis as a presenting manifestation of silent gastric cardia adenocarcinoma.

Pituitary metastases are very rare in cancer patients and often originate from lung or breast tumors. They usually occur in patients with known metastatic disease, but rarely may be the first presentation of the primary tumor. We present the case of a 58 years-old-man who reported a three-month history of polyuria-polydipsia syndrome, generalized asthenia, panhypopituitarism and bitemporal hemianopsia. Brain-MRI showed a voluminous pituitary mass causing posterior sellar enlargement and compression of the surrounding structures including pituitary stalk, optic chiasm, and optic nerves. The patient underwent neurosurgical removal of the mass. Histological examination revealed a poorly differentiated adenocarcinoma of uncertain origin. A total body CT scan showed a mass in the left kidney that was subsequently removed. Histological features were consistent with a clear cell carcinoma. However, endoscopic examination of the digestive tract revealed an ulcerating and infiltrating adenocarcinoma of the gastric cardia. Total body PETCT scan with 18F-FDG confirmed an isolated area of accumulation in the gastric cardia, with no hyperaccumulation at other sites. To the best of our knowledge, there are no reports of pituitary metastases from gastric cardia adenocarcinoma. Our patient presented with symptoms of sellar involvement and without evidence of other body metastases. Therefore, sudden onset of diabetes insipidus and visual deterioration should lead to the suspicion of a rapidly growing pituitary mass, which may be the presenting manifestation of a primary extracranial adenocarcinoma. Histological investigation of the pituitary mass can guide the diagnostic workup, which must however be complete.

Case report Primary intracranial mucosa-associated lymphoid tissue lymphoma presenting as two primary tumors involving the cavernous sinus and extra-axial dura, respectively.

Primary intracranial mucosa-associated lymphoid tissue (MALT) lymphoma is a rare type of brain tumor, with only a few reported cases worldwide that mostly have only one lesion with conventional magnetic resonance imaging (MRI) findings. Here, we present a special case of intracranial MALT lymphoma with two mass lesions radiographically consistent with meningiomas on MRI before the operation. A 66-year-old woman was admitted to the hospital with intermittent right facial pain for 1 year, aggravated for the last month. Brain MRI showed two extracerebral solid masses with similar MR signal intensity. One mass was crescent-shaped beneath the skull, and the other was in the cavernous sinus area. Lesions showed isointensity on T1WI and T2WI and an intense homogeneous enhancement after contrast agent injection. Both lesions showed hyperintensity in amide proton transfer-weighted images. The two masses were all surgically resected. The postoperative pathology indicated extranodal marginal zone B-cell lymphoma of MALT. To improve awareness of intracranial MALT lymphoma in the differential diagnosis of extra-axial lesions among clinicians, we present this report and briefly summarize previously reported cases to describe the clinical, pathological, radiological, and treatment features.

A novel risk model based on the correlation between the expression of basement membrane genes and immune infiltration to predict the invasiveness of pituitary adenomas.

Invasive pituitary adenomas (IPAs) are common tumors of the nervous system tumors for which invasive growth can lead to difficult total resection and a high recurrence rate. The basement membrane (BM) is a special type of extracellular matrix and plays an important role in the invasion of pituitary adenomas (PAs). The aim of this study was to develop a risk model for predicting the invasiveness of PAs by analyzing the correlation between the expression of BM genes and immune infiltration. Four datasets, featuring samples IPAs and non-invasive pituitary adenomas (NIPAs), were obtained from the Gene Expression Omnibus database (GEO). R software was then used to identify differentially expressed genes (DEGs) and analyze their functional enrichment. Protein-protein interaction (PPI) network was used to screen BM genes, which were analyzed for immune infiltration this led to the generation of a risk model based on the correlation between the expression of BM genes and immunity. A calibration curve and receiver operating characteristic (ROC) curve were used to evaluate and validate the model. Subsequently, the differential expression levels of BM genes between IPA and NIPA samples collected in surgery were verified by Quantitative Polymerase Chain Reaction (qPCR) and the prediction model was further evaluated. Finally, based on our analysis, we recommend potential drug targets for the treatment of IPAs. The merged dataset identified 248 DEGs that were mainly enriching in signal transduction, the extracellular matrix and channel activity. The PPI network identified 11 BM genes from the DEGs Using a variety of bioinformatics methods, we developed a novel risk model to predict the probability of PAs invasion based on the correlation between 11 BM genes and immune infiltration. These findings may facilitate closer surveillance and early diagnosis to prevent or treat IPAs in patients and improve the clinical awareness of patients at high risk of IPAs.

Survey of understanding and awareness of fertility preservation in pediatric patients Is conversation about fertility preservation unpleasant for pediatric patients

To verify understanding and awareness of fertility preservation (FP) in pediatric patients undergoing FP treatments. A questionnaire survey was conducted before and after explanation of fertility issues and FP treatments for patients 6-17 years old who visited or were hospitalized for the purpose of ovarian tissue cryopreservation (OTC) or oocyte cryopreservation (OC), or sperm cryopreservation between October 2018 and April 2022. This study was approved by the institutional review board at St. Marianna University School of Medicine (No. 4123, UMIN000046125). Participants in the study comprised 36 children (34 girls, 2 boys). Overall mean age was 13.3 ± 3.0 years. The underlying diseases were diverse, with leukemia in 14 patients (38.9%), brain tumor in 4 patients (11.1%). The questionnaire survey before the explanation showed that 19 patients (52.8%) wanted to have children in the future, but 15 (41.7%) were unsure of future wishes to raise children. And most children expressed some degree of understanding of the treatment being planned for the underlying disease (34, 94.4%). Similarly, most children understood that the treatment would affect their fertility (33, 91.7%). When asked if they would like to hear a story about how to become a mother or father after FP which including information of FP, half answered Dont mind (18, 50.0%). After being provided with information about FP treatment, all participants answered that they understood the adverse effects on fertility of treatments for the underlying disease. Regarding FP treatment, 32 children (88.9%) expressed understanding for FP and 26 (72.2%) wished to receive FP. Fear and Pain and Costs were frequently cited as concerns about FP. Following explanations, 33 children (91.7%) answered Happy I heard the story and no children answered, Wish I hadnt heard the story. Finally, 28 of the 34 girls (82.4%) underwent OTC and one girl underwent OC. The fact that all patients responded positively to the explanations of FP treatment is very informative. This is considered largely attributable to the patients themselves being involved in the decision-making process for FP. Explanations of FP for children appear valid if age-appropriate explanations are provided.

Anti-leucine-rich glioma inactivated protein 1 encephalitis with sleep disturbance as the first symptom A case report and review of literature.

Anti-leucine-rich glioma inactivated protein 1 (anti-LGI1) encephalitis is an infrequent type of autoimmune encephalitis (AE) characterized by acute or subacute cognitive and psychiatric disturbance, facio-brachial dystonic seizures (FBDSs), and hyponatremia. Anti-LGI1 AE has increasingly been considered a primary form of AE. Early identification and treatment of this disease are clearly very important. Here, we report that a male patient developed severe anti-LGI1 encephalitis, which was initially misdiagnosed as a sleep disturbance. He was hospitalized for epileptic seizures and typical FBDSs half a month after he developed sleep disturbances. LGI1 antibodies were detected in his cerebrospinal fluid and serum (1100 and 13.2, respectively), which led to the diagnosis of classic anti-LGI1 AE. No obvious abnormality was observed on brain computed tomography images. T2-weighted fluid-attenuated inversion recovery and T2-weighted scans of brain magnetic resonance imaging (MRI) showed slightly elevated signals within the left basal ganglia area. No tumor was detected within the brain of this patient using MRI. After hormone and antiepileptic drug treatment, the patients symptoms improved significantly. Anti-LGI1 antibody-associated encephalitis has characteristic clinical manifestations, such as cognitive impairment, psychiatric symptoms, seizures, sleep disorders, hyponatremia, and FBDSs. LGI1 antibodies are present in the serum andor cerebrospinal fluid, but their production is sensitive to immunosuppressants, and this disease has a relatively good prognosis. In particular, we should be aware of the possibility of anti-LGI1 antibody-associated encephalitis in adolescents with sleep disorders to avoid missed diagnoses and misdiagnoses.

Correlation of Target Volumes on Magnetic Resonance Imaging and Prostate-Specific Membrane Antigen Brain Scans in the Treatment Planning of Glioblastomas.

Imaging of gliomasglioblastomas has always been challenging. Many magnetic resonance imaging (MRI) techniques are available for imaging glioblastomas. MRI cannot always differentiate tumor from nonspecific changes and postoperative changes in brain tissue. Among the new positron emission tomography-computed tomography (PET-CT) tracers, gallium-68 prostate-specific membrane antigen (Ga-68 PSMA-11 PET-CT) appears to be the most promising one. The absence of uptake by normal brain parenchyma leads to high tumor-to-background ratio leading to better visualization of the tumor. The aim of this study was to assess the correlation of target volumes on MRI and PSMA brain scans in the treatment planning of glioblastomas. Twenty-four patients in the age group of 5-75 years with histologically proven glioblastoma were included in the study following maximum safe resection. Simulation for treatment planning was done with Ga-68 PSMA PET-CT brain with IV iodine-based contrast. The pre- and postoperative MRI images were fused with PSMA simulation images. Gross tumor volumes (GTVs) contoured on T1-contrast MRI and on PSMA scans were compared. GTV contoured on MRI and PSMA brain scans showed complete overlap in 17 patients. In seven patients, the target volumes drawn on Ga-68 PSMA brain scans were slightly smaller than the target volumes drawn on MRI brain scans. This difference in volumes could be due to postoperative changes which showed enhancement on the MRI scan. Ga-68 PSMA PET-CT shows good correlation with MRI brain in the evaluation and RT planning in glioblastomas. Tumor necrosis and postoperative changes did not show PSMA uptake. Precise target delineation on PSMA PET-CT can potentially result in smaller and more accurate GTVs, which in turn would result in less RT-induced side effects.

Vestibular Schwannoma Leading to Contacting Aneurysm Rupture An Unusual Presentation.

Subarachnoid hemorrhage (SAH) is a rare manifestation of brain tumors, being even rarer in vestibular schwannomas. We report the second case of a posterior circulation aneurysm close to the tumor capsule, responsible for SAH as an initial manifestation of a vestibular schwannoma. A 67-year-old female was admitted to the Emergency Department with sudden onset of nausea and headache. A diagnosis of a SAH and a tumor of the right cerebellopontine angle was made. An angiography showed an aneurysm in the dependency of the right anterior inferior cerebellar artery (AICA), juxtaposed to the tumor capsule. The patient underwent surgery, the tumor was removed, and the aneurysm was treated. This case highlights that SAH in patients with vestibular schwannoma may originate from a contact aneurysm. Although exceedingly rare, surgeons should consider this scenario in vestibular schwannoma presenting with SAH, and angiography is important for its diagnosis.

Fc gamma receptor IIb in tumor-associated macrophages and dendritic cells drives poor prognosis of recurrent glioblastoma through immune-associated signaling pathways.

Liquid biopsy in pediatric brain tumors.

Malignant primary brain tumors are the most common cancer in children aged 0-14 years, and are the most common cause of death among pediatric cancer patients. Compared to other cancers, pediatric brain tumors have been difficult to diagnose and study given the high risk of intracranial biopsy penetrating through vital midline structures, where the majority of pediatric brain tumors originate (Ostrom et al., 2015). Furthermore, the vast majority of these tumors recur. With limitations in the ability to monitor using clinical and radiographic methods alone, minimally invasive methods such as liquid biopsy will be crucial to our understanding and treatment. Liquid biopsy of blood, urine, and cerebrospinal fluid (CSF) can be used to sample cfDNA, ctDNA, RNA, extracellular vesicles, and tumor-associated proteins. In the past year, four seminal papers have made significant advances in the use of liquid biopsy in pediatric brain tumor patients (Liu et al., 2021 Cantor et al., 2022 Miller et al., 2022 Pagès et al., 2022). In this review, we integrate the results of these studies and others to discuss how the newest technologies in liquid biopsy are being developed for molecular diagnosis and treatment response in pediatric brain tumors.

Dapsone Protects Against Lithium-Pilocarpine-Induced Status Epilepticus in Rats through Targeting Tumor Necrosis Factor-α and Nitrergic Pathway.

Status epilepticus (SE) results in permanent neuronal brain damage in the central nervous system. One of the complex etiologies underlying SE pathogenesis is neuroinflammation. Dapsone has been recently considered as a potential neuroprotective agent in neuroinflammatory conditions. Therefore, the present study aims to investigate effects of dapsone on lithium-pilocarpine-induced SE in rats and assess whether tumor necrosis factor-alpha (TNF-α) and nitric oxide (NO) pathway participate in this effect. SE was established by injecting lithium chloride (127 mgkg, intraperitoneally i.p.) and pilocarpine (60 mgkg, i.p.). The animals received pre-treatment dapsone (2, 5, 10, and 20 mgkg, oral gavage) and post-treatment dapsone (10 mgkg). Subsequently, seizure score and mortality rate were documented. To assess the underlying signaling pathway, L-N Dapsone (10 mgkg) pre-and post-treatment significantly attenuated the increased seizure score and mortality rate due to lithium-pilocarpine-induced SE. The development of SE in animals was associated with higher TNF-α and NO metabolites levels, which notably decreased in the dapsone-treated rats. Moreover, co-administration of NOS inhibitors with dapsone markedly reversed the anti-epileptic effects of dapsone and caused an escalation in TNF-α level but a significant reduction in NO concentration level. It seems that dapsone may exert an anti-epileptic effect on lithium-pilocarpine-induced SE through TNF-α inhibition and modulation of the nitrergic pathway.

Glioma-derived CCL2 and CCL7 mediate migration of immune suppressive CCR2

Glioblastoma (GBM) is the most common and malignant primary brain tumor, resulting in poor survival despite aggressive therapies. GBM is characterized in part by a highly heterogeneous and immunosuppressive tumor microenvironment (TME) made up predominantly of infiltrating peripheral immune cells. One significant immune cell type that contributes to glioma immune evasion is a population of immunosuppressive, hematopoietic cells, termed myeloid-derived suppressor cells (MDSCs). Previous studies suggest that a potent subset of myeloid cells, expressing monocytic (M)-MDSC markers, distinguished by dual expression of chemokine receptors CCR2 and CX3CR1, utilize CCR2 to infiltrate into the TME. This study evaluated the T cell suppressive function and migratory properties of CCR2

Transcriptome and single-cell analysis reveal the contribution of immunosuppressive microenvironment for promoting glioblastoma progression.

GBM patients frequently exhibit severe local and systemic immunosuppression, limiting the possible efficacy of immunotherapy strategies. The mechanism through which immunosuppression is established in GBM tumors is the key to successful personalized immunotherapies. We divided GBM patients into subtypes according to the expression characteristics of the TME typing-related signature matrix. WGCNA analysis was used to get co-expressed gene modules. The expression activity of hub genes retrieved from co-expressed modules was validated in two single-cell datasets. Then, cell-cell interaction was calculated. Four subtypes were identified in the TCGA and CGGA RNA-seq datasets simultaneously, one of which was an immunosuppressive subtype rich in immunosuppressive factors with low lymphocyte infiltration and an IDH1 mutation. Three co-expressed gene modules related to the immunosuppressive subtype were identified. These three modules are associated with the inflammatory response, angiogenesis, hypoxia, and carbon metabolism, respectively. The genes of the inflammatory response were mainly related to myeloid cells, especially TAM, angiogenesis was related to blood vessels hypoxia and glucose metabolism were related to tumors, TAM, and blood vessels. Moreover, there was enhanced interaction between tumor cells and TAM. This research successfully found the immunosuppressive subtype and the major cell types, signal pathways, and molecules involved in the formation of the immunosuppressive subtype and will provide new clues for the improvement of GBM personalized immunotherapy in the future.

Serplulimab plus chemotherapy as first-line treatment for extensive-stage small-cell lung cancer A cost-effectiveness analysis.

The ASTRUM-005 trial (NCT04063163) revealed that combination serplulimab plus chemotherapy (etoposide and carboplatin EC) treatment was associated with survival advantages relative to chemotherapy alone in patients diagnosed with extensive-stage small-cell lung cancer (ES-SCLC). As these immuno-chemotherapeutic regimens are extremely expensive, however, it is critical that the relative cost-effectiveness of combination serplulimab and chemotherapy treatment as a first-line treatment for ES-SCLC patients be examined in detail. The cost-effectiveness of combined serplulimab plus chemotherapeutic treatment was examined using a comprehensive Markov model with a 10-year boundary, enabling the calculation of overall cost, life years (LYs), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER). Model instability was interrogated through one-way and probabilistic sensitivity analyses. Serplulimab plus chemotherapy or chemotherapy alone respectively yielded 1.217 QALYs (2.243 LYs) and 0.885 QALYs (1.661 LYs) with corresponding total costs of $11,202 and $7,194, with an ICER of $12,077 per QALY ($6,883 per LY). This model was most strongly influenced by the utility of progression-free survival. Probabilistic sensitivity analysis showed that serplulimab plus chemotherapy had a 91.6% probability of being cost-effective at a willingness-to-pay (WTP) of $37,653 per QALY (3 × capita gross domestic product of China in 2021). In subgroup analyses, this combination treatment regimen was found to be most cost-effective in patients who were former smokers, had an ECOG performance status of 0, and were diagnosed with brain metastases. From a payer perspective in China, combination serplulimab plus chemotherapy treatment represents a cost-effective first-line intervention for ES-SCLC patients.

PROS1 shapes the immune-suppressive tumor microenvironment and predicts poor prognosis in glioma.

Glioma is the most malignant cancer in the brain. As a major vitamin-K-dependent protein in the central nervous system, PROS1 not only plays a vital role in blood coagulation, and some studies have found that it was associated with tumor immune infiltration. However, the prognostic significance of PROS1 in glioma and the underlying mechanism of PROS1 in shaping the tumor immune microenvironment (TIME) remains unclear. The raw data (including RNA-seq, sgRNA-seq, clinicopathological variables and prognosis, and survival data) were acquired from public databases, including TCGA, GEPIA, CGGA, TIMER, GEO, UALCAN, and CancerSEA. GO enrichment and KEGG pathway analyses were performed using cluster profiler package and visualized by the ggplot2 package. GSEA was conducted using R package cluster profiler. Tumor immune estimation resource (TIMER) and spearman correlation analysis were applied to evaluate the associations between infiltration levels of immune cells and the expression of PROS1. qRT-PCR and WB were used to assay the expression of PROS1. Wound-healing assay, transwell chambers assays, and CCK-8 assays, were performed to assess migration and proliferation. ROC and KM curves were constructed to determine prognostic significance of PROS1 in glioma. The level of PROS1 expression was significantly increased in glioma in comparison to normal tissue, which was further certificated by qRT-PCR and WB in LN-229 and U-87MG glioma cells. High expression of PROS1 positively correlated with inflammation, EMT, and invasion identified by CancerSEA, which was also proved by downregulation of PROS1 could suppress cells migration, and proliferation in LN-229 and U-87MG glioma cells. GO and KEGG analysis suggested that PROS1 was involved in disease of immune system and T cell antigen receptor pathway. Immune cell infiltration analysis showed that expression of PROS1 was negatively associated with pDC and NK CD56 bright cells while positively correlated with Macrophages, Neutrophils in glioma. Immune and stromal scores analysis indicated that PROS1 was positively associated with immune score. The high level of PROS1 resulted in an immune suppressive TIME Increased expression of PROS1 was correlated with malignant phenotype and associated with poor prognosis in glioma. Besides, PROS1 could be a possible biomarker and potential immunotherapeutic target through promoting the glioma immunosuppressive microenvironment and inducing tumor-associated macrophages M2 polarization.

Cerebral mucormycosis masquerading as brain metastasis from lung cancer A case report.

We report a rare case of concurrent pulmonary and cerebral mucormycosis initially misdiagnosed as a metastatic tumor. A 66-year-old man with a complaint of progressive right-sided limb weakness for 3 days. Head MRI showed a left parietal occupying lesion with severe edema, and a chest CT scan showed a parenchymal mass with speculation and pleural invasion in his left lung. The patient was initially diagnosed with brain metastases from lung cancer and underwent a craniotomy. Many fungal hyphae were found in the left parietal lesion, and the final pathological diagnosis of intracranial mucormycosis. After craniotomy and an entire course of treatment with liposomal amphotericin B, the patient was completely cured of both intracranial and pulmonary occupying lesions. We hope that this case experience will help expand neurosurgeons differential diagnosis and treatment of such diseases.

Dextromethorphan improves locomotor activity and decreases brain oxidative stress and inflammation in an animal model of acute liver failure.

Hepatic encephalopathy (HE) is a serious clinical problem leading to severe neurological disorders and death. No specific treatment is available for the management of HE-associated neurological damage. This study aimed to evaluate the effect of dextromethorphan (DXM) on oxidative stress and disturbed locomotor activity in an animal model of HE. In the current study, BALBc mice received acetaminophen (APAP 1000 mgkg, intraperitoneally IP). Dextromethorphan (0.5, 1, 5, 10 mgkg, subcutaneously SC) was injected in three doses (every 6 h), starting two hours after acetaminophen. Animals locomotor activity, brain and plasma ammonia levels, as well as biomarkers of oxidative stress and inflammatory cytokines in the brain tissue, were assessed 24 hours after acetaminophen injection. It was found that APAP administration was significantly associated with liver damage and increased plasma biomarkers of liver injury. Ammonia levels in plasma and brain tissue of APAP-treated mice also increased significantly. There was also a significant difference in motor activity between the control and APAP-treated animals. The acute liver injury also increased the brain level of pro-inflammatory cytokines (tumor necrosis factor a TNF-a, interleukin 6 IL-6, and interleukin 1b IL-1b). It was found that DXM could significantly improve the motor activity of animals in all doses and decrease the biomarkers of inflammation and oxidative stress in the brain tissue of animals with hyperammonemia. The effect of dextromethorphan on oxidative stress and inflammation seems to be a major mechanism for its neuroprotective properties in HE. Based on these data DXM could be applied as an effective pharmacological option against HE-associated brain injury.

New natural compound inhibitors of PDGFRA (platelet-derived growth factor receptor α) based on computational study for high-grade glioma therapy.

High-grade glioma (HGG) is a malignant brain tumor that is common and aggressive in children and adults. In the current medical paradigm, surgery and radiotherapy are the standard treatments for HGG patients. Despite this, the overall prognosis is still very bleak. Studies have shown that platelet-derived growth factor receptor α (PDGFRA) is an essential target to treat tumors and inhibiting the activity of PDGFRA can improve the prognosis of HGG. Thus, PDGFRA inhibitors are critical to developing drugs and cancer treatment. The purpose of this study was to screen lead compounds and candidate drugs with potential inhibitors against platelet-derived growth factor receptor α (PDGFRA) from the drug library (ZINC database) in order to improve the prognosis of patients with high-grade glioma (HGG). In our study, we selected Imatinib as the reference drug. A series of computer-aided technologies, such as Discovery Studio 2019 and Schrodinger, were used to screen and assess potential inhibitors of PDGFRA. The first step was to calculate the LibDock scores and then analyze the pharmacological and toxicological properties. Following this, we docked the small molecules selected in the previous steps with PDGFRA to study their docking mechanism and affinity. In addition, molecular dynamics simulation was used to determine whether the ligand-PDGFRA complex was stable in nature. Two novel natural compounds 1 and 2 (ZINC000008829785 and ZINC000013377891) from the ZINC database were found binding to PDGFRA with more favorable interaction energy. Also, they were predicted with less Ames mutagenicity, rodent carcinogenicity, non-developmental toxic potential, and tolerant with cytochrome P450 2D6 (CYP2D6). The dynamic simulation analysis demonstrated that ZINC000008829785-PDGFRA and ZINC000013377891-PDGFRA dimer complex had more favorable potential energy compared with Imatinib, and they can exist in natural environments stably. ZINC000008829785 and ZINC000013377891 might provide a solid foundation for drugs that inhibit PDGFRA in HGG. In addition to being safe drug candidates, these compounds had important implications for improving drugs targeting PDGFRA.

NS-HGlio A generalizable and repeatable HGG segmentation and volumetric measurement AI algorithm for the longitudinal MRI assessment to inform RANO in trials and clinics.

Accurate and repeatable measurement of high-grade glioma (HGG) enhancing (Enh.) and T2FLAIR hyperintensityedema (Ed.) is required for monitoring treatment response. 3D measurements can be used to inform the modified Response Assessment in Neuro-oncology criteria. We aim to develop an HGG volumetric measurement and visualization AI algorithm that is generalizable and repeatable. A single 3D-Convoluted Neural Network, NS-HGlio, to analyze HGG on MRIs using 5-fold cross validation was developed using retrospective (557 MRIs), multicentre (38 sites) and multivendor (32 scanners) dataset divided into training (70%), validation (20%), and testing (10%). Six neuroradiologists created the ground truth (GT). Additional Internal validation (IV, three institutions) using 70 MRIs, and External validation (EV, single institution) using 40 MRIs through measuring the Dice Similarity Coefficient (DSC) of Enh., Ed. ,and Enh. Ed. (WholeLesionWL) tumor tissue and repeatability testing on 14 subjects from the TCIA MGH-QIN-GBM dataset using volume correlations between timepoints were performed. IV Preoperative median DSC Enh. 0.89 (SD 0.11), Ed. 0.88 (0.28), WL 0.88 (0.11). EV Preoperative median DSC Enh. 0.82 (0.09), Ed. 0.83 (0.11), WL 0.86 (0.06). IV Postoperative median DSC Enh. 0.77 (SD 0.20), Ed 0.78. (SD 0.09), WL 0.78 (SD 0.11). EV Postoperative median DSC Enh. 0.75 (0.21), Ed 0.74 (0.12), WL 0.79 (0.07). Repeatability testing Intraclass Correlation Coefficient of 0.95 Enh. and 0.92 Ed. NS-HGlio is accurate, repeatable, and generalizable. The output can be used for visualization, documentation, treatment response monitoring, radiation planning, intra-operative targeting, and estimation of Residual Tumor Volume among others.

A rare case of brain metastatic of primary mediastinal yolk sac tumor.

Primary yolk sac tumors are extragonadal germ cell tumors commonly seen in children and young adults. They are more common in men. Germ cells tumor on histopathological characteristics is classified as seminoma and non-seminomatous (NSGC). The rarest form of NSGC is an extragonadal yolk sac tumor of mediastinum. Clinical presentations are not specific and may imitate other chronic disease such as other malignancies or tuberculosis such as chest discomfort, vena cava superior syndrome, fever, weight loss, and chronic cough. Immunohistochemistry showed a positive result in Alpha-fetoprotein and pan-cytokeratin. Due to its rarity, brain metastases clinical signs and symptoms, anatomical sites, and characteristics are less well documented. However, the metastatic brain process gave similar histological findings to the primary site. Additional radiological and laboratory tests can be carried out to identify other metastatic processes. Standardized treatment of primary mediastinal sac tumors with brain metastasis has not yet been established. Combining chemotherapy, surgery and radiation treatment could improve overall outcomes and prognosis. We present a scarce case of primary mediastinal yolk sac tumor with metastatic brain process in a 32-year-old male with a short survival period.

Clinical effect of high-flow revascularization in microsurgery combined with endoscopic endonasal surgery for skull base tumors with intracranial and extracranial involvement.

The objective of the study is to investigate the surgical methods and clinical effects of high-flow revascularization in microsurgery combined with endoscopic endonasal surgery for skull base tumors with intracranial and extracranial involvement. The relationships between skull base tumors and internal carotid artery (ICA), tumor location and size, and the extent of tumor invasion were assessed. Preoperative CT perfusion (CTP), magnetic resonance (MR) perfusion-weighted imaging (PWI) (MR-PWI), and digital subtraction angiography (DSA) were performed to evaluate collateral circulation and brain tissue perfusion. Then craniotomy through the fronto-orbitozygomatic approach was performed, based on which four cases received extended middle skull base approachDolenc approach Fukushima bypass type I, and six cases received extended middle skull base approachFukushima bypass type III. After surgery, DSA, CT angiogram (CTA), and CTPPWI were performed to evaluate the patency of the reconstructed vessels and cerebral perfusion, and contrast-enhanced MRI to evaluate the degree of tumor resection. All patients were followed up for 6-12 months. Among the 10 cases investigated, gross total resection was achieved in 8 cases, subtotal resection in 1 case, and partial resection in 1 case, as confirmed by CT and enhanced MRI. The patency of revascularization vessels was observed using fluorescein angiography during the operation in all patients and via DSA and CTA postoperatively in nine patients. One patient underwent ventilator-assisted ventilation because of respiratory failure and failed to undergo DSA and CTA. Regarding postoperative complications, one patient developed watershed cerebral infarction on the operated side but no sequelae after drug treatment, three patients developed facial numbness, which improved after 3 months, and two patients experienced worsened diplopia. After 6 to 12 months of follow-up on the nine evaluable patients, the Glasgow Outcome Scale (GOS) was 4-5 after surgery. In addition, 6-month follow-up results showed that one patient with clival chondrosarcoma developed recurrence on contrast-enhanced MRI, while no relapse was observed in the other patients. For skull base tumors with intracranial and extracranial invasion and involving the ICA, revascularization might improve the total resection rate and reduce the recurrence rate and risk of intraoperative bleeding and postoperative ischemia.

Engineering placenta-like organoids containing endogenous vascular cells from human-induced pluripotent stem cells.

The placenta is an essential organ that maintains the health of both the fetus and its mother. Understanding the development of human placenta has been hindered by the limitations of existing animal models and monolayer cell cultures. Models that can recapitulate the essential aspects of human placental multicellular components and vasculature are still lacking. Herein, we presented a new strategy to establish placenta-like organoids with vascular-like structures from human-induced pluripotent stem cells in a defined three-dimensional (3D) culture system. The resulting placenta-like tissue resembles first-trimester human placental development in terms of complex placental components and secretory function. The multicellular tissue was characterized by the inclusion of trophoblasts (cytotrophoblasts, syncytiotrophoblasts, extravillous trophoblasts, and other endogenous vascular cells), which were identified by immunofluorescence, flow cytometry analyses, real-time quantitative reverse transcription polymerase chain reaction and single-cell RNA-seq. Moreover, the 3D tissue was able to secrete the placenta-specific hormone human chorionic gonadotropin β (hCG-β) and vascular endothelial growth factor A (VEGFA). The tissue responded to the inflammatory factor tumor necrosis factor-α (TNF-α) and VEGF receptor inhibitors. This new model system can represent the major features of placental cellular components, and function, which have not been realized in 2D monolayer cultures. The developed tissue system might open new avenues for studying normal early human placental development and its disease states.

Relationship between serum brain-derived neurotrophic factor and cognitive impairment in children with sleep-disordered breathing.

As an important neuroprotective factor, the brain-derived neurotrophic factor (BDNF) may have a key role in cognitive impairment in children with sleep-disordered breathing (SDB). The main aim of this study was to compare the levels of BDNF and tyrosine kinase receptor B (TrkB) in normal children and those with obstructive sleep apnea (OSA) and primary snoring (PS) and to explore a possible link between BDNFTrkB, inflammation, and SDB with cognitive impairment in children. A total of 44 OSA children and 35 PS children who completed polysomnography between October 2017 and October 2019 were enrolled. At the same time, 40 healthy children during the same period were included as a control. Enzyme-linked immunosorbent assay was used to measure serum indices of BDNF, TrkB, interleukin-1beta (IL-1β), and tumor necrosis factor-alpha (TNF-α). Correlation and pooled analyses were performed between the cognitive scores and four serological indicators. Logistic regression was used to analyze the risk factors for cognitive impairment. Significant differences were found in serum BDNF, TrkB, IL-1β, and TNF-α between the three groups (all The levels of serum BDNF and TrkB were related to cognitive impairment in children with SDB. Also, BDNF and TrkB could be used as noninvasive and objective candidate markers and predictive indices of cognitive impairment in children with SDB.

Usefulness of Serum Soluble Interleukin-2 Receptor Levels for Differentiating between PCNSL and SCNSL.

Serum soluble interleukin-2 receptor (sIL-2R) is a practical tumor marker that is elevated in hematogenous tumors. The purpose of this study was to determine the usefulness of serum sIL-2R for differentiating among malignant brain tumors, including primary central nervous system lymphoma (PCNSL) and secondary central nervous system lymphoma (SCNSL). This study retrospectively investigated the sIL-2R levels in 130 patients with various types of malignant brain tumors, including PCNSL patients (n 48) and SCNSL (n 8) metastatic brain tumors (MTs, n 16) and glioblastoma (GBM, n 58). The median sIL-2R level (UmL) of the PCNSL, SCNSL, MTs, and GBM groups were 489.7, 1024.8, 413.3, and 332.7 respectively. The sIL-2R level was significantly higher in the SCNSL group than in the PCNSL or other groups. The area under the ROC curve generated from the sIL-2R level was 0.826 (sensitivity 0.875, specificity 0.667, cutoff value 521 UmL) for differentiating SCNSL from PCNSL and 0.685 (sensitivity 0.667, specificity 0.707, cutoff value 342 UmL) for differentiating PCNSL from GBM. Measurement of sIL-2R level was convenient and useful to differentiate between SCNSL and PCSNL, both of which demand different treatment strategies.

Surgical Treatment of Mesial Temporal Lobe Epilepsy Focusing on Anatomical Understanding.

Surgical treatment is an effective option for medically intractable epilepsy. Amygdalohippocampectomy for mesial temporal lobe epilepsy is a surgically remediable epileptic syndrome. It is a well-established surgery and various approaches to the mesial temporal lobe have been reported. To reduce the complication rate, surgeons should have sufficient knowledge of anatomy in the mesial temporal region. Here, we summarize the surgical treatments for mesial temporal lobe epilepsy, focusing on anatomical understanding. We described in detail the surgical anatomy of amygdalohippocampectomy and various approaches to the mesial temporal region. In addition, we describe hippocampal transection aimed at preserving memory function, which is an alternative surgery in patients without hippocampal sclerosis. An anatomical understanding of the mesial temporal region helps surgeons not only in the field of epilepsy surgery, but also in other fields of neurosurgery, such as brain tumor and vascular surgery.

Predictors of Survival After Stereotactic Radiosurgery for Untreated Single Non-Small Cell Lung Cancer Brain Metastases 5- and 10-year Results.

Stereotactic radiosurgery (SRS) presents as a good treatment option for smaller, deep-seated brain metastases (BMs). This study aims to determine predictors of SRS failure for patients with non-small cell lung cancer BMs. This was a retrospective study of single non-small cell lung cancer BMs treated using SRS. We included patients >18 years with a single, previously untreated lesion. Primary outcome was treatment failure, defined as BMs dimension increase above the initial values. Demographic, clinical, and radiological data were collected to study potential predictors of treatment failure. Worse rates of progression-free survival (PFS) were associated with heterogeneous contrast enhancement (18.1 ± 4.1 vs. 41.9 ± 4 months P < 0.001). Better rates of PFS were associated with volumes <1.06 cm Contrast-homogeneous metastases and lesions <1.06 cm

Effect of Dexmedetomidine versus Propofol on Intraoperative Seizure Onset During Awake Craniotomy A Retrospective Study.

The effect of dexmedetomidine (DEX) compared with propofol on intraoperative seizures (IOSs) detected using electrocorticography during awake craniotomy for resection of brain tumors is unknown. This investigation aimed to compare IOS rate in patients receiving DEX versus propofol as sedative agent. In this retrospective single-center study, awake craniotomies performed from January 2014 to December 2019 were analyzed. All IOSs detected by electrocorticography along with vital signs were recorded. Of 168 adults enrolled in the study, 58 were administered DEX and 110 were administered propofol. IOSs occurred more frequently in the DEX group (22%) versus the propofol group (11%) (P 0.046). A higher incidence of bradycardia was also observed in the DEX group (P < 0.001). Higher incidence of hypertension and a higher mean heart rate were recorded in the propofol group (P 0.006 and P < 0.001, respectively). No serious adverse events requiring active drug administration were noted in either group. At univariate regression analysis, DEX demonstrated a tendency to favor IOS onset but without statistical significance (odds ratio 2.36, P 0.051). Patients in both groups had a similar epilepsy outcome at the 1-year postoperative follow-up. IOSs detected with electrocorticography during awake craniotomy occurred more frequently in patients receiving DEX than propofol. However, patients receiving DEX were not shown to be at a statistically significant greater risk for IOS onset. DEX is a valid alternative to propofol during awake craniotomy in patients affected by tumor-related epilepsy.

Nanoparticle biodistribution coefficients A quantitative approach for understanding the tissue distribution of nanoparticles.

The objective of this manuscript is to provide quantitative insights into the tissue distribution of nanoparticles. Published pharmacokinetics of nanoparticles in plasma, tumor and 13 different tissues of mice were collected from literature. A total of 2018 datasets were analyzed and biodistribution of graphene oxide, lipid, polymeric, silica, iron oxide and gold nanoparticles in different tissues was quantitatively characterized using Nanoparticle Biodistribution Coefficients (NBC). It was observed that typically after intravenous administration most of the nanoparticles are accumulated in the liver (NBC 17.56 %IDg) and spleen (NBC 12.1 %IDg), while other tissues received less than 5 %IDg. NBC values for kidney, lungs, heart, bones, brain, stomach, intestine, pancreas, skin, muscle and tumor were found to be 3.1 %IDg, 2.8 %IDg, 1.8 %IDg, 0.9 %IDg, 0.3 %IDg, 1.2 %IDg, 1.8 %IDg, 1.2 %IDg, 1.0 %IDg, 0.6 %IDg and 3.4 %IDg, respectively. Significant variability in nanoparticle distribution was observed in certain organs such as liver, spleen and lungs. A large fraction of this variability could be explained by accounting for the differences in nanoparticle physicochemical properties such as size and material. A critical overview of published nanoparticle physiologically-based pharmacokinetic (PBPK) models is provided, and limitations in our current knowledge about in vitro and in vivo pharmacokinetics of nanoparticles that restrict the development of robust PBPK models is also discussed. It is hypothesized that robust quantitative assessment of whole-body pharmacokinetics of nanoparticles and development of mathematical models that can predict their disposition can improve the probability of successful clinical translation of these modalities.

Long-term postoperative health-related quality of life in patients with subfrontal meningiomas.

Subfrontal meningiomas grow insidiously in areas with high cerebral compliance and a relative scarcity of eloquent function. Symptoms develop progressively, are nonspecific, and include anosmia, changes in personality and cognition, depressive symptoms, headaches, visual disturbances, and seizures. Patients with subfrontal meningiomas carry the highest risk of developing psychological symptoms, which makes patient-reported outcome in terms of long-term health-related quality of life (HRQOL), anxiety, and depression of particular importance. This observational study aimed to investigate long-term HRQOL, anxiety, and depression in patients with subfrontal meningiomas who underwent a bifrontal craniotomy (subfrontal) approach between 2008 and 2017 at a single tertiary center. Correlations between preoperative, perioperative, and postoperative factors and HRQOL, anxiety, and depression were analyzed to detect prognostic factors. Seventy-seven consecutive patients who underwent operations at Rigshospitalet, Copenhagen, Denmark, between 2008 and 2017 were retrospectively analyzed. Patients were prospectively invited to respond to the Functional Assessment of Cancer Therapy-General, Functional Assessment of Cancer Therapy-Brain, and Hospital Anxiety and Depression Scale. Information regarding preoperative, perioperative, and postoperative factors were collected from the patients medical records and scans. Patients with subfrontal meningiomas exhibited better HRQOL and lower levels of anxiety and depression than general populations and other meningioma and glioblastoma cohorts. The only statistically significant prognostic factors for long-term HRQOL were number of symptoms at diagnosis and whether patients were discharged home or to a local hospital postoperatively. Tumor and peritumoral brain edema volumes were not prognostic factors. Patients with subfrontal meningiomas exhibited better long-term postoperative HRQOL and were less likely to have anxiety or depression than the reference populations. This information on long-term prognosis is very valuable for patients, next of kin, and neurosurgeons and has not been previously studied in detail.

Leptomeningeal metastasis in patients with non-small cell lung cancer after stereotactic radiosurgery for brain metastasis.

Stereotactic radiosurgery (SRS) is an effective treatment for brain metastases (BMs) in patients with non-small cell lung cancer (NSCLC). However, factors associated with the development of post-SRS leptomeningeal metastasis (LM) remain unclear. The authors analyzed the incidence and risk factors of LM development in patients with NSCLC and BMs after SRS and examined the survival outcomes and prognostic factors after LM development. This retrospective study included patients with NSCLC treated with SRS for MRI-diagnosed BM from 2002 to 2021. The authors recorded various clinical and demographic data, including age, sex, tumor histology, molecular profile of tumors, extracranial disease status, previous craniotomy, Karnofsky Performance Status, systemic treatments, tumor volume, and number of BMs. The management and survival outcomes after LM diagnosis were also recorded. LM developed in 13.7% of patients with NSCLC and BMs after SRS treatment. Large initial tumor volume and more than 5 BM lesions, but not EGFR mutation status and post-SRS treatment, were associated with LM development after SRS. Multivariate analysis revealed that chemotherapy and targeted therapy after LM were associated with better survival in patients with LM after SRS. This study is the first to evaluate the risk factors for LM in a relatively large cohort of patients with NSCLC after SRS. In patients with BMs harboring risk factors for subsequent LM, such as initial tumor volume and number of metastatic lesions, aggressive therapies with high CNS penetrating ability should be considered.

Optimizing maximum resection of glioblastoma Raman spectroscopy versus 5-aminolevulinic acid.

The objective of this study was to assess and compare the potential of 5-aminolevulinic acid (5-ALA) and Raman spectroscopy (RS) in detecting tumor-infiltrated brain in patients with glioblastoma (GBM). Between July 2020 and October 2021, the authors conducted a prospective clinical trial with 15 patients who underwent neurosurgical treatment of newly diagnosed and histologically verified GBM. A solid contrast-enhancing tumor core and peritumoral tissue were investigated intraoperatively for cancer cells by using 5-ALA and RS to achieve pathology-tailored maximum resection. In each case, a minimum of 10 biopsies were sampled from navigation-guided areas. Two neuropathologists examined the biopsies for the presence of neoplastic cells. The detection performance of 5-ALA and RS alone and in combination was assessed. Pre- and postoperative MRI, Karnofsky Performance Status (KPS), and National Institutes of Health Stroke Scale (NIHSS) scores were compared, and median progression-free survival (PFS) was evaluated. A total of 185 biopsy samples were harvested from the contrast-enhancing tumor core (n 19) and peritumoral tissue (n 166). In the tumor core, 5-ALA and RS each showed a sensitivity of 100%. In the peritumoral tissue, 5-ALA was less sensitive than RS in detecting cancer (46% vs 69%) but showed higher specificity (81% vs 57%). When the two methods were combined, the accuracy of tumor detection was increased by about 10%. Pathology-tailored resection led to a 52% increase in resection volume comparing the volume of preoperative contrast enhancement with the postoperative resection cavity on MRI (p 0.0123). Eloquent brain involvement prevented gross-total resection in 4 patients. Four weeks after surgery, mean KPS (p 0.7637) and NIHSS scores (p 0.3146) were not significantly different from preoperative values. Of the 13 patients who had received postoperative chemoradiotherapy, 4 did not show any progression after a median follow-up of 14 months. The remaining 9 patients had a median PFS of 8 months. According to the study data, RS is capable of detecting tumor-infiltrated brain with higher sensitivity but lower specificity than the current standard of 5-ALA. With further technological and workflow advancements, RS in combination with protoporphyrin IX fluorescence may contribute to pathology-tailored glioma resection in the future.

Development and validation of a machine learning algorithm for predicting diffuse midline glioma, H3 K27-altered, H3 K27 wild-type high-grade glioma, and primary CNS lymphoma of the brain midline in adults.

Preoperative diagnosis of diffuse midline glioma, H3 K27-altered (DMG-A) and midline high-grade glioma without H3 K27 alteration (DMG-W), as well as midline primary CNS lymphoma (PCNSL) in adults, is challenging but crucial. The aim of this study was to develop a model for predicting these three entities using machine learning (ML) algorithms. Thirty-three patients with DMG-A, 35 with DMG-W, and 35 with midline PCNSL were retrospectively enrolled in the study. Radiomics features were extracted from contrast-enhanced T1-weighted MR images. Two radiologists evaluated the conventional MRI features of the tumors, such as shape. Patient age, tumor volume, and conventional MRI features were considered clinical features. The data set was randomly stratified into 70% training and 30% testing cohorts. Predictive models based on the clinical features, radiomics features, and integration of clinical and radiomics features were established through ML. The performances of the models were evaluated by calculating the area under the receiver operating characteristic curve, accuracy, sensitivity, and specificity. Subsequently, 10 patients with DMG-A, 10 with DMG-W, and 12 with PCNSL were enrolled from another institution to validate the established models. The predictive models based on clinical features, radiomics features, and the integration of clinical and radiomics features through the support vector machine algorithm had the optimal accuracies in the training, testing, and validation cohorts, and the accuracies in the testing cohort were 0.871, 0.892, and 0.903, respectively. Age, 2 radiomics features, and 3 conventional MRI features were the 6 most significant features in the established integrated model. The integrated prediction model established by ML provides high discriminatory accuracy for predicting DMG-A, DMG-W, and midline PCNSL in adults.

Comprehensive analysis of pyroptosis-related gene signatures for glioblastoma immune microenvironment and target therapy.

Glioblastoma (GBM) is a malignant brain tumour, but its subtypes (mesenchymal, classical, and proneural) show different prognoses. Pyroptosis is a programmed cell death relating to tumour progression, but its association with GBM is poorly understood. In this work, we collected 73 GBM samples (the Xiangya GBM cohort) and reported that pyroptosis involves tumour-microglia interaction and tumour response to interferon-gamma. GBM samples were grouped into different subtypes, cluster 1 and cluster 2, based on pyroptosis-related genes. Cluster 1 samples manifested a worse prognosis and had a more complicated immune landscape than cluster 2 samples. Single-cell RNA-seq data analysis supported that cluster 1 samples respond to interferon-gamma more actively. Moreover, the machine learning algorithm screened several potential compounds, including nutlin-3, for cluster 1 samples as a novel treatment. In vitro experiments supported that cluster 1 cell line, T98G, is more sensitive to nutlin-3 than cluster 2 cell line, LN229. Nutlin-3 can trigger oxidative stress by increasing DHCR24 expression. Moreover, pyroptosis-resistant genes were upregulated in LN229, which may participate against nutlin-3. Therefore, we hypothesis that GBM may be able to upregulate pyroptosis resistant related genes to against nutlin-3-triggered cell death. In summary, we conclude that pyroptosis highly associates with GBM progression, tumour immune landscape, and tumour response to nutlin-3.

T cell exhaustion in malignant gliomas.

Despite advances in understanding tumor biology, malignant gliomas remain incurable. While immunotherapy has improved outcomes in other cancer types, comparable efficacy has not yet been demonstrated for primary cancers of the central nervous system (CNS). T cell exhaustion, defined as a progressive decrease in effector function, sustained expression of inhibitory receptors, metabolic dysfunction, and distinct epigenetic and transcriptional alterations, contributes to the failure of immunotherapy in the CNS. Herein, we describe recent advances in understanding the drivers of T cell exhaustion in the glioma microenvironment. We discuss the extrinsic and intrinsic factors that contribute to exhaustion and highlight potential avenues for reversing this phenotype. Our ability to directly target specific immunosuppressive drivers in brain cancers would be a major advance in immunotherapy.

Radiotherapy and paclitaxel plus pazopanib or placebo in anaplastic thyroid cancer (NRGRTOG 0912) a randomised, double-blind, placebo-controlled, multicentre, phase 2 trial.

Anaplastic thyroid cancer is a rare and aggressive cancer with no standard radiotherapy-based local treatment. Based on data suggesting synergy between pazopanib and paclitaxel in anaplastic thyroid cancer, NRG Oncology did a double-blind, placebo-controlled, randomised phase 2 clinical trial comparing concurrent paclitaxel and intensity-modulated radiotherapy (IMRT) with the addition of pazopanib or placebo with the aim of improving overall survival in this patient population. Eligible patients were aged 18 years or older with a pathological diagnosis of anaplastic thyroid cancer, any TNM stage, Zubrod performance status of 0-2, no recent haemoptysis or bleeding, and no brain metastases. Patients were enrolled from 34 centres in the USA. Initially, a run-in was done to establish safety. In the randomised phase 2 trial, patients in the experimental group (pazopanib) received 2-3 weeks of weekly paclitaxel (80 mgm The safety run-showed the final dosing regimen to be safe based on two out of nine participants having adverse events of predefined concern. Between June 23, 2014, and Dec 30, 2016, 89 patients were enrolled to the phase 2 trial, of whom 71 were eligible (36 in the pazopanib group and 35 in the placebo group 34 48% males and 37 52% females). At the final analysis (data cutoff March 9, 2020), with a median follow-up of 2·9 years (IQR 0·002-4·0), 61 patients had died. Overall survival was not significantly improved with pazopanib versus placebo, with a median overall survival of 5·7 months (95% CI 4·0-12·8) in the pazopanib group versus 7·3 months (4·3-10·6) in the placebo group (hazard ratio 0·86, 95% CI 0·52-1·43 one-sided log-rank p0·28). 1-year overall survival was 37·1% (95% CI 21·1-53·2) in the pazopanib group and 29·0% (13·2-44·8) in the placebo group. The incidence of grade 3-5 adverse events did not differ significantly between the treatment groups (pazopanib 88·9% 32 of 36 patients and placebo 85·3% 29 of 34 patients p0·73). The most common clinically significant grade 3-4 adverse events in the 70 eligible treated patients (36 in the pazopanib group and 34 in the placebo group) were dysphagia (13 36% vs 10 29%), radiation dermatitis (8 22% vs 13 38%), increased alanine aminotransferase (12 33% vs none), increased aspartate aminotransferase (eight 22% vs none), and oral mucositis (five 14% vs eight 24%). Treatment-related serious adverse events were reported for 16 (44%) patients on pazopanib and 12 (35%) patients on placebo. The most common serious adverse events were dehydration and thromboembolic event (three 8% each) in patients on pazopanib and oral mucositis (three 8%) in those on placebo. There was one treatment-related death in each group (sepsis in the pazopanib group and pneumonitis in the placebo group). To our knowledge, this study is the largest randomised anaplastic thyroid cancer study that has completed accrual showing feasibility in a multicenter NCI National Clinical Trials Network setting. Although no significant improvement in overall survival was recorded in the pazopanib group, the treatment combination was shown to be feasible and safe, and hypothesis-generating data that might warrant further investigation were generated. National Cancer Institute and Novartis.

Rapid ossification of a giant post-operative occipital pseudomeningocele following posterior fossa surgery.

Pseudomeningocele formation following posterior fossa surgery is a well-recognised complication, occurring in up to 33% of operated cases in some series. Ossification of a cranial pseudomeningocele is, however, an exceptionally rare event with only three prior reported cases. We present the unique case of a paediatric patient who developed rapid ossification of a giant occipital pseudomeningocele following posterior fossa surgery. An 8-year-old female patient underwent a midline posterior fossa craniotomy for resection of an exophytic brainstem low-grade glioma. Post-surgery, the patient developed pan-ventricular hydrocephalus and a large occipital pseudomeningocele, which initially increased in size despite a successful endoscopic third ventriculostomy (ETV) being performed. At approximately 3 months post-surgery, reduction of the pseudomeningocele was observed with associated prominent ossification of the pseudomeningocele wall on computed tomography (CT) imaging. Surgical excision was subsequently undertaken, and intra-operatively, a large ossified pseudomeningocele was found. Follow-up MRI 1 month later demonstrated almost complete resolution of the pseudomeningocele with an associated reduction in the degree of pan-ventricular ventriculomegaly. This case highlights that ossification of even giant pseudomeningoceles can occur over a time period of just a few months and clinicians should consider ossification whenever a change in size or consistency of a post-operative pseudomeningocele is encountered.

PVA-Microbubbles as a Radioembolization Platform Formulation and the In Vitro Proof of Concept.

This proof-of-concept study lays the foundations for the development of a delivery strategy for radioactive lanthanides, such as Yttrium-90, against recurrent glioblastoma. Our appealing hypothesis is that by taking advantage of the combination of biocompatible polyvinyl alcohol (PVA) microbubbles (MBs) and endovascular radiopharmaceutical infusion, a minimally invasive selective radioembolization can be achieved, which can lead to personalized treatments limiting off-target toxicities for the normal brain. The results show the successful formulation strategy that turns the ultrasound contrast PVA-shelled microbubbles into a microdevice, exhibiting good loading efficiency of Yttrium cargo by complexation with a bifunctional chelator. The selective targeting of Yttrium-loaded MBs on the glioblastoma-associated tumor endothelial cells can be unlocked by the biorecognition between the overexpressed α

Discovering Glioma Tissue through Its Biomarkers Detection in Blood by Raman Spectroscopy and Machine Learning.

The most commonly occurring malignant brain tumors are gliomas, and among them is glioblastoma multiforme. The main idea of the paper is to estimate dependency between glioma tissue and blood serum biomarkers using Raman spectroscopy. We used the most common model of human glioma when continuous cell lines, such as U87, derived from primary human tumor cells, are transplanted intracranially into the mouse brain. We studied the separability of the experimental and control groups by machine learning methods and discovered the most informative Raman spectral bands. During the glioblastoma development, an increase in the contribution of lactate, tryptophan, fatty acids, and lipids in dried blood serum Raman spectra were observed. This overlaps with analogous results of glioma tissues from direct Raman spectroscopy studies. A non-linear relationship between specific Raman spectral lines and tumor size was discovered. Therefore, the analysis of blood serum can track the change in the state of brain tissues during the glioma development.

Tumor Treating Fields (TTFields) Induce Cell Junction Alterations in a Human 3D In Vitro Model of the Blood-Brain Barrier.

In a recent study, we showed in an in vitro murine cerebellar microvascular endothelial cell (cerebEND) model as well as in vivo in rats that Tumor-Treating Fields (TTFields) reversibly open the blood-brain barrier (BBB). This process is facilitated by delocalizing tight junction proteins such as claudin-5 from the membrane to the cytoplasm. In investigating the possibility that the same effects could be observed in human-derived cells, a 3D co-culture model of the BBB was established consisting of primary microvascular brain endothelial cells (HBMVEC) and immortalized pericytes, both of human origin. The TTFields at a frequency of 100 kHz administered for 72 h increased the permeability of our human-derived BBB model. The integrity of the BBB had already recovered 48 h post-TTFields, which is earlier than that observed in cerebEND. The data presented herein validate the previously observed effects of TTFields in murine models. Moreover, due to the fact that human cell-based in vitro models more closely resemble patient-derived entities, our findings are highly relevant for pre-clinical studies.

Tyrosine Kinase Inhibitors for Glioblastoma Multiforme Challenges and Opportunities for Drug Delivery.

Glioblastoma multiforme (GBM) is an aggressive brain tumor with high mortality rates. Due to its invasiveness, heterogeneity, and incomplete resection, the treatment is very challenging. Targeted therapies such as tyrosine kinase inhibitors (TKIs) have great potential for GBM treatment, however, their efficacy is primarily limited by poor brain distribution due to the presence of the blood-brain barrier (BBB). This review focuses on the potential of TKIs in GBM therapy and provides an insight into the reasons behind unsuccessful clinical trials of TKIs in GBM despite the success in treating other cancer types. The main section is dedicated to the use of promising drug delivery strategies for targeted delivery to brain tumors. Use of brain targeted delivery strategies can help enhance the efficacy of TKIs in GBM. Among various drug delivery approaches used to bypass or cross BBB, utilizing nanocarriers is a promising strategy to augment the pharmacokinetic properties of TKIs and overcome their limitations. This is because of their advantages such as the ability to cross BBB, chemical stabilization of drug in circulation, passive or active targeting of tumor, modulation of drug release from the carrier, and the possibility to be delivered via non-invasive intranasal route.

Intranasal Delivery of Liposomes to Glioblastoma by Photostimulation of the Lymphatic System.

The blood-brain barrier (BBB) limits the delivery of majority of cancer drugs and thereby complicates brain tumor treatment. The nasal-brain-lymphatic system is discussed as a pathway for brain drug delivery overcoming the BBB. However, in most cases, this method is not sufficient to achieve a therapeutic effect due to brain drug delivery in a short distance. Therefore, it is necessary to develop technologies to overcome the obstacles facing nose-to-brain delivery of promising pharmaceuticals. In this study, we clearly demonstrate intranasal delivery of liposomes to the mouse brain reaching glioblastoma (GBM). In the experiments with ablation of the meningeal lymphatic network, we report an important role of meningeal pathway for intranasal delivery of liposomes to the brain. Our data revealed that GBM is characterized by a dramatic reduction of intranasal delivery of liposomes to the brain that was significantly improved by near-infrared (1267 nm) photostimulation of the lymphatic vessels in the area of the cribriform plate and the meninges. These results open new perspectives for non-invasive improvement of efficiency of intranasal delivery of cancer drugs to the brain tissues using nanocarriers and near-infrared laser-based therapeutic devices, which are commercially available and widely used in clinical practice.

Novel Development of Nanoparticles-A Promising Direction for Precise Tumor Management.

Although the clinical application of nanoparticles is still limited by biological barriers and distribution, with the deepening of our understanding of nanoparticles over the past decades, people are gradually breaking through the previous limitations in the diagnosis and treatment of tumors, providing novel strategies for clinical decision makers. The transition of nanoparticles from passive targeting to active tumor-targeting by abundant surface-modified nanoparticles is also a development process of precision cancer treatment. Different particles can be used as targeted delivery tools of antitumor drugs. The mechanism of gold nanoparticles inducing apoptosis and cycle arrest of tumor cells has been discovered. Moreover, the unique photothermal effect of gold nanoparticles may be widely used in tumor therapy in the future, with less side effects on surrounding tissues. Lipid-based nanoparticles are expected to overcome the blood-brain barrier due to their special characteristics, while polymer-based nanoparticles show better biocompatibility and lower toxicity. In this paper, we discuss the development of nanoparticles in tumor therapy and the challenges that need to be addressed.

Recent Development of Radiofluorination of Boron Agents for Boron Neutron Capture Therapy of Tumor Creation of

Boron neutron capture therapy (BNCT) is a binary therapeutic technique employing a boron agent to be delivered to the tumor site followed by the irradiation of neutrons. Biofunctional moleculesnanoparticles labeled with F-18 can provide an initial pharmacokinetic profile of patients to guide the subsequent treatment planning procedure of BNCT. Borono phenylalanine (BPA), recognized by the

Management of Brain Cancer and Neurodegenerative Disorders with Polymer-Based Nanoparticles as a Biocompatible Platform.

The blood-brain barrier (BBB) serves as a protective barrier for the central nervous system (CNS) against drugs that enter the bloodstream. The BBB is a key clinical barrier in the treatment of CNS illnesses because it restricts drug entry into the brain. To bypass this barrier and release relevant drugs into the brain matrix, nanotechnology-based delivery systems have been developed. Given the unstable nature of NPs, an appropriate amount of a biocompatible polymer coating on NPs is thought to have a key role in reducing cellular cytotoxicity while also boosting stability. Human serum albumin (HSA), poly (lactic-co-glycolic acid) (PLGA), Polylactide (PLA), poly (alkyl cyanoacrylate) (PACA), gelatin, and chitosan are only a few of the significant polymers mentioned. In this review article, we categorized polymer-coated nanoparticles from basic to complex drug delivery systems and discussed their application as novel drug carriers to the brain.

Identification of Therapeutic Targets for Medulloblastoma by Tissue-Specific Genome-Scale Metabolic Model.

Medulloblastoma (MB), occurring in the cerebellum, is the most common childhood brain tumor. Because conventional methods decline life quality and endanger children with detrimental side effects, computer models are needed to imitate the characteristics of cancer cells and uncover effective therapeutic targets with minimum toxic effects on healthy cells. In this study, metabolic changes specific to MB were captured by the genome-scale metabolic brain model integrated with transcriptome data. To determine the roles of sphingolipid metabolism in proliferation and metastasis in the cancer cell, 79 reactions were incorporated into the MB model. The pathways employed by MB without a carbon source and the link between metastasis and the Warburg effect were examined in detail. To reveal therapeutic targets for MB, biomass-coupled reactions, the essential genesgene products, and the antimetabolites, which might deplete the use of metabolites in cells by triggering competitive inhibition, were determined. As a result, interfering with the enzymes associated with fatty acid synthesis (FAs) and the mevalonate pathway in cholesterol synthesis, suppressing cardiolipin production, and tumor-supporting sphingolipid metabolites might be effective therapeutic approaches for MB. Moreover, decreasing the activity of succinate synthesis and GABA-catalyzing enzymes concurrently might be a promising strategy for metastatic MB.

Thymine-Modified Nanocarrier for Doxorubicin Delivery in Glioblastoma Cells.

Brain tumor glioblastoma is one of the worst types of cancer. The blood-brain barrier prevents drugs from reaching brain cells and shields glioblastoma from treatment. The creation of nanocarriers to improve drug delivery and internalization effectiveness may be the solution to this issue. In this paper, we report on a new nanocarrier that was developed to deliver the anticancer drug doxorubicin to glioblastoma cells. The nanocarrier was obtained by nanoemulsion polymerization of diallyl disulfide with 1-allylthymine. Diallyl disulfide is a redox-sensitive molecule involved in redox cell activities, and thymine is a uracil derivative and one of the well-known bioactive compounds that can enhance the pharmacological activity of doxorubicin. Doxorubicin was successfully introduced into the nanocarrier with a load capacity of about 4.6%. Biological studies showed that the doxorubicin nanocarrier composition is far more cytotoxic to glioblastoma cells (T98G) than it is to cancer cells (M-HeLa) and healthy cells (Chang liver). The nanocarrier improves the penetration of doxorubicin into T98G cells and accelerates the cells demise, as is evident from flow cytometry and fluorescence microscopy data. The obtained nanocarrier, in our opinion, is a promising candidate for further research in glioblastoma therapy.

An Amperometric Biomedical Sensor for the Determination of Homocysteine Using Gold Nanoparticles and Acetylene Black-Dihexadecyl Phosphate-Modified Glassy Carbon Electrode.

A novel nanocomposite film composed of gold nanoparticles and acetylene black-dihexadecyl phosphate was fabricated and modified on the surface of a glassy carbon electrode through a simple and controllable dropping and electropolymerization method. The nanocomposite film electrode showed a good electrocatalytic response to the oxidation of homocysteine and can work as an amperometric biomedical sensor for homocysteine. With the aid of scanning electron microscopy, energy dispersive X-ray technology and electrochemical impedance spectroscopy, the sensing interface was characterized, and the sensing mechanism was discussed. Under optimal conditions, the oxidation peak current of homocysteine was linearly increased with its concentration in the range of 3.0 µmolL1.0 mmolL, and a sensitivity of 18 nA(μmolL) was obtained. Furthermore, the detection limit was determined as 0.6 µmolL, and the response time was detected as 3 s. Applying the nanocomposite film electrode for monitoring the homocysteine in human blood serum, the results were satisfactory.

Biomarkers of Drug Resistance in Temporal Lobe Epilepsy in Adults.

Temporal lobe epilepsy (TLE) is the most common type of focal epilepsy in adults. Experimental and clinical data indicate that neuroinflammation and neurodegeneration accompanying epileptogenesis make a significant contribution to the chronicity of epilepsy and the development of drug resistance in TLE cases. Changes in plasma and serum concentrations of proteins associated with neuroinflammation and neurodegeneration can be predictive biomarkers of the course of the disease. This study used an enzyme-linked immunosorbent assay of the following plasma proteins brain-derived neurotrophic factor (

Independent and Combined Effects of Probiotics and Prebiotics as Supplements or Food-Rich Diets on a Propionic-Acid-Induced Rodent Model of Autism Spectrum Disorder.

The link between nutrition and autism spectrum disorder (ASD) as a neurodevelopmental condition, which is clinically presented as significant delays or deviations in interaction and communication, has provided a fresh point of view and signals that nutrition may play a role in the etiology of ASD, as well as playing an effective role in treatment by improving symptoms. In this study, 36 male albino rat pups were used. They were randomly divided into five groups. The control group was fed only a standard diet and water for the 30 days of the experiment. The second group, which served as a propionic acid (PPA)-induced rodent model of ASD, received orally administered PPA (250 mgkg body weight (BW)) for 3 days, followed by feeding with a standard diet until the end of the experiment. The three other groups were given PPA (250 mgkg body weight (BW)) for 3 days and then fed a standard diet and orally administered yogurt (3 mLkg BWday), artichokes (400 mLkg BWday), and a combination of

Pre-Surgery Patient Health Contributes to Aggravated Sino-Nasal Outcome and Quality of Life after Pituitary Adenomectomy.

A Novel Generative Adversarial Network-Based Approach for Automated Brain Tumour Segmentation.

Gamma Knife Radiosurgery Irradiation of Surgical Cavity of Brain Metastases Factor Analysis and Gene Mutations.

(1) Background Surgical resection for the removal of brain metastases often fails to prevent tumor recurrence within the surgical cavity hence, researchers are divided as to the benefits of radiation treatment following surgical resection. This retrospective study assessed the effects of post-operative stereotactic radiosurgery (SRS) on local tumor control and overall survival. (2) Methods This study examined the demographics, original tumor characteristics, and surgical outcomes of 97 patients who underwent Gamma Knife Radiosurgery (GKRS) treatment (103 brain metastases). Kaplan-Meier plots and Cox regression were used to correlate clinical features to tumor control and overall survival. (3) Results The overall tumor control rate was 75.0% and overall 12-month survival was 89.6%. Tumor control rates in the radiation group versus the non-radiation group were as follows 12 months (83.1% vs. 57.7%) and 24 months (66.1% vs. 50.5%). During the 2-year follow-up period after SRS, the intracranial response rate was higher in the post-craniotomy radiation group than in the non-radiation group (

Artificial Intelligence and Precision Medicine A New Frontier for the Treatment of Brain Tumors.

Brain tumors are a widespread and serious neurological phenomenon that can be life- threatening. The computing field has allowed for the development of artificial intelligence (AI), which can mimic the neural network of the human brain. One use of this technology has been to help researchers capture hidden, high-dimensional images of brain tumors. These images can provide new insights into the nature of brain tumors and help to improve treatment options. AI and precision medicine (PM) are converging to revolutionize healthcare. AI has the potential to improve cancer imaging interpretation in several ways, including more accurate tumor genotyping, more precise delineation of tumor volume, and better prediction of clinical outcomes. AI-assisted brain surgery can be an effective and safe option for treating brain tumors. This review discusses various AI and PM techniques that can be used in brain tumor treatment. These new techniques for the treatment of brain tumors, i.e., genomic profiling, microRNA panels, quantitative imaging, and radiomics, hold great promise for the future. However, there are challenges that must be overcome for these technologies to reach their full potential and improve healthcare.

Factors Associated with Unplanned Transfer of Patients with Brain Tumor from Inpatient Rehabilitation Unit to Primary Acute Care Units.

Inpatient rehabilitation should be assessed to improve each functional domain in patients with brain tumor. However, no previous study has reported risk factors for unplanned transfer of this patient population to primary acute care units during a comprehensive inpatient rehabilitation. The objective of this study was to investigate the percentage of unplanned transfer of brain tumor rehabilitation inpatients to primary acute care units compared with stroke patients and factors associated with such unplanned transfer. Data of 137 patients with brain tumor who were transferred to the department of physical and rehabilitation medicine were retrospectively reviewed. For comparison, data of 438 patients with subacute stroke were also obtained. Included patients were divided into an unplanned transfer group and a control group based on whether they required a transfer to another department for acute care before completing their comprehensive inpatient rehabilitation. Reasons for unplanned transfers were classified based on medical or surgical conditions. The incidence of unplanned transfers to the medical or surgical department was significantly higher in patients with brain tumor (15.3%) than in stroke patients (7.1%) (

Web-Based Nomograms for Overall Survival and Cancer-Specific Survival of Bladder Cancer Patients with Bone Metastasis A Retrospective Cohort Study from SEER Database.

Our study aimed to explore the prognostic factors of bladder cancer with bone metastasis (BCBM) and develop prediction models to predict the overall survival (OS) and cancer-specific survival (CSS) of BCBM patients. A total of 1438 patients with BCBM were obtained from the SEER database. Patients from 2010 to 2016 were randomly divided into training and validation datasets (73), while patients from 2017 were divided for external testing. Nomograms were established using prognostic factors identified through Cox regression analyses and validated internally and externally. The concordance index (C-index), calibration plots, and time-dependent receiver operating characteristic (ROC) curves were used to evaluate the discrimination and calibration of nomogram models, while decision curve analyses (DCA) and Kaplan-Meier (KM) curves were used to estimate the clinical applicability. Marital status, tumor metastasis (brain, liver, and lung), primary site surgery, and chemotherapy were indicated as independent prognostic factors for OS and CSS. Calibration plots and the overall C-index showed a novel agreement between the observed and predicted outcomes. Nomograms revealed significant advantages in OS and CSS predictions. AUCs for internal and external validation were listed as follows for OS, 3-month AUCs were 0.853 and 0.849 6-month AUCs were 0.873 and 0.832 12-month AUCs were 0.825 and 0.805 for CSS, 3-month AUCs were 0.849 and 0.847 6-month AUCs were 0.870 and 0.824 12-month AUCs were 0.815 and 0.797, respectively. DCA curves demonstrated good clinical benefit, and KM curves showed distinct stratification performance. The nomograms as web-based tools were proved to be accurate, efficient, and clinically beneficial, which might help in patient management and clinical decision-making for BCBM patients.

HMNet Hierarchical Multi-Scale Brain Tumor Segmentation Network.

An accurate and efficient automatic brain tumor segmentation algorithm is important for clinical practice. In recent years, there has been much interest in automatic segmentation algorithms that use convolutional neural networks. In this paper, we propose a novel hierarchical multi-scale segmentation network (HMNet), which contains a high-resolution branch and parallel multi-resolution branches. The high-resolution branch can keep track of the brain tumors spatial details, and the multi-resolution feature exchange and fusion allow the networks receptive fields to adapt to brain tumors of different shapes and sizes. In particular, to overcome the large computational overhead caused by expensive 3D convolution, we propose a lightweight conditional channel weighting block to reduce GPU memory and improve the efficiency of HMNet. We also propose a lightweight multi-resolution feature fusion (LMRF) module to further reduce model complexity and reduce the redundancy of the feature maps. We run tests on the BraTS 2020 dataset to determine how well the proposed network would work. The dice similarity coefficients of HMNet for ET, WT, and TC are 0.781, 0.901, and 0.823, respectively. Many comparative experiments on the BraTS 2020 dataset and other two datasets show that our proposed HMNet has achieved satisfactory performance compared with the SOTA approaches.

First Clinical Report of the Intraoperative Macro- and Micro-Photodiagnosis and Photodynamic Therapy Using Talaporfin Sodium for a Patient with Disseminated Lumbar Medulloblastoma.

Photodiagnosis (PD) and photodynamic therapy (PDT) using the second-generation photosensitizer talaporfin sodium together with an exciting laser for primary intracranial malignant tumors is well recognized in Japan, and many medical institutions are introducing this new therapeutic option. In particular, intraoperative PDT using talaporfin sodium for infiltrating tumor cells in the cavity walls after the resection of malignant glioma is now covered by health insurance after receiving governmental approvement, and this method has been recommended in therapeutic guidelines for primary malignant brain tumors in Japan. On the other hand, experimental and clinical studies on the development of novel therapeutic strategies for malignant spinal cord tumors have not been reported to date, although their histological features are almost identical to those of intracranial malignant tumors. Therefore, the clinical outcomes of malignant spinal cord tumors have been less favorable than those of malignant brain tumors. In this report, we performed the PD and PDT using talaporfin sodium on a patient with a metastatic lumbar lesion that was detected on magnetic resonance image (MRI) 50 months after the resection of cerebellar medulloblastoma who presented with lumbago and sciatica. We were able to detect the target lesion in the conus medullaris using a surgical microscope, and detected the disseminated medulloblastoma cells floating in the cerebrospinal fluid using a compact fluorescence microscope. Furthermore, we performed PDT to the resected lumbar lesion with the adjuvant platinum-based chemotherapy, and the patient survived a meaningful life for more than 2 years after the lumbar surgery. This report describes the first case of a human patient in whom the efficacy of PD and PDT was demonstrated for a malignant spinal cord tumor.

Neuroprotective Effects and Metabolomics Study of Protopanaxatriol (PPT) on Cerebral IschemiaReperfusion Injury In Vitro and In Vivo.

Stroke, one of the leading causes of disability and death worldwide, is a severe neurological disease that threatens human life. Protopanaxatriol (PPT), panaxatriol-type saponin aglycone, is a rare saponin that exists in

ProNGF Expression and Targeting in Glioblastoma Multiforme.

Glioblastoma multiforme (GBM) is the most lethal adult brain cancer. Temozolomide (TMZ), the standard chemotherapeutic drug used in GBM, has limited benefit and alternate therapies are needed to improve GBM treatment. Nerve growth factor (NGF) and its precursor proNGF are increasingly recognized as stimulators of human tumor progression. The expression and stimulatory effect of NGF on GBM cell growth has previously been reported, but the status of proNGF in GBM is unreported. In this study, we have investigated proNGF expression and biological activity in GBM. A clinical cohort of GBM (

Comparative Evaluation of Reproducibility of Phage-Displayed Peptide Selections and NGS Data, through High-Fidelity Mapping of Massive Peptide Repertoires.

Phage-displayed peptide selections generate complex repertoires of several hundred thousand peptides as revealed by next-generation sequencing (NGS). In repeated peptide selections, however, even in identical experimental in vitro conditions, only a very small number of common peptides are found. The repertoire complexities are evidence of the difficulty of distinguishing between effective selections of specific peptide binders to exposed targets and the potential high background noise. Such investigation is even more relevant when considering the plethora of in vivo expressed targets on cells, in organs or in the entire organism to define targeting peptide agents. In the present study, we compare the published NGS data of three peptide repertoires that were obtained by phage display under identical experimental in vitro conditions. By applying the recently developed tool PepSimili we evaluate the calculated similarities of the individual peptides from each of these three repertoires and perform their mappings on the human proteome. The peptide-to-peptide mappings reveal high similarities among the three repertoires, confirming the desired reproducibility of phage-displayed peptide selections.

Fluoride in the Central Nervous System and Its Potential Influence on the Development and Invasiveness of Brain Tumours-A Research Hypothesis.

The purpose of this review is to attempt to outline the potential role of fluoride in the pathogenesis of brain tumours, including glioblastoma (GBM). In this paper, we show for the first time that fluoride can potentially affect the generally accepted signalling pathways implicated in the formation and clinical course of GBM. Fluorine compounds easily cross the blood-brain barrier. Enhanced oxidative stress, disruption of multiple cellular pathways, and microglial activation are just a few examples of recent reports on the role of fluoride in the central nervous system (CNS). We sought to present the key mechanisms underlying the development and invasiveness of GBM, as well as evidence on the current state of knowledge about the pleiotropic, direct, or indirect involvement of fluoride in the regulation of these mechanisms in various tissues, including neural and tumour tissue. The effects of fluoride on the human body are still a matter of controversy. However, given the growing incidence of brain tumours, especially in children, and numerous reports on the effects of fluoride on the CNS, it is worth taking a closer look at these mechanisms in the context of brain tumours, including gliomas.

α-Synuclein Induces Neuroinflammation Injury through the

The aggregation of α-synuclein (α-syn) promotes neuroinflammation and neuronal apoptosis, which eventually contribute to the pathogenesis of Parkinsons disease (PD). Our microarray analysis and experimental data indicated a significant expression difference of the long noncoding RNA

Antibody Profiling and In Silico Functional Analysis of Differentially Reactive Antibody Signatures of Glioblastomas and Meningiomas.

Studies on tumor-associated antigens in brain tumors are sparse. There is scope for enhancing our understanding of molecular pathology, in order to improve on existing forms, and discover new forms, of treatment, which could be particularly relevant to immuno-oncological strategies. To elucidate immunological differences, and to provide another level of biological information, we performed antibody profiling, based on a high-density protein array (containing 8173 human transcripts), using IgG isolated from the sera of

Emerging Perspectives on the Antiparasitic Mebendazole as a Repurposed Drug for the Treatment of Brain Cancers.

Repurposing approved non-antitumor drugs is a promising and affordable strategy in drug discovery to identify new therapeutic uses different from the original medical indication that may help increase the number of possible, effective anticancer drugs. The use of drugs in ways other than their original FDA-approved indications could offer novel avenues such as bypassing the chemoresistance and recurrence seen with conventional therapy and treatment moreover, it can offer a safe and economic strategy for combination therapy. Recent works have demonstrated the anticancer properties of the FDA-approved drug Mebendazole. This synthetic benzimidazole proved effective against a broad spectrum of intestinal Helminthiasis. Mebendazole can penetrate the blood-brain barrier and has been shown to inhibit the malignant progression of glioma by targeting signaling pathways related to cell proliferation, apoptosis, or invasionmigration, or by increasing the sensitivity of glioma cells to conventional chemotherapy or radiotherapy. Moreover, several preclinical models and ongoing clinical trials explore the efficacy of Mebendazole in multiple cancers, including acute myeloid leukemia, brain cancer, oropharyngeal squamous cell carcinoma, breast cancer, gastrointestinal cancer, lung carcinoma, adrenocortical carcinoma, prostate cancer, and head and neck cancer. The present review summarizes central literature regarding the anticancer effects of MBZ in cancer cell lines, animal tumor models, and clinical trials to suggest possible strategies for safe and economical combinations of anticancer therapies in brain cancer. Mebendazole might be an excellent candidate for the treatment of brain tumors because of its efficacy both when used as monotherapy and in combination as an enhancement to standard chemotherapeutics and radiotherapy, due to its effectiveness on tumor angiogenesis inhibition, cell cycle arrest, apoptosis induction, and targeting of critical pathways involved in cancer such as Hedgehog signaling. Therefore, attention to MBZ repurposing has recently increased because of its potential therapeutic versatility and significant clinical implications, such as reducing medical care costs and optimizing existing therapies. Using new treatments is essential, particularly when current therapeutics for patients with brain cancer fail.

Emerging Roles of Hedgehog Signaling in Cancer Immunity.

Hedgehog-GLI (HH) signaling plays an essential role in embryogenesis and tissue homeostasis. Aberrant activation of the pathway through mutations or other mechanisms is involved in the development and progression of numerous types of cancer, including basal cell carcinoma, medulloblastoma, melanoma, breast, prostate, hepatocellular and pancreatic carcinomas. Activation of HH signaling sustains proliferation, suppresses cell death signals, enhances invasion and metastasis, deregulates cellular metabolism and promotes angiogenesis and tumor inflammation. Targeted inhibition of the HH pathway has therefore emerged as an attractive therapeutic strategy for the treatment of a wide range of cancers. Currently, the Smoothened (SMO) receptor and the downstream GLI transcriptional factors have been investigated for the development of targeted drugs. Recent studies have revealed that the HH signaling is also involved in tumor immune evasion and poor responses to cancer immunotherapy. Here we focus on the effects of HH signaling on the major cellular components of the adaptive and innate immune systems, and we present recent discoveries elucidating how the immunosuppressive function of the HH pathway is engaged by cancer cells to prevent immune surveillance. In addition, we discuss the future prospect of therapeutic options combining the HH pathway and immune checkpoint inhibitors.

Increased Expression of the Δ133p53β Isoform Enhances Brain Metastasis.

The Δ133p53β isoform is increased in many primary tumors and has many tumor-promoting properties that contribute to increased proliferation, migration and inflammation. Here we investigated whether Δ133p53β contributed to some of the most aggressive tumors that had metastasized to the brain.

Metal Complexes as Promising Matrix Metalloproteinases Regulators.

Nowadays, cancers and dementia, such as Alzheimers disease, are the most fatal causes of death. Many studies tried to understand the pathogenesis of those diseases clearly and develop a promising way to treat the diseases. Matrix metalloproteinases (MMPs) have been reported to be involved in the pathology of cancers and AD through tumor cell movement and amyloid degradation. Therefore, control of the levels and actions of MMPs, especially MMP-2 and MMP-9, is necessary to care for andor cure cancer and AD. Various molecules have been examined for their potential application as regulators of MMPs expression and activity. Among the molecules, multiple metal complexes have shown advantages, including simple synthesis, less toxicity and specificity toward MMPs in cancer cells or in the brain. In this review, we summarize the recent studies and knowledge of metal complexes (e.g., Pt-, Ru-, Au-, Fe-, Cu-, Ni-, Zn-, and Sn-complexes) targeting MMPs and their potentials for treating andor caring the most fatal human diseases, cancers and AD.

PolyploidMultinucleated Giant and Slow-Cycling Cancer Cell Enrichment in Response to X-ray Irradiation of Human Glioblastoma Multiforme Cells Differing in Radioresistance and TP53PTEN Status.

Radioresistance compromises the efficacy of radiotherapy for glioblastoma multiforme (GBM), the most devastating and common brain tumor. The present study investigated the relationship between radiation tolerance and formation of polyploidmultinucleated giant (PGCCMGCC) and quiescentsenescent slow-cycling cancer cells in human U-87, LN-229, and U-251 cell lines differing in

Kalkitoxin A Potent Suppressor of Distant Breast Cancer Metastasis.

Bone metastasis resulting from advanced breast cancer causes osteolysis and increases mortality in patients. Kalkitoxin (KT), a lipopeptide toxin derived from the marine cyanobacterium

Tumor Necrosis Factor (TNF)-α-Stimulated Gene 6 (TSG-6) A Promising Immunomodulatory Target in Acute Neurodegenerative Diseases.

Tumor necrosis factor (TNF)-α-stimulated gene 6 (TSG-6), the first soluble chemokine-binding protein to be identified in mammals, inhibits chemotaxis and transendothelial migration of neutrophils and attenuates the inflammatory response of dendritic cells, macrophages, monocytes, and T cells. This immunoregulatory protein is a pivotal mediator of the therapeutic efficacy of mesenchymal stemstromal cells (MSC) in diverse pathological conditions, including neuroinflammation. However, TSG-6 is also constitutively expressed in some tissues, such as the brain and spinal cord, and is generally upregulated in response to inflammation in monocytesmacrophages, dendritic cells, astrocytes, vascular smooth muscle cells and fibroblasts. Due to its ability to modulate sterile inflammation, TSG-6 exerts protective effects in diverse degenerative and inflammatory diseases, including brain disorders. Emerging evidence provides insights into the potential use of TSG-6 as a peripheral diagnostic andor prognostic biomarker, especially in the context of ischemic stroke, whereby the pathobiological relevance of this protein has also been demonstrated in patients. Thus, in this review, we will discuss the most recent data on the involvement of TSG-6 in neurodegenerative diseases, particularly focusing on relevant anti-inflammatory and immunomodulatory functions. Furthermore, we will examine evidence suggesting novel therapeutic opportunities that can be afforded by modulating TSG-6-related pathways in neuropathological contexts and, most notably, in stroke.

Different Approaches to Study Molecular Blueprint and Biological Behavior of Brain Tumors Editorial to the Special Issue Advances in Molecular Genetics of Brain Tumors.

Cancer remains one of the leading causes of mortality worldwide ....

Recommendations from Latinx Trans and Non-Binary Individuals to Promote Cancer Prevention in Puerto Rico and Florida.

Latinx trans and non-binary individuals (LTNB) face increased cancer-related health disparities. Studies evidence how barriers at the individual, provider and organizational levels drive cancer disparities among LTNB individuals. These barriers increase the emotional discomfort associated with testing and disengagement from cancer prevention efforts. Moreover, there are no guidelines or interventions that address cancer prevention specifically among LTNB individuals. There is a need to develop interventions informed by the LTNB communities to promote cancer prevention and screening. The study aims to describe the recommendations provided by LTNB individuals to foster cancer screening and prevention in the communities residing in Puerto Rico and Florida. We conducted two online focus groups with a total of 15 LTNB participants. Participants were recruited using non-probabilistic purposive sampling. We used rapid-qualitative analysis for data interpretation. Findings are gathered in three main themes (1) recommendations for promoting cancer prevention screening among providers (2) specific recommendations to promote cancer screening among LTBN individuals and (3) recommendations on delivery formats to foster cancer prevention. These results evidence the need and feasibility of developing community informed tailored interventions targeting cancer screening and preventative care to reduce cancer-related health disparities among the LTNB population.

The Impact of Ellagitannins and Their Metabolites through Gut Microbiome on the Gut Health and Brain Wellness within the Gut-Brain Axis.

Ellagitannins (ETs) are a large group of bioactive compounds found in plant-source foods, such as pomegranates, berries, and nuts. The consumption of ETs has often been associated with positive effects on many pathologies, including cardiovascular diseases, neurodegenerative syndromes, and cancer. Although multiple biological activities (antioxidant, anti-inflammatory, chemopreventive) have been discussed for ETs, their limited bioavailability prevents reaching significant concentrations in systemic circulation. Instead, urolithins, ET gut microbiota-derived metabolites, are better absorbed and could be the bioactive molecules responsible for the antioxidant and anti-inflammatory activities or anti-tumor cell progression. In this review, we examined the dietary sources, metabolism, and bioavailability of ETs, and analyzed the last recent findings on ETs, ellagic acid, and urolithins, their intestinal and brain activities, the potential mechanisms of action, and the connection between the ET microbiota metabolism and the consequences detected on the gut-brain axis. The current in vitro, in vivo, and clinical studies indicate that ET-rich foods, individual gut microbiomes, or urolithin types could modulate signaling pathways and promote beneficial health effects. A better understanding of the role of these metabolites in disease pathogenesis may assist in the prevention or treatment of pathologies targeting the gut-brain axis.

A Novel Lightweight CNN Architecture for the Diagnosis of Brain Tumors Using MR Images.

Over the last few years, brain tumor-related clinical cases have increased substantially, particularly in adults, due to environmental and genetic factors. If they are unidentified in the early stages, there is a risk of severe medical complications, including death. So, early diagnosis of brain tumors plays a vital role in treatment planning and improving a patients condition. There are different forms, properties, and treatments of brain tumors. Among them, manual identification and classification of brain tumors are complex, time-demanding, and sensitive to error. Based on these observations, we developed an automated methodology for detecting and classifying brain tumors using the magnetic resonance (MR) imaging modality. The proposed work includes three phases pre-processing, classification, and segmentation. In the pre-processing, we started with the skull-stripping process through morphological and thresholding operations to eliminate non-brain matters such as skin, muscle, fat, and eyeballs. Then we employed image data augmentation to improve the model accuracy by minimizing the overfitting. Later in the classification phase, we developed a novel lightweight convolutional neural network (lightweight CNN) model to extract features from skull-free augmented brain MR images and then classify them as normal and abnormal. Finally, we obtained infected tumor regions from the brain MR images in the segmentation phase using a fast-linking modified spiking cortical model (FL-MSCM). Based on this sequence of operations, our framework achieved 99.58% classification accuracy and 95.7% of dice similarity coefficient (DSC). The experimental results illustrate the efficiency of the proposed framework and its appreciable performance compared to the existing techniques.

Upstaging and Downstaging in Gliomas-Clinical Implications for the Fifth Edition of the World Health Organization Classification of Tumors of the Central Nervous System.

In 2021, the 5th edition of the WHO Classification of Tumors of the Central Nervous System (WHO-CNS5) was published as the sixth volume of the international standard for brain and spinal cord tumor classification. The most remarkable practical change in the current classification involves grading gliomas according to molecular characterization. IDH mutant (10%) and IDH wild-type tumors (90%) are two different entities that possess unique biological features and various clinical outcomes regarding treatment response and overall survival. This article presents two comparative cases that highlight the clinical importance of these new classification standards. The first clinical case aimed to provide a comprehensive argument for determining the IDH status in tumors initially appearing as low-grade astrocytoma upon histologic examination, thus underlining the importance of the WHO-CNS5. The second case showed the implications of the histologic overdiagnosis of glioblastoma using the previous classification system with a treatment span of 7 years that proceeded through full-dose re-irradiation up to metronomic therapy. The new WHO-CNS5 classification significantly impacted complex neurooncological cases, thus changing the initial approach to a more precise therapeutic management.

Spinal Metastasis in a Patient with Supratentorial Glioblastoma with Primitive Neuronal Component A Case Report with Clinical and Molecular Evaluation.

Glioblastoma (GBM) is regarded as an aggressive brain tumor that rarely develops extracranial metastases. Despite well-investigated molecular alterations in GBM, there is a limited understanding of these associated with the metastatic potential. We herein present a case report of a 43-year-old woman with frontal GBM with primitive neuronal component who underwent gross total resection followed by chemoradiation. Five months after surgery, the patient was diagnosed with an intraspinal GBM metastasis. Next-generation sequencing analysis of both the primary and metastatic GBM tissues was performed using the Illumina TruSight Tumor 170 assay. The number of single nucleotide variants observed in the metastatic sample was more than two times higher. Mutations in

DNA Damage Response and Repair in Boron Neutron Capture Therapy.

Boron neutron capture therapy (BNCT) is an approach to the radiotherapy of solid tumors that was first outlined in the 1930s but has attracted considerable attention recently with the advent of a new generation of neutron sources. In BNCT, tumor cells accumulate

Computer-Aided Early Melanoma Brain-Tumor Detection Using Deep-Learning Approach.

Brain tumors affect the normal functioning of the brain and if not treated in time these cancerous cells may affect the other tissues, blood vessels, and nerves surrounding these cells. Today, a large population worldwide is affected by the precarious disease of the brain tumor. Healthy tissues of the brain are suspected to be damaged because of tumors that become the most significant reason for a large number of deaths nowadays. Therefore, their early detection is necessary to prevent patients from unfortunate mishaps resulting in loss of lives. The manual detection of brain tumors is a challenging task due to discrepancies in appearance in terms of shape, size, nucleus, etc. As a result, an automatic system is required for the early detection of brain tumors. In this paper, the detection of tumors in brain cells is carried out using a deep convolutional neural network with stochastic gradient descent (SGD) optimization algorithm. The multi-classification of brain tumors is performed using the ResNet-50 model and evaluated on the public Kaggle brain-tumor dataset. The method achieved 99.82% and 99.5% training and testing accuracy, respectively. The experimental result indicates that the proposed model outperformed baseline methods, and provides a compelling reason to be applied to other diseases.

Therapy Defining at Initial Diagnosis of Primary Brain Tumor-The Role of

Primary malignant brain tumors are heterogeneous and infrequent neoplasms. Their classification, therapeutic regimen and prognosis have undergone significant development requiring the innovation of an imaging diagnostic. The performance of enhanced magnetic resonance imaging depends on blood-brain barrier function. Several studies have demonstrated the advantages of static and dynamic amino acid PETCT providing accurate metabolic status in the neurooncological setting. The aim of our single-center retrospective study was to test the primary diagnostic role of amino acid PETCT compared to enhanced MRI. Emphasis was placed on cases prior to intervention, therefore, a certain natural bias was inevitable. In our analysis for newly found brain tumors

Impact of Liver Metastases and Number of Metastatic Sites on Immune-Checkpoint Inhibitors Efficacy in Patients with Different Solid Tumors A Retrospective Study.

ICIs have dramatically improved patient outcomes in different malignancies. However, the impact of liver metastases (LM) and number of metastatic sites (MS) remains unclear in patients treated with single-agent anti-PD(L)1. We aimed to assess the prognostic impact of LM and MS number on progression-free survival (PFS) and overall survival (OS) in a large single-arm retrospective multicentric cohort (IMMUCARE) of patients treated with anti-PD(L)-1 for different solid tumors. A total of 759 patients were enrolled from January 2012 to October 2018. The primary tumor types were non-small cell lung cancer (71%), melanoma (19%), or urologic cancer (10%). At the time of ICI initiation, 167 patients (22%) had LM and 370 patients (49%) had more than MS. LM was associated with a shorter median PFS of 1.9 months (95% CI 1.8-2.5) vs. 4.0 months (95% CI 3.6-5.4) in patients without LM ( The presence of LM or multiple MS were associated with poorer survival outcomes in patients treated with anti-PD(L)-1.

Indisulam Reduces Viability and Regulates Apoptotic Gene Expression in Pediatric High-Grade Glioma Cells.

Pediatric high-grade glioma (pHGG) is one of the most aggressive brain tumors. Treatment includes surgery, radiotherapy, chemotherapy, or combination therapy in children older than 3-5 years of age. These devastating tumors are influenced by the hypoxic microenvironment that coordinatively increases the expression of carbonic anhydrases (CA9 and CA12) that are involved in pH regulation, metabolism, cell invasion, and resistance to therapy. The synthetic sulphonamide Indisulam is a potent inhibitor of CAs. The aim of this study was to evaluate the effects of Indisulam on CA9 and CA12 enzymes in pHGG cell lines. Our results indicated that, under hypoxia, the gene and protein expression of CA9 and CA12 are increased in pHGG cells. The functional effects of Indisulam on cell proliferation, clonogenic capacity, and apoptosis were measured in vitro. CA9 and CA12 gene and protein expression were analyzed by RT-PCR and western blot. The treatment with Indisulam significantly reduced cell proliferation (dose-time-dependent) and clonogenic capacity (

An Update on Circular RNA in Pediatric Cancers.

Circular RNAs (circRNAs) are a class of single-stranded closed noncoding RNA molecules which are formed as a result of reverse splicing of mRNAs. Despite their relative abundance, only recently there appeared an increased interest in the understanding of their regulatory importance. Among their most relevant characteristics are high stability, abundance and evolutionary conservation among species. CircRNAs are implicated in several cellular functions, ranging from miRNA and protein sponges to transcriptional modulation and splicing. Additionally, circRNAs aberrant expression in pathological conditions is bringing to light their possible use as diagnostic and prognostic biomarkers. Their use as indicator molecules of pathological changes is also supported by their peculiar covalent closed cyclic structure which bestows resistance to RNases. Their regulatory role in cancer pathogenesis and metastasis is supported by studies involving human tumors that have investigated different expression profiles of these molecules. As endogenous competitive RNA, circRNAs can regulate tumor proliferation and invasion and they arouse great consideration as potential therapeutic biomarkers and targets for cancer. In this review, we describe the most recent findings on circRNAs in the most common pediatric solid cancers (such as brain tumors, neuroblastomas, and sarcomas) and in more rare ones (such as Wilms tumors, hepatoblastomas, and retinoblastomas).

Correction Gonçalves et al. Macrophage and Lymphocyte Infiltration Is Associated with Volumetric Tumor Size but Not with Volumetric Growth in the Tübingen Schwannoma Cohort.

The authors would like to make a correction to their published paper ....

Multimodal Deep Learning-Based Prognostication in Glioma Patients A Systematic Review.

Malignant brain tumors pose a substantial burden on morbidity and mortality. As clinical data collection improves, along with the capacity to analyze it, novel predictive clinical tools may improve prognosis prediction. Deep learning (DL) holds promise for integrating clinical data of various modalities. A systematic review of the DL-based prognostication of gliomas was performed using the Embase (Elsevier), PubMed MEDLINE (National library of Medicine), and Scopus (Elsevier) databases, in accordance with PRISMA guidelines. All included studies focused on the prognostication of gliomas, and predicted overall survival (13 studies, 81%), overall survival as well as genotype (2 studies, 12.5%), and response to immunotherapy (1 study, 6.2%). Multimodal analyses were varied, with 6 studies (37.5%) combining MRI with clinical data 6 studies (37.5%) integrating MRI with histologic, clinical, and biomarker data 3 studies (18.8%) combining MRI with genomic data and 1 study (6.2%) combining histologic imaging with clinical data. Studies that compared multimodal models to unimodal-only models demonstrated improved predictive performance. The risk of bias was mixed, most commonly due to inconsistent methodological reporting. Overall, the use of multimodal data in DL assessments of gliomas leads to a more accurate overall survival prediction. However, due to data limitations and a lack of transparency in model and code reporting, the full extent of multimodal DL as a resource for brain tumor patients has not yet been realized.