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Long-term administration of CU06-1004 ameliorates cerebrovascular aging and BBB injury in aging mouse model.

Age-related changes in the cerebrovasculature, including blood-brain barrier (BBB) disruption and vascular dementia, are emerging as potential risks for many neurodegenerative diseases. Therefore, the endothelial cells that constitute the cerebrovasculature may play key roles in preventing brain injury. Our previous study showed that CU06-1004, an endothelial cell dysfunction blocker, prevented vascular leakage, enhanced vascular integrity in ischemic reperfusion injury, and promoted the normalization of tumor vasculature. Here, we evaluated the effects of CU06-1004 on age-related cerebrovascular functional decline in the aged mouse brain. In this study, we investigated the protective effects of CU06-1004 against oxidative stress-induced damage in human brain microvascular endothelial cells (HBMECs). HBMECs were treated with hydrogen peroxide (H These findings suggest that CU06-1004 may represent a promising therapeutic approach for delaying age-related cerebrovascular impairment and improving cognitive function in old age.

The collateral activity of RfxCas13d can induce lethality in a RfxCas13d knock-in mouse model.

The CRISPR-Cas13 system is an RNA-guided RNA-targeting system and has been widely used in transcriptome engineering with potentially important clinical applications. However, it is still controversial whether Cas13 exhibits collateral activity in mammalian cells. Here, we find that knocking down gene expression using RfxCas13d in the adult brain neurons caused death of mice, which may result from the collateral activity of RfxCas13d rather than the loss of target gene function or off-target effects. Mechanistically, we show that RfxCas13d exhibits collateral activity in mammalian cells, which is positively correlated with the abundance of target RNA. The collateral activity of RfxCas13d could cleave 28s rRNA into two fragments, leading to translation attenuation and activation of the ZAKα-JNKp38-immediate early gene pathway. These findings provide new mechanistic insights into the collateral activity of RfxCas13d in mammalian cells and warn that the biosafety of the CRISPR-Cas13 system needs further evaluation before application to clinical treatments.

A case report of an ischaemic stroke, caused by a primary cardiac intimal sarcoma.

Intimal sarcomas are an extremely rare type of primary cardiac malignancy. They most commonly present with symptoms of cardiac dysfunction. We present a case of intimal sarcoma identified without any cardiac signs or symptoms. Cardiac sarcomas historically carry a very poor prognosis. A 57-year-old man presented with a sudden onset of left limb weakness and disorientation. MRI brain identified an acute ischaemic stroke in the right anterior temporal lobe. Four months later, he presented again with transient left arm weakness. The patient had a normal cardiovascular examination and ECG. All other initial investigations for cryptogenic stroke were non-contributory. The patient did not initially get an echocardiogram. When this investigation was performed, after his second presentation, a large pedunculated mass was present in his left atrium. This was resected and identified histologically as a primary intimal sarcoma of his left atrium. The patient was treated with post-operative radiotherapy but declined chemotherapy. He recovered well post-operatively but subsequently passed away 14 months after diagnosis. It is possible for primary cardiac malignancies to present with only symptoms of systemic emboli. For this reason, echocardiography is a crucial investigation in cases of cryptogenic stroke. Some stroke guidelines do not definitively support routine echocardiography. Primary intimal cardiac sarcoma is a very rare condition with a poor prognosis. The literature is limited to case reports and optimal management is with surgical resection where possible. The role of post operative radiotherapy and chemotherapy is uncertain.

Single-cell spatial immune landscapes of primary and metastatic brain tumours.

Single-cell technologies have enabled the characterization of the tumour microenvironment at unprecedented depth and have revealed vast cellular diversity among tumour cells and their niche. Anti-tumour immunity relies on cell-cell relationships within the tumour microenvironment

143D, a novel selective KRAS

The KRAS

GPR162 activates STING dependent DNA damage pathway as a novel tumor suppressor and radiation sensitizer.

In the treatment of most malignancies, radiotherapy plays a significant role. However, the resistance of cancer cells to ionizing radiation (IR) is the main reason for the failure of radiotherapy, which causes tumor recurrence and metastasis. In this study, we confirmed that GPR162, an orphan receptor in the G-protein-coupled receptor family, acted as a novel radiotherapy sensitizer by interacting with the stimulator of interferon genes (STING), which targeted DNA damage responses, activated IRF3, accelerated the activation of type I interferon system, promoted the expression of chemokines including CXCL10 and CXCL4, and inhibited the occurrence and development of tumors. Interestingly, the activation of STING by overexpression of GPR162 was independent of the classical pathway of cGAS. STING inhibitors could resist the antitumor effect of overexpression of GPR162 in IR-induced mouse models. In addition, most solid tumors showed low expression of GPR162. And the higher expression of GPR162 indicated a better prognosis in patients with lung adenocarcinoma, liver cancer, breast cancer, etc. In summary, these results suggested that GPR162 may serve as a potential sensitizer of radiotherapy by promoting radiotherapy-induced STING-IFN production and increasing the expression of chemokines including CXCL10 and CXCL4 in DNA damage response, providing an alternative strategy for improving cancer radiotherapy.

Qualitative and Quantitative Magnetic Resonance Imaging Phenotypes May Predict CDKN2AB Homozygous Deletion Status in Isocitrate Dehydrogenase-Mutant Astrocytomas A Multicenter Study.

Cyclin-dependent kinase inhibitor (CDKN)2AB homozygous deletion is a key molecular marker of isocitrate dehydrogenase (IDH)-mutant astrocytomas in the 2021 World Health Organization. We aimed to investigate whether qualitative and quantitative MRI parameters can predict CDKN2AB homozygous deletion status in IDH-mutant astrocytomas. Preoperative MRI data of 88 patients (mean age ± standard deviation, 42.0 ± 11.9 years 40 females and 48 males) with IDH-mutant astrocytomas (76 without and 12 with CDKN2AB homozygous deletion) from two institutions were included. A qualitative imaging assessment was performed. Mean apparent diffusion coefficient (ADC), 5th percentile of ADC, mean normalized cerebral blood volume (nCBV), and 95th percentile of nCBV were assessed via automatic tumor segmentation. Logistic regression was performed to determine the factors associated with CDKN2AB homozygous deletion in all 88 patients and a subgroup of 47 patients with histological grades 3 and 4. The discrimination performance of the logistic regression models was evaluated using the area under the receiver operating characteristic curve (AUC). In multivariable analysis of all patients, infiltrative pattern (odds ratio OR 4.25, The presence of an infiltrative pattern, larger maximal diameter, and higher 95th percentile of the nCBV may be useful MRI biomarkers for CDKN2AB homozygous deletion in IDH-mutant astrocytomas.

Polyhedral Oligomeric Silsesquioxane-Based Nanoparticles for Efficient Chemotherapy of Glioblastoma.

Glioblastoma (GBM) is the most common lethal brain tumor with dismal treatment outcomes and poor response to chemotherapy. As the regulatory center of cytogenetics and metabolism, most tumor chemotherapeutic molecules exert therapeutic effects in the nucleus. Nanodrugs showing the nuclear aggregation effect are expected to eliminate and fundamentally suppress tumor cells. In this study, a nanodrug delivery system based on polyhedral oligomeric silsesquioxane (POSS) is introduced to deliver drugs into the nuclei of GBM cells, effectively enhancing the therapeutic efficacy of chemotherapy. The nanoparticles are modified with folic acid and iRGD peptides molecules to improve their tumor cell targeting and uptake via receptor-mediated endocytosis. Nuclear aggregation allows for the direct delivery of chemotherapeutic drug temozolomide (TMZ) to the tumor cell nuclei, resulting in more significant DNA damage and inhibition of tumor cell proliferation. Herein, TMZ-loaded POSS nanoparticles can significantly improve the survival of GBM-bearing mice. Therefore, the modified POSS nanoparticles may serve as a promising drug-loaded delivery platform to improve chemotherapy outcomes in GBM patients.

Anti-depression targets and mechanism study of Kaixin San.

This study identified the anti-depression targets of Kaixin San(KXS) in the brain tissue with quottarget fishingquot strategy, and explored the target-associated pharmacological signaling pathways to reveal the anti-depression molecular mechanism of KXS. The Balbc mouse model of depression was established by chronic unpredictable mild stress(CUMS) and the anti-depression effect of KXS was evaluated by forced swimming test and sucrose preference test. KXS active components were bonded to the benzophenone-modified magnetic nanoparticles by photocrosslinking reaction for capturing target proteins from cortex, thalamus and hippocampus of depressive mice. The target proteins were identified by liquid chromatography-mass spectrometrymass spectrometry(LC-MSMS). The enrichment analysis on signaling pathways was performed by Cytoscape. The potential biological functions of targets were verified by immunohistochemistry and Western blot assay. The results showed that KXS significantly improved the behavioral indexes. There were 64, 91, and 44 potential targets of KXS identified in cortex, thalamus, and hippocampus, respectively, according to the target identification experiment. The functions of these targets were mainly associated with vasopressin-regulated water reabsorption, salmonella infection, thyroid hormone synthesis, and other signaling pathways. Besides, the results of immunohistochemistry and Western blot showed that KXS up-regulated the expressions of argipressine(AVP) in the cortex, heat shock protein 60(HSP60), cytochrome C oxidase 4(COX4), and thyrotropin-releasing hormone(TRH) in the thalamus, and down-regulated the expressions of tumor necrosis factor-α(TNF-α) and nuclear factor kappa B(NF-κB) p65 in the thalamus. Therefore, KXS may exert anti-depression effect through regulating vasopressin signaling pathway in the cortex and inflammation, energy metabolism, and thyroid hormone signaling pathways in the thalamus, and the effect of KXS on hippocampus is not significant.

Mechanism of total flavonoids of Rhododendra simsii in alleviating ischemic brain injury.

This study explores the effect of total flavonoids of Rhododendra simsii(TFR) on middle cerebral artery occlusion(MCAO)-induced cerebral injury in rats and oxygen-glucose deprivationreoxygenation(OGDR) injury in PC12 cells and the underlying mechanism. The MCAO method was used to induce focal ischemic cerebral injury in rats. Male SD rats were randomized into sham group, model group, and TFR group. After MCAO, TFR(60 mg·kg(-1)) was administered for 3 days. The content of tumor necrosis factor-α(TNF-α), interleukin-1(IL-1), and interleukin-6(IL-6) in serum was detected by enzyme-linked immunosorbent assay(ELISA). The pathological changes of brain tissue and cerebral infarction were observed based on hematoxylin and eosin(HE) staining and 2,3,5-triphenyltetrazolium chloride(TTC) staining. RT-qPCR and Western blot were used to detect the mRNA and protein levels of calcium release-activated calcium channel modulator 1(ORAI1), stromal interaction molecule 1(STIM1), stromal intera-ction molecule 2(STIM2), protein kinase B(PKB), and cysteinyl aspartate specific proteinase 3(caspase-3) in brain tissues. The OGDR method was employed to induce injury in PC12 cells. Cells were randomized into the normal group, model group, gene silencing group, TFR(30 μg·mL(-1)) group, and TFR(30 μg·mL(-1))gene overexpression plasmid group. Intracellular Ca(2) concentration and apoptosis rate of PC12 cells were measured by laser scanning confocal microscopy and flow cytometry. The effect of STIM-ORAI-regulated store-operated calcium entry(SOCE) pathway on TFR was explored based on gene silencing and gene overexpression techniques. The results showed that TFR significantly alleviated the histopathological damage of brains in MCAO rats after 3 days of admini-stration, reduced the contents of TNF-α, IL-1, and IL-6 in the serum, down-regulated the expression of ORAI1, STIM1, STIM2, and caspase-3 genes, and up-regulated the expression of PKB gene in brain tissues of MCAO rats. TFR significantly decreased OGDR induced Ca(2) overload and apoptosis in PC12 cells. However, it induced TFR-like effect by ORAI1, STIM1 and STIM2 genes silencing. However, overexpression of these genes significantly blocked the effect of TFR in reducing Ca(2) overload and apoptosis in PC12 cells. In summary, in the early stage of focal cerebral ischemia-reperfusion injury and OGDR-induced injury in PC12 cells TFR attenuates ischemic brain injury by inhibiting the STIM-ORAI-regulated SOCE pathway and reducing Ca(2) overload and inflammatory factor expression, and apoptosis.

Recommendations on the use of item libraries for patient-reported outcome measurement in oncology trials findings from an international, multidisciplinary working group.

The use of item libraries for patient-reported outcome (PRO) measurement in oncology allows for the customisation of PRO assessment to measure key health-related quality of life concepts of relevance to the target population and intervention. However, no high-level recommendations exist to guide users on the design and implementation of these customised PRO measures (item lists) across different PRO measurement systems. To address this issue, a working group was set up, including international stakeholders (academic, independent, industry, health technology assessment, regulatory, and patient advocacy), with the goal of creating recommendations for the use of item libraries in oncology trials. A scoping review was carried out to identify relevant publications and highlight any gaps. Stakeholders commented on the available guidance for each research question, proposed recommendations on how to address gaps in the literature, and came to an agreement using discussion-based methods. Nine primary research questions were identified that formed the scope and structure of the recommendations on how to select items and implement item lists created from item libraries. These recommendations address methods to drive item selection, plan the structure and analysis of item lists, and facilitate their use in conjunction with other measures. The findings resulted in high-level, instrument-agnostic recommendations on the use of item-library-derived item lists in oncology trials.

First-line nivolumab plus ipilimumab for metastatic non-small cell lung cancer, including patients with ECOG performance status 2 and other special populations CheckMate 817.

CheckMate 817, a phase 3B study, evaluated flat-dose nivolumab plus weight-based ipilimumab in patients with metastatic non-small cell lung cancer (NSCLC). Here, in this research, we report on first-line treatment in patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1 (cohort A) and special populations (cohort A1 ECOG PS 2 or ECOG PS 0-1 with untreated brain metastases, renal impairment, hepatic impairment, or controlled HIV infection). Cohorts A and A1 received nivolumab 240 mg every 2 weeks plus ipilimumab 1 mgkg every 6 weeks. The primary endpoint was the incidence of grade 3-4 and grade 5 immune-mediated adverse events (IMAEs adverse events (AEs) deemed potentially immune-related, occurring <100 days of last dose, and treated with immune-modulating medication (except endocrine events)) and treatment-related select AEs (treatment-related AEs with potential immunological etiology requiring frequent monitoringintervention, reported between first dose and 30 days after the last dose) in cohort A efficacy endpoints were secondaryexploratory. In cohort A1, safetyefficacy assessment was exploratory. The most common grade 3-4 IMAEs were pneumonitis (5.1%), diarrheacolitis (4.9%), and hepatitis (4.6%) in cohort A (N391) and diarrheacolitis (3.5%), hepatitis (3.5%), and rash (3.0%) in cohort A1 (N198). The most common grade 3-4 treatment-related select AEs were hepatic (5.9%), gastrointestinal (4.9%), and pulmonary (4.6%) events in cohort A and gastrointestinal (4.0%), skin (3.5%), and endocrine (3.0%) events in cohort A1. No grade 5 IMAEs or treatment-related select AEs occurred. Treatment-related deaths occurred in 4 (1.0%) and 3 (1.5%) patients in cohorts A and A1, respectively. Three-year overall survival (OS) rates were 33.7% and 20.5%, respectively. Flat-dose nivolumab plus weight-based ipilimumab was associated with manageable safety and durable efficacy in cohort A, consistent with data from phase 3 metastatic NSCLC studies. Special populations of cohort A1 including patients with ECOG PS 2 or ECOG PS 0-1 with untreated brain metastases had manageable treatment-related toxicity and clinically meaningful 3-year OS rate. NCT02869789.

Safety of craniotomy for brain tumor resection in octogenarians and older patients - a matched - cohort analysis.

The incidence of brain tumors has increased in elderly population overtime. Their eligibility to a major surgery remains a questionable subject. This study evaluated prognostic factors and 30-days morbidity and mortality in octogenarian population who underwent craniotomy for resection of brain tumor. A total of 154 patients were divided into two different groups patients above 80 years old and patients below 65 years old. In both groups, patients were stratified based on diagnosis with benign tumors meningioma and malignant tumors high-grade gliomas and metastases. Multivariable logistic regression model with backward elimination method was utilized to identify the independent risk factors for 30-days readmission and post-operative complications. The analysis revealed no significant difference in 30-day readmission ( Octogenarians can withstand craniotomy without any significant increase in 30-day readmission, 30-day mortality and post-operative complications as compared to patients younger than age 65. The ASA score (>3) andor KPS (<70) were the most important prognostic factors for 30-days readmission and mortality.

Longitudinal study on MRI and neuropathological findings Neither DSC-perfusion derived rCBVmax nor vessel densities correlate between newly diagnosed and progressive glioblastoma.

When evaluating MRIs for glioblastoma progression, previous scans are usually included into the review. Nowadays dynamic susceptibility contrast (DSC)-perfusion is an essential component in MR-diagnostics of gliomas, since the extent of hyperperfusion upon first diagnosis correlates with gene expression and survival. We aimed to investigate if this initial perfusion signature also characterizes the glioblastoma at time of progression. If so, DSC-perfusion data from the initial diagnosis could be of diagnostic benefit in follow-up assessments. We retrospectively identified 65 patients with isocitrate dehydrogenase wildtype glioblastoma who had received technically identical DSC-perfusion measurements at initial diagnosis and at time of first progression. We determined maximum relative cerebral blood volume values (rCBVmax) by standardized re-evaluation of the data including leakage correction. In addition, the corresponding tissue samples from 24 patients were examined histologically for the maximum vessel density within the tumor. Differences (paired t-test Wilcoxon matched pairs test) and correlations (Spearman) between the measurements at both timepoints were calculated. The rCBVmax was consistently lower at time of progression compared to rCBVmax at time of first diagnosis (p < .001). There was no correlation between the rCBVmax values at both timepoints (r .12). These findings were reflected in the histological examination, with a lower vessel density in progressive glioblastoma (p .01) and no correlation between the two timepoints (r -.07). Our results suggest that the extent of hyperperfusion in glioblastoma at first diagnosis is not a sustaining tumor characteristic. Hence, the rCBVmax at initial diagnosis should be disregarded when reviewing MRIs for glioblastoma progression.

High 18F-FDG Uptake in a Papillary Craniopharyngioma of the Third Ventricle.

Craniopharyngioma is a benign tumor classified as grade 1 by the World Health Organization Classification of Tumors of the Central Nervous System. We present a rare case of a high-18F-FDG-avidity papillary craniopharyngioma of the third ventricle. A 65-year-old man underwent CT and MRI examinations for gait disturbance, lower-limb weakness, and urinary incontinence, and an oval solid tumor that extended from the suprasellar region to the third ventricle was identified. 18F-FDG PETCT showed high accumulation (SUVmax, 22.3) in the tumor. A transventricular endoscopic tumor biopsy led to the diagnosis of papillary craniopharyngioma.

18FDG PETCT Tumoral and Neurologic Therapeutic Response in a Case of Anti-GABABR Paraneoplastic Limbic Encephalitis.

A 70-year-old man with a history of small cell lung carcinoma 2 years earlier was addressed for the suspicion of a paraneoplastic limbic encephalitis. Brain 18FDG PETCT revealed a bilateral amygdalian and hippocampal hypermetabolism, confirming a limbic encephalitis, and concurrent whole-body 18FDG PETCT showed a small cell lung carcinoma plurifocal metastatic recurrence, consistent with a paraneoplastic limbic encephalitis. 18FDG PETCT follow-up under chemotherapy revealed an almost complete normalization of brain metabolism and a partial metabolic response of the metastatic recurrence, consistent with the good clinical neurological evolution of the patient. This case highlights the clinical-metabolic imaging correlation in paraneoplastic limbic encephalitis.

Pharmacological evaluation of carvacrol anti-migraine potential.

Migraine is a devitalizing neurovascular disorder that affects millions of people worldwide. This study was directed against the determination of the effectiveness of carvacrol against migraine. In silico results revealed that carvacrol possesses specific scoring values of - 4.4 to - 6 against selected targets. In vivo studies showed that carvacrol (25-50 mgKg) decreased migraine pain by reversing thermal allodynia, mechanical allodynia, number of head-scratching, and light phobicity in rats. Levels of glutathione, glutathione-s-transferase, and catalase enhanced in the cortex and trigeminal nucleus caudalis of the animals brain tissues, i.e., cortex and trigeminal nucleus caudalis with the use of carvacrol, while a significant decrease in lipid peroxide level was seen. Histopathological evaluation showed improvement in cellular architecture and a decrease in expression of certain inflammatory markers such as tumor necrosis factor-alpha, nuclear factor kappa B, interleukin-18, and prostaglandin E2 validated by enzyme-linked immune sorbent assay, immunohistochemistry, and western blot analysis. This study indicates that carvacrol exhibits binding affinities against different targets involved in migraine pathology and possesses anti-migraine action, mediated through anti-inflammatory and anti-oxidant pathways.

Association between the morphological features of the central sulcus and the somatomotory representation anatomo-functional evaluation of neuroplasticity through nTMS.

In recent years navigated transcranial magnetic stimulation (nTMS) has emerged as a useful tool for the preoperative mapping of brain cortical areas surrounding neoplastic tissues allowing for maximal safe tumor resection and minimizing new postoperative permanent neurological deficits. Three patients presenting with an intrinsic brain tumor (one metastasis from mammary carcinoma, one high-grade glioma, and one low-grade glioma) located within or in close relationship to the central sulcus were enrolled for this study. The MRI-based morphological and nTMS mapping of the central sulcus of the intact hemisphere was complemented by the examination of the contralateral region harboring the lesion. The findings were independently compared, in search of evidence of tumor-induced neuroplasticity andor signs of parenchymal dislocationinfiltration caused by the tumor. An individual description of each mapping session is provided. Significant discrepancies were observed between morphological MRI and functional nTMS mapping in two patients, demonstrating a tumor-induced shift of distinct cortical areas controlling hand andor facial movements. In the cases of gliomas, a lower MT was detected in the lesioned hemisphere, possibly due to increased electrical excitability caused by the tumor itself. The integration of MRI-based morphological mapping of the central sulcus with the detection of its somatomotor representations through nTMS can assist neurosurgeons when planning the resection of a motor-eloquent tumor, stratifying the risks of secondary neurological deficits. The combination of the two preoperative techniques is able to disclose tumor-induced neural plasticity subsequently guiding a more precise resection.

Apparent Diffusion Coefficient in the Differentiation of Common Pediatric Brain Tumors in the Posterior Fossa Different Region-of-Interest Selection Methods for Time Efficiency, Measurement Reproducibility, and Diagnostic Utility.

This study aimed to explore the diagnostic ability of apparent diffusion coefficient (ADC) values obtained from different region of interest (ROI) measurements in tumor parenchyma for differentiating posterior fossa tumors (PFTs) and the correlations between ADC values and Ki-67. Seventy-three pediatric patients with PFTs who underwent conventional diffusion-weighted imaging were recruited in this study. Five different ROIs were manually drawn by 2 radiologists (ROI-polygon, ROI-3 sections, ROI-3-5 ovals, ROI-more ovals, and ROI-whole). The interreaderintrareader repeatability, time required, diagnostic ability, and Ki-67 correlation analysis of the ADC values based on these ROI strategies were calculated. Both interreader and intrareader reliabilities were excellent for ADC values among the different ROI strategies (intraclass correlation coefficient, 0.899-0.992). There were statistically significant differences in time consumption among the 5 ROI selection methods (P < 0.001). The time required for the ROI-3-5 ovals was the shortest (32.23 ± 5.14 seconds), whereas the time required for the ROI-whole was the longest (204.52 ± 92.34 seconds). The diagnostic efficiency of the ADC values showed no significant differences among the different ROI measurements (P > 0.05). The ADC value was negatively correlated with Ki-67 (r -0.745 to -0.798, all P < 0.0001). The ROI-3-5 ovals method has the best interobserver repeatability, the shortest amount of time spent, and the best diagnostic ability. Thus, it is considered an effective measurement to produce ADC values in the evaluation of pediatric PFTs.

POTENTIAL PROTECTIVE EFFECTS OF NIMODIPINE FROM CEREBRAI ISCHEMIA REPERFUSION INJURY IN RATS.

The aim To see whether nimodipine had neuroprotective effects in cerebral ischemiareperfusion injury. Materials and methods A total of 28 adult male Sprauge-dawley rats weighting 200-300 g were distributed randomly into 4 groups (7 animals in each group) sham (neck dissection without bilateral common carotid artery occlusion), control (bilateral common carotid artery occlusion for 30 minutes and reperfusion for 1 hour), vehicle (7 days of daily carboxymethylcellulose by oral gavage followed by bilateral carotid artery occlusion and reperfusion), and nimodipine-treated rats (7 days of 3 mgkgday of oral Azelnidipine pretreatment then bilateral common carotid artery occlusion and reperfusion). Besides assessment of histological changes and brain infarct volume, the brain tissues were sectioned to estimate NF-κB p65, IL-6, IL-10, TNF-α, ICAM-1 and total anti-oxidant capacity. Results Cerebral NF-κB p65, IL-6, IL-10, TNF-α, ICAM-1, in addition to cerebral infarct size were markedly increased in control and vehicle related to sham rats, while total anti-oxidant capacity was considerably decreased. Treatment with nimodipine resulted in remarkable increment of total anti-oxidant capacity, while NF-κB p65, IL-6, TNF-α, and ICAM-1 showed great reduction. Cerebral IL-10 levels didnt change by nimodipine treatment. Histologically, control and vehicle rats showed severe brain ischemic changes which is dramatically reduced by nimodipine treatment. Conclusions Our study results revealed that nimodipine can greatly decrease cerebral infarct size and reduce histological ischemic injury in male rats subjected to cerebral ischemia reperfusion. The neuroprotective actions of nimodipine possibly originated from its anti-inflammatory and antioxidative effects. Nimodipine protection was unrelated to IL-10.

MiR-146a encapsulated liposomes reduce vascular inflammatory responses through decrease of ICAM-1 expression, macrophage activation, and foam cell formation.

Vascular insults can create an inflammatory cascade involving endothelial cell, smooth muscle cell, and macrophage activation which can eventually lead to vascular disease such as atherosclerosis. Several studies have identified microRNA 146as (miR-146a) anti-inflammatory potential based on its role in regulating the nuclear factor kappa beta (NF-κβ) pathway. Therefore, in this study, we introduced exogenous miR-146a encapsulated by liposomes to lipopolysaccharide (LPS) stimulated vascular cells and macrophages to reduce inflammatory responses. First, the miR-146a encapsulated liposomes showed uniform size (radius 96.4 ± 4.22 nm) and round shape, long term stability (at least two months), high encapsulation efficiency (69.73 ± 0.07%), and were well transfected to human aortic endothelial cells (HAECs), human aortic smooth muscle cells (SMCs), and human differentiated monocytes (U937 cells). In addition, we demonstrated that miR-146a encapsulated liposomes reduced vascular inflammation responses in HAECs and SMCs through inhibition of ICAM-1 expression and decreased monocyte adhesion. In macrophages, miR-146a liposome treatment demonstrated decreased production of proinflammatory cytokines, tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β), as well as reduced oxidized low-density lipoprotein (ox-LDL) uptake and foam cell formation. Thus, based on these results, miR-146a encapsulated liposomes may be promising for reducing vascular inflammation by targeting its multiple associated mediators.

Intraoperative Cortico-Cortical Evoked Potentials for Monitoring Language Function during Brain Tumor Resection in Anesthetized Patients.

Cortico-cortical evoked potentials (CCEPs) have been used to map the frontal (FLA) and parietal (PLA) cortical regions related to language function. However, they have usually been employed as a complementary method during sleep-awake surgery. Five male and two female patients received surgery for tumors located near language areas. Six patients received general anesthesia and the sleep-awake method was used for patients with tumors located near the cortical language areas. We performed motor and somatosensory mapping with CCEPs to identify language areas and we monitored responses during surgery based on the mapping results. Electrocorticography was performed throughout the surgery. Single pulses of 1 ms duration at 5-20 mA were delivered by direct cortical stimulation using one grid at one region (e.g., FLA) and then recording using a second gird at another area (i.e., PLA). Next, reversed stimulation (from PLA to FLA) was performed. The charge density for electrical stimulation was computed. Sensibility, specificity, predictive positive values, and predicted negative values were also computed for warning alterations of CCEPs. Gross tumor resection was achieved in four cases. The first postsurgical day showed language alterations in three patients, but one year later six patients remained asymptomatic and one patient showed the same symptomatology as previously. Seizures were observed in two patients that were easily jugulated. CCEPs predicted warning events with high sensibility and specificity. Postsurgical language deficits were mostly transitory. Although the latency between frontal and parietal regions showed symmetry, the amplitude and the relationship between amplitude and latency were different for FLA than for PLA. The charge density elicited by CCEPs ranged from 442 to 1768 μCcm2. CCEPs have proven to be a reliable neurophysiological technique for mapping and monitoring the regions associated with language function in a small group of anesthetized patients. The high correlation between warning events and postsurgical outcomes suggested a high sensitivity and specificity and CCEPs can be used systematically in patients under general anesthesia. Nevertheless, the small number of studied patients suggests considering these results cautiously.

Migration Capacity of Stem Cells from Human Exfoliated Deciduous Teeth Towards Glioma.

Stem cells from human exfoliated deciduous teeth (SHED) are a mesenchymal stem cell type and have recently attracted attention for their high proliferative rate, multipotency, and immunosuppressive properties. However, SHED have not yet been investigated for anticancer properties. We therefore investigated whether SHED can be used as a treatment modality, particularly for anti-glioma therapy. SHED exhibited strong migration ability towards malignant glioma in both Our findings indicate that SHED can potentially be applied to track malignant glioma.

Recurrent Glioblastoma Ongoing Clinical Challenges and Future Prospects.

Virtually all glioblastomas treated in the first-line setting will recur in a short period of time, and the search for alternative effective treatments has so far been unsuccessful. Various obstacles remain unresolved, and no effective salvage therapy for recurrent glioblastoma can be envisaged in the short term. One of the main impediments to progress is the low incidence of the disease itself in comparison with other pathologies, which will be made even lower by the recent WHO classification of gliomas, which includes molecular alterations. This new classification helps refine patient prognosis but does not clarify the most appropriate treatment. Other impediments are related to clinical trials glioblastoma patients are often excluded from trials due to their advanced age and limiting neurological symptoms there is also the question of how best to measure treatment efficacy, which conditions the design of trials and can affect the acceptance of results by oncologists and medicine agencies. Other obstacles are related to the drugs themselves most treatments cannot cross the blood-brain-barrier or the brain-to-tumor barrier to reach therapeutic drug levels in the tumor without producing toxicity the drugs under study may have adverse metabolic interactions with those required for symptom control identifying the target of the drug can be a complex issue. Additionally, the optimal method of treatment - local vs systemic therapy, the choice of chemotherapy, irradiation, targeted therapy, immunotherapy, or a combination thereof - is not yet clear in glioblastoma in comparison with other cancers. Finally, in addition to curing or stabilizing the disease, glioblastoma therapy should aim at maintaining the neurological status of the patients to enable them to return to their previous lifestyle. Here we review currently available treatments, obstacles in the search for new treatments, and novel lines of research that show promise for the future.

People often experience cognitive deterioration of various degrees, from early-stage mild cognitive impairment to severe cognitive decline. Cognitive deterioration is related to many diseases and studied to alleviated inflammation reaction or oxidative stress. In the present study, the levels of various memory-related proteins brain-derived neurotrophic factor (BDNF), amyloid beta (Aβ) 42, Aβ40, interleukin-6 and tumor necrosis factor-alpha were measured. Among

Primary cerebral epithelioid angiosarcoma a case report.

Primary cerebral epithelioid angiosarcoma (PCEA) is a rare malignant tumor of the central nervous system. To the best of our knowledge, only three cases have been reported in the English language literature thus far. Here, we report a fourth case in a 73-year-old man admitted for headache. Radiological examination revealed a mass in the right occipital lobe, which was removed by right occipital craniotomy. Histopathological examination revealed epithelioid angiosarcoma. The patient received radiotherapy after resection but survived for only nine months due to recurrence of the tumor and his declining further surgery. In this report, we add to the knowledge base on this exceedingly rare tumor, review the small number of relevant cases published previously, and analyze and summarize the clinical and pathological characteristics, treatment options and prognosis of this cancer.

SLERT, as a novel biomarker, orchestrates endometrial cancer metastasis via regulation of BDNFTRKB signaling.

Recent evidence suggests that the box HACA small nucleolar RNA (snoRNA)-ended long noncoding RNA (lncRNA), SLERT, plays a critical role in gene regulation. However, its role in cancer remains undetermined. Herein, we explored its implication in human endometrial cancer (EC). EC plasma and tissue samples were collected for the detection of SLERT expression using qRT-PCR method. The functional investigation was tested by CCK-8 and transwell assays. Luciferase reporter, RNA pull-down, and immunoprecipitation (RIP) assays were used to determine the regulatory network involved in SLERT. The in vivo effect of SLERT was tested by caudal vein lung metastasis model. Stable knockdown of SLERT significantly inhibited EC cell (KLE and AN3CA) migration and invasion, while it did not affect cell viability. SLERT induced epithelial-mesenchymal transition (EMT) via elevating N-cadherin and Vimentin and downregulating E-cadherin. Further investigation showed that SLERT directly binds to METTL3, increasing the m Our findings, for the first time, uncover the metastasis-promoting effect of SLERT in EC via in vitro and in vivo evidence, providing a potential therapeutic target for metastatic EC treatment.

CAR T cells engineered immune cells to treat brain cancers and beyond.

Malignant brain tumors rank among the most challenging type of malignancies to manage. The current treatment protocol commonly entails surgery followed by radiotherapy andor chemotherapy, however, the median patient survival rate is poor. Recent developments in immunotherapy for a variety of tumor types spark optimism that immunological strategies may help patients with brain cancer. Chimeric antigen receptor (CAR) T cells exploit the tumor-targeting specificity of antibodies or receptor ligands to direct the cytolytic capacity of T cells. Several molecules have been discovered as potential targets for immunotherapy-based targeting, including but not limited to EGFRvIII, IL13Rα2, and HER2. The outstanding clinical responses to CAR T cell-based treatments in patients with hematological malignancies have generated interest in using this approach to treat solid tumors. Research results to date support the astounding clinical response rates of CD19-targeted CAR T cells, early clinical experiences in brain tumors demonstrating safety and evidence for disease-modifying activity, and the promise for further advances to ultimately assist patients clinically. However, several variable factors seem to slow down the progress rate regarding treating brain cancers utilizing CAR T cells. The current study offers a thorough analysis of CAR T cells promise in treating brain cancer, including design and delivery considerations, current strides in clinical and preclinical research, issues encountered, and potential solutions.

Superenhancers as master gene regulators and novel therapeutic targets in brain tumors.

Transcriptional deregulation, a cancer cell hallmark, is driven by epigenetic abnormalities in the majority of brain tumors, including adult glioblastoma and pediatric brain tumors. Epigenetic abnormalities can activate epigenetic regulatory elements to regulate the expression of oncogenes. Superenhancers (SEs), identified as novel epigenetic regulatory elements, are clusters of enhancers with cell-type specificity that can drive the aberrant transcription of oncogenes and promote tumor initiation and progression. As gene regulators, SEs are involved in tumorigenesis in a variety of tumors, including brain tumors. SEs are susceptible to inhibition by their key components, such as bromodomain protein 4 and cyclin-dependent kinase 7, providing new opportunities for antitumor therapy. In this review, we summarized the characteristics and identification, unique organizational structures, and activation mechanisms of SEs in tumors, as well as the clinical applications related to SEs in tumor therapy and prognostication. Based on a review of the literature, we discussed the relationship between SEs and different brain tumors and potential therapeutic targets, focusing on glioblastoma.

Spatially resolved transcriptomic profiling of degraded and challenging fresh frozen samples.

Spatially resolved transcriptomics has enabled precise genome-wide mRNA expression profiling within tissue sections. The performance of methods targeting the polyA tails of mRNA relies on the availability of specimens with high RNA quality. Moreover, the high cost of currently available spatial resolved transcriptomics assays requires a careful sample screening process to increase the chance of obtaining high-quality data. Indeed, the upfront analysis of RNA quality can show considerable variability due to sample handling, storage, andor intrinsic factors. We present RNA-Rescue Spatial Transcriptomics (RRST), a workflow designed to improve mRNA recovery from fresh frozen specimens with moderate to low RNA quality. First, we provide a benchmark of RRST against the standard Visium spatial gene expression protocol on high RNA quality samples represented by mouse brain and prostate cancer samples. Then, we test the RRST protocol on tissue sections collected from five challenging tissue types, including human lung, colon, small intestine, pediatric brain tumor, and mouse bonecartilage. In total, we analyze 52 tissue sections and demonstrate that RRST is a versatile, powerful, and reproducible protocol for fresh frozen specimens of different qualities and origins.

Proteogenomics of diffuse gliomas reveal molecular subtypes associated with specific therapeutic targets and immune-evasion mechanisms.

Diffuse gliomas are devastating brain tumors. Here, we perform a proteogenomic profiling of 213 retrospectively collected glioma tumors. Proteogenomic analysis reveals the downstream biological events leading by EGFR-, IDH1-, TP53-mutations. The comparative analysis illustrates the distinctive features of GBMs and LGGs, indicating CDK2 inhibitor might serve as a promising drug target for GBMs. Further proteogenomic integrative analysis combined with functional experiments highlight the cis-effect of EGFR alterations might lead to glioma tumor cell proliferation through ERK5 medicates nucleotide synthesis process. Proteome-based stratification of gliomas defines 3 proteomic subgroups (S-Ne, S-Pf, S-Im), which could serve as a complement to WHO subtypes, and would provide the essential framework for the utilization of specific targeted therapies for particular glioma subtypes. Immune clustering identifies three immune subtypes with distinctive immune cell types. Further analysis reveals higher EGFR alteration frequencies accounts for elevation of immune check point protein PD-L1 and CD70 in T-cell infiltrated tumors.

Methodological considerations on segmenting rhabdomyosarcoma with diffusion-weighted imaging-What can we do better

Diffusion-weighted MRI is a promising technique to monitor response to treatment in pediatric rhabdomyosarcoma. However, its validation in clinical practice remains challenging. This study aims to investigate how the tumor segmentation strategy can affect the apparent diffusion coefficient (ADC) measured in pediatric rhabdomyosarcoma. A literature review was performed in PubMed using search terms relating to MRI and sarcomas to identify commonly applied segmentation strategies. Seventy-six articles were included, and their presented segmentation methods were evaluated. Commonly reported segmentation strategies were then evaluated on diffusion-weighted imaging of five pediatric rhabdomyosarcoma patients to assess their impact on ADC. We found that studies applied different segmentation strategies to define the shape of the region of interest (ROI)(outline 60%, circular ROI 27%), to define the segmentation volume (2D 44%, multislice 9%, 3D 21%), and to define the segmentation area (excludes edge 7%, excludes other region 19%, specific area 27%, whole tumor 48%). In addition, details of the segmentation strategy are often unreported. When implementing and comparing these strategies on in-house data, we found that excluding necrotic, cystic, and hemorrhagic areas from segmentations resulted in on average 5.6% lower mean ADC. Additionally, the slice location used in 2D segmentation methods could affect ADC by as much as 66%. Diffusion-weighted MRI studies in pediatric sarcoma currently employ a variety of segmentation methods. Our study shows that different segmentation strategies can result in vastly different ADC measurements, highlighting the importance to further investigate and standardize segmentation.

Arterial Supply of the Basal Ganglia A Fiber Dissection Study.

The basal ganglia, a group of subcortical nuclei located deep in the insular cortex, are responsible for many functions such as motor learning, emotion, and behavior control. Nowadays, because it has been shown that deep brain stimulation and insular tumor surgery can be performed by endovascular treatment, the importance of the vascular anatomy of the basal ganglia is being increasingly recognized. To explain the arterial blood supply of the basal ganglia using white matter dissection. The Klingler protocol was used to prepare 12 silicone-injected human hemispheres. The dissections were performed from lateral to medial with the fiber dissection technique to preserve arteries. The globus pallidus blood supply came from the medial lenticulostriate, lateral lenticulostriate, and anterior choroidal arteries the substantia nigra and subthalamic nucleus were supplied by the branches of posterior cerebral artery the putamen was supplied by the lateral and medial lenticulostriate arteries and the caudate nucleus was supplied by the lateral lenticulostriate and medial lenticulostriate arteries and the recurrent artery of Heubner. Knowledge of the detailed anatomy of the basal ganglia and its vascular supply is essential for avoiding postoperative ischemic complications in surgeries related to the insula. In addition, knowledge of this anatomy and vascular relationship opens the doors to endovascular deep brain stimulation treatment. This study provides a 3-dimensional understanding of the blood supply to the basal ganglia by examining it using the fiber dissection technique. Further studies could use advanced imaging modalities to explore the vascular relationships with critical structures in the brain.

Neuron-oligodendrocyte potassium shuttling at nodes of Ranvier protects against inflammatory demyelination.

Multiple sclerosis (MS) is a progressive inflammatory-demyelinating disease of the central nervous system. Increasing evidence suggests that vulnerable neurons in MS exhibit fatal metabolic exhaustion over time, a phenomenon hypothesized to be caused by chronic hyperexcitability. Axonal Kv7 (outward rectifying) and oligodendroglial Kir4.1 (inward rectifying) potassium channels have important roles in regulating neuronal excitability at and around nodes of Ranvier. Here, we studied the spatial and functional relationship between neuronal Kv7 and oligodendroglial Kir4.1 channels and assessed the transcriptional and functional signatures of cortical and retinal projection neurons under physiological and inflammatory-demyelinating conditions. We found that both channels became dysregulated in MS and experimental autoimmune encephalomyelitis (EAE) with Kir4.1 channels being chronically downregulated and Kv7 channel subunits being transiently upregulated during inflammatory demyelination. Further, we observed that pharmacological Kv7 channel opening with retigabine reduced neuronal hyperexcitability in human and EAE neurons, improved clinical EAE signs and rescued neuronal pathology in oligodendrocyte-Kir4.1-deficient mice. In summary, our findings indicate that neuron-oligodendrocyte compensatory interactions promote resilience through Kv7 and Kir4.1 channels and suggest pharmacological activation of nodal Kv7 channels as a neuroprotective strategy against inflammatory demyelination.

Next-generation antigen-presenting cell immune therapeutics for gliomas.

Antigen presentation machinery and professional antigen-presenting cells (APCs) are fundamental for an efficacious immune response against cancers, especially in the context of T cell-centric immunotherapy. Dendritic cells (DCs), the gold standard APCs, play a crucial role in initiating and maintaining a productive antigen-specific adaptive immunity. In recent decades, ex vivo-differentiated DCs from circulating CD14 monocytes have become the reference for APC-based immunotherapy. DCs loaded with tumor-associated antigens, synthetic peptides, or RNA activate T cells with antitumor properties. This strategy has paved the way for the development of alternative antigen-presenting vaccination strategies, such as monocytes, B cells, and artificial APCs, that have shown effective therapeutic outcomes in preclinical cancer models. The search for alternative APC platforms was initiated by the overall limited clinical impact of DC vaccines, especially in indications such as gliomas, a primary brain tumor known for resistance to any immune intervention. In this Review, we navigate the APC immune therapeutics past, present, and future in the context of primary brain tumors.

NMDA receptors expression activity in anaplastic astrocytomas.

To study the relationship of NMDA receptors expression activity with proliferative activity and genetic properties of anaplastic astrocytomas, as well as the survival of patients with this disease. To solve this problem, we compared the expression activity of the least studied NMDA receptors in the context under consideration, detected using immunofluorescent studies and polymerase chain reaction, with the results of histological and molecular studies, the proliferative activity of neoplasms, and the survival of patients. The expression activity of NMDA receptors is higher in astrocytomas, grade 3, which do not carry mutations in We have shown for the first time the significant role of NMDA receptors in the progression of diffuse astrocytomas, which can become the basis for creating new therapeutic and diagnostic tools. Изучение связи активности экспрессии NMDA Для решения поставленной задачи мы сопоставили активность экспрессии наименее изученных в данном контексте NMDA Было показано, что активность экспрессии NMDA Впервые показана существенная роль NMDA

Selective Inhibition of PI3K Isoforms in Brain Tumors Suppresses Tumor Growth by Increasing Radiosensitivity.

Glioblastoma (GBM) is a malignant brain tumor with poor prognosis. Radioresistance is a major challenge in the treatment of brain tumors. The development of several types of tumors, including GBM, involves the phosphoinositide 3-kinase (PI3K)protein kinase B (AKT) signaling pathway. Upon activation, this pathway induces radioresistance. In this study, we investigated whether additional use of selective inhibitors of PI3K isoforms would enhance radiosensitivity in GBM. We evaluated whether radiation combined with PI3K isoform selective inhibitors can suppress radioresistance in GBM. Glioma 261 expressing luciferase (GL261- Suppression of the PI3KAKT signaling pathway increased radiosensitivity, and PI3K-α inhibition had similar effects on PI3K-pan inhibition in vitro. The combination of radiotherapy and PI3K-α isoform inhibitor suppressed tumor growth and extended survival in vivo. This study verified that PI3K-α isoform inhibition improves radiosensitivity, resulting in tumor growth suppression and extended survival in GBM mice.

Clinical Outcomes of Moderately Hypofractionated Concurrent Chemoradiotherapy for Newly Diagnosed Glioblastoma.

Hypofractionated radiotherapy (HypoRT) has recently been implemented in patients with glioblastoma (GBM) receiving concurrent temozolomide. Lymphopenia during treatment (LDT) is considered an important prognostic factor of clinical outcomes for GBM. We aimed to investigate the outcomes of HypoRT. Among 223 patients with GBM, 145 and 78 were treated with conventionally fractionated RT (ConvRT, 60 Gy in 30 fractions) and HypoRT (58.5 Gy in 25 fractions), respectively. To balance characteristics between the two groups, propensity score matching (PSM) was performed. Patients in the HypoRT group were older and had smaller tumors than those in the ConvRT group ( HypoRT with 58.5 Gy in 25 fractions could provide comparable oncologic outcomes and significantly reduce the ALC changes. In addition, HypoRT decreased the LDT. Further investigation should be warranted to suggest the significance of reduced LDT through HypoRT affecting survival outcomes.

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Glioblastoma is the most common form of primary brain cancer in adults, and the disease has a serious prognosis. Although great progress has been made in molecular characteristics, no major breakthroughs in treatment have been achieved for many years. In this article we present a clinical review of current diagnostics and treatment, as well as the challenges and opportunities inherent in developing improved and more personalised treatment.

Leptomeningeal metastasis from neuroendocrine carcinoma of the cervix illustrative case.

Leptomeningeal carcinomatosis is a rare feature of metastasis that is characterized by thickening and increased contrast enhancement throughout the meninges of the central nervous system (CNS). Leptomeningeal disease (LMD) can occur as spread from primary CNS tumors or as a manifestation of metastasis to the CNS from primary tumor sites outside the CNS. Leptomeningeal disease is, however, rare in cervical cancer, in which metastasis occurs typically from local invasion. The authors discuss the case of CNS metastasis with LMD from the rare neuroendocrine carcinoma of the cervix (NECC). Cervical cancer infrequently metastasizes to the CNS, but NECC is an aggressive variant with greater metastatic potential. Many of these patients will have previously received pelvic radiation, limiting their candidacy for craniospinal radiation for LMD treatment due to field overlap. This illustrative case documents the first known case of NECC CNS metastasis accompanied by LMD treated with intrathecal chemotherapy. Reported is the first known case of NECC with CNS metastasis accompanied by LMD. The authors highlight the potentially critical role of intrathecal chemotherapy, in addition to radiotherapy, in treating leptomeningeal metastasis from cervical cancer.

Rapidly progressive diffuse leptomeningeal glioneuronal tumor in an adult female illustrative case.

Diffuse leptomeningeal glioneuronal tumor (DLGNT) is a rare brain tumor only recently classified by the World Health Organization in 2016 and has few reports on its incidence in adults. The authors describe a case of DLGNT presenting in a 47-year-old female with seizures, cranial neuropathies, and communicating hydrocephalus with rapid clinical progression. Workup demonstrated progressive leptomeningeal enhancement of the skull base, cranial nerves, and spine, and communicating hydrocephalus. Elevated serum rheumatological markers and early response to systemic corticosteroids and immunosuppressant therapy complicated the diagnosis. Multiple biopsy attempts were required to obtain diagnostic tissue. Pathology demonstrated hypercellularity surrounding leptomeningeal vessels with nuclear atypia, staining positive for GFAP, Olig2, S100, and synaptophysin. Molecular pathology demonstrated loss of chromosome 1p, BRAF overexpression but no rearrangement, and H3K27 mutation. Repeat cerebrospinal fluid (CSF) diversion procedures were required for hydrocephalus management due to high CSF protein content. This report describes a rare, aggressive, adult presentation of DLGNT. Leptomeningeal enhancement and communicating hydrocephalus should raise suspicion for this disease process. Biopsy at early stages of disease progression is essential for early diagnosis and prompt treatment. Further study into the variable clinical presentation, histological and molecular pathology, and optimal means of diagnosis and management is needed.

Treatment of adverse radiation effects with Boswellia serrata after failure of pentoxifylline and vitamin E illustrative cases.

Adverse radiation effects (AREs) can occur after stereotactic radiosurgery (SRS), and symptomatic cases are often treated with corticosteroids, pentoxifylline, and vitamin E. The supplement 5-Loxin (Boswellia serrata) is an extract of Indian frankincense that inhibits vascular endothelial growth factor expression and has been shown to reduce perilesional edema in brain tumor patients undergoing fractionated radiation. Three patients underwent SRS for meningioma or metastasis and developed symptomatic AREs at 4 to 8 months. They were initially treated with corticosteroids, pentoxifylline, and vitamin E with transient improvement followed by recurrent neurological symptoms and imaging findings as steroids were tapered off. All patients were rescued by the administration of 5-Loxin with resolution of neurological symptoms and imaging changes, discontinuation of steroids, and no medication side effects. The authors early experience with 5-Loxin has been encouraging, and this supplement has become the authors first-line treatment for acute radiation effects after SRS. The author reserves bevacizumab for significant mass effect or failure of oral therapy. 5-Loxin has many advantages including low cost, ease of use, and patient tolerability. More experience is needed to confirm the role of 5-Loxin in the upfront treatment of AREs.

Glioblastoma treatment slowly moves toward change novel druggable targets and translational horizons in 2022.

Glioblastoma (GBM) is the most common primary brain tumor in adults. GBM treatment options have been the same for the past 30 years and have only modestly extended survival, despite aggressive multimodal treatments. The progressively better knowledge of GBM biology and a comprehensive analysis of its genomic profile have elucidated GBM heterogeneity, contributing to a more effective molecular classification and to the development of innovative targeted therapeutic approaches. This article reports all the noteworthy innovations for immunotherapy and targeted therapy, providing insights into the current advances in trial designs, including combination therapies with immuno-oncology agents and target combinations. GBM molecular heterogeneity and brain anatomical characteristics critically restrain drug effectiveness. Nevertheless, stimulating insights for future research and drug development come from innovative treatment strategies for GBM, such as multi-specific off-the-shelf CAR-T therapy, oncolytic viral therapy and autologous dendritic cell vaccination. Disappointing results from targeted therapies-clinical trials are mainly due to complex interferences between signaling pathways and biological processes leading to drug resistance hence, it is imperative in the future to develop combinatorial approaches and multimodal therapies.

Impact of COVID-19 pandemic on neuropathology service Experience at one Canadian center.

The COVID-19 pandemic has had a significant impact on medical services. Many countries postponed nonemergent procedures to preserve hospital resources for the unprecedented situation. Surgical backlogs caused by the COVID-19 pandemic have been evaluated by different groups. However, the impact of this pandemic on pathology and specifically neuropathology (NP) services has received limited attention. In this study, we reviewed all NP reports of the London Health Sciences Centre from January 2018 (2 years before the pandemic declaration) until the end of the year 2021. Demographic information and pathology details were collected. For tumors, site, histopathology types, and WHO grading were analyzed. In nontumoral specimens, pathological diagnoses were compared in pre- and postpandemic time. The total number of NP samples reached its lowest in April 2020, corresponding to the first Ontario provincial lockdown, and fluctuated throughout the studied period. Among the different types of NP surgical specimens, muscle and epilepsy-related specimens showed a more significant reduction, compared to neoplastic specimens. In 2020, the proportion of tumor specimens from patients older than 40 years of age increased. Similarly, the proportion of high-grade glioma and brain metastasis diagnoses also increased. Lastly, we observed a marked increase in biopsies for temporal arteritis and other inflammatory lesions.

Prolactin in headache and migraine A systematic review of clinical studies.

To systemically review clinical studies investigating the role of prolactin and its receptors in headache and migraine. Migraine prevalence is more common in women compared to men. As prolactin is a crucial regulator of the hypothalamus-pituitary-gonadal axis, prolactin and its receptors might contribute to signaling mechanisms underlying migraine. In this systematic review, we searched PubMed and EMBASE with the terms prolactin, hyperprolactinemia, macroprolactinemia, hypoprolactinemia, migraine, headache, head pain and trigeminal pain pathway for clinical studies investigating prolactin signaling in headache and migraine. Two reviewers independently screened 841 articles for population, intervention, comparison, outcome, and study design. Studies were restricted to the English language and were excluded if they had a nonexperimental methodology. Nineteen clinical studies met the inclusion criteria and were included in the qualitative and quantitative analysis. The main findings were that serum prolactin levels were found to be higher in individuals with migraine compared to healthy controls, and prolactinomas (prolactin-secreting pituitary adenomas) were correlated with higher incidence of headache in otherwise healthy individuals and migraine attacks in individuals with migraine. Considerable evidence suggests a key role of prolactin and its receptors in migraine pathophysiology. Further randomized and placebo-controlled clinical studies targeting prolactin signaling are needed to further clarify influences of prolactin in migraine attack initiation.

Changes in the characteristics of patients treated for brain metastases with repeat stereotactic radiotherapy (SRT) a retrospective study of 184 patients.

Brain metastases (BMs) are the leading cause of intracranial malignant neoplasms in adults. WHO, Karnofsky performance status (KPS), age, number of BMs, extracerebral progression (ECP), recursive partitioning analysis (RPA), diagnosis-specific graded prognostic assessment (Ds-GPA) are validated prognostic tools to help clinicians decide on treatment. No consensus exists for repeat stereotactic radiotherapy (SRT) for BMs. The aim of this study was to review the changes in patient characteristics treated with repeated SRTs. The data of patients treated between 2010 and 2020 with at least two courses of SRT without previous whole brain radiotherapy (WBRT) were reviewed. Age, WHO, KPS, ECP, type of systemic treatment, number of BMs were recorded. RPA, Ds-GPA and brain metastasis velocity (BMV) were calculated. 184 patients were treated for 915 BMs and received two to six SRTs for local or distant brain recurrence. The median number of BMs treated per SRT was 1 (range 1-6), for a median of 4 BMs treated during all sessions (range 2-19). WHO, Ds-GPA and RPA were stable between each session of SRT, whereas KPS was significantly better in SRT1 than in the following SRT. The number of BMs was not significantly different between each SRT, but there was a tendency for more BM at SRT1 (p 0.06). At SRT1, patients had largest BM and undergo more surgery than during the following SRT (p < 0.001). 6.5%, 37.5% and 56% of patients were classified as high, intermediate, and low BMV, respectively, at the last SRT session. There was almost perfect concordance between the BMV-grade calculated at the last SRT session and at SRT2 (r 0.89 p < 0.001). Repeated SRT doesnt lead to a marked alteration in the general condition, KPS was maintained at over 70% for more than 95% of patients during all SRTs. Long survival can be expected, especially in low-grade BMV patients. WBRT shouldnt be aborted, especially for patients developing more than twelve BMs annually.

Clinical and genomic features in patients with second primary glioblastoma following first primary renal cell carcinoma.

To explore the potential pathogenesis and clinical features of second primary glioblastoma (spGBM) following first primary renal cell carcinoma (fpRCC). Patients with spGBM after fpRCC were enrolled from our institution and the SEER dataset. Sanger sequencing, whole genome sequencing, and immunehistochemistry were used to detect molecular biomarkers. Four and 122 cases from our institution and the SEER dataset, respectively, were collected with an overall median age of 69 years at spGBM diagnosis following fpRCC. The median interval time between fpRCC and spGBM was 50.7 months and 4 years, for the four and 122 cases respectively. The median overall survival time was 11.2 and 6.0 months for the two datasets. In addition, spGBM patients of younger age (< 75 years) or shorter interval time (< 1 year) had favorable prognosis (p 0.081 and 0.05, respectively). Moreover, the spGBM cases were molecularly classified as TERT only paired with TP53 mutation, PIK3CA mutation, EGFR alteration, low tumor mutation burden, and stable microsatellite status. This is the first study to investigate the pathogenesis and clinical features of spGBM following spRCC. We found that spGBMs are old-age related, highly malignant, and have short survival time. Moreover, they might be misdiagnosed and treated as brain metastases from RCC. Thus, the incidence of spGBMs after fpRCC is underestimated. Further studies are needed to investigate the underlying molecular mechanisms and clinical biomarkers for the development of spGBM following fpRCC.

Modeling of intracranial tumor treating fields for the treatment of complex high-grade gliomas.

Increasing the intensity of tumor treating fields (TTF) within a tumor bed improves clinical efficacy, but reaching sufficiently high field intensities to achieve growth arrest remains challenging due in part to the insulating nature of the cranium. Using MRI-derived finite element models (FEMs) and simulations, we optimized an exhaustive set of intracranial electrode locations to obtain maximum TTF intensities in three clinically challenging high-grade glioma (HGG) cases (i.e., thalamic, left temporal, brainstem). Electric field strengths were converted into therapeutic enhancement ratios (TER) to evaluate the predicted impact of stimulation on tumor growth. Concurrently, conventional transcranial configurations were simulatedoptimized for comparison. Optimized intracranial TTF were able to achieve field strengths that have previously been shown capable of inducing complete growth arrest, in 98-100% of the tumor volumes using only 0.54-0.64 A current. The reconceptualization of TTF as a targeted, intracranial therapy has the potential to provide a meaningful survival benefit to patients with HGG and other brain tumors, including those in surgically challenging, deep, or anatomically eloquent locations which may preclude surgical resection. Accordingly, such an approach may ultimately represent a paradigm shift in the use of TTFs for the treatment of brain cancer.

Updates on the WHO diagnosis of IDH-mutant glioma.

The WHO classification of Tumors of the Central Nervous System represents the international standard classification for brain tumors. In 2021 the 5th edition (WHO CNS5) was published, and this review summarizes the changes regarding IDH-mutant gliomas and discusses unsolved issues and future perspectives. This review is based on the 5th edition of the WHO Blue Book of CNS tumors (WHO CNS5) and relevant related papers. Major changes include taxonomy and nomenclature of IDH-mutant gliomas. Essential and desirable criteria for classification were established considering technical developments. For the first time molecular features are not only relevant for the classification of IDH-mutant gliomas but may impact grading as well. WHO CNS5 classification moves forward towards a classification which is founded on tumor biology and serves clinical needs. The rapidly increasing knowledge on the molecular landscape of IDH-mutant gliomas is expected to further refine classification and grading in the future.

Aquaporins in Tumor.

Recent researches have demonstrated that aquaporins (AQPs), including water-selective channels, aquaglyceroporins and superaquaporins, are generally expressed in various tumors, such as lung, colorectal, liver, brain, breast tumors, etc. Therefore, it is imperative to study the accurate relationship between AQPs and tumor, which may provide innovative approaches to treat and prevent tumor development. In this chapter, we mainly reviewed the expression and pathophysiological function of AQPs in tumor, and summarize recent work on AQPs in tumor. Although, the underlying mechanism of AQP in tumor is not very clear, growing evidences suggest that cell migration, adhesion, angiogenesis, and division contribute to tumor development, in which AQPs might be involved. Therefore, it is still necessary to conduct further studies to determine the specific roles of AQPs in the tumor.

Aquaporins in Nervous System.

Aquaporins (AQPs) mediate water flux between the four distinct water compartments in the central nervous system (CNS). In the present chapter, we mainly focus on the expression and function of the nine AQPs expressed in the CNS, which include five members of aquaporin subfamily AQP1, AQP4, AQP5, AQP6, and AQP8 three members of aquaglyceroporin subfamily AQP3, AQP7, and AQP9 and one member of superaquaporin subfamily AQP11. In addition, AQP1, AQP2, and AQP4 expressed in the peripheral nervous system are also reviewed. AQP4, the predominant water channel in the CNS, is involved both in the astrocyte swelling of cytotoxic edema and the resolution of vasogenic edema and is of pivotal importance in the pathology of brain disorders such as neuromyelitis optica, brain tumors, and neurodegenerative disorders. Moreover, AQP4 has been demonstrated as a functional regulator of recently discovered glymphatic system that is a main contributor to clearance of toxic macromolecule from the brain. Other AQPs are also involved in a variety of important physiological and pathological process in the brain. It has been suggested that AQPs could represent an important target in treatment of brain disorders like cerebral edema. Future investigations are necessary to elucidate the pathological significance of AQPs in the CNS.

Transmission of NLRP3-IL-1β Signals in Cerebral Ischemia and Reperfusion Injury from Microglia to Adjacent Neuron and Endothelial Cells via IL-1βIL-1R1TRAF6.

The pyrin domain-containing protein 3 (NLRP3) inflammasome drives the profound cerebral ischemia and reperfusion injury (IR) and mediates the secretion of IL-1β (interleukin-1β), which exerts a subsequent cascade of inflammatory injury. The NLRP3-activated-microglial manipulation in adjacent neuronal and endothelial NLRP3 activation has been confirmed in our previous studies. In the present study, we extended the cognition of how microglia mediated neuronal and endothelial NLRP3-IL-1β signaling during cerebral ischemia and reperfusion injury. In vitro, Neuro-2a and bEND3 cells were cultured alone or co-cultured with BV2 cells and oxygen-glucose deprivationreoxygenation (OGDR) was performed. In vivo, transient middle cerebral artery occlusion (tMCAO) rat models and lentiviral silencing targeting IL-1R1 were performed. The NLRP3 inflammasome activation was evaluated by enzyme-linked immunosorbent assay, western blotting, immunoprecipitation, immunohistochemistry, and immunofluorescence. In the co-culture system after OGDR treatment, NLRP3 inflammasomes in neurons and endothelial cells were activated by microglial IL-1β via IL-1βIL-1R1TRAF6 signaling pathway, with the basal protein level of NLRP3. In addition, ruptured lysosomes engulfing ASC specks which were possibly secreted from microglia triggered the enhanced NLRP3 expression. In cortices of tMCAO rats at 24 h of reperfusion, silencing IL-1R1, mainly presented in neurons and endothelial cells, was efficient to block the subsequent inflammatory damage and leukocyte brain infiltration, leading to better neurological outcome. Neuronal and endothelial NLRP3 inflammasomes were activated by microglia in cerebral ischemia and reperfusion injury mainly via IL-1βIL-1R1TRAF6 signaling, which might be therapeutically targetable.

Evolution of Longevity as a Species-Specific Trait in Mammals.

From the evolutionary point of view, the priority problem for an individual is not longevity, but adaptation to the environment associated with the need for survival, food supply, and reproduction. We see two main vectors in the evolution of mammals. One is a short lifespan and numerous offspring ensuring reproductive success (r-strategy). The other one is development of valuable skills in order compete successfully (K-strategy). Species with the K-strategy should develop and enhance specific systems (anti-aging programs) aimed at increasing the reliability and adaptability, including lifespan. These systems are signaling cascades that provide cell repair and antioxidant defense. Hence, any arbitrarily selected long-living species should be characterized by manifestation to a different extent of the longevity-favoring traits (e.g., body size, brain development, sociality, activity of body repair and antioxidant defense systems, resistance to xenobiotics and tumor formation, presence of neotenic traits). Hereafter, we will call a set of such traits as the gerontological success of a species. Longevity is not equivalent to the evolutionary or reproductive success. This difference between these phenomena reaches its peak in mammals due to the development of endothermy and cephalization associated with the cerebral cortex expansion, which leads to the upregulated production of oxidative radicals by the mitochondria (and, consequently, accelerated aging), increase in the number of non-dividing differentiated cells, accumulation of the age-related damage in these cells, and development of neurodegenerative diseases. The article presents mathematical indicators used to assess the predisposition to longevity in different species (including the standard mortality rate and basal metabolic rate, as well as their derivatives). The properties of the evolution of mammals (including the differences between modern mammals and their ancestral forms) are also discussed.

Molecular Identity Changes of Tumor-Associated Macrophages and Microglia After Magnetic Resonance Imaging-Guided Focused Ultrasound-Induced Blood-Brain Barrier Opening in a Mouse Glioblastoma Model.

An orthotopically allografted mouse GL26 glioma model (Ccr2

Foreign accent syndrome as a heralding manifestation of transformation to small cell neuroendocrine prostate cancer.

A man in his 50s with metastatic hormone-sensitive prostate cancer, receiving androgen deprivation therapy and abiraterone acetateprednisone, presented with an uncontrollable Irish brogue accent despite no Irish background, consistent with foreign accent syndrome (FAS). He had no neurological examination abnormalities, psychiatric history or MRI of the brain abnormalities at symptom onset. Imaging revealed progression of his prostate cancer, despite undetectable prostate-specific antigen levels. Biopsy confirmed transformation to small cell neuroendocrine prostate cancer (NEPC). Despite chemotherapy, his NEPC progressed resulting in multifocal brain metastases and a likely paraneoplastic ascending paralysis leading to his death. We report FAS as the presenting manifestation of transformation to small cell NEPC, a previously undescribed phenomenon. His presentation was most consistent with an underlying paraneoplastic neurological disorder (PND), despite a negative serum paraneoplastic panel. This report enhances the minimal existing literature on FAS and PNDs associated with transformed NEPC.

Interventions facilitating the involvement of relatives of patients with acquired brain injury or malignant brain tumour through the course of disease a scoping review protocol.

Research identifying the needs of relatives of patients with an acquired brain injury or malignant brain tumours is emerging, and the importance of relative involvement is widely acknowledged. However, the intention of involvement does not seem to be present in current practice and healthcare professionals routines. The complexity of involvement of relatives is comprehensive, and there is a lack of overview of interventions facilitating and enhancing involvement of relatives. This scoping review aims to identify and map the available evidence on interventions facilitating involvement of relatives of patients with acquired brain injury or malignant brain tumour throughout the disease trajectory. The proposed scoping review will be performed following the Joanna Briggs Institutes methodology for scoping reviews. Published and unpublished literature in English, Scandinavian and German from January 2010 to August 2022 will be considered. The searches will be conducted using electronic bibliographic databases. This scoping review will consider studies describing interventions provided by multidisciplinary healthcare professionals. The key aspects of the interventions could, for example, be educational, informational, emotional, social or physical support aiming towards involvement of the relatives. This scoping review will consider all study designs, except for literature reviews of all types and designs. The data will be extracted using a data extraction tool developed to record specific data, including details of authors, year of publication, country, setting, study population, study design and key aspects of the intervention (mode, duration, intensity, provider) and type of primary and secondary outcomes applied to measure the interventions. The results will be presented in tabular form, accompanied by a descriptive summary related to the objective of the present scoping review. This scoping review is conducted as part of a larger postdoc project, which has been approved by the Danish Data Protection Agency (ID P-2020-547). The results will be disseminated through a peer-reviewed journal and presented at local, national and international conferences on brain injuries and brain cancer.

Identification of epigenetically regulated genes distinguishing intracranial from extracranial melanoma metastases.

Despite remarkable advances in treating patients with metastatic melanoma, management of melanoma brain metastases remains challenging. Recent evidence suggests that epigenetic reprogramming is an important mechanism for the adaptation of melanoma cells to the brain environment. In this study, methylomes and transcriptomes of a cohort of matched melanoma metastases were evaluated by integrated omics data analysis. The identified 38 candidate genes displayed distinct promoter methylation and corresponding gene expression changes in intracranial compared to extracranial metastases. The 11 most promising genes were validated on protein level in both tumor and surrounding normal tissue using immunohistochemistry. For 8 of them, STK10, PDXK, WDR24, CSPP1, NMB, RASL11B, pPRKCZPRKCZ, pGRB10, a significantly different protein expression in intracranial versus extracranial metastases was confirmed in accordance with the underlying promoter methylation and gene expression changes. The observed changes imply a distinct intracranial phenotype with increased AKT phosphorylation and higher frequency of proliferating cells. Knockdown of PRKCZ or GRB10 altered the expression of pAKT and decreased the viability of a brain-specific melanoma cell line. In summary, epigenetically regulated cancer-relevant alterations were identified, that provide insights into the molecular mechanisms that discriminate brain from other organ metastases, which could be exploited by targeting the affected signaling pathways.

The Use of Carbon Fiber-Reinforced Instrumentation in patients with Spinal Oncologic Tumors A Systematic Review of Literature and Future Directions.

Metastatic spine tumors affect over 30% of patients who have been diagnosed with cancer. While techniques in surgical intervention have undoubtedly evolved, there are some pitfalls when spinal instrumentation is required for stabilization following tumor resection. However, the use of carbon-fiber reinforced polyetheretherketone (CFR-PEEK) implants has become increasingly popular due to improved radiolucency and positive osteobiologic properties. Here, we present a systematic review describing the use of CFR-PEEK coated instrumentation in the oncologic population while identifying advantages and potential shortcomings of these devices. In accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, a systematic review was conducted in March 2022 to identify articles detailing the use of CFR-PEEK implants for spinal instrumentation in patients with primary and secondary spine tumors. The search was performed using the PubMed, Scopus, and Embase databases. An initial search returned total of 85 articles among the three databases used. After the exclusion of duplicates and screening of abstracts, 21 full text articles were examined for eligibility. Eleven articles were excluded due to not fitting our inclusion and exclusion criteria. Ten articles were subsequently eligible for full text review. CFR-PEEK possesses a similar safety and efficacy profile to titanium implants but has distinct advantages. It limits artifact, increases early detection of local tumor recurrence, increases radiotherapy dose accuracy, and is associated with low complication rates (9.96%) - making it a promising alternative for the demands unique to the treatmentoutcome of spinal oncologic patients.

Bias-force guided simulations combined with experimental validations towards GPR17 modulators identification.

Glioblastoma Multiforme (GBM) is known to be by far the most aggressive brain tumor to affect adults. The median survival rate of GBM patients is < 15 months, while the GBM cells aggressively develop resistance to chemo- and radiotherapy with their self-renewal capacity which suggests the pressing need to develop novel preventative measures. We have recently proved that GPR17 -an orphan G protein-coupled receptor- is highly expressed on the GBM cell surface and it has a vital role to play in the disease progression. Despite the progress made on GBM downregulation, there still remain difficulties in developing a promising modulator for GPR17, till date. Here, we have performed robust virtual screening combined with biased-force pulling molecular dynamic (MD) simulations to predict high-affinity GPR17 modulators followed by experimental validation. Initially, the database containing 1379 FDA-approved drugs were screened against the orthosteric binding pocket of the GPR17. The external bias-potentials were then applied to the screened hits during the MD simulations which enabled to predict a spectrum of rupture peak force values that were used to select four approved drugs -ZINC000003792417 (Sacubitril), ZINC000014210457 (Victrelis), ZINC000001536109 (Pralatrexate) and ZINC000003925861 (Vorapaxar)- as top hits. The hits selected turns out to demonstrate unique dissociation pathways, interaction pattern, and change in polar network over time. Subsequently the selected hits with GPR17 were measured by inhibiting the forskolin-stimulated cAMP accumulation in GBM cell lines, LN229 and SNB19. The ex vivo validations shows that Sacubitril drug can act as a full agonist, while Vorapaxar functions as a partial agonist for GPR17. The pEC

Intraoperative thermal infrared imaging in neurosurgery machine learning approaches for advanced segmentation of tumors.

Surgical resection is one of the most relevant practices in neurosurgery. Finding the correct surgical extent of the tumor is a key question and so far several techniques have been employed to assist the neurosurgeon in preserving the maximum amount of healthy tissue. Some of these methods are invasive for patients, not always allowing high precision in the detection of the tumor area. The aim of this study is to overcome these limitations, developing machine learning based models, relying on features obtained from a contactless and non-invasive technique, the thermal infrared (IR) imaging. The thermal IR videos of thirteen patients with heterogeneous tumors were recorded in the intraoperative context. Time (TD)- and frequency (FD)-domain features were extracted and fed different machine learning models. Models relying on FD features have proven to be the best solutions for the optimal detection of the tumor area (Average Accuracy 90.45% Average Sensitivity 84.64% Average Specificity 93,74%). The obtained results highlight the possibility to accurately detect the tumor lesion boundary with a completely non-invasive, contactless, and portable technology, revealing thermal IR imaging as a very promising tool for the neurosurgeon.

Evolution of flash visual evoked potentials to monitor visual pathway integrity during tumor resection illustrative cases and literature review.

Flash visual evoked potentials (fVEPs) provide a means to interrogate visual system functioning intraoperatively during tumor resection in which the optic pathway is at risk for injury. Due to technical limitations, fVEPs have remained underutilized in the armamentarium of intraoperative neurophysiological monitoring (IONM) techniques. Here we review the evolution of fVEPs as an IONM technique with emphasis on the enabling technological and intraoperative improvements. A combined approach with electroretinography (ERG) has enhanced feasibility of fVEP neuromonitoring as a practical application to increase safety and reduce error during tumor resection near the prechiasmal optic pathway. The major advance has been towards differentiating true cases of damage from false findings. We use two illustrative neurosurgical cases in which fVEPs were monitored with and without ERG to discuss limitations and demonstrate how ERG data can clarify false-positive findings in the operating room. Standardization measures have focused on uniformity of photostimulation parameters for fVEP recordings between neurosurgical groups.

Risk for hydrocephalus, hygroma, and tumor dissemination after ventricular opening during resection of supratentorial neoplasms in children.

The possibility that ventricular opening generates postoperative complications after surgical tumor treatment often restricts the degree of tumor resection. This study aims to determine whether the ventricular opening is associated with more complications in surgeries for resectioning supratentorial intra-axial brain tumors in the pediatric population. A retrospective review analysis was performed of patients treated at IOPGRAACC between 2002 and 2020 under 19 years of age and underwent surgery for supratentorial intra-axial primary brain tumor resection. Data were collected from 43 patients. Glial tumor was more common than non-glial (65% vs. 35%, p 0.09). The ventricular opening was not related to neoplastic spreads to the neuroaxis (6% vs. 0, p > 0.9) or leptomeningeal (3% vs. 0, p > 0.9). Of the patients whose ventricle was opened, 10% developed hydrocephalus requiring treatment, while none of the patients in the group without ventricular opening developed hydrocephalus (p 0.5). There was also no statistical difference regarding ventriculitis. Postoperative subdural hygroma formation correlated with the ventricular opening (43% vs. 0, p 0.003). The survival at 1, 5, and 10 years of cases with the ventricular opening was 93.2%, 89.7%, and 75.7%, respectively, while in cases without ventricular opening, it was 100%, 83%, and 83%, respectively, respectively, with no statistical difference between the mortality curves. Our study demonstrated that ventricular violation was not associated with the occurrence of significant complications. It was related to the formation of subdural hygroma, which did not require additional treatment.

Induction of apoptosis in glioma cells by lycorine via reactive oxygen species generation and regulation of NF-κB pathways.

Glioma is an extremely aggressive primary brain tumor, which is highly resistant to chemotherapy, presenting a therapeutic challenge. Here, we explored the anti-glioma effects and the underlying mechanism of lycorine, an isoquinoline alkaloid isolated from lycoris on glioma cells. We found that lycorine could dose dependently inhibit C6 glioma cell growth and induce cell apoptosis and intracellular reactive oxygen species (ROS) production. The half-maximal inhibitory concentration (IC

Risk prediction in early childhood SHH medulloblastoma treated with radiation-avoiding chemotherapy Evidence for more than two subgroups.

The prognostic impact of clinical risk factors and DNA methylation patterns in sonic hedgehog (SHH)-activated early childhood desmoplasticnodular medulloblastoma (DMB) or medulloblastoma with extensive nodularity (MBEN) were evaluated to better identify patients at risk for relapse. Hundred-forty-four patients with DMB (n99) or MBEN (n45) aged <5 years and treated with radiation-sparing approaches, including intraventricular methotrexate in 132 patients, were evaluated. Patients with DMB had less favorable 5-year progression-free survival than MBEN (5y-PFS, 71% DMB vs 93% MBEN). Patients age >3 years was associated with more unfavorable 5y-PFS (47% >3 years vs 85% <1 year vs 84% 1-3 years). DNA methylation profiles available (n78) were reclassified according to the 2021 WHO classification into SHH-1 (n39), SHH-2 (n38), and SHH-3 (n1). Hierarchical clustering delineated two subgroups among SHH-2 SHH-2a (n19) and SHH-2b (n19). Patients with SHH-2b medulloblastoma were older, predominantly displayed DMB histology, and were more often located in the cerebellar hemispheres. Chromosome 9q losses were more frequent in SHH-2b, while few chromosomal alterations were observed in SHH-2a. SHH-2b medulloblastoma carried a significantly increased relapse risk (5y-PFS 58% SHH-2b vs 83% SHH-1 vs 95% SHH-2a). Subclassification of SHH-2 with key clinical and cytogenetic characteristics was confirmed using two independent cohorts (total n188). Gene mutation analysis revealed a correlation of SHH-2a with SMO mutations. These data suggest further heterogeneity within early childhood SHH-DMBMBEN SHH-2 splits into a very low-risk group SHH-2a enriched for MBEN histology and SMO mutations, and SHH-2b comprising older DMB patients with higher risk of relapse.

DROEG a method for cancer drug response prediction based on omics and essential genes integration.

Predicting therapeutic responses in cancer patients is a major challenge in the field of precision medicine due to high inter- and intra-tumor heterogeneity. Most drug response models need to be improved in terms of accuracy, and there is limited research to assess therapeutic responses of particular tumor types. Here, we developed a novel method DROEG (Drug Response based on Omics and Essential Genes) for prediction of drug response in tumor cell lines by integrating genomic, transcriptomic and methylomic data along with CRISPR essential genes, and revealed that the incorporation of tumor proliferation essential genes can improve drug sensitivity prediction. Concisely, DROEG integrates literature-based and statistics-based methods to select features and uses Support Vector Regression for model construction. We demonstrate that DROEG outperforms most state-of-the-art algorithms by both qualitative (prediction accuracy for drug-sensitiveresistant) and quantitative (Pearson correlation coefficient between the predicted and actual IC50) evaluation in Genomics of Drug Sensitivity in Cancer and Cancer Cell Line Encyclopedia datasets. In addition, DROEG is further applied to the pan-gastrointestinal tumor with high prevalence and mortality as a case study at both cell line and clinical levels to evaluate the model efficacy and discover potential prognostic biomarkers in Cisplatin and Epirubicin treatment. Interestingly, the CRISPR essential gene information is found to be the most important contributor to enhance the accuracy of the DROEG model. To our knowledge, this is the first study to integrate essential genes with multi-omics data to improve cancer drug response prediction and provide insights into personalized precision treatment.

Brain Metastases from Biliary Tract Cancer Case Series and Clinicogenomic Analysis.

Limited data from small series have suggested that brain metastases from biliary tract cancers (BrM-BTC) affect ≤2% of patients with BTC. We sought to review our experience with patients with BrM-BTC and to identify associations of tumor-related molecular alterations with outcomes. A retrospective review of patients with BTC seen at a tertiary referral center from 2005 to 2021 was performed patients with BrM-BTC were identified, and clinical and molecular data were collected. Twenty-one of 823 patients with BTC (2.6%) developed BrM. For patients with BrM-BTC, median follow-up time was 27.9 months after primary BTC diagnosis and 3.1 months after BrM diagnosis. Median time from primary diagnosis to diagnosis of BrM was 14.4 range, 1.1-66.0 months. Median overall survival (OS) from primary diagnosis was 31.5 2.9-99.8 months and median OS from BrM diagnosis was 4.2 0.2-33.8 months. Patients who underwent BrM-directed therapy trended toward longer OS following BrM diagnosis than patients receiving supportive care only (median 6.5 vs 0.8 months, P .060). The BrM-BTC cohort was enriched for BRAF (30%), PIK3CA (25%), and GNAS (20%) mutations. patients with BrM-BTC with BRAF mutations trended toward longer OS following BrM diagnosis (median 13.1 vs 4.2 months, P .131). This is the largest series of patients with BrM-BTC to date and provides molecular characterization of this rare subgroup of patients with BTC. Patients with BrM-BTC may be more likely to have BRAF mutations. With advances in targeted therapy for patients with BTC with actionable mutations, continued examination of shifting patterns of failure, with emphasis on BrM, is warranted.

Benign lesions with

Although FAPI, as a pan-tumor tracer, shows high expression in the malignancy imaging, FAPI uptake is also seen in some benign lesions. The purpose of this study was to retrospectively analyze the characteristics of benign lesions with FAPI uptake on The electronic medical and imaging records of patients undergoing A total of 44 patients ( Our studies have shown that in addition to malignant tumors, certain benign lesions also show uptake of FAPI, and it is necessary for doctors to distinguish these benign lesions from true malignant tumors. Benign lesions may also show FAPI expression, which may make the differential diagnosis of benign and malignant lesions difficult and should be alerted by physicians.

Polymorphisms in

Central nervous system tumors, especially astrocytomas, are the solid neoplasms with the highest incidence and mortality rates in childhood. The diagnosis is based on histopathological characteristics, but molecular methods have been increasingly used. Translationally controlled tumor protein (TCTP) protein, encoded by the tumor protein, translationally controlled 1 (

Neurosurgery still pivotal in the diagnostics and treatment of brain tumor patients.

Treatment of adult patients with brain tumors is a multi-disciplinary effort involving several medical disciplines neurosurgery, oncology, neurology, neuropathology, neuroradiology, and rehabilitation medicine. While the brain tumor field has gone through vast diagnostical changes during the last decade, the hopes of similar achievements in the systemic treatment of these patients with new methods have so far not been fulfilled. As such, neurosurgery still has a pivotal role in the diagnostics and treatment of brain tumor patients. Improved preoperative evaluation of the tumor and adjacent anatomical and functional brain areas, together with advanced microsurgical techniques, intraoperative mapping and monitoring, as well as new minimally invasive techniques, makes brain tumor surgery safer. Indeed, it is now possible to safely operate patients previously considered to have too unfavorable risk-benefit ratio. This article aims at presenting an overview of current neurosurgical treatments of brain tumors.

Correlation between ITGB2 expression and clinical characterization of glioma and the prognostic significance of its methylation in low-grade glioma(LGG).

Glioma is the most common primary tumor in the brain.Integrin beta 2(ITGB2) is a member of the leukocyte integrin family (leukocyte integrin), participating in lymphocyte recycling and homing, cell adhesion, and cell surface-mediated signal transduction. However, few studies on ITGB2 in gliomas have been reported yet.This study first discussed the relationship between ITGB2 expression and clinical characterization of glioma and the prognostic significance of its methylation in low-grade glioma. We collected Clinical data and transcription of glioma patients from TCGA, CGGA, and Rembrant datasets to analyze the differential expression of ITGB2 mRNA in glioma tissues and normal tissues. The box polts to evaluated the expression patterns of ITGB2 in different molecular subtypes. Receiver operating characteristic curve (ROC) were used to evaluate and verify the reliability of the model. Kaplan-Meier survival curves to evaluated the relationship between the level of ITGB2 mRNA expression and overall survival (OS). Using cox regression analysis to verify the ability of ITGB2 as an independent predictor of OS in glioma patients. We use TIMER to analyze and visualize the association between immune infiltration levels and a range of variables. The methylation of GBMLGG patients were obtained from the TCGA database through the biological portal. ITGB2 can be a potential marker for mesenchymal molecular subtype gliomas. COX regression analysis shows that ITGB2 is an independent predictive marker of OS in malignant glioma patients. Biological processes show that ITGB2 has involved glioma immune-related activities, especially closely related to B cells, CD4Tcells, macrophages, neutrophils, and dendritic cells. ITGB2 is negatively regulated by ITGB2 methylation, resulting in low expression in LGG tissues. Low expression of ITGB2 and high methylation indicate good OS in patients with LGG. The ITGB2 methylation risk score (ITMRS) obtained from the ITGB2 methylation CpG site can better predict the OS of LGG patients. We used univariate and multivariate cox regression analysis of methylationsites, used the R language predict function to obtain the risk score of these ITGB2 methylation sites(ITMRS). ITGB2 can be used as a potential marker of mesenchymal molecular subtypes of gliomas and as an independent predictive marker of OS in patients with malignant gliomas. The ITMRS we established can be used as an independent prognostic factor for LGG and provide a new idea for the diagnosis and treatment of LGG.

Is prolactin receptor signaling a target in dopamine-resistant prolactinomas

The hypothalamic neuroendocrine catecholamine dopamine regulates the lactotroph function, including prolactin (PRL) secretion, proliferation, and apoptosis. The treatment of PRL-secreting tumors, formerly known as prolactinomas, has relied mainly on this physiological characteristic, making dopamine agonists the first therapeutic alternative. Nevertheless, the group of patients that do not respond to this treatment has few therapeutical options. Prolactin is another physiological regulator of lactotroph function, acting as an autocrineparacrine factor that controls PRL secretion and cellular turnover, inducing apoptosis and decreasing proliferation. Furthermore, the signaling pathways related to these effects, mainly JAKSTAT and PI3KAkt, and MAPK, have been extensively studied in prolactinomas and other tumors as therapeutic targets. In the present work, the relationship between PRL pathophysiology and prolactinoma development is explored, aiming to comprehend the value of PRL and PRLR-associated pathways as exploratory fields alternative to dopamine-related approaches, which are worth physiological characteristics that might be impaired and can be potentially restored or upregulated to provide more options to the patients.

PLEKHA4 Is a Prognostic Biomarker and Correlated with Immune Infiltrates in Glioma.

Gliomas are the most common and life-threatening intracranial tumors. Immune infiltration of the tumor microenvironment significantly affects tumor prognosis in glioma. Recently, PLEKHA4 was reported to be upregulated in melanoma and closely associated with tumor genesis and development, but its role in glioma is poorly understood. Our aim was to investigate the expression, functional role, and prognostic value of PLEKHA4 in glioma. The expression levels of PLEKHA4 in 33 types of cancer in the TCGA (The Cancer Genome Atlas) database were collected via the UCSC Xena browser. The clinical samples of glioma patients were downloaded from the TCGA database. Immunohistochemistry was used to verify PLEKHA4 expression in tumor tissues. We assessed the influence of PLEKHA4 on survival of glioma patients by survival module and GEPIA. Then, we downloaded datasets of glioma from TCGA and investigated the correlations between the clinical characteristics and PLEKHA4 expression using logistic regression. Moreover, we used TIMER to explore the collection of PLEKHA4 expression and immune infiltration level in glioma and to analyze cumulative survival in glioma. Gene Set Enrichment Analysis (GSEA) was performed using the TCGA dataset. PLEKHA4 transcript levels were significantly upregulated in multiple cancer types, including gliomas. Moreover, immunohistochemical analysis verified that PLEKHA4 was overexpressed in gliomas compare to the corresponding normal tissues. Univariable survival and multivariate cox analysis show that increased PLEKHA4 expression significantly correlated with age, tumor grade, IDH mutation status, and 1p19q codel status, and higher PLEKHA4 had shorter OS, DSS, and PFI. Specifically, PLEKHA4 expression level had significant positive correlations with infiltrating levels of B cell, CD4 T cells, CD8 T cells, macrophages, neutrophils, and DCs in glioma, and upregulation of PLEKHA4 expression was significantly related to immune cell biomarkers and immune checkpoint expression in glioma. In addition, several GO and Kyoto Encyclopedia of Genes and Genomes (KEGG) items associated with immune response, JAK STAT signal pathway, and cell cycle were significantly enriched in the high PLEKHA4 expression phenotype pathway. Our findings proposed that PLEKHA4 was an independent prognostic biomarker and correlated with immune infiltrates in glioma, and targeting PLEKHA4 might improve immunotherapy in glioma. Of course, these findings also need basic experiments and further clinical trials to confirm in the future.

Endovascular Chemotherapy Selective Targeting for Brain Cancer.

Establishing an effective and robust management option for brain cancers has proven to bean elusive challenge for the fields of neurosurgery and neuro-oncology. Despite decades of research efforts to improve treatment outcomes and increase patient survivability, brain cancer remains among the most fatal of all cancer classes. A significant barrier to this endeavor is the blood-brain barrier, a major protective border for brain tissue that primarily precludes the optimal delivery of chemotherapeutic drugs to the patients brain circulation through tight junction formations and selective transporter proteins. This issue is often compounded by tumor location, particularly in inoperable regions near functional brain parenchyma. These obstacles necessitate the development of selectively targeted delivery of chemotherapeutic agents, such as endovascular super-selective intra-arterial injections. Recent experimental studies demonstrate the effectiveness of focused ultrasound to unseal the blood-brain barrier selectively and reversibly. Together, these new technologies can be leveraged to circumvent the limited permeability of the blood-brain barrier, thus improving drug delivery to tumoral locations and potentially enabling a more effective treatment alternative to surgical resection. This review attempts to place into context the necessity of these newer selective chemotherapeutic modalities by briefly highlighting commonly encountered brain cancers and explaining the prominent challenges that face chemotherapy delivery, as well as describing the current preclinical and clinical progress in the development of facilitatory focused ultrasound with selective endovascular chemotherapy.

Matrix-Assisted Laser DesorptionIonization (MALDI) Mass Spectrometry Imaging of L-4-Phenylalanineboronic Acid (BPA) in a Brain Tumor Model Rat for Boron Neutron Capture Therapy (BNCT).

Boron neutron capture therapy (BNCT) is a cell-selective particle therapy for cancer using boron containing drugs. Boron compounds are accumulated in high concentration of tens ppm level of boron in target tumors to cause lethal damage to tumor tissue. The examination of boron distribution in target tumor and normal tissue is important to evaluate the efficiency of therapy. The matrix-assisted laser desorptionionization (MALDI) mass spectrometry imaging (MSI) is a powerful tool to visualize the distribution of target analyte in biological samples. In this manuscript, we report a trial to visualize the distribution of a typical BNCT drug, L-4-phenylalanine boronic acid (BPA) in a brain tumor model rat using MALDI-MSI technique. We performed a MALDI-MSI with high mass resolution targeting to BPAH

Case report Concurrent malignant triton tumor and relapsed pituitary adenoma in the sellar region.

Malignant triton tumor (MTT) is a rare kind of malignant peripheral nerve sheath tumors, histologically characterized by rhabdomyoblastic differentiation. There are limited reports of MTT occurring in the intracranial area. The treatment modality consisting of total surgical resection plus post-operative radiotherapy is generally accepted. However, even with optimal treatment, most patients will die within a few months. We report a 71-year-old man with a history of pituitary adenoma, who underwent surgical treatment and postoperative gamma knife therapy. Magnetic resonance imaging (MRI) of the brain revealed a mass with two distinctive components in the sellar area. Postoperative pathology found that the lesion consisted of a MTT and a relapsed pituitary adenoma. The present case is the first report of MTT that occurred in the sellar area. It is also the first case of intracranial MTT with other concurrent tumors (relapsed pituitary tumors). Meanwhile, this case has a clear history of radiation therapy, suggesting that the occurrence of MTT may be related to radiation.

Predictive models for the risk and prognosis of bone metastasis in patients with newly-diagnosed esophageal cancer A retrospective cohort study.

Esophageal cancer (EC) is a common malignant tumor worldwide, and patients with both EC and bone metastasis (BM) have a poor prognosis. We aimed to determine the risk and prognostic factors for BM in patients with newly diagnosed EC and to conduct two nomograms to predict the probability of BM and overall survival after BM. Data from patients with EC from 2010 to 2015 were reviewed in the Surveillance, Epidemiology, and End Results (SEER) database. We divided participants into training and validation cohorts using univariate and multivariate logistic regression analyses and Cox regression models to explore the risk and prognostic factors of BM, respectively. Moreover, two nomograms were developed for predicting the risk and prognosis of BM in patients with EC. Then we used receiver operating characteristic curves, decision curve analysis, and calibration curves to evaluate the nomogram models. The overall survival of patients with EC and BM was analyzed using the Kaplan-Meier method. A total of 10,730 patients with EC were involved, 735 of whom had BM at the time of diagnosis. Histologic type, sex, age, N stage, primary site, liver, lung, and brain metastases, and tumor differentiation grade were identified as independent BM risk factors. Histological type, chemotherapy, brain, liver, and lung metastases were identified as prognostic risk factors for patients with EC and BM. We developed diagnostic and prognostic nomograms according to the results. Receiver operating characteristic curves, calibration, and Kaplan-Meier curves, and decision curve analysis all indicated that both nomograms had great clinical predictive ability and good clinical application potential. Two novel nomograms were constructed to predict the risk and prognosis of BM in patients with EC. These prediction models can effectively assist clinicians in clinical decision-making based on their good accuracy and reliability.

PDQ Cancer Information Summaries

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

PDQ Cancer Information Summaries

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

PDQ Cancer Information Summaries

This PDQ cancer information summary has current information about the treatment of childhood central nervous system atypical teratoid and rhabdoid tumor. It is meant to inform and help patients, families, and caregivers. It does not give formal guidelines or recommendations for making decisions about health care. Editorial Boards write the PDQ cancer information summaries and keep them up to date. These Boards are made up of experts in cancer treatment and other specialties related to cancer. The summaries are reviewed regularly and changes are made when there is new information. The date on each summary (Date Last Modified) is the date of the most recent change. The information in this patient summary was taken from the health professional version, which is reviewed regularly and updated as needed, by the PDQ Pediatric Treatment Editorial Board.

Predictive nomograms for early death in metastatic bladder cancer.

Metastatic bladder cancer (MBC) is an incurable malignancy, which is prone to early death. We aimed to establish models to evaluating the risk of early death in patients with metastatic bladder cancer. The data of 1,264 patients with MBC registered from 2010 to 2015 were obtained from the Surveillance, Epidemiology, and End Results (SEER) database. We utilized X-tile software to determine the optimal cut-off points of age and tumor size in diagnosis. Univariate and multivariate logistic regression analyses were used to identify significant independent risk factors for total early death and cancer-specific early death, then we construct two practical nomograms. In order to validate our prediction models, we performed calibration plots, receiver operating characteristics (ROCs) curves, decision curve analysis (DCA) and clinical impact curve (CIC). A total of 1,216 patients with MBC were included in this study. 463 patients died prematurely (≤3 months), and among them 424 patients died of cancer-specific early death. The nomogram of total premature death was created by surgery, chemotherapy, tumor size, histological type, liver metastases, and nomogram of cancer-specific early death was based on surgery, race, tumor size, histological type, chemotherapy, and metastases (liver, brain). Through the verify of calibration plots, receiver operating characteristics (ROCs) curves, decision curve analysis (DCA) and clinical impact curve (CIC), we concluded that nomogram were a valid tool with excellent clinical utility to help clinicians predict premature death in MBC patients. The nomograms derived from the analysis of patients with MBC, which can provide refined prediction of premature death and furnish clinicians with useful ideas for patient-specific treatment options and follow-up scheduling.

Clinical feasibility of miniaturized Lissajous scanning confocal laser endomicroscopy for indocyanine green-enhanced brain tumor diagnosis.

Intraoperative real-time confocal laser endomicroscopy (CLE) is an alternative modality for frozen tissue histology that enables visualization of the cytoarchitecture of living tissues with spatial resolution at the cellular level. We developed a new CLE with a Lissajous scanning pattern and conducted a study to identify its feasibility for fluorescence-guided brain tumor diagnosis. Conventional hematoxylin and eosin (HE) histological images were compared with indocyanine green (ICG)-enhanced CLE images in two settings (1) experimental study with in vitro tumor cells and ex vivo glial tumors of mice, and (2) clinical evaluation with surgically resected human brain tumors. First, CLE images were obtained from cultured U87 and GL261 glioma cells. Then, U87 and GL261 tumor cells were implanted into the mouse brain, and HE staining was compared with CLE images of normal and tumor tissues When ICG was incubated In conclusion, the newly developed CLE with Lissajous laser scanning can be a helpful intraoperative device for the diagnosis, detection of tumor-free margins, and maximal safe resection of brain tumors.

Initial clinical experience with magnetic resonance-guided radiotherapy in pediatric patients Lessons learned from a single institution with proton therapy.

Magnetic resonance-guided radiotherapy (MRgRT) is increasingly used in a variety of adult cancers. To date, published experience regarding the use of MRgRT in pediatric patients is limited to two case reports. We report on the use of MRgRT for pediatric patients at our institution during a four-year period and describe important considerations in the selection and application of this technology in children. All patients treated with MRgRT since inception at our institution between 42018 and 42022 were retrospectively reviewed. We also evaluated all pediatric patients treated at our institution during the same period who received either imaging or treatment using our magnetic resonance-guided linear accelerator (MR Linac). We summarize four clinical cases where MRgRT was selected for treatment in our clinic, including disease outcomes and toxicities and describe our experience using the MR Linac for imaging before and during treatment for image fusion and tumor assessments. Between 42018 and 42022, 535 patients received MRgRT at our center, including 405 (75.7%) with stereotactic ablative radiotherapy (SABR). During this period, 347 distinct radiotherapy courses were delivered to pediatric patients, including 217 (62.5%) with proton therapy. Four pediatric patients received MRgRT. One received SABR for lung metastasis with daily adaptive replanning and a second was treated for liver metastasis using a non-adaptive workflow. Two patients received fractionated MRgRT for an ALK-rearranged non-small cell lung cancer and neuroblastoma. No Grade 2 or higher toxicities were observed or reported during MRgRT or subsequent follow-up. Twelve patients underwent MR imaging without contrast during treatment for brain tumors to assess for tumorcystic changes. Two patients treated with other modalities underwent MR simulation for target volume delineation and organ at risk sparing due to anatomic changes during treatment or unexpected delays in obtaining diagnostic MR appointments. In four pediatric patients treated with MRgRT, treatment was well tolerated with no severe acute effects. At our center, most pediatric patients are treated with proton therapy, but the cases selected for MRgRT demonstrated significant organ at risk sparing compared to alternative modalities. In particular, MRgRT may provide advantages for thoracicabdominalpelvic targets using gated delivery and adaptive replanning, but selected patients treated with fractionated radiotherapy may also benefit MRgRT through superior organ at risk sparing.

Case report Somatic mutations in microtubule dynamics-associated genes in patients with WNT-medulloblastoma tumors.

Medulloblastoma (MB) is the most common pediatric brain tumor which accounts for about 20% of all pediatric brain tumors and 63% of intracranial embryonal tumors. MB is considered to arise from precursor cell populations present during an early brain development. Most cases (70%) of MB occur at the age of 1-4 and 5-9, but are also infrequently found in adults. Total annual frequency of pediatric tumors is about 5 cases per 1 million children. WNT-subtype of MB is characterized by a high probability of remission, with a long-term survival rate of about 90%. However, in some rare cases there may be increased metastatic activity, which dramatically reduces the likelihood of a favorable outcome. Here we report two cases of MB with a histological pattern consistent with desmoplasticnodular (DP) and classic MB, and genetically classified as WNT-MB. Both cases showed putative causal somatic protein truncating mutations identified in microtubule-associated genes

Case report Autoimmune encephalitis with multiple auto-antibodies with reversible splenial lesion syndrome and bilateral ovarian teratoma.

Reversible splenial lesion syndrome (RESLES) is a spectrum of disease radiologically characterized by reversible lesions caused by multiple factors, primarily involving the splenium of the corpus callosum (SCC). The most common causes of RESLES include infection, antiepileptic drug use and withdrawal, and severe metabolic disorders. Nevertheless, cases of autoimmune encephalitis (AE) are uncommon. A 26-year-old female computer programming engineer with no previous medical or psychiatric history reported to the psychiatric hospital due to a 3-day episode of irritability, babbling, limb stiffness, sleepwalking, hallucinations, and paroxysmal mania. Brain MRI revealed abnormal signals of the SCC. Lumbar puncture was performed and further testing for auto-antibodies was conducted in both the CSF and serum. CSF of the patient was positive for anti-NMDAR (titer of 13.2) antibodies, and serum was also positive for anti-NMDAR (titer of 132) as well as mGluR5 (titer of 110) antibodies. Enhanced CT of the pelvis showed an enlarged pelvic mass bilateral ovarian teratomas (mature teratoma and immature teratoma) were evaluated, which were pathologically confirmed after transabdominal left adnexal resection, right ovarian biopsy, and ovarian cystectomy. The patient considerably improved after intravenous administration of steroids, immunoglobulin, oral prednisone, surgical treatment, and chemotherapy. A follow-up MRI revealed completely resolved lesions. During a 3-month follow-up, the patient experienced complete resolution of symptoms without any sign of recurrence and tumors. The titer of the anti-NMDAR antibody decreased to 110 in serum. Herein, we report a rare case of AE with overlapping auto-antibodies, along with RESLES and bilateral ovarian teratomas. The current case provides the possibility of the concurrence of mGluR5 antibodies in anti-NMDAR encephalitis. However, the underlying mechanism remains elusive. Furthermore, we provide additional evidence that overlapping antibodies-related pathology may be one of the many causes of RESLES. Nonetheless, caution should be observed in interpreting the observation, considering that this is a single-case study.

The antihypertensive effect of remote ischemic conditioning in spontaneously hypertensive rats.

Limb remote ischemic conditioning (LRIC) may be an effective method to control hypertension. This study investigated whether LRIC decreases blood pressure by regulating the hypertensive inflammatory response in spontaneously hypertensive rats (SHR). The SHR and aged-matched Wistar rats with different ages were randomly assigned to the SHR group, SHRLRIC group, Wistar group, and Wistar LRIC group. LRIC was conducted by tightening a tourniquet around the upper thigh and releasing it for three cycles daily (10 mins x3 cycles). Blood pressure, the percentage of monocytes and T lymphocytes, and the concentration of pro-inflammatory cytokines in the blood were analyzed. The blood pressure of SHR was significantly higher than that of age-matched Wistar rats. LRIC decreased blood pressure in SHR at different ages (4, 8, and 16 weeks old), but had no effect on the blood pressure in Wistar rats. Flow cytometry analysis showed that blood monocytes and CD8 T cells of SHR were higher than those of Wistar rats. LRIC significantly decreased the percentage of monocytes and CD8 T cells in SHR. Consistent with the changes of immune cells, the levels of plasma IL-6 and TNF-α in SHR were also higher. And LRIC attenuated the plasma IL-6 and TNF-α levels in SHR. LRIC may decreased the blood pressure via modulation of the inflammatory response in SHR.

Triggering receptor expressed on myeloid cells 2 (TREM2) is expressed in myeloid cells of the central nervous system (CNS), which mediate the immunological response in a variety of diseases. Uncertain is the function of TREM2 in glioma and tumor immune responses. In this research, the expression patterns of TREM2 in glioma were analyzed, along with its prognostic value and functional roles. TREM2 expression is increased in glioblastomas, gliomas with a mesenchymal subtype, gliomas with wild-type isocitrate dehydrogenase, and gliomas without 1p19q deletion, all of which suggest the aggressiveness and poor prognosis of gliomas. Gene ontology, KEGG, and Gene set variation analyses indicated that TREM2 may serve as an immune response mediator. However, the function of T cells against tumor cells was negatively correlated with TREM2, suggesting that TREM2 may suppress tumor immunity. Further investigation demonstrated a correlation between TREM2 expression and immune checkpoint expression. CIBERSORT research revealed a link between a higher TREM2 expression level and the enrichment of tumor-associated macrophages, especially M2 subtype. Single-cell analysis and multiple immunohistochemical staining results showed that microglia and macrophage cells expressed TREM2. Immunofluorescent staining indicated that knocking down the expression of TREM2 would result in a decrease in M2 polarization. TREM2 was discovered to be an independent prognostic factor in glioma. In conclusion, our findings revealed that TREM2 was significantly expressed in microglia and macrophage cells and was intimately associated with the tumor immune microenvironment. Thus, it is expected that small-molecule medications targeting TREM2 or monoclonal antibodies would enhance the efficacy of glioma immunotherapy.

Interferon gamma-related gene signature based on anti-tumor immunity predicts glioma patient prognosis.

DL-3-n-butylphthalide (NBP) alleviates poststroke cognitive impairment (PSCI) by suppressing neuroinflammation and oxidative stress.

Currently, the recovery of cognitive function has become an essential part of stroke rehabilitation. DL-3-n-butylphthalide (NBP) is a neuroprotective reagent and has been used in stroke treatment. Clinical studies have confirmed that NBP can achieve better cognitive outcomes in ischemic stroke patients than in healthy controls. In this study, we aimed to investigate the influences of NBP on cognitive function in an ischemic reperfusion (IR) rat model. Our results showed that NBP profoundly decreased neurological scores, reduced cerebral infarct areas and enhanced cerebral blood flow (CBF). NBP potently alleviated poststroke cognitive impairment (PSCI) including depression-like behavior and learning, memory and social cognition impairments, in IR rats. NBP distinctly suppressed the activation of microglia and astrocytes and improved neuron viability in the ischemic brain. NBP inhibited the expression of inflammatory cytokines, including interleukin-6 (IL-6), interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), by targeting the nuclear factor kappa Binducible nitric oxide synthase (NF-κBiNOS) pathway and decreased cerebral oxidative stress factors, including reactive oxygen species (ROS) and malondialdehyde (MDA), by targeting the kelch like ECH associated protein 1nuclear factor-erythroid 2 p45-related factor 2 (Keap1Nrf2) pathway in the ischemic brain. The current study revealed that NBP treatment improved neurological function and ameliorated cognitive impairment in IR rats, possibly by synergistically suppressing inflammation and oxidative stress.

Case report Anti-

We herein detail our experience with a unique patient with a primary central nervous system (PCNS) B-cell lymphoma concomitant with anti- A 73-year-old Japanese woman presented with acute pyrexia, agitation, and disturbance of consciousness. She gradually developed a reduction in speech frequency and truncal dystonia causing abnormal posture. Brain magnetic resonance imaging (MRI) demonstrated high-intensity lesions in the bilateral frontal lobes, and her cerebrospinal fluid revealed mild pleocytosis. She was diagnosed with acute encephalitis and treated with acyclovir and intravenous dexamethasone however, no improvement was observed. She was transferred to our hospital 6 weeks after the onset of her symptoms, and anti-NMDAR antibodies were identified in her cerebrospinal fluid through indirect immunolabeling with rat brain frozen sections and cell-based assays with NR1NR2 transfected HEK cells. Follow-up MRI showed enlargement of the lesions in the right frontal lobe with gadolinium enhancement, suggesting a brain tumor. Stereotactic surgery was implemented, with subsequent pathological examination revealing that the tumor was consistent with diffuse large B-cell lymphoma (DLBCL) without evidence of systemic satellite lesions. Stereotactic irradiative therapies were then added to her treatment regimen, which partly improved her neurological symptoms with only mild cognitive dysfunction still remaining. A decrease in anti-NMDAR antibody titer was also confirmed after immunotherapy and tumor removal. We herein report our experience with a novel case of PCNS-DLBCL masquerading as anti-NMDAR encephalitis that satisfied the diagnostic criteria of proNMDARE. Treatment, including tumor removal, ameliorated disease severity and antibody titers of the patient. Our findings suggest that anti-NMDAR antibody-associated autoimmunity can be triggered by PCNS B-cell tumors, although primary brain tumors need to be excluded before establishing a diagnosis of autoimmune encephalitis.

Resting state network mapping in individuals using deep learning.

Resting state functional MRI (RS-fMRI) is currently used in numerous clinical and research settings. The localization of resting state networks (RSNs) has been utilized in applications ranging from group analysis of neurodegenerative diseases to individual network mapping for pre-surgical planning of tumor resections. Reproducibility of these results has been shown to require a substantial amount of high-quality data, which is not often available in clinical or research settings. In this work, we report voxelwise mapping of a standard set of RSNs using a novel deep 3D convolutional neural network (3DCNN). The 3DCNN was trained on publicly available functional MRI data acquired in Our results indicate this method can be applied in individual subjects and is highly resistant to both noisy data and fewer RS-fMRI time points than are typically acquired. Further, our results show core regions within each network that exhibit high average probability and low STD. The 3DCNN algorithm can generate individual RSN localization maps, which are necessary for clinical applications. The similarity between 3DCNN mapping results and task-based fMRI responses supports the association of specific functional tasks with RSNs.

hPG

Currently, the long-term prognosis and survival rate of patients with high-grade glial tumors remains poor and there are no biomarkers. hPG The PROGLIO study is a pilot, single-center, longitudinal study that primarily seeks to evaluate circulating plasma hPG ClinicalTrials.gov, ID NCT05157594 registered on October 27, 2021.

A Deep Probabilistic Sensing and Learning Model for Brain Tumor Classification With Fusion-Net and HFCMIK Segmentation.

Astrocytoma and IDH1-Wildtype Glioblastoma (GBM) Cells Colonize Tumor Vessels and Deploy Vascular Mimicry.

Gliomas are the most prevalent type of malignant brain tumors with a very dismal prognosis. Angiogenesis in glioma has recently gotten more attention and its molecular aspects have been published however, these were not complemented with ultrastructural evidence. Our ultrastructural examination of glioma vessels reveals several unique and critical features related to their mechanisms of progression and metastasis strategy. The detailed ultrastructural survey of 18

An RNA seq-based reference landscape of human normal and neoplastic brain.

In order to better understand the relationship between normal and neoplastic brain, we combined five publicly available large-scale datasets, correcting for batch effects and applying Uniform Manifold Approximation and Projection (UMAP) to RNA-seq data. We assembled a reference Brain-UMAP including 702 adult gliomas, 802 pediatric tumors and 1409 healthy normal brain samples, which can be utilized to investigate the wealth of information obtained from combining several publicly available datasets to study a single organ site. Normal brain regions and tumor types create distinct clusters and because the landscape is generated by RNA seq, comparative gene expression profiles and gene ontology patterns are readily evident. To our knowledge, this is the first meta-analysis that allows for comparison of gene expression and pathways of interest across adult gliomas, pediatric brain tumors, and normal brain regions. We provide access to this resource via the open source, interactive online tool Oncoscape, where the scientific community can readily visualize clinical metadata, gene expression patterns, gene fusions, mutations, and copy number patterns for individual genes and pathway over this reference landscape.

Automated Tumor Segmentation and Brain Tissue Extraction from Multiparametric MRI of Pediatric Brain Tumors A Multi-Institutional Study.

Brain tumors are the most common solid tumors and the leading cause of cancer-related death among all childhood cancers. Tumor segmentation is essential in surgical and treatment planning, and response assessment and monitoring. However, manual segmentation is time-consuming and has high interoperator variability. We present a multi-institutional deep learning-based method for automated brain extraction and segmentation of pediatric brain tumors based on multi-parametric MRI scans. Multi-parametric scans (T1w, T1w-CE, T2, and T2-FLAIR) of 244 pediatric patients (n215 internal and n29 external cohorts) with de novo brain tumors, including a variety of tumor subtypes, were preprocessed and manually segmented to identify the brain tissue and tumor subregions into four tumor subregions, i.e., enhancing tumor (ET), non-enhancing tumor (NET), cystic components (CC), and peritumoral edema (ED). The internal cohort was split into training (n151), validation (n43), and withheld internal test (n21) subsets. DeepMedic, a three-dimensional convolutional neural network, was trained and the model parameters were tuned. Finally, the network was evaluated on the withheld internal and external test cohorts. Dice similarity score (median±SD) was 0.91±0.100.88±0.16 for the whole tumor, 0.73±0.270.84±0.29 for ET, 0.79±190.74±0.27 for union of all non-enhancing components (i.e., NET, CC, ED), and 0.98±0.02 for brain tissue in both internalexternal test sets. Our proposed automated brain extraction and tumor subregion segmentation models demonstrated accurate performance on segmentation of the brain tissue and whole tumor regions in pediatric brain tumors and can facilitate detection of abnormal regions for further clinical measurements. We proposed automated tumor segmentation and brain extraction on pediatric MRI.The volumetric measurements using our models agree with ground truth segmentations. The current response assessment in pediatric brain tumors (PBTs) is currently based on bidirectional or 2D measurements, which underestimate the size of non-spherical and complex PBTs in children compared to volumetric or 3D methods. There is a need for development of automated methods to reduce manual burden and intra- and inter-rater variability to segment tumor subregions and assess volumetric changes. Most currently available automated segmentation tools are developed on adult brain tumors, and therefore, do not generalize well to PBTs that have different radiological appearances. To address this, we propose a deep learning (DL) auto-segmentation method that shows promising results in PBTs, collected from a publicly available large-scale imaging dataset (Childrens Brain Tumor Network CBTN) that comprises multi-parametric MRI scans of multiple PBT types acquired across multiple institutions on different scanners and protocols. As a complementary to tumor segmentation, we propose an automated DL model for brain tissue extraction.

Functional genomic analysis of adult and pediatric brain tumor isolates.

Adult and pediatric tumors display stark differences in their mutation spectra and chromosome alterations. Here, we attempted to identify common and unique gene dependencies and their associated biomarkers among adult and pediatric tumor isolates using functional genetic lethal screens and computational modeling. We performed CRISRP-Cas9 lethality screens in two adult glioblastoma (GBM) tumor isolates and five pediatric brain tumor isolates representing atypical teratoid rhabdoid tumors (ATRT), diffuse intrinsic pontine glioma, GBM, and medulloblastoma. We then integrated the screen results with machine learning-based gene-dependency models generated from data from >900 cancer cell lines. We found that >50% of candidate dependencies of 280 identified were shared between adult GBM tumors and individual pediatric tumor isolates. 68% of screen hits were found as nodes in our network models, along with shared and tumor-specific predictors of gene dependencies. We investigated network predictors associated with ADAR, EFR3A, FGFR1 (pediatric-specific), and SMARCC2 (ATRT-specific) gene dependency among our tumor isolates. The results suggest that, despite harboring disparate genomic signatures, adult and pediatric tumor isolates share a preponderance of genetic dependences. Further, combining data from primary brain tumor lethality screens with large cancer cell line datasets produced valuable insights into biomarkers of gene dependency, even for rare cancers. Our results demonstrate that large cancer cell lines data sets can be computationally mined to identify known and novel gene dependency relationships in adult and pediatric human brain tumor isolates. Gene dependency networks and lethality screen results represent a key resource for neuro-oncology and cancer research communities. We also highlight some of the challenges and limitations of this approach.

Identification of glioblastoma stem cell-associated lncRNAs using single-cell RNA-sequencing datasets.

Glioblastoma multiforme (GBM) is an aggressive, heterogeneous grade IV brain tumor. Glioblastoma stem cells (GSCs) initiate the tumor and are known culprits of therapy resistance. Mounting evidence has demonstrated a regulatory role of long non-coding RNAs (lncRNAs) in various biological processes, including pluripotency, differentiation, and tumorigenesis. A few studies have suggested that aberrant expression of lncRNAs is associated with GSCs. However, a comprehensive single-cell analysis of the GSC-associated lncRNA transcriptome has not been carried out. Here, we analyzed recently published single-cell RNA-sequencing datasets of adult human GBM tumors, GBM organoids, GSC-enriched GBM tumors, and developing human brains to identify lncRNAs highly expressed in GBM. To categorize GSC populations in the GBM tumors, we used the GSC marker genes SOX2, PROM1, FUT4, and L1CAM. We found three major GSC population clusters radial glia, oligodendrocyte progenitor cells, and neurons. We found 10â€100 lncRNAs significantly enriched in different GSC populations. We also validated the level of expression and localization of several GSC-enriched lncRNAs using qRT-PCR, single-molecule RNA FISH, and sub-cellular fractionation. We found that the radial glia GSC-enriched lncRNA

Area postrema neurons mediate interleukin-6 function in cancer-associated cachexia.

Interleukin-6 (IL-6) has been long considered a key player in cancer-associated cachexia

An RNA seq-based reference landscape of human normal and neoplastic brain.

In order to better understand the relationship between normal and neoplastic brain, we combined five publicly available large-scale datasets, correcting for batch effects and applying Uniform Manifold Approximation and Projection (UMAP) to RNA-seq data. We assembled a reference Brain-UMAP including 702 adult gliomas, 802 pediatric tumors and 1409 healthy normal brain samples, which can be utilized to investigate the wealth of information obtained from combining several publicly available datasets to study a single organ site. Normal brain regions and tumor types create distinct clusters and because the landscape is generated by RNA seq, comparative gene expression profiles and gene ontology patterns are readily evident. To our knowledge, this is the first meta-analysis that allows for comparison of gene expression and pathways of interest across adult gliomas, pediatric brain tumors, and normal brain regions. We provide access to this resource via the open source, interactive online tool Oncoscape, where the scientific community can readily visualize clinical metadata, gene expression patterns, gene fusions, mutations, and copy number patterns for individual genes and pathway over this reference landscape.

Germline loss-of-function

Pituitary adenomas (PAs) are common, usually benign tumors of the anterior pituitary gland which, for the most part, have no known genetic cause. PAs are associated with major clinical effects due to hormonal dysregulation and tumoral impingement on vital brain structures. Following the identification of a loss-of-function variant (p.Arg703Gln) in the