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A Novel 5-Aminolevulinic Acid-Enabled Surgical Loupe System-A Consecutive Brain Tumor Series of 11 Cases.

The concept of maximally safe resection (MSR) has been shown to improve clinical outcomes in the treatment of high-grade gliomas (HGGs). To achieve MSR, surgical adjuncts such as functional imaging, neuronavigation, intraoperative mapping, ultrasound, and fluorescence-guided surgery are routinely used. 5-Aminolevulinic acid (5-ALA) is an oral agent that has been increasingly adopted in fluorescence-guided resection of HGG. In randomized clinical trials of 5-ALA, it has been shown to increase the extent of resection and progression-free survival in HGG. Current commercially available 5-ALA detection systems are all microscope-based and can sometimes be cumbersome to use. To present our experience using a novel 5-ALA-enabled surgical loupe system. 5-ALA-enabled loupes were used in 11 consecutive patients with either suspected HGG on magnetic resonance imaging or recurrence of known lesions. Lesion appearance was examined under white light, 5-ALA loupes, and a 5-ALA microscope. Tumor specimens were checked for fluorescence and sent for pathologic examination. In our experience, a 5-ALA-enabled surgical loupe system offers excellent visualization of 5-ALA in patients with HGG. In 10 of 11 patients, fluorescent tissue was confirmed to be high-grade glioma by pathology. In 1 patient, tissue was not fluorescent, and final pathology was World Health Organization grade I meningioma. A 5-ALA-enabled surgical loupe system offers excellent intraoperative visualization of 5-ALA fluorescence in HGG and can be a viable surgical adjunct for achieving MSR of HGG.

Development of Potent Immune Modulators Targeting Stimulator of Interferon Genes Receptor.

Stimulator of interferon genes (STING) is an endoplasmic reticulum-membrane protein that plays important roles in cancer immunotherapy by activating innate immune responses. We designed and synthesized STING modulators and characterized compounds

The effects of androgen deprivation on working memory and quality of life in prostate cancer patients The roles of hypothalamic connectivity.

Androgen deprivation therapy (ADT) has been associated with adverse effects on the brain. ADT alters testosterone levels via its action on the hypothalamus-pituitary-gonadal axis and may influence hypothalamic functions. Given the wide regional connectivity of the hypothalamus and its role in regulating cognition and behavior, we assessed the effects of ADT on hypothalamic resting state functional connectivity (rsFC) and their cognitive and clinical correlates. In a prospective observational study, 22 men with nonmetastatic prostate cancer receiving ADT and 28 patients not receiving ADT (controls), matched in age, years of education, and Montreal Cognitive Assessment score, participated in N-back task and quality of life (QoL) assessments and brain imaging at baseline and at 6 months. Imaging data were processed with published routines and the results of a group by time flexible factorial analysis were evaluated at a corrected threshold. ADT and control groups did not differ in N-back performance or QoL across time points. Relative to controls, patients receiving ADT showed significantly higher hypothalamus-right mid-cingulate cortex (MCC) and precentral gyrus (PCG) rsFC during follow-up versus baseline. Further, the changes in MCC and PCG rsFC were correlated positively with the change in QoL score and 0-back correct response rate, respectively, in patients with undergoing ADT. Six-month ADT affects hypothalamic functional connectivity with brain regions critical to cognitive motor and affective functions. Elevated hypothalamic MCC and PCG connectivity likely serve to functionally compensate for the effects of ADT and sustain attention and overall QoL. The longer-term effects of ADT remain to be investigated.

Short TE downfield magnetic resonance spectroscopy in a mouse model of brain glioma.

Enhanced cell proliferation in tumors can be associated with altered metabolic profiles and dramatic microenvironmental changes. Downfield magnetic resonance spectroscopy (MRS) has received increasing attention due to its ability to report on labile resonances of molecules not easily detected in upfield Experiments were performed in vivo in an immunocompetent glioma mouse model at 9.4 T using a cryogenic coil. iRE-MRS spectra were acquired in N 6 glioma-bearing mice (voxel size 2.2 Short TE tumor spectra exhibited large qualitative differences compared to control spectra. Most peaks appeared modulated, with strong attenuation of NAA (∼7.82, 7.86 ppm) and changes in relative peak areas between 6.75 and 8.49 ppm. Peak areas tended to be smaller for DF In-vivo downfield

Accelerated hypofractionated radiation for elderly or frail patients with a newly diagnosed glioblastoma A pooled analysis of patient-level data from 4 prospective trials.

The standard of care for elderly or frail patients with glioblastoma (GBM) is 40 Gy in 15 fractions of radiotherapy. However, this regimen has a lower biological effective dose (BED) compared with the Stupp regimen of 60 Gy in 30 fractions. It is hypothesized that accelerated hypofractionated radiation of 52.5 Gy in 15 fractions (BED equivalent to Stupp) is safe and efficacious. Elderly or frail patients with GBM treated with 52.5 Gy in 15 fractions were pooled from 3 phase 12 studies and a prospective observational study. Overall survival (OS) and progression-free survival (PFS) were defined time elapsing between surgerybiopsy and death from any cause or progression of disease. Sixty-two newly diagnosed patients were eligible for this pooled analysis of individual patient data. The majority (66%) had a Karnofsky performance status (KPS) score <70. The median age was 73 years. The median OS and PFS were 10.3 and 6.9 months, respectively. Patients with KPS scores ≥70 and <70 had a median OS of 15.3 and 9.5 months, respectively. Concurrent chemotherapy was an independent prognostic factor for improved PFS and OS. Grade 3 neurologic toxicity was seen in 2 patients (3.2%). There was no grade 45 toxicity. This is the only analysis of elderlyfrail patients with GBM prospectively treated with a hypofractionated radiation regimen that is isoeffective to the Stupp regimen. Treatment was well tolerated and demonstrated excellent OS and PFS compared with historical studies. This regimen gives the elderlyfrail population an alternative to regimens with a lower BED. Randomized trials are needed to validate these results.

A phase 2 study of sorafenib combined with conventional therapies in refractory central nervous system leukemia.

Patients with refractory central nervous system leukemia (CNSL) have a dismal prognosis and lack effective therapy. Case reports have shown that sorafenib is effective against brain metastases, including leukemia. To explore the efficacy of sorafenib combined with conventional therapies for refractory CNSL, a phase 2 study was conducted. The primary end point was the complete remission rate (CRR) within 8 weeks of treatment. Secondary end points included the overall response rate (ORR), event-free survival (EFS), overall survival (OS), and adverse events (AEs). Twenty-six patients with refractory CNSL were enrolled they included 17 with isolated CNSL, 7 with hematological relapse, and 2 with another extramedullary relapse. After 8 weeks of treatment, 21 patients achieved complete remission, 2 achieved partial remission, and 3 achieved no remission for a CRR of 80.8% (95% CI, 62.1%-91.5%) and an ORR of 88.5% (95% CI, 71.0%-96.0%). Twenty patients survived, and 6 died. The 2-year EFS and OS rates were 75.0% (95% CI, 54.5%-88.3%) and 76.9% (95% CI, 54.2%-90.4%), respectively. Six patients experienced grade 3 or 4 treatment-related AEs, including moderate chronic graft-vs-host disease (n 3), grade 3 or 4 acute graft-vs-host disease (n 2), and grade 3 skin rash (n 1). No treatment-related deaths occurred during the therapy of refractory CNSL. Sorafenib combined with conventional therapies is effective and safe for refractory CNSL. Sorafenib combined with conventional therapies is effective and safe for refractory central nervous system leukemia.

Acrolein, an endogenous aldehyde induces synaptic dysfunction in vitro and in vivo Involvement of RhoAROCK2 pathway.

Acrolein, an unsaturated aldehyde, is increased in the brain of Alzheimers disease (AD) patients and identified as a potential inducer of sporadic AD. Synaptic dysfunction, as a typical pathological change occurring in the early stage of AD, is most closely associated with the severity of dementia. However, there remains a lack of clarity on the mechanisms of acrolein inducing AD-like pathology and synaptic impairment. In this study, acrolein-treated primary cultured neurons and mice were applied to investigate the effects of acrolein on cognitive impairment and synaptic dysfunction and their signaling mechanisms. In vitro, ROCK inhibitors, Fasudil, and Y27632, could attenuate the axon ruptures and synaptic impairment caused by acrolein. Meanwhile, RNA-seq distinct differentially expressed genes in acrolein models and initially linked activated RhoARho-kinase2 (ROCK2) to acrolein-induced synaptic dysfunction, which could regulate neuronal cytoskeleton and neurite. The Morris water maze test and in vivo field excitatory postsynaptic potential (fEPSP) were performed to evaluate spatial memory and long-term potential (LTP), respectively. Acrolein induced cognitive impairment and attenuated LTP. Furthermore, the protein level of Synapsin 1 and postsynaptic density 95 (PSD95) and dendritic spines density were also decreased in acrolein-exposed mice. These changes were improved by ROCK2 inhibitor Fasudil or in ROCK2

Spatial charting of single-cell transcriptomes in tissues.

Single-cell RNA sequencing methods can profile the transcriptomes of single cells but cannot preserve spatial information. Conversely, spatial transcriptomics assays can profile spatial regions in tissue sections, but do not have single-cell resolution. Here, we developed a computational method called CellTrek that combines these two datasets to achieve single-cell spatial mapping through coembedding and metric learning approaches. We benchmarked CellTrek using simulation and in situ hybridization datasets, which demonstrated its accuracy and robustness. We then applied CellTrek to existing mouse brain and kidney datasets and showed that CellTrek can detect topological patterns of different cell types and cell states. We performed single-cell RNA sequencing and spatial transcriptomics experiments on two ductal carcinoma in situ tissues and applied CellTrek to identify tumor subclones that were restricted to different ducts, and specific T cell states adjacent to the tumor areas. Our data show that CellTrek can accurately map single cells in diverse tissue types to resolve their spatial organization.

Fatty acid oxidation fuels glioblastoma radioresistance with CD47-mediated immune evasion.

Glioblastoma multiforme (GBM) remains the top challenge to radiotherapy with only 25% one-year survival after diagnosis. Here, we reveal that co-enhancement of mitochondrial fatty acid oxidation (FAO) enzymes (CPT1A, CPT2 and ACAD9) and immune checkpoint CD47 is dominant in recurrent GBM patients with poor prognosis. A glycolysis-to-FAO metabolic rewiring is associated with CD47 anti-phagocytosis in radioresistant GBM cells and regrown GBM after radiation in syngeneic mice. Inhibition of FAO by CPT1 inhibitor etomoxir or CRISPR-generated CPT1A

Basal Ganglia Iron Content Increases with Glioma Severity Using Quantitative Susceptibility Mapping A Potential Biomarker of Tumor Severity.

Gliomas have been found to alter iron metabolism and transport in ways that result in an expansion of their intracellular iron compartments to support aggressive tumor growth. This study used deep neural network trained quantitative susceptibility mapping to assess basal ganglia iron concentrations in glioma patients. Ninety-two patients with brain lesions were initially enrolled in this study and fifty-nine met the inclusion criteria. Susceptibility-weighted images were collected at 3.0 T and used to construct quantitative susceptibility maps via a deep neural network-based method. The regions of interest were manually drawn within basal ganglia structures and the mean voxel intensities were extracted and averaged across multiple slices. One-way ANCOVA tests were conducted to compare the susceptibility values of groups of patients based on tumor grade while controlling for age, sex, and tumor type. The mean basal ganglia susceptibility for patients with grade IV tumors was higher than that for patients with grade II tumors ( The basal ganglia iron content increased with glioma severity. Basal ganglia iron levels may thus be a useful biomarker in glioma prognosis and treatment, especially with regard to iron-based cancer therapies.

Final Report on Clinical Outcomes and Tumor Recurrence Patterns of a Pilot Study Assessing Efficacy of Belinostat (PXD-101) with Chemoradiation for Newly Diagnosed Glioblastoma.

Glioblastoma (GBM) is highly aggressive and has a poor prognosis. Belinostat is a histone deacetylase inhibitor with blood-brain barrier permeability, anti-GBM activity, and the potential to enhance chemoradiation. The purpose of this clinical trial was to assess the efficacy of combining belinostat with standard-of-care therapy. Thirteen patients were enrolled in each of control and belinostat cohorts. The belinostat cohort was given a belinostat regimen (500-750 mgm

Epiglottic Cyst With Slurred Speech Misdiagnosed as Acute Cerebral Infarction A Case Report.

Epiglottic cysts are cysts that occur under the mucosa of the epiglottis. Patients with severe cysts may have difficulty in breathing. Slurred speech usually occurs in cerebrovascular diseases, especially with slurred speech as the starting symptom. We describe the case of a patient with slurred speech as the first symptom. The patient was a 53-year-old man with slurred speech as the first symptom, and he was initially considered to have an acute cerebral infarction. However, the results of the cranial magnetic resonance imaging examination did not support the diagnosis. The possibility of neck tumor recurrence was considered based on past medical history. The findings of a computed tomography examination of the neck suggested an epiglottic cyst. The effect of anti-inflammatory and surgical treatment was significant, and speech returned to normal. This case emphasizes that neurologists need to be vigilant when dealing with patients with slurred speech, which may be one of the clinical manifestations of epiglottic cysts.

Infantile Choroid Plexus Papilloma with Multiple Peritumoral Cysts.

Infantile choroid plexus papilloma (CPP) associated with multiple peritumoral cysts is a rare variant of CPP, and clinical course and optimal management are largely unknown. A 9-month-old boy presented with a large solid tumor in the left lateral ventricle associated with multiple peritumoral cysts, arachnoid cysts, and hydrocephalus containing xanthochromic fluid with high protein content. Shrinkage of these cysts and resolution of hydrocephalus were achieved after total resection of the hypervascular solid part of the tumor. Histological examination confirmed the solid part of the tumor as CPP and showed that the wall of the peritumoral cysts consisted of reactive gliosis without neoplastic cells. Follow-up magnetic resonance imaging 12 months after surgery revealed that these cysts remained stable. CPP with nonenhancing peritumoral cysts can be managed by resection of only the solid part of the tumor without permanent cerebrospinal fluid diversion.

Systematic Review of Epigenetic Therapies for Treatment of IDH-mutant Glioma.

Isocitrate dehydrogenase (IDH) mutations are present in 70% of World Health Organization grade II and III gliomas. IDH mutation induces accumulation of the oncometabolite 2-hydroxyglutarate. Therefore, therapies targeting reversal of epigenetic dysregulation in gliomas have been suggested. However, the utility of epigenetic treatments in gliomas remains unclear. Here, we present the first clinical systematic review of epigenetic therapies in treatment of IDH-mutant gliomas and highlight their safety and efficacy. We conducted a systematic search of electronic databases from 2000 to January 2021 following PRISMA guidelines. Articles were screened to include clinical usage of epigenetic therapies in case reports, prospective case series, or clinical trials. Primary and secondary outcomes included safetytolerability of epigenetic therapies and progression-free survivaloverall survival, respectively. A total of 133 patients across 8 clinical studies were included in our analysis. IDH inhibitors appear to have the best safety profile, with an overall grade 3grade 4 adverse event rate of 9%. Response rates to IDH-mutant inhibitors were highest in nonenhancing gliomas (stable disease achieved in 55% of patients). In contrast, histone deacetylase inhibitors demonstrate a lower safety profile with single-study adverse events as high as 28%. IDH inhibitors appear promising given their benign toxicity profile and ease of monitoring. Histone deacetylase inhibitors appear to have a narrow therapeutic index, as lower concentrations do not appear effective, while increased doses can produce severe immunosuppressive effects. Preliminary data suggest that epigenetic therapies are generally well tolerated and may control disease in certain patient groups, such as those with nonenhancing lesions.

Amelioration of oxidative stress utilizing nanoemulsion loaded with bromocriptine and glutathione for the management of Parkinsons disease.

Parkinsons disease (PD) is triggered by the formation of free radicals in dopaminergic neurons, which results in oxidative stress-induced neurodegeneration. The objective of the work was to relieve oxidative stress by employing intranasal delivery of Bromocriptine Mesylate (BRM) and Glutathione (GSH) loaded nanoemulsion for the better management of PD. The depth of permeation of the nanoemulsion was assessed through confocal laser scanning microscopy (CLSM) which revealed higher nanoemulsion permeation in contrast to suspension. Biocompatibility of nanoemulsion was confirmed by nasal cilio toxicity study. The DPPH study showed that the nanoemulsion had significant antioxidant activity. Biochemical estimation studies in Wistar rats were carried out in order to determine the effect of nanoemulsion on oxidative stress. The levels of GSH, superoxide dismutase (SOD), and catalase (CAT) were significantly enhanced and the level of thiobarbituric acid reactive substances (TBARS) was significantly reduced after the intranasal administration of nanoemulsion in the haloperidol-induced model of PD. Furthermore, the levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) were also determined which reduced significantly after the administration of nanoemulsion. The oxidative stress levels were lowered with nanoemulsion, showing the combined antioxidant capability of BRM and GSH. The neuroprotective effect of the prepared nanoemulsion was confirmed by histopathological studies. Pharmacokinetic study revealed a higher concentration of BRM and GSH in the brain of Wistar rats after intranasal administration of nanoemulsion with a higher BrainPlasma ratio. A higher value of AUC

Pharmacological Postconditioning by Protocatechuic Acid Attenuates Brain Injury in Ischemia-Reperfusion (IR) Mice Model Implications of Nuclear Factor Erythroid-2-Related Factor Pathway.

Ischemia-reperfusion (IR) injury often follows cardiovascular aberrations that predispose the patient to be neurological and cognitive abnormalities. Pharmacological postconditioning (pPoCo) aims to mitigate IR origin cerebral infarction and neurobehavioral impairment. Protocatechuic acid (PCA) is a natural polyphenol possessing anti-oxidant and anti-inflammatory activities. This study investigated the effects of PCA pPoCo using a global IR mice prototype. Mice were injected PCA (50 and 100 mgkg) immediately after bilateral common carotid artery occlusion (17 min) followed by 24 h reperfusion. Trigonelline (10 mgkg) was administered separately before IR surgery to assess the role of the Nrf2 pathway in PCA and IR treated mice. Results displayed neurological deficits 24 h post-reperfusion, and IR triggered sensorimotor and memory deficits that were attenuated by PCA. PCA pPoCo increased antioxidants and Nrf2 expression in the brain against IR injury. In IR mice, PCA pPoCo attenuated lipid peroxidation, inflammatory cytokines (tumor necrosis factor-α, interleukin-1β, interleukin-6), and myeloperoxidase activity. Histopathology revealed a decrease in total infarct area (TTC staining) and cortical neuron density by IR surgery that was attenuated by PCA. Trigonelline antagonized beneficial effects of PCA pPoCo and attenuated Nrf2 pathway in IR mice model. PCA pPoCo dose-dependently improves neurobehavioral functions against global IR injury via the Nrf2 mechanism.

Inhibition of lncRNA NEAT1 sensitizes medulloblastoma cells to cisplatin through modulating the miR-23a-3p-glutaminase (GLS) axis.

Medulloblastoma (MB) is a commonly occurring brain malignancy in adolescence. Currently, the combination of chemotherapy with subsequent irradiation is a regular therapeutic strategy. However, high dosage of chemotherapy is associated with drug resistance and side effects. The long non-coding RNA nuclear paraspeckle assembly transcript 1 (NEAT1), which is frequently overexpressed in diverse human tumors, is correlated with worse survival rate in cancer patients. Currently, the precise roles of NEAT1 in MB and chemoresistance remain unclear. Our study aimed to investigate the biological functions of NEAT1 in cisplatin-resistant medulloblastoma. We report that NEAT1 was significantly upregulated in medulloblastoma patient specimens. Silencing NEAT1 significantly suppressed MB cell proliferation and sensitized MB cells to cisplatin. In cisplatin-resistant MB cell line, DAOY Cis R, NEAT1 expression, and glutamine metabolism were remarkably upregulated in cisplatin-resistant cells. Under low glutamine supply, cisplatin-resistant cells displayed increased cisplatin sensitivity. Bioinformatical analysis and luciferase assay uncovered that NEAT1 functions as a ceRNA of miR-23a-3p to downregulate its expressions in MB cells. Moreover, miR-23a-3p was apparently downregulated in MB patient tissues and cisplatin resistant MB cells. We identified GLS (glutaminase), a glutamine metabolism enzyme, was directly targeted by miR-23a-3p in MB cells. Rescue experiments demonstrated restoration of miR-23a-3p in NEAT1-overexpressing DAOY cisplatin resistant cells successfully overcame the NEAT1-promoted cisplatin resistance by targeting GLS. In general, our results revealed new molecular mechanisms for the lncRNA-NEAT1-mediated cisplatin sensitivity of MB.

Therapy-resistant and -sensitive lncRNAs, SNHG1 and UBL7-AS1 promote glioblastoma cell proliferation.

The current treatment options for glioblastoma (GBM) can result in median survival of 15-16 months only, suggesting the existence of therapy-resistant factors. Emerging evidence suggests that long non-coding RNAs (lncRNAs) play an essential role in the development of various brain tumors, including GBM. This study aimed to identify therapy-resistant and therapy-sensitive GBM associated lncRNAs and their role in GBM. We conducted a genome-wide transcriptional survey to explore the lncRNA landscape in 195 GBM brain tissues. Cell proliferation was evaluated by CyQuant assay and Ki67 immunostaining. Expression of MAD2L1 and CCNB2 was analyzed by western blotting. We identified 51 lncRNAs aberrantly expressed in GBM specimens compared with either normal brain samples or epilepsy non-tumor brain samples. Among them, 27 lncRNAs were identified as therapy-resistant lncRNAs that remained dysregulated after both radiotherapy and chemoradiotherapy while 21 lncRNAs were identified as therapy-sensitive lncRNAs whose expressions were reversed by both radiotherapy and chemoradiotherapy. We further investigated the potential functions of the therapy-resistant and therapy-sensitive lncRNAs and demonstrated their relevance to cell proliferation. We also found that the expressions of several lncRNAs, including SNHG1 and UBL7-AS1, were positively correlated with cell-cycle genes expressions. Finally, we experimentally confirmed the function of a therapy-resistant lncRNA, SNHG1, and a therapy-sensitive lncRNA, UBL7-AS1, in promoting cell proliferation in GBM U138MG cells. Our

Quality-of-life and toxicity in cancer patients treated with multiple courses of radiation therapy.

Treatment of metastatic cancer patients with multiple repeat courses of radiotherapy has become more frequent due to their improved overall survival. However, very little is known about their long-term outcome. This analysis reports on the quality-of-life, hematologic toxicity, patient-reported experiences and satisfaction, and psychological distress of cancer patients treated with multiple repeat radiotherapy. All patients treated with ≥5 courses of radiotherapy between 2011 and 2019 at the Department of Radiation Oncology, University Hospital Zurich (USZ) were screened for this study. A course of radiotherapy was defined as all treatment sessions to one anatomical site under one medical indication. All patients completed two questionnaires EORTC QLQ-C30 questionnaire for quality-of-life and a questionnaire evaluating psychological distress and patient-reported experiences. Hematologic toxicities were assessed via a recent blood sample. Of n 33 patients treated with ≥5 radiotherapy courses and being alive, 20 (60.6%) participated in this study. The most common primary tumor was non-small cell lung cancer (n 14, 42.4%). The most common sites of irradiation were brain (n 78, 37.1%) and bone metastases (n 59, 28.1%). All participating patients reported that they had experienced a subjective benefit from multiple repeat radiotherapy and denied increased side effects in later radiotherapy courses. Yet, 45% (n 9) of the patients reported an increase of psychological distress with increasing numbers of radiotherapy treatments. While global health status was stable, patients having received multiple repeat radiotherapy reported increased fatigue (p <0.006). Blood analysis showed significantly reduced hemoglobin and lymphocyte levels compared to the healthy population (p <0.03). Patient-reported experiences and satisfaction of long-term cancer patients treated with multiple repeat radiotherapy are positive. However, increased levels of fatigue and significantly reduced hemoglobin and lymphocyte levels were observed. These data indicate the need to further investigate the effects of multiple courses of radiotherapy in chronic cancer patients.

Multifunctional Targeting Liposomes of Epirubicin Plus Resveratrol Improved Therapeutic Effect on Brain Gliomas.

The inability of many therapeutic molecules to cross the blood-brain barrier (BBB) combined with poor penetration into tumor tissue leads to difficult challenges for treatment of brain tumors. In order to settle these hurdles, we developed a novel multifunctional targeting carrier which enables drugs to transport across the BBB and targets brain tumor tissues. In the multifunctional targeting liposomes, the natural compound resveratrol (RES) was incorporated into the lipid bilayer membranes of liposomes, while p-aminophenyl-α-D-manno-pyranoside (MAN) and wheat germ agglutinin (WGA) were conjugated to the liposomal surface. Epirubicin (EPI) as an anticancer drug was then loaded into liposomes. Then, liposomes were characterized by evaluation on particle size, zeta potential and apparent morphology. The epirubicin plus resveratrol liposomes modified with WGA and MAN were applied to glioma cells and BBB model in vitro and C6 glioma-bearing rats in vivo. The multifunctional targeting liposomes were round shaped with a smooth surface and uniform particle size. In consideration of the SRB results, the multifunctional targeting liposomes indicated a significant inhibitory effect, suggesting that MAN plus WGA generated robust drug delivery effects into the brain tumor cells. The glioma cells after administering epirubicin plus resveratrol liposomes modified with WGA and MAN displayed the most significant uptake and apoptosis conducted by flow cytometry. In the multifunctional targeting effects assay, the epirubicin plus resveratrol liposomes modified with WGA and MAN exhibited the strongest effects of crossing the BBB and then targeting brain tumor cells. In tumor-bearing rats after applying multifunctional targeting liposomes, the median survival time was evidently observed as being markedly longer than other controls. The epirubicin plus resveratrol liposomes modified with WGA and MAN exhibited strong ability to improve epirubicin and resveratrol transporting across the BBB and therapeutic effect on brain glioma, showing multifunctional targeting capability.

High BMP4 expression in lowintermediate risk BCP-ALL identifies children with poor outcomes.

Pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) outcome has improved in the last decades, but leukemic relapses are still one of the main problems of this disease. Bone morphogenetic protein 4 (BMP4) was investigated as a new candidate biomarker with potential prognostic relevance, and its pathogenic role was assessed in the development of disease. A retrospective study was performed with 115 pediatric patients with BCP-ALL, and BMP4 expression was analyzed by quantitative reverse transcription polymerase chain reaction in leukemic blasts at the time of diagnosis. BMP4 mRNA expression levels in the third (upper) quartile were associated with a higher cumulative incidence of relapse as well as a worse 5-year event-free survival and central nervous system (CNS) involvement. Importantly, this association was also evident among children classified as having a nonhigh risk of relapse. A validation cohort of 236 patients with BCP-ALL supported these data. Furthermore, high BMP4 expression promoted engraftment and rapid disease progression in an NSG mouse xenograft model with CNS involvement. Pharmacological blockade of the canonical BMP signaling pathway significantly decreased CNS infiltration and consistently resulted in amelioration of clinical parameters, including neurological score. Mechanistically, BMP4 favored chemoresistance, enhanced adhesion and migration through brain vascular endothelial cells, and promoted a proinflammatory microenvironment and CNS angiogenesis. These data provide evidence that BMP4 expression levels in leukemic cells could be a useful biomarker to identify children with poor outcomes in the low-intermediate-risk groups of BCP-ALL and that BMP4 could be a new therapeutic target to blockade leukemic CNS disease.

Endovascular Therapy is Effective for Large Vessel Occlusion Despite Concurrent Cancer.

Ischemic stroke and concurrent cancer is increasingly recognized. However, optimal management is uncertain. As mechanical thrombectomy has become the standard of care for large vessel occlusion, more patients with cancer are presenting for embolectomy. However, it is unknown whether this subgroup has the same benefit profile described in multiple randomized trials for thrombectomy for large vessel occlusion. Our objective was to retrospectively evaluate a North American embolectomy database for safety and outcomes in patients with active cancer. A case series of 284 embolectomies over 30 months at a single North American stroke center were divided into thrombectomy patients with active cancer(n25) and those without active cancer (n259). We compared patient characteristics, procedural characteristics, and procedural outcomes between patients with and without active cancer. Univariate and multivariate analysis of angiographic outcomes, postoperative hemorrhage, and functional outcome was performed. Of the 284 thrombectomy cases, 9% were performed on patients with active cancer. Active cancer patients had a similar recanalization grade and post-operative hemorrhage rate, compared to patients without cancer. Active cancer patients had a significantly higher 90 day mortality (40% vs 20%, p0.018). On multivariate analysis, good functional outcome (mRS 0-2) was not impacted by active cancer. However, when mRS was evaluated as an ordinal shift analysis, worse functional outcome was associated with active cancer (OR 2.98 95% CI, 1.29 to 6.59), greater age, NIHSS> 10, and ASPECTS<9. This single center retrospective series of active cancer patients undergoing thrombectomy for large vessel occlusion demonstrates similar rates of recanalization, post-operative hemorrhage, and good outcomes. While the active cancer group has a high short-term mortality, the potential to maintain quality of life in the survivors makes thrombectomy reasonable in this patient population. Awareness of ischemic stroke as a complication of cancer and the safety of thrombectomy in this population are important as this population subtype is expected to grow with improved oncology and stroke care.

The Lost Productivity Cost of Premature Mortality Owing to Cancers in Iran Evidence From the GLOBOCAN 2012 to 2018 Estimates.

Estimation of the lost productivity cost of premature deaths because of cancers can provide invaluable information for identifying the priorities and resource needs in the design of cancer control strategies. This study aimed to estimate the premature mortality costs because of cancers using GLOBOCAN estimates in Iran. In this study, we estimated the lost productivity cost of premature deaths because of cancers in Iran from 2012 and 2018, using the human capital approach with respect to the cancer site, sex, and age. Data on cancer mortality were extracted from the GLOBOCAN reports. In addition, economic information, such as annual income, employment rate, housekeeping rate, and gross domestic product, was extracted from the World Bank Data and the Statistical Center of Iran. A discount rate of 3% was applied and costs were reported in constant 2017 international dollars. From 2012 and 2018, the lost productivity cost of premature deaths because of cancers increased by 18% in Iran ($2453 million in 2012 and $2887 million in 2018). In contrast, the number of deaths and the years of life lost because of cancers increased by approximately 8%. The mortality cost was approximately 35% and 56% higher in men than in women in 2012 and 2018, respectively. Stomach, colorectal, esophageal, and breast cancers accounted for > 40% of total cancer mortality costs in 2012. Stomach cancer, brain cancer, nervous system cancer, lung cancer, and leukemia were responsible for 57% of cancer mortality costs in 2018. Based on the findings, the lost productivity costs of premature mortality because of cancers have increased significantly in Iran. Overall, evidence-based policy making for managing the costs of cancers and resource allocation depends on analyzing epidemiological and economic data in the health sector. This study presented helpful findings on cancer mortality costs to support evidence for decision making in healthcare systems.

Update from the 5th Edition of the World Health Organization Classification of Head and Neck Tumors Overview of the 2022 WHO Classification of Head and Neck Neuroendocrine Neoplasms.

This review article provides a brief overview of the new WHO classification by adopting a question-answer model to highlight the spectrum of head and neck neuroendocrine neoplasms which includes epithelial neuroendocrine neoplasms (neuroendocrine tumors and neuroendocrine carcinomas) arising from upper aerodigestive tract and salivary glands, and special neuroendocrine neoplasms including middle ear neuroendocrine tumors (MeNET), ectopic or invasive pituitary neuroendocrine tumors (PitNET formerly known as pituitary adenoma) and Merkel cell carcinoma as well as non-epithelial neuroendocrine neoplasms (paragangliomas). The new WHO classification follows the IARCWHO nomenclature framework and restricts the diagnostic term of neuroendocrine carcinoma to poorly differentiated epithelial neuroendocrine neoplasms. In this classification, well-differentiated epithelial neuroendocrine neoplasms are termed as neuroendocrine tumors (NET), and are graded as G1 NET (no necrosis and < 2 mitoses per 2 mm

Poly-guanidine shows high cytotoxicity in glioma cell cultures and glioma stem cells.

Glioblastoma multiforme (GBM) is a malignant CNS tumor with a poor prognosis. GBM shows aberrant glycosylation with hypersialylation. This property is a potential target for therapy. This study investigates the growth inhibitory efficacy of poly-guanidine (GuaDex), with an affinity for sialic acid (Sia). Glioma cell cultures and patient-derived glioma cell lines (PDGCLs) expressing Prominin-1 (CD133) were used. Human fibroblasts and astrocyte-derived cells were used as controls. Temozolomide (standard GBM drug, TMZ) and DMSO were used as a comparison. GuaDex at 1-10 µM concentrations, were incubated for 3.5-72 h and with PDGCLs cells for 6-24 h. The cytotoxicity was estimated with a fluorometric cytotoxicity assay (FMCA). Fluorescence-labelled GuaDex was used to study the cell interactions. Sia expression was confirmed with a fluorescence labelled Sia binding lectin. Expression of glial fibrillary acidic protein was determined. GuaDex induction of growth inhibition was fast, showing after less than 5 min incubation while the control cells were not affected even after 50 min incubation. The growth inhibitory effect on PDGCLs spheroids was persistent still showing after 4 weeks post-treatment. The growth inhibition of GuaDex was induced at low µM concentrations while TMZ induced only a slight inhibition at mM concentrations. GuaDex efficacy appears significant and warrants further studies.

Relevant pharmacologic interactions in the concurrent management of brain tumor-related epilepsy and venous thromboembolism a systematic review.

Co-administration of direct oral anticoagulants (DOACs) with antiepileptic drugs (AEDs) is increasingly common in brain tumor patients. We therefore performed a systematic review of the current evidence for potential drug interactions between DOACs and AEDs in this patient population. We conducted a systematic review of the literature via PubMed according to PRISMA guidelines (last accessed December 15, 2021). Included were clinical studies and case reports, written in English language and published between 2010 and 2021, that investigated concurrent clinical use of AEDs with DOACs for any indication. Non-English articles, articles not related to our research question, review articles and commentaries were excluded. Full-text articles were evaluated for possible confounding factors and results were summarized using a data table highlighting the key characteristics of each article. We identified a total of 122 unique articles, of which 27 were deemed relevant to our research question. Of these, 8 articles were clinical studies (n 295,415 patients) and 19 were case reports (n 25 patients). Only 3 clinical studies and 2 case reports reported interactions between AEDs and DOACs in patients with active cancer and none reported interactions in patients with brain tumors. We have identified low (class IV) level evidence of potential drug interactions between DOACs and AEDs. Even though there is no current report of interactions in brain tumor patients, neuro-oncology providers should be aware of the emerging evidence regarding drug interactions between DOACs and AEDs and take this into consideration when concurrently prescribing these to patients.

Clinicopathological risk factors for a poor prognosis of primary central nervous system lymphoma in elderly patients in the Tohoku and Niigata area a multicenter, retrospective, cohort study of the Tohoku Brain Tumor Study Group.

Clinicopathological risk factors for a poor prognosis were investigated in elderly patients with malignant lymphoma of the central nervous system. A total of 82 pathologically confirmed, CD20-positive, diffuse large B-cell lymphoma patients aged 71 years or older who underwent therapeutic intervention in the Tohoku and Niigata area in Japan were retrospectively reviewed. A univariate analysis was performed by the log-rank test using the Kaplan-Meier method. A Cox proportional hazards model was used for multivariate analysis of risk factors. Of the 82 patients, 39 were male and 43 were female, and their median age at onset was 75 years. At the end of the study, there were 34 relapse-free patients (41.5%), 48 relapse cases (58.5%), median progression-free survival was 18 months, and median overall survival (OS) was 26 months there were 41 deaths and 41 survivors. Multivariate analysis of median OS showed that Karnofsky Performance Status less than 60% 3 months after treatment (p 0.022, hazard ratio (HR) 2.591) was the clinical risk factor, and double expressor lymphoma (p 0.004, HR 3.163), expression of programmed death-ligand 1 in tumor infiltrating lymphocytes or tumor-associated macrophages (p < 0.001, HR 5.455), and Epstein-Barr virus infection (p 0.031, HR 5.304) were the pathological risk factors.

How I do it Surgical Resection of a Recurrent Chondromyxoid Fibroma by Micro-Endoscopic Combination Technique.

The surgical resection of the tumor spreading into the cavernous sinus (CS) is complicated and challenging. We report a left recurrent CS chondromyxoid fibroma occupying the clival-petrous apex-parasellar-suprasellar area, which was totally removed by the micro-endo combination technique via the middle cranial fossa extradural approach. This case demonstrates the value of the micro-endoscopic combination technique for complicated skull base surgery.

Pan-cancer analysis of necroptosis-related gene signature for the identification of prognosis and immune significance.

Necroptosis is a novel programmed cell death mode independent on caspase. A number of studies have revealed that the induction of necroptosis could act as an alternative therapeutic strategy for drug-resistant tumors as well as affect tumor immune microenvironment. Gene expression profiles and clinical data were downloaded from XENA-UCSC (including The Cancer Genome Atlas and Genotype-Tissue Expression), Gene Expression Omnibus, International Cancer Genome Consortium and Chinese Glioma Genome Atlas. We used non-negative matrix factorization method to conduct tumor classification. The least absolute shrinkage and selection operator regression was applied to establish risk models, whose prognostic effectiveness was examined in both training and testing sets with Kaplan-Meier analysis, time-dependent receiver operating characteristic curves as well as uni- and multi-variate survival analysis. Principal Component Analysis, t-distributed Stochastic Neighbor Embedding and Uniform Manifold Approximation and Projection were conducted to check the risk group distribution. Gene Set Enrichment Analyses, immune infiltration analysis based on CIBERSORT, EPIC, MCPcounter, ssGSEA and ESTIMATE, gene mutation and drug sensitivity between the risk groups were also taken into consideration. There were eight types of cancer with at least ten differentially expressed necroptosis-related genes which could influence patients prognosis, namely, adrenocortical carcinoma (ACC), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), acute myeloid leukemia (LAML), brain lower grade glioma (LGG), pancreatic adenocarcinoma (PAAD), liver hepatocellular carcinoma (LIHC), skin cutaneous melanoma (SKCM) and thymoma (THYM). Patients could be divided into different clusters with distinct overall survival in all cancers above except for LIHC. The risk models could efficiently predict prognosis of ACC, LAML, LGG, LIHC, SKCM and THYM patients. LGG patients from high-risk group had a higher infiltration level of M2 macrophages and cancer-associated fibroblasts. There were more CD8 T cells, Th1 cells and M1 macrophages in low-risk SKCM patients tumor microenvironment. Gene mutation status and drug sensitivity are also different between low- and high-risk groups in the six cancers. Necroptosis-related genes can predict clinical outcomes of ACC, LAML, LGG, LIHC, SKCM and THYM patients and help to distinguish immune infiltration status for LGG and SKCM.

Coronary artery disease, left ventricular function and cardiac biomarkers determine all-cause mortality in cancer patients-a large monocenter cohort study.

Cancer patients are at risk of suffering from cardiovascular diseases (CVD). Nevertheless, the impact of cardiovascular comorbidity on all-cause mortality (ACM) in large clinical cohorts is not well investigated. In this retrospective cohort study, we collected data from 40,329 patients who were subjected to cardiac catherization from 012006 to 122017 at University Hospital Heidelberg. The study population included 3666 patients with a diagnosis of cancer prior to catherization and 3666 propensity-score matched non-cancer patients according to age, gender, diabetes and hypertension. 5-year ACM in cancer patients was higher with a reduced left ventricular function (LVEF < 50% 68.0% vs 50.9%) or cardiac biomarker elevation (high-sensitivity cardiac troponin T (hs-cTnT 64.6% vs 44.6%) and N-terminal brain natriuretic peptide (NT-proBNP 62.9% vs 41.4%) compared to cancer patients without cardiac risk. Compared to non-cancer patients, NT-proBNP was found to be significantly higher (median NT-proBNP cancer 881 ngL, IQR 254 3983 ngL vs non-cancer 668 ngL, IQR 179 2704 ngL p < 0.001, Wilcoxon-rank sum test) and turned out to predict ACM more accurately than hs-cTnT (NT-proBNP AUC 0.74 hs-cTnT AUC 0.63 p < 0.001, DeLongs test) in cancer patients. Risk factors for atherosclerosis, such as diabetes and age (> 65 years) were significant predictors for increased ACM in cancer patients in a multivariate analysis (OR diabetes 1.96 (1.39-2.75) p < 0.001 OR age > 65 years 2.95 (1.68-5.4) p < 0.001, logistic regression). Our data support the notion, that overall outcome in cancer patients who underwent cardiac catherization depends on cardiovascular comorbidities. Therefore, particularly cancer patients may benefit from standardized cardiac care.

Prognostic significance of therapy-induced myelosuppression in newly diagnosed glioblastoma.

Myelosuppression is the major toxicity encountered during temozolomide chemoradiotherapy for newly diagnosed glioblastoma. We assessed the association of myelosuppression (neutropenia, thrombocytopenia, anemia, and lymphopenia) during temozolomide chemoradiotherapy alone or in combination with experimental agents with progression-free survival (PFS) or overall survival (OS) in 2073 patients with newly diagnosed glioblastoma enrolled into five clinical trials CENTRIC, CORE, EORTC 26082, AVAglio, and EORTC 26981. A landmark Cox model was used. For each primary association analysis, a significance level of 1.7% was used. Lower neutrophil counts at baseline were associated with better PFS (P .011) and OS (P < .001), independently of steroid intake. Females experienced uniformly more myelotoxicity than males. Lymphopenia during concomitant chemoradiotherapy was associated with OS (P .009) low-grade (1-2) lymphopenia might be associated with superior OS (HR 0.78, 98.3% CI 0.58-1.06), whereas high-grade (3-4) lymphopenia might be associated with inferior OS (HR 1.08, 98.3% CI 0.75-1.54). There were no associations of altered hematological parameters during concomitant chemoradiotherapy with PFS. During maintenance chemoradiotherapy, no significant association was found between any parameter of myelosuppression and PFS or OS, although exploratory analysis at 5% significance level indicated that either mild-to-moderate (HR 0.76, 95% CI 0.62-0.93) or high-grade lymphopenia (HR 0.65, 95% CI 0.46-0.92) was associated with superior OS (P .013), but not PFS. The association of higher neutrophil counts at baseline with inferior PFS and OS requires further prospective evaluation. The link of therapy-induced lymphopenia to better outcome may guide the design for immunotherapy trials in newly diagnosed glioblastoma.

VCAM-1-targeted MRI Improves Detection of the Tumor-brain Interface.

Despite optimal local therapy, tumor cell invasion into normal brain parenchyma frequently results in recurrence in patients with solid tumors. The aim of this study was to determine whether microvascular inflammation can be targeted to better delineate the tumor-brain interface through vascular cell adhesion molecule-1 (VCAM-1)-targeted MRI. Intracerebral xenograft rat models of MDA231Br-GFP (breast cancer) brain metastasis and U87MG (glioblastoma) were used to histologically examine the tumor-brain interface and to test the efficacy of VCAM-1-targeted MRI in detecting this region. Human biopsy samples of the brain metastasis and glioblastoma margins were examined for endothelial VCAM-1 expression. The interface between tumor and surrounding normal brain tissue exhibited elevated endothelial VCAM-1 expression and increased microvessel density. Tumor proliferation and stemness markers were also significantly upregulated at the tumor rim in the brain metastasis model. T2-weighted MRI, following intravenous administration of VCAM-MPIO, highlighted the tumor-brain interface of both tumor models more extensively than gadolinium-DTPA-enhanced T1-weighted MRI. Sites of VCAM-MPIO binding, evident as hypointense signals on MR images, correlated spatially with endothelial VCAM-1 upregulation and bound VCAM-MPIO beads detected histologically. These findings were further validated in an orthotopic medulloblastoma model. Finally, the tumor-brain interface in human brain metastasis and glioblastoma samples was similarly characterized by microvascular inflammation, extending beyond the region detectable using conventional MRI. This work illustrates the potential of VCAM-1-targeted MRI for improved delineation of the tumor-brain interface in both primary and secondary brain tumors.

A prospective study of social competence in survivors of pediatric brain and solid tumors.

Survivors of pediatric brain tumors are at increased risk for difficulties with social competence, including poor social information processing (SIP) and peer relationships. Improved survival rates heighten the need to better understand these challenges and if they are specific to survivors of pediatric brain tumors versus survivors of other childhood cancers. Fifty-one survivors of pediatric brain tumors and 34 survivors of pediatric solid tumors completed evaluations of SIP and peer relationship quality within six months of completing treatment and one year later. Caregivers completed a measure of social skills. Linear mixed models evaluated differences between survivors of pediatric brain and solid tumors on SIP and social skills and how indices of SIP were associated with peer relationships over time. The two groups did not differ on indices of SIP or social skills over time. A three-way interaction between measures of SIP, group, and time predicted peer relationships. Survivors of pediatric solid tumors showed a positive association between baseline social skills and theory of mind and peer relationships over time, whereas survivors of pediatric brain tumors showed an inverse association between baseline social skills and theory of mind and peer relationships over time. Findings revealed unanticipated associations between baseline SIP and social skills and peer relationships over time among survivors of pediatric brain tumors. Additional research is needed to elucidate the factors most influential on peer relationships in this group to inform interventions.

Blood exosomes-based targeted delivery of cPLA2 siRNA and metformin to modulate glioblastoma energy metabolism for tailoring personalized therapy.

Targeting glioblastoma (GBM) energy metabolism through multiple metabolic pathways has emerged as an effective therapeutic approach. Dual inhibition of phospholipid and mitochondrial metabolism with cytoplasmic phospholipase A2 (cPLA2) knockdown and metformin treatment could be a potential strategy. However, the strategic prerequisite is to explore a carrier capable of co-delivering the therapeutic combination to cross the blood-brain barrier (BBB) and preferentially accumulate at the GBM site. Blood exosomes (Exos) were selected as the combination delivery carriers. The cellular uptake of Exos and the therapeutic effects of the combination strategy were evaluated in primary GBM cells. In vivo GBM-targeted delivery efficiency and anti-GBM efficacy were tested in a patient-derived xenograft (PDX) model. Here, we showed that the Exos-mediated cPLA2 siRNAmetformin combined strategy could regulate GBM energy metabolism for personalized treatment. Genomic analysis and experiments showed that polymerase 1 and transcript release factor (PTRF, a biomarker of GBM) positively regulated the uptake of Exos by GBM cells, confirming the feasibility of the delivery strategy. Further, Exos could co-load cPLA2 siRNA (sicPLA2) and metformin and co-deliver them across the BBB and into GBM tissue. The mitochondrial energy metabolism of GBM was impaired with this combination treatment (Exos-MetsicPLA2). In the PDX GBM model, systemic administration of Exos-MetsicPLA2 reduced tumor growth and prolonged survival. Our findings demonstrated that Exos-based combined delivery of sicPLA2 and metformin selectively targeted the GBM energy metabolism to achieve antitumor effects, showing its potential as a personalized therapy for GBM patients.

Integrative Clinical, Radiological, and Molecular Analysis for Predicting Remission and Recurrence of Cushing Disease.

Adrenocorticotropin (ACTH)-secreting pituitary tumors (ACTHomas) are associated with severe comorbidities and increased mortality. Current treatments mainly focus on remission and prevention of persistent disease and recurrence. However, there are still no useful biomarkers to accurately predict the clinical outcome after surgery, long-term remission, or disease relapse. This work aimed to identify clinical, biochemical, and molecular markers for predicting long-term clinical outcome and remission in ACTHomas. A retrospective multicenter study was performed with 60 ACTHomas patients diagnosed between 2004 and 2018 with at least 2 years follow-up. Clinicalbiochemical variables were evaluated yearly. Molecular expression profile of the somatostatinghrelindopamine regulatory systems components and of key pituitary factors and proliferation markers were evaluated in tumor samples after the first surgery. Clinical variables including tumor size, time until diagnosisfirst surgery, serum prolactin, and postsurgery cortisol levels were associated with tumor remission and relapsed disease. The molecular markers analyzed were distinctly expressed in ACTHomas, with some components (ie, SSTR1, CRHR1, and MKI67) showing instructive associations with recurrence andor remission. Notably, an integrative model including selected clinical variables (tumor sizepostsurgery serum cortisol), and molecular markers (SSTR1CRHR1) can accurately predict the clinical evolution and remission of patients with ACTHomas, generating a receiver operating characteristic curve with an area under the curve of 1 (P < .001). This study demonstrates that the combination of a set of clinical and molecular biomarkers in ACTHomas is able to accurately predict the clinical evolution and remission of patients. Consequently, the postsurgery molecular profile represents a valuable tool for clinical evaluation and follow-up of patients with ACTHomas.

Time to Steroid Independence After Laser Interstitial Thermal Therapy vs Medical Management for Treatment of Biopsy-Proven Radiation Necrosis Secondary to Stereotactic Radiosurgery for Brain Metastasis.

Radiation necrosis (RN) after stereotactic radiosurgery (SRS) for brain metastases (BM) can result in significant morbidity, compounded by the effects of extended steroid therapy. Laser interstitial thermal therapy (LITT) is a minimally invasive procedure that can offer definitive treatment for RN while potentially obviating the need for prolonged steroid use. To compare LITT vs medical management (MM) in the treatment of RN. A multicenter, retrospective study was performed of SRS-treated patients with BM who developed biopsy-proven RN and were treated with LITT or MM. Clinical outcome data were compared by treatment modality. Seventy-two patients met criteria with a median follow-up of 10.0 months (4.2-25.1), and 57 patients (79%) underwent LITT. Four MM (27%) and 3 LITT patients (5%) demonstrated radiographic progression (P .031) at a median of 5.3 and 4.0 months (P .40). There was no significant difference in overall survival (LITT median of 15.2 vs 11.6 months, P .60) or freedom from local progression (13.6 vs 7.06 months, P .40). Patients stopped steroid therapy earlier in the LITT cohort at a median of 37 days compared with 245 days (P < .001). When controlled for follow-up duration, patients treated with LITT were 3 times more likely to be weaned off steroids before the study end point (P .003). These data suggest that LITT for treatment of biopsy-proven RN after SRS for BM significantly decreases time to steroid independence. Prospective trials should be designed to further validate the utility of LITT for RN and its impact on steroid-induced morbidity.

Malignant Pineal Parenchymal Tumors in Adults A National Cancer Database Analysis.

Limited retrospective data exist on malignant pineal parenchymal tumors (PPTs) in adults, and there are no large previous studies that review clinical outcomes across the 3 treatment arms of surgery, radiotherapy, and chemotherapy. As a result, optimal disease management has yet to be defined. To evaluate treatment trends and perform survival analysis in adult PPT. The National Cancer Database was queried for histologically confirmed PPT diagnosed from 2007 to 2016. Univariate and multivariate Cox regressions were used to evaluate the prognostic impact of covariates. Kaplan-Meier survival curves were generated for comparative subanalyses. Of the 251 patients who met inclusion criteria, 172 had PPTs of intermediate differentiation (PPTID) and 79 had pineoblastoma. A plurality of patients with pineoblastoma were treated with trimodal therapy (39.1%), whereas patients with PPTID were commonly treated with either surgery alone or surgery and radiation (33.7% each). Factors independently associated with improved overall survival include younger patient age, female sex, lower comorbidity score, lower tumor grade, and treatment with surgery or radiation (each P < .05). Subanalyses confirm the effect of radiation on survival in patients with grade III PPTID with subtotal resection however, no survival benefit of adjuvant radiation is demonstrated in patients with grade II PPTID with subtotal resection. Although radiotherapy and surgery were found to increase survival in all patients with PPT, there was no demonstrable survival benefit of adjuvant radiation in surgically treated patients with grade II PPTID. This suggests that adjuvant radiotherapy may not add significant survival benefit in many adult patients with grade II PPTID.

A light-gated transcriptional recorder for detecting cell-cell contacts.

Technologies for detecting cell-cell contacts are powerful tools for studying a wide range of biological processes, from neuronal signaling to cancer-immune interactions within the tumor microenvironment. Here, we report TRACC (Transcriptional Readout Activated by Cell-cell Contacts), a GPCR-based transcriptional recorder of cellular contacts, which converts contact events into stable transgene expression. TRACC is derived from our previous protein-protein interaction recorders, SPARK (Kim et al., 2017) and SPARK2 (Kim et al., 2019), reported in this journal. TRACC incorporates light gating via the light-oxygen-voltage-sensing (LOV) domain, which provides user-defined temporal control of tool activation and reduces background. We show that TRACC detects cell-cell contacts with high specificity and sensitivity in mammalian cell culture and that it can be used to interrogate interactions between neurons and glioma, a form of brain cancer.

Prognosis of Patients With Brainstem Glioblastoma Based on age, surgery and radiotherapy A SEER Database Analysis.

Identification of N6-Methyladenosine-Related lncRNAs as a Prognostic Signature in Glioma.

N6-methyladenosine (m6A) modification is the most abundant modification in long noncoding RNAs (lncRNAs). Current studies have shown that the abnormal expression of m6A-related genes is closely associated with the tumorigenesis and progression of glioma. However, the role of m6A-related lncRNAs in glioma development is still unclear. Herein, we screened 566 m6A-related lncRNAs in glioma from The Cancer Genome Atlas (TCGA) database. The expression pattern of these lncRNAs could cluster samples into two groups, in which various classical tumor-related functions and the tumor immune microenvironment were significantly different. Subsequently, a nine-factor m6A-related lncRNA prognostic signature (MLPS) was constructed by using a LASSO regression analysis in the training set and was validated in the test set and independent datasets. The AUC values of the MLPS were 0.881, 0.918 and 0.887 for 1-, 3- and 5-year survival in the training set, respectively, and 0.856, 0.916 and 0.909 for 1-, 3-, and 5-year survival in the test set, respectively. Stratification analyses of the MLPS illustrated its prognostic performance in gliomas with different characteristics. Correlation analyses showed that the infiltrations of monocytes and tumor-associated macrophages (TAMs) were significantly relevant to the risk score in the MLPS. Moreover, we detected the expression of four MLPS factors with defined sequences in glioma and normal cells by using RT-PCR. Afterwards, we investigated the functions of LNCTAM34A (one of the MLPS factors) in glioma cells, which have rarely been reported.

Do We Need Radiotherapy in Grade II Ependymoma

The debate on whether radiotherapy (RT) is an essential part of primary treatment in patients with grade II ependymoma (G2E) is still ongoing, and this study aimed to evaluate its role. A retrospective analysis of all the consecutive patients treated due to G2E in years 1985-2019 was performed. The group consisted of 116 patients with a small predominance of woman (55% vs. 45%) and the location of the tumor in the brain (58% vs. 42%). All had surgery as the primary treatment with 47% R0 resection. Radical RT was applied in 81 patients. In majority of cases (91%), patients received local irradiation. Median follow-up was 65 months, and during that time, 17 patients died. Five- and 10-year overall survival (OS) of the whole group was 87% and 83%. Radical surgery (R0 vs. R12) improved OS ( RT in the case of patients with G2E is a valuable treatment of the recurrent disease. Patients with brain lesions after nonradical surgery might benefit from the local irradiation in terms of PFS.

Deep Learning Model for Intracranial Hemangiopericytoma and Meningioma Classification.

Intracranial hemangiopericytomasolitary fibrous tumor (SFTHPC) is a rare type of neoplasm containing malignancies of infiltration, peritumoral edema, bleeding, or bone destruction. However, SFTHPC has similar radiological characteristics as meningioma, which had different clinical managements and outcomes. This study aims to discriminate SFTHPC and meningioma We enrolled 236 patients with histopathological diagnosis of SFTHPC (n 144) and meningioma (n 122) from 2010 to 2020 in Xiangya Hospital. Radiological features were extracted manually, and a radiological diagnostic model was applied for classification. And a deep learning pretrained model ResNet-50 was adapted to train T1-contrast images for predicting tumor class. Deep learning model attention mechanism was visualized by class activation maps. Our study reports that SFTHPC was found to have more invasion to venous sinus (

Preliminary Clinical Application of RGD-Containing Peptides as PET Radiotracers for Imaging Tumors.

Angiogenesis is a common feature of many physiological processes and pathological conditions. RGD-containing peptides can strongly bind to integrin αvβ3 expressed on endothelial cells in neovessels and several tumor cells with high specificity, making them promising molecular agents for imaging angiogenesis. Although studies of RGD-containing peptides combined with radionuclides, namely,

Classification of Gliomas and Germinomas of the Basal Ganglia by Transfer Learning.

Germ cell tumors (GCTs) are neoplasms derived from reproductive cells, mostly occurring in children and adolescents at 10 to 19 years of age. Intracranial GCTs are classified histologically into germinomas and non-germinomatous germ cell tumors. Germinomas of the basal ganglia are difficult to distinguish based on symptoms or routine MRI images from gliomas, even for experienced neurosurgeons or radiologists. Meanwhile, intracranial germinoma has a lower incidence rate than glioma in children and adults. Therefore, we established a model based on pre-trained ResNet18 with transfer learning to better identify germinomas of the basal ganglia. This retrospective study enrolled 73 patients diagnosed with germinoma or glioma of the basal ganglia. Brain lesions were manually segmented based on both T1C and T2 FLAIR sequences. The T1C sequence was used to build the tumor classification model. A 2D convolutional architecture and transfer learning were implemented. ResNet18 from ImageNet was retrained on the MRI images of our cohort. Class activation mapping was applied for the model visualization. The model was trained using five-fold cross-validation, achieving a mean AUC of 0.88. By analyzing the class activation map, we found that the models attention was focused on the peri-tumoral edema region of gliomas and tumor bulk for germinomas, indicating that differences in these regions may help discriminate these tumors. This study showed that the T1C-based transfer learning model could accurately distinguish germinomas from gliomas of the basal ganglia preoperatively.

White Matter Tracts and Diffuse Lower-Grade Gliomas The Pivotal Role of Myelin Plasticity in the Tumor Pathogenesis, Infiltration Patterns, Functional Consequences and Therapeutic Management.

For many decades, interactions between diffuse lower-grade glioma (LGG) and brain connectome were neglected. However, the neoplasm progression is intimately linked to its environment, especially the white matter (WM) tracts and their myelin status. First, while the etiopathogenesis of LGG is unclear, this tumor seems to appear during the adolescence, and it is mostly located within anterior and associative cerebral areas. Because these structures correspond to those which were myelinated later in the brain maturation process, WM myelination could play a role in the development of LGG. Second, WM fibers and the myelin characteristics also participate in LGG diffusion, since glioma cells migrate along the subcortical pathways, especially when exhibiting a demyelinated phenotype, which may result in a large invasion of the parenchyma. Third, such a migratory pattern can induce functional (neurological, cognitive and behavioral) disturbances, because myelinated WM tracts represent the main limitation of neuroplastic potential. These parameters are critical for tailoring an individualized therapeutic strategy, both (i) regarding the timing of active treatment(s) which must be proposed earlier, before a too wide glioma infiltration along the WM bundles, (ii) and regarding the anatomic extent of surgical resection and irradiation, which should take account of the subcortical connectivity. Therefore, the new science of connectomics must be integrated in LGG management, based upon an improved understanding of the interplay across glioma dissemination within WM and reactional neural networks reconfiguration, in order to optimize long-term oncological and functional outcomes. To this end, mechanisms of activity-dependent myelin plasticity should be better investigated.

Improving Brain Metastases Outcomes Through Therapeutic Synergy Between Stereotactic Radiosurgery and Targeted Cancer Therapies.

Brain metastases are the most common form of brain cancer. Increasing knowledge of primary tumor biology, actionable molecular targets and continued improvements in systemic and radiotherapy regimens have helped improve survival but necessitate multidisciplinary collaboration between neurosurgical, medical and radiation oncologists. In this review, we will discuss the advances of targeted therapies to date and discuss findings of studies investigating the synergy between these therapies and stereotactic radiosurgery for non-small cell lung cancer, breast cancer, melanoma, and renal cell carcinoma brain metastases.

RDAU-Net Based on a Residual Convolutional Neural Network With DFP and CBAM for Brain Tumor Segmentation.

Due to the high heterogeneity of brain tumors, automatic segmentation of brain tumors remains a challenging task. In this paper, we propose RDAU-Net by adding dilated feature pyramid blocks with 3D CBAM blocks and inserting 3D CBAM blocks after skip-connection layers. Moreover, a CBAM with channel attention and spatial attention facilitates the combination of more expressive feature information, thereby leading to more efficient extraction of contextual information from images of various scales. The performance was evaluated on the Multimodal Brain Tumor Segmentation (BraTS) challenge data. Experimental results show that RDAU-Net achieves state-of-the-art performance. The Dice coefficient for WT on the BraTS 2019 dataset exceeded the baseline value by 9.2%.

Long noncoding RNAs as promising biomarkers in cancer.

Despite many advances in diagnosis and therapy (surgery, radiation therapy, chemotherapy), cancer remains one of the most important public health problems worldwide. Every day, the role of exosomes in cancer development and metastasis is being better described. Liquid biopsy was developed for early detection of cancer through minimally invasive and serial examinations of body fluids, with the advantage of tracking tumor progression in real time. Exosomes are extracellular membrane vesicles with a diameter of 30-100 nm, which are secreted by various types of cells and are present in most biological fluids. For a long time, they were considered non-functional cellular components, and today it has already been proven that they are a means of intercellular information exchange. They can move bioactive molecules such as proteins, lipids, RNA and DNA. Several studies have shown that their contents, including proteins and noncoding nucleic acids, may be of particular interest as biomarkers of diseases. The vast majority of gene transcripts are actually characterized as noncoding RNAs (ncRNAs) and are clusters of RNAs that do not encode functional proteins. They can be small, about 20 nucleotides in length, and are known as microRNAs (miRNAs), or transcripts over 200 nucleotides in length, defined as long noncoding RNAs (lncRNAs). LncRNAs are a large group of ncRNAs over 200 nucleotides in length. LncRNAs, as regulatory factors, play an important role in complex cellular processes such as apoptosis, growth, differentiation, proliferation, etc. Recently, the results of many studies have also shown their essential role in carcinogenesis. Endogenous lncRNAs can be secreted by tumor cells into human biological fluids in the form of microvesicles, exosomes, or protein complexes, thereby forming circulating lncRNAs that are not degraded by RNA and are in a stable state. Aberrant expression of lncRNAs has been observed in cancer patients. In this context, endogenous lncRNAs can regulate the basic characteristics of cancer cells by controlling the expression of oncogenes associated with their suppressive and oncogenic functions. Therefore, circulating lncRNAs can be excellent biomarkers in cancer as well. This paper provides an overview of current research on the functional role of lncRNAs in cancer and their potential clinical applications as diagnostic biomarkers and therapeutic targets for cancer.

MRI Brain Tumor Image Classification Using a Combined Feature and Image-Based Classifier.

Brain tumor classification plays a niche role in medical prognosis and effective treatment process. We have proposed a combined feature and image-based classifier (CFIC) for brain tumor image classification in this study. Carious deep neural network and deep convolutional neural networks (DCNN)-based architectures are proposed for image classification, namely, actual image feature-based classifier (AIFC), segmented image feature-based classifier (SIFC), actual and segmented image feature-based classifier (ASIFC), actual image-based classifier (AIC), segmented image-based classifier (

Characterization of the Immune Cell Infiltration Landscape and a New Prognostic Score in Glioblastoma.

Glioblastoma (GBM) is the most aggressive, malignant primary brain tumor, which has abundant tumor-infiltrating immune cells and stroma in the tumor microenvironment (TME). So far, the TME landscape of GBM has not been elucidated. GBM samples were retrieved from TCGA and GEO databases. We used ESTIMATE and CIBERSORT algorithms to calculate risk score associated with TME, and immune cell infiltration (ICI) score of each patient is calculated by PCA. GSEA analysis is explored for each subgroup. Finally, the patient prognosis in different ICI score subgroup is determined. Two ICI clusters are determined in 208 GBM patients, and 207 differentially expressed genes (DGEs) are found between ICI clusters. And then, two gene clusters were determined. Finally, we obtained ICI score for each patient using principal component analysis (PCA). Patients were divided into high and low ICI score subgroups by setting the median as cutoff. Through GSEA, we found ECM-receptor interaction, mTOR signaling pathway, pathways in cancer, TGF-beta signaling pathway, and other immunosuppressive pathway related genes in the low ICI score group. Furthermore, patients with high ICI score group have more better prognosis. Targeting the stroma in GBM may be an effective new therapeutic approach, and the ICI score is an effective potential prognostic classifier of GBM.

Risk Factors for Brain Metastasis of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a common malignancy with high mortality, especially in HCC patients with brain metastases (BMS). However, few studies have investigated the risk factors for BMS among HCC patients based on large-scale population. The study involved clinical data of 36,091 patients who met the inclusion criteria from the SEER database, from 2004 to 2016. Univariate analysis and multifactor logistics regression analysis was used to analyze risk factors affecting BMS among HCC patients. This study revealed that BMS occurred in 108 of 36,091 patients, with an incidence of 0.33%. Median survival was 7 months for patients with BMS, but 12 months for patients without BMS. Univariate analysis showed that pathological low differentiation and undifferentiation, lymph node metastasis, no surgical treatment, and no chemotherapy and radiotherapy increased risk of BMS (

Multimode imaging characteristics and treatment of uveal schwannoma.

To delineate the different imaging characteristics of uveal schwannoma from melanoma and discuss the optimal treatment strategy for intraocular schwannoma. Case series of three patients diagnosed with intraocular schwannoma was collected at Zhongshan Ophthalmic Center, Guangzhou, China from July 2014 to December 2020. All the study patients underwent ultrasonography and magnetic resonance imaging (MRI). The clinical features, therapeutic strategies, and prognoses of all patients were reviewed. Ultrasonography of all three patients (all females, mean age, 39y, age range, 23-54y) showed low to medium reflectivity with a homogeneous internal structure. MRI of all three patients demonstrated isointensity on T1-weighted imaging spin-echo (T1WI SE) images and hypointense on fast spin-echo T2-weighted images (FSE T2WI) images with respect to the brain. Minimally invasive pars plana vitrectomy (PPV) and local resection of the tumor was performed for all patients, and the diagnosis of schwannoma was confirmed by histopathological examination. The present study indicates that ultrasonography and MRI features of uveal schwannoma may contribute to the differentiation of uveal schwannoma from melanoma, and the optimal therapy for intraocular schwannoma is minimally invasive PPV and local resection.

Tumor Suppressing Subtransferable Candidate 4 Expression Prevents Autophagy-Induced Cell Death Following Temozolomide Treatment in Glioblastoma Cells.

Glioblastoma (GBM) is the most common and aggressive type of brain cancer in adults, with temozolomide (TMZ) being widely used as the standard chemotherapy drug for its treatment. However, GBM frequently becomes resistant to TMZ treatment due to various mechanisms including amplification and mutations of the epidermal growth factor receptor (EGFR), where EGFR variant III (EGFRvIII) is the most common EGFR mutation. Autophagy (macroautophagy) is an intracellular self-degradation process involving the lysosome. It mainly plays a pro-cell survival role contributing to drug resistance in cancers including GBM, but, under some conditions, it can induce cell death called autophagy-induced cell death (AuICD). We recently published that TSSC4 (tumor suppressing subtransferable candidate 4) is a novel tumor suppressor and a novel autophagy inhibitor that inhibits cancer cell growth through its interacting with the autophagy protein LC3. In this brief research report, we demonstrate that cell death induced by TMZ in GBM cells is inhibited by overexpression of TSSC4. TSSC4 overexpression also prevents TMZ-induced autophagy but not when TSSC4 is mutated in its conserved LC3-interacting region. When EGFRvIII was expressed in GBM cells, TSSC4 protein was increased and TMZ-induced cell death was decreased. Knockout of TSSC4 in EGFRvIII-expressing GBM cells increased TMZ-induced autophagy and cell death. This cell death was decreased by autophagy inhibition, suggesting that TSSC4 downregulation promotes TMZ-induced AuICD. This indicates that TSSC4 is a novel target to sensitize GBM cells to TMZ treatment.

The N6-Methylandenosine-Related Gene

Gliomas account for 75% of all primary malignant brain tumors in adults and are associated with high mortality. Emerging evidence has demonstrated that baculoviral inhibitor of apoptosis repeat containing 5 (

Comprehensive Analysis of the Tumor Immune Microenvironment Landscape in Glioblastoma Reveals Tumor Heterogeneity and Implications for Prognosis and Immunotherapy.

Glioblastoma (GBM) is a fatal brain tumor with no effective treatment. The specific GBM tumor immune microenvironment (TIME) may contribute to resistance to immunotherapy, a tumor therapy with great potential. Thus, an in-depth understanding of the characteristics of tumor-infiltrating immune cells is essential for exploring biomarkers in GBM pathogenesis and immunotherapy. We estimated the relative abundances of 25 immune cell types in 796 GBM samples using single sample gene set enrichment analysis (ssGSEA). Unsupervised clustering was used to identify different GBM-associated TIME immune cell infiltration (GTMEI) patterns. The GTMEIscore system was constructed with principal component analysis (PCA) to determine the immune infiltration pattern of individual tumors. We revealed three distinct GTMEI patterns with different clinical outcomes and modulated biological pathways. We developed a scoring system (GTMEIscore) to determine the immune infiltration pattern of individual tumors. We comprehensively analyzed the genomic characteristics, molecular subtypes and clinicopathological features as well as proteomic, phosphoproteomic, acetylomic, lipidomic and metabolomic properties associated with the GTMEIscore and revealed many novel dysregulated pathways and precise targets in GBM. Moreover, the GTMEIscore accurately quantified the immune status of many other cancer types. Clinically, the GTMEIscore was found to have significant potential therapeutic value for chemotherapyradiotherapy, immune checkpoint inhibitor (ICI) therapy and targeted therapy. For the first time, we employed a multilevel and multiplatform strategy to construct a multidimensional molecular map of tumors with different immune infiltration patterns. These results may provide theoretical basises for identifying more effective predictive biomarkers and developing more effective drug combination strategies or novel immunotherapeutic agents for GBM.

5-Methylcytosine Related LncRNAs Reveal Immune Characteristics, Predict Prognosis and Oncology Treatment Outcome in Lower-Grade Gliomas.

5-Methylcytosine (m5C) methylation is an important RNA modification pattern that can participate in oncogenesis and progression of cancers by affecting RNA stability, expression of oncogenes, and the activity of cancer signaling pathways. Alterations in the expression pattern of long non-coding RNAs (lncRNAs) are potentially correlated with abnormalities in the m5C regulation features of cancers. Our aim was to reveal the mechanisms by which lncRNAs regulated the m5C process, to explore the impact of aberrant regulation of m5C on the biological properties of lower-grade gliomas (LGG), and to optimize current therapeutic. By searching 1017 LGG samples from the Cancer Genome Atlas and Chinese Glioma Genome Atlas, we first clarified the potential impact of m5C regulators on LGG prognosis in this study and used univariate Cox analysis and least absolute shrinkage and selection operator regression to explore clinically meaningful lncRNAs. Consequently, we identified four lncRNAs, including LINC00265, CIRBP-AS1, GDNF-AS1, and ZBTB20-AS4, and established a novel m5C-related lncRNAs signature (m5CrLS) that was effective in predicting prognosis. Notably, mutation rate, WHO class II, IDH mutation, 1p19q co-deletion and MGMT promoter methylation were increased in the low m5CrLS score group. Patients with increased m5CrLS scores mostly showed activation of tumor malignancy-related pathways, increased immune infiltrating cells, and decreased anti-tumor immune function. Besides, the relatively high expression of immune checkpoints also revealed the immunosuppressed state of patients with high m5CrLS scores. In particular, m5CrLS stratification was sensitive to assess the efficacy of LGG to temozolomide and the responsiveness of immune checkpoint blockade. In conclusion, our results revealed the molecular basis of LGG, provided valuable clues for our understanding of m5C-related lncRNAs, and filled a gap between epigenetics and tumor microenvironment.

Conventional Therapies Deplete Brain-Infiltrating Adaptive Immune Cells in a Mouse Model of Group 3 Medulloblastoma Implicating Myeloid Cells as Favorable Immunotherapy Targets.

Medulloblastoma is the most common childhood brain cancer. Mainstay treatments of radiation and chemotherapy have not changed in decades and new treatment approaches are crucial for the improvement of clinical outcomes. To date, immunotherapies for medulloblastoma have been unsuccessful, and studies investigating the immune microenvironment of the disease and the impact of current therapies are limited. Preclinical models that recapitulate both the disease and immune environment are essential for understanding immune-tumor interactions and to aid the identification of new and effective immunotherapies. Using an immune-competent mouse model of aggressive

The Future of Cross-Continental Telemedicine in the Management of Complicated Endocrine Patients and Its Suitability Based on a Case Report.

Telemedicine is rapidly evolving to provide increased access to high-quality healthcare, and it has gained more traction during the current COVID-19 pandemic. Telemedicine was mostly restricted to remote areas, but with the COVID-19 pandemic, it has been adopted by hospitals and its use has increased significantly. In addition, international collaboration has also increased, and we present a case report from Nigeria whereby a patient was diagnosed with a pituitary tumor through telemedicine, and he underwent successful surgery. This case report highlights the opportunity for collaboration beyond borders and for health care professionals to work with developing countries to improve patients care.

Reirradiation for Rare Head and Neck Cancers Orbit, Auditory Organ, and Salivary Glands.

We analyzed the efficacy and toxicity following reirradiation for locoregional recurrence of rare head and neck tumors. We retrospectively analyzed 17 patients who had received reirradiation for rare head and neck tumors. Primary tumor sites included nine ears (auditory organ), four salivary glands, and four orbits. The median follow-up time was 13.2 months for surviving patients. The median survival time was 12.6 months with one- and two-year survival rates of 53.1% and 44.3%, respectively. Nine out of 17 patients experienced local failure. The one- and two-year local control rates were 42.4% and 31.8%, respectively. The median survival times were 12.6, 5.3, and 11.0 months for orbit, auditory organ, and salivary glands, respectively. Three patients experienced grade 3 toxicity, including meningitis, brain necrosis, and facial nerve disorders. No grade ≥4 toxicities were observed. Reirradiation of rare head and neck tumors is feasible, with acceptable toxicity.

Case Report Successful ABO-Incompatible Deceased Donor Kidney Transplantation in an Infant Without Pre-transplant Immunological Treatment.

ABO blood group antibodies have not been generated or are at low titer during early infancy. Therefore, in theory, ABO-incompatible kidney transplantation (ABOi KT) may be successfully achieved in small infants without any pre-transplant treatment. We report here the first ABO-incompatible deceased donor kidney transplantation (ABOi DDKT) in an infant. The recipient infant was ABO blood group O, and the donor group A. The recipient was diagnosed with a Wilms tumor gene 1 (WT1) mutation and had received peritoneal dialysis for 4 months prior to transplant. At 7 months and 27 days of age, the infant underwent bilateral native nephrectomy and single-kidney transplantation from a 3-year-old brain-dead donor. No pre- or post-transplantation antibody removal treatment was performed, since the recipients anti-iso-hemagglutinin-A Ig-MG antibody titers were both low (12) before transplantation and have remained at low levels or undetectable to date. At 11 months post-transplant, the recipient is at home, thriving, with normal development and graft function. This outcome suggests that ABOi DDKT without antibody removal preparatory treatment is feasible in small infants, providing a new option for kidney transplantation in this age range.

Urinary bladder metastasis from primary breast cancer, a rare and challenging diagnosis. A case report and literature review.

and Importance Liver, lung, bone and brain are usual sites for breast cancer metastases. However, colorectal, prostate and cervical tumors may directly invade the urinary bladder (UB), but hematogenous spread from distant organs like the breast, is extremely rare and may indicate poor prognosis. Here we describe the case of a 78-year-old female patient who was diagnosed with de novo metastatic breast cancer initially to the bone and pleura with effusion, and then to the brain. Five years after her initial diagnosis, she presented with urinary symptoms and bilateral hydronephrosis. Work up showed diffuse thickening of the UB with no invasion from nearby structures biopsy confirmed metastatic carcinoma of breast origin. Adenocarcinoma of the UB is uncommon. Distinguishing primary adenocarcinoma of the UB from secondary involvement is often challenging. When encountered, involvement by a secondary tumor, either by direct extension or distant metastasis, should be considered. Immunohistochemical stains are essential in reaching an accurate diagnosis. Breast cancer rarely metastasizes to the urinary bladder and prognosis is usually poor. Detailed medical history, imaging, and immunohistochemical studies on biopsy specimen should help reach accurate diagnosis.

Immunotherapy for a POLE Mutation Advanced Non-Small-Cell Lung Cancer Patient.

Currently, the predictive role of POLE mutations for immunotherapy is under intense investigation. The POLE gene encodes one of the four subunits of DNA polymerase important for DNA replication and repair. POLE mutations are related to other favorable predicative factors such as high expression of PD-L1, high TMB, and infiltration of CD8

Peripheral inflammation and depressed mood independently predict neurocognitive worsening over 12 years.

Neurocognitive (NC) impairment in people with HIV (PWH) is associated with important adverse outcomes, but no markers exist to predict long-term NC decline. We evaluated depressed mood and markers of persistent inflammation, oxidative stress and altered amyloid processing (all common in PWH) as predictors of NC worsening over 12 years. PWH were enrolled and followed longitudinally in the CNS HIV Antiretroviral Effects Research (CHARTER) study at six US sites. At entry we quantified biomarkers in blood of inflammation (interleukin-6 IL-6, C-reactive protein CRP, monocyte chemoattractant protein type 1 MCP-1, D-dimer, soluble sCD14 (sCD14), soluble tumor necrosis factor receptor - type II sTNFR-II, neopterin, and soluble CD40 ligand sCD40L, oxidative stress (protein carbonyls, 8-oxo-2-deoxyguanosine 8-oxo-dG) and altered amyloid processing amyloid beta (Aβ)-42, soluble amyloid precursor protein-α (sAPPα) using commercial immunoassays. The Beck Depression Inventory-II (BDI-II) assessed depressed mood at entry. NC decline over 12 years was evaluated using the published and validated summary (global) regression-based change score (sRBCS). A factor analysis reduced dimensionality of the biomarkers. Univariable and multiple regression models tested the relationship between baseline predictors and the outcome of neurocognitive decline. Participants were 191 PWH, 37 (19.4%) women, 46.6% African American, 43.5% non-Hispanic white, 8.83% Hispanic, 15.7% white, 1.6% other at study entry mean (SD) age 43.6 (8.06) years, estimated duration of HIV infection (median, IQR) 9.82 4.44, 14.5 years, nadir CD4 104μL (19,205), current CD4 568μL (356, 817), and 80.1% had plasma HIV RNA <50 cmL. Participants were enrolled between 2003 and 2007 median (IQR) duration of follow-up 12.4 9.69, 16.2 years. Three biomarker factors were identified Factor (F)1 (IL-6, CRP), F2 (sTNFR-II, neopterin) and F3 (sCD40L, sAPPα). Participants with higher F1, reflecting worse systemic inflammation at baseline, and higher F3, had greater decline in global neurocognition (r ​ ​-0.168, p ​ ​0.0205 and r ​ ​-0.156, p ​ ​0.0309, respectively). Of the F1 components, higher CRP levels were associated with worse decline (r ​ ​-0.154, p ​ ​0.0332), while IL-6 did not (r ​ ​-0.109, p ​ ​0.135). NC change was not significantly related to F2, nor to demographics, nadir and current CD4, viral suppression or baseline NC comorbidity ratings. Individuals with worse depressed mood at entry also experienced more NC decline (r ​ ​-0.1734, p ​ ​0.0006). Together BDI-II (p ​ ​0.0290), F1 (p ​ ​0.0484) and F3 (p ​ ​0.0309) contributed independently to NC decline (p ​ ​0.0028) their interactions were not significant. Neither CRP nor IL-6 correlated significantly with depression. PWH with greater systemic inflammation and more depression at entry had greater NC decline over 12 years. Understanding the basis of this inflammatory state might be particularly important. These findings raise the possibility that targeted anti-inflammatory or antidepressant therapies may help prevent NC worsening in PWH with depression and inflammation.

Peripheral inflammatory cytokines and motor symptoms in persons with Parkinsons disease.

Many of the motor symptoms of Parkinsons disease (PD) impact quality of life and are not fully ameliorated by current pharmacological and surgical treatments. A better understanding of the pathophysiology underlying these symptoms is needed. Previous research has suggested that inflammation may play a significant role in PD pathophysiology and progression, but there is limited research exploring how inflammation directly relates to motor symptoms in PD. Thus, the purpose of this study was to evaluate associations between peripheral immune inflammatory markers and motor symptoms of PD, specifically, tremor, bradykinesia, and postural and gait instability. We hypothesized that peripheral inflammatory cytokines would predict the severity of motor symptoms in persons with PD, and that there will be higher levels of peripheral inflammatory cytokine markers in persons with PD when compared to age-matched healthy older adults. Twenty-six participants with PD and fourteen healthy older adults completed the study. For participants with PD, the motor section of the Unified Parkinsons Disease Rating Scale (UPDRS) was recorded and scored by two Movement Disorders Neurologists masked to the study. A blood sample was collected from both participants with PD and the healthy older adults. Through the MILLIPLEX® map High Sensitivity Human Cytokine Kit, key inflammation-related markers were analyzed (TNF- Results revealed significantly higher levels of IL-6 in persons with PD when compared to healthy older adults ( Overall, these results are consistent with a growing body of literature that implicates inflammatory cytokines in the PD, and further suggests that inflammatory cytokines, or lack thereof, may be associated with tremor in persons with PD.

Updates in the classification of ependymal neoplasms The 2021 WHO Classification and beyond.

Ependymal neoplasms occur at all ages and encompass multiple tumor types and subtypes that develop in the supratentorial compartment, the posterior fossa, or the spinal cord. Clinically, ependymomas represent a very heterogeneous group of tumors from rather benign subependymomas to very aggressive and often deadly childhood ependymomas of the posterior fossa. Newly identified biological markers and classification schemes, e. g. based on global DNA methylation profiling, have led to the definition of 10 types of ependymal tumors and an improved prediction of patients outcome by applying the new classification system. While the exact genetic basis for several ependymoma types still remains unclear, the knowledge about ependymoma driving events has significantly increased within the last decade and contributed to a classification based on molecular characteristics and localization rather than histological features alone. Convincing evidence is now pointing towards gene fusions involving ZFTA or YAP1 causing the development of supratentorial ependymomas. Also, H3, EZHIP, or TERT mutations have been detected in a fraction of infratentorial ependymal tumors. Finally, MYCN amplifications have recently been identified in spinal ependymomas, in addition to the previously known mutations in NF2. This review summarizes how recent findings regarding biology, molecular tumor typing, and clinical outcome have impacted the classification of ependymomas as suggested by the updated 2021 WHO CNS tumor classification system. We focus on changes compared to the previous classification of 2016 and discuss how a formal grading could evolve in the future and guide clinicians to treat ependymoma patients.

Intratumoral heterogeneity of MYC drives medulloblastoma metastasis and angiogenesis.

Intratumoral heterogeneity is crucially involved in metastasis, resistance to therapy, and cancer relapse. Amplifications of the proto-oncogene MYC display notable heterogeneity at the single-cell level and are associated with a particularly dismal prognosis in high-risk medulloblastomas (MBs). The aim of this study was to establish the relevance of interclonal cross-talk between MYC-driven and non-MYC-driven MB cells. We used fluorescence in situ hybridization, single-cell transcriptomics, and immunohistochemistry, in vitro isogenic cell models, non-targeted proteomics, mass spectrometry-based metabolite quantification, HUVECs tube formation assay, and orthotopic in vivo experiments to investigate interclonal cross-talk in MB. We found that the release of lactate dehydrogenase A (LDHA) from MYC-driven cells facilitates metastatic seeding and outgrowth, while secretion of dickkopf WNT signaling pathway inhibitor 3 from non-MYC-driven cells promotes tumor angiogenesis. This tumor-supporting interaction between both subclones was abrogated by targeting the secretome through pharmacological and genetic inhibition of LDHA, which significantly suppressed tumor cell migration. Our study reveals the functional relevance of clonal diversity and highlights the therapeutic potential of targeting the secretome to interrupt interclonal communication and progression in high-risk MB.

Lorlatinib for Previously Treated ALK-Positive Advanced NSCLC Primary Efficacy and Safety From a Phase 2 Study in Peoples Republic of China.

Lorlatinib was found to have activity in ALK-positive NSCLC in a global phase 1 and 2 study. We report an ongoing phase 2 study in Chinese patients with ALK-positive advanced or metastatic NSCLC. Open-label, dual-cohort study (NCT03909971) patients had progressive disease after ALK tyrosine kinase inhibitor treatment (cohort 1 previous crizotinib cohort 2 one ALK tyrosine kinase inhibitor other than crizotinib ±prior crizotinib), more than or equal to one unirradiated extracranial target lesion, and Eastern Cooperative Oncology Group performance status of 0 to 2. Patients received oral lorlatinib 100 mg once daily in continuous 21-day cycles. Primary end point objective response in cohort 1 by independent central radiology (ICR) according to Response Evaluation Criteria in Solid Tumors version 1.1. Analyses were based on patients receiving more than or equal to one dose. At data cutoff (August 10, 2020), 109 patients were enrolled (cohort 1 n 67 cohort 2 n 42). A total of 47 patients in cohort 1 (70.1%, 95% confidence interval CI 57.7-80.7, p < 0.0001 primary end point) and 20 patients in cohort 2 (47.6%, 95% CI 32.0-63.6, secondary end point) achieved objective response by ICR. Median progression-free survival was not reached in cohort 1 and was 5.6 months in cohort 2. In patients with brain lesions at baseline, 29 of 36 patients in cohort 1 (80.6%, 95% CI 64.0-91.8) and 10 of 21 patients in cohort 2 (47.6%, 95% CI 25.7-70.2) achieved objective intracranial response by ICR. Hypercholesterolemia (92.7%) and hypertriglyceridemia (90.8%) (cluster terms) were common treatment-related adverse events (TRAEs). Nine patients (8.3%) had serious TRAEs one permanently discontinued from treatment because of TRAEs. Lorlatinib was found to have a robust and durable response and high intracranial objective response in previously treated Chinese patients with ALK-positive NSCLC.

Depression in breast cancer patients Immunopathogenesis and immunotherapy.

Depression is a common and recurrent mental illness with a complicated etiology, but the specific pathogenesis is not clear. Breast cancer increases susceptibility to depression, which leads to a poor prognosis. Rapid advances in the understanding of tumor immunology and neuroimmunology have provided new evidence for the pathogenesis of depression. Dysfunction of immune cells and cytokines cause depression by affecting tryptophan metabolism, serotonin levels, and blood-brain barrier permeability. Dysregulation of cytokines or intestinal flora may be shared between patients with depression and breast cancer. This review presents an overview of immune dysregulation in breast cancer patients with depression and proposes future alternative research directions and interventions.

Glioblastoma multiforme targeted delivery of docetaxel using bevacizumab-modified nanostructured lipid carriers impair in vitro cell growth and in vivo tumor progression.

Glioblastoma multiforme (GBM) is the most common malignant brain cancer, characterized by high invasiveness and poor prognosis. Docetaxel (DTX) is a chemotherapeutic drug with promising anti-tumor properties. However, conventional intravenous formulations exhibit side effects of systemic biodistribution and low brain bioavailability, limiting their clinical use. The current work aimed to evaluate the effect of DTX-loaded nanostructured lipid carriers (NLC) functionalized with bevacizumab (BVZ-NLC-DTX) against GBM using in vitro and in vivo models. The NLC was obtained by the fusion-emulsification method followed by sonication, with narrow size distribution, negative zeta potential, and low polydispersity index. NLC showed DTX entrapment efficiency above 90%. BVZ coupling efficiency was 62% and BVZ integrity after functionalization was confirmed by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). Calorimetry studies confirmed thermal stability and molecular dispersion of DTX in the lipid matrix. NLC showed a sustained DTX release over 84 h. In vitro anti-tumor assays shown that BVZ-NLC-DTX selectively increased the cytotoxic of DTX in cells overexpressing VEGF (U87MG and A172), but not in peripheral blood mononuclear cells (PMBCs), promoting cell death by apoptosis. BVZ functionalization did not impair cellular uptake. An in vivo orthotopic rat model demonstrated that free-DTX was not capable of reducing tumor growth whereas BVZ-NLC-DTX reduced up to 70% tumor volume after 15-days of treatment. Therefore, this study contributes to understanding new nanotechnology-based vehicles capable of reaching the brain more efficiently and repurposing the use of anti-cancer drugs in GBM treatment.

Whats new in molecular genetic pathology 2022 immune checkpoint inhibitor biomarkers and select solid tumors.

Predictive biomarker testing plays a critical role in targeted immuno-oncology, including the use of immune checkpoint inhibitors (ICI) for various solid tumors. Molecular advancements in cancers of the breast, kidney and brain have continued to propel tumor classification and precision therapy.

Improvement of sleep by resistant dextrin prebiotic in type 2 diabetic women coincides with attenuation of metabolic endotoxemia involvement of gut-brain axis.

Resistant dextrin, as a prebiotic and functional food, may possess favorable effects in type 2 diabetes. This study was conducted to assess whether supplementation with resistant dextrin can improve sleep and quality of life in obese type 2 diabetic women. In this randomized controlled trial, female obese type 2 diabetic patients (n 76) were randomly assigned into intervention group (n 38) and placebo group (n 38), and received 10 g day It is concluded that resistant dextrin improves sleep and QOL in obese women with type 2 diabetes. Its beneficial effects may be attributed in part to modulation of glycemia, metabolic endotoxemia and subsequently a decrease in biomarkers of inflammation and HPA axis activity. © 2022 Society of Chemical Industry.

Pediatric brain tumors a bibliometric analysis.

The purpose of this study was to identify tendency and current issues in research on pediatric brain tumors over the past 20 years and to help researchers and investors explore new directions for future research in this subject. Web of Science Core Collection was used for article selection and CiteSpace 5.8.R 1 was used for bibliometric analyses with these articles. The overall h-index was found to be 131 in the analysis made in a total of 4019 publications on the subject between the years 2000 and 2021. A total of 16,101 authors have published articles on pediatric brain tumors. The most active author in this field was Michael D. Taylor (h-index 105). The publication which received the strongest citation burst among publications was published in 2016 by Louis et al. published in Acta Neuropathologica, and its content is the World Health Organizations classification of central nervous system tumors. Considering the country contribution, the USA is seen in the leading position. The most publications on the subject were followed by the Journal of Clinical Oncology. By examining the studies on childhood brain tumors carried out around the world, the subjects that can be determined as the focus were tried to be highlighted. And it has been seen that the scientific and industrial community should work together and the financial support for multidisciplinary studies should increase.

Social skills group training in adolescents with disabilities A systematic review.

Group social skills interventions (GSSIs) are offered to youth with Autism Spectrum Disorder (ASD) to improve social functioning. This systematic review focused on the adolescent population, including a wider range of disabilities. To evaluate effectiveness of GSSIs at improving social functioning in adolescents with congenital, acquired or developmental disabilities. Databases, trial registries and dissertations were systematically searched and a meta-analysis of randomized controlled trials conducted. Study screening, risk-of-bias assessment and Grading of Recommendations Assessment, Development and Evaluation were completed. Sixteen studies (n 1119), 15 with adolescents with ASD and one with brain tumor survivors, revealed GSSIs reduced social impairment on the Social Responsiveness Scale (mean difference (MD) 9.68, 95% CI 5.63-13.73 P < 0.001), increased social skills on the Social Skill Improvement System Rating Scales (SMD 0.38, 95% CI 0.10-0.65 P 0.007), and improved adolescent social knowledge on the Test of Adolescent Social Skills (MD 7.43 points, 95% CI 5.36-9.50 P < 0.001). There is moderate certainty evidence that GSSIs improve social responsiveness, social skills and knowledge, and low certainty of evidence to improve social participation for adolescents with ASD. High quality randomized studies are required to inform clinical practice with adolescents with other disabilities. Current evidence for group social skills interventions (GSSIs) is for adolescents with autism (ASD). GSSIs likely improve social knowledge and reduce impairments in adolescents with ASD, however the effect of GSSIs on social participation is not well understood. Only one randomized trial investigated GSSIs in another population of adolescents, highlighting the need for more high-quality studies including adolescents with other disabilities.

Potential molecular mechanisms and clinical progress in liver metastasis of breast cancer.

Breast cancer is the most common malignant tumor in women and the leading cause of cancer death in women. About 30% of breast cancer patients have metastasis every year, which greatly increases the mortality rate of breast cancer. The main target organs for metastasis are bone, brain, liver and lung. The breast cancer liver metastasis (BCLM) mechanism is not fully clarified. This is a complex process involving multiple factors, which is not only related to the microenvironment of the primary tumor and liver, but also regulated by a variety of signaling pathways. Clarifying these mechanisms is of great help to guide clinical treatment. With the in-depth study of BCLM, a variety of new treatment schemes such as targeted therapy and endocrine therapy provide new ideas for the cure of BCLM. In this review, we will summarize the molecular mechanism and treatment of BCLM.

Beneficial effects of Lactococcus lactis subsp. cremoris LL95 treatment in an LPS-induced depression-like model in mice.

Clinical evidence suggests that neuroinflammation, activation of the immune system, and the composition of the intestinal microbiota are involved in the pathology of depression. This study evaluated the effectiveness of a probiotic intervention using Lactococcus lactis subsp. cremoris LL95 in ameliorating mood disorders in a lipopolysaccharide (LPS)-induced depression-like mouse model. C57BL6 mice were randomly divided into four groups and treated with 5 mgkg LPS via intraperitoneal injection to induce depression-like symptoms, followed by oral administration of LL95 for one week (1 × 10

Low incidence of hemorrhagic complications both during and after surgical procedures in patients maintained on prasugrel single antiplatelet therapy.

Prasugrel (Pra) is a third-generation thienopyridine that inhibits platelet aggregation via irreversible blockade of P2Y12 receptors. While several published studies have examined the use of Pra and acetylsalicylic acid (ASA) in coronary and neurovascular stenting procedures, there is only anecdotal evidence regarding the use of Pra as single antiplatelet therapy (SAPT) in open surgical procedures. This topic has become important because previous studies have revealed that neurovascular devices with antithrombotic coatings can be implanted using non-invasive procedures in patients maintained on Pra SAPT. Patients who underwent open surgery under Pra SAPT between March 2020 and February 2022 were evaluated retrospectively. Adequate platelet inhibition both before and after the procedures was verified in all patients using Multiplate (Roche Diagnostics) and VerifyNow (Accriva) tests. Intraoperative and postoperative hemorrhagic events were recorded based on reviews of the procedure reports and interviews with the surgeons. The study enrolled 21 patients who underwent 23 open surgical procedures while maintained on Pra SAPT. The procedures included one extirpation of a brain arteriovenous malformation, seven extra-intracranial bypass surgeries, four ventriculoperitoneal shunts, one eye enucleation for an intractable orbital infection, two gastrostomies, one bone flap reinsertion after craniectomy, one decompressive craniectomy, one case requiring cranial surgical wound care, one colporrhaphy, one transurethral resection of urinary bladder cancer, two tumor oophorectomyhysterectomy procedures, and one aneurysm clipping. None of the 23 procedures resulted in excessive intraoperative or postoperative hemorrhage. In a small retrospective series of patients who required antiplatelet therapy for neurovascular indications, Pra SAPT resulted in no significant increase in the incidence of perioperative and postoperative hemorrhagic complications.

Cathepsin V Molecular characteristics and significance in health and disease.

Human cysteine cathepsins form a family of eleven proteases (B, C, F, H, K, L, O, S, V, W, XZ) that play important roles in a considerable number of biological and pathophysiological processes. Among them, cathepsin V, also known as cathepsin L2, is a lysosomal enzyme, which is mainly expressed in cornea, thymus, heart, brain, and skin. Cathepsin V is a multifunctional endopeptidase that is involved in both the release of antigenic peptides and the maturation of MHC class II molecules and participates in the turnover of elastin fibrils as well in the cleavage of intra- and extra-cellular substrates. Moreover, there is increasing evidence that cathepsin V may contribute to the progression of diverse diseases, due to the dysregulation of its expression andor its activity. For instance, increased expression of cathepsin V is closely correlated with malignancies (breast cancer, squamous cell carcinoma, or colorectal cancer) as well vascular disorders (atherosclerosis, aortic aneurysm, hypertension) being the most prominent examples. This review aims to shed light on current knowledge on molecular aspects of cathepsin V (genomic organization, protein structure, substrate specificity), its regulation by protein and non-protein inhibitors as well to summarize its expression (tissue and cellular distribution). Then the core biological and pathophysiological roles of cathepsin V will be depicted, raising the question of its interest as a valuable target that can open up pioneering therapeutic avenues.

Mind the gap IgG4-related disease mimicking infectious cerebral mass lesions.

Cerebral intraparenchymal masses represent usually a neoplastic, or infectious differential diagnostic workup in neurology or infectious disease units. Our patient was an 82-year-old male presenting with seizures, cerebral masses and a history of past treated pulmonary tuberculosis. Initial workup included a differential diagnosis of an infectious massmultiple abscess. After exclusion of infectious or primary neoplastic origins by negative HIV serology, the absence of immune suppression, endocarditic lesions, negative results of blood cultures and bronchoalveolar lavage, negative cerebrospinal fluid workout on spinal tap led to exclusion of infectious causes. A surgical procedure was performed to access one of the lesions. This yielded a firm, cyst-like mass of histiocytic granulomatous tissue with a conspicuous plasmacellular component and a relevant IgG4 plasmacellular component consistent with IgG4-related disease. Steroid treatment determined conspicuous improvement and led to discharge of the patient. Parenchymal IgG4-related disease may be included as a new entity in the differential diagnosis of single or multiple cerebral masses in addition to infectious or neoplastic etiology.

Nonepileptic attacks in patients with brain tumor-related epilepsy.

Epileptic seizures are well recognized as a presenting symptom in patients with brain tumors, however much less is known about coexisting nonepileptic attack disorder (NEAD) in this population. Establishing a diagnosis of NEAD can be challenging, especially in those with concomitant epilepsy. Nonepileptic attack disorder is associated with a high rate of morbidity, often due to coexisting psychological factors which may require the input of multiple services. In an era where early aggressive management of tumors is enabling patients to live longer, the associated psychological impact of adjusting to physical disease is increasingly apparent. In this case series, we present a narrative summary of 9 patients referred to neurology with brain tumor-related epilepsy (BTRE) over a five-year period (2015-2020) who also experienced NEAD. We describe their tumor characteristics, treatment course, and factors potentially contributing to their presentation. We conducted a case note review of patients presenting to the epilepsy service with BTRE, in whom NEAD was diagnosed based on clinical features and correlation with their EEG. Patients ranged in age from 26 to 63 years. Two patients were diagnosed with grade 1, three with grade 2 and four with grade 3 tumors. Tumors localized to frontal or temporal regions in seven cases. All patients presented initially with BTRE and developed nonepileptic seizures subsequently. Four patients developed NEAD within 1 month of their tumor diagnosis. One patient developed NEAD 79 months following diagnosis. The diagnosis of NEAD was established in 8 patients by direct visualization of attacks (two during concomitant EEG recording). In the remaining patient, diagnosis was based on history (patient and witness). Six patients were diagnosed with concomitant low mood and or anxiety and three were commenced on antidepressant medication. At the time of last review, the predominant attacks were nonepileptic in all but one patient.

DualMMP-GAN Dual-scale multi-modality perceptual generative adversarial network for medical image segmentation.

Multi-modality magnetic resonance imaging (MRI) can reveal distinct patterns of tissue in the human body and is crucial to clinical diagnosis. But it still remains a challenge to obtain diverse and plausible multi-modality MR images due to expense, noise, and artifacts. For the same lesion, different modalities of MRI have big differences in context information, coarse location, and fine structure. In order to achieve better generation and segmentation performance, a dual-scale multi-modality perceptual generative adversarial network (DualMMP-GAN) is proposed based on cycle-consistent generative adversarial networks (CycleGAN). Dilated residual blocks are introduced to increase the receptive field, preserving structure and context information of images. A dual-scale discriminator is constructed. The generator is optimized by discriminating patches to represent lesions with different sizes. The perceptual consistency loss is introduced to learn the mapping between the generated and target modality at different semantic levels. Moreover, generative multi-modality segmentation (GMMS) combining given modalities with generated modalities is proposed for brain tumor segmentation. Experimental results show that the DualMMP-GAN outperforms the CycleGAN and some state-of-the-art methods in terms of PSNR, SSMI, and RMSE in most tasks. In addition, dice, sensitivity, specificity, and Hausdorff95 obtained from segmentation by GMMS are all higher than those from a single modality. The objective index obtained by the proposed methods are close to upper bounds obtained from real multiple modalities, indicating that GMMS can achieve similar effects as multi-modality. Overall, the proposed methods can serve as an effective method in clinical brain tumor diagnosis with promising application potential.

Anti-VEGFR2 monoclonal antibody(MSB0254) inhibits angiogenesis and tumor growth by blocking the signaling pathway mediated by VEGFR2 in glioblastoma.

Angiogenesis is a key physiological process that plays a key role in glioblastoma (GBM) progression and displays therapeutic resistance to antiangiogenic therapies. In this study, we aimed to identify whether vascular endothelial growth factor receptor 2(VEGFR2)monoclonal antibodies(mab)could inhibit tumorigenicity and the formation of vascular mimicry (VM) in GBM. The bioinformatic analysis from TCGA, CGGA, and TCPA databases and Immunohistochemistry (IHC) revealed that VEGFR2 is highly expressed in glioma tissues and results in a poor prognosis and is positively associated with VM markers (CD34 and PAS). The anti-VEGFR2 monoclonal antibodies(MSB0254)could inhibit the invasion, migration, and VM formation of U251 and primary glioma cells in vitro. In vivo, MSB0254 (m) could not only inhibit the growth of transplanted tumors of U251 and GL261 cells, but also significantly inhibit the expression of CD34, VEGFR2, Ki67, MMP2, MMP9 and reduce the expression of CD34PAS and inhibit VM formation. The VEGFR2 monoclonal antibody could inhibit the angiogenesis and tumor growth of GBM by blocking the signaling pathway mediated by VEGFR2. It may become a new supplementary treatment for GBM.

Subpial en bloc resection improves extent of resection in infiltrating gliomas - A propensity matched comparative cohort analysis.

Surgery remains the mainstay of glioma therapy and extent of resection is an important prognostic factor. Optimization of surgical outcomes is essential and to this end the technique of resection can potentially play an important role. Based on patterns of glioma growth and extrapolating from other solid cancer surgical principles, a subpial dissection combined with an en-bloc resection (SPER) technique appears to have advantages METHODS We performed a propensity matched analysis comparing gliomas that were resected using SPER versus a standard piecemeal debulking technique at our centre. Potentially confounding factors (including eloquent location, use of intraoperative imaging, surgeon experience) were adjusted for in the matching of the two cohorts. Outcomes included postoperative morbidity and blinded radiological review documented postoperative ischemia (on diffusion weighted MR imaging - DWI) as well as extent of resection. In 57 gliomas (23 SPER and 34 standard), the gross total resection (GTR) rates were significantly higher with SPER (91 vs 65%). Postoperative DWI revealed significant ischemia in almost 50% of cases in either group, though many did not have postoperative deficits. Arterial ischemia was higher in the standard surgery group and this was associated with a significantly higher risk (seven times) of resulting in prolonged neurological deficits. SPER is a useful technique which increases the GTR rates in gliomas undergoing resection. It is associated with lower incidence of arterial ischemia in the postoperative period and this can result in improved long term functional outcomes.

Long noncoding RNA LINC01296 regulates the cell proliferation, migration and invasion in neuroblastoma.

Neuroblastoma (NB) is a childhood cancer that often occurs in the sympathetic nervous system. Previous reports showed that long non-coding RNAs (lncRNAs) could affect the progress of NB, but the mechanism is still indistinct. In this study, we unfolded the roles of LINC01296 in NB tissues and cells. The level of LINC01296, microRNA-584-5p (miR-584-5p), miR-34a-5p and mRNA of tripartite motif-containing 59 (TRIM59) were indicated by quantitative real-time polymerase chain reaction (qRT-PCR) in NB tissues. The capacities of NB cells were validated by MTT assay, Edu assay, transwell assay and flow cytometry analysis. The interplay between miR-584-5pmiR-34a-5p and LINC01296 or TRIM59 were detected by dual-luciferase reporter assay. Finally, the in vivo experiment was implemented to verify the effect of LINC01296 in vivo. The level of LINC01296 and TRIM59 were increased, whereas miR-584-5p and miR-34a-5p levels were reduced in NB tissues in contrast to that in normal tissues. For functional analysis, LINC01296 deficiency inhibited the cell vitality, cell proliferation, migration and invasion in NB cells, whereas promoted cell apoptosis. Moreover, miR-584-5p and miR-34a-5p were validated to act as a tumor repressive effect in NB cells by restraining TRIM59. The results also showed that LINC01296 could regulate the development of NB. In mechanism, LINC01296 acted as a miR-584-5p and miR-34a-5p sponge to modulate TRIM59 expression. In addition, LINC01296 knockdown also attenuated tumor growth in vivo. LINC01296 promotes the progression of NB by increasing TRIM59 expression via regulating miR-584-5p and miR-34a-5p, which also offered an underlying targeted therapy for NB treatment.

Liquid Biopsy Testing for the Management of Patient with Non-Small Cell Lung Cancer Carrying a Rare Exon-20 EGFR Insertion.

Increasing evidence suggests that liquid biopsy might play a relevant role in the management of metastatic non-small cell lung cancer (NSCLC) patients. Here, we show how the Molecular Tumor Board (MTB) in our cancer center employed liquid biopsy to support therapeutic decisions in a patient with NSCLC carrying a rare EGFR mutation. A 44-year-old woman, never-smoker with an EGFR, ALK, and ROS1-negative lung adenocarcinoma and multiple brain metastases received systemic therapy and surgery before being referred to our Institute. The MTB suggested NGS testing of tumor biopsy that revealed a rare exon-20 EGFR insertion (p.His773dup c.23152316insCCA) and EGFR amplification. The MTB recommended treatment with erlotinib and follow-up with liquid biopsy, by using both cell-free DNA (cfDNA) and circulating tumor cells (CTCs). An increase of EGFR mutation levels in cfDNA revealed resistance to treatment about 6 months before clinical progression. Extremely low levels of EGFR p.T790M were detected at progression. Based on preclinical data suggesting activity of osimertinib against EGFR exon-20 insertions, the MTB recommended treatment with brain and bone radiotherapy and osimertinib. A dramatic reduction of EGFR mutation levels in the cfDNA was observed after 4 weeks of treatment. The PET scan demonstrated a metabolic partial remission that was maintained for 9 months. This case supports the evidence that liquid biopsy can aid in the management of metastatic NSCLC. It also suggests that treatment with osimertinib might be a therapeutic option in patients with EGFR exon-20 insertions when a clinical trial is not available.

Esophageal carcinoma as a portal of entry for brainstem abscess formation.

Cerebral abscess formation is a serious and life-threatening clinical entity, secondary to contiguous spread, hematogenous dissemination or direct inoculation. We present the case of a 61-year-old woman with a recent diagnosis of a locally advanced squamous cell carcinoma of the esophagus who was diagnosed with a brainstem abscess. In literature we only found three cases reporting cerebral abscess formation in patients with esophageal carcinoma. Our case report is considered exceptional given the abscess localization in the pons. The abscess was successfully treated with stereotactic drainage and antibiotics. This report emphasizes the importance of gastrointestinal tract evaluation in patients with diagnosis of cerebral abscess when no other cause is found. Brain abscesses must be recognized as a potentially fatal complication of esophageal carcinoma.

Optimizing the tumor shrinkage threshold for evaluating immunotherapy efficacy for advanced non-small-cell lung cancer.

The rise of immune checkpoint inhibitors (ICIs) in recent years has coincided with unusual clinical response patterns. Modification of the sum of longest diameters (SLD)-based threshold that reflecting dynamic change of the tumor burden and predicting response to ICIs, may markedly improve current treatment regimens. The baseline and post-treatment SLD of target lesion was recorded and the maximum percent change of the SLD from baseline was designated as SLD-change score. The optimal cut-off value was obtained using the X-tile program. The relationship between SLD-change score and survival outcome (PFS, OS) was evaluated. 10% cut-off value of SLD-change score was found to be most distinctive for PFS. Responders defined according to this cut-off value showed a significant improvement for PFS and OS. Bone metastasis and brain metastasis were also two independent prognostic factors of PFS and OS, respectively. 10% SLD change score could discriminate for ICIs treatment response, which holds great promise in promoting the development of precise immunotherapeutic strategy.

p16

Approximately 50% of patients with metastatic HER2-positive (HER2) breast cancer develop brain metastases (BCBMs). We report that the tumor suppressor p16

Proteomics and metabolomics approach in adult and pediatric glioma diagnostics.

The diagnosis of glioma is mainly based on imaging methods that do not distinguish between stage and subtype prior to histopathological analysis. Patients with gliomas are generally diagnosed in the symptomatic stage of the disease. Additionally, healing scar tissue may be mistakenly identified based on magnetic resonance imaging (MRI) as a false positive tumor recurrence in postoperative patients. Current knowledge of molecular alterations underlying gliomagenesis and identification of tumoral biomarkers allow for their use as discriminators of the state of the organism. Moreover, a multiomics approach provides the greatest spectrum and the ability to track physiological changes and can serve as a minimally invasive method for diagnosing asymptomatic gliomas, preceding surgery and allowing for the initiation of prophylactic treatment. It is important to create a vast biomarker library for adults and pediatric patients due to their metabolic differences. This review focuses on the most promising proteomic, metabolomic and lipidomic glioma biomarkers, their pathways, the interactions, and correlations that can be considered characteristic of tumor grade or specific subtype.

Exosomal microRNAs induce tumor-associated macrophages via PPARγ during tumor progression in SHH medulloblastoma.

Medulloblastoma (MB), the most common malignant pediatric brain tumor, is composed of at least four molecular subgroups with distinct clinical characteristics. The sonic hedgehog (SHH) subgroup exhibits the most abundant tumor-associated microgliamacrophages (TAMs) infiltration. SHH-MB patients treated by anti-SHH drugs showed high drug resistance. However, the comprehensive role of TAMs in SHH-MB remains enigma. The aim of this study is to explore the mechanism of TAM activationpolarization in SHH-MB and discover a potential immunotherapeutic target to reduce drug resistance. We first analyzed expression profiles of immuno-microenvironment (IME) in four subgroups of 48 MB tumors using NanoString PanCancer IO360 panel and found TAMs were the major component of IME in SHH-MBs. We further distinguished M1M2-like TAMs in tumors and found M2-like macrophages, rather than microglia, were enriched in SHH-MBs. In transgenic SHH-MB mice, these TAMs had close relationship with tumor progression. Polarization of the TAMs could be induced by MB-derived exosomes in vitro. We then screened SHH MB-derived exosomal miRNAs and their target genes using RNA sequencing and luciferase assay to clarify their roles in regulating TAM polarization. We found down-regulated let-7i-5p and miR-221-3p can induce M2-like polarization of TAMs via upregulating peroxisome proliferator activated receptor gamma (PPARγ). Finally, we demonstrated the PPARγ antagonist efficiently improved the antitumor activity of SMO inhibitor in vivo, which may be related to inhibition of M2-like TAMs. Our findings suggest a potential therapeutic strategy for SHH-MB by targeting tumor-supportive M2-like TAMs to enhance the therapeutic effect of SMO inhibitors.

LncRNA RMRP accelerates autophagy-mediated neurons apoptosis through miR-3142TRIB3 signaling axis in alzheimers disease.

Alzheimers disease (AD) is a major neurodegenerative disorder. The functions of lncRNA RMRP have been characterized mainly in various human cancers. However, the functional network of RMRP in AD progression remains unknown. Human serum samples, AD transgenic (Tg) mice as well as SH-SY5Y cells were used in this study. The RNA expression patterns of RMRP, miR-3142 and TRIB3 were assessed by quantitative real-time PCR (qRT-PCR). Levels of apoptosis- or autophagy-associated biomarkers and TRIB3 level were evaluated using immunohistochemistry (IHC), western blotting or immunofluorescence assays, respectively. Bioinformatics methods and luciferase assays were used to predict and validate the interactions among RMRP, miR-3142, and TRIB3. Flow cytometry, TUNEL staining and EdU assays were used to examine the apoptosis and proliferation of neurons, respectively. The elevated RMRP and TRIB3 expressions and activation of autophagy were observed in AD. Knockdown of RMRP restrained neuronal apoptosis and autophagy activation in vitro and in vivo. Interestingly, TRIB3 overexpression reversed the biological effects of RMRP silencing on Aβ These data illustrated that knockdown of RMRP inhibited autophagy and apoptosis via regulating miR-3142TRIB3 axis in AD, suggesting that inhibition of RMRP maybe a therapeutic strategy for AD.

Coexistence of craniopharyngioma and cranial fibrous dysplasia a case series of clinicopathological study.

Craniopharyngioma (CP) and cranial fibrous dysplasia (CFD) are rare embryonic benign cranial diseases that most commonly present during childhood or adolescence. The coexistence of CP and CFD is extremely rare and has not yet been reported. We retrospectively reviewed the data of five patients with concomitant CP and CFD treated at Beijing Tiantan Hospital from January 2003 to January 2021 and summarized their clinicopathological features, treatment modalities, and outcomes. We also performed a comprehensive literature review, tested the patients for characteristic GNAS gene mutations related to CFD, and tested the CP specimens for corresponding Gsα protein to explore the potential connection leading to the coexistence of CP and CFD. The cohort comprised four men and one woman (median age, 39 years). The symptoms mainly included headache, dizziness, fatigue, polyuriapolydipsia, hypogonadism, and blurred vision. CFD most commonly involved the sphenoid bone (n 4). Four patients underwent surgery to remove the CP (one trans-sphenoidal and three transcranial resections) complete and subtotal resection were achieved in two patients, respectively. The tumor subtype was adamantinomatous in three patients and unknown in one. The common postoperative complications were panhypopituitarism, diabetes insipidus, and hypothyroidism. The mean follow-up duration was 57.2 months. Two patients required postoperative hormone replacement therapy. Three patients underwent genetic study of the tumor specimens GNAS mutations were not detected, but these patients were positive for Gsα protein. Although a definite causative relationship has not been proved, the coexistence of CP and CFD means that potential interplay or an atypical fibrous dysplasia course as uncommon manifestations of CP cannot be excluded. It is more challenging to initiate prompt diagnosis and appropriate treatment for concomitant CP and CFD than for solitary CP because of skull base deformations. Current management strategies are aimed at surgical treating the CP and regularly monitoring the CFD.

New diagnosis of cancer in mild and moderatesevere traumatic brain injury patients in a 12-year population-based study.

Traumatic brain injury (TBI) has been reported as a risk factor for brain cancer development. However, the magnitude of the impact of TBI on systemic cancer development has not been clarified. A retrospective longitudinal cohort study was conducted using the Taiwan Longitudinal Health Insurance Database between January 2000 and December 2011. A total of 35,306 patients were initially enrolled, and 14,795 patients with mild TBI and 14,795 patients with moderatesevere TBI were matched using the National Health Insurance Research Database in Taiwan. The Cox proportional hazard regression model was used to estimate the hazard ratio (HR) of TBI adjusted for potential confounding factors. After matching, the results showed that patients with moderatesevere TBI had a high mortality rate (17.7% vs. 10.4%) and shorter time interval from TBI to death (mean 3.6 years vs. 5.8 years). No differences were observed in cancer incidence (4.1% vs. 4.1%) or risk factors for mortality between mild and moderatesevere TBI patients. However, patients aged between 46 and 55 years, female patients, and patients with pre-existing renal disease had a significant higher cancer incidence risk in moderatesevere TBI compared with mild TBI patients. The top 15 most common cancers showed that mild TBI patients had a higher percentage of head and neck cancer. The overall mortality rate in all TBI patients diagnosed with cancer was about 50%, and the cancer-specific mortality is approximately 85% in death of TBI patients with cancer. We concluded that the incidence risk of a new cancer diagnosis and mortality risk of TBI patients with cancer between the mild TBI and moderatesevere TBI patients were not significantly different.

Preservation of language function by mapping the arcuate fasciculus using intraoperative corticocortical evoked potential under general anesthesia in glioma surgery.

Intraoperative language mapping under general anesthesia is imperative for brain tumor surgery because awake surgery is not always feasible. Monitoring corticocortical evoked potential (CCEP) is known to be a useful method for tracking neuronal connectivity and localizing functional areas. The authors evaluated the clinical benefit of intraoperative CCEP monitoring for language function preservation in patients undergoing glioma surgery. Between January 2019 and June 2021, the authors performed a total of 29 consecutive glioma surgeries using CCEP monitoring under general anesthesia because of a risk of speech impairment these were analyzed. Language area mapping was implemented by the anterior language area to posterior language area CCEP method for arcuate fasciculus mapping, and tumor resection was performed while avoiding the localized language areas. Language function before and after surgery was evaluated by the Controlled Oral Word Association Test (COWAT). Intraoperative CCEP was successfully monitored in 25 patients (86.2%), and a valid signal was undetectable in the other 4 patients. Language function evaluation was possible before and after surgery in a total of 20 patients. Overall, the preservation rate of language function was 65.0%, and the deterioration rate was 35.0% after tumor resection with CCEP monitoring. Among those 8 patients with preoperative COWAT scores ≥ 18, 5 patients (62.5%) successfully preserved their language function, with COWAT scores > 18 after tumor resection. Among the 12 patients with preoperative deteriorated language function (COWAT score < 18), 8 patients (66.7%) showed improvement or preserved language function after surgery. Intraoperative CCEP monitoring of the arcuate fasciculus is an acceptable technology for the preservation of language function under general anesthesia in glioma surgery in patients in whom awake surgery is not feasible.

Single-cell landscapes of primary glioblastomas and matched explants and cell lines show variable retention of inter- and intratumor heterogeneity.

Glioblastomas (GBMs) are aggressive brain tumors characterized by extensive inter- and intratumor heterogeneity. Patient-derived models, such as organoids and explants, have recently emerged as useful models to study such heterogeneity, although the extent to which they can recapitulate GBM genomic features remains unclear. Here, we analyze bulk exome and single-cell genome and transcriptome profiles of 12 IDH wild-type GBMs, including two recurrent tumors, and of patient-derived explants (PDEs) and gliomasphere (GS) lines derived from these tumors. We find that PDEs are genetically similar to, and variably retain gene expression characteristics of, their parent tumors. Notably, PDEs appear to exhibit similar levels of transcriptional heterogeneity compared with their parent tumors, whereas GS lines tend to be enriched for cells in a more uniform transcriptional state. The approaches and datasets introduced here will provide a valuable resource to help guide experiments using GBM-derived models, especially in the context of studying cellular heterogeneity.

The Biological Activity of 3-O-Acetyl-11-keto-β-Boswellic Acid in Nervous System Diseases.

Frankincense is a hard gelatinous resin exuded by Boswellia serrata. It contains a complex array of components, of which acetyl-11-keto-beta-boswellic acid (AKBA), a pentacyclic triterpenoid of the resin class, is the main active component. AKBA has a variety of physiological actions, including anti-infection, anti-tumor, and antioxidant effects. The use of AKBA for the treatment of mental diseases has been documented as early as ancient Greece. Recent studies have found that AKBA has anti-aging and other neurological effects, suggesting its potential for the treatment of neurological diseases. This review focuses on nervous system-related diseases, summarizes the functions and mechanisms of AKBA in promoting nerve repair and regeneration after injury, protecting against ischemic brain injury and aging, inhibiting neuroinflammation, ameliorating memory deficits, and alleviating neurotoxicity, as well as having anti-glioma effects and relieving brain edema. The mechanisms by which AKBA functions in different diseases and the relationships between dosage and biological effects are discussed in depth with the aim of increasing understanding of AKBA and guiding its use for the treatment of nervous system diseases.

Impact of phospholipase C β1 in glioblastoma a study on the main mechanisms of tumor aggressiveness.

Glioblastoma represents the most lethal brain tumor in adults. Several studies have shown the key role of phospholipase C β1 (PLCβ1) in the regulation of many mechanisms within the central nervous system suggesting PLCβ1 as a novel signature gene in the molecular classification of high-grade gliomas. This study aims to determine the pathological impact of PLCβ1 in glioblastoma, confirming that PLCβ1 gene expression correlates with gliomas grade, and it is lower in 50 glioblastoma samples compared to 20 healthy individuals. PLCβ1 silencing in cell lines and primary astrocytes, leads to increased cell migration and invasion, with the increment of mesenchymal transcription factors and markers, as Slug and N-Cadherin and metalloproteinases. Cell proliferation, through increased Ki-67 expression, and the main survival pathways, as β-catenin, ERK12 and Stat3 pathways, are also affected by PLCβ1 silencing. These data suggest a potential role of PLCβ1 in maintaining a normal or less aggressive glioma phenotype.

A pan-cancer analysis on the carcinogenic effect of human adenomatous polyposis coli.

Adenomatous polyposis coli (APC) is the most commonly mutated gene in colon cancer and can cause familial adenomatous polyposis (FAP). Hypermethylation of the APC promoter can also promote the development of breast cancer, indicating that APC is not limited to association with colorectal neoplasms. However, no pan-cancer analysis has been conducted. We studied the location and structure of APC and the expression and potential role of APC in a variety of tumors by using The Cancer Genome Atlas and Gene Expression Omnibus databases and online bioinformatics analysis tools. The APC is located at 5q22.2, and its protein structure is conserved among H. sapiens, M. musculus with C. elaphus hippelaphus. The APC identity similarity between homo sapiens and mus musculus reaches 90.1%. Moreover, APC is highly specifically expressed in brain tissues and bipolar cells but has low expression in most cancers. APC is mainly expressed on the cell membrane and is not detected in plasma by mass spectrometry. APC is low expressed in most tumor tissues, and there is a significant correlation between the expressed level of APC and the main pathological stages as well as the survival and prognosis of tumor patients. In most tumors, APC gene has mutation and methylation and an enhanced phosphorylation level of some phosphorylation sites, such as T1438 and S2260. The expressed level of APC is also involved in the level of CD8 T-cell infiltration, Tregs infiltration, and cancer-associated fibroblast infiltration. We conducted a gene correlation study, but the findings seemed to contradict the previous analysis results of the low expression of the APC gene in most cancers. Our research provides a comparative wholesale understanding of the carcinogenic effects of APC in various cancers, which will help anti-cancer research.

Synthesis and Development of a Novel First-in-Class Cofilin Inhibitor for Neuroinflammation in Hemorrhagic Brain Injury.

Intracerebral hemorrhage (ICH) is devastating among stroke types with high mortality. To date, not a single therapeutic intervention has been successful. Cofilin plays a critical role in inflammation and cell death. In the current study, we embarked on designing and synthesizing a first-in-class small-molecule inhibitor of cofilin to target secondary complications of ICH, mainly neuroinflammation. A series of compounds were synthesized, and two lead compounds SZ-3 and SK-1-32 were selected for further studies. Neuronal and microglial viabilities were assessed by 3-4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide (MTT) assay using neuroblastoma (SHSY-5Y) and human microglial (HMC-3) cell lines, respectively. Lipopolysaccharide (LPS)-induced inflammation in HMC-3 cells was used for neurotoxicity assay. Other assays include nitric oxide (NO) by Griess reagent, cofilin inhibition by F-actin depolymerization, migration by scratch wound assay, tumor necrosis factor (TNF-α) by enzyme-linked immunosorbent assay (ELISA), protease-activated receptor-1 (PAR-1) by immunocytochemistry and Western blotting (WB), and protein expression levels of several proteins by WB. SK-1-32 increased neuronalmicroglial survival, reduced NO, and prevented neurotoxicity. However, SZ-3 showed no effect on neuronalmicroglial survival but prevented microglia from LPS-induced inflammation by decreasing NO and preventing neurotoxicity. Therefore, we selected SZ-3 for further molecular studies, as it showed potent anti-inflammatory activities. SZ-3 decreased cofilin severing activity, and its treatment of LPS-activated HMC-3 cells attenuated microglial activation and suppressed migration and proliferation. HMC-3 cells subjected to thrombin, as an in vitro model for hemorrhagic stroke, and treated with SZ-3 after 3 h showed significantly decreased NO and TNF-α, significantly increased protein expression of phosphocofilin, and decreased PAR-1. In addition, SZ-3-treated SHSY-5Y showed a significant increase in cell viability by significantly reducing nuclear factor-κ B (NF-κB), caspase-3, and high-temperature requirement (HtrA2). Together, our results support the novel idea of targeting cofilin to counter neuroinflammation during secondary injury following ICH.

Polystyrene nanoplastics penetrate across the blood-brain barrier and induce activation of microglia in the brain of mice.

Microplastics (MPs) have been well demonstrated as potential threats to the ecosystem, whereas the neurotoxicity of MPs in mammals remains to be elucidated. The current study was designed to investigate whether 50 nm polystyrene nanoplastics (PS-NPs) could pass through the blood-brain barrier (BBB), and to elucidate the underlying mechanisms and the following neurotoxic manifestation. In vivo study showed that PS-NPs (0.5-50 mgkg. bw PS-NPs for 7 days) significantly induced the increase of permeability of BBB, and dose-dependently accumulated in the brain of mice. In addition, PS-NPs were found to be present in microglia, and induced microglia activation and neuron damage in the mouse brain. In vitro studies using the immortalized human cerebral microvascular endothelial cell (hCMECD3), the most commonly used cell model for BBB-related studies, revealed that PS-NPs could be internalized into cells, and caused reactive oxygen species (ROS) production, nuclear factor kappa-B (NF-κB) activation, tumor necrosis factors α (TNF-α) secretion, and necroptosis of hCMECD3 cells. Furthermore, PS-NPs exposure led to disturbance of the tight junction (TJ) formed by hCMECD3, as demonstrated by the decline of transendothelial electrical resistance (TEER) and decreased expression of occludin. Lastly, PS-NPs exposure resulted in the activation of murine microglia BV2 cells, and the cell medium of PS-NPs-exposed BV2 induced obvious damage to murine neuron HT-22 cells. Collectively, these results suggest that PS-NPs could pass through BBB and induce neurotoxicity in mammals probably by inducing activation of microglia.