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Treatment of Adult Gliomas A Current Update.

Gliomas are the most common type of primary brain tumor in adults. Glioma treatment requires a multidisciplinary approach involving surgery, radiotherapy, and chemotherapy. Multiple trials have been conducted to establish the appropriate choice of treatment to achieve long-term survival and better quality of life. This review provides up-to-date evidence regarding treatment strategies for gliomas.

Classification and Diagnosis of Adult Glioma A Scoping Review.

Gliomas are primary central nervous system tumors that arise from glial progenitor cells. Gliomas have been classically classified morphologically based on their histopathological characteristics. However, with recent advances in cancer genomics, molecular profiles have now been integrated into the classification and diagnosis of gliomas. In this review article, we discuss the clinical features, imaging findings, and molecular profiles of adult-type diffuse gliomas based on the new 2021 World Health Organization Classifications of Tumors of the central nervous system.

Brain Tumor Rehabilitation Symptoms, Complications, and Treatment Strategy.

Brain tumors are receiving increasing attention in cancer rehabilitation due to their high rate of neurological deterioration. Motor dysfunction, cognitive deterioration, and emotional problems are commonly present in patients with brain tumors. Other medical complications, such as seizures, headache, and dysphagia are also common. An individualized multidisciplinary rehabilitation intervention is necessary to treat functional impairment due to the tumor itself andor treatment-related dysfunction. Herein, we discuss rehabilitation treatment strategies in relation to the neurological and functional complications that commonly occur in patients with brain tumors.

HER2-positive metastatic breast cancer with brain metastases responds favorably to pyrotinib and trastuzumab-based treatment A case report and literature review.

For HER2-positive metastatic breast cancer patients with the brain involved at initial diagnosis, there was no standard regimen before 2022 when the HER2CLIMB trial published its final overall survival analysis, and the prognosis is relatively poor under the current treatment strategy. We herein reported a case of a female patient who was initially diagnosed with HER2-positive metastatic breast cancer with brain metastases, receiving pyrotinib and trastuzumab-based systematic therapy after palliative craniocerebral radiotherapy as the first-line systematic therapy. During the treatment, the tumor lesions showed obvious regression, and chemotherapy drugs were gradually removed from the regimen. The patient continued receiving trastuzumab and pyrotinib for HER2-targeted therapy. She had achieved more than 26 months of progression-free survival and the disease was stable during the evaluation in April 2022. Radiotherapy followed by dual HER2-targeted therapy of macromolecular monoclonal antibodies trastuzumab and micromolecular TKI pyrotinib plus chemotherapy could be an alternative option for this subtype of patients and need to be further verified by future clinical trials.

The efficacy of preoperative MRI features in the diagnosis of meningioma WHO grade and brain invasion.

The preoperative MRI scans of meningiomas were analyzed based on the 2021 World Health Organization (WHO) Central Nervous System (CNS) Guidelines, and the efficacy of MRI features in diagnosing WHO grades and brain invasion was analyzed. The data of 675 patients with meningioma who underwent MRI in our hospital from 2006 to 2022, including 108 with brain invasion, were retrospectively analyzed. Referring to the WHO Guidelines for the Classification of Central Nervous System Tumors (Fifth Edition 2021), 17 features were analyzed, with age, sex and meningioma MRI features as risk factors for evaluating WHO grade and brain invasion. The risk factors were identified through multivariable logistic regression analysis, and their receiver operating characteristic (ROC) curves for predicting WHO grades and brain invasion were generated, and the area under the curve (AUC), sensitivity and specificity were calculated. Univariate analysis showed that sex, tumor size, lobulated sign, peritumoral edema, vascular flow void, bone invasion, tumor-brain interface, finger-like protrusion and mushroom sign were significant for diagnosing meningioma WHO grades, while these features and ADC value were significant for predicting brain invasion (P < 0.05). Multivariable logistic regression analysis showed that the lobulated sign, tumor-brain interface, finger-like protrusion, mushroom sign and bone invasion were independent risk factors for diagnosing meningioma WHO grades, while the above features, tumor size and ADC value were independent risk factors for diagnosing brain invasion (P < 0.05). The tumor-brain interface had the highest efficacy in evaluating WHO grade and brain invasion, with AUCs of 0.779 and 0.860, respectively. Combined, the variables had AUCs of 0.834 and 0.935 for determining WHO grade and brain invasion, respectively. Preoperative MRI has excellent performance in diagnosing meningioma WHO grade and brain invasion, while the tumor-brain interface serves as a key factor. The preoperative MRI characteristics of meningioma can help predict WHO grade and brain invasion, thus facilitating complete lesion resection and improving patient prognosis.

Circulating exosomal immuno-oncological checkpoints and cytokines are potential biomarkers to monitor tumor response to anti-PD-1PD-L1 therapy in non-small cell lung cancer patients.

Immune checkpoint inhibitors (ICIs) including anti-PD-1 and anti-PD-L1 antibodies, have significantly changed the treatment outcomes of NSCLC patients with better overall survival. However, 15-40% of the patients still fail to respond to ICIs therapy. Identification of biomarkers associated with responses are mandated in order to increase the efficacy of such therapy. In this study we evaluated 27 serum-derived exosomal immuno-oncological proteins and 44 cytokineschemokines before and after ICIs therapy in 17 NSCLC patients to identify surrogate biomarkers for treatmentmonitoring patient stratification for maximum therapeutic benefit. We first confirmed the identity of the isolated exosomes to have their specific markers (CD63, CD81, HSP70 and CD91). We have demonstrated that baseline concentration of exosomal-PD-L1 (p<0.0001), exosomal-PD-L2 (p0.0413) and exosomal-PD-1 (p0.0131) from NSCLC patients were significantly higher than their soluble-free forms. Furthermore, the exosomal-PD-L1 was present in all the patients (100%), while only 71% of patients expressed tissue PD-L1. This indicates that exosomal-PD-L1 is a more reliable diagnostic biomarker. Interestingly, exosomal-PD-L2 expression was significantly higher (p0.0193) in tissue PD-L1-negative patients compared to tissue PD-L1-positive patients. We have also shown that immuno-oncological proteins isolated from pre-ICIs treated patients were significantly higher in exosomes compared to their soluble-free counterparts (CD152, p0.0008 CD80, p0.0182 IDO, p0.0443 Arginase, p<0.0001 Nectin-2, p<0.0001 NT5E, p<0.0001 Siglec-7, p<0.0001 Siglec-9, p0.0335 CD28, p0.0092 GITR, p<0.0001 MICA, p<0.0001). Finally, the changes in the expression levels of exosomal immuno-oncological proteinscytokines and their correlation with tumor response to ICIs treatment were assessed. There was a significant downregulation of exosomal PD-L1 (p0.0156), E-Cadherin (p0.0312), ULBP1 (p0.0156), ULBP3 (p0.0391), MICA (p0.0391), MICB (p0.0469), Siglec7 (p0.0078) and significant upregulation of exosomal PD-1 (p0.0156) and IFN- γ (p0.0156) in responding patients. Non-responding patients showed a significant increase in exosomal-PD-L1 (p0.0078). Furthermore, responding-patients without liver-metastasis showed significant-upregulation of PD-1 (p0.0070), and downregulation of ULBP1 (p0.0137) and Siglec-7 (p0.0037). Non-responding patients had significant-downregulation of ULBP3 (p0.0317) in patient without brain-metastasis and significant-upregulationdownregulation of PD-L1 and ULBP3 (p0.02620.0286) in patients with pulmonary-metastasis. We demonstrated for the first time that exosomal immuno-oncological proteinscytokines are potential biomarkers to monitor response to ICIs therapy and can predict the clinical outcomes in NSCLC patients.

Limitations of radiosensitization by direct telomerase inhibition to treat high-risk medulloblastoma.

Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Previous studies have elucidated the genomic landscape of MB leading to the recognition of four core molecular subgroups (WNT, SHH, group 3 and group 4) with distinct clinical outcomes. Group 3 has the worst prognosis of all MB. Radiotherapy (RT) remains a major component in the treatment of poor prognosis MB but is rarely curative alone and is associated with acute and long-term toxicities. A hallmark of cancer cells is their unlimited proliferative potential which correlates closely with telomere length. The vast majority of malignant tumors activate telomerase to maintain telomere length, whereas this activity is barely detectable in most normal human somatic tissues, making telomerase inhibition a rational therapeutic target in the setting of cancer recurrence and therapy resistance. We and others have previously shown that short telomeres confer sensitivity to ionizing radiation (IR) suggesting that telomerase inhibition mediated telomere shortening will improve the efficacy of RT while minimizing its side effects. Here, we investigated the efficacy of the combination of IR with IMT, a potent telomerase inhibitor, in an

A whole-genome scan for Artemisinin cytotoxicity reveals a novel therapy for human brain tumors.

The natural compound Artemisinin is the most widely used antimalarial drug worldwide. Based on its cytotoxicity, it is also used for anticancer therapy. Artemisinin and its derivates are endoperoxides that damage proteins in eukaryotic cells their definite mechanism of action and host cell targets, however, have remained largely elusive. Using yeast and haploid stem cell screening, we demonstrate that a single cellular pathway, namely porphyrin (heme) biosynthesis, is required for the cytotoxicity of Artemisinins. Genetic or pharmacological modulation of porphyrin production is sufficient to alter its cytotoxicity in eukaryotic cells. Using multiple model systems of human brain tumor development, such as cerebral glioblastoma organoids, and patient-derived tumor spheroids, we sensitize cancer cells to dihydroartemisinin using the clinically approved porphyrin enhancer and surgical fluorescence marker 5-aminolevulinic acid, 5-ALA. A combination treatment of Artemisinins and 5-ALA markedly and specifically killed brain tumor cells in all model systems tested, including orthotopic patient-derived xenografts in vivo. These data uncover the critical molecular pathway for Artemisinin cytotoxicity and a sensitization strategy to treat different brain tumors, including drug-resistant human glioblastomas.

Ring finger protein 10 improves pirarubicin-induced cardiac inflammation by regulating the AP-1Meox2 signaling pathway.

Pirarubicin (THP) is widely used in clinical antitumor therapy, but its cardiotoxicity seriously affects the therapeutic effect in patients. In the study, we investigated the role of ring finger protein 10 (RNF10) in cardiotoxicity induced by THP. A cardiac toxicity model in Sprague-Dawley (SD) rats induced by THP was established. Changes in diet, weight, electrocardiogram (ECG), and echocardiography were observed. Serum levels of brain natriuretic peptide (BNP), creatine kinase MB (CK-MB), cardiac troponin T (cTnT), and lactate dehydrogenase (LDH) were measured. The expression of RNF10 in myocardium was observed by immunohistochemistry. The expressions of RNF10, activator protein-1 (AP-1), mesenchyme homeobox 2 (Meox2), total nuclear factor (NF)-κB p65 (T-P65), phosphorylated NF-κB p65 (PP65), monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor (TNF)-α, interleukin (IL)-6, and mature IL-1β were detected by Western blot. A THP-induced H9c2 myocardial cell injury model was established. RNF10 was downregulated or overexpressed by RNF10 siRNA and a RNF10 lentiviral vector, respectively. Then, cell viability was measured. The expression of RNF10 in H9c2 cells was observed by immunofluorescence. All of the above signaling pathways were verified by Western blots. THP caused a series of cardiotoxic manifestations in SD rats. Our studies suggested that THP caused cardiac inflammation by inhibiting the expression of RNF10, while overexpression of RNF10 antagonized the cardiotoxicity induced by THP. Our study showed RNF10 improved THP-induced cardiac inflammation by regulating the AP-1Meox2 signaling pathway. RNF10 may be a new target to treat THP-induced cardiotoxicity.

Antiplatelet medications and intracranial hemorrhage in patients with primary brain tumors.

Spontaneous intracranial hemorrhage (ICH) is a frequent and severe consequence of primary brain tumors. The safety of antiplatelet medications in this patient population is undefined. The primary objective was to determine whether antiplatelet medications are associated with an increased risk of ICH in patients with primary brain tumors. We performed a matched, retrospective cohort study of patients with the diagnosis of primary brain tumor treated at our institution between 2010 and 2021. Radiographic images of all potential ICH events underwent blinded review. The primary end point of the study was the cumulative incidence of ICH at 1 year after tumor diagnosis. A total of 387 patients with primary brain tumors were included in the study population (130 exposed to antiplatelet agents, 257 not exposed). The most common malignancy was glioblastoma (n256, 66.1%). Among the intervention cohort, 119 patients received aspirin monotherapy. The cumulative incidence of any ICH at 1 year was 11.0% (95% confidence interval CI, 5.3 - 16.6) in those receiving antiplatelet medications and 13.0% (95% CI, 8.5 - 17.6) in those not receiving antiplatelet medications (Gray test p 0.6). The cumulative incidence of major ICH was similar between the cohorts (3.3% in antiplatelet cohort vs 2.9% in control cohort, p 1.0). This study did not observe an increased incidence of ICH in patients with primary brain tumors exposed to antiplatelet medications.

Intracranial nanomedicine-gel with deep brain-penetration for glioblastoma therapy.

Glioblastoma Multiforme (GBM) is one of the challenging tumors to treat as it recurs, almost 100%, even after surgery, radiation, and chemotherapy. In many cases, recurrence happens within 2-3cm depth of the resected tumor margin, indicating the inefficacy of current anti-glioma drugs to penetrate deep into the brain tissue. Here, we report an injectable nanoparticle-gel system, capable of providing deep brain penetration of drug up to 4 cm, releasing in a sustained manner up to >15 days. The system consists of ∼222 nm sized PLGA nanoparticles (NP-222) loaded with an anti-glioma drug, Carmustine (BCNU), and coated with a thick layer of polyethylene glycol (PEG). Upon release of the drug from PLGA core, it will interact with the outer PEG-layer leading to the formation of PEG-BCNU nanocomplexes of size ∼33 nm (BCNU-NC-33), which could penetrate >4 cm deep into the brain tissue compared to the free drug (< 5 mm). In vitro drug release showed sustained release of drug for 15 days by BCNU-NP gel, and enhanced cytotoxicity by BCNU-NC-33 drug-nanocomplexes in glioma cell lines. Ex vivo goat-brain phantom studies showed drug diffusion up to 4 cm in tissue and in vivo brain-diffusion studies showed almost complete coverage within the rat brain (∼1.2 cm), with ∼55% drug retained in the tissue by day-15, compared to only ∼5% for free BCNU. Rat orthotopic glioma studies showed excellent anti-tumor efficacy by BCNU-NP gel compared to free drug, indicating the potential of the gel-system for anti-glioma therapy. In effect, we demonstrate a unique method of sustained release of drug in the brain using larger PLGA nanoparticles acting as a reservoir while deep-penetration of the released drug was achieved by in situ formation of drug-nanocomplexes of size <50 nm which is less than the native pore size of brain tissue (> 100 nm). This method will have a major impact on a challenging field of brain drug delivery.

Germline TP53 pathogenic variants and breast cancer A narrative review.

Approximately 10% of breast cancers are associated with the inheritance of a pathogenic variant (PV) in one of the breast cancer susceptibility genes. Multiple breast cancer predisposing genes, including TP53, are responsible for the increased breast cancer risk. Tumor protein-53 (TP53) germline PVs are associated with Li-Fraumeni syndrome, a rare autosomal dominant inherited cancer predisposition syndrome associated with early-onset pediatric and multiple primary cancers such as soft tissue and bone sarcomas, breast cancer, brain tumors, adrenocortical carcinomas and leukemias. Women harboring a TP53 PV carry a lifetime risk of developing breast cancer of 80-90%. The aim of the present narrative review is to provide a comprehensive overview of the criteria for offering TP53 testing, prevalence of TP53 carriers among patients with breast cancer, and what is known about its prognostic and therapeutic implications. A summary of the current indications of secondary cancer surveillance and survivorship issues are also provided. Finally, the spectrum of TP53 alteration and testing is discussed. The optimal strategies for the treatment of breast cancer in patients harboring TP53 PVs poses certain challenges. Current guidelines favor the option of performing mastectomy rather than lumpectomy to avoid adjuvant radiotherapy and subsequent risk of radiation-induced second primary malignancies, with careful consideration of radiation when indicated post-mastectomy. Some studies suggest that patients with breast cancer and germline TP53 PV might have worse survival outcomes compared to patients with breast cancer and wild type germline TP53 status. Annual breast magnetic resonance imaging (MRI) and whole-body MRI are recommended as secondary prevention.

Predictors and trajectories of fear of cancer recurrence in Chinese breast cancer patients.

Fear of cancer recurrence (FCR) is one of the most common and aversive psychological phenomena among cancer patients. This study explored the trajectories of FCR over the 18 months following discharge, and evaluated the associations between baseline demographic and clinical variables and FCR trajectories among Chinese women treated for breast cancer. This is a longitudinal prospective study. All participants were asked to completed a battery of questionnaires (FCR-7, PHQ-9, GAD-7 and MPQ-VAS) at baseline, 6, 12, and 18 months after discharge. Generalized linear mixed model and group-based trajectory analyses were conducted. Three hundred women with breast cancer were recruited. Latent class growth modeling analysis showed that three-group trajectory solution was the best fitting (i.e., intermediate level-stable group (63.3%), low level-increasing group (18.3%), and high level-decreasing group (18.3%). Patients reported significant higher FCR at baseline assessment compared to other time points. Significant positive associations were found between anxiety, depression and FCR. Patients who had no baseline depression (estimate -2.14, 95% CI -2.78-(-1.51), P < 0.001) or anxiety (estimate -2.77, 95% CI -3.44-(-2.10), P < 0.001) tended to report significant lower FCRs over time. Women with nonemild life stress exhibited significant lower FCRs than those with moderatehigh life stress, and participants with a family history of cancer or pessimism reported higher FCRs. >60% of the breast cancer women showed intermediate level-stable FCRs over the 18 months after discharge. Baseline anxiety, depression, life stress, family cancer history and pessimism predicts higher FCR levels. Clinical teams responsible for continuing patient care following treatment should develop clearer strategies for management of FCR.

Longitudinal DNA methylation analysis of adult-type IDH-mutant gliomas.

Diffuse gliomas are the most prevalent malignant primary brain tumors in adults and remain incurable despite standard therapy. Tumor recurrence is currently inevitable, which contributes to a persistent high morbidity and mortality in these patients. In this study, we examined the genome-wide DNA methylation profiles of primary and recurrent adult-type IDH-mutant gliomas to elucidate DNA methylation changes associated with tumor progression (with or without malignant transformation). We analyzed DNA methylation profiles of 37 primary IDH-mutant gliomas and 42 paired recurrences using the DNA methylation EPIC beadChip array. DNA methylation-based classification reflected the tumor progression over time. We observed a methylation subtype switch in a proportion of IDH-mutant astrocytomas the primary tumors were subclassified as low-grade astrocytomas, which progressed to high-grade astrocytomas in the recurrent tumors. The CNS WHO grade 4 IDH-mutant astrocytomas did not always resemble methylation subclasses of higher grades. The number of differentially methylated CpG sites increased over time, and astrocytomas accumulated more differentially methylated CpG sites than oligodendrogliomas during tumor progression. Few differentially methylated CpG sites were shared between patients. We demonstrated that DNA methylation profiles are mostly maintained during IDH-mutant glioma progression, but CpG site-specific methylation alterations can occur.

Conductive and elastic bottlebrush elastomers for ultrasoft electronics.

Understanding biological systems and mimicking their functions require electronic tools that can interact with biological tissues with matched softness. These tools involve biointerfacing materials that should concurrently match the softness of biological tissue and exhibit suitable electrical conductivities for recording and reading bioelectronic signals. However, commonly employed intrinsically soft and stretchable materials usually contain solvents that limit stability for long-term use or possess low electronic conductivity. To date, an ultrasoft (i.e., Youngs modulus <30 kPa), conductive, and solvent-free elastomer does not exist. Additionally, integrating such ultrasoft and conductive materials into electronic devices is poorly explored. This article reports a solvent-free, ultrasoft and conductive PDMS bottlebrush elastomer (BBE) composite with single-wall carbon nanotubes (SWCNTs) as conductive fillers. The conductive SWCNTBBE with a filler concentration of 0.4 - 0.6 wt% reveals an ultralow Youngs modulus (<11 kPa) and satisfactory conductivity (>2 Sm) as well as adhesion property. Furthermore, we fabricate ultrasoft electronics based on laser cutting and 3D printing of conductive and non-conductive BBEs and demonstrate their potential applications in wearable sensing, soft robotics, and electrophysiological recording.

Acoustofluidic assembly of primary tumor-derived organotypic cell clusters for rapid evaluation of cancer immunotherapy.

Cancer immunotherapy shows promising potential for treating breast cancer. While patients may have heterogeneous treatment responses for adjuvant therapy, it is challenging to predict an individual patients response to cancer immunotherapy. Here, we report primary tumor-derived organotypic cell clusters (POCCs) for rapid and reliable evaluation of cancer immunotherapy. By using a label-free, contactless, and highly biocompatible acoustofluidic method, hundreds of cell clusters could be assembled from patient primary breast tumor dissociation within 2 min. Through the incorporation of time-lapse living cell imaging, the POCCs could faithfully recapitulate the cancer-immune interaction dynamics as well as their response to checkpoint inhibitors. Superior to current tumor organoids that usually take more than two weeks to develop, the POCCs can be established and used for evaluation of cancer immunotherapy within 12 h. The POCCs can preserve the cell components from the primary tumor due to the short culture time. Moreover, the POCCs can be assembled with uniform fabricate size and cell composition and served as an open platform for manipulating cell composition and ratio under controlled treatment conditions with a short turnaround time. Thus, we provide a new method to identify potentially immunogenic breast tumors and test immunotherapy, promoting personalized cancer therapy.

Impact of GAP-43, Cx43 and actin expression on the outcome and overall survival in diffuse and anaplastic gliomas.

Distant intercellular communication in gliomas is based on the expansion of tumor microtubuli, where actin forms cytoskeleton and GAP-43 mediates the axonal conus growth. We aimed to investigate the impact of GAP-43 and actin expression on overall survival (OS) as well as crucial prognostic factors. FFPE tissue of adult patients with diffuse and anaplastic gliomas, who underwent first surgery in our center between 2010 and 2019, were selected. GAP-43, Cx43 and actin expression was analyzed using immunohistochemistry and semi-quantitatively ranked. 118 patients with a median age of 46 years (IqR 35-57) were evaluated. 48 (41%) presented with a diffuse glioma and 70 (59%) revealed anaplasia. Tumors with higher expression of GAP-43 (p 0.024, HR 1.71rank) and actin (p < 0.001, HR 2.28rank) showed significantly reduced OS. IDH1 wildtype glioma demonstrated significantly more expression of all proteins GAP-43 (p 0.009), Cx43 (p 0.003) and actin (p < 0.001). The same was confirmed for anaplasia (GAP-43 p 0.028, actin p 0.029), higher proliferation rate (GAP-43 p 0.016, actin p 0.038), contrast-enhancement in MRI (GAP-43 p 0.023, actin p 0.037) and age (GAP-43 p 0.004, actin p < 0.001 Cx43 n.s. in all groups). The intercellular distant communication network in diffuse and anaplastic gliomas formed by actin and GAP-43 is associated with a negative impact on overall survival and with unfavorable prognostic features. Cx43 did not show relevant impact on OS.

Systematic review of meningiomas revealed by spontaneous intracranial hemorrhage clinicopathological features, outcomes and rebleeding rate.

Meningiomas are rarely revealed by an intracranial hemorrhage (ICH). Rebleeding occurrence rate and time of onset are unknown. Here we performed a systematic review of the literature of meningiomas revealed by ICH. We retrospectively collected all meningiomas revealed by spontaneous intracranial hemorrhage published between January 1980 and December 2021. We reported clinicopathological features of meningiomas revealed by ICH. We also estimated rebleeding rate and time to onset. 92 studies met all inclusion criteria led to a total of 120 cases. Mean age was 56.3 years, with 66 (55%) female. 79 (66%) cases were conscious before surgery, 20 (17%) were in coma and 17 (14%) were unconscious after deterioration. The most frequent bleeding type were subdural hemorrhage (N 49, 41%) followed by intraparenchymal hemorrhage (IPH) (N 44, 37%), Subarachnoid hemorrhage (SAH) (N 22, 18%) and intraventricular hemorrhage (IVH) (N 5, 4%). IPH and Hindbrainventricular locations are associated with poor outcome (p 0.031 and < 0.001 respectively). Among the 19 patients who did not undergo surgical resection of the meningioma, 14 (74%) experienced rebleeding with a median occurrence of 120 days (IQ 90 -). Rebleeding occurs earlier if type of bleeding is SAH or IVH and for hindbrain location (both p < 0.01). Intracranial hemorrhage is a rare presentation of meningiomas. Hindbrain and ventricular tumor location and IPH are associated with poor outcome. Rebleeding rate is high and premature. It occurs earlier if the first bleeding was SAH or IVH and for hindbrain location.

Efficacy and safety of early anti-inflammatory drug therapy for secondary injury in traumatic brain injury.

Brain injury following head trauma occurs in two stages, namely an early stage attributable to mechanical damage and a delayed stage resulting primarily from neuroinflammation. In this study, we examined early pro-inflammatory cytokine upregulation in an animal model of traumatic brain injury (TBI) and examined the effects of early anti-inflammatory therapy on neuroinflammation, neuropathology, and systemic inflammatory activity. Seven-week-old C24BL6 mice (20-25 g) were subjected to sham treatment or closed skull impact from a 30-g round weight dropped 15 cm onto the cortical midpoint. Model mice were then randomly assigned to receive intraperitoneal phosphate-buffered saline (control), 20 mgkg cyclosporine A (CsA), 2 mgkg dexamethasone, or 5 mgkg cholecalciferol 1 h post-TBI. Body weight, brain weight, cytokine expression in the brain and draining lymph nodes (DLNs), and histopathological changes were measured at multiple times post-TBI. Body weight did not significantly differ among the groups, whereas the brain-to-body weight ratio was significantly lower in the control group 7 days post-TBI. The peak expression of tumor necrosis factor-α, interleukin (IL)-1β, and IL-6 in the brain and DLNs 6 h post-TBI was significantly lower in the dexamethasone and CsA groups. Conversely, peak IL-10 expression in the brain and DLNs was elevated in the cholecalciferol group. Control mice exhibited earlier and more severe neuroinflammatory damage than those in the experimental groups. The administration of anti-inflammatory drugs or vitamin D analogs in the early period following TBI might help to reduce secondary injury from neuroinflammation.

ProBDNF signaling is involved in periodontitis-induced depression-like behavior in mouse hippocampus.

Increasing evidence supports the association between periodontitis and depression. However, the specific mechanisms remain to be further elucidated. The present study aimed to mechanistically investigate the regional roles of proBDNF (the precursor of brain-derived neurotrophic factor) in periodontitis induced depression-like behavior in mice. Experimental periodontitis model was established by periodontal injection of Porphyromonas gingivalis lipopolysaccharide (Pg-LPS) in 8-week-old male Bdnf-HAHA mice for 3 weeks. The depression-like behaviors, spontaneous exploratory activity and the level of anxiety were assessed by behavior tests. The activation of microglia and astrocytes, as well as the expression of Interleukin (IL)-1β and Tumor necrosis factor (TNF)-α in the hippocampus, prefrontal cortex, and cortex were further assessed by immunofluorescence and western blots. The levels of IL-1β in blood serum and expression of occludin as well as claudin5 in the hippocampus, prefrontal cortex, and cortex were further determined by enzyme-linked immunosorbent assay and western blot. Finally, the expression of proBDNF, its receptors, and mature BDNF (mBDNF), as well as neuronal activity were measured by western blots and immunofluorescence. Pg-LPS successfully induced periodontitis in mice and caused obvious depression-like behavior. Furthermore, we observed an increased activation of astrocytes and microglia, as well as a significant increase in expression of IL-1β and TNF-α in the hippocampus of mice treated with Pg-LPS, with elevated level of IL-1β in serum and decreased expression of occludin and claudin5 in the hippocampus. Importantly, we found that the levels of proBDNF and its receptors, SorCS2 and p75NTR, were increased significantly however, the level of mBDNF was decreased, therefor leading to greater ratio of proBDNFmBDNF. In addition, we also detected decreased neuronal activity in the hippocampus of mice treated with Pg-LPS. Our results indicate that Pg-LPS-induced periodontitis could cause depression-like behaviors in mice, and the proBDNF signaling is involved in the process.

PyRaDiSe A Python package for DICOM-RT-based auto-segmentation pipeline construction and DICOM-RT data conversion.

Despite fast evolution cycles in deep learning methodologies for medical imaging in radiotherapy, auto-segmentation solutions rarely run in clinics due to the lack of open-source frameworks feasible for processing DICOM RT Structure Sets. Besides this shortage, available open-source DICOM RT Structure Set converters rely exclusively on 2D reconstruction approaches leading to pixelated contours with potentially low acceptance by healthcare professionals. PyRaDiSe, an open-source, deep learning framework independent Python package, addresses these issues by providing a framework for building auto-segmentation solutions feasible to operate directly on DICOM data. In addition, PyRaDiSe provides profound DICOM RT Structure Set conversion and processing capabilities thus, it applies also to auto-segmentation-related tasks, such as dataset construction for deep learning model training. The PyRaDiSe package follows a holistic approach and provides DICOM data handling, deep learning model inference, pre-processing, and post-processing functionalities. The DICOM data handling allows for highly automated and flexible handling of DICOM image series, DICOM RT Structure Sets, and DICOM registrations, including 2D-based and 3D-based conversion from and to DICOM RT Structure Sets. For deep learning model inference, extending given skeleton classes is straightforwardly achieved, allowing for employing any deep learning framework. Furthermore, a profound set of pre-processing and post-processing routines is included that incorporate partial invertibility for restoring spatial properties, such as image origin or orientation. The PyRaDiSe package, characterized by its flexibility and automated routines, allows for fast deployment and prototyping, reducing efforts for auto-segmentation pipeline implementation. Furthermore, while deep learning model inference is independent of the deep learning framework, it can easily be integrated into famous deep learning frameworks such as PyTorch or Tensorflow. The developed package has successfully demonstrated its capabilities in a research project at our institution for organs-at-risk segmentation in brain tumor patients. Furthermore, PyRaDiSe has shown its conversion performance for dataset construction. The PyRaDiSe package closes the gap between data science and clinical radiotherapy by enabling deep learning segmentation models to be easily transferred into clinical research practice. PyRaDiSe is available on httpsgithub.comubern-miapyradise and can be installed directly from the Python Package Index using pip install pyradise.

Interpretable features fusion with precision MRI images deep hashing for brain tumor detection.

Brain tumor is a deadly disease that can affect people of all ages. Radiologists play a critical role in the early diagnosis and treatment of the 14,000 persons diagnosed with brain tumors on average each year. The best method for tumor detection with computer-aided diagnosis systems (CADs) is Magnetic Resonance Imaging (MRI). However, manual evaluation using conventional approaches may result in a number of inaccuracies due to the complicated tissue properties of a large number of images. Therefore a precision medical image hashing approach is proposed that combines interpretability and feature fusion using MRI images of brain tumors, to address the issue of medical image retrieval. A precision hashing method combining interpretability and feature fusion is proposed to recover the problem of low image resolutions in brain tumor detection on the Brain-Tumor-MRI (BT-MRI) dataset. First, the dataset is pre-trained with the DenseNet201 network using the Comparison-to-Learn method. Then, a global network is created that generates the salience map to yield a mask crop with local region discrimination. Finally, the local network features inputs and public features expressing the local discriminant regions are concatenated for the pooling layer. A hash layer is added between the fully connected layer and the classification layer of the backbone network to generate high-quality hash codes. The final result is obtained by calculating the hash codes with the similarity metric. Experimental results with the BT-MRI dataset showed that the proposed method can effectively identify tumor regions and more accurate hash codes can be generated by using the three loss functions in feature fusion. It has been demonstrated that the accuracy of medical image retrieval is effectively increased when our method is compared with existing image retrieval approaches. Our method has demonstrated that the accuracy of medical image retrieval can be effectively increased and potentially applied to CADs.

Noninvasively evaluating the grade and IDH mutation status of gliomas by using mono-exponential, bi-exponential diffusion-weighted imaging and three-dimensional pseudo-continuous arterial spin labeling.

To noninvasively assess the diagnostic performance of diffusion-weighted imaging (DWI), bi-exponential intravoxel incoherent motion imaging (IVIM) and three-dimensional pseudo-continuous arterial spin labeling (3D pCASL) in differentiating lower-grade gliomas (LGGs) from high-grade gliomas (HGGs), and predicting the isocitrate dehydrogenase (IDH) mutation status. Ninety-five patients with pathologically confirmed grade 2-4 gliomas with preoperative DWI, IVIM and 3D pCASL were enrolled in this study. The Students t test and Mann-Whitney U test were used to evaluate differences in parameters of DWI, IVIM and 3D pCASL between LGG and HGG as well as between mutant and wild-type IDH in grade 2 and 3 diffusion astrocytoma receiver operator characteristic (ROC) analysis was used to assess the diagnostic performance. The value of ADC The combination of IVIM and 3D pCASL can be used in prediction histologic grade and IDH mutation status of glioma noninvasively.

Indigenous peoples and inclusion in clinical and genomic research Understanding the history and navigating contemporary engagement.

Despite significant improvements in pediatric cancer survival outcomes, there remain glaring disparities in under-represented racial and ethnic groups that warrant mitigation by the scientific and clinical community. To address and work towards eliminating such disparities, the Pacific Pediatric Neuro-Oncology Consortium (PNOC) and Childrens Brain Tumor Network (CBTN) established a Diversity, Equity, and Inclusion (DEI) working group in 2020. The DEI working group is dedicated to improving access to care for all pediatric patients with central nervous system (CNS) tumors, broadening diversity within the research community, and providing sustainable data-driven solutions. To this end, the DEI working group aims to coordinate regular educational sessions centered on critical DEI topics in pediatric research and clinical care of pediatric patients, with a focus on pediatric neuro-oncology. In April 2022, the group led a moderated panel of experts on Indigenous Peoples rights and participation in clinical research activities. The following paper serves to provide the scientific community a perspective on how to prioritize the inclusion of Indigenous Peoples in research with cultural sensitivity and with the intent of improving not only representation, but patient outcomes regardless of patient race, ethnicity, or socioeconomic background.

Dynamics of cachexia-associated inflammatory changes in the brain accompanying intra-abdominal fibrosarcoma growth in Wistar rats.

Accumulated data indicate that inflammation affecting brain structures participates in the development of cancer-related cachexia. However, the mechanisms responsible for the induction and progression of cancer-related neuroinflammation are still not fully understood. Therefore, we studied the time-course of neuroinflammation in selected brain structures and cachexia development in tumor-bearing rats. After tumor cells inoculation, specifically on the 7th, 14th, 21st, and 28th day of tumor growth, we assessed the presence of cancer-associated cachexia in rats. Changes in gene expression of inflammatory factors were studied in selected regions of the hypothalamus, brain stem, and circumventricular organs. We showed that the initial stages of cancer growth (7th and 14th day after tumor cells inoculation), are not associated with cachexia, or increased expression of inflammatory molecules in the brain. Even when we did not detect cachexia in tumor-bearing rats by the 21st day of the experiment, the inflammatory brain reaction had already started, as we found elevated levels of interleukin 1 beta, interleukin 6, tumor necrosis factor alpha, and glial fibrillary acidic protein mRNA levels in the nucleus of the solitary tract. Furthermore, we found increased interleukin 1 beta expression in the locus coeruleus and higher allograft inflammatory factor 1 expression in the vascular organ of lamina terminalis. Ultimately, the most pronounced manifestations of tumor growth were present on the 28th day post-inoculation of tumor cells. In these animals, we detected cancer-related cachexia and significant increases in interleukin 1 beta expression in all brain areas studied. We also observed significantly decreased expression of the glial cell activation markers allograft inflammatory factor 1 and glial fibrillary acidic protein in most brain areas of cachectic rats. In addition, we showed increased expression of cluster of differentiation 163 and cyclooxygenase 2 mRNA in the hypothalamic paraventricular nucleus, A1C1 neurons, and area postrema of cachectic rats. Our data indicate that cancer-related cachexia is associated with complex neuroinflammatory changes in the brain. These changes can be found in both hypothalamic as well as extrahypothalamic structures, while their extent and character depend on the stage of tumor growth.

Translationally controlled tumor protein restores impaired memory and altered synaptic protein expression in animal models of dementia.

This study describes the effects of translationally controlled tumor protein (TCTP) on mice with memory impairment caused by scopolamine (SCO) administration. Specifically, memory functions and expression levels of hippocampal synaptic proteins in 7- to 12-month-old SCO-treated wild-type (WT-SCO) mice were compared to those of TCTP-overexpressing (TG) and TCTP knocked-down (KD) mice similarly treated with SCO. Passive-avoidance tasks were performed with WT, TG, and KD mice for four weeks after intraperitoneal injection of SCO or saline followed by an acquisition test. After completing behavioral studies, hippocampi of all mice groups were collected and their synaptic protein contents were subjected to Western blotting or immunohistochemical analyses, and compared with those of 5x familial Alzheimers disease (5xFAD) mice and postmortem AD patients. Results of passive avoidance tests revealed that SCO-induced memory impairment was repaired in TCTP-TG mice, but not in TCTP-KD mice. Hippocampal expression levels of synaptophysin, synapsin-1, and PSD-95 were increased in TCTP-TG mice treated with SCO (TG-SCO) but decreased in TCTP-KD mice treated with SCO (KD-SCO). Decreased levels of TCTP, synaptophysin, and PSD-95 were also found in hippocampi of 5xFAD mice and AD patients. Expression levels of p-CREBCREB and brain-derived neurotrophic factor (BDNF) in TCTP-TG and TG-SCO mice were similar to or increased compared to those in WT mice, but decreased in TCTP-KD and KD-SCO mice. BDNF immunoreactivity was restored in CA1 regions of hippocampi of TG-SCO mice, but not in KD-SCO mice. These results suggest that TCTP can restore damaged memory in mice possibly through restored synaptic protein expression.

Secondary dystonia following parenchymal brain tumors.

Secondary dystonia has been associated with diverse etiologies. Dystonia associated with brain tumors has not been well characterized. To characterize dystonia and relationship with parenchymal brain tumors. We present six patients (1.03%) with dystonia related to parenchymal brain tumors, among 580 screened cases. Contralateral hemidystonia was observed in four cases, followed by focal limb (n 1) and cervical dystonia (n 1). Dystonia presented during the phase of tumor growth in four cases, and following tumor treatment in two, one case had re-emergent dystonia. Tumors were low-grade (WHO I or II) and located in the basal ganglia (n 3), cortical areas (n 2), thalamus (n 1) and cerebral peduncle (n 1). Secondary dystonia may be caused by brain tumors in diverse locations including basal ganglia, cortex and thalamus. It may be the presenting symptom of brain tumor or follow surgical resection combined with ancillary therapy.

Neurosurgical management of proton beam therapy-induced moyamoya syndrome.

Proton beam therapy (PBT) is an increasingly used treatment modality for pediatric patients with brain tumors. Moyamoya syndrome (MMS) is well recognized as a complication of traditional photon radiotherapy, however its association with PBT is less well described. The authors discuss their initial experience with the neurosurgical management of MMS secondary to PBT in a large-volume pediatric neurovascular service. The authors performed a retrospective case review of consecutive children referred for neurosurgical management of MMS after PBT between 2009 and 2022. Patient demographic characteristics, oncological history and treatment, interval between PBT and MMS diagnosis, and MMS management were recorded. Clinical outcome at last review was classified as good if the modified Rankin Scale (mRS) score was ≤ 2 andor the patient attended mainstream education without additional assistance. Poor outcome was defined as mRS score ≥ 3 andor the patient received additional educational support. The recorded radiological outcomes included angiographic analysis of stenosis, evidence of brain ischemiainfarction on MRI, and postsurgical angiographic revascularization. Ten patients were identified. Oncological diagnosis included craniopharyngioma (n 6), optic pathway glioma (1), ependymoma (1), Ewing sarcoma (1), and rhabdosarcoma (1). The median (interquartile range IQR) age at PBT was 5.1 (2.7-7.9) years. The median (IQR) age at MMS diagnosis was 7.8 (5.7-9.3) years. The median time between PBT and diagnosis of MMS was 20 (15-41) months. Six patients had poor functional status after initial oncological treatment and prior to diagnosis of MMS. All 10 patients had endocrine dysfunction, 8 had visual impairment, and 4 had behavioral issues prior to MMS diagnosis. Four patients had a perioperative ischemic event 2 after tumor surgery, 1 after MMS surgical revascularization, and 1 after receiving a general anesthetic for an MRI scan during oncological surveillance. Seven children were treated with surgical revascularization, whereas 3 were managed medically. The incidence of ischemic events per cerebral hemisphere was reduced after surgical revascularization only 1 patient of 7 had an ischemic event during the follow-up period after surgery. No children moved from good to poor functional status after MMS diagnosis. MMS can occur after PBT. Magnetic resonance angiography sequences should be included in surveillance MRI scans to screen for MMS, and families should be counseled about this complication. Management at a high-volume pediatric neurovascular center, including selective use of revascularization surgery, appears to maintain functional status in these children.

Enhanced brain entry of checkpoint-inhibitory therapeutic antibodies facilitated by intraarterial NEO100 in mouse models of brain-localized malignancies.

Immune checkpoint-inhibitory therapeutic antibodies have shown striking activity against several types of cancers but are less effective against brain-localized malignancies, in part due to the protective effect of the blood-brain barrier (BBB). The authors hypothesized that intraarterial (IA) delivery of a novel compound, NEO100, has the potential to safely and reversibly open the BBB to enable brain-targeted therapeutic activity of checkpoint-inhibitory antibodies. Immunocompetent mice with syngeneic glioblastoma or melanoma cells implanted into their brains were subjected to a single IA injection of NEO100 to open their BBB. One dose of murine anti-PD-1PD-L1 antibody was either coinjected with NEO100 or separately injected intravenously. Brain penetration of these antibodies and levels of CD8 T cell infiltrate into the tumor microenvironment were quantitated and animal survival was monitored. IA NEO100 enabled the increased accumulation of checkpoint-inhibitory antibodies in the brain, along with greater numbers of T cells. In both malignancy models, a single intervention of IA NEO100 combined with antibody resulted in the long-term survival of animals. Antibody treatment in the absence of NEO100 was far less effective. BBB opening by IA NEO100 facilitates brain tumor access by checkpoint-inhibitory antibodies and enables their therapeutic activity, along with increased levels of T-cell recruitment.

Triphasic response after endoscopic craniopharyngioma resection and its dependency on infundibular preservation or sacrifice.

Surgery is the primary treatment for craniopharyngioma with the preservation of hypothalamic function of paramount importance. Infundibular preservation is debated, as maximal resection decreases recurrence rates but causes hypopituitarism. A triphasic response of diabetes insipidus (DI), syndrome of inappropriate antidiuretic hormone secretion (SIADH), and recurrent DI has been described after pituitary surgery, but the impact of infundibular preservation on the triphasic response following craniopharyngioma resection has not been well established. The authors objective was to assess postoperative fluid and sodium balance and differences in ADH imbalance management following endonasal craniopharyngioma resection based on infundibular transection status. This is a retrospective cohort study of 19 patients with craniopharyngioma treated with endoscopic endonasal resection between 2014 and 2021. Resection was dichotomized into infundibular transection or preservation. Postoperative triphasic response, time to DI, and time to ADH replacement were compared using Fishers exact test and Kaplan-Meier analysis. Based on surgeon impression, 10 patients had infundibular transection and 9 had infundibular preservation. Overall, 16 patients experienced DI, 12 experienced persistent DI, and 6 experienced SIADH. A postoperative triphasic response occurred in 40% (n 4) of transection patients without preoperative DI and 11% (n 1) of preservation patients without preoperative DI. The median time to postoperative DI (0.5 vs 18.0 hours, p 0.022) and median time to ADH replacement therapy (4.5 vs 24 hours, p 0.0004) were significantly shorter in the transection group than in the preservation group. Following endonasal craniopharyngioma resection, the triphasic response occurs in nearly half of infundibular transection cases. DI begins earlier with infundibular transection. On the basis of the study findings in which no patients met the criteria for SIADH or were endocrinologically unstable after postoperative day 6, it is reasonable to suggest that otherwise stable patients can be discharged at or before postoperative day 6 when ADH fluctuations have normalized and endocrinopathy is appropriately managed with oral desmopressin. Infundibular transection status may impact postoperative hormonal replacement strategies, but additional studies should evaluate their efficacies.

Cancer aggravation due to persistent pain signals with the increased expression of pain-related mediators in sensory neurons of tumor-bearing mice.

A growing body of evidence suggests that intractable pain reduces both the quality of life and survival in cancer patients. In the present study, we evaluated whether chronic pain stimuli could directly affect cancer pathology using tumor-bearing mice. For this purpose, we used two different models of chronic pain in mice, neuropathic pain and persistent postsurgical pain, with Lewis lung carcinoma (LLC) as tumor cells. We found that tumor growth was dramatically promoted in these pain models. As well as these pain models, tumor growth of LLC, severe osteosarcoma (AXT) and B16 melanoma cells was significantly promoted by concomitant activation of sensory neurons in AAV6-hM3Dq-injected mice treated with the designer drug clozapine-N-oxide (CNO). Significant increases in mRNA levels of vascular endothelial growth factor-A (Vegfa), tachykinin precursor 1 (Tac1) and calcitonin-related polypeptide alpha (Calca) in the ipsilateral side of dorsal root ganglion of AAV6-hM3Dq-injected mice were observed by concomitant activation of sensory neurons due to CNO administration. Moreover, in a model of bone cancer pain in which mice were implanted with AXT cells into the right femoral bone marrow cavity, the survival period was significantly prolonged by repeated inhibition of sensory neurons of AAV6-hM4Di-injected mice by CNO administration. These findings suggest that persistent pain signals may promote tumor growth by the increased expression of sensory-located peptides and growth factors, and controlling cancer pain may prolong cancer survival.

Mesenchymal non-meningothelial tumors of the central nervous system a literature review and diagnostic update of novelties and emerging entities.

The fifth edition of the World Health Organization Classification of Tumors of the Central Nervous System (CNS) now includes mesenchymal tumors that occur uniquely or frequently in the CNS. Moreover, this version has aligned the terminology of mesenchymal tumors with their soft tissue counterparts. New tumor types have been added, such as the intracranial mesenchymal tumor, FET-CREB fusion-positive, the CIC-rearranged sarcoma, and the Primary intracranial sarcoma, DICER1-mutant. Other entities (such as rhabdomyosarcoma) have remained in the current WHO classification because these tumor types may present specificities in the CNS as compared to their soft tissue counterparts. Based on an extensive literature review, herein, we will discuss these newly recognized entities in terms of clinical observation, radiology, histopathology, genetics and outcome, and consider strategies for an accurate diagnosis. In light of this literature analysis, we will also introduce some potentially novel tumor types.

Dosimetric comparison of two dose expansion methods in intensity modulated radiotherapy for breast cancer.

To explore the dosimetric difference between IMRT-VB plan based on the establishment of external expansion structure and virtual bolus (VB) and IMRT-SF based on the skin flash (SF) tool of the Eclipse treatment planning system in postoperative chest wall target intensity modulation radiotherapy plan of breast cancer. Twenty patients with breast cancer were randomly selected as subjects to develop IMRT-VB plan based on virtual bolus and IMRT-SF plan based on skin flash tool of Eclipse treatment planning system. The planning target volume, monitor unit (MU) of every single treatment and the dosimetric parameters of organ at risk (OARs) were recorded. Paired t-test was used for normal distribution data while nonparametric paired Wilcoxon rank sum test was used for non-normal distribution data. Both IMRT-VB and IMRT-SF plan can expand outward to the chest wall skin and meet the dose requirements of clinical prescription. The conformal index, the homogeneity index, D Our study indicated that IMRT-SF plan displayed clinical application superiority compared to IMRT-VB plan, and the operation steps of which are simpler and faster. Besides, IMRT-SF plan took advantages in achieve effective external expansion of skin dose intensity and OARs protection.

The Role of the Cerebellum in Visual-Spatial Memory in Pediatric Posterior Fossa Tumor Survivors.

The cerebellum is involved in motor and non-motor functions. Cerebellar lesions can underlie the disruption of various executive functions. The violation of executive functions in cerebellar lesions is a serious problem, since children, after completing treatment, must return to school, finish their education, and get a profession. One of the important executive functions is working memory, which contributes to academic success. Deficits of verbal working memory in cerebellar tumors have been studied, in contrast to visual-spatial working memory. To assess this issue, 101 patients who survived cerebellar tumors and 100 healthy control subjects performed a visual-spatial working memory test. As a result, in children who survived cerebellar tumors, visual-spatial working memory is impaired compared to the control group. Moreover, with age, and hence the time since the end of treatment, the number of elements that children can retain in visual-spatial working memory increases, but still remains smaller compared to the control group. Our findings complement the idea of cerebellar involvement in visual-spatial working memory and suggest that it is disrupted by cerebellar lesions in children.

Splitting the reward Differences in inflammatory marker associations with neural connectivity between reward anticipation and reward outcome in adolescents at high risk for depression.

Adolescent depression is associated with both dysfunction in neural reward processing and peripheral inflammatory markers (PIMs), such as interleukin-6 (IL-6), C-reactive-protein (CRP), and tumor-necrosis factor alpha (TNFα). Few adolescent studies have examined neural-inflammatory marker associations and associated behavioral correlates, which would contribute to a better understanding of developmental processes linked to depression. 36 adolescents at high risk of depression completed an fMRI reward task (during anticipation and outcome), blood draw for PIMs (IL-6, CRP, and TNFα), and a behavioral task assessing motivation to expend effort. Analyses examined associations of task-dependent functional connectivity (FC ventral striatum to frontal and default mode network brain regions), and if the interaction of PIMs and task-dependent FC predicted motivation to expend effort. For anticipation contrast, TNFα was associated with increased task-dependent FC between the LVS and PCCvmPFC. In moderation analyses, for anticipation contrasts, the combination of higher IL-6 and stronger FC (LVS-precuneusPCC) was associated with lower motivation to expend effort, while for outcome contrasts, the combination of higher IL-6 and stronger FC (VS-precuneusPCC) was associated with greater motivation to expend effort. Our findings in adolescents during an important developmental time period suggest that PIMs are directly linked to greater FC between the VS and DMN brain regions during win anticipation, consistent with prior studies. Effects of PIMs on motivation to expend effort may vary the strengthtype of neural reward processing (anticipation or outcome), which could guide better understanding how inflammatory markers and neural reward substrates contribute to development of depression in high-risk adolescents.

Knockdown of PDCD4 ameliorates neural cell apoptosis and mitochondrial injury through activating the PI3KAKTmTOR signal in Parkinsons disease.

Parkinsons disease (PD) is a complex neurodegenerative disorder and hampers normal living. It has been reported that programmed cell death 4 (PDCD4) is associated with tumor suppression, inflammatory response, and apoptosis. The aim of this study was to investigate the role of PDCD4 in PD. The in vivo and in vitro PD models were established by MPTP-induced mice and MMP stimulated MN9D cells, respectively. The expression of PDCD4 was detected by western blot. The MN9D cell viability and apoptosis were determined by MTT and flow cytometry assay. Moreover, the MN9D cell mitochondrial injury was evaluated by JC-1 staining. In this study, PDCD4 was highly expressed in brain tissue of MPTP-induced PD mouse model. In a loss-function experiments, knockdown of PDCD4 promoted MN9D cell viability and allayed MPP-triggered MN9D cell apoptosis. Furthermore, knockdown of PDCD4 ameliorated MPP-evoked MN9D cell mitochondrial injury. Mechanically, knockdown of PDCD4 abolished the effect of MMP stimulation via activating phosphoinositide 3-kinase(PI3K)AKTmammalian target of rapamycin (mTOR) signal. Notably, the protective effects of shPDCD4 on cell apoptosis and mitochondrial injury were suppressed by PI3K inhibitor LY294002. In summary,knockdown of PDCD4 ameliorates neural cell apoptosis and mitochondrial injury through activating the PI3KAKTmTOR signal, providing a novel target for PD treatment. All data generated or analyzed during this study are included in this published article.

Modulation of blood-brain tumor barrier for delivery of magnetic hyperthermia to brain cancer.

Glioblastoma (GBM) is the most invasive brain tumor and remains lack of effective treatment. The existence of blood-brain tumor barrier (BBTB) constitutes the greatest barrier to non-invasive delivery of therapeutic agents to tumors in the brain. Here, we propose a novel approach to specifically modulate BBTB and deliver magnetic hyperthermia in a systemic delivery mode for the treatment of GBM. BBTB modulation is achieved by targeted delivering fingolimod to brain tumor region via dual redox responsive PCL-SeSe-PEG (poly (ε-caprolactone)-diselenium-poly (ethylene glycol)) polymeric nanocarrier. As an antagonist of sphingosine 1-phosphate receptor-1 (S1P

Co-administration of JQ1, a bromodomain-containing protein 4 inhibitor, enhances the antitumor effect of combretastatin A4, a microtubule inhibitor, while attenuating its cardiotoxicity.

Combretastatin A4 (CA4) inhibits microtubule polymerization, and clinical trials of the prodrug, CA4 disodium phosphate (CA4DP), as an anti-cancer agent have been conducted. However, CA4DP has not been marketed to date because the margin between the effective dose and the cardiotoxic dose is insufficient. Meanwhile, bromodomain-containing protein 4 (BRD4) has been reported to be required for recovery from mitotic arrests induced by anti-microtubule drugs. BRD4 has also been reported to be involved in the progression of heart failure. Therefore, we hypothesized that the combined use of CA4DP with BRD4 inhibitors can enhance the antitumor effect and attenuate CA4DP-induced cardiotoxicity. In this study, the antitumor effect and cardiotoxicity caused by the co-administration of CA4DP with JQ1, a BRD4 inhibitor, were evaluated. CA4 or JQ1 alone reduced the viability of cultured canine mammary tumor cells (CHMp-13a). Viability was further reduced by co-administration, through the suppression of c-Myc. BRD4 positivity in CHMp-13a cytoplasm showed a significant increase when treated with CA4 alone, while the increase was not significant following co-administration. In CHMp-13a xenograft-transplanted mice, co-administration of CA4DP and JQ1 suppressed tumor growth significantly. In CA4DP-induced cardiac injury model rats, echocardiography showed a CA4DP-induced decrease in cardiac function and histopathology showed cardiomyocyte necrosis. Meanwhile, these cardiac changes tended to be milder following the co-administration of CA4DP and JQ1. These results suggest that CA4DP-JQ1 co-administration enhances the antitumor effect of CA4DP while attenuating its cardiotoxicity and therefore potentially open the doors to the development of a novel cancer chemotherapy with reduced cardiotoxicity risks.

Morin post-treatment surpassed calpeptin in ameliorating 3-NP-induced cortical neurotoxicity via modulation of glutamatecalpain axis, Kidins220, and BDNFTrkBAKTCREB trajectory.

The neuroprotective capacity of morin hydrate (MH), a potent antioxidant flavonoid, and calpeptin (CP), a calpain inhibitor, was documented against different insults but not Huntingtons disease (HD). Accordingly, we aim to assess the neuroprotective potential of MH andor CP in a 3-nitropropionic acid (3-NP)-induced HD model. The 3-NP-treated rats were post-treated with saline, MH, CP, or MH CP for a week. Post-treatment with MH andor CP amended motor function (beam walking test) and short- long-term spatial memory (novel object recognition test) and improved cortical microscopic architecture. On the molecular level, MH, and to a lesser extent CP, inhibited the cortical contentexpression of glutamate, calpain, and Kidins220 and abated the inflammatory molecules, nuclear factor (NF)-κB, tumor necrosis factor-α, and interleukin-1β, as well as lipid peroxidation. However, MH, but barely CP, activated the molecules of the neuroprotective trajectory viz., brain-derived neurotrophic factor (BDNF), tropomyosin-related kinase receptor B (TrkB), protein kinase B (AKT), and cAMP response element-binding protein (CREB). Compared to the single treatments, the combination regimen mediated further reductions in the cortical contents of glutamate, calpain, and Kidins220, effects that extended to entail the anti-inflammatoryanti-oxidant potentials of MH and to a greater extent CP. However, the combination of MH strengthened the fair effect of CP on the survival signaling pathway BDNFTrkBAKTCREB. In conclusion, MH, CP, and especially their combination, afforded neuroprotection against HD through curbing the glutamatecalpain axis, Kidins220, as well as NF-κB-mediated neuroinflammationoxidative stress, besides activating the BDNFTrkBAKTCREB hub that was partly dependent on calpain inhibition.

Reorganization and Plasticity of the Language Network in Patients with Cerebral Gliomas.

Language is organized in large-scale networks in the human brain that show a strong potential for flexible interactions and adaptation. Neuroplasticity is the central mechanism that allows such dynamic modulation to changing conditions across the life span and is particularly important for network reorganization after brain lesions. Most studies on language reorganization focused on language recovery after stroke. Yet, a strong degree of adaptive neuroplasticity can also be observed in patients with brain tumors in language-eloquent brain areas. This review discusses key mechanisms for neural reorganization in patients with brain tumors. Our main aim is to elucidate the underlying mechanisms for intra- and interhemispheric plasticity in the language network in these patients. The following reorganization patterns are discussed 1) Persisting function within the tumor 2) Reorganization in perilesional regions 3) Reorganization in a distributed network of the affected hemisphere 4) Reorganization to the contralesional hemisphere. In this context, we shed light on language-related reorganization patterns in frontal and temporo-parietal areas and discuss their functional relevance. We also address tumor-related changes in structural and functional connectivity between eloquent brain regions. Thereby, we aim to expand the general understanding of the plastic potential of the neural language network and facilitate clinical decision-making processes for effective, function-preserving tumor treatment.

Molecular aspects of brain metastases in breast cancer.

Brain metastases (BM) are a common and devastating manifestation of breast cancer (BC). BM are particularly frequent in the HER2-positive and triple-negative breast cancer phenotypes and usually occur following the metastatic spread to extracranial sites. Several genes mediating BM and biomarkers predicting their risk in BC have been reported in the past decade. These findings have advanced the understanding of BM pathobiology and paved the way for developing new therapeutic strategies but they still warrant a thorough clinical validation. Hence, a better understanding of the mechanistic aspects of BM and delineating the interactions of tumor cells with the brain microenvironment are of utmost importance. This review discusses the molecular basis of the metastatic cascade the epithelial-mesenchymal transition, cancer, and tumor microenvironment interaction and intravasation, priming of the metastatic niche in the brain, and survival in the new site. We also outline the postulated mechanisms of BC cells brain tropism. Finally, we discuss advances in the field of biomarkers (both tissue-based and liquid-based) that predict BM from BC.

Activation of retinal glial cells contributes to the degeneration of ganglion cells in experimental glaucoma.

Elevation of intraocular pressure (IOP) is a major risk factor for neurodegeneration in glaucoma. Glial cells, which play an important role in normal functioning of retinal neurons, are well involved into retinal ganglion cell (RGC) degeneration in experimental glaucoma animal models generated by elevated IOP. In response to elevated IOP, mGluR I is first activated and Kir4.1 channels are subsequently inhibited, which leads to the activation of Müller cells. Müller cell activation is followed by a complex process, including proliferation, release of inflammatory and growth factors (gliosis). Gliosis is further regulated by several factors. Activated Müller cells contribute to RGC degeneration through generating glutamate receptor-mediated excitotoxicity, releasing cytotoxic factors and inducing microglia activation. Elevated IOP activates microglia, and following morphological and functional changes, these cells, as resident immune cells in the retina, show adaptive immune responses, including an enhanced release of pro-inflammatory factors (tumor neurosis factor-α, interleukins, etc.). These ATP and Toll-like receptor-mediated responses are further regulated by heat shock proteins, CD200R, chemokine receptors, and metabotropic purinergic receptors, may aggravate RGC loss. In the optic nerve head, astrogliosis is initiated and regulated by a complex reaction process, including purines, transmitters, chemokines, growth factors and cytokines, which contributes to RGC axon injury through releasing pro-inflammatory factors and changing extracellular matrix in glaucoma. The effects of activated glial cells on RGCs are further modified by the interplay among different types of glial cells. This review is concluded by presenting an in-depth discussion of possible research directions in this field in the future.

Chemotherapy how to reduce its adverse effects while maintaining the potency

Chemotherapy is one of the widely used anticancer treatments that involves the use of powerful cytotoxic drugs to stop tumor growth by targeting rapidly dividing cells through various mechanisms, which will be elucidated in this review. Introduced during the early twentieth century, chemotherapy has since lengthened the longevity of innumerable cancer patients. However, the increase in lifespan is at the expense of quality of life as patients are at risk of developing short-term and long-term side effects following chemotherapy, such as alopecia (hair loss), chemotherapy-induced peripheral neuropathy, chemotherapy-induced nausea and vomiting, cardiotoxicity, diarrhea, infertility, and chemo brain. Currently, a number of these chemotherapy-induced adverse effects are managed through supportive care and approved treatments, while the rest of the side effects are unavoidable. Hence, chemotherapeutic drugs associated with inevitable side effects are only administered when their therapeutic role outweighs their chemotoxicity, thus severely limiting the potency of chemotherapy in treating malignancy. Therein, the potential approaches to alleviating side effects of chemotherapy ranging from pharmaceutical drugs to alternative therapies will be discussed in this review in hopes of increasing the tolerance and effectiveness of future chemotherapeutic treatments.

Dopamine Receptors in Breast Cancer Prevalence, Signaling, and Therapeutic Applications.

Breast cancer (BC) is the most common malignancy among women, with over one million cases occurring annually worldwide. Although therapies against estrogen receptors and HER2 have improved response rate and survival, patients with advanced disease, who are resistant to anti-hormonal therapy andor to chemotherapy, have limited treatment options for reducing morbidity and mortality. These limitations provide major incentives for developing new, effective, and personalized therapeutic interventions. This review presents evidence on the involvement of dopamine (DA) and its type 1 receptors (D1R) in BC. DA is produced in multiple peripheral organs and is present in the systemic circulation in significant amounts. D1R is overexpressed in 30% of BC cases and is associated with advanced disease and shortened patient survival. Activation of D1R, which signals via the cGMPPKG pathway, results in apoptosis, inhibition of cell invasion, and increased chemosensitivity in multiple BC cell lines. Fenoldopam, a peripheral D1R agonist that does not penetrate the brain, dramatically suppressed tumor growth in mouse models with D1R-expressing BC xenografts. It is proposed that D1R should serve as a novel diagnosticprognostic factor through the use of currently available D1R detection methods. Fenoldopam, which is FDA-approved to treat renal hypertension, could be repurposed as an effective therapeutic agent for patients with D1R-expressing tumors. Several drugs that interfere with the cGMPPKG pathway and are approved for treating other diseases should also be considered as potential treatments for BC.

Progress in Tuberous Sclerosis Complex Renal Disease.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that affects both fetal development and postnatal tissue growth, resulting in altered brain structures and a tumor predisposition syndrome. Although every organ system is affected by the disease, kidney involvement is a leading cause of death in adults with TSC. Over the past decade, significant progress has been made in understanding the renal disease. This review focuses on the cystic and solid renal lesions in TSC, including their pathobiology and treatment.

Pretherapy Ferumoxytol-enhanced MRI to Predict Response to Liposomal Irinotecan in Metastatic Breast Cancer.

Purpose To investigate ferumoxytol (FMX)-enhanced MRI as a pretreatment predictor of response to liposomal irinotecan (nal-IRI) for thoracoabdominal and brain metastases in women with metastatic breast cancer (mBC). Materials and Methods In this phase 1 expansion trial (ClinicalTrials.gov identifier, NCT01770353 27 participants), 49 thoracoabdominal (19 participants mean age, 48 years ± 11 SD) and 19 brain (seven participants mean age, 54 years ± 8) metastases were analyzed on MR images acquired before, 1-4 hours after, and 16-24 hours after FMX administration. In thoracoabdominal metastases, tumor transverse relaxation rate (R

Communication in the context of glioblastoma treatment A qualitative study of what matters most to patients, caregivers and health care professionals.

Patients with glioblastoma have a poor prognosis and treatment is palliative in nature from diagnosis. It is therefore critical that the benefits and burdens of treatments are clearly discussed with patients and caregivers. To explore experiences and preferences around glioblastoma treatment communication in patients, family caregivers and healthcare professionals. Qualitative design. A thematic analysis of semi-structured interviews. A total of 15 adult patients with glioblastoma, 13 caregivers and 5 healthcare professionals were recruited from Leeds Teaching Hospitals NHS Trust. Four themes were identified (1) In glioblastoma treatment communication, where prognosis is poor and treatmentwill not result in cure, building trusting relationships, maintaining a sense of control and being well-informed are identified as critical.

Awake craniotomy with dexmedetomidine during resection of brain tumours located in eloquent regions.

An awake craniotomy (AC) is the gold standard for the resection of supra-tentorial brain tumours in eloquent areas. Intraoperative monitoring on-demand of essential eloquent brain functions and the increasing need to preserve higher intellectual functions during surgery requires a unique anaesthetic approach during AC. Dexmedetomidine is considered the first-choice pharmacological agent for sedation during AC. Twenty-six patients with a single brain tumour located in areas of eloquent brain function were enrolled in this prospective study. The patients underwent AC under conscious sedation. Motor-evoked potentials and brainstem-evoked auditory potentials were measured using neurophysiological tests during surgery to assess brain potentials. Intraoperative brain relaxation was reached using a modified Bristow scale. Neuromonitoring and psychological tests were maintained until meningeal closure. All operations were carried out successfully, and no reoperations were needed. No significant impact on circulatory and respiratory parameters was observed during conscious sedation based on dexmedetomidine. Neither instrumental airway support nor conversion to general anaesthesia was necessary. Brain relaxation was good in 84% of cases. Intraoperative epileptic episodes were observed in 15% of the patients. Neuro-logical and psychological monitoring was satisfactory. Unaltered muscle force was observed postoperatively in 88% of the patients. AC performed under conscious sedation, and dexmedetomidine infusion without instrumental airway support, was safe and well-tolerated by patients with comfortable physiological sleep for most of the procedure. This approach to AC was associated with minimal risk of perioperative adverse events and may be particularly beneficial in patients with severe comorbidities.

Transatlantic progress in measurement of cognitive outcomes in paediatric oncology trials.

The importance of measuring quality of survival within paediatric oncology trials is increasingly recognised. However, capturing neuropsychological outcomes and other aspects of quality of survival in the context of large or multinational trials can be challenging. We provide examples of protocols designed to address this challenge recently employed in clinical trials in the USA and Europe. We discuss their respective strengths and challenges, obstacles encountered and future opportunities for transatlantic collaboration.

Adult intracranial ependymoma - relevance of DNA methylation profiling for diagnosis, prognosis and treatment.

A methylation-based classification of ependymoma has recently found broad application. However, the diagnostic advantage and implications for treatment decisions remain unclear. Here, we retrospectively evaluate the impact of surgery and radiotherapy on outcome after molecular reclassification of adult intracranial ependymomas. Tumors diagnosed as intracranial ependymomas from 170 adult patients collected from eight diagnostic institutions were subjected to DNA methylation profiling. Molecular classes, patient characteristics, and treatment were correlated with progression-free survival (PFS). The classifier indicated an ependymal tumor in 73.5%, a different tumor entity in 10.6% and non-classifiable tumors in 15.9% of cases, respectively. The most prevalent molecular classes were posterior fossa ependymoma group B (EPN-PFB, 32.9%), posterior fossa subependymoma (PF-SE, 25.9%), and supratentorial ZFTA fusion-positive ependymoma (EPN-ZFTA, 11.2%). With a median follow-up of 60.0 months, the 5- and 10-year-PFS rates were 64.5% and 41.8% for EPN-PFB, 67.4% and 45.2% for PF-SE and 60.3% and 60.3% for EPN-ZFTA. In EPN-PFB, but not in other molecular classes, gross total resection (p0.009) and postoperative radiotherapy (p0.007) were significantly associated with improved PFS in multivariable analysis. Histological tumor grading (WHO 2 vs. 3) was not a predictor of prognosis within molecularly defined ependymoma classes. DNA methylation profiling improves diagnostic accuracy and risk stratification in adult intracranial ependymoma. The molecular class of PF-SE is unexpectedly prevalent among adult tumors with ependymoma histology and relapsed as frequently as EPN-PFB, despite the supposed benign nature. Gross total resection and radiotherapy may represent key factors in determining the outcome of EPN-PFB patients.

A population-based investigation How to identify high-risk T1-2N0 esophageal cancer patients

Newly diagnosed T1-2N0 esophageal cancer (EC) is generally deemed as early local disease, with distant metastases (DM) easily overlooked. This retrospective study aimed to describe the metastatic patterns, identify risk factors and established a risk prediction model for DM in T1-2N0 EC patients. A total of 4623 T1-2N0 EC patients were identified in the Surveillance, Epidemiology and End Results (SEER) database from 2004 to 2018. Multivariable logistic regression was used to identify risk factors for DM. A nomogram was developed for presentation of the final model. Of 4623 T1-2N0 patients, 4062 (87.9%) had M0 disease and 561 (12.1%) had M1 disease. The most common metastatic site was liver ( We identified independent predictive factors for DM, as well as for BoM, BrM, LiM and LuM. Above all, a practical and convenient nomogram with a great accuracy to predict DM probability for T1-2N0 EC patients was established.

Identification and validation of a muscle failure index to predict prognosis and immunotherapy in lung adenocarcinoma through integrated analysis of bulk and single-cell RNA sequencing data.

It was previously reported that the production of exerkines is positively associated with the beneficial effects of exercise in lung adenocarcinoma (LUAD) patients. This study proposes a novel scoring system based on muscle failure-related genes, to assist in clinical decision making. A comprehensive analysis of bulk and single cell RNA sequencing (scRNA-seq) of early, advanced and brain metastatic LUAD tissues and normal lung tissues was performed to identify muscle failure-related genes in LUAD and to determine the distribution of muscle failure-related genes in different cell populations. A novel scoring system, named MFI (Muscle failure index), was developed and validated. The differences in biological functions, immune infiltration, genomic alterations, and clinical significance of different subtypes were also investigated. First, we conducted single cell analysis on the dataset GSE131907 and identified eight cell subpopulations. We found that four muscle failure-related genes (BDNF, FNDC5, IL15, MSTN) were significantly increased in tumor cells. In addition, IL15 was widely distributed in the immune cell population. And we have validated it in our own clinical cohort. Then we created the MFI model based on 10 muscle failure-related genes using the LASSO algorithm, and MFI remained an independent prognostic factor of OS in both the training and validation cohorts. Moreover, we generated MFI in the single-cell dataset, in which cells with high MFI received and sent more signals compared to those with low MFI. Biological function analysis of both subtypes revealed stronger anti-tumor immune activity in the low MFI group, while tumor cells with high MFI had stronger metabolic and proliferative activity. Finally, we systematically assessed the immune cell activity and immunotherapy responses in LUAD patients, finding that the low MFI group was more sensitive to immunotherapy. Overall, our study can improve the understanding of the role of muscle failure-related genes in tumorigenesis and we constructed a reliable MFI model for predicting prognosis and guiding future clinical decision making.

CCKAR is a biomarker for prognosis and asynchronous brain metastasis of non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is the most common histological type of lung cancer, and brain metastasis (BM) is the most lethal complication of NSCLC. The predictive biomarkers and risk factors of asynchronous BM are still unknown. A total of 203 patients with NSCLC were enrolled into our cohort and followed up. The clinicopathological factors such as tumor size, T stage, lymphatic invasion, metastasis and asynchronous BM were investigated. CCKAR expression in NSCLC and resected BM was assessed by IHC, and CCKAR mRNAs in NSCLC and para-tumor tissues were estimated by qRT-PCR. The correlations between CCKAR expression, BM and other clinicopathological factors were assessed by chi-square test, and prognostic significance of CCKAR was estimated by univariate and multivariate analyses. CCKAR was highly expressed in NSCLC tissues compared with para-tumor tissues. CCKAR expression in NSCLC was significantly associated with asynchronous BM. The BM percentages for NSCLC patients with low and high CCKAR were surprisingly 5.2% and 66.6%, respectively. CCKAR expression and BM were unfavorable factors predicting unfavorable outcome of NSCLC. Moreover, CCKAR expression in NSCLC was an independent risk factor of asynchronous BM. CCKAR is a prognostic biomarker of NSCLC. CCKAR expression in NSCLC is positively associated with asynchronous BM, and is a risk factor of asynchronous BM from NSCLC.

Gamma Knife Radiosurgery Modulates micro-RNA Levels in Patients with Brain Metastasis.

The relation between micro-RNA (miRNA) modulation and immune cell activity in high-dose radiation settings is not clearly understood. To investigate the role of stereotactic radiosurgery (SRS) in (i) the regulation of tumor-suppressor and oncogenic miRNAs as well as (ii) its effect on specific immune cell subsets in patients with metastatic brain tumors (MBT). 9 MBT patients who underwent gamma knife-based stereotactic radiosurgery (GKRS) and 8 healthy individuals were included. Serum samples were isolated at three-time intervals (before GKRS, 1 hour, and 1-month post-GKRS). Expressions of tumor-suppressor (miR-124) and oncogenic (miR-21, miR-181a, miR-23a, miR-125b, and miR-17) miRNAs were quantified by qPCR. The lymphocytic frequency (CD3, CD4, CD8, CD56, CD19, and CD16) was investigated by means of flow cytometry. The median age was 64 years (range 50-73 years). The median prescription dose was 20Gy (range 16Gy-24Gy), all delivered in a single fraction. The median overall survival and progression-free survival were 7.8 months (range1.7-14.9 months) and 6.7 months (range1.1-11.5 months), respectively. Compared to healthy controls, baseline levels of oncogenic miRNAs were significantly higher, while tumor-suppressing miRNA levels remained markedly lower in MBT patients prior to GKRS. Following GKRS, there was a reduction in the expression of miR-21, miR-17, and miR-181a simultaneously, increased expression increased of miR-124 was observed. No significant difference in immune cell subsets was noted post GKRSIn a similar fashion. We noted no correlation between patient characteristics, radiosurgery data, miRNA expression, and immune cell frequency. For this specific population with MBT disease, our data suggest that stereotactic radiosurgery may modulate the expression of circulating tumor-suppressor and oncogenic miRNAs, ultimately enhancing key anti-tumoral responses. Further evaluation with larger cohorts is warranted.

Glioblastoma as a novel drug repositioning target Updated state.

Glioblastoma multiforme (GBM) is an aggressive form of adult brain tumor that can arise from a low-grade astrocytoma. In recent decades, several new conventional therapies have been developed that have significantly improved the prognosis of patients with GBM. Nevertheless, most patients have a limited long-term response to these treatments and survive < 1 year. Therefore, innovative anti-cancer drugs that can be rapidly approved for patient use are urgently needed. One way to achieve accelerated approval is drug repositioning, extending the use of existing drugs for new therapeutic purposes, as it takes less time to validate their biological activity as well as their safety in preclinical models. In this review, a comprehensive analysis of the literature search was performed to list drugs with antiviral, antiparasitic, and antidepressant properties that may be effective in GBM and their putative anti-tumor mechanisms in GBM cells.

A Case of Hypertrophic Pulmonary Osteoarthropathy Associated with Pulmonary Pleomorphic Carcinoma.

Hypertrophic pulmonary osteoarthropathy(HPO)is a tumor-associated syndrome that features the triad of clubbed fingers, periosteal bone growth in long bones, and arthritis, and is often associated with an adenocarcinoma or squamous cell carcinoma. This report presents details of a case of HPO associated with pleomorphic carcinoma, which was relieved by treatment. A 47-year-old woman was presented with a complaint of generalized arthralgia. A physical examination showed swollen joints in the body and clubbed fingers. Chest CT revealed a mass shadow in the left upper lobe and ultrasound- guided biopsy findings led to a diagnosis of non-small cell lung cancer. Furthermore, bone scintigraphy indicated symmetrical accumulation in bones and joints throughout the body. A right upper lobectomy was performed along with combined chest wall resection and mediastinal lymph node dissection with an open chest, and the presence of lung cancer complicated with HPO was indicated. Pathological examination results revealed a diagnosis of pleomorphic carcinoma(pT4N0M0, Stage ⅢA). Systemic arthralgia was resolved on the first postoperative day. One year after surgery, a solitary brain metastasis developed and was removed, with no recurrence at the time of writing. Joint symptoms related to HPO can be expected to improve with treatment of pulmonary lesions, thus aggressive procedures for diagnosis and treatment are desirable.

Two Cases of Trousseau Syndrome during Chemotherapy.

Case 1 is a 56-year-old man. During postoperative adjuvant chemotherapy for pancreatic cancer, weakness in the right upper and lower limbs appeared, and a head CT scan was performed, but no abnormal findings were noted. Diffusion- weighted MRI scan of the head showed multiple cerebral infarcts, and a diagnosis of Trousseau syndrome was made. Case 2 is an 86-year-old man. During chemotherapy for postoperative recurrence of distal bile duct carcinoma, he developed weakness in the right upper and lower limbs, and a head MRI scan was performed. Diffusion-weighted MRI showed scattered high-signal areas, and a diagnosis of Trousseau syndrome was made. Trousseau syndrome is a condition in which stroke is caused by hypercoagulability associated with malignant tumor. The initial symptoms of cerebral infarction in patients with cancer are similar to those of chemotherapy-induced adverse events and brain metastases, and therefore, a head MRI scan is recommended even if there is no obvious abnormality on head CT scan.

Brain Metastasis Arising from Gastric Cancer during Long-Term Treatment Using Nivolumab.

Metastasis to the central nervous system from gastric cancer is exceedingly uncommon. We report a gastric cancer patient with cerebral metastasis during the period when durable response was obtained by systemic drug treatment using nivolumab. A 78-year-old male was referred to our hospital for further examination following diagnosis of gastric cancer by a local medical doctor. Esophagogastroduodenoscopy showed a slightly elevated lesion with central depressed area in the upper-third of the stomach, and analysis of biopsy specimens revealed an adenocarcinoma. The patient underwent laparoscopic total gastrectomy with lymph nodes dissection followed by Roux-en-Y reconstruction, resulting in submucosal invasive carcinoma and no lymph node metastasis. The patient developed solitary splenic metastasis measuring 4.2 cm after 28 months later, and the patient underwent a splenectomy, since there was no evidence of further metastatic lesions in any other organs. Subsequently, the patient was received S-1 plus oxaliplatin chemotherapy based on negative immunohistochemical staining of the resected specimens for human epidermal growth factor receptor 2. Four months after the splenectomy, the patient developed multiple liver metastases and was treated with ramucirumab plus paclitaxel. Because of disease progression, the patient was administered 3 mgkg, iv, nivolumab every 2 weeks. After 4 courses of systemic treatment using nivolumab, abdominal computed tomography revealed marked shrinkage of the liver metastases. After 12 courses of nivolumab, the liver metastases had disappeared completely. The patient developed hypothyroidism, which could be controlled by thyroid hormone replacement treatment. The patient continues to receive nivolumab, and there is no evidence of disease recurrence in the 33 month period since starting nivolumab. However, he developed cerebral metastases after 69 months after surgery, complaining of articulation disorder. The patient underwent tumor resection by craniotomy followed by radiation therapy however, he died 3 months after the operation. Although brain metastasis arising from gastric cancer is rare, future identification of risk factors and development of novel treatments are desired by further investigations and accumulation of these cases.

Adjuvant Capecitabine for Residual Disease after Standard Neoadjuvant Chemotherapy Among Patients with Triple-Negative Breast Cancer.

CREATE-X trial demonstrated the effectiveness of additional capecitabine therapy in prolonging disease-free survival among patients who are HER2 negative, especially those with triple-negative breast cancer who had residual invasive disease after standard neoadjuvant chemotherapy. We investigated our data regarding adjuvant capecitabine for residual disease. Ten patients were enrolled, and the average age of the patients was 54.2 years. All patients completed 8 courses of treatment all adverse events were Grade 2 or lower. Five-year disease-free survival rate was 70.0% in an average observation period of 40.9 months. Three patients recurred within 2 years, and all patients had brain metastasis. In the CREATE-X trial, the rate of disease-free survival was 69.8% in the capecitabine group versus 56.1% in the control group our results were same as those of CREATE-X. Brain metastasis may be detected by the early phase of enhanced brain MRI.

Report of Multidisciplinary Treatment for Sisters with Li-Fraumeni Syndrome.

Li-Fraumeni syndrome(LFS)is a hereditary cancer disorder caused by germline variant in TP53 and characterized by various malignancies. Multidisciplinary treatment is needed for tumors of LFS, however, radiation therapy is a relative contraindication because of frequent development of secondary malignancy such as sarcoma in the irradiated field. Case 1 A 22- year-old woman who was diagnosed with LFS by genetic test when she developed upper rectal cancer. Her rectal tumor with marked bilateral lateral lymph node dissection was successfully removed by low anterior resection with extensive lateral lymph node dissection. She underwent resection for ovarian metastasis followed by chemotherapy and radiotherapy but subsequently died by the disease 32 months postoperatively. Case 2(elder sister of Case 1) A brain tumor was identified in the left high frontal lobe to the parietal lobe because of consciousness disorder, after the genetic diagnosis of LFS. The brain tumor was successfully resected. Histological examination revealed diffuse astrocytoma(WHO grade Ⅱ). Local recurrence was observed 46 months later, and radiation therapy was performed. Six months have passed since radiation therapy, no exacerbation of local recurrence has been observed.

Improved QOL in a Case of Breast Cancer with Meningeal Carcinomatosis Treated with Radiation Therapy and Intrathecal Chemotherapy.

A 50s woman was diagnosed with left local-advanced breast cancer(pT4bN2aM0, stage ⅢB, estrogen-receptor positive and human epidermal growth factor-2 negative)in 2016. Neoadjuvant therapy consisting of 4 courses of epirubicin plus cyclophosphamide and 4 courses of docetaxel were administered. After neoadjuvant therapy, a mastectomy with axillary node dissection was performed. And after surgery, she was received radiation and endocrine therapy. In May 2019, multiple bone metastases were detected. We administered endocrine therapy. In February 2020, she developed leg paralysis and malignant cells were collected from the cerebrospinal fluid. She was diagnosed with meningeal carcinomatosis without brain metastasis from breast cancer. To improve quality of life, we started radiation therapy, intrathecal chemotherapy and systemic chemotherapy. After 3 months of these therapies, leg paralysis was improved and quality of life was maintained for 9 months. Herein, we report a case of meningeal carcinomatosis without brain metastasis from breast cancer which is improved by radiation therapy, intrathecal chemotherapy and systemic chemotherapy.

A Case of Stage Ⅳ Breast Cancer Invaded Chest Wall Successfully Resected with Local and Systemic Therapy.

A 54-year-old woman with massive exudates and bleeding in her huge right breast tumor had diagnosed Stage Ⅳ breast cancer, T4cN1M1(PUL, BRA, LYM), with ER positive and HER2 negative subtype confirmed with biological testing. She was treated with stereotactic radio surgery(SRS)for metastatic brain tumors before chemotherapy. Primary systemic chemotherapy, the regimen was EC followed by docetaxel effectively decreased the breast tumor, chest wall invasion, and other metastatic sites. After adding SRS for a new brain tumor lesion, mastectomy with a skin graft and lymphadenectomy were performed. Histological assessment showed free margins, decreased Ki-67 labeling index, ypN0, and histological Grade 1b breast tumor. After the surgery, PMRT and hormonal therapy were applied. The patient remained disease-free after surgery. Locally advanced breast cancer with brain metastasis that could be significantly reduced by sufficient therapeutic dose intensity. Aggressive radiation therapy for brain metastasis may improve local control in patients with Stage Ⅳ breast cancer.

Functional Graphene for Peritumoral Brain Microenvironment Modulation Therapy in Glioblastoma.

Peritumoral brain invasion is the main target to cure glioblastoma. Chemoradiotherapy and targeted therapies fail to combat peritumoral relapse. Brain inaccessibility and tumor heterogeneity explain this failure, combined with overlooking the peritumor microenvironment. Reduce graphene oxide (rGO) provides a unique opportunity to modulate the local brain microenvironment. Multimodal graphene impacts are reported on glioblastoma cells in vitro but fail when translated in vivo because of low diffusion. This issue is solved by developing a new rGO formulation involving ultramixing during the functionalization with polyethyleneimine (PEI) leading to the formation of highly water-stable rGO-PEI. Wide mice brain diffusion and biocompatibility are demonstrated. Using an invasive GL261 model, an anti-invasive effect is observed. A major unexpected modification of the peritumoral area is also observed with the neutralization of gliosis. In vitro, mechanistic investigations are performed using primary astrocytes and cytokine array. The result suggests that direct contact of rGO-PEI

Tsc2 mutation rather than Tsc1 mutation dominantly causes a social deficit in a mouse model of tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that is associated with neurological symptoms, including autism spectrum disorder. Tuberous sclerosis complex is caused by pathogenic germline mutations of either the TSC1 or TSC2 gene, but somatic mutations were identified in both genes, and the combined effects of TSC1 and TSC2 mutations have been unknown. The present study investigated social behaviors by the social interaction test and three-chambered sociability tests, effects of rapamycin treatment, and gene expression profiles with a gene expression microarray in Tsc1 and Tsc2 double heterozygous mutant (TscD TscD It is unclear whether the signaling pathway also plays a critical role in autism spectrum disorders not caused by Tsc1 and Tsc2 mutations. These findings suggest that TSC1 and TSC2 double mutations cause autistic behaviors similarly to TSC2 mutations, although significant changes in gene expression were attributable to the double mutations. These findings contribute to the knowledge of genotype-phenotype correlations in TSC and suggest that mutations in both the TSC1 and TSC2 genes act in concert to cause neurological symptoms, including autism spectrum disorder.

Proteomic analysis predicts anti-angiogenic resistance in recurred glioblastoma.

Recurrence is common in glioblastoma multiforme (GBM) because of the infiltrative, residual cells in the tumor margin. Standard therapy for GBM consists of surgical resection followed by chemotherapy and radiotherapy, but the median survival of GBM patients remains poor ( 1.5 years). For recurrent GBM, anti-angiogenic treatment is one of the common treatment approaches. However, current anti-angiogenic treatment modalities are not satisfactory because of the resistance to anti-angiogenic agents in some patients. Therefore, we sought to identify novel prognostic biomarkers that can predict the therapeutic response to anti-angiogenic agents in patients with recurrent glioblastoma. We selected patients with recurrent GBM who were treated with anti-angiogenic agents and classified them into responders and non-responders to anti-angiogenic therapy. Then, we performed proteomic analysis using liquid-chromatography mass spectrometry (LC-MS) with formalin-fixed paraffin-embedded (FFPE) tissues obtained from surgical specimens. We conducted a gene-ontology (GO) analysis based on protein abundance in the responder and non-responder groups. Based on the LC-MS and GO analysis results, we identified potential predictive biomarkers for anti-angiogenic therapy and validated them in recurrent glioblastoma patients. In the mass spectrometry-based approach, 4957 unique proteins were quantified with high confidence across clinical parameters. Unsupervised clustering analysis highlighted distinct proteomic patterns (n 269 proteins) between responders and non-responders. The GO term enrichment analysis revealed a cluster of genes related to immune cell-related pathways (e.g., TMEM173, FADD, CD99) in the responder group, whereas the non-responder group had a high expression of genes related to nuclear replisome (POLD) and damaged DNA binding (ERCC2). Immunohistochemistry of these biomarkers showed that the expression levels of TMEM173 and FADD were significantly associated with the overall survival and progression-free survival of patients with recurrent GBM. The candidate biomarkers identified in our protein analysis may be useful for predicting the clinical response to anti-angiogenic agents in patients with recurred GBM.

Elucidation of the mechanisms underlying tumor aggravation by the activation of stress-related neurons in the paraventricular nucleus of the hypothalamus.

A growing body of evidence suggests that excess stress could aggravate tumor progression. The paraventricular nucleus (PVN) of the hypothalamus plays an important role in the adaptation to stress because the hypothalamic-pituitary-adrenal (HPA) axis can be activated by inducing the release of corticotropin-releasing hormone (CRH) from the PVN. In this study, we used pharmacogenetic techniques to investigate whether concomitant activation of CRH

Effects of whole-brain radiation therapy on the blood-brain barrier in immunocompetent and immunocompromised mouse models.

Approximately 20% of all cancer patients will develop brain metastases in their lifespan. The standard of care for patients with multiple brain metastases is whole-brain radiation therapy, which disrupts the blood-brain barrier. Previous studies have shown inflammatory mediators play a role in the radiation-mediated increase in permeability. Our goal was to determine if differential permeability post-radiation occurs between immunocompetent and immunocompromised mice. We utilized a commissioned preclinical irradiator to irradiate brains of C57Bl6J wild-type and athymic nude mice. Acute (3-24 h) effects on blood-brain barrier integrity were evaluated with our in-situ brain perfusion technique and quantitative fluorescent and phosphorescent microscopy. The presence of inflammatory mediators in the brain and serum was determined with a proinflammatory cytokine panel. Blood-brain barrier integrity and efflux transporter activity were altered in the immunocompetent mice 12 h following irradiation without similar observations in the immunocompromised mice. We observed increased TNF-α concentrations in the serum of wild-type mice immediately post-radiation and nude mice 12 h post-radiation. The brain concentration of CXCL1 was also increased in both mouse strains at the 12-h time point. The immune response plays a role in the magnitude of blood-brain barrier disruption following irradiation in a time- and size-dependent manner.

Relationship between brain metastasis and thyroid transcription factor 1.

Brain metastases (BMs) are common in lung adenocarcinomas (ACs). Thyroid transcription factor 1 (TTF-1) is important in the diagnosis of AC. This study aimed to examine the relationship between TTF-1 and BM for the first time in literature. The data of 137 patients with AC that developed BM between 2009 and 2020 were retrospectively analyzed. A total of 137 patients, 120 (87.6%) male, and 17 (12.4%) female were examined. Their mean age was 59.78 ± 0.82 years. The Eastern Cooperative Oncology Group (ECOG) performance score was 0-1 (< 2) for 39 (28.5%) patients and 2-4 (≤ 2) for 98 (71.5%). TTF-1 was positive in 100 (73%) patients and negative in 37 (27%). More than five BMs were present in 102 (74.4%) patients and less than five in 35 (25.6%). All the patients received whole-brain radiotherapy. None of the patients was suitable for surgery or radiosurgery. The median survival time was 6.4 95% confidence interval (CI), 5.67-7.1 months. The survival time was 7 (95% CI, 5.91-8.09) months for the TTF-1 () patients and 5.8 (95% CI, 4.1-7.5) months for the TTF-1 (-) patients. In the univariate analysis, there was a significant relationship between survival time and age (p 0.047), TTF-1 (p 0.024), and ECOG performance score (p 0.002). The multivariance analysis revealed a significant relationship between survival and TTF-1 (p 0.034) and ECOG score (p 0.007). We found a correlation between survival time and ECOG performance score and TTF-1. TTF-1 can be used as a biomarker to monitor prognosis in the follow-up and treatment of patients with AC that develop BM.

Integrative multi-omics networks identify PKCδ and DNA-PK as master kinases of glioblastoma subtypes and guide targeted cancer therapy.

Despite producing a panoply of potential cancer-specific targets, the proteogenomic characterization of human tumors has yet to demonstrate value for precision cancer medicine. Integrative multi-omics using a machine-learning network identified master kinases responsible for effecting phenotypic hallmarks of functional glioblastoma subtypes. In subtype-matched patient-derived models, we validated PKCδ and DNA-PK as master kinases of glycolyticplurimetabolic and proliferativeprogenitor subtypes, respectively, and qualified the kinases as potent and actionable glioblastoma subtype-specific therapeutic targets. Glioblastoma subtypes were associated with clinical and radiomics features, orthogonally validated by proteomics, phospho-proteomics, metabolomics, lipidomics and acetylomics analyses, and recapitulated in pediatric glioma, breast and lung squamous cell carcinoma, including subtype specificity of PKCδ and DNA-PK activity. We developed a probabilistic classification tool that performs optimally with RNA from frozen and paraffin-embedded tissues, which can be used to evaluate the association of therapeutic response with glioblastoma subtypes and to inform patient selection in prospective clinical trials.

Nuclear condensates of YAP fusion proteins alter transcription to drive ependymoma tumourigenesis.

Nuclear localization of HIPPO-YAP fusion proteins has been implicated in supratentorial ependymoma development. Here, unexpectedly, we find that liquid-liquid phase separation, rather than nuclear localization, of recurrent patient-derived YAP fusions, YAP-MAMLD1 and C11ORF95-YAP, underlies ependymoma tumourigenesis from neural progenitor cells. Mutagenesis and chimaera assays demonstrate that an intrinsically disordered region promotes oligomerization of the YAP fusions into nuclear, puncta-like, membrane-less condensates. Oligomerization and nuclear condensates induced by YAP fusion with a coiled-coil domain of transcriptional activator GCN4 also promote ependymoma formation. YAP-MAMLD1 concentrates transcription factors and co-activators, including BRD4, MED1 and TEAD, in condensates while excluding transcriptional repressive PRC2, and induces long-range enhancer-promoter interactions that promote transcription and oncogenic programmes. Blocking condensate-mediated transcriptional co-activator activity inhibits tumourigenesis, indicating a critical role of liquid phase separation for YAP fusion oncogenic activity in ependymoma. YAP fusions containing the intrinsically disordered region features are common in human tumours, suggesting that nuclear condensates could be targeted to treat YAP-fusion-induced cancers.

Cytochrome P450 3A4 (CYP3A4), one of the most important members of the cytochrome P450 subfamily, is a crucial catalyst in the metabolism of numerous drugs. As it catalyzes numerous processes for drug activation or inactivation, the pharmacological activities and clinical outcomes of anticancer drugs metabolized by CYP3A4 are highly dependent on the enzymes activity and expression. Due to the complexity of tumor microenvironments and various influencing factors observed in human

Usefulness of a Rim-Enhancing Pattern on the Contrast-Enhanced 3D-FLAIR Sequence and MRI Characteristics for Distinguishing Meningioma and Malignant Dural-Based Tumor.

Meningiomas are the most common type of extra-axial dural-based tumors however, malignant dural-based tumors can mimic meningiomas on imaging. The aim of this study was to determine the efficacy of differentiating meningiomas from malignant dural-based tumors by using rim-enhancement patterns on a contrast-enhanced FLAIR sequence and MR imaging characteristics. This retrospective study included 102 patients with meningiomas and 31 patients with malignant dural-based tumors who underwent pretreatment MR imaging. The rim-enhancement patterns on contrast-enhanced FLAIR and MR imaging characteristics, including the dural tail sign, hyperostosis, bony destruction, leptomeningeal enhancement, peritumoral edema, T2-weighted signal intensity, and tumor enhancement were evaluated. Complete rim enhancement of the tumor-brain interface on contrast-enhanced FLAIR (contrast-enhanced-FLAIR rim sign) was present in most meningiomas (91102, 89.2%) and at significantly greater frequency than in malignant dural-based tumors (231, 6.5%) ( The rim-enhancement pattern on contrast-enhanced FLAIR could help differentiate meningiomas and malignant dural-based tumors. The presence of complete rim enhancement on contrast-enhanced FLAIR was a robust predictive sign for meningioma.

WDR5 represents a therapeutically exploitable target for cancer stem cells in glioblastoma.

Glioblastomas (GBMs) are heterogeneous, treatment-resistant tumors driven by populations of cancer stem cells (CSCs). However, few molecular mechanisms critical for CSC population maintenance have been exploited for therapeutic development. We developed a spatially resolved loss-of-function screen in GBM patient-derived organoids to identify essential epigenetic regulators in the SOX2-enriched, therapy-resistant niche and identified WDR5 as indispensable for this population. WDR5 is a component of the WRAD complex, which promotes SET1 family-mediated Lys4 methylation of histone H3 (H3K4me), associated with positive regulation of transcription. In GBM CSCs, WDR5 inhibitors blocked WRAD complex assembly and reduced H3K4 trimethylation and expression of genes involved in CSC-relevant oncogenic pathways. H3K4me3 peaks lost with WDR5 inhibitor treatment occurred disproportionally on POU transcription factor motifs, including the POU5F1(OCT4)SOX2 motif. Use of a SOX2OCT4 reporter demonstrated that WDR5 inhibitor treatment diminished cells with high reporter activity. Furthermore, WDR5 inhibitor treatment and WDR5 knockdown altered the stem cell state, disrupting CSC in vitro growth and self-renewal, as well as in vivo tumor growth. These findings highlight the role of WDR5 and the WRAD complex in maintaining the CSC state and provide a rationale for therapeutic development of WDR5 inhibitors for GBM and other advanced cancers.

Nasal administration of a temozolomide-loaded thermoresponsive nanoemulsion reduces tumor growth in a preclinical glioblastoma model.

Glioblastoma (GB) is the worst and most common primary brain tumor. Temozolomide (TMZ), an alkylating agent, is widely used for treating primary and recurrent high-grade gliomas. However, at least 50% of TMZ treated patients do not respond to TMZ and the development of chemoresistance is a major problem. Here, we designed a lipid nanoemulsion containing a thermoresponsive polymer (poloxamer 407) aiming to improve TMZ release into the brain via nasal delivery. Increasing amounts of poloxamer 407 were added to preformed nanoemulsions (250 nm-range) obtained by spontaneous emulsification. The influence of the polymer concentration (from 2.5% to 12.5%) and temperature on viscosity was clearly evidenced. Such effect was also noticed on the mucoadhesiveness of formulations, as well as TMZ release rate and retentionpermeation through nasal porcine mucosa using Franz-type diffusion cells. From these results, a formulation containing 10% of poloxamer (NTMZ-P10) was selected for further experiments by nasal route. A significantly higher TMZ amount was observed in the brain of rats from NTMZ-P10 in comparison with controls. Finally, our results show that formulation reduced significantly tumor growth by three-fold 103.88 ± 43.67 mm

Exosomes multifaceted nanoplatform for targeting brain cancers.

At the moment, anaplastic changes within the brain are challenging due to the complexity of neural tissue, leading to the inefficiency of therapeutic protocols. The existence of a cellular interface, namely the blood-brain barrier (BBB), restricts the entry of several macromolecules and therapeutic agents into the brain. To date, several nano-based platforms have been used in laboratory settings and in vivo conditions to overcome the barrier properties of BBB. Exosomes (Exos) are one-of-a-kind of extracellular vesicles with specific cargo to modulate cell bioactivities in a paracrine manner. Regarding unique physicochemical properties and easy access to various biofluids, Exos provide a favorable platform for drug delivery and therapeutic purposes. Emerging data have indicated that Exos enable brain penetration of selective cargos such as bioactive factors and chemotherapeutic compounds. Along with these statements, the application of smart delivery approaches can increase delivery efficiency and thus therapeutic outcomes. Here, we highlighted the recent advances in the application of Exos in the context of brain tumors.

Multiple synchronous malignancies in an infant with concomitant homozygous

Hereditary cancer predisposition accounts for more than 10% of all cancers in pediatric age group and this is increasingly recognized as an important entity because of modern sequencing techniques. We report a rare association of two concurrent cancer predisposition syndromes,

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Clinical Factors, Management, and Outcomes of Patients Under 18 Years Old With Central Nervous System Tumors Single-Center Experience in Peru.

Few reports on clinical factors, treatment, and survival in children and adolescents with Central nervous system tumors in low-income and middle-income countries in Latin America exist. We retrospectively reviewed such data in all cases of patients younger than 18 years with brain tumors diagnosed in a single tertiary care center in Peru from 2007 through 2017. Variables were analyzed for association with overall survival and event-free survival by using the Kaplan-Meier method and the Cox hazards ratio regression. Seventy-five patients data were analyzed (40 boys, 35 girls mean age7.7 y). The main clinical symptoms were headache, vomiting, difficulty walking, and visual disturbances. The most frequent clinical signs were hydrocephalus, cerebellar signs, visual abnormalities, and focal motor signs. The median time to diagnosis was 12 weeks. Tumor resection was performed in 68 patients, and 37 patients received postoperative radiotherapy. The most frequent histologic subtypes were low-grade gliomas and medulloblastomas. Overall survival rates at 1 and 5 years of disease were 78% (CI 95%, 0.67 to 0.86) and 74% (CI 95%, 0.62 to 0.82), respectively, and the 5-year event-free survival rate was 62% (CI 95%, 0.47 to 0.73). Although diagnosis occurred late in our cohort, the survival rate was higher than that in other Latin American countries.

Combination toripalimab and bevacizumab for an elderly urothelial carcinoma patient with brain metastasis who failed rapidly after radiotherapy a case report and literature review.

Brain metastasis is a rare refractory event in patients with urothelial carcinoma. Platinum-based chemotherapy is the recommended first-line standard therapy for all metastasis urothelial carcinoma patients eligible for cisplatin or carboplatin. Patients ineligible for platinum may receive immunotherapy. No clear evidence exists that UC with brain metastasis is sensitive to immunotherapy, and the optimal treatment for patients with BM is uncertain. We evaluated the safety and efficacy of combined immunotherapy and antivascular therapy in an elderly patient with urothelial carcinoma with brain metastasis, and summarize the currently available evidence. First, she underwent a left nephrectomy and left ureterectomy and recovered well postoperatively. The postoperative pathologic findings were consistent with urothelial carcinoma. Approximately 2 years later, the patient developed impaired limb movement on the right side and underwent MRI, which revealed lesions in the left frontal lobe and suggested brain metastasis. The brain metastasis responded to local radiotherapy but progressed again in a short time. Then, the patient was administered toripalimab at 240 mg combined with bevacizumab at 300 mg every 3 weeks. After 1cycle of treatment, the patient achieved a quick response, and symptoms improved significantly. Repeat evaluation imaging demonstrated that the lesions in the brain and lung were significantly smaller and evaluation showed partial response. The treatment was well tolerated and the patient remained in partial response until the last follow-up by July 2022, 6 months after the initiation of treatment. This case suggests that immune checkpoint blockade combined with antivascular therapy might be a new possibility for patients with metastatic urothelial carcinoma, including brain metastases.

Survival in a consecutive series of 467 glioblastoma patients Association with prognostic factors and treatment at recurrence at two independent institutions.

Therapy of recurrent glioblastoma (GBM) is challenging due to lack of standard treatment. We investigated physicians treatment choice at recurrence and prognostic and predictive factors for survival in GBM patients from Norways two largest regional hospitals. Clinicopathological data from n 467 patients treated at Haukeland and Oslo university hospitals from January 2015 to December 2017 was collected. Data included tumour location, promoter methylation of O6 methylguanine-DNA methyltransferase (MGMT) and mutation of isocitrate dehydrogenase (IDH), patient age, sex, extent of resection at primary diagnosis and treatment at successive tumour recurrences. Cox-proportional hazards regression adjusting for multiple risk factors was used. Median overall survival (OS) was 12.1 months and 21.4% and 6.8% of patients were alive at 2 and 5 years, respectively. Median progression-free survival was 8.1 months. Treatment at recurrence varied but was not associated with difference in overall survival (OS) (p 0.201). Age, MGMT hypermethylation, tumour location and extent of resection were independent prognostic factors. Patients who received 60 Gray radiotherapy with concomitant and adjuvant temozolomide at primary diagnosis had 16.1 months median OS and 9.3% were alive at 5 years. Patients eligible for gamma knifestereotactic radiosurgery alone or combined with chemotherapy at first recurrence had superior survival compared to chemotherapy alone (p<0.001). At second recurrence, combination chemotherapy with or without bevacizumab were both superior to no treatment. Treatment at recurrence differed between the institutions but there was no difference in median OS, indicating that it is the disease biology that dictates patient outcome.

Use of Trametinib in Children and Young Adults With Progressive Low-Grade Glioma and Glioneuronal Tumors.

Low-grade gliomasglioneuronal tumors comprise one-third of all pediatric-type CNS tumors. These tumors are generally caused by activating mutations in the mitogen-activated protein kinase (MAPK) pathway. Targeted drugs, such as trametinib, have shown promise in other cancers and are being utilized in low-grade gliomas. A retrospective chart review was conducted to evaluate radiographic response, visual outcomes, tolerability, and durability of response in progressive circumscribed low-grade gliomas treated with trametinib. Eleven patients were treated with trametinib. The best radiographic response was 211 partial response, 311 minor response, 311 stable disease, and 313 progressive disease. In the patients with partial or minor response, the best response was seen after longer durations of therapy 4 of 5 best responses occurred after at least 9 months of therapy with a median of 21 months. Patients with optic pathway tumors showed at least stable vision throughout treatment, with 3 having improved vision on treatment. Trametinib is effective and well-tolerated in patients with progressive low-grade glioma. Best responses were seen after a longer duration of therapy in those with a positive response. Patients with optic pathway lesions showed stable to improved vision while on treatment.

The fibroblast growth factor receptor inhibitor, derazantinib, has strong efficacy in human gastric tumor models and synergizes with paclitaxel in vivo.

Derazantinib (DZB) is an inhibitor of fibroblast growth factor receptors 1-3 (FGFR1-3), with additional activity against colony-stimulating-factor-1 receptor (CSF1R). We have profiled the activity of DZB in gastric cancer (GC) as monotherapy and combined with paclitaxel, and explored means of stratifying patients for treatment. The antiproliferative potency of DZB in vitro was quantified in 90 tumor cell lines and shown to correlate significantly with FGFR expression (<0.01) but not with FGFR DNA copy-number (CN) or FGFR mutations. In four GC cell lines in vitro, little or no synergy was observed with paclitaxel. In athymic nude mice, bearing cell-line derived xenografts (CDX) or patient-derived xenograft (PDX) GC models, DZB efficacy correlated highly significantly with FGFR gene expression (r2 0.58 P 0.0003 n 18), but not FGFR mutations or DNA-CN. In FGFR-driven GC models, DZB had comparable efficacy to three other FGFR inhibitors and was more efficacious than paclitaxel. DZB had dose-dependent plasma pharmacokinetics but showed low brain penetration at all doses. GC models (one CDX and six PDX) were tested for sensitivity to the combination of DZB and paclitaxel and characterized by immunohistochemistry. The combination showed synergy (5) or additivity (2), and no antagonism, with synergy significantly associated (P < 0.05) with higher levels of M2-type macrophages. The association of strong efficacy of the combination in vivo with M2 macrophages, which are known to express CSF1R, and the absence of synergy in vitro is consistent with the tumor microenvironment also being a factor in DZB efficacy and suggests additional means by which DZB could be stratified for cancer treatment in the clinic.

Cognitive Dysfunction Biomarkers in Patients With Rheumatoid Arthritis A Systematic Review.

During the last years, a growing number of studies have investigated the link between cognitive dysfunction and rheumatoid arthritis (RA), highlighting the potential pathogenic role of several clinical, psychological, and biological factors. We aimed to investigate serological and cerebrospinal fluid biomarkers in humans and its association with cognitive dysfunction in patients with RA. We performed a systematic review using PRISMA (Preferred Reported Items for Systematic Reviews and Meta-analysis) protocol. A systematic search was conducted in the PubMedMEDLINE, EMBASE, LILACS, Scopus, and Google Scholar databases from inception up to November 2021. The inclusion criteria for studies were defined based on the participants involved, type of exposure, type of comparison group, outcome of interest, and study design. Five original studies were included, which provided data from 428 participants. Among plasma proteins, SHH was increased and TTR was reduced in patients with mild cognitive impairment anti-myelin basic protein and anti-myelin oligodendrocyte glycoprotein negatively correlated with memory, executive function, and attention. S100β negatively correlated with memory and executive functions some lymphocyte subpopulations positively correlated with attention, memory, and executive functions. Interleukin 2 IL-2, IL-4, IL-6, and tumor necrosis factor α negatively correlated with memory and positively correlated with executive functions. Interleukin 1β negatively correlated with global cognitive dysfunction and positively correlated with logical thinking. Interleukin 10 and brain-derived neurotrophic factor negatively correlated with memory. Despite the relative scarcity of studies on this subject and the heterogeneity of results, we identified possible biomarkers for cognitive deficits in the RA population. Further longitudinal studies are warranted to clarify these associations and the establishment of possible biomarkers for cognitive deficits in RA.

Increased Circulating Chemokines and Macrophage Recruitment in Growing Vestibular Schwannomas.

There is evidence that macrophage infiltration in the tumor microenvironment promotes vestibular schwannoma (VS) growth. Efficacy of bevacizumab in NF2-associated VS demonstrates the value of therapies targeting the microvascular tumor microenvironment, and tumor-associated macrophages (TAMs) may represent another druggable target. To characterize the relationship between growth, TAM infiltration, and circulating monocyte chemokines in a large cohort of patients with VS. Immunostaining for Iba1 (macrophages), CD31 (endothelium), and fibrinogen (permeability) was performed on 101 growing and 19 static sporadic VS. The concentrations of monocyte-specific chemokines were measured in the plasma of 50 patients with growing VS and 25 patients with static VS. The Iba1 cell count was significantly higher in growing as compared with static VS (592 vs 226×20 HPF, P <0.001). Similarly, the CD31 % surface area was higher in growing VS (2.19% vs 1.32%, P .01). There was a positive correlation between TAM infiltration and VS growth rate, which persisted after controlling for the effect of tumor volume (aR2 0.263, P <0.001). The plasma concentrations of several monocytic chemokines were higher in patients with growing rather than static VS. There is a strong positive correlation between TAM infiltration and volumetric growth of VS, and this relationship is independent of tumor size. There is a colinear relationship between TAM infiltration and tumor vascularity, implying that inflammation and angiogenesis are interlinked in VS. Chemokines known to induce monocyte chemotaxis are found in higher concentrations in patients with growing VS, suggestive of a potential pathophysiological mechanism.

A Pilot Study to Develop Paraneoplastic Cerebellar Degeneration Mouse Model.

Modeling paraneoplastic neurological diseases to understand the immune mechanisms leading to neuronal death is a major challenge given the rarity and terminal access of patients autopsies. Here, we present a pilot study aiming at modeling paraneoplastic cerebellar degeneration with Yo autoantibodies (Yo-PCD). Female mice were implanted with an ovarian carcinoma cell line expressing CDR2 and CDR2L, the known antigens recognized by anti-Yo antibodies. To boost the immune response, we also immunized the mice by injecting antigens with diverse adjuvants and immune checkpoint inhibitors. Ataxia and gait instability were assessed in treated mice as well as autoantibody levels, Purkinje cell density, and immune infiltration in the cerebellum. We observed the production of anti-Yo antibodies in the CSF and serum of all immunized mice. Brain immunoreaction varied depending on the site of implantation of the tumor, with subcutaneous administration leading to a massive infiltration of immune cells in the meningeal spaces, choroid plexus, and cerebellar parenchyma. However, we did not observe massive Purkinje cell death nor any motor impairments in any of the experimental groups. Self-sustained neuro-inflammation might require a longer time to build up in our model. Unusual tumor antigen presentation andor intrinsic, species-specific factors required for pro-inflammatory engagement in the brain may also constitute strong limitations to achieve massive recruitment of antigen-specific T-cells and killing of antigen-expressing neurons in this mouse model.

Cardiovascular Manifestations in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a systemic inflammatory disorder that characteristically affects the joints. RA has extra-articular manifestations that can impact multiple organ systems including the heart, lungs, eyes, skin, and brain. Cardiovascular involvement is a leading cause of mortality in RA. Cardiovascular manifestations of RA include accelerated atherosclerosis, heart failure, pericarditis, myocarditis, endocarditis, rheumatoid nodules, and amyloidosis. Inflammation is an important mediator of endothelial dysfunction and is a key driver of cardiovascular risk and complications in patients with RA. Prompt identification of cardiac pathologies in patients with RA is essential for appropriate management and treatment. Choosing the most appropriate treatment regimen is based on individual patient factors. In this article, we provide a comprehensive review of the epidemiology, pathophysiology, clinical manifestations, diagnosis, and medical management of cardiovascular manifestations of RA. We also discuss the relationship between anti-rheumatic medications, specifically non-steroidal anti-inflammatory drugs, corticosteroids, methotrexate, statins, tumor necrosis factor inhibitors, interleukin-6 inhibitors, Janus kinase inhibitors, and cardiovascular disease.

Multimodal In Vivo Tracking of Chimeric Antigen Receptor T Cells in Preclinical Glioblastoma Models.

Iron oxide nanoparticles have been used to track the accumulation of chimeric antigen receptor (CAR) T cells with magnetic resonance imaging (MRI). However, the only nanoparticle available for clinical applications to date, ferumoxytol, has caused rare but severe anaphylactic reactions. MegaPro nanoparticles (MegaPro-NPs) provide an improved safety profile. We evaluated whether MegaPro-NPs can be applied for in vivo tracking of CAR T cells in a mouse model of glioblastoma multiforme. We labeled tumor-targeted CD70CAR (8R-70CAR) T cells and non-tumor-targeted controls with MegaPro-NPs, followed by inductively coupled plasma optical emission spectroscopy, Prussian blue staining, and cell viability assays. Next, we treated 42 NRG mice bearing U87-MGeGFP-fLuc glioblastoma multiforme xenografts with MegaPro-NP-labeledunlabeled CAR T cells or labeled untargeted T cells and performed serial MRI, magnetic particle imaging, and histology studies. The Kruskal-Wallis test was conducted to evaluate overall group differences, and the Mann-Whitney U test was applied to compare the pairs of groups. MegaPro-NP-labeled CAR T cells demonstrated significantly increased iron uptake compared with unlabeled controls (P < 0.01). Cell viability, activation, and exhaustion markers were not significantly different between the 2 groups (P > 0.05). In vivo, tumor T2 relaxation times were significantly lower after treatment with MegaPro-NP-labeled CAR T cells compared with untargeted T cells (P < 0.01). There is no significant difference in tumor growth inhibition between mice injected with labeled and unlabeled CAR T cells. MegaPro-NPs can be used for in vivo tracking of CAR T cells. Because MegaPro-NPs recently completed phase II clinical trial investigation as an MRI contrast agent, MegaPro-NP is expected to be applied to track CAR T cells in cancer immunotherapy trials in the near future.

Probiotic Formulation VSL3 Interacts with Mesenchymal Stromal Cells To Protect Dopaminergic Neurons via Centrally and Peripherally Suppressing NOD-Like Receptor Protein 3 Inflammasome-Mediated Inflammation in Parkinsons Disease Mice.

Systemic immunomodulation is increasingly recognized among the beneficial effects of mesenchymal stromal cells (MSCs) in treatment of Parkinsons disease (PD), while the underlying mechanism is not fully understood. With the growing popularity of using probiotics as an adjuvant approach in PD treatment, concerns about the added effects of probiotics have been raised. In addition to the molecular mechanism mediating the neuroprotective effects of MSCs, the combined effects of a probiotic formulation, VSL3, and MSC infusion were also evaluated in PD mice. The animals were weekly treated with human MSCs (hMSCs) via the tail vein, VSL3 via the gastrointestinal tract, or their combination six times. hMSCs, VSL3 alone, and their combination markedly ameliorated the decreased striatal dopamine content, loss of dopaminergic neurons in the substantia nigra, increased levels of proinflammatory cytokines in serum, as well as tumor necrosis factor alpha (TNF-α) and interleukin-1β (IL-1β) mRNAs in striatum and peripheral tissues induced by MPTP. Furthermore, hMSCs, VSL3, and their combination notably downregulated mRNA expression of NOD-like receptor protein 3 (NLRP3) and caspase-1 in brain and peripheral tissues of PD mice. These results suggest that hMSCs, VSL3, and their combination prevent neurodegenerative changes in PD mice via anti-inflammatory activities in both the central and peripheral systems, possibly through suppressing the NLRP3 inflammasome. Moreover, two-way analysis of variance (ANOVA) indicated that VSL3 interacts with hMSCs to attenuate neurodegeneration and inhibit NLRP3 inflammasome-mediated inflammation without altering the effects of hMSCs. Major findings of our study support the usage of probiotic formulation VSL3 as an adjuvant therapy to hMSC infusion in PD treatment.

Response to Preoperative Dexamethasone Predicts Postoperative Neurological Improvement of Focal Neurological Deficits in Patients With Brain Metastases.

Steroids are used ubiquitously in the preoperative management of patients with brain tumor. The rate of improvement in focal deficits with steroids and the prognostic value of such a response are not known. To determine the rate at which focal neurological deficits respond to preoperative corticosteroids in patients with brain metastases and whether such an improvement could predict long-term recovery of neurological function after surgery. Patients with brain metastases and related deficits in language, visual field, or motor domains who received corticosteroids before surgery were identified. Characteristics between steroid responders and nonresponders were compared. Ninety six patients demonstrated a visual field (13 patients), language (19), or motor (64) deficit and received dexamethasone in the week before surgery (average cumulative dose 43 mg average duration 2.7 days). 38.5% of patients deficits improved with steroids before surgery, while 82.3% of patients improved by follow-up. Motor deficits were more likely to improve both preoperatively (P .014) and postoperatively (P .010). All 37 responders remained improved at follow-up whereas 42 of 59 (71%) of nonresponders ultimately improved (P < .001). All other clinical characteristics, including dose and duration, were similar between groups. A response to steroids before surgery is highly predictive of long-term improvement postoperatively in brain metastasis patients with focal neurological deficits. Lack of a response portends a somewhat less favorable prognosis. Duration and intensity of therapy do not seem to affect the likelihood of response.

Self-perception of cognitive functions in patients with neurological impairments as measured against a translated Cognitive Change Index.

The primary purpose of the study was to compare the results of neuropsychological assessments with results obtained using a translated Cognitive Change Index (CCI) on patients with diagnosed brain pathology. Our study included 54 patients diagnosed with neurologic pathology (stroke, TBI, or brain tumor) at the University Rehabilitation Institute Soca (average age 51 years, SD 15 years). The results of neuropsychological evaluations and anamnestic data were also obtained for the clinical subsample. Confirmatory factor analysis of the translated CCI performed on responses of 151 normative elderly participants supported a one-factor structure of the questionnaire. Cronbachs α was 0.77 in the clinical sample. A significant correlation was found between lower scores for attention and visual abilities using objective measurement tools and a persons self-assessment of impairment in their own cognitive functions (score on CCI). Individuals can perceive that their attention and visual abilities are impaired when those abilities also score low in diagnostic tests.

Spontaneous early-onset neurodegeneration in the brainstem and spinal cord of NSG, NOG, and NXG mice.

The spectrum of background, incidental, and experimentally induced lesions affecting NSG and NOG mice has been the subject of intense investigation. However, comprehensive studies focusing on the spontaneous neuropathological changes of these immunocompromised strains are lacking. This work describes the development of spontaneous early-onset neurodegeneration affecting both juvenile and adult NSG, NOG, and NXG mice. The study cohort consisted of 367 NSG mice of both sexes (including 33 NSG-SGM3), 61 NOG females (including 31 NOG-EXL), and 4 NXG females. These animals were primarily used for preclinical CAR T-cell testing, generation of humanized immune system chimeras, andor tumor xenograft transplantation. Histopathology of brain and spinal cord and immunohistochemistry (IHC) for AIF-1, GFAP, CD34, and CD45 were performed. Neurodegenerative changes were observed in 57.6% of the examined mice (affected mice age range was 6-36 weeks). The lesions were characterized by foci of vacuolation with neuronal degenerationdeath and gliosis distributed throughout the brainstem and spinal cord. IHC confirmed the development of gliosis, overexpression of CD34, and a neuroinflammatory component comprised of CD45-positive monocyte-derived macrophages. Lesions were significantly more frequent and severe in NOG mice. NSG males were considerably more affected than NSG females. Increased lesion frequency and severity in older animals were also identified. These findings suggest that NSG, NOG, and NXG mice are predisposed to the early development of identical neurodegenerative changes. While the cause of these lesions is currently unclear, potential associations with the genetic mutations shared by NSG, NOG, and NXG mice as well as unidentified viral infections are considered.

EDEM2 is a diagnostic and prognostic biomarker and associated with immune infiltration in glioma A comprehensive analysis.

Glioma is a highly common pathological brain tumor. Misfolded protein response, which is strongly associated with the growth of cancerous tumors, is mediated by the gene, endoplasmic reticulum degradation-enhancing alpha-mannosidase-like protein 2. However, this gene has not been linked to glioma. To assess the same, we used The Cancer Genome Atlas, Chinese Glioma Genome Atlas, and Genotype-Tissue Expression datasets. The gene was overexpressed in gliomas. This overexpression was linked to unfavorable clinical characteristics, such as the World Health Organization grade, isocitrate dehydrogenase mutation, and the combined loss of the short arm chromosome 1 and the long arm of chromosome 19. Quantitative polymerase chain reaction experiments and immunohistochemistry on clinical samples from our institution verified the genes expression and clinical importance. The Human Protein Atlas website verified the messenger ribonucleic acid expression of the gene in glioma cell lines, and immunohistochemistry verified the presence of its protein. A previous survival study indicated that its high expression is substantially related to a bad prognosis. It was identified as an independent predictor of primary glioma prognosis using multivariate Cox regression analysis. To forecast individual survival, we created a nomogram based on this (concordance-index 0.847). Additionally, functional annotation demonstrated its major role in the control of the extracellular matrix and immune system. The scratch assay and transwell migration assay confirmed the decreased invasive ability of U251 glioma cells with the gene knockdown. Its increased expression was found to be related to the extent of macrophage infiltration using the CIBERSORT, ESTIMATE, Single-sample Gene Set Enrichment Analysis, and Tumor Immune Single-Cell Hub (TISCH) algorithms. The Tumor Immune Dysfunction and Exclusion algorithm revealed that the gene can accurately predict the response of immunotherapy (area under the receiver operating characteristic curve 0.857). Further, isocitrate dehydrogenase 1 mutation is typically more frequent when the gene expression is high. Finally, five medicines targeting this gene were discovered utilizing the molecular docking program and drug sensitivity analysis of the RNAactDrug website. Low expression of the gene inhibited glioma cell invasion. Therefore, the gene is helpful for the diagnosis, prognosis, and case-specific immunotherapy of glioma.

Pediatric diffuse midline glioma H3K27- altered A complex clinical and biological landscape behind a neatly defined tumor type.

The 2021 World Health Organization Classification of Tumors of the Central Nervous System, Fifth Edition (WHO-CNS5), has strengthened the concept of tumor grade as a combination of histologic features and molecular alterations. The WHO-CNS5 tumor type Diffuse midline glioma, H3K27-altered, classified within the family of Pediatric-type diffuse high-grade gliomas, incarnates an ideally perfect integrated diagnosis in which location, histology, and genetics clearly define a specific tumor entity. It tries to evenly characterize a group of neoplasms that occur primarily in children and midline structures and that have a dismal prognosis. Such a well-defined pathological categorization has strongly influenced the pediatric oncology community, leading to the uniform treatment of most cases of H3K27-altered diffuse midline gliomas (DMG), based on the simplification that the mutation overrides the histological, radiological, and clinical characteristics of such tumors. Indeed, multiple studies have described pediatric H3K27-altered DMG as incurable tumors. However, in biology and clinical practice, exceptions are frequent and complexity is the rule. First of all, H3K27 mutations have also been found in non-diffuse gliomas. On the other hand, a minority of DMGs are H3K27 wild-type but have a similarly poor prognosis. Furthermore, adult-type tumors may rarely occur in children, and differences in prognosis have emerged between adult and pediatric H3K27-altered DMGs. As well, tumor location can determine differences in the outcome patients with thalamic and spinal DMG have significantly better survival. Finally, other concomitant molecular alterations in H3K27 gliomas have been shown to influence prognosis. So, when such additional mutations are found, which one should we focus on in order to make the correct clinical decision Our review of the current literature on pediatric diffuse midline H3K27-altered DMG tries to address such questions. Indeed, H3K27 status has become a fundamental supplement to the histological grading of pediatric gliomas however, it might not be sufficient alone to exhaustively define the complex biological behavior of DMG in children and might not represent an indication for a unique treatment strategy across all patients, irrespective of age, additional molecular alterations, and tumor location.

Adherence to Prophylactic Anticonvulsant Guidelines for Newly Diagnosed Brain Tumor Patients A Quality Improvement Study.

Clinical guidelines suggest that prophylactic antiepileptic drugs (AEDs) should be given to newly diagnosed seizure-naive brain tumor patients for up to 1 week after craniotomy. Yet, data suggest that prophylactic AEDs are used up to 12 months after surgery. A quality improvement project was implemented to improve adherence to evidence-based prophylactic AED guidelines. A quasi-experimental, pre- and post-test intervention design was used to assess the effect of a multiphase intervention on guideline adherence and prophylactic anticonvulsant prescription rates. The 16-week intervention consisted of provider education sessions, provider alerts, documentation templates, and a weekly audit and feedback. Participants included four providers and newly diagnosed seizure-naive brain tumor patients. Measures included guideline adherence rates and AED prescription rates extracted from chart review, and a provider attitude and knowledge survey. Analyses included descriptive statistics, Wilcoxon signed-rank tests, and Chi-square tests. Guideline adherence increased significantly ( This project highlights the important role of provider education, provider alerts, a documentation template, and audit and feedback in improving guideline adherence rate. Findings suggest that the combination intervention and weekly audit and feedback strategy can improve guideline adherence to prophylactic anticonvulsant use in seizure-naive newly diagnosed brain tumor patients. By following prophylactic AED guideline recommendations, clinicians can avoid the potential side effects of anticonvulsant-induced cognitive, behavioral, and psychiatric issues that can impair patients quality of life.

Virotherapy combined with anti-PD-1 transiently reshapes the tumor immune environment and induces anti-tumor immunity in a preclinical PDAC model.

Pancreatic ductal adenocarcinoma (PDAC) is largely refractory to cancer immunotherapy with PD-1 immune checkpoint blockade (ICB). Oncolytic virotherapy has been shown to synergize with ICB. In this work, we investigated the combination of anti-PD-1 and oncolytic measles vaccine in an immunocompetent transplantable PDAC mouse model. We characterized tumor-infiltrating T cells by immunohistochemistry, flow cytometry and T cell receptor sequencing. Further, we performed gene expression profiling of tumor samples at baseline, after treatment, and when tumors progressed. Moreover, we analyzed systemic anti-tumor and anti-viral immunity. Combination treatment significantly prolonged survival compared to monotherapies. Tumor-infiltrating immune cells were increased after virotherapy. Gene expression profiling revealed a unique, but transient signature of immune activation after combination treatment. However, systemic anti-tumor immunity was induced by virotherapy and remained detectable even when tumors progressed. Anti-PD-1 treatment did not impact anti-viral immunity. Our results indicate that combined virotherapy and ICB induces anti-tumor immunity and reshapes the tumor immune environment. However, further refinement of this approach may be required to develop its full potential and achieve durable efficacy.

Pre-clinical efficacy evaluation of human umbilical cord mesenchymal stem cells for ischemic stroke.

This study explored the underlying therapeutic mechanism of human umbilical cord mesenchymal stem cells (hUCMSCs) for ischemic stroke (IS), and determined the optimal administration time windows and dose-effect relationship. The levels of SDF-1α, IL-10, IL-6, TNF-α, BDNF, IL-1β, and VEGF-A factors in serum and brain tissue lysate were measured by ELISA. The pathological status of brain tissues was evaluated by Hematoxylin-Eosin (HE) staining, and apoptosis of nerve cells was detected by tunel. The protein expression of CXCR-4, NeuN, and Nestin in the brain tissues was assessed through immunofluorescence. The balance beam, forelimb muscle strength, and limb placement were tested on MCAO rats at different time points and doses. The infarct area of the rat brain tissues was measured at the end of the experiment. The hUCMSC treatment during the acute phase of MCAO significantly reduced the secretion of IL-6, TNF-α, IL-1β but increased IL-10 in serum, and the levels of SDF-α and BDNF in serum and brain tissues lysate were also increased. The pathological results showed that there were more neurons in the treatment group compared to the model group. Immunofluorescence assays showed that the expression of CXCR4、Nestin、NeuN was relatively higher than that in the model group. The d4 and d7 treatment significantly improves the motor function, promotes the recovery of forelimb muscle strength, increases the forelimb placement rate and reduces the scope of cerebral infarction, but the d14 treatment group has less therapeutic effect compared to the d4 and d7 treatment. The 2×10 The hUCMSCs can inhibit the infiltration of inflammatory cells in the brain tissue, and promote the repair of brain tissue structure and function. Early intervention by injecting high-dose of hUCMSCs can significantly improve the recovery of neurologicalmotor function and reduce the size of cerebral infarction in rats.

Positive regulators of T cell functions as predictors of prognosis and microenvironment characteristics of low-grade gliomas.

Low-grade gliomas (LGG) are one of the most prevalent types of brain cancers. The efficacy of immunotherapy in LGG is limited compared to other cancers. Immunosuppression in the tumor microenvironment (TME) of LGG is one of the main reasons for the low efficacy of immunotherapy. Recent studies have identified 33 positive regulators of T cell functions (TPRs) that play a critical role in promoting the proliferation, activity, and functions of multiple immunocytes. However, their role in the TME of LGG has not been investigated. This study aimed to construct a risk model based on these TPRs and to detect the significance of immunotypes in predicting LGG prognosis and immunotherapy efficacy. A total of 688 LGGs and 202 normal brain tissues were extracted from The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), and Genotype-Tissue Expression (GTEx) databases. The NMF R package was used to identify TRP-related subtypes. The TPR prognostic model was established using the least absolute shrinkage and selection operator (LASSO) algorithm to predict the overall survival of LGG samples. The Subtype 2 patients had worse survival outcomes, suppressed immune function, and higher immune cell infiltration. A risk regression model consisting of 14 TPRs was established, and its performance was validated in CGGA325 cohorts. The low-risk group exhibited better overall survival, immune microenvironment, and immunotherapy response, as determined Our study identified two distinct TPR subtypes and built a TPR signature to elucidate the characteristics of T cell proliferation in LGG and its association with immune status and prognosis. These findings shed light on possible immunotherapeutic strategies for LGGs.

The relationship between connexin-43 expression and Ki67 in non-glial central nervous system tumors.

Advanced intercellular communication is a known oncogenic factor. In the central nervous system, Connexin-43 (Cx43) forms this junctional networking. Moreover, it correlates with the proliferation rate, and thus behavior, of gliomas. We assessed the expression of Cx43 and its relationship to Ki67 in other common central nervous system tumors. The expression of Cx43 and Ki67 were assessed in formalin-fixed paraffin embedded samples of human brain metastases, meningiomas, and neurinomas using immunohistochemistry. Neurinomas and meningiomas were jointly evaluated due to similar non-malignant behavior. A total of 14 metastases of different extracerebral carcinomas, 6 meningiomas, and 10 neurinomas were evaluated. Five (36%) metastases and 5 (31%) meningiomasneurinomas showed minor expression, whereas 6 (43%) metastases and 2 (13%) meningiomasneurinomas showed no Cx43 expression at all. In 3 (21%) metastases and 9 (56%) meningiomasneurinomas, moderate or strong expression of Cx43 was identified. The higher expression of Cx43 in meningiomas and neurinomas directly correlated with Ki67, r 0.53 ( The expression of Cx43 as a marker of cell-to-cell networking exposed a significant correlation with the Ki67-defined proliferation index in case of primary central nervous system neuroectodermal neoplasms. However, it does not seem to play a comparable role in metastases with extracerebral origin.

Environmental signals perceived by the brain abate pro-metastatic monocytes by dampening glucocorticoids receptor signaling.

While positive social-behavioral factors predict longer survival in cancer patients, the underlying mechanisms are unknown. Since tumor metastasis are the major cancer mortality factor, we investigated how an enriched environment (EE) conductive to enhanced sensory, cognitive and motor stimulation impact metastatic progression in lungs following intravasation in the circulation. We find that mice housed in EE exhibited reduced number of lung metastatic foci compared to control mice housed in a standard environment (SE). Compared to SE mice, EE mice increased lung inflammation as early as 4 days after circulating tumor cells extravasation. The impact of environmental signals on lung metastasis is independent of adrenergic receptors signaling. By contrast, we find that serum corticosterone levels are lower in EE mice and that glucocorticoid receptor (GR) antagonist reduces the number of lung metastasis in SE mice. In addition, the difference of the number of lung metastasis between SE and EE mice is abolished when inflammatory monocytes are rendered deficient in GR signaling. This decreased GR signaling in inflammatory monocytes of SE mice results in an exacerbated inflammatory profile in the lung. Our study shows that not only EE reduces late stages of metastatic progression in lungs but disclose a novel anti-tumor mechanism whereby GR-dependent reprogramming of inflammatory monocytes can inhibit metastatic progression in lungs. Moreover, while inflammatory monocytes have been shown to promote cancer progression, they also have an anti-tumor effect, suggesting that their role is more complex than currently thought.

PMCA inhibition reverses drug resistance in clinically refractory cancer patient-derived models.

Cancer cells have developed molecular strategies to cope with evolutionary stressors in the dynamic tumor microenvironment. Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α) is a metabolic rheostat that regulates diverse cellular adaptive behaviors, including growth and survival. However, the mechanistic role of PGC1α in regulating cancer cell viability under metabolic and genotoxic stress remains elusive. We investigated the PGC1α-mediated survival mechanisms in metabolic stress (i.e., glucose deprivation-induced metabolic stress condition)-resistant cancer cells. We established glucose deprivation-induced metabolic stress-resistant cells (selected cells) from parental tumor cells and silenced or overexpressed PGC1α in selected and parental tumor cells. Several in vitro and in vivo mouse experiments were conducted to elucidate the contribution of PGC1α to cell viability in metabolic stress conditions. Interestingly, in the mouse xenograft model of patient-derived drug-resistant cancer cells, each group treated with an anti-cancer drug alone showed no drastic effects, whereas a group that was co-administered an anti-cancer drug and a specific PMCA inhibitor (caloxin or candidate 13) showed marked tumor shrinkage. Our results suggest that PGC1α is a key regulator of anti-apoptosis in metabolic and genotoxic stress-resistant cells, inducing PMCA expression and allowing survival in glucose-deprived conditions. We have discovered a novel therapeutic target candidate that could be employed for the treatment of patients with refractory cancers.