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A new comprehensive grading for giant pituitary adenomas SLAP grading.

Explanation-Driven Deep Learning Model for Prediction of Brain Tumour Status Using MRI Image Data.

Cancer research has seen explosive development exploring deep learning (DL) techniques for analysing magnetic resonance imaging (MRI) images for predicting brain tumours. We have observed a substantial gap in explanation, interpretability, and high accuracy for DL models. Consequently, we propose an explanation-driven DL model by utilising a convolutional neural network (CNN), local interpretable model-agnostic explanation (LIME), and Shapley additive explanation (SHAP) for the prediction of discrete subtypes of brain tumours (meningioma, glioma, and pituitary) using an MRI image dataset. Unlike previous models, our model used a dual-input CNN approach to prevail over the classification challenge with images of inferior quality in terms of noise and metal artifacts by adding Gaussian noise. Our CNN training results reveal 94.64% accuracy as compared to other state-of-the-art methods. We used SHAP to ensure consistency and local accuracy for interpretation as Shapley values examine all future predictions applying all possible combinations of inputs. In contrast, LIME constructs sparse linear models around each prediction to illustrate how the model operates in the immediate area. Our emphasis for this study is interpretability and high accuracy, which is critical for realising disparities in predictive performance, helpful in developing trust, and essential in integration into clinical practice. The proposed method has a vast clinical application that could potentially be used for mass screening in resource-constraint countries.

Dietary Fiber as a Counterbalance to Age-Related Microglial Cell Dysfunction.

With increasing age, microglia shift toward a pro-inflammatory phenotype that may predispose individuals to neurodegenerative disease. Because fiber fermentation in the colon produces bioactive short-chain fatty acids (SCFAs e.g., acetate, butyrate, and propionate) that signal through the gut-brain axis, increasing dietary fiber may prevent or reverse age-related dysregulation of microglia. Adult (3-4 months old) and aged (23-24 months old) male and female mice were given

A Three-Surgeon-Six-Hand Operation Using a 4K-3D Exoscope for Neurological Surgery A Case Report.

Advances in digital imaging including evolving of 3-dimensional (3D) exoscope has allowed its use as an alternative to microscopes in neurosurgery. The exoscope can concede wide space around the operating table and patient. Here, we show a three-surgeon-six-hand operative approach using a 4K-3D exoscope. Practical advantages and disadvantages of this approach are discussed. A 58-year-old male was refered with a 60 mm diameter meningioma in the right frontal convexity. The tumor removal was done by an operator and two assistants with a scrub nurse while viewing images displayed on a 55-inch monitor with integrated 4K and 3D visualization technology retrieved by KINEVO®. Meaningful communication between the operator and two assistants allowed for simultaneous, and precise surgical procedures. Gross total removal was achieved without damaging the brain. The ocular-free, openness of 4K-3D exoscope allows for a three-surgeon-six-handed operation, which leads to simultaneous surgical maneuvers by multiple hands, shorter operative time, flexibleintermittent brain retraction made by two assistants, and educational benefits owing to the surgical procedure being visually shared.

Improving Minimum Cross-Entropy Thresholding for Segmentation of Infected Foregrounds in Medical Images Based on Mean Filters Approaches.

Mean-based thresholding methods are among the most popular techniques that are used for images segmentation. Thresholding is a fundamental process for many applications since it provides a good degree of intensity separation of given images. Minimum cross-entropy thresholding (MCET) is one of the widely used mean-based methods for images segmentation it is based on a classical mean that remains steady and limited value. In this paper, to improve the efficiency of MCET, dedicated mean estimation approaches are proposed to be used with MCET, instead of using the classical mean. The proposed mean estimation approaches, for example, alpha trim, harmonic, contraharmonic, and geometric, tend to exclude the negative impact of the undesired parts from the mean computation process, such as noises, local outliers, and gray intensity levels, and then provide an improvement for the thresholding process that can reflect good segmentation results. The proposed technique adds a profound impact on accurate images segmentation. It can be extended to other applications in object detection. Three data sets of medical images were applied for segmentation in this paper, including magnetic resonance imaging (MRI) Alzheimers, MRI brain tumor, and skin lesion. The unsupervised and supervised evaluations were used to conduct the efficiency of the proposed method.

Evaluation and Monitoring of Endometrial Cancer Based on Magnetic Resonance Imaging Features of Deep Learning.

This study was aimed to compare and analyze the magnetic resonance imaging (MRI) manifestations and surgical pathological results of endometrial cancer (EC) and to explore the clinical research of MRI in the diagnosis and staging of EC.

IP-Se-06, a Selenylated Imidazo1,2-

Glioblastoma multiforme (GBM) is a notably lethal brain tumor associated with high proliferation rate and therapeutic resistance, while currently effective treatment options are still lacking. Imidazo1,2-

The Function of NF-Kappa B During Epilepsy, a Potential Therapeutic Target.

The transcriptional regulator nuclear factor kappa B (NF-κB) modulates cellular biological activity by binding to promoter regions in the nucleus and transcribing various protein-coding genes. The NF-κB pathway plays a major role in the expressing genes related to inflammation, including chemokines, interleukins, and tumor necrosis factor. It also transcribes genes that can promote neuronal survival or apoptosis. Epilepsy is one of the most common brain disorders and it not only causes death worldwide but also affects the day-to-day life of affected individuals. While epilepsy has diverse treatment options, there remain patients who are not sensitive to the existing treatment methods. Recent studies have implicated the critical role of NF-κB in epilepsy. It is upregulated in neurons, glial cells, and endothelial cells, due to neuronal loss, glial cell proliferation, blood-brain barrier dysfunction, and hippocampal sclerosis through the glutamate and γ-aminobutyric acid imbalance, ion concentration changes, and other mechanisms. In this review, we summarize the functional changes caused by the upregulation of NF-κB in the central nervous system during different periods after seizures. This review is the first to deconvolute the complicated functions of NF-κB, and speculate that the regulation of NF-κB can be a safe and effective treatment strategy for epilepsy.

Papillary thyroid microcarcinomas (PTMCs) have been attributed to the recent increased incidence of thyroid cancer. Although indolent, a subset of PTMC could potentially develop distant metastasis (DM). This study aimed to evaluate the clinico-pathological features and molecular characteristics of PTMC and identify the risk factors for DM in PTMC patients from Middle Eastern ethnicity. We retrospectively analyzed 210 patients with histologically confirmed PTMC. Clinico-pathological associations for DM, Among the PTMC patients included in this cohort, DM was noted in 6.0% (11184), whereas tumor relapse occurred in 29184 (15.8%). Of the 11 cases with DM, lung metastasis occurred in 8 cases, bone metastasis in 2 cases and brain metastasis in 1 case. Presence of extrathyroidal extension and male sex were significantly associated with DM. Molecular analysis showed Our study indicates a surprisingly high frequency of

Resolution of radiation necrosis with bevacizumab following radiation therapy for primary CNS lymphoma.

Radiation necrosis (RN) is a rare but serious adverse effect following treatment with radiation therapy. No standard of care exists for the management of RN, and efforts to prevent and treat RN are limited by a lack of insight into the pathomechanics and molecular drivers of RN. This case series describes the outcomes of treatment with bevacizumab (BV) in two primary CNS lymphoma (PCNSL) patients who developed symptomatic biopsy-proven RN after whole brain radiation (WBRT) with a stereotactic radiosurgery (SRS) boost. Patient 1 is a 52 year-old female with PCNSL treated with WBRT followed by an SRS boost. She developed symptomatic biopsy-proven RN, and initial treatment with tocopherol and pentoxifylline was unsuccessful. A 100% clinical and radiographic response was achieved with 4 cycles of BV. Patient 2, a 48 year-old male with PCNSL, presented with seizures and biopsy-proven RN after radiation therapy. Initial empiric treatment with tocopherol and pentoxifylline was unsuccessful. A 100% clinical and radiographic response was achieved with 3 cycles of BV. Monitoring for RN in patients with PCNSL treated with radiation therapy is warranted. BV is an efficacious treatment and a viable alternative to corticosteroids or surgical intervention.

Neuroinflammation in a Rat Model of Tourette Syndrome.

Tourette syndrome (TS) is a group of childhood-onset chronic neuropsychiatric disorders characterized by tics, i.e., repetitive, sudden, and involuntary movements or vocalizations, which is often associated with various psychopathological andor behavioral comorbidities, including attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), anxiety, depression, and sleep disorders and have a worse prognosis. The mechanism of TS is still not clear. The relationship between immune activation, neuroinflammation, and neuropsychiatric disorders has attracted much attention in the past two decades. To explore the underlying mechanism in TS, the relationship between neuroinflammation and behavioral alterations in TS rats was investigated in this study. A total of 36 Sprague-Dawley male rats were divided into three groups randomly as follows the TS, control (CON), and drug intervention groups. The TS rat group was treated with haloperidol (Hal) (the TS Hal group). The TS rat model was established using 3,3-iminodipropionitrile (IDPN), which is a well-known animal model of TS. The behavioral syndromes, brain tissue cytokines, like interleukin (IL)-6 and tumor necrosis factor-alpha (TNF-α), and microglial activation of the three groups were assessed. The behavioral scores of rats in the TS group and the TS Hal group were higher than those in the CON group ( The IDPN-induced TS rats had significant neuroinflammation in the brain, and the interaction between dopamine (DA) dysregulation and immune dysfunction may play a vital role in the pathogenic mechanisms of TS.

High-Grade Glioma Treatment Response Monitoring Biomarkers A Position Statement on the Evidence Supporting the Use of Advanced MRI Techniques in the Clinic, and the Latest Bench-to-Bedside Developments. Part 1 Perfusion and Diffusion Techniques.

Summarize evidence for use of advanced MRI techniques as monitoring biomarkers in the clinic, and highlight the latest bench-to-bedside developments. Experts in advanced MRI techniques applied to high-grade glioma treatment response assessment convened through a European framework. Current evidence regarding the potential for monitoring biomarkers in adult high-grade glioma is reviewed, and individual modalities of perfusion, permeability, and microstructure imaging are discussed (in Part 1 of two). In Part 2, we discuss modalities related to metabolism andor chemical composition, appraise the clinic readiness of the individual modalities, and consider post-processing methodologies involving the combination of MRI approaches (multiparametric imaging) or machine learning (radiomics). High-grade glioma vasculature exhibits increased perfusion, blood volume, and permeability compared with normal brain tissue. Measures of cerebral blood volume derived from dynamic susceptibility contrast-enhanced MRI have consistently provided information about brain tumor growth and response to treatment it is the most clinically validated advanced technique. Clinical studies have proven the potential of dynamic contrast-enhanced MRI for distinguishing post-treatment related effects from recurrence, but the optimal acquisition protocol, mode of analysis, parameter of highest diagnostic value, and optimal cut-off points remain to be established. Arterial spin labeling techniques do not require the injection of a contrast agent, and repeated measurements of cerebral blood flow can be performed. The absence of potential gadolinium deposition effects allows widespread use in pediatric patients and those with impaired renal function. More data are necessary to establish clinical validity as monitoring biomarkers. Diffusion-weighted imaging, apparent diffusion coefficient analysis, diffusion tensor or kurtosis imaging, intravoxel incoherent motion, and other microstructural modeling approaches also allow treatment response assessment more robust data are required to validate these alone or when applied to post-processing methodologies. Considerable progress has been made in the development of these monitoring biomarkers. Many techniques are in their infancy, whereas others have generated a larger body of evidence for clinical application.

The Subventricular Zone in Glioblastoma Genesis, Maintenance, and Modeling.

Glioblastoma (GBM) is a malignant tumor with a median survival rate of 15-16 months with standard care however, cases of successful treatment offer hope that an enhanced understanding of the pathology will improve the prognosis. The cell of origin in GBM remains controversial. Recent evidence has implicated stem cells as cells of origin in many cancers. Neural stemprecursor cells (NSCs) are being evaluated as potential initiators of GBM tumorigenesis. The NSCs in the subventricular zone (SVZ) have demonstrated similar molecular profiles and share several distinctive characteristics to proliferative glioblastoma stem cells (GSCs) in GBM. Genomic and proteomic studies comparing the SVZ and GBM support the hypothesis that the tumor cells and SVZ cells are related. Animal models corroborate this connection, demonstrating migratory patterns from the SVZ to the tumor. Along with laboratory and animal research, clinical studies have demonstrated improved progression-free survival in patients with GBM after radiation to the ipsilateral SVZ. Additionally, key genetic mutations in GBM for the most part carry regulatory roles in the SVZ as well. An exciting avenue towards SVZ modeling and determining its role in gliomagenesis in the human context is human brain organoids. Here we comprehensively discuss and review the role of the SVZ in GBM genesis, maintenance, and modeling.

Tumor Treating Fields Suppression of Ciliogenesis Enhances Temozolomide Toxicity.

Tumor Treating Fields (TTFields) are low-intensity, alternating intermediate-frequency (200 kHz) electrical fields that extend survival of glioblastoma patients receiving maintenance temozolomide (TMZ) chemotherapy. How TTFields exert efficacy on cancer over normal cells or interact with TMZ is unclear. Primary cilia are microtubule-based organelles triggered by extracellular ligands, mechanical and electrical field stimulation and are capable of promoting cancer growth and TMZ chemoresistance. We found in both low- and high-grade patient glioma cell lines that TTFields ablated cilia within 24 h. Halting TTFields treatment led to recovered frequencies of elongated cilia. Cilia on normal primary astrocytes, neurons, and multiciliatedependymal cells were less affected by TTFields. The TTFields-mediated loss of glioma cilia was partially rescued by chloroquine pretreatment, suggesting the effect is in part due to autophagy activation. We also observed death of ciliated cells during TTFields by live imaging. Notably, TMZ and TTFields have opposing effects on glioma ciliogenesis. TMZ-induced stimulation of ciliogenesis in both adherent cells and gliomaspheres was blocked by TTFields. Surprisingly, the inhibitory effects of TTFields and TMZ on tumor cell recurrence are linked to the relative timing of TMZ exposure to TTFields and ARL13B

Comprehensive Assessment of Selected Immune Cell Subpopulations Changes in Chemotherapy-Naïve Germ Cell Tumor Patients.

The pattern of immune cell distribution in testicular germ cell tumors (GCT) significantly differs from the immune environment in normal testicular tissues. The present study aimed to evaluate the role of different leukocyte subpopulation in GCTs. A cohort of 84 chemotherapy-naïve GCT patients was analyzed. Immunophenotyping of peripheral blood leukocyte subpopulations was carried out by flow cytometry. In addition, the data assessing the immunophenotypes and the baseline clinicopathological characteristics of the included subjects were statistically evaluated. Their prognostic value for the assessment of progression-free survival (PFS) and overall survival (OS) was estimated. The percentage of different innateadaptive immune cell subpopulations was significantly associated with poor risk-related clinical features, including the number of metastatic sites, presence of retroperitoneal, mediastinal, lung, brain and non-pulmonary visceral metastases as well as with the S-stage and International Germ Cell Consensus Classification Group (IGCCCG) risk groups. In univariate analysis, the percentages of neutrophils, eosinophils, dendritic cells type 2, lymphocytes and T cytotoxic cells were significantly associated with PFS, while the neutrophil, non-classical monocyte and lymphocyte percentage were associated with OS. However, all these outcome correlations were not independent of IGCCCG in multivariate analysis. The data indicated a link among different innateadaptive peripheral immune cell subpopulations in GCT patients. In addition, the association between these subpopulations and tumor characteristics was also investigated. The findings of the present study may contribute to a deeper understanding of the interactions between cancer and innateadaptive immune response in GCT patients.

Surgical Management of Brain Metastasis Challenges and Nuances.

Brain metastasis is the most common type of intracranial tumor. The contemporary management of brain metastasis is a challenging issue and traditionally has carried a poor prognosis as these lesions typically occur in the setting of advanced cancer. However, improvement in systemic therapy, advances in radiation techniques and multimodal therapy tailored to the individual patient, has given hope to this patient population. Surgical resection has a well-established role in the management of brain metastasis. Here we discuss the evolving role of surgery in the treatment of this diverse patient population.

Case Report ALK-Positive Histiocytosis With

Anaplastic lymphoma kinase (ALK)-positive histiocytosis is a rare type of histiocytosis that could affect multiple systems in children and adults. 10 cases of ALK-positive histiocytosis invading the central nervous system (CNS) have been reported. Herein, we report a case of ALK-positive histiocytosis invading the central nervous system and lungs and the details of follow-up of tumor dynamic changes during treatment. An 18-month-old boy was underweight and had slow growth of almost 3 months duration. The child could not stand and walk independently, and his language and intelligence development occurred later than those of his peers. Cranial magnetic resonance imaging revealed a giant suprasellar lesion with isosignal, measuring approximately 5.1× 3.6× 4.0 cm on T1-weighted imaging, with an obvious mass effect. Nodular, slightly low-signal shadows were also observed in the left temporal pole and left hippocampus, measuring approximately 1.0 cm × 0.7 cm× 0.5 cm and 0.9 cm× 0.8 cm × 0.5 cm on T1-weighted, respectively. The child underwent partial resection of the suprasellar lesion, and a diagnosis of ALK-positive histiocytosis was made histologically. Subsequently, the patient received chemotherapy (CHOP regimen) and anti-ALK therapy (crizotinib). The lesions were gradually shrinking without dissemination and the changes of intracranial and lung lesions were monitored with imaging during therapy. Unfortunately, the child died 8 months after the first surgery because of worsening intracranial infection. ALK-positive histiocytosis may involve the central nervous system and disseminate intracranially. ALK-positive histiocytosis should be considered for the differential diagnosis of suprasellar lesions.

Are there country-specific differences in the use of pegvisomant for acromegaly in clinical practice An analysis from ACROSTUDY.

A comprehensive picture of pegvisomant use for treating acromegaly in routine clinical practice in different countries is lacking. We aimed, therefore, to document country-specific behaviors in real-life pegvisomant use, and the main safety and effectiveness outcomes in the ACROSTUDY. ACROSTUDY is an open-label, non-interventional, post-marketing safety surveillance study. A descriptive analysis was performed using data from the six top-recruiter ACROSTUDY countries, i.e., Germany (n 548 patients), Italy (n 466), France (n 312), USA (n 207), Spain (n 200) and the Netherlands (n 175). These nations accounted for > 85% of the ACROSTUDY cases. The mean pegvisomant dose at treatment start was lowest in the Netherlands (9.4 mgday), whereas it ranged between 10.9 and 12.6 mgday in the other countries. At year 5, the mean pegvisomant dose was around 15 mgday in all countries, except France (18.1 mgday). At starting pegvisomant, patients treated with monotherapy ranged between 15% in the Netherlands and 72% in Spain. Monotherapy remained lowest over time in the Netherlands. In all countries, the percentage of patients with normal IGF-1 increased steeply from < 20% at baseline to 43-58% at month 6 and 51-67% at year 1. After that, we observed minor changes in the rate of acromegaly control in all countries. The Netherlands peaked in disease control at year 2 (72%). The proportion of patients reporting changes in pituitary tumor size was generally low. Serious treatment-related adverse events were < 5% in all countries. Our study provided a detailed summary of real-life use of pegvisomant in the six top-recruiter ACROSTUDY nations.

Diffuse midline gliomas with H3K27 alteration in children a clinicopathological analysis of forty-one cases.

Pituicytoma a clinicopathological analysis of twenty-one cases.

TMZ magnetic temperature-sensitive liposomes-mediated magnetothermal chemotherapy induces pyroptosis in glioblastoma.

Glioblastoma (GBM) is the most fatal and common type of primary malignant tumors in central nervous system. Chemotherapy drugs are difficult to reach the encephalic region effectively due to blood-brain barrier (BBB), but functional nanoparticle drug carriers can help to solve the problem. Herein, we developed a controllable drug carrier called temozolomide magnetic temperature-sensitive liposomes (TMZFe-TSL) to investigate its feasibility and molecular mechanisms on GBM. Our research found TMZFe-TSL exposed to alternating magnetic field (AMF) could induce significantly GBM cell death and promote the production of ROS. It also showed that the expression of NLRP3, CASP1 and N-GSDMD was upregulated compared to the control group, while the expression of CASP3 showed a reverse change. The results indicated that TMZFe-TSL exposed to the AMF was capable of inducing GBM cells death. And the way and mechanisms of cell death may involve in ROS and pyroptosis, but not apoptosis.

Investigation of anti-cancer effects of new pyrazino1,2-abenzimidazole derivatives on human glioblastoma cells through 2D in vitro model and 3D-printed microfluidic device.

Recent studies show targeted therapy of new pyrazino1,2-abenzimidazole derivatives with COX-II inhibitory effects on different cancer cells. This study aimed to investigate 2D cell culture and 3D spheroid formation of glioblastoma multiforme (GBM) cells using a microfluidic device after exposure to these compounds. After isolating astrocytes from human GBM samples, IC The obtained results showed that both compounds have positive effects in reducing G2M cell population and GBM cell migration. Furthermore, real-time gene expression data showed that L1 and L2 significantly impact the upregulation of P21 and P53 and down-regulation of cyclin D1, MMP2, and MMP9. On the other hand, GBM spheroids exposed to L1 and L2 become smaller with fewer live cells. Our data on human isolated astrocyte cells in 2D and 3D cell culture conditions showed that L1 and L2 compounds could reduce GBM cells invasion by controlling gene expressions associated with migration and proliferation. Moreover, designing microfluidic platform and related cell culture protocols facilitates the broad screening of 3D multicellular tumor spheroids derived from GBM tumor biopsies and provides effective drug development for brain gliomas.

Mismatch repair deficiency and clinical implications in prostate cancer.

Despite recent therapeutic advances, castration-resistant prostate cancer (CRPC) remains a lethal disease and novel therapies are needed. Precision oncology provides an avenue for developing effective tailored approaches for treating malignancies based on a tumors molecular profile. Indeed, the presence of mismatch repair deficiency (MMRd) has proven to be an important predictive biomarker for response to immune checkpoint blockade across multiple tumor types, including prostate cancer, and represents a major precision oncology success story. The mismatch repair (MMR) system is integral to maintaining genomic fidelity during cellular replication. Cancers with deficiencies in this system accumulate high numbers of mutations and express many neoantigens that may be recognized by the immune system. The checkpoint inhibitor pembrolizumab has recently been approved for all cancers that are MMR deficient, and several retrospective series have specifically shown that pembrolizumab is effective in MMRd prostate cancer. Although the prevalence of MMRd in CRPC is low (approximately 3%-5% of cases), this is an important subset of men that require a unique therapeutic approach. This review will focus on MMRd in prostate cancer, highlighting the clinical implications, role of immunotherapy, and areas of future research.

Soluble TGFBI aggravates the malignancy of cholangiocarcinoma through activation of the ITGB1 dependent PPARγ signalling pathway.

Cholangiocarcinoma is a devastating cancer with a poor prognosis. Previous reports have presented conflicting results on the role of transforming growth factor-β-induced protein (TGFBI) in malignant cancers. Currently, our understanding of the role of TGFBI in cholangiocarcinoma is ambiguous. The aim of the present study was to investigate the role of TGFBI in human cholangiocarcinoma. Iterative patient partitioning (IPP) scoring and consecutive elimination methods were used to select prognostic biomarkers. mRNA and protein expression levels were determined using Gene Expression Omnibus (GEO), Western blot and ELISA analyses. Biological activities of selected biomarkers were examined using both in vitro and in vivo assays. Prognostic values were assessed using Kaplan-Meier and Liptaks z score analyses. TGFBI was selected as a candidate cholangiocarcinoma biomarker. GEO database analysis revealed significantly higher TGFBI mRNA expression levels in cholangiocarcinoma tissues compared to matched normal tissues. TGFBI protein was specifically detected in a soluble form in vitro and in vivo. TGFBI silencing evoked significant anti-cancer effects in vitro. Soluble TGFBI treatment aggravated the malignancy of cholangiocarcinoma cells both in vitro and in vivo through activation of the integrin beta-1 (ITGB1) dependent PPARγ signalling pathway. High TGFBI expression was associated with a poor prognosis in patients with cholangiocarcinoma. Our data suggest that TGFBI may serve as a promising prognostic biomarker and therapeutic target for cholangiocarcinoma.

Ultrasound-targeted microbubble destruction (UTMD)-mediated miR-150-5p attenuates oxygen and glucose deprivation-induced cardiomyocyte injury by inhibiting TTC5 expression.

Cardiomyocyte injury is a typical feature in cardiovascular diseases. Changes in cardiomyocytes strongly affect the progression of cardiovascular diseases. This work aimed to investigate the biological function and potential mechanism of action of miR-150-5p in cardiomyocytes. A myocardial ischemia (MI) injury rat model was constructed to detect miR-150-5p and tetratricopeptide repeat domain 5 (TTC5) expression during heart ischemia injury. Primary cardiomyocytes were isolated for in vitro study. CCK-8 assays were used to detect cardiomyocyte viability. Western blots were used to detect TTC5 and P53 expression. qPCR was utilized to measure RNA expression of miR-150-5p and TTC5. The TUNEL assay was used to determine cell apoptosis. ELISA was used to determine cytokine (TNF-α, IL-1β, IL-6, and IL-8) levels in heart tissues and cell culture supernatants. A dual-luciferase reporter assay was carried out to verify the binding ability between miR-150-5p and TTC5. Oxygen-glucose deprivation (OGD) treatment significantly inhibited cell viability. Ultrasound-targeted microbubble destruction (UTMD)-mediated uptake of miR-150-5p inverted these results. Additionally, UTMD-mediated uptake of miR-150-5p retarded the effects of OGD treatment on cell apoptosis. Besides, UTMD-mediated uptake of miR-150-5p counteracted the effects of OGD treatment on the inflammatory response by regulating cytokine (TNF-α, IL-1β, IL-6, and IL-8) levels. For the mechanism of the protective effect on the heart, we predicted and confirmed that miR-150-5p bound to TTC5 and inhibited TTC5 expression. UTMD-mediated uptake of miR-150-5p attenuated OGD-induced primary cardiomyocyte injury by inhibiting TTC5 expression. This discovery contributes toward further understanding the progression of primary cardiomyocyte injury.

Optimization of hippocampus sparing during whole brain radiation therapy with simultaneous integrated boost-tutorial and efficacy of complete directional hippocampal blocking.

Hippocampus-avoidance whole brain radiotherapy with simultaneous integrated boost (HA-WBRTSIB) is a complex treatment option for patients with multiple brain metastases, aiming to prevent neurocognitive decline and simultaneously increase tumor control. Achieving efficient hippocampal dose reduction in this context can be challenging. The aim of the current study is to present and analyze the efficacy of complete directional hippocampal blocking in reducing the hippocampal dose during HA-WBRTSIB. A total of 30 patients with multiple metastases having undergone HA-WBRTSIB were identified. The prescribed dose was 30 Gy in 12 fractions to the whole brain, with 98% of the hippocampus receiving ≤ 9 Gy and 2% ≤ 17 Gy and with SIB to metastasesresection cavities of 36-51 Gy in 12 fractions. Alternative treatment plans were calculated using complete directional hippocampal blocking and compared to conventional plans regarding target coverage, homogeneity, conformity, dose to hippocampi and organs at risk. All alternative plans reached prescription doses. Hippocampal blocking enabled more successful sparing of the hippocampus, with a mean dose of 8.79 ± 0.99 Gy compared to 10.07 ± 0.96 Gy in 12 fractions with the conventional method (p < 0.0001). The mean dose to the whole brain (excluding metastases and hippocampal avoidance region) was 30.52 ± 0.80 Gy with conventional planning and 30.28 ± 0.11 Gy with hippocampal blocking (p 0.11). Target coverage, conformity and homogeneity indices for whole brain and metastases, as well as doses to organs at risk were similar between planning methods (p > 0.003). Complete directional hippocampal blocking is an efficient method for achieving improved hippocampal sparing during HA-WBRTSIB.

Discovery of Thieno2,3-

Endocrine therapies in the treatment of early and metastatic estrogen receptor α positive (ERα) breast cancer (BC) are greatly limited by

Improving the Safety of Mesenchymal Stem Cell-Based

Human mesenchymal stem cells (MSCs) are multipotent stem cells that have been intensively studied as therapeutic tools for a variety of disorders. To enhance the efficacy of MSCs, therapeutic genes are introduced using retroviral and lentiviral vectors. However, serious adverse events (SAEs) such as tumorigenesis can be induced by insertional mutagenesis. We generated lentiviral vectors encoding the wild-type herpes simplex virus thymidine kinase (HSV-TK) gene and a gene containing a point mutation that results in an alanine to histidine substitution at residue 168 (TK(A168H)) and transduced expression in MSCs (MSC-TK and MSC-TK(A168H)). Transduction of lentiviral vectors encoding the TK(A168H) mutant did not alter the proliferation capacity, mesodermal differentiation potential, or surface antigenicity of MSCs. The MSC-TK(A168H) cells were genetically stable, as shown by karyotyping. MSC-TK(A168H) responded to ganciclovir (GCV) with an half maximal inhibitory concentration (IC

SMARCA4-Deficient Undifferentiated Tumor of Lung Mass-A Rare Tumor With the Rarer Occurrence of Brain Metastasis A Case Report and Review of the Literature.

Among thoracic tumors, these include subsets of a relatively newly described and yet to be fully characterized tumor entity SMARCA4-deficient Undifferentiated Tumor (SMARCA4-dUT). Mutations of SMARCA4 (SWISNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4) gene and loss of BRG1 (Brahma-related gene-1) is the underlying molecular hallmark of SMARCA4-dUT. They mostly involved the mediastinum, lung, andor pleura showing undifferentiated round cell or rhabdoid morphology associated with aggressive clinical behavior. The pathogenesis of these tumors is still not clear. Morphologically, SMARAC4-dUT is differentiated from SMARCA4-dNSCLC by the presence of squamous and solid components in the latter. Immunohistochemically SMARC4-dUT has characteristic loss of SMARCA4 and SMARCA2 and strong expression of SOX2, CD34, and SALL4. Common sites of metastasis include lymph nodes, bones, and adrenal glands but rarely brain metastasis. We present a unique and rare case of a 76-year-old male with a right lung mass with documented pathology of SMARCA4-dUT and was found to have multiple brain metastases.

Recurrence of Anti-N-Methyl-D-Aspartate Receptor Encephalitis A Cohort Study in Central China.

To investigate factors that could impact or predict the probability of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis recurrence in central China. From November 2014 to October 2020, observational data of anti-NMDAR encephalitis inpatients in our institution were collected and analyzed prospectively. The demographics, clinical characteristics, tumor status, lesion locations on MRI and immunotherapies, etc. had entered into a Cox regression model for the identification of the factors associated with relapse-free survival. We enrolled 113 patients in a row (median age 28 years, range 1-61 years). The gender distribution was not statistically significant ( Anti-NMDAR encephalitis can recur in around one out of every six cases, and symptoms are generally milder than when it first appears. Recurrence is not related to the severity in the acute phase or the prognosis at follow-up. Patients with ≥3 abnormal sites on MRI or lesions located in the brainstem at onset must be alert to the possibility of recurrence.

Nomogram Predicts Risk and Prognostic Factors for Bone Metastasis of Pancreatic Cancer A Population-Based Analysis.

The overall survival (OS) of pancreatic cancer (PC) patients with bone metastasis (BM) is extremely low, and it is pretty hard to treat bone metastasis. However, there are currently no effective nomograms to predict the diagnosis and prognosis of pancreatic cancer with bone metastasis (PCBM). Therefore, it is of great significance to establish effective predictive models to guide clinical practice. We screened patients from Surveillance Epidemiology and End Results (SEER) database between 2010 and 2016. The independent risk factors of PCBM were identified from univariable and multivariable logistic regression analyses, and univariate and multivariate Cox proportional hazards regression analyses were used to determine independent prognostic factors affecting the prognosis of PCBM. In addition, two nomograms were constructed to predict the risk and prognosis of PCBM. We used the area under the curve (AUC), C-index and calibration curve to determine the predictive accuracy and discriminability of nomograms. The decision curve analysis (DCA) and Kaplan-Meier(K-M) survival curves were employed to further confirm the clinical effectiveness of the nomogram. Multivariable logistic regression analyses revealed that risk factors of PCBM included age, primary site, histological subtype, N stage, radiotherapy, surgery, brain metastasis, lung metastasis, and liver metastasis. Using Cox regression analyses, we found that independent prognostic factors of PCBM were age, race, grade, histological subtype, surgery, chemotherapy, and lung metastasis. We utilized nomograms to visually express data analysis results. The C-index of training cohort was 0.795 (95%CI 0.758-0.832), whereas that of internal validation cohort was 0.800 (95%CI 0.739-0.862), and the external validation cohort was 0.787 (95%CI 0.746-0.828). Based on AUC of receiver operating characteristic (ROC) analysis, calibration plots, and decision curve analysis (DCA), we concluded that the risk and prognosis model of PCBM exhibits excellent performance. Nomogram is sufficiently accurate to predict the risk and prognostic factors of PCBM, allowing for individualized clinical decisions for future clinical work.

Residual Block Based Nested U-Type Architecture for Multi-Modal Brain Tumor Image Segmentation.

Multi-modal magnetic resonance imaging (MRI) segmentation of brain tumors is a hot topic in brain tumor processing research in recent years, which can make full use of the feature information of different modalities in MRI images, so that tumors can be segmented more effectively. In this article, convolutional neural networks (CNN) is used as a tool to improve the efficiency and effectiveness of segmentation. Based on this, Dense-ResUNet, a multi-modal MRI image segmentation model for brain tumors is created. The Dense-ResUNet consists of a series of nested dense convolutional blocks and a U-Net shaped model with residual connections. The nested dense convolutional blocks can bridge the semantic disparity between the feature maps of the encoder and decoder before fusion and make full use of different levels of features. The residual blocks and skip connection can extract pixel information from the image and skip the link to solve the traditional deep traditional CNN network problem. The experiment results show that our Dense-ResUNet can effectively help to extract the brain tumor and has great clinical research and application value.

ABC6 Consensus Assessment by a Group of German Experts.

The first International Consensus Conference for Advanced Breast Cancer (ABC1) took place 10 years ago in November 2011. The rationale was - and still is - to standardize treatment of advanced breast cancer (ABC) based on the available evidence and to ensure that worldwide all breast cancer patients receive adequate treatment and access to new therapies. The 6th International Consensus Conference for ABC (ABC6) took place from November 4 to 6, 2021 and was the first in a purely online format, due to the COVID-19 pandemic. In the present manuscript, a working group of German breast cancer experts comments on the voting results of the ABC6 panelists regarding their applicability for routine clinical practice in Germany. The ABC6 votes mainly include modified or new statements. With regard to all statements not modified for the ABC6 consensus, the German experts refer to the published paper of the ABC5 consensus. The German experts base their comments on the current recommendations of the Breast Committee of the Gynecological Oncology Working Group (Arbeitsgemeinschaft Gynäkologische Onkologie, AGO Mamma). ABC6 focused on new treatment options and their implications for clinical practice. Optimal therapy sequencing for example was one of the issues. To solve the challenge of a more individualized treatment, precision medicine is fundamental. Oligometastatic disease, brain metastases and adequate supportive and palliative care were also addressed. Of special interest was the treatment of inoperable locally advanced breast cancer, which was discussed as a separate topic. As in previous years, patient advocates from around the world were an integral part of the ABC6 conference and had a major input into the consensus.

Case Report New CDKN1B Mutation in Multiple Endocrine Neoplasia Type 4 and Brief Literature Review on Clinical Management.

The fourth type of multiple endocrine neoplasia (MEN) is known as a rare variant of MEN presenting a MEN1-like phenotype and originating from a germline mutation in CDKN1B. However, due to the small number of cases documented in the literature, the peculiar clinical features of MEN4 are still largely unknown, and clear indications about the clinical management of these patients are currently lacking. In order to widen our knowledge on MEN4 and to better typify the clinical features of this syndrome, we present two more cases of subjects with MEN4, and through a review of the current literature, we provide some possible indications on these patients management. The first report is about a man who was diagnosed with a metastatic ileal G2-NET at the age of 34. Genetic analysis revealed the mutation p.I119T (c.356T>C) of exon 1 of CDKN1B, a mutation already reported in the literature in association with early-onset pituitary adenomas. The second report is about a 76-year-old woman with a multifocal pancreatic G1-NET. Genetic analysis identified the CDKN1B mutation c.482C>G (p.S161C), described here for the first time in association with MEN4 and currently classified as a variant of uncertain significance. Both patients underwent biochemical and imaging screening for MEN1-related diseases without any pathological findings. According to the cases reported in the literature, hyperparathyroidism is the most common clinical feature of MEN4, followed by pituitary adenoma and neuroendocrine tumors. However, MEN4 appears to be a variant of MEN with milder clinical features and later onset. Therefore, these patients might need a different and personalized approach in clinical management and a peculiar screening and follow-up strategy.

Pharmacokinetics of metronomic temozolomide in cerebrospinal fluid of children with malignant central nervous system tumors.

Although temozolomide is widely used in the treatment of childhood central nervous system (CNS) tumors, information on its pharmacokinetic profile in the brain or cerebrospinal fluid (CSF) is sparse. This study aimed at investigating whether measurable and clinically relevant concentrations of temozolomide are reached and maintained in CSF for continuous oral administration in pediatric patients. A population pharmacokinetic model was developed to quantify CSF penetration of temozolomide. Eleven pediatric CNS tumor patients (aged 4-14 years) treated with oral temozolomide using a metronomic schedule (24-77 mgm Median temozolomide concentrations in plasma and CSF were 0.96 (range 0.24-5.99) µgml and 0.37 (0.06-1.76) µgml, respectively. A two-compartment model (centralplasma 1, CSF 2) with first-order absorption, first-order elimination, and a transit compartment between CSF and plasma adequately described the data. Population mean estimates for clearance (CL) and the volume of distribution in the central compartment (V Metronomic oral temozolomide penetrates into the CSF in pediatric patients, with even higher concentration levels compared to adults.

Selective histone methyltransferase G9a inhibition reduces metastatic development of Ewing sarcoma through the epigenetic regulation of NEU1.

Ewing sarcoma (EWS) is an aggressive bone and soft tissue tumor with high susceptibility to metastasize. The underlying molecular mechanisms leading to EWS metastases remain poorly understood. Epigenetic changes have been implicated in EWS tumor growth and progression. Linking epigenetics and metastases may provide insight into novel molecular targets in EWS and improve its treatment. Here, we evaluated the effects of a selective G9a histone methyltransferase inhibitor (BIX01294) on EWS metastatic process. Our results showed that overexpression of G9a in tumors from EWS patients correlates with poor prognosis. Moreover, we observe a significantly higher expression of G9a in metastatic EWS tumor as compared to either primary or recurrent tumor. Using functional assays, we demonstrate that pharmacological G9a inhibition using BIX01294 disrupts several metastatic steps in vitro, such as migration, invasion, adhesion, colony formation and vasculogenic mimicry. Moreover, BIX01294 reduces tumor growth and metastases in two spontaneous metastases mouse models. We further identified the sialidase NEU1 as a direct target and effector of G9a in the metastatic process in EWS. NEU1 overexpression impairs migration, invasion and clonogenic capacity of EWS cell lines. Overall, G9a inhibition impairs metastases in vitro and in vivo through the overexpression of NEU1. G9a has strong potential as a prognostic marker and may be a promising therapeutic target for EWS patients.

Parafoveal and peripapillary vessel density in pediatric and juvenile craniopharyngioma patients.

We assessed the retinal microvascular alterations detected by optical coherence tomography angiography (OCT-A) in pediatric and juvenile craniopharyngioma (CP) patients with chiasmal compression. We included 15 eyes of 15 pediatric or juvenile CP patients and 18 eyes of 18 healthy subjects. The evaluation of vessel density from the superficial retinal capillary plexus (SRCP), the deep retinal capillary plexus, and the radial peripapillary capillary (RPC) segments was obtained by OCT-A. The association between vessel density measures and functional and structural measurements was also analyzed. There were significant reductions in the nasal sector of the SRCP (p < 0.0001) and all sectors of the RPC segment vessel density (nasal, temporal, and superior p < 0.0001, inferior p 0.0015) in CP patients postoperatively compared to the healthy subjects. The peripapillary retinal nerve fiber layer (r 0.6602, p 0.0074) and ganglion cell-inner plexiform layer thicknesses (r 0.7532, p 0.0030) were associated with RPC segment vessel density. Visual acuity (r - 0.5517, p 0.0330) and temporal visual field sensitivity loss (r 0.5394, p 0.0465) showed an association with SRCP vessel density. In pediatric and juvenile patients with CP, parafoveal and peripapillary vascular changes following chiasmal compression were observed. The changes in vascular structures were closely related to structural and functional outcomes.

Mutations of the DNA repair gene PNKP in a patient with microcephaly, seizures, and developmental delay (MCSZ) presenting with a high-grade brain tumor.

Polynucleotide Kinase-Phosphatase (PNKP) is a bifunctional enzyme that possesses both DNA 3-phosphatase and DNA 5-kinase activities, which are required for processing termini of single- and double-strand breaks generated by reactive oxygen species (ROS), ionizing radiation and topoisomerase I poisons. Even though PNKP is central to DNA repair, there have been no reports linking PNKP mutations in a Microcephaly, Seizures, and Developmental Delay (MSCZ) patient to cancer. Here, we characterized the biochemical significance of 2 germ-line point mutations in the PNKP gene of a 3-year old male with MSCZ who presented with a high-grade brain tumor (glioblastoma multiforme) within the cerebellum. Functional and biochemical studies demonstrated these PNKP mutations significantly diminished DNA kinasephosphatase activities, altered its cellular distribution, caused defective repair of DNA singledouble stranded breaks, and were associated with a higher propensity for oncogenic transformation. Our findings indicate that specific PNKP mutations may contribute to tumor initiation within susceptible cells in the CNS by limiting DNA damage repair and increasing rates of spontaneous mutations resulting in pediatric glioma associated driver mutations such as ATRX and TP53.

A Nationwide Questionnaire Survey on Awake Craniotomy in Japan.

The number of awake craniotomies is increasing because of its beneficial features. However, not enough information is available regarding the current status of awake craniotomy in Japan. To evaluate the current status of awake craniotomy in institutes, a nationwide questionnaire survey was conducted. From June to August 2019, we conducted a questionnaire survey on awake craniotomy in the neurosurgery department of 45 institutes that perform awake craniotomies in Japan. Responses were obtained from 39 institutes (response rate, 86.7%). The main methods of awake craniotomy were almost the same in all institutes. Twenty-six institutes (66.7%) had fewer than 10 awake craniotomies (low-volume institutes) per year, and 13 high-volume institutes (33.3%) performed more than 10 awake craniotomies annually. Some institutes experienced a relatively high frequency of adverse events. In 11 institutes (28.2%), the frequency of intraoperative seizures was more than 10%. An intraoperative seizure frequency of 1%-9%, 10%-29%, and over 30% was identified in 12 (92%), 0 (0%), and 1 (8%) of the high-volume institutes, which was significantly less than in 16 (62%), 10 (38%), and 0 (0%) of the low-volume institutes (p 0.0059). The routine usage of preoperative antiepileptic drugs was not different between them, but the old type was used more often in the low-volume institutes (p 0.0022). Taken together, the annual number of awake craniotomies was less than 10 in over two-thirds of the institutes. Fewer intraoperative seizures were reported in the high-volume institutes, which tend not to preoperatively use the old type of antiepileptic drugs.

The Neuroprotective Effect of α-Lipoic Acid andor Metformin against the Behavioral and Neurochemical Changes Induced by Hypothyroidism in Rat.

The present study evaluates the neuroprotective effect of α-lipoic acid (ALA) andor metformin (MET) on the behavioral and neurochemical changes induced by hypothyroidism. Rats were divided into control, rat model of hypothyroidism induced by propylthiouracil, and rat model of hypothyroidism treated with ALA, MET, or their combination. Behaviorally, hypothyroid rats revealed impaired memory and reduced motor activity as indicated from the novel object recognition test and open-field test, respectively. Hypothyroidism induced a significant increase in lipid peroxidation (malondialdehyde MDA) and a significant decrease in reduced glutathione (GSH) and nitric oxide (NO) in the cortex and hippocampus. These were associated with a significant increase in tumor necrosis factor-α (TNF-α) and a significant decrease in brain-derived neurotrophic factor (BDNF). Hypothyroidism decreased significantly the levels of serotonin (5-HT), norepinephrine (NE), and dopamine (DA) and reduced the activities of acetylcholinesterase (AchE) and Na, K-ATPase in the cortex and hippocampus. Treatment of hypothyroid rats with ALA andor MET showed an improvement in memory function and motor activity. Moreover, ALA andor MET prevented the increase in MDA and TNF-α, and the decline in GSH, NO, BDNF, 5-HT, NE, and DA. It also restored AchE and Na, K-ATPase activities in the studied brain regions. ALA andor MET has a potential neuroprotective effect against the adverse behavioral and neurochemical changes induced by hypothyroidism in rats.

Category guided attention network for brain tumor segmentation in MRI.

Clinical role of serum histone deacetylase 4 measurement in acute ischemic stroke Relation to disease risk, severity, and prognosis.

Histone deacetylase 4 (HDAC4) is engaged in the pathophysiology of acute ischemic stroke (AIS) through modulating atherosclerosis, inflammation and neurocyte death. This study aimed to investigate the clinical role of HDAC4 in AIS. Serum samples were collected from 176 AIS patients and 80 controls for HDAC4 detection by enzyme-linked immunosorbent assay (ELISA). In AIS patients, disease severity was assessed by National Institute of Health Stroke Scale (NIHSS) score and their recurrence-free survival (RFS) and overall survival (OS) were calculated, inflammatory cytokines and adhesion molecules were detected by ELISA. HDAC4 was declined in AIS patients vs. controls (p < 0.001), it also had certain ability of distinguishing AIS patients from controls with an area under curve of 0.748 (95% confidence interval 0.689-0.806). Among AIS patients, HDAC4 was negatively linked with NIHSS score (p < 0.001) but no other clinical features (all p > 0.05). Moreover, HDAC4 was negatively related to interleukin (IL)-17 (p 0.010) and tumor necrosis factor alpha (p 0.001), while it was not correlated with IL-1β (p 0.081) or IL-6 (p 0.074). Furthermore, HDAC4 was negatively associated with intercellular cell adhesion molecule-1 (p < 0.001) and vascular cell adhesion molecule-1 (p 0.003). During a median follow-up of 19.0 months, 17 (9.7%) patients had recurrence and 10 (5.7%) patients died. Additionally, high HDAC4 was linked with prolonged RFS (p 0.044) but not OS (p 0.079). HDAC4 possesses the potential to monitor disease risk, inflammation and estimate recurrence of AIS, while further study with larger scale is needed to verify our findings.

Role of Dynamic Parameters of 18F-DOPA PETCT in Pediatric Gliomas.

PET with 18F-DOPA can be used to evaluate grading and aggressiveness of pediatric cerebral gliomas. However, standard uptake parameters may underperform in circumscribed lesions and in diffuse pontine gliomas. In this study, we tested whether dynamic 18F-DOPA PET could overcome these limitations. Patients with available dynamic 18F-DOPA PET were included retrospectively. Static parameters (tumorstriatum ratio TS and tumorcortex ratio TN) and dynamic ones, calculated on the tumor time activity curve (TAC), including time-to-peak (TTP), slope steepness, the ratio between tumor and striatum TAC steepness (dynamic slope ratio DSR), and TAC shape (accumulation vs plateau), were evaluated as predictors of highlow grading (HG and LG) and of progression-free survival and overall survival. Fifteen patients were included TS, TN, TTP, TAC slope steepness, and DSR were not significantly different between HG and LG. The accumulation TAC shape was more prevalent in the LG than in the HG group (75% vs 27%). On progression-free survival univariate analysis, TAC accumulation shape predicted longer survival (P < 0.001), whereas TN and DSR showed borderline significance on multivariate analyses, only TAC shape was retained (P < 0.01, Harrell C index, 0.93-0.95). On overall survival univariate analysis, TN (P < 0.05), DSR (P < 0.05), and TAC accumulating shape predicted survival (P < 0.001) once more, only this last parameter was retained in the multivariate models (P < 0.05, Harrell C index, 0.86-0.89). Dynamic 18F-DOPA PET analysis outperforms the static parameter evaluation in grading assessment and survival prediction. Evaluation of the curve shape is a simple-to-use parameter with strong predictive power.

Construction of a novel microRNA-based signature for predicting the prognosis of glioma.

Texture Enhancement of Medical Images for Efficient Disease Diagnosis with Optimized Fractional Derivative Masks.

For the past two decades, fractional-order derivatives have been used to model many systems in science and engineering with more accuracy than existing integer-order derivatives. Many of these applications have been employed in the image processing field. It is undeniable that an image enhancement algorithm is very much desirable for medical image analysis to diagnose various kinds of diseases more efficiently. These requirements demand that the image should be of high quality. Hence, accurate edge-detection and denoising models are required in medical image processing, improving, and enhancing the contrast of an image to attain a better texture and avoid noise. In this study, we employ and compare the conventional methods and recent and most popular fractional-order-based methods for medical image analysis texture enhancement. To make a fair comparison, the fractional-order operators are optimized for all images with gray wolf optimizer while considering the performance metric mean squared error. The results showed that fractional differential-based operators perform better than conventional integer-order operators for texture enhancement of medical images.

Brain-Targeted Codelivery of Bcl-2Bcl-xl and Mcl-1 Inhibitors by Biomimetic Nanoparticles for Orthotopic Glioblastoma Therapy.

Glioblastoma (GBM) is among the most treatment-resistant solid tumors and often recurrs after resection. One of the mechanisms through which GBM escapes various treatment modalities is the overexpression of anti-apoptotic Bcl-2 family proteins (

Social determinants of health and the prediction of 90-day mortality among brain tumor patients.

Within the neurosurgical oncology literature, the effect of structural and socioeconomic factors on postoperative outcomes remains unclear. In this study, the authors quantified the effects of social determinant of health (SDOH) disparities on hospital complications, length of stay (LOS), nonroutine discharge, 90-day readmission, and 90-day mortality following brain tumor surgery. The authors retrospectively reviewed the records of brain tumor patients who had undergone resection at a single institution in 2017-2019. The prevalence of SDOH disparities among patients was tracked using International Classification of Diseases Ninth and Tenth Revisions (ICD-9 and ICD-10) codes. Bivariate (Mann-Whitney U-test and Fishers exact test) and multivariate (logistic and linear) regressions revealed whether there was an independent relationship between SDOH status and postoperative outcomes. The patient cohort included 2519 patients (mean age 55.27 ± 15.14 years), 187 (7.4%) of whom experienced at least one SDOH disparity. Patients who experienced an SDOH disparity were significantly more likely to be female (OR 1.36, p 0.048), Black (OR 1.91, p < 0.001), and unmarried (OR 1.55, p 0.0049). Patients who experienced SDOH disparities also had significantly higher 5-item modified frailty index (mFI-5) scores (p < 0.001) and American Society of Anesthesiologists (ASA) classes (p 0.0012). Experiencing an SDOH disparity was associated with a significantly longer hospital LOS (p 0.0036), greater odds of a nonroutine discharge (OR 1.64, p 0.0092), and greater odds of 90-day mortality (OR 2.82, p 0.0016) in the bivariate analysis. When controlling for patient demographics, tumor diagnosis, mFI-5 score, ASA class, surgery number, and SDOH status, SDOHs independently predicted hospital LOS (coefficient 1.22, p 0.016) and increased odds of 90-day mortality (OR 2.12, p 0.028). SDOH disparities independently predicted a prolonged hospital LOS and 90-day mortality in brain tumor patients. Working to address these disparities offers a new avenue through which to reduce patient morbidity and mortality following brain tumor surgery.

Predictive Factors for Postoperative Opioid Use in Elective Endoscopic Endonasal Skull Base Surgery.

In 2017, the United States opioid epidemic was declared a public health emergency. Increased efforts have been made to understand and reduce patient opioid use in neurosurgery. However, the factors associated with postoperative opioid use remain understudied in endoscopic endonasal skull base surgery (EESBS). We identified the demographic and surgical factors associated with postoperative opioid use in EESBS. A retrospective review was conducted of patients who underwent elective EESBS between January 2015 and December 2020. Patient demographics, relevant clinical history, and operative data were collected and analyzed. Total opioid use was calculated 24, 48, and 72 hours postoperatively. Multivariable linear regression analyses were performed to identify factors associated with opioid use. There were 454 patients included. A history of anxietydepression and younger patient age were associated with a significant increase in opioid use at 24 (28.2 MME, p < 0.001), 48 (53.4 MME, p < 0.001), and 72 (89.4 MME, p < 0.001) hours after surgery. Nasoseptal flap use was significantly associated with increased opioid use at 24 (12.8 MME, p < 0.49) and 48 (19.6 MME, p < 0.048) h postoperatively while controlling for intraoperative variables and surgical approach (trans-sellar vs. expanded). No significant association was observed for patient sex, history of migraines, preoperative opioid use, length of surgery, or surgical approach. In patients undergoing EESBS, patient history of anxietydepression, younger patient age, and nasoseptal flap use are associated with increased postoperative opioid use. Knowledge of these risk factors may guide perioperative prescribing patterns to both adequately control postoperative pain and reduce opioid use. 4 Laryngoscope, 2022.

Neuro-oncologic Emergencies.

Patients with brain and spine tumors are at high risk of presenting cancer-related complications at disease presentation or during active treatment and are usually related to the type and location of the lesion. Here, we discuss presentation and management of the most common emergencies affecting patients with central nervous system neoplastic lesions. Tumor-related emergencies encompass complications in patients with central nervous system neoplasms, as well as neurologic complications in patients with systemic malignancies. Brain tumor patients are at high risk of developing multiple complications such as intracranial hypertension, brain herniation, intracranial bleeding, spinal cord compression, and others. Neuro-oncologic emergencies require immediate attention and multi-disciplinary care. These emergent situations usually need rapid decision-making and management on an inpatient basis.

Intraoperative ultrasound in brain tumor surgery A review and implementation guide.

Accurate and reliable intraoperative neuronavigation is crucial for achieving maximal safe resection of brain tumors. Intraoperative MRI (iMRI) has received significant attention as the next step in improving navigation. However, the immense cost and logistical challenge of iMRI precludes implementation in most centers worldwide. In comparison, intraoperative ultrasound (ioUS) is an affordable tool, easily incorporated into existing theatre infrastructure, and operative workflow. Historically, ultrasound has been perceived as difficult to learn and standardize, with poor, artifact-prone image quality. However, ioUS has dramatically evolved over the last decade, with vast improvements in image quality and well-integrated navigation tools. Advanced techniques, such as contrast-enhanced ultrasound (CEUS), have also matured and moved from the research field into actual clinical use. In this review, we provide a comprehensive and pragmatic guide to ioUS. A suggested protocol to facilitate learning ioUS and improve standardization is provided, and an outline of common artifacts and methods to minimize them given. The review also includes an update of advanced techniques and how they can be incorporated into clinical practice.

A phase 1 study of IDH305 in patients with IDH1

Isocitrate dehydrogenase enzyme 1 (IDH1) mutations at 132nd amino acid residue (R132) result in the cellular accumulation of the oncometabolite, 2-hydroxyglutarate (2-HG). IDH305 is an orally bioavailable, brain-penetrant, mutant-selective allosteric IDH1 inhibitor demonstrating target engagement in preclinical models. This first-in human study was designed to identify the recommended dose for expansionmaximum tolerated dose of IDH305 in patients with IDH1 IDH305 was given at doses 75-750 mg twice daily in 41 patients with IDH1 IDH305 exhibited rapid absorption with mean T Due to potentially narrow therapeutic window, the study was prematurely halted and recommended phase 2 dose could not be declared. Clinicaltrials.gov identifier NCT02381886.

Application of the anthraquinone drug rhein as an axial ligand in bifunctional Pt(IV) complexes to obtain antiproliferative agents against human glioblastoma cells.

Octahedral Pt(IV) prodrugs are an effective way to combine cisplatin-like moieties and a second drug to obtain selective and stimuli responsive bifunctional antiproliferative compounds. Recently, two bifunctional Pt(IV) complexes have shown interesting

A Review on the Design, Synthesis, and Structure-activity Relationships of Benzothiazole Derivatives against Hypoxic Tumors.

There has been a growing body of studies on benzothiazoles and benzothiazole derivatives as strong and effective anti-tumor agents against lung, liver, pancreas, breast, and brain tumors. Due to the highly proliferative nature of the tumor cells, the oxygen levels get lower than that of normal tissues in the tumor microenvironment. This situation is called hypoxia and has been associated with increased ability for carcinogenesis. For the drug design and development strategies, the hypoxic nature of the tumor tissues has been exploited more aggressively. Hypoxia itself acts as a signal initiating system to activate the pathways that eventually lead to the spread of the tumor cells into the different tissues, increases the rate of DNA damage, and eventually ends up with more mutation levels that may increase the drug resistance. As one of the major mediators of hypoxic response, hypoxia-inducible factors (HIFs) have been shown to activate angiogenesis, metastasis, apoptosis resistance, and many other protumorigenic responses in cancer development. In the current review, we will be discussing the design, synthesis, and structureactivity relationships of benzothiazole derivatives against hypoxic tumors such as lung, liver, pancreas, breast, and brain as potential anti-cancer drug candidates. The focus points of the study will be the biology behind carcinogenesis and how hypoxia contributes to the process, recent studies on benzothiazole and its derivatives as anti-cancer agents against hypoxic cancers, conclusions, and future perspectives. We believe that this review will be useful for researchers in the field of drug design during their studies to generate novel benzothiazole-containing hybrids against hypoxic tumors with higher efficacies.

De Novo Intrahepatic Cholangiocarcinoma After Deceased Donor Liver Transplant in an Adult Patient.

Survival after liver transplant has progressively improved over recent decades. Recurrent or de novo malignancy, however, remains a major cause of patient death after transplant. Here, we have described a patient who developed de novo intrahepatic cholangiocarcinoma in the graft liver after orthotopic liver transplant. The 48-year-old male patient had end-stage liver disease from hepatitis B-related liver cirrhosis and a Model for End-Stage Liver Disease score of 26 and was listed for liver transplant. Recurrent esophageal variceal hemorrhage, severe ascites, and splenomegaly had complicated the liver disease. He underwent emergent whole organ, deceased donor liver transplant for liver cirrhosis. The donor liver was procured through the standard donation after brain death process from a 72-year-old man who died of intracranial hemorrhage. The graft weighted 1500 g and had normal color, and cold ischemia time was 5 hours upon arrival at our hospital. The patients early postoperative course was uneventful. Two months posttransplant, the patient presented to the emergency department with fever, abdominal pain, and skin rash. Computed tomography revealed a focal biliary stricture in the right hepatic duct. Magnetic resonance cholangiopancreatography identified intrahepatic duct dilatations. Subsequent endoscopic retrograde cholangiography demonstrated marked intra- and extrahepatic biliary dilatation. We considered it to be a benign stricture and inserted plastic stents. He recovered from biliary stricture-related cholangitis. Approximately 10 months posttransplant, the patient was admitted with fever and skin rash. Marked dilatation of the intrahepatic bile duct was shown with a poorly enhancing tumor in the right lobe of the graft. Percutaneous transhepatic biliary drainage and tumor biopsy confirmed intrahepatic cholangiocarcinoma. We believe this to be the first case of de novo intrahepatic cholangiocarcinoma in a patient with hepatitis B-related end-stage liver disease after liver transplant without primary sclerosing cholangitis.

Inferior fronto-occipital fascicle displacement in temporoinsular gliomas using diffusion tensor imaging.

Brain tumors can result in displacement or destruction of important white matter tracts such as the inferior fronto-occipital fascicle (IFOF). Diffusion tensor imaging (DTI) can assess the extent of this effect and potentially provide neurosurgeons with an accurate map to guide tumor resection analyze IFOF displacement patterns in temporoinsular gliomas based on tumor grading and topography in the temporal lobe and assess whether these patterns follow a predictable pattern, to assist in maximal tumor resection while preserving IFOF function. Thirty-four patients with temporal gliomas and available presurgical MRI were recruited. Twenty-two had insula infiltration. DTI deterministic region of interest (ROI)-based tractography was performed using commercial software. Tumor topographic imaging characteristics analyzed were as follows location in the temporal lobe and extent of extratemporal involvement. Qualitative tractographic data obtained from directional DTI color maps included type of involvement (displacededematous-infiltrateddestroyed) and displacement direction. Quantitative tractographic data of ipsi- and contralateral IFOF included whole tract volume, fractional anisotropy, and fractional anisotropy of a 2-dimensional coronal ROI on the tract at the point of maximum tumor involvement. The most common tract involvement pattern was edematousinfiltrative displacement. Displacement patterns depended on main tumor location in the temporal lobe and presence of insular involvement. All tumors showed superior displacement pattern. In lateral tumors, displacement tendency was medial. In medial tumors, displacement tendency was lateral. When we add insular involvement, the tendency was more medial displacement. A qualitative and quantitative assessment supported these results. IFOF displacement patterns are reproducible and suitable for temporoinsular gliomas presurgical planning.

Pituitary MRI in Cushings disease - an update.

Pituitary MRI is essential in the diagnosis of ACTH-dependent Cushings syndrome, but its results are inconsistent. The demonstration of a sellar image compatible with the diagnosis of corticotropinoma varies from 40% to 90%, depending on the centre where the imaging is performed. In fact, the expertise of the neuroradiologist, use of a Tesla 3.0 MRI and choice of sequences are fundamental. The T2 and 3D gradient echo sequences after gadolinium injection are the most informative and today allow the detection of macro- and microadenomas in almost all cases. The diagnosis of numerous picoadenomas (<3-4 mm) is more challenging. The 2D and 3D spin echo or delayed T1 SE or FLAIR sequences after gadolinium can be used as a complement or to confirm a suspicious image. Characterization of corticotropinomas remains problematic. However, the correct assessment of so-called incidentalomas by recognizing artifacts, anatomical variants and frequent Rathkes cleft cysts eliminates around 90% of the incidentalomas that mimic pituitary adenomas, as repetitively reported in the literature. For the time being, there is reason to believe that hybrid imaging combining PET and MRI such as 11C-methionine PET coregistered with volumetric MRI will solve the diagnosis of corticotropinomas in the near future.

The Circular RNA circSKA3 Facilitates the Malignant Biological Behaviors of Medulloblastoma via miR-520 hCDK6 Pathway.

Circular RNAs (circRNAs) are reported to participate in the development of diverse human malignancies. This work investigated the mechanism of circSKA3 in modulating medulloblastoma progression. A total of 15 cases of medulloblastoma were collected in this work. Daoy cells were used to construct cell models. The expression level of circSKA3, microRNA-520 h (miR-520 h), and cyclin-dependent kinase 6 (CDK6) mRNA in tissues or cells was examined by quantitative real-time polymerase chain reaction (qRT-PCR). Western blot was employed to detect CDK6 protein expression. CCK-8 experiment, Transwell assay, and flow cytometry were applied to detect the regulatory effects of circSKA3 on cell proliferation, migration, invasion, and cell cycle. Dual-luciferase reporter gene experiment was executed to determine the relationship between circSKA3 and miR-520 h, and between miR-520 h and CDK6. circSKA3 was remarkably up-modulated in medulloblastoma tissues. CircSKA3 depletion markedly suppressed Daoy cell viability, migration, invasion, and cell cycle progression. CircSKA3 overexpression induced the opposite effects. circSKA3 could decoyed miR-520 h, which targeted the 3 UTR of CDK6. circSKA3 expression in medulloblastoma tissues was negatively correlated with miR-520 h expression and positively correlated with CDK6 expression. Rescue experiments revealed that miR-520 h down-modulation or CDK6 overexpression remarkably counteracted the inhibitory effect of circSKA3 knockdown on Daoy cells. circSKA3 facilitates medulloblastoma progression through miR-520 hCDK6.

Inhibitory effects of temozolomide on glioma cells is sensitized by RSL3-induced ferroptosis but negatively correlated with expression of ferritin heavy chain 1 and ferritin light chain.

Invasive growth of glioblastoma makes residual tumor unremovable by surgery and leads to disease relapse. Temozolomide is widely used first-line chemotherapy drug to treat glioma patients, but development of temozolomide resistance is almost inevitable. Ferroptosis, an iron-dependent form of non-apoptotic cell death, is found to be related to temozolomide response of gliomas. However, whether inducing ferroptosis could affect invasive growth of glioblastoma cells and which ferroptosis-related regulators were involved in temozolomide resistance are still unclear. In this study, we treated glioblastoma cells with RSL3, a ferroptosis inducer, in vitro (cell lines) and in vivo (subcutaneous and orthotopic animal models). The treated glioblastoma cells with wild-type or mutant IDH1 were subjected to RNA sequencing for transcriptomic profiling. We then analyze data from our RNA sequencing and public TCGA glioma database to identify ferroptosis-related biomarkers for prediction of prognosis and temozolomide resistance in gliomas. Analysis of transcriptome data from RSL3-treated glioblastoma cells suggested that RSL3 could inhibit glioblastoma cell growth and suppress expression of genes involved in cell cycle. RSL3 effectively reduced mobility of glioblastoma cells through downregulation of critical genes involved in epithelial-mesenchymal transition. Moreover, RSL3 in combination with temozolomide showed suppressive efficacy on glioblastoma cell growth, providing a promising therapeutic strategy for glioblastoma treatment. Although temozolomide attenuated invasion of glioblastoma cells with mutant IDH1 more than those with wild-type IDH1, the combination of RSL3 and temozolomide similarly impaired invasive ability of glioblastoma cells in spite of IDH1 status. Finally, we noticed that both ferritin heavy chain 1 and ferritin light chain predicted unfavorable prognosis of glioma patients and were significantly correlated with mRNA levels of methylguanine methyltransferase as well as temozolomide resistance. Altogether, our study provided rationale for combination of RSL3 with temozolomide to suppress glioblastoma cells and revealed ferritin heavy chain 1 and ferritin light chain as biomarkers to predict prognosis and temozolomide resistance of glioma patients.

Inhibition of triple negative breast cancer-associated inflammation, tumor growth and brain colonization by targeting monoacylglycerol lipase.

While the prevalence of breast cancer metastasis in the brain is significantly higher in triple negative breast cancers (TNBCs), there is a lack of novel andor improved therapies for these patients. Monoacylglycerol lipase (MAGL) is a hydrolase involved in lipid metabolism that catalyzes the degradation of 2-arachidonoylglycerol (2-AG) linked to generation of pro- and anti-inflammatory molecules. Here, we targeted MAGL in TNBCs, using a potent carbamate-based inhibitor AM9928 (hMAGL IC

Sex-Dependent Analysis of Temozolomide-Induced Myelosuppression and Effects on Survival in a Large Real-life Cohort of Patients With Glioma.

To investigate the association of radiochemotherapy-induced cytopenia with sex and its potential effect on survival in patients with glioma. We retrospectively analyzed cytopenia during temozolomide-based concomitant radiochemotherapy in 492 patients with glioma. Histologic grading, molecular pathology, surgical procedures, adjuvant chemotherapy subsequent to the radiochemotherapy phase, and overall survival (OS) were recorded. The extent of cytopenia was correlated with sex and outcome. Treatment-induced severe cytopenia (leukocytopenia, lymphocytopenia, neutropenia, and thrombocytopenia) was more frequent in women than men (44 vs 18% Our analysis of treatment-induced cytopenia in a large cohort of patients with glioma confirms that women are at higher risk and demonstrates an association of cytopenia with shortened survival in women. This study provides Class II evidence that women with glioma treated with temozolomide-based concomitant radiochemotherapy have more frequent treatment-induced severe cytopenia than men and that severe myelosuppression correlates with worse OS in women.

FOSL1 promotes proneural-to-mesenchymal transition of glioblastoma stem cells via UBC9CYLDNF-κB axis.

Proneural (PN) to mesenchymal (MES) transition (PMT) is a crucial phenotypic shift in glioblastoma stem cells (GSCs). However, the mechanisms driving this process remain poorly understood. Here, we report that Fos-like antigen 1 (FOSL1), a component of AP1 transcription factor complexes, is a key player in regulating PMT. FOSL1 is predominantly expressed in the MES subtype, but not PN subtype, of GSCs. Knocking down FOSL1 expression in MES GSCs leads to the loss of MES features and tumor-initiating ability, whereas ectopic expression of FOSL1 in PN GSCs is able to induce PMT and maintain MES features. Moreover, FOSL1 facilitates ionizing radiation (IR)-induced PMT and radioresistance of PN GSCs. Inhibition of FOSL1 enhances the anti-tumor effects of IR by preventing IR-induced PMT. Mechanistically, we find that FOSL1 promotes UBC9-dependent CYLD SUMOylation, thereby inducing K63-linked polyubiquitination of major nuclear factor κB (NF-κB) intermediaries and subsequent NF-κB activation, which results in PMT induction in GSCs. Our study underscores the importance of FOSL1 in the regulation of PMT and suggests that therapeutic targeting of FOSL1 holds promise to attenuate molecular subtype switching in patients with glioblastomas.

Macrophage inhibitory cytokine-1 in cancer Beyond the cellular phenotype.

Despite technological advances in diagnostic abilities and improved treatment methods, the burden of cancers remains high, leading to significant morbidity and mortality. One primary reason is that cancer cell secretory factors modulate the tumor microenvironment, supporting tumor growth and circumvents anticancer activities of conventional therapies. Macrophage inhibitory cytokine-1 (MIC-1) is a pleiotropic cytokine elevated in various cancers. MIC-1 regulates various cancer hallmarks, including sustained proliferation, tumor-promoting inflammation, avoiding immune destruction, inducing invasion, metastasis, angiogenesis, and resisting cell death. Despite these facts, the molecular regulation and downstream signaling of MIC-1 in cancer remain elusive, partly because its receptor (GFRAL) was unknown until recently. Binding of MIC-1 to GFRAL recruits the coreceptor tyrosine kinase RET to execute its downstream signaling. So far, studies have shown that GFRAL expression is restricted to the brain stem and is responsible for MIC-1GFRALRET-mediated metabolic disorders. Nevertheless, abundant levels of MIC-1 expression have been reported in all cancer types and have been proposed as a surrogate biomarker. Given the ubiquitous expression of MIC-1 in cancers, it is crucial to understand both upstream regulation and downstream MIC-1GFRALRET signaling in cancer hallmark traits.

Cancer risks among studies of medical diagnostic radiation exposure in early life without quantitative estimates of dose.

There is accumulating evidence of excess risk of cancer in various populations exposed at acute doses below several tens of mSv or doses received over a protracted period. There is also evidence that relative risks are generally higher after radiation exposures in utero or in childhood. We reviewed and summarised evidence from 89 studies of cancer following medical diagnostic exposure in utero or in childhood, in which no direct estimates of radiation dose are available. In all of the populations studied exposure was to sparsely ionizing radiation (X-rays). Several of the early studies of in utero exposure exhibit modest but statistically significant excess risks of several types of childhood cancer. There is a highly significant (p < 0.0005) negative trend of odds ratio with calendar period of study, so that more recent studies tend to exhibit reduced excess risk. There is no significant inter-study heterogeneity (p > 0.3). In relation to postnatal exposure there are significant excess risks of leukaemia, brain and solid cancers, with indications of variations in risk by cancer type (p 0.07) and type of exposure (p 0.02), with fluoroscopy and computed tomography scans associated with the highest excess risk. However, there is highly significant inter-study heterogeneity (p < 0.01) for all cancer endpoints and all but one type of exposure, although no significant risk trend with calendar period of study. Overall, this large body of data relating to medical diagnostic radiation exposure in utero provides support for an associated excess risk of childhood cancer. However, the pronounced heterogeneity in studies of postnatal diagnostic exposure, the implied uncertainty as to the meaning of summary measures, and the distinct possibilities of bias, substantially reduce the strength of the evidence from the associations we observe between radiation imaging in childhood and the subsequent risk of cancer being causally related to radiation exposure.

Cerebral nocardiosis in a patient treated with pembrolizumab a first case report.

Checkpoints inhibitors (CPIs) are increasingly used for the treatment of several malignancies. The most common side effects are Immune Related Adverse Events, while infectious complications are rare, especially cerebral nocardiosis. Here, we report the first clinical case of a cerebral nocardiosis revealed after seizure in a patient treated by pembrolizumab for a metastatic lung cancer, in the absence of any additional immunosuppressive therapy or risk factors for cerebral nocardiosis. The extended evaluation including a brain CT-scan did not reveal any lesion before pembrolizumab. Nevertheless, the 3-month delay between the start of Pembrolizumab and the diagnosis of cerebral nocardiosis suggests that the infection occurred prior to the CPI. Unfortunately, the patient died during treatment for cerebral nocardiosis, while the lung cancer tumor mass had decreased by 80% after the sixth cycle of pembrolizumab. This case report emphasizes that clinicians should consider diagnoses other than metastasis in a patient with a brain mass and metastatic cancer treated with CPI, such as opportunistic infections or IRAE.

Superficial siderosis and nonobstructive hydrocephalus due to subependymoma in the ventricle An illustrative case report.

Intraventricular tumors can generally result in obstructive hydrocephalus as they grow. Rarely, however, some intraventricular tumors develop superficial siderosis (SS) and trigger hydrocephalus, even though the tumor has hardly grown. Here, we present an illustrative case of SS and nonocclusive hydrocephalus caused by subependymoma of the lateral ventricles. A 78-year-old man with an intraventricular tumor diagnosed 7 years ago had been suffering from gait disturbance for 2 years. He also developed cognitive impairment. Intraventricular tumors showed little growth on annual magnetic resonance imaging (MRI). MRI T2-star weighted images (T2WI) captured small intratumoral hemorrhages from the beginning of the follow-up. Three years before, at the same time as the onset of ventricular enlargement, T2WI revealed low intensity in the whole tumor and cerebral surface. Subsequent follow-up revealed that this hemosiderin deposition had spread to the brain stem and cerebellar surface, and the ventricles had expanded further. Cerebrospinal fluid (CSF) examination revealed xanthochromia. The tumor was completely removed Some intraventricular tumors cause SS and nonobstructive hydrocephalus due to microbleeding, even in the absence of tumor growth. T2WI and, if necessary, timely CSF examination can allow identification of presymptomatic SS. This follow-up strategy may provide a favorable course by facilitating early intervention in patients with intraventricular lesions, not just subependymomas.

Identification of CD101 in Glioma A Novel Prognostic Indicator Expressed on M2 Macrophages.

Glioma represents the most common primary intracranial malignancy worldwide, with low overall survival rates and limited therapeutic options. The protein CD101, mainly expressed on several immune cells, has been demonstrated to exert potent effects on blunting T cell immune responses across infectious and autoimmunity diseases. Nevertheless, the prognostic value of CD101 expression and its role in the immune microenvironment of various malignancies currently remains elusive. Herein, by adopting bioinformatics methodology, we comprehensively illustrated the potential function and predictive value of CD101 in stratifying clinical prognosis among patients with glioma, for which a high CD101 level predicted an unfavorable clinical outcome in glioma patients. Results from enrichment analyses manifested that CD101 predominantly expressed on the tumor-associated macrophages and was significantly associated with the immune regulatory processes, as evidenced by its positive correlation with immune-related genes and the putative infiltration of immune cells. Evidence provided by

Large-Scale G Protein-Coupled Olfactory Receptor-Ligand Pairing.

G protein-coupled receptors (GPCRs) conserve common structural folds and activation mechanisms, yet their ligand spectra and functions are highly diverse. This work investigated how the amino-acid sequences of olfactory receptors (ORs)-the largest GPCR family-encode diversified responses to various ligands. We established a proteochemometric (PCM) model based on OR sequence similarities and ligand physicochemical features to predict OR responses to odorants using supervised machine learning. The PCM model was constructed with the aid of site-directed mutagenesis,

Outcome of Childhood Cerebellar Pilocytic Astrocytoma A Series With 20 Years of Follow Up.

Cerebellar pilocytic astrocytoma (PCA) is one of the few CNS tumors that can be cured with gross-total removal (GTR). In this series, we had 39 patients diagnosed with cerebellar PCA, 27 patients (70%) had GTR, and mean follow-up period was 62 months with no tumor recurrence. To assess the long-term outcome of childhood cerebellar PCA treated at our institute during the period 2000-2020 and to highlight our surgical protocol. Retrospective review of all patients under 18 years of age who were diagnosed with cerebellar PCA and had surgical excision between 2000 and 2020 at the Medical City of King Saud University. The study included 39 patients 17 males and 22 females, the mean age was 8.4 years. Radiologically, the tumor was solid in eight patients, cystic in 15 patients, and mixed components were found in 16 patients. The lesion was located in the right cerebellar hemisphere in 12 patients, left cerebellar hemisphere in five patients, and midline 22 patients. The tumor size ranged from 2 to 7 cm in its greatest diameter, it was <5 cm in 13 patients and >5 cm in 26 patients. Thirty-one patients had preoperative hydrocephalus. GTR of the tumor was achieved in 27 patients and subtotal resection (STR) was done in 12 patients, 18 patients required permanent ventriculoperitoneal (V-P) shunt, and five patients had postoperative radiotherapy. Postoperative complications included infection in two patients, cerebellar mutism in two patients, and significant neurologic disability in four patients. The duration of follow-up ranged from 0 to 240 months (mean follow-up period 62.0 months). The outcome at 10 years was good in 30 patients, fair in four patients, poor in four patients, and one patient died. Recurrence was documented in nine patients, seven of them had GTR and two had STR. GTR, if achievable, is curative for childhood cerebellar PCA. Many posterior fossa surgical complications could be avoided with watertight dural closure. Although new dural substitutes are available we prefer using autologous grafts (pericranium). It is easy to harvest pericranial graft from the external ventricular drain (EVD) site. The insertion of EVD synchronously with GTR of the tumor and gradual weaning of EVD could avoid the insertion of V-P shunt.

Cellular Telephone Use and the Risk of Brain Tumors Update of the UK Million Women Study.

The ongoing debate of whether use of cellular telephones increases the risk of developing a brain tumor was recently fueled by the launch of the fifth generation of wireless technologies. Here, we update follow-up of a large-scale prospective study on the association between cellular telephone use and brain tumors. During 1996-2001, 1.3 million women born in 1935-1950 were recruited into the study. Questions on cellular telephone use were first asked in median year 2001 and again in median year 2011. All study participants were followed via record linkage to National Health Services databases on deaths and cancer registrations (including nonmalignant brain tumors). During 14 years follow-up of 776 156 women who completed the 2001 questionnaire, a total of 3268 incident brain tumors were registered. Adjusted relative risks for ever vs never cellular telephone use were 0.97 (95% confidence interval 0.90 to 1.04) for all brain tumors, 0.89 (95% confidence interval 0.80 to 0.99) for glioma, and not statistically significantly different to 1.0 for meningioma, pituitary tumors, and acoustic neuroma. Compared with never-users, no statistically significant associations were found, overall or by tumor subtype, for daily cellular telephone use or for having used cellular telephones for at least 10 years. Taking use in 2011 as baseline, there were no statistically significant associations with talking for at least 20 minutes per week or with at least 10 years use. For gliomas occurring in the temporal and parietal lobes, the parts of the brain most likely to be exposed to radiofrequency electromagnetic fields from cellular telephones, relative risks were slightly below 1.0. Our findings support the accumulating evidence that cellular telephone use under usual conditions does not increase brain tumor incidence.

Short communication Serum levels of brain-derived neurotrophic factor and association with pro-inflammatory cytokines in acute and recovered anorexia nervosa.

Brain-derived neurotrophic factor (BDNF) is a neuroprotective molecule known to be involved in neuroplasticity, learning and memory. Additionally, it may mitigate the effects of inflammation on the brain. There is inconclusive evidence as to whether reductions in BDNF found in AN are related to features associated with the illness such as changes in inflammatory markers and comorbidities, and whether they persist after recovery. This cross-sectional study measured BDNF and 36 inflammatory markers in the serum of individuals recovered from AN (rec-AN n 24), with acute AN (n 56), and healthy controls (n 51). We (a) compared BDNF concentrations between AN, rec-AN and controls including four pre-determined covariates (b) assessed the relationship between BDNF and body mass index, eating disorder (ED) psychopathology and depression and (c) correlated BDNF with inflammatory markers, stratified by group. The AN group showed reductions in BDNF compared to controls and rec-AN. BDNF was negatively associated with depression and ED psychopathology in the whole sample, but not the AN sample. BDNF was positively correlated with three inflammatory markers in the control group (interleukin (IL)-8, Eotaxin-3, tumor necrosis factor (TNF)-α) and negatively correlated with one (IL-16). The only pro-inflammatory marker associated with BDNF in the AN group was TNF-α, and no pro-inflammatory markers were associated with BDNF in the rec-AN group. These results indicate that BDNF serum concentrations may be a state marker of AN. In people with acute AN, BDNF levels seem to be linked to TNF-α signalling. However, BDNF concentrations do not appear to reflect AN symptom severity.

Molecular genetic testing in the management of pituitary disease.

Most pituitary tumours occur sporadically without a genetically identifiable germline abnormality, a small but increasing proportion present with a genetic defect that predisposes to pituitary tumour development, either isolated (e.g., aryl hydrocarbon receptor-interacting protein, AIP) or as part of a tumour-predisposing syndrome (e.g., multiple endocrine neoplasia (MEN) type 1, Carney complex, McCune-Albright syndrome or pituitary tumour and paraganglioma association). Genetic alterations in sporadic pituitary adenomas may include somatic mutations (e.g., GNAS, USP8). In this review, we take a practical approach which genetic syndromes should be considered in case of different presentation, such as tumour type, family history, age of onset and additional clinical features of the patient. Review of the recent literature in the field of genetics of pituitary tumours. Genetic testing in the management of pituitary disease is recommended in a significant minority of the cases. Understanding the genetic basis of the disease helps to identify patients and at-risk family members, facilitates early diagnosis and therefore better long-term outcome and opens up new pathways leading to tumorigenesis. We provide a concise overview of the genetics of pituitary tumours and discuss the current challenges and implications of these genetic findings in clinical practice.

Next-generation sequencing identifies HOXA6 as a novel oncogenic gene in low grade glioma.

Low grade glioma is one of the most common lethal cancers in the human nervous system. Emerging evidence has demonstrated that homeobox A cluster (HOXA) gene family plays a critical role in the transcriptional regulation as well as cancer initiation and progression. However, the expression, biological functions and upstream regulatory mechanism of 11 HOXAs in low grade glioma are not yet clear. In this study, we utilized various public databases and bioinformatics analyzed, including TCGA, CGGA, Rembrandt, HPA, LinkedOmics, cBioPortal, TISDIB, single-sample GSEA (ssGSEA), TIMER, LnCeVar, LASSO regression, Cox regression, Kaplan-Meier plot, and receiver operating, characteristic (ROC) analyses, GDSC and CTRP databases to analyzed the mRNA and protein expression profiles, gene mutation, clinical features, diagnosis, prognosis, signaling pathway, TMB, immune subtype, immune cell infiltration, immune modulator, ceRNA network and drug sensitivity of 11 HOXAs. Growth curve and transwell assays were utilized to study the biological characteristics of HOXA6 in LGG progression. In the present study, we found that 11 HOXAs (HOXA1, HOXA2, HOXA3, HOXA4, HOXA5, HOXA6, HOXA7, HOXA9, HOXA10, HOXA11 and HOXA3) were consistently up-regulated in LGG tissues and GBM tissues. Up-regulated of the HOXAs expression were significantly correlated with higher tumor stage, IDH mutation status, 1p19q co-deletion, histological type and primary therapy outcome. Survival analyses showed that higher expression of HOXA1, HOXA2, HOXA3, HOXA4, HOXA5, HOXA7, HOXA9, HOXA10, HOXA11 and HOXA13 were correlated with shorter overall survival (OS), disease-specific survival (DSS) and progression-free survival (PFS) in LGG patients. Univariate and multivariate analyses revealed that HOXA1, HOXA6 expression and tumor grade, age, primary therapy outcome and age were independent factors affecting the prognosis of LGG patients. ROC curve analysis of HOXAs showed that HOXAs had a high accuracy (AUC > 0.80) in predicting LGG. Furthermore, gene functional enrichment analysis indicated that HOXAs mainly involved in the inflammatory response and immune regulation signaling pathway. CNV and DNA methylation significantly affect the expression of HOXAs. Finally, we uncover that HOXAs expression are highly correlated with immune cells infiltrate, immune modulator and drug sensitivity. We also uncover that the HOXAs related ceRNA network in LGG. More importantly, we found that HOXA6 was highly expressed in LGG cells lines and significantly affected their proliferation and migration abilities. In conclusion, our data demonstrated that HOXA was correlated with progression and immune infiltration, and could serve as a prognostic biomarker for LGG.

Endocrine disorders after primary gamma knife radiosurgery for pituitary adenomas A systematic review and meta-analysis.

Gamma Knife radiosurgery (GKRS) is feasible for pituitary adenomas, but post-surgery GKRS may cause severe hormone deficits. We reviewed the literature on primary GKRS for pituitary adenoma focusing on radiation-induced hormone deficiencies. PubMed, Web-of-Science, Scopus, and Cochrane were searched upon the PRISMA guidelines to include studies describing primary GKRS for pituitary adenomas. Pooled-rates of GKRS-induced hormone deficiencies and clinical-radiological responses were analyzed with a random-effect model meta-analysis. We included 24 studies comprising 1381 patients. Prolactinomas were the most common (34.2%), and 289 patients had non-functioning adenomas (20.9%). Median tumor volume was 1.6cm Primary GKRS for pituitary adenoma may correlate with lower rates of radiation-induced hypopituitarism (11.4%) than post-surgery GKRS (18-32%). Minimal doses to normal pituitary structures and long-term endocrine follow-up are of primary importance.

Learning and memory impairment induced by 1,4-butanediol is regulated by ERK12-CREB-BDNF signaling pathways in PC12 cells.

1,4-butanediol (1,4-BD) is a known γ-hydroxybutyric acid (GHB) precursor which affects the nervous system after ingestion, leading to uncontrolled behavioral consequences. In the present study, we investigated whether 1,4-BD induces oxidative stress and inflammation in PC12 cells and evaluated the toxic effects of 1,4-BD associates with learning and memory. CCK-8 results revealed a dose-effect relationship between the cell viability of PC12 cells and 1,4-BD when the duration of action was 2 h or 4 h. Assay kits results showed that 1,4-BD decreased the levels of Glutathione (GSH), Glutathione peroxidase (GSH-px), Superoxide dismutase (SOD), Acetylcholine (Ach) and increased the levels of Malondialdehyde (MDA), Nitric oxide (NO) and Acetylcholinesterase (AchE). Elisa kits results indicated that 1,4-BD decreased the levels of synaptophysin I (SYN-1), Postsynaptic density protein-95 (PSD-95), Growth associated protein-43 (GAP-43) and increased the levels of Tumor necrosis factor alpha (TNF-α) and Interleukin- 6 (IL-6). RT-PCR results showed that the mRNA levels of PSD-95, SYN-1 and GAP-43 were significantly decreased. The expression of phosphorylation extracellular signal-regulated protein kinase 12 (p-ERK12), phosphorylation cAMP response element binding protein (p-CREB) and brain-derived neurotrophic factor (BDNF) proteins were significantly decreased in PC12 cells by protein blotting. Overall, these results suggest that 1,4-BD may affect synaptic plasticity via the ERK12-CREB-BDNF pathway, leading to Ach release reduction and ultimately to learning and memory impairment. Furthermore, oxidative stress and inflammation induced by 1,4-BD may also result in learning and memory deficits. These findings will enrich the toxicity data of 1.4-BD associated with learning and memory impairment.

Molecular subgrouping of ependymoma across three anatomic sites and their prognostic implications.

The 2021 WHO classification stratifies ependymoma (EPN) into nine molecular subgroups according to the anatomic locations which outperforms histological grading. We aimed at molecularly reclassifying 200 EPN using immunohistochemistry (IHC) and sequencing for ZFTA fusions in supratentorial (ST) EPN. Further, we assessed the utility of L1CAM, cyclinD1, and p65 markers in identifying ZFTA fusion. Demographic profiles, histologic features, molecular subgroups and clinical outcome were retrospectively analyzed. IHC for L1CAM, cyclinD1, p65, H3K27me3, and H3K27M and sequencing for ZFTA fusion were performed. ZFTA fusions were identified in 44.8% ST EPN. p65 displayed the highest specificity (93.8%), while L1CAM had the highest sensitivity (92.3%) in detecting ZFTA fusions. The negative predictive value approached 96.6% and sensitivity improved to 96.2% with combinatorial IHC (L1CAM, cyclinD1, p65). H3K27me3 loss (PF-A) was noted in 65% PF EPN. Our results provide evidence that a combination of two of three (L1CAM, p65, and cyclinD1) can be used as surrogate markers for predicting fusion. ZFTA fusion, and its surrogate markers in ST, and H3K27me3 and younger age (< 5 years) in PF showed significant correlation with PFS and OS on univariate and Kaplan-Meier analysis. On multivariate analysis, H3K27me3 loss and younger age group are associated with poor clinical outcome.

Trastuzumab Deruxtecan Improves Progression-Free Survival and Intracranial Response in Patients with HER2-Positive Metastatic Breast Cancer and Brain Metastases.

In the phase III DESTINY-Breast03 trial, trastuzumab deruxtecan improved progression-free survival (PFS) relative to trastuzumab emtansine across all patients with HER2-positive metastatic breast cancer, including a 75% improvement in PFS among those with baseline brain metastases.

Artificial Intelligence for Survival Prediction in Brain Tumors on Neuroimaging.

Survival prediction of patients affected by brain tumors provides essential information to guide surgical planning, adjuvant treatment selection, and patient counseling. Current reliance on clinical factors, such as Karnofsky Performance Status Scale, and simplistic radiological characteristics are, however, inadequate for survival prediction in tumors such as glioma that demonstrate molecular and clinical heterogeneity with variable survival outcomes. Advances in the domain of artificial intelligence have afforded powerful tools to capture a large number of hidden high-dimensional imaging features that reflect abundant information about tumor structure and physiology. Here, we provide an overview of current literature that apply computational analysis tools such as radiomics and machine learning methods to the pipeline of image preprocessing, tumor segmentation, feature extraction, and construction of classifiers to establish survival prediction models based on neuroimaging. We also discuss challenges relating to the development and evaluation of such models and explore ethical issues surrounding the future use of machine learning predictions.

Vagus Nerve Stimulation for Tumor-Related Epilepsy Does It Make Sense

Seizure is a common presenting symptom for those with brain tumor due to its unique pathogenesis. Several choices of antiepileptic drug are available to use, but some patients can still go on to develop tumor-related refractory epilepsy. Vagus nerve stimulation is becoming a popular option for those with medical refractory epilepsy but no brain tumor due to its effectiveness. There are very few studies available that address the topic of using vagus nerve stimulation for tumor-related epilepsy. Here we discuss the evidence of using vagus nerve stimulation for refractory tumor-related epilepsy and its challenges and gaps moving forward.

Case Report Primary Duodenal Melanoma with Brain Metastasis.

Malignant duodenal tumors can be primary or secondary. Although the most common primary tumor involving the duodenum is an adenocarcinoma, primary malignant melanomas arising in the small intestine are exceedingly rare and remain a controversial clinical entity. In this report, we present a unique case of primary duodenal melanoma with brain metastasis managed successfully by surgical excision, stereotactic radiation, and adjuvant immunotherapy.

Metabonomic study of biochemical changes in serum of PCPA-induced insomnia rats after treatment with Suanzaoren Decoction.

Suanzaoren Decoction(SZRD) is a classical formula for the clinical treatment of insomnia. This study analyzed the effect of SZRD on endogenous metabolites in insomnia rats based on metabonomics and thereby explored the anti-insomnia mechanism of SZRD. To be specific, DL-4-chlorophenylalanine(PCPA) was used to induce insomnia in rats. Then pathological changes of the liver and brain were observed and biochemical indexes such as 5-hydroxytryptamine(5-HT), dopamine(DA), glutamate(Glu), γ-aminobutyric acid(GABA), and norepinephrine(NE) in the hippocampus and prostaglandin D2(PGD2), tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β), and IL-6 in the serum of rats were detected. On this basis, the effect of SZRD on PCPA-induced insomnia rats was preliminarily assessed. The metabolic profile of rat serum samples was further analyzed by ultra-performance liquid chromatography-quadrupole-time of flight-tandem mass spectrometry(UPLC-Q-TOF-MSMS). Principal component analysis(PCA) and orthogonal partial least squares-discriminant analysis(OPLS-DA) were combined with t-test and variable importance in projection(VIP) to identify differential metabolites, and MetaboAnalyst 5.0 was employed for pathway analysis. The results showed that SZRD could improve the pathological changes of brain and liver tissues, increase the levels of neurotransmitters 5-HT, DA, and GABA in hippocampus and the level of PGD2 in hypothalamic-pituitary-adrenal axis(HPA axis), and reduce the levels of IL-1β and TNF-α in serum of insomnia rats. Metabonomics analysis yielded 12 significantly changed potential metabolites 5-aminovaleric acid, N-acetylvaline, L-proline, L-glutamate, L-valine, DL-norvaline, D(-)-arginine, pyroglutamic acid, 1-methylguanine, L-isoleucine, 7-ethoxy-4-methylcoumarin, and phthalic acid mono-2-ethylhexyl ester(MEHP), which were related with multiple biochemical processes including metabolism of D-glutamine and D-glutamate, metabolism of alanine, aspartate, and glutamate, metabolism of arginine and proline, arginine biosynthesis, glutathione metabolism. These metabolic changes indicated that SZRD can improve the metabolism in insomnia rats by regulating amino acid metabolism.

Pineal germinoma in a young adult A case report.

Intracranial germinomas (GN) are rare cancers that primarily affect children, making them rarer still in adults. Standard treatment for this neoplasm includes neoadjuvant chemotherapy (NC) followed by radiotherapy (RT) or RT at a higher dose and larger field. These recommendations are based on studies focused mostly on children it is currently unclear whether this treatment is applicable to adults. We present a case of a 23-year-old adult male with no underlying pathologies, drug allergies, or family history of cancer, who presented for medical evaluation with blurred vision, diplopia, forgetfulness, and weight loss starting 3-4 months before the evaluation. Clinical examination indicated Parinauds Syndrome. Magnetic resonance imaging (MRI) and computed tomography (CT) revealed a pineal tumor with ependymal dissemination in both lateral ventricles, which was causing obstructive hydrocephalus. The patient had surgery consisting of ventriculostomy, Holter shunt insertion, cisternal ventricular intubation, and cisterna magna anastomosis to improve ventricular drainage. Pathology confirmed pineal germinoma. Cerebrospinal fluid cytology and MRI of the axis were negative. Four cycles of NC were given to the patient (carboplatin, etoposide, and ifosfamide), with reduced dosage. Once a partial volumetric response was confirmed, whole-ventricular radiotherapy (WVR) was initiated with a total tumor bed dose of 45 Gy over 25 sessions in 5 weeks. Optimum clinical results were observed, and no short-term (<90 day) radiation toxicity was observed. The patient was able to resume his normal activities soon after treatment. Follow-ups over 2 years post-surgery indicated continued control of the lesion and absence of symptoms except for mild diplopia. Although this is a case report, these data suggest that a reduced NC course and WVR may effectively treat adult GN. This protocol likely decreases the risk of undesirable NC and RT secondary effects, while providing excellent local control however, using a narrower RT field is not recommended.

Neferine attenuates doxorubicin-induced fibrosis and hypertrophy in H9c2 cells.

Doxorubicin (DOX), an anthracycline antineoplastic candidate is used to treat various malignancies. Around 41% of patients undergoing DOX treatment develop acute cardiotoxicity. Preventing DOX-induced cardiac fibrosis and hypertrophy helps in evading cardiac remodeling leading to cardiomyopathy and heart failure. Neferine, an alkaloid from the lotus has numerous pharmacological activities. The present study was designed to evaluate the protective effect of neferine on DOX-mediated fibrosis and hypertrophy. DOX-induced fibrosis involves activation of transforming growth factor-β1 (TGF-β1), matrix metalloproteinase 2 (MMP-2), and MMP-9 with concomitant downregulation of tissue inhibitors of MMPs (TIMP)-1 and TIMP-2 expressions in H9c2 cardiomyoblasts. Furthermore, DOX treatment also resulted in hypertrophy with the increased cell volume and overexpression of hypertrophy markers calcineurin, brain natriuretic peptide, and atrial natriuretic peptide. Finally, DOX treatment resulted in apoptosis through activation of p53. Pretreatment with neferine markedly activated SIRT1 expression and modulated the expression levels of TGF-β1 and p53, thereby significantly reducing DOX-induced fibrosis, hypertrophy, and apoptosis in H9c2 cardiomyoblasts.

Energy Landscape Analysis of the Epithelial-Mesenchymal Transition Network.

The epithelial-mesenchymal transition (EMT) is a key developmental program that is often activated during the cancer invasion, metastasis, and drug resistance. However, it remains a critical question to elucidate the mechanisms of EMT. For example, how to quantify the global stability and stochastic transition dynamics of EMT under fluctuations is yet to be clarified. Here, we describe a framework and detailed steps for stochastic dynamics analysis of EMT. Starting from the underlying EMT gene regulatory network, we quantify the energy landscape of the EMT computationally. Multiple steady-state attractors are identified on the landscape surface, characterizing different cell phenotypes. The kinetic transition paths based on large deviation theory delineate the transition processes between different attractors quantitatively. The EMT or the reverse process, the mesenchymal-epithelial transition (MET), can be achieved by either a direct transition or a step-wise transition that goes through an intermediate state, depending on different extracellular environments. The landscape and transition paths presented in this chapter provide a new physical and quantitative picture to understand the underlying mechanisms of the EMT process. The approach for landscape and path analysis can be extended to other biological networks.

Clinical and Epidemiological Study of Intracranial Tumors in Children and Identification of Diagnostic Biomarkers for the Most Common Tumor Subtype and Their Relationship with the Immune Microenvironment Through Bioinformatics Analysis.

Brain tumors are the second most common pediatric malignancy and have poor prognosis. Understanding the pathogenesis of tumors at the molecular level is essential for clinical treatment. We conducted a retrospective study on the epidemiology of brain tumors in children based on clinical data obtained from a neurosurgical center. After identifying the most prevalent tumor subtype, we identified new potential diagnostic biomarkers through bioinformatics analysis of the public database. All children (0-15 years) with brain tumors diagnosed histopathologically between 2010 and 2020 at the Department of Neurosurgery, Xijing Hospital, were reviewed retrospectively for age distribution, sex predilection, native location, tumor location, symptoms, and histological grade, and identified the most common tumor subtypes. Two datasets (GSE44971 and GSE44684) were downloaded from the Gene Expression Omnibus database, whereas the GSE44971 dataset was used to screen the differentially expressed genes between normal and tumor samples. Gene ontology, disease ontology, and gene set enrichment analysis enrichment analyses were performed to investigate the underlying mechanisms of differentially expressed genes in the tumor. Combined with methylation data in the GSE44684 dataset, we further analyzed the correlation between methylation and gene expression levels. Two algorithms, LASSO and SVM-RFE, were used to select the hub genes of the tumor. The diagnostic value of the hub genes was assessed using the receiver operating characteristic (ROC) curve. Finally, we further evaluated the relationship between the hub gene and the tumor microenvironment and immune gene sets. Overall, 650 children from 18 provinces in China were included in this study. The male-to-female ratio was 1.411, and the number of patients reached a peak in the 10-15-year-old group (41.4%).The most common symptoms we encountered in our institute were headache and dizziness 250 (28.2%), and nausea and vomiting 228 (25.7%). The predominant location is supratentorial, with a supratentorial to infratentorial ratio of 1.741. Low-grade tumors (WHO III) constituted 60.9% of all cases and were predominant in every age group. According to basic classification, the most common tumor subtype is pilocytic astrocytoma (PA). A total of 3264 differentially expressed genes were identified in the GSE44971 dataset, which are mainly involved in the process of neural signal transduction, immunity, and some diseases. Correlation analysis indicated that the expression of 45 differentially expressed genes was negatively correlated with promoter DNA methylation. Next, we acquired five hub genes (NCKAP1L, GPR37L1, CSPG4, PPFIA4, and C8orf46) from the 45 differentially expressed genes by intersecting the LASSO and SVM-RFE models. The ROC analysis revealed that the five hub genes had good diagnostic value for patients with PA (AUC > 0.99). Furthermore, the expression of NCKAP1L was negatively correlated with immune, stromal, and estimated scores, and positively correlated with immune gene sets. This study, based on the data analysis of intracranial tumors in children in a single center over the past 10 years, reflected the clinical and epidemiological characteristics of intracranial tumors in children in Northwest China to a certain extent. PA is considered the most common subtype of intracranial tumors in children. Through bioinformatics analysis, we suggested that NCKAP1L, GPR37L1, CSPG4, PPFIA4, and C8orf46 are potential biomarkers for the diagnosis of PA.

The role of artificial intelligence in paediatric neuroradiology.

Imaging plays a fundamental role in the managing childhood neurologic, neurosurgical and neuro-oncological disease. Employing multi-parametric MRI techniques, such as spectroscopy and diffusion- and perfusion-weighted imaging, to the radiophenotyping of neuroradiologic conditions is becoming increasingly prevalent, particularly with radiogenomic analyses correlating imaging characteristics with molecular biomarkers of disease. However, integration into routine clinical practice remains elusive. With modern multi-parametric MRI now providing additional data beyond anatomy, informing on histology, biology and physiology, such metric-rich information can present as information overload to the treating radiologist and, as such, information relevant to an individual case can become lost. Artificial intelligence techniques are capable of modelling the vast radiologic, biological and clinical datasets that accompany childhood neurologic disease, such that this information can become incorporated in upfront prognostic modelling systems, with artificial intelligence techniques providing a plausible approach to this solution. This review examines machine learning approaches than can be used to underpin such artificial intelligence applications, with exemplars for each machine learning approach from the world literature. Then, within the specific use case of paediatric neuro-oncology, we examine the potential future contribution for such artificial intelligence machine learning techniques to offer solutions for patient care in the form of decision support systems, potentially enabling personalised medicine within this domain of paediatric radiologic practice.

Integrative spatial analysis of cell morphologies and transcriptional states with MUSE.

Spatial transcriptomics enables the simultaneous measurement of morphological features and transcriptional profiles of the same cells or regions in tissues. Here we present multi-modal structured embedding (MUSE), an approach to characterize cells and tissue regions by integrating morphological and spatially resolved transcriptional data. We demonstrate that MUSE can discover tissue subpopulations missed by either modality as well as compensate for modality-specific noise. We apply MUSE to diverse datasets containing spatial transcriptomics (seqFISH, STARmap or Visium) and imaging (hematoxylin and eosin or fluorescence microscopy) modalities. MUSE identified biologically meaningful tissue subpopulations and stereotyped spatial patterning in healthy brain cortex and intestinal tissues. In diseased tissues, MUSE revealed gene biomarkers for proximity to tumor region and heterogeneity of amyloid precursor protein processing across Alzheimer brain regions. MUSE enables the integration of multi-modal data to provide insights into the states, functions and organization of cells in complex biological tissues.

Methylation and copy number profiling emerging tools to differentiate osteoblastoma from malignant mimics

Rearrangements of the transcription factors FOS and FOSB have recently been identified as the genetic driver event underlying osteoid osteoma and osteoblastoma. Nuclear overexpression of FOS and FOSB have since then emerged as a reliable surrogate marker despite limitations in specificity and sensitivity. Indeed, osteosarcoma can infrequently show nuclear FOS expression and a small fraction of osteoblastomas seem to arise independent of FOSFOSB rearrangements. Acid decalcification and tissue preservation are additional factors that can negatively influence immunohistochemical testing and make diagnostic decision-making challenging in individual cases. Particularly aggressive appearing osteoblastomas, also referred to as epithelioid osteoblastomas, and osteoblastoma-like osteosarcoma can be difficult to distinguish, underlining the need for additional markers to support the diagnosis. Methylation and copy number profiling, a technique well established for the classification of brain tumors, might fill this gap. Here, we set out to comprehensively characterize a series of 77 osteoblastomas by immunohistochemistry, fluorescence in-situ hybridization as well as copy number and methylation profiling and compared our findings to histologic mimics. Our results show that osteoblastomas are uniformly characterized by flat copy number profiles that can add certainty in reaching the correct diagnosis. The methylation cluster formed by osteoblastomas, however, so far lacks specificity and can be misleading in individual cases.

Protection against glutathione depletion-associated oxidative neuronal death by neurotransmitters norepinephrine and dopamine Protein disulfide isomerase as a mechanistic target for neuroprotection.

Oxidative stress is extensively involved in neurodegeneration. Clinical evidence shows that keeping the mind active through mentally-stimulating physical activities can effectively slow down the progression of neurodegeneration. With increased physical activities, more neurotransmitters would be released in the brain. In the present study, we investigated whether some of the released neurotransmitters might have a beneficial effect against oxidative neurodegeneration in vitro. Glutamate-induced, glutathione depletion-associated oxidative cytotoxicity in HT22 mouse hippocampal neuronal cells was used as an experimental model. We showed that norepinephrine (NE, 50 µM) or dopamine (DA, 50 µM) exerted potent protective effect against glutamate-induced cytotoxicity, but this effect was not observed when other neurotransmitters such as histamine, γ-aminobutyric acid, serotonin, glycine and acetylcholine were tested. In glutamate-treated HT22 cells, both NE and DA significantly suppressed glutathione depletion-associated mitochondrial dysfunction including mitochondrial superoxide accumulation, ATP depletion and mitochondrial AIF release. Moreover, both NE and DA inhibited glutathione depletion-associated MAPKs activation, p53 phosphorylation and GADD45α activation. Molecular docking analysis revealed that NE and DA could bind to protein disulfide isomerase (PDI). In biochemical enzymatic assay in vitro, NE and DA dose-dependently inhibited the reductive activity of PDI. We further revealed that the protective effect of NE and DA against glutamate-induced oxidative cytotoxicity was mediated through inhibition of PDI-catalyzed dimerization of the neuronal nitric oxide synthase. Collectively, the results of this study suggest that NE and DA may have a protective effect against oxidative neurodegeneration through inhibition of protein disulfide isomerase and the subsequent activation of the MAPKs‒p53‒GADD45α oxidative cascade.

GRP78 blockade overcomes intrinsic resistance to UBA1 inhibitor TAK-243 in glioblastoma.

Glioblastoma multiforme (GBM) is the most aggressive malignant primary brain tumor of the central nervous system. Despite continuous progression in treatment options for GBM like surgery, radiotherapy, and chemotherapy, this disease still has a high rate of recurrence. The endoplasmic reticulum (ER) stress pathway is associated with chemotherapeutic drug resistance. The UBA1 inhibitor TAK-243 can induce strong ER stress. However, the sensitivity of TAK-243 varies greatly in different tumor cells. This study evaluated the antitumor effects of the GRP78 inhibitor, HA15, combined with TAK-243 on GBM in the preclinical models. HA15 synergistically enhanced the sensitivity of GBM cells to TAK-243. When compared with TAK-243 monotherapy, HA15 combined with TAK-243 significantly inhibited GBM cell proliferation. It also induced G2M-phase arrest in the cell cycle. In vivo studies showed that HA15 combined with TAK-243 significantly inhibited the growth of intracranial GBM and prolonged survival of the tumor-bearing mice. Mechanistically, HA15 and TAK-243 synergistically activated the PERKATF4 and IRE1αXBP1 signaling axes, thereby eventually activating PARP and the Caspase families, which induced cell apoptosis. Our data provided a new strategy for improving the sensitivity of GBM to TAK-243 treatment and experimental basis for further clinical trials to evaluate this combination therapy.

Pre-clinical safety and therapeutic efficacy of a plant-based alkaloid in a human colon cancer xenograft model.

A high-throughput drug screen revealed that veratridine (VTD), a natural plant alkaloid, induces expression of the anti-cancer protein UBXN2A in colon cancer cells. UBXN2A suppresses mortalin, a heat shock protein, with dominant roles in cancer development including epithelial-mesenchymal transition (EMT), cancer cell stemness, drug resistance, and apoptosis. VTD-dependent expression of UBXN2A leads to the deactivation of mortalin in colon cancer cells, making VTD a potential targeted therapy in malignant tumors with high levels of mortalin. VTD was used clinically for the treatment of hypertension in decades past. However, the discovery of newer antihypertensive drugs and concerns over potential neuro- and cardiotoxicity ended the use of VTD for this purpose. The current study aims to determine the safety and efficacy of VTD at doses sufficient to induce UBXN2A expression in a mouse model. A set of flow-cytometry experiments confirmed that VTD induces both early and late apoptosis in a dose-dependent manner. In vivo intraperitoneal (IP) administration of VTD at 0.1 mgkg every other day (QOD) for 4 weeks effectively induced expression of UBXN2A in the small and large intestines of mice. Liquid chromatography-tandem mass spectrometry (LC-MSMS) assays on tissues collected from VTD-treated animals demonstrated VTD concentrations in the low pgmg range. To address concerns regarding neuro- and cardiotoxicity, a comprehensive set of behavioral and cardiovascular assessments performed on C57BL6NHsd mice revealed that VTD generates no detectable neurotoxicity or cardiotoxicity in animals receiving 0.1 mgkg VTD QOD for 30 days. Finally, mouse xenograft experiments in athymic nude mice showed that VTD can suppress tumor growth. The main causes for the failure of experimental oncologic drug candidates are lack of sufficient safety and efficacy. The results achieved in this study support the potential utility of VTD as a safe and efficacious anti-cancer molecule.

Hypofractionated Gamma Knife Radiosurgery Institutional Experience on Benign and Malignant Intracranial Tumors.

We investigated the treatment outcomes and complications associated with hypofractionated GKRS for the treatment of benign and malignant intracranial tumors. Patients with intracranial tumors not candidate or refusing surgery were evaluated to assess eligibility to undergo hypofractionated Gamma Knife radiosurgery (GKRS). Targeted volumes were calculated using the GammaPlan A total of 41 patients, affected with 6 different histologies, were treated and followed-up for a median of 12 months (range4-24 months). Meningiomas were the most common tumors (33, 80.5%), followed by brain metastases (4, 9.7%). At last follow-up, 33 patients (80.5%) had stable disease, 8 tumor regression (19.5%), and 0 tumor progression. No acute radiation toxicity was observed. Death was reported in 3 patients (7.3%) due to malignant tumor progression. Our hypofractionated GKRS protocol proved to be effective and safe in the treatment of patients with benign and malignant intracranial tumors. Local tumor control was achieved in all patients, with 8 patients showing tumor regression and no cases of acute radiation toxicity.

Chemotherapy Can Synergize With Adoptive Immunotherapy to Inhibit Medulloblastoma Growth.

In the age of ever-increasing developments in targeted cancer treatments, new immune-based approaches for brain tumor therapy represent an attractive avenue. Despite encouraging pre-clinical data, results in patients have been sub-optimal, likely due to tumor-induced immune suppression and intrinsic resistance to immune attack. Chemotherapy and biologic agents may be able to disrupt these mechanisms and restore tumor sensitivity to immune attack. In this study, we explore whether a combination of gemcitabine and rapamycin can sensitize medulloblastoma cells to immunotherapy in vitro and in vivo. With the commercial medulloblastoma cell line, Daoy, we explored the concentrations of combinations of Gemcitabine with rapamycin needed to induce cytotoxicity. Next, we used flow cytometry to assess the cytotoxicity of chemotherapy-treated Daoy cells with the addition of anti-tumor T-cells, generated from naive T-cells stimulated in the presence of Daoy lysate-pulsed dendritic cells. Then, we examined the efficacy of chemotherapy alone versus chemotherapy plus immunotherapy in tumor growth inhibition of subcutaneous medulloblastoma xenografts. Rapamycin alone at <1,000 nM had moderate activity against Daoy cells in vitro and IC Combining immunotherapy and chemo-biologic therapy inhibit medulloblastoma cell and xenograft growth, and may offer an effective treatment for patients with medulloblastoma.

All-stage targeted therapy for glioblastoma based on lipid membrane coated cabazitaxel nanocrystals.

Glioblastoma (GBM) is the most aggressive brain tumor with poor prognosis and frequent recurrence. The blood-brain barrier (BBB), blood-brain tumor barrier (BBTB) hinder the entry of therapeutics into the glioma region. Vasculogenic mimicry (VM) formed by invasive glioma cells is also related to recurrence of GBM. VAP is a D-peptide ligand of GRP78 protein overexpressed on BBTB, VM, and glioma cells but not on normal tissues. Besides, p-hydroxybenzoic acid (pHA) can effectively traverse the BBB. Herein we developed an all-stage glioma-targeted cabazitaxel (CBZ) nanocrystal loaded liposome modified with a Y shaped targeting ligand composed of pHA and VAP (pV-LipcNC). The pure drug nanocrystal core provided high drug loading, while lipid membrane promoted the stability and circulation time. pV-LipcNC exhibited excellent glioma homing, barriers crossing, and tumor spheroid penetrating capability in vitro. Treatment of pV-LipcNC displayed enhanced CBZ accumulation in glioma and anti-glioma effect with a median survival time (53 days) significantly longer than that of cNC loaded liposomes modified with either single ligand (42 days for VAP and 45 days for pHA) in the murine orthotopic GBM model. These results indicated pV-LipcNC could traverse the BBB and BBTB, destruct VM, and finally kill glioma cells to realize all-stage glioma therapy.

Epilepsy-related white matter network changes in patients with frontal lobe glioma.

Epilepsy is a common symptom in patients with frontal lobe glioma. Tumor-related epilepsy was recently considered a type of network disease. Glioma can severely influence the integrity of the white matter network. The association between white matter network changes and presurgical epilepsy remains unclear in glioma patients. This study aims to identify alterations to the subcortical brain networks caused by glioma and glioma-related epilepsy. Sixty-one patients with frontal lobe gliomas were enrolled and stratified into the epileptic and non-epileptic groups. Additionally, 14 healthy participants were enrolled after matching for age, sex, and education level. All participants underwent diffusion tensor imaging. Graph theoretical analysis was applied to reveal topological changes in their white matter networks. Regions affected by tumors were excluded from the analysis. Global efficiency was significantly decreased (p 0.008), while the shortest path length increased (p 0.02) in the left and right non-epileptic groups compared to the controls. A total of five edges exhibited decreased fiber count in the non-epileptic group (p < 0.05, false discovery rate-corrected). The topological properties and connectional edges showed no significant differences when comparing the epileptic groups and the controls. Additionally, the degree centrality of several nodes connected to the alternated edges was also diminished. Compared to the controls, the epilepsy groups showed raletively intact WM networks, while the non-epileptsy groups had damaged network with lower efficiency and longer path length. These findings indicated that the occurrence of glioma related epilepsy have association with white matter network intergrity.

Early age of onset and broad cancer spectrum persist in MSH6- and PMS2-associated Lynch syndrome.

This study aimed to characterize MSH6PMS2-associated mismatch repair-deficient (MMR-D)microsatellite instability-high (MSI-H) tumors, given revised guidelines suggesting more modest phenotypes. Patients who consented to Institutional Review Board-approved protocols of tumorgermline sequencing or Lynch syndrome registry at a single institution from February 2005 to January 2021 with germline, heterozygous MSH6PMS2 pathogeniclikely pathogenic variants were identified. Clinical data were abstracted and correlated with MMRmicrosatellite instability status using nonparametric tests. We identified 243 patients (133 sequencing, 110 registry) with germline MSH6PMS2 pathogeniclikely pathogenic variants 186 (77%) had >1 cancer. Of 261 pooled tumors, colorectal cancer (CRC) and endometrial cancer (EC) comprised 55% and 43% of cancers in MSH6 and PMS2, respectively 192 tumors underwent molecular assessments and 122 (64%) were MMR-DMSI-H (77 in MSH6, 45 in PMS2). MMR-DMSI-H cancers included CRC (n 56), EC (n 35), small bowel cancer (n 6), ovarian cancer (n 6), urothelial cancer (n 5), pancreasbiliary cancer (n 4), gastricesophageal cancer (n 3), nonmelanoma skin tumors (n 3), prostate cancer (n 2), breast cancer (n 1), and central nervous systembrain cancer (n 1). Among MMR-DMSI-H CRC and EC, median age of diagnosis was 51.5 (range 27-80) and 55 (range 39-74) years, respectively 9 of 56 (16%) MMR-DMSI-H CRCs were diagnosed at age <35 years. MSH6PMS2 heterozygotes remain at risk for a broad spectrum of cancers, with 16% of MMR-DMSI-H CRCs presenting before upper threshold of initiation of colonoscopy per guidelines.

Advances in Intraarterial Chemotherapy Delivery Strategies and Blood-Brain Barrier Disruption.

Chemotherapeutics play a significant role in the management of most brain tumors. First pass effect, systemic toxicity, and more importantly, the blood-brain barrier pose significant challenges to the success of chemotherapy. Over the last 80 years, different techniques of intraarterial chemotherapy delivery have been performed in many studies but failed to become standard of care. The purpose of this article is to review the history of intraarterial drug delivery and osmotic blood-brain barrier disruption, identify the challenges for clinical translation, and identify future directions for these approaches.

Detection of bladder cancer with feature fusion, transfer learning and CapsNets.

This paper confronts two approaches to classify bladder lesions shown in white light cystoscopy images when using small datasets the classical one, where handcrafted-based features feed pattern recognition systems and the modern deep learning-based (DL) approach. In between, there are alternative DL models that had not received wide attention from the scientific community, even though they can be more appropriate for small datasets such as the human brain motivated capsule neural networks (CapsNets). However, CapsNets have not yet matured hence presenting lower performances than the most classic DL models. These models require higher computational resources, more computational skills from the physician and are more prone to overfitting, making them sometimes prohibitive in the routine of clinical practice. This paper shows that carefully handcrafted features used with more robust models can reach similar performances to the conventional DL-based models and deep CapsNets, making them more useful for clinical applications. Concerning feature extraction, it is proposed a new feature fusion approach for Ta and T1 bladder tumor detection by using decision fusion from multiple classifiers in a scheme known as stacking of classifiers. Three Neural Networks perform classification on three different feature sets, namely Covariance of Color Histogram of Oriented Gradients, proposed in the ambit of this paper Local Binary Patterns and Wavelet Coefficients taken from lower scales. Data diversity is ensured by a fourth Neural Network, which is used for decision fusion by combining the outputs of the ensemble elements to produce the classifier output. Both Feed Forward Neural Networks and Radial Basis Functions are used in the experiments. Contrarily, DL-based models extract automatically the best features at the cost of requiring huge amounts of training data, which in turn can be alleviated by using the Transfer Learning (TL) strategy. In this paper VGG16 and ResNet-34 pretrained in ImageNet were used for TL, slightly outperforming the proposed ensemble. CapsNets may overcome CNNs given their ability to deal with objects rotational invariance and spatial relationships. Therefore, they can be trained from scratch in applications using small amounts of data, which was beneficial for the current case, improving accuracy from 94.6% to 96.9%.

The efficacy of temozolomide combined with levetiracetam for glioblastoma (GBM) after surgery a study protocol for a double-blinded and randomized controlled trial.

Temozolomide is applied as the standard chemotherapy agent in patients with glioblastoma (GBM) after surgery. However, the benefit of this treatment for patients is limited by the invasive growth of gliomas and drug resistance. There are indications from fundamental experimental and retrospective studies that levetiracetam has the potential to improve the survival rate of patients with GBM. However, it has yet to be determined whether the combination of temozolomide and levetiracetam is more effective than standard temozolomide chemotherapy. Therefore, we designed a randomized clinical trial to investigate the therapeutic effect of the new combined regime for treating GBM. This is a double-blind and randomized clinical trial conducted in a single center. One hundred forty-two patients will be recruited and screened for the inclusion and exclusion criteria. Then, eligible participants will be randomly assigned to an experimental group or a control group in a 11 ratio. Based on the administration of radiation therapy (RT), participants in the experimental group will be prescribed levetiracetam plus temozolomide chemotherapy for 34 weeks while participants in the control group will receive placebo tablets plus temozolomide for the same duration. A 3-year follow-up will be conducted on all patients after intervention. Accordingly, the primary outcome will be progression-free survival (PFS). The secondary endpoints include overall survival (OS), the Karnofsky Performance Status (KPS), the objective response rate (ORR), and adverse event incidence. It is expected that the results of this trial will provide high-level evidence regarding the clinical benefits of levetiracetam and temozolomide combined in the treatment of GBM. Chinese Clinical Trial Registry, ChiCTR2100049941 . Registered on 14 August 2021.

Non-coding RNAs in the regulation of blood-brain barrier functions in central nervous system disorders.

The blood-brain barrier (BBB) is an essential component of the neurovascular unit that controls the exchanges of various biological substances between the blood and the brain. BBB damage is a common feature of different central nervous systems (CNS) disorders and plays a vital role in the pathogenesis of the diseases. Non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNA (lncRNAs), and circular RNAs (circRNAs), are important regulatory RNA molecules that are involved in almost all cellular processes in normal development and various diseases, including CNS diseases. Cumulative evidences have demonstrated ncRNA regulation of BBB functions in different CNS diseases. In this review, we have summarized the miRNAs, lncRNAs, and circRNAs that can be served as diagnostic and prognostic biomarkers for BBB injuries, and demonstrated the involvement and underlying mechanisms of ncRNAs in modulating BBB structure and function in various CNS diseases, including ischemic stroke, hemorrhagic stroke, traumatic brain injury (TBI), spinal cord injury (SCI), multiple sclerosis (MS), Alzheimers disease (AD), vascular cognitive impairment and dementia (VCID), brain tumors, brain infections, diabetes, sepsis-associated encephalopathy (SAE), and others. We have also discussed the pharmaceutical drugs that can regulate BBB functions via ncRNAs-related signaling cascades in CNS disorders, along with the challenges, perspective, and therapeutic potential of ncRNA regulation of BBB functions in CNS diseases.

Efficacy and safety of adjuvant EGFR-TKIs for resected non-small cell lung cancer a systematic review and meta-analysis based on randomized control trials.

Postoperative adjuvant cisplatin-based chemotherapy had been the standard care in patients with completely resected high-risk stage IB to IIIA non-small cell lung cancer (NSCLC) for decades. However, the survival benefits were far from satisfactory in clinical practice. Thus, this meta-analysis was performed to compare the efficacy and safety of adjuvant epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in patients with resected NSCLC based on updated literature and research. A systematic literature search based on random control trials (RCTs) was conducted with keywords on PubMed, Embase and the Cochrane library databases. All articles compared EGFR-TKIs to placebo or chemotherapy as adjuvant therapies for early-stage resected NSCLC. A meta-analysis was performed to generate combined hazard ratio (HR) with 95% confidence intervals (CI) for disease-free survival (DFS), overall survival (OS), and risk ratio (RR) with 95% CI for disease recurrence and adverse events (AEs). The Stata statistical software (version 14.0) was used to synthesis the data. A total of 9 RCTs comprising 3098 patients were included. Adjuvant EGFR-TKIs could significantly prolong DFS in patient with resected NSCLC harboring epidermal growth factor receptor (EGFR) mutations (HR 0.46, 95% CI 0.29-0.72), but had no impact on OS (HR 0.87, 95% CI 0.69-1.11). The subgroup analyses indicated that adjuvant EGFR-TKIs were superior in regard to DFS in most subgroups, including varied smoking status, EGFR mutations type, gender, age, Eastern Cooperative Oncology Group performance status and adenocarcinoma. Osimertinib resulted in decreased brain recurrence than first generation of EGFR-TKIs (RR 0.12, 95% CI 0.04-0.34 vs. RR 1.07, 95% CI 0.64-1.78, respectively). The AEs were generally manageable and tolerable. The incidence of high-grade (≥ 3) AEs including diarrhea (RR 5.68, 95% CI 2.94-10.98) and rash (RR 27.74, 95% CI 11.43-67.30) increased after adjuvant EGFR-TKIs treatment. Adjuvant EGFR-TKIs therapy could significantly prolong DFS in patients with completely resected early-stage EGFR mutation-positive NSCLC, but had no impact on OS. Adjuvant EGFR-TKIs could be an important treatment option in patients with resected early-stage EGFR-mutant NSCLC.