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Pemetrexed for Recurrent Primary Central Nervous System Lymphoma in the Elderly Results of a Retrospective Study.

Primary central nervous system lymphoma (PCNSL) is an aggressive, destructive, and rapidly progressive malignant brain tumor. Although aggressive therapies were studied trying to increase the median survival of PCNSL, the high relapse rate of PCNSL is still a big problem for the oncology medicine. A retrospective study was made to evaluate the efficacy and safety of pemetrexed in the treatment of patients with recurrent PCNSL. Twenty-three confirmed recurrent PCNSL patients were selected during April 2012 and August 2016. Dexamethasone, B After the treatment, 7 patients were in complete remission, 6 patients in partial remission, 4 patients in stable condition, and 6 patients in progression. There were 56.5% and 73.9% in the overall response rate and the disease control rate, respectively. The median overall survival (OS) was 6.6 months (95% CI, 4.6-8.6). This study has been the first time to evaluate the safety and effectiveness of pemetrexed on elderly recurrent PCNSL patients. Results demonstrate that using high-dose pemetrexed might be a feasible and effective treatment for recurrent PCNSL in the elderly, and clinical trials should be conducted to further confirm it.

Cancer Metabolism The Role of Immune Cells Epigenetic Alteration in Tumorigenesis, Progression, and Metastasis of Glioma.

Glioma is a type of brain and spinal cord tumor that begins in glial cells that support the nervous system neurons functions. Age, radiation exposure, and family background of glioma constitute are risk factors of glioma initiation. Gliomas are categorized on a scale of four grades according to their growth rate. Grades one and two grow slowly, while grades three and four grow faster. Glioblastoma is a grade four gliomas and the deadliest due to its aggressive nature (accelerated proliferation, invasion, and migration). As such, multiple therapeutic approaches are required to improve treatment outcomes. Recently, studies have implicated the significant roles of immune cells in tumorigenesis and the progression of glioma. The energy demands of gliomas alter their microenvironment quality, thereby inducing heterogeneity and plasticity change of stromal and immune cells

A Simple-To-Use Nomogram for Predicting Early Death in Metastatic Renal Cell Carcinoma A Population-Based Study.

Metastatic renal cell carcinoma (mRCC) is usually considered to have a poor prognosis, which has a high risk of early death (≤3 months). Our aim was to developed a predictive nomogram for early death of mRCC. The SEER database was accessed to obtain the related information of 6,005 mRCC patients between 2010 and 2015. They were randomly divided into primary cohort and validation cohort in radio of 73. The optimal cut-off point regarding age at diagnosis and tumor size were identified by the X-tile analysis. Univariate and multivariate logistic regression models were applied to determine significant independent risk factors contributed to early death. A practical nomogram was constructed and then verified by using calibration plots, receiver operating characteristics (ROCs) curve, and decision curve analysis (DCA). There were 6,005 patients with mRCC included in the predictive model, where 1,816 patients went through early death (death within ≤3 months of diagnosis), and among them 1,687 patients died of mRCC. Based on 11 significant risk factors, including age, grade, The nomogram may play a major part in distinguishing the early death of mRCC patients, which can assist clinicians in individualized medicine.

Diagnostic accuracy of imaging approaches for early tumor detection in children with Li-Fraumeni syndrome.

The Toronto protocol for cancer surveillance in children with Li-Fraumeni syndrome has been adopted worldwide. To assess the diagnostic accuracy of the imaging used in this protocol. We conducted a blinded retrospective review of imaging modalities in 31 pediatric patients. We compared imaging findings with the reference standards, which consisted of (1) histopathological diagnosis, (2) corresponding dedicated imaging or subsequent surveillance imaging or (3) clinical outcomes. We individually analyzed each modalitys diagnostic performance for cancer detection and assessed it on a per-study basis for chest and abdominal regional whole-body MRI (n115 each), brain MRI (n101) and abdominalpelvic US (n292), and on a per-lesion basis for skeletonsoft tissues on whole-body MRI (n140). Of 763 studieslesions, approximately 80% had reference standards that identified 4 (0.7%) true-positive, 523 (85.3%) true-negative, 5 (0.8%) false-positive, 3 (0.5%) false-negative and 78 (12.7%) indeterminate results. There were 3 true-positives on whole-body MRI and 1 true-positive on brain MRI as well as 3 false-negatives on whole-body MRI. Sensitivities and specificities of tumor diagnosis using a worst-case scenario analysis were, respectively, 40.0% (95% confidence interval CI 7.3%, 83.0%) and 38.2% (95% CI 29.2%, 48.0%) for skeletonsoft tissues on whole-body MRI sensitivity non-available and 97.8% (95% CI 91.4%, 99.6%) for chest regional whole-body MRI 100.0% (95% CI 5.5%, 100.0%) and 96.8% (95% CI 90.2%, 99.2%) for abdominal regional whole-body MRI sensitivity non-available and 98.3% (95% CI 95.3, 99.4) for abdominalpelvic US and 50.0% (95% CI 2.7%, 97.3%) and 93.8% (95% CI 85.6%, 97.7%) for brain MRI. Considerations for optimizing imaging protocol, defining criteria for abnormalities, developing a structured reporting system, and practicing consensus double-reading may enhance the diagnostic accuracy for tumor surveillance.

Machine Learning Identification of Immunotherapy Targets in Low-Grade Glioma Using RNA Sequencing Expression Data.

Immunotherapy has revolutionized cancer treatment in the past decade, but significant hurdles remain. Human studies with immune checkpoint inhibitors targeting programmed cell death protein have demonstrated suboptimal efficacy in the setting of low-grade gliomas (LGGs). Identification of mechanisms leading to inadequate anti-tumor immunity is paramount. The current study evaluates and validates barriers to immunotherapy using a novel machine learning algorithm. We utilized The Cancer Genome Atlas (TCGA) to generate expression levels of 28 immune genes related to known immunotherapeutic targets or lymphocyte cytolytic activity. We created training and testing groups and 3 machine learning models to determine the genes most highly correlated to cytolytic activity (CYT). The 3 models were run through multiple regression by exhaustive selection, LASSO, and random forest. We validated computational results by comparing expression of pertinent genes in patient-derived glioma samples. Our models demonstrated linearity, a low mean-squared error, and consistent results with respect to the most important variables. Expression of ICOS, IDO1, and CD40 were the most important variables in all models and demonstrated positive correlation with CYT. Other variables included TIGIT and CD137. Genetic analysis from 3 IDH-mutants (IDHm) and 3 IDH-wild type (IDHwt) patient-derived glioma samples validated TCGA data and demonstrated lower levels of CYT in IDHm gliomas compared with IDHwt. This novel methodology has elucidated 3 potential targets for immunotherapy development in LGGs. We also demonstrated a novel method of analyzing data using advanced statistical techniques that can be further used in developing treatments for other diseases as well.

Evaluation of the immediate effects of a single transcranial direct current stimulation session on astrocyte activation, inflammatory response, and pain threshold in naïve rats.

Transcranial direct current stimulation (tDCS) has demonstrated clinical benefits such as analgesia, anti-inflammatory, and neuroprotective effects. However, the mechanisms of action of a single tDCS session are poorly characterized. The present study aimed to evaluate the effects of a single tDCS session on pain sensitivity, inflammatory parameters, and astrocyte activity in naive rats. In the first experiment, sixty-day-old male Wistar rats (n 95) were tested for mechanical pain threshold (von Frey test). Afterward, animals were submitted to a single bimodal tDCS (0.5 mA, 20 min) or sham-tDCS session. According to the group, animals were re-tested at different time intervals (30, 60, 120 min, or 24 h) after the intervention, euthanized, and the cerebral cortex collected for biochemical analysis. A second experiment (n 16) was performed using a similar protocol to test the hypotheses that S100B levels in the cerebrospinal fluid (CSF) are altered by tDCS. Elisa assay quantified the levels of tumor necrosis factor-alfa (TNF-α), interleukin-10 (IL10), S100 calcium-binding protein B (S100B), and Glial fibrillary acidic protein (GFAP). Data were analyzed using ANOVA and independent t-test (P < 0.05). Results showed that tDCS decreased pain sensitivity (30 and 60 min), cerebral TNF-α and S100B levels (30 min). CSF S100B levels increased 30 min after intervention. There were no differences in IL10 and GFAP levels. TCDS showed analgesic, anti-inflammatory, and neuroprotective effects in naive animals. Therefore, this non-invasive and inexpensive therapy may potentially be a preemptive alternative to reduce pain, inflammation, and neurodegeneration in situations where patients will undergo medical procedures (e.g., surgery).

Brain metastases Not all tumors are created equal.

Metastases are the main cause of death in cancer patients. In a recent issue of Cell, Gonzalez et al. (2022) analyze gene expression on the single-cell level in brain metastases from various primary tumors. By profiling metastatic tumor cells and their niche, they demonstrate distinctive and shared features across metastases.

Promoter and enhancer RNAs regulate chromatin reorganization and activation of miR-10bHOXD locus, and neoplastic transformation in glioma.

miR-10b is silenced in normal neuroglial cells of the brain but commonly activated in glioma, where it assumes an essential tumor-promoting role. We demonstrate that the entire miR-10b-hosting HOXD locus is activated in glioma via the cis-acting mechanism involving 3D chromatin reorganization and CTCF-cohesin-mediated looping. This mechanism requires two interacting lncRNAs, HOXD-AS2 and LINC01116, one associated with HOXD3HOXD4miR-10b promoter and another with the remote enhancer. Knockdown of either lncRNA in glioma cells alters CTCF and cohesin binding, abolishes chromatin looping, inhibits the expression of all genes within HOXD locus, and leads to glioma cell death. Conversely, in cortical astrocytes, enhancer activation is sufficient for HOXDmiR-10b locus reorganization, gene derepression, and neoplastic cell transformation. LINC01116 RNA is essential for this process. Our results demonstrate the interplay of two lncRNAs in the chromatin folding and concordant regulation of miR-10b and multiple HOXD genes normally silenced in astrocytes and triggering the neoplastic glial transformation.

Regulation of Drug Transport Proteins-From Mechanisms to Clinical Impact A White Paper on Behalf of the International Transporter Consortium.

Membrane transport proteins are involved in the absorption, disposition, efficacy, andor toxicity of many drugs. Numerous mechanisms (e.g., nuclear receptors, epigenetic gene regulation, microRNAs, alternative splicing, post-translational modifications, and trafficking) regulate transport protein levels, localization, and function. Various factors associated with disease, medications, and dietary constituents, for example, may alter the regulation and activity of transport proteins in the intestine, liver, kidneys, brain, lungs, placenta, and other important sites, such as tumor tissue. This white paper reviews key mechanisms and regulatory factors that alter the function of clinically relevant transport proteins involved in drug disposition. Current considerations with in vitro and in vivo models that are used to investigate transporter regulation are discussed, including strengths, limitations, and the inherent challenges in predicting the impact of changes due to regulation of one transporter on compensatory pathways and overall drug disposition. In addition, translation and scaling of in vitro observations to in vivo outcomes are considered. The importance of incorporating altered transporter regulation in modeling and simulation approaches to predict the clinical impact on drug disposition is also discussed. Regulation of transporters is highly complex and, therefore, identification of knowledge gaps will aid in directing future research to expand our understanding of clinically relevant molecular mechanisms of transporter regulation. This information is critical to the development of tools and approaches to improve therapeutic outcomes by predicting more accurately the impact of regulation-mediated changes in transporter function on drug disposition and response.

Ganoderma tsugae prevents cognitive impairment and attenuates oxidative damage in d-galactose-induced aging in the rat brain.

Lingzhi has long been regarded as having life-prolonging effects. Research in recent years has also reported that Lingzhi possesses anti-tumor, anti-inflammatory, immunomodulatory, hepatoprotective, and anti-lipogenic effects. The D-galactose (D-gal, 100 mgkgday)-induced aging Long-Evans rats were simultaneously orally administered a DMSO extract of Ganoderma tsugae (GTDE, 200 μgkgday) for 25 weeks to investigate the effects of GTDE on oxidative stress and memory deficits in the D-galactose-induced aging rats. We found that GTDE significantly improved the locomotion and spatial memory and learning in the aging rats. GTDE alleviated the aging-induced reduction of dendritic branching in neurons of the hippocampus and cerebral cortex. Immunoblotting revealed a significant increase in the protein expression levels of the superoxide dismutase-1 (SOD-1) and catalase, and the brain-derived neurotrophic factor (BDNF) in rats that received GTDE. D-gal-induced increase in the lipid peroxidation product 4-hydroxynonenal (4-HNE) was significantly attenuated after the administration of GTDE, and pyrin domain-containing 3 protein (NLRP3) revealed a significant decrease in NLRP3 expression after GTDE administration. Lastly, GTDE significantly reduced the advanced glycosylation end products (AGEs). In conclusion, GTDE increases antioxidant capacity and BDNF expression of the brain, protects the dendritic structure of neurons, and reduces aging-induced neuronal damage, thereby attenuating cognitive impairment caused by aging.

A Study on Prevalence and Determinants of Ototoxicity During Treatment of Childhood Cancer (SOUND) Protocol for a Prospective Study.

Some children with central nervous system (CNS) and solid tumors are at risk to develop ototoxicity during treatment. Up to now, several risk factors have been identified that may contribute to ototoxicity, such as platinum derivates, cranial irradiation, and brain surgery. Comedication, like antibiotics and diuretics, is known to enhance ototoxicity, but their independent influence has not been investigated in childhood cancer patients. Recommendations for hearing loss screening are missing or vary highly across treatment protocols. Additionally, adherence to existing screening guidelines is not always optimal. Currently, knowledge is lacking on the prevalence of ototoxicity. The aim of the Study on Prevalence and Determinants of Ototoxicity During Treatment of Childhood Cancer (SOUND) is to determine the feasibility of audiological testing and to determine the prevalence and determinants of ototoxicity during treatment for childhood cancer in a national cohort of patients with solid and CNS tumors. The SOUND study is a prospective cohort study in the national childhood cancer center in the Netherlands. The study aims to include all children aged 0 to 19 years with a newly diagnosed CNS or solid tumor. Part of these patients will get audiological examination as part of their standard of care (stratum 1). Patients in which audiological examination is not the standard of care will be invited for inclusion in stratum 2. Age-dependent audiological assessments will be pursued before the start of treatment and within 3 months after the end of treatment. Apart from hearing loss, we will investigate the feasibility to screen patients for tinnitus and vertigo prevalence after cancer treatment. This study will also determine the independent contribution of antibiotics and diuretics on ototoxicity. This study was approved by the Medical Research Ethics Committee Utrecht (Identifier 20-417M). Currently, we are in the process of recruitment for this study. The SOUND study will raise awareness about the presence of ototoxicity during the treatment of children with CNS or solid tumors. It will give insight into the prevalence and independent clinical and cotreatment-related determinants of ototoxicity. This is important for the identification of future high-risk patients. Thereby, the study will provide a basis for the selection of patients who will benefit from innovative otoprotective intervention trials during childhood cancer treatment that are currently being prepared. Netherlands Trial Register NL8881 httpswww.trialregister.nltrial8881. DERR1-10.219634297.

Peritoneal metastasis of a brainstem anaplastic ganglioglioma in a 2-year-old boy case report and literature review.

Anaplastic gangliogliomas (AGG) are rare tumors of the central nervous system (CNS) that commonly affect children and young adults, with an unusual infratentorial presentation, which is related to hydrocephalus and a worse prognosis. We report a case of a brainstem AGG in a 2-year-old boy who underwent a ventriculoperitoneal shunting (VPS) and later presented peritoneal metastasis. We also reviewed the related literature. Even though rare, disease dissemination through VPS should be sought in patients with CNS tumors and VPS who develop new abdominal symptoms. The early diagnosis and intervention may minimize morbidity and improve quality of life of such patients.

Methylation classifiers Brain tumors, sarcomas, and whats next.

Tumor classification has evolved over the last decades with technical progress contributing much to our current concepts. Among diagnostic hallmarks, novelties were immunostaining, Fluorescence in situ hybridization, Sanger sequencing followed by massive parallel DNA sequencing, and recently, epigenetic analyses have entered the stage. Although each of these techniques was revolutionary and, in some way, also disruptive in certain diagnostic fields, it took years to decades for broad implementation into standard pathological-diagnostic algorithms. In contrast, DNA methylation profiling has been accepted in short time as a game changer with lasting impact on brain tumor classification and with potential for classification of other tumor types. This review provides a brief introduction in DNA methylation-based tumor classification. We present why DNA methylation signatures are attractive diagnostic biomarkers, discuss present achievements and future aims and explain the integration of methylation-based classifiers in diagnostic procedure. Finally, we provide an outlook on the challenges and opportunities associated with DNA methylation-based tumor profiling.

Gastrointestinal Biopsy Obtained During Cancer Screening, a Biological Marker for α-Synucleinopathy

The hallmark alteration in α-synucleinopathies, α-synuclein, is observed not only in the brain but also in the peripheral tissues, particularly in the intestine. This suggests that endoscopic biopsies performed for colon cancer screening could facilitate the assessment of α-synuclein in the gastrointestinal (GI) tract. Using immunohistochemistry for α-synuclein, we assessed whether GI biopsies could be used to confirm an ongoing α-synucleinopathy. Seventy-four subjects with cerebral α-synucleinopathy in various Braak stages with concomitant GI biopsies were available for study. In 81% of the subjects, α-synuclein was seen in the mucosalsubmucosal GI biopsies. Two subjects with severe cerebral α-synucleinopathy and a long delay between biopsy and death displayed no α-synuclein pathology in the gut, and 11 subjects with sparse cerebral α-synucleinopathy displayed GI α-synuclein up to 36 years prior to death. The finding that there was no GI α-synuclein in 19% of the subjects with cerebral α-synucleinopathy, and α-synuclein was observed in the gut of 11 subjects (15%) with sparse cerebral α-synucleinopathy even many years prior to death is unexpected and jeopardizes the use of assessment of α-synuclein in the peripheral tissue for confirmation of an ongoing cerebral α-synucleinopathy.

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Exosomal HMGA2 protein from EBV-positive NPC cells destroys vascular endothelial barriers and induces endothelial-to-mesenchymal transition to promote metastasis.

Increased vascular permeability facilitates metastasis. Cancer-secreted exosomes are emerging mediators of cancer-host crosstalk. Epstein-Barr virus (EBV), identified as the first human tumor-associated virus, plays a crucial role in metastatic tumors, especially in nasopharyngeal carcinoma (NPC). To date, whether and how exosomes from EBV-infected NPC cells affect vascular permeability remains unclear. Here, we show that exosomes from EBV-positive NPC cells, but not exosomes from EBV-negative NPC cells, destroy endothelial cell tight junction (TJ) proteins, which are natural barriers against metastasis, and promote endothelial-to-mesenchymal transition (EndMT) in endothelial cells. Proteomic analysis revealed that the level of HMGA2 protein was higher in exosomes derived from EBV-positive NPC cells compared with that in exosomes derived from EBV-negative NPC cells. Depletion of HMGA2 in exosomes derived from EBV-positive NPC cells attenuates endothelial cell dysfunction and tumor cell metastasis. In contrast, exosomes from HMGA2 overexpressing EBV-negative NPC cells promoted these processes. Furthermore, we showed that HMGA2 upregulates the expression of Snail, which contributes to TJ proteins reduction and EndMT in endothelial cells. Moreover, the level of HMGA2 in circulating exosomes is significantly higher in NPC patients with metastasis than in those without metastasis and healthy negative controls, and the level of HMGA2 in tumor cells is associated with TJ and EndMT protein expression in endothelial cells. Collectively, our findings suggest exosomal HMGA2 from EBV-positive NPC cells promotes tumor metastasis by targeting multiple endothelial TJ and promoting EndMT, which highlights secreted HMGA2 as a potential therapeutic target and a predictive marker for NPC metastasis.

eccDNAdb a database of extrachromosomal circular DNA profiles in human cancers.

Extrachromosomal circular DNA (eccDNA) elements are circular DNA molecules that are derived from but are independent of chromosomal DNA. EccDNA is emerging as a rising star because of its ubiquitous existence in cancers and its crucial role in oncogene amplification and tumor progression. In the present study, whole-genome sequencing (WGS) data of cancer samples were downloaded from public repositories. Afterwards, eccDNAs were identified from WGS data via bioinformatic analyses. To leverage database coverage, eccDNAs were also collected by manual curation of literatures. Gene expression and clinical data were downloaded from TCGA and CCLE and then used to investigate the roles of eccDNAs in cancers. Finally, the first integrated database of eccDNAs, eccDNAdb, was developed. eccDNAdb currently includes 1270 eccDNAs, which were identified in 480 samples (of 42 cancers) after analyzing a total number of 3395 tumor samples (of 57 cancers) including patient tissues, patient-derived xenografts, and cancer cell lines. A total number of 54,901 eccDNA genes were annotated and included in the database as well. With the integration of gene expression, clinical information and chromatin accessibility data, eccDNAdb enables users to easily determine the biological function and clinical relevance of eccDNAs in human cancers. In conclusion, eccDNAdb is freely accessible at httpwww.eccdnadb.org . To our knowledge, eccDNAdb is the first database in the eccDNA research field. It is expected to provide insight for novel cancer therapies.

Understanding the molecular basis of anorexia and tissue wasting in cancer cachexia.

Cancer cachexia syndrome is a major cause of morbidity and mortality in cancer patients in the advanced stage. It is a devastating disorder characterized by nutritional impairment, weakness, and wasting, and it affects treatment success and quality of life. Two major symptoms of cancer cachexia are anorexia and weight loss. Weight loss in cachexia is not reversed through increased food intake, suggesting that anorexia and weight loss in cancer patients are regulated by independent molecular mechanisms. Although the wasting phenotype mostly occurs in skeletal muscle and adipose tissue, other organs, such as the brain, liver, pancreas, heart, and gut, are also involved in cachexia. Thus, cachexia is a multiorgan syndrome. Although the molecular basis of cancer cachexia-induced weight loss is known, the mechanism underlying anorexia is poorly understood. Here, we highlight our recent discovery of a new anorexia mechanism by which a tumor-derived humoral factor induces cancer anorexia by regulating feeding-related neuropeptide hormones in the brain. Furthermore, we elucidated the process through which anorexia precedes tissue wasting in cachexia. This review article aims to provide an overview of the key molecular mechanisms of anorexia and tissue wasting caused by cancer cachexia.

Differentiating solitary brain metastases from glioblastoma by radiomics features derived from MRI and 18F-FDG-PET and the combined application of multiple models.

This study aimed to explore the ability of radiomics derived from both MRI and 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) images to differentiate glioblastoma (GBM) from solitary brain metastases (SBM) and to investigate the combined application of multiple models. The imaging data of 100 patients with brain tumours (50 GBMs and 50 SBMs) were retrospectively analysed. Three model sets were built on MRI, 18F-FDG-PET, and MRI combined with 18F-FDG-PET using five feature selection methods and five classification algorithms. The model set with the highest average AUC value was selected, in which some models were selected and divided into Groups A, B, and C. Individual and joint voting predictions were performed in each group for the entire data. The model set based on MRI combined with 18F-FDG-PET had the highest average AUC compared with isolated MRI or 18F-FDG-PET. Joint voting prediction showed better performance than the individual prediction when all models reached an agreement. In conclusion, radiomics derived from MRI and 18F-FDG-PET could help differentiate GBM from SBM preoperatively. The combined application of multiple models can provide greater benefits.

Are anti-glutamic acid decarboxylase 65-kDa isoform antibodies related to diabetes or brain tumor

Antibodies against the 65-kDa isoform of glutamic acid decarboxylase (GAD65) are biomarkers of autoimmune disorders and are more common in non-neurological autoimmune diseases than in neurological disorders. As for the central nervous system (CNS), it is well known that GAD65 is primarily associated with stiff-person syndrome, cerebellar ataxia, epilepsy, and paraneoplastic neurological syndrome. However, GAD65 antibodies have not been reported in patients with brain tumors. This study presents the case of a 62-year-old man who manifested rapidly progressive dizziness with gradually worsening physical disturbance and unstable gait in the 2 months prior to consultation. Antibodies against GAD65 were detected in his serum. Brain magnetic resonance imaging (MRI) showed abnormal signals in the corpus callosum, the semi-oval center in both hemispheres, and the area below the frontal cortex, along with enhanced intracranial lesions in the same regions. Positron emission tomography-computed tomography (PET-CT) showed high metabolism in the corpus callosum, which protruded into both ventricles. Due to signs of malignancy, the patient was diagnosed with a malignant glioma. This case raises awareness on the fact that anti-GAD65 antibodies may be associated with CNS neoplastic lesions. Early recognition of anti-GAD antibodies could be of great importance for the early diagnosis and targeted treatment of neoplastic lesions, and could lead to better prognosis.

Transplantation of umbilical cord blood-derived mesenchymal stem cells as therapy for adriamycin induced-cardiomyopathy.

Umbilical cord blood-derived mesenchymal stem cells (UCBMSCs) have been reported to possess cardioprotective effects in diseases. However, its effects on cardiomyopathy remain unclear. This study aimed to the therapeutic effects of UCBMSC transplantation on adriamycin (ADR)-induced cardiomyopathy. UCBMSCs isolated from human UCB were identified by detecting surface markers (CD29, CD90, CD34, and CD45) using flow cytometry. The effect of UCBMSCs on left ventricular end-diastolic dimension (LVEDD), left ventricular systolic end-diastolic diameter (LVESD), left ventricular ejection fraction (LVEF), and left ventricular fraction shortening (LVFS) were determined by echocardiography. Histological changes were observed by HE and Masson staining. The serum levels of collagen-I (Col-I), brain natriuretic peptide (BNP), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), creatine kinase (CK), CK-MB, interleukin (IL)-6, IL-10, and tumor necrosis factor alpha (TNF-α) were measured by corresponding kits. The protein levels of IL-6, IL-10, and TNF-α were measured by Western blotting. The isolated UCBMSCs manifested the positive expression of CD29 and CD90, and the negative expression of CD34 and CD45. UCBMSC transplantation significantly reduced LVEDD and LVESD, and increased LVEF and LVFS in ADR-induced cardiomyopathy model rats. Cardiac injury and high collagen deposition in model rats were alleviated by UCBMSC treatment. Moreover, UCBMSCs decreased the serum levels of Col-I, BNP, AST, LDH, CK, CK-MB, IL-6, IL-10, and TNF-α in model rats. Overall, UCBMSCs exert the therapeutic effects on ADR-induced cardiomyopathy through recovering the myocadiac function and alleviating the inflammatory response.

Phantosmia Among Pediatric, Adolescent, and Young Adult Patients Receiving Proton Beam Therapy.

Phantosmia, an underreported toxicity of brain radiation therapy (RT), is defined as an olfactory disorder resulting in a malodorous phantom smell. This study aimed to characterize the incidence of phantosmia in patients treated with intensity modulated proton therapy (IMPT). In this institutional review board-approved retrospective study, the electronic medical record of a pencil beam scanning-only proton center was queried for patients ≤39 years of age who received IMPT for primary intracranial, metastatic intracranial, skull base, nasopharyngeal or sinonasal neoplasms between August 2019 and December 2020. Patient, clinical, and phantosmia-related characteristics were collected. The olfactory region was defined to include the olfactory bulb and tract. Phantosmia severity was graded by intervention use (mild, no intervention moderate, supportive treatment severe, RT discontinuation). Ninety-nine patients met the inclusion criteria. Twelve patients (12.1%) reported phantosmia. Patients described perceiving a chlorine, broccoli, stale water, metallic, or noxious smell. Of the patients who reported phantosmia, median age was 17 (12-33) years, 66.7% were male, and 91.7% had intracranial tumors. None of the patients had prior RT. Chemoradiotherapy treatment did not correlate with phantosmia development (odds ratio, 1.09 95% confidence interval, 0.32-3.70 In the first-ever study examining radiation-induced phantosmia among children and young adults treated with IMPT, all affected patients received irradiation dose to the olfactory region. Physician awareness of phantosmia, especially in the context of CSI, may improve the patient experience and treatment compliance. A prospective study is needed to elucidate frequency, severity, and phantosmia mechanism.

Purposeful irradiation of the epidural space to enhance local control without compromising cord sparing in spine radiosurgery

The epidural space is a frequent site of cancer recurrence after spine stereotactic radiosurgery (SSRS). This may be due to microscopic disease in the epidural space which is underdosed to obey strict spinal cord dose constraints. We hypothesized that the epidural space could be purposefully irradiated to prescription dose levels, potentially reducing the risk of recurrence in the epidural space without increasing toxicity. SSRS clinical treatment plans with spinal cord contours, spinal planning target volumes (PTV Seventeen SSRS plans meeting the above criteria were identified. Supplemented plans had higher doses to the epidural low-dose regions at all prescription levels. Epidural PTV D Purposefully targeting the epidural space in SSRS may increase control in the epidural space without significantly increasing the risk of spinal cord toxicity. A clinical trial of this approach should be considered.

In Silico Analysis of the Correlation of KIF2C with Prognosis and Immune Infiltration in Glioma.

Glioblastoma (GBM) is one of the most commonly pivotal malignant caners. Numerous reports have revealed the crucial roles of immune infiltration in the initiation and progression of GBM. In this study, we first identified differentially expressed genes (DEGs) in the progression of GBM using CGGA databases. Totally, 156 upregulated DEGs and 251 downregulated DEGs were revealed. By constructing a protein-protein interaction network, KIF2C was identified as a hub gene in GBM. Further analysis revealed an evidently positive association existing in KIF2C expression and the advanced stages of gliomas. Higher expression of KIF2C was in WHO grade IV samples relative to that in grade III and grade II samples. In addition, our results showed that KIF2C was higher in IDH1 wild-type samples than IDH1 mutant glioma samples, in 1p19q noncodel samples than 1p19q code glioma samples, and in recurrent samples than primary glioma samples. Moreover, our results showed that higher expression of KIF2C correlated with shorter survival time in both primary and recurrent gliomas and could act as a potential biomarker for the prognosis of GBM. Further analysis demonstrated that higher expression of KIF2C was related to higher levels of endothelial cell, T cell CD8 naïve, common lymphoid progenitor, T cell CD4 Th2, T cell CD4 Th2, macrophage, macrophage M1, T cell CD4 memory, and T cell CD4 effector memory, but was related to lower levels of NK cell, B cell plasma, T cell CD4 Th1, T cell regulatory (Tregs), neutrophil, and T cell NK. We thought this study could provide potential biomarkers for the prediction of prognosis and immune infiltration of gliomas.

Transcriptomic Portraits and Molecular Pathway Activation Features of Adult Spinal Intramedullary Astrocytomas.

In this study, we report 31 spinal intramedullary astrocytoma (SIA) RNA sequencing (RNA-seq) profiles for 25 adult patients with documented clinical annotations. To our knowledge, this is the first clinically annotated RNA-seq dataset of spinal astrocytomas derived from the intradural intramedullary compartment. We compared these tumor profiles with the previous healthy central nervous system (CNS) RNA-seq data for spinal cord and brain and identified SIA-specific gene sets and molecular pathways. Our findings suggest a trend for SIA-upregulated pathways governing interactions with the immune cells and downregulated pathways for the neuronal functioning in the context of normal CNS activity. In two patient tumor biosamples, we identified diagnostic

A cerebellopontine angle metastatis of a male breast cancer Case report.

Male breast cancer is rare, less than 1% of mens cancers. The tumors occurring in the cerebellopontine angle remain a rare entity. Features suggestive of metastasis are acute onset, rapid progression of symptoms. We report a case of a 72-year-old man had a mastectomy and an axillary lymph node dissection for a breast cancer 22 years prior to this report. The patient was admitted with deterioration of level of consciousness with intracranial hypertension syndrome. The magnetic resonance imaging showed a cystic lesion in the left cerebellar hemisphere and the prepontine cistern. We proceeded to a large tumor resection. On the follow up, the patient presented a delayed emergence. A CT scan showed a small hematoma at the surgical site and triventricular hydrocephalus for which the patient underwent a ventriculoperitoneal shunt. This is the first described cerebellopontine angle metastasis of a male breast cancer and the first described case of a metastatic triple hormone negative breast cancer to the brain.

Artificial Intelligence Algorithm-Based Positron Emission Tomography (PET) and Magnetic Resonance Imaging (MRI) in the Treatment of Glioma Biopsy.

This study was aimed at exploring the application value of positron emission tomography (PET) magnetic resonance imaging (MRI) technology based on convolutional neural network (CNN) in the biopsy and treatment of intracranial glioma. 35 patients with preoperatively suspicious gliomas were selected as the research objects. Their imaging images were processed using CNN. They were performed with the preoperative head MRI, fluorodeoxyglucose (FDG) PET, and ethylcholine (FECH) PET scans to construct the cancer tissue contours. In addition, the performance of CNN was evaluated, and the postoperative pathology of patients was analyzed. The results suggested that the CNN-based PET MRI technology showed a recognition accuracy of 97% for images. Semiquantitative analysis was adopted to analyze the standard uptake value (SUV). It was found that the SUV

Multiplicity does not significantly affect outcomes in brain metastasis patients treated with surgery.

Brain metastasis quantity may be a negative prognostic factor for patients requiring resection of at least one lesion. We retrospectively reviewed patients who underwent surgical resection of brain metastases from July 2018 to June 2019 at our institution, and examined outcomes including overall survival (OS), progression free survival (PFS), and rates of local failure (LF). Patients were grouped according to the number of metastases at the time of surgery (single vs multiple). We identified 130 patients who underwent surgical resection as the initial treatment modality. At the time of surgery, 87 patients had only one lesion (control) and 43 had multiple (>1). Two-year OS for the entire cohort was 46%, with equal rates in both the multiple metastases group and the control group ( Having more than one metastasis does not negatively impact outcomes in patients treated with surgery. In carefully selected patients, especially those with large tumors, surgery should be considered regardless of the total number of lesions.

Management of brain metastasis. Surgical resection versus stereotactic radiotherapy a meta-analysis.

Treatment of metastatic brain tumors often involves radiotherapy with or without surgical resection as the first step. However, the indications for when to use surgery are not clearly defined for certain tumor sizes and multiplicity. This study seeks to determine whether resection of brain metastases versus exclusive radiotherapy provided improved survival and local control in cases where metastases are limited in number and diameter. According to PRISMA guidelines, this meta-analysis compares outcomes from treatment of a median number of brain metastases ≤ 4 with a median diameter ≤ 4 cm with exclusive radiotherapy versus surgery followed by radiotherapy. Four randomized control trials and 11 observational studies (1693 patients) met inclusion criteria. For analysis, studies were grouped based on whether radiation involved stereotactic radiosurgery (SRS) or whole-brain radiotherapy (WBRT). In both analyses, there was no difference in survival between surgery ± SRS versus SRS alone two years after treatment (OR 1.89 (95% CI 0.47-7.55, The higher incidence of local tumor recurrence for surgical patients suggests that more prospective studies are needed to clarify outcomes for treatment of 1-4 metastasis less than 4 cm diameter.

Thalamic Tumors in a Pediatric Population Surgical Outcomes and Utilization of High-Definition Fiber Tractography and the Fiber Tracking Technique.

This study aimed to assess the operability of thalamic tumors since they are generally considered to be inoperable and to have poor outcomes. Advancements in neuroimaging, neuronavigational technology, and intraoperative neurophysiological monitoring allow accurate planning and safe resection. Clinical data and reports of 10 pediatric patients with thalamic tumors were retrieved retrospectively. All 10 patients underwent surgical intervention. Diffusion tensor tractography (DTI) was used preoperatively to select the safest surgical route. Intraoperative MRI and postoperative MRI were used to evaluate the extent of resection. There were three gross total resections (GTRs), two subtotal resections (STRs), two partial resections (PRs), and three biopsies. All patients had unilateral thalamic tumors. Different surgical approaches were used according to the relationship with the internal capsule and corticospinal tract and according to the preoperative DTI. Five patients had pilocytic astrocytoma, two had diffuse pediatric-type high-grade glioma, one had ganglioglioma, one had pediatric-type diffuse low-grade glioma, and one had atypical teratoid rhabdoid tumor (ATRT). The outcomes of low-grade tumors were favorable, especially for those who underwent resection, and those of high-grade tumors were poor regardless of the extent of resection. Our review shows that surgical resection of thalamic tumors can be done safely and offers favorable outcomes for patients with low-grade tumors, even without adjuvant therapy. Our study provides further evidence for thalamic tumors operability and safe resection.

The neuroinflammatory marker sTNFR2 relates to worse cognition and tau in women across the Alzheimers disease spectrum.

Despite women showing greater Alzheimers disease (AD) prevalence, tau burden, and immuneneuroinflammatory response, whether neuroinflammation impacts cognition differently in women versus men and the biological basis of this impact remain unknown. We examined sex differences in how cerebrospinal fluid (CSF) neuroinflammation relates to cognition across the aging-mild cognitive impairment (MCI)-AD continuum and the mediating role of phosphorylated tau (p-tau) versus other AD biomarkers. Participants included 284 individuals from the Alzheimers Disease Neuroimaging Initiative study. CSF neuroinflammatory markers included interleukin-6, tumor necrosis factor α, soluble tumor necrosis factor receptor 2 (sTNFR2), and chitinase-3-like protein 1. AD biomarkers were CSF p-tau We found a sex-by-sTNFR2 interaction on Mini-Mental State Examination and Clinical Dementia Rating-Sum of Boxes. Higher levels of sTNFR2 related to poorer cognition in women only. Among biomarkers, only p-tau Women may be more susceptible than men to the adverse effects of sTNFR2 on cognition with a potential etiological link with tau to these effects.

Targeted delivery of a STING agonist to brain tumors using bioengineered protein nanoparticles for enhanced immunotherapy.

Immunotherapy is emerging as a powerful tool for combating many human diseases. However, the application of this life-saving treatment in serious brain diseases, including glioma, is greatly restricted. The major obstacle is the lack of effective technologies for transporting therapeutic agents across the blood-brain barrier (BBB) and achieving targeted delivery to specific cells once across the BBB. Ferritin, an iron storage protein, traverses the BBB via receptor-mediated transcytosis by binding to transferrin receptor 1 (TfR1) overexpressed on BBB endothelial cells. Here, we developed bioengineered ferritin nanoparticles as drug delivery carriers that enable the targeted delivery of a small-molecule immunomodulator to achieve enhanced immunotherapeutic efficacy in an orthotopic glioma-bearing mouse model. We fused different glioma-targeting moieties on self-assembled ferritin nanoparticles via genetic engineering, and RGE fusion protein nanoparticles (RGE-HFn NPs) were identified as the best candidate. Furthermore, RGE-HFn NPs encapsulating a stimulator of interferon genes (STING) agonist (SR717RGE-HFn NPs) maintained stable self-assembled structure and targeting properties even after traversing the BBB. In the glioma-bearing mouse model, SR717RGE-HFn NPs elicited a potent local innate immune response in the tumor microenvironment, resulting in significant tumor growth inhibition and prolonged survival. Overall, this biomimetic brain delivery platform offers new opportunities to overcome the BBB and provides a promising approach for brain drug delivery and immunotherapy in patients with glioma.

The Higher Expression of CDCA2 Associated with Poor Prognosis in Glioma.

Glioma is the most common primary intracranial tumor and is related to poor clinical outcomes. The developments of sensitive markers can be applied to reveal the mechanisms involved in the progression of glioma. This study examined CDCA2 expression in glioma samples and its significance in predicting glioma patient outcome. GEPIA and GEO datasets were used to explore the expression of CDCA2 in glioma. Kaplan-Meier and multivariate assays were applied to delve into the prognostic values of CDCA2 expression in glioma patients using CGGA datasets. Our group also determined the associations between CDCA2 and clinical characteristics. Coexpression analysis was performed. In this research, we observed that CDCA2 expression was distinctly upregulated in glioma specimens compared with nontumor specimens. The prognosis of glioma with high CDCA2 expression was distinctly worse compared with that of glioma with low CDCA2 expression. Additionally, multivariate Cox regression analysis revealed that high CDCA2 expression was an independent poor prognostic indicator for glioma patients. High expression of CDCA2 was positively associated with advanced clinical progression. Coexpression analysis revealed that CDCA2 could be positively related to ASPM, SKA1, DLGAP5, NCAPG, and CDCA8 and was negatively associated with ETNPPL, LDHD, MRVI1, CBX7, and CENPJ. Overall, our findings revealed that CDCA2 might serve as an independent prognosis indicator for glioma.

Sevoflurane inhibits the malignant phenotypes of glioma through regulating miR-146b-5pNFIB axis.

Sevoflurane is a common used inhaled anesthetic that was reported to regulate the progression of multiple cancers. Here, we aimed to investigate the function and regulatory mechanism underlying sevoflurane in glioma cells. A172 and U251 cells were treated with different concentrations of sevoflurane. Colony formation, EdU satining and 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT), flow cytometry, and transwell assays were performed to evaluate cell proliferation, apoptosis, migration and invasion, respectively. CircVCAN, microRNA-146b-5p (miR-146b-5p) and nuclear factor I B (NFIB) expression levels were assessed by real-time quantitative PCR (RT-qPCR) or western blot. Bioinformatics analysis and dual-luciferase reporter assay were applied to evaluate the correlation between miR-146b-5p and circVCAN or NFIB. A xenograft glioma mice model was established to verify the effect of sevoflurane on tumor growth in vivo. Sevoflurane (Sev) inhibited proliferation, migration, invasion, and elevated apoptosis of A172 and U251 cells. Sevoflurane treatment inhibited the expression of circVCAN and NFIB, but elevated the expression of miR-146b-5p in glioma cells. Overexpression of circVCAN alleviated the inhibition effects of sevoflurane on the malignant phenotypes of glioma in vitro and in vivo. Besides, miR-146b-5p is a target of circVCAN and negatively regulated NFIB expression. Overexpression of miR-146b-5p partly reversed the effects of circVCAN in Sev-treated glioma cells. Furthermore, miR-146b-5p deletion enhanced glioma progression in sevoflurane treated glioma cells by targeting NFIB. Moreover, circVCAN could upregulate NFIB expression by sponging miR-146b-5p in Sev-treated glioma cells. Sevoflurane alleviated proliferation, migration and invasion, but enhanced apoptosis of glioma cells through regulating circVCANmiR-146b-5pNFIB axis.

Anti-inflammatory, Antioxidant, and Antiapoptotic Action of Metformin Attenuates Ethanol Neurotoxicity in the Animal Model of Fetal Alcohol Spectrum Disorders.

Fetal alcohol exposure has permanent effects on the brain structure, leading to functional deficits in several aspects of behavior, including learning and memory. Alcohol-induced neurocognitive impairment in offsprings is included with activation of oxidative- inflammatory cascade followed with wide apoptotic neurodegeneration in several brain areas, such as the hippocampus. Metformin is the first-line treatment for diabetic patients. It rapidly crosses the blood-brain barrier (BBB) and exerts antioxidant, anti-inflammatory, and neuroprotective effects. In this study, we evaluated the protective effects of metformin on ethanol-related neuroinflammation, as well as neuron apoptosis in the hippocampus of adult male rat in animal model of fetal alcohol spectrum disorders. Treatment with ethanol in milk solution (5.25 and 27.8 gkg, respectively) was conducted by intragastric intubation at 2-10 days after birth. To examine the antioxidant and anti-inflammatory properties of metformin, an ELISA assay was performed for determining the tumor necrosis factor-α (TNF-α) and antioxidant enzyme concentrations. Immunohistochemical staining was conducted for evaluating the glial fibrillary acidic protein (GFAP) and cleaved caspase-3 expression. Based on the results, metformin caused a significant increase in the superoxide dismutase (SOD) (P < 0.05) and glutathione peroxidase (GSH-Px) (P < 0.01) activities. On the other hand, it reduced the concentrations of TNF-α and malondialdehyde, compared to the ethanol group (P < 0.01). In the metformin group, there was a reduction in cell apoptosis in the hippocampus, as well as GFAP-positive cells (P < 0.01). Overall, apoptotic signaling, regulated by the oxidative inflammatory cascade, can be suppressed by metformin in adult brain rats following animal model of fetal alcohol spectrum disorders.

The safety and efficacy of anlotinib in combination with stereotactic radiotherapy for the treatment of brain metastases from non-small cell lung cancer.

Combined Nasal Endoscopic and Subfrontal Craniotomy for Resection Tumors of Anterior Skull Base.

Sinonasal tumors invading anterior skull base is difficult to treat in Otorhinolaryngology and Neurosurgery. Treatment requires the collaboration of ear, nose and throat (ENT) and neurosurgeon to remove the tumor completely. This study was to evaluate the outcome of combined technique nasal endoscopic and subfrontal approach in case of sinonasal tumors involving anterior skull base. Retrospective cross-sectional study. The study was a cross-sectional study that had taken place at Otorhinolaryngology and Neurosurgery Department of Cho Ray Hospital, Vietnam. All 45 patients were enrolled and underwent the surgery. 71.1% of these cases were malignant tumors. The ratio of sinonasal malignant tumor is squamous cell carcinoma and esthesioneuroblastoma were 24.4% and 11.1%, respectively. All the cases were diagnosed as sinonasal tumor invading anterior skull base and successfully removed by combining nasal endoscopic approach with subfrontal craniotomy. The combined nasal endoscopic with subfrontal craniotomy for resection nasoethmoid tumor invading the brain show a good result. This technique is an important adjunct that contribute to the treatment of anterior skull base tumor involving the brain.

Epidermal growth factor receptor-targeted therapy for the treatment of non-small cell lung cancer a review of phase II and III trials.

Epidermal growth factor receptor (EGFR) is one of the most common driver gene mutations in non-small-cell lung cancer (NSCLC). EGFR-tyrosine kinase inhibitors (TKIs) monotherapy and EGFR-TKI combined with chemotherapy or anti-angiogenesis drugs have significantly prolonged the survival of patients with EGFR-mutant NSCLC. However, disease progression caused by acquired resistance to EGFR-TKIs is inevitable. And patients with EGFR exon 20ins showed limited efficacy to EGFR-TKIs. In this review, we initially evaluated the efficacy of existing treatments for EGFR-mutant NSCLC. Second, we reviewed the ongoing phase II and III clinical trials, provided the latest results, discussed the scientific rationale of these trials and the potential development issues. The application of EGFR-TKIs has greatly changed the therapeutic strategies for advanced and resected NSCLC with EGFR mutations, and the 5-year overall survival (OS) rate for advanced NSCLC was close to 40%. The current research direction for the treatment of patients with EGFR mutations focuses on the following three aspects uncommon EGFR mutation subtypes, brain metastases, and EGFR TKI-based combination therapy. Future studies on EGFR-mutant NSCLC therapy will focus on overcoming EGFR-TKI-related resistance, preventing drug resistance in advance, and developing bispecific antibody drugs.

Secretory carcinoma of the salivary gland, a rare entity An international multi-institutional study.

Secretory carcinoma (SC) of the salivary gland is a rare entity with limited published literature on cytomorphology. The authors present the largest cohort to date of SC fine-needle aspiration (FNA) cases. FNA cases of histologically confirmed SC were retrospectively retrieved from 12 academic institutions in the United States, Italy, Finland, and Brazil. The collated data included patient demographics, imaging findings, cytopathologic diagnoses according to the Milan System for Reporting Salivary Gland Cytopathology, cytomorphologic characteristics, and immunohistochemicalmolecular profiles. In total, 40 SCs were identified (male-to-female ratio, 1426) in patients with a mean age of 52 years (age range, 13-80 years). Ultrasound imagining revealed a hypoechoic, ovoid, poorly defined, or lobulated mass. The most common primary site was the parotid gland (30 of 40 tumors). Regional lymph node metastasis (9 patients) and distant metastasis (4 patients brain, liver, lungs, and mediastinum) were noted. Two patients died of disease. FNA smears were cellular and demonstrated mainly large, round cells with intracytoplasmic vacuoles or granules and round-to-oval nuclei with smooth nuclear contour, minimal irregularities, and prominent nucleoli arranged predominantly in clusters, papillary formations, and single cells. The background was variable and contained inflammatory cells, mucin, or proteinaceous material. The diagnoses were malignant (19 of 38 tumors 50%), suspicious for malignancy (10 of 38 tumors 26%), salivary gland neoplasm of uncertain malignant potential (7 of 38 tumors 18%), and atypia of undetermined significance (2 of 38 tumors 6%) according to the Milan System for Reporting Salivary Gland Cytopathology. Two malignant cases (2 of 40 tumors 5%) were metastases. The neoplastic cells were immunoreactive for S100 (23 of 24 tumors), mammaglobin (18 of 18 tumors), GATA-3 (13 of 13 tumors), AE1AE3 (7 of 7 tumors), and vimentin (6 of 6 tumors). ETV6-NTRK3 fusion was detected in 32 of 33 tumors by fluorescence in situ hybridization (n 32) and next-generation sequencing (n 1). Familiarity with cytomorphologic features and the immunohistochemicalmolecular profile of SC can enhance diagnostic accuracy.

Pott Puffy Tumor Caused by Dental Infection A Case Report and Literature Review.

Pott puffy tumor (PPT), first described by Sir Percivall Pott in 1760, is a rare clinical entity characterized by a subperiosteal abscess associated with osteomyelitis of the frontal bone caused by direct or hematogenous spread. Although rare in this modern age of antibiotics, this tumor usually occurs as a complication of sinusitis. Moreover, intracranial complications such as subdural abscess, meningitis, sinus thrombosis, or brain abscess can occur concomitantly with the underlying sinusitis, despite the administration of antibiotics. Herein, we present the case of a 48-year-old man who was diagnosed with PPT using computed tomography and treated medically and surgically. The infection remained uncontrollable after surgery and drain removal, owing to the persistence of the original dental focus of the infection. This case highlights the importance of treating the source of the infection in addition to the local area of inflammation, to facilitate complete infection control in PPT.

Machine Learning-Based Analysis and Prediction of Unplanned 30-Day Readmissions After Pituitary Adenoma Resection A Multi-Institutional Retrospective Study With External Validation.

Unplanned readmission after transsphenoidal resection of pituitary adenoma can occur in up to 10% of patients but is unpredictable. To develop a reliable system for predicting unplanned readmission and create a validated method for stratifying patients by risk. Data sets were retrospectively collected from the National Surgical Quality Improvement Program and 2 tertiary academic medical centers. Eight machine learning classifiers were fit to the National Surgical Quality Improvement Program data, optimized using Bayesian parameter optimization and evaluated on the external data. Permutation analysis identified the relative importance of predictive variables, and a risk stratification system was built using the trained machine learning models. Readmissions were accurately predicted by several classification models with an area under the receiving operator characteristic curve of 0.76 (95% CI 0.68-0.83) on the external data set. Permutation analysis identified the most important variables for predicting readmission as preoperative sodium level, returning to the operating room, and total operation time. High-risk and medium-risk patients, as identified by the proposed risk stratification system, were more likely to be readmitted than low-risk patients, with relative risks of 12.2 (95% CI 5.9-26.5) and 4.2 (95% CI 2.3-8.7), respectively. Overall risk stratification showed high discriminative capability with a C-statistic of 0.73. In this multi-institutional study with outside validation, unplanned readmissions after pituitary adenoma resection were accurately predicted using machine learning techniques. The features identified in this study and the risk stratification system developed could guide clinical and surgical decision making, reduce healthcare costs, and improve the quality of patient care by better identifying high-risk patients for closer perioperative management.

Clinical Usefulness of 18 F-FET PET in a Pediatric Patient With Suspected Demyelinating Disease.

An 11-year-old boy who presented with headache and progressive right-sided weakness exhibited cortical swelling in the parafalcine area of both frontoparietal high convexity and splenium portion of corpus callosum on brain MRI. This suggested the possibility of encephalopathy, but required differential diagnosis from brain tumor. 18 F-FET ( O -(2- 18 Ffluoroethyl)- l -tyrosine) PETCT identified increased uptake along the parafalcine area of the frontoparietal lobes and the splenium portion of the corpus callosum. The relatively low target-to-background ratios were more indicative of inflammatory changes such as demyelinating disease. The patient recovered after empirical steroid and immunoglobulin treatment. Clinically, the patient was diagnosed with acute disseminated encephalomyelitis.

18F-Labeled WBC PETCT Scan in a Case of Recurrent Glioblastoma Multiforme, Presented as Pyrexia of Unknown Origin.

Neoplastic causes account for approximately 10% to 20% cases of PUO (pyrexia of unknown origin). The mechanisms by which malignancies induce fever are not fully understood. The release of pyrogenic cytokines either directly from tumor cells or from macrophages responding to tumor are likely to play a major role, which acts on the hypothalamus, causing a change in the thermostatic set point. We present a case of recurrent glioblastoma multiforme, who presented with PUO. 18F-FDG-labeled leukocyte PETCT scan done for localization of infective focus demonstrated significant tracer accumulation at the periphery of the recurrent brain lesion. Subsequent excisional biopsy from the lesion was suggestive of noninfected recurrent glioblastoma multiforme.

Successful Management of Combined BK Nephropathy and Nocardiosis in a Renal Transplant Recipient Case Report.

Nocardiosis is a life-threatening infection in immunocompromised patients. The prevalence of the disease ranges from 2.3% to 5% in renal allograft recipients. Here, we describe a case of BK nephropathy associating with nocardiosis with successful recovery. The 54-year-old male patient had end-stage kidney disease due to diabetic nephropathy associated with diabetic retinopathy, hypertension, and dyslipidemia. He started hemodialysis in October 2017 2 years later, he underwent a deceased donor kidney transplant with 2 HLA mismatches and high panel reactive antibodies. He received desensitization with intravenous immunoglobulin and rituximab, received thymoglobulin as induction, and was maintained on prednisolone, mycophenolate mofetil, and tacrolimus. His serum creatinine decreased to a nadir of 90 μmolL. He developed graft dysfunction, which was proven to be due to BK nephropathy. Therefore, mycophenolate mofetil was replaced with leflunomide in addition to intravenous immunoglobulin therapy. Ten months later, he had an accidental fall and sought an orthopedic evaluation. Magnetic resonance imaging of the lumbar spine and pelvis revealed lumbar spondylosis, avascular necrosis of the femoral head, and obturator muscle abscess. He was explored surgically, but the surgeon found no abscess or avascular hip necrosis. The patients blood grew Nocardia, and he was readmitted and started imipenem and linezolid empirically. Brain and chest computed tomography scans ruled out any central nervous system or pulmonary involvement, but a bone scan revealed osteomyelitis of the right superior pubic ramus and prepubic swelling, which was confirmed by computed tomography to be an abscess in both obturator externus and internus. He continued the same antibiotics for 6 months based on culture and sensitivity. At follow-up, the patient has shown stable graft function (creatinine 155 μmolL) with improved BK viremia with immunosuppression minimization. In renal transplant recipients, successful management of combined BK nephropathy and nocardiosis was feasible with minimization of immunosuppression and proper antimicrobial therapy.

Ependymoma Evaluation and Management Updates.

To review state of art and relevant advances in the molecular genetics and management of ependymomas of children and adults. Ependymomas may occur either in the brain or in the spinal cord. Compared with intracranial ependymomas, spinal ependymomas are less frequent and exhibit a better prognosis. The new WHO classification of CNS tumors of 2021 has subdivided ependymomas into different histomolecular subgroups with different outcome. The majority of studies have shown a major impact of extent of resection thus, a complete resection must be performed, whenever possible, at first surgery or at reoperation. Conformal radiotherapy is recommended for grade 3 or incompletely resected grade II tumors. Proton therapy is increasingly employed especially in children to reduce the risk of neurocognitive and endocrine sequelae. Craniospinal irradiation is reserved for metastatic disease. Chemotherapy is not useful as primary treatment and is commonly employed as salvage treatment for patients failing surgery and radiotherapy. Standard treatments are still the mainstay of treatment the discovery of new druggable pathways will hopefully increase the therapeutic armamentarium in the near future.

Interleukin-1 Mediates Ischemic Brain Injury via Induction of IL-17A in γδ T Cells and CXCL1 in Astrocytes.

As a prototypical proinflammatory cytokine, interleukin-1 (IL-1) exacerbates the early post-stroke inflammation, whereas its neutralization is protective. To further investigate the underlying cell-type-specific IL-1 effects, we subjected IL-1 (αβ) knockout (Il1

Implications of immune cells in oncolytic herpes simplex virotherapy for glioma.

Despite current progress in treatment, glioblastoma (GBM) remains a lethal primary malignant tumor of the central nervous system. Although immunotherapy has recently achieved remarkable survival effectiveness in multiple malignancies, none of the immune checkpoint inhibitors (ICIs) for GBM have shown anti-tumor efficacy in clinical trials. GBM has a characteristic immunosuppressive tumor microenvironment (TME) that results in the failure of ICIs. Oncolytic herpes simplex virotherapy (oHSV) is the most advanced United States Food and Drug Administration-approved virotherapy for advanced metastatic melanoma patients. Recently, another oHSV, Delytact

Analysis of the genomic landscapes of Barbadian and Nigerian women with triple negative breast cancer.

Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype that disproportionately affects women of African ancestry (WAA) and is often associated with poor survival. Although there is a high prevalence of TNBC across West Africa and in women of the African diaspora, there has been no comprehensive genomics study to investigate the mutational profile of ancestrally related women across the Caribbean and West Africa. This multisite cross-sectional study used 31 formalin-fixed paraffin-embedded (FFPE) samples from Barbadian and Nigerian TNBC participants. High-resolution whole exome sequencing (WES) was performed on the Barbadian and Nigerian TNBC samples to identify their mutational profiles and comparisons were made to African American, European American and Asian American sequencing data obtained from The Cancer Genome Atlas (TCGA). Whole exome sequencing was conducted on tumors with an average of 382 × coverage and 4335 × coverage for pooled germline non-tumor samples. Variants detected at high frequency in our WAA cohorts were found in the following genes NBPF12, PLIN4, TP53 and BRCA1. In the TCGA TNBC cases, these genes had a lower mutation rate, except for TP53 (32% in our cohort 63% in TCGA-African American 67% in TCGA-European American 63% in TCGA-Asian). For all altered genes, there were no differences in frequency of mutations between WAA TNBC groups including the TCGA-African American cohort. For copy number variants, high frequency alterations were observed in PIK3CA, TP53, FGFR2 and HIF1AN genes. This study provides novel insights into the underlying genomic alterations in WAA TNBC samples and shines light on the importance of inclusion of under-represented populations in cancer genomics and biomarker studies.

Polycomb-mediated gene regulation in human brain development and neurodevelopmental disorders.

The neocortex is considered the seat of higher cognitive function in humans. It develops from a sheet of neural progenitor cells, most of which eventually give rise to neurons. This process of cell fate determination is controlled by precise temporal and spatial gene expression patterns that in turn are affected by epigenetic mechanisms including Polycomb group (PcG) regulation. PcG proteins assemble in multiprotein complexes and catalyze repressive posttranslational histone modifications. Their association with neurodevelopmental disease and various types of cancer of the central nervous system, as well as observations in mouse models, has implicated these epigenetic modifiers in controlling various stages of cortex development. The precise mechanisms conveying PcG-associated transcriptional repression remain incompletely understood and are an active field of research. PcG activity appears to be highly context-specific, raising the question of species-specific differences in the regulation of neural stem and progenitor regulation. In this review, we will discuss our growing understanding of how PcG regulation affects human cortex development, based on studies in murine model systems, but focusing mostly on findings obtained from examining impaired PcG activity in the context of human neurodevelopmental disorders and cancer. Furthermore, we will highlight relevant experimental approaches for functional investigations of PcG regulation in human cortex development.

Role of sirtuin 1 in the brain development in congenital hypothyroidism rats via the regulation of p53 signaling pathway.

The present study aimed to investigate the expression, role, and underlying mechanism of action of sirtuin 1 (SIRT1) in congenital hypothyroidism (CH). A CH model was established in rats, and neuronal cells were isolated from the hippocampal tissues of normal rats. Free thyroxine (fT4) and thyroid-Stimulating hormone (TSH) concentrations were determined to confirm CH model conduction. The cognitive behavior of rats with CH was examined using open field and forced swimming tests. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting were used to detect the expression levels of SIRT1, p53, B-cell lymphoma-extra-large (Bcl-xl), Bcl-2-associated X (Bax), and cytochrome c in the hippocampal tissues and neuronal cells. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay and flow cytometry were performed to evaluate cell viability and apoptosis, respectively. The results revealed that SIRT1 was expressed at low levels in the hippocampal tissues of rats with CH. Moreover, overexpression of SIRT1 in the hippocampal tissues of rats with CH and improved rat behavior, while reducing the CH-induced nerve cell apoptosis. In addition, this overexpression increased the viability, inhibited apoptosis, and reduced the expression of p53, Bax, and cytochrome c, while increasing the expression of Bcl-xl in cultured neurons. In contrast, SIRT1-small interfering RNA exhibited the opposite effects in cultured neurons. In conclusion, SIRT1 plays a role in the occurrence and development of CH by regulating nerve cell apoptosis.

Identification and Validation of the Prognostic Impact of Metastatic Prostate Cancer Phenotypes.

Castration-sensitive metastatic prostate cancer is heterogeneous. Our objective is to identify metastatic prostate cancer phenotypes and their prognostic impact on survival. The National Cancer Database was queried. The Surveillance, Epidemiology, and End Results database was used for validation. Patterns were split into nonregional lymph node, bone only, and visceral (any brainliverlung). Hazard ratios (HR) with 95% confidence intervals (CI) were calculated for the univariate and multivariate Cox proportional hazards regression models, odds ratios were calculated, Kaplan-Meier curves were generated, and a nomogram of the multivariate regression model was created. The training set included 13,818 men bone only was most common (n 11,632, 84.2%), then nonregional lymph node (n 1388, 10.0%), and any visceral (brainliverlung n 798, 5.8%). Risk of death was increased by metastases to a visceral organ versus nonregional lymph node (HR 2.26 95% CI 2.00, 2.56), bone only metastases versus nonregional lymph node (HR 1.57 95% CI 1.43, 1.72), T-stage 4 versus 1 (HR 1.27 95% CI 1.17, 1.36), Grade Group 5 versus 1 (HR 1.93 95% CI 1.61, 2.31), PSA > 20 ngmL versus < 10 ngmL (HR 1.32 95% CI 1.23, 1.42), and age ≥ 80 versus < 50 (HR 1.96 95% CI 1.69, 2.29). On internal validation, the model had C-indices 20.5%, 22.7%, and 14.6% higher than the current staging system for overall survival, 1-year, and 5-year survival, respectively. We developed and validated prognostic metastatic prostate cancer phenotypes that can assist risk stratification to potentially personalize therapy. Our nomogram (httpstinyurl.comprostate-met) may be used to predict survival.

Breast cancer metastasis to brain results in recruitment and activation of microglia through annexin-A1formyl peptide receptor signaling.

Despite advancements in therapies, brain metastasis in patients with triple negative subtype of breast cancer remains a therapeutic challenge. Activated microglia are often observed in close proximity to, or within, malignant tumor masses, suggesting a critical role that microglia play in brain tumor progression. Annexin-A1 (ANXA1), a glucocorticoid-regulated protein with immune-regulatory properties, has been implicated in the growth and metastasis of many cancers. Its role in breast cancer-microglia signaling crosstalk is not known. The importance of microglia proliferation and activation in breast cancer to brain metastasis was evaluated in MMTV-Wnt1 spontaneous mammary tumor mice and BALBc mice injected with 4T1 murine breast cancer cells into the carotid artery using flow cytometry. 4T1 induced-proliferation and migration of primary microglia and BV2 microglia cells were evaluated using 2D and coculture transwell assays. The requirement of ANXA1 in these functions was examined using a CrisprCas9 deletion mutant of ANXA1 in 4T1 breast cancer cells as well as BV2 microglia. Small molecule inhibition of the ANXA1 receptor FPR1 and FPR2 were also examined. The signaling pathways involved in these interactions were assessed using western blotting. The association between lymph node positive recurrence-free patient survival and distant metastasis-free patient survival and ANXA1 and FPR1 and FPR2 expression was examined using TCGA datasets. Microglia activation is observed prior to brain metastasis in MMTV-Wnt1 mice with primary and secondary metastasis in the periphery. Metastatic 4T1 mammary cancer cells secrete ANXA1 to promote microglial migration, which in turn, enhances tumor cell migration. Silencing of ANXA1 in 4T1 cells by CrisprCas9 deletion, or using inhibitors of FPR1 or FPR2 inhibits microglia migration and leads to reduced activation of STAT3. Finally, elevated ANXA1, FPR1 and FPR2 is significantly associated with poor outcome in lymph node positive patients, particularly, for distant metastasis free patient survival. The present study uncovered a network encompassing autocrineparacrine ANXA1 signaling between metastatic mammary cancer cells and microglia that drives microglial recruitment and activation. Inhibition of ANXA1 andor its receptor may be therapeutically rewarding in the treatment of breast cancer and secondary metastasis to the brain.

Insight about the characteristics and surgical resectability of adult pilocytic astrocytoma tertiary center experience.

Pilocytic astrocytoma is a benign brain tumor that most commonly arises in children. Rarely, this tumor may also arise in adults. Surgical removal of the tumor is the main treatment. In children, the tumor most commonly arises in the cerebellum, a part of the brain where surgical accessibility is good, and complete removal of the tumor significantly decreases the possibility of it recurring. In adults, the tumor is more likely to arise in critical areas of the brain or in areas of limited surgical accessibility, thus, making surgery especially challenging, and preventing complete removal. Moreover, studies found that the probability of the tumor recurring in adults is higher than in children. Studies discussing the properties of pilocytic astrocytoma in adults reported varying results. This is mainly due to the small number of patients studied. The rarity of this tumor makes it hard for large primary studies to be conducted. In this article, we report the characteristics and outcomes of 15 adult patients treated in a single center in Jordan. In our patients, the mean age was 25 years (range 18–56), and the tumor was located above the tentorium in 47%. Complete and near-complete removal was possible in 40%. The mean duration of follow-up after surgery was 11 months (range 1–76). The tumor recurred in only one patient. We aim to provide more data on this rare disease and contribute further to understanding its properties.

A multi-institutional pilot clinical trial of spectroscopic MRI-guided radiation dose escalation for newly diagnosed glioblastoma.

Glioblastomas (GBMs) are aggressive brain tumors despite radiation therapy (RT) to 60 Gy and temozolomide (TMZ). Spectroscopic magnetic resonance imaging (sMRI), which measures levels of specific brain metabolites, can delineate regions at high risk for GBM recurrence not visualized on contrast-enhanced (CE) MRI. We conducted a clinical trial to assess the feasibility, safety, and efficacy of sMRI-guided RT dose escalation to 75 Gy for newly diagnosed GBMs. Our pilot trial (NCT03137888) enrolled patients at 3 institutions (Emory University, University of Miami, Johns Hopkins University) from September 2017 to June 2019. For RT, standard tumor volumes based on T2-FLAIR and T1w-CE MRIs with margins were treated in 30 fractions to 50.1 and 60 Gy, respectively. An additional high-risk volume based on residual CE tumor and ChoNAA (on sMRI) ≥2× normal was treated to 75 Gy. Survival curves were generated by the Kaplan-Meier method. Toxicities were assessed according to CTCAE v4.0. Thirty patients were treated in the study. The median age was 59 years. 30% were MGMT promoter hypermethylated 7% harbored IDH1 mutation. With a median follow-up of 21.4 months for censored patients, median overall survival (OS) and progression-free survival were 23.0 and 16.6 months, respectively. This regimen appeared well-tolerated with 70% of grade 3 or greater toxicity ascribed to TMZ and 23% occurring at least 1 year after RT. Dose-escalated RT to 75 Gy guided by sMRI appears feasible and safe for patients with newly diagnosed GBMs. OS outcome is promising and warrants additional testing. Based on these results, a randomized phase II trial is in development.

Volumetric modulated arc radiosurgery for brain metastases from breast cancer A single-center study.

Whole-brain radiation therapy (WBRT) and stereotactic radiosurgery (SRS) are two treatment modalities commonly utilized to treat brain metastases (BMs). The purpose of this study is to analyse retrospectively the local control and survival of patients with BMs of breast cancer (BC) treated via radiosurgery using Volumetric Modulated Arc Therapy (VMAT-RS). 18 patients with 41 BMs of BC and treated by VMAT-RS were studied. They were classified according to the molecular subtype of BC and the modified breast graded prognostic assessment -GPA- index. Patients presented 1-4 BMs, which were treated with 5 non-coplanar VMAT arcs. The spatial distribution of BMs, the influence of receptor status on the location of the lesions and survival assessed via the Kaplan-Meier model were analyzed. The median survival time (MST) was 19.7 months. Statistically significant differences were determined in the MST according to the Karnofsky performance status ( The VMAT-RS is a technique with an overall survival comparable to other radiosurgery techniques. The baseline situation at the time of treatment, the modified breast-GPA and the molecular subtypes, are factors that significantly influence patient survival. La radioterapia holocraneal (WBRT) y la radiocirugía estereotáctica (SRS) son dos modalidades de tratamiento comúnmente empleados para el tratamiento de las metástasis cerebrales (BMs). El propósito de este estudio es analizar de forma retrospectiva el control local y la supervivencia de los pacientes con BMs de cáncer de mama (BC) tratados mediante radiocirugía empleando arcoterapia volumétrica modulada (VMAT-RS). Se analizaron 18 pacientes con 41 BMs de BC tratados mediante VMAT-RS. Se clasificaron según el subtipo molecular de BC y el GPA ( La mediana del tiempo de supervivencia (MST) fue de 19.7 meses. Se hallaron diferencias estadísticamente significativas en el MST según el índice de Karnofsky ( VMAT-RS es una técnica con una supervivencia global comparable a otras técnicas de radiocirugía. La situación basal en el momento del tratamiento, el GPA modificado de cáncer de mama así como los subtipos moleculares de cáncer de mama, son factores que influyen de forma significativa en la supervivencia de los pacientes.

Recurrent Radiation-Induced Cavernous Malformation After Gamma Knife Stereotactic Radiosurgery for Brain Metastasis.

Cavernous malformations are a rare complication of radiation therapy reported most commonly as a late complication after cranial irradiation for pediatric malignancies. However, cavernous malformations after stereotactic radiosurgery in adult patients are not well characterized. We present a case of a 67-year-old female with metastatic breast cancer who received Gamma Knife stereotactic radiosurgery for brain metastases and developed a cavernous malformation at the site of a treated metastasis 30 months after treatment. She underwent resection and did well until 55 months later, when she developed symptomatic recurrence of cavernous malformation without evidence of tumor recurrence, requiring repeat resection. This represents the first reported case of radiation-induced cavernous malformation treated with stereotactic radiosurgery for brain metastases, who later developed a recurrence of the cavernous malformation. As patients with brain metastases are living longer and are increasingly treated with stereotactic radiosurgery, awareness of cavernous malformation as a potential complication and the risk of recurrence is critical to ensure appropriate diagnosis and management.

Primary intramedullary spinal gliosarcoma An unusual presentation.

Gliosarcoma is a biphasic central nervous system malignancy composed of glial and mesenchymal components. It is recognized as a rare variant of glioblastoma with unique histology, immunostaining properties, and natural history. Although usually described to primarily involve the brain, a search of the published literature revealed four reported cases of gliosarcoma arising in the spinal cord. This report describes the case of a 35-year-old woman with progressive back pain with loss of sensation and power of both lower limbs. Magnetic resonance imaging showed an intramedullary unifocal space-occupying lesion in her thoracolumbar spinal cord. Subtotal resection and subsequent histopathological and immunohistochemical studies confirmed the diagnosis of gliosarcoma of the spinal cord. This report further establishes the clinical entity of primary spinal gliosarcoma and proposes the need to consider this possibility among the differential diagnoses of a space-occupying spinal lesion.

Can a signature molecular-profile define disparate survival in BRAF-positive Gliosarcoma and identify novel targets for therapeutic intervention

Gliosarcoma (GS) has a low incidence but is aggressively invasive, with poor-survival. Even though GS is recognized as a different subgroup from glioblastoma (GB), there is no molecular panel available to define its clinical outcome. The objective was to identify the molecular imprint of GS in terms of expression of human telomerase reverse transcriptase (hTERT), high mobility group A1 (HMGA-1), kinesin superfamily protein-14 (KIF-14), epidermal growth factor receptor (EGFR) markers with reference to disparate prognosis and identify plausible targets for intervention. We retrieved 9-GS samples from a cohort of 57-GB patients during a 36 months study period and compared them with 10 molecularly typed GB-samples and 15 controls. Conventional-immunohistochemistry (IHC) was used for histopathology of GS and immunofluorescence-IHC was performed for quantification of identified marker-panel. Statistical tools for non-parametric data were used for inferring results. GS was confirmed by reticulin-staining and positivity for glial fibrillary acidic protein, Vimentin, smooth muscle actin. Immune-reactivity for BRAF-V600Ewas present in both glial and sarcomatous cells and negative expression of isocitrate dehydrogenase, ATRX, TP53.Comparison between GS, GB, and control tissues showed that the expression of markers reached significance (P < 0.0001), without the influence of confounders. Significant correlation of EGFR was found with hTERT (r 0.77), HMGA-1 (r 0.72), KIF-14 (r 0.82) suggesting that their combined analysis can define prognosis. To establish the diagnostic accuracy (threshold ≥80% specificity), AUC for EGFR was 0.78 (>3.95), KIF-14 0.97 (>7.45), hTERT 0.63 (>23.86), and HMGA-1 0.53 (>15.45). This is the first evidence-based investigation presenting differential expression of proliferation and stemness markers hTERT, HMGA-1, KIF-14 in-correlation with EGFR, indicating a plausible-association between survival and disease-progression in individual GS-cases. It can serve as a model for further studies in this glioma-subgroup and the designing of a target panel for personalized treatment.

Managing brain tumors in pregnancy The oncologists struggle with maternal-fetal conflict.

The diagnosis of malignancy, particularly brain tumors, in pregnancy is uncommon but poses a complex dilemma for the management of both the patient and her fetus, as the interplay of disease with the physiological state of pregnancy affects both outcomes. The routine evaluations (symptomatology, imaging, and hormonal assessments) and treatments (surgery, radiation therapy, and chemotherapy) that are commonplace in brain tumor management may need to be omitted or modified keeping in mind the risk to offspring. Multidisciplinary care and extensive prenatal and perinatal counseling and monitoring are essential. In this review, we discuss the available data addressing these issues and factors which may affect considerations of therapeutic abortions, changes in surgical or medical practices, and outcomes thereof.

Nasopharyngeal carcinoma misdiagnosed as pituitary tumor with multiple cranial neuropathies.

Multiple cranial neuropathies have been reported in nasopharyngeal carcinoma. Nasopharyngeal carcinoma is an uncommon cause of multiple cranial nerve palsies. However, it is difficult to diagnose at the early stage furthermore, it can be easily misdiagnosed as inflammation, pituitary tumor, etc. A 38-year-old female patient had an ipsilateral 3

The Utility of Early Brain MRI for Patients with Neurofibromatosis Type 1 and Optic Pathway Glioma A Long-Term Follow-Up in a Tertiary Referral Hospital.

Screening studies have shown detection of optic pathway gliomas (OPGs) in 8 to 31% of children with neurofibromatosis type 1 (NF1). Many of those affected show prolonged indolent phases, but others develop vision disturbances even before diagnosis and treatment. We assessed the clinical presentation at diagnosis, location, natural progression, and risk factors for impaired vision of OPG. The clinical database of the NF1 multidisciplinary clinic of Schneider Childrens Medical Center of Israel was reviewed for all patients diagnosed and followed with NF1 during 2007 to 2019. OPG was diagnosed by hyperintensity and thickening along the optic pathway on T2-weighted brain magnetic resonance imaging (MRI), with or without contrast enhancement. Of 257 children with NF1 who underwent MRI, 57 (22%) were diagnosed with OPG 31 (54%) were females. Twenty-five (44%) had familial NF1. Fifteen (26%) who exhibited tumor progression and worsening in ophthalmic examinations required treatment. Post-chiasmatic glioma was a predictive factor for treatment (

Xanthogranulomatous Colloid Cyst in a 13-Year-Old Boy A Case Report and Surgical Implications.

Colloid cysts are relatively uncommon lesions in the pediatric population. The xanthogranulomatous (XG) variant is very rare with less than 30 reported cases. In this report, the patient was a 13-year-old boy who presented with transient episodes of headache with blurring of vision. His MRI brain showed a T2 hyperintense well-defined cystic lesion, with an eccentrically located T2 hypointense partially enhancing nodule, at the foramen of Monro. He underwent middle frontal gyrus transcortical, transchoroidal gross total excision of the cyst. The histopathology of the lesion revealed an XG colloid cyst. The patient recovered well from the procedure and was relieved of the symptoms. XG colloid cyst may present with altered radiological features compared to the normal variant. This can pose a diagnostic dilemma, and it is important to differentiate it from a craniopharyngioma or a parasitic cyst, as in our case. When considered preoperatively, surgeons should be conscious to review their surgical strategies. Stereotactic aspiration of the XG cyst should be avoided as contents are thicker and heterogeneous than the usual. The spillage of cyst contents should be prevented. Also, the XG cysts are likely to have a poor cyst-fornix or -choroid plexus interface due to inflammation limiting complete resection.

3D patient-derived tumor models to recapitulate pediatric brain tumors In Vitro.

Brain tumors are the leading cause of cancer-related deaths in children. Tailored therapies need preclinical brain tumor models representing a wide range of molecular subtypes. Here, we adapted a previously established brain tissue-model to fresh patient tumor cells with the goal of establishing3D in vitro culture conditions for each tumor type.Wereported our findings from 11 pediatric tumor cases, consisting of three medulloblastoma (MB) patients, three ependymoma (EPN) patients, one glioblastoma (GBM) patient, and four juvenile pilocytic astrocytoma (Ast) patients. Chemically defined media consisting of a mixture of pro-neural and pro-endothelial cell culture medium was found to support better growth than serum-containing medium for all the tumor cases we tested. 3D scaffold alone was found to support cell heterogeneity and tumor type-dependent spheroid-forming ability both properties were lost in 2D or gel-only control cultures. Limited in vitro models showed that the number of differentially expressed genes between in vitro vs. primary tissues, are 104 (0.6%) of medulloblastoma, 3,392 (20.2%) of ependymoma, and 576 (3.4%) of astrocytoma, out of total 16,795 protein-coding genes and lincRNAs. Two models derived from a same medulloblastoma patient clustered together with the patient-matched primary tumor tissue both models were 3D scaffold-only in Neurobasal and EGM 11 (vv) mixture and differed by a 1-mo gap in culture (i.e., 6wk versus 10wk). The genes underlying the in vitrovs. in vivo tissue differences may provide mechanistic insights into the tumor microenvironment. This study is the first step towards establishing a pipeline from patient cells to models to personalized drug testing for brain cancer.

The influence of cystathionine on neurochemical quantification in brain tumor in vivo MR spectroscopy.

To evaluate the ability of the PRESS sequence (T Twenty-three subjects with a glioma were retrospectively included based on the availability of both MEGA-PRESS and PRESS acquisitions at 3T, and the presence of the cystathionine signal in the edited MR spectrum. In eight subjects, the PRESS acquisition was performed also in normal tissue. Metabolite quantification was performed using LCModel and simulated basis sets. The LCModel analysis for the PRESS data was performed with and without cystathionine. All subjects with glioma had detectable cystathionine levels >1 mM with Cramér-Rao lower bounds (CRLB) <15%. The mean cystathionine concentrations were 3.49 ± 1.17 mM for MEGA-PRESS and 2.20 ± 0.80 mM for PRESS data. Cystathionine concentrations showed a significant correlation between the two MRS methods (r 0.58, p .004), and it was not detectable in normal tissue. Using PRESS, 19 metabolites were quantified with CRLB <50% for more than half of the subjects. The metabolites that were significantly (p < .0028) and mostly affected by the omission of cystathionine were aspartate, betaine, citrate, γ-aminobutyric acid (GABA), and serine. Cystathionine was detectable by PRESS in all the selected gliomas, while it was not detectable in normal tissue. The omission from the spectral analysis of cystathionine led to severe biases in the quantification of other neurochemicals that may play key roles in cancer metabolism.

Therapeutic difficulties in an aggressive ACTH-secreting pituitary adenoma.

Not required for Clinical Vignette.

Osilodrostat - an emerging drug for the medical management of Cushings disease.

Cushings disease (CD) is a rare endocrine disorder characterized by the overproduction of adrenocorticotropic hormone (ACTH) by pituitary adenoma followed by hypercortisolaemia with severe complications. Although transsphenoidal resection of the defined pituitary adenoma has been the treatment of choice for the past decades, it does not always result in long-term remission - 10-30% of cases show ineffective surgical treatment or tumour recurrence even after initial success. Pharmacological therapies for cortisol reduction are often required for those who either cannot undergo pituitary surgery or when the surgery has failed, and patients still present with the persistent disease. Osilodrostat is a potent oral steroidogenesis inhibitor that has lately been shown as an effective adjuvant therapy in the management of patients with CD. In this article, we review the recent reports on the efficacy and safety of osilodrostat in clinical settings.

Effects of combined aerobic-strength training and yoga on quality of life and related parameters in women with pituitary adenoma after surgery a randomized crossover study.

The pituitary gland is responsible for hormonal balance in the body, and disruption of hormonal balance in patients with pituitary adenoma (PA) indirectly affects the quality of life. This study aimed to examine the effects of yoga and combined aerobic and strength training (AST) on quality of life and related parameters such as sleep, fatigue, emotional state, sexual function, and cognitive status in women with PA. Ten women with PA were included in this randomized crossover study. Group 1 (n 5, mean age 52 ± 13.5 years) received AST for the first 6 weeks, a 2-week washout period, and yoga for the second 6 weeks. Group 2 (n 5, mean age 41.8 ± 14 years) received the yoga program first, followed by the AST program. Participants were assessed using the following tools before and after each exercise intervention Functional Assessment of Cancer Therapy-Brain (FACT-Br) (quality of life), Pittsburg Sleep Quality Index, Fatigue Severity Scale (FSS), Female Sexual Function Index (FSFI), Hospital Anxiety and Depression Scale (HADS), and Montreal Cognitive Assessment Scale (MOCA). FACT-Br scores were higher after the yoga program, HADS anxiety score was lower after the AST program, and MOCA scores increased after both exercise programs (P < 0.05). FSS score decreased after both exercise programs, but not significantly. In addition, nonsignificant decreases in HADS anxiety and depression scores and increased FSFI scores were observed after the yoga program. AST and yoga have positive effects on the quality of life in PA. We recommend yoga and AST as a supportive therapy for this population that may face comorbidities after surgical and medical treatment. Our results indicate these patients may benefit from physiotherapist-guided exercise programs.

PSMG3-AS1 enhances glioma resistance to temozolomide via stabilizing c-Myc in the nucleus.

Glioblastoma (GBM) is the main form of primary brain malignancies with a dismal prognosis partly due to its invasive growth and rapid relapse. GBM frequently developed resistance to current standard-of-care therapeutic modalities, including surgery, radiation and chemotherapy, of which temozolomide (TMZ) is the most widely used first-line anti-GBM drug. Despite the intense efforts of the past decades, the underlying mechanisms of GBM resistance to TMZ remain largely unclear. Here we show that the long noncoding RNA (lncRNA) PSMG3-AS1 is significantly upregulated in GBM and its expression correlates with the grade of glioma, with the highest level observed in GBM (Grade IV glioma). We also demonstrated that PSMG3-AS1 mediates the resistance of GBM to TMZ, as knockdown of PSMG3-AS1 remarkably increased the sensitivity whereas overexpression of PSMG3-AS1 in sensitive GBM cell line induced a resistance phenotype to TMZ. Mechanistically, PSMG3-AS1 directly binds to c-Myc and thus stabilizes c-Myc in the nucleus to promote the survival of GBM cells under treatment of TMZ. Our data demonstrated an unreported role of PSMG3-AS1 in TMZ resistance and provide a potential novel target to tackle TMZ resistance in GBM.

Hypothetical generalized framework for a new imaging endpoint of therapeutic activity in early phase clinical trials in brain tumors.

Imaging response assessment is a cornerstone of patient care and drug development in oncology. Cliniciansclinical researchers rely on tumor imaging to estimate the impact of new treatments and guide decision making for patients and candidate therapies. This is important in brain cancer, where associations between tumor sizegrowth and emerging neurological deficits are strong. Accurately measuring the impact of a new therapy on tumor growth early in clinical development, where patient numbers are small, would be valuable for decision making regarding late-stage development activation. Current attempts to measure the impact of a new therapy have limited influence on clinical development, as determination of progression, stability or response does not currently account for individual tumor growth kinetics prior to the initiation of experimental therapies. Therefore, we posit that imaging-based response assessment, often used as a tool for estimating clinical effect, is incomplete as it does not adequately account for growth trajectories or biological characteristics of tumors prior to the introduction of an investigational agent. Here, we propose modifications to the existing framework for evaluating imaging assessment in primary brain tumors that will provide a more reliable understanding of treatment effects. Measuring tumor growth trajectories prior to a given intervention may allow us to more confidently conclude whether there is an anti-tumor effect. This updated approach to imaging-based tumor response assessment is intended to improve our ability to select candidate therapies for later-stage development, including those that may not meet currently sought thresholds for response and ultimately lead to identification of effective treatments.

Cerebrovascular Dysregulation in Patients with Glioma Assessed with Time-shifted BOLD fMRI.

Background Microscopic vascular events, such as neovascularization and neurovascular uncoupling, are common in cerebral glioma. Mapping the cerebrovascular network remodeling at the macroscopic level may provide an alternative approach to assess hemodynamic dysregulation in patients with glioma. Purpose To investigate cerebrovascular dynamics and their relevance to tumor aggressiveness by using time-shift analysis (TSA) of the systemic low-frequency oscillation (sLFO) of the resting-state blood oxygenation level-dependent signal and a decision tree model. Materials and Methods In this retrospective study, 96 patients with histologically confirmed cerebral glioma were consecutively included (March 2012 to February 2017). TSA was performed to quantify the temporal properties of sLFO signals. Alteration in the time-shift properties was assessed in the tumor region and the contralesional hemisphere relative to the brains of healthy controls by using the Mann-Whitney

Nuclear Tkt promotes ischemic heart failure via the cleaved Parp1Aif axis.

Transketolase (Tkt), an enzyme in pentose phosphate pathway, has been reported to regulate genome instability and cell survival in cancers. Yet, the role of Tkt after myocardial ischemic injury remains to be elucidated. Label-free proteomics revealed dramatic elevation of Tkt in murine hearts after myocardial infarction (MI). Lentivirus-mediated Tkt knockdown ameliorated cardiomyocyte apoptosis and preserved the systolic function after myocardial ischemic injury. In contrast, Tkt overexpression led to the opposite effects. Inducible conditional cardiomyocyte Tkt-knockout mice were generated, and cardiomyocyte-expressed Tkt was found to play an intrinsic role in the ischemic heart failure of these model mice. Furthermore, through luciferase assay and chromatin immunoprecipitation, Tkt was shown to be a direct target of transcription factor Krüppel-like factor 5 (Klf5). In cardiomyocytes under ischemic stress, Tkt redistributed into the nucleus. By binding with the full-length poly(ADP-ribose) polymerase 1 (Parp1), facilitating its cleavage, and activating apoptosis inducible factor (Aif) subsequently, nuclear Tkt demonstrated its non-metabolic functions. Overall, our study confirmed that elevated nuclear Tkt plays a noncanonical role in promoting cardiomyocyte apoptosis via the cleaved Parp1Aif pathway, leading to the deterioration of cardiac dysfunction.

The posterior fossa syndrome questionnaire using science to inform practice.

Up to 34% of patients with medulloblastoma develop posterior fossa syndrome (PFS) following brain tumor resection and have increased risk of long-term neurocognitive impairments. Lack of agreement in conceptualization and diagnosis of PFS calls for improvements in diagnostic methods. The current study aimed to describe psychometric properties of a new posterior fossa syndrome questionnaire (PFSQ). The PFSQ was informed by prior research and developed by a multidisciplinary team with subject matter expertise. Participants (N 164 63.4% Male 78.7% White M PFSQ items ataxia (100.00%), dysmetria (95.45%), and speechlanguage changes (79.55%) were most sensitive. However, ataxia (26.50%) and dysmetria (46.61%) demonstrated low specificity. Speechlanguage changes (81.36%), mutism (95.76%), orofacial apraxia (98.29%) and irritability (96.61%) had high specificity. A principal component analysis found four components (1) speechlanguage changes, (2) apraxias (including mutism), (3) motororomotor, and (4) emotional lability. The PFSQ is a dimensional diagnostic approach that can be used to improve diagnostic consistency across clinical and research groups to help accelerate understanding of PFS etiology, identify surgical correlates of risk, predict long-term impairments, and develop targeted interventions. Additional measure validation, including correlation with symptom resolution, is required.

Diaph3 underlines tumor cell heterogeneity in glioblastoma with implications for treatment modalities resistance.

Glioblastoma (GBM) is the most aggressive central nervous system (CNS) tumor with astrocytic differentiation. The growth pattern of GBM mimics that of the precursor cell migration during the fetal development of the brain. Diaphanous homolog (Diaph3) has been established to play a role in both CNS maturation and cancer progression as it is required both for cell migration and division. Furthermore, Diaph3 has been shown to play a role in malignant disease progression through hyperactivation of the EGFRMEKERK in loss of expression and its overexpression correlating to hyperactivity of the mTOR pathway, both of which are with a well-established role in GBM. Herein, we aimed at establishing the diagnostic role of Diaph3 immunohistochemistry expression patterns in GBM and their possible implications for molecular response to different therapies. The study utilized a retrospective nonclinical approach. Results of Diaph3 immunohistochemical expression were compared to healthy controls and reactive gliosis and statistically analyzed for correlation with neuroradiological tumor parameters and patient survival. Healthy controls showed individual weakly positive cells, while reactive gliosis controls showed a strong expression in astrocytic projections. GBM samples showed a heterogeneous positive reaction to Diaph3, mean number of positive cells 62.66%, median 61.5, range 12-96%. Areas of migrating cells showed a strong diffuse cytoplasmic reaction. Cells located in the tumor core and those in areas of submeningeal aggregation had no antibody expression. Statistical analysis revealed no correlation with tumor size or patient survival. The different expression pattern of Diaph3 in healthy controls, reactive gliosis and GBM shows promise as a clinical differentiating marker. Despite Diaph3 expression not correlating with survival and tumor size in GBM, there is an accumulating body of evidence that Diaph3 correlates with mTOR activity and can thus be used as a predictor for response to rapamycin and taxanes, clinical studies of which have shown promising, if mixed results in GBM.

Effect of mannitol on platelet function during elective craniotomy in adult patients with brain tumor.

Mannitol is used in the treatment of raised intracranial pressure (ICP). The aim of this study was to investigate whether mannitol (MAN) leads to a relevant deterioration in platelet function in routine neurosurgical procedures. Thirty-eight patients undergoing elective craniotomy due to a brain tumor with elevated ICP were included. After induction of anaesthesia a blood sample was taken (T1). The patients then received 1 g-kg-1 MAN within 30 minutes. The second blood sample (T2) was obtained 60 minutes after T1. Blood samples were examined by means of aggregometry (Multiplate®) and PFA-100® tests. No patient had clinical signs of increased bleeding. We could not find any deterioration in the aggregometry using Multiplate®, neither in the adenosinediphosphate (ADP), the arachidonic acid (ASPI), or the thrombin receptor activating protein (TRAP) test. PFA-100® closing times (cT) showed a significant prolongation between T1 and T2 collagenadenosindiphosphate (COLADP) test 79s 7099 and 91s 81109 p0.002) collagenepinephrine (COLEPI) test 109s 92129 and 122s 94159 p0.0004). A subgroup analysis showed that the patients who received isotonic balanced infusions only, had no prolongation of cT, whereas the patients who received additionally gelatine solution had a significant prolongation. 78s 7098 and 91s 82133 p0.0004). COLEPI test 111s 92128 and 127s 103146 p0.0026). Except for individual outliers, the measured values were in the normal range. In this study, we found no clinically relevant deterioration of platelet function in neurosurgical patients with increased ICP after administration of MAN. Changes that occurred were all within normal ranges.

Effects of glibenclamide against early brain injury in rat after subarachnoid hemorrhage.

Early brain injury (EBI) after subarachnoid hemorrhage (SAH) is a new therapeutic target. Sulfonylurea receptor 1 (SUR1) is expressed in nerve cells, glial cells, and vascular endothelial cells in EBI. SUR1 promotes intracellular inflow of Na and Ca ions, resulting in cell swelling and depolarization, and finally cell death. Glibenclamide reduced cerebral edema and mortality in a basic study of cerebral ischemia. However, the effects of glibenclamide on EBI have not been fully elucidated. This study examined the inhibitory effect of glibenclamide on EBI. Rats were divided into the sham group, SAH-control group, and SAH-glibenclamide group. The water content of the brain was measured using the dry-wet method. In addition, the brain was divided into the cortex, putamen, and hippocampus, and expression of inflammatory cytokines was evaluated by the polymerase chain reaction method. In addition, microglia in the brain were evaluated immunohistologically. Water content of the brain was significantly decreased in the SAH-glibenclamide group compared to the SAH-control group. Interleukin-1beta (IL-1β), tumor necrosis factor alpha (TNFα), and nuclear factor-kappa B significantly increased in the cerebral cortex after SAH. IL-1β and TNFα in the cortex were significantly decreased in the SAH-glibenclamide group compared to the SAH-control group. Immunohistochemical staining confirmed that SAH causes extensive microglial activation in the brain, which was suppressed by glibenclamide. The present study showed that glibenclamide suppressed cerebral edema and activation of microglia and hypersecretion of inflammatory cytokines. Glibenclamide is a potential therapeutic method which may significantly improve the functional prognosis.

New insights into the genetic etiology of Alzheimers disease and related dementias.

Characterization of the genetic landscape of Alzheimers disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosedproxy AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloidtau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future ADdementia or progression from mild cognitive impairment to ADdementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.

Disease-associated KBTBD4 mutations in medulloblastoma elicit neomorphic ubiquitylation activity to promote CoREST degradation.

Medulloblastoma is the most common malignant brain tumour in children. Genomic studies have identified distinct disease subgroups wntwingless (WNT), sonic hedgehog (SHH), and non-WNTnon-SHH, comprising group 3 and group 4. Alterations in WNT and SHH signalling form the pathogenetic basis for their subgroups, whereas those for non-WNTnon-SHH tumours remain largely elusive. Recent analyses have revealed recurrent in-frame insertions in the E3 ubiquitin ligase adaptor Kelch Repeat and BTB Domain Containing 4 (KBTBD4) in cases of group 34 medulloblastoma. Critically, group 34 tumours with KBTBD4 mutations typically lack other gene-specific alterations, such as MYC amplification, indicating KBTBD4 insertion mutations as the primary genetic driver. Delineating the role of KBTBD4 mutations thus offers significant opportunities to understand tumour pathogenesis and to exploit the underpinning mechanisms therapeutically. Here, we show a novel mechanism in cancer pathogenesis whereby indel mutations in KBTBD4 drive its recognition of neo-substrates for degradation. We observe that KBTBD4 mutants promote the recruitment and ubiquitylation of the REST Corepressor (CoREST), which forms a complex to modulate chromatin accessibility and transcriptional programmes. The degradation of CoREST promoted by KBTBD4 mutation diverts epigenetic programmes inducing significant alterations in transcription to promote increased stemness of cancer cells. Transcriptional analysis of >200 human group 3 and 4 medulloblastomas by RNA-seq, highlights the presence of CoREST and stem-like signatures in tumours with KBTBD4 mutations, which extend to a further sub-set of non-mutant tumours, suggesting CoREST alterations as a novel pathogenetic mechanism of wide relevance in groups 3 and 4. Our findings uncover KBTBD4 mutation as a novel driver of epigenetic reprogramming in non-WNTnon-SHH medulloblastoma, establish a novel mode of tumorigenesis through gain-of-function mutations in ubiquitin ligases (neo-substrate recruitment) and identify both mutant KBTBD4 and CoREST complexes as new druggable targets for improved tumour-specific therapies.

SWISNF chromatin remodeler complex within the reward pathway is required for behavioral adaptations to stress.

Enduring behavioral changes upon stress exposure involve changes in gene expression sustained by epigenetic modifications in brain circuits, including the mesocorticolimbic pathway. Brahma (BRM) and Brahma Related Gene 1 (BRG1) are ATPase subunits of the SWISNF complexes involved in chromatin remodeling, a process essential to enduring plastic changes in gene expression. Here, we show that in mice, social defeat induces changes in BRG1 nuclear distribution. The inactivation of the Brg1Smarca4 gene within dopamine-innervated regions or the constitutive inactivation of the BrmSmarca2 gene leads to resilience to repeated social defeat and decreases the behavioral responses to cocaine without impacting midbrain dopamine neurons activity. Within striatal medium spiny neurons, Brg1 gene inactivation reduces the expression of stress- and cocaine-induced immediate early genes, increases levels of heterochromatin and at a global scale decreases chromatin accessibility. Altogether these data demonstrate the pivotal function of SWISNF complexes in behavioral and transcriptional adaptations to salient environmental challenges.

16α-18F-fluoro-17β-Fluoroestradiol (FES) Clinical Applications for Patients With Breast Cancer.

Estrogen receptor (ER) is highly expressed in 70%-80% of breast cancers and plays a central role in prognosis and treatment selection for patients with breast cancer. The gold standard for determining ER status in breast cancer has been pathology however, tissue samples are invasive to obtain and only provide information on individual lesions. It is increasingly recognized that there is often spatial and temporal heterogeneity of ER status between lesions, which limits our ability to make decisions based on only one or a few tissue samples. Likewise, it is increasingly recognized that ER may be present, but not functional, thus knowledge of the ER status on pathology is not sufficient to determine the role ER plays in oncogenesis in individual patients or to make optimal treatment decisions. 16α-18F-fluoro-17β-Fluoroestradiol (FES) is a radiolabeled form of estrogen that binds to ER and allows non-invasive, whole-body evaluation of functional ER. FES has been shown to correlate with ER immunohistochemistry, successfully demonstrate ER heterogeneity, and provide high diagnostic accuracy for the detection of ER-positive tumors. FES was FDA approved May 20, 2020, as a diagnostic agent for the detection of ER-positive lesions as an adjunct to biopsy in patients with recurrent or metastatic breast cancer. FES has demonstrated sensitive detection of ER-positive malignancy in several anatomic sites, including bone, lymph nodes, and brain. Visualization of liver lesions is hampered by physiologic liver and biliary excretion of FES. Potential clinical applications of FES include selecting appropriate patients for hormonal therapies, assessing ER-status in lesions that are difficult to biopsy, solving clinical dilemmas when there are inconclusive results from other diagnostic studies, systemic staging of ER-positive breast cancers with low metabolic activity and not well visualized by FDG, and selecting optimal dosage for current or novel ER-targeted therapies to abrogate ER function and oncogenesis. FES binding to ER is blocked by selective estrogen receptor modulators, such as tamoxifen, and selective estrogen degraders, such as fulvestrant. Patients will need to be withdrawn from these treatments prior to FES imaging. The aim of this review is to provide an overview of FES PET, how it is performed, potential clinical applications, limitations, and what may be on the horizon for this growing tool for the care of patients with breast cancer.

Late metachronous cerebral metastasis of pancreatic adenocarcinoma of the tail of the pancreas a case report.

Pancreatic cancer is one of the leading causes of cancer mortality and one of the most lethal malignant neoplasms worldwide. It is known for its local tumor extension to the liver other common sites include the lung, distant lymph nodes, and bone. Brain metastases are extremely rare and represent less than 0.6% of all brain metastases. We report the case of a 66-year-old Caucasian female known to have adenocarcinoma of the tail of the pancreas treated with chemotherapy. During follow-up, thoracoabdominal computed tomography scans did not reveal any residual tumor or any metastasis. Moreover, tumor markers were within normal limits. She presented to the emergency department of our institution following an episode of a generalized tonic-clonic seizure 5 years following the initial diagnosis. Brain magnetic resonance imaging revealed an expansive left frontal intraaxial lesion compatible with high-grade glioma. The patient underwent surgical treatment. Histological examination revealed pancreatic metastasis. Thought to be rare, metachronous cerebral pancreatic metastasis should be kept in mind in patients with pancreatic cancer. Early diagnosis and complete surgical resection play a key role in the survival of these patients.

Verbal fluency as a quick and simple tool to help in deciding when to refer patients with a possible brain tumour.

Patients with brain tumours often present with non-specific symptoms. Correctly identifying who to prioritise for urgent brain imaging is challenging. Brain tumours are amongst the commonest cancers diagnosed as an emergency presentation. A verbal fluency task (VFT) is a rapid triage test affected by disorders of executive function, language and processing speed. We tested whether a VFT could support identification of patients with a brain tumour. This proof-of-concept study examined whether a VFT can help differentiate patients with a brain tumour from those with similar symptoms (i.e. headache) without a brain tumour. Two patient populations were recruited, (a) patients with known brain tumour, and (b) patients with headache referred for Direct-Access Computed-Tomography (DACT) from primary care with a suspicion of a brain tumour. Semantic and phonemic verbal fluency data were collected prospectively. 180 brain tumour patients and 90 DACT patients were recruited. Semantic verbal fluency score was significantly worse for patients with a brain tumour than those without (P < 0.001), whether comparing patients with headache, or patients without headache. Phonemic fluency showed a similar but weaker difference. Raw and incidence-weighted positive and negative predictive values were calculated. We have demonstrated the potential role of adding semantic VFT score performance into clinical decision making to support triage of patients for urgent brain imaging. A relatively small improvement in the true positive rate in patients referred for DACT has the potential to increase the timeliness and efficiency of diagnosis and improve patient outcomes.

Vesicular Approach Review on Nanocarriers bearing Curcumin and Applications.

Phytoconstituents have been used to treat a variety of human diseases for a long time, but their use in pharmaceuticals is limited because of their low aqueous solubility. Researchers have created vesicular systems to address many of the issues associated with the bioavailability and therapeutic efficacy of poorly water-soluble drugs and target the drug to the desired location in the body. Several vesicular nanocarrier systems have been developed. Review contrasts various vesicular drug delivery systems, including liposomes, sphingosomes, emulsomes, niosomes, ethosomes, virosomes, phytosomes, aquasomes, proniosomes, transfersomes, pharmacosomes. Vesicular drug delivery systems have caused a scientific revolution, which has resulted in the development of novel dosage forms. This review aims to illustrate the applications, advantages, and disadvantages of the vesicular approach as nanocarriers bearing curcumin and widely used in gene delivery, tumor-targeting to the brain, oral formulations, and resolving various problems associated with drug stability and permeability issues. Nanocarriers also has wide application as green nanocomposites and for antitubercular drugs depending on their physical properties.

MiR-222-3p inhibits formation of medulloblastoma stem-like cells by targeting Notch2c-myc signaling pathway.

Medulloblastoma (MB) is an embryonal tumor of the cerebellum, which commonly occurs in childhood. Herein, we investigated the effects of miR-222-3p on the formation of MB stem-like cells Quantitative real-time PCR (qRT-PCR) or western blotting was performed to determine the expression of miR-222-3p and Notch2, c-myc, proliferating cell nuclear antigen (PCNA), and caspase-3. Luciferase reporter gene, RNA immunoprecipitation (RIP), and RNA pull-down assay were applied to confirm the interaction between miR-222-3p and Notch2. Cell growth was examined by Cell Counting Kit-8. Cell cycle distribution and the number of stem cell marker CD133 miR-222-3p expression was decreased and Notch2 expression was increased in human medulloblastoma cells. miR-222-3p overexpression inhibited cell viability and the sphere formation, induced cell cycle arrest, decreased the number of CD133 MiR-222-3p suppressed cell viability, altered cell cycle distribution, and inhibited the formation of MB stem-like cells

Intraoperative AIRO mobile computer tomography in frameless stereotactic procedures.

Multiple factors can affect the accuracy of neuronavigation, that is a relevant issue, particularly for frameless stereotactic procedures, where precision and optimal image-guidance is crucial for the surgical performance, workflow, and outcome. To investigate the impact of AIRO Mobile Computer Tomography in frameless stereotactic approaches. A retrospective study on 12 patients was performed. All the procedures were deployed using a frameless stereotactic technique, both for the collection of biopsy pathological specimens for diagnosis and insertion of drainage in the treatment of intracranial cystic lesions. Twelve patients (eight males, four females) underwent the frameless stereotactic procedure. Mean age at surgery was 55 (±5 SE). The mean volume of the lesion was 23.85 cm The AIRO-CT resulted feasible with a potential utility for stereotactic procedures. We showed how it could grant the efficacy of the stereotactic procedures reducing some technical and physical sources of inaccuracy, also enhancing safety and allowing prompt detection and management of intraoperative complications.

A Novel and Effective Brain Tumor Classification Model Using Deep Feature Fusion and Famous Machine Learning Classifiers.

Brain tumors are difficult to treat and cause substantial fatalities worldwide. Medical professionals visually analyze the images and mark out the tumor regions to identify brain tumors, which is time-consuming and prone to error. Researchers have proposed automated methods in recent years to detect brain tumors early. These approaches, however, encounter difficulties due to their low accuracy and large false-positive values. An efficient tumor identification and classification approach is required to extract robust features and perform accurate disease classification. This paper proposes a novel multiclass brain tumor classification method based on deep feature fusion. The MR images are preprocessed using min-max normalization, and then extensive data augmentation is applied to MR images to overcome the lack of data problem. The deep CNN features obtained from transfer learned architectures such as AlexNet, GoogLeNet, and ResNet18 are fused to build a single feature vector and then loaded into Support Vector Machine (SVM) and K-nearest neighbor (KNN) to predict the final output. The novel feature vector contains more information than the independent vectors, boosting the proposed methods classification performance. The proposed framework is trained and evaluated on 15,320 Magnetic Resonance Images (MRIs). The study shows that the fused feature vector performs better than the individual vectors. Moreover, the proposed technique performed better than the existing systems and achieved accuracy of 99.7% hence, it can be used in clinical setup to classify brain tumors from MRIs.

Brain tumor segmentation based on region of interest-aided localization and segmentation U-Net.

Since magnetic resonance imaging (MRI) has superior soft tissue contrast, contouring (brain) tumor accurately by MRI images is essential in medical image processing. Segmenting tumor accurately is immensely challenging, since tumor and normal tissues are often inextricably intertwined in the brain. It is also extremely time consuming manually. Late deep learning techniques start to show reasonable success in brain tumor segmentation automatically. The purpose of this study is to develop a new region-of-interest-aided (ROI-aided) deep learning technique for automatic brain tumor MRI segmentation. The method consists of two major steps. Step one is to use a 2D network with U-Net architecture to localize the tumor ROI, which is to reduce the impact of normal tissues disturbance. Then a 3D U-Net is performed in step 2 for tumor segmentation within identified ROI. The proposed method is validated on MICCAI BraTS 2015 Challenge with 220 high Gliomas grade (HGG) and 54 low Gliomas grade (LGG) patients data. The Dice similarity coefficient and the Hausdorff distance between the manual tumor contour and that segmented by the proposed method are 0.876 ±0.068 and 3.594±1.347 mm, respectively. These numbers are indications that our proposed method is an effective ROI-aided deep learning strategy for brain MRI tumor segmentation, and a valid and useful tool in medical image processing.

Mechanical Failure After Total En Bloc Spondylectomy and Salvage Surgery.

Total en bloc spondylectomy (TES) is a curative surgical method for spinal tumors. After resecting the 3 spinal columns, reconstruction is of paramount importance. We present cases of mechanical failure and suggest strategies for salvage surgery. The medical records of 19 patients who underwent TES (9 for primary tumors and 10 for metastatic tumors) were retrospectively reviewed. Previously reported surgical techniques were used, and the surgical extent was 1 level in 16 patients and 2 levels in 3 patients. A titanium-based mesh-type interbody spacer filled with autologous and cadaveric bone was used for anterior support, and a pedicle screwrod system was used for posterior support. Radiotherapy was performed in 11 patients (pre-TES, 5 post-TES, 6). They were followed up for 59 ± 38 months (range, 11-133 months). During follow-up, 8 of 9 primary tumor patients (89%) and 5 of 10 metastatic tumor patients (50%) survived (mean survival time, 124 ± 8 months vs. 51 ± 13 months p 0.11). Mechanical failure occurred in 3 patients (33%) with primary tumors and 2 patients (20%) with metastatic tumors (p 0.63). The mechanical failure-free time was 94.4 ± 14 months (primary tumors, 95 ± 18 months metastatic tumors, 68 ± 16 months p 0.90). Revision surgery was performed in 4 of 5 patients, and bilateral broken rods were replaced with dual cobalt-chromium alloy rods. Repeated rod fractures occurred in 1 of 4 patients 2 years later, and the third operation (with multiple cobalt-chromium alloy rods) was successful for over 6 years. Considering the difficulty of reoperation and patients suffering, preemptive use of a multiple-rod system may be advisable.

Novel electrochemical immunosensor for O

The detection of methylation level in O

Juvenile and adult xanthogranuloma A 30-year single-center experience and review of the disorder and its relationship to other histiocytoses.

Juvenile xanthogranuloma (JXG) is the most common type of non-Langerhans cell histiocytosis whose cell of origin, etiology and pathogenesis are not fully understood. We aimed to provide an update on histopathologic and immunophenotypic profile of this well-characterized entity whose relationship to the other histiocytoses has received renewed attention in light of recent molecular genetic studies. A retrospective review of all the cases with the pathologic diagnosis of xanthogranuloma was performed on our archives from 1989 to 2019. A total of 525 patients with 547 lesions diagnosed as JXG were identified with the median age of 4.5 years, a male predominance (MF ratio 1.31) and a predilection for the head and neck region (40.8%). Cutaneous lesions comprised 76.8% cases and another 15.7% presented within soft tissues. The most common non-soft tissue, extracutaneous lesions included the brain (2.6%), and lungs (1.8%). Three basic histopathologic patterns were identified early classic (EJXG) (14.2%), classic (CJXG) (45.3%), and transitional JXG (TJXG) (40.5%). Multinucleated giant cells, either Touton or non-Touton, were most frequently present in CJXG followed by TJXG. Mitosis was rare (<110 high-power field) among different patterns. There was an association among the patterns and lymphocytic infiltrates (P 0.036), and presence of Touton or non-Touton giant cells (P < 0.001 for both) but not for mitotic count (P 0.105) or eosinophilic infiltrates (P 0.465). Additionally, there was a correlation between age groups and presence of non-Touton giant cells (P 0.012) but not for Touton cells (P 0.127). We have demonstrated that immunophenotypic expression of the lesion was not associated with age at diagnosis nor morphologic pattern factor XIIIa 192204 (94.1%), CD11c 7577 (97.4%), CD4 8284 (97.6%), CD68 200201 (99.5%), CD163 1515 (100%), CD1a 1110 (0.9%), S-100 48152 (31.6%), CD31 1521 (71.4%), and vimentin 104105 (99.0%). We have documented in a substantial series of cases of JXG that there is a correlation between one of the three basic histopathologic patterns with age at diagnosis, but with a consistent immunophenotype among the three patterns. Considering sensitivity and specificity rates, we suggest that a combination of CD11c, CD4, CD1a and either CD163 (preferred) or CD68 stains provides more specific diagnostic yield in the differentiation of JXG from other histiocytic disorders. JXG is also discussed in terms of its relationship and distinction from other similar histiocytic disorders in the context of MAPKERK pathway mutations.

ZFTA (Zinc Finger Translocation Associated) Fusion in Supratentorial Ependymomas Low Prevalence in South Asians and No Correlation with Survival.

Supratentorial ependymomas (STEs) are an aggressive group of ependymomas, topographically distinct from their posterior fossa and spinal counterparts. Zinc finger translocation associated (ZFTA) fusion-positive cases have been reported to account for the majority of STEs, although data on its association with poorer outcomes are inconsistent. We assessed the prevalence of the ZFTA fusion by reverse-transcription polymerase chain reaction and fluorescence in situ hybridization in a cohort of 61 patients (68 samples) with STE. Our primary outcome was to determine the role of the ZFTA fusion on progression-free and overall survival of patients with STE. Our secondary objectives were to assess the impact of ZFTA fusion on nuclear factor (NF)-kB pathway signaling via surrogate markers of this pathway, namely COX-2, CCND1, and L1 cell adhesion molecule. ZFTA fusion was noted in 21.3% of STEs in our cohort. The presence of this rearrangement did not significantly impact the progression-free or overall survival of patients with STEs and was not associated with upregulation of markers of the NF-kB pathway. Only gross total resection was significantly associated with better progression-free survival. In contradiction to previous reports from across the world, the ZFTA fusion is far less prevalent among our population. It does not appear to drive NF-kB signaling or significantly affect outcomes. Gross total resection must be attempted in all cases of STE and adjuvant radiation andor chemotherapy employed when gross total resection is not achieved.

Breast cancer survivors typhoid vaccine responses Chemotherapy, obesity, and fitness make a difference.

To investigate breast cancer survivors inflammatory responses to typhoid vaccine as a window into their innate immune response to novel pathogens. This double-blind crossover trial randomized 158 breast cancer survivors to either the vaccinesaline placebo or the placebovaccine sequence. The relative contributions of age, cardiorespiratory fitness (VO The vaccine produced larger IL-6, IL-1Ra, and WBC responses than placebo, ps < 0.0001. Prior chemotherapy, higher central obesity, and lower VO This study provided novel data on chemotherapys longer-term adverse immune consequences. The data also have an important public health message even relatively low levels of fitness can benefit the innate immune response to a vaccine.

Efficacy and Safety of Apatinib for Radiation-induced Brain Injury Among Patients With Head and Neck Cancer An Open-Label, Single-Arm, Phase 2 Study.

The treatment of radiation-induced brain injury (RI) caused by radiation therapy for head and neck cancer is challenging. Antiangiogenic therapy is a promising treatment. Apatinib is an oral tyrosine kinase inhibitor that selectively inhibits vascular endothelial growth factor receptor 2. We aimed to assess the efficacy and safety of apatinib in patients with RI. In this phase 2, open-label, single-arm, prospective study, we recruited patients aged 35 to 80 years with prior radiation therapy history for head and neck cancer who had newly diagnosed RI at the Sun Yat-sen Memorial Hospital, China. Apatinib was administered at a dosage of 250 mg once daily orally for 4 weeks. A Simon minimax 2-stage design was performed. The primary outcome was the proportion of patients with overall clinical efficacy, defined as a radiographic response of ≥25% reduction in baseline brain edema volume on magnetic resonance fluid attenuated inversion recovery images at week 4. Secondary end points were the overall improvement rate of brain necrosis, neurologic function, and safety. We screened 37 patients, 36 of whom were enrolled between October 17, 2019, and August 3, 2020. At the cutoff date, 36 patients were assessed for efficacy and safety (19 were enrolled in stage 1 and 17 in stage 2). Of the 36 patients evaluated for overall clinical efficacy, 22 patients (61.1% 95% CI, 43.5%-76.9%) achieved the primary end point at week 4. Among the 31 patients with brain necrosis lesions, 19 patients (61.3% 95% CI, 42.2%-78.2%) showed improvement of brain necrosis. The most common grade 1 to 2 adverse events were hand-foot syndrome, fatigue, and hypertension There were no treatment-related grade 4 to 5 toxic effects. Oral apatinib shows promising efficacy and is well-tolerated in patients with RI. Further randomized controlled studies are warranted.

In vivo self-assembled drug nanocrystals for metastatic breast cancer all-stage targeted therapy.

Chemotherapy is still the mainstay treatment for metastatic triple-negative breast cancers (TNBC) currently in clinical practice. The unmet needs of chemotherapy for metastatic TNBC are mainly from the insufficient drug delivery and unavailable targeting strategy that thwart the whole progression of metastatic TNBC. The in vivo ligands-mediated active targeting efficiency is usually affected by protein corona. While, the protein corona-bridged natural targeting, in turn, provides a new way for specific drug delivery. Herein, we develop a novel metastatic progression-oriented in vivo self-assembled Cabazitaxel nanocrystals (CNC) delivery system (PCCNC) through the CNC automatically absorbing functional plasma proteins (transferrin, apolipoprotein A-IV and apolipoprotein E) in vivo, aiming to achieve the simultaneously targeted delivery to primary tumors, circulating tumor cells and metastatic lesions. With the unique advantages of superhigh drug-loading and protein corona empowered active targeting properties to tumor cells, HUVECs, active-platelets and blood-brain barrierblood-tumor barrier, the PCCNC exhibits a significantly improved therapeutic effect in metastatic TNBC therapy compared with free drug and CNC-loaded liposomes.

The spindle assembly checkpoint and the spatial activation of Polo kinase determine the duration of cell division and prevent tumor formation.

The maintenance of a restricted pool of asymmetrically dividing stem cells is essential for tissue homeostasis. This process requires the control of mitotic progression that ensures the accurate chromosome segregation. In addition, this event is coupled to the asymmetric distribution of cell fate determinants in order to prevent stem cell amplification. How this coupling is regulated remains poorly described. Here, using asymmetrically dividing Drosophila neural stem cells (NSCs), we show that Polo kinase activity levels determine timely Cyclin B degradation and mitotic progression independent of the spindle assembly checkpoint (SAC). This event is mediated by the direct phosphorylation of Polo kinase by Aurora A at spindle poles and Aurora B kinases at centromeres. Furthermore, we show that Aurora A-dependent activation of Polo is the major event that promotes NSC polarization and together with the SAC prevents brain tumor growth. Altogether, our results show that an AuroraPolo kinase module couples NSC mitotic progression and polarization for tissue homeostasis.

Understanding glioblastoma invasion using physically-guided neural networks with internal variables.

Microfluidic capacities for both recreating and monitoring cell cultures have opened the door to the use of Data Science and Machine Learning tools for understanding and simulating tumor evolution under controlled conditions. In this work, we show how these techniques could be applied to study Glioblastoma, the deadliest and most frequent primary brain tumor. In particular, we study Glioblastoma invasion using the recent concept of Physically-Guided Neural Networks with Internal Variables (PGNNIV), able to combine data obtained from microfluidic devices and some physical knowledge governing the tumor evolution. The physics is introduced in the network structure by means of a nonlinear advection-diffusion-reaction partial differential equation that models the Glioblastoma evolution. On the other hand, multilayer perceptrons combined with a nodal deconvolution technique are used for learning the go or grow metabolic behavior which characterises the Glioblastoma invasion. The PGNNIV is here trained using synthetic data obtained from in silico tests created under different oxygenation conditions, using a previously validated model. The unravelling capacity of PGNNIV enables discovering complex metabolic processes in a non-parametric way, thus giving explanatory capacity to the networks, and, as a consequence, surpassing the predictive power of any parametric approach and for any kind of stimulus. Besides, the possibility of working, for a particular tumor, with different boundary and initial conditions, permits the use of PGNNIV for defining virtual therapies and for drug design, thus making the first steps towards in silico personalised medicine.

Presurgical cognitive status in patients with low-grade glioma and epilepsy Testing the effects of seizures, antiseizure medications, and tumor localization.

Low-grade gliomas (LGGs) are frequently associated with epilepsy. There are few studies addressing the impact of seizures, antiseizure medications (ASMs), and lesion localization on presurgery cognitive functioning. We tested the relation between the above-mentioned variables in a continuous series of 73 young patients (mean age 38.3 years ± 11.7) affected by LGGs and epilepsy. The anatomical areas, involved in this sample, were the left insula with surrounding cortical and subcortical areas, the right precentral gyrusrolandic operculum, and the white matter and cortical regions beneath. Patients presurgery cognitive status was within the normal range, with borderline performance for some tasks. We tested whether lower scores were related with lesion or with epilepsy-related factors. Multiple regression identified variables that predict test scores. The Token test score was predicted by a model (p .0078) containing the DT2T1 MRI, corrected for seizure features. Object naming performance was predicted by a model (p .0113) containing the localization, the DT2T1 MRI, corrected for sex, EEG, and onset. Verbal fluency score was predicted by a model (p .0056) containing the localization and the DT2T1 MRI, corrected for AEDs and EEG. Working memory score was predicted by a model (p .0117) containing Engel class, the DT2T1 MRI, corrected for sex. Clock drawing score was predicted by a model (p < .0001) containing the Engel class, AEDs, and EEG. TMT A score was predicted by a model (p .0022) containing localization, corrected for EEG. TMT B-A score was predicted by a model (p .0373) containing localization. Voxel Lesion Symptom Mapping analyses carried out on patients lesion volumes confirmed that patients level of performance correlated with lesion-related variables. This preliminary study indicates that the presurgical level of performance for language tasks and for cognitive flexibility and shifting is mainly predicted by lesion-related variables, working memory by both lesion and epilepsy-related variables. Epilepsy clinical and instrumental characteristics predicted performance for visuospatial planning.

Suppression of RPL34 Inhibits Tumor Cell Proliferation and Promotes Apoptosis in Glioblastoma.

Accumulating evidence indicates Ribosomal protein 34 (RPL34) promotes tumor malignance and its expression is associated with poor prognosis in multiple cancer cells. However, the physiological role and biological mechanism of RPL34 in glioblastoma (GBM) remain unclear. Hence, this study aimed to investigate the expression and the role of RPL34 in GBM. A total of 59 glioma samples and 12 normal brains for epilepsy surgery were used to determine the underlying mechanisms and the biological behaviors of RPL34 in GBM. In this study, we identified that RPL34 expression was significantly (p < 0.05) enriched in GBM tumors compared with low-grade glioma and normal brain, and its expression was associated with poor survival. Additionally, RPL34 was functionally required for tumor proliferation in vitro. Mechanically, inhibition of RPL34 induced glioma cell apoptosis by activation of BadCaspase7PARP signaling pathway. The RPL34 promotes cell survival in GBM and could be a potential therapeutic target for GBM.

Surgical management and outcomes of intracranial metastatic Wilms tumor in the pediatric population a case series.

Approximately 1 to 2% of patients with Wilms tumor (WT), or nephroblastoma, will have metastasis to the brain. Due to the rarity of intracranial metastasis, the clinical characteristics, prognosis, and a standardized treatment approach to this occurrence remain poorly understood. Here we review the surgical management and treatment outcome of WT patients with intracranial metastasis at our institution. A retrospective chart review of patients with WT at the Childrens Hospital of Philadelphia was performed from 2007 to 2021. Clinical characteristics, operative details, radiographic studies, pathology, and patient outcomes were collected and analyzed. A total of 3 patients with histologically confirmed intracranial metastatic disease from WT were identified with a mean age of 5.7 years (range 3-10 years). 2 of the 3 patients were male. The mean time from diagnosis of primary WT to development of central nervous system metastasis was 15.3 months. Both supratentorial (n 3) and infratentorial (n 1) sites of metastasis were observed. Surgical resection was performed, and gross total resection was achieved in all 3 patients. All cases had favorable histology with no anaplasia and received whole-brain irradiation and chemotherapy. Two of 3 patients had a good neurologic function at postoperative follow-up. One patient died from their disease 4 months after resection of the brain metastasis. In WT patients with limited systemic disease burden, the combination of surgery, chemotherapy, and radiotherapy may play a role in enhancing survival when intracranial metastasis is present, despite the perioperative risk associated with surgery.

Evaluation of the efficacy and safety of TAS0313 in adults with recurrent glioblastoma.

TAS0313 is a multi-epitope long peptide vaccine targeting several cancer-associated antigens highly expressed in multiple cancer types, including glioblastoma (GBM). This cohort of a Phase 2 part evaluated the efficacy and safety of TAS0313 in patients with GBM. TAS0313 (27 mg) was administered subcutaneously on Days 1, 8 and 15 of Cycles 1 and 2, and Day 1 of subsequent cycles in 21-day cycles. The primary endpoint was the objective response rate (ORR). The secondary endpoints were the disease control rate, progression-free survival (PFS) and 6- and 12-month progression-free survival rates (PFR) and safety. Immunological response was assessed as an exploratory endpoint. The best overall response was partial response in 1 patient, and the ORR (95% CI) was 11.1% (0.3-48.2%) in the per-protocol set (n 9). A further 3 patients achieved stable disease, for a disease control rate (95% CI) of 44.4% (13.7-78.8%). Median (95% CI) PFS was 1.7 (1.3-NE) months and 6- and 12-month PFRs (95% CI) were 22.2% (3.4-51.3%) each. Common (≥ 20% incidence) treatment-related adverse events (AEs) were injection site reactions (n 8, 80.0%), followed by pyrexia (n 7, 70.0%), and malaise, injection site erythema and injection site pruritus (n 2, 20.0% each). There were no grade 4 or 5 treatment-related AEs. No deaths occurred during the study. In some patients, TAS0313 treatment was confirmed to increase cytotoxic T lymphocyte and immunoglobulin G levels compared with baseline. TAS0313, a multi-epitope long peptide vaccine, demonstrated promising efficacy and acceptable safety in patients with recurrent GBM. JapicCTI-183824 (Date of registration Jan 11, 2018).

Photon versus proton whole ventricular radiotherapy for non-germinomatous germ cell tumors A report from the Childrens Oncology Group.

To determine if proton therapy reduces doses to cranial organs at risk (OARs) as compared to photon therapy in children with non-germinomatous germ cell tumors (NGGCT) receiving whole ventricular radiotherapy (WVRT). Dosimetric data for patients with NGGCT prospectively enrolled in stratum 1 of the Childrens Oncology Group study ACNS1123 who received 30.6 Gy WVRT were compared. Target segmentation was standardized using a contouring atlas. Doses to cranial OARs were compared between proton and photon treatments. Clinically relevant dose-volume parameters that were analyzed included mean dose and dose to 40% of the OAR volume (D40). Mean and D40 doses to the supratentorial brain, cerebellum, and bilateral temporal, parietal, and frontal lobes were statistically significantly lower amongst proton-treated patients, as compared to photon-treated patients. In a subgroup analysis of patients uniformly treated with a 3-mm planning target volume, patients who received proton therapy continued to have statistically significantly lower doses to brain OARs. Children treated with proton therapy for WVRT had lower doses to normal brain structures, when compared to those treated with photon therapy. Proton therapy should be considered for patients receiving WVRT for NGGCT.