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Soft Coagulation Monopolar Suction for Rapid Resection of Supratentorial Brain Tumors Feasibility of a New Technique and Outcomes.

The aims of this study were to evaluate the feasibility of a new rapid tumor resection technique using soft coagulation monopolar suction (SCMS) and to strengthen neurosurgeons understanding, use, and attention to this new electrosurgical technique. The rapid surgical resection technique used herein comprised monopolar suction in soft coagulation mode applied by the ERBE VIO 300s workstation and conventional microsurgical suction. We applied this technique to supratentorial tumors in 12 patients (5 with glioblastomas, 4 with astrocytomas, 2 with metastases, and one with lymphoma) as the SCMS group. The conventional bipolar electrocautery and suction method was used for another 12 patients (non-SCMS group). The surgical results and perioperative complications were retrospectively evaluated. Radiographic and histologic analyses were performed to describe the degree of thermal damage. The mean estimated operative time and total blood loss were 3.63 ± 0.61 hours (P 0.0048) and 308.33 ± 172.99 mL (P 0.0482) in the SCMS group, respectively, and these values were significantly lower than those in the non-SCMS group (4.33 ± 0.49 hours and 466.67 ± 196.95 mL, respectively). No significant differences in perioperative complications, Karnofsky Performance Status scores, perioperative area edema volumes, perioperative ischemic areas, or mean residual tumors were observed between the groups. Histological examination revealed that SCMS produced uniform coagulation and completely obstructed most small vessel structures on the tumor surface. This new technique involving SCMS allows for a smooth surgical procedure and appears to be safe and feasible for the rapid resection of supratentorial brain tumors. Thus, neurosurgeons should consider using this technique in the future.

GABA

The Sonic hedgehog-activated subgroup of medulloblastoma (SHH-MB) is one of the most common malignant pediatric brain tumors. Recent clinical studies and genomic databases indicate that GABA

Morus mesozygia leaf extract ameliorates behavioral deficits, oxidative stress and inflammation in Complete Freunds adjuvant-induced arthritis in rats.

Morus mesozygia Stapf (Moraceae), otherwise referred to as African mulberry, is utilized domestically as a remedy for a variety of inflammatory disorders including rheumatism. The anti-arthritic effect of the ethylacetate fraction of M. mesozygia leaf extract (EAFMm) was assessed on complete Freunds adjuvant (CFA)-induced arthritis in male Wistar rats. Groups of male Wistar rats were injected with CFA (0.2 mL 10 mgmL) in the plantar surface of their right hind paws and treated orally with EAFMm (50 and 100 mgkg) or its vehicle daily for 28 days. The effect on joint inflammation and mechanical nociception threshold, behavioral deficits (spontaneous motor activity in the open field test and depressive-like symptoms in the forced swim test) was evaluated. The levels and activities of the biomarkers of oxidative-nitrosative stress (reduced glutathione, superoxide dismutase, nitrite, and malondialdehyde) and inflammatory markers TNF-α, IL-6, COX-2, NFκB and myeloperoxidase were also analysed. The EAFMm at the doses of 50 and 100 mgkg produced a dose dependent reduction in joint inflammation and mechanical hyperalgesia, and as well improved behavioral deficits like spontaneous motor activity and depressive-like behavior. The EAFMm also significantly reduced oxido-nitrosative stress response in the joint and brain tissues. It also decreased TNF-α, interleukin-6 levels and myeloperoxidase enzyme activities in joints and brain tissues of rats. Furthermore, EAFMm attenuated the activity of NFκB and reduced the cyclooxygenase -2 protein expression level in joint tissues. The ethylacetate fraction of Morus mesozygia leaf extract demonstrated anti-arthritic activity and ameliorated co-morbid depressive-like behavior via inhibition of oxidative stress and inflammation in a rat model of arthritis.

Graded Prognostic Assessment (GPA) for Patients With Lung Cancer and Brain Metastases Initial Report of the Small Cell Lung Cancer GPA and Update of the Non-Small Cell Lung Cancer GPA Including the Effect of Programmed Death Ligand 1 and Other Prognostic Factors.

Patients with lung cancer and brain metastases represent a markedly heterogeneous population. Accurate prognosis is essential to optimally individualize care. In prior publications, we described the graded prognostic assessment (GPA), but a GPA for patients with small cell lung cancer (SCLC) has never been reported, and in non-small cell lung cancer (NSCLC), the effect of programmed death ligand 1 (PD-L1) was unknown. The 3-fold purpose of this work is to provide the initial report of an SCLC GPA, to evaluate the effect of PD-L1 on survival in patients with NSCLC, and to update the Lung GPA accordingly. A multivariable analysis of prognostic factors and treatments associated with survival was performed on 4183 patients with lung cancer (3002 adenocarcinoma, 611 nonadenocarcinoma, 570 SCLC) with newly diagnosed brain metastases between January 1, 2015, and December 31, 2020, using a multi-institutional retrospective database. Significant variables were used to update the Lung GPA. Overall median survival for lung adenocarcinoma, SCLC, and nonadenocarcinoma was 17, 10, and 8 months, respectively, but varied widely by GPA from 2 to 52 months. In SCLC, the significant prognostic factors were age, performance status, extracranial metastases, and number of brain metastases. In NSCLC, the distribution of molecular markers among patients with lung adenocarcinoma and known primary tumor molecular status revealed alterationsexpression in PD-L1 50% to 100%, PD-L1 1% to 49%, epidermal growth factor receptor, and anaplastic lymphoma kinase in 32%, 31%, 30%, and 7%, respectively. Median survival of patients with lung adenocarcinoma and brain metastases with 0, 1% to 49%, and ≥50% PD-L1 expression was 17, 19, and 24 months, respectively (P < .01), confirming PD-L1 is a prognostic factor. Previously identified prognostic factors for NSCLC (epidermal growth factor receptor and anaplastic lymphoma kinase status, performance status, age, number of brain metastases, and extracranial metastases) were reaffirmed. These factors were incorporated into the updated Lung GPA with robust separation between subgroups for all histologies. Survival for patients with lung cancer and brain metastases has improved but varies widely. The initial report of a GPA for SCLC is presented. For patients with NSCLC-adenocarcinoma and brain metastases, PD-L1 is a newly identified significant prognostic factor, and the previously identified factors were reaffirmed. The updated indices establish unique criteria for SCLC, NSCLC-nonadenocarcinoma, and NSCLC-adenocarcinoma (incorporating PD-L1). The updated Lung GPA, available for free at brainmetgpa.com, provides an accurate tool to estimate survival, individualize treatment, and stratify clinical trials.

DNA methylation-based age acceleration observed in IDH wild-type glioblastoma is associated with better outcome-including in elderly patients.

Elderly patients represent a growing proportion of individuals with glioblastoma, who however, are often excluded from clinical trials owing to poor expected prognosis. We aimed at identifying age-related molecular differences that would justify and guide distinct treatment decisions in elderly glioblastoma patients. The combined DNA methylome (450 k) of four IDH wild-type glioblastoma datasets, comprising two clinical trial cohorts, was interrogated for differences based on the patients age, DNA methylation (DNAm) age acceleration (DNAm age Horvath-clock minus patient age), DNA methylation-based tumor classification (Heidelberg), entropy, and functional methylation of DNA damage response (DDR) genes. Age dependent methylation included 19 CpGs (p-value ≤ 0.1, Bonferroni corrected), comprising a CpG located in the ELOVL2 gene that is part of a 13-gene forensic age predictor. Most of the age related CpGs (n 16) were also associated with age acceleration that itself was associated with a large number of CpGs (n 50,551). Over 70% age acceleration-associated CpGs (n 36,348) overlapped with those associated with the DNA methylation based tumor classification (n 170,759). Gene set enrichment analysis identified associated pathways, providing insights into the biology of DNAm age acceleration and respective commonalities with glioblastoma classification. Functional methylation of several DDR genes, defined as correlation of methylation with gene expression (r ≤ -0.3), was associated with age acceleration (n 8), tumor classification (n 12), or both (n 4), the latter including MGMT. DNAm age acceleration was significantly associated with better outcome in both clinical trial cohorts, whereof one comprised only elderly patients. Multivariate analysis included treatment (RT, RTTMZ→TMZ TMZ, RT), MGMT promoter methylation status, and interaction with treatment. In conclusion, DNA methylation features of age acceleration are an integrative part of the methylation-based tumor classification (RTK I, RTK II, MES), while patient age seems hardly reflected in the glioblastoma DNA methylome. We found no molecular evidence justifying other treatments in elderly patients, not owing to frailty or co-morbidities.

Nitrogen-doped graphene quantum dots induce ferroptosis through disrupting calcium homeostasis in microglia.

Along with the wild applications of nitrogen-doped graphene quantum dots (N-GQDs) in the fields of biomedicine and neuroscience, their increasing exposure to the public and potential biosafety problem has gained more and more attention. Unfortunately, the understanding of adverse effects of N-GQDs in the central nervous system (CNS), considered as an important target of nanomaterials, is still limited. After we found that N-GQDs caused cell death, neuroinflammation and microglial activation in the hippocampus of mice through the ferroptosis pathway, microglia was used to assess the molecular mechanisms of N-GQDs inducing ferroptosis because it could be the primary target damaged by N-GQDs in the CNS. The microarray data suggested the participation of calcium signaling pathway in the ferroptosis induced by N-GQDs. In microglial BV2 cells, when the calcium content above the homeostatic level caused by N-GQDs was reversed, the number of cell death, ferroptosis alternations and excessive inflammatory cytokines release were all alleviated. Two calcium channels of L-type voltage-gated calcium channels (L-VGCCs) in plasma membrane and ryanodine receptor (RyR) in endoplasmic reticulum (ER) took part in N-GQDs inducing cytosolic calcium overload. L-VGCCs and RyR calcium channels were also involved in promoting the excess iron influx and triggering ER stress response, respectively, which both exert excessive ROS generation and result in the ferroptosis and inflammation in BV2 cells. N-GQDs exposure caused ferroptosis and inflammatory responses in hippocampus of mice and cultured microglia through activating two calcium channels to disrupt intracellular calcium homeostasis. The findings not only posted an alert for biomedical applications of N-GQDs, but also highlighted an insight into mechanism researches of GQDs inducing multiple types of cell death in brain tumor therapy in the future.

Determining the applicability of the RSNA radiology lexicon (RadLex) in high-grade glioma MRI reporting-a preliminary study on 20 consecutive cases with newly diagnosed glioblastoma.

The implementation of a collective terminology in radiological reporting such as the RSNA radiological lexicon (RadLex) yields many benefits including unambiguous communication of findings, improved education, and fostering data mining for research purposes. While some fields in general radiology have already been evaluated so far, this is the first exploratory approach to assess the applicability of the RadLex terminology to glioblastoma (GBM) MRI reporting. Preoperative brain MRI reports of 20 consecutive patients with newly diagnosed GBM (mean age 68.4 ± 10.8 years 12 males) between January and October 2010 were retrospectively identified. All terms related to the tumor as well as their frequencies of mention were extracted from the MRI reports by two independent neuroradiologists. Every item was subsequently analyzed with respect to an equivalent RadLex representation and classified into one of four groups as follows 1. verbatim RadLex entity, 2. synonymousmultiple equivalent(s), 3. combination of RadLex concepts, or 4. no RadLex equivalent. Additionally, verbatim entities were categorized using the hierarchical RadLex Tree Browser. A total of 160 radiological terms were gathered. 123160 (76.9%) items showed literal RadLex equivalents, 9160 (5.6%) items had synonymous (non-verbatim) or multiple counterparts, 21160 (13.1%) items were represented by means of a combination of concepts, and 7160 (4.4%) entities could not eventually be transferred adequately into the RadLex ontology. Our results suggest a sufficient term coverage of the RadLex terminology for GBM MRI reporting. If applied extensively, it may improve communication of radiological findings and facilitate data mining for large-scale research purposes.

Neuroimaging appearance of hypothalamic hamartomas in monozygotic twins with Pallister-Hall syndrome case report and review of the literature.

Pallister-Hall syndrome (OMIM 146510) is a rare autosomal dominant condition caused by a mutation in the GLI3 gene. The cardinal feature of Pallister-Hall syndrome is the presence of hypothalamic hamartomas, which may manifest with seizures, panhypopituitarism and visual impairment. In Pallister-Hall syndrome, dysplastic histogenetic processes responsible for hypothalamic hamartomas are thought to disrupt early craniofacial development. The clinical presentation of Pallister-Hall syndrome may include characteristic facies (low-set and posteriorly angulated ears, short nose with flat nasal bridge), cleft palate and uvula, bifid epiglottis and laryngotracheal cleft, limb anomalies (e.g., polysyndactyly, short limbs and nail dysplasia), anal atresia, genitourinary abnormalities and congenital heart defects. We report the case of two monochorionic diamniotic twins diagnosed with Pallister-Hall syndrome during the neonatal period, after the identification of a hypothalamic hamartoma on day 1 by cerebral ultrasound scan, later confirmed by brain magnetic resonance imaging. Cerebral ultrasound and magnetic resonance imaging presentations were identical in both twins. We review previously published cases (four reports) of hypothalamic hamartomas identified via cerebral ultrasound and compare reported ultrasonographic features. Main differential diagnoses based on cerebral ultrasound findings are discussed. Full description of typical magnetic resonance imaging appearance is also provided. This is the first case reported in the literature of monochorionic diamniotic twins affected by genetically confirmed Pallister-Hall syndrome with identical hypothalamic hamartomas at cerebral ultrasound and magnetic resonance imaging. Moreover, this paper adds to the existing literature on the sonographic appearance of hypothalamic hamartomas. Considering the consistency in hypothalamic hamartomas sonographic appearance, we support the use of cerebral ultrasound as a first-line neuroimaging modality in case of clinical suspicion of Pallister-Hall syndrome.

The role of microRNA in the pathogenesis of glial brain tumors.

Gliomas are the most common and fatal primary brain tumor in adults. Gliomas are highly invasive tumors with the highest mortality among all primary malignant brain tumors. Until now, the molecular mechanism that is responsible for glioma tumorigenesis and progression remains unclear. MicroRNAs (miRNAs) are short non-coding RNAs with 18-22 nucleotides in length which function as key regulators of various biological processes through negative control over gene expression at the post-transcriptional level. MiRNA dysregulation plays a key role in cancer oncogenesis, including the development and progression of gliomas. MiRNAs regulate a wide range of tumor processes including cell proliferation, differentiation, angiogenesis, invasion and apoptosis. In addition, microRNAs can be selectively packaged, secreted, and transported between cells in exosomes that are able to cross the blood-brain barrier (BBB) and are readily available in almost all types of human body fluids, making them promising biomarkers for gliomas. Increasing evidence has shown that miRNAs play an important role in glioma. For example, a large number studies indicated that this miRNA-21could affect on a variety of cellular and molecular pathways such as insulin-like growth factor (IGF)-binding protein-3 (IGFBP3), RECK, and TIMP3. Exosomal miR-21 may has key roles in gliomas pathogenesis. These findings indicated that miR-21 has critical roles in gliomas pathogenesis and could be used as diagnostic and therapeutic biomarkers for glioma patients. Profiling miRNAs expression in various human pathological conditions is a rapidly growing field, and it is likely that the knowledge gained from these studies regarding the genesis of gliomas will have the potential in the field of minimally invasive therapy with miRNA to improve the prognosis of patients with this pathology.

Intracranial Metastatic Disease Present Challenges, Future Opportunities.

Intracranial metastatic disease (IMD) is a prevalent complication of cancer that significantly limits patient survival and quality of life. Over the past half-century, our understanding of the epidemiology and pathogenesis of IMD has improved and enabled the development of surveillance and treatment algorithms based on prognostic factors and tumor biomolecular characteristics. In addition to advances in surgical resection and radiation therapy, the treatment of IMD has evolved to include monoclonal antibodies and small molecule antagonists of tumor-promoting proteins or endogenous immune checkpoint inhibitors. Moreover, improvements in the sensitivity and specificity of imaging as well as the development of new serological assays to detect brain metastases promise to revolutionize IMD diagnosis. In this review, we will explore current treatment principles in patients with IMD, including the emerging role of targeted and immunotherapy in select primary cancers, and discuss potential areas for further investigation.

Prepontine and Meckels Cave Dermoid Cyst MR and CT Findings with Literature Review.

Dermoid cysts (DCs) are benign, congenital tumors that comprise 0.04-0.6% of all intracranial tumors. DC rupture is a rare complication and usually occurs spontaneously. The most common localisations of intracranial DCs are the posterior fossa, and suprasellar and parasellar regions. The presentations of DCs are highly variable. They are often detected incidentally on computed tomography (CT) or magnetic resonance imaging (MRI) scans while investigating the cause of seizure or headache. Prepontine cystern is a rare localisation for intracranial DCs. To the best of our knowledge, only four cases have been reported in the literature so far. We present MRI and CT findings of a patient with DC, which ruptured into the subarachnoid space extending from the right Meckels cave to the prepontine cistern. Key Words Dermoid cysts, Meckels cave, Prepontine cistern, Rupture.

Radiogenomic Predictors of Recurrence in Glioblastoma-A Systematic Review.

Glioblastoma, as the most aggressive brain tumor, is associated with a poor prognosis and outcome. To optimize prognosis and clinical therapy decisions, there is an urgent need to stratify patients with increased risk for recurrent tumors and low therapeutic success to optimize individual treatment. Radiogenomics establishes a link between radiological and pathological information. This review provides a state-of-the-art picture illustrating the latest developments in the use of radiogenomic markers regarding prognosis and their potential for monitoring recurrence. Databases PubMed, Google Scholar, and Cochrane Library were searched. Inclusion criteria were defined as diagnosis of glioblastoma with histopathological and radiological follow-up. Out of 321 reviewed articles, 43 articles met these inclusion criteria. Included studies were analyzed for the frequency of radiological and molecular tumor markers whereby radiogenomic associations were analyzed. Six main associations were described radiogenomic prognosis, MGMT status, IDH, EGFR status, molecular subgroups, and tumor location. Prospective studies analyzing prognostic features of glioblastoma together with radiological features are lacking. By reviewing the progress in the development of radiogenomic markers, we provide insights into the potential efficacy of such an approach for clinical routine use eventually enabling early identification of glioblastoma recurrence and therefore supporting a further personalized monitoring and treatment strategy.

Magnetic Resonance-Based Synthetic Computed Tomography Using Generative Adversarial Networks for Intracranial Tumor Radiotherapy Treatment Planning.

The purpose of this work is to develop a reliable deep-learning-based method that is capable of synthesizing needed CT from MRI for radiotherapy treatment planning. Simultaneously, we try to enhance the resolution of synthetic CT. We adopted pix2pix with a 3D framework, which is a conditional generative adversarial network, to map the MRI data domain into the CT data domain of our dataset. The original dataset contains paired MRI and CT images of 31 subjects 26 pairs were used for model training and 5 were used for model validation. To identify the correctness of the synthetic CT of models, all of the synthetic CTs were calculated by the quantized image similarity formulas cosine angle distance, Euclidean distance, mean square error, peak signal-to-noise ratio, and mean structural similarity. Two radiologists independently evaluated the satisfaction score, including spatial, detail, contrast, noise, and artifacts, for each imaging attribute. The mean (±standard deviation) of the structural similarity indices (CAD, L2 norm, MSE, PSNR, and MSSIM) between five real CT scans and the synthetic CT scans were 0.96 ± 0.015, 76.83 ± 12.06, 0.00118 ± 0.00037, 29.47 ± 1.35, and 0.84 ± 0.036, respectively. For synthetic CT, radiologists rated the results as evincing excellent satisfaction in spatial geometry and noise level, good satisfaction in contrast and artifacts, and fair imaging details. The similarity index and clinical evaluation results between synthetic CT and original CT guarantee the usability of the proposed method.

Utility of Keratins as Biomarkers for Human Oral Precancer and Cancer.

Human oral cancer is the single largest group of malignancies in the Indian subcontinent and the sixth largest group of malignancies worldwide. Squamous cell carcinomas (SCC) are the most common epithelial malignancy of the oral cavity, constituting over 90% of oral cancers. About 90% of OSCCs arise from pre-existing, potentially malignant lesions. According to WHO, OSCC has a 5-year survival rate of 45-60%. Late diagnosis, recurrence, and regional or lymph nodal metastases could be the main causes of the high mortality rates. Biomarkers may help categorize and predict premalignant lesions as high risk of developing malignancy, local recurrence, and lymph nodal metastasis. However, at present, there is a dearth of such markers, and this is an area of ongoing research. Keratins (K) or cytokeratins are a group of intermediate filament proteins that show paired and differentiation dependent expression. Our laboratory and others have shown consistent alterations in the expression patterns of keratins in both oral precancerous lesions and tumors. The correlation of these changes with clinicopathological parameters has also been demonstrated. Furthermore, the functional significance of aberrant keratins 818 expression in the malignant transformation and progression of oral tumors has also been documented. This article reviews the literature that emphasizes the value of keratins as biomarkers for the prognostication of human oral precancers and cancers.

Safety and Efficacy of Sorafenib and Lenvatinib in Patients Who Underwent Surgery or Whole-Brain Radiotherapy for Brain Metastasis of Hepatocellular Carcinoma.

Surgery or whole-brain radiotherapy (WBRT) for the management of brain metastasis of hepatocellular carcinoma (HCC) is associated with improved survival. However, the efficacy of multi-tyrosine kinase inhibitors (TKIs) and possible bleeding complications have not been studied in these patients. Therefore, this study aimed at investigating TKI safety and efficacy in these patients. We retrospectively reviewed 39 patients who underwent surgery or WBRT for brain metastasis of HCC. Intracranial tumor bleeding rates were compared between patients who did and did not receive TKIs. Survival outcomes were analyzed using the log-rank and Cox regression tests. A total of 22 and 7 patients received sorafenib and lenvatinib, respectively. The intracranial tumor bleeding rates were 61.5% and 70% in patients who did and did not receive TKIs, respectively (

Prevalence and Risk Factors Associated with Tumors and Other Structural Anomalies in Brain MRI Performed to Rule out Secondary Headache A Multicenter Observational Study.

Headache disorders (HDs) are among the most common conditions of the central nervous system, with an estimated prevalence of 50% in adult population. The aim of this work is to analyze the prevalence of structural anomalies that may explain HDs in MRI exams performed to rule out secondary headache in real-world practice, as well as risk factors associated with these lesions. We conducted a retrospective observational study based on a consecutive case series of all patients that underwent brain MRI due to headache from 1 January 2019 to 31 May 2019. We included patients from six MRI diagnostic centers accounting for four provinces of Andalusia (southern Spain). Bivariate and multivariate logistical regression models were performed to identify risk factors associated with the outcomes (1) presence of a structural finding potentially explaining headache, (2) presence of intracranial space-occupying lesions (SOLs), and (3) presence of intracranial tumors (ITs). Of the analyzed sample (1041 patients), a structural finding that could explain headache was found in 224 (21.5%) patients. SOLs were found in 50 (6.8%) patients and ITs in 12 (1.5%) patients. The main factors associated with structural abnormalities were female sex (OR, 1.35 95% CI, 1.02-1.85), accompanying symptoms (OR, 1.34 95% CI, 1.05-1.89), use of gadolinium-based contrast agents (OR, 1.89 95% CI, 1.31-2.72) and previously known conditions potentially explaining headache (OR, 2.44 95% CI, 1.55-3.84). Female sex (

Syndecan-3 as a Novel Biomarker in Alzheimers Disease.

Early diagnosis of Alzheimers disease (AD) is of paramount importance in preserving the patients mental and physical health in a fairly manageable condition for a longer period. Reliable AD detection requires novel biomarkers indicating central nervous system (CNS) degeneration in the periphery. Members of the syndecan family of transmembrane proteoglycans are emerging new targets in inflammatory and neurodegenerative disorders. Reviewing the growing scientific evidence on the involvement of syndecans in the pathomechanism of AD, we analyzed the expression of the neuronal syndecan, syndecan-3 (SDC3), in experimental models of neurodegeneration. Initial in vitro studies showed that prolonged treatment of tumor necrosis factor-alpha (TNF-α) increases SDC3 expression in model neuronal and brain microvascular endothelial cell lines. In vivo studies revealed elevated concentrations of TNF-α in the blood and brain of APPSWE-Tau transgenic mice, along with increased SDC3 concentration in the brain and the liver. Primary brain endothelial cells and peripheral blood monocytes isolated from APPSWE-Tau mice exhibited increased SDC3 expression than wild-type controls. SDC3 expression of blood-derived monocytes showed a positive correlation with amyloid plaque load in the brain, demonstrating that SDC3 on monocytes is a good indicator of amyloid pathology in the brain. Given the well-established role of blood tests, the SDC3 expression of monocytes could serve as a novel biomarker for early AD detection.

Long-Term Effect of Porcine Brain Enzyme Hydrolysate Intake on Scopolamine-Induced Memory Impairment in Rats.

No study has revealed the effect of porcine brain enzyme hydrolysate (PBEH) on memory impairment. We aimed to examine the hypothesis that PBEH intake modulates memory deficits and cognitive behavior in scopolamine (SC)-induced amnesia rats, and its mechanism, including gut microbiota changes, was determined. Sprague-Dawley male rats had intraperitoneal injections of SC (2 mgkg body weightday) at 30 min after daily feeding of casein (MD-control), PBEH (7 mg total nitrogenmL) at 0.053 mL (Low-PBEH), 0.159 mL (Medium-PBEH), 0.478 mL (High-PBEH), or 10 mg donepezil (Positive-control) per kilogram body weight per day through a feeding needle for six weeks. The Normal-control rats had casein feeding without SC injection. PBEH dose-dependently protected against memory deficits determined by passive avoidance test, Y-maze, water-maze, and novel object recognition test in SC-induced rats compared to the MD-control. The High-PBEH group had a similar memory function to the Positive-control group. Systemic insulin resistance determined by HOMA-IR was lower in the PBEH groups than in the Normal-control but not the Positive-control. In parallel with systemic insulin resistance, decreased cholesterol and increased glycogen contents in the hippocampus in the Medium-PBEH and High-PBEH represented reduced brain insulin resistance. PBEH intake prevented the increment of serum TNF-α and IL-1β concentrations in the SC-injected rats. Hippocampal lipid peroxide and TNF-α contents and mRNA TNF-α and IL-1β expression were dose-dependently reduced in PBEH and Positive-control. PBEH decreased the hippocampal acetylcholinesterase activity compared to the MD-control, but not as much as the Positive-control. PBEH intake increased the α-diversity of the gut microbiota compared to the MD-control, and the gut microbiota community was separated from MD-control. In metagenome function analysis, PBEH increased the energy metabolism-related pathways of the gut microbiota, including citric acid cycle, oxidative phosphorylation, glycolysis, and amino acid metabolism, which were lower in the MD-control than the Normal-control. In conclusion, alleviated memory deficit by PBEH was associated potentially with not only reducing acetylcholinesterase activity but also improving brain insulin resistance and neuroinflammation potentially through modulating gut microbiota. PBEH intake (1.5-4.5 mL of 7 mg total nitrogenmL for human equivalent) can be a potential therapeutic agent for improving memory impairment.

Natural Compounds as Promising Adjuvant Agents in The Treatment of Gliomas.

In humans, glioblastoma is the most prevalent primary malignant brain tumor. Usually, glioblastoma has specific characteristics, such as aggressive cell proliferation and rapid invasion of surrounding brain tissue, leading to a poor patient prognosis. The current therapy-which provides a multidisciplinary approach with surgery followed by radiotherapy and chemotherapy with temozolomide-is not very efficient since it faces clinical challenges such as tumor heterogeneity, invasiveness, and chemoresistance. In this respect, natural substances in the diet, integral components in the lifestyle medicine approach, can be seen as potential chemotherapeutics. There are several epidemiological studies that have shown the chemopreventive role of natural dietary compounds in cancer progression and development. These heterogeneous compounds can produce anti-glioblastoma effects through upregulation of apoptosis and autophagy allowing the promotion of cell cycle arrest interfering with tumor metabolism and permitting proliferation, neuroinflammation, chemoresistance, angiogenesis, and metastasis inhibition. Although these beneficial effects are promising, the efficacy of natural compounds in glioblastoma is limited due to their bioavailability and blood-brain barrier permeability. Thereby, further clinical trials are necessary to confirm the in vitro and in vivo anticancer properties of natural compounds. In this article, we overview the role of several natural substances in the treatment of glioblastoma by considering the challenges to be overcome and future prospects.

Pediatric Brain Tumors Signatures from the Intact Proteome.

The present investigation aimed to explore the intact proteome of tissues of pediatric brain tumors of different WHO grades and localizations, including medulloblastoma, pilocytic astrocytoma, and glioblastoma, in comparison with the available data on ependymoma, to contribute to the understanding of the molecular mechanisms underlying the onset and progression of these pathologies. Tissues have been homogenized in acidic water-acetonitrile solutions containing proteases inhibitors and analyzed by LC-high resolution MS for proteomic characterization and label-free relative quantitation. Tandem MS spectra have been analyzed by either manual inspection or software elaboration, followed by experimentaltheoretical MS fragmentation data comparison by bioinformatic tools. Statistically significant differences in proteinpeptide levels between the different tumor histotypes have been evaluated by ANOVA test and Tukeys post-hoc test, considering a

Insights into Infusion-Based Targeted Drug Delivery in the Brain Perspectives, Challenges and Opportunities.

Targeted drug delivery in the brain is instrumental in the treatment of lethal brain diseases, such as glioblastoma multiforme, the most aggressive primary central nervous system tumour in adults. Infusion-based drug delivery techniques, which directly administer to the tissue for local treatment, as in convection-enhanced delivery (CED), provide an important opportunity however, poor understanding of the pressure-driven drug transport mechanisms in the brain has hindered its ultimate success in clinical applications. In this review, we focus on the biomechanical and biochemical aspects of infusion-based targeted drug delivery in the brain and look into the underlying molecular level mechanisms. We discuss recent advances and challenges in the complementary field of medical robotics and its use in targeted drug delivery in the brain. A critical overview of current research in these areas and their clinical implications is provided. This review delivers new ideas and perspectives for further studies of targeted drug delivery in the brain.

Zingerone Modulates Neuronal Voltage-Gated Na

Zingerone (ZO), a nontoxic methoxyphenol, has been demonstrated to exert various important biological effects. However, its action on varying types of ionic currents and how they concert in neuronal cells remain incompletely understood. With the aid of patch clamp technology, we investigated the effects of ZO on the amplitude, gating, and hysteresis of plasmalemmal ionic currents from both pituitary tumor (GH

LPPR5 Expression in Glioma Affects Growth, Vascular Architecture, and Sunitinib Resistance.

Despite intensive research, glioblastoma remains almost invariably fatal. Various promising drugs targeting specific aspects of glioma biology, in addition to or as an alternative to antiproliferative chemotherapy, were not successful in larger clinical trials. Further insights into the biology of glioma and the mechanisms behind the evasive-adaptive response to targeted therapies is needed to help identify new therapeutic targets, prognostics, or predictive biomarkers. As a modulator of the canonically oncogenic Rho-GTPase pathway, Lipid phosphate phosphatase-related protein type 5 (LPPR5) is pivotal in influencing growth, angiogenesis, and therapeutic resistance. We used a GL261 murine orthotopic allograft glioma model to quantify the tumor growth and to obtain tissue for histological and molecular analysis. Epicortical intravital epi-illumination fluorescence video microscopy of the tumor cell spheroids was used to characterize the neovascular architecture and hemodynamics. GL261-glioma growth was delayed and decelerated after LPPR5 overexpression (LPPR5

Effects of Ultra-Short Pulsed Electric Field Exposure on Glioblastoma Cells.

Glioblastoma multiforme (GBM) is the most common brain cancer in adults. GBM starts from a small fraction of poorly differentiated and aggressive cancer stem cells (CSCs) responsible for aberrant proliferation and invasion. Due to extreme tumor heterogeneity, actual therapies provide poor positive outcomes, and cancers usually recur. Therefore, alternative approaches, possibly targeting CSCs, are necessary against GBM. Among emerging therapies, high intensity ultra-short pulsed electric fields (PEFs) are considered extremely promising and our previous results demonstrated the ability of a specific electric pulse protocol to selectively affect medulloblastoma CSCs preserving normal cells. Here, we tested the same exposure protocol to investigate the response of U87 GBM cells and U87-derived neurospheres. By analyzing different in vitro biological endpoints and taking advantage of transcriptomic and bioinformatics analyses, we found that, independent of CSC content, PEF exposure affected cell proliferation and differentially regulated hypoxia, inflammation and P53cell cycle checkpoints. PEF exposure also significantly reduced the ability to form new neurospheres and inhibited the invasion potential. Importantly, exclusively in U87 neurospheres, PEF exposure changed the expression of stem-nessdifferentiation genes. Our results confirm this physical stimulus as a promising treatment to destabilize GBM, opening up the possibility of developing effective PEF-mediated therapies.

Polyunsaturated Fatty Acid-Enriched Lipid Fingerprint of Glioblastoma Proliferative Regions Is Differentially Regulated According to Glioblastoma Molecular Subtype.

Glioblastoma (GBM) represents one of the deadliest tumors owing to a lack of effective treatments. The adverse outcomes are worsened by high rates of treatment discontinuation, caused by the severe side effects of temozolomide (TMZ), the reference treatment. Therefore, understanding TMZs effects on GBM and healthy brain tissue could reveal new approaches to address chemotherapy side effects. In this context, we have previously demonstrated the membrane lipidome is highly cell type-specific and very sensitive to pathophysiological states. However, little remains known as to how membrane lipids participate in GBM onset and progression. Hence, we employed an ex vivo model to assess the impact of TMZ treatment on healthy and GBM lipidome, which was established through imaging mass spectrometry techniques. This approach revealed that bioactive lipid metabolic hubs (phosphatidylinositol and phosphatidylethanolamine plasmalogen species) were altered in healthy brain tissue treated with TMZ. To better understand these changes, we interrogated RNA expression and DNA methylation datasets of the Cancer Genome Atlas database. The results enabled GBM subtypes and patient survival to be linked with the expression of enzymes accounting for the observed lipidome, thus proving that exploring the lipid changes could reveal promising therapeutic approaches for GBM, and ways to ameliorate TMZ side effects.

Olfactory Neuroblastoma Re-Evaluating the Paradigm of Intracranial Extension and Cyst Formation.

The purpose of the current study was to assess the prevalence of cyst formation at the brain-tumor interface in olfactory neuroblastoma. We used the UCLA patient-based Pathology and Radiology Head and Neck Database (UPPR HAND) to identify the largest patient cohort reported to date with imaging and pathology data. Eighteen of thirty-one patients (58.1%) had evidence of intracranial extension on MRI, while four (22.0%) demonstrated cyst formation at the brain-tumor interface. The extent of intracranial extension was by far the strongest predictor for intracranial cyst formation, regardless of Hyams tumor grade, using a binary logistics regression model (

Multichamber Involvement of Metastatic Cardiac Melanoma.

A 30-year-old man with a history of an in-situ melanoma of the forehead was referred for cardiac evaluation because of tachycardia and elevated levels of serum troponin. The transthoracic echocardiogram revealed multiple masses attached to the walls of both ventricles and the right atrium (RA). A large mass was occupying almost one third of the right ventricle (RV), resulting in reduction of the end-diastolic RV volume and tachycardia. A cardiac magnetic resonance imaging confirmed multifocal myocardial infiltration and intracavitary masses and excluded the presence of thrombus in any of the cardiac chambers. Diffuse metastatic involvement in the liver, the spleen, and the brain by computed tomography precluded surgical management. Being BRAF-unmutated, the patient was initially treated with a combination of nivolumab and ipilimumab. One month later, the cardiac metastases in RA and left ventricle were unchanged on echocardiogram, while the tumor in RV was enlarged occupying the majority of the chamber, resulting in further reduction of the cardiac output and tachycardia. The treatment was changed to a combination of dacarbazine and carboplatin, but the patient eventually died two months later. Heart is not a common metastatic site of melanoma and cardiac involvement is usually clinically silent making ante mortem diagnosis difficult. Multimodalidy imaging plays a pivotal role in the diagnostic work up. Cardiac melanoma metastases indicate an advance stage disease with poor prognosis.

Screening the Significant Hub Genes by Comparing Tumor Cells, Normoxic and Hypoxic Glioblastoma Stem-like Cell Lines Using Co-Expression Analysis in Glioblastoma.

Glioblastoma multiforme (GBM) is categorized by rapid malignant cellular growth in the central nervous system (CNS) tumors. It is one of the most prevailing primary brain tumors, particularly in human male adults. Even though the combination therapy comprises surgery, chemotherapy, and adjuvant therapies, the survival rate is on average 14.6 months. Glioma stem cells (GSCs) have key roles in tumorigenesis, progression, and counteracting chemotherapy and radiotherapy. In our study, firstly, the gene expression dataset GSE45117 was retrieved and differentially expressed genes (DEGs) were spotted. The co-expression network analysis was employed on DEGs to find the significant modules. The most significant module resulting from co-expression analysis was the turquoise module. The turquoise module related to the tumor cells, hypoxia, normoxic treatments of glioblastoma tumor (GBT), and GSCs were screened. Sixty-one common genes in the turquoise module were selected generated through the co-expression analysis and protein-protein interaction (PPI) network. Moreover, the GO and KEGG pathway enrichment results were studied. Twenty common hub genes were screened by the NetworkAnalyst web instrument constructed on the PPI network through the STRING database. After survival analysis via the Kaplan-Meier (KM) plotter from The Cancer Genome Atlas (TCGA) database, we identified the five most significant hub genes strongly related to the progression of GBM. We further observed these five most significant hub genes also up-regulated in another GBM gene expression dataset. The protein-protein interaction (PPI) network of the turquoise module genes was constructed and a KEGG pathway enrichments study of the turquoise module genes was performed. The VEGF signaling pathway was emphasized because of the strong link with GBM. A gene-disease association network was further constructed to demonstrate the information of the progression of GBM and other related brain neoplasms. All hub genes assessed through this study would be potential markers for the prognosis and diagnosis of GBM.

Alternative Promoters of

The ionotropic glutamate receptor 6 (

Tumor Heterogeneity and Molecular Characteristics of Glioblastoma Revealed by Single-Cell RNA-Seq Data Analysis.

Glioblastoma multiforme (GBM) is the most common infiltrating lethal tumor of the brain. Tumor heterogeneity and the precise characterization of GBM remain challenging, and the disease-specific and effective biomarkers are not available at present. To understand GBM heterogeneity and the disease prognosis mechanism, we carried out a single-cell transcriptome data analysis of 3389 cells from four primary IDH-WT (isocitrate dehydrogenase wild type) glioblastoma patients and compared the characteristic features of the tumor and periphery cells. We observed that the marker gene expression profiles of different cell types and the copy number variations (CNVs) are heterogeneous in the GBM samples. Further, we have identified 94 differentially expressed genes (DEGs) between tumor and periphery cells. We constructed a tissue-specific co-expression network and protein-protein interaction network for the DEGs and identified several hub genes, including

Brain Vascular Microenvironments in Cancer Metastasis.

Primary tumours, particularly from major solid organs, are able to disseminate into the blood and lymphatic system and spread to distant sites. These secondary metastases to other major organs are the most lethal aspect of cancer, accounting for the majority of cancer deaths. The brain is a frequent site of metastasis, and brain metastases are often fatal due to the critical role of the nervous system and the limited options for treatment, including surgery. This creates a need to further understand the complex cell and molecular biology associated with the establishment of brain metastasis, including the changes to the environment of the brain to enable the arrival and growth of tumour cells. Local changes in the vascular network, immune system and stromal components all have the potential to recruit and foster metastatic tumour cells. This review summarises our current understanding of brain vascular microenvironments, fluid circulation and drainage in the context of brain metastases, as well as commenting on current cutting-edge experimental approaches used to investigate changes in vascular environments and alterations in specialised subsets of blood and lymphatic vessel cells during cancer spread to the brain.

Glioblastoma in the Elderly Review of Molecular and Therapeutic Aspects.

Glioblastoma (GBM) is the most aggressive primary brain tumour. As GBM incidence is associated with age, elderly people represent a consistent subgroup of patients. Elderly people with GBM show dismal prognosis (about 6 months) and limited response to treatments. Age is a negative prognostic factor, which correlates with clinical frailty, poorer tolerability to surgery or adjuvant radio-chemotherapy, and higher occurrence of comorbidities andor secondary complications. The aim of this paper is to review the clinical and molecular characteristics, current therapeutic options, and prognostic factors of elderly patients with GBM.

Mechanisms of Cell Cycle Arrest and Apoptosis in Glioblastoma.

Cells of glioblastoma, the most frequent primary malignant brain tumor, are characterized by their rapid growth and infiltration of adjacent healthy brain parenchyma, which reflects their aggressive biological behavior. In order to maintain their excessive proliferation and invasion, glioblastomas exploit the innate biological capacities of the patients suffering from this tumor. The pathways involved in cell cycle regulation and apoptosis are the mechanisms most commonly affected. The following work reviews the regulatory pathways of cell growth in general as well as the dysregulated cell cycle and apoptosis relevant mechanisms observed in glioblastomas. We then describe the molecular targeting of the current established adjuvant therapy and present ongoing trials or completed studies on specific promising therapeutic agents that induce cell cycle arrest and apoptosis of glioblastoma cells.

Imaging Cancer-Associated Fibroblasts (CAFs) with FAPi PET.

The tumor microenvironment (TME) surrounding tumor cells is a complex and highly dynamic system that promotes tumorigenesis. Cancer-associated fibroblasts (CAFs) are key elements in TME playing a pivotal role in cancer cells proliferation and metastatic spreading. Considering the high expression of the fibroblast activation protein (FAP) on the cell membrane, CAFs emerged as appealing TME targets, namely for molecular imaging, leading to a pan-tumoral approach. Therefore, FAP inhibitors (FAPis) have recently been developed for PET imaging and radioligand therapy, exploring the clinical application in different tumor sub-types. The present review aimed to describe recent developments regarding radiolabeled FAP inhibitors and evaluate the possible translation of this pan-tumoral approach in clinical practice. At present, the application of FAPi-PET has been explored mainly in single-center studies, generally performed in small and heterogeneous cohorts of oncological patients. However, preliminary results were promising, in particular in low FDG-avid tumors, such as primary liver and gastro-entero-pancreatic cancer, or in regions with an unfavorable tumor-to-background ratio at FDG-PETCT (i.e., brain), and in radiotherapy planning of head and neck tumors. Further promising results have been obtained in the detection of peritoneal carcinomatosis, especially in ovarian and gastric cancer. Data regarding the theranostics approach are still limited at present, and definitive conclusions about its efficacy cannot be drawn at present. Nevertheless, the use of FAPi-based radio-ligand to treat the TME has been evaluated in first-in-human studies and appears feasible. Although the pan-tumoral approach in molecular imaging showed promising results, its real impact in day-to-day clinical practice has yet to be confirmed, and multi-center prospective studies powered for efficacy are needed.

Curcumin Suppresses Lead-Induced Inflammation and Memory Loss in Mouse Model and In Silico Molecular Docking.

This study examined the efficacy of curcumin (Cur) against lead (Pb)-induced oxidative damage, inflammation, and cholinergic dysfunction. Institute for Cancer Research (ICR) mice received Pb (II) acetate in drinking water (1%) with or without Cur via oral gavage. Blood and brain tissues were collected for investigation. Pb increased the inflammatory markers and oxidative parameters, which were ameliorated by Cur administration. Cur treatment also improved memory loss, learning deficit, and cholinergic dysfunction via elevating acetylcholinesterase (AChE) enzymatic activity and protein expression. In silico molecular docking supported the results Cur had a potent binding affinity for AChE receptors, tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2), phosphorylations of IκB kinase (IKK), extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (p38). According to the chemical absorption, distribution, metabolism, excretion, and toxicity (ADMET) profile, Cur could serve as a potential candidate for Pb detoxication substance via exerting antioxidant activity. Taken together, our results suggest that Cur is a natural compound that could be used for the treatment of neurodegenerative disorders via suppressing lead-induced neurotoxicity.

A Novel MRI Diagnosis Method for Brain Tumor Classification Based on CNN and Bayesian Optimization.

Brain tumor is one of the most aggressive diseases nowadays, resulting in a very short life span if it is diagnosed at an advanced stage. The treatment planning phase is thus essential for enhancing the quality of life for patients. The use of Magnetic Resonance Imaging (MRI) in the diagnosis of brain tumors is extremely widespread, but the manual interpretation of large amounts of images requires considerable effort and is prone to human errors. Hence, an automated method is necessary to identify the most common brain tumors. Convolutional Neural Network (CNN) architectures are successful in image classification due to their high layer count, which enables them to conceive the features effectively on their own. The tuning of CNN hyperparameters is critical in every dataset since it has a significant impact on the efficiency of the training model. Given the high dimensionality and complexity of the data, manual hyperparameter tuning would take an inordinate amount of time, with the possibility of failing to identify the optimal hyperparameters. In this paper, we proposed a Bayesian Optimization-based efficient hyperparameter optimization technique for CNN. This method was evaluated by classifying 3064 T-1-weighted CE-MRI images into three types of brain tumors (Glioma, Meningioma, and Pituitary). Based on Transfer Learning, the performance of five well-recognized deep pre-trained models is compared with that of the optimized CNN. After using Bayesian Optimization, our CNN was able to attain 98.70% validation accuracy at best without data augmentation or cropping lesion techniques, while VGG16, VGG19, ResNet50, InceptionV3, and DenseNet201 achieved 97.08%, 96.43%, 89.29%, 92.86%, and 94.81% validation accuracy, respectively. Moreover, the proposed model outperforms state-of-the-art methods on the CE-MRI dataset, demonstrating the feasibility of automating hyperparameter optimization.

Selective Targeting of Protein Kinase C (PKC)-θ Nuclear Translocation Reduces Mesenchymal Gene Signatures and Reinvigorates Dysfunctional CD8

Protein kinase C (PKC)-θ is a serinethreonine kinase with both cytoplasmic and nuclear functions. Nuclear chromatin-associated PKC-θ (nPKC-θ) is increasingly recognized to be pathogenic in cancer, whereas its cytoplasmic signaling is restricted to normal T-cell function. Here we show that nPKC-θ is enriched in circulating tumor cells (CTCs) in patients with triple-negative breast cancer (TNBC) brain metastases and immunotherapy-resistant metastatic melanoma and is associated with poor survival in immunotherapy-resistant disease. To target nPKC-θ, we designed a novel PKC-θ peptide inhibitor (nPKC-θi2) that selectively inhibits nPKC-θ nuclear translocation but not PKC-θ signaling in healthy T cells. Targeting nPKC-θ reduced mesenchymal cancer stem cell signatures in immunotherapy-resistant CTCs and TNBC xenografts. PKC-θ was also enriched in the nuclei of CD8

Benchmarking Safety Indicators of Surgical Treatment of Brain Metastases Combined with Intraoperative Radiotherapy Results of Prospective Observational Study with Comparative Matched-Pair Analysis.

Intraoperative radiotherapy (IORT) of the operative cavity for surgically treated brain metastasis (BM) has gained increasing prominence with respect to improved local tumor control. However, IORT immediately performed at the time of surgery might be associated with increased levels of perioperative adverse events (PAEs). In the present study, we performed safety metric profiling in patients who had undergone surgery for BM with and without IORT in order to comparatively analyze feasibility of IORT as an adjuvant radiation approach. Between November 2020 and October 2021, 35 patients were surgically treated for BM with IORT at our neuro-oncological center. Perioperative complication profiles were collected in a prospective observational cohort study by means of patient safety indicators (PSIs), hospital-acquired conditions (HACs), and specific cranial-surgery-related complications (CSCs) as high-standard quality metric tools and compared to those of an institutional cohort of 388 patients with BM resection without IORT in a balanced comparative matched-pair analysis. Overall, 4 out of 35 patients (11%) with IORT in the course BM resection suffered from PAEs, accounting for 3 PSIs (9%) and 1 HAC (3%). Balanced matched-pair analysis did not reveal significant differences in the perioperative complication profiles between the cohorts of patients with and without IORT (

Ion Channel Drugs Suppress Cancer Phenotype in NG108-15 and U87 Cells Toward Novel Electroceuticals for Glioblastoma.

Glioblastoma is a lethal brain cancer that commonly recurs after tumor resection and chemotherapy treatment. Depolarized resting membrane potentials and an acidic intertumoral extracellular pH have been associated with a proliferative state and drug resistance, suggesting that forced hyperpolarization and disruption of proton pumps in the plasma membrane could be a successful strategy for targeting glioblastoma overgrowth. We screened 47 compounds and compound combinations, most of which were ion-modulating, at different concentrations in the NG108-15 rodent neuroblastomaglioma cell line. A subset of these were tested in the U87 human glioblastoma cell line. A FUCCI cell cycle reporter was stably integrated into both cell lines to monitor proliferation and cell cycle response. Immunocytochemistry, electrophysiology, and a panel of physiological dyes reporting voltage, calcium, and pH were used to characterize responses. The most effective treatments on proliferation in U87 cells were combinations of NS1643 and pantoprazole retigabine and pantoprazole and pantoprazole or NS1643 with temozolomide. Marker analysis and physiological dye signatures suggest that exposure to bioelectric drugs significantly reduces proliferation, makes the cells senescent, and promotes differentiation. These results, along with the observed low toxicity in human neurons, show the high efficacy of electroceuticals utilizing combinations of repurposed FDA approved drugs.

Tumor Connectomics Mapping the Intra-Tumoral Complex Interaction Network Using Machine Learning.

The high-level relationships that form complex networks within tumors and between surrounding tissue is challenging and not fully understood. To better understand these tumoral networks, we developed a tumor connectomics framework (TCF) based on graph theory with machine learning to model the complex interactions within and around the tumor microenvironment that are detectable on imaging. The TCF characterization model was tested with independent datasets of breast, brain, and prostate lesions with corresponding validation datasets in breast and brain cancer. The TCF network connections were modeled using graph metrics of centrality, average path length (APL), and clustering from multiparametric MRI with IsoSVM. The Matthews Correlation Coefficient (MCC), Area Under the Curve-ROC, and Precision-Recall (AUC-ROC and AUC-PR) were used for statistical analysis. The TCF classified the breast and brain tumor cohorts with an IsoSVM AUC-PR and MCC of 0.86, 0.63 and 0.85, 0.65, respectively. The TCF benign breast lesions had a significantly higher clustering coefficient and degree centrality than malignant TCFs. Grade 2 brain tumors demonstrated higher connectivity compared to Grade 4 tumors with increased degree centrality and clustering coefficients. Gleason 7 prostate lesions had increased betweenness centrality and APL compared to Gleason 6 lesions with AUC-PR and MCC ranging from 0.90 to 0.99 and 0.73 to 0.87, respectively. These TCF findings were similar in the validation breast and brain datasets. In conclusion, we present a new method for tumor characterization and visualization that results in a better understanding of the global and regional connections within the lesion and surrounding tissue.

Efficient Radiomics-Based Classification of Multi-Parametric MR Images to Identify Volumetric Habitats and Signatures in Glioblastoma A Machine Learning Approach.

Glioblastoma (GBM) is a fast-growing and aggressive brain tumor of the central nervous system. It encroaches on brain tissue with heterogeneous regions of a necrotic core, solid part, peritumoral tissue, and edema. This study provided qualitative image interpretation in GBM subregions and radiomics features in quantitative usage of image analysis, as well as ratios of these tumor components. The aim of this study was to assess the potential of multi-parametric MR fingerprinting with volumetric tumor phenotype and radiomic features to underlie biological process and prognostic status of patients with cerebral gliomas. Based on efficiently classified and retrieved cerebral multi-parametric MRI, all data were analyzed to derive volume-based data of the entire tumor from local cohorts and The Cancer Imaging Archive (TCIA) cohorts with GBM. Edema was mainly enriched for homeostasis whereas necrosis was associated with texture features. The proportional volume size of the edema was about 1.5 times larger than the size of the solid part tumor. The volume size of the solid part was approximately 0.7 times in the necrosis area. Therefore, the multi-parametric MRI-based radiomics model reveals efficiently classified tumor subregions of GBM and suggests that prognostic radiomic features from routine MRI examination may also be significantly associated with key biological processes as a practical imaging biomarker.

Correlation of Intraoperative 5-ALA-Induced Fluorescence Intensity and Preoperative

5-Aminolevulinic acid (5-ALA) is widely employed to assist fluorescence-guided surgery for malignant brain tumors. Positron emission tomography with Adult patients with supratentorial astrocytic gliomas who underwent preoperative MET-PET and surgical tumor resection using 5-ALA were enrolled in this prospective study. The regional tumor uptake of MET-PET was expressed as the ratio of standardized uptake volume max to that of the normal contralateral frontal lobe. A spectrometric fluorescence detection system measured tumor specimens ex vivo fluorescence intensity at 635 nm. Ki-67 index and IDH mutation status were assessed by histopathological analysis. Use of an antiepileptic drug (AED) and contrast enhancement pattern on MRI were also investigated. Thirty-two patients, mostly with Glioblastoma IDH wild type (46.9%) and anaplastic astrocytoma IDH mutant (21.9%), were analyzed. When the fluorescence intensity was ranked into four groups, the strongest fluorescence group exhibited the highest mean MET-PET uptake and Ki-67 index values. When rearranged into fluorescence Visible or Non-visible groups, the Visible group had significantly higher MET-PET uptake and Ki-67 index compared to the Non-visible group. Contrast enhancement on MRI and IDH wild type tumors were more frequent among the Visible group. AED use did not correlate with 5-ALA-induced fluorescence intensity. In astrocytic glioma surgery, visible 5-ALA-induced fluorescence correlated with high MET-PET uptake, along with a high Ki-67 index.

Hemodynamic Imaging in Cerebral Diffuse Glioma-Part A Concept, Differential Diagnosis and Tumor Grading.

Diffuse gliomas are the most common primary malignant intracranial neoplasms. Aside from the challenges pertaining to their treatment-glioblastomas, in particular, have a dismal prognosis and are currently incurable-their pre-operative assessment using standard neuroimaging has several drawbacks, including broad differentials diagnosis, imprecise characterization of tumor subtype and definition of its infiltration in the surrounding brain parenchyma for accurate resection planning. As the pathophysiological alterations of tumor tissue are tightly linked to an aberrant vascularization, advanced hemodynamic imaging, in addition to other innovative approaches, has attracted considerable interest as a means to improve diffuse glioma characterization. In the present part A of our two-review series, the fundamental concepts, techniques and parameters of hemodynamic imaging are discussed in conjunction with their potential role in the differential diagnosis and grading of diffuse gliomas. In particular, recent evidence on dynamic susceptibility contrast, dynamic contrast-enhanced and arterial spin labeling magnetic resonance imaging are reviewed together with perfusion-computed tomography. While these techniques have provided encouraging results in terms of their sensitivity and specificity, the limitations deriving from a lack of standardized acquisition and processing have prevented their widespread clinical adoption, with current efforts aimed at overcoming the existing barriers.

Occurrence of Total and Proteinase K-Resistant Alpha-Synuclein in Glioblastoma Cells Depends on mTOR Activity.

Alpha-synuclein (α-syn) is a protein considered to be detrimental in a number of degenerative disorders (synucleinopathies) of which α-syn aggregates are considered a pathological hallmark. The clearance of α-syn strongly depends on autophagy, which can be stimulated by inhibiting the mechanistic target of rapamycin (mTOR). Thus, the overexpression of mTOR and severe autophagy suppression may produce α-syn accumulation, including the proteinase K-resistant protein isoform. Glioblastoma multiforme (GBM) is a lethal brain tumor that features mTOR overexpression and severe autophagy inhibition. Cell pathology in GBM is reminiscent of a fast, progressive degenerative disorder. Therefore, the present work questions whether, as is analogous to neurons during degenerative disorders, an overexpression of α-syn occurs within GBM cells. A high amount of α-syn was documented in GBM cells via real-time PCR (RT-PCR), Western blotting, immunohistochemistry, immuno-fluorescence, and ultrastructural stoichiometry, compared with the amount of β- and γ-synucleins and compared with the amount of α-syn counted within astrocytes. The present study indicates that (i) α-syn is overexpressed in GBM cells, (ii) α-syn expression includes a proteinase-K resistant isoform, (iii) α-syn is dispersed from autophagy-like vacuoles to the cytosol, (iv) α-syn overexpression and cytosol dispersion are mitigated by rapamycin, and (v) the α-syn-related GBM-like phenotype is mitigated by silencing the SNCA gene.

PD-L1miR-155 Interplay in Pediatric High-Grade Glioma.

High-grade pediatric glioma (p-HGG-WHO 2021, formerly GBM-WHO 2016), as a common, aggressive, and highly lethal primary brain malignancy in adults, accounts for only 3-15% of primary brain tumors in pediatric patients. After leukemia, brain malignancies are the second most common in the pediatric population and first in incidences concerning solid tumors. This study was designed on the basis of 14 pediatric patients hospitalized at Childrens Memorial Health Institute in Warsaw, Poland, due to p-HGG treatment. All the patients had a histopathological diagnosis performed by an experienced neuropathologist according to WHO guidelines (WHO 2016 Grade IV Glioblastoma). A significant correlation was found between the miR-155 concentration and the level of PD-L1 expression in p-HGG tumor tissue. Very few reports have indicated PD-L1 expression in pediatric patients.

Curious case of bilateral non-resolving vitritis - Unmasking the masquerade on ultra-widefield imaging.

Recognizing vitreous haze (VH) patterns on ultra-widefield imaging (UWFI) in nonresolving vitritis can reduce delay in suspecting vitreoretinal lymphoma (VRL) and in performing an early vitreous biopsy for definitive diagnosis. To demonstrate role of UWFI in providing a clue for suspecting VRL in case of bilateral nonresolving dense vitritis and demonstrate precautions for high yield of lymphoma cells on vitreous biopsy. A 52-year-old healthy phakic lady came with gradual, painless blurred vision OS>OD for 6 months. Treated elsewhere for OU vitritis with steroids (local and systemic), anti-tubercular therapy for 2 months, and azathioprine, she had no improvement. Presenting best-corrected visual acuty was counting fingers OD and hand movement OS. Anterior segment OU was quiet. Fundus showed OD 3 and OS 4 vireous haze (VH). UWFI showed aurora borealis pattern of VH (OS>OD) and string of pearls OD. Ultrasonography B-scan OU showed complete posterior vitreous detachment and attached retina. OU VRL was suspected. MRI brain and orbit with contrast was found to be normal. After stopping steroids for 2 weeks, OS underwent pars plana vitrectomy (PPV) and intravitreal (IV) methotrexate 400 mcg0.1 ml rituximab 1mg0.1ml. Vitreous sample sent for cytology and immunohistochemistry showed diffuse large B-cell non-Hodgkins lymphoma with CD20 and MUM1-positive cells. OD underwent two IV rituximab injections at monthly interval initially followed by PPV with IV rituximab and methotrexate. The patient remained in remission during close follow-up. Recognizing VH patterns on UWFI can reduce the delay in the diagnosis of VRL and early initiation of treatment. VH patterns in VRL depend on state of vitreous liquefaction and syneresis. Aurora borealis pattern on UWFI results from linear opacities with lymphoma cells uniformly aligned along formed vitreous fibrils. String of pearls pattern results from clumps of lymphoma cells and inflammatory material over the scaffold of vitreous fibrils. These patterns provide high index of suspicion for considering VRL as d iagnosis.IV rituximab has minimal side effects and has been effective in managing VRL with isolated ocular involvement. httpsyoutu.beuTplGPStmrM.

Effects of statins on mortality and neurologic outcomes in patients with traumatic brain injury a meta-analysis.

Analysis and management of delayed cerebrospinal fluid rhinorrhea after invasive pituitary adenoma surgery.

Cinnamic Acid Improved Lipopolysaccharide-Induced Depressive-Like Behaviors by Inhibiting Neuroinflammation and Oxidative Stress in Mice.

Recent evidence indicates that neuroinflammation and oxidative stress play vital roles in the pathological process of major depressive disorder (MDD). Cinnamic acid (CA), a naturally occurring organic acid, has been reported to ameliorate neuroinflammation and oxidative stress for treatment of diabetes-related memory deficits. Here, we explored whether CA pretreatment ameliorated lipopolysaccharide (LPS)-induced depressive-like behaviors in mice by suppressing neuroinflammation and by improving oxidative stress status. The mice were treated with CA, vehicle, or fluoxetine as a positive control. After 14 days, LPS (1 mgkg, i.p.) or saline was administered. The depression-like behaviors were examined by the sucrose preference test (SPT), the forced swimming test (FST), and the tail suspension test (TST). Furthermore, the levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), superoxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA), and brain-derived neurotrophic factor (BDNF) in the hippocampus and cortex of mice were assayed. Our results demonstrated that CA pretreatment at the doses of 100 and 200 mgkg significantly attenuated depressive-like behaviors in the TST, FST, and SPT. In addition, not only the upregulation of pro-inflammatory cytokines (IL-6 and TNF-α) but also oxidative stress parameters including SOD, GSH, and MDA in the hippocampus and cortex of mice treated with LPS were dramatically improved by CA pretreatment. Finally, CA pretreatment strikingly ameliorated the downregulation of BDNF induced by LPS in the hippocampus and cortex of mice. Our results indicated that CA may have therapeutic potential for MDD treatment through attenuating the LPS-induced inflammation and oxidative stress along with significant improvement of BDNF impairment.

Cranial transposition and revascularization of autologous omentum a novel surgical technique for resection of recurrent glioblastoma multiforme.

Glioblastoma multiforme (GBM) patients continue to suffer a poor prognosis. The blood brain barrier (BBB) comprises one of the obstacles for therapy, creating a barrier that decreases the bioavailability of chemotherapeutic agents in the central nervous system. Previously, a vascularized temporoparietal fascial scalp flap (TPFF) lining the resection cavity was introduced in a trial conducted in our institution, in newly-diagnosed GBM patients in an attempt to bypass the BBB after initial resection. In this paper, we report on a new technique to bypass the BBB after re-resection and potentially to allow tumor antigens to be surveilled by the immune system. The study aims to assess the feasibility of performing a cranial transposition and revascularization of autologous omentum after re-resection of GBM. Laparoscopically harvested omental free flap was transposed to the resection cavity by a team consisting of neurosurgeons, otolaryngologists, and general surgeons. This was done as part of a single center, single arm, open-label, phase I study. Autologous abdominal omental tissue was harvested laparoscopically on its vascularized pedicle in 2 patients, transposed as a free flap, revascularized using external carotid artery, and carefully laid into the tumor resection cavity. Patients did well postoperatively returning to baseline activities. Graft viability was confirmed by cerebral angiogram. Omental cranial transposition of a laparoscopically harvested, vascularized flap, into the cavity of re-resected GBM patients is feasible and safe in the short term. Further studies are needed to ascertain whether such technique can improve progression free survival and overall survival in these patients.

T lymphocytes as dynamic regulators of glioma pathobiology.

The brain tumor microenvironment contains numerous distinct types of nonneoplastic cells, which each serve a diverse set of roles relevant to the formation, maintenance, and progression of these central nervous system cancers. While varying in frequencies, monocytes (macrophages, microglia, and myeloid-derived suppressor cells), dendritic cells, natural killer cells, and T lymphocytes represent the most common nonneoplastic cellular constituents in low- and high-grade gliomas (astrocytomas). Although T cells are conventionally thought to target and eliminate neoplastic cells, T cells also exist in other states, characterized by tolerance, ignorance, anergy, and exhaustion. In addition, T cells can function as drivers of brain cancer growth, especially in low-grade gliomas. Since T cells originate in the blood and bone marrow sinuses, their capacity to function as both positive and negative regulators of glioma growth has ignited renewed interest in their deployment as immunotherapeutic agents. In this review, we discuss the roles of T cells in low- and high-grade glioma formation and progression, as well as the potential uses of modified T lymphocytes for brain cancer therapeutics.

The Establishment of a Noninvasive Bioluminescence-Specific Viral Encephalitis Model by Pseudorabies Virus-Infected NF-κBp-Luciferase Mice.

Encephalitis is a rare brain inflammation that is most commonly caused by a viral infection. In this study, we first use an in vivo imaging system (IVIS) to determine whether NF-κBp-luciferase expression could be detected in the brain of pseudorabies virus (PRV)-infected NF-κBp-luciferase mice and to evaluate proinflammatory mediators in a well-described mouse model of PRV encephalitis. In in vitro studies, we used murine microglia (BV-2) cells to demonstrate the PRV-induced encephalitis model entailing the activation of microglia cells. The results indicate that PRV-induced neuroinflammation responses through the induction of IL-6, TNF-α, COX-2, and iNOS expression occurred via the regulation of NF-κB expression in BV-2 cells. In in vivo studies, compared with MOCK controls, the mice infected with neurovirulent PRV exhibited significantly elevated NF-κB transcription factor activity and luciferase protein expression only in the brain by IVIS. Mild focal necrosis was also observed in the brain. Further examination revealed biomarkers of inflammation, including inducible cyclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS), and tumor necrosis factor (TNF)-α and interleukin (IL)-6, both of which constituted proinflammatory cytokines. PRV infection stimulated inflammation and COX-2 and iNOS expression of IL-6 and TNF-α. The presented results herein suggest that PRV induces iNOS and COX-2 expression in the brain of NF-κBp-luciferase mice via NF-κB activation. In conclusion, we used NF-κBp-luciferase mice to establish a specific virus-induced encephalitis model via PRV intranasal infection. In the future, this in vivo model will provide potential targets for the development of new therapeutic strategies focusing on NF-κB inflammatory biomarkers and the development of drugs for viral inflammatory diseases.

The Combined Use of 5-ALA and Chlorin e6 Photosensitizers for Fluorescence-Guided Resection and Photodynamic Therapy under Neurophysiological Control for Recurrent Glioblastoma in the Functional Motor Area after Ineffective Use of 5-ALA Preliminary Results.

The treatment of glial brain tumors is an unresolved problem in neurooncology, and all existing methods (tumor resection, chemotherapy, radiotherapy, radiosurgery, fluorescence diagnostics, photodynamic therapy, etc.) are directed toward increasing progression-free survival for patients. Fluorescence diagnostics and photodynamic therapy are promising methods for achieving gross total resection and additional treatment of residual parts of the tumor. However, sometimes the use of one photosensitizer for photodynamic therapy does not help, and the time until tumor relapse barely increases. This translational case report describes the preliminary results of the first combined use of 5-ALA and chlorin e6 photosensitizers for fluorescence-guided resection and photodynamic therapy of glioblastoma, which allowed us to perform total resection of tumor tissue according to magnetic resonance and computed tomography images, remove additional tissue with increased fluorescence intensity without neurophysiological consequences, and perform additional therapy. Two months after surgery, no recurrent tumor and no contrast uptake in the tumor bed were detected. Additionally, the patient had ischemic changes in the access zone and along the periphery and cystic-glial changes in the left parietal lobe.

LncRNA BBOX1-AS1 promotes pituitary adenoma progression via sponging miR-361-3pE2F1 axis.

Pituitary adenoma is one of the most common intracranial tumors, more and more studies have shown that long non-coding RNA (lncRNA) plays a very important role in pituitary adenoma. However, there are few reports on the function of lncRNA BBOX1-AS1 in pituitary adenomas, and further exploration is needed. The objective of this research is to figure out what function BBOX1-AS1 plays in pituitary adenoma and how it regulates it. The expression of the E2F1, miR-361-3p and BOX1-AS1 genes was measured using a quantitative real-time PCR method. The functional involvement of BBOX1-AS1 in pituitary adenoma was examined utilizing the Transwell assay, western blot assays and the cell counting kit-8. RNA immunoprecipitation and luciferase reporter assays revealed that miR-361-3p binds to E2F1 or BBOX1-AS1. In addition, in-vivo assays were carried out. The expression of BBOX1-AS1 in pituitary adenoma tissues and cells has been increased, according to our findings. Furthermore, it is also noted that downregulation of BBOX1-AS1causes the inhibition of pituitary adenoma cells which result in invasion, apoptosis and proliferation, as well as boosting tumor development in vivo . In addition, BBOX1-AS1 knockdown inhibited tumor development in vivo . We identify BBOX1-AS1 bind to miR-361-3p and to suppress its expression in a negative way. Moreover, miR-361-3p has been shown to bind with E2F1 and inhibit its expression. E2F1 also corrected miR-361-3p-mediated cell invasion, proliferation and apoptosis in BBOX1-AS1-dysregulated pituitary adenoma cells in rescue tests. BBOX1-AS1 increases pituitary adenoma malignant activity by sponging miR-361-3p to upregulate E2F1 expression, which may lead to a new path in pituitary adenoma therapeutic attempts.

Oophorectomy improves pituitary activin inhibitory function preventing lactotroph hyperplasia development.

Among pituitary adenomas, prolactinomas are the most frequently diagnosed (about 50%). Dopamine agonists are generally effective in the treatment of prolactinomas. However, a subset of about 25% of patients does not respond to these agents. The management of drug-resistant prolactinomas remains a challenge for endocrinologists and new inhibitory treatments are needed. Pituitary activins inhibit lactotroph function. Its expression and action were found reduced in animal models of lactotroph hyperplasia (female mice overexpressing the B subunit of the human chorionic gonadotrophin and female mice knockout for dopamine receptor type 2). In these models, an oophorectomy avoids prolactinoma development. Hormonal replacement with oestradiol andor progesterone is not enough to reach the tumor size observed in transgenic females. We postulated that the loss of gonadal inhibins after an oophorectomy contributes to prevent hyperplasia development. Here, we demonstrated that an oophorectomy at 2 months age recovers the following in adulthood (i) pituitary activin expression, (ii) activin receptor expression specifically in lactotroph population, (iii) activin biological activity in lactotrophs with a concomitant reduction of Pit-1 expression. To summarize, when an oophorectomy is performed, inhibins are lost and the inhibitory action of pituitary activins on lactotroph population is recovered, helping to prevent lactotroph hyperplasia development. These results emphasize the importance of the inhibitory action of activins on lactotroph function, positioning activins as a good therapeutic target for the treatment of resistant prolactinomas.

All-Around Real Label Supervision Cyclic Prototype Consistency Learning for Semi-Supervised Medical Image Segmentation.

Semi-supervised learning has substantially advanced medical image segmentation since it alleviates the heavy burden of acquiring the costly expert-examined annotations. Especially, the consistency-based approaches have attracted more attention for their superior performance, wherein the real labels are only utilized to supervise their paired images via supervised loss while the unlabeled images are exploited by enforcing the perturbation-based unsupervised consistency without explicit guidance from those real labels. However, intuitively, the expert-examined real labels contain more reliable supervision signals. Observing this, we ask an unexplored but interesting question can we exploit the unlabeled data via explicit real label supervision for semi-supervised training To this end, we discard the previous perturbation-based consistency but absorb the essence of non-parametric prototype learning. Based on the prototypical networks, we then propose a novel cyclic prototype consistency learning (CPCL) framework, which is constructed by a labeled-to-unlabeled (L2U) prototypical forward process and an unlabeled-to-labeled (U2L) backward process. Such two processes synergistically enhance the segmentation network by encouraging morediscriminative and compact features. In this way, our framework turns previous unsupervised consistency into new supervised consistency, obtaining the all-around real label supervision property of our method. Extensive experiments on brain tumor segmentation from MRI and kidney segmentation from CT images show that our CPCL can effectively exploit the unlabeled data and outperform other state-of-the-art semi-supervised medical image segmentation methods.

Cold Plasma Discharge Tube Enhances Antitumoral Efficacy of Temozolomide.

Glioblastoma (GBM) is a fatal human brain tumor with a low survival rate. Temozolomide (TMZ) has been widely used in GBM therapy with noticeable side effects. Cold plasma is an ionized gas that is generated near room temperature. Here, we demonstrated the enhancement therapeutic efficacy of TMZ via using a cold plasma source based on nonequilibrium plasma in a sealed glass tube, named a radial cold plasma discharge tube (PDT). The PDT affected glioblastoma cells function just by its electromagnetic (EM) emission rather than any chemical factors in the plasma. The PDT selectively increased the cytotoxicity of TMZ on two typical glioblastoma cell lines, U87MG and A172, compared with normal astrocyte cell line hTERTE6E7 to some extent. Furthermore, on the basis of a patient-derived xenograft model, our preliminary in vivo studies demonstrated the drastically improved mean survival days of the tumor-barrier mice by more than 100% compared to control. The PDT is not only independent of continuous helium supply but is also capable of resisting the interference of environmental changes. Thus, the PDT was a stable and low-cost cold atmospheric plasma source. In short, this study is the first to demonstrate the promising application of PDTs in GBM therapy as a noninvasive and portable modality.

MEN4, the MEN1 Mimicker A Case Series of three Phenotypically Heterogenous Patients With Unique CDKN1B Mutations.

Germline CDKN1B pathogenic variants result in multiple endocrine neoplasia type 4 (MEN4), an autosomal dominant hereditary tumor syndrome variably associated with primary hyperparathyroidism, pituitary adenoma, and duodenopancreatic neuroendocrine tumors. To report the phenotype of 3 unrelated cases each with a unique germline CDKN1B variant (of which 2 are novel) and compare these cases with those described in the current literature. Three case studies, including clinical presentation, germline, and tumor genetic analysis and family history. Two tertiary University Hospitals in Sydney, New South Wales, and 1 tertiary University Hospital in Canberra, Australian Capital Territory, Australia. Phenotype of the 3 cases and their kindred molecular analysis and tumor p27kip1 immunohistochemistry. Family A The proband developed multiglandular primary hyperparathyroidism, a microprolactinoma and a multifocal nonfunctioning duodenopancreatic neuroendocrine tumor. Family B The proband was diagnosed with primary hyperparathyroidism from a single parathyroid adenoma. Family C The proband was diagnosed with a nonfunctioning pituitary microadenoma and ectopic Cushings syndrome from an atypical thymic carcinoid tumor. Germline sequencing in each patient identified a unique variant in CDKN1B, 2 of which are novel (c.179G > A, p.Trp60 c.475G > A, p.Asp159Asn) and 1 previously reported (c.374375delCT, p.Ser125). Germline CDKN1B pathogenic variants cause the syndrome MEN4. The phenotype resulting from the 3 pathogenic variants described in this series highlights the heterogenous nature of this syndrome, ranging from isolated primary hyperparathyroidism to the full spectrum of endocrine manifestations. We report the first described cases of a prolactinoma and an atypical thymic carcinoid tumor in MEN4.

Brain Metastases among Cancer Patients Diagnosed from 2010-2017 in Canada Incidence Proportion at Diagnosis and Estimated Lifetime Incidence.

The incidence of BM among Canadian cancer patients is unknown. We aimed to estimate IP of BM at the time of cancer diagnosis and during the lifetime of patients with selected primary cancers. Data on BM at diagnosis from 2010-2017 was obtained from the CCR. Site-specific IPs of BM were estimated from provincial registries containing ≥90% complete data on BM. The CCR IP estimates and the IP estimates from literature were applied to the total diagnosed primary cancers to estimate the number of concurrent BM and lifetime BM from 2010-2017 in Canada, respectively. The annual average number of patients with BM at diagnosis from all cancer sites was approximately 3227. The site-specific IPs of BM at diagnosis were lung (9.42% 95% CI 9.16-9.68%), esophageal (1.58% 95% CI 1.15-2.02%), kidneyrenal pelvis (1.33% 95% CI 1.12-1.54%), skin melanoma (0.73% 95% CI 0.61-0.84%), colorectal (0.22% 95% CI 0.18-0.26%), and breast (0.21% 95% CI 0.17-0.24%). Approximately 76,546 lifetime BM cases (or 5.70% of selected fifteen primary cancers sites) were estimated to have occurred from the 2010-2017 cancer patient cohort. These findings reflect results of population analyses in the US and Denmark. We recommend improved standardization of the collection of BM data within the CCR.

Real-World Management and Outcomes of Crizotinib-Treated ROS1-Rearranged NSCLC A Retrospective Canadian Cohort.

The use, safety and effectiveness of crizotinib as part of the management of ROS1-rearranged NSCLC patients in a real-world Canadian clinical cohort was the focus of this retrospective review. Twenty-one ROS1-rearranged patients with advancedmetastatic disease receiving crizotinib between 2014-2020 were identified crizotinib demonstrated tolerability and effectiveness in this population where outcomes were similar to those described in other crizotinib-treated real-world cohorts, but lower than those of the PROFILE 1001 clinical trial population. Systemic anti-cancer therapy prior to crizotinib initiation occurred in half of the study cohort, with platin-pemetrexed and immune checkpoint inhibitors being most common. Platin-pemetrexed showed good effectiveness in this cohort, but despite high prevalence of upregulated PD-L1 expression, immune checkpoint inhibitors showed poor effectiveness in his cohort. Among all systemic therapies received, crizotinib showed the most effective disease control, although longer intervals between diagnosis and crizotinib initiation were more common among those showing a lack of clinical response to crizotinib, and patients with brain metastases at the time of crizotinib initiation also showed increased diagnosis to crizotinib initiation intervals and decreased clinical response to crizotinib. This study reveals crizotinib has clinical benefit, but timely identification of ROS1-rearrangements and initiation targeted therapies appears important to maximize outcome in this population.

Current Advances in the Management of Adult Craniopharyngiomas.

Craniopharyngiomas (CPs) are slow growing, histologically benign intracranial tumors located in the sellar-suprasellar region. Although known to have low mortality, their location and relationship to the adjacent neural structures results in patients having significant neurologic, endocrine, and visual comorbidities. The invasive nature of this tumor makes complete resection a challenge and contributes to its recurrence. Additionally, these tumors are bimodally distributed, being treated with surgery, and are followed by other adjuncts, such as focused radiation therapy, e.g., Gamma knife. Advances in surgical techniques, imaging tools, and instrumentations have resulted in the evolution of surgery using endoscopic techniques, with residual components being treated by radiotherapy to target the residual tumor. Advances in molecular biology have elucidated the main pathways involved in tumor development and recurrence, but presently, no other treatments are offered to patients, besides surgery, radiation, and endocrine management, as the disease and tumor evolve. We review the contemporary management of these tumors, from the evolution of surgical treatments, utilizing standard open microscopic approaches to the more recent endoscopic surgery, and discuss the current recommendations for care of these patients. We discuss the developments in radiation therapy, such as radiosurgery, being used as treatment strategies for craniopharyngioma, highlighting their beneficial effects on tumor resections while decreasing the rates of adverse outcomes. We also outline the recent chemotherapy modalities, which help control tumor growth, and the immune landscape on craniopharyngiomas that allow the development of novel immunotherapies.

The Role of Surgical Approaches in the Multi-Modal Management of Adult Craniopharyngiomas.

Craniopharyngiomas are rare, benign primary brain tumors that arise from remnants of the craniopharyngeal duct epithelium within the sellar and suprasellar region. Despite their benign biology, they may cause significant morbidity, secondary to involvement of nearby eloquent neural structures, such as the pituitary gland, hypothalamus, and optic apparatus. Historically, aggressive surgical resection was the treatment goal to minimize risk of tumor recurrence via open transcranial midline, anterolateral, and lateral approaches, but could lead to clinical sequela of visual, endocrine, and hypothalamic dysfunction. However, recent advances in the endoscopic endonasal approach over the last decade have mostly supplanted transcranial surgery as the optimal surgical approach for these tumors. With viable options for adjuvant radiation therapy, targeted medical treatment, and alternative minimally invasive surgical approaches, the management paradigm for craniopharyngiomas has shifted from aggressive open resection to more minimally invasive but maximally safe resection, emphasizing quality of life issues, particularly in regards to visual, endocrine, and hypothalamic function. This review provides an update on current multi-modal approaches for craniopharyngiomas, highlighting the modern surgical treatment paradigm for this disease entity.

Dextromethorphan reduces prenatal lipopolysaccharide exposure-induced dopaminergic neuronal loss and cytokine changes in offspring.

Maternal infection during pregnancy may affect fetal brain development and increase the risk of developing neurological and mental disorders later in life in offspring. In this study, we used low-dose lipopolysaccharide (LPS) injection to mimic mild maternal infection at a critical time window for fetal dopamine (DA) and serotonin (5-HT) neuron development. The affected offspring exhibited reduction of dopaminergic and serotonergic neurons and anxiety- and depression-related behaviors in adulthood. In the current study, we evaluated whether dextromethorphan (DM, 30 mgkg), an over-the-counter antitussive drug with anti-inflammatory and neuroprotective properties, could reduce the adverse effects of maternal infection mimicked by LPS exposure. We discovered that DM application did not change the baseline serum interleukin-6 (IL-6) and tumor necrosis factor α (TNFα) levels in the LPS-exposed offspring. However, DM treatment could reduce the heightened immune responses induced by a postnatal LPS challenge test in prenatal LPS-exposed offspring. The neuroprotective effect of DM was only seen in DA neurons but not in 5-HT neurons. We concluded that DM treatment can partially protect the offspring against the adverse effects of LPS-induced maternal immune activation. The reduction in heightened immune responses and dopaminergic neuronal loss in LPS-exposed offspring could potentially reduce the risk of DA-related neurological and psychiatric disorders later in life.

Long non-coding RNA H19 promotes leukocyte inflammation in ischemic stroke by targeting the miR-29bC1QTNF6 axis.

Inflammatory processes induced by leukocytes are crucially involved in the pathophysiology of acute ischemic stroke. This study aimed to elucidate the inflammatory mechanism of long non-coding RNA (lncRNA) H19-mediated regulation of C1q and tumor necrosis factor 6 (C1QTNF6) by sponging miR-29b in leukocytes during ischemic stroke. H19 and miR-29b expression in leukocytes of patients with ischemic stroke and rats with middle cerebral artery occlusion were measured by real-time polymerase chain reaction. H19 siRNA and miR-29b antagomir were used to knock down H19 and miR-29b, respectively. We performed in vivo and in vitro experiments to determine the impact of H19 and miR-29b on C1QTNF6 expression in leukocytes after ischemic injury. H19 and C1QTNF6 upregulation, as well as miR-29b downregulation, was detected in leukocytes of patients with stroke. Moreover, miR-29b could bind C1QTNF6 mRNA and repress its expression, while H19 could sponge miR-29b to maintain C1QTNF6 expression. C1QTNF6 overexpression promoted the release of IL-1β and TNF-α in leukocytes, further exacerbated blood-brain barrier disruption, and aggravated the cerebral ischemic injury. Our findings confirm that H19 promotes leukocyte inflammation by targeting the miR-29bC1QTNF6 axis in cerebral ischemic injury.

Endocannabinoid signaling in glioma.

High-grade gliomas constitute the most frequent and aggressive form of primary brain cancer in adults. These tumors express cannabinoid CB

Disruption of GMNC-MCIDAS multiciliogenesis program is critical in choroid plexus carcinoma development.

Multiciliated cells (MCCs) in the brain reside in the ependyma and the choroid plexus (CP) epithelia. The CP secretes cerebrospinal fluid that circulates within the ventricular system, driven by ependymal cilia movement. Tumors of the CP are rare primary brain neoplasms mostly found in children. CP tumors exist in three forms CP papilloma (CPP), atypical CPP, and CP carcinoma (CPC). Though CPP and atypical CPP are generally benign and can be resolved by surgery, CPC is a particularly aggressive and little understood cancer with a poor survival rate and a tendency for recurrence and metastasis. In contrast to MCCs in the CP epithelia, CPCs in humans are characterized by solitary cilia, frequent TP53 mutations, and disturbances to multiciliogenesis program directed by the GMNC-MCIDAS transcriptional network. GMNC and MCIDAS are early transcriptional regulators of MCC fate differentiation in diverse tissues. Consistently, components of the GMNC-MCIDAS transcriptional program are expressed during CP development and required for multiciliation in the CP, while CPC driven by deletion of Trp53 and Rb1 in mice exhibits multiciliation defects consequent to deficiencies in the GMNC-MCIDAS program. Previous studies revealed that abnormal NOTCH pathway activation leads to CPP. Here we show that combined defects in NOTCH and Sonic Hedgehog signaling in mice generates tumors that are similar to CPC in humans. NOTCH-driven CP tumors are monociliated, and disruption of the NOTCH complex restores multiciliation and decreases tumor growth. NOTCH suppresses multiciliation in tumor cells by inhibiting the expression of GMNC and MCIDAS, while Gmnc-Mcidas overexpression rescues multiciliation defects and suppresses tumor cell proliferation. Taken together, these findings indicate that reactivation of the GMNC-MCIDAS multiciliogenesis program is critical for inhibiting tumorigenesis in the CP, and it may have therapeutic implications for the treatment of CPC.

Efficacy of PD-1 Inhibitor Combined with Bevacizumab in Treatment of Advanced Endometrial Cancer Patients with Mismatch Repair Deficiency (dMMR)High-Level Microsatellite Instability (MSI-H).

BACKGROUND Mismatch repair deficiency (dMMR) is associated with endometrial cancers, yet it remains unknown how this information could be incorporated into adjuvant treatment paradigms. We performed this cohort study to identify the effect of dMMR status on the prognosis of patients with advanced endometrial cancer treated with PD-1 inhibitor and bevacizumab. MATERIAL AND METHODS We enrolled 93 patients with advanced endometrial cancer and divided them into an observation group (n52) and a control group (n41) according to the treatment. The control group was treated with bevacizumab combined with paclitaxel chemotherapy, while the observation group was treated with PD-1inhibitor combined with bevacizumab. The basic characteristics and overall survival times were compared between the 2 groups. RESULTS There was no significant difference in age, course of disease, clinical stage, or pathological type. The proportion of patients with dMMR and high-level microsatellite instability (MSI-H) were balanced in the 2 groups. Patients in the observation group had longer overall survival than those in the control group (33.2 months vs 21.8 months). Moreover, in the observation group, the median OS of dMMR patients was not detected, while the median OS of PMMR patients was 29.2 months (P<0.01). In the control group, the median OS of dMMR patients was 12.4 months, and that of PMMR patients was 24.1 months (P<0.01). CONCLUSIONS Advanced endometrial cancer patients with dMMRMSI-H treated with PD-1 inhibitor plus bevacizumab had longer overall survival (OS) than those treated with bevacizumab plus paclitaxel chemotherapy.

Arterial Spin Labeling for Pediatric Central Nervous System Diseases Techniques and Clinical Applications.

Dynamic susceptibility contrast (DSC) and arterial spin labeling (ASL) are techniques used to evaluate brain perfusion using MRI. DSC requires dynamic image acquisition with a rapid administration of gadolinium-based contrast agent. In contrast, ASL obtains brain perfusion information using magnetically labeled blood water as an endogenous tracer. For the evaluation of brain perfusion in pediatric neurological diseases, ASL has a significant advantage compared to DSC, CT, and single-photon emission CTpositron emission tomography because of the lack of radiation exposure and contrast agent administration. However, in ASL, optimization of several parameters, including the type of labeling, image acquisition, background suppression, and postlabeling delay, is required, because they have a significant effect on the quantification of cerebral blood flow (CBF).In this article, we first review recent technical developments of ASL and age-dependent physiological characteristics in pediatric brain perfusion. We then review the clinical implementation of ASL in pediatric neurological diseases, including vascular diseases, brain tumors, acute encephalopathy with biphasic seizure and late reduced diffusion (AESD), and migraine. In moyamoya disease, ASL can be used for brain perfusion and vessel assessment in pre- and post-treatment. In arteriovenous malformations, ASL is sensitive to detect small degrees of shunt. Furthermore, in vascular diseases, the implementation of ASL-based time-resolved MR angiography is described. In neoplasms, ASL-derived CBF has a high diagnostic accuracy for differentiation between low- and high-grade pediatric brain tumors. In AESD and migraine, ASL may allow for accurate early diagnosis and provide pathophysiological information.

A Comparison of Long-Term Treatment Outcomes Between Giant and Nongiant Craniopharyngiomas.

There is limited literature on outcomes after surgical treatment of giant craniopharyngiomas in adult and pediatric patients. A retrospective review of 159 patients undergoing surgery for craniopharyngiomas at a single institution was performed. Patients with giant craniopharyngiomas (maximum dimension ≥4.5 cm) were compared with nongiant tumors in terms of various clinical and radiological parameters and long-term surgical outcomes. Extent of resection was determined by postoperative magnetic resonance imaging. Factors associated with post-treatment obesity were also analyzed. Giant craniopharyngiomas (n 66) were characterized by higher rates of childhood presentation, visual impairment, neurological deficits, multicompartmental involvement, and hydrocephalus as compared with nongiant tumors (n 139). Giant tumors also were less likely to undergo transsphenoidal resection and were associated with a higher rate of postoperative neurological morbidity. There were no significant differences between the 2 groups in terms of extent of resection, use of postoperative radiation therapy, and long-term endocrinological outcomes. Overall recurrence rates over a mean follow-up period of 4.1 years were similar between giant and nongiant tumors however, recurrences after presumed gross total resectionnear total resection were significantly higher in the former subgroup versus the latter (39.4% vs. 18.4% P 0.044). Risk factors for post-treatment obesity in giant craniopharyngiomas included adult age (P 0.001), preoperative obesity (P 0.003), and hypothalamic involvement (P 0.012). Gross total resectionnear total resection of giant craniopharyngiomas can be achieved at rates comparable to nongiant tumors. However, there remains a greater risk of postoperative neurological morbidity. Radiation therapy mitigates the risk of recurrence on long-term follow-up.

Extracting clinical named entity for pituitary adenomas from Chinese electronic medical records.

Pituitary adenomas are the most common type of pituitary disorders, which usually occur in young adults and often affect the patients physical development, labor capacity and fertility. Clinical free texts noted in electronic medical records (EMRs) of pituitary adenomas patients contain abundant diagnosis and treatment information. However, this information has not been well utilized because of the challenge to extract information from unstructured clinical texts. This study aims to enable machines to intelligently process clinical information, and automatically extract clinical named entity for pituitary adenomas from Chinese EMRs. The clinical corpus used in this study was from one pituitary adenomas neurosurgery treatment center of a 3A hospital in China. Four types of fine-grained texts of clinical records were selected, which included notes from present illness, past medical history, case characteristics and family history of 500 pituitary adenoma inpatients. The dictionary-based matching, conditional random fields (CRF), bidirectional long short-term memory with CRF (BiLSTM-CRF), and bidirectional encoder representations from transformers with BiLSTM-CRF (BERT-BiLSTM-CRF) were used to extract clinical entities from a Chinese EMRs corpus. A comprehensive dictionary was constructed based on open source vocabularies and a domain dictionary for pituitary adenomas to conduct the dictionary-based matching method. We selected features such as part of speech, radical, document type, and the position of characters to train the CRF-based model. Random character embeddings and the character embeddings pretrained by BERT were used respectively as the input features for the BiLSTM-CRF model and the BERT-BiLSTM-CRF model. Both strict metric and relaxed metric were used to evaluate the performance of these methods. Experimental results demonstrated that the deep learning and other machine learning methods were able to automatically extract clinical named entities, including symptoms, body regions, diseases, family histories, surgeries, medications, and disease courses of pituitary adenomas from Chinese EMRs. With regard to overall performance, BERT-BiLSTM-CRF has the highest strict F1 value of 91.27% and the highest relaxed F1 value of 95.57% respectively. Additional evaluations showed that BERT-BiLSTM-CRF performed best in almost all entity recognition except surgery and disease course. BiLSTM-CRF performed best in disease course entity recognition, and performed as well as the CRF model for part of speech, radical and document type features, with both strict and relaxed F1 value reaching 96.48%. The CRF model with part of speech, radical and document type features performed best in surgery entity recognition with relaxed F1 value of 95.29%. In this study, we conducted four entity recognition methods for pituitary adenomas based on Chinese EMRs. It demonstrates that the deep learning methods can effectively extract various types of clinical entities with satisfying performance. This study contributed to the clinical named entity extraction from Chinese neurosurgical EMRs. The findings could also assist in information extraction in other Chinese medical texts.

The Benefit Of Positron Emission TomographyComputed Tomography In Stage I And Stage II Melanomas With High-Risk Decisiondx-Melanoma Scores.

Early detection of melanoma is instrumental as the 5-year survival decreases from 93.3% to <50% when metastases are present. 297 patients at our institution had biopsies sent for DDx-M between 2014 and 2021. Patients found to have Class 2 melanomas received additional screening with yearly Within 3 years of follow-up, 866 (12.1%) patients had metastases detected by We suggest all patients with initial stage II or above melanomas receive a DDx-M score and those with class 2 receive yearly

Suppressive Effect of Autocrine FGF21 on Autophagy-Deficient Hepatic Tumorigenesis.

Mice with hepatocyte-specific deletion of

A CTNNB1-altered medulloblastoma shows the immunophenotypic, DNA methylation and transcriptomic profiles of SHH-activated, and not WNT-activated, medulloblastoma.

Recent advancements in molecular characterisation have identified four principal molecular groups of medulloblastoma WNT, SHH, group 3 and group 4. Each has its characteristic clinical features, signature genetic alterations and distinct DNA methylome profiles. Thus far, CTNNB1 mutations have been considered pathognomonic of WNT-activated medulloblastoma. Furthermore, it has been shown that CTNNB1 mutations dominantly drive the WNT-activated phenotype in medulloblastoma, even in the presence of alterations in the SHH pathway. We herein report an illustrative case that challenges this belief-a medulloblastoma with a pathogenic CTNNB1 mutation that otherwise showed the histopathology, immunophenotype and methylation and transcriptomic profiles of an SHH-activated medulloblastoma. Detailed molecular analyses, including whole exome sequencing, transcriptome analysis and DNA methylation profiling with DKFZ brain tumour classifier and St. Jude MLPnet neural network classifier analyses, have been performed on the tumour. Our example emphasises the diagnostic value of the immunohistochemistry panel with YAP1, GAB1 and β-catenin and DNA methylation profiling, combined with exome sequencing, in the characterisation of medulloblastoma. CTNNB1 mutations are not specific for WNT-activated medulloblastoma, and different CTNNB1 mutations have diverse oncogenic potential.

Descriptive Epidemiology of Ependymal Tumors in Gironde, France Results from the Gironde Registry for the 2000-2018 Period.

The Gironde Central Nervous System (CNS) Tumor Registry, in collaboration with the French National Cancer Institute, is the largest population-based registry focused exclusively on primary CNS tumors in France and represents a population of 1.62 million. This report focuses on ependymal tumors to refine current knowledge and provide up-to-date data on the epidemiology of these rare tumors. All of the ependymal tumors were extracted from the Gironde CNS Tumor Registry for the years 2000-2018. Demographic and clinical characteristics, incidence rates, and time trends as well as survival outcomes were analyzed. One hundred forty-four ependymal tumors were retrieved, which represented 2.3% of all the CNS tumors recorded in the same period. Histological subtype was significantly dependent on age and topography in the CNS. The median age at diagnosis was 46 years. The annual incidence rates varied between 0.15100,000 (2004) and 0.96100,000 (2016), with a significant increase over the study period by 4.67% per year. Five-year and 10-year OS rates were 87% and 80%, respectively. An increase in the incidence of ependymal tumors was observed over the past two decades. Further studies are needed to confirm this result and provide etiological clues.

Role of surgery in multifocal glioblastoma.

The management of multifocal glioblastomas is a point of constant discussion amongst neuro-oncologists. Best outcomes in glioblastoma management come from gross total resection (GTR) followed by concomitant radiation and chemotherapy (CCRT). Multifocal disease is resistant to GTR. Conventional management of these lesion is usually biopsy only followed by CCRT. Recent evidence has shown that there may be some benefit to attempting GTR of the largest lesion whenever safe to do so.

Non-enhancing intraventricular tumours in adults.

Intraventricular tumours are relatively uncommon among all brain tumours, and non-enhancing lesions, mostly subependymoma, are even less frequently reported. Select cases of subependymoma can show variable contrast enhancement as well. Gross total surgical resection is recommended for treating these lesions, with no significant role of adjuvant chemotherapy or radiotherapy.

Musculoskeletal Metastasis From Soft-tissue Sarcomas A Review of the Literature.

Soft-tissue sarcomas are a rare and extremely heterogeneous group of cancers, representing <1% of all human malignancies. The lungs are the most common site of distant metastasis, followed by the bone, lymph nodes, liver, brain, and subcutaneous tissue. Clinical experience suggests that skeletal metastasis is part of the natural history affecting the prognosis and quality of life in these patients. Approximately 2.2% of patients have skeletal metastasis at diagnosis. However, up to 10% will develop skeletal metastasis after a mean interval of 21.3 months. Although systemic therapy with conventional chemotherapy remains the primary treatment modality for those with metastatic sarcoma, increased survival has been achieved in selected patients who receive multimodality therapy, including surgery, for their metastatic disease. The 5-year overall survival of patients with isolated bone metastases was 41.2% (26.9% to 54.9%), which decreased to 32.9% (21.2% to 45.1%) in the setting of combined bone and lung metastases. Moreover, the resection of the primary soft-tissue sarcoma is a predictor of survival, resulting in a 58% decrease in mortality after surgery (hazard ratio, 0.42, P 0.013). Understanding the effect of these metastases on patient survival may influence imaging, surveillance, and treatment decisions.

Effects of antifibrinolytics on systemic and cerebral inflammation after traumatic brain injury.

Administration of antifibrinolytic medications, including tranexamic acid (TXA), may reduce head injury-related mortality. The effect of these medications on post-traumatic brain injury (TBI) inflammatory response is unknown. The goal of this study was to investigate the role of available antifibrinolytic medications on both systemic and cerebral inflammation after TBI. An established murine weight drop model was used to induce a moderate TBI. Mice were administered 1, 10, or 100 mgkg of TXA, 400 mgkg of aminocaproic acid (Amicar, Hospira, Lake Forest, IL), 100 kIUkg of aprotonin, or equivalent volume of normal saline (NS) 10 minutes after recovery. Mice were euthanized at 1, 6, or 24 hours. Serum and cerebral tissue were analyzed for neuron-specific enolase and inflammatory cytokines. Hippocampal histology was evaluated at 30 days for phosphorylated tau accumulation. One hour after TBI, mice given TXA displayed decreased cerebral cytokine concentrations of tumor necrosis factor α (TNF-α) and, by 24 hours, displayed decreased concentrations of cerebral TNF-α, interleukin (IL)-6, and monocyte chemoattractant protein 1 compared with TBI-NS. However, serum concentrations of TNF-α and macrophage inflammatory protein 1α (MIP-1α) were significantly elevated from 1 to 24 hours in TBI-TXA groups compared with TBI-NS. The concentration of phosphorylated tau was significantly decreased in a dose-dependent manner in TBI-TXA groups compared with TBI-NS. By contrast, Amicar administration increased cerebral cytokine levels of IL-6 1 hour after TBI, with serum elevations noted in TNF-α, MIP-1α, and monocyte chemoattractant protein 1 at 24 hours compared with TBI-NS. Aprotonin administration increased serum TNF-α, IL-6, and MIP-1α from 1 to 24 hours without differences in cerebral cytokines compared with TBI-NS. Tranexamic acid administration may provide acute neuroinflammatory protection in a dose-dependent manner. Amicar administration may be detrimental after TBI with increased cerebral and systemic inflammatory effects. Aprotonin administration may increase systemic inflammation without significant contributions to neuroinflammation. While no antifibrinolytic medication improved systemic inflammation, these data suggest that TXA may provide the most beneficial inflammatory modulation after TBI.

Extramedullary Infiltration in Pediatric Acute Myeloid Leukemia on Surveillance Magnetic Resonance Imaging and its Relationship With Established Risk Factors.

Extramedullary infiltration (EMI) is a rare condition defined by the accumulation of myeloid tumor cells beyond the bone marrow. The clinical significance is still controversial. This study was aimed to evaluate the incidence, characteristics, and prognostic significance of EMI on complete magnetic resonance imaging (MRI) investigation in newly diagnosed pediatric acute myeloid leukemia (AML) patients who are asymptomatic without clinical evidence to suspect EMI. Retrospective clinical and radiologic review of 121 patients with MRI examination at the time of initial diagnosis of AML without any clinical evidence suggestive of EMI was performed. Patients were divided into 2 groups according to the presence or absence of EMI, and the relationship between EMI and established risk factors was analyzed. Initial white blood cell count, the occurrence of an event (including relapse, death, and primary refractory disease), survival status, and detailed information on cytogeneticmolecular status was performed by a thorough review of electronic medical records system. All patients underwent full imaging evaluation with the contrast-enhanced whole body and some regional MRI at the time of initial diagnosis. The median age at diagnosis was 10.77 years (range, 0.37 to 18.83 y). Based on the risk stratification system of AML, 36, 45, and 40 patients are classified as low-risk, intermediate-risk, and high-risk groups, respectively. MRI at the time of the initial diagnosis of AML revealed 35 of 121 patients (28.9%) with EMI. The most common site of EMI was a skull, followed by the lower extremity bone and meninges of the brain. The median age at diagnosis was significantly younger in patients with EMI (7.87 vs. 11.08 y, P0.0212). Low incidence of FLT3ITD mutation, low incidence of AML-ETO gene rearrangement, and the larger extent and more severe degree of bone marrow involvement was related with EMI. However, there was no significant prognostic difference in event-free survival and overall survival regardless of the presence of EMI in the overall patient population and each risk group. The location of EMI occurrence was also not related to prognosis. Even if EMI symptoms are not evident, surveillance MRI scans at the initial diagnosis of pediatric AML patients are very helpful in detecting a significant number of EMIs. Younger age, some molecular features, and more severe bone marrow involvement of AML patients were related with EMI. However, there was no significant prognostic difference between patients with or without EMI regardless of risk group. Further prospective investigation is necessary to validate the prognostic effect of EMI in a larger group of patients with different risk groups.

Safety of growth hormone replacement in survivors of cancer and intracranial and pituitary tumours a consensus statement.

Growth hormone (GH) has been used for over 35 years, and its safety and efficacy has been studied extensively. Experimental studies showing the permissive role of GHinsulin-like growth factor 1 (IGF-I) in carcinogenesis have raised concerns regarding the safety of GH replacement in children and adults who have received treatment for cancer and those with intracranial and pituitary tumours. A consensus statement was produced to guide decision-making on GH replacement in children and adult survivors of cancer, in those treated for intracranial and pituitary tumours and in patients with increased cancer risk. With the support of the European Society of Endocrinology, the Growth Hormone Research Society convened a Workshop, where 55 international key opinion leaders representing 10 professional societies were invited to participate. This consensus statement utilized (1) a critical review paper produced before the Workshop, (2) five plenary talks, (3) evidence-based comments from four breakout groups, and (4) discussions during report-back sessions. Current evidence reviewed from the proceedings from the Workshop does not support an association between GH replacement and primary tumour or cancer recurrence. The effect of GH replacement on secondary neoplasia risk is minor compared to host- and tumour treatment-related factors. There is no evidence for an association between GH replacement and increased mortality from cancer amongst GH-deficient childhood cancer survivors. Patients with pituitary tumour or craniopharyngioma remnants receiving GH replacement do not need to be treated or monitored differently than those not receiving GH. GH replacement might be considered in GH-deficient adult cancer survivors in remission after careful individual riskbenefit analysis. In children with cancer predisposition syndromes, GH treatment is generally contraindicated but may be considered cautiously in select patients.

Prediction of microvascular invasion in hepatocellular carcinoma with expert-inspiration and skeleton sharing deep learning.

Radiological prediction of microvascular invasion (MVI) of hepatocellular carcinoma (HCC) is essential but few models were clinically implemented because of limited interpretability and generalizability. Based on 2096 patients in three independent HCC cohorts, we established and validated an MVI predicting model. First, we used data from the primary cohort to train a 3D-ResNet network for MVI prediction and then optimised the model with expert-inspired training for model construction. Second, we implemented the model to the other two cohorts using three implementation strategies, the original model implementation, data sharing model implementation and skeleton sharing model implementation, the latter two of which used part of the cohorts data for fine-tuning. The areas under the receiver operating characteristic curve (AUCs) were calculated to compare the performances of different models. For the MVI predicting model, the AUC of the expert-inspired model was 0.83 (95% CI 0.77-0.88) compared to 0.54 (95% CI 0.46-0.62) of model before expert-inspiring. Taking this model as an original model, AUC on the second cohort was 0.76 (95% CI 0.67-0.84). The AUC was improved to 0.83 (95% CI 0.77-0.90) with the data-sharing model, and further improved to 0.85 (95% CI 0.79-0.92) with the skeleton sharing model. The trend that the skeleton sharing model had an advantage in performance was similar in the third cohort. We established an expert-inspired model with better predictive performance and interpretability than the traditional constructed model. Skeleton sharing process is superior to data sharing and direct model implementation in model implementation.

Update on the clinical management of multiple endocrine neoplasia type 1.

This review provides an overview of novel insights in the clinical management of patients with Multiple Endocrine Neoplasia Type 1, focusing on the last decade since the last update of the MEN1 guidelines. With regard to Diagnosis Mutation-negative patients with 23 main manifestations have a different clinical course compared to mutation-positive patients. As for primary hyperparathyroidism subtotal parathyroidectomy is the initial procedure of choice. Current debate centres around the timing of initial parathyroidectomy as well as the controversial topic of unilateral clearance in young patients. For duodenopancreatic neuroendocrine tumours (NETs), the main challenge is accurate and individualized risk stratification to enable personalized surveillance and treatment. Thymus NETs remain one of the most aggressive MEN1-related tumours. Lung NETs are more frequent than previously thought, generally indolent, but rare aggressive cases do occur. Pituitary adenomas are most often prolactinomas and nonfunctioning microadenomas with an excellent prognosis and good response to therapy. Breast cancer is recognized as part of the MEN1 syndrome in women and periodical screening is advised. Clinically relevant manifestations are already seen at the paediatric age and initiating screening in the second decade is advisable. MEN1 has a significant impact on quality of life and US data show a significant financial burden. In conclusion, patient outcomes have improved, but much is still to be achieved. For care tailored to the needs of the individual patient and improving outcomes on an individual basis, studies are now needed to define predictors of tumour behaviour and effects of more individualized interventions.

Incidence of brain metastases in patients with early HER2-positive breast cancer receiving neoadjuvant chemotherapy with trastuzumab and pertuzumab.

The addition of pertuzumab (P) to trastuzumab (H) and neoadjuvant chemotherapy (NAC) has decreased the risk of distant recurrence in early stage HER2-positive breast cancer. The incidence of brain metastases (BM) in patients who achieved pathological complete response (pCR) versus those who do not is unknown. In this study, we sought the incidence of BM in patients receiving HP-containing NAC as well as survival outcome. We reviewed the medical records of 526 early stage HER2-positive patients treated with an HP-based regimen at Memorial Sloan Kettering Cancer Center (MSKCC), between September 1, 2013 to November 1, 2019. The primary endpoint was to estimate the cumulative incidence of BM in pCR versus non-pCR patients secondary endpoints included disease free-survival (DFS) and overall survival (OS). After a median follow-up of 3.2 years, 7 out of 286 patients with pCR had a BM while 5 out of 240 non-pCR patients had a BM. The 3-year DFS was significantly higher in the pCR group compared to non-pCR group (95% vs 91 %, p 0.03) and the same trend was observed for overall survival. In our cohort, despite the better survival outcomes of patients who achieved pCR, we did not observe appreciable differences in the incidence of BM by pCRnon-pCR status. This finding suggests that the BM incidence could not be associated with pCR. Future trials with new small molecules able to cross the blood brain barrier should use more specific biomarkers rather than pCR for patients selection.

Novel CaMKII-δ Inhibitor Hesperadin Exerts Dual Functions to Ameliorate Cardiac IschemiaReperfusion Injury and Inhibit Tumor Growth.

Cardiac ischemiareperfusion (IR) injury has emerged as an important therapeutic target for ischemic heart disease, the leading cause of morbidity and mortality worldwide. At present, there is no effective therapy for reducing cardiac IR injury. CaMKII (Ca A small-molecule kinase inhibitor library and a high-throughput screening system for the kinase activity assay of CaMKII-δ9 (the most abundant CaMKII-δ splice variant in human heart) were used to screen for CaMKII-δ inhibitors. Using cultured neonatal rat ventricular myocytes, human embryonic stem cell-derived cardiomyocytes, and in vivo mouse models, in conjunction with myocardial injury induced by IR (or hypoxiareoxygenation) and CaMKII-δ9 overexpression, we sought to investigate the protection of hesperadin against cardiomyocyte death and cardiac diseases. BALBc nude mice with xenografted tumors of human cancer cells were used to evaluate the in vivo antitumor effect of hesperadin. Based on the small-molecule kinase inhibitor library and screening system, we found that hesperadin, an Aurora B kinase inhibitor with antitumor activity in vitro, directly bound to CaMKII-δ and specifically blocked its activation in an ATP-competitive manner. Hesperadin functionally ameliorated both IR- and overexpressed CaMKII-δ9-induced cardiomyocyte death, myocardial damage, and heart failure in both rodents and human embryonic stem cell-derived cardiomyocytes. In addition, in an in vivo BALBc nude mouse model with xenografted tumors of human cancer cells, hesperadin delayed tumor growth without inducing cardiomyocyte death or cardiac injury. Here, we identified hesperadin as a specific small-molecule inhibitor of CaMKII-δ with dual functions of cardioprotective and antitumor effects. These findings not only suggest that hesperadin is a promising leading compound for clinical therapy of cardiac IR injury and heart failure, but also provide a strategy for the joint therapy of cancer and cardiovascular disease caused by anticancer treatment.

SPI1-induced downregulation of FTO promotes GBM progression by regulating pri-miR-10a processing in an m6A-dependent manner.

As one of the most common post-transcriptional modifications of mRNAs and noncoding RNAs, N

Cerebral corridor creator for resection of trigone ventricular tumors Two case reports.

Resection of deep intracranial tumors requires significant brain retraction, which frequently causes brain damage. In particular, tumor in the trigone of the lateral ventricular presents a surgical challenge due to its inaccessible location and intricate adjacent relationships with essential structures such as the optic radiation (OR) fibers. New brain retraction systems have been developed to minimize retraction-associated injury. To date, there is little evidence supporting the superiority of any retraction system in preserving the white matter tract integrity. This report illustrates the initial surgical excision in two patients using a new retraction system termed the cerebral corridor creator (CCC) and demonstrates its advantage in protecting OR fibers. We report two patients with nonspecific symptoms, who had trigone ventricular lesions that involved the neighboring OR identified on preoperative diffusion tensor imaging (DTI). Both patients underwent successful surgical excision using the CCC. Total tumor removal was achieved without additional neurological deficit. DTI showed that the OR fibers were preserved along the surgical field. Preoperative symptoms were alleviated immediately after surgery. Clinical outcomes were improved according to the Glasgow-Outcome-Scale and Activity-of-Daily-Living Scale assessments. In the two cases, the CCC was a safe and useful tool for creating access to the deep trigonal area while preserving the white matter tract integrity. The CCC is thus a promising alternative brain retractor.

Multiple different remote epidural hematomas after craniotomy A case report.

Epidural hematoma is one of the common postoperative complications after craniotomy. However, multiple remote epidural hematomas in different sites, including supratentorial and infratentorial regions, are exceedingly rare. We present a rare case in which three remote epidural hematomas occurred after craniotomy. A 21-year-old woman was admitted with a headache for 1 mo, vomiting, and rapid vision loss for 1 wk. Brian magnetic resonance imaging indicated a right thalamic tumor. The intraoperative diagnosis was a cystic tumor, posterior cerebral artery aneurysm, and vascular malformation. The operation was successful. Unfortunately, the patient developed three extradural hematomas within 48 h. Family members consented to the first two hematoma evacuations but refused the third. More attention should be paid to this kind of rare complication. Adequate preoperative evaluation is important, especially for acute patients. Monitoring neural function and early computed tomography scanning of the brain after surgery should be highlighted.

Artificial Intelligence Algorithm-Based Intraoperative Magnetic Resonance Navigation for Glioma Resection.

The study aimed to analyze the application value of artificial intelligence algorithm-based intraoperative magnetic resonance imaging (iMRI) in neurosurgical glioma resection. 108 patients with glioma in a hospital were selected and divided into the experimental group (intraoperative magnetic resonance assisted glioma resection) and the control group (conventional surgical experience resection), with 54 patients in each group. After the resection, the tumor resection rate, NIHSS (National Institute of Health Stroke Scale) score, Karnofsky score, and postoperative intracranial infection were calculated in the two groups. The results revealed that the average tumor resection rate in the experimental group was significantly higher than that in the control group (

Clinical validation of a spectroscopic liquid biopsy for earlier detection of brain cancer.

Diagnostic delays impact the quality of life and survival of patients with brain tumors. Earlier and expeditious diagnoses in these patients are crucial to reduce the morbidities and mortalities associated with brain tumors. A simple, rapid blood test that can be administered easily in a primary care setting to efficiently identify symptomatic patients who are most likely to have a brain tumor would enable quicker referral to brain imaging for those who need it most. Blood serum samples from 603 patients were prospectively collected and analyzed. Patients either had non-specific symptoms that could be indicative of a brain tumor on presentation to the Emergency Department, or a new brain tumor diagnosis and referral to the neurosurgical unit, NHS Lothian, Scotland. Patient blood serum samples were analyzed using the Dxcover® Brain Cancer liquid biopsy. This technology utilizes infrared spectroscopy combined with a diagnostic algorithm to predict the presence of intracranial disease. Our liquid biopsy approach reported an area under the receiver operating characteristic curve of 0.8. The sensitivity-tuned model achieves a 96% sensitivity with 45% specificity (NPV 99.3%) and identified 100% of glioblastoma multiforme patients. When tuned for a higher specificity, the model yields a sensitivity of 47% with 90% specificity (PPV 28.4%). This simple, non-invasive blood test facilitates the triage and radiographic diagnosis of brain tumor patients while providing reassurance to healthy patients. Minimizing time to diagnosis would facilitate the identification of brain tumor patients at an earlier stage, enabling more effective, less morbid surgical and adjuvant care.

Interleukin-10 Attenuates Behavioral, Immune and Neurotrophin Changes Induced by Chronic Central Administration of Interleukin-1β in Rats.

Activated microglia can trigger pro-inflammatory cytokine releases and neuroinflammation, which may inhibit astrocytes to produce neurotrophins and anti-inflammatory factors. Both eventually lead to neuron apoptosis or death. Furthermore, effective antidepressant or anti-dementia treatments can reduce pro-inflammatory cytokines, while enhance interleukin (IL)-10 production. However, the underline mechanism by which IL-10 modulates glial cell function, hence improves cognitive impairment or depression-like behavior is unknown. This study evaluated whether and how IL-10 attenuated chronic IL-1β administration-induced behavioral changes and the possible involved mechanisms. Rats received intracerebroventricular injection of IL-1β andor IL-10 for 14 days. Then animal memory and depression-like behavior, pro-inflammatory cytokines, glial activities, expression of brain-derived neurotrophic factor (BDNF), Trk B, p75, and apoptosis-related genes were studied. Compared to controls, significantly increased latent time and swimming distance in the Morris-water-maze, decreased sucrose consumption, and decreased locomotor and center zone entries in the open-field were found in rats administrated with IL-1β. These changes were associated with the reduction of GFAP expression, and concentrations of BDNF and anti-inflammatory cytokine IL-10, but the increase in the expressions of CD11b, TrkB, p75, and Caspase-3, the ratio of BaxBcl-2, and the concentrations of IL-1β, tumor necrosis factor-α, and IL-6. IL-10 treatment markedly attenuated IL-1β-induced above changes, except for the expressions of neurotrophin receptors. IL-10-improved behavioral changes may be through suppressing microglia activity and inflammation, while restoring astrocyte function and BDNF expression.

Real-world effectiveness of immunotherapies in pre-treated, advanced non-small cell lung cancer Patients A systematic literature review.

Clinical trials have shown immunotherapy (IO) to be more effective than chemotherapy in pre-treated, advanced non-small cell lung cancer (NSCLC). However, there is a lack of understanding of its effectiveness in clinical practice, and among patient groups that are often underrepresented in trials. We aimed to summarize the existing real-world evidence (RWE) on the survival outcomes of IO in second- or higher line in advanced NSCLC. We conducted a systematic review of real-world observational studies that reported overall survival (OS) estimates with IO, primarily nivolumab, pembrolizumab or atezolizumab, in adult, previously treated advanced or recurrent NSCLC patients. Meta-analysis was conducted using random-effect models to pool 1- and 2-year OS rates across studies. Additional subgroups were examined among patients treated with IO, including the elderly, those with poor performance status (PS) and those exhibiting metastasis. In total, 66 studies were included, of which 46 (70%) included a nivolumab-specific study arm. Pooled 1-year and 2-year OS rates with nivolumab monotherapy were 45.6% (95% CI 43.4-47.8) and 28.0% (95% CI 24.8-31.4), respectively, compared to 43.9% (95% CI 39.1-48.8) and 20.4% (95% CI 14.7-27.6) in the mixed immune checkpoint inhibitors (ICI) group. OS rates with nivolumab were slightly lower in elderly compared to non-elderly populations. Poor PS was associated with worse survival rates, with a pooled one-year OS estimate of 27.1% in PS ≥ 2 vs 51.6% in PS < 2. The pooled 2-year OS rate with nivolumab in patients with and without brain metastases was 22.1% and 26.1% respectively, and this difference was significant in 36% of individual studies. While the OS benefits of IO seen in real-world studies among pre-treated, advanced NSCLC patients are consistent with pivotal clinical trials, these tend to vary for the more vulnerable patient groups, such as patients with poor PS, which are often excluded from trials. Further research is needed to investigate findings in patients with brain and liver metastases.

Single brain metastasis versus glioblastoma multiforme a VOI-based multiparametric analysis for differential diagnosis.

The authors purpose was to create a valid multiparametric MRI model for the differential diagnosis between glioblastoma and solitary brain metastasis. Forty-one patients (twenty glioblastomas and twenty-one brain metastases) were retrospectively evaluated. MRIs were analyzed with Olea Sphere According to ROC analysis, the area under the curve was 88%, 78% and 74%, respectively, for mean ADC VOI values of the solid component, the mean and max rCBV values in the perilesional edema and the PSR. The cumulative ROC curve of these parameters reached an area under the curve of 95%. Using perilesional max rCBV > 1.37, PSR > 75% and mean lesional ADC < 1 × 10 Lower values of ADC in the enhancing tumor, a higher percentage of SR in perfusion curves and higher values of rCBV in the peritumoral edema closed to the lesion are strongly indicative of GB than solitary BM.

The C-glucosyl flavone isoorientin pretreatment attenuates the methylglyoxal-induced mitochondrial dysfunction in the human neuroblastoma SH-SY5Y cells role for the AMPK-PI3KAktNrf2γ-GCLGSH axis.

The reactive dicarbonyl methylglyoxal (MG) behaves as a pro-oxidant agent, causing redox dysfunction and cell death by different mechanisms in mammalian cells. MG is also a mitochondrial toxicant, impairing the oxidative phosphorylation (OXPHOS) system and leading to bioenergetics and redox collapses. MG induces glycation and exerts an important role in neurodegenerative and cardiovascular diseases. Isoorientin (ISO), a C-glucosyl flavone found in Aspalathus linearis, Fagopyrum esculentum, and Passiflora edulis, among others, is an antioxidant and anti-inflammatory molecule. ISO is a potent inducer of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), the master modulator of the redox environment in mammals. We investigated here whether ISO would prevent the mitochondria-related redox and bioenergetics impairments induced by MG in the human neuroblastoma SH-SY5Y cells. The cells were administrated with ISO at 20 μM for 18 h prior to the exposure to MG at 500 μM for further 24 h. It was observed that ISO efficiently prevented the mitochondrial impairments caused by MG. ISO upregulated the activity of the enzyme γ-glutamate-cysteine ligase (γ-GCL), consequently stimulating the synthesis of glutathione (GSH). The inhibition of γ-GCL, adenosine monophosphate-activated protein kinase (AMPK), and phosphoinositide 3-kinaseAkt (PI3KAkt) suppressed the beneficial effects induced by ISO on the MG-challenged cells. Moreover, silencing of Nrf2 blocked the ISO-dependent γ-GCL and GSH upregulation and the effects on the mitochondria of the MG-challenged cells. Then, ISO caused mitochondrial protection by an AMPK-PI3KAktNrf2γ-GCLGSH-dependent manner in MG-administrated SH-SY5Y cells.

Neuroprotective effects of carvacrol against cadmium-induced neurotoxicity in rats role of oxidative stress, inflammation and apoptosis.

Cadmium (Cd), is a heavy metal reported to be associated with oxidative stress and inflammation. In this paper, we investigated the possible protective effects of carvacrol against Cd-induced neurotoxicity in rats. Adult male Sprague Dawley rats were treated orally with Cd (25 mgkg body weight) and with carvacrol (25 and 50 mgkg body weight) for 7 days. Carvacrol decreased the levels of malondialdehyde (MDA), glial fibrillary acidic protein (GFAP) and monoamine oxidase (MAO), and significantly increased the levels of glutathione (GSH) and activities of catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) in brain tissue. Additionally, carvacrol alleviated the in levels of inflammation and apoptosis related proteins involving p38 mitogen-activated protein kinase (p38 MAPK), cyclooxygenase-2 (COX-2), nuclear factor kappa B (NF-κB), B-cell lymphoma-3 (Bcl-3), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), myeloperoxidase (MPO), prostaglandin E2 (PGE2), neuronal nitric oxide synthase (nNOS), inducible nitric oxide synthase (iNOS), cysteine aspartate specific protease-3 (caspase-3) and Bcl-2 associated X protein (Bax) in the Cd-induced neurotoxicity. Carvacrol also decreased the mRNA expression of matrix metalloproteinases (MMP9 and MMP13), as well as 8-hydroxy-2-deoxyguanosine (8 - OHdG) level, a marker of oxidative DNA damage. Collectively, our findings indicated that carvacrol has a beneficial effect in ameliorating the Cd-induced neurotoxicity in the brain of rats.

A volume matched comparison of survival after radiosurgery in non-small cell lung cancer patients with one versus more than twenty brain metastases.

Treatment of patients with a large number of brain metastases using radiosurgery remains controversial. In this study we sought to conduct a volume matched comparison to evaluate the clinical outcome of patients with > 20 brain metastases and compared it with patents with solitary brain tumor form non-small cell lung cancer (NSCLC). Between 2014 and 2020, 26 NSCLC patients (925 tumors) underwent stereotactic radiosurgery (SRS) for > 20 metastases in a single procedure (median margin dose 16 Gy, median cumulative tumor volume 4.52 cc) 56 patients underwent SRS for a single metastasis (median margin dose 18 Gy, median volume 4.74 cc). The overall survival (OS), local tumor control (LC), adverse radiation effect (ARE) risk, and incidence of new tumor development were compared. No difference in OS was found between patients with > 20 brain metastases (median OS 15 months) and patients with solitary metastasis (median OS 12 months p 0.3). In the solitary tumor cohort, two of 56 (3.5%) tumors progressed whereas in the > 20 cohort only 3 of 925 (0.3%) tumors showed progression (p 0.0013). The rate of new tumor development was significantly higher in patients with > 20 tumors (p 0.0001). No significant difference of ARE rate was found (7.5% for > 20 tumors vs. 8.7% for single metastasis). Patients with > 20 tumors showed significantly better LC with similar OS compared to patients with solitary tumors. Current guidelines that restrict the role of SRS to patients with 1-4 tumors should be revised.

Central nervous system immune interactome is a function of cancer lineage, tumor microenvironment, and STAT3 expression.

BACKGROUNDImmune cell profiling of primary and metastatic CNS tumors has been focused on the tumor, not the tumor microenvironment (TME), or has been analyzed via biopsies.METHODSEn bloc resections of gliomas (n 10) and lung metastases (n 10) were analyzed via tissue segmentation and high-dimension Opal 7-color multiplex imaging. Single-cell RNA analyses were used to infer immune cell functionality.RESULTSWithin gliomas, T cells were localized in the infiltrating edge and perivascular space of tumors, while residing mostly in the stroma of metastatic tumors. CD163 macrophages were evident throughout the TME of metastatic tumors, whereas in gliomas, CD68, CD11cCD68, and CD11cCD68CD163 cell subtypes were commonly observed. In lung metastases, T cells interacted with CD163 macrophages as dyads and clusters at the brain-tumor interface and within the tumor itself and as clusters within the necrotic core. In contrast, gliomas typically lacked dyad and cluster interactions, except for T cell CD68 cell dyads within the tumor. Analysis of transcriptomic data in glioblastomas revealed that innate immune cells expressed both proinflammatory and immunosuppressive gene signatures.CONCLUSIONOur results show that immunosuppressive macrophages are abundant within the TME and that the immune cell interactome between cancer lineages is distinct. Further, these data provide information for evaluating the role of different immune cell populations in brain tumor growth and therapeutic responses.FUNDINGThis study was supported by the NIH (NS120547), a Developmental research project award (P50CA221747), ReMission Alliance, institutional funding from Northwestern University and the Lurie Comprehensive Cancer Center, and gifts from the Mosky family and Perry McKay. Performed in the Flow Cytometry Cellular Imaging Core Facility at MD Anderson Cancer Center, this study received support in part from the NIH (CA016672) and the National Cancer Institute (NCI) Research Specialist award 1 (R50 CA243707). Additional support was provided by CCSG Bioinformatics Shared Resource 5 (P30 CA046592), a gift from Agilent Technologies, a Research Scholar Grant from the American Cancer Society (RSG-16-005-01), a Precision Health Investigator Award from University of Michigan (U-M) Precision Health, the NCI (R37-CA214955), startup institutional research funds from U-M, and a Biomedical Informatics Data Science Training Grant (T32GM141746).

Olfactory Outcomes After Middle Turbinate Resection in Endoscopic Transsphenoidal Surgery A Prospective Randomized Study.

Endoscopic endonasal transsphenoidal surgery is safe and effective for sellar and parasellar tumor removal. Partial middle turbinate (MT) resection is sometimes performed to optimize the surgical field and facilitate postoperative care. Disturbances in olfaction are concerning because of the lack of randomized studies in this field. Prospective randomized trial. Single academic medical center. We resected the lower halves of bilateral MTs in the resected group and laterally fractured bilateral MTs in the preserved group. Olfactory outcomes and sinonasal conditions were assessed by using the validated Taiwan Smell Identification Test and Lund-Kennedy Endoscopy Score, respectively. Forty-nine patients were enrolled in the final analysis, of whom 23 underwent partial MT resection. The average Taiwan Smell Identification Test result was 36.9 one month after surgery, with a significant change of -4.4 ± 3.1 (mean ± SD Endoscopic endonasal transsphenoidal surgery may affect olfaction at 1 month after surgery, and olfactory function is expected to return after 3 months. Partial MT resection did not result in additional olfactory loss. It is safe to perform partial MT resection during surgery without compromising the olfactory outcomes.

A volume-independent conformity index for stereotactic radiosurgery.

To develop a volume-independent conformity metric called the Gaussian Weighted Conformity Index (GWCI) to evaluate stereotactic radiosurgeryradiotherapy (SRSSRT) plans for small brain tumors. A signed bi-directional local distance (BLD) between the prescription isodose line and the target contour is determined for each point along the tumor contour (positive distance represents under-coverage). A similarity score function (SF) is derived from Gaussian function, penalizing under- and over-coverage at each point by assigning standard deviations of the Gaussian function. Each point along the dose line contour is scored with this SF. The average of the similarity scores determines the GWCI. A total of 40 targets from 18 patients who received Gamma-Knife SRSSRT treatments were analyzed to determine appropriate penalty criteria. The resulting GWCIs for test cases already deemed clinically acceptable are presented and compared to the same cases scored with the New Conformity Index to determine the influence of tumor volumes on the two conformity indices (CIs). A total of four penalty combinations were tested based on the signed BLDs from the 40 targets. A GWCI of 0.9 is proposed as a cutoff for plan acceptability. The GWCI exhibits no target volume dependency as designed. A limitation of current CIs, volume dependency, becomes apparent when applied to SRSSRT plans. The GWCI appears to be a more robust index, which penalizes over- and under-coverage of tumors and is not skewed by the tumor volume.

Loss of H3K27 Trimethylation Promotes Radiotherapy Resistance in Medulloblastoma and Induces an Actionable Vulnerability to BET Inhibition.

Medulloblastoma has been categorized into four subgroups based on genetic, epigenetic, and transcriptional profiling. Radiation is used for treating medulloblastoma regardless of the subgroup. A better understanding of the molecular pathways determining radiotherapy response could help improve medulloblastoma treatment. Here, we investigated the role of the EZH2 (enhancer of zeste 2 polycomb repressive complex 2 subunit)-dependent histone H3K27 trimethylation in radiotherapy response in medulloblastoma. The tumors in 47.2% of patients with group 3 and 4 medulloblastoma displayed H3K27me3 deficiency. Loss of H3K27me3 was associated with a radioresistant phenotype, high relapse rates, and poor overall survival. In H3K27me3-deficient medulloblastoma cells, an epigenetic switch from H3K27me3 to H3K27ac occurred at specific genomic loci, altering the transcriptional profile. The resulting upregulation of EPHA2 stimulated excessive activation of the prosurvival AKT signaling pathway, leading to radiotherapy resistance. Bromodomain and extraterminal motif (BET) inhibition overcame radiation resistance in H3K27me3-deficient medulloblastoma cells by suppressing H3K27ac levels, blunting EPHA2 overexpression, and mitigating excessive AKT signaling. In addition, BET inhibition sensitized medulloblastoma cells to radiation by enhancing the apoptotic response through suppression of Bcl-xL and upregulation of Bim. This work demonstrates a novel mechanism of radiation resistance in medulloblastoma and identifies an epigenetic marker predictive of radiotherapy response. On the basis of these findings, we propose an epigenetically guided treatment approach targeting radiotherapy resistance in patients with medulloblastoma. This study demonstrates a novel epigenetic mechanism of radiation resistance in medulloblastoma and identifies a therapeutic approach to improve outcomes in these patients.

Long-Term Risks of Hemorrhage and Adverse Radiation Effects of Stereotactic Radiosurgery for Brain Arteriovenous Malformations.

The information about long-term risks of hemorrhage and late adverse radiation effects (AREs) after stereotactic radiosurgery for brain arteriovenous malformations (AVMs) is lacking. To evaluate the long-term risks of hemorrhage and late ARE rates in patients with AVM treated with Gamma Knife surgery (GKS). We examined 1249 patients with AVM treated with GKS. The Spetzler-Martin grade was I in 313 patients (25%), II in 394 (32%), III in 458 (37%), and IVV in 84 (7%). The median treatment volume was 2.5 cm3, and the median marginal dose was 20 Gy. The median follow-up period was 61 months. The 5- and 10-year nidus obliteration rates were 63% and 82%, respectively. The 5- and 10-year cumulative hemorrhage rates were 7% and 10%, respectively. The annual hemorrhage rate was 1.5% for the first 5 years post-GKS, which decreased to 0.5% thereafter. During the follow-up period, 42 symptomatic cyst formationschronic encapsulated hematomas (CFsCEHs, 3%) and 3 radiation-induced tumors (0.2%) were observed. The 10- and 15-year cumulative CFCEH rates were 3.7% and 9.4%, respectively. GKS is associated with reduced hemorrhage risk and high nidus obliteration rates in patients with AVM. The incidence of late AREs tended to increase over time. The most common ARE was CFCEH, which can be safely removed however, careful attention should be paid to the long-term development of fatal radiation-induced tumors.