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Cellular and molecular features related to exceptional therapy response and extreme long-term survival in glioblastoma.

Glioblastoma Multiforme (GBM) remains the most common malignant primary brain tumor with a dismal prognosis that rarely exceeds beyond 2 years despite extensive therapy, which consists of maximal safe surgical resection, radiotherapy, andor chemotherapy. Recently, it has become clear that GBM is not one homogeneous entity and that both intra-and intertumoral heterogeneity contributes significantly to differences in tumoral behavior which may consequently be responsible for differences in survival. Strikingly and in spite of its dismal prognosis, small fractions of GBM patients seem to display extremely long survival, defined as surviving over 10 years after diagnosis, compared to the large majority of patients. Although the underlying mechanisms for this peculiarity remain largely unknown, emerging data suggest that still poorly characterized both cellular and molecular factors of the tumor microenvironment and their interplay probably play an important role. We hereby give an extensive overview of what is yet known about these cellular and molecular features shaping extreme long survival in GBM.

Hemorrhagic presentation of previously silent brain tumors.

Acute presentation with intracranial hemorrhage owing to a previously silent brain tumor (BT) is rare. Although any BT can bleed, the frequency and type of bleeding varies across tumor types. We aimed to retrospectively review our experience with 55 patients with BTs presenting with ICH. Signs of increased intracranial pressure were the most common symptoms. The temporal lobe was the most common lesion site (n22). Hemorrhages were mainly confined to the tumor margins (HCTs) (n34). Extensive intraparenchymal hemorrhages (EIHs) were mainly associated with moderatelyseverely decreased levels of consciousness (LOCs) (n1516). High-grade glioma (HGGT) (n25) was the leading pathological diagnosis followed by metastasis (MBT) (n1655). The hemorrhage type was associated with the pathological diagnosis of the tumor. Patients with HGGT (n1925) and MBT (n916) mainly presented with HCTs, whereas low-grade gliomas (LGGT) primarily caused EIHs (n67). Hemorrhagic presentation is a rare occurrence in BTs. Among all, MBT and HGGT are responsible for majority of the cases. Importantly, despite their relatively benign characteristics, LGGTs mainly result in extensive parenchymal destruction once they bleed. Maximum surgical resection of hemorrhagic BTs and decompression of the affected brain regions followed by histological confirmation of the diagnosis should be the main goals of treatment in cases with hemorrhagic BTs.

Pharmacological inhibition of serine synthesis enhances temozolomide efficacy by decreasing O

Glioblastoma (GBM) is the most malignant primary tumor in the central nervous system of adults. Temozolomide (TMZ), an alkylating agent, is the first-line chemotherapeutic agent for GBM patients. However, its efficacy is often limited by innate or acquired chemoresistance. Cancer cells can rewire their metabolic programming to support rapid growth and sustain cell survival against chemotherapies. An example is the de novo serine synthesis pathway (SSP), one of the main branches from glycolysis that is highly activated in multiple cancers in promoting cancer progression and inducing chemotherapy resistance. However, the roles of SSP in TMZ therapy for GBM patients remain unexplored. In this study, we employed NCT503, a highly selective inhibitor of phosphoglycerate dehydrogenase (PHGDH, the first rate-limiting enzyme of SSP), to study whether inhibition of SSP may enhance TMZ efficacy in MGMT-positive GBMs. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), flowcytometry and colony formation assays demonstrated that NCT503 worked synergistically with TMZ in suppressing GBM cell growth and inducing apoptosis in T98G and U118 cells in vitro. U118 and patient-derived GBM subcutaneous xenograft models showed that combined NCT503 and TMZ treatment inhibited GBM growth and promoted apoptosis more significantly than would each treatment alone in vivo. Mechanistically, we found that NCT503 treatment decreased MGMT expression possibly by modulating the Wntβ-catenin pathway. Moreover, intracellular levels of reactive oxygen species were elevated especially when NCT503 and TMZ treatments were combined, and the synergistic effects could be partially negated by NAC, a classic scavenger of reactive oxygen species. Taken together, these results suggest that NCT503 may be a promising agent for augmenting TMZ efficacy in the treatment of GBM, especially in TMZ-resistant GBMs with high expression of MGMT. Pharmacological inhibition of the serine synthesis pathway with a highly selective inhibitor NCT503 synergistically works with temozolomide in inhibiting O

Evaluation of an EZH2 inhibitor in patient-derived orthotopic xenograft models of pediatric brain tumors alone and in combination with chemo- and radiation therapies.

Brain tumors are the leading cause of cancer-related death in children. Tazemetostat is an FDA-approved enhancer of zeste homolog (EZH2) inhibitor. To determine its role in difficult-to-treat pediatric brain tumors, we examined EZH2 levels in a panel of 22 PDOX models and confirmed EZH2 mRNA over-expression in 9 GBM (34.6 ± 12.7-fold) and 11 medulloblastoma models (6.2 ± 1.7 in group 3, 6.0 ± 2.4 in group 4) accompanied by elevated H3K27me3 expression. Therapeutic efficacy was evaluated in 4 models (1 GBM, 2 medulloblastomas and 1 ATRT) via systematically administered tazemetostat (250 and 400 mgkg, gavaged, twice daily) alone and in combination with cisplatin (5 mgkg, i.p., twice) andor radiation (2 Gyday × 5 days). Compared with the untreated controls, tazemetostat significantly (P

Phenotyping clonal populations of glioma stem cell reveals a high degree of plasticity in response to changes of microenvironment.

The phenotype of glioma-initiating cells (GIC) is modulated by cell-intrinsic and cell-extrinsic factors. Phenotypic heterogeneity and plasticity of GIC is an important limitation to therapeutic approaches targeting cancer stem cells. Plasticity also presents a challenge to the identification, isolation, and propagation of purified cancer stem cells. Here we use a barcode labelling approach of GIC to generate clonal populations over a number of passages, in combination with phenotyping using the established stem cell markers CD133, CD15, CD44, and A2B5. Using two cell lines derived from isocitrate dehydrogenase (IDH)-wildtype glioblastoma, we identify a remarkable heterogeneity of the phenotypes between the cell lines. During passaging, clonal expansion manifests as the emergence of a limited number of barcoded clones and a decrease in the overall number of clones. Dual-labelled GIC are capable of forming traceable clonal populations which emerge after as few as two passages from mixed cultures and through analyses of similarity of relative proportions of 16 surface markers we were able to pinpoint the fate of such populations. By generating tumour organoids we observed a remarkable persistence of dominant clones but also a significant plasticity of stemness marker expression. Our study presents an experimental approach to simultaneously barcode and phenotype glioma-initiating cells to assess their functional properties, for example to screen newly established GIC for tumour-specific therapeutic vulnerabilities. The authors barcoded glioma-initiating cells (GIC) using combinations of virally encoded fluorophores. GIC show a strong tendency to form clonal populations over as few as two passages. Combined with stem cell marker phenotyping and computational analysis, they could trace the fate of such populations. This model presents an approach for rapid assessment of newly established GIC to assess tumour-specific vulnerabilities.

Sporadic and Lynch syndrome-associated mismatch repair-deficient brain tumors.

Mismatch repair-deficient (MMRD) brain tumors are rare among primary brain tumors and can be induced by germline or sporadic mutations. Here, we report 13 MMRD-associated (9 sporadic and 4 Lynch syndrome) primary brain tumors to determine clinicopathological and molecular characteristics and biological behavior. Our 13 MMRD brain tumors included glioblastoma (GBM) IDH-wildtype (n 9) including 1 gliosarcoma, astrocytoma IDH-mutant WHO grade 4 (n 2), diffuse midline glioma (DMG) H3 K27M-mutant (n 1), and pleomorphic xanthoastrocytoma (PXA) (n 1). Next-generation sequencing using a brain tumor-targeted gene panel, microsatellite instability (MSI) testing, Sanger sequencing for germline MMR gene mutation, immunohistochemistry of MMR proteins, and clinicopathological and survival analysis were performed. There were many accompanying mutations, suggesting a high tumor mutational burden (TMB) in 77%, but TMB was absent in one case of GBM, IDH-wildtype, DMG, and PXA, respectively. MSH2, MLH1, MSH6, and PMS2 mutations were found in 31%, 31%, 31% and 7% of patients, respectively. MSI-high and MSI-low were found in 50% and 8% of these gliomas, respectively and 34% was MSI-stable. All Lynch syndrome-associated GBMs had MSI-high. In addition, 77% (1013) had histopathologically multinucleated giant cells. The progression-free survival tended to be poorer than the patients with no MMRD gliomas, but the number and follow-up duration of our patients were insufficient to get statistical significance. In the present study, we found that the most common MMRD primary brain tumor was GBM IDH-wildtype. The genetic profile of MMRD GBM was different from that of conventional GBM. MMRD gliomas with TMB and MSI-H may be sensitive to immunotherapy but resistant to temozolomide. Our findings can help develop better treatment options. The authors examined 13 mismatch repair-deficient (MMRD)-associated primary brain tumors to determine molecular characteristics and biological behavior. MMRD occurred after chemotherapy and radiotherapy in two cases. The genetic profile of MMRD glioblastoma was different from that of conventional glioblastoma. Half of the MMRD-gliomas and all Lynch syndrome-associated GBMs were high in microsatellite instability. These tumors had high mutational burdens and tended to have shorter progression-free survival than glioma without MMRD.

Predicting 1p19q co-deletion status from magnetic resonance imaging using deep learning in adult-type diffuse lower-grade gliomas a discovery and validation study.

Determination of 1p19q co-deletion status is important for the classification, prognostication, and personalized therapy in diffuse lower-grade gliomas (LGG). We developed and validated a deep learning imaging signature (DLIS) from preoperative magnetic resonance imaging (MRI) for predicting the 1p19q status in patients with LGG. The DLIS was constructed on a training dataset (n 330) and validated on both an internal validation dataset (n 123) and a public TCIA dataset (n 102). The receiver operating characteristic (ROC) analysis and precision recall curves (PRC) were used to measure the classification performance. The area under ROC curves (AUC) of the DLIS was 0.999 for training dataset, 0.986 for validation dataset, and 0.983 for testing dataset. The F1-score of the prediction model was 0.992 for training dataset, 0.940 for validation dataset, and 0.925 for testing dataset. Our data suggests that DLIS could be used to predict the 1p19q status from preoperative imaging in patients with LGG. The imaging-based deep learning has the potential to be a noninvasive tool predictive of molecular markers in adult diffuse gliomas. The authors developed a deep learning model predictive of 1p19q status from preoperative imaging in 555 lower-grade gliomas (LGG), and achieved an area under the curve (AUC) of 0.983 in the testing dataset. They reveal that developing deep learning imaging signatures could be a noninvasive tool for predicting molecular markers in LGG.

Phospholipase Cγ1 (PLCG1) overexpression is associated with tumor growth and poor survival in IDH wild-type lower-grade gliomas in adult patients.

Gliomas are the most common and recalcitrant intracranial tumors, approximately a quarter of which are classified as lower-grade gliomas (WHO II-III). Although the prognosis of lower-grade gliomas (LGGs) is significantly better than that of higher-grade gliomas, as a highly heterogeneous tumor type, the prognosis of LGGs varies greatly based on the molecular diagnosis. IDH wild-type used to be regarded as a dismal prognostic biomarker in LGGs however, several studies revealed that IDH wild-type LGGs might not always be equivalent to glioblastoma (WHO IV). Hence, we hypothesize that underlying biological events in LGGs can result in different prognosis. In our study, transcriptome profiling was performed in 24 samples of LGG, and the results showed that the expression of phospholipase Cγ1 (PLCG1) was significantly correlated with IDH12 status and patients clinical outcome. Furthermore, the cancer genome atlas (TCGA) and the Chinese glioma genome atlas (CGGA) databases verified that elevated PLCG1 expression was associated with tumor progression and poor survival in LGG patients. Moreover, PLCG1-targeted siRNA dramatically affected the growth, migration and invasiveness of IDH wild-type LGG cell lines. In in vitro and in vivo experiments, the PLC-targeted drug significantly suppressed the tumor growth of IDH wild-type LGG cell lines in vitro and tumors in mouse models. Taken together, our results demonstrated that higher PLCG1 expression was associated with tumor growth and worse prognosis in IDH wild-type LGGs and PLCG1 could serve as a potential therapeutic target for IDH wild-type LGG patients. The mRNA expression levels of phospholipase Cγ1 (PLCG1) are much higher in IDH wild-type (IDHwt) lower-grade gliomas (LGGs) than in that of IDH mutant (IDHmut) LGGs. Higher PLCG1expression in IDHwt LGGs indicates poor clinical outcome. PLCG1 amplification may act as the key mechanism of PLCG1 upregulation. Depletion of PLCG1 expression can inhibits proliferation and invasion of IDHwt LGG cell lines in vitro and in vivo. The PLC inhibitor U73122 may therefore be a potential therapeutical agent for IDHwt LGGs.

Circulating tumor DNA profiling for childhood brain tumors Technical challenges and evidence for utility.

Cell-free DNA (cfDNA) profiling as liquid biopsy has proven value in adult-onset malignancies, serving as a patient-specific surrogate for residual disease and providing a non-invasive tool for serial interrogation of tumor genomics. However, its application in neoplasms of the central nervous system (CNS) has not been as extensively studied. Unique considerations and methodological challenges exist, which need to be addressed before cfDNA studies can be incorporated as a clinical assay for primary CNS diseases. Here, we review the current status of applying cfDNA analysis in patients with CNS tumors, with special attention to diagnosis in pediatric patients. Technical concerns, evidence for utility, and potential developments are discussed. Cell-free DNA (cfDNA) profiling as liquid biopsy is of clinical utility in carcinomas of adult-onset. However, its application in childhood cancers, including brain tumors, has not been as extensively studied. In this article, we review the current status of applying cfDNA analysis for pediatric central nervous system neoplasms. Technical challenges, evidence for utility based on current literature, and potential future developments are discussed.

Grading of adult diffuse gliomas according to the 2021 WHO Classification of Tumors of the Central Nervous System.

The grading of gliomas based on histological features has been a subject of debate for several decades. A consensus has not yet been reached because of technical limitations and inter-observer variations. While the traditional grading system has failed to stratify the risk of IDH-mutant astrocytoma, canonical histological and proliferative markers may be applicable to the risk stratification of IDH-wild-type astrocytoma. Numerous studies have examined molecular markers in order to obtain more clinically relevant information that will improve the risk stratification of gliomas. The CDKN2AB homozygous deletion for IDH-mutant astrocytoma and the following three criteria for IDH-wild-type astrocytoma the concurrent gain of whole chromosome 7 and loss of whole chromosome 10, TERT promoter mutations, and EGFR amplification, were identified as independent molecular markers of the worst clinical outcomes. Therefore, the 2021 World Health Organization (WHO) Classification of Tumors of the Central Nervous System adopted these molecular markers into the revised grading criteria of IDH-mutant and -wild-type astrocytoma, respectively, as a grading system within tumor types. Of note, several recent studies have shown that some low-grade IDH-wild-type astrocytoma lacking both the molecular glioblastoma signature and genetic alterations typical of pediatric-type gliomas may demonstrate a relatively indolent clinical course, suggesting the existence of lower-grade adult IDH-wild-type astrocytoma. In terms of oligodendroglioma, IDH-mutant, and 1p19q codeleted, consistent makers that predict poor outcomes have not yet been identified, and, thus, the current criteria have remained unchanged. Molecular testing to fulfill the revised WHO criteria is, however, not always available worldwide, and in that case, an integrated diagnosis combining all available complementary information is highly recommended. This review discusses controversial issues surrounding legacy grading systems and newly identified potential genetic markers of adult diffuse gliomas and provides perspectives on future grading systems. The 5th edition of WHO Classification of Tumors of the Central Nervous System adopted new molecular markers into the revised grading criteria of IDH-mutant and -wild-type astrocytoma, i.e., the CDKN2AB homozygous deletion for IDH-mutant astrocytoma and the following three criteria for IDH-wild-type astrocytoma the concurrent gain of whole chromosome 7 and loss of whole chromosome 10, TERT promoter mutations, and EGFR amplification, as independent molecular markers of the highest grade.

Anti-tumor effects of vitamin D in glioblastoma mechanism and therapeutic implications.

Glioma is the most prevalent primary brain tumor in adults among which glioblastoma is the most malignant and lethal subtype. Its common resistance to conventional chemotherapeutics calls for the development of alternative or concomitant treatment. Taking advantage of its endocrine function as a neurosteroid, vitamin D has become a target of interest to be used in conjunction with different chemotherapies. In this article, we review the mechanisms through which vitamin D and its analogs induce anti-tumor activity in glioblastoma, and the practical issues relevant to their potential application based on in vitro and in vivo studies. Vitamin D has largely been reported to promote cell cycle arrest and induce cell death to suppress tumor growth in glioblastoma. Glioblastoma cells treated with vitamin D have also shown reduced migratory and invasive phenotypes, and reduced stemness. It is worth noting that vitamin D analogs are able to produce similar inhibitory actions without causing adverse effects such as hypercalcemia in vivo. Upregulation of vitamin D receptors by vitamin D and its analogs may also play a role in enhancing its anti-tumor activity. Based on current findings and taking into consideration its potential cancer-protective effects, the clinical application of vitamin D in glioblastoma treatment and prevention will be discussed. With some study findings subject to controversy, further investigation is warranted to elucidate the mechanism of action of vitamin D and to evaluate relevant issues regarding its treatment efficacy and potential clinical application. Vitamin D has recently emerged as a neurosteroid and a regulator of various physiological functions. It has been widely reported to promote tumor-suppressive effects, however this proposal remains controversial. This article reviews the anti-tumoral mechanisms of vitamin D in glioblastoma, current evidence of its therapeutic application as a supplement to standard chemotherapy, and its potential applications for cancer prevention it endeavors to offer insight into new means of overcoming chemoresistance and improving glioma patient survival.

A convolutional neural network model for survival prediction based on prognosis-related cascaded Wx feature selection.

Great advances in deep learning have provided effective solutions for prediction tasks in the biomedical field. However, accurate prognosis prediction using cancer genomics data remains challenging due to the severe overfitting problem caused by curse of dimensionality inherent to high-throughput sequencing data. Moreover, there are unique challenges to perform survival analysis, arising from the difficulty in utilizing censored samples whose events of interest are not observed. Convolutional neural network (CNN) models provide us the opportunity to extract meaningful hierarchical features to characterize cancer subtype and prognosis outcomes. On the other hand, feature selection can mitigate overfitting and reduce subsequent model training computation burden by screening out significant genes from redundant genes. To accomplish model simplification, we developed a concise and efficient survival analysis model, named CNN-Cox model, which combines a special CNN framework with prognosis-related feature selection cascaded Wx, with the advantage of less computation demand utilizing light training parameters. Experiment results show that CNN-Cox model achieved consistent higher C-index values and better survival prediction performance across seven cancer type datasets in The Cancer Genome Atlas cohort, including bladder carcinoma, head and neck squamous cell carcinoma, kidney renal cell carcinoma, brain low-grade glioma, lung adenocarcinoma (LUAD), lung squamous cell carcinoma, and skin cutaneous melanoma, compared with the existing state-of-the-art survival analysis methods. As an illustration of model interpretation, we examined potential prognostic gene signatures of LUAD dataset using the proposed CNN-Cox model. We conducted protein-protein interaction network analysis to identify potential prognostic genes and further analyzed the biological function of 13 hub genes, including ANLN, RACGAP1, KIF4A, KIF20A, KIF14, ASPM, CDK1, SPC25, NCAPG, MKI67, HJURP, EXO1, HMMR, whose high expression is significantly associated with poor survival of LUAD patients. These findings confirmed that CNN-Cox model is effective in extracting not only prognosis factors but also biologically meaningful gene features. The codes are available at the GitHub website httpsgithub.comwangwangCCChenCNN-Cox.

Solitary Sclerotic Fibroma of Right Cerebellopontine Angle.

Sclerotic fibroma (storiform collagenoma) is a fibrotic tumor that occurs mainly in patients with Cowden syndrome, but it can also occur in isolation, as detailed in previous reports (Rapini RP, 1989 and Weary PE, 1972).

Carnosol inhibits cerebral ischemia-reperfusion injury by promoting AMPK activation.

Carnosol is a phytopolyphenol (diterpene) found and extracted from plants of Mediterranean diet, which has anti-tumor, anti-inflammatory and antioxidant effects. However, its role in ischemic stroke has not been elucidated. Primary neurons subjected to oxygen-glucose deprivation (OGD) was used to investigate the effect of carnosol in vitro. A mouse MCAO model was used to evaluate the effect of carnosol on ischemic stroke in vivo. The mRNA level of inflammatory and apoptosis-related genes was determined by RT-PCR. The protein level of total and phosphorylated AMPK was determined by WB. HE and Immunofluorescent assay was used to investigate the necrosis, inflammation and apoptosis in brain tissue. Carnosol protected the activity of primary neurons subjected to oxygen-glucose deprivation (OGD) in vitro, as well as inhibited inflammation and apoptosis. Furthermore, carnosol could significantly reduce the infarct and edema volume and protect against neurological deficit in vivo, and had a significant inhibitory effect on brain neuroinflammation and apoptosis. Mechanically, carnosol could activate AMPK, and the effect of carnosol on cerebral ischemia-reperfusion injury cell model could be abolished by AMPK phosphorylation inhibitor. Carnosol has a protective effect on ischemic stroke, and this effect is achieved through AMPK activation. Our study demonstrates the protective effect of carnosol on cerebral ischemia-reperfusion injury and provides a new perspective for the clinical treatment of ischemic stroke.

Antidiabetic drug sitagliptin blocks cyclophosphamide cerebral neurotoxicity by activating Nrf2 and suppressing redox cycle imbalance, inflammatory iNOSNONF-κB response and caspase-3Bax activation in rats.

Cyclophosphamide (CYP) is a classic DNA-interacting anticancer agent with broad application in chemotherapy. However, CYP cerebral neurotoxicity is a worrisome side effect for clinicians and patients. Strategies to mitigate the underlying oxidative inflammatory cascades and neuroapoptosis induced by CYP are urgently needed. Herein, we have repurposed an antidiabetic drug, sitagliptin (STG), for a possible abrogation of CYP-induced cerebral neurotoxicity in rats. Healthy rats were administered STG (20 mgkg body weight) for 5 days prior to neurotoxicity induced by CYP (200 mgkg body weight, ip) on day 5 only, and rats were sacrificed after 24 h post-CYP injection. CYP caused profound increases in the cerebral levels of nitric oxide (NO), acetylcholinesterase (AChE), malondialdehyde (MDA), interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), nuclear factor-kappaB (NF-κB), inducible nitric oxide synthase (iNOS), caspase-3 and Bax protein compared to the control. Furthermore, CYP markedly depressed the activities of glutathione peroxidase (GPx), catalase (CAT) and superoxide dismutase (SOD), along with levels of reduced glutathione (GSH) and nuclear factor erythroid 2-related factor2 (Nrf2) compared to the control (p < 0.05). Interestingly, STG pretreatment inhibited the CYP-induced alterations in caspase-3, Bax, pro-inflammatory cytokines, NO, iNOS, AChE, NF-κB, and restored the cerebral antioxidant apparatus, including the Nrf2 and histopathological abrasions. Therefore, these findings show that STG could be repurposed to prevent CYP-induced cerebral toxicity in the brain.

Pituitary apoplexy and SARS-CoV-2 (COVID-19) infection.

Coronavirus disease (SARS-CoV-2COVID-19) is responsible for a wide variety of extrapulmonary manifestations, among which direct or indirect neurological compromise stands out. Pituitary apoplexy is a clinical and neurosurgical entity of variable severity, usually associated with a pituitary adenoma. Literature is scarce regarding the association between these diseases. This paper reports a case of pituitary apoplexy, manifested concomitantly to the diagnosis of COVID 19 in a patient with unknown pituitary macroadenoma, and its therapeutic management, reviewing the mechanisms potentially underlying the link between both entities. La infección por coronavirus (SARS-CoV-2COVID-19) es responsable de un diverso rango de manifestaciones extrapulmonares entre las cuales se destaca el compromiso neurológico directo o indirecto. La apoplejía hipofisaria es una entidad médica y neuroquirúrgica de gravedad variable que suele asociarse a la presencia de un adenoma subyacente. Un escaso número de reportes han vinculado estas dos enfermedades entre sí. Este trabajo describe un caso de apoplejía hipofisaria manifestada clínicamente en forma concomitante al diagnóstico de COVID 19, en un paciente con macroadenoma hipofisario desconocido y su manejo terapéutico, revisando los mecanismos potencialmente subyacentes al nexo entre ambas entidades.

Atrial myxoma and associated Cushing syndrome Carney complex.

A 33-year-old woman with a history of high blood pressure since she was 8 years old, hypothyroidism, polycystic ovary syndrome, metabolic syndrome, multiple nevi, and a maternal family history of death at age 50 due to malignant high blood pressure and heart failure. Cushings syndrome secondary to a secretory pituitary microadenoma was diagnosed, being the cause of secondary arterial hypertension, and ruling out other causes such as renal stenosis and coarctation of the aorta. A transthoracic and transesophageal echocardiogram was performed, which detected a left atrial myxoma. Given the presence of an atrial myxoma, Cushings syndrome and polycystic ovary syndrome, a diagnosis of Carney Complex was made due to the presence of positive Stratakis criteria. The cardiac tumor was resected, and pathology confirmed that it was an atrial myxoma. She evolved clinically stable in outpatient controls in a 6-month follow-up. Resection of the pituitary microadenoma is planned as a curative treatment for Cushings syndrome and arterial hypertension. Mujer de 33 años, con antecedentes de hipertensión arterial desde los 8 años, hipotiroidismo, síndrome de ovario poliquístico, síndrome metabólico, nevos múltiples y antecedente familiar materno de muerte a los 50 años por hipertensión arterial maligna e insuficiencia cardiaca. Se diagnosticó síndrome de Cushing secundario a un microadenoma hipofisario secretor, siendo la causa de la hipertensión arterial secundaria, y descartándose otras causas como estenosis renal y coartación de aorta. Se realizó u n ecocardiograma transtorácico y transesofágico que detectaron un mixoma auricular izquierdo. Ante la presencia de un mixoma auricular, síndrome de Cushing y síndrome de ovario poliquístico se llegó al diagnóstico de Complejo de Carney por la presencia de criterios de Stratakis positivos. Se realizó la resección del tumor cardiaco, y la anatomía patológica confirmó que se trataba de un mixoma auricular. Evolucionó clínicamente estable en controles ambulatorios en un seguimiento de 6 meses, y se planifica la resección del microadenoma hipofisario como tratamiento curativo del síndrome de Cushing y la hipertensión arterial.

Liquid biopsies the future of cancer early detection.

Cancer is a worldwide pandemic. The burden it imposes grows steadily on a global scale causing emotional, physical, and financial strains on individuals, families, and health care systems. Despite being the second leading cause of death worldwide, many cancers do not have screening programs and many people with a high risk of developing cancer fail to follow the advised medical screening regime due to the nature of the available screening tests and other challenges with compliance. Moreover, many liquid biopsy strategies being developed for early detection of cancer lack the sensitivity required to detect early-stage cancers. Early detection is key for improved quality of life, survival, and to reduce the financial burden of cancer treatments which are greater at later stage detection. This review examines the current liquid biopsy market, focusing in particular on the strengths and drawbacks of techniques in achieving early cancer detection. We explore the clinical utility of liquid biopsy technologies for the earlier detection of solid cancers, with a focus on how a combination of various spectroscopic and -omic methodologies may pave the way for more efficient cancer diagnostics.

An initial study on the predictive value using multiple MRI characteristics for Ki-67 labeling index in glioma.

Ki-67 labeling index (LI) is an important indicator of tumor cell proliferation in glioma, which can only be obtained by postoperative biopsy at present. This study aimed to explore the correlation between Ki-67 LI and apparent diffusion coefficient (ADC) parameters and to predict the level of Ki-67 LI noninvasively before surgery by multiple MRI characteristics. Preoperative MRI data of 166 patients with pathologically confirmed glioma in our hospital from 2016 to 2020 were retrospectively analyzed. The cut-off point of Ki-67 LI for glioma grading was defined. The differences in MRI characteristics were compared between the low and high Ki-67 LI groups. The receiver operating characteristic (ROC) curve was used to estimate the accuracy of each ADC parameter in predicting the Ki-67 level, and finally a multivariate logistic regression model was constructed based on the results of ROC analysis. ADC There was a negative correlation between ADC parameters and Ki-67 LI, and the multivariate logistic regression model combined with peritumoral edema and ADC parameters could improve the prediction ability of Ki-67 LI.

Cystic versus non-cystic silent corticotrophic adenomas clinical and histological analysis of 62 cases after microscopic transsphenoidal surgery-a retrospective, single-center study.

Silent corticotrophic adenomas (SCAs) represent a rare group of non-functioning adenomas with a potentially aggressive clinical course. Cystic component is a very common finding among SCAs, but its clinical relevance has not yet been investigated. The aim of this study was to analyze clinical features of cystic and non-cystic SCAs, perioperative complications after microscopic transsphenoidal surgery, clinical outcome after first and repeat surgery along with risk factors for recurrence. We conducted a retrospective analysis of 62 silent corticotrophic adenomas treated at our university medical center via microscopic transsphenoidal surgery between January 2008 and July 2019. Parameters investigated included histology, invasiveness, intratumoral haemorrhage or cystic component on MRI, perioperative alteration of visual field, tumor size, pre- and postoperative ACTH, FSH, GH, LH, TSH, prolactin, cortisol, free T4, free T3, IGF-1, estrogen and testosterone levels, perioperative complications, neoadjuvant and adjuvant therapy along with clinical outcomes. A total of 62 patients were analyzed. The mean follow up was 28.3 months. Tumors with a cystic component occur statistically significant more often among male than non-cystic (80.6% vs. 44.4%, p 0.02) and display lower rates of cavernous sinus invasion and sphenoid sinus invasion were significantly lower for cystic lesions comparing to non-cystic tumors (42.3% vs. 69.4%, p 0.04 and 3.8% vs. 47.2%, p < 0.001). GTR after MTS was not statistically significant higher by cystic SCAs (80% vs. 57.1%, p 0.09). Cystic lesions were also associated with higher risk of hyperprolactinemia (19.4% vs. 2.8%, p 0.02) and only densely granulated cystic SCAs presented with preoperative intratumoral hemorrhage (19.2% vs. 0%, p 0.01). Mean duration of first surgery was significantly shorter for cystic SCAs (71.6(± 18.7) vs. 94.8(± 31.1) minutes, p 0.01). Preoperative pituitary insufficiency (25% vs. 16.7%, p 0.49), intraoperative CSF space opening (21.1% vs. 37.5%, p 0.32), along with postoperative new pituitary insufficiency (15% vs. 10%, p 0.67) or diabetes insipidusSIADH (10% vs. 13.3%, p > 0.99) with histological markers such as Ki67 (21.1% vs. 13.8%, p 0.70) and p53 expression (6.3% vs. 0%, p 0.39) as well as mitotic rate (5.3% vs. 10.3%, p > 0.99) were comparable between both groups. The presence of cystic component did not affect the tumor recurrence (10% vs. 16%, p 0.68). Mean duration of surgery was first surgeries was not statistically shorter than repeat surgeries (85.4 ± 29.1 vs. 93.8 ± 28 min, p 0.15). Patients undergoing first surgery had a higher probability of gross total resection (74.4% vs. 30%, p 0.01) and lower probability of intraoperative CSF space opening (26% vs. 58.3%, p 0.04) as well as a lower rate of preoperative anterior pituitary insufficiency (20% vs. 58.3%, p 0.01). The incidence of new postoperative anterior pituitary insufficiency (10% vs. 0%, p 0.57) and transient diabetes insipidusSIADH (12% vs. 8.3%, p > 0.99) between those groups were comparable. No statistical difference was observed between patients with remission and with recurrent tumor regarding cortisol and ACTH levels, incidence of different histological subgroups, invasively growing tumors and lesions with cystic components as well as the percentage of cases with increased Ki67 proliferation index, p53 expression and mitotic indices. Our study presents one of the largest available cohorts of SCAs after microscopic transsphenoidal surgery and first clinical analysis of cystic versus non-cystic SCAs so far. We also performed the first comparison of index and repeat surgeries for this tumor entity. Cystic tumors presented with characteristic clinical aspects like male predominance, higher risk of hyperprolactinemia as well as lower rates of cavernous sinus and sphenoid sinus invasion comparing to non-cystic lesions. Mean duration of first surgery was significantly shorter for cystic SCAs. Moreover preoperative intratumoral hemorrhage had 100% specificity and 60% sensitivity for densely granulated cystic SCAs. All these clinical hallmarks may suggest a novel subgroup of SCAs with distinct clinical and biological features, however further clinical and molecular investigations are required. Second surgeries are associated with a higher incidence of preoperative pituitary insufficiency, and a higher risk of subtotal resection, and a higher probability of CSF space opening intraoperatively compared to first surgeries. On the other hand, the risk of new postoperative pituitary insufficiency was higher after first surgeries. In our cohort of patients, no prognostic factor for recurrence among histological diagnosis, Ki67-proliferation index, p53 expression, number of mitoses, invasive growth or cystic lesions for SCAs could be detected.

T cell-independent eradication of experimental glioma by intravenous TLR78-agonist-loaded nanoparticles.

Glioblastoma, the most common and aggressive primary brain tumor type, is considered an immunologically cold tumor with sparse infiltration by adaptive immune cells. Immunosuppressive tumor-associated myeloid cells are drivers of tumor progression. Therefore, targeting and reprogramming intratumoral myeloid cells is an appealing therapeutic strategy. Here, we investigate a β-cyclodextrin nanoparticle (CDNP) formulation encapsulating the Toll-like receptor 7 and 8 (TLR78) agonist R848 (CDNP-R848) to reprogram myeloid cells in the glioma microenvironment. We show that intravenous monotherapy with CDNP-R848 induces regression of established syngeneic experimental glioma, resulting in increased survival rates compared with unloaded CDNP controls. Mechanistically, CDNP-R848 treatment reshapes the immunosuppressive tumor microenvironment and orchestrates tumor clearing by pro-inflammatory tumor-associated myeloid cells, independently of T cells and NK cells. Using serial magnetic resonance imaging, we identify a radiomic signature in response to CDNP-R848 treatment and ultrasmall superparamagnetic iron oxide (USPIO) imaging reveals that immunosuppressive macrophage recruitment is reduced by CDNP-R848. In conclusion, CDNP-R848 induces tumor regression in experimental glioma by targeting blood-borne macrophages without requiring adaptive immunity.

Distribution and surgical management of visceral Ewing sarcoma among children and adolescents.

Ewing sarcoma (EWS) is a highly malignant tumor of bone and soft tissue that occasionally arises from viscera. Visceral EWS (V-EWS) is challenging to manage given its varied organ distribution and often late-stage presentation. We aimed to characterize our institutional experience with V-EWS, focusing on its surgical management, and to compare V-EWS outcomes against those with osseous (O-EWS) and soft tissue EWS (ST-EWS). Retrospective review of all EWS patients ≤21 years presenting to a single institution between 2000 and 2022. Patient- and disease-specific characteristics were compared. Overall and relapse-free survival were estimated using Kaplan Meier methods and log-rank test. 156 EWS patients were identified 117 O-EWS, 20 ST-EWS, and 19 V-EWS. V-EWS arose in the kidney (n 5), lung (n 5), intestine (n 2), esophagus (n 1), liver (n 1), pancreas (n 1), adrenal gland (n 1), vagina (n 1), brain (n 1), and spinal cord (n 1). No significant demographic differences were detected between EWS groups. V-EWS was more frequently metastatic at presentation (63.2% p 0.005), yet no significant overall or relapse-free survival differences emerged between EWS groups, with similar follow-up intervals. While V-EWS required multiple unique operative strategies to gain primary control, no significant difference in treatment strategies appeared between groups. Surgery-only primary control was associated with improved overall and relapse-free survival in all groups. V-EWS presents unique management challenges in children and adolescents given its variable sites of origin. This large cohort is the first to describe the surgical management and outcomes of V-EWS, demonstrating more frequent metastatic presentation, while achieving similar survival across groups. Level 2 - Cohort Study.

Oral chronic toxicity and carcinogenicity study of alpha-glycosyl isoquercitrin (AGIQ) in Sprague Dawley rats.

alpha-Glycosyl isoquercitrin (AGIQ) is a flavonoid that possesses antioxidative and tumor suppressive capabilities and is marketed as a food additive in Japan. The aim of this study was to assess the potential for oral chronic toxicity and carcinogenicity of AGIQ in male and female Sprague Dawley rats following up to 5.0% dietary exposure. In the chronic toxicity study, rats were exposed to AGIQ or vehicle for one year with a 6-month interim termination point for the carcinogenicity study, rats were treated for 24 months. No signs of AGIQ-related toxicity clinically or histologically were observed for up to one year except for yellow discoloration of bone. In the carcinogenicity study, a statistically significant increase in the incidence of malignant glioma of the brain or spinal cord was observed in female rats exposed to 5.0% AGIQ compared to those exposed to control feed. A Scientific Advisory Panel of experienced neuropathologists reviewed the gliomas (routine stains and glial cell markers) and concluded that the gliomas were a rare, spontaneous, rat-specific neoplasm malignant microglial tumor. The lesions could not definitively be attributed to AGIQ exposure and have limited implications with respect to predicting human cancer risk.

Macrophage cell membrane infused biomimetic liposomes for glioblastoma targeted therapy.

Glioblastoma (GBM) is a highly aggressive malignant brain tumor currently without an effective treatment. Inspired by the recent advances in cell membrane biomimetic nanocarriers and by the key role of macrophages in GBM pathology, we developed macrophage membrane liposomes (MML) for GBM targeting. For the first time, it was assessed the role of macrophage polarization states in the effectiveness of these drug delivery systems. Interestingly, we observed that MML derived from M2 macrophages (M2 MML) presents higher uptake and increased delivery of the anticarcinogenic drug doxorubicin compared to M1 macrophage-derived nanocarriers (M1 MML) and control liposomes (CL). Moreover, the lowest uptake by macrophages of MML reveals promising immune escaping properties. Notably, M2 macrophages unveiled a higher expression of integrin CD49d, a crucial protein involved in the bilateral communication of macrophages with tumor cells. Therefore, our findings suggest the potential of using M2 macrophage membranes to develop novel nanocarriers targeting GBM.

MARCO is a potential prognostic and immunotherapy biomarker.

Macrophage receptor with collagenous structure (MARCO), a novel immune checkpoint expressed on tumor-associated macrophages, has antitumor therapeutic properties. However, the association between MARCO and patient prognosis, immune infiltration, and ICI immunotherapy needs to be studied urgently. MARCO distribution in cancer tissues was investigated using the TCGA and GTEx databases. The PrognoScan and KM Plotter databases was used to assess the MARCO prognosis. TIMER2.0, GEPIA, cBioPortal, and GSEA all confirmed the link between MARCO and immune infiltration, mutation profile, and enrichment pathway analysis. Data visualization was implemented by R language. In general, MARCO had a substantial impact on the prognosis of cancer patients and was expressed differently in cancer and adjacent normal tissues. High expression of MARCO was associated with poorer OS in bladder urothelial carcinoma (BLCA), breast invasive carcinoma (BRCA), lung squamous cell carcinoma (LUSC), colon adenocarcinoma (COAD), and prostate adenocarcinoma (PRAD). However, high expression of MARCO had a better PFI in brain lower-grade glioma (LGG) and skin cutaneous melanoma (SKCM). We discovered that MARCO expression was lowest in pancreatic adenocarcinoma (PAAD) and rectum adenocarcinoma (READ) stage 1, BLCA stage 2, LUSC and stomach adenocarcinoma (STAD) stage 3, and liver hepatocellular carcinoma (LIHC) stage 4. Subsequently, we analyzed the correlation between MARCO and 47 immune checkpoints and observed that MARCO was positively connected with CD80, CD86, and leukocyte-associated immunoglobulin-like receptor 1(LAIR1) in most cancers. In COAD, MARCO has the most microsatellite instability (MSI). In addition, we discovered that high expression of MARCO patients had a better prognosis after immune checkpoint inhibitor (ICI) treatment in SKCM. Finally, GSEA revealed a significant correlation between MARCO and TNFNFκB signaling, KRAS signaling, PI3KAKTmTOR pathway, IL-6-STAT3 signaling, TGFβ pathway, and p53 pathway. This study comprehensively investigated the relationship between MARCO and clinical prognosis, immune infiltration, and ICI immunotherapy in various cancers. We demonstrated the potential of MARCO as an emerging biomarker, exploring new avenues for future tumor immunotherapy.

Recovery of neurosurgical high-frequency electroporation injury in the canine brain can be accelerated by 7,8-dihydroxyflavone.

Although traumatic brain injury (TBI) occurs in a very short time, the biological consequence of a TBI, such as Alzheimers disease, may last a lifetime. To date, effective interventions are not available to improve recovery from a TBI. Herein we aimed to ascertain whether recovery of neurosurgical high-frequency irreversible electroporation (HFIRE) injury in brain tissues can be accelerated by 7,8-dihydroxyflavone (7,8-DHF). The HFIRE injury was induced in the right parietal cortex of 8 adult healthy and neurologically intact male dogs. Two weeks before HFIRE injury, each dog was administered orally with or without 7,8-DHF (30 mgkg) once daily for consecutive 2 weeks (n 4 for each group). The values of blood-brain barrier (BBB) disruption, brain edema, and cerebral infarction volumes were measured. The concentrations of beta-amyloid, interleukin-1β, interleukin-6 and tumor necrosis factor-α in the cerebrospinal fluid were measured biochemically. The BBB disruption, brain edema, infarction volumes, and maximal cross-section area caused by HFIRE injury in canine brain were significantly attenuated by 7,8-DHF therapy (P < 0.0001). Additionally, 7,8-DHF significantly reduced the HFIRE-induced cerebral overproduction of beta-amyloid and proinflammatory cytokines in the cerebrospinal fluid (P < 0.0001) in dogs with HFIRE. Recovery of neurosurgical HFIRE injury in canine brain tissues can be accelerated by 7,8-DHT via ameliorating BBB disruption as well as cerebral overproduction of both beta-amyloid and proinflammatory cytokines.

A Two-Step Feature Selection Radiomic Approach to Predict Molecular Outcomes in Breast Cancer.

Breast Cancer (BC) is the most common cancer among women worldwide and is characterized by intra- and inter-tumor heterogeneity that strongly contributes towards its poor prognosis. The Estrogen Receptor (ER), Progesterone Receptor (PR), Human Epidermal Growth Factor Receptor 2 (HER2), and Ki67 antigen are the most examined markers depicting BC heterogeneity and have been shown to have a strong impact on BC prognosis. Radiomics can noninvasively predict BC heterogeneity through the quantitative evaluation of medical images, such as Magnetic Resonance Imaging (MRI), which has become increasingly important in the detection and characterization of BC. However, the lack of comprehensive BC datasets in terms of molecular outcomes and MRI modalities, and the absence of a general methodology to build and compare feature selection approaches and predictive models, limit the routine use of radiomics in the BC clinical practice. In this work, a new radiomic approach based on a two-step feature selection process was proposed to build predictors for ER, PR, HER2, and Ki67 markers. An in-house dataset was used, containing 92 multiparametric MRIs of patients with histologically proven BC and all four relevant biomarkers available. Thousands of radiomic features were extracted from post-contrast and subtracted Dynamic Contrast-Enanched (DCE) MRI images, Apparent Diffusion Coefficient (ADC) maps, and T2-weighted (T2) images. The two-step feature selection approach was used to identify significant radiomic features properly and then to build the final prediction models. They showed remarkable results in terms of F1-score for all the biomarkers 84%, 63%, 90%, and 72% for ER, HER2, Ki67, and PR, respectively. When possible, the models were validated on the TCGATCIA Breast Cancer dataset, returning promising results (F1-score 88% for the ERER- classification task). The developed approach efficiently characterized BC heterogeneity according to the examined molecular biomarkers.

Aging-related gut microbiota dysbiosis initiates gut inflammation and microbiota dysbiosis, which induce the occurrence of psychiatric disorders including dementia. The alleviation of gut microbiota dysbiosis by probiotics is suggested to be able to alleviate psychiatric disorders including cognitive impairment (CI). Therefore, to understand how probiotics could alleviate CI, we examined the effects of anti-inflammatory

Hispidin in the Medicinal Fungus Protects Dopaminergic Neurons from JNK Activation-Regulated Mitochondrial-Dependent Apoptosis in an MPP

Degenerative diseases of the brain include Parkinsons disease (PD), which is associated with moveable signs and is still incurable. Hispidin belongs to polyphenol and originates primarily from the medicinal fungi Inonotus and Phellinus, with distinct biological effects. In the study, MES23.5 cells were induced by 1-methyl-4-phenylpyridinium (MPP

Towards Developing Novel Prostate Cancer Recurrence Suppressors Acute Toxicity of Pseurotin A, an Orally Active PCSK9 Axis-Targeting Small-Molecule in Swiss Albino Mice.

The proprotein convertase subtilisin kexin type 9 (PCSK9) emerged as a molecular target of great interest for the management of cardiovascular disorders due to its ability to reduce low density lipoprotein (LDL) cholesterol by binding and targeting at LDLR for lysosomal degradation in cells. Preliminary studies revealed that pseurotin A (PsA), a spiro-heterocyclic γ-lactam alkaloid from several marine and terrestrial

Neuroprotectant Effects of Hibiscetin in 3-Nitropropionic Acid-Induced Huntingtons Disease via Subsiding Oxidative Stress and Modulating Monoamine Neurotransmitters in Rats Brain.

Previously reported data suggest that hibiscetin, isolated from To investigate possible toxicities in animals, oral acute toxicity studies of hibiscetin were undertaken, and results revealed the safety of hibiscetin in animals with a maximum tolerated dose. Wistar rats were divided into four groups ( The hibiscetin-treated group exhibits a substantial restoration of MBW than the 3-NPA control group. Furthermore, 3-NPA caused a substantial alteration in biochemical, neurotransmitter monoamines, and neuroinflammatory parameters which were restored successfully by hibiscetin. The current study linked the possible role of hibiscetin by offering neuroprotection in experimental animal models.

Primary Stereotactic Radiosurgery Provides Favorable Tumor Control for Intraventricular Meningioma A Retrospective Analysis.

The surgical resection of intraventricular meningiomas (IVMs) remains challenging because of their anatomically deep locations and proximity to vital structures, resulting in non-negligible morbidity and mortality rates. Stereotactic radiosurgery (SRS) is a safe and effective treatment option, providing durable tumor control for benign brain tumors, but its outcomes for IVMs have rarely been reported. Therefore, the goal of the present study was to evaluate the SRS outcomes for IVMs at our institution. This retrospective observational study included 11 patients with 12 IVMs with a median follow-up period of 52 months (range, 3-353 months) treated with SRS using the Leksell Gamma Knife. Nine (75%) tumors were located in the trigone of the lateral ventricle, two (17%) in the body of the lateral ventricle, and one (8%) in the third ventricle. Tumor control was achieved in all cases, and seven (55%) decreased in size. Post-SRS perifocal edema was observed in four (37% three asymptomatic and one symptomatic but transient) patients, all of which were resolved by the last follow-up. SRS appears to provide safe and excellent tumor control for IVMs. A longer follow-up with a larger number of cases is desired for a more solid conclusion.

Clinicopathological and Treatment Patterns of Combined Small-Cell Lung Carcinoma with Future Insight to Treatment A Population-Based Study.

Primary lung cancer is the most common cause of cancer-related mortality in the United States (US). Approximately 90% of lung cancers are associated with smoking and the use of other tobacco products. Based on histology, lung cancers are divided into small-cell lung carcinomas (SCLCs) and non-small-cell lung carcinomas (NSCLCs). Most SCLCs are of the pure subtype, while the rare combined SCLCs contain elements of both small-cell and non-small-cell morphologies. This study sought to evaluate the demographics, clinical factors, molecular abnormalities, treatment approaches, and survival outcomes with combined SCLC and NSCLCs. Data on 2126 combined SCLC patients was extracted from the Surveillance Epidemiology and End Result (SEER) database from 2000 to 2018. Data extracted for analyses included age, sex, race, tumor size, tumor location, metastasis status, stage at diagnosis, treatment received, and treatment outcomes. Multivariate analysis was performed using Statistical Product and Service Solutions (SPSS) software. The patients had a median age of 68 years 43.9% of the patients were female and 56.1% were male 84.5% were White and 11.7% were African Americans. The majority of patients had a poorly differentiated disease at 29.6% 17% were undifferentiated, 3.2% were moderately differentiated, and 0.8% were well differentiated. Chemotherapy was the most common treatment modality (45.3%) 17% underwent surgery only, 10.3% underwent surgery followed by adjuvant chemotherapy, and 10% underwent radiation after surgery. Five-year cancer-specific survival was 15.2% with surgery alone, and combined surgery and chemotherapy provided the highest percentages (38.3% and 34.7%, respectively). Females had significantly higher 1- and 5-year cancer-specific survival rates compared to males (59.3% and 29.9% vs. 48.0% and 23.7, respectively Combined SCLC is overall very rare. However, the frequency of presentation with combined SCLC is on the rise, in part due to improvements in diagnostic techniques. Despite advances in therapies, treating combined SCLC is challenging, and novel therapies are not utilized, owing to low rates of targetable mutations. Combined SCLC has higher survival rates if well differentiated.

Subependymal Giant Cell Astrocytomas in Tuberous Sclerosis Complex-Current Views on Their Pathogenesis and Management.

Introduction, Tuberous sclerosis complex (TSC) is an autosomal-dominant disorder caused by mutations inactivating TSC1 or TSC2 genes and characterized by the presence of tumors involving many organs, including the brain, heart, kidneys, and skin. Subependymal giant cell astrocytoma (SEGA) is a slow-growing brain tumor almost exclusively associated with TSC. Despite the fact that SEGAs are benign, they require well-considered decisions regarding the timing and modality of pharmacological or surgical treatment. In TSC children and adolescents, SEGA is the major cause of mortality and morbidity. Until recently, surgical resection has been the standard therapy for SEGAs but the discovery of the role of the mTOR pathway and the introduction of mTOR inhibitors to clinical practice changed the therapeutic landscape of these tumors. In the current paper, we discuss the pros and cons of mTOR inhibitors and surgical approaches in SEGA treatment. In 2021, the International Tuberous Sclerosis Complex Consensus Group proposed a new integrative strategy for SEGA management. In the following review, we discuss the proposed recommendations and report the results of the literature search for the latest treatment directions.

Artificial Neural Networks in Lung Cancer Research A Narrative Review.

Artificial neural networks are statistical methods that mimic complex neural connections, simulating the learning dynamics of the human brain. They play a fundamental role in clinical decision-making, although their success depends on good integration with clinical protocols. When applied to lung cancer research, artificial neural networks do not aim to be biologically realistic, but rather to provide efficient models for nonlinear regression or classification. We conducted a comprehensive search of EMBASE (via Ovid), MEDLINE (via PubMed), Cochrane CENTRAL, and Google Scholar from April 2018 to December 2022, using a combination of keywords and related terms for artificial neural network, lung cancer, non-small cell lung cancer, diagnosis, and treatment. Artificial neural networks have shown excellent aptitude in learning the relationships between the inputoutput mapping from a given dataset, without any prior information or assumptions about the statistical distribution of the data. They can simultaneously process numerous variables, managing complexity hence, they have found broad application in tasks requiring attention. Lung cancer is the most common and lethal form of tumor, with limited diagnostic and treatment methods. The advances in tailored medicine have led to the development of novel tools for diagnosis and treatment. Artificial neural networks can provide valuable support for both basic research and clinical decision-making. Therefore, tight cooperation among surgeons, oncologists, and biostatisticians appears mandatory.

The Association of Integrins β3, β4, and αVβ5 on Exosomes, CTCs and Tumor Cells with Localization of Distant Metastasis in Breast Cancer Patients.

Integrins are cell adhesion receptors, which play a role in breast cancer invasion, angiogenesis, and metastasis. Moreover, it has been shown that exosomal integrins provide organotropic metastasis in a mouse model. In our study, we aimed to investigate the expression of integrins β3, β4, and αVβ5 on exosomes and tumor cells (circulating tumor cells and primary tumor) and their association with the localization of distant metastasis. We confirmed the association of exosomal integrin β4 with lung metastasis in breast cancer patients. However, we were unable to evaluate the role of integrin β3 in brain metastasis due to the rarity of this localization. We established no association of exosomal integrin αVβ5 with liver metastasis in our cohort of breast cancer patients. The further evaluation of β3, β4, and αVβ5 integrin expression on CTCs revealed an association of integrin β4 and αVβ5 with liver, but not the lung metastases. Integrin β4 in the primary tumor was associated with liver metastasis. Furthermore, an in-depth analysis of phenotypic characteristics of β4 tumor cells revealed a significantly increased proportion of E-cadherin and CD44CD24- cells in patients with liver metastases compared to patients with lung or no distant metastases.

Insights into the Peritumoural Brain Zone of Glioblastoma

Despite the efforts made in recent decades, glioblastoma is still the deadliest primary brain cancer without cure. The potential role in tumour maintenance and progression of the peritumoural brain zone (PBZ), the apparently normal area surrounding the tumour, has emerged. Little is known about this area due to a lack of common definition and due to difficult sampling related to the functional role of peritumoural healthy brain. The aim of this work was to better characterize the PBZ and to identify genes that may have role in its malignant transformation. Starting from our previous study on the comparison of the genomic profiles of matched tumour core and PBZ biopsies, we selected

Rare Phytocannabinoids Exert Anti-Inflammatory Effects on Human Keratinocytes via the Endocannabinoid System and MAPK Signaling Pathway.

Increasing evidence supports the therapeutic potential of rare cannabis-derived phytocannabinoids (pCBs) in skin disorders such as atopic dermatitis, psoriasis, pruritus, and acne. However, the molecular mechanisms of the biological action of these pCBs remain poorly investigated. In this study, an experimental model of inflamed human keratinocytes (HaCaT cells) was set up by using lipopolysaccharide (LPS) in order to investigate the anti-inflammatory effects of the rare pCBs cannabigerol (CBG), cannabichromene (CBC), Δ

Reactivity Graph Yields Interpretable IgM Repertoire Signatures as Potential Tumor Biomarkers.

Combining adaptive and innate immunity induction modes, the repertoire of immunoglobulin M (IgM) can reflect changes in the internal environment including malignancies. Previously, it was shown that a mimotope library reflecting the public IgM repertoire of healthy donors (IgM IgOme) can be mined for efficient probes of tumor biomarker antibody reactivities. To better explore the interpretability of this approach for IgM, solid tumor-related profiles of IgM reactivities to linear epitopes of actual tumor antigens and viral epitopes were studied. The probes were designed as oriented planar microarrays of 4526 peptide sequences (as overlapping 15-mers) derived from 24 tumor-associated antigens and 209 cancer-related B cell epitopes from 30 viral antigens. The IgM reactivity in sera from 21 patients with glioblastoma multiforme, brain metastases of other tumors, and non-tumor-bearing neurosurgery patients was thus probed in a proof-of-principle study. A graph representation of the binding data was developed, which mapped the cross-reactivity of the mixture of IgM (poly)specificities, delineating different antibody footprints in the features of the graph-neighborhoods and cliques. The reactivity graph mapped the major features of the IgM repertoire such as the magnitude of the reactivity (titer) and major cross-reactivities, which correlated with blood group reactivity, non-self recognition, and even idiotypic specificities. A correlation between an aspect of this image of the IgM IgOme, namely, small cliques reflecting rare self-reactivities and the capacity of subsets of the epitopes to separate the diagnostic groups studied was found. In this way, the graph representation helped the feature selection in its filtering step and provided reduced feature sets, which, after recursive feature elimination, produced a classifier containing 51 peptide reactivities separating the three diagnostic groups with an unexpected efficiency. Thus, IgM IgOme approaches to repertoire studies is greatly augmented when selfviral antigens are used and the data are represented as a reactivity graph. This approach is most general, and if it is applicable to tumors in immunologically privileged sites, it can be applied to any solid tumors, for instance, breast or lung cancer.

Editorial to Special Issue Glioblastoma Recapitulating the Key Breakthroughs and Future Perspective.

Glioblastoma (GBM) remains the most common and aggressive malignant primary brain tumor ....

Ion Channels in Gliomas-From Molecular Basis to Treatment.

Ion channels provide the basis for the nervous systems intrinsic electrical activity. Neuronal excitability is a characteristic property of neurons and is critical for all functions of the nervous system. Glia cells fulfill essential supportive roles, but unlike neurons, they also retain the ability to divide. This can lead to uncontrolled growth and the formation of gliomas. Ion channels are involved in the unique biology of gliomas pertaining to peritumoral pathology and seizures, diffuse invasion, and treatment resistance. The emerging picture shows ion channels in the brain at the crossroads of neurophysiology and fundamental pathophysiological processes of specific cancer behaviors as reflected by uncontrolled proliferation, infiltration, resistance to apoptosis, metabolism, and angiogenesis. Ion channels are highly druggable, making them an enticing therapeutic target. Targeting ion channels in difficult-to-treat brain tumors such as gliomas requires an understanding of their extremely heterogenous tumor microenvironment and highly diverse molecular profiles, both representing major causes of recurrence and treatment resistance. In this review, we survey the current knowledge on ion channels with oncogenic behavior within the heterogeneous group of gliomas, review ion channel gene expression as genomic biomarkers for glioma prognosis and provide an update on therapeutic perspectives for repurposed and novel ion channel inhibitors and electrotherapy.

Recent Advances on Surface-Modified GBM Targeted Nanoparticles Targeting Strategies and Surface Characterization.

Glioblastoma multiforme (GBM) is the most common malignant brain tumor, associated with low long-term survival. Nanoparticles (NPs) developed against GBM are a promising strategy to improve current therapies, by enhancing the brain delivery of active molecules and reducing off-target effects. In particular, NPs hold high potential for the targeted delivery of chemotherapeutics both across the blood-brain barrier (BBB) and specifically to GBM cell receptors, pathways, or the tumor microenvironment (TME). In this review, the most recent strategies to deliver drugs to GBM are explored. The main focus is on how surface functionalizations are essential for BBB crossing and for tumor specific targeting. We give a critical analysis of the various ligand-based approaches that have been used to target specific cancer cell receptors and the TME, or to interfere with the signaling pathways of GBM. Despite the increasing application of NPs in the clinical setting, new methods for ligand and surface characterization are needed to optimize the synthesis, as well as to predict their in vivo behavior. An expert opinion is given on the future of this research and what is still missing to create and characterize a functional NP system for improved GBM targeting.

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Despite the fact that sorafenib is recommended for the treatment of oncological diseases of the liver, kidneys, and thyroid gland, and recently it has been used for combination therapy of brain cancer of various genesis, there are still significant problems for its widespread and effective use. Among these problems, the presence of the blood-brain barrier of the brain and the need to use high doses of sorafenib, the existence of mechanisms for the redistribution of sorafenib and its release in the brain tissue, as well as the high resistance of gliomas and glioblastomas to therapy should be considered the main ones. Therefore, there is a need to create new methods for delivering sorafenib to brain tumors, enhancing the therapeutic potential of sorafenib and reducing the cytotoxic effects of active compounds on the healthy environment of tumors, and ideally, increasing the survival of healthy cells during therapy. Using vitality tests, fluorescence microscopy, and molecular biology methods, we showed that the selenium-sorafenib (SeSo) nanocomplex, at relatively low concentrations, is able to bypass the mechanisms of glioblastoma cell chemoresistance and to induce apoptosis through Ca

Raman Spectroscopy as a Tool to Study the Pathophysiology of Brain Diseases.

The Raman phenomenon is based on the spontaneous inelastic scattering of light, which depends on the molecular characteristics of the dispersant. Therefore, Raman spectroscopy and imaging allow us to obtain direct information, in a label-free manner, from the chemical composition of the sample. Since it is well established that the development of many brain diseases is associated with biochemical alterations of the affected tissue, Raman spectroscopy and imaging have emerged as promising tools for the diagnosis of ailments. A combination of Raman spectroscopy andor imaging with tagged molecules could also help in drug delivery and tracing for treatment of brain diseases. In this review, we first describe the basics of the Raman phenomenon and spectroscopy. Then, we delve into the Raman spectroscopy and imaging modes and the Raman-compatible tags. Finally, we center on the application of Raman in the study, diagnosis, and treatment of brain diseases, by focusing on traumatic brain injury and ischemia, neurodegenerative disorders, and brain cancer.

Targeting the Retinoic Acid Pathway to Eradicate Cancer Stem Cells.

All-

Comparative Efficacy of ALK Inhibitors for Treatment-Naïve ALK-Positive Advanced Non-Small Cell Lung Cancer with Central Nervous System Metastasis A Network Meta-Analysis.

Central nervous system (CNS) metastases and acquired resistance complicate the treatment of anaplastic lymphoma kinase (ALK) rearrangement-positive (ALK-p) advanced non-small cell lung cancer (NSCLC). Thus, this review aimed to provide a comprehensive overview of brain metastasis, acquired resistance, and prospects for overcoming these challenges. A network meta-analysis of relevant phase III randomized controlled trials was performed to compare the efficacies of multiple ALK inhibitors by drug and generation in overall patients with ALK-p untreated advanced NSCLC and a subgroup of patients with CNS metastases. The primary endpoint was progression-free survival (PFS). Generation-specific comparison results showed that third-generation ALK inhibitors were significantly more effective than second-generation ALK inhibitors in prolonging the PFS of the subgroup of patients with CNS metastases. Drug-specific comparison results demonstrated that lorlatinib was the most effective in prolonging PFS, followed by brigatinib, alectinib, ensartinib, ceritinib, crizotinib, and chemotherapy. While lorlatinib was superior to brigatinib for PFS in the overall patient population, no significant difference between the two was found in the subgroup of patients with CNS metastases. These results can serve as a foundation for basic, clinical, and translational research and guide clinical oncologists in developing individualized treatment strategies for patients with ALK-p, ALK inhibitor-naive advanced NSCLC.

4-Methylumbelliferone Targets Revealed by Public Data Analysis and Liver Transcriptome Sequencing.

4-methylumbelliferone (4MU) is a well-known hyaluronic acid synthesis inhibitor and an approved drug for the treatment of cholestasis. In animal models, 4MU decreases inflammation, reduces fibrosis, and lowers body weight, serum cholesterol, and insulin resistance. It also inhibits tumor progression and metastasis. The broad spectrum of effects suggests multiple and yet unknown targets of 4MU. Aiming at 4MU target deconvolution, we have analyzed publicly available data bases, including 1. Small molecule library Bio Assay screening (PubChemBioAssay) 2. GO pathway databases screening 3. Protein Atlas Database. We also performed comparative liver transcriptome analysis of mice on normal diet and mice fed with 4MU for two weeks. Potential targets of 4MU public data base analysis fall into two big groups, enzymes and transcription factors (TFs), including 13 members of the nuclear receptor superfamily regulating lipid and carbohydrate metabolism. Transcriptome analysis revealed changes in the expression of genes involved in bile acid metabolism, gluconeogenesis, and immune response. It was found that 4MU feeding decreased the accumulation of the glycogen granules in the liver. Thus, 4MU has multiple targets and can regulate cell metabolism by modulating signaling via nuclear receptors.

Natural Killer Cell-Based Immunotherapy against Glioblastoma.

Glioblastoma (GBM) is the most aggressive and malignant primary brain tumor in adults. Despite multimodality treatment involving surgical resection, radiation therapy, chemotherapy, and tumor-treating fields, the median overall survival (OS) after diagnosis is approximately 2 years and the 5-year OS is poor. Considering the poor prognosis, novel treatment strategies are needed, such as immunotherapies, which include chimeric antigen receptor T-cell therapy, immune checkpoint inhibitors, vaccine therapy, and oncolytic virus therapy. However, these therapies have not achieved satisfactory outcomes. One reason for this is that these therapies are mainly based on activating T cells and controlling GBM progression. Natural killer (NK) cell-based immunotherapy involves the new feature of recognizing GBM via differing mechanisms from that of T cell-based immunotherapy. In this review, we focused on NK cell-based immunotherapy as a novel GBM treatment strategy.

Oleracone F Alleviates Cognitive Impairment and Neuropathology in APPswePSEN1dE9 Mice by Reducing the Expression of Vascular Cell Adhesion Molecule and Leukocyte Adhesion to Brain Vascular Endothelial Cells.

Alzheimers disease (AD) is the most common neurodegenerative disease and the blood-brain barrier dysfunction has been suggested as a key pathological feature of the disease. Our research group successfully established a synthetic protocol for oleracones, a novel series of flavonoids isolated from the plant extract of

The Tumor Immune Microenvironment in Primary CNS Neoplasms A Review of Current Knowledge and Therapeutic Approaches.

Primary CNS neoplasms are responsible for considerable mortality and morbidity, and many therapies directed at primary brain tumors have proven unsuccessful despite their success in preclinical studies. Recently, the tumor immune microenvironment has emerged as a critical aspect of primary CNS neoplasms that may affect their malignancy, prognosis, and response to therapy across patients and tumor grades. This review covers the tumor microenvironment of various primary CNS neoplasms, with a focus on glioblastoma and meningioma. Additionally, current therapeutic strategies based on elements of the tumor microenvironment, including checkpoint inhibitor therapy and immunotherapeutic vaccines, are discussed.

PARIN5, a Novel Thrombin Receptor Antagonist Modulates a Streptozotocin Mice Model for Diabetic Encephalopathy.

Diabetic encephalopathy (DE) is an inflammation-associated diabetes mellitus (DM) complication. Inflammation and coagulation are linked and are both potentially modulated by inhibiting the thrombin cellular protease-activated receptor 1 (PAR1). Our aim was to study whether coagulation pathway modulation affects DE. Diabetic C57BL6 mice were treated with PARIN5, a novel PAR1 modulator. Behavioral changes in the open field and novel object recognition tests, serum neurofilament (NfL) levels and thrombin activity in central and peripheral nervous system tissue (CNS and PNS, respectively), brain mRNA expression of tumor necrosis factor α (TNF-α), Factor X (FX), prothrombin, and PAR1 were assessed. Subtle behavioral changes were detected in diabetic mice. These were accompanied by an increase in serum NfL, an increase in central and peripheral neural tissue thrombin activity, and TNF-α, FX, and prothrombin brain intrinsic mRNA expression. Systemic treatment with PARIN5 prevented the appearance of behavioral changes, normalized serum NfL and prevented the increase in peripheral but not central thrombin activity. PARIN5 treatment prevented the elevation of both TNF-α and FX but significantly elevated prothrombin expression. PARIN5 treatment prevents behavioral and neural damage in the DE model, suggesting it for future clinical research.

Oligorecurrent Non-Small-Cell Lung Cancer Treated by Chemo-Radiation Followed by Immunotherapy and Intracranial Radiosurgery A Case Report and Mini Review of Literature.

Locally advanced non-small-cell lung cancer still represents a grey zone in terms of the best treatment choice and optimal clinical outcomes. Indeed, most patients may be suitable to receive different treatments with similar outcomes such as chemo-radiotherapy (CHT-RT) followed by immunotherapy (IO) or surgery followed by adjuvant localsystemic therapies. We report a clinical case of a patient submitted to primary thoracic surgery who developed a mediastinal nodal recurrence successfully treated by CHT-RT-IO. Subsequently, a single brain lesion was found to have been successfully treated by single fraction stereotactic ablative radiotherapy. The patient is still on follow-up and she is free from disease having a good quality of life. In this report, we also perform a mini review about the role of CHT-RT followed by IO in treating loco-regional relapse after surgery. The role of SABR after IO is also evaluated, finding that it is safe and well tolerated. More robust and larger clinical data are needed in this particular setting to better define the role of the combination of systemic and local treatments in the management of intrathoracic and intracranial relapse for patients already submitted to CHT-RT followed by immunotherapy.

Association of the Telomerase Reverse Transcriptase rs10069690 Polymorphism with the Risk, Age at Onset and Prognosis of Triple Negative Breast Cancer.

Telomerase reverse transcriptase (TERT) plays a key role in the maintenance of telomere DNA length. The rs10069690 single nucleotide variant, located in intron 4 of TERT, was found to be associated with telomere length and the risk of estrogen receptor-negative but not-positive breast cancer. This study aimed at analysis of the association of rs10069690 genotype and TERT expression with the risk, age at onset, prognosis, and clinically and molecularly relevant subtypes of breast cancer. Accordingly, rs10069690 was genotyped in a hospital-based case-control study of 403 female breast cancer patients and 246 female controls of a Central European (Austrian) study population, and the mRNA levels of TERT were quantified in 106 primary breast tumors using qRT-PCR. We found that in triple-negative breast cancer patients, the minor rs10069690 TT genotype tended to be associated with an increased breast cancer risk (OR, 1.87 95% CI, 0.75-4.71

Irisin Modulates Inflammatory, Angiogenic, and Osteogenic Factors during Fracture Healing.

Bone fractures are a widespread clinical event due to accidental falls and trauma or bone fragility they also occur in association with various diseases and are common with aging. In the search for new therapeutic strategies, a crucial link between irisin and bone fractures has recently emerged. To explore this issue, we subjected 8-week-old C57BL6 male mice to tibial fracture, and then we treated them with intra-peritoneal injection of r-Irisin (100 µgkgweekly) or vehicle as control. At day 10 post fracture, histological analysis showed a significant reduced expression of inflammatory cytokines as tumor necrosis factor-alpha (TNFα) (

In Vivo Studies on Radiofrequency (100 kHz-300 GHz) Electromagnetic Field Exposure and Cancer A Systematic Review.

The increasing exposure of the human population to radiofrequency electromagnetic fields has increased concern about its possible health effects. The aim of this systematic review is to provide an update of the state of the research on this topic, through a quantitative analysis, to assess the increased risk of tumor incidence in laboratory animals (rodents) without limitations of species, strain, sex or genotype. The review was conducted according to the PRISMA guideline and individual studies were assessed by referring to the OHAT Risk of Bias Rating Tool for Human and Animal Studies. A total of 27 studies were considered eligible for the evaluation of tumor incidence a meta-analysis was carried out on 23 studies to assess the possible increased risk of both malignant and benign tumors onset at the systemic level or in different organstissues. A significant association between exposure to RF and the increaseddecreased risk of cancer does not result from the meta-analysis in most of considered tissues. A significant increaseddecreased risk can be numerically observed only in heart, CNSbrain, and intestine for malignant tumors. Nevertheless, the assessment of the body of evidence attributes low or inadequate evidence for an association between RF exposure and the onset of neoplasm in all tissues.

Cancer Stem Cell and Aggressiveness Traits Are Promoted by Stable Endothelin-Converting Enzyme-1c in Glioblastoma Cells.

Glioblastoma (GBM) is the most common and aggressive type of brain tumor due to its elevated recurrence following treatments. This is mainly mediated by a subpopulation of cells with stemness traits termed glioblastoma stem-like cells (GSCs), which are extremely resistant to anti-neoplastic drugs. Thus, an advancement in the understanding of the molecular processes underlying GSC occurrence should contribute significantly towards progress in reducing aggressiveness. High levels of endothelin-converting enzyme-1 (ECE1), key for endothelin-1 (ET-1) peptide activation, have been linked to the malignant progression of GBM. There are four known isoforms of ECE1 that activate ET-1, which only differ in their cytoplasmic N-terminal sequences. Isoform ECE1c is phosphorylated at Ser-18 and Ser-20 by protein kinase CK2, which increases its stability and hence promotes aggressiveness traits in colon cancer cells. In order to study whether ECE1c exerts a malignant effect in GBM, we designed an ECE1c mutant by switching a putative ubiquitination lysine proximal to the phospho-serines Lys-6-to-Arg (i.e., K6R). This ECE1c

Encoding and Decoding of p53 Dynamics in Cellular Response to Stresses.

In the cellular response to stresses, the tumor suppressor p53 is activated to maintain genomic integrity and fidelity. As a transcription factor, p53 exhibits rich dynamics to allow for discrimination of the type and intensity of stresses and to direct the selective activation of target genes involved in different processes including cell cycle arrest and apoptosis. In this review, we focused on how stresses are encoded into p53 dynamics and how the dynamics are decoded into cellular outcomes. Theoretical modeling may provide a global view of signaling in the p53 network by coupling the encoding and decoding processes. We discussed the significance of modeling in revealing the mechanisms of the transition between p53 dynamic modes. Moreover, we shed light on the crosstalk between the p53 network and other signaling networks. This review may advance the understanding of operating principles of the p53 signaling network comprehensively and provide insights into p53 dynamics-based cancer therapy.

An Ensemble Model for the Diagnosis of Brain Tumors through MRIs.

Automatic brain tumor detection in MR Images is one of the basic applications of machine vision in medical image processing, which, despite much research, still needs further development. Using multiple machine learning techniques as an ensemble system is one of the solutions that can be effective in achieving this goal. In this paper, a novel method for diagnosing brain tumors by combining data mining and machine learning techniques has been proposed. In the proposed method, each image is initially pre-processed to eliminate its background region and identify brain tissue. The Social Spider Optimization (SSO) algorithm is then utilized to segment the MRI Images. The MRI Images segmentation allows for a more precise identification of the tumor region in the image. In the next step, the distinctive features of the image are extracted using the SVD technique. In addition to removing redundant information, this strategy boosts the speed of the processing at the classification stage. Finally, a combination of the algorithms Naïve Bayes, Support vector machine and K-nearest neighbor is used to classify the extracted features and detect brain tumors. Each of the three algorithms performs feature classification individually, and the final output of the proposed model is created by integrating the three independent outputs and voting the results. The results indicate that the proposed method can diagnose brain tumors in the BRATS 2014 dataset with an average accuracy of 98.61%, sensitivity of 95.79% and specificity of 99.71%. Additionally, the proposed method could diagnose brain tumors in the BTD20 database with an average accuracy of 99.13%, sensitivity of 99% and specificity of 99.26%. These results show a significant improvement compared to previous efforts. The findings confirm that using the image segmentation technique, as well as the ensemble learning, is effective in improving the efficiency of the proposed method.

Brain Tumor at Diagnosis From Cognition and Behavior to Quality of Life.

The present narrative review aims to discuss cognitive-emotional-behavioral symptoms in adults with brain tumors at the time of diagnosis. The PubMed database was searched considering glioma, pituitary adenoma, and meningioma in adulthood as pathologies, together with cognitive, neuropsychological, or behavioral aspects. Although a significant number of studies describe cognitive impairment after surgery or treatment in adults with brain tumors, only few focus on cognitive-emotional-behavioral symptoms at diagnosis. Furthermore, the importance of an effective communication and its impact on patients quality of life and compliance with treatment are seldom discussed. Adults with brain tumors have needs in terms of cognitive-emotional-behavioral features that are detectable at the time of diagnosis more research is needed to identify effective communication protocols in order to allow a higher perceived quality of life in these patients.

Role of Ensemble Deep Learning for Brain Tumor Classification in Multiple Magnetic Resonance Imaging Sequence Data.

The biopsy is a gold standard method for tumor grading. However, due to its invasive nature, it has sometimes proved fatal for brain tumor patients. As a result, a non-invasive computer-aided diagnosis (CAD) tool is required. Recently, many magnetic resonance imaging (MRI)-based CAD tools have been proposed for brain tumor grading. The MRI has several sequences, which can express tumor structure in different ways. However, a suitable MRI sequence for brain tumor classification is not yet known. The most common brain tumor is glioma, which is the most fatal form. Therefore, in the proposed study, to maximize the classification ability between low-grade versus high-grade glioma, three datasets were designed comprising three MRI sequences T1-Weighted (T1W), T2-weighted (T2W), and fluid-attenuated inversion recovery (FLAIR). Further, five well-established convolutional neural networks, AlexNet, VGG16, ResNet18, GoogleNet, and ResNet50 were adopted for tumor classification. An ensemble algorithm was proposed using the majority vote of above five deep learning (DL) models to produce more consistent and improved results than any individual model. Five-fold cross validation (K5-CV) protocol was adopted for training and testing. For the proposed ensembled classifier with K5-CV, the highest test accuracies of 98.88 ± 0.63%, 97.98 ± 0.86%, and 94.75 ± 0.61% were achieved for FLAIR, T2W, and T1W-MRI data, respectively. FLAIR-MRI data was found to be most significant for brain tumor classification, where it showed a 4.17% and 0.91% improvement in accuracy against the T1W-MRI and T2W-MRI sequence data, respectively. The proposed ensembled algorithm (MajVot) showed significant improvements in the average accuracy of three datasets of 3.60%, 2.84%, 1.64%, 4.27%, and 1.14%, respectively, against AlexNet, VGG16, ResNet18, GoogleNet, and ResNet50.

Evaluation of the HD-GLIO Deep Learning Algorithm for Brain Tumour Segmentation on Postoperative MRI.

In the context of brain tumour response assessment, deep learning-based three-dimensional (3D) tumour segmentation has shown potential to enter the routine radiological workflow. The purpose of the present study was to perform an external evaluation of a state-of-the-art deep learning 3D brain tumour segmentation algorithm (HD-GLIO) on an independent cohort of consecutive, post-operative patients. For 66 consecutive magnetic resonance imaging examinations, we compared delineations of contrast-enhancing (CE) tumour lesions and non-enhancing T2FLAIR hyperintense abnormality (NE) lesions by the HD-GLIO algorithm and radiologists using Dice similarity coefficients (Dice). Volume agreement was assessed using concordance correlation coefficients (CCCs) and Bland-Altman plots. The algorithm performed very well regarding the segmentation of NE volumes (median Dice 0.79) and CE tumour volumes larger than 1.0 cm

MR Intensity Normalization Methods Impact Sequence Specific Radiomics Prognostic Model Performance in Primary and Recurrent High-Grade Glioma.

This study investigates the impact of different intensity normalization (IN) methods on the overall survival (OS) radiomics models performance of MR sequences in primary (pHGG) and recurrent high-grade glioma (rHGG). MR scans acquired before radiotherapy were retrieved from two independent cohorts (rHGG C1 197, pHGG C2 141) from multiple scanners (15, 14). The sequences are T1 weighted (w), contrast-enhanced T1w (T1wce), T2w, and T2w-FLAIR. Sequence-specific significant features (SF) associated with OS, extracted from the tumour volume, were derived after applying 15 different IN methods. Survival analyses were conducted using Cox proportional hazard (CPH) and Poisson regression (POI) models. A ranking score was assigned based on the 10-fold cross-validated (CV) concordance index (C-I), mean square error (MSE), and the Akaike information criterion (AICs), to evaluate the methods performance. Scatter plots of the 10-CV C-I and MSE against the AIC showed an impact on the survival predictions between the IN methods and MR sequences (C1C2 C-I range 0.62-0.710.61-0.72, MSE range 0.20-0.420.13-0.22). White stripe showed stable results for T1wce (C1C2 C-I 0.710.65, MSE 0.210.14). Combat (0.680.62, 0.220.15) and histogram matching (HM, 0.670.64, 0.220.15) showed consistent prediction results for T2w models. They were also the top-performing methods for T1w in C2 (Combat 0.67, 0.13 HM 0.67, 0.13) however, only HM achieved high predictions in C1 (0.66, 0.22). After eliminating IN impacted SF using Spearmans rank-order correlation coefficient, a mean decrease in the C-I and MSE of 0.05 and 0.03 was observed in all four sequences. The IN method impacted the predictive power of survival models thus, performance is sequence-dependent.

Forecasting Molecular Features in IDH-Wildtype Gliomas The State of the Art of Radiomics Applied to Neurosurgery.

The fifth edition of the WHO Classification of Tumors of the Central Nervous System (CNS), published in 2021, marks a step forward the future diagnostic approach to these neoplasms. Alongside this, radiomics has experienced rapid evolution over the last several years, allowing us to correlate tumor imaging heterogeneity with a wide range of tumor molecular and subcellular features. Radiomics is a translational field focused on decoding conventional imaging data to extrapolate the molecular and prognostic features of tumors such as gliomas. We herein analyze the state-of-the-art of radiomics applied to glioblastoma, with the goal to estimate its current clinical impact and potential perspectives in relation to well-rounded patient management, including the end-of-life stage. A literature review was performed on the PubMed, MEDLINE and Scopus databases using the following search items radiomics and glioma, radiomics and glioblastoma, radiomics and glioma and IDH, radiomics and glioma and TERT promoter, radiomics and glioma and EGFR, radiomics and glioma and chromosome. A total of 719 articles were screened. Further quantitative and qualitative analysis allowed us to finally include 11 papers. This analysis shows that radiomics is rapidly evolving towards a reliable tool. Further studies are necessary to adjust radiomics potential to the newest molecular requirements pointed out by the 2021 WHO classification of CNS tumors. At a glance, its application in the clinical routine could be beneficial to achieve a timely diagnosis, especially for those patients not eligible for surgery andor adjuvant therapies but still deserving palliative and supportive care.

Sodium Fluorescein-Guided Surgery for Resection of Brain Metastases from Lung Cancer A Consecutive Case Series Study and Literature Review.

(1) Introduction and objective Surgical resection plays an important role in the multidisciplinary treatment of lung cancer patients with brain metastases (BMs). Precisely distinguishing the tumor border intraoperatively to improve and maximize the extent of resection (EOR) without causing permanent neurological defects is crucial but still challenging. Therefore, we introduced our experience of utilizing sodium fluorescein (SF) in microneurosurgery of BMs from lung cancer. This study aims to evaluate whether the use of SF-guided surgery has a positive impact on postoperative outcomes. (2) Materials and methods A retrospective study was performed to collect data on a consecutive case series of patients with BMs from lung cancer who underwent surgical resection from January 2020 to December 2021 at the Department of Neuro-Oncology, Chongqing University Cancer Hospital. A total of 52 patients were enrolled, of which 23 received SF-guided surgery and 29 did not. EOR was assessed pre- and postoperatively on T1 contrast-enhanced MRI. Clinical and epidemiological data as well as follow-up were gathered and analyzed. (3) Results Compared with the non-SF-guided group, the SF-guided group revealed a significantly better EOR (87.0% vs. 62.1%) and a lower incidence of local recurrence (8.7% vs. 34.5%). Survival benefits were seen in patients with NSCLC, patients who were undergoing SF-guided surgery, and patients receiving postoperative systemic therapy. (4) Conclusions SF-guiding under the YELLOW 560 nm filter is a safe and feasible tool for improving the EOR in patients with BMs from lung cancer, leading to better local recurrence control and prolonged survival.

Meta-Analysis of Modulated Electro-Hyperthermia and Tumor Treating Fields in the Treatment of Glioblastomas.

Glioblastoma is one of the most difficult to treat and most aggressive brain tumors, having a poor survival rate. The use of non-invasive modulated electro-hyperthermia (mEHT) and Tumor Treating Fields (TTF) devices has been introduced in the last few decades, both of which having proven anti-tumor effects. A meta-analysis of randomized and observational studies about mEHT and TTF was conducted. A total of seven and fourteen studies about mEHT and TTF were included, with a total number of 450 and 1309 cases, respectively. A 42% 95% confidence interval (95% CI) 25-59% 1-year survival rate was found for mEHT, which was raised to 61% (95% CI 32-89%) if only the studies conducted after 2008 were investigated. In the case of TTF, 1-year survival was 67% (95% CI 53-81%). Subgroup analyses revealed that newly diagnosed patients might get extra benefits from the early introduction of the devices (mEHT all studies 73% vs. 37%, Our meta-analysis showed that both mEHT and TTF can improve glioblastoma survival, and the most benefit may be achieved in newly diagnosed cases.

Childhood Brain Tumors A Review of Strategies to Translate CNS Drug Delivery to Clinical Trials.

Brain and spinal tumors affect 1 in 1000 people by 25 years of age, and have diverse histological, biological, anatomical and dissemination characteristics. A mortality of 30-40% means the majority are cured, although two-thirds have life-long disability, linked to accumulated brain injury that is acquired prior to diagnosis, and after surgery or chemo-radiotherapy. Only four drugs have been licensed globally for brain tumors in 40 years and only one for children. Most new cancer drugs in clinical trials do not cross the blood-brain barrier (BBB). Techniques to enhance brain tumor drug delivery are explored in this review, and cover those that augment penetration of the BBB, and those that bypass the BBB. Developing appropriate delivery techniques could improve patient outcomes by ensuring efficacious drug exposure to tumors (including those that are drug-resistant), reducing systemic toxicities and targeting leptomeningeal metastases. Together, this drug delivery strategy seeks to enhance the efficacy of new drugs and enable re-evaluation of existing drugs that might have previously failed because of inadequate delivery. A literature review of repurposed drugs is reported, and a range of preclinical brain tumor models available for translational development are explored.

Longitudinal Evaluation of Brain Plasticity in Low-Grade Gliomas fMRI and Graph-Theory Provide Insights on Language Reorganization.

Language reorganization may represent an adaptive phenomenon to compensate tumor invasion of the dominant hemisphere. However, the functional changes over time underlying language plasticity remain unknown. We evaluated language function in patients with low-grade glioma (LGG), using task-based functional MRI (tb-fMRI), graph-theory and standardized language assessment. We hypothesized that functional networks obtained from tb-fMRI would show connectivity changes over time, with increased right-hemispheric participation. We recruited five right-handed patients (4M, mean age 47.6Y) with left-hemispheric LGG. Tb-fMRI and language assessment were conducted pre-operatively (pre-op), and post-operatively post-op1 (4-8 months), post-op2 (10-14 months) and post-op3 (16-23 months). We computed the individual functional networks applying optimal percolation thresholding. Language dominance and hemispheric connectivity were quantified by laterality indices (LI) on fMRI maps and connectivity matrices. A fixed linear mixed model was used to assess the intra-patient correlation trend of LI values over time and their correlation with language performance. Individual networks showed increased inter-hemispheric and right-sided connectivity involving language areas homologues. Two patterns of language reorganization emerged Threefive patients demonstrated a left-to-codominant shift from pre-op to post-op3 (type 1). Twofive patients started as atypical dominant at pre-op, and remained unchanged at post-op3 (type 2). LI obtained from tb-fMRI showed a significant left-to-right trend in all patients across timepoints. There were no significant changes in language performance over time. Type 1 language reorganization may be related to the treatment, while type 2 may be tumor-induced, since it was already present at pre-op. Increased inter-hemispheric and right-side connectivity may represent the initial step to develop functional plasticity.

Mapping Resection Progress by Tool-Tip Tracking during Brain Tumor Surgery for Real-Time Estimation of Residual Tumor.

Surgical resection continues to be the primary initial therapeutic strategy in the treatment of patients with brain tumors. Computerized cranial neuronavigation based on preoperative imaging offers precision guidance during craniotomy and early tumor resection but progressively loses validity with brain shift. Intraoperative MRI (iMRI) and intraoperative ultrasound (iUS) can update the imaging used for guidance and navigation but are limited in terms of temporal and spatial resolution, respectively. We present a system that uses time-stamped tool-tip positions of surgical instruments to generate a map of resection progress with high spatial and temporal accuracy. We evaluate this system and present results from 80 cranial tumor resections. Regions of the preoperative tumor segmentation that are covered by the resection map (True Positive Tracking) and regions of the preoperative tumor segmentation not covered by the resection map (True Negative Tracking) are determined for each case. We compare True Negative Tracking, which estimates the residual tumor, with the actual residual tumor identified using iMRI. We discuss factors that can cause False Positive Tracking and False Negative Tracking, which underestimate and overestimate the residual tumor, respectively. Our method provides good estimates of the residual tumor when there is minimal brain shift, and line-of-sight is maintained. When these conditions are not met, surgeons report that it is still useful for identifying regions of potential residual.

Plasma nanoDSF Denaturation Profile at Baseline Is Predictive of Glioblastoma EGFR Status.

Glioblastoma (GBM) is the most frequent and aggressive primary brain tumor in adults. Recently, we demonstrated that plasma denaturation profiles of glioblastoma patients obtained using Differential Scanning Fluorimetry can be automatically distinguished from healthy controls with the help of Artificial Intelligence (AI). Here, we used a set of machine-learning algorithms to automatically classify plasma denaturation profiles of glioblastoma patients according to their EGFR status. We found that Adaboost AI is able to discriminate

Pediatric Acute Myeloid Leukemia Post Cytotoxic Therapy-Retrospective Analysis of the Patients Treated in Poland from 2005 to 2022.

Acute P.myeloid leukemia post cytotoxic therapy (AML-pCT) is rare complication of cancer treatment in childhood. The objective of the study was to identify clinical characteristics and provide an analysis of the outcomes in pediatric AML-pCT. We retrospectively analyzed the data of 40 children with AML-pCT, treated from 2005 to 2020 within the Polish Pediatric Leukemia and Lymphoma Study Group. The most common primary malignancies were acute lymphoblastic leukemia (32.5%) and brain tumors (20%). The median latency period was 2.9 years (range 0.7-12.9). Probabilities of overall (OS), event-free (EFS), and relapse-free survival (RFS) in the whole cohort were 0.49 ± 0.08, 0.43 ± 0.08, and 0.64 ± 0.10, respectively. Significant improvements in outcomes were observed in patients treated from 2015-2022 (two induction cycles followed by stem cell transplantation-SCT in 69% of patients) compared to 2005-2014 (four induction cycles followed by SCT in 49% of patients). The probability of EFS increased from 0.30 ± 0.10 to 0.67 ± 0.12 (

Advances in the Molecular Landscape of Lung Cancer Brain Metastasis.

Lung cancer is one of the most frequent tumors that metastasize to the brain. Brain metastasis (BM) is common in advanced cases, being the major cause of patient morbidity and mortality. BMs are thought to arise via the seeding of circulating tumor cells into the brain microvasculature. In brain tissue, the interaction with immune cells promotes a microenvironment favorable to the growth of cancer cells. Despite multimodal treatments and advances in systemic therapies, lung cancer patients still have poor prognoses. Therefore, there is an urgent need to identify the molecular drivers of BM and clinically applicable biomarkers in order to improve disease outcomes and patient survival. The goal of this review is to summarize the current state of knowledge on the mechanisms of the metastatic spread of lung cancer to the brain and how the metastatic spread is influenced by the brain microenvironment, and to elucidate the molecular determinants of brain metastasis regarding the role of genomic and transcriptomic changes, including coding and non-coding RNAs. We also present an overview of the current therapeutics and novel treatment strategies for patients diagnosed with BM from NSCLC.

MMP-9 as Prognostic Marker for Brain Tumours A Comparative Study on Serum-Derived Small Extracellular Vesicles.

Matrix metalloproteinase-9 (MMP-9) degrades the extracellular matrix, contributes to tumour cell invasion and metastasis, and its elevated level in brain tumour tissues indicates poor prognosis. High-risk tissue biopsy can be replaced by liquid biopsy however, the blood-brain barrier (BBB) prevents tumour-associated components from entering the peripheral blood, making the development of blood-based biomarkers challenging. Therefore, we examined the MMP-9 content of small extracellular vesicles (sEVs)-which can cross the BBB and are stable in body fluids-to characterise tumours with different invasion capacity. From four patient groups (glioblastoma multiforme, brain metastases of lung cancer, meningioma, and lumbar disc herniation as controls), 222 serum-derived sEV samples were evaluated. After isolating and characterising sEVs, their MMP-9 content was measured by ELISA and assessed statistically (correlation, paired

Intracranial Solitary Fibrous Tumour Management A French Multicentre Retrospective Study.

Intracranial solitary fibrous tumour (iSFT) is an exceptional mesenchymal tumour with high recurrence rates. We aimed to analyse the clinical outcomes of newly diagnosed and recurrent iSFTs. We carried out a French retrospective multicentre ( Eighty-eight patients were included with a median age of 54.5 years. New iSFT cases were treated with gross tumour resection (GTR) ( GTR provided benefits as a first treatment for iSFTs. However, approximately 40% of patients experienced relapse, which remains a challenging state.

EGFR Pathway Expression Persists in Recurrent Glioblastoma Independent of Amplification Status.

Glioblastoma mortality is driven by tumour progression or recurrence despite administering a therapeutic arsenal consisting of surgical resection, radiation, and alkylating chemotherapy. The genetic changes underlying tumour progression and chemotherapy resistance are poorly understood. In this study, we sought to define the relationship between EGFR amplification status, EGFR mRNA expression, and EGFR pathway activity. We compared RNA-sequencing data from matched primary and recurrent tumour samples ( In the setting of glioblastoma recurrence, the EGFR pathway was overexpressed regardless of EGFR-amplification status, suggesting a common genomic endpoint in recurrent glioblastoma, although EGFR amplification did associate with higher EGFR mRNA expression. Three of forty patients in the study cohort had EGFR-amplified tumours and received targeted EGFR therapy. Their molecular subtypes and clinical outcomes did not significantly differ from patients who received conventional chemotherapy. Our findings suggest that while the EGFR amplification may confer a unique molecular profile in primary glioblastoma, pathway analysis reveals upregulation of the EGFR pathway in recurrence, regardless of amplification status. As such, the EGFR pathway may be a key mediator of glioblastoma progression.

The Relationship between Cancer and Dementia An Updated Review.

The risk of cancer and dementia increases with age, raising complex questions about whether it is appropriate to continue cancer treatment in older patients. There is emerging research suggesting the association between cancer and dementia. However, the mechanistic underpinnings are still under investigation. Progress has already been made toward understanding the cognitive effects associated with cancer therapy. Such associations raise awareness about the need to establish better prevention methods and early screening in clinical practice. Additionally, recent studies have suggested possible therapeutic strategies for better preserving cognitive function and reducing the risk for dementia before patients start cancer treatment. We review the current literature and summarize the incidence and mechanisms of cognitive impairment in patients with lung cancer, breast cancer, head and neck cancer, gastric cancer, prostate cancer, colorectal cancer, and brain tumorbrain metastasis following different kinds of therapies. Possible risk factors are suggested to identify the early onset of cognitive changes in cancer patients and provide more insight into the pathophysiological process of dementia.

Associated Factors of Spontaneous Hemorrhage in Brain Metastases in Patients with Lung Adenocarcinoma.

Hemorrhage in brain metastases (BMs) from lung cancer is common and associated with a poor prognosis. Research on associated factors of spontaneous hemorrhage in patients with BMs is limited. This study aimed to investigate the predictive risk factors for BM hemorrhage and assess whether hemorrhage affects patient survival. We retrospectively evaluated 159 BMs from 80 patients with lung adenocarcinoma from January 2017 to May 2022. Patients were classified into hemorrhagic and non-hemorrhagic groups. Patient demographics, lung cancer molecular subtype, treatment type, and tumor-node-metastasis stage were compared between the groups. Multivariate generalized estimating equation (GEE) analysis and gradient boosting were performed. To determine whether BM hemorrhage can stratify overall survival after BM (OSBM), univariate survival analysis was performed. In the univariate analysis, hemorrhagic BMs were significantly larger and had a history of receiving combination therapy with tyrosine kinase inhibitor (TKI) and intracranial radiation ( Hemorrhage in BMs from lung adenocarcinomas may be associated with BM tumor size and a combination of TKI and intracranial radiotherapy. BM hemorrhage did not affect OSBM.

Immune Microenvironment and Immunotherapies for Diffuse Intrinsic Pontine Glioma.

Diffuse intrinsic pontine glioma (DIPG) is a primary glial glioma that occurs in all age groups but predominates in children and is the main cause of solid tumor-related childhood mortality. Due to its rapid progression, the inability to operate and insensitivity to most chemotherapies, there is a lack of effective treatment methods in clinical practice for DIPG patients. The prognosis of DIPG patients is extremely poor, with a median survival time of no more than 12 months. In recent years, there have been continuous breakthroughs for immunotherapies in various hematological tumors and malignant solid tumors with extremely poor prognoses, which provides new insights into tumors without effective treatment strategies. Meanwhile, with the gradual development of stereotactic biopsy techniques, it is gradually becoming easier and safer to obtain live DIPG tissue, and the understanding of the immune properties of DIPG has also increased. On this basis, a series of immunotherapy studies of DIPG are under way, some of which have shown encouraging results. Herein, we review the current understanding of the immune characteristics of DIPG and critically reveal the limitations of current immune research, as well as the opportunities and challenges for immunological therapies in DIPG, hoping to clarify the development of novel immunotherapies for DIPG treatment.

GBM Cells Exhibit Susceptibility to Metformin Treatment According to TLR4 Pathway Activation and Metabolic and Antioxidant Status.

Glioblastoma (GBM) is an aggressive brain cancer associated with poor overall survival. The metabolic status and tumor microenvironment of GBM cells have been targeted to improve therapeutic strategies. TLR4 is an important innate immune receptor capable of recognizing pathogens and danger-associated molecules. We have previously demonstrated the presence of TLR4 in GBM tumors and the decreased viability of the GBM tumor cell line after lipopolysaccharide (LPS) (TLR4 agonist) stimulation. In the present study, metformin (MET) treatment, used in combination with temozolomide (TMZ) in two GBM cell lines (U87MG and A172) and stimulated with LPS was analyzed. MET is a drug widely used for the treatment of diabetes and has been repurposed for cancer treatment owing to its anti-proliferative and anti-inflammatory actions. The aim of the study was to investigate MET and LPS treatment in two GBM cell lines with different metabolic statuses. MET treatment led to mitochondrial respiration blunting and oxidative stress with superoxide production in both cell lines, more markedly in U87MG cells. Decreased cell viability after MET TMZ and MET LPS TMZ treatment was observed in both cell lines. U87MG cells exhibited apoptosis after MET LPS TMZ treatment, promoting increased ER stress, unfolded protein response, and BLC2 downregulation. LPS stimulation of U87MG cells led to upregulation of

Anti-Vimentin Nanobody Decreases Glioblastoma Cell Invasion In Vitro and In Vivo.

Glioblastoma (GBM) is the most common primary brain tumour and one of the deadliest cancers. In addition to late diagnosis and inadequate treatment, the extremely low survival rate is also due to the lack of appropriate therapeutic biomarkers and corresponding therapeutic agents. One of the potential therapeutic biomarkers is the intermediate filament vimentin, which is associated with epithelial-mesenchymal transition (EMT). The purpose of this study was to analyse the effect of the anti-vimentin nanobody Nb79 on cell invasion in vitro and in vivo. To further our understanding of the mechanism of action, we investigated the association between Nb79 and EMT in GBM and GBM stem cells by analysing the expression levels of key EMT-related proteins. The expression of vimentin in glioma tissues and cells was determined by RT-qPCR. An invasion assay was performed on differentiated glioblastoma cell line U-87 MG and stem cell line NCH421k in vitro as well as in vivo in zebrafish embryos. The effect of Nb79 on expression of EMT biomarkers beta-catenin, vimentin, ZEB-1 and ZO1 was determined by Western blot and immunocytochemistry. Our study shows that vimentin is upregulated in glioblastoma tissue compared to lower grade glioma and non-tumour brain tissue. We demonstrated that treatment with Nb79 reduced glioblastoma cell invasion by up to 64% in vitro and up to 21% in vivo. In addition, we found that the tight junction protein ZO-1 had higher expression on the cell membrane, when treated with inhibitory anti-vimentin Nb79 compared to control. In conclusion, our results suggest that anti-vimentin nanobody Nb79 is a promising tool to target glioblastoma cell invasion.

The In Vivo Intervention and Relative Mechanism of Genistein on the Inflammation and Thrombophilia in Lymphoma-Bearing Mice.

To investigate the in vivo intervention and relative mechanism of Genistein (GEN) on tumor-associated inflammatory and tumor thrombophilia in lymphoma-bearing mice. Forty female Balbc mice aged 5-6 weeks were injected with murine-derived Pro B-cell lymphoma cell line 38B9 to establish a lymphoma mouse model, which was randomly divided into control group, tumor-bearing group, GEN drug intervention group and cyclophosphamide (CTX）drug intervention group. Histopathologic was used to evaluate the tumorigenesis. Tumor formation was observed, and tumor tissues were collected of HE and immunohistochemical staining. ELISA and flow cytometry were used to detect the expression of inflammatory factors and the changes of thrombus indices in plasma after intervention of GEN and Cyclophosphamide (CTX) respectively. Immunohistochemistry method was used to detect the expression of CD19 in tomor tissues of tummor bearing mice. After 14 days of tumor bearing, the mice were tumorigenic. The lymphoma cells were diffusely distributed in the tumor tissue and the expression of CD19 in the tumor tissue was positive. The inflammatory factors such as IL-6, NETs and CLEC-2, and thrombotic indices such as TF, FIB and D-D in lymphoma-bearing mice were significantly higher than those before tumor-injection and lower than those after drug-intervention (all Tumor-associated inflammation and thrombophilia exist in lymphoma-bearing mice. GEN shows better anti-inflammatory and anti-thrombotic effects compared with CTX by interfering with tumor inflammatory factors. 金雀异黄素对淋巴瘤小鼠炎性易栓状态的体内干预及相关机制. 探讨金雀异黄素（Genistein，GEN）对淋巴瘤鼠体内肿瘤相关炎性及易栓状态的干预及其机制. 将40只5-6周龄Balbc雌性小鼠予以鼠源性Pro B细胞淋巴瘤细胞株38B9构建淋巴瘤荷瘤鼠模型，并随机分为对照组、荷瘤未干预、GEN干预和环磷酰胺（Cyclophosphamide，CTX）干预共4组，每组10只。采用组织病理学评估成瘤情况，观察成瘤情况，取肿瘤组织行HE及免疫组化染色。采用ELISA和FCM法等分别检测GEN和CTX干预后血浆中炎性细胞因子分泌水平和血栓指标的变化。采用免疫组化法检测CD19在瘤体小鼠瘤组织中的表达. 小鼠荷瘤14 d后均成瘤，瘤体组织中淋巴瘤细胞呈弥散分布，荷瘤鼠瘤体组织的CD19表达为阳性。荷瘤鼠体内炎性指标IL-6、NETs及CLEC-2和血栓指标TF、FIB及D-D均明显高于荷瘤前（均 荷瘤淋巴瘤小鼠体内存在肿瘤相关炎性及易栓状态。 GEN通过干预肿瘤炎性因子达到的抗炎和抗易栓作用优于CTX.

Morinda officinalis oligosaccharides mitigate depression-like behaviors in hypertension rats by regulating Mfn2-mediated mitophagy.

Patients with hypertension have a risk of depression. Morinda officinalis oligosaccharides (MOOs) have anti-depressant properties. In this study, we aimed to determine whether MOOs can improve the symptoms of depression in individuals with hypertension. Dahl salt-sensitive rats fed with a high-salt diet were stimulated by chronic unpredictable mild stress to mimic hypertension with depression. Primary astrocytes and neurons were isolated from these rats. Astrocytes underwent LPS stimulation to simulate the inflammatory astrocytes during depression. MOOs were administrated at 0.1 mggday in vivo and 1.25, 2.5, and 5 mgmL in vitro. Mitophagy was inhibited using 5 mM 3-methyladenine (3-MA). Astrocyte-mediated neurotoxicity was detected by co-culturing astrocytes and neurons. MOOs decreased systolic pressure, diastolic pressure, and mean arterial pressure, thereby improving depression-like behavior, including behavioral despair, lack of enthusiasm, and loss of pleasure during hypertension with depression. Furthermore, MOOs inhibited inflammation, astrocytic dysfunction, and mitochondrial damage in the brain. Then, MOOs promoted autophagosome and lysosome enriched in mitochondria in LPS-stimulated astrocytes. MOOs suppressed mitochondrial damage and the release of tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-1β in astrocytes undergoing LPS stimulation. Importantly, MOOs rescued the impaired neurons co-cultured with astrocytes. The effects of MOOs on LPS-stimulated astrocytes were reversed by 3-MA. Finally, MOOs upregulated LPS-downregulated Mfn2 expression in astrocytes. Mfn2 inhibition partly reversed the effects of MOOs on hypertension with depression. Intriguingly, Mfn2 suppression activated PI3KAktmTOR pathway during MOOs treatment. Astrocytes develop neuroinflammation in response to mitochondrial damage during hypertension with depression. MOOs upregulated Mfn2 expression to activate the PI3KAktmTOR pathway-mediated mitophagy, thereby removing impaired mitochondria in astrocytes. 1. MOOs have anti-hypertensive and anti-depressive properties. 2. MOOs inhibit inflammation and injury in astrocytes during hypertension with depression. 3. MOOs induce mitophagy activation in inflammatory astrocytes with mitochondrial damage. 4. MOOs upregulate Mfn2 expression in astrocytes. 5. Mfn2 activates mitophagy to resist mitochondrial damage in astrocytes.

Acute promyelocytic leukaemia population-based study of epidemiology and outcome with ATRA and oral-ATO from 1991 to 2021.

The epidemiology and treatment of acute promyelocytic leukaemia (APL) are changing. We have incorporated oral arsenic trioxide (oral-ATO) into inductionmaintenance. Newly-diagnosed APL from 1991 to 2021 divided into three 10-year periods were studied to define its epidemiology and how oral-ATO impacted on its outcome. Primary endpoints included APL incidence, early deaths (ED, first 30 days), and overall survival (OS). Secondary endpoints included post-30-day OS, relapse-free survival (RFS), and incidence of second cancers. APL occurred in 374 males and 387 females at a median age of 44 (1-97) years. Annual incidences increased progressively, averaging 0.32 per 100,000 people. All-trans retinoic acid (ATRA)-based and oral-ATO-based regimens were used in 469 and 282 patients. There were 144 EDs, occurring almost exclusively in ATRA-based inductions (N 139), being more with males, age > 50 years, leucocyte > 10 × 10 There was an increasing incidence of APL, and all survivals were superior with the use of oral-ATO-based regimens. This study formed part of the Acute Promyelocytic Leukaemia Asian Consortium Project (ClinicalTrials.gov identifier NCT04251754).

Regression analysis on forward modeling of diffuse optical tomography system for carcinoma cell detection.

The forward model design was employed in the Diffuse Optical Tomography (DOT) system to determine the optimal photonic flux in soft tissues like the brain and breast. Absorption coefficient (mua), reduced scattering coefficient (mus), and photonic flux (phi) were the parameters subjected to optimization. The Box-Behnken Design (BBD) method of the Response Surface Methodology (RSM) was applied to enhance the Diffuse Optical Tomography experimental system. The DC modulation voltages applied to different laser diodes of 850 nm and 780 nm wavelengths and spacing between the source and detector are the two factors operating on three optimization parameters that predicted the result through two-dimensional tissue image contours. The analysis of the Variance (ANOVA) model developed was substantial (R

Loss of phosphatase CTDNEP1 potentiates aggressive medulloblastoma by triggering MYC amplification and genomic instability.

MYC-driven medulloblastomas are highly aggressive childhood brain tumors, however, the molecular and genetic events triggering MYC amplification and malignant transformation remain elusive. Here we report that mutations in CTDNEP1, a CTD nuclear-envelope-phosphatase, are the most significantly enriched recurrent alterations in MYC-driven medulloblastomas, and define high-risk subsets with poorer prognosis. Ctdnep1 ablation promotes the transformation of murine cerebellar progenitors into Myc-amplified medulloblastomas, resembling their human counterparts. CTDNEP1 deficiency stabilizes and activates MYC activity by elevating MYC serine-62 phosphorylation, and triggers chromosomal instability to induce p53 loss and Myc amplifications. Further, phosphoproteomics reveals that CTDNEP1 post-translationally modulates the activities of key regulators for chromosome segregation and mitotic checkpoint regulators including topoisomerase TOP2A and checkpoint kinase CHEK1. Co-targeting MYC and CHEK1 activities synergistically inhibits CTDNEP1-deficient MYC-amplified tumor growth and prolongs animal survival. Together, our studies demonstrate that CTDNEP1 is a tumor suppressor in highly aggressive MYC-driven medulloblastomas by controlling MYC activity and mitotic fidelity, pointing to a CTDNEP1-dependent targetable therapeutic vulnerability.

Gastrointestinally absorbable lactoferrin-heparin conjugate with anti-angiogenic activity for treatment of brain tumor.

Glioblastoma multiforme (GBM) is a central nervous system disease with poor prognosis. Curative treatments for GBM involve chemotherapy, radiotherapy, and surgical pathways. Recently, antiangiogenic therapy through medications has been tried to slow tumor growth, but the drugs can induce side effects. To overcome these limitations, we developed a new orally absorbable form of heparin that can attenuate angiogenic activity by binding to growth factors around the tumor tissue. We conjugated lactoferrin (Lf) to heparin because Lf can be orally absorbed, and it interacts with the lactoferrin receptor (Lf-R) expressed on the intestine, blood-brain barrier (BBB), and glioma tumor masses. We successfully conjugated Lf and heparin by amide bond formation, as evidenced by advanced physicochemical properties such as pharmacokinetics and stability in acidic condition. This new material inhibited angiogenesis in vitro without toxicity. In addition, Lf-heparin administered orally to GBM orthotopic mice was absorbed in the small intestine and delivered specifically to the brain tumor by receptor transcytosis (Lf-R). Lf-heparin further attenuated angiogenesis progression in GBM orthotopic mice. Based on these results, Lf-heparin shows potential as a new oral medication for treatment of glioblastoma.

Pediatric Neurosurgical Capacity for the Care of Children With CNS Tumors Worldwide A Cross-Sectional Assessment.

Efforts to address inequities in the treatment of pediatric CNS tumors and the burden of childhood cancer globally have prompted the designation of low-grade glioma as one of six index cancers for the World Health Organization Global Initiative for Childhood Cancer. Understanding the importance of neurosurgical interventions and evaluating pediatric neurosurgical capacity may identify critical interventions to improve outcomes for children with low-grade glioma and other CNS tumors. An online, cross-sectional survey assessing pediatric neurosurgical practice and capacity was distributed to members of the International Society of Pediatric Neurosurgery. The survey included 36 items covering domains including patient volume, available infrastructure, scope of practice, case distribution, and multidisciplinary care. Responses from 196 individuals from 61 countries, spanning all WHO regions, were included. Ninety-six (49.0%) were from high-income countries, 57 (29.1%) were from upper-middle-income countries, 42 (21.4%) were from lower-middle-income countries (LMICs), and 1 was (0.5%) from a low-income country. Most respondents had a catchment population of ≥ 1 million and indicated the availability of basic neurosurgical resources such as a dedicated neurosurgical operating theater and surgical microscope. The presence of a neurosurgical intensive care unit, inpatient rehabilitation services, and infection monitoring showed similar availability across country groups. Quantitative scoring of 13 infrastructure and service items established that fewer resources were available in low-income countriesLMICs and upper-middle-income countries compared with high-income countries. The volume of pediatric CNS tumor cases and case distribution did not vary according to World Bank country groups. This study provides a comprehensive evaluation of pediatric neurosurgical capacity across the globe, establishing variability of resources on the basis of the country income level. Our findings suggest that pediatric neurosurgeons in LMICs may benefit from key neurosurgical instrumentation and increased support for multidisciplinary brain tumor programs and childhood cancer research efforts.

Role of the Peli1-RIPK1 Signaling Axis in Methamphetamine-Induced Neuroinflammation.

Severe neurological inflammation is one of the main symptoms of methamphetamine (meth)-induced brain injury. Studies have demonstrated that meth exposure facilitates neuroinflammation via Pellino E3 ubiquitin protein ligase 1 (Peli1)-mediated signaling. However, the involved mechanisms remain incompletely understood. Herein, we used Peli1

Intraoperative photodynamic therapy in complex treatment of malignant gliomas.

Treatment of malignant gliomas is an extremely difficult objective associated with difficult choice of correct strategy. Photodynamic therapy is still not the treatment standard in these patients although this approach significantly improves treatment outcomes in surgery of gliomas. To demonstrate the possibilities of chlorin e6-mediated photodynamic therapy for malignant glial tumors. There were 161 patients with malignant supratentorial glial tumors who were treated at the Polenov Russian Neurosurgery Institute between 2009 and 2016. Eighty patients comprised the main group (photodynamic therapy), 81 ones - control group (without photodynamic therapy). Photodynamic therapy in complex treatment of malignant brain gliomas significantly increases overall survival in patients with Grade III gliomas up to 39.1±5.5 months (control group - 22.8±3.3 months) and Grade IV gliomas up to 20.7±4.7 months (control group - 13.5±2.3 months) ( Лечение злокачественных глиом — экстремально сложная задача, зачастую с трудным выбором тактики. Фотодинамическая терапия до сих пор не является стандартом в помощи таким пациентам, несмотря на то, что результаты использования данной методики в хирургии глиом доказывают статистически значимое улучшение результатов лечения. Продемонстрировать возможности фотодинамической терапии злокачественных глиальных опухолей с использованием хлорина E6. В исследование вошел 161 пациент со злокачественной глиальной опухолью супратенториальной локализации, находившийся на лечении в РНХИ им. проф. А.Л. Поленова с 2009 по 2016 г. Из них 80 больных составили основную группу (с фотодинамической терапией), 81 — группу сравнения (без фотодинамической терапии). Фотодинамическая терапия в структуре комплексной терапии злокачественных глиом головного мозга достоверно увеличивает медиану общей выживаемости у пациентов с grade III глиомами до 39,1±5,5 мес (основная группа — 22,8±3,3 мес), grade IV глиомами — до 20,7±4,7 мес (группа сравнения — 13,5±2,3 мес) (

Surgical treatment of tumors of the supplementary motor area.

After surgical treatment of tumors of the supplementary motor area (SMA) post-operative speech andor motor neurological deficit may occur. To determinate frequency and reversibility of such deficit and identify risk factors for its development. We retrospectively analyzed postoperative outcomes in 34 patients with SMA tumors. Pre- and postoperative neurological status, localization of tumors, extent of resection relative to adjacent regions and relationship of tumor with white matter tracts were assessed. We also analyzed the influence of these factors on the risk of postoperative neurological impairment. Postoperative neurological impairment occurred in 47% of cases. Complete or significant regression was observed in all patients within 5.7 month after surgery. Major risk factors were lesion of dominant hemisphere ( Surgery for SMA tumors is safe and followed by favorable functional outcomes. При хирургическом лечении опухолей, локализованных в дополнительной моторной области, возможно возникновение речевого иили двигательного неврологического дефицита. Определение частоты и обратимости такого дефицита, возникающего при поражении дополнительной моторной области, и выявление факторов риска его развития. Ретроспективно изучены результаты хирургического лечения 34 пациентов с объемными образованиями в дополнительной моторной области (ДМО). Оценивались неврологический статус в пред- и послеоперационном периоде, локализация опухоли, объем резекции и ее протяженность относительно смежных регионов, взаимоотношение опухоли с трактами. Проведен анализ влияния этих факторов на вероятность развития послеоперационного дефицита. В 47% случаев в послеоперационном периоде образовался неврологический дефицит, полный или значительный регресс которого был отмечен в 100% случаев при контрольном осмотре в среднем через 5,7 мес после операции. Основными факторами развития дефицита были операция на доминантном полушарии ( Удаление опухолей ДМО безопасно и имеет относительно благоприятные исходы в функциональном статусе пациентов.

Belvarafenib penetrates the BBB and shows potent antitumor activity in a murine melanoma brain metastasis model.

Brain metastasis is a common complication in melanoma patients with BRAF and NRAS mutations and has a poor prognosis. Although BRAF inhibitors are clinically approved, their poor brain penetration limits their efficacy in brain metastasis. Thus, melanoma brain metastasis still requires better treatment. Belvarafenib, a pan-RAF inhibitor, has reported antitumor activity in melanoma with RAF and RAS mutations in animal models and patients. However, brain permeability and antitumor efficacy on brain metastasis have not been determined. This study confirmed the brain penetration of belvarafenib, the antitumor activity on BRAF and NRAS mutant melanoma, and the efficacy on melanoma within the brain. Belvarafenib strongly suppressed melanoma in BRAF V600E mutant A375SM tumor-bearing mice. It also significantly inhibited tumor growth in NRAS mutant SK-MEL-30 and K1735 tumor-bearing mice and synergized to enhance the antitumor activity combined with cobimetinib or atezolizumab. Belvarafenib was penetrated at considerable levels into the brains of mice and rats following oral administration. The exposure of belvarafenib in the brain was similar to or higher than that in plasma, and this high brain penetration differed significantly from that of other BRAF inhibitors with low brain penetration. Most importantly, belvarafenib strongly reduced tumor burden and markedly improved survival benefits in mice intracranially implanted with A375SM melanoma. These results demonstrated that belvarafenib, which has favorable BBB permeability, and potent antitumor activity on the tumors with BRAFNRAS mutations, may be a promising therapeutic option for patients with BRAFNRAS mutant melanoma brain metastasis.

Cytokine- and Vascular Endothelial Growth Factor-Related Gene-Based Genome-Wide Association Study of Low-Dose Ketamine Infusion in Patients with Treatment-Resistant Depression.

Ketamine may work as an anti-inflammatory agent, and it increases the levels of vascular endothelial growth factor (VEGF) in patients with treatment-resistant depression. However, whether genes related to pro-inflammatory and anti-inflammatory cytokines and VEGF may predict the treatment response to ketamine remains unknown.Therefore the aim of this study was to analyze whether specific genes related to inflammatory processes and VEGF were associated with treatment response to low-dose ketamine in patients with treatment-resistant depression. Based on the genome data from our clinical trial, this study was a secondary analysis of candidate genes correlated with different timepoints of depressive symptoms. In total, 65 patients with treatment-resistant depression (n 21 for ketamine 0.5 mgkg, 20 for ketamine 0.2 mgkg, and 24 for normal saline) were genotyped for 684,616 single nucleotide polymorphisms. Genes associated with 80 cytokines (i.e., interleukin IL-1, IL-6, tumor necrosis factor-α, and adiponectin) and VEGF (i.e., VEGF and VEGF receptors) were selected for the gene-based genome-wide association study on the antidepressant effect of a ketamine infusion. Specific single nucleotide polymorphisms, including rs2540315 and rs75746675 in IL1R1 and rs79568085 in VEGFC, were related to the rapid (within 240 min) antidepressant effect of a ketamine infusion specific single nucleotide polymorphisms, such as Affx-20131665 in PIGF and rs8179353, rs8179353, and rs8179353 in TNFRSF8, were associated with the sustained (up to 2 weeks) antidepressant effect of low-dose (combined 0.5 mgkg and 0.2 mgkg) ketamine. Our findings further revealed that genes related to both anti-inflammatory and pro-inflammatory cytokines (i.e., IL-1, IL-2, IL-6, tumor necrosis factor-α, C-reactive protein, and adiponectin) and VEGF-FLK signaling predicted the treatment response to a ketamine infusion in patients with treatment-resistant depression. The synergic modulation of inflammatory and VEGF systems may contribute to the antidepressant effect of ketamine. University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) number UMIN000016985.

Breast Cancer to Meningioma A Rare Case of Tumor-to-Tumor Metastasis.

Tumor-to-tumor metastasis (TTM) is defined as the hematogenous metastasis within a primary host tumor from a donor neoplasm. Since there is insufficient evidence regarding the pathophysiology, clinical course, and management of TTM, there are no precise guidelines for its management. A 73-year-old female patient diagnosed with breast cancer was found to have convexity meningioma. Since the size of tumor and peritumoral brain edema increased during follow-up period, the meningioma was treated with surgical resection. Postoperatively, histopathologic examination confirmed metastasis of invasive ductal carcinoma within a secretory meningioma. The final diagnosis was TTM of breast cancer in meningioma. Here, we report a rare case of intra-meningioma metastasis and a review of literature to provide a better understanding of this rare phenomenon.

A Rare Occurrence of Primarily Extranodal Spinal Epidural Lymphoma With Spinal Cord Compression and Invasion to the Thoracic Cavity.

A 41-year-old man suffered from progressive radiculomyelopathy caused by spinal epidural mass primarily encasing the spinal cord at the cervicothoracic vertebrae that extended into the thoracic cavity through the neural foramen. An urgent decompressive laminectomy and epidural tumor resection were performed to prevent neurological deterioration and effective spinal cord decompression. The histopathologic diagnosis was diffuse large B-cell lymphoma. As first-line treatment for stage II extranodal lymphoma, he received 6 cycles of R-CHOP (rituximabcyclophosphamide, hydroxydaunorubicin, Oncovin, and prednisone) chemotherapy. Consequently, follow-up positron-emission tomography CT and MR images demonstrated a complete metabolic response (Deauville score 1). This rare occurrence of primarily extranodal spinal epidural lymphoma with limited disease will be presented in a literature review.

MRI-Based Classification of Rathkes Cleft Cyst and Its Clinical Implication.

Rathkes cleft cysts (RCCs) are benign tumors of the pituitary gland. Small, asymptomatic RCCs do not require surgical treatment, whereas surgical treatment is required for symptomatic RCCs. We retrospectively reviewed medical records of patients with an RCC who were diagnosed and managed in our institution between April 2004 and April 2020 and generated two different cohorts the observation (n114) and the surgical group (n99). Their initial MRI signal characteristics were analyzed. The natural course focusing on cyst size was observed in the observation group and postoperative visual and endocrine outcomes were evaluated in the surgical group. The characterization of MRI signals of cyst contents in both T1-weighted (T1W) and T2-weighted (T2W) images revealed nine combinations for our 213 patients. Among 115 patients with a high T2W signal, the cysts showed hypo-, iso-, and hyper-intensity on T1W images in 72, 39, and 44 patients, respectively Type S-low, Type S-iso, and Type S-high. One more major group of 35 patients showed RCCs with hyperintensity on the T1W images and hypointensity on the T2W images named as Type M. In the comparison between observation and surgical groups, we identified only two major groups in which the number of patients in the surgical and observation groups was statistically different more Type S-low in a surgical group ( MRI characteristics help to predict the natural course of RCCs. We identified subgroups of RCCs which are more or less likely to require surgical intervention.

Brain Invasion and Trends in Molecular Research on Meningioma.

Meningiomas are the most common primary brain tumors in adults. The treatment of non-benign meningiomas remains a challenging task, and after the publication of the 2021 World Health Organization classification, the importance of molecular biological classification is emerging. In this article, we introduce the mechanisms of brain invasion in atypical meningioma and review the genetic factors involved along with epigenetic regulation. First, it is important to understand the three major steps for brain invasion of meningeal cells 1) degradation of extracellular matrix by proteases, 2) promotion of tumor cell migration to resident cells by adhesion molecules, and 3) neovascularization and supporting cells by growth factors. Second, the genomic landscape of meningiomas should be analyzed by major categories, such as germline mutations in

The Role of Hypoxia in Brain Tumor Immune Responses.

Oxygen is a vital component of living cells. Low levels of oxygen in body tissues, known as hypoxia, can affect multiple cellular functions across a variety of cell types and are a hallmark of brain tumors. In the tumor microenvironment, abnormal vasculature and enhanced oxygen consumption by tumor cells induce broad hypoxia that affects not only tumor cell characteristics but also the antitumor immune system. Although some immune reactions require hypoxia, hypoxia generally negatively affects immunity. Hypoxia induces tumor cell invasion, cellular adaptations to hypoxia, and tumor cell radioresistance. In addition, hypoxia limits the efficacy of immunotherapy and hinders antitumor responses. Therefore, understanding the role of hypoxia in the brain tumor, which usually does not respond to immunotherapy alone is important for the development of effective anti-tumor therapies. In this review, we discuss recent evidence supporting the role of hypoxia in the context of brain tumors.

Medulloblastoma Current Perspectives and Recent Advances.

Medulloblastoma is the most common embryonal tumor of the central nervous system in childhood. Combined multimodality approaches, including surgery, radiation, and chemotherapy, have improved the outcome of medulloblastoma. Advances in genomic research have shown that medulloblastoma is not a biologically or clinically discrete entity. Previously, the risk was divided according to histology, presence of metastasis, degree of resection, and age at diagnosis. Through the development of integrated genomics, new biology-based risk stratification methods have recently been proposed. It is also important to understand the genetic predisposition of patients with medulloblastoma. Therefore, treatment goal aimed to improve the survival rate with minimal additional adverse effects and reduced long-term sequelae. It is necessary to incorporate genetic findings into the standard of care, and clinical trials that reflect this need to be conducted.

Role of Radiotherapy in Patients With Relapsed Medulloblastoma.

During the last three decades, the management of medulloblastoma (MBL) has made enormous progress with a multidisciplinary approach, incorporating surgery, radiotherapy (RT), and chemotherapy. Despite this improvement, 20%-30% of patients with MBL remain at risk of disease recurrence, with its relapse being possibly fatal. To date, the salvage treatment for relapse remains challenging, and various approaches have been suggested for the retreatment. In this review, I have described the characteristics of patients with relapsed MBL, patterns of relapse and the most commonly prescribed treatment. Further, I have reviewed the studies on re-irradiation and its associated issues to conclusively suggest the RT recommendations for patients with relapsed MBL.

Advances in Brain Metastasis Models.

To obtain achievements in addressing the clinical challenges of brain metastasis, we need a clear understanding of its biological mechanisms. Brain metastasis research is challenged by many practical scientific barriers. Depending on the purpose of the study, experimental brain metastasis models

Molecular Biology of Brain Metastases.

Brain metastases (BMs) often occur in patients with lung cancer, breast cancer, and melanoma and are the leading cause of morbidity and mortality. The incidence of BM has increased with advanced neuroimaging and prolonged overall survival of cancer patients. With the advancement of local treatment modalities, including stereotactic radiosurgery and navigation-guided microsurgery, BM can be controlled long-term, even in cases with multiple lesions. However, radiationchemotherapeutic agents are also toxic to the brain, usually irreversibly and cumulatively, and it remains difficult to completely cure BM. Thus, we must understand the molecular events that begin and sustain BM to develop effective targeted therapies and tools to prevent local and distant treatment failure. BM most often spreads hematogenously, and the blood-brain barrier (BBB) presents the first hurdle for disseminated tumor cells (DTCs) entering the brain parenchyma. Nevertheless, how the DTCs cross the BBB and settle on relatively infertile central nervous system tissue remains unknown. Even after successfully taking up residence in the brain, the unique tumor microenvironment is marked by restricted aerobic glycolysis metabolism and limited lymphocyte infiltration. Brain organotropism, certain phenotype of primary cancers that favors brain metastasis, may result from somatic mutation or epigenetic modulation. Recent studies revealed that exosome secretion from primary cancer or over-expression of proteolytic enzymes can pre-condition brain vasculoendothelial cells. The concept of the metastatic niche, where resident DTCs remain dormant and protected from systemic chemotherapy and antigen exposure before proliferation, is supported by clinical observation of BM in patients clearing systemic cancer and experimental evidence of the interaction between cancer cells and tumor-infiltrating lymphocytes. This review examines extant research on the metastatic cascade of BM through the molecular events that create and sustain BM to reveal clues that can assist the development of effective targeted therapies that treat established BMs and prevent BM recurrence.