Datasets:

Gaborandi

/

Brain_Tumor_pubmed_abstracts

like 2

Neuronal-Activity Dependent Mechanisms of Small Cell Lung Cancer Progression.

Neural activity is increasingly recognized as a critical regulator of cancer growth. In the brain, neuronal activity robustly influences glioma growth both through paracrine mechanisms and through electrochemical integration of malignant cells into neural circuitry via neuron-to-glioma synapses, while perisynaptic neurotransmitter signaling drives breast cancer brain metastasis growth. Outside of the CNS, innervation of tumors such as prostate, breast, pancreatic and gastrointestinal cancers by peripheral nerves similarly regulates cancer progression. However, the extent to which the nervous system regulates lung cancer progression, either in the lung or when metastatic to brain, is largely unexplored. Small cell lung cancer (SCLC) is a lethal high-grade neuroendocrine tumor that exhibits a strong propensity to metastasize to the brain. Here we demonstrate that, similar to glioma, metastatic SCLC cells in the brain co-opt neuronal activity-regulated mechanisms to stimulate growth and progression. Optogenetic stimulation of cortical neuronal activity drives proliferation and invasion of SCLC brain metastases. In the brain, SCLC cells exhibit electrical currents and consequent calcium transients in response to neuronal activity, and direct SCLC cell membrane depolarization is sufficient to promote the growth of SCLC tumors. In the lung, vagus nerve transection markedly inhibits primary lung tumor formation, progression and metastasis, highlighting a critical role for innervation in overall SCLC initiation and progression. Taken together, these studies illustrate that neuronal activity plays a crucial role in dictating SCLC pathogenesis in both primary and metastatic sites.

B-cells Drive Response to PD-1 Blockade in Glioblastoma Upon Neutralization of TGFβ-mediated Immunosuppression.

Immunotherapy has revolutionized cancer treatment but has yet to be translated into brain tumors. Studies in other solid tumors suggest a central role of B-cell immunity in driving immune-checkpoint-blockade efficacy. Using single-cell and single-nuclei transcriptomics of human glioblastoma and melanoma brain metastasis, we found that tumor-associated B-cells have high expression of checkpoint molecules, known to block B-cell-receptor downstream effector function such as plasmablast differentiation and antigen-presentation. We also identified TGFβ-1TGFβ receptor-2 interaction as a crucial modulator of B-cell suppression. Treatment of glioblastoma patients with pembrolizumab induced expression of B-cell checkpoint molecules and TGFβ-receptor-2. Abrogation of TGFβ using different conditional knockouts expanded germinal-center-like intratumoral B-cells, enhancing immune-checkpoint-blockade efficacy. Finally, blocking αVβ8 integrin (which controls the release of active TGFβ) and PD-1 significantly increased B-cell-dependent animal survival and immunological memory. Our study highlights the importance of intratumoral B-cell immunity and a remodeled approach to boost the effects of immunotherapy against brain tumors.

Radiomic Analysis to Predict Histopathologically Confirmed Pseudoprogression in Glioblastoma Patients.

Pseudoprogression mimicking recurrent glioblastoma remains a diagnostic challenge that may adversely confound or delay appropriate treatment or clinical trial enrollment. We sought to build a radiomic classifier to predict pseudoprogression in patients with primary isocitrate dehydrogenase wild type glioblastoma. We retrospectively examined a training cohort of 74 patients with isocitrate dehydrogenase wild type glioblastomas with brain magnetic resonance imaging including dynamic contrast enhanced T1 perfusion before resection of an enhancing lesion indeterminate for recurrent tumor or pseudoprogression. A recursive feature elimination random forest classifier was built using nested cross-validation without and with O A classifier constructed with cross-validation on the training cohort achieved an area under the receiver operating curve of 81% for predicting pseudoprogression. This was further improved to 89% with the addition of O Our results suggest that radiomic analysis of contrast T1-weighted images and magnetic resonance imaging perfusion images can assist the prompt diagnosis of pseudoprogression. Validation on external and independent data sets is necessary to verify these advanced analyses, which can be performed on routinely acquired clinical images and may help inform clinical treatment decisions.

piR-36249 and DHX36 together inhibit testicular cancer cells progression by upregulating OAS2.

PIWI-interacting RNAs (piRNAs) are a class of noncoding RNAs originally reported in the reproductive system of mammals and later found to be aberrantly expressed in tumors. However, the function and mechanism of piRNAs in testicular cancer are not very clear. The expression level and distribution of piR-36249 were detected by RT-qPCR and immunofluorescence staining assay. Testicular cancer cell (NT2) progression was measured by CCK8 assay, colony formation assay and wound healing assay. Cell apoptosis was assessed by flow cytometry and western blot. RNA sequencing and dual-luciferase reporter assay were conducted to identify the potential targets of piR-36249. The relationship between piR-36249 and piR-36249 is significantly downregulated in testicular cancer tissues compared to tumor-adjacent tissues. Functional studies demonstrate that piR-36249 inhibits testicular cancer cell proliferation, migration and activates the cell apoptosis pathway. Mechanically, we identify that piR-36249 binds to the 3UTR of 2-5-oligoadenylate synthetase 2 ( All these data suggest that piR-36249, together with DHX36, functions in inhibiting the malignant phenotype of testicular cancer cells by upregulating OAS2 protein and that piR-36249 may be used as a suppressor factor to regulate the development of testicular cancer.

Advances in applications of head mounted devices (HMDs) Physical techniques for drug delivery and neuromodulation.

Head-mounted medical devices (HMDs) are disruptive inventions representing laboratories and clinical institutions worldwide are climbing the apexes of brain science. These complex devices are inextricably linked with a wide range knowledge containing the Physics, Imaging, Biomedical engineering, Biology and Pharmacology, particularly could be specifically designed for individuals, and finally exerting integrated bio-effect. The salient characteristics of them are non-invasive intervening in human brains physiological structures, and alterating the biological process, such as thermal ablating the tumor, opening the BBB to deliver drugs and neuromodulating to enhance cognitive performance or manipulate prosthetic. The increasing demand and universally accepted of them have set off a dramatic upsurge in HMDs studies, seminal applications of them span from clinical use to psychiatric disorders and neurological modulation. With subsequent pre-clinical studies and human trials emerging, the mechanisms of transcranial stimulation methods of them were widely studied, and could be basically came down to three notable approach magnetic, electrical and ultrasonic stimulation. This review provides a comprehensive overviews of their stimulating mechanisms, and recent advances in clinic and military. We described the potential impact of HMDs on brain science, and current challenges to extensively adopt them as promising alternative treating tools.

Past, present and future of Focused Ultrasound as an adjunct or complement to DIPGDMG therapy A consensus of the 2021 FUSF DIPG meeting.

Diffuse Intrinsic Pontine Glioma (DIPG), now known as Diffuse Midline Glioma (DMG) is a devastating pediatric brain tumor with limited treatment options and a very poor prognosis. Despite more than 250 clinical trials aimed to treat children diagnosed with DMG, no curative therapies currently exist for this patient population. A major obstacle has been the intact blood brain barrier (BBB) which prevents most therapeutics from crossing into the tumor bed. Focused Ultrasound (FUS) is an emerging, noninvasive medical technology which has been shown in both preclinical and clinical research to disrupt the blood brain barrier safely and temporarily. FUS blood brain barrier opening has been studied in combination with chemotherapies in preclinical DMG models, and this technology is now being investigated in clinical trials for the treatment of pediatric brain tumors. Focused ultrasound has additional mechanisms of action, including sonodynamic therapy and radiation sensitization, that hold promise as future DMG therapies as well. This paper, largely based off the proceedings from a workshop held by the Focused Ultrasound Foundation in October of 2021, summarizes the current state of the field of focused ultrasound for DIPGDMG, including preclinical, technical, and clinical summaries in addition to recommended next steps for continued advancement of the game changing technology of Focused Ultrasound.

Frontal lobe low-grade tumors seizure outcome a pooled analysis of clinical predictors.

Seizures present in 50-90 % of cases with low-grade brain tumors. Frontal lobe epilepsy is associated with dismal seizure outcomes compared to temporal lobe epilepsy. Our objective is to conduct a systematic review, report our case series, and perform a pooled analysis of clinical predictors of seizure outcomes in frontal lobe low-grade brain tumors. Searches of five electronic databases from January 1990 to June 2022 were reviewed following PRISMA guidelines. Individual patient data was extracted from 22 articles that fit the inclusion criteria. A single-surgeon case series from our institution was also retrospectively reviewed and analyzed through a pooled cohort of 127 surgically treated patients with frontal lobe low-grade brain tumors. The mean age at surgery was 30.8 years, with 50.4 % of patients diagnosed as oligodendrogliomas. The majority of patients (81.1 %) were seizure-free after surgery (Engel I). On the multivariate analysis, gross total resection (GTR) (OR 8.77, 95 % CI 1.99-47.91, p 0.006) and awake resection (OR 9.94, 95 % CI 1.93-87.81, p 0.015) were associated with seizure-free outcome. A Kaplan-Meier curve showed that the probability of seizure freedom fell to 92.6 % at 3 months, and to 85.5 % at 27.3 months after surgery. Epilepsy from tumor origin demands a balance between oncological management and epilepsy cure. Our pooled analysis suggests that GTR and awake resections are positive predictive factors for an Engel I at more than 6 months follow-up. To validate these findings, a longer-term follow-up and larger cohorts are needed.

F. nucleatum facilitates oral squamous cell carcinoma progression via GLUT1-driven lactate production.

Tumor-resident microbiota has been documented for various cancer types. Oral squamous cell carcinoma (OSCC) is also enriched with microbiota, while the significance of microbiota in shaping the OSCC microenvironment remains elusive. We used bioinformatics and clinical sample analysis to explore relationship between F. nucleatum and OSCC progression. Xenograft tumor model, metabolic screening and RNA sequencing were performed to elucidate mechanisms of pro-tumor role of F. nucleatum. We show that a major protumorigenic bacterium, F. nucleatum, accumulates in invasive margins of OSCC tissues and drives tumor-associated macrophages (TAMs) formation. The mechanistic dissection shows that OSCC-resident F. nucleatum triggers the GalNAc-Autophagy-TBC1D5 signaling, leading to GLUT1 aggregation in the plasma membrane and the deposition of extracellular lactate. Simultaneous functional inhibition of GalNAc and GLUT1 efficiently reduces TAMs formation and restrains OSCC progression. These findings suggest that tumor-resident microbiota affects the immunomodulatory and protumorigenic microenvironment via modulating glycolysis and extracellular lactate deposition. The targeted intervention of this process could provide a distinct clinical strategy for patients with advanced OSCC. This work was supported by the National Natural Science Foundation of China for Key Program Projects (82030070, to LC) and Distinguished Young Scholars (31725011, to LC), as well as Innovation Team Project of Hubei Province (2020CFA014, to LC).

G2 checkpoint targeting via Wee1 inhibition radiosensitizes EGFRvIII-positive glioblastoma cells.

The gene of the Epidermal growth factor receptor (EGFR) is one of the most frequently altered genes in glioblastoma (GBM), with deletions of exons 2-7 (EGFRvIII) being amongst the most common genomic mutations. EGFRvIII is heterogeneously expressed in GBM. We already showed that EGFRvIII expression has an impact on chemosensitivity, replication stress, and the DNA damage response. Wee1 kinase is a major regulator of the DNA damage induced G2 checkpoint. It is highly expressed in GBM and its overexpression is associated with poor prognosis. Since Wee1 inhibition can lead to radiosensitization of EGFRvIII-negative (EGFRvIII-) GBM cells, we asked, if Wee1 inhibition is sufficient to radiosensitize also EGFRvIII-positive (EGFRvIII) GBM cells. We used the clinically relevant Wee1 inhibitor adavosertib and two pairs of isogenetic GBM cell lines with and without endogenous EGFRvIII expression exhibiting different TP53 status. Moreover, human GBM samples displaying heterogenous EGFRvIII expression were analyzed. Expression of Wee1 was assessed by Western blot and respectively immunohistochemistry. The impact of Wee1 inhibition in combination with irradiation on cell cycle and cell survival was analyzed by flow cytometry and colony formation assay. Analysis of GBM cells and patient samples revealed a higher expression of Wee1 in EGFRvIII cells compared to their EGFRvIII- counterparts. Downregulation of EGFRvIII expression by siRNA resulted in a strong decrease in Wee1 expression. Wee1 inhibition efficiently abrogated radiation-induced G2-arrest and caused radiosensitization, without obvious differences between EGFRvIII- and EGFRvIII GBM cells. We conclude that the inhibition of Wee1 is an effective targeting approach for the radiosensitization of both EGFRvIII- and EGFRvIII GBM cells and may therefore represent a promising new therapeutic option to increase response to radiotherapy.

Neural dynamics supporting longitudinal plasticity of action naming across languages MEG evidence from bilingual brain tumor patients.

Previous evidence suggests that distinct ventral and dorsal streams respectively underpin the semantic processing of object and action knowledge. Recently, we found that brain tumor patients with dorsal gliomas in frontoparietal hubs show a selective longitudinal compensation (post-vs. pre-surgery) during the retrieval of lexico-semantic information about actions (but not objects), indexed by power increases in beta rhythms (13-28 Hz). Here, we move one-step further and ask whether a similar organizational principle also stands across the different languages a bilingual speaks. To test this hypothesis, we combined a picture-naming task with MEG recordings and evaluated highly proficient Spanish-Basque bilinguals undergoing surgery for tumor resection in left frontoparietal regions. We assessed patients before and three months after surgery. At the behavioral level, we observed a similar performance across sessions irrespectively of the language at use, suggesting overall successful function preservation. At the oscillatory level, we found longitudinal selective power increases in beta for action naming in Spanish and Basque. Nevertheless, tumor resection triggered a differential reorganization of the L1 and the L2, with the latter one additionally recruiting the right hemisphere. Overall, our results provide evidence for (i) the specific involvement of frontoparietal regions in the semantic retrievalrepresentation of action knowledge across languages (ii) a key role of beta oscillations as a signature of language compensation and (iii) the existence of divergent plasticity trajectories in L1 and L2 after surgery. By doing so, they provide new insights into the spectro-temporal dynamics supporting postoperative recovery in the bilingual brain.

Alpha lipoic acid treatment in late middle age improves cognitive function Proteomic analysis of the protective mechanisms in the hippocampus.

Alpha lipoic acid (ALA), a powerful antioxidant, has the potential to relieve age-related cognitive impairment and neurodegenerative disease. Clinical randomized controlled studies have demonstrated the cognitive improvement effects of lipoic acid in Alzheimers disease (AD). In the present study, we examined the effects of ALA on cognitive function in ageing mice and its protective mechanisms. Eighteen-month-old male C57BL6J mice received ALA or normal saline for 2 months. The Morris water maze test revealed improved cognitive function in animals that received ALA. Furthermore, tandem Mass Tags (TMT) based liquid chromotography with mass spectrometrymass spectrometry (LC-MSMS) was established to identify the target proteins. The results showed that 10 proteins were changed significantly. Gene Ontology (GO) analysis indicated that the upregulated proteins were enriched in terminal bouton, synaptic transmission and lipid transporter activity while the down-regulated proteins were involved in nuclear transcription factor-κB binding, apoptosis and mitogen-activated protein kinase binding. Based on the GO results, two upregulated proteins oxysterol-binding protein-related protein 10 (OSBPL10) and oligophrenin 1 (OPHN1), and one downregulated protein, CDK5 regulatory subunit-associated protein 3 (CDK5rap3), were validated through Western blotting. The results were consistent with the proteomic results. Modulation of synaptic transmission, lipid transporter activity and neuroinflammation appears to be the mechanisms of ALA in the aged brain.

Elevated labile iron in castration-resistant prostate cancer is targetable with ferrous iron-activatable antiandrogen therapy.

Clinical responses to second generation androgen signaling inhibitors (e.g., enzalutamide) in metastatic castration-resistant prostate cancer (mCRPC) are variable and transient, and are associated with dose limiting toxicities, including rare but severe CNS effects. We hypothesized that changes to iron metabolism coincident with more advanced disease might be leveraged for tumor-selective delivery of antiandrogen therapy. Using the recently described chemical probes SiRhoNox and

Region-related focal loss for 3D brain tumor MRI segmentation.

In the brain tumor magnetic resonance image (MRI) segmentation, although the 3D convolution networks (CNNs) has achieved state-of-the-art results, the class and hard-voxel imbalances in the 3D images have not been well addressed. Voxel independent losses are dependent on the setting of class weights for the class imbalance issue, and are hard to assign each class equally. Region-related losses cannot correctly focus on hard voxels dynamically and not be robust to misclassification of small structures. Meanwhile, repeatedly training on the additional hard samples augmented by existing methods would bring more class imbalance, overfitting and incorrect knowledge learning to the model. A novel region-related loss with balanced dynamic weighting while alleviating the sensitivity to small structures is necessary. In addition, we need to increase the diversity of hard samples in the training to improve the performance of model. The proposed Region-related Focal Loss (RFL) reshapes standard Dice Loss (DL) by up-weighting the loss assigned to hard-classified voxels. Compared to DL, RFL adaptively modulate its gradient with an invariant focalized point that voxels with lower-confidence than it would achieve a larger gradient, and higher-confidence voxels would get a smaller gradient. Meanwhile, RFL can adjust the parameters to set where and how much the network is focused. In addition, an Intra-classly Transformed Augmentation network (ITA-NET) is proposed to increase the diversity of hard samples, in which the 3D registration network and intra-class transfer layer are used to transform the shape and intensity respectively. A selective hard sample mining(SHSM) strategy is used to train the ITA-NET for avoiding excessive class imbalance. Source code (in Tensorflow) is available at httpsgithub.comlb-whuRFLITA. The experiments are carried out on public data set Brain Tumor Segmentation Challenge 2020 (BratS2020). Experiments with BraTS2020 online validation set show that proposed methods achieve an average Dice scores of 0.905, 0.821, and 0.806 for whole tumor (WT), tumor core (TC) and enhancing tumor (ET), respectively. Compared with DL (baseline), the proposed RFL significantly improves the Dice scores by an average of 1%, and for the small region ET it can even increase by 3%. And the proposed method combined with ITA-NET improves the Dice scores of ET and TC by 5% and 3% respectively. The proposed RFL can converge with a invariant focalized point in the training of segmentation network, thus effectively alleviating the hard-voxel imbalance in brain tumor MRI segmentation. The negative region term of RFL can effectively reduce the sensitivity of the segmentation model to the misclassification of small structures. The proposed ITA-NET can increase the diversity of hard samples by transforming their shape and transfer their intra-class intensity, thereby effectively improving the robustness of the segmentation network to hard samples.

Type-2 Diabetes, Pancreatic Amylin, and Neuronal Metabolic Remodeling in Alzheimers Disease.

Type-2 diabetes raises the risk for Alzheimers disease (AD)-type dementia and the conversion from mild cognitive impairment to dementia, yet mechanisms connecting type-2 diabetes to AD remain largely unknown. Amylin, a pancreatic β-cell hormone co-secreted with insulin, participates in the central regulation of satiation, but also forms pancreatic amyloid in persons with type-2 diabetes and synergistically interacts with brain amyloid β (Aβ) pathology, in both sporadic and familial Alzheimers disease (AD). Growing evidence from studies of tumor growth, together with early observations in skeletal muscle, indicates amylin as a potential trigger of cellular metabolic reprogramming. Because the blood, cerebrospinal fluid, and brain parenchyma in humans with AD have increased concentrations of amylin, amylin-mediated pathological processes in the brain may involve neuronal metabolic remodeling. This review summarizes recent progress in understanding the link between prediabetic hypersecretion of amylin and risk of neuronal metabolic remodeling and AD and suggests nutritional and medical effects of food constituents that might prevent andor ameliorate amylin-mediated neuronal metabolic remodeling.

Analysis of clinical prognosis of endoscopic salvage surgery in patients with rT2 recurrent nasopharyngeal carcinoma.

Efficacy and influencing factors of surgery combined with neoadjuvant chemoradiotherapy in the treatment of children with non-orbital head and neck rhabdomyosarcoma.

Exaggerated levels of some specific TLRs, cytokines and chemokines in Japanese encephalitis infected BV2 and neuro 2A cell lines associated with worst outcome.

Japanese encephalitis (JE) disease, a viral brain fever is caused by Japanese encephalitis virus (JEV). Despite the availability of effective vaccines against this deadly infection, JE is the leading cause of epidemic viral encephalitis in children in South-east Asia. There is no treatment available for the JE disease which might be due to incomplete understanding of the pathogenesis of JE virus. The JEV infections lead to permanent neurological deficits even in those who survive from the infection. Activated microglia may play a potentially detrimental role by eliciting the expression of pro-inflammatory cytokines such as interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α) influencing the surrounding brain tissue. Microglial activation, proinflammatory cytokine release and leukocytes trafficking are associated following JEV infection in central nervous system (CNS). How the pattern recognition receptors sense the viral nucleic acid and how the microglial and neuronal cells behaves following JEV infection is still unelucidated. There is scarcity of data on the expression levels of toll like receptors (TLRs), cytokines and chemokines in JEV infection in invitro model. To explore the molecular mechanisms of JEV infection of microglial cells and neuronal cells, we studied the expression profile of TLRs, cytokines and chemokines in JEV infected microglial cell line BV2 and Neuronal cell line Neuro 2A. For the present study, we developed the mouse model of encephalitis by intracerebral (IC) injection of JE virus for virus propagation, disease progression and damage study. Our results demonstrate the exaggerated release of some specific TLRs, cytokines and chemokines in invitro cell culture of microglial and Neuro 2A cell line, which are associated with bad outcome in invivo study.

Customizing delivery nano-vehicles for precise brain tumor therapy.

Although some tumor has become a curable disease for many patients, involvement of the central nervous system (CNS) is still a major concern. The blood-brain barrier (BBB), a special structure in the CNS, protects the brain from bloodborne pathogens via its excellent barrier properties and hinders new drug development for brain tumor. Recent breakthroughs in nanotechnology have resulted in various nanovehicless (NPs) as drug carriers to cross the BBB by different strategys. Here, the complex compositions and special characteristics of causes of brain tumor formation and BBB are elucidated exhaustively. Additionally, versatile drug nanovehicles with their recent applications and their pathways on different drug delivery strategies to overcome the BBB obstacle for anti-brain tumor are briefly discussed. Customizing nanoparticles for brain tumor treatments is proposed to improve the efficacy of brain tumor treatments via drug delivery from the gut to the brain. This review provides a broad perspective on customizing delivery nano-vehicles characteristics facilitate drug distribution across the brain and pave the way for the creation of innovative nanotechnology-based nanomaterials for brain tumor treatments.

Cellular senescence in malignant cells promotes tumor progression in mouse and patient Glioblastoma.

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults, yet it remains refractory to systemic therapy. Elimination of senescent cells has emerged as a promising new treatment approach against cancer. Here, we investigated the contribution of senescent cells to GBM progression. Senescent cells are identified in patient and mouse GBMs. Partial removal of p16

A diffusion tensor imaging-based prognostic classification for surgery of intrinsic lesions involving the motor pathways.

Different adjuncts critical role in improving the neurological outcome in intrinsic brain lesions affecting eloquent areas is demonstrated by their more diffuse utilization. Neurosurgeons often rely on pre- and intraoperative Diffusion Tensor Imaging (DTI) tractography to improve the operative strategy and prognosis. We aimed at identifying and validating a diffusion tensor imaging (DTI)- based classification considering the relationship between the brain lesion and corticospinal tract (CST) to predict a reduction of MEPs > 50% during surgical excision of lesions involving the motor pathways. We included patients consecutively enrolled at our Institution between April 2020 and September 2022 and identified three patterns of increasing complexity according to the relationship between the lesion and the CST as identified on preoperative DTI. The outcome measures were the intraoperative occurrence of >50% MEP reduction and the neurological outcome defined as unchanged, improved, or worsened. Eighty-three patients were included. A statistically significant linear trend between higher rates of MEPs reduction and higher classification grades was observed (p0.001), with 0.60 sensitivity, specificity0.88, accuracy0.83, and AUC0.75. Higher grades were associated with worse neurological outcomes (p0.02). The classification proved reliable in anticipating an intraoperative MEPs reduction and in predicting the neurological outcome. Applying this knowledge to patients undergoing surgery for lesions involving the motor pathways could help counsel the patient, plan the surgical strategy, enhance the operative teamwork and improve the patients prognosis.

Insult to Short-range White Matter Connectivity in Childhood Brain Tumor Survivors.

Children treated for brain tumors are at an increased risk for cognitive impairments due to the impact of radiation therapy on developing white matter (WM). Although damage to long-range WM is well-documented in pediatric brain tumor survivors, the impact of radiation therapy on short-range WM remains unelucidated. We sought to clarify whether radiation treatment impacts short-range WM by completing a virtual dissection of these connections and comparing their microstructural properties between brain tumor survivors and typically developing children. T1-weighted and diffusion-weighted magnetic resonance images were acquired for twenty-six brain tumor survivors and twenty-six typically developing children. Short-range white matter was delineated using a novel, whole-brain approach. A random forest classifier was used to identify short-range connections with the largest differences in microstructure between patients and typically developing children. The random forest classifier identified differences in short-range WM microstructure across the brain with an accuracy of 87.5%. Nine connections showed the largest differences in short-range WM between patients and typically developing children. For these connections, fractional anisotropy (FA) and axial diffusivity (AD) were significantly lower in patients. Short-range connections in the posterior fossa were disproportionately affected, suggesting that greater radiation exposure to the posterior fossa was more injurious to short-range WM. Lower cranio-spinal radiation dose did not predict reduced toxicity to short-range WM. Our findings indicate that treatment for medulloblastoma resulted in changes in short-range WM in patients. Lower FA and AD may reflect altered microstructural organization and coherence of these connections, especially in the posterior fossa. Short-range WM may be especially sensitive to the effect of cranio-spinal radiation therapy resulting in compromise to these connections regardless of dose.

Serum claudin-5 levels among patients with unipolar and bipolar depression in relation to the pro-inflammatory cytokine tumor necrosis factor-alpha levels.

Accumulating evidence indicates that inflammation and neurovascular unit (NVU) dysfunction contribute to depression via disrupted blood-brain barrier (BBB) integrity. Claudin-5, an endothelial tight-junction protein expressed in the NVU and contributing to BBB integrity, has been implicated in psychiatric disorders, including major depressive disorder (MDD) and schizophrenia. In an animal model of depressive-like behavior, the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-α) was found to affect BBB permeability and claudin-5 expression of NVU endothelial cells. To the best of the authors knowledge, this study is the first to assess the relationship between serum claudin-5 and TNF-α levels, during major depressive episodes (MDEs). Serum levels of claudin-5 and TNF-α of 40 patients diagnosed with current MDE 19 with MDD and 21 with bipolar disorder (BD) and 28 matched healthy controls (HCs) were analyzed. Claudin-5 and TNF-α serum levels in the MDE group were significantly higher than in the HC one. Discrete analysis according to MDE type indicated significantly increased claudin-5 serum levels in BD but not in MDD patients, compared to HCs, even after controlling for confounders. In the MDE group, a significant positive correlation was found between claudin-5 and TNF-α serum levels. In complementary analysis, serum levels of the pro-inflammatory cytokine interleukin-6 were significantly higher among MDE patients compared to HCs, however, no significant correlation was found with claudin-5 levels. In conclusion, as indicated by preclinical studies, our clinical study suggests a possible specific interaction between the NVUBBB marker claudin-5 and the inflammatory marker TNF-α in the pathogenesis of depression.

Clinical Effects and Adverse Events Associated With Desflurane Use in Adult Patients Undergoing Supratentorial Craniotomy A Systematic Review.

Desflurane is an inhalational anesthetic agent with an appealing recovery profile. The present systematic review investigates the clinical effects and adverse events associated with desflurane use during supratentorial craniotomy for brain tumor resection in adults in comparison with other inhalational and intravenous anesthetic agents. A literature search was conducted across the MEDLINE, Library of Congress and LISTA (EBSCO) databases from January 2001 to January 2021. Twelve studies published between 2003 and 2020 were included in this systematic review. Desflurane was compared with either isoflurane, sevoflurane, or propofol for anesthesia maintenance. Brain relaxation scores showed no statistically significant difference between desflurane and the other anesthetic agents. Recovery timepoints, such as time to recovery, time to eye opening, time to extubation, time to follow commands, and time to reach a modified Aldrete score ≥9 were significantly shorter with desflurane in the majority of studies. Systemic hemodynamic variables (mean arterial pressure and heart rate) and cerebral hemodynamics (intracranial pressure and cerebrospinal fluid pressure) were comparable between desflurane and other anesthetic agents in each study. The results of this systematic review demonstrate that desflurane is associated with few adverse events when used for anesthesia maintenance in adult patients undergoing supratentorial brain tumor surgery. Large, prospective, comprehensive studies, utilizing standardized parameter evaluation could provide higher levels of evidence to support these findings.

Strategies for the Treatment of Infantile Soft Tissue Sarcomas With BCOR Alterations.

BCOR alterations are described in ultra-rare infantile soft tissue sarcomas including primitive myxoid mesenchymal tumor of infancy and undifferentiated round cell sarcoma (URCS). Previous reports often describe dismal outcomes. Thus, we undertook a retrospective, multi-institutional study of infants with BCOR-rearranged soft tissue sarcomas. Nine patients aged 6 weeks to 15 months were identified. One tumor carried a BCORCCNB3 fusion, whereas 7 tumors harbored internal tandem duplication of BCOR, including 4 cases classified as primitive myxoid mesenchymal tumor of infancy, 1 case as URCS, and 2 cases characterized by a hybrid morphology in our evaluation. Four patients underwent upfront surgery with residual disease that progressed locally after a median of 2.5 months. Locoregional recurrences were observed in hybrid patients, and the URCS case recurred with brain metastases. Complete radiographic responses after chemotherapy were achieved in patients treated with vincristinedoxorubicincyclophosphamide alternating with ifosfamideetoposide, vincristinedoxorubicincyclophosphamide alternating with cyclophosphamideetoposide (regimen I), and ifosfamidecarboplatinetoposide. Seven patients received radiotherapy. With a median of 23.5 months off therapy, 8 patients are with no evidence of disease. In our study, observation was inadequate for the management of untreated postsurgical residual disease. Tumors demonstrated chemosensitivity with anthracycline-based regimens and ifosfamidecarboplatinetoposide. Radiotherapy was required to achieve durable response in most patients.

Methylphenidate Reversal of Executive Dysfunction in a Patient with Bi-Frontal Lobe Glioblastoma.

An elderly man with advanced glioblastoma developed neuro-cognitive deficits that were reversed by methylphenidate. After tumor resection from the right frontal lobe, he received cranial irradiation, temozolomide and Tumor Treating Fields (TTFields). MRI afterwards showed enhancements near the resection cavity and the contralateral frontal lobe. The patient experienced mild executive dysfunction that was not limiting his activities. Adjuvant temozolomide was started along with TTFields. After 2 cycles, his brain MRI showed stable disease, but he exhibited significant executive dysfunction. Methylphenidate improved his neuro-cognitive slowing in cycles 3 and 4. His disease eventually progressed during the 5th cycle, and he experienced a marked decline in activities. Repeat head MRI revealed tumor progression and cerebral edema. Treatments were discontinued while dexamethasone improved his neurological functions and bevacizumab biosimilar was later added. This case demonstrates the activity of methylphenidate for managing executive dysfunction in patients with glioblastoma while minimizing the use of dexamethasone.

Correlation between metastatic patterns and age in patients with metastatic primary liver cancer A population-based study.

Primary liver cancer is usually diagnosed at advanced stages with distant metastasis, underlying the high metastatic rate and mortality in patients. This study aimed to analyse the metastatic patterns and prognosis of primary liver cancer, and its relationship with age and several other factors, such as histological variants, TNM stage, and grade. We included data from 5274 patients from the Surveillance, Epidemiology, and End Results (SEER) database of the American National Cancer Institute diagnosed with primary liver cancer with metastatic disease between 2010 and 2015. The correlation between the metastatic patterns of primary liver cancer and age was evaluated. The hazard ratio (HR) and 95% confidence intervals (CI) for overall survival were calculated by applying univariate Cox analysis, while the correlation between the metastatic patterns and age was analysed by applying multivariate Cox analysis. We also plotted Kaplan-Meier curves to illustrate the correlation between overall survival (OS) and various factors. Several factors were associated with poorer prognosis, including age>60 years, histologic type of spindle cell variant, higher grade, no surgery, tumour size ≥ 1 cm, and lung metastasis. The rate of metastasis increased with age. Older patients (> 50 years) were prone to bone metastasis, while less likely to have lung metastasis compared with younger patients (< 50 years). Patients with lung metastasis had a higher risk of being diagnosed with metastasis in other locations. Furthermore, surgery significantly reduced mortality and primary site surgery in particular, mitigated the risk of bone and lung metastases. Our study shows the correlation of prognosis and metastatic patterns with age and several other factors. The findings can hopefully provide knowledge that will allow a better diagnosis and management of elderly patients with primary liver cancer.

Adjuvant Temozolomide Chemotherapy With or Without Interferon Alfa Among Patients With Newly Diagnosed High-grade Gliomas A Randomized Clinical Trial.

High-grade gliomas (HGGs) constitute the most common and aggressive primary brain tumor, with 5-year survival rates of 30.9% for grade 3 gliomas and 6.6% for grade 4 gliomas. The add-on efficacy of interferon alfa is unclear for the treatment of HGG. To compare the therapeutic efficacy and toxic effects of the combination of temozolomide and interferon alfa and temozolomide alone in patients with newly diagnosed HGG. This multicenter, randomized, phase 3 clinical trial enrolled 199 patients with newly diagnosed HGG from May 1, 2012, to March 30, 2016, at 15 Chinese medical centers. Follow-up was completed July 31, 2021, and data were analyzed from September 13 to November 24, 2021. Eligible patients were aged 18 to 75 years with newly diagnosed and histologically confirmed HGG and had received no prior chemotherapy, radiotherapy, or immunotherapy for their HGG. All patients received standard radiotherapy concurrent with temozolomide. After a 4-week break, patients in the temozolomide with interferon alfa group received standard temozolomide combined with interferon alfa every 28 days. Patients in the temozolomide group received standard temozolomide. The primary end point was 2-year overall survival (OS). Secondary end points were 2-year progression-free survival (PFS) and treatment tolerability. A total of 199 patients with HGG were enrolled, with a median follow-up time of 66.0 (95% CI, 59.1-72.9) months. Seventy-nine patients (39.7%) were women and 120 (60.3%) were men, with ages ranging from 18 to 75 years and a median age of 46.9 (95% CI, 45.3-48.7) years. The median OS of patients in the temozolomide plus interferon alfa group (26.7 95% CI, 21.6-31.7 months) was significantly longer than that in the standard group (18.8 95% CI, 16.9-20.7 months hazard ratio HR, 0.64 95% CI, 0.47-0.88 P .005). Temozolomide plus interferon alfa also significantly improved median OS in patients with O6-methylguanine-DNA methyltransferase (MGMT) unmethylation (24.7 95% CI, 20.5-28.8 months) compared with temozolomide (17.4 95% CI, 14.1-20.7 months HR, 0.57 95% CI, 0.37-0.87 P .008). Seizure and influenzalike symptoms were more common in the temozolomide plus interferon alfa group, with 2 of 100 (2.0%) and 5 of 100 (5.0%) patients with grades 1 and 2 toxic effects, respectively (P .02). Finally, results suggested that methylation level at the IFNAR12 promoter was a marker of sensitivity to temozolomide plus interferon alfa. Compared with the standard regimen, temozolomide plus interferon alfa treatment could prolong the survival time of patients with HGG, especially the MGMT promoter unmethylation variant, and the toxic effects remained tolerable. ClinicalTrials.gov Identifier NCT01765088.

Phase I Study and Cell-Free DNA Analysis of T-DM1 and Metronomic Temozolomide for Secondary Prevention of HER2-Positive Breast Cancer Brain Metastases.

Preclinical data showed that prophylactic temozolomide (TMZ) significantly prevented breast cancer brain metastasis. We present results of a phase I trial combining T-DM1 with TMZ for the prevention of additional brain metastases after previous occurrence and local treatment in HER2 breast cancer patients. Eligible patients had HER2 breast cancer with brain metastases and were within 12 weeks of WBRT, SRS andor surgery. Standard doses of T-DM1 were administered IV every 21 d (3.6 mgkg) and TMZ was given PO daily in a 33 phase I dose escalation design at 30, 40 or 50 mgm2, continuously. DLT period was one 21d cycle. Primary endpoint was safety and recommended phase 2 dose. Symptom questionnaires, brain MRI and systemic CT scans were performed every 6 weeks. Cell-free DNA sequencing (cfDNAseq) was performed on patients plasma and CSF. Twelve women enrolled, nine (75%) with prior SRS therapy and 3 (25%) with prior WBRT. Grade 3 or 4 AEs included thrombocytopenia (112), neutropenia (112), lymphopenia (612) and decreased CD4 (612), requiring pentamidine for PJP prophylaxis. No DLT was observed. Four patients on the highest TMZ dose underwent dose reductions. At trial entry, 612 patients had tumor mutations in CSF, indicating ongoing metastatic colonization despite a clear MRI. Median follow-up on study was 9.6m (2.8-33.9) only two patients developed new parenchymal brain metastases. Tumor mutations varied with patient outcome. Metronomic TMZ in combination with standard dose T-DM1 shows low-grade toxicity and potential activity in secondary prevention of HER2 brain metastases.

Novel Murine Glioblastoma Models That Reflect the Immunotherapy Resistance Profile of Human Disease.

The lack of murine glioblastoma models that mimic the immunobiology of human disease has impeded basic and translational immunology research. We therefore developed murine glioblastoma stem cell lines derived from Nestin-CreERT2QkLL Trp53LL PtenLL (QPP) mice driven by clinically relevant genetic mutations common in human glioblastoma. This study aims to determine the immune sensitivities of these QPP lines in immunocompetent hosts and underlying mechanisms. The differential responsiveness of QPP lines was assessed in the brain and flank in untreated, anti-PD-1, or anti-CTLA-4 treated mice. The impact of genomic landscape on responsiveness of each tumor was measured through whole exome sequencing. The immune microenvironments of sensitive (QPP7) versus resistant (QPP8) lines were compared in the brain using flow cytometry. Drivers of flank sensitivity versus brain resistance were also measured for QPP8. QPP lines are syngeneic to C57BL6J mice and demonstrate varied sensitivities to T cell immune checkpoint blockade ranging from curative responses to complete resistance. Infiltrating tumor immune analysis of QPP8 reveals improved T cell fitness and augmented effector to suppressor ratios when implanted subcutaneously (sensitive), which are absent upon implantation in the brain (resistant). Upregulation of PD-L1 across the myeloid stroma acts to establish this state of immune privilege in the brain. In contrast, QPP7 responds to checkpoint immunotherapy even in the brain likely resulting from its elevated neoantigen burden. These syngeneic QPP models of glioblastoma demonstrate clinically-relevant profiles of immunotherapeutic sensitivity and potential utility for both mechanistic discovery and evaluation of immune therapies.

Mitochondria metabolism sets the species-specific tempo of neuronal development.

Neuronal development in the human cerebral cortex is considerably prolonged compared with that of other mammals. We explored whether mitochondria influence the species-specific timing of cortical neuron maturation. By comparing human and mouse cortical neuronal maturation at high temporal and cell resolution, we found a slower mitochondria development in human cortical neurons compared with that in the mouse, together with lower mitochondria metabolic activity, particularly that of oxidative phosphorylation. Stimulation of mitochondria metabolism in human neurons resulted in accelerated development in vitro and in vivo, leading to maturation of cells weeks ahead of time, whereas its inhibition in mouse neurons led to decreased rates of maturation. Mitochondria are thus important regulators of the pace of neuronal development underlying human-specific brain neoteny.

Choriocarcinoma masquerading as lumbar spinal tumor Case report and literature review.

Choriocarcinoma is a highly invasive gestational trophoblastic neoplasm, usually metastasis to lung and brain, but occurrence of choriocarcinoma following spontaneous abortion presenting as a vertebral tumor is extremely rare, to the best of our knowledge. Because of the poor diagnosis and high malignancy, the low progression-free survival follows up. We here are reporting a case of choriocarcinoma that presented with vertebral tumor induced paralysis of limbs and incontinence of urine. Combined with the childbearing history, high β-human chorionic gonadotrophinin levels, and imaging examination, a clinical diagnosis was made exactly. Till the pathological results after the operation of lumbar spinal canal tumorectomy, the diagnosis was exactly clear. After performing the laminectomy, the fierce bleeding follows up, just did the temporary limited decompression. Because of the vertebral artery embolization, lumbar spinal canal tumorectomy, spinal canal and root canal decompression, subdural decompression and hematoma removal were performed. After performing the operation and chemotherapy timely and positively, the patient lost consciousness and died due to the pulmonary embolism at last. This is the first case report describing choriocarcinoma with metastases to the spine amongst Chinese population as well. Early metastasis is one of the marked tendencies of choriocarcinoma, but spine metastasis and the related spinal oppressional symptoms were found instead of vaginal bleeding in this case, which is indeed rare.

Intracerebral and pituitary metastatic eccrine carcinoma prolonged survival using stereotactic radiosurgery.

Eccrine gland carcinoma (EC) is a rare skin neoplasm that uncommonly spreads to the brain or pituitary gland. We describe the role of multiple stereotactic radiosurgery (SRS) procedures to manage recurrent brain metastases of this rare disease. Retrospective chart review was completed to obtain details for this report. The study was performed under IRB study on medical record only and was exempt from patients consent. A 59-year-old female underwent surgical excision of a right parietal scalp EC. Over the next 13 years, the patient underwent initial fractionated whole brain radiation therapy after she developed multiple brain metastases followed by systemic chemotherapy for extracranial disease. Because of repeated development of new brain disease, three SRS procedures were performed to treat a total of 50 brain metastases and a pituitary metastasis (PM). The patient expired from progressive systemic cancer spread 13 years after her initial surgical excision. Due to the rarity of metastatic EC to the brain, no standard treatment paradigm has emerged. Using multimodality options that included local excision of the original skin tumor, followed by radiation, systemic chemotherapy, and three SRS procedures, long-term survival was possible in this unusual case.

The effect of musicality on language recovery after awake glioma surgery.

Awake craniotomy is increasingly used to resect intrinsic brain tumors while preserving language. The level of musical training might affect the speed and extend of postoperative language recovery, as increased white matter connectivity in the corpus callosum is described in musicians compared to non-musicians. In this cohort study, we included adult patients undergoing treatment for glioma with an awake resection procedure at two neurosurgical centers and assessed language preoperatively (T1) and postoperatively at three months (T2) and one year (T3) with the Diagnostic Instrument for Mild Aphasia (DIMA), transferred to We enrolled forty-six patients, between June 2015 and September 2021, and divided in group A (non-musicians, With first study on this topic, we support that musicality contributes to language recovery after awake glioma surgery, possibly attributed to a higher white matter connectivity at the anterior part of the corpus callosum. Our conclusion should be handled with caution and interpreted as hypothesis generating only, as most of our results were not significant. Future studies with larger sample sizes are needed to confirm our hypothesis.

The interplay between prolactin and cardiovascular disease.

Hyperprolactinemia can be caused by several conditions and its effects on the hypothalamic-pituitary-gonadal axis are understood in more detail. Nevertheless, in recent decades, other metabolic effects have been studied and data pointed to a potential increased cardiovascular disease (CVD) risk. A recent study showed a decrease in total and LDL- cholesterol only in men with prolactinoma treated with dopamine agonists (DA) supporting the previous results of a population study with increased CVD risk in men harboring prolactinoma. However, other population studies did not find a correlation between prolactin (PRL) levels and CVD risk or mortality. There is also data pointing to an increase in high-density lipoprotein levels, and decreases in triglycerides, carotid-intima-media thickness, C-reactive protein, and homocysteine levels in patients with prolactinoma on DA treatment. PRL was also implicated in endothelial dysfunction in pre and postmenopausal women. Withdrawal of DA resulted in negative changes in vascular parameters and an increase in plasma fibrinogen. It has been shown that PRL levels were positively correlated with blood pressure and inversely correlated with dilatation of the brachial artery and insulin sensitivity, increased homocysteine levels, and elevated D-dimer levels. Regarding possible mechanisms for the association between hyperprolactinemia and CVD risk, they include a possible direct effect of PRL, hypogonadism, and even effects of DA treatment, independently of changes in PRL levels. In conclusion, hyperprolactinemia seems to be associated with impaired endothelial function and DA treatment could improve CVD risk. More studies evaluating CVD risk in hyperprolactinemic patients are important to define a potential indication of treatment beyond hypogonadism.

Natural killer cell therapy potentially enhances the antitumor effects of bevacizumab plus irinotecan in a glioblastoma mouse model.

Various combination treatments have been considered to attain the effective therapy threshold by combining independent antitumor mechanisms against the heterogeneous characteristics of tumor cells in malignant brain tumors. In this study, the natural killer (NK) cells associated with bevacizumab (Bev) plus irinotecan (Iri) against glioblastoma multiforme (GBM) were investigated. For the experimental design, NK cells were expanded and activated by K562 cells expressing the OX40 ligand and membrane-bound IL-18 and IL-21. The effects of Bev and Iri on the proliferation and NK ligand expression of GBM cells were evaluated through MTT assay and flow cytometry. The cytotoxic effects of NK cells against Bev plus Iri-treated GBM cells were also predicted

Perioperative corticosteroid treatment impairs tumor-infiltrating dendritic cells in patients with newly diagnosed adult-type diffuse gliomas.

Adult-type diffuse gliomas are malignant primary brain tumors characterized by very poor prognosis. Dendritic cells (DCs) are key in priming antitumor effector functions in cancer, but their role in gliomas remains poorly understood. In this study, we characterized tumor-infiltrating DCs (TIDCs) in adult patients with newly diagnosed diffuse gliomas by using multi-parametric flow cytometry and single-cell RNA sequencing. We demonstrated that different subsets of DCs are present in the glioma microenvironment, whereas they are absent in cancer-free brain parenchyma. The largest cluster of TIDCs was characterized by a transcriptomic profile suggestive of severe functional impairment. Patients undergoing perioperative corticosteroid treatment showed a significant reduction of conventional DC1s, the DC subset with key functions in antitumor immunity. They also showed phenotypic and transcriptional evidence of a more severe functional impairment of TIDCs. Overall, the results of this study indicate that functionally impaired DCs are recruited in the glioma microenvironment. They are severely affected by dexamethasone administration, suggesting that the detrimental effects of corticosteroids on DCs may represent one of the mechanisms contributing to the already reported negative prognostic impact of steroids on glioma patient survival.

Expert guidance on prophylaxis and treatment of dermatologic adverse events with Tumor Treating Fields (TTFields) therapy in the thoracic region.

Tumor Treating Fields (TTFields) are electric fields, delivered via wearable arrays placed on or near the tumor site, that exert physical forces to disrupt cellular processes critical for cancer cell viability and tumor progression. As a first-in-class treatment, TTFields therapy is approved for use in newly diagnosed glioblastoma, recurrent glioblastoma, and pleural mesothelioma. Additionally, TTFields therapy is being investigated in non-small cell lung cancer (NSCLC), brain metastases from NSCLC, pancreatic cancer, ovarian cancer, hepatocellular carcinoma, and gastric adenocarcinoma. Because TTFields therapy is well tolerated and delivery is locoregional, there is low risk of additive systemic adverse events (AEs) when used with other cancer treatment modalities. The most common AE associated with TTFields therapy is mild-to-moderate skin events, which can be treated with topical agents and may be managed without significant treatment interruptions. Currently, there are no guidelines for oncologists regarding the management of TTFields therapy-related skin AEs in the thoracic region, applicable for patients with pleural mesothelioma or NSCLC. This publication aims to provide guidance on preventing, minimizing, and managing dermatologic AEs in the thoracic region to help improve patient quality of life and reduce treatment interruptions that may impact outcomes with TTFields therapy.

The Recurrent-Specific Regulation Network of Prognostic Stemness-Related Signatures in Low-Grade Glioma.

Gliomas including astrocytomas, oligodendrogliomas, mixed oligoastrocytic, and mixed glioneuronal tumors are an important group of brain tumors. Based on the 2016 WHO classification for tumors in the central nervous system, gliomas were classified into four grades, from I to IV, and brain lower grade glioma (LGG) consists of grade II and grade III. Patients with LGG may undergo recurrence, which makes clinical treatment tough. Stem cell-like features of cancer cells play a key role in tumors biological behaviors, including tumorigenesis, development, and clinical prognosis. In this article, we quantified the stemness feature of cancer cells using the mRNA stemness index (mRNAsi) and identified stemness-related key genes based on correlation with mRNAsi. Besides, hallmark gene sets and translate factors (TFs) which were highly related to stemness-related key genes were identified. Therefore, a recurrency-specific network was constructed and a potential regulation pathway was identified. Several online databases, assay for transposase-accessible chromatin using sequencing (ATAC-seq), single-cell sequencing analysis, and immunohistochemistry were utilized to validate the scientific hypothesis. Finally, we proposed that aurora kinase A (AURKA), positively regulated by Non-SMC Condensin I Complex Subunit G (NCAPG), promoted E2F target pathway in LGG, which played an important role in LGG recurrence.

Exploring the relationships between hormone receptor, HER2 status, and bone involvement in the first distant metastases of in Chinese breast cancer patients who lacked HER2 targeted therapy.

This retrospective study explored the relationship between hormone receptor (HR), human epidermal growth factor receptor 2 (HER2) status, and bone involvement in the first distant metastases (DM) of Chinese breast cancer (BC) patients who lacked the HER2 targeted therapy. Such therapy was rarely received due to its lag approval or high cost in China compared with the developed countries. All eligible women with primary unilateral stage I - III BC and first DM diagnosed in 2008-2018 at one cancer center were identified for enrollment. Based on chart records, a full or nopartial compliance status of endocrine therapy (ET) was assigned for HR-positive patients. Multivariate logistic regression was used to estimate the adjusted odd ratio (aOR), its 95%CI and p value. Four hundred eighteen patients had an average age of 50.7 years and median disease-free survival of 27.1 months at DM. Bone, lung, liver and brain metastasis rates in patients were 55.7%, 34.7%, 33.0% and 8.1%, respectively. Compared to HR-negative patients, HR-positive patients with the full and nonpartial compliance of ET were significantly associated with higher risk of bone involvement with an aOR of 2.329 (1.316 - 1.741, p 0.004) and 2.317 (1.330 - 4.036, p 0.003), respectively. No difference of such risk was found between the two groups of ET compliance (p 0.984) nor between HER2-negative and HER2-positive patients (aOR 0.827, p 0.431). Stratified analyses further indicated that HR-positive was associated with bone involvement only in HER2-negative BC patients (p 0.006-0.015). HR-positive tumors are significantly associated with bone involvement in HER2-negative metastatic BC patients. ET does not appear to impact this association. HER2 status per se is not associated with such risk.

Up-front single-session radiosurgery for large brain metastases-volumetric responses and outcomes.

Patients presenting with large brain metastases (LBM) pose a management challenge to the multidisciplinary neuro-oncologic team. Treatment options include surgery, whole-brain or large-field radiation therapy (WBRT), stereotactic radiosurgery (SRS), or a combination of these. To determine if corticosteroid therapy followed by SRS allows for efficient minimally invasive care in patients with LBMs not compromised by mass effect. We analyzed the change in tumor volume to determine the efficacy of single-session SRS in the treatment of LBM in comparison to other treatment modalities. Twenty-nine patients with systemic cancer and brain metastasis (≥ 2.7 cm in greatest diameter) who underwent single-session SRS were included. Among 29 patients, 69% of patients had either lung, melanoma, or breast cancer. The median initial tumor size (maximal diameter) was 32 mm (range 28-43), and the median initial tumor volume was 9.56 cm Initial high-dose corticosteroid therapy followed by prompt single-stage SRS is a safe and efficacious method to manage patients with LBMs (defined as ≥ 2.7 cm).

Reprogramming systemic and local immune function to empower immunotherapy against glioblastoma.

The limited benefits of immunotherapy against glioblastoma (GBM) is closely related to the paucity of T cells in brain tumor bed. Both systemic and local immunosuppression contribute to the deficiency of tumor-infiltrating T cells. However, the current studies focus heavily on the local immunosuppressive tumor microenvironment but not on the co-existence of systemic immunosuppression. Here, we develop a nanostructure named Nano-reshaper to co-encapsulate lymphopenia alleviating agent cannabidiol and lymphocyte recruiting cytokine LIGHT. The results show that Nano-reshaper increases the number of systemic T cells and improves local T-cell recruitment condition, thus greatly increasing T-cell infiltration. When combined with immune checkpoint inhibitor, this therapeutic modality achieves 83.3% long-term survivors without recurrence in GBM models in male mice. Collectively, this work unveils that simultaneous reprogramming of systemic and local immune function is critical for T-cell based immunotherapy and provides a clinically translatable option for combating brain tumors.

Diagnostic Accuracy of Arterial Spin-Labeling, Dynamic Contrast-Enhanced, and DSC Perfusion Imaging in the Diagnosis of Recurrent High-Grade Gliomas A Prospective Study.

For patients with high-grade gliomas, the appearance of a new, enhancing lesion after surgery and chemoradiation represents a diagnostic dilemma. We hypothesized that MR perfusion without and with contrast can differentiate tumor recurrence from radiation necrosis. In this prospective study, we performed 3 MR perfusion methods arterial spin-labeling, DSC, and dynamic contrast enhancement. For each lesion, we measured CBF from arterial spin-labeling, uncorrected relative CBV, and leakage-corrected relative CBV from DSC imaging. The volume transfer constant and plasma volume were obtained from dynamic contrast-enhanced imaging without and with T1 mapping using modified Look-Locker inversion recovery (MOLLI). The diagnosis of tumor recurrence or radiation necrosis was determined by either histopathology for patients who underwent re-resection or radiologic follow-up for patients who did not have re-resection. There were 26 patients with 32 lesions, 19 lesions with tumor recurrence and 13 lesions with radiation necrosis. Compared with radiation necrosis, lesions with tumor recurrence had higher CBF ( In the differentiation of tumor recurrence from radiation necrosis in a newly enhancing lesion, the diagnostic value of arterial spin-labeling-derived CBF is similar to that of DSC and dynamic contrast-enhancement-derived blood volume.

TFR2 regulates ferroptosis and enhances temozolomide chemo-sensitization in gliomas.

Glioma is a common type of brain tumor with high incidence and mortality rates. Iron plays an important role in various physiological and pathological processes. Iron entry into the cell is promoted by binding the transferrin receptor 2 (TFR2) to the iron-transferrin complex. This study was designed to assess the association between TFR2 and ferroptosis in glioma. Lipid peroxidation levels in glioma cells were assessed by determination of lipid reactive oxygen species (ROS), glutathione content, and mitochondrial membrane potential. The effect of TFR2 on TMZ sensitivity was examined by cell viability assays, flow cytometry, and colony formation assays. We found that Low TFR2 expression predicted a better prognosis for glioma patients. And overexpression of TFR2 promoted the production of reactive oxygen species and lipid peroxidation in glioma cells, thereby further promoting ferroptosis. This could be reversed by the ferroptosis inhibitors Fer-1 and DFO (both inhibitors of ferroptosis). Moreover, TFR2 potentiated the cytotoxic effect of TMZ (temozolomide) via activating ferroptosis. In conclusion, we found that TFR2 induced ferroptosis and enhanced TMZ sensitivity in gliomas. Our findings might provide a new treatment strategy for glioma patients and improve their prognosis.

First ground-based, high-field, cryogen-free, mobile intraoperative magnetic resonance imaging system.

Accurately targeting specific regions of interest in the brain is pivotal for the success of neurosurgical procedures. For example, the outcome of brain tumor resection is improved dramatically when surgeons are better able to define surgical borders. Intraoperative magnetic resonance imaging (iMRI) helps reduce the risk of damaging critical areas of the brain and makes it possible to confirm a successful resection or determine the need for further resection prior to closing a patients head and finalizing the surgery. Here we present a ground-based, iMRI system with a mobile 1-T cryogen-free imager. An ex-vivo experimental test of the novel iMRI system is performed to demonstrate preoperative and intraoperative imaging. The ground-based, mobile iMRI system presented here was successfully used to obtain intraoperative MR images without moving the imaging target or compromising conventional surgical techniques. The success of this experiment constitutes a major milestone towards the installation of a ground-based, high-field, mobile iMRI system in a hospital setting.

Combination of hyaluronic acid conjugates with immunogenic cell death inducer and CpG for glioblastoma local chemo-immunotherapy elicits an immune response and induces long-term survival.

The efficacy of standard glioblastoma (GBM) treatments has been limited due to the highly immunosuppressive tumor immune microenvironment, interpatient tumor heterogenicity and anatomical barriers, such as the blood brain barrier. In the present work, we hypothesized that a new local therapy based on the combination of doxorubicin (DOX) as an immunogenic cell death (ICD) inducer and CpG, a Toll-like receptor (TLR)-9 agonist, would act synergistically to eradicate GBM. DOX and CpG were first tested in an orthotopic GL261 GBM model showing enhanced survival. To improve the outcome with a reduced dose, we designed bioresponsive hyaluronic acid (HA)-drug conjugates for effective in situ chemoimmunotherapy. HA was derivatized with CpG. The new HA-CpG conjugate showed high efficacy in re-educating protumoral M2-like microglia into an antitumoral M1-like phenotype, inducing the expression of immune-stimulatory cytokines. DOX was also conjugated to HA. DOX conjugation increased ICD induction in GL261 cells. Finally, a combination of the conjugates was explored in an orthotopic GL261 GBM model. The local delivery of combined HA-DOX HA-CpG into the tumor mass elicited antitumor CD8

Pituitary Stalk Stretch Predicts Postoperative Diabetes Insipidus After Pituitary Macroadenoma Transsphenoidal Resection.

Manipulation of the pituitary stalk, posterior pituitary gland, and hypothalamus during transsphenoidal pituitary adenoma resection can cause disruption of water electrolyte regulation leading to diabetes insipidus (DI). To determine whether pituitary stalk stretch is an independent risk factor for postoperative DI after pituitary adenoma resection. A retrospective review was performed of patients undergoing endoscopic endonasal resection of pituitary macroadenoma between July 2010 and December 2016 by a single neurosurgeon. We analyzed preoperative and postoperative imaging metrics to assess predictors for postoperative DI. Of the 234 patients undergoing resection, 41 (17.5%) developed postoperative DI. DI was permanent in 10 (4.3%) and transient in 31 (13.2%). The pituitary stalk stretch, measured as the change in stalk length from preoperative to postoperative imaging, was greater in the DI compared with the non-DI group (10.1 mm vs 5.9 mm, P < .0001). The pituitary stalk stretch was associated with DI with significant difference in mean pituitary stalk stretch between non-DI group vs DI group (5.9 mm vs 10.1 mm, P < .0001). Multivariate analysis revealed that pituitary stalk stretch >10 mm was a significant independent predictor of postoperative DI odds ratios 2.56 (1.10-5.96), P .029. When stratified into transient and permanent DI, multivariable analysis showed that pituitary stalk stretch >10 mm was a significant independent predictor of transient DI odds ratios 2.71 (1.0-7.1), P .046 but not permanent DI. Postoperative pituitary stalk stretch after transsphenoidal pituitary adenoma surgery is an important factor for postoperative DI. We propose a reconstruction strategy to mitigate stalk stretch.

Novel Merging of CT and MRI to Allow for Safe Navigation into Kambins Triangle for Percutaneous Lumbar Interbody Fusion-Initial Case Series Investigating Safety and Efficacy.

For percutaneous lumbar fusion (percLIF), magnetic resonance imaging and computed tomography are critical to defining surgical corridors. Currently, these scans are performed separately, and surgeons then use fluoroscopy or neuromonitoring to guide instruments through Kambins triangle. However, anatomic variations and intraoperative positional changes are possible, meaning that safely accessing Kambins triangle remains a challenge because nerveroot visualization without endoscopes has not been thoroughly described. To overcome the known challenges of percLIF and reduce the likelihood of iatrogenic injuries by showing real-time locations of neural and bony anatomy. The authors demonstrate an intraoperative navigational platform that applies nerve root segmentation and image fusion to assist with percLIF. Five patients from a single institution were included. Of the 5 patients, the mean age was 71 ± 8 years and 3 patients (60%) were female. One patient had general anesthesia while the remaining 4 patients underwent awake surgery with spinal anesthesia. The mean area for the L4-L5 Kambins triangle was 76.1 ± 14.5 mm 2 . A case example is shown where the side of approach was based on the fact that Kambins triangle was larger on one side compared with the other. The mean operative time was 170 ± 17 minutes, the mean blood loss was 32 ± 16 mL, and the mean hospital length of stay was 19.6 ± 8.3 hours. No patients developed postoperative complications. This case series demonstrates the successful and safe application of nerve segmentation using magnetic resonance imagingcomputed tomography fusion to perform percLIF and provide positive patient outcomes.

Brain Glucose Sensing and the Problem of Relative Hypoglycemia.

Relative hypoglycemia is an often-overlooked complication of diabetes characterized by an increase in the glycemic threshold for detecting and responding to hypoglycemia. The clinical relevance of this problem is linked to growing evidence that among patients with critical illness, higher blood glucose in the intensive care unit is associated with higher mortality among patients without diabetes but lower mortality in patients with preexisting diabetes and an elevated prehospitalization HbA1c. Although additional studies are needed, the cardiovascular stress associated with hypoglycemia perception, which can occur at normal or even elevated glucose levels in patients with diabetes, offers a plausible explanation for this difference in outcomes. Little is known, however, regarding how hypoglycemia is normally detected by the brain, much less how relative hypoglycemia develops in patients with diabetes. In this article, we explore the role in hypoglycemia detection played by glucose-responsive sensory neurons supplying peripheral vascular beds andor circumventricular organs. These observations support a model wherein relative hypoglycemia results from diabetes-associated impairment of this neuronal glucose-sensing process. By raising the glycemic threshold for hypoglycemia perception, this impairment may contribute to the increased mortality risk associated with standard glycemic management of critically ill patients with diabetes.

Curcumin attenuates memory impairments and long-term potentiation deficits by damping hippocampal inflammatory cytokines in lipopolysaccharide-challenged rats.

Neuroinflammation is a key pathological event triggering neurodegenerative process, resulting in neurologic sequelae. Curcumin (cur) has recently received increasing attention due to its anti-inflammatory properties. Therefore, we investigated the protective effects of curcumin on lipopolysaccharide (LPS)-induced memory impairments, long-term potentiation (LTP) deficits, hippocampal inflammatory cytokines, and neuronal loss in male rats. Rats were randomly divided into four groups as follows (1) Vehicle (2) cur (3) LPS and (4) curLPS. Following curcumin pretreatment (50 mgkg, per oral via gavage, 14 consecutive days), animals received a single dose of LPS (1 mgkg, intraperitoneally) or saline. Twenty-four hours after LPSor saline administration, passive avoidance test (PAT), hippocampal LTP, inflammatory cytokines (TNFα, IL-1β), and neuronal loss were assessed in hippocampal tissue of rats. Our results indicated that pretreatment with curcumin in LPS-challenged rats attenuates memory impairment in PAT, which was accompanied by significant increase in the field excitatory post-synaptic potential (fEPSP) slope and population spike (PS) amplitude. Hence, pretreatment with curcumin in LPS-treated rats decreased hippocampal concentration of tumor necrosis factor-alpha (TNF-α) and interleukin-1β (IL-1β), as well as reduced neuronal loss in the hippocampal tissue. This study provide evidence that pretreatment with curcumin attenuates LPS-induced memory impairment and LTP deficiency, which may be partly related to the amelioration of inflammatory cytokines and neuronal loss in the hippocampal tissue.

Imaging in a new pediatric brain tumor-a supratentorial neuroepithelial tumor with PLAGL1 fusion.

Molecular diagnostics have dramatically influenced the classification of tumor groups in the 2021 WHO CNS tumor classification. Studies focusing on molecular diagnostics continue to identify new tumors. Soon after the summary of the new classification was published, Supratentorial Neuroepithelial Tumor with PLAGL1 Fusion was described as a distinct entity. Although this new entity is defined pathologically, its imaging features are undefined. This case report discusses the imaging findings and possible differential diagnosis of the new tumor.

Diabetes Mellitus Management in the Context of Cranial Tumors.

The study of the relationship between cancer and diabetes mellitus (DM) has been under investigation for many decades. Particularly in the field of neurology and neurosurgery, increasing emphasis has been put on the examination of comorbid DM in patients with cranial tumors. Namely, as the most common and invasive type of malignant adult brain tumor, glioblastoma (GBS) has been the focus of said research. Several mechanisms have been described in the attempt to elucidate the underlying association between DM and GBS, with the metabolic phenomenon known as the Warburg effect and its consequential downstream effects serving as the resounding culprits in recent literature. Since the effect seen in cancers like GBS exploits an upregulated form of aerobic glycolysis, the role of a sequela of DM, known as hyperglycemia, will be investigated. In particular, in the treatment of GBS, surgical resection and subsequent chemotherapy andor radiotherapy are used in conjunction with corticosteroid therapy, the latter of which has been linked to hyperglycemia. Unsurprisingly, comorbid DM patients are significantly susceptible to this disposition. Further, this fact is reflected in recent literature that demonstrates the impact of hyperglycemia on cancer advancement and patient outcomes in several preclinical and clinical studies. Thus, this review will aim to underline the significance of diabetes and glycemic control via standard-of-care treatments such as metformin administration, as well as to describe emerging treatments such as the signaling modulation of insulin-like growth factor and the employment of the ketogenic diet.

Distinguishing Brain Metastasis Progression From Radiation Effects After Stereotactic Radiosurgery Using Longitudinal GRASP Dynamic Contrast-Enhanced MRI.

Differentiating brain metastasis progression from radiation effects or radiation necrosis (RN) remains challenging. Golden-angle radial sparse parallel (GRASP) dynamic contrast-enhanced MRI provides high spatial and temporal resolution to analyze tissue enhancement, which may differ between tumor progression (TP) and RN. To investigate the utility of longitudinal GRASP MRI in distinguishing TP from RN after gamma knife stereotactic radiosurgery (SRS). We retrospectively evaluated 48 patients with brain metastasis managed with SRS at our institution from 2013 to 2020 who had GRASP MRI before and at least once after SRS. TP (n 16) was pathologically confirmed. RN (n 16) was diagnosed on either resected tissue without evidence of tumor or on lesion resolution on follow-up. As a reference, we included a separate group of patients with non-small-cell lung cancer that showed favorable response with tumor control and without RN on subsequent imaging (n 16). Mean contrast washin and washout slopes normalized to the superior sagittal sinus were compared between groups. Receiver operating characteristic analysis was performed to determine diagnostic performance. After SRS, progression showed a significantly steeper washin slope than RN on all 3 follow-up scans (scan 1 0.29 ± 0.16 vs 0.18 ± 0.08, P .021 scan 2 0.35 ± 0.19 vs 0.18 ± 0.09, P .004 scan 3 0.32 ± 0.12 vs 0.17 ± 0.07, P .002). No significant differences were found in the post-SRS washout slope. Post-SRS washin slope differentiated progression and RN with an area under the curve (AUC) of 0.74, a sensitivity of 75%, and a specificity of 69% on scan 1 an AUC of 0.85, a sensitivity of 92%, and a specificity of 69% on scan 2 and an AUC of 0.87, a sensitivity of 63%, and a specificity of 100% on scan 3. Longitudinal GRASP MRI may help to differentiate metastasis progression from RN.

Pre-clinical models for evaluating glioma targeted immunotherapies.

Gliomas have an extremely poor prognosis in both adult and pediatric patient populations as these tumors are known to grow aggressively and respond poorly to standard of care treatment. Currently, treatment for gliomas involves surgical resection followed by chemoradiation therapy. However, some gliomas, such as diffuse midline glioma, have more limited treatment options such as radiotherapy alone. Even with these interventions, the prognosis for those diagnosed with a glioma remains poor. Immunotherapy is highly effective for some cancers and there is great interest in the development of effective immunotherapies for the treatment of gliomas. Clinical trials evaluating the efficacy of immunotherapies targeted to gliomas have largely failed to date, and we believe this is partially due to the poor choice in pre-clinical mouse models that are used to evaluate these immunotherapies. A key consideration in evaluating new immunotherapies is the selection of pre-clinical models that mimic the glioma-immune response in humans. Multiple pre-clinical options are currently available, each one with their own benefits and limitations. Informed selection of pre-clinical models for testing can facilitate translation of more promising immunotherapies in the clinical setting. In this review we plan to present glioma cell lines and mouse models, as well as alternatives to mouse models, that are available for pre-clinical glioma immunotherapy studies. We plan to discuss considerations of model selection that should be made for future studies as we hope this review can serve as a guide for investigators as they choose which model is best suited for their study.

Secreted PGK1 and IGFBP2 contribute to the bystander effect of miR-10b gene editing in glioma.

MicroRNA-10b (miR-10b) is an essential glioma driver and one of the top candidates for targeted therapies for glioblastoma and other cancers. This unique miRNA controls glioma cell cycle and viability via an array of established conventional and unconventional mechanisms. Previously reported CRISPR-Cas9-mediated miR-10b gene editing of glioma cells

Low-grade epilepsy-associated neuroepithelial tumors Tumor spectrum and diagnosis based on genetic alterations.

Brain tumors can always result in seizures when involving the cortical neurons or their circuits, and they were found to be one of the most common etiologies of intractable focal seizures. The low-grade epilepsy-associated neuroepithelial tumors (LEAT), as a special group of brain tumors associated with seizures, share common clinicopathological features, such as seizure onsets at a young age, a predilection for involving the temporal lobe, and an almost benign course, including a rather slow growth pattern and thus a long-term history of seizures. Ganglioglioma (GG) and dysembryoplastic neuroepithelial tumor (DNET) are the typical representatives of LEATs. Surgical treatments with complete resection of tumors and related epileptogenic zones are deemed the optimal way to achieve postoperative seizure control and lifetime recurrence-free survival in patients with LEATs. Although the term LEAT was originally introduced in 2003, debates on the tumor spectrum and the diagnosis or classification of LEAT entities are still confusing among epileptologists and neuropathologists. In this review, we would further discuss these questions, especially based on the updated classification of central nervous system tumors in the WHO fifth edition and the latest molecular genetic findings of tumor entities in LEAT entities.

Empirical planning target volume modeling for high precision MRI guided intracranial radiotherapy.

Magnetic resonance image-guided radiotherapy for intracranial indications is a promising advance however, uncertainties remain for both target localization after translation-only MR setup and intrafraction motion. This investigation quantified these uncertainties and developed a population-based planning target volume (PTV) model to explore target and organ-at-risk (OAR) volumetric coverage tradeoffs. Sixty-six patients, 49 with a primary brain tumor and 17 with a post-surgical resection cavity, treated on a 1.5T-based MR-linac across 1329 fractions were included. At each fraction, patients were setup by translation-only fusion of the online T1 MRI to the planning image. Each fusion was independently repeated offline accounting for rotations. The six degree-of-freedom difference between fusions was applied to transform the planning CTV at each fraction (CTV For the left-rightanterior-posteriorsuperior-inferior axes, mean ± SD of the rotational fusion differences were 0.1 ± 0.80.1 ± 0.8-0.2 ± 0.9°. Covering 98 % of the CTV An evidence-based PTV model was developed for brain cancer patients treated on the MR-linac. Informed by this model, we have clinically adopted a 3 mm PTV margin for conventionally fractionated intracranial patients.

Rb deficiency, neuronal survival and neurodegeneration In search of the perfect mouse model.

Three decades following the introduction of the first Rb knockout (KO) mouse model, the role of this critical protein in regulating brain development during embryogenesis and beyond remains a major scientific interest. Rb is a tumor suppressor gene known as the master regulator of the G1S checkpoint and control of cell cycle progression in stem and progenitor cells, but also their differentiated progeny. Here, we review the recent literature about the various Rb conditional Knockout (cKO) and inducible Knockout (iKO) models studied thus far, highlighting how findings should always be interpreted in light of the model and context under inquiry especially when studying the role of Rb in neuronal survival. There is indeed evidence of age-specific, cell type-specific and region-specific effects following Rb KO in the embryonic and the adult mouse brain. In terms of modeling neurodegenerative processes in human diseases, we discuss cell cycle re-entry (CCE) as a candidate mechanism underlying the increased vulnerability of Rb-deficient neurons to cell death. Notably, mouse models may limit the extent to which CCE due to Rb inactivation can mimic the pathological course of these disorders, such as Alzheimers disease. These remarks ought to be considered in future research when studying the consequences of Rb inactivation on neuronal generation and survival in rodents and their corresponding clinical significance in humans.

Positive association between nonalcoholic fatty liver disease and growth hormone deficiency in patients with nonfunctioning pituitary adenoma.

Non-alcoholic fatty liver disease (NAFLD) is characterized by growth hormone deficiency (GHd). We investigated the association between NAFLD and GHd in patients with nonfunctioning pituitary adenomas (NFPA). We recruited patients with NFPA who underwent transsphenoidal adenectomy between January 2005 and December 2018. Pituitary function was determined by the insulin tolerance test, thyroid hormone assay, and gonadal hormone levels. NAFLD was defined as a hepatic steatosis index greater than 36. Among 278 patients (mean age, 44.2 years 58.6% n163 female), 103 (37.0%) had GHd, 139 (50.0%) had hypogonadism, and 75 (27.0%) had NAFLD. The prevalence of NAFLD was significantly higher in patients with GHd than in those without (36.9% vs. 21.1%, p0.01). Even after adjusting for age, total cholesterol level, gonadal function, and prolactin level, patients with GHd had approximately two-fold higher prevalence of NALFD than those without GHd (adjusted odds ratio OR1.85, 95% confidence interval CI1.05-3.28, p0.03). Among female patients, the prevalence of NALFD was significantly higher in those with GHd than in those without (adjusted OR2.39, 95% CI1.03-5.55, p0.04) whereas, among male patients, the prevalence of NAFLD was statistically similar between those with and without GHd (p>0.05). In addition, gonadal function did not affect the prevalence of NAFLD in patients with NFPA (29.3% with eugonadism vs. 47.8% with hypogonadism, p0.14). Among patients with NFPA, the prevalence of NAFLD was two-fold higher in patients with GHd than that in those without GHd. Thus, screening for NAFLD might be required in NFPA patients with GHd.

Corrigendum Case report Cryptogenic giant brain abscess caused by

This corrects the article DOI 10.3389fneur.2022.1007435..

The different trends in the burden of neurological and mental disorders following dietary transition in China, the USA, and the world An extension analysis for the Global Burden of Disease Study 2019.

The highly processed western diet is substituting the low-processed traditional diet in the last decades globally. Increasing research found that a diet with poor quality such as western diet disrupts gut microbiota and increases the susceptibility to various neurological and mental disorders, while a balanced diet regulates gut microbiota and prevents and alleviates the neurological and mental disorders. Yet, there is limited research on the association between the disease burden expanding of neurological and mental disorders with a dietary transition. We compared the disability-adjusted life-years (DALYs) trend by age for neurological and mental disorders in China, in the United States of America (USA), and across the world from 1990 to 2019, evaluated the dietary transition in the past 60 years, and analyzed the association between the burden trend of the two disorders with the changes in diet composition and food production. We identified an age-related upward pattern in disease burden in China. Compared with the USA and the world, the Chinese neurological and mental disorders DALY percent was least in the generation over 75 but rapidly increased in younger generations and surpassed the USA andor the world in the last decades. The age-related upward pattern in Chinese disease burdens had not only shown in the presence of cardiovascular diseases, neoplasms, and diabetes mellitus but also appeared in the presence of depressive disorders, Parkinsons disease, Alzheimers disease and other dementias, schizophrenia, headache disorders, anxiety disorders, conduct disorders, autism spectrum disorders, and eating disorders, successively. Additionally, the upward trend was associated with the dramatic dietary transition including a reduction in dietary quality and food production sustainability, during which the younger generation is more affected than the older. Following the increase in total calorie intake, alcohol intake, ratios of animal to vegetal foods, and poultry meat to pulses, the burdens of the above diseases continuously rose. Then, following the rise of the ratios of meat to pulses, eggs to pulses, and pork to pulses, the usage of fertilizers, the farming density of pigs, and the burdens of the above disease except diabetes mellitus were also ever-increasing. Even the usage of pesticides was positively correlated with the burdens of Parkinsons disease, schizophrenia, cardiovascular diseases, and neoplasms. Contrary to China, the corresponding burdens of the USA trended to reduce with the improvements in diet quality and food production sustainability. Our results suggest that improving diet quality and food production sustainability might be a promising way to stop the expanding burdens of neurological and mental disorders.

Engineered Microparticles for Treatment of Murine Brain Metastasis by Reprograming Tumor Microenvironment and Inhibiting MAPK Pathway.

Brain metastases (BRM) are common in advanced lung cancer. However, their treatment is challenging due to the blood-brain barrier (BBB) and the immunosuppressive tumor microenvironment (ITME). Microparticles (MPs), a type of extracellular vesicle, can serve as biocompatible drug delivery vehicles that can be further modulated with genetic engineering techniques. MPs prepared from cells induced with different insults are compared and it is found that radiation-treated cell-released microparticles (RMPs) achieve optimal targeting and macrophage activation. The enzyme ubiquitin-specific protease 7 (USP7), which simultaneously regulates tumor growth and reprograms M2 macrophages (M2Φ), is found to be expressed in BRM. Engineered RMPs are then constructed that comprise 1) the RMP carrier that targets and reprograms M2Φ 2) a genetically expressed SR-B1-targeting peptide for improved BBB permeability and 3) a USP7 inhibitor to kill tumor cells and reprogram M2Φ. These RMPs successfully cross the BBB and target M2Φ in vitro and in vivo in mice, effectively reprogramming M2Φ and improving survival in a murine BRM model. Therapeutic effects are further augmented when combined with immune checkpoint blockade. This study provides proof-of-concept for the use of genetically engineered MPs for the treatment of BRM.

Stem cells, organoids and their applications for human diseases Special issue of BMB Reports in 2023.

Studying human biology has been challenging with conventional animal models or two-dimensional (2D) cultured cell lines. Recent advances in stem cell biology have made it possible to culture stem cells in vitro, leading to the establishment of in vitro three-dimensional (3D) organ-like structures known as organoids. Organoids are self-organizing 3D miniature tissues that mimic the tissue architecture and functionality of in vivo counterparts. Currently, organoids can be established for multiple tissues such as the intestine, brain, kidney, prostate, pancreas, liver, bladder, heart, and retina, either from pluripotent stem cells (PSCs), including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), or adult stem cells (AdSCs). In addition to normal organoids, patient-derived tumor organoids have been established from various human tumors such as pancreatic, colorectal, breast, liver, prostate, and bladder tumors. Also, bioengineering technologies including biomaterial and scaffold fabrication, bioprinting, and microfluidics have been recently applied to create more mature and complex organoids and miniature tissues in vitro. Incorporating recently advanced computational analyses including multi-omics profiling and bioinformatics further facilitated the process of using human organoids as a novel platform for human disease modeling, drug screening to identify potential targets and novel therapeutics, and the development of precision medicine and regenerative therapies. BMB Reports 2023 56(1) 1.

Anti-inflammatory effects of β-FNA are sex-dependent in a pre-clinical model of LPS-induced inflammation.

Inflammation is present in neurological and peripheral disorders. Thus, targeting inflammation has emerged as a viable option for treating these disorders. Previous work indicated pretreatment with beta-funaltrexamine (β-FNA), a selective mu-opioid receptor (MOR) antagonist, inhibited inflammatory signaling in vitro in human astroglial cells, as well as lipopolysaccharide (LPS)-induced neuroinflammation and sickness-like-behavior in mice. This study explores the protective effects of β-FNA when treatment occurs 10 h after LPS administration and is the first-ever investigation of the sex-dependent effects of β-FNA on LPS-induced inflammation in the brain and peripheral tissues, including the intestines. Male and female C57BL6J mice were administered LPS followed by treatment with β-FNA-immediately or 10 h post-LPS. Sickness- and anxiety-like behavior were assessed using an open-field test and an elevated-plus-maze test, followed by the collection of whole brain, hippocampus, prefrontal cortex, cerebellumbrain stem, plasma, spleen, liver, large intestine (colon), proximal small intestine, and distal small intestine. Levels of inflammatory chemokinescytokines (interferon γ-induced-protein, IP-10 (CXCL10) monocyte-chemotactic-protein 1, MCP-1 (CCL2) interleukin-6, IL-6 interleukin-1β, IL-1β and tumor necrosis factor-alpha, TNF-α) in tissues were measured using an enzyme-linked immunosorbent assay. Western blot analysis was used to assess nuclear factor-kappa B (NF-κB) expression. There were sex-dependent differences in LPS-induced inflammation across brain regions and peripheral tissues. Overall, LPS-induced CXCL10, CCL2, TNF-α, and NF-κB were most effectively downregulated by β-FNA and β-FNA effects differed across brain regions, peripheral tissues, timing of the dose, and in some instances, in a sex-dependent manner. β-FNA reduced LPS-induced anxiety-like behavior most effectively in female mice. These findings provide novel insights into the sex-dependent anti-inflammatory effects of β-FNA and advance this agent as a potential therapeutic option for reducing both neuroinflammation an intestinal inflammation.

This study aimed to describe We retrospectively analysed 98 children newly diagnosed with DIPG who underwent In univariate analysis, imaging characteristics significantly associated with shorter PFS and OS included a higher uniformity grade, higher TBRs, larger MTV, and higher TLMU. In multivariate analysis, larger MTV at diagnosis, shorter symptom duration, and no treatment were significantly correlated with shorter PFS and OS. The PET imaging features were not correlated with H3 K27M mutation status. Although several imaging features were significantly associated with PFS and OS, only MTV, indicating the size of the active tumour, was identified as a strong independent prognostic factor.

Comparison of Three Survival Scores in a Series of Patients ≥80 Years of Age Irradiated for Bone Metastases.

Very elderly patients irradiated for bone metastases likely benefit from individualized treatments. A specific survival score was created for this group and compared to existing instruments. Ninety-six patients aged 80 irradiated for bone metastases were retrospectively evaluated. Dose-fractionation regimen plus twelve characteristics were evaluated for survival. In the Cox regression model, performance status and tumor type were significant and used for the score, which included three groups (5-7, 8-12, and 14 points) with 6-month survival rates of 15%, 52%, and 90%. Positive predictive values (PPVs) regarding death ≤6 months were 85% (new score), 100% (previous 65 score), and 84% (previous score for any age). The new instrument and the 65 score were also very accurate regarding survival. Since PPV regarding death was calculated from only four patients for the 65 score, this PPV may be less conclusive than that for the new instrument. The new score appears useful for patients aged 80 irradiated for bone metastases.

Prognostic Factors and Independent Validation of a Risk Stratification Model in Octogenarian Patients Irradiated for Brain Metastases.

This study aimed at validation of a prognostic model, originally developed by Rades et al., in an age-restricted, particularly vulnerable subgroup of patients with brain metastases, because international variations in clinical practice and survival outcomes may impact on the performance of survival prediction tools. Retrospectively, data from a single institution were analyzed. The study included 50 patients managed with palliative whole-brain radiotherapy. The Rades et al. score was assigned and the resulting 3 prognostic strata compared. The 3-month survival rates for the 3 strata were 0, 35, and 41%, respectively (p<0.001 pooled over all strata, log-rank test for Kaplan-Meier curves). However, the prognostic impact of extracranial metastases suggested by Rades et al., together with the performance status and number of brain metastases in their study of 94 patients, was absent. In contrast, cancer type (better survival for breast and melanoma) and lack of steroid treatment were significant in the present study. The original Rades et al. score is a useful prognostic model in our validation database. However, additional factors, such as primary cancer type and need to prescribe corticosteroids, appear to play a role and might therefore be considered when performing future large-scale studies.

Cumulative Incidence of Thromboembolism and Prognostic Impact of Stroke in

Cancer and ischemic stroke are closely associated. Thromboembolism susceptibility in lung cancer may differ depending on oncogenic alterations. However, the clinical characteristics of thromboembolism in patients with BRAF-mutant non-small-cell lung cancer remain unknown. Thus, this study aimed to evaluate the cumulative incidence of thromboembolism in this population and describe such cases in detail. We retrospectively investigated consecutive patients with BRAF V600E-mutant non-small-cell lung cancer. Cumulative incidence was calculated using a competing risk analysis. Of 10 patients with BRAF-V600E mutant lung cancer, five developed a total of seven thromboembolic events, showing a 1-year cumulative incidence of 43% (95% confidence interval11-72%). These events consisted of four cancer-related stroke (CRS) events and three venous events including deep vein thrombosis or pulmonary embolism. Of note, most of the early thrombotic events were CRS. Two patients with CRS had multiple brain infarctions during anticancer drug therapy, characterized by high D-dimer levels, resulting in short-term mortality (13 and 22 days after stroke onset). A substantial proportion of patients with BRAF V600E-mutant lung cancer experienced thromboembolism during their disease course. CRS of undetermined source may predict a worse prognosis in this population.

Risk of Neurological Decline in Patients With Temporal Lobe Brain Masses.

The objective of this study was to assess which clinical and radiographic findings may be associated with neurological decline in patients with temporal lobe mass lesions. This represents a retrospective cohort study. Neurological decline was defined as a decline in Glasgow Coma Scale of 2 or more or new anisocoria. Adult patients aged 18 to 89 years with isolated temporal lobe, intra-axial, contrast-enhancing masses diagnosed between 112010 and 12312020 were included. Clinical and radiographic findings were collected for each patient. Linear regression analysis was used to identify findings predictive of neurological decline. Patients with neurological decline were compared to stable patients to identify factors that may increase risk for neurological decline. A total of 71 patients met the inclusion criteria. Four out of the 71 patients experienced neurological decline, representing an incidence of 6%. Linear regression analysis identified only radiographic transtentorial herniation as a predictor of neurological decline (β0.26, p0.03). A midline shift greater than 5 mm (100% vs. 40% odds ratio1.12, 95% confidence interval1.00-1.32 p0.05) and radiographic transtentorial herniation (75% vs. 18% odds ratio32.12, 95% confidence interval3.91-264.18 p0.03) were significantly more prevalent in patients with neurological decline and were associated with an increased risk of neurological decline. Radiographic transtentorial herniation and a midline shift greater than 5 mm may be useful findings to suggest an increased risk of neurological decline in patients with masses of the temporal lobe. This knowledge may be useful to neurosurgeons and physicians in other specialties to best care for this patient population.

Modulation of Neutrophil Function by Recombinant Human IgG1 Fc Hexamer in the Endogenous KBxN Mouse Model of Rheumatoid Arthritis.

Neutrophils are a pivotal cell type in the KBxN mouse model of rheumatoid arthritis and play an essential role in the progression of the arthritis. They are readily activated by immune complexes (ICs) via their FcγRs to release IL-1β in addition to other cytokines, which are inducing cartilage destruction. Neutrophils also release neutrophil-active chemokines to recruit themselves in an autocrine manner to perpetuate tissue destruction. FcγR-expression on neutrophils is of crucial importance for the recognition of ICs. In this study, due to its high avidity for binding to FcγRs, we investigated the potential anti-inflammatory effect of a recombinant IgG1 Fc hexamer (rFc-µTP-L309C) on neutrophils in the KBxN mouse model of endogenously generated chronic arthritis. 200 mgkg rFc-µTP-L309C and human serum albumin (HSA), used as controls, were administered subcutaneously every other day. Mouse ankle joints were monitored daily to generate a clinical score. Immunohistology was used to evaluate neutrophil infiltration and TUNEL to assess apoptosis. ELISA was used to measure IL-1β. Treatment with rFc-µTP-L309C, but not HSA, was able to significantly ameliorate the arthritis in the KBxN mice. Significant neutrophil infiltration into the ankle joint was found, but treatment with rFc-µTP-L309C resulted in significantly less neutrophil infiltration. There was no significant influence of rFc-µTP-L309C on neutrophil death or apoptosis. Less neutrophil infiltration could not be correlated to chemokine-mediated migration. Significantly less IL-1β was measured in mice treated with rFc-µTP-L309C. In the endogenous KBxN mouse model of rheumatoid arthritis, amelioration can be explained in part by inhibition of neutrophil infiltration into the joints as well as inhibition of IL-1β production. Given the observed inhibitory properties on neutrophils, rFc-µTP-L309C may be a potential therapeutic candidate to treat autoimmune and inflammatory conditions in which neutrophils are the predominant cell type involved in pathogenesis.

The Burden of Surviving Childhood Medulloblastoma A Population-Based, Matched Cohort Study in Ontario, Canada.

Survivors of childhood medulloblastoma suffer from substantial late effects. We characterized these sequelae using real-world health services data in a population-based cohort of medulloblastoma survivors. All 5-year medulloblastoma survivors diagnosed age < 18 years between 1987 and 2015 in Ontario, Canada, were identified and matched 15 with population controls. Index date was 5 years from latest pediatric cancer event. Linkage to provincial administrative health data allowed for comparison of cumulative incidences of several adverse outcomes. Two hundred thirty survivors, 81.3% of whom had received craniospinal irradiation, were matched with 1,150 controls. The 10-year postindex cumulative incidence of all-cause mortality was 7.9% (95% CI, 3.9 to 11.8) in survivors versus 0.6% (95% CI, 0.1 to 1.1) in controls (hazard ratio HR, 21.5 95% CI, 9.8 to 54.0). The cumulative incidence of stroke was higher in survivors (4.8% 95% CI, 2.2 to 9.0) compared with controls (0.1 95% CI, 0.01 to 0.7 HR, 45.6 95% CI, 12.8 to 289.8). Hearing loss requiring an amplification device was present in 24.9% (95% CI, 18.8 to 31.4) of survivors versus 0.3% (95% CI, 0.1 to 1.0) of controls (HR, 96.3 95% CI, 39.7 to 317.3). Disability support prescription claims were submitted by 44.5% (95% CI, 37.1 to 51.6) of survivors versus 5.5% (95% CI, 4.2 to 7.1) of controls (HR, 10.0 95% CI, 7.3 to 13.6). Female survivors were significantly less likely to deliver a liveborn child compared with controls (HR, 0.2 95% CI, 0.1 to 0.7). Survivors of medulloblastoma have significant long-term medical sequelae, increased all-cause mortality, and are frequently dependent on disability supports. Efforts to reduce the toxicity of current therapy, specifically incorporating molecularly informed risk stratification to spare low- and intermediate-risk survivors the toxicity of treatment, are urgently needed. These findings should prompt a re-evaluation of our current treatment approaches where research focused on late-effect interventions should be prioritized.

Quantifying stiffness and forces of tumor colonies and embryos using a magnetic microrobot.

Stiffness and forces are two fundamental quantities essential to living cells and tissues. However, it has been a challenge to quantify both 3D traction forces and stiffness (or modulus) using the same probe in vivo. Here, we describe an approach that overcomes this challenge by creating a magnetic microrobot probe with controllable functionality. Biocompatible ferromagnetic cobalt-platinum microcrosses were fabricated, and each microcross (about 30 micrometers) was trapped inside an arginine-glycine-apartic acid-conjugated stiff poly(ethylene glycol) (PEG) round microgel (about 50 micrometers) using a microfluidic device. The stiff magnetic microrobot was seeded inside a cell colony and acted as a stiffness probe by rigidly rotating in response to an oscillatory magnetic field. Then, brief episodes of ultraviolet light exposure were applied to dynamically photodegrade and soften the fluorescent nanoparticle-embedded PEG microgel, whose deformation and 3D traction forces were quantified. Using the microrobot probe, we show that malignant tumor-repopulating cell colonies altered their modulus but not traction forces in response to different 3D substrate elasticities. Stiffness and 3D traction forces were measured, and both normal and shear traction force oscillations were observed in zebrafish embryos from blastula to gastrula. Mouse embryos generated larger tensile and compressive traction force oscillations than shear traction force oscillations during blastocyst. The microrobot probe with controllable functionality via magnetic fields could potentially be useful for studying the mechanoregulation of cells, tissues, and embryos.

Analysis of regulatory sequences in exosomal DNA of NANOGP8.

Exosomes participate in intercellular communication by transporting functionally active molecules. Such cargo from the original cells comprising proteins, micro-RNA, mRNA, single-stranded (ssDNA) and double-stranded DNA (dsDNA) molecules pleiotropically transforms the target cells. Although cancer cells secrete exosomes carrying a significant level of DNA capable of modulating oncogene expression in a recipient cell, the regulatory mechanism is unknown. We have previously reported that cancer cells produce exosomes containing NANOGP8 DNA. NANOGP8 is an oncogenic paralog of embryonic stem cell transcription factor NANOG and does not express in cells since it is a pseudogene. However, in this study, we evaluated NANOGP8 expression in glioblastoma multiforme (GBM) tissue from a surgically removed brain tumor of a patient. Significantly higher NANOGP8 transcription was observed in GBM cancer stem cells (CSCs) than in GBM cancer cells or neural stem cells (NSCs), despite identical sequences of NANOGP8-upstream genomic region in all the cell lines. This finding suggests that upstream genomic sequences of NANOGP8 may have environment-dependent promoter activity. We also found that the regulatory sequences upstream of exosomal NANOGP8 GBM DNA contain multiple core promoter elements, transcription factor binding sites, and segments of human viruses known for their oncogenic role. The exosomal sequence of NANOGP8-upstream GBM DNA is different from corresponding genomic sequences in CSCs, cancer cells, and NSCs as well as from the sequences reported by NCBI. These sequence dissimilarities suggest that exosomal NANOGP8 GBM DNA may not be a part of the genomic DNA. Exosomes possibly acquire this DNA from other sources where it is synthesized by an unknown mechanism. The significance of exosome-bestowed regulatory elements in the transcription of promoter-less retrogene such as NANOGP8 remains to be determined.

Assessment of oligoclonal bands in cerebrospinal fluid and serum of dogs with meningoencephalitis of unknown origin.

Meningoencephalitis of unknown origin (MUO) is an inflammatory disease of the canine central nervous system (CNS) that shares several features with multiple sclerosis (MS) in humans. In approximately 95% of MS patients, ≥ two immunoglobulin G (IgG) oligoclonal bands (OCBs) are detectable exclusively in the cerebrospinal fluid (CSF). To investigate OCBs in CSF and serum in dogs affected by MUO, intervertebral disc disease (IVDD), idiopathic epilepsy (IE), intracranial neoplasia (IN), steroid-responsive meningitis-arteritis (SRMA), and diseases outside the CNS. We hypothesize that the highest prevalence of CSF-specific OCBs (≥ two OCBs uniquely in the CSF) would be found in dogs affected by MUO. Client-owned dogs (n 121) presented to the neurology service due to neurological deficits. Prospective study. Measurement of IgG concentration in CSF and serum via a canine IgG ELISA kit. OCB detection via isoelectric focusing (IEF) and immunoblot. Presence of CSF-specific OCBs was significantly higher in dogs with MUO (57%) compared to 22% in IN, 6% in IE, 15% in SRMA, 13% in IVDD, and 0% in the non-CNS group (p < .001). Dogs with MUO were 9.9 times more likely to show CSF-specific OCBs than all other diseases together (95% confidence interval, 3.7-26.4 p < .001). MUO showed the highest prevalence of CSF-specific OCBs, indicating an inflammatory B cell response. Future studies are needed to evaluate the prevalence in the specific MUO subtypes and a possible similarity with human MS.

PGC-1α degradation suppresses mitochondrial biogenesis to confer radiation resistance in glioma.

Radiotherapy is a major component of standard-of-care treatment for gliomas, the most prevalent type of brain tumor. However, resistance to radiotherapy remains a major concern. Identification of mechanisms governing radioresistance in gliomas could reveal improved therapeutic strategies for treating patients. Here, we report that mitochondrial metabolic pathways are suppressed in radioresistant gliomas through integrated analyses of transcriptomic data from glioma specimens and cell lines. Decreased expression of peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α), the key regulator of mitochondrial biogenesis and metabolism, correlated with glioma recurrence and predicted poor prognosis and response to radiation therapy of glioma patients. The subpopulation of glioma cells with low-mitochondrial-mass exhibited reduced expression of PGC-1α and enhanced resistance to radiation treatment. Mechanistically, PGC-1α was phosphorylated at serine (S) 636 by DNA-dependent protein kinase (DNA-PK) in response to irradiation. Phosphorylation at S636 promoted the degradation of PGC-1α by facilitating its binding to the E3 ligase RNF34. Restoring PGC-1α activity with expression of PGC-1α S636A, a phosphorylation-resistant mutant, or a small molecule PGC-1α activator ZLN005 increased radiosensitivity of resistant glioma cells by reactivating mitochondria-related ROS production and inducing apoptotic effects both in vitro and in vivo. In summary, this study identified a self-protective mechanism in glioma cells in which radiation-induced degradation of PGC-1α and suppression of mitochondrial biogenesis play a central role. Targeted activation of PGC-1α could help improve response to radiation therapy in glioma patients.

Survival after resection of brain metastasis impact of synchronous versus metachronous metastatic disease.

Patients with brain metastasis (BM) from solid tumors are in an advanced stage of cancer. BM may occur during a known oncological disease (metachronous BM) or be the primary manifestation of previously unknown cancer (synchronous BM). The time of diagnosis might decisively impact patient prognosis and further treatment stratification. In the present study, we analyzed the prognostic impact of synchronous versus (vs.) metachronous BM occurrence following resection of BM. Between 2013 and 2018, 353 patients had undergone surgical therapy for BM at the authors neuro-oncological center. Survival stratification calculated from the day of neurosurgical resection was performed for synchronous vs. metachronous BM diagnosis. Non-small-cell lung carcinoma (NSCLC) was the most common tumor entity of primary site (43%) followed by gastrointestinal cancer (14%) and breast cancer (13%). Synchronous BM occurrence was present in 116 of 353 patients (33%), metachronous BM occurrence was present in 237 of 353 patients (67%). NSCLC was significantly more often diagnosed via resection of the BM (56% synchronous vs. 44% metachronous situation, p 0.0001). The median overall survival for patients with synchronous BM diagnosis was 12 months (95% confidence interval (CI) 7.5-16.5) compared to 13 months (95% CI 9.6-16.4) for patients with metachronous BM diagnosis (p 0.97). The present study indicates that time of BM diagnosis (synchronous vs. metachronous) does not significantly impact patient survival following surgical therapy of BM. These results suggest that the indication for neurosurgical BM resection should be made regardless of a synchronous or a metachronous time of BM occurrence.

A shift from simple to sophisticated using intensity-modulated radiation therapy in conventional nonstereotactic palliative radiotherapy.

The authors aimed to highlight trends in, and evidence underlying the use of highly conformal radiotherapy (RT) techniques in conventional nonstereotactic palliative RT. The authors reviewed palliative-intent and curative-intent studies relevant to the use of intensity-modulated radiation therapy (IMRT) for the delivery of nonstereotactic conventional regimens to the brain, head and neck, thorax, abdomen and pelvis, and bone metastases. The use of IMRT has become standard with certain indications for brain metastases such as hippocampus-avoidinglimiting whole brain RT. IMRT in the treatment of bone metastases is increasing at many institutions despite limited data comparing its effectiveness with that of fluoroscopy-based and three-dimensional conformal radiation therapy techniques. There is scant data describing the use of IMRT for palliation in other extracranial anatomic sites guidance for its use in these settings must be gleaned almost exclusively from curative-intent randomized trials, consensus recommendations and contouring atlases. Consistent with historical technology shifts in RT practice, the uptake of highly conformal techniques such as IMRT for conventional palliative RT will likely outpace rigorous evaluations of their advantages and disadvantages relative to simpler techniques. Opportunities exist in virtually all anatomic sites for observational and randomized studies to evaluate the clinical impacts of these modern techniques in the palliative setting.

Current state and guidance on arterial spin labeling perfusion MRI in clinical neuroimaging.

This article focuses on clinical applications of arterial spin labeling (ASL) and is part of a wider effort from the International Society for Magnetic Resonance in Medicine (ISMRM) Perfusion Study Group to update and expand on the recommendations provided in the 2015 ASL consensus paper. Although the 2015 consensus paper provided general guidelines for clinical applications of ASL MRI, there was a lack of guidance on disease-specific parameters. Since that time, the clinical availability and clinical demand for ASL MRI has increased. This position paper provides guidance on using ASL in specific clinical scenarios, including acute ischemic stroke and steno-occlusive disease, arteriovenous malformations and fistulas, brain tumors, neurodegenerative disease, seizuresepilepsy, and pediatric neuroradiology applications, focusing on disease-specific considerations for sequence optimization and interpretation. We present several neuroradiological applications in which ASL provides unique information essential for making the diagnosis. This guidance is intended for anyone interested in using ASL in a routine clinical setting (i.e., on a single-subject basis rather than in cohort studies) building on the previous ASL consensus review.

Exploring the Epigenetic Regulated Modulation of Fibroblast Growth Factor 21 Involvement in High-Fat Diet Associated Parkinsons Disease in Rats.

Imbalance in brain glucose metabolism and epigenetic modulation during the disease course of insulin resistance (IR) associated with Parkinsons disease (PD) risk remains a prime concern. Fibroblast growth factor 21 (FGF21), the metabolic hormone, improves insulin sensitivity and elicits anti-diabetic properties. Chronic stress during brain IR may modulate the FGF21 expression and its dynamic release via epigenetic modifications. Metformin regulates and increases the expression of FGF21 which can be modulating in obesity, diabetes, and IR. Hence, this study was designed to investigate the FGF21 expression modulation via an epigenetic mechanism in PD and whether metformin (MF), an autophagy activator, and sodium butyrate (NaB), a pan histone deacetylase inhibitor, alone and in combination, exert any therapeutic benefit in PD pathology exacerbated by high-fat diet (HFD). Our results portray that the combination treatment with MF and NaB potentially attenuated the abnormal lipid profile and increased motor performance for the rats fed with HFD for 8 weeks followed by intrastriatal 6-hydroxy dopamine administration. The enzyme-linked immunosorbent assay (ELISA) estimations of C-reactive protein, tumor necrosis factor-α, interleukin-1 beta and 6, and FGF21 exhibited extensive downregulation after treatment with the combination. Lastly, mRNA, western blot, histological, and cresyl violet staining depicted that the combination treatment can restore degenerated neuronal density and increase the protein level compared to the disease group. The findings from the study effectively conclude that the epigenetic mechanism involved in FGF21 mediated functional abnormalities in IR-linked PD pathology. Hence, combined treatment with MF and NaB may prove to be a novel combination in ameliorating IR-associated PD in rats, probably via the upregulation of FGF21 expression.

Glioblastoma Spheroid Invasion through Soft, Brain-Like Matrices Depends on Hyaluronic Acid-CD44 Interactions.

Increased secretion of hyaluronic acid (HA), a glycosaminoglycan abundant in the brain extracellular matrix (ECM), correlates with worse clinical outcomes for glioblastoma (GBM) patients. GBM cells aggressively invade the brain parenchyma while encountering spatiotemporal changes in their local ECM, including HA concentration. To investigate how varying HA concentrations affect GBM invasion, patient-derived GBM cells are cultured within a soft, 3D matrix in which HA concentration is precisely varied and cell migration observed. Data demonstrate that HA concentration can determine the invasive activity of patient-derived GBM cells in a biphasic and highly sensitive manner, where the absolute concentration of HA at which cell migration peaked is specific to each patient-derived line. Furthermore, evidence that this response relies on phosphorylated ezrin, which interacts with the intracellular domain of HA-engaged CD44 to effectively link the actin cytoskeleton to the local ECM is provided. Overall, this study highlights CD44-HA binding as a major mediator of GBM cell migration that acts independently of integrins and focal adhesion complexes and suggests that targeting HA-CD44-ezrin interactions represents a promising therapeutic strategy to prevent tumor cell invasion in the brain.

Management of brain tumour related epilepsy (BTRE) a narrative review and therapy recommendations.

Brain Tumour Related Epilepsy (BTRE) has a significant impact on Quality of Life with implications for driving, employment, and social activities. Management of BTRE is complex due to the higher incidence of drug resistance and the potential for interaction between anti-cancer therapy and anti-seizure medications (ASMs). Neurologists, neurosurgeons, oncologists, palliative care physicians and clinical nurse specialists treating these patients would benefit from up-to-date clinical guidelines. We aim to review the current literature and to outline specific recommendations for the optimal treatment of BTRE, encompassing both Primary Brain Tumours (PBT) and Brain Metastases (BM). A comprehensive search of the literature since 2000 on BTRE was carried out in PubMed, MEDLINE and EMCARE. A broad search strategy was used, and the evidence evaluated and graded based on the Oxford Centre for Evidence-Based Medicine Levels of Evidence. Seizure frequency varies between 10 and 40% in patients with Brain Metastases (BM) and from 30% (high-grade gliomas) to 90% (low-grade gliomas) in patients with PBT. In patients with BM, risk factors include number of BM and melanoma histology. In patients with PBT, BTRE is more common in patients with lower grade histology, frontal and temporal tumours, presence of an IDH mutation and cortical infiltration. All patients with BTRE should be treated with ASMs. Non-enzyme inducing ASMs are recommended as first line treatment for BTRE, but up to 50% of patients with BTRE due to PBT remain resistant. There is no proven benefit for the use of prophylactic ASMs, although there are no randomised trials testing newer agents. Surgical and oncological treatments i.e. radiotherapy and chemotherapy improve BTRE. Vagus Nerve Stimulation has been used with partial success. The review highlights the relative dearth of high-quality evidence for the management of BTRE and provides a framework for further studies aiming to improve seizure control, quality of life, and indications for ASMs.KEY POINTSOffer levetiracetam or lamotrigine to all patients with primary or metastatic brain tumours who have seizure(s), irrespective of whether these are partial or generalised.ASM withdrawal for patients in remission is not recommended due to high rates of seizure recurrence.ASM prophylaxis is not generally recommended in the management of seizure-naïve patients.Both levetiracetam and lamotrigine are safe in pregnancy and breastfeeding.

Predictive biomarkers for the responsiveness of recurrent glioblastomas to activated killer cell immunotherapy.

Recurrent glioblastoma multiforme (GBM) is a highly aggressive primary malignant brain tumor that is resistant to existing treatments. Recently, we reported that activated autologous natural killer (NK) cell therapeutics induced a marked increase in survival of some patients with recurrent GBM. To identify biomarkers that predict responsiveness to NK cell therapeutics, we examined immune profiles in tumor tissues using NanoString nCounter analysis and compared the profiles between 5 responders and 7 non-responders. Through a three-step data analysis, we identified three candidate biomarkers (TNFRSF18, TNFSF4, and IL12RB2) and performed validation with qRT-PCR. We also performed immunohistochemistry and a NK cell migration assay to assess the function of these genes. Responders had higher expression of many immune-signaling genes compared with non-responders, which suggests an immune-active tumor microenvironment in responders. The random forest model that identified TNFRSF18, TNFSF4, and IL12RB2 showed a 100% accuracy (95% CI 73.5-100%) for predicting the response to NK cell therapeutics. The expression levels of these three genes by qRT-PCR were highly correlated with the NanoString levels, with high Pearsons correlation coefficients (0.419 (TNFRSF18), 0.700 (TNFSF4), and 0.502 (IL12RB2)) their prediction performance also showed 100% accuracy (95% CI 73.54-100%) by logistic regression modeling. We also demonstrated that these genes were related to cytotoxic T cell infiltration and NK cell migration in the tumor microenvironment. We identified TNFRSF18, TNFSF4, and IL12RB2 as biomarkers that predict response to NK cell therapeutics in recurrent GBM, which might provide a new treatment strategy for this highly aggressive tumor.

Specific organ metastases and prognosis in lung adenocarcinoma.

This study aims to characterize the specific organ metastatic rates in lung adenocarcinoma (LUAD) patients and identify the prognosis-associated factors. Using the Surveillance, Epidemiology and End Results database, 40 117 patients diagnosed with positive histology as the only primary LUAD were included. We stratified patients by diagnosed year, age, sex, raceethnicity, marital status, insurance, location, TNM stage, organ-specific metastases, surgery, chemotherapy, and radiation therapy. We performed multivariable logistic and Cox regression to identify the factors associated with the presence of specific organ metastases and prognosis predictors. For the 40 117 LUAD patients, 43.69%, 26.25%, 19.66%, 10.60%, and 17.89% had specific organ, bone, brain, liver, and lung metastases, respectively. The average survival in patients with organ metastases was 12.19 months, compared to 36.40 months in patients without metastases. In different kinds of metastatic organ cohorts, the longest average survival was 12.60 months in the lung metastases cohort, and the shortest was 8.43 months in liver metastases cohort. In total, 571 patients with metastases received surgery, which was significantly associated with decreased mortality (hazard ratio 1.82, 95% confidence interval 1.65-2.01, p < 0.01). Patients received surgery of lobectomy or extended (251 of 571, 43.96%) displayed the longest average survival (35.16 months) patients (294 of 571, 51.49%) received sub-lobar resection, had the average survival (19.90 months) patients received local tumor destruction (26 of 571, 4.55%) had the shortest average survival (13.73 months). This study provides insights into the specific organ metastatic rates and prognosis in LUAD patients on a population level. These findings suggest that surgery resection should be taken into consideration in the treatment for these LUAD patients.

Neurons as stromal drivers of nervous system cancer formation and progression.

Similar to their pivotal roles in nervous system development, neurons have emerged as critical regulators of cancer initiation, maintenance, and progression. Focusing on nervous system tumors, we describe the normal relationships between neurons and other cell types relevant to normal nerve function, and discuss how disruptions of these interactions promote tumor evolution, focusing on electrical (gap junctions) and chemical (synaptic) coupling, as well as the establishment of new paracrine relationships. We also review how neuron-tumor communication contributes to some of the complications of cancer, including neuropathy, chemobrain, seizures, and pain. Finally, we consider the implications of cancer neuroscience in establishing risk for tumor penetrance and in the design of future anti-tumoral treatments.

B7-H6 enhances F-actin rearrangement by targeting c-MYC activation to promote medulloblastoma migration and invasion.

Medulloblastoma (MB) is childrens most common primary malignant primitive neuro-ectodermal tumor. Group 3 MB showed a higher propensity to metastasis, which is molecularly characterized by c-MYC gene amplification. The activation of c-MYC promotes the remodeling of the F-actin cytoskeleton to enhance metastasis. The B7 homologue 6 (B7-H6) is associated with the manifold essential hallmarks of tumorigenesis. In this study, we will explore whether B7-H6 regulates the reorganization of F-actin by elevating the c-MYC expression to promote metastasis. The Daoy cell line was used to act as the cell model of medulloblastoma. Small interfering RNA and the plasmid were used to downregulate and upregulate the expression of B7-H6 in Daoy cells. Transwell assays withwithout the matrigel matrix were used to detect migration and invasion of Daoy cells. Western blots were used to detect the expression of related proteins. Immunofluorescence staining was used to observe the impact of B7-H6 on the c-MYC F-actin axis. B7-H6 improved migration and invasion in the Daoy cell line. B7-H6 enhanced the rearrangement of F-actin and activated the expression of MMP-9 and MMP-2. B7-H6 promoted the remodeling of F-actin by targeting c-MYC activation to reinforce migration and invasion. B7-H6 acts as a promoter of migration and invasion in medulloblastoma by activating the c-MYC F-actin axis.

Long-term outcomes of fractionated proton beam therapy for benign or radiographic intracranial meningioma.

Benign intracranial meningioma is one of the most common primary brain neoplasms. Proton therapy has been increasingly utilized for nonoperative management of this neoplasm, yet few long-term outcomes studies exist. The medical records of a total of 59 patients with 64 lesions were reviewed under a prospective outcomes tracking protocol for histologically proven or radiographically benign meningioma. The patients were treated with proton therapy at the University of Florida Proton Therapy Institute between 2007 and 2019 and given a median dose of 50.4 GyRBE at 1.8 GyRBE (relative biological effectiveness) (range 48.6-61.2 GyRBE) in once-daily treatments. With a median clinical and imaging follow-up of 6.3 and 4.7 years, the rates of 5-year actuarial local progression and cumulative incidence of grade 3 or greater toxicity were 6% (95% confidence interval CI 1%-14%), and 2% (95% CI < 1%-15%), respectively. Two patients experienced local progression after 5 years. The 5-year actuarial overall survival rate was 87% (95% CI 74-94%). Fractionated PBT up to 50.4 GyRBE is a safe and highly effective therapy for treating benign intracranial meningioma.

A Homozygous PPP1R21 Splice Variant Associated with Severe Developmental Delay, Absence of Speech, and Muscle Weakness Leads to Activated Proteasome Function.

PPP1R21 acts as a co-factor for protein phosphatase 1 (PP1), an important serinethreonine phosphatase known to be essential for cell division, control of glycogen metabolism, protein synthesis, and muscle contractility. Bi-allelic pathogenic variants in PPP1R21 were linked to a neurodevelopmental disorder with hypotonia, facial dysmorphism, and brain abnormalities (NEDHFBA) with pediatric onset. Functional studies unraveled impaired vesicular transport as being part of PPP1R21-related pathomechanism. To decipher further the pathophysiological processes leading to the clinical manifestation of NEDHFBA, we investigated the proteomic signature of fibroblasts derived from the first NEDHFBA patient harboring a splice-site mutation in PPP1R21 and presenting with a milder phenotype. Proteomic findings and further functional studies demonstrate a profound activation of the ubiquitin-proteasome system with presence of protein aggregates and impact on cellular fitness and moreover suggest a cross-link between activation of the proteolytic system and cytoskeletal architecture (including filopodia) as exemplified on paradigmatic proteins including actin, thus extending the pathophysiological spectrum of the disease. In addition, the proteomic signature of PPP1R21-mutant fibroblasts displayed a dysregulation of a variety of proteins of neurological relevance. This includes increase proteins which might act toward antagonization of cellular stress burden in terms of pro-survival, a molecular finding which might accord with the presentation of a milder phenotype of our NEDHFBA patient.

Allogeneic CAR T Cells Targeting DLL3 Are Efficacious and Safe in Preclinical Models of Small Cell Lung Cancer.

Small cell lung cancer (SCLC) is an aggressive disease with limited treatment options. Delta-like ligand 3 (DLL3) is highly expressed on SCLC and several other types of neuroendocrine cancers, with limited normal tissue RNA expression in brain, pituitary, and testis, making it a promising CAR T-cell target for SCLC and other solid tumor indications. A large panel of anti-DLL3 scFv-based CARs were characterized for both in vitro and in vivo activity. To understand the potential for pituitary and brain toxicity, subcutaneous or intracranial tumors expressing DLL3 were implanted in mice and treated with mouse cross-reactive DLL3 CAR T cells. A subset of CARs demonstrated high sensitivity for targets with low DLL3 density and long-term killing potential in vitro. Infusion of DLL3 CAR T cells led to robust antitumor efficacy, including complete responses, in subcutaneous and systemic SCLC in vivo models. CAR T-cell infiltration into intermediate and posterior pituitary was detected, but no tissue damage in brain or pituitary was observed, and the hormone-secretion function of the pituitary was not ablated. In summary, the preclinical efficacy and safety data presented here support further evaluation of DLL3 CAR T cells as potential clinical candidates for the treatment of SCLC.

Deep Learning for Noninvasive Assessment of H3 K27M Mutation Status in Diffuse Midline Gliomas Using MR Imaging.

Determination of H3 K27M mutation in diffuse midline glioma (DMG) is key for prognostic assessment and stratifying patient subgroups for clinical trials. MRI can noninvasively depict morphological and metabolic characteristics of H3 K27M mutant DMG. This study aimed to develop a deep learning (DL) approach to noninvasively predict H3 K27M mutation in DMG using T2-weighted images. Retrospective and prospective. For diffuse midline brain gliomas, 341 patients from Center-1 (27 ± 19 years, 184 males), 42 patients from Center-2 (33 ± 19 years, 27 males) and 35 patients (37 ± 18 years, 24 males). For diffuse spinal cord gliomas, 133 patients from Center-1 (30 ± 15 years, 80 males). 5T and 3T, T2-weighted turbo spin echo imaging. Conventional radiological features were independently reviewed by two neuroradiologists. H3 K27M status was determined by histopathological examination. The Dice coefficient was used to evaluate segmentation performance. Classification performance was evaluated using accuracy, sensitivity, specificity, and area under the curve. Pearsons Chi-squared test, Fishers exact test, two-sample Students t-test and Mann-Whitney U test. A two-sided P value <0.05 was considered statistically significant. In the testing cohort, Dice coefficients of tumor segmentation using DL were 0.87 for diffuse midline brain and 0.81 for spinal cord gliomas. In the internal prospective testing dataset, the predictive accuracies, sensitivities, and specificities of H3 K27M mutation status were 92.1%, 98.2%, 82.9% in diffuse midline brain gliomas and 85.4%, 88.9%, 82.6% in spinal cord gliomas. Furthermore, this study showed that the performance generalizes to external institutions, with predictive accuracies of 85.7%-90.5%, sensitivities of 90.9%-96.0%, and specificities of 82.4%-83.3%. In this study, an automatic DL framework was developed and validated for accurately predicting H3 K27M mutation using T2-weighted images, which could contribute to the noninvasive determination of H3 K27M status for clinical decision-making. 2 Technical Efficacy Stage 2.

Epstein-Barr virus-associated primary intracranial leiomyosarcoma in an immunocompetent patient illustrative case.

Primary intracranial leiomyosarcomas (PILMSs) are extremely rare tumors arising from smooth muscle connective tissue. PILMSs have been shown to be associated with Epstein-Barr virus (EBV). Thus far, EBV-associated PILMS has been exclusively described in immunocompromised patients. A 40-year-old male presented with a 2-year history of left-sided headaches, nausea, and vomiting. Magnetic resonance imaging demonstrated a large, heterogeneously enhancing, lobulated, dura-based mass arising from the left middle cranial fossa with associated edema and mass effect. The patient underwent an uncomplicated resection of suspected meningioma neuropathology revealed the exceedingly rare diagnosis of EBV-associated PILMS. Follow-up testing for human immunodeficiency virus (HIV) and other immunodeficiencies confirmed the patients immunocompetent status. Primary intracranial smooth muscle tumors are often misdiagnosed as meningiomas due to their similar appearance on imaging. PILMSs have a poor prognosis and gross total resection is the mainstay of treatment in the absence of clear recommendations for management. Prompt diagnosis and resection are important therefore, these tumors should be included in the differential of dura-based tumors, especially among immunocompromised patients. Although EBV-associated PILMSs usually occur in immunocompromised individuals, their presence cannot be ruled out in immunocompetent patients.

Neurofeedback Treatment Affects Affective Symptoms, But Not Perceived Cognitive Impairment in Cancer Patients Results of an Explorative Randomized Controlled Trial.

EEG biofeedback (NF) is an established therapy to enable individuals to influence their own cognitive-emotional state by addressing changes in brainwaves. Psycho-oncological approaches of NF in cancer patients are rare and effects are hardly studied. The aim of this explorative, randomized controlled trial was to test the effectiveness of an alpha and theta NF training protocol, compared to mindfulness based therapy as an established psycho-oncological treatment. Of initially 62 screened patients, 56 were included (inclusion criteria were cancer independent of tumor stage, age >18 years, German speaking exclusion criteria suicidal ideation, brain tumor). Randomization and stratification (tumor stage) was conducted by a computer system. Participants got 10 sessions over 5 weeks, in (a) an NF intervention (n 21 13 female, 8 male MAge 52.95(10 519) range 31 to 73 years)) or (b) a mindfulness group therapy as control condition (CG n 21 ie, 15 female, 6 male MAge 50.33(8708) range 32 to 67 years)). Outcome parameters included self-reported cognitive impairment (PCI) as primary outcome, and secondary outcomes of emotional distress (DT, PHQ-8, GAD-7), fatigue (MFI-20), rumination (RSQ), quality of life (QoL, EORTC-30 QoL), self-efficacy (GSE), and changes in EEG alpha, and theta-beta band performance in the NF condition. No changes in cognitive impairment were found ( This is the first study to investigate NF technique with regard to basic mechanisms of effectiveness in a sample of cancer patients, compared to an established psycho-oncological intervention in this field. Though there were no changes in cognitive impairment, present data show that NF improves affective symptoms comparably to mindfulness-based therapy and even more pronounced in QoL and self-efficacy.Trial registration ID DRKS00015773.

Dosimetric Analysis of Intra-Fraction Motion Detected by Surface-Guided Radiation Therapy During Linac Stereotactic Radiosurgery.

Stereotactic radiosurgery (SRS) immobilization with an open face mask is more comfortable and less invasive than frame based, but concerns about intrafraction motion must be addressed. Surface-guided radiation therapy (SGRT) is an attractive option for intrafraction patient monitoring because it is continuous, has submillimeter accuracy, and uses no ionizing radiation. The purpose of this study was to investigate the dosimetric consequences of uncorrected intrafraction patient motion detected during frameless linac-based SRS. Fifty-five SRS patients were monitored during treatment using SGRT between January 1, 2017, and September 30, 2020. If SGRT detected motion >1 mm, imaging was repeated and the necessary shifts were made before continuing treatment. For the 25 patients with intrafraction 3-dimensional vector shifts of ≥1 mm, we moved the isocenter in the planning system using the translational shifts from the repeat imaging and recalculated the plans to determine the dosimetric effect of the shifts. Planning target volume (PTV) coverage, minimum gross tumor volume (GTV) dose (relative and absolute), and normal brain V12 were evaluated. Wilcoxon signed rank tests were used to compare planned and simulated dosimetric parameters and median 2 sample tests were used to investigate these differences between cone and multileaf collimator (MLC) plans. For simulated plans, V12 increased by a median of 0.01 cc ( SGRT detected clinically meaningful intrafraction motion during frameless SRS, which could lead to large underdoses and increased normal brain dose if uncorrected.

Succinate dehydrogenase complex subunit C Role in cellular physiology and disease.

Succinate dehydrogenase complex subunit C (

Coping in the role as next of kin of a person with a brain tumour a qualitative metasynthesis.

Being the next of kin of a person with a brain tumour is a stressful experience. For many, being a next of kin involves fear, insecurity and overwhelming responsibility. The purpose of this study was to identify and synthesise qualitative original studies that explore coping in the role as next of kin of a person with a brain tumour. A qualitative metasynthesis guided by Sandelowski and Barrosos guidelines was used. The databases Medline, CHINAL and PsycINFO were searched for studies from January 2000 to 18 January 2022. Inclusion criteria were qualitative original studies that aimed to explore coping experience by the next of kin of a person with brain tumour. The next of kin had to be 18 years of age or older. Of a total of 1476 screened records data from 20 studies, including 342 participants (207 females, 81 males and 54 unclassified) were analysed into metasummaries and a metasynthesis. The metasynthesis revealed that the next of kin coping experiences were characterised by two main themes (1) coping factors within the next of kin and as a support system, such as their personal characteristics, perceiving the role as meaningful, having a support system, and hope and religion (2) coping strategies-control and proactivity, including regaining control, being proactive and acceptance. Next of kin of patients with brain tumours used coping factors and coping strategies gathered within themselves and in their surroundings to handle the situation and their role. It is important that healthcare professionals suggest and facilitate these coping factors and strategies because this may reduce stress and make the role of next of kin more manageable.

Observation of the delineation of the target volume of radiotherapy in adult-type diffuse gliomas after temozolomide-based chemoradiotherapy analysis of recurrence patterns and predictive factors.

Radiation therapy is the cornerstone of treatment for adult-type diffuse gliomas, but recurrences are inevitable. Our study assessed the prognosis and recurrence pattern of different radiotherapy volumes after temozolomide-based chemoradiation in our institution. The treatment plans were classified into two groups, the plan 1 intentionally involved the entire edema area while plan 2 did not. Retrospectively investigate the differences in outcomes of 118 adult-type diffuse gliomas patients between these two treatment plans. Then, patients who underwent relapse were selected to analyze their recurrence patterns. Continuous dynamic magnetic resonance images (MRI) were collected to categorized the recurrence patterns into central, in-field, marginal, distant, and cerebrospinal fluid dissemination (CSF-d) recurrence. Finally, the clinical and molecular characteristics which influenced progression were analyzed. Plan 1 (n 63) showed a median progression-free survival (PFS) and overall survival (OS) of 9.5 and 26.4 months while plan 2 (n 55) showed a median PFS and OS of 9.4 and 36.5 months (p 0.418 p 0.388). Treatment target volume had no effect on the outcome in patients with adult-type diffuse gliomas. And there was no difference in radiation toxicity (p 0.388). Among the 90 relapsed patients, a total of 58 (64.4%) patients had central recurrence, 10 (11.1%) patients had in-field recurrence, 3 (3.3%) patients had marginal recurrence, 11 (12.2.%) patients had distant recurrence, and 8 (8.9%) patients had CSF-d recurrence. By treatment plans, the recurrence patterns were similar and there was no significant difference in survival. Reclassifying the progression pattern into local and non-local groups, we observed that oligodendroglioma (n 10) all relapsed in local and no difference in PFS and OS between the two groups (p > 0.05). Multivariable analysis showed that subventricular zone (SVZ) involvement was the independent risk factor for non-local recurrence in patients with GBM (p < 0.05). In our study, deliberately including or not the entire edema had no impact on prognosis and recurrence. Patients with varied recurrence patterns had diverse clinical and genetic features.

MRI-based brain tumor detection using convolutional deep learning methods and chosen machine learning techniques.

Detecting brain tumors in their early stages is crucial. Brain tumors are classified by biopsy, which can only be performed through definitive brain surgery. Computational intelligence-oriented techniques can help physicians identify and classify brain tumors. Herein, we proposed two deep learning methods and several machine learning approaches for diagnosing three types of tumor, i.e., glioma, meningioma, and pituitary gland tumors, as well as healthy brains without tumors, using magnetic resonance brain images to enable physicians to detect with high accuracy tumors in early stages. A dataset containing 3264 Magnetic Resonance Imaging (MRI) brain images comprising images of glioma, meningioma, pituitary gland tumors, and healthy brains were used in this study. First, preprocessing and augmentation algorithms were applied to MRI brain images. Next, we developed a new 2D Convolutional Neural Network (CNN) and a convolutional auto-encoder network, both of which were already trained by our assigned hyperparameters. Then 2D CNN includes several convolution layers all layers in this hierarchical network have a 22 kernel function. This network consists of eight convolutional and four pooling layers, and after all convolution layers, batch-normalization layers were applied. The modified auto-encoder network includes a convolutional auto-encoder network and a convolutional network for classification that uses the last output encoder layer of the first part. Furthermore, six machine-learning techniques that were applied to classify brain tumors were also compared in this study. The training accuracy of the proposed 2D CNN and that of the proposed auto-encoder network were found to be 96.47% and 95.63%, respectively. The average recall values for the 2D CNN and auto-encoder networks were 95% and 94%, respectively. The areas under the ROC curve for both networks were 0.99 or 1. Among applied machine learning methods, Multilayer Perceptron (MLP) (28%) and K-Nearest Neighbors (KNN) (86%) achieved the lowest and highest accuracy rates, respectively. Statistical tests showed a significant difference between the means of the two methods developed in this study and several machine learning methods (p-value < 0.05). The present study shows that the proposed 2D CNN has optimal accuracy in classifying brain tumors. Comparing the performance of various CNNs and machine learning methods in diagnosing three types of brain tumors revealed that the 2D CNN achieved exemplary performance and optimal execution time without latency. This proposed network is less complex than the auto-encoder network and can be employed by radiologists and physicians in clinical systems for brain tumor detection.

Risk of seizures in a population of women with BRCA-positive metastatic breast cancer from an electronic health record database in the United States.

Incidence and risk factors for seizures among women with advanced breast cancer (BC) and brain metastases are not well characterized across treatment-related or clinical subtypes. This study leveraged a large real-world dataset to describe incidence and risk factors for seizures in BRCA-associated metastatic breast cancer. The Optum® de-identified electronic health records database was used. Females with a BC diagnoses between 2008 and 2018, with clinic visits 12 months before BC index date, evidence of BRCA mutation (BRCA), evidence of metastasis, and no previous cancers were included. Analyses were stratified by the overall BRCA cohort and 4 molecular phenotypes HER2HR- (human epidermal growth factor 2hormone receptor), HER2-HR, HER2HR, and triple negative BC (TNBC HER2-HR-). Seizures were identified using diagnosis codes and natural language processing. Incidence, occurrence rates, and cumulative incidence of seizures from the diagnosis of metastasis to the end of follow up were calculated. Comparisons were made between phenotypes and stratified on PARP inhibitor use, diagnosed brain metastases, history of seizures, and anticonvulsants use before BC. All comparisons included age at metastasis, number of prior lines of treatment, and metastasis location as covariates. 27.8% of 7941 BRCA patients had ≥1 seizure over a mean follow-up time of 2.35 years. Incidence and occurrence rates were 11.83 (95% CI 11.35-12.33) and 201.3 (95% CI 198.05-204.50), respectively, per 100 person-years. HER2-HR and TNBC patients had the lowest and highest seizure incidence rates, respectively (10.94 95% CI 10.23-11.71 and 16.83 95% CI 15.34-18.46). With HER2-HR as the reference group in a competing risk analysis, TNBC (hazard ratio, HR 1.35 95%CI 1.21, 1.52 p < 0.001) and HER2HR- (HR 1.29 95%CI 1.07, 1.56 p < 0.01) patients had a greater risk of seizures. Patients with diagnosed brain metastases or a history of seizures had higher seizure rates. Incidence trended higher with PARP inhibitor use, but patient numbers were low. This study provides novel real-world evidence on seizure incidence rates in BRCA BC patients, even those without diagnosed brain metastases, and underscores the need to understand patients tumor phenotypes when assessing seizure risk. These findings may have implications for clinical practice and assessment of benefit-risk ratios of new therapeutic agents.

TRIM8 a double-edged sword in glioblastoma with the power to heal or hurt.

Glioblastoma multiforme (GBM) is an aggressive primary brain tumor and one of the most lethal central nervous system tumors in adults. Despite significant breakthroughs in standard treatment, only about 5% of patients survive 5 years or longer. Therefore, much effort has been put into the search for identifying new glioma-associated genes. Tripartite motif-containing (TRIM) family proteins are essential regulators of carcinogenesis. TRIM8, a member of the TRIM superfamily, is abnormally expressed in high-grade gliomas and is associated with poor clinical prognosis in patients with glioma. Recent research has shown that TRIM8 is a molecule of duality (MoD) that can function as both an oncogene and a tumor suppressor gene, making it a double-edged sword in glioblastoma development. This characteristic is due to its role in selectively regulating three major cellular signaling pathways the TP53p53-mediated tumor suppression pathway, NFKBNF-κB, and the JAK-STAT pathway essential for stem cell property support in glioma stem cells. In this review, TRIM8 is analyzed in detail in the context of GBM and its involvement in essential signaling and stem cell-related pathways. We also discuss the basic biological activities of TRIM8 in macroautophagyautophagy, regulation of bipolar spindle formation and chromosomal stability, and regulation of chemoresistance, and as a trigger of inflammation.

Clinical Evaluation of IDH Mutation Status in Formalin-Fixed Paraffin-Embedded Tissue in Gliomas.

Determination of isocitrate dehydrogenase (IDH) 12 mutational status is crucial for a glioma diagnosis. It is common for IDH mutational status to be determined via a two-step algorithm that utilizes immunohistochemistry studies for IDH1 R132H, the most frequent variant, followed by next-generation sequencing studies for immunohistochemistry-negative or immunohistochemistry-equivocal cases. The objective of this study was to evaluate adding a rapid real-time polymerase chain reaction (RT-PCR) assay to the testing algorithm. METHODS We validated a modified, commercial, qualitative, RT-PCR assay with the ability to detect 14 variants in IDH12 in formalin-fixed paraffin-embedded glioma tumor specimens. The assay was validated using 51 tumor formalin-fixed paraffin-embedded specimens. During clinical implementation of this assay, 48 brain tumor specimens were assessed for IDH result concordance and turnaround time to result. Concordance between the RT-PCR and sequencing and IHC studies was 100%. This RT-PCR assay also showed concordant results with IHC for IDH1 R132H for 11 of the 12 (92%) tumor specimens with IDH mutations. The RT-PCR assay yielded faster results (average 2.6 days turnaround time) in comparison to sequencing studies (17.9 days), with complete concordance. In summary, we report that this RT-PCR assay can reliably be performed on formalin-fixed paraffin-embedded specimens and has a faster turnaround time than sequencing assays and can be clinically implemented for determination of IDH mutation status for patients with glioma.

Perilesional resection technique of glioblastoma intraoperative ultrasound and histological findings of the resection borders in a single center experience.

The surgical goal in glioblastoma treatment is the maximal safe resection of the tumor. Currently the lack of consensus on surgical technique opens different approaches. This study describes the perilesional technique and its outcomes in terms of the extent of resection, progression free survival and overall survival. Patients included (n 40) received a diagnosis of glioblastoma and underwent surgery using the perilesional dissection technique at San Gerardo Hospitalbetween 2018 and 2021. The tumor core was progressively isolated using a circumferential movement, healthy brain margins were protected with Cottonoid patties in a shingles on the roof fashion, then the tumorwas removed en bloc. Intraoperative ultrasound (iOUS) was used and at least 1 bioptic sample of healthy margin of the resection was collected and analyzed. The extent of resection was quantified. Extent of surgical resection (EOR) and progression free survival (PFS)were safety endpoints of the procedure. Thirty-four patients (85%) received a gross total resection(GTR) while 3 (7.5%) patients received a sub-total resection (STR), and 3 (7.5%) a partial resection (PR). The mean post-operative residual volume was 1.44 cm Perilesional resection is an efficient technique which aims to bring the surgeon to a safe environment, carefully reaching the healthy brain before removing the tumoren bloc. This technique can achieve excellent tumor margins, extent of resection, and preservation of apatients functions.

Metabolic rewiring in MYC-driven medulloblastoma by BET-bromodomain inhibition.

Medulloblastoma (MB) is the most common malignant brain tumour in children. High-risk MB patients harbouring MYC amplification or overexpression exhibit a very poor prognosis. Aberrant activation of MYC markedly reprograms cell metabolism to sustain tumorigenesis, yet how metabolism is dysregulated in MYC-driven MB is not well understood. Growing evidence unveiled the potential of BET-bromodomain inhibitors (BETis) as next generation agents for treating MYC-driven MB, but whether and how BETis may affect tumour cell metabolism to exert their anticancer activities remains unknown. In this study, we explore the metabolic features characterising MYC-driven MB and examine how these are altered by BET-bromodomain inhibition. To this end, we employed an NMR-based metabolomics approach applied to the MYC-driven MB D283 and D458 cell lines before and after the treatment with the BETi OTX-015. We found that OTX-015 triggers a metabolic shift in both cell lines resulting in increased levels of myo-inositol, glycerophosphocholine, UDP-N-acetylglucosamine, glycine, serine, pantothenate and phosphocholine. Moreover, we show that OTX-015 alters ascorbate and aldarate metabolism, inositol phosphate metabolism, phosphatidylinositol signalling system, glycerophospholipid metabolism, ether lipid metabolism, aminoacyl-tRNA biosynthesis, and glycine, serine and threonine metabolism pathways in both cell lines. These insights provide a metabolic characterisation of MYC-driven childhood MB cell lines, which could pave the way for the discovery of novel druggable pathways. Importantly, these findings will also contribute to understand the downstream effects of BETis on MYC-driven MB, potentially aiding the development of new therapeutic strategies to combat medulloblastoma.