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Perspectives on miRNAs directly targeting BDNF for cancer diagnosis and treatment (Review).

MicroRNA (miRNA), a non‑coding single‑stranded RNA molecule with a length of 21‑25 nucleotides transcripts, has been identified to play important roles in tumorigenesis and shows great potential applications in cancer diagnosis, prognosis and therapy. Brain derived neurotrophic factor (BDNF) is a member of the nerve growth factor family and usually serves as a biomarker in neurological and neuropsychiatric diseases for diagnosis and treatment by regulating its high‑affinity receptor TrkB (Tyrosine Kinase Receptor B). Abnormal expression of BDNF is also closely related to the development of cancer, cancer‑related pain and depression. However, little significant progress has been made in the application of BDNF in cancers. Recent studies have shown that the expression of BDNF is directly regulated by a cluster of miRNAs. This review concluded and discussed the role and mechanism of miRNAs targeting BDNF in cancers, and provided novel insights into the diagnosis and therapy of cancer in the future.

Susceptibility artifact morphology is more conspicuous on susceptibility-weighted imaging compared to T2 gradient echo sequences in the brains of dogs and cats with suspected intracranial disease.

Susceptibility-weighted imaging (SWI) has been found to be more reliable in the detection of vessels and blood products than T2-weighted gradient echo (GE) in several human brain diseases. In veterinary medicine, published information on the diagnostic usefulness of SWI is lacking. The aim of this retrospective observational study was to investigate the value of SWI compared to T2-weighted GE images in a population of dogs and cats with presumed, MRI-based diagnoses grouped as neoplastic (27), cerebrovascular (14), inflammatory (14), head trauma (5), other pathologies (4), or that were normal (36). Areas of signal void (ASV) were assessed based on shape, distribution, number, and conspicuity. Presence of ASV was found in 31 T2-weighted GE and 40 SWI sequences the conspicuity of lesions increased in 92.5% of cases with SWI. A 44.7% increase in the number of cerebral microbleeds (CMBs) was identified within the population using SWI (110) compared to T2-weighted GE (76). Linear ASV presumed to be abnormal vascular structures, as are reported in humans, were identified in 12 T2-weighted GE and 19 SWI sequences. In presumed brain tumors, abnormal vascular structures were detected in 11 of 27 (40.7%) cases on T2-weighted GE and in 16 of 27 (59.3%) cases on SWI, likely representing tumor neovascularization amorphous ASV interpreted as presumed hemorrhages on T2-weighted GE were diagnosed as vessels on SWI in five of 27 (18.5%) cases. Since SWI shows ASV more conspicuously than T2-weighted GE, the authors advocate the use of SWI in veterinary patients.

Proton radiotherapy for glioma and glioblastoma.

Radiotherapy (RT) continues to be an important component of treatment of glioma, particularly high-grade glioma and glioblastoma multiforme (GBM). GBM is one of the most aggressive central nervous system (CNS) tumors, with high rates of recurrence and very low rates of long-term survival. However, outcomes in these patients are improving with modern genetic profiling and multimodal therapy, which leads to more consideration for the risk for toxicities associated with traditional photon-based RT. Proton therapy (PT) is an increasingly available method to reduce off-target irradiation in CNS tumors due to the intrinsic properties of heavy-particle irradiation. Here, we review currently available data examining the used of PT in glioma patients, including dose escalation for GBM, re-irradiation (reRT) of recurrent glioma, and the potential cognitive sparing effects of conventional dose PT. We discuss the incorporation of PT into the multimodal therapy of GBM patients, and how the aggressive nature of the disease poses a unique challenge to PT study design. We also describe how PT may provide the most feasible method for implementing high rate FLASH RT and the implications for glioma patients. We conclude with a discussion of ongoing clinical trials, the necessity of continued research, and how we interpret and incorporate available data into our current practice.

A high-density 3-dimensional culture model of human glioblastoma for rapid screening of therapeutic resistance.

Glioblastoma is among the most lethal cancers, with no known cure. A multitude of therapeutics are being developed or in clinical trials, but currently there are no ways to predict which patient may benefit the most from which drug. Assays that allow prediction of the tumors response to anti-cancer drugs may improve clinical decision-making. Here, we present a high-density 3D primary cell culture model for short-term testing from resected glioblastoma tissue that is set up on the day of surgery, established within 7 days and viable for at least 3 weeks. High-density 3D cultures contain tumor and host cells, including microglia, and retain key histopathological characteristics of their parent tumors, including proliferative activity, expression of the marker GFAP, and presence of giant cells. This provides a proof-of-concept that 3D primary cultures may be useful to model tumor heterogeneity. Importantly, we show that high-density 3D cultures can be used to test chemotherapy response within a 2-3-week timeframe and are predictive of patient response to Temozolomide therapy. Thus, primary high-density 3D cultures could be a useful tool for brain cancer research and prediction of therapeutic resistance.

Antisense-oligonucleotide co-micelles with tumor targeting peptides elicit therapeutic effects by inhibiting microRNA-21 in the glioblastoma animal models.

miRNA-21 (miR-21) is highly expressed in glioblastoma, facilitating tumor growth by blocking the expression of apoptosis-related genes. Therefore, an antisense microRNA oligonucleotide (AMO) against miR-21 was suggested as a therapeutic nucleic acid for glioblastoma. AMO21 co-micelles were developed with tumor-targeting T7 peptides as an AMO21 delivery system by intranasal administration. Cholesterol-conjugated AMO21 (AMO21c) was mixed with cholesterol-conjugated T7 peptides (T7c) to produce tumor-targeted co-micelles. Physical characterization was performed by dynamic light scattering, gel retardation assay, scanning electron microscope and heparin competition assay. In vitro transfection efficiency to C6 glioblastoma cells was measured by flow cytometry. The AMO21cT7c co-micelles were administered by intranasal instillation into the brain of intracranial glioblastoma rat models. Scrambled T7 (scrT7) and scrambled AMO21c (scrAMO21c) were used as a negative control. The therapeutic effects of the AMO21cT7c co-micelles were evaluated by real time RT-PCR, immunohistochemistry, TUNEL assay, and Nissl staining. The formation of the AMO21cT7c co-micelles was confirmed in gel retardation and heparin competition assays. The highest delivery efficiency in vitro was achieved at a 110 wt ratio of AMO21cT7c. The AMO21cT7c co-micelles had higher delivery efficiency into C6 glioblastoma cells than naked AMO21c or AMO21clipofectamine complexes. After intranasal administration into the intracranial glioblastoma models, the delivery efficiency of the co-micelles into the brain was also higher than those of naked AMO21c and AMO21cscrambled T7c. Thanks to their enhanced delivery efficiency, the AMO21cT7c co-micelles downregulated miR-21, inducing the production of the pro-apoptotic phosphatase and tensin homolog (PTEN) and programmed cell death 4 (PDCD4) proteins in the tumor tissues. The tumor size was reduced by the AMO21cT7c co-micelles more effectively than naked AMO21c, AMO21clipofectamine, or scrAMO21cT7c treatment. The results suggest that the co-micelles of AMO21c and T7c may be an efficient delivery system into a brain tumor through intranasal administration.

EANO guideline on rational molecular testing of gliomas, glioneuronal and neuronal tumors in adults for targeted therapy selection.

The mainstay of treatment for adult patients with gliomas, glioneuronal and neuronal tumors consists of combinations of surgery, radiotherapy and chemotherapy. For many systemic cancers, targeted treatments are a part of standard of care, however the predictive significance of most of these targets in CNS tumors remains less well studied. Despite that, there is an increasing use of advanced molecular diagnostics that identify potential targets, and tumor agnostic regulatory approvals on targets also present in CNS tumors have been granted. This raises the question when and for which targets it is meaningful to test in adult patients with CNS tumors. This evidence based guideline reviews the evidence available for targeted treatment for alterations in the RASMAPK pathway (BRAF, NF1), in growth factor receptors (EGFR, ALK, FGFR, NTRK, PDGFRA, ROS1), in cell cycle signaling (CDK46, MDM24, TSC12) and altered genomic stability (mismatch repair, POLE, high TMB, HRD) in adult patients with gliomas, glioneuronal and neuronal tumors. At present, targeted treatment for BRAF p.V600E alterations is to be considered part of standard of care for patients with recurrent gliomas, pending regulatory approval. For approved tumor agnostic treatments for NTRK fusions and high TMB, the evidence for efficacy in adult patients with CNS tumors is very limited, and treatment should preferably be given within prospective clinical registries and trials. For targeted treatment of CNS tumors with FGFR fusions or mutations, clinical trials are ongoing to confirm modest activity so far observed in basket trials. For all other reviewed targets, evidence of benefit in CNS tumors is currently lacking, and testingtreatment should be in the context of available clinical trials.

Hypoxia-induced ROS aggravate tumor progression through HIF-1α-SERPINE1 signaling in glioblastoma.

Hypoxia, as an important hallmark of the tumor microenvironment, is a major cause of oxidative stress and plays a central role in various malignant tumors, including glioblastoma. Elevated reactive oxygen species (ROS) in a hypoxic microenvironment promote glioblastoma progression however, the underlying mechanism has not been clarified. Herein, we found that hypoxia promoted ROS production, and the proliferation, migration, and invasion of glioblastoma cells, while this promotion was restrained by ROS scavengers

Spatial transcriptome analysis of long non-coding RNAs reveals tissue specificity and functional roles in cancer.

Long non-coding RNAs (lncRNAs) play a significant role in maintaining tissue morphology and functions, and their precise regulatory effectiveness is closely related to expression patterns. However, the spatial expression patterns of lncRNAs in humans are poorly characterized. Here, we constructed five comprehensive transcriptomic atlases of human lncRNAs covering thousands of major tissue samples in normal and disease states. The lncRNA transcriptomes exhibited high consistency within the same tissues across resources, and even higher complexity in specialized tissues. Tissue-elevated (TE) lncRNAs were identified in each resource and robust TE lncRNAs were refined by integrative analysis. We detected 1 to 4684 robust TE lncRNAs across tissues the highest number was in testis tissue, followed by brain tissue. Functional analyses of TE lncRNAs indicated important roles in corresponding tissue-related pathways. Moreover, we found that the expression features of robust TE lncRNAs made them be effective biomarkers to distinguish tissues TE lncRNAs also tended to be associated with cancer, and exhibited differential expression or were correlated with patient survival. In summary, spatial classification of lncRNAs is the starting point for elucidating the function of lncRNAs in both maintenance of tissue morphology and progress of tissue-constricted diseases.

Resection of supratentorial brain metastases with intraoperative radiotherapy. Is it safe Analysis and experiences of a single center cohort.

Intraoperative Radiotherapy (ioRT) is an emerging treatment option in oncologic surgery for various diseases including intraaxial brain lesions to improve surgical outcome and accelerate the adjuvant oncologic therapy. Despite its use in glioma surgery, the application and data regarding ioRT in the treatment of brain metastases (BMs) is sparse. Here were report the largest series of supratentorial BMs treated with resection and ioRT according to functional outcome and adverse events. We performed a retrospective chart review analysis of patients undergoing surgery for BMs following an interdisciplinary tumor board decision in every case with ioRT at our institution. Patient properties, functional status (Karnofsky Performance ScoreKPS) before and after surgery as well as oncologic (disease, recursive partitioning analysis, lesion size) and operative parameters were analyzed until hospital discharge. Adverse events (AE) were recorded until 30 days after surgery and rated according to the Clavien Dindo Grading (CDG) scale. 70 patients (40 female) with various oncologic diseases were identified and analyzed. Six underwent prior RT. Mean age was 66 ± 11 years. Preoperative median KPS was 80% with a mean BM volume of 3.2 ± 1.2 cm Surgery for supratentorial BMs with ioRT seems safe and feasible. Further studies on the benefit regarding oncologic outcome need to be performed.

Positive Expression of Retinol-Binding Protein 4 Is Related to the Malignant Clinical Features Leading to Poor Prognosis of Glioblastoma.

Retinol-binding protein 4 (RBP4) is a monomeric-binding protein belonging to the lipocalin protein family, which has been reported to be dysregulated in several malignancies such as breast cancer and lung cancer. However, the expression and function of RBP4 in glioblastoma (GBM) are completely unknown. TCGA datasets were used for analyzing the mRNA level of RBP4 in GBM and its clinical relevance. A retrospective GBM cohort ( Both the higher mRNA level and protein level of RBP4 in GBM tissues were significantly correlated with poorer patients overall survival. Multivariate analysis identified RBP4 as a novel independent prognostic predictor in GBM patients. Overexpression of RBP4 resulted in enhanced GBM proliferation capacity, which was consistent with clinical findings on the positive correlation between RBP4 level and tumor size. Meanwhile, overexpressing RBP4 promoted GBM cell migration and invasion, while silencing RBP4 led to the opposite results. RBP4 overexpression in tumor tissues is correlated with poorer prognosis of GBM patients, which functions by promoting GBM proliferation and invasion, thus, may serve as an invaluable predictive biomarker and therapeutic target.

Subungual Metastasis from Ovarian Cancer Case Report and Brief Review of the Literature.

Visceral solid cancers can metastasize in almost any organ, including the skin and its appendages. We report here the case of a 19-year-old Caucasian girl carrying a diagnosis of malignant germ cell tumor of the ovary, with pulmonary and brain metastases, that developed a painful red-violaceous subungual papule of the 4th finger of the left hand, associated with an over-curvature of the nail plate. Dermoscopy was characterized initially by different shades of pink and red, while after few weeks, it showed black pigmentation due to subcorneal hematomas, hemorrhagic crusts, and a rainbow pattern. Histology confirmed a diagnosis of a metastasis from a poorly differentiated carcinoma of ovarian origin. A brief review on the diagnosis and treatment of subungual metastases is reported.

Identifying new biomarkers of aggressive Group 3 and SHH medulloblastoma using 3D hydrogel models, single cell RNA sequencing and 3D OrbiSIMS imaging.

The most common malignant brain tumour in children, medulloblastoma (MB), is subdivided into four clinically relevant molecular subgroups, although targeted therapy options informed by understanding of different cellular features are lacking. Here, by comparing the most aggressive subgroup (Group 3) with the intermediate (SHH) subgroup, we identify crucial differences in tumour heterogeneity, including unique metabolism-driven subpopulations in Group 3 and matrix-producing subpopulations in SHH. To analyse tumour heterogeneity, we profiled individual tumour nodules at the cellular level in 3D MB hydrogel models, which recapitulate subgroup specific phenotypes, by single cell RNA sequencing (scRNAseq) and 3D OrbiTrap Secondary Ion Mass Spectrometry (3D OrbiSIMS) imaging. In addition to identifying known metabolites characteristic of MB, we observed intra- and internodular heterogeneity and identified subgroup-specific tumour subpopulations. We showed that extracellular matrix factors and adhesion pathways defined unique SHH subpopulations, and made up a distinct shell-like structure of sulphur-containing species, comprising a combination of small leucine-rich proteoglycans (SLRPs) including the collagen organiser lumican. In contrast, the Group 3 tumour model was characterized by multiple subpopulations with greatly enhanced oxidative phosphorylation and tricarboxylic acid (TCA) cycle activity. Extensive TCA cycle metabolite measurements revealed very high levels of succinate and fumarate with malate levels almost undetectable particularly in Group 3 tumour models. In patients, high fumarate levels (NMR spectroscopy) alongside activated stress response pathways and high Nuclear Factor Erythroid 2-Related Factor 2 (NRF2 gene expression analyses) were associated with poorer survival. Based on these findings we predicted and confirmed that NRF2 inhibition increased sensitivity to vincristine in a long-term 3D drug treatment assay of Group 3 MB. Thus, by combining scRNAseq and 3D OrbiSIMS in a relevant model system we were able to define MB subgroup heterogeneity at the single cell level and elucidate new druggable biomarkers for aggressive Group 3 and low-risk SHH MB.

Brain magnetic resonance spectroscopy to differentiate recurrent neoplasm from radiation necrosis A systematic review and meta-analysis.

Postradiation treatment necrosis is one of the most serious late sequelae and appears within 6 months. The magnetic resonance spectroscopy imaging (MRSI) has been used for the detection of brain tumors. The study aimed to determine the radiological accuracy and efficacy in distinguishing recurrent brain tumor from radiation-induced necrosis by identifying pseudoprogression. The research was performed in accordance with the preferred reporting items for systematic review and meta-analysis guidelines. International electronic databases including 15 English sources were investigated. A total of 4281 papers with 2159 citations from 15 databases from 2011 to 2021 met the search strategies of magnetic resonance (MR) spectroscopy in recurrent brain tumors and postradiation necrosis. Nine studies were enrolled in the meta-analysis with a total of 354 patients (203 male and 151 female) whose average age ranged from 4 to 74 years. Anbarloui et al., Elias et al., Nemattalla et al., Smith et al., Zeng et al., and Weybright et al. showed strong evidence of heterogeneity regarding cholineN-acetylaspartate (ChoNAA) ratio in the evaluation of the nine studies. Elias et al., Nemattalla et al., Bobek-Billewicz et al., and Smith et al. showed a high heterogeneity in Chocreatine (Cr) ratio. Elias et al., Nemattalla et al., Smith et al., and Weybright et al. revealed high heterogeneity in NAACr ratio estimates. MR spectroscopy is effective in distinguishing recurrent brain tumors from necrosis. Our meta-analysis revealed that ChoNAA, ChoCr, and NAACr ratios were significantly better predictor of detected recurrent tumor. Therefore, the MRSI is an informative tool in the distinction of tumor recurrence versus necrosis.

Geometric and dosimetric consequences of intra-fractional movement in single isocenter non-coplanar stereotactic radiosurgery.

To investigate the geometric and dosimetric impacts of intra-fractional movement for patients with single or multiple brain metastasis treated using Varian Hyperarc™ mono-isocentric radiosurgery. A total of 50 single or hypo-fractionated Hyperarc™ treatment courses (118 lesions) were included in the analysis. Intra-fractional translational and rotational movements were quantified according to the post-treatment cone-beam CT (CBCT). Geometric displacements of all targets were calculated individually based on the assessed head movement in each treatment fraction and their relationships with treatment time and target-to-isocenter distances were studied. For dosimetric analysis, only single-fraction treatments (56 lesions) were included. Re-planning was performed with 0, 1, and 2 mm planning target volume (PTV) margins. Doses were then re-calculated on rotated CT images with isocenter shifted which emulate the change in patient treatment position. Target coverage, target and normal brain doses before and after intra-fractional movement were compared. The mean 3D target displacements was 0.6 ± 0.3 (SD) mm. Target shifts for patients treated within 10 min were significantly smaller than those treated in longer sessions. No correlation was found between target shift and target-to-isocenter distance as the origin of head rotation was not located at the isocenter. Loss of target coverage and minimum Gross Tumor Volume (GTV) dose due to intra-fractional movement were apparent only when no margin was used, leading to an extra 23% of the targets violating the dose acceptance criteria, in contrast, the effects on normal brain V Although intra-fractional movements during Hyperarc™ treatments were small, there were substantial dosimetric effects due to the sharp dose fall-off near target boundaries. These effects could be mitigated by using a 1 mm PTV margin and maintaining the effective treatment time to within 10 min.

A case of pituitary gland abscess associated with granulomatous hypophysitis.

Granulomatous hypophysitis is a rare disease that presents with chronic inflammation of the pituitary gland. In this study, we reported a case of granulomatous hypophysitis associated with a pituitary abscess. A 39-year-old woman presented with a 2-year history of infertility. For the past six months, she has suffered from amenorrhea, decreased libido, headaches, and vertigo. She was referred to our hospital with a suspected diagnosis of nonfunctioning pituitary adenoma based on her presentation and brain MRI findings. She underwent trans-sphenoidal surgery (TSS). Direct observation during surgery revealed drainage of malodor pus and pituitary gland abscess. The histopathological evaluation also showed granulomatous hypophysitis and neutrophilic microabscess formation. The patient was initially treated with high doses of ceftriaxone (2 g twice daily) and metronidazole (500 mg (mg) four times per day). Also, the patient received cortisol replacement therapy after the operation. After obtaining the antibiogram and culture results, the treatment regimen was continued for 4 weeks postoperatively, followed by amoxicillin-clavulanate (500125 mg three times daily) for a total duration of 12 weeks. The patient recovered uneventfully and the postoperative MRI was normal without any remnant lesions.

Serum complement proteins rather than inflammatory factors is effective in predicting psychosis in individuals at clinical high risk.

Immunologicalinflammatory factors are implicated in the development of psychosis. Complement is a key driver of inflammation however, it remains unknown which factor is better at predicting the onset of psychosis. This study aimed to compare the alteration and predictive performance of inflammation and complement in individuals at clinical high risk (CHR). We enrolled 49 individuals at CHR and 26 healthy controls (HCs). Twenty-five patients at CHR had converted to psychosis (converter) by the 3-year follow-up. Inflammatory cytokines, including interleukin (IL)-1β, 6, 8, 10, tumor necrosis factor-alpha (TNF-alpha), macrophage colony-stimulating factor levels, and complement proteins (C1q, C2, C3, C3b, C4, C4b, C5, C5a, factor B, D, I, H) were measured by enzyme-linked immunosorbent assay at baseline. Except for TNF- alpha, none of the inflammatory cytokines reached a significant level in either the comparison of CHR individuals and HC or between CHR-converters and non-converters. The C5, C3, D, I, and H levels were significantly lower (C5, p 0.006 C3, p 0.009 D, p 0.026 I, p 0.016 H, p 0.019) in the CHR group than in the HC group. Compared to non-converters, converters had significantly lower levels of C5 (p 0.012) and C5a (p 0.007). None of the inflammatory factors, but many complement factors, showed significant correlations with changes in general function and symptoms. None of the inflammatory markers, except for C5a and C5, were significant in the discrimination of conversion outcomes in CHR individuals. Our results suggest that altered complement levels in the CHR population are more associated with conversion to psychosis than inflammatory factors. Therefore, an activated complement system may precede the first-episode of psychosis and contribute to neurological pathogenesis at the CHR stage.

Rationally designed donepezil-based hydroxamates modulate Sig-1R and HDAC isoforms to exert anti-glioblastoma effects.

The pursuit of activating the HDAC inhibitory template towards additional mechanisms spurred us to design dual modulators (Sig-1R agonist - HDAC inhibitor) via utilization of the core structural unit of donepezil (an FDA-approved anti-Alzheimers agent) as a surface recognition part. Literature precedents coupled with our experience rendered us with several insights that led to the inclusion of chemically diverse linkers and hydroxamic acid (zinc-binding motif) as the other components of HDAC inhibitory pharmacophore. With this envisionment and clarity, donepezil-based HDAC inhibitory adducts were furnished and exhaustively explored for their anti-GBM efficacy. Resultantly, a magnificently potent HDAC inhibitor 10 IC

Contraception in breast cancer survivors from the FEERIC case-control study (performed on behalf of the Seintinelles research network).

To compare the prevalence of contraception in breast cancer (BC) patients at risk of unintentional pregnancy (i.e. not currently pregnant or trying to get pregnant) and matched controls. The FEERIC study (Fertility, Pregnancy, Contraception after BC in France) is a prospective, multicenter case-control study, including localized BC patients aged 18-43 years, matched for age and parity to cancer-free volunteer controls in a 12 ratio. Data were collected through online questionnaires completed on the Seintinelles research platform. In a population of 1278 women at risk of unintentional pregnancy, the prevalence of contraception at study inclusion did not differ significantly between cases (340431, 78.9%) and controls (666847, 78.6%, p 0.97). Contrarily, the contraceptive methods used were significantly different, with a higher proportion of copper IUD use in BC survivors (59.5% versus 25.0% in controls p < 0.001). For patients at risk of unintentional pregnancy, receiving information about chemotherapy-induced ovary damage at BC diagnosis (OR 2.47 95%CI 1.39-4.37 and anti-HER2 treatment (OR 2.46, 95% CI 1.14-6.16) were significantly associated with the use of a contraception in multivariate analysis. In this large French study, BC survivors had a prevalence of contraception use similar to that for matched controls, though almost one in five women at risk of unintentional pregnancy did not use contraception. Dedicated consultations at cancer care centers could further improve access to information and contraception counseling.

Impact of nanoparticles on amyloid β-induced Alzheimers disease, tuberculosis, leprosy and cancer a systematic review.

Nanotechnology is an interdisciplinary domain of science, technology and engineering that deals with nano-sized materialsparticles. Usually, the size of nanoparticles lies between 1 and 100 nm. Due to their small size and large surface area-to-volume ratio, nanoparticles exhibit high reactivity, greater stability and adsorption capacity. These important physicochemical properties attract scientific community to utilize them in biomedical field. Various types of nanoparticles (inorganic and organic) have broad applications in medical field ranging from imaging to gene therapy. These are also effective drug carriers. In recent times, nanoparticles are utilized to circumvent different treatment limitations. For example, the ability of nanoparticles to cross the blood-brain barrier and having a certain degree of specificity towards amyloid deposits makes themselves important candidates for the treatment of Alzheimers disease. Furthermore, nanotechnology has been used extensively to overcome several pertinent issues like drug-resistance phenomenon, side effects of conventional drugs and targeted drug delivery issue in leprosy, tuberculosis and cancer. Thus, in this review, the application of different nanoparticles for the treatment of these four important diseases (Alzheimers disease, tuberculosis, leprosy and cancer) as well as for the effective delivery of drugs used in these diseases has been presented systematically. Although nanoformulations have many advantages over traditional therapeutics for treating these diseases, nanotoxicity is a major concern that has been discussed subsequently. Lastly, we have presented the promising future prospective of nanoparticles as alternative therapeutics. In that section, we have discussed about the futuristic approach(es) that could provide promising candidate(s) for the treatment of these four diseases.

Clinical outcome of patients with isolated central nervous system progression on first-line pertuzumab and trastuzumab treatment for HER2-positive metastatic breast cancer in a real-life cohort.

More than 10% of HER2-positive metastatic breast cancer (mBC) will develop Central Nervous System (CNS) metastases as first and isolated site of relapse on trastuzumab and pertuzumab first-line therapy. However, few clinical data are available to guide the best strategy in this setting. Patients experiencing isolated CNS progression on trastuzumab and pertuzumab first-line therapy were retrospectively identified from the French Epidemiological Strategy and Medical Economics (ESME) real-life database between 2008 and 2016. Among 995 patients treated with first-line trastuzumab and pertuzumab for HER2-positive mBC, 132 patients (13%) experienced isolated CNS progression with a median time of 12 months after mBC diagnosis. Twelves patients did not receive any treatment and were excluded from the analysis. Among the 120 patients considered, 76 (63%) received CNS-directed local therapy, 73 (60%) continued trastuzumab and pertuzumab, whereas 47 (39%) started another systemic treatment. After a median follow-up of 21 months, there was no difference in progression-free survival for patient who continued trastuzumab-pertuzumab or switched to another systemic treatment. In multivariate analysis, trastuzumab-pertuzumab continuation was associated with longer OS (HR 0,28 IC 95% 0,14-0,54 p < 0,001). mOS was not reached (95% 37.6-NE) and was 23.2 months (95% CI 15.5-53.6) in patients who continued trastuzumab and pertuzumab therapy and in patients who switched for another systemic therapy, respectively. In this real-life cohort, trastuzumab-pertuzumab continuation after local treatment for isolated CNS progression did not negatively impact PFS and OS. Prospective trials and assessment of new strategies are warranted in this specific situation.

Short and long-term prognostic value of intraoperative motor evoked potentials in brain tumor patients a case series of 121 brain tumor patients.

Iatrogenic neurologic deficits adversely affect patient outcomes following brain tumor resection. Motor evoked potential (MEP) monitoring allows surgeons to assess the integrity of motor-eloquent areas in real-time during tumor resection to lessen the risk of iatrogenic insult. We retrospectively associate intraoperative transcranial and direct cortical MEPs (TC-MEPs, DC-MEPs) to early and late post-operative motor function to prognosticate short- and long-term motor recovery in brain tumor patients undergoing surgical resection in peri-eloquent regions. We reviewed 121 brain tumor patients undergoing craniotomies with DC-MEP andor TC-MEP monitoring. Motor function scores were recorded at multiple time-points up to 1 year postoperatively. Sensitivity, specificity, and positive and negative predictive values (PPV, NPV) were calculated at each time point. The sensitivity, specificity, PPV, and NPV of TC-MEP in the immediate postoperative period was 17.5%, 100%, 100%, and 69.4%, respectively. For DC-MEP monitoring, the respective values were 25.0%, 100%, 100%, and 68.8%. By discharge, sensitivity had increased for both TC-MEP and DC MEPs to 43.8%, and 50.0% respectively. Subset analysis on patients without tumor recurrenceprogression at long term follow-up (n 62 pts, 51.2%) found that all patients with stable monitoring maintained or improved from preoperative status. One patient with transient intraoperative TC-MEP loss and permanent DC-MEP loss suffered a permanent deficit. Brain tumor patients who undergo surgery with intact MEP monitoring and experience new postoperative deficits likely suffer transient deficits that will improve over the postoperative course in the absence of disease progression.

A multiphoton transition activated iron based metal organic framework for synergistic therapy of photodynamic therapychemodynamic therapychemotherapy for orthotopic gliomas.

Although photodynamic therapy (PDT) has exhibited good potential in therapy of gliomas, the limited penetration depth of light and the obstacle of the blood-brain barrier (BBB) lead to unsatisfactory treatment effects. Herein, a multifunctional nanodrug (UMD) was constructed with up-conversion nanoparticles (NaGdF

Prognosis prediction and risk factors for triple-negative breast cancer patients with brain metastasis A population-based study.

Brain metastasis (BM) in triple-negative breast cancer (TNBC) patients is associated with significant morbidity and mortality. In this research we aimed to develop a nomogram to predict the prognosis of TNBC patients with BMs (TNBC-BM) and explore the potential risk factors. We used data from the Surveillance, Epidemiology, and End Results (SEER) database. A prognostic nomogram was built and validated based on patients with BM at newly diagnosed TNBC (nTNBC-BM). Its effect on TNBC patients with BM was also validated in an extended group. The prognostic effect of treatment and risk factors for nTNBC-BM were further tested. A nomogram was constructed and validated to predict overall survival (OS) in TNBC-BM patients. For patients with BM diagnosed at the initial treatment or later course, the C-index (0.707, 0.801, and 0.685 in the training, validation, and extended groups, respectively) and calibration plots showed the acceptable prognostic accuracy and clinical applicability of the model. Surgery on the primary tumor and chemotherapy were found to confer significantly better OS (11 months vs. 4 months 5 months vs. 3 months, respectively). In addition, advanced tumornodal stage and bilateral cancer were associated with a higher risk of nTNBC-BM. We developed a sensitive and discriminative nomogram to predict OS in TNBC-BM patients, both at initial diagnosis and the latter course. nTNBC-BM patients may benefit more from surgery and chemotherapy than from radiotherapy. In addition, in the predictive model, TNBC patients harboring advanced tumornodal stages and bilateral tumors were more likely to have BM at initial diagnosis.

A review on microrobots driven by optical and magnetic fields.

Due to their small sizes, microrobots are advantageous for accessing hard-to-reach spaces for delivery and measurement. However, their small sizes also bring challenges in on-board powering, thus usually requiring actuation by external energy. Microrobots actuated by external energy have been applied to the fields of physics, biology, medical science, and engineering. Among these actuation sources, light and magnetic fields show advantages in high precision and high biocompatibility. This paper reviews the recent advances in the design, actuation, and applications of microrobots driven by light and magnetic fields. For light-driven microrobots, we summarized the uses of optical tweezers, optoelectronic tweezers, and heat-mediated optical manipulation techniques. For magnetically driven microrobots, we summarized the uses of torque-driven microrobots, force-driven microrobots, and shape-deformable microrobots. Then, we compared the two types of field-driven microrobots and reviewed their advantages and disadvantages. The paper concludes with an outlook for the joint use of optical and magnetic field actuation in microrobots.

Oligodendroglioma metastasizing to cervical lymph node Rare entity diagnosed on fine-needle aspiration cytology.

Extra neural metastasis of central nervous system oligodendroglioma is very rare. Oligodendroglioma is the seventh most frequently occurring neoplasm of central nervous system (CNS) with metastasis outside the CNS. According to literature, presence of metastasis in CNS was most frequently detected in patients of glioblastoma (41.4%), medulloblastoma (26.7%), ependymomas (16.4%), astrocytoma (10.3%) and oligodendroglioma (5.27%). A 38-year-old male patient presented with loss of vision and swelling on left side of neck since last 1 week measuring 3 x 2 cm. He was operated for brain tumor 7 years back, which was diagnosed as oligodendroglioma. Ultrasound sonography revealed multiple hypoechoic lymph nodes in bilateral cervical region largest measuring 4.5 x 1.9 cm in left submandibular region. FNA of left submandibular lymph node was done, which revealed deposits of poorly differentiated malignancy. Cell block was prepared for carrying out ancillary studies which showed positivity for glial fibrillary acidic protein (GFAP), S-100 and negativity for cytokeratin (CK), epithelial membrane antigen (EMA), LCA and progesterone receptor (PR). Based on previous history of oligodendroglioma, cytological and immunohistochemistry (IHC) findings a diagnosis of metastatic oligodendroglioma was made. Metastasis of oligodendroglioma to cervical lymph node should also be considered as one of the differential diagnoses. Diagnosing metastatic CNS tumor is extremely challenging for pathologists. It is essential to have the clinical information of a previous CNS tumor, including the histologic type and immunophenotype. Besides common malignancies of cervical lymph node, we should also think of CNS metastasis so that patient management will be early and proper.

Dosimetric evaluation of iodine-125 brachytherapy for brain tumors using MR guidance combined with a three-dimensional non co-planar template.

To investigate the consistency between preoperative and postoperative dosimetry when Thirty patients with brain tumors (metastatic or gliomas) underwent radioactive All mean postoperative dosimetries were calculated. Target coverage parameters D90, D100, %CTV100, %CTV150, and %CTV200 were 143.6 cGy, 76.6 cGy, 88.2%, 63.1%, and 41.4%, respectively. The values of implant quality indices CI, EI, and HI were 0.75, 0.14, and 0.28, respectively. No significant differences between most preoperative and postoperative dosimetric parameters were found (p > 0.05). The differences were also insignificant for organs at risk. Postoperative %CTV150 and %CTV200 were higher than the preoperative, whereas postoperative HI was significantly lower than in the treatment plan. Magnetic resonance guidance combined with 3DNPT allows accurate positioning and direction in

Virtual Trials Causally-validated treatment effects efficiently learned from an observational cancer registry.

Randomized controlled trials (RCTs) offer a clear causal interpretation of treatment effects, but are inefficient in terms of information gain per patient. Moreover, because they are intended to test cohort-level effects, RCTs rarely provide information to support precision medicine, which strives to choose the best treatment for an individual patient. If causal information could be efficiently extracted from widely available real-world data, the rapidity of treatment validation could be increased, and its costs reduced. Moreover, inferences could be made across larger, more diverse patient populations. We created a virtual trial by fitting a multilevel Bayesian survival model to treatment and outcome records self-reported by 451 brain cancer patients. The model recovers group-level treatment effects comparable to RCTs representing over 3200 patients. The model additionally discovers the feature-treatment interactions needed to make individual-level predictions for precision medicine. By learning from heterogeneous real-world data, virtual trials can generate more causal estimates with fewer patients than RCTs, and they can do so without artificially limiting the patient population. This demonstrates the value of virtual trials as a complement to large randomized controlled trials, especially in highly heterogeneous or rare diseases.

How many brain metastases can be treated with stereotactic radiosurgery before the radiation dose delivered to normal brain tissue rivals that associated with standard whole brain radiotherapy

Clinical trial data comparing outcomes after administration of stereotactic radiosurgery (SRS) or whole-brain radiotherapy (WBRT) to patients with brain metastases (BM) suggest that SRS better preserves cognitive function and quality of life without negatively impacting overall survival. Here, we estimate the maximum number of BM that can be treated using single and multi-session SRS while limiting the dose of radiation delivered to normal brain tissue to that associated with WBRT. Multiple-tumor SRS was simulated using a Monte Carlo - type approach and a pre-calculated dose kernel method. Tumors with diameters ≤36 mm were randomly placed throughout the contoured brain parenchyma until the brain mean dose reached 3 Gy, equivalent to the radiation dose delivered during a single fraction of a standard course of WBRT (a total dose of 30 Gy in 10 daily fractions of 3 Gy). Distribution of tumor sizes, dose coverage, selectivity, normalization, and maximum dose data used in the simulations were based on institutional clinical metastases data. The mean number of tumors treated, mean volume of healthy brain tissue receiving > 12 Gy (V12) per tumor, and total tumor volume treated using mixed tumor size distributions were 12.7 ± 4.2, 2.2 cc, and 12.9 cc, respectively. Thus, we estimate that treating 12-13 tumors per day over 10 days would deliver the dose of radiation to healthy brain tissue typically associated with a standard course of WBRT. Although in clinical practice, treatment with SRS is often limited to patients with ≤15 BM, our findings suggest that many more lesions could be targeted while still minimizing the negative impacts on quality of life and neurocognition often associated with WBRT. Results from this in silico analysis require clinical validation.

2,2-((1R,3R,4S)-4-methyl-4-vinylcyclohexane-1,3-diyl) bis(prop-2-en-1-amine), a bisamino derivative of β-Elemene, inhibits glioblastoma growth through downregulation of YAP signaling.

β-Elemene, a compound extracted from Chinese herb

Aberrant Notch signaling in gliomas a potential landscape of actionable converging targets for combination approach in therapies resistance.

The current therapeutic protocols and prognosis of gliomas still depend on clinicopathologic and radiographic characteristics. For high-grade gliomas, the standard of care is resection followed by radiotherapy plus temozolomide chemotherapy. However, treatment resistance develops due to different mechanisms, among which is the dynamic interplay between the tumor and its microenvironment. Different signaling pathways cause the proliferation of so-called glioma stem cells, a minor cancer cell population with stem cell-like characteristics and aggressive phenotype. In the last decades, numerous studies have indicated that Notch is a crucial pathway that maintains the characteristics of resistant glioma stem cells. Data obtained from preclinical models indicate that downregulation of the Notch pathway could induce multifaceted drug sensitivity, acting on the expression of drug-transporter proteins, inducing epithelial-mesenchymal transition, and shaping the tumor microenvironment. This review provides a brief overview of the published data supporting the roles of Notch in drug resistance and demonstrates how potential novel strategies targeting Notch could become an efficacious action to improve the therapy of high-grade glioma to overcome drug resistance.

Gut microbiota in brain tumors An emerging crucial player.

In recent decades, various roles of the gut microbiota in physiological and pathological conditions have been uncovered. Among the many interacting pathways between the host and gut flora, the gut-brain axis has drawn increasing attention and is generally considered a promising way to understand and treat brain tumors, one of the most lethal neoplasms. In this narrative review, we aimed to unveil and dissect the sophisticated mechanisms by which the gut-brain axis exerts its influence on brain tumors. Furthermore, we summarized the latest research regarding the gastrointestinal microbial landscape and the effect of gut-brain axis malfunction on different brain tumors. Finally, we outlined the ongoing developing approaches of microbial manipulation and their corresponding research related to neuro-malignancies. Collectively, we recapitulated the advances in gut microbial alterations along with their potential interactive mechanisms in brain tumors and encouraged increased efforts in this area.

Acute toxicities and cumulative dose to the brain of repeated sessions of stereotactic radiotherapy (SRT) for brain metastases a retrospective study of 184 patients.

Stereotactic radiation therapy (SRT) is a focal treatment for brain metastases (BMs) thus, 20 to 40% of patients will require salvage treatment after an initial SRT session, either because of local or distant failure. SRT is not exempt from acute toxicity, and the acute toxicities of repeated SRT are not well known. The objective of this study was to analyze the acute toxicities of repeated courses of SRT and to determine whether repeated SRT could lead to cumulative brain doses equivalent to those of whole-brain radiotherapy (WBRT). Between 2010 and 2020, data from 184 patients treated for 915 BMs via two to six SRT sessions for local or distant BM recurrence without previous or intercurrent WBRT were retrospectively reviewed. Patients were seen via consultations during SRT, and the delivered dose, the use of corticosteroid therapy and neurological symptoms were recorded and rated according to the CTCAEv4. The dosimetric characteristics of 79% of BMs were collected, and summation plans of 76.6% of BMs were created. 36% of patients developed acute toxicity during at least one session. No grade three or four toxicity was registered, and grade one or two cephalalgy was the most frequently reported symptom. There was no significant difference in the occurrence of acute toxicity between consecutive SRT sessions. In the multivariate analysis, acute toxicity was associated with the use of corticosteroid therapy before irradiation (OR 2.6 p 0.01), BMV grade (high vs. low grade OR 5.17 p 0.02), and number of SRT sessions (3 SRT vs. 2 SRT OR 2.64 p 0.01). The median volume equivalent to the WBRT dose (V Repeated SRT for local or distant recurrent BM is well tolerated, without grade three or four toxicity, and does not cause more acute neurological toxicity with repeated SRT sessions. Moreover, even for patients treated for more than ten BMs, the V

Dosimetric quality of HyperArc in boost radiotherapy for single glioblastoma comparison with CyberKnife and manual VMAT.

Stereotactic radiotherapy (SRT) and hypo-fractionated radiotherapy are feasible treatment options for single glioblastoma multiforme when combined with conventional radiotherapy or delivered alone. HyperArc (HA), a novel linac-based method with 4 noncoplanar arcs, has been introduced into stereotactic radiosurgery (SRS) for single and multiple metastases. In this study, we compared the dosimetric quality of HyperArc with the well-established CyberKnife (CK) and conventional VMAT methods of SRT for a single, large target. Sixteen patients treated in our center with their clinical CK plans were enrolled, and the linac-based plans were designed in silico. From the aspect of normal tissue protection and treatment efficacy, we compared the conformity index (CI), gradient index (GI), homogeneity index (HI), dose distribution in planning target volume, dose in the normal brain tissue, and mean dose of several organs at risk (OARs). All of the data were evaluated with nonparametric Kruskal‒Wallis tests. We further investigated the relationship of the dose distribution with the tumor volume and its location. The results showed that with a higher CI (0.94 ± 0.03) and lower GI (2.57 ± 0.53), the HA plans generated a lower dose to the OARs and the normal tissue. Meanwhile, the CK plans achieved a higher HI (0.35 ± 0.10) and generated a higher dose inside the tumor. Although manual VMAT showed slight improvement in dose quality and less monitoring units (2083 ± 225), HA can save half of the delivery time of CK (37 minutes) on average. HA plans have higher conformity and spare OARs with lower normal tissue irradiation, while CK plans achieve a higher mean dose in tumors. HA with 4 arcs is sufficient in dosimetric quality for a single tumor with great convenience in planning and treatment processes compared with conventional VMAT. The tumor size and location are factors to be considered when selecting treatment equipment.

Unraveling the effect of the inflammatory microenvironment in spermatogenesis progression.

Experimental autoimmune orchitis (EAO) is a chronic inflammatory disorder that causes progressive spermatogenic impairment. EAO is characterized by high intratesticular levels of nitric oxide (NO) and tumor necrosis factor alpha (TNFα) causing germ cell apoptosis and Sertoli cell dysfunction. However, the impact of this inflammatory milieu on the spermatogenic wave is unknown. Therefore, we studied the effect of inflammation on spermatogonia and preleptotene spermatocyte cell cycle progression in an EAO context and through the intratesticular DETA-NO and TNFα injection in the normal rat testes. In EAO, premeiotic germ cell proliferation is limited as a consequence of the undifferentiated spermatogonia (CD9

Cellular plasticity and myeloid inflammation in the adult brain are independent of the transcriptional modulator DREAM.

The downstream regulatory element antagonist modulator (DREAM) modulates ion channel function and gene transcription. Functionally, DREAM is implicated in physiological and pathological processes including cell proliferation, inflammation, and nociception. Despite its multiple functions and robust expression in forebrain tissue, neurons and glial cells, the role of DREAM in regard to cellular plasticity and tumor necrosis factor (TNF)-mediated inflammation is largely unexplored. Here, we demonstrate that adult hippocampal neurogenesis as well as the density and plasticity of glial cells in the hippocampus and thalamus are independent of the presence of DREAM. Further, DREAM deletion does not alter the regional myeloid response and inflammatory gene expression induced by chronic peripheral inflammation in mice overexpressing human TNF. Our data suggest that despite their highly dynamic regulation, neural cell plasticity and adult neurogenesis in the hippocampus do not depend on the multifunctional protein DREAM. Furthermore, TNF-mediated myeloid inflammation in the brain persists in the absence of DREAM.

Apatinib combined with temozolomide treatment for pseudoprogression in glioblastoma A case report.

Glioblastoma is the most common malignant tumor of the central nervous system, which originates from glial cells and corresponding precursors. Due to its strong invasion and rapid growth, the prognosis of patients after treatment is very poor and easy to relapse. In August 2015, a 48 years old man with a relapse of glioblastoma. The patient was diagnosed by computed tomography, magnetic resonance imaging, and pathological biopsy in this case report. The patient underwent 2 surgeries, radiotherapy, and multiple regular chemotherapy sessions over the next 6 years. Apatinib, an inhibitor of vascular endothelial growth factor receptor 2 was given to treat recurrent glioma. It was found that radiotherapy combined with temozolomide administration often increased the size of the original lesion or produced a new glioblastoma lesion. The lesion development was similar to tumor progression, which was called pseudoprogression. And it significantly prolonged the survival of this patient. Surgery, radiotherapy and chemotherapy with apatinib and temozolomide are effective to treat the patients with pseudoprogression in glioblastoma.

Peritoneal carcinomatosis secondary to metastatic lung cancer complicated with acute suppurative appendicitis A case report and literature review.

Lung cancer (LC) is a malignant tumor with the highest morbidity and mortality in the world. The most common metastatic sites of LC are the brain (47%), bone (36%), liver (22%), adrenal glands (15%), thoracic cavity (11%) and distant lymph nodes (10%). Peritoneal carcinomatosis (PC) is a rare clinical event in LC patients. Considering the rarity and nonspecific clinical symptoms of peritoneal metastasis among LC patients, a case of peritoneal metastasis secondary to LC incidentally observed by laparoscopic appendectomy is unusual. Here, we present a 53-year-old never-smoker woman who presented to the emergency department with a 2-day history of pain in the right abdominal quadrant. Later, laparoscopy revealed acute suppurative appendicitis accompanied by a peritoneal metastatic mass. The patient was diagnosed with PC secondary to metastatic LC complicated with acute suppurative appendicitis by immunohistochemistry. Positron emission tomography computed tomography (PET CT) findings further strengthen the evidence of PC from LC. Based on the results of genomic analysis, the patient received targeted therapy with osimertinib 80 mgd. Due to the discovery of new targets, the use of molecular therapies improved progression-free survival (PFS) and overall survival (OS), which increases the chance of identifying peritoneal metastasis of LC. For LC patients with abdominal symptoms, clinicians should be aware of the possibility of peritoneal metastasis from LC, especially for patients diagnosed with lung adenocarcinoma or with pleural effusion.

Immune Exosomes Loading Self-Assembled Nanomicelles Traverse the Blood-Brain Barrier for Chemo-immunotherapy against Glioblastoma.

Effective drug delivery and prevention of postoperative recurrence are significant challenges for current glioblastoma (GBM) treatment. Poor drug delivery is mainly due to the presence of the blood-brain barrier (BBB), and postoperative recurrence is primarily due to the resistance of GBM cells to chemotherapeutic drugs and the presence of an immunosuppressive microenvironment. Herein, a biomimetic nanodrug delivery platform based on endogenous exosomes that could efficiently target the brain without targeting modifications and co-deliver pure drug nanomicelles and immune adjuvants for safe and efficient chemo-immunotherapy against GBM is prepared. Inspired by the self-assembly technology of small molecules, tanshinone IIA (TanIIA) and glycyrrhizic acid (GL), which are the inhibitors of signal transducers and activators of transcription 3 from traditional Chinese medicine (TCM), self-assembled to form TanIIA-GL nanomicelles (TGM). Endogenous serum exosomes are selected to coat the pure drug nanomicelles, and the CpG oligonucleotides, agonists of Toll-like receptor 9, are anchored on the exosome membrane to obtain immune exosomes loaded with TCM self-assembled nanomicelles (CpG-EXOTGM). Our results demonstrate that CpG-EXOTGM can bind free transferrin in blood, prolong blood circulation, and maintain intact structures when traversing the BBB and targeting GBM cells. In the GBM microenvironment, the strong anti-GBM effect of CpG-EXOTGM is mainly attributed to two factors (i) highly efficient uptake by GBM cells and sufficient intracellular release of drugs to induce apoptosis and (ii) stimulation of dendritic cell maturation and induction of tumor-associated macrophages polarization by CpG oligonucleotides to generate anti-GBM immune responses. Further research found that CpG-EXOTGM can not only produce better efficacy in combination with temozolomide but also prevent a postoperative recurrence.

Tumor region associated with specific processing speed outcomes.

Processing speed (PS) is a vulnerable cognitive skill in pediatric cancer survivors as a consequence of treatments and, less consistently, tumor region. Studies conventionally examine graphomotor PS emerging research suggests other aspects of PS may be impacted. This study examined types of PS in pediatric brain tumor survivors to determine which aspects are impaired. Given discordance across studies, we additionally investigated the relationship between brain region and PS. The sample consisted of 167 pediatric brain tumor patients (100 supratentorial). PS (oral naming, semantic fluency, phonemic fluency, motor speed, graphomotor speed, visual scanning) was gathered via clinical neuropsychological assessment. To examine PS by region, infratentorial and supratentorial groups were matched on age at diagnosis and neuropsychological assessment, and time since diagnosis. The whole sample performed below normative means on measures of oral naming (p < .001), phonemic fluency (p < .001), motor speed (p .03), visual scanning (p < .001), and graphomotor speed (p < .001). Only oral naming differed by region (p .03), with infratentorial tumors associated with slower performance. After controlling for known medical and demographic risk factors, brain region remained a significant predictor of performance (p .04). Among the whole sample, greater than expected proportions of patients with impairment (i.e., >1 standard deviation below the normative mean) were seen across all PS measures. Infratentorial tumors had higher rates of impairments across all PS measures except phonemic fluency. Results indicate pediatric brain tumor survivors demonstrate weaknesses in multiple aspects of PS, suggesting impairments are not secondary to peripheral motor slowing alone. Additionally, tumor region may predict some but not all neuropsychological outcomes in this population.

Current Approaches to Craniopharyngioma Management.

Craniopharyngiomas (CP) are rare noncancerous brain tumors located in the skull base. To date, CP remain challenging-to-resect tumors, owing to their difficult location and invasive potential, with profound adverse effects for the patient if left to grow. Indeed, gross total resection may also be accompanied by unwelcome sequalae, underscoring the need for continued investigation. In the present work, we provide a scoping review of current CP management, with emphasis on our knowledge of their genesis, available treatment options, post-intervention clinical outcomes. Leading theories of CP development are (1) the embryonic theory, explaining the development of adamantinomatous CP from epithelial remnants of Rathkes pouch and (2) the metaplastic theory, which describes papillary CP development as a result of adenohypophyseal cell metaplasia. Treatment may include surgery, intracystic therapy, or irradiation depending on tumor size, history and location. However, whether a single ideal approach and timing for CP intervention exists remains debated. We appraise and critique these areas with priority for emerging basic results and innovation.

Stereotactic needle biopsy and laser ablation of geographically distinct lesions through a novel magnetic resonance imaging-compatible cranial stereotaxic frame illustrative case.

Current technologies that support stereotactic laser ablation (SLA) of geographically distinct lesions require placement of multiple bolts or time-consuming, intertrajectory adjustments. Two geographically distinct nodular lesions were safely biopsied and laser ablated in a 62-year-old woman with recurrent glioblastoma using the ClearPoint Array frame, a novel magnetic resonance imaging-compatible stereotactic frame designed to support independent parallel trajectories without intertrajectory frame adjustment. Here, the authors provide a proof-of-principle case report demonstrating that geographically distinct lesions can be safely biopsied and ablated through parallel trajectories supported by the ClearPoint Array frame without intertrajectory adjustment.

The Fast Cognitive Evaluation (FaCE) a screening tool to detect cognitive impairment in patients with cancer.

Cancer-related cognitive impairment (CRCI) is one of the most concerning conditions experienced by patients living with cancer and has a major impact on their quality of life. Available cognitive assessment tools are too time consuming for day-to-day clinical setting assessments. Importantly, although shorter, screening tools such as the Montreal Cognitive Assessment or the Mini-Mental State Evaluation have demonstrated a ceiling effect in persons with cancer, and thus fail to detect subtle cognitive changes expected in patients with CRCI. This study addresses this lack of cognitive screening tools by developing a novel tool, the Fast Cognitive Evaluation (FaCE).A population of 245 patients with 11 types of cancer at different illness and treatment time-points was enrolled for the analysis. FaCE was developed using Rasch Measurement Theory, a model that establishes the conditions for a measurement tool to be considered a rating scale.FaCE shows excellent psychometric properties. The population size was large enough to test the set of items (item-reliability-index0.96). Person-reliability (0.65) and person-separation (1.37) indexes indicate excellent internal consistency. FaCEs scale is accurate (reliable) with high discriminant ability between cognitive levels. Within the average testing time of five minutes, FaCE assesses the main cognitive domains affected in CRCI.FaCE is a rapid, reliable, and sensitive tool for detecting even minimal cognitive changes over time. This can contribute to early and appropriate interventions for better quality of life in patients with CRCI. In addition, FaCE could be used as a measurement tool in research exploring cognitive disorders in cancer survivors.

Brain relaxation using desflurane anesthesia and total intravenous anesthesia in patients undergoing craniotomy for supratentorial tumors a randomized controlled study.

Satisfactory brain relaxation is essential in neurosurgery. Desflurane anesthesia and propofol-based total intravenous anesthesia (TIVA) have different effects on cerebral hemodynamics, potentially contributing to discrepant brain relaxation. The purpose of this study was to compare the effects of desflurane and TIVA on brain relaxation in patients undergoing craniotomy for supratentorial tumors. In this randomized, controlled study, we enrolled patients aged 18-60 years, with ASA I-III, who were scheduled to undergo elective craniotomy for supratentorial tumors. Patients were randomly assigned in a 11 ratio to receive desflurane anesthesia or TIVA. The primary outcome was the proportion of satisfactory brain relaxation. Secondary outcomes included emergence and extubation times, recovery of cognitive function and postoperative complications. Of 369 patients who were assessed for eligibility, 111 were randomized and 110 were included in the modified intention-to-treat analysis (55 in the desflurane group and 55 in the TIVA group). The proportion of satisfactory brain relaxation was similar between the two groups 69% in the desflurane group and 73% in the TIVA group (RR 0.950, 95% CI 0.748-1.207 P 0.675). Patients assigned to the desflurane group had shorter emergence (10 8-13 min vs. 13 10-20 min, P < 0.001) and extubation times (13 10-18 min vs. 17 13-23 min, P < 0.001), and better recovery of cognitive function at 15 min after extubation (16 0-24 vs. 0 0-20, P 0.003), but experienced increased postoperative nausea and vomiting (PONV) (16 29% vs. 6 11% P 0.017) and tachycardia (22 40% vs. 9 16%, P 0.006) during recovery. Desflurane anesthesia and TIVA provide similar brain relaxation in patients without intracranial hypertension undergoing elective craniotomy. Desflurane accelerates the recovery from anesthesia but is associated with increased PONV and tachycardia during the recovery period. Clinicaltrial.gov (NCT04691128). Date of registration December 31, 2020.

Goal-Directed Fluid Therapy and major postoperative complications in elective craniotomy. A retrospective analysis of a before-after multicentric study.

Goal-Directed Fluid Therapy (GDFT) is recommended to decrease major postoperative complications. However, data are lacking in intra-cranial neurosurgery. We evaluated the efficacy of a GDFT protocol in a beforeafter multi-centre study in patients undergoing elective intra-cranial surgery for brain tumour. Data were collected during 6 months in each period (beforeafter). GDFT was performed in high-risk patients ASA score IIIIV andor preoperative Glasgow Coma Score (GCS) < 15 andor history of brain tumour surgery andor tumour greater size ≥ 35 mm andor mid-line shift ≥ 3 mm andor significant haemorrhagic risk. Major postoperative complication was a composite endpoint re-intubation after surgery, a new onset of GCS < 15 after surgery, focal motor deficit, agitation, seizures, intra-cranial haemorrhage, stroke, intra-cranial hypertension, hospital-acquired related pneumonia, surgical site infection, cardiac arrythmia, invasive mechanical ventilation ≥ 48 h and in-hospital mortality. From July 2018 to January 2021, 344 patients were included in 3 centers 171 in the before and 173 in the after (GDFT) period. Thirty-six (21.1%) patients displayed a major postoperative complication in the Before period, and 50 (28.9%) in the After period (p 0.1). In the propensity score analysis, we matched 48 patients in each period 9 (18.8%) patients in the After period and 14 (29.2%) patients in the Before period displayed a major perioperative complication (p 0.2). Sixty-two (35.8%) patients received GDFT in the After period, with great heterogeneity among centers (p < 0.05). In our before-after study, GDFT was not associated with a decrease in postoperative major complications in elective intra-cranial neurosurgery.

MHC II immunogenicity shapes the neoepitope landscape in human tumors.

Despite advances in predicting physical peptide-major histocompatibility complex I (pMHC I) binding, it remains challenging to identify functionally immunogenic neoepitopes, especially for MHC II. By using the results of >36,000 immunogenicity assay, we developed a method to identify pMHC whose structural alignment facilitates T cell reaction. Our method predicted neoepitopes for MHC II and MHC I that were responsive to checkpoint blockade when applied to >1,200 samples of various tumor types. To investigate selection by spontaneous immunity at the single epitope level, we analyzed the frequency spectrum of >25 million mutations in >9,000 treatment-naive tumors with >100 immune phenotypes. MHC II immunogenicity specifically lowered variant frequencies in tumors under high immune pressure, particularly with high TCR clonality and MHC II expression. A similar trend was shown for MHC I neoepitopes, but only in particular tissue types. In summary, we report immune selection imposed by MHC II-restricted natural or therapeutic T cell reactivity.

Patient-specific identification of genome-wide DNA-methylation differences between intracranial and extracranial melanoma metastases.

Melanomas frequently metastasize to distant organs and especially intracranial metastases still represent a major clinical challenge. Epigenetic reprogramming of intracranial metastases is thought to be involved in therapy failure, but so far only little is known about patient-specific DNA-methylation differences between intra- and extracranial melanoma metastases. Hierarchical clustering of the methylomes of 24 patient-matched intra- and extracranial melanoma metastases pairs revealed that intra- and extracranial metastases of individual patients were more similar to each other than to metastases in the same tissue from other patients. Therefore, a personalized analysis of each metastases pair was done by a Hidden Markov Model to classify methylation levels of individual CpGs as decreased, unchanged or increased in the intra- compared to the extracranial metastasis. The predicted DNA-methylation alterations were highly patient-specific differing in the number and methylation states of altered CpGs. Nevertheless, four important general observations were made (i) intracranial metastases of most patients mainly showed a reduction of DNA-methylation, (ii) cytokine signaling was most frequently affected by differential methylation in individual metastases pairs, but also MAPK, PI3KAkt and ECM signaling were often altered, (iii) frequently affected genes were mainly involved in signaling, growth, adhesion or apoptosis, and (iv) an enrichment of functional terms related to channel and transporter activities supports previous findings for a brain-like phenotype. In addition, the derived set of 17 signaling pathway genes that distinguished intra- from extracranial metastases in more than 50% of patients included well-known oncogenes (e.g. PRKCA, DUSP6, BMP4) and several other genes known from neuronal disorders (e.g. EIF4B, SGK1, CACNG8). Moreover, associations of gene body methylation alterations with corresponding gene expression changes revealed that especially the three signaling pathway genes JAK3, MECOM, and TNXB differ strongly in their expression between patient-matched intra- and extracranial metastases. Our analysis contributes to an in-depth characterization of DNA-methylation differences between patient-matched intra- and extracranial melanoma metastases and may provide a basis for future experimental studies to identify targets for new therapeutic approaches.

The CDK inhibitor AT7519 inhibits human glioblastoma cell growth by inducing apoptosis, pyroptosis and cell cycle arrest.

Glioblastoma multiforme (GBM) is the most lethal primary brain tumor with a poor median survival of less than 15 months. However, clinical strategies and effective therapies are limited. Here, we found that the second-generation small molecule multi-CDK inhibitor AT7519 is a potential drug for GBM treatment according to high-throughput screening via the Approved Drug Library and Clinical Compound Library (2718 compounds). We found that AT7519 significantly inhibited the cell viability and proliferation of U87MG, U251, and patient-derived primary GBM cells in a dose-dependent manner. Furthermore, AT7519 also inhibited the phosphorylation of CDK12 and arrested the cell cycle at the G1-S and G2-M phases. More importantly, AT7519 induced intrinsic apoptosis and pyroptosis via caspase-3-mediated cleavage of gasdermin E (GSDME). In the glioblastoma intracranial and subcutaneous xenograft assays, tumor volume was significantly reduced after treatment with AT7519. In summary, AT7519 induces cell death through multiple pathways and inhibits glioblastoma growth, indicating that AT7519 is a potential chemical available for GBM treatment.

Ectopic recurrence of craniopharyngioma in the posterior fossa Case report and review of the literature.

Craniopharyngiomas are benign epithelial tumors which may very occasionally recur in ectopic locations. We present two cases of ectopic recurrence, both in the posterior fossa, and provide a review of the literature with basic statistics. Two patients admitted to our institution with posterior fossa lesions underwent gross total resection. Pathological studies showed adamantinomatous craniopharyngiomas (ACP). Both patients had a prior history of suprasellar tumor surgery. We also reviewed the related data and undertook a basic statistical analysis. We found 67 cases of ectopic recurrent craniopharyngioma (including the present cases) 51 cases were adamantinomatous (76%), 6 papillary (9%) and 10 unknown (15%). 18 cases occurred in the posterior fossa, all of them diagnosed as the ACP subtype. The intervals until recurrence were 15.15 years for posterior fossa recurrences and 5.75 years for supratentorial cases. Student t test showed significant differences in time to recurrence (p 0.002). Gross total resection was performed in 53 cases (79%), subtotal resectionradiotherapy in 3 (5%) and 11 (16%) cases were treated with other options. Ectopic recurrence is a rare but possible event. Those in the posterior fossa may appear later than in the supratentorial space. ACP is likely to be the most common subtype in these cases, possibly due to its more aggressive behavior compared to the papillary subtype. Long term follow-up should be performed to detect ectopic recurrences. Ectopic recurrences are often surgically accessible and gross total resection should be achieved.

Combining high throughput array synthesis and growth algorithm to discover TNF-α binders with new structures and properties.

Identifying new chemical structures against protein targets of interest represents one of the major challenges in drug discovery. As the major experimental method, high throughput screenings are performed with existing chemical libraries, thus restricting its capability to explore high molecular diversity. Herein, we report the use of high throughput array synthesis technology, in combination with growth algorithm, to discover binders for proinflammatory cytokine TNF-α. After 6 iterations of Library design - Array synthesis - Screening (i-LAS), one identified compound T17 has shown a kd value of 14.8 μM, and can rescue L929 cells from TNF-α mediated cytotoxicity. Further engineering T17 in various forms of oligomers have led to low nM binders. More interestingly, through tuning the multi-valent interaction with TNF-α, the high affinity oligomers can be switched from inhibitors to activators, leading to the hypothesis of an oligomerization-induced receptor activation mechanism. The i-LAS technology has allowed us to discover new binder structures, which can be further engineered into molecules with novel properties.

Hybrid Optimization Algorithm Enabled Deep Learning Approach Brain Tumor Segmentation and Classification Using MRI.

The unnatural and uncontrolled increase of brain cells is called brain tumors, leading to human health danger. Magnetic resonance imaging (MRI) is widely applied for classifying and detecting brain tumors, due to its better resolution. In general, medical specialists require more details regarding the size, type, and changes in small lesions for effective classification. The timely and exact diagnosis plays a major role in the efficient treatment of patients. Therefore, in this research, an efficient hybrid optimization algorithm is implemented for brain tumor segmentation and classification. The convolutional neural network (CNN) features are extracted to perform a better classification. The classification is performed by considering the extracted features as the input of the deep residual network (DRN), in which the training is performed using the proposed chronological Jaya honey badger algorithm (CJHBA). The proposed CJHBA is the integration of the Jaya algorithm, honey badger algorithm (HBA), and chronological concept. The performance is evaluated using the BRATS 2018 and Figshare datasets, in which the maximum accuracy, sensitivity, and specificity are attained using the BRATS dataset with values 0.9210, 0.9313, and 0.9284, respectively.

PDQ Cancer Information Summaries

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of adult central nervous system tumors. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions. This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

PDQ Cancer Information Summaries

This PDQ cancer information summary has current information about the treatment of childhood brain stem glioma. It is meant to inform and help patients, families, and caregivers. It does not give formal guidelines or recommendations for making decisions about health care. Editorial Boards write the PDQ cancer information summaries and keep them up to date. These Boards are made up of experts in cancer treatment and other specialties related to cancer. The summaries are reviewed regularly and changes are made when there is new information. The date on each summary (Date Last Modified) is the date of the most recent change. The information in this patient summary was taken from the health professional version, which is reviewed regularly and updated as needed, by the PDQ Pediatric Treatment Editorial Board.

Long-term outcomes after a transcranial microsurgical approach to craniopharyngiomas a 20-year clinical follow-up study.

Craniopharyngioma (CP) is a mostly benign tumor that is nonetheless one of most formidable skull base lesions. CP tends to recur, and scarce clinical results are available regarding its long-term outcomes. From February 1996 to April 2002, craniopharyngiomas primarily resected by open surgery in a single-center and single-surgeon practice were screened. Medical information regarding patients baseline, tumor parameters, endocrinological results, complications, and quality of life in those patients with a follow-up longer than 20 years were reviewed. Nineteen out of 187 patients who met the inclusion criteria were eligible, and 78.9% of the patients were admitted due to visual deficits. The transcranial approach was mostly applied for the first attempt of opening resection, with 94.7% gross total resection. The size of the tumor ranged from 25 to 45 mm with a mean maximal diameter of 34.7 mm. Although 7 out of 19 patients received an extra procedure, 6 patients (31.5%) regained fertility, with 3 women bearing a total of 5 children and 3 men fathering a total of 4 children, during the 21.4-year follow-up (range 20.0-23.3 years). The mean Karnofsky Performance Status (KPS) score was 97.9 (range 80-100) at the last follow-up, and the physical and mental 36-Item Short Form Health Survey (SF-36) scores were 88.0 and 80.5, respectively. The tumor sizes of the patients who regained fertility were not significantly different from those of the patients who remained infertile (t 1.29, P > 0.2). The time interval from prior surgery to tumor resection for recurrent cases ranged from 0.3 to 17.4 years (mean, 7.3 years). There was no significant difference in the time until tumor recurrence in the patients who underwent a second surgery, a third surgery, or a fourth surgery. The satisfactory results in the present study revealed favorable long-term outcomes following the transcranial management of CPs, with acceptable endocrinological function and tumor-free survival. A decisive policy of open surgery with the objective of radical tumor removal remains a valid method for the primary treatment of CPs, aiming to avoid retreatment after tumor recurrence involving vital hypothalamic structures or hydrocephalus.

Phagocytosis of glioma cells enhances the immunosuppressive phenotype of bone marrow-derived macrophages.

Tumor-associated macrophages (TAMs) play a crucial role in immunosuppression. However, how TAMs are transformed into immunosuppressive phenotypes and influence the tumor microenvironment (TME) is not fully understood. Here, we utilized single-cell RNA sequencing and whole-exome sequencing data of glioblastoma (GBM) tissues and identified a subset of TAMs dually expressing macrophage and tumor signatures, which were termed double-positive TAMs. Double-positive TAMs tended to be bone marrow-derived macrophages (BMDMs) and were characterized by immunosuppressive phenotypes. Phagocytosis of glioma cells by BMDMs in vitro generated double-positive TAMs with similar immunosuppressive phenotypes to double-positive TAMs in the GBM TME of patients. The double-positive TAMs were transformed into M2-like macrophages and drove immunosuppression by expressing immune checkpoint proteins CD276, PD-L1, and PD-L2 and suppressing the proliferation of activated T cells. Together, glioma cell phagocytosis by BMDMs in the TME leads to the formation of double-positive TAMs with enhanced immunosuppressive phenotypes, shedding light on the processes driving TAM-mediated immunosuppression in GBM.

Labeling Assembly of Hydrophilic Methionine into Nanoparticle for Mild-Heat Mediated Immunometabolic Therapy.

Methionine metabolism has a significant impact on T cells survival and activation even in comparison to arginine, a well-documented amino acid in metabolic therapy. However, hydrophilic methionine is hardly delivered into TME due to difficult loading and rapid diffusion. Herein, the labeling assembly of methionine into nanoparticle is developed to overcome high hydrophilicity for mild-heat mediated immunometabolic therapy. The strategy is to first label methionine with protocatechualdehyde (as the tag) via reversible Schiff-base bond, and then drive nanoassembly of methionine (MPCFe) mediated by iron ions. In this fashion, a loading efficiency of 40% and assembly induced photothermal characteristics can be achieved. MPCFe can accumulate persistently in tumor up to 36 h due to tumor-selective aggregation in acidic TME. A mild heat of 43 °C on tumor by light irradiation stimulated the immunogenic cell death and effectively generated CD8

Nomogram for predicting survival of patients with anaplastic ependymoma in the brain and spinal cord.

Anaplastic ependymoma is a rare tumor. Although this tumor is rare, it still has high research value. Based on current knowledge, articles on anaplastic ependymoma in the brain and spinal cord are extremely limited. We retrospectively extracted data of 305 patients with anaplastic ependymoma in the brain and spinal cord from the Surveillance, Epidemiology, and End Results database (SEER) between 1988 and 2015, which was analyzed in R software. The statistical significance indicators were identified by the COX regression analysis. The Nomogram visualized the model and was corrected by the C-index, AUC and calibration curve. The results of the analysis showed age and treatment were found to be statistical significance in this study. Based on this study, the models C-index was 0.777, and the area under the curve (AUC) value of the time-dependent ROC curve at 2-Year, 3-Year, and 5-Year was 0.758, 0.775 and 0.788. These showed a good discriminatory ability. Finally, a nomogram was constructed. And the nomogram was validated by validation curve. At last, the two risk factors (including age and treatment) were identified to the independent prognostic factors for patients with anaplastic ependyma in the spinal cord and brain. Meanwhile, our model can accurately assess the disease-specific survival rate of these patients, and can provide recommendations on treatment options.

Quantification and Proteomic Characterization of β-Hydroxybutyrylation Modification in the Hearts of AMPKα2 Knockout Mice.

AMP-activated protein kinase alpha 2 (AMPKα2) regulates energy metabolism, protein synthesis, and glucolipid metabolism myocardial cells. Ketone bodies produced by fatty acid β-oxidation, especially β-hydroxybutyrate, are fatty energy-supplying substances for the heart, brain, and other organs during fasting and long-term exercise. They also regulate metabolic signaling for multiple cellular functions. Lysine β-hydroxybutyrylation (Kbhb) is a β-hydroxybutyrate-mediated protein posttranslational modification. Histone Kbhb has been identified in yeast, mouse, and human cells. However, whether AMPK regulates protein Kbhb is yet unclear. Hence, the present study explored the changes in proteomics and Kbhb modification omics in the hearts of AMPKα2 knockout mice using a comprehensive quantitative proteomic analysis. Based on mass spectrometry (LC-MSMS) analysis, the number of 1181 Kbhb modified sites in 455 proteins were quantified between AMPKα2 knockout mice and wildtype mice 244 Kbhb sites in 142 proteins decreased or increased after AMPKα2 knockout (fold change >1.5 or <11.5, p < 0.05). The regulation of Kbhb sites in 26 key enzymes of fatty acid degradation and tricarboxylic acid cycle was noted in AMPKα2 knockout mouse cardiomyocytes. These findings, for the first time, identified proteomic features and Kbhb modification of cardiomyocytes after AMPKα2 knockout, suggesting that AMPKα2 regulates energy metabolism by modifying protein Kbhb.

A Phase II Single-arm Study of Palbociclib in Patients With HER2-positive Breast Cancer With Brain Metastases and Analysis of ctDNA in Patients With Active Brain Metastases.

Palbociclib is highly efficacious and well tolerated in hormone-receptor positive (HR) metastatic breast cancer (BC) but its activity for HER2 BC with brain metastases (BM) is unknown. In a single-arm phase II study we evaluated palbociclib with trastuzumab for patients with HER2 MBC and BM. The primary endpoint was BM response rate. Circulating tumor DNA (ctDNA) was evaluated at baseline, and in a subset of patients at cycle 3 and progression. We also retrospectively identified additional patients with metastatic BC, active BM, and a ctDNA assessment prior to therapy for BM. Twelve patients with HER2 MBC were enrolled, 4 with HR and 8 with HR- disease. No responses were seen. Best response was stable disease for 6 patients and progressive disease for 6 patients. The median PFS was 2.2 months, interquartile range (IQR) was 1.56 to 3.63 months. The median OS was 13.1 months and IQR was 9.4 to 23.8 months The CNS was the primary site of progression for all patients. The median variant allele fraction (VAF) of the dominant variant in each patient was 0.18% (interquartile range IQR 0.12%-0.47%) with a median number of somatic alterations of 1. We additionally evaluated ctDNA results from 26 patients with BC and active BM, among whom the median VAF was 11.8% (IQR 3.9%-27.3%) with a median number of alterations was 6 (IQR 4-9). Notably, progressive systemic disease was significantly less frequent in the trial cohort compared with additional retrospectively identified patients (8% vs. 81%). Palbociclib did not demonstrate activity in HER2 MBC with BM. Patients with progressive BM but stable, responding, or absent systemic disease have low VAF and number of alterations detected by ctDNA analysis from blood.

Fused deep learning paradigm for the prediction of o6-methylguanine-DNA methyltransferase genotype in glioblastoma patients A neuro-oncological investigation.

The O6-methylguanine-DNA methyltransferase (MGMT) is a deoxyribonucleic acid (DNA) repairing enzyme that has been established as an essential clinical brain tumor biomarker for Glioblastoma Multiforme (GBM). Knowing the status of MGMT methylation biomarkers using multi-parametric MRI (mp-MRI) helps neuro-oncologists to analyze GBM and its treatment plan. The hand-crafted radiomics feature extraction of GBMs subregions, such as edema(ED), tumor core (TC), and enhancing tumor (ET) in the machine learning (ML) framework, was investigated using support vector machine(SVM), K-Nearest Neighbours (KNN), random forest (RF), LightGBM, and extreme gradient boosting (XGB). For tissue-level analysis of the promotor genes in GBM, we used the deep residual neural network (ResNet-18) with 3D architecture, followed by EfficientNet-based investigation for variants as B0 and B1. Lastly, we analyzed the fused deep learning (FDL) framework that combines ML and DL frameworks. Structural mp-MRI consisting of T1, T2, FLAIR, and T1GD having a size of 400 and 185 patients, respectively, for discovery and replication cohorts. Using the CV protocol in the ResNet-3D framework, MGMT methylation status prediction in mp-MRI gave the AUC of 0.753 (p < 0.0001) and 0.72 (p < 0.0001) for the discovery and replication cohort, respectively. We presented that the FDL is ∼7% superior to solo DL and ∼15% to solo ML. The proposed study aims to provide solutions for building an efficient predictive model of MGMT for GBM patients using deep radiomics features obtained from mp-MRI with the end-to-end ResNet-18 3D and FDL imaging signatures.

Subclonal evolution and expansion of spatially distinct THY1-positive cells is associated with recurrence in glioblastoma.

Glioblastoma(GBM) is a lethal disease characterized by inevitable recurrence. Here we investigate the molecular pathways mediating resistance, with the goal of identifying novel therapeutic opportunities. We developed a longitudinal in vivo recurrence model utilizing patient-derived explants to produce paired specimens(pre- and post-recurrence) following temozolomide(TMZ) and radiation(IR). These specimens were evaluated for treatment response and to identify gene expression pathways driving treatment resistance. Findings were clinically validated using spatial transcriptomics of human GBMs. These studies reveal in replicate cohorts, a gene expression profile characterized by upregulation of mesenchymal and stem-like genes at recurrence. Analyses of clinical databases revealed significant association of this transcriptional profile with worse overall survival and upregulation at recurrence. Notably, gene expression analyses identified upregulation of TGFβ signaling, and more than one-hundred-fold increase in THY1 levels at recurrence. Furthermore, THY1-positive cells represented <10% of cells in treatment-naïve tumors, compared to 75-96% in recurrent tumors. We then isolated THY1-positive cells from treatment-naïve patient samples and determined that they were inherently resistant to chemoradiation in orthotopic models. Additionally, using image-guided biopsies from treatment-naïve human GBM, we conducted spatial transcriptomic analyses. This revealed rare THY1 regions characterized by mesenchymalstem-like gene expression, analogous to our recurrent mouse model, which co-localized with macrophages within the perivascular niche. We then inhibited TGFBRI activity in vivo which decreased mesenchymalstem-like protein levels, including THY1, and restored sensitivity to TMZIR in recurrent tumors. These findings reveal that GBM recurrence may result from tumor repopulation by pre-existing, therapy-resistant, THY1-positive, mesenchymal cells within the perivascular niche.

Let Us Not Forget About Bleeding A Case Report and Brief Literature Review on Hemorrhagic Vestibular Schwannoma.

Hemorrhagic vestibular schwannoma (HVS) consisting of acute intratumoral and subarachnoid hemorrhage is a rare phenomenon. We present the case of a 31-year-old woman who attended the Otorhinolaryngology department with right-sided intense tinnitus, dizziness, imbalance, and headache. Brain computed tomography revealed a spontaneous hyperdensity in the posterior fossa with marked deformation of the brainstem, middle cerebral peduncle, and cerebellum, with the near collapse of the fourth ventricle. Ophthalmology evaluation confirmed bilateral papilledema. Brain magnetic resonance imaging confirmed a voluminous 33 x 28 x 29 mm extra-axial lesion centered on the right pontine-cerebellar angle cistern, extending from the plane of the trigeminal nervetent of the cerebellum. The acoustic pore was enlarged. The patient underwent retrosigmoid craniotomy and microscopic tumor resection showing significant improvement in the follow-up. Pathological findings confirmed HVS. Delayed treatment of HVS can increase morbidity or even be fatal. The objective of this work is to describe and revise HVS, in order to bring awareness to this uncommon entity.

Novel MRI deformation-heterogeneity radiomic features are associated with molecular subgroups and overall survival in pediatric medulloblastoma Preliminary findings from a multi-institutional study.

Medulloblastoma (MB) is a malignant, heterogenous brain tumor. Advances in molecular profiling have led to identifying four molecular subgroups of MB (WNT, SHH, Group 3, Group 4), each with distinct clinical behaviors. We hypothesize that (1) aggressive MB tumors, growing heterogeneously, induce pronounced local structural deformations in the surrounding parenchyma, and (b) these local deformations as captured on Gadolinium (Gd)-enhanced-T1w MRI are independently associated with molecular subgroups, as well as overall survival in MB patients. In this work, a total of 88 MB studies from 2 institutions were analyzed. Following tumor delineation, Gd-T Multi-class comparison via ANOVA yielded significant differences between deformation magnitudes obtained for Group 3, Group 4, and SHH molecular subgroups, observed up to 60-mm outside the tumor edge. Additionally, Kaplan-Meier survival analysis showed that the local deformation statistics, combined with the current clinical risk-stratification approaches (molecular subgroup information and Changs classification), could identify significant differences between high-risk and low-risk survival groups, achieving better performance results than using any of these approaches individually. These preliminary findings suggest there exists significant association of our tumor-induced deformation descriptor with overall survival in MB, and that there could be an added value in using the proposed radiomic descriptor along with the current risk classification approaches, towards more reliable risk assessment in pediatric MB.

Minor histological components predict the recurrence of patients with resected stage I acinar- or papillary-predominant lung adenocarcinoma.

Invasive lung adenocarcinoma is composed of five different histological subgroups with diverse biological behavior and heterogeneous morphology, the acinarpapillary-predominant lung adenocarcinomas are the most common subgroups and recognized as an intermediate-grade group. In the real world, clinicians primarily consider predominant patterns and ignore the impact of minor components in the prognosis of lung adenocarcinoma. The study evaluated the clinicopathologic characteristics of the lepidic, solid, and micropapillary patterns as non-predominant components and whether the minimal patterns had prognostic value on acinarpapillary-predominant lung adenocarcinomas. A total of 153 acinarpapillary-predominant lung adenocarcinoma patients with tumor size ≤4 cm were classified into four risk subgroups based on the presence of lepidic and micropapillarysolid components MPS The risk subgroups based on the non-predominant patterns were associated with differentiation ( Regardless of the proportion, the presence of micropapillarysolid components and the absence of lepidic patterns are aggressive factors of DFS in patients with resected stage I acinar- or papillary-predominant lung adenocarcinoma.

Endoscopic endonasal resection of an epidermoid cyst in the cavernous sinus A case report and literature review.

Epidermoid cysts of cavernous sinus (CS) are rare congenital neoplasms of the central nervous system. In previous literature reports, the treatment for CS epidermoid cysts was mainly microsurgical resection, and the surgical methods included simple microsurgery and endoscope-assisted microsurgery. The present case report demonstrates the first case of complete resection of a CS epidermoid cyst by a simple endoscopic endonasal transcavernous (EET) approach. A 54-year-old woman presented with chronic persistent headaches and occasional syncope. Brain MRI demonstrated a space-occupying lesion of the left CS, and digital substruction angiography (DSA) showed a small aneurysm at the beginning of the left ophthalmic artery. Thrombotic therapy of carotid-ophthalmic aneurysms was performed first, and the patient underwent resection of the CS lesion secondary. Considering the location of the lesion and the neuroendoscopy technology and experience of the doctor, we made bold innovations and used an EET approach to achieve complete resection of the lesion. The postoperative pathological results were consistent with the characteristics of epidermoid cyst. During the 1-year follow up, the patient showed no apparent signs of recurrence on head MRI. Epidermoid cyst of cavernous sinus is a rare benign occupying lesion in cavernous sinus. Reviewing the previous literature, the main treatment is microneurosurgery, and neuroendoscopy is only used as an auxiliary equipment. We present the first case of complete endoscopic resection of CS epidermoid cyst by EET approach according to CARE guidelines, aiming to share the new surgical plan for CS epidermoid cyst and provide more surgical options for this disease for neurosurgery colleagues.

The function of p53 and its role in Alzheimers and Parkinsons disease compared to age-related macular degeneration.

The protein p53 is the main human tumor suppressor. Since its discovery, extensive research has been conducted, which led to the general assumption that the purview of p53 is also essential for additional functions, apart from the prevention of carcinogenesis. In response to cellular stress and DNA damages, p53 constitutes the key point for the induction of various regulatory processes, determining whether the cell induces cell cycle arrest and DNA repair mechanisms or otherwise cell death. As an implication, aberrations from its normal functioning can lead to pathogeneses. To this day, neurodegenerative diseases are considered difficult to treat, which arises from the fact that in general the underlying pathological mechanisms are not well understood. Current research on brain and retina-related neurodegenerative disorders suggests that p53 plays an essential role in the progression of these conditions as well. In this review, we therefore compare the role and similarities of the tumor suppressor protein p53 in the pathogenesis of Alzheimers (AD) and Parkinsons disease (PD), two of the most prevalent neurological diseases, to the age-related macular degeneration (AMD) which is among the most common forms of retinal degeneration.

Rapid Response to Sotorasib of a Patient With

The efficacy of sotorasib for patients with

3D collagen microchamber arrays for combined chemotherapy effect evaluation on cancer cell numbers and migration.

Breast cancer metastasis involves complex mechanisms, particularly when patients are undergoing chemotherapy. In tissues, tumor cells encounter cell-cell interactions, cell-microenvironment interactions, complex nutrient, and drug gradients. Currently, two-dimensional cell culture systems and animal models are challenging to observe and analyze cell responses to microenvironments with various physical and bio-chemical conditions, and microfluidic technology has been systematically developed to address this dilemma. In this study, we have constructed a combined chemotherapy evaluation chip (CCEC) based on microfluidic technology. The chip possesses 192 diamond-shaped microchambers containing MDA-MB-231-RFP cells, and each microchamber is composed of collagen to mimic breast cancer and its surrounding microenvironment. In addition, by adding medium containing different drugs to the medium channels of CCEC, composite drug (paclitaxelgemcitabine7rh and paclitaxelfluorouracilPP2) concentration gradients, and single drug (paclitaxel, gemcitabine, 7rh, fluorouracil, PP2) concentration gradients have been established in the five collagen regions, respectively, so that each localized microchamber in the regions has a unique drug microenvironment. In this way, we evaluated the composite and single chemotherapy efficacy on the same chip by statistically analyzing their effects on the numbers and migration of the cell. The quantitative results in CCECs reveal that the inhibition effects on the numbers and migration of MDA-MB-231-RFP cell under the composite drug gradients are more optimal than those of the single drugs. Besides, the cancer cell inhibition effect between the groups composed of two drugs has also been compared, that is the paclitaxelgemcitabine, paclitaxelfluorouracil, and paclitaxelPP2 have better cell numbers and migration inhibition effects than paclitaxel7rh. The results indicate that the bio-mimetic and high-throughput combined chemotherapy evaluation platform can serve as a more efficient and accurate tool for preclinical drug development and screening.

Role of non-coding RNAs and exosomal non-coding RNAs in retinoblastoma progression.

Retinoblastoma (RB) is a rare aggressive intraocular malignancy of childhood that has the potential to affect vision, and can even be fatal in some children. While the tumor can be controlled efficiently at early stages, metastatic tumors lead to high mortality. Non-coding RNAs (ncRNAs) are implicated in a number of physiological cellular process, including differentiation, proliferation, migration, and invasion, The deregulation of ncRNAs is correlated with several diseases, particularly cancer. ncRNAs are categorized into two main groups based on their length, i.e. short and long ncRNAs. Moreover, ncRNA deregulation has been demonstrated to play a role in the pathogenesis and development of RB. Several ncRNAs, such as miR-491-3p, miR-613,and SUSD2 have been found to act as tumor suppressor genes in RB, but other ncRNAs, such as circ-E2F3, NEAT1, and TUG1 act as tumor promoter genes. Understanding the regulatory mechanisms of ncRNAs can provide new opportunities for RB therapy. In the present review, we discuss the functional roles of the most important ncRNAs in RB, their interaction with the genes responsible for RB initiation and progression, and possible future clinical applications as diagnostic and prognostic tools or as therapeutic targets.

Therapeutic role of memantine for the prevention of cognitive decline in cancer patients with brain metastasis receiving whole-brain radiotherapy a narrative review.

Brain metastases are the most common central nervous system tumors. The mainstay treatment for this tumor in low to middle income countries is whole brain radiation therapy. Irreversible cognitive decline is associated with the use of whole brain radiotherapy. Several pharmacologic and nonpharmacologic options have been employed in studies focusing on the prevention of cognitive decline following whole-brain radiation therapy. Memantine use has been shown to provide some benefit in reducing the rate of decline in cognitive function and time to cognitive failure. The objective of this review article is to provide a summary on available primary literature on the therapeutic role of memantine for the prevention of cognitive decline in cancer patients with brain metastasis receiving whole brain radiotherapy. As metástases cerebrais são os tumores mais comuns do sistema nervoso central. O tratamento principal para este tumor em países de baixa e média renda é a radioterapia de cérebro inteiro. O declínio cognitivo irreversível está associado ao uso de radioterapia cerebral total. Várias opções farmacológicas e não farmacológicas têm sido empregadas em estudos com foco na prevenção do declínio cognitivo após radioterapia de cérebro inteiro. O uso de memantina demonstrou fornecer algum benefício na redução da taxa de declínio na função cognitiva e no tempo até a falha cognitiva. O objetivo deste artigo de revisão foi fornecer um resumo da literatura primária disponível sobre o papel terapêutico da memantina para a prevenção do declínio cognitivo em pacientes com câncer com metástase cerebral recebendo radioterapia cerebral total.

Case report

A rare pituitary tumor associated with hyperthyroidism and acromegaly.

Mixed pituitary TSHGH adenomas are rare adenomas associated with acromegaly andor thyrotoxicosis, with or without varying degrees of goiter. In this report, we show a case of pituitary adenoma producing both GH and TSH simultaneously. A 27-year-old man was diagnosed with pituitary adenoma based on various symptoms and clinical findings. For further examination and treatment, he was hospitalized in our institution. It was likely that this subject had pituitary adenoma producing both GH and TSH. In brain magnetic resonance imaging, there was a giant tumor in the sellar region. After the diagnosis of mixed pituitary TSHGH adenoma, he was treated with octreotide, then underwent tumor resection, and then received hydrocortisone acetate and levothyroxine sodium. After then, GH and IGF-1 levels were suppressed and thyroid function was normalized. Postoperative immunohistochemistry reports showed GH () but TSH (-), which may be insensitive to the antibody used to detect TSH or combined with other factors. The diagnosis of mixed pituitary TSHGH adenoma must be combined with clinical manifestations, immunohistochemical staining and relevant hormone levels, and genetic testing if necessary for comprehensive judgment. For patients with large adenomas, it is recommended to use somatostatin analogs to restore TH levels and control the excessive secretion of GH levels before surgery.

Emerging trends and hot spots on electrical impedance tomography extrapulmonary applications.

Electrical impedance tomography (EIT) develops rapidly in technology and applications. Nowadays EIT is used in multiple clinical and experimental scenarios including pulmonary, brain, and tissue monitoring, etc. The present study explores the research trends and hotspots on EIT extrapulmonary application research by bibliometrics analysis. Publications on EIT extrapulmonary applications between 1987 and 2021 were retrieved from the Web of Science Core Collection database. For precise screening, search strategy electrical impedance tomography plus hemodynamic or brain or nerve or cancer or venous or vessel or tumor or veterinary or tissue or cell or wearable or application and excluding lung, ventilation respiratory, pulmonary, algorithm, current, voltage or electrode were used. CiteSpace and VOSviewer were used to analyze the publication features, collaboration, keywords co-occurrence, and co-cited reference. A total of 506 articles were finally identified. The global publication numbers on extrapulmonary applications gradually increased yearly in the past 30 years. The US, UK, and China contributed most three publications concerning EIT extrapulmonary applications. tissues, conductivity, model were research hotspots, and cutaneous melanoma, microstructure, diagnosis were recent topics (Portions of this research have previously been presented in poster form). Overall, EIT extrapulmonary applications bibliometrics analysis provides a unique insight into research focus, current trends, and future directions.

ERK phosphorylation disrupts the intramolecular interaction of capicua to promote cytoplasmic translocation of capicua and tumor growth.

Activation of receptor tyrosine kinase signaling inactivates capicua (CIC), a transcriptional repressor that functions as a tumor suppressor,

Multi-omics analyses of tumor-associated immune-infiltrating cells with the novel immune checkpoint protein tyrosine phosphatase 1B (PTP1B) in extracellular matrix of brain-lower-grade-glioma (LGG) and uveal-melanoma (UVM).

Immune checkpoint inhibitors represented by PD-1 have greatly changed the way cancer is treated. In addition to PD-1, new immune checkpoints are constantly excavated to better treat cancer. Recently, protein tyrosine phosphatase 1B (PTP1B) was identified as a new immune checkpoint and played a critical role in the treatment of tumors by inhibiting the proliferation and cytotoxicity of T cells induced by tumor antigen. To explore the targeting role of PTP1B in precision tumor therapy, we deeply analyzed the expression and prognosis of PTP1B in all tumors. Survival analysis results indicated that PTP1B was highly expressed in most tumor tissues and indicated poor prognosis in acute-myeloid-leukemia (LAML), brain-lower-grade-glioma (LGG), kidney-renal clear-cell-carcinoma (KIRC) and uveal-melanoma (UVM). The methylation status of PTP1B in these four tumors exhibited hypomethylation and mutation landscape showed that PTP1B had its specific characteristics in genomic instability and heterogeneity. The homologous recombination deficiency (HRD) and loss of heterozygosity (LOH) were positive related to PTP1B expression in liver-hepatocellular-carcinoma (LIHC) and kidney-chromophobe (KICH), while the immunescore and immune infiltration displayed a significant positive correlation with PTP1B expression in LGG and UVM. Drug sensitivity tests showed that the PTP1B inhibitor MSI-1436 had a sensitivity effect suppressing tumor cell viability and suggested it enhanced the efficacy of PD-1 inhibitors in cancers.

Pan-cancer analysis of ASB3 and the potential clinical implications for immune microenvironment of glioblastoma multiforme.

Ankyrin repeat and SOCS Box containing 3 (ASB3) is an E3 ubiquitin ligase. It has been reported to regulate the progression of some cancers, but no systematic pan-cancer analysis has been conducted to explore its function in prognosis and immune microenvironment. In this study, mRNA expression data were downloaded from TCGA and GTEx database. Next generation sequencing data from 14 glioblastoma multiforme (GBM) samples by neurosurgical resection were used as validation dataset. Multiple bioinformatics methods (ssGSEA, Kaplan-Meier, Cox regression analysis, GSEA and online tools) were applied to explore ASB3 expression, gene activity, prognosis of patients in various cancers, and its correlation with clinical information, immune microenvironment and pertinent signal pathways in GBM. The biological function of ASB3 in tumor-infiltrating lymphocytes (TILs) was verified using an animal model. We found that ASB3 was aberrant expressed in a variety of tumors, especially in GBM, and significantly correlated with the prognosis of cancer patients. The level of ASB3 was related to the TMB, MSI and immune cell infiltration in some cancer types. ASB3 had a negative association with immune infiltration and TME, including regulatory T cells (Tregs), cancer-associated fibroblasts, immunosuppressors and related signaling pathways in GBM. ASB3 overexpression reduced the proportion of Tregs in TILs. GSEA and PPI analysis also showed negative correlation between ASB3 expression and oncogenetic signaling pathways in GBM. A comprehensive pan-cancer analysis of ASB3 showed its potential function as a biomarker of cancer prognosis and effective prediction of immunotherapy response. This study not only enriches the understanding of the biological function of ASB3 in pan-cancer, especially in GBM immunity, but also provides a new reference for the personalized immunotherapy of GBM.

Research progress in immune microenvironment and immunotherapy of brain metastasis in non-small cell lung cancer.

In recent years, the rise of immunotherapy has comprehensively changed the treatment pattern of advanced non-small cell lung cancer(NSCLC). With the understanding of the immune microenvironment in brain metastasis, patients with advanced lung cancer with brain metastasis, who usually were previously excluded from clinical studies, gradually gained attention from researchers. The development from immune monotherapy to combination with chemotherapy significantly improved the survival prognosis of patients with brain metastases from lung cancer. This review aimed to briefly elucidate the mechanism of the immune microenvironment, and summarized the latest research progress of immunotherapy for NSCLC patients with brain metastasis. 近年来，免疫治疗的兴起全面改变了晚期非小细胞肺癌的治疗格局。随着对肿瘤免疫微环境的研究渐深，常被临床研究排除在外的肺癌晚期脑转移患者逐渐被研究者们关注，从免疫单药治疗发展到免疫联合治疗，极大程度改善了脑转移肺癌患者的生存预后。本文旨在阐述转移灶的免疫微环境基础，同时回顾并总结近年来非小细胞肺癌脑转移免疫治疗的最新研究进展。.

Feasibility and acceptability of the Resilient Living program among persons with stroke or brain tumor and their family caregivers.

Practice guidelines and research results emphasize the need for dyadic interventions targeting psychosocial outcomes such as depression, anxiety, social function, physical function, and health-related quality of life. Resilience interventions have been proposed as one strategy to influence these outcomes. The objective of this observational pilot study was to determine the feasibility and acceptability of the Resilient Living program among persons with stroke or brain tumor (BT) admitted for comprehensive acute inpatient rehabilitation andor their family caregivers. A secondary aim was to gather preliminary data to assess the effects of the program on quality of life, stress, anxiety, physical function, sleep disturbance, fatigue, resilience, dyadic coping, and caregiver role overload. The Resilient Living program is a psychosocial intervention with a focus on building resilience skills. Feasibility and acceptability outcomes were assessed at the end of the study. Quantitative outcome measures were collected at baseline, 12 weeks, and 6 months post the intervention. Eight patients and eight caregivers completed the study. The intervention was feasible with this population. Participants found the intervention useful and appreciated the flexibility of an online program however, finding time to engage in it was challenging. Recruitment of eligible patients with acquired brain disorders and their caregivers as a dyad was challenging. The study confirms prior research suggesting that interventions targeting resilience are feasible, but larger studies with more rigorous methods are needed to appreciate the influence of resilience interventions in persons with brain disorders and their caregivers. Further research is needed to identify the characteristics of those most likely to benefit from resilience interventions and the optimal timing of such interventions.

Clinical utility of soluble CD163 and its diagnostic and prognostic value in a variety of neurological disorders.

Nowadays, many people suffer from Neurological Diseases (NDs), particularly neurodegenerative diseases. Hence, there is an urgent need to discover new and more effective diagnostic and prognostic biomarkers as well as therapeutic strategies for the treatment of NDs. In this context, detecting biomarkers can provide helpful information on various levels of NDs. Up to now, there has been a lot of progress in recognizing these diseases, but they are not completely clear yet. NDs are associated with inflammatory conditions and there are several differences in NDs immune biomarkers compared to normal conditions. Among these biomarkers, soluble CD163 (sCD163) levels (as a new biomarker) increase in biofluids, relating to the activation of macrophagemicroglia and inflammation levels in NDs. ADAM17TACE and ADAM10 are the responsible enzymes for producing sCD163 from macrophages. Increased shedding of CD163 is caused by inflammatory stimuli, and a function has been hypothesized for sCD163 in immunological suppression. When the body confronts an inflammation or infection, the concentration of sCD163 drives up. sCD163 is stable and can be easily quantified in the serum. In addition to its role as a biomarker, sCD163 can be a good modulator of adaptive immune suppression after stroke. sCD163, with a long half-life, has been proposed to be a surrogate for some critical markers such as Tumor Necrosis Factor-α (TNF-α). Furthermore, sCD163 production can be regulated by some regentsapproaches such as zidovudine, nanotechnology, combination antiretroviral treatment, and aprepitant. Considering the importance of the issue, the critical role of sCD163 in NDs was highlighted for novel diagnostic and prognostic purposes.

Stereotactic radiosurgery for pituitary and cavernous sinus metastases.

Metastases extending to the pituitary gland and cavernous sinus are extremely rare however, advances in neuroimaging have increased the reported incidence. Stereotactic radiosurgery (SRS) affords the precise delivery of focused radiation to minimize adverse radiation effects. This study assessed the efficacy and safety of SRS in the treatment of pituitary and cavernous sinus metastases. Analysis was performed on 23 patients with pituitary and cavernous sinus metastases who underwent treatment using SRS between 1996 and 2021. The cohort was categorized into 2 groups in terms of metastasis location pituitary involvement (Group 1, n 11) and cavernous sinus involvement (Group 2, n 12). Overall survival, local tumor control, and distal tumor control rates were compared between the two groups using Kaplan-Meier analysis. The median age of the cohort was 52.2 years and the median tumor volume was 4.5 mL. Overall survival rates were as follows 1 year (72.9%), 2 years (51.8%), and 3 years (45.3%). Local tumor control rates were as follows 1 year (82.3%), 2 years (82.3%), and 3 years (65.9%). Visual deficit and hypopituitarism were the most common presentations in Group 1, whereas cranial nerve deficit was the most common presentation in Group 2. SRS appears to be a safe and effective therapy for the treatment of pituitary and cavernous sinus metastases. GKRS is a relatively simple procedure, which places minimal stress on the patient, thereby facilitating further anti-cancer treatment. Considering the limited survival duration in cases of metastasis, it is very likely that post-GKRS complications (e.g., new onset cranial nerve deficit and hypopituitarism) would not become an issue before patient passes away.

The clinicopathological features and prognosis of multifocal high-grade gliomas in adults with

To explore the clinicopathological features and prognosis of multifocal high-grade gliomas (M-HGGs) with Four adult patients with All patients were IDH wild-type and TERT wild-type, and P53 was overexpressed. A patient with the We describe the clinicopathological features and outcomes of 4 adult M-HGGs patients with

CD171 Multi-epitope peptide design based on immuno-informatics approach as a cancer vaccine candidate for glioblastoma.

Glioblastoma (GB) is a common primary malignancy of the central nervous system, and one of the highly lethal brain tumors. GB cells can promote therapeutic resistance and tumor angiogenesis. The CD171 is an adhesion molecule in neuronal cells that is expressed in glioma cells as a regulator of brain development during the embryonic period. CD171 is one of the immunoglobulin-like CAMs (cell adhesion molecules) families that can be associated with prognosis in a variety of human tumors. The multi-epitope peptide vaccines are based on synthetic peptides with a combination of both B-cell epitopes and T-cell epitopes, which can induce specific humoral or cellular immune responses. Moreover, Cholera toxin subunit B (CTB), a novel TLR agonist was utilized in the final construct to polarize CD4 T cells toward T-helper 1 to induce strong cytotoxic T lymphocytes (CTL) responses. In the present study, several immune-informatics tools were used for analyzing the CD171 sequence and studying the important characteristics of a designed vaccine. The results included molecular docking, molecular dynamics simulation, immune response simulation, prediction and validation of the secondary and tertiary structure, physicochemical properties, solubility, conservancy, toxicity as well as antigenicity and allergenicity of the promising candidate for a vaccine against CD171. The immuno-informatic analyze suggested 12 predicted multi-epitope peptides, whose construction consists of 582 residues long. Therewith, cloning adaptation of the designed vaccine was performed, and eventually sequence was inserted into pET30a () vector for the application of the anti-glioblastoma vaccine development.Communicated by Ramaswamy H. Sarma.

Review of the Recent Changes in the WHO Classification for Pediatric Brain and Spinal Cord Tumors.

Periodic updates to the World Health Organization (WHO) classification system for central nervous system (CNS) tumors reflect advances in the pathological diagnosis, categorization, and molecular underpinnings of primary brain, spinal cord, and peripheral nerve tumors. The 5th edition of the WHO Classification of CNS Tumors was published in 2021. This review discusses the guiding principles of the revision, introduces the more common new diagnostic entities, and describes tumor classification and nomenclature changes that are relevant for pediatric neurological surgeons. Revisions to the WHO CNS tumor classification system introduced new diagnostic entities, restructured and renamed other entities with particular impact in the diffuse gliomas and CNS embryonal tumors, and expanded the requirements for incorporating both molecular and histological features of CNS tumors into a unified integrated diagnosis. Many of the new diagnostic entities occur at least occasionally in pediatric patients and will thus be encountered by pediatric neurosurgeons. New nomenclature impacts the terminology that is applied in communication between pathologists, surgeons, clinicians, and patients. Requirements for molecular information in tumor diagnosis is expected to refine diagnostic categories while also introducing practical considerations for intra-operative consultation, preliminary histological evaluation, and triaging of neurosurgical tissue samples for histology, molecular testing, and clinical trial requirements. Pediatric brain tumor diagnosis and clinical management is a multidisciplinary effort that is rapidly advancing in the molecular era. Interdisciplinary collaboration is critical for providing the best care for pediatric CNS tumor patients. Pediatric neurosurgeons and their local neuropathologists and neuro-oncologists must work collaboratively to put the most current CNS tumor diagnostic guidelines into standard practice.

Objective response rate (ORR) targets for recurrent glioblastoma clinical trials based on the historic association between ORR and median overall survival.

Durable objective response rate (ORR) remains a meaningful endpoint in recurrent cancer however, the target ORR for single arm recurrent glioblastoma trials has not been based on historic information or tied to patient outcomes. The current study reviewed 68 treatment arms comprising 4,793 patients in past trials in recurrent glioblastoma in order to judiciously define target ORRs for use in recurrent glioblastoma trials. ORR was estimated at 6.1%95% CI 4.23 8.76% for cytotoxic chemotherapies (ORR7.59% for CCNU, 7.57% for TMZ, 0.64% for CPT-11, and 5.32% for other agents), 3.37% for biologic agents, 7.97% for (select) immunotherapies, and 26.8% for anti-angiogenic agents. ORRs were significantly correlated with median overall survival (mOS) across chemotherapy (R20.4078,P<0.0001), biologics (R20.4003,P0.0003), and immunotherapy trials (R20.8994,P<0.0001), but not anti-angiogenic agents (R20, P0.8937). Pooling data from chemotherapy, biologics, and immunotherapy trials, a meta-analysis indicated a strong correlation between ORR and mOS (R20.3900, P<0.0001 mOSweeks1.4xORR24.8). Assuming an ineffective cytotoxic (control) therapy has ORR7.6%, the average ORR for lomustine and temozolomide trials, a sample size of ≥40 patients with target ORR>25% is needed to demonstrate statistical significance compared to control with a high level of confidence (P<0.01) and adequate power (>80%). Given this historic data and potential biases in patient selection, we recommend that well-controlled, single-arm phase II studies in recurrent glioblastoma should have a target ORR >25% (which translates to a median OS of approximately 15 months) and a sample size of ≥40 patients, in order to convincingly demonstrate antitumor activity. Crucially, this response needs to have sufficient durability, which was not addressed in the current study.

Reduced Graphene Oxide UWB Array Sensor High Performance for Brain Tumor Imaging and Detection.

A low cost, with high performance, reduced graphene oxide (RGO) Ultra-wide Band (UWB) array sensor is presented to be applied with a technique of confocal radar-based microwave imaging to recognize a tumor in a human brain. RGO is used to form its patches on a Taconic substrate. The sensor functioned in a range of 1.2 to 10.8 GHz under UWB frequency. The sensor demonstrates high gain of 5.2 to 14.5 dB, with the small size of 90 mm × 45 mm

Radiochemical Synthesis of 4-

Central nervous system tumors related to gliomas are of neuroectodermal origin and cover about 30% of all primary brain tumors. Glioma is not susceptible to any therapy and surgical attack remains one of the main approaches to its treatment. Preoperative tumor imaging methods, such as positron emission tomography (PET), are currently used to distinguish malignant tissue to increase the accuracy of glioma removal. However, PET is lacking a specific visualization of cells possessing certain molecular markers. Here, we report an application of aptamers to enhancing specificity in imaging tumor cells bearing the epidermal growth factor receptor (EGFR). Glioblastoma is characterized by increased EGFR expression, as well as mutations of this receptor associated with active division, migration, and adhesion of tumor cells. Since 2021, EGFR has been included into the WHO classification of gliomas as a molecular genetic marker. To obtain conjugates of aptamers GR20 and GOL1-specific to EGFR, a 4-

Targeting Copper in Cancer Imaging and Therapy A New Theragnostic Agent.

Copper is required for cancer cell proliferation and tumor angiogenesis. Copper-64 radionuclide (

Splenic Metastatic Choriocarcinoma with Nontraumatic Splenic Rupture A Case Report and Literature Review.

Choriocarcinoma is a highly malignant trophoblastic tumor that occurs mostly in women of childbearing age. The main mode of metastasis is hematogenous metastasis. The most common sites of metastasis are the lung, vagina and brain, while splenic metastasis is rare. Because of its rapid development, extensive metastasis can occur in a short period, and some patients only show metastatic symptoms, which are often missed or misdiagnosed as ectopic pregnancy or other diseases. We describe a rare case of splenic metastatic choriocarcinoma with acute abdominal pain caused by nontraumatic splenic rupture. In addition, we review the previous literature on splenic metastasis of choriocarcinoma and summarize the clinical manifestations, management measures and prognoses. Our case and literature review indicate that splenic metastatic choriocarcinoma is rare and difficult to distinguish from splenic ectopic pregnancy and other diseases. Clinicians should strengthen their understanding of this disease and avoid misdiagnosis.

Spheno-Orbital Meningioma and Vision Impairment-Case Report and Review of the Literature.

(1) Background Spheno-orbital meningioma (SOM) is a very rare subtype of meningioma which arises from the sphenoid ridge with an orbital extension. It exhibits intraosseous tumor growth with hyperostosis and a widespread soft-tissue growth at the dura. The intra-orbital invasion results in painless proptosis and slowly progressing visual impairment. (2) Methods We present a case of a 46-year-old woman with SOM and compressive optic nerve neuropathy related to it. Her corrected distance visual acuity (CDVA) was decreased to 20100, she had extensive visual field (VF) scotoma, dyschromatopsia, impaired pattern-reversal visual-evoked potential (PVEP), and decreased thicknesses of the retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC), measured with the swept-source optical coherence tomography (SS-OCT), and a pale optic nerve disc in her left eye. Brain CT and MRI showed a lesion at the base of the anterior cranial fossa, involving the sphenoid wing and orbit. Pterional craniotomy and a partial removal of the tumor at the base of the skull and in the left orbit with the resection of the lesional dura mater and bony defect reconstruction were performed. (3) Results The histological examination revealed meningothelial meningioma (WHO G1). Decreased CDVA and VF defects completely recovered, and the color vision score and PVEP improved following the surgery, but RNFL and GCC remained impaired. No tumor recurrence was observed at a follow-up of 78 months. (4) Conclusions Optic nerve dysfunction has the capacity to improve once the compression has been relieved despite the presence of the structural features of optic nerve atrophy.

Fetal Brain Tumors, a Challenge in Prenatal Diagnosis, Counselling, and Therapy.

Fetal brain tumors are a rare entity with an overall guarded prognosis. About 10% of congenital brain tumors are diagnosed during fetal life. They differ from the postnatally encountered pediatric brain tumors with respect to location and tumor type. Fetal brain tumors can be benign or malignant and infiltrate or displace adjacent brain structures. Due to their high mitotic rate, they can show rapid growth. Outcome depends on age of diagnosis, size, and histological tumor type. Findings like polyhydramnios and macrocephaly encountered on routine ultrasound are frequently associated. Detailed prenatal anomaly scan and subsequent fetal magnetic resonance imaging (MRI) may identify the brain tumor and its severity. Both maternal and fetal prognosis should be included in prenatal counselling and decision making.

Imaging of Indocyanine Green-Human Serum Albumin (ICG-HSA) Complex in Secreted Protein Acidic and Rich in Cysteine (SPARC)-Expressing Glioblastoma.

Glioblastoma is the most common and fatal primary glioma and has a severe prognosis. It is a challenge for neurosurgeons to remove brain tumor tissues completely by resection. Meanwhile, fluorescence-guided surgery (FGS) is a technique used in glioma surgery to enhance the visualization of tumor edges to clarify the extent of tumor resection. Indocyanine green (ICG) is the only FDA-approved NIR fluorescent agent. It non-covalently binds to human serum albumin (HSA). Secreted protein acidic and rich in cysteine (SPARC) is an extracellular glycoprotein expressed in gliomas and binds to albumin, suggesting that it plays an important role in tumor uptake of the ICG-HSA complex. Here we demonstrate the binding properties of HSA or SPARC to ICG using surface plasmon resonance and saturation binding assay. According to in vitro and in vivo studies, the results showed that the uptake of ICG-HSA complex was higher in SPARC-expressing glioblastoma cell line and tumor region compared with the uptake of free ICG. Here, we visualized the SPARC-dependent uptake of ICG and ICG-HSA complex in U87MG. Our results demonstrated that the ICG-HSA complex is likely to be used as an efficient imaging agent targeting SPARC-expressing tumors, especially glioblastoma.

The Role of Hyperexcitability in Gliomagenesis.

Glioblastoma is the most common malignant primary brain tumor. Recent studies have demonstrated that excitatory or activity-dependent signaling-both synaptic and non-synaptic-contribute to the progression of glioblastoma. Glutamatergic receptors may be stimulated via neuron-tumor synapses or release of glutamate by the tumor itself. Ion currents generated by these receptors directly alter the structure of membrane adhesion molecules and cytoskeletal proteins to promote migratory behavior. Additionally, the hyperexcitable milieu surrounding glioma increases the rate at which tumor cells proliferate and drive recurrent disease. Inhibition of excitatory signaling has shown to effectively reduce its pro-migratory and -proliferative effects.

Simultaneous Antagonism at H3RD2RD3R Reduces Autism-like Self-Grooming and Aggressive Behaviors by Mitigating MAPK Activation in Mice.

Dysregulation in brain neurotransmitters underlies several neuropsychiatric disorders, e.g., autism spectrum disorder (ASD). Also, abnormalities in the extracellular-signal-regulated kinase (ERK)mitogen-activated protein kinase (MAPK) pathway pave the way for neuroinflammation, neurodegeneration, and altered learning phenotype in ASD. Therefore, the effects of chronic systemic administration of the multiple-targeting antagonist ST-713 at the histamine H3 receptor (H3R) and dopamine D2D3 receptors (D2D3R) on repetitive self-grooming, aggressive behaviors, and abnormalities in the MAPK pathway in BTBR T Itpr3tfJ (BTBR) mice were assessed. The results showed that ST-713 (2.5, 5, and 10 mgkg, i.p.) mitigated repetitive self-grooming and aggression in BTBR mice (all

A Comparison of PET Tracers in Recurrent High-Grade Gliomas A Systematic Review.

Humans with high-grade gliomas have a poor prognosis, with a mean survival time of just 12-18 months for patients who undergo standard-of-care tumor resection and adjuvant therapy. Currently, surgery and chemoradiotherapy serve as standard treatments for this condition, yet these can be complicated by the tumor location, growth rate and recurrence. Currently, gadolinium-based, contrast-enhanced magnetic resonance imaging (CE-MRI) serves as the predominant imaging modality for recurrent high-grade gliomas, but it faces several drawbacks, including its inability to distinguish tumor recurrence from treatment-related changes and its failure to reveal the entirety of tumor burden (de novo or recurrent) due to limitations inherent to gadolinium contrast. As such, alternative imaging modalities that can address these limitations, including positron emission tomography (PET), are worth pursuing. To this end, the identification of PET-based markers for use in imaging of recurrent high-grade gliomas is paramount. This review will highlight several PET radiotracers that have been implemented in clinical practice and provide a comparison between them to assess the efficacy of these tracers.

Induction of Oxidative Stress in SH-SY5Y Cells by Overexpression of hTau40 and Its Mitigation by Redox-Active Nanoparticles.

Abnormally phosphorylated tau protein is the principal component of neurofibrillary tangles, accumulating in the brain in many neurodegenerative diseases, including Alzheimers disease. The aim of this study was to examine whether overexpression of tau protein leads to changes in the redox status of human neuroblastoma SH-SY5Y cells. The level of reactive oxygen species (ROS) was elevated in tau-overexpressing cells (TAU cells) as compared with cells transfected with the empty vector (EP cells). The level of glutathione was increased in TAU cells, apparently due to overproduction as an adaptation to oxidative stress. The TAU cells had elevated mitochondrial mass. They were more sensitive to 6-hydroxydopamine, delphinidin, 4-amino-TEMPO, and nitroxide-containing nanoparticles (NPs) compared to EP controls. These results indicate that overexpression of the tau protein imposes oxidative stress on the cells. The nitroxide 4-amino-TEMPO and nitroxide-containing nanoparticles (NPs) mitigated oxidative stress in TAU cells, decreasing the level of ROS. Nitroxide-containing nanoparticles lowered the level of lipid peroxidation in both TAU and EP cells, suggesting that nitroxides and NPs may mitigate tau-protein-induced oxidative stress.

Tumor Microenvironment and Metabolism Role of the Mitochondrial Melatonergic Pathway in Determining Intercellular Interactions in a New Dynamic Homeostasis.

There is a growing interest in the role of alterations in mitochondrial metabolism in the pathoetiology and pathophysiology of cancers, including within the array of diverse cells that can form a given tumor microenvironment. The exhaustion in natural killer cells and CD8 t cells as well as the tolerogenic nature of dendritic cells in the tumor microenvironment seems determined by variations in mitochondrial function. Recent work has highlighted the important role played by the melatonergic pathway in optimizing mitochondrial function, limiting ROS production, endogenous antioxidants upregulation and consequent impacts of mitochondrial ROS on ROS-dependent microRNAs, thereby impacting on patterned gene expression. Within the tumor microenvironment, the tumor, in a quest for survival, seeks to dominate the dynamic intercellular interactions by limiting the capacity of cells to optimally function, via the regulation of their mitochondrial melatonergic pathway. One aspect of this is the tumors upregulation of kynurenine and the activation of the aryl hydrocarbon receptor, which acts to metabolize melatonin and increase the N-acetylserotoninmelatonin ratio, with effluxed N-acetylserotonin acting as a brain-derived neurotrophic factor (BDNF) mimic via its activation of the BDNF receptor, TrkB, thereby increasing the survival and proliferation of tumors and cancer stem-like cells. This article highlights how many of the known regulators of cells in the tumor microenvironment can be downstream of the mitochondrial melatonergic pathway regulation. Future research and treatment implications are indicated.

Microcapsule-Based Dose-Dependent Regulation of the Lifespan and Behavior of Adipose-Derived MSCs as a Cell-Mediated Delivery System In Vitro Study.

The development of biohybrid drug delivery systems (DDS) based on mesenchymal stemstromal cells (MSCs) is an important focus of current biotechnology research, particularly in the areas of oncotheranostics, regenerative medicine, and tissue bioengineering. However, the behavior of MSCs at sites of inflammation and tumor growth is relevant to potential tumor transformation, immunosuppression, the inhibition or stimulation of tumor growth, metastasis, and angiogenesis. Therefore, the concept was formulated to control the lifespan of MSCs for a specific time sufficient for drug delivery to the target tissue by varying the number of internalized microcontainers. The current study addressed the time-dependent in vitro assessment of the viability, migration, and division of human adipose-derived MSCs (hAMSCs) as a function of the dose of internalized polyelectrolyte microcapsules prepared using a layer-by-layer technique. Polystyrene sulfonate (PSS)-poly(allylamine hydrochloride) (PAH)-coated spherical micrometer-sized (diameter 2-3 µm) vaterite (CaCO

Peripheral Inflammatory Markers TNF-α and CCL2 Revisited Association with Parkinsons Disease Severity.

One of the major mediators of neuroinflammation in PD is tumour necrosis factor alpha (TNF-α), which, similar to other cytokines, is produced by activated microglia and astrocytes. Although TNF-α can be neuroprotective in the brain, long-term neuroinflammation and TNF release can be harmful, having a neurotoxic role that leads to death of oligodendrocytes, astrocytes, and neurons and, therefore, is associated with neurodegeneration. Apart from cytokines, a wide family of molecules with homologous structures, namely chemokines, play a key role in neuro-inflammation by drawing cytotoxic T-lymphocytes and activating microglia. The objective of the current study was to examine the levels of the serum TNF-α and CCL2 (Chemokine (C-C motif) ligand 2), also known as MCP-1 (Monocyte Chemoattractant Protein-1), in PD patients compared with healthy controls. We also investigated the associations between the serum levels of these two inflammatory mediators and a number of clinical symptoms, in particular, disease severity and cognition. Such an assessment may point to their prognostic value and provide some treatment hints. PD patients with advanced stage on the Hoehn-Yahr scale showed an increase in TNF-α levels compared with PD patients with stages 1 and 2 (

Matched Analyses of Brain Metastases versus Primary Non-Small Cell Lung Cancer Reveal a Unique microRNA Signature.

Distant spreading of tumor cells to the central nervous system in non-small cell lung cancer (NSCLC) occurs frequently and poses major clinical issues due to limited treatment options. RNAs displaying differential expression in brain metastasis versus primary NSCLC may explain distant tumor growth and may potentially be used as therapeutic targets. In this study, we conducted systematic microRNA expression profiling from tissue biopsies of primary NSCLC and brain metastases from 25 patients. RNA analysis was performed using the nCounter Human v3 miRNA Expression Assay, NanoString technologies, followed by differential expression analysis and in silico target gene pathway analysis. We uncovered a panel of 11 microRNAs with differential expression and excellent diagnostic performance in brain metastasis versus primary NSCLC. Five microRNAs were upregulated in brain metastasis (miR-129-2-3p, miR-124-3p, miR-219a-2-3p, miR-219a-5p, and miR-9-5p) and six microRNAs were downregulated in brain metastasis (miR-142-3p, miR-150-5p, miR-199b-5p, miR-199a-3p, miR-199b-5p, and miR-199a-5p). The differentially expressed microRNAs were predicted to converge on distinct target gene networks originating from five to twelve core target genes. In conclusion, we uncovered a unique microRNA profile linked to two target gene networks. Our results highlight the potential of specific microRNAs as biomarkers for brain metastasis in NSCLC and indicate plausible mechanistic connections.

Reclassification of TCGA Diffuse Glioma Profiles Linked to Transcriptomic, Epigenetic, Genomic and Clinical Data, According to the 2021 WHO CNS Tumor Classification.

In 2021, the fifth edition of the WHO classification of tumors of the central nervous system (WHO CNS5) was published. Molecular features of tumors were directly incorporated into the diagnostic decision tree, thus affecting both the typing and staging of the tumor. It has changed the traditional approach, based solely on histopathological classification. The Cancer Genome Atlas project (TCGA) is one of the main sources of molecular information about gliomas, including clinically annotated transcriptomic and genomic profiles. Although TCGA itself has played a pivotal role in developing the WHO CNS5 classification, its proprietary databases still retain outdated diagnoses which frequently appear incorrect and misleading according to the WHO CNS5 standards. We aimed to define the up-to-date annotations for gliomas from TCGAs database that other scientists can use in their research. Based on WHO CNS5 guidelines, we developed an algorithm for the reclassification of TCGA glioma samples by molecular features. We updated tumor type and diagnosis for 828 out of a total of 1122 TCGA glioma cases, after which available transcriptomic and methylation data showed clustering features more consistent with the updated grouping. We also observed better stratification by overall survival for the updated diagnoses, yet WHO grade 3

Bacterial DNAemia in Alzheimers Disease and Mild Cognitive Impairment Association with Cognitive Decline, Plasma BDNF Levels, and Inflammatory Response.

Microbial dysbiosis (MD) provokes gut barrier alterations and bacterial translocation in the bloodstream. The increased blood bacterial DNA (BB-DNA) may promote peripheral- and neuro-inflammation, contributing to cognitive impairment. MD also influences brain-derived neurotrophic factor (BDNF) production, whose alterations contribute to the etiopathogenesis of Alzheimers disease (AD). The purpose of this study is to measure BB-DNA in healthy elderly controls (EC), and in patients with mild cognitive impairment (MCI) and AD to explore the effect on plasma BDNF levels (pBDNF), the inflammatory response, and the association with cognitive decline during a two-year follow-up. Baseline BB-DNA and pBDNF were significantly higher in MCI and AD than in EC. BB-DNA was positively correlated with pBDNF in AD, plasma Tumor necrosis factor-alpha (TNF-α), and Interleukin-10 (IL-10) levels in MCI. AD patients with BB-DNA values above the 50th percentile had lower baseline Mini-Mental State Examination (MMSE). After a two-year follow-up, AD patients with the highest BB-DNA tertile had a worse cognitive decline, while higher BB-DNA levels were associated with higher TNF-α and lower IL-10 in MCI. Our study demonstrates that, in early AD, the higher the BB-DNA levels, the higher the pBDNF levels, suggesting a defensive attempt BB-DNA seems to play a role in the AD severityprogression in MCI, higher BB-DNA may trigger an increased inflammatory response.