Systematic Review of Cerebrospinal Fluid Biomarker Discovery in Neuro-Oncology: A Roadmap to Standardization and Clinical Application.

Effective diagnosis, prognostication, and management of CNS malignancies traditionally involves invasive brain biopsies that pose significant risk to the patient. Sampling and molecular profiling of cerebrospinal fluid (CSF) is a safer, rapid, and noninvasive alternative that offers a snapshot of the intracranial milieu while overcoming the challenge of sampling error that plagues conventional brain biopsy. Although numerous biomarkers have been identified, translational challenges remain, and standardization of protocols is necessary. Here, we systematically reviewed 141 studies (Medline, SCOPUS, and Biosis databases; between January 2000 and September 29, 2022) that molecularly profiled CSF from adults with brain malignancies including glioma, brain metastasis, and primary and secondary CNS lymphomas. We provide an overview of promising CSF biomarkers, propose CSF reporting guidelines, and discuss the various considerations that go into biomarker discovery, including the influence of blood-brain barrier disruption, cell of origin, and site of CSF acquisition (eg, lumbar and ventricular). We also performed a meta-analysis of proteomic data sets, identifying biomarkers in CNS malignancies and establishing a resource for the research community.

Homology Modeling, Molecular Dynamics Simulation, and Prediction of Bovine TLR2 Heterodimerization.

Toll-like receptor 2 (TLR2) is a major membrane-bound receptor with ligand and species specificity that activates the host immune response. Heterodimerization of TLR2 with TLR1 (TLR2/1) or TLR6 (TLR2/6), triggered by ligand binding, is essential to initiating the signaling pathway. Bovine TLR2 (bTLR2) heterodimerization has not been defined yet compared with human and mouse TLR2s (hTLR2 and mTLR2). The aim of the present study was to model bovine TLRs (TLRs 1, 2 and 6) and create the heterodimeric forms of the bovine TLR2 using molecular dynamics (MD) simulations. We compared the intermolecular interactions in bTLR2/1-PAM3 and bTLR2/6-PAM2 with the hTLR2 and mTLR2 complexes through docking simulations and subsequent MD analyses. The present computational findings showed that bTLR2 dimerization could have a biological function and activate the immune response, similar to hTLR2 and mTLR2. Agonists and antagonists that are designed for hTLR2 and mTLR2 can target bTLR2. However, the experimental approaches to comparing the functional immune response of TLR2 across species were missing in the present study. This computational study provides a structural analysis of the bTLR2 interaction with bTLR1 and bTLR6 in the presence of an agonist/antagonist and reveals the three-dimensional structure of bTLR2 dimerization. The present findings could guide future experimental studies targeting bTLR2 with different ligands and lipopeptides.

The Prevalence of Seizures in Brain Metastasis Patients on Anticonvulsant Prophylaxis: A Systematic Review and Meta-Analysis.

BACKGROUND: Brain metastasis (BM) prognosis is incredibly poor and is often associated with considerable morbidity. Seizures are commonly present in these patients, and their biopsychosocial impact can be dangerous. The use of antiepileptic drugs (AEDs) as primary prophylaxis remains controversial. This systematic review and meta-analysis aim to evaluate the efficacy of AED prophylaxis in patients with BM. METHODS: MEDLINE via PubMed, Web of Science, EMBASE, and Cochrane were searched for articles pertinent to AED prophylaxis use in patients with BM. Patients with BM previously treated for cancer who were seizure naive at the time of inclusion were included. Data regarding patient characteristics, type of AED, prior treatments, and groups at a high risk of seizure were extracted. Seizure prevalence was obtained. RESULTS: Eight studies were included in this systematic review and meta-analysis; 1902 total patients with BM were included, with 381 receiving antiepileptic prophylaxis, and 1521 receiving no prophylaxis. Although the odds of a seizure in the treatment group was found to be 1.158 times the odds of a seizure in the control group, the odds ratio was not statistically significant (t-statistic = 0.62, P value = 0.5543). CONCLUSIONS: There was no significant difference in the odds of seizure development in control groups compared to patients receiving prophylactic antiepileptic therapy. As patients with BM present with heterogeneity in tumor characteristics and receive various treatment modalities, future research is needed to identify groups that may benefit more significantly from AED prophylaxis.

Analysis of anemia and iron supplementation among glioblastoma patients reveals sex-biased association between anemia and survival.

The association between anemia and outcomes in glioblastoma patients is unclear. We analyzed data from 1346 histologically confirmed adult glioblastoma patients in the TriNetX Research Network. Median hemoglobin and hematocrit levels were quantified for 6 months following diagnosis and used to classify patients as anemic or non-anemic. Associations of anemia and iron supplementation of anemic patients with median overall survival (median-OS) were then studied. Among 1346 glioblastoma patients, 35.9% of male and 40.5% of female patients were classified as anemic using hemoglobin-based WHO guidelines. Among males, anemia was associated with reduced median-OS compared to matched non-anemic males using hemoglobin (HR 1.24; 95% CI 1.00-1.53) or hematocrit-based cutoffs (HR 1.28; 95% CI 1.03-1.59). Among females, anemia was not associated with median-OS using hemoglobin (HR 1.00; 95% CI 0.78-1.27) or hematocrit-based cutoffs (HR: 1.10; 95% CI 0.85-1.41). Iron supplementation of anemic females trended toward increased median-OS (HR 0.61; 95% CI 0.32-1.19) although failing to reach statistical significance whereas no significant association was found in anemic males (HR 0.85; 95% CI 0.41-1.75). Functional transferrin-binding assays confirmed sexually dimorphic binding in resected patient samples indicating underlying differences in iron biology. Anemia among glioblastoma patients exhibits a sex-specific association with survival.

Clinical outcomes of MR-guided laser interstitial thermal therapy corpus callosum ablation in drug-resistant epilepsy: a systematic review and meta-analysis.

OBJECTIVE: The goal of this systematic review and meta-analysis was to provide an updated analysis of studies investigating outcomes, morbidity, and mortality associated with MR-guided laser interstitial thermal therapy (MRgLITT) corpus callosum ablation (CCA). METHODS: Study inclusion criteria for screening required that studies report on human subjects only, including patients aged 1-52 years diagnosed with drug-resistant epilepsy who underwent CCA. Sixteen articles published between 2016 and 2023 were included for the systematic review and analysis, including 4 case reports, 11 case series, and 1 case-control study. Altogether, 85 pediatric and adult patients undergoing CCA were included in the systematic review (46 patients younger and 39 patients older than 21 years). The main outcome of seizure freedom was measured using the decrease in the frequency of atonic seizures following surgery, percentage of atonic seizure freedom following surgery, and percentage of overall seizure freedom following surgery. These measurements were made using data from the last follow-up for patients with at least 6 months of follow-up post-CCA. RESULTS: The extent of CCA differed across the pooled cohorts, including anterior two-thirds CCA (38.89%, n = 35) and posterior one-third CCA for completion of a prior partial CCA (22.22%, n = 20), complete CCA (27.78%, n = 25), or CCA of residual white matter in the case of subtotal initial ablation (5.56%, n = 5). Overall, 12.94% of the patients undergoing CCA experienced operational complications. The most common operative complications across 90 CCA operations were probe malpositioning (n = 6), hemorrhage (n = 5), off-target extension of splenium ablation to the thalamus (n = 1), infection (n = 1), and postoperative CSF leak (n = 1). Neurological deficits following CCA were reported as transient in 18.82% and permanent in 4.71% of patients across all studies. The most common neurological deficits were disconnection syndrome (n = 4) or transient hemiplegia (supplementary motor area-like syndrome; n = 4). The 6-month overall seizure freedom rate was 18.87% of 53 patients, and the atonic seizure freedom rate was 46.28% of 52 patients postoperatively. CCA resulted in an average decrease in atonic seizure rate from 8.30 to 1.65 atonic seizures per day (average decrease 80.12%). CONCLUSIONS: CCA is associated with an acceptable complication profile, and most patients experience a meaningful reduction in target seizure semiologies. Accurate MRgLITT probe placement is likely important for maximizing CCA while avoiding collateral damage. Avoidable complications of CCA include off-target ablation (and associated deficits), hemorrhage, and future surgery for residual CCA to palliate continued seizures.

Congenital Pediatric Hydrocephalus in the Brazilian Public Health System: The Reality of a Middle-Income Country in the Past 13 Years.

BACKGROUND: Congenital hydrocephalus is a significant challenge in neurosurgery, particularly in resource-limited settings. This study focuses on the congenital hydrocephalus in Brazil, a developing country, over the past 13 years. METHODS: This study is a retrospective analysis of congenital hydrocephalus treatment and outcomes using data records on DATASUS from January 2008 to July 2021. Demographics, cost of hospitalizations, amount paid to professionals, mortality, and mean length of stay (LOS) were analyzed. Statistical analysis was conducted to determine significant associations between these indicators and pediatric hydrocephalus. RESULTS: DATASUS recorded 8493 cases of congenital hydrocephalus in the studied period, with a prevalence of 24.28 per 100,000 newborns, mostly linked to spina bifida. Congenital hydrocephalus caused 60.83 ± 13.98 neonatal deaths per year, with the highest rate among 32-36 weeks gestational age. Acquired hydrocephalus led to 1063 infant deaths, whereas congenital hydrocephalus resulted in 3122 deaths, with no clear trend by the years. White infants had the highest mortality. A total of 33,184 shunt procedures were performed, with an average cost of $715.37 per procedure. The mortality model showed no significant effects of cost or professionals' salary, but a significant effect of LOS on hospitalization costs was observed. CONCLUSIONS: Pediatric hydrocephalus in Brazil's public health system is a significant burden. Congenital hydrocephalus prevalence and mortality emphasize the need for early diagnosis and treatment. Early diagnosis, prenatal care, and adequate resources are crucial. This study offers insights into congenital hydrocephalus, highlighting challenges and future directions for improved care.

Photodynamic Therapy for Glioblastoma: Illuminating the Path toward Clinical Applicability.

Glioblastoma (GBM) is the most common adult brain cancer. Despite extensive treatment protocols comprised of maximal surgical resection and adjuvant chemo-radiation, all glioblastomas recur and are eventually fatal. Emerging as a novel investigation for GBM treatment, photodynamic therapy (PDT) is a light-based modality that offers spatially and temporally specific delivery of anti-cancer therapy with limited systemic toxicity, making it an attractive option to target GBM cells remaining beyond the margins of surgical resection. Prior PDT approaches in GBM have been predominantly based on 5-aminolevulinic acid (5-ALA), a systemically administered drug that is metabolized only in cancer cells, prompting the release of reactive oxygen species (ROS), inducing tumor cell death via apoptosis. Hence, this review sets out to provide an overview of current PDT strategies, specifically addressing both the potential and shortcomings of 5-ALA as the most implemented photosensitizer. Subsequently, the challenges that impede the clinical translation of PDT are thoroughly analyzed, considering relevant gaps in the current PDT literature, such as variable uptake of 5-ALA by tumor cells, insufficient tissue penetrance of visible light, and poor oxygen recovery in 5-ALA-based PDT. Finally, novel investigations with the potential to improve the clinical applicability of PDT are highlighted, including longitudinal PDT delivery, photoimmunotherapy, nanoparticle-linked photosensitizers, and near-infrared radiation. The review concludes with commentary on clinical trials currently furthering the field of PDT for GBM. Ultimately, through addressing barriers to clinical translation of PDT and proposing solutions, this review provides a path for optimizing PDT as a paradigm-shifting treatment for GBM.

Local immunotherapy of glioblastoma: A comprehensive review of the concept.

Despite advancements in standard treatments, the prognosis of Glioblastoma (GBM) remains poor, prompting research for novel therapies. Immunotherapy is a promising treatment option for GBM, and many immunotherapeutic agents are currently under investigation. Chimeric antigen receptor (CAR) T cells are rapidly evolving in immunotherapy of GBM with many clinical trials showing efficacy of CAR T cells exerting anti-tumor activity following recognition of tumor-associated antigens (TAAs). Exhaustion in CAR T cells can reduce their capacity for long-term persistence and anti-tumor action. Local immunotherapy, which targets the tumor microenvironment and creates a more hospitable immunological environment for CAR T cells, has the potential to reduce CAR T cell exhaustion and increase immunity. Tertiary lymphoid structures (TLS) are ectopic lymphoid-like formations that can develop within the tumor microenvironment or in other non-lymphoid tissues. As a comprehensive local immunotherapy tool, the incorporation of TLS into an implanted biodegradable scaffold has amazing immunotherapeutic potential. The immune response to GBM can be improved even further by strategically inserting a stimulator of interferon genes (STING) agonist into the scaffold. Additionally, the scaffold's addition of glioma stem cells (GSC), which immunotherapeutic approaches may use to target, enhances the removal of cancer cells from their source. Furthermore, it has been demonstrated that GSCs have an impact on TLS formation, which helps to create a favorable tumor microenvironment. Herein, we overview local delivery of a highly specific tandem AND-gate CAR T cell along with above mentioned components. A multifaceted approach that successfully engages the immune system to mount an efficient targeted immune response against GBM is provided by the integration of CAR T cells, TLS, STING agonists, and GSCs within an implantable biodegradable scaffold. This approach offers a promising therapeutic approach for patients with GBM.

Suicidal ideation and attempts in brain tumor patients and survivors: A systematic review.

Background: Subsequent to a diagnosis of a brain tumor, psychological distress has been associated with negative effects on mental health as well as suicidality. The magnitude of such impact has been understudied in the literature. We conducted a systematic review to examine the impact of a brain tumor on suicidality (both ideation and attempts). Methods: In accordance with the PRISMA guidelines, we searched for relevant peer-reviewed journal articles on PubMed, Scopus, and Web of Science databases from inception to October 20, 2022. Studies investigating suicide ideation and/or attempt among patients with brain tumors were included. Results: Our search yielded 1,998 articles which were screened for eligibility. Seven studies consisting of 204,260 patients were included in the final review. Four studies comprising 203,906 patients (99.8%) reported elevated suicidal ideation and suicide attempt incidence compared with the general population. Prevalence of ideation and attempts ranged from 6.0% to 21.5% and 0.03% to 3.33%, respectively. Anxiety, depression, pain severity, physical impairment, glioblastoma diagnosis, male sex, and older age emerged as the primary risk factors associated with increased risk of suicidal ideation and attempts. Conclusion: Suicidal ideation and attempts are increased in patients and survivors of brain tumors compared to the general population. Early identification of patients exhibiting these behaviors is crucial for providing timely psychiatric support in neuro-oncological settings to mitigate potential harm. Future research is required to understand pharmacological, neurobiological, and psychiatric mechanisms that predispose brain tumor patients to suicidality.

Hyaluronan regulates sperm-induced inflammatory response by enhancing sperm attachment to bovine endometrial epithelial cells via CD44: in-silico and in-vitro approaches.

Recently, we reported that sperm induce cluster of differentiation 44 (CD44) expression and Toll-like receptor 2 (TLR2)-mediated inflammatory response in bovine uterus. In the present study, we hypothesized that the interaction between CD44 of bovine endometrial epithelial cells (BEECs) and hyaluronan (HA) affects sperm attachment and thereby enhancing TLR2-mediated inflammation. To test our hypothesis, at first, in-silico approaches were employed to define the binding affinity of HA for CD44 and TLR2. Further, an in-vitro experiment using the sperm-BEECs co-culture model was applied to investigate the effect of HA on sperm attachment and inflammatory response. Here, low molecular weight (LMW) HA at different concentrations (0, 0.1, 1, or 10 µg/mL) was incubated with BEECs for 2 h followed by the co-culture without- or with non-capacitated washed sperm (106/ml) for additional 3 h was performed. The present in-silico model clarified that CD44 is a high-affinity receptor for HA. Moreover, TLR2 interactions with HA oligomer (4- and 8-mers) target a different subdomain (h-bonds) compared to TLR2-agonist (PAM3) which targets a central hydrophobic pocket. However, the interaction of LMW HA (32-mers) with TLR2 revealed no stability of HA at any pocket of TLR2. Notably, the immunofluorescence analysis revealed the HA localization in both endometrial stroma and epithelia of ex-vivo endometrial explant. Moreover, ELISA showed significant levels of HA in BEECs culture media. Importantly, BEECs pretreatment with HA prior to sperm exposure increased the number of attached sperm to BEECs, and upregulated the transcriptional levels of pro-inflammatory genes (TNFA, IL-1B, IL-8, and PGES) in BEECs in response to sperm. However, BEECs treated with HA only (no sperm exposure) did not show any significant effect on the transcript abundance of pro-inflammatory genes when compared to the non-treated BEECs. Altogether, our findings strongly suggest a possible cross-talk between sperm and endometrial epithelial cells via HA and HA binding receptors (CD44 and TLR2) to induce a pro-inflammatory response in bovine uterus.

Sperm activate TLR2/TLR1 heterodimerization to induce a weak proinflammatory response in the bovine uterus.

Toll-like receptor 2 (TLR2) signaling pathway is involved in the sperm-triggered uterine inflammatory response at insemination, but its precise mechanism at molecular-level remains unknown. According to the ligand specificity, TLR2 forms a heterodimer with TLR1 or TLR6 as an initial step to mediate intracellular signaling, leading to a specific type of immune response. Hence, the present study aimed to identify the active TLR2 heterodimer (TLR2/1 or TLR2/6) that is involved in sperm-uterine immune crosstalk in bovine using various models. First, in-vitro (bovine endometrial epithelial cells, BEECs) and ex-vivo (bovine uterine explant) models were employed to test different TLR2 dimerization pathways in endometrial epithelia after exposure to sperm or TLR2 agonists; PAM3 (TLR2/1 agonist), and PAM2 (TLR2/6 agonist). Additionally, in-silico approaches were performed to confirm the dimer stability using de novo protein structure prediction model for bovine TLRs. The in-vitro approach revealed that sperm triggered the mRNA and protein expression of TLR1 and TLR2 but not TLR6 in BEECs. Moreover, this model disclosed that activation of TLR2/6 heterodimer, triggers a much stronger inflammatory response than TLR2/1 and sperm in bovine uterine epithelia. In the ex-vivo model that mimics the intact uterine tissue at insemination, sperm also induced the protein expression of both TLR1 and TLR2, but not TLR6, in bovine endometrium, particularly in uterine glands. Importantly, PAM3 and sperm induced similar and low mRNA expression of pro-inflammatory cytokines and TNFA protein to a lesser extent than PAM2 in endometrial epithelia. This implied that sperm might trigger a weak inflammatory response via TLR2/TLR1 activation which is similar to that of PAM3. Additionally, the in-silico analyses showed that the existence of bridging ligands is essential for heterodimer stability in bovine TLR2 with either TLR1 or TLR6. Altogether, the present findings revealed that sperm utilize TLR2/1, but not TLR2/6, heterodimerization to trigger a weak physiological inflammatory response in the bovine uterus. This might be the way to remove excess dead sperm remaining in the uterine lumen without tissue damage for providing an ideal uterine environment for early embryo reception and implantation.

The current state of the art of primary motor mapping for tumor resection: A focused survey.

INTRODUCTION: Cortical and subcortical motor mapping has advanced the notion of maximal safe resection of intra-axial brain tumours, thereby preserving neurological functions as well as improving survival. Despite being an age-old and established neurosurgical procedure across the world, the strategy and techniques involved in motor mapping have a gamut of variation due to a lack of defined standard protocols. METHODS: We disseminated a structured survey among focused group of neurosurgeons with established practices involving brain mapping. It consisted of 40 questions, split into five sections assessing the practice description, general approach for motor mapping, preference for asleep versus awake mapping, operative techniques and approach to representative tumor cases. Practice-patterns during primary motor mapping for brain tumours were analysed from responses of 51 neurosurgeons. RESULTS: 60.8 % felt that any lesion even near (without infiltration) was suffice to define "involvement" of the cortical/subcortical motor pathways. 82.4 % felt that motor mapping was necessary for brain tumours involving motor pathways, irrespective of the tumor histology or patient age. 90.2 % opined that tumor location was the predominant factor affecting their choice between awake or asleep mapping. 31.4 % believed that all cases should be performed awake unless patient-related medical, psychological, or anaesthetic contraindications exist, whereas 45.1 % felt that all cases should be performed asleep unless language mapping is required. MRI, DTI-based tractography and intra-operative fluorescence were the most commonly employed surgical adjuncts. CONCLUSIONS: The data from this survey may serve as a preliminary foundation for a more standardized approach to patient selection and the approach to motor mapping for brain tumors.

Risk of mortality in COVID-19 patients: a meta- and network analysis.

Understanding the most relevant hematological/biochemical characteristics, pre-existing health conditions and complications in survivors and non-survivor will aid in predicting COVID-19 patient mortality, as well as intensive care unit (ICU) referral and death. A literature review was conducted for COVID-19 mortality in PubMed, Scopus, and various preprint servers (bioRxiv, medRxiv and SSRN), with 97 observational studies and preprints, consisting of survivor and non-survivor sub-populations. This meta/network analysis comprised 19,014 COVID-19 patients, consisting of 14,359 survivors and 4655 non-survivors. Meta and network analyses were performed using META-MAR V2.7.0 and PAST software. The study revealed that non-survivors of COVID-19 had elevated levels of gamma-glutamyl transferase and creatinine, as well as a higher number of neutrophils. Non-survivors had fewer lymphocytes and platelets, as well as lower hemoglobin and albumin concentrations. Age, hypertension, and cerebrovascular disease were shown to be the most influential risk factors among non-survivors. The most common complication among non-survivors was heart failure, followed by septic shock and respiratory failure. Platelet counts, creatinine, aspartate aminotransferase, albumin, and blood urea nitrogen levels were all linked to ICU admission. Hemoglobin levels preferred non-ICU patients. Lower levels of hemoglobin, lymphocytes, and albumin were associated with increased mortality in ICU patients. This meta-analysis showed that inexpensive and fast biochemical and hematological tests, as well as pre-existing conditions and complications, can be used to estimate the risk of mortality in COVID-19 patients.

Early costs and complications of first-line low-grade glioma treatment using a large national database: Limitations and future perspectives.

Introduction: Diffuse Low-grade gliomas (DLGG, WHO Grade II) are a heterogenous group of tumors comprising 13-16% of glial tumors. While maximal safe resection is endorsed as the best approach to DLGG, compared to more conservative interventions like stereotactic biopsy, the added costs and risks have not been systematically evaluated. The purpose of this study was to better understand the complication rates and costs associated with each intervention. Methods: A retrospective cohort study using data from the IBM Watson Health MarketScan® Commercial Claims and Encounters database was conducted, using the International Classification of Diseases, Ninth Revision (ICD-9) codes corresponding to DLGG (2005-2014). Current Procedure Terminology, 4th Edition (CPT-4) codes were used to differentiate resection and biopsy cohorts. Inverse weighting by the propensity score was used to balance baseline potential confounders (age, sex, pre-op seizure, geographic region, year, Charleston Comorbidity Index). Complication rates, hospital mortality, readmission, and costs were compared between groups. Results: We identified 5,784 and 3,635 patients undergoing resection and biopsy, respectively, for initial DLGG management. Resection was associated with greater 30-day complications (29.17% vs. 26.34%; p < 0.05). However, this association became non-significant after inverse propensity weighting (adjusted odds ratio = 1.09; 0.98-1.20). There was no statistically significant difference in unadjusted, 30-day hospital mortality (p = 0.06) or re-admission (p = 0.52). Resection was associated with higher 90-day total costs (p < 0.0001) and drug costs (p < 0.0001). Biopsy was associated with greater index procedure costs (p < 0.0001). Long-term outcomes and evaluation of DLGG subtypes was not possible given limitations in the metrics recorded in MarketScan and lack of specificity in the ICD coding system. Conclusion: Resection was not associated with an increase in the adjusted complication rate after balancing for baseline prognostic factors. Total costs and drug costs were higher with resection of DLGG, but the index procedure costs were higher for biopsy. This data should help to facilitate prospective health economic analyses in the future to understand the cost-effectiveness, and impact on quality of life, for DLGG interventions. However, the use of large national databases for studying long-term outcomes in DLGG management should be discouraged until there is greater specificity in the ICD coding system for DLGG subtypes.

Electrocorticography-Guided Resection Enhances Postoperative Seizure Freedom in Low-Grade Tumor-Associated Epilepsy: A Systematic Review and Meta-Analysis.

BACKGROUND: Low-grade cerebral neoplasms are commonly associated with medically intractable epilepsy. Despite increasing evidence that epileptogenic brain regions commonly extend beyond visible tumor margins, the utility of extended surgical resections leveraging intraoperative electrocorticography (ECoG) remains unclear. OBJECTIVE: To determine whether ECoG-guided surgery is associated with improved postoperative seizure control. METHODS: We performed a systematic review and meta-analysis encompassing both adult and pediatric populations. The primary outcome measure was postoperative seizure freedom as defined by Engel class I outcome. Class I/II outcome served as a secondary measure. Relevant clinical and operative data were recorded. A random-effects meta-analysis based on the pooled odds ratio (OR) of seizure freedom was performed on studies that reported comparative data between ECoG-guided surgery and lesionectomy. RESULTS: A total of 31 studies encompassing 1115 patients with medically refractory epilepsy met inclusion criteria. Seven studies reported comparative data between ECoG-guided surgery and lesionectomy for meta-analysis. Tumor resection guided by ECoG was associated with significantly greater postoperative seizure freedom (OR 3.95, 95% CI 2.32-6.72, P < .0001) and class I/II outcome (OR 5.10, 95% CI 1.97-13.18, P = .0008) compared with lesionectomy. Postoperative adverse events were rare in both groups. CONCLUSION: These findings provide support for the utilization of ECoG-guided surgery to improve postoperative seizure freedom in cases of refractory epilepsy associated with low-grade neoplasms. However, this effect may be attenuated in the presence of concomitant cortical dysplasia, highlighting a need for improved presurgical and intraoperative monitoring for these most challenging cases of localization-related epilepsy.

Cerebrospinal fluid methylome-based liquid biopsies for accurate malignant brain neoplasm classification.

BACKGROUND: Resolving the differential diagnosis between brain metastases (BM), glioblastomas (GBM), and central nervous system lymphomas (CNSL) is an important dilemma for the clinical management of the main three intra-axial brain tumor types. Currently, treatment decisions require invasive diagnostic surgical biopsies that carry risks and morbidity. This study aimed to utilize methylomes from cerebrospinal fluid (CSF), a biofluid proximal to brain tumors, for reliable non-invasive classification that addresses limitations associated with low target abundance in existing approaches. METHODS: Binomial GLMnet classifiers of tumor type were built, in fifty iterations of 80% discovery sets, using CSF methylomes obtained from 57 BM, GBM, CNSL, and non-neoplastic control patients. Publicly-available tissue methylation profiles (N = 197) on these entities and normal brain parenchyma were used for validation and model optimization. RESULTS: Models reliably distinguished between BM (area under receiver operating characteristic curve [AUROC] = 0.93, 95% confidence interval [CI]: 0.71-1.0), GBM (AUROC = 0.83, 95% CI: 0.63-1.0), and CNSL (AUROC = 0.91, 95% CI: 0.66-1.0) in independent 20% validation sets. For validation, CSF-based methylome signatures reliably distinguished between tumor types within external tissue samples and tumors from non-neoplastic controls in CSF and tissue. CSF methylome signals were observed to align closely with tissue signatures for each entity. An additional set of optimized CSF-based models, built using tumor-specific features present in tissue data, showed enhanced classification accuracy. CONCLUSIONS: CSF methylomes are reliable for liquid biopsy-based classification of the major three malignant brain tumor types. We discuss how liquid biopsies may impact brain cancer management in the future by avoiding surgical risks, classifying unbiopsiable tumors, and guiding surgical planning when resection is indicated.

Multi-level analysis reveals the association between diabetes, body mass index, and HbA1c in an Iraqi population.

Type 2 diabetes (T2D) known as a complex metabolic disorder may cause health problems and changes in blood biochemical markers. A growing number of studies have looked into several biomarkers and their connections with T2D risk. However, few have explored the interconnection of these biomarkers, as well as the prospective alterations in the diabetes biomarker correlation network. We conducted a secondary analysis in order to introduce a multi-level approach to establish a relationship between diabetes, pre-diabetes, blood biochemical markers, age, and body mass index (BMI). The dataset was obtained from the Mendeley Data (available at https://data.mendeley.com/datasets/wj9rwkp9c2/1 . In this study, three groups were established: non-diabetic (n = 103), pre-diabetic (n = 53), and diabetic (n = 844). According to the Heatmap analysis, non-diabetic and pre-diabetic individuals had the lowest BMI, age, and HbA1c. Diabetes and pre-diabetes were correlated with BMI (r = 0.58 and - 0.27, respectively), age (r = 0.47 and - 0.28, respectively), and HbA1c (r = 0.55 and - 0.21, respectively) using Pearson analysis. Using multivariate analysis, we found that diabetes, BMI, age, HbA1c, cholesterol, triglyceride, LDL, VLDL, and HDL were all associated. Network analysis revealed a connection between BMI and diabetes at the highest cut-off point. Moreover, receiver operating characteristic (ROC) analysis validated the network findings, revealing that BMI (area under the ROC curve, AUC = 0.95), HbA1c (AUC = 0.94), and age (AUC = 0.84) were the best predictors of diabetes. In conclusion, our multi-step study revealed that identifying significant T2D predictors, such as BMI and HbA1c, required a series of mathematical analyses.

Leveraging the CSF proteome toward minimally-invasive diagnostics surveillance of brain malignancies.

Background: Diagnosis and prognostication of intra-axial brain tumors hinges on invasive brain sampling, which carries risk of morbidity. Minimally-invasive sampling of proximal fluids, also known as liquid biopsy, can mitigate this risk. Our objective was to identify diagnostic and prognostic cerebrospinal fluid (CSF) proteomic signatures in glioblastoma (GBM), brain metastases (BM), and primary central nervous system lymphoma (CNSL). Methods: CSF samples were retrospectively retrieved from the Penn State Neuroscience Biorepository and profiled using shotgun proteomics. Proteomic signatures were identified using machine learning classifiers and survival analyses. Results: Using 30 µL CSF volumes, we recovered 755 unique proteins across 73 samples. Proteomic-based classifiers identified malignancy with area under the receiver operating characteristic (AUROC) of 0.94 and distinguished between tumor entities with AUROC ≥0.95. More clinically relevant triplex classifiers, comprised of just three proteins, distinguished between tumor entities with AUROC of 0.75-0.89. Novel biomarkers were identified, including GAP43, TFF3 and CACNA2D2, and characterized using single cell RNA sequencing. Survival analyses validated previously implicated prognostic signatures, including blood-brain barrier disruption. Conclusions: Reliable classification of intra-axial malignancies using low CSF volumes is feasible, allowing for longitudinal tumor surveillance.

Lesion network mapping of ectopic craniopharyngioma identifies potential cause of psychosis: a case report.

We report the case of a patient with craniopharyngioma who demonstrated ectopic spread to the right temporal lobe and concurrent local recurrence, 10 years after her initial diagnosis. The patient additionally demonstrated new-onset psychotic symptoms of uncertain etiology during her admission. Lesion network mapping identified the ectopic lesion as a putative cause for her psychosis. These findings were substantiated after the resection of the ectopic lesion and subsequent resolution of her psychiatric symptoms. This report adds to the rare accounts of ectopic craniopharyngioma, while highlighting the utility of network-based analyses in peri-operative tumor evaluation and the assessment of atypical neuropsychiatric phenomena.

Characterization of the minimal residual disease state reveals distinct evolutionary trajectories of human glioblastoma.

Recurrence of solid tumors renders patients vulnerable to advanced, treatment-refractory disease state with mutational and oncogenic landscape distinctive from initial diagnosis. Improving outcomes for recurrent cancers requires a better understanding of cell populations that expand from the post-therapy, minimal residual disease (MRD) state. We profile barcoded tumor stem cell populations through therapy at tumor initiation, MRD, and recurrence in our therapy-adapted, patient-derived xenograft models of glioblastoma (GBM). Tumors show distinct patterns of recurrence in which clonal populations exhibit either a pre-existing fitness advantage or an equipotency fitness acquired through therapy. Characterization of the MRD state by single-cell and bulk RNA sequencing reveals a tumor-intrinsic immunomodulatory signature with prognostic significance at the transcriptomic level and in proteomic analysis of cerebrospinal fluid (CSF) collected from patients with GBM. Our results provide insight into the innate and therapy-driven dynamics of human GBM and the prognostic value of interrogating the MRD state in solid cancers.