Enhancing Single-Frame Supervision for Better Temporal Action Localization.

Temporal action localization aims to identify the boundaries and categories of actions in videos, such as scoring a goal in a football match. Single-frame supervision has emerged as a labor-efficient way to train action localizers as it requires only one annotated frame per action. However, it often suffers from poor performance due to the lack of precise boundary annotations. To address this issue, we propose a visual analysis method that aligns similar actions and then propagates a few user-provided annotations (e.g., boundaries, category labels) to similar actions via the generated alignments. Our method models the alignment between actions as a heaviest path problem and the annotation propagation as a quadratic optimization problem. As the automatically generated alignments may not accurately match the associated actions and could produce inaccurate localization results, we develop a storyline visualization to explain the localization results of actions and their alignments. This visualization facilitates users in correcting wrong localization results and misalignments. The corrections are then used to improve the localization results of other actions. The effectiveness of our method in improving localization performance is demonstrated through quantitative evaluation and a case study.

Risk factors for postoperative ventriculoperitoneal shunt requirement in pediatric patients with brain tumors invading or adjacent to CSF circulation pathways.

OBJECTIVE: Hydrocephalus is a common comorbidity of brain tumors in children that may persist following brain tumor resection. This study aimed to explore perioperative risk factors associated with postoperative ventriculoperitoneal shunt (VPS) placement for tumors located at or adjacent to the CSF circulation pathway. METHODS: Patients aged 0-18 years with tumors invading or adjacent to the CSF circulation pathways who underwent brain tumor resection between October 2015 and September 2021 were included in this study. The outcome metric was whether patients underwent VPS placement within 6 months of tumor resection. Patients were followed up every 3-6 months after surgery. Demographic and perioperative imaging characteristics, clinical variables, and long-term treatments, including radiotherapy or chemotherapy, were included in the analysis. RESULTS: Two hundred sixty-five children were included in this study. Of these patients, 38 (14.34%) underwent VPS placement within 6 months of tumor resection. One hundred thirty-two patients (49.81%) presented with preoperative hydrocephalus. Results from the multivariate analysis showed that medulloblastoma (OR 4.15, 95% CI 1.74-9.91, p = 0.001), lateral/third ventricle tumors (OR 4.07, 95% CI 1.33-12.30, p = 0.014), postoperative intraventricular hematoma (OR 3.36, 95% CI 1.53-7.38, p = 0.003), and presence of subdural hygroma in the nonoperated area within 48 hours after tumor resection (OR 2.78, 95% CI 1.15-6.74, p = 0.024) were independent risk factors for postoperative VPS placement. CONCLUSIONS: Postoperative lateral/third ventricle hematoma and subdural hygroma in the nonoperated area, anatomical location, and tumor histology may be potential risk factors for a postoperative VPS after brain tumor resection.

Motion correction of 3D dynamic contrast-enhanced ultrasound imaging without anatomical B-Mode images: Pilot evaluation in eight patients.

BACKGROUND: Dynamic contrast-enhanced ultrasound (DCE-US) is highly susceptible to motion artifacts arising from patient movement, respiration, and operator handling and experience. Motion artifacts can be especially problematic in the context of perfusion quantification. In conventional 2D DCE-US, motion correction (MC) algorithms take advantage of accompanying side-by-side anatomical B-Mode images that contain time-stable features. However, current commercial models of 3D DCE-US do not provide side-by-side B-Mode images, which makes MC challenging. PURPOSE: This work introduces a novel MC algorithm for 3D DCE-US and assesses its efficacy when handling clinical data sets. METHODS: In brief, the algorithm uses a pyramidal approach whereby short temporal windows consisting of three consecutive frames are created to perform local registrations, which are then registered to a master reference derived from a weighted average of all frames. We applied the algorithm to imaging studies from eight patients with metastatic lesions in the liver and assessed improvements in original versus motion corrected 3D DCE-US cine using: (i) frame-to-frame volumetric overlap of segmented lesions, (ii) normalized correlation coefficient (NCC) between frames (similarity analysis), and (iii) sum of squared errors (SSE), root-mean-squared error (RMSE), and r-squared (R2 ) quality-of-fit from fitted time-intensity curves (TIC) extracted from a segmented lesion. RESULTS: We noted improvements in frame-to-frame lesion overlap across all patients, from 68% ± 13% without correction to 83% ± 3% with MC (p = 0.023). Frame-to-frame similarity as assessed by NCC also improved on two different sets of time points from 0.694 ± 0.057 (original cine) to 0.862 ± 0.049 (corresponding MC cine) and 0.723 ± 0.066 to 0.886 ± 0.036 (p ≤ 0.001 for both). TIC analysis displayed a significant decrease in RMSE (p = 0.018) and a significant increase in R2 goodness-of-fit (p = 0.029) for the patient cohort. CONCLUSIONS: Overall, results suggest decreases in 3D DCE-US motion after applying the proposed algorithm.

Outcomes following surgical interventions for hypothalamic hamartomas: protocol for a systematic review and individual patient data meta-analysis.

INTRODUCTION: Hypothalamic hamartomas (HHs) are deep-seated congenital lesions that typically lead to pharmacoresistant epilepsy and a catastrophic encephalopathic syndrome characterised by severe neuropsychological impairment and decline in quality of life. A variety of surgical approaches and technologies are available for the treatment of HH-related pharmacoresistant epilepsy. There remains, however, a paucity of literature directly comparing their relative efficacy and safety. This protocol aims to facilitate a systematic review and meta-analysis that will characterise and compare the probability of seizure freedom and relevant postoperative complications across different surgical techniques performed for the treatment of HH-related pharmacoresistant epilepsy. METHODS AND ANALYSIS: This protocol was developed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Individual Participant Data guidelines. Three major databases, PubMed, Embase and Scopus, will be systematically searched from database inception and without language restrictions for relevant articles using our predefined search strategy. Title-abstract and full text screening using inclusion and exclusion criteria created a priori will be performed by two independent reviewers to identify eligible articles. Conflicts will be resolved via discussion with a third team member. Following data extraction of both study-level and individual patient data (IPD), a study-level and IPD meta-analysis will be performed. Study-level analysis will focus on assessing the degree of heterogeneity in the data and quantifying overall seizure outcomes for each surgical technique. The IPD analysis will use multivariable regression to determine perioperative predictors of seizure freedom and complications that can guide patient and technique selection. ETHICS AND DISSEMINATION: This work will not require ethics approval as it will be solely based on previously published and available data. The results of this review will be shared via conference presentation and submission to peer-reviewed neurosurgical journals. PROSPERO REGISTRATION: CRD42022378876.

Lumbar Decompression with and without Fusion for Lumbar Stenosis with Spondylolisthesis: A Cost Utility Analysis.

STUDY DESIGN: Markov model. OBJECTIVE: To compare the cost-effectiveness of lumbar decompression alone (DA) with lumbar decompression with fusion (DF) for the management of adults undergoing surgery for lumbar stenosis with associated degenerative spondylolisthesis. SUMMARY OF BACKGROUND DATA: Rates of lumbar fusion have increased for all indications in the United States over the last 20 years. Recent randomized controlled trial data, however, have suggested comparable functional outcomes and lower reoperation rates for lumbar decompression and fusion as compared to lumbar decompression alone in the treatment of lumbar stenosis with degenerative spondylolisthesis. MATERIALS AND METHODS: A multi-state Markov model was constructed from the U.S. payer perspective of a hypothetical cohort of patients with LSS requiring surgery. Data regarding clinical improvement, costs, and reoperation were generated from contemporary randomized trial evidence, meta-analyses of recent prospective studies, and large retrospective cohorts. Base case, one-way sensitivity analysis, and probabilistic sensitivity analyses were conducted and results were compared to a willingness to pay threshold of $100,000 (in 2022 USD) over a 2-year time horizon. A discount rate of 3% was utilized. RESULTS: The incremental cost and utility of decompression with fusion relative to decompression alone were $12,778 and 0.00529 QALYs. The corresponding ICER of $2,416,281 far exceeded a willingness to pay threshold of $100,000. In sensitivity analysis, the results varied the most with respect to rate of improvement after lumbar decompression alone, rate of improvement after lumbar decompression and fusion, and odds ratio of reoperation between the two groups. 0% of one-way and probabilistic sensitivity analyses achieved cost-effectiveness at the willingness to pay threshold. CONCLUSIONS: Within the context of contemporary surgical data, DF is not cost effective compared with DA in the surgical management of LSS over a 2-year time horizon.

Development of an online calculator for the prediction of seizure freedom following pediatric hemispherectomy using the Hemispherectomy Outcome Prediction Scale (HOPS).

OBJECTIVES: Although hemispheric surgeries are among the most effective procedures for drug-resistant epilepsy (DRE) in the pediatric population, there is a large variability in seizure outcomes at the group level. A recently developed HOPS score provides individualized estimation of likelihood of seizure freedom to complement clinical judgement. The objective of this study was to develop a freely accessible online calculator that accurately predicts the probability of seizure freedom for any patient at 1-, 2-, and 5-years post-hemispherectomy. METHODS: Retrospective data of all pediatric patients with DRE and seizure outcome data from the original Hemispherectomy Outcome Prediction Scale (HOPS) study were included. The primary outcome of interest was time-to-seizure recurrence. A multivariate Cox proportional-hazards regression model was developed to predict the likelihood of post-hemispheric surgery seizure freedom at three time points (1-, 2- and 5- years) based on a combination of variables identified by clinical judgment and inferential statistics predictive of the primary outcome. The final model from this study was encoded in a publicly accessible online calculator on the International Network for Epilepsy Surgery and Treatment (iNEST) website (https://hops-calculator.com/). RESULTS: The selected variables for inclusion in the final model included the five original HOPS variables (age at seizure onset, etiologic substrate, seizure semiology, prior non-hemispheric resective surgery, and contralateral fluorodeoxyglucose-positron emission tomography [FDG-PET] hypometabolism) and three additional variables (age at surgery, history of infantile spasms, and magnetic resonance imaging [MRI] lesion). Predictors of shorter time-to-seizure recurrence included younger age at seizure onset, prior resective surgery, generalized seizure semiology, FDG-PET hypometabolism contralateral to the side of surgery, contralateral MRI lesion, non-lesional MRI, non-stroke etiologies, and a history of infantile spasms. The area under the curve (AUC) of the final model was 73.0%. SIGNIFICANCE: Online calculators are useful, cost-free tools that can assist physicians in risk estimation and inform joint decision-making processes with patients and families, potentially leading to greater satisfaction. Although the HOPS data was validated in the original analysis, the authors encourage external validation of this new calculator.

Hemispheric epilepsy surgery for hemimegalencephaly: The UCLA experience.

OBJECTIVES: Hemimegalencephaly (HME) is a rare congenital brain malformation presenting predominantly with drug-resistant epilepsy. Hemispheric disconnective surgery is the mainstay of treatment; however, little is known about how postoperative outcomes compare across techniques. Thus we present the largest single-center cohort of patients with HME who underwent epilepsy surgery and characterize outcomes. METHODS: This observational study included patients with HME at University of California Los Angeles (UCLA) from 1984 to 2021. Patients were stratified by surgical intervention: anatomic hemispherectomy (AH), functional hemispherectomy (FH), or less-than-hemispheric resection (LTH). Seizure freedom, functional outcomes, and operative complications were compared across surgical approaches. Regression analysis identified clinical and intraoperative variables that predict seizure outcomes. RESULTS: Of 56 patients, 43 (77%) underwent FH, 8 (14%) underwent AH, 2 (4%) underwent LTH, 1 (2%) underwent unknown hemispherectomy type, and 2 (4%) were managed non-operatively. At median last follow-up of 55 months (interquartile range [IQR] 20-92 months), 24 patients (49%) were seizure-free, 17 (30%) required cerebrospinal fluid (CSF) shunting for hydrocephalus, 9 of 43 (21%) had severe developmental delay, 8 of 38 (21%) were non-verbal, and 15 of 38 (39%) were non-ambulatory. There was one (2%) intraoperative mortality due to exsanguination earlier in this cohort. Of 12 patients (29%) requiring revision surgery, 6 (50%) were seizure-free postoperatively. AH, compared to FH, was not associated with statistically significant improved seizure freedom (hazard ratio [HR] = .48, p = .328), although initial AH trended toward greater odds of seizure freedom (75% vs 46%, p = .272). Younger age at seizure onset (HR = .29, p = .029), lack of epilepsia partialis continua (EPC) (HR = .30, p = .022), and no contralateral seizures on electroencephalography (EEG) (HR = .33, p = .039) independently predicted longer duration of seizure freedom. SIGNIFICANCE: This study helps inform physicians and parents of children who are undergoing surgery for HME by demonstrating that earlier age at seizure onset, absence of EPC, and no contralateral EEG seizures were associated with longer postoperative seizure freedom. At our center, initial AH for HME may provide greater odds of seizure freedom with complications and functional outcomes comparable to those of FH.

Cluster-Aware Grid Layout.

Grid visualizations are widely used in many applications to visually explain a set of data and their proximity relationships. However, existing layout methods face difficulties when dealing with the inherent cluster structures within the data. To address this issue, we propose a cluster-aware grid layout method that aims to better preserve cluster structures by simultaneously considering proximity, compactness, and convexity in the optimization process. Our method utilizes a hybrid optimization strategy that consists of two phases. The global phase aims to balance proximity and compactness within each cluster, while the local phase ensures the convexity of cluster shapes. We evaluate the proposed grid layout method through a series of quantitative experiments and two use cases, demonstrating its effectiveness in preserving cluster structures and facilitating analysis tasks.

Advances in Development of Selective Antitumor Inhibitors That Target PARP-1.

Cancer is a major threat to the lives and health of people around the world, and the development of effective antitumor drugs that exhibit fewer toxic effects is an important aspect of cancer treatment. PARP inhibitors are antitumor drugs that target pathways involved in DNA-damage repair. The currently approved PARP inhibitors include olaparib, niraparib, rucaparib, talazoparib, fuzuloparib, and pamiparib. Hematological toxicities associated with the simultaneous inhibition of PARP-1 and PARP-2 have limited the clinical applications of these drugs. The present review introduces the necessity for research on the development of selective PARP-1 inhibitors from the perspective of structural and functional mechanisms of PARP-1 inhibition. A review of recently reported selective PARP-1 inhibitors provides the foundation for exploring novel strategies for designing selective PARP-1 inhibitors from the perspective of structure-activity relationships combined with computer simulations.

MNK, mTOR or eIF4E-selecting the best anti-tumor target for blocking translation initiation.

Overexpression of eIF4E is common in patients with various solid tumors and hematologic cancers. As a potential anti-cancer target, eIF4E has attracted extensive attention from researchers. At the same time, mTOR kinases inhibitors and MNK kinases inhibitors, which are directly related to regulation of eIF4E, have been rapidly developed. To explore the optimal anti-cancer targets among MNK, mTOR, and eIF4E, this review provides a detailed classification and description of the anti-cancer activities of promising compounds. In addition, the structures and activities of some dual-target inhibitors are briefly described. By analyzing the different characteristics of the inhibitors, it can be concluded that MNK1/2 and eIF4E/eIF4G interaction inhibitors are superior to mTOR inhibitors. Simultaneous inhibition of MNK and eIF4E/eIF4G interaction may be the most promising anti-cancer method for targeting translation initiation.

Postnatal Myelomeningocele Repair in the United States: Rates and Disparities Before and After the Management of Myelomeningocele Study Trial.

BACKGROUND AND OBJECTIVES: Evolving technologies have influenced the practice of myelomeningocele repair (MMCr), including mandatory folic acid fortification, advances in prenatal diagnosis, and the 2011 Management of Myelomeningocele Study (MOMS) trial demonstrating benefits of fetal over postnatal MMCr in select individuals. Postnatal MMCr continues to be performed, especially for those with limitations in prenatal diagnosis, health care access, anatomy, or personal preference. A comprehensive, updated national perspective on the trajectory of postnatal MMCr volumes and patient disparities is absent. We characterize national trends in postnatal MMCr rates before and after the MOMS trial publication (2000-2010 vs 2011-2019) and examine whether historical disparities persist. METHODS: This retrospective, cross-sectional analysis queried Nationwide Inpatient Sample data for postnatal MMCr admissions. Annual and race/ethnicity-specific rates were calculated using national birth registry data. Time series analysis assessed for trends relative to the year 2011. Patient, admission, and outcome characteristics were compared between pre-MOMS and post-MOMS cohorts. RESULTS: Between 2000 and 2019, 12 426 postnatal MMCr operations were estimated nationwide. After 2011, there was a gradual, incremental decline in the annual rate of postnatal MMCr. Post-MOMS admissions were increasingly associated with Medicaid insurance and the lowest income quartiles, as well as increased risk indices, length of stay, and hospital charges. By 2019, race/ethnicity-adjusted rates seemed to converge. The mortality rate remained low in both eras, and there was a lower rate of same-admission shunting post-MOMS. CONCLUSION: National rates of postnatal MMCr gradually declined in the post-MOMS era. Medicaid and low-income patients comprise an increasing majority of MMCr patients post-MOMS, whereas historical race/ethnicity-specific disparities are improving. Now more than ever, we must address disparities in the care of MMC patients before and after birth.

Patterns in Decompression and Fusion Procedures for Patients With Lumbar Stenosis After Major Clinical Trial Results, 2016 to 2019.

Importance: Use of lumbar fusion has increased substantially over the last 2 decades. For patients with lumbar stenosis and degenerative spondylolisthesis, 2 landmark prospective randomized clinical trials (RCTs) published in the New England Journal of Medicine in 2016 did not find clear evidence in favor of decompression with fusion over decompression alone in this population. Objective: To assess the national use of decompression with fusion vs decompression alone for the surgical treatment of lumbar stenosis and degenerative spondylolisthesis from 2016 to 2019. Design, Setting, and Participants: This retrospective cohort study included 121 745 hospitalized adult patients (aged ≥18 years) undergoing 1-level decompression alone or decompression with fusion for the management of lumbar stenosis and degenerative spondylolisthesis from January 1, 2016, to December 31, 2019. All data were obtained from the National Inpatient Sample (NIS). Analyses were conducted, reviewed, or updated on June 9, 2023. Main Outcome and Measure: The primary outcome of this study was the use of decompression with fusion vs decompression alone. For the secondary outcome, multivariable logistic regression analysis was used to evaluate factors associated with the decision to perform decompression with fusion vs decompression alone. Results: Among 121 745 eligible hospitalized patients (mean age, 65.2 years [95% CI, 65.0-65.4 years]; 96 645 of 117 640 [82.2%] non-Hispanic White) with lumbar stenosis and degenerative spondylolisthesis, 21 230 (17.4%) underwent decompression alone, and 100 515 (82.6%) underwent decompression with fusion. The proportion of patients undergoing decompression alone decreased from 2016 (7625 of 23 405 [32.6%]) to 2019 (3560 of 37 215 [9.6%]), whereas the proportion of patients undergoing decompression with fusion increased over the same period (from 15 780 of 23 405 [67.4%] in 2016 to 33 655 of 37 215 [90.4%] in 2019). In univariable analysis, patients undergoing decompression alone differed significantly from those undergoing decompression with fusion with regard to age (mean, 68.6 years [95% CI, 68.2-68.9 years] vs 64.5 years [95% CI, 64.3-64.7 years]; P < .001), insurance status (eg, Medicare: 13 725 of 21 205 [64.7%] vs 53 320 of 100 420 [53.1%]; P < .001), All Patient Refined Diagnosis Related Group risk of death (eg, minor risk: 16 900 [79.6%] vs 83 730 [83.3%]; P < .001), and hospital region of the country (eg, South: 7030 [33.1%] vs 38 905 [38.7%]; Midwest: 4470 [21.1%] vs 23 360 [23.2%]; P < .001 for both comparisons). In multivariable logistic regression analysis, older age (adjusted odds ratio [AOR], 0.96 per year; 95% CI, 0.95-0.96 per year), year after 2016 (AOR, 1.76 per year; 95% CI, 1.69-1.85 per year), self-pay insurance status (AOR, 0.59; 95% CI, 0.36-0.95), medium hospital size (AOR, 0.77; 95% CI, 0.67-0.89), large hospital size (AOR, 0.76; 95% CI, 0.67-0.86), and highest median income quartile by patient residence zip code (AOR, 0.79; 95% CI, 0.70-0.89) were associated with lower odds of undergoing decompression with fusion. Conversely, hospital region in the Midwest (AOR, 1.34; 95% CI, 1.14-1.57) or South (AOR, 1.32; 95% CI, 1.14-1.54) was associated with higher odds of undergoing decompression with fusion. Decompression with fusion vs decompression alone was associated with longer length of stay (mean, 2.96 days [95% CI, 2.92-3.01 days] vs 2.55 days [95% CI, 2.49-2.62 days]; P < .001), higher total admission costs (mean, $30 288 [95% CI, $29 386-$31 189] vs $16 190 [95% CI, $15 189-$17 191]; P < .001), and higher total admission charges (mean, $121 892 [95% CI, $119 566-$124 219] vs $82 197 [95% CI, $79 745-$84 648]; P < .001). Conclusions and Relevance: In this cohort study, despite 2 prospective RCTs that demonstrated the noninferiority of decompression alone compared with decompression with fusion, use of decompression with fusion relative to decompression alone increased from 2016 to 2019. A variety of patient- and hospital-level factors were associated with surgical procedure choice. These results suggest the findings of 2 major RCTs have not yet produced changes in surgical practice patterns and deserve renewed focus.

Fangchinoline derivatives inhibits PI3K signaling in vitro and in vivo in non-small cell lung cancer.

Fangchinoline (Fan) are extracted from the traditional Chinese medicine Stephania tetrandra S., which is a bis-benzyl isoquinoline alkaloids with anti-tumor activity. Therefore, 25 novel Fan derivatives have been synthesized and evaluated for their anti-cancer activity. In CCK-8 assay, these fangchinoline derivatives displayed higher proliferation inhibitory activity on six tumor cell lines than the parental compound. Compared to the parent Fan, compound 2h presented the anticancer activity against most cancer cells, especially A549 cells, with an IC50 value of 0.26 µM, which was 36.38-fold, and 10.61-fold more active than Fan and HCPT, respectively. Encouragingly, compound 2h showed low biotoxicity to the human normal epithelial cell BEAS-2b with an IC50 value of 27.05 µM. The results indicated compound 2h remarkably inhibited the cell migration by decreasing MMP-2 and MMP-9 expression and inhibited the proliferation of A549 cells by arresting the G2/M cell cycle. Meanwhile, compound 2h could also induce A549 cell apoptosis by promoting endogenous pathways of mitochondrial regulation. In nude mice presented that the growth of tumor tissues was markedly inhibited by the consumption of compound 2h in a dose-dependent manner, and it was found that compound 2h could inhibit the mTOR/PI3K/AKT pathway in vivo. In docking analysis, high affinity interaction between 2h and PI3K was responsible for drastic kinase inhibition by the compound. To conclude, this derivative compound may be useful as a potent anti-cancer agent for treatment of NSCLC.

The antihyperuricemia activity of Astragali Radix through regulating the expression of uric acid transporters via PI3K/Akt signalling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Astragali Radix (AR) is the dry root of the leguminous plants Astragalus membranaceus (Fisch) Beg. var. mongholicus (Beg) Hsiao, and Astragalus membranaceus (Fisch) Bge., being used as a medicinal and edible resource. AR is used in traditional Chinese medicine prescriptions to treat hyperuricemia, but this particular effect is rarely reported, and the associated mechanism of action is still need to be elucidated. AIM OF THE STUDY: To research the uric acid (UA)-lowering activity and mechanism of AR and the representative compounds through the constructed hyperuricemia mouse and cellular models. MATERIALS AND METHODS: In our study, the chemical profile of AR was analysed by UHPLC-QE-MS, as well as the mechanism of action of AR and the representative compounds on hyperuricemia was studied through the constructed hyperuricemia mouse and cellular models. RESULTS: The main compounds in AR were terpenoids, flavonoids and alkaloids. Mice group treated with the highest AR dosage showed significantly lower (p < 0.0001) serum uric acid (208 ± 9 µmol/L) than the control group (317 ± 11 µmol/L). Furthermore, UA increased in a dose-dependence manner in urine and faeces. Serum creatinine and blood urea nitrogen standards, as well as xanthine oxidase in mice liver, decreased (p < 0.05) in all cases, indicating that AR could relieve acute hyperuricemia. UA reabsorption protein (URAT1 and GLUT9) was down-regulated in AR administration groups, while the secretory protein (ABCG2) was up-regulated, indicating that AR could promote the excretion of UA by regulating UA transporters via PI3K/Akt signalling pathway. CONCLUSION: This study validated the activity, and revealed the mechanism of AR in reducing UA, which provided experimental and clinical basis for the treatment of hyperuricemia with it.

Comparison of Hemispheric Surgery Techniques for Pediatric Drug-Resistant Epilepsy: An Individual Patient Data Meta-analysis.

BACKGROUND AND OBJECTIVES: Hemispheric surgery effectively treats unihemispheric pediatric drug-resistant epilepsy (DRE) by resecting and/or disconnecting the epileptic hemisphere. Modifications to the original anatomic hemispherectomy have generated multiple functionally equivalent, disconnective techniques for performing hemispheric surgery, termed functional hemispherotomy. While a myriad of hemispherotomy variants exist, all of them can be categorized according to the anatomic plane they are performed in, which includes vertical approaches at or near the interhemispheric fissure and lateral approaches at or near the Sylvian fissure. This meta-analysis of individual patient data (IPD) aimed to compare seizure outcomes and complications between the hemispherotomy approaches to better characterize their relative efficacy and safety in the modern neurosurgical treatment of pediatric DRE, given emerging evidence that outcomes may differ between them. METHODS: CINAHL, Embase, PubMed, and Web of Science were searched from inception to September 9, 2020, for studies reporting IPD from pediatric patients with DRE who underwent hemispheric surgery. Outcomes of interest were seizure freedom at last follow-up, time-to-seizure recurrence, and complications including hydrocephalus, infection, and mortality. The χ2 test compared the frequency of seizure freedom and complications. Multivariable mixed-effects Cox regression controlling for predictors of seizure outcome was performed on propensity score-matched patients to compare time-to-seizure recurrence between approaches. Kaplan-Meier curves were made to visualize differences in time-to-seizure recurrence. RESULTS: Fifty-five studies reporting on 686 unique pediatric patients treated with hemispheric surgery were included for meta-analysis. Among the hemispherotomy subgroup, vertical approaches resulted in a greater proportion of seizure free patients (81.2% vs 70.7%, p = 0.014) than lateral approaches. While there were no differences in complications, lateral hemispherotomy had higher rates of revision hemispheric surgery due to incomplete disconnection and/or recurrent seizures than vertical hemispherotomy (16.3% vs 1.2%, p < 0.001). After propensity score matching, vertical hemispherotomy approaches independently conferred longer time-to-seizure recurrence than lateral hemispherotomy approaches (hazard ratio 0.44, 95% CI 0.19-0.98). DISCUSSION: Among functional hemispherotomy techniques, vertical hemispherotomy approaches confer more durable seizure freedom than lateral approaches without compromising safety. Future prospective studies are required to definitively determine whether vertical approaches are indeed superior and how it should influence clinical guidelines for performing hemispheric surgery.

Presurgical MRI-Based Radiomics Models for Predicting Cerebellar Mutism Syndrome in Children With Posterior Fossa Tumors.

BACKGROUND: Current studies have indicated that tumoral morphologic features are associated with cerebellar mutism syndrome (CMS), but the radiomics application in CMS is scarce. PURPOSE: To develop a model for CMS discrimination based on multiparametric MRI radiomics in patients with posterior fossa tumors. STUDY TYPE: Retrospective. POPULATION: A total of 218 patients (males 132, females 86) with posterior fossa tumors, 169 of which were included in the MRI radiomics analysis. The MRI radiomics study cohort (169) was split into training (119) and testing (50) sets with a ratio of 7:3. FIELD/SEQUENCE: All the MRI were acquired under 1.5/3.0 T scanners. T2-weighted image (T2W), T1-weighted (T1W), fluid attenuated inversion recovery (FLAIR), diffusion-weighted imaging (DWI). ASSESSMENT: Apparent diffusion coefficient (ADC) maps were generated from DWI. Each MRI dataset generated 1561 radiomics characteristics. Feature selection was performed with univariable logistic analysis, correlation analysis, and least absolute shrinkage and selection operator (LASSO) penalized logistic regression. Significant clinical features were selected with multivariable logistic analysis and used to constructed the clinical model. Radiomics models (based on T1W, T2W, FLAIR, DWI, ADC) were constructed with selected radiomics features. The mix model was based on the multiparametric MRI radiomics features. STATISTICAL TEST: Multivariable logistic analysis was utilized during clinical features selection. Models' performance was evaluated using the area under the receiver operating characteristic (AUC) curve. Interobserver variability was assessed using Cohen's kappa. Significant threshold was set as P < 0.05. RESULTS: Sex (aOR = 3.72), tumor location (aOR = 2.81), hydrocephalus (aOR = 2.14), and tumor texture (aOR = 5.08) were significant features in the multivariable analysis and were used to construct the clinical model (AUC = 0.79); totally, 33 radiomics features were selected to construct radiomics models (AUC = 0.63-0.93). Seven of the 33 radiomics features were selected for the mix model (AUC = 0.93). DATA CONCLUSION: Multiparametric MRI radiomics may be better at predicting CMS than single-parameter MRI models and clinical model. EVIDENCE LEVEL: 4. TECHNICAL EFFICACY: 2.

Chi3l1 Is a Modulator of Glioma Stem Cell States and a Therapeutic Target in Glioblastoma.

Chitinase 3-like 1 (Chi3l1) is a secreted protein that is highly expressed in glioblastoma. Here, we show that Chi3l1 alters the state of glioma stem cells (GSC) to support tumor growth. Exposure of patient-derived GSCs to Chi3l1 reduced the frequency of CD133+SOX2+ cells and increased the CD44+Chi3l1+ cells. Chi3l1 bound to CD44 and induced phosphorylation and nuclear translocation of ß-catenin, Akt, and STAT3. Single-cell RNA sequencing and RNA velocity following incubation of GSCs with Chi3l1 showed significant changes in GSC state dynamics driving GSCs towards a mesenchymal expression profile and reducing transition probabilities towards terminal cellular states. ATAC-seq revealed that Chi3l1 increases accessibility of promoters containing a Myc-associated zinc finger protein (MAZ) transcription factor footprint. Inhibition of MAZ downregulated a set of genes with high expression in cellular clusters that exhibit significant cell state transitions after treatment with Chi3l1, and MAZ deficiency rescued the Chi3L-induced increase of GSC self-renewal. Finally, targeting Chi3l1 in vivo with a blocking antibody inhibited tumor growth and increased the probability of survival. Overall, this work suggests that Chi3l1 interacts with CD44 on the surface of GSCs to induce Akt/ß-catenin signaling and MAZ transcriptional activity, which in turn upregulates CD44 expression in a pro-mesenchymal feed-forward loop. The role of Chi3l1 in regulating cellular plasticity confers a targetable vulnerability to glioblastoma. SIGNIFICANCE: Chi3l1 is a modulator of glioma stem cell states that can be targeted to promote differentiation and suppress growth of glioblastoma.

Single-cell RNA sequencing and spatial transcriptomics reveal cancer-associated fibroblasts in glioblastoma with protumoral effects.

Cancer-associated fibroblasts (CAFs) were presumed absent in glioblastoma given the lack of brain fibroblasts. Serial trypsinization of glioblastoma specimens yielded cells with CAF morphology and single-cell transcriptomic profiles based on their lack of copy number variations (CNVs) and elevated individual cell CAF probability scores derived from the expression of 9 CAF markers and absence of 5 markers from non-CAF stromal cells sharing features with CAFs. Cells without CNVs and with high CAF probability scores were identified in single-cell RNA-Seq of 12 patient glioblastomas. Pseudotime reconstruction revealed that immature CAFs evolved into subtypes, with mature CAFs expressing actin alpha 2, smooth muscle (ACTA2). Spatial transcriptomics from 16 patient glioblastomas confirmed CAF proximity to mesenchymal glioblastoma stem cells (GSCs), endothelial cells, and M2 macrophages. CAFs were chemotactically attracted to GSCs, and CAFs enriched GSCs. We created a resource of inferred crosstalk by mapping expression of receptors to their cognate ligands, identifying PDGF and TGF-ß as mediators of GSC effects on CAFs and osteopontin and HGF as mediators of CAF-induced GSC enrichment. CAFs induced M2 macrophage polarization by producing the extra domain A (EDA) fibronectin variant that binds macrophage TLR4. Supplementing GSC-derived xenografts with CAFs enhanced in vivo tumor growth. These findings are among the first to identify glioblastoma CAFs and their GSC interactions, making them an intriguing target.

Seizure outcomes in children with Sturge-Weber syndrome undergoing epilepsy surgery: An individual participant data meta-analysis.

BACKGROUND: A subpopulation of patients with Sturge-Weber syndrome (SWS) develop medically intractable epilepsy. There is a paucity of literature on preoperative factors that predict postoperative seizure outcomes in these patients. An individual participant data meta-analysis (IPDMA) was performed to discern preoperative variables associated with favorable seizure outcomes in pediatric SWS patients undergoing epilepsy surgery. METHODS: PubMed, Cochrane, Web of Science, and Scopus were independently queried following PRISMA guidelines. Studies that reported seizure outcomes in individual pediatric SWS patients were selected. Preoperative demographic variables and disease characteristics were recorded and evaluated in a time-to-event fashion via Cox regression and Kaplan-Meier analysis with log-rank test. RESULTS: A total of 18 studies with 108 patients were included for meta-analysis. Median age at seizure onset was 4.5 months, and 85 patients (78.7%) were seizure-free at last follow-up (median: 72 months). On multivariable Cox regression, no variables were independent predictors of post-operative seizure freedom duration, including the extent of hemispheric resection. There were also no differences in time-to-seizure recurrence on Kaplan-Meier analysis when comparing those treated with hemispheric surgery and those with less than hemispheric surgery (p = 0.52). CONCLUSION: This IPDMA showed that both resective and hemispheric epilepsy surgery achieve favorable and comparable seizure outcomes in pediatric SWS patients. The best available evidence using IPD suggests that resective surgery may be an appropriate alternative to hemispheric epilepsy surgery in well-selected patients. Prospective multi-institutional studies with greater follow-up are warranted to further investigate predictors of seizure outcome in pediatric SWS patients.

Epidemiological characteristics, clinical presentations, and prognoses of pediatric brain tumors: Experiences of national center for children's health.

Background: We aimed to describe the epidemiological characteristics, clinical presentations, and prognoses in a national health center for children. Methods: From January 2015 to December 2020, 484 patients aged 0-16 years, who were diagnosed with brain tumors and received neurosurgery treatment, were enrolled in the study. Pathology was based on the World Health Organization 2021 nervous system tumor classification, and tumor behaviors were classified according to the International Classification of Diseases for Oncology, third edition. Results: Among the 484 patients with brain tumors, the median age at diagnosis was 4.62 [2.19, 8.17] years (benign tumors 4.07 [1.64, 7.13] vs. malignant tumors 5.36 [2.78, 8.84], p=0.008). The overall male-to-female ratio was 1.33:1(benign 1.09:1 vs. malignant 1.62:1, p=0.029). Nausea, vomiting, and headache were the most frequent initial symptoms. The three most frequent tumor types were embryonal tumors (ET, 22.8%), circumscribed astrocytic gliomas (20.0%), and pediatric-type diffuse gliomas (11.0%). The most common tumor locations were the cerebellum and fourth ventricle (38.67%), the sellar region (22.9%) and ventricles (10.6%). Males took up a higher proportion than females in choroid plexus tumors (63.6%), ET (61.1%), ependymal tumors (68.6%), and germ cell tumors (GCTs, 78.1%). Patients were followed for 1 to 82 months. The overall 5-year survival rate was 77.5%, with survival rates of 91.0% for benign tumors and 64.6% for malignant tumors. Conclusion: Brain tumors presented particularly sex-, age-, and regional-dependent epidemiological characteristics. Our results were consistent with previous reports and might reflect the real epidemiological status in China.