bluuebunny/crossref_metadata_2025 huggingface dataset:
PLP_FS: prediction of lysine phosphoglycerylation sites in protein using support vector machine and fusion of multiple F_Score feature selection
Authors: Sohrawordi Md , Hossain Md Ali , Hasan Md Al Mehedi
Published: August 2022

A newly invented post-translational modification (PTM), phosphoglycerylation, has shown its essential role in the construction and functional properties of proteins and dangerous human diseases. Hence, it is very urgent to know about the molecular mechanism behind the phosphoglycerylation process to develop the drugs for related diseases. But accurately identifying of phosphoglycerylation site from a protein sequence in a laboratory is a very difficult and challenging task. Hence, the construction of an efficient computation model is greatly sought for this purpose. A little number of computational models are currently available for identifying the phosphoglycerylation sites, which are not able to reach their prediction capability at a satisfactory level. Therefore, an effective predictor named PLP_FS has been designed and constructed to identify phosphoglycerylation sites in this study. For the training purpose, an optimal number of feature sets was obtained by fusion of multiple F_Score feature selection techniques from the features generated by three types of sequence-based feature extraction methods and fitted with the support vector machine classification technique to the prediction model. On the other hand, the k-neighbor near cleaning and SMOTE methods were also implemented to balance the benchmark dataset. The suggested model in 10-fold cross-validation obtained an accuracy of 99.22%, a sensitivity of 98.17% and a specificity of 99.75% according to the experimental findings, which are better than other currently available predictors for accurately identifying the phosphoglycerylation sites.
Characterizing phenotypic diversity of trehalose biosynthesis mutants in multiple wild strains of Saccharomyces cerevisiae
Authors: Chen Anqi , Smith Jeremy R , Tapia Hugo , Gibney Patrick A
Published: August 2022

In the yeast Saccharomyces cerevisiae, trehalose-6-phospahte synthase (Tps1) and trehalose-6-phosphate phosphatase (Tps2) are the main proteins catalyzing intracellular trehalose production. In addition to Tps1 and Tps2, 2 putative regulatory proteins with less clearly defined roles also appear to be involved with trehalose production, Tps3 and Tsl1. While this pathway has been extensively studied in laboratory strains of S. cerevisiae, we sought to examine the phenotypic consequences of disrupting these genes in wild strains. Here we deleted the TPS1, TPS2, TPS3, and TSL1 genes in 4 wild strains and 1 laboratory strain for comparison. Although some tested phenotypes were not shared between all strains, deletion of TPS1 abolished intracellular trehalose, caused inability to grow on fermentable carbon sources and resulted in severe sporulation deficiency for all 5 strains. After examining tps1 mutant strains expressing catalytically inactive variants of Tps1, our results indicate that Tps1, independent of trehalose production, is a key component for yeast survival in response to heat stress, for regulating sporulation, and growth on fermentable sugars. All tps2Δ mutants exhibited growth impairment on nonfermentable carbon sources, whereas variations were observed in trehalose synthesis, thermosensitivity and sporulation efficiency. tps3Δ and tsl1Δ mutants exhibited mild or no phenotypic disparity from their isogenic wild type although double mutants tps3Δ tsl1Δ decreased the amount of intracellular trehalose production in all 5 strains by 17–45%. Altogether, we evaluated, confirmed, and expanded the phenotypic characteristics associated trehalose biosynthesis mutants. We also identified natural phenotypic variants in multiple strains that could be used to genetically dissect the basis of these traits and then develop mechanistic models connecting trehalose metabolism to diverse cellular processes.
Assessment of Objective and Subjective Cognitive Function in Patients With Treatment-Resistant Depression Undergoing Repeated Ketamine Infusions
Authors: Phillips Jennifer L , Van Geel Amanda , Burhunduli Patricia , Vasudev Dominique , Batten Lisa A , Norris Sandhaya , Talbot Jeanne , Ortiz Abigail , Owoeye Olabisi , Blier Pierre
Published: August 2022

Background

Subanesthetic ketamine infusions can elicit rapid and sustained antidepressant effects, yet the potential cognitive impact of ketamine has not been thoroughly examined. This study measured changes in objective and subjective cognitive function following repeated ketamine treatment.

Methods

Thirty-eight patients with treatment-resistant depression were administered cognitive assessments before and after undergoing 7 i.v. ketamine infusions (0.5 mg/kg over 40 minutes) within a clinical trial examining the efficacy of single and repeated administrations. Depression severity and perceived concentration were evaluated with the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Quick Inventory of Depressive Symptoms Self-Report.

Results

Twenty-three participants (60.5%) responded after repeated infusions (≥50% decrease in MADRS total scores). We measured significant improvements in several cognitive domains, including attention, working memory, verbal, and visuospatial memory (effect sizes ranging from Cohen d = 0.37–0.79). Cognitive changes were attributed to reduction in depressive symptoms except for improvement in verbal memory, which remained significant after adjustment for change in MADRS total score (P = .029, η p2 = 0.13). Only responders reported improvement in subjective cognitive function with repeated ketamine administration (MADRS item 6, P < .001, d = 2.00; Quick Inventory of Depressive Symptoms Self-Report item 10, P < .001, d = 1.36).

Conclusion

A short course of repeated ketamine infusions did not impair neurocognitive function in patients with treatment-resistant depression. Further research is required to understand the potential mediating role of response and remission on improved cognitive function accompanying ketamine treatment as well as to examine longer-term safety outcomes. ClinicalTrials.gov identifier NCT01945047
Hodge–Riemann Relations for Schur Classes in the Linear and Kähler Cases
Authors: Ross Julius , Toma Matei
Published: August 2022

We prove a version of the Hodge–Riemann bilinear relations for Schur polynomials of Kähler forms and for Schur polynomials of positive forms on a complex vector space.
Stable Torsion Length
Authors: Avery Chloe I , Chen Lvzhou
Published: August 2022

The stable torsion length in a group is the stable word length with respect to the set of all torsion elements. We show that the stable torsion length vanishes in crystallographic groups. We then give a linear programming algorithm to compute a lower bound for stable torsion length in free products of groups. Moreover, we obtain an algorithm that exactly computes stable torsion length in free products of finite groups. The nature of the algorithm shows that stable torsion length is rational in this case. As applications, we give the 1st exact computations of stable torsion length for nontrivial examples.
Patient judgments about hypertension control: the role of patient numeracy and graph literacy
Authors: Shaffer Victoria A , Wegier Pete , Valentine K D , Duan Sean , Canfield Shannon M , Belden Jeffery L , Steege Linsey M , Popescu Mihail , Koopman Richelle J
Published: August 2022

Objective

To assess the impact of patient health literacy, numeracy, and graph literacy on perceptions of hypertension control using different forms of data visualization.

Materials and Methods

Participants (Internet sample of 1079 patients with hypertension) reviewed 12 brief vignettes describing a fictitious patient; each vignette included a graph of the patient’s blood pressure (BP) data. We examined how variations in mean systolic blood pressure, BP standard deviation, and form of visualization (eg, data table, graph with raw values or smoothed values only) affected judgments about hypertension control and need for medication change. We also measured patient’s health literacy, subjective and objective numeracy, and graph literacy.

Results

Judgments about hypertension data presented as a smoothed graph were significantly more positive (ie, hypertension deemed to be better controlled) then judgments about the same data presented as either a data table or an unsmoothed graph. Hypertension data viewed in tabular form was perceived more positively than graphs of the raw data. Data visualization had the greatest impact on participants with high graph literacy.

Discussion

Data visualization can direct patients to attend to more clinically meaningful information, thereby improving their judgments of hypertension control. However, patients with lower graph literacy may still have difficulty accessing important information from data visualizations.

Conclusion

Addressing uncertainty inherent in the variability between BP measurements is an important consideration in visualization design. Well-designed data visualization could help to alleviate clinical uncertainty, one of the key drivers of clinical inertia and uncontrolled hypertension.
Determination of Carcinogenic Primary Aromatic Amines Contained as Impurities in Synthetic Organic Colorants
Authors: Kawakami Tsuyoshi , Obama Tomoko , Tahara Maiko , Ikarashi Yoshiaki
Published: August 2022

Background

Several primary aromatic amines (PAAs) have been designated carcinogenic or suspected of carcinogenicity. Several kinds of PAAs may occur either via the reduction of azo compounds or as impurities in azo colorants or other agents.

Objective

An analytical method was developed and applied to determine whether certain PAAs are present as impurities in synthetic organic colorants.

Method

Target chemicals were analyzed by the ultrasound extraction of the synthetic organic colorant with a hydrochloric acid solution containing 20% methanol, followed by conversion from an acidic to alkaline solution, and then extraction using a diatomaceous earth column.

Results

We analyzed certain PAAs in 38 synthetic organic colorants, resulting in the detection of 2,4-dimethylaniline in four samples at 1.2 to 19 μg/g, o-toluidine in three samples at 1.0 to 3.4 μg/g, p-phenylazoaniline in two samples at 74 to 305 μg/g, and, in one sample each, 2,4,5-trimethylaniline (13 μg/g), 5-nitro-o-toluidine (12 μg/g), and 2-methyl-4–(2-tolylazo)aniline (13 μg/g). Nearly all PAAs were determined to be starting materials for colorant synthesis, although p-phenylazoaniline in Yellow No. 407 was apparently a byproduct formed during synthesis. For Red No. 225, in which high concentrations of p-phenylazoaniline were detected, additional samples were purchased from five companies, and p-phenylazoaniline was detected at concentrations of 88 to 370 μg/g in all samples.

Conclusions

A method to analyze certain PAAs contained as impurities in synthetic organic colorants was developed, and the actual status of them in colorants was clarified.

Highlights

The analytical method developed in this study for the determination of certain PAAs contained as impurities in synthetic organic colorants may be used to improve the safety of colorants.
Effect of microbial inoculation and storage length on the fermentation profile and nutritive value of high-moisture corn ensiled at 2 different dry matter concentrations
Authors: Saylor Benjamin A , Heinzen Celso , Diepersloot E Cole , Ferraretto Luiz F
Published: August 2022

The objective of this experiment was to evaluate the effect of microbial inoculation and storage length on the fermentation profile and nutrient composition of high-moisture corn (HMC) ensiled at 2 different dry matter (DM) concentrations. High-moisture corn was harvested when kernel DM concentrations were approaching 65% as-fed, and either left undried (HMC65; 67.6% DM) or dried at 40 °C to approximately 70% DM (HMC70; 71.0% DM), and then ensiled in quadruplicate vacuum pouches untreated (CON) or after one of the following inoculant treatments: 6.36 × 105 cfu of Lentilactobacillus buchneri DSM 12856, Lactiplantibacillus plantarum DSM 12836, and Pediococcus acidilactici DSM 16243 per g of HMC (LBLP); or 3.0 × 105 cfu of Lentilactobacillus buchneri DSM 12856, Lentilactobacillus diolivorans DSM 32074, and P. acidilactici DSM 16243 per g of HMC (LBLD). Vacuum pouches were allowed to ferment for 7, 14, 28, or 56 d. A three-way interaction was observed (P = 0.01) for the pH of HMC, where CON for HMC70 was greatest across storage lengths and HMC65 treatments generally had a lower pH than other treatments. Concentrations of total acids were greater (P = 0.001) in HMC65 than HMC70 and greater (P = 0.001) in HMC treated with LBLP and LBLD than CON. An interaction between DM concentration, microbial inoculation, and storage length was observed (P = 0.05) for concentrations of acetic acid. At 14 d, acetic acid concentrations were greater in HMC65 treated with LBLD than other treatments. Likewise, at 56 d, concentrations of acetic acid were greatest in HMC65 treated with LBLD, followed by HMC70 treated with LBLD. An interaction between DM concentration, microbial inoculation, and storage length was observed (P = 0.05) for 7-h starch disappearance (starchD). Across all DM concentration and inoculant treatment combinations, starchD increased with increasing storage length. StarchD was also generally greater for HMC65 treatments compared to HMC70, with small differences among inoculants. Results suggest that microbial inoculation can improve fermentation of HMC by increasing the production of antifungal acetic acid, but that DM concentration at ensiling remains a primary determinant of HMC fermentability.
The Benefits of Trade Secret Legal Protection: Evidence from Firms’ Cost Structure Decisions
Authors: Gao Feng , Wang Xue , Yin Benda
Published: August 2022

We investigate whether better trade secret legal protection permits a firm to shift resources from protecting trade secrets to expanding its fixed operation capacity, thus reducing cost elasticity. We employ the staggered adoption of the Inevitable Disclosure Doctrine (IDD) by US state courts as a plausibly exogenous shock that improves trade secret legal protection. We find a reduction, on average, in cost elasticity in firms headquartered in the IDD recognition states relative to those in non-affected states. This change in cost structure is concentrated in firms with trade secrets. These results highlight that the optimal choice of fixed resources is affected by the extent of trade secret protection. Further, we find that firm value is higher for trade secret firms after the IDD adoption. Overall, our empirical evidence suggests that trade secret legal protection is beneficial for firms with trade secrets.
Controlling Voices in Fourteenth-Century Salzburg: Singing and Identity in the ‘MÖnch von Salzburg’ Songs
Authors: Murray David
Published: August 2022

The songs attributed to the so-called ‘Mönch von Salzburg’ offer a vivid picture of the late fourteenth-century ecclesiastical court of Archbishop Pilgrim von Pucheim. Against the background of historical and legal documentation from Salzburg, this article explores the way these songs negotiate the desires and anxieties of a mixed clerical-courtly milieu with a particular concern for regulating the human voice in both artistic and social senses. Taking as my central example Dy trumpet, one of the earliest pieces of recorded secular polyphony in the German world, I examine how both the singing and composition of song at Pilgrim’s court offered ways to certify one’s vocal interventions as positive and thereby to assure curial kudos. In a final section, I consider how later, non-curial recipients of these songs were able to vehicularize these courtly voices to their own advantage.
Observational signatures of stellar explosions driven by relativistic jets
Authors: Eisenberg Moshe , Gottlieb Ore , Nakar Ehud
Published: August 2022

The role of relativistic jets in unbinding the stellar envelope during a supernova (SN) associated with a gamma-ray burst (GRB) is unclear. To study that, we explore observational signatures of stellar explosions that are driven by jets. We focus on the final velocity distribution of the outflow in such explosions and compare its observational imprints to SN/GRB data. We find that jet-driven explosions produce an outflow with a flat distribution of energy per logarithmic scale of proper velocity. The flat distribution seems to be universal as it is independent of the jet and the progenitor properties that we explored. The velocity range of the flat distribution for typical GRB parameters is γβ ≈ 0.03–3, where γ is the outflow Lorentz factor and β is its dimensionless velocity. A flat distribution is seen also for collimated choked jets where the highest outflow velocity decreases with the depth at which the jet is choked. Comparison to observations of SN/GRBs strongly disfavors jets as the sole explosion source in these events. Instead, in SN/GRB the collapsing star seems to deposit its energy into two channels – a quasi-spherical (or wide angle) channel and a narrowly collimated one. The former carries most of the energy and is responsible for the SN sub-relativistic ejecta while the latter carries 0.01–0.1 of the total outflow energy and is the source of the GRB. Intriguingly, the same two channels, with a similar energy ratio, were seen in the binary neutron star merger GW170817, suggesting that similar engines are at work in both phenomena.
Transcription-coupled donor DNA expression increases homologous recombination for efficient genome editing
Authors: Gao Kaixuan , Zhang Xuedi , Zhang Zhenwu , Wu Xiangyu , Guo Yan , Fu Pengchong , Sun Angyang , Peng Ju , Zheng Jie , Yu Pengfei , Wang Tengfei , Ye Qinying , Jiang Jingwei , Wang Haopeng , Lin Chao-Po , Gao Guanjun
Published: August 2022

Genomes can be edited by homologous recombination stimulated by CRISPR/Cas9 [clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated peptide 9]-induced DNA double-strand breaks. However, this approach is inefficient for inserting or deleting long fragments in mammalian cells. Here, we describe a simple genome-editing method, termed transcription-coupled Cas9-mediated editing (TEd), that can achieve higher efficiencies than canonical Cas9-mediated editing (CEd) in deleting genomic fragments, inserting/replacing large DNA fragments and introducing point mutations into mammalian cell lines. We also found that the transcription on DNA templates is crucial for the promotion of homology-directed repair, and that tethering transcripts from TEd donors to targeted sites further improves editing efficiency. The superior efficiency of TEd for the insertion and deletion of long DNA fragments expands the applications of CRISPR for editing mammalian genomes.
BSCI-06 COMPREHENSIVE ANALYSIS OF THE IMMUNOGENOMICS OF TRIPLE NEGATIVE BREAST CANCER BRAIN METASTASES FROM LCCC1419
Authors: Van Swearingen Amanda , Routh Eric , Sambade Maria , Vensko Steven , McClure Marni , Woodcock Mark , Chai Shengjie , Cuaboy Luz , Wheless Amy , Garrett Amy , Carey Lisa , Hoyle Alan , Parker Joel , Vincent Benjamin , Anders Carey
Published: August 2022

BACKGROUND

Triple negative breast cancer (TNBC) lacks expression of hormone receptors (estrogen and progesterone receptors, ER and PR) and HER2. Almost 50% of patients with metastatic TNBC will develop brain metastases (BrM), often with concurrent progressive extracranial disease. While immunotherapy has shown promise in the treatment of advanced TNBC, the immune profile of BrM remains largely unknown. To inform the development of immunotherapy strategies in this aggressive disease, we characterized the genomic and immune landscape of TNBC BrM and matched primary tumors.

METHODS

Formalin-fixed, paraffin-embedded samples of BrM and primary tumors of patients with clinical TNBC (n=25, n=9 matched pairs) from the LCCC1419 biobank at UNC-Chapel Hill were analyzed by whole exome (WES) and RNA sequencing, with matched blood DNA sequenced for identification of somatic variants. Mutational and copy number alteration analyses, neoantigen prediction, and transcriptomic analysis of the tumor immune microenvironment were performed.

RESULTS

Primary and BrM tissues were confirmed as TNBC and of the basal intrinsic subtype. Compared to primary tumors, BrM demonstrated higher tumor mutational burden. Neoantigen prediction showed elevated cancer testis antigen- and endogenous retrovirus-derived MHC class I-binding peptides in both primary tumors and BrM, and predicted single nucleotide variants (SNV)-derived peptides were significantly higher in BrM. BrM demonstrated reduced immune gene signature expression, although a signature associated with fibroblast-associated wound healing was elevated in BrM. Metrics of T and B cell receptor diversity were also reduced in BrM.

CONCLUSIONS

BrM harbored higher mutational burden and SNV-derived neoantigen expression along with reduced immune gene signature expression relative to primary TNBC. Further research will expand these findings to other breast cancer subtypes. Exploration of immunomodulatory approaches including vaccine applications and immune checkpoint inhibition to enhance anti-tumor immunity in TNBC BrM are warranted.
BSCI-10 TAPPING INTO GLIOMAS’ SECRETS: CSF PROTEOMICS FOR BIOMARKER DISCOVERY, GLIOMA MONITORING, AND THERAPEUTIC RESPONSE ASSESSMENT
Authors: Riviere-Cazaux Cecile , Ikram Samar , Chantigian Siobhan , Rahman Masum , Warrington Arthur , Burns Terry
Published: August 2022

INTRODUCTION

Rapid, detailed feedback is needed to understand the individualized biological impacts of novel glioma therapies. We are performing glioma biomarker discovery by serial cerebrospinal fluid (CSF) sampling from Ommaya reservoirs to determine how the CSF proteome can reveal early longitudinal intelligence regarding glioma status, biology, and therapeutic response.

METHODS

Global proteomic analysis of CSF was performed on the Somalogic platform − an aptamer-based technology for highly sensitive and specific analysis of over 7,000 proteins. Discovery analysis comprised of the top-500 ranked proteins in CSF from seven patients with high-grade gliomas (HGG) versus non-glioma controls. The top-500 HGG proteins were then preliminarily filtered to include only proteins that met two additional criteria of decrease with resection and increase with recurrence in individual paired patient samples.

RESULTS

Proteomic enrichment analysis revealed a conserved HGG CSF proteomic signature defined by 79 proteins, including ones known to be over-expressed in solid tumor malignancies, such as retinoblastoma binding protein 4, heat shock protein 90, and sorcin. The HGG proteomic signature was consistently enriched in an independent validation cohort consisting of 13 gliomas diverse in primary versus recurrent status, subtype, and grade, when compared to control CSF samples. Encouragingly, proteins in the HGG signature decreased in the two patients for whom CSF was collected prior to and after resection (both at POD16 and POD18) with decreased tumor burden.

CONCLUSION

Our preliminary data demonstrate the ability to gain detailed, individualized insights regarding glioma biology, tumor burden, and evolution through global CSF proteomics acquired from longitudinal neurosurgical access to unique gliomas.
BSCI-11 GB5121 IS A NOVEL, IRREVERSIBLE, COVALENT BTK INHIBITOR WITH HIGH SELECTIVITY AND CNS-PENETRANCE FOR TREATMENT OF CNS MALIGNANCIES
Authors: Yusuf Isharat , Guimond David , Naiman Zachary , Schiff Theodore , Clemons Bryan , Paulson Bryanna , Hou Kay , Meadows Kristen Taylor , Rose Mark , Carter Laura
Published: August 2022

Inhibitors of Bruton’s tyrosine kinase (BTK) are approved treatments for several B cell lymphomas. However, they are characterized by modest selectivity and/or limited central nervous system (CNS) exposure which is important in instances of CNS disease. GB5121 is an orally available, selective, irreversible, covalent small molecule BTK inhibitor that was designed to address these limitations. Here, GB5121 was profiled for selectivity, potency, inactivation kinetics and CNS penetrance in comparison to ibrutinib. GB5121 pharmacodynamic properties were evaluated using both cell-free enzymatic and cell-based functional assays, showing nM potency for BTK inhibition and rapid BTK inactivation kinetics (Kinact/Ki) in both peripheral and CNS tissue, a critical parameter for irreversible inhibitors. In a kinome scan, GB5121 exhibited high kinase selectivity against 349 kinases with only TEC/TXK demonstrating >50% inhibition at 1 µM; GB5121 did not inhibit phosphorylation of EGFR in a cell-based assay. When compared with other BTK inhibitors, GB5121 showed superior CNS target occupancy using a probe-based ELISA measuring free BTK in the brain of mice receiving 3 daily oral doses. GB5121 also demonstrated significantly higher brain to plasma ratio in mice with an intact blood brain barrier. In non-human primates, a 1:1 brain to plasma concentration ratio was demonstrated for GB5121 for up to 8 hours with both oral (30 mg/kg) and IV (2 mg/kg) doses. Together, these features differentiate GB5121 from both FDA-approved BTK inhibitors, as well as those currently under clinical investigation. Our data supports the use of GB5121 in clinical trials where BTK is a known driver of malignancies, including CNS lymphoma. This research has been previously presented at the AACR Annual Meeting 2022.
BSCI-19 A LENTIVIRAL CRISPR SCREEN FOR EPIGENETIC MODULATORS OF ANTIGENS TARGETED BY CAR T CELLS IN GLIOBLASTOMA
Authors: Jordan Walter T , Jangde Nitish , Ayad Nagi
Published: August 2022

Glioblastoma (GBM) is the most common adult brain tumor and is very difficult to treat. One promising treatment strategy is CAR T cell therapy, in which T cells are used to target and kill cancer cells. However, CAR T cell therapy is not always effective, and more work is needed to realize its potential. One strategy for improving the efficacy of CAR T cell therapy is to increase the expression of targeted antigens on the surface of cancer cells. Our goal in these studies is to identify pathways that could be modulated to increase expression of the targeted antigens. Focusing on epigenetic proteins, we performed a lentiviral CRISPR screen in the human GBM cell line LN18. A lentiviral library was used to knock out various epigenetic genes in these cells in vitro. Following transduction, we use flow cytometry to examine surface expression of antigens currently being targeted in GBM clinical trials of CAR T cells, e.g. - GD2, B7-H3, etc. Cells with increased expression of the antigens of interest were selected using FACS. Genomic DNA was isolated from these cells and sequencing was performed to determine which epigenetic genes had been knocked out. Results showed multiple genes contributing to increased surface expression of targeted antigens. Future studies will determine whether small molecule inhibitors of the identified epigenetic pathways selectively induce up-regulation of these antigens in GBM cells in vivo.
CLRM-09 FIRST-LINE Tumor TREATING FIELDS (200 KHZ) THERAPY FOR NEWLY-DIAGNOSED GLIOBLASTOMA: THE PHASE 3 TRIDENT TRIAL (EF-32)
Authors: Shi Wenyin , Kleinberg Lawrence , Jeyapalan Suriya A , Goldlust Samuel A , Nagpal Seema , Roberge David , Nishikawa Ryo , Grossman Rachel , Glas Martin
Published: August 2022

BACKGROUND

Tumor Treating Fields therapy (TTFields; 200 kHz) comprise alternating electric fields that disrupt cancer cell division, and is approved for newly diagnosed glioblastoma (ndGBM), recurrent GBM and mesothelioma. In the phase 3 EF-14 trial, TTFields/temozolomide (TMZ) significantly increased overall survival (OS) and progression-free survival (PFS) vs TMZ alone in patients with ndGBM. TTFields-related adverse events (AEs) were mainly dermatological with no increases in systemic toxicity. In preclinical models, the addition of TTFields to radiotherapy (RT) increased the therapeutic effect. Additionally, TTFields added to RT/TMZ was reported as feasible and well-tolerated in 2 clinical pilot phase 2 studies.

MATERIALS AND METHODS

TRIDENT (EF-32; NCT04471844) is an international, phase 3 randomized trial comparing TTFields (200 KHz, ≥18 h/day)/RT/TMZ vs RT/TMZ alone. Adult patients (N=950; ≥18 years of age [≥22 years of age; US]) with histologically confirmed ndGBM, Karnofsky Performance Status ≥70, life expectancy ≥3 months, adequate organ function and eligible for RT/TMZ will be enrolled. Patients will be stratified by extent-of-resection and MGMT promoter methylation status and randomized 1:1 to receive continuous TTFields/RT/TMZ or RT/TMZ during the investigational period. Subsequently, all patients will receive TTFields/6 cycles of maintenance TTFields/TMZ; TTFields will continue for 24 months or until second disease progression per Response Assessment in Neuro-Oncology (RANO). The primary endpoint is median OS. Secondary endpoints include median PFS (RANO), 1- and 2-year survival rates, overall radiological response (RANO), PFS6, PFS12, severity and frequency of AEs and quality-of-life, OS per TTFields duration-of-usage. The study is powered at 80% to detect a hazard ratio of <0.8 (5% type I error). The study is currently open to enrolment in Austria, Belgium, Czech Republic, France, Germany, Israel, Switzerland, and across the US.
CLRM-12 TITLE: STEREOTACTIC RADIOSURGERY (ADJUVANT OR NEOADJUVANT) COMPARED TO HIPPOCAMPAL AVOIDANCE WHOLE BRAIN RADIATION THERAPY WITH SIMULTANEOUS INTEGRATED BOOST FOR LIMITED BRAIN METASTASES (SRS-CHART): PHASE III OPEN-LABEL PARALLEL-GROUP RANDOMIZED CONTROLLED TRIAL
Authors: Dasgupta Archya , Selvarajan Jeevi , Chatterjee Abhishek , Moiyadi Aliasgar , Shetty Prakash , Singh Vikas , Sahu Arpita , Bhattacharya Kajari , Sridhar Epari , Sahay Ayushi , Shah Aekta , Joshi Kishore , Kinhikar Rajesh , Kannan Sadhana , Gupta Tejpal
Published: August 2022

BACKGROUND

Surgery is indicated for large or symptomatic lesions in patients with limited brain metastasis (BM), followed by adjuvant stereotactic radiosurgery (A-SRS) to the cavity. Emerging evidence suggests promising role of neoadjuvant SRS (NA-SRS) before surgery with potentially lesser risk of leptomeningeal disease (LMD) and radionecrosis (RN). Hippocampal avoidance whole brain radiotherapy (HA-WBRT) results in better neurocognitive outcomes than standard WBRT, and use of simultaneous integrated boost (SIB) to surgical cavity can improve the local control. Absence of high-quality evidence forms the basis of current study comparing these three treatment strategies.

OBJECTIVES

Primary endpoint is 1-year event-free survival (EFS) a composite endpoint comprising any local failure, LMD, DBF, symptomatic RN, or death as events. Other endpoints include individual endpoints and longitudinal neuro-cognitive function and quality-of-life assessment.

METHODS

Target population includes adults with newly diagnosed BM (≤3 lesions) with life expectancy >1 year and one target lesion needing surgery. Patients will be randomized (1:1:1) to A-SRS (control arm) or one of two test arms (NA-SRS or HA-WBRT-SIB). In A-SRS arm, patients will receive single fraction (16-20Gy) or hypofractionated-SRS (24-27Gy/3 fractions or 30-32.5Gy/5 fractions) based on volume and location of cavity and other intact BM. In the test arms, patients will be allocated to either NA-SRS group (single/multi-fraction) followed by surgery within 2 weeks or HA-WBRT (30Gy/10 fractions) with SIB to cavity plus other intact BM (40-50Gy/10 fractions) combined with memantine within 6 weeks of surgery. A sample size of 168 patients is required to prove the superiority of test arms individually compared to the control arm with assumption of 1-year EFS of 43% versus 25% with a hazard ratio of 0.6 (two-sided alpha=0.05, power=80%, and 15% attrition rate).

DISCUSSION

The study will generate level 1 evidence investigating the role of NA-SRS or HA-WBRT-SIB compared to A-SRS in limited brain metastases.
CLRM-21 RISK FACTORS ASSOCIATED WITH THE PRESENCE OF BRAIN METASTASIS AT THE MOMENT OF DIAGNOSIS IN LUNG CANCER PATIENTS: RETROSPECTIVE CASE SERIES
Authors: Martín-Abreu Carla M , Fariña-Jerónimo Helga , Plata-Bello Julio
Published: August 2022

BACKGROUND

Lung cancer (LC) is the second most frequent neoplasm worldwide and it is commonest origin of brain metastases (BM). The aim of this study is to identify clinical, histological and molecular variables associated with a higher risk of BM at diagnosis in LC patients.

METHODS

A retrospective single-centre case series analysis of patients with a new diagnosis of LC (from 2015 to 2018) was performed. A total of 723 newly diagnosed LC patients were identified and only those with a brain imaging study were included. Non-parametric statistical tests were used to compare patients with or without metastases at diagnosis. Uni- and multivariate analysis was performed to identify risk factors associated with the presence of BM. Statistical significance was considered when p<0.05.

RESULTS

185 patients with newly diagnosed LC and brain imaging at diagnosis were included (mean age 64.69 years [SD= 10.34]; 71.9% male). 40% of patients had BM at diagnosis. No significant differences in clinical, histological and molecular variables were identified. In any case, survival analysis showed that BM at diagnosis was associated with worse overall survival (Log-Rank test, p<0.01). Univariate analysis showed that presenting neurological symptoms (OR=19.5, p<0.0001 CI [7.895-47.65]), adenocarcinoma (OR= 2.113, p<0.014 CI [1.160-3.849]), small cell carcinoma (OR=0.372, p<0.008 CI [0. 179-0.773]) and visceral metastases (OR= 14.444, p<0.0001 CI [6.161-33.86]) or metastases limited to the thorax (OR= 0.019, p<0.001 CI [0.003-0.146]) were associated with BM at diagnosis. However, only neurological symptoms (OR= 20.290, p<0.0001 CI [4.953-83.118]), visceral metastases (OR= 4.451, p<0.010 CI [1.458-13.777]) and/or metastases limited to the thorax (OR= 0.066, p<0.024 CI [0.006-0.010]) reached statistical significance in multivariate analysis.

CONCLUSIONS

Neurological symptoms and the presence of visceral metastases are independent predictors of developing BM at diagnosis in LC patients. However, LC disease confined to the thorax is associated with a lower risk of developing BM.
SPIN-01 RADIATION THERAPY ALONE VERSUS RADIATION THERAPY PLUS RADIOFREQUENCY ABLATION/VERTEBRAL AUGMENTATION FOR SPINE METASTASIS: TRIAL IN PROGRESS
Authors: Kotecha Rupesh , Schiro Brian , Sporrer Justin , Rubens Muni , Avendano Maria , Appel Haley , Tom Martin , Mehta Minesh
Published: August 2022

BACKGROUND

Spine metastases are a common occurrence in cancer patients and result in pain, neurologic deficits, decline in performance status, disability, inferior quality of life (QOL), and reduction in ability to receive cancer-directed therapies. Conventional external beam radiation therapy (EBRT) is associated with modest rates of pain relief, high rates of disease recurrence, low response rates for those with radioresistant histologies, and limited improvement in neurologic deficits. The addition of radiofrequency ablation/percutaneous vertebral augmentation (RFA/PVA) to index sites together with EBRT may improve pain response rates and corresponding quality of life.

METHODS/DESIGN

This is a single-center, prospective, randomized, controlled trial in patients with spine metastases from T5-L5, stratified according to tumor type (radioresistant vs. radiosensitive) in which patients in each stratum are randomized in a 2:1 ratio to either RFA/PVA and EBRT or EBRT alone. All patients are treated with EBRT to a dose of 20-30 Gy in 5-10 fractions. The target parameters are measured and recorded at the baseline clinic visit, and daily at home with collection of weekly measurements at 1, 2, and 3 weeks after treatment, and at 3, 6, 12, and 24 months following treatment with imaging and QOL assessments.

DISCUSSION

The primary objective of this randomized trial is to determine whether RFA/PVA in addition to EBRT improves pain control compared to palliative EBRT alone for patients with spine metastases, defined as complete or partial pain relief (measured using the Numerical Rating Pain Scale [NRPS]) at 3 months. Secondary objectives include determining whether combined modality treatment improves the rapidity of pain response, duration of pain response, patient reported pain impact, health utility, and overall QOL. The results from this study will be used to allow for comparisons to alternative treatment approaches. This trial was activated 5/2020 and is open to accrual.
LOCL-07 LOCO-REGIONAL INFUSION OF GB-13 (IL13.E13K-PE4E) AS A POTENTIALLY PROMISING TREATMENT FOR RECURRENT HIGH-GRADE GLIOMA
Authors: Rechberger Julian , Khatua Soumen , Campian Jian , Sarkaria Jann , Schwartz Jonathan , Daniels David , Schrecengost Randy
Published: August 2022

INTRODUCTION

High grade gliomas (HGG) are devastating diseases with largely unchanged survival outcomes despite decades of research. Recent studies suggest the interleukin 13 receptor subunit alpha 2 (IL-13Rα2) is selectively upregulated in up to 80% of HGG, including glioblastoma (GBM) and diffuse midline gliomas (DMG) harboring H3K27 alterations. Immunotoxins targeting IL-13Rα2 have been demonstrated as safe and have shown some benefit for patients with HGG in previous phase I/II and III clinical trials. We hypothesized that by using GB-13 (IL13.E13K-PE4E), a novel peptide-toxin that binds IL-13Rα2 with high specificity and possesses a Pseudomonas exotoxin moiety, we would enhance the anti-tumor effects of this immunotherapy for HGG in vitro and in vivo while decreasing off-target toxicity.

METHODS

We examined the pharmacological effects of GB-13 in multiple patient-derived cell lines and rodent models of HGG. GBM and DMG lines were used to confirm IL-13Rα2 expression and sensitivity towards GB-13. Tumor naïve rats were evaluated for toxicity, and orthotopic PDX mice were used to monitor tumor size and survival following loco-regional infusion of GB-13.

RESULTS

GB-13 induced a potent cytotoxic response strongly predicated on IL-13Rα2 expression in vitro. No treatment-related adverse effects were noted after 7-day continuous intracranial infusion of GB-13 in tumor naïve rats. Further, in IL-13Rα2-upregulated orthotopic PDX mice, direct intratumoral administration of GB-13 via convection-enhanced delivery abrogated tumor growth and prolonged survival.

CONCLUSIONS

Given these promising results as well as the critical need for novel therapies in CNS malignancies, we are progressing to human trials using GB-13 targeting recurrent HGG. Ongoing safety studies in tumor-bearing animals will be able to define dose levels for the initial adult study-arm and the following pediatric study-arm. In this Phase 1 clinical trial, we hypothesize that loco-regional infusion of GB-13 will safely enhance tumor clearance by causing selective killing of IL-13Rα2-upregulated HGG cells.
MMAP-02 A POPULATION - BASED STUDY ON RADIATION THERAPY FOR BRAIN METASTASIS FROM MALIGNANT MELANOMA IN BRITISH COLUMBIA: EVALUATING THE IMPACT OF IMMUNOTHERAPY AND STEREOTACTIC TECHNIQUES
Authors: Bahl Gaurav , Nguyen Thao
Published: August 2022

BACKGROUND

To evaluate population-based outcomes for patients with brain metastasis from malignant melanoma, treated using radiation therapy, and to assess the impact of immunotherapy (IMT) and stereotactic radiation techniques (SRT).

METHODS

Data was obtained from the BC Cancer Registry for all patients diagnosed with Melanoma in British Columbia, between 1st Jan 2005 and 31st Dec 2018. A total of 5133 patients were identified. These patients had received 2244 courses of RT, of which 461 were directed to the Brain, in 419 unique individuals. The median age was 62 years and majority, 89.5% (n=375), had cutaneous melanomas while 44 had mucosal or choroidal primary sites of disease. A total of 106 (25.3%) patients received IMT, and pembrolizumab was most commonly used (n=48). Over 85% of patients (n=358) received Whole Brain Radiation Therapy (WBRT) alone, with 20 Gy/5 being the most common dose fractionation. Stereotactic Radio-Surgery (SRS) or SRT alone was used in 31 patients, while 30 patients received a combination of SRS/SRT and WBRT. The most used fractionation for SRS was 30Gy/1 (n=9), and for SRT was 35 Gy/5 (n=25). Overall Survival (OS) was calculated from the date of starting radiation therapy.

RESULTS

After a median follow-up of 43 months (95% CI: 18.2 - 67.7), a total of 377 patients had died, with a Median Survival of 2 months (95% CI: 1.46 - 2.53 months) and a 2 year OS of 11.7%. On univariate analysis, age over 65, use of IMT, and SRS/SRT had a significant impact on 2-year OS (14.5% vs 7.4%, p<0.0001; 27.6% vs 6.7%, p<0.0001; and, 38.7% vs. 7.1% p <0.0001, respectively). These factors retained statistical significance on multi-variable analysis. The 2 year OS for patients who received IMT and SRS/SRT alone (n=22) was 54.7%.

CONCLUSION

Selected patients treated aggressively with SRS/SRT and IMT have a median survival of >25 months and a 2-year OS > 50%.
NEIM-07 DIFFERENTIAL DIAGNOSIS OF TUMOR RECURRENCE AND RADIATION NECROSIS AFTER STEREOTACTIC RADIOTHERAPY FOR BRAIN METASTASES WITH 320-ROW ADCT PERFUSION IMAGE AND T1/T2 MATCH: RADIOLOGICAL AND PATHOLOGICAL ANALYSIS
Authors: Mitsuya Koichi , Deguchi Shoichi , Ito Shohei , Asakura Koiku , Nakashima Kazuaki , Oishi Takuma , Sugino Takashi , Hayashi Nakamasa
Published: August 2022

BACKGROUND AND PURPOSE

Radiation necrosis occurs from 6 months to several years following stereotactic irradiation (STI) for brain metastases when tumor recurrences are also most likely. Conventional MR imaging does not provide sufficient information to differentiate between radiation necrosis and tumor recurrence. Methionine-PET, FDG-PET and MR spectroscopy sometimes lead to false positive findings. We applied 320-row area detector CT perfusion imaging for the differentiation because it shows vascularity of lesions in the whole brain. MR T1/T2 match sign also evaluate because it is convenient diagnostic method.

METHOD

Between October 2006 and September 2021, 48 lesions enlarged in 46 patients 3 to 122 months (median: 11 months) after STI. Differential diagnosis was performed with CT perfusion imaging and MR T1/T2 match sign. To calculate the regional cerebral blood volume (rCBV), the regions of interest (ROIs) were located in the enhanced areas. The lesions progressively increased in size or became symptomatic were resected and diagnosed by pathological examination.

RESULTS

Mean age was 63 years, and 60% were male. Primary were lung 31, breast 9, kidney 3, colon 2, melanoma 2, and uterus 1. Mean time to progression from STI was 11 months (range; 3-122). Pathological diagnosis revealed 38 lesions (79%) had tumor recurrence, and 10 (21%) had radiation necrosis. A cut off value rCBV of greater than 3.0 analyzed by ROC curve provided the best sensitivity and specificity for identifying recurrent metastatic tumors, at 89% and 100%, respectively. T1/T2 match sign was provided sensitivity and specificity for identifying recurrent tumors, at 84% and 90%, respectively. To estimate intralesional pathological heterogeneity, contradistinction of CBV map and T1/T2 match sign is useful for the choice of intraoperative maneuver.

CONCLUSION

Perfusion CT imaging and T1/T2 match sign demonstrated reliable methods for differentiating tumor recurrence from radiation necrosis after STI.
SPCR-04 EFFECTS OF BRAIN METASTASES ON NEUROCOGNITIVE FUNCTION: BASELINE RESULTS OF A LONGITUDINAL TRIAL
Authors: Higazy Randa , Ramotar Matthew , Liu Zhihui Amy , Santiago Anna T , Kosyak Natalya , Liu Geoffrey , Simpson Rebecca , Shultz David B , Edelstein Kim
Published: August 2022

PURPOSE

Neurocognitive dysfunction is common in patients with advanced metastatic cancer. The contribution of brain metastases (BrMets) to neurocognitive outcomes is uncertain. We examined the impact of BrMets on cognitive outcomes before CNS-directed treatment and compared findings to patients with advanced metastatic cancer without BrMets. Here we present results from an ongoing prospective, longitudinal study.

METHODS

English-speaking adults followed at the brain metastases and lung cancer clinics underwent neurocognitive testing using a standardized battery (prior to cranial radiotherapy, if applicable), with follow-up assessments 3, 6, 9, 12, 18, and 24 months later. We calculated z-scores and impairment rates for composite neurocognitive function and memory, attention/working memory, processing speed and executive function domains. Impairment was defined according to International Cancer and Cognition Task Force criteria.

RESULTS

78 patients with BrMets (50% female; mean age (SD):61(11) years) and 28 patients with metastatic non-small cell lung cancer (mNSCLC) with no known BrMets (71% female; age 67(9) years) were included. Baseline neurocognitive composite scores were impaired in both groups (BrMets: 61.5%; nonBrMets: 60.7%). Impairment rates varied between groups and across domains (BrMets vs nonBrMets: memory: 35.9%vs25.0%; attention/working memory: 35.8%vs21.4%; processing speed: 10.3%vs7.1%; executive function: 44.0%vs35.7%). Subgroup comparisons between BrMets patients with mNSCLC (N=29) and mNSCLC patients without BrMets, none of whom had targetable mutations, revealed no differences in impairment rates, but BrMets patients had slower processing speed than nonBrMets patients (mean(SD): -0.6(1.4) vs -0.1(1.9); Wilcoxon signed-rank test, p = 0.043).

CONCLUSION

Neurocognitive impairment in patients with advanced cancers is common. Our preliminary findings demonstrate no clear difference in cognitive outcomes between patients with BrMets and those with advanced metastatic disease not involving the brain. Our work examining how neurocognitive outcomes evolve over time in patients with and without BrMets, and demographic, disease, and treatment variables associated with those outcomes, is ongoing.
SYST-04 PRELIMINARY REPORT OF A CLINICAL TRIAL EVALUATING THE SAFETY AND EFFICIENCY OF NEOADJUVANT CAMRELIZUMAB AND APATINIB IN PATIENTS WITH RECURRENT HIGH-GRADE GLIOMAS: A PROSPECTIVE, PHASE II, SINGLE-ARM STUDY
Authors: Lin Fuhua , Guo Chengcheng , Yang Qunying , Chen Yinsheng , Ke Chao , Sai Ke , Zhang Ji , Jiang Xiaobing , Hu Wanming , Xi Shaoyan , Zhou Jian , Li Depei , Zhou Zhihuan , Zhao Qinqin , Cao Xi , Chen Zhongping
Published: August 2022

High-grade glioma is the most common malignant primary brain tumor in the central nervous system. Multiple strategies such as surgery, radiotherapy, and chemotherapy have been used, but the prognosis of patients with high-grade glioma remains poor. No standard treatment exists for recurrent gliomas; however, combination therapies of programmed cell death protein 1 blockades with antiangiogenic agents have demonstrated promising effects in different solid tumors. We have initiated a clinical trial designed to evaluate the safety and efficiency of neoadjuvant therapy using camrelizumab and apatinib in patients with recurrent highgrade gliomas. In this prospective, Phase II, singlearm study, patients with recurrent highgrade gliomas will receive singledose intravenous injection of camrelizumab (200 mg) and daily oral administration of apatinib (250 mg/day for 7 days) 14 days before surgery for recurrent tumor. Sequential therapy will begin 2 weeks after surgery with the biweekly injection of camrelizumab and 4 weeks after surgery with the daily administration of apatinib. Treatment of camrelizumab and apatinib will be continued until disease progression or unacceptable toxicity or death. The trial is planned to enroll 30 patients. Up-to date (March 31, 2022), 12 patients had been enrolled, in which, 9 were GBM. Three patients died, while 4 cases on trial more than 6 months, the longest already 1 year. Although an evaluation is still impossible to be conducted yet, some patients have shown a promising outcome. We will present updated results on the meeting. These preliminary data suggest that this study would be worthwhile. This study was approved by the Ethics Committee of Sun Yatsen University Cancer Center (Guangzhou, China; approval No. SLB202014901). This study was registered with ClinicalTrials.gov under identifier NCT04588987.