The type II RAF inhibitor tovorafenib in relapsed/refractory pediatric low-grade glioma: The phase 2 FIREFLY-1 trial

BRAF genomic alterations are the most common oncogenic drivers in pediatric low-grade glioma (pLGG). Arm 1 (n = 77) of the ongoing phase 2 FIREFLY-1 (PNOC026) trial investigated the efficacy of the oral, selective, central nervous system-penetrant, type II RAF inhibitor tovorafenib (420 mg 

Oncolytic HSV-1 G207 immunovirotherapy for pediatric high-grade gliomas

BACKGROUND: Outcomes in children and adolescents with recurrent or progressive high-grade glioma are poor, with a historical median overall survival of 5.6 months. Pediatric high-grade gliomas are largely immunologically silent or cold, with few tumor-infiltrating lymphocytes. Preclinically, pediatric brain tumors are highly sensitive to oncolytic virotherapy with genetically engineered herpes simplex virus type 1 (HSV-1) G207, which lacks genes essential for replication in normal brain tissue. METHODS: We conducted a phase 1 trial of G207, which used a 3+3 design with four dose cohorts of children and adolescents with biopsy-confirmed recurrent or progressive supratentorial brain tumors. Patients underwent stereotactic placement of up to four intratumoral catheters. The following day, they received G207 (10 RESULTS: Twelve patients 7 to 18 years of age with high-grade glioma received G207. No dose-limiting toxic effects or serious adverse events were attributed to G207 by the investigators. Twenty grade 1 adverse events were possibly related to G207. No virus shedding was detected. Radiographic, neuropathological, or clinical responses were seen in 11 patients. The median overall survival was 12.2 months (95% confidence interval, 8.0 to 16.4); as of June 5, 2020, a total of 4 of 11 patients were still alive 18 months after G207 treatment. G207 markedly increased the number of tumor-infiltrating lymphocytes. CONCLUSIONS: Intratumoral G207 alone and with radiation had an acceptable adverse-event profile with evidence of responses in patients with recurrent or progressive pediatric high-grade glioma. G207 converted immunologically cold tumors to hot. (Supported by the Food and Drug Administration and others; ClinicalTrials.gov number, NCT02457845.)

An Investigation of the Swelling Kinetics of Bentonite Systems Using Particle Size Analysis

Particles size distribution (PSD) is introduced as a tool for analysis of bentonite aggregation and swelling kinetics. Raw Ca-bentonite was purified using a combined wet sieving and sedimentation processes, followed by thermochemical treatment with Na 2 CO 3 to increase its swelling capacity. The detailed analysis of the PSD shows a strong correlation between the PSD and the swelling process. For the chemically treated raw bentonite, PSD revealed two different peaks representing unswelled and swelled particles along with some aggregates. The swelling is shown to be a kinetically controlled process that depends on time, temperature, and bentonite chemical composition. At the beginning of the chemical treatment, the effect of aggregates was more dominant; therefore, the viscosity did not increase much with particle size. However, the combined chemical and thermal treatment has enhanced the Na-activation process and boosted bentonite swelling. The rheological measurements have shown enhancement in the viscosity and confirmed the PSD findings. The same optimal treatment conditions are obtained from both rheological measurements and PSD analysis. A model is developed based on classical reaction rate kinetics and used to describe the conversion from unswelled to swelled particles. The PSD has a strong correlation with the physical properties of the suspension such as the viscosity. The swelling rate fits a second order model with a rate constant, k, in the range 0.002 to 0.124 h 1 and an activation energy, E, of 87 kJ/mol. PSD analysis together with the developed kinetic model are powerful tools for studying the swelling kinetics of bentonites.Scopu

An open-label multi-center phase 1 safety study of BXQ-350 in children and young adults with relapsed solid tumors, including recurrent malignant brain tumors

BACKGROUND: BXQ-350 is a novel anti-neoplastic agent composed of saposin C (SapC) and phospholipid dioleoylphosphatidyl-serine sodium (DOPS) that selectively binds tumor cell phosphatidylserine (PS), inducing apoptosis. BXQ-350 has demonstrated preclinical antitumor effects in high-grade gliomas (HGG) and clinical activity in adult patients with recurrent HGG. METHODS: A phase 1 study was conducted in pediatric patients with relapsed/refractory solid tumors, including recurrent brain tumors. Primary objectives were to characterize safety and determine maximum tolerated dose (MTD) and preliminary antitumor activity. Sequential dose cohorts were assessed up to 3.2 mg/kg using an accelerated titration design. Each cycle was 28 days; dosing occurred on days 1-5, 8, 10, 12, 15, and 22 of cycle 1, and day 1 of subsequent cycles, until disease progression or toxicity. RESULTS: Nine patients, median age 10 years (range: 4-23), were enrolled. Seven patients (78%) had central nervous system (CNS) and two (22%) had non-CNS tumors. Eight patients completed cycle 1. No dose limiting toxicity (DLT) or BXQ-350-related serious adverse events (SAEs) were observed. Six patients experienced at least one adverse event (AE) considered possibly BXQ-350-related, most were grade ≤2. One patient with diffuse intrinsic pontine glioma experienced stable disease for 5 cycles. The study was terminated after part 1 to focus development on the frontline setting. CONCLUSION: No DLTs or BXQ-350-related SAEs were reported, and the maximal planned dose of 3.2 mg/kg IV was tolerable. Limited safety and efficacy data support continued BXQ-350 development in pediatric HGG; however, early discontinuations for progression suggest novel therapies be assessed at earlier disease stages

The type II RAF inhibitor tovorafenib in relapsed/refractory pediatric low-grade glioma: the phase 2 FIREFLY-1 trial

BRAF genomic alterations are the most common oncogenic drivers in pediatric low-grade glioma (pLGG). Arm 1 (n = 77) of the ongoing phase 2 FIREFLY-1 (PNOC026) trial investigated the efficacy of the oral, selective, central nervous system-penetrant, type II RAF inhibitor tovorafenib (420 mg m$^{-}$$^{2}$ once weekly; 600 mg maximum) in patients with BRAF-altered, relapsed/refractory pLGG. Arm 2 (n = 60) is an extension cohort, which provided treatment access for patients with RAF-altered pLGG after arm 1 closure. Based on independent review, according to Response Assessment in Neuro-Oncology High-Grade Glioma (RANO-HGG) criteria, the overall response rate (ORR) of 67% met the arm 1 prespecified primary endpoint; median duration of response (DOR) was 16.6 months; and median time to response (TTR) was 3.0 months (secondary endpoints). Other select arm 1 secondary endpoints included ORR, DOR and TTR as assessed by Response Assessment in Pediatric Neuro-Oncology Low-Grade Glioma (RAPNO) criteria and safety (assessed in all treated patients and the primary endpoint for arm 2, n = 137). The ORR according to RAPNO criteria (including minor responses) was 51%; median DOR was 13.8 months; and median TTR was 5.3 months. The most common treatment-related adverse events (TRAEs) were hair color changes (76%), elevated creatine phosphokinase (56%) and anemia (49%). Grade ≥3 TRAEs occurred in 42% of patients. Nine (7%) patients had TRAEs leading to discontinuation of tovorafenib. These data indicate that tovorafenib could be an effective therapy for BRAF-altered, relapsed/refractory pLGG. ClinicalTrials.gov registration: NCT04775485

Primary central nervous system germ cell tumors in children and young adults: A review of controversies in diagnostic and treatment approach

Primary central nervous system (CNS) germ cell tumors (GCT) are a rare heterogenous group of cancers, arising most commonly in the second decade of life. Through several clinical trials conducted around the world by various groups, the treatment approach for CNS GCT has advanced substantially with generally improved overall outcomes. In recent years, the goal of clinical trials has been focused on reduction of the radiotherapy burden and minimization of long-term toxicity. This review summarizes the current diagnostic and treatment regimens for CNS GCT, examines the controversies associated with these approaches, gaps in contemporary knowledge, and underscores the challenges we face. We also explore future directions in the management of CNS GCT with the ultimate overall aim of preserving curative outcomes, identifying novel biomarkers, and mitigating neurocognitive, endocrine, and psychological toxicity through prospective clinical studies

Carbon Mineralization by Reaction with Steel-Making Waste: A Review

Carbon capture and sequestration (CCS) is taking the lead as a means for mitigating climate change. It is considered a crucial bridging technology, enabling carbon dioxide (CO2) emissions from fossil fuels to be reduced while the energy transition to renewable sources is taking place. CCS includes a portfolio of technologies that can possibly capture vast amounts of CO2 per year. Mineral carbonation is evolving as a possible candidate to sequester CO2 from medium-sized emissions point sources. It is the only recognized form of permanent CO2 storage with no concerns regarding CO2 leakage. It is based on the principles of natural rock weathering, where the CO2 dissolved in rainwater reacts with alkaline rocks to form carbonate minerals. The active alkaline elements (Ca/Mg) are the fundamental reactants for mineral carbonation reaction. Although the reaction is thermodynamically favored, it takes place over a large time scale. The challenge of mineral carbonation is to offset this limitation by accelerating the carbonation reaction with minimal energy and feedstock consumption. Calcium and magnesium silicates are generally selected for carbonation due to their abundance in nature. Industrial waste residues emerge as an alternative source of carbonation minerals that have higher reactivity than natural minerals; they are also inexpensive and readily available in proximity to CO2 emitters. In addition, the environmental stability of the industrial waste is often enhanced as they undergo carbonation. Recently, direct mineral carbonation has been investigated significantly due to its applicability to CO2 capture and storage. This review outlines the main research work carried out over the last few years on direct mineral carbonation process utilizing steel-making waste, with emphasis on recent research achievements and potentials for future research