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

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

\ua9 2023, The Author(s).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

Global burden of metabolic diseases, 1990-2021

BACKGROUND: Common metabolic diseases, such as type 2 diabetes mellitus (T2DM), hypertension, obesity, hypercholesterolemia, and metabolic dysfunction-associated steatotic liver disease (MASLD), have become a global health burden in the last three decades. The Global Burden of Disease, Injuries, and Risk Factors Study (GBD) data enables the first insights into the trends and burdens of these metabolic diseases from 1990 to 2021, highlighting regional, temporal and differences by sex.METHODS: Global estimates of disability-adjusted life years (DALYs) and deaths from GBD 2021 were analyzed for common metabolic diseases (T2DM, hypertension, obesity, hypercholesterolemia, and MASLD). Age-standardized DALYs (mortality) per 100,000 population and annual percentage change (APC) between 1990 and 2021 were estimated for trend analyses. Estimates are reported with uncertainty intervals (UI).RESULTS: In 2021, among five common metabolic diseases, hypertension had the greatest burden (226 million [95 % UI: 190-259] DALYs), whilst T2DM (75 million [95 % UI: 63-90] DALYs) conferred much greater disability than MASLD (3.67 million [95 % UI: 2.90-4.61]). The highest absolute burden continues to be found in the most populous countries of the world, particularly India, China, and the United States, whilst the highest relative burden was mostly concentrated in Oceania Island states. The burden of these metabolic diseases has continued to increase over the past three decades but has varied in the rate of increase (1.6-fold to 3-fold increase). The burden of T2DM (0.42 % [95 % UI: 0.34-0.51]) and obesity (0.26 % [95 % UI: 0.17-0.34]) has increased at an accelerated rate, while the rate of increase for the burden of hypertension (-0.30 % [95 % UI: -0.34 to -0.25]) and hypercholesterolemia (-0.33 % [95 % UI: -0.37 to -0.30]) is slowing. There is no significant change in MASLD over time (0.05 % [95 % UI: -0.06 to 0.17]).CONCLUSION: In the 21st century, common metabolic diseases are presenting a significant global health challenge. There is a concerning surge in DALYs and mortality associated with these conditions, underscoring the necessity for a coordinated global health initiative to stem the tide of these debilitating diseases and improve population health outcomes worldwide.</p

Imports and isotopes: a modern baseline study for interpreting Iron Age and Roman trade in fallow deer antlers

The European Fallow deer (Dama dama dama) became extinct in the British Isles and most of continental Europe at the time of the Last Glacial Maximum, with the species becoming restricted to an Anatolian refugium (Masseti et al. 2008). Human-mediated reintroductions resulted in fallow populations in Rhodes, Sicily, Mallorca, Iberia and other parts of western Europe (Sykes et al. 2013). Eventually, the species was brought to Britain by the Romans during the 1st century AD, with a breeding population being established at Fishbourne Roman Palace (Sykes et al. 2011). The human influence on the present-day distribution of the species makes it particularly interesting from a zooarchaeological perspective. This paper describes my MSc research, as part of the AHRC-funded project Dama International: Fallow Deer and European Society 6000 BC–AD 1600, looking at antlers from Iron Age and Roman sites in Britain for evidence of trade in body parts and whether this can be elucidated by a parallel stable isotope study of modern fallow antlers of known provenance

Effect of milling conditions on structure and magnetic properties of nanocrystalline cobalt

Milling process conditions are related to magnetic properties of nanocrystalline Co material. Experiments are carried out varying plateau rotation and vial velocities. Coercivity, crystallite size and percentage of the cubic phase are analyzed using a statistical methodology based on artificial neural network. Predicted results show that the combination of low plateau rotation velocity and high vial velocity can enhance the cubic phase formation and consequently the coercivit

Methods of the rational choice of a labyrinth seal design for gas pumping units

This present paper describes a method of improving the labyrinth seal design by the development of three-dimensional parametric computer of its model and an anal-ysis of its work for gas pumping units (GPU) using the finite-element method. The authors have improved design labyrinth seal of the GPU according to the criterion of minimum pressure in the last gap by Gauss-Seidel method of optimization, which will increase GPU operational efficiency by reducing flowing medium at various operating modes of GPU. It is shown that change of geometrical sizes and form of creating more compact part of labyrinth seal with inclination them toward greater pressure for an angle of 80° decrease leakages of gas, that in same time considerably influences on the expense of working environment on the output of labyrinth sea

Study of defect admissibility in gas pipelines based on fracture mechanics

Bearing in mind the considerable distances between natural gas fields and consumers’ appliances, transport by gas pipelines remains the most competitive means. These gas pipelines which are generally made of steel pipes may contain however several types of defects of various origins and which are susceptible to initiate cracks which may grow under some circumstances to such extent as to lead to fracture. Failures of gas pipelines may have serious consequences and may lead to catastrophes from ecological and financial viewpoints. It is therefore interesting to study the defect admissibility so as to maximize safety and minimize exploitation costs through a simplified method based on the Failure Assessment Diagram (FAD). The latter is used in conjunction with Finite Element Analysis (FEM) applied to fracture mechanics to help decision making as to whether a given defect present in a pipe is acceptable or no

Study of life and mechanical properties of welded joints of big diameter pipelines

The increase in transportation capacities of pipe-lines necessitates the introduction of new construction tubes and new production technologies. Tubes should be produced according to pipe-lines service parameters. It is therefore useful to produce tubes which vary in diameter, in construction and mainly in the type of steel used for their production. For pipe of great diameter, destined to support high pressure, we use welded tubes made of controlled rolled steel and low alloyed improved steel. Tubes are the main constituents of pipe-lines. Their quality, the properties of their material and their welded joints determine to a high degree the possible deficiencies, stoppages and failures of pipe-lines. This is the reason why it is important to determine the requirements on tube steel and welded joints in terms of the service parameters of pipe-lines in order to avoid their rupture. The welded joints of tubes are subjected to complex static and dynamic loading, which takes place during pipe transportation, and during realization and exploitation of pipelines. The welding process of big diameter pipes is characterized by a great volume of melted metal and a large heat affected zone of the parent metal. The temperature in the vicinity of the weld joints varies from the melting temperature at the joint to lower temperatures in adjacent zones. In the region of the parent metal subjected to this temperature variation important alterations in the structure and in properties of the material take place. This is why it is estimated important to study this zone in which there is a reduction in the plasticity and the resilience of the metal and consequently there will be an increase in the probability of crack formation. The creation of a mechanical non-homogeneity in this zone reduces the work capacity of the weld joints and the reliability of pipe-lines reduces. It is in this context that the paper presented includes two parts: The first part is concerned with the hardness distribution and the resilience variation as a function of the temperature distribution in the heat affected zone of pipe. The second part considers the influence of the weld joint shape and the loading regime of the pipe-lines on their weld joints life in the big diameter pipes. This work shows how the bearing capacity of the weld joints wary with the mechanical non-homogeneity of weld properties and quality with their weld shape and with the relative thickness of the diameter layer in the welding. On the other hand this study shows the resilience variations in weld joints and in the parent metal of the pipes in the as bought state and after their mechanical ageing. The stress and strain concentration resulting from irrational configuration of welded joints cause the strength of weld subjected to cyclic loading to be diminished. This has lead to finish this work by the determination of the life specimens taken from weld joints in tubes and subjected to cyclic loads during testin