interferon alfa-2a (Proquiferon)

Feasibility and safety of pegunigalsidase alfa infusion during hemodialysis: first case report in a Fabry patient with kidney failure.

Riccio Eleonora E, Gambardella Jessica J, Cuomo Vincenzo V, Iaccarino Guido G et al.

Successful Translational Prediction of Bedaquiline's Phase 2a Clinical Trial Results against Tuberculosis: The Zebrafish as a New Approach Methodology.

van Lieshout Bart B, Hanuun Aanisah A, van Hasselt J G Coen JGC, van Wijk Rob C RC

Tuberculosis remains an urgent global health crisis that requires an accelerated development of novel regimens. Rodent and rabbit studies currently inform early translational predictions. However, the zebrafish (Danio rerio) embryo/larva, as a New Approach Methodology, provides an ethical, cost-effective, and high-throughput non-mammalian disease model to study early anti-tuberculosis drug pharmacology and bridge the gap between in vitro drug screens and (confirmatory) rodent experiments. This study aimed to translate the bedaquiline exposure-response relationship from zebrafish to humans to predict two phase 2a trial results in order to strengthen the use of zebrafish as a New Approach Methodology for translational anti-tuberculosis pharmacology. An established exposure-response relationship for bedaquiline in zebrafish against Mycobacterium marinum as a tuberculosis disease model was combined with a clinical population pharmacokinetic model to predict bacterial burden profiles from two published phase 2a clinical trials (25 to 400 mg daily). This translation incorporated the minimum inhibitory concentration ratio between Mycobacterium marinum and Mycobacterium tuberculosis to scale the zebrafish bedaquiline EC50 to humans. Clinical simulations based on the scaled zebrafish exposure-response relationship demonstrated that accounting for in vitro drug sensitivity resulted in close alignment with observed bacterial burden across all doses and timepoints, with a mean absolute percentage error of 10.37% and a root mean squared error of 0.74 log10 colony-forming units per milliliter of sputum. These findings demonstrate that early-phase clinical results for bedaquiline in tuberculosis can be successfully predicted from pharmacokinetics-pharmacodynamics in the zebrafish tuberculosis disease model. These results help advance the zebrafish as a resource-efficient and sustainable New Approach Methodology for tuberculosis drug development.

Complement activation linked to type II interferon signaling in Still disease.

Huijsmans Freya M C H FMCH, Thalheim Tabea T, Bodelón Alejandra A, Rogani Greta G et al.

Still disease (SD) is an autoinflammatory syndrome characterized by innate immune dysregulation. While complement can drive inflammation, its involvement in SD remains to be defined. Thus, we aimed to assess complement activation in SD. Complement was assessed using transcriptomic, proteomic, and in vitro approaches. RNA sequencing of monocytes was performed in healthy donors (n=15), non-systemic juvenile idiopathic arthritis (JIA, n=8), and SD patients at onset (n=19), remission (n=18), and macrophage activation syndrome (n=2). Whole-blood NanoString analysis of complement and interferon-related gene expression was conducted in SD (active n=41, inactive n=33) and JIA patients (n>600). Complement products and inflammatory mediators were measured by Luminex and ELISA. Functional complement activity was evaluated in SD (active n=30, inactive n=67) and JIA sera (n=12). In vitro assays examined monocytic C1q induction and complement-mediated CD8+ T cell activation. Transcriptomic analysis of monocytes from SD patients at onset revealed enrichment of the complement cascade compared to patients in remission (Padj=3.7×10-36), ranking among the top ten upregulated pathways. Classical complement genes (C1QB/C1QC) were markedly upregulated in onset SD compared to remission SD and JIA patients. Active SD patients showed increased C1q, C3a, C5a, and terminal complement complex protein levels, with enhanced functional classical complement activity. Whole-blood C1QB/C1QC expression correlated with interferon-related markers, including IL-18, CXCL9 and CXCL10. Recombinant IFN-γ induced monocytic C1q, while C1q enhanced IFN-γ production by CD8+ T cells, supporting a feed-forward loop. SD is characterized by complement activation with marked upregulation of C1q, which is closely linked to IFN-γ/type-II signaling.

Beam geometry optimization and convergence mode evaluation for knowledge-based planning of hippocampal avoidance whole-brain radiotherapy: A cross-platform study with quantitative scorecard assessment.

Lam Anh A, Luca Kirk K, Kaur Mandeep M, Shah Keyur D KD et al.

Hippocampal avoidance whole-brain radiotherapy (HA-WBRT) is used to treat brain metastases while preserving cognitive function by sparing the hippocampi. Volumetric modulated arc therapy (VMAT) is commonly used due to its ability to generate conformal dose distributions. However, treatment planning remains challenging due to the need for sharp dose fall-off near centrally located hippocampi without compromising whole-brain coverage. This study evaluated the dosimetric impact of a four-arc hybrid geometry (4A-HG) and convergence mode settings for HA-WBRT using a knowledge-based planning (KBP) workflow across two linac platforms. Twenty HA-WBRT patients prescribed 30 Gy in 10 fractions were retrospectively studied. Plans were generated using a KBP model on two linac platforms with different collimation systems: Halcyon and Edge. Four arc configurations were evaluated, including three open-field geometries with different numbers of arcs (2A, 3A, and 4A) and 4A-HG. The 4A-HG consists of two open-field arcs and two partial-field arcs with superior-inferior field restriction near the hippocampal region, which allows improved dose modulation near the hippocampus to potentially enhance hippocampal sparing. Jaw tracking was enabled for all Edge plans. Each arc configuration was combined with three convergence modes ("Off," "On," and "Extended") on both linac platforms, yielding 24 plans per patient. Plans were normalized so that 95% of the planning target volume (PTV) received 100% of prescription dose. Plan quality was evaluated using Radiation Therapy Oncology Group (RTOG) 0933 metrics, as well as by a dosimetric scorecard incorporating PTV D100% and the Paddick conformity index (PCI). Statistical comparisons were performed using Friedman tests with Holm correction. Patient-specific quality assurance (QA) was performed for the five highest-monitor-unit (MU) plans on each platform. The proposed 4A-HG consistently improved target coverage and hippocampal sparing compared with conventional open-field arc configurations. Notably, PTV D100% was significantly improved with 4A-HG on the Edge with the "On" and "Extended" convergence modes (all p < 0.05 compared with other arc configurations). For example, with the "On" convergence mode, mean PTV D100% across 20 patients increased from 19.433 Gy with 2A to 20.011 Gy with 4A-HG (p = 0.009). The 4A-HG also achieved the highest mean PCI using the "Extended" mode (0.940 on Halcyon, 0.944 on Edge). Hippocampus Dmax was significantly reduced with 4A-HG on Halcyon across all modes (p < 0.01) and on Edge for "On" and "Extended" modes (p < 0.05). On Halcyon, the mean hippocampus Dmax decreased from 14.446 Gy to 13.662 Gy when changing the arc configuration from 2A to 4A-HG using the "Extended" mode, with a similar reduction observed on Edge (12.945 Gy to 12.566 Gy). More extensive convergence mode settings further improved plan quality, with the highest mean score (157/184) achieved on Edge using 4A-HG under the "Extended" mode. These improvements were associated with increased MUs; however, all QA results met institutional criteria. The 4A-HG arc configuration and the more extensive convergence mode settings improved plan quality for HA-WBRT within a KBP workflow across two linac platforms. These findings support the clinical implementation of the proposed planning strategies for VMAT-based HA-WBRT.