PURPOSE STELLAR (ClinicalTrials.gov identifier: NCT02796261 ) was a phase III, randomized, open-label trial of eflornithine + lomustine versus lomustine monotherapy in patients with recurrent grade 3 astrocytoma. METHODS At trial initiation, eligibility criteria included: age ≥18 years, anaplastic astrocytoma (2016 WHO CNS Tumor classification [WHO CNS4]), first recurrence ≥6 months after radiation and temozolomide (TMZ), Karnofsky performance status ≥70, and no imaging findings consistent with grade 4 glioblastoma. Random assignment (1:1) was stratified by isocitrate dehydrogenase ( IDH ) mutation, age, resection extent, and geography. Patients received eflornithine (2.8 g/m 2 orally, every 8 hours [2 weeks on, 1 week off]) + lomustine (90 mg/m 2 orally, once every 6 weeks), or lomustine monotherapy (110 mg/m 2 once every 6 weeks). The primary end point was overall survival (OS). RESULTS Among 343 patients randomly assigned across 74 sites in eight countries, there was no difference in survival between eflornithine + lomustine and lomustine monotherapy (median OS 23.4 v 20.3 months, hazard ratio [HR], 0.94). Following changes in classification and grading in the 2021 WHO CNS5, a subset analysis of patients with IDH- mutant, grade 3 astrocytoma (n = 196), defined in 2024, before unblinding, showed clinically meaningful improvements in median OS with eflornithine + lomustine versus lomustine monotherapy (34.9 v 23.5 months, HR, 0.64) and median progression-free survival (PFS, 15.8 v 7.2 months, HR, 0.57). No differences were observed among patients with CNS grade 4 disease. Grade ≥3 treatment-emergent adverse events of relevance were related to reversible myelosuppression (eflornithine + lomustine 42% v lomustine monotherapy 29% of patients) and hearing impairment (24% v 0%). No new safety signals were identified. CONCLUSION Clinically meaningful improvements were observed; eflornithine + lomustine doubled PFS and improved OS in patients with recurrent IDH -mutant, grade 3 astrocytoma, but not grade 4 tumors, after prior radiotherapy and TMZ, consistent with its cytostatic mechanism of action.
Multi‐modality biological dose optimization for combined carbon‐ion and proton radiation therapy
Abstract Background Carbon ion radiotherapy (CIRT), characterized by its Bragg peak and a reduced lateral scattering compared to proton radiotherapy (PT), offers excellent dose conformity in radiation treatment. Meanwhile, compared to PT, CIRT causes more complex and severe DNA damage in tumor cells, which results in a higher relative biological effectiveness (RBE), making it particularly advantageous in treating radioresistant and hypoxia tissues than conventional radiotherapy. However, CIRT's high RBE and the nuclear fragmentation dose tail outside the target presents challenges in sparing organ at risk (OARs). Combining PT and CIRT offers a potential hybrid modality that leverages the biological effectiveness of carbon ions while minimizing normal tissue toxicity with high biological damage. Purpose Despite the potential of combining PT and CIRT, balancing their respective advantages while mitigating disadvantages remains a significant challenge. This study aims to develop an optimized treatment approach that automatically adjusts the relative contributions of protons and carbon ions, improving target dose conformity while minimizing biological impact on OARs. Methods We propose a biological optimization framework for multi‐modality combining PT and CIRT (CCIPRT). The biological dose is modeled as the product of the physical dose and RBE. Through iterative Jacobian‐based linearization, the biological dose of carbon ion is expressed in a linear model, enabling the formulation of a linear least‐square objective. The biological dose of proton is formulated as a linear model using the physical dose and dose‐averaged linear energy transfer (LET). The joint optimization problem is then solved using iterative convex relaxation and the alternating direction method of multipliers. For comparison, single‐modality PT and CIRT were also implemented. Results When the target dose of CCIPRT is prescribed in terms of the physical dose, compared to PT, CCIPRT increased the mean biological dose in the target by 37.7%, 29.6%, and 31.1% for brain, lung, and abdomen, respectively; compared to CIRT, CCIPRT reduced the biological dose in CTV1cm (ring surrounding CTV with 1 cm width) by 47.2%, 32.3%, and 40.4% for brain, lung, and abdomen, respectively. When the target dose of CCIPRT is prescribed in terms of the biological dose, compared to PT, CCIPRT achieved higher conformity index (CCIPRT: 0.96 and 0.97; PT: 0.93 and 0.96 for brain and liver cases, respectively) and reduced the dose in CTV1cm by 9.5% and 7.0% for brain and liver cases, respectively; compared to CIRT, CCIPRT enhanced healthy tissue sparing, reducing the dose to the body by 7.5% and 9.2% for brain and liver cases, respectively. Conclusions A novel multi‐modality CCIPRT treatment planning is developed with demonstrated superior performance over single‐modality PT or CIRT, with enhanced biological effectiveness and dose conformity compared to PT and reduced OAR dose compared to CIRT.
Rapid and Sensitive Detection of Thrombospondin-2 Using Nanoparticle Sensors for Cancer Screening and Prognosis
Thrombospondin-2 (THBS2) is a prevailing prognostic biomarker implicated in different cancer types, such as deadly colorectal, pancreas, and triple-negative breast cancers. While the current methods for cancer-relevant protein detection, such as enzyme-linked immunosorbent assay (ELISA), mass spectrometry, and immunohistochemistry, are feasible at advanced stages, they have shortcomings in sensitivity, specificity, and accessibility, particularly at low concentrations in complex biological fluids for early detection. Here, we propose and demonstrate a modular, in-solution assay design concept, Nanoparticle-Supported Rapid Electronic Detection (NasRED), as a versatile cancer screening and diagnostic platform. NasRED utilizes antibody-functionalized gold nanoparticles (AuNPs) to capture target proteins from a minute amount of sample (<10 µL) and achieve optimal performance with a short assay time by introducing active fluidic forces that act to promote biochemical reaction and accelerate signal transduction. This rapid (15 min) process serves to form AuNP clusters upon THBS2 binding and subsequently precipitate such clusters, resulting in color modulation of the test tubes that is dependent on the THBS2 concentration. Finally, a semiconductor-based, portable electronic device is used to digitize the optical signals for the sensitive detection of THBS2. High sensitivity (femtomolar level) and a large dynamic range (five orders of magnitude) are obtained to analyze THBS2 spiked in PBS, serum, whole blood, saliva, cerebrospinal fluids, and synovial fluids. High specificity is also preserved in differentiating THBS2 from other markers such as cancer antigen (CA) 19-9 and bovine serum albumin (BSA). This study highlights NasRED’s potential to enhance cancer prognosis and screening by offering a cost-effective, accessible, and minimally invasive solution.
APOE4 impairs microglia‐astrocyte response in Alzheimer’s disease by inducing TGFβ‐mediated checkpoints
AbstractBackgroundAPOE ε4 is the strongest genetic risk factor for late‐onset Alzheimer’s disease (AD). The contribution of microglial APOE4 to AD pathogenesis is unknown, although APOE has the most enriched gene expression in neurodegenerative microglia (MGnD).MethodGeneration of CX3CR1‐CREERT2 mice crossed to APOE‐KI(E3 and E4)fl/fl: APP/PS1 and APOE‐KI(E3 and E4)fl/fl: P301S mice. Microglia and astrocytes were isolated and sequenced using either bulk RNA‐seq (MGnD‐Paradigm) or single‐cell RNA‐seq. Crosstalk between cells was determined using the NichenetR database and validated using 1) recombinant Lgals3 intracranial injection into APP/PS1 mice and 2) adoptive transfer of microglia, from APOE3‐KI, APOE4‐KI, and APOE4‐cKO mice challenged with labeled apoptotic neurons, into WT mice and isolation of astrocytes. Validation in the brain of AD donors carrying the APOE e3/3 and e3/4 alleles.ResultHere we show, in mice and in humans, a negative role of microglial APOE4 in the induction of MGnD response to neurodegeneration. Deletion of microglial APOE4 restores MGnD phenotype, associated with neuroprotection in P301S tau transgenic mice, and decreases pathology in APP/PS1 mice. MGnD‐astrocyte crosstalk associated with b‐amyloid (Ab) plaque encapsulation and clearance is mediated via Lgals3 signaling following microglial APOE4 deletion. In the brain of AD donors carrying the APOE ε4 allele, we found a sex‐dependent reciprocal induction of AD risk factors associated with suppression of MGnD genes in females, including LGALS3, as compared to APOE ε3/3 carriers. Mechanistically, APOE4‐mediated induction of ITGB8‐TGFb signaling impairs MGnD response via upregulation of TGFb‐mediated microglial homeostatic checkpoints, including INPP5D. Microglial deletion of Inpp5d restores MGnD‐astrocyte crosstalk and facilitates plaque clearance in APP/PS1 mice. Genetic and pharmacological blocking of ITGB8‐TGFb signaling enhanced MGnD response associated with increased plaque clearance in AD mice.ConclusionWe identify the microglial APOE4‐ITGB8‐TGFb pathway as a negative regulator of microglia‐astrocyte response to AD pathology, and restoring MGnD phenotype via blocking ITGB8‐TGFb signaling may provide new molecular targets to modulate and restore functional microglia in AD.
3: PHASE 2 STUDY INTERIM RESULTS OF RBT-1 EFFECT ON POSTOPERATIVE COURSE IN ELECTIVE CABG/VALVE SURGERY
S1421 Safety and Efficacy of Long-Term Treatment With Lirentelimab, A Monoclonal Antibody Against Siglec-8, in Patients With Eosinophilic Gastritis and/or Duodenitis