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Introduction Large-scale production of mammalian cells is pivotal for applications in biotechnology, regenerative medicine, and therapeutic manufacturing. However, current bioreactor technologies face significant technical and economic challenges, including excessive cell aggregation, shear stress-induced cell death, batch-to-batch inconsistencies, and limited scalability. We propose that engineering a cell-friendly microenvironment can enhance culture efficiency. Previously, we developed alginate hydrogel microtubes (AlgTubes) that significantly improved cell density and growth rates; however, AlgTubes lack adhesion sites essential for anchorage-dependent cells and frequently break, causing cell leakage and production inconsistencies. Methods To address these limitations, we reinforced AlgTubes with collagen nanofibers, creating collagen-alginate hybrid hydrogel microtubes (ColAlgTubes). Collagen was integrated to form a dense nanofiber network interwoven with the alginate mesh, with the dual aim of enhancing mechanical properties and providing cell adhesion sites. ColAlgTubes were fabricated to maintain cell mass within a 400 μm diameter to ensure efficient nutrient exchange and waste removal. Results ColAlgTubes successfully formed a reinforced hybrid hydrogel structure in which the collagen nanofiber network improved the mechanical integrity of the alginate matrix while supplying adhesion sites for anchorage-dependent cells. The optimized 400 μm diameter microenvironment supported high cell viability, rapid proliferation, and exceptional yields of 5 × 10 8 cells/mL. Discussion These results demonstrate that ColAlgTubes overcome the key limitations of AlgTubes by combining structural reinforcement with biological functionality. The improved mechanical properties reduce tube breakage and cell leakage, while collagen-derived adhesion sites broaden compatibility to anchorage-dependent cell types. With their scalability, cost-effectiveness, and high efficiency, ColAlgTubes represent a transformative solution for large-scale mammalian cell production across biotechnology, regenerative medicine, and therapeutic manufacturing.

BACKGROUND AND OBJECTIVES: Pediatric large-volume brain arteriovenous malformations (AVMs) carry a substantial lifelong hemorrhage risk, neurological symptoms, and treatment morbidity. Single-session stereotactic radiosurgery (SRS) is often unsuitable due to constraints on dose-volume toxicity. Volume-staged SRS (VS-SRS) enables sequential dosing of large nidus volumes, potentially enhancing safety while maintaining efficacy. Evidence in children remains limited. We aimed to evaluate outcomes of VS-SRS for large AVMs in pediatric patients. METHODS: A multicenter retrospective cohort was assembled from 21 centers, including patients aged younger than 21 years treated with VS-SRS for AVMs >10 cm 3 . Clinical and radiological end points included obliteration, hemorrhage, and permanent symptomatic radiation-induced changes (RIC). RESULTS: A total of 103 patients were included (median age 14 years; IQR, 12-17). The median nidus volume at first stage was 18.2 cm 3 (IQR, 12.3-25.6). Median prescription dose per stage was 17 Gy (IQR, 16-18). The median clinical follow-up from the first stage was 57.5 months (IQR, 25-138). Obliteration occurred in 42 of 103 patients (40.8%), with actuarial rates of 6.9% (95% CI: 2.8-14) at 3 years and 29% (95% CI: 20-39) at 5 years. Hemorrhage occurred in 17 of 103 patients (16.5%) during follow-up, and permanent RIC was observed in 9 of 103 patients (8.7%). CONCLUSION: VS-SRS is a reasonably safe, selected option for pediatric large-volume AVMs when microsurgical or endovascular cure is not feasible or prudent. Delivering ≥17 Gy per stage while limiting each treatment volume to <15 cm 3 supports durable nidus control with acceptable toxicity. VS-SRS represents a key modality in multidisciplinary management of this historically difficult-to-treat population.

OBJECTIVE Ruptured, large pediatric arteriovenous malformations (AVMs) pose a significant management challenge due to high rerupture risk and the morbidity of conventional treatments. Volume-staged stereotactic radiosurgery (VS-SRS) has emerged as an alternative; however, evidence for its use in this specific population is limited. This study aimed to evaluate the long-term efficacy and safety of VS-SRS for ruptured, large AVMs in a dedicated pediatric cohort. METHODS This international, multicenter, retrospective cohort study from 21 centers analyzed outcomes for 42 pediatric patients (age < 18 years) with previously ruptured, large AVMs treated with VS-SRS. The primary outcome was complete AVM obliteration, and secondary outcomes included post-SRS hemorrhage, radiation-induced changes (RICs), and favorable outcome. Favorable outcome in this study was defined as obliteration without post-SRS hemorrhage or permanent RIC. RESULTS At the initial SRS, the median patient age was 14.5 years, and the median AVM volume was 15.0 cm 3 ; most AVMs were high grade (Spetzler-Martin grades IV and V). With a median follow-up of 41.5 months, complete AVM obliteration was achieved in 21 patients (50.0%). The cumulative obliteration rate was 37% at 5 years and 56% at 10 years. Patients with a nidus volume of ≤ 10 cm 3 had significantly higher cumulative obliteration rates than those with a nidus volume > 10 cm 3 (log-rank test, p = 0.021). Similarly, patients treated with a prescription dose > 17 Gy showed significantly higher cumulative obliteration rates compared to those treated with a dose ≤ 17 Gy (log-rank test, p = 0.012). The cumulative 5-year incidences of hemorrhage and RICs following VS-SRS were 19% and 7%, respectively. In multivariable analysis, only larger total AVM volume was an independent predictor of a lower likelihood of favorable outcome (hazard ratio 0.89, 95% CI 0.80–0.99; p = 0.036). CONCLUSIONS In this multicenter pediatric cohort, VS-SRS for ruptured, large AVMs provides a reasonable chance of long-term obliteration, but generally acceptable risks of post-SRS hemorrhage and RICs exist. VS-SRS should be considered as an option for pediatric patients with large, ruptured AVMs.

LBA5 Background: Available 2L therapies offer limited clinical benefit in mPDAC with reported mPFS of 3–4 mo and mOS of 6–7 mo. Aberrant RAS pathway activation is the key driver of PDAC, with oncogenic RAS mutations (mut) identified in >90% of cases, most commonly at codon G12. Daraxonrasib is an oral, RAS(ON) multi-selective, tri-complex inhibitor of the active, GTP-bound state of mutant and wild type RAS. Methods: RASolute 302 (NCT06625320) is a global, randomized, open-label, Ph 3 study in pts with 2L mPDAC and ECOG PS 0-1. Pts were randomized 1:1 to receive daraxonrasib 300 mg PO QD or investigator’s choice of SOC cytotoxic chemo. Dual primary endpoints were OS and PFS by BICR in the RAS G12 mutant (RAS G12) population. Key secondary endpoints included OS and PFS by BICR in the overall population, ORR by BICR in RAS G12 and overall populations. Results: 248 pts were randomized to daraxonrasib and 252 to chemo. Baseline characteristics were balanced between arms. At data cutoff (Feb 10, 2026; mFU: 8.5 mo), all primary and key secondary endpoints were met. Statistically significant, clinically meaningful improvements in OS and PFS were observed with daraxonrasib vs chemo in the RAS G12 and overall populations (Table). Gr ≥3 TRAEs occurred in 43.6% of pts receiving daraxonrasib vs 57.5% receiving chemo. The most common (≥10%) Gr ≥3 TRAEs were rash (13.7%) and stomatitis (12.0%) for daraxonrasib; neutrophil decrease (18.2%) and anemia (16.4%) for chemo. TRSAEs occurred in 10.8% of pts receiving daraxonrasib vs 18.7% receiving chemo. Discontinuation due to TRAEs occurred in 1.2% of pts for daraxonrasib vs 11.2% for chemo. Median/mean daraxonrasib dose intensity was 93.1%/84.7%. Conclusions: Daraxonrasib demonstrated unprecedented improvements in OS and PFS vs chemo in pts with 2L mPDAC with or without an identified tumor RAS mut. Daraxonrasib was generally well tolerated, with a manageable safety profile and with no new safety signals. Results support daraxonrasib as the new SOC for 2L mPDAC. Clinical trial information: NCT06625320 . RAS G12 Overall b Daraxonrasibn=228 Chemo n=231 Daraxonrasib n=248 Chemo n=252 OS Median; mos(95% CI) 13.2(10.0–NE) 6.6(5.4–8.2) 13.2(10.0–NE) 6.7(5.8–8.0) HR(95% CI)P-value 0.40(0.30-0.54)<0.0001 0.40(0.30-0.53)<0.0001 PFS a Median; mos(95% CI) 7.3(6.3–8.1) 3.5(2.9–3.8) 7.2(5.7–7.5) 3.6(2.9–4.2) HR(95% CI)P-value 0.45(0.34-0.59)<0.0001 0.49(0.38-0.64)<0.0001 ORR a %(95% CI) 33.2(27.0–39.9) 11.8(7.8–16.8) 31.6(25.8–38.0) 11.2(7.5–15.9) a By BICR. b RAS G12, G13 or Q61 mut or no RAS mut identified.

Ziftomenib - a potent, selective, oral menin inhibitor - is approved as monotherapy for adults with relapsed/refractory (R/R) NPM1-mutated acute myeloid leukemia (NPM1-m AML). The KOMET-007 phase 1 trial investigated clinical activity and tolerability of ziftomenib in combination with standard therapies for R/R and newly diagnosed AML. Here, we report outcomes of adults with R/R NPM1-m AML treated with ziftomenib plus venetoclax/azacitidine. In phase 1a, patients received ziftomenib 200, 400, or 600 mg once daily with standard doses of venetoclax/azacitidine. In phase 1b, ziftomenib 600 mg was selected for expansion. Sixty-seven patients were treated (27 phase 1a; 40 phase 1b). Median age was 66 years, and 55% were men. Median number of prior therapies was 1 (range 1-8); 55% received prior venetoclax and 22% had prior transplantation. Most common (≥20%) grade ≥3 treatment-emergent adverse events were leukopenia (34%), thrombocytopenia (28%), febrile neutropenia and neutropenia (25% each). Six patients developed QTc prolongation (1 ziftomenib-related; grade 1), and 2 experienced differentiation syndrome (grade 3); all events were successfully managed. In patients receiving ziftomenib 600 mg, composite complete remission (CRc) rate was 46% (22/48), with 67% (12/18) achieving central measurable residual disease (MRD) negativity (&lt;0.01% threshold). In venetoclax-naïve and -exposed patients, CRc rates were 70% (16/23) and 24% (6/25), with MRD-negativity rates of 75% (9/12) and 50% (3/6), respectively. Median duration of response was 8.6 months, and median overall survival was not reached. The combination of ziftomenib 600 mg with venetoclax/azacitidine was well tolerated with deep and durable clinical activity in R/R NPM1-m AML. This trial was registered at www.ClinicalTrials.gov as #NCT05735184.

TPS5632 Background: Concurrent chemoradiation therapy (CCRT) is the standard of care for locally advanced cervical cancer (LACC); however, outcomes remain suboptimal in patients with high-risk disease. Recent studies suggest that integration of immunotherapy (IO) with definitive chemoradiation, or induction chemotherapy prior to CCRT improves outcomes. Whether treatment intensification with induction systemic therapy and IO prior to CCRT and IO further improves disease control remains unknown. Induction chemotherapy may reduce tumor burden, eradicate micrometastatic disease, and improve tumor immunogenicity prior to definitive CCRT. Preclinical and clinical data support synergy between systemic therapy or radiotherapy and immune checkpoint blockade, providing the rationale for evaluating an induction strategy incorporating chemotherapy and immunotherapy before standard CCRT with immunotherapy, followed by maintenance immunotherapy. Optional tumor tissue and blood samples will be collected for exploratory correlative analyses, including immune and molecular biomarkers associated with response, resistance, and patterns of failure. Methods: NRG-GY037 is a prospective, multi-institutional phase III randomized trial conducted through NRG Oncology. A total of 336 patients will be enrolled (168 per arm). Patients will be stratified by FIGO stage (III vs. IVA) and presence or absence of para-aortic lymph nodes (N2). The primary endpoint is progression free survival (PFS). The study has 90% power to detect PFS hazard ratio of 0.65 in the experimental arm. Treatment: Patients with previously untreated, high-risk LACC are randomized to receive either induction chemotherapy with pembrolizumab for 6 weeks followed by CCRT with pembrolizumab and pembrolizumab maintenance, or standard CCRT with pembrolizumab followed by pembrolizumab maintenance. Major Eligibility Criteria: Eligible patients have histologically confirmed cervical carcinoma (squamous, adenocarcinoma, or adenosquamous), TNM T3 and T4 disease, N0-2, ECOG performance status 0–1, and no prior definitive therapy for cervical cancer. Current Enrollment Status: The trial is actively accruing patients. No efficacy or safety data are available at the time of submission. Clinical Trial Registration: ClinicalTrials.gov identifier: NCT07061977. Clinical trial information: NCT07061977 .

TPS10057 Background: Ewing sarcoma (EWS) is an aggressive tumor of the bone and soft tissue primarily affecting adolescents and young adults. For patients with recurrent disease, outcomes remain poor with 5-year survival rates of 10%–15%, highlighting the need for novel approaches. STEAP1 is highly expressed in EWS cell lines, xenograft models, and patient tumor samples 1 and is transcriptionally regulated by EWSR1::FLI1 , the main oncogenic driver in EWS. Xaluritamig, a humanized bispecific XmAb 2+1 T-cell engager targeting STEAP1 and CD3, has demonstrated potent, antigen-dependent T-cell–mediated lysis of STEAP1-expressing EWS cell lines 1 and induced robust in vivo antitumor activity in EWS xenograft models with concomitant CD8+ T-cell activation. In metastatic castration-resistant prostate cancer, another STEAP1-expressing solid malignancy, xaluritamig has shown meaningful antitumor activity and a manageable safety profile 2 supporting its clinical evaluation in R/R EWS. Methods: This ongoing, phase 1b, single-arm, open-label, two-part, multicenter study (NCT07297979) is evaluating xaluritamig in pediatric, adolescent, and adult patients with a histologic diagnosis of EWS and an EWSR1 :: ETS fusion gene locally confirmed by next-generation sequencing. Patients must have R/R EWS following ≥1 line of systemic therapy and Karnofsky or Lansky performance status ≥70. Part 1 (dose confirmation) consists of cohort 1 (age ≥12 years) and cohort 2 (age ≥2 to <12 years), and part 2 (dose expansion) includes patients aged ≥2 years with no upper age limit at enrollment. This study includes a 21-day screening period, a treatment period, a safety follow-up period, and a long-term follow-up period. Patients receive xaluritamig every 2 weeks once reaching the target dose until radiographic disease progression per RECIST v1.1, clinical disease progression, unacceptable toxicity, initiation of other anticancer therapy not permitted per protocol, withdrawal of consent, death, or end of study as determined by the sponsor, whichever is earlier. Primary endpoints are safety, tolerability, and determination of recommended dose(s) for expansion. Secondary endpoints are pharmacokinetics, preliminary antitumor activity, and immunogenicity. Biomarker evaluation as an exploratory endpoint includes assessment of serum cytokines, other pro-inflammatory markers, immune-cell subsets, circulating tumor DNA, STEAP1 protein expression, and tumor genomic profile and their association with safety and efficacy. CRS mitigation plan includes step-up dosing, steroid premedication, and administration of interleukin-6 inhibitors as needed. Site activation commenced in January 2026 and enrollment is ongoing. 1. Nolan-Stevaux O. Cancer Res. 2020;80(16_Suppl):DDT02–03. 2. Kelly WK, Danila DC, Lin CC, et al. Cancer Discov . 2024;14(1):76-89. Clinical trial information: NCT07297979 .