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e15501 Background: CP is the backbone of first-line therapy for recurrent or metastatic ASCC. In practice, Q3-week CP has been explored as a potential alternative to the standard (d1,8,15 Q28-day cycle) dosing, though its efficacy is not known. This study evaluated CP scheduling and clinical survival associations in metastatic ASCC. Methods: This multicenter retrospective cohort study included patients with metastatic ASCC treated with first-line CP, identified using the Mayo Data Explorer database. Electronic health records were reviewed to collect baseline clinical characteristics, treatment regimens, responses, progression-free survival (PFS), and overall survival (OS). Descriptive statistics were used to summarize patient demographics. Survival was estimated using Kaplan–Meier methods. Multivariable Cox proportional hazards models were used to compare survival by dosing schedule, adjusting for age, ECOG performance status, HPV (p16) status, liver metastasis, and prior chemoradiation. Results: 54 patients treated between 2020-2025 with first-line CP for metastatic ASCC were included. Baseline patient demographics were balanced between dosing groups (Table 1). Median follow-up time was 26.2 months. For Q3-week CP (n = 21), median PFS and OS were 9.8 (95% CI 8.1, NR) and 27.0 (95% CI 15.7, NR) months, respectively, while median PFS was 6.5 (95% CI 4.5,15.3) months with standard CP (n = 33) and median OS was not reached (95% CI 11.2, NR). Response rate was 76% with Q3-week and 60.6% with standard CP (p = 0.23) dosing. Survival outcomes were similar when comparing Q3-week CP relative to standard CP dosing using multivariable analysis (PFS HR 0.68, 95% CI 0.33–1.41; OS HR 1.67, 95% CI 0.67–4.14). Higher ECOG and liver metastasis were independently associated with inferior outcomes, while HPV was associated with improved survival. Subsequent therapy patterns were similar between CP schedule groups. Ten patients (16.9%) received local therapy, and 24 of 28 patients with progression received further systemic therapy, including 21 (87.5%) treated with immunotherapy. Conclusions: Survival outcomes were similar across dosing schedules, suggesting Q3-week CP may be a reasonable alternative to standard CP, with potential to reduce treatment-related burden in metastatic ASCC. Future analysis will compare toxicity profiles between CP dosing schedules, including in combination with PD1 inhibitors given the results of the POD1UM-303 trial. Patient demographics (n=54). Variable Q3-week CP (n=21) Standard CP (n=33) p-value Sex Female 16 (76.2%) 24 (72.7%) 0.77 Male 5 (23.8%) 9 (27.3%) Age Median (Q1, Q3) 62 (50.5, 69) 64 (55.5, 70) 0.57 BMI Median (Q1, Q3) 27.1 (21.9, 34.4) 27.4 (22.5, 31.7) 0.72 ECOG 0 9 (42.9%) 11 (34.4%) 0.53 ≥ 1 12 (57.1%) 21 (65.6%) Confirmed HPV (p16) Positive 16 (76.2%) 24 (72.7%) 0.77 Prior chemoradiation Yes 17 (81.0%) 21 (63.6%) 0.17

3510 Background: Patients with RAS-mutated mCRC have limited treatment options. Chemotherapy in combination with bevacizumab (Bev) has been the standard first-line treatment for the past two decades, yet the prognosis for these patients remains poor. Onvansertib (Onv), a selective PLK1 inhibitor, has previously demonstrated synergy with chemotherapy in the second line setting. The Phase 2 randomized CRDF-004 trial evaluated onvansertib plus standard-of-care (SoC; FOLFIRI or FOLFOX with Bev) in as first-line RAS-mutated mCRC. Methods: Patients with first-line KRAS or NRAS mutant mCRC were randomized to SoC alone or SoC plus onvansertib (20 mg or 30 mg). The primary endpoint was objective response rate (ORR) as determined by a blinded-independent central review (BICR) using RECIST v1.1. Key secondary endpoints included progression-free survival (PFS), duration of response, and safety. PFS was assessed by BICR and investigator assessments combined. Results are presented in the intent-to-treat population (ITT). Results: At the data cutoff of 22 Jan 2026,110 patients were randomized with a median follow up of approximately 10 months. Baseline characteristics were relatively balanced across arms. Onv 30 mg + FOLFIRI + Bev demonstrated numerically higher ORR (n = 13/18, 72.2%, 95% CI: 46.5, 90.3) compared with the FOLFIRI + Bev control arm (n = 8/19, 42.1%, 95% CI: 20.3, 66.5), the FOLFOX + Bev control arm (n = 8/18, 44.4%, 95% CI: 21.5, 69.2) and the combined control arms (SoC: n = 16/37, 43.2%, 95% CI: 27.1-60.5). Onv 30mg + FOLFIRI + Bev demonstrated a p-value of 0.051 for confirmed ORR vs. SoC; and a p-value of 0.045 for the 6-month ORR compared to FOLFIRI + Bev (n = 10/18, 55.6%, 95% CI: 30.8-78.5 vs. n = 4/19, 21.1%, 95% CI: 6.1-45.6, respectively). The median PFS for the control arms was 10.97 months (95% CI: 7.52, NR) for FOLFIRI + Bev, 9.89 months (95% CI: 9.43, NR) for FOLFOX + Bev and 10.97 months (95% CI: 9.43-15.44) for the combined SoC arms. The median PFS in the Onv 30mg+ FOLFIRI + Bev arm was not reached (95% CI: 9.72-NR). The PFS HR of 30mg + Onv +FOLFIRI + Bev vs FOLFIRI + Bev was 0.38 (95% CI: 0.12-1.17) and vs SoC was 0.37 (95% CI: 0.13-1.02, p = 0.048). The clinical benefit from Onv treatment was further evidenced by the 12-month PFS rates, 61.9% (95% CI: 40.1, 95.8) in the Onv 30 mg + FOLFIRI + Bev arm vs. 28.4% (95% CI: 9.3, 86.9) in the FOLFIRI + Bev arm, and 30.1% (95% CI: 13.8-65.7) in the SoC. Onvansertib was well tolerated, with no unexpected toxicities observed; the most common grade ≥3 adverse event was neutropenia. PK data support moving forward with the onvansertib 30mg dose with FOLFIRI + Bev. Conclusions: Onvansertib plus FOLFIRI and bevacizumab demonstrated improved antitumor activity and manageable safety in first-line RAS-mutated mCRC. These results support further clinical and support planned confirmatory Phase 3 evaluation. Clinical trial information: NCT06106308 .

Abstract Rationale Clear and accurate communication is essential in critical care, yet patients with non-English language preferences (NELP) often face limited access to professional interpreters. Although machine translation has been explored in healthcare, most studies have focused on written translation. Their use in real-time, two-way interpretation specifically for high-stakes ICU conversations remains largely unexamined. To bridge this gap, we developed AI-TransLATE (AI-enhanced Transition to Language-Agnostic Transcultural Engagement), a voice-to-voice multilingual interpretation tool designed to support real-time interactions in critical care. Following successful initial validation, we evaluated clinicians’ perceptions of its usability in simulated ICU encounters and compared its performance with commercially available AI tools, including Gemini and ChatGPT. Methods We developed three standardized ICU role-play scenarios focused on shared decision-making regarding ECMO, tracheostomy, and comfort care, designed to encourage natural, unscripted dialogue. Clinicians were asked to use the AI translation tools during these encounters in Spanish, Chinese, or Arabic, while a bilingual research team member acted as the patient’s family member. After each simulation, participants completed a post-session survey evaluating communication quality, satisfaction (using a 5-point Likert scale), and usability through the System Usability Scale (SUS). Results Eighteen clinicians participated, including residents, fellows, and attending physicians with an average of 3.6 ± 1.2 years of postgraduate experience. Fifty-four post-simulation surveys were completed across Arabic, Chinese, and Spanish languages comparing AI-TransLATE, ChatGPT, and Google Gemini. Participants rated the simulation as realistic across all cases (ECMO = 3.94 ± 0.66; Tracheostomy = 4.22 ± 0.43; Comfort Care = 4.06 ± 0.42; p = 0.32). Satisfaction was highest for AI-TransLATE (4.11 ± 0.68) and ChatGPT (4.00 ± 0.69) but lowest for Gemini (2.06 ± 1.00; p < 0.001). Willingness to use in real life followed the same trend. (AI-TransLATE = 4.00 ± 0.69, ChatGPT = 3.89 ± 0.96, Gemini = 2.00 ± 1.03 (p < 0.001)). SUS scores supported these findings (AI-TransLATE = 71.25 ± 13.35; ChatGPT = 72.22 ± 15.57; Gemini = 40.28 ± 21.30; p < 0.001), corresponding to good usability for AI-TransLATE and ChatGPT and poor usability for Gemini. Clinicians mentioned interruptions, uneven translation flow, and difficulty judging accuracy, but appreciated it when the AI-TransLATE conveyed tone and intonation, enabling smoother, more natural communication. Conclusion Overall, AI-TransLATE and ChatGPT demonstrated strong usability and satisfaction, showing promise as clinical communication tools; however, further validation in real-world ICU settings is warranted, and data privacy and confidentiality remain important considerations. This abstract is funded by: Critical care research committee mayo clinic

PURPOSE External beam radiation therapy (EBRT) has gained delayed acceptance as a recommended first-line treatment modality for patients with hepatocellular carcinoma (HCC), given limited evidence that it improves overall survival (OS). We analyzed individual patient data (IPD) from an international cohort to assess OS among patients with HCC treated with EBRT. METHODS We performed a systematic review of publications that assessed EBRT, met prespecified technical standards for HCC, and reported OS (search date December 15, 2022). Corresponding authors were invited to submit IPD for the study. We performed Kaplan-Meier survival analyses to determine OS and restricted mean survival time (RMST) stratified by Barcelona Clinic Liver Cancer (BCLC) stage and treatment status (ie, treatment-naïve and experienced). We performed random effects Cox proportional hazards modeling to assess clinical characteristics associated with OS. RESULTS Data were provided on 4,913 patients treated with EBRT with a median follow-up time of 5.0 years. The median OS was 6.8 years (95% CI, 5.7 to 8.7) for BCLC-0 and 4.6 years (95% CI, 4.1 to 5.1) for BCLC-A. Among treatment-naïve patients, the median OS was not reached (95% CI, 8.6 to not reached) for BCLC-0 and was 5.4 years (95% CI, 4.5 to 6.7) for BCLC-A. In multivariable models, more advanced BCLC stage, higher tumor burden, worse performance status, and Child-Pugh class B or C were associated with a higher risk of mortality. Ablative radiation dose and more recent year of treatment were associated with a reduced risk of death. CONCLUSION To our knowledge, this study represents the largest multinational cohort of patients with HCC treated with EBRT. OS outcomes with EBRT for very early- and early-stage HCC appear to be comparable with resection, thermal ablation, and other ablative locoregional therapies. These data support the inclusion of EBRT in the BCLC HCC clinical decision-making process.

Abstract We present chromosome-level, phased diploid genome assemblies of two widely used human fibroblast cell lines: BJ (46,XY) and IMR-90 (46,XX). Using Oxford Nanopore, PacBio HiFi, and Hi-C sequencing data, we generated assemblies spanning 5.9 and 6.0 Gbp with diploid quality values exceeding QV 60. To validate structural integrity, we developed KaryoScope, an alignment-free tool for generating computational karyograms from k-mer feature databases. We identify >50 000 structural variants relative to T2T-CHM13v2.0, the majority of which are heterozygous and cell-line-specific. Combining reference-based and de novo gene annotation, we uncover a previously unreported 1 Mbp homozygous duplication at the 16p11.2 locus in BJ, demonstrating that even karyotypically normal cell lines can harbor clinically relevant submicroscopic rearrangements. We show that mapping publicly available short-read, RNA-seq, and ChIP-seq data to sample-matched diploid assemblies substantially improves read alignment and enables haplotype phasing of 23%–28% of short reads. The BJ and IMR-90 assemblies and associated variant calls are publicly available as a resource for the research community.

Abstract Intercellular communication between multiple myeloma (MM) cells and osteoclast precursor cells (pre-OCs) contributes extensively to the occurrence and development of myeloma-related bone destruction. However, key interacting modes and the exchanged substances involved in this communication remain unclear. In this study, we discover that tunneling nanotubes (TNTs) directly connect MM and pre-OCs. Using the stable isotope labeling with amino acids in cell culture assay and a positive-negative double selection strategy, we identify filamin A (FLNA) as a major protein transported from MM to pre-OCs. FLNA acts as a molecular clutch linking extracellular matrix–bound MAC1 to the cytoskeleton, activating Rho and MAPK signaling pathways and promoting F-actin polymerization, which subsequently enhances osteoclast differentiation by modulating cellular stiffness, traction force, and deformability. In addition, FLNA directly binds vinculin and promotes its recruitment to podosomes, thereby enhancing the functions of podosomes and the bone resorption capacity of osteoclasts. The conditional depletion of Flna in mice suppresses podosome activity and reduces stiffness, traction force, and deformability in pre-OCs, leading to significantly impaired osteoclast differentiation and increased bone mass. In the Vk∗MYC mouse model of myeloma, the administration of the TNT inhibitor latrunculin B disrupts FLNA transport to osteoclasts and alleviates osteolytic bone disease. These findings highlight the critical role of MM-transferred FLNA in osteoclastogenesis and suggest that targeting TNTs may represent a therapeutic strategy to limit pathological bone resorption associated with MM.

BACKGROUND Perineural spread (PNS) of colorectal carcinoma (CRC) is a rare and challenging diagnosis. Its clinical and radiological presentation is often subtle and can overlap with radiation-induced neuropathy and malignant nerve tumors, complicating timely diagnosis. The role of circulating tumor DNA (ctDNA) in the detection of PNS has not been previously described. OBSERVATIONS A 48-year-old man with a history of rectal cancer and perineural invasion presented with progressive, refractory sciatic neuropathic pain. Conventional surveillance imaging was initially negative despite subtle rising of carcinoembryonic antigen and ctDNA levels. Subsequent MRI revealed abnormalities of the lumbosacral plexus and sciatic nerve, and fascicular biopsy confirmed metastatic CRC involving the sciatic nerve, establishing the diagnosis of PNS. LESSONS This case highlights PNS as a rare but important consideration in patients with focal neuropathic symptoms and prior CRC. Circulating tumor DNA positivity may serve as an early indicator of occult tumor activity even within the nerves when imaging is equivocal. However, currently histopathological confirmation remains the only definitive method to distinguish PNS from alternative diagnoses and is essential to guide appropriate management. https://thejns.org/doi/10.3171/CASE25997