Citations

Background: Hepatocellular carcinoma (HCC) has a poor long-term prognosis due to high recurrence and cirrhosis-related mortality, even after potentially curative treatments such as liver transplantation (LT), surgical resection, or ablation. This study aimed to identify factors associated with ≥10-year survival in HCC patients. Methods: A retrospective cohort study was conducted among HCC patients diagnosed between 2004 and 2022 using the National Cancer Database. Multivariable Cox regression was used to identify predictors of overall survival, and logistic regression was used to identify predictors of ≥10-year survival. Results: Among 249,600 HCC patients, 177,585 (71.2%) died within 5 years, 8613 (3.5%) died at 5–10 years, 54,988 (22.0%) were alive with <10 years of follow-up, and 8219 (3.3%) survived ≥10 years. LT, resection, and ablation were performed in 6.6%, 9.3%, and 11% of patients, respectively. Compared with ablation as the reference group, LT [adjusted odds ratio (aOR) 11.96, 95% confidence interval (CI): 11.27–13.29] and resection (aOR: 2.83, 95% CI: 2.57–3.08) increased the odds of ≥10-year survival, while non-curative treatments reduced the odds compared with ablation (aOR: 0.50, 95% CI: 0.47–0.55). Cox regression results were consistent with the logistic model, confirming the association. Decision tree analysis confirmed LT as the dominant determinant of long-term survival. Black individuals were associated with lower odds of ≥10-year survival (aOR: 0.88, 95% CI: 0.820–0.96) and decreased likelihood of receiving LT (aOR: 0.73, 95% CI: 0.55–0.96). Conclusions: LT offers the best chance of ≥10-year survival in HCC. Ensuring equitable access is essential, especially for Black patients who have lower transplant rates and worse outcomes.

The major barrier to clinical translation of αCD137 immunotherapy is separating antitumor efficacy from hepatotoxicity driven by IFN-γ–producing CD8 T cells. We propose a strategy to limit toxicity by promoting contraction of excessively expanded CD8 T cells. We identify CD11c + KLRG1 + effector CD8 T cells (CD11c + T E ) as the primary source of IFN-γ, recirculating between blood and secondary lymphoid organs (SLOs), where they undergo apoptosis during contraction. We show that lymphotoxin β receptor (LTβR) signaling restrains this contraction. Mechanistically, lymphotoxin-expressing B cells activate LTβR in fibroblastic reticular cells (FRCs), suppressing apoptosis of CD11c + T E cells in the spleen and sustaining their systemic circulation and liver infiltration. Pharmacological LTβR blockade abrogates hepatotoxicity by reducing the accumulation of IFN-γ–producing CD11c + T E cells while preserving tumor-specific CD8 T cell responses. These findings identify LTβR as a key regulator of effector CD8 T cell persistence and support the use of LTβR antagonists to improve the safety of αCD137-based immunotherapy.

53BP1 nuclear bodies are dynamic structures with properties resembling biomolecular condensates, but the molecular determinants that govern 53BP1 higher-order assembly at DNA double-strand breaks (DSBs) remain to be established. Here, we show that 53BP1 condensation is stimulated by phosphatidylinositol 3-phosphate (PI(3)P) in vitro through a highly specific interaction with its C-terminal tandem BRCT domain (tBRCT). Consequently, mutational inactivation of the 53BP1 tBRCT domain compromised PI(3)P binding and suppressed 53BP1 optodroplet formation in vivo. We further show that rapid 53BP1 clustering following DNA damage precedes its stable assembly on DSB-flanking chromatin, requires its tBRCT, and is suppressed by sequestration of nuclear PI(3)P. Taken together, our findings identify PI(3)P binding as a mechanism that promotes the formation and maturation of 53BP1 condensate-like assemblies on damaged chromatin.

Abstract Background: [212Pb]VMT-a-NET is a novel, next generation alpha therapy agent for advanced somatostatin receptor 2 positive (SSTR2+) neuroendocrine tumors (NETs). Here, we present safety and efficacy update from the dose-finding phase 1/2a clinical trial (NCT05636618). Methods: Adults with well-differentiated unresectable or metastatic NETs, who were peptide receptor radionuclide therapy-naïve, showed progressive disease after at least one prior line of systemic therapy and demonstrated SSTR2-expression on PET images were treated with up to four cycles of study therapy at the assigned dose level. Participants were followed for dose-limiting toxicity (DLT) observation up to 42 days after the first dose. Efficacy was evaluated by investigators according to RECIST criteria v1.1. Results: As of 10-Dec-2025 (data cut-off [DCO]) a total of 56 participants were enrolled into Cohorts 1, 2 and 3, and received at least 1 dose of [212Pb]VMT-a-NET (n=2 in Cohort 1, n=46 in Cohort 2, and n=8 in Cohort 3 at a dose level of 2.5 mCi, 5 mCi, and 6 mCi, respectively). For data analysis purposes, participants were categorized into two different groups: a safety group and an efficacy group. The safety group included all participants treated by the DCO (n=56), while the efficacy group included only the Cohort 1 participants (n=2) and the first half of participants treated in Cohort 2 (n=23). Among all participants treated with at least 1 dose of [212Pb]VMT-a-NET (n=56), no DLTs, no grade 5 adverse events (AEs), no treatment-related discontinuations, no serious renal complications, no dysphagia and no clinically significant treatment-related myelosuppression were observed. Median follow-up time for all patients treated was 40 weeks (range: 6-97). Among the 25 participants followed for efficacy (n=2 in Cohort 1 and n=23 in Cohort 2), 19 out of 25 were with no progression as of the DCO. Median follow-up time for participants included in the efficacy group was 49 weeks (range: 6-97). Investigator-assessed RECIST v1.1 objective responses were observed in 9 out of 23 participants (39%) enrolled in the first half of Cohort 2 (8 confirmed). The 2 patients enrolled in Cohort 1 at 2.5 mCi still have stable disease after 2 years of follow up. Updated safety outcomes for all participants along with updated efficacy findings for participants in Cohorts 1 and 2 with sufficient maturity will be presented during the congress. Conclusions: Treatment with [212Pb]VMT-α-NET continues to be well-tolerated among all patients treated (n=56), and to show promising efficacy at the dose levels of 2.5 mCi and 5 mCi. The study is ongoing with Cohort 3 (6 mCi) currently open for enrollment. Citation Format: Thorvardur R. Halfdanarson, Richard L. Wahl, Vineeth Sukrithan, Brandon R. Mancini, Seyed A. Mosallaie, Savitha Balaraman, Gregory S. Sibley, Jason Starr, Lowell B. Anthony, Chih Y. Liao, Samuel H. Mehr, Jared Weiss, Robert A. Ramirez, Lucia Baratto, Wenjing Yang, Alaa Hanna, Stephen M. Keefe, Markus Puhlmann, Vikas Prasad. [212Pb]VMT-a-NET in advanced SSTR2+ neuroendocrine tumors: safety and preliminary efficacy results from dose-finding cohorts 1,2 and 3 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT088.

Abstract Background Estimating effective dose (E) for CT is often done with dose‐length product (DLP) and effective dose conversion factors, a.k.a. k ‐factors. Previous studies have primarily focused on k ‐factor values derived from certain fixed‐sized phantoms but have not extensively explored all the contributing factors and associated variations in E. Purpose In this study, we investigated the contributing factors and variations of E using k ‐factors as surrogates in adult and pediatric CT exams and provided empirical formula to estimate a comprehensive new set of k ‐factors. Methods Effective dose was estimated using NCICT (National Cancer Institute, USA), including organ and effective dose conversion coefficient library estimated by Monte‐Carlo radiation transport techniques. The k ‐factors were derived as a surrogate of DLP‐normalized E, via E/DLP (unit: mSv/mGy·cm). We examined the variations of effective dose estimates for different phantom and scan parameters represented by the calculations of k ‐factors. This included variations in patient sex, weight, height, kVp, and scan length across typical adult and pediatric CT examinations of anatomical regions such as the head, neck, chest, abdomen, and pelvis. Multivariable regression analyses with/without standardization were conducted to evaluate the significance of the dependency of k ‐factors on the studied parameters. Tube current modulation (TCM) parameters, modeled as a function of patient attenuation using variable modulation strengths, were also incorporated to reflect realistic clinical CT dose variations. Results The variations of DLP‐normalized E were substantially affected by multiple factors, exceeding 100% for adults (weight for adult pelvis) and more than 200% for pediatrics (height for pediatric head). The analysis of standardized regression coefficients revealed that patient weight is the most critical factor, except for head scans in adults, where scan length and patient height are the main determinants. In pediatric CT, both patient weight and height had critical impact. Similarly, for pediatric head CT scans, patient height and scan length are the dominant factors, as observed in adults. Consequently, the k ‐factors have a wide range, from 0.0099 to 0.0357 mSv/mGy·cm for adult chest and from 0.0085 to 0.0363 mSv/mGy·cm for adult abdomen. Empirical formulas to estimate k ‐factors were obtained based on multi‐variable regression with adjusted R square ranging from 0.71 to 0.93. Based on NCICT's TCM model, the use of TCM resulted in an additional average variation of 110% in the k ‐factor compared to non‐TCM results. Conclusions Our study demonstrated the large variations of DLP‐normalized effective dose. Standardized coefficients revealed that patient weight, height and/or scan length were the most crucial determinants. Depending on the specific TCM model used, even greater variations may be observed. This work also provided a practical framework for estimating CT effective dose using the traditional k ‐factor method with updated new conversion factors.

Abstract Purpose The purpose of this systematic review was to compare the inter‐ and intra‐observer reliability of Kellgren–Lawrence (KL) grading versus minimum joint space width (mJSW) measurement on knee radiographs, and to examine the influence of rater type, radiographic view and atlas‐based training. Methods A systematic search of PubMed/MEDLINE, Embase, Scopus and Web of Science was conducted through July 2025 following Preferred Reporting Items for Systematic reviews and Meta‐Analyses (PRISMA) guidelines. Studies reporting inter‐ and/or intra‐observer reliability for KL or mJSW on standard knee radiographs were included. Extracted data included kappa ( κ ) and intraclass correlation coefficient (ICC) values, rater expertise, radiographic view and atlas usage. Raters were categorized as expert, trainee/non‐expert or artificial intelligence (AI)‐assisted/automated. Results Twenty‐four studies (10,394 radiographs) met the inclusion criteria. Inter‐observer reliability was generally higher for mJSW (mean ICC = 0.82 ± 0.17) compared with KL (mean k = 0.72 ± 0.17), with similar trends observed for intra‐observer reliability. Experts and AI‐assisted systems outperformed trainees/non‐experts for both metrics. Reliability improved with semiflexed posteroanterior/Rosenberg views and atlas‐guided training. Conclusion This systematic review demonstrates that mJSW measurement generally shows higher reproducibility than KL grading. Reliability improved with expertise, standardized imaging and structured training, and AI‐assisted approaches performed comparably to expert raters. Quantitative mJSW should complement KL grading, particularly when combined with alignment measures, to enhance consistency and clinical relevance of radiographic assessment. Level of Evidence Level III.

Abstract Background Repotrectinib, a next-generation ROS1/TRK tyrosine kinase inhibitor, is approved for ROS1 fusion-positive non-small cell lung cancer and NTRK fusion-positive solid tumors. Its side effects and safety management strategies require further characterization. Patients and Methods The safety profile of repotrectinib (treatment-emergent/related adverse events [TEAEs/TRAEs]) was established in patients who initiated treatment at the recommended dose (160 mg daily [QD] for 14 days, then 160 mg twice daily [BID]) across all cohorts of the global, multicenter phase 1/2 TRIDENT-1 study. AE management strategies were outlined. Results In 472 patients, the most common TRAEs (dizziness [58%] and dysgeusia [50%]) were likely TRK inhibition-related. Median relative dose intensity was 90%; 14% (n = 66/472) of patients did not increase their initial QD dose to BID (mostly due to CNS AEs). Rates of dizziness (median onset, 7 days) were similar in patients with/without baseline brain metastases. Dose modifications downgraded severity or resolved dizziness in 78% of patients; 58% of patients had pharmacologic intervention without dose modification. Dizziness was downgraded/resolved in 62% (n = 120/195) of patients who did not receive dose modification or pharmacologic intervention. Treatment-related cognitive impairment and weight gain occurred in 19% and 12% of patients, respectively. Treatment-emergent withdrawal pain occurred in 14% of patients (median resolution time, 2.1 weeks). Dose interruption and reduction from TRAEs occurred in 39% and 38% of patients, respectively; 10% reported later re-escalation back to 160 mg BID. Conclusion Many repotrectinib AEs, including neurological AEs secondary to TRK inhibition, were mitigated with appropriate management, including dose modification and/or pharmacologic intervention.