Citations

PURPOSE The combination of the Bruton tyrosine kinase inhibitor ibrutinib with bendamustine-rituximab for first-line treatment of mantle cell lymphoma (MCL) prolonged progression-free survival (PFS), but without improvement in overall survival (OS), likely because of toxicity. Acalabrutinib was shown to be efficacious and less toxic than ibrutinib in a head-to-head trial in chronic lymphocytic leukemia and therefore might lead to better outcomes in MCL. METHODS Patients 65 years and older with previously untreated MCL received acalabrutinib (100 mg twice daily) or placebo (until disease progression or unacceptable toxicity), plus six cycles of bendamustine (90 mg/m 2 once daily; days 1 and 2) and rituximab (375 mg/m 2 as a single dose; day 1) followed by rituximab maintenance in responding patients for 2 years. Crossover to acalabrutinib at disease progression was permitted. The primary end point was PFS per the independent review committee; overall response rate and OS were secondary end points. RESULTS In total, 598 patients were randomly assigned, with 299 in each arm. At a median follow-up of 49.8 months using the reverse Kaplan-Meier method, the median PFS was 66.4 months in the acalabrutinib arm and 49.6 months in the placebo arm (hazard ratio [HR], 0.73 [95% CI, 0.57 to 0.94]; P = .0160). Benefit was seen across all subgroups, including those with high-risk features. Overall response/complete response rates were 91.0%/66.6% and 88.0%/53.5% in the acalabrutinib and placebo arms, respectively. OS was not significantly different (HR, 0.86 [95% CI, 0.65 to 1.13]; P = .27). Grade 3 or greater adverse events were reported in 88.9% and 88.2% in the acalabrutinib and placebo arms, respectively. CONCLUSION The combination of acalabrutinib with bendamustine-rituximab significantly improved PFS. Clinical benefit of acalabrutinib with bendamustine-rituximab was achieved with manageable toxicity.

Abstract The complementarity and clinical utility of combining liquid biopsies and radiomic image analysis has not been demonstrated. ctDNA minimal residual disease after chemoradiotherapy (CRT) for non–small cell lung cancer (NSCLC) is highly prognostic, but on-treatment biomarkers are needed to enable response-adapted therapies. In this study, we analyzed 418 patients with NSCLC undergoing CRT to develop and validate a novel dynamic risk model that accurately predicts ultimate progression-free survival during treatment. We optimize tissue-free variant calling from plasma samples to facilitate ctDNA monitoring and demonstrate the importance of accounting for persistent clonal hematopoiesis variants. We show that mid-CRT ctDNA concentration is prognostic for disease progression and integrate additional pre-CRT risk factors, including radiomics, into a combined model that improves outcome prediction. Our results suggest that tumor features, radiomics, and mid-CRT ctDNA analysis are complementary and can identify patients at high and low risk of progression to potentially enable response-adapted therapies. Significance: This study demonstrates that combining tumor features, radiomics, and ctDNA analysis improves outcome prediction in NSCLC treated with CRT therapy. Our integrated model could enable personalized and response-adapted therapies to reduce toxicity and improve outcomes in patients. See related commentary by Anagnostou and Aggarwal, p. 1534

Abstract Background The prevalence of delirium in intensive care units (ICUs) is high and has a major impact on patient outcomes. Aim To describe delirium assessment instruments, prevalence, interventions and barriers in delirium management in adult and paediatric ICUs; and to explore the association between delirium prevalence and reported interventions and barriers at unit level. Study Design A secondary analysis of the cross‐sectional World Delirium Awareness Day Delirium Survey on 15 March 2023. This was a prospective study to assess the one‐day point delirium prevalence, practices and quality improvement efforts across healthcare systems. Data was analysed descriptively and using multiple linear regression. Results Data of 1612 assessments in 123 ICUs from three German‐speaking countries were analysed. The most frequently used delirium assessment instrument was the Intensive Care Delirium Screening Checklist (43.9%, n = 54). The prevalence of delirium at 8 AM was 18.6% and at 8 PM 20.4% from the 94 ICUs included in the regression analyses. Prevalence for adult and paediatric and mixed ICUs are comparable. Main reported over all unit‐level interventions were ‘pain management’ (95.9%, n = 118), ‘mobilization’ (94.3%, n = 116) and ‘verbal re‐orientation’ (84.6%, n = 104). Main reported over all unit‐level barriers were ‘shortage of staff’ (53.7%, n = 66) and ‘patients who are difficult to assess’ (44.7%, n = 55). Interventions such as ‘avoidance of bladder tubes/catheters’ in all ICUs, ‘use of ear plugs and/or sleep glasses’ in adult ICUs and ‘mobilization’ in paediatric and mixed ICUs were associated with reduced delirium prevalence. Across all ICUs, as well as in both adult and paediatric ICUs, ‘lack of appropriate scores for delirium assessment’ was identified as a significant barrier. Conclusions One fifth of assessed ICU patients suffer from delirium. Several reported unit‐level interventions and barriers may have an impact on delirium prevalence, suggesting an approach for future studies and clinical practice. Relevance to Clinical Practice In clinical practice, unit‐level ‘avoidance of bladder tubes/catheters’, ‘use of ear plugs and/or sleep glasses’ and ‘mobilization’ may be used as delirium prevention and treatment interventions.

Abstract Gliomas are highly malignant brain tumors with poor prognosis and short survival. Nicotinamide adenine dinucleotide (NAD+) plays a critical role in cancer progression, yet anti-cancer therapies targeting NAD+ synthesis have had limited clinical success due to an incomplete understanding of its mechanisms. Here, we demonstrate the essential role of the NAD+ synthase nicotinamide mononucleotide adenylyltransferase (NMNAT) in glioma progression and its novel contribution to nuclear atypia. Analysis of the patient glioma transcriptomics dataset (GAPIA) indicated a strong correlation between high NMNAT transcription levels and poorer disease-free survival in low grade glioma (LGG) and glioblastoma multiforme (GBM). Utilizing quantitative statistical analysis to assess the size and circularity of about 3 million cells in glioma tissue samples from 19 patients, we identified the significant association between NMNAT1 protein level and increased nuclear atypia in different types of gliomas. Mechanistic studies in human glioma cells and a Drosophila glial neoplasia model revealed that NMNAT enhances glioma growth by promoting NAD+-dependent post-translational modifications poly(ADP-ribosyl)ation (PARylation) and deacetylation of p53, thereby attenuating the pro-apoptotic activity of p53. Additionally, NMNAT1 disrupts nuclear lamina integrity by altering lamin A/C distribution, further contributing to nuclear atypia and glioma progression. These findings uncover a novel tumorigenic mechanism involving NMNAT's regulation of nuclear architecture and NAD+-mediated metabolic signaling pathways, highlighting its roles in glioma growth and nuclear atypia. This study underscores NMNAT as a potential therapeutic target in glioma treatment. Citation Format: Jiaqi Liu, Xianzun Tao, Yi Zhu, Xiang Gao, Tijana Canic, Kai Ruan, Zoraida Diaz-Perez, Sakir Humayun Gultekin, Priyamvada Rai, Qunfeng Dong, Grace Zhai. NMNAT-mediated NAD+ metabolism promotes glioma growth by modulating p53 post-translational modifications and nuclear atypia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB060.

Abstract Background: Tumor-informed circulating tumor (ct) DNA testing is recognized as a powerful predictor of CRC recurrence. However, the benefit of systemic therapy to prevent or delay clinical recurrence in patients (pts) with molecular recurrence after curative surgery remains uncertain. Methods: Pts with CRC who had undergone curative resection of primary and/or metastatic sites + standard of care (SoC) adjuvant treatment, if applicable, were enrolled in ALTAIR study if they (1) prospectively tested positive for ctDNA using a clinically validated, personalized assay (Signatera™, Natera, Inc.) within 3 months before enrollment and (2) had no recurrence on radiological (CT) imaging. Pts were randomized to receive FTD/TPI or placebo for 6 months. CT scans and ctDNA analyses were conducted every 2 months in the first year, every 3 months in the second year, and every 6 months in the third year. The primary endpoint was disease-free survival (DFS), with secondary endpoints including ctDNA clearance, overall survival (OS), and adverse events. The study assumed a median DFS of 8 months in the placebo group, an HR of 0.667 for the FTD/TPI group, 0.05 significance level, 0.80 power, 2-year enrollment, and 1-year follow-up, requiring 240 pts and 190 DFS events. Baseline ctDNA levels were evaluated by mean tumor molecules (MTM)/ml. Results: Between July 2020 and June 2023, 243 pts were enrolled and randomized to FTD/TPI (n=122) or placebo (n=121). Baseline characteristics were balanced, and 96.3% of pts received SoC treatment postoperatively. FTD/TPI group had a median DFS of 9.30 months vs. 5.55 months in the placebo group, which did not reach statistical significance in the primary population (HR, 0.79; 95% CI, 0.60-1.05; P = 0.107). The benefit was highly pronounced, however, in stage IV pts (HR: 0.53, P = 0.012). In addition, after excluding pts with low ctDNA levels (<0.179 MTM/mL, threshold determined by ROC analysis) from both arms, significant benefit with FTD/TPI was observed in the primary population, resulting in an improved DFS (N=154, HR: 0.61 95% CI: 0.43-0.85; P = 0.003) with a median DFS of 8.12 months for FTD/TPI vs. 3.89 months for placebo; consistent with these findings, a trend toward higher ctDNA clearance rate was observed for the FTD/TPI group (8.33%), compared to placebo (4.05%).OS data remain immature, with 24 events reported across both arms. Grade ≥3 adverse events occurred in 73.0% of the FTD/TPI arm versus 3.3% in the placebo arm, with no new safety signals. Conclusions: Although statistical significance was not reached in the primary population, FTD/TPI showed benefit in pts with high molecular tumor burden and/ or Stage IV disease, resulting in improved DFS. Citation Format: Hideaki Bando, Jun Watanabe, Masahito Kotaka, Nobuhisa Matsuhashi, Eiji Oki, Yoshito Komatsu, Manabu Shiozawa, Keiji Hirata, Yuji Miyamoto, Kun-Huei Yeh, Shruti Sharma, Vasily Aushev, Adham Jurdi, Minetta C. Liu, Alexey Aleshin, Ichiro Takemasa, Daisuke Kotani, Akihito Sato, Toshihiro Misumi, Yoshiaki Nakamura, Qian Shi, Hiroya Taniguchi, Takeshi Kato, Takayuki Yoshino. A randomized, double-blind, phase III study comparing trifluridine/tipiracil (FTD/TPI) versus placebo in patients with molecular residual disease following curative resection of colorectal cancer (CRC): The ALTAIR Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT131.

AbstractINTRODUCTIONHigher male prevalence in sporadic behavioral variant frontotemporal dementia (bvFTD) has been reported. We hypothesized differences in phenotypes between genetic and sporadic bvFTD females resulting in underdiagnosis of sporadic bvFTD females.METHODSWe included genetic and sporadic bvFTD patients from two multicenter cohorts. We compared behavioral and cognitive symptoms, and gray matter volumes, between genetic and sporadic cases in each sex.RESULTSFemales with sporadic bvFTD showed worse compulsive behavior (p = 0.026) and language impairments (p = 0.024) compared to females with genetic bvFTD (n = 152). Genetic bvFTD females had smaller gray matter volumes than sporadic bvFTD females, particularly in the parietal lobe.DISCUSSIONFemales with sporadic bvFTD exhibit a distinct clinical phenotype compared to females with genetic bvFTD. This difference may explain the discrepancy in prevalence between genetic and sporadic cases, as some females without genetic mutations may be misdiagnosed due to atypical bvFTD symptom presentation.Highlights Sex ratio is equal in genetic behavioral variant of frontotemporal dementia (bvFTD), whereas more males are present in sporadic bvFTD. Distinct neuropsychiatric phenotypes exist between sporadic and genetic bvFTD in females. Phenotype might explain the sex ratio difference between sporadic and genetic cases.

Background Parkinsonism following hypoxic ischemic damage of the basal ganglia is an uncommon phenomenon that has been infrequently reported. However, only a few cases have noted improvement of symptoms with dopaminergic therapy. We report the clinical and imaging features of five patients with post-anoxic parkinsonism responsive to dopamine supplementation. Objective To describe a retrospective case series of five cases of dopamine-responsive post-anoxic parkinsonism. Methods We identified all the cases using the Mayo Clinic Data Management System utilizing advanced data explorer search engine for any patients evaluated for post anoxic parkinsonism and its associated acronyms from 2000–2024. Clinical features, neuroimaging, medication trials, and responses were obtained from chart review of identified patients. Results Five patients met the inclusion criteria. All patients underwent anoxic events followed by development of parkinsonism. Patients exhibited parkinsonism described as combinations of bradykinesia, rigidity, tremor, and postural instability. All patients underwent evaluation by a neurologist, MRI imaging, and treatment by dopaminergic agents. Of the five patients, four received carbidopa/levodopa whereas one received a dopamine agonist. All patients were clinically followed for a median of approximately 4 years and showed improvement in parkinsonism. Conclusions Parkinsonism following a hypoxic ischemic insult is a rare occurrence but response to dopaminergic therapy in those cases is even more scarcely described. Our cases series provides important implications for treatment options for patients with post anoxic parkinsonism.

AbstractFunctionally gradient materials emulate nature's ability to seamlessly blend properties through variations in material composition, unlocking advanced engineering applications such as biomedical devices and high‐performance composites. Additive manufacturing, particularly stereolithography, enables sophisticated 3D geometries with diverse materials. However, current stereolithography‐based multi‐material 3D printing is constrained by time‐intensive material switching and compromised interfacial properties. To overcome these challenges, we present dynamic fluid‐assisted micro continuous liquid interface production (DF‐µCLIP), a high‐speed multi‐material 3D printing platform that integrates varying compositions in a fully continuous fashion. By utilizing the polymerization‐free “dead zone”, vliquid resins are seamlessly replenished within a resin bath equipped with dynamic fluidic channels and a synchronized material supply system. DF‐µCLIP achieves ultra‐fast printing speeds of 90 mm/hour with 7.4 µ m pixel‐1 resolution while enabling on‐the‐fly material transitions. This strategy enhances mechanical strength at multi‐material interface through entangled polymer networks and promotes seamless material transitions between distinct materials ilike fragile hydrogels and rigid polymers, addressing interfacial failure caused by mismatch of swelling behavior. Additionally, dynamic material replenishment with real‐time composition control enables continuous gradient printing instead of the conventional step‐wise controlled gradient. Demonstrations include polymers with gradient color transitions and gradient carbon nanotube (CNT) composites with seamlessly varying conductivity.

Abstract Background: Cancer-associated fibroblasts (CAFs) are a highly diverse cell population that plays a crucial role in shaping the tumor microenvironment (TME). Their spatial interactions within the TME remain to be systematically characterized, and the factors driving their phenotypic heterogeneity are not yet fully understood. Recent advancements in single-cell spatial transcriptomics technologies and cell segmentation approaches enable the precise measurement of thousands of transcripts at subcellular resolution. Combined with innovative bioinformatics, these advancements have unlocked unprecedented opportunities for in-depth characterization of CAFs and their interactions within the TME. Methods: We conducted a comprehensive spatial transcriptomic analysis of CAFs across 8 cancer types, using the CosMx and MERSCOPE platforms to profile nearly 6 million cells as part of our discovery cohorts. We developed a novel computational method to spatially cluster CAF subpopulations and defined four distinct spatial CAF subtypes. We further examined their phenotypic differences, spatial niche organization, and interactions with neighboring cells. Additionally, we investigated the influence of CAF subtypes on immune cell phenotypes and infiltration levels. To validate our findings, we employed multiple spatial platforms, including Visium, Xenium, COMET, CODEX, and IMC, to ensure reproducibility across diverse technologies. Moreover, we performed correlative studies in large-cohorts with rich clinical data to evaluate the clinical significance of these CAF subtypes. Results: Our approach provided an unprecedented high-resolution examination of the spatial phenotypes of CAFs in large, complex tissues, uncovering novel insights. We comprehensively characterized CAFs across various solid tumor types and identified four conserved spatial CAF subtypes. These subtypes are characterized by distinct cell organizational patterns, neighboring cell compositions, interaction networks, and transcriptomic features. Moreover, they demonstrate significant correlations with the abundance, distribution, and phenotypes of tumor-infiltrating immune cells, as well as associations with tumor histopathological features and clinical outcomes. Conclusions: Our study provides a pan-cancer, high-resolution characterization of CAF spatial organization and interactions in solid tumors and identified conserved spatial CAF subtypes linked to distinct organizational patterns. Our findings reveal that the transcriptomic states and phenotypes of CAFs are significantly shaped by their interactions with neighboring cancer and immune cells. Beyond offering novel insights into the spatial heterogeneity of CAFs, this work paves the way for developing strategies to effectively target and modulate CAFs for therapeutic benefit. Citation Format: Yunhe Liu, Ansam Sinjab, Jimin Min, Guangchun Han, Francesca Paradiso, Yuanyuan Zhang, Yang Liu, Ruiping Wang, Guangsheng Pei, Kyung Serk Cho, Enyu Dai, Akshay Basi, Jared K. Burks, Kimal I. Rajapakshe, Yanshuo Chu, Jiahui Jiang, Daiwei Zhang, Xinmiao Yan, Paola A. Guerrero, Alejandra Serrano, Mingyao Li, Tae Hyun Hwang, Andrew Futreal, Jaffer A. Ajani, Luisa M Solis Soto, Amir A. Jazaeri, Humam Kadara, Anirban Maitra, Linghua Wang. Spatial subtypes and cellular interactions of cancer-associated fibroblasts revealed by single-cell spatial omics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 166.