Citations

Enteroblastic, hepatoid, and clear cell carcinomas are rare subtypes of colorectal carcinoma (CRC) with histologic and immunohistochemical (IHC) overlap. We assessed 37 CRCs that possibly represent these subtypes. Provisional criteria for each subtype, along with case photomicrographs and IHC data, were circulated among the authors to provide diagnostic interpretations. Based on plurality consensus, the carcinomas were classified as enteroblastic (n=13), hepatoid (n=6), and clear cell (n=18). Unanimous agreement was reached in 18% (3 clear cell, 3 hepatoid). Interobserver analysis revealed a mean pairwise Cohen κ of 0.63 (range: 0.32 to 0.91), with the hepatoid subtype eliciting the greatest consensus. Clear cell areas were the most likely to intermix with areas of conventional CRC ( P <0.001). Seven patients (20%) had inflammatory bowel disease (mostly linked to enteroblastic CRC). Twenty-three of 34 patients (68%) had nodal metastasis, and 12 (32%) had distant metastasis (mostly to the liver) at presentation. Median recurrence-free survival was 17 months, with enteroblastic cases the most likely to recur (54%, P =0.015). Median follow-up length was 27 months, with 14 patients (40%) dying of disease (representing 7 enteroblastic, 4 hepatoid, and 3 clear cell CRC). Mutations were identified in TP53 (n=8) , APC (n=3) , FBXW7 (n=2), and KRAS (n=1). Inflammatory bowel disease significantly worsened recurrence-free survival on multivariate analysis, while distant metastasis significantly worsened both recurrence-free and overall survival on multivariate analysis. Enteroblastic, hepatoid, and clear cell CRC demonstrate morphologic and IHC overlap, leading to interobserver variability in diagnosis. Given potential differences in clinical correlations and outcomes, more refined criteria are likely necessary.

Common sex chromosome aneuploidies (SCAs) often present with cognitive and cardiovascular dysfunction in humans. To address SCA effects on gene expression and DNA methylation in relevant cell types, we differentiated neural precursor cells (NPCs) and cardiomyocytes (CMs) from human induced pluripotent stem cells (hiPSCs) with different numbers of sex chromosomes, including isogenic and independent lines. As expected, the expression of genes that escape X inactivation (escapees) mostly increases with the number of inactive X chromosomes (Xi). However, allelic analysis shows dampening of escapees specifically on the Xi in XXY compared to XX in both NPCs and CMs, revealing a novel type of dosage compensation in SCA. In contrast, Y-linked gene expression is higher in XXY versus XY NPCs, but the opposite is observed in CMs. This may explain the greater number of differentially expressed autosomal genes in NPCs versus CMs with an added Y chromosome, while effects of added X chromosomes are similar between cell types. Concordantly, changes in autosomal DNA methylation are mainly driven by the presence of a Y chromosome. These findings highlight the cell-type specificity of sex-linked and autosomal gene regulation in SCA conditions.

Abstract Skin biopsies analyzed with α-synuclein seed amplification assays (SAAs) are a simple way to clinically interrogate the presence of α-synuclein aggregates. We determined the accuracy of skin biopsy SAA in predicting the clinical diagnoses of Parkinson disease (PD), PD with dementia (PDD) and dementia with Lewy bodies (DLB). Blinded SAAs were performed in 3 independent laboratories. Subjects diagnosed with PD, PDD and DLB were analyzed together as group 1, clinically unaffected subjects as group 2 and those with risk factors for LBD as group 3. Punch biopsies were taken from the posterior neck and analyzed by the 3 labs in 6 separate SAAs. Pairwise agreement between labs and assays ranged from excellent (kappa 0.82) to moderate (kappa 0.40-0.68). Sensitivity across assays ranged between 50.0% and 61.3%; specificity ranged between 68.6% and 100%. Comparisons of group 1 vs group 2 produced the greatest specificities, between 77.3% and 100%. In 17 cases that subsequently came to autopsy, 93% of SAAs were positive in those at the neocortical LBD stage but in only &lt;10% of those at lower stages. Skin biopsy α-synuclein SAA may be useful as a diagnostic and progression biomarker in Lewy body dementia clinical trials.

Extracellular vesicles derived from mesenchymal stem cells (MSC-EVs) exhibit great therapeutic potential in ischemia-associated conditions and diseases such as myocardial infarction, ischemic stroke, and wound healing. Enhancing the therapeutic efficacy of MSC-EVs could advance their clinical application. Diverse cargos (proteins, mRNA, microRNA, etc.) in MSC-EVs contribute to the therapeutic effects in various diseases. Vascular endothelial growth factor (VEGF) is one of the primary driving molecules in promoting angiogenesis and protecting endothelial cells lining blood vessels from apoptosis. In this study, we explored the feasibility of engineering parent MSCs with VEGF mRNA to potentiate therapeutic effects of their derived EVs. We first detected elevated levels of VEGF mRNA and protein in transfected MSCs and demonstrated the bioactivity of secreted VEGF by an angiogenesis assay. Furthermore, EVs derived from VEGF mRNA-engineered MSCs (VEGF-MSC-EVs) contained high levels of VEGF mRNA and protein and showed superior ability to protect human umbilical vein endothelial cells (HUVECs) from apoptosis compared to EVs derived from control MSCs (control MSC-EVs). To our knowledge, this is the first report demonstrating that VEGF-MSC-EVs boost therapeutic efficacy by promoting endothelial cell survival. Our findings offer a novel approach for cell-free therapy in ischemia-associated conditions and diseases.

Abstract Inherited susceptibility plays a critical role in prostate cancer (PCa) risk. Using large biobank and case-control datasets, we evaluated the contribution of both common variants and rare germline pathogenic variants (PVs) to overall PCa risk. The Prostate Cancer Exome Sequencing Consortium currently includes 427,388 male participants (51,452 PCa cases and 375,936 controls) with whole-exome sequencing data from ten biobanks and studies: UK Biobank (14,669 cases/195,600 controls), All of Us Research Program (7,577/75,226), African Ancestry Prostate Cancer Consortium (7,176/4,675), Mayo Clinic Biobank (6,031/15,084), Mass General Brigham Biobank (3,393/14,095), Geisinger’s MyCode Community Health Initiative (3,026/15,130), UCLA ATLAS Precision Medicine Biobank (2,850/16,904), Penn Medicine Biobank (2,598/16,255), Colorado Center for Personalized Medicine (2,269/13,399), and Malmo Diet and Cancer (1,863/9,568). Based on self-reported race/ethnicity and estimated genetic ancestry, the cases comprise approximately 79% European, 18% African, and 3% other ancestry populations. Single-variant association analyses tested all variants on chromosomes 1-22 and X with a minor allele count ≥ 5. In gene-based analyses, PVs were defined as rare variants (minor allele frequency [MAF] &lt; 1% in controls) that had either a Variant Effect Predictor (VEP) impact score of “high” or a pathogenic or likely pathogenic ClinVar classification. Associations were estimated using Firth logistic regression, adjusting for age and the top ten genetic principal components. Results from individual studies were combined using fixed-effect meta-analysis. In single-variant association analyses, 496 variants reached genome-wide significance (p&lt;5×10-8; MAF&gt;0.02%). Among these, 458 (92%) variants mapped to previously known risk regions, including three rare PVs in HOXB13 (rs138213197), CHEK2 (rs555607708), and FAM111A (rs533676902). Characterization of the remaining 38 variants is ongoing. Gene-based analyses identified significant associations (p&lt;2.4×10-6) for eight genes: HOXB13 (OR=3.7, 95% CI=3.3-4.2), BRCA2 (OR=2.0, 95% CI=1.7-2.3), CHEK2 (OR=1.6, 95% CI=1.5-1.8), ATM (OR=1.6, 95% CI=1.4-1.9), FAM111A (OR=1.4, 95% CI=1.3-1.5), BIK (OR=1.4, 95% CI=1.2-1.6), SAMHD1 (OR=2.1, 95% CI=1.6-2.7), and SMOC2 (OR=3.2, 95% CI=2.0-5.1). All genes except SMOC2 have been previously implicated in PCa susceptibility. Among cancer predisposition and DNA repair genes, nominal associations were also observed for XRCC2 (OR=1.6, 95% CIs=1.2-2.3) and BRCA1 (OR=1.2, 95% CI=1.0-1.4), whereas the association was not significant for PALB2 (OR=1.2, 95% CI=0.9-1.5). These findings reinforce the role of rare germline PVs, particularly in cancer predisposition and DNA repair genes, in PCa susceptibility. As additional studies are incorporated into the Consortium, we expect this work to provide a more comprehensive characterization of the genetic architecture of PCa. Citation Format: Yifan Zhang, Shuyan Cheng, Nicholas Boddicker, Matthew Lebo, Alexander S. Berry, Roni Haas, Ryan Hausler, Tokhir Dadaev, Heena Desai, Alex A. Rodriguez, Ravi K. Madduri, Andrew Hill, Xin Sheng, Susan M. Gundell, Mine Cicek, Penn Medicine Biobank, Olle Melander, Chris R. Gignoux, Isla P. Garraway, Bogdan Pasaniuc, Paul C. Boutros, Matt Oetjens, Adam S. Kibel, Robert J. Klein, Zsofia Kote-Jarai, Fergus J. Couch, Kara N. Maxwell, Burcu F. Darst, David V. Conti, Christopher A. Haiman, Fei Chen. Genetic risk of prostate cancer: Insights from the Prostate Cancer Sequencing Consortium [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 LB390.

Abstract Real-time, proactive detection has become a necessity as health systems face converging pressures that legacy tools cannot solve: rising acuity, workforce strain, and persistent quality gaps that erode margins, capacity, and reputation. Clinical decision support has historically lagged because rudimentary rules-based systems drown clinicians in false alerts, eroding trust without reliably changing outcomes at the bedside. Bayesian Health’s real-time clinical intelligence platform was built to close this gap by continuously synthesizing multimodal EHR data (vitals, labs, medications, procedures, and longitudinal history) to learn patient-specific baselines and surface only the most actionable, high-precision signals to care teams. Across diverse health systems, this platform has been used to enable earlier recognition and intervention for a range of high-impact conditions, improving both bedside care and system performance. This talk will focus on concrete, real-world applications of the platform for sepsis, clinical deterioration, and palliative care needs, illustrating how earlier detection and workflow-integrated interventions drive measurable gains in clinical outcomes and margins, and why the value of early, precise detection is amplified in high-risk populations such as oncology patients, whose higher baseline acuity and treatment-related toxicities both elevate their risk of harm and make emerging deterioration harder to recognize. Case Study: Detecting Sepsis within a Oncology Patient Subpopulation. Background: Sepsis remains one of the leading causes of in-hospital mortality, and traditional rules-based alerts have struggled to deliver timely, actionable detection without overwhelming clinicians with false alarms. Oncology patients experience an elevated risk for sepsis and septic shock, and those who experience sepsis are more likely to suffer in-hospital mortality than non-cancer patients with sepsis. Early recognition of sepsis onset is challenging due to the overlap between signs of sepsis and inflammation and tumor- and treatment-related toxicities. We investigated the ability of Bayesian Health’s real-time artificial intelligence-based computational algorithm to perform timely detection of sepsis onset in hospitalized patients with cancer. This algorithm ingests data directly from the electronic health record, such as vital signs, laboratory results, medications, procedures, and patient-specific historical results, processing it in a continuous manner to flag presence of sepsis as early as possible. Methods: Analysis included 7480 adult emergency and inpatient encounters from three tertiary and quaternary academic centers (Cleveland Clinic Main Campus, Sinai Hospital of Baltimore, and Strong Memorial Hospital) and one community hospital (Cleveland Clinic Fairview Hospital) with sufficient data for inclusion (age ≥ 18, presence in an emergency or inpatient care unit, and at least one measurement of a panel of vital signs). Patients with cancer (including subgroups of solid tumor and hematologic malignancy) were identified by current or past recorded diagnoses (ICD-10 codes). All included patient records underwent a multi-tiered retrospective adjudication process. An automated screen labeled records with no evidence of infection or organ dysfunction as non-sepsis, removing them from need for manual review. Two independent physicians then adjudicated a sample of the eliminated records in addition to each remaining record for both presence of sepsis and time of onset, with a third physician reconciling disagreements. Evaluation of the algorithm included all discrete flags generated by the system during a period of time it was not in clinical use and not visible to care teams. Results: In the overall population, 3.1% of all patients and 6.0% of cancer patients were adjudicated to have had sepsis, including zero from a sample of 200 of the records marked as non-sepsis in automated screening. The detection algorithm identified sepsis with high and consistent accuracy across all patients and across cancer patients, including those with solid tumors and with hematologic malignancies (Table). A flag for sepsis occurred in 85.8% of all sepsis patients and 86.1% of cancer patients with sepsis within 4 days of sepsis onset. Sepsis was present in 24.2% of all cancer patients flagged (22.9% of solid tumor patients and 27.9% of hematologic malignancy patients). Compared to patients who were never flagged, all patients who were flagged, whether they had sepsis or not, were more likely to experience in-hospital mortality (7.9% vs 0.3%, p &lt; 0.001) or ICU transfer (38.2% vs 7.9%, p &lt; 0.001). This was also true within oncology patients (in-hospital mortality: 8.8% vs 0.4%, p &lt; 0.001; ICU transfer: 34.7% vs 9.7%, p &lt; 0.001). Implementation of an automated sepsis detection system with high accuracy in populations such as cancer patients, who have elevated risk of poor outcomes following sepsis, provides an opportunity to meaningfully improve timely delivery of care and reduce subsequent morbidity and mortality while minimizing alert fatigue for clinicians. Citation Format: Suchi Saria, Varesh Prasad, Nicasia Beebe-Wang, Ellie Zhang, Neri Cohen, David Graham, Conrad Gleber, James Morrison, Jacob Strand, Alexandra Tallman. Real-time multimodal AI enables individualized care in challenging subpopulations [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 PL03-03.

The phase III AUGMENT trial (ClinicalTrials.gov identifier: NCT01938001 ) demonstrated improved efficacy for lenalidomide plus rituximab (R 2 ) versus rituximab with placebo (R-placebo) in patients with relapsed or refractory (R/R) indolent non-Hodgkin lymphoma (iNHL). Here, we present the long-term follow-up results and prespecified subgroup analyses of patients with follicular lymphoma (FL), including those 70 years and older. Patients with R/R grade 1 to 3a iNHL were randomly assigned 1:1 to receive R 2 or R-placebo. In this long-term follow-up report, progression-free survival (PFS) was assessed per the investigator. Secondary end points included overall survival (OS) and safety. Of the 358 randomly assigned patients (intent-to-treat [ITT] population), 295 had FL (≥70 years, n = 66). At long-term follow-up (median, 65.9 months), in the ITT iNHL population, PFS (hazard ratio [HR], 0.50 [95% CI, 0.38 to 0.66]) and OS (HR, 0.59 [95% CI, 0.37 to 0.95]) were improved with R 2 versus R-placebo. Safety findings were consistent with the primary analysis. Improved long-term efficacy with R 2 versus R-placebo and manageable safety with R 2 were observed in patients with FL, including those 70 years and older. With a follow-up of >5 years, data from the AUGMENT trial continue to support the use of R 2 as a standard of care for patients with R/R iNHL.

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 Context Patients with mild autonomous cortisol secretion (MACS) have higher rates of vertebral fractures compared to patients with non-functioning adrenal nodules, yet bone density is not always reduced. Objective To characterize the effect of MACS on bone density, metabolism, and microstructure as measured by high-resolution peripheral quantitative computed tomography (HR-pQCT). Design Cross-sectional study, 2019-2022 Setting Tertiary referral center Participants Seventy-five patients with MACS and 75 age-, sex-, and gonadal status–matched referent subjects. Measurements Bone turnover markers, dual-energy x-ray absorptiometry (DXA) scan, and HR-pQCT. Outcomes Areal and volumetric bone mineral density (aBMD, vBMD), trabecular bone score (TBS), microstructural parameters including trabecular bone volume to total volume (BV/TV) ratio. Results While no differences in aBMD were observed at any skeletal site, patients with MACS had decreased TBS (1.389 vs 1.475, P &lt; .001) and lower osteocalcin concentration (17.1 vs 19.5 ng/mL, P = .030) than referent subjects. On HR-pQCT at the tibia, patients with MACS had reduced trabecular BV/TV (0.220 vs 0.233, P = .015) compared to referent subjects. On multivariable analysis, MACS was associated with lower TBS (odds ratio [OR] per SD decrease 2.87 [1.65-5.00]), lower trabecular BV/TV at the radius (OR per SD decrease 2.58 [1.33-5.00]), and lower trabecular BV/TV at the tibia (OR per SD decrease 4.06 [2.10-7.86]). Conclusion Patients with MACS have microstructural deterioration that may not be evident on routine DXA aBMD testing.

Abstract We evaluated outcomes by management type for patients with stage IA nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) in the Global NLPHL One Working Group retrospective database of 2243 patients with stages I to IV disease diagnosed from 1992 to 2021 at 38 international institutions. A total of 779 patients had stage IA disease with median age of 35 years (range, 3-89) and median follow-up of 6.1 years. The 6-year progression-free survival (PFS) and overall survival were 86.3% and 97.7%, respectively. Outcomes were analyzed for the 2 groups: complete resection and unresected disease. Patients with a complete resection and observation alone (n = 99) had a 6-year PFS of 65.5% vs 90.5% for those who received radiotherapy (RT) (n = 53). Patients with unresected disease (n = 627; 80.5%) had a 6-year PFS of 62.0% for rituximab alone (n = 31), 89.6% for RT alone (n = 325), 76.8% for ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) alone (n = 40), and 94.3% for ABVD plus RT (n = 130). A total of 127 patients relapsed (16.3%), of which 25 (19.7%) had transformation. Our analysis suggests the following: (1) RT improves the PFS in patients with completely resected disease; (2) rituximab or ABVD alone does not appear to achieve a durable response; and (3) chemotherapy was not observed to add additional PFS benefit when used in combination with RT. Thus, for stage IA NLPHL, RT alone is likely sufficient for definitive treatment.