Citations

Abstract Background: HPV16 (human papillomavirus) is a leading cause of oropharyngeal cancer (OPC) in the US. Antibodies to HPV16 early antigens are detectable in serum samples up to two decades before diagnosis and are potential biomarkers for early detection. In this study, we have developed and compared three custom HPV16 serology platforms for detection of OPC: MSD (Meso Scale Discovery) electrochemiluminescent detection, RAPID ELISA, and a novel semi-quantitative lateral flow assay (LFA) using a custom android application. Methods: For the MSD platform, recombinant HPV 16 antigens (E1, E2, E6, E7) were synthesized in mammalian cells and printed on multiplexed arrays. In RAPID ELISA, GST-tagged antigens (E1, E2, E6, E7) were expressed using mammalian in vitro transcription and translation and bound IgG detected. For the LFA, His-tagged recombinant proteins (HPV16 CE2 184-365aa and HPV16 E7) were synthesized, printed, and antibodies detected with protein G conjugated nanoparticles. Archived serum samples drawn from newly-diagnosed OPC patients (n = 60), with matching saliva samples (n=54, MSD assay only) were obtained from Mayo Clinic. Unmatched controls (n = 46) were obtained from AT Still. For the lateral flow assay, colorimetric image analysis was done using a titration curve of known concentration of monoclonal antibody. We optimized the biomarker panel (E2, E6, and E7 for MSD and ELISA, and for LFA E2, and E7) by using multiparametric analysis and plotting the receiver operating curves to the test performance, and assays were compared using the Cohen’s kappa statistic. Results: At 98% specificity, the MSD HPV16 serologic assay achieved 88% sensitivity, similar to RAPID ELISA, and the LFA assay at 85% sensitivity. The signal intensities for saliva samples were weaker at 24% sensitivity. The Cohen’s kappa value ranged from 0.74 to 0.78 for the comparison between all three assays. There was only one sample among all the cases that was negative by all three serology tests. Conclusion: All three assays have strong concordance for the detection of HPV16 early antigen serology. All the tests can facilitate large scale HPV serology research. Citation Format: Akshansh Kaushik, David Routman, Tej Patel, Joshua Eger, Padhmavathy Yuvaraj, Kathleen R. Bartemes, Marisa D. Griesel, Danielle E. Hunter, Katie Van Abel, Anu Mathew, Mingyue Wang, Leonid Dzantiev, Martin Stengelin, Jacob N. Wohlstadter, Ann Spolarich, Kristina R. Dahlstrom, Jennifer Blain Christen, Erich Sturgis, Karen Anderson. HPV serology for rapid detection of HPV positive oropharyngeal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5099.

Abstract Background: Cellular immunotherapy has transformed cancer treatment, but success in solid tumors remains limited by long manufacturing times, high costs, and the need for viral vectors that permanently modify DNA. To address this, we examined electroporation (EP) and mechanoporation (MP) approach to transfect T cells with mRNA to enable the development of a bedside immune cell editing platform. NKG7, natural killer cell granule-7, was previously demonstrated to play key function in activating T-cell cytotoxicity function. mRNA transfection of T cells with NKG-7 can increase these cells’ anti-tumor cell killing. We examine EP and MP methods for NKG7 transfection in primary peripheral blood mononuclear cells (PBMCs) from healthy donors. Method: Synthetic Clean Cap mRNAs encoding NKG7 or NKG7 with membrane-bound cRNA IL-2 were introduced into PBMCs by electroporation (MaxCyte) or mechanoporation (Portal Bio). T cell expression of NKG7 and IL-2 were analyzed by CytoFlex flow and Kaluza. Result: The yield at EP and MP were comparable at 0.615+/-0.09% and 0.597+/-0.16%, respectively. Viability were high at above 80% for 3 days after EP and MP. NKG7 and NKG7+cIL-2 mRNA transfection led to different NKG7 expression kinetics in T-cells and between EP and MP. With EP, CD4 T-cells showed an increase in NKG7 expressions with the highest MFI ratio (NKG7 MFI/ IgG MFI) compared to mock EP at Day 1 for the NKG7 -only EP (1.25 ± 0.38) and at Day 2 for NKG7+cIL-2 EP (1.20 ± 0.27). CD8+ T cells displayed a similar trend, with peak NKG7 expression at Day 1 for NKG7 EP (1.22 ± 0.76) and Day 2 for NKG7+cIL-2 EP (1.21 ± 0.90). However, MP did not enhance NKG7 expression in CD4+ T cells. NKG7 expression peaked at Day 1 for both NKG7 (1.28 ± 0.42) and NKG7 + cIL-2 (1.24 ± 0.20). IL2 expression peaked at Day 1 for both EP and MP: EP, CD4+ T (91.5% ± 4.4), CD8+ T (92.7% ± 12.8); MP, CD4+ T (88.9% ± 31.7), CD8+ T (84.7% ± 9.6). Functional assays for anti-tumor cell killing of these transfected cells are currently ongoing. Conclusions: We report that EP of PBMC can transfect all cell populations. MP may yield comparable yield, viability and NKG7 expression in CD8 T cells compared to EP, but without the need to isolate CD8 T cells from PBMC. EP and MP method can be used for bedside immune cell transfection depending on the target and cell populations of interest. Citation Format: Chen Wu, Christoph Schaefers, Malvika Gupta, Kevin Regan, Zuoyi Shao, Andre De Menezes Silva Corraes, Virginia Van Keulen, Jacob Hirdler, Tobias Peikert, Timothy D. Wiltshire, Haidong Dong, Yi Lin. A non-viral mRNA engineering platform for rapid, same-day immune-cell therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5198.

Abstract Introduction Revascularization to prevent limb loss is not feasible or represents a very high risk in a significant proportion of patients with chronic limb-threatening ischaemia (CLTI). No standard definition currently exists to define this population of patients. The aim of this study was to develop a consensus-based, multidomain definition to improve clinical assessment and reporting of studies in people with ‘no option’ (NO) or ‘poor option’ (PO) CLTI. Methods A modified Delphi process was conducted with 164 specialists from 30 countries. Two iterative survey rounds were used to reach consensus, defined as ≥70% agreement with a score of ≥7 on a nine-point scale. Results Some 164 international vascular specialists participated in the study, averaging 19 years of experience. A multidomain framework including arterial disease anatomy, biology, risk, function, and context (ABRFC) achieved 83% consensus. A ‘desert foot’ was defined as the absence of distal arterial revascularization targets on advanced non-invasive imaging, invasive digital subtraction angiography, and at least one failed endovascular revascularization attempt (81.6% agreement). Inadequate autogenous bypass conduit was defined as the lack of usable autologous vein across all four limbs (85% agreement). Patients were classified as NO for revascularization if they present with ‘desert foot’, prohibitive medical risk, a non-functional limb, or in those patients who refused arterial revascularization. PO revascularization patients combined factors such as severe infection, lack of autologous vein, or treatment non-compliance (72.1% agreement). Conclusion This consensus study established a structured, expert-validated definition of no option or poor option for revascularisation of patients with CLTI. The multidomain ABRFC framework provides a foundation for standardized clinical assessment, trial design, and future guideline development.

Abstract Background: Chronic inflammation is implicated in ovarian carcinogenesis, but how different inflammation-related exposures individually or jointly affect histotype-specific associations remains unclear. Materials and Methods: We pooled data from 16 case-control studies in the Ovarian Cancer Association Consortium to evaluate associations of eight inflammation-related factors (anti-inflammatory: aspirin use, tubal ligation (TL); pro-inflammatory: endometriosis, obesity, lifetime ovulatory cycles (LOC), smoking, pelvic inflammatory disease (PID), polycystic ovary syndrome (PCOS)) with epithelial ovarian cancer (OvC) by histologic subtype. We examined individual associations and clustering of risk factors across histotypes and computed population attributable risk (PAR) for each factor. We assessed additive and multiplicative interactions for exposure combinations. Results: Associations with OvC risk differed by histotype (e.g., high-grade serous: aspirin: OR=0.90; 95%CI 0.82, 0.99; TL: OR=0.80; 95%CI 0.73, 0.88; overall serous: endometriosis: OR=1.17; 95%CI 1.03, 1.31; high LOC: OR=1.42; 95%CI 1.28, 1.58; obesity (low-grade serous): OR=1.50; 95%CI 1.14, 1.98). Clustering analyses showed highly correlated risk profiles in endometrioid and clear cell (r=0.91). High-grade serous and mucinous profiles were moderately correlated with endometrioid and clear cell (r=0.60) tumors. The profile for low-grade serous (r=0.36) tumors was distinct from other histotypes. PAR estimates suggested modifying aspirin use, TL, and LOCs could substantially reduce burdens of endometrioid, clear cell and mucinous tumors. Out of 28 exposure combinations tested in overall OvC and 189 by histotype, we observed 12 interactions. Not using aspirin regularly showed positive additive interactions with obesity and high LOCs, particularly in endometrioid tumors (obesity relative excess risk due to interaction (RERI)=0.74, 95%CI 0.31, 1.18; Pint=0.001 for; LOCs RERI=0.80, 95%CI 0.03, 1.56; Pint=0.04). Not using aspirin regularly also showed a positive additive interaction with endometriosis in clear cell tumors (RERI=1.77, 95%CI 0.03, 3.52; Pint=0.05). Lack of TL showed positive interactions with obesity in endometrioid (RERI=0.86, 95%CI 0.17, 1.53; Pint=0.01) and mucinous (RERI=1.10, 95%CI 0.23, 1.97; Pint=0.01) tumors, while negative additive interactions were observed for smoking and endometriosis in endometrioid tumors (RERI=-1.12, 95%CI -2.19, -0.05; Pint=0.04). A multiplicative interaction was observed between obesity and endometriosis in mucinous tumors (Pint=0.01). Conclusion: The findings suggest ovarian tumorigenesis is strongly shaped by pro- and anti-inflammatory pathways that act largely independently. Further examining these pathways may clarify the origins of histotype heterogeneity and guide prevention strategies. Citation Format: Maxwell Akonde, Britton Trabert, SHELLEY TWOROGER, Allan Jensen, Kathryn L. Terry, Joshua Sampson, Hoda Anton-Culver, David Bowtell, Elisa V. Bandera, Angela Brooks-Wilson, Andrew Berchuck, Daniel William Cramer, Linda S. Cook, Julie M. Cunningham, Jennifer A. Doherty, Ellen L. Goode, Marc T. Goodman, Holly Ruth Harris, Susanne K. Kjaer, Nhu Le, Alice Wen-Ron Lee, Francesmary Modugno, Kirsten B. Moysich, Celeste Pearce, Malcolm C. Pike, Harvey A. Risch, Mary A. Rossing, Joellen M. Schildkrau, Daniel O. Stram, Rebecca Sutphen, David Van Den Berg, Penelope M. Webb, Anna Wu, Argyrios Ziogas, Nicolas A. Wentzensen. Inflammation-related exposures and histotype- specific ovarian cancer risk in the Ovarian Cancer Association Consortium (OCAC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6261.

Abstract Introduction: Pathological complete response (pCR) is a strong prognostic marker, but survival outcomes comparing treatment to control do not reliably align with treatment-control differences in pCR rates in breast cancer. A novel Bayesian hierarchical framework models treatments within trials, allowing us to predict treatment effects on distant recurrence-free survival (DRFS) from pCR with greater accuracy. Methods: We analyzed 12 neoadjuvant breast cancer trials (6,000 patients, all HR/HER2 subtypes; including I-SPY2). The framework of Burzykowski, Molenberghs & Buyse (2005) is extended to a novel arm-based hierarchical structure providing a distribution of pCR and DRFS treatment effects controlling for subtype (HR/HER2), N and T stage, grade, and calendar year. Three held-out trials (877 patients; 26 regimens; med follow-up >4 years) validate predictions of DRFS treatment benefit from pCR. All data was used to estimate treatment-effect correlation and the surrogate threshold effect (STE). Analyses were repeated for Residual Cancer Burden Index (binary RCB01, continuous RCB). Results: Predicted probability of DRFS benefit closely matched actual DRFS follow-up (mean absolute error 0.06; Pearson r = 0.9). Across all trials, pCR showed moderate surrogacy (ρ = 0.82, R2 = 0.67). A 60% increase in pCR odds achieves ≥95% probability of DRFS benefit (STE = OR of 1.60). RCB outperforms pCR across all metrics, with 92% sensitivity and 93% specificity for detecting DRFS benefit in 26 validation regimens (Table 1). Conclusion: This novel Bayesian meta-analytic framework reveals that pCR, RCB01 and continuous RCB reliably predict survival benefit across heterogeneous trials, with RCB performing the best in an external validation. This provides a statistical foundation for accelerated approval decisions using robust early biomarkers in modern neoadjuvant trial designs by accurately predicting survival at the treatment arm level. Citation Format: Keli S. Santos-Parker, Jessica R. Santos-Parker, W. Fraser Symmans, Laura J. Esserman, Christina Yau, Angie DeMichele, Laura van't Veer, Doug Yee, Fabien Reyal, Helena Earl, Jean Abraham, David Cameron, Peter Hall, Judy Boughey, Matthew Goetz, Gabe Sonke, Miguel Martín, Sara López-Tarruella, Priyanka Sharma, Rachel Freiberg, Jane Perlmutter, Aditya Bardia, Martin Eklund, Rachel Freiberg, Lajos Pusztai. A novel statistical framework for surrogate endpoint prediction of survival in neoadjuvant breast cancer trials [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1401.

Abstract Background: Liquid biopsy approaches for cancer detection often rely on tissue-specific methylation or fragmentation features to infer tumor origin. However, a pan-aerodigestive cancer detection strategy is clinically valuable given shared risk exposures, field cancerization, and frequent diagnostic ambiguity among lung, esophageal, and head & neck cancers. We hypothesized that advanced-stage disease exhibits convergent chromatin remodeling, producing a dominant malignancy-associated fragmentomic signal that supersedes subtler tissue-of-origin patterns. Methods: Whole-genome EM-seq (∼15×) was performed on plasma cfDNA from 120 patients with stage III/IV aerodigestive cancers (lung, esophageal, head & neck; squamous and adenocarcinoma) and 60 age-matched controls. Four fragmentomic modalities were assessed: (1) genome-wide fragmentation in 5-Mb bins (DELFI-like), (2) NMF spectral components, (3) 4-mer end motifs, and (4) promoter-centric nucleosome scores (Griffin). All preprocessing occurred strictly within each training fold of a repeated stratified 10-fold CV (100 repeats) to prevent data leakage. No test-sample information was used in training. Hyperparameters were tuned only within training partitions. Random Forest classifiers were trained under this fully nested scheme. Results: The multimodal classifier robustly detected advanced aerodigestive malignancies with a mean AUROC 0.86 and AUPRC 0.94. However, modality dissection revealed a clear performance hierarchy: nucleosome positioning (Griffin) alone achieved AUROC 0.85 and AUPRC 0.93, nearly matching the full integrated model, whereas end motifs performed poorly (AUROC 0.61). Biological interpretation demonstrated prominent nucleosome depletion centered at promoters of proliferation-associated genes, indicating a convergent epigenetic state of promoter opening across late-stage aerodigestive malignancies. Conclusions: Advanced aerodigestive cancers exhibit a dominant, convergent chromatin remodeling signature detectable in plasma cfDNA, driven primarily by altered nucleosome positioning. In late-stage disease, this shared malignancy-associated fragmentomic signal outweighs tissue-of-origin-dependent patterns. These findings highlight the utility of nucleosome-based fragmentomics not merely for detection, but for resolving diagnostic ambiguity in patients with indeterminate masses and for monitoring total tumor burden in high-risk aerodigestive malignancies. Citation Format: Axel Misael Hidalgo, Ayesha Hashmi, Jeff Szymanski, Pradeep Chauhan, Lilli Greiner, Faridi Qaium, Daniel J. Ma, David M. Routman, Katie M. Van Abel, Aadel A. Chaudhuri.. Convergent chromatin remodeling enables pan-aerodigestive detection of advanced malignancies in plasma cfDNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3862.

ABSTRACT We report on the 2025 International ICU Diary Conference that provided a comprehensive update on current knowledge, innovations and global practices related to ICU diaries. Held in a 6‐week online format, the event featured 23 speakers and was attended by mean 69.7 (SD 20.5) participants per session. Topics included development of ICU diaries, use in special settings, digital diaries, survivors' and families' experiences, Post‐Intensive‐Care Syndrome and follow‐up and implementation projects. Highlights were innovative solutions for digital diaries and the report of persons with lived and living experiences with diaries, changing the focus on humanising critical care. Relevance for Practice ICU diaries support patient‐ and family‐centred care and should be implemented more widely across healthcare systems. Their successful adoption requires contextual adaptation and policy support, with future development likely to be shaped by the increasing use of digital ICU diaries.

Background: Pancreatitis significantly alters the microbial composition of the oral and intestinal compartments, causing dysbiosis that may contribute to disease mechanisms and potentially serve as a basis for diagnosis or treatment. Objective: To determine whether the oral or gut microbial signature can classify chronic pancreatitis (CP). Methods: Stool samples (n=707) were collected from participants in the Prospective Evaluation of Chronic Pancreatitis for Epidemiologic and Translational Studies (PROCEED). Samples were distributed among 200 healthy (HC), 310 CP, 49 acute pancreatitis (AP), and 148 recurrent acute pancreatitis (RAP). In addition, saliva samples were collected for a subset of participants (n=156). Whole genome sequencing was performed to assess microbiome composition. Machine learning algorithms were utilized to identify a signature with microbial features predictive of CP. Results: Gut alpha diversity was significantly decreased in AP, RAP, and CP compared with HC, with CP exhibiting the lowest diversity. In contrast, oral microbial diversity showed no significant variation across groups. Beta diversity analysis revealed distinct gut microbiome compositions between HC and pancreatitis subtypes, with CP showing the most pronounced differences. Random forest models using gut microbial species demonstrated robust predictive performance for CP using a minimum of 10 species (Area under the curve—AUC: 0.834; accuracy: 0.774). Despite similarities in gut microbiome composition across pancreatitis subtypes, a unique gut microbial signature for CP was identified highlighting the microbiome’s potential in CP diagnosis. Conclusion: Our study reveals a gut microbial signature predictive of CP using machine learning models in a large US multi-institutional cohort.

RET fusions appear in 1%-2% of non–small cell lung cancers (NSCLCs). The results from the ARROW study (ClinicalTrials.gov identifier: NCT03037385 ) supported US Food and Drug Administration approval of pralsetinib, an oral selective RET inhibitor, for metastatic RET -altered NSCLC and RET fusion–positive thyroid cancers. ARROW was a phase I/II open-label study of pralsetinib 400 mg once daily in RET fusion–positive NSCLCs. Coprimary end points were overall response rate (ORR) and safety. Key secondary end points included duration of response, progression-free survival, and overall survival (OS). At data lock (May 20, 2024), 281 patients initiated pralsetinib (median treatment duration, 15.0 months). ORR (measurable disease patients; n = 259) was 78% (95% CI, 69 to 86) for treatment-naïve patients and 63% (95% CI, 54 to 71) for prior platinum-based chemotherapy patients. Median OS was 44.3 months (95% CI, 30.9 to 53.1), 50.1 months (95% CI, 28.3 to not reached) in treatment-naïve patients, and 39.7 months (95% CI, 27.8 to 53.2) in prior platinum patients. Common grade ≥3 treatment-related adverse events were anemia (21%), hypertension (15%), and decreased neutrophils (13%). Three treatment-related deaths occurred (pneumonia, n = 2; interstitial lung disease and rhabdomyolysis, n = 1 each). Safety was consistent with previous ARROW reports; no hypersensitivity was reported in patients receiving prior immunotherapies. Pralsetinib produced robust, durable responses with manageable safety in treatment-naïve and previously treated patients with RET fusion–positive NSCLCs, confirming previous findings with longer follow-up.