Citations

Abstract Oncology Advanced Practice Providers (APPs), including Advanced Practice Registered Nurses, Physician Assistants, and Clinical Pharmacists (CPs), play a vital role in delivering high-quality, patient-centered cancer care across the United States. Despite their widespread presence in oncology practices, APPs remain underutilized in cancer clinical research, representing a missed opportunity to expand trial access and improve patient outcomes. Clinical trials are essential to advancing oncology care, yet participation remains critically low among adult patients. Given Oncology APPs’ and CPs’ central role in cancer care delivery, their meaningful engagement in oncology clinical trial research is imperative as the standard of oncology care. This position article, with contributions from 5 professional societies, presents solutions and resources to barriers limiting APPs’ and CPs’ involvement in cancer clinical research, including gaps in education, role expectations, limited protected time, restrictive policies, insufficient financial support, and underrecognition of contributions. Integrating APPs and CPs more fully into the clinical research enterprise is essential to improving trial access, patient outcomes, closing equity gaps, and accelerating innovation in oncology care.

Abstract Background Some centres advocate preoperative radiotherapy in patients with pancreatic cancer and arterial involvement despite a lack of Level 1 evidence on survival benefit. Although it has been suggested that preoperative radiotherapy may increase the risk of postpancreatectomy haemorrhage (PPH) and morbidity, evidence is again lacking. This study investigated the association between preoperative radiotherapy and both PPH and major morbidity following arterial divestment/resection during pancreatic adenocarcinoma resection after chemotherapy. Methods Consecutive patients diagnosed with pancreatic adenocarcinoma and > 180° arterial involvement who were treated with preoperative chemotherapy with or without radiotherapy followed by pancreatic resection with arterial divestment/resection were included in the study. Logistic regression analyses including propensity score-based overlap weighting were performed to investigate associations between radiotherapy and in-hospital PPH grade B/C and major morbidity, expressed as adjusted risk differences (aRDs). Results Overall, 246 patients undergoing pancreatic resection with arterial resection (169, 69%) or divestment (77, 31%) were included. Radiotherapy was not associated with PPH (aRD 6%; 95% confidence interval (c.i.) −3 to 14), regardless of arterial divestment (aRD 3%; 95% c.i. −5 to 11) or arterial resection (aRD 12%; 95% c.i. 1 to 23; Pinteraction = 0.189). Radiotherapy was associated with a 14% (95% c.i. 2 to 25) higher risk of major morbidity, especially after arterial resection (aRD 27%; 95% c.i. 11 to 43) compared with arterial divestment (aRD −12%; 95% c.i. −35 to 11; Pinteraction = 0.006) and after external beam radiotherapy (aRD 21%; 95% c.i. 8 to 32) compared with stereotactic body radiotherapy (aRD −12%; 95% c.i. −27 to 6; Pinteraction = 0.0001). Ninety-day mortality was increased, albeit not significantly, after preoperative radiotherapy (10 (8%) versus 3 (3%) deaths with versus without preoperative radiotherapy, respectively; P = 0.067). Conclusions Radiotherapy before resection of pancreatic cancer with > 180° arterial involvement was associated with an increased risk of postoperative major morbidity when arterial resection, but not arterial divestment, was performed. This risk should be taken into account when considering preoperative radiotherapy in patients who may require arterial resection.

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.

Abstract Purpose The aim was to evaluate the ability of four large language models (LLMs) (OpenAI's ChatGPT‐3.5, Microsoft 365 Copilot, DeepSeek‐R1, and Google Gemini 2.5 Pro) to develop treatment options when presented with clinical cases published in the maxillofacial prosthodontics literature. Materials and Methods Six maxillofacial case reports were fed to the LLMs following a prompt that requested prosthodontic treatment options from the perspective of a prosthodontist. Expert evaluators scored the relevance, clarity, depth, focus, and coherence of the responses. Statistical analyses, including descriptive statistics, two‐way analysis of variance (ANOVA), post hoc Tukey tests, Pearson correlation analyses, and intraclass correlation coefficients (ICCs), were performed ( α < 0.05). Results There were significant differences among the total mean relevance ( p = 0.003), clarity ( p = 0.006), depth ( p < 0.001), focus ( p < 0.001), and coherence ( p < 0.001) scores of chatbots. Copilot consistently scored the lowest, and Gemini or DeepSeek scored the highest for all five factors. Depth ( p = 0.006), focus ( p = 0.024), and coherence ( p = 0.013) scores of senior prosthodontists were slightly higher than those of junior prosthodontists. Pearson correlation analysis revealed positive correlations between the total mean scores for all five factors ( p < 0.001). Conclusions The study demonstrates the ability of LLMs to develop maxillofacial prosthetic treatment plans tailored to specific clinical scenarios. There were significant differences between the abilities of the LLMs evaluated in this study. Copilot scored the lowest for all factors evaluated, and Gemini and/or DeepSeek scored the highest.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC) provide recommendations for the treatment of patients with NSCLC, including diagnosis, primary disease management, surveillance, and subsequent treatment. The panel has updated the list of recommended targeted therapies based on recent FDA approvals and clinical data. This selection from the NCCN Guidelines for NSCLC focuses on treatment recommendations for advanced or metastatic NSCLC with actionable biomarkers.

Abstract Background: Cholangiocarcinoma (CCA) is an aggressive hepatobiliary malignancy with limited treatment options. CCA exhibits a distinct desmoplastic and tolerogenic tumor immune microenvironment (TIME) characterized by elevated bile acid concentrations resulting from obstructive cholestasis and dysregulated bile acid metabolism. TGR5 is an essential component of bile acid signaling. We hypothesize that bile acids promote CCA progression by establishing an immunosuppressive TIME through TGR5 signaling, which can be therapeutically targeted using SBI-364, a novel potent small molecule TGR5 inhibitor. Methods: Single-cell RNA sequencing (scRNA-seq) of immune cells from human intrahepatic (iCCA) and perihilar (pCCA) CCA tumors were conducted. Therapeutic studies were performed using syngeneic murine models of iCCA (PMID: 38458319), a novel syngeneic model of pCCA, and patient-derived xenograft (PDX) models. In collaboration with Sanford Burnham Prebys, SBI-364, a first in-class competitive TGR5 antagonist, was assessed in vivo. Additionally, we performed co-culture experiments with bile acid +/- SBI-364-treated murine bone marrow-derived monocytic myeloid-derived suppressor cells (M-MDSCs) and CD8+ T cells to assess functional immunosuppressive effects. Results: Human scRNA-seq revealed significantly increased TGR5 (GPBAR1) expression predominantly in myeloid cell populations within the CCA TIME. SBI-364 treatment significantly reduced tumor burden in both syngeneic orthotopic iCCA models and a novel pCCA model that recapitulates the anatomic characteristics of perihilar CCA. In contrast, NOD/SCID mice bearing PDX535 (predicted sensitive) and PDX136 (predicted resistant), SBI-364 treatment did not achieve tumor reduction, suggesting that TGR5 inhibition predominantly attenuates tumor progression through modulation of bile acid-immune cell interactions. SBI-364 treated murine tumors had a significant reduction in immunosuppressive macrophages expressing interleukin-10 and M-MDSCs compared to vehicle treated tumors. Furthermore, bile acid-treated M-MDSCs exhibited enhanced suppression of CD8+ T cell proliferation and function, an effect that was abrogated by SBI-364 co-treatment. Conclusion: We demonstrate that TGR5 inhibition represents a promising therapeutic strategy across multiple immunocompetent preclinical CCA models. We demonstrate that the bile-acid TGR5 axis promotes CCA progression via immunosuppressive myeloid cells. Specifically, TGR5 signaling potentiates the immunosuppressive capacity of M-MDSCs, contributing to an immunosuppressive niche that facilitates tumor progression. These results establish TGR5 as a rational therapeutic target for overcoming immune evasion in cholangiocarcinoma. Citation Format: Enis Hikmet Ozmert, Binbin Li, Jingchun Yang, Hannah Elizabeth Stumpf, Jessica R. Willhite, Danielle Carlson, Jennifer L. Tomlinson, Jon Covel, Raghuveer Ramachandra, Steven Olson, Rory L. Smoot, Sumera Ilyas. Therapeutic targeting of TGR5 abrogates bile acid driven myeloid cell immunosuppression in cholangiocarcinoma [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 2896.

Abstract 5-Fluorouracil (5FU)-based chemotherapy remains a front-line treatment for most patients with colorectal cancer. However, approximately 30% of patients who receive 5FU experience severe, life-threatening toxicity. Dihydropyrimidine dehydrogenase (DPD, DPYD gene) mediates the rate determining step in 5FU catabolism. Deleterious genetic variations in DPYD have been associated with elevated concentrations of circulating 5FU and significantly increased risk for 5FU toxicity. Five deleterious variants in DPYD have been identified as clinical biomarkers of toxicity and have led to prospective genotyping and differential dosing recommendations for carriers of these variants, as noted on recent updates to the FDA label for the 5-FU prodrug capecitabine. Our previous studies also established the importance of epigenetic control of DPD expression. In this study, we used existing epigenetic repositories to identify candidate enhancer elements for DPYD. We selected 20 novel high-priority putative enhancers for further study using a combination of reporter assays and CRISPRi applied across multiple cell models. Further studies will investigate means to target these regulatory mechanisms as a means to increase localized efficacy of 5-FU-based therapies in colorectal cancer. Citation Format: Hannah Marie Krause, Julia Magee, Kelly Bouchonville, Lauryn Allyn Hahn, Ryan Jonathan Swartz, Brianna Bembenek, Lulu Jiang, Steven M. Offer. Characterizing the critical role of enhancer-gene regulation in 5-fluorouracil toxicity and resistance [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 3140.

Abstract Background: Cholangiocarcinoma (CCA) is an aggressive hepatobiliary malignancy with marked molecular heterogeneity, limited systemic treatment options, and poor prognosis. Chemoresistance and KRAS mutations remain major therapeutic challenges. Dysregulation of the Hippo pathway, particularly YAP/TAZ hyperactivation, drives CCA progression and resistance. TEAD, the essential transcriptional partner of YAP/TAZ, represents a promising target. IAG933 is a novel oral pan-TEAD inhibitor designed to disrupt YAP/TAZ-TEAD interactions. RMC-6236, a pan-KRAS inhibitor, has also gained attention. Combined TEAD and KRAS inhibition may overcome resistance and improve efficacy in CCA. Methods: We evaluated IAG933 in human (HuCCT1, RBE) and murine (SB1, FAC) CCA cell lines. Cells were treated with IAG933 alone or in combination with GemCis or RMC-6236. Cell viability assays were used to determine IC50 values and calculate combination indexes (CI). TEAD activity was assessed by luciferase reporter and qRT-PCR of YAP/TAZ target genes (CTGF, CYR61, NUAK2). Transcriptomic alterations were analyzed by RNA sequencing. In vivo efficacy was evaluated in syngeneic orthotopic and patient-derived xenograft (PDX) models. Results: IAG933 suppressed TEAD-dependent transcription (IC50 ≈ 500 nM) and downregulated YAP/TAZ target genes. Combination with GemCis or RMC-6236 produced synergistic effects (CI &lt; 1) in all CCA lines. Transcriptomic analysis revealed activation of oxidative stress response pathways, particularly SOD2 upregulation. MitoSOX staining confirmed increased mitochondrial ROS after treatment. In vivo, IAG933 monotherapy suppressed tumor growth similarly to GemCis. Dual TEAD and KRAS inhibition achieved marked tumor regression and significantly delayed tumor regrowth after treatment cessation in KRAS-mutant PDX models. Conclusion: IAG933 effectively suppresses YAP/TAZ-TEAD signaling and inhibits CCA growth. While the combination with GemCis showed limited additional benefit due to strong single-agent efficacy, synergy with RMC-6236 produced durable antitumor effects, particularly in run-out studies, delaying regrowth in KRAS-mutant models. These findings highlight IAG933 as a promising therapeutic candidate targeting the Hippo-TEAD pathway, with potential benefit in KRAS-mutant CCA. Citation Format: Hidemi Nishi,Erik Jessen,Danielle M. Carlson,Amro M. Abdelrahman,Enis H. Ozmert,J. Pedro Fincatto Safi,Brandon A. Wilbanks,Shelby K. Yee,Jack W. Sample,Nathan W. Werneburg,Rory L. Smoot. TEAD inhibition by IAG933 as a novel therapeutic strategy for cholangiocarcinoma [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 3081.

Abstract Dihydropyrimidine dehydrogenase (DPD, encoded by the DPYD gene) is the rate-limiting enzyme in the catabolism of the widely used chemotherapeutic drug 5-fluorouracil (5-FU). Genetic variations in DPYD are predictive biomarkers of 5-FU toxicity. One such biomarker, rs75017182 (the causal allele linked to the “HapB3” haplotype), has been suggested to promote alternative splicing of DPYD, leading to expression of an inactive proteoform. However, carriers of rs75017182 exhibit only moderately increased risk of 5-FU toxicity and modestly decreased ex vivo DPD activity compared to carriers of another well-studied splice variant, rs3918290 (*2A). We hypothesized that, unlike *2A, the rs75017182 variant does not cause obligate alternative splicing but instead promotes partial alternative splicing. To test this, we generated dual-fluorescent minigene reporter constructs containing either the G (wildtype) or C (variant) allele. In our minigene system, alternative splicing was elevated in cells transfected with C-containing vectors via flow cytometry, though levels were lower than those observed in a parallel *2A model. To investigate contributions of other variants in LD with rs75017182, we expanded the reporter to include additional relevant genomic regions. The analyses were complemented by the study of in vivo splicing in cells engineered to harbor various combinations of variants and in lymphoblastoid lines carrying specific genotype combinations. Overall, our findings demonstrate that rs75017182-C promotes only partial alternative splicing, eliciting a modest decrease in DPD activity and explaining its comparatively weak association with severe 5-FU toxicity. Additional variants in LD have a minimal impact on splicing and 5-FU sensitivity. Citation Format: Lauryn Allyn Hahn, Ryan Schwartz, Hannah Marie Krause, Lulu Jiang, Brianna Bembenek, Kelly Bouchonville, Steven M. Offer. Partial alternative splicing in carriers of DPYD rs75017182 explains modest association with severe 5-FU toxicity to 5-FU [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 3137.

Abstract Our team has demonstrated that lymphatic exudate collected via surgical drains (“lymph”) is a proximal biofluid rich in ctDNA and prognostic of recurrence in HPV-independent Head and Neck Cancer (HPV- HNSCC). Other analytes such as proteins, metabolites, and cells are also abundant in lymph. To understand the liquid tumor microenvironment (TME) immediately after tumor resection, we characterized lymph at 24 hrs in HNSCC. We performed a multi-omic survey, demonstrating that lymph is distinct from plasma and represents a largely unexplored source of biomarkers relevant to immune modulation and metastasis.Metabolomics and proteomics were run on lymph supernatant and plasma. Proteomic screening was performed via Olink and normalized to internal standards for quantitative analysis. Metabolomic samples were assayed via LC-MS and normalized. 16s libraries were sequenced utilizing Illumina and analyzed in QIIME. 16s sequencing on 6 patients indicated an array of bacterial genera present in post-surgical lymph with consistency across patients. The distribution consisted primarily of microbes native to the oral cavity, suggesting post-surgical lymph may reflect the native microbiome prior to surgery. Pathogenic blooms were observed in a subset of patients. Ongoing analysis will correlate microbiome data with both cancer and surgical outcomes.Metabolite profiling was performed on post-surgical lymph and matched plasma from 4 patients, including 3 who recurred within 1 year of surgery. The metabolite profile in lymph of all 4 patients was more diverse than plasma with higher metabolite abundance per mL. 13% of identified metabolites were &gt;2-fold enriched in lymph. Lymph from recurred patients showed high levels of saturated and monounsaturated fatty acids, reported to be associated with metastasis. Post-surgical lymph has a unique and largely uncharted metabolome to mine for biomarkers associated with recurrence.Proteomes were compared between lymph and plasma from 44 HPV-HNSCC patients. This cohort consists of 25 recurred (REC) and 19 patients with no evidence of disease (NED) with &gt;1 year of follow up. Lymph and plasma displayed highly non-overlapping protein repertoires. The mean absolute volcano score was 25.2, indicating a strong global difference between lymph and plasma. Lymph was significantly enriched in 91 proteins (p range 4.1e-47 to 0.037), many associated with inflammation. REC lymph was also enriched in inflammatory markers compared to NED, including IL-1a, TNF, and TSLP (p = 0.002, 0.015, 0.003, respectively), which have been implicated in cancer metastasis, invasion, and angiogenesis. Lymph hits were largely non-overlapping with plasma, indicating the opportunity for novel biomarker discovery in this fluid.Analysis of the microbiome, metabolome, and proteome of post-surgical lymph reveals a rich and differentiated tumor-adjacent biofluid to study biomarkers relevant to metastasis and the TME. Citation Format: Zachary Costliow, Seka Lazare, Zhuosheng Gu, Adam Harmon, Maciej Pacula, Megan Rivera, Aadel A. Chaudhuri, Jose P. Zevallos, Jessalyn Marie Ubellacker, Wendy Winckler. Multi-omicsinpostoperative lymphatic exudate in HPV-negative head and neck 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 6137.