Citations

Objective: In this study, we evaluate the utility of ctDNA analysis in a large cohort of patients for whom ctDNA testing was ordered commercially with real-world application. Summary Background Data: Circulating tumor DNA (ctDNA) has emerged as a prognostic and predictive biomarker for assessing post-surgical molecular residual disease (MRD) and response to treatment. Methods: A real-world data analysis was performed using commercial ctDNA testing (SignateraTM) from patients (N=795, n=5,971 plasma samples) with stage I-III colon cancer treated at multiple US institutions. The association of ctDNA detection within the MRD window, during surveillance, and the impact of ACT was correlated with patient outcomes. Results: ctDNA-positive patients during the MRD window and surveillance showed significantly shorter DFS compared to ctDNA-negative patients (hazard ratio (HR): 9.85, P<0.0001; HR: 26.91, P<0.0001). Multivariate analysis of the MRD window revealed ctDNA-positivity as the most significant factor associated with inferior DFS (adjHR: 7.7, P<0.001). MRD-positive patients who received ACT showed improved DFS compared to patients observed post-surgery (adjHR: 6.1, FDR adj P=0.0007). No ACT benefit was observed in MRD-negative patients (adj HR: 1.20, FDR adj P=0.768). On evaluating ctDNA dynamics from MRD to surveillance, patients who remained ctDNA-positive or converted from negative to positive showed a significantly inferior DFS (HR: 34.40, P<0.0001; HR: 13.65, P<0.0001) compared to persistently ctDNA-negative patients. Conclusions: Postsurgical ctDNA detection is prognostic of relapse and potentially predictive of ACT benefit in patients with resectable colon cancer, which may enable personalized surveillance, intervention, and/or trial options, ultimately improving patient outcomes.

Abstract Background Research is limited on the impacts of menopause, defined as the permanent cessation of ovarian function and decline of reproductive hormones, on gastrointestinal symptom severity and disease progression in women with inflammatory bowel disease (IBD). This review synthesizes current evidence on the impact of menopause, menopause transition, and hormonal therapy (HT) on disease activity, IBD and menopause symptom severity, and disease progression among individuals with IBD. Methods A systematic literature review was reported following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines and preregistered at PROSPERO (CRD42024564901). Five databases were searched without date restrictions. Data extraction and risk-of-bias assessment were performed independently by multiple reviewers. Results were qualitatively synthesized. Results Of 1667 records, 15 studies met inclusion criteria (5 cohort, 3 case-control, 7 cross-sectional) with IBD sample sizes from 37 to 1367. Evidence on HT and IBD risk was mixed: some studies linked HT to increased ulcerative colitis risk while others found no significant association after adjusting for confounders. Women with IBD experience earlier menopause than healthy control subjects. While most women reported no change in IBD symptoms postmenopause, a minority reported symptom worsening. HT may reduce flare severity. Women with IBD reported more severe vulvovaginal symptoms and had distinct vaginal microbiome profiles compared with healthy control subjects. Conclusions Few studies have explored the relationship between menopause and IBD. There is a need for continued research on the relationship between IBD disease activity and menopause symptoms to create tailored interventions to improve women’s health with IBD across the lifespan.

Abstract Background: Despite recent advances in the treatment of triple negative breast cancer (TNBC) many patients are still suffering from early recurrence, therapy resistance, and organ metastasis 1 to 3 years post-chemotherapy. TNBC cells with stem cell-like properties are resistant to standard of care chemotherapy and are responsible for early tumor relapse and poor outcome. Up-regulation of PD-L1 expression in Cancer Stem Cells (CSCs) has been associated with immune evasion capacity and promotion of their stem-like properties. In this study we identify two druggable stemness target, Aurora-A Kinase (AURKA) and NOTCH3, with positive feedback on intra-tumoral PD-L1 expression and cancer cell plasticity. Methods: MDA-MB 231, MDA-MB 231 LM and SUM149-PT TNBC cells were used both in 2D and 3D environment. Unique TNBC cells were established from metastatic PDX models. TNBC cells were treated with Alisertib (AURKA inhibitor, 50nM) or AV353 (NOTCH3 inhibitor, 200ng). Immunofluorescence and immunoblot were used to compare different biomarker expression. ALDH was measured using Aldefluor kit. Apoptotic cells were quantified in real-time using IncuCyte S3. In vivo studies; 1x106 MDA MB 231/LM cells were injected into the mammary fat pad of NSG-female mice and treated with Alisertib or AV353. Control groups were treated with pacebo. Results: Our study shows that AURKA and NOTCH3 pharmacological blockade reduced nuclear/undruggable PD-L1, that is not achieved clinically by using FDA-approved immune checkpoint inhibitors (ICIs). Significantly, following stemness-targeted therapy with alisertib or AV353, reduction of intra-tumoral PD-L1 resulted in inhibition of tumor growth, decreased levels of CD44 expression, increased CD8+ T-cell tumor infiltration, impairment in the enrichment of ALDHhigh CSCs and enhanced chemosensitivity. In vivo pharmacological blockade of AURKA and NOTCH3 signaling pathways induced inhibition of tumor growth, apoptosis, and impairment of organ metastases. Conclusions: This study demonstrates that selective AURKA and NOTCH3 pharmacological blockade results in the inhibition of cancer cell plasticity that is linked to reduction of undruggable nuclear PD-L1 in TNBC cells. Our findings provide the strong preclinical rationale to develop novel clinical trials for patients with advanced TNBC that are refractory to chemotherapy and show limited response to FDA-approved ICIs. Citation Format: Antonino Bonaventura D'Assoro, Matthew Goetz, Carol Lange, Roberto Leon-Ferre, Tufia Haddad, James Ingle, Annapaola Montagner, Andrew Takchi, Ellie Babadi, Lucio Miele, Urban Lendahl, Urban Lendahl. Pharmacological blockade of AURKA and NOTCH3 oncogenic pathways to inhibit cancer cell plasticity in triple negative breast cancer [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 5978.

Abstract Morphological hip abnormalities (MHAs) significantly influence lifelong prognosis of the hip, contributing to early-onset osteoarthritis and impaired functionality. Developmental dysplasia of the hip (DDH) and femoroacetabular impingement (FAI) represent key pathologies, resulting from insufficient or excessive femoral head coverage, respectively. These abnormalities alter hip biomechanics, leading to structural damage, pain, and accelerated joint degeneration. Advances in genetic research have illuminated the interplay between genetics and mechanical loading in shaping hip morphology. Genes associated with osteoarthritis, DDH, and FAI include COL1A1, MMP13, and IL-6. Genes associated with FAI and osteoarthritis include ADAMTS4. Genes associated with DDH and osteoarthritis include FRZB, CX3CR1, ASPN, DKK1, PDRG1, GDF5, UQCC1, and TGF-β1. The mechanisms linking morphological derangements to symptomatic osteoarthritis remain incompletely understood. Multimodal approaches integrating imaging, biomechanics, and genetics may uncover distinct disease subtypes, enabling personalized interventions. Early detection of MHAs is critical in preventing early-onset osteoarthritis. Incorporating advanced imaging techniques, such as statistical shape modelling, can enhance the understanding of complex 3D hip morphologies and their progression to osteoarthritis. Future research should explore the genetic underpinnings of other morphologic hip conditions, including Slipped Capital Femoral Epiphysis and Legg–Calvé–Perthes disease, to refine preventive and therapeutic strategies. A comprehensive approach combining genetics, imaging, and clinical insights holds promise for mitigating the lifelong impact of MHAs.

Abstract Background and Aims Inflammatory bowel disease (IBD) is associated with altered mucus and increased intestinal permeability (IP). Prior reports on permeability in IBD typically used lactulose-to-mannitol ratio (LMR). Food contamination with 12C-mannitol is a significant potential confounder in IP assessment. We aimed to compare small intestinal (SI) and colonic (COL) permeability in IBD, both active (ACT) and in remission (REM), to normal healthy volunteers (NHV). Methods Inflammatory bowel disease activity was based on Simple Endoscopic Score for Crohn’s Disease (SES-CD) and Mayo endoscopy score for ulcerative colitis (UC). We performed 24-hour IP test using 100 mg 13C-mannitol and 1000 mg lactulose with urine collected during 0-2, 2-8, and 8-24 hours. The primary endpoint was mg excretion of 13C-mannitol and lactulose during 2-24 hours reflecting SI and COL permeability. Results Among 17 CD patients, 7 were ACT (SES-CD &gt;6), and 10 REM (SES-CD 0-2). Among 20 UC patients, 10 had ACT (Mayo score 2-3), and 10 REM (Mayo score 0-1). Urinary excretions over 2-24 hours were higher for IBD than NHV: 13C-mannitol (13.8 [IQR 8.8, 18.7] NHV; 18.4 [15.6, 29.9] REM; 19.7 [13.8, 23.6] ACT, P = .003) and lactulose (1.8 [1.3, 3.1] NHV; 3.6 [2.0, 5.0] REM; 3.5 [2.0, 6.6] ACT, P = .006). There was no difference between ACT and REM for any timed urine collection. LMR at 2-24 hours (or 2-8 and 8-24 hours) were not statistically significant between the 3 groups (0.014 [0.010, 0.021] NHV; 0.016 [0.010, 0.023] REM; 0.016 [0.012, 0.038] ACT, P = .237). Conclusions Intestinal permeability is increased in IBD using validated in vivo assay relative to NHV; increased IP in IBD persists during remission.

The NCCN Guidelines for Head and Neck Cancers address tumors arising in the oral cavity (including mucosal lip), pharynx, larynx, and paranasal sinuses, as well as occult primary cancer, salivary gland cancer, and mucosal melanoma (MM). The specific site of disease, stage, and pathologic findings guide treatment (eg, the appropriate surgical procedure, radiation targets, dose and fractionation of radiation, indications for systemic therapy). The NCCN Head and Neck Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel’s most recent recommendations regarding management of nasopharynx cancer and ongoing research in this area.

Abstract Purpose Developing large‐scale, standardized radiographic registries for anterior cruciate ligament (ACL) injuries with artificial intelligence (AI) tools can enhance personalized orthopaedics. We propose deploying Artificial Intelligence for Knee Imaging Registration and Analysis (AKIRA), a trio of deep learning (DL) algorithms, to automatically classify and annotate radiographs. We hypothesize that algorithms can efficiently organize radiographs based on laterality, projection, identify implants and classify osteoarthritis (OA) grade. Methods A collection of 20,836 knee radiographs from all time points of treatment (mean orthopaedic follow‐up 70.7 months; interquartile range [IQR]: 6.8–172 months) were aggregated from 1628 ACL‐injured patients (median age 26 years [IQR: 19–42], 57% male). Three DL algorithms (EfficientNet, YOLO [You Only Look Once] and Residual Network) were employed. Radiograph laterality and projection (anterior‐posterior [AP], lateral, sunrise, posterior‐anterior, hip–knee–ankle and Camp‐Coventry intercondylar [notch]) were labelled by a DL model. Manually provided labels of metal fixation implants were used to develop a DL object detection algorithm. The degree of OA, both as measured by specific Kellgren–Lawrence (KL) grades, as well as based on a binarized label of OA (defined as KL Grade ≥2), on standing AP radiographs were classified using a DL algorithm. Individual model performances were evaluated on a subset of images prior to the deployment of AKIRA to registry construction using all ACL radiographs. Results The classification algorithms showed excellent performance in classifying radiographic laterality (F1 score: 0.962–0.975) and projection (F1 score: 0.941–1.0). The object detection algorithm achieved high precision–recall (area under the precision‐recall curve: 0.695–0.992) for identifying various metal fixations. The KL classifier reached concordances of 0.39–0.40, improving to 0.81–0.82 for binary OA labels. Sequential deployment of AKIRA following internal validation processed and labelled all 20,836 images with the appropriate views, implants, and the presence of OA within 88 min. Conclusion AKIRA effectively automated the classification and object detection in a large radiograph cohort of ACL injuries, creating an AI‐enabled radiographic registry with comprehensive details on laterality, projection, implants and OA. Study Design Cross‐sectional study. Level of Evidence Level IV.

Introduction There is no prospective data to guide the utilization of peri-transplant radiation (PTRT) in patients with relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL). In retrospective analyses, PTRT has been associated with local disease control, however evidence supporting improved progression free survival (PFS) is less well defined (Milgrom SA et al Cancer. 2017; 123(8):1363-1371). Furthermore, the added benefit of PTRT in the era of recent advancement in salvage strategies, including brentuximab vedotin (BV) and checkpoint inhibitors (CPI), is unclear. In a multicenter, retrospective analysis, we evaluated the impact of PTRT on PFS for patients with R/R cHL. Methods We identified consecutive pts ≥7 years old at time of diagnosis with R/R cHL treated with autologous stem cell transplant (ASCT) at 5 US academic institutions between 2010-2021. PTRT was defined as radiation administered within 3 months of ASCT. The primary objective was to compare the post-ASCT PFS, defined as the time from ASCT to subsequent relapse or death from any cause, between the two groups. Univariable and Multivariable Cox regression was performed to evaluate the impact of various relevant clinical factors on post-ASCT PFS. Results A total of 958 eligible pts were identified ( Table 1). The median age at cHL diagnosis was 31 (range, 7-72). At the time of first relapse/primary refractory disease, 406 (54%) pts had early-stage disease, 167 (24%) pts had bulky disease (≥5.0 cm), 308 (36%) pts had extra-nodal disease, 182 (22%) pts had B-symptoms (B-sx), and 338 (45%) had primary refractory disease. A total of 302 (32%) pts received &gt;1 line of salvage before ASCT. Salvage treatment at any time point before ASCT included chemotherapy only for 457 (48%) patients, BV(+/- chemotherapy) for 308 (32%) patients, and CPI (+/- BV or +/- chemotherapy) for 193 (20%) patients. In total, 239 (24.9%) pts received PTRT, 139 (58.1%) before ASCT and 100 (41.8%) after ASCT. Among pts with available dosing information (23.3%), the median radiation dose administered was 28 Gy. The most common doses administered were 30 Gy in 77 (31.7%) pts, 36 Gy in 62 (27.8%) pts, and 18 Gy in 43 (19.2%) pts. Radiated sites included mediastinum in 172 (80.7%) pts, neck/cervical lymph nodes in 68 (31.9%) pts, and supra/infra clavicular region and axilla, each in 31 (14.6%) pts. Compared to the 719 pts that did not receive PTRT, patients treated with PTRT were more likely to have early stage disease (73% vs 47%, p&lt;0.001), bulky disease (30% vs 22%, p = 0.048), primary refractory disease (56% vs 40%, p &lt;0.001), &gt;1 line of salvage treatment prior to ASCT (40% vs 29%, p&lt;0.001), and &lt;CR prior to ASCT (36% vs 27%, p = 0.007) (Table 1). Patients treated with PTRT were less likely to have RT at initial diagnosis (5.9% vs 22%, p&lt;0.001), extra-nodal disease (19% vs 42%, p&lt;0.001), B-sx (17% vs 25%, p=0.035), salvage treatment that included CPI (11% vs 23%, p&lt;0.001), and BV maintenance (20 vs 31%, p&lt;0.001). After a median follow up from ASCT of 4.5 years (range, 2.4-7.2), 2-year PFS was 76% (73%, 79%) and 5-year PFS was 70% (67%, 73%). In univariable analysis, receipt of PTRT showed non-significant reduced hazard for PFS (HR 0.79, 95% CI 0.59-1.05, p = 0.093) (Figure 1). In a multivariable model, PTRT showed significant association with PFS (HR 0.56, 95% CI 0.36-0.88, p=0.009) when adjusting for other clinically relevant factors at relapse such as stage, B-sx, bulk, primary refractory disease, BV(+/- chemotherapy) or CPI (+/- BV or +/- chemotherapy) in salvage, PET response prior to ASCT, and BV maintenance after ASCT. To determine if specific subgroups benefited from PTRT, we tested for interaction effects between PTRT and clinically relevant factors. Only bulk (HR 0.37, 95% CI 0.16-0.85, p=0.013) and B-sx (HR 0.45, 95% CI 0.20-1.02, p=0.041) showed significant interaction with PTRT.Among pts with bulky disease, 5-year PFS was significantly improved with receipt of PTRT (81% vs 62%, p=0.013). Conclusion In this large multi-center analysis of pts with R/R cHL undergoing ASCT, there was no significant difference in PFS regardless of receipt of PTRT. However, after adjusting for known clinically relevant factors, receipt of PTRT was significantly associated with PFS and was particularly beneficial for patients with bulky disease or B-sx at relapse. We found decreased utilization of PTRT in pts receiving CPI-based salvage; therefore the role for PTRT for pts receiving CPI-based salvage is unclear.

Background: For patients with relapsed and refractory (R/R) classical Hodgkin lymphoma (HL), the standard of care remains salvage therapy followed by autologous stem cell transplant (ASCT) for responding patients. Historical data suggest 40% of patients may relapse after ASCT, and these patients have generally a poor median overall survival (OS) of less than 2 years (Moskowitz et al., Br J Haematol. 2009;146(2):158-62). However, since these reports, the treatment landscape of R/R HL has dramatically improved, most notably with the introduction of two novel therapies, brentuximab vedotin (BV) and anti-PD1 agents. To refine our understanding of clinical outcomes in this context, we characterized patients who relapsed after ASCT in the modern era. Methods: We used a multicenter retrospective patient database at 5 transplant centers in the United States to identify patients with HL aged ≥ 12 years at diagnosis who had received ASCT on or after 1/1/2010. The primary objective was to determine the median OS for patients who relapsed after ASCT (post-ASCT-relapse OS), defining survival as the time from relapse after ASCT to subsequent death from any cause. Univariable Cox regression was performed to evaluate the impact of various factors on post-ASCT OS. Outcomes by era were evaluated using three different eras based on approval dates of novel agents: (1) pre-BV approval (pre-7/31/2011), (2) post-BV approval (8/1/2011-4/30/2016), (3) post-anti-PD1 approval (5/1/16-present). Results: A total of 215 patients were identified. The median age at ASCT was 34. Before ASCT, 128 patients (62%) had no exposure to novel agents, 76 patients (35%) had received BV and no anti-PD-1 therapy, and 11 patients (5.1%) had received anti-PD-1 therapy with or without BV. Conditioning was mostly with BEAM (59%) or CBV (32%). The median time to relapse after ASCT was 6 months (range: 1-109 months). Nearly half all relapses (47%) occurred within 6 months of ASCT. Only 14% of relapses occurred after 1 year. Among 126 patients with available treatment information, the median number of post-ASCT lines of therapy was 2 (IQR: 1, 4). Therapy for post-ASCT relapse included BV and no anti-PD-1 therapy in 41 patients (29%), anti-PD-1 therapy with or without BV for 70 patients (50%), and no novel agents for only 15 patients (11%). The median followup time from the date of ASCT among survivors was 5.0 (IQR: 2.8, 7.8) years. The median post-ASCT-relapse OS was not reached ( Figure 1). The 2- and 5-year post-ASCT-relapse OS were 75% (95% CI: 70%-81%) and 59% (95% CI: 53%-67%), respectively. On univariable Cox regression for post-ASCT-relapse OS ( Table 1), time to relapse greater than 6 (HR 0.55, 95% CI 0.35-0.85) or 12 months (HR 0.53, 95% CI 0.29-0.96) were significantly associated with improved post-ASCT-relapse OS. Increasing age at relapse was associated with worse OS (HR 1.05, 95% CI 1.04-1.07). Receipt of a novel agent (compared to chemotherapy alone) as the first salvage regimen for post-ASCT relapse was associated with improved post-ASCT OS (BV: HR 0.43, 95% CI 0.20-0.96; anti-PD-1: HR 0.44, 95% CI 0.18-1.08). Outcomes improved over time as regulatory approvals for novel agents occurred (post-BV-approval: HR 0.70, 95% CI 0.39-1.24; post-anti-PD-1 approval: HR 0.45, 95% CI 0.23-0.91). Conclusion: We show prolonged overall survival post-ASCT relapse compared to historical data likely due to the introduction of BV and anti-PD1 agents. This report represents one of the largest datasets of post-ASCT relapse in cHL, and this data should serve as an updated benchmark for future evaluations.