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ABSTRACT Objectives While maxillary sinus fungal balls (MSFB) can be associated with odontogenic conditions (MSFBO), MSFBO clinical and dental features have not been compared to odontogenic sinusitis (ODS). This multicenter study aimed to compare characteristics of MSFB, MSFBO, and ODS. Methods A multicenter international retrospective cohort study was conducted on adults with MSFBs and ODS who underwent sinus surgery. First in MSFBs, it was determined whether different dental conditions were more likely in FB versus non‐FB sides. Second, clinical features and dental pathologies were compared between MSFBO and ODS. For analyses, dental conditions were considered individually and as two groups: infectious pathologies and dental/oral procedures with indwelling metallic materials. Results After exclusions, there were 203 MSFBs and 163 ODS. Among MSFBs, 141 were MSFBOs. FB sides were associated with sinus protrusion of root canal treatment (RCT) materials ( p = 0.040) and dental implants ( p = 0.040). Compared to MSFBO, ODS patients were younger, more likely to have MS purulence (OR = 40.9, p < 0.010), more likely associated with apical periodontitis (OR = 2.59, p = 0.010) and oroantral fistulas (OR = 6.94, p = 0.020), and less likely associated with extruded RCT materials (OR = 0.01, p = 0.010) and protruded midface screws (OR < 0.01, p = 0.010). Comparing purulent MSFBO and ODS, ODS was more associated with infectious dental pathologies ( p < 0.009). Conclusion Compared to MSFBs, MSFBOs were associated with RCT extrusion and implant protrusion. Compared to MSFBOs, ODS was more likely purulent and associated with infectious dental pathologies. While ODS is often distinct from MSFBO, the two conditions can coexist, and surgeons must determine whether patients have infectious dental pathology requiring treatment with both conditions. Level of Evidence 4.

Case: Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by progressive heterotopic ossification. Scoliosis may develop and progress rapidly, especially during adolescence. We report 4 patients with FOP and scoliosis during early adolescence: A 12-year-old girl underwent T4-S2 posterior spinal fusion (PSF); another 12-year-old girl underwent T4-S2 PSF; a 13-year-old boy underwent T3-L4 PSF; and a 14-year-old girl was managed nonoperatively because the complex deformity and ankylosed shoulders could not be adequately balanced with surgery. Conclusion: In patients with FOP, surgical intervention can reduce thoracic deformity and improve pulmonary function but carries substantial risks, including heterotopic ossification.

Importance Youth mental health crises have been increasing over the last decade, and there is an urgent need for clinicians to be more knowledgeable about patients with high emergency department (ED) utilization. Several disparities in ED utilization and outcomes have already been identified; however, little data exist on disparities affecting youths with histories of out-of-home placement (OOHP). Objective To explore whether history of OOHP is associated with increased length of stay among child and adolescent patients who present to the emergency department with psychiatric symptoms. Design, Setting, and Participants This retrospective, electronic health record (EHR)–based, cross-sectional study included patients aged 17 years or younger with a child and adolescent psychiatric consultation placed in the Mayo Clinic Rochester ED between January 1, 2021, and June 30, 2024. The Mayo Clinic Rochester is a tertiary referral center that serves as a regional hub for both primary and specialized psychiatric care. Main Outcomes and Measures The primary outcome was the length of stay in the ED. Secondary outcomes were use of physical and pharmacological restraint. Associations between OOHP and length of stay were examined via linear mixed-effects regression models with length of stay log transformed. Results Of the 1572 care encounters (median [IQR] age, 14,9 [13.3-16.3] years) among 1119 unique patients, there were 1244 with no history of OOHP and 328 with history of OOHP. Among the OOHP group, 158 (48%) were male and 170 (52%) female; 11 (4%) American Indian or Alaska Native, 7 (2%) Asian, 49 (16%) Black, 43 (14%) Hispanic, and 222 (71%) White. Among the 1244 encounters without OOHP, 820 (66%) were among female patients and 423 (34%) male; 21 (2%) American Indian or Alaska Native, 47 (4%) Asian, 121 (10%) Black, 125 (10%) Hispanic, and 971 (80%) White. Children and adolescents with history of OOHP were observed to spend 24% (95% CI, 12%-36%) more time in the ED even when adjusting for age at admission, sex, insurance, number of prior diagnoses, presenting concerns, and reasons for prolonged boarding ( P = .004). Children and adolescents with history of OOHP had 2.05 (95% CI, 1.69-2.48) higher odds of being physically restrained ( P &amp;lt; .001) and 2.15 (95% CI, 1.79-2.58) higher odds of receiving pharmacologic restraints ( P &amp;lt; .001) while in the ED. Conclusions and Relevance In this cross-sectional study of 1572 care encounters among 1119 patients, history of OOHP was associated with longer lengths of stay in the emergency department for children and adolescents who presented for mental health concerns. The findings highlight the need for further research on ways to mitigate the risk of extended emergency department stays for children with OOHP.

Abstract Generative artificial intelligence (AI) is rapidly populating medical records with synthetic or partially AI-generated content, creating a feedback loop where future models are increasingly at risk of training on uncurated AI-generated data. However, the clinical consequences of this AI-generated data contamination remain unexplored. Here, we show that in the absence of mandatory human verification, this self-referential cycle drives a rapid erosion of pathological variability and diagnostic reliability of medical data at population scale. By analysing more than 800,000 synthetic data points across clinical text generation, vision–language reporting, and medical image synthesis, we find that models progressively converge toward generic phenotypes regardless of the model architectures. Specifically, rare but critical findings, including pneumothorax and effusions, vanish from the synthetic content generated by AI models, while demographic representations skew heavily toward middle-aged male phenotypes. Crucially, this degradation is masked by false diagnostic confidence. Models continue to issue reassuring reports while failing to detect life-threatening pathology, with false reassurance rates tripling to 40%. Blinded physician evaluation confirms that this decoupling of confidence and accuracy renders AI-generated documentation clinically useless after just two generations. We systematically evaluate three mitigation strategies that can be easily integrated into existing clinical workflows, finding that while synthetic volume scaling fails to prevent collapse, mixing real data with quality-aware filtering effectively preserves diversity. Ultimately, our results suggest that without policy-mandated human oversight, the deployment of generative AI threatens to degrade the very healthcare data ecosystems it relies upon.

Introduction Placental inflammation is a major contributor to preterm birth (PTB), and there are currently few targeted strategies to prevent PTB and its associated adverse neonatal outcomes. Serum amyloid A (SAA), particularly the isoforms SAA1 and SAA2, are well-recognized inflammatory markers, but their functional roles in placental inflammation remain poorly defined. Methods Using a translational mouse model of sub-chronic maternal inflammation, we investigated the immune mechanisms and therapeutic potential of siRNA-mediated targeting of Saa2 (siSaa2). Placental expression patterns of SAA2 were examined in vivo , and macrophage responses to extracellular SAA2 were modeled in vitro using RAW264.7 cells to assess downstream P2X7R-dependent signaling and functional outcomes. Results SAA2 is primarily induced in placental trophoblast and endothelial compartments during inflammation, where it acts as an extracellular inflammatory mediator. In vitro , we model macrophage responses to extracellular SAA2 using RAW264.7 cells to examine downstream P2X7R-dependent signaling and functional outcomes. Maternal administration of siSaa2 improved PTB rates, placental morphology and fetal brain development. Additionally, SAA1 and SAA2 exhibited distinct expression patterns in the mouse and human placenta. Discussion These findings identify placental SAA2 as a key inflammatory mediator in inflammation-associated PTB and demonstrate that targeted silencing of Saa2 represents a potential therapeutic strategy to mitigate placental injury and adverse fetal outcomes.

837 Background: A recent randomized trial suggested that CR may influence ICI activity in patients with lung cancer. However, the same has not been established in GI cancers, where reports have shown mixed results with variable definitions of 'early' vs 'late' IT. We evaluated multiple approaches to assess the impact of CR on first-line ICI in GI malignancies. Methods: This retrospective study included patients from three Mayo Clinic sites (N=455). Both previously reported IT cutoffs and a new cutoff derived from ROC analysis were evaluated. Patients were categorized by the median of all ITs, the median of the first four ITs, and whether ≥20% of ITs occurred before the identified cutoff. Univariate and multivariate Cox regression (adjusting for age, MSI status, type of cancer, metastasis status, number of cycles, and receipt of chemotherapy with ICI) assessed associations with OS. KM analyses were performed to illustrate survival differences. The primary endpoint was OS. Results: When patients were categorized based on whether ≥20% of infusions occurred before 14:00 (ROC-derived cutoff), a significant association with OS was observed. On univariate analysis, early infusion timing was associated with improved survival (HR 2.30, 95% CI 1.58–3.32, p <0.001). This remained significant after multivariable adjustment (HR 2.11, 95% CI 1.41–3.16, p < 0.001). Median OS was 14.2 months in the early group vs 3.8 months in the late group (log-rank p < 0.001). Using previously defined cutoffs, categorization by the median IT of all infusions or the median of the first four infusions did not demonstrate a significant association with OS in either univariate or multivariate Cox regression analyses. Conclusions: These findings highlight the potential role of infusion timing as a chronotherapy factor in GI cancers. Given the retrospective design and heterogeneous population, prospective studies are warranted to validate this signal and clarify its clinical relevance. Baseline demographics of patients by infusion timing (early vs late). Variables Early N=412 (%) LateN=43(%) Total N=455(%) p-value Age <70 249(60.4) 21(48.8) 270 (59.3) 0.1 >70 163(39.6) 22(51.2) 185 (40.7) Gender F 118(28.6) 16(37.2) 134 (29.5) 0.3 M 294(71.4) 27(62.8) 321 (70.5) Cancer Type Gastroesophageal 109 (26.5) 8 (18.6) 117 (25.7) 0.1 Hepatocellular 159 (38.6) 24 (55.8) 183 (40.2) Biliary 86 (20.9) 4 (9.3) 90 (19.8) MSI-H 58 (14.1) 7 (16.3) 65 (14.3) Metastasis No 150 (36.4) 22 (51.2) 172 (37.8) 0.1 Yes 262 (63.6) 21 (48.8) 283 (62.2) Immunotherapy Cycle Number <6 189 (45.9) 33 (76.7) 222 (48.8) <0.001 >6 223 (54.1) 10 (23.3) 233 (51.2)

64 Background: The incidence of eoCRC (diagnosed at age <50) is increasing. We have previously shown higher rates of severe anxiety and depression in this group compared to adults diagnosed at age ≥50 (average-onset CRC, aoCRC). We assessed the impact of ePROM collection coupled with a CC-based supportive care intervention on symptom burden in patients with eoCRC. Methods: The Enhanced, EHR-facilitated Cancer Symptom Control (E2C2) trial was a cluster-randomized, pragmatic trial conducted at Mayo Clinic Rochester and within the Mayo Clinic Health System (in Minnesota and Wisconsin) between 2019 and 2023. Enrolled patients serially reported the severity of six SPPADE symptoms (Sleep deficit, Pain, Physical function impairment, Anxiety, Depression, and Energy deficit/fatigue) on 11-point numerical rating scales. Symptom scores were interpreted as none to mild (0-3), moderate (4-6), or severe (7-10). Those with moderate symptoms were offered symptom management education and self-management materials, while those with severe symptoms were offered the option to work with a symptom care manager. In this post hoc analysis we examined the effects of the intervention on change in symptom scores among those with eoCRC, and using the Kaplan-Meier method, the median time to improvement to a mild/moderate level in those with a severe symptom, comparing eoCRC with aoCRC. Results: Among 4,422 patients with CRC, 887 had eoCRC. Forty-six percent of patients were female ( p =0.61), and a greater proportion of eoCRC patients were of a non-white race (11.6% vs 4.7%), lived in an urban setting (65.6% vs 50.5%), had a Bachelor’s degree or higher (36.8% vs 24.4%), were employed (78.5% vs 36.7%), on a non-government insurance plan (83.4% vs 35.3%), single (19.7% vs 11.2%) or married (74.2% vs 67.9%), and had metastatic disease (54.8% vs 46.1%, p <0.0001 for all). Compared to a pre-intervention baseline, the mean change in symptom scores for eoCRC patients following the intervention demonstrated improvements in anxiety (-0.238), depression (-0.134), and fatigue (-0.146, p <0.05 for all). Time to symptom improvement from severe to mild/moderate was longer for anxiety and depression in eoCRC patients compared to aoCRC patients (Table 1). Conclusions: Collection of ePROMs coupled with a CC-based intervention led to improvements in anxiety, depression, and fatigue among eoCRC patients, although time to symptom improvement was longer among eoCRC patients compared to aoCRC patients. Time to improvement of severe symptom (months), median (95% CI). eoCRC aoCRC p -value Sleep 4.2 (3.1-5.8) 3.8 (2.7-5.4) 0.4 Pain 4.1 (3.0-7.5) 3.2 (2.3-5.0) 0.5 Physical function impairment 3.1 (1.9-6.3) 2.8 (2.2-4.2) 0.5 Anxiety 4.3 (3.4-9.1) 2.6 (2.0-3.5) 0.009 Depression 4.3 (2.6-7.5) 2.6 (2.1-3.5) 0.04 Fatigue 4.3 (3.7-9.5) 3.4 (2.7-4.2) 0.06

622 Background: Colorectal small and large cell neuroendocrine carcinoma (SCNEC and LCNEC) comprise <1% of colorectal cancers and have poor prognosis. Detailed survival information is limited due to rarity. We analyzed survival outcomes using Survival, Epidemiology, and End Result (SEER) database (2000-2022) and compared with NETs and adenocarcinoma (AC). Methods: All patients with SCNEC, LCNEC, NETs or AC with colorectal primaries were extracted. AJCC stage was calculated with 8 th ed. TNM classification. Kaplan-Meier estimator, log-rank test, and Cox regression (including AJCC stage, surgery, radiation, and chemotherapy variables) were used to analyze survival outcomes. Results: Comparing colon and rectal primaries, the only significant mOS difference was in stage IV SCNEC (2 vs 7 months, p<0.0001). Comparing LCNEC and SCNEC, the only significant mOS difference was in stage IV colon SCNEC and LCNEC (2 vs 5 months, p<0.0001). Stage III and IV colorectal SCNEC and LCNEC had significantly shorter mOS than stage III and IV AC and NETs. In multivariate Cox regressions, surgery and chemotherapy were associated with significantly improved survival for both SCNEC and LCNEC at both primaries (p<0.001), while radiation was never significant. Conclusions: Most colorectal SCNEC and LCNEC patients present with stage IV disease. Stage IV colon SCNEC had significantly shorter mOS than both stage IV colon LCNEC and stage IV rectal SCNEC. Further research should explore early diagnosis and effective therapies for this rare, aggressive malignancy. Median overall survival (months) Colon SCNEC (n/mOS) Colon LCNEC (n/mOS) Colon NETs (n/mOS) Colon AC (n/mOS) SCNEC vs NETs in colon: P-value LCNEC vs NETs in colon: P-value SCNEC vs AC in colon: P-value LCNEC vs AC in colon: P-value SCNEC vs LCNEC in colon: P-value Rectal SCNEC (n/mOS) Rectal LCNEC (n/mOS) Rectal NETs (n/mOS) Rectal AC (n/mOS) SCNEC vs NETs in rectum: P-value LCNEC vs NETs in rectum: P-value SCNEC vs AC in rectum P-value LCNEC vs AC in rectum SCNEC vs LCNEC in rectum: P-value Colon SCNEC vs rectal SCNEC P-value Colon LCNEC vs rectal LCNEC: P-value Stage I 19/32 17/122 4496/NA 114,213/144 <0.0001 <0.0001 <0.0001 0.34 0.25 27/23 10/28 5185/NA 54,702/160 <0.0001 <0.0001 <0.0001 0.00047 0.88 0.99 0.24 Stage II 17/38 30/49 259/NA 121,757/106 0.0015 <0.0001 0.4 0.0068 0.65 17/16 3/NA 33/NA 38,417/106 <0.0001 0.57 <0.0001 0.87 0.3 0.065 0.55 Stage III 40/14 107/13 582/184 104,793/82 <0.0001 <0.0001 <0.0001 <0.0001 0.48 50/19 37/17 103/102 46,687/107 <0.0001 <0.0001 <0.0001 <0.0001 0.45 0.48 0.47 Stage IV 245/2 217/5 393/49 83,542/13 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 260/7 57/6 158/36 36,652/17 <0.0001 <0.0001 <0.0001 <0.0001 0.25 <0.0001 0.95

561 Background: For patients with aHCC, second-line treatment options are not well established. The primary aim of this study was to evaluate the efficacy of Futi, an FGFR 1-4 inhibitor, in combination with Pem as a second line therapy in patients with FGF19-expressing aHCC. Methods: Patients aged ≥ 18 years, with histological/cytological diagnosis or radiological diagnosis of HCC, Child-Pugh (CP) class A-B7, Barcelona Clinic Liver Cancer (BCLC) A, B or C, ECOG performance status of 0-2, and FGF19+, by in-situ hybridization or immunohistochemistry, received Futi 20 mg once daily plus i.v. Pem 200mg every 3 weeks. The primary endpoint was progression-free survival at 6 months (PFS6). Secondary endpoints include overall survival (OS). The study was designed to enroll 22 evaluable patients to detect PFS6 from 25% (historical control) to 47%, assuming a 1-sided alpha of 0.1 with 80% power. All patients provided written consent. Eligible patients with consent who started treatment are considered evaluable. Results: The study was closed to enrollment early at the request of funding agency due to poor accrual. Between 8/2021 and 3/2024, 14 patients enrolled with 1 patient withdrawing consent before beginning protocol treatment. Among 13 evaluable patients, median age was 72 (range: 60-87) years, 7 (53.8%) were male, 12 CP A (92.3%), 7 BCLC C (53.8%), with 7 (53.8%) having received prior liver directed therapy. Median PFS was 15 weeks (95% confidence interval [CI]: 9.0-Not Estimable) and PFS6 was 23.1% (95% CI: 8.6%, 62.3%). Objective response rate was 0% (95% CI: 0%, 24.71%) and stable disease occurred in 7 (53.9%) of patients. Median OS was 55.7 weeks (95% CI: 47.3-NE). Nine (69.2%) patients experienced at least 1 grade 3+ adverse event (AE), and 2 (15.4%) patients experienced at least a grade 4+ AE. One patient had a grade 5 AE unrelated to study treatment (acute kidney injury). Most commonly reported AEs (occurring in more than 31% of patients) were hyperphosphatemia (76.9%), fatigue (69.3%), diarrhea (61.6%), AST (53.9%) and ALT (46.2%), dry eye (38.5%), nail changes (38.5%), rash-maculo-papular (38.5%), and mucositis oral (38.5%). Conclusions: This prospective study evaluated the use of a targeted treatment in combination with immunotherapy following first line immune-based therapy. This combination had modest activity as a second line therapy for patients with aHCC but did not meet the primary endpoint. The safety profile was acceptable and consistent with prior reports. An optimal second-line regimen remains a critical need. Clinical trial information: NCT04828486 .

451 Background: In first-line E/GEJ/G adenocarcinoma, anti-PD-1 + chemotherapy improves outcomes, yet many patients do not respond. Beyond PD-L1 CPS, tumor-intrinsic biomarkers of primary resistance remain limited. We applied a validated IFN-γ–linked T cell-inflamed (Tinfl) framework to define exclusionary programs and nominate targets. Methods: Bulk RNAseq was analyzed from TCGA ESCA/STAD adenocarcinoma (n=79, discovery) and a de novo Mayo cohort of pretreatment samples (n=74, validation) with harmonized survival and response data. Tinfl scores (160-gene signature) defined quartiles (Q1 cold, Q4 hot). Cold versus hot tumors were compared by edgeR + limma-voom to identify differentially expressed genes (DEGs) (Bioconductor v3.20). Pathway and upstream-regulator/causal-network analyses used Ingenuity Pathway Analysis seeded by top DEGs (|log2FC|>1.5, p<0.05). Survival was assessed by Cox proportional hazards models (two-sided α=0.05) and KM log-rank testing (α=0.05). A 14-gene Tinfl-weighted cold signature produced a per-sample composite score. Results: In the Mayo cohort, median age was 62 years; 72% were stage IV at diagnosis; 24% were HER2-positive and 3% MSI-H; primary sites were GEJ/esophagus/gastric 50%/34%/16%; PD-L1 CPS <1/1–5/6–49/≥50 occurred in 18%/46%/27%/4%; patients received a mean of 2.4 lines of therapy. Across discovery and validation cohorts, Tinfl-cold tumors showed significantly higher expression of developmental and lineage transcription factors (HOXC12, HOXC13, ZIC1, DLX3, EVX1), an oncofetal post-transcriptional hub (IGF2BP1), cancer-testis and piRNA components (MAGEA4, TDRD12, THEG), and neuronal or transport genes (GABRQ, KCNF1, LDLRAD1, SLC6A10P) (logFC >2, p<0.05). Pathway analysis highlighted chromatin and lineage regulators (KAT6A, SIRT1, LEF1), TGF-β signaling (TGFBR2), and repressors of innate DNA/IFN sensing (TREX1, IRF2BP2) (Z-score >2, p<0.05). The 14-gene Tinfl-weighted cold signature was higher in cold versus hot tumors (p<0.05) and showed a directional association with inferior overall survival in the Mayo validation cohort. Among patients who received first-line anti-PD-1–containing regimens, several signature members and the composite score were higher in non-responders (p<0.05). Conclusions: Using a discovery–validation design, we define tumor-intrinsic expression pathways that characterize Tinfl-cold E/GEJ/G adenocarcinoma. We also derive a concise 14-gene Tinfl-weighted cold signature that is enriched in non-responders and associated with inferior overall survival. Targetable nodes such as IGF2BP1 and MAGEA4, together with chromatin and Wnt/TGF-β regulators, support rational combinations with PD-1 blockade. Planned validation in a third cohort, single-cell confirmation of tumor-cell expression, and in vivo cytokine profiling in knockdown models will refine mechanisms and nominate clinical candidates.