Citations

Introduction: Young-onset esophageal adenocarcinoma (EAC) often presents at advanced stages and is associated with poor outcomes. We aimed to examine the epidemiology of young-onset Barrett’s esophagus (BE) using the TriNetX database. Methods: Young-onset BE patients (age 18 to younger than 50 y) with esophagogastroduodenoscopy (EGD) within 1 year before index BE diagnosis between 2014 and 2023 were included. Negative binomial regression was used to evaluate incident-time trends, and logistic regression to assess for independent predictors of young-onset BE. Results: BE diagnosis was present in 76,691 (3.3%) of 2,337,786 patients that underwent EGD, of which 14,120 (18%) had prevalent young-onset BE. BE dysplasia/EAC was present in 6% of young-onset patients at initial diagnosis. Conventional BE risk factors also predicted young-onset BE: GERD (OR=2.4), White race (OR=2.4), male sex (OR=2.2), smoking (OR=1.2), and obesity (OR=1.1). Each additional risk factor increased the probability of BE prevalence by 74% in young patients versus 54% in older patients. The prevalence of young-onset BE was 4.5% with GERD and ≥3 additional risk factors, and 2.3% when ≥3 risk factors were present. Discussion: Young-onset BE accounts for 18% of all BE cases, demonstrates a striking 6% rate of dysplasia/neoplasia at initial diagnosis, and has a prevalence of 4.5% in those with GERD and ≥3 risk factors. These findings suggest that young-onset BE is an important patient population that merits further study. Additional studies are necessary to study the cost-effectiveness of BE screening in younger patients with multiple risk factors.

Abstract Background Postoperative spinal implant infections (PSIIs) are a serious complication of instrumented spinal fusion. Although debridement with implant retention is standard for early infection, the optimal duration of antimicrobial therapy remains uncertain. Methods We conducted a multicenter retrospective cohort study across 10 US academic centers, including adults with early PSII (≤90 days after fusion surgery) from 2017 to 2021. We excluded patients who experienced treatment failure within 6 weeks of debridement. The primary outcome was treatment failure. Antibiotic therapy effect was analyzed as a time-varying exposure using adjusted Cox proportional hazards models. Secondary analyses included 12-week landmark and clone-censor-weighted models to compare durations ≤ 12 weeks versus >12 weeks. Results A total of 116 patients out of 499 (23.2%) experienced treatment failure during a median follow-up of 3.2 years. Among patients who remain failure-free 6 weeks from debridement, being on antibiotics was not associated with treatment failure (adjusted hazard ratio [aHR] 0.71; 95% CI .48–1.07; P = .10). In a 12-week landmark analysis limited to 359 patients who were not on indefinite suppressive antibiotic therapy, treatment durations > 12 weeks did not significantly reduce the risk of failure (aHR 1.01; 95% CI .62–1.64; P = .99). Results were consistent in the clone-censor-weight sensitivity analysis (aHR 0.85; 95% CI .62–1.16; P = .30). Conclusions Prolonged antibiotic therapy was not associated with improved outcomes in early PSII managed with debridement and implant retention. These results support shorter, individualized antibiotic courses in patients with adequate surgical source control.

Abstract INTRODUCTION Sleep and circadian rest–activity rhythm (RAR) disruption may bidirectionally relate to Alzheimer's disease (AD). Down syndrome (DS), the most common genetic cause of AD, presents sleep disorders, yet RAR patterns across the DS‐associated AD continuum remain uncharacterized. METHODS We analyzed 7‐day wrist actigraphy in 140 adults with DS (108 asymptomatic; 32 AD dementia) and 41 unimpaired controls. General linear models, adjusted for age, sex, sleep efficiency, and obstructive sleep apnea (OSA) severity, tested group differences, with interaction terms included to evaluate group‐specific associations. RESULTS DS showed lower relative amplitude and higher nocturnal activity, already in asymptomatic individuals. Rhythm strength declined further with AD progression, while regularity and phase timing remained preserved until dementia. Findings were independent of sleep duration and OSA. DISCUSSION Adults with DS showed early RAR disturbance that progressed across the AD continuum, paralleling sporadic AD. Circadian RAR features may be scalable biomarkers of AD progression.

ABSTRACT In 2018, the International Niemann‐Pick Disease Alliance (INPDA) and the International Niemann‐Pick Disease Registry (INPDR) developed and published comprehensive clinical management guidelines to support inclusive and standardized care pathways in Niemann‐Pick disease type C (NPC)—an ultra‐rare, autosomal recessive, neurovisceral lysosomal disorder. Since then, advances in diagnostics, care, and the approval of two novel disease‐modifying agents have underscored the need to revise these guidelines to ensure safe, consistent, and high‐quality care for those affected by NPC. In response, the INPDA and INPDR convened a multidisciplinary Guidelines Development Group (GDG) comprising individuals with NPC expertise from 14 countries across five continents, representing a broad range of specialties, as well as patients and families involved in NPC care. Informed by a comprehensive literature review and two meetings, the GDG systematically reviewed, revised, and updated the 2018 guideline statements, re‐evaluating the level of evidence, strength of recommendations, and expert agreement for each. The resulting 2025 consensus clinical management guidelines constitute a timely, up‐to‐date, and internationally applicable resource for the diagnosis, treatment, and holistic management of individuals with NPC. These guidelines serve as a critical resource for specialist centers, hospital‐based medical teams, staff involved in NPC patient care, family physicians and other primary caregivers, and, importantly, patients and their families.

Abstract Purpose To report historical patterns of pharmaceutical expenditures, to identify factors that may influence future spending, and to predict growth in drug spending in 2026 in the United States, with a focus on the nonfederal hospital and clinic sectors. Methods Historical patterns were assessed by examining data on drug purchases from manufacturers using the IQVIA National Sales Perspectives database. Factors that may influence drug spending in hospitals and clinics in 2026 were reviewed—including new drug approvals, patent expirations, and potential new policies or legislation. Focused analyses were conducted for biosimilars, cancer drugs, endocrine drugs, generics, specialty drugs, and vaccines. For nonfederal hospitals, clinics, and overall (all sectors), estimates for growth of pharmaceutical expenditures in 2026 were made based on a combination of quantitative analyses and expert opinion. Results In 2025, overall pharmaceutical expenditures in the US grew 12.7% compared to 2024, for a total of $915.2 billion. Utilization (a 9.3% increase) drove this increase, while growth due to new drugs (0.9%) and price increases (1.2%) had a modest impact. Tirzepatide was the new top drug in 2025, followed by semaglutide and apixiban. Drug expenditures were $42.9 billion (a 9.6% increase) and $190.5 billion (a 19.0% increase) in nonfederal hospitals and in clinics, respectively. In clinics, volume drove drug expense growth, contributing with a 13.6% increase, while price and new drugs each contributed with a 2.7% increase. In nonfederal hospitals, expenditure growth was driven by increases in volume (4.6%), new products (3.7%), and prices (1.5%). Several new drugs that will influence spending are expected to be approved in 2026. Specialty, endocrine, and cancer drugs will continue to drive expenditures. Conclusion For 2026, we expect overall prescription drug spending to rise by 10.0% to 12.0%, whereas in clinics and hospitals we anticipate increases of 14.0%-16.0% and 4.0%-6.0%, respectively, compared to 2025. These national estimates of future pharmaceutical expenditure growth may not be representative of any health system because of the myriad of local factors that influence actual spending

Background We analysed the association between host genetic risk scores (GRSs) predicting efavirenz (EFV) plasma levels and exposure and suicidal behaviours in participants in one of several global antiretroviral therapy (ART) clinical trials linked to the International Network for Strategic Initiatives in Global HIV Trials (INSIGHT). Methods We conducted a matched case–control study (two controls per case) on suicide or grade-4 suicidal ideation/attempts or depression. Cases and controls were matched by EFV initiation strategy, study, and follow-up time. CYP2B6-based GRS classified participants as extensive, intermediate, or slow metabolisers. EFV and its metabolites (8-hydroxy-EFV and 7-hydroxy-EFV) were measured in plasma. Conditional logistic regression was used to analyse the associations between GRS categories, EFV levels, and suicidal behaviour. Results Among 74 cases and 146 controls, 128 (58.2%) started EFV-containing first-line treatment. Of the treatment-experienced participants, 35% were on EFV at entry. Pre-existing psychiatric conditions and recreational drug-use were more common in cases (16.2%, 25.7%) than in controls (0.7%, 9.6%). On comparing cases to controls, more cases were extensive metabolisers (52% vs. 45%), but there were fewer slow metabolisers (8% vs. 13%). The unadjusted odds ratio (OR) for suicidal behaviour per one more minor allele was 0.76 (95% CI: 0.49–1.18). The OR for being a case vs. a control was 0.57 (95% CI: 0.38–0.86) per doubling of the EFV plasma level. Conclusion CYP2B6-based GRS for cytochrome P450 enzymatic activity appeared not to be associated with suicidal behaviour in individuals living with HIV treated with EFV-containing ART combinations. CYP2B6-based GRS effectively predicted EFV exposure, but suicidal behaviour appeared more likely in extensive (normal) metabolisers.

Abstract Introduction: Fibroblast growth factor receptor 2 and 3 (FGFR2 and FGFR3) are metabolic genes overexpressed in malignant epithelia. In colorectal cancer (CRC), intimate crosstalk between FGFR2/3 and epidermal growth factor receptor (EGFR) pathways has been suggested but is not fully elucidated. As a result, this study investigated associations between FGFR2/3 expression levels and clinical outcomes in patients with metastatic CRC (mCRC) enrolled in the phase III clinical trial CALGB /SWOG 80405. Methods: Data from 433 patients with mCRC enrolled in the CALGB/SWOG 80405 trial were analyzed. Patients received either bevacizumab (bev, n = 226) or cetuximab (cet, n = 207) plus chemotherapy as first-line treatment. Tumor RNA was extracted from FFPE samples and processed through the HiSeq 2500 (Ilumina) platform. Median overall survival (OS) and progression-free survival (PFS) curves were evaluated in all treatment subgroups and stratified according to high (H), medium (M), and low (L) FGFR 2 and 3 gene expression levels. Likelihood ratio tests, hazard ratios (HRs), and 95% confidence intervals (CIs) were calculated using Cox proportional hazards multivariate models, adjusting for age, sex, ECOG performance status, tumor location, number of metastatic sites, KRAS status, consensus molecular subtypes, and treatment arm. Results: Both FGFR2 and FGFR3 expression levels were associated with outcomes in patients treated with cetuximab. FGFR2-L tumors showed significantly longer OS compared to the M (HR = 1.04; 95%CI 0.71-1.51) and H (HR = 1.56; 95%CI 1.06-2.28) expression groups (35.7 vs. 31.2 vs. 23.7 months, p = 0.017). In contrast, FGFR3-L tumors were associated with shorter OS compared to the M (HR = 0.63; 95%CI 0.44-0.92) and H (HR = 0.59; 95%CI 0.41-0.85) expression groups (24.7 vs 32.4 vs 37.1 months, p = 0.0009). Significant differences in PFS were not observed. A nominally significant interaction was found between treatment and FGFR3 expression for both PFS (p = 0.02) and OS (p = 0.0003), but no interaction with FGFR2 expression. No significant associations were detected in patients treated with bev. Neither FGFR2 nor FGFR3 suggested to be prognostic markers after multivariate adjustment analyses. Conclusions: Our findings suggest a predictive role of FGFR3 in patients with mCRC undergoing anti-EGFR treatment. Differences in survival within the cet subgroup suggest that EGFR inhibitor efficacy may be modulated by FGFR2/3 signaling activity. Interestingly, FGFR2 and FGFR3 expressions were inversely and positively correlated with improved OS. The findings suggest that FGFR2 signaling minimizes the specific effects of cetuximab, while FGFR3 signaling amplifies its therapeutic effects. Further studies should determine whether these associations are seen in other anti-EGFR inhibitors and detail the mechanistic interaction between FGFR and EGFR pathways. Citation Format: Steve Soto Trujillo, Yan Yang, Michela Bartolini, Shivani Soni, Pooja Mittal, Fang-Shu Ou, Lesly Torres-Gonzalez, Unnati Hemant Shah, Jae Ho Lo, Yitzhar Goretsky, Wu Zhang, Alan Venook, Sandra Algaze, Joshua Millstein, Heinz-Josef Lenz. Differences in survival outcomes among metastatic colorectal cancer patients across fibroblast growth factor receptor 2 and 3 expression levels [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 6751.

Abstract Background. Mitophagy plays a crucial role in removing dysfunctional mitochondria to maintain cellular homeostasis but also has been implicated in cancer tumorigenesis. Previously, we showed that genetic variation in mitophagy pathway genes holds a predictive value in metastatic CRC (mCRC) patients (pts) treated with bevacizumab-based chemotherapy. In this study, we analyzed the correlation between tumor expression profiles of genes associated with PINK1/Parkin and BNIP3/NIX/FUNDC1 mitophagy pathways with clinical outcome in a large phase III randomized clinical trial CALGB SWOG 80405. Method. We analyzed 433 pts with mCRC treated with first-line chemotherapy in combination with the targeted agents bevacizumab (Bev, n = 226) or cetuximab (Cet, n = 207). Tumor RNA isolated from FFPE samples was sequenced using the HiSeq 2500 platform (Illumina). Median Overall survival (mOS) and median progression-free survival (mPFS) were compared across pts groups divided into high, medium, and low tertiles based on mitophagy-related gene (BNIP3, BNIP3L, PINK1, PRKN) expression levels. Likelihood ratio tests, hazard ratios (HRs), and 95% confidence intervals (CIs) were calculated using multivariable Cox proportional hazards models, adjusting for age, sex, ECOG performance status, tumor location, number of metastatic sites, KRAS status, Consensus Molecular Subtypes, and treatment arm. Results: Overall, BNIP3L demonstrated significant prognostic value for both PFS and OS after adjustment for multiple testing (false discovery rate [FDR] < 0.05). Tumors with low BNIP3L expression showed longer PFS and OS compared to those with medium or high expression levels (mPFS 14.8 vs. 10.0 vs. 9.2 months, HR 1.16, 95% CI 1.04 - 1.29p = 0.0182; mOS: 37.4 vs. 30.2 vs. 24.4 months, HR 1.22, 95% CI 1.09 - 1.38, p = 0.0036), independent of treatment. In pts treated with Cet, high PRKN expression was associated with improved PFS and OS (mPFS: 8.9 vs. 10.3 vs. 14.6 months, HR 0.79; 95% CI 0.69 - 0.91, p = 7.3e-05; mOS: 21.2 vs. 27.7 vs. 41.1 months, HR 0.87; 95% CI 0.75 - 1.01, p = 0.00084), whereas low PINK1 expression was significantly associated with longer OS (mOS: 24.9 vs. 30.9 vs. 39.2 months, HR 1.23; 95% CI 1.04 -1.46, p = 0.013). No significant associations were observed in Bev-treated patients for PRKN or PINK1. No significant results were found for BNIP3 expression analysis. Conclusion. Mitophagy is a crucial player in CRC biology due to its tumor-intrinsic (mitochondrial bioenergetics) and microenvironment (interacts with immune components) effects. Our study highlights the prognostic value of BNIP3L and predictive potential of PINK1 and PRKN, suggesting a potential combinatorial therapeutic approach using mitochondrial targeting drugs and targeted agents e.g Cet, which warrants further investigation. Support: Genentech; Clinicaltrials.gov Identifier: NCT00265850 Citation Format: Shivani Soni, Yan Yang, Michela Bartolini, Pooja Mittal, Fang-Shu Ou, Lesly Torres-Gonzalez, Unnati Hemant Shah, Jae Ho Lo, Steve Soto Trujillo, Yitzhar Goretsky, Wu Zhang, Alan P. Venook, Sandra Algaze, Joshua Millstein, Heinz-Josef Lenz. Correlation of mitophagy related genes expression and clinical outcome in metastatic colorectal cancer patients enrolled in CALGB (Alliance)/SWOG 80405 [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 1011.

Abstract Background: Endometrial cancer (EC) remains a major gynecologic malignancy driven in part by aberrant estrogen receptor (ER) signaling. The active tamoxifen metabolite (Z)-endoxifen exhibits dual SERM/SERD-like activity, modulating ER function while exerting additional noncanonical antiproliferative effects. Understanding (Z)-endoxifen’s mechanisms of action and its interaction with cell-cycle regulators is critical to optimizing targeted therapy in EC. This study investigated the molecular and functional effects of (Z)-endoxifen, alone and in combination with the CDK4/6 inhibitor abemaciclib, across diverse EC models to define mechanistic activity and translational potential. Methods: ER+ (Ishikawa, HCI-EC23, patient derived organoid U1561.005) and ER-variable (ARK1, ARK2) EC models were treated with estrogen (0-10 nM), (Z)-endoxifen (125 nM-10 µM) or fulvestrant (0-2.5 μM), and abemaciclib (0-10 μM), as single agents or in combination. Cell viability was assessed using luminescence-based assays. Dose-response analyses and combinatorial synergy were evaluated to determine endocrine sensitivity, ER dependency, and downstream cell-cycle effects. Results: Estrogen induced biphasic proliferative responses in ER+ models, confirming ligand-driven mitogenic signaling. (Z)-Endoxifen monotherapy suppressed viability across all cell lines, demonstrating superior potency to fulvestrant and activity independent of ER expression status. Mechanistically, (Z)-endoxifen abrogated estrogen-induced proliferative peaks, consistent with ER antagonism and potential receptor degradation, while also exerting ER-independent effects suggestive of cell-cycle modulation. Abemaciclib monotherapy inhibited viability in both ER+ and ER− models, and its combination with (Z)-endoxifen yielded strong synergistic activity (Chou-Talalay combination index < 1), including in ER-negative ARK2 and the ER+ U1561.005 organoid. This synergy likely arises from concurrent disruption of ER signaling and CDK4/6-cyclin D regulatory pathways. Conclusions: (Z)-Endoxifen demonstrates dual ER-dependent and ER-independent activity in EC preclinical models. Synergy was observed in combination a CDK 4/6 inhibitor. These findings broaden the current understanding of (Z)-endoxifen’s efficacy and support further exploration of its potential therapeutic role in ER-driven and mixed-phenotype EC, including evaluation of responses across ER expression levels. Citation Format: Grace Choong, Xiaonan Hou, Sandra Suarez Hammer, Scott M. Blackburn, John Weroha, Steven C. Quay. (Z)-endoxifen modulates estrogen receptor and cell-cycle signaling to induce synergistic antiproliferative effects with CDK4/6 inhibition in endometrial cancer models [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 405.