Citations

Background: Prior research has revealed gender disparities in the financial relationships between industry and orthopaedic surgeons. Despite attempts to level the playing field, it remains unclear whether these efforts have reduced or eliminated gender disparities in financial relationships between industry and orthopaedic surgeons. Methods: The Centers for Medicare and Medicaid Services (CMS) Open Payments database was queried from January 1, 2024, to December 31, 2024 for orthopaedic surgeons receiving “consulting fee” or “royalty or license” payments of $1,000 or more. Surgeon characteristics were recorded from the CMS database and public sources. Total payment amounts and number of payments were calculated. Characteristics were compared by gender between those receiving any industry payment, consulting payment, and royalty payment. Multivariable linear regression analyses were used to identify factors associated with payment amount and number of payments. Results were compared with a study using similar data from 2016 to 2017. Results: A total of 3,714 surgeons received industry payments, with 3,514 (95%) being men. Of those receiving royalty payments (n = 1,374), 1.5% (n = 21) were women. Of those receiving consulting payments (n = 3,122), 6.2% (n = 194) were women. Men (β = 1.57 [95% confidence interval [CI]: 0.41-2.73, p = 0.008), years of experience (β = 0.09 [95% CI: 0.07-0.12], p < 0.001), and adult reconstruction (β = 1.77 [95% CI: 0.76-2.79], p = 0.001) were associated with a greater total number of payments. Hand surgery (β = −2.57 [95% CI: 3.97 to −1.17], p < 0.001), pediatrics (β = −2.62 [95% CI: 4.60 to −0.64], p = 0.01), and sports (β = −1.12 [95% CI: 2.08 to −0.16], p = 0.02) were associated with the fewer total number of payments. Men (β = 0.34 [95% CI: 0.10-0.57], p = 0.004), years of experience (β = 0.051 [95% CI: 0.046-0.056], p < 0.001), and adult reconstruction (β = 0.47 [95% CI: 0.27-0.68], p < 0.001) were associated with greater payment amounts, while hand (β = −0.96 [95% CI: 1.24 to −0.68], p < 0.001) and pediatrics (β = −0.79 [95% CI: 1.18 to −0.39], p < 0.001) were associated with lower payment amounts. When examining trends over time, men received 1.57 (2024) vs. 5.17 (2016-2017) additional payments and 40% (2024) vs. 197% (2016-2017) larger payments compared with women. Conclusions: Gender disparities in financial relationships (i.e., number of payments and payment amounts) between industry and orthopaedic surgeons persist, though are improved compared with prior research from about a decade ago.

Radioactive seed localization (RSL) using 125 I is widely employed for the surgical resection of nonpalpable breast lesions due to its precision and scheduling flexibility. Although clinical experience supports its safety, quantifying radiation dose to surrounding healthy breast tissue remains important for establishing conservative operational guidelines, including acceptable implant duration prior to surgery. In this study, cumulative dose to healthy breast tissue from an implanted 125 I localization seed was evaluated using two independent computational approaches: a simplified hemispherical breast model implemented in MATLAB and a Monte Carlo simulation developed in Mathematica. Both models incorporated dosimetric parameters from AAPM Task Group 43, including the dose-rate constant, radial dose function, and two-dimensional anisotropy function, along with tissue properties consistent with International Commission on Radiological Protection recommendations. Results from both models demonstrated that cumulative dose decreases rapidly with increasing distance from the seed and increases slowly with implantation time due to the low dose rate and long half-life of 125 I. At a distance of 1 cm, cumulative dose reached approximately 3–4 cGy after 5 d and approximately 50 cGy only after extended implantation times exceeding 200 d. Agreement between the MATLAB and Monte Carlo models was within expected limits given differences in deterministic and stochastic modeling approaches. These findings indicate that radiation dose to healthy breast tissue from RSL remains well below thresholds associated with deterministic effects for clinically relevant implantation times. The results support the use of a conservative “no later than” removal date while reaffirming the radiological safety and practical advantages of 125 I seed localization in breast cancer surgery.

Objectives: To analyze the association between primary infertility and infertility type with the age of natural menopause. Methods: This is a retrospective cohort study reviewing a subset of women from the Mayo Primary Infertility Cohort (MPIC). The MPIC is a cohort of 1,001 women diagnosed with primary infertility and 1,001 age-matched referent women. In this study, we included all women at risk for natural menopause and further evaluated those who had reported natural menopause in the medical record. We compared the risk of natural menopause using Cox proportional hazard models with infertility status and infertility type as covariates. In those with documented menopause during the study period, the association between primary infertility and early and premature menopause was analyzed with χ 2 testing. We evaluated the association between age at natural menopause, primary infertility status, and infertility type in this group using linear regression. Results: In all, 461 women with primary infertility, with 530 referent individuals, were at risk of natural menopause, and of these, 340 women with infertility and 346 referent women underwent documented natural menopause on review of medical records. Women with primary infertility had an increased risk of natural menopause (hazard ratio: 1.25, 95% CI: 1.06-1.46) and underwent menopause 1 year earlier than referent individuals (β=−1.17, 95% CI: −1.82 to −0.52) after adjustment for body mass index, tobacco use, race, menstrual cycle regularity, and previous contraception use. Women with primary infertility were more likely to undergo early menopause (age 40-45) than referent women (7.6% vs. 3.0%, P =0.01). Compared with referent women, women with endometriosis underwent menopause 2.75 years earlier (95% CI: −4.38 to −1.13, P =0.0009), and women with unexplained infertility underwent menopause 1.45 years earlier (95% CI: −2.26 to −0.64, P =0.0005). Conclusions: Women with primary infertility had an increased risk of early menopause and collectively underwent menopause 1 year earlier than women without a history of primary infertility.

Abstract Germline variants in DDX41 are the most frequent genetic predisposition to adult hematologic malignancies. The most common variants are truncating, implicating loss of function in the pathogenesis. However, non-truncating variants account for 30-40% of cases, and their impact on essential DDX41 functions remains unknown. We utilized a genetic complementation assay to assess the functionality of 10 recurrent germline non-truncating variants of DDX41. All variants restored viability to Ddx41 -deficient hematopoietic progenitor cells at exogenous expression levels. In contrast, the hotspot mutant p.R525H, which is somatically acquired at disease onset in >50% of patients, failed to restore viability. CRISPR-based modeling in cell lines and mice revealed heterogeneity: some variants were non-functional at endogenous expression levels whereas others maintained complete functionality, supporting normal cell proliferation and even lifelong hematopoiesis in a homozygous setting. Notably, co-expression of p.R525H with some variants caused impaired hematopoietic progenitor cell viability, indicating a dominant-negative effect of p.R525H. In contrast, other variants, all classified as variants of unknown significance, were unaffected by the presence of p.R525H. A screen of 100 disease-associated variants confirmed that many non-truncating germline variants are susceptible to p.R525H-mediated dominant-negative effects, whereas wild-type DDX41 is not. These findings indicate that DDX41 variant curation is complicated by variable effects on functionality and variant-specific interactions with somatically-acquired DDX41 mutations. The dominant-negative effect of p.R525H provides a mechanistic basis for the conclusion of recent patient cohort analyses that co-occurrence with a somatic hotspot mutation is a reliable indicator of DDX41-driven disease in carriers of non-truncating variants.

ABSTRACT Legionella species are important causes of community-acquired pneumonia. The diagnostic performance and clinical implications of a fluorescence resonance energy transfer (FRET)-based real-time PCR assay targeting the Legionella 5S rRNA gene were evaluated, with emphasis on melting temperature (Tm) analysis to differentiate detected species and associated clinical outcomes. A retrospective multicenter cohort study of adults with laboratory-confirmed Legionella infection between 2019 and 2025 was conducted. PCR crossing point (Cp) and Tm data were analyzed and compared with species identified in culture from respiratory specimens. Associations between Tm and clinical outcomes were assessed using multivariable logistic regression. Among 51,489 PCR tests performed, 823 (1.6%) were positive. Among 376 Legionella infections, PCR demonstrated the highest diagnostic yield. Among patients undergoing all three diagnostic tests, the addition of PCR increased detection from 49% with urine antigen and culture combined to 100% ( P < 0.001). Of 189 PCR-positive patient specimens with available Tm data, Tm showed a bimodal distribution, being either <66°C or ≥66°C. A Tm cutoff of ≥66°C discriminated L. pneumophila / L. longbeachae from other Legionella species with excellent performance (AUC, 1.00). Overall, 29.6% of infections had a Tm <66°C, consistent with non- pneumophila/ non- longbeachae Legionella species. Infections due to L. pneumophila / L. longbeachae , which correspond to high Tm values in the study assay, were independently associated with ICU admission (adjusted odds ratio, 2.85; 95% CI, 1.33–6.11; P = 0.007), but not 90-day mortality. Real-time PCR targeting the Legionella 5S rRNA gene provides superior detection compared to culture and/or urine antigen testing and enables higher-risk species discrimination through Tm analysis. IMPORTANCE Nearly one-third of Legionella infections in this cohort were attributable to non- pneumophila species, highlighting limitations of diagnostic strategies reliant on Legionella urine antigen testing or L. pneumophila PCR. The findings suggest that species-level inference can be derived from melting-temperature data generated during routine PCR testing. Incorporating validated melting-temperature interpretation into reporting workflows may improve epidemiologic surveillance and clinical understanding of characteristics of Legionella pneumonia.

TPS3182 Background: MTAP deletion in solid tumors causes intracellular accumulation of methylthioadenosine (MTA) which partially inhibits activity of the key methylating enzyme, protein arginine methyltransferase 5 (PRMT5) and creates synthetic lethal dependencies on PRMT5 and methionine adenosyltransferase 2A (MAT2A), the rate limiting step in the synthesis of PRMT5 substrate, S-adenosyl methionine. PRMT5 and MAT2A are essential to transcription modulation, gene splicing, and DNA damage response. IDE892 is an MTA-cooperative PRMT5 inhibitor designed to exploit this vulnerability in MTAPdel tumors. Preclinical studies report robust antitumor activity with IDE892 monotherapy in MTAPdel xenograft models and an enhanced response when combined with IDE397 (an allosteric MAT2A inhibitor). IDE892-001 is a Phase 1 study evaluating safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antitumor activity of IDE892 alone and in combination with IDE397. Methods: IDE892-001 is an ongoing, open-label, multicenter four-part study: IDE892 monotherapy dose escalation (Part 1), monotherapy dose expansion in MTAPdel NSCLC (Part 2), IDE892 + IDE397 dose escalation (Part 3), and combination expansion in MTAPdel NSCLC (Part 4). Adults with advanced or metastatic MTAPdel solid tumors including lung, urothelial, gastrointestinal cancers (including pancreatic and biliary tract cancers) and mesothelioma are eligible following disease progression on standard therapies. Key exclusion criteria include symptomatic brain metastases, cardiac disease, active severe infection, and prior treatment with a PRMT5 or MAT2A inhibitor. Part 1 uses a Bayesian optimal interval design to determine maximum tolerated dose (MTD) and recommended doses for expansion (RDE). Part 3 uses a modified toxicity probability interval design to evaluate escalating combinations of IDE892 and IDE397. Oral treatment is given QD in 21-day cycles until progression or unacceptable toxicity. Serial blood samples are collected for PD analyses. Imaging will be performed every 6 weeks through week 24, then every 9–12 weeks. Efficacy endpoints will be assessed by RECIST v1.1. Primary objectives for dose-escalation cohorts (Parts 1 and 3) are safety and tolerability, including determination of MTD/RDE. In expansion cohorts (Parts 2 and 4), co-primary objectives include safety and preliminary antitumor activity (objective response rate and duration of response). Secondary endpoints for all parts include PK of IDE892 alone and in combination with IDE397. Exploratory assessments include progression free survival, changes in circulating and tumor-based markers of PRMT5 pathway modulation, molecular predictors of response, exposure–response relationships, and metabolite characterization. Clinical trial information: NCT07277413 .

TPS10057 Background: Ewing sarcoma (EWS) is an aggressive tumor of the bone and soft tissue primarily affecting adolescents and young adults. For patients with recurrent disease, outcomes remain poor with 5-year survival rates of 10%–15%, highlighting the need for novel approaches. STEAP1 is highly expressed in EWS cell lines, xenograft models, and patient tumor samples 1 and is transcriptionally regulated by EWSR1::FLI1 , the main oncogenic driver in EWS. Xaluritamig, a humanized bispecific XmAb 2+1 T-cell engager targeting STEAP1 and CD3, has demonstrated potent, antigen-dependent T-cell–mediated lysis of STEAP1-expressing EWS cell lines 1 and induced robust in vivo antitumor activity in EWS xenograft models with concomitant CD8+ T-cell activation. In metastatic castration-resistant prostate cancer, another STEAP1-expressing solid malignancy, xaluritamig has shown meaningful antitumor activity and a manageable safety profile 2 supporting its clinical evaluation in R/R EWS. Methods: This ongoing, phase 1b, single-arm, open-label, two-part, multicenter study (NCT07297979) is evaluating xaluritamig in pediatric, adolescent, and adult patients with a histologic diagnosis of EWS and an EWSR1 :: ETS fusion gene locally confirmed by next-generation sequencing. Patients must have R/R EWS following ≥1 line of systemic therapy and Karnofsky or Lansky performance status ≥70. Part 1 (dose confirmation) consists of cohort 1 (age ≥12 years) and cohort 2 (age ≥2 to <12 years), and part 2 (dose expansion) includes patients aged ≥2 years with no upper age limit at enrollment. This study includes a 21-day screening period, a treatment period, a safety follow-up period, and a long-term follow-up period. Patients receive xaluritamig every 2 weeks once reaching the target dose until radiographic disease progression per RECIST v1.1, clinical disease progression, unacceptable toxicity, initiation of other anticancer therapy not permitted per protocol, withdrawal of consent, death, or end of study as determined by the sponsor, whichever is earlier. Primary endpoints are safety, tolerability, and determination of recommended dose(s) for expansion. Secondary endpoints are pharmacokinetics, preliminary antitumor activity, and immunogenicity. Biomarker evaluation as an exploratory endpoint includes assessment of serum cytokines, other pro-inflammatory markers, immune-cell subsets, circulating tumor DNA, STEAP1 protein expression, and tumor genomic profile and their association with safety and efficacy. CRS mitigation plan includes step-up dosing, steroid premedication, and administration of interleukin-6 inhibitors as needed. Site activation commenced in January 2026 and enrollment is ongoing. 1. Nolan-Stevaux O. Cancer Res. 2020;80(16_Suppl):DDT02–03. 2. Kelly WK, Danila DC, Lin CC, et al. Cancer Discov . 2024;14(1):76-89. Clinical trial information: NCT07297979 .

e16159 Background: Pivotal trials established atezolizumab-bevacizumab and durvalumab-tremelimumab as first-line therapies for unresectable hepatocellular carcinoma (HCC). Atezolizumab plus bevacizumab demonstrated superior survival outcomes compared to sorafenib for unresectable HCC in the IMbrave150 trial in 2020, while durvalumab plus tremelimumab showed superior survival in the HIMALAYA trial in 2022. However, data on head-to-head comparison of these two combinations as first-line systemic therapy for the patient with decompensated HCC are limited. This study aims to compare survival outcomes between these two treatment regimens in decompensated HCC patients to address a critical gap in the current literature, as decompensated patients have largely been excluded from clinical trials. Methods: This retrospective study utilized electronic health records from 146 U.S. healthcare organizations within the TriNetX Network. Adults aged ≥21 years diagnosed with decompensated HCC receiving atezolizumab/bevacizumab and durvalumab/tremelimumab from 10/21/2022 to 8/20/2024 were included. The comparison group received atezolizumab/bevacizumab, and the control group received durvalumab/tremelimumab. The primary outcome was all-cause mortality. A 1:1 propensity score matching was conducted to balance baseline characteristics (age, gender, race/ethnicity, lab results including liver function tests, platelet counts, INR, gamma glutamyl transferase, alpha-fetoprotein, and underlying liver diseases). Kaplan–Meier survival analysis and Cox regression was used to estimate the mortality risk. Subgroup analysis was stratified by HCC etiology. Results: A total of 302 and 664 patients received durvalumab/tremelimumab, atezolizumab/bevacizumab, respectively. After propensity matching, 253 patients per group were included. Median OS was 283 days with durvalumab/tremelimumab and 391 days with atezolizumab/bevacizumab. The two treatment regimens showed no significant difference in survival (hazard ratio [HR]: 0.875, 95% confidence intervals [CI] 0.696–1.101, p=0.254). Subgroup analyses demonstrated no significant differences in survival between the two groups of patients in MASLD (HR: 0.698, 95% CI: 0.468–1.040), alcohol associated liver disease (HR: 0.821, 95% CI: 0.603–1.118), and chronic viral hepatitis (HR: 0.852, 95% CI: 0.596–1.219). Conclusions: There was no statistically significant difference in survival outcomes between atezolizumab plus bevacizumab and durvalumab plus tremelimumab in patients with decompensated advanced HCC. These results support current real-world practice in which both regimens may be considered viable first-line treatment options in this high-risk population with liver decompensation.