Citations

Abstract Background: The association of TILs with pathologic complete response (pCR) and survival in HER2+ breast cancer is not well established with several prior studies showing inconsistent results. In this secondary analysis of EA1181, we evaluated the association between stromal TILs (sTILs) and pCR rates. Methods: EA1181 (NCT04266249) enrolled patients (pts) with anatomic clinical stage II/III HER2+ breast cancer who preoperatively received 4 cycles of trastuzumab and pertuzumab with 12 weeks of paclitaxel or docetaxel q3w x 4 (THP), followed by surgery. sTILs density was assessed on full-face hematoxylin and eosin (H&E)-stained tumor biopsy sections. sTILs scores were analyzed per protocol as a continuous variable (every 10% increment) and as a categorical variable (<10% vs 10-60% vs >60% as per Denkert et al, 2018), and also with an exploratory 30% cutoff commonly used in TNBC. Cox proportional hazards models were used to examine the association between sTILs and pCR, adjusting for available baseline factors. The associations between sTILs (by category) and clinicopathologic characteristics were examined using Fishers’ exact test. Results: Among 2141 pts with HER2+ BC treated on EA1181, H&E slides were available for 1328 (62%). The study population evaluated for sTILs was comparable to the overall population. pCR rates were 44.5% overall, 64% for HER2+/ER- and 33% for HER2+/ER+ disease. sTILs distribution was: 623 (47%) <10%, 698 (52%) 10-60%, and 7 (0.5%) >60%, which led us to merge the latter two groups (705 [53%] had ≥10% sTILs). In univariable and multivariable analyses, increasing sTILs (as a continuous variable) were associated with increasing pCR rates in both HER2+/ER+ and HER2+/ER- disease (p<0.001; Table). sTILs analyzed as a categorical variable (<10% vs ≥10%) were significantly associated with pCR for all patients (combined) and for those with HER2+/ER+ disease. In exploratory analysis using a cutoff of <30% vs ≥30% sTILs, an association with pCR was also seen in univariable analysis for both HER2+/ER+ disease (p<0.001) and HER2+/ER- disease (p=0.045), though in multivariable analysis with clinical factors, sTILs >30% remained a significant predictor for pCR only in HER2+/ER+ disease. Additional exploratory analysis with other molecular biomarkers, intrinsic subtypes, and immune signatures will be presented. Conclusion: sTILs were associated with pCR after THP, further supporting the important role of immune mechanisms in HER2+ breast cancer, and highlighting a potentially robust predictive tool to assess pathologic response. Baseline sTILs could potentially inform the preoperative design of future trials of therapy optimalization. Association of baseline sTILs with recurrence free survival in EA1181 will be reported in the future. Citation Format: S. S. Badve, F. Zhao, N. Tung, Y. Gokmen-Polar, C. C. O'Sullivan, A. Prat, E. P. Winer, J. L. Wright, A. Recht, A. C. Weiss, J. A. Tjoe, S. M. Feldman, G. B. Rocque, M. Smith, N. Unni, S. Sardesai, S. Tang, S. Modi, W. J. Irvin, P. Villagrassa, C. Battelli, A. K. Krie, N. Bagegni, M. A. George, M. L. Telli, V. F. Borges, N. D’Abreo, P. Shah, K. D. Miller, A. H. Partridge, L. A. Carey, A. M. DeMichele, A. C. Wolff, ECOG-ACRIN.Tumor infiltrating lymphocytes (TILs) and pathologic complete response (pCR) in stage II/III HER2+ breast cancer treated with taxane, trastuzumab, and pertuzumab (THP): secondary results from the ECOG-ACRIN EA1181/CompassHER2 pCR trial [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr GS1-04.

Background: Lithium, the gold standard treatment of bipolar disorder (BD), is thought to cause nephropathy in long-term users. However, the role of confounding variables linked to BD in exerting this adverse effect remains unclear. Objectives: This paper evaluates kidney function in patients with affective disorders who are taking lithium compared to patients not on lithium treatment. Design: This article is a systematic review and meta-analysis. Data sources and methods: A comprehensive search of publications up to October 2023 within Cochrane, Embase, PubMed, Scopus, Web of Science, and CINAHL databases was performed. Three assessors screened and extracted data from eligible observational studies. Risk of bias assessment was done with the ROBINS-E tool. Eligible studies were comparative studies of adult patients with diagnoses of affective disorders, including BD on lithium, with control groups not on lithium, reporting kidney function outcomes. Results: Mean estimated Glomerular filtration rate (eGFR) showed less favorable outcomes in the lithium group compared to the non-lithium group ( n = 1622, MD = −11.14 ml/min/1.73 m 2 , 95% CI: −16.61, −5.68, I 2 = 86%). The mean annual eGFR decline comparison favored the non-lithium group ( n = 13,280, MD = 0.13 ml/min/1.73 m 2 , 95% CI: 0.06, 0.20, I 2 = 0%). Serum creatinine concentration (mg/dl) was found to be higher in the lithium compared to non-lithium groups ( n = = 1704, MD = 0.05, 95% CI: 0.03, 0.07, I 2 = 3%). New or progressing chronic kidney disease events were not found to be statistically different between the lithium and control groups ( n = = 17,740, OR = 2.16, 95% CI: 0.59, 7.94, I 2 = 99%). The high heterogeneity in this meta-analysis limits the reliability and interpretability of our results. Conclusion: Kidney function, as measured by eGFR, was decreased in the lithium-taking groups versus the non-lithium groups. Continuous monitoring and discussion of risks and benefits with patients, especially those with a baseline of reduced kidney function, is imperative. Trial registration: This review was registered prospectively with PROSPERO (CRD42024517414).

Background The use of 3D imaging with navigation bronchoscopy has increased with the introduction of mobile cone-beam CT (mCBCT). Shape-sensing robotic-assisted bronchoscopy (ssRAB) integrated with mCBCT has been introduced to correct for CT to body divergence (CT-BD) during the biopsy of peripheral pulmonary nodules (PPNs). Methods Prospective observational multicentre study, enrolling patients with a PPN of ≤20 mm suspicious for malignancy, assessing tool-in-lesion (TIL), diagnostic yield, sensitivity for malignancy and incidence of pneumothorax or airway bleeding. Non-malignant index biopsies were followed for 12 months. Descriptive statistics are reported for all variables along with 95% CI for primary endpoints. Results 155 consecutive patients were enrolled at six centres. Median nodule size was 14.0 mm (IQR 11.0–17.0), with 54.8% of nodules (85/155) in the upper lobes, 25.8% (40/155) with CT bronchus sign present and median distance to the nearest pleural surface of 8.2 mm (IQR 1.8–20.0). TIL was achieved in 154/155 (99.4%, 95% CI 96.5 to 100.0) procedures. A median of two (IQR 1–3) mCBCT spins were performed, with median dose area product of 25.7 Gy · cm 2 (IQR 11.0–46.7). Diagnostic yield per the American Thoracic Society/American College of Chest Physicians (ATC/ACCP) definition was 89.0% (n=138/155; 95% CI 83.0 to 93.5) and sensitivity for malignancy was 91.5% (95% CI 86.4 to 96.5). No pneumothorax (0%, 95% CI 0.0 to 2.4) and two Nashville Grade three bleeding events were reported (1.3%, 95% CI 0.2 to 4.6). Interpretation The first prospective multicentre study of integrated ssRAB and mCBCT for small peripheral nodules resulted in diagnostic outcomes similar to those reported for transthoracic biopsy with a more favourable safety profile. Trial registration number ClinicalTrials.gov ID: NCT05562895 .

Background: Indications for TAVR explant have been established, although limited data exist regarding pre-TAVR baseline characteristics that predict eventual explantation. Methods: The TriNetX network, a database comprising medical records from over 105 institutions, was used. Two cohorts were created: those who underwent TAVR without explant and those requiring subsequent TAVR explant and SAVR. Predictors of explantation were analyzed by multivariate models. Results: Among the 63,377 patients undergoing TAVR, 273 (0.4%) required explantation. Patients in the explant group were younger (69.1 ± 11.3 vs. 78.1 ± 8.8 years; p < 0.001), more likely to have a thoracic aortic aneurysm (TAA) (10.6% vs. 4.7%; p < 0.001) and had higher LDL levels (88.2 ± 41.3 vs. 80.7 ± 34.6 mg/dL; p = 0.011). They also had increased post-TAVR rates of acute kidney injury (9.2% vs. 5.2%; p = 0.004) and paravalvular leak (5.9% vs. 0.9%; p < 0.001). Age at TAVR (HR 1.04; CI 1.03–1.06), baseline TAA (HR 1.69; CI 1.09–2.63), history of infective endocarditis (HR 1.92; CI 1.10–3.35), and higher LDL (HR 1.02; 95% CI 1.00–1.03) were independent predictors for explantation. Conclusions: Younger age at TAVR, TAA, history of endocarditis, and elevated baseline LDL were notable predictors of explantation. These findings highlight the necessity of pre-procedural assessment and follow-up in high-risk patients to optimize TAVR durability.

ABSTRACT We disclose an efficient transformation of the relatively common pyrroloiminoquinone discorhabdin alkaloids from Alaskan Latrunculia spp. to the complex ring system of aleutianamine by an acid catalyzed process that mimics the proposed endogenous genesis from 3‐dihydrodienyl discorhabdin precursors. The azepine ring system is formed by a concerted 1,2‐alkyl shift of a proposed thiocarbenium‐iminium dication and this mechanism is supported by extensive density functional theory (DFT) analysis. Additional in vitro biological data further supports the aleutianamines as novel and highly potent inhibitors of multidrug resistant cancer lines exemplified further with cytotoxicity toward chemotherapy resistant chromophobe renal cell carcinoma (IC 50 = 130 nM). This report provides a key transformation that allows the incorporation of either synthetic or biosynthetic starting materials leading to the generation of the aleutianamine complex ring system in just a single step from the discorhabdin ring system.

ABSTRACT We disclose an efficient transformation of the relatively common pyrroloiminoquinone discorhabdin alkaloids from Alaskan Latrunculia spp. to the complex ring system of aleutianamine by an acid catalyzed process that mimics the proposed endogenous genesis from 3‐dihydrodienyl discorhabdin precursors. The azepine ring system is formed by a concerted 1,2‐alkyl shift of a proposed thiocarbenium‐iminium dication and this mechanism is supported by extensive density functional theory (DFT) analysis. Additional in vitro biological data further supports the aleutianamines as novel and highly potent inhibitors of multidrug resistant cancer lines exemplified further with cytotoxicity toward chemotherapy resistant chromophobe renal cell carcinoma (IC 50 = 130 nM). This report provides a key transformation that allows the incorporation of either synthetic or biosynthetic starting materials leading to the generation of the aleutianamine complex ring system in just a single step from the discorhabdin ring system.

ABSTRACT Background Factor XI/XIa inhibitors are emerging anticoagulants with potential to reduce bleeding complications in atrial fibrillation (AF) patients. This meta‐analysis evaluated their efficacy and safety compared to direct oral anticoagulants (DOACs) and explored dose optimization. Methods A systematic search of PubMed, Cochrane, and Embase was conducted through March 2025 following PRISMA guidelines. Randomized controlled trials (RCTs) comparing Factor XI/XIa inhibitors with DOACs in AF patients were included. Outcomes assessed were major bleeding, stroke, systemic embolism, all‐cause and cardiovascular mortality and serious adverse events. Risk ratios (RR) with 95% confidence intervals (CI) were pooled using a Mantel‐Haenszel random‐effects model. Heterogeneity was evaluated with the I² statistic, and evidence certainty assessed by the GRADE approach. Trial Sequential Analysis (TSA) was performed. Results Three RCTs including 16,772 patients (mean age 73 years, CHA₂DS₂‐VASc 3.9–5) were analyzed. Factor XI/XIa inhibitors significantly reduced major bleeding (RR: 0.41, 95% CI: 0.36–0.46, I² = 0%) compared to DOACs. However, stroke risk was increased (RR: 3.42, 95% CI: 2.62–4.46), particularly with asundexian 50 mg (RR: 4.02). No significant differences were observed in all‐cause mortality (RR: 0.82) or cardiovascular death (RR: 1.05). Systemic embolism risk was higher (RR: 4.26), while serious adverse events were comparable (RR: 0.95). TSA indicated encouraging safety outcomes but highlighted the need for further large‐scale studies. Conclusion Factor XI/XIa inhibitors lower major bleeding risk in AF patients but increase stroke and systemic embolism rates without impacting mortality.

Background: Loeys–Dietz syndrome (LDS) is an autosomal dominant aortopathy characterized by aggressive aneurysm formation and arterial dissections. Pregnancy-related outcomes and timing of LDS diagnosis remain poorly characterized. Methods: Demographics, genetic, obstetric, and vascular data was collected from genetically or clinically confirmed individuals with LDS seen at the three Mayo Clinic sites from 2018 to 2025. Aneurysm progression, new aneurysm formation, and arterial dissections were recorded across all vascular beds. Vascular events were assessed during pregnancy, within 12 months postpartum, and during breastfeeding. Comparative analyses were performed between women with and without a history of pregnancy, and a single-arm descriptive analysis was conducted among patients who experienced vascular complications during the peripartum period. Continuous variables were compared using the Mann–Whitney U test, while categorical variables were analyzed using chi-square or Fisher exact tests. Results: Of 47 women with LDS, 24 had a history of pregnancy, accounting for 54 pregnancies. In the comparative analysis, age at LDS diagnosis differed significantly between women with and without a prior pregnancy: women without prior pregnancy were diagnosed at a younger age (median 23.5 years [IQR 10.8–41.0], n = 23) than those who had been pregnant (median 53.5 years [IQR 43.0–59.3], n = 24). Among pregnant women, the median age at first pregnancy was 28 years (IQR 23–34); only 4 (16.7%) knew their diagnosis before pregnancy. Of 54 pregnancies, 40 (74.1%) resulted in live birth, with 23 (57.5%) vaginal and 17 (42.5%) cesarean deliveries; preterm delivery occurred in 1 (2.5%) pregnancy, and postpartum hemorrhage in 2 (5.0%). No maternal deaths, aortic dissections, or uterine ruptures occurred during gestation or the first postpartum year. In addition, 14 women (58.3%) developed aneurysms, 6 (25.0%) experienced at least one arterial dissection, and 7 (29.2%) required surgical repair, predominantly involving the ascending and abdominal aorta. The prevalence of vascular complications did not differ significantly between groups. Conclusions: In this LDS cohort, pregnancy and the early postpartum period were not accompanied by acute aortic catastrophes, despite frequent diagnostic delay. Although women without prior pregnancy were diagnosed at a younger age, the overall burden of vascular and morphologic complications did not differ significantly by pregnancy history. These findings highlight the importance of long-term cardiovascular follow-up in women with LDS.

Abstract Aims Artificial intelligence electrocardiography (AI-ECG) algorithms are emerging tools for identifying individuals at risk of atrial fibrillation (AF). We evaluated the predictive performance of a validated AI-ECG algorithm for incident AF in UK Biobank participants with AF risk factors, irrespective of prevalent cardiovascular disease, and its incremental value when added to clinical predictors. Methods and results The AI-ECG tool was applied to sinus rhythm ECGs from UK-Biobank participants with risk factors for AF but no AF. Model performance was evaluated using time-dependent ROC-AUC and Harrell’s C-index. Multivariable Cox regression was used to identify clinical risk factors associated with incident AF and to quantify the contribution of AI-ECG. A total of 21 842 participants (56% male) were included. The median follow-up time was 3.7 years (IQR 0.5–5.4) The ECG-AI tool achieved a ROC-AUC of 0.73 (95% CI 0.68–0.78) at 1 and 0.69 (95% CI 0.66–0.72) at 3 years. A multivariable Cox regression model using clinical parameters achieved a ROC-AUC of 0.71 (95% CI 0.66–0.75) at 1 and 0.71 (95% CI 0.68–0.74) at 3 years. By adding ECG-AI to the clinical Cox regression model, the ROC-AUC increased to 0.75 (95%CI 0.71–0.80) at 1 and 0.74 (95% CI 0.71–0.77) at 3 years. AI-ECG showed a hazard ratio of 1.23 per decile increase (95% CI 1.18–1.27). Conclusion An AI-ECG algorithm improved the prediction of incident AF when added to a clinical parameter-based model over a median follow-up time of 3.7 years among individuals with comorbidities predisposing to AF who may benefit from targeted screening and preventive strategies.

BACKGROUND: Lipodermatosclerosis (LDS) is a type of sclerosing panniculitis that predominantly involves the lower extremities and is characterized by erythema, hemosiderin pigmentation, and sclerotic skin lesions. LDS is a common reason for specialty consultations across clinical settings, including dermatology, vascular medicine, and occasionally the emergency department or internal medicine services. METHODS: To further evaluate the prevalence of venous hypertension in patients with LDS at the authors’ institution, they retrospectively reviewed the findings of lower extremity Doppler ultrasonography with or without segmental pressure (ie, venous ultrasonography) performed for adult patients with biopsy-confirmed LDS who were treated at the Clinic from January 1, 2000, through September 30, 2022. RESULTS: A total of 430 patients were included in the study. Venous ultrasonography findings were abnormal for 327 (76.0%) patients, whereas the other 103 (23.9%) patients had normal findings. Venous hemodynamics studies, including air plethysmography and continuous-wave Doppler ultrasonography, were performed for 33 patients with normal venous ultrasonography findings. Of these patients, 7 had mild valvular incompetence, 12 had abnormal calf muscle pump function, and 2 had pulsatility (backflow in the peripheral vein with elevated right atrial pressure) evident on continuous-wave Doppler ultrasonography. CONCLUSIONS: Overall, the findings extend previous observations that venous abnormalities are commonly present in patients with LDS and may contribute to its pathogenesis. However, a few patients with LDS have normal venous hemodynamics, which suggests that other factors also contribute to LDS pathogenesis.