Citations

This case report describes a 65-year-old man who experienced complete remission of cavin-4 immunoglobulin G (IgG) rippling muscle disease after receiving rituximab therapy.

Background: There is growing support for high-efficacy disease-modifying therapy (DMT) in multiple sclerosis (MS), but escalation (ESC) approaches remain common. Objective: To describe decision-making in a pragmatic trial of early high-efficacy treatment (EHT) versus ESC. Methods: DELIVER-MS is a multi-center, pragmatic, randomized controlled trial (RCT) with a parallel observational study (OBS), which enrolled treatment-naïve people with RRMS in 31 UK/US sites. Primary outcome was as follows: 36-month brain volume loss according to initial treatment approach (EHT vs. ESC). Stepwise multivariable logistic regression was used to predict participation in RCT versus OBS and choice of EHT versus ESC within the OBS cohort. Results: In total, 816 people with MS were enrolled. Participants declined randomization due to preference for a particular DMT (85%), efficacy concerns (20%), and safety concerns (9%). RCT versus OBS participation was associated with lower relapse rate ( p = 0.043) and greater brain parenchymal fraction ( p = 0.002). Among 374 in the OBS cohort, 125 (33%) chose ESC and 249 (67%) chose EHT. People commencing EHT had higher education attainment ( p < 0.001) and relapse rate ( p = 0.025). Conclusion: Baseline DELIVER-MS data demonstrate that participants with milder disease are more likely to participate in RCT. The choice of EHT versus ESC was associated with demographic factors and disease activity. Clinical trial registration: NCT03535298

Abstract Background and Aims A simple diagnostic method able to reliably exclude left main (LM) coronary artery disease (CAD) or LMCAD-equivalent would expand implementation of an initial non-invasive strategy in patients with chronic coronary syndrome (CCS). This study assessed the diagnostic utility of an approach using clinical and ECG stress testing (EST) variables in excluding LMCAD/LMCAD-equivalent in CCS patients. Methods In a multicentre case-control study, CCS patients undergoing invasive coronary angiography (CAG) after a maximal EST were evaluated. Cases were patients with angiographic ≥ 50% LM stenosis or ≥70% stenosis of both proximal left anterior descending and proximal circumflex arteries, matched with similar patients without them (controls) in a 1:3 ratio. A risk model developed through logistic regression was internally and externally validated. Results Three hundred and thirty-five cases were matched with 797 controls. The model area under the curve (AUC) was .78. Assuming LMCAD prevalence of 5% and a misclassification cost ratio of 1:100 (ratio of cost of performing CAG in a control to cost of not performing CAG in a case), negative predictive value was 98.2%. Thus, CAG could be safely avoided in 41% of patients, missing one LMCAD/LMCAD-equivalent diagnosis for every 58 CAGs safely spared in patients without them. Conclusions Among CCS patients, LMCAD/LMCAD-equivalent can be excluded with high negative predictive value through a model based on clinical and EST parameters, allowing initial non-invasive management of most patients able to exercise. This approach is potentially useful particularly in communities where access to computed tomography coronary angiography is limited.

Abstract Repetitive head impacts sustained during American football have been associated with neuropathological changes such as white matter shear injuries. However, the impact of specific factors, such as age of first exposure and cumulative head impact burden, on white matter integrity remains unclear. This study investigated in vivo white matter microstructural changes using diffusion tensor imaging and tract-based spatial statistics in 165 male former American football players (mean age 57.3 years, range 45–74) and 52 unexposed asymptomatic male controls (mean age 59.4 years, range 45–74) in the DIAGNOSE CTE Research Project. Compared to controls, former football players exhibited significantly higher fractional anisotropy (FA) in 1.97% of the white matter skeleton (1552 voxels; Cohen’s d = 0.587) and higher tissue-corrected FA (FAt) in 1.48% of the white matter skeleton (1004 voxels; Cohen’s d = 0.616). No significant differences were observed for mean diffusivity, axial diffusivity, radial diffusivity, or free water between football players and controls. Among football players, there were no significant differences in the white matter microstructure between players diagnosed with traumatic encephalopathy syndrome and those without the diagnosis. Lower FA was significantly associated with older age (P &lt; 0.00001) and an earlier age of first exposure to tackle football (P &lt; 0.01), while lower FAt was associated with greater cumulative head impact burden, specifically higher linear acceleration (P &lt; 0.04) and rotational force (P &lt; 0.02). This study highlights the influential role of exposure factors on white matter microstructure in former American football players, as well as the utility of diffusion tensor imaging to aid in characterizing the long-term effects of repetitive head impacts in contact sport athletes.

Background Intermittent fasting (IF) represents a dietary strategy with known metabolic benefits, however its safety and applicability in patients with chronic kidney disease (CKD) remains poorly understood. AI chatbots’ reliability for clinical and dietary guidance in clinically complex areas remains underexplored. No study has examined AI performance on IF in patients with CKD. This study evaluated the accuracy, consistency, readability, and quality of responses generated by ChatGPT-5 and Claude 4.5 Sonnet regarding IF in CKD. Methods Twenty-five patient-centered questions spanning seven clinical domains were developed by two board-certified nephrologists and submitted independently to ChatGPT-5 and Claude 4.5 Sonnet twice per model. Prompts were submitted under standard and unmodified user conditions without customized system instructions to represent a zero-shot evaluation that is illustrative of typical patient use. Responses were evaluated for accuracy, consistency (comparatively between responses), and appropriateness by the evaluators. Response readability and quality were assessed using the Flesch-Kincaid Grade Level (FKGL) formula and the DISCERN instrument respectively. Results Both ChatGPT-5 and Claude 4.5 Sonnet demonstrated identical accuracy scores during the first question prompts with notable improvement upon re-prompting after 24-hours. Both models demonstrated an identical internal consistency at 90%. ChatGPT-5 produced responses at the middle school level, better aligned with the US adult health literacy benchmark, while Claude 4.5 Sonnet generated responses at the high school level. DISCERN scoring was comparable between chatbots indicative of good response quality. Both chatbots had similar performance regarding individual subdomains. Conclusions Both chatbots illustrated clinically accurate and cautious responses to questions regarding IF in CKD. ChatGPT-5 responses were better suited to the average health literacy of the general United States adult population. Despite our findings, we do not recommend either chatbot be used as the primary source for clinical counseling regarding IF in CKD. It is important for clinicians to help to guide patients toward evidence-based clinical information.

TPS655 Background: Early (14-28 day) on-treatment suppression of tumor proliferation during neoadjuvant endocrine therapy (NET) is strongly associated with favorable long-term outcomes in estrogen receptor–positive (ER+) HER2– breast cancer. In premenopausal women, tamoxifen with or without ovarian function suppression (OFS) results in suboptimal Ki-67 suppression compared with aromatase inhibitor + OFS. (Z)-endoxifen (ENDX), the active metabolite of tamoxifen, dually inhibits ER signaling and PKCβ1-mediated AKT activation, supporting its evaluation as an alternative NET strategy in this population. Methods: EVANGELINE (NCT05607004) is an ongoing, multicenter, open-label Phase 2 study evaluating daily 40 mg ENDX plus goserelin administered every 28 days as neoadjuvant therapy in premenopausal women with ER+/HER2–, cT2–3, cN0–1 breast cancer. The primary objective is to determine the proportion of patients with baseline Ki-67 >10% who achieve Ki-67 ≤10% after 4 weeks of therapy. A Simon two-stage design is used to test whether the Week 4 Ki-67 ≤10% rate is at least 65%, with 20 patients enrolled into the first stage and, if promising, another 25 patients enrolled into the second stage (cohort A). A parallel cohort of 20 patients with baseline Ki-67 ≤10% (cohort B) is enrolled to assess objective response rate (ORR) at 24 weeks per RECIST v1.1. Secondary objectives include examining safety and tolerability, residual cancer burden, and PEPI score. Correlative analyses include examining effect of treatment on select tumor and plasma biomarkers. Clinical trial information: NCT05607004 .

TPS11598 Background: Fibroblast Activation Protein (FAP) is expressed on the surface of cancer-associated fibroblasts and is involved in the formation, maintenance, and spread of tumors. Sarcoma frequently demonstrates high expression of FAP on the tumor cells themselves in contrast to other solid tumors, where it is mainly expressed on CAFs within the tumor stroma. Radioligand therapies utilizing alpha emitting isotopes such as Ac-225 have emerged as promising treatment strategies across multiple targets and indications in oncology. Ac-225 and its daughter radionuclides emit high-energy alpha particles capable of inducing double-stranded DNA breaks, leading to significant cytotoxic effects within cells. Early clinical data for other Ac-225-labeled compounds have shown promising outcomes, particularly in settings where traditional therapies have failed. [Ac-225] RTX-2358 (Ratio Therapeutics Inc, Boston, MA) is a novel FAP-targeted radioligand designed for specific high-affinity binding, resulting in prolonged tumor residence and limited normal tissue uptake. This sustained tumor retention leads to extended delivery of cytotoxic radiation to FAP-expressing tumors. A beta-emitting analog, [Lu-177]RTX-2358, has been administered to more than 25 patients under the German §13.2b compassionate use framework across multiple tumor types. Longitudinal SPECT imaging performed as late as 14 days after administration demonstrated persistent tumor retention with minimal washout. Based on time–activity curve analysis from these data, tumor biological half-time is estimated to be well in excess of 1,000 hours. Renal clearance was observed to be consistent with that reported for established lutetium-177–labeled radioligand therapies. Methods: This study is a seamless Phase 1 / 2 dose escalation study. The Phase 1 portion consists of a 3 x 3 dose escalation design, with patients treated in 3 planned dose escalation cohorts (7.5, 11.25 and 15 MBq) with up to 6, 8-week cycles of [Ac-225]RTX-2358. Backfill of phase 1 cohorts is permitted to facilitate selection of the recommended administered activity level for the subsequent Phase 2 expansion cohort. Dose escalation / de-escalation decisions will be made by a Safety Review Committee. Patients over 18yrs with a history of histologically confirmed relapsed or refractory soft tissue sarcoma (measurable disease per RECIST v1.1) are eligible if they have a positive [Cu-64]LNTH-1363S FAP PET, an ECOG PS 0 to 1, and adequate organ reserve and renal function. Recruitment of the first cohort was completed in December 2025. The ATLAS Study: NCT07156565 Clinical trial information: NCT07156565 .

e20511 Background: Trop-2 ADCs have emerged as a novel therapeutic approach in NSCLC that is refractory to chemotherapy and immune checkpoint inhibitors. Comparative interpretation of the efficacy of multiple Trop-2 ADCs, including Sacituzumab tirumotecan (Sac-TMT), Datopotamab deruxtecan (Dato-DXd), and Sacituzumab govitecan (SG), is limited. We therefore conducted a systematic review, IPD survival analysis, and meta-analysis to evaluate the efficacy and PROs of Trop-2 ADCs compared with chemotherapy in NSCLC. Methods: A systematic search was conducted from inception to October 31, 2025, across PubMed, Scopus, Cochrane, and CT.gov. Clinical trials evaluating Overall Survival (OS) and Progression-free survival (PFS) in patients treated with Trop-2 ADC alone or compared with Chemotherapy were included. IPD were extracted from the Kaplan-Meier curves of clinical trials for reconstruction using the KMfromIPD website by MD Anderson, which stratified the data by treatment group. Outcomes included OS, PFS, and time to deterioration (TTD). The cumulative data were analyzed using R 4.5.1 and RStudio. RevMan version 5.4.1 was used for the meta-analysis of subgroups. Heterogeneity was assessed using the I 2 statistic. Results: Of 513 articles, 7 phase 1/2 single-arm and 4 randomized control trials were included, comprising 2,619 patients.Trop-2 ADCs were associated with improved OS (Median 15.6 vs 12.5 months; HR 0.78, 95% CI 0.69-0.88; p < 0.0001) and PFS (Median 5.5 vs 4.1 months; HR 0.66, 95% CI 0.59-0.74; p < 0.0001). Sac-TMT demonstrated the greatest OS benefit (OS 23.3 months; HR 0.40). Further drug classes are depicted in Table 1. PROs assessment showed TROP-2 ADCs were associated with longer time to deterioration in global quality of life and dyspnea-free survival compared to chemotherapy (HR 0.8 and 0.69), (p = 0.04 and p < 0.0001, respectively). Exploratory subgroup analysis showed improved OS among patients with actionable gene alteration (AGA) treated with Trop-2 ADCs (HR 0.58, p < 0.00001). However, no significant difference was observed in either treatment arm among patients without AGA (HR 0.89, p = 0.15). Conclusions: Trop-2 ADCs were associated with improved survival and PROs compared with chemotherapy in NSCLC, with variability across agents. Sac-TMT has shown higher OS and PFS. Dato Dxd had a favorable PFS; however, the OS was not superior to chemo. Furthermore, SG showed no favorable clinical outcomes compared with the chemo group. These findings support the continued development of Trop-2-directed therapies and highlight the need for prospective comparative trials and biomarker-driven patient selection. Drug N mOS (months) HR p- value mPFS (months) HR p- value Sac-TMT 386 23.32 0.4 <0.000001 7.5 0.5 <0.000001 Dato-DXd 486 13.2 0.95 0.55 5.02 0.71 <0.000001 SG 347 12.61 1.02 0.82 4.18 0.87 0.05

e18524 Background: Venetoclax (Ven) in combination with hypomethylating agents (HMA) is FDA-approved front-line therapy for elderly or unfit patients with newly-diagnosed acute myeloid leukemia (ND-AML); however, majority relapse or are refractory ( Pratz AJH 2024 ). We examined survival outcomes in the setting of frontline Ven-HMA failure. Methods: ND-AML patients with failure to achieve complete remission (CR/CRi) or loss of CR/CRi after front-line Ven+HMA, excluding post-transplant relapse were retrospectively studied. Response was evaluated per European Leukemia Net 2022 criteria ( Dohner Blood 2022 ). Results: 356 patients with ND-AML (median age 75 years; 65% males; 55% secondary) receiving frontline Ven+HMA (median; 3 cycles (1-26), had refractory [n=219 (62%)], or relapsed disease [137 (38%)]. At diagnosis, karyotype was complex in 142/347 (41%). Mutations involved TP53 (29)%, ASXL1 (19%), RUNX1 (17%), SRSF2 (15%), KRAS/NRAS (13%), IDH2 (7%), FLT3-ITD (7%), NPM1 (6%) and IDH1 (5%). At treatment failure, complex karyotype was present in 72/180 (40%), including 55 from baseline. In 137 patients with paired NGS, mutations persisted in TP53 (88%), IDH1 (86%), IDH2 (78%), NPM1 (75%), K/NRAS (73%), RUNX1 (70%), FLT3-ITD (65%) mutations. Mutations were acquired in a minority [ IDH1 / IDH2 (2% each) TP53 (3%), NPM1 (4%), FLT3-ITD (5%) K/NRAS (6%)]. Clearance of mutations were infrequent for TP53 (12%) and IDH1 (14%). At median follow-up of 4 months (mo) (0-80) from the time of relapse/refractory disease, 320 (90%) patients have died, with median survival of 4 mo (1-2-3 yr survival 19%/8%/5%). On multivariate analysis, peripheral blasts >20%, complex karyotype, and wild-type IDH1 were independent predictors of inferior survival, while allogeneic stem cell transplant (ASCT) was associated with improved survival. A 3-point prediction model based on peripheral blasts ≥20%, complex karyotype, and wild-type IDH1 stratified patients into low-, intermediate-, and high-risk groups, with median survival of 7, 3, 2 months, respectively (p<0.01). 13 patients underwent ASCT (median survival; 22.5 mo; 3-yr survival 33%), from low (n=10) or intermediate-risk groups (n=3). Salvage therapy (n=170, 48%) yielded CR/CRi of 31% for Ven+HMA (n=36), 54% intensive chemotherapy (n=26), 50% FLT3 inhibitors (i) (n=22), 37% IDH1/2i (n=19), 25% other regimens (n=69). Median survival was similar: Ven+HMA 8 mo, intensive chemotherapy 10 mo, FLT3i 6.5 mo, IDH1/2i 14 mo, other regimens 6 mo, but inferior with supportive care (2 mo; p<0.01). Conclusions: The current study identifies peripheral blasts ≥20%, complex karyotype, and wild-type IDH1 as predictors of inferior survival in ND-AML relapsed/refractory to front-line Ven+HMA and underlines that while no specific salvage therapy conferred superior outcomes, ASCT was indispensable for long-term survival.