Citations

Abstract Therapeutic resistance limits the efficacy of radiation therapy in many tumors and provides a compelling rationale to develop novel treatments to enhance radiation sensitivity. DNA-dependent protein kinase (DNA-PK) is a major mediator of DNA repair following radiation, and DNA-PK inhibitors are effective radiosensitizers. WNC0901 is a potent DNA-PK inhibitor in both a cell-free kinase assay (IC50 = 0.073 nM) and a cell-based assay (IC50 = 76 nM). WNC0901 has a 30-fold specificity for DNA-PK relative to other PI3K-related kinases. In a broader kinome screen (363 kinases), 1 μM WNC0901 resulted in >25% inhibition of only five other kinases. There is robust inhibition of radiation-induced DNA-PK autophosphorylation (Ser-2056), as analyzed by Western blotting, with maximal effect at 300 nM WNC0901 in A549 (lung carcinoma), U2OS (osteosarcoma), and HT29 (colorectal) cells. The efficacy of WNC0901 as a radiosensitizer was evaluated in clonogenic assays across these same three radioresistant tumor models. Following treatment with graded concentrations of WNC0901 (0-1000 nM) combined with 2.5 Gy radiation, maximal effects were observed at a 300 nM concentration in A549 (88-fold reduction in relative clonogenic survival compared to RT alone, p<0.001), U2OS (5.8-fold decrease, p=0.002), and HT29 (59-fold decrease, p=0.008) In a full radiation clonogenic, the sensitizer enhancement ratio at 10% survival (SER10) was 3.8 (A549), 2.3 (U2OS), and 1.8 (HT29). In vitro metabolism studies have identified demethylated WNC0901 (WNC0901-M) as a major metabolite. Similar to the parent drug, WNC0901-M is a potent DNA-PK inhibitor with maximal radiosensitizing effects of the metabolite observed at 300nM with SER10 of 2.4 (A549), 1.9 (U2OS), and 1.8 (HT29). The in vivo efficacy of 50 mg/kg WNC0901 combined with 8 Gy was evaluated and compared to another DNA-PK inhibitor, 50 mg/kg peposertib, in A549 tumor heterotopic xenografts. Compared to placebo (median time to endpoint 63 days) or RT alone (median 72 days), the combination of WNC0901 and RT significantly delayed tumor regrowth (median 169 days; p=0.002 compared to RT). Interestingly, peposertib + RT was ineffective (median 83 days; p=0.332 compared to RT). In a second study, similarly robust sensitizing effects of WNC0901 was observed in HT29 xenografts (placebo - median 45 days; RT - median 75 days; RT + WNC0901 - median >110 days; p=.03 relative to RT). Together, these findings demonstrate the robust radiosensitizing effects of WNC0901 in radioresistant tumors and provide a rationale for continued development of this drug. Citation Format: Jessica L. Abraham, Ann C. Mladek, Sonia Jain, Shiv K. Gupta, Paul A. Decker, Matthew L. Kosel, Katrina K. Bakken, Brett L. Carlson, Lauren L. Ott, Danielle M. Burgenske, Jeanette E. Eckel-Passow, Wei Zhong, Jann N. Sarkaria. WNC0901 is a novel DNA-PK inhibitor and potent radiosensitizer of otherwise radioresistant solid tumors [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 6608.

ABSTRACT Recent advances in the diagnosis and management of reflux disease were the central focus of the inaugural Gatherings in Esophagology (GiE), which convened experts across gastroenterology, surgery, otolaryngology, pulmonology, and basic research. The sessions highlighted innovations in reflux monitoring—including high‐resolution manometry, wireless pH monitoring, and novel salivary biomarkers—while critically evaluating their diagnostic accuracy and clinical utility. Presentations explored the limitations of traditional proton‐pump inhibitor therapy, the emergence of potassium‐competitive acid blockers as a new class of acid suppressants, and the evolving role of adjunctive treatments such as mucosal protectants, reflux reducers, and neuromodulators for refractory symptoms. The discourse extended to advanced interventional procedures, including transoral incisionless fundoplication, magnetic sphincter augmentation, and the RefluxStop device, with discussion of patient selection, efficacy, and complication management. Discussants emphasized the pathophysiology and management of extraesophageal manifestations of reflux, the interplay between reflux and pulmonary disease, and the diagnostic challenges in pediatric populations. The meeting also addressed the integration of behavioral therapies, the role of the microbiome, and the application of artificial intelligence in reflux diagnostics. Collectively, these insights underscore a shift toward precision medicine in reflux disease, emphasizing individualized diagnostic strategies and tailored therapeutic approaches to improve patient outcomes.

Abstract Introduction Hypertrophic cardiomyopathy (HCM) is a genetic heart disease inherited in an autosomal dominant pattern. Studies have shown that novel first-in-class targeted myosin inhibitor-Mavacamten significantly improves LV diastolic function, systolic anterior motion measures, exercise capacity and left ventricular outflow (LVOT) obstruction in patients with obstructive hypertrophic cardiomyopathy (oHCM). HCM primarily affects the left side of the heart, making pulmonary hypertension (PH) a common complication. However, the clinical significance and prognostic impact of PH in HCM are not yet fully understood. Purpose This study evaluated the effects of Mavacamten on echo-Doppler-derived pulmonary artery systolic pressure (PASP) in oHCM patients. Methods 70 Adult patients (53% male, mean age 60±12 years) meeting the imaging criteria for oHCM and receiving Mavacamten treatment were identified. Baseline clinical and imaging characteristics were analyzed. The impact of Mavacamten on echo-Doppler-derived PASP was assessed. Clinical and echocardiographic follow-ups were conducted at a median of 12 weeks (IQR: 7–24 weeks) and 74 weeks (IQR: 38–97 weeks) after the baseline echocardiographic assessment. Results The mean PASP of the cohort was 32 ± 10 mmHg, with 39% of patients having PASP >30 mmHg. When stratified by baseline PASP (using a 30-mmHg cut-off ), patients with elevated PASP were older and had more pronounced diastolic dysfunction. At the first follow-up, PASP decreased from 33 ± 10 mmHg to 29 ± 6 mmHg, and at the second follow-up, it further decreased to 27 ± 9 mmHg (p < 0.001). PASP decrease was more pronounced in patients with elevated PASP at baseline (Figures 1, 2). When analyzing changes in echocardiographic parameters over time according to baseline PASP levels, the group with elevated PASP at baseline demonstrated more pronounced changes. While LVOT gradient changed significantly from baseline to both follow-ups in both the elevated and normal PASP groups, certain parameters of diastolic dysfunctions including the E/e' ratio, showed significant changes only in the elevated PASP group (Figure 1). We observed that in univariate regression analysis, age was significantly associated with elevated baseline PASP along with MR and echocardiographic parameters indicative of diastolic dysfunction such as left atrial volume index (LAVI), TR velocity, and E/e. In multivariate analysis TR velocity remained significantly associated with PASP (β=23.05, 95% CI 3.17 to 167.8; p=0.002), highlighting a significant relationship between diastolic dysfunction parameters and PASP. Conclusion This study demonstrates that Mavacamten therapy significantly improves echocardiographic parameters and reduces PASP in patients with oHCM, with particularly pronounced benefits in those with elevated baseline PASP. These findings highlight the potential of Mavacamten as a targeted therapy for addressing both LVOT obstruction and associated PH in oHCM.Changes of echocardiographic parameters PASP over time in oHCM

Introduction: Cerebral amyloid angiopathy (CAA) is a progressive cerebrovascular disease caused by amyloid-beta (Aβ) deposition in cerebral vasculature. While CAA is a recognized cause of intracerebral hemorrhage (ICH) and cognitive decline, emerging evidence suggests that seizures are among a broader array of CAA clinical manifestations. However, the risk of seizures and status epilepticus in CAA remains poorly characterized. This study aimed to estimate incidence of seizures and status epilepticus in CAA using real-world data. Methods: A retrospective, longitudinal study was conducted using a nationally representative sample of administrative claims from US Medicare and commercial insurance beneficiaries (2017–2024). Patients with CAA (aged > 50 years with > 1 physician encounter with a validated ICD-10 code (I68.0)) were matched 1:4 to age- and sex-matched controls. The primary outcome was occurrence of seizure, ascertained using validated ICD-10 codes during acute care; the secondary outcome was hospitalization for status epilepticus. Follow-up continued until the end of enrollment or death. Descriptive statistics summarized patient characteristics and Poisson regression estimated incidence rates with 95% CIs. Cox proportional hazards regression assessed associations between CAA and outcomes of interest vs controls, adjusted for chronic kidney disease, liver disease, prior ICH, and seizure history. Results: We included 7294 patients with CAA and 29176 controls (median age: 77 years; 53.7% women; median follow-up: 29.4 months). Patients with CAA had higher rates of prior ICH (32.4% vs 0.5%) and prior seizure (18.7% vs 1.8%) than controls. The incidence rate of seizures was higher in patients with CAA than controls: 8.1 per 100 person-years (PY; 95% CI: 7.6–8.6) vs 0.4 per 100 PY (95% CI: 0.4–0.5). In the CAA cohort, seizure incidence rate was higher for those with prior ICH than those with no ICH history: 13.6 per 100 PY (95% CI: 12.5–14.8) vs 5.7 per 100 PY (95% CI: 5.2–6.3). Status epilepticus rates were higher in patients with CAA than controls: 0.7 per 100 PY (95% CI: 0.6–0.9) vs 0.03 per 100 PY (95% CI: 0.02–0.04). Adjusted models showed that CAA was associated with higher risk of seizures (HR: 6.7, 95% CI: 5.8–7.7) and status epilepticus (HR: 8.1, 95% CI: 4.8–13.7) than controls (Table 1). Conclusions: Patients with CAA have an increased risk of seizures and status epilepticus. These findings broaden the possible clinical spectrum of CAA.

Background: Generative AI and synthetic media have enabled realistic human Embodied Conversational Agents (ECAs) or avatars. A subset of this technology replicates faces and voices to create realistic likenesses. When combined with avatars, these methods enable the creation of “digital twins” of physicians, offering patients scalable, 24/7 clinical communication outside the immediate clinical environment. This study evaluated surgical patient perceptions of an AI-generated surgeon avatar for postoperative education. Methods: We conducted a pilot feasibility study with 30 plastic surgery patients at Mayo Clinic, USA (July–August 2025). A bespoke interactive surgeon avatar was developed in Python using the HeyGen IV model to reproduce the surgeon’s likeness. Patients interacted with the avatar through natural voice queries, which were mapped to predetermined, pre-recorded video responses covering ten common postoperative topics. Patient perceptions were assessed using validated scales of usability, engagement, trust, eeriness, and realism, supplemented by qualitative feedback. Results: The avatar system reliably answered 297 of 300 patient queries (99%). Usability was excellent (mean System Usability Scale score = 87.7 ± 11.5) and engagement high (mean 4.27 ± 0.23). Trust was the highest-rated domain, with all participants (100%) finding the avatar trustworthy and its information believable. Eeriness was minimal (mean = 1.57 ± 0.48), and 96.7% found the avatar visually pleasing. Most participants (86.6%) recognized the avatar as their surgeon, although many still identified it as artificial; voice resemblance was less convincing (70%). Interestingly, participants with prior exposure to deepfakes demonstrated consistently higher acceptance, rating usability, trust, and engagement 5–10% higher than those without prior exposure. Qualitative feedback highlighted clarity, efficiency, and convenience, while noting limitations in realism and conversational scope. Conclusions: The AI-generated physician avatar achieved high patient acceptance without triggering uncanny valley effects. Transparency about the synthetic nature of the technology enhanced, rather than diminished, trust. Familiarity with the physician and institutional credibility likely played a key role in the high trust scores observed. When implemented transparently and with appropriate safeguards, synthetic physician avatars may offer a scalable solution for postoperative education while preserving trust in clinical relationships.

Abstract Introduction: The Duffy null variant (genotype or phenotype) is associated with lower circulating absolute neutrophil counts (ANC) without increased risk for infection. It is found in ~66% of people identifying as Black or African American vs <1% of people of Asian or European ancestry. Many ANC reference intervals (RI) are not representative of the Duffy null population. There are no adult Duffy null WBC RI and no pediatric Duffy null ANC or WBC RI. Thus, we aimed to assess Duffy null ANC and WBC distributions as well as develop WBC and ANC RI for adults and pediatrics. Methods: Twenty-three sites across the United States collected samples with all sites excluding participants with conditions or medications that could impact ANC or WBC. Only Duffy null participants were included. Sex, race, ethnicity, age, sample collection type, practice setting, Duffy testing method, ANC, and WBC were recorded. The non-parametric method for determining lower limit of normal (LLN), upper limit of normal (ULN), and 90% confidence intervals (CI) around the limits was performed according to the Clinical and Laboratory Standards Institute guidelines. Specific ULN and LLN are not reported as these are preliminary data. The Mann-Whitney U test was used to compare sex and prior data; differences by age groups were assessed with Kruskal-Wallis test. Results: 316 participants 18+ years-old (y/o) were assessed of whom 62.3% (n=197) are female, 97.5% (n=308) identified as Black or African American, and 94.9% (n=300) identified as non-Hispanic. Median age was 47 y/o (IQR: 32-60.5). Median ANC was 2600/uL (IQR: 1860-3530; range: 400-7400); 28.6% (n=90) of participants had ANC <2000/uL, 13.6% (n=43) had ANC <1500/uL, and 2.5% (n=8) had <1000/uL. The 90% CI around the LLN was 810-1070/uL and 5570-7130/uL around the ULN. Consistent with prior data, there was a difference in median ANC by sex (male: 2400/uL; female: 2710/uL; p=0.02). There was no significant difference between this ANC data and previously published Duffy null ANC data (p=0.28). Median WBC was 5.4x109/L (IQR: 4.4-6.5; range: 2.10-11.64) with 4.1% (n=13) of participants with WBC <3.0x109/L. The 90% CI around the LLN is 3.68-4.30x109/L and 11.02-12.97x109/L around the ULN. 515 participants between 0-17 y/o were assessed with 51.8% (n=267) females, 94.8% (n=488) identified as Black or African American, and 94.0% (n=484) identified as non-Hispanic. Among pediatric participants, 56.8% (n=291) had ANC <2000/uL, 38.7% (n=198) had ANC <1500/uL, and 14.4% (n=74) had ANC <1000/uL. For those <1 y/o (n=29), median ANC was 950/uL (IQR: 840-1360; range: 111-3910). There are currently too few samples to predict ULN and LLN. Median WBC was 8.85x109/L (IQR: 7.03-10.16; range: 4.17-13.53). For those 1-5 y/o (n=143), median ANC was 1735/uL (IQR: 1100-2550; range: 207-5810) with a 90% CI around the LLN of 207-820/uL and 4020-5810/uL around the ULN. Median WBC was 6.72x109/L (IQR: 5.64-8.25; range: 3.68-12.97). For those 6-11 y/o (n=128), median ANC was 1590/uL (IQR: 1090-2470; range: 420-5490) with a 90% CI around the LLN of 420-910/uL and 4340-5490/uL around the ULN. Median WBC was 5.42x109/L (IQR: 4.45-6.70; range: 2.80-10.50). For those 12-17 y/o (n=215), median ANC was 2190/uL (IQR: 1460-2930; range: 204-5850) with a 90% CI around the LLN of 540-930/uL and 4350-5510/uL around the ULN. Median WBC was 5.06x109/L (IQR: 4.26-6.20; range of 2.04-9.91). There is a significant difference in ANC by age category (p<0.0001). Conclusion: This is the first report of healthy pediatric Duffy null ANC and WBC data and the first large-scale verification of adult Duffy null ANC and WBC data. Final RI are expected in September 2025. Among adults with the Duffy null phenotype, ANC LLN are likely between 810-1070/uL. Pediatric ANC LLN are likely as low as 207-820/uL (1-5 y/o), 420-910/uL (6-11 y/o), and 540-930/uL (12-17 y/o). These findings redefine “normal” as a significant proportion of healthy participants have ANC or WBC below current RI or below thresholds typically defined as disease. Limitations include heterogeneous sample populations and collection methods. Future analyses will assess differences between collection sites or methods. Ultimately, this work lays the foundation for a more scientifically sound and equitable approach to medical care by ensuring that RI accurately reflects health for the entire community. Healthcare systems are strongly encouraged to adopt Duffy null-specific ANC and WBC RI.

Abstract Introduction: Brexucabtagene autoleucel (Brexu-cel) is a CD19-targeted chimeric antigen receptor (CAR-)T cell therapy approved for treatment of relapsed/refractory (r/r) B-ALL. Brexu-cel's approval was founded on data from the ZUMA-3 trial, in which 78 patients (pts) were treated at the pivotal dose of 1x10e6 CAR-T cells/kg, resulting in a complete remission (CR) rate of 73%. Three-year follow-up from ZUMA-3 demonstrated median relapse-free and overall survival (RFS/OS) of 11.6 and 25.6 months (mos) for all treated pts. Amongst responders, the median OS was 60.4 mos for those who did not receive a subsequent allogeneic hematopoietic cell transplant (HCT) (n=43), but only 36.3 months for those who did (n=14). This has led some to conclude that HCT may not be beneficial following brexu-cel therapy for r/r B-ALL; however, it must be noted that 29 (37%) of the pts treated on ZUMA-3 received brexu-cel for post-HCT relapse. T cells collected from individuals who relapse in the post-HCT setting are largely of donor origin, making the CAR-T product comparable to a genetically modified donor lymphocyte infusion (DLI). The immunology at play in this scenario may be different from that in which CAR-T cells are of truly autologous origin. Methods: The Real-World Outcomes Collaborative for CAR-T in ALL (ROCCA) consortium database includes pt characteristics and outcomes of brexu-cel therapy given as standard-of-care across 41 US institutions. We identified pts who achieved an MRD negative (neg) CR by either flow cytometry (minimum sensitivity 10e-4) or NGS following brexu-cel for r/r Ph neg B-ALL and categorized them into three groups with regard to use of HCT: Never HCT, Pre-CAR HCT, or Post-CAR HCT. Pts who received second HCT following brexu-cel for post-HCT relapse (n=9) were excluded. Pt/disease characteristics, RFS, and OS were assessed for each group, landmarked at 73 days after brexu-cel infusion (the median time to consolidative allogeneic HCT). Results: In the ROCCA database we identified 165 pts who achieved MRD neg CR following brexu-cel, amongst whom 69 never underwent HCT, 49 were transplanted pre-CAR (ie, brexu-cel served as a genetically modified DLI), and 47 underwent post-CAR consolidative HCT while in CR. The median follow-up is 373 days. The median age was higher in the Never HCT group (49, range 19-83) in comparison with the Pre-CAR HCT (40, 24-72) and Post-CAR HCT (34, 18-70) groups. Thirty-five percent were >60yo in the Never HCT group vs 20% in the Pre-CAR HCT and 9% in the Post-CAR HCT groups. Ph-like disease was present in 38%, 29%, and 43% of the Never HCT, Pre-CAR HCT, and Post-CAR HCT groups, respectively (p=0.35). No significant differences were observed in pre-apheresis bone marrow blasts, presence of CNS disease at apheresis, prior blinatumomab or inotuzumab treatment, or use of bridging therapy across the groups, though there was a higher prevalence of non-CNS extramedullary disease in the Pre- and Post-CAR HCT groups (32, 39%) vs the Never HCT group (13%) (p=0.004). A minority of pts in all groups were deemed to be in MRD neg CR prior to apheresis (6-20%). Median RFS was 260 days in the Never HCT group and not reached in the Pre- and Post-CAR HCT groups (p=0.002), with respective 1-yr RFS of 38%, 64%, and 67%. Median OS was not reached in any group and was similar for all at 1-yr at 68-79% (p=0.13). Characteristics of those in the Never HCT group who were least likely to relapse included age >60 (OR 0.22, CI 0.07-0.73 vs age 18-39, p=0.024) and those with non-Ph-like B-ALL (OR 0.33, CI 0.12-0.94, vs Ph-like, p=0.037) in univariate analyses. Conclusions: Real-world data regarding outcomes following brexu-cel therapy allow evaluation of the role for consolidative allogeneic HCT, which remains one of the most important unresolved questions in the use of CAR-T therapy for r/r B-ALL. This analysis demonstrates that a first consolidative HCT after achieving MRD neg CR with brexu-cel is associated with a significant decrease in relapse. Additionally, use of brexu-cel for post-HCT relapse is also associated with a significantly lower risk of relapse compared with those who never received an allogeneic HCT. With the current duration of followup, OS is not significantly different across the three groups. These data suggest there is a benefit for relapse-free survival in pts receiving an allogeneic HCT at some point in the course of treatment for r/r Ph neg B-ALL.

Purpose: Literature on early mobilization and exercise training in patients recovering from acute heart failure (AHF) is promising. However, there lacks uniformity in the time of initiation, exercise prescription, safety criteria, and termination criteria. Thus, the aim was to develop a mobilization algorithm for patients recovering from AHF. Methods: A modified web-based Delphi process was undertaken involving 15 panelists from across the globe. In Round 1, new variables, modifications to suggested variables, and agreement-disagreement within the panelists were obtained. In Round 2, agreement on a 5-point Likert scale was obtained. In Round 3, the algorithm was compiled, and excluded statements were discussed via web-based calls. The new variables were grouped into themes via an inductive process. The level of agreement and rating for each statement were analyzed using descriptive statistics, including frequency and percentages. We used Kappa statistics to examine the level of agreement between the panelists for each criterion. The consensus criterion was defined a priori as statements with a mean rating of ≥4 on the 5-point Likert scale by ≥70% of the panelists and Kendall’s coefficient of concordance ( W ) of ≥0.3 between panelists. Results: From Round 1, 54 new variables were obtained. More than two-thirds (118/170, 69%) of statements reached consensus and reported a fair level of agreement between panelists ( W ≥ 0.3). The final algorithm with all its criteria received a 100% (13/13) consensus. Conclusion: Physician-referral criteria, physiotherapy assessment process, exercise prescription, safety criteria, and termination criteria were formulated for early mobilization and exercise training for patients recovering from AHF.

Abstract BACKGROUND Mirdametinib is the first FDA-approved MEK1/2 inhibitor for both adults and children ≥2 years with NF1 who have symptomatic PN not amenable to complete resection. We report results from the phase 2b ReNeu trial (NCT03962543), including the LTFU. METHODS In ReNeu, mirdametinib was administered in 3-weeks-on/1-week-off 28-day cycles. Following the 24-cycle treatment phase, patients could continue mirdametinib in an optional LTFU. We report results through June 12, 2024, approximately 9 months from the previous data cutoff. RESULTS Fifty-eight adults and 56 children received mirdametinib. Median (range) duration of treatment was 21.8 (0.4, 54.4) months in adults and 25.4 (1.6, 48.5) months in children. Among LTFU-eligible patients, 26/31 (84%) adults and 32/37 (86%) children entered LTFU. Confirmed objective response rate (ORR, treatment+LTFU phases) was 47% (27/58; 95%CI, 33%, 60%) in adults and 55% (31/56; 95%CI, 42%, 69%) in children. Among confirmed responders, 18 adults and 19 children achieved a deep response (best target PN volume reduction from baseline of >50%). Median (range) best percentage change from baseline in target PN volume was –41% (–90%, 13%) in adults and –43% (–98%, 48%) in children. Median duration of response (DoR) was not reached for either age cohort. Treatment-related adverse events (TRAEs) in ≥25% of patients were dermatitis acneiform, diarrhea, nausea, and vomiting in adults; and diarrhea, dermatitis acneiform, and paronychia in children. Grade ≥3 TRAEs occurred in 17% of adults and 25% of children. Dose interruptions, dose reductions, and discontinuations due to TRAEs occurred in 9%, 17%, and 22%, respectively, of adults, and 14%, 14%, and 9%, respectively, of children. CONCLUSIONS Improved confirmed ORR was observed with longer duration of mirdametinib, with additional deep responses achieved in both adults and children. Mirdametinib continued to be well tolerated with a manageable safety profile and no new safety signals in the LTFU.