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Abstract Background Standardizing beam modeling in the treatment planning system is challenging due to machine‐specific configuration variations. Because of the proton therapy system (PTS) complexity and continuous development, there is no vendor's representative (“golden”) beam data like in LINACs at this stage. Purpose The primary goal of this study is to create a PTS‐specific repository of source model parameters and beam commissioning data for scanning proton therapy treatment planning systems and establish a set of reference values with associated bands of variations for this data. Methods We conducted a survey of 31 PTSs at 27 proton therapy centers to gather beam commissioning source model parameters used in their treatment planning system, ensuring a diverse selection of PTSs from major vendors: Hitachi, IBA, Varian, and Mevion. For each proton therapy center, we collected (i) beam meterset calibration in protons per MU, (ii) in‐air spot size at isocenter in terms of standard deviation in x‐ (crossline, σ x ) and y‐ (inline, σ y ) directions, (iii) in‐air angular spread at isocenter in x‐direction (θ x ) and y‐direction (θ y ) and (iv) distal falloff. For each PTS, we plotted each parameter as a function of nominal energy and performed polynomial regression analysis with optimal model selection based on Akaike Information Criterion. We calculated intraclass correlation coefficients (ICC) to quantify inter‐PTS variability and generated uncertainty bands representing standard deviations across PTSs for each parameter. Additionally, we computed percentage deviations of each individual PTS from the overall multi‐vendor mean to identify systematic vendor‐specific patterns and outliers across the 31 total PTSs analyzed. Results Multi‐vendor beam parameter analysis across 31 PTSs revealed systematic vendor‐specific patterns in inter‐PTS consistency and energy dependencies. Beam meterset calibration demonstrated excellent inter‐PTS consistency across most vendors (ICC: Varian ProBeam ≈ 0, IBA Proteus ONE = 0.006, Mevion S250i with HYPERSCAN = 0.015), with IBA Proteus PLUS systems showing moderate variation (ICC = 0.156 for the dedicated nozzle, ICC = 0.248, for the universal nozzle). Spot size and angular spread variability were highly vendor‐dependent, ranging from excellent consistency in IBA Proteus ONE to substantial variation in IBA Proteus PLUS with the universal nozzle (angular spread ICC = 0.566). Distal falloff maintained excellent consistency across all vendors (ICC < 0.023), indicating reliable energy spread characteristics. Uncertainty band analysis revealed characteristic energy‐dependent patterns, with most systems showing larger uncertainties at lower energies for spot size and angular spread, while IBA Proteus PLUS with the universal nozzle exhibited the largest uncertainty bands overall. Percentage deviation analysis demonstrated vendor‐specific clustering patterns, with some systems showing systematic positive or negative deviations from the multi‐vendor mean. Conclusions The reference data provided in this work will help to cross‐check the beam model during treatment planning system commissioning. Furthermore, this information is useful for Monte Carlo applications and research, where beam characteristics are required to set up phase space parameters, thereby avoiding the need to model the entire PTS. Finally, the results of this study will have indispensable educational value by providing valuable insights into the characteristics and capabilities of different PTSs.

Abstract Background: Parenteral DNA methyltransferase inhibitors (DNMTi) such as azacitidine and decitabine (DEC), including an attenuated 3-day regimen, are recommended in the NCCN Guidelines for patients (pts) with lower-risk myelodysplastic syndromes (LR-MDS) with clinically significant cytopenias. However, parenteral administration requires frequent clinic visits, which imposes a substantial burden on pts, particularly those requiring long-term therapy. Oral DMTIs offer more flexible dosing and maintenance of pts' autonomy. Oral DEC-cedazuridine (DEC-C) is a fixed-dose combination tablet containing DEC (35 mg) and cedazuridine (100 mg). ASTX727-03 (NCT03502668) is a randomized, open-label, multicenter, phase 1/2 clinical trial evaluating safety, efficacy, and pharmacokinetics (PK) of various DEC-C doses and regimens in pts with LR-MDS. Phase 1 identified a 5-day regimen of DEC 10 mg/cedazuridine 100 mg as the optimized low-dose (LD) regimen. Phase 2 compares this LD regimen with the attenuated standard-dose (SD) regimen. Here, we report phase 2 results on efficacy, safety, PK, and pharmacodynamic (PD) data. Methods: Adults (aged ≥18 years) with International Prognostic Scoring System (IPSS) low-risk or Intermediate-1 MDS, ECOG PS 0−2, and ≥1 cytopenia or red blood cell (RBC) transfusion dependence were randomized 1:1 to receive oral DEC-C LD (10 mg x 5 days) or SD (35 mg x 3 days). The primary endpoint was hematologic response. Secondary endpoints included PK, PD (by LINE-1 demethylation), time to bone marrow blasts &gt;5%, leukemia-free survival (LFS), overall survival (OS), and safety. Results: As of October 31, 2024, 81 pts were treated (LD arm: n=40; SD arm: n=41) and completed a median of 8.8 months on treatment. At cutoff, 17 (42.5%) and 12 (28.6%) LD and SD pts, respectively, were still continuing the study; 9 (22.5%) and 6 (14.6%) pts respectively, had discontinued treatment due to hematopoietic stem cell transplant. Median age was 70 (LD) and 75 (SD) years; 75.0% (LD) and 68.3% (SD) had IPSS Int-1 risk MDS and 60.0% vs 41.5% had IPSS-Molecular Lower-Risk MDS (very low, low, or moderate-low). Low-risk prognostic scoring system risk distribution was similar: Category 1 (2.5% vs 4.9%), Category 2 (47.5% vs 46.3%), and Category 3 (50.0% vs 48.8%). After a median follow-up of 29.3 months, median OS was 23.9 months (95% confidence interval [CI]: 13.0, not estimable [NE]) in the LD arm vs 26.0 months (95% CI: 19.4, 28.5) in the SD arm. Median LFS was 23.8 months (95% CI: 13.0, NE) and 25.7 months (95% CI: 17.8, 26.5), respectively. Hematologic improvement per International Working Group 2006 criteria was achieved in 27.5% (LD) and 26.8% (SD) of pts. Among RBC transfusion–dependent pts, 52.4% (LD) and 37.5% (SD) achieved ≥56-day independence and 47.6% (LD) and 20.8% (SD) achieved ≥112-day independence. Pts received a median of 10 (LD) and 9 (SD) cycles. Delayed cycles occurred in 72.5% (LD) vs 82.9% (SD) of pts; dose reductions occurred in 40.0% (LD) and 46.3% (SD) of pts. Both treatment regimens caused a decrease in blood counts, reaching a nadir before recovering in each cycle. Neutropenia was more pronounced during early cycles and was more severe in the SD arm. Blood counts across all lineages remained stable or improved through ≥12 cycles with the LD arm, suggesting a more favorable safety and tolerability profile. Grade ≥3 adverse events (AEs) occurred in 85.0% and 90.2% of pts in the LD and SD arms, respectively; treatment discontinuation due to AEs occurred in 2.5% and 17.1% of pts, respectively. Most commonly reported treatment-emergent AEs were anemia (42.5% LD, 39.0% SD), fatigue (32.5% LD, 43.9% SD), and thrombocytopenia (37.5% LD, 39.0% SD). Three deaths occurred in the trial: 2 in the LD arm, which were both unrelated to study treatment, and 1 in the SD arm (Pseudomonal bacteremia in Cycle 1), which was treatment related. Total AUC0–24 was 199 ng*h/mL in the LD arm and 465 ng*h/mL in the SD arm; AUC for all cycles of the LD arm was approximately half of the SD arm. Maximal % LINE-1 demethylation rate was lower with LD than SD, but narrowed by Cycle 3. Conclusion: LD oral DEC-C demonstrated comparable clinical benefit to SD oral DEC-C, with improved safety and tolerability, including fewer dose modifications and less severe myelosuppression. These findings support LD DEC-C as a potential optimal regimen for pts with LR-MDS. Clinical trial registration: NCT03502668

Abstract Background: Clostridioidesdifficile infection (CDI) represents a significant infectious complication in both Chimeric Antigen Receptor(CAR) T-cell therapy and hematopoietic stem cell transplant (HSCT) recipients. We sought to investigate the incidence and outcomesof CDI among various CAR-T therapy products. Methods: This retrospective study used the 2022 National Inpatient Sample Database to identify and include adult patients with a primary diagnosis of four hematologic malignancies (Non-Hodgkin Lymphoma (NHL), Multiple Myeloma (MM), Acute Lymphoblastic Leukemia (ALL), and Acute Myeloid Leukemia (AML). In this cohort, we isolated patients who developed CDI using ICD-10 codes. Subgroup analysis was performed based on the type of CAR-T cell therapy and HSCT recipients. Multivariate regression analysis was performed to identify independent risk factors for CDI and mortality. A p-value &lt; 0.05 was considered statistically significant. Results: A total of 8,739 patients with CDI were identified among 507,559 patients with four hematologic malignancies, representing an overall incidence of 1.72%. Patients receiving CAR-T cell therapy (5% vs 2%, p&lt;0.05), bone marrow transplant (BMT, 3% vs 2%, p&lt;0.05), and those with a history of BMT (6% vs 2%, p&lt;0.05) were at significantly higher risk for CDI. Among individual CAR-T products, the incidence was: for CD19-directed CAR-T, Brexu-cel 5%, Axi-cel 6%, Tisa-cel 5%, and Liso-cel 3%; for BCMA-directed CAR-T, Ide-cel 4% and Cilta-cel 5%. There was no significant difference in CDI rates between these individual CAR-T products. Among CAR-T recipients by cancer type, CDI incidence was NHL 5%, MM 4%, ALL 7%, and AML 5% (p=0.79). Multivariate regression identified history of HSCT (OR 2.11, 95% CI 1.09–4.08), cytokine release syndrome (OR 1.7; 1.26–2.52), protein-energy malnutrition (OR 2.08; 1.83–2.36), graft versus host disease (OR 2.52; 2.02–3.15), and female sex (OR 1.23; 1.10–1.38) as significant independent risk factors for CDI (all p&lt;0.05). Overall mortality in those with CDI was 6% compared to 5% without, and mortality increased substantially to 36% in those requiring surgical intervention for CDI. Conclusion: In patients with hematologic malignancies, identifying risk factors and rates of CDI in CAR-T cell therapy is essential for prompt recognition and effective management. Future research on optimizing CDI screening protocol and prevention strategies can help reduce mortality and morbidity in this immunocompromised population.

PURPOSE The ECOG-ACRIN E3311 phase II trial demonstrated outstanding disease control (90.6% 54-month progression-free survival) after transoral surgery (TOS) with de-escalated, risk-based postoperative management in resectable human papillomavirus–associated oropharyngeal cancer. The goal of de-escalation was functional preservation. The objective of this work was to evaluate clinician-graded modified barium swallow (MBS) studies from E3311 over time and across arms for (1) aspiration and high-grade pharyngeal residue rates, (2) differences in swallow safety and efficiency, and (3) accuracy of site clinicians reporting against central MBS review. METHODS Eight hundred eighty-five MBS studies were performed on 314 patients from 50 of 59 sites at baseline, post-TOS, and 6 and 24 months postradiotherapy (RT). Swallow outcomes (aspiration, high-grade residue) were recorded by site clinicians. A subset of 414 MBS studies was centrally graded using penetration-aspiration scale scores and the Dynamic Imaging Grade of Swallowing Toxicity (DIGEST) scale. RESULTS Aspiration, residue, and dysphagia rates significantly increased from baseline to post-TOS ( P < .01) and then decreased modestly at 6 and 24 months. At 6 months, swallow outcomes favored the 50- versus 60-Gy arm, with significantly lower aspiration and high-grade dysphagia rates, but this difference was not maintained at 24 months. MBS results reported by site clinicians demonstrated substantial agreement with those assessed by the central laboratory (PABAK, 0.75-0.84; P < .01). CONCLUSION Swallowing worsened after TOS but improved by 6 and 24 months despite adjuvant therapy. De-escalated adjuvant RT at 50 Gy reduced acute aspiration. Site-reported MBS metrics strongly aligned with DIGEST, showing potential as an accessible metric in cooperative group settings.

Purpose of review Cardiac amyloidosis is an infiltrative cardiomyopathy with characteristic echocardiographic findings. Echocardiography is the initial imaging test to identify restrictive cardiomyopathies, and timely diagnosis is important for treatment and prognosis. This review outlines key echocardiographic “red flags,” structural and functional findings, and emerging diagnostic tools that enhance early recognition and monitoring of cardiac amyloidosis. Recent findings Classic echocardiographic red flags for cardiac amyloidosis include increased ventricular wall thickness, biatrial enlargement, pericardial effusion, and a granular myocardial appearance. Tissue Doppler imaging shows reduced mitral annular velocities, while advanced disease presents with restrictive filling patterns. Global longitudinal strain with apical sparing is a hallmark finding that distinguishes cardiac amyloidosis from other cardiomyopathies. Left atrial strain has been proposed as a prognostic marker for thromboembolism in cardiac amyloidosis. Evidence shows variability in strain measurements across different vendors, which is an important consideration when comparing results between institutions in both research and clinical practice. Echocardiography can be used in conjunction with multimodal imaging techniques in order to monitor disease progression. Summary Echocardiography is the initial diagnostic test of choice and several findings can suggest cardiac amyloidosis. Advances in echocardiographic techniques have enabled earlier detection of cardiac involvement and now play a central role in both diagnosis and ongoing treatment monitoring.

Importance Treatment for cognitive dysfunction due to postacute sequelae of long COVID (ie, symptoms of fatigue, malaise, weakness, confusion that persist beyond 12 weeks after an initial COVID infection) remains a significant unmet need. Objective To test evidence-based rehabilitation strategies for improving cognitive symptoms in persons with long COVID. Design, Setting, and Participants This was a 5-arm, multicenter, randomized clinical trial of 3 remotely delivered interventions conducted between August 17, 2023, and June 10, 2024. The study took place at 22 trial sites and included the screening of individuals with cognitive long COVID. Interventions Participants were randomized to 1 of 5 arms: adaptive computerized cognitive training (BrainHQ [Posit Science]), cognitive-behavioral rehabilitation involving both group and individual counseling sessions (PASC-Cognitive Recovery [PASC-CoRE]) paired with BrainHQ, and transcranial direct current stimulation (tDCS) paired with BrainHQ. Two comparator arms were included as follows: unstructured computer puzzles and games (active comparator) and sham tDCS paired with BrainHQ. The interventions occurred 5 times per week over 10 weeks. Main Outcomes and Measures Cognitive and behavioral in-person assessments were performed at baseline, midintervention, at the end of intervention, and 3 months after the end of the intervention. The primary outcome measure was the modified Everyday Cognition Scale 2 (ECog2) completed at the end of the intervention compared to the baseline visit based on participant self-report looking back over the prior 7 days. Results A total of 378 individuals were screened, from which there were 328 participants (median [IQR] age, 48.0 [37.0-58.0] years; 241 female [73.5%]; race: 15 Asian [4.6%], 47 Black [14.3%], and 235 White [71.6%]; ethnicity: 52 Hispanic [15.9%]). None of the 3 active interventions demonstrated benefits on the modified ECog2 in the intention-to-treat population by the end of the intervention period. The adjusted differences in mean change were 0.0 (95% CI, −0.2 to 0.2) for BrainHQ vs active comparator, 0.1 (95% CI, −0.1 to 0.3) for PASC-CoRE + BrainHQ vs active comparator, 0.0 (95% CI, −0.2 to 0.2) for tDCS-active + BrainHQ vs tDCS-sham + BrainHQ, and 0.1 (95% CI, −0.1 to 0.3) for PASC-CoRE + BrainHQ vs BrainHQ alone. Secondary participant-reported outcomes and neuropsychological tests showed no differential benefits for any treatment arm. All 5 arms demonstrated some improvements over time on the modified ECog2 and on secondary outcomes. There were no serious adverse events attributable to the interventions. Conclusions and Relevance This phase 2 randomized clinical trial failed to demonstrate differential benefits for online cognitive training, a structured cognitive rehabilitation program, and tDCS for cognitive long COVID. Trial Registration ClinicalTrials.gov Identifier: NCT05965739 .

Importance Advances in Alzheimer disease (AD) have shifted research focus to earlier disease stages, necessitating more scalable approaches to identify cognitively unimpaired individuals with amyloid β (Aβ) pathology. Objective To assess the utility of plasma phosphorylated tau 217 (p-tau217) for classifying Aβ status in cognitively unimpaired individuals, both as a stand-alone test and in a 2-step approach where positive plasma results were confirmed using a second modality (Aβ positron emission tomography [PET] or cerebrospinal fluid [CSF]). Design, Setting, and Participants This cross-sectional cohort study used data collected between June 2009 and March 2024. We included 2916 cognitively unimpaired participants from 12 international independent observational cohorts in the US, Europe, Australia, and Canada with available plasma p-tau217 levels and CSF or PET Aβ biomarkers. Performance comparisons between mass spectrometry and immunoassay-based p-tau217 measurements were also performed (n = 964). Exposures Plasma p-tau217 levels measured by immunoassay. Main Outcome and Measures Aβ status, determined by CSF or Aβ PET biomarkers. Results Participants had a mean (SD) age of 66.9 (9.9) years; 971 (33.3%) were Aβ positive by either CSF or PET, 1667 (57.2%) were women, and 1108 (38.1%) carried at least 1 APOE ε4 allele. As a stand-alone test, plasma p-tau217 achieved a positive predictive value (PPV) of 79% (95% CI, 74-84) and an overall accuracy of 81% (95% CI, 80-82). In a 2-step workflow, the PPV and accuracy significantly increased to 91% (95% CI, 86-95). While this approach required screening of 677 individuals with plasma p-tau217 to identify 100 Aβ-positive individuals, compared to 536 participants when using PET alone, it reduced the need for PET testing to 124. Immunoassays demonstrated comparable PPVs to mass spectrometry (80% [95% CI, 74-86] vs 85% [95% CI, 81-90]; P = .12) but significantly lower overall accuracy (82% [95% CI, 79-84]% vs 88 [95% CI, 86-90]; P &amp;lt; .001) and true Aβ-positive detection rate (49% [95% CI, 43-55] vs 69% [95% CI, 64-75]; P &amp;lt; .001). Conclusions and Relevance The findings highlight the potential of plasma p-tau217 as a stand-alone test—or when used in a sequential 2-step approach alongside PET or CSF testing—as a cost-effective, scalable, and minimally burdensome strategy for identifying preclinical AD. Tailored screening workflows that incorporate p-tau217 can improve efficiency in participant selection for preclinical AD trials and, in the future, help guide access to disease-modifying treatments.

Abstract Introduction There is convincing evidence that overall adiposity increases the risks of several cancers. Whether the distribution of adiposity plays a similar role is unclear. Methods We used 2-sample Mendelian randomization (MR) to examine causal relationships of 5 adiposity distribution traits (abdominal subcutaneous adipose tissue (ASAT); visceral adipose tissue (VAT); gluteofemoral adipose tissue (GFAT); liver fat; and pancreas fat) with the risks of 12 obesity-related cancers (endometrial, ovarian, breast, colorectal, pancreas, multiple myeloma, liver, kidney (renal cell), thyroid, gallbladder, esophageal adenocarcinoma, and meningioma). Results Sample size across all genome-wide association studies (GWAS) ranged from 8407 to 728 896 (median: 57 249). We found evidence that higher genetically predicted ASAT increased the risks of endometrial cancer, liver cancer, and esophageal adenocarcinoma (odds ratios (OR) and 95% confidence intervals (CI) per standard deviation (SD) higher ASAT = 1.79 (1.18 to 2.71), 3.83 (1.39 to 10.53), and 2.34 (1.15 to 4.78), respectively). Conversely, we found evidence that higher genetically predicted GFAT decreased the risks of breast cancer and meningioma (ORs and 95% CIs per SD higher genetically predicted GFAT = 0.77 (0.62 to 0.97) and 0.53 (0.32 to 0.90), respectively). We also found evidence for an effect of higher genetically predicted VAT and liver fat on increased liver cancer risk (ORs and 95% CIs per SD higher genetically predicted adiposity trait = 4.29 (1.41 to 13.07) and 4.09 (2.29 to 7.28), respectively). Discussion Our analyses provide novel insights into the relationship between adiposity distribution and cancer risk. These insights highlight the potential importance of adipose tissue distribution alongside maintaining a healthy weight for cancer prevention.

Introduction/Objectives: Little is known about the prevalence of patient-reported social risk factors and the use of the HOUSES Index, a simple, reliable method of assessing socioeconomic status (SES) based on publicly available housing data, in a predominantly rural, primary care population. Methods: We conducted a cross-sectional analysis of adult patients paneled to family medicine clinicians in a US Midwest health system as of December 31, 2022. Patients’ listed address determined HOUSES Index as quartile rank (Q1 lowest SES) and rural/urban status. Social risk data including housing, food, transportation, finances, and violence were collected from health record questionnaires. A mixed effect model was used to assess associations between social risk, HOUSES Index, and rurality. Results: Of the 352 355 patients included, rural patients were more likely than urban patients to report all social risk factors and had lower SES as measured by HOUSES quartiles. In the mixed effects analysis, HOUSES quartile was independently predictive of reporting an at-risk social risk factor (Q1 vs Q4 OR = 2.27, 95% CI = 2.19-2.37), but rurality was not (OR = 1.02, 95% CI = 0.97-1.07) after adjusting for HOUSES. Conclusions: The increased prevalence of social risk factors among rural residents is largely explained by individual SES measured by HOUSES Index.

This retrospective propensity-matched cohort study assessed the association between sodium-glucose co-transporter-2 inhibitor (SGLT2i) use and cardiovascular outcomes in patients with acute myocardial infarction (AMI) without a history of heart failure. Using the TriNetX U.S. Collaborative Network, we identified 1440 matched patients (720 SGLT2i+ vs 720 SGLT2i−) with preserved ejection fraction and no prior heart failure. Nearly 90% of patients had diabetes. The primary outcome was major adverse cardiovascular events (MACE), defined as a composite of MI, stroke, heart failure, and all-cause mortality. At 1 year, MACE occurred in 17.4% of SGLT2i+ versus 22.0% of SGLT2i− patients (odds ratio [OR] 0.746, 95% CI 0.574-0.969; P = .028), and all-cause mortality occurred in 3.1% versus 7.6%, respectively (OR 0.389, 95% CI 0.234-0.645; P < .001). SGLT2i use was also associated with lower risks of major bleeding. Findings were consistent over long-term follow-up. While the observed associations suggest potential cardioprotective effects of SGLT2i post-MI in patients without heart failure, residual confounding cannot be excluded. The observed reduction in bleeding events is novel and warrants further investigation in prospective studies.