Citations

BACKGROUND: It is unknown whether cardiac resynchronization therapy (CRT) improves systemic metabolomic profile by enhancing left ventricular function. The observational cohort study aimed to investigate the effect of CRT on left ventricular ejection fraction (LVEF) and circulating plasma metabolites in patients who had heart failure with reduced LVEF. METHODS: We prospectively screened patients with ischemic cardiomyopathy and nonischemic cardiomyopathy who received CRT with a defibrillator for LVEF ≤35% according to current guidelines. Clinical assessment included echocardiography and device interrogation. Blood samples for metabolomic analysis were collected before CRT and at 6-month follow-up. Plasma was subjected to gas chromatography-mass spectrometry and 1 H nuclear magnetic resonance-based metabolomic analysis. RESULTS: Totally 92 patients were enrolled, with a mean age of 67.3±11.3 years (37.0% female). LVEF was significantly improved from 28.9±7.6% at baseline to 36.0±11.3% at 6 months ( P <0.001) and to 40.1±12.6% at 12 months ( P <0.001). After CRT, 42 metabolite features were significantly decreased compared with the baseline. The ketone bodies, including 3-hydroxybutyrate ( P <0.001) and acetone ( P =0.01), were reduced. A branched-chain amino acid, isoleucine, was also decreased after CRT ( P =0.01). These metabolomic changes were mainly observed in the nonischemic cardiomyopathy group, while the metabolomic profile in the ischemic cardiomyopathy group was characterized by enhanced amino acid oxidation and elevated levels of lactate and pyruvate. The improvement in LVEF positively correlated with the ratio of changes in ketone bodies and isoleucine. CONCLUSIONS: CRT may modulate the systemic plasma metabolomic profile, which correlated with improvement in left ventricular function in patients with severe heart failure with reduced ejection fraction.

Abstract Background Synthetic control arms (SCAs) derived from historical trial data can complement randomized controlled trials (RCTs), particularly in oncology where feasibility, ethical, and cost constraints may limit conventional trial designs. However, their validity for overall survival (OS) remains uncertain. We evaluated the feasibility and limitations of constructing SCAs from the ARCAD metastatic colorectal cancer (mCRC) database across multiple treatment lines. Methods Seven landmark RCTs representing first-, second-, and third-line settings were selected. External control arms were constructed from ARCAD individual patient-level data using propensity score matching based on key clinical and biological variables from a validated ARCAD prognostic score, with adjustment for geographic region and time era when needed. A prespecified two-step benchmarking framework assessed: (1) control-arm OS reproducibility and (2) virtual trial comparisons between matched synthetic controls and original RCT experimental arms. Agreement was evaluated using hazard ratios (HRs) and Z-tests. Results A total of 28,022 patients met the inclusion criteria. ARCAD-derived SCAs were successfully constructed for all selected RCTs and closely reproduced control-arm OS. After matching, baseline characteristics were well balanced, with minimal differences between included and excluded patients. Virtual trials showed concordant treatment-effect estimates with the original RCTs, with a median absolute HR deviation of 0.05 and no significant differences by Z-tests (P&gt;.05). Survival outcomes were consistently reproduced across treatment lines. Conclusion ARCAD-derived SCAs reliably reproduced control-arm OS and benchmark treatment-effect estimates from landmark RCTs in mCRC. Despite limitations related to residual confounding and missing data, this framework supports benchmarking, trial design, and exploratory analyses when conventional control arms are impractical.

Abstract Purpose Traditional adverse event (AE) reporting in oncology trials focuses on the single worst CTCAE grade, which may underrepresent chronic or recurrent toxicity burden. We applied a longitudinal toxicity framework to compare toxicity profiles of chemotherapy with or without cetuximab in metastatic colorectal cancer. Patients and Methods We pooled two randomized first-line trials in the ARCAD database. AEs examined were diarrhea, rash, hand-foot syndrome (HFS), fatigue, anorexia, and mucositis. Outcomes included grade ≥3 AE, time to first occurrence of maximum grade, early onset (≤6 weeks), and AEL, a normalized measure of cumulative toxicity burden over treatment. Analyses were adjusted for chemotherapy backbone, ECOG performance status, sex, primary tumor location, dose reduction, and treatment duration. Results Compared with Chemotherapy alone (n = 564), Chemotherapy plus cetuximab (n = 738) was associated with higher grade ≥3 rash (21% vs 0.5%; adjusted odds ratio [OR] 49.89, 95% CI 15.8–157.4), higher rash AEL (0.257 vs 0.069; adjusted mean difference 0.22, 95% CI 0.21–0.23), and more frequent early-onset maximum rash (67% vs 34%; adjusted OR 4.28, 95% CI 2.72–6.74). Rash AEL remained higher with cetuximab within maximum-grade strata. HFS showed higher grade ≥3 risk and overall AEL with cetuximab, but no within-grade AEL difference, indicating higher overall HFS burden reflected grade distribution rather than within-grade chronicity. No consistent differences were observed for other AEs. Conclusions Incorporating onset timing and AEL distinguished persistent toxicity burden from isolated peak events. This framework may support comparative tolerability assessment when chronic toxicity burden is central to decision-making.

PURPOSE Adherence to operative standards and thorough documentation of surgical technique are critical, particularly in multidisciplinary clinical trials. We sought to evaluate variability in the performance and documentation of oncologically relevant aspects of technical surgery among patients enrolled in Alliance A021501, a phase 2 National Clinical Trials Network randomized clinical trial of neoadjuvant therapy for borderline resectable pancreatic adenocarcinoma. METHODS We reviewed the primary operative and pathology reports of all enrolled patients who underwent complete pancreatic resection. Operative techniques and pathologic end points with potential to influence recurrence and survival were evaluated. RESULTS Fifty-one of 126 study participants (40.5%) underwent complete pancreatectomy. The extent of lymphadenectomy was documented in 36 (70.6%) operative reports, and 5 (9.8%) reports outlined the specific lymph node stations removed. Periadventitial dissection of the superior mesenteric artery was described in 25 of 50 (50.0%) operative reports. Immediate histopathologic analysis of the hepatic duct and pancreatic parenchyma margins was documented in 29 of 50 (58.0%) and 32 of 49 (65.3%) reports, respectively, and presence or absence of residual disease following resection was documented in 9 of 51 (17.6%) reports. Specimen orientation was documented in 19 of 51 (37.3%) pathology reports, and 30 of 49 (61.2%) pathology reports stated the distance between the tumor and final SMA margin. CONCLUSION Even in this rigorously controlled, multicenter, randomized pancreatic cancer clinical trial, performance of key elements of technical surgery was inconsistent, and documentation was incomplete. Standardization of technique and documentation in clinical trials and within clinical practice should be addressed to improve quality assurance and trial interpretability.

ABSTRACT Aims Metabolic dysfunction‐associated steatotic liver disease (MASLD) is increasingly linked to cognitive decline, yet the hepatic factors associated with imaging‐derived neurovascular coupling (NVC) remain unclear. This study aimed to investigate whether liver stiffness or liver fat content was more closely associated with resting‐state CBF‐ReHo surrogate measures. Materials and Methods A total of 130 participants including 98 MASLD patients and 32 age‐ and education‐matched healthy controls (HCs) underwent clinical assessment, neuropsychological testing, and multi‐modal MRI. Liver stiffness and fat content were quantified using MR elastography (MRE) and MRI‐proton density fat fraction (PDFF). Imaging‐derived NVC was assessed using global cerebral blood flow (CBF)‐regional homogeneity (ReHo) coupling and voxel‐wise CBF/ReHo ratios, interpreted as resting‐state surrogates rather than direct stimulus‐evoked NVC. Multivariable regression and exploratory mediation analyses were employed. Results Compared to HCs and patients with lower liver stiffness (MASLD_low), those with higher liver stiffness (MASLD_high) showed reduced global CBF‐ReHo coupling and altered CBF/ReHo ratios, primarily localized to the bilateral superior temporal pole/superior temporal gyrus (TPOsup). In multivariable regression, liver stiffness remained independently associated with TPOsup CBF/ReHo ratios ( p < 0.001). Exploratory mediation analysis showed a statistically significant indirect association between hepatocellular injury markers and TPOsup CBF/ReHo ratios involving MRE‐derived liver stiffness (95% CI: 0.0795–0.2790). Conclusions Within this cohort and the observed PDFF range, MRE‐derived liver stiffness was more closely associated with imaging‐derived NVC surrogate measures than liver fat content in MASLD. These findings are hypothesis‐generating and require validation in longitudinal studies.

Abstract Purpose: Pancreatic ductal adenocarcinoma (PDAC) frequently recurs after neoadjuvant therapy (NT) and curative-intent resection. Although major pathologic response predicts favorable outcomes, most patients achieve only minor response with a heterogeneous recurrence risk. We asked whether the spatial organization of residual PDAC encodes clinically relevant biology beyond residual tumor burden. Experimental Design: In a retrospective cohort of 203 patients with resected PDAC treated with NT and restricted to minor pathologic response, routine hematoxylin and eosin (H&E) whole-slide images were segmented into cancer and stroma using an artificial intelligence–enabled pipeline. Spatial composition (patch density, edge density) and configuration (compactness/complexity, intermixing) were quantified and tested for associations with disease-free survival (DFS) using multivariable models adjusted for standard clinicopathologic factors. Results: Shorter DFS was associated with a fragmented, interface-rich tumor–stroma ecology featuring higher edge density and diversity and reduced homotypic aggregation, independent of clinicopathologic variables. Two spatial risk models were independently prognostic: (i) cancer mean shape index plus stromal shape index variability [adjusted hazard ratio (HR), 1.71; P = 0.003] and (ii) mean stromal patch area plus edge density (adjusted HR, 2.19; P = 0.002). Both models stratified outcomes in which pathologic response grading and residual cancer area did not. High-risk configurations were further associated with reduced intratumoral tumor-infiltrating lymphocyte (TIL) density and infiltration ratio, with relative TIL accumulation at the cancer periphery and within the stroma, consistent with an immune-excluded phenotype. Conclusions: Residual cancer–stroma topology quantified from standard H&E slides yields independent prognostic signals after NT in PDAC, provides a cellular immune correlate for spatial risk, and motivates prospective validation and spatially informed adjuvant strategies.

PURPOSE Social determinants of health (SDOH) shape cancer treatment access, adherence, and outcomes, yet their collection and use within National Clinical Trials Network (NCTN) studies remain poorly defined. This study examined how demographic and SDOH-related variables were historically collected and published to identify gaps that constrain the study of social context within NCTN trials. METHODS Participant-level data from completed phase III trials for gastrointestinal (GI) cancers conducted by the Alliance for Clinical Trials in Oncology (Alliance) or its legacy groups from 1999 to 2018 were pooled. Thirteen measures were assessed: four demographic and nine SDOH-related. The proportion of individual participants with data collected for each measure was evaluated. Data utilization was evaluated for all primary articles and via targeted review of related publications using the number either reporting subgroups or publishing analyses for each measure. RESULTS A total of 12,701 participants across 11 trials were included. All trials collected demographic measures (<2% of patients missing), insurance status (1% missing), and ZIP code (3% missing). Education level was collected in two trials (28% missing) with marital and employment status collected in one trial (41% missing for both). No trials collected data on other SDOH-related measures. Education level was the only SDOH-related measure reported in primary articles, and none reported analysis of SDOH-related measures. Of the 149 related publications, <2% reported or analyzed any SDOH-related measure. CONCLUSION Across Alliance and NCTN legacy group phase III trials for GI cancers, demographic variables have been consistently collected and frequently reported or analyzed, whereas SDOH-related measures are inconsistently collected and rarely published in the literature. These findings demonstrate a historical absence of routine SDOH data capture and utilization within NCTN trials.

Abstract Background The multicentre ALaCaRT and ACOSOG Z6051 randomized trials were unable to demonstrate non-inferiority of laparoscopic versus open surgery for rectal cancer with respect to a composite pathology metric indicating successful resection. Neither trial was individually powered to detect differences in long-term recurrence or survival. This planned meta-analysis determined long-term oncological outcomes of laparoscopic versus open proctectomy for rectal adenocarcinoma. Methods This prospective meta-analysis included individual patient data from patients with cT1–3 N0–2 M0 rectal adenocarcinoma enrolled in the ALaCaRT and ACOSOG Z6051 trials. Pathologically successful resection was defined as complete or near-complete total mesorectal excision, a clear circumferential resection margin (CRM; &gt; 1 mm), and a clear distal resection margin (&gt; 1 mm). The non-inferiority margin for disease-free survival (DFS) was an absolute difference of 5% at least 3 years after surgery. Results The combined data set included 935 patients (65.6% men, mean age 60.7 years, mean body mass index 26.7 kg/m2) randomized to open (457 patients) or laparoscopic (478 patients) proctectomy. Pathologically successful resection was lower in the laparoscopic than open group (85.1% versus 89.9%, respectively; pooled estimate 4.6% difference; 95% confidence interval (c.i.) −8.6% to −0.5%). The median follow-up was 60.2 (interquartile range 49.9–61.1) months. Three-year DFS was 75.2% (95% c.i. 71.1% to 79.2%) and 76.5% (95% c.i. 72.5% to 80.6%) for the laparoscopic and open groups, respectively (pooled estimate difference −1.5%; 95% c.i. −7.2% to 4.2%). Non-inferiority of laparoscopic surgery was not demonstrated because the lower one-sided 95% c.i. (−6.3% to 100%) crossed −5%. Three-year locoregional recurrence was higher in laparoscopic than open group (5.4% (95% c.i. 3.3% to 7.5%) versus 2.0% (95% c.i. 0.7% to 3.4%), respectively; pooled estimate 3.1% difference (95% c.i. 0.6% to 5.6%)). A clear CRM was the most significant and only pathological predictor of both DFS (P &lt; 0.0001) and overall survival (P &lt; 0.0001). Conclusion Laparoscopic proctectomy led to a lower rate of pathologically successful resection and a higher rate of locoregional recurrence at 3 years. The possibility of subsequent poorer DFS or overall survival rate requires further evaluation, because this analysis was not specifically powered for these endpoints.

Background: Colorectal neuroendocrine carcinomas (NECs), including small cell (SCNEC) and large cell (LCNEC) subtypes, are rare but aggressive malignancies with limited population-level data. Moreover, prior studies have limited stratification by histologic subtype and anatomic location, despite evidence of disease heterogeneity in colorectal malignancies. This study aimed to characterize the clinical characteristics, treatment patterns, and outcomes of colorectal NEC by histologic subtype and tumor location, and to compare them with neuroendocrine tumors (NETs) and adenocarcinomas (ACs). Methods: A retrospective cohort review was conducted utilizing the SEER database from 2000 to 2022 to identify patients with colorectal SCNEC, LCNEC, NET, and AC. Demographic, clinical, therapeutic and survival data were analyzed and compared using Kaplan–Meier methods, log-rank tests, and Cox proportional hazards regression. Results: A total of 790 SCNEC, 498 LCNEC, 31,200 NET, and 638,898 AC cases were identified. SCNEC and LCNEC were associated with advanced stage at diagnosis (66% and 55% stage IV, respectively) and inferior survival outcomes compared to NET and AC (median OS (mOS) of 7 and 8 months for SCNEC and LCNEC, respectively, p = 0.0002). Stratified by location, colonic SCNEC had the poorest survival (mOS 5 months), worse than rectal SCNEC (mOS 9 months); this pattern was not observed in LCNEC. Surgical resection was associated with improved OS in both NEC subtypes (HR range 0.25–0.56, all p < 0.012). Radiation therapy was associated with improved survival in NEC overall (SCNEC HR 0.58; LCNEC HR 0.71, both p < 0.05), with the observed benefit appearing greatest in rectal NEC. Demographic factors were associated with survival in NET and AC but had no significant impact in NEC. Conclusions: Colorectal SCNEC and LCNEC are highly aggressive malignancies with poor outcomes, with SCNEC demonstrating modestly inferior outcomes compared to LCNEC. This study demonstrates that both histologic subtype and anatomic site of disease are important determinants of prognosis and treatment response. This supports the concept that colorectal NEC represents a biologically heterogeneous disease, with colonic SCNEC showing the worst outcomes and rectal NEC associated with a potential enhanced response to radiation. These findings support the need for further prospective and molecular studies to better define treatment approaches and targeted therapies for these rare malignancies.

Abstract Objective . Phase gating is a critical technique to mitigate tumor motion during radiotherapy, particularly in spot-scanned particle therapy where internal motion can interfere with dynamic spot scanning patterns and, simultaneously, introducing substantial range uncertainties. However, the current commercial state of the art in real-time phase prediction is challenged by patient-specific breathing variability as well as detection and delivery system latencies. This leads to suboptimal efficiency, mis-timed radiation delivery and requires frequent manual intervention. This study aims to improve phase prediction accuracy using deep learning (DL)-based time series forecasting to enable more accurate dose delivery. Approach . Retrospective breathing waveforms from 69 proton therapy patients, sampled at 30 Hz, were labeled with inspiratory peaks and assigned subjective regularity scores (four levels). DL models with various architectures were trained using waveform amplitude to predict current or future breathing phases. Model performance was evaluated using mean squared error, phase binning accuracy, and timing deviation for radiation on/off events. Bayesian optimization was used for hyperparameter tuning. Results were compared between models and against a commercial algorithm currently in clinical use. Main Results . The curated waveform dataset included 165 242 s for training, 24 057 s for validation, and 30 322 s for testing, with an additional 40 604 s from separate patients for extended validation. The long short-term memory and temporal fusion transformer models significantly outperformed the commercial algorithm, improving phase prediction accuracy by nearly 20% and reducing timing deviations across all regularity levels. Significance . DL-based time series forecasting may substantially improve breathing phase prediction accuracy over current clinically available methods, offering a more precise and reliable approach to phase-gated radiation delivery.