Citations

Background: Doxorubicin (DOX) is an effective chemotherapy but limited by severe cardiotoxicity. Chemokine receptors CXCR4 and CXCR7 are involved in regulating cardiac survival, inflammation, and fibrosis, yet their specific roles in DOX-induced cardiotoxicity (DICT) remain unclear. Objective: We investigated the cardioprotective effects of TC14012, a dual-target CXCR4 antagonist and CXCR7 agonist, against DICT. Methods: Male C57BL/6J mice received chronic or acute DOX administration with twice-weekly TC14012 treatment. Cardiac function was evaluated by echocardiography. Markers of cardiac fibrosis and inflammation were assessed. RNA-seq analysis was performed to explore associated molecular pathways. Key pathways were validated in cardiac cells and bone marrow-derived mast cells. Results: TC14012 significantly improved cardiac function, indicated by preservation of ejection fraction and fractional shortening, and increased survival rates optimally at 5 mg/kg, which were accompanied with reductions in cardiac collagen deposition and infiltration of macrophages and neutrophils. RNA-seq revealed that TC14012 protecting against DICT was associated with a remarkable stimulation of signals involving in cardiac contraction and energy reserve metabolism processes, particularly glycogen and glucan metabolism that are crucial for meeting the cardiac energy demand in response to DOX induction. These signals could be further enriched into AMPK signalling pathway and validated by enhancement of cardiac AMPK phosphorylation both in vivo and in vitro . Meanwhile, TC14012’s cardioprotective effects were accompanied by a reduction in signals involving in cardiac mast cell activation and degranulation, which could be enriched into Rap1 signalling pathway and validated by TC14012 inhibiting mast cell activation and Rap1-GTP activity in vitro . Importantly, TC14012 did not compromise DOX’s antitumor efficacy in EL-4 lymphoma-bearing mice. Conclusions: TC14012 may prevent DICT by activating CXCR7-AMPK signalling to reprogram cardiomyocyte metabolism and antagonizing CXCR4-Rap1 signalling to blunt mast cell-mediated sentinel effects without compromising the anticancer efficacy DOX.

465 Background: Molecular testing is crucial in advancing precision medicine, enabling oncologists to tailor targeted treatment strategies for cancer patients (pts). The National Comprehensive Cancer Network (NCCN) and ASCO guidelines recommend comprehensive biomarker testing for pts with mPC. However, compliance can vary considerably among institutions. This study aimed to assess current practices of molecular testing in diverse healthcare settings across the state of Florida and identify opportunities for improvement to optimize outcomes for pts diagnosed with mPC. Methods: We conducted a detailed 12-question survey, distributed both electronically and in-person to evaluate the molecular testing practices of healthcare providers throughout the state. The survey assessed multiple parameters including adherence to testing, reviewing test results to guide treatment decisions, and the availability of different supportive resources in biomarker testing. This initiative was executed in partnership with the Florida Society of Clinical Oncology and industry partners. Results: A total of 40 responses were collected from 11 institutions in Florida, including 5 academic centers and 6 community-based hospitals. Notably, 22.5% of respondents reported that their institutions either do not fully comply with NCCN guidelines or lack protocols to identify eligible pts and 67.5% stated they are responsible for their own biomarker education and updates. Only 56.4% consistently review molecular testing results during disease progression to guide treatment decisions. Nearly all institutions lack clinical decision support tools in the electronic medical records (EMR) to support testing, and 82.5% receive biomarker results outside the EMR. Additionally, 38.5% lack a standard process for obtaining prior authorization for testing. Furthermore, 38.5% lack a multidisciplinary review process for genetic test results, and 76.3% reported that their biomarker testing process does not involve geneticists or genetic counselors. Conclusions: Our study identified critical gaps in adherence to biomarker testing guidelines with many practices lacking decision support tools across healthcare institutions in Florida. Potential areas for improvement include better standardization of result integration into EMR, targeted educational initiatives, and stronger multidisciplinary collaborations. The implementation of these measures aims to improve the quality of care and outcomes for pts with mPC.

Abstract Chimeric antigen receptor (CAR) T-cell (CAR-T) treatment for B-cell acute lymphoblastic leukemia (ALL) induces high initial response rates, but most patients relapse. Low disease burden (often defined as <5% blasts in the bone marrow) is associated with better outcomes. CAR HEMATOTOX (HT) is a score using prelymphodepletion hematologic and inflammatory parameters to predict outcomes in lymphoma. Here, we assess its prognostic utility in a large multicenter adult B-cell ALL cohort. Patients who received brexucabtagene autoleucel across 33 centers in North America were included as part of the Real-World Outcomes Collaborative of CAR-T in Adult ALL (ROCCA) consortium. An independent cohort of 61 patients with ALL treated with an investigational CD19 CAR-T therapy at 1 center was also described. Among 199 ROCCA consortium patients, 43 (22%) patients with HTlow scores had lower rates of delayed neutrophil recovery than those with HThigh scores (26% vs 52%, P = .002) and fewer severe infections (2.5% vs 18.8%, P = .011). They also had higher response rates, overall survival (OS), and event-free survival (EFS), as well as lower nonrelapse mortality and cumulative incidence of relapse. The survival differences remained significant after multivariable adjustment for disease burden and other covariates. In the investigational cohort of 61 patients, patients with HTlow scores had improved OS and EFS, as well as higher peak CAR-T expansion. In summary, CAR HT score is a prognostic factor independent of disease burden in adult ALL. HTlow score is associated with superior outcomes after CD19 CAR-Ts and higher CAR-T expansion in a single-center cohort. These trials were registered at www.clinicaltrials.gov as #NCT01044069 and #NCT01860937.

Background: Chronic nonspecific low back pain (CNLBP) is a prevalent, disabling condition worldwide. Tuina, a traditional Chinese manual therapy, has shown potential benefits, but evidence remains limited. Objective: This study evaluated the effectiveness and safety of Tuina therapy in managing CNLBP in a U.S. population. Methods: A prospective, single-blind, randomized controlled trial was conducted at Mayo Clinic Rochester campus (February 2020-April 2024). 204 participants with CNLBP were randomized into 3 groups: Tuina (N = 68), physical therapy (N = 68), or a combination of both (N = 68). Each group received 6 treatments over 2 months. The primary outcome was pain intensity (VAS); secondary outcomes included disability (ODI), quality of life (SF-36), and adverse events. Additionally, participants completed a satisfaction survey at the end of the trial. Research Electronic Data Capture (REDCap) was used for survey data collection. Data was assessed by analysis of variance (ANOVA) for the multiple repeated measurements, Kruskal-Wallis tests, while Chi-square tests, and Bonferroni correction in SAS software. Results: 185 subjects completed the study. Significant decreases in VAS, ODI, and SF-36 Overall Physical scores were found from baseline, to post treatment and follow-up in all groups ( P < .05), while there were no significant differences in VAS, ODI, or SF-36 outcomes between the Tuina group and the other 2 groups. There were 4 adverse events observed in the trial, 1 in the Physical therapy group and 3 in the Mixed group. Only 1 transient low back pain after Tuina therapy was observed in the Mixed group but did not require treatment. The high percentage of patients who received the Tuina program was extremely helpful (n = 94/126, 77.0%). The willingness to recommend was significantly higher for Tuina compared to physical therapy (Mixed group [N = 59/62, 95.2%], Tuina group [N = 57/64, 91.9%], and physical therapy group [N = 31/59, 59.6%] ( P < .05). Conclusion: Tuina therapy showed comparable benefits to physical therapy and combined treatment of both in improving pain, function, and quality of life in patients with CNLBP. With high patient satisfaction and a favorable safety profile, Tuina appears to be a safe and acceptable non-invasive treatment option. Further studies are needed to validate these findings in the future.

Abstract BRCA-associated homologous recombination deficiency (HRD) is present in ~ 50% of high-grade serous carcinomas (HGSC) and predicts sensitivity to platinum-based therapy. However, there is little understanding of why some patients with BRCA-deficient tumors experience unexpectedly poor outcomes. We profiled 154 tumors, enriched for patients with BRCA-deficient tumors that experienced short overall survival (≤ 3 years, n = 42), using whole-genome, transcriptome, and methylation analyses. All but one BRCA-deficient tumor exceeded an accepted HRD genomic scarring threshold. However, patients with BRCA1-deficient HGSC with a more elevated HRD score survived significantly longer. Patients with BRCA2-deficient HGSC and loss of NF1 survived twice as long as those without NF1 loss, whereas PIK3CA or RAD21 amplification defined BRCA2-deficient HGSC with exceptionally short survival. BRCA1-deficient tumors in short survivors had evidence of immunosuppressive c-kit signaling and EMT. In a large HGSC cohort (n = 1,389) including 282 individuals with pathogenic germline BRCA variants (gBRCApv), the location of the mutation within functional domains stratified clinical outcomes. Notably, residual disease after primary surgery had limited prognostic effect in gBRCApv-carriers compared to non-carriers. Our findings indicate that tumor HR proficiency in the context of therapy response and survival is not a binary property, and highlight genomic and immune modifiers of outcomes in BRCA-deficient HGSC.

Abstract Background Completing adjuvant chemotherapy and reducing toxicities are critical for maximizing survival after a colon cancer diagnosis. Sex, as a biological variable, may affect colon cancer chemotherapy completion, toxicities, and survival differently. Methods From a National Cancer Institute–sponsored trial conducted among patients with stage III colon cancer (Cancer and Leukemia Group B (Alliance)/Southwest Oncology Group 80702), we included 2201 patients receiving the standard adjuvant chemotherapy regimen of fluorouracil, leucovorin, and oxaliplatin. We calculated relative dose intensity to indicate chemotherapy completion and considered reduced relative dose intensity (values &lt;85%) as a clinically significant deviation from standard fluorouracil, leucovorin, and oxaliplatin. Using National Cancer Institute’s Common Terminology Criteria for Adverse Events, we defined severe adverse events (grade ≥3) as the occurrence of any following event, including neutrophil count decrease, nausea, platelet count decrease, hypertension, peripheral neuropathy, diarrhea, fatigue, gastritis, creatinine level increase, gastric ulcer, myocardial ischemia, and cerebral ischemia. The primary survival outcome was disease-free survival (time from enrollment to colon cancer recurrence or death from any cause), and secondary survival outcomes were recurrence-free and overall survival. Results Compared with men, women were at statistically significantly higher risks of experiencing reduced relative dose intensity (adjusted odds ratio = 1.59, 95% CI = 1.29 to 1.96; P &lt; .001) and severe advance events (adjusted odds ratio = 1.72, 95% CI = 1.41 to 2.11; P &lt; .001). Yet, women had statistically significantly better disease-free survival (adjusted hazard ratio = 0.72, 95% CI = 0.59 to 0.87; P &lt; .001) as well as better recurrence-free and overall survival. Conclusions Our findings suggested that women with colon cancer are more likely to have worse chemotherapy completion rates and more severe adverse events, but they have better survival. Sex as a biological variable warrants further consideration in chemotherapy administration and survivorship management after colon cancer diagnosis.

Abstract Background Lung adenocarcinoma in never-smokers is a major public health burden, especially among East Asian women. Polygenic risk scores (PRSs) are promising for risk stratification but are primarily developed in European-ancestry populations. We aimed to develop and validate single- and multi-ancestry PRSs for East Asian never-smokers to improve lung adenocarcinoma risk prediction. Methods PRSs were developed using genome-wide association study summary statistics from East Asian (8002 cases; 20 782 controls) and European (2058 cases; 5575 controls) populations. Single-ancestry models included a PRS with 25 single nucleotide variants (PRS-25), PRS clumping and thresholding (CT), and LDpred2; multi-ancestry models included LDpred2 plus European PRS-128, PRS-CSx, and clumping and thresholding, super learning, empirical Bayes (CT-SLEB). Performance was evaluated in independent East Asian data from the Female Lung Cancer Consortium and externally validated in the Nanjing Lung Cancer Cohort. We assessed predictive accuracy via area under the curve operating procedure (AUC), with 10-year and (ages 30-80 years) absolute risks estimates. Results The best multi-ancestry PRS, using East Asian and European data via CT-SLEB, outperformed the best East Asian-only (LDpred2; AUC = 0.629, 95% confidence interval [CI] = 0.618 to 0.641), achieving an AUC of 0.640 (95% CI = 0.629 to 0.653) and odds ratio of 1.71 (95% CI = 1.61 to 1.82) per standard deviation increase. Nanjing Lung Cancer Cohort validation confirmed robust performance (AUC = 0.649, 95% CI = 0.623 to 0.676). The top 20% PRS group had a 3.92-fold higher lung adenocarcinoma risk than the bottom 20%. Further, the top 5% PRS group reached a 6.69% lifetime absolute risk. Notably, this group reached the average population 10-year lung adenocarcinoma risk at age 50 years (0.42%) by age 41 years, 9 years earlier. Conclusions Multi-ancestry PRS approaches enhance lung adenocarcinoma risk stratification in East Asian never-smokers, with consistent external validation, suggesting future clinical utility.

Précis: Glaucoma patients with significant visual field defects show poorer driving performance, higher collision risks, and a greater likelihood of driving cessation. They face difficulties with lane maintenance, slower hazard responses, and self-regulation while driving. Purpose: Glaucoma is a chronic, progressive optic neuropathy associated with visual field (VF) defects, which in advanced disease has been shown to affect patients’ activities of daily living. This systematic review qualitatively analyzes existing literature that explores the impact of glaucomatous VF loss on the driving performance of glaucoma patients, the extent of driving limitation and cessation, as well as the risk of motor vehicle collisions (MVCs). Methods: A literature search of MEDLINE and Embase (via Ovid), PubMed, Cochrane Library, and Web of Science databases was performed for studies published from 2003 to 2023, with the terms “glaucoma,” “visual field defect/disorder,” and “driving,” followed by selective vetting based on inclusion criteria. Within studies, data pertaining to study design, subject demographics, VF defect characteristics, driving performance and related outcomes were extracted. Results: Initial search yielded 835 studies, with 20 studies selected. Three more studies were included through hand-searching, with a total of 23 studies included for final review. Moderate to severe VF defects resulted in poorer driving performance, with slower response times to road hazards, decreased ability for lane maintenance, and increased difficulty driving at night. Patients with more severe VF defects and with bilateral glaucoma were more likely to limit or cease driving compared with those with milder and unilateral glaucoma. A greater severity of VF loss was associated with a higher risk of MVCs. Conclusion: More severe glaucomatous VF and bilateral glaucoma is associated with worse driving performances and a higher risk of MVCs, in both simulator and real-world settings.

ABSTRACT Background Ventricular tachycardia (VT) is a major contributor to sudden cardiac death among patients with ischemic heart disease (IHD). While catheter ablation reduces the arrhythmic burden, the impact on long‐term outcomes remains uncertain. We assess the efficacy of catheter ablation in patients with IHD. Methods We performed a meta‐analysis by systematically searching electronic databases from inception to April 2025. Pairwise, reconstructed time‐to‐event data meta‐analyses and Trial Sequential analyses were conducted. Results A total of seven studies (1192 participants) were included. Among patients with IHD with ICD, VT ablation was associated with a significant reduction in ICD shocks (RR = 0.50, 95% CI = [0.34–0.74]), a trend toward reduced VT storm (RR = 0.64, 95% CI = [0.40–1.04], p = 0.07), and lower rates of cardiovascular hospitalization (RR = 0.73, 95% CI = [0.53–1.01], p = 0.06) compared to ICD alone. However, no significant differences were observed when compared to patients receiving ICD plus antiarrhythmic drugs (AADs). VT ablation showed no significant impact on mortality or VT/VF recurrence compared to either ICD alone or ICD with AADs. Reconstructed Kaplan–Meier analysis for all‐cause mortality showed no significant difference between VT ablation and AAD + ICD. Trial Sequential Analysis provided conclusive evidence for VT/VF recurrence, while further data is required for other outcomes. Conclusion Among patients with IHD with ICD, VT ablation reduces ICD shocks, VT storm, and cardiovascular hospitalizations compared to ICD‐only therapy, but offers no significant advantage over ICD combined with AADs. VT ablation does not impact overall mortality or the recurrence of VT/VF. Trial sequential analysis confirmed conclusive evidence for VT/VF recurrence, while additional data is needed for other outcomes.