Citations

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.

Evaluation of T-cell receptor (TCR) β-chain constant region 1 (TRBC1) expression is an alternative T-cell clonality assessment method. However, evaluation of TRBC1 immunohistochemistry (IHC) for distinguishing mycosis fungoides (MF)/Sezary syndrome (SS) from reactive inflammatory infiltrates in skin is incomplete. We evaluated the utility of a novel dual TRBC1-CD3 IHC stain in skin biopsies with MF/SS (n=40), reactive (n=24), or atypical T-cell infiltrates indeterminant for MF/SS (n=9). Twenty of 24 reactive cases showed clear polytypic TRBC1 expression (median percent TRBC1 positivity among CD3-positive T cells [%TRBC1+] 50% in dermis, 42.5% in epidermis among all cases), while 34/40 MF/SS were clearly monotypic (%TRBC1+ either ≤20% or ≥85%) (sensitivity 85.0%, specificity 91.7%, positive predictive value 94.4%, negative predictive value 78.6%). Discordance between TRBC1 expression and diagnosis was associated with few neoplastic/monotypic T cells and/or lack of physical separation between neoplastic and non-neoplastic populations. Among patch/plaque MF/SS, TRBC1 showed similar diagnostic sensitivity (80.0% vs. 86.7%) and high categorical correlation (monotypic vs. not monotypic, 80%) with TCR gene rearrangement results. TRBC1 interpretation was reproducible, with ≥2/3 and 3/3 pathologists rendering identical interpretations in 100% and 86% of cases, respectively, after independent review and 100% agreement following collective review. Digital image analysis confirmed visual %TRBC1+ accuracy ( r =0.9749, P <0.0001). On the basis of these results, we propose %TRBC1+ cutoffs of <25% or >75% for establishing T-cell monotypia in skin. Considering such thresholds, TRBC1-CD3 evaluation facilitated diagnostic refinement in 7/9 (78%) atypical cases. Overall, TRBC1-CD3 IHC clearly and rapidly aids diagnosis of cutaneous T-cell proliferations.

Abstract Background Acupuncture, a key modality in traditional Chinese medicine, is gaining global recognition as a complementary therapy and a subject of increasing scientific interest. However, fragmented and unstructured acupuncture knowledge spread across diverse sources poses challenges for semantic retrieval, reasoning, and in-depth analysis. To address this gap, we developed AcuKG, a comprehensive knowledge graph that systematically organizes acupuncture-related knowledge to support sharing, discovery, and artificial intelligence–driven innovation in the field. Methods AcuKG integrates data from multiple sources, including online resources, guidelines, PubMed literature, ClinicalTrials.gov, and multiple ontologies (SNOMED CT, UBERON, and MeSH). We employed entity recognition, relation extraction, and ontology mapping to establish AcuKG, with human-in-the-loop to ensure data quality. Two cases evaluated AcuKG’s usability: (1) how AcuKG advances acupuncture research for obesity and (2) how AcuKG enhances large language model (LLM) application on acupuncture question-answering. Results AcuKG comprises 1839 entities and 11 527 relations, mapped to 1836 standard concepts in 3 ontologies. Two use cases demonstrated AcuKG’s effectiveness and potential in advancing acupuncture research and supporting LLM applications. In the obesity use case, AcuKG identified highly relevant acupoints (eg, ST25, ST36) and uncovered novel research insights based on evidence from clinical trials and literature. When applied to LLMs in answering acupuncture-related questions, integrating AcuKG with GPT-4o and LLaMA 3 significantly improved accuracy (GPT-4o: 46% → 54%, P = .03; LLaMA 3: 17% → 28%, P = .01). Conclusion AcuKG is an open dataset that provides a structured and computational framework for acupuncture applications, bridging traditional practices with acupuncture research and cutting-edge LLM technologies.

PURPOSE Large language models (LLMs) have demonstrated remarkable versatility in oncology applications, such as cancer staging and survival analysis. Despite their potential, ethical concerns such as data privacy breaches, bias in training data, lack of transparency, and risks associated with erroneous outputs pose significant challenges to their adoption in high-stakes oncology settings. Therefore, we aim to explore the ethical challenges associated with LLM-based applications in oncology and evaluate emerging techniques designed to address these issues. METHODS Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses framework, a systematic review was conducted to evaluate publications related to ethical issues of LLMs in oncology across eight academic databases (eg, PubMed, Web of Science, and Embase) between January 1, 2019, and December 31, 2024. RESULTS The search retrieved 4,319 published articles, of which 65 publications were preserved and included in our analysis. We identified six prevalent ethical challenges in oncology, including trust, equity, privacy, transparency, nonmaleficence, and accountability. We then evaluated emerging technical solutions to mitigate ethical challenges and summarized evaluation metrics used to assess these solutions' effectiveness. CONCLUSION This review provides actionable recommendations for responsibly deploying LLMs in oncology, ensuring adherence to ethical guidelines, and fostering improved patient outcomes. By bridging technical and clinical perspectives, this review offers a foundational framework for advancing ethical artificial intelligence applications in oncology and highlights areas for future research.

Abstract Objectives To develop a volume of interest (VOI) imaging technique in multi-detector-row helical CT to reduce radiation dose or improve image quality within the VOI. Methods A deep-learning method based on a residual U-Net architecture, named VOI-Net, was developed to correct truncation artifacts in VOI helical CT. Three patient cases, a chest CT of interstitial lung disease and 2 abdominopelvic CT of liver tumour, were used for evaluation through simulation. Results VOI-Net effectively corrected truncation artifacts (root mean square error [RMSE] of 5.97 ± 2.98 Hounsfield Units [HU] for chest, 3.12 ± 1.93 HU, and 3.71 ± 1.87 HU for liver). Radiation dose was reduced by 71% without sacrificing image quality within a 10-cm diameter VOI, compared to a full scan field of view (FOV) of 50 cm. With the same total energy deposited as in a full FOV scan, image quality within the VOI matched that at 350% higher radiation dose. A radiologist confirmed improved lesion conspicuity and visibility of small linear reticulations associated with ground-glass opacity and liver tumour. Conclusions Focusing radiation on the VOI and using VOI-Net in a helical scan, total radiation can be reduced or higher image quality equivalent to those at higher doses in standard full FOV scan can be achieved within the VOI. Advances in knowledge A targeted helical VOI imaging technique enabled by a deep-learning-based artifact correction method improves image quality within the VOI without increasing radiation dose.

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.

Chimeric antigen receptor (CAR) T-cell infusion has led to improved outcomes in patients with B-lymphoblastic leukemia, B-cell lymphoma, and multiple myeloma. The spectrum of post-CAR T-cell hematolymphoid abnormalities is expanding, although they remain under-recognized. Pathologists play a key role in characterizing hematolymphoid proliferation after CAR T-cell therapy. This review presents clinical and pathologic findings of common hematolymphoid proliferation after CAR T-cell therapy, illustrated by selected cases. A review of the literature is presented in the context of individual cases, and our current understanding of the pathomechanism is discussed. Infused CAR T-cells undergo a series of four phases: distribution, expansion, contraction, and persistence. In the expansion phase, transient peripheral blood lymphocytosis occurs, reaching a peak two weeks post-infusion. Delayed contraction of CAR T-cells may give rise to hemophagocytic lymphohistiocytosis-like syndrome. Immune effector cell-associated enterocolitis presents in the persistence phase, about 3–6 months after infusion. Pathologic findings include a T-cell infiltrate in the intestinal mucosa and changes resembling graft versus host disease (GVHD). This entity requires differentiation from infections and from T-cell neoplasms, including those derived from CAR T-cells. Secondary myeloid malignancies follow the same pathways as therapy-related myeloid neoplasm but present with a shorter median latency. It is essential for pathologists to recognize post-CAR T-cell hematolymphoid proliferation to support clinical decision making in a high-risk patient population.

ABSTRACT Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disease that is caused by mutations in PKD genes. Glucagon‐like peptide‐1 (GLP‐1) receptor agonists (GLP‐1RAs) are a class of medications that mimic the actions of the hormone GLP‐1, conferring beneficial effects on weight management and other metabolic conditions. However, whether GLP‐1RA plays a kidney‐protective action in ADPKD remains unknown. In this study, we define the role and mechanisms of one of the most popular GLP‐1RA agonists, Semaglutide, in ADPKD. We show that the expression of GLP‐1R is decreased in Pkd1 mutant renal epithelial cells and kidneys. Treatment with Semaglutide delays cyst growth in aggressive and long‐lasting Pkd1 mutant mouse models. Treatment with Semaglutide (1) decreases glucose uptake, ATP generation, and glycolysis, (2) deactivates PKD‐associated signaling pathways, including Rb, S6, and Stat3, resulting in a decrease in cell proliferation, (3) deactivates NF‐kB signaling pathways, resulting in a decrease in the expression of cytokines and the recruitment of macrophages, (4) normalizes mitochondrial morphology and function, (5) induces Pkd1 mutant renal epithelial cell death, (6) induces ketosis characterized by an increase in serum level of beta‐hydroxybutyrate (BHB) and the activation of AMPK, and (7) alleviates renal fibrosis through deactivation of TGF‐b signaling in Pkd1 mutant mouse kidneys. This study highlights the potential of GLP‐1R agonists as a novel therapeutic strategy for ADPKD treatment.

Abstract Background and Aims Type 1 short QT syndrome (SQT1) is a genetic channelopathy caused by gain-of-function variants in KCNH2, resulting in shortened cardiac repolarization and QT intervals, which predispose patients to ventricular arrhythmias and sudden cardiac death. This study aimed to investigate the therapeutic efficacy of KCNH2-specific suppression-and-replacement (KCNH2-SupRep) gene therapy in a transgenic rabbit model of SQT1. Methods KCNH2-SupRep was developed by combining a KCNH2-shRNA with its corresponding shRNA-immune KCNH2-cDNA into an AAV9 vector, delivered directly into the aortic root (1 × 1010 vg/kg). Therapeutic efficacy was evaluated in vivo by electrocardiogram, ex vivo by optical mapping, and at cellular levels by patch-clamp, calcium imaging, and qPCR in ventricular cardiomyocytes (VCMs). Results In vivo, KCNH2-SupRep normalized the heart rate-corrected QT interval (QTc) in SQT1 rabbits, without affecting repolarization heterogeneity. Ex vivo, KCNH2-SupRep corrected the action potential duration (APD90) and resolved the increased apicobasal APD90 heterogeneity observed in untreated (UT)-SQT1 hearts, supporting an antiarrhythmic effect, which was further validated by reduced re-entry formation in silico. At cellular levels, KCNH2-SupRep prolonged APD90 in VCMs from SupRep-SQT1 rabbits closer to wildtype levels compared with UT- and sham-SQT1. Additionally, KCNH2-SupRep restored the cellular surrogate of the electro-mechanical window and normalized IKr in nearly 50% of VCMs, in line with a 50%–60% suppression of the mutant KCNH2 transcript. Conclusions This proof-of-concept study is the first to demonstrate the efficacy of gene therapy for SQT1 in a medium-sized animal model. KCNH2-SupRep gene therapy successfully corrected the pathologic phenotype in vivo, ex vivo, and at cellular levels in transgenic SQT1 rabbits.

Abstract Background Cabozantinib is indicated for hepatocellular carcinoma (HCC) following first-line (1L) sorafenib, but the 1L standard has shifted to immuno-oncology (IO)-based regimens. This study evaluated real-world outcomes among patients with advanced HCC receiving second-line (2L) cabozantinib following 1L therapies, including newer regimens. Patients and Methods US claims data were used to identify adults with advanced HCC initiating 2L cabozantinib monotherapy (index date). Patients were stratified into three 1L treatment cohorts: IO monotherapy/IO + IO combination therapy; IO + non–IO combination therapy; or tyrosine kinase inhibitor (TKI) monotherapy. Real-world time to treatment discontinuation (rwTTD), real-world time to next treatment or death (rwTNTD), real-world overall survival (rwOS), and cabozantinib dosing were assessed collectively and by cohort. Adverse events were assessed before/after cabozantinib initiation. Results Among 148 patients who received 2L cabozantinib, 28 were in the IO monotherapy/IO + IO combination therapy cohort, 54 in the IO + non–IO combination therapy cohort, and 66 in the TKI monotherapy cohort. Median rwTTD among all patients was 3.2 months; median rwTNTD was 7.6 months; 12-month rwOS rate was 61.6%. There were no significant differences in these outcomes among the three cohorts. Overall, 44.6% of patients initiated 2L cabozantinib at 60 mg/day, of whom 39.4% required a dose reduction; 37.8% initiated at 40 mg/day, of whom 16.1% had a dose reduction. Adverse event rates were similar before/after cabozantinib initiation. Conclusions Cabozantinib shows consistent effectiveness and safety in the 2L HCC setting following prior TKIs or IO-based regimens in real-world clinical practice. These findings may inform 2L treatment decisions.