Clinical and Experimental Medicine最新文献

Clear cell renal cell carcinoma (ccRCC) remains a major clinical challenge, with high rates of recurrence and limited long-term survival despite surgical resection and VEGF-targeted therapy. Immune checkpoint inhibitors (ICIs)-targeting PD-1, PD-L1, and CTLA-4-have revolutionized first-line systemic treatment, particularly in combination with VEGF tyrosine kinase inhibitors or as dual ICI regimens. However, primary and acquired resistance, immune-related adverse events (irAEs), and heterogeneous treatment responses limit the durability of benefit in many patients. This review aims to address a central question: how can immunotherapy for ccRCC evolve from incremental survival extension to durable, potentially curative control? We highlight emerging strategies-including next-generation checkpoint inhibitors (LAG-3, TIM-3, TIGIT), bispecific T cell engagers, cytokine-based agents, CAR-T and TCR-T therapies, and cancer vaccines-designed to enhance and sustain anti-tumor immunity. In parallel, we examine the role of multi-omic and spatial biomarkers, such as PBRM1 mutations, interferon-γ signatures, single-cell spatial atlases, and gut microbiome profiles, in refining patient selection and predicting therapeutic outcomes. This review uniquely integrates mechanistic insights with translational advances, providing a forward-looking synthesis of precision immunotherapy in ccRCC. We also emphasize rational combination strategies, biomarker-guided personalization, and irAE management as key priorities to overcome resistance and improve long-term outcomes.

Clear cell renal carcinoma (ccRCC) is a prevalent kidney cancer with limited effective biomarkers for prognosis and treatment guidance. Despite advancements, a significant portion of ccRCC cases progress to advanced stages, necessitating novel diagnostic tools. Here, we investigated the expression of MUC1 and its soluble form, CA15-3, in ccRCC, evaluating their potential as biomarkers for angiogenesis and response to sunitinib therapy. Molecular analyses showed that MUC1 expression was associated with angiogenesis, epithelial-mesenchymal transition, hypoxia/metabolism regulation, and complement system activation. In particular MUC1 overexpression correlated with increased microvascular density in vitro and in vivo models. Elevated CA15-3 levels were associated with tumor burden and predict clinical response to sunitinib in metastatic ccRCC. Metabolomic analysis showed that sunitinib-responding tumors were characterized by specific metabolic changes involving glucose and lipid metabolism, in association with impaired oxidative phosphorylation. MUC1 expressing ccRCC is a high angiogenic tumor that presents characteristics of increased aggressiveness, and a specific metabolic profile. Serum CA15-3 is a marker of poor survival and predicts response of sunitinib in patients with metastatic disease.

Hereditary angioedema (HAE), a rare genetic disorder, is classified into 3 types: Type 1 (low C1 esterase inhibitor [C1-INH]), Type 2 (dysfunctional C1-INH), and HAE-nl-C1INH (normal C1-INH levels). This study aimed to compare characteristics among individuals with HAE Type 1/2 and HAE-nl-C1INH. A cross-sectional online survey was conducted (June 2020-September 2021) among adults with HAE to capture various patient-specific data and health care utilization. Statistical analyses included Fisher exact test, t test, and odds ratios (OR) with 95% confidence intervals (CI). Eighty-nine participants were included (HAE Type 1/2, n = 44; HAE-nl-C1INH, n = 45). No significant differences in demographics, treatment characteristics, and HAE triggers were observed between groups. Participants with HAE-nl-C1INH were less likely to be diagnosed before 18 years of age (4% vs. 32%; OR, 0.10; 95% CI, 0.02-0.50) and had higher odds of experiencing frequent HAE attacks (47% vs. 14%; OR, 5.5; 95% CI, 2.0-15.7) than those with HAE Type 1/2. Participants with HAE-nl-C1INH also had increased odds of orofacial-laryngeal swelling (31% vs. 16%; OR, 2.3; 95% CI, 1.1-4.7), more frequent doctor visits (> 1 visit/month: 31% vs. 11%; OR, 3.5; 95% CI, 1.1-10.8), and more concomitant conditions (93% vs. 77%; OR, 3.8; 95% CI, 1.6-9.2). The total health-related quality of life score was significantly worse in participants with HAE-nl-C1INH (53.6 vs. 38.2; p = 0.0001). Participants with HAE-nl-C1INH experience a significantly greater disease burden than those with HAE Type 1/2, emphasizing the need for improved diagnosis, targeted treatment strategies, and a deeper understanding of the prevalence and pathophysiology of HAE-nl-C1INH.

Sarcopenia and arthritis, characterized by age-related progressive loss of skeletal muscle mass and function, profoundly impact the well-being of older adults. Our study endeavors to explore the unclear genetic structure between them. Using advanced statistical genetic approaches and genome-wide association study (GWAS) summary statistics, we explored the shared genetic basis among multiple manifestations of sarcopenia and four distinct arthritic conditions: osteoarthritis, rheumatoid arthritis, psoriatic arthritis, and gouty arthritis. We employed global and local genetic methods to gain potential shared biological mechanisms and determine binary local genetic correlations. Cross-phenotype association GWAS studies have revealed many genetic variations associated with complex traits. Transcriptome-wide association studies were conducted using weights from various human tissues to identify risk loci. We functionally annotated genomic multi-markers and fine-mapping colocalization by conducting the whole-genome unified testing of molecular characteristics. Significant correlations between sarcopenia and arthritis were detected through comprehensive and local genetic correlation analyses. At the genomic level, we identified 19 unique bivariate regions, including chr3q27.3, chr5q35.3, and chr12q13.2-q13.3, involving multiple human genes such as KBM7, GM12878, and IMR90. Gene enrichment analyses revealed that the selected loci primarily signaled through elementary pathways, including central nervous system neuron axonogenesis, glutamatergic synapse, and beta-catenin binding. Specifically, GDF5 and DNAJC27 were prioritized as the most probable candidate genes via transcriptomics. Our study has identified pleiotropic genomic regions linking sarcopenia and arthritis, providing novel insights into their genetic mechanisms.

Background: Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant plasma cell disorder whose prevalence increases with age and may progress to multiple myeloma. The tumor microenvironment plays a crucial role in MGUS pathogenesis and progression. Systemic immune-inflammatory markers can reflect tumor microenvironment(TME) dynamics, but their association with MGUS odds remains understudied.

Methods: This cross-sectional study analyzed data from 12,080 adults aged ≥ 50 years (including 350 MGUS cases) in the National Health and Nutrition Examination Survey (NHANES III and 1999-2004 cycles). Multivariable logistic regression assessed associations between systemic immune-inflammatory markers [lymphocyte-to-monocyte ratio(LMR), Platelet-to-lymphocyte ratio(PLR), Hemoglobin, albumin, lymphocyte, platelet score(HALP), and their individual components] and MGUS. Generalized additive models identified nonlinear relationships and threshold effects across stratified groups.

Results: Higher LMR quartiles were positively associated with MGUS prevalence (Q4 vs. Q1: OR = 1.454, 95% CI 1.048-2.016), while elevated monocyte counts (OR = 0.624, 95% CI 0.456-0.853) and albumin levels (OR = 0.446, 95% CI 0.317-0.627) correlated with reduced MGUS odds. Nonlinear analysis revealed a U-shaped association between PLR and MGUS. There are race-specific nonlinear correlations involving LMR, PLR, and lymphocyte counts with MGUS.

Conclusions: Systemic immune-inflammatory markers are significantly associated with MGUS odds in older adults, highlighting their potential for early detection and longitudinal monitoring.

Multi-disciplinary treatment (MDT) has become a routine practice in clinical cancer diagnosis and treatment, playing an indispensable role in clinical decision-making. By integrating expertise from multiple disciplines, MDT provides patients with individualized diagnosis and treatment strategies. However, there is not yet a specialized clinical data visualization tool for MDT. This paper develops a novel clinical data analysis visualization tool for MDT, which analyzes in-depth and displays patient data comprehensively. Specifically, this tool designs a latent Dirichlet allocation (LDA)-based visualization model for clinical unstructured data, and Z-Score-3σ transformation and hierarchical strategies for clinical structural data. Moreover, we propose to predict personalized anti-tumor drug efficacy based on topic keywords. The results showed that, compared with users who did not use the tool, the time cost in MDT decision-making for users who used the tool was reduced by 26.17%. Furthermore, the proposed drug efficacy prediction method achieved an accuracy rate of 71.08% on a dataset of 958 patients with non-small cell cancer treated with anti-tumor drugs. The proposed tool is potentially helpful for doctors in MDT tasks by vividly visualizing the large-scale complex clinical data and improving the MDT efficiency.

The treatment of corticosteroid-resistant or dependent primary immune thrombocytopenia (ITP) remains a clinical challenge. This study aims to evaluate the efficacy and safety of eltrombopag (Elt) in combination with cyclosporine A (CsA) in adults with primary ITP who are corticosteroid-resistant or dependent. This prospective phase II trial enrolled 28 patients from December 2020 to December 2023. All patients fulfilled the diagnostic criteria for ITP and were refractory to prior glucocorticoid (GC) therapy, defined as meeting at least one of the following criteria: (1) GC-resistant (failure to respond to both standard-dose prednisone and high-dose dexamethasone regimens); (2) GC-dependent (relapse during tapering or after discontinuation of GCs). The patients were administered combination therapy consisting of Elt with an initial dose of 50 mg taken nightly, and CsA at a dosage of 3-5 mg/kg/day targeting a trough concentration of 150-250 µg/L, with dose adjustments made in accordance with platelet counts. Efficacy was evaluated at the 8-week mark, with a response defined as a platelet count of ≥ 30 × 10⁹/L and a two-fold increase from baseline, in the absence of bleeding that required clinical intervention. Patients who achieved a response continued with maintenance therapy with the same regimen. Among the 25 evaluable patients, 92.0% (23/25) achieved a response (platelet count ≥ 30 × 10⁹/L), with 72.0% (18/25) attaining a complete response (platelet count ≥ 100 × 10⁹/L). The median time to response was 14 days, the median bleeding score decreased from 2.0 to 1.0, and 78.3% (18/23) maintained remission. Adverse events were systematically evaluated using the Common Terminology Criteria for Adverse Events version 5.0. The most frequently observed adverse events included gingival hyperplasia (60.7%, predominantly Grade 1), hirsutism (35.7%, all Grade 1), and infections (10.7%, including two fatal cases). The combination of Elt and CsA shows rapid and durable efficacy in adults with corticosteroid-resistant or dependent ITP, but necessitates careful monitoring for CsA-related toxicities and infections, contributing to clinical treatment of adult refractory ITP patients. This trial was registered in the Chinese Clinical Trial Registry under the number ChiCTR2000040991.

The present study aims to investigate the relationship between blood selenium and NAFLD. Data were obtained from the National Health and Nutrition Examination Survey (2017-2020), a total of 3940 eligible participants were included in this study. Multivariable logistic regression, subgroup analyses, and smooth curve fitting assessed the blood selenium-NAFLD relationship. A piecewise linear regression model identified potential thresholds. Model robustness was evaluated using multiple imputation. Among 3,940 participants, NAFLD prevalence was 45% (n = 1,173). Compared to the lowest blood selenium quartile (Q1: 103.10-169.49 µg/L), the adjusted odds ratios for NAFLD were 1.44 (95% CI: 1.16-1.78; P < 0.01) in Q3 (184.56-201.29 µg/L) and 1.26 (95% CI: 1.02-1.57; P = 0.035) in Q4 (201.30-562.23 µg/L) after full covariate adjustment (Q2 was non-significant). Each 1-standard deviation increase in log-transformed blood selenium corresponded to an adjusted odds ratios of 1.16 (95% CI: 1.08-1.26) for NAFLD. Gender significantly modified this association (P for interaction < 0.05). Adjusted smooth curve fitting demonstrated a significant non-linear positive dose-response relationship (P for non-linearity = 0.026). Elevated blood selenium concentration is significantly associated with an increased risk of NAFLD in US adults, exhibiting a non-linear dose-response pattern. This finding requires confirmation in future prospective cohort studies. Such association, if confirmed, will be of considerable public health relevance given the epidemic of NAFLD.