Background: Both sarcopenia and cancers are common geriatric diseases leading to huge socioeconomic burdens. The causal impact of sarcopenia on selected site-specific cancers and the potential mediator was not clarified. Methods: Two-step, two-sample Mendelian randomization was performed to explore the causal impacts of sarcopenia on selected site-specific cancers with or without adjustment for body fat percentage (BF%), physical activity and smoking, and to evaluate proportions of the causal effects mediated by gastroesophageal reflux disease (GERD). Genetic instruments of sarcopenia-related traits, GERD, and selected site-specific cancers based on genome-wide association study were obtained from the UK Biobank, TRICL, and Japan Biobank. By searching relevant studies in PubMed, EMBASE, Cochrane Library, and Web of Science, we collected the data on the prognostic effects of sarcopenia on non-small cell lung cancer (NSCLC) for meta-analysis. Results: Lower appendicular lean mass (ALM) showed casual association with increased risks of lung adenocarcinoma, melanoma, non-melanoma skin cancer, and lymphomas. Genetically predicted lower frailty whole-body lean mass (WBLM) were associated with a higher risk of lung squamous cell carcinoma (LUSC), gastric cancer, and lymphomas. Walking pace was casually correlated with decreased risks of LUSC and cervical cancer. These causal associations were largely independent of BF%, physical activity and smoking. Further analysis showed that GERD acted as a mediator affecting the causal associations between WBLM/walking pace and LUSC, with mediation proportions of 44.23% (95% CI: 0.07–81.36%) and 86.10% (95% CI: 36.41–135.8%) for the effects of WBLM and walking pace on LUSC, respectively. Systematic review and meta-analysis demonstrated that NSCLC patients with sarcopenia had a lower overall survival (HR = 2.49, 95% CI: 2.11–2.93), progression-free survival (HR = 1.89, 95% CI: 1.10–3.24), and recurrence-free survival rates (HR = 2.03, 95% CI: 1.40–2.95). Conclusion: Our findings suggest that interventions prioritizing muscle function, especially improving walking pace, may be more effective for reducing sarcopenia-related LUSC risk than solely increasing muscle mass, with gastroesophageal reflux disease (GERD) representing a potential – but still exploratory – intervention target along this pathway.

4176 Background: Extrapulmonary neuroendocrine carcinoma (EP-NEC) is a poorly differentiated and highly aggressive malignancy with poor prognosis. Platinum (cisplatin or carboplatin) plus etoposide (EC/EP) remains the standard first-line regimen. However, clinical outcomes are suboptimal, highlighting the need for more effective strategies. Camrelizumab is a programmed cell death-1 (PD-1) inhibitor, and apatinib is a vascular endothelial growth factor receptor-2 (VEGFR2) inhibitor. Both have demonstrated antitumor activity in multiple solid tumors. Therefore, we investigated a sequential regimen consisting of induction EC/EP plus camrelizumab followed by maintenance camrelizumab plus apatinib in treatment-naive patients with advanced or metastatic EP-NEC. Methods: This multicenter, single-arm trial enrolled patients with previously untreated advanced or metastatic EP-NEC. Patients received 4–6 cycles of induction therapy with cisplatin (25 mg/m² iv, d1-3, q3w) or carboplatin (AUC = 5 iv, d1, q3w) plus etoposide (100 mg/m² iv, d1-3, q3w) in combination with camrelizumab (200 mg iv, d1, q3w). Patients without disease progression received maintenance camrelizumab (200 mg iv, q3w) plus apatinib (250 mg, qd) until progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Tumor response was assessed every 6 weeks per RECIST v1.1. The trial is registered on ClinicalTrials.gov, NCT05142865. Results: As of January 2026, 30 patients were enrolled (median age of 59.5 years, range 30–73), and all 30 patients were evaluable for efficacy. The ORR was 66.7% and the DCR was 83.3%. Median PFS was 9.87 months (95% CI, 6.23–NA). Median OS was not reached, and the 1-year OS rate was 74.6%. All patients experienced adverse events (AEs), with grade ≥3 AEs observed in 43.3% (13/30). Grade ≥3 AEs were mainly hematologic toxicities, including anemia (13.3%), neutropenia (13.3%) and thrombocytopenia (13.3%). Common non-hematologic AEs included elevated transaminases (43.3%), mainly grade 1–2, with grade ≥3 events in 10.0%. Conclusions: Induction EC/EP plus camrelizumab followed by maintenance camrelizumab plus apatinib showed encouraging activity and manageable safety in treatment-naive advanced or metastatic EP-NEC. Further studies are warranted to confirm these findings. Clinical trial information: NCT05142865 .

e15617 Background: Microsatellite stable (MSS) colorectal cancer (CRC) with unresectable liver metastases has limited effective third-line options. This study evaluated the efficacy and safety of transarterial chemoembolization/ hepatic arterial infusion chemotherapy (TACE/HAIC) combined with bevacizumab and tislelizumab in this setting. Methods: This single-center, prospective, observational study enrolled 21 patients with MSS CRC and unresectable liver metastases who failed at least two prior systemic therapies. One patient was excluded per protocol, leaving 20 evaluable patients. All received at least one cycle of TACE/HAIC combined with bevacizumab and tislelizumab. Primary endpoints was overall response rate(ORR) after 1 month of receiving the first combination therapy. Secondary endpoints included progression-free survival (PFS) , overall survival (OS), disease control rate (DCR), safety, and exploration of predictive biomarkers. Results: After the first efficacy assessment, the DCR was 70% (14/20 patients with stable disease, SD). No complete or partial responses were observed. The 6-month and 12-month PFS rates were 68.0% and 42.0%, respectively. Median PFS was 7.0 months and OS were 12.0 months (OS data immature, follow-up ongoing). Patients with < 2 extrahepatic metastatic sites had significantly longer PFS (6.5 vs. 3.2 months, P = 0.03). Grade ≥3 adverse events occurred in 29.4% of patients, primarily neutropenia (11.8%), hypertension (8.8%), and liver dysfunction (5.9%), with no treatment-related deaths. Exploratory biomarker analysis suggested that lower baseline BMI (< 24 kg/m²) was associated with better outcomes (P < 0.05), and a greater decrease in absolute lymphocyte count (ALC) after treatment correlated with progressive disease (PD). Conclusions: The combination of TACE/HAIC, bevacizumab, and tislelizumab demonstrated promising disease control and survival benefit with a manageable safety profile as a third-line therapy for MSS CRC with unresectable liver metastases. Baseline BMI and extrahepatic metastatic burden may help identify patients more likely to benefit. Further studies are warranted to optimize the regimen and validate predictive biomarkers. Clinical trial information: ChiCTR2500101315.

This guideline provides standardized requirements and quality control measures for human gallbladder cancer organoids, supporting their reliable application in research and precision medicine. It aims to promote methodological consistency, facilitate international collaboration, and accelerate translational research and clinical implementation.

This guideline establishes a comprehensive framework for the application of patient-derived pancreatic cancer organoids. It outlines the stringent technical requirements and testing methods necessary to ensure high fidelity to the original tumor tissue, including morphological assessment, pathological biomarker expression (e.g., CK19, CK7), and genetic concordance (e.g., NRG1, KRAS). By standardizing protocols for in vitro culture, microbiological safety, and STR authentication, this consensus aims to ensure the reproducibility, safety, and stability of organoid models, thereby accelerating their integration into basic research, drug discovery, and precision medicine.

Nitrogen metabolism plays a key role in maintaining normal physiological functions of the organism and cell proliferation and differentiation. Nitrogen metabolism in normal human body maintains a dynamic balance to meet the body’s demand for synthesis of biological macromolecules such as proteins and nucleic acids. However, in the process of tumor development, the nitrogen metabolism of tumor cells is reprogrammed to meet the demand of rapid proliferation, showing significantly different metabolic characteristics from normal cells. Key enzymes in the tumor microenvironment affect nitrogen metabolism through multiple mechanisms, providing essential nitrogen sources and energy for tumor cells. In-depth exploration of the regulatory mechanisms of tumor nitrogen metabolism not only helps to reveal the molecular basis of tumor development, but also provides a theoretical basis for the development of new tumor therapeutic strategies. In this paper, the relationship between nitrogen metabolism and tumors is systematically elaborated from the characteristics of nitrogen metabolism in normal people, the reprogramming of nitrogen metabolism in tumor patients, the influence of key enzymes on nitrogen metabolism in the tumor microenvironment, as well as the mechanism of tumor nitrogen metabolism regulation, etc., so as to provide references for the related research.

Background: Lung adenocarcinoma (LUAD), the most prevalent and clinically heterogeneous form of lung cancer, lacks robust biomarkers for prognosis and immunotherapy response prediction. This study aimed to identify key prognostic genes and develop a predictive framework to guide personalized treatment strategies. Methods: We integrated summary data-based Mendelian randomization (SMR) with machine learning to identify LUAD-associated genes. RNA-sequencing and clinical data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) were analyzed. A prognostic model was constructed with 101 combinations of 10 machine learning algorithms and validated via receiver operating characteristic (ROC) curve and concordance index analyses. Single-cell RNA-sequencing and spatial transcriptomic data were further examined to clarify the therapeutic implications of the identified genes. Results: SMR identified 316 LUAD-associated genes, among which 33 were associated with prognosis according to univariate Cox regression. The optimal model combining random survival forest and ridge regression achieved superior predictive accuracy, with the area under the curves for 1-, 3-, and 5-year survival being 0.757, 0.707, and 0.686, respectively. High-risk patients exhibited distinct immune microenvironment suppression, reduced tumor mutation burden, and diminished immunotherapy responsiveness as compared to their low-risk counterparts. Single-cell and spatial transcriptomic analyses identified interactions between cancer cells and stromal cells as potential therapeutic targets. Conclusions: The integrative approach employed in this study identified prognostic biomarkers and immunotherapy response predictors for patients with LUAD, offering a machine learning-driven framework for risk stratification and precision oncology. The findings underscore the clinical utility of combining genetic epidemiology with advanced analytics to optimize therapeutic strategies.

The efficacy and safety of conventional first-line chemotherapeutic regimens for the treatment of advanced biliary tract carcinomas (ABTCs) have been unsatisfactory. We aimed to explore alternative chemotherapeutic regimens capable of providing improved efficacy and fewer side-effects. Multicentre, randomised, phase II clinical trial. Patients with unresectable advanced-stage tumors, or those who have developed recurrence or metastasis following initial radical surgery, between January 2021 and November 2022 were included. The participants were randomised to either a gemcitabine-cisplatin group (GC) or an albumin-paclitaxel-cisplatin group (NC). Progression-free survival (PFS) was the primary outcome, whereas overall survival (OS), and objective response rate (ORR) were the secondary outcomes. The trial enrolled 75 patients and had a median follow-up period of 11 months. The median PFS (mPFS) was 7.8 m (95 https://www.chictr.org.cn/showproj.html?proj=38440 .

Abstract Purpose Hepatocellular carcinoma (HCC) is a highly aggressive tumor characterized by significant heterogeneity and invasiveness, leading to a lack of precise individualized treatment strategies and poor patient outcomes. This necessitates the urgent development of accurate patient stratification methods and targeted therapies based on distinct tumor characteristics. Experimental Design By integrating gene expression data from The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC), and Gene Expression Omnibus (GEO), we identified subtypes through a multi-omics consensus clustering approach amalgamated from 10 clustering techniques. Subsequently, we developed a prognostic model, employing machine learning algorithms, based on subtype classification features. Finally, by analyzing single cell sequencing data, we investigated the mechanisms driving prognostic variations among distinct subtypes. Results First, we developed a novel consensus clustering method that categorizes liver cancer patients into two subtypes, CS1 and CS2. Second, we constructed a prognostic prediction model, which demonstrated superior predictive accuracy compared to several models published in the past five years. Finally, we observed differences between CS1 and CS2 in various metabolic pathways, biological processes, and signaling pathways, such as fatty acid metabolism, hypoxia levels, PI3K-AKT and MIF signaling pathway.

Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD-1) or programmed death ligand 1(PD-L1) respond well to deficient-microsatellite(dMMR) colorectal cancer and poorly to proficient-microsatellite (pMMR) CRC. Anti-vascular therapy is the standard backline treatment regimen for advanced metastatic colorectal cancer and also potentiates the immunotherapeutic efficacy of CRC by promoting immune cell infiltration and remodeling the tumor immune microenvironment (TIME). However, it is not clear whether combining radiotherapy, anti-vascular and anti-PD-1 can affect the efficacy of pMMR CRC. In this experiment, we investigated the antitumor efficacy of radiotherapy combined with fruquintinib and tirelizumab in pMMR CRC mice. CT26 cellular hormonal tumor corresponding to pMMR CRC. A mouse model with subcutaneous transplanted tumors is established, divided into control, radiotherapy (IR), fruquintinib + tirelizumab (F+T), and radiotherapy + fruquintinib + tirelizumab (IR+F+T) groups. Immunofluorescence (IF) experiments were conducted to investigate the number and function of tumor vessels. Immunohistochemistry (IHC) and flow cytometry (FC) were utilized to examine immune cell infiltration and alterations within the TIME. Compared to the control group, tumor growth was significantly inhibited after treatment. When compared to IR and F+T, IR+F+T demonstrated a remarkable suppression of tumor growth. The quantitative analysis results showed a significant decrease in Ki-67 positive cells in the target tumors with IR+F+T compared to IR and F+T. The TUNEL results indicated that treatment promoted tumor cell apoptosis, and the effect was further enhanced with triple combinational therapy. Both F+T and IR+F+T repressed CD31 expression and improved the ratio of α-SMA+/CD31+ in tumor tissue, yet there was no significant difference between the two groups. The immunohistochemistry and flow cytometry results demonstrated that triple combinational therapy increased tumor-infiltrating CD8+ T cells and significantly elevated the proportions of CD8, CD69, and CD86. Both F+T and IR+F+T boosted PD-L1 expression, with no significant difference between them. Combined irradiation on top of fruquintinib and tirelizumab treatment enhanced the efficiency in CT26 murine CRC syngeneic tumor model. There was no significant effect of radiotherapy on the anti-angiogenesis of fruquintinib and the promotion of normal vascular function. Irradiation promoted CD8+ T cell and dendritic cell infiltration and activation. Mingsheng Zhang, Qingqing Yu, Huiying Hou, Xiaoting Su, Qin Huang, Hong Qiu, Le Huang, Liang Zhuang, Qiang Fu, Yanmei Zou, Li Sun, Liu Huang, Shunfang Liu, Fei Liu, Xianglin Yuan. Efficacy and mechanism of radiotherapy combined with fruquintinib and tirelizumab in mCRC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1828.

Supplementary Figure 1. Study time frame.

Synthetic lethality (SL) is a breakthrough concept in cancer therapy that describes a scenario in which the simultaneous inactivation of two genes leads to cell death, whereas inactivation of either gene alone does not. The rise of clustered regularly interspaced short palindromic repeat (CRISPR)-CRISPR-associated nuclease 9 (Cas9) technology has provided a new tool for exploring this phenomenon, enabling genome editing and screening. This review evaluates the advancements achieved by CRISPR technology in identifying novel therapeutic targets and comprehending the processes of drug resistance using the concept of SL in cancer cells. This review explores the fundamental concept of SL and its application in cancer therapy, highlighting how the CRISPR-Cas9 system functions and how CRISPR-based screening can be leveraged to identify synthetic lethal genes and investigate the mechanisms of drug resistance. We summarize important research in related fields from recent years, demonstrating the role of CRISPR screening in revealing cancer cellular pathways and identifying new drug targets. We also summarize the clinical trials of related drugs currently underway, and anticipate that with the continuous development of CRISPR technology, its integration with cancer genetics and immuno-oncology will bring new hope to patients with drug-resistant cancers.

Lung cancer is the leading cause of cancer-related deaths globally.In recent years,with the widespread use of genetic testing,epidermal growth factor receptor-tyrosine kinase inhibitor（EGFR-TKI）-targeted drugs have been efficacious to patients with lung adenocarcinoma exhibiting EGFR mutations.However,resistance to treatment is inevitable and eventually leads to tumor progression,recurrence,and reduction in the overall treatment efficacy.Lung cancer stem cells play a crucial role in the development of resistance toward EGFR-TKItargeted therapy for lung adenocarcinoma.Lung cancer stem cells possess self-renewal,multilineage differentiation,and unlimited proliferation capabilities,which efficiently contribute to tumor formation and ultimately lead to tumor recurrence and metastasis.In this study,we evaluated the origin,markers,stemness index,relevant classic studies,resistance mechanisms,related signaling pathways,and strategies for reversing lung cancer stem cell resistance to EGFR-TKIs to provide new insights on delaying or reducing resistance and to improve the treatment efficacy of patients with EGFR-mutated lung adenocarcinoma in the future.

Hepatocellular carcinoma(HCC) is an aggressive malignancy that is highly prevalent worldwide. It is often diagnosed at an advanced stage,which poses chal enges for curative treatment and leads to an unfavorable prognosis. The introduction of targeted therapy drugs, such as tyrosine kinase inhibitors, and immunotherapeutic drugs, including immune checkpoint inhibitors, has substantially improved the therapeutic effectiveness for advanced HCC. However, their efficacy remains suboptimal, owing to challenges related to patient responsiveness and drug resistance. To address these challenges, researchers have investigated combination therapies, including targeted immunotherapy, and triple therapies based on targeted immunotherapy, such as a combination of radiotherapy and targeted immunotherapy. In addition, they conducted a comprehensive investigation of potential new targets and drugs, yielding a series of significant findings. This review presents an outline of the treatment mechanisms and associated clinical research findings on mainstream targeted therapies, immunotherapies, and combination therapies. It also summarizes the current status of combination therapies for advanced HCC and anticipates future developments and trends in this field.

AbstractPurpose: This study aimed to evaluate the efficacy and safety of camrelizumab plus apatinib with or without stereotactic body radiotherapy (SBRT) as first-line therapy for patients with hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT). Patients and Methods: This is a multicenter, open-label, noncomparative, randomized trial that recruited patients with HCC with type II/III/IV PVTT, who had not previously received systemic therapy. Patients were randomly assigned (2:1) to receive camrelizumab (200 mg, every 3 weeks) and apatinib (250 mg, every day) with or without SBRT [95% planning target volume (PTV), 36–40 Gy/6–8 Gy]. The primary endpoint was overall survival (OS), and the secondary endpoints were progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), duration of response, time to progression, and safety. Results: Sixty patients were enrolled and randomly assigned to two prospective cohorts. Median OS were 12.7 months [95% confidence interval (CI), 10.2–not available (NA)] and 8.6 months (95% CI, 5.6–NA), and median PFS were 4.6 months (95% CI, 3.3–7.0) and 2.5 months (95% CI, 2.0–7.6) for the SBRT and non-SBRT cohorts, respectively. The ORR and DCR were 47.5% and 72.5% in the SBRT cohort, and 20.0% and 40.0% in the non-SBRT cohort. The most common treatment-related adverse events of any grade were hypertension (55.0%), hand-foot syndrome (51.7%), and leukopenia (50.0%). Grade ≥ 3 was reported in 13 (21.7%) patients. Conclusions: First-line treatment with camrelizumab–apatinib combined with or without SBRT showed clinical benefits in patients with HCC with PVTT, with an acceptable safety profile. Thus, these combination regimens may be potential options for such patients.

Background:Methylation modification patterns play a crucial role in human cancer progression, especially in gastrointestinal cancers. We aimed to use methylation regulators to classify patients with gastric adenocarcinoma and build a model to predict prognosis, promoting the application of precision medicine.Methods:We obtained RNA sequencing data and clinical data from The Cancer Genome Atlas (TCGA) database (n=335) and Gene Expression Omnibus (GEO) database (n=865). Unsupervised consensus clustering was used to identify subtypes of gastric adenocarcinoma. We performed functional enrichment analysis, immune infiltration analysis, drug sensitivity analysis, and molecular feature analysis to determine the clinical application for different subtypes. The univariate Cox regression analysis and the LASSO regression analysis were subsequently used to identify prognosis-related methylation regulators and construct a risk model.Results:Through unsupervised consensus clustering, patients were divided into two subtypes (cluster A and cluster B) with different clinical outcomes. Cluster B included patients with a better prognosis outcome and who were more likely to respond to immunotherapy. We then successfully built a predictive model and found five methylation-related genes (CHAF1A, CPNE8, PHLDA3, SPARC, and EHF) potentially significant to the prognosis of patients. The 1-, 3-, and 5-year areas under the curve of the risk model were 0.712, 0.696, and 0.759, respectively. The risk score was an independent prognostic factor and had the highest concordance index among common clinical indicators. Meanwhile, the tumor microenvironment, sensitivity of chemotherapeutic drugs, molecular features, and oncogenic dedifferentiation differed significantly across the risk groups and subtypes.Conclusions:We classified patients with gastric adenocarcinoma based on methylation regulators, which has positive implications for first-line clinical treatment. The prognostic model could predict the prognosis of patients and help to promote the development of precision medicine.

KRAS mutation is the most frequent type of genetic mutation in non-small cell lung cancer (NSCLC), especially in lung adenocarcinoma. However, KRAS mutation can affect many biological processes and the mechanisms underlying KRAS mutation-mediate carcinogenesis in NSCLC have not been fully understood. In this research, we found that KRASG12C mutation was associated with the upregulation of T-LAK cell-originated protein kinase (TOPK), which is a well-known serine/threonine MAPK-like protein kinase implicated in tumorigenesis. The overexpression of TOPK significantly promoted the malignant phenotype of A549 cells, and TOPK silencing impaired the malignant phenotype with KRASG12C mutation. Moreover, we demonstrated that TOPK level was regulated by MAPK/ERK signalling and the transcription factor Elk1. TOPK was also found to promote the activation of NF-κB signalling in A549 cells with KRASG12C mutation via facilitating the phosphorylation of TAK1. In the in vivo tumorigenesis model, the administration of TOPK inhibitor OTS514 enhanced the anticancer effect of 5-FU, and the combinatory use of OTS514 and KRASG12C inhibitor AMG510 showed synergistic anti-tumour effect. These results suggest that KRAS-TOPK axis contributes to the progression of NSCLC and targeting this axis could synergize with anticancer effect of the existing chemotherapeutics.

目的:利用生物信息学工具在结肠腺癌中(COAD)构建预后相关竞争内源性RNA(ceRNA)网络并进行综合分析.方法:从肿瘤基因组图谱(TCGA)数据库中下载COAD的RNA测序(RNA-seq)数据和miRNA测序(miRNA-seq)数据及相应的患者临床信息,筛选差异表达的mRNAs(DEmRNAs)、lncRNAs(DElncRNAs)和miRNAs(DEmiRNAs).对所有DEmRNAs进行功能和通路富集分析,以及蛋白互作网络(PPI)分析.根据这些差异RNAs之间的调控关系构建了COAD的ceRNA网络.用Kaplan-Meier曲线评估差异RNAs对COAD患者总生存率(OS)的影响,结合患者相关的临床信息分析差异基因的表达模式与其他临床特征之间的相关性.用c-bioportal和TIMER数据库分析DElncRNAs与免疫相关分子及浸润细胞的关系.结果:我们构建的ceRNA网络中有5个DElncRNAs(C2orf48、HOTAIR、KCNQ1OT1、LINC00355和MIR31HG)、2个DEmiRNAs(miR-145和miR-152)和6个DEmRNAs(FAM46C、FJX1、MACC1、SLC16A9、TPM2和ULBP2)与患者的OS显著相关.此外,预后相关lncRNAs中有4个被证实还与其它某些临床特征相关,KCNQ1 OT1、MIR31 HG和PD-L1表达之间也存在显著相关性.结论:本研究在COAD中构建了一个新的ceRNA调节网络,并确定了C2orf48、HOTAIR、KCNQ1OT1、LINC00355和MIR31HG可作为COAD潜在标志预后、靶向治疗以及免疫治疗反应的生物标志物.