Chinese Journal of Cancer Research最新文献

Objective: A risk-based sequential screening strategy, from questionnaire-based assessment to biomarker measurement and then to endoscopic examination, has the potential to enhance gastric cancer (GC) screening efficiency. We aimed to evaluate the ability of five common stomach-specific serum biomarkers to further enrich high-risk individuals for GC in the questionnaire-identified high-risk population.

Methods: This study was conducted based on a risk-based screening program in Ningxia Hui Autonomous Region, China. We first performed questionnaire assessment involving 23,381 individuals (7,042 outpatients and 16,339 individuals from the community), and those assessed as "high-risk" were then invited to participate in serological assays and endoscopic examinations. The serological biomarker model was derived based on logistic regression, with predictors selected via the Akaike information criterion. Model performance was evaluated by the area under the receiver operating characteristic curve (AUC).

Results: A total of 2,011 participants were ultimately included for analysis. The final serological biomarker model had three predictors, comprising pepsinogen I (PGI), pepsinogen I/II ratio (PGR), and anti-Helicobacter pylori immunoglobulin G (anti-H. pylori IgG) antibodies. This model generated an AUC of 0.733 (95% confidence interval: 0.655-0.812) and demonstrated the best discriminative ability compared with previously developed serological biomarker models. As the risk cut-off value of our model rose, the detection rate increased and the number of endoscopies needed to detect one case decreased.

Conclusions: PGI, PGR, and anti-H. pylori IgG could be jointly used to further enrich high-risk individuals for GC among those selected by questionnaire assessment, providing insight for the development of a multi-stage risk-based sequential strategy for GC screening.

Objective: Pathologic complete response (pCR) following neoadjuvant therapy (NAT) for gastric cancer (GC) is rare but associated with a favorable prognosis. This study aims to reassess the optimal response population (ORP) following NAT by evaluating the prognostic outcomes associated with various T and N stages, utilizing multicenter data from China.

Methods: Patients who underwent NAT following radical gastrectomy at 10 tertiary hospitals in China between 2008 and 2021 were included. The ORP was introduced to explore the disease-free survival (DFS), overall survival (OS), recurrence patterns, and influencing factors following propensity score matching (PSM).

Results: A total of 1,076 patients were enrolled in this study (median follow-up period: 60 months). We defined ORP as a pCR or tumor infiltration of the mucosal or submucosal layer without lymph node metastasis (pCR or ypT1N0) after NAT. The ORP group comprised 136 patients (12.6%), while the non-ORP group comprised 940 patients (87.4%). After applying a 1:4 PSM, we obtained an ORP group of 136 patients and non-ORP group of 544 patients. Survival analysis demonstrated that both the 3-year OS (before PSM: 89.0% vs. 55.0%, P<0.001; after PSM: 89.0% vs. 55.4%, P<0.001) and DFS (before PSM: 85.8% vs. 49.7%, P<0.001; after PSM: 85.8% vs. 50.6%, P<0.001) were significantly superior in the ORP group compared to that in the non-ORP group. Remarkably, adjuvant chemotherapy did not impact the prognosis of patients in the ORP group (3-year OS: 89.0% vs. 89.7%, P=0.988; 3-year DFS: 84.9% vs. 89.7%, P=0.700).

Conclusions: This study reevaluates patients with ORP following NAT, providing a more comprehensive and accurate depiction of the potential beneficiary group and survival outcomes in patients with locally advanced GC.

The intricate interactions between immune cells and tumors exert a profound influence on cancer progression and therapeutic efficacy. Within the tumor microenvironment, exosomes have emerged as pivotal mediators of intercellular communication, with their cargo of non-coding RNAs (ncRNAs) serving as key regulatory elements. This review examines the multifaceted roles of immune cell-derived exosomal ncRNAs in tumor biology. The involvement of various immune cells, including T cells, B cells, natural killer cells, macrophages, neutrophils, and myeloid-derived suppressor cells, in utilizing exosomal ncRNAs to regulate tumor initiation and progression is explored. Additionally, the biogenesis and delivery mechanisms of these immune cell-derived exosomal ncRNAs are discussed, alongside their potential clinical applications in cancer.

Objective: Lymphovascular invasion (LVI) is a crucial step in metastasis and is closely associated with poor prognosis in patients with breast cancer. However, its clinical and molecular characteristics remain insufficiently defined. We aimed to identify molecular targets for LVI-positive (LVI+) breast cancer and predict patient prognosis via the analysis of genomic variations using targeted sequencing.

Methods: We established a large-scale targeted sequencing cohort of 4,079 breast cancer samples, which included 3,159 early-stage and locally advanced patients with available LVI statuses. Comparisons of somatic mutation frequencies and germline pathogenic/likely pathogenic (P/LP) mutation frequencies, mutational signature analyses, and mutual exclusivity and co-occurrence analyses were performed to identify key genomic features involved in LVI+ patients. Additionally, Kaplan-Meier survival analysis was conducted to further explore the prognostic value of co-mutations in LVI+ cases.

Results: We observed that LVI+ patients with the hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) and triple-negative breast cancer (TNBC) subtypes exhibited worse disease-free survival. Notably, HR+/HER2- and HER2+ breast cancer patients with LVI displayed distinct genomic features compared with LVI- tumors. Specifically, LVI+ HR+/HER2- tumors exhibited greater frequencies of somatic mutations in TP53 and ESR1, germline BRCA2 P/LP variations, and an enrichment of clock-like single-base substitution (SBS)1 mutational signatures. In contrast, LVI+ HER2+ tumors demonstrated a higher incidence of somatic PIK3CA mutations and increased activity of the apolipoprotein B mRNA editing enzyme catalytic polypeptide (APOBEC)-associated SBS2 signature. Furthermore, we revealed that the co-mutation of TP53 and NF1 could serve as a potential prognostic marker for LVI+ HR+/HER2- patients.

Conclusions: Our findings provide a comprehensive overview of the genomic characteristics of LVI in breast cancer, thereby offering insights that may help in refining precision treatment strategies for LVI+ breast cancer patients.

Objective: Radiotherapy (RT) is the definitive treatment for stage II nasopharyngeal carcinoma (NPC), which is classified as stages IA and IB in the latest ninth edition of American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC). A crucial question is whether concurrent chemo-radiotherapy (CCRT) could derive additional benefits to this recent "down-staging" subgroup of NPC patients. This study aimed to interrogate clinical and radiomic features for predicting 5-year progression-free survival (PFS) of stage II NPC treated with RT alone or CCRT.

Methods: Imaging and clinical data of 166 stage II NPC (eighth edition AJCC/UICC) patients were collected. Data were allocated into training, internal testing, and external testing sets. For each case, 851 radiomic features were extracted and 10 clinical features were collected. Radiomic and clinical features most associated with the 5-year PFS were selected separately. A combined model was developed using multivariate logistic regression by integrating selected features and treatment option to predict 5-year PFS. Model performances were evaluated by area under the receiver operating curve (AUC), prediction accuracy, and decision curve analysis. Survival analyses including Kaplan-Meier analysis and Cox regression model were performed for further analysis.

Results: Thirteen radiomic features, three clinical features, and treatment option were considered for model development. The combined model showed higher prognostic performance than using either. For the merged testing set (internal and external testing sets), AUC is 0.76 (combined) vs. 0.56-0.80 (clinical or radiomic alone) and accuracy is 0.75 (combined) vs. 0.62-0.73 (clinical or radiomic alone). Kaplan-Meier analysis using the combined model showed significant discrimination in PFS of the predicted low-risk and high-risk groups in the training and internal testing cohorts (P<0.05).

Conclusions: Integrating with clinical and radiomic features could provide prognostic information on 5-year PFS under either treatment regimen, guiding individualized decisions of chemotherapy based on the predicted treatment outcome.

Objective: Lynch syndrome (LS) increases the risk of various cancers, including colorectal cancer, endometrial cancer and gastric cancer (GC). The incidence of LS among microsatellite instability-high (MSI-H) GC and their association in South Korea remains underexplored. This study investigates LS-associated pathogenic germline variants in MSI-H GC patients using whole-exome sequencing (WES) on normal tissues.

Methods: This retrospective study included patients who underwent gastrectomy for GC at Soonchunhyang University Bucheon and Cheonan Hospitals from January 2011 to October 2023. Among 1,537 patients screened for MSI status, 127 (8.3%) were identified as MSI-H. WES was performed on normal tissues from 123 patients. Pathogenic/likely pathogenic (P/LP) variants in mismatch repair (MMR) genes were identified using in silico models and protein loss assessments in corresponding tumor tissues.

Results: Of the 127 MSI-H GC cases, characteristics aligned with typical MSI-H GC. The average age was 70.02 years, with 98 (77.2%) located in the lower body and 81 (63.8%) of the intestinal type. All five MSI markers were positive in 46.5% of cases, whereas four markers were positive in 27.6%. Of the MSI-H GCs, 10 LS candidates were identified. Three patients had known P/LP variants [MLH1 (c.1758dup), MSH6 (c.3261dup), MSH2 (c.1241T>C)]. Seven patients had variants of unknown significance (VUS) in MMR genes. Six (4.9%) patients were identified as having LS or possible LS, including one patient with the MLH1 (c.1153C>T) variant previously classified as VUS but now considered LS-associated.

Conclusions: This large-scale screening for LS in MSI-H GC patients using retrospective samples confirmed the lower incidence of LS than those of colorectal or endometrial cancer and GC patients in Western countries, emphasizing the need for clinical consideration in managing MSI-H GC patients.

Objective: Cytotoxic T lymphocytes (CTLs) play a crucial role in the therapeutic approach to hepatocellular carcinoma (HCC). Recent research has indicated that junctional adhesion molecule-like protein (JAML) enhances the antitumor activity of CD8+ T cells. Our study investigates the role of JAML+ CD8+ T cells in HCC.

Methods: We utilized time-of-flight mass cytometry and an orthotopic mouse model of HCC to examine histone modifications in tumor-infiltrating immune cells undergoing immunotherapy. Flow cytometry was used to assess CD4+ T cells differentiation and JAML expression in CD8+ T cells infiltrating HCC. Correlation analysis revealed a strong positive correlation between lactate dehydrogenase A+ (LDHA+) CD4+ T cells and JAML+ CD8+ T cells. Subsequently, we evaluated the therapeutic effects of an agonistic anti-JAML antibody, both alone and combined with immunotherapy. Finally, RNA sequencing was conducted to identify potential regulatory mechanisms.

Results: Immunotherapy significantly increased the percentage of CD8+ T cells infiltrating HCC and induced histone modifications, such as H3K18 lactylation (H3K18la) in CD4+ T cells. Flow cytometry analysis revealed that lactate promotes the differentiation of CD4+ T cells into Th1 cells. LDHA, an enzyme that converts pyruvate to lactate, plays a key role in this process. Correlation analysis revealed a strong positive relationship between LDHA+ CD4+ T cells and JAML+ CD8+ T cells in patients who responded to immunotherapy. Moreover, high JAML expression in CD8+ T cells was associated with a more favorable prognosis. In vivo experiments demonstrated that agonistic anti-JAML antibody therapy reduced tumor volume and significantly prolonged the survival of tumor-bearing mice, independent of the effects of anti-programmed cell death protein ligand-1 antibody (αPD-L1)-mediated immunotherapy. Pathway enrichment analysis further revealed that JAML enhances CTL responses through the oxidative phosphorylation pathway.

Conclusions: Activation of JAML enhances CTL responses in HCC treatment, independent of αPD-L1-mediated immunotherapy, providing a promising strategy for advanced HCC.

[This corrects the article DOI: 10.21147/j.issn.1000-9604.2024.02.02.].

Serotonin (5-hydroxytryptamine, 5-HT), a neurotransmitter known for its roles in the central nervous system, showing dual effects in various pathological conditions, including tumor progression and wound healing. This review explores the complex and context-dependent actions of 5-HT, highlighting its contrasting roles in promoting tumor growth and facilitating wound repair. 5-HT can enhance tumor growth, survival, and metastasis via its receptors, but it also accelerates wound healing by stimulating cell proliferation, migration, and angiogenesis. This duality emphasizes the intricate balance of 5-HT and its receptors in the body. We discuss the synthesis, storage, secretion, and metabolism of 5-HT, as well as the classification and mechanisms of its receptors (5-HTRs) in different cell types under pathological conditions. We further examine the potential roles of 5-HT in both tumor progress and wound healing, proposing targeted strategies for each disease state. For tumors, "blocking therapy" involving receptor antagonists or gene silencing may inhibit tumor progression, while "activation therapy" can stimulate wound healing by enhancing receptor activation on skin cells. Challenges in clinical application, including issues related to targeting, specificity, and dosage, are addressed, alongside the promise of nanotechnology for improving targeted drug delivery. The review also explores emerging research on 5-HT's interaction with the immune system, offering insights into potential immunotherapeutic strategies for both cancer and wound healing. By balancing 5-HT's diverse effects, personalized treatments can be developed to optimize therapeutic outcomes in both contexts.