Abstract Background: The study aims to investigate the expression level of Thrombospondin 2 (TSP2) in Gastric Cancer (GC) and determine the relationship between TSP2 and clinical characteristics and prognosis. Methods: The online database Gene Expression Profile Interactive Analysis (GEPIA) was used to analyze the mRNA expression level of TSP2 in GC. The Kaplan-Meier plotter prognostic analysis tool was used to evaluate the influence of TSP2 expression on clinical prognosis in GC patients. The expression level of TSP2 was analyzed in paraffin-embedded GC samples and adjacent normal tissues by immunohistochemistry. The relationship between clinicopathological characteristics and prognosis of GC patients. Next, the relationship between clinicopathological characteristics and prognosis of GC patients was assessed. Transwell experiment was used to evaluate the effect of TSP2 on the invasion and migration of HGC27 and AGS cells. Results: Compared with normal tissues, the expression of TSP2 mRNA in GC was significantly up-regulated, and it was closely related to the clinical stage of GC. The high expression of TSP2 significantly affected the OS, FP and PPS of patients with GC. Among them, the expression level of TSP2 did not affect the prognosis of patients with GC in N0 subgroup, but significantly affected the prognosis of patients with GC in N (1+2+3)subgroup. The protein expression level of TSP2 in GC tissue was significantly higher than in normal tissues (P<0.01). The overall survival (OS) rate of patients with high TSP2 expression was lower than the low TSP2 expression group ( P =0.013). Knockdown of TSP2 can significantly inhibit the growth of GC cells. Proliferation, migration, invasion ability, and TSP2 expression level significantly correlate with mismatch repair genes such as PMS2, MSH6, MSH2, and MLH1 ( P <0.05). Conclusion : The expression of TSP2 in GC is significantly increased, closely related to the metastasis and mismatch repair process of GC patients and affected GC patients' prognosis. It is a potential marker and treatment target for the prognosis of GC patients.
Abstract Background This meta-analysis aimed to evaluate the comparative diagnostic efficacy of [ 18 F]FDG PET/CT and [ 18 F] FDG PET/MRI in detecting bone metastases in breast cancer patients. Methods An extensive search was conducted in the PubMed, Embase, Web of Science, and Cochrane Library databases to identify available publications up to February 2023. Studies were included if they evaluated the diagnostic efficacy of [ 18 F]FDG PET/CT and [ 18 F]FDG PET/MRI in patients with breast cancer bone metastases. Sensitivity and specificity were assessed using the DerSimonian and Laird method, followed by transformation via the Freeman-Tukey double inverse sine transformation. Results 16 articles (including 4 head-to-head comparison articles) involving 1,261 patients were included in the meta-analysis. The overall sensitivity of [ 18 F]FDG PET/CT in patient-based analysis, lesion-based analysis, and head-to-head comparison were 0.73, 0.89, and 0.87, respectively, while the overall sensitivity of [ 18 F]FDG PET/MRI were 0.99, 0.99, and 0.99. The results indicated that [ 18 F]FDG PET/MRI appears to a higher sensitivity in comparison to [ 18 F]FDG PET/CT(all P < 0.05). In contrast, the overall specificity of [ 18 F]FDG PET/CT in patient-based analysis, lesion-based analysis, and head-to-head comparison were 1.00, 0.99, and 1.00, respectively, while the overall specificity of [ 18 F]FDG PET/MRI were 1.00, 0.99, and 0.98. These results suggested that [ 18 F]FDG PET/CT has a similar level of specificity compared to [ 18 F]FDG PET/MRI. Conclusions Our meta-analysis indicates that [ 18 F]FDG PET/MRI demonstrates superior sensitivity and similar specificity to [ 18 F]FDG PET/CT in detecting bone metastases in breast cancer patients. Further prospective research is required to confirm these findings and assess the clinical application of these techniques.
Background: This study aimed to determine the potential roles of RNA N6-methyladenosine (m6A) modification of tumor microenvironment (TME) cell infiltration in breast cancer (BRCA).Methods: We evaluated the m6A modification patterns of 1204 samples in The Cancer Genome Atlas (TCGA) database, including 1091 BRCA samples and 113 normal samples based on 23 m6A regulators, and correlated their modification patterns with TME cell-infiltrating characteristics. A m6A regulator score model was established based on TCGA-BRCA RNA sequencing data of m6A regulators. By using weighted coexpression network analysis (WGCNA), we identified m6A-related lncRNAs and mRNAs. Models of m6A-related mRNA or lncRNA scores were also established and compared. The m6A regulator score model was validated across GSE20685 datasets.Results: The expression patterns of seven m6A regulators (KIAA1429, ELAVL1, YTHDC1, YTHDF2, WTAP, YTHDF1, and YTHDF3) were found to influence the survival rates of patients. Two distinct m6A modification patterns were identified. The TME cell-infiltrating characteristics and m6A regulator expression differed under these two patterns, especially in regulatory T cells. m6A regulator, m6A-related mRNA, and m6A-related lncRNA scores could predict the prognoses of patients with BRCA, and their accuracies in predicting 5-year survival were 0.65, 0.73, and 0.61, respectively. High scores indicated a lower survival probability at early stages. However, compared with the other two systems, the m6A regulator score seemed easier to manipulate and was more stable.Conclusions: m6A regulators and their associated lncRNA and mRNA contribute to the individualized prediction of BRCA prognosis, and these RNAs can be used as potential biomarkers of BRCA that specifically target m6A modification.Funding Information: This research was supported by National Natural Science Foundation of China [81871943 to JC]; Guangdong Provinvial Clinical Research Center for Digestive Diseases [2020B1111170004]; Guangzhou High-level Key Clinical Specialty Construction Project[No.9];The Project of Key Medical Discipline in Guangzhou [2021-2023].Declaration of Interests: The authors have no conflicts of interest to declare.Ethics Approval Statement: N/a.
Background: An increasing number of studies had shown that tertiary lymphoid structure (TLS) plays an important role in tumor progression.However, the prognostic role of TLS in various tumors remains controversial.This meta-analysis aims to investigate the clinicopathological and prognostic values of TLS in solid tumors.Methods: A systematic search was conducted in PubMed, EMBASE and Cochrane Library undated to November 2, 2020.Odds ratios of clinical parameters, hazard ratio (HR) of overall survival (OS), relapse-free survival (RFS), disease-free survival (DFS) and relapse rate were calculated in order to evaluate the relationship between TLS expression and clinicopathological or prognostic values in different tumors.Result: 27 eligible studies including 6647 patients with different types of tumors were analyzed.High TLS expression was associated with a longer OS (HR = 0.66, 95% CI: 0.50 -0.86, P = 0.002) and RFS (HR = 0.61, 95% CI: 0.47 -0.79, P = 0.0001).Moreover, high TLS levels in tumor were associated with a low risk of recurrence (HR = 0.43, 95% CI: 0.32 -0.57, P < 0.0001).However, there was no relationship between TLS expression and DFS.Meanwhile, high TLS expression was associated with smaller tumor size (P < 0.00001) and higher tumor infiltrating lymphocytes (TILs).Furthermore, the subgroup analysis showed high TLS expression that may be associated with a lower clinical grading and N stage in breast cancer and colorectal cancer.Conclusion: High TLS expression is associated with the longer OS and RFS in solid tumors, and a lower risk of cancer relapse.Meanwhile, high TLS expression is also associated with a smaller tumor size, higher infiltration of TILs, lower clinical grading and N stage in the tumor.Therefore, high TLS expression in the tumor is a favorable prognostic biomarker for solid tumor patients.
Objective Haematogenous dissemination is a prevalent route of colorectal cancer (CRC) metastasis. However, as the gatekeeper of vessels, the role of tumour pericytes (TPCs) in haematogenous metastasis remains largely unknown. Here, we aimed to investigate the heterogeneity of TPCs and their effects on CRC metastasis. Design TPCs were isolated from patients with CRC with or without liver metastases and analysed by single-cell RNA sequencing (scRNA-seq). Clinical CRC specimens were collected to analyse the association between the molecular profiling of TPCs and CRC metastasis. RNA-sequencing, chromatin immunoprecipitation-sequencing and bisulfite-sequencing were performed to investigate the TCF21-regulated genes and mechanisms underlying integrin α5 on TCF21 DNA hypermethylation. Pericyte-conditional Tcf21 -knockout mice were constructed to investigate the effects of TCF21 in TPCs on CRC metastasis. Masson staining, atomic force microscopy, second-harmonic generation and two-photon fluorescence microscopy were employed to observe perivascular extracellular matrix (ECM) remodelling. Results Thirteen TPC subpopulations were identified by scRNA-seq. A novel subset of TCF21 high TPCs, termed ‘matrix–pericytes’, was associated with liver metastasis in patients with CRC. TCF21 in TPCs increased perivascular ECM stiffness, collagen rearrangement and basement membrane degradation, establishing a perivascular metastatic microenvironment to instigate colorectal cancer liver metastasis (CRCLM). Tcf21 depletion in TPCs mitigated perivascular ECM remodelling and CRCLM, whereas the coinjection of TCF21 high TPCs and CRC cells markedly promoted CRCLM. Mechanistically, loss of integrin α5 inhibited the FAK/PI3K/AKT/DNMT1 axis to impair TCF21 DNA hypermethylation in TCF21 high TPCs. Conclusion This study uncovers a previously unidentified role of TPCs in haematogenous metastasis and provides a potential diagnostic marker and therapeutic target for CRC metastasis.
An immunosuppressive tumor microenvironment limits the efficacy of immunotherapy, thus patients with MSS and pMMR mCRC often face great challenges.In this phase II trial, patients received Gamma Knife SBRT combined with Tislelizumab. P Biomarker analysis was performed pre- and post-treatment. From November 2022 to July 2024, 13 of 20 patients achieved PR, 6 achieved SD. mPFS was 10.7 months (95% CI, 6.4-15.0). With no grade 4 events noted, common adverse events included nausea (65%), anemia (55%), and fatigue (45%). For patients who had not responded to first and second-line therapies, the combo of Gamma Knife SBRT and tislelizumab showed high efficacy and reasonable safety. Significant post-radiotherapy improvements in the tumor’s immunosuppressive microenvironment. These results imply that patients with pMMR/MSS/MSI-L mCRC who were unresponsive to the first and second-line chemotherapy, Gamma Knife SBRT with tislelizumab provides a safe and powerful later-line treatment alternative.
Neoantigen-targeted immunotherapy is a rapidly advancing field that holds great promise for treating cancer. The recognition of antigens by immune cells is a crucial step in tumor-specific killing, and neoantigens generated by mutations in cancer cells possess high immunogenicity and are selectively expressed in tumor cells, making them an attractive therapeutic target. Currently, neoantigens find utility in various domains, primarily in the realm of neoantigen vaccines such as DC vaccines, nucleic acid vaccines, and synthetic long peptide vaccines. Additionally, they hold promise in adoptive cell therapy, encompassing tumor-infiltrating cells, T cell receptors, and chimeric antigen receptors which are expressed by genetically modified T cells. In this review, we summarized recent progress in the clinical use of tumor vaccines and adoptive cell therapy targeting neoantigens, discussed the potential of neoantigen burden as an immune checkpoint in clinical settings. With the aid of state-of-the-art sequencing and bioinformatics technologies, together with significant advancements in artificial intelligence, we anticipated that neoantigens will be fully exploited for personalized tumor immunotherapy, from screening to clinical application.
Abstract An immunosuppressive tumor microenvironment limits the efficacy of immunotherapy, thus patients with MSS and pMMR mCRC often face great challenges.In this phase II trial, patients received Gamma Knife SBRT combined with Tislelizumab. P Biomarker analysis was performed pre- and post-treatment. From November 2022 to July 2024, 13 of 20 patients achieved PR, 6 achieved SD. mPFS was 10.7 months (95% CI, 6.4-15.0). With no grade 4 events noted, common adverse events included nausea (65%), anemia (55%), and fatigue (45%). For patients who had not responded to first and second-line therapies, the combo of Gamma Knife SBRT and tislelizumab showed high efficacy and reasonable safety. Significant post-radiotherapy improvements in the tumor’s immunosuppressive microenvironment. These results imply that patients with pMMR/MSS/MSI-L mCRC who were unresponsive to the first and second-line chemotherapy, Gamma Knife SBRT with tislelizumab provides a safe and powerful later-line treatment alternative. Statement of significance This study offers a safe and powerful option for pMMR/MSS/MSI-L mCRC patients fail to first and second-line chemotherapy. And discover Gamma Knife SBRT contributed to potentially converting the suppressive “cold” tumor immune microenvironment into an activated “hot” microenvironment conducive to immunotherapy efficacy in pMMR CRC.
Background. Colorectal cancer (CRC) is the third most common malignancies worldwide. Ferroptosis is a programmed, iron-dependent cell death observed in cancer cells. However, the prognostic potential and immunotherapy biomarker potential of ferroptosis-related genes (FRGs) in CRC patients remains to be clarified. Methods. At first, we comprehensively analysed the different expression and prognosis of related FRGs in CRC patients based on TCGA cohort. The relationship between functional enrichment of these genes and immune microenvironment in CRC was investigated using the TCGA database. Prognostic model was constructed to determine the association between FRGs and the prognosis of CRC. Relative verification was done based on the GEO database. Meanwhile, the ceRNA network of FRGs in the model was also performed to explore the regulatory mechanisms. Results. Eight differentially expressed FRGs were associated with the prognosis of CRC patients. Patients from the TCGA database were classified into the A, B, and C FRG clusters with different features. And FRG scores were constructed to quantify the FRG pattern of individual patients with colorectal cancer. The CRC patients with higher FRG score showed worse survival outcomes, higher immune dysfunction, and lower response to immunotherapy. The prognostic model showed a high accuracy for predicting the OS of CRC. Finally, a ceRNA network was analysed to show the concrete regulation mechanisms of critical FRGs in CRC. Conclusions. The FRG risk score prognostic model based on 8 FRGs exhibit superior predictive performance, providing a novel prognostic model with a high accuracy for CRC patients. Moreover, FRG score can be the potential biomarker of the response of immunotherapy for CRC.
Background: Neuroendocrine carcinoma of the breast (NECB) is a rare subtype of breast cancer, comprising only 0.1% to 5% of all breast cancer cases. Despite its rarity, it is important to gain a better understanding of the epidemiological, clinical, and prognostic features of NECB. The purpose of the study was to obtain population-based evaluations of the epidemiological and survival outcomes of NECB. Methods: The data of patients with neuroendocrine carcinoma diagnosed and enrolled between 2000 and 2017 were obtained from the Surveillance, Epidemiology, and End Results (SEER) database. Descriptive statistical analyses were used to assess the distribution and tumor-related characteristics of these patients. Kaplan-Meier curves and univariate and multivariate Cox proportional risk models were used to analyze variables that might be associated with prognosis. Results: This study included 7,856 patients with neuroendocrine carcinoma. The median age of the patients was 64 years, and most of them were female, White, and diagnosed at ≥60 years old. The most common pathological type was neoplasm. Survival analysis indicated that there were significant differences in age, marital status, registration location, American Joint Committee on Cancer (AJCC) stage, breast subtype, surgery of primary tumor, and no cancer cause surgery patients with NECB. The results also indicated that treatment with surgery, including surgery of primary tumor, surgery combined with radiation, and no cancer cause surgery, were all effective in improving the prognosis compared with not providing surgical treatment. Conclusions: In conclusion, NECB is a very rare lesion for which age, marital status, registration location, and surgery, AJCC stage, breast subtype were found to be independent prognostic factors.
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