World Journal of Oncology最新文献

Background: The aim of the study was to identify the factors that cause delays in treatment initiation, such as race, gender, education, income status, and associated health comorbidities, as these can increase mortality.

Methods: We utilized the Surveillance, Epidemiology, and End Results (SEER) database to identify contributing factors such as sociodemographics that impact time from diagnosis to treatment initiation (TTI) in lung cancer, breast cancer, colorectal cancer (CRC) and prostate cancer from 2015 to 2020 in 991,772 patients. Variables studied included age, sex, race, marital status, geographic location, household income, stage, and grade. Two-way analysis of variance (ANOVA) was utilized to determine if significant differences existed between the effects on TTI with respect to the variables. TTI was measured in months. Based on the aforementioned variables, propensity scores were created for odds of receiving late treatment exceeding 1 month from diagnosis. Patients were matched 1:1. Based on the propensity score, a competing risk regression model was utilized to determine risk factors associated with late treatment.

Results: Similar trends were noted among all cancers. With respect to gender, in breast cancer, TTI was shorter in males (1.02 months) compared to females at 1.24 (P < 0.001). A longer time to TTI was noted in patients greater than 65 years with lung cancer (1.38 months, P < 0.001). Shorter TTI was evident across all cancers for White patients (P < 0.001). Shorter TTI was noted among married versus widowed, divorced, or single patients. Patients with lower income and non-metropolitan regions had shorter TTI among all cancers. More aggressive cancers had shorter TTI. Propensity matched competing risks hazard analysis revealed similar results with younger patients, those living in metropolitan regions, those earning greater than $35,000, and localized and well-differentiated cancers being at greater risk of having a treatment delay greater than 1 month.

Conclusion: Health disparities still exist today, and this becomes more evident in our study as age, sex, and race, among other factors, can cause delays in time from diagnosis of cancer to treatment initiation, potentially negatively affecting survival in these populations.

Background: Tyrosine kinase inhibitors (TKIs) are first-line therapies for hepatocellular carcinoma (HCC), but the drug resistance restricts the long-term clinical outcomes. This study aimed to investigate the expression patterns and possible clinical significance of a TKI-resistant gene zeste white 10 (ZW10) in HCC.

Methods: Clustered regularly interspaced short palindromic repeats (CRISPR) screening was conducted to obtain TKI-resistant genes. Pan-cancer analysis was employed to analyze the expression landscape of the critical TKI-resistant gene ZW10. Transcriptional expression data for ZW10 were obtained from 76 centers, including 3,312 HCC samples and 2,703 noncancerous tissues. A summary receiver operating characteristic (SROC) curve was built to evaluate ZW10 expression characteristics in HCC. Unpaired two-sample Wilcoxon method was conducted to analyze ZW10 expression levels in HCC of various etiologies. Univariate Cox method was employed to assess the prognostic value of ZW10. Moreover, the gene function within HCC cell lines, the TKI treatment responses, key pathways, and tumor microenvironment of ZW10 were bioinformatically investigated. Drug prediction and molecular docking techniques were used to explore the potency of ZW10 as a novel therapeutic target.

Results: The abundance of small guide RNA (sgRNA) corresponding to ZW10 gene was decreased in the whole genome CRISPR knockout library (LogFC = -1.19), indicating that ZW10 may participate in TKI resistance. The differential expression landscape of ZW10 was found in various malignancies including HCC, which was associated with poorer prognosis. Pooled standardized mean difference (SMD) of ZW10 mRNA expression was 0.47 (95% confidence interval (CI): 0.32 - 0.63), the area under SROC was 0.76 (95% CI: 0.72 - 0.79), the sensitivity was 0.63 (95% CI: 0.53 - 0.72), and the specificity was 0.77 (95% CI: 0.67 - 0.84). ZW10 was investigated significant for the growth of HCC cells. Nucleocytoplasmic transport was the possible pathway that ZW10 involved. High level of ZW10 was reversely associated with TKI responses and the abundance of immune cell infiltration. Mocetinostat and capecitabine were predicted to be the potential inhibitors targeting ZW10 with a minimum binding energy of -8.2 and -7.1 kcal/mol, respectively.

Conclusions: ZW10 is considered a TKI-resistant and tumor-supportive gene, which is also a promising novel prognostic biomarker for HCC or a therapeutic target for overcoming TKI resistance.

Background: Hepatocellular carcinoma (HCC) is an arterialized tumor; thus, anti-angiogenesis targeted therapy is in clinical practice. Herein, we hypothesized that HCC with high angiogenesis is biologically aggressive with worse survival.

Methods: Angiogenesis score (AS) was derived from the Molecular Signatures Database (MSigDB) Hallmark Angiogenesis Gene Set, and median was used to divide high versus low groups. Transcriptome of HCC patients of The Cancer Genome Atlas (TCGA, n = 386) and GSE76427 (n = 115) cohorts were analyzed.

Results: High AS correlated with angiogenesis-related gene expressions. Both microvascular and lymphatic endothelial cell infiltrations were higher in high angiogenesis HCC. Surprisingly, no survival difference was seen with varying levels of angiogenesis. High angiogenesis significantly enriched tumor aggravating signaling pathways: glycolysis, Notch, Hedgehog, KRAS, epithelial mesenchymal transition, and transforming growth factor-beta (TGF-β) in Gene Set Enrichment Analysis (GSEA), but also infiltrated less CD8⁺ T cells and T-helper 1 cells, and higher M1 macrophages and conventional dendritic cells (cDCs) with elevated cytolytic activity score in both cohorts. In agreement, immune response-related gene sets: inflammatory response, tumor necrosis factor-alpha (TNF-α) signaling, allograft rejection, interferon-alpha, and interferon-gamma were all enriched to high angiogenesis HCC. Programmed cell death protein 1 (PD1), programmed death ligand 1 (PD-L1), programmed death ligand 2 (PD-L2), and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) were higher in high angiogenesis HCC in TCGA, but not in GSE76427 cohort.

Conclusions: Angiogenesis quantified using transcriptome of HCC patients demonstrated that it is associated with aggressive biology but also with tumor immunogenicity and immune response that counterbalance and did not reflect in survival. Given high expression of immune checkpoint molecules, we cannot help but speculate that immunotherapy may be useful for high angiogenesis HCC patients.

Malignant biliary obstruction can, in rare cases, arise from metastases to the biliary tree from distant primary tumors. This phenomenon often poses a diagnostic challenge, as bile duct metastases may clinically and radiologically mimic primary biliary tumors, such as cholangiocarcinoma. We present a unique case of solitary, synchronous intraductal biliary metastasis in a patient with colorectal adenocarcinoma that led to biliary obstruction. The patient initially presented with a new diagnosis of colon cancer at the hepatic flexure and was found, on cross-sectional imaging, to have biliary obstruction due to an intraductal mass. Initially, the nature of the intraductal lesion was uncertain; however, it was ultimately confirmed through histopathological examination to be metastatic colorectal adenocarcinoma. This case underscores the difficulty of distinguishing metastatic biliary obstruction from primary biliary tumors and highlights the importance of considering metastatic disease in atypical presentations of biliary masses. We discuss several key radiologic and histopathological features that may help differentiate intraductal colorectal adenocarcinoma metastases from primary biliary tumors.

Background: Tumor necrosis factor-alpha (TNF-α) is a pro-inflammatory cytokine implicated in the pathogenesis and progression of various cancers, including breast cancer. Elevated TNF-α levels have been associated with cancer progression, metastasis, and treatment outcomes. This systematic review aimed to synthesize existing evidence on the relationship between TNF-α levels and breast cancer.

Methods: A systematic search of observational studies published from inception to June 2024 was conducted in PubMed, ScienceDirect, Sage Journals, and Google Scholar to identify studies examining TNF-α levels in breast cancer patients compared to healthy controls, as well as its association with metastasis, response to chemotherapy, and survival outcomes. Inclusion criteria were applied to select eligible studies, resulting in nine studies that met the criteria for this review.

Results: Eight eligible studies reported that breast cancer patients exhibited higher TNF-α levels than healthy controls. Two studies indicated that TNF-α levels were elevated in patients with metastatic breast cancer. Additionally, two studies found that patients with higher TNF-α levels tended to have a poorer response to chemotherapy. One study revealed that patients with elevated TNF-α levels had a lower mean survival time.

Conclusions: Elevated TNF-α levels are significantly associated with breast cancer progression, metastasis, and poorer treatment outcomes. These findings underscore the potential of TNF-α as a biomarker for breast cancer prognosis and therapeutic response. Further research is warranted to explore the underlying mechanisms and validate TNF-α as a target for therapeutic intervention in breast cancer management.

Background: Sirtuin 6 (Sirt6) is expressed at increased levels in many tumors and may be involved in immunoregulation. The present study investigated how Sirt6 in tumor cells affects immune surveillance.

Methods: The human tumor cell lines A2780, HeLa, Huh7, MBA-MD-231, SMMC-7721 and SW480 were incubated with UBCS039, a target-selective activator of Sirt6, to stimulate Sirt6 activity. These cells, following washing to remove residual UBCS039, were cultured with human naive CD4⁺ T cells in the Transwell to observe the T cell differentiation. Regulatory T cells (Tregs) among CD4⁺ T cells and the levels of various cytokines and adenosine (ADO), an immunosuppressive metabolite, in the culture medium, were measured via flow cytometry. The treated tumor cells were examined via transcriptomic analysis. The transcriptomic results, as well as programmed cell death protein-1 (PD-1), programmed cell death-ligand 1 (PD-L1) and Sirt6 expression in tumor cells and CD4⁺ T cells were verified via real-time polymerase chain reaction (PCR).

Results: Following culture with UBSC039-pretreated tumor cells, the proportion of Tregs among CD4⁺ T cells was significantly increased. PD-L1 and Sirt6 expressions in UBS039-pretreated tumor cells and PD-1 expression in cocultured CD4⁺ T cells were also increased. Moreover, the ADO level increased, and the interleukin (IL)-10, interferon (IFN)-α2, IFN-γ and monocyte chemoattractant protein-1 (MCP-1) levels decreased in the coculture medium. Transcriptomic analysis revealed significant downregulation of the antitumor genes BASP1, CPS1, GNG11, MFAP5, NNMT and SMOC1, upregulation of the tumor-promoting genes FOXA2, GSTP1, RASEF and ZNF844, and activation of adherens junctions, tumor necrosis factor (TNF)-signaling and the circadian rhythm pathway in UBCS039-pretreated SMMC-7721 cells. The above results were verified in all six cell lines.

Conclusions: The present study suggested that increased Sirt6 expression and activity in tumor cells can suppress immune surveillance by increasing Treg, ADO, PD-1 and PD-L1 levels, decreasing IFN-γ production, and altering tumor-promoting and antitumor gene expression in the microenvironment.

Background: Treatment-related amenorrhea (TRA) is a common side effect of treatment in premenopausal patients with breast cancer, with important consequences for patient counseling and management. Its occurrence and potential influence on survival outcomes remain active areas of investigation. This study aimed to evaluate the incidence, risk factors, and prognostic significance of TRA in patients with breast cancer.

Methods: This is a retrospective cohort study. Patients were interviewed during and after chemotherapy to assess their menstrual status. Sociodemographic, clinical, and treatment data of patients were also collected. TRA was classified into early amenorrhea (EA) and late amenorrhea (LA) based on the duration of amenorrhea. Univariable and multivariable logistic regression were used to identify risk factors of EA and LA. Kaplan-Meier curves and Cox proportional hazards analyses were used to investigate the impact of EA and LA on 3-year overall survival (OS).

Results: There were 81 patients who were eligible for the final analysis. Of these subjects, 14 (17.3%) developed no amenorrhea, 67 (82.7%) developed EA, and 45 (55.6%) developed LA. We did not find any significant independent risk factor for EA. Age > 45 years (odds ratio (OR): 4.00; confidence interval (CI): 1.23 - 13.01; P = 0.021) and the usage of hormonal therapy (OR: 4.96; CI: 1.58 - 15.53; P = 0.006) independently significantly increase the risk of LA, whereas a metastatic disease status decreased the risk (OR: 0.20; CI: 0.04 - 0.90; P = 0.036). Both EA (hazard ratio (HR) = 0.262, CI: 0.105 - 0.653; P = 0.002) and LA (HR = 0.234, CI: 0.091 - 0.604; P = 0.001) were associated with an improved 3-year OS rate.

Conclusions: Age > 45 years and the usage of hormonal therapy are risk factors for LA, while metastatic disease was associated with a decreased risk. Both EA and LA had a significant association with favorable 3-year OS. These findings enable clinicians to provide personalized guidance, tailor treatment strategies, and improve the outcomes of premenopausal patients with breast cancer. Standardization of how TRA is defined and assessed in future studies is essential to improve comparability and enhance the understanding of its clinical implications.

Background: Vascular endothelial growth factor-A (VEGFA) is a key inducer of angiogenesis, responsible for generating new blood vessels in the tumor microenvironment (TME) and facilitating metastasis. Notably, Avastin, which targets VEGFA, failed to demonstrate any significant benefit in clinical trials for breast cancer (BC). This study aimed to investigate the clinical relevance of VEGFA gene expression in BC.

Methods: A total of 7,336 BC patients across eight independent cohorts: ISPY2 (GSE173839), Sweden Cancerome Analysis Network-Breast (SCAN-B) (GSE96058), Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), GSE25066, GSE163882, GSE34138, GSE20194, and The Cancer Genome Atlas (TCGA), were analyzed. The calculated median VEGFA expression level was used to stratify these cohorts into high and low groups.

Results: High VEGFA was associated with worse disease-free, disease-specific, and overall survival in the METABRIC cohort, with findings supported by the SCAN-B cohort, which also showed worse overall survival (all P < 0.02). High VEGFA expression was seen in triple-negative breast cancer (TNBC) but not in BC with lymph node metastasis. Additionally, there was a significant correlation between high VEGFA expression and higher silent and non-silent mutations, single-nucleotide variant (SNV) neoantigens, homologous recombination defect, intratumoral heterogeneity, in the TCGA cohort. In the TCGA, METABRIC, and SCAN-B cohorts, high VEGFA BC was also associated with higher cell proliferation: higher Ki67 gene expression, higher Nottingham histological grade, and consistent enrichment of all the Hallmark cell proliferation-related gene sets. Unexpectedly, the angiogenesis gene set was not enriched in any of the cohorts and showed no association with infiltrations of lymphatic or blood vascular endothelial cells besides pericytes. High VEGFA BC had significantly less infiltration of anti-cancer immune cells but higher infiltration of pro-cancer immune cells in TCGA, METABRIC, and SCAN-B cohorts. Interestingly, BC, which had a pathological complete response (pCR) after anthracycline- and taxane-based neoadjuvant therapy, was associated with significantly heightened VEGFA expression in both estrogen receptor (ER)+/human epidermal growth factor receptor 2 (HER2)- and TNBC subtypes in the GSE25066 cohort and after immunotherapy in ER+/ HER2- subtype, but not TNBC in the ISPY2 cohort.

Conclusions: Our research indicates that high VEGFA BC confers high cell proliferation, reduced immune cell infiltration, and poorer survival, but allows better response to anthracycline- and taxane-based chemotherapy, and immunotherapy.