World Journal of Oncology最新文献

Background: The prognosis for urothelial carcinoma remains poor, with limited therapeutic options, emphasizing the need for further research into targeted therapies. The prognostic and predictive significance of human epidermal growth factor receptor 2 (HER2) expression in urothelial carcinoma remains unclear, with previous studies reporting conflicting results.

Methods: We conducted a retrospective analysis of advanced urothelial carcinoma cases diagnosed between January 2017 and December 2022. HER2 status was prospectively determined using the Leica CB11 antibody on available biopsy specimens. Patient data, tumor characteristics, and survival outcomes were retrieved from hospital records for analysis.

Results: Of the 84 patients initially identified with muscle-invasive disease, HER2 immunohistochemistry (IHC) was performed on 50 samples. Among these, 54% exhibited HER2 scores ≥ 1+, with 22% classified as HER2-positive (3+ score by IHC), 10% as equivocal (2+ score by IHC), and 22% as HER2-low (1+ score by IHC). The distribution of HER2 score ≥ 1+ tumors included 25.7% in the bladder, 20.0% in the renal pelvis, and none in the ureter. HER2-positive (3+ score by IHC) tumors were all histological grade 3. Among these patients, 13.4% presented with localized disease, 20% with locally advanced disease, and 50% with metastatic disease at the time of diagnosis. Notably, 42.8% of recurrent tumors originating from the renal pelvis and 62.5% of those from the bladder exhibited HER2 scores ≥ 1+. Among patients diagnosed with non-metastatic disease, 100% with renal pelvis tumors and 75% with bladder tumors experienced metastatic recurrence if they were HER2-positive (3+ score by IHC). The overall survival for HER2-negative patients was 31.0 months (95% confidence interval (CI): 15.29 - 66.70) compared to 13.0 months (95% CI: 7.32 - 18.68) in the HER2 score ≥ 1+ population (P = 0.0029).

Conclusions: In this cohort of Mexican patients with urothelial carcinoma, HER2 expression was observed in 54.4% of cases. HER2-positive (+3 by IHC) tumors were associated with higher histological grade and worse prognostic outcomes, including increased recurrence, progression, and mortality.

Background: Peritumoral lidocaine infiltration prior to excision is associated with better survival in breast cancer (BC), which led us to hypothesize that innervation to the tumor affects its biology and patient survival. Activity-regulated cytoskeleton-associated protein (ARC) gene expression is known to be regulated by neuronal activity. Therefore, we studied the clinical relevance of ARC gene expression as a surrogate of neuronal activity in BC.

Methods: Sweden Cancerome Analysis Network - Breast (SCAN-B (GSE96058), n = 3,273) cohort and The Cancer Genome Atlas (TCGA, n = 1,069) were analyzed.

Results: High ARC expression was significantly associated with smaller tumor size, without lymph node metastasis, and less stage IV disease in one cohort, but not validated by the other. Estrogen receptor-positive (ER⁺)/human epidermal growth factor receptor 2-negative (HER2^-) and luminal A expressed significantly higher ARC compared to the other subtypes in both cohorts (P < 0.005). High ARC BC was significantly associated with lower Nottingham histological grade and lower Ki67 gene expression consistently in ER⁺/HER2^- but not triple negative breast cancer (TNBC) in both cohorts (P < 0.001). Cell proliferation-related gene sets in the Hallmark collection (E2F targets, G2M checkpoint, and mitotic spindle) were significantly enriched to low ARC BC in ER⁺/HER2^- but not TNBC in TCGA. The stromal cells (fibroblasts, vascular endothelial cells, and adipocytes) were all significantly infiltrated in high ARC ER⁺/HER2^-, but not in TNBC, except for neurons. Homologous recombination deficiency, intratumor heterogeneity, fraction altered, silent or non-silent mutation rate were all significantly lower in high ARC ER⁺/HER2^- but not TNBC. Although there was no difference in single nucleotide variant or indel neoantigens, tumor infiltrating lymphocytes, and cytolytic activity by ARC expression regardless of subtype, multiple immune cells were significantly infiltrated in high ARC ER⁺/HER2^-, including CD8, CD4 memory cells, helper type II T cells, regulatory T cells, M2 macrophages, and B cells (all P < 0.03 in both cohorts), but not in TNBC. Disease-specific and overall survival were significantly improved in high ARC ER⁺/HER2^- consistently in both cohorts (all P < 0.05), but this was not the case in TNBC.

Conclusion: ARC gene expression was associated with less cancer cell proliferation, high infiltration of stromal cells and immune cells, and better survival in the ER⁺/HER2^- but not TNBC subtype.

Background: In the present day, hepatocellular carcinoma (HCC) remains a formidable threat to human health. Actin-related protein 10 (ACTR10) is related to tyrosine kinase inhibitor (TKI) resistance. A comprehensive analysis of ACTR10 in HCC will further our understanding of the molecular mechanisms underlying this resistance phenomenon, shedding light on potential therapeutic strategies for combating TKI resistance in HCC.

Methods: We conducted an integration of high-throughput datasets across various centers, analyzing ACTR10 expression using the Cancer Cell Line Encyclopedia (CCLE) and assessing its implications through clustered regularly interspaced short palindromic repeats (CRISPR) knockout screen. Pathogenic mechanisms were elucidated through enrichment analysis. Prognostic assessment utilized Kaplan-Meier survival and univariate Cox analyses. An integrated analysis of gene expression profiles related to TKI in HCC was conducted, and TKI resistance mechanisms were explored through enrichment analysis. Potential therapeutic drugs were identified using the Drug Gene Budger database and molecular docking techniques.

Results: The standardized mean difference (SMD) of 0.34 (95% confidence interval (CI): 0.22 - 0.45, P < 0.05) and ACTR10-dependent growth in HCC cells confirm its upregulation in HCC. The area under the summary receiver operating characteristic (sROC) curve was 0.69, indicating moderate discriminative ability of ACTR10 in HCC patients. ACTR10 exerts its pro-cancer effect by influencing RNA splicing, mRNA processing and nucleocytoplasmic transport. A hazard ratio of 2.19 (95% CI: 1.56 - 3.08, P < 0.05) identifies ACTR10 as an independent prognostic risk factor. Additionally, the SMD of 0.88 (95% CI: 0.01 - 0.76, P < 0.05) validates ACTR10 as a TKI-resistance gene, mediating resistance via enhanced exocytosis, autophagy, and apoptosis in HCC patients. Trichostatin A emerges as a prospective targeted agent for HCC.

Conclusion: The upregulation of ACTR10 accelerates HCC progression, promotes TKI resistance, and emerges as a prospective target for the treatment of HCC.

Background: The effectiveness of immune checkpoint therapy highlights the need to understand abnormal programmed cell death protein-1 (PD-1) expression in nasopharyngeal carcinoma (NPC), especially when treatments fail, or resistance develops. Interferon gamma (IFN-γ) signaling is crucial for regulating programmed cell death-ligand 1 (PD-L1) expression. Our study focuses on interferon gamma receptor 2 (IFNGR2), an essential part of the IFN-γ pathway, and its impact on malignant traits in NPC.

Methods: The expression levels of IFNGR2 and PD-L1 were accessed using quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). To understand the cellular phenotypic effects, small interfering RNA (siRNA)/short hairpin RNA (shRNA) knockdown techniques were used to evaluate cell viability, clonogenic survival, migration and invasion, immunohistochemistry, and tumor formation assays. The relationship between IFNGR2 and microRNAs (miRNAs)/circular RNAs (circRNAs) will be verified using methods such as circRNA stability assay, rescue, and dual-luciferase reporter assay.

Results: IFNGR2 was significantly overexpressed in NPC, and its expression positively correlated with PD-L1 levels. This overexpression contributed to increased cell proliferation, migration, invasion, clonogenicity, and tumor growth. Additionally, we identified an oncogenic circular RNA, circ_001377, and uncovered a novel mechanism by which upregulation of circ_001377 competitively bound to miR-498-3p. This interaction reduced miR-498-3p's ability to target IFNGR2. As a result, the diminished miR-498-3p led to increased IFNGR2 expression, which subsequently activated the IFN-γ signaling pathway and drove abnormal PD-L1 expression.

Conclusions: IFNGR2 is an oncogenic factor in NPC. The circ_001377/miR-498-3p interaction drives IFNGR2 upregulation and PD-L1 overexpression, suggesting that targeting this axis could improve therapeutic outcomes.

Background: Chemotherapy has a substantial role in decreasing the risk of recurrence and mortality in breast cancer (BC) in a dose-dependent manner where a low relative dose intensity (RDI) is associated with unfavorable outcomes. Several baseline clinicopathological factors, including pro-inflammatory biomarkers, were found to be significant determinants of low RDI. This study aimed to explore the occurrence of low RDI and its influencing factors in women with BC.

Methods: This cross-sectional study recruited 172 women with stage I-IV BC who received first-line chemotherapy. We collected patients' clinical, pathological, and treatment data and analyzed the pre-chemotherapy C-reactive protein (CRP) and interleukin (IL)-6 levels using a quantitative enzyme-linked immunosorbent assay (ELISA). We calculated the RDI based on the actual and planned delivered chemotherapy dose (mg/m²) and duration (weeks). RDI less than 85% was defined as "low". Multivariate analysis with logistic regression was conducted to determine the association between pre-chemotherapy parameters and RDI < 85%.

Results: The mean CRP level was 10.82 ± 19.17 mg/L (0.00 - 151.73 mg/L) and the mean IL-6 level was 1.12 ± 3.41 pg/mL (0.00 - 27.67 pg/mL). The average RDI for all patients was 93±8.19%. An RDI < 85% occurred in 23 patients (13.4%). The presence of diabetes mellitus (odds ratio (OR): 4.78, 95% confidence interval (CI): 1.03 - 22.27, P = 0.046), triple-negative tumors (OR: 6.45, 95% CI: 1.39 - 29.83, P = 0.017), and IL-6 levels > 0.5 pg/mL (OR: 3.45, 95% CI: 1.01 - 11.79, P = 0.049) was associated with an increased low RDI risk.

Conclusion: The proportion of BC patients receiving a low chemotherapy RDI in our study was comparable to published literature and drove close monitoring of patients at risk to provide adequate management.

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Background: Gut microbiota (GM) is associated with both the occurrence and development of pancreatic cancer (PC), and immune cells potentially play a role in this process. This study sought to evaluate the causative effect of GM on PC and to ascertain possible immune cell mediators.

Methods: The study primarily employed a two-step, two-sample Mendelian randomization (MR) analysis to explore the causal relationship between GM and PC within the European population, placing particular emphasis on the application of the inverse variance weighted (IVW) approach. Additionally, mediation analysis was conducted to explore the potential influence of immune cells as mediators.

Results: The MR analysis revealed a significant association between Geminocystis and the risk of PC. Increased abundance of Geminocystis was positively associated with the risk of PC (odds ratio (OR): 2.580, 95% confidence interval (CI): 1.050 - 6.342). The validity of the outcomes was also verified by the sensitivity analysis. The mediation MR analysis showed that the B-cell absolute count served as a partial intermediary in the causal link between Geminocystis and the risk of PC, contributing to 15.321% of the mediating impact.

Conclusion: This MR study demonstrated that Geminocystis has a causal relationship with PC and potentially mediates B-cell absolute count in the TBNK panel.

Background: The incidence of cardiotoxicity events in patients who use 5-fluorouracil (5-FU) and capecitabine monotherapy remains unclear since previous studies reported the prevalence in patients who used combination regimens. We aimed to systematically review and meta-analyze the incidence of cardiotoxicity in fluorouracil and capecitabine monotherapy users.

Methods: The study protocol was registered with PROSPERO (CRD42023441627). Systematic searches were conducted in five databases (CINAHL, OpenGrey, PubMed, ScienceDirect, and Scopus). The Cochrane Risk-of-Bias tool and the Risk Of Bias In Non-randomized Studies were used to evaluate the risk of bias. Pooled prevalence and 95% confidence interval (CI) were calculated using the DerSimonian-Laird random effect models. The funnel plot was used to assess the publication bias.

Results: Eighty studies were included. There were 24 randomized controlled trials (RCTs) with low to high risk of bias and 56 non-RCTs with critical risk of bias. The pooled prevalence of cardiotoxicity from 5-FU was 3.5% (95% CI: 2.7 - 4.2; P < 0.001; I² = 73.86%). The pooled prevalence of cardiotoxicity in capecitabine users was 2.8% (95% CI: 1.6 - 4.0; P < 0.001; I² = 72.62%).

Conclusions: The prevalence of cardiotoxicity from 5-FU and capecitabine was classified as common. Cardiotoxicity may have not been associated with the cumulative dose of 5-FU or capecitabine.

The increasing global incidence of breast cancer underscores the significance of breast reconstruction in enhancing patients' quality of life. Breast reconstruction primarily falls into two categories: implant-based techniques and autologous tissue transfers. In this study, we present a comprehensive review of various aspects of implant-based reconstruction, including different types of implants, surgical techniques, and their respective advantages and disadvantages. For autologous breast reconstruction, we classified flaps and optimal harvest sites and provided detailed insights into the characteristics, benefits, and potential complications associated with each flap type. In addition, this review explores the emerging role of fat grafting, which has received increasing attention in recent years. Despite advancements, there remains substantial scope for further improvements in breast reconstruction, emphasizing not only aesthetic outcomes, but also a reduction in complications and postoperative recovery. By offering a comprehensive overview of the historical evolution, current landscape, and future prospects of breast reconstruction, this review aims to provide readers with a comprehensive understanding of breast cancer management strategies.

Background: Bladder cancer patients unable to receive cystectomy or who choose to pursue organ-sparing approach are managed with definitive (chemo)radiotherapy. However, this standard of care has not evolved in decades and disease recurrence and survival outcomes remain poor. Identifying novel therapies to combine with radiotherapy (RT) is therefore paramount to improve overall patient outcomes and survival. One approach is to find cellular mechanisms that can be targeted to increase the radiosensitivity of bladder cancer. The stress-activated kinase directly downstream from p38 mitogen-activated protein kinase (MAPK), mitogen-activated protein kinase activated protein kinase 2 (MAPKAPK2 or MK2), has been shown to enhance cancer-mediated inflammation, mesenchymal gene expression, and in vivo tumor growth. Here we examined the impact that MK2 knockdown (KD) has on bladder cancer cell radiosensitivity.

Methods: We utilized short hairpin RNA (shRNA) KD of MK2 using lentiviral transfection in the bladder cancer cell lines, T24 and HTB9. We compared the growth of KD cells to wild type using colony formation assays, proliferation assays and cell counts to determine differences in cell growth. Apoptosis was examined by annexin-based flow cytometry and western blots. Flow cytometry was also used for cell cycle analysis.

Results: KD clones showed a greater than 90% inhibition of MK2 expression as determined by western blot. Clonogenic assays exhibited an increase in radiosensitivity among the MK2 KD bladder cancer cells. These data were supported with proliferation assays that displayed a greater reduction in cell number following RT in MK2 KD bladder cancer cells. Annexin V binding in bladder cancer cells suggested increased apoptosis in MK2 KD cells. This was confirmed by comparing the amount of cleaved caspase products for the caspases 3 and 8 to scrambled control (SCR), and the release of cytochrome C into the cytosol. Both cell types showed disruptions in the cell cycle but at different points in the cycle.

Conclusion: These results show that MK2 controls irradiation-induced apoptosis in bladder cancer cells.