Magnetic resonance imaging-based lymph node radiomics for predicting the metastasis of evaluable lymph nodes in rectal cancer.

BACKGROUND: Lymph node (LN) staging in rectal cancer (RC) affects treatment decisions and patient prognosis. For radiologists, the traditional preoperative assessment of LN metastasis (LNM) using magnetic resonance imaging (MRI) poses a challenge. AIM: To explore the value of a nomogram model that combines Conventional MRI and radiomics features from the LNs of RC in assessing the preoperative metastasis of evaluable LNs. METHODS: In this retrospective study, 270 LNs (158 nonmetastatic, 112 metastatic) were randomly split into training (n = 189) and validation sets (n = 81). LNs were classified based on pathology-MRI matching. Conventional MRI features [size, shape, margin, T2-weighted imaging (T2WI) appearance, and CE-T1-weighted imaging (T1WI) enhancement] were evaluated. Three radiomics models used 3D features from T1WI and T2WI images. Additionally, a nomogram model combining conventional MRI and radiomics features was developed. The model used univariate analysis and multivariable logistic regression. Evaluation employed the receiver operating characteristic curve, with DeLong test for comparing diagnostic performance. Nomogram performance was assessed using calibration and decision curve analysis. RESULTS: The nomogram model outperformed conventional MRI and single radiomics models in evaluating LNM. In the training set, the nomogram model achieved an area under the curve (AUC) of 0.92, which was significantly higher than the AUCs of 0.82 (P < 0.001) and 0.89 (P < 0.001) of the conventional MRI and radiomics models, respectively. In the validation set, the nomogram model achieved an AUC of 0.91, significantly surpassing 0.80 (P < 0.001) and 0.86 (P < 0.001), respectively. CONCLUSION: The nomogram model showed the best performance in predicting metastasis of evaluable LNs.

Thermal ablation with and without adjuvant systemic therapy: a nationwide multicenter observational cohort study of solitary colorectal liver metastases.

BACKGROUND: Thermal ablation is routinely used for solitary colorectal liver metastases (SCLM), but the added value of adjuvant systemic therapy in SCLM remains unclear. This study aimed to compare the long-term outcomes for SCLM treated by ablation alone (AB) versus ablation plus systemic therapy (AS). METHODS: This multicenter retrospective study using nationwide data from fourteen institutions between October 2010 and May 2023, 369 patients with initial SCLM smaller than 5 cm, no extrahepatic metastases, and colorectal cancer R0 resection treated by thermal ablation were included. The crude analysis was used to analyze eligible cases between the two groups. The propensity score matching (PSM) to control for potential confounders in each matched group. Subgroup analyses were performed to identify specific survival benefits. RESULTS: 61.2% (226/369) of eligible patients were treated with AS and 38.8% (143/369) with AB. During the median follow-up period of 8.8 years, 1-/3-/5-year DFS/OS rates did not differ between the two groups, when analyzed via PSM (P=0.52/0.08). Subgroup analysis revealed that AS was significantly associated with better OS than AB in patients with plasma CEA >5 ug/L (P=0.036), T (III-IV) category of primary cancer (P=0.034), or clinical risk score (1-2) (P=0.041). In each matched group, we did find a significant difference in drug-related adverse events (P<0.001) between AS group (24.1%, 28/116) and AB group (0.0%, 0/116). CONCLUSIONS: For patients with plasma CEA >5 ug/L, T (III-IV) category of primary cancer, or clinical risk score (1-2), thermal ablation plus systemic therapy appeared to be associated with improved overall survival. Thermal ablation was equally effective in disease-free survival for treating solitary colorectal liver metastasis, whether with or without adjuvant systemic therapy.

Microwave ablation versus liver resection for primary intrahepatic cholangiocarcinoma within Milan criteria: a long-term multicenter cohort study.

Background: Ablation has been recommended by worldwide guidelines as first-line treatment for hepatocellular carcinoma (HCC), while evidence regarding its efficacy for primary intrahepatic cholangiocarcinoma (iCCA) is lacking. We aimed to study the efficacy of ablation in treating iCCA by comparing its prognosis with surgery. Methods: In this real-world multicenter cohort study from January 2009 to June 2022, 10,441 iCCA patients from ten tertiary hospitals were identified. Patients who underwent curative-intent microwave ablation (MWA) or liver resection (LR) for tumors within Milan criteria were included. One-to-many propensity score matching (PSM) at variable ratios (1:n ≤4) was used to balance baseline characteristics. Mediation analysis was applied to identify potential mediators of the survival difference. Findings: 944 patients were finally enrolled in this study, with 221 undergoing MWA and 723 undergoing LR. After PSM, 203 patients in the MWA group were matched with 588 patients in the LR group. The median follow-up time was 4.7 years. Compared with LR, MWA demonstrated similar overall survival (5-year 44.8% versus 40.4%; HR 0.96, 95% CI 0.71-1.29, P = .761). There was an improvement in the 5-year disease-free survival rate for MWA from 17.1% during the period of 2009-2016 to 37.3% during 2017-2022, becoming comparable to the 40.8% of LR (P = .129). The proportion of ablative margins ≥5 mm increased from 25% to 61% over the two periods, while this proportion of surgical margins was 62% and 77%, respectively. 34.5% of DFS disparity can be explained by the mediation effect of margins (P < .0001). Similar DFS was observed when both ablative and surgical margins exceeded 5 mm (HR 0.83, 95% CI 0.52-1.32, P = .41). Interpretation: MWA may be considered as a viable alternative to LR for iCCA within Milan criteria when an adequate margin can be obtained. Funding: National Natural Science Foundation of China.

Quantitative parameters in novel spectral computed tomography for assessing gastric cancer and cell proliferation.

OBJECTIVES: To investigate the diagnostic ability of novel spectral CT-derived parameters for gastric cancer histological types and Ki-67 expression. METHODS: A total of 72 patients with histologically proven gastric cancer (GC) were retrospectively included in this study. All patients underwent dual-phase enhanced abdominal spectral CT. The arterial (AP) and venous phase (VP) slope of the spectral curve (λHU), iodine concentration (IC), normalized IC (NIC), effective atomic number (Zeff) and iodine-no-water concentration were retrospectively compared between patients with low and high Ki-67 expression levels and with different histological types in GC patients. The ROI was outlined independently by two senior physicians, and the average of three measurements at the largest level was taken. In addition, interobserver reproducibility was assessed by Bland-Altman analysis. Correlations between quantitative parameters and Ki-67 expression levels were assessed by Spearman's correlation coefficients. RESULTS: The values between the mucinous group and nonmucinous carcinoma group were significantly different in both phases. The IC, NIC, and iodine-no-water concentration in the VP were significantly different among the Ki-67_L, Ki-67_M, and Ki-67_H groups. Spearman rank correlation analysis demonstrated a positive correlation between Ki-67 expression levels and IC, NIC, and iodine-no-water concentration in the VP, with correlation coefficients of 0.304, 0.424, and 0.322, respectively. CONCLUSION: Quantitative spectral parameters can discriminate between low and high Ki-67 expression and different histological types in GC. The NIC, IC and iodine-no-water concentration can be useful parameters for evaluating of Ki-67 expression levels.

Biomimetic black phosphorus nanosheets codeliver CDK9 and BRD4 inhibitors for gastric cancer targeted therapy.

Combining the BRD4 and CDK9 inhibitors can trigger the significant down-regulation of the MYC oncogene as well as anti-apoptotic genes and induce tumor cell apoptosis by synergistically impairing RNA synthesis in cancer cells. However, the lack of tumor-targeting capacity and the different pharmacokinetic curves of these two inhibitors may impair the antitumor activity of simultaneous CDK9 and BRD4 inhibition. Herein, CDK9 inhibitor (CI) and BRD4 inhibitor (BI) were codelivered by macrophage membrane-encapsulated black phosphorus nanosheets (M@BP) for the treatment of gastric cancer (GC) via the high expression of BRD4 and CDK9. BP with prominent biocompatibility exhibited a high drug loading efficiency for both CI and BI and could efficiently decrease the expression of the MYC oncogene. More importantly, BP could also serve as a phototherapy agent collaborating with CDK9 and BRD4 inhibition for GC therapy upon near-infrared (NIR) irradiation. Furthermore, the introduction of a macrophage membrane endowed BP with tumor-targeting ability, which could simultaneously deliver CI and BI to tumor tissues. In a murine orthotopic GC model, M@BP could efficiently target and accumulate in the tumor tissues, exhibiting an excellent photothermal effect. The tumor growth monitoring demonstrated that the combination of CI and BI codelivered by M@BP significantly inhibited the tumor progress than the single inhibitors, and the inhibition effect could be further enhanced upon NIR irradiation. Taken together, M@BP with tumor-targeting capacity and high drug loading efficiency for CI and BI could efficiently block the activation of CDK9 and BRD4, exhibiting excellent antitumor activity under NIR irradiation without systemic toxicity in an orthotopic GC model.

Efficacy and safety of anlotinib-based treatment in metastatic breast cancer patients.

Objective: To evaluate the efficacy and safety of anlotinib-based treatment in metastatic breast cancer (MBC) patients with failure of standard treatment. Methods: We collected the medical data of 56 female patients with the diagnosis of MBC and had failed the standard treatment before. These patients received at least two cycles of anlotinib-based treatment as the second-line or beyond treatment between October 2019 and April 2022 in Jiangsu Cancer Hospital. The primary endpoint of our study was progression-free survival (PFS), and it was estimated with Kaplan-Meier. The second end points were disease control rate (DCR), objective response rate (ORR), and side effects. Results: The median PFS time of a total of 56 patients was 5.7 months (95% CI, 3.17-8.22months). The ORR and DCR was 28.6% and 71.4%, respectively. In second-line, third-line, and beyond treatment, the median PFS was 11.7 months, 8.7 months, and 4.7 months, respectively. In different subtype of breast cancer, the median PFS was 5.6 months, 5.7months, and 6.4 months in human epidermal growth factor receptor 2 positive (HER2+), hormone receptor positive and HER2 negative (HR+/HER2-), and triple negative breast cancer (TNBC) patients, respectively. Most adverse effects were clinically manageable, and the most common events were platelet count decrease (35.7%), hand-foot syndrome (19.6%), diarrhea (19.6%), and fatigue (17.9%). The most common grade 3 and 4 adverse events were platelet count decrease (25.0%), diarrhea (7.1%), and oral mucositis (5.4%). Conclusion: Anlotinib-based treatment showed good efficacy and manageable toxicity in multi-line treatment of MBC patients who failed the standard treatment.

Methylation patterns of Lys9 and Lys27 on histone H3 correlate with patient outcome and tumor progression in lung cancer.

BACKGROUNDS: Histone methylation is recognized as an important component of the epigenetic mechanisms of cancer initiation and progression. Previous studies have demonstrated that aberrant alterations in histone methylation are associated with lung cancer. However, novel and specific epigenetic biomarkers for monitoring lung adenocarcinoma remain unknown. METHODS: A retrospective clinicopathological analysis was performed on 71 lung adenocarcinoma (LUAD) patients who received complete ablative surgical treatment. Tissue arrays were made from the paraffin-embedded LUAD tumor tissues, and these, together with corresponding normal tissues, were examined through immunohistochemistry for several markers: histone 3 lysine 9 di-methylation (H3K9me2), histone 3 lysine 9 tri-methylation (H3K9me3), and histone 3 lysine 27 tri-methylation (H3K27me3). The expression level of each marker was analyzed according to the histological classification and clinical prognosis data. RESULTS: Compared with peri-cancerous tissues, cancerous tissues distinctly expressed higher proportions of H3K9me2, H3K9me3, and H3K27me3. A higher expression pattern of H3K27me3 was associated with the poorly differentiation and unfavorable prognosis in LUAD. Based on histological types, it was found that the H3K27me3 level of patients with micropapillary type is high, and it is related to worse prognosis. CONCLUSIONS: The findings of this study show that the H3K27me3 and micropapillary type are malignant clinical factors of LUAD. H3K27me3 reduction is a novel epigenetic biomarker for defining high-risk LUAD and predicting worse prognosis. Immunohistochemical evaluation of H3K27me3 expression is an economic, easily available, and readily adaptable method.

MicroRNA-370-3p shuttled by breast cancer cell-derived extracellular vesicles induces fibroblast activation through the CYLD/Nf-κB axis to promote breast cancer progression.

Breast cancer is a malignancy arising in the mammary epithelial tissues. Recent studies have indicated the abundance of microRNAs (miRNAs) in extracellular vesicles (EVs), and their interactions have been illustrated to exert crucial roles in the cell-to-cell communication. The present study focused on investigating whether EV-delivered miR-370-3p affects breast cancer. Initially, the miR-370-3p expression pattern was examined in the cancer-associated fibroblasts (CAFs), normal fibroblasts (NFs), and cancerous cells-derived EVs. The relation of miR-370-3p to CYLD was assessed using luciferase activity assay. Afterwards, based on ectopic expression and depletion experiments in the MCF-7 breast cancer cells, we evaluated stemness, migration, invasion, and sphere formation ability, and EMT, accompanied with measurement on the expression patterns of pro-inflammatory factors and nuclear factor-kappa B (NF-κB) signaling-related genes. Finally, tumorigenesis and proliferation were analyzed in vivo using a nude mouse xenograft model. The in vitro experiments revealed that breast cancer cell-derived EVs promoted NF activation, while activated fibroblasts contributed to enhanced stemness, migration, invasion, as well as EMT of cancerous cells. In addition, EVs could transfer miR-370-3p from breast cancer cells to NFs, and EV-encapsulated miR-370-3p was also found to facilitate fibroblast activation. Mechanistically, EV-encapsulated miR-370-3p downregulated the expression of CYLD through binding to its 3'UTR and activated the NF-κB signaling pathway, thereby promoting the cellular functions in vitro and in vivo in breast cancer. Taken together, EVs secreted by breast cancer cells could carry miR-370-3p to aggravate breast cancer through downregulating CYLD expression and activating the NF-κB signaling pathway.

Application of ultrasound-guided seminal vesicle radiography combining CT three-dimensional reconstruction technique in transurethral seminal vesiculoscopy.

For the treatment of ejaculatory duct obstruction, transurethral seminal vesiculoscopy (TSV) is the most common method, but the success rate is much lower than studies that have reported. So we developed a new ultrasound-guided seminal vesicle radiography (UGSVR) combining CT three-dimensional reconstruction (CT-TR) technique to improve the success rate of TSV. Between June 2018 and November 2019, 32 patients were enrolled and randomly assigned to two groups: experimental group (UGSvR combining CT-TR) and control group (standard evaluation). Baseline information, including age, smoking history and body mass index (BMI), was compared preoperatively. Surgical parameters included success rates (SR), surgical time (ST), catheter days (CD), length of hospital stays (HS) and complications were compared between groups. There were no statistically significant differences in baseline data between the two groups (all p > .05). There were no significant differences in the CD, HS and complications between the two groups (all p > .05), but the differences in ST and SR were statistically significant (p < .05). In conclusion, this new technique of UGSvR combining CT-TR was achieving a satisfactory increase in the success rate of TSV, while not increasing the incidence of complications, compared to normal evaluation before TSV operation.

miR-214 regulates papillary thyroid carcinoma cell proliferation and metastasis by targeting PSMD10.

MicroRNAs (miRNAs) have important effects on cancer occurrence and development by adjusting gene expression. The aim of the present study was to examine the role of miR­214 in papillary thyroid carcinoma cell proliferation and metastasis, and its molecular mechanisms. miR­214 was demonstrated to be markedly downregulated in papillary thyroid carcinoma tissues and cells compared with normal, and this was significantly associated with lymph node metastasis, tumor size and TNM stage. Upregulation of miR­214 significantly decreased cell proliferation, and promoted cell apoptosis and cell cycle arrest in papillary thyroid carcinoma cell lines in vitro. By contrast, downregulation of miR­214 resulted in the opposite effects. In addition, miR­214 mimics significantly decreased papillary thyroid carcinoma cell migration and invasion, which was correlated with decreased expression levels of matrix metallopeptidase (MMP)­2 and MMP­9. Restoration of miR­214 expression in papillary thyroid carcinoma cells decreased the activities associated with epithelial­mesenchymal transition (EMT). Furthermore, proteasome 26S subunit non­ATPase 10 (PSMD10) was predicted to be a target of miR­214. Experimental results demonstrated that miR­214 negatively regulated PSMD10 expression by targeting its 3' untranslated region directly. Knockdown of PSMD10 reduced papillary thyroid carcinoma cell clone formation, migration and invasion, most likely by repressing glycogen synthase kinase (GSK)­3ß/ß­catenin and AKT signaling. Finally, a negative correlation was observed between the expression levels of miR­214 and PSMD10 in papillary thyroid carcinoma tissues. Taken together, these data suggested that miR­214 might be a candidate target for the treatment of papillary thyroid carcinoma.

MicroRNA-142-5p Overexpression Inhibits Cell Growth and Induces Apoptosis by Regulating FOXO in Hepatocellular Carcinoma Cells.

Abnormal expression of microRNA (miR)-142-5p has been reported in hepatocellular carcinoma (HCC). However, little information is available regarding the functional role of miR-142-5p in HCC. We aimed to explore the effects of miR-142-5p aberrant expression on HCC cell growth and cell apoptosis, as well as the underlying mechanism. Human HCC cell lines HepG2 and SMMC-7721 cells were transfected with miR-142-5p mimic, inhibitor, or a corresponding negative control. Cell viability, cell cycle distribution, and cell apoptosis were then analyzed. In addition, protein expression of Forkhead box, class O (FOXO) 1 and 3, a Bcl-2-interacting mediator of cell death (Bim), procaspase 3, and activated caspase 3 was measured. After transfection with miR-142-5p inhibitor, FOXO1 and FOXO3 were overexpressed, and then the cell viability and cell apoptosis were determined again. The relative cell viability in both HepG2 and SMMC-7721 cells was significantly reduced by miR-142-5p overexpression (p < 0.05). miR-142-5p overexpression displayed a significant blockage at the G1/S transition and significantly increased the percentages of G0/G1 phase. Moreover, the results showed that miR-142-5p overexpression significantly induced cell apoptosis and statistically elevated the protein expression levels of FOXO1, FOXO3, Bim, procaspase 3, and activated caspase 3. However, the cells transfected with miR-142-5p inhibitor showed contrary results. Additionally, the effects of miR-142-5p inhibitor on cell viability and apoptosis were reversed by overexpression of FOXO. In conclusion, our results suggest that miR-142-5p overexpression shows an important protective role in HCC by inhibiting cell growth and inducing apoptosis. These effects might be by regulating FOXO expression in HCC cells.

Focal adhesion kinase: important to prostaglandin E2-mediated adhesion, migration and invasion in hepatocellular carcinoma cells.

Prostaglandin E2 has been implicated in cell growth and metastasis in many types of cancers. However, the effects of PGE2 and its mechanism on cell adhesion, migration, and invasion have not been clarified yet. In this study, we found PGE2 treatment significantly increased the cell adhesion, migration, and invasion in hepatocellular carcinoma (HCC) cells. In addition, the effects of PGE2 were found to be associated with focal adhesion kinase (FAK). PGE2 treatment increased the phosphorylation and synthesis of FAK in a dose-dependent manner. RNA interference targeting FAK suppressed PGE2-mediated cell adhesion and migration. Furthermore, the downstream proteins of FAK, paxillin and Erk2, were also activated by PGE2. PGE2 treatment increased the phosphorylation and synthesis of paxillin in a dose-dependent manner. PGE2 treatment also induced the phosphorylation of Erk2. PD98059, the specific inhibitor of MEK, suppressed PGE2-mediated cell adhesion and migration. However, it had no effect on PGE2-induced activation and synthesis of FAK. These results demonstrated that PGE2 greatly induced HCC cell adhesion, migration, and invasion by activating FAK/paxillin/Erk pathway.

Prostaglandin E2 enhances mitogen-activated protein kinase/Erk pathway in human cholangiocarcinoma cells: involvement of EP1 receptor, calcium and EGF receptors signaling.

COX-2-derived PGE2 has been implicated in the development of various types of cancers. However, the exact mechanism of PGE2-induced cancer cell proliferation and survival is still unclear. In the current study, the mechanism underlying PGE2-enhanced Erk phosphorylation in human cholangiocarcinoma cells was determined. The intracellular concentration of calcium in three cholangiocarcinoma cell lines was measured using a laser confocal scanning microscope and the expression levels of Erk and EGFR phosphorylation were determined by Western blot analyses. The activation of EP1 receptors involved in PGE2-stimulated Erk activation and increasing the intracellular concentration of calcium was elucidated using selective EP1 receptor subtype antagonists and agonist. The intracellular calcium chelator, BAPTA-AM, was shown to block PGE2-induced Erk and EGFR phosphorylation. PGE2-induced Erk phosphorylation was abrogated by pretreatment with the EGF receptor kinase inhibitor, AG1478. Our findings suggest that in human cholangiocarcinoma cells, PGE2-enhanced phosphorylation of Erk is, at least in part, mediated through EP1 receptors and EGFR phosphorylation induced by increases in the intracellular concentration of calcium.