Exosomal microRNAs in hepatocellular carcinoma, expanding research field.

In this editorial we comment on the review by Wang et al published in the recent issue of the World Journal of Gastroenterology in 2023. Small extracellular vesicles (exosomes) play important roles in the tumor microenvironment. In this review, the authors introduce the following points: (1) The composition and function of exosomal microRNAs (miRNAs) of different cell origins in hepatocellular carcinoma (HCC); (2) the crosstalk between exosomal miRNAs from stromal cells and immune cells in the tumor microenvironment and the progression of HCC; and (3) the potential applicability of exosomal miRNAs derived from mesen-chymal stem cells in the treatment of HCC. In addition, the potential applicability of exosomal miRNAs derived from mesenchymal stem cells in the treatment of HCC was introduced. In this review, the authors give us an overview of the exosomal RNA and summarize the function of exosomal RNA in HCC, which provides a deeper understanding of exosomal miRNAs to the readers.

[Latest Findings on the Function of Immune Metabolism in Tumor Immunity].

Metabolic reprogramming, an important hallmark of cancer, helps cancer achieve rapid proliferation. Metabolic changes in tumors regulate multiple metabolic pathways of immune cells, thereby suppressing antitumor immunity. Recent studies have been focused on in-depth investigation into the changes in the metabolism of glucose, amino acids, and lipids. Researchers have also conducted in-depth exploration of the interactive metabolic regulation of tumor cells and immune cells. Targeting various metabolic mechanisms while combining available anti-tumor therapies and enhancing the anti-tumor effects of immunotherapy by satisfying the metabolic demands of immune cells has offered new perspectives for therapies targeting the immune metabolism of tumors and enhancing anti-tumor immune responses. Studies on novel immune checkpoint molecules and cellular immunotherapies are also ongoing. Herein, we reviewed the latest findings on the mechanisms of immune metabolism underlying tumor immunosuppression and their application in immunotherapy. We also suggested some ideas for the future development of the regulation of immune metabolism.

The clinical and prognostic factors for biliary neuroendocrine neoplasm: a study based on the SEER database.

BACKGROUND: In this study, we aimed at elucidating the postoperative survival and prognostic factors in patients with biliary neuroendocrine neoplasm (NEN). METHODS: Cases of biliary system NEN and adenocarcinoma from 1975 to 2016 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. A propensity score matching (PSM) method was used to adjust baseline differences in clinicopathological characteristics in our analysis. The Kaplan-Meier analysis was carried out for survival analysis. RESULTS: A total of 233 patients with biliary system NEN were enrolled in this study, of which 119 patients' lesions located in gallbladder, while the others' located in bile duct. The postoperative overall survival of bile duct NEN is significantly longer than that of gallbladder NEN (P < 0.001). For gallbladder NENs, surgery method (P = 0.020) and lymph node metastasis (P = 0.018) were identified as independent prognostic factors. In terms of ampulla of vater (AOV) NENs, age (P = 0.017) and lymph node metastasis (P = 0.006) were identified as independent prognostic factors, while grade (P = 0.002) and lymph node metastasis (P = 0.036) were identified as independent prognostic factors for extrahepatic bile duct (EBD) NENs. PSM analysis indicated that patients with biliary duct NENs have a better postoperative prognosis than biliary duct adenocarcinoma. CONCLUSIONS: Patients with NEN have better overall survival than patients with adenocarcinoma. Gallbladder NEN has an adverse prognosis than that of biliary tract NEN. The pathological subtype, differentiation, lymph node metastasis, surgery method, and lymph node resection could affect the postoperative prognosis of the gallbladder and biliary tract NEN.

Samonella typhi infection-related appendicitis: A case report.

BACKGROUND: Acute appendicitis is one of the most common acute abdominal emergencies around the world, which is always associated with infection. Infection with Salmonella typhi, an enteric pathogen, is a rare cause of acute appendicitis. We here report a patient with acute appendicitis associated with Samonella typhi infection, accompanied with spleen and kidney infarction, providing a rare example for a common surgical emergency. CASE SUMMARY: A 25-year-old Pakistani man presented to the hospital with a 3-d history of fevers, vomiting, and abdominal pain. Computed tomography (CT) revealed a thickened intestinal wall of the ileocecal junction with multiple enlarged lymph nodes nearby. He was diagnosed with acute appendicitis and received laparoscopic appendectomy, which showed mild inflammation of the appendix. After the surgery, the patient presented again with a high fever (> 39 °C) and diarrhea. A CT angiography scan indicated spleen and kidney infarction. According to the blood culture, the diagnosis was finally clear to be Samonella typhi infection. The pyrexia and enteric symptoms were relieved after the application of intravenous levofloxacin. CONCLUSION: This case, characterized by the combination of Salmonella typhi infection, acute appendicitis, and renal and splenic infraction, serves as a rare example for a common surgical emergency.

[Tracking Research Progress in the Modulatory Role of Gut Microbiome in Immune Checkpoint Inhibitors Applied in Cancer Treatment].

In recent years, immunotherapy, as an emerging anti-tumor therapy, has shown great potential in the treatment of both solid and hematologic tumors. There is increasing preclinical and clinical evidence linking the composition of gut microbiome with the efficacy as well as adverse effects of immune checkpoint inhibitor anti-tumor therapy. We summarized in this review the modulatory role of the gut microbiome in antitumor therapy with different immune checkpoint inhibitors. We also discussed the limitations of existing research and prospective development of the further clinical strategies.

The Biological Function of TUSC7/miR-1224-3p Axis in Triple-Negative Breast Cancer.

BACKGROUND: Triple-negative breast cancers (TNBC), comprising about 20% of breast cancers, have a poor prognosis. Currently, there is no effective target therapy for TNBC. LncRNA TUSC7 has been identified as a tumor suppressor in osteosarcoma and colorectal cancer. In this study, we investigated the clinical significance and the biological function of TUSC7 in breast cancer. METHODS: We retrospectively evaluated the expression level and clinical significance of TUSC7 in 90 paired breast cancer tissues and normal tissues. The proliferation, migration, and invasion assays were performed to investigate the biological function of TUSC7 in breast cancer. Finally, microarray, a luciferase reporter assay, and quantitative real-time polymerase chain reaction (qPCR) were used to explore the potential underlying mechanism of tumor suppressor role of TUSC7. RESULTS: Low TUSC7 expression was found to be an independent prognostic factor of poor overall survival (OS) in TNBC patients. Ectopic expression of TUSC7 inhibited tumor cell growth both in vitro and in vivo. TUSC7 overexpression significantly promoted the sensitivity of MDA-MB-468 cells to paclitaxel and carboplatin. In terms of the mechanism, TUSC7 might perform its biological function through binding with miR-1224-3P and regulating its expression level. Besides, genes in cell cycle pathways, such as BUB3 (budding uninhibited by benzimidazoles 3) and TGF-ß (targeting transforming growth factor ß) pathways were downregulated, and genes involved in the MAPK (mitogen-activated protein kinase) (TGFBR2, transforming growth factor-beta receptor 2), PI3K-AKT (phosphoinositide 3-kinase- AKT serine/threonine kinase 1) and NF-κB (nuclear factor-kappa B subunit) pathways were upregulated in TUSC7 knockdown MDA-MB-231 cells. CONCLUSION: The low TUSC7 expression is an independent prognostic factor of poor OS of TNBC patients. TUSC7 might inhibit breast cancer cell growth and metastasis both in vitro and vivo through binding with miR-1224-3P and regulating MAPK, PI3K/AKT, and NF-κB signaling pathways.

Clinical correlation of cadherin-17 marker with advanced tumor stages and poor prognosis of cholangiocarcinoma.

BACKGROUND AND OBJECTIVES: In this retrospective study, we examined the CA17 tissue expression and analyzed its clinical significance in cholangiocarcinoma (CCA). MATERIALS AND METHODS: Immunohistochemistry was performed to assess CA17 expression on tissue microarrays in a training cohort enrolling 120 CCA patients and a validation cohort comprising 60 CCA patients. Image pro plus was applied to score the staining intensity and expression level of CA17 marker. Kaplan-Meier analysis, Cox's proportional hazards regression, and nomogram were applied to evaluate the prognostic significance of CA17. RESULTS: CA17 cancer biomarker over-expression was significantly observed in CCA compared to their non-tumor counterparts, and positively correlated with aggressive tumor phenotypes, like lymph node metastasis. Meanwhile, patients with high expression of CA17 correlated with worse postoperative overall survival (OS) and recurrence-free survival. Besides, multivariate analysis identified that CA17 expression was an independent prognostic factor for cholangiocarcinoma patients, which indicated that the CA17 could be more efficient than serum CA19-9 in predicting the OS of CCA patients. Notably, the nomogram integrating CA17 expression had better prognostic performance as compared with current TNM staging systems. CONCLUSION: CA17 was an independent adverse prognostic factor for CCA patients' survival, which may serve as a promising prognostic biomarker for CCA patients.

The distribution of immune cells within combined hepatocellular carcinoma and cholangiocarcinoma predicts clinical outcome.

BACKGROUND: This study aimed to investigate the clinical relevance of the immune microenvironment in patients with combined hepatocellular carcinoma and cholangiocarcinoma (cHCC-ICC). PATIENTS AND METHODS: The density of tumor-infiltrating CD3+ , CD8+ , CD163+ , and Foxp3+ immune cells, as well as Programmed cell death 1, Programmed cell death-ligand 1, and Tumor necrosis factor receptor superfamily member 4, was measured in the peritumor liver, tumor invasive margin, and intratumor subregions of 56 cHCC-ICC by immunohistochemistry. The immune index was established to stratify patients. Prognostic significance of immune cell subsets and immune indices was evaluated. RESULTS: The distribution of immune cells was highly heterogeneous among different subregions of cHCC-ICC. As compared with the hepatocellular carcinoma (HCC) component, the lower density of CD8+ T cells and higher intensity of Foxp3+ Tregs and immune checkpoints in the intrahepatic cholangiocarcinoma (ICC) component may indicate a stronger immune evasive ability of ICC. Based on clustering classification or a combination of random forest and lasso-cox, two models of immune indices were established and both were identified as independent prognostic factors for cHCC-ICC patients. The selected immune variables in the immune prognostic models derived from both HCC and ICC subregions, indicating that the prognosis of cHCC-ICC patients was a complex interaction of both components. CONCLUSIONS: The immune contexture was heterogeneous among different subregions of cHCC-ICC patients and contributed differently to patient prognosis. Immune score based on the densities of immune cells might serve as a promising prognostic predictor for cHCC-ICC patients.

CCL15 Recruits Suppressive Monocytes to Facilitate Immune Escape and Disease Progression in Hepatocellular Carcinoma.

Chemokines play a key role in orchestrating the recruitment and positioning of myeloid cells within the tumor microenvironment. However, the tropism regulation and functions of these cells in hepatocellular carcinoma (HCC) are not completely understood. Herein, by scrutinizing the expression of all chemokines in HCC cell lines and tissues, we found that CCL15 was the most abundantly expressed chemokine in human HCC. Further analyses showed that CCL15 expression was regulated by genetic, epigenetic, and microenvironmental factors, and negatively correlated with patient clinical outcome. In addition to promoting tumor invasion in an autocrine manner, CCL15 specifically recruited CCR1+ cells toward HCC invasive margin, approximately 80% of which were CD14+ monocytes. Clinically, a high density of marginal CCR1+ CD14+ monocytes positively correlated with CCL15 expression and was an independent index for dismal survival. Functionally, these tumor-educated monocytes directly accelerated tumor invasion and metastasis through bursting various pro-tumor factors and activating signal transducer and activator of transcription 1/3, extracellular signal-regulated kinase 1/2, and v-akt murine thymoma viral oncogene homolog signaling in HCC cells. Meanwhile, tumor-derived CCR1+ CD14+ monocytes expressed significantly higher levels of programmed cell death-ligand 1, B7-H3, and T-cell immunoglobulin domain and mucin domain-3 that may lead to immune suppression. Transcriptome sequencing confirmed that tumor-infiltrating CCR1+ CD14+ monocytes were reprogrammed to upregulate immune checkpoints, immune tolerogenic metabolic enzymes (indoleamine and arginase), inflammatory/pro-angiogenic cytokines, matrix remodeling proteases, and inflammatory chemokines. Orthotopic animal models confirmed that CCL15-CCR1 axis forested an inflammatory microenvironment enriched with CCR1+ monocytes and led to increased metastatic potential of HCC cells. Conclusion: A complex tumor-promoting inflammatory microenvironment was shaped by CCL15-CCR1 axis in human HCC. Blockade of CCL15-CCR1 axis in HCC could be an effective anticancer therapy.

Radiomics score: a potential prognostic imaging feature for postoperative survival of solitary HCC patients.

BACKGROUND: Radiomics is an emerging field in oncological research. In this study, we aimed at developing a radiomics score (rad-score) to estimate postoperative recurrence and survival in patients with solitary hepatocellular carcinoma (HCC). METHODS: A total of 319 solitary HCC patients (training cohort: n = 212; validation cohort: n = 107) were enrolled. Radiomics features were extracted from the artery phase of preoperatively acquired computed tomography (CT) in all patients. A rad-score was generated by using the least absolute shrinkage and selection operator (lasso) logistic model. Kaplan-Meier and Cox's hazard regression analyses were used to evaluate the prognostic significance of the rad-score. Final nomograms predicting recurrence and survival of solitary HCC patients were established based on the rad-score and clinicopathological factors. C-index and calibration statistics were used to assess the performance of nomograms. RESULTS: Six potential radiomics features were selected out of 110 texture features to formulate the rad-score. Low rad-score positively correlated with aggressive tumor phenotypes, like larger tumor size and vascular invasion. Meanwhile, low rad-score was significantly associated with increased recurrence and reduced survival. In addition, multivariate analysis identified the rad-score as an independent prognostic factor (recurrence: Hazard ratio (HR): 2.472, 95% confident interval (CI): 1.339-4.564, p = 0.004;survival: HR: 1.558, 95%CI: 1.022-2.375, p = 0.039). Notably, the nomogram integrating rad-score had a better prognostic performance as compared with traditional staging systems. These results were further confirmed in the validation cohort. CONCLUSIONS: The preoperative CT image based rad-score was an independent prognostic factor for the postoperative outcome of solitary HCC patients. This score may be complementary to the current staging system and help to stratify individualized treatments for solitary HCC patients.

Spatial and temporal clonal evolution of intrahepatic cholangiocarcinoma.

BACKGROUND & AIMS: Intrahepatic cholangiocarcinoma (ICC) is the second-most lethal primary liver cancer. Little is known about intratumoral heterogeneity (ITH) and its impact on ICC progression. We aimed to investigate the ITH of ICC in the hope of helping to develop new therapeutic strategies. METHODS: We obtained 69 spatially distinct regions from six operable ICCs. Patient-derived primary cancer cells (PDPCs) were established for each region, followed by whole-exome sequencing (WES) and multi-level validation. RESULTS: We observed widespread ITH for both somatic mutations and clonal architecture, shaped by multiple mechanisms, like clonal "illusion", parallel evolution and chromosome instability. A median of 60.3% of mutations were heterogeneous, among which 85% of the driver mutations were located on the branches of tumor phylogenetic trees. Many truncal and clonal driver mutations occurred in tumor suppressor genes, such as TP53, SMARCB1 and PBRM1 that are involved in DNA repair and chromatin-remodeling. Genome doubling occurred in most cases (5/6) after the accumulation of truncal mutations and was shared by all intratumoral sub-regions. In all cases, ongoing chromosomal instability is evident throughout the evolutionary trajectory of ICC. The recurrence of ICC1239 provided evidence to support the polyclonal metastatic seeding in ICC. The change of mutation landscape and internal diversity among subclones during metastasis, such as the loss of chemoresistance mediator, can be used for new treatment strategies. Targeted therapy against truncal alterations, such as IDH1, JAK1, and KRAS mutations and EGFR amplification, was developed in 5/6 patients. CONCLUSIONS: Integrated investigations of spatial ITH and clonal evolution may provide an important molecular foundation for enhanced understanding of tumorigenesis and progression in ICC. LAY SUMMARY: We applied multiregional whole-exome sequencing to investigate the evolution of intrahepatic cholangiocarcinoma (ICC). The results revealed that many factors, such as parallel evolution and chromosome instability, may participate and promote the branch diversity of ICC. Interestingly, in one patient with primary and recurrent metastatic tumors, we found evidence of polyclonal metastatic seeding, indicating that symbiotic communities of multiple clones existed and were maintained during metastasis. More realistically, some truncal alterations, such as IDH1, JAK1, and KRAS mutations and EGFR amplification, could be promising treatment targets in patients with ICC.

CK7/CK19 index: A potential prognostic factor for postoperative intrahepatic cholangiocarcinoma patients.

BACKGROUND AND OBJECTIVES: Frequently aberrant expression of cytokeratin 7 (CK7) and cytokeratin 19 (CK19) have been observed in several human cancers. In this retrospective study, we aimed at investigating the prognostic significance of CK7 and CK19 in intrahepatic cholangiocarcinoma (ICC). METHODS: Immunohistochemistry was performed to assess CK7 and CK19 expression on tissue microarrays in training cohort enrolling 214 ICC patients and validation cohort comprising 108 ICC patients. Kaplan-Meier analysis, Cox's proportional hazards regression, and nomogram were applied to evaluate the prognostic significance of both CKs. RESULTS: Both CK7 and CK19 expression were significantly up-regulated in ICC compared to their non-tumor counterparts, and positively correlated with aggressive tumor phenotypes, like lymph node metastasis and larger tumor size. Furthermore, high expression of either CK7 or CK19 predicted a significantly dismal postoperative survival. Integrated analysis of CK7 and CK19 expression was identified as a better indicator for survival probability. Notably, the nomogram integrating CK7/CK19 index had a perfect prognostic performance as compared with current staging systems. The results were further confirmed in the validation cohort. CONCLUSIONS: CK7/CK19 index was an independent adverse prognostic factor for ICC patients' survival, and may be helpful to improve postoperative risk stratification and individualized treatment strategies.

A New Preoperative Prognostic System Combining CRP and CA199 For Patients with Intrahepatic Cholangiocarcinoma.

OBJECTIVES: In this study, we aimed at investigating the preoperatively available prognostic factors for intrahepatic cholangiocarcinoma (ICC) patients and proposing a new preoperative prognostic scoring system for ICC. METHODS: A total of 246 consecutive ICC patients who underwent curative hepatectomy were enrolled retrospectively and were randomly divided into training (n=164) and validation cohorts (n=82) at a ratio of 2:1. The prognostic factors were investigated in both cohorts using multivariate Cox's proportional hazards regression model. RESULTS: Multivariate analyses identified that two preoperative factors (serum C-reactive protein (CRP) levels >4.1 mg/l (hazard ratio (HR): 2.75, 95% CI: 1.65-4.73, P<0.001) and carbohydrate antigen 19-9 (CA19-9) levels >300 mg/ml (HR: 3.76, 95% CI: 2.18-6.49)) were independent prognostic factors for postoperative survival in the training cohort. The results were further confirmed in the validation cohort. On the basis of these data, a preoperative prognostic score (PPS) was established by allocating 0 or 1 point to the two factors, respectively. Then, both in the training and validation cohorts, the PPS showed the power to stratify patients into three distinct groups (groups with scores 2, 1, and 0) with significant difference in the risk of postoperative death. CONCLUSIONS: A new preoperative scoring system consisting of preoperative CRP and CA19-9 levels could effectively predict postoperative survival of ICC patients.