Multifaceted roles of lymphatic and blood endothelial cells in the tumor microenvironment of hepatocellular carcinoma: A comprehensive review.

The tumor microenvironment is a complex network of cells, extracellular matrix, and signaling molecules that plays a critical role in tumor progression and metastasis. Lymphatic and blood vessels are major routes for solid tumor metastasis and essential parts of tumor drainage conduits. However, recent studies have shown that lymphatic endothelial cells (LECs) and blood endothelial cells (BECs) also play multifaceted roles in the tumor microenvironment beyond their structural functions, particularly in hepatocellular carcinoma (HCC). This comprehensive review summarizes the diverse roles played by LECs and BECs in HCC, including their involvement in angiogenesis, immune modulation, lymphangiogenesis, and metastasis. By providing a detailed account of the complex interplay between LECs, BECs, and tumor cells, this review aims to shed light on future research directions regarding the immune regulatory function of LECs and potential therapeutic targets for HCC.

Non-alcoholic fatty liver disease: pathogenesis and models.

Non-alcoholic fatty liver disease (NAFLD) is a complex disease characterized by a massive accumulation of lipids in the liver, with a continuous progression of simple steatosis, non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma. Non-alcoholic fatty liver disease is associated with obesity, insulin resistance, and metabolic syndrome; it is a severe public health risk and is currently the most common liver disease of the world. In addition to the fatty infiltration of the liver in non-alcoholic fatty liver disease patients, the field of liver transplantation faces similar obstacles. NAFLD and NASH primarily involve lipotoxicity, inflammation, oxidative stress, and insulin resistance. However, the precise mechanisms and treatments remain unclear. Therapeutic approaches encompass exercise, weight control, as well as treatments targeting antioxidants and anti-inflammatory pathways. The role of animal models in research has become crucial as a key tool to explore the molecular mechanisms and potential treatments for non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Here, we summarized the current understanding of the pathogenesis of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis and discussed animal models commonly used in recent years.

Merged hepatopulmonary features in hepatoid adenocarcinoma of the lung: a systematic review.

This study aimed to provide diagnostic clues for patients with elevated serum alpha-fetoprotein (AFP) in the absence of liver tumors and rectify some previously confused concepts about hepatoid carcinoma of the lung through a systematic review on hepatoid adenocarcinoma of the lung (HAL). A thorough search for original articles on HAL published prior to November 2020 was performed using the PubMed, EBSCOhost, Embase, WanFang Data, and China National Knowledge Infrastructure (CNKI) databases. Ninety-four patients from 88 studies met the eligibility criteria. HAL was rare and mainly occurred among male Asian smokers in their 60 s, presenting with cough, hemoptysis, chest pain, dyspnea and/or weight loss, as well as elevated serum AFP with a mass usually in the right upper lung lobe but no liver masses. Hepatoid differentiation regions, acinar or papillary structures in tumor tissues, and positive immunohistochemical expression of AFP, HepPar-1, and CK8/18 were crucial indicators for the diagnosis of HAL. Surgery-based strategies were recommended for stage I-III patients, while stage IV patients were mainly treated with chemotherapy-based strategy. The 1-, 3-, and 5-year overall survival rates were 40%, 35%, and 19%, respectively. The 1-year relapse-free survival rate was 58%. The postoperative monitoring of AFP contributed to the early detection of tumor recurrence, with a positive rate of 71.43%. In conclusion, patients with elevated serum AFP levels without any detectable hepatic lesions should be evaluated for the possibility of HAL.

Risk of adverse events in advanced hepatocellular carcinoma with immune checkpoint therapy: A systematic review and meta-analysis.

AIMS: To evaluate risk of adverse events (AEs) in advanced hepatocellular carcinoma (AHCC) with immune checkpoint therapy in this setting. METHODS: A systematic search of original articles published until November 2019 was performed using PubMed, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials. And a meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. RESULTS: A total of eight studies, including 597 patients, met the eligibility criteria. The median cohort size of patients was 75 (range: 18-267). The pooled incidence rates of grade≥3 AEs and fatal adverse events (FAEs) at last follow-up were 20.87 per 100 person-years (95% CI: 11.00-39.59, I2=91.0%) and 4.98 per 100 person-years (95% CI: 1.83-13.56, I2=82.8%). Subgroup analyses showed that pembrolizumab had a lower risk of grade≥3 AEs, but a higher risk of FAEs, when compared with nivolumab and tremelimumab. Meta-regression showed significant correlation between grade≥3 AEs rate and proportion of Child-Pugh A stage. Fatigue (16.9%), adrenal insufficiency (8.5%) and rash (6.8%) were involved in common non-laboratory AEs. CONCLUSIONS: Immune checkpoint therapy significantly increases the risk of AEs in AHCC patients. And the risk of grade≥3 AEs is associated with Child-Pugh classification. Future retrospective analyses and prospective cohort studies are warranted to evaluate the safety of immune checkpoint therapy in AHCC.

Acute rejection after liver transplantation is less common, but predicts better prognosis in HBV-related hepatocellular carcinoma patients.

BACKGROUND: With a novel finding of significantly lower incidence of acute rejection (AR) in patients with hepatocellular carcinoma (HCC) after liver transplantation, compared with those with benign end-stage liver disease (BESLD), in a large national cohort, we analyzed the correlations among the perioperative immuno-inflammation status, postoperative AR, and prognosis in HCC and BESLD patients with same etiology of hepatitis B virus (HBV), who underwent liver transplantation. METHODS: Patients who underwent liver transplantation due to HBV-related HCC or BESLD and experienced AR between September 2008 and April 2017 were analyzed retrospectively and followed up until April 2018. HCC patients with AR were matched with those without AR according to tumor stage and immunosuppressant concentration, at a 1:3 ratio. Preoperative immuno-inflammation status and prognosis of patients in both groups were compared. RESULTS: The overall incidences of AR in patients with HCC and BESLD were 8.60% and 10.61%, respectively. The postoperative 28-day incidence of AR was significantly lower in HCC compared with BESLD patients (3.23% vs 7.08%, p = 0.031). Compared with BESLD patients, the rejection activity index and perioperative CD4/CD8 ratio were significantly lower (p = 0.047 and p < 0.001, respectively), while platelet/lymphocyte ratio was significantly higher in HCC patients (p = 0.041). Later tumor stage in HCC patients was associated with higher systemic immuno-inflammation index, neutrophil/lymphocyte ratio, monocyte/lymphocyte ratio, platelet/lymphocyte ratio, aspartate aminotransferase/lymphocyte ratio, C-reactive protein/albumin ratio and fibrinogen level, and lower CD4/CD8 ratio before transplantation. In HCC patients with AR, the percentage of regulatory T cells (CD4+/CD25+) and the level of IL-10 significantly decreased (p = 0.0023, < 0.0001, respectively), while Th1/Th2 ratio, levels of IFN-γ and IL-2 markedly increased before transplantation (p = 0.0018, 0.0059, 0.0416, respectively). Preoperative monocyte/lymphocyte ratio was an independent risk factor for overall and recurrence-free survival after liver transplantation in HCC patients (p = 0.025, < 0.001, respectively). The 1-, 3-, and 5-year survival rates were 76%, 71% and 53% in the AR group, and 67%, 37% and 25% in the non-AR group (p = 0.042). CONCLUSION: Preoperative tumor-related immunosuppression may persist after liver transplantation in HCC patients, and reduce the incidence of AR. AR after liver transplantation may indicate a better prognosis in HCC patients.

microRNA-29a regulates liver tumor-initiating cells expansion via Bcl-2 pathway.

MicroRNAs (miRNAs) participate in tumorigenesis, progression, recurrence and drug resistance of hepatocellular carcinoma (HCC). However, few miRNAs have been identified and entered clinical practice. Herein, we report that miR-29a is downregulated in tumor-initiating cells (T-ICs) and has an important function in liver T-ICs. Functional studies revealed that miR-29a knockdown promotes liver T-ICs self-renewal and tumorigenesis. Conversely, a forced miR-29a expression inhibits liver T-ICs self-renewal and tumorigenesis. Mechanistically, we find that miR-29a downregulates Bcl-2 via binding its mRNA 3'UTR in liver T-ICs. The correlation between miR-29a and Bcl-2 is validated in human HCC tissues. Furthermore, the miR-29a expression determines the responses of hepatoma cells to sorafenib treatment. Analysis of patient-derived xenografts (PDXs) further demonstrated that the miR-29a high patients are more sensitive to sorafenib treatment. In conclusion, our findings revealed the crucial role of the miR-29a in liver T-ICs expansion and sorafenib response, rendering miR-29a as an optimal target for the prevention and intervention of HCC.

Two case reports and literature review for hepatic epithelioid angiomyolipoma: Pitfall of misdiagnosis.

BACKGROUND: Hepatic epithelioid angiomyolipoma (HEAML) is a rare liver disease and is easily misdiagnosed. Enhanced recognition of HEAML is beneficial to the differential diagnosis of rare liver diseases. CASE SUMMARY: We presented two cases of HEAML in Changzheng Hospital, Naval Medical University, and then collected and analyzed all reports about HEAML recorded in PubMed, MEDLINE, China Science Periodical Database, and VIP database from January 2000 to March 2018. A total of 409 cases of HEAML in 97 reports were collected, with a ratio of men to women of 1:4.84 and an age range from 12 years to 80 years (median 44 years). Among the patients with clinical symptoms mentioned, 61.93% (205/331) were asymptomatic, 34.74% (115/331) showed upper or right upper quadrant abdomen discomfort, while a few of them showed abdominal mass, gastrointestinal symptoms, low fever, or weight loss. The misdiagnosis rate of HEAML was as high as 40.34% (165/409) due to its nonspecific imaging findings. Most of the tumors were solitary and round in morphology, with clear boundaries. Ultrasound scan indicated low echo with internal nonuniformity and rich blood supply in most cases. Computer tomography/magnetic resonance imaging enhanced scan showed varied characteristics. The ratio of fast wash-in and fast wash-out, fast wash-in and slow wash-out, and delayed enhancement was roughly 4:5:1. A definite diagnosis of HEAML depended on the pathological findings of the epithelioid cells in lesions and the expression of human melanoma black 45, smooth muscle actin, melanoma antigen, and actin by immunohistochemical staining. HEAML had a relatively low malignant rate of 3.91%. However, surgical resection was the main treatment for HEAML, due to the difficulty diagnosing before operation. CONCLUSION: HEAML is a rare and easily misdiagnosed disease, and it should be diagnosed carefully, taking into account clinical course, imaging, pathological ,and immunohistochemical findings.