Cross-organ single-cell integration identifies liver-specific fibroblast programs and HGF-MET/AGT-AGTR1B axes that link fibrosis to hepatocarcinogenesis.

The Mutational and Transcriptional Landscapes of Hepatocarcinogenesis in a Rat Model.

Hepatology Basic Science

Is the measurement of tumor marker levels effective for monitoring patients after the treatment of hepatocellular carcinoma? RECOMMENDATIONFor patients in whom tumor marker levels were elevated before treatment, tumor markers measured after treatment may serve as useful indices of the effects of treatment.(grade C1) 30

Incidence and Expected Probability of Liver Cirrhosis and Hepatocellular Carcinoma After Fontan Operation.

IntroductionIn the UK, hepatocellular carcinoma (HCC) has the largest increase in cancer mortality of all cancers over the last decade. Although it is well known that the most important risk...

Liver diseases causes approximately 2 million death per year worldwide. Aberrant apoptosis is associated with the progression of liver fibrosis and cirrhosis, even for hepatocellular carcinoma (HCC). HCC is one of major causes of cancer death worldwide due to high heterogeneity and recurrence. Immune scores could be used to link HCC disease-free survival and to identify several microenvironment-related genes. MAPK signaling plays an important role in liver fibrogenesis and HCC. ERK activation is associated with aggressive HCC, resulting in short overall survival. In this study, the immune responses of liver fibrosis and HCC mediated by ERK signaling were investigated. Both WT and Erk2 deficient mice were fed with choline-deficient diet to induce liver cirrhosis. Erk2 deficient livers have less degree of liver cirrhosis than WT livers. Our preliminary data suggested there was a significant increasement in the percentages of regulatory T cells in Erk2 deficient splenocytes. The percentages of follicular T cells were similar in WT and Erk2 deficient splenocytes. However, there was no significant differences in Erk2 deficient hepatic CD4 T cells for regulatory T cells and follicular T cells. In addition, Egr1 is one of ERK signaling downstream transcription factors. In HCC, there were about 10-fold differences in gene expression in the Egr1high and Egr1low group and the differential gene expression was identified. In hepatotoxicity, there was about more than 100 genes involved in HCC, 50~70 genes in liver cirrhosis, liver inflammation and liver necrosis/cell death. Therefore, MAPK signaling plays an important role in regulating the immune responses in the liver cirrhosis and HCC progression.

Time-dependent events in natural history of occult hepatitis B virus infection: the importance of population-based long-term follow-up study with repeated measurements

Telomere Dysfunction and DNA Damage Checkpoints in Diseases and Cancer of the Gastrointestinal Tract

Hepatocellular carcinoma (HCC) is one of the major causes of morbidity, mortality and healthcare expenditure in patients with chronic liver disease. There are no consensus guidelines on diagnosis and management of HCC in India. The Indian National Association for Study of the Liver (INASL) set up a Task-Force on HCC in 2011, with a mandate to develop consensus guidelines for diagnosis and management of HCC, relevant to disease patterns and clinical practices in India. The Task-Force first identified various contentious issues on various aspects of HCC and these issues were allotted to individual members of the Task-Force who reviewed them in detail. The Task-Force used the Oxford Center for Evidence Based Medicine-Levels of Evidence of 2009 for developing an evidence-based approach. A 2-day round table discussion was held on 9th and 10th February, 2013 at Puri, Odisha, to discuss, debate, and finalize the consensus statements. The members of the Task-Force reviewed and discussed the existing literature at this meeting and formulated the INASL consensus statements for each of the issues. We present here the INASL consensus guidelines (The Puri Recommendations) on prevention, diagnosis and management of HCC in India.

Early detection of small HCC and differentiation between HCC from AC metastatic to the liver is very essential for surgical pathologists, due to different treatment modalities. Immunohistochemistry plays a very important role in such conditions. In our study, we aimed to identify the diagnostic benefits of Arginase-1, FTCD& MOC-31 in the early detection of HCC in normal or cirrhotic liver, differentiation between HCC and metastatic ACs to the liver, and for early detection of small micro-metastases from ACs to liver. We included 20 samples from liver cirrhosis, 10 samples from normal liver tissue, 30 samples from primary HCCs in the liver, and 30 samples from metastatic ACs to the liver. We have evaluated Arginase-1, FTCD, and MOC-31 expression using immunohistochemistry. The sensitivity of Arginase-1 expression in differentiation between HCC and metastatic carcinoma was 93.3% and the specificity was 93.3%. The sensitivity of FTCD expression in differentiation between HCC and normal or cirrhotic liver and early detection of well-differentiated HCC was 90% and the specificity was 86.7%. The sensitivity of MOC-31 expression in differentiation between HCC and metastatic carcinoma was 90% and the specificity was 90%. The sensitivity of combination of panel of Arginase 1 + FTCD + MOC 31 expression in differentiation between HCC, metastatic carcinoma, and normal and cirrhotic liver was 93.3% and the specificity was 93.3%. The combination of Arginase 1 + FTCD + MOC 31 expression was helpful in diagnosing most cases of HCC and metastatic carcinoma with high sensitivity and specificity.

Recognizing the significant prevalence of hepatocellular carcinoma (HCC) in Saudi Arabia, and the difficulties often faced in early and accurate diagnoses, evidence-based management, and the need for appropriate referral of HCC patients, the Saudi Association for the Study of Liver diseases and Transplantation (SASLT) formed a multi-disciplinary task force to evaluate and update the previously published guidelines by the Saudi Gastroenterology Association. These guidelines were later reviewed, adopted and endorsed by the Saudi Oncology Society (SOS) as its official HCC guidelines as well. The committee assigned to revise the Saudi HCC guidelines was composed of hepatologists, oncologists, liver surgeons, transplant surgeons, and interventional radiologists. Two members of the task force served as guidelines editors. A wide based search on all published reports on all aspects of the epidemiology, natural history, risk factors, diagnosis, and management of HCC was performed. All available literature was critically examined and available evidence was then classified according to its strength. The whole document and the recommendations were then discussed in details by members and consensus was obtained. All recommendations in these guidelines were based on the best available evidence, but were tailored to the patients treated in Saudi Arabia. We hope that these guidelines will improve HCC patient care and enhance the multidisciplinary care needed for these patients.

Epidemiology of hepatocellular carcinoma in the United States: where are we? Where do we go?

Previous research has demonstrated that the conversion of hepatocellular carcinoma (HCC) to intrahepatic cholangiocarcinoma (iCCA) can be stimulated by manipulating the tumor microenvironment linked with necroptosis. However, the specific cells regulating the necroptosis microenvironment have not yet been identified. Additionally, further inquiry into the mechanism of how the tumor microenvironment regulates necroptosis and its impact on primary liver cancer(PLC) progression may be beneficial for precision therapy. We recruited a single-cell RNA sequencing dataset (scRNA-seq) with 34 samples from 4 HCC patients and 3 iCCA patients, and a Spatial Transcriptomic (ST) dataset including one each of HCC, iCCA, and combined hepatocellular-cholangiocarcinoma (cHCC-CCA). Quality control, dimensionality reduction and clustering were based on Seurat software (v4.2.2) process and batch effects were removed by harmony (v0.1.1) software. The pseudotime analysis (also known as cell trajectory) in the single cell dataset was performed by monocle2 software (v2.24.0). Calculation of necroptosis fraction was performed by AUCell (v1.16.0) software. Switch gene analysis was performed by geneSwitches(v0.1.0) software. Dimensionality reduction, clustering, and spatial image in ST dataset were performed by Seurat (v4.0.2). Tumor cell identification, tumor subtype characterization, and cell type deconvolution in spot were performed by SpaCET (v1.0.0) software. Immunofluorescence and immunohistochemistry experiments were used to prove our conclusions. Analysis of intercellular communication was performed using CellChat software (v1.4.0). ScRNA-seq analysis of HCC and iCCA revealed that necroptosis predominantly occurred in the myeloid cell subset, particularly in FCGBP + SPP1 + tumor-associated macrophages (TAMs), which had the highest likelihood of undergoing necroptosis. The existence of macrophages undergoing necroptosis cell death was further confirmed by immunofluorescence.Regions of HCC with poor differentiation, cHCC-CCA with more cholangiocarcinoma features, and the tumor region of iCCA shared spatial colocalization with FCGBP + macrophages, as confirmed by spatial transcriptomics, immunohistochemistry and immunofluorescence. Pseudotime analysis showed that premalignant cells could progress into two directions, one towards HCC and the other towards iCCA and cHCC-CCA. Immunofluorescence and immunohistochemistry experiments demonstrated that the number of macrophages undergoing necroptosis in cHCC-CCA was higher than in iCCA and HCC, the number of macrophages undergoing necroptosis in cHCC-CCA with cholangiocarcinoma features was more than in cHCC-CCA with hepatocellular carcinoma features. Further investigation showed that myeloid cells with the highest necroptosis score were derived from the HCC_4 case, which had a severe inflammatory background on pathological histology and was likely to progress towards iCCA and cHCC-CCA. Switchgene analysis indicated that S100A6 may play a significant role in the progression of premalignant cells towards iCCA and cHCC-CCA. Immunohistochemistry confirmed the expression of S100A6 in PLC, the more severe inflammatory background of the tumor area, the more cholangiocellular carcinoma features of the tumor area, S100A6 expression was higher. The emergence of necroptosis microenvironment was found to be significantly associated with FCGBP + SPP1 + TAMs in PLC. In the presence of necroptosis microenvironment, premalignant cells appeared to transform into iCCA or cHCC-CCA. In contrast, without a necroptosis microenvironment, premalignant cells tended to develop into HCC, exhibiting amplified stemness-related genes (SRGs) and heightened malignancy.

The immunobiology of hepatocellular carcinoma in humans and mice: Basic concepts and therapeutic implications

Genomic and transcriptomic somatic alterations of hepatocellular carcinoma in non-cirrhotic livers