The role and application of fibroblast activating protein.

Fibroblast activation protein-α (FAP), a type-II transmembrane serine protease, is rarely expressed in normal tissues but highly abundant in pathological diseases, including fibrosis, arthritis, and cancer. Ever since its discovery, we have deciphered its structure and biological properties and continue to investigate its roles in various diseases while attempting to utilize it for targeted therapy. To date, no significant breakthroughs have been made in terms of efficacy. However, in recent years, several practical applications in the realm of imaging diagnosis have been discovered. Given its unique expression in a diverse array of pathological tissues, the fundamental biological characteristics of FAP render it a crucial target for disease diagnosis and immunotherapy. To obtain a more comprehensive understanding of the research progress of FAP, its biological characteristics, involvement in diseases, and recent targeted application research have been reviewed. Moreover, we explored its development trend in the direction of clinical diagnoses and treatment.

Safety and efficacy of postoperative adjuvant therapy with atezolizumab and bevacizumab after radical resection of hepatocellular carcinoma.

BACKGROUND: The effects of postoperative adjuvant therapy for high-risk recurrent hepatocellular carcinoma (HCC) in immunotherapy are still under investigation. This study evaluated the preventive effects and safety of postoperative adjuvant therapy, including atezolizumab, and bevacizumab, against the early recurrence of HCC with high-risk factors. METHODS: The complete data of HCC patients who underwent radical hepatectomy with or without postoperative adjuvant therapy after two-year follow-up were analyzed retrospectively. The patients were divided into high-risk or low-risk groups based on HCC pathological characteristics. High-risk recurrence patients were divided into postoperative adjuvant treatment and control groups. Due to the difference in approaches in postoperative adjuvant therapies, they were divided into transarterial chemoembolization (TACE), atezolizumab, and bevacizumab (T + A), and combination (TACE+T + A) groups. The two-year recurrence-free survival rate (RFS), overall survival rate (OS), and associated factors were analyzed. RESULTS: The RFS in the high-risk group was significantly lower than that in the low-risk group (P = 0.0029), and the two-year RFS in the postoperative adjuvant treatment group was significantly higher than that in the control group (P = 0.040). No severe complications were observed in those who received atezolizumab and bevacizumab or other therapy. CONCLUSION: Postoperative adjuvant therapy was related to two-year RFS. TACE, T + A, and the combination of these two approaches were comparable in reducing the early recurrence of HCC without severe complications.

Activation of Sphingomyelin Phosphodiesterase 3 in Liver Regeneration Impedes the Progression of Colorectal Cancer Liver Metastasis Via Exosome-Bound Intercellular Transfer of Ceramides.

BACKGROUND & AIMS: The machinery that prevents colorectal cancer liver metastasis (CRLM) in the context of liver regeneration (LR) remains elusive. Ceramide (CER) is a potent anti-cancer lipid involved in intercellular interaction. Here, we investigated the role of CER metabolism in mediating the interaction between hepatocytes and metastatic colorectal cancer (CRC) cells to regulate CRLM in the context of LR. METHODS: Mice were intrasplenically injected with CRC cells. LR was induced by 2/3 partial hepatectomy (PH) to mimic the CRLM in the context of LR. The alteration of corresponding CER-metabolizing genes was examined. The biological roles of CER metabolism in vitro and in vivo were examined by performing a series of functional experiments. RESULTS: Induction of LR augmented apoptosis but promoted matrix metalloproteinase 2 (MMP2) expression and epithelial-mesenchymal transition (EMT) to increase the invasiveness of metastatic CRC cells, resulting in aggressive CRLM. Up-regulation of sphingomyelin phosphodiesterase 3 (SMPD3) was determined in the regenerating hepatocytes after LR induction and persisted in the CRLM-adjacent hepatocytes after CRLM formation. Hepatic Smpd3 knockdown was found to further promote CRLM in the context of LR by abolishing mitochondrial apoptosis and augmenting the invasiveness in metastatic CRC cells by up-regulating MMP2 and EMT through promoting the nuclear translocation of ß-catenin. Mechanistically, we found that hepatic SMPD3 controlled the generation of exosomal CER in the regenerating hepatocytes and the CRLM-adjacent hepatocytes. The SMPD3-produced exosomal CER critically conducted the intercellular transfer of CER from the hepatocytes to metastatic CRC cells and impeded CRLM by inducing mitochondrial apoptosis and restricting the invasiveness in metastatic CRC cells. The administration of nanoliposomal CER was found to suppress CRLM in the context of LR substantially. CONCLUSIONS: SMPD3-produced exosomal CER constitutes a critical anti-CRLM mechanism in LR to impede CRLM, offering the promise of using CER as a therapeutic agent to prevent the recurrence of CRLM after PH.

Nonalcoholic steatohepatitis critically rewires the ischemia/reperfusion-induced dysregulation of cardiolipins and sphingolipids in mice.

Background: Lipid dysregulation plays a fundamental role in nonalcoholic steatohepatitis (NASH), which is an emerging critical risk factor that aggravates hepatic ischemia/reperfusion (I/R) injury. However, the specific lipids that mediate the aggressive I/R injury in NASH livers have not yet been identified. Methods: The mouse model of hepatic I/R injury on NASH was established on C56B/6J mice by first feeding the mice with a Western-style diet to induce NASH, then the NASH mice were subjected to surgical procedures to induce hepatic I/R injury. Untargeted lipidomics were performed to determine hepatic lipids in NASH livers with I/R injury through ultra-high performance liquid chromatography coupled with mass spectrometry. The pathology associated with the dysregulated lipids was examined. Results: Lipidomics analyses identified cardiolipins (CL) and sphingolipids (SL), including ceramides (CER), glycosphingolipids, sphingosines, and sphingomyelins, as the most relevant lipid classes that characterized the lipid dysregulation in NASH livers with I/R injury. CER were increased in normal livers with I/R injury, and the I/R-induced increase of CER was further augmented in NASH livers. Metabolic pathway analysis revealed that the enzymes involved in the synthesis and degradation of CER were highly upregulated in NASH livers with I/R injury, including serine palmitoyltransferase 3 (Sptlc3), ceramide synthase 2 (Cers2), neutral sphingomyelinase 2 (Smpd3), and glucosylceramidase beta 2 (Gba2) that produced CER, and alkaline ceramidase 2 (Acer2), alkaline ceramidase 3 (Acer3), sphingosine kinase 1 (Sphk1), sphingosine-1-phosphate lyase (Sgpl1), and sphingosine-1-phosphate phosphatase 1 (Sgpp1) that catalyzed the degradation of CER. CL were not affected by I/R challenge in normal livers, but CL was dramatically reduced in NASH livers with I/R injury. Consistently, metabolic pathway analyses revealed that the enzymes catalyzing the generation of CL were downregulated in NASH-I/R injury, including cardiolipin synthase (Crls1) and tafazzin (Taz). Notably, the I/R-induced oxidative stress and cell death were found to be aggravated in NASH livers, which were possibly mediated by the reduction of CL and accumulation of CER. Conclusions: The I/R-induced dysregulation of CL and SL were critically rewired by NASH, which might potentially mediate the aggressive I/R injury in NASH livers.

Integrated Proteomics and Bioinformatics to Identify Potential Prognostic Biomarkers in Hepatocellular Carcinoma.

BACKGROUND: Liver hepatocellular carcinoma (HCC) is the third most common cause of death by cancer and has a high mortality world-widely. Approximately 75-85% of primary liver cancers are caused by HCC. Uncovering novel genes with prognostic significance would shed light on improving the HCC patient's outcome. OBJECTIVE: In this research, we aim to identify novel prognostic biomarkers in hepatocellular carcinoma. METHODS: Integrated proteomics and bioinformatics analysis were performed to investigate the expression landscape of prognostic biomarkers in 24 paired HCC patients. RESULTS: As a result, eight key genes related to prognosis, including ACADS, HSD17B13, PON3, AMDHD1, CYP2C8, CYP4A11, SLC27A5, CYP2E1, were identified by comparing the weighted gene co-expression network analysis (WGCNA), proteomic differentially expressed genes (DEGs), proteomic turquoise module, The Cancer Genome Atlas (TCGA) cohort DEGs of HCC. Furthermore, we trained and validated eight pivotal genes integrating these independent clinical variables into a nomogram with superior accuracy in predicting progression events, and their lower expression was associated with a higher stage/risk score. The Gene Set Enrichment Analysis (GSEA) further revealed that these key genes showed enrichment in the HCC regulatory pathway. CONCLUSION: All in all, we found that these eight genes might be the novel potential prognostic biomarkers for HCC and also provide promising insights into the pathogenesis of HCC at the molecular level.

ACOX2 is a prognostic marker and impedes the progression of hepatocellular carcinoma via PPARα pathway.

Hepatocellular carcinoma (HCC) has been extensively studied as one of the most aggressive tumors worldwide. However, its mortality rate remains high due to ideal diagnosis and treatment strategies. Uncovering novel genes with prognostic significance would shed light on improving the HCC patient's outcome. In our study, we applied data-independent acquisition (DIA) quantitative proteomics to investigate the expression landscape of 24 paired HCC patients. A total of 1029 differentially expressed proteins (DEPs) were screened. Then, we compared DEPs in our cohort with the differentially expressed genes (DEGs) in The Cancer Genome Atlas, and investigated their prognostic significance, and found 183 prognosis-related genes (PRGs). By conducting protein-protein interaction topological analysis, we identified four subnetworks with prognostic significance. Acyl-CoA oxidase 2 (ACOX2) is a novel gene in subnetwork1, encodes a peroxisomal enzyme, and its function in HCC was investigated in vivo and in vitro. The lower expression of ACOX2 was validated by real-time quantitative PCR, immunohistochemistry, and Western blot. Cell Counting Kit-8 assay, wound healing, and transwell migration assay were applied to evaluate the impact of ACOX2 overexpression on the proliferation and migration abilities in two liver cancer cell lines. ACOX2 overexpression, using a subcutaneous xenograft tumor model, indicated a tumor suppressor role in HCC. To uncover the underlying mechanism, gene set enrichment analysis was conducted, and peroxisome proliferator-activated receptor-α (PPARα) was proposed to be a potential target. In conclusion, we demonstrated a PRG ACOX2, and its overexpression reduced the proliferation and metastasis of liver cancer in vitro and in vivo through PPARα pathway.

Electrolyte disorders are ERAS-associated in patients undergoing hepato-pancreato-biliary surgery.

PURPOSE: Emerging evidences have raised concerns about electrolyte disorders caused by restrictive fluid management in the enhanced recovery after surgery (ERAS) protocol. This study aims to investigate the morbidity and treatment of electrolyte disorders associated with ERAS in patients undergoing hepato-pancreato-biliary (HPB) surgery. METHODS: Clinical data from 157 patients under the ERAS program and 166 patients under the traditional (Non-ERAS) program after HPB surgery were retrospectively analyzed. Risk factors and predictive factors of postoperative electrolyte disorders were analyzed by logistic regression analysis and receiver operator characteristic (ROC) curve analysis, respectively. RESULTS: The average of intravenous fluid, sodium, chloride, and potassium supplementation after surgery were significantly lower in the ERAS group. Hypokalemia was the most common type of electrolyte disorders in the ERAS group, whose incidence was substantially increased compared to that in the Non-ERAS group [28.77% vs. 8.97%, p < 0.001, on postoperative (POD) 5]. Logistic regression analysis identified the ERAS program and age as independent risk factors of hypokalemia. ROC curve analysis identified serum potassium levels below 3.76 mmol/L on POD 3 (area under curve 0.731, sensitivity 58.54%, specificity 82.69%) as a predictive factor for postoperative hypokalemia in ERAS patients. Oral supplementation at an average of 35.41 mmol potassium per day was effective in restoring the ERAS-associated hypokalemia. CONCLUSIONS: ERAS procedures were particularly associated with a lower supplementation of potassium and a higher incidence of hypokalemia in patients after HPB surgery. Oral potassium supplementation could be an adopted ERAS program for the elderly undergoing HPB surgery.

Sirtuin 1 activation alleviates primary biliary cholangitis via the blocking of the NF-κB signaling pathway.

This report sought to establish the mechanistic role of sirtuin-1 (Sirt1), a NAD+-dependent deacetylase in the modulation of primary biliary cholangitis (PBC) pathogenesis. 64 PBC patients (diagnosed based on practice guidelines for American Association for the Study of Liver Diseases) and 60 healthy controls were included in this study. Clinically, the mRNA expression level of Sirt1 in macrophages differentiated from peripheral blood mononuclear cells (PBMCs) of PBC subjects substantially decreased when compared with the healthy controls but not in other Sirt family genes (Sirt2-7). Consistent with clinical results, a PBC murine model showed that levels of Sirt1 significantly decreased in the liver and Kupffer cells of mice treated with polyinosinic/polycytidylic acid (poly I:C) for 16 weeks. A TAK1 inhibitor (NG25) prevented the poly I:C-induced Sirt1 protein level decreasing in Kupffer cells but not MAPK inhibitor. Sirt1 activators resveratrol (RSV) and SRT1720 (SRT) ameliorated poly I:C-induced hepatic injury observed via histopathologic analysis and decreased aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in the PBC murine model. Furthermore, Sirt1 activators significantly reduced pro-inflammatory cytokines levels such as interleukin-1 beta (IL-1ß), IL-6, interferon-gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α) in serum in poly I:C-induced mice. In addition, Sirt1 activators significantly inhibited the phosphorylated and acetylated levels of the RelA/p65 subunit of the nuclear transcription factor (NF-κB) but not the interferon regulatory factor (IRF) 3 in poly I:C-injured mice livers. Significantly, RSV improved the interaction between Sirt1 and p65, which may contribute to the decreased activity of NF-κB. In summary, the Sirt1 signaling pathway plays an essential role in the development of PBC and this may represent a novel approach and target for the treatment of PBC.

miR-942 promotes proliferation and metastasis of hepatocellular carcinoma cells by inhibiting RRM2B.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death. MicroRNA-942 (miR-942) plays a critical role in promoting proliferation and metastasis of cancer cells and is associated with poor prognosis in some types of cancers. However, the prognostic value of miR-942 and its functional role in HCC remain unclear. MATERIALS AND METHODS: Real-time PCR (RT-PCR) was used to detect the expression of miR-942 in HCC tissues and adjacent normal liver tissues. Next, the correlations between miR-942 expression and clinicopathological parameters including the survival rate were analyzed. Interaction between miR-942 and ribonucleotide reductase regulatory TP53 inducible subunit M2B (RRM2B) was determined by RT-PCR, Western blot and luciferase assay. The biological influence of miR-942 on HCC cell lines was studied using CCK-8 assay, colony formation assay and transwell assay in vitro. Western blot and RT-PCR were used to analyze the change of downstream genes after miR-942 mimics transfection. RESULTS: miR-942 was significantly up-regulated in HCC. Its high expression was associated with serum alanine transaminase level (P=0.0350), tumor size (P=0.0195), T stage (P=0.0045) and lymphatic metastasis (P=0.0013). High expression of miR-942 was associated with shorter overall survival and disease-free survival time of HCC patients. RRM2B was validated as a target gene of miR-942. miR-942 mimics markedly promoted the malignant phenotypes of Huh7 and MHCC97H cell lines, while its inhibitor had the opposite effect. miR-942 can regulate the downstream genes of RRM2B including Egr-1 and PTEN, markers of epithelial-mesenchymal transition and matrix metalloproteinases. CONCLUSION: miR-942 may serve as a potential biomarker for HCC and its inhibitor may be a therapeutic agent for the treatment of this deadly disease.

Expression of microRNA-30c via lentivirus vector inhibits the proliferation and enhances the sensitivity of highly aggressive ccRCC Caki-1 cells to anticancer agents.

The clear cell renal cell carcinoma (ccRCC) is one of the most fatal urologic tumors, and the prognosis remains very poor for advanced or metastatic ccRCC. This study reveals the roles of microRNA (miR)-30c in regulating a highly aggressive ccRCC cell line proliferation by targeting MTA-1, which is a key mediator for human cancer metastasis. Results from quantitative real-time polymerase chain reaction showed that the expression of MTA-1, the target of miR-30c, was significantly higher in metastatic ccRCC specimens than in nonmetastatic ccRCC or nontumor specimens. Accordingly, endogenous miR-30c is at a much lower level in highly aggressive ccRCC Caki-1 cells than nontumor or ccRCC cell lines. Expression of miR-30c via lentivirus vector inhibits the proliferation, anchorage-independent growth, in vitro invasion or migration, or in vivo growth of Caki-1 cells by repressing MTA-1 protein expression. miR-30c also enhances the sensitivity of Caki-1 cells to anticancer agents, including sorafenib and paclitaxel. These data reveal the potential application of miR-30c and that its targeting gene, MTA-1, would be a potential target in metastatic ccRCC treatment.

Identification of risk factors for intraoperative hemobilia and its correlation with early postoperative complications in patients with hepatolithiasis.

BACKGROUND: This study intends to determine the risk factor(s) for intraoperative hemobilia in patients with hepatolithiasis and examine whether the occurrence of intraoperative hemobilia influences the rate of early postoperative complications. METHODS: A retrospective analysis of 867 eligible patients was performed. Patients were divided into 2 groups: group A (hemobilia, n = 76) and group B (nonhemobilia, n = 791). RESULTS: The incidence of intraoperative hemobilia was 8.8% (76/867). Independent risk factors of intraoperative hemobilia for patients with hepatolithiasis were interval between surgery and latest attack of acute cholangitis less than or equal to 38.8 days; preoperative attack of acute severe cholangitis; and intrahepatic duct stricture. Group A had a higher incidence of early postoperative complications than group B. Shorter interval between surgery and latest attack of acute cholangitis correlated with intraoperative hemobilia and postoperative complications. CONCLUSION: The severity and time of onset of preoperative acute cholangitis influence the risk of intraoperative hemobilia, which is positively correlated with early postoperative complications.

Analyzing risk factors for early postoperative bile leakage based on Clavien classification in bile duct stones.

OBJECTIVES: To identify the risk factors of bile leakage, with different severity, based on Clavien-Dindo complication classification system. MATERIALS AND METHODS: A retrospective analysis of 943 eligible patients was performed. Sixty-eight patients, with bile leakage, were divided into 2 groups: mild bile leakage (grades I, II, n = 41) and severe bile leakage (grades III, IV, V, n = 27). Twenty-five potential factors were analyzed, by multivariate regression analyses, to identify independent risk factors of bile leakage. RESULTS: The independent risk factors of bile leakage, for the entire cohort, included attacks of acute cholangitis within 1 month, associated biliary-enteric anastomosis (BEA), associated hepatectomy and previous biliary surgery. The independent risk factors for patients with mild bile leakage were attacks of acute cholangitis within 1 month, associated hepatectomy, and a history of previous biliary surgery. Similarly, the independent risk factors for patients with severe bile leakage were attacks of acute cholangitis within 1 month, associated hepatectomy, and associated BEA. CONCLUSIONS: Risk factors for mild and severe postoperative bile leakage, in bile duct stones, were different.

Identification of risk and prognostic factors for patients with clonorchiasis-associated intrahepatic cholangiocarcinoma.

BACKGROUND: Intrahepatic cholangiocarcinoma caused by clonorchiasis (CICC) has a poor prognosis, and there have been insufficient studies regarding risk and prognostic factors. We aimed to identify CICC-associated factors. METHODS: A retrospective analysis of 127 eligible patients with CICC was performed with 254 clonorchiasis cases used as matched controls to identify risk factors for CICC. The main outcomes analyzed included overall survival (OS) and disease-free survival (DFS). RESULTS: Out of 127 surgeries, R0 resection was performed in 61 patients, R1 in 32 patients, and R2 in 22 patients; nonresection surgery was performed in 12 patients. Median OS for the entire cohort was 29.5 months. Median OS and DFS for 61 patients with R0 resection were 52.4 months and 41.5 months, respectively. We found independent risk factors for CICC were duration of raw fish consumption of ≥28 years (p < 0.001) and hepatitis B virus infection (p = 0.040). R0 resection (p < 0.001), well or moderately differentiated tumor (p = 0.019), and stage I to II tumor (p < 0.001) predicted improved OS for CICC. Serum carcinoembryonic antigen level of ≤5 ng/ml (p = 0.029) and stage I to II tumor (p < 0.001) predicted improved DFS. CONCLUSIONS: Duration of raw fish consumption ≥28 years and hepatitis B virus infection were significant risk factors for CICC in patients with clonorchiasis. For patients with CICC, curative resection is an effective treatment. Higher tumor differentiation and earlier American Joint Committee on Cancer stage predicted good prognosis. Serum carcinoembryonic antigen level was found to predict the possibility of recurrence after curative resection.

Enhanced proliferation and defective activation-induced cell death of CD4+ T cells in childhood asthma.

BACKGROUND: Hyperactivation of CD4+ T cells in peripheral blood and airway tissues has been suggested to play a key role in the development and maintenance of chronic inflammation in childhood asthma. However, the underlying mechanisms are not yet clear. OBJECTIVE: To investigate alterations in serum levels of T helper cell-related cytokines, mitogen-stimulated CD4+ T cell proliferation and activation-induced cell death (AICD) in childhood asthma. METHODS: 21 children with untreated asthma and 21 healthy volunteers (age and gender matched) participated in this study. Th1/Th2/Th17 cytokines in serum were analyzed by flow cytometry. CD4+ T cells were isolated from participants by using immuno-magnetic beads and were stimulated by phytohemagglutinin (PHA). Cell proliferation was evaluated with a Cell Counting Kit-8 (CCK-8). Activation induced cell death (AICD) of CD4+ T cells was also induced by PHA and apoptosis was assayed by annexin V/PI staining. Quantitative RT-PCR was carried out to analyze Fas and FasL mRNA expression. FLIPL, caspase-8 and Bcl-2 were detected by western blot analysis. RESULTS: In children with asthma, the proliferative capacity of CD4+ T cells was enhanced and AICD was inhibited significantly, while serum IL-4, IL-10 and TNF were markedly higher compared with the control group. Fas mRNA expression in the asthma group was obviously lower than that in the control group, while no change was detected in FasL mRNA expression. Western blot analysis showed that the levels of the anti-apoptotic proteins, FLIPL and Bcl-2 in CD4+ T cells of the asthma group were significantly higher than in the control group. Spearman's correlation tests showed that only IL-4 correlated positively with FLIPL and Bcl-2 expression, while IL-10 and TNF were unrelated to FLIPL and Bcl-2 expression. CONCLUSIONS: These results indicate that enhanced proliferation and defective AICD of CD4+ T cells influence the T cell-mediated inflammatory reaction in childhood asthma and that increased IL-4, FLIPL and Bcl-2 expression and decreased Fas expression jointly participate in these changes in cell proliferation and apoptosis.ression and decreased Fas expression jointly participate in these changes in cell proliferation and apoptosis.

Analysis of risk factors for pancreatic duct stones formation in patients with alcoholic chronic pancreatitis.

BACKGROUND: Alcoholic chronic pancreatitis (ACP) is the dominant cause of chronic pancreatitis (CP). As a main complication of CP, the formation of pancreatic duct stones (PDS) compromises pancreatic function and symptomatic patients are often subjected to aggressive treatments. The present study aimed to identify PDS risk factors in patients with ACP. METHODS: A retrospective analysis of 93 ACP patients was performed; patients were divided into two groups: ACP with PDS (n = 48) and ACP without PDS (n = 45). Fourteen potential factors were analyzed by univariate and multivariate analyses to identify independent risk factors of PDS formation in ACP patients. A comparison of demographic and clinical characteristics between ACP patients with PDS and non-ACP patients with PDS (n = 43) was also carried out. RESULTS: ACP accounted for 47.7% (93/195) of CP in this cohort. Among ACP patients, the morbidity of PDS was 51.6% (48/93). Significant risk factors of PDS formation for ACP patients included duration of drinking ≥24.7 years (OR, 9.036; 95% CI, 2.737-29.837; p < 0.001); daily alcohol consumption ≥147.0 g (OR, 3.147; 95% CI, 1.040-9.522; p = 0.042); and MPD narrowing (OR, 7.245; 95% CI, 2.205-23.811; p = 0.001). Shorter periods between diagnosis and PDS formation (PDP) were observed in ACP patients than non-ACP patients. CONCLUSIONS: Alcohol consumption accelerates the progression of PDS formation in patients with CP.

Identification of prognostic factors and the impact of palliative resection on survival of patients with stage IV hepatolithiasis-associated intrahepatic cholangiocarcinoma.

BACKGROUND: Hepatolithiasis-associated intrahepatic cholangiocarcinoma (IHHCC) has a poor prognosis, because of lower curative resection rate when diagnosed in the advanced stage. There has been insufficient data regarding prognostic factors and the impact of palliative resection on its outcome. METHODS: A retrospective analysis of 78 eligible patients with stage IV IHHCC was performed. The potential prognostic factors were assessed by univariate and multivariate analyses. Patients were divided into groups A (margin positive) and B (nonresection) based on surgical methods. Demographic and operative data were compared. RESULTS: Of 78 surgeries, R1 was achieved in 11, R2 in 21 and nonresection in 46 patients. Median overall survival (OS) of the entire cohort was 10.5 months. Surgery (P < 0.01), tumor differentiation (P = 0.03), AJCC stage (P < 0.01), and serum CEA levels (P < 0.01) were independent prognostic factors. Significant differences were achieved in OS (P < 0.01), operation time (P < 0.01), estimated blood loss (P < 0.01), and postoperative complications (P = 0.02) between groups A and B. CONCLUSIONS: For patients with stage IV IHHCC, palliative resection is a rational and effective treatment. Normal serum CEA levels, higher tumor differentiation, and stage IVa predict good prognosis in stage IV IHHCC.