Sarcopenia predicts an adverse prognosis in patients with combined hepatocellular carcinoma and cholangiocarcinoma after surgery.

BACKGROUND: The prognostic value of sarcopenia in combined hepatocellular carcinoma and cholangiocarcinoma (cHCC-CC) patients after surgery has not been evaluated, while the efficacy of the available tumor stage for cHCC-CC remains controversial. METHODS: All consecutive cHCC-CC patients after surgery were retrieved. The patients were stratified by the sex-specific medians of the psoas muscle index into groups with or without sarcopenia. Prognosis was analyzed using the Kaplan-Meier (K-M) method, and the K-M curves were adjusted by inverse probability weighting (IPW). A nomogram based on Cox regression analysis was established and further compared with primary liver cancer (PLC) stages by internal validation based on bootstrap resampling and k-fold cross-validation. RESULTS: A total of 153 patients were stratified into sarcopenia and non-sarcopenia groups. The sarcopenia group revealed statistically worse overall survival (OS) and disease-free survival (DFS) using the K-M method and K-M curves adjusted by IPW. Multivariate Cox regression analyses suggested sarcopenia as an independent risk factor for OS (HR = 1.55; p = 0.040) and DFS (HR = 1.55; p = 0.019). Subgroup analysis based on baseline variables showed sarcopenia as a stable risk factor for the prognosis. Our nomogram outperformed PLC stages in prognostic prediction, as evidenced by the best c-index, area under the curve, and positive improvement of the net reclassification index and integrated discrimination improvement. A fivefold cross-validation revealed consistent results. Decision curve analysis revealed higher net benefits of the nomogram than PLC stages. CONCLUSIONS: Sarcopenia is an independent and stable risk factor for the prognosis of cHCC-CC patients after surgery. Our nomogram might aid high-risk patient identification and clinical decisions.

Distribution and density of tertiary lymphoid structures predict clinical outcome in intrahepatic cholangiocarcinoma.

BACKGROUND & AIMS: The prognostic value and clinical relevance of tertiary lymphoid structures (TLSs) in intrahepatic cholangiocarcinoma (iCCA) remain unclear. Thus, we aimed to investigate the prognostic value and functional involvement of TLSs in iCCA. METHODS: We retrospectively included 962 patients from 3 cancer centers across China. The TLSs at different anatomic subregions were quantified and correlated with overall survival (OS) by Cox regression and Kaplan-Meier analyses. Multiplex immunohistochemistry (mIHC) was applied to characterize the composition of TLSs in 39 iCCA samples. RESULTS: A quaternary TLS scoring system was established for the intra-tumor region (T score) and peri-tumor region (P score) respectively. T scores positively correlated with favorable prognosis (p <0.001), whereas a high P score signified worse survival (p <0.001). mIHC demonstrated that both T follicular helper and regulatory T cells were significantly increased in intra-tumoral TLSs compared to peri-tumoral counterparts (p <0.05), and regulatory T cell frequencies within intra-tumoral TLSs were positively associated with P score (p <0.05) rather than T score. Collectively, the combination of T and P scores stratified iCCAs into 4 immune classes with distinct prognoses (p <0.001) that differed in the abundance and distribution pattern of TLSs. Patients displaying an immune-active pattern had the lowest risk, with 5-year OS rates of 68.8%, whereas only 3.4% of patients with an immune-excluded pattern survived at 5 years (p <0.001). The C-index of the immune class was statistically higher than the TNM staging system (0.73 vs. 0.63, p <0.001). These results were validated in an internal and 2 external cohorts. CONCLUSIONS: The spatial distribution and abundance of TLSs significantly correlated with prognosis and provided a useful immune classification for iCCA. T follicular helper and regulatory T cells may play a critical role in determining the functional orientation of spatially different TLSs. LAY SUMMARY: Tertiary lymphoid structures (TLSs) are associated with favorable prognosis in a number of cancers. However, their role in intrahepatic cholangiocarcinoma (iCCA) remains unclear. Herein, we comprehensively evaluated the spatial distribution, abundance, and cellular composition of TLSs in iCCA, and revealed the opposite prognostic impacts of TLSs located within or outside the tumor. This difference could be mediated by the different immune cell subsets present within the spatially distinct TLSs. Based on our analysis, we were able to stratify iCCAs into 4 immune subclasses associated with varying prognoses.

[Lipid Metabolic Reprogramming and Metabolic Stress in Liver Cancer].

Recent studies have shown that tumor microenvironment plays an important regulatory role in the growth and metastasis of liver cancer. Metabolic reprogramming represents a series of adaptive metabolic alterations that liver cancer cells undertake when they are under metabolic stress caused by glucose deficiency and hypoxia microenvironment, and lipid reprogramming is an important part of it. Previous studies have revealed a variety of lipid types with altered metabolic patterns in liver cancer cells, and have, to a certain extent, investigated the biological functions and regulatory mechanisms of these lipid metabolic reprogramming processes. However, there are still many lipid metabolic reprogramming processes that have not received thorough investigation, and little is known about their roles and mechanisms in the pathogenesis and development of liver cancer. In addition, how to accomplish the goal of treating liver cancer by targeting key regulatory factors in lipid metabolic reprogramming still remains a major challenge in translational medical research. This paper introduced the sources of lipids and the main functions and driving factors of lipid metabolic reprogramming in liver cancer cells, attempting to provide a theoretical basis and potential therapeutic targets for the treatment of liver cancer through regulating or restricting lipid metabolic reprogramming.

[A Review of Progress of the Relation Between Stress Response and Diabetes Mellitus].

Stress response is an adaptive process of the organism to confront environmental perturbation. Moderate stress response induces the organism to establish effective adaptive strategies for survival, while excessive stress response results in stress injury, which is a major cause of a variety of physical or psychological diseases, including diabetes mellitus. Diabetes mellitus is a typical stress-related disease, with numerous evidence indicating that the development and progression of diabetes mellitus are closely related to stress response, such as metabolic stress, oxidative stress and endoplasmic reticulum stress. However, the detailed mechanisms of stress response mediated regulation of diabetes mellitus and how to prevent or treat diabetes mellitus via modification of stress response remain to be further investigated. Here, we will introduce the definition and regulatory mechanisms of stress response, as well as discuss the biological functions and mechanisms of various stress responses during the pathogenesis of diabetes mellitus. This review highlights recent advances of stress medicine associated with diabetes mellitus, in order to provide theoretical basis and reference for prevention and treatment of diabetes mellitus. Future studies should focus on elucidating the clinical application potential of the key factors of stress response that mediate the pathogenesis of diabetes mellitus, as well as boosting the related translational medicine studies.

Nomogram Models for Predicting Risk and Prognosis of Newly Diagnosed Ovarian Cancer Patients with Liver Metastases - A Large Population-Based Real-World Study.

Background: Previous studies about liver metastases (LM) in newly diagnosed ovarian cancer (NDOC) patients based on Surveillance, Epidemiology, and End Results (SEER) program disregarded selection bias of missing data. Methods: We identified Data of NDOC patients from SEER between 2010 and 2016, presented a comprehensive description of this dataset, and limited possible biases due to missing data by applying multiple imputation (MI). We determined predictive factors for underlying LM development in NDOC patients and evaluated prognostic factors in NDOC patients with LM (OCLM). We then established predictive nomograms, assessed by the concordance index, calibration curve, decision curve analysis (DCA), and clinical impact curves (CIC). Results: The amount of missing data for different variables in SEER dataset ranges from 0 to 36.11%. The results between complete dataset and MI datasets are similar. LM prevalence in NDOC patients was 7.18%, and median overall survival for OCLM patients was 11 months. The C-index of risk nomogram for LM development in the training cohort (TC) and validation cohort (VC) were 0.764 and 0.759, respectively. The C-index and integrated area under curve within five years of prognostic nomogram for OCLM patients in the TC and VC were 0.743 and 0.773, 0.714 and 0.733, respectively. For both nomograms, DCA revealed favorable clinical use and calibration curves suggested good consistency. Conclusion: The risk nomogram is expected to aid clinicians in identifying high-risk groups of LM development in NDOC patients for intensive screening. The prognostic nomogram could facilitate individualized prediction and stratification for clinical trials in OCLM patients.

Nicotinamide induces liver regeneration and improves liver function by activating SIRT1.

Nicotinamide (Nam) has recently been characterized as an agent for tissue regeneration due to the observed pro­proliferation effects. However, the effect of Nam on liver regeneration remains undetermined. In the present study, the potency of Nam as a regimen to promote liver regeneration and restore liver function was evaluated following partial hepatectomy (PH) on C57BL/6 mice. Ki­67 immunohistochemical and cell cycle analyses demonstrated that exogenous Nam supplementation promoted the proliferation of hepatocytes and accelerated the recovery of liver tissue. The addition of Nam protected liver function following PH, as evidenced by hematoxylin and eosin staining of liver tissue morphology and measurement of serum liver injury markers. Notably, immunoblotting results revealed that the expression and activity of NAD­dependent protein deacetylase sirtuin­1 (SIRT1) were significantly upregulated following treatment with Nam, suggesting that Nam may promote liver regeneration through activation of SIRT1. The present study demonstrated that Nam regulated the process of liver regeneration and improved liver function by activating SIRT1, suggesting that Nam has the potency to be used for promoting liver regeneration following surgical resection.

Transarterial chemoembolization plus iodine-125 implantation for hepatocellular carcinoma: a systematic review and meta-analysis.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common malignancy in liver. Transarterial chemoembolization (TACE) is recommended as an effective treatment in advanced HCC patients. Recent studies showed iodine-125 seed (a low-energy radionuclide) can provide long-term local control and increase survival for HCC patients. The aim of the study was to evaluate the outcome of TACE plus iodine-125 seed in comparison with TACE alone for HCC. METHODS: A comprehensive search of studies among PubMed, Embase, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews was conducted with published date from the earliest to January 10th, 2018. No language restrictions were applied, while only prospective randomized controlled trials (RCTs) or non-randomized controlled trials (non-RCTs) were eligible for a full-text review. The primary outcome was overall survival (OS), response rate (the rate of partial atrophy or complete clearance of the tumor lesion) and adverse events (AEs). The odds ratios (ORs) were combined using either fixed-effects model or random-effects model. All statistical analyses were performed using the Stata 12.0 software. RESULTS: 9 studies were included, involving 894 patients. Among them, 473 patients received combined therapy of TACE plus iodine-125 implantation, compared with 421 patients with TACE alone. Patients receiving combined therapy of TACE plus iodine-125 showed significantly improvement in 1-year OS (OR = 4.47, 95% confidence intervals (CI): 2.97-6.73; P < 0.001), 2-year OS (OR = 4.72, 95% CI: 2.63-8.47; P < 0.001). No significant publication bias was observed in any of the measured outcomes. CONCLUSIONS: Based on these findings, TACE plus iodine-125 implantation achieves better clinical efficacy compared with TACE alone in the treatment of HCC.

Identification of The Aberrantly Expressed LncRNAs in Hepatocellular Carcinoma: A Bioinformatics Analysis Based on RNA-sequencing.

Hepatocellular carcinoma (HCC) is one of the most prevalent subtypes of liver cancer worldwide. LncRNAs have been demonstrated to be associated with the progression of HCC, but a systematic identification and characterization of their clinical roles and molecular mechanisms in HCC has not been conducted. In this study, the aberrantly expressed lncRNAs in HCC tissues were analyzed based on TCGA RNA-seq data. 1162 lncRNAs were found to be aberrantly expressed in HCC tissues, including 232 down-regulated lncRNAs and 930 up-regulated lncRNAs. The top 5 lncRNAs with the highest diagnostic accuracy were further analyzed to evaluate their clinical value and potential mechanism in HCC. Kaplan-Meier curves showed that higher expressions of DDX11-AS1 and AC092171.4 were in correlation with poorer survival in HCC patients. Significant difference was also observed when comparing the expression levels of DDX11-AS1 and SFTA1P in different clinical parameters (p < 0.05). GO analysis showed that genes regulated by the 5 lncRNAs were enriched in certain pathways, such as PI3K pathway. Moreover, GSEA analysis on the expression of DDX11-AS1 showed that DDX11-AS1 affected the gene expressions involved in HCC proliferation, differentiation and cell cycle, indicating an essential role of DDX11-AS1 in hepatocarcinogenesis.

Exosomal MicroRNA-10a Is Associated with Liver Regeneration in Rats through Downregulation of EphA4.

BACKGROUND: MicroRNAs (miRNAs) have been reported to play vital roles in liver regeneration. Previous studies mainly focused on the functions of intracellular miRNAs, while the functions of circulating exosomal miRNAs in liver regeneration remain largely unknown. The aim of this study was to identify the key exosomal miRNA that played vital roles in liver regeneration. METHODS: The Sprague-Dawley male rats were assigned to 70% partially hepatectomized group (n = 6) and sham surgery group (n = 6). The peripheral blood of both groups was collected 24 h after surgery. The exosomal miRNAs were extracted, and microarray was used to find out the key miRNA implicated in liver regeneration. Adenovirus was used to overexpress the key miRNA in rats, and proliferating cell nuclear antigen (PCNA) staining was applied to study the effect of key miRNA overexpression on liver regeneration. Western blotting was used to validate the predicted target of the key miRNA. RESULTS: Exosomal miR-10a was upregulated more than nine times in hepatectomized rats. The level of miR-10a was increased in the early phase of liver regeneration, reached the top at 72 h postsurgery, and decreased to perioperative level 168 h after surgery. Moreover, enforced expression of miR-10a by adenovirus facilitated the process of liver regeneration as evidenced by immunohistochemical staining of PCNA. Erythropoietin-producing hepatocellular receptor A4 (EphA4) has been predicted to be a target of miR-10a. The protein level of EphA4 was decreased in the early phase of liver regeneration, reached the bottom at 72 h postsurgery, and rose to perioperative level 168 h after surgery, which was negatively correlated with miR-10a, confirming that EphA4 served as a downstream target of miR-10a. Moreover, inhibition of EphA4 by rhynchophylline could promote the proliferation of hepatocytes by regulating the cell cycle. CONCLUSION: Exosomal miR-10a might accelerate liver regeneration through downregulation of EphA4.