Embolization alone is as effective as TACE for unresectable HCC: systematic review and meta-analysis of randomized controlled trails.

BACKGROUND: Despite transarterial chemoembolization (TACE) was recommended as first line therapy for intermediate hepatocellular carcinoma (HCC), the efficacy of transarterial embolization (TAE) has not been widely recognized. This work was to determine whether TAE was as effective and safe as TACE for unresectable HCC. METHODS: We performed a systematic search of electronic databases and other sources for randomized controlled studies (RCTs) comparing TAE with TACE for unresectable HCC. Results were expressed as Hazard Ratio (HR) for survival and Odds Ratio (OR) for dichotomous outcomes using RevMan 5.4.1. RESULTS: We included 6 trials with 683 patients. The risk of bias of included RCTs was from unclear to high risk. There were no significant differences between TACE and TAE for progression-free survival (HR 0.83, 95% CI 0.45-1.55; p = 0.57), overall survival (HR 1.10, 95% CI 0.90-1.35; p = 0.36), and objective response rate (OR 1.17, 95% CI 0.80-1.71; p = 0.42) without obvious publication bias. Sensitivity analyses confirmed the robustness of the results. TAE group reported similar or less adverse effects than TACE group in all the studies. CONCLUSIONS: Our study demonstrated that TAE was as effective as TACE. Since TAE was simpler, cheaper and had less adverse effects than TACE, TAE should be a better choice in most cases where TACE was indicated for unresectable HCC.

Necroptosis-Mediated Synergistic Photodynamic and Glutamine-Metabolic Therapy Enabled by a Biomimetic Targeting Nanosystem for Cholangiocarcinoma.

Targeted delivery of glutamine metabolism inhibitors holds promise for cholangiocarcinoma therapy, yet effective delivery vehicles remain a challenge. This study reports the development of a biomimetic nanosystem, termed R-CM@MSN@BC, integrating mesoporous organosilicon nanoparticles with reactive oxygen species-responsive diselenide bonds for controlled release of the glutamine metabolism inhibitor bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl) ethyl sulfide (BPTES) and the photosensitizer Ce6. Erythrocyte membrane coating, engineered with Arg-Gly-Asp (RGD) peptides, not only enhanced biocompatibility but also improved tumor targeting and tissue penetration. Upon laser irradiation, R-CM@MSN@BC executed both photodynamic and glutamine-metabolic therapies, inducing necroptosis in tumor cells and triggering significant immunogenic cell death. Time-of-flight mass cytometry analysis revealed that R-CM@MSN@BC can remodel the immunosuppressive tumor microenvironment by polarizing M1-type macrophages, reducing infiltration of M2-type and CX3CR1+ macrophages, and decreasing T cell exhaustion, thereby increasing the effectiveness of anti-programmed cell death ligand 1 immunotherapy. This strategy proposed in this study presents a viable and promising approach for the treatment of cholangiocarcinoma.

A NRF2 Regulated and the Immunosuppressive Microenvironment Reversed Nanoplatform for Cholangiocarcinoma Photodynamic-Gas Therapy.

Photodynamic therapy (PDT) is a minimally invasive and controllable local cancer treatment for cholangiocarcinoma (CCA). However, the efficacy of PDT is hindered by intratumoral hypoxia and the presence of an antioxidant microenvironment. To address these limitations, combining PDT with gas therapy may be a promising strategy to enhance tumor oxygenation. Moreover, the augmentation of oxidative damage induced by PDT and gas therapy can be achieved by inhibiting NRF2, a core regulatory molecule involved in the antioxidant response. In this study, an integrated nanotherapeutic platform called CMArg@Lip, incorporating PDT and gas therapies using ROS-responsive liposomes encapsulating the photosensitizer Ce6, the NO gas-generating agent L-arginine, and the NRF2 inhibitor ML385, is successfully developed. The utilization of CMArg@Lip effectively deals with challenges posed by tumor hypoxia and antioxidant microenvironment, resulting in elevated levels of oxidative damage and subsequent induction of ferroptosis in CCA. Additionally, these findings suggest that CMArg@Lip exhibits notable immunomodulatory effects, including the promotion of immunogenic cell death and facilitation of dendritic cell maturation. Furthermore, it contributes to the anti-tumor function of cytotoxic T lymphocytes through the downregulation of PD-L1 expression in tumor cells and the activation of the STING signaling pathway in myeloid-derived suppressor cells, thereby reprogramming the immunosuppressive microenvironment via various mechanisms.

Expanded polytetrafluoroethylene (ePTFE)-covered stents versus bare stents for transjugular intrahepatic portosystemic shunt in people with liver cirrhosis.

BACKGROUND: Transjugular intrahepatic portosystemic shunt (TIPS) is a widely used procedure for management of uncontrolled upper gastrointestinal bleeding and refractory ascites in people with liver cirrhosis. However, nearly half of the people experience shunt dysfunction and recurrent symptoms within one year of the procedure. Expanded polytetrafluoroethylene (ePTFE)-covered stents are assumed to decrease shunt dysfunction by approximately 20% to 30%. OBJECTIVES: To evaluate the benefits and harms associated with the use of expanded polytetrafluoroethylene (ePTFE)-covered stents versus bare stents in transjugular intrahepatic portosystemic shunts (TIPSs) for managing people with liver cirrhosis. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was 28 February 2023. SELECTION CRITERIA: Randomised clinical trials comparing ePTFE-covered stents versus bare stents in TIPS for treatment of people with liver cirrhosis. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were 1. all-cause mortality, 2. procedure-related complications, and 3. health-related quality of life. Our secondary outcomes were 4. upper gastrointestinal bleeding, 5. recurrence of ascites, 6. hepatic encephalopathy, 7. kidney failure, 8. early thrombosis, 9. non-serious adverse events, and 10. shunt dysfunction. We used GRADE to assess certainty of evidence. We analysed outcome data at the maximum follow-up, except for the 'early thrombosis' outcome for which it was within 12 weeks after the TIPS procedure. MAIN RESULTS: We included four trials with 565 randomised participants (age range: 18 to 75 years; male range: 63.6% to 75.0%). A total of 527 participants provided data for analyses because of losses to follow-up. Two trials were conducted in China; one in France; and one in France, Spain, and Canada. Participants were classified with cirrhosis Child-Pugh class A, B, or C, and for some, the class was not reported. We used intention-to-treat principle (four trials) and per-protocol analysis (one trial) to meta-analyse the data. One trial compared ePTFE-covered stents versus bare stents of the same diameter and three trials compared ePTFE-covered stents versus stents of different diameters. ePTFE-covered stents versus bare stents of the same diameter One trial with 258 participants compared 8 mm covered stent versus 8 mm bare stent. Mortality in the covered stent group is possibly lower than in the bare stent group (risk ratio (RR) 0.63, 95% confidence interval (CI) 0.43 to 0.92; low-certainty evidence). Upper gastrointestinal bleeding (RR 0.54, 95% CI 0.35 to 0.84), recurrence of ascites (RR 0.42, 95% CI 0.20 to 0.87), and shunt dysfunction (RR 0.42, 95% CI 0.28 to 0.61) occurred more often in the bare stent group than in the covered stent group (all low-certainty evidence). There was no difference in hepatic encephalopathy between groups (RR 1.10, 95% CI 0.76 to 1.61; very low-certainty evidence). The trial did not report data on procedure-related complications, health-related quality of life, early thrombosis, and segmental liver ischaemia (a non-serious adverse event). ePTFE-covered stents versus bare stents of different stent diameters Three trials compared ePTFE-covered stents versus bare stents of different diameters (10.5 (standard deviation (SD) 0.9) mm versus 11.7 (SD 0.8) mm; 8 mm versus 10 mm; and one trial used 10-mm stents that could be dilated from 8 mm to 10 mm). There was no evidence of a difference between the ePTFE-covered stents versus bare stents groups in mortality (RR 0.75, 95% CI 0.48 to 1.16; 3 trials, 269 participants), procedure-related complications (RR 0.53, 95% CI 0.05 to 5.57; 1 trial, 80 participants), upper gastrointestinal bleeding (RR 0.46, 95% CI 0.15 to 1.38; 3 trials, 269 participants), hepatic encephalopathy (RR 0.93, 95% CI 0.66 to 1.30; 3 trials, 269 participants), and kidney failure (RR 7.59, 95% CI 0.40 to 143.92; 1 trial, 121 participants) (all very low-certainty evidence). Recurrence of ascites (RR 0.30, 95% CI 0.11 to 0.85; 3 trials, 269 participants; low-certainty evidence), shunt dysfunction (RR 0.50, 95% CI 0.28 to 0.92; 3 trials, 269 participants; low-certainty evidence), and early thrombosis (RR 0.28, 95% CI 0.09 to 0.82; I2 = 0%; 3 trials, 261 participants; very low-certainty evidence) occurred more often in the bare stents group. There was no evidence of a difference in segmental liver ischaemia (RR 5.25, 95% CI 0.26 to 106.01; 1 trial, 80 participants; very low-certainty evidence). No trial presented data on health-related quality of life. Funding One trial did not clearly report funding sources. The remaining three trials declared that they had no funding with vested interests. AUTHORS' CONCLUSIONS: Based on the small number of trials with insufficient sample size and events, and study limitations, we assessed the overall certainty of evidence in the predefined outcomes as low or very low. Therefore, we are uncertain which of the two interventions (ePTFE-covered stents or bare stents of the same diameter and ePTFE-covered stents versus bare stents of different stent diameters) is effective for the evaluated outcomes. None of the four trials reported data on health-related quality of life, and data on complications were either missing or rarely reported. We lack high-quality trials to evaluate the role of ePTFE-covered stents for TIPS for managing people with liver cirrhosis.

LncRNA LZTS1-AS1 induces proliferation, metastasis and inhibits autophagy of pancreatic cancer cells through the miR-532 /TWIST1 signaling pathway.

The 5 year survival rate after diagnosis of pancreatic cancer (PANC) is less than 5%, and it is one of the malignant tumors with the worst prognosis. Identification of novel oncogenes involved in the occurrence of pancreatic cancer is of great significance to improve the overall survival of PANC patients. Our previous study found that miR-532 is a key factor in PANC occurrence and development, and this study further explored its mechanism. We found that the expression of lncRNA LZTS1-AS1 was elevated in PANC tumor tissues and cells, and correlated with poor prognosis. In vitro experiments confirmed that LZTS1-AS1 could promote proliferation, oncogenicity, migration, and invasion of PANC cells, and inhibit apoptosis and autophagy. However, miR-532 had the completely opposite effect, and inhibition of miR-532 counteracted the effect of LZTS1-AS1 on PANC cells. Dual luciferase gene reporter assay and RNA immunoprecipitation assay confirmed the targeting relationship between LZTS1-AS1 and miR-532, and their expression levels were negatively correlated in PANC tissues. Overexpression of TWIST1 could counteract the effect of miR-532 in PANC cells, and the expression levels of both were negatively changed in PANC tissues and cells. Our results suggest that lncRNA LZTS1-AS1 acts as an oncogene to promote the metastasis of PANC and inhibit autophagy, and its mechanism may be to regulate TWIST1 through sponge miR-532. This study provides novel biomarkers and therapeutic targets for PANC.

Expression and Clinical Significance of HIF-1α in Follicular Fluid and Granulosa Cells in Infertile PCOS Patients.

The present study aimed to determine the clinical predictive significance of HIF-1α in follicular development and assisted reproductive technology (ART). We collected follicular fluid (FF) and granulosa cells (GCs) from PCOS (polycystic ovary syndrome) patients (experimental group) and other patients who were infertile due to tubal factors or male factors (control group) with IVF/ICSI-ET. The localization and expression of HIF-1α in GCs were determined by immunofluorescence staining. HIF-1α protein and mRNA expression were detected by enzyme-linked immunosorbent assay and quantitative real-time PCR, respectively. To clarify the regulation of HIF-1α by TGF-ß1, we added the HIF-1α-specific blocker YC-1 to GCs. The serum AMH, LH, LH/FSH, testosterone, BMI and the number of oocytes retrieved in the PCOS group were significantly higher, while the cleavage rate was significantly lower, than those in the control group. HIF-1α protein was expressed in the cytoplasm of GCs. The expression of HIF-1α protein in the FF of the PCOS group was significantly lower than that in the control group. However, the expression of HIF-1α protein in GCs between the two groups was not significantly different. HIF-1α protein was highly expressed in large FF (follicular diameter ≥ 14 mm). Compared with the control group, the expression of HIF-1α mRNA in GCs of the PCOS group was significantly lower. The results showed a significant positive correlation between HIF-1α and TGF-ß1 expression. We found that both HIF-1α and TGF-ß1 were involved in the development of PCOS follicular development. The mutual regulation of HIF-1α and TGF-ß1 may be one of the important mechanisms of the occurrence and development of PCOS.

High PPT1 expression predicts poor clinical outcome and PPT1 inhibitor DC661 enhances sorafenib sensitivity in hepatocellular carcinoma.

BACKGROUND: Adaptive resistance and side effects of sorafenib treatment result in unsatisfied survival of patients with hepatocellular carcinoma (HCC). Palmitoyl-protein thioesterase 1 (PPT1) plays a critical role in progression of various cancers. However, its role on prognosis and immune infiltrates in HCC remains unclarified. METHODS: By data mining in the Cancer Genome Atlas databases, the role of PPT1 in HCC were initially investigated. Furthermore, HCC cell lines Hep 3B and Hep 1-6 were treated with DC661 or siRNA against PPT1. The biological function of PPT1 was determined by CCK-8 test, colony formation assay, TUNEL staining, immunofluorescence staining, Western blot test, and PI-Annexin V apoptosis assays in vitro. Animal models of subcutaneous injection were applied to investigate the therapeutic role of targeting PPT1. RESULTS: We found that PPT1 levels were significantly upregulated in HCC tissues compared with normal tissues and were significantly associated with a poor prognosis. Multivariate analysis further confirmed that high expression of PPT1 was an independent risk factor for poor overall survival of HCC patients. We initially found that PPT1 was significantly upregulated in sorafenib-resistant cell lines established in this study. Upon sorafenib treatment, HCC cells acquired adaptive resistance by inducing autophagy. We found that DC661, a selective and potent small-molecule PPT1-inhibitor, induced lysosomal membrane permeability, caused lysosomal deacidification, inhibited autophagy and enhanced sorafenib sensitivity in HCC cells. Interestingly, this sensitization effect was also mediated by the induction mitochondrial pathway apoptosis. In addition, the expression level of PPT1 was associated with the immune infiltration in the HCC tumor microenvironment, and PPT1 inhibitor DC661 significantly enhanced the anti-tumor immune response by promoting dendritic cell maturation and further promoting CD8+ T cell activation. Moreover, DC661 combined with sorafenib was also very effective at treating tumor models in immunized mice. CONCLUSIONS: Our findings suggest that targeting PPT1 with DC661 in combination with sorafenib might be a novel and effective alternative therapeutic strategy for HCC.

Chemo-photodynamic therapy with light-triggered disassembly of theranostic nanoplatform in combination with checkpoint blockade for immunotherapy of hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a common malignant tumor with high rate of metastasis and recurrence. Although immune checkpoint blockade (ICB) has emerged as a promising type of immunotherapy in advanced HCC, treatment with ICB alone achieves an objective remission rate less than 20%. Thus, combination therapy strategies is needed to improve the treatment response rate and therapeutic effect. METHODS:  A light-triggered disassembly of nanoplatform (TB/PTX@RTK) co-loaded an aggregation induced emission (AIE) photosensitizer (TB) and paclitaxel (PTX) was prepared for on-command drug release and synergistic chemo-photodynamic therapy (chemo-PDT). Nano-micelles were characterized for drug loading content, hydrodynamic size, absorption and emission spectra, reactive oxygen species production, and PTX release from micelles. The targeted fluorescence imaging of TB/PTX@RTK micelles and the synergistic anti-tumor efficacy of TB/PTX@RTK micelles-mediated chemo-PDT combined with anti-PD-L1 were assessed both in vitro and in vivo. RESULTS: The TB/PTX@RTK micelles could specifically accumulate at the tumor site through cRGD-mediated active target and facilitate image-guided PDT for tumor ablation. Once irradiated by light, the AIE photosensitizer of TB could produce ROS for PDT, and the thioketal linker could be cleaved by ROS to precise release of PTX in tumor cells. Chemo-PDT could not only synergistically inhibit tumor growth, but also induce immunogenic cell death and elicit anti-tumor immune response. Meanwhile, chemo-PDT significantly upregulated the expression of PD-L1 on tumor cell surface which could efficiently synergize with anti-PD-L1 monoclonal antibodies to induce an abscopal effect, and establish long-term immunological memory to inhibit tumor relapse and metastasis. CONCLUSION: Our results suggest that the combination of TB/PTX@RTK micelle-mediated chemo-PDT with anti-PD-L1 monoclonal antibodies can synergistically enhance systemic anti-tumor effects, and provide a novel insight into the development of new nanomedicine with precise controlled release and multimodal therapy to enhance the therapeutic efficacy of HCC.

High BLM Expression Predicts Poor Clinical Outcome and Contributes to Malignant Progression in Human Cholangiocarcinoma.

Molecular mechanisms underlying the tumorigenesis of a highly malignant cancer, cholangiocarcinoma (CCA), are still obscure. In our study, the CCA expression profile data were acquired from The Cancer Genome Atlas (TCGA) database, and differentially expressed genes (DEGs) in the TCGA-Cholangiocarcinoma (TCGA-CHOL) data set were utilized to construct a co-expression network via weighted gene co-expression network analysis (WGCNA). The blue gene module associated with the histopathologic grade of CCA was screened. Then, five candidate hub genes were screened by combining the co-expression network with protein-protein interaction (PPI) network. After progression and survival analyses, bloom syndrome helicase (BLM) was ultimately identified as a real hub gene. Moreover, the receiver operating characteristic (ROC) curve analysis suggested that BLM had a favorable diagnostic and predictive recurrence value for CCA. The gene set enrichment analysis (GSEA) results for a single hub gene revealed the importance of cell cycle-related pathways in the CCA progression and prognosis. Furthermore, we detected the BLM expression in vitro, and the results demonstrated that the expression level of BLM was much higher in the CCA tissues and cells relative to adjacent non-tumor samples and normal bile duct epithelial cells. Additionally, after further silencing the BLM expression by small interfering RNA (siRNA), the proliferation and migration ability of CCA cells were all inhibited, and the cell cycle was arrested. Altogether, a real hub gene (BLM) and cell cycle-related pathways were identified in the present study, and the gene BLM may be involved in the CCA progression and could act as a reliable biomarker for potential diagnosis and prognostic evaluation.

A composite risk model predicts disease progression in early stages of COVID-19: A propensity score-matched cohort study.

BACKGROUND: Recently, studies on COVID-19 have focused on the epidemiology of the disease and clinical characteristics of patients, as well as on the risk factors associated with mortality during hospitalization in critical COVID-19 cases. However, few research has been performed on the prediction of disease progression in particular group of patients in the early stages of COVID-19. METHODS: The study included 338 patients with COVID-19 treated at two hospitals in Wuhan, China, from December 2019 to March 2020. Predictors of the progression of COVID-19 from mild to severe stages were selected by the logistic regression analysis. RESULTS: COVID-19 progression to severe and critical stages was confirmed in 78 (23.1%) patients. The average value of the neutrophil-to-lymphocyte ratio (NLR) was higher in patients in the disease progression group than in the improvement group. Multivariable logistic regression analysis revealed that elevated NLR, LDH and IL-10 were independent predictors of disease progression. The optimal cut-off value of NLR was 3.75. The values of the area under the curve, reflecting the accuracy of predicting COVID-19 progression by NLR was 0.739 (95%CI: 0.605-0.804). The risk model based on NLR, LDH and IL-10 had the highest area under the ROC curve. CONCLUSIONS: The performed analysis demonstrates that high concentrations of NLR, LDH and IL-10 were independent risk factors for predicting disease progression in patients at the early stage of COVID-19. The risk model combined with NLR, LDH and IL-10 improved the accuracy of the prediction of disease progression in patients in the early stages of COVID-19.

Systemic immune-inflammation index predicts postoperative acute kidney injury in hepatocellular carcinoma patients after hepatectomy.

ABSTRACT: The systemic immune-inflammation index (SII) is an independent prognostic predictor of hepatocellular carcinoma (HCC). The present investigation examined whether an association exists between preoperative SII value and postoperative acute kidney injury (pAKI) in HCC patients.The study included 479 hepatitis B virus (HBV)-associated HCC patients undergoing hepatectomy. The SII was calculated as P × N/L, where P, N, and L represent the counts of platelets, neutrophils, and lymphocytes in routine blood test, respectively. After propensity score matching, logistic regression analysis was used to explore independent predictors of pAKI in HCC patients.pAKI was confirmed in 51 patients (10.8%). The average SII value was higher in patients with pAKI than patients without pAKI. After multivariate logistic regression analysis, SII, history of hypertension, and tumor size, among others, were found to be predictors of pAKI. The optimal threshold value of SII for predicting pAKI was found to be 547.84 × 109/L. Multivariate analysis performed after propensity score matching confirmed that SII ≥ 547.84 × 109/L was an independent predictor of pAKI.The preoperative SII qualifies as a novel, independent predictor of pAKI in HCC patients with HBV infection who underwent hepatectomy.

Primary hepatic mucosa-associated lymphoid tissue lymphoma: case report and literature review.

BACKGROUND: The prevalence of primary hepatic mucosa-associated lymphoid tissue (MALT) lymphomas is extremely low. Here, we describe a case of this disease misdiagnosed as hepatocellular carcinoma (HCC) and review relevant literature to prevent future misdiagnoses. CASE PRESENTATION: a 58-year-old woman complained about abdominal pain for more than four months. About two months prior, she came to our hospital with elevated levels of HBV DNA and positive HBsAg and HBcAb. After two months of entecavir treatment, HBV DNA decreased to a normal level. She returned to the hospital with worsened abdominal pain for over a month. Magnetic resonance imaging and systemic positron emission tomography-computed tomography identified two nodes in the liver, and she was diagnosed with HCC. The patient then underwent a laparoscopic hepatectomy. Microscopic examination showed a diffuse infiltrate of small-to-medium-sized lymphocytes and lymphoepithelial lesions. Immunohistochemical staining showed that most of the lymphoid cells were strongly positive for CD20, CD79a, BCL2, IgM and weakly positive for IgD, while negative for CD3, CD10, BCL6, MUM1, CD43, CD5, cyclin D1, CD23, CD30, and PD1. The Ki-67 index of lymphoid cells was 5%. Further pathologic analysis confirmed the diagnosis of primary hepatic MALT lymphoma. The patient received antiviral treatment and recovered well with no sign of relapse for 17 months. CONCLUSIONS: Primary hepatic MALT lymphoma is an uncommon disease that is difficult to diagnose and has no widely accepted treatment. Surgical resection is a good choice for both diagnosis and local therapy, and strict follow-up of the patient is essential.

Laparoscopic resection of hepatic epithelioid hemangioendothelioma: report of eleven rare cases and literature review.

BACKGROUND: Hepatic epithelioid hemangioendothelioma (HEHE) is an extremely rare borderline tumor of vascular endothelial origin. Laparoscopic resection of HEHE has never been reported. METHODS: The clinical data of eleven patients with HEHE (4 women and 7 men) who were diagnosed and treated at the Union Hospital (Wuhan, China), and Wuhan Asia General Hospital (Wuhan, China), between March 2012 and July 2020 were analyzed retrospectively. RESULTS: The mean age of HEHE patients was 42.4 ± 13.9 years (range 22-67 years). All patients underwent laparoscopic surgery alone or in combination with radiofrequency ablation. Most tumors showed aggressive growth or metastasis. By immunohistochemistry, tumor cells were positive for CD31, CD34, ERG, PCK, FLi-1, TFE-3, and Ki-67 (labeling index range, 5-15%). In one of the patients, the tumor was accompanied by partial necrosis with a local appearance of epithelioid angiosarcoma. Postoperative adjuvant treatment included chemotherapy, sorafenib, and Huaier granule. As of July 2020, the median follow-up duration was 36 months (range, 9-60 months), with 2 (18.2%) patients experiencing tumor recurrence. CONCLUSIONS: This is the first report of laparoscopic hepatectomy of HEHE. Curative laparoscopic hepatectomy might be an acceptable treatment for appropriate HEHE patients.

Long-term surveillance of intrahepatic cholangiocarcinoma diagnosed after 20 years follow-up for hepatic hemangioma: a case report and literature review.

Intrahepatic cholangiocarcinoma is the second most common primary malignancy of liver with poor prognosis. Four patients of intrahepatic cholangiocarcinoma were diagnosed after several years' observation with hepatic hemangioma in recent reports. Herein, we present a rare case of much longer surveillance of intrahepatic cholangiocarcinoma diagnosed after 20 years follow up for hepatic hemangioma. An asymptomatic 74-year old Chinese man was admitted to our hospital for a recent enlarged liver mass lesion, after 20 years follow-up for hepatic hemangioma. He was first diagnosed with a hemangioma in segment 8 of liver by abdominal ultrasound in February 1994, on basis of slightly hyperechoic feature with 1.6 × 1.1 cm in size. The mass lesion has enlarged markedly since 2013, which was confirmed by ultrasonography, computed tomography, magnetic resonance imaging, and positron emission tomography. Thus, hepatectomy was performed and histological characteristic revealed that the mass lesion was intrahepatic cholangiocarcinoma. This is the longest disease course of intrahepatic cholangiocarcinoma ever reported, which may change the former understanding of the biological behavior of intrahepatic cholangiocarcinoma and is worthy of further study.

Long non-coding RNA MVIH promotes cell proliferation, migration, invasion through regulating multiple cancer-related pathways, and correlates with worse prognosis in pancreatic ductal adenocarcinomas.

We aimed to explore the effect of long non-coding RNA MVIH (lnc-MVIH) on cell proliferation, migration as well as invasion, and investigate the landscape of its molecular mechanism in pancreatic ductal adenocarcinomas (PDAC). Control overexpression (OE-NC group) and lnc-MVIH overexpression (OE-MVIH group) plasmids were transfected in BxPC-3 cells; control knock-down (KD-NC group) and lnc-MVIH knock-down (KD-MVIH group) plasmids were transfected in PANC-1 cells. Cellular functions were measured and mRNA sequencing was conducted. In 70 PDAC patients, lnc-MVIH expression in tumor and adjacent tissues was detected. Lnc-MVIH expression was higher in human PDAC cell lines than human normal pancreatic ductal epithelial cell line. Cell proliferation, migration and invasion were increased in OE-MVIH group compared to OE-NC group, but decreased in KD-MVIH group compared to KD-NC group. mRNA sequencing showed 145 differentially expressing genes (DEGs) upregulated in OE-MVIH group vs. OE-NC group and downregulated in KD-MVIH group vs. KD-NC group, and 51 DEGs downregulated in OE-MVIH group vs. OE-NC group and upregulated in KD-MVIH group vs. KD-NC group. These DEGs were enriched in several cancer-related pathways (including Hippo signaling pathway, cell cycle, Forkhead box O signaling pathway, apoptosis and advanced glycation end products-RAGE signaling pathway), and the effect of lnc-MVIH on regulating these DEGs was further validated by RT-qPCR. In PDAC patients, lnc-MVIH expression was increased in tumor tissue and correlated with advanced tumor size, lymph node metastasis, TNM stage and poor OS. In conclusion, lnc-MVIH might be a potential therapeutic target which regulated multiple cancer-related pathways in PDAC.

Bmi1 drives hepatocarcinogenesis by repressing the TGFß2/SMAD signalling axis.

Bmi1 is overexpressed in one-third of hepatocellular carcinoma (HCC) patients and acts as an oncogene in hepatocarcinogenesis. However, the underlying mechanism is unclear. The role of TGFß signalling in HCC is not well defined as well. Here, we report that TGFß2 is a target of Bmi1 in HCC and has a tumour-suppressing role. In Bmi1-knockout mouse livers and HCC cell lines, TGFß2/SMAD cascade proteins were upregulated. TGFß2 expression was inversely correlated with Bmi1 expression in human and mouse HCC tissues. In vitro, Bmi1 knockdown activated TGFß2/SMAD signalling and led to cell apoptosis via upregulation of p15 and p21. TGFß2 inhibition rescued the inhibitory effect of Bmi1 knockdown on HCC cell survival, proliferation, and cell-cycle progression. In vivo, restoration of TGFß2 expression blocked Bmi1/Ras-driven hepatocarcinogenesis in mice. Chromatin immunoprecipitation and luciferase reporter assays revealed that Bmi1 repressed TGFß2 expression by binding to its promoter as a co-factor of polycomb repressor complex 1. Our findings elucidate the molecular mechanism underlying hepatic Bmi1-driven carcinogenesis and highlight the importance of TGFß2 as a tumour suppressor in HCC development.

Retrospective analysis of sorafenib efficacy and safety in Chinese patients with high recurrence rate of post-hepatic carcinectomy.

Background: There is no guideline recommendation for preventing hepatocellular carcinoma (HCC) recurrence after hepatic resection. Moreover, an unmet need exists on the effectiveness of sorafenib therapy in recurrent HCC. Purpose: We therefore assessed the efficacy and safety of sorafenib in Chinese HCC patients with high risk of recurrence. Patients and methods: Data were collected retrospectively from 15 Chinese research centers from January 1, 2012 to November 15, 2013, by chart reviews of patients with moderate-advanced HCC who received hepatic carcinectomy. The primary end point was recurrence-free survival rate at 1 year in patients with a high recurrence risk. Secondary end points included 1-year survival rate, time to recurrence and safety assessment. Results: A total of 209 high-risk patients (sorafenib, n=98; control, n=111) who underwent carcinectomy were analyzed. There was no significant difference in the proportion of patients with recurrence-free survival at 1 year between the sorafenib and control (70.43% vs 68.90%: χ2=0.007, P=0.934). One-year survival rate was significantly higher with sorafenib than observed with control (95.5% vs 83.35%; χ2=7.441, P=0.006). Time to recurrence between sorafenib and control groups was similar. Incidences of all the adverse events (AEs) were similar in both the groups and transaminase elevation was most common in both groups (20.37% vs 24.79%). Thrombocytopenia incidence was significantly lower with the sorafenib group than with control (1.85% vs 9.40%; P=0.015). Conclusion: Sorafenib may be considered as a feasible option in the treatment of HCC recurrence.

Higd1a Protects Cells from Lipotoxicity under High-Fat Exposure.

Hypoxia-inducible gene domain family member 1A (Higd1a) has recently been reported to protect cells from hypoxia by helping to maintain normal mitochondrial function. The potential induction of Higd1a under high-fat exposure and whether it could protect cells from oxidative stress attracted our attention. Initially, 0.4 mM oleic acid and 0.2 mM palmitate were added to the growth media of HepG2 and LO2 cells for 72 hours. We discovered increased Higd1a expression, and knocking down Higd1a impaired mitochondrial transmembrane potential and induced cell apoptosis. We then identified that elevated reactive oxygen species (ROS) is responsible for increased Higd1a expression. Furthermore, we found that ROS promoted Higd1a expression by upregulating HIF-1a and PGC-1a expressions, and these two proteins could exert synergistic effects in inducing Higd1a expression. Taken together, these data suggest that Higd1a plays positive roles in protecting cells from oxidative stress, and ROS could induce Higd1a expression by upregulating PGC-1a and HIF-1a expressions.

Supplementary Sorafenib Therapies for Hepatocellular Carcinoma-A Systematic Review and Meta-Analysis: Supplementary Sorafenib for Liver Cancer.

BACKGROUND: Hepatocellular carcinoma (HCC) is the third deadliest cancer worldwide. Sorafenib is considered a supplementary treatment to surgical or locoregional therapies for improving outcomes. We evaluated the efficacy of sorafenib as a supplementary therapy for HCC. METHODS: We conducted a meta-analysis including 11 randomized controlled trials. Patients with HCC and studies in which sorafenib was administered alone and compared with placebo or those in which sorafenib was administered in combination with another treatment and compared with that treatment alone were included. The overall effects (OEs) on overall survival and time to progression were pooled as hazard ratios. RESULTS: The OEs of sorafenib as a first-line therapy versus placebo for unresectable HCC were 0.62 [95% confidence interval (CI): 0.50-0.77] and 0.58 (95% CI: 0.47-0.70), respectively. The OEs of sorafenib as a second-line therapy versus placebo for progressive HCC were 0.73 (95% CI: 0.47-1.13) and 0.54 (95% CI: 0.30-0.97), respectively. The OEs of sorafenib as an adjuvant therapy versus placebo for early HCC were 1.00 (95% CI: 0.76-1.30) and 0.89 (95% CI: 0.74-1.08), respectively. The OEs of sorafenib combined with transarterial chemoemboliztion (TACE) versus placebo combined with TACE were 0.80 (95% CI: 0.54-1.21) and 0.85 (95% CI: 0.70-1.04), respectively. The OEs of sorafenib as an adjuvant to TACE versus placebo as an adjuvant to TACE for intermediate HCC were 1.06 (95% CI: 0.69-1.64) and 0.65 (95% CI: 0.31-1.36), respectively. CONCLUSIONS: Sorafenib was effective as a first-line therapy for unresectable HCC, but it was ineffective as a second-line or adjuvant therapy. Sorafenib did not increase the efficacy of TACE.

Dysregulation, functional implications, and prognostic ability of the circadian clock across cancers.

It has been proposed that the circadian rhythm generally plays important roles in tumor suppression, but there is also evidence that disruption of the canonical circadian pathway has anticancer effects. In this study, we systematically analyzed the aberrances of circadian clock genes across cancers based on data from The Cancer Genome Atlas (TCGA). These data showed that the frequencies of mutations and copy number alterations in core clock genes (PER1/2/3, CLOCK, CRY1/2, and ARNTL) were low, but that the expression levels of core clock genes were downregulated by the higher levels of DNA methylation in most tumors. The circadian clock index (CCI) was established through a principal component analysis, and this measure well represents the overall expression of the core clock genes. In fact, the CCI was significantly lower in hepatocellular carcinoma with HBV infection than in other cancers. Furthermore, pathways such as the MAPK, JAK-STAT, and immune-related signaling pathways were enriched in tumors with high CCI values. Interestingly, the CCI was generally positively related to the immunophenoscores and immunophenotypes of tumors. Additionally, the expression levels of core clock genes and the CCI were also generally positively related to survival across cancers. Taken together, the results of this study provide a comprehensive analysis of circadian clock aberrances in cancer, and the results should aid further investigations of the molecular mechanisms of cancer and the development of therapeutic strategies.