Activation of AMPK pathway by low­dose donafenib and atorvastatin combination improves high­fat diet­induced metabolic dysfunction­associated steatotic liver disease.

Metabolic dysfunction­associated steatotic liver disease (MASLD) is an increasingly significant global health burden for which there is currently no effective treatment. The present study aimed to explore the underlying mechanisms and investigate the effects of donafenib and atorvastatin in MASLD. The effects of donafenib and atorvastatin on the activity and lipid metabolism of HepG2 cells were analyzed in vitro. A rat model of MASLD was established induced by a high­fat diet in vivo. H&E and Oil red O staining were used to observe the improvement in MASLD, western blotting analysis was used to detect the expression of proteins related to fat metabolism and immunofluorescence was used to detect reactive oxygen species (ROS) levels. In vitro, donafenib and atorvastatin inhibited lipid accumulation in HepG2 cells. In vivo, donafenib and atorvastatin activated the AMP­activated protein kinase (AMPK) pathway, downregulated the expressions of proteins related to fatty acid synthesis (sterol regulatory element­binding protein­1, 3­hydroxy­3­methylglutaryl­CoA reductase and fatty acid synthase) and upregulated the expression of proteins related to fatty acid ß­oxidation (carnitine palmitoyl­transferase 1C and acyl­CoA oxidase). The levels of free fatty acids, cholesterol and triglycerides in the liver and serum decreased in all three treatment groups. Additionally, donafenib and atorvastatin reduced oxidative stress in the liver tissue and decreased ROS levels. Low­dose donafenib combined with atorvastatin improved MASLD by regulating fatty acid metabolism and reducing oxidative stress through activation of the AMPK signaling pathway.

Transjugular intrahepatic portosystemic shunt for the treatment of hepatic sinusoidal obstruction syndrome caused by pyrrolizidine alkaloids: A multicenter retrospective study.

Purpose: To assess the impact of transjugular intrahepatic portosystemic shunt (TIPS) on clinical outcomes and liver histology in patients with hepatic sinusoidal obstruction syndrome (HSOS) caused by pyrrolizidine alkaloids (PA), and compare these results with those of patients who received supportive treatment alone. Materials and methods: From June 2015 to August 2022, 164 patients diagnosed with PA-HSOS in six tertiary care centers were retrospectively included in this study and divided into TIPS group (n = 69) and supportive treatment (ST) group (n = 95). The main endpoint was to determine whether TIPS placement could improve survival in PA-HSOS patients. The clinical symptoms associated with portal hypertension were also evaluated in this study. Additionally, a small TIPS-subgroup of 7 patients received liver biopsies before and after TIPS for histological analysis. Results: The incidence of death was markedly lower in the TIPS group than in the ST group (log-rank p = 0.026). Multivariate Cox model revealed that group assignment (hazard ratio (HR) 5.146; 95 % confidence interval (CI) 1.587-16.687; p = 0.006), total bilirubin (HR 1.029; 95 % CI 1.020-1.038; p < 0.001), and INR (HR 13.291; 95 % CI 3.637-48.566; p < 0.001) were independent predictors for mortality. In addition, TIPS placement reduced the risk of complications associated with portal hypertension but did not increase the rate of overt hepatic encephalopathy (log-rank p = 0.731). Furthermore, six of 7 TIPS patients receiving liver biopsies improved after TIPS placement, and one patient developed fibrosis. Conclusions: TIPS placement decreased the mortality and risk of complications associated with portal hypertension. Histological evaluation in a few patients showed a potential improvement by TIPS.

Synergistic Effects of Nanoscale CaO2 Combined with PD-1 Inhibitors in the Treatment of Hepatocellular Carcinoma: A Promising Combination.

Purpose: To explore the effect of calcium peroxide nanoparticles (CaO2 NPs) combined with programmed cell death protein 1 (PD-1) inhibitors in the treatment of liver cancer and its related mechanism. Methods: Hepa1-6 cells were cultured to construct the Hepa1-6 mouse liver cancer model. In vivo mechanism study, a unilateral tumor model was established. Eighteen tumor-bearing mice were randomly divided into the control group (intra-tumoral injection of PBS solution) and the experimental group (intra-tumoral injection of CaO2 NPs). A hypoxic probe, pH probe, and micro-CT were used to evaluate the effect of CaO2 NPs on improving hypoxia, neutralizing acidity, and inducing calcium overload within the tumor. To study the effect of CaO2 NPs combined with PD-1 inhibitors on proximal and distal tumors, the bilateral tumor model was established. Forty tumor-bearing mice were randomly divided into the control group (intra-tumoral/intra-peritoneal injection of PBS solution), CaO2 NPs group (intra-tumoral injection of CaO2 NPs), PD-1 group (intra-peritoneal injection of PD-1 inhibitor), and the combination group (intra-tumoral injection of CaO2 NPs and intra-peritoneal injection of PD-1 inhibitors). The administered side was recorded as the proximal tumor. Tumor volume and body weight were measured every 2 days after treatment. On day 8, serum and tumor samples were collected. The immune factors in serum (Interferon-γ (IFN-γ), Tumour necrosis factor-α (TNF-α), Interleukin-2 (IL-2), and Interleukin-10 (IL-10)) and tumor tissue (IFN-γ and TNF-α) were detected by ELISA. H&E staining was used to detect tumor necrosis. Immunohistochemical staining was used to detect the amount of CD4+ and CD8+ T cells within the tumor. By analyzing the tumor volume, pathological indexes, and immune-related indexes, the effects of CaO2 NPs combined with PD-1 inhibitors on proximal and distal tumors were evaluated, and they mediated immunomodulatory effects (including local and systemic immunity), and their effects on tumor burden were studied. In addition, a unilateral tumor model was established to study the effect of CaO2 NPs combined with PD-1 inhibitors on survival time. Results: The results of in vivo mechanism study showed that CaO2 NPs can improve hypoxia, neutralize acidity, and induce calcium overload within tumors. The results of the study on the effect of CaO2 NPs combined with PD-1 inhibitor on proximal and distal tumors showed that, compared with the other three groups, the bilateral tumor burden of the combination group was significantly reduced, the intra-tumoral infiltration of CD8+ and CD4+ T cells were significantly increased, the secretion of anti-tumor immune factors in tumor and serum was increased, and the secretion of pro-tumor immune factors was decreased. Mice in the combination group showed the longest survival compared with the other groups. Conclusion: CaO2 NPs can improve hypoxia, neutralize acidity, and induce calcium overload within tumors, so as to reduce tumor burden and realize an immunosuppressive tumor transformation to a hot tumor, and play a synergistic role with PD-1 inhibitors in anti-liver cancer.

Ginkgetin exhibits antifibrotic effects by inducing hepatic stellate cell apoptosis via STAT1 activation.

Liver fibrosis affects approximately 800 million patients worldwide, with over 2 million deaths each year. Nevertheless, there are no approved medications for treating liver fibrosis. In this study, we investigated the impacts of ginkgetin on liver fibrosis and the underlying mechanisms. The impacts of ginkgetin on liver fibrosis were assessed in mouse models induced by thioacetamide or bile duct ligation. Experiments on human LX-2 cells and primary mouse hepatic stellate cells (HSCs) were performed to explore the underlying mechanisms, which were also validated in the mouse models. Ginkgetin significantly decreased hepatic extracellular matrix deposition and HSC activation in the fibrotic models induced by thioacetamide (TAA) and bile duct ligation (BDL). Beneficial effects also existed in inhibiting hepatic inflammation and improving liver function. In vitro experiments showed that ginkgetin markedly inhibited HSC viability and induced HSC apoptosis dose-dependently. Mechanistic studies revealed that the antifibrotic effects of ginkgetin depend on STAT1 activation, as the effects were abolished in vitro after STAT1 silencing and in vivo after inhibiting STAT1 activation by fludarabine. Moreover, we observed a meaningful cross-talk between HSCs and hepatocytes, in which IL-6, released by ginkgetin-induced apoptotic HSCs, enhanced hepatocyte proliferation by activating STAT3 signaling. Ginkgetin exhibits antifibrotic effects by inducing HSC apoptosis via STAT1 activation and enhances hepatocyte proliferation secondary to HSC apoptosis via the IL-6/STAT3 pathway.

Beneficial effects of ginkgetin on improving nonalcoholic steatohepatitis characterized by bulk and single-cell RNA sequencing analysis.

Background and aims: Nonalcoholic steatohepatitis (NASH) has become one of the major causes of cirrhosis and liver failure. However, there are currently no approved medications for managing NASH. Our study was designed to assess the effects of ginkgetin on NASH and the involved mechanisms. Methods: We constructed a mouse model of NASH by high-fat diet for 24 weeks. The effects of ginkgetin on NASH were evaluated by histological study, Western blot, and biochemical analysis. RNA Sequencing (RNA-Seq) analysis was used to investigate the alteration in gene expression and signaling pathways at bulk and single-cell levels. Results: Administration of ginkgetin resulted in a marked improvement in hepatic lipid accumulation, inflammation, and fibrosis in the NASH model. And these results were supported by bulk RNA-Seq analysis, in which the related signaling pathways and gene expression were markedly downregulated. Furthermore, single-cell RNA-Seq (scRNA-Seq) analysis revealed that the effects of ginkgetin on NASH were associated with the reprogramming of macrophages, hepatic stellate cells, and endothelial cells. Especially, ginkgetin induced a marked decrease in macrophages and a shift from pro-inflammatory to anti-inflammatory phenotype in NASH mice. And the NASH-associated macrophages (NAMs), which emerge during NASH, were also significantly downregulated by ginkgetin. Conclusion: Ginkgetin exhibits beneficial effects on improving NASH, supported by bulk and single-cell RNA-Seq. Our study may promote pharmacological therapy for NASH and raise the existent understanding of NASH.

Reversion of liver cirrhosis after endovascular treatment in Chinese patients with Budd-Chiari syndrome.

AIMS: To investigate the impact of endovascular (EV) treatment on liver cirrhosis in Chinese patients with Budd-Chiari syndrome (BCS). METHODS: From September 2011 to March 2022, 97 patients from four hospitals in China who were diagnosed with primary BCS complicated with liver cirrhosis and received EV treatment were retrospectively enrolled in this study for clinical analysis. In addition, liver tissues for basic research were acquired from 25 patients between June 2022 and March 2023, including six with benign liver tumors, 11 with BCS before EV treatment, and eight with EV-treated BCS. Liver cirrhosis was assessed by clinical outcomes, histological studies, and the expression of related genes at the mRNA and protein levels. RESULTS: The patients with BCS had better liver function after EV treatment, evidenced by an increased albumin level and reduced total bilirubin, ALT, and AST. The imaging findings suggested an amelioration of liver cirrhosis and portal hypertension, including increased portal vein velocity (13.52 ± 8.89 cm/s vs. 17.51 ± 6.67 cm/s, p < 0.001) and decreased liver stiffness (30.37 ± 6.39 kPa vs. 23.70 ± 7.99 kPa, p < 0.001), portal vein diameter (14.97 ± 3.42 mm vs. 13.36 ± 2.89 mm, p < 0.001), and spleen volume (870.00 ± 355.61 cm3 vs. 771.36 ± 277.45 cm3 , p < 0.001). Furthermore, histological studies revealed that EV treatment resulted in a restoration of liver architecture with reduced extracellular matrix deposition. Meanwhile, hepatic angiogenesis and inflammation, which have a close relationship with cirrhosis, were also inhibited. In addition, the state of hepatocytes switches from apoptosis to proliferation after EV treatment. CONCLUSIONS: BCS-induced liver cirrhosis could be reversed by EV treatment from macroscopic to microscopic dimensions. Our study may provide further insights into understanding BCS and treating cirrhosis.

Misdiagnosis of Systemic Lupus Erythematosus Combined with Urinary Tuberculosis Leading to Tuberculous Meningitis: A Case Report and Literature Review.

Purpose: To explore the lessons learned from the misdiagnosis of systemic lupus erythematosus (SLE) combined with urinary tuberculosis leading to tuberculous meningitis (TBM) and the diagnosis and treatment of TBM through case reports and review of the literature. Methods: We report a case of an SLE patient presenting with urinary tuberculosis infection misdiagnosed as interstitial cystitis and complex urinary tract infection, who developed neurological infection after a cystocentesis biopsy and was eventually diagnosed with TBM. In addition, all cases of SLE combined with TBM from January 1975 to February 2022 were summarised and reviewed to compare current diagnostic and treatment strategies for the disease. Results: The patient suddenly developed neurological symptoms after cystocentesis biopsy, and we detected Mycobacterium tuberculosis in the macrogenomic next-generation sequence (mNGS) of the cerebrospinal fluid. We therefore excluded interstitial cystitis and neuropsychiatric lupus to confirm the diagnosis of Mycobacterium tuberculosis infection leading to urinary tract tuberculosis and TBM. Conclusion: SLE is complicated by urological tuberculosis, surgery triggering hematogenous dissemination leading to tuberculous meningitis. At the same time, the lack of specificity in the clinical presentation of patients makes it easy to misdiagnose neuropsychiatric lupus and delay treatment, so timely and accurate diagnosis and effective anti-tuberculosis treatment are essential.

Mild Prolongation of Prothrombin Time Does Not Affect the Safety and Prognosis of Transjugular Intrahepatic Portal Shunt: Based on Real-World Data.

BACKGROUND/AIMS: The aim was to investigate the safety and prognosis of transjugular intrahepatic portal shunt in patients with mildly prolonged prothrombin time. MATERIALS AND METHODS: Two hundred fifty-three patients with portal hypertension who received transjugular intrahepatic portal shunt from November 2015 to May 2021 in Wuhan Union Hospital were retrospectively selected. According to the preoperative prothrombin time, they were divided into 2 groups: 126 patients in the non-clinical significance group (prothrombin time prolongation <3 seconds) and 127 patients in the clinical significance group (3 seconds ≤ prothrombin time prolongation <6 seconds). A line chart of postoperative liver and kidney function was drawn, and Kaplan-Meier curve was used to analyze and compare the prognosis of the 2 groups. RESULTS: Transjugular intrahepatic portal shunt was successfully performed in all patients; the technical success rate was 100%, and no puncture-related complications occurred during perioperative period. The mean preoperative prothrombin time was 14.9 ± 0.7 seconds in the non-clinical significance group and 17.2 ± 0.8 seconds in the clinical significance group. During follow-up, 1-year stent dysfunction rates in the non-clinical significance group and clinical significance group were 3.5% and 6.9%, respectively, with no statistically significant difference (hazard ratio = 0.77, 95% CI = 0.30-1.93, log-rank P = .575). In addition, there were no significant differences in the cumulative survival rate (log rank P = .255), rebleeding rate (log-rank P = .392), and incidence of hepatic encephalopathy (log-rank P = .404) between the 2 groups. Subgroup analysis of the clinical significance group showed no significant difference in safety and prognosis between the 2 subgroups. CONCLUSION: Transjugular intrahepatic portal shunt is safe for portal hypertension patients with prothrombin time prolongation <6 seconds. There was no significant difference in prognosis between the non-clinical significance group and the clinical significance group.

Changes and influencing factors of liver volume after transjugular intrahepatic portosystemic shunt: a retrospective cohort study.

Background: Liver volume is an important measure of liver reserve and helps to determine the course of liver disease. This study aimed to observe the dynamic changes of liver volume after transjugular intrahepatic portosystemic shunt (TIPS) and analyze the related factors. Methods: Clinical data of 168 patients who underwent TIPS procedures between February 2016 and December 2021 were collected and analyzed retrospectively. The changes in liver volume after TIPS in the patients were observed, and the independent predictors affecting increases in liver volume were analyzed using a multivariable logistic regression model. Results: The mean liver volume was decreased by 12.9% at 2±1 months post TIPS and rebounded at 9±3 months post TIPS, but did not recover to its pre-TIPS level completely. Most patients (78.6%) had decreased liver volume at 2±1 months post TIPS, and in multivariable logistic regression, a lower albumin (ALB) level, a lower subcutaneous fat area at L3 (L3-SFA), and a higher degree of ascites were identified as independent factors predicting increased liver volume. The risk score model for predicting increased liver volume was Logit(P)=1.683-0.078 (ALB) -0.01 (pre TIPS L3-SFA) +0.996 (grade 3 ascites =1; non-grade 3 ascites =0). The area under the curve of the receiver operating characteristic curve was 0.729, and the cut-off value was 0.375. The rate of liver volume change at 2±1 months post TIPS was significantly correlated with that of spleen volume change (R2=0.378, P<0.001). The rate of subcutaneous fat change at 9±3 months post TIPS was significantly correlated with that of liver volume change (R2=0.782, P<0.001). In patients with a liver volume increase, the mean computed tomography value (Hounsfield units) decreased significantly after TIPS placement (65.9±17.7 vs. 57.8±18.2, P=0.009). Conclusions: Liver volume was decreased at 2±1 months post TIPS and slightly increased at 9±3 months post TIPS; however, it did not recover to its pre-TIPS level completely. A lower ALB level, a lower L3-SFA, and a higher degree of ascites were all predictors for increased liver volume post TIPS.

Management of traumatic peripheral artery pseudoaneurysm: A 10-year experience at a single center.

Purpose: This study aimed to report our 10-year experience with the management of iatrogenic (penetrating trauma) and traumatic (blunt or penetrating trauma) peripheral artery pseudoaneurysms, based on data from a tertiary referral center. Methods: From January 2012 to December 2021, the medical records of consecutive patients with iatrogenic and traumatic peripheral artery pseudoaneurysms were retrospectively reviewed. Patient demographics, clinical features, imaging data, treatment details, and follow-up results were analyzed. Results: Sixty-one consecutive patients were included in this study; 48 (79%) were men and 13 (21%) women, with a mean age of 49.4 â€‹± â€‹13.4 years (range 24-73 years). There were 42 patients (69%) who underwent open surgery, 18 (29%) undergoing endovascular embolization or stent implantation, and one (2%) undergoing ultrasound-guided thrombin injection. All patients successfully underwent open or interventional treatment. The median follow-up was 46.8 months (2.5-117.9 months), and the overall reintervention rate was 10%. Of these, one (5%) patient in the interventional treatment group and five (12%) patients in the open surgery group underwent reintervention. The overall complication rate was 8%, with complications occurring only in the open surgery group. No deaths occurred in the peri-operative period. No late complications, such as thrombosis or pseudoaneurysm recurrence, were observed. Conclusion: Peripheral artery pseudoaneurysms arising from iatrogenic or traumatic causes can be effectively treated by both open surgery and interventional procedures in selected patients with acceptable mid- and long-term outcomes.

Aerobic exercise and vitamin E improve high-fat diet-induced NAFLD in rats by regulating the AMPK pathway and oxidative stress.

BACKGROUND AND AIMS: Non-alcoholic fatty liver disease (NAFLD) has emerged as a major chronic liver disease. We explored simple and effective ways to improve NAFLD and investigate the mechanism of action. METHODS: NAFLD was induced in 40 rats fed a high-fat diet (HFD). Magnetic resonance imaging was used to evaluate the progression and improvement of NAFLD. The treatment-related interventions included aerobic exercise (E) and vitamin E (VE) supplementation. Expression levels of proteins related to fat metabolism were also assessed. The activities of antioxidant enzymes in the liver and serum lipid metabolism were analyzed using biochemical methods. RESULTS: Aerobic exercise and vitamin E effectively improved NAFLD in rats, resulting in decreased hepatic fat accumulation, reduced hepatocyte ballooning, and decreased triglyceride levels. Combination therapy achieved the best effect. Both aerobic exercise and vitamin E activate the AMPK pathway to phosphorylate acetyl-CoA carboxylase (ACC) and reduce fatty acid synthesis. The expression of sterol regulatory element-binding protein-1 (SREBP-1) was decreased significantly in the treated groups, particularly in the E + VE + HFD group. The expression of carnitine palmitoyl-transferase 1C (CPT1C) significantly increased in the treated groups, particularly in the E + VE + HFD group. Compared with the control group, reactive oxygen species (ROS) in the E + HFD group were slightly decreased, while that in the VE + HFD group were significantly decreased, with the even greater reduction observed in the E + VE + HFD group. CONCLUSION: Aerobic exercise and vitamin E supplementation can improve HFD-induced NAFLD in rats by regulating the AMPK pathway and reducing oxidative stress.

Systemic lupus erythematosus complicated with cryptococcal meningitis: A case report.

RATIONALE: Patients with systemic lupus erythematosus (SLE) complicated with cryptococcal meningitis (CM) are easy to be misdiagnosed as neuropsychiatric lupus or tuberculous meningitis due to the lack of specificity of clinical symptoms, which may delay treatment. Through this case, we considered early improvement of India ink stain of cerebrospinal fluid (CSF) and metagenomic next generation sequences to determine whether there is microbial infection, and gave the idea of empirical anti-infection therapy, so as to make early diagnosis and slow down the progression of the disease. PATIENT CONCERNS: We report the case of a 40-year-old female with SLE for 10 years. Five days ago she came down with a fever and a headache. DIAGNOSIS, INTERVENTIONS, AND OUTCOMES: India ink stain of CSF in patients with SLE shows Cryptococcus neoformans growth. Combined with imaging findings, the patient was diagnosed with CM. The patient improved after 3 weeks of antifungal therapy with amphotericin B 42 mg/d and flucytosine 6000 mg/d. LESSONS: The possibility of CM should be considered when SLE patients have sudden headache and fever. India ink stain of CSF and metagenomic next generation sequences should be actively improved in the early stage of the disease to identify whether there is microbial infection, and early empirical anti-infection treatment should be given to reduce mortality.

Intraarterial Thrombolytic Treatment for Visual Deficits Caused by Hyaluronic Acid Filler: Efficacy, Safety, and Prognostic Factors.

BACKGROUND: The benefits of intraarterial thrombolytic treatment (IATT) in reversing hyaluronic acid (HA)-related visual deficits remain unclear. This study aimed to report a 5-year experience in the treatment of visual deficits resulting from HA embolization by IATT in a tertiary medical center. METHODS: From December of 2015 to June of 2021, the medical records of consecutive patients with HA-related visual deficits who underwent IATT were reviewed retrospectively. The demographics, clinical features, imaging data, treatment details, and follow-up results of the patients were analyzed. RESULTS: A total of 72 consecutive patients were analyzed, including five men (6.9%) men and 67 women (3.1%), aged 29.3 ± 7.6 years (range, 17 to 50 years). Thirty-two patients (44.4%) showed preserved visual acuity, and 40 (55.6%) exhibited no light perception on admission. Ocular motility disorders were detected in 63 patients (87.5%), ptosis was detected in 61 patients (84.7%), and facial skin changes were detected in 54 patients (75%). The technical success rate of IATT was 100%, with successful recanalization of the occlusive artery. No procedure-related complications were detected, and all skin injuries, ptosis, and ocular motility disorders were healed. Improved visual acuity was detected in 26 cases (36.1%). In the binary logistic regression model, only preoperative preserved visual acuity was independently associated with a good outcome. CONCLUSIONS: IATT for selective patients with HA-related visual deficits is efficient and safe. Preoperative preserved visual acuity was independently associated with a good outcome after IATT. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Improvement of sarcopenia is beneficial for prognosis in cirrhotic patients after TIPS placement.

BACKGROUND: The relationship between the improvement of sarcopenia and post-TIPS prognosis has not been fully investigated. AIMS: To assess what level of sarcopenia improvement is required for potential benefits to post-TIPS prognosis. METHODS: In this retrospective study, 109 cirrhotic patients with sarcopenia who underwent TIPS between February 2016 and January 2021 were included. The change in skeletal muscle index (SMI) at 6 months post-TIPS was assessed and the correlations of SMI improvement with clinical outcomes were analyzed. RESULTS: During follow up, 59 (65.6%) patients reversed from sarcopenic to non-sarcopenic, and the cumulative mortality (8.5 % vs. 26.0%, log rank P = 0.013) and incidence of overt hepatic encephalopathy (OHE) (18.6% vs. 44.0%, log rank P = 0.004) in patients who reversed were significantly lower than who did not. SMI improvement rate was identified as an independent risk factor for mortality and OHE. In addition, the cumulative survival rate of patients with sarcopenia reversal or SMI improvement rate > 10.4% was significantly higher than that of patients with an SMI improvement rate ≤ 10.4% (92.5% vs. 58.6%, log rank P < 0.001). CONCLUSION: Reversal of sarcopenia or significant SMI improvement by TIPS could reduce the risk of death and OHE.

The impact of thrombocytopenia on variceal bleeding in cirrhotic patients with transjugular intrahepatic portosystemic shunt.

Thrombocytopenia is the most frequent haematologic disorder in patients with cirrhosis, and it is perceived as a contributory factor for bleeding events. Cirrhosis patients with portal hypertension (PHT) is often accompanied with mild to moderate thrombocytopenia when they treated with transjugular intrahepatic portosystemic shunt (TIPS). To address whether the risk of variceal hemorrhage after TIPS varies with different platelet count in patients with normal platelet count and thrombocytopenia, we conducted the retrospective controlled study to evaluate the association of platelet count with the risk of variceal bleeding after TIPS. 304 patients were selected to the study. Propensity score matching was performed to adjust for potential selection bias. 63 patients from each group could be paired. Cox proportional hazards models were used to evaluate the association between platelet and variceal bleeding after TIPS. Platelet counts of two groups are 185.0 ± 98.7 × 109/L (normal platelet count) and 70.6 ± 39.3 × 109/L (thrombocytopenia) respectively. The bleeding rates of two groups in overall cohort are 10.9% (normal platelet count) and 12.9% (thrombocytopenia). After matched, the bleeding rates of two groups are 11.1% (normal platelet count) and 14.3% (thrombocytopenia) There was no statistically significant difference in bleeding rates between the two groups, either in the whole cohort (P = 0.671) or in the matched cohort (P = 0.593). Platelet count was not associated with bleeding events after TIPS (hazard ratio (HR) 95% confidence interval: 0.986-1.005, P = 0.397 in normal platelet count and 95% confidence interval: 0.968-1.020, P = 0.648 in thrombocytopenia). Thrombocytopenia in patients with cirrhosis was not associated with the risk of variceal bleeding episodes post-TIPS. Thrombocytopenia should not be viewed as an absolute contraindication for TIPS.

Sarcopenia Defined by Psoas Muscle Thickness Predicts Mortality After Transjugular Intrahepatic Portosystemic Shunt.

PURPOSE: To assess and compare the value of psoas muscle thickness at the level of the third lumbar (L3) vertebra (TPML) or umbilicus (TPMU) and skeletal muscle index (SMI) for diagnosing sarcopenia and predicting mortality in patients undergoing transjugular intrahepatic portosystemic shunt (TIPS). MATERIALS AND METHODS: Two hundred forty-nine patients undergoing TIPS were included in this retrospective study. The cut-offs of L3-SMI for sarcopenia were 42.0 cm2/m2 in men and 38.0 cm2/m2 in women. The cut-offs for TPML/height and TPMU/height to predict mortality was established using a receiver-operating characteristic analysis. The Kaplan-Meier and Cox regression were used for survival analyses. RESULTS: Compared with TPMU/height, TPML/height was more consistent with L3-SM for the diagnosis of sarcopenia (Kappa coefficient: 0.63 vs. 0.36 in men; 0.61 vs. 0.45 in women). The Cox analysis showed that both TPML/height and TPMU/height were independent risk factors for mortality. The optimal cut-off values of TPML/height and TPMU/height for mortality in men and women were 11.2 mm/m, 9.4 mm/m, 18.4 mm/m, 15.1 mm/m, respectively. There were 119 (47.8%), 87 (34.9%), and 82 (32.9%) patients diagnosed with sarcopenia in the TPMU/height, TPML/height, and L3-SMI models, respectively. Kaplan-Meier analysis showed that the overall survival was significantly lower in the sarcopenia group in all three models. CONCLUSION: TPMU/height and TPML/height have a similar survival prognostic value as L3-SMI. TPML/height has better consistency with L3-SMI in diagnosing sarcopenia and is a more stable alternative to L3-SMI for diagnosing sarcopenia in patients undergoing TIPS.

Predictors of Improvement of Sarcopenia after Transjugular Intrahepatic Portosystemic Shunt Creation in Cirrhotic Patients.

To investigate the risk factors affecting the improvement of sarcopenia after transjugular intrahepatic portosystemic shunt (TIPS) in cirrhotic patients, this study retrospectively analyzed the data of 111 cirrhotic patients with sarcopenia who underwent TIPS creation. Computed tomography-based measurement of skeletal muscle area was used to calculate skeletal muscle index (SMI) in all patients at baseline and 6 months after TIPS creation. Multivariate logistic regression analysis was used to identify independent risk factors, which showed a significant increase in 6-month post-TIPS SMI compared with that at baseline in both men and women (for both, P < .001). Pre-TIPS SMI (odds ratio [OR], 0.93; 95% CI, 0.87-0.99; P = .031) and change in portal pressure gradient (OR, 1.13; 95% CI, 1.03-1.24; P = .009) were found to be independent risk factors for experiencing substantial improvement in post-TIPS SMI.

Nanoscale CaO2 materials for synergistic transarterial chemoembolization in a VX2 orthotopic rabbit liver cancer model.

Transcatheter arterial chemoembolization (TACE) is extensively used in the treatment of hepatocellular carcinoma (HCC), but its efficacy is usually limited to secondary tumor hypoxia and other progressive exacerbation of the abnormal tumor microenvironment (TME). Herein, we synthesized polyvinyl pyrrolidone (PVP)-coated CaO2 nanoparticles (CaO2 NPs) and applied them as a synergistic agent to improve the antitumor efficacy of TACE. After injection into the tumor, CaO2 NPs reacted with water to generate abundant oxygen, hydroxyl ions (OH-), and calcium ions (Ca2+), thereby relieving tumor hypoxia, neutralizing acid, and overloading Ca2+ to mediate antitumor effects. Moreover, the effect of chemotherapeutic drugs within the TACE was improved due to the modulated TME. CaO2 NPs efficiently regulated the TME and improved the antitumor effect of doxorubicin under hypoxia conditions in vitro. Compared to other groups, the TACE+CaO2 NPs group achieved the lowest tumor growth rate, highest tumor necrosis rate, lowest expression of histological markers associated with hypoxia and angiogenesis (HIF-α, VEGF, and CD31), and highest CD8+ T cell recruitment in vivo. Thus, these findings demonstrated that CaO2 NPs provide synergy for TACE therapy in the VX2 orthotopic rabbit liver cancer model, suggesting that they have a potential broad clinical application. STATEMENT OF SIGNIFICANCE: The efficacy of transcatheter arterial chemoembolization (TACE) for treatment of hepatocellular carcinoma is usually limited to secondary tumor hypoxia and other progressive exacerbation of the abnormal tumor microenvironment (TME). To address this issue, we synthesized CaO2 nanoparticles (CaO2 NPS) which would react with water to generate abundant oxygen, hydroxyl ions (OH-), and calcium ions (Ca2+), thereby relieving tumor hypoxia, neutralizing the acidic TME, and inducing Ca2+ overloading. The efficacy of CaO2 NPs in combination with TACE was investigated in an orthotopic rabbit liver cancer model, and the results showed the great synergetic antitumor effect of TACE and CaO2 NPs.

A VEGFR targeting peptide-drug conjugate (PDC) suppresses tumor angiogenesis in a TACE model for hepatocellular carcinoma therapy.

Transcatheter arterial chemoembolization (TACE) has become the preferred therapy for unresectable advanced hepatocellular carcinoma (HCC). However, the embolization of tumor-feeding arteries by TACE always leads to hypoxia-related tumor angiogenesis, which limited the therapeutic effect for HCC. In this paper, we used a VEGFR targeting peptide VEGF125 - 136 (QKRKRKKSRYKS) to conjugate with a lytic peptide (KLUKLUKKLUKLUK) to form a peptide-drug conjugate (PDC). We used cell affinity assay to detect the peptide binding ability to VEGFR highly expressed cell lines, and CCK8, cell apoptosis to confirm the cellular toxicity for different cell lines. Meanwhile, we created a VX2 tumor-bearing rabbit model to assess the in vivo anti-tumor effect of the peptide conjugate in combination with TAE. HE staining was used to verify the in vivo safety of the peptide conjugate. IHC was used to assess the anti-angiogenesis and cell toxicity of the peptide conjugate in tumor tissues. The peptide conjugate could not only target VEGFR in cell surface and inhibit VEGFR function, but also have potent anti-cancer effect. We luckily found the peptide conjugate showed potent cytotoxicity for liver cancer cell Huh7 (IC50 7.3 ± 0.74 µM) and endothelial cell HUVEC (IC50 10.7 ± 0.292 µM) and induced cell apoptosis of these two cell lines. We also found the peptide conjugate inhibited cell migration of HUVEC through wound healing assay. Besides, these peptides also showed better in vivo anti-tumor effect than traditional drug DOX through TACE in VX2 rabbit tumor model, and efficiently inhibit angiogenesis in tumor tissues with good safety. In conclusion, our work may provide an alternative option for clinical HCC therapy via TACE combination.

Efficacy and safety of transjugular intrahepatic portosystemic shunt for the treatment of schistosomiasis-induced portal hypertension: a retrospective case series.

BACKGROUND AND AIM: The aim of this study was to evaluate the efficacy and safety of transjugular intrahepatic portosystemic shunt (TIPS) in the treatment of portal hypertension caused by schistosomiasis. METHODS: This study included 43 patients with schistosomiasis-induced portal hypertension treated with TIPS in our institution from December 2015 to May 2021. The demographic, imaging, clinical and follow-up data of patients were recorded retrospectively to evaluate the efficacy and safety of the procedure. RESULTS: All patients were successfully implanted with stents to establish shunt, and 90.7% of the patients were in good postoperative condition with no complications. After TIPS, the Yerdel grade of portal vein thrombosis decreased, and the portal pressure gradient decreased from 27.0 ± 4.9 mmHg to 11.3 ± 3.8 mmHg (P < 0.001). Bleeding was effectively controlled, with a postoperative rebleeding rate of 9.3%, which was an 87.9% reduction from the preoperative rate. The cumulative incidence of postoperative refractory ascites, shunt dysfunction, overt hepatic encephalopathy (OHE) and death were all similar to those of TIPS for nonschistosomiasis portal hypertension. There were no differences in liver and kidney function and blood coagulation indexes before and 3 months after TIPS. Albumin was identified as an independent risk factor for mortality after TIPS for schistosomal liver fibrosis. CONCLUSION: TIPS can be used as a well-tolerated and effective treatment for schistosomiasis-induced portal hypertension, effectively reduce portal pressure gradient and improve portal vein thrombosis.