Management of anastomotic biliary stricture through utilizing percutaneous transhepatic cholangioscopy.

AIM: Occurrence of anastomotic biliary stricture (AS) remains an essential issue following hepatobiliary surgeries, and percutaneous transhepatic cholangioscopy (PTCS) has great therapeutic significance in handling refractory AS for patients with altered gastrointestinal anatomy after cholangio-jejunostomy. This present study aimed to investigate feasibility of PTCS procedures in AS patients for therapeutic indications. MATERIALS AND METHODS: This study was a single-center, retrospective cohort study with a total number of 124 consecutive patients who received therapeutic PTCS due to AS. Clinical success rate, required number, and adverse events of therapeutic PTCS procedures as well as patients survival state were reviewed. RESULTS: These 124 patients previously underwent choledochojejunostomy or hepatico-jejunostomy, and there was post-surgical altered gastrointestinal anatomy. Overall, 366 therapeutic PTCS procedures were performed for these patients through applying rigid choledochoscope, and the median time of PTCS procedures was 3 (1-11). Among these patients, there were 34 cases (27.32%) accompanied by biliary strictures and 100 cases (80.65%) were also combined with biliary calculi. After therapeutic PTCS, most patients presented with relieved clinical manifestations and improved liver functions. The median time of follow-up was 26 months (2-86 months), and AS was successfully managed through PTCS procedures in 104 patients (83.87%). During the follow-up period, adverse events occurred in 81 cases (65.32%), most of which were tackled through supportive treatment. CONCLUSION: PTCS was a feasible, safe and effective therapeutic modality for refractory AS, which may be a promising alternative approach in clinical cases where the gastrointestinal anatomy was changed after cholangio-jejunostomy.

Associations of fatty acids with the risk of biliary tract calculus and inflammation: a Mendelian randomization study.

BACKGROUND: The presence of gallstones in both the gallbladder and bile ducts is referred to as cholelithiasis. The prevalence of cholecystolithiasis and bile duct stones differs. Observational and Mendelian randomization (MR) studies have elucidated the significant contributing role of numerous fatty acids (FAs) in the development of cholelithiasis. Despite numerous studies about cholelithiasis, evidence on the relationship between serum FA levels and cholecystolithiasis, as well as bile duct stones with or without inflammation, remains insufficient. METHODS: A two-sample MR study was designed to clarify the impact of serum FA levels on various bile duct inflammatory diseases. The summary statistics of single nucleotide polymorphisms (SNPs) associated with fatty acids were obtained from the UK Biobank (UKB) and included data from 114,999 participants. The researchers obtained GWAS summary statistics for cholecystolithiasis and bile duct stones in 463,010 and 361,194 European participants, including cases with and without inflammation. No sample overlap between the exposure and outcome was verified through the "mr-lap" package. The SNPs were screened to identify instrumental variables (IVs). Cochran's Q test was applied for heterogeneity assessment. Inverse variance weighting (IVW) (fixed effects or random effects), MR-Egger regression and weighted median methods were used for MR. Multivariable MR was applied to determine the direct effect of each exposure on the outcome. A false discovery rate (FDR) was applied to adjust for multiple testing correction based on the Benjamini-Hochberg method. Finally, the FinnGen Consortium was used to validate some results. RESULTS: The overall concentration of polyunsaturated fatty acids (PUFAs) in the serum was negatively associated with the risk of calculus of the gallbladder with acute cholecystitis (IVW, OR = 0.996, P = 0.038, CI 0.992-0.999; weighted median, OR = 0.995, P = 0.025, CI 0.991-0.999). The percentage of PUFAs to total monounsaturated fatty acids(MUFAs) (IVW, OR = 0.998, P = 0.045, CI 0.997-0.999) and the percentage of PUFAs to total FAs (IVW, OR = 0.997, P = 0.025, CI 0.995-0.999) had a protective role against cholecystitis. The percentage of PUFAs to total FAs had a protective role against calculus of the gallbladder without cholecystitis (IVW, OR = 0.995, P = 0.026, CI 0.990-0.999; MR Egger, OR = 0.99, P = 0.03, CI 0.982-0.998; weighted median, OR = 0.991, P = 5.41e-06, CI 0.988-0.995). Conversely, the percentage of MUFAs to total FAs increased the risk for cholecystitis (IVW, OR = 1.001, P = 0.034, CI 1.0001-1.002). However, there were no causal effects of the above exposures on the outcomes through multivariable MR and multiple testing correction. Finally, the causal effects of the above exposures on cholecystitis were validated in the FinnGen Consortium, which suggested that the percentage of PUFAs to total FAs (IVW, OR = 0.744, P = 0.021, CI 0.579-0.957) had a protective role against cholecystitis. CONCLUSION: These Mendelian randomization findings suggested that more attention should be focused on people who have low serum PUFA levels, which may have a potential role in the occurrence of calculus of the gallbladder or cholecystitis rather than calculus of the bile duct without cholangitis or cholecystitis.

Exosomes derived from TGF-ß1-pretreated mesenchymal stem cells alleviate biliary ischemia-reperfusion injury through Jagged1/Notch1/SOX9 pathway.

BACKGROUND: This study aimed to evaluate the efficacy of exosomes (EXO) derived from TGF-ß1-pretreated mesenchymal stem cells (MSCs) on biliary ischemia reperfusion injury (IRI) and further reveal the possible mechanisms. METHODS: Bone marrow-derived MSCs were treated with exogenous TGF-ß1, Jagged1/Notch1/SOX9 pathway inhibitor LY450139, or their combination. Then, EXO were isolated from the culture supernatants and further characterized. After establishing IRI model of biliary epithelial cells (EpiCs), EXO derived from differently-treated MSCs were applied to detect their protective effects on EpiCs, and LY450139 was applied in EpiCs to detect the possible mechanisms after treatment with MSCs-EXO. EXO derived from differently-treated MSCs were further injected into the hepatic artery immediately after establishment of intrahepatic biliary IRI for animal studies. RESULTS: Pretreatment with TGF-ß1 significantly enhanced MSCs-EXO production and elevated the levels of massive miRNAs associated with anti-apoptosis and tissue repair, which were evidently decreased after TGF-ß1 plus LY450139 cotreatment. Notable improvement was observed in EpiCs after MSCs-EXO treatment, evidenced by reduced cellular apoptosis, increased cellular proliferation and declined oxidative stress, which were more evident in EpiCs that were treated with EXO derived from TGF-ß1-pretreated MSCs. However, application of EXO derived from TGF-ß1 plus LY450139-cotreated MSCs reversely enhanced cellular apoptosis, decreased cellular proliferation and anti-oxidants production. Interestingly, LY450139 application in EpiCs after treatment with MSCs-EXO also reversed the declined cellular apoptosis and enhanced oxidative stress induced by TGF-ß1 pretreatment. In animal studies, administration of EXO derived from TGF-ß1-pretreated MSCs more effectively attenuated biliary IRI through reducing oxidative stress, apoptosis, inflammation and enhancing the expression levels of TGF-ß1 and Jagged1/Notch1/SOX9 pathway-related markers, which were reversed after administration of EXO derived from TGF-ß1 plus LY450139-cotreated MSCs. CONCLUSION: Our results provided a vital insight that TGF-ß1 pretreatment endowed MSCs-EXO with stronger protective effects to improve biliary IRI via Jagged1/Notch1/SOX9 pathway.

Efficiency of percutaneous transhepatic cholangioscopy in the treatment of biliary complications after liver transplantation.

BACKGROUND: Percutaneous transhepatic cholangioscopy (PTCS) has provided an alternative therapeutic option for handling refractory biliary complications in liver transplanted recipients. This study aimed to evaluate short-term PTCS efficiency in the management of biliary complications following liver transplantation. METHODS: Clinical data of 25 patients who received therapeutic PTCS due to biliary complications after liver transplantation were retrospectively analyzed. RESULTS: Therapeutic PTCS was successfully performed in 25 patients. Biliary complications were anastomotic strictures in seven cases, intrahepatic cholangiolithiasis in four cases, extra-and intrahepatic cholangiolithiasis in three cases, choledocholithiasis complicated with anastomotic strictures in four cases, intrahepatic cholangiolithiasis complicated with non-anastomotic strictures in one case, intrahepatic cholangiolithiasis complicated with anastomotic strictures in five cases, intrahepatic cholangiolithiasis complicated with anastomotic strictures and ischemic cholangitis in one case. The median time between liver transplantation and first PTCS was 24 months, and median times of PTCS was 2.6. Clinical manifestations were significantly improved in most patients after PTCS, and biliary complications were successfully managed through PTCS in 15 cases, which were partially effective in eight cases and ineffective in two cases. PTCS was more effective in tackling anastomotic strictures and cholangiolithiasis. CONCLUSION: PTCS was an effective therapeutic modality for treating refractory biliary complications following liver transplantation.

Successful treatment of stage IIIB intrahepatic cholangiocarcinoma using neoadjuvant therapy with the PD-1 inhibitor camrelizumab: A case report.

BACKGROUND: The prognosis of intrahepatic cholangiocarcinoma (ICC) with lymph node metastasis is poor. The feasibility of surgery is not certain, which is a contraindication according to the National Comprehensive Cancer Network guidelines. The role of immunotherapy as a neoadjuvant therapy for ICC is not clear. We herein describe a case of ICC with lymph node metastasis that was successfully treated with neoadjuvant therapy. CASE SUMMARY: A 60-year-old man with a liver tumor was admitted to our hospital. Enhanced computed tomography and magnetic resonance imaging revealed a space-occupying lesion in the right lobe of the liver. Multiple subfoci were found around the tumor, and the right posterior branch of the portal vein was invaded. Liver biopsy indicated poorly differentiated cholangiocytes. According to the American Joint Committee on Cancer disease stage classification, ICC with hilar lymph node metastasis (stage IIIB) and para-aortic lymph node metastasis was suspected. A report showed that two patients with stage IIIB ICC achieved a complete response (CR) 13 mo and 16 mo after chemotherapy with a PD-1 monoclonal antibody. After multidisciplinary consultation, the patient was given neoadjuvant therapy, surgical resection and lymph node dissection, and postoperative adjuvant therapy. After three rounds of PD-1 immunotherapy (camrelizumab) and two rounds of gemcitabine combined with cisplatin regimen chemotherapy, the tumor size was reduced. Therefore, a partial response was achieved. Exploratory laparotomy found that the lymph nodes of Group 16 were negative, and the tumor could be surgically removed. Therefore, the patient underwent right hemihepatectomy plus lymph node dissection. The patient received six rounds of chemotherapy and five rounds of PD-1 treatment postoperatively. After 8 mo of follow-up, no recurrence was found, and a CR was achieved. CONCLUSION: Neoadjuvant therapy combined with surgical resection is useful for advanced-stage ICC. This is the first report of successful treatment of stage IIIB ICC using neoadjuvant therapy with a PD-1 inhibitor.

Nrf2 deficiency causes hepatocyte dedifferentiation and reduced albumin production in an experimental extrahepatic cholestasis model.

The transcription factor Nrf2 modulates the initiation and progression of a number of diseases including liver disorders. We evaluated whether Nrf2 mediates hepatic adaptive responses to cholestasis. Wild-type and Nrf2-null mice were subjected to bile duct ligation (BDL) or a sham operation. As cholestasis progressed to day 15 post-BDL, hepatocytes in the wild-type mice exhibited a tendency to dedifferentiate, indicated by the very weak expression of hepatic progenitor markers: CD133 and tumor necrosis factor-like weak induced apoptosis receptor (Fn14). During the same period, Nrf2 deficiency augmented this tendency, manifested by higher CD133 expression, earlier, stronger, and continuous induction of Fn14 expression, and markedly reduced albumin production. Remarkably, as cholestasis advanced to the late stage (40 days after BDL), hepatocytes in the wild-type mice exhibited a Fn14+ phenotype and strikingly upregulated the expression of deleted in malignant brain tumor 1 (DMBT1), a protein essential for epithelial differentiation during development. In contrast, at this stage, hepatocytes in the Nrf2-null mice entirely inhibited the upregulation of DMBT1 expression, displayed a strong CD133+/Fn14+ phenotype indicative of severe dedifferentiation, and persistently reduced albumin production. We revealed that Nrf2 maintains hepatocytes in the differentiated state potentially via the increased activity of the Nrf2/DMBT1 pathway during cholestasis.

Preoperative identification of microvascular invasion in hepatocellular carcinoma by XGBoost and deep learning.

PURPOSE: Microvascular invasion (MVI) is a valuable predictor of survival in hepatocellular carcinoma (HCC) patients. This study developed predictive models using eXtreme Gradient Boosting (XGBoost) and deep learning based on CT images to predict MVI preoperatively. METHODS: In total, 405 patients were included. A total of 7302 radiomic features and 17 radiological features were extracted by a radiomics feature extraction package and radiologists, respectively. We developed a XGBoost model based on radiomics features, radiological features and clinical variables and a three-dimensional convolutional neural network (3D-CNN) to predict MVI status. Next, we compared the efficacy of the two models. RESULTS: Of the 405 patients, 220 (54.3%) were MVI positive, and 185 (45.7%) were MVI negative. The areas under the receiver operating characteristic curves (AUROCs) of the Radiomics-Radiological-Clinical (RRC) Model and 3D-CNN Model in the training set were 0.952 (95% confidence interval (CI) 0.923-0.973) and 0.980 (95% CI 0.959-0.993), respectively (p = 0.14). The AUROCs of the RRC Model and 3D-CNN Model in the validation set were 0.887 (95% CI 0.797-0.947) and 0.906 (95% CI 0.821-0.960), respectively (p = 0.83). Based on the MVI status predicted by the RRC and 3D-CNN Models, the mean recurrence-free survival (RFS) was significantly better in the predicted MVI-negative group than that in the predicted MVI-positive group (RRC Model: 69.95 vs. 24.80 months, p < 0.001; 3D-CNN Model: 64.06 vs. 31.05 months, p = 0.027). CONCLUSION: The RRC Model and 3D-CNN models showed considerable efficacy in identifying MVI preoperatively. These machine learning models may facilitate decision-making in HCC treatment but requires further validation.

Achievement of complete response to nivolumab in a patient with advanced sarcomatoid hepatocellular carcinoma: A case report.

BACKGROUND: Sarcomatoid hepatocellular carcinoma (SHC) is a rare subtype of hepatocellular carcinoma (HCC), with a high recurrence rate after surgery. In addition to limited effective treatment for the advanced stage of SHC, the prognosis of patients with this malignancy is worse than that of patients with conventional HCC. CASE SUMMARY: We present the case of a 54-year-old man with SHC who underwent radical segmental hepatectomy, which relapsed 4 mo after surgery due to lymphatic metastasis in the porta hepatis. Although a second surgery was performed, new metastasis developed in the mediastinal lymph nodes. Therefore, sorafenib and lenvatinib were sequentially administered as first- and second-line systemic therapies, respectively. However, progressive disease was confirmed based on a recurrent hepatic lesion and new metastatic lesion in the abdominal cavity. Percutaneous transhepatic cholangial drainage was performed to alleviate the biliary obstruction. Because the tumor was strongly positive for programmed death-ligand 1, the patient was started on nivolumab. Imaging studies revealed that after two cycles of immunotherapy, the metastatic lesions decreased to undetectable levels. CONCLUSION: The patient experienced continuous complete remission for 8 mo. Immune checkpoint inhibitors are useful for the treatment of advanced SHC.

Efficacy of Hepatic Resection vs. Radiofrequency Ablation for Patients With Very-Early-Stage or Early-Stage Hepatocellular Carcinoma: A Population-Based Study With Stratification by Age and Tumor Size.

Background: Because of the poor health conditions of elderly patients (age >65) with very-early-stage and early-stage hepatocellular carcinoma (HCC), primary treatment via hepatic resection (HR), or radiofrequency ablation (RFA) must be considered. However, few studies have examined this issue. Methods: A retrospective cohort was obtained from the Surveillance, Epidemiology, and End Results (SEER) database from 2004 to 2015. Patients were grouped by tumor size (0-20, 21-30, 31-35, and 31-50 mm) and age (>65 and ≤65). Overall survival (OS) and disease-specific survival (DSS) were assessed. Results: In total, 1912 patients aged >65 and 2,784 patients aged ≤65 were analyzed after propensity score matching (PSM). For patients >65 with tumors ≤20 mm, OS and DSS did not differ significantly between the RFA and HR groups (p = 0.47 and p = 0.76, respectively). For patients with tumors measuring 21-30 mm, the HR group had better OS and a trend toward better DSS compared with the RFA group (p = 0.03 and p = 0.09, respectively). For patients with tumors measuring 31-50 mm, the HR group had better OS and DSS compared with the RFA group (p < 0.001 for both). For patients <65, the HR group had better OS and DSS compared with the RFA group for all tumor sizes. Conclusions: For elderly patients (age >65), RFA is recommended for tumors ≤20 mm. For patients older than 65 with tumors measuring 21-50 mm and for those younger than 65 with tumors of any size, HR is the better choice.

Aging aggravates hepatic ischemia-reperfusion injury in mice by impairing mitophagy with the involvement of the EIF2α-parkin pathway.

Hepatic ischemia-reperfusion (I/R) injury fundamentally influences the performance of aged liver grafts. The significance of mitophagy in the age dependence of sensitivity to I/R injury remains poorly understood. Here, we show that aging aggravated hepatic I/R injury with decreased mitophagy in mice. The enhancement of mitophagy resulted in significant protection against hepatic I/R injury. Parkin, an E3 ubiquitin ligase, was found depleted by I/R in aged livers. In oxygen-glucose deprivation reperfusion (OGD-Rep.)-treated L02 cells, parkin silencing impaired mitophagy and aggravated cell damage through a relative large mitochondrial membrane potential transition. The phosphorylation of the endoplasmic reticulum stress response protein EIF2α, which was also reduced in the aged liver, induced parkin expression both in vivo and vitro. Forty-six hepatic biopsy specimens from liver graft were collected 2 hours after complete revascularization, followed by immunohistochemical analyses. Parkin expression was negatively correlated to donor age and the peak level of aspartate aminotransferase within first week after liver transplantation. Our translational study demonstrates that aging aggravated hepatic I/R injury by impairing the age-dependent mitophagy function via an insufficient parkin expression and identifies a new strategy to evaluate the capacity of an aged liver graft in the process of I/R through the parkin expression.

Preoperative Alfa-Fetoprotein and Fibrinogen Predict Hepatocellular Carcinoma Recurrence After Liver Transplantation Regardless of the Milan Criteria: Model Development with External Validation.

BACKGROUND/AIMS: Patient selection is critically important in improving the outcomes of liver transplantation for hepatocellular carcinoma. The aim of the current study was to identify biochemical measures that could affect patient prognosis after liver transplantation. METHODS: A total of 119 patients receiving liver transplantation for hepatocellular carcinoma were used to construct a model for predicting recurrence. The results were validated using an independent sample of 109 patients from independent hospitals. All subjects in both cohorts met the Hangzhou criteria. RESULTS: Analysis of the discovery cohort revealed an association of recurrence with preoperative fibrinogen and AFP levels. A mathematical model was developed for predicting probability of recurrence within 5 years: Y = logit(P) = -4.595 + 0.824 ×fibrinogen concentration (g/L) + 0.641 × AFP score (1 for AFP<=20ng/ml, 2 for 20 400ng/ml). At a cutoff score of -0.85, the area under the curve (AUC) was 0.819 in predicting recurrence (vs. 0.655 when using the Milan criteria). In the validation cohort, this model had reasonable performance in predicting 5-year overall survival (68.8% vs. 28.1% in using the -0.85 cutoff, p< 0.001) and disease-free survival (65.7% vs. 25.9%, p< 0.001). The sensitivity and specificity were 77.0% and 62.5%, respectively. The AUC of this newly developed model was similar to that with the Milan criteria (0.698 vs. 0.678). Surprisingly, the DFS in patients with score <= -0.85 under this model but not meeting the Milan criteria was similar to that in patients meeting the Milan criteria (53.8% vs. 60.0%, p=0.380). CONCLUSIONS: Preoperative AFP and fibrinogen are useful in predicting recurrence of hepatocellular carcinoma after liver transplantation.

Biomass-Based Carbon Nanofibers Prepared by Electrospinning for Supercapacitor.

Biomass-based carbon nanofibers were prepared by double-nozzle electrospinning the aqueous solution of acid treated the waste medicine Aconitum sinomontanum Nakai extraction and poly-acrylonitrile followed by thermal treatment in an inert atmosphere. The structural, constituent and surface properties of biomass-based carbon nanofibers were investigated by means of spectroscopic, microscopy, energy spectrometer and Brunauer-Emmet-Teller (BET) techniques. The results showed that the biomass-based carbon nanofibers had abundant pore structure and large specific surface area. The electrochemical performance of supercapacitor electrodes with the nanofibers was studied. This electrode showed a capacitance of 295 F/g at the current density of 1 A/g in 6 mol/L aqueous KOH electrolyte, and 98.5% capacity retention after 1000 charge/discharge cycles at the current density of 2 A/g. This indicate that the activate biomass-based carbon nanofibers have a good electrochemical stability.

Surgical resection versus liver transplantation for hepatocellular carcinoma within the Hangzhou criteria: a preoperative nomogram-guided treatment strategy.

BACKGROUND: With the expansion of surgical criteria, the comparative efficacy between surgical resection (SR) and liver transplantation (LT) for hepatocellular carcinoma is inconclusive. This study aimed to develop a prognostic nomogram for predicting recurrence-free survival of hepatocellular carcinoma patients after resection and explored the possibility of using nomogram as treatment algorithm reference. METHODS: From 2003 to 2012, 310 hepatocellular carcinoma patients within Hangzhou criteria undergoing resection or liver transplantation were included. Total tumor volume, albumin level, HBV DNA copies and portal hypertension were included for constructing the nomogram. The resection patients were stratified into low- and high-risk groups by the median nomogram score of 116. Independent risk factors were identified and a visually orientated nomogram was constructed using a Cox proportional hazards model to predict the recurrence risk for SR patients. RESULTS: The low-risk SR group had better outcomes compared with the high-risk SR group (3-year recurrence-free survival rate, 71.1% vs 35.9%; 3-year overall survival rate, 89.8% vs 78.9%, both P<0.001). The high-risk SR group was associated with a worse recurrence-free survival rate but similar overall survival rate compared with the transplantation group (3-year recurrence-free survival rate, 35.9% vs 74.1%, P<0.001; 3-year overall survival rate, 78.9% vs 79.6%, P>0.05). CONCLUSIONS: This nomogram offers individualized recurrence risk evaluation for hepatocellular carcinoma patients within Hangzhou criteria receiving resection. Transplantation should be considered the first-line treatment for high-risk patients.

The impact of chemotherapy-associated hemoglobin on prognosis of colorectal cancer patients receiving adjuvant chemotherapy.

BACKGROUND AND OBJECTIVE: The association of chemotherapy-associated hemoglobin and survival of colorectal cancer (CRC) receiving adjuvant chemotherapy is uncertain. We sought to explore the prognostic value of chemotherapy-associated hemoglobin in CRC receiving adjuvant chemotherapy and the best cut point affecting prognosis. METHODS: Three hundred and twenty stage II and III CRC patients receiving adjuvant FOLFOX chemotherapy from March 2003 to March 2012 were enrolled. The associations between chemotherapy-associated hemoglobin (the absolute levels of post-chemotherapy) or chemotherapy-associated hemoglobin change (change between the pre- and post-chemotherapy hemoglobins) and disease free survival (DFS) or overall survival (OS) of CRC, and the best cut point were investigated. RESULTS: Log rank test showed the best cut points for chemotherapy-associated hemoglobin and chemotherapy-associated hemoglobin change were respectively 90 g/L, 30 g/L. Cox regression model showed chemotherapy-associated hemoglobin < 90 g/L was the independent prognostic factor for DFS (HR, 2.221; 95% CI = 1.157-4.262), OS (HR, 2.058; 95% CI = 1.009-4.197), respectively, but no association of chemotherapy-associated hemoglobin change ⩾ 30g/L and DFS (HR, 2.063; 95% CI = 0.929-4.583), OS (HR, 1.386; 95% CI = 0.553-3.471) was found. CONCLUSIONS: Chemotherapy-associated hemoglobin < 90 g/L has a significant prognostic value in CRC receiving adjuvant chemotherapy, which is a significant biomarker in the individualized management and may suggest the simple indication for the treatment of anemia in adjuvant chemotherapy in CRC.

Negative Association Between MR-Spectroscopic Glutamate Markers and Gray Matter Volume After Alcohol Withdrawal in the Hippocampus: A Translational Study in Humans and Rats.

BACKGROUND: Both chronic alcohol consumption and alcohol withdrawal lead to neural tissue damage which partly recovers during abstinence. This study investigated withdrawal-associated changes in glutamatergic compounds, markers of neuronal integrity, and gray matter volumes during acute alcohol withdrawal in the hippocampus, a key region in development and maintenance of alcohol dependence in humans and rats. METHODS: Alcohol-dependent patients (N = 39) underwent magnetic resonance imaging (MRI) and MR spectroscopy (MRS) measurements within 24 hours after the last drink and after 2 weeks of abstinence. MRI and MRS data of healthy controls (N = 34) were acquired once. Our thorough quality criteria resulted in N = 15 available spectra from the first and of N = 21 from the second measurement in patients, and of N = 19 from healthy controls. In a translational approach, chronic intermittent ethanol-exposed rats and respective controls (8/group) underwent 5 MRS measurements covering baseline, intoxication, 12 and 60 hours of withdrawal, and 3 weeks of abstinence. RESULTS: In both species, higher levels of markers of glutamatergic metabolism were associated with lower gray matter volumes in the hippocampus in early abstinence. Trends of reduced N-acetylaspartate levels during intoxication persisted in patients with severe alcohol withdrawal symptoms over 2 weeks of abstinence. We observed a higher ratio of glutamate to glutamine during alcohol withdrawal in our animal model. CONCLUSIONS: Due to limited statistical power, we regard the results as preliminary and discuss them in the framework of the hypothesis of withdrawal-induced hyperglutamatergic neurotoxicity, alcohol-induced neural changes, and training-associated effects of abstinence on hippocampal tissue integrity.

Therapeutic potentials of umbilical cord-derived mesenchymal stromal cells for ischemic-type biliary lesions following liver transplantation.

BACKGROUND AIMS: Ischemic-type biliary lesions are severe, graft-threatening complications after orthotopic liver transplantation, and a novel and efficient therapeutic strategy is urgently needed. Due to the immunosuppressive and regenerative properties, mesenchymal stromal cells (MSCs) could be an interesting candidate. METHODS: We initiated safety and efficacy of human umbilical cord-derived MSC (UC-MSC) transfusions for patients with ischemic-type biliary lesions after liver transplantation. From January 2013 to June 2014, 12 ischemic-type biliary lesions patients were recruited as the MSCs group in this phase I, prospective, single-center clinical study. Patients in this group received six doses of UC-MSCs (about 1.0 × 106 MSCs per kilogram body weight through peripheral intravenous infusion). The traditional therapeutic protocol was applied during October 2003 to December 2012 in 70 ischemic-type biliary lesions patients who were treated as the control group. Liver function tests, the need for interventional therapies and graft survival rate were chosen to evaluate the therapeutic efficacy of MSC treatment. Adverse events were closely monitored up to 2 years after MSC transfusions. RESULTS: No significant MSC-related adverse events were observed during the trial. Compared with baseline, the levels of total bilirubin, γ-glutamyl transferase and alkaline phosphatase were decreased after UC-MSC treatment at week 20 and week 48. Interventional therapies were performed in 64.3% (45/70) of patients in the control group and 33.3% (4/12) of patients in the MSCs groups. MSC therapy significantly decreased the need for interventional therapies (P = 0.046). The 1- and 2-year graft survival rates were higher in the MSCs group (100% and 83.3%, respectively) than in the control group (72.9% and 68.6%, respectively). CONCLUSIONS: The UC-MSC transfusions are clinically safe and short-term favorable, which may become a novel treatment for patients with ischemic-type biliary lesions after liver transplantation.

ACC GABA levels are associated with functional activation and connectivity in the fronto-striatal network during interference inhibition in patients with borderline personality disorder.

Impulsivity often develops from disturbed inhibitory control, a function mainly regulated by γ-Aminobutyric acid (GABA) levels in the anterior cingulate cortex (ACC) and the fronto-striatal system. In this study, we combined MRS GABA measurements and fMRI to investigate neurochemical and neurofunctional correlates of interference inhibition, further emphasizing the direct relationship between those two systems, as well as their relations to impulsivity in patients with BPD. In addition to BOLD activation, task-dependent functional connectivity was assessed by a generalized psychophysiological interactions approach. Full factorial analyses were performed via SPM to examine the main effect (within-group associations) as well as the interaction term (group differences in the association slope). The UPPS scales were used to evaluate impulsivity traits. Compared to healthy controls (HCs), BPD patients exhibited significantly less ACC-caudate functional connectivity during interference inhibition. ACC GABA levels in BPD patients but not in HCs were positively related to the magnitude of activation in several fronto-striatal regions (e.g. ACC, frontal regions, putamen, caudate,) and the strength of ACC-caudate functional connectivity during interference inhibition. The strength of the correlations of GABA with connectivity significantly differs between the two groups. Moreover, among all the UPPS impulsivity subscales, UPPS sensation seeking in the BPD group was related to GABA and was also negatively related to the task-dependent BOLD activation and functional connectivity in the fronto-striatal network. Finally, mediation analyses revealed that the magnitude of activation in the caudate and the strength of ACC-caudate functional connectivity mediated the relationship between ACC GABA levels and UPPS sensation seeking in patients with BPD. Our findings suggest a disconnectivity of the fronto-striatal network in BPD patients during interference inhibition, particularly for patients with higher impulsivity. The ACC GABAergic system seems to play a crucial role in regulating regional BOLD activations and functional connectivity in this network, which are further associated with impulsive sensation seeking in BPD.

Survival analysis of sirolimus-based immunosuppression in liver transplantation in patients with hepatocellular carcinoma.

AIM: To investigate the effect of a sirolimus-based immunosuppressive protocol on tumor recurrence and survival after liver transplantation (LT) in hepatocellular carcinoma (HCC) patients. METHODS: We retrospectively analyzed 142 HCC patients who underwent LT in our hospital from January 2006 to January 2012. The patients were divided into the sirolimus (SRL) group (62 cases) and non-sirolimus (control) group (80 cases). Disease-free survival (DFS) and tumor-bearing survival after tumor recurrence were compared using the Kaplan-Meier method. RESULTS: No significant difference in DFS was observed between the two groups. Furthermore, DFS showed no significant differences in the subgroups of patients who met the Milan criteria, exceeded the Milan criteria but met the University of California, San Francisco (UCSF) criteria, or exceeded the UCSF criteria between the two groups. In the control group, 21 patients who were administered SRL after tumor recurrence had a median tumor-bearing survival time of 12months (3-34months), while 14 patients who did not experience a change in their immunosuppressive protocol after tumor recurrence had a median tumor-bearing survival time of 8months (6-22months). There was a significant difference in the tumor-bearing survival time between these patients (P=0.039). CONCLUSIONS: Not all HCC patients benefited from the sirolimus-based immunosuppressive protocol after LT. However, sirolimus may prolong the survival time of patients after tumor recurrence.

Pretransplant Elevated Plasma Fibrinogen Level is a Novel Prognostic Predictor for Hepatocellular Carcinoma Recurrence and Patient Survival Following Liver Transplantation.

BACKGROUND: Elevated plasma fibrinogen is associated with tumour progression and poor outcomes in several cancers. The present study investigated the prognostic value of preoperative fibrinogen in hepatocellular carcinoma (HCC) patients after liver transplantation (LT). MATERIAL AND METHODS: We analyzed the preoperative plasma fibrinogen levels of 41 patients who underwent LT for HCC. The cut-off value for elevated level of fibrinogen was determined by using a receiver operating characteristic (ROC) curve analysis. Cox regression analysis was performed to analyze the relationship between elevated fibrinogen level and HCC recurrence. The disease-free survival (DFS) and overall survival (OS) rate after transplantation were calculated by Kaplan-Meier method and compared by log-rank test. RESULTS: The fibrinogen levels were significantly higher in patients with tumor recurrence (3.31±0.98 g/L) compared with those in patients without recurrence (2.39±0.89 g/L) (P<0.01). A cut-off value for elevated fibrinogen level of 2.675 g/L was defined. Cox regression analysis showed that the relative risk for tumor recurrence increased by 6.871 times for patients with elevated fibrinogen. Eleven patients in the elevated fibrinogen group (21 cases) developed recurrence, while only 2 in the normal fibrinogen group (20 cases) developed recurrence. There were significant differences in DFS and OS between the elevated fibrinogen group and normal fibrinogen group (5-year DFS and OS of 44.0% and 42.9% vs. 89.2% and 80.0%, respectively, P<0.05). Vascular invasion and fibrinogen level ≥2.675 g/L were the independent prognostic predictors of tumor recurrence and poor outcome. CONCLUSIONS: Pretransplant elevated fibrinogen levels are associated with tumor recurrence and poor prognosis in hepatocellular carcinoma patients after liver transplantation.