Long-term survival analysis of ultrasound-guided percutaneous microwave ablation for hepatocellular carcinoma conforming to the Milan criteria: primary versus recurrent HCC.

BACKGROUND: This study compared long-term outcomes between patients with initial hepatocellular carcinoma (IHCC) and those with recurrent HCC (RHCC) treated with microwave ablation (MWA). METHODS: This retrospective study included 425 patients with HCCs (294 IHCCs and 131 RHCCs) within the Milan criteria who were treated with ultrasound-guided percutaneous MWA between January 2008 and November 2021. All patients with RHCC had previously undergone MWA for initial HCC. Overall survival (OS) and recurrence-free survival (RFS) rates were compared between the IHCC and RHCC groups before and after propensity score matching (PSM). RESULTS: Before matching, the 1-, 3-, 5-, and 10-year OS rates in the IHCC group were 95.9%, 78.5%, 60.2%, and 42.5%, respectively, which were significantly higher than those in the RHCC group (93.8%, 70.0%, 42.0%, and 6.6%, respectively). This difference remained significant after PSM. However, subgroup analyses suggested that there were no significant differences in OS rates between IHCC and RHCC in patients with solitary HCC ≤3.0 cm, AFP ≤200 ng/mL, ablative margins ≥0.5 cm, or Albumin-Bilirubin (ALBI) grade 1. RFS was significantly higher in IHCC than in RHCC before and after PSM, as well as in subgroup analyses. ALBI grade (hazard ratio (HR), 2.38; 95% CI: 1.46-3.86; p < 0.001), serum AFP level (HR, 2.07; 95% CI: 1.19-3.62; p = 0.010) and ablative margins (HR, 0.18; 95% CI: 0.06-0.59; p = 0.005) were independent prognostic factors for OS of RHCC. Serum AFP(HR, 1.29; 95% CI: 1.02-1.63, p = 0.036) level was the only factor associated with RFS in RHCC. CONCLUSIONS: MWA yielded comparable OS in IHCC and RHCC patients with solitary HCC ≤3.0 cm, AFP ≤200 ng/mL, ablative margins ≥0.5 cm, or ALBI grade 1.

Prevalence and effect on prognosis of sarcopenia in patients with primary biliary cholangitis.

Background: Sarcopenia adversely affects the treatment outcomes in Cirrhosis and NAFLD. However, such research is limited in primary biliary cholangitis (PBC) patients. This study was performed to examine the prevalence of sarcopenia and its impact on PBC patients' prognoses. Methods: This study enrolled confirmed PBC patients who had an abdominal CT scan. Sarcopenia was determined by the L3-skeletal muscle index with a Chinese population-based cut-off value. Laboratory test values and liver stiffness measurements values were obtained from the electronic medical records. Results: In total, 174 PBC patients with a median age of 54 (IQR, 48, 62) years old, were enrolled. 45 (25.9%) patients among them were diagnosed with sarcopenia. Univariate and multivariate logistic regression results illustrated that male gender (OR = 9.152, 95%CI = 3.131-26.751, p < 0.001) and LSM ≥ 12.8 kPa (OR = 4.539, 95%CI = 1.651, 12.478, p = 0.003) were the independent risk factors of sarcopenia in PBC patients. In the prognosis analysis, sarcopenia was determined as a risk factor for indicating adverse events in PBC patients (HR = 4.058, 95%CI = 1.955-8.424, p < 0.001) by Cox proportional hazards regression. Conclusion: The current findings illustrate that comprehensive evaluation and management of sarcopenia may contribute to the improvement of treatment outcomes and life quality of PBC patients.

Early versus late recurrence of hepatocellular carcinoma after microwave ablation: patterns, treatments, and post-recurrence survival.

Introduction Recurrence after microwave ablation (MWA) has not been extensively studied. We aimed to investigate the patterns, treatments, and survival of patients with hepatocellular carcinoma (HCC) who experienced early and late recurrence after MWA. Methods This retrospective study included patients with HCC recurrence after MWA as the initial treatment from January 2008 to December 2021. Recurrence patterns, treatments, and outcomes between patients with early and late HCC recurrence were compared. Prognostic factors of post-recurrence survival (PRS) were identified by multivariable Cox regression analyses. Results Among 222 patients, 128 developed early recurrence (≤2 years after MWA) and 94 had late recurrence (>2 years). Majority of the recurrent HCC were intrahepatic-only recurrence, within the Milan criteria, and received potentially curative treatment. No significant differences in the recurrence patterns, vascular invasion, tumor staging, post-recurrence treatments or median PRS (35.0 vs 33.0 months, p=0.523) were identified between patients with early and late recurrence. Multivariable analyses suggested that multiple tumor number (hazard ratio (HR), 1.54; 95% CI: 1.03-2.30, p=0.038), extra-hepatic recurrence (HR, 2.14, 95% CI: 1.16-3.92, p=0.015), vascular invasion (HR, 2.37, 95% CI: 1.18-4.76, p=0.038) and higher ALBI grade (HR, 2.18, 95% CI: 1.54-3.08, p<0.001) were independent risk factors of worse PRS, while curative treatment after recurrence (HR, 0.59, 95% CI: 0.38-0.92, p=0.038) was associated with better PRS. Conclusions No differences in recurrence patterns, post-recurrent treatments or PRS were found between HCC patients with early and late recurrence following MWA. Tumor burden and patients' liver function reserve should be considered to decide the optimal post-recurrence treatment after MWA.

Hypercholesterolemia Is Associated With Dysregulation of Lipid Metabolism and Poor Prognosis in Primary Biliary Cholangitis.

BACKGROUND & AIMS: Hypercholesterolemia is frequently diagnosed in patients with primary biliary cholangitis (PBC). However, its association with the prognosis and lipid metabolism is unknown. In this study, we aimed to investigate the prognostic value of baseline total cholesterol (TC) levels in PBC and characterized the associated lipid metabolism. METHODS: Five hundred and thirty-one patients with PBC without prior cirrhosis-related complications were randomly divided into the derivation and validation cohorts at a ratio of 7:3. Complete clinical data were obtained and analyzed. The endpoints were defined as liver-related death, liver transplantation, and cirrhosis-related complications. Lipidomics was performed in 89 patients and 28 healthy controls. RESULTS: Baseline TC was independently associated with poor liver-related outcomes, and adjusted C-statistics were 0.80 (95% confidence interval [CI]: 0.74-0.85) and 0.88 (95% CI: 0.78-0.91) in the derivation and validation cohorts, respectively. The predictive ability of TC for disease outcomes was stable over time and comparable with the Globe score. The 200 mg/dL cut-off optimally divided patients into low- and high-TC groups. A combination of TC and Globe score provided a more accurate stratification of patients into risk subgroups. Lipidomics indicated an up-regulation of lipid families in high-TC patients. Pathway analysis of 66 up-regulated lipids revealed the dysregulation of glycerophospholipid and sphingolipid metabolism in high-TC patients, which were associated with poor liver-related outcomes. CONCLUSIONS: Our results indicate that patients with PBC having baseline TC levels above 200 mg/dL have unique lipidome characteristics and are at a higher risk of poor liver-related outcomes.

Identifying optimal candidates for autologous peripheral blood stem cell therapy in patients with decompensated liver cirrhosis: a prognostic scoring system.

BACKGROUND: Stem cell transplantation shows great potential to improve the long-term survival of cirrhosis patients. However, therapeutic effects may not be homogeneous across the whole study population. This study constructed an easy-to-use nomogram to improve prognostic prediction and aid in treatment decision making for cirrhotic patients. METHODS: From August 2005 to April 2019, 315 patients with decompensated cirrhosis receiving autologous peripheral blood stem cell (PBSC) transplantation were enrolled in this study. They were randomly classified into training (2/3) and validation (1/3) groups. A predictive model was developed using Cox proportional hazard models and subsequently validated. The predictive performance of the model was evaluated and also compared with other prognostic models. RESULTS: Age, creatinine, neutrophil-to-lymphocyte ratio, and Child-Turcotte-Pugh class were included in the nomogram as prognostic variables. The nomogram showed high discrimination power concerning the area under receiver operating characteristic curves (3/5-year AUC: 0.742/0.698) and good consistency suggested by calibration plots. Patients could be accurately stratified into poor- and good-outcome groups regarding liver-transplantation free survival after receiving PBSC therapy (P < 0.001). Compared with poor-outcome group, the liver function of patients listed for liver transplantation in the good-outcome group was significantly improved (P < 0.001). Besides, our nomogram achieved a higher C-index (0.685, 95% CI 0.633-0.738) and better clinical utility compared with other conventional prognostic models. CONCLUSIONS: The proposed nomogram facilitated an accurate prognostic prediction for patients with decompensated cirrhosis receiving PBSC transplantation. Moreover, it also held the promise to stratify patients in clinical trials or practice to implement optimal treatment regimens for individuals.

Prognostic significance of liver stiffness in patients with primary biliary cholangitis: validation of Baveno VII criteria.

BACKGROUND: The role of liver stiffness measurements (LSM) in patients with primary biliary cholangitis (PBC) remains to be further elucidated. AIMS: To clarify the prognostic role of LSM and to validate the "novel concepts" proposed by the Baveno VII Working Group. METHODS: An analysis of the prognostic significance of LSM was performed involving 672 patients. RESULTS: LSM and ΔLSM/ΔT were independent risk factors for liver decompensation, liver transplantation, or liver-related death (primary outcomes, p < 0.001, both). A rule of 5 kPa for LSM (10-15-20 kPa) could be used to denote progressively higher relative risks of primary outcomes. Patients with LSM < 10 kPa have a negligible 3-year risk of primary outcomes (< 1%). Cut-off values of 10 and 15 kPa can be used to classify PBC patients into low-, medium-, and high-risk groups. A clinically significant decrease in LSM, evaluated at 6, 12, or 24 months elastography tests, was associated with a substantially reduced risk of primary outcomes (p < 0.05, all), which can be defined as a decrease in LSM of > - 20% associated with LSM < 20 kPa or any decrease to LSM < 10 kPa. A clinically significant increase in LSM, evaluated at 6, 12, or 24 months elastography tests, was associated with a substantially raised risk of primary outcomes (p < 0.05, all), which can be defined as an increase in LSM of ≥ + 20% or any increase to LSM ≥ 15 kPa. CONCLUSIONS: LSM can be used to monitor disease progression and predict long-term prognosis in patients with PBC.

Effectiveness of Fenofibrate in Treatment-Naive Patients With Primary Biliary Cholangitis: A Randomized Clinical Trial.

INTRODUCTION: Primary biliary cholangitis (PBC) is a progressive autoimmune liver disease, and patients with inadequate response to ursodeoxycholic acid (UDCA) treatment show reduced long-term survival. Recent studies have shown that fenofibrate is an effective off-label therapy for PBC. However, prospective studies on biochemical response including the timing of fenofibrate administration are lacking. This study is aimed to evaluate the efficacy and safety of fenofibrate in UDCA treatment-naive patients with PBC. METHODS: A total of 117 treatment-naive patients with PBC were recruited from the Xijing Hospital for a 12-month randomized, parallel, and open-label clinical trial. Study participants were assigned to receive either UDCA standard dose (UDCA-only group) or fenofibrate at a daily dose of 200 mg in addition to UDCA (UDCA-Fenofibrate group). RESULTS: The primary outcome was biochemical response percentage in patients according to the Barcelona criterion at 12 months. In the UDCA-Fenofibrate group, 81.4% (69.9%-92.9%) of patients achieved the primary outcome and 64.3% (51.9%-76.8%) in the UDCA-only group achieved the primary outcome ( P = 0.048). There was no difference between the 2 groups in noninvasive measures of liver fibrosis and biochemical markers other than alkaline phosphatase at 12 months. Creatinine and transaminases levels in the UDCA-Fenofibrate group increased within the first month, then returned to normal, and remained stable thereafter until the end of the study, even in patients with cirrhosis. DISCUSSION: In this randomized clinical trial in treatment-naive patients with PBC, the combination of fenofibrate and UDCA resulted in a significantly higher biochemical response rate. Fenofibrate seemed to be well-tolerated in patients.

Prediction and evaluation of high-risk patients with primary biliary cholangitis receiving ursodeoxycholic acid therapy: an early criterion.

BACKGROUND AND AIMS: Current treatment guidelines recommend ursodeoxycholic acid (UDCA) as the first-line treatment for new-diagnosed primary biliary cholangitis (PBC) patients. However, up to 40% patients are insensitive to UDCA monotherapy, and evaluation of UDCA response at 12 months may result in long period of ineffective treatment. We aimed to develop a new criterion to reliably identify non-response patients much earlier. METHODS: Five hundred sixty-nine patients with an average of 59 months (Median: 53; IQR:32-79) follow-up periods were randomly divided into either the training (70%) or the validation cohort (30%). The efficiency of different combinations of total bilirubin (TBIL), alkaline phosphatase (ALP), and aspartate aminotransferase (AST) threshold values to predict outcomes was assessed at 1, 3 or 6 month after the initiation of UDCA therapy. The endpoints were defined as adverse outcomes, including liver-related death, liver transplantation and complications of cirrhosis. Adverse outcome-free survival was compared using various published criteria and a proposed new criterion. RESULTS: A new criterion of evaluating UDCA responses at 1 month was established as: ALP ≤ 2.5 × upper limit of normal (ULN) and AST ≤ 2 × ULN, and TBIL ≤ 1 × ULN (Xi'an criterion). The 5 year adverse outcome-free survival rate of UDCA responders, defined by Xi'an criterion, was 97%, which was significantly higher than that of those non-responders (64%). An accurate distinguishing high-risk patients' capacity of Xi'an criterion was confirmed in both early and late-stage PBC. CONCLUSIONS: Xi'an criterion has a similar or even higher ability to distinguish high-risk PBC patients than other published criteria. Xi'an criterion can facilitate early identification of patients requiring new therapeutic approaches.

Near-infrared-dye labeled tumor vascular-targeted dimer GEBP11 peptide for image-guided surgery in gastric cancer.

Introduction: Positive resection margins occur in about 2.8%-8.2% gastric cancer surgeries and is associated with poor prognosis. Intraoperative guidance using Nearinfrared (NIR) fluorescence imaging is a promising technique for tumor detection and margin assessment. The goal of this study was to develop a tumor-specific probe for real-time intraoperative NIR fluorescence imaging guidance. Methods: The tumor vascular homing peptide specific for gastric cancer, GEBP11, was conjugated with a near-infrared fluorophore, Cy5.5. The binding specificity of the GEBP11 probes to tumor vascular endothelial cells were confirmed by immunofluorescent staining. The ability of the probe to detect tumor lesions was evaluated in two xenograft models. An orthotopic gastric cancer xenograft model was used to evaluate the efficacy of the GEBP11 NIR probes in real-time surgical guidance. Results: In vitro assay suggested that both mono and dimeric GEBP11 NIR probes could bind specifically to tumor vascular epithelial cells, with dimeric peptides showed better affinity. In tumor xenograft mice, live imaging suggested that comparing with free Cy5.5 probe, significantly stronger NIR signals could be detected at the tumor site at 24-48h after injection of mono or dimeric GEBP11 probes. Dimeric GEBP11 probe showed prolonged and stronger NIR signals than mono GEBP11 probe. Biodistribution assay suggested that GEBP11 NIR probes were enriched in gastric cancer xenografts. Using dimeric GEBP11 NIR probes in real-time surgery, the tumor margins and peritoneal metastases could be clearly visualized. Histological examination confirmed the complete resection of the tumor. Conclusion: (GEBP11)2-ACP-Cy5.5 could be a potential useful probe for intraoperative florescence guidance in gastric cancer surgery.

Efficacy and safety of fenofibrate addition therapy in patients with cirrhotic primary biliary cholangitis with incomplete response to ursodeoxycholic acid.

Fenofibrate (FF) has shown potential benefits in patients with primary biliary cholangitis (PBC) who have an incomplete response to ursodeoxycholic acid (UDCA). However, the efficacy and safety of FF in patients with cirrhosis remain unclear. To evaluate the efficacy and safety of additional FF therapy in patients with PBC-related cirrhosis with an incomplete response to UDCA, we conducted a retrospective analysis comparing the clinical results of additional FF therapy and continued UDCA monotherapy. A total of 59 patients were included; 27 cases underwent UDCA monotherapy and 32 cases underwent UDCA combined with FF therapy. A significant difference in alkaline phosphatase (ALP) normalization was achieved in the FF group compared to the UDCA group (37% vs. 11%, respectively; p = 0.020). Additional FF therapy was an independent risk factor for ALP normalization (hazard ratio, 7.679; 95% confidence interval, 2.059-28.633; p = 0.003). Hepatic deterioration was experienced by 40% versus 48% (p = 0.562) while 11% vs. 37% (p = 0.111) experienced liver-related mortality or liver transplantation in the FF and UDCA groups, respectively. Compared to UDCA monotherapy, additional FF therapy was associated with lower United Kingdom (UK)-PBC risk score and surrogate serum indices of liver fibrosis. After 12 months of add-on FF therapy, median ALP level and UK-PBC risk score decreased 35% and 52% from baseline (p = 0.001 and 0.210, respectively). Serum aminotransferase, triglyceride, and cholesterol decreased progressively, while total bilirubin, serum creatinine, blood urea, estimated glomerular filtration rate, aspartate aminotransferase-to-platelet ratio index, and fibrosis-4 index remained stable in FF-treated cirrhotic cases during follow-up. No significant adverse effects associated with additional FF therapy were observed in our cohort. Conclusion: Additional FF therapy was associated with higher ALP normalization rates and lower UK-PBC risk scores in patients with cirrhotic PBC with an incomplete response to UDCA. In addition, FF therapy seemed safe and well tolerated with a low frequency of adverse effects in patients with cirrhosis.

Mesenchymal stem cell-derived exosomes protect against liver fibrosis via delivering miR-148a to target KLF6/STAT3 pathway in macrophages.

BACKGROUND: Despite emerging evidence on the therapeutic potential of mesenchymal stem cells (MSCs) for liver fibrosis, the underlying mechanisms remain unclear. At present, MSC-derived exosomes (MSC-EXOs) are widely accepted as crucial messengers for intercellular communication. This study aimed to explore the therapeutic effects of MSC-EXOs on liver fibrosis and identify the mechanisms underlying the action of MSC-EXOs. METHODS: Carbon tetrachloride was used to induce a liver fibrosis model, which was intravenously administered with MSCs or MSC-EXOs to assess treatment efficacy. The resulting histopathology, fibrosis degree, inflammation and macrophage polarization were analyzed. RAW264.7 and BMDM cells were used to explore the regulatory effects of MSC-EXOs on macrophage polarization. Then, the critical miRNA mediating the therapeutic effects of MSC-EXOs was screened via RNA sequencing and validated experimentally. Furthermore, the target mRNA and downstream signaling pathways were elucidated by luciferase reporter assay, bioinformatics analysis and western blot. RESULTS: MSCs alleviated liver fibrosis largely depended on their secreted exosomes, which were visualized to circulate into liver after transplantation. In addition, MSC-EXOs were found to modulate macrophage phenotype to regulate inflammatory microenvironment in liver and repair the injury. Mechanically, RNA-sequencing illustrates that miR-148a, enriched in the MSC-EXOs, targets Kruppel-like factor 6 (KLF6) to suppress pro-inflammatory macrophages and promote anti-inflammatory macrophages by inhibiting the STAT3 pathway. Administration of miR-148a-enriched MSC-EXOs or miR-148a agomir shows potent ameliorative effects on liver fibrosis. CONCLUSIONS: These findings suggest that MSC-EXOs protect against liver fibrosis via delivering miR-148a that regulates intrahepatic macrophage functions through KLF6/STAT3 signaling and provide a potential therapeutic target for liver fibrosis.

Symptoms Burden and Health-related Quality of Life in Chinese Patients with Primary Biliary Cholangitis.

BACKGROUND AND AIMS: Primary biliary cholangitis (PBC) is a chronic liver disease that negatively affects the health-related quality of life (HRQoL) of patients. Furthermore, the HRQoL of Chinese patients has been neglected for a long time. The present study aimed to assess the HRQoL of Chinese patients with PBC and explore the clinical variables correlating to the improvement of itch and fatigue. METHODS: This was an observational, cross-sectional study. The PBC-40 and itch numerical rating scales were used to evaluate the symptoms and HRQoL of patients. RESULTS: A total of 383 patients were recruited, and 86.4% were female, with a median age of 55 years (range: 49-63 years). We found that females had significantly higher scores than males in symptoms (p=0.033) and cognitive domains (p=0.021), and the fatigue domain was higher in elderly patients (p=0.007). Meanwhile, patients whose body mass index was <18.5 had the highest scores in the symptoms (p=0.009), fatigue (p=0.010), and cognitive (p=0.019) domains. Age at participation (odds ratio [OR]=1.068, p=0.015) and albumin level at 12 months after ursodeoxycholic acid treatment (OR=208.807, p=0.025) were independent factors that affected the improvement of the itch and fatigue domains, respectively. CONCLUSIONS: The HRQoL of Chinese patients with PBC was significantly impaired depending on sex, age, and body mass index. Age and albumin level were significantly associated with the improvement of itch and fatigue, respectively. Therefore, treatment and support aimed at these two factors can be provided to improve the HRQoL of patients.

Erythrocyte count is associated with prognosis in Chinese patients with primary biliary cholangitis.

Erythroid parameters have been indicated to be important prognostic factors for liver diseases. The present study aimed to evaluate the prognostic value of the erythrocyte count in Chinese patients with primary biliary cholangitis (PBC) and develop a prognostic model. The clinical data of 301 patients with PBC were retrospectively reviewed. Univariate and multivariate Cox regression analysis was performed to identify potential prognostic risk factors. Bivariate correlation analysis was used to determine the correlation coefficient of the erythrocyte count and biochemical indices. The prognostic values of different factors were compared by receiver operating characteristic (ROC) curve analysis. A novel prognostic model was constructed using multivariate logistic regression. Multivariate regression analysis suggested that the erythrocyte count was an independent risk factor/prognostic index (P=0.042). The erythrocyte count in peripheral blood decreased as the histological stage progressed (P<0.001). The erythrocyte count was correlated with albumin, liver stiffness and Fibrosis-4. Compared with that of platelets, the area under the ROC curve of the erythrocyte count was significantly greater. A similar area under the ROC curve was determined for the erythrocyte count, albumin and total bilirubin (P>0.05). A novel prognostic model was established as follows: P=1/{1 + e-[6.140-3.193 × Ln(erythrocyte count) -0.184 × albumin + 0.827 × Ln(total bilirubin)]}. The novel model had a comparable prognostic value to that of the GLOBE score and UK-PBC risk score, and had a better performance than the Mayo risk score at baseline (0.838 vs. 0.787). In conclusion, the erythrocyte count is an independent risk factor/prognostic index in Chinese patients with PBC. It was correlated with liver function and fibrosis in Chinese patients. The novel model incorporating the erythrocyte count and biochemical indices at baseline may serve as a prognostic tool in Chinese patients with PBC (Trial registration number, ChiCTR-ONRC-10002070; date of registration, 2010-05-10).

Clinical efficacy of TACE combined with Apatinib in the treatment of advanced hepatocellular carcinoma.

PURPOSE: To explore the therapeutic efficacy and clinical safety of transcatheter arterial chemoembolization (TACE) combined with Apatinib in patients with advanced hepatocellular carcinoma (HCC). METHODS: 88 patients with advanced HCC admitted to our hospital from March 2015 to March 2016 were randomly assigned into group A (TACE) or B (TACE combined with Apatinib). Therapeutic efficacy and adverse events were recorded by follow-up data every three months after treatment. Disease control rate (DCR) and objective response rate (ORR) in both groups were calculated based on 18-month follow-up records. RESULTS: Nine months after treatment, DCR and ORR in group A were 81.82% and 36.36%, respectively, and 95.45% and 63.64% in group B. Disease-free survival (DFS) in group A and B was 11.15 and 16.5 months, respectively. No significant differences in the adverse event incidence (fever, abdominal pain, nausea and vomiting) after embolization were found between the two groups (p>0.05). The incidence of hypertension, hand-foot syndrome, and proteinuria in group B was significantly higher than those in group A (p<0.05). Adverse events were all alleviated after symptomatic treatment. CONCLUSIONS: The therapeutic efficacy of TACE combined with Apatinib in HCC treatment is higher compared to TACE alone, which may be related to the inhibition of tumor angiogenesis. TACE combined with Apatinib can improve the prognosis and prolong the overall survival (OS) of HCC patients.

Long-term Outcomes of Autologous Peripheral Blood Stem Cell Transplantation in Patients With Cirrhosis.

BACKGROUND & AIMS: Peripheral blood stem cells (PBSCs) mobilized with colony-stimulating factor can promote liver regeneration and increase liver function in patients with liver diseases. However, the long-term effects of stem cell treatments on survival and risk of hepatocellular carcinoma (HCC) in patients with cirrhosis have not been determined. We investigated the long-term effects of autologous stem cell transplantation and risk of HCC in patients with cirrhosis. METHODS: We performed a retrospective analysis of 2 cohorts of patients with decompensated cirrhosis who received transplantations of autologous PBSCs (n = 282) or standard medical treatment (SMT, n = 286) in China from January 1, 2006, through December 31, 2016. Patients were followed up until death or liver transplantation. Mortality data were obtained by case records and confirmed by telephone calls. Survival time was calculated and HCC was confirmed by computed tomography or ultrasound. We used propensity score matching to adjust the differences between the 2 groups. Survival and incidence of HCC were analyzed and Cox proportional hazard regression was used to determine the prognostic factors. RESULTS: After propensity score matching, time of survival was significantly higher in the PBSC group than the SMT group (P = .001). The adjusted rate of 5-year survival was 71.2% in the PBSC group and 52.1% in the SMT group. The overall incidence of HCC did not differ significantly between the PBSC and SMT groups (21.1% vs 20.4%; P = .999). Significant improvement of liver functions was observed at 1 year, 2 years, 3 years, and 5 years after PBSC transplantation compared with the SMT group. CONCLUSIONS: In a long-term analysis of patients with decompensated cirrhosis, autologous transplants of PBSCs significantly improved long-term survival compared with a control group. PBSC transplant did not appear to increase the risk of HCC.

Characterisation of Lamp2-deficient rats for potential new animal model of Danon disease.

Danon disease (DD) is caused by the absence or malfunction of lysosomal-associated membrane protein 2 (LAMP2). Although Lamp2-deficient mice and DD patients have similar characteristics, these mice have clear limitations and are clinically inconsistent. The aim of our paper is to outline the characteristics of Lamp2-deficient rats and to contrast this model with currently available DD mouse models. The baseline levels of some serum enzymes were elevated in Lamp2y/- rats along with hypercholesterolemia and hyperglycaemia at 8 weeks. Echocardiography showed that IVSd (1.500 ± 0.071 vs. 2.200 ± 1.147, P < 0.01) and LVPWd (1.575 ± 0.063 vs. 1.850 ± 0.029, P < 0.01) were significantly increased, and GCS (-13.20 ± 0.4814 vs. -6.954 ± 0.665) and GRS (21.42 ± 1.807 vs. 7.788 ± 1.140) were sharply decreased. Meanwhile, substantial myocyte disruption, hypertrophic muscle fibres, interstitial fibrosis and microvascular hyperplasia could be observed in the heart tissue. Lamp2y/- rats also displayed abnormal behaviours in the open field and fear conditioning tests. Notably, Lamp2y/- rats manifested other system dysfunctions, such as retinopathy, chronic kidney injury and sterility. Based on these results, Lamp2-deficient rats exhibited greater similarity to DD patients in terms of onset and multisystem lesions than did mouse models, and these rats could be used as a valuable animal model for DD.

Endoscopic Ultrasound-Guided Fine-Needle Aspiration Cytology Combined With Automated Quantitative DNA Cytometry Can Improve the Value in the Detection of Pancreatic Malignancy.

OBJECTIVES: Quantitative DNA-image cytometry (ICM) is used to diagnose malignancy via detecting changes in DNA content. We aimed to estimate the value of cytology, DNA-ICM, and their combination in diagnosing pancreatic malignancy. METHODS: One hundred twenty-one endoscopic ultrasound-guided fine-needle aspiration samples from 116 patients suspected for pancreatic malignancy were examined by cytology and DNA-ICM. Their results and the final diagnoses (malignancy or not) were collected. Diagnostic values were compared among cytology, DNA-ICM, and their combination. RESULTS: The DNA-ICM had a lower sensitivity and accuracy than cytology (64.2% vs 81.1%; 71.9% vs 85.1%). The combination of the techniques significantly improved the diagnostic accuracy compared with that of cytology or DNA-ICM alone (0.932 vs 0.905, P = 0.02; 0.932 vs 0.821, P < 0.0001). Using the Youden index, we determined that one cell with DI (DNA index) ≥2.5 is the optimal cutoff value for DNA-ICM to diagnose pancreatic malignancy. After adoption of this criterion, the sensitivity and accuracy were improved to 74.7% and 80.2% with DNA-ICM and 90.5% and 92.6% with the combined method. CONCLUSIONS: The DNA-ICM is an effective complementary method to cytology in diagnosing pancreatic malignancy. Although the diagnostic value for DNA-ICM is lower than that of cytology, an improved value was obtained after their combination.

A Critical Evaluation of Liver Pathology in Humans with Danon Disease and Experimental Correlates in a Rat Model of LAMP-2 Deficiency.

Danon disease is a genetic deficiency in lysosome-associated membrane protein 2 (LAMP-2), a highly glycosylated constituent of the lysosomal membrane and characterized by a cardiomyopathy, skeletal muscle myopathy, and cognitive impairment. Patients, however, often manifest hepatic abnormalities, but liver function has not been well evaluated and the syndrome is relatively uncommon. Hence, we have taken advantage of a rat that has been deleted of LAMP-2 to study the relative role of LAMP-2 on liver function. Interestingly, rats deficient in LAMP-2 develop a striking increase in serum alkaline phosphatase (ALP) and a decrease in bile flow compared with wild-type littermates. Importantly and by ultrastructural analysis, deficient rats manifest dilated canaliculi that lack microvilli with evidence of bile-containing bodies. Moreover, following bile duct ligation, LAMP-2-deficient rats develop rapid and severe evidence of advanced cholestasis, with an increase in serum bilirubin, as early as 6 h later. In wild-type control rats, multidrug resistance-associated protein 2 (Mrp2) normally concentrates at the bile canalicular membranes to secrete conjugated bilirubin into bile. However, in LAMP-2y/- rats, Mrp2 was detected in hepatocytes compared with other canalicular proteins including P-glycoproteins, dipeptidyl peptidase IV (CD26), and aminopeptidase (CD13). Our data further suggest that LAMP-2 interacts with the membrane cytoskeletal proteins radixin and F-actin in determining the localization of integral membrane proteins.

Risk Genes of Inflammatory Bowel Disease in Asia: What Are the Most Important Pathways Affected?

Genetic factors play an important role in the pathogenesis of inflammatory bowel disease (IBD), and IBD is now recognized as a complex disease that results from interplay between genetic and environment factors. To date, over 160 IBD-susceptible loci have been identified using genome-wide association studies (GWAS). The risk genes identified in these studies are involved in various pathways in innate and adaptive immune response such as innate bacterial sensing, autophagy and interleukin-23 receptor/T-helper cell 17 pathway. It was initially believed that the genetic backgrounds of Asian IBD patients differ from that of other populations. Recent GWAS and meta-analysis found that there is pervasive sharing of risk loci between the East and West. Overlapping risk genes between populations of different ancestries indicate that pathways underlying the etiology of IBD may be common between Asia and other areas. However, the importance of individual pathways may be different in Asia from the Western countries. Identifying the most important pathways affected in Asian IBD patients may provide a better understanding of pathogenesis of IBD in Asia and improve the clinical management of the patients.

Chromatin accessibility mapping identifies mediators of basal transcription and retinoid-induced repression of OTX2 in medulloblastoma.

Despite an emerging understanding of the genetic alterations giving rise to various tumors, the mechanisms whereby most oncogenes are overexpressed remain unclear. Here we have utilized an integrated approach of genomewide regulatory element mapping via DNase-seq followed by conventional reporter assays and transcription factor binding site discovery to characterize the transcriptional regulation of the medulloblastoma oncogene Orthodenticle Homeobox 2 (OTX2). Through these studies we have revealed that OTX2 is differentially regulated in medulloblastoma at the level of chromatin accessibility, which is in part mediated by DNA methylation. In cell lines exhibiting chromatin accessibility of OTX2 regulatory regions, we found that autoregulation maintains OTX2 expression. Comparison of medulloblastoma regulatory elements with those of the developing brain reveals that these tumors engage a developmental regulatory program to drive OTX2 transcription. Finally, we have identified a transcriptional regulatory element mediating retinoid-induced OTX2 repression in these tumors. This work characterizes for the first time the mechanisms of OTX2 overexpression in medulloblastoma. Furthermore, this study establishes proof of principle for applying ENCODE datasets towards the characterization of upstream trans-acting factors mediating expression of individual genes.