Chemical reprogramming of human somatic cells to pluripotent stem cells.

Cellular reprogramming can manipulate the identity of cells to generate the desired cell types1-3. The use of cell intrinsic components, including oocyte cytoplasm and transcription factors, can enforce somatic cell reprogramming to pluripotent stem cells4-7. By contrast, chemical stimulation by exposure to small molecules offers an alternative approach that can manipulate cell fate in a simple and highly controllable manner8-10. However, human somatic cells are refractory to chemical stimulation owing to their stable epigenome2,11,12 and reduced plasticity13,14; it is therefore challenging to induce human pluripotent stem cells by chemical reprogramming. Here we demonstrate, by creating an intermediate plastic state, the chemical reprogramming of human somatic cells to human chemically induced pluripotent stem cells that exhibit key features of embryonic stem cells. The whole chemical reprogramming trajectory analysis delineated the induction of the intermediate plastic state at the early stage, during which chemical-induced dedifferentiation occurred, and this process was similar to the dedifferentiation process that occurs in axolotl limb regeneration. Moreover, we identified the JNK pathway as a major barrier to chemical reprogramming, the inhibition of which was indispensable for inducing cell plasticity and a regeneration-like program by suppressing pro-inflammatory pathways. Our chemical approach provides a platform for the generation and application of human pluripotent stem cells in biomedicine. This study lays foundations for developing regenerative therapeutic strategies that use well-defined chemicals to change cell fates in humans.

Macrophage-Derived Cathepsin S Remodels the Extracellular Matrix to Promote Liver Fibrogenesis.

BACKGROUND & AIMS: Liver fibrosis is an intrinsic wound-healing response to chronic injury and the major cause of liver-related morbidity and mortality worldwide. However, no effective diagnostic or therapeutic strategies are available, owing to its poorly characterized molecular etiology. We aimed to elucidate the mechanisms underlying liver fibrogenesis. METHODS: We performed a quantitative proteomic analysis of clinical fibrotic liver samples to identify dysregulated proteins. Further analyses were performed on the sera of 164 patients with liver fibrosis. Two fibrosis mouse models and several biochemical experiments were used to elucidate liver fibrogenesis. RESULTS: We identified cathepsin S (CTSS) up-regulation as a central node for extracellular matrix remodeling in the human fibrotic liver by proteomic screening. Increased serum CTSS levels efficiently predicted liver fibrosis, even at an early stage. Secreted CTSS cleaved collagen 18A1 at its C-terminus, releasing endostatin peptide, which directly bound to and activated hepatic stellate cells via integrin α5ß1 signaling, whereas genetic ablation of Ctss remarkably suppressed liver fibrogenesis via endostatin reduction in vivo. Further studies identified macrophages as the main source of hepatic CTSS, and splenectomy effectively attenuated macrophage infiltration and CTSS expression in the fibrotic liver. Pharmacologic inhibition of CTSS ameliorated liver fibrosis progression in the mouse models. CONCLUSIONS: CTSS functions as a novel profibrotic factor by remodeling extracellular matrix proteins and may represent a promising target for the diagnosis and treatment of liver fibrosis.

COSMIC-based mutation database enhances identification efficiency of HLA-I immunopeptidome.

BACKGROUND: Neoantigens have emerged as a promising area of focus in tumor immunotherapy, with several established strategies aiming to enhance their identification. Human leukocyte antigen class I molecules (HLA-I), which present intracellular immunopeptides to T cells, provide an ideal source for identifying neoantigens. However, solely relying on a mutation database generated through commonly used whole exome sequencing (WES) for the identification of HLA-I immunopeptides, may result in potential neoantigens being missed due to limitations in sequencing depth and sample quality. METHOD: In this study, we constructed and evaluated an extended database for neoantigen identification, based on COSMIC mutation database. This study utilized mass spectrometry-based proteogenomic profiling to identify the HLA-I immunopeptidome enriched from HepG2 cell. HepG2 WES-based and the COSMIC-based mutation database were generated and utilized to identify HepG2-specific mutant immunopeptides. RESULT: The results demonstrated that COSMIC-based database identified 5 immunopeptides compared to only 1 mutant peptide identified by HepG2 WES-based database, indicating its effectiveness in identifying mutant immunopeptides. Furthermore, HLA-I affinity of the mutant immunopeptides was evaluated through NetMHCpan and peptide-docking modeling to validate their binding to HLA-I molecules, demonstrating the potential of mutant peptides identified by the COSMIC-based database as neoantigens. CONCLUSION: Utilizing the COSMIC-based mutation database is a more efficient strategy for identifying mutant peptides from HLA-I immunopeptidome without significantly increasing the false positive rate. HepG2 specific WES-based database may exclude certain mutant peptides due to WES sequencing depth or sample heterogeneity. The COSMIC-based database can effectively uncover potential neoantigens within the HLA-I immunopeptidomes.

Analysis of Sonazoid contrast-enhanced ultrasound for predicting the risk of microvascular invasion in hepatocellular carcinoma: a prospective multicenter study.

OBJECTIVES: The aim of this study was to evaluate the potential of Sonazoid contrast-enhanced ultrasound (SNZ-CEUS) as an imaging biomarker for preoperative prediction of microvascular invasion (MVI) in hepatocellular carcinoma (HCC). METHODS: From August 2020 to March 2021, we conducted a prospective multicenter study on the clinical application of Sonazoid in liver tumor; a MVI prediction model was developed and validated by integrating clinical and imaging variables. Multivariate logistic regression analysis was used to establish the MVI prediction model; three models were developed: a clinical model, a SNZ-CEUS model, and a combined model and conduct external validation. We conducted subgroup analysis to investigate the performance of the SNZ-CEUS model in non-invasive prediction of MVI. RESULTS: Overall, 211 patients were evaluated. All patients were split into derivation (n = 170) and external validation (n = 41) cohorts. Patients who had MVI accounted for 89 of 211 (42.2%) patients. Multivariate analysis revealed that tumor size (> 49.2 mm), pathology differentiation, arterial phase heterogeneous enhancement pattern, non-single nodular gross morphology, washout time (< 90 s), and gray value ratio (≤ 0.50) were significantly associated with MVI. Combining these factors, the area under the receiver operating characteristic (AUROC) of the combined model in the derivation and external validation cohorts was 0.859 (95% confidence interval (CI): 0.803-0.914) and 0.812 (95% CI: 0.691-0.915), respectively. In subgroup analysis, the AUROC of the SNZ-CEUS model in diameter ≤ 30 mm and ˃ 30 mm cohorts were 0.819 (95% CI: 0.698-0.941) and 0.747 (95% CI: 0.670-0.824). CONCLUSIONS: Our model predicted the risk of MVI in HCC patients with high accuracy preoperatively. CLINICAL RELEVANCE STATEMENT: Sonazoid, a novel second-generation ultrasound contrast agent, can accumulate in the endothelial network and form a unique Kupffer phase in liver imaging. The preoperative non-invasive prediction model based on Sonazoid for MVI is helpful for clinicians to make individualized treatment decisions. KEY POINTS: • This is the first prospective multicenter study to analyze the possibility of SNZ-CEUS preoperatively predicting MVI. • The model established by combining SNZ-CEUS image features and clinical features has high predictive performance in both derivation cohort and external validation cohort. • The findings can help clinicians predict MVI in HCC patients before surgery and provide a basis for optimizing surgical management and monitoring strategies for HCC patients.

Efficacy of treatment based on TKIs in combination with PD-1 inhibitors for unresectable recurrent hepatocellular carcinoma.

BACKGROUND AND OBJECTIVE: The recurrence occurs within 5 years in up to 70% of hepatocellular carcinoma (HCC) patients who received radical liver resection, and most patients are no longer suitable for repeat surgery. There are limited treatment options for unresectable recurrent HCC. This study aimed to explore the potential efficacy of treatment based on TKIs in combination with PD-1 inhibitors for unresectable recurrent HCC. METHODS: Forty-four patients with unresectable recurrent HCC after radical surgery between January 2017 and November 2022 were retrospectively collected and screened. All patients received the combination therapy of tyrosine kinase inhibitors (TKIs) and programmed cell death protein 1 (PD-1) inhibitors, and 18 of these patients received trans-arterial chemoembolization (TACE) or TACE combined with radiofrequency ablation (RFA). Two patients who received TKIs in combination with PD-1 inhibitors eventually obtained repeat surgery, with one patient undergoing a repeat hepatectomy and one patient receiving a liver transplant. RESULTS: The median survival for these patients was 27.0 months (95% confidence interval [CI] 21.2, 32.8), with a 1-year overall survival (OS) rate of 83.6% (95% CI 77.9%, 89.3%). Median progression-free survival (PFS) was 15.0 months (95.0% CI 12.1, 17.9), with a 1-year PFS rate of 77.0% (95% CI 70.6%, 83.4%). The two patients who underwent repeat surgery had a survival time of 34 and 37 months after the combined treatment with no recurrence, respectively, as of November 2022. CONCLUSION: The combination of TKIs and PD-1 inhibitors for unresectable recurrent HCC is effective and can prolong the survival of patients in this group.

Long-term survival and portal vein patency with novel PVTT surgery approach in advanced HCC patients with Vp3/4 PVTT following combination therapy of TKIs and PD-1 inhibitors.

BACKGROUND: It is controversial whether patients with hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) should undergo salvage surgery following the combination therapy of tyrosine kinase inhibitors (TKIs) and programmed cell death protein 1 (PD-1) inhibitors. This study aimed to elucidate the efficiency and safety of salvage surgery following combination therapy, while also summarizing a novel surgical approach for Vp3/4 PVTT. METHODS: Between April 2019 and December 2022, a consecutive series of unresectable HCC patients with PVTT who received salvage surgery following combination therapy were enrolled. Evaluation included perioperative and long-term follow-up outcomes. The complete removal of Vp3/4 PVTT was achieved using a novel surgical approach characterized by "longitudinal incision and transverse suturing" and "angle-to-straight conversion". RESULTS: Forty patients including 22 patients with Vp3 and 18 patients with Vp4 were included. Long-term follow-up showed similar rates of portal vein patency (Vp3: 95.5%, Vp4:94.4%, p = 0.900), and 3-year portal vein patency rates were 95.0%. There were no significant differences observed in combination therapy-related adverse events (p = 0.253) and perioperative complications (p = 0.613) between the Vp3 and Vp4 groups. The recurrence patterns were similar between the two groups (p = 0.131). There were no significant differences in overall survival (OS) and recurrence-free (RFS) survival between the Vp3 and Vp4 groups (OS p = 0.457, RFS p = 0.985). Patients who achieved a pathological complete response had significantly better RFS (p = 0.011). CONCLUSION: Salvage surgery after combination therapy demonstrated favorable efficacy and safety. The novel surgical approach for PVTT can effectively achieve complete removal of PVTT and ensured long-term portal vein patency.

Comparison of survival benefit between salvage surgery after conversion therapy versus surgery alone for hepatocellular carcinoma with portal vein tumor thrombosis: a propensity score analysis.

BACKGROUND: Salvage surgery after conversion therapy with a combination of tyrosine kinase inhibitor and anti-programmed death-1 antibody has shown improved survival benefits in patients with hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT). We aimed to compare the survival benefits in a retrospective cohort of patients with HCC with PVTT who underwent salvage surgery after conversion therapy and surgery alone. METHODS: From January 2015 to October 2021, we selected patients diagnosed with HCC with PVTT who underwent liver resection at Chinese PLA General Hospital. The primary endpoint in the comparison of survival benefits between conversion therapy and surgery-alone groups was recurrence-free survival. Propensity score matching was applied to reduce any potential bias in the study. RESULTS: The 6-, 12-, and 24-month recurrence-free survival rates in the conversion and surgery alone groups were 80.3% vs 36.5%, 65.4% vs 29.4%, and 56% vs 21%, respectively. On multivariable Cox regression analyses, conversion therapy significantly reduced HCC-related mortality and HCC recurrence rates compared with surgery alone. CONCLUSIONS: For patients with HCC with PVTT, surgery after conversion therapy is in relationship with increased survival in comparison with surgery alone.

Construction and validation of a novel signature based on epithelial-mesenchymal transition-related genes to predict prognosis and immunotherapy response in hepatocellular carcinoma by comprehensive analysis of the tumor microenvironment.

Immunotherapy has yielded encouraging results in the treatment of advanced hepatocellular carcinoma (HCC). However, the relationship between epithelial-mesenchymal transition (EMT) and immunotherapy for HCC has not been adequately explained. In this study, we comprehensively analyzed a bulk RNA sequence dataset of 365 HCC patients in The Cancer Genome Atlas (TCGA) dataset. Subsequently, we constructed a prognostic signature based on 6 EMT-related genes and divided 365 HCC patients into high- and low-risk groups. The predictive efficacy of the signature was well validated in different clinical subgroups and in two independent external datasets. We further explored the relationship between prognostic signature and immunotherapy response in terms of immune cell infiltration, somatic mutations, tumor mutation burden (TMB), microsatellite instability (MSI), immune checkpoint-associated gene expression, single-nucleotide variants (SNV) neoantigens, cancer testicular antigens (CTA) scores, and tumor immune dysfunction and exclusion (TIDE) scores. We validated the predictive efficacy of prognostic signature for immunotherapy response using external independent immunotherapy data. Real-time quantitative polymerase chain reaction (qRT-PCR) was used to validate EMT-related gene overexpression in HCC tissue samples. Prognostic signature was an independent risk factor affecting the prognosis of HCC patients and has shown superiority in predicting patient survival compared to other clinical factors. Compared with the low-risk group, the proportion of Activated_CD4_T_cell, Type_2_T_helper_cel, and macrophages were higher in the tumor microenvironment of HCC patients in the high-risk group, while the Activated_CD8_T_cell and CD56bright_natural_killer_cell proportions were lower. The prognostic signature was positively correlated with TMB scores, MSI scores, SNV neoantigens scores, expression levels of immune checkpoint-related genes, and TIDE scores, and patients in the high-risk group were more suitable for immunotherapy. qRT-PCR confirms overexpression of 6 EMT-related genes in HCC tissues for the construction of prognostic signature. Our novel prognostic signature can effectively predict the prognosis and immunotherapy response of HCC patients. In the future, it will be an effective tool for physicians to screen suitable immunotherapy populations and improve response rates and overall survival (OS).

Prognostic role of tumor mutation burden in hepatocellular carcinoma after radical hepatectomy.

BACKGROUND AND AIM: This study aimed to assess the potential relationship between tumor mutation burden (TMB) and the recurrence risk of hepatocellular cancer (HCC) after curative resection and tried to develop a reliable TMB based nomogram. METHODS: This retrospective study was conducted in 128 patients (40 patients suffered from a recurrence of HCC) who had received radical hepatectomy by the same surgical team. A nomogram model was constructed using the R and EmpowerStats software. RESULTS: TMB was not associated with maximum tumor size and the presence of microvascular invasion (MVI). In the whole population or subgroups, the recurrence-free survival (RFS) rate was significantly lower in the TMB high group. In multivariate analysis, TMB (hazard ratio [HR], 10.12; 95% confidence interval [CI], 5.03-20.31; P < .001), large tumor diameter (HR, 2.91; 95% CI, 1.51-5.63; P = .001), presence of MVI (HR, 1.93; 95% CI, 1.03-3.65; P = .042) were independent predictors of RFS. The predictive power of the nomogram integrating TMB, tumor size and MVI was higher than model only incorporating tumor size and MVI. CONCLUSION: This study demonstrated for the first time that higher TMB was associated with poor prognosis in patients with HCC who had received curative resection, and a TMB based nomogram model had a well predictive performance for RFS in this population.

Raddeanin A suppresses lung cancer cell proliferation via induction of apoptosis and increased production of ROS.

At present, in vitro cell experiments have confirmed that RaddeaninA can effectively inhibit the proliferation of some tumor cells, but the effect of RaddeaninA on lung cancer cells has not been observed. Therefore, this study explored its effect on lung cancer cells and its mechanism of action. Human lung cancer cell lines were treated with serum-free medium and varied concentrations of Raddeanin A. Cell proliferation and apoptosis were determined using MTT, and flow cytometric assays, respectively. The intracellular level of ROS was determined using DCFH-DA assay. Protein and mRNA expressions of bax, bcl-2 and cyt c were measured using Western blotting and qRT-PCR. RaddeaninA treatment can promote PC-9 cell apoptosis in a time and dose-dependent manner (p<0.05). Treatment of PC-9 cells with Raddeanin significantly and dose-dependently increased the activities of caspase-9 and caspase-3 (p<0.05), and led to significant and dose-dependent increases in ROS levels (p<0.05). Treatment of PC-9 cells with Raddeanin A led to significant and dose-dependent decreases in mitochondrial membrane potential (p<0.05). It significantly and dose-dependently upregulated bax mRNA and protein expressions, but down-regulated bcl-2 mRNA and protein expressions significantly and dose-dependently (p<0.05). On the other hand, Raddeanin significantly and dose-dependently down-regulated cytoplasmic bax protein expression, while upregulating cyt c expression (p<0.05). Similarly, bax protein expression was significantly and dose-dependently upregulated in mitochondria, but the corresponding cyt c expression was significantly and dose-dependently down-regulated (p<0.05). Raddeanin A is a potential and effective lung cancer chemotherapy drug, which can induce lung cancer cell apoptosis and inhibit proliferation.

Laparoscopic anatomical liver resection guided by real-time indocyanine green fluorescence imaging: experience and lessons learned from the initial series in a single center.

BACKGROUND: Anatomical liver resection is an established procedure for primary hepatic tumors. Laparoscopic anatomical hepatectomy has been proven to be technically achievable from S1 to S8 in experienced hands. The indocyanine green (ICG) fluorescence imaging technique offers a novel tool of intraoperative visualization in hepatobiliary surgery. This study aims to investigate the feasibility of laparoscopic anatomical liver resection based on segmental staining using real-time ICG fluorescence. METHODS: From December 2015 to October 2017, 36 patients in our institute underwent lap-ALR using real-time ICG fluorescence mapping of the tumor-bearing portal territory. The procedural and perioperative data were collected and analyzed. RESULTS: In our case series, we successfully performed the fashion of positive staining mostly in segmentectomy or sub-segmentectomy by individually injecting 5-10 ml of ICG (0.025 mg/ml) into its feeding portal branch guided by intraoperative ultrasound, and the negative staining mainly for sectionectomy, hemihepatectomy and multi-segmentectomy by interrupting the Glissonean pedicle serving the tumor-bearing segments and systemically injecting 1 ml of ICG (2.5 mg/ml). Our total successful rate of staining is 53%. No conversion to laparotomy, Clavien III-IV complication or 90-day mortality occurred. Valuable technical feedback, experience and lessons are learned from this initial practice. CONCLUSIONS: Real-time ICG fluorescence imaging adds much precision to laparoscopic anatomical hepatectomy. The success of segmental staining requires a high proficiency of IOUS and skillful interpretation of preoperative 3D simulation. Decision-making on the fashions of positive and negative staining have been initially recommended. Multi-centered practice and technical modification are necessary to standardize its application.

Long-term consequences of stopping HBIG and/or nucleotide analogues in liver transplant recipients administered hepatitis B vaccination to prevent HBV reinfection.

BACKGROUND: The long-term administration of nucleotide analogues (NAs) and hepatitis B immune globulin (HBIG) comprises standard prophylaxis for patients with hepatitis B virus (HBV)-related liver diseases to prevent HBV reinfection after liver transplantation (LT). However, prolonging the prophylaxis strategy involves safety issues, such as the development of escape mutations and/or emerging resistant strains, and is also associated with high costs; further, it remains unclear how long prophylactic treatment should be continued. METHOD: Liver transplantation recipients responding to hepatitis B vaccination due to HBV-related liver diseases were retrospectively analysed after stopping HBIG and/or NAs, administered to prevent HBV reinfection, after long-term follow-up. The safety and effectiveness of the strategy were then evaluated for these responders. RESULT: Seventy-eight responders were enrolled. All responders discontinued HBIG, among which 36 stopped both HBIG and NAs. During follow-up, four recipients experienced HBV reinfection, which was associated with HBV escape mutations, after the withdrawal of both HBIG and NAs. No death or graft loss occurred in recipients during the follow-up period. CONCLUSION: A careful withdrawal of HBIG and/or NAs is feasible and safe for responders to hepatitis B vaccination receiving transplants for HBV-related liver diseases.

The Predictive Role of Tenascin-C and Cellular Communication Network Factor 3 (CCN3) in Post Hepatectomy Liver Failure in a Rat Model and 50 Patients Following Partial Hepatectomy.

BACKGROUND Matricellular proteins of the extracellular matrix (ECM) include tenascin-C (TNC) and cellular communication network factor 3 (CCN3). This study aimed to investigate the role of TNC and CCN3 as prognostic factors for post hepatectomy liver failure (PHLF) in a rat model of partial hepatectomy and 50 patients following partial hepatectomy. MATERIAL AND METHODS Sprague-Dawley rats underwent 85% (n=53) or 90% hepatectomy (n=53) in the partial hepatectomy (PHx) model. TNC and CCN3 mRNA expression in residual liver tissue was evaluated using quantitative reverse transcription-polymerase chain reaction (qRT-PCR), and enzyme-linked immunoassay (ELISA) determined the serum levels of TNC and CCN3. In 50 patients who underwent partial hepatectomy, TNC and CCN3 serum levels were measured on postoperative day 1 and day 3. RESULTS In the rat partial hepatectomy model, mRNA and serum levels of TNC and CCN3 were significantly increased within the first 24 h, and were higher in the 90% PHx group compared with the 85% PHx group. Fifty patients who underwent partial hepatectomy, included patients with PHLF (n=12) and patients without PHLF (n=38). Multivariate analysis confirmed that serum levels on postoperative day 3 TNChigh+CCN3high was a significant predictor of PHLF, which was associated with more than twice the risk of severe morbidity when compared with the low-risk patients (80% vs. 30%) and a significantly longer hospital stay (17 days vs. 8 days). CONCLUSIONS Further studies are needed to evaluate the potential role of the matricellular proteins, TNC and CCN3 as early clinical predictors for PHLF.

Risk factors for and management of ischemic-type biliary lesions following orthotopic liver transplantation: A single center experience.

INTRODUCTION: Biliary complications can cause morbidity, graft loss, and mortality after liver transplantation. The most troublesome biliary complications are ischemic-type biliary lesions (ITBL), which occur since transplants can now be performed after the donor has undergone circulatory death. The exact origin of this type of biliary complication remains unknown. MATERIAL AND METHODS: A total of 528 patients were retrospectively analyzed following liver transplantation after excluding 30 patients with primary sclerosing cholangitis and those lost to follow-up from January 2007 to January 2014. The incidence of and risk factors for ITBL were evaluated. RESULTS: Cold ischemia time (CIT) (P = 0.042) and warm ischemia time (WIT) (P = 0.006) were found to be independent risk factors for the development of ITBL. Use of the cytochrome P450 (CYP) 3A5 genotype assay to guide individualization of immunosuppressive medications resulted in significantly fewer ITBL (P = 0.027. Autoimmune hepatitis might be a risk factor for ITBL, as determined using univariate analysis (P = 0.047). CONCLUSIONS: Efforts should be taken to minimize risk factors associated with ITBL, such as CIT and WIT. The CYP3A5 genotype assay should be used to guide selection of immunosuppressive therapy in an effort to reduce the occurrence of ITBL.

S100A4 promotes liver fibrosis via activation of hepatic stellate cells.

BACKGROUND & AIMS: S100A4 has been linked to the fibrosis of several organs due to its role as a fibroblast-specific marker. However, the role of S100A4 itself in the development of fibrosis has not been much investigated. Here, we determined whether S100A4 regulates liver fibrogenesis and examined its mechanism by focusing on the activation of hepatic stellate cells (HSCs). METHODS: S100A4 deficient mice were used to determine the role of S100A4 in liver fibrogenesis. The effect of S100A4 on HSC activation was estimated by using primary mouse HSCs and the human HSC cell line LX-2. Serum levels of S100A4 in cirrhotic patients were determined by ELISA. RESULTS: S100A4 was found to be secreted by a subpopulation of macrophages and to promote the development of liver fibrosis. It accumulated in the liver during the progression of liver fibrosis and activated HSCs in mice. In vitro studies demonstrated that S100A4 induced the overexpression of alpha-smooth muscle actin through c-Myb in HSCs. Both, the selective depletion of S100A4-expressing cells and knockdown of S100A4 in the liver by RNA interference, resulted in a reduction of liver fibrosis following injury. Importantly, increased S100A4 levels in both the liver tissue and serum correlated positively with liver fibrosis in humans. CONCLUSIONS: S100A4 promotes liver fibrosis by activating HSCs, which may represent a potential target for anti-fibrotic therapies.

[Detection of total and covalently closed circular HBV DNA in liver transplant recipients due to HBV-associated liver diseases].

OBJECTIVE: To investigate the levels of hepatitis B virus (HBV) total DNA and covalently closed circular (ccc) DNA in liver transplant recipients due to HBV-associated liver diseases and detemaine their clinical significance. METHODS: Sixty patients undergoing liver transplantation (LT) due to HBV-associated liver diseases were enrolled for the study. Levels of HBV total and ccc DNA in plasma, liver and PBMCs were measured by RT-PCR. RESULTS: The ratio of male:female participants was 48:12. The mean age was 52.98+/-9.40 years old, and the median duration post-LT was 72 (25-128) months. 59 of the patients had no detectable HBV DNA in plasma.Four patients had detectable levels of total HBV DNA in PBMCs, but no detectable ccc DNA. Five patients had detectable levels of total HBV DNA in liver, and two of those also had detectable levels of ccc DNA. One patients who had detectable HBV DNA in PBMCs suffered HBV recurrence. CONCLUSION: The liver transplant recipients with detectable levels of HBV total and ccc DNA in PBMCs and liver should be considered high risk for HBV recurrence following LT.

[Percutaneous nephroscopic necrosectomy for post-operatively resident infection of severe acute pancreatitis].

OBJECTIVE: To investigate the method and effect of percutaneous nephroscopic necrosectomy (PNN) for post-operatively resident infection of severe acute pancreatitis (SAP). METHODS: Data of the 15 SAP patients with post-operatively resident infection treated by PNN from June 2008 to December 2014 in Chinese People's Liberation Army General Hospital were reviewed. Twelve of the patients underwent the laparotomy within 1 week, 1 in 3(rd) week, 1 in 4(th) week and the other one on the 127(th) day. All of the referrals firstly received (multi-)percutaneous catheter drainage (PCD), and then PNN operation according to the disease, followed by continuous irrigation-drainage. RESULTS: Eleven patients were healed after received only one PNN operation, 2 patients for twice, 1 for three times and 1 for four times. The average post-operative time of hospital stay was 66.2 days (10-223 days). The complications after operation contained colon fistula (n = 1), abdominal hemorrhage (n = 1), pancreatic pseudocyst (n = 1), severe pulmonary infection (n = 1). Three patients eventually died. CONCLUSIONS: Percutaneous nephroscopic necrosectomy is a minimally invasive approach which could prevent the complicated re-laparotomy operation, result in less complication. It is an ideal method for treating SAP patients with post-operatively resident infection.

[A retrospective cohort study regarding the effect of sirolimus-based immunosuppression protocol on the long-term survival of hepatocellular carcinoma patients after liver transplantation].

OBJECTIVE: To evaluate the influence of sirolimus on the long-term survival of patients after orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HCC). METHODS: Clinic data of 165 consecutive patients who underwent OLT for HCC from February 2005 to March 2012 was analyzed retrospectively. Among them, 94 patients were treated with a sirolimus-based immunosuppressive protocol after OLT, while the other 71 patients with a FK506-based protocol. Postoperative survival time, survival, disease-free survival (DFS) and tumor recurrence rates between the two groups were compared. RESULTS: The 2 groups were comparable in all clinicopathologic parameters. The sirolimus-based group had higher patient survival rates than the control group at 1-year (87% vs. 97%, P = 0.03), 2-year (80% vs. 88%), 3-year (76% vs. 85%) and 5-year (63% vs. 75%). The 1-year, 2-year, 3-year and 5-year recurrence rates were 12% vs. 3%, 17% vs. 9%, 21% vs. 9% (P = 0.04) and 31% vs. 16% (P = 0.03). Early and mid-HCC (I - II stage) of 131 cases (control group 61 cases, sirolimus-based group of 70 patients). The 1-year, 2-year, 3-year and 5-year survival rates were 90% vs. 97% , 80% vs. 90%, 78% vs. 86% and 65% vs. 82% (P = 0.04) and recurrence rates were 10% vs. 3%, 16% vs. 8%, 18% vs. 8% and 29% vs. 11% (P = 0.01). CONCLUSION: The sirolimus-based immunosuppressive protocol reduce long-term postoperative recurrence rate and improve the survival rate of patients after OLT for HCC significantly (especially early-mid HCC).