Transjugular mesenteric-caval shunt for portal vein cavernous transformation with recurrent variceal bleeding: preliminary results.

OBJECTIVES: This study aimed to evaluate the feasibility, safety, and efficacy of the transjugular mesenteric-caval shunt (TMCS) as a treatment for the cavernous transformation of the portal vein (CTPV) and recurrent variceal bleeding. METHODS: This retrospective case series was conducted with approval from the institutional review board. It involved seven patients diagnosed with CTPV and recurrent variceal bleeding who underwent the TMCS procedure. We analyzed the rate of procedural complications, incidents of rebleeding, stent stenosis, hepatic encephalopathy, and overall survival to assess treatment outcomes. RESULTS: The TMCS was successfully performed in all seven patients without any life-threatening complications. Postoperatively, one patient developed a lung infection and pleural effusion, which resolved with appropriate treatment. Additionally, two patients experienced an increase in total bilirubin levels, but there was no further deterioration in liver function. The median portal pressure gradient significantly decreased from a preoperative value of 27 mmHg (range 20-36 mmHg) to a postoperative value of 6 mmHg (range 4-11 mmHg). A notable improvement was observed in one cirrhotic patient, with liver function progressing from Child-Pugh class B (score 9) to class A (score 6). Over a median follow-up period of 14 months (range 7-18 months), none of the patients encountered rebleeding, stent stenosis, hepatic encephalopathy, or mortality. CONCLUSION: The TMCS appears to be a viable and effective alternative for managing CTPV with recurrent variceal bleeding. Its long-term outcome requires further evaluation. CLINICAL RELEVANCE STATEMENT: TMCS provides a promising treatment for patients with life-threatening CTPV complications when occluded portal vein cannot be recanalized and portal vein recanalization TIPS is not an option. KEY POINTS: Performing TIPS in patients with portal vein cavernoma is complex due to the requirement for recanalization of the occluded portal vein. Creating a mesenteric-caval shunt through a transjugular approach is a feasible technique. Establishing a TMCS provides a means to manage life-threatening complications arising from portal vein cavernoma.

Hepatic hydrothorax does not increase the risk of death after transjugular intrahepatic portosystemic shunt in cirrhosis patients.

OBJECTIVES: Hepatic hydrothorax (HH) is a predictor of poor survival in cirrhosis patients. However, whether HH increases the mortality risk of cirrhosis patients treated with transjugular intrahepatic portosystemic shunt (TIPS) is unknown. Our objective was to evaluate the influence of HH on the survival of cirrhosis patients after TIPS. METHODS: Cirrhosis patients with portal hypertension complications were selected from a prospective database of consecutive patients treated with TIPS in Xijing Hospital from January 2015 to June 2021. Cirrhosis patients with HH were treated as the experimental group. A control group of cirrhosis patients without HH was created using propensity score matching. Survival after TIPS and the related risk factors were analysed. RESULTS: There were 1292 cirrhosis patients with portal hypertension complications treated with TIPS, among whom 255 patients had HH. Compared with patients without HH, patients with HH had worse liver function (MELD, 12 vs. 10, p < 0.001), but no difference in survival after TIPS was observed. After propensity score matching, 243 patients with HH and 243 patients without HH were enrolled. There was no difference in cumulative survival between patients with and without HH. Cox regression analysis showed that HH was not associated with survival after TIPS, and main portal vein thrombosis (> 50%) was a prognostic factor of long-term survival after TIPS in cirrhosis patients (hazard ratio, 1.386; 95% CI, 1.030-1.865, p = 0.031). CONCLUSION: Hepatic hydrothorax does not increase the risk of death after TIPS in cirrhosis patients. KEY POINTS: • Hepatic hydrothorax is a decompensated event of cirrhosis and increases the risk of death. • Hepatic hydrothorax is associated with worse liver function. • Hepatic hydrothorax does not increase the mortality of cirrhosis treated with TIPS.

Systematic profiling and identification of the peptide-mediated interactions between human Yes-associated protein and its partners in esophageal cancer.

Human Yes-associated protein (YAP) is involved in the Hippo signaling pathway and serves as a coactivator to modulate gene expression, which contains a transactivation domain (TD) responsible for binding to the downstream TEA domain family (TEAD) of transcription factors and two WW1/2 domains that recognize the proline-rich motifs (PRMs) present in a variety of upstream protein partners through peptide-mediated interactions (PMIs). The downstream YAP TD-TEAD interactions are closely associated with gastric cancer, and a number of therapeutic agents have been developed to target the interactions. In contrast, the upstream YAP WW1/2-partner interactions are thought to be involved in esophageal cancer but still remain largely unexplored. Here, we attempted to elucidate the complicated PMIs between the YAP WW1/2 domains and various PRMs of YAP-interacting proteins. A total of 106 peptide segments carrying the class I WW-binding motif [P/L]Px[Y/P] were extracted from 22 partner candidates, which are potential recognition sites of YAP WW1/2 domains. Structural and energetic analyses of the intermolecular interactions between the domains and peptides created a systematic domain-peptide binding profile, from which a number of biologically functional PMIs were identified and then substantiated in vitro using fluorescence spectroscopy assays. It is revealed that: (a) The sequence requirement for the partner recognition site binding to YAP WW1/2 domains is a decapeptide segment that contains a core PRM motif as well as two three-residue extensions from each side of the motif; the core motif and extended sections are responsible for the binding stability and recognition specificity of domain-peptide interaction, respectively. (b) There is an exquisite difference in the recognition specificity of the two domains; the LPxP and PPxP appear to more prefer WW1 than WW2, whereas the WW2 can bind more effectively to LPxY and PPxY than WW1. (c) WW2 generally exhibits a higher affinity to the panel of recognition site candidates than WW1. In addition, a number of partner peptides were found as promising recognition sites of the two domains and/or to have a good selectivity between the two domains. For example, the DVL1 peptide was determined to have moderate affinity to WW2 and strong selectivity for WW2 over WW1. Hydrogen bonds play a central role in selectivity.

Risk Stratification Based on Chronic Liver Failure Consortium Acute Decompensation Score in Patients With Child-Pugh B Cirrhosis and Acute Variceal Bleeding.

BACKGROUND AND AIMS: Optimal candidates for early transjugular intrahepatic portosystemic shunt (TIPS) in patients with Child-Pugh B cirrhosis and acute variceal bleeding (AVB) remain unclear. This study aimed to test the hypothesis that risk stratification using the Chronic Liver Failure Consortium Acute Decompensation score (CLIF-C ADs) may be useful to identify a subgroup at high risk of mortality or further bleeding that may benefit from early TIPS in patients with Child-Pugh B cirrhosis and AVB. APPROACH AND RESULTS: We analyzed the pooled individual data from two previous studies of 608 patients with Child-Pugh B cirrhosis and AVB who received standard treatment between 2010 and 2017 in China. The concordance index values of CLIF-C ADs for 6-week and 1-year mortality (0.715 and 0.708) were significantly better than those of active bleeding at endoscopy (0.633 [P < 0.001] and 0.556 [P < 0.001]) and other prognostic models. With X-tile software identifying an optimal cutoff value, patients were categorized as low risk (CLIF-C ADs <48), intermediate risk (CLIF-C ADs 48-56), and high risk (CLIF-C ADs >56), with a 5.6%, 16.8%, and 25.4% risk of 6-week death, respectively. Nevertheless, the performance of CLIF-C ADs for predicting a composite endpoint of 6-week death or further bleeding was not satisfactory (area under the receiver operating characteristics curve [AUC], 0.588). A nomogram incorporating components of CLIF-C ADs and albumin, platelet, active bleeding, and ascites significantly improved the prediction accuracy (AUC, 0.725). CONCLUSIONS: In patients with Child-Pugh B cirrhosis and AVB, risk stratification using CLIF-C ADs identifies a subgroup with high risk of death that may derive survival benefit from early TIPS. With improved prediction accuracy for 6-week death or further bleeding, the data-driven nomogram may help to stratify patients in randomized trials. Future external validation of these findings in patients with different etiologies is required.

Sorafenib may enhance antitumour efficacy in hepatocellular carcinoma patients by modulating the proportions and functions of natural killer cells.

Dysfunction of natural killer (NK) cells is associated with poor prognosis in hepatocellular carcinoma (HCC). We explored the phenotypic and functional characteristics of peripheral blood NK cells in HCC patients following sorafenib treatment.Peripheral blood samples were collected from 60 HCC patients in a single centre (2015~2017) and 45 healthy donors. The percentage and cytoplasmic granule production of NK cells were analysed. Subset proportions were evaluated for their associations with the modified Response Evaluation Criteria in Solid Tumors (mRECIST), time to progression, and median overall survival (OS).Compared with baseline, the percentages of total and CD56dimCD16+ NK cells increased after two months of treatment, while the percentage of CD56brightCD16- NK cells decreased, leading to a dramatically reduced ratio of CD56bright and CD56dim NK cells (ratiobri/dim). Patients with low ratiobri/dim exhibited better mRECIST responses and longer median OS than those with high ratiobri/dim. The expression levels of granzyme B and perforin in total NK cells and in both subsets of cells were increased after treatment.This study showed that sorafenib could affect the proportions and functions of peripheral CD56brightCD16- and CD56dimCD16+ NK cells, which was associated with the outcomes including OS of HCC patients.

Prevalence of prothrombotic factors in patients with Budd-Chiari syndrome or non-cirrhotic nonmalignant portal vein thrombosis: A hospital-based observational study.

BACKGROUND AND AIM: Comprehensive investigations on the prothrombotic factors of splanchnic vein thrombosis (SVT), including Budd-Chiari syndrome (BCS) and non-cirrhotic nonmalignant portal vein thrombosis (PVT), in Eastern patients are scarce. METHODS: Between March 2012 and July 2017, 812 consecutive patients, including 418 BCS and 394 non-cirrhotic nonmalignant PVT patients, were admitted to Xijing Hospital (a Chinese tertiary academic hospital) and screened for prothrombotic factors. Odds ratios (ORs), 95% confidence intervals (CIs), and P-trends were calculated by using conditional logistic regression. RESULTS: The prevalence of myeloproliferative neoplasms (MPNs) was only 6.3% among BCS patients but 28.3% among PVT patients. Notably, the presence of MPNs was associated with a higher risk of hepatic vein-type BCS (OR 9.9, 95% CI 3.6-26.7, P-trend < 0.001) and extensive thrombosis in PVT (OR 4.1, 95% CI 1.9-8.9, P-trend < 0.001). Calreticulin mutations existed in 2.7% of SVT patients. Furthermore, the prevalence of antiphospholipid antibody syndrome and protein C, protein S, or antithrombin deficiency in BCS patients was 7.3% and 22.5%, respectively, similar to that in patients with PVT (7.4% and 25.7%). In addition, factor V Leiden mutation, prothrombin G20210A mutation, and paroxysmal nocturnal hemoglobinuria were identified in < 1% of both BCS and PVT patients. CONCLUSION: There is a significant positive association between MPNs and hepatic vein-type BCS or non-cirrhotic nonmalignant PVT with extensive thrombosis. Additionally, calreticulin mutations should be tested in JAK2V617F -negative SVT patients in China. However, screening for factor V Leiden mutation, prothrombin G20210A mutation, and paroxysmal nocturnal hemoglobinuria may be unnecessary.

Identifying optimal candidates for early TIPS among patients with cirrhosis and acute variceal bleeding: a multicentre observational study.

OBJECTIVES: Early placement of transjugular intrahepatic portosystemic shunt (TIPS) has been shown to improve survival in high-risk patients (Child-Pugh B plus active bleeding at endoscopy or Child-Pugh C 10-13) with cirrhosis and acute variceal bleeding (AVB). However, early TIPS criteria may overestimate the mortality risk in a significant proportion of patients, and the survival benefit conferred by early TIPS in such patients has been questioned. Alternative criteria have been proposed to refine the criteria used to identify candidates for early TIPS. Nevertheless, the true survival benefit provided (or not) by early TIPS compared with standard treatment in the different risk categories has not been investigated in specifically designed comparative studies. DESIGN: We collected data on 1425 consecutive patients with cirrhosis and AVB who were admitted to 12 university hospitals in China between December 2010 and June 2016. Of these, 206 patients received early TIPS, and 1219 patients received standard treatment. The Fine and Gray competing risk regression model was used to compare the outcomes between the two groups that were stratified based on the currently available risk stratification systems after adjusting for liver disease severity and other potential confounders. RESULTS: Overall, early TIPS was associated with an 80% relative risk reduction (RRR) in mortality at 6 weeks (adjusted HR=0.20; 95% CI: 0.10 to 044; p<0.001) and 51% RRR at 1 year (adjusted HR=0.49, 95% CI: 0.32 to 0.73; p<0.001) compared with standard treatment. In stratification analyses, the RRRs in mortality did not significantly differ among the risk categories. However, the absolute risk reductions (ARRs) of mortality were more pronounced in high-risk patients. The ARRs at 6 weeks were -2.1%, -10.2% and -32.4% in Model for End-stage Liver Disease (MELD) ≤11, 12-18 and ≥19 patients and were -1.5%, -9.1% and -23.2% in Child-Pugh A, B and C patients, respectively (interaction tests, p<0.001 for both criteria). The ARRs for mortality at 1 year were -1.7%, -5.4% and -32.7% in MELD ≤11, 12-18 and ≥19 patients, respectively, and -3.6%, -5.2% and -20.3% in Child-Pugh A, B and C patients, respectively (interaction tests, p<0.001 for both criteria). After adjusting for liver disease severity and other potential confounders, a survival benefit was observed in MELD ≥19 or Child-Pugh C patients but not in MELD ≤11 or Child-Pugh A patients. In MELD 12-18 patients, a survival benefit was observed within 6 weeks but not at 1 year. In Child-Pugh B patients, a survival benefit was observed in those with active bleeding but not those without active bleeding. However, the evaluation of active bleeding was associated with a high interobserver variability. Furthermore, early TIPS was associated with a significantly reduced incidence of failure to control bleeding or rebleeding and new or worsening ascites, without increasing the risk of overt hepatic encephalopathy. CONCLUSIONS: Early TIPS was associated with improved survival in patients with MELD ≥19 or Child-Pugh C cirrhosis but not in patients with MELD ≤11 or Child-Pugh A cirrhosis. For MELD 12-18 or Child-Pugh B patients, future studies addressing optimal selection criteria for early TIPS remain highly warranted.

Hand-foot-skin reaction of grade ≥ 2 within sixty days as the optimal clinical marker best help predict survival in sorafenib therapy for HCC.

Background & Aims Sorafenib-related adverse events have been reported as clinical surrogates for treatment response in hepatocellular carcinoma (HCC); however, no consensus has been reached regarding the definition of responders. We evaluated the predictive abilities of different definitions for sorafenib response based on treatment-emergent adverse events, aiming to identify the most discriminatory one as a clinical marker. Methods From January 2010 to December 2014, 435 consecutive HCC patients treated with sorafenib were enrolled. Considering the type, severity and timing of adverse events, twelve different categories of sorafenib response were defined. By comparing their discriminatory abilities for survival, an indicative criterion was defined, the prognostic value of which was evaluated by time-dependent multivariate analysis, validated in various subsets and confirmed by landmark analysis. Results Using concordance (C)-index analysis and time-dependent receiver operating characteristic curves, the development of a hand-foot-skin reaction ≥ grade 2 within 60 days of sorafenib initiation (2HFSR60) showed the highest discriminating value. Based on this criterion, 161 (37.0%) sorafenib responders achieved decreased risk of death by 47% (adjusted HR 0.53, 95%CI 0.43-0.67, P < 0.001) and likelihood of progression by 26% (adjusted HR 0.74, 95%CI 0.58-0.96, P = 0.020) compared with non-responders. Notably, 2HFSR60 remained an effective discriminator among most subgroups and had superior predictive ability to previous definitions, even according to the landmark analysis. Conclusions Our study demonstrated that 2HFSR60, with the best discriminatory ability compared to currently available definitions of sorafenib-related adverse events, could be the optimal clinical marker to identify sorafenib responders with decreased risk of death by half.

Early-Recurrent Overt Hepatic Encephalopathy Is Associated with Reduced Survival in Cirrhotic Patients after Transjugular Intrahepatic Portosystemic Shunt Creation.

PURPOSE: To investigate the role of early overt hepatic encephalopathy (OHE) as a clinical marker of prognosis in cirrhosis with a transjugular intrahepatic portosystemic shunt (TIPS) and to assess the relationship between recurrence of OHE and survival after TIPS. METHODS: From January 2012 to December 2013, a retrospective study of consecutive patients with cirrhosis and a TIPS was performed at a single institution. A total of 304 patients (196 males; mean age, 52 years) were enrolled during the study period. The mean Model for End-Stage Liver Disease (MELD) score was 11.6. Time-dependent Cox regression was applied to estimate the predictive ability of early OHE (within 3 months after TIPS) and the effect of its frequency on survival. RESULTS: During a median follow-up of 28.3 months, 115 patients experienced OHE after the TIPS procedure; of these, 54 had at least 2 OHE episodes. Long-term survival worsened in patients with early OHE (hazard ratio [HR] = 2.75; 95% confidence interval [CI]: 1.75-4.32; P < .001). When early OHE was further divided into early-recurrent and single OHE, death was more common in patients with early-recurrent OHE (P < .001) than in patients with early-single OHE (P = .24). After adjustment by MELD score, ascites, serum albumin, indication for TIPS, and age, patients with early-recurrent OHE had a lower probability of survival (HR = 2.91; 95% CI: 1.04-4.89; P < .001). Furthermore, landmark and propensity score analyses confirmed the predictive value of early-recurrent OHE. CONCLUSIONS: Early recurrence of OHE was associated with an increased risk of mortality for patients with cirrhosis who underwent TIPS.

Efficacy and safety of variceal embolization for primary prophylaxis in cirrhosis patients with challenges in standard treatments: preliminary results.

Objectives: Nonselective beta blockers (NSBBs) or endoscopic therapies are currently recommended by guidelines for preventing the first variceal bleed in patients with high-risk varices. However, there is a lack of detailed treatment strategies for patients who are intolerant to both NSBBs and endoscopic approaches. Our study aimed to assess the efficacy and safety of variceal embolization as a primary prophylaxis method in cirrhosis patients who are not suitable candidates for NSBBs or endoscopic treatments. Methods: The study included 43 cirrhotic patients with high-risk varices who were candidates for primary prophylaxis against variceal bleeding. These patients underwent variceal embolization at the Xijing Hospital between January 2020 and June 2022. The primary endpoint was the occurrence of bleeding from varices, and the secondary endpoints were the recurrence of varices and the emergence of complications. Results: The procedure of variceal embolization had a success rate of 93.0% (40 out of 43 patients). Over a 2-year follow-up period, the rate of variceal bleeding was 11.6% (5 out of 43 patients), the recurrence rate of varices was 14.0% (6 out of 43 patients), and the rate of severe complications was limited to 2.3% (1 out of 43 patients). Conclusion: Variceal embolization is a viable primary prophylactic intervention for cirrhotic patients who are at risk of variceal bleeding when standard treatments, such as NSBBs or endoscopic therapies, are difficult to perform.

Transjugular intrahepatic collateral-systemic shunt is effective for cavernous transformation of the portal vein with variceal bleeding.

BACKGROUND: The transjugular intrahepatic portal collateral-systemic shunt (transcollateral TIPS) is used to treat portal hypertension-related complications in patients with cavernous transformation of the portal vein (CTPV) and whose main portal vein cannot be recanalized. It is still not clear whether transcollateral TIPS can be as effective as portal vein recanalization-transjugular intrahepatic portosystemic shunt (PVR-TIPS). This study aimed to evaluate the efficacy and safety of transcollateral TIPS in the treatment of refractory variceal bleeding with CTPV. METHODS: Patients with refractory variceal bleeding caused by CTPV were selected from the database of consecutive patients treated with TIPS in Xijing Hospital from January 2015 to March 2022. They were divided into the transcollateral TIPS group and the PVR-TIPS group. The rebleeding rate, overall survival, shunt dysfunction, overt hepatic encephalopathy (OHE) and operation-related complications were analyzed. RESULTS: A total of 192 patients were enrolled, including 21 patients with transcollateral TIPS and 171 patients with PVR-TIPS. Compared with the patients with PVR-TIPS, the patients with transcollateral TIPS had more noncirrhosis (52.4 vs. 19.9%, p = 0.002), underwent fewer splenectomies (14.3 vs. 40.9%, p = 0.018), and had more extensive thromboses (38.1 vs. 15.2%, p = 0.026). There were no differences in rebleeding, survival, shunt dysfunction, or operation-related complication rates between the transcollateral TIPS and PVR-TIPS groups. However, the OHE rate was significantly lower in the transcollateral TIPS group (9.5 vs. 35.1%, p = 0.018). CONCLUSION: Transcollateral TIPS is an effective treatment for CTPV with refractory variceal bleeding.

Portal Fibrotic Cord is Associated with Transjugular Intrahepatic Portosystemic Shunt Failure and Death in Cirrhotic Patients.

Background and Aims: Occlusive portal vein thrombosis (PVT) often causes portal hypertension-related complications in cirrhotic patients. Transjugular intrahepatic portosystemic shunt (TIPS) is an effective treatment for this difficult problem. However, the factors influencing TIPS success and overall survival in patients with occlusive PVT are unknown. This study investigated the factors influencing TIPS success and overall survival in cirrhotic patients with occlusive PVT. Methods: Cirrhotic patients with occlusive PVT were selected from a prospective database of consecutive patients treated with TIPS in Xijing Hospital between January 2015 and May 2021. Baseline characteristics, TIPS success rate, complications, and survival were collected, and the factors associated with the TIPS success rate and transplant-free survival were analyzed. Results: A total of 155 cirrhotic patients with occlusive PVT were enrolled. TIPS succeeded in 126 (81.29%) cases. The 1-year survival rate was 74%. Compared with those without, patients with portal fibrotic cord had a lower TIPS success rate (39.02% vs. 96.49%, p<0.001), shorter median overall survival (300 vs. 1,730 days, p<0.001) and more operation-related complications (12.20% vs. 1.75%, p<0.01). Logistic regression analysis found that portal fibrotic cord (odds ratio 0.024) was a risk factor for TIPS failure. Univariate and multivariate analysis showed that portal fibrotic cord was an independent predictor of death (hazard ratio 2.111; 95% CI: 1.094-4.071, p=0.026). Conclusions: Portal fibrotic cord increased the TIPS failure rate and is a risk factor for poor prognosis in cirrhotic patients.

Electric Insulating Irrigations Mitigates Esophageal Injury Caused by Button Battery Ingestion.

Objective: Accidental ingestion of button batteries (BB), usually occurred in children and infants, will rapidly erode the esophagus and result in severe complications, even death. It has been recommended that treatment of this emergent accident as soon as possible with drinking of pH-neutralizing viscous solutions such as honey and sucralfate before surgical removal can mitigate the esophageal injury. Recently, we reported that the electric insulating solutions such as edible oils could mitigate tissue damage in BB-exposed esophageal segments. In this study, we compared the protective effect of kitchen oil with honey or sucralfate, the recommended pH-neutralizing beverages, and with their mixture on esophageal injury caused by BB ingestion in pig esophageal segments and in living piglets. Methods: Effect of olive oil irrigations was compared to that of honey or sucralfate irrigations in the BB-damaged esophageal segments freshly collected from the local abattoir and in live Bama miniature piglets with the proximal esophagus exposed to BB for 60 min. Also, the effect of olive oil and honey mixture (MOH) irrigations was assessed in live animals. The BB voltage was recorded before insertion and after its removal. Gross and histological analysis of the esophageal injury was performed after BB exposure in segmented fresh esophagus and 7 days after BB exposure in live animals, respectively. Results: Olive oil irrigations demonstrated better protective effect against BB-induced esophageal damage, compared to honey or sucralfate for BB-induced esophageal damage in vitro. But in vivo study showed that olive oil alone exacerbated esophageal injury because all esophagi irrigated with olive oil perforated. Surprisingly, irrigations with the MOH showed considerable protective effect for BB-induced esophageal damage in live animals, significantly better than irrigations with honey alone. The MOH decreased BB discharge, reduced area of surface injury, attenuated injured depth of esophageal wall thickness, and downed the mucosal injury index in comparison to using honey alone. Conclusion: Irrigations with olive oil alone couldn't prevent the BB discharge and is harmful for BB ingestion before surgical removal. However, mixed with honey, olive oil very effectively prevents the BB discharging and produces better esophageal protection than honey.

Scaffold-based analysis of nonpeptide oncogenic FTase inhibitors using multiple similarity matching, binding affinity scoring and enzyme inhibition assay.

Oncogenic protein farnesyltransferase (FTase) is a key enzyme responsible for the lipid modification of a large and important number of proteins including Ras, which has been recognized as a druggable target of diverse cancers. Here, we report a systematic scaffold-based analysis to investigate the affinity, selectivity and cross-reactivity of nonpeptide inhibitors across ontology-enriched, disease-associated FTase mutants, by integrating multiple similarity matching, binding affinity scoring and enzyme inhibition assay. It is revealed that nonpeptide inhibitors are generally insensitive to FTase mutations; many of them cannot definitely select for wild-type target over mutant enzymes. Therefore, off-target is observed as a common phenomenon for the untargeted consequence of targeted therapies with FTase inhibition. This is not unexpected if considering that the enzyme active site is highly conserved in composition, configuration and function. The off-target, on the one hand, causes nonpeptide inhibitors with adverse drug reactions and, on the other hand, makes the inhibitors as promising candidates for the new use of old drugs. To practice the latter, a number of unexpected mutant-inhibitor interactions involved in cancer signaling pathways are uncovered in the created profile, from which several nonpeptide inhibitors are identified as insensitive to a drug-resistant mutation. Structural analysis suggests that the inhibitor ligands can bind to the mutant active site in a similar manner with wild-type target, although their nonbonded interactions appear to be impaired moderately upon the mutation.

Exploratory Analysis to Identify Candidates Benefitting from Combination Therapy of Transarterial Chemoembolization and Sorafenib for First-Line Treatment of Unresectable Hepatocellular Carcinoma: A Multicenter Retrospective Observational Study.

INTRODUCTION: The benefits of combining transarterial chemoembolization (TACE) and sorafenib (TACE-S) over TACE alone for treatment of unresectable hepatocellular carcinoma (HCC) remain controversial. Yet, such populations are heterogeneous in terms of baseline characteristics. OBJECTIVE: To investigate the predictors of survival benefits from added sorafenib and identify the potential candidates for TACE-S. METHODS: This multicenter observational study was conducted in 17 Chinese tertiary hospitals for patients with unresectable, liver-confined HCC. Eligible patients with performance status score of ≤1 and Child-Pugh score of ≤7 were treated with TACE or TACE-S. Interactions between treatment and baseline variables were evaluated to find indicators for survival benefits, based on which the patients were stratified. Multivariate models adjusted for baseline characteristics or propensity score were used to compare overall survival (OS) and time to tumor progression (TTP). RESULTS: From January 2009 to December 2015, 1,719 consecutive patients received TACE (n = 1,406) or TACE-S (n = 313). Although TACE-S compared with TACE improved TTP (adjusted hazard ratio [HR] 0.75, p = 0.008), no difference in OS was observed (adjusted HR 0.87, p = 0.090). Nevertheless, the tumor burden (sum of maximum diameter of largest tumor [cm] and tumor number) and albumin-bilirubin (ALBI) score independently predicted the survival benefits from added sorafenib (interaction p< 0.001). For patients with either moderate tumor burden (7-13) or low ALBI score (no more than -2.8) defined as candidates, TACE-S prolonged OS (adjusted HR 0.73, p = 0.003) and TTP (adjusted HR 0.72, p = 0.014) compared to TACE alone, whereas its superiority disappeared in non-candidates. CONCLUSIONS: Not all unresectable HCC patients but those with moderate tumor burden or low ALBI score achieve survival benefits from TACE-S compared with TACE alone. Future randomized controlled trials focusing on the subset are warranted.

TIPSS for variceal bleeding in patients with idiopathic non-cirrhotic portal hypertension: comparison with patients who have cirrhosis.

BACKGROUND: In patients with idiopathic non-cirrhotic portal hypertension (INCPH), the usual recommended strategy for management of variceal bleeding is the same as that in cirrhosis. However, this policy has been challenged by the different natural history between INCPH and cirrhosis. AIM: To compare outcomes after transjugular intrahepatic portosystemic shunt (TIPSS) between INCPH and cirrhotic patients admitted for variceal bleeding. METHODS: Between March 2001 and September 2015, 76 consecutive patients with biopsy-proven INCPH undergoing TIPSS for variceal bleeding in a tertiary-care centre were included. 76 patients with cirrhotic portal hypertension receiving TIPSS for variceal bleeding, and matched for age, sex, Child-Pugh class, stent type and index year of TIPSS creation served as controls. RESULTS: Patients with INCPH, compared to those with cirrhosis, had significantly lower mortality (11% vs 36% at 5 years, adjusted HR, 0.37; 95% CI 0.15-0.87, P = 0.022), overt hepatic encephalopathy (16% vs 33% at 5 years, adjusted HR, 0.35; 95% CI 0.16-0.75, P = 0.007) and hepatic impairment, despite similar rates of further bleeding (33% vs 32% at 5 years, adjusted HR, 0.72; 95% CI 0.36-1.44, P = 0.358), and shunt dysfunction (35% vs 36% at 5 years, adjusted HR, 0.84; 95% CI 0.41-1.72, P = 0.627). These findings were consistent across different relevant subgroups. CONCLUSIONS: Patients with INCPH treated with TIPSS for variceal bleeding had similar progression of portal hypertension (further bleeding and shunt dysfunction) but fewer complications of liver disease (overt hepatic encephalopathy and hepatic insufficiency) and lower mortality rate compared with cirrhotic patients with comparable liver function.

Early TIPS with covered stents versus standard treatment for acute variceal bleeding in patients with advanced cirrhosis: a randomised controlled trial.

BACKGROUND: The survival benefit of early placement of transjugular intrahepatic portosystemic shunts (TIPS) in patients with cirrhosis and acute variceal bleeding is controversial. We aimed to assess whether early TIPS improves survival in patients with advanced cirrhosis and acute variceal bleeding. METHODS: We did an investigator-initiated, open-label, randomised controlled trial at an academic hospital in China. Consecutive patients with advanced cirrhosis (Child-Pugh class B or C) and acute variceal bleeding who had been treated with vasoactive drugs plus endoscopic therapy were randomly assigned (2:1) to receive either early TIPS (done within 72 h after initial endoscopy [early TIPS group]) or standard treatment (vasoactive drugs continued to day 5, followed by propranolol plus endoscopic band ligation for the prevention of rebleeding, with TIPS as rescue therapy when needed [control group]). Randomisation was done by web-based randomisation system using a Pocock and Simon's minimisation method with Child-Pugh class (B vs C) and presence or absence of active bleeding as adjustment factors. The primary outcome was transplantation-free survival, analysed in the intention-to-treat population, excluding individuals subsequently found to be ineligible for enrolment. This study is registered with ClinicalTrials.gov, number NCT01370161, and is completed. FINDINGS: From June 26, 2011, to Sept 30, 2017, 373 patients were screened and 132 patients were randomly assigned to the early TIPS group (n=86) or to the control group (n=46). After exclusion of three individuals subsequently found to be ineligible for enrolment (two patients in the early TIPS group with non-cirrhotic portal hypertension or hepatocellular carcinoma, and one patient in the control group due to non-cirrhotic portal hypertension), 84 patients in the early TIPS group and 45 patients in the control group were included in the intention-to-treat population. 15 (18%) patients in the early TIPS group and 15 (33%) in the control group died; two (2%) patients in the early TIPS group and one (2%) in the control group underwent liver transplantation. Transplantation-free survival was higher in the early TIPS group than in the control group (hazard ratio 0·50, 95% CI 0·25-0·98; p=0·04). Transplantation-free survival at 6 weeks was 99% (95% CI 97-100) in the early TIPS group compared with 84% (75-96; absolute risk difference 15% [95% CI 5-48]; p=0·02) and at 1 year was 86% (79-94) in the early TIPS group versus 73% (62-88) in the control group (absolute risk difference 13% [95% CI 2-28]; p=0·046). There were no significant differences between the two groups in the incidence of hepatic hydrothorax (two [2%] of 84 patients in the early TIPS group vs one [2%] of 45 in the control group; p=0·96), spontaneous bacterial peritonitis (one [1%] vs three [7%]; p=0·12), hepatic encephalopathy (29 [35%] vs 16 [36%]; p=1·00), hepatorenal syndrome (four [5%] vs six [13%]; p=0·10), and hepatocellular carcinoma (four [5%] vs one [2%]; p=0·68). There was no significant difference in the number of patients who experienced other serious adverse events (ten [12%] vs 11 [24%]; p=0·07) or non-serious adverse events (21 [25%] vs 19 [42%]; p=0·05) between groups. INTERPRETATION: Early TIPS with covered stents improved transplantation-free survival in selected patients with advanced cirrhosis and acute variceal bleeding and should therefore be preferred to the current standard of care. FUNDING: National Natural Science Foundation of China, National Key Technology R&D Program, Optimized Overall Project of Shaanxi Province, Boost Program of Xijing Hospital.

Angioplasty with versus without routine stent placement for Budd-Chiari syndrome: a randomised controlled trial.

BACKGROUND: Angioplasty recanalisation is recommended as the first-line interventional procedure for Budd-Chiari syndrome, but subsequent restenosis is common. We aimed to test whether use of routine, non-selective stenting in angioplasty could improve patency and treatment efficacy with adequate safety in Budd-Chiari syndrome. METHODS: We did a randomised controlled trial, for which patients aged 18-75 years with Budd-Chiari syndrome with membranous obstruction or short-length stenosis (≤4 cm), and a Child-Pugh score of less than 13 were considered eligible. Patients were excluded if they had obstruction not amenable to angioplasty, were recommended to be treated with transjugular intrahepatic portosystemic shunt or liver transplantation, or had contraindications for angioplasty. Eligible patients were randomly assigned (1:1) to an angioplasty-only group or an angioplasty plus routine stenting group, with use of a web-based allocation system (Pocock and Simon's minimisation method, stratified by obstruction features and Child-Pugh score). Recanalisation procedures were done within 24 h of randomisation. The statistician and investigators responsible for data collection data and endpoint assessment were masked to group allocation. The primary outcome was the proportion of patients free of restenosis, analysed in the intention-to-treat population. The study is registered on ClinicalTrials.gov (NCT02201485) and is completed. FINDINGS: Between July 28, 2014, and Sept 29, 2017, 88 (59%) of 150 screened patients were enrolled and assigned either the angioplasty-only group (n=45) or the angioplasty plus routine stenting group (n=43). During a median follow-up period of 27 months (IQR 19-41), the angioplasty plus routine stenting group had significantly higher proportion of patients free of restenosis (42 [98%] of 43 patients) than did the angioplasty-only group (27 [60%] of 45 patients; p<0·0001). In the survival analysis, 3-year restenosis-free survival was 96·0% (95% CI 88·6-100·0) in the routine stenting group versus 60·4% (46·4-78·7) in the angioplasty-only group (log-rank p<0·0001). The hazard ratio for restenosis was 0·04 (95% CI 0·01-0·31) in favour of routine stenting, with an absolute risk reduction of 35·6% (95% CI 24·2-55·0). Two (5%) patients in the angioplasty plus routine stenting group and one (2%) patient in the angioplasty-only group died during follow-up. One (2%) patient from the angioplasty plus routine stenting group had puncture site haematoma, which was not related to stenting. No stent fracture or migration occurred. Anticoagulation-related adverse events occurred in five (11%) patients from angioplasty alone group and five (12%) patients from angioplasty plus routine stenting group. INTERPRETATION: Routine stenting with angioplasty is superior to angioplasty alone for preventing restenosis in patients with Budd-Chiari syndrome with short-length stenosis and is safe to use as part of first-line invasive treatment. Further validation is needed in similar settings and other regions in which different characteristics of Budd-Chiari syndrome are more prevalent. FUNDING: National Natural Science Foundation of China, National Key Technology R&D Programme, Optimised Overall Project of Shaanxi Province, Boost Programme of Xijing Hospital.

Association between non-variceal spontaneous portosystemic shunt and outcomes after TIPS in cirrhosis.

BACKGROUND: Whether pre-existing nonvariceal spontaneous portosystemic shunts (SPSSs) in cirrhotic patients affect outcomes after transjugular intrahepatic portosystemic shunt (TIPS) and whether they need to be closed remains unclear. AIM: To assess the effects of the presence or embolization of SPSSs on outcomes after TIPS for cirrhosis. METHODS: From January 2004 to December 2014, 903 consecutive cirrhotic patients who underwent TIPS in a tertiary-care center were included, of which 715 patients had no SPSS (N-SPSS group), 144 patients had an SPSS without embolization (SPSS group), and 44 had an SPSS with embolization (SPSS + E group). RESULTS: During a median follow-up period of 27.7 months, 368 (41%) patients experienced overt hepatic encephalopathy (OHE), 256 (28%) experienced clinical relapse, 164 (18%) developed shunt dysfunction, and 379 (42%) died. The SPSS group had a higher risk of OHE compared with the N-SPSS and SPSS + E groups (adjusted HR [95%CI]: N-SPSS vs SPSS vs SPSS + E: 1 vs 1.36 [1.06-1.75] vs 0.77 [0.46-1.29]; p = 0.027). In stratification analysis, a higher risk of OHE was only observed in patients with a large SPSS (SPSS diameter ≥6 mm) but not a small SPSS. Additionally, SPSS embolization was associated with a lower risk of OHE among patients with a large SPSS (adjust HR = 0.51; 95% CI: 0.29-0.91; p = 0.034). The risks of clinical relapse (p = 0.584), shunt dysfunction (p = 0.267), and mortality (p = 0.4743) did not significantly differ among groups. CONCLUSIONS: Among cirrhotic patients undergoing TIPS, a pre-existing large SPSS was associated with a higher risk of OHE, which could be decreased by SPSS embolization. There was no clear association between the presence/embolization of an SPSS and post-TIPS clinical relapse, shunt dysfunction or mortality.