Safety and efficacy of adjunct tirofiban treatment following mechanical thrombectomy for acute ischemic stroke patients with large vessel occlusion (LVO) resulting in successful reperfusion.

BACKGROUND AND PURPOSE: Tirofiban administration after mechanical thrombectomy (MT) remains controversial. This study aimed to investigate the efficacy and safety of adjunct tirofiban treatment following MT for acute ischemic stroke (AIS) patients with large vessel occlusion (LVO) that resulted in successful reperfusion on digital subtraction angiography (DSA). METHODS: This retrospective study was conducted in Zhengzhou University University People's Hospital, an advanced stroke center in China. Consecutive patients with AIS who underwent endovascular therapy (EVT) were enrolled from June 2018 to January 2022. The safety endpoints were symptomatic intracerebral hemorrhage (sICH), total intracranial hemorrhage (ICH), and 3-month mortality. The efficacy endpoints were 3-month modified Rankin scale (mRS) score and 24-h neurological improvement. RESULTS: A total of 145 consecutive patients with AIS who underwent MT were analyzed, of whom 51 (35.2%) patients were in the tirofiban group. There were 30 (20.7%) patients with sICH, 50 (34.5%) patients suffered from ICH within 24-h post-MT, and 47 (32.4%) dead at 3-month. Besides, 31 (21.4%) patients achieved excellent clinical outcomes (mRS, 0-1), and 24-h neurological improvement was found in 29 (20.0%) patients. No statistically significant differences were found in safety outcomes on sICH, total ICH, and 3-month mortality, as well as efficacy outcomes on 3-month mRS scores (0-1) and 24-h neurological improvement between the two groups (P > 0.05 for all). Additionally, tirofiban was associated with 3-month mRS scores of 0-2 (adjusted odds ratio (OR), 3.75; 95% confidence interval (CI), 1.41-10.02, P = 0.008). CONCLUSION: Adjunct tirofiban treatment following MT for AIS patients with LVO that resulted in successful reperfusion on DSA was not correlated with the increased risk of safety endpoints on sICH, ICH, and 3-month mortality, and it may be associated with a lower 3-month mRS score.

Unequal Efficacy of Different Infarct Location in Predicting Futile Recanalization of Patients With Acute Ischemic Stroke.

Objectives: Endovascular thrombectomy (EVT) is a standard treatment for acute ischemic stroke (AIS) caused by large vessel occlusion, while futile recanalization is the main factor influencing the prognosis. The present study aimed to investigate the efficacy of different infarct sites in predicting futile recanalization of patients with AIS. Methods: Data were obtained from two multicenter, prospective, randomized, and controlled trials, which were concurrently conducted in China. Cases achieving a successful recanalization and with complete data of preoperative Alberta Stroke Program Early CT score (ASPECTS) and 90-day follow-up were included. The ASPECTS subregions were used to mark different infarct locations in the two cerebral hemispheres. First, the distribution of each ASPECTS subregion in the left and right hemispheres and the whole brain was analyzed, respectively. Then, the regions associated with futile recanalization were initially assessed by a univariate model. Afterward, a multivariate logistic regression model was used to identify the efficacy of different infarct sites in predicting futile recanalization. Results: A total of 336 patients were included in this study with a median age of 65 years (IQR: 51-74), of whom 210 (62.50%) patients were male, and 189 (56.25%) met the definition of futile recanalization. The correlation between each ASPECTS subregion and poor outcome was different when it was restricted to a specific cerebral hemisphere. Moreover, in the left hemisphere, the internal capsule region (OR: 1.42, 95%CI: 1.13-1.95, P = 0.03) and the M3 region (OR: 2.26, 95%CI: 1.36-3.52, P = 0.001), and in the right hemisphere, M6 region (OR: 2.24, 95%CI: 1.32-3.36, P = 0.001) showed significantly higher efficacy in predicting futile recanalization. Conclusion: The efficacy of different infarct locations in predicting futile recanalization is different. Different preoperative patterns of the high-efficiency regions in the infarction core or penumbra can guide the thrombectomy decision-making.

Metabolic Dysfunction-associated Fatty Liver Disease is Associated with Greater Impairment of Lung Function than Nonalcoholic Fatty Liver Disease.

Background and Aims: We compared lung function parameters in nonalcoholic fatty liver disease (NAFLD) and metabolic dysfunction-associated fatty liver disease (MAFLD), and examined the association between lung function parameters and fibrosis severity in MAFLD. Methods: In this cross-sectional study, we randomly recruited 2,543 middle-aged individuals from 25 communities across four cities in China during 2016 and 2020. All participants received a health check-up including measurement of anthropometric parameters, biochemical variables, liver ultrasonography, and spirometry. The severity of liver disease was assessed by the fibrosis (FIB)-4 score. Results: The prevalence of MAFLD was 20.4% (n=519) and that of NAFLD was 18.4% (n=469). After adjusting for age, sex, adiposity measures, smoking status, and significant alcohol intake, subjects with MAFLD had a significantly lower predicted forced vital capacity (FVC, 88.27±17.60% vs. 90.82±16.85%, p<0.05) and lower 1 s forced expiratory volume (FEV1, 79.89±17.34 vs. 83.02±16.66%, p<0.05) than those with NAFLD. MAFLD with an increased FIB-4 score was significantly associated with decreased lung function. For each 1-point increase in FIB-4, FVC was diminished by 0.507 (95% CI: -0.840, -0.173, p=0.003), and FEV1 was diminished by 0.439 (95% CI: -0.739, -0.140, p=0.004). The results remained unchanged when the statistical analyses was performed separately for men and women. Conclusions: MAFLD was significantly associated with a greater impairment of lung function parameters than NAFLD.

Association of Preoperative Coagulability With Incidence and Extent of Portal Vein Tumor Thrombus and Survival Outcomes in Hepatocellular Carcinoma After Hepatectomy: A Large-Scale, Multicenter Study.

BACKGROUND: Occurrence of portal vein tumor thrombus (PVTT) worsens the outcomes of hepatocellular carcinoma (HCC) and imparts high economic burden on society. Patients with high risks of having hypercoagulation are more likely to experience thrombosis. Herein, we examined how preoperative international normalized ratio (INR) was related to the incidence and extent of PVTT, and associated with survival outcomes in HCC patients following R0 liver resection (LR). METHODS: Patients with HCC and PVTT were enrolled from six major hospitals in China. The overall survival (OS) and recurrence-free survival (RFS) rates of individuals with different INR levels were assessed with Cox regression analysis as well as Kaplan-Meier method. RESULTS: This study included 2207 HCC patients, among whom 1005 patients had concurrent PVTT. HCC patients in the Low INR group had a significantly higher incidence of PVTT and more extensive PVTT than the Normal and High INR groups (P<0.005). Of the 592 HCC subjects who had types I/II PVTT following R0 LR, there were 106 (17.9%), 342 (57.8%) and 144 (24.3%) patients in the High, Normal and Low INR groups, respectively. RFS and OS rates were markedly worse in patients in the Low INR group relative to those in the Normal and High INR groups (median RFS, 4.87 versus 10.77 versus 11.40 months, P<0.001; median OS, 6.30 versus 11.83 versus 12.67 months, P<0.001). CONCLUSION: Preoperative INR influenced the incidence and extent of PVTT in HCC. Particularly, patients with HCC and PVTT in the Low INR group had worse postoperative prognosis relative to the High and Normal INR groups.

Endovascular Management of Intracranial Atherosclerosis-Related Large Vessel Occlusion With the A Direct Aspiration First-Pass Thrombectomy Compared With Solumbra Technique.

Background: To investigate the effect of the A Direct Aspiration First-Pass Thrombectomy (ADAPT) vs. Solumbra technique in the treatment of acute intracranial atherosclerosis-related large vessel occlusion (LVO). Methods: Patients with acute atherosclerosis-related LVO who had undergone endovascular treatment were retrospectively enrolled into two groups: The Solumbra and ADAPT groups. The clinical data were analyzed. Results: Patients (104) were enrolled with 48 in the Solumbra and 56 in the ADAPT group. The mean time from femoral access to recanalization was significantly (P < 0.05) shorter in the ADAPT than in the Solumbra group. The recanalization time at the first line was significantly shorter in the ADAPT group than in the Solumbra group (17 ± 10.21 vs. 26 ± 15.55 min, P = 0.02). However, the rate of switching to the alternative was significantly higher in the ADAPT group than that in the Solumbra group (46.42 vs. 33.33%, P = 0.01). Eighty-two patients had eventual recanalization, resulting in a final recanalization rate of 78.85%. At 3-month clinical follow-up for all patients, the good prognosis rate reached 51.92% with good prognosis in 24 patients (50%) in the Solumbra and 30 (53.57%) in the ADAPT group. The rate of symptomatic intracranial hemorrhage was 18.75% (n = 9) in the Solumbra and 19.64% (n = 11) in the ADAPT group. The mortality rate was 21.15% (22/104). Among 80 (76.92%) patients who had angiographic follow-up (3-30 months), five (6.25%) patients experienced in-stent stenosis, and two (2.5%) experienced asymptomatic stent occlusion. Conclusion: In patients with acute intracranial atherosclerosis-related LVO, clinical outcomes treated using the ADAPT technique are comparable with those using the Solumbra technique, and more patients need additional remedial measures if treated with the ADAPT technique.

Susceptibility and interactions between Aedes mosquitoes and Zika viruses.

Zika virus disease is caused by Zika virus infection, as transmitted by Aedes spp. mosquitoes. Many of the Zika virus strains isolated from patients display different pathogenicities toward humans. The vector mosquitoes for Zika virus are mainly of the Aedes genus, especially Aedes aegypti and Aedes albopictus. However, susceptibility and interactions between Aedes spp. mosquitoes and Zika viruses remain unclear. In this study, we chose two Zika virus strains (FSS13025 and PRVABC59) with different abilities to infect the primary vector mosquitoes Ae. aegypti and Ae. albopictus. The transcriptomes and small RNA profiles of infected and uninfected mosquitoes were comparatively analyzed, and differentially expressed genes were functionally examined using RNA interference. According to the results, the susceptibility of PRVABC59 was higher than that of FSS13025 in Aedes vector mosquitoes, and Ae. aegypti was more susceptible to Zika virus than was Ae. albopictus. For PRVABC59 infection, specific differential expression profiles correlated with Ae. aegypti and Ae. albopictus, and susceptibility was significantly affected when three targeted genes were successfully knocked down. Compared with PRVABC59, infection of Ae. albopictus with FSS13025 generated more 21-nt virus small interference RNA. It can be concluded that the susceptibility of vector Aedes spp. mosquitoes to Zika viruses varies and that the interactions between mosquitoes and Zika virus correlate with susceptibility.

Association of Preoperative Hypercoagulability with Poor Prognosis in Hepatocellular Carcinoma Patients with Microvascular Invasion After Liver Resection: A Multicenter Study.

BACKGROUND: Microvascular invasion (MVI) predicts poor prognosis in patients with hepatocellular carcinoma (HCC). HCC patients with hypercoagulability are prone to develop thrombosis; however, the relationship between preoperative coagulability state, as reflected by the international normalized ratio (INR) level, and MVI remains unclear. METHODS: From January 2009 to December 2012, HCC patients who underwent R0 liver resection (LR) from four cancer centers entered into this study. The overall survival (OS) and recurrence-free survival (RFS) rates were compared using the Kaplan-Meier method and Cox regression analysis. RESULTS: Of the 2509 HCC patients who were included into this study, 1104 were found to have MVI in the resected specimens. These patients were divided into the low (n = 151), normal (n = 796), and high (n = 157) INR subgroups based on the preoperative INR levels. The low INR subgroup had a significantly higher incidence of MVI than the normal or high INR subgroups (61.6% vs. 41.6% vs. 44.6%; p < 0.001). HCC patients with MVI were significantly more likely to have a low preoperative INR level (p < 0.001); the INR level (p < 0.001) was an independent risk factor of OS and RFS. HCC patients with MVI in the low INR subgroup had significantly worse RFS and OS than the normal or high INR subgroups (median RFS 13.5 vs. 20.2 vs. 21.6 months, p < 0.001; median OS 35.5 vs. 59.5 vs. 57.0 months, p < 0.001). CONCLUSIONS: Preoperative hypercoagulability was associated with poor long-term prognosis in HCC patients with MVI after R0 LR.

Adjuvant transarterial chemoembolization improves survival outcomes in hepatocellular carcinoma with microvascular invasion: A systematic review and meta-analysis.

BACKGROUND: The benefits of adjuvant transarterial chemoembolization (TACE) in hepatocellular carcinoma (HCC) patients with microvascular invasion (MVI) remain controversial. We compared the efficacy and safety of adjuvant TACE and hepatic resection (HR) alone for HCC patients with MVI. METHODS: The PubMed, EMBASE, Cochrane Library, VIP, Wan Fang, and Sino Med databases were systematically searched to compare adjuvant TACE and HR alone for the treatment of HCC with MVI from inception to January 1, 2019. The study outcomes, including overall survival (OS) and disease-free survival (DFS), were extracted independently by two authors. RESULTS: 12 trials involving 2190 patients were evaluated. A meta-analysis of 11 studies suggested that the 1-, 3-, and 5-year overall survival (OS) rates (OR = 0.33, P < 0.001; OR = 0.49, P < 0.001; and OR = 0.59, P < 0.01; respectively), favored adjuvant TACE over HR alone. 11 studies were included in the meta-analysis of DFS, and adjuvant TACE showed better 1-, 3-, and 5-DFS (OR = 0.45, P < 0.001; OR = 0.50, P < 0.001; and OR = 0.58, P < 0.001; respectively) compared to HR alone. Subgroup analysis demonstrated that adjuvant TACE could benefit HCC patients with MVI with tumor diameter >5 cm or multinodular tumors. CONCLUSION: Adjuvant TACE may improve OS and DFS for HCC patients with MVI compared to HR alone and should be recommended for selected HCC patients with MVI. However, these results need to be validated through further high-quality clinical studies. LAY SUMMARY: The benefits of adjuvant TACE in HCC patients with microvascular invasion remain controversial. Twelve studies involving 2190 patients were include in our meta-analysis. Adjuvant TACE may improve OS and DFS for HCC patients with MVI compared to HR alone and should be recommended for selected HCC patients with MVI.

Long non-coding RNA DILC suppresses bladder cancer cells progression.

Accumulative researches have demonstrated the critical functions of long non-coding RNAs (lncRNAs) in the progression of malignant tumors, including bladder cancer (BC). Our previous studies showed that lnc-DILC was an important tumor suppressor gene in both liver cancer and colorectal cancer. However, the role of lnc-DILC in BC remains to be elucidated. In the present study, we for first found that lnc-DILC was downregulated in human bladder cancer tissues. Lnc-DILC overexpression suppressed the proliferation, metastasis and expansion of bladder cancer stem cells (CSCs). Mechanically, lnc-DILC suppressed BC cells progression via STAT3 pathway. Special STAT3 inhibitor S3I-201 diminished the discrepancy of growth, metastasis and self-renewal ability between lnc-DILC-overexpression BC cells and their control cells, which further confirmed that STAT3 was acquired for lnc-DILC-disrupted BC cell growth, metastasis and self-renewal. Taken together, our results suggest that lnc-DILC is a novel bladder tumor suppressor and indicate that lnc-DILC inhibits BC progression via inactivating STAT3 signaling.

Postoperative adjuvant sorafenib improves survival outcomes in hepatocellular carcinoma patients with microvascular invasion after R0 liver resection: a propensity score matching analysis.

BACKGROUND: Microvascular invasion (MVI) is a major determinant of survival outcome for hepatocellular carcinoma (HCC). This study aimed to investigate the efficacy of postoperative adjuvant Sorafenib (PA-Sorafenib) in HCC patients with MVI after R0 liver resection (LR). METHODS: The data of patients who underwent R0 LR for HCC with histologically confirmed MVI at the Eastern Hepatobiliary Surgery Hospital were retrospectively analyzed. The survival outcomes for patients who underwent PA-Sorafenib were compared with those who underwent R0 LR alone. Propensity score matching (PSM) analysis was performed. RESULTS: 728 HCC patients had MVI in the resected specimens after R0 resection, with 581 who underwent LR alone and 147 patients who received in additional adjuvant sorafenib. PSM matched 113 patients in each of these two groups. The overall survival (OS) and recurrence free survival (RFS) were significantly better for patients in the PA-sorafenib group (for OS: before PSM, P = 0.003; after PSM, P = 0.007), (for RFS: before PSM, P = 0.029; after PSM, P = 0.001), respectively. Similar results were obtained in patients with BCLC 0-A, BCLC B and Child-Pugh A stages of disease. CONCLUSIONS: PA-Sorafenib was associated with significantly better survival outcomes than LR alone for HCC patients with MVI.

A nomogram to predict early postoperative recurrence of hepatocellular carcinoma with portal vein tumour thrombus after R0 liver resection: A large-scale, multicenter study.

BACKGROUND: Portal vein tumour thrombus (PVTT) is a significant poor prognostic factor for hepatocellular carcinoma (HCC). Patients with PVTT limited to a first-order branch or above of the main portal vein (MPV) could benefit from R0 liver resection (LR). A nomogram is needed to predict early postoperative recurrence (ER) in HCC patients with PVTT and to guide selection of these patients for adjuvant therapy to reduce postoperative recurrence risks. METHODS: HCC patients with PVTT limited to a first-order branch or above of the MPV after R0 LR as an initial therapy were included. A nomogram using data from a retrospective training cohort was developed with the Cox regression model. The model was tested in a prospective internal validation cohort and three external validation cohorts. RESULTS: Of 979 patients, 657 developed postoperative ER (67.1%). ER occurred in 165 of 264 patients (62.5%) in the training cohort, 146 of 218 patients (70.0%) in the internal validation cohort, and 204 of 284 patients (71.8%), 77 of 113 patients (68.1%), and 65 of 100 patients (65%) in the three external validation cohorts, respectively. The nomogram included the following variables: hepatitis B surface antigen (HBsAg), PVTT, HBV DNA, satellite nodules, α-fetoprotein, and tumour diameter. The ROC were 0.836, 0.763, 0.802, 0.837, and 0.846 in predicting ER in the five respective cohorts. CONCLUSION: A nomogram was developed and validated to predict postoperative ER in patients with HCC with PVTT after R0 LR. This nomogram could select appropriate patients with high ER risks for postoperative adjuvant therapy.

Methylation-Mediated Silencing of GATA5 Gene Suppresses Cholangiocarcinoma Cell Proliferation and Metastasis.

Cholangiocarcinoma (CCA) is one of the most common hepatic and biliary malignancies, accounting for about 3% of all gastrointestinal tumors. GATA5 is a transcription factor capable of suppressing the development of various human cancer types. Transcriptional inactivation and CpG island (CGI) methylation of GATA3 and GATA5, two members of the GATA family of transcription factors, have been observed in some human cancers. But whether high-density CGI methylation of GATA5 is associated with the clinical course of CCA patients has not been clarified. Herein, we observed reduced expression of GATA5 in CCA tissues compared with noncancerous tissues. Treatment with the demethylating agent 5-aza-2'-deoxycytidine restored GATA5 expression in CCA cell lines. Furthermore, GATA5 expression was downregulated after treatment with IL-6 in human intrahepatic biliary epithelial cells. Upregulated GATA5 inhibited CCA cell growth and metastasis. Mechanistically, GATA5 suppressed CCA cell growth and metastasis via Wnt/ß-catenin pathway. Specific ß-catenin inhibitor or siRNA abolished the discrepancy of the proliferation and metastasis capacity between GATA5-overexpression CCA cells and their control cells, which further confirmed that Wnt/ß-catenin was required in GATA5-inhibited CCA cell growth and metastasis.

Application of retrievable Solitaire AB stents in the endovascular treatment of acute ischemic stroke.

Purpose: Retrievable stents are widely used in acute ischemic stroke (AIS); however, the results remain unclear in Chinese patients. This study aimed to explore the usefulness of Solitaire AB stents in AIS. Materials and Methods: Seventy-three AIS patients treated with Solitaire AB stents for thrombectomy of large artery occlusion of anterior circulation in January 2014-June 2015 were retrospectively evaluated. Recanalization was assessed with the Thrombolysis In Cerebral Ischemia (TICI) scale. Clinical outcomes were assessed according to the National Institute of Health Stroke Scale (NIHSS) and the modified Rankin Scale (mRS). Operation-related complications were recorded. The main factors affecting successful recanalization with Solitaire AB were analyzed. Results: The 73 patients enrolled included 39 males and 34 females (median age of 59 [31-78] years); 77 Solitaire AB stents were used. The initial recanalization rate with Solitaire AB as the first thrombectomy method was 53.42% (39/73; recanalization group). Among the 34 patients with failed stent retrieval, 32 underwent other treatments; the final arterial recanalization rate was 89.04% (65/73). Perioperative embolization events and symptomatic intracranial hemorrhage (sICH) occurred in 5 and 8 patients, respectively. The mean NIHSS score was 9.12±3.86 one week after thrombectomy, significantly lower compared with admission values. In 31 patients (42.47%), NIHSS score decreased by >8. Good functional independence (mRS score≤2) was achieved in 39 patients (53.42%) at 90 days; 12 patients (16.44%) died. Compared with the recanalization group, the remaining patients showed lower AF and higher LAA percentages. Conclusion: Solitaire AB stents are useful in the endovascular treatment of AIS.

The HLF/IL-6/STAT3 feedforward circuit drives hepatic stellate cell activation to promote liver fibrosis.

BACKGROUND AND AIMS: Liver fibrosis is a wound-healing response that disrupts the liver architecture and function by replacing functional parenchyma with scar tissue. Recent progress has advanced our knowledge of this scarring process, but the detailed mechanism of liver fibrosis is far from clear. METHODS: The fibrotic specimens of patients and HLF (hepatic leukemia factor)PB/PB mice were used to assess the expression and role of HLF in liver fibrosis. Primary murine hepatic stellate cells (HSCs) and human HSC line Lx2 were used to investigate the impact of HLF on HSC activation and the underlying mechanism. RESULTS: Expression of HLF was detected in fibrotic livers of patients, but it was absent in the livers of healthy individuals. Intriguingly, HLF expression was confined to activated HSCs rather than other cell types in the liver. The loss of HLF impaired primary HSC activation and attenuated liver fibrosis in HLFPB/PB mice. Consistently, ectopic HLF expression significantly facilitated the activation of human HSCs. Mechanistic studies revealed that upregulated HLF transcriptionally enhanced interleukin 6 (IL-6) expression and intensified signal transducer and activator of transcription 3 (STAT3) phosphorylation, thus promoting HSC activation. Coincidentally, IL-6/STAT3 signalling in turn activated HLF expression in HSCs, thus completing a feedforward regulatory circuit in HSC activation. Moreover, correlation between HLF expression and alpha-smooth muscle actin, IL-6 and p-STAT3 levels was observed in patient fibrotic livers, supporting the role of HLF/IL-6/STAT3 cascade in liver fibrosis. CONCLUSIONS: In aggregate, we delineate a paradigm of HLF/IL-6/STAT3 regulatory circuit in liver fibrosis and propose that HLF is a novel biomarker for activated HSCs and a potential target for antifibrotic therapy.

Chronic inflammation-elicited liver progenitor cell conversion to liver cancer stem cell with clinical significance.

The substantial heterogeneity and hierarchical organization in liver cancer support the theory of liver cancer stem cells (LCSCs). However, the relationship between chronic hepatic inflammation and LCSC generation remains obscure. Here, we observed a close correlation between aggravated inflammation and liver progenitor cell (LPC) propagation in the cirrhotic liver of rats exposed to diethylnitrosamine. LPCs isolated from the rat cirrhotic liver initiated subcutaneous liver cancers in nonobese diabetic/severe combined immunodeficient mice, suggesting the malignant transformation of LPCs toward LCSCs. Interestingly, depletion of Kupffer cells in vivo attenuated the LCSC properties of transformed LPCs and suppressed cytokeratin 19/Oval cell 6-positive tumor occurrence. Conversely, LPCs cocultured with macrophages exhibited enhanced LCSC properties. We further demonstrated that macrophage-secreted tumor necrosis factor-α triggered chromosomal instability in LPCs through the deregulation of ubiquitin D and checkpoint kinase 2 and enhanced the self-renewal of LPCs through the tumor necrosis factor receptor 1/Src/signal transducer and activator of transcription 3 pathway, which synergistically contributed to the conversion of LPCs to LCSCs. Clinical investigation revealed that cytokeratin 19/Oval cell 6-positive liver cancer patients displayed a worse prognosis and exhibited superior response to sorafenib treatment. CONCLUSION: Our results not only clarify the cellular and molecular mechanisms underlying the inflammation-mediated LCSC generation but also provide a molecular classification for the individualized treatment of liver cancer. (Hepatology 2017;66:1934-1951).