MELD 3.0 Score for Predicting Survival in Patients with Cirrhosis After Transjugular Intrahepatic Portosystemic Shunt Creation.

BACKGROUND AND AIMS: The selection of appropriate candidates for transjugular intrahepatic portosystemic shunt (TIPS) is important and challenging. To validate the Model for End-Stage Liver Disease (MELD) 3.0 in predicting mortality in patients with cirrhosis after TIPS creation. METHODS: A total of 855 consecutive patients with cirrhosis from December 2011 to October 2019 who underwent TIPS placement were retrospectively reviewed. The prognostic value of the MELD 3.0, MELD, MELD-Na, Child-Pugh and FIPS score was assessed using Harrell's C concordance index (c-index). The Hosmer-Lemeshow test was used to test the goodness of fit of all models and the calibration plot was drawn. RESULTS: The c-index of the MELD 3.0 in predicting 3-month mortality was 0.727 (0.645-0.808), which were significantly superior to the MELD (0.663 [0.565-0.761]; P = 0.015), MELD-Na (0.672 [0.577-0.768]; P = 0.008) and FIPS (0.582 [0.477-0.687]; P = 0.015). The Child-Pugh score reached c-indices of 0.754 (0.673-0.835), 0.720 (0.649-0.792), 0.705 (0.643-0.766) and 0.665 (0.614-0.716) for 3-month, 6-month, 1-year, and 2-year mortality, respectively, which seems comparable to MELD 3.0. A MELD 3.0 of 14 could be used as a cut-off point for discriminating between high- and low-risk patients. The MELD 3.0 could stratify patients with Child-Pugh grade B (log-rank P < 0.001). The Child-Pugh score could stratify patients defined as low risk by MELD 3.0 (log-rank P < 0.001). CONCLUSIONS: The MELD 3.0 was significantly superior to the MELD, MELD-Na and FIPS scores in predicting mortality in patients with cirrhosis after TIPS creation.

Efficacy and safety of galcanezumab for migraine: evidences from direct and indirect comparisons.

BACKGROUND: The optimal dose of galcanezumab for patients with migraine remains uncertain. Therefore, we conducted a network meta-analysis to assess the comparative effectiveness of various doses of galcanezumab for this group of patients. METHODS: A systematically search was implemented in several databases including the PubMed, Ovid MEDILNE, Ovid EMBASE and Cochrane Library from inception of the databases until 31 August 2020. Only randomized clinical trials of adults with migraine that assessed galcanezumab therapy and reported clinical outcomes were included. The primary efficacy outcome was monthly change in migraine headache days (MHDs). The primary safety outcome was treatment-emergent adverse events (TEAEs). RESULTS: Overall, eight randomized clinical trials included 4,720 patients, were assessed in our systematic review. In terms of efficacy, galcanezumab 120 and 240 mg significantly reduced monthly MHDs (MD -2.02, 95% CrI -2.62 to -1.42; MD -2.06, 95% CrI -2.74 to -1.36, respectively) compared to the placebo. In terms of safety, galcanezumab 120, 150 mg and 240 mg significantly increased incidences of adverse events (RR 1.11, 95% CrI 1.03-1.20; RR 1.85, 95% CrI 1.27-2.81; RR 1.15, 95% CrI 1.06-1.24, respectively). CONCLUSIONS: Galcanezumab 240 mg offers the first level in terms of efficacy outcomes and galcanezumab 150 mg ranks the first level in terms of increasing treatment-emergent adverse events among adult patients with migraine. Attention should be devoted to the potential risk of adverse events, especially for injection site pain when the drug is administered subcutaneously.

Using genotype to assist clinical surveillance: a retrospective study of Chinese familial adenomatous polyposis patients.

Without treatment, familial adenomatous polyposis (FAP) patients will inevitably develop colorectal cancer (CRC) during lifetime. Yet, surgical trauma is a high risk of desmoid tumor (DT), one of the main causes of death in FAP patients. So far, the timing for colectomy is primarily based on the clinician's experience and the patient's preference; most patients undergo surgery at mid-20's. In this study, we analyzed the germline mutation distribution in 35 FAP patients from different families, 16 of them diagnosed with DTs. We also investigated the association between the molecular alterations and the clinicopathological features. Capture-based targeted sequencing using a panel of 520 genes was performed on tumor tissue and paired normal mucosa or white blood cells from 18 FAP probands who were initially diagnosed with CRC. Of all 35 FAP patients, 30 (85.7%) of them harbored germline APC mutations scattered from codon 161 to 1578. The mutations in the 16 DT patients scattered from codon 457 to 1578. All three patients with the mutation at the 3' of 1444 codon were diagnosed with DT. The percentage of high-risk DT (stage III or IV) harboring mutations at the 5' of 1062 or 1062-1578 was 14.3% and 77.8%, respectively, and all three patients with 3' of 1399 codon mutation had high risk. In addition, by using public database, we compared 140 FAP patients with DT to all 1880 FAP patients on the Leiden Open Variation Database and found that the odd ratio of DT in codon 159 to 495 was 0.34, while in codon 1310 to 2011 was 2.36. Compared to sporadic CRCs, the somatic spectrum of FAP CRCs was similar to the early onset CRCs, with higher TP53 (94.1%) and lower somatic APC mutations (65.7%), but the KRAS mutation rate was the highest (58.5%). One of the 18 FAP CRCs was identified as microsatellite instability-high (MSI-H), with tumor mutation burden (TMB) of 115.65 mut/Mb. Given that no TP53 mutations were detected in the low- and high-grade adenomas, ctDNA TP53 sequencing might be used for the close monitoring before FAP colectomy. In conclusion, except mutations at the 5' end of APC (5' to 495), all FAP patients need to consider the risk of DT after colectomy. The chance of life-threating DTs was higher in patients with 3' 1062 codon mutation and peaked in patients with 3' 1399 codon mutation. Scheduled monitoring of TP53 ctDNA is proposed to be a novel tool for optimizing the operation time.

Validating the prognostic value of Freiburg index of posttransjugular intrahepatic portosystemic shunt survival score and classic scores in Chinese patients with implantation of transjugular intrahepatic portosystemic shunt.

BACKGROUND AND AIMS: It is important and challenging to evaluate the survival of cirrhotic patients undergoing transjugular intrahepatic portosystemic shunt (TIPS). We aimed to validate the Freiburg index of post-TIPS survival (FIPS) score and classic scores for predicting mortality in Chinese patients after TIPS creation. METHODS: A total of 709 consecutive patients with cirrhosis from December 2011 to July 2018 who underwent TIPS placement were retrospectively reviewed. The prognostic value of the FIPS score, the model for end-stage liver disease (MELD) score, Child-Pugh score and Chronic Liver Failure Consortium Acute Decompensation score was validated with the receiver operating characteristic (ROC) curve and DeLong et al. test. RESULTS: The MELD-Na score was superior to the FIPS score in predicting 1-month mortality [AUROC, 0.727 (0.692-0.759) vs. 0.588 (0.551-0.625); P = 0.048]. The MELD and MELD-Na scores were significant superior to the FIPS score in predicting 3-month mortality [AUROC, 0.730 (0.696-0.762) vs. 0.598 (0.561-0.634); P = 0.044 and 0.740 (0.706-0.772) vs. 0.598 (0.561-0.634); P = 0.028]. Subgroup analyses revealed that Child-Pugh score was better than FIPS score in predicting 3-month mortality [AUROC, 0.797 (0.745-0.843) vs. 0.578 (0.517-0.637); P = 0.049] in nonviral cirrhosis group. CONCLUSION: Classic scores still had good risk stratification and predictive ability of post-TIPS mortality. The FIPS score was not superior to the classic scores in the current Chinese cohort. The MELD and MELD-Na scores were significantly superior to the FIPS score in predicting 3-month mortality.

Tranexamic Acid for Adult Patients with Spontaneous Intracerebral Hemorrhage: A Systematic Review with Meta-analysis.

BACKGROUND: The effects of tranexamic acid on spontaneous intracerebral hemorrhage in reducing hematoma expansion and mortality as well as its role in thromboembolic complications and in the improvement of functional outcomes remain substantially uncertain. OBJECTIVE: The objective of this systematic review was to evaluate the efficacy and safety of tranexamic acid in patients with spontaneous intracerebral hemorrhage. METHODS: Several databases were searched from inception up to 20 June, 2021. We included randomized controlled trials that compared tranexamic acid with placebo or no treatment for the management of intracerebral hemorrhage. The primary outcomes were hematoma expansion and 90-day mortality. The secondary outcomes were hemorrhagic volume change, thromboembolic complications, and functional outcomes. RESULTS: Overall, six trials with 2800 patients were included in this meta-analysis. Tranexamic acid was associated with a reduced risk of hematoma expansion (relative risk 0.87, 95% confidence interval [CI] 0.77-0.99, p = 0.03, I2 = 0%, six trials with 2800 participants) and a lessening of hematoma volume change (mean difference - 1.28, 95% CI - 2.44 to - 0.12; p = 0.03; I2 = 0%, four trials with 2626 participants), without a corresponding higher rate of major thromboembolic complications (relative risk 1.20, 95% CI 0.85-1.69; p = 0.80; I2 = 0%, five trials with 2759 participants). The present analysis also demonstrated that tranexamic acid had no effect on reducing 90-day mortality (relative risk 1.02, 95% CI 0.88-1.19; p = 0.80; I2 = 0%, five trials with 2770 participants). CONCLUSIONS: In adults with spontaneous intracerebral hemorrhage, tranexamic acid reduced the risk of intracerebral hemorrhage growth compared with the control. The effects on 90-day mortality remained inconclusive. Further studies should report death within 24 h and death due to bleeding whenever possible.

Pharmacological Treatment in the Management of Chronic Subdural Hematoma.

Background: Several pharmacological treatments have been used to treat patients with chronic subdural hematoma (CSDH), although little is known about the comparative effectiveness of different classes of medication. We performed a Bayesian network meta-analysis to compare and rank the efficacy and safety of five drug regimens to determine the best treatment for this group of patients. Methods: We systematically searched PubMed, Medline, clinicaltrials.gov, the Cochrane database, and Embase to identify relevant randomized clinical trials (RCTs) comparing drug treatments in adult patients with CSDH. A network meta-analysis was conducted using a Bayesian framework. Random- and fixed-effects models were used to pool the network results, and the preferred model was selected by comparing the deviance information criteria (DIC). Efficacy outcomes included recurrence requiring surgery, changes in hematoma volume, and a good recovery. The safety outcomes were treatment-related adverse events and all-cause mortality. Results: In this Bayesian network meta-analysis, available data were obtained from 12 eligible trials, including 2,098 patients and 5 techniques. Compared to placebo, atorvastatin (RR: 0.45, 95% CrI: 0.24-0.81) and dexamethasone (RR: 0.38, 95% CrI: 0.22-0.63) were similarly effective in reducing recurrence requiring surgery by 55% and 62%, respectively. Dexamethasone (RR: 0.46, 95% CrI: 0.23-0.91) was more effective in reducing recurrence requiring surgery than goreisan. Additionally, atorvastatin reduced the hematoma volume to a greater extent than placebo (MD: -7.44, 95% CrI: -9.49 to -5.43) or goreisan (MD: -14.09, 95% CrI: -23.35 to -4.82). Moreover, tranexamic acid (MD: -12.07, 95% CrI: -21.68 to -2.29) reduced the hematoma volume to a greater extent than goreisan. No significant differences were detected between drugs and placebo with regard to a good recovery. In terms of safety, dexamethasone (RR: 1.96, 95% CrI: 1.20-3.28) increased the risk of mortality compared to placebo. Conclusion: These findings suggest that dexamethasone is the best treatment to reduce recurrence and atorvastatin is the best treatment to reduce hematoma volume in patients with CSDH. However, clinicians should pay close attention to the elevated risk of all-cause mortality and potential adverse events caused by dexamethasone. Future well-designed RCTs with more participants are needed to verify these findings. Clinical Trial Registration: http://osf.io/u9hqp.

Cancer-Associated Fibroblasts Regulate Bladder Cancer Invasion and Metabolic Phenotypes through Autophagy.

Recently, both cancer-associated fibroblasts (CAFs) and autophagy have been proven to play an important role in tumor development, including bladder cancer (BCa). However, the real mechanisms remain largely unclear. Here, we reconstruct a mimic tumor microenvironment to explore the interaction between CAFs and the BCa cell line T24 using a coculture system. Autophagy in CAFs was induced or inhibited by rapamycin or siRNA, respectively. After coculture with CAFs, T24 cell proliferation, invasion, and aerobic glycolysis were tested in vitro. Rapamycin induced and siAtg5 inhibited autophagy in CAFs. Enhanced autophagy in CAFs promoted cell proliferation and invasion in T24 cells in vitro, while there was no significant difference between the autophagy-inhibited group and the controls. Lactate concentration was elevated in both rapamycin-treated and siAtg5-treated groups compared with the control group. In addition, the expression levels of MCT1, MCT4, HK2, SLC2A1, and MMP-9 were all increased in T24 cells in the autophagy-enhanced group. Our results indicated that CAFs could regulate BCa invasion and metabolic phenotypes through autophagy, providing us with new alternative treatments for BCa in the future.

Efficacy and Safety of Monoclonal Antibody Against Calcitonin Gene-Related Peptide or Its Receptor for Migraine: A Systematic Review and Network Meta-analysis.

Background: The optimal monoclonal antibody against calcitonin gene-related peptide (CGRP) for adult patients with migraine has yet to be determined. Therefore, we aimed to compare the effectiveness of different monoclonal antibodies against CGRP or its receptor for adult patients with migraine through a network meta-analysis of randomized controlled trials. Methods: We systematically searched the MEDILNE, Embase, ClinicalTrials.gov, and Cochrane Library databases for relevant publications from inception until October 30, 2020. Only randomized clinical trials of adults with migraine that assessed any calcitonin gene-related peptide monoclonal antibody and reported clinical outcomes were included. The primary outcomes were changes in monthly migraine days and treatment-emergent adverse events Results: We initially retrieved 2,070 publications, and ultimately, 18 randomized clinical trials totaling 8,926 patients were included. In terms of efficacy, eptinezumab (MD -1.43, 95% CrI -2.59 to -0.36), erenumab (MD -1.61, 95% CrI -2.40 to -0.84), fremanezumab (MD -2.19, 95% CrI -3.15 to -1.25), and galcanezumab (MD -2.10, 95% CrI -2.76 to -1.45) significantly reduced MMDs compared with placebo. In terms of safety, only galcanezumab increased the incidences of TEAEs (RR 1.11, 95% CrI 1.01-1.22) and serious adverse events (RR 2.95, 95% CrI 1.41-6.87) compared with placebo. Conclusion: Most drugs performed similarly and were superior to placebo in most of our analyses. Further head-to-head research on different types of CGRP monoclonal antibodies is necessary to validate the present findings.

Acquired multiple mutations ALK I1171N, L1196M and G1202R mediate lorlatinib resistance in EML4-ALK-rearranged malignant pleural mesothelioma: a case report.

EML4-ALK rearranged malignant pleural mesothelioma (MPM) is rare and its responses to anaplastic lymphoma kinase (ALK) inhibitors, including alectinib and lorlatinib, remain unexplored. In this case report, we describe a patient with EML4-ALK-rearranged stage IIIB MPM who was administered with alectinib and lorlatinib as first-line and fourth-line therapy, respectively. He had remarkable response evaluated as partial response on both regimens lasting approximately 3.5 months on each regimen. His plasma samples were collected during the treatment course and submitted for targeted sequencing to understand the molecular mechanisms of his therapeutic resistance. Sequencing analysis revealed the emergence of ALK I1171N and L1196M at alectinib progression. Meanwhile, ALK I1171N, L1196M, and G1202R mutations were identified at lorlatinib progression, wherein L1196M is confirmed to be in cis to G1202R. We speculate that these multiple mutations synergistically mediated his resistance to both alectinib and lorlatinib. Our report describes the detection of EML4-ALK rearrangement in a patient with MPM who had remarkable therapeutic response with ALK inhibitors. Moreover, our case also revealed acquired mechanisms of lorlatinib resistance mediated by multiple mutations ALK I1171N, L1196M, and G1202R, contributing an incremental step to our understanding of the complexity of acquired resistance mechanisms in sequential ALK inhibitor therapy. The reviews of this paper are available via the supplemental material section.

Prognostic Factors for Acute Transjugular Intrahepatic Portosystemic Shunt Occlusion Using Expanded Polytetrafluoroethylene-Covered Stent.

BACKGROUND: The expanded polytetrafluoroethylene (ePTFE)-covered stent has been widely used in the transjugular intrahepatic portosystemic shunt (TIPS) procedure. However, the epidemiologic data of acute TIPS occlusion (ATO) and the underlying mechanisms are scarce. AIMS: The purpose of this study was to evaluate the incidence and prognostic factors for ATO within 1 week in TIPS recipients using ePTFE-covered stents. METHODS: We identified 222 patients who underwent ePTFE-covered TIPS creation for complications of portal hypertension between June 2015 and June 2017 at a large tertiary center. Medical records and TIPS procedure data were retrospectively reviewed, and the influence of these variables on ATO was assessed by multivariate logistic regression analysis. RESULTS: TIPS technical success was achieved in 219 patients (98.6%). Two patients were excluded due to missing data, leaving 217 patients for final analysis. ATO occurred in nine patients (4.1%). Blood flow was restored by balloon angioplasty (n = 4), additional stent insertion (n = 4), and parallel TIPS (n = 1). In multivariable logistic regression, intrastent stenosis (HR 43.871; 95% CI 3.816, 504.373; P = 0.002), previous splenectomy (HR 26.843; 95% CI 2.106, 342.124; P = 0.011), and stent shortening in the hepatic vein (HR 11.54; 95% CI 1.021, 130.416; P = 0.048) were demonstrated as independent significant risk factors for ATO. CONCLUSIONS: These findings suggest that the intrastent stenosis, previous splenectomy, and stent shortening in the hepatic vein are vital prognostic factors for ATO in TIPS recipients. Individualized post-TIPS management strategy was required.

Comprehensive characterization of protein 4.1 expression in epithelium of large intestine.

The protein 4.1 family consists of four members, 4.1R, 4.1N, 4.1B and 4.1G, each encoded by a distinct gene. All 4.1 mRNAs undergo extensive alternative splicing. Functionally, they usually serve as adapters that link actin-based cytoskeleton to plasma membrane proteins. It has been reported that 4.1 proteins are expressed in most animal cell types and tissues including epithelial cells and epithelial tissues. However, the expression of 4.1 proteins in large intestine has not been well characterized. In the present study, we performed RT-PCR, western blot and immunohistochemistry analysis to characterize the transcripts, the protein expression and cellular localization of 4.1 proteins in the epithelia of mouse large intestine. We show that multiple transcripts derive from each gene, including eight 4.1R isoforms, four 4.1N isoforms, four 4.1B isoforms and six 4.1G isoforms. However, at the protein level, only one or two major bands were detected, implying that not all transcripts are translated and/or the proteins do not accumulate at detectable levels. Immunohistochemistry revealed that 4.1R, 4.1N and 4.1B are all expressed at the lateral membrane as well as cytoplasm of epithelial cells, suggesting a potentially redundant role of these proteins. Our findings not only provide new insights into the structure of protein 4.1 genes but also lay the foundation for future functional studies.

A 130-kDa protein 4.1B regulates cell adhesion, spreading, and migration of mouse embryo fibroblasts by influencing actin cytoskeleton organization.

Protein 4.1B is a member of protein 4.1 family, adaptor proteins at the interface of membranes and the cytoskeleton. It is expressed in most mammalian tissues and is known to be required in formation of nervous and cardiac systems; it is also a tumor suppressor with a role in metastasis. Here, we explore functions of 4.1B using primary mouse embryonic fibroblasts (MEF) derived from wild type and 4.1B knock-out mice. MEF cells express two 4.1B isoforms: 130 and 60-kDa. 130-kDa 4.1B was absent from 4.1B knock-out MEF cells, but 60-kDa 4.1B remained, suggesting incomplete knock-out. Although the 130-kDa isoform was predominantly located at the plasma membrane, the 60-kDa isoform was enriched in nuclei. 130-kDa-deficient 4.1B MEF cells exhibited impaired cell adhesion, spreading, and migration; they also failed to form actin stress fibers. Impaired cell spreading and stress fiber formation were rescued by re-expression of the 130-kDa 4.1B but not the 60-kDa 4.1B. Our findings document novel, isoform-selective roles for 130-kDa 4.1B in adhesion, spreading, and migration of MEF cells by affecting actin organization, giving new insight into 4.1B functions in normal tissues as well as its role in cancer.