Mixed-Genotype HCV Direct Acting Antiviral Outcomes: A CANUHC Analysis.

The prevalence of mixed hepatitis C virus (HCV) genotype infection in a representative Canadian HCV cohort is reported and virological response with direct acting antiviral (DAA) treatment was evaluated. 3272 HCV-positive participants were enrolled, of which 2945 (90.0%) initiated DAA therapy. 0.8% were identified with mixed genotype infection. Overall sustained virological response (SVR) was 99.1% and did not differ based on mixed genotype status. Any historical disadvantage to achieving cure with HCV treatment in mixed genotype infection has been overcome by current DAA regimens.

Therapies for Cirrhotic Cardiomyopathy: Current Perspectives and Future Possibilities.

Cirrhotic cardiomyopathy (CCM) is defined as cardiac dysfunction associated with cirrhosis in the absence of pre-existing heart disease. CCM manifests as the enlargement of cardiac chambers, attenuated systolic and diastolic contractile responses to stress stimuli, and repolarization changes. CCM significantly contributes to mortality and morbidity in patients who undergo liver transplantation and contributes to the pathogenesis of hepatorenal syndrome/acute kidney injury. There is currently no specific treatment. The traditional management for non-cirrhotic cardiomyopathies, such as vasodilators or diuretics, is not applicable because an important feature of cirrhosis is decreased systemic vascular resistance; therefore, vasodilators further worsen the peripheral vasodilatation and hypotension. Long-term diuretic use may cause electrolyte imbalances and potentially renal injury. The heart of the cirrhotic patient is insensitive to cardiac glycosides. Therefore, these types of medications are not useful in patients with CCM. Exploring the therapeutic strategies of CCM is of the utmost importance. The present review summarizes the possible treatment of CCM. We detail the current status of non-selective beta-blockers (NSBBs) in the management of cirrhotic patients and discuss the controversies surrounding NSBBs in clinical practice. Other possible therapeutic agents include drugs with antioxidant, anti-inflammatory, and anti-apoptotic functions; such effects may have potential clinical application. These drugs currently are mainly based on animal studies and include statins, taurine, spermidine, galectin inhibitors, albumin, and direct antioxidants. We conclude with speculations on the future research directions in CCM treatment.

Phytochemistry and Pharmacology of Sesquiterpenoids from Atractylodes DC. Genus Rhizomes.

The rhizomes of the genus Atractylodes DC. consist of various bioactive components, including sesquiterpenes, which have attracted a great deal of research interest in recent years. In the present study, we reviewed the previously published literatures prior to November 2023 on the chemical structures, biosynthetic pathways, and pharmacological activities of the sesquiterpenoids from this genus via online databases such as Web of Science, Google Scholar, and ScienceDirect. Phytochemical studies have led to the identification of more than 160 sesquiterpenes, notably eudesmane-type sesquiterpenes. Many pharmacological activities have been demonstrated, particularly anticancer, anti-inflammatory, and antibacterial and antiviral activities. This review presents updated, comprehensive and categorized information on the phytochemistry and pharmacology of sesquiterpenes in Atractylodes DC., with the aim of offering guidance for the future exploitation and utilization of active ingredients in this genus.

A randomized-controlled trial of SOF/VEL/VOX with or without ribavirin for retreatment of chronic hepatitis C.

BACKGROUND & AIMS: The combination of sofosbuvir, velpatasvir and voxilaprevir (SOF/VEL/VOX) is recommended for the retreatment of patients with HCV infection in whom previous direct-acting antiviral (DAA) treatment failed. However, whether ribavirin further increases the therapeutic efficacy of SOF/VEL/VOX retreatment remains unclear. We aimed to test this hypothesis in a randomized-controlled trial. METHODS: We randomly assigned 315 patients with DAA treatment failure from five Egyptian sites into two groups. Group A (n = 158) received SOF/VEL/VOX for 12 weeks, and group B (n = 157) received SOF/VEL/VOX + weight-based ribavirin for 12 weeks. Therapeutic efficacy was defined as SVR12 (sustained virologic response 12 weeks after treatment end). Safety and tolerability were evaluated by monitoring treatment-related adverse events (AEs) and laboratory abnormalities. RESULTS: Males comprised 53.9% of group A and 57.1% of group B (p = 0.58); mean ages were 51.8 and 47.3 years in group A and B, respectively. Seventeen patients in each group were lost to follow-up. SVR12 rates were 87.3% (138/158) by intention-to-treat analysis and 97.8% (138/141) by per-protocol analysis in group A; and 87.9% (138/157) and 98.5% (138/140), respectively, in group B (p = n.s. for intention-to-treat and per-protocol analyses). Both regimens were well-tolerated, with no deaths and only one serious AE (anemia) in group B, which required ribavirin discontinuation. Fifty-five patients in group A vs. 77 in group B experienced any AE (p = 0.002). CONCLUSION: This randomized-controlled trial showed equal, high efficacy of both regimens for the retreatment of previous DAA failures, although ribavirin was associated with more AEs. Therefore SOF/VEL/VOX monotherapy should be the preferred retreatment strategy. CLINCIALTRIALS. GOV NUMBER: NCT04695769. IMPACT AND IMPLICATIONS: HCV treatment guidelines recommend retreatment of direct-acting antiviral (DAA) treatment failures with the combination of sofosbuvir, velpatasvir and voxilaprevir (SOF/VEL/VOX) for 12 weeks. However, whether ribavirin exerts an additional/synergistic effect remains unclear. The present study confirmed that SOF/VEL/VOX without ribavirin is the best regimen for retreatment of DAA treatment failures, and thus will help guide clinicians caring for patients who are not cured with a first course of DAA therapy.

Oxidative Mechanisms and Cardiovascular Abnormalities of Cirrhosis and Portal Hypertension.

In patients with portal hypertension, there are many complications including cardiovascular abnormalities, hepatorenal syndrome, ascites, variceal bleeding, and hepatic encephalopathy. The underlying mechanisms are not yet completely clarified. It is well known that portal hypertension causes mesenteric congestion which produces reactive oxygen species (ROS). ROS has been associated with intestinal mucosal injury, increased intestinal permeability, enhanced gut bacterial overgrowth, and translocation; all these changes result in increased endotoxin and inflammation. Portal hypertension also results in the development of collateral circulation and reduces liver mass resulting in an overall increase in endotoxin/bacteria bypassing detoxication and immune clearance in the liver. Endotoxemia can in turn aggravate oxidative stress and inflammation, leading to a cycle of gut barrier dysfunction → endotoxemia → organ injury. The phenotype of cardiovascular abnormalities includes hyperdynamic circulation and cirrhotic cardiomyopathy. Oxidative stress is often accompanied by inflammation; thus, blocking oxidative stress can minimize the systemic inflammatory response and alleviate the severity of cardiovascular diseases. The present review aims to elucidate the role of oxidative stress in cirrhosis-associated cardiovascular abnormalities and discusses possible therapeutic effects of antioxidants on cardiovascular complications of cirrhosis including hyperdynamic circulation, cirrhotic cardiomyopathy, and hepatorenal syndrome.

Cardiovascular events after liver transplantation: MACE hurts.

The curative therapy for patients with end-stage liver disease is liver transplantation. However, liver transplantation challenges the cardiovascular system, and is associated with major adverse cardiovascular events (MACE). Immediately after implantation of the liver graft, changes in cardiac preload and afterload increase the cardiac workload. Longer-term postoperatively, a more sedentary lifestyle and enhanced appetite increase obesity and body mass index. Immunosuppressants may also affect the cardiovascular system. All these factors that liver recipients encounter impact the function of the cardiovascular system. Cardiac events are the third-leading cause of death in liver recipients. This review describes the pertinent factors that predispose to development of MACE after liver transplantation, and how to predict these cardiovascular events in the post-transplant period. We review the roles of metabolic syndrome, renal dysfunction, non-alcoholic fatty liver disease, diagnostic tests such as imaging and biomarkers, and parameters such as systolic and diastolic dysfunction, and QT interval prolongation in cardiovascular events. We summarize the current literature on scoring systems to predict cardiovascular events.

Soluble TREM-1, as a new ligand for the membrane receptor Robo2, promotes hepatic stellate cells activation and liver fibrosis.

Triggering receptor expressed on myeloid cells-1 (TREM-1) exists in two forms: a transmembrane form and a soluble form (sTREM-1). The levels of sTREM-1 are elevated in supernatants of activated HSCs. However, the role of sTREM-1 in HSC activation and liver fibrosis remains undefined. Previous studies have primarily focused on the transmembrane form of TREM-1; we innovatively observed the function of sTREM-1 as a ligand in liver fibrosis and screened its receptor. Here, recombinant sTREM-1 was used as a stimulator which induced HSC activation and further aggravated liver fibrosis. Then, screening for sTREM-1 interacting membrane receptors was performed using pull-down assay followed by mass spectrometry, and the membrane receptor roundabout guidance receptor 2 (Robo2) was identified as a candidate receptor for sTREM-1. The interaction between sTREM-1 and Robo2 was verified by pull-down and immunofluorescence. The role of Robo2 on sTREM-1-induced HSC activation and its downstream signal pathways was assessed by knockdown of Robo2 in LX-2 cells. Furthermore, HSC-specific knockdown of Robo2 was achieved in a mouse model of liver fibrosis by using a recombinant adeno-associated virus (AAV) vector to confirm the role of the receptor, and we proved that Robo2 knockdown inhibited the activation of HSC and liver fibrosis, which also led to the inactivation of Smad2/3 and PI3K/Akt pathways in sTREM-1-induced HSC activation and liver fibrosis. In conclusion, sTREM-1 acts as a new ligand of Robo2; the binding of sTREM-1 to Robo2 initiates the activation of the downstream Smad2/3 and PI3K/Akt signalling pathways, thereby promoting HSC activation and liver fibrosis.

Advances in cirrhotic cardiomyopathy.

PURPOSE OF REVIEW: Cirrhotic cardiomyopathy (CCM) is a well-recognized entity. When patients with CCM encounter challenges such as liver transplantation, overt cardiac dysfunction manifests, leading to morbidity and mortality. Although revised diagnostic criteria for CCM have recently been proposed, these still need to be validated. RECENT FINDINGS: Previous reviews have summarized the mechanisms of CCM, such as abnormalities of the ß-adrenergic pathway, cardiac plasma membrane biophysical and biochemical properties, and electrophysiological changes. Cardiomyocyte apoptosis, inflammation, and oxidative stress also play important roles. The present review details further mechanisms of CCM, which include myosin heavy chain isoform shifts and abnormalities in cellular calcium transients. Additionally, we review recent studies on therapeutic strategies. Recent work underscores the importance of CCM in the natural history of the immediate and medium-term postoperative period after liver transplantation. Appropriate management strategies for CCM remain the area of greatest unmet need, requiring much further research. SUMMARY: CCM is a clinically relevant syndrome affecting patients with cirrhosis, leading to increased morbidity and mortality. New diagnostic criteria have been recently proposed by an expert working group. The pathogenic mechanisms remain incompletely clarified and optimal management strategies need much further study.

LR12 Promotes Liver Repair by Improving the Resolution of Inflammation and Liver Regeneration in Mice with Thioacetamide- (TAA-) Induced Acute Liver Failure.

BACKGROUND: Triggering receptor expressed on myeloid cells-1 (TREM-1) controls the mobilization of inflammatory cells in response to injury and consequently enhances liver damage. LR12 is a TREM-1 inhibitory peptide. However, the role of LR12 in acute liver failure (ALF) has remained elusive. This study was aimed at indicating whether LR12 could promote liver repair in mice with thioacetamide- (TAA-) induced ALF. METHODS: BALB/c mice were intraperitoneally injected with TAA, followed by intravenous injection of LR12. Damage and regeneration of the liver were assessed. LO2 cells and macrophages were used to assess the therapeutic effects of LR12. RESULTS: Mice treated with TAA for 24 h developed ALF, while liver inflammation was alleviated after LR12 treatment. Moreover, LR12 promoted hepatocyte regeneration in mice with TAA-induced ALF. In vitro, the supernatant from TAA+LR12-treated macrophages promoted the proliferation of LO2 cells. Cytokine protein microarray analysis suggested that LR12 promoted the secretion of C-C chemokine ligand 20 (CCL20) from macrophages. Besides, neutralization of CCL20 blocked the effects of LR12, thus inhibited the proliferation of LO2 cells in vitro, aggregated the liver inflammation, and restrained hepatocyte regeneration in ALF mice in vivo. Furthermore, we also found that LR12 activated the p38 mitogen-activated protein kinase (MAPK) pathway in hepatocytes through promoting the secretion of CCL20 from macrophages. CONCLUSIONS: LR12 could improve the resolution of inflammation and liver regeneration in mice with TAA-induced ALF by promoting the secretion of CCL20 from macrophages and activating the p38 MAPK pathway. Therefore, LR12 could be an attractive therapeutic target for the treatment of ALF.

Impaired myosin isoform shift and calcium transients contribute to cellular pathogenesis of rat cirrhotic cardiomyopathy.

BACKGROUND & AIMS: Cirrhotic cardiomyopathy is a recently recognized entity, but detailed cellular and molecular mechanisms remain unclarified. We aimed to elucidate the role of myosin heavy chain isoform shifts and their relation to calcium transients in the contractile kinetics of cirrhotic rats. METHODS: Cirrhosis was induced in male Lewis Brown-Norway rats by bile duct ligation (BDL). Myosin heavy chain (MHC) isoform distribution was evaluated by gel electrophoresis. Contractile force, Ca2+ transients and cell shortening were studied at varied frequency and extracellular [Ca2+ ]. T-tubular integrity was analysed by power spectrum analysis of images of myocytes stained with di-8-ANEPPS. RESULTS: Compared with sham controls, the phenotypes of cirrhotic rats were as follows: (a) alpha-myosin heavy chain shifted to beta-MHC isoform; (b) mild loss of T-tubular integrity in myocytes; (c) a reduced maximum and rate of rise of the Ca2+ transient (max F/Fo ); (d) a reduction in both the rate of rise and fall of contraction; (e) decreased maximal force-generating capacity; (f) loss of the inotropic effect of increased stimulus frequency; (g) unchanged sensitivity of force development to varied extracellular [Ca2+ ] and (h) increased spontaneous diastolic sarcomere length fluctuations. CONCLUSION: Cardiomyocytes and ventricular trabeculae in a cirrhotic rat model showed features of typical heart failure including systolic and diastolic prolongation, impaired force-frequency relation and decreased force-generating capacity. Impaired myosin isoform shift and calcium transients are important contributory mechanisms underlying the pathogenesis of the heart failure phenotype seen in cirrhosis.

Cirrhotic Cardiomyopathy.

PURPOSE OF REVIEW: Cirrhotic cardiomyopathy is a syndrome of depressed cardiac function in patients with cirrhosis. We aimed to review the historical background, pathophysiology and pathogenesis, diagnostic definitions, clinical relevance, and management of this syndrome. RECENT FINDINGS: An inflammatory phenotype underlies the pathogenesis: gut bacterial translocation with endotoxemia stimulates cytokines and cardiodepressant factors, such as nitric oxide and endocannabinoids. Cardiomyocyte plasma membrane biochemical and biophysical changes also play a pathogenic role. These factors lead to impaired beta-adrenergic function. Proposed new echocardiographic criteria for the diagnosis of cirrhotic cardiomyopathy include systolic global longitudinal strain and indices of diastolic dysfunction. Cardiac dysfunction participates in the pathogenesis of hepatorenal syndrome and increased morbidity/mortality of cirrhotic patients to hemorrhage, infection, and surgery, including liver transplantation. There is no specific treatment, although ß-adrenergic blockade and supportive management have been proposed, but it needs further study. Cirrhotic cardiomyopathy is a clinically relevant syndrome afflicting patients with established cirrhosis. Optimum management remains unclear, and further study is needed in this area.

Interactions Between Platelets and Inflammatory Monocytes Affect Sickness Behavior in Mice With Liver Inflammation.

BACKGROUND & AIMS: Patients with inflammatory liver disease commonly develop debilitating symptoms, called sickness behaviors, which arise via changes in brain function. Monocytes that produce tumor necrosis factor interact with cerebral endothelial cells to activate microglial cells and promote sickness behavior. Platelets regulate inflammation, and aggregates of monocytes and platelets are increased in the circulation of patients with liver disease. We investigated the role of platelets in inducing inflammatory features of circulating monocytes and promoting sickness behaviors in mice with cholestatic liver injury. METHODS: We performed bile-duct ligations or sham surgeries on C57BL/6 or toll-like receptor 4 (TLR4)-knockout mice to induce liver inflammation. Liver inflammation was also induced in a separate group of mice by administration of concanavalin A. Circulating platelets, aggregates of monocytes and platelets, and activation of microglial cells were measured by flow cytometry. To deplete platelets, mice were given anti-thrombocyte serum or normal rabbit serum (control) 4 days after surgery. Interactions between monocytes and cerebral endothelial cells were analyzed by intravital microscopy. Sickness behaviors were quantified based on time spent by adult mice engaging in social behaviors toward a juvenile mouse, compared with time spent in nonsocial behavior or remaining immobile. RESULTS: Aggregates of monocytes and platelets in circulation of mice increased significantly following bile-duct ligation. Platelet-monocyte interactions were required for activation of inflammatory monocytes and production of tumor necrosis factor. Platelet depletion greatly reduced adhesive interactions between inflammatory monocytes and adhesive interactions with cerebral endothelial cells and activation of the microglia, as well as development of sickness behavior. Furthermore, TLR4 signaling was important for aggregation of monocytes and platelets, and development of sickness behavior following bile-duct ligation. These findings were confirmed in mice with concanavalin A-induced liver injury. CONCLUSIONS: In mice with liver inflammation, we found TLR4 and aggregates of monocytes and platelets to regulate microglial activation and development of sickness behavior. These findings might lead to new therapeutic strategies for liver disease-associated symptoms.

A Dynamic Model for Predicting Outcome in Patients with HBV Related Acute-On-Chronic Liver Failure.

INTRODUCTION AND AIM: Accurately predicting the prognosis of individual patient is crucial in the management of ACLF. We aimed to establish a specific prognostic model for HBV-related ACLF patients treated with nucleoside analog (NA). MATERIAL AND METHODS: We prospectively collected 205 ACLF cases diagnosed according to the APASL criteria. A dynamic prognostic model based on APASL criteria was established and validated. To demonstrate that the model is also applicable to those within EASL criteria, we divided the patients into two groups: met APASL criteria only (group A, n = 123); met both APASL and EASL criteria (group B, n = 82). Its prognostic accuracy was also compared with chronic liver failure-sequential organ failure assessment (CLIF-SOFA) score in group B. RESULTS: The model is: R = 0.94 x Bilirubin + 0.53 x evolution of Bilirubin - 0.45 x PT-A - 0.22 x evolution in PT-A -0.1 x PLT + 10 x anti-HBe. The area under receiver operating characteristic curve (AUC) of the model for predicting 90-day mortality was 0.86, which was significantly higher than that of model for end stage liver disease(MELD), MELD-Na, CLIF-SOFA, ΔMELD (7d) and ΔMELD-Na (7d), ΔCLIF- SOFA(7d) (all p < 0.01). The AUC of our model in the validation group was 0.79 which was superior to MELD (0.45) CLIF-SOFA (0.53) score in group B patients (p < 0.01). CONCLUSION: In conclusion, the model was superior to the conventional methods in predicting the outcomes of patients with HBV related ACLF treated with NA. It is the first description of a novel prognostic model using consecutive data in patients with HBV-induced acute-on-chronic liver failure (ACLF) treated by nucleoside analogs.

Cirrhotic cardiomyopathy: Implications for liver transplantation.

The majority of patients on a waiting list for liver transplantation have end-stage liver disease. Because of the marked peripheral vasodilatation of end-stage cirrhosis that masks a latent myocardial dysfunction, cardiac abnormalities in the resting state are usually subclinical and escape the attention of physicians. However, when challenged, the systolic and diastolic contractile responses are attenuated. In addition to these contractile abnormalities, morphological changes, such as enlargement or hypertrophy of cardiac chambers, and electrophysiological repolarization changes, including a prolonged QT interval, can be observed. The constellation of these cardiac abnormalities is termed cirrhotic cardiomyopathy. Liver transplantation induces significant cardiovascular stress. Clamping of the inferior vena cava and portal vein, hemorrhage and blood/volume infusion, and ischemia/reperfusion all cause hemodynamic fluctuation. The changing cardiac preload and afterload status increases the cardiac workload, and thus, the previously subclinical ventricular dysfunction may manifest as overt heart failure during the operative and perioperative periods. Cardiac dysfunction contributes to morbidity and mortality associated with liver transplantation. Cardiovascular events are the third leading cause of death in liver recipients. However, because liver transplantation is the only definitive treatment for end-stage liver failure and also appears to reverse cardiac abnormalities, it is important to understand the challenges of the heart in liver transplantation. This review focuses on cardiac status before, during, and after liver transplantation. Liver Transplantation 23 826-835 2017 AASLD.

Blunted cardiac response to hemorrhage in cirrhotic rats is mediated by local macrophage-released endocannabinoids.

BACKGROUND & AIMS: Cirrhosis is associated with blunted cardiovascular response to stimuli such as hemorrhage, but the mechanism remains unclear. We aimed to clarify the role of endocannabinoids in blunted hemorrhage response in cirrhotic rats. METHODS: Cirrhosis was induced by bile duct ligation (BDL). Hemodynamics were measured. Cannabinoid receptor-1 (CB1) antagonist, AM251, and macrophage inhibitor gadolinium chloride (GdCl3) were administered. Myocardial levels of anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) were measured and resident monocytes and macrophages quantified by immunohistochemistry. Isolated cardiomyocyte contractility was measured before and after incubation with monocytes from BDL and sham controls. RESULTS: Hemorrhage significantly decreased arterial pressure and left ventricular dP/dT. After hemorrhage, these changes quickly reversed in controls, but were severely prolonged in BDL rats. Chronic AM251 treatment restored this impaired response. AEA and 2-AG levels were increased in BDL hearts and further increased after hemorrhage. Sham hearts showed virtually no monocytes or macrophages before or after hemorrhage, whereas BDL hearts had significantly more white blood cells which further increased after hemorrhage. GdCl3 treatment significantly reduced cardiac endocannabinoid levels both at baseline and after hemorrhage. This treatment also restored cardiovascular response to hemorrhage in BDL rats but did not affect sham controls. Monocytes isolated from BDL rats more potently inhibited cardiomyocyte contractility than sham control monocytes. CONCLUSIONS: The cirrhotic heart showed increased monocyte recruitment and endocannabinoid levels. CB1 blockade or GdCl3 treatment restored blunted cardiovascular response to hemorrhage. Endocannabinoids released by monocytes blunt cardiac response to hemorrhage. Preventing monocyte recruitment or blocking endocannabinoid signaling may improve cardiovascular homeostasis in cirrhosis.

Cardiomyocyte apoptosis contributes to pathogenesis of cirrhotic cardiomyopathy in bile duct-ligated mice.

Cirrhotic cardiomyopathy is defined as systolic and diastolic dysfunctions, electrophysiological changes and macroscopic structural changes. However, the underlying mechanisms of this syndrome remain unclear. A possible role of myocardial apoptosis in the pathogenesis has not been previously examined. We hypothesized that dysregulation of apoptotic signalling participates in cardiac dysfunction in the cirrhotic heart. Therefore, we evaluated apoptotic pathways in the hearts of mice with chronic BDL (bile duct ligation). A cirrhotic cardiomyopathy model was induced by BDL in mice. Left ventricular geometry and volumes were evaluated by MRI. Intrinsic and extrinsic apoptotic pathways were evaluated by immunohistochemical staining and Western blot analysis. Fas-mediated apoptosis was inhibited by in vivo administration of an anti-FasL (Fas ligand) monoclonal antibody, and subsequently cardiac contractility was measured in isolated cardiomyocytes. BDL-mice showed significantly more PARP [poly(ADP-ribose) polymerase] staining than sham controls (18.2±11.4 compared with 6.7±5.3; P<0.05). Fas protein expression and PARP cleavage were activated, whereas FLIP (Fas-associated death domain-like interleukin 1ß-converting enzyme-inhibitory protein) was decreased compared with sham controls. The Bcl-2/Bax ratio was increased in BDL-mice compared with sham controls. Anti-FasL monoclonal antibody injection in BDL-mice improved systolic and diastolic dysfunctions in cardiomyocytes, but had no effect in sham controls. A net pro-apoptotic balance exists in BDL hearts, mainly mediated by activation of the extrinsic pathway, and abrogation of apoptosis improved contractility. These results suggest that apoptosis contributes to depressed cardiac contractility in a murine model of cirrhotic cardiomyopathy.

Second-Line Treatment after Failure of Immune Checkpoint Inhibitors in Hepatocellular Carcinoma: Tyrosine Kinase Inhibitor, Retrial of Immunotherapy, or Locoregional Therapy?

Background: Immune checkpoint inhibitor (ICI)-based therapy such as atezolizumab plus bevacizumab or durvalumab plus tremelimumab became mainstream first-line systemic treatment in advanced hepatocellular carcinoma (HCC) patients since remarkably superior efficacy of ICI-based therapy compared to tyrosine kinase inhibitors (TKIs) was reported in two recent randomized controlled trials (RCTs) (IMbrave150, HIMALAYA). However, the optimal second-line therapy after treatment failure of first-line ICI-based therapy remains unknown as no RCT has examined this issue. Summary: Therefore, at present, most clinicians are empirically treating patients with TKIs or retrial of ICI or locoregional treatment (LRT) modality such as transarterial therapy, radiofrequency ablation, and radiation therapy in this clinical setting without solid evidence. In this review, we will discuss current optimal strategies for second-line treatment after the failure of first-line ICI-based therapy by reviewing published studies and ongoing prospective trials. Key Messages: Clinicians should consider carefully whether to treat the patients with TKI, other ICI-based therapy, or LRT in this situation by considering several factors including liver function reserve, performance status, adverse events of previous therapy, and presence of lesion that can consider LRT such as oligoprogression and vascular invasion. In the meantime, we await the results of ongoing prospective trials to elucidate the best management options.

Cardiomyopathy in cirrhosis: From pathophysiology to clinical care.

Cirrhotic cardiomyopathy (CCM) is defined as systolic or diastolic dysfunction in the absence of prior heart disease or another identifiable cause in patients with cirrhosis, in whom it is an important determinant of outcome. Its underlying pathogenic/pathophysiological mechanisms are rooted in two distinct pathways: 1) factors associated with portal hypertension, hyperdynamic circulation, gut bacterial/endotoxin translocation and the resultant inflammatory phenotype; 2) hepatocellular insufficiency with altered synthesis or metabolism of substances such as proteins, lipids, carbohydrates, bile acids and hormones. Different criteria have been proposed to diagnose CCM; the first in 2005 by the World Congress of Gastroenterology, and more recently in 2019 by the Cirrhotic Cardiomyopathy Consortium. These criteria mainly utilised echocardiographic evaluation, with the latter refining the evaluation of diastolic function and integrating global longitudinal strain into the evaluation of systolic function, an important addition since the haemodynamic changes that occur in advanced cirrhosis may lead to overestimation of systolic function by left ventricular ejection fraction. Advances in cardiac imaging, such as cardiac magnetic resonance imaging and the incorporation of an exercise challenge, may help further refine the diagnosis of CCM. Over recent years, CCM has been shown to contribute to increased mortality and morbidity after major interventions, such as liver transplantation and transjugular intrahepatic portosystemic shunt insertion, and to play a pathophysiologic role in the genesis of hepatorenal syndrome. In this review, we discuss the pathogenesis/pathophysiology of CCM, its clinical implications, and the role of cardiac imaging modalities including MRI. We also compare diagnostic criteria and review the potential diagnostic role of electrocardiographic QT prolongation. At present, no definitive medical therapy exists, but some promising potential treatment strategies for CCM are reviewed.

Clinical outcomes of esophageal squamous cell carcinoma in patients with cirrhosis.

Purpose: Alcohol consumption is a strong risk factor for both cirrhosis and esophageal squamous cell carcinoma (ESCC). Few studies have been conducted on the treatment of ESCC in patients with cirrhosis. This study aimed to analyze the clinical outcomes of ESCC in patients with cirrhosis. Materials and methods: Medical records of patients with esophageal cancer between January 2009 and December 2023 were retrospectively reviewed. A total of 479 patients with ESCC were included and divided into cirrhotic (n = 69) and non-cirrhotic (n = 410) groups. Clinical outcomes and survival according to treatment were compared between these groups. Results: The cirrhotic group was younger (median age 64 years vs. 69 years, p = 0.022) and had a higher proportion of male (97.1 % vs. 88.3 %, p = 0.042) than the non-cirrhotic group. Patients with cirrhosis were less likely to undergo surgery (31.9 % vs. 47.8 %, p = 0.015) and were more likely to receive no active cancer treatment (26.1 % vs. 13.7 %, p = 0.010). Overall survival was lower in the cirrhotic group (hazard ratio [HR], 1.41; 95 % confidence interval [CI], 1.01-1.99; p = 0.045), however, no difference was found between Child-Pugh class A patients and those in the non-cirrhotic group (HR, 1.04 [95 % CI, 0.69-1.56]; p = 0.864). Postoperative mortality was significantly higher in cirrhotic group (27.3 % vs. 8.7 %, p = 0.011). Upon performing concurrent chemoradiotherapy (CRT), the clinical complete response rate (84.2 % vs. 43.3 %, p = 0.004) was better in the cirrhotic group. CRT yielded better overall survival for patients with cancer in the resectable stages in the cirrhotic group compared to surgery (HR, 0.19 [95 % CI, 0.42-0.84]; p = 0.029]. Conclusions: In patient with ESCC and cirrhosis, chemoradiotherapy may be a better treatment option than surgery.