A high level of secreted phosphoprotein 1 is associated with macrophage infiltration and poor prognosis in hepatocellular carcinoma

Background and aims:Secreted phosphoprotein 1(SPP1)functions in several physiological processes.The role of SPP1 expression in the prognosis and tumor immunity of hepatocellular carcinoma(HCC)is unknown.The aim of this study was to investigate the expression pattern of SPP1 in HCC and its correlation with prognosis and tumor immunity.Methods:Clinical and gene expression data of The Cancer Genome Atlas-liver hepatocellular carcinoma(LIHC)cohort and 11 other HCC datasets were collected.The Kaplan–Meier method and Cox regression analysis were used to analyze the prognostic value of SPP1.The DESeq2 package in R was used to analyze SPP1-related genes.Gene Ontology analysis and gene set enrichment analysis were used to determine the biological function of SPP1 in HCC.The single sample Gene Set Enrichment Analysis(ssGSEA)method was used to analyze the immune infiltrates of HCC.Illumina human methylation 450 data and level 3 HTSeq-FPKM data from The Cancer Genome Atlas-LIHC were used to analyze the effects of DNA methylation level on SPP1 expression.Results:SPP1 was overexpressed in HCC and correlated with T stage,histological grade,adjacent hepatic tissue inflammation,and vascular invasion in HCC.The analysis of survival rates indicated that high SPP1 levels were associated with poor overall survival in HCC.Functional analysis showed that SPP1 is related to tumor immunity,especially macrophage infiltration.Aberrant demethylation of the promoter region is one of the mechanisms underlying the increase of SPP1 in HCC.Conclusion:Our results indicate that SPP1 is an independent prognostic factor for HCC and is correlated with the clinical features and macrophage infiltration in HCC.

More precise measurement of irregular splenic volume in cirrhotic patients with portal hypertension

Background and aims:Splenomegaly often occurs in cirrhotic patients with portal hypertension(PHT),and therefore,the efficacy and accuracy of conventional methods for measuring splenic volume are a matter of question in these patients.Here,we developed a novel approach to assess true splenic volume more precisely.Methods:High-quality thin-slice computed tomography data of 112 cirrhotic patients with PHT were obtained and reviewed.Both the conventional measurement and a novel formula obtained from 3-dimensional reconstruction software were used to estimate splenic volume,and the accuracy was compared and verified.Results:In PHT patients,the splenic volume calculated using the conventional method was significantly less than that calculated using the 3-dimensional software.We found that the splenic volume was significantly positively correlated with splenic indices of length(L),thickness(T),and width(W)and also the diameter of the splenic vein.Using these indices,we propose 2 novel formulas using the software to estimate the splenic volume more accurately:SV=69.686 L+53.077 W+103.525 T+314.510 diameter of splenic vein 2266.209(p<0.01,R^(2)=0.805).And a more practical simplified formula:SV'=0.504× L× W×T+319.762 diameter of splenic vein 81.66(p<0.01,R^(2)=0.784).Conclusion:Although the conventional formula has been widely used for years,it is not suitable for an enlarged spleen.We developed 2 novel formulas for estimating splenic volume from clinical data that were more appropriate for cirrhotic patients with PHT.

Visual analysis of mesenchymal stem cell research in liver disease based on bibliometrics

The research of mesenchymal stem cells(MSCs)in the field of liver diseases has received more and more attention.This paper introduces the current situation,hot spots,and development trends in this field.Compre-hensive searches were conducted using Web of Science Core Collection from January 1,2000 to December 13,2021 with the following keywords:TS(topic)¼(liver*OR hepatic*OR hepatocyte)AND TS(topic)¼(Mesen-chymal stem cell*).VOSviewer(version 1.6.16)and CiteSpace V are used as bibliometric tools to analyze and visualize the knowledge graph.A total of 4452 papers were included in this study,and the number of research papers on MSCs in the field of liver diseases increased from January 2000 to December 2020.Eighty-four countries and regions have published articles on research in this field,among which China and the United States are the main two countries of publication.Based on the keyword burst detection,we find that the research in this field has shifted from basic research to clinical application,from medical research to interdisciplinary research.Tissue engineering and regenerative medicine are the frontier fields of MSCs research in liver diseases.Multicountry,multi-author cooperation,and multi-disciplinary intersection are the research trends in this field.Exocrine body,obesity,and tissue engineering are the hotspots in this field.

The pathophysiological mechanism between hypopituitarism and nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease(NAFLD)is a common chronic metabolic liver disease worldwide.It is closely related to diseases of the cardiovascular system and chronic kidney disease.It can also occur secondary to many other diseases.Current research shows that patients with hypopituitarism have a high risk of developing NAFLD.After the adenohypophysis is dominated by hypothalamic hormones,hormones are secreted to act on the corresponding tissues or organs.It is characterized by a decrease in the thyroid hormone,cortisol,and growth hormone levels.In this review,we analyzed the mechanisms related to NAFLD through thyroid secretion,growth hormone secretion,sex hormone,and prolactin axes in patients with hypopituitarism,which will provide information and a theoretical basis for clinical diagnosis and treatment.

Targeting hepatocellular carcinoma growth and metabolism:A synergistic approach with para-toluenesulfonamide and radiofrequency ablation

Background and aims:Hepatocellular carcinoma(HCC)is one of the most prevalent and lethal forms of cancer,posing challenges to standard treatment methods.Radiofrequency ablation(RFA)has emerged as a valuable technique for the local control of advanced HCC,especially in cases unsuitable for surgical resection.Paratoluenesulfonamide(PTS)has demonstrated antitumor properties in various cancers,yet its efficacy against HCC remains underexplored.The present study aims to investigate the therapeutic potential of PTS in HCC and examine potential synergistic effects with RFA.Methods:PTS was injected directly into subcutaneous tumor tissues and its effects on cell survival,gene expression,and metabolic activity in HCC cells were evaluated.The effect of PTS and RFA in combination on HCC growth was examined using a nude mouse model of subcutaneous HCC.Data were visualized using heat maps.Results:PTS inhibited the survival of HCC cells in a dose-dependent manner,modulating the expression of key genes related to cell survival,apoptosis,epithelial–mesenchymal transition,and proliferation.The combination of PTS and RFA markedly enhanced the inhibition of HCC tumor growth and induced alterations in cellular metabolism.Conclusion:Combining PTS and RFA may be a promising approach to improve the efficacy of HCC treatment.

Diagnostic performance comparisons of two commonly used multi-biomarker-based scores for detection of hepatocellular carcinoma in non-alcoholic fatty liver disease

Background and aims:The ASAP and GALAD scores are widely used diagnostic models for detecting hepatocellular carcinoma(HCC),incorporating factors such as sex,age,alpha-fetoprotein(AFP),protein induced by vitamin K absence or antagonist-Ⅱ(PIVKA-Ⅱ),and lens culinaris agglutinin-reactive fraction of AFP(AFP-L3%).This study compares the diagnostic efficacy of the ASAP and GALAD scores in the early detection of HCC in patients with non-alcoholic fatty liver disease(NAFLD).Methods:NAFLD patients with and without HCC were recruited from 12 Chinese tertiary hospitals.Serum levels of AFP,PIVKA-II,and AFP-L3%were measured.The diagnostic accuracy of individual biomarkers,the ASAP score,and the GALAD score in detecting NAFLD-HCC at various stages was evaluated using receiver operating characteristic(ROC)curves and area under the curve(AUC)values.Results:In a cohort of 147 NAFLD-HCC cases and 460 NAFLD controls,both the ASAP and GALAD scores outperformed individual biomarkers in detecting NAFLD-HCC.The ASAP score demonstrated a high AUC of 0.910(sensitivity:80.3%,specificity:92.8%)for identifying NAFLD-HCC at all stages,surpassing AFP(AUC:0.716,P<0.001),PIVKA-II(AUC:0.849,P<0.001),AFP-L3%(AUC:0.663,P<0.001),and the GALAD score(AUC:0.882,P?0.014).Comparable results were observed for early-stage NAFLD-HCC and for detecting HCC in NAFLD patients with or without cirrhosis.Conclusion:The ASAP score,which excludes the AFP-L3%indicator,demonstrated superior performance in differentiating NAFLD-HCC compared to the GALAD score,suggesting its potential for early screening of HCC in NAFLD patients.

Precise cell therapy for liver fibrosis: Endothelial cell and macrophage therapy

Liver fibrosis is typically caused by chronic viral hepatitis and,more recently,fatty liver disease associated with obesity.There are currently no approved drugs for liver cirrhosis,and liver transplantation is limited by donor scarcity,thus driving the investigation of novel therapeutic strategies.The development of liver fibrosis presents with stage-and zone-dependent characteristics that manifest as distinct dynamic changes during vascularization and extracellular matrix(ECM)deposition.However,current cellular therapies do not consider the spatiotem-poral variations of liver fibrosis without identifying the precise location and stage to administer the intervention to achieve optimal therapeutic effects.Herein,we focus on endothelial cell(EC)and macrophage therapy for liver fibrosis because of their important roles in regulating the spatiotemporal changes of vascularization and ECM deposition during liver fibrosis progression.Overall,this review summarizes the stage-dependent EC and macrophage therapy for liver fibrosis,elucidates their respective mechanisms,and exemplifies potential strategies to realize precise cell therapy by targeting specific liver zones.

MAFLD was more easily diagnosed than NAFLD in liver transplant recipients with abnormal liver function

Background and aims:Nonalcoholic fatty liver disease(NAFLD)is hepatic steatosis that is require the exclusion of certain etiologies,including drug usage or alcoholic consumption.Conversely,metabolic dysfunction-associated fatty liver disease(MAFLD)needs not to.In this study,we aimed to examine whether MAFLD is more easily diagnosed than NAFLD in liver transplant(LT)recipients with abnormal liver function.Methods:In this cross-sectional study,LT recipients with abnormal liver function were investigated for the prevalence of MAFLD and NAFLD.Results:We recruited 57 LT recipients with abnormal liver function at a referral hospital.Among these patients,the prevalence of MAFLD and NAFLD was 37.8%and 11.1%,respectively.17 patients showed hepatic steatosis,with an average NAFLD activity score of 3.5 and a fibrosis score of 1.0.Compared with non-MAFLD patients,MAFLD patients had a significant difference in fasting blood glucose levels(p?0.009).Among 17 MAFLD patients,12 were overweight and four were diagnosed with diabetes mellitus.The majority of MAFLD diagnoses were based on body mass index(70.6%)and diabetes mellitus history(23.5%),biomarkers that are easily obtained.At 6,12,24,and 36 months after LT,MAFLD patients had higher levels of fasting blood glucose(6 months:p?0.004,12 months:p?0.038)and higher trend of body mass index value and plasma triglyceride level but no significance.Conclusions:MAFLD was more easily diagnosed in LT recipients with abnormal liver function and higher in prevalence than NAFLD.A larger sample size research is required to validate these conclusions.

Systematic treatment in unresectable hepatocellular carcinoma:The most concerns

The most frequent causes of hepatocellular carcinoma(HCC)are chronic infection with hepatitis B or C virus,alcoholic liver disease,and fatty liver disease[1].The molecular pathological heterogeneity of HCC is obvious,which may be the main reason for the great difference in efficacy of different patients after receiving systematic therapy.

Free fatty acid-induced miR-22 inhibits gluconeogenesis via SIRT-1-mediated PGC-1α expression in nonalcoholic fatty liver disease

Background and aims:Free fatty acids(FFAs)are one of the important regulators of the progression of nonalcoholic fatty liver disease.The FFAs are shown to modulate the metabolic status of the liver by modulating several cellular pathways in hepatocytes.Here,we elucidated the role of miR-22 in modulating FFAs-mediated gluconeogenesis.Methods:Huh7 and WRL68 cells were transfected with nonspecific miRNA,miR-22 premiRs or anti-miR-22 oligos followed by incubation with palmitic acid,oleic acid,and linoleic acid(300μM each)for 48 and 72 h after transfection.The expression of miR-22 was performed using real-time polymerase chain reaction and Western blots were performed for SIRT-1,PGC-1α,PEPCK,and glucose-6-phosphatase.Three groups of C57BL/6 mice(6 mice per group)were fed with standard diet,choline sufficient L-amino acid defined diet or choline-deficient L-amino acid defined(CDAA)diet for 6,18,32,or 54 weeks.Triglycerides content was measured in the serum.Expression of miR-22 and the protein expression of gluconeogenic enzymes were analyzed in the tissue samples.Results:Incubation of miR-22-transfected cells with FFAs inhibited the expression of SIRT-1,PGC-1α,PEPCK,and glucose-6-phosphatase,while miR-22 expression was increased.These changes were reversed when the cells were transfected with anti-miR-22 oligos.CDAA-fed mice showed the significant increase in triglycerides content and miR-22 expression,while there was an inhibition of SIRT-1,PGC-1α,PEPCK,and glucose-6-phosphatase expression in CDAA-fed mice.

The transjugular intrahepatic portosystemic shunt: Smaller stent diameters are required to optimize pressure response

Background and aims:The present treatment goal of the transjugular intrahepatic portosystemic shunt(TIPS)is a portosystemic pressure gradient of
12 mmHg or its reduction by>50%.This study relates the stent diameter to the reduction of the pressure gradient and attempts to predict the appropriate stent diameter necessary to reach the treatment goal.Methods:Pressure response,super response,and poor response were investigated in 208 de-novo TIPS patients and defined as post-TIPS gradients between>6 and 12 mmHg,
6 mmHg,or not reaching the goal(>12 mmHg,reduction<50%),respectively.Pressures were related to the smallest stent diameters measured by planimetry of the radiographic image.Results:Responders(65%),super responders(26%),or poor responders(9%)had comparable stent diameters of 7.21.0 mm,but different post-TIPS gradients(9.71.9 mmHg,4.51.5 mmHg,and 14.21.4 mmHg,p<0.001),relative reduction of pre-TIPS gradients(51.711.4%,73.611.1%,and 34.09.1%,p<0.001),and specific reduction per mm of stent diameter(7.52.0%/mm,10.12.0%/mm,and 4.81.4%/mm,p<0.001).Prediction of the stent diameter required to reach response was not possible.Only two super responders had a stent diameter of<6 mm.Super and poor responders differed by the increase in the right atrial pressure(+5.0 mmHg vs.+3.1 mmHg,p=0.026)and reduction in the portal vein pressure(-8.6 mmHg vs.-4.6 mmHg,p<0.001).Conclusion:Most patients reached the treatment goal with stent diameters of<8 mm.Overtreatment(super response,gradient ≤6 mmHg)can be prevented by stent diameters as small as 6 mm.The individual response was not related to the stent diameter and not predictable.Cardiac dysfunction may play an important role by its effect on the right atrial(preload)and portal pressure(afterload).

Advanced therapies for congenital biliary tract malformation:From bench to bedside

Congenital biliary tract malformations are a series of rare but extremely serious diseases that mainly include biliary atresia and biliary hypoplasia(referred to as Alagille syndrome).The rapid progression of biliary atresia and Alagille syndrome results in jaundice,cholestatic liver disease,cirrhosis,and even liver failure.In most cases,supportive or clinically specific therapies cannot achieve satisfactory outcomes.Therefore,liver transplantation(especially living donor liver transplantation)may be required.As many studies have elucidated the role of genetic factors and the molecular mechanism of congenital biliary tract malformations,experimental therapies such as organoid transplantation,cell therapy,and immunotherapy have been proved to be feasible.These advanced methods have shown outstanding advantages,particularly in patients with end-stage biliary tract malformations,surgery failure,and other problems that cannot be solved by conventional therapies.This review article discusses the potential pathogenesis of and promising therapeutic strategies for biliary tract malformations.

Clinical characteristics of hepatopulmonary syndrome and hepatorenal syndrome and associated therapeutic potential of transjugular intrahepatic portosystemic shunt

Hepatorenal syndrome(HRS)and hepatopulmonary syndrome(HPS)are two serious complications of liver disease,causing damage not only to the liver but also to the kidneys,lungs,and heart.HRS and HPS affect the patient's circulatory and respiratory systems,with poor prognosis and high mortality in clinical practice.There is a lack of effective treatment other than liver transplantation.Transjugular intrahepatic portosystemic shunt(TIPS)is an effective tool to prolong the survival of patients with advanced liver disease and is mainly used to treat portal hypertension and ascites because it can effectively reduce portal pressure.Studies on the treatment of both of these complications with TIPS are limited and deserve further study because the therapeutic effects of TIPS have the potential to improve the prognosis of severe liver disease.This article reviews the clinical features of HRS and HPS,the consequences of these syndromes,and the potential mechanistic effects after TIPS intervention.

Exploratory study of microparticle transcatheter arterial chemoembolization combined with resection for huge hepatocellular carcinoma

Objective:To investigate the safety and clinical efficacy of microparticle transcatheter arterial chemoembolization(mTACE)combined with surgical resection for the treatment of huge hepatocellular carcinoma(hHCC;
10 cm).Methods:A retrospective descriptive study was conducted to gather the clinical data of nine patients with hHCCs treated with mTACE combined with resection in Beijing Tsinghua Changgung Hospital from December 2016 to July 2020.The outcome were as follows:(1)the excellent effect and adverse reactions of mTACE and(2)the efficacy and safety of perioperative resection.Count data were expressed as absolute numbers and percentages.The measurement data of the normal distribution is represented by XS,and the measurement data of the skewed distribution are represented by M(range).A paired t-test was used to compare the data of the same patient.p values<0.05 are considered statistically significant.Results:(1)Regarding the efficacy and safety of mTACE,all nine hHCCs were treated with mTACE one time.The tumor necrosis rate after particle TACE was(77.615.7)%(51.7%–100%);according to the modified response evaluation criteria in solid tumors,the objective response was partial response in eight patients and complete response in one patient.The alpha fetoprotein(AFP)level was abnormal in six cases(>20 ng/mL),of which three cases exceeded the maximum value(>30,000 ng/mL)pre-mTACE.In six patients with abnormal AFP levels,the AFP level decreased in five patients,with a median percentage of 74.5%(35.2%–96.0%).The PIVKA-II level in nine patients was>40 mAU/mL before mTACE and decreased to varying degrees after mTACE.The median percentage of decline was 76.0%(4.5%–99.8%).The maximum diameter of the tumor decreased from(13.91.9)cm(11.0–16.4 cm)to(12.81.9)cm(10.4–15.6 cm)(P?0.001)before surgical resection.Prior to the surgical resection,the tumor volume decreased from(897244)mL(436–1250 mL)to(750291)mL(260–1130 mL)(P?0.001),and the residual liver volume/standard liver volume increased from(42.812.8)%(25.8%–61.3%)to(50.214.9)%(28.8%–67.4%)(P?0.008).All patients had embolism syndrome such as fever and abdominal pain in varying degrees,and no serious complications such as liver abscess,liver and kidney failure,or ectopic embolism were noted.(2)For perioperative efficacy and safety,all lesions were successfully resected in(3111)days(14–48 days)after mTACE.The operation time was(39579)min(296–540 min),and the amount of intraoperative bleeding was(433158)mL(200–600 mL).Complications such as biliary fistula,abdominal bleeding,liver and kidney failure,or abdominal infection were not found.The postoperative hospital stay was(134)days(9–19 days).No tumor invasion was found at the cutting edge,and hepatic vein invasion was observed in one case.(3)The follow-up ended in November 2021,with a median follow-up of 34 months(16–46 months).Recurrence or distant metastasis occurred in four patients,of which two patients died.The survival times were 18 and 31 months,respectively.The other two patients were followed up for 34 and 41 months.The remaining five patients were followed up for 16–46 months without antitumor treatment or disease progression.Conclusions:mTACE combined with tumor resection is feasible for the treatment of patients with hHCC,which needs to be further confirmed by prospective studies.

Intrahepatic cholestasis of pregnancy is associated with increased risk of hepatobiliary disease and adverse fetal outcomes: A systematic review and meta-analysis

Background and aims:The aim of this study was to review the literature and perform a meta-analysis to clarify the association between intrahepatic cholestasis of pregnancy and risks of long-term maternal hepatobiliary disease as well as adverse fetal outcomes including preterm birth,meconium-stained amniotic fluid,and stillbirth.Methods:This systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.A comprehensive literature search was performed using Cochrane,Embase,and PubMed databases to identify observational or cohort studies comparing pregnant women with intrahepatic cholestasis of pregnancy(ICP)to pregnant women without ICP.Data from the included studies were analyzed using the Review Manager 5.4.1 software.Results:The meta-analysis showed a significant association between ICP and the risk of hepatobiliary diseases(pooled risk ratio[RR]:2.81,95%confidence interval[CI]:2.66–2.97,p<0.00001),hepatitis C(HC):a significant association between ICP and risk of HC(pooled RR:4.02,95%CI:3.12–5.19,p<0.00001),meconium-stained amniotic fluid(MSAF):ICP was significantly associated with an increased risk of MSAF(pooled RR:1.91,95%CI:1.65–2.21,p<0.00001),and preterm birth:the meta-analysis demonstrated a significant association between ICP and preterm birth(pooled RR:2.11,95%CI:2.01–2.21,p<0.00001).Conclusion:ICP demonstrated statistically significant associations with increased risks of hepatobiliary disease,HC,MSAF,and preterm birth.

Anatomical hepatectomy for achieving textbook outcome for perihilar cholangiocarcinoma treated with curative-intent resection: A multicenter study

Background and aim:The textbook outcome(TO)is a comprehensive measure that is superior to individual measures for analysis of surgical quality of care.Anatomical hepatectomy(AH)is beneficial in terms of short-term outcomes in patients undergoing resection.This study was performed to investigate the association between AH and achieving the TO for patients with perihilar cholangiocarcinoma(pCCA)treated with curative-intent resection.Methods:This study involved patients who underwent curative-intent resection for newly diagnosed pCCA from January 2013 to January 2018 at three hospitals in China.All patients were divided into two groups according to the type of hepatectomy:the AH group and non-AH group.The incidence and distribution of achieving the TO were compared between the two groups.Univariable and multivariable logistic regression analyses were used to identify independently predictive factors associated with achieving the TO in patients with pCCA.Results:In total,333 patients were enrolled[AH group,225(67.6%);non-AH group,108(32.4%)].The incidence of achieving the TO in all patients was 24.3%,and the incidence was significantly higher in the AH than non-AH group(30.7%vs.11.1%,respectively).Multivariable analysis revealed that AH,total bilirubin concentration of<34μmol/L,maximum tumor size of<3 cm,no macrovascular invasion,and no lymph node metastasis were independently associated with a higher incidence of achieving the TO.Conclusions:The TO was achieved in approximately one-fourth of patients with pCCA who underwent curative-intent resection.The use of AH was more conducive to achieving the TO in patients with pCCA.

Artificial intelligence-based pathological analysis of liver cancer:Current advancements and interpretative strategies

In recent years,significant advances have been achieved in liver cancer management with the development of artificial intelligence(AI).AI-based pathological analysis can extract crucial information from whole slide images to assist clinicians in all aspects from diagnosis to prognosis and molecular profiling.However,AI techniques have a“black box”nature,which means that interpretability is of utmost importance because it is key to ensuring the reliability of the methods and building trust among clinicians for actual clinical implementation.In this paper,we provide an overview of current technical advancements in the AI-based pathological analysis of liver cancer,and delve into the strategies used in recent studies to unravel the“black box”of AI's decision-making process.

HCC case management-related challenges:Think outside the box!

To the Editor,Hepatocellular carcinoma(HCC)is a common primary liver malig-nancy that mainly occurs in chronic liver disease patients with under-lying cirrhosis.HCC incidence has increased globally in the last two decades.The incidence is expected to increase until 2030 in certain geographical regions,namely Asia and Africa.This increase is owing to the high endemic prevalence of viral etiologies(i.e.,hepatitis virus B/C(HBV/HCV))that result in chronic liver disease and HCC.

Anxiety and depression in older adult patients undergoing elective liver surgery in allopatry medical treatment

Background:Allopatry medical treatment is common in China.However,allopatry medical therapy can result in many problems,including a negative psychological impact on patients.Patients undergoing liver surgery often experience anxiety and depression.To understand the psychological status of older adult patients undergoing surgery better,this study was designed to investigate the incidence of anxiety and depression in older adult patients undergoing elective liver surgery and to analyze factors associated with it in allopatry medical therapy.Methods:A total of 173 older adult patients undergoing elective liver surgery were included in the study.Patients were evaluated using the hospital anxiety and depression scale(HADS).The contributing factors affecting the psychological state of older adult patients undergoing elective surgery were analyzed using a linear regression method.Results:The HADS-A(hospital anxiety and depression scale-anxiety).The correlation(scale)score of the older adult patients undergoing elective liver surgery was(8.69
2.38),including 53 asymptomatic patients,86 suspicious patients,and 34 symptomatic patients.The HADS-D(hospital anxiety and depression scale-depression)score was(8.31
2.90),including 83 asymptomatic patients,56 suspicious patients,and 34 symptomatic patients.Multivariate analysis showed that residence and complication grade(Clavien–Dindo Classification of Surgical Complications or Accordion Severity Grading System)significantly correlated with the anxiety level of patients undergoing elective surgery.Residence,a requirement of blood transfusion,total transfusion volume,and Accordion complication grade showed a significant correlation with depression in patients undergoing elective surgery.Conclusions:Anxiety and depression in older adult patients undergoing elective liver surgery were common.Regional differences(local patients vs non local patients)and the severity of complications were the risk factors for anxiety and depression in older adult patients undergoing elective liver surgery.Reducing both regional differences and the severity of complications would be beneficial to alleviate the risk of anxiety and depression in older adult patients undergoing elective liver surgery and thus promote their physical and mental health.

Tumor-immune Co-evolution in hepatocellular carcinoma and itsimplication for immunotherapy resistance

1.Introduction In recent years,investigators have witnessed great progress in understanding the tumor microenvironment(TME)and evolution,which has been accompanied by a substantial number of newly developed targeted therapies and immunotherapies.Tumors are capable of escaping immune surveillance in the context of both spontaneous immune response and immunotherapies,and these two immune evasion processes share many overlapping mechanisms,such as human leukocyte antigen loss of heterozygosity(HLA-LOH)and immunoediting[1].For hepatocellular carcinoma(HCC),numerous treatment strategies targeting the TME have been proposed in recent years[2,3].Among these strategies,immune-checkpoint inhibitors(ICIs)have been found to be a promising therapeutic choice[4–6].The combination of atezolizumab(anti--programmed death-ligand 1,PD-L1)and bevacizumab(anti-vascular endothelial growth factor,VEGF)antibodies demonstrated significantly better overall and progression-free survival than the kinase inhibitor sorafenib in patients with unresectable HCC in a phase III trial[4],and this combination was established as a first-line treatment for advanced HCC.However,the response rate for ICIs was limited[4–6],and it was reported that nonalcoholic steatohepatitis-related HCC was less responsive to ICIs than other HCCs[7].Given the clinical importance of tolerance to immunotherapy in HCC,tumor-immune co-evolution deserves more attention and may provide novel ideas for developing new combination therapies that target multiple mechanisms of immunotherapy resistance.