Efficacy of ginseng-based Renshenguben oral solution for cancer-related fatigue among patients with advanced-stage hepatocellular carcinoma:A prospective multicenter cohort study

Background:Cancer-related fatigue(CRF)is a common and debilitating symptom experienced by patients with advanced-stage cancer,especially those undergoing antitumor therapy.This study aimed to evaluate the efficacy and safety of Renshenguben(RSGB)oral solution,a ginseng-based traditional Chinese medicine,in alleviating CRF in patients with advanced hepatocellular carcinoma(HCC)receiving antitumor treatment.Methods:In this prospective,open-label,controlled,multicenter study,patients with advanced HCC at BCLC stage C and a brief fatigue inventory(BFI)score of≥4 were enrolled.Participants were assigned to the RSGB group(RSGB,10 mL twice daily)or the control group(with supportive care).Primary and secondary endpoints were the change in multidimensional fatigue inventory(MFI)score,and BFI and functional assessment of cancer therapy-hepatobiliary(FACT-Hep)scores at weeks 4 and 8 after enrollment.Adverse events(AEs)and toxicities were assessed.Results:A total of 409 participants were enrolled,with 206 assigned to the RSGB group.At week 4,there was a trend towards improvement,but the differences were not statistically significant.At week 8,the RSGB group exhibited a significantly lower MFI score(P<0.05)compared to the control group,indicating improved fatigue levels.Additionally,the RSGB group showed significantly greater decrease in BFI and FACT-Hep scores at week 8(P<0.05).Subgroup analyses among patients receiving various antitumor treatments showed similar results.Multivariate linear regression analyses revealed that the RSGB group experienced a significantly substantial decrease in MFI,BFI,and FACT-Hep scores at week 8.No serious drug-related AEs or toxicities were observed.Conclusions:RSGB oral solution effectively reduced CRF in patients with advanced HCC undergoing antitumor therapy over an eight-week period,with no discernible toxicities.These findings support the potential of RSGB oral solution as an adjunctive treatment for managing CRF in this patient population.

Biomarkers for hepatocellular carcinoma based on body fluids and feces

Novel non-/minimally-invasive and effective approaches are urgently needed to supplement and improve current strategies for diagnosis and management of hepatocellular carcinoma(HCC).Overwhelming evidence from published studies on HCC has documented that multiple molecular biomarkers detected in body fluids and feces can be utilized in early-diagnosis,predicting responses to specific therapies,evaluating prognosis before or after therapy,as well as serving as novel therapeutic targets.Detection and analysis of proteins,metabolites,circulating nucleic acids,circulating tumor cells,and extracellular vesicles in body fluids(e.g.,blood and urine)and gut microbiota(e.g.,in feces)have excellent capabilities to improve different aspects of management of HCC.Numerous studies have been devoted in identifying more promising candidate biomarkers and therapeutic targets for diagnosis,treatment,and monitoring responses of HCC to conventional therapies,most of which may improve diagnosis and management of HCC in the future.This review aimed to summarize recent advances in utilizing these biomarkers in HCC and discuss their clinical significance.

Early diagnosis and therapeutic strategies for hepatocellular carcinoma:From bench to bedside

Hepatocellular carcinoma(HCC)is the fourth leading cause of cancer-related deaths worldwide.The prognosis of patients with HCC remains poor largely due to the late diagnosis and lack of effective treatments.Despite being widely used,alpha-fetoprotein serology and ultrasonography have limited diagnostic performance for early-stage HCC.The emergence of omics strategies has contributed to significant advances in the development of non-invasive biomarkers for the early diagnosis of HCC including proteins,metabolites,circulating tumor deoxyribonucleic acid,and circulating non-coding ribonucleic acid.Early diagnosis is beneficial to patients as it increases the proportion who can be treated with curative treatment,thus prolonging survival outcomes.Currently,multiple clinical trials involving locoregional,systemic therapies,and combinations of these modalities are changing therapeutic strategies for different stage HCC.Success in several preclinical trials that involve immunotherapeutic innovations has created the potential to complement and enforce other treatment strategies in the future.This review summarizes the most recent advances in noninvasive early molecular detection,current therapy strategies,and potential immunotherapeutic innovations of HCC.

Statins, diabetes, obesity, nonalcoholic fatty liver disease, and hepatocellular carcinoma

To the Editor:We read with great interest the recent article by Chang et al.[1].By analyzing the data of 1350 cirrhotic patients,the authors concluded that statin significantly decreases the risk of decompensation of cirrhosis,mortality and hepatocellular carcinoma(HCC)incidence,and these effects are dose dependent.

Grading severity of microscopic vascular invasion was independently associated with recurrence and survival following hepatectomy for solitary hepatocellular carcinoma

Background:Hepatectomy is the preferred treatment for solitary hepatocellular carcinoma(HCC)without macrovascular invasion and distant metastasis,but long-term survival remains unsatisfactory in certain patients.We sought to identify whether the grading severity of microscopic vascular invasion(MVI)was associated with recurrence and survival among patients with solitary HCC.Methods:Consecutive patients who underwent hepatectomy for solitary HCC were identified from a multicenter prospectively-collected database.Patients were categorized into three groups according to the MVI grading system proposed by the Liver Cancer Pathology Group of China:M0(no MVI),M1(1-5 sites of MVI occurring≤1.0 cm away from the tumor),and M2(>5 sites occurring≤1.0 cm or any site occurring>1 cm away from the tumor).Recurrence-free survival(RFS)and overall survival(OS)were compared among the groups.Results:Among 227 patients,97(42.7%),83(36.6%),and 47(20.7%)patients had M0,M1,and M2,respectively.Median RFS rates among patients with M0,M1,and M2 were 38.3,35.1,11.6 months,respectively,while OS rates were 66.8,62.3,30.6 months,respectively(both P<0.001).Multivariate Cox-regression analyses demonstrated that both M1 and M2 were independent risk factors for RFS(hazard ratio 1.20,95%CI:1.03-1.89,P=0.040;and hazard ratio 1.67,95%CI:1.06-2.64,P=0.027)and OS(hazard ratio 1.28,95%CI:1.05-2.07,P=0.035;and hazard ratio 1.97,95%CI:1.15-3.38,P=0.013).Conclusions:Grading severity of MVI was independently associated with RFS and OS after hepatectomy for solitary HCC.Enhanced surveillance for recurrence and potentially adjuvant therapy may be considered for patients with MVI,especially individuals with more severe MVI grading(M2).

Association of Pringle maneuver with postoperative recurrence and survival following hepatectomy for hepatocellular carcinoma: a multicenter propensity score and competing-risks regression analysis

Background:The application of Pringle maneuver(PM)during hepatectomy reduces intraoperative blood loss and the need for perioperative transfusion,but its effect on long-term recurrence and survival for patients with hepatocellular carcinoma(HCC)remains controversial.We sought to determine the association between the application of PM and post-hepatectomy oncologic outcomes for patients with HCC.Methods:Patients who underwent curative hepatectomy for HCC at 9 Chinese hospitals from January 2010 to December 2018 were identified.Using two propensity score methods[propensity score matching(PSM)and inverse probability of treatment weight(IPTW)],cumulative recurrence rate and cancer-specific mortality(CSM)were compared between the patients in the PM and non-PM groups.Multivariate competing-risks regression models were performed to adjust for the effect of non-cancer-specific mortality and other prognostic risk factors.Results:Of the 2,798 included patients,2,404 and 394 did and did not adopt PM(the PM and non-PM groups),respectively.The rates of intraoperative blood transfusion,postoperative 30-day mortality and morbidity were comparable between the two groups(all P>0.05).In the PSM cohort by the 1:3 ratio,compared to 382 patients in the non-PM group,1,146 patients in the PM group also had the higher cumulative 5-year recurrence rate and CSM(63.9%and 39.1%vs.55.3%and 31.6%,both P<0.05).Similar results were also yielded in the entire cohort and the IPTW cohort.Multivariate competing-risks regression analyses demonstrated that no application of the PM was independently associated with lower recurrence rate and CSM based on various analytical cohorts[hazard ratio(HR),0.82 and 0.77 in the adjusted entire cohort,HR 0.80 and 0.73 in the PSM cohort,and HR 0.80 and 0.76 in the IPTW cohort,respectively].Conclusions:The findings suggested that no application of PM during hepatectomy for patients with HCC reduced the risk of postoperative recurrence and cancer-specific death by approximately 20–25%.

Navigating the future of liver disease research:A roadmap for iLIVER

The rising global impact of liver disorders,such as non-alcoholic fatty liver disease(NAFLD),viral hepatitis,and hepatocellular carcinoma(HCC),stands as a daunting hurdle in modern healthcare.These ailments,now major causes of global morbidity and mortality,exert a profound strain on health systems and affect the life quality of patients.The World Health Organization's estimates reveal liver conditions lead to around 2 million deaths annually,with viral hepatitis contributing to 1.34 million of these,underscoring the critical need for enhanced research and novel therapeutic interventions.Additionally,the escalating incidence of NAFLD,intertwined with the worldwide obesity crisis,is swiftly rising,affecting about 25%of the global population[1].This surge underscores an urgent call for extensive investigative work across molecular science,clinical applications,and public health initiatives.

Emerging role of molecular diagnosis and personalized therapy for hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is a prevalent malignancy worldwide,ranking as the sixth most common malignancy and the third leading cause of cancer-related mortality.Late diagnosis,limited management options,and its complex etiology contribute to the poor prognosis and high mortality rates.Recent advances in understanding the molecular mechanisms of HCC and innovations in high-throughput sequencing technologies have led to the development of molecular diagnostics and personalized therapies for this challenging malignancy.This review provides a comprehensive overview of research on the molecular diagnosis and individualized treatment for HCC.We highlight key advances and potential future directions and discuss the application of next-generation sequencing technologies to identify and characterize genetic and epigenetic alterations in HCC patients.These technologies may aid in the selection of targeted therapies,prediction of treatment response,and monitoring disease progression.Furthermore,we explore the role of liquid biopsy in HCC diagnosis,prognosis prediction,and treatment monitoring,focusing on circulating tumor cells,circulating tumor DNA,and extracellular vesicles.We also explore the evolving landscape of personalized therapy for HCC,including targeted therapies against key oncogenic signaling pathways,immune checkpoint inhibitors,tumor-agnostic therapies,and innovative cellbased therapies.We discuss the challenges and opportunities that lie ahead in the quest to improve HCC patient outcomes through the integration of molecular diagnostics and individualized precision therapies.We emphasize the need for multi-interdisciplinary collaboration,refinement of predictive and prognostic biomarkers,and the development of more effective combination strategies for HCC management in the new area of precision medicine.

Predictors and long-term prognosis of early and late recurrence for patients undergoing hepatic resection of hepatocellular carcinoma: a large-scale multicenter study

Recurrence is common among patients undergoing hepatic resection for hepatocellular carcinoma(HCC),which greatly limits long-term survival.We aimed to identify predictors and long-term prognosis of early and late recurrence after HCC resection.Methods:Multicenter data of patients who underwent HCC resection between 2002 and 2016 were analyzed.Recurrence was divided into early(≤2 years)and late recurrence(>2 years after surgery).Predictors of early and late recurrence,and prognostic factors of post-recurrence survival(PRS)were identified by univariate and multivariate analyses.Results:Among 1,426 patients,554(38.8%)and 348(24.4%)developed early and late recurrence,respectively.Independent predictors associated with early recurrence included preoperative alpha-fetoprotein level>400μg/L,resection margin<1 cm,and tumor size>5.0 cm,multiplicity,macrovascular and microvascular invasion,and satellites of the initial tumor at the first diagnosis of HCC;independent predictors associated with late recurrence included male,cirrhosis,and tumor size>5.0 cm,multiplicity,macrovascular and microvascular invasion,and satellites of the initial tumor.Patients with early recurrence had a lower likelihood of undergoing potentially curative treatments for recurrence(37.2%vs.48.0%,P<0.001)and a worse median PRS(13.5 vs.36.6 months,P<0.001)vs.patients who had late recurrence.Multivariate analysis revealed that early recurrence and irregular postoperative surveillance were independently associated with worse PRS[hazard ratio(HR)=1.250,95%CI:1.016-1.538,P=0.035;and HR=1.983,95%CI:1.677-2.345,P<0.001].Conclusions:Predictors associated with early and late recurrence after curative resection for patients with HCC were generally same,although several did differ.Patients with late recurrence had better long-term survival than patients with early recurrence.

Association of tumor morphology with long-term prognosis after liver resection for patients with a solitary huge hepatocellular carcinoma-a multicenter propensity score matching analysis

Background:A solitary hepatocellular carcinoma(HCC)without macrovascular invasion and distant metastasis,regardless of tumor size,is currently classified as early-stage disease by the latest Barcelona Clinic Liver Cancer(BCLC)staging system.While the preferred treatment is surgical resection,the association of tumor morphology with long-term survival outcomes after liver resection for a solitary huge HCC of≥10 cm has not been defined.Methods:Patients who underwent curative liver resection for a solitary huge HCC were identified from a multicenter database.Preoperative imaging findings were used to define spherical-or ellipsoidal-shaped lesions with smooth edges as balloon-shaped HCCs(BS-HCCs);out-of-shape lesions or lesions of any shape with matt edges were defined as non-balloon-shaped HCCs(NBS-HCCs).The two groups of patients with BS-HCCs and NBS-HCCs were matched in a 1:1 ratio using propensity score matching(PSM).Clinicopathologic characteristics,long-term overall survival(OS)and recurrence-free survival(RFS)were assessed.Results:Among patients with a solitary huge HCC,74 pairs of patients with BS-HCC and NBS-HCC were matched.Tumor pathological features including proportions of microvascular invasion,satellite nodules,and incomplete tumor encapsulation in the BS-HCC group were lower than the NBS-HCC group.At a median follow-up of 50.7 months,median OS and RFS of all patients with a solitary huge HCC after PSM were 27.8 and 10.1 months,respectively.The BS-HCC group had better median OS and RFS than the NBS-HCC group(31.9 vs.21.0 months,P=0.01;and 19.7 vs.6.4 months,P=0.015).Multivariate analyses identified BS-HCC as independently associated with better OS(HR=0.592,P=0.009)and RFS(HR=0.633,P=0.013).Conclusions:For a solitary huge HCC,preoperative imaging on tumor morphology was associated with prognosis following resection.In particular,patients with BS-HCCs had better long-term survival following liver resection versus patients with large NBS-HCCs.

Reply to: The letter to the editor “More details are needed about the use of multicenter propensity score matching analysis” by Feng et al.

We thank Dr.Feng and his colleagues for their interest and thoughtful commentaries on our recently published study on the association between tumor morphology and prognosis of solitary huge hepatocellular carcinoma(HCC)after curative liver resection(1).Based on propensity score matching(PSM)analysis,the present study demonstrated that balloon-shaped HCC(BS-HCC)was independently associated with better overall survival(OS)and recurrence-free survival(RFS)after surgery.

Association of family history with long-term prognosis in patients undergoing liver resection of HBV-related hepatocellular carcinoma

Background:Family history is a risk factor for the development of hepatocellular carcinoma(HCC).The aim of the current study was to investigate the association between family history of HCC and long-term oncologic prognosis among patients undergoing curative liver resection for hepatitis B virus(HBV)-related HCC.Methods:Patients who underwent curative liver resection of HBV-related HCC between 2003 and 2013 were consecutively enrolled.Family history was defined as a self-reported history of HCC in a first-degree relative.Propensity score matching(PSM)and multivariable Cox-regression analyses were performed to compare overall survival(OS)and recurrence-free survival(RFS)among patients with and without a family history.Results:Among 1,112 patients,183(16.5%)patients had a family history of HCC.Using PSM,179 pairs of patients with and without a family history were created that had no differences in the baseline characteristics and operative variables.On matched analysis,family history was associated with decreased OS and RFS after curative-intent resection of HBV-related HCC in the propensity matching cohort(P=0.042 and 0.006,respectively).On multivariable Cox-regression analyses,a family history of HCC was associated with decreased OS(HR:1.574;95%CI:1.171–2.116;P=0.003)and RFS(HR:1.534;95%CI:1.176–2.002;P=0.002)after adjusting for other prognostic risk factors.Conclusions:Family history was associated with decreased OS and RFS rates among patients undergoing curative liver resection of HBV-related HCC.

Exosomes as mediators of tumor immune escape and immunotherapy in hepatocellular carcinoma

Hepatocellular carcinoma(HCC),a typical inflammatory-related cancer,mainly occurs in patients with chronic liver diseases.Moreover,the liver is an immunologically privileged apparatus with multiple immunosuppressive cell groups.The long process of inflammation-mediated carcinogenesis turns the HCC tumor microenvironment(TME)into one with strong immunosuppression,facilitating the immune escape of HCC cells.Accumulated data have manifested that tumor-associated cell-derived exosomes carry diverse molecular cargoes(e.g.,proteins and nucleic acids)for mediating cell-to-cell communication and are implicated in TME remodeling to promote tumor-infiltrating immune cell reprogramming,ultimately creating a tumor-friendly microenvironment.Characterized by several intrinsic attributes,such as good stability(bilayer-like structure)and high biocompatibility(cell secretion),exosomes can be modified or engineered as nanocarriers to deliver tumor-specific antigens or antitumor drugs to targeted cells or organs,thus effectively triggering the HCC cell elimination by the immune system.This review aimed to highlight the pivotal role of exosomes in regulating immune escape mechanisms in HCC and recent advances in exosome-mediated immunotherapy for HCC.

Wu Mengchao:A blade warrior against liver cancer

China is a big nation primarily affected by liver cancer with the number of patients with liver cancer accounting more than 50%worldwide.1,2 Dr.Wu Mengchao(August 1922-May 2021;Fig.1)has devoted almost all his energy and wisdom to fighting against liver cancer for more than half a century.Dr.Wu graduated from the Tongji University School of Medicine in 1949.In 1960,Dr.Wu worked as the chief surgeon completing the first case of surgical resection for liver cancer in China.