Prognostic role of artificial intelligence among patients with hepatocellular cancer:A systematic review

BACKGROUND Prediction of survival after the treatment of hepatocellular carcinoma(HCC)has been widely investigated,yet remains inadequate.The application of artificial intelligence(AI)is emerging as a valid adjunct to traditional statistics due to the ability to process vast amounts of data and find hidden interconnections between variables.AI and deep learning are increasingly employed in several topics of liver cancer research,including diagnosis,pathology,and prognosis.AIM To assess the role of AI in the prediction of survival following HCC treatment.METHODS A web-based literature search was performed according to the Preferred Reporting Items for Systemic Reviews and Meta-Analysis guidelines using the keywords“artificial intelligence”,“deep learning”and“hepatocellular carcinoma”(and synonyms).The specific research question was formulated following the patient(patients with HCC),intervention(evaluation of HCC treatment using AI),comparison(evaluation without using AI),and outcome(patient death and/or tumor recurrence)structure.English language articles were retrieved,screened,and reviewed by the authors.The quality of the papers was assessed using the Risk of Bias In Non-randomized Studies of Interventions tool.Data were extracted and collected in a database.RESULTS Among the 598 articles screened,nine papers met the inclusion criteria,six of which had low-risk rates of bias.Eight articles were published in the last decade;all came from eastern countries.Patient sample size was extremely heterogenous(n=11-22926).AI methodologies employed included artificial neural networks(ANN)in six studies,as well as support vector machine,artificial plant optimization,and peritumoral radiomics in the remaining three studies.All the studies testing the role of ANN compared the performance of ANN with traditional statistics.Training cohorts were used to train the neural networks that were then applied to validation cohorts.In all cases,the AI models demonstrated superior predictive performance compared with traditional statistics with significantly improved areas under the curve.CONCLUSION AI applied to survival prediction after HCC treatment provided enhanced accuracy compared with conventional linear systems of analysis.Improved transferability and reproducibility will facilitate the widespread use of AI methodologies.

Platelet-to-lymphocyte ratio in the setting of liver transplantation for hepatocellular cancer: A systematic review and meta-analysis

AIM To perform a systematic review and meta-analysis on platelet-to-lymphocyte ratio(PLR) as a risk factor for post-transplant hepatocellular cancer(HCC) recurrence. METHODS A systematic literature search was performed using PubM ed. Participants of any age and sex, who underwent liver transplantation for HCC were considered following these criteria:(1) studies comparing pre-transplant low vs high PLR values;(2) studies reporting post-transplant recurrence rates; and(3) if more than one study was reported by the same institute, only the most recent was included. The primary outcome measure was set for HCC recurrence after transplantation. RESULTS A total of 5 articles, published between 2014 and 2017, fulfilled the selection criteria. As for the quality of the reported studies, all the investigated articles presented an overall high quality. A total of 899 cases were investigated: 718 cases(80.0%) were males. Three studies coming from European countries and one from Japan presented HCV as the main cause of cirrhosis. On the opposite, one Chinese study presented a greater incidence of HBV-related cirrhotic cases. In all the studies apart one, the PLR cut-off value of 150 was reported. At meta-analysis, high PLR value was associated with a significant increase in recurrence after transplantation(OR = 3.33; 95%CI: 1.78-6.25; P < 0.001). A moderate heterogeneity was observed among the identified studies according to the Higgins I^2 statistic value.CONCLUSION Pre-transplant high PLR values are connected with an increased risk of post-operative recurrence of hepatocellular cancer. More studies are needed for better clarify the biological mechanisms of this results.

Combination treatment with comprehensive cryoablation and immunotherapy in metastatic hepatocellular cancer

AIM: To retrospectively assess the effect of comprehensive cryosurgery (ablation of intraand extra-hepatic tumors) plus dendritic cell-cytokine-induced killer cell immunotherapy in metastatic hepatocellular cancer. METHODS: We divided 45 patients into cryo-immunotherapy (21 patients), cryotherapy (n = 12), immunotherapy (n = 5) and untreated (n = 7) groups. Overall survival (OS) after diagnosis of metastatic hepatocellular cancer was assessed after an 8-year follow-up. RESULTS: Median OS was higher following cryo-immu-notherapy (32 mo) or cryotherapy (17.5 mo; P < 0.05) than in the untreated group (3 mo) and was higher in the cryo-immunotherapy group than in the cryotherapy group (P < 0.05). In the cryo-immunotherapy group, median OS was higher after multiple treatments (36.5 mo) than after a single treatment (21 mo; P < 0.05). CONCLUSION: Cryotherapy and, especially, cryoimmunotherapy significantly increased OS in metastatic hepatocellular cancer patients. Multiple cryo-immunotherapy was associated with a better prognosis than single cryo-immunotherapy.

Long acting octreotide in the treatment of advanced hepatocellular cancer and overexpression of somatostatin receptors: Randomized placebo-controlled trial

AIM: To estimate if and to what extent long acting octreotide (LAR) improves survival and quality of life in patients with advanced hepatocellular carcinoma (HCC). METHODS: A total of 127 cirrhotics, stages A-B, due to chronic viral infections and with advanced HCC, were enrolled in the study. Scintigraphy with 111Indium labeled octreotide was performed in all cases. The patients with increased accumulation of radionuclear compound were randomized to receive either oral placebo only or octreotide/octreotide LAR only as follows: octreotide 0.5mg s.c. every 8 h for 6 wk, at the end of wk 4-8 octreotide LAR 20 mg i.m. and at the end of wk 12 and every 4 wk octreotide LAR 30mg i.m.. Follow-up was worked out monthly as well as the estimation of quality of life (QLQ-C30 questionnaire). Patients with negative somatostatin receptors (SSTR) detection were followed up in the same manner. RESULTS: Scintigraphy demonstrated SSTR in 61 patients. Thirty were randomized to receive only placebo and 31 only octreotide. A significantly higher survival time was observed for the octreotide group (49 ± 6 wk) as compared to the control group (28 ± 1 wk) and to the SSTR negative group (28 ± 2 wk), LR = 20.39, df = 2, P < 0.01. The octreotide group presented 68.5% lower hazard ratio [95% CI (47.4%-81.2%)]. During the f irst year, a 22%, 39% and 43% decrease in the QLQ-C30 score was observed in each group respectively.CONCLUSION: The proposed therapeutic approach has shown to improve the survival and quality of life in SSTR positive patients with advanced HCC.

Carcinogenesis on the background of liver fibrosis: Implications for the management of hepatocellular cancer

Hepatocellular carcinoma(HCC) is now the second leading cause of cancer-related deaths globally and many patients have incurable disease. HCC predominantly occurs in the setting of liver cirrhosis and is a paradigm for inflammation-induced cancer. The causes of chronic liver disease promote the development of transformed or premalignant hepatocytes and predisposes to the development of HCC. For HCC to grow and progress it is now clear that it requires an immunosuppressive niche within the fibrogenic microenvironment of cirrhosis. The rationale for targeting this immunosuppression is supported by responses seen in recent trials with checkpoint inhibitors. With the impact of immunotherapy, HCC progression may be delayed and long term durable responses may be seen. This makes the management of the underlying liver cirrhosis in HCC even more crucial as studies demonstrate that measures of liver function are a major prognostic factor in HCC. In this review, we discuss the development of cancer in the setting of liver inflammation and fibrosis, reviewing the microenvironment that leads to this tumourigenic climate and the implications this has for patient management.

Growth factor receptors and related signalling pathways as targets for novel treatment strategies of hepatocellular cancer

Growth factors and their corresponding receptors are commonly overexpressed and/or dysregulated in many cancers including hepatocellular cancer (HCC). Clinical trials indicate that growth factor receptors and their related signalling pathways play important roles in HCC cancer etiology and progression, thus providing rational targets for innovative cancer therapies. A number of strategies including monoclonal antibodies, tyrosine kinase inhibitors ("small molecule inhibitors") and antisense oligonucleotides have already been evaluated for their potency to inhibit the activity and downstream signalling cascades of these receptors in HCC. First clinical trials have also shown that multi-kinase inhibition is an effective novel treatment strategy in HCC. In this respect sorafenib, an inhibitor of Raf-, VEGF- and PDGF-signalling, is the first multi-kinase inhibitor that has been approved by the FDA for the treatment of advanced HCC. Moreover, the serine-threonine kinase of mammalian target of rapamycin (mTOR) upon which the signalling of several growth factor receptors converge plays a central role in cancer cell proliferation. mTOR inhibition of HCC is currently also being studied in preclinical trials. As HCCs represent hypervascularized neoplasms, inhibition of tumour vessel formation via interfering with the VEGF/VEGFR system is another promising approach in HCC treatment. This review will summarize the current status of the various growth factor receptor-based treatment strategies and in view of the multitude of novel targeted approaches, the rationale for combination therapies for advanced HCC treatment will also be taken into account.

Association of twelve polymorphisms in three onco-lncRNA genes with hepatocellular cancer risk and prognosis:A case-control study

AIM To evaluate the association of 12 tag single nucleotide polymorphisms(tag SNPs) in three onco-long non-coding RNA(lnc RNA) genes(HOTTIP,CCAT2,MALAT1) with the risk and prognosis of hepatocellular cancer(HCC). METHODS Twelve tag SNPs covering the three onco-lnc RNAs were genotyped by the KASP method in a total of 1338 samples,including 521 HCC patients and frequencymatched 817 controls. The samples were obtained from an unrelated Chinese population at the First Hospital ofChina Medical University from 2012-2015. The expression quantitative trait loci(e QTL) analyses were conducted to explore further the potential function of the promising SNPs. RESULTS Three SNPs in HOTTIP,one promoter SNP in MALAT1,and one haplotype of HOTTIP were associated with HCC risk. The HOTTIP rs17501292,rs2067087,and rs17427960 SNPs were increased to 1.55-,1.20-,and 1.18-fold HCC risk under allelic models(P = 0.012,0.017 and 0.049,respectively). MALAT1 rs4102217 SNP was increased to a 1.32-fold HCC risk under dominant models(P = 0.028). In addition,the two-way interaction of HOTTIP rs17501292-MALAT1 rs619586 polymorphisms showed a decreased effect on HCC risk(P interaction = 0.028,OR = 0.30) and epistasis with each other. HOTTIP rs3807598 variant genotype showed significantly longer survival time in HBV negative subgroup(P = 0.049,HR = 0.12),and MALAT1 rs591291 showed significantly better prognosis in female and HBV negative subgroups(P = 0.022,HR = 0.37; P = 0.042,HR = 0.25,respectively). In the study,no significant effect was observed in e QTL analysis. CONCLUSION Specific lnc RNA(HOTTIP and MALAT1) SNPs have potential to be biomarkers for HCC risk and prognosis.

Liver resection for early hepatocellular cancer: Comparison of centers in 3 different countries

AIM To compare patients who underwent resection of early stage hepatocellular cancer(HCC) in three different countries. METHODS This retrospective study characterizes 573 stage Ⅰ/Ⅱ HCC patients treated with liver resection in 3 tertiaryreferral centers: Tokyo(n = 250), Honolulu(n = 146) and Shanghai(n = 177).RESULTS Shanghai patients were younger, predominantly male, hepatitis-B seropositive(94%) and cirrhotic(93%). Tokyo patients were older and more likely to have hepatitis-C(67%), smaller tumors, low albumin, and normal alpha-fetoprotein. The Honolulu cohort had the largest tumors and 30% had no viral hepatitis. Ageadjusted mortality at 1 and 5-years were lower in theTokyo cohort compared to Honolulu and there was no difference in mortality between Shanghai and Honolulu cohorts. Elevated alpha-fetoprotein, low albumin and tumor > 5 cm were associated with increased 1-year mortality. These factors and cirrhosis were independently associated with increased 5-year mortality. Independent risk factors of survival varied when examined separately by center. CONCLUSION The profile of early-stage HCC patients is strikingly different across countries and likely contributes to survival differences. Underlying differences in patient populations including risk factors/comorbidities influencing disease progression may also account for variation in outcomes.

Analytical Image Fusion in the Detection of Intrahepatic Hepatocellular Cancer

Purpose: Since HCC lesions are generally characterized by lower Hounsfield unit value (HU) values and higher tracer uptake (SUV or Standardized Uptake Values), we intended to determine if normalizing the SUV by the HU, for the lesion and normal liver would improve sensitivity and specificity. Material and Methods: Twenty-three consecutive patients with HCC diagnosed clinically or pathologically underwent C11-Acetate (C11-A) and F18-FDG (FDG) PET/CT imaging before surgery during a 424-day interval. After exclusion of treated or calcified lesions, 44 lesions are included in this study. The original metrics are the maximum SUV (SUVmax) and maximum or average HU (HUmax or HUmean) for lesions and normal liver. For the normal liver, an average SUV (SUVmean) was included. The derived values are the ratios of SUV/HU values. The efficacy is the fraction of outcomes of non-overlapping metrics between lesion and normal liver. Results: For FDG the efficacy is 0.489 for the lesions SUVmax versus normal liver SUVmax. For lesion SUVmax/HUmean versus normal liver SUVmax/HUmax, the efficacy is 1.00. For C11-A the corresponding values are 0.045 and 0.920. Conclusion: Normalizing SUV values for changes in HU values increases the contrast between normal liver and lesions. Analytical fusion can be very effective.

Barcelona Clinic Liver Cancer Classification and Treatment of Hepatocellular Carcinoma in a Côte d’Ivoire University Hospital

Context/Objectives: Hepatocellular carcinoma occurs mainly and increasingly in developing countries, where the prognosis is particularly poor. The Barcelona Clinic Liver Cancer classification is used to guide the treatment of hepatocellular carcinoma. The aim of this retrospective study was to describe the Barcelona Clinic Liver Cancer classification and the treatment of hepatocellular carcinoma in a University Hospital in Côte d’Ivoire. Methods: Patients with hepatocellular carcinoma hospitalized in the hepato-gastroenterology unit of the University Hospital of Yopougon from 01 January 2012 to 30 June 2017 were included. The diagnosis of hepatocellular carcinoma was based on the presence of hepatic nodules on the abdominal ultrasound scan, typical images with the helical scanner associated or not with an increase of the α-fetoprotein higher than 200 ng/ml or with histology. Demographic, clinical, biological and radiological data were determined at the time of diagnosis. Patients were classified according to the Barcelona Clinic Liver Cancer classification. Their treatment was specified. Results: There were 258 patients whose median age was 48.1 years. Viral hepatitis B virus was the primary cause of hepatocellular carcinoma in 64.7% of cases. The severity of the underlying cirrhosis was Child-Pugh A in 12.1%, B in 63.6% and C in 24.3% of cases. The median size of the tumor was 63 mm. The α-fetoprotein level was higher than 200 mg/ml in 56.03% of cases. The Eastern Cooperative Oncology Group (ECOG)/World Health Organization (WHO) system was ≥2 in 82.9%. The Barcelona Clinic Liver Cancer classification was A in 1.3%, B in 0%, C in 55.2% and D in 43.5% of patients. There was no transplantation or hepatic resection. Very few patients (1.9%) received radio-frequency curative therapy. The treatment was predominantly symptomatic in 97.8% of patients. During hospitalization 43.7% of patients died. Conclusion: Hepatocellular carcinoma occurs on a liver with severe cirrhosis at a late stage. This does not allow cure treatment and explains a high mortality rate during hospitalization. Hepatitis B virus is the main risk factor and immunization at birth will reduce the incidence of this cancer in Africa.

Fuzheng Yiliu Granule(扶正抑瘤颗粒)Inhibits the Growth of Hepatocellular Cancer by Regulating Immune Function and Inducing Apoptosis In Vivo and In Vitro

Objective：To study the inhibitory effect of Fuzheng Yiliu Granule（扶正抑瘤颗粒,FYG） on hepatocellular cancer（HCC） and investigate the mechanism mediating its bioactivity.Methods：H22 tumor-bearing ICR mice were treated with FYG[3.6 g/（kg·d）]for 5 days.Tumor volume and tumor weight,percentages of CD3~＋,CD4~＋,CD8~＋,and natural killer（NK） cells in peripheral blood,tumor apoptosis and serum levels of interleukin-2（IL-2）,and tumor necrosis factor-α（TNF-α） were evaluated.FYG-containing serum was prepared from SD rats treated for 7 days[high dose 3.6 g/（kg·d）;middle dose 1.8 g/（kg·d）;low dose 0.9 g/（kg·d）].Cell cycle,cell viability,and apoptosis were evaluated after HepG2 cell line was cultured in FYG-containing serum for 48 h.The levels of IL-2 and TNF-αin FYG-containing serum were also determined.Results：FYG produced a potent antitumor effect（P0.01） and induced marked apoptosis of the tumor tissue（P0.05）.Mice treated with FYG had higher percentages of CD3~＋ and CD4~＋（P0.05）,and more NK cells（P0.01） in the peripheral blood than those in the animals treated with normal saline.Mice receiving FYG had the highest serum levels of IL-2 and TNF-α（P0.01）.High-dose FYG-containing serum significantly decreased HepG2 cell viability,inhibited cell proliferation（P0.05）,and induced apoptosis（P0.01）.In addition,the levels of IL-2 and TNF-αof highdose -containing serum were higher than the blank serum（P0.01）.Conclusion：FYG could inhibit HCC growth by regulating immune function and inducing apoptosis of tumor cells in vivo and in vitro.

Ten-year survival and recurrence of hepatocellular cancer

Aim:Long-term survival after hepatocellular cancer(HCC)is difficult to achieve likely related to recurrence.This study aimed to identify factors that were predictive of 10-year survival after the diagnosis of HCC.Methods:In a prospectively collected database of 1374 HCC cases(1993-2019),we identified 70 patients who survived over 10 years regardless of treatment.We then identified 164 patients in the entire cohort who either had liver resection or transplant,and died before 10 years.Demographics,tumor characteristics,treatment,recurrence and treatment of recurrence were compared.Results:Of the 10-year survivors,36 underwent transplant,27 had liver resection and 7 patients had only locoregional therapy.Compared to the non-survivors,the 10-year survivors were younger and had fewer comorbidities or recurrence,smaller tumor size,lower AST,ALT,AFP,platelets,neutrophil-to-lymphocyte ratio.Multivariate analysis showed only age and diabetes to be negative predictors.Recurrence occurred in 24 survivors(34.3%)with mean time to recurrence with standard deviation 57.1±42.6 months compared to 80 non-survivors(48.7%)with mean time to recurrence of 15.3±14.8 months.For hepatic resection,10-year survivors had longer time to recurrence compared to non-survivors(median:31.3 months).Conclusion:Long-term survivors mostly occur after resection or transplant,but 10%of our cohort survived 10 years with only locoregional therapy.Underlying health status maybe an important predictor of 10-year survival for ;patients receiving liver resections.Recurrence of HCC occurs in both 10-year survivors and non-survivors,but later recurrence with aggressive treatment of the recurrence may allow for 10-year survival.

A double-edged sword:The HBV-induced non-coding RNAs alterations in hepatocellular carcinoma

Non-coding RNAs are speculated to exert important regulatory functions at the level of gene expression,oncogenesis,and many other pathologies.Hepatitis B virus(HBV)infection is a leading cause of hepatocellular carcinoma(HCC),and some studies have shown that the expression of non-coding RNAs has an assignable effect on the development of HBV-induced HCC.In this context,the functions and molecular mechanisms of the HBVinduced non-coding RNA expression in the development of hepatoma have attracted increasing attention.This review covers the progress in the exploration of the relationship between HBV-induced hepatoma and non-coding RNA expression,cataloging the recent reports about the roles of non-coding RNAs in HBV-induced hepatoma into five classes,including(1)modulation of metabolism in hepatic cancer,(2)aggravation of inflammation and hepatic fibrosis,(3)alteration of the tumor immune microenvironment,(4)non-coding RNA N6-methyladenosine modification,and a seemingly opposite process,(5)the suppression of the progression of HBV-related HCC.All evidence supports non-coding RNAs as promising novel targets for the early diagnosis and treatments for HCC.

Cancer stem cell markers correlate with early recurrence and survival in hepatocellular carcinoma

AIM:To investigate whether expression of cancer stem cell(CSC)markers is associated with recurrence and survival in hepatocellular carcinoma(HCC)patients.METHODS:A consecutive series of 90 HCC patients who underwent curative hepatectomy between April2007 and April 2009 were analyzed.Of the 90 patients,38(42%)experienced recurrence within two years of surgery.To adjust for baseline differences between this early recurrence group and the other patients,propensity-score matching was used to generate 25 pairs of patients.Immunohistochemistry was used to compare expression of CD133,CD90,and epithelial cell adhesion molecule(EpCAM)in liver tissues from propensity score-matched patients and from 10 healthy adults.Associations of the three markers with HCC,clinicopathological characteristics,early recurrence,and survival time were explored.RESULTS:The expression of all three CSC markers was significantly higher in HCC tissue than in healthy liver tissue(P<0.001 for all).Among the HCC clinicopathology characteristics examined,the absence of tumor capsule was associated with CD133 expression(P=0.005);higher histopathology grade and larger tumor size were associated with CD90 expression(P=0.010 and 0.034,respectively);and elevated serum alpha-fetoprotein levels were associated with EpCAM expression(P=0.021).Expression of CD90 and EpCAM was significantly higher in the early recurrence group than in other patients(P=0.001 and 0.045,respectively),whereas CD133 expression was not significantly different between the two groups(P=0.440).Multivariate analysis identified only CD90 expression as significantly associated with early recurrence.Log-rank analysis identified expression of both CD90 and EpCAM as significantly associated with survival time of HCC patients.Cox regression identified EpCAM expression as an independent predictor of survival time.CONCLUSION:Expression of CD133,CD90,and EpCAM CSC markers may be linked to HCC tumor onset and/or progression.In addition,EpCAM expression is associated with shorter survival time,while CD90 expression is associated with early HCC recurrence.

Cancer nanotechnology: Enhancing tumor cell response to chemotherapy for hepatocellular carcinoma therapy

Hepatocellular carcinoma(HCC)is one of the deadliest cancers due to its complexities,reoccurrence after surgical resection,metastasis and heterogeneity.In addition to sorafenib and lenvatinib for the treatment of HCC approved by FDA,various strategies including transarterial chemoembolization,radiotherapy,locoregional therapy and chemotherapy have been investigated in clinics.Recently,cancer nanotechnology has got great attention for the treatment of various cancers including HCC.Both passive and active targetings are progressing at a steady rate.Herein,we describe the lessons learned from pathogenesis of HCC and the understanding of targeted and non-targeted nanoparticles used for the delivery of small molecules,monoclonal antibodies,miRNAs and peptides.Exploring current efficacy is to enhance tumor cell response of chemotherapy.It highlights the opportunities and challenges faced by nanotechnologies in contemporary hepatocellular carcinoma therapy,where personalized medicine is increasingly becoming the mainstay.Overall objective of this review is to enhance our understanding in the design and development of nanotechnology for treatment of HCC.

Hepatic cancer stem cells and drug resistance: Relevance in targeted therapies for hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of most common malignancies in the world. Systemic treatments for HCC, particularly for advanced stages, are limited by the drug resistance phenomenon which ultimately leads to therapy failure. Recent studies have indicated an association between drug resistance and the existence of the cancer stem cells (CSCs) as tumor initiating cells. The CSCs are resistant to conventional chemotherapies and might be related to the mechanisms of the ATP Binding Cassette (ABC) transporters and alterations in the CSCs signaling pathways. Therefore, to contribute to the development of new HCC treatments, further information on the characterization of CSCs, the modulation of the ABC transporters expression and function and the signaling pathway involved in the self renewal, initiation and maintenance of the cancer are required. The combination of transporters modulators/inhibitors with molecular targeted therapies may be a potent strategy to block the tumoral progression. This review summarizes the association of CSCs, drug resistance, ABC transporters activities and changes in signaling pathways as a guide for future molecular therapy for HCC.

Systematic review of the outcomes of surgical resection for intermediate and advanced Barcelona Clinic Liver Cancer stage hepatocellular carcinoma:A critical appraisal of the evidence

AIM To perform a systematic review to determine the survival outcomes after curative resection of intermediate and advanced hepatocellular carcinomas(HCC).METHODS A systematic review of the published literature was performed using the PubM ed database from 1 st January 1999 to 31 st Dec 2014 to identify studies that reported outcomes of liver resection as the primary curative treatment for Barcelona Clinic Liver Cancer(BCLC) stage B or C HCC. The primary end point was to determine the overall survival(OS) and disease free survival(DFS) of liver resection of HCC in BCLC stage B or C in patients with adequate liver reserve(i.e., Child's A or B status). The secondary end points were to assess the morbidity and mortality of liver resection in large HCC(defined as lesions larger than 10 cm in diameter) and to compare the OS and DFS after surgical resection of solitary vs multifocal HCC.RESULTS We identified 74 articles which met the inclusion criteria and were analyzed in this systematic review. Analysis of the resection outcomes of the included studies were grouped according to(1) BCLC stage B or C HCC,(2) Size of HCC and(3) multifocal tumors. The median 5-year OS of BCLC stage B was 38.7%(range 10.0-57.0); while the median 5-year OS of BCLC stage C was 20.0%(range 0.0-42.0). The collective median 5-year OS of both stages was 27.9%(0.0-57.0). In examining the morbidity and mortality following liver resection in large HCC, the pooled RR for morbidity [RR(95%CI) = 1.00(0.76-1.31)] and mortality [RR(95%CI) = 1.15(0.73-1.80)] were not significant. Within the spectrum of BCLC B and C lesions, tumors greater than 10 cm were reported to have median 5-year OS of 33.0% and multifocal lesions 54.0%.CONCLUSION Indication for surgical resection should be extended to BCLC stage B lesions in selected patients. Further studies are needed to stratify stage C lesions for resection.

Hepatocellular carcinoma staging systems: Hong Kong liver cancer vs Barcelona clinic liver cancer in a Western population

BACKGROUND Despite being the world’s most widely used system for staging and therapeutic guidance in hepatocellular carcinoma(HCC)treatment,the Barcelona clinic liver cancer(BCLC)system has limitations,especially regarding intermediate-grade(BCLC-B)tumors.The recently proposed Hong Kong liver cancer(HKLC)staging system appears useful but requires validation in Western populations.AIM To evaluate the agreement between BCLC and HKLC staging on the management of HCC in a Western population,estimating the overall patient survival.METHODS This was a retrospective study of HCC patients treated at a university hospital in southern Brazil between 2011 and 2016.Demographic,clinical,and laboratory data were collected.HCC staging was carried out according to the HKLC and BCLC systems to assess treatment agreement.Overall survival was estimated based on the treatment proposed in each system.RESULTS A total of 519 HCC patients were assessed.Of these,178(34.3%)were HKLC-I;95(18.3%)HKLC-IIA;47(9.1%)HKLC-IIB;29(5.6%)HKLC-IIIA;30(5.8%)HKLCIIIB;75(14.4%)HKLC-IV;and 65(12.5%)HKLC-V.According to the BCLC,25(4.9%)were BCLC-0;246(47.4%)BCLC-A;107(20.6%)BCLC-B;76(14.6%)BCLCC;and 65(12.5%)BCLC-D.The general agreement between the two systems was 80.0%-BCLC-0 and HKLC-I(100%);BCLC-A and HKLC-I/HKLC-II(96.7%);BCLC-B and HKLC-III(46.7%);BCLC-C and HKLC-IV(98.7%);BCLC-D and HKLC-V(41.5%).When sub-classifying BCLC-A,HKLC-IIB,HKLC-IIIA and HKLC-IIIB stages according to the up-to-7 in/out criterion,13.4,66.0,100 and 36.7%,respectively,of the cases were classified as up-to-7 out.CONCLUSION In a Western population,the general agreement between the two systems was 80.0%,although in BCLC-B cases the agreement was low,suggesting that some individuals could be candidates for the curative treatment recommended by the HKLC.The authors suggest that the BCLC system should be routinely employed,although for BCLC-B cases it should be associated with the HKLC system.

Diagnostic value of cancer-testis antigen mRNA in peripheral blood from hepatocellular carcinoma patients

AIM:To evaluate the diagnostic value of cancer-testis antigen(CTA) mRNA in peripheral blood samples from hepatocellular carcinoma(HCC) patients.METHODS:Peripheral blood samples were taken from 90 patients with HCC before operation.Expression of melanoma antigen-1(MAGE-1),synovial sarcoma X breakpoint-1(SSX-1),and cancer-testis-associated protein of 11 kDa(CTp11) mRNA in peripheral blood mononuclear cells(PBMC) was tested by nested reverse transcriptspolymerase chain reaction(RT-PCR).Serum α-fetoprotein(AFP) in these patients was also determined.RESULTS:The positive rate of MAGE-1,SSX-1 and CTp11 transcripts was 37.7%,34.4%,31.1% in PBMC samples,and 74.4%,73.3%,62.2% in their resected tumor samples,respectively.The positive rate for at least one of the transcripts of three CTA genes was 66.7% in PBMC samples and 91.1% in their resected tumor samples.MAGE-1,SSX-1 and/or CTp11 mRNA were not detected in the PBMC of those patients from whom the resected tumor samples were MAGE-1,SSX-1 and/or CTp11 mRNA negative,nor in the PBMC samples from 20 healthy donors and 10 cirrhotic patients.Among the 90 patients,the serum AFP in 44 patients met the general diagnostic standard(AFP > 400 μg/L) for HCC,and was negative(AFP ≤ 20 μg/L) or positive with a low concentration(20 μg/L < AFP ≤ 400 μg/L) in the other patients.The positive rate for at least one of the transcripts of three CTA genes in PBMC samples from the AFP negative or positive patients with a low concentration was 69.2% and 45.0%,respectively.Of the 90 patients,71(78.9%) were diagnosed as HCC by nested RT-PCR and serum AFP.Although the positive rate for at least one of the transcripts of three CTA genes in PBMC samples from 53 patients at TNM stage or was obviously higher than that in PBMC samples from 37 patients at stage or(77.9% vs 51.4%,P = 0.010),the CTA mRNA was detected in 41.7% and 56.0% of PBMC samples from HCC patients at stages andrespectively.CONCLUSION:Detecting MAGE-1,SSX-1 and CTp11 mRNA in PBMC improves the total diagnostic rate of HCC.

Incomplete radiofrequency ablation promotes the development of CD133+cancer stem cells in hepatocellular carcinoma cell line HepG2 via inducing SOX9 expression

Background: Cancer stem cells(CSCs) accelerate the growth of hepatocellular carcinoma(HCC) residual after incomplete radiofrequency ablation(In-RFA). The present study aimed to detect the effects of In-RFA on stemness transcription factors(STFs) expression which are important for the production and function of CSCs, and to find which STFs promote HCC stemness after In-RFA. Methods: HepG2 cells were used for in vitro and in vivo studies. Flow cytometry and sphere-formation assays were used to detect the level and function of CD133~+ CSCs in the models. PCR array and ELISA were applied to analyze the altered expression of 84 STFs in CD133~+ CSCs in two models. Specific lentiviral shRNA was used to knockdown STFs expression, followed by detecting In-RFA’s effects on the levels and function of CD133~+ CSCs. Results: In-RFA was identified to induce CD133~+ CSCs and increase their tumorigenesis ability in vitro and in vivo. The mRNA levels of 84 STFs in CD133~+ CSCs were detected by PCR array, showing that 15 and 22 STFs were up-regulated in two models, respectively. Meanwhile, the mRNA levels of seven common STFs were up-regulated in both models. ELISA assay demonstrated that only the protein of sex determining region Y-box 9(SOX9) was up-regulated in both models, the protein levels of the other 6 common STFs did not increase in both models. Finally, SOX9 was identified to play an important role in inducing, maintaining stemness and promoting tumorigenesis ability of CD133~+ CSCs in both models. Conclusion: In-RFA-induced SOX9 stimulates CD133~+ CSCs proliferation and increases their tumorigenesis ability, suggesting that SOX9 may be a good target for HCC treatment.