Cancer Of The Liver Italian Program Research Articles

Case report: Massive hepatocellular carcinoma with complete response to the non-surgical systematic treatment strategy

BackgroundThe five-year recurrence rate of hepatocellular carcinoma (HCC) remains as high as 70%. A complete clinical response has not been observed without surgical resection. Here, we report a rare case of clinical complete response and long-term survival in a patient with massive HCC receiving treatment with immunotherapy, anti-angiogenic therapy, and radiotherapy.Case descriptionA 38-year-old woman presented to our hospital for abdominal pain that persisted for 3 months. She was diagnosed as Barcelona Clinic Liver Cancer(BCLC) stage A, with a Cancer of the Liver Italian Program (CLIP) score of 3, American Joint Committee on Cancer (AJCC) Tumor-Node-Metastasis (TNM) staging systems stage IB. She refused surgical resection and trans-arterial chemoembolization and accepted a non-invasive systematic treatment strategy involving immunotherapy, anti-angiogenic therapy, and radiotherapy. Her tumor burden decreased, and she experienced partial response before radiotherapy. Following radiotherapy, she experienced a complete clinical response and has been alive for more than 36 months after her initial presentation. She is currently alive.ConclusionA non-invasive systematic treatment strategy is a potential radical treatment option for patients with massive HCC.

Nomogram to Predict the Long-Term Overall Survival of Early-Stage Hepatocellular Carcinoma after Radiofrequency Ablation

Our objective was to develop a predictive nomogram that could estimate the long-term survival of patients with very early/early-stage hepatocellular carcinoma (HCC) undergoing radiofrequency ablation (RFA). For this retrospective study, we enrolled 950 patients who initially received curative RFA for HCC at Barcelona Clinic Liver Cancer (BCLC) stages 0 and A between 2002 and 2016. Factors predicting poor survival after RFA were investigated through a Cox proportional hazard model. The nomogram was constructed using the investigated variables influencing overall survival (OS). After a median follow-up time of 6.25 years, 400 patients had died, and 17 patients had received liver transplantation. The 1-,3-,5-,7-, and 10-year OS rates were 94.5%, 73.5%, 57.9%, 45.7%, and 35.8%, respectively. Multivariate analysis showed that age greater than 65 years, albumin-bilirubin (ALBI) grades 2 and 3, AST-to-platelet ratio index (APRI) greater than 1, tumor size larger than 3 cm, diabetes mellitus, end-stage renal disease, and tumor number greater than 1 were significantly associated with poor OS. The nomogram was constructed using these seven variables. The validation results showed a good concordance index of 0.683. When comparing discriminative ability to tumor, node, and metastasis (TNM), BCLC, and Cancer of the Liver Italian Program (CLIP) staging systems, our nomogram had the highest C-index for predicting mortality. This nomogram provides useful information on prognosis post-RFA as a primary treatment and aids physicians in decision-making.

Rapid Decline of Estimated Glomerular Filtration Rate and its Effect on Mortality Risk of Patients with Hepatocellular Carcinoma

Background: In patients with Hepatocarcinoma (HCC), the association between the rapid decline of kidney function and clinical outcomes is still unknown, although kidney-liver crosstalk is comprehensively studied. Objectives: We aimed to investigate the prevalence and determinants of the rapid decline of kidney function and its potential prognostic role and influence on mortality in HCC patients treated by percutaneous injection therapy (PEIT). Methods: This prospective cohort included 114 HCC, with 64.9% males and a mean age of 65.17 years. The rapid decline of kidney function was defined according to kidney disease improving global outcome (KDIGO). The cancer of the liver Italian program (CLIP) score was calculated to predict survival. Multivariable logistic regression analysis for rapid estimated glomerular filtration rate (eGFR) decline was performed after evaluating individual covariates. Multivariable Cox regression models for rapid eGFR decline and mortality were analyzed. Results: During a median follow-up of 31 months, 43.85% of patients presented a rapid decline in eGFR. The baseline eGFR was significantly higher in the group with the rapid decline of kidney function: 86.08 ± 19.17 mL/min/1.73m2 vs. 75.53 ± 25.7 mL/min/1.73 m2 (P = 0.001). The CLIP score (hazard ratio [HR] = 2.55, 95% confidence interval [CI]: 1.70 - 3.84, P < 0.001) was independently associated with rapid eGFR decline. In Cox regression, rapid eGFR decline was independently associated with mortality (HR = 3.49, 95%CI: 1.28 - 9.56, P = 0.015). Conclusions: Nearly half of the HCC patients presented a rapid eGFR decline. The HCC severity evaluated by the CLIP score was an independent predictor of the rapid decline of kidney function. The rapid decline in eGFR was associated with a higher mortality risk in HCC patients, independent of other known risk factors.

A Novel Prognostic Score Based on Artificial Intelligence in Hepatocellular Carcinoma: A Long-Term Follow-Up Analysis.

ObjectiveT cell immunity plays an important role in anti-tumor effects and immunosuppression often leads to the development and relapse of cancer. This study aimed to investigate the effect of T cell numbers on the long-term prognosis of patients with hepatocellular carcinoma (HCC) and construct an artificial neural network (ANN) model to evaluate its prognostic value.MethodsWe enrolled 3,427 patients with HCC at Beijing Ditan Hospital, Capital Medical University, and randomly divided them into two groups of 1,861 and 809 patients as the training and validation sets, respectively. Cox regression analysis was used to screen for independent risk factors of survival in patients with HCC. These factors were used to build an ANN model using Python. Concordance index, calibration curve, and decision curve analysis were used to evaluate the model performance.ResultsThe 1-year, 3-year, 5-year, and 10-year cumulative overall survival (OS) rates were 66.9%, 45.7%, 34.9%, and 22.6%, respectively. Cox multivariate regression analysis showed that age, white blood cell count, creatinine, total bilirubin, γ-GGT, LDH, tumor size ≥ 5 cm, tumor number ≥ 2, portal vein tumor thrombus, and AFP ≥ 400 ng/ml were independent risk factors for long-term survival in HCC. Antiviral therapy, albumin, T cell, and CD8 T cell counts were independent protective factors. An ANN model was developed for long-term survival. The areas under the receiver operating characteristic (ROC) curve of 1-year, 3-year, and 5-year OS rates by ANNs were 0.838, 0.833, and 0.843, respectively, which were higher than those of the Barcelona Clinic Liver Cancer (BCLC), tumor node metastasis (TNM), Okuda, Chinese University Prognostic Index (CUPI), Cancer of the Liver Italian Program (CLIP), Japan Integrated Staging (JIS), and albumin–bilirubin (ALBI) models (P < 0.0001). According to the ANN model scores, all patients were divided into high-, middle-, and low-risk groups. Compared with low-risk patients, the hazard ratios of 5-year OS of the high-risk group were 8.11 (95% CI: 7.0-9.4) and 6.13 (95% CI: 4.28-8.79) (P<0.0001) in the training and validation sets, respectively.ConclusionHigh levels of circulating T cells and CD8 + T cells in peripheral blood may benefit the long-term survival of patients with HCC. The ANN model has a good individual prediction performance, which can be used to assess the prognosis of HCC and lay the foundation for the implementation of precision treatment in the future.

Safety and Long-Term Survival Outcome in Patients With Unresectable Barcelona Clinic Liver Cancer (BCLC) Stages C and D Advanced Hepatocellular Carcinoma Treated With 40 μm Drug-Eluting Bead Transcatheter Arterial Chemoembolization.

BackgroundTo evaluate the safety, treatment response, and overall survival (OS) following drug-eluting bead transarterial chemoembolization (DEB-TACE) using doxorubicin-loaded 40 μm microspheres in patients with advanced hepatocellular carcinoma (HCC).MethodsThis was a single-center retrospective evaluation of patients with unresectable HCC without extrahepatic spread and Barcelona Clinic Liver Cancer (BCLC) stages C and D disease who underwent DEB-TACE between August 2015 and January 2018. Pre-treatment data included demographics, medical history, cancer staging, tumor size, laboratory results, and prior treatments for HCC. Follow-up data included the date of DEB-TACE treatments or microwave ablation (MWA) procedures, laboratory test results, adverse events, treatment response, and the date and cause of death.ResultsThirty-two patients met the study inclusion criteria. Eighteen patients (56.3%) underwent a single DEB-TACE and 14 patients (43.8%) had two to five DEB-TACE procedures. Five patients (15.6%) had MWA following initial DEB-TACE. Mild postembolization syndrome occurred in six patients (18.8%) during a 30-day period following initial DEB-TACE. Seven patients (21.9%) experienced worsening ascites, pleural fluid, or encephalopathy during the study observation period. Three patients had moderate to severe worsening liver function tests 90 days post-procedure. Seventeen patients (53.1%) had a complete or partial response and nine patients (28.1%) had disease progression. Median OS was 15.0±14.4 months from the time of initial DEB-TACE, with 63% and 33% of patients still alive at 12 and 24 months. Multivariate analyses identified that Okuda Stage (P=0.03) and Cancer of the Liver Italian Programme (CLIP) score (P=0.05) were significantly associated with overall survival after adjusting for other covariates. There were four HCC-related deaths during the 30-day post-procedure period.ConclusionDEB-TACE with small 40 μm doxorubicin-loaded microspheres is a safe and effective treatment for unresectable patients with BCLC stages C and D advanced HCC. Patients with advanced, high-risk unresectable HCC should be considered for DEB-TACE as opposed to supportive or palliative care alone.

Evaluation of staging systems to predict prognosis in hepatocellular carcinoma patients treated with radioembolization

PurposeTo compare the prognostic accuracy of nine staging systems, some of which are well-known and some of which have only been more recently described, for patients with unresectable HCC treated with radioembolization (RE). Materials and methodsIndividual scores or classes for the following staging systems were recorded or calculated for patients (n = 89) with unresectable HCC who underwent RE at a single tertiary care center from January 2008 to October 2016: Eastern Cooperative Oncology Group, Barcelona Clinic Liver Cancer, Hong Kong Liver Cancer, Okuda, Cancer of the Liver Italian Program (CLIP), Model for End Stage Liver Disease, Child-Pugh (CP) Categorical and Numeric, and Albumin-Bilirubin. For each staging system, a cox proportional hazards regression model was fit to the data and log-rank test statistics, concordance indices, Akaike Information Criteria (AIC) and other diagnostic statistics were calculated. ResultsOf the nine staging systems analyzed, the basic discriminatory ability assessed with the log-rank test (rejected at the α = .05-level) was significant for two of the systems: CP Numeric (p < .001) and CLIP (p < .05). Out of these two systems, CP Numeric system had a higher prognostic accuracy than CLIP with the lowest AIC (464.90), the highest optimism-corrected pseudo R2 (0.16), and the highest estimated concordance index (0.64). ConclusionAs applied to our patient population, the CP Numeric system contained the most predictive prognostic information for patients with HCC undergoing radioembolization. However, all evaluated staging systems performed suboptimally, and the relative superiority of any of the systems remains unclear when ranking them according to common practice. Further evaluation of current ranking methodologies is recommended.

Prognostic Value of Microvascular Invasion in Eight Existing Staging Systems for Hepatocellular Carcinoma: A Bi-Centeric Retrospective Cohort Study.

BackgroundMicrovascular invasion (MVI) is a significant risk factor affecting survival outcomes of patients after R0 liver resection (LR) for hepatocellular carcinoma (HCC). However, whether the existing staging systems of hepatocellular carcinoma can distinguish the prognosis of patients with MVI and the prognostic value of MVI in different subtypes of hepatocellular carcinoma remains to be clarified.MethodsA dual-center retrospective data set of 1,198 HCC patients who underwent R0 LR was included in the study between 2014 and 2016. Baseline characteristics and staging information were collected. Homogeneity and modified Akaike information criterion (AICc) were compared between each system. And the prognostic significance of MVI for overall survival (OS) was studied in each subgroup.ResultsIn the entire cohort, there were no significant survival differences between Cancer of the Liver Italian Program (CLIP) score 2 and 3 (p = 0.441), and between Taipei Integrated Scoring System (TIS) score 3 and 4 (p = 0.135). In the MVI cohort, there were no significant survival differences between Barcelona Clinic Liver Cancer stages B and C (p=0.161), CLIP scores 2 and 3 (p = 0.083), TIS scores 0 and 1 (p = 0.227), TIS scores 2 and 3 (p =0.794), Tokyo scores 3 and 4 (p=0.353), and American Joint Committee on Cancer Tumor-Node-Metastasis 7th stage I and II (p=0.151). Among the eight commonly used HCC staging systems, the Hong Kong Liver Cancer (HKLC) staging system showed the highest homogeneity and the lowest AICc value in both the entire cohort and MVI cohort. In each subgroup of the staging systems, MVI generally exhibited poor survival outcomes.ConclusionsThe HKLC staging system was the most accurate model for discriminating the prognosis of MVI patients, among the eight staging systems. Meanwhile, our findings suggest that MVI may be needed to be incorporated into the current HCC staging systems as one of the grading criteria.

Neutrophil-to-Apolipoprotein A1 Ratio Predicted Overall Survival in Hepatocellular Carcinoma Receiving Transarterial Chemoembolization.

The purpose of this study was to investigate the predictive capability of neutrophil-to-apolipoprotein A1 ratio (NAR) for predicting overall survival (OS) among patients with hepatocellular carcinoma (HCC) receiving transarterial chemoembolization (TACE). We investigated the clinical features of 554 patients with HCC receiving TACE and assessed NAR's predictive value for OS with 222 patients (the discovery cohort) and 332 patients (the validation cohort). The association of NAR with circulation lectin-type oxidized low-density lipoprotein receptor-1-positive (LOX-1+ ) polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) was illustrated. Multivariate Cox regression revealed that lymphocyte count; Tumor, Node, Metastasis (TNM) stage; and NAR were independent prognostic factors in the discovery cohort. The validation cohort confirmed the independent prognostic value of TNM stage and NAR. Patients with low NAR (<2.7) displayed significantly increased OS in the discovery cohort (59.8 months vs. 21 months), the validation group (38.0 months vs. 23.6 months), and the total cohort (44.1 months vs. 22.0 months). A Cox proportional hazards model was used to combine Cancer of the Liver Italian Program (CLIP) score with discretized NAR. C-index illustrated that NAR-integrated CLIP score was the best model compared with NAR and CLIP score. Furthermore, NAR-CLIP presented superior predictive capacity for 10-, 20-, 30-, 40-, 50-, and 60-month survival compared with CLIP score by survival receiver-operator characteristic analysis in the discovery cohort, validation cohort, and total cohort. NAR was significantly associated with LOX-1+ PMN-MDSCs by linear regression. This study identified NAR as an independent predictor for OS among patients with HCC receiving TACE. NAR reflected circulation LOX-1+ PMN-MDSC level. The present study identified neutrophil-to-apolipoprotein A1 ratio (NAR) as an independent predictor for overall survival among patients with hepatocellular carcinoma receiving transarterial chemoembolization. NAR reflected circulation level of lectin-type oxidized low-density lipoprotein receptor-1-positive polymorphonuclear myeloid-derived suppressor cells.

A Powerful Nomogram Based on the Novel D-Index to Predict Prognosis After Surgical Resection of Hepatocellular Carcinoma.

PurposeConventional staging and scoring systems such as the Tumor, Node, and Metastasis; Cancer of the Liver Italian Program; Barcelona Clinic Liver Cancer; and Okuda have failed to predict overall survival (OS) in patients with resected primary hepatocellular carcinoma. Thus, we aimed to establish a novel D-index and nomogram to improve prognostic accuracy.Patients and MethodsWe selected 396 patients who underwent liver resection between January 2007 and February 2015 at the First Affiliated Hospital of Wenzhou Medical University. These patients were randomly divided into the training and validation groups in a ratio of 7:3.ResultsWe generated a nomogram using five independent risk factors, including the D-index (calculated by total bilirubin × tumor size/the ratio of fat-to-muscle area 0.5) in the training set. The predictive performance of the nomogram was similar in both the training and validation cohorts according to the concordance index. The nomogram demonstrated the strongest predictive power for 1-year, 3-year, and 5-year OS, with the area under the receiving operating characteristic curve being 0.8486, 0.7785, and 0.752, respectively. The calibration curves exhibited stable capabilities in both cohorts. The stratification of the Kaplan-Meier curve was significant (P < 0.001).ConclusionThe associated nomogram of the D-index demonstrated a powerful and accurate predictive ability for OS in patients with primary hepatocellular carcinoma.

Matrix Metalloproteinase-11 Gene Polymorphisms as a Risk for Hepatocellular Carcinoma Development in Egyptian Patients.

Background:Chronic hepatitis C (CHC) virus infection is one of major risk factors of hepatocellular carcinoma (HCC) in Egypt, which is a major cause of cancer mortalityin the world. Matrix metalloproteinase-11 (MMP-11) has an important role in tumor migration and metastasis. Therefore, this study aimed to determine relation between MMP-11 gene polymorphisms and risk of HCC development among Egyptian cirrhotic patients. Subjects and methods: Two hundred and sixty patients were included, 140 of them with HCC on top of CHC and 120 patients with post CHC liver cirrhosis (LC) as well as 140 subjects were enrolled in the study as healthy controls. Two single nucleotide polymorphisms (SNPs) rs738791 and rs738792 for MMP-11 gene were done using real-time PCR. Results:Combination of CT and TT allele of rs738791 genotypes was more significantly frequent in HCC compared to LC patients and controls, however, a higher frequency of T allele was found in HCC patients compared to LC and controls. In spite of lake of significant difference between patient groups regarding the rs738792 genotypes, the CC genotype was considered a risk of developing portal vein thrombosis, and was associated with advanced tumor stage, increased tumor size, higher Cancer of the Liver Italian Program [CLIP] score, more advanced Barcelona stage [D] and with child Pugh class [C]. Conclusion:Genetic variations in MMP-11 may be implicated in post HCV-HCC development and might be dependable biomarkers for HCC progression.

Integrating baseline MR imaging biomarkers into BCLC and CLIP improves overall survival prediction of patients with hepatocellular carcinoma (HCC).

We aimed to evaluate the independent predictive role of baseline imaging biomarkers for overall survival (OS) and transplant-free survival (TFS) in patients with HCC and assess the incremental value of these biomarkers to current staging systems. In this retrospective IRB approved study, the clinical, laboratory, and imaging parameters of 304 HCC patients were collected. Cox regression model was utilized to identify the potential predictors of survival. Recursive partitioning test was utilized to identify the optimal ADC cutoff for stratifying patients' OS. Patients were stratified based on Barcelona Clinic Liver Cancer (BCLC) and Cancer of the Liver Italian Program (CLIP). Binary ADC value (above vs. below the cutoff) and tumor margin (well- vs. ill-defined) were integrated into BCLC and CLIP. OS and TFS was compared for patients based on standard criteria with and without imaging biomarkers. At baseline, patients with low tumor ADC and well-defined tumor margin (favorable imaging biomarkers) had longer survival, as compared to those with high ADC and ill-defined tumor margin (unfavorable imaging biomarkers) (median OS of 43months vs. 7months, respectively) (p < 0.001). Tumor ADC and tumor margin remained strong independent predictors of survival after adjustment for demographics, BCLC and CLIP staging, and tumor burden. Incorporating ADC and tumor margin improved performance of OS prediction by 9% in BCLC group and 6% in CLIP group. Incorporating ADC and tumor margin to current staging systems for HCC significantly improve prediction of OS and TFS of these criteria. • ADC and tumor margin are predictors of overall survival in HCC patients, independent of clinical, laboratory, and other imaging variables. • Adding ADC and tumor margin improved the prognostic value of BCLC and CLIP criteria by 9% and 6%, respectively. • High ADC and ill-defined tumor margin at baseline predicted poor survival, regardless of patient's liver function and general health status.

"Six-and-twelve" score for outcome prediction of hepatocellular carcinoma following transarterial chemoembolization. In-depth analysis from a multicenter French cohort.

The “six-and-twelve” (6&12) score is a new hepatocellular carcinoma (HCC) prognostic index designed for recommended transarterial chemoembolization (TACE) candidates. Quick and easy to use by the sum of tumor size (cm) and number, this model identifies three groups with different survival time (the sum is ≤ 6; or > 6 but ≤ 12; or > 12); a survival benefit with TACE can be expected for HCC patients with a score not exceeding twelve. Recently, Wang ZW et al showed that the “6&12” model was the best system correlated with radiological response after the first TACE. Thus, we wanted to assess its survival prediction ability as well as its prognostic value and compared it to other systems (Barcelona Clinic Liver Cancer, Hong Kong Liver Cancer (HKLC) staging, Albumin-Bilirubin grade, tumor nodularity, infiltrative nature of the tumor, alpha-fetoprotein, Child-Pugh class, and Performance Status score, Cancer of the Liver Italian Program, Model to Estimate Survival for HCC scores, up-to-seven criteria) different from Wang ZW et al study in a multicenter French cohort of HCC including only recommended TACE candidates retrospectively enrolled. As previously demonstrated, we show that the "6&12” score can classify survival within this French cohort, with a prognostic value comparable to that of other systems, except HKLC staging. More importantly, the “6&12” score simplicity and ability in patients’ stratification outperform other systems for a routine clinical practice.

Prognostic value of the albumin-bilirubin grade in patients with hepatocellular carcinoma and other liver diseases.

One of the most commonly used systems for grading liver function in hepatocellular carcinoma (HCC) patients is the Child-Pugh (CP) score. However, the CP scoring system is not without its shortcomings: for example, the cut-off values for the parameters are calculated arbitrarily and the assessment of ascites and hepatic encephalopathy is subjective. More recently, an alternative to traditional CP grade has emerged in the form of albumin-bilirubin (ALBI) grade. The predictive value provided for HCC patients by the ALBI grade is comparable to that of the CP grade; however, it can also surpass CP grade by greatly reducing subjectivity and further subdividing CP A patients into several different groups, thus improving the prognosis judgment and helping to inform clinicians’ optimal decision-making. The application of the ALBI grade into currently used HCC staging systems such as the Barcelona Clinic Liver Cancer (BCLC) staging system, the Cancer of the Liver Italian Program (CLIP) staging system, and the Japan Integrated Staging (JIS) score, etc., as well as newly produced systems like the ALBI-PLT grade, the ALBI and progression disease (ALBI-PD) grade and Modified Intermediate Stage of Liver Cancer (MICAN) criteria, greatly elevates prognostic power.

Diagnostic role of collagen-III and matrix metalloproteinase-1 for early detection of hepatocellular carcinoma

ABSTRACTBackground: As the poor prognosis of hepatocellular carcinoma (HCC) is mostly due to late detection at an advanced stage there is a strong need for establishing more effective strategies for early identification. We hypothesized that collagen-III and matrix metalloproteinase-1 (MMP-1) and their ratio (CMR) are effective markers for identifying early-HCC when used alongside serum AFP, alkaline phosphatase and bilirubin.Methods: We recruited 148 patients with HCC, 133 with cirrhosis and 121 with fibrosis. Liver fibrosis was staged according to METAVIR, HCC was diagnosed by on histological findings or typical imaging characteristics by ultrasound and computed tomography. Collagen-III and MMP-1 were identified based on Western blotting and quantified in sera using ELISA, liver function tests (LFTs) by routine methods.Results: Patients with HCC showed a significantly (P < 0.05) higher collagen-III and collagen-III/MMP-1 ratio (CMR) than fibrotic and cirrhotic patients. Patients with HCC showed significantly (P < 0.05) lower concentration of MMP-1 than those without. As expected, numerous LFTs were also abnormal. A score of AFP, alkaline phosphatase and bilirubin together with CMR (the HCC-ABC test) was then constructed, This yielded ROC area under curves of 0.85 (95% CI 0.79–0.98) for identifying small tumour size (<3 cm), 0.87 (0.79–0.98) for identifying CLIP (0–1) [Cancer of the Liver Italian Program] disease severity, and 0.87 (0.74–0.93) for identifying BCLC disease severity (all p < 0.001), which is each case exceeded the predictive value of AFP.Conclusion: HCC-ABC diagnostic Test is a promising index for HCC early detection with a high degree of accuracy that may facilitate therapy.

Utility of scoring systems combining the product of tumor number and size with liver function for predicting the prognosis of patients with hepatocellular carcinoma after hepatectomy.

Our previous study reported the effectiveness of the product of tumor number and size (NxS factor) as a predictor of the prognosis of patients with hepatocellular carcinoma (HCC) following hepatectomy. The aim of the present study was to validate the prognostic value of scoring systems based on the NxS factor for HCC. The records of 940 patients who underwent hepatectomy for HCC at Osaka University Graduate School of Medicine and Osaka International Cancer Institute were analyzed. The discriminatory abilities of the mathematical integrated model for tumor staging (MITS) score, which combines the NxS factor with liver function, and known prognostic systems, including the Japan Integrated Staging system, the Barcelona Clinic Liver Cancer, Cancer of the Liver Italian Program and the Tokyo system, were compared. Firstly, the present study demonstrated that a higher NxS factor was associated with decreased disease-free survival (DFS) and overall survival (OS) in patients with HCC (P<0.05). Subsequently, univariate analysis of DFS and OS curves revealed significant differences among all NxS factor and liver damage combinations (MITS-LD score; score 0 vs. score 1; score 1 vs. score 2; score 2 vs. score 3; all P<0.05) and all NxS factor and albumin-bilirubin (ALBI) score combinations (MITS-ALBI score; score 0 vs. score 1; score 1 vs. score 2; score 2 vs. score 3; all P<0.05). Furthermore, multivariate Cox proportional hazards model analysis demonstrated that there were significant differences in DFS [Hazard Ratio (HR); score 0 vs. score 1 (1.48); score 1 vs. score 2 (1.27); score 2 vs. score 3 (1.64); all P<0.05] and OS [HR; score 0 vs. score 1 (1.34); score 1 vs. score 2 (1.29); score 2 vs. score 3 (1.64); all P<0.05] among patients with different MITS-LD scores, and there were significant differences in DFS [HR; score 0 vs. score 1 (1.38); score 1 vs. score 2 (1.43); score 2 vs. score 3 (1.60); all P<0.05] among patients with different MITS-ALBI scores. The NxS factor may be a comprehensive measure of tumor burden for predicting the prognosis of patients with HCC following liver resection, and MITS scores could be an improved scoring system for predicting the prognosis of patients with HCC after hepatectomy.

Preoperative lymphocyte-to-monocyte ratio is useful for stratifying the prognosis of hepatocellular carcinoma patients with a low Cancer of the Liver Italian Program score undergoing curative resection.

Background and AimAlthough the Cancer of the Liver Italian Program (CLIP) score is useful for prognostication of patients with hepatocellular carcinoma (HCC), a previous study has reported that the CLIP score was unable to stratify the postoperative outcomes of HCC patients in whom the score was low (0‐1). Recent studies have reported that the preoperative lymphocyte‐to‐monocyte ratio (LMR) is useful for prognostication of patients with various cancer.MethodsWe reviewed 329 HCC patients with a low CLIP score (0‐1) undergoing curative resection. This study had the approval of the Institutional Review Board (28068). Multivariate analyses were carried out to detect clinical factors correlating with overall survival (OS). Kaplan‐Meier analysis and the log‐rank test were used for comparison of OS.ResultsMultivariate analysis showed that LMR (<4.35/≥4.35) was significantly associated with OS (hazard ratio [HR], 2.022; 95% CI, 1.141‐3.583; P = 0.016) as well as portal vein invasion (HR, 2.410; 95%CI, 1.258‐4.618; P = 0.008). Kaplan‐Meier analysis and the log‐rank test showed a significant difference in OS and relapse‐free survival between patients with high LMR and those with low LMR.ConclusionPreoperative LMR is useful for stratifying the prognosis of HCC patients with a low CLIP score (0‐1) undergoing curative resection.

Combined preoperative albumin-bilirubin (ALBI) and serum γ-glutamyl transpeptidase (GGT) predicts the outcome of hepatocellular carcinoma patients following hepatic resection.

Background: Liver function is an important prognostic factor for patients with hepatocellular carcinoma. The purpose of this study was to develop and validate a nomogram integrating the albumin-bilirubin (ALBI) and serum γ-glutamyl transpeptidase (GGT) level to predict postoperative overall survival (OS) and disease-free survival (DFS) of hepatocellular carcinoma (HCC).Methods: The effect of combined of ALBI and GGT on HCC prognosis was investigated using univariate and multivariate Cox analyses. The nomogram for OS and DFS were developed, respectively, and their predictive ability was compared with other conventional staging systems, including the American Joint Commission on Cancer (AJCC), Barcelona Clinic Liver Cancer (BCLC) and the Cancer of the Liver Italian Program (CLIP).Results: Combined ALBI and GGT was highly associated with OS (P<0.001) and DFS (P<0.001) of HCC patients treated with hepatic resection. In addition, the C-index of the OS (0.706±0.034) or DFS (0.674±0.032) nomogram in the training cohort was larger than AJCC, BCLC and CLIP. The Akaike information criterion (AICs) of the OS (2178.405) or DFS (2961.018) nomogram in the training cohort was smaller than above staging systems. The results suggested that the OS or DFS nomogram was the most powerful model to predict HCC prognosis. The similar trend was observed in the validation cohort.Conclusion: The novel nomogram integrating ALBI and GGT was highly associated with OS and DFS of postoperative HCC patients.

Effectiveness of stereotactic ablative radiotherapy in patients with advanced hepatocellular carcinoma unsuitable for transarterial chemoembolization.

Background:Stereotactic ablative radiotherapy (SABR) can deliver tumoricidal doses and achieve long-term control in early hepatocellular carcinoma (HCC). However, limited studies have investigated the safety and effectiveness of SABR in patients with advanced diseases that is unsuitable for transarterial chemoembolization (TACE).Methods:In this observational study, we reviewed the medical records of patients with Barcelona Clinic Liver Cancer (BCLC) stage C disease treated with linear accelerator-based SABR between 2008 and 2016. Their tumors were either refractory to TACE or TACE was contraindicated. Overall survival (OS), in-field progression-free survival (IFPFS), and out-field progression-free survival were calculated using Kaplan–Meier analysis. The Cox regression model was used to examine the effects of variables. Treatment-related toxicities were scored according to the Common Terminology Criteria for Adverse Events (version 4.03) and whether patients developed radiation-induced liver disease (RILD) after SABR.Results:This study included 32 patients. The mean maximal tumor diameter and tumor volumes were 4.7 cm and 135.9 ml, respectively. Patients received linear accelerator-based SABR with a median prescribed dose of 48 Gy (30–60 Gy) in three to six fractions. Based on the assessment of treatment response by using the Response Evaluation Criteria in Solid Tumors (version 1.1), 19% of patients achieved a complete response and 53% achieved a partial response. After a median follow-up of 18.1 months (4.0–65.9 months), 10, 19, and 9 patients experienced in-field failure, out-field hepatic recurrence, and extrahepatic metastases, respectively. The estimated 2-year OS and IFPFS rates were 54.4% and 62.7%, respectively. In a multivariate analysis, a pretreatment Cancer of the Liver Italian Program (CLIP) score of ⩾2 (p = 0.01) was a prognostic factor for shorter OS, and a biologically effective dose (BED) of < 85 Gy10 (p = 0.011) and a Child–Pugh score of ⩾6 (p = 0.014) were prognostic factors for inferior IFPFS. In this study five and eight patients developed classic and nonclassic RILD, respectively.Conclusions:SABR can serve as a salvage treatment for patients with HCC with BCLC stage C disease unsuitable for TACE, in particular, in those with a baseline CLIP score of ⩽1. A BED10 of ⩾85 Gy is an appropriate prescribed dose for tumor control. Because out-field relapse is the major cause of treatment failure, SABR in combination with novel systemic modalities should be investigated in future studies.

Staging systems of hepatocellular carcinoma: A review.

Staging of hepatocellular carcinoma (HCC) is necessary for guiding prognostication, management, and research purposes that further aid in the improvement of existing clinical and epidemiological health services. Though there are some new staging systems for HCC developed in different parts of the world, there is no globally accepted staging system that allows for comparison of current management protocols among heterogeneous populations. In this review, we discuss the evolution and applicability in clinical practice of different clinical staging systems of HCC-Okuda, CLIP (Cancer of the Liver Italian Program) score, MESIAH (Model to Estimate Survival In Ambulatory HCC patients) score, ITA.LI.CA (Italian Liver Cancer) score, BCLC (Barcelona Clinic Liver Cancer) staging, HKLC (Hong Kong Liver Cancer) staging, and the Alberta algorithm. This review aims to highlight the main criteria for assessing the prognosis of HCC that these different staging systems take into account, their strengths and limitations for use in modern clinical practice. Despite the limitations of the BCLC staging system, it remains the most validated and reliable system for prognostication. However, there is a need to update the BCLC staging system to include recent data on locoregional and systemic therapies for HCC, expanded criteria for transplantation, and systemic therapy for hepatitis C infection.

Is there an optimal staging system or liver reserve model that can predict outcome in hepatocellular carcinoma?

Many staging systems and liver reserve models have been proposed to predict hepatocellular carcinoma (HCC) prognosis. However, there is no consensus as to which model provides the best prognostic value. We aimed to investigate the prognostic role of 8 noninvasive models including the albumin-bilirubin index (ALBI), AST to platelet ratio index (APRI), Barcelona Clinic Liver Cancer (BCLC), Cancer of the Liver Italian Program (CLIP) system, Child-Pugh (CP) class, Fibrosis-4 (FIB-4) score, model for end-stage liver disease (MELD) score, and platelet-albumin-bilirubin index (PALBI) in patients with HCC. This is a retrospective study of 900 HCC patients. Patients who underwent transplantation were excluded. The Kaplan-Meier method was used to estimate the survival probabilities. Multivariate cox proportional hazard models were used to calculate the survival trend. P<0.05 was considered significant. The area under receiver operating characteristic curve (AUC) was calculated to test the discriminatory power over 1- and 3-year mortality and recurrence. For predicting 1- and 3-year mortality, the CLIP score provided the highest AUC value, followed by the BCLC stage and the PALBI grade. For predicting 3-year recurrence, the CLIP score demonstrated the highest discriminative power followed by the PALBI grade, ALBI grade and BCLC system. However, all included models were found to be poor predictors for recurrence. The CLIP score is more accurate prognostic model to predict mortality and recurrence than the BCLC stage. Regarding the liver reserve models, the PALBI is the most accurate prognostic models among 6 models to predict mortality and recurrence.