• HCC
• IGF-CTP score
• immunotherapy
• prognostic biomarker

• Biomarkers, Tumor/blood
• Carcinoma, Hepatocellular/blood
• Carcinoma, Hepatocellular/pathology
• Case-Control Studies
• Female
• Humans
• Liver Neoplasms/blood
• Liver Neoplasms/pathology
• Male
• Predictive Value of Tests
• Prognosis
• Proportional Hazards Models
• Risk Factors
• Severity of Illness Index

• P30 CA016672 NCI NIH HHS
• R01 CA186566 NCI NIH HHS
• R21 CA190945 NCI NIH HHS
• R01 CA244845 NCI NIH HHS
• K07 CA106458 NCI NIH HHS
• R01 CA151533 NCI NIH HHS
• R01 CA183793 NCI NIH HHS
• R03 ES011481 NIEHS NIH HHS
• R21 CA170035 NCI NIH HHS
• R01 CA178744 NCI NIH HHS

Background: Sorafenib was the first systemic therapy approved for the treatment of Child-Turcotte-Pugh (CTP) class A patients with advanced hepatocellular carcinoma (HCC). However, there are no biomarkers to predict survival and treatment outcomes and guide HCC systemic therapy. Type 1 insulin-like growth factor (IGF-1)/CTP composite score has emerged as a potential hepatic reserve assessment tool. Our study investigated the association of the IGF/CTP score with overall survival (OS) and progression-free survival (PFS) of HCC patients treated with sorafenib.

Materials and Methods: In this prospective study, patients with HCC were treated with sorafenib and followed up until progression/death. We calculated the IGF/CTP score and used the Kaplan-Meier method and log-rank test to estimate and compare the time-to-event outcomes between patient subgroups.

Results: 171 patients were included, 116 of whom were CTP class A. Median PFS for IGF/CTP score AA and AB patients were 6.88 and 4.28 months, respectively (p = 0.1359). Median OS for IGF/CTP score AA and AB patients were 14.54 and 7.60 months, respectively (p = 0.1378). The PFS and OS was superior in AA patients, but the difference was not significant, likely due to the sample size. However, there was a significant difference in early OS and PFS curves between AA and AB (p = 0.0383 and p = 0.0099), respectively.

Conclusions: In CTP class A patients, IGF/CTP score B was associated with shorter PFS and OS, however, study was underpowered to reach statistical significance. If validated in larger cohorts, IGF/CTP score may serve as stratification tool in clinical trials, a hepatic reserve assessment tool for HCC outcomes prediction and to assist in therapy decisions.

• Child-Pugh
• IGF-1
• hepatocellular carcinoma
• liver reserve
• sorafenib

The clinical significance of the sodium-potassium ATPase regulator FXYD domain-containing ion transport regulator 3 (FXYD3) has been demonstrated in a number of types of cancer. However, the role of this protein in human hepatocellular carcinoma (HCC) remains to be elucidated. In the present study, 217 HCC tissue samples were analyzed to evaluate the expression and prognostic significance of FXYD3 in HCC. Reverse transcription-quantitative polymerase chain reaction was used to analyze the mRNA expression of FXYD3 in 80 primary HCC specimens and paired non-cancerous liver tissue samples, while western blotting was used to analyze the protein expression level of FXYD3 in another 24 pairs. These analyses demonstrated that the expression level of FXYD3 was significantly increasedb at the mRNA and protein levels in HCC tumor tissues compared with adjacent non-cancerous tissues. Immunohistochemical analysis of 137 paraffin-embedded HCC tissue samples indicated that the expression of FXYD3 was associated with HCC clinicopathological characteristics. Kaplan-Meier analysis demonstrated that patients with high FXYD3 protein expression (n=60) experienced significantly poorer overall survival time compared with patients with low FXYD3 protein expression (n=77) (P<0.001). Multivariate analysis demonstrated that FYXD3 protein expression level (hazard ratio, 2.137; 95% confidence interval, 1.224–3.732; P=0.008) was an independent prognostic factor in patients with HCC. Overall, the results indicated that FXYD3 expression levels were higher in HCC tumor tissues than in adjacent non-cancerous tissues, and that the FXYD3 protein may serve as a prognostic marker for HCC.

• FXYD domain-containing ion transport regulator 3
• human hepatocellular carcinoma
• overall survival
• prognosis
• sodium-potassium ATPase

• Hepatocellular carcinoma
• Recurrence
• Survival
• Tumor doubling time

Previous studies have supported an association between serum insulin-like growth factor-1 (IGF1) and IGF-binding protein 3 (IGFBP3) levels and hepatocellular carcinoma (HCC), but the results were inaccurate. It has recently been proposed that IGF1 and IGFBP3 play roles in the time-to-progression (TTP) and overall survival (OS) of HCC patients. Our results revealed that serum IGF1 level is predictive of the progression and survival of HCC patients.

HCC was associated with a significant reduction in serum IGF-1 and IGFBP-3 levels compared to cirrhosis (p = 0.037). Low serum IGF1 levels were predictive of a shorter TTP (OR, 2.74; 95% confidence interval [CI], 1.92–3.90) and poorer OS (odds ratio [OR], 2.20; 95% CI, 1.81–2.68) in HCC patients. The IGF1/IGFBP3 molar ratio was not significantly associated with the risk of HCC (OR, 1.311; 95% CI, 0.761–2.260).

We conducted a comprehensive literature search in PubMed, EMBASE, and the Cochrane Library. Twenty studies met the inclusion criteria and were subjected to statistical analysis. The geometric mean and standard deviation (SD) of serum IGF1 and IGFBP3 levels in the healthy, cirrhosis, and HCC groups were calculated. Pooled odds ratios (ORs) were calculated using a fixed-effects model to analyse the association of serum IGF1 level with the progression and survival of HCC patients.

Serum IGF1 and IGFBP3 levels were positively associated with the incidence of HCC. Serum IGF1 level is an independent prognostic factor for the progression and survival of HCC patients.

• IGF-binding protein-3
• hepatocellular carcinomas
• insulin-like growth factor-1
• overall survival
• time-to-progression

• hepatocellular carcinoma
• yucatan miniature pigs
• diethylnitrosamine
• animal models
• preclinical studies

• Adenoma/blood
• Adenoma/chemically induced
• Adenoma/pathology
• Animals
• Carcinoma, Hepatocellular/blood
• Carcinoma, Hepatocellular/chemically induced
• Carcinoma, Hepatocellular/pathology
• Diethylnitrosamine
• Disease Models, Animal
• Embolism/chemically induced
• Female
• Growth Hormone/blood
• Insulin-Like Growth Factor I/metabolism
• Interleukin-6/blood
• Janus Kinase 2/analysis
• Liver Neoplasms, Experimental/blood
• Liver Neoplasms, Experimental/chemically induced
• Liver Neoplasms, Experimental/pathology
• Portal Vein
• Receptors, Somatomedin/analysis
• STAT3 Transcription Factor/analysis
• STAT5 Transcription Factor/analysis
• Swine
• Swine, Miniature
• Time Factors
• Vascular Endothelial Growth Factor A/blood
• alpha-Fetoproteins/metabolism

• P30 CA015704 NCI NIH HHS
• P30 CA016672 NCI NIH HHS
• R01 CA151533 NCI NIH HHS

The Child-Turcotte-Pugh score (CTP) is the standard tool for hepatic reserve assessment in hepatocellular carcinoma (HCC). Recently, we reported that integrating plasma insulin-like growth factor-1 (IGF-1) level into the CTP score was associated with better patient risk stratification in two U.S. independent cohorts. Our current study aimed to validate the IGF-CTP score in patients who have different demographics and risk factors.

We prospectively recruited 100 Egyptian patients and calculated their IGF-CTP score compared to CTP score. C-index was used to compare the prognostic significance of the two scoring systems. Finally, we compared our results with our U.S. cohorts published data.

IGF-CTP score showed significant better patient stratification compared to CTP score in the international validation cohort. Among CTP class A patients, who usually considered for active treatment and clinical trial enrollment, 32.5% were reclassified as IGF-CTP class B with significantly shorter OS than patients reclassified as class A with hazard ratio [HR] = 6.15, 95% confidence interval [CI] = 2.18-17.37.

IGF-CTP score showed significantly better patient stratification and survival prediction not only in the U.S. population but also in international validation population, who had different demographics and HCC risk factors.

• Child-Pugh
• IGF-1
• hepatocellular carcinoma
• liver reserve
• validation

• IGF-I
• chronic liver disease
• growth hormone

Hepatocellular carcinoma (HCC) is a major health concern worldwide and the third cause of cancer-related death. Despite advances in treatment as well as careful surveillance programs, the mortality rates in most countries are very high. In contrast to other cancers, the prognosis and treatment of HCC depend on the tumor burden in addition to patient’s underlying liver disease and liver functional reserve. Moreover, there is considerable geographic and institutional variation in both risk factors attributable to the underlying liver diseases and the management of HCC. Therefore, although many staging and/or scoring systems have been proposed, there is currently no globally accepted system for HCC due to the extreme heterogeneity of the disease. The aim of this review is to focus on currently available staging systems as well as those newly reported in the literatures since 2012. Moreover, we describe problems with currently available staging systems and attempts to modify and/or add variables to existing staging systems.

• Hepatocellular carcinoma
• Staging system
• Scoring system
• Prognosis

Hepatocellular carcinoma (HCC) is one of the most common malignancies leading to high mortality rates in the general population; in cirrhotic patients, it is the primary cause of death. The diagnosis is usually delayed in spite of at-risk population screening recommendations, i.e., patients infected with hepatitis B or C virus. Hepatocarcinogenesis hinges on a great number of genetic and molecular abnormalities that lead to tumor angiogenesis and foster their dissemination potential. The diagnosis is mainly based on imaging studies such as computed tomography and magnetic resonance, in which lesions present a characteristic classical pattern of early arterial enhancement followed by contrast medium “washout” in late venous phase. On occasion, when imaging studies are not conclusive, biopsy of the lesion must be performed to establish the diagnosis. The Barcelona Clinic Liver Cancer staging method is the most frequently used worldwide and recommended by the international guidelines of HCC management. Currently available treatments include tumor resection, liver transplant, sorafenib and loco-regional therapies (alcoholization, radiofrequency ablation, chemoembolization). The prognosis of hepatocarcinoma is determined according to the lesion’s stage and in cirrhotic patients, on residual liver function. Curative treatments, such as liver transplant, are sought in patients diagnosed in early stages; patients in more advanced stages, were not greatly benefitted by chemotherapy in terms of survival until the advent of target molecules such as sorafenib.

• Hepatocellular carcinoma
• Surveillance
• Liver transplant
• Sorafenib
• Catheter ablation

Child-Turcotte-Pugh (CTP) score is the standard tool to assess hepatic reserve in hepatocellular carcinoma (HCC), and CTP-A is the classic group for active therapy. However, CTP stratification accuracy has been questioned. We hypothesized that plasma insulin-like growth factor 1 (IGF-1) is a valid surrogate for hepatic reserve to replace the subjective parameters in CTP score to improve its prognostic accuracy.

We retrospectively tested plasma IGF-1 levels in the training set (n = 310) from MD Anderson Cancer Center. Recursive partitioning identified three optimal IGF-1 ranges that correlated with overall survival (OS): greater than 50ng/mL = 1 point; 26 to 50ng/mL = 2 points; and less than 26ng/mL = 3 points. We modified the CTP score by replacing ascites and encephalopathy grading with plasma IGF-1 value (IGF-CTP) and subjected both scores to log-rank analysis. Harrell’s C-index and U-statistics were used to compare the prognostic performance of both scores in both the training and validation cohorts (n = 155). All statistical tests were two-sided.

Patients’ stratification was statistically significantly stronger for IGF-CTP than CTP score for the training (P = .003) and the validation cohort (P = .005). Patients reclassified by IGF-CTP relative to their original CTP score were better stratified by their new risk groups. Most important, patients classified as A by CTP but B by IGF-CTP had statistically significantly worse OS than those who remained under class A by IGF-CTP in both cohorts (P = .03 and P < .001, respectively, from Cox regression models). AB patients had a worse OS than AA patients in both the training and validation set (hazard ratio [HR] = 1.45, 95% confidence interval [CI] = 1.03 to 2.04, P = .03; HR = 2.83, 95% CI = 1.65 to 4.85, P < .001, respectively).

The IGF-CTP score is simple, blood-based, and cost-effective, stratified HCC better than CTP score, and validated well on two independent cohorts. International validation studies are warranted.

• hepatocellular carcinoma
• methodology
• observational studies
• randomized, clinical trials
• sorafenib

• Antiangiogenic therapy
• Hepatocellular carcinoma
• Predictive marker
• Prognosis

• Ablation Techniques
• Benzenesulfonates/therapeutic use
• Carcinoma, Hepatocellular/diagnosis
• Carcinoma, Hepatocellular/therapy
• Chemoembolization, Therapeutic
• Embolization, Therapeutic/methods
• Humans
• Liver Neoplasms/diagnosis
• Liver Neoplasms/therapy
• Liver Transplantation
• Niacinamide/analogs & derivatives
• Phenylurea Compounds
• Protein Kinase Inhibitors/therapeutic use
• Pyridines/therapeutic use
• Radiosurgery
• Sorafenib