To effectively prevent recurrence, improve the prognosis and increase the survival rate of primary liver cancer (PLC) patients with radical cure, the Chinese Society of Hepatology, Chinese Medical Association, invited clinical experts and methodologists to develop the Consensus on the Tertiary Prevention of Primary Liver Cancer, which was based on the clinical and scientific advances on the risk factors, histopathology, imaging finding, clinical manifestation, and prevention of recurrence of PLC. The purpose is to provide a current basis for the prevention, surveillance, early detection and diagnosis, and the effective measures of PLC recurrence.

The significance of the current study was to determine normative levels of PIVKA-II and AFP in patients with unresectable HCC and healthy participants. The second goal was to assess the roles of PIVKA-II and AFP in predicting radiological response after loco-regional therapy.

This prospective cohort study enrolled consecutive samples of HCC patients and healthy controls. Venous blood samples were obtained at baseline and after interventions to determine serum levels of PIVKA-II and AFP using the chemiluminescent microparticle immunoassay method. Radiologic responses were determined based on the WHO criteria.

Fifty-four HCC patients (mean age 58.9 years, 49 males) and 40 healthy controls (mean age 33.5 years, 26 males) were recruited. The median serum levels of PIVKA-II and AFP in HCC vs. healthy controls were 988.4 vs. 24.2 mAU/ml and 13.6 vs. 1.7 ng/ml, respectively (both p < 0.001). With ROC curve analysis, the area under the curve (AUC) for PIVKA-II was 0.95 95% CI [0.90-0.99], and for AFP it was 0.98, 95% CI [0.95-1.0]). The cut-off value for PIVKA-II was 41.4 mAU/ml, and AFP was 4.8 ng/ml. PIVKA-II levels correlated significantly with radiological responses (r = 0.64, p = 0.02) but not AFP (r = 0.09, p = 0.2).

PIVKA-II and AFP levels are distinctive between unresectable HCC and healthy controls. However, PIVKA-II, not AFP, can predict the radiological response after loco-regional therapy.

Surgical resection and radiofrequency ablation are preferred options for early-stage disease, with 5-year recurrence rates as high as 70% when patients are treated according to guidelines. With increasing availability of therapeutic options, including but not limited to, immune-checkpoint inhibitors (ICI), tyrosine kinase inhibitors, antiangiogenics, and adoptive cell therapies, understanding the causes of recurrence and identifying its predictors should be priorities in the hepatocellular carcinoma (HCC) research agenda.

Current knowledge of HCC predictors of recurrence is reviewed, and recent insights about its underlying mechanisms are presented. In addition, results from recent clinical trials investigating treatment combinations are critically appraised.

HCC recurrence is either due to progressive growth of microscopic residual disease, or to de novo cancer development in the context of a diseased liver, each occurring in an early (<2years) vs. late (≥2 years) fashion. Collectively, morphological, proteomic, and transcriptomic data suggest vascular invasion and angiogenesis as key drivers of HCC recurrence. Agents aimed at blocking either of these two hallmarks should be prioritized at the moment of early-stage HCC clinical trial design. Emerging results from clinical trials testing ICI in early-stage HCC underscore the importance of defining the best treatment sequence and the most appropriate combination strategies. Lastly, as different responses to systemic therapies are increasingly defined according to the HCC etiology, patient enrolment into clinical trials should take into account the biological characteristics of their inherent disease.

The high morbidity and mortality of hepatocellular carcinoma (HCC) has encouraged the search for new biomarkers to be used alongside alpha-foetoprotein (AFP) and imaging tests. The aim of this study was to evaluate the clinical contribution of protein induced by vitamin K absence or antagonist-II (PIVKA-II) for HCC monitoring after liver transplantation (LT) and compare it with AFP, a routinely used tumour marker. A total of 46 HCC patients (Milan criteria) were enrolled in this study. Serum levels of PIVKA-II and AFP were measured before and after transplantation. Clinical features were determined for all the patients that were included. Significant correlations were found between PIVKA-II expression levels and some clinicopathological features, such as tumour size and number of pre-transplant transarterial chemoembolizations (TACEs). Serum levels of PIVKA-II and AFP decreased significantly after LT and increased in patients with tumour recurrence. Serum PIVKA-II levels may play an important role in predicting disease severity. Furthermore, monitoring PIVKA-II levels in HCC transplant recipients reflects the tumor early recurrence after transplantation and could be used, complementing AFP and imaging tests, as a novel biomarker of this pathology.

The role of des-γ-carboxy prothrombin (DCP) in patients undergoing radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) needs to be clarified.

174 HCC patients that underwent RFA were enrolled. We calculated the HLs of DCP from the available values before and on first day after ablation and assessed the correlation between HLs of DCP and RFA efficacy.

Of 174 patients, 63 with pre-ablation DCP concentrations of ≥80 mAU/mL were analyzed. The ROC analysis showed the optimal cut-off value of HLs of DCP for predicting RFA response was 47.5 h. Therefore, we defined short HLs of DCP < 48 h as a predictor of favorable treatment response. Of 43 patients with a complete radiological response, 34 (79.1%) had short HLs of DCP. In 36 patients with short HLs of DCP, 34 (94.4%) had a complete radiologic response. The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value were 79.1%, 90.0%, 82.5%, 94.4%, and 66.7%. During the 12-month follow-up, patients who had short HLs of DCP had a better disease-free survival rate than patients with long HLs of DCP (p < 0.001).

Short HLs of DCP < 48 h calculated on the first day post-RFA are a useful predictor for treatment response and recurrence-free survival after RFA.

The role of Alfa-fetoprotein (AFP) in the management of hepatocellular carcinoma (HCC) is still debated, with differences in recommendations between international guidelines. We analyzed the relationship of the clinicopathological profile, prognostic features, and survival outcomes with baseline serum AFP levels in patients with HCC.

Retrospective analysis of a prospectively accrued dataset of consecutive HCC patients was done.

508 treatment naive patients were included in the analysis. AFP at presentation was normal (<10 ng/ml) in 18% patients. Patients with very high AFP (>400 ng/ml) had poor hepatic reserves (higher mean serum bilirubin, AST, ALT, INR, and lower mean albumin) and advanced disease at presentation (higher incidence of extrahepatic metastasis, and less proportion of patients with well-differentiated tumors). AFP >400 ng/ml was an independent predictor for presence of portal vein tumor thrombosis (PVTT) (OR, 4.08; 95% CI, 2.34-7.12; P < 0.001), higher tumor size (OR, 2.19; 95% CI, 1.36-3.54, P = 0.001) and advanced BCLC stage (OR, 4.19; 95% CI, 2.51-7.03; P < 0.001). Two-third of patients with small HCC (MTD <3 cm) and more than half with early-stage HCC (BCLC stage 0/A) had elevated AFP levels. No significant relationship was seen between overall survival (OS) and baseline AFP in patients who underwent surgery, but median OS in patients subjected to nonsurgical therapies was 19.4,10.5 and 5.7 months in patients having AFP <10 ng/ml, 10-400 ng/ml and >400 ng/ml respectively (P = 0.003). AFP >400 ng/ml was an independent predictor of survival in patients receiving any form of therapy (HR = 2.23; 95% CI = 1.19-4.18, P = 0.012).

AFP as a biomarker still has a significant role to play in the management of HCC patients and is here to stay till the search for an ideal biomarker in HCC is over.

An elevated preoperative aspartate aminotransferase-to-lymphocyte ratio index (ALRI) may predict poor survival in various cancers. However, the prognostic value of aminotransferase-to-lymphocyte ratio index (ALRI) in patients with hepatocellular carcinoma (HCC) remains to be determined.

A retrospective cohort study was conducted among 983 patients with HCC in our hospital from February 2007 to March 2016. A propensity-score matching (PSM) was performed to correct the selection bias and confounding factors. The risk of death and recurrence was plotted over aminotransferase-to-lymphocyte ratio index (ALRI) using the locally weighted scatterplot smoothing (LOWESS)-smoothed fit curve. Time-dependent receiver operating characteristic (ROC) and Kaplan-Meier method analysis was utilized to the role of aminotransferase-to-lymphocyte ratio index (ALRI) in HCC. Multivariate analysis was conducted to identify independent prognostic factors associated with overall survival (OS) and recurrence-free survival (RFS).

With the increase of aminotransferase-to-lymphocyte ratio index (ALRI), the risk of recurrence and death in HCC patients increases. In time-dependent ROC analysis, the AUC of aminotransferase-to-lymphocyte ratio index (ALRI) for predicting 1-, 3- and 5-year OS were 0.668 (95% CI: 0.596-0.740), 0.605 (95% CI: 0.560-0.649) and 0.613 (95% CI: 0.570-0.656), respective. The AUC of aminotransferase-to-lymphocyte ratio index (ALRI) for predicting 1-, 3- and 5-year RFS were 0.598 (95% CI: 0.555-0.641), 0.590 (95% CI: 0.552-0.628) and 0.604 (95% CI: 0.562-0.646), respectively. HCC patients with high aminotransferase-to-lymphocyte ratio index (ALRI) had a poor overall survival. Moreover, cox regression analysis revealed that aminotransferase-to-lymphocyte ratio index (ALRI) was an independent factor affecting the prognosis of HCC patients.

Elevated preoperative aminotransferase-to-lymphocyte ratio index (ALRI) is a noninvasive, simple, and effective predictor in the prognosis of patients with HCC.

We explored the ability of delta α-fetoprotein (ΔAFP) to detect recurrence in patients with liver cancer treated with hepatectomy.

A total of 1,846 patients diagnosed with local liver cancer who underwent hepatectomy at Sun Yat-sen University Cancer Center were enrolled in the present study. Receiver operating characteristic curve analysis was used to determine the cutoff value of ΔAFP at the last follow-up or recurrence.

Recurrence occurred in 51.5% (950/1,846) of liver cancer patients. The cutoff value of ΔAFP was 1.295 ng/mL in our model. Sensitivity in our model was higher than the normal range for AFP level for detecting recurrence (59.8% vs. 43.8%), but specificity was similar (98.4% vs. 99.8%). ΔAFP in preoperative AFP-positive patients (77.16% vs. 63.28%) and AFP-negative patients (31.20% vs. 11.70%) was more sensitive than normal AFP. ΔAFP was superior to AFP in the early (78.13% vs. 63.75%) or late recurrence (56.08% vs. 39.75%) of liver cancer. Moreover, in 18.3% of patients with recurrence (174/950), ΔAFP detected recurrence earlier than computed tomography/magnetic resonance imaging by 158.33 days. ΔAFP during follow-up indicated a worse prognosis after hepatectomy.

The cutoff value of ΔAFP is more sensitive for monitoring recurrence than a normal AFP level in liver cancer patients.

We have confirmed the diagnostic value of protein induced by vitamin K absence or antagonist-II (PIVKA-II) in a French cohort of patients with hepatocellular carcinoma (HCC). Herein, we aim to study the biological response under treatment and the prognostic value of PIVKA-II serum level in patients treated for HCC.

Patients with primary HCC developed chronic liver disease with serum PIVKA-II, and alpha-fetoprotein (AFP) levels available at baseline and after first HCC treatment [within 3 months (M1-M3) and/or within 6-9 months (M6-M9)] were included.

A total of 94 patients were included. Median follow-up was 23 months (range 11-31 months). PIVKA-II levels significantly decreased from baseline to M1-M3 (P = 0.002) and to M6-M9 (P = 0.035). By multivariate analysis, biological response (M1-M3/baseline PIVKA-II ratio) independently and significantly predicted overall survival (OS). A ratio below 0.73 was able to identify patients with the better prognosis in the total population [OS: 27 months (range 17-31) vs. 17 (range 9-25); P = 0.008] and in patients who had transarterial chemoembolization or selective internal radiation therapy as first treatment approach [OS: 26 months (range 14-31) vs. 16 (range 9-25); P = 0.002 and 2-year OS of 73% vs. 30%; P = 0.009]. PIVKA-II serum levels at baseline and PIVKA-II biological response were significantly associated with radiological response.

PIVKA-II serum level seems to be a good prognostic and promising biomarker for early monitoring treatment outcomes for patients with HCC.

To assess the efficacy of combined therapy involving bland transarterial embolization using gelatin sponge particles (bland GS-TAE) followed by transarterial chemoembolization using lipiodol mixed with anticancer agents and GS particles (Lip-TACE) to reduce the adverse events and increase the therapeutic effect of Lip-TACE in the treatment of huge (≥10 cm) hepatocellular carcinoma (HCC).

Twenty-one consecutive patients with huge HCCs (≥10 cm in diameter) were enrolled in this study. First, bland GS-TAE was performed to reduce the tumor volume, and then Lip-TACE was performed to control the remaining tumor at intervals of around three weeks. Tumor response, survival, and adverse events of this combined therapy were assessed.

The tumor response was assessed three months after combined TACE, with complete response in 38.1% and partial response in 57.1% of cases. Severe adverse events were seen in two patients, acute cholecystitis and tumor rupture. The median survival time was 2.7 years, and the one-, two-, three-, and five-year overall survival rates were 76.2%, 66.7%, 42.9%, and 25.0%, respectively.

Combined therapy involving bland GS-TAE followed by Lip-TACE can be performed safety and may improve survival in patients with huge HCCs.

To investigate the prognostic values of the change of α-fetoprotein within 1 week after resection of hepatocellular carcinoma.

We retrospectively analyzed patients with hepatocellular carcinoma who underwent curative hepatectomy as primary therapy at Zhongshan Hospital, Fudan University (Shanghai, China) from 2009 to 2011. We measured serum α-fetoprotein before (α-fetoprotein0) and 1 week after (α-fetoprotein7) hepatectomy, calculated change of α-fetoprotein, namely the α-fetoprotein response by the formula: AR = lgAFP7/lgAFP0 (lg = log10), analyzed the relationship between patient survival and α-fetoprotein response, and explored the potential clinical implications of the α-fetoprotein response. The results were validated in an independent cohort of patients from the same institute.

A total of 841 eligible patients were analyzed. We determined that the optimal cutoff value of the α-fetoprotein response was 0.8135 and subsequently classified patients from the exploration cohort into the α-fetoprotein responder (α-fetoprotein response ≤ 0.8135; n = 452) and α-fetoprotein nonresponder (α-fetoprotein response > 0.8135; n = 146). Multivariate Cox analysis showed that the α-fetoprotein response independently predicted overall survival (OS) and recurrence-free survival (RFS) time after resection (both P < .001). In patients with a higher risk of tumor recurrence (either single tumor with microvascular invasion or multiple tumors), α-fetoprotein responders were associated with better survival than the nonresponders (P < .05). The results were validated by propensity score matched population and another independent cohort.

The α-fetoprotein response is a reliable and simple predictive marker for evaluating the oncological effect of surgical resection for hepatocellular carcinoma with positive α-fetoprotein before resection, independent of tumor features.

Resminostat is an oral inhibitor of class I, IIB, and IV histone deacetylases. This phase I/II study compared the safety and efficacy of resminostat plus sorafenib versus sorafenib monotherapy as first-line therapy for advanced hepatocellular carcinoma (HCC).

In phase I, resminostat (400 mg or 600 mg/day on days 1 to 5 every 14 days) was administered with sorafenib (800 mg/day for 14 days) to determine the recommended dose for phase II. In phase II, patients were randomized (1:1) to sorafenib monotherapy or resminostat plus sorafenib. The primary endpoint was time-to-progression (TTP).

Nine patients (3: 400 mg, 6: 600 mg) were enrolled in phase I, and the recommended dose of resminostat was determined to be 400 mg/day. Then 170 patients were enrolled in phase II. Median TTP/overall survival (OS) were 2.8/14.1 months with monotherapy versus 2.8/11.8 months with combination therapy (Hazard Ratio [HR]: 0.984, p = 0.925/HR: 1.046, p = 0.824). The overall incidence of adverse events was similar in both groups (98.8% versus 100.0%). However, thrombocytopenia ≥ Grade 3 was significantly more frequent in the combination therapy group (34.5% versus 2.4%, p < 0.001). Subgroup analysis revealed that median TTP/OS was 1.5/6.9 months for monotherapy versus 2.8/13.1 months for combination therapy (HR: 0.795, p = 0.392/HR: 0.567, p = 0.065) among patients with a normal-to-high baseline platelet count (≥ 150 × 10³/mm³).

In patients with advanced HCC, first-line therapy with resminostat at the recommended dose plus sorafenib showed no significant efficacy advantage over sorafenib monotherapy.

To investigate whether the change in pre-/post-operation serum alpha-fetoprotein (AFP) levels is a predictive factor for hepatocellular carcinoma (HCC) outcomes.

We retrospectively analyzed 334 HCC patients who underwent hepatic resection at our hospital between January 2006 and December 2016. The patients were classified into three groups according to their change in serum AFP levels: (1) the normal group, pre-AFP ≤ 20 ng/mL and post-AFP ≤ 20 ng/mL; (2) the response group, pre-AFP > 20 ng/mL and post-AFP decrease of ≥ 50% of pre-AFP; and (3) the non-response group, pre-AFP level > 20 ng/mL and post-AFP decrease of < 50% or higher than pre-AFP level, or any pre-AFP level < 20 ng/mL but post-AFP >20 ng/mL.

Univariate and multivariate analyses revealed that multiple tumors [hazard ratio (HR): 1.646, 95%CI: 1.15-2.35, P < 0.05], microvascular invasion (mVI) (HR: 1.573, 95%CI: 1.05-2.35, P < 0.05), and the non-response group (HR: 2.425, 95% CI: 1.42-4.13, P < 0.05) were significant independent risk factors for recurrence-free survival. Similarly, multiple tumors (HR: 1.99, 95%CI: 1.12-3.52, P < 0.05), mVI (HR: 3.24, 95%CI: 1.77-5.90, P < 0.05), and the non-response group (HR: 3.62, 95%CI: 1.59-8.21, P < 0.05) were also significant independent risk factors for overall survival. The non-response group had significantly lower overall survival rates and recurrence-free survival rates than both the normal group and the response group (P < 0.05). Thus, patients with no response regarding post-surgery AFP levels were associated with poor outcomes.

Serum AFP responses are significant prognostic factors for the surgical outcomes of HCC patients, suggesting post-resection AFP levels can direct the management of HCC patients.

To investigate the status of somatostatin receptors (SSTRs) in resected hepatocellular carcinoma (HCC).

Transcript and protein levels of SSTR2, SSTR3 and SSTR5 were investigated, with real-time polymerase chain reaction (PCR) and manual and automated immunohistochemistry (IHC), in 53 resected HCCs and paired non-tumour tissues. SSTR1, SSTR4, SSTR5TMD4 and SSTR5TMD5 were analysed with real-time PCR. SSTR3 and SSTR5 transcripts were expressed in ~25% of HCCs, but not in adjacent non-tumour tissues. SSTR1 and SSTR2 transcripts were overexpressed in 42% and 32% of HCCs, respectively. SSTR4, SSTR5TMD4 and SSTR5TMD5 were not detected. Membrane staining for SSTR2 was detected in 38% of HCCs, whereas SSTR5 protein was detectable in only 11% of HCCs. SSTR3 protein was detected in the majority of HCCs and adjacent non-tumour liver tissues, but membrane staining was <20% of that in HCCs. The results obtained with the two IHC methods were highly correlated (P < 0.0001). Statistical analyses also showed a positive correlation between SSTR2 membrane staining and cytokeratin 19 expression (P = 0.04), serum α-fetoprotein level (P = 0.002), and poor differentiation (P = 0.05).

Membrane SSTR2 is detected reliably in HCCs by IHC, and is a potential therapeutic target, as it is coexpressed with markers of poor prognosis.

Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related death in the world. Radical treatment of HCC in early stages results in a long disease-free period and improved overall survival. The choice of optimal management strategy for HCC mainly depends on the severity of the underlying liver disease. For patients with decompensated liver cirrhosis and HCC within Milan criteria (MC), liver transplant (LT) is the choice of treatment. However, for patients with good residual liver reserve and HCC within MC, selection of other curative treatments such as liver resection (LR) or radiofrequency ablation may be a reasonable alternative. For patients without cirrhosis, LR can result in an overall survival similar to that provided by LT. Therefore, it is an accepted alternative to LT especially in areas with organ shortage. However, the cumulative 5-year recurrence rate of HCC post LR might be as high as 70%. For initial transplant-eligible (within MC) patients with recurrent HCC post LR, salvage liver transplant (SLT) was first proposed in 2000. However, most patients with recurrent HCC considered for SLT are untransplantable cases due to HCC recurrence beyond MC or comorbidity. Thus, the strategy of opting for SLT results in the loss of the opportunity of LT for these patients. Some authors proposed the concept of "de principe liver transplant" (i.e., prophylactic LT before HCC recurrence) to prevent losing the chance of LT for these potential candidates. Factors associated with the failure of SLT will be dissected and discussed in three parts: Patient, tumor, and underlying liver disease. Regarding patient-related factors, the rate of transplantability depends on patient compliance. Patients without regular follow-up tend to develop HCC recurrence beyond MC at the time of tumor detection. Advancing age is another factor related to severe comorbidities when LT is considered for HCC recurrence, and these elderly candidates become ineligible as time goes by. Regarding tumor-related factors, histopathological features of the resected specimen are used mostly for determining the prognosis of early HCC recurrences. Such prognostic factors include the presence of microvascular invasion, poor tumor differentiation, the presence of microsatellites, the presence of multiple tumors, and the presence of the gene-expressing signature associated with aggressive HCC. These prognostic factors might be used as a selection tool for SLT or prophylactic LT, while remaining mindful of the fact that most of them are also prognostic factors for post-transplant HCC recurrence. Regarding underlying liver disease-related factors, progression of chronic viral hepatitis and high viral load may contribute to the development of late (de novo) HCC recurrence as a consequence of sustained inflammatory reaction. However, correlation between the severity of liver fibrosis and tumor recurrence is still controversial. Some prognostic scoring systems that integrate these three factors have been proposed to predict recurrence patterns after LR for HCC. Theoretically, after excluding patients with high risk of post-transplant HCC recurrence, either by observation of a cancer-free period or by measurement of biological factors (such as alpha fetoprotein), prophylactic LT following curative resection of HCC could be considered for selected patients with high risk of recurrence to provide longer survival.

Des-γ-carboxy prothrombin (DCP) is a representative tumor marker of hepatocellular carcinoma (HCC), and its values are occasionally very high in HCC cases. The current study aimed to clarify the postoperative half-life of DCP as a prognostic factor.

This retrospective study enrolled 177 patients who had undergone liver resection as an initial treatment for HCC. Three DCP half-life groups were defined as follows: within the normal range, half-life shorter than 4 days, and half-life of 4 days or longer. The overall and recurrence-free survival rates were estimated and compared among the three groups.

There were 140 patients in the group with a DCP half-life in the normal range, 19 patients in the group with a DCP half-life shorter 4 days, and 18 patients in the group with a DCP half-life of 4 days or longer. A multivariate analysis showed that only a postoperative DCP half-life of 4 days or longer was an independent prognostic risk factor for overall and recurrence-free survival (respective hazard ratios of 2.92 and 4.19; P < 0.001). The group with a preoperative DCP value lower than 1400 mAU/mL, the median value of DCP in the current study, included no patients from the group with a half-life shorter than 4 days. The overall and recurrence-free survival rates in the group with a half-life of 4 days or longer were significantly poorer (P < 0.001) than in the group that had a half-life shorter than 4 days (P = 0.002) with a preoperative DCP status of 1400 mAU/mL or more.

The current study showed for the first time that a prolonged half-life of DCP is an independent prognostic risk factor for survival and recurrence after liver resection with curative intent.

Hepatitis B (HBV)-associated hepatocellular carcinoma (HCC) is often associated with alpha-fetoprotein (AFP) production. Although serum AFP has been demonstrated to be a prognostic factor for patient survival, optimal cutoff levels remain unclear.

Patients with HBV-associated HCC treated by primary liver resection were prospectively followed at a single institution between 1995 and 2008. AFP level was categorized into quintiles for Kaplan–Meier analysis and multivariable Cox proportional hazards regression models.

Best 5-year survival after surgery was observed for patients with AFP in the first quintile (1.4-4.1 ng/mL), with progressively worse outcomes for patients in each increasing quintile. AFP was associated with overall survival (HR = 1.61; 95 % CI 1.30-1.98), disease-free survival (HR = 1.26; 95 % CI 1.10-1.44), and 2-year recurrence (HR = 1.30; 95 % CI 1.07-1.57) in multivariate analysis. Noncirrhotic patients (Ishak 1-5) with AFP in quintile 1 had 94 % 5-year survival, compared with 0 % survival for patients with AFP in quintile 5 (2,332.7-327,560.0 ng/mL) and Ishak stage 6 cirrhosis.

Preoperative serum AFP is an independent predictor of prognosis among HBV-HCC patients following surgical resection. Categorizing AFP into quintiles creates the opportunity to observe differences in outcomes even at low serum levels within the normal range. Additionally, combining AFP quintiles and fibrosis staging provides a predictive model of prognosis for HCC. Thus, even small differences in AFP within the normal range may impact prognosis and disease progression for HBV-HCC.

The postresection alpha-fetoprotein (AFP) in cirrhotic patients with hepatocellular carcinoma (HCC) may predict overall survival (OS) and recurrence beyond Milan criteria (MC) among the subgroup of initially transplantable patients.

All patients with cirrhosis resected for HCC between January 1990 and December 2010 in a single institution and presenting a serum AFP value > 15 ng/ml at diagnosis were included. The postresection AFP was analyzed as a dichotomized variable: normalization (norm + group) or not (norm - group) within the 90-day postresection period.

Among 271 resected patients, 141 patients (52%) had a level of serum AFP ≥ 15 ng/ml at diagnosis. Five-year OS and median survival were 42% and 52 months in group norm + versus 20% and 23 months in the group norm - (P = 0.009). On multivariate analysis, the absence of AFP normalization was an independent factor of poor OS as well as microvascular invasion, and satellites nodules. Among theoretically transplantable patients, independent predictors of recurrence beyond MC were the absence of AFP normalization (risk ratio (RR) 5.02 [1.53-16.34]) and microvascular invasion (RR 4.76 [1.42-15.34]).

The postresection AFP has an independent prognostic value. Transplantable patients resected for HCC without 90-day AFP normalization should be discussed for early liver transplantation.

To compare the assessment of response and prognosis of patients to sorafenib treatment by the Response Evaluation Criteria in Solid Tumors (RECIST), modified RECIST (mRECIST), α-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP).

Sixty-six patients with advanced hepatocellular carcinoma (HCC) treated with sorafenib were enrolled in this retrospective study. The response to treatment was evaluated by RECIST, mRECIST and changes in AFP and DCP.

The median survival time of all patients was 8.6 months. The median time to radiological progression was 3.3 months. The response rates [complete response (CR) + partial response (PR)] by RECIST and mRECIST were 3.0 and 9.0%, respectively, while the disease control rates [CR + PR + stable disease (SD)] were 50 and 50%, respectively. Assessment by mRECIST of overall survival provided a better stratification of the patients according to the response to treatment (p = 0.009) than RECIST (p = 0.09). Assessment of overall survival by a change in AFP ratio of ≤ 1 at 8 weeks was better than that of >1 at 8 weeks (p = 0.002). The DCP ratio was not useful for assessment of overall survival. Multivariate analysis identified mRECIST response (CR + PR + SD; p = 0.001), AFP ratio at 8 weeks (≤ 1; p = 0.046) and Child-Pugh A before treatment (p = 0.012) as significant and independent determinants of survival. The combination of AFP ratio at 8 weeks, assessment by mRECIST and Child-Pugh score before treatment allows stratification of prognosis of patients treated with sorafenib.

The combination of mRECIST and AFP ratio is useful for the assessment of prognosis of patients with advanced HCC treated with sorafenib.

There is no worldwide consensus on clinical application of staging systems that have been proposed for hepatocellular carcinoma (HCC). This study evaluated the predictors of survival and compared the prognosis predictability according to staging systems of HCC.

We analyzed the medical records of 142 patients who were consecutively diagnosed as HCC in hepatitis B virus (HBV)-endemic area. To analyze the survival predictors and probability of staging systems, Kaplan-Meier method and Cox proportional hazard model were used. And to compare the discriminatory ability and predictive power of staging systems for prognosis and survival, likelyhood ratio χ(2) test and Akaike information criterion were applied.

Overall median survival of HCC patients was 24 months and 1-, 2-, and 3-year survival rate was 61.3, 49.4, and 45.7%, respectively. Child-Pugh classification (P=0.038) and portal vein thrombosis (PVT) (P=0.022) were ascertained as independent predictors of survival. Although all the staging systems showed a progressive decrease in survival as the tumor stage progressively advanced, the Japan Integrated Staging (JIS) and Chinese University Prognostic Index (CUPI) showed the highest homogeneity (small differences in survival among patients in the same stages), and the best monotonicity of gradient (the survival of patients in earlier stages is longer than the survival of patients in more advanced stages within the same system), respectively.

In HBV-endemic area, Child-Pugh classification and PVT were independent predictors for survival, and JIS and CUPI were the most powerful staging systems to predict the prognosis of HCC.

α-Fetoprotein (AFP) and prothrombin induced by the absence of vitamin K or antagonist-II (PIVKA-II) are useful tumor markers for hepatocellular carcinoma (HCC). However, little is known about the clinical characteristics and prognosis of HCC with different levels of AFP and PIVKA-II.

Consecutive 1447 HCC patients were assigned to four groups according to the cutoff values of AFP (400 ng/ml) and PIVKA-II (100 mAU/ml): both values high (AP), one of the values high (Ap and aP), and both values low (ap). The clinical characteristics and the prognosis of group ap were compared with those of the other groups.

HCC patients in group ap were more asymptomatic at diagnosis, and had smaller size, fewer numbers, and earlier stages of HCC, and more preserved liver functions (all, P<0.001). The survival rate of group ap was significantly higher than those of the other groups (P<0.001). In multivariate analysis, the combined status of AFP and PIVKA-II values were independent predictors for survival (P<0.001), together with tumor size, number, portal vein thrombosis, Child-Pugh class, and treatment modality.

HCC patients with low values of both AFP and PIVKA-II had more favorable clinical characteristics and showed a better prognosis than those with elevated levels of AFP or PIVKA-II.

Alpha-fetoprotein (AFP), des-γ-carboxy prothrombin (DCP), and lens culinaris agglutinin-reactive fraction of AFP (AFP-L3) have been developed with the intent to detect hepatocellular carcinoma (HCC) and for the surveillance of at-risk patients. However, at present, none of these tests can be recommended to survey cirrhotic patients at risk for HCC development because of their suboptimal ability for routine clinical practice in HCC diagnosis. Starting from these considerations, these markers have been therefore routinely and successfully used as predictors of survival and HCC recurrence in patients treated with curative intent. All these markers have been largely used as predictors in patients treated with hepatic resection or locoregional therapies, mainly in Eastern countries. In recent studies, AFP has been proposed as predictor of recurrence after liver transplantation and as selector of patients in the waiting list. Use of AFP modification during the waiting list for LT is still under investigation, potentially representing a very interesting tool for patient selection. The development of a new predictive model combining radiological and biological features based on biological markers is strongly required. New genetic markers are continuously discovered, but they are not already fully available in the clinical practice.

Serum alpha-fetoprotein (AFP) is frequently used to predict posthepatectomy outcomes in patients with hepatocellular carcinoma (HCC), but its predictive value is still not established. Therefore, we assessed the prognostic significance of AFP status.

Of 525 patients undergoing curative hepatectomy for HCC, 290 had preoperative AFP levels of ≥20 ng/mL (AFP-positive group) and 235 had AFP levels of <20 ng/mL (AFP-negative group). We compared the 2 groups with respect to time-to-recurrence, using the inverse probability of treatment weighted (IPTW) for the entire cohort and propensity score matching, and the cumulative incidence of HCC-specific mortality using competing risks regression.

During follow-up (median duration 64 months, range 2-137 months), HCC recurred in 54.9 % of the AFP-negative group and 52.4 % of the AFP-positive group; there was no death without recurrence. After IPTW adjustment, time-to-recurrence did not differ in the 2 groups (hazard ratio [HR] 0.86, 95 % confidence interval [95 % CI] 0.66-1.12; P = 0.28). In a propensity-score matched cohort (152 pairs), time-to-recurrence data were similar to those obtained by IPTW adjustment (HR 0.91, 95 % CI 0.65-1.25; P = 0.55). There was no difference in recurrence pattern (site and stage) or treatment between the 2 groups even after propensity-score matching. The adjusted HR evaluating the impact of AFP positivity on the risk of HCC-specific mortality was 0.77 (95 % CI 0.54-1.08; P = 0.13) A multivariable competing risks analysis also failed to reveal a significant correlation between baseline AFP level and HCC-specific mortality in the AFP-positive group.

Preoperative AFP levels are not useful for predicting recurrence or survival endpoints following curative hepatectomy for HCC.