Proposal of an integrated staging system using albumin-bilirubin grade and serum alpha-fetoprotein values for predicting postoperative prognosis of recurrent hepatocellular carcinoma.

BACKGROUND: Because repeat hepatectomy for recurrent hepatocellular carcinoma is a potentially invasive procedure, it is necessary to identify patients who truly benefit from repeat hepatectomy. Albumin-bilirubin grading has been reported to predict survival in patients with hepatocellular carcinoma. However, as prognosis also depends on tumor factors, a staging system that adds tumor factors to albumin-bilirubin grading may lead to a more accurate prognostication in patients with recurrent hepatocellular carcinoma. METHODS: Albumin-bilirubin grading and serum alpha-fetoprotein levels were combined and the albumin-bilirubin-alpha-fetoprotein score was created ([albumin-bilirubin grading = 1; 1 point, 2 or 3; 2 points] + [alpha-fetoprotein<75 ng/mL, 0 points; ≥5, 1 point]). Patients were classified into three groups, and their characteristics and survival were evaluated. The predictive ability of the albumin-bilirubin-alpha-fetoprotein score was compared with that of the Cancer of the Liver Italian Program and the Japan Integrated Stage scores. RESULTS: Albumin-bilirubin-alpha-fetoprotein score significantly stratified postoperative survival (albumin-bilirubin-alpha-fetoprotein score = 1/2/3: 5-year recurrence-free survival [%]: 22.4/20.7/0.0, p < 0.001) and showed the highest predictive value for survival among the integrated systems (albumin-bilirubin-alpha-fetoprotein score/Japan Integrated Stage/Cancer of the Liver Italian Program: 0.785/0.708/0.750). CONCLUSIONS: Albumin-bilirubin-alpha-fetoprotein score is useful for predicting the survival of patients with recurrent hepatocellular carcinoma undergoing repeat hepatectomy.

Effectiveness of Chemotherapy on Long-Term Survival in a Case of Advanced Juvenile Hepatocellular Carcinoma Without Viral Hepatitis Infection.

Hepatocellular carcinoma (HCC) usually occurs in settings of cirrhosis and chronic hepatitis B or C virus (HBV and HCV, respectively) infection; it is extremely rare in patients <40 years of age since viral- or alcohol-induced chronic hepatitis develops over a prolonged period. Juvenile HCC is mostly associated with persistent HBV infection; cases unrelated to HBV or HCV infection (non-B, non-C juvenile HCC) are sporadic and treated in the same way as classical HCC. A woman in her late 30s was diagnosed with HCC in a healthy liver; her imaging findings were typical of HCC with bone metastasis. She was administered a combination of tyrosine kinase inhibitors, immune checkpoint inhibitors, and vascular endothelial growth factor inhibitors. Throughout chemotherapy, the liver reserve was Grade A on the Child-Pugh classification and tumor markers remained under control without marked elevation. Our patient is the first reported long-term survivor of unresectable non-B, non-C juvenile HCC following chemotherapeutic treatment.

Clinical Characteristics and Survival of Hepatocellular Carcinoma: Insights from Single-Centre Experience in Saudi Arabia.

Background Hepatocellular carcinoma (HCC) represents the most common primary liver malignancy, with a high fatality rate. Relatively, Saudi Arabia has a high incidence of HCC, which is detected in later stages with a poor prognosis. This study aims to investigate the patterns, outcomes, and mortality predictors of HCC in Saudi Arabia. Method A retrospective study from April 2018 to June 2022 included patients with HCC who were diagnosed and managed at the Najran Oncology Center, Saudi Arabia. Through our cancer registry, the patients' clinical, laboratory, radiological, and survival profiles were extracted and analyzed to assess factors associated with mortality using a univariate analysis. The overall survival was calculated by the Kaplan-Meier method. Results The study involved 52 patients with an average age of 74.6 years, predominantly male (the male-to-female ratio is 2.25:1). Viral infections were the primary cause of liver disease in 40.3% (n=21) of patients. At diagnosis, the Child-Pugh class distribution included 23.1% (n=12) patients in class A, 36.5% (n=19) patients in class B, and 40.4% (n=21) patients in class C. Uninodular tumors with ≤50% liver extension were observed in 65.4% (n=34) of cases, and 30.8% (n=16) had portal vein thrombosis. Elevated alpha-fetoprotein (AFP) levels were noted in 48.1% (n=25) of patients, with 23.1% (n=12) exceeding 400 ng/mL. Curative resection was performed in 32.7% (n=17) of patients. The mean survival time was 23±11.8 months (median of 22.5 months, minimum of six, and maximum of 49 months). Relapse occurred in seven (13.5%) cases, while new metastasis occurred in 20 (38.5%) cases. During the study period, 26 (50.0%) patients died. The main cause of death was disease progression in 15 (28.8%) patients. Univariate analysis showed that AFP>400 ng/mL (OR: 4.68; 95% CI: 1.87-11.66, p=0.001), presence of relapse (OR: 0.16; 95% CI: 0.03-0.78, p=0.023), abdominal ascites (OR: 3.38; 95% CI: 1.25-9.14, p=0.016), advanced the Cancer of the Liver Italian Program (CLIP) score (OR: 0.60; 95% CI: 0.41-0.88, p=0.009) were associated with higher mortality rate and were statistically significant. Conclusion Most cases of HCC in our patients were attributed to viral hepatitis, with the majority having liver cirrhosis. Higher AFP (>400 ng/mL), relapse, abdominal ascites, and a higher cancer CLIP score were associated with poorer outcomes. Targeted screening and health education should be advocated; in addition, social determinants should be proactively addressed.

Radiographic and serologic response in patients with unresectable hepatocellular carcinoma receiving systemic antineoplastic treatments: A trial-level analysis.

BACKGROUND: In a disease like unresectable hepatocellular carcinoma, overall survival is an inadequate outcome measure for evaluating the effectiveness of treatments given the high risk of death from liver failure. There is an unmet need for reliable alternative end points for clinical trials and daily clinical practice. To evaluate treatment response in patients with unresectable or metastatic hepatocellular carcinoma (mHCC), imaging-related end points are often used, whereas serologic end points have been developed for patients with serum alpha-fetoprotein levels >20 ng/mL. The objective of this study was to evaluate clinical trials that report concomitant assessment of radiographic and serologic response in patients with mHCC. METHODS: After a systematic review, studies that evaluated response according to radiographic and serologic criteria were selected. A correlation between progression-free survival (PFS) and overall survival (OS) was performed, and a linear regression of each response-related outcome measure with OS was reported. Finally, the effect of eight baseline variables on OS and response-related measures was evaluated. RESULTS: Twenty-six studies were included, including 16 first-line studies and 10 second-line studies. PFS and response rates demonstrated a significant relationship with OS, whereas disease control rates did not. The responses were correlated with OS, particularly in the first-line setting, after targeted therapy, and whenever assessment was early. Among the baseline variables, only performance status had a prognostic role, whereas hepatitis B virus-related liver disease was associated with higher radiographic response rates. CONCLUSIONS: PFS and radiographic and serologic response rates appear to be reliable intermediate end points in patients with mHCC who are undergoing systemic antineoplastic therapy. However, the serologic response is available earlier.

Metabolic management after sustained virologic response in elderly patients with hepatitis C virus: A multicenter study.

AIMS: Hepatocellular carcinoma (HCC) develops even in patients with hepatitis C virus (HCV) eradication by direct-acting antiviral agents. Fatty liver and metabolic dysfunction are becoming major etiologies of HCC. We aimed to evaluate the impact of metabolic dysfunction-associated steatotic liver disease (MASLD), a new definition of steatotic liver disease, on the development of HCC after HCV eradication. METHODS: We enrolled 1280 elderly patients with HCV eradication and no history of HCC. We evaluated α-fetoprotein (AFP), Fibrosis-4 index and MASLD after 24 weeks of sustained virological response. Decision tree analysis was used to investigate factors associated with HCC development after HCV eradication. RESULTS: A total of 86 patients (6.7%) developed HCC during the follow-up period (35.8 ± 23.7 months). On multivariate analysis, serum AFP level (HR 1.08, CI 1.04-1.11, P = 0.0008), Fibrosis-4 index (HR 1.17, CI 1.08-1.26, P = 0.0007), and MASLD (HR 3.04, CI 1.40-6.58, P = 0.0125) at 24 weeks of sustained virological response were independent factors associated with HCC development. In decision tree analysis, the initial classifier for HCC development was AFP ≥7 ng/mL. However, in patients with AFP <7 ng/mL, MASLD, rather than Fibrosis-4 index, was the classifier for HCC development. No significant difference was observed in the cumulative incidence of HCC between patients with AFP ≥7 ng/mL and patients with AFP <7 ng/mL and MASLD. CONCLUSION: MASLD at 24 weeks of sustained virological response is a risk factor for HCC development in elderly patients with HCV eradication. Additionally, decision tree analysis revealed that MASLD was associated with HCC development, even in patients with serum AFP levels <7 ng/mL.

Diagnostic algorithm for subcentimeter hepatocellular carcinoma using alpha-fetoprotein and imaging features on gadoxetic acid-enhanced MRI.

OBJECTIVE: To investigate the role of serum alpha-fetoprotein (AFP) in diagnosing subcentimeter hepatocellular carcinoma (HCC) on gadoxetic acid-enhanced MRI (EOB-MRI). METHODS: This study retrospectively enrolled treatment-naïve patients with chronic hepatitis B who had a solitary subcentimeter observation on EOB-MRI from January 2017 to March 2023. Final diagnosis was confirmed by pathology for HCC and pathology or follow-up for benign controls. The AFP cutoff value for HCC was determined using Youden's index. Diagnostic criteria were developed according to significant findings in logistic regression analyses based on AFP and imaging features. The diagnostic performance of possible criteria was compared to the diagnostic hallmarks of HCC (arterial-phase hyperintensity and portal-phase hypointensity). RESULTS: A total of 305 patients (mean age, 51.5 ± 10.7 years; 153 men) were divided into derivation and temporal validation cohorts. Four findings, namely AFP >13.7 ng/mL, arterial-phase hyperintensity, portal-phase hypointensity, and transitional-phase hypointensity, were predictors of HCC. A new criterion (at least three of the four findings) showed higher sensitivity than the diagnostic hallmarks (derivation cohort, 71.6% vs. 52.3%, p < 0.001; validation cohort, 75.0% vs. 47.5%, p = 0.003) without decreasing specificity (derivation cohort, 92.5% vs. 92.5%, p > 0.999; validation cohort, 92.0% vs. 92.0%, p > 0.999). Another criterion (all four findings) achieved a slightly higher specificity than the diagnostic hallmark (derivation cohort, 99.1% vs. 92.5%, p = 0.023; validation cohort, 100.0% vs. 92.0%, p = 0.134). Subgroup analysis for hepatobiliary hypointense observations yielded similar results. CONCLUSION: Including AFP in the diagnostic algorithm may improve the diagnostic performance for subcentimeter HCC. CLINICAL RELEVANCE STATEMENT: Combining imaging features on gadoxetic acid-enhanced MRI with alpha-fetoprotein may enhance the diagnostic performance for subcentimeter HCC in treatment-naïve patients with chronic hepatitis B. KEY POINTS: • The traditional diagnostic hallmark of HCC (arterial-phase hyperintensity and portal-phase hypointensity) shows modest diagnostic performance for subcentimeter HCC on EOB-MRI. • Serum alpha-fetoprotein > 13.7 ng/mL, arterial-phase hyperintensity, portal-phase hypointensity, and transitional-phase hypointensity were independent predictors for subcentimeter HCC. • A criterion of at least three of the four above findings achieved a higher sensitivity without decreasing specificity.

Maternal First-Trimester Alpha-Fetoprotein and Placenta-Mediated Pregnancy Complications.

BACKGROUND: Maternal serum markers used for trisomy 21 screening are associated with placenta-mediated complications. Recently, there has been a transition from the traditional first-trimester screening (FTS) that included PAPP-A (pregnancy-associated plasma protein-A) and beta-hCG (human chorionic gonadotropin), to the enhanced FTS test, which added first-trimester AFP (alpha-fetoprotein) and PlGF (placental growth factor). However, whether elevated first-trimester AFP has a similar association with placenta-mediated complications to that observed for elevated second-trimester AFP remains unclear. Our objective was to estimate the association of first-trimester AFP with placenta-mediated complications and compare it with the corresponding associations of second-trimester AFP and other first-trimester serum markers. METHODS: Retrospective population-based cohort study of women who underwent trisomy 21 screening in Ontario, Canada (2013-2019). The association of first-trimester AFP with placenta-mediated complications was estimated and compared with that of the traditional serum markers. The primary outcome was a composite of stillbirth or preterm placental complications (preeclampsia, birthweight less than third centile, or placental abruption). RESULTS: A total of 244 990 and 96 167 women underwent FTS and enhanced FTS test screening, respectively. All markers were associated with the primary outcome, but the association for elevated first-trimester AFP (adjusted relative risk [aRR], 1.57 [95% CI, 1.37-1.81]) was weaker than that observed for low PAPP-A (aRR, 2.48 [95% CI, 2.2-2.8]), low PlGF (aRR, 2.28 [95% CI, 1.97-2.64]), and elevated second-trimester AFP (aRR, 1.97 [95% CI, 1.81-2.15]). When the models were adjusted for all 4 enhanced FTS test markers, elevated first-trimester AFP was no longer associated with the primary outcome (aRR, 0.77 [95% CI, 0.58-1.02]). CONCLUSIONS: Unlike second-trimester AFP, elevated first-trimester AFP is not an independent risk factor for placenta-mediated complications.

Mesenchymal Hamartoma With Elevated Alpha-Fetoprotein: A Diagnostic Pitfall.

Mesenchymal hamartoma (MH) is a benign liver tumor accounting for 3% to 8% of all liver tumors in children, commonly manifesting before 3 years of life. Distinguishing MH from hepatoblastoma and other liver tumors relies on imaging and alpha-fetoprotein (which is usually within normal range in MH), before histologic examination. We report a case of a hepatic MH associated with elevated alpha-fetoprotein, leading to a misdiagnosis of hepatoblastoma and the administration of chemotherapy. We draw the attention to the diagnostic difficulty and pitfalls related to alpha-fetoprotein elevation in the setting of a liver tumor, and we highlight the importance of imaging and histology in establishing the diagnosis.

Preparation and application of patient-derived xenograft mice model of colorectal cancer.

Objectives: Patient-derived xenograft (PDX) model becomes a more and more important tool for tumor research. This study aimed to establish a colorectal cancer PDX model and verify its applicability. Materials and Methods: Fresh human colorectal cancer tissue was surgically removed and subcutaneously inoculated into immunodeficient mice to establish the PDX model. Hematoxylin and eosin (HE) staining and immunohistochemical staining were used to evaluate the model. The successful PDX model was selected to study the efficacy of capecitabine in treating colorectal cancer. Results: HE staining showed that the PDX mice model of colorectal cancer could preserve the histological characteristics of the primary tumor. Immunohistochemistry staining showed α-fetoprotein (AFP), carcinoembryonic antigen (CEA), and E-cadherin were strongly positively expressed in primary human and PDX tumor tissues, with a high degree of similarity. Capecitabine significantly inhibited PDX tumor growth and reduced the expression of AFP and CEA proteins in the tumor tissues (all P s<0.05). Conclusion: We successfully established a colorectal cancer PDX model, and the PDX model could retain the histological and biological characteristics of the primary tumor. Using this PDX model, we revealed that capecitabine at a dose of 300-400 mg/kg can effectively treat colorectal cancer, and no significant difference in toxicity was found among different dose groups. The current work provides a feasible framework for establishing and validating the PDX tumor model to better facilitate the evaluation of drug efficacy and safety.

Diagnostic efficacy of alpha-fetoprotein and alpha-fetoprotein L3% in hepatitis B virus-related early-stage hepatocellular carcinoma / 临床肝胆病杂志

‍ ObjectiveTo investigate the diagnostic efficacy and optimal cut-off values of alpha-fetoprotein （AFP） and alpha-fetoprotein variant L3 （AFP-L3） in hepatitis B virus （HBV）-related early-stage hepatocellular carcinoma （HCC）. MethodsA total of 1 080 patients with HBV-related HCC （HBV-HCC） who were diagnosed for the first time and not yet treated in The Third Affiliated Hospital of Sun Yat-Sen University from January 2019 to July 2022 were enrolled as HCC group in the study， among whom there were 620 patients with CNLC Ⅰ‍a-‍Ⅱ‍a HCC， and in addition， 346 patients with HBV-related chronic hepatitis B （CHB group） and 293 patients with HBV-related liver cirrhosis （LC group） were enrolled as controls. The diagnostic efficacy of AFP and AFP-L3% in screening for HBV-related early-stage HCC was analyzed， including sensitivity， specificity， and the area under the ROC curve （AUC）. The Mann-Whitney U test was used for comparison of continuous data with skewed distribution between two groups； the Kruskal-Wallis H test was used for comparison between multiple groups， and the Bonferroni method was used for further comparison between two groups. ResultsThe HCC group had significantly higher levels of AFP and AFP-L3% than the CHB group and the LC group （H=542.479 and 418.974， both P<0.001）. In early-stage HCC， AFP and AFP-L3% had an optimal cut-off value of 8.7 ng/mL and 5%， respectively， and AFP alone had the largest AUC of 0.816， with a sensitivity of 66.9% and a specificity of 85.1%. There was no significant difference in AUC between AFP-L3%+AFP and AFP alone （Z=0.609， P=0.543）， but both AFP-L3%+AFP and AFP alone had a significantly larger AUC than AFP-L3% alone （AFP vs AFP-L3%： Z=8.173， P<0.001； AFP+AFP-L3% vs AFP-L3%： Z=8.802， P<0.001）. ConclusionAFP has a good value and is superior to AFP-L3% in the diagnosis of HBV-related early-stage HCC， and the screening cut-off value of AFP should be lowered in order to improve the detection rate of early-stage HCC.

Performance of laminin γ2 in diagnosing hepatocellular carcinoma and in microvascular invasion / 中华肝胆外科杂志

Objective:To analyze the value of laminin γ2 (LAMC2) in the diagnosis of hepatocellular carcinoma (HCC) and the difference in patients with different types of microvascular invasion (MVI).Methods:A cohort of 100 patients with HCC who underwent surgical treatment at the Faculty of Hepato-Pancreato-Biliary Surgery, Chinese PLA General Hospital from January 2021 to March 2022 were prospectively enrolled. There were 80 males and 20 females, aged (55.7±11.1) years. The data of 17 patients with hepatic hemangioma without cirrhosis who underwent operation at the same hospital during the study period were collected to serve as the control group (6 males, 11 females), aged (42.8±9.8) years. LAMC2 in serum was determined by enzyme linked immunosorbent assay. The levels of alpha-fetoprotein (AFP) and LAMC2 were compared between the two groups, and receiver operating characteristic (ROC) curves were drawn to compare these two markers in the diagnosis of HCC. The LAMC2 of different MVI patients were compared.Results:The levels of LAMC2 and AFP were 1 334.2(838.9, 2 656.0) pg/ml and 19.0(4.6, 778.6) μg/L in the HCC group, which were significantly higher than 375.2(221.2, 691.7)pg/ml and 3.3(2.5, 3.5) μg/L in the control group ( Z=-4.32, -4.63, both P<0.001). The areas under the ROC curve were 0.829(95% CI: 0.748-0.892) for LAMC2 and 0.852(95% CI: 0.769-0.910) for AFP, and was 0.949(95% CI: 0.911-0.988) for using both in the diagnoses. The diagnostic efficacy of combining LAMC2 and AFP was significantly better than that of LAMC2 alone and AFP alone (area under ROC: Z=3.15, 3.07, P=0.002, 0.002). When the patients were divided into the M0 group (61 patients), the M1 Group (25 patients) and the M2 Group (14 patients) based on MVIs, the concentrations of LAMC2 were 1 168.6(834.3, 2 521.4) pg/ml, 942.2(614.0, 2 056.6) pg/ml and 3 128.4(1 852.7, 7 191.3) pg/ml, respectively. The level of LAMC2 in the M2 group was significantly higher than that in the M0 and M1 groups ( Z=-3.46, -3.32, P=0.001, 0.004). Conclusion:The diagnostic efficacy of LAMC2 combined with AFP for HCC was significantly higher than that of either LAMC2 alone or AFP alone. Serum LAMC2 levels were significant different among the groups of HCC patients with different types of MVI.

Serum alpha-fetoprotein in predicting survival of patients with BCLC C hepatocellular carcinoma treated by salvage surgery after downstaging therapy / 中华肝胆外科杂志

Objective:To analyze the value of alpha-fetoprotein(AFP) in predicting survival of patients who underwent salvage surgery after tumor downstaging therapy in patients with advanced hepatocellular carcinoma.Methods:The data of 50 patients with Barcelona Clinic Liver Cancer Staging (BCLC) C hepatocellular carcinoma treated at the Faculty of Hepato-Pancreato-Biliary Surgery, Chinese PLA General Hospital from December 2018 to December 2021 were collected. There were 45 males and 5 females, with the age of (53.0±10.5) years. The patients were divided into two groups based on the serum AFP level after tumor downstaging therapy, AFP normal group ( n=27, AFP≤20 μg/L) and the control group ( n=23, AFP>20 μg/L). Patient survival and tumor recurrence were followed up by outpatient review or telephone follow-up. The survival rate was calculated by the Kaplan-Meier method and compared by the log-rank test. The efficacy of combined immunotargeted therapy were compared between the two groups. Univariate and multivariate Cox regression analysis were carried to analyse the factors influcing prognosis. Results:The median survival time was not reached in both groups. The 1-year and 2-year cumulative survival rates were 95.0% and 88.2% in the normal group and 73.4% and 54.1% in the control group, respectively. The median relapse-free survival time of the normal group was not reached, and the median relapse-free survival time of the control group was 11 months. The 1-year recurrence-free survival rate was 78.1% in the normal group and 39.5% in the control group. The cumulative survival rate and relapse-free survival rate in the normal group were significantly higher than those in the control group (χ 2=7.60, 8.83, P=0.006, 0.003). The complete response, partial response and pathological complete response of tumors in the normal group were significant better than those in the control group. Multivariate Cox regression analysis showed that patients with serum AFP >20 μg/L ( HR=2.952, 95% CI: 1.023-8.517, P=0.045) after immunotherapy combined with targeted therapy had an increased risk of postoperative recurrence. Conclusion:The reduction of serum AFP to normal after downstaging therapy could be used as a prognostic indicator of salvage surgical in patients with BCLC C hepatocellular carcinoma, and AFP was related to the efficacy of downstaging therapy in patients.

The diagnostic value of CT-guided puncture biopsy combined with serum gamma-glutamyltransferase and abnormal prothrombin in serum alpha-fetoprotein negative primary liver cancer / 中国医师进修杂志

Objective:To investigate the diagnostic value of CT-guided puncture biopsy combined with serum gamma-glutamyltransferase (GGT) and abnormal prothrombin (PIVKA-Ⅱ) in serum alpha-fetoprotein(AFP) negative primary liver cancer (PHC).Methods:Eighty patients with AFP negative PHC treatment in Fuyang Women and Children′s Hospital from January 2018 to March 2021 were selected as AFP negative PHC group, and another 85 patients diagnosed with benign liver tumor during the same period were selected as the control group retrospectively. The patients of the two groups underwent CT-guided biopsy and the levels of GGT and PIVKA-Ⅱ were detected. The single diagnostic value and combined diagnostic value of AFP negative PHC were analyzed by receiver operating characteristic (ROC) curve.Results:Seventy-five of the 80 patients in the AFP negative PHC group were confirmed as liver malignant lesions by biopsy, with a coincidence of 93.75%, and 84 of the 85 patients in the control group were confirmed as liver benign lesions by biopsy, with a coincidence of 98.82%. The levels of AFP, GGT and PIVKA-Ⅱ in AFP negative PHC group were significantly higher than those in the control group: (175.67 ± 39.58) μg/L vs. (18.74 ± 7.42) μg/L, (1 245.37 ± 255.41) U/L vs. (486.63 ± 89.05) U/L, (385.49 ± 30.27) AU/L vs. (25.84 ± 7.66) AU/L, there were statistical differences ( P<0.05). Spearman correlation analysis showed that serum AFP was positively correlated with GGT and PIVKA-Ⅱ ( r = 0.858 and 0.429, P<0.05). The results of ROC curve showed that the area under curve of CT-guided biopsy combined with GGT and PIVKA-Ⅱ in the diagnosis of AFP negative PHC was 0.877, the sensitivity was 91.19%, the specificity was 87.34%. Conclusions:CT-guided biopsy combined with GGT and PIVKA-Ⅱ detection of AFP negative PHC can effectively improve the diagnostic value.

Value of a scoring system based on the serum levels of alpha-fetoprotein and alkaline phosphatase in predicting the prognosis of patients with resectable hepatocellular carcinoma / 临床肝胆病杂志

Objective To establish a scoring system based on the preoperative serum levels of alpha-fetoprotein (AFP) and alkaline phosphatase (ALP), and to investigate its value in predicting the prognosis of patients with resectable hepatocellular carcinoma (HCC). Methods A retrospective analysis was performed for 154 HCC patients who underwent hepatectomy as the initial treatment in Tianjin First Central Hospital from January 2016 to August 2019. The receiver operating characteristic (ROC) curve was used to determine the optimal cut-off values of serum AFP and ALP; the Kaplan-Meier curve and the log-rank test were used for survival analysis to evaluate the relationship between the AFP-ALP score and disease-free survival (DFS); univariate and multivariate Cox regression analyses were used to identify the independent prognostic factors for HCC patients. The independent samples t -test was used for comparison of normally distributed continuous data between groups, and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between groups; the chi-square test was used for comparison of categorical data between groups. Results The ROC curve analysis showed that serum AFP had an optimal cut-off value of 250.0 ng/mL and an area under the ROC curve (AUC) of 0.674 (95% confidence interval [ CI ]: 0.580-0.767) in predicting DFS, while serum ALP had an optimal cut-off value of 95.5 U/L and an AUC of 0.745 (95% CI : 0.652-0.838). The survival analysis showed that high preoperative serum levels of AFP (≥250.0 ng/mL) and ALP (≥95.5 U/L) were significantly associated with the poor prognosis of HCC patients ( P < 0.001). Based on the AFP-ALP score, all HCC patients were further divided into 0-point group (AFP < 250.0 ng/mL and ALP < 95.5 U/L), 1-point group (AFP≥250.0 ng/mL, ALP < 95.5 U/L; or AFP < 250.0 ng/mL, ALP ≥95.5 U/L), and 2-point group (AFP≥250.0 ng/mL and ALP≥95.5 U/L). The survival curves showed that the 0-, 1-, and 2-point groups had a median DFS of 60.0 (56.7-67.3) months, 20.0 (1.4-36.6) months, and 13.0(7.9-18.0) months, respectively, and there were significant survival differences between the three groups ( P < 0.05). Serum AFP-ALP score (1 point vs 0 point: hazard ratio [ HR ]=4.060, 95% confidence interval [ CI ]: 2.050-8.039, P < 0.001; 2 points vs 0 point: HR =4.583, 95% CI : 2.385-8.805, P < 0.001) was an independent prognostic factor for HCC patients. Conclusion The scoring system based on the serum levels of AFP and ALP can effectively identify HCC patients with poor prognosis, and therefore, it might be used as a simple and reliable tool for prognostic assessment in the clinical treatment of HCC.

Value of alpha-fetoprotein response in evaluating the efficacy of sorafenib combined with camrelizumab in treatment of advanced hepatocellular carcinoma / 临床肝胆病杂志

Objective To investigate the value of alpha-fetoprotein (AFP) response in evaluating the clinical efficacy and safety of sorafenib combined with camrelizumab in the treatment of advanced hepatocellular carcinoma (HCC). Methods Clinical data were collected from 48 patients with advanced HCC who were treated with sorafenib combined with camrelizumab in The First Affiliated Hospital of Xinjiang Medical University from September 2020 to February 2022, and according to the level of AFP response after treatment, they were divided into response group with 32 patients (AFP after 6-8 months of treatment was reduced by more than 20% compared with baseline AFP) and non-response group with 16 patients (AFP after 6-8 months of treatment was reduced by less than 20% compared with baseline AFP). The Mann-Whitney U test was used for comparison of continuous data between groups, and the chi-square test was used for comparison of categorical data between groups. Survival curves were plotted, and univariate and multivariate Cox regression analyses were used to investigate the independent risk factors for overall survival (OS). Progression free survival (PFS) time, OS time, and treatment outcome were compared between the two groups. Results No patient achieved clinical remission in either group. Compared with the non-response group, the response group had significantly higher objective response rate (21.88% vs 0, χ 2 =2.530, P =0.112) and disease control rate (84.38% vs 43.75%, χ 2 =6.668, P =0.010). Compared with the non-response group, the response group had longer PFS time (9.9 months vs 6.8 months) and OS time (13.8 months vs 11.1 months). Early non-response of AFP (hazard ratio [ HR ]=2.624, 95% confidence interval [ CI ]: 1.097-6.277, P =0.030) and extrahepatic metastasis ( HR =0.392, 95% CI : 0.157-0.978, P =0.045) were independently associated with a shorter PFS time. No adverse event leading to drug withdrawal was observed in the study. Conclusion Early AFP response has a high clinical value in predicting the efficacy of sorafenib combined with camrelizumab in the treatment of advanced HCC and the prognosis of such patients.

Baseline characteristics associated with survival in patients with hepatocellular carcinoma.

Background and Aim: Hepatocellular carcinoma (HCC) is one of the most common and most lethal cancers worldwide. The objective of this study was to investigate the relationship between basal parameters and survival characteristics in patients with HCC. Materials and Methods: The records of 1447 HCC patients of a tertiary center during the period 2000-2017 were screened retrospectively. The demographic details; basal clinical, laboratory, and radiological characteristics; treatments; and survival time were recorded and prognostic scores were calculated. Results: A total of 788 patients with HCC (male/female: 623/165; mean age: 60.5±10.9 years) were included in the study. The median length of survival was 26.3 months (95% confidence interval [CI], 22.3-30.4 months). The 5-year survival rate was 28.1%. The number and diameter of the tumors; platelet count; platelet-to-lymphocyte ratio; level of aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyl transferase; portal and hepatic vein involvement; and an alpha-fetoprotein level of <9.6 ng/mL were found to be independently related to survival. Conclusion: The positive predictive value of the prognostic index derived from independent survival-related parameters for 5- and 10-year survival or overall survival was approximately 86%. Integration of this prognostic index to the criteria used in making treatment decisions for patients with HCC should be considered.

Differential diagnosis between alpha-fetoprotein-negative hepatocellular carcinoma without cirrhosis and hepatic focal nodular hyperplasia / 中华肝胆外科杂志

Objective:To study the clinical and MRI features of alpha-fetoprotein-negative hepatocellular carcinoma without cirrhosis to compare with those of hepatic focal nodular hyperplasia (FNH) to arrive at a correct differential diagnosis.Methods:The data of 105 patients who underwent liver surgery for alpha-fetoprotein-negative hepatocellular carcinomas without cirrhosis at Zhongshan Hospital, Fudan University and the Traditional Chinese Medical Hospital of Nantong from March 2017 to November 2020 were retrospectively studied. There were 109 lesions in 95 males and 10 females. These patients had the age of (60.2±9.9) years. The data of 88 patients who were diagnosed to have hepatic FNH during the study period were collected, and there were 99 lesions in 36 males and 52 females. These patients had the age of (32.8±9.5) years. Variables including age, history of hepatitis B virus infection, T 1 weighted imaging (T 1WI), T 2 weighted imaging (T 2WI), diffusion-weighted imaging (DWI), apparent diffusion coefficient (ADC), enhancement mode, lesion shape, lesion boundary and capsule were compared between the two groups. Results:The age and the proportion of patients with a history of hepatitis B in the alpha-fetoprotein-negative hepatocellular carcinoma and without cirrhosis group were significantly higher than those in the hepatic FNH group (both P<0.05). The proportion of lesions with quasi-circular shape, clear boundary and with capsule in hepatocellular carcinoma group were significantly higher than those in the hepatic FNH group (all P<0.05). There were also significant differences in the T 1WI, T 2WI, enhancement modes, DWI, and ADC map between the two groups of lesions (all P<0.05). The areas under the receiver operating characteristic curve for the alpha-fetoprotein-negative hepatocellular carcinoma without cirrhosis by the age >45.5 year, with a history of hepatitis B, with clear lesion boundary, with a "washin and washout" enhanced mode and with lesion encapsulation were 0.97(95% CI: 0.95-0.99), 0.79(95% CI: 0.72-0.85), 0.78(95% CI: 0.72-0.85), 0.94(95% CI: 0.90-0.97), 0.99(95% CI: 0.98-1.00) respectively. Conclusions:The presence of a capsule, clear lesion boundary and "washin and washout" enhanced mode are helpful in differentiating alpha-fetoprotein-negative hepatocellular carcinoma without cirrhosis with hepatic FNH.

Utility of serum neuropilin-1 and angiopoietin-2 as markers of hepatocellular carcinoma.

This study aimed to assess the diagnostic value of two serum angiogenetic markers neuropilin-1 (NRP-1) and angiopoietin-2 (ANG-2) in patients with hepatocellular carcinoma (HCC) and their relation to tumor characteristics. 149 subjects were recruited and divided into 50 patients with recently diagnosed HCC, 49 patients with cirrhosis on top of hepatitis C virus infection, and 50 healthy subjects. Serum NRP-1 and ANG-2 were estimated by ELISA. Alpha-fetoprotein (AFP) levels were measured using fluorescence immunoassay. Serum NRP-1 and ANG-2 levels were significantly higher in patients with HCC (2221.8±1056.6 pg/mL and 3018.5±841.4 pg/mL) than healthy subjects (219.3±61.8 pg/mL and 2007.7±904.8 pg/mL) and patients with cirrhosis (1108.9±526.6 pg/mL and 2179.1±599.2 pg/mL), respectively. In multivariate logistic regression analysis, NRP-1 and AFP were the only independent factors of HCC development and correlated positively with each other (r=0.781, p<0.001). Receiver operating characteristic curve analysis showed that the area under the curve (AUC) of NRP-1 was higher than that of ANG-2 in discriminating HCC from patients with cirrhosis (0.801 vs 0.748, p=0.250) and healthy subjects (0.992 vs 0.809, p<0.001). The AUC of NRP-1 was detected to be increased (0.994) when combined estimation with AFP was performed. Elevated serum NRP-1 and ANG-2 levels were detected in patients with HCC with tumor numbers >3, tumor size ≥5 cm, tumor stages B/C according to the Barcelona Clinic Liver Cancer staging system, vascular invasion, and distant metastasis. In conclusion, NRP-1 is a potential serological marker for HCC diagnosis and is better than ANG-2. It is feasible to be estimated in combination with AFP to enhance its diagnostic power. High serum NRP-1 and ANG-2 levels are associated with advanced HCC tumor characteristics.

Elevated serum alpha-fetoprotein levels are associated with poor prognosis of hepatocellular carcinoma after surgical resection: A systematic review and meta-analysis.

BACKGROUND AND STUDY AIMS: The relationship between the alpha-fetoprotein (AFP) level and the prognosis of hepatocellular carcinoma (HCC) after surgical resection remains unknown. This study aims to assess this relationship. PATIENTS AND METHODS: PubMed and Web of Science were systematically utilised. Meta-analysis was conducted for the outcomes of the recurrence-free survival (RFS) and the overall survival (OS) by comparing the high AFP group with the low AFP group. RESULTS: The studies included 61 manuscripts with 35,461 patients. The summary hazard ratio (HR) for RFS was 1.501 (95% CI 1.355-1.662; Z = 7.81, P < 0.00001) when comparing the high AFP group with the low AFP group. Sensitivity analysis only included adjusted HRs, with the summary HR being 1.563 (95% CI 1.381-1.768; Z = 7.10, P < 0.00001). The summary HR for OS was 1.565 (95% CI 1.439-1.701; Z = 10.52, P < 0.00001) when comparing two AFP groups. Sensitivity analysis showed that the summary HR was 1.611 (95% CI 1.456-1.782; Z = 9.24, P < 0.00001). CONCLUSION: Our meta-analysis indicated that elevated serum AFP levels are associated with poor prognosis of HCC after surgical resection.

Clinical outcomes of patients with a high alpha-fetoprotein level but without evident recurrence on CT or MRI in surveillance after curative-intent treatment for hepatocellular carcinoma.

PURPOSE: Multiphasic CT or MRI and serum alpha-fetoprotein (AFP) are widely used for posttreatment surveillance of hepatocellular carcinoma (HCC). This study aimed to investigate the clinical outcomes of patients with high posttreatment AFP but without evident recurrence on CT or MRI after curative-intent treatment of HCC. METHODS: We retrospectively analyzed 121 patients presenting with high posttreatment AFP (> 20 ng/mL) without evident recurrence on multiphasic CT or MRI during surveillance after curative-intent surgical resection or radiofrequency ablation (RFA) for HCC. The time interval from the first event of high posttreatment AFP to imaging-evident recurrence (TimeAFP-Imaging recurrence) was estimated using the Kaplan-Meier method. Cox regression analyses were performed to assess the associated factors with TimeAFP-Imaging recurrence. RESULTS: The median TimeAFP-Imaging recurrence was 20.0 months (95% CI 13.0-28.0 months), and the estimated 6-month and 1-year cumulative incidences of imaging-evident recurrence were 24.4% and 40.1%, respectively. In multivariate Cox analyses, late onset of AFP elevation (> 3 months after treatment) was an independent predictor of shorter TimeAFP-Imaging recurrence (HR 2.11, P = 0.015) if using variables available at the first event of AFP elevation, while non-normalization of AFP at the next follow-up was an independent predictor of shorter TimeAFP-Imaging recurrence (HR 3.65, P < 0.001) if using variables including the follow-up data. CONCLUSION: In the surveillance setting after curative-intent treatment of HCC, patients presenting with high posttreatment AFP without evident recurrence on CT or MRI may frequently progress to imaging-evident recurrence. In high-risk patients, an extensive diagnostic workup or close monitoring is needed to detect HCC recurrence earlier.