Introduction

Hepatocellular carcinoma (HCC) is considered the sixth most prevalent malignant tumor in the world, and it ranks first in Egypt. Early detection of HCC is of great value, as early stages can be treated with curative modalities. Current surveillance programs depend on ultrasonography with or without alpha-fetoprotein (AFP) measurement, but the ultrasonography is operator-dependent and has many limitations, while AFP is neither adequately sensitive nor specific. Serum Annexin A2 has the potential to be a promising biomarker for the early detection of HCC.

Aims & Methods

The aim of the present study is to evaluate the potential contribution of serum annexin A2 in the detection of hepatocellular carcinoma. This case-control study included four groups:
Group A: Early hepatocellular carcinoma; BCLC stages 0 and A.
Group B: Advanced hepatocellular carcinoma; BCLC Stage C.
Group C: liver cirrhosis without HCC.
Group D: healthy subjects as a control group.
Chronic hepatitis C was the cause of cirrhosis in the three groups (A, B, and C). All of them attained sustained virological response (SVR) after receiving treatment with direct-acting antiviral medications (DAAs). ​Subjects with other liver cirrhosis causes, those with active hepatitis C viremia, those with combined hepatitis B virus infection, and those with any other malignancy were excluded.
Assuming a common standard deviation (14.6) using the F test (one-way ANOVA power analysis), at significance level.05, a sample size of 100 participants (25 per group) was needed to achieve 80% power to detect an overall difference of at least .35 ng/mL in the mean of serum annexin A2 between the studied 4 groups.
Both serum AFP and annexin A2 were measured in all included subjects.

Results

One hundred subjects were included in the study, 25 in each group. There were no statistically significant differences between groups regarding age and sex. The 3 diseased groups were not statistically significantly different regarding the modified Child-Pugh scores (median was 5), ALBI grading, MELD scores, platelet counts, INR, albumin, and total serum bilirubin levels.
By ROC curve analysis, at a cut-off point >12 (ng/ml), AFP was a statistically significant discriminator between HCC patients (group A+B) and patients with liver cirrhosis (group C), with an area under the ROC curve (AUC) = 0.670 (95% CI 0.550 to 0.789) (p =.017), sensitivity of 60.00%, specificity of 76.00%, positive predictive value (PPV) of 83.30%, and negative predictive value (NPV) of 48.70%, but at the same cut-off point, AFP is not a statistically significant discriminator between patients with early HCC (group A) and patients with liver cirrhosis (group C) with an AUC of 0.619 (95% CI 0.450 to 0.783) (p =.148), with a sensitivity of 52.00%, a specificity of 76.00%, a PPV of 68.40%, and a NPV of 61.30%.
Serum annexin A2 levels showed a significant difference between the advanced HCC and the early HCC groups compared to the group of healthy individuals (group D) (p<.001). Annexin A2 levels were also significantly higher between the early HCC and advanced HCC groups when compared to the cirrhosis-only group (p =.005 and p<.001, respectively). Moreover, annexinA2 levels were significantly higher in the advanced HCC group when compared to the early HCC group (p =.003). Annexin A2 was also higher in the cirrhosis-only group than in the healthy group (p =.002).
By ROC curve analysis, at a cut-off point >7.7 (ng/ml), serum annexin A2 was a statistically excellent discriminator between HCC patients (group A+B) and patients with liver cirrhosis (group C) with an AUC of 0.962 (95% CI 0.910 to 1.000) (p<0001), with a sensitivity of 98.00%, a specificity of 88.00%, a PPV of 94.2%, and a NPV of 95.7%. At the same cut-off point, annexinA2 is a statistically significant discriminator between patients with early HCC (group A) and those with liver cirrhosis (group C), with an AUC of 0.934 (95% CI 0.851 to 1.000) (p >.001), a sensitivity of 96.00%, a specificity of 88.00%, a PPV of 88.90%, and a NPV of 95.7%.

Conclusion

Serum annexin A2 is a promising biomarker that can improve the sensitivity of HCC detection among patients with liver cirrhosis after HCV eradication using DAAs.

Introduction

To the best of our knowledge, there is no study addressed the HCC recurrence rates after radiofrequency ablation (RFA) in those achieved long-term sustained virologic response (SVR) before HCC development versus SVR for less than 2 years or no SVR before HCC occurrence.

Aims & Methods

The study aimed to identify the predictors of early HCC recurrence after RFA and explore the relationship with SVR duration among patients with HCV-related liver cirrhosis.
This study is a retrospective one that included patients with HCV-related liver cirrhosis and HCC who had RFA. Those with positive HBsAg, alcohol-associated liver disease, patients with other known causes of chronic liver disease, and patients with locoregional therapy other than RFA were excluded. A fine needle aspiration biopsy was done at the time of the RFA. A 2-year retrospective follow-up was done. Those with missing data, lost follow-up, or died before any HCC recurrence were excluded. A total of 64 patients were included in the study.

Results

During the 2-year follow-up starting from the date of RFA procedure, 26 patients (40.6%) experienced HCC recurrence. There were no statistically significant differences between those who experienced HCC recurrence and those who did not regarding age, sex, baseline hemoglobin levels, platelets, white blood cell counts, ALT, AST, INR, albumin, total bilirubin, FIB-4, MELD, ALBI, and Child-Pugh scores. Also, there were no statistically significant differences between the two groups regarding the number of lesions. On the other hand, the mean size of the largest lesions was significantly larger in the HCC recurrence group. The mean was 4.3±0.78 cm in the HCC recurrence group, while it was 3.38±1.05 cm in the non-recurrence group (p<0.001). Also, the baseline AFP was significantly higher in the HCC recurrence group. The median was 225 (IQR 90–894) ng/ml, against 11.3 (IQR 7.5–70) ng/ml in the non-recurrence group (p<0.001).
Those who received DAAs 2 years before HCC occurrence showed the least incidence of HCC recurrence (p = 0.001). Regarding the pathological grade, 65.4% of the HCC recurrence group had grade III HCC, 34.6% had grade II, and no one of them had grade I HCC on histopathological examination. The difference was statistically significant (p=0.012).
On multivariate regression analysis, it was found that AFP significantly increased the odds of HCC recurrence (OR = 1.004, 95% CI 1.001–1.007, p = 0.016). Also, the increase in size of the largest lesion significantly increased the risk of HCC recurrence (OR = 3.039, 95% CI = 1.514–6.1, p = 0.025). Receiving successful DAA therapy 2 years before the occurrence of HCC significantly decreased the odds of HCC recurrence (OR = 0.016, 95% CI 0.028–0.413, p = 0.016). On the other hand, the histopathological grade of HCC failed to show a significant change in the odds of HCC recurrence.

Conclusion

In conclusion, larger tumor size and higher pre-ablation AFP levels predicts HCC recurrence after RFA, while long-term SVR for more than 2 years before HCC occurrence predicts lower rates of HCC recurrence after RFA.

Introduction

Hepatitis C virus (HCV) infection is one of the leading causes of liver cirrhosis and hepatocellular carcinoma. Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of activated immature myeloid cells that are characterized by different specific surface molecules, they express each of CD11b+CD33+ and lack expression of HLA-DR. MDSC are immunosuppressive cells that decrease immune cell activation and induce immunological tolerance in inflammation and cancer. Under normal conditions, MDSC remain in the bone marrow until differentiation; however, under pathological conditions these cells arrest at various stages of development, migrate out of the bone marrow in an immature state and, accumulate in circulation and peripheral lymphoid organs, causing negative regulation of immune responses via various mechanisms, primarily T cell suppression. MDSC are known to increase in patients with chronic hepatitis C virus infection. But it is not clear till now if eradication of HCV using directly acting antivirals can restore normal levels of MDSC on long term or not.

Aims & Methods

This study aimed to assess the levels of MDSC in patients with previous chronic hepatitis C after achieving sustained virologic response (SVR) for at least 2 years using sofosbuvir containing regimens.
This study was a case-control one. Fifty five subjects were involved in the study. All patients had completed DAAs therapy 2-3 years before involvement. Estimation of (CD33+ HLA-DR– CD11b+) expressing cells by flow cytometry was done and levels were compared between HCV patients achieved SVR for 2-3 years and healthy control without any current or previous chronic disease.

Results

MDSC were significantly higher among patients with eradicated HCV for 2-3 years than in healthy controls (4.98% (IQR=3.3 – 7.7) vs 3.09% (1.4 – 3.9), p = 0.001)

Conclusion

Normal MDSC levels are not restored after eradication of HCV using directly acting antivirals even after passage of 2 years on viral eradication. Clinical implications and consequences of these findings should be further investigated.

Introduction

Hepatocellular Carcinoma (HCC) is a major type of primary liver cancer and one of the most frequent human malignant neoplasm. Owing to the lack of reliable clinical HCC markers, fewer than 20% of patients are diagnosed at a stage where curative treatment can be performed. Aldo-keto reductase family 1 member Bl0 (Akr 1 Bl0), cancer-related oxireductase was originally identified as a gene whose expression was upregulated in human HCC but was low in normal liver tissue. Akr l Bl0 upregulation was observed in several studies in certain chronic liver diseases such as chronic hepatitis B and C and steatohepatitis, which are widely recognized to represent a precancerous condition of HCC.

Aims & Methods

The aim is to investigate the role of serum AKR1B10 as a screening test for early detection of HCC in HCV related liver cirrhosis.
Methods: The study was carried out on 60 Egyptian patients with HCV related liver cirrhosis (Liver cirrhosis (LC) group: 30 patients with HCV related liver cirrhosis without HCC and HCC group: 30 patients with HCV related liver cirrhosis and HCC) and 20 healthy volunteers as controls from Menoufia University Hospitals (Egypt). They underwent history taking, physical examination and laboratory investigations (CBC, liver profile {ALT, AST, albumin, bilirubin, INR}, urea, creatinine, AFP, HBsAg, HCV Ab and serum AKR1B10). Abdominal ultrasonography was done for all patients and controls. HCC is further confirmed by triphasic CT. Patients with malignancy other than HCC, advanced HCC, received previous treatment for HCC, age <18 years old, HCC with distant metastasis and chronic liver disease other than HCV were excluded from the study.

Results

In HCC group, All patients had single lesion, 40% (n=12) in left lobe and 60% (n=18) in right lobe. HCC size was 5.7±2.5 cm (range 4.3 to 8.2 cm). No portal vein thrombosis was detected. In HCC group, according to BCLC classification, 22 patients (73.3%) were in A2 stage and 8 (26.7%) in A3 stage. According to TNM classification, all patients were in stage T1bN0M0. Serum AKR1B10 (pg/ml) was significantly higher in HCC group (3837.7±334.7) than LC (1176±187.7) and control group (664.7±402.2) (P˂0.001 for all). Also serum AKR1B10 (pg/ml) was significantly higher in LC group than in control group (P˂0.001). AFP level (ng/ml) was significantly higher in HCC group (6173±14080) than LC (12.7±5.6) and control group (7.2±4.3) (P˂0.001 for both). Also AFP level (ng/ml) was significantly higher in LC group than control group (P˂0.001). Serum AKR1B10 (pg/ml) at cutoff level >0.95 have 86.7% sensitivity and 70% specificity for detection of HCC. AFP at cutoff level >17.9 ng/ml have 67% sensitivity and 88% specificity for detection of HCC. Combined Serum AKR1B10 and AFP have 97.6% sensitivity and 100% specificity for detection of HCC. There was no significant difference between HCC and LC group as regard MELD score (19.6±0.5 and 19.5±0.5 respectively), APRI score (1.48±0.68 and 1.67±0.94 respectively), FIB-4 (2.05±1.79 and 2.35±2.26 respectively) and Child-Pugh score (6.3±1.5 and 5.9±0.3 respectively) (P˃0.05). In LC group, 27 patients (90%) were in Child class A, 3 patients (10%) were in Child class B. In HCC group, 24 patients (80%) were Child A, 6 patients (20%) were Child B.

Conclusion

AKR1B10 could be used as a diagnostic biomarker for early detection of HCC in HCV‑related cirrhosis, as it showed significant upregulation in patients with HCC in comparison with non‑HCC patients.

References

- Han C, Gao L, Bai H, Dou X. Identification of a role for serum aldo‑keto reductase family 1 member B10 in early detection of hepatocellular carcinoma. Oncol Lett. 2018;16(6):7123-30
-Murata, A, Genda, T, Ichida, T, Amano, N, Sato, S, et al. Pretreatment AKR1B10 expression predicts the risk of hepatocellular carcinoma development after hepatitis C virus eradication. World J Gastroenterol. 2016;22(33):7569-78
- Mori M, Genda T, Ichida T, Murata A, Kamei M, Tsuzura H, et al. Aldo‐keto reductase family 1 member B10 is associated with hepatitis B virus‐related hepatocellular carcinoma risk. Hepatol Res. 2017;47(3):E85-93
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-Ye X, Li C, Zu X, Lin M, Liu Q, Liu J, et al. a large-scale multicenter study validates aldo-keto reductase family 1 member B10 as a prevalent serum marker for detection of hepatocellular carcinoma. Hepatology. 2019;69(6):2489-501
- Kanno M, Kawaguchi K, Honda M, Horii R, Takatori H, Shimakami T, et al. Serum aldo-keto reductase family 1 member B10 predicts advanced liver fibrosis and fatal complications of nonalcoholic steatohepatitis. J Gastroenterol. 2019;54(6):549- 57

Introduction

Direct-acting antivirals (DAA) have revolutionized the treatment landscape for chronic hepatitis C (CHC), yielding notably high sustained virological response (SVR) rates. While SVR is associated with reduced hepatocellular carcinoma (HCC) risk, recent studies emphasize the importance of ongoing surveillance, particularly in patients with advanced fibrosis (F3-F4), mainly within the initial three years post-SVR.

Aims & Methods

The aim of this study was to assess the risk of hepatocellular carcinoma over a five-year period following DAA-induced SVR in a real-life cohort of F3-F4 patients.
Data were retrospectively collected from CHC F3-F4 patients initiating DAA treatment between February 2015 and January 2017 at a tertiary center. Statistical analysis was performed with SPSS 29.0 (significance level ≤0.05).

Results

Out of 239 patients included (69.5% male; median age: 58 years), a SVR at 12 weeks rate of 96.6% was achieved. Among those with SVR and continued follow-up (n=229), 5.2% (n=12) developed HCC over the five-year period, with 50% occurring more than three years post-SVR.
The annual HCC incidence rate was 1.1 cases/100 person-years (33.3% HCC-related mortality rate). Most HCC cases occurred in males (75%) and cirrhotic patients (75%, Child-Pugh A: 77.8%). The mean alpha-fetoprotein level at HCC diagnosis was 156.1 ng/mL. Additionally, 75% of patients who developed HCC had other co-factors for liver disease, mainly metabolic. Comparing the presence of other liver disease co-factors, no statistically significant difference was found between those who developed HCC and those who did not during the five-year follow-up period (p-value 0.267).

Conclusion

The incidence rate of HCC post- SVR has been reported to be 0.9-2.96/100 person-years for DAA therapy, consistent with the findings of this investigation. Nevertheless, our study underscores that the risk of HCC persists for at least five years following SVR, warranting long-term surveillance. Contrary to previous research, there is insufficient evidence to support the involvement of other co-factors in HCC development.

Disclosure

Hsu CC, Gopalakrishna H, Mironova M, Lee MH, Chen CJ, Yang HI, Wiese M, Chang KM, Wright EC, Abijo T, Feld JJ, Kaplan DE. Risk of Hepatocellular Carcinoma After Spontaneous Clearance of Hepatitis C Virus and in Noncirrhosis Chronic Hepatitis C Patients With Sustained Virological Response: A Systematic Review. Clin Infect Dis. 2023 Aug 14;77(Suppl 3):S245-S256. doi: 10.1093/cid/ciad380. PMID: 37579210; PMCID: PMC10425144.
Li M, Li Y, Zhang Y, Wang X, Lin C. Five-year follow-up of sustained virological response with hepatitis C infection after direct-acting antiviral therapy: A single-center retrospective study. Medicine (Baltimore). 2024 Feb 16;103(7):e37212. doi: 10.1097/MD.0000000000037212. PMID: 38363923; PMCID: PMC10869073.

Introduction

Hepatocellular carcinoma (HCC), accounting for 80% of primary liver cancers, is the third leading cause of cancer-related mortality globally and the fifth in the Philippines. Early detection remains challenging due to asymptomatic early stages. Current screening using ultrasonography with or without alpha fetoprotein (AFP) has limitations (63% sensitivity, 84% specificity), highlighting the need for better biomarkers. AFP screening alone may miss approximately 35% to 59% of HCC cases. Moreover, a significant proportion of HCC patients, particularly those with small tumors, do not exhibit elevated AFP levels, resulting in false-negative diagnoses. These limitations highlight the need for complementary biomarkers that can improve the sensitivity and specificity of HCC detection. Protein Induced by Vitamin K Absence-II (PIVKA-II) has demonstrated superior sensitivity (74.5%) and specificity (91.7%), particularly in AFP-normal patients, who constitute the gap that is 30–50% of HCC cases.

Aims & Methods

The study aims to evaluate and compare the diagnostic accuracy of PIVKA-II versus AFP in detecting HCC among AFP-normal patients, with a specific focus on sensitivity, specificity, and area under the curve (AUC) for early-stage disease detection. The present study is a meta-analysis included 4 studies involving at least 146 AFP-normal patients. The studies evaluated the diagnostic accuracy of PIVKA-II in detecting HCC in AFP-normal patients. Relevant case-control studies published from January 2016 to 2025 were systematically identified using PubMed, applying strict inclusion criteria focusing on diagnostic accuracy (sensitivity, specificity, AUC). Only peer-reviewed, English-language studies were included. Study quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool. Statistical analysis employed Meta-DiSc software (v1.4), using a random-effects model due to observed study heterogeneity.

Results

The meta-analysis demonstrated that PIVKA-II is an effective diagnostic biomarker for HCC among AFP-normal patients. For detecting any-stage HCC, the pooled sensitivity was 80%, specificity was 90%, and the AUC was 0.9376. For early-stage HCC, sensitivity was 79%, specificity 82%, and AUC 0.888, both reflecting excellent diagnostic performance.

Conclusion

This meta-analysis provides compelling evidence supporting the diagnostic accuracy of PIVKA-II (DCP) in detecting hepatocellular carcinoma (HCC) among AFP-normal patients. These findings suggest that PIVKA-II is a highly effective biomarker for identifying HCC, particularly in AFP-normal patients, who may otherwise go undiagnosed using AFP alone. The results reinforce the superiority of PIVKA-II over AFP in HCC detection, especially in early-stage disease, where timely diagnosis is critical for improving patient outcomes. Given the high AUC values observed, PIVKA-II should be considered for routine use in HCC screening and surveillance programs, particularly for patients with normal AFP levels. Its incorporation into multimodal screening strategies has the potential to significantly improve early diagnosis, enabling more timely interventions and ultimately improving survival outcomes for patients at risk of HCC.

References

• Best, J., Bechmann, L. P., Sowa, J. P., Sydor, S., Dechêne, A., Pflanz, K., ... & Gerken, G. (2020). Role of PIVKA-II and AFP in hepatocellular carcinoma detection. Journal of Hepatology, 72(5), 855-865.
• Fu, S. J., Wang, X. P., Chen, H. L., Wang, L., Zhao, Y. J., & Zheng, S. S. (2021). Diagnostic performance of PIVKA-II in hepatocellular carcinoma: A systematic review and meta-analysis. World Journal of Gastroenterology, 27(8), 719-735.
• Han, S., Lee, S. W., Kim, S. H., Lee, H. L., Kim, H. J., & Chung, H. S. (2020). Diagnostic performance of PIVKA-II in hepatocellular carcinoma detection: A meta-analysis. Clinical and Molecular Hepatology, 26(1), 90-101.
• Sun, H., Chen, Y., Wang, H., Ding, X., & He, J. (2020). Comparative analysis of PIVKA-II and AFP in diagnosis and monitoring of hepatocellular carcinoma. World Journal of Gastroenterology, 26(18), 2218-2230.

Introduction

Hepatitis C virus (HCV) infection is a key driver of hepatocellular carcinoma (HCC) development and progression. However, the impact of HCV eradication in patients undergoing systemic therapy remains poorly understood.

Aims & Methods

This study aimed to assess the safety and efficacy of direct-acting antiviral (DAA) therapy in patients receiving Atezolizumab plus Bevacizumab (AtezoBeva). This multicenter study retrospectively enrolled consecutive patients with HCV-related unresectable or advanced HCC undergoing AtezoBeva therapy between 2021 and 2024. Patients were stratified into three groups based on their HCV treatment status: group A (n=22), who received concurrent DAA therapy with AtezoBeva; group B (n=95), who had completed DAA therapy at least six months before initiating AtezoBeva; and group C (n=22), with active HCV infection. The impact of DAA treatment on overall survival (OS), time to progression (TTP), progression-free survival (PFS), time to decompensation (TTD), and decompensation-free survival (DFS) was evaluated. Additionally, the incidence of treatment-related adverse events (trAEs) was recorded.

Results

Group A demonstrated a significantly prolonged median OS (42.8 months [95%CI: 33.3–NA]) compared to Group B (26.8 months [95%CI: 17.1–NA]; p=0.03) and group C (19.7 months [95%CI: 14.7–NA]; p=0.01). TTP was longer in group A (40.6 months [95%CI: 17.68–NA]) than in group C (14.6 months [95%CI: 5.06–NA]; p=0.02), whereas no significant difference was observed between group A and group B (20 months [95%CI: 12.29–NA]). Median PFS was markedly extended in group A (40.6 months [95%CI: 22.47–NA]) compared to group B (15 months [95%CI: 11.96–23.4]; p=0.009) and group C (13.3 months [95%CI: 5.06–NA]; p=0.002). Moreover, group A exhibited a higher disease control rate than the other groups. In the multivariate time-dependent analysis, achieving sustained virologic response (SVR) during AtezoBeva therapy was independently associated with a reduced risk of mortality (HR 0.29 [95%CI: 0.12–0.69]; p=0.005) and disease progression (HR 0.1 [95%CI: 0.05–0.72]; p=0.02). Notably, post-DAA decompensation rates were significantly lower in group A (4.5%) compared to groups B (26.3%) and C (36.4%), translating into a superior DFS. The incidence of grade ≥3 treatment-related AEs was comparable across groups.

Conclusion

Achieving SVR during AtezoBeva therapy significantly enhances oncological outcomes in patients with unresectable or advanced HCC. These findings highlight the potential for an integrated therapeutic approach to optimize systemic treatment efficacy, particularly in patients eligible for conversion strategies.

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