HCV-related Hepatocellular Carcinoma Research Articles

The clinical significance of long non-coding RNAs MALAT1 and CASC2 in the diagnosis of HCV-related hepatocellular carcinoma.

Globally, hepatocellular carcinoma (HCC) is the second most common cause of cancer-related death due to a lack of early predictive and/or diagnostic tools. Thus, research for a new biomarker is important. LncRNAs play a functional role in target gene regulation and their deregulation is associated with several pathological conditions including HCC. This study aimed to explore the diagnostic potential of two LncRNAs MALAT1 and CASC2 in HCC compared to the routinely used diagnostic biomarker. The current study is a case-control study carried out at Fayoum University Hospital and conducted on 89 individuals. The study included three groups of 36 HCC patients on top of HCV(HCC/HCV), 33 HCV patients, and 20 healthy volunteers as a control group. All study subjects were subjected to radiological examinations. The determination of CBC was performed by the automated counter and liver function tests by the enzymatic method were performed. In addition, HCV RNA quantification and the expression level of two LncRNAs (MALAT1 and CASC2) were performed by qRT-PCR. The results revealed a statistically significant difference between study groups regarding liver function tests with a higher mean in HCC/HCV group. Also, serum MALAT1 significantly up-regulated in HCV (11.2±2.8) and HCC/HCV (4.56±1.4) compared to the control group. Besides, serum CASC2 levels in the HCV group were significantly upregulated (14.9±3.6), while, downregulated in the HCC group (0.16± 0.03). Furthermore, The ROC analysis for diagnostic efficacy parameters indicated that CASC2 has higher accuracy (94.6%) and sensitivity (97.2%) for HCC diagnosis than AFP with an accuracy of (90.9%), sensitivity (69.4%), and MALAT1 showed an accuracy of (56.9%), sensitivity (72.2%). Our study results indicated that CASC2 is a promising biomarker and is considered better and could help in HCC diagnosis on top of HCV than MALAT1 and the routine biomarker AFP.

Outcome of MAFLD-related HCC in Egyptian patients: a single center study

BackgroundGlobally, MAFLD becomes in the top list of causes of liver disease. Its effect ranges from steatosis, metabolic steato-hepatitis to MAFLD-related cirrhosis and hepatocellular carcinoma. There is a growing evidence that MAFLD-related HCC seems to be different from HCCs of other causes pathologically, so the purpose of our study was to assess the effect of MAFLD on the prognosis of HCC regarding outcome after management of HCC and survival rate in comparison to a group of patients with HCV-related HCC.ResultsTwenty-nine patients with MAFLD related HCC were included in group A, while 58 patients with HCV related HCC were enrolled as group B. Both groups were matched regarding age and gender. The mean age in group A and B was 58.86 (±8.47) years and 60/05(± 6.83) years respectively. Comparison between both groups regarding tumor burden and characteristics of HCC, type of management, and post intervention follow-up showed no significant statistical difference between both groups except for lymph node metastases which was higher in patients with HCV related HCC with p = 0.045. Also, a significant difference between both studied groups regarding AFP was detected; the median of AFP in MAFLD-related HCC was (7.2 ng/ml) but much higher in HCV-related HCC group (129.2 ng/ml) with p = 0.001.ConclusionOur data showed no significant difference between the two studied groups regarding outcome of HCC or survival rate except for AFP level before and after management which was higher in HCV patients related HCC. Although both of inclusion and exclusion criteria were strict to the criteria, so the number of participants in the research were not large enough; to our knowledge, this is the first study on MAFLD-HCC in Egypt and Africa. More studies on prospective bases are essentially needed to stand on solid conclusion about the nature and outcome of MAFLD-related HCC.

Serum interleukin-10 and alpha-fetoprotein: A combined diagnostic approach for hepatocellular carcinoma in Egyptians with HCV

PurposeHepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. Although alpha-fetoprotein (AFP) has been used for 60+ years as an HCC diagnostic serum marker, its accuracy is debated. Notably, the role of interleukin 10 (IL-10) in cancer development and metastasis is elevated in various tumor types, including HCC and chronic HCV infection. Our study aimed to investigate the diagnostic performance of IL-10 and AFP as biomarkers for HCV-induced HCC in an Egyptian population. MethodsEighty participants were recruited and categorized into three groups: HCV-related HCC (n=40), HCV-related cirrhosis (n=40), and control (n=20).The collected blood samples were analyzed to evaluate liver function, AFP levels, and IL-10 levels. ResultsOur analysis showed that AFP demonstrated low sensitivity (40% false-negative) and low specificity (33% false-positive).IL-10 levels were significantly higher (P < 0.001) in patients with HCC than in the cirrhosis and control groups. The serum AFP and IL-10 combination revealed significantly increased sensitivity (97.5%), diagnostic accuracy (71.1%), AUC (0.798), PPV (73.3%), and NPV ( 69.5%) when compared with either of them alone. Conclusionthe reliability of AFP as a major HCC marker was poor. However, IL-10 levels are a novel biomarker for the degree of HCC inflammation, considering IL-10’s potential role in HCV-HCC development. We suggest combining AFP with IL-10 to improve the diagnostic and prognostic value of HCC considerably. Future research on these biomarkers should prioritize their clinical validity, prognostic usefulness, and compatibility with other therapeutic approaches as immunotherapy

Achieving SVR in patients with hepatitis C-related HCC is associated with an improvement in overall survival: real word data

Aims: The optimal timing for DAA therapy initiation in patients with chronic hepatitis C (CHC) and HCC is still debated. The aim of our study was to provide real-world data on virological response and overall survival in patients with hepatitis C-related HCC. Methods: Retrospectively, we included patients with HCV-related HCC between 2015 and 2020. The primary outcome was to compare the SVR rate in the patients with active or historical HCC who were treated with DAA therapy. The secondary outcome was to measure the overall survival of those patients. Results: 98 patients were included, and the majority were cirrhotic with compensated liver disease. 71.4% received DAA therapy at the time of initial HCC diagnosis and 11.2% received HCV treatment at the time of HCC recurrence (Active HCC cohort). 17.3% had previously received HCC treatment, but there was no evidence of recurrence at the time of DAA (Historical HCC Cohort). The SVR rate was 81.6%, but decreased to 75.7% in patients with active HCC. The presence of active HCC and the number of HCC nodules were the only factors associated with not achieving SVR in the multivariate analysis. The median survival was higher in those who achieved SVR. Active HCC and failure to achieve SVR were the main factors associated with mortality. Conclusions: Treating hepatitis C in patients with HCC is feasible with significant rates of SVR, even if SVR rates decrease in patients with active HCC and these patients require more than one DAA therapy. Failure to achieve SVR is one of the main factors associated with mortality.

Liver biopsy in the post-hepatitis C virus era in Japan

In Japan, liver biopsies were previously crucial in evaluating the severity of hepatitis caused by the hepatitis C virus (HCV) and diagnosing HCV-related hepatocellular carcinoma (HCC). However, due to the development of effective antiviral treatments and advanced imaging, the necessity for biopsies has significantly decreased. This change has resulted in fewer chances for diagnosing liver disease, causing many general pathologists to feel less confident in making liver biopsy diagnoses. This article provides a comprehensive overview of the challenges and potential solutions related to liver biopsies in Japan. First, it highlights the importance of considering steatotic liver diseases as independent conditions that can coexist with other liver diseases due to their increasing prevalence. Second, it emphasizes the need to avoid hasty assumptions of HCC in nodular lesions, because clinically diagnosable HCCs are not targets for biopsy. Third, the importance of diagnosing hepatic immune-related adverse events caused by immune checkpoint inhibitors is increasing due to the anticipated widespread use of these drugs. In conclusion, pathologists should be attuned to the changing landscape of liver diseases and approach liver biopsies with care and attention to detail.

Hepatitis B virus-related hepatocellular carcinoma has superior overall survival compared with other etiologies.

Whether the etiology of chronic liver disease (CLD) impacts the overall survival (OS) of patients with hepatocellular carcinoma (HCC) remains unclear. We aim to clarify this issue. Between 2011 and 2020, 3941 patients who were newly diagnosed with HCC at our institution were enrolled in this study. In patients with multiple CLD etiologies, etiology was classified using the following hierarchy: hepatitis C virus (HCV) > hepatitis B virus (HBV) > alcohol-related > all negative. All negative was defined as negative for HCV, HBV, and alcohol use disorder. Among 3941 patients, 1407 patients were classified with HCV-related HCC, 1677 patients had HBV-related HCC, 145 patients had alcohol-related HCC, and 712 patients had all-negative HCC. Using the all-negative group as the reference group, multivariate analysis showed that HBV is an independent predictor of mortality (hazard ratio: 0.856; 95% confidence interval: 0.745-0.983; p = 0.027). Patients with HBV-related HCC had superior OS compared with patients with other CLD etiologies (p<0.001). Subgroup analyses were performed, for Barcelona Clinic Liver Cancer (BCLC) stages 0-A (p<0.001); serum alpha-fetoprotein (AFP) levels≧20 ng/ml (p<0.001); AFP levels < 20 ng/ml (p<0.001); age > 65 years (p<0.001); and the use of curative treatments (p = 0.002). No significant difference in OS between HBV and other etiologies was observed among patients aged ≤ 65 years (p = 0.304); with BCLC stages B-D (p = 0.973); or who underwent non-curative treatments (p = 0.1). Patients with HBV-related HCC had superior OS than patients with other HCC etiologies.

Predictive Value of Serum CYFRA21-1 and CK19-2G2 for Tumor Aggressiveness and Overall Survival in Hepatitis C-Related Hepatocellular Carcinoma Among Egyptians: A Prospective Study.

Cytokeratin 19 fragment 21-1 (CYFRA 21-1) and cytokeratin 19 fragment 2G2 (CK 19-2G2) are two soluble fragments of cytokeratin 19 (CK 19) that can be detected in serum. CK 19-positive hepatocellular carcinoma (HCC) is characterized by anaggressive behavior and a poor outcome. This study aimed to assess the prognostic value of serum CYFRA 21-1 and CK 19-2G2 in predicting tumor aggressiveness and overall survival (OS) in patients with hepatic C virus (HCV)-related HCC. The current study included 138 patients with HCV-related HCC recruited from the Hepatobiliary and Interventional Radiology Units at Alexandria's main university hospitals and 40 healthy individuals as controls. Patients were assessed for clinical, radiological tumor characteristics, and aggressiveness index. Baseline serum CYFRA 21-1 and CK 19-2G2 levels were measured by enzyme-linked immunosorbent assay. Elevated CYFRA 21-1 levels were associated with tumors size ≥ 5 cm (p < 0.001), malignant portal vein thrombosis (mPVT) (p < 0.001), distant metastasis (p = 0.030), ill-defined/infiltrative pattern (p = 0.010), and aggressiveness index > 4 (p = 0.045). Elevated CK19-2G2 levels were not associated with any clinical or radiological characteristics. Either or both elevated serum CYFRA 21-1 and CK 19-2G2 in combination with alpha-feto protein (AFP) ≥ 400 ng/ml have a better predictability for mPVT and ill-defined/infiltrative patterns (sensitivity (10-25%) and specificity (96-100%)). Elevated levels of CYFRA 21-1, CK 19-2G2, or AFP ≥ 400 ng/ml were associated with decreased 1-year OS. Either or both elevated serum CYFRA 21-1 and CK 19-2G2 levels when added to AFP ≥ 400 ng/ml are specific but less sensitive biomarkers for predicting tumor aggressiveness. These biomarkers can be used independently to predict reduced 1-year OS in Egyptian patients with HCV-related HCC.

Antiviral Therapy Utilization and 10-Year Outcomes in Resected Hepatitis B Virus- and Hepatitis C Virus-Related Hepatocellular Carcinoma.

There are limited data on antiviral treatment utilization and its impact on long-term outcomes of hepatitis B virus (HBV)- and hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) after hepatic resection. We aimed to determine the utilization and impact of antivirals in HBV- and HCV-related HCC. This cohort study included 1,906 participants (1,054 HBV-related HCC and 852 HCV-related HCC) from 12 international sites. All participants had HBV- or HCV-related HCC and underwent curative surgical resection. The primary outcome was the utilization of antiviral therapy, and the secondary outcome was long-term overall survival (OS). The mean (±standard deviation [SD]) age was 62.1 (±11.3) years, 74% were male, and 84% were Asian. A total of 47% of the total cohort received antiviral therapy during a mean (±SD) follow-up of 5.0 (±4.3) years. The overall antiviral utilization for participants with HBV-related HCC was 57% and declined over time, from 65% before 2010, to 60% from 2010 to 2015, to 47% beyond 2015, P < .0001. The overall utilization of antivirals for HCV-related HCC was 35% and increased over time, from 24% before 2015 to 74% from 2015 and beyond, P < .0001. The 10-year OS was lower in untreated participants for both HBV (58% v 61%) and HCV participants (38% v 82%; both P < .0001). On multivariable Cox regression analysis adjusted for relevant confounders, antiviral therapy initiated before or within 6 months of HCC diagnosis was independently associated with lower mortality in both HBV- (adjusted hazard ratio [aHR], 0.60 [95% CI, 0.43 to 0.83]; P = .002) and HCV-related HCC (aHR, 0.18 [95% CI, 0.11 to 0.31]; P < .0001). Antiviral therapy is associated with long-term survival in people with HBV- or HCV-related HCC who undergo curative resection but is severely underutilized.

Racial and ethnic disparities in untreated patients with hepatitis C virus-related hepatocellular carcinoma but not in those with sustained virologic response.

Racial and ethnic disparities exist for hepatitis C virus (HCV) treatment and hepatocellular carcinoma (HCC) survival. To evaluate the impact of HCV treatment on such disparities. In a retrospective cohort study, we analysed 6069 patients with HCV-related HCC (54.2% Asian, 30.1% White, 8.5% Black, and 7.3% Hispanic) from centres in the United States and Asia. The mean age was 61, 60, 59 and 68, respectively, for White, Black, Hispanic and Asian patients. Black patients were most likely to have Barcelona Clinic Liver Cancer stage D, vascular invasion and distant metastasis (23% vs. 5%-15%, 20% vs. 10%-17% and 10% vs. 5%-7%, respectively; all p < 0.0001). Treatment rate with direct-acting antiviral agents (DAA) was 35.9% for Asian, 34.9% for White, 30.3% for Hispanic (30.3%), and 18.7% for Black patients (p < 0.0001). Among those untreated or without sustained virologic response (SVR), 10-year survival rates were 35.4, 27.5, 19.3 and 14.0, respectively, for Asian, Hispanic, White and Black patients (p < 0.0001). There were no statistically significant differences among those with SVR (p = 0.44). On multivariable analysis adjusted for relevant confounders, there was no statistically significant association between survival and being Hispanic (aHR: 0.68, p = 0.26) or Black (aHR: 1.18, p = 0.60) versus White. There was a significant association between being Asian American and survival (aHR: 0.24, p = 0.001; non-U.S. Asian: aHR: 0.66, p = 0.05), and for SVR (aHR: 0.30, p < 0.0001). DAA treatment rates were suboptimal. Racial and ethnic disparities resolved with HCV cure. Early diagnosis and improved access to HCV treatment is needed for all patients with HCV infection.

Mean platelet volume and platelet distribution width as predicting biomarkers of hepatitis C related hepatocellular carcinoma

Background and Aims: Besides their role in hemostasis and thrombosis; platelets have roles in innate and adaptive immune responses, atherosclerosis, lymphatic vessel development, angiogenesis and carcinogenesis .The relation between platelets and cancer is well-known and thrombocytosis may occur as a paraneoplastic syndrome. Several studies reported a correlation of high platelet count with poor prognosis in different malignancies. The aim of this study was to explore the predictive values of platelet count (PLC), mean platelet volume (MPV) &amp; platelet distribution width (PDW) in HCV related HCC, as well as their association with tumor burden. Method: The study was conducted on two groups of patients, group 1; included patients with naive HCV related HCC and group 2; included patients with chronic HCV cirrhosis. Liver biochemical tests, AFP, serum creatinine, multi-phasic contrast enhanced abdominal CT and or MRI were done at baseline for all cases. In Group 1, non-invasive diagnosis of HCC in cirrhotic patients according to the EASL guidelines &amp; Barcelona Clinic Liver Cancer (BCLC) staging was done. In Group 2, liver cirrhosis was diagnosed through liver histology or a combination of radiographic, clinical, and laboratory findings. CBC was done for all participating patients using automated hematology analyzer with reporting of PLC, MPV&amp; PDW. Results: Group 1 included 144 patients, while group 2 included 116 patients. In group 1, the age was significantly older &amp; the number of males was significantly higher. PLC was significantly lower in group 1 than group 2. In group 1, PLC was &lt; 150× 109/L (thrombocytopenia) in 71.6% of the cases, while it was normal in 28.4% of them. The median HCC diameter was significantly larger in patients with normal PLC than thrombocytopenic patients. There was significant positive correlation of PLC with BCLC stage. PLC was significantly higher in late than early BCLC stage. In group 1; PLC at cut off value of 134.5×109/L predicted late BCLC stages; with sensitivity of 44.1%, specificity of 82.5%, AUC of 0.65 &amp; p = 0.006. There was insignificant difference between both groups regarding PDW. There was insignificant difference between both groups regarding PDW. There was insignificant difference between both groups regarding the MPV. In group 1; PDW was ≥14.5% in 79% &amp; &lt;14.5% in 21% of the patients while MPV was ≥10.4 fl in 52.1% of the patients &amp; &lt;10.4 fl in 47.9% of them. There was insignificant correlation of MPV &amp; PDW with BCLC stage. PDW at cut off value of 15.05% predicted HCV related HCC with sensitivity = 62, 2%, specificity = 58, 1 %, AUC = 57, 8 %, p = 0.043. There was significant negative correlation of the MPV with serum AFP level. MPV was significantly smaller in late than early BCLC stage. On multivariate logistic regression analysis, gender, patient status of performance (PS), Alpha fetoprotein (AFP), PLC, Albumin -Bilirubin (ALBI) grade and Model of End stage Liver Disease (MELD) score, were significant predictors of HCV related HCC, while age, PDW, MPV and Child -Turcotte -Pugh (CTP) score were not significant predictors. Conclusion: PLC was significant predictors of HCV related HCC. HCV related HCC patients with normal PLC had larger tumor diameter. PLC positively correlated with BCLC stage. In HCV related HCC cases, PLC at cut off value of 134.5×109/L may predict late BCLC stages. PDW at cut off 15.05% may predict HCV related HCC. MPV was significantly smaller in late than early BCLC stages &amp; it negatively correlated with serum AFP level. MPV was not significant predictors of HCV related HCC.

To study the demographic profile of HCC patients and the pattern of clinical characteristics in a tertiary care centre of north western India

Hepatocellular carcinoma (HCC) is a prevalent malignancy globally and the fifth most common cancer worldwide. This retrospective study, spanning six years, explores the shifting etiological patterns of HCC in Northwestern India, particularly influenced by factors like Hepatitis B and C endemics, alcohol consumption, and vaccination programs. Data from 164 HCC patients reveal a significant shift, with Hepatitis C surpassing Hepatitis B as the primary etiological factor. The study highlights the distinctive HCC profile in Northwestern India, emphasizing the imperative to address HCV as a silent precursor to HCC and the need for enhanced surveillance and intervention strategies. The findings underscore the significance of controlling alcohol abuse, managing cirrhosis complications, and the urgency for improved diagnostic markers beyond AFP. The study prompts a reevaluation of vaccination interventions and advocates for heightened screening measures to detect and mitigate HCV-related HCC at earlier stages.

Treatment rates and factors associated with direct-acting antiviral therapy for insured patients with hepatitis C-related hepatocellular carcinoma - A real-world nationwide study.

Since the inception of the interferon-free direct-acting antiviral agents (DAAs) for hepatitis C virus (HCV) infection, guidelines as to who should receive this potentially curative treatment have evolved. Treatment with DAAs is now considered for all patients except for those considered moribund. To determine the DAA treatment rate for patients with HCV-related hepatocellular carcinoma (HCC). This was a retrospective study from January 2015 to March 2021 of a national sample of privately insured patients with HCV-related HCC using Optum's Clinformatics® Data Mart (CDM) Database - a large, de-identified, adjudicated claims database. We identified 3922 patients with HCV-related HCC: 922 (23.5%) received DAA. Compared to untreated patients, DAA-treated patients were younger (65.2 ± 7.5 vs. 66.4 ± 7.5 years, p < 0.001), more frequently saw a gastroenterology/infectious disease (GI/ID) physician (41.2% vs. 34.2%), and had decompensated cirrhosis (56% vs. 53%, p = 0.001). In multivariable analysis, younger age (HR: 0.98, 95% CI: 0.97-0.99, p < 0.001), GI/ID care (HR: 3.06, 95% CI: 2.13-4.51, p < 0.001), and having cirrhosis (compensated: HR: 1.60, 95% CI: 1.18-2.21, p = 0.003; decompensated: HR: 1.45, 95% CI: 1.07-1.98, p = 0.02) were associated with receiving DAA treatment, but not sex, race, or ethnicity. DAA-treated patients had significantly higher 5-year survival than untreated patients (47.2% vs. 35.2%, p < 0.001). Following adjustment for age, sex, race/ethnicity, Charlson Comorbidity Index, and HCC treatment, receiving DAA treatment was associated with lower mortality (aHR: 0.61, 95% CI: 0.53-0.69, p < 0.001). DAA treatment remains underutilised in insured patients with HCV-related HCC; fewer than one in four patients received treatment. Seeing a specialist and having decompensated cirrhosis were predictors for DAA treatment; additional efforts are needed to increase awareness of HCV treatment.

HCV and HCC Tango-Deciphering the Intricate Dance of Disease: A Review Article.

Hepatitis C virus (HCV) is a major cause of hepatocellular carcinoma (HCC) accounting for around one-third of all HCC cases. Prolonged inflammation in chronic hepatitis C (CHC), maintained through a variety of pro- and anti-inflammatory mediators, is one of the aspects of carcinogenesis, followed by mitochondrial dysfunction and oxidative stress. Immune response dysfunction including the innate and adaptive immunity also plays a role in the development, as well as in the recurrence of HCC after treatment. Some of the tumor suppressor genes inhibited by the HCV proteins are p53, p73, and retinoblastoma 1. Mutations in the telomerase reverse transcriptase promoter and the oncogene catenin beta 1 are two more important carcinogenic signaling pathways in HCC associated with HCV. Furthermore, in HCV-related HCC, numerous tumor suppressor and seven oncogenic genes are dysregulated by epigenetic changes. Epigenetic regulation of gene expression is considered as a lasting "epigenetic memory", suggesting that HCV-induced changes persist and are associated with liver carcinogenesis even after cure. Epigenetic changes and immune response dysfunction are recognized targets for potential therapy of HCC.

Circulating D-dimer level may predict tumor burden in chronic hepatitis C related hepatocellular carcinoma

Introduction: Coagulation and fibrinolysis activation has been implicated in angiogenesis, tumor cell invasion, tumor progression and metastatic spread. D-dimer is a biomarker that globally indicates the activation of hemostasis and fibrinolysis. Aim: To study the correlation of circulating D-dimer level with the tumor grade in HCV related HCC. Methods: HCC was diagnosed by non- invasive method in cirrhotic patients according to EASL criteria using contrast enhanced abdominal CT and or MRI. After metastatic work up, HCC grade was described as grade one if it was within Milan criteria (one nodule &lt;5cm or up to 3 nodules; the largest is &lt;3cm without vascular invasion or extra- hepatic involvement); grade two if it was beyond Milan criteria but non –metastatic &amp; grade three if it was metastatic (vascular invasion, lymph node metastasis, distant metastasis). BCLC staging depending on HCC burden, Child -Turcotte-Pugh (CTP) class and ECOG performance status (PST), was done for all studied cases. Chromic HCV was diagnosed by 4th generation ELIZA for HCV antibody and confirmed by quantitative PCR for HCV RNA. Circulating D dimer level, serum AFP level, liver biochemical tests, serum creatinine &amp; complete blood count were measured for all studied cases. Patients with history of previous treatment for HCC; recent benign thrombo-embolic disorder or renal impairment were excluded. Results: Fifty chronic HCV related HCC cases; 43 males and 7 females with age 62.2±7.4 years were enrolled. Circulating D-dimer level was significantly higher in HCC grade 2 and 3 than HCC grade 1 [(400-800) versus (0-400 ng/ml), p=0.001] &amp; in BCLC stage D than BCLC stage C HCC [(400-800) versus (0-700 ng/ml), p=0.021].There was significant positive correlation between circulating D-dimer level and HCC size and HCC grade (r =0.35, p = 0.012, r =0.33, p = 0.016 respectively). There was also significant positive correlation between circulating D-dimer level and both serum AFP level (r =0.45, p=0.001) and ECOG performance status (r =0.4, p = 0.002). Serum level of circulating D-dimer at cut off level ≥300 ng/ml can predict HCC grade beyond Milan criteria (G2&amp; 3) with PPV of 77.1%, NPV of 73.3%, AUC= 0.8 and p &lt;0.0005.Also, serum AFP level at cut off ≥394.5 can predict HCC grades beyond Milan criteria with PPV of 89.3%, NPV of 72.7%, AUC= 0.81 and P&lt;0.0005. Conclusion: In HCV related HCC, circulating D-dimer level was positively correlated with HCC grade and largest tumor size with higher level in HCC grades 2&amp;3 as well as BCLC stage D. Cut off level of circulating D-dimer level of ≥300 ng/ml can predict HCC grades beyond Milan criteria.

Well-controlled viremia reduces the progression of hepatocellular carcinoma in chronic viral hepatitis patients treated with lenvatinib.

Lenvatinib has been approved as one of the first-line treatments for advanced hepatocellular carcinoma (HCC) due to its high treatment efficacy being non-inferior to sorafenib. Previous studies have shown well-controlled viremia contributes to the prognosis of HCC patients receiving first-line sorafenib; hence, we postulated this association might also exist in HCC patients with lenvatinib treatment. From April 2018 to December 2021, 201 unresectable HCC patients with first-line lenvatinib treatment in our institute were assessed. High-effect nucleoside analogues were administered for hepatitis B virus (HBV) control, while direct-acting antivirals were used for hepatitis C virus (HCV) elimination. Based on our previous study, well-controlled viremia was defined as patients who had undetectable viremia, or who had been receiving antivirals at least 6 months before lenvatinib. This study enrolled 129 patients, including 85 patients with HBV-related HCC (HBV-HCC) and 44 patients with HCV-related HCC (HCV-HCC), respectively. Progression-free survival (PFS) and overall survival (OS) rates between the two groups were not different. Before administration of lenvatinib, 57.1% of the HBV-HCC patients and 88.4% of the HCV-HCC patients had well-controlled viremia, and their PFS (8.8 vs. 3.1 months, p < 0.001) and OS (30.2 vs. 12.8 months, p = 0.041) were better than those who had uncontrolled viremia; moreover, well-controlled viremia reduced tumor progression in multivariate analysis (Hazard ratio: 0.41, 95% confidence interval: 0.25-0.68, p = 0.001) after adjusting for albumin-bilirubin grade and concurrent treatment. HBV or HCV infection was not associated with tumor progression of HCC patients receiving lenvatinib, but viremia, controlled or not, was.

The Potential Role of Circulating Long Miscellaneous RNAs in the Diagnosis and Prognosis of Hepatitis C Related Hepatocellular Carcinoma.

Ribonucleic acids (RNAs) are important regulators of gene expression and crucial for the progression of hepatocellular carcinoma (HCC). This study was designed to determine the diagnostic and prognostic utility of the circulating long miscellaneous RNAs; LINC01419, AK021443, and AF070632 in HCV-related HCC patients. Real-time PCR was used to measure their relative expression levels in the plasma of 194 HCV patients, 120 HCV-related HCC patients and 120 healthy controls. LINC01419 and AK021443 expression levels had significantly increasing linear trend estimates while AF070632 was dramatically downregulated in HCC compared to HCV. Interestingly, LINC01419 and AK021443 served as more significant diagnostic biomarkers for HCC than AF070632 and AFP. Multivariate analysis with cox regression revealed that the high expression of AK021443 [HR = 10.06, CI95%: 3.36-30.07], the high expression of LINC01419 [HR 4.13, CI95%: 1.32-12.86], and the low expression of AF070632 [HR = 2.70, CI95%: 1.07-6.81] were significant potential prognostic factors for HCC. Besides, the Kaplan-Meier analysis showed that HCC patients with high LIN01419 and AK021443 and low AF070632 expression levels had shorter OS. The circulating LINC01419 and AK021443 can be used as noninvasive potential biomarkers for diagnosis and prognosis of HCV-related HCC patients than AF070632 providing new targets for limiting the progression of the disease.

Temporal change in aetiology and clinical characteristics of hepatocellular carcinoma in a large cohort of patients in New South Wales, Australia.

Viral hepatitis, alcohol-related liver disease (ARLD) and nonalcoholic fatty liver disease (NAFLD) are the main risk factors for hepatocellular carcinoma (HCC) in many countries. In Australia, given the access to hepatitis C virus (HCV) direct-acting antiviral (DAA) therapy since 2016, a temporal change in HCC aetiology was hypothesized. This study evaluated the temporal change in the aetiology and characteristics of HCC in New South Wales (NSW). Patients diagnosed with HCC, admitted to three public hospitals in NSW between 2008 and 2021, were included in the analyses. We assessed the annual frequency of each HCC aetiology and the distribution of HCC characteristics in participants. Among 1370 patients, the most common HCC etiologies were HCV (n = 483, 35%), ARLD (n = 452, 33%), NAFLD (n = 347, 25%) and hepatitis B virus (n = 301, 22%). The proportion of HCV-related HCC was the highest in 2011-2016 (41%) and significantly declined to 30% in 2017-2021 (odds ratio [OR], 0.53 [95% confidence interval (CI), 0.35-0.79]; P = 0.002). The proportion of HCC diagnosed at an early stage (Barcelona Clinic Liver Cancer stage O/A) increased from 41% in 2008-2009 to 56% in 2020-2021 (OR per annum, 1.05 [95% CI,1.02-1.08]; P = 0.002), and the proportion of patients receiving potentially curative HCC management increased from 29% in 2008-2009 to 41% in 2020-2021 (OR per annum, 1.06 [95% CI,1.03-1.10]; P < 0.001). The contribution of HCV to HCC burden has been decreasing in the DAA era, suggesting the role of HCV elimination in decreasing HCC risk. Increasing frequency of less advanced HCC at diagnosis over time suggests improved HCC surveillance.

Artificial intelligence-based prediction of molecular and genetic markers for hepatitis C-related hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the main cause of mortality from cancer globally. This paper intends to classify public gene expression data of patients with Hepatitis C virus-related HCC (HCV+HCC) and chronic HCV without HCC (HCV alone) through the XGboost approach and to identify key genes that may be responsible for HCC. The current research is a retrospective case-control study. Public data from 17 patients with HCV+HCC and 35 patients with HCV-alone samples were used in this study. An XGboost model was established for the classification by 10-fold cross-validation. Accuracy (AC), balanced accuracy (BAC), sensitivity, specificity, positive predictive value, negative predictive value, and F1 score were utilized for performance assessment. AC, BAC, sensitivity, specificity, positive predictive value, negative predictive value, and F1 scores from the XGboost model were 98.1, 97.1, 100, 94.1, 97.2, 100, and 98.6%, respectively. According to the variable importance values from the XGboost, the HAO2, TOMM20, GPC3, and PSMB4 genes can be considered potential biomarkers for HCV-related HCC. A machine learning-based prediction method discovered genes that potentially serve as biomarkers for HCV-related HCC. After clinical confirmation of the acquired genes in the following medical study, their therapeutic use can be established. Additionally, more detailed clinical works are needed to substantiate the significant conclusions in the current study.

Clinical Outcomes of Carbon-Ion Radiotherapy for Large-Sized (≥4cm) Hepatocellular Carcinoma

Radical treatment options for bulky unresectable locally advanced hepatocellular carcinoma (HCC) are limited. The purpose of this study is to evaluate the safety and efficacy of carbon-ion radiotherapy (C-ion RT) for bulky (≥4cm) locally advanced HCC. We performed a retrospective cohort study of patients with bulky (≥4cm) locally advanced HCC treated by C-ion RT between April 2000 and March 2020 in our institution. The eligibility criteria for this study were: (1) the treatment protocols of 45.0-48.0 Gy/2 fractions or 52.8-60.0 Gy/4 fractions, which proven the safety and efficacy in the past clinical trials; (2) Tumors within 3 intrahepatic lesions and with a maximum tumor diameter of 4 cm or greater; (3) N0M0 status; (4) an Eastern Cooperative Oncology Group performance status of 0 to 2; (5) controllable ascites; (6) Child-Pugh grade was A or B. Overall survival (OS), progression-free survival (PFS), and local control rate (LC) were calculated by the Kaplan-Meier method, and Cox regression analysis was used for multivariate analysis. Adverse events were evaluated by CTCAE ver. 5.0. JMP® 12 (SAS Institute Inc., Cary, NC, USA) was used for all analyses. We defined p < 0.05 as statistically significant. A total of 187 patients met the criteria and were evaluated. The median patient age was 73 years (range, 37-90), and 139 of 187 patients were male. Child-Pugh grade was A in 163 patients and B in 24. Modified albumin-bilirubin (mALBI) grade was 1 in 96 patients, 2a in 50, and 2b in 41. The number of HCV-related HCC cases was in 80, HBV in 32 and non-B and non-C in 75. In 51 patients, identification of vascular invasion to the first-order branch of the portal vein and/or major hepatic vein was confirmed. The median maximum tumor diameter was 5.1 cm (4.0-13.5 cm). In 76 patients, C-ion RT were treated for recurrence. With a median follow-up period of 25.9 months (range, 1.1-215.1), 2-year overall survival, progression-free survival and local control rates were 68.3% (95% confidence interval [CI], 64.7-72.0%), 39.0% (95% CI, 35.2 - 42.8%) and 86.7% (95% CI, 84.7 - 89.7%), respectively. Late adverse events were observed in 3 patients (1.6%) with Grade 3 liver dysfunction and in 3 patients (1.6%) with Grade 3 skin disorders, but there were no cases of Grade 4 or higher. Multivariate analysis of prognostic factors for overall survival revealed that mALBI grade in 2b(HR:3.13, 1.97-4.78, p<0.0001), tumor status in recurrent treatment (HR:1.50, 1.02-2.21, p = 0.039), the number of tumors in 2 or more (HR:2.16, 1.01-2.17, p = 0.045), and maximum tumor diameter in larger than 6 cm (HR:2.34, 1.50-3.61, p = 0.0001) were the predominant prognostic factors, while age, presence of vascular invasion, AFP and DCP were not. The safety and efficacy of C-ion RT for bulky (≥4cm) locally advanced HCC was demonstrated. These results suggested that C-ion RT may be a new treatment option for locally advanced bulky HCC with no curative treatment options.

Long-Term Clinical Outcome of Carbon Ion Radio Therapy for Hepatocellular Carcinoma in the Caudate Lobe

Surgical resection is the first-line treatment for hepatocellular carcinoma in the caudate lobe (caudate HCC), but it is often difficult due to the tumor's location. In addition, radiofrequency ablation and transcatheter arterial chemoembolization are also difficult for the same reason. This study aimed to evaluate the safety and efficacy of carbon-ion radiation therapy (C-ion RT) for caudate HCC. We performed a retrospective cohort study of patients with hepatocellular carcinoma treated by C-ion RT between April 2000 and March 2020 in our institution. The eligibility criteria for this study were: (1) located mainly in the caudate lobe (2) the treatment protocols of 45.0-48.0 Gy/2 fractions or 52.8-60.0 Gy/4 fractions, which proved the safety and efficacy in the past clinical trials; (3) N0M0 status; (4) an Eastern Cooperative Oncology Group performance status (PS) of 0 to 2; (5) controllable ascites. The prescribed dose (Gy) used in this study is relative biological effectiveness (RBE) weighted dose. Overall survival (OS), progression-free survival (PFS), and local control rate (LC) were calculated by the Kaplan-Meier method. Adverse events were evaluated by NCI-CTCAE ver. 5.0. SPSS software version 27.0 (IBM Inc.) was used for all analyses. We defined p-value < 0.05 as statistically significant. A total of 25 patients met the criteria and were evaluated. The median patient age was 73 years (range 58-89), and 21 of 25 patients were male. The number of patients with PS 0 was 22, PS 1 was 1, and PS 2 was 2. The number of HBV-related HCC cases was in 8, HCV-related HCC cases was in 11, and non-B and non-C cases was in 6. The median maximum tumor diameter was 3.0 cm (1.1-4.8 cm). In 6 patients, identification of vascular invasion to the main trunk of the portal vein and/or major hepatic vein was confirmed. The Child-Pugh (CP) grade was A in 21 patients and B in 4. The modified albumin-bilirubin (mALBI) grade 1 is in 17 patients, 2a in 4, 2b in 4. Prescribed doses were 45 Gy / 2 fr in 3 cases, 48 Gy / 2 fr in 12 cases, 52.8 Gy / 4 fr in 7 cases, and 60 Gy / 4 fr in 3 cases. With a median follow-up period of 43.6 months (range 0.3-85.0), 3-year OS, PFS, and LC were 74% (95% confidence interval [CI], 54.8-93.8%), 32% (95% CI, 11.8-51.4%), and 93% (95% CI, 79.4-106%), respectively. All patients had no Grade 2 or higher adverse events during the observation period. The safety and efficacy of C-ion RT for caudate HCC were demonstrated. These results suggested that C-ion RT may be a promising treatment option for patients with caudate HCC.