Frequency Of Hepatocellular Carcinoma Research Articles

Frequency of hepatocellular carcinoma in patients with hepatitis C receiving treatment with directly antiviral agents

Background and Aims: Hepatitis C infection is one of leading causes of liver cirrhosis and a considerable proportion of hepatocellular carcinoma worldwide. Despite the very high efficacy of Directly Acting Viral Agents (DAAs) on clearance of hepatitis C their role remains controversial on development of Hepatocellular Carcinoma. The Aim of this study is to analyze hepatocellular occurrence in hepatitis C patients after achieving Sustained virologic response on directly acting viral agent. Methods and Material: It is prospective study conducted on outpatients in the Hepato-gastroenterology department of Asian Institute of Medical Science Hospital Hyderabad from 21-10-2018 to 20-04-2019. All patients who fulfilled the criteria were enrolled, their baseline demographic characteristics, Child Pugh Class, MELD score, alpha-fetoprotein level and Ultrasound liver before and after treatment collected. Duration of DAAs treatment and type of DAAs used also noted. Hepatocellular carcinoma labelled when Triphasic CT scan liver shows typical characters of hepatocellular carcinoma i.e. arterial phase hyperenhancement and delayed washout on portal and venous phase or ultrasound liver shows focal liver lesion with alpha-fetoprotein level more than 300ng/ml. Results: One hundred fifty-seven patients of chronic hepatitis C enrolled in the study after exclusion criteria.

Frequency of Hepatocellular Carcinoma in HCV Patients Treated with Direct-Acting Antiviral Drugs

Frequency of Hepatocellular Carcinoma in HCV Patients Treated with Direct-Acting Antiviral Drugs

Direct-acting antivirals for hepatitis C virus-infected patients with hepatocellular carcinoma.

BACKGROUNDHepatocellular carcinoma (HCC) in hepatitis C virus (HCV)-infected patients has a high risk of recurrence. Although eradication of HCV is expected to reduce this risk, the risk in patients with a history of HCC may be high after treatment with direct-acting antivirals (DAAs).AIMTo determine the risk factors for HCC recurrence in patients with HCV and a history of HCC.METHODSThe risk of HCC recurrence in patients with a history of HCC and/or of HCC occurrence in patients without a history of HCC after DAA therapy was retrospectively analyzed in 311 HCV patients treated at our institution and several neighboring hospitals. The frequency and predictors of HCC recurrence/ occurrence after DAA treatment were included in these analyses. The clinical course of HCC before and after DAA treatment was also evaluated.RESULTSHCV patients with a history of HCC were older and had greater progression of liver fibrosis and diabetes than patients without a history of HCC. Median recurrence-free survival (RFS) was 1092 d in patients with a history of HCC, and post-DAA HCC recurrence/occurrence was observed in 29 patients (53.7%) with and 5 (1.9%) without a history of HCC over 6 years (P < 0.001). RFS in patients with a history of HCC did not differ significantly before and after DAA treatment. The frequency of HCC recurrence/occurrence in patients with a history of HCC was lower after than before DAA treatment. Multivariate analysis showed that the incidence rate of HCC recurrence/occurrence before DAA treatment was the only independent predictor of HCC recurrence/occurrence after DAA treatment. Liver function was well preserved and clinical course was good in patients with HCC recurrence/occurrence after DAA therapy.CONCLUSIONDAA therapy in patients infected with HCV is also effective in patients with a history of HCC. Curative treatment for HCC is desirable before DAA therapy. The frequency of HCC recurrence/occurrence before DAA therapy was associated with a significantly increased risk of HCC recurrence after DAA therapy. Careful observation after DAA therapy is required in patients with a history of HCC.

Phospholipids in non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease, or NAFLD – is a pathology that usually has a metabolic cause and is not caused by excessive alcohol consumption. NAFLD is the most frequent chronic liver disease worldwide and is accompanied by a high financial burden for the patient and the healthcare system. NAFLD is generally considered a “benign disease” with low progression to fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Nevertheless, due to the large number of affected patients, the prevalence of cirrhosis of the liver has gradually increased, and in fact it represents the third cause of liver transplantation in the world. Moreover, even if the frequency of HCC in patients with NAFLD is lower than in patients with HCV/HBV cirrhosis, the absolute number of HCC associated with NASH is higher due to the higher number of patients with NAFLD. It is likely that the importance of this disease will continue to grow in the future, when new treatments and prevention programs for hepatitis C and B reduce the size of viral liver infections. Many aspects of the disease have yet to be solved. It is very important to understand the mechanisms underlying the occurrence and development of NAFLD, the features of the clinic and diagnosis, as well as the tactics of management and treatment of patients with non-alcoholic fatty liver disease. It is important for patients to get a complete understanding of NAFLD so that they can play an active role in the treatment of their disease.

Clinical Significance of Telomerase Reverse-Transcriptase Promoter Mutations in Hepatocellular Carcinoma.

Simple SummaryActivating mutations in the promoter region of TERT (TERTp) gene are frequently observed in low- and high-grade dysplastic nodules and defined as early events in hepatocellular carcinoma development. This study shows that the nucleotide change G>A at position −124 in the TERTp region is very common in hepatocellular carcinoma. The concordance rate between droplet digital PCR (ddPCR) (63.6%) and Sanger sequencing (52.1%) detection methods is good (83.5%). HCC patients carrying the TERTp mutation had lower levels of the tumour biomarker Ca19-9 but showed reduced survival. The presence of TERTp mutations may represent a prognostic signature in liver cancer.Telomerase reactivation during hepatocarcinogenesis is recurrently caused by two point mutations occurring most frequently at the nucleotide −124 (95%) and occasionally at the nucleotide −146 (<5%) upstream of the TERT translational start site in hepatocellular carcinoma (HCC). In this study, we designed a droplet digital PCR (ddPCR) assay to detect TERT promoter (TERTp) nucleotide change G>A at position −124 and to quantify the mutant allele frequency (MAF) in 121 primary liver cancers, including 114 HCC along with 23 autologous cirrhotic tissues, five cholangiocarcinoma (CC), and two hepato-cholangiocarcinoma (HCC-CC). All cases were evaluated for tumour markers such as α-fetoprotein (AFP), carbohydrate antigen 19-9 (CA19-9), and carcinoembryonic antigen (CEA). We compared the sensitivity of ddPCR and Sanger sequencing and investigated the prognostic relevance of TERTp mutations. The TERTp G>A transition was identified in 63.6% and 52.1% of HCC samples by ddPCR and Sanger sequencing, respectively. One out of 23 (4.3%) peri-tumour tissues tested positive only by ddPCR. One out of five CC (20%) and none of the HCC-CC were found concordantly mutated by the two methods. The TERTp MAF ranged from 2% to 66%, and the large majority (85.5%) of mutated samples showed a value above 20%. A statistically significant correlation was found between TERTp mutation and tumour size (p = 0.048), while an inverse correlation was observed with CA19-9 levels (p = 0.0105). Moreover, HCC patients with TERTp −124A had reduced survival. In conclusion, the single nucleotide variation G>A at position −124 in TERTp, detected either by ddPCR or by Sanger sequencing, showed a remarkable high frequency in HCC. Such mutation is associated with lower levels of CA19-9 and reduced survival in HCC patients suggesting that the TERTp status may represent a distinct signature of liver cancer subgroups.

Profile of different Hepatitis B virus integration frequency in hepatocellular carcinoma patients

Hepatitis B virus (HBV) DNA integration is closely related to the occurrence of liver cancer. However, current studies mostly focus on the detection of the viral integration sites, ignoring the relationship between the frequency of viral integration and liver cancer. Thus, this study uses previous data to distinguish the breakpoints according to the integration frequency and analyzes the characteristics of different groups. This analysis revealed that three sets of breakpoints were characterized by its own integrated sample frequency, breakpoint distribution, and affected gene pathways. This result indicated an evolution in the virus integration sites in the process of tumor formation and development. Therefore, our research clarified the characteristics and differences in the sites of viral integration in tumors and adjacent tissues, and clarified the key signaling pathways affected by viral integration. Hence, these findings might be of great significance in the understanding of the role of viral integration frequency in hepatocellular carcinoma.

TSC2 Mutations Were Associated with the Early Recurrence of Patients with HCC Underwent Hepatectomy.

PurposeTo explore the value of Tuberous sclerosis complex 2 (TSC2) mutations in evaluating the early recurrence of hepatocellular carcinoma (HCC) patients underwent hepatectomy.Patients and MethodsA total of 183 HCC patients were enrolled. Next-generation sequencing was performed on tumor tissues to analyze genomic alterations, tumor mutational burden and variant allele fraction (VAF). The associations between TSC2 mutations and recurrence rate within 1 year, RFS and OS after hepatectomy were analyzed.ResultsOur results showed that TSC2 mutation frequency in HCC was 12.6%. Compared to patients without TSC2 mutation, the proportion of microvascular invasion (MVI) and Edmondson grade III–IV was significantly higher in patients with a TSC2 mutation (p<0.05). The VAF of mutated TSC2 was higher in patients with maximum diameter of tumor >5cm or MVI than that of other patients (p<0.05). The frequency of TP53 mutation was significantly higher in patients with a TSC2 mutation than those without TSC2 mutation (p=0.003). Follow-up analysis showed that patients with a TSC2 mutation had significantly higher recurrence rate within 1 year (p=0.015) and poorer median recurrence-free survival (RFS) (p=0.010) than patients without TSC2 mutation. TSC2 mutations did not significantly affect overall survival of patients (p=0.480). The multivariate analysis results showed that the Barcelona Clinic Liver Cancer (BCLC) B-C stage, TSC2 mutations and preoperative serum alpha-fetoprotein level ≥400μg/L were independently associated with recurrence within 1 year after hepatectomy (HR=8.628, 95% CI: 3.836–19.405, p=0.000; HR=3.885, 95% CI: 1.295–11.653, p=0.015; HR=2.327, 95% CI: 1.018–5.323, p=0.045; respectively), and poorer RFS after hepatectomy (HR=3.070, 95% CI: 1.971–4.783, p=0.000; HR=1.861, 95% CI: 1.061–3.267, p=0.030; HR=1.715, 95% CI: 1.093–2.693, p=0.019; respectively).ConclusionTSC2 mutations were significantly associated with MVI in liver para-carcinoma tissue and Edmondson grade III–IV in patients with HCC and were independently associated with recurrence within 1 year and poorer RFS after hepatectomy. The TSC2 mutation may be a potential predictor for early recurrence in HCC patients underwent hepatectomy.

Pan-cancer circulating tumor DNA detection in over 10,000 Chinese patients

Circulating tumor DNA (ctDNA) provides a noninvasive approach to elucidate a patient’s genomic landscape and actionable information. Here, we design a ctDNA-based study of over 10,000 pan-cancer Chinese patients. Using parallel sequencing between plasma and white blood cells, 14% of plasma cell-free DNA samples contain clonal hematopoiesis (CH) variants, for which detectability increases with age. After eliminating CH variants, ctDNA is detected in 73.5% of plasma samples, with small cell lung cancer (91.1%) and prostate cancer (87.9%) showing the highest detectability. The landscape of putative driver genes revealed by ctDNA profiling is similar to that in a tissue-based database (R2 = 0.87, p < 0.001) but also shows some discrepancies, such as higher EGFR (44.8% versus 25.2%) and lower KRAS (6.8% versus 27.2%) frequencies in non-small cell lung cancer, and a higher TP53 frequency in hepatocellular carcinoma (53.1% versus 28.6%). Up to 41.2% of plasma samples harbor drug-sensitive alterations. These findings may be helpful for identifying therapeutic targets and combined treatment strategies.

Hepatocellular Carcinoma in Acute Hepatic Porphyrias: Results from the Longitudinal Study of the U.S. Porphyrias Consortium

The risk for hepatocellular carcinoma (HCC) is increased in acute hepatic porphyrias (AHP). The aim of this study was to explore the clinicopathologic characteristics, outcomes, and frequency of HCC in patients with AHP in the United States. This cross-sectional analysis evaluated patients with HCC in a multicenter, longitudinal study of AHP. Among 327 patients with AHP, 5 (1.5%) were diagnosed with HCC. Of the 5 HCC cases, 4 had acute intermittent porphyria and 1 had variegate porphyria, confirmed by biochemical and/or genetic testing. All patients were white females, with a median age of 27years (range 21-75) at diagnosis. The median age at HCC diagnosis was 69years (range 61-74). AHP was asymptomatic in 2 patients; 2 reported sporadic attacks; and 1 reported recurrent attacks (>4 attacks/year). All patients had a single HCC lesion on liver imaging that was 1.8-6.5 centimeters in diameter. Serum alpha fetoprotein levels were below 10ng/mL in all 4 patients with available results. Four patients underwent liver resection, and 1 was treated with radioembolization. No significant inflammation or fibrosis was found in adjacent liver tissues of 3 patients who underwent liver resection. Two patients developed recurrence of HCC at 22 and 26months following liver resection. All patients are alive with survival times from HCC diagnosis ranging from 26-153months. In this U.S. study, 1.5% of patients with AHP had HCC. HCC in AHP occurred in the absence of cirrhosis, which contrasts with other chronic liver diseases. Patients with AHP, regardless of clinical attacks, should be screened for HCC, beginning at age 50. The pathogenesis of hepatocarcinogenesis in AHP is unknown and needs further investigation.

Abstract 1637: ATP-citrate lyase transgenic mice frequently develop lymphoma/leukemia spontaneously

Abstract ATP-citrate lyase (ACLY) catalyzes the generation of acetyl-CoA from citrate. ACLY expression is upregulated and/or ACLY is phosphorylated in several types of cancer. We generated ACLY transgenic mice (Tg) to examine the role of ACLY in carcinogenesis. (Materials and methods) Using human ACLY cDNA under the ROSA26 promoter, Tg with a C57BL background was established. We observed the Tg without treatment. Statistical analyses were performed using the Chi-square and Fisher's exact test. (Results) Of 24 male (M) Tg, aged 24–30 months, 14 (58%), 7 (29%), and 1 (4%) spontaneously developed lymphoma/leukemia (LL), lung carcinoma (LC), and small intestinal carcinoma (SIC), respectively. Since some C57BL mouse colonies are genetically susceptible to LL, and we have previously examined human cases of carcinoma, the Tg were back-crossed with C3H mice, which are resistant to LL and susceptible to carcinoma, especially hepatocellular carcinoma (HCC). A total of 129 (M: 67, female (F): 62) Tg were observed for 18 months. Forty-nine C3H mice (M: 19, F: 30) from the same colony were used as controls. Multiple tumors were counted individually. Seventy-three Tg (57%; M: 41, 61%; F: 32, 52%) and 8 controls (16%; M: 4, 21%; F: 4, 13%) developed cancer. The Tg developed significantly more tumors (total (T), M, F: all p&amp;lt;0.05), including 33 HCC (26%; M: 22, 33%; F: 11, 18%), 28 LL (22%; M: 12, 18%; F: 16, 26%), 7 LC (5%; M: 6, 9%; F: 1, 2%), 4 sarcomas (Sa)(3%; M: 2, 3%; F: 2, 3%), 2 SIC (2%; M: 2, 3%; F: 0), 2 skin appendage carcinomas (SAC) (2%; M: 0; F: 2, 3%), and 1 ovarian cancer (Ov) (1%; F: 1, 2%), than the control mice, which developed 7 HCC (14%; M: 4, 21%; F: 3, 10%), 1 LC (2%; M: 1, 5%; F: 0), and 1 Ov (2%; F: 1, 3%). No LL was seen in the controls. The frequency of HCC did not differ significantly between the Tg and controls (T, M, F: all p&amp;gt;0.05). (Discussion) ACLY was reported to be related to the carcinogenesis of anaplastic large cell lymphoma (Basappa J. et al. Blood 2015 126:465). This study suggests that ACLY might contribute to LL development. Table:Summary of developed cancersNumberTotal cancerHCCLLLCSICSaSACOvACLY12973(57%)*33(26%)28(22%)7(5%)2(2%)4(3%)2(2%)1(1%)Male6741(61%)**22(33%)12(18%)6(9%)2(3%)2(3%)0-Female6232(52%)***11(18%)16(26%)1(2%)02(3%)2(3%)1(2%)Control498(16%)*7(14%)01(2%)0001(2%)Male194(21%)**4(21%)01(5%)000-Female304(13%)***3(10%)000001(3%)*, **, ***; p&amp;lt;0.05 Citation Format: Hiroaki Kanda, Kimie Nomura, Toshihiko Iizuka, Mutsunori Fujiwara, Yuichi Ishikawa, Toshiro Migita. ATP-citrate lyase transgenic mice frequently develop lymphoma/leukemia spontaneously [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1637.

Dampened VEPH1 activates mTORC1 signaling by weakening the TSC1/TSC2 association in hepatocellular carcinoma

Abnormal activation of mTORC1 signaling occurs at high frequency in hepatocellular carcinoma (HCC). However, the underlying causes of this aberrant activation remain elusive. In this study, we identified ventricular zone expressed pleckstrin homology domain-containing 1 (VEPH1) as a novel tumor suppressor that acts via the mTORC1 axis. We performed quantitative reverse-transcription PCR (92 pairs), western blot (30 pairs), and immunostaining (225 cases) assays in HCC tissue samples to evaluate VEPH1 expression. We explored the functional effects of VEPH1 on tumor growth and metastasis. Molecular and biochemical strategies were used to gain insight into mechanisms underlying the tumor-suppressive function of VEPH1. VEPH1 is frequently silenced in HCC tissues, primarily resulting from let-7d upregulation. Decreased VEPH1 expression is associated with poor prognosis and aggressive tumor phenotypes in patients with HCC. VEPH1 mediates its tumor-suppressing activity through regulation of cell proliferation, migration and invasion invitro and invivo. The VEPH1 fragments 580-625aa and 447-579 aa bind directly to TSC1 (719-1,164aa) and TSC2 (1-420 aa), respectively, enhancing TSC1/TCS2 binding and promoting translocation of TSC2 to the membrane, which leads to increased TSC2 Ser1387 phosphorylation. Subsequently, Rheb is inactivated by the GTPase activity of TSC2, inhibiting mTORC1 signaling and contributing to changes in HCC carcinogenesis and metastasis. Rapamycin, the mTOR inhibitor, can inhibit the pro-tumorigenic effect of VEPH1 knockdown. Loss of VEPH1 correlates with decreased TSC2 Ser1387 phosphorylation and increased mTOR activity in HCC specimens. The loss of VEPH1 leads to aberrantly activated mTORC1 signaling in HCC; rapamycin (or rapalogs) may serve as an effective treatment option for patients with HCC and dampened VEPH1 expression. Abnormally activated mammalian target of rapamycin (mTOR) signaling is associated with poor tumor differentiation, early tumor recurrence and worse overall survival in patients with hepatocellular carcinoma. Herein, we identify low VEPH1 expression as a potential cause of abnormally activated mTOR signaling in hepatocellular carcinoma tissues. mTOR inhibitors could thus be an effective treatment option for patients with HCC and low VEPH1 expression.

Transcriptomic profiling of long non-coding RNAs in non-virus associated hepatocellular carcinoma.

Due to falling prevalence of viral hepatitis (VH), obesity, alcoholism and related liver diseases have become increasingly frequent and important as causes of hepatocellular carcinoma (HCC). However, mechanisms underlying hepatocarcinogenesis and tumor progression in VH-negative HCC remain poorly understood. Long non-coding RNAs (lncRNAs) have been implicated in pathogenesis of human diseases, including HCC. Here, by analyzing 20 clinical samples' RNA-sequencing data generated from 8 VH-negative and 2 VH-positive HCC patients, we have identified and characterized 1,514 candidate lncRNAs. For differentially expressed genes (DEGs) between tumor tissues and adjacent non-tumor tissues (P < 0.05, |FC| > 2), the upregulated genes were mainly involved in the cell proliferation, and the downregulated genes mediated the metabolic processes and responses to oxidative stress, inflammation and toxic substances. Furthermore, the lncRNA-mRNA co-expression network was constructed, by which two genetic aberrations with high frequency in HCC, SPATA46 and TMEM78, were identified. In addition, we identified 16 DEGs between tumor issues from VH-negative and VH-positive HCC patients with aim to explore gene expression differences that could be involved in the pathogenesis of HCC with varying etiology. In conclusion, we performed the comprehensive analysis of lncRNA and mRNA expression profiles, which could provide valuable insights into the underlying genetic alteration in non-virus associated HCC.

Lack of hotspot mutations other than TP53 R249S in aflatoxin B1 associated hepatocellular carcinoma

Abstract Objective Despite the recent advances in diagnosis and treatment of hepatocellular carcinoma (HCC), it is still a major health problem. Therefore, understanding the molecular mechanism is very important. Our aim is to investigate the molecular basis of aflatoxin B1 (AFB1) induced HCC other than the hotspot TP53 p.Arg249Ser (c.747G&gt;T) (R249S) mutation. Methods 525 genes previously reported to be involved in carcinogenesis with mutations in different cancer types were analyzed by next generation sequencing for 525 cancer-gene panel (Roche/NimbleGen) in one tumor sample (T29) and one cell line (MAHLAVU) carrying TP53 R249S mutation. Additionally, ARID2 and BCORL1 genes were analyzed by Sanger sequencing for MAHLAVU and Primary Liver Carcinoma/Poliomyelitis Research Foundation/5 (PLC/PRF/5) cell lines. Results No other common gene mutations were found in the analyzed T29 and MAHLAVU samples and also no genetic variation possibly associated with AFB1 was detected in PLC/PRF/5 cell line and 68 COSMIC HCC samples. Likewise, no pathogenic mutation was detected in ARID2 and BCORL1 genes of MAHLAVU and PLC/PRF/5 cell lines. Conclusion No fingerprint mutations were detected in the analyzed genes. To the best of our knowledge, other hotspot mutations appear to be absent if not at a very low frequency in HCC carrying TP53 R249S mutation.

Analysis of the Liver Transplant Waiting List in Our Center

BackgroundLiver transplantation (LT) is an important treatment for acute liver failure and end-stage liver disease. Due to the limited supply of livers, there are still thousands of candidates waiting for transplantation in Turkey. We aimed to analyze LT waiting list access by demographics and etiology, particularly the diagnosis of hepatocellular carcinoma (HCC), which has been prioritized for LT in recent years. Materials and MethodsBetween 2011 and 2018, all patients listed for LT in our center were retrospectively reviewed. Demographic features, etiology of liver disease, waiting time, Model for End-Stage Liver Disease (MELD) score, and survival data were recorded. Differences between the LT group and deceased patients on the waiting list were evaluated. ResultsDuring this period, 266 patients were included in the LT waiting list. Only 119 patients (44.7%) underwent LT (men, 94; women, 25; mean age, 53 years), whereas 103 (38%) died (men, 60; women, 43; mean age, 53 years) in the waiting period. Seventeen patients were status 1A or 1B and of these, 7 patients died from fulminant hepatic failure. MELD score was significantly higher in deceased group (28 ± 7 vs 25 ± 6; P = .014). The frequency of HCC was significantly higher in LT group (29% vs 11%; P = .002). Overall survival of the patients in the waiting list with and without liver transplantation were 63% and 41%, respectively. ConclusionsHCC is one of the leading etiologies that is considered for cadaveric LT from the waiting list in our center. These patients had slightly lower MELD scores compared to deceased patients with shorter waiting times. We recommend early referral and close monitoring of the patients who are LT candidates.

ERADICATION OF HCV INFECTION IN PATIENTS WITH LIVER CIRRHOSIS: FACTOR OF CANCER PREVENTION OR CARCINOGENESIS?

Hepatocellular carcinoma (HCC) is one of the most common causes of death from cancer and is the final stage of chronic liver disease, usually occurring in patients with cirrhosis (CP). Chronic infection with hepatitis C virus (HCV) leads to progressive liver inflammation and cirrhosis because this virus specifically affects liver tissue. Previously used interferon therapy had a relatively low efficiency and very high risks of side effects. During the period of administration of interferon (IFN) schemes it was proved that elimination of the virus significantly reduced risk of liver cancer development. Discovery of direct-acting antiviral (DAA ) drugs have revolutionized HCV therapy with virus elimination rate of more than 95 % and an excellent safety profile. However, the risk of transformation of liver cirrhosis into hepatocellular carcinoma is still high even after complete eradication of the virus. Numerous studies have shown conflicting results on the possible relationship between the use of new antiviral drugs and the increase in the frequency of newly diagnosed or recurrent hepatocellular carcinoma. Thus, the long-term prognosis in terms of risk for HCC development among patients with sustained virological response (SVR) remains unclear.The purpose of the studywas to analyze the literature on the effect of antiviral therapy of chronic hepatitis C with interferon-containing regimens and drugs of direct antiviral action on the risk of developing or recurring hepatocellular carcinoma.Material and Methods. We analyzed publications available from PubMed, S copus, E-library, Web of S cience using the key words “hepatocellular carcinoma”, “chronic hepatitis C”, “direct-acting antiviral drugs”, “liver cirrhosis”, “interferons”, and “sustained virological response”. Of the 99 studies found, 21 were used to write a systematic review.Results.Eradication of the virus reduces the risks of HCC. Despite reports on high risk of occurrence or recurrence of hepatocellular carcinoma in patients with cirrhosis after treatment with DAA s compared with interferon-containing regimens, there is not enough data confirming the direct link between the use of DAA s and the development of hepatocellular carcinoma. No statistically significant difference in the frequency of HCC between patients treated with interferon or DAA s was detected.Conclusion.Eradication of the virus is the most significant factor in the prevention of HCC; therefore, treatment of CHC should not be delayed due to the risk of HCC. Patients with liver cirrhosis require a long period of follow-up, even after successful treatment of chronic hepatitis C with DAA drugs. Stratification of HCC risk requires further research.

Induction of specific CD8(+) T cells against hepatocellular carcinoma-associated neoantigens

Objective: To predict the tumor neoantigen peptides in hepatocellular carcinoma (HCC), and examine their specific immune effects against the tumor cells without injury to normal cells. Methods: The data of whole-genome sequencing and exome sequencing of HCC tumor and matched non-tumor liver tissues were analyzed to confirm the HCC-associated somatic mutations. Based on the HLA phenotype of the patients, we used NetMHC software to predict the neoantigen epitopes with high binding affinity to their MHC-I molecules. The predicted peptides with mutation sites included were synthesized. GPL10687 platform was applied to examine the gene expression difference between tumor and normal tissues of the selected genes in GSE25097, one of the GEO databases. The quantitative real-time PCR (qRT-qPCR) and immunohistochemistry were used to confirm the expressions in tumors and normal tissues of the selected genes. By using the predicted peptides, we induced the generation of antigen-specific CD8(+) cytotoxic T lymphocytes (CTLs) and examined their specific effects against tumor cells. Results: The mutation frequency of TP53 (tumor protein p53) was 40%, and LAMA3 (Laminin Subunit Alpha 3) was 8% in the analyzed HCC tissues. In GSE25097 database, TP53 and LAMA3 mRNA levels in tumors were 1.57±0.02 and 1.37±0.10, which were significantly increased than those in matched no-tumor tissue (0.54±0.01 and 0.36±0.01, P<0.05). The differences of expression levels of TP53 and LAMA3 in tumor and no-tumor tissues were validated by using qRT-qPCR and immunohistochemistry in 10 HCC tissues. The mRNA levels of TP53 and LAMA3 in tumors were 0.24±0.03 and 0.13±0.06, which were significantly elevated than those in matched no-tumor tissue (0.11±0.01 and 0.01±0.01, P<0.05). Among the Chinese population, HLA-A2 and HLA-A11 and HLA-A24 accounted for 70%, representing the major MHC-I molecules. The CTLs induced by predicted peptides showed cytotoxicity to the targets pulsed with mutated peptide, with no effect on the target pulsed with normal peptide and on normal cells. Conclusions: TP53 and LAMA3 existed relative higher mutation frequency in HCC, and expressed higher in tumor tissues. The induced CTLs by predicted peptides derived from mutation-associated protein could specific kill the target cells without injury to normal cells.

Hepatocellular carcinoma in patients with autoimmune hepatitis - a systematic review of the literature published between 1989-2016.

Background and aimsLiver cancer is one of the most common cause of deaths from cancer. Hepatocellular carcinoma (HCC) was reported at a frequency of 7% of patients with autoimmune hepatitis (AIH) - related cirrhosis in 1988. We aimed to provide a systematic literature review on the frequency of HCC in patients with AIH, after the discovery of hepatitis C virus (HCV), in order to avoid any possible confounding etiology.MethodsA literature search of the PubMed database between 1989–2016 was performed, using the relevant keywords “hepatocellular carcinoma” and “autoimmune hepatitis”. We followed the PRISMA statement guidelines during the preparation of this review.ResultsEleven studies (n=8,460 patients with AIH) were retained for the final analysis. HCC was diagnosed in 0–12.3% of the AIH patients included in these studies. The overall occurrence of HCC in patients with AIH was estimated in two studies, at 5.1% and 6.2%, respectively. In patients with AIH and cirrhosis, the percentage of HCC varied between 0.2%–12.3%. The proportion of HCC in patients with AIH without cirrhosis was estimated at 1.03%. The percentage of cirrhosis in AIH patients varied from 18.7% to 83.3% in Japan, and from 12% to 50.2% in the other areas. The mean follow-up of the patients with AIH was of 10 years.ConclusionsThe development of HCC in patients with AIH appeared to be similar before and after the discovery of HCV, and it was mainly associated to cirrhosis. The number of patients developing cirrhosis in relation with AIH was impressive. The long evolution of AIH to cirrhosis and, eventually, to HCC, has been be suggested.

Incidence and risk factors of hepatocellular carcinoma change over time in patients with hepatitis C virus infection who achieved sustained virologic response.

In patients with chronic hepatitis C, hepatocellular carcinoma (HCC) occurs at a certain frequency, even if a sustained virologic response (SVR) is achieved by antiviral treatment. Old age, liver fibrosis, and high post-treatment α-fetoprotein (AFP) level are typical risk factors of post-SVR HCC. We examined whether the frequencies and factors of HCC in patients with an SVR achieved from interferon treatment changed. Methods Among patients prospectively registered for pegylated interferon and ribavirin treatment, 2021 with an SVR without HCC development during the treatment period were followed up. The mean observation period was 49.5 ± 26.2months. The multivariable Cox regression analysis showed that older age, diabetes mellitus, advanced liver disease, and higher post-treatment AFP level were the independent risk factors throughout the observation period. The annual occurrence rate of HCC was 0.74% in the third year, 0.54% in the fourth year, and 0.40% in the fifth year; it gradually decreased from the third year. Because the time course hazards for HCC changed at 48months, we separately analyzed its risk factors before and after this change point. The multivariable Cox regression analysis showed that the four above-mentioned factors were significantly related to HCC development within 4years. Conversely, the univariable Cox regression analysis only identified diabetes mellitus as a significant factor for HCC development after 4years. The frequency of HCC in hepatitis C patients who achieved an SVR from interferon treatment decreased during the observation period, and its risk factors changed between the early and late periods.

The frequency of occurrence of Hepatocellular Carcinoma after direct antiviral therapy in Hepatitis C virus patients.

Objective:To study the frequency of occurrence of hepatocellular carcinoma (HCC) in hepatitis C virus patients treated with direct acting antiviral (DAA) agents.Methods:This hospital based cross-sectional study was conducted in Mayo Hospital, Lahore from June, 2016 to January, 2018. Total 300 patients with HCV genotype 3, selected via Non-Probability Purposive Sampling technique, without prior or concurrent history of HCC, were given DAA agents and were followed up for 6 months after completion of therapy. Results were based on Quantitative PCR to assess Sustained Virological Response (SVR) and Ultrasound Abdomen to look for the appearance of any new lesion. Data was presented as mean ±SD, frequency and percentages and was analyzed using SPSS Version 24.0.Results:Out of 300 patients, 179 (59.7%) were males and 121(40.3%) were females. Mean age of the patients was 55.08 ± 5.602 years. 214(71.3%) patients had compensated cirrhosis at the start of treatment and 86(28.7%) had decompensated cirrhosis. SVR was achieved in 200(93.4%) out of 214 patients with compensated cirrhosis and in 76(88.3%) out of 86 patients with decompensated cirrhosis. At six months post- treatment, 10(3.33%) patients developed HCC,2(0.7%) in the compensated group and 8(2.7%) in the decompensated group, out of which 5(6.6%) patients had achieved SVR.Conclusion:The frequency of HCC following DAA agents is significant (3.3%) even after achieving SVR. Caution must be exercised in prescribing DAA agents to HCV patients keeping this complication of HCC in mind.

Validation of Liver Imaging Reporting and Data System 2017 (LI-RADS) Criteria for Imaging Diagnosis of Hepatocellular Carcinoma.

The Liver Imaging Reporting and Data System (LI-RADS) is being adapted by many clinical practices. To support continuation of its use, LI-RADS (LR) is in need of multicenter validation studies of recent LI-RADS iterations. Furthermore, while both gadoxetate and extracellular agents have been incorporated into LI-RADS, comparison of the diagnostic performance between the two has yet to be determined. To evaluate the rate, diagnostic performance, and interreader reliability (IRR) of LI-RADS 2017 for hepatocellular carcinoma, including LR major and ancillary features, with both gadoxetate and extracellular agent-enhanced MRI against a reference standard of histopathology or imaging follow-up. Retrospective. In all, 114 patients with 144 observations were included who met LR 2017 criteria for at risk and had at least one hepatic observation on liver MRI performed with either gadoxetate (n = 52) or an extracellular agent (n = 92) between 2010-2016, with histopathology (n = 103) or follow-up imaging (n = 41). 1.5 and 3.0T/T1 -T2 WI, diffusion-weighted imaging. Three radiologists independently assessed major/ancillary features and assigned overall LI-RADS category for every observation. Diagnostic performance of LR5/TIV+LR5 for identifying hepatocellular carcinoma (HCC) was compared between contrast agents with a generalized estimating equation. Weighted kappa was performed for interrater reliability. The frequency of HCCs among LR1, LR2, LR3, L4, LR5, LRTIV+LR5, and LRM observations were: 0% (all readers), 0-12.5%, 11.4-26.9%, 50-76%, 83.0-95.1%, 83.3-100.0%, and 45.0-65.0%, respectively. Sensitivity of LR5/LRTIV+LR5 for HCC was 59.7-71.4% and specificity 85.0-96.8%. LI-RADS specificity and positive predictive value for observations imaged with gadoxetate was higher than extracellular agent for the most inexperienced reader (R3) (P = 0.009-0.034). IRR for LI-RADS categorization was substantial (k = 0.661). Increasing numerical LI-RADS 2017 categories demonstrate a greater percentage of HCCs. LR5/TIV+LR5 demonstrates excellent specificity and fair sensitivity for HCC. MRI with gadoxetate in liver transplant candidates may be beneficial for less experienced readers, although further large-scale prospective studies are needed. 4 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2019;49:e205-e215.