Types Of Hepatocellular Carcinoma Research Articles

TAF1B depletion leads to apoptotic cell death by inducing nucleolar stress and activating p53-miR-101 circuit in hepatocellular carcinoma.

TAF1B (TATA Box Binding Protein (TBP)-Associated Factor) is an RNA polymerase regulating rDNA activity, stress response, and cell cycle. However, the function of TAF1B in the progression of hepatocellular carcinoma (HCC) is unknown. In this study, we intended to characterize the crucial role and molecular mechanisms of TAF1B in modulating nucleolar stress in HCC. We analyzed the differential expression and prognostic value of TAF1B in hepatocellular carcinoma based on The Cancer Genome Atlas (TCGA) database, tumor and paraneoplastic tissue samples from clinical hepatocellular carcinoma patients, and typical hepatocellular carcinoma. We detected cell proliferation and apoptosis by lentiviral knockdown of TAF1B expression levels in HepG2 and SMMC-7721 cells using clone formation, apoptosis, and Western blotting (WB) detection of apoptosis marker proteins. Simultaneously, we investigated the influence of TAF1B knockdown on the function of the pre-initiation complex (PIC) by WB, and co-immunoprecipitation (Co-IP) and chromatin immunoprecipitation (ChIP) assays verified the interaction between the complexes and the effect on rDNA activity. Immunofluorescence assays measured the expression of marker proteins of nucleolus stress, fluorescence in situ hybridization (FISH) assays checked the rDNA activity, and qRT-PCR assays tested the pre-rRNA levels. Regarding molecular mechanisms, we investigated the role of p53 and miR-101 in modulating nucleolar stress and apoptosis. Finally, the impact of TAF1B knockdown on tumor growth, apoptosis, and p53 expression was observed in xenograft tumors. We identified that TAF1B was highly expressed in hepatocellular carcinoma and associated with poor prognosis in HCC patients. TAF1B depletion modulated nucleolar stress and apoptosis in hepatocellular carcinoma cells through positive and negative feedback from p53-miR-101. RNA polymerase I transcription repression triggered post-transcriptional activation of miR-101 in a p53-dependent manner. In turn, miR-101 negatively feeds back through direct inhibition of the p53-mediated PARP pathway. These findings broaden our comprehension of the function of TAF1B-mediated nucleolar stress in hepatocellular carcinoma and may offer new biomarkers for exploring prospective therapeutic targets in HCC.

Contrast-enhanced ultrasound for the diagnosis of hepatocellular carcinoma in adults with chronic liver disease.

Hepatocellular carcinoma occurs mostly in people with chronic liver disease. Worldwide, it ranks sixth in terms of incidence of cancer, and fourth in terms of cancer-related deaths. Contrast-enhanced ultrasound (CEUS) is used as an add-on test to confirm the presence of focal liver lesions suspected as hepatocellular carcinoma after prior diagnostic tests such as abdominal ultrasound or measurement of alpha-foetoprotein, or both. According to guidelines, a single contrast-enhanced imaging investigation, with either computed tomography (CT) or magnetic resonance imaging (MRI), may show the typical hepatocellular carcinoma hallmarks in people with cirrhosis, which will be sufficient to diagnose hepatocellular carcinoma. However, a significant number of hepatocellular carcinomas show atypical imaging features, and therefore, are missed at imaging. Dynamic CEUS images are obtained similarly to CT and MRI images. CEUS differentiates between arterial and portal venous phases, in which sonographic hepatocellular carcinoma hallmarks, such as arterial hyperenhancement and subsequent washout appearance, are investigated. The advantages of CEUS over CT and MRI include real-time imaging, use of contrast agents that do not contain iodine and are not nephrotoxic, and quick image acquisition. Despite the advantages, the use of CEUS in the diagnostic algorithm for HCC remains controversial, with disagreement on relevant guidelines. There is no clear evidence of the benefit of surveillance programmes in terms of overall survival as the conflicting results can be a consequence of an inaccurate detection, ineffective treatment, or both. Therefore, assessing the diagnostic accuracy of CEUS may clarify whether the absence of benefit could be related to underdiagnosis. Furthermore, an assessment of the accuracy of CEUS for the diagnosis of hepatocellular carcinoma is needed for either diagnosing hepatocellular carcinoma or ruling it out in people with chronic liver disease who are not included in surveillance programmes. 1. To assess the diagnostic accuracy of contrast-enhanced ultrasound (CEUS) for the diagnosis of hepatocellular carcinoma of any size and at any stage in adults with chronic liver disease, in a surveillance programme or in a clinical setting. 2. To assess the diagnostic accuracy of CEUS for the diagnosis of resectable hepatocellular carcinoma in people with chronic liver disease and identify potential sources of heterogeneity in the results. We used standard, extensive Cochrane search methods. The last date of search was 5 November 2021. We included studies assessing the diagnostic accuracy of CEUS for the diagnosis of hepatocellular carcinoma in adults with chronic liver disease, with cross-sectional designs, using one of the acceptable reference standards, such as pathology of the explanted liver, and histology of resected or biopsied focal liver lesion with at least a six-month follow-up. We used standard Cochrane methods to screen studies, extract data, and assess the risk of bias and applicability concerns, using the QUADAS-2 checklist. We used the bivariate model and provided estimates of summary sensitivity and specificity. We assessed the certainty of the evidence using GRADE. We presented uncertainty-of-the-accuracy estimates using 95% confidence intervals (CIs). We included 23 studies with 6546 participants. Studies were published between 2001 and 2021. We judged all 23 studies at high-risk of bias in at least one domain, and 13/23 studies at high concern for applicability. Most studies used different reference standards to exclude the presence of the target condition. The time interval between the index test and the reference standard was rarely defined. We also had major concerns on their applicability due to the characteristics of the participants. - CEUS for hepatocellular carcinoma of any size and stage: sensitivity 77.8% (95% CI 69.4% to 84.4%) and specificity 93.8% (95% CI 89.1% to 96.6%) (23 studies, 6546 participants; very low-certainty evidence). - CEUS for resectable hepatocellular carcinoma: sensitivity 77.5% (95% CI 62.9% to 87.6%) and specificity 92.7% (95% CI 86.8% to 96.1%) (13 studies, 1257 participants; low-certainty evidence). The observed heterogeneity in the results remains unexplained. The sensitivity analyses, including only studies with clearly prespecified positivity criteria and only studies in which the reference standard results were interpreted with no knowledge of the results about the index test, showed no differences in the results. We found that by using CEUS, as an add-on test following abdominal ultrasound, to diagnose hepatocellular carcinoma of any size and stage, 22% of people with hepatocellular carcinoma would be missed, and 6% of people without hepatocellular carcinoma would unnecessarily undergo further testing or inappropriate treatment. As to resectable hepatocellular carcinoma, we found that 23% of people with resectable hepatocellular carcinoma would incorrectly be unresected, while 8% of people without hepatocellular carcinoma would undergo further inappropriate testing or treatment. The uncertainty resulting from the high risk of bias of the included studies, heterogeneity, and imprecision of the results and concerns on their applicability limit our ability to draw confident conclusions.

The prognostic value and clinical significance of mitophagy-related genes in hepatocellular carcinoma.

Background: Mitophagy has been found to play a significant part in the cancer process in a growing number of studies in recent years. However, there is still a lack of study on mitophagy-related genes’ (MRGs) prognostic potential and clinical significance in hepatocellular carcinoma (HCC). Methods: We employed bioinformatics and statistical knowledge to examine the transcriptome data of HCC patients in the TCGA and GEO databases, with the goal of constructing a multigene predictive model. Then, we separated the patients into high- and low-risk groups based on the score. The model’s dependability was determined using principal components analysis (PCA), survival analysis, independent prognostic analysis, and receiver operating characteristic (ROC) analysis. Following that, we examined the clinical correlations, pharmacological treatment sensitivity, immune checkpoint expression, and immunological correlations between patients in high and low risk groups. Finally, we evaluated the variations in gene expression between high- and low-risk groups and further analyzed the network core genes using protein-protein interaction network analysis. Results: Prognostic models were built using eight genes (OPTN, ATG12, CSNK2A2, MFN1, PGAM5, SQSTM1, TOMM22, TOMM5). During validation, the prognostic model demonstrated high reliability, indicating that it could accurately predict the prognosis of HCC patients. Additionally, we discovered that typical HCC treatment medicines had varying impacts on patients classified as high or low risk, and that individuals classified as high risk are more likely to fail immunotherapy. Additionally, the high-risk group expressed more immunological checkpoints. The immunological status of patients in different risk categories varies as well, and patients with a high-risk score have a diminished ability to fight cancer. Finally, PPI analysis identified ten related genes with potential for research. Conclusion: Our prognostic model had good and reliable predictive ability, as well as clinical diagnosis and treatment guiding significance. Eight prognostic MRGs and ten network core genes merited further investigation.

A Case Report of Fibrolamellar Hepatocellular Carcinoma in a Young Adult

Among the four histopathological variants of hepatocellular carcinoma, Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare variant of hepatocellular carcinoma (HCC). It occurs in less than 1 % cases of hepatocellular carcinoma with distinct features as compared to classical HCC. It differs from typical HCC in terms of epidemiology, etiology, clinical presentation and prognosis. In this case report we are going to present a case of fibrolamellar variety of HCC in a 20-year young male with no history of previous liver disease and no characteristics features on Computed Tomography (CT) scan when compared with typical HCC. After discussing in multidisciplinary meeting, he underwent non anatomical liver resection which remained uneventful. Histopathology of the biopsy sample revealed FLHCC. No neoadjuvant therapy was given. Patient was kept on 1 year follow-up and no recurrence or metastasis occurred.

Prognosis of Single Early-Stage Hepatocellular Carcinoma (HCC) with CEUS Inconclusive Imaging (LI-RADS LR-3 and LR-4) Is No Better than Typical HCC (LR-5)

Simple SummaryThe European (EASL) and American (AASLD) guidelines for the management of hepatocellular carcinoma (HCC) suggest different management of nodules with indeterminate imaging in cirrhosis. In particular, nodules classified as LR-3 and LR-4 by the CEUS LI-RADS algorithm (indeterminate for HCC) are suggested to be biopsied according the EASL guidelines, but may be only monitored with follow-up imaging, with biopsy left to selected LR-4/LR-M cases, according to the AASLD ones. The present study shows that CEUS LI-RADS classes LR-3 and LR-4 HCC have no better clinical outcome than typical HCC (LR-5). Such data support the EASL policy, aimed at conclusive diagnostic investigations of indeterminate nodules up to obtaining histological proof to avoid leaving aggressive HCC not timely treated.The American College of Radiology (ACR) released the Liver Imaging Report and Data System (LI-RADS) scheme, which categorizes hepatic nodules in risk classes from LR-1 to LR-5 (according to the degree of risk to be HCC) and LR-M (probable malignancy not specific for HCC). The aim of this study was to test whether HCC with different LR patterns on CEUS have different overall survival (OS) and recurrence-free survival (RFS). We retrospectively enrolled 167 patients with the first definitive diagnosis of single HCC (by using CT/MRI or histological techniques if CT/MRI were inconclusive) for whom CEUS examination was available. The median size of HCC lesions was 2.2 cm (range 1.0–7.2 cm). According to CEUS LI-RADS classification, 28 patients were in LR-3, 48 in LR-4, 83 in LR-5, and 8 in LR-M. Patient liver function and nodule characteristics were not statistically different between CEUS LI-RADS classes. Using univariate analysis, CEUS LI-RADS class was not found to be a predictor of survival (p = 0.347). In conclusion, HCC showing the CEUS LI-RADS classes LR-3 and LR-4 have no better clinical outcome than typical HCC. Such data support the EASL policy, aimed at conclusive diagnostic investigations of indeterminate nodules up to obtaining histological proof to avoid leaving aggressive HCC not timely treated.

Interventional Radiology Image-Guided Locoregional Therapies (LRTs) and Immunotherapy for the Treatment of HCC.

Simple SummaryInterventional radiology image-guided locoregional therapies for the treatment of HCC have demonstrated to be characterized by immunomodulatory effects on the tumoral microenvironment, and, possibly, systemic. Immunotherapy has gained an important role in the treatment of HCC over the last several years. Currently, there is great interest in combining locoregional therapies with immunotherapy, as this could open a new chapter in the history of HCC treatment. In this review, after describing the immune system changes caused by the tumor, we describe, for each locoregional therapy, technique and immunomodulatory effects. Then, we describe the current status of immunotherapy in HCC and report the ongoing clinical studies testing the combination treatment.Image-guided locoregional therapies (LRTs) are a crucial asset in the treatment of hepatocellular carcinoma (HCC), which has proven to be characterized by an impaired antitumor immune status. LRTs not only directly destroy tumor cells but also have an immunomodulating role, altering the tumor microenvironment with potential systemic effects. Nevertheless, the immune activation against HCC induced by LRTs is not strong enough on its own to generate a systemic significant antitumor response, and it is incapable of preventing tumor recurrence. Currently, there is great interest in the possibility of combining LRTs with immunotherapy for HCC, as this combination may result in a mutually beneficial and synergistic relationship. On the one hand, immunotherapy could amplify and prolong the antitumoral immune response of LRTs, reducing recurrence cases and improving outcome. On the other hand, LTRs counteract the typical immunosuppressive HCC microenvironment and status and could therefore enhance the efficacy of immunotherapy. Here, after reviewing the current therapeutic options for HCC, we focus on LRTs, describing for each of them the technique and data on its effect on the immune system. Then, we describe the current status of immunotherapy and finally report the recently published and ongoing clinical studies testing this combination.

Long-term persistence of hepatocarcinogenic potential of a non-hypervascular hypointense nodule on EOB-MRI after the eradication of hepatitis C virus.

Non-hypervascular hypointense nodules (NHHNs) on gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (EOB-MRI) have a high likelihood of hypervascularization progressing to typical hypervascular hepatocellular carcinoma (HCC). NHHNs that were present before the start of anti-hepatitis C virus (HCV) therapy is a risk marker for HCC development after achieving sustained virologic response (SVR). In this report, we show a patient without a previous history of HCC in whom HCC developed by hypervascularization of NHHN after SVR. This patient achieved SVR more than 8years before NHHN developed into HCC, and during this time NHHN had been present but had remained unchanged in size and imaging features as shown by repeated EOB-MRI. Hepatocarcinogenic potential of NHHNs persist for a long time after SVR, despite the eradication of HCV.

Mixed pancreatic hepatoid carcinoma: A surgical case report and literature review.

BackgroundHepatoid carcinoma (HC) is a rare type of malignant tumor that shared similar features of morphology and immunohistochemistry with hepatocellular carcinoma (HCC). Pancreatic HC exists as either pure or mixed type. Mixed pancreatic HC is extremely rare, with only a few cases reported in the literature to date. Because of the rarity of mixed pancreatic HC, its clinical features including incidence, characteristics, and prognosis remain unclear. We herein report a case of a 49-year-old man who was diagnosed with mixed pancreatic HC with neuroendocrine differentiation and was treated with pancreaticoduodenectomy and adjuvant chemotherapy. We also review the existing case reports in literature.PresentationA 49-year-old man was admitted to our hospital after a chronic abdominal pain in the upper right quadrant. Abdominal ultrasound revealed only one low-density retroperitoneal mass measured at 20 × 48 mm in size in the pancreatic-duodenal junction, whereas contrast-enhanced computed tomography (CT) revealed three lymphatic neoplasms measured at 28 × 22 × 30 mm, 27 × 33 × 38 mm and 22 × 35 × 48 mm in size in the retroperitoneal pancreatic-duodenal junction. Ultrasound-guided tumor biopsy was performed. Pathological reading of tumor biopsy suspected of Paraganglioma/pheochromocytoma. Laparotomic retroperitoneal tumoral resection and lymphadenectomy was then performed. Histological reading was lymphatic metastasis of primary pancreatic hepatocellular carcinoma with neuroendocrine differentiation, which were immunohistochemically positive for CKAE1/AE3, Hepatocyte paraffin 1, Chromogranin. After three weeks of the first surgery, the patient was assigned with Positron Emission Tomography - Computed Tomography (PET-CT) before adjuvant chemotherapy, revealing a low-density high-metabolism mass, 26 × 28 mm in size within the parenchyma of pancreatic head. Laparotomic pancreaticoduodenectomy and standard lymphadenectomy was performed to resect one mass, which revealed the same immunohistology features with the first mass. The patient was followed up with FOLFIRINOX protocol, and after 12 cycles, there was no evidence of postoperative recurrence.DiscussionThere are few reported cases describing pancreatic hepatoid carcinoma, especially mixed form with other histological associated component. Neuroendocrine differentiation is the majority associated component with 62.5% of all cases of mixed – type form.ConclusionPrimary pancreatic hepatocellular carcinoma with neuroendocrine differentiation was rare, biopsy and immunohistochemistry appeared with high diagnostic value in this case. The prognosis of pancreatic HC depends on the extent and tumor eradication, and in this case we recorded no postoperative complications and no recurrence in the 6-month follow-up period.

Characteristics and prognosis of patients with large well-differentiated hepatocellular carcinoma who have undergone resection

BackgroundLarge well-differentiated hepatocellular carcinoma (HCC) ≥ 3 cm (defined as atypical HCC) is uncommon. We evaluated the characteristics and outcomes of atypical HCC patients underwent liver resection (LR). MethodsThis retrospective study enrolled patients who underwent LR for HCC from 2007 to 2017. Patient characteristics and overall survival (OS) were compared between patients with atypical HCC and patients with typical HCC (moderate-to-undifferentiated HCC ≥ 3 cm). ResultsAmong 598 patients, 51 (8.5%) had atypical HCC. Patients with atypical HCC had higher rates of non-hepatitis B or C infections (p = 0.02) and American Joint Committee on Cancer T1 pathology (p < 0.001), a lower rate of alpha-fetoprotein >20 ng/ml (p < 0.001) and a longer OS (p < 0.001) than those with typical HCC. Multivariate analysis showed that atypical HCC was associated with OS (HR = 0.50, 95% CI = 0.27–0.91, p = 0.02). ConclusionsPatients with atypical HCC have a higher rate of non-hepatitis B or C infections and a lower rate of aggressive tumor biologic behavior. Atypical HCC is an independent predictor of OS.

Deep learning-assisted differentiation of pathologically proven atypical and typical hepatocellular carcinoma (HCC) versus non-HCC on contrast-enhanced MRI of the liver.

To train a deep learning model to differentiate between pathologically proven hepatocellular carcinoma (HCC) and non-HCC lesions including lesions with atypical imaging featureson MRI. This IRB-approved retrospective study included 118 patients with 150 lesions (93 (62%) HCC and 57 (38%) non-HCC) pathologically confirmed through biopsies (n = 72), resections (n = 29), liver transplants (n = 46), and autopsies (n = 3). Forty-seven percent of HCC lesions showed atypical imaging features (not meeting Liver Imaging Reporting and Data System [LI-RADS] criteria for definitive HCC/LR5). A 3D convolutional neural network (CNN) was trained on 140 lesions and tested for its ability to classify the 10 remaining lesions (5 HCC/5 non-HCC). Performance of the model was averaged over 150 runs with random sub-sampling to provide class-balanced test sets. A lesion grading system was developed to demonstrate the similarity between atypical HCC and non-HCC lesions prone to misclassification by the CNN. The CNN demonstrated an overall accuracy of 87.3%. Sensitivities/specificities for HCC and non-HCC lesions were 92.7%/82.0% and 82.0%/92.7%, respectively. The area under the receiver operating curve was 0.912. CNN's performance was correlated with the lesion grading system, becoming less accurate the more atypical imaging features the lesions showed. This study provides proof-of-concept for CNN-based classification of both typical- and atypical-appearing HCC lesions on multi-phasic MRI, utilizing pathologically confirmed lesions as "ground truth." • A CNN trained on atypical appearing pathologically proven HCC lesions not meeting LI-RADS criteria for definitive HCC (LR5) can correctly differentiate HCC lesions from other liver malignancies, potentially expanding the role of image-based diagnosis in primary liver cancer with atypical features. • The trained CNN demonstrated an overall accuracy of 87.3% and a computational time of < 3ms which paves the way for clinical application as a decision support instrument.

Hepatocellular carcinoma with tumor thrombus in bile duct: A proposal of new classification according to resectability of primary lesion.

BACKGROUNDHepatocellular carcinoma (HCC) with tumor thrombus in the bile duct (BDTT) is easily misdiagnosed or mistreated due to the clinicopathological diversity of the thrombus and its relationship with primary lesions.AIMTo propose a new classification for HCC with BDTT in order to guide its diagnosis and treatment.METHODSA retrospective review of the diagnosis and treatment experience regarding seven typical HCC patients with BDTT between January 2010 and December 2019 was conducted.RESULTSBDTT was preoperatively confirmed by computed tomography/magnetic resonance imaging in only four patients. Three patients with recurrent HCC and one patient with first-occurring HCC had no visible intrahepatic tumors; of these, misdiagnosis occurred in two patients, and three patients died. One patient was mistreated as having common bile duct stones, and another patient with a history of multiple recurrent HCC was misdiagnosed until obvious biliary dilation could be detected. Only one patient who received hepatectomy accompanied by BDTT extraction exhibited disease-free survival during the follow-up period. A new classification was proposed for HCC with BDTT as follows: HCC with microscopic BDTT (Type I); resectable primary or recurrent HCC mass in the liver with BDTT (Type II); BDTT without an obvious HCC mass in the liver (Type III) and BDTT accompanied with unresectable intra- or extrahepatic HCC lesions (Type IV).CONCLUSIONWe herein propose a new classification system for HCC with BDTT to reflect its pathological characteristics and emphasize the significance of primary tumor resectability in its treatment.

Atypical magnetic resonance imaging features and differential diagnosis of hepatocellular carcinoma

ObjectiveHepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver. We aimed to summarize and analyze the atypical magnetic resonance imaging (MRI) features of HCC to improve its diagnostic accuracy.MethodsWe retrospectively analyzed MRI data for 66 patients with HCC with atypical MRI features confirmed by operation and pathology.ResultsTwelve patients had high signals and 18 patients had significant decreases in opposed phase signals in T1WI plain scans. Nine patients had high signals and six patients had large cystic lesions in apparent diffusion coefficient images. Dynamic enhancement showed progressive enhancement in 15 patients, ring enhancement in three, irregular patchy enhancement in three, ‘nodule-in-nodule’ enhancement in six, delayed central patchy enhancement in six, delayed central ‘star-like aristate scars’ (T2WI revealed high signal intensity) in 21, and poor blood supply in three patients.ConclusionsMRI can make a clear diagnosis of typical HCC, and atypical cases can also be distinguished from other tumors or tumor-like lesions by MRI. The analysis of atypical signs may improve the diagnostic accuracy of MRI for HCC.

Abstract 3715: Long-chain non-coding RNA H19-miR-152-3p axis regulates AFP expression in hepatocellular carcinoma

Abstract Background: Serum alpha-fetoprotein (AFP) is the most widely used serological marker used to diagnose hepatocellular carcinoma (HCC). High expression of AFP is significantly associated with early postoperative recurrence and poor prognosis. However, the upstream regulation mechanism of AFP expression is not fully understood, and the role of long-chain non-coding RNA (lncRNA) in AFP expression regulation has not been reported. Methods: HCC cases from The Cancer Genome Atlas (TCGA) database were divided into 3 groups: (1) AFP&amp;lt;10ng/ml, (2) 10ng/ml≤AFP&amp;lt;1000ng/ml, and (3) AFP≥1000ng/ml. The differential expression and co-expression of lncRNAs and miRNAs with AFP among the 3 groups was analyzed. lncRNA-ceRNA for AFP expression regulation was constructed by using LncATLAS to predict lncRNAs localization, miRWalk3.0 to predict miRNA-AFP targets, and LncBase Predicted v.2 to predict miRNA-lncRNA targets. Results: In the 3 groups, 32 lncRNAs were differentially expressed (P&amp;lt;0.05). SNHG7, SNHG3, SNHG8, DSCR9, KCNQ1OT1, SNHG6, GAS5, SNHG11, H19, TMEM191A, and MEG3 were significantly positively correlated with AFP expression (r&amp;gt;0, P&amp;lt;0.05). SEC22B and SRD5A2 were significantly negatively correlated with AFP expression (r&amp;lt;0, P&amp;lt;0.05). Among the positively correlated lncRNAs, SNHG7, SNHG3, SNHG8, SNHG6, GAS5, and H19 were mainly located in the HepG2 cytoplasm, DSCR9, KCNQ1OT1, SNHG11, and MEG3 were mainly located in the HepG2 nucleus, and TMEM191A had no location information in HepG2 cells. We found 134 differentially expressed miRNAs (P&amp;lt;0.05), and hsa-miR-196a-5p, hsa-miR-18a-5p, hsa-miR-148b-3p, hsa-miR-483-5p, hsa-miR-1307-3p, hsa-miR-1301-3p, hsa-miR-222-5p, hsa-miR-18a-3p, hsa-miR-501-5p, hsa-miR-483-3p, hsa-miR-222-3p, hsa-miR-19a-3p, and hsa-miR-221-3p were significantly positively correlated with AFP expression (r&amp;gt;0, P&amp;lt;0.05). hsa-miR-99a-5p, hsa-miR-152-3p, hsa-miR-125b-2-3p, hsa-let-7c-5p, and hsa-miR-1295b-5p were significantly negatively correlated with AFP expression (r&amp;lt;0, P&amp;lt;0.05). Among the negatively correlated miRNAs, hsa-miR-152-3p, hsa-miR-125b-2-3p, and hsa-let-7c-5p were predicted to be able to target the AFP 3' UTR. LncRNAs were predicted for the 3 miRNAs mentioned above. At the LncBase score&amp;gt;0.60, 769 pairs of miRNA-lncRNA interaction were recognized. These predicted lncRNAs were then intersected with the 6 cytoplasm-located lncRNAs. H19 satisfied the constraints, and therefore, a lncRNA H19-miR-152-3p-AFP ceRNA was proposed. Conclusions: Our study revealed that the proposed H19-miR-152-3p-AFP pathway affects the expression of AFP in HCC, suggesting that the H19-miR-152-3p axis may play an important role in the development of typical AFP-positive HCC. Citation Format: Yang Ke, Xiang Kui, Hang Jiang, Tiangen Wu, Cheng Zhang, Jian Zhou, Jinze Li, Heng Zhang, Yueqiang Song, Juan Zhao, Huafeng Duan, Lin Wang, Yan Wang. Long-chain non-coding RNA H19-miR-152-3p axis regulates AFP expression in hepatocellular carcinoma [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 3715.

Intrahepatic cholangiocellular carcinoma with radiological enhancement patterns mimicking hepatocellular carcinoma.

Non-invasive diagnosis of hepatocellular carcinoma (HCC) in cirrhotic patients requires demonstration of wash-in and wash-out on contrast-enhanced imaging. Recent studies have reported misclassification of mass-forming intrahepatic cholangiocarcinoma (MFCCC) as HCC. We aimed to analyze the contrast enhancement patterns of MFCCC, focusing especially on lesions mimicking HCC. We retrospectively evaluated all consecutive patients with MFCCC who underwent surgery between 2007 and 2017. Patients with mixed HCC-MFCCC were excluded. Two expert radiologists reviewed preoperative CT and MRI. Full-nodule hyperenhancement in the arterial phase in conjunction with hypoenhancement in the portal/late phase was classified as an "HCC-like pattern". Imaging of MFCCCs with an HCC-like pattern was reviewed by an additional radiologist blinded to clinical data. Ninety-two patients were analyzed. All patients were investigated with multiphase CT and 85 with MRI. Twelve tumors (13%) showed full-nodule arterial hyperenhancement. Of these, four were hypoenhancing in the portal/late phase. Overall, 4/92 (4%) MFCCCs (4/45 in patients with cirrhosis/hepatitis, 9%) showed an HCC-like pattern accounting for misclassification as HCC on imaging review. HCC-like MFCCCs accounted for 9% of single tumors ≤ 50mm. All HCC-like MFCCCs occurred in patients with cirrhosis or hepatitis, whereas only 47% of non-HCC-like MFCCCs did so (p = 0.053). After a median follow-up of 29months, all patients with HCC-like MFCCCs are alive and disease free (median 64months). In conclusion, MFCCC was misdiagnosed as typical HCC in 4% of all cases and in 9% of patients with single tumors ≤ 50mm or with cirrhosis/hepatitis. The risk of misdiagnosis should be considered prior to treatment planning.

A method to establish a c-Myc transgenic mouse model of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) remains one of the most lethal malignant cancers worldwide. HCC mouse models are widely used to explore the molecular pathogenesis of HCC and to test novel drug candidates.The advantages of this mouse model are as follows:•This method developed a H11LNL-Myc knock-in HCC mouse model by crossing H11LNL-Myc heterozygous mice with (albumin (Alb))-cre transgenic mice to generate c-Myc/Alb-cre double positive mice.•The c-Myc/Alb-cre double-positive mice exhibited a typical HCC phenotype, and showed accelerated tumor initiation and rapid HCC progression. Early stage HCC tumors (2–3 mm in diameter) were observed in male mice at the age of 47 days and in female mice at the age of 60 days.•Approximately 3 months later, the HCC tumors had progressed to a late stage (> 1 cm in diameter), and 100% of the male and female mice had HCC.

Diagnostic efficacy of dynamic liver imaging using qualitative diagnostic algorithm versus LI-RADS v2018 lexicon for atypical versus classical HCC lesions: A decade of experience from a tertiary liver institute

ObjectiveTo analyze and evaluate the diagnostic performance of conventional diagnostic (qualitative) imaging features versus LI-RADSv2018 lexicon for indeterminate and atypical Hepatocellular carcinoma (HCC) on dynamic liver imaging with reference to histopathology. Patients and methodsThis retrospective study (June 2009–June 2019) evaluated the performance characteristics of conventional imaging findings, versus the Liver Imaging Reporting and Data System (LIRADS) v2018, for interpretation of indeterminate and atypical HCC, in patients who underwent subsequent histopathological analysis (gold standard). A total of 100,457 dynamic hepatobiliary CT and MR examinations were performed over ten years at our institute. Using current international imaging guidelines, 3218 patients were found to have suspected liver cancer lesions on imaging. Classical enhancement pattern of typical HCC was seen in 2916 of these patients. These patients did not require further biopsy. We enrolled, the remaining (n = 302) patients, who underwent biopsy, into our study group. Two radiologists, blinded to pathology findings, reviewed and classified these lesions, in consensus, according to LI-RADS® lexicon and as per ‘conventional’ (Indeterminate, Atypical HCC, Classical HCC, other malignancies) imaging. The histopathology diagnosis was considered as the final diagnosis. Alpha feto protein (AFP) levels amongst various subgroups were compared. Statistical analysis was performed to calculate the efficacy of LIRADS versus qualitative imaging parameters in comparison with histopathology. ResultsA total of n = 302 patients, [89 % men (n = 269), mean age 57.08 ± 12.43 years] underwent biopsy for suspected liver lesions. Qualitative imaging had 92.3 % (CI 88.53–94.91) sensitivity, 41.4 % (CI 25.51–59.26) specificity, positive predictive value (PPV) of 93.7 % (CI 90.11–96.02), negative predictive value (NPV) of 36.4 % (CI 22.19–53.38), positive likelihood ratio (PLHR) of 1.575 (CI 1.40–1.77) and negative likelihood ratio of (NLHR) 0.19 (CI 0.13-0.26). It correctly classified 87.4 % of lesions diagnosed on pathology. In comparison, LI-RADS was found to have 92 % sensitivity, 55.5 % specificity, 97 % PPV, 30.3 %, NPV, PLHR 2.068 (CI 1.62–2.64), NLHR 0.15 (CI 0.11-0.18) and 89.7 % diagnostic accuracy. A total of 38 patients (17 false negative, 21 false positive lesions) had discordant diagnoses on imaging versus histopathology. The kappa agreement between LIRADs and qualitative Imaging was found to be 0.77 ± .07 (p < 0.001). LIRADS and qualitative imaging collectively had 97 % sensitivity, 30 % specificity, 91.9 % PPV, 55.6 % NPV, PLHR of 1.39 (CI 1.27–1.51) and NLHR of 0.09 (0.048-0.19) which was better than, either reporting system, independently. ConclusionIt was observed that the LI-RADS v2018 lexicon with qualitative imaging as a combination technique added extra value in interpretation of atypical HCC or indeterminate lesions on dynamic CT and MRI compared to either as ‘stand- alone’ reporting systems.

Interactome analysis of gene expression profiles identifies CDC6 as a potential therapeutic target modified by miR-215-5p in hepatocellular carcinoma

Background: Illustrating the pathogenesis of hepatocellular carcinoma (HCC) pathogenesis as well as identifying specific biomarkers are of great significance.Methods: The original CEL files were obtain from Gene Expression Omnibus, then affymetrix package was used to preprocess the CEL files, the function of DEGs were investigated by multiple bioinformatics approach. Finally, typical HCC cell lines and tissue samples were using to validate the role of CDC6 in vitro. Bioinformatics software was used to predict potential microRNA of CDC6. Luciferase assay was used to verify the interactions between CDC6 and microRNA.Results: A total of 445 DEGs were identified in HCC tissues based on two GEO datasets. GSEA results showed that the significant enriched gene sets were only associated with cell cycle signaling pathway. In the co-expression analysis, there were 370 hub genes from the blue modules were screened. We integrated DEGs, hub genes, TCGA cohort and GSEA analyses to further obtain 10 upregulated genes for validation. These genes were overexpressed in HCC tissues and negatively associated with overall and disease-free survival in HCC patients and related to immune cell infiltration in HCC microenvironments. Finally, Cell Division Cycle 6 (CDC6) was highlighted as one of the most probable genes among the 10 candidates participating in cancer process. The expression of CDC6 either in public datasets and HCC tissues sample were commonly high than the non-cancerous counterpart. Furthermore, we recognized that miR-215-5p, could directly bind to the 3'UTR of CDC6. In addition, CDC6 promoted proliferation via regulation of G1 phase checkpoint and was negative regulated by miR-215-5p to involve in the proliferation of HCC.Conclusion: Our study suggested that CDC6 served as a potential therapeutic target for HCC.

Normal Alpha-Fetoprotein Hepatocellular Carcinoma: Are They Really Normal?

Introduction: serum alpha-fetoprotein (AFP) was routinely employed as a tumor marker for screening, diagnosis, and treatment follow-up of hepatocellular carcinoma (HCC). However, a substantial proportion of HCC patients had normal AFP level even at an advanced disease status. Few studies to date had tried to explore the nature and behavior of this normal AFP HCC (N-HCC). The purpose of this study was to investigate the clinicopathological characteristics and survival outcome of N-HCC after operation. In addition, potential tumor markers for N-HCC were also sought in an attempt to augment diagnostic ability. Methods: between 2005 and 2015, patients with hepatocellular carcinoma who were treated with hepatectomy in Chang Gung Memorial Hospital Linkou branch were divided into two groups according to their preoperative serum AFP level (<15 ng/mL: NHCC; ≥15 ng/mL: abnormal AFP HCC (A-HCC)). Patient demographic data and clinicopathological variables were collected. Kaplan–Meier and Cox regression multivariate analyses were performed to identify significant risk factors for disease-free survival (DFS) and overall survival (OS) for N-HCC. ELISA and immunohistochemical (IHC) studies were employed to determine the diagnostic accuracy of various tumor markers. Results: a total of 1616 patients (78% male) who underwent liver resection for HCC were included in this study. Of them, 761 patients (47.1%) were N-HCC. N-HCC patients were significantly older with more comorbidities and less hepatitis virus infections. Furthermore, N-HCC had fewer early recurrences (49.6% vs. 60.8%, p < 0.001) and better DFS (44.6 months vs. 23.6 months, p < 0.001) and OS (94.5 months vs. 81.7 months, p < 0.001). Both ELISA and IHC studies demonstrated that glypican-3 (GPC3) would be a promising diagnostic tumor marker for N-HCC. Conclusion: N-HCC patients were significantly older and had less hepatitis virus infections or cirrhosis. Their tumors tended to be smaller, less vascular invaded, and well-differentiated. The carcinogenesis of N-HCC may thus not be identical to that of typical HCC. GPC3 would be a promising tumor marker for diagnosing N-HCC. Further study is warranted to validate our findings.

The emergence of non-hypervascular hypointense nodules on Gd-EOB-DTPA-enhanced MRI in patients with chronic hepatitis C.

Intrahepatic non-hypervascular hypointense nodules (NHHNs) detected during the hepatobiliary phase of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (EOB-MRI) have the potential to transition into typical hypervascular hepatocellular carcinoma (HCC). However, the incidence and risk factors for the emergence of these nodules in patients with chronic hepatitis C virus (HCV) infection are unknown. To investigate the incidence and risk factors for NHHNs in patients with chronic HCV infection in a longitudinal follow-up study METHODS: EOB-MRI was performed in 608 patients with chronic HCV infection and no history of HCC. The characteristics of patients with and without NHHNs were compared. In patients without NHHNs at baseline, the incidence of NHHN emergence and associated risk factors were analysed. NHHNs were detected at baseline in 93 of 608 patients (15.3%). Among 515 patients without NHHNs at baseline, the 1-year, 3-year and 5-year incidence of NHHN emergence was 1.8%, 9.8% and 16.4%, respectively. Only FIB-4 index was independently associated with the emergence of NHHNs in multivariate analyses. Whereas NHHNs emerged in 24.1% of patients with FIB-4 index≥3.25 at 5years, none emerged in patients with FIB-4 index<1.45. In patients with chronic HCV infection, advanced liver fibrosis is an important risk factor for the presence or emergence of NHHNs.

2376 Diffuse Large B-Cell Lymphoma Presenting With Typical Features of HCC on Liver Imaging: A Diagnostic Conundrum

INTRODUCTION: Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. HCC can be solely diagnosed on cross-sectional imaging (CT or MRI) if a lesion meets the diagnostic criteria according to the Liver Imaging Reporting and Data System (LI-RADS), which has above 90% specificity. HCC commonly metastasizes to lungs, regional lymph nodes, kidney, bone marrow and adrenals but metastases to the spleen are rare. We present a case of liver masses with typical HCC characteristics on liver MRI which was ultimately proven to be diffuse large B-cell lymphoma (DLBCL) on liver biopsy. CASE DESCRIPTION/METHODS: 38-year-old Vietnamese male with no past medical history was admitted with significant weight loss, fatigue and abdominal discomfort. He did not have a history of high risk behaviors or recent foreign travel. Physical exam revealed hepatomegaly. On labs, CBC was normal, T-bili 0.7, Alk Phos 147, AST 89, ALT 50, Albumin 3 g/dL, INR 1.1, creatinine 0.7. HBV serology was positive for HBsAg, anti-HBc and anti-HBe and was negative for HBeAg. HBV DNA was 497 IU/ml. HIV, HCV and HDV serology were negative. CT abdomen showed numerous liver lesions, largest of which was 10.4 cm and a single 8.1 cm splenic lesion. MRI showed several large, rounded and well-circumscribed liver lesions demonstrating arterial hyperenhancement, washout and pseudocapsule consistent with diagnosis of HCC (LI-RADS 5). MRI confirmed a single lesion on spleen (Figure 1), suspicious for metastasis. Tumor markers (AFP, CEA, CA 19-9) were within normal range. Lactate dehydrogenase (LDH) was 1200. Given elevated LDH and a spleen lesion, liver biopsy was done which showed high grade DLBCL (Figure 2). Systemic staging tests did not reveal any other tumor sites. Patient was started on tenofovir and chemotherapy with excellent response (Figure 3). DISCUSSION: Liver biopsy is rarely required to diagnose HCC if certain diagnostic criteria are met on cross sectional imaging, even without significantly elevated AFP. Extranodal lymphoma with liver and spleen involvement can present with lab and imaging abnormalities which can mimic HCC, as in our case. Markedly elevated LDH and spleen lesion raised suspicion for a different diagnosis. Undiagnosed or untreated advanced DLBCL can limit survival to a few months while hepatic involvement can also cause liver failure. In conclusion, a biopsy should be considered for liver lesions diagnosed as HCC on cross sectional imaging when atypical features, in our case elevated LDH and spleen lesion, are present.