Hot topics in hepatocellular carcinoma

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Anti-ganglioside antibodies and celiac disease

We describe our own experience on the prevalence of a wider range of anti-ganglioside antibodies and their clinical significance in CD patients. Using a commercially available ELISA kit (IMMCO Diagnostics, Buffalo, NY, USA), we studied anti-GM1, anti-GD1b, and anti-GQ1b serum IgG and IgM antibodies in 22 adult patients (median age 35, range: 19–56 years; three males, 19 females) with CD and neurological manifestations, including eight cases of idiopathic cerebellar ataxia, seven cases with epilepsy (without cerebral calcifications), two with multiple sclerosis, three with attention/memory impairment, and two with peripheral neuropathies. In all cases, diagnosis of CD was confirmed by endoscopic duodenal biopsy, revealing different grades of villous atrophy (from 3a to 3c, according to the modified Marsh classification). In all CD patients, intestinal villous atrophy was associated with a positivity for serological CD markers (anti-endomysial and/or anti-tissue transglutaminase antibodies) further supporting the diagnosis of CD. All available data, regarding CD diagnosis, diagnostic work-up, histopathology and treatment were obtained from the hospital digital database

Current guidelines for the management of celiac disease: A systematic review with comparative analysis

Wheat and other gluten-containing grains are widely consumed, providing approximately 50% of the caloric intake in both industrialised and developing countries. The widespread diffusion of gluten-containing diets has rapidly led to a sharp increase in celiac disease prevalence. This condition was thought to be very rare outside Europe and relatively ignored by health professionals and the global media. However, in recent years, the discovery of important diagnostic and pathogenic milestones has led to the emergence of celiac disease (CD) from obscurity to global prominence. These modifications have prompted experts worldwide to identify effective strategies for the diagnosis and follow-up of CD. Different scientific societies, mainly from Europe and America, have proposed guidelines based on CD's most recent evidence

Evaluation of Toxicant-Associated Fatty Liver Disease and Liver Neoplastic Progress in Sprague-Dawley Rats Treated with Low Doses of Aflatoxin B1 Alone or in Combination with Extremely Low Frequency Electromagnetic Fields

The term toxicant-associated fatty liver disease (TAFLD) has been proposed to describe fatty liver diseases connected to toxicants other than alcohol. Aflatoxins are mycotoxins commonly found as contaminants in foods and feeds, which are known liver toxicants and potential candidates as potential causes of TAFLD. Aflatoxin B1 (AFB1) was administered at low doses to Sprague-Daw-ley (SD) rats, alone or in combination with S-50 Hz an extremely low frequency electromagnetic field (ELFEMF), to study the evolution of TAFLD, preneoplastic and neoplastic lesions of the liver and the potential enhancing effect of lifespan exposure to ELFEMF. Steatosis, inflammation and foci of different types were significantly increased in both aflatoxin-treated males and females, which is consistent with a pattern of TAFLD. A significant increase in adenomas, cystic dilation of biliary ducts, hepatocellular hyperplasia and hypertrophy and oval cell hyperplasia were also observed in treated females only. The administration of low doses of AFB1 caused TAFLD in SD rats, inducing liver lesions encompassing fatty infiltration, foci of different types and adenomas. Furthermore, the pattern of change observed in preneoplastic liver lesions often included liver steatosis and steato-hepatitis (TASH). ELFEMF did not result in any enhancing or toxic effect in the liver of SD rats

Hepatocellular adenoma: An unsolved diagnostic enigma

Hepatocellular adenoma (HCA) is a rare benign liver tumour associated with the use of oral contraceptives or other steroid medications which occurs predominantly in young and middle-aged women. Unlike other benign liver tumours, an HCA may be complicated by bleeding and malignant transformation. HCAs have been divided into four subtypes based on molecular and pathological features: hepatocyte nuclear factor 1\u3b1-mutated HCA, inflammatory HCA, \u3b2-catenin-mutated HCA, and unclassified HCA. \u3b2-catenin-mutated HCA has the highest risk of haemorrhage or malignant transformation. In the latest upgrade of the guidelines regarding the management of benign liver tumours published in 2016 by the European Association for the Study of the Liver, magnetic resonance imaging (MRI) was recognized to be superior to all other imaging modalities in detecting HCAs and in being able to subtype HCAs up to 80%, with positive identification of 1\u3b1-mutated HCA or inflammatory HCA achievable with > 90% specificity. This review analyzed the imaging features of HCA using MRI with hepato-specific contrast agents, focusing on the limitations in the HCA characterization

Experience with regorafenib in the treatment of hepatocellular carcinoma

Regorafenib is a diphenylurea oral multikinase inhibitor, structurally comparable to sorafenib, which targets a variety of kinases implicated in angiogenic and tumor growth-promoting pathways. Regorafenib was the first agent to positively show significant survival advantage as a second-line therapy in patients with unresectable hepatocellular carcinoma (HCC) who had previously failed first-line treatment with sorafenib. Recent evidence has shown that its antitumor efficacy is due to a comprehensive spectrum of tumor neo-angiogenesis and proliferation inhibition and immunomodulatory effects on the tumor microenvironment, which plays a crucial role in tumor development. This review addresses the rationale and supporting evidence for regorafenib’s efficacy in HCC that led to regorafenib’s approval as a second-line therapy. In addition, we review proof from clinical practice studies that validate the RESORCE trial results. We discuss regorafenib’s potential role in the newly emerging therapeutic strategy based on combination with immune checkpoint blockade and its possible extensibility to patient categories not enrolled in the registrative study

Aflatoxin B1 DNA-Adducts in Hepatocellular Carcinoma from a Low Exposure Area

Aflatoxin B1 (AFB1) is a class 1 carcinogen with an ascertained role in the development of hepatocellular carcinoma (HCC) in high exposure areas. Instead, this study aimed to assay whether chronic/intermittent, low-dose AFB1 consumption might occur in low-exposure geographical areas, ultimately accumulating in the liver and possibly contributing to liver cancer. AFB1-DNA adducts were assayed by immunostaining in liver tissues from three Italian series of twenty cirrhosis without HCC, 131 HCC, and 45 cholangiocarcinoma, and in an AFB1-induced HCC rat model. CD68, TP53 immunostaining, and TP53 RFLP analysis of R249S transversion were used to characterize cell popula-tions displaying AFB1-DNA adducts. Twenty-five HCCs displayed AFB1-adducts both in neoplastic hepatocytes and in cells infiltrating the tumor and non-tumor tissues. Nuclear immunostaining was observed in a few cases, while most cases showed cytoplasmic immunostaining, especially in CD68-positive tumor-infiltrating cells, suggestive for phagocytosis of dead hepatocytes. Similar patterns were observed in AFB1-induced rat HCC, though with higher intensity. Cholangiocarcinoma and cirrhosis without HCC did not displayAFB1-adducts, except for one case. Despite not providing a causal relationship with HCC, these findings still suggest paying attention to detection and control measures for aflatoxins to ensure food safety in low exposure areas

Hepatic Steatosis in Patients with Celiac Disease: The Role of Packaged Gluten-Free Foods

Background: An increased risk of nonalcoholic fatty liver disease (NAFLD) in patients with celiac disease (CD) adhering to a gluten-free diet (GFD) was recently reported. The nutritional composition of packaged gluten-free foods (PGFF) has been proposed as a possible cause. This hypothesis has not been investigated further, since a systematic structural nutritional interview for all patients would be problematic in clinical practice. Methods: We administered a simple questionnaire based on a Recency, Frequency, and Monetary value (RFM) analysis (a cornerstone of direct marketing segmentation) to consecutive CD patients on a GFD for >6 months and verified its association with NAFLD. Subgroup analyses were performed to understand whether specific patterns of PGFF consumption were significantly associated with NAFLD. Results: Amongst 147 patients (female 82%, median age 42 years), 45 (30.6%) had NAFLD. Total RFM score (adjusted odds ratio = 1.223, 95% CI: 1.059–1.413, p = 0.006), body mass index, and total cholesterol and triglycerides were independently related to NAFLD, and “Bread and bakery” (p = 0.002), “salty convenience” (p = 0.005), and “sweet convenience” (p = 0.049) products were significantly related with NAFLD. Also, questions about the number of purchased PGFF in the last month (monetary value) and different categories of PGFF consumed in the last week (recency) were particularly able to identify NAFLD patients. Conclusions: The specific GFD dietary habits of CD patients were correlated with the degree of risk of NAFLD. Information was obtained through a questionnaire which could be used in clinical practice to favor a patient-tailored approach and in future studies to verify the reproducibility of our results in different geographical areas

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)

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

Radiological Features of Microvascular Invasion of Hepatocellular Carcinoma in Patients with Non-Alcoholic Fatty Liver Disease

Background: The aim of the present study was to evaluate the presence and the prognostic value of the radiological signs of microvascular invasion (MVI) of hepatocellular carcinoma (HCC) in patients with non-alcoholic fatty liver disease (NAFLD). Methods: Between January 2015 and December 2017, all patients (91 patients) with de novo HCC or HCC recurrence occurring at least 2 years after the last treatment in NAFLD (36 patients) or with hepatitis C virus (HCV) liver disease (55 patients) were included. Each HCC was treated with liver resection and transplantation to obtain the anatomopathological confirmation of MVI. All patients had at least one available computed tomography (CT) scan or magnetic resonance imaging (MRI) performed no more than one month prior to the treatment. The clinical data of each patient, tumor burden (diameter, margins, two-trait predictor of venous invasion (TTPVI), and peritumoral enhancement), the recurrence rate (RR) after a 1-year follow-up, and the time to recurrence (TTR) were collected. Results: The NAFLD–HCC nodules were larger as compared to HCV–HCC (51 mm vs. 36 mm, p = 0.004) and showed a higher prevalence of TTPVI (38.9 vs. 20.0%, p = 0.058). At multivariate analysis, nodule diameter >50 mm was found to be the only independent prognostic factor of TTPVI (hazard ratio: 21.3, 95% confidence interval: 4.2–107.7, p < 0.001), and the presence of TTPVI was confirmed to be the only independent prognostic factors of recurrence (hazard ratio: 2.349, 95% confidence interval: 1.369–4.032, p = 0.002). No correlations were found between TTR and irregular tumor margins or peritumoral enhancement. Conclusion: The NAFLD–HCC patients had larger tumors at diagnosis and showed a more frequent presence of radiological signs of MVI as compared to the HCV–HCC patients. The MVI was related to a more rapid recurrence after curative treatments, demonstrating the prognostic value of this radiological diagnosis