Cirrhosis Classification Based on Texture Classification of Random Features

Accurate staging of hepatic cirrhosis is important in investigating the cause and slowing down the effects of cirrhosis. Computer-aided diagnosis (CAD) can provide doctors with an alternative second opinion and assist them to make a specific treatment with accurate cirrhosis stage. MRI has many advantages, including high resolution for soft tissue, no radiation, and multiparameters imaging modalities. So in this paper, multisequences MRIs, including T1-weighted, T2-weighted, arterial, portal venous, and equilibrium phase, are applied. However, CAD does not meet the clinical needs of cirrhosis and few researchers are concerned with it at present. Cirrhosis is characterized by the presence of widespread fibrosis and regenerative nodules in the hepatic, leading to different texture patterns of different stages. So, extracting texture feature is the primary task. Compared with typical gray level cooccurrence matrix (GLCM) features, texture classification from random features provides an effective way, and we adopt it and propose CCTCRF for triple classification (normal, early, and middle and advanced stage). CCTCRF does not need strong assumptions except the sparse character of image, contains sufficient texture information, includes concise and effective process, and makes case decision with high accuracy. Experimental results also illustrate the satisfying performance and they are also compared with typical NN with GLCM

Validation of volatile organic compounds for the assessment of liver disease

Chronic liver disease is one of the few conditions with increasing morbidity and mortality rates. Up to 75% of individuals with cirrhosis are diagnosed during a decompensation episode, at which point the prognosis is poor. Cirrhotic patients also have an annual risk of 2 to 4% of developing hepatocellular carcinoma (HCC). HCC is currently the fourth leading cause of cancer-related mortality worldwide, which is at least in part due to late diagnosis and inadequate screening. Gas chromatography-mass spectrometry (GC-MS) analysis of volatile organic compounds (VOCs) in breath has the potential to form the basis of a non-invasive diagnostic test for chronic liver disease and HCC. However, exhaled VOCs can be influenced by multiple confounding factors and the equipment used to collect and analyse breath can be cost prohibitive. The aims of my PhD were four-fold. Firstly, to develop and validate a novel, cost-effective breath collection device and to formulate a standard operating procedure for its use in clinical studies. Secondly, to analyse the VOC profile of background room air within common clinical sampling locations and to assess their potential impact upon the collection of breath samples. Thirdly, to investigate a methodology for sample splitting using GC-MS as a way of facilitating sample analysis across multiple mass spectrometry platforms. With the information garnered from this methodology work, my final aim was to perform a clinical study to profile the VOCs in the exhaled breath of patients with cirrhosis, HCC, and normal liver parenchyma. Prior to this, I also performed a critical analysis of the pre-existing literature on VOCs for assessment of liver disease to help guide my study design. Analysis of the novel breath collection device revealed acceptable repeatability for a wide range of VOCs and optimum settings for flow rates and volumes of breath were determined and included within a standard operating procedure. Profiling the background air volatiles in sampling locations identified specific VOC signatures for each location. Breath samples did not separate by location but monitoring of background volatiles in parallel to breath sampling remains important for identification of contaminant VOCs. Splitting of desorbed breath samples via GC-MS and recollection of two samples back on to one thermal desorption tube provides the best discrimination between samples. For my main clinical study, breath samples of 149 patients were analysed using GC-MS. Elevated levels of limonene and 2-pentanone were identified in those with hepatopathology, validating the results of previous studies. Additional VOCs were also discovered as candidate biomarkers and further studies are required to validate these findings. The results of my clinical study have added to the existing literature that specific VOCs in exhaled breath have the potential to form a non-invasive diagnostic test for hepatopathology that could potentially help enhance earlier diagnosis of liver disease and reverse the trend in mortality rates.Open Acces

Endoplasmic reticulum stress sensor ATF6 as an immunometabolic modulator in hepatic tumorigenesis

The liver is the site of the sixth most common form of primary cancer - represented mainly by hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). Although the recent increment of knowledge on immunological, metabolic, and genetic mechanisms - from a systemic to a single cell level approach - led to consistent implementation of the therapeutic management of liver diseases and improved quality of life in patients, new challenges became apparent in the development of arising therapeutic strategies for pathologies accompanied by chronic inflammation, like liver cancer. Elevated endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) have been observed in precancerous diseases associated with the development of liver cancer, such as hepatic viral infection and nonalcoholic steatohepatitis (NASH)1 . In the context of liver diseases, the inositol requiring enzyme 1 (IRE1 and the protein kinase R (PKR)–like ER kinase (PERK) branches of UPR have been intensively investigated, whereas the role of activating transcription factor 6 (ATF6) in hepatic diseases has remained elusive2 . In this study, by employing different genetically modified mouse models and cell lines, I tried to examine and illustrate the role of ATF6 in hepatic tumorigenesis. In the first place, I analyzed the publicly available databases of liver cancer, the liver biopsy from healthy donors and NASH-diagnosed patients, para-tumor and tumor tissue from liver cancer patients, and tissues from liver cancer mouse models for the expression of ATF6 at both mRNA and protein levels. Strikingly, I detected a significant increase in ATF6 mRNA and protein expression in the diseased areas compared to their corresponding controls. Moreover, by doing immunohistochemistry, I identified the activation of ATF6 in the diseased tissues, indicated by the nuclear localization of ATF6. Based on these observations, I worked on the generation of hepatocyte-specific nuclear-ATF6 (nATF6) overexpression mice. In a mouse model of hepatocyte-specific activation of the ATF6 branch of UPR, I observed that transgenic homozygous mice die shortly after birth, whereas their heterozygous counterparts can survive for more than one year instead, suggesting a dose-effect. Heterozygous mice develop hepatomegaly, liver damage, and cholestasis at their young ages. Strikingly, the heterozygous mice progress to liver cancer with a tumor incidence of 100% at 12 months. To investigate the underlying mechanisms of the pro-tumorigenic effects by persistent ATF6 activation, I performed RNA-seq, proteomic and metabolic analysis on the liver of the heterozygous animals. I found out that ATF6 is intensively involved in the regulation of hepatic glucose, lipid, and amino acid metabolism. The sustained activation of the ATF6 arm of UPR in hepatocytes induces hepatocyte cell death and shifts the cellular metabolism to support the energy and building blocks requirements for compensatory proliferation. The high rate of hepatocyte turnover and constant ER stress lead to oxidative stress and hepatic inflammation, resulting in hepatic tumor onset. Meanwhile, the metabolic switch in hepatocytes deprives nutrients in the surrounding environment and further suppresses the anti-tumor function of immune cells. In the end, I generated hepatocyte-specific ATF6 knockout mice, and I challenged this mouse model with different carcinogenic treatments. Surprisingly, I found ATF6 knockout confers general hepato-protection to mice in response to these treatments, indicating a potential clinical application of ATF6 inhibition in anti-tumor therapie

Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) represents one of the most significant global health issues, given its high prevalence and the challenging nature and physiology of the liver and hepatic surgery, in its many forms. This means that the most appropriate management for HCC should incorporate a multidisciplinary approach, combining the expertise from several different specialties. This book showcases the various steps in the development, diagnosis, staging, and management of HCC and provides views and thoughts from true experts in the field. As such, it is a useful resource for any physician or surgeon, whether training or practicing, who is interested in caring for patients with HCC

Liver Tumors

This book is oriented towards clinicians and scientists in the field of the management of patients with liver tumors. As many unresolved problems regarding primary and metastatic liver cancer still await investigation, I hope this book can serve as a tiny step on a long way that we need to run on the battlefield of liver tumors

NASH and Systemic Complications

Nonalcoholic fatty liver disease (NAFLD) is known as the hepatic manifestation of the metabolic syndrome, and while most patients develop simple steatosis, up to one-third can develop nonalcoholic steatohepatitis (NASH). NASH is a chronic inflammatory condition of the liver that can further progress to fibrosis and cirrhosis, which may eventually lead to liver failure and death. While we have increased our mechanistic knowledge regarding the pathogenesis of NASH within the last decade, treatment options are still limited and liver biopsies have remained the gold standard for diagnosis. To achieve major clinical breakthroughs for NASH patients, it is not sufficient to use a single animal model, since each model has specific limitations. Furthermore, we should rely more on alternative models such as organ-on-a-chip, which will enable us to explore unknown aspects of disease pathogenesis much faster and serve as clinically relevant surrogates for murine models. Another important direction for the improvement of patient health is to pay more attention to extrahepatic, organ-specific and systemic effects, which are associated with NASH. The articles in this Special Issue include an up-to-date overview of the rapidly developing technologies, novel targets for intervention and insights in the field in NASH. Additionally, these articles describe the major challenges in the field, strategies to overcome them and suggestions for future directions. To improve patient’s outcome, clinicians, as well as scientists with biomedical, nutrition, physics and mathematics backgrounds, should join forces. Although challenges remain, the future of the field seems promising as these novel technologies and developments are expected to lead to progress in NASH