Jan Bornschein

Hepatocellular Carcinoma – Epidemiological Trends and Risk Factors

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide with about 600,000 patients dying from the disease annually. In 70–90%, HCC develops on the background of chronic liver cirrhosis or inflammation. Risk factors and etiologies vary among geographical regions. In regions with a high incidence the majority of cases are related to HBV and HCV hepatitis. In developed countries, in addition to virus-related HCC, high consumption of alcohol as well as non-alcoholic fatty liver disease often in the context of metabolic syndromes are the prevalent causes. Improvement in clinical management of patients with liver cirrhosis and the control of related complications are the key for the rising incidence of HCC. This review gives an overview on epidemiological trends and risk factors and their mechanisms involved in the hepatocarcinogenesis. Knowledge of these factors will help to improve current concepts for prevention, screening and treatment of this disease.

Mutational signatures in esophageal adenocarcinoma define etiologically distinct subgroups with therapeutic relevance

Esophageal adenocarcinoma (EAC) has a poor outcome, and targeted therapy trials have thus far been disappointing owing to a lack of robust stratification methods. Whole-genome sequencing (WGS) analysis of 129 cases demonstrated that this is a heterogeneous cancer dominated by copy number alterations with frequent large-scale rearrangements. Co-amplification of receptor tyrosine kinases (RTKs) and/or downstream mitogenic activation is almost ubiquitous; thus tailored combination RTK inhibitor (RTKi) therapy might be required, as we demonstrate in vitro. However, mutational signatures showed three distinct molecular subtypes with potential therapeutic relevance, which we verified in an independent cohort (n = 87): (i) enrichment for BRCA signature with prevalent defects in the homologous recombination pathway; (ii) dominant T>G mutational pattern associated with a high mutational load and neoantigen burden; and (iii) C>A/T mutational pattern with evidence of an aging imprint. These subtypes could be ascertained using a clinically applicable sequencing strategy (low coverage) as a basis for therapy selection.

Lack of association between gene polymorphisms of Angiotensin converting enzyme, Nod-like receptor 1, Toll-like receptor 4, FAS/FASL and the presence of Helicobacter pylori-induced premalignant gastric lesions and gastric cancer in Caucasians

BackgroundSeveral polymorphisms of genes involved in the immunological recognition of Helicobacter pylori and regulating apoptosis and proliferation have been linked to gastric carcinogenesis, however reported data are partially conflicting. The aim of our study was to evaluate potential associations between the presence of gastric cancer (GC) and high risk atrophic gastritis (HRAG) and polymorphisms of genes encoding Angiotensin converting enzyme (ACE), Nod-like receptor 1 (NOD1), Toll-like receptor 4 (TLR4) and FAS/FASL.MethodsGene polymorphisms were analyzed in 574 subjects (GC: n = 114; HRAG: n = 222, controls: n = 238) of Caucasian origin. ACE I/D (rs4646994), NOD1 796G>A (rs5743336), TLR4 3725G>C (rs11536889), FAS 1377G>A (rs2234767), FAS 670A>G (rs1800682) and FASL 844T>C (rs763110) were genotyped by different PCR approaches and restriction fragment length polymorphism analysis.ResultsFrequencies of genotypes in our study are similar to the data reported on subjects of Caucasian ethnicity. There was a tendency for NOD1 796G/G genotype to be associated with increased risk of HRAG (62.4% vs. 54.5% in controls, p = 0.082). FAS 670G/G genotype was more frequent in HRAG when compared to controls, 23.9% and 17.2% respectively, however it failed to reach significance level (p = 0.077). We did not find any significant associations for all polymorphisms in relation to GC or HRAG. NOD1 796G>A and TLR4 3725G>C gene polymorphisms were also not associated with Helicobacter pylori infection.ConclusionsACE, NOD1, TRL4 and FAS/FASL gene polymorphisms are not linked with gastric carcinogenesis in Caucasians, and therefore they should not be considered as potential biomarkers for identifying individuals with higher risk for GC.

Serological assessment of gastric mucosal atrophy in gastric cancer

BackgroundNon-invasive tools for gastric cancer screening and diagnosis are lacking. Serological testing with the detection of pepsinogen 1 (PG1), pepsinogen 2 (PG2) and gastrin 17 (G17) offers the possibility to detect preneoplastic gastric mucosal conditions. Aim of this study was to assess the performance of these serological tests in the presence of gastric neoplasia.MethodsHistological and serological samples of 118 patients with gastric cancer have been assessed for tumor specific characteristics (Laurén type, localisation), degree of mucosal abnormalities (intestinal metaplasia, atrophy) and serological parameters (PG1, PG2, PG1/2-ratio, G17, H. pylori IgG, CagA status). Association of the general factors to the different serological values have been statistically analyzed.ResultsPatients with intestinal type gastric cancer had lower PG1 levels and a lower PG1/2-ratio compared to those with diffuse type cancer (p = 0.003). The serum levels of PG2 itself and G17 were not significantly altered. H. pylori infection in general had no influence on the levels of PG1, PG2 and G17 in the serum of gastric cancer patients. There was a trend towards lower PG1 levels in case of positive CagA-status (p = 0.058). The degree of both intestinal metaplasia and atrophy correlated inversely with serum levels for PG1 and the PG1/2-ratio (p < 0.01). Laurén-specific analysis revealed that this is only true for intestinal type tumors. Univariate ANOVA revealed atrophy and CagA-status as the only independent factors for low PG1 and a low PG1/2-ratio.ConclusionsGlandular atrophy and a positive CagA status are determinant factors for decreased pepsinogen 1 levels in the serum of patients with gastric cancer. The serological assessment of gastric atrophy by analysis of serum pepsinogen is only adequate for patients with intestinal type cancer.

Helicobacter pylori: clinical management.

Purpose of review Progress continues in our understanding of the role of Helicobacter pylori infection in gastroduodenal as well as extragastric disorders. This review gives an overview on selected areas of the H. pylori infection and their clinical implications. Recent findings Indications for therapy have been extended and now include idiopathic thrombocytopenic purpura, iron deficiency anemia, and vitamin B12 deficiency. New data are presented on the role of H. pylori in neurodegenerative disorders and in the metabolic syndrome. H. pylori is associated with a (small) increase in the risk for colorectal adenoma and colon cancer. The biggest challenge is the selection of new therapies and treatment strategies because of the increasing failure of standard triple therapies. The best option in high clarithromycin resistance areas is bismuth-based quadruple therapy. Probiotic bacteria and yeasts reduce adverse effects of standard H. pylori eradication regimens. In gastric cancer prevention, screening programs based on the serological detection of preneoplastic conditions may prove useful. Summary New algorithms for preventing H. pylori-induced disease and eradicating the organism should be individualized.

Gastric Cancer: Clinical Aspects, Epidemiology and Molecular Background

The validity and usefulness of the 7th edition of the UICC tumor node metastasis classification in the context of clinical management of gastric cancer are discussed. The most relevant new agent in gastric cancer therapy is trastuzumab for HER2‐positive gastric carcinomas. This marks the success of continuous effort of translational research. Trastuzumab, initially applied in palliative settings, is currently being evaluated also in neoadjuvant treatment regimens. Several new meta‐analyses support the carcinogenic effect of high salt intake and smoking in the context of Helicobacter pylori infection. Further data have become available on the efficacy of protective agents, acetyl salicylic acid/nonsteroidal anti‐inflammatory drugs, and antioxidants. In search for a successful prevention strategy, the focus is on the identification of individuals at high risk who demand screening (testing) and surveillance. Serological assessment of gastric mucosal abnormalities with increased risk for gastric cancer development is extensively studied, and new data are presented from Asia as well as from Europe. New high‐throughput techniques combined with bioinformatic vector analysis open the gate to the identification of new potential diagnostic and therapeutic targets. Furthermore, these approaches allow us to elucidate the interplay of bacterial virulence factors and the host’s immune response as well as H. pylori‐associated alterations of mucosal gene expression.

Antibiotic susceptibility of Helicobacter pylori in central Germany and its relationship with the number of eradication therapies.

Objectives Helicobacter pylori eradication rates show a constant decline over the last few years. The main reason for H. pylori treatment failure is the increasing antibiotic resistance. We assessed antibiotic susceptibility of H. pylori in a region of mid-Germany and analyzed the relationship of antibiotic resistance with the number of eradication therapies over a period of 7 years (2005–2012). Methods H. pylori strains were isolated from 436 patients who underwent gastroscopy for different clinical indications. Susceptibility to amoxicillin, clarithromycin, metronidazole, tetracycline, levofloxacin, and rifabutin was determined using the E-test. Results Primary, secondary, and tertiary resistances against clarithromycin were 7.5, 63.2, and 75.4%, respectively. Primary, secondary, and tertiary resistances to levofloxacin were 11.7, 17.6, and 36.4% and to metronidazole were 32.7, 63.2, and 80.1%, respectively. The resistance rates against tetracycline and rifabutin were comparatively low (<5%), even in patients with previous exposure to these antibiotics. Resistance to rifabutin increased to 6.2% in patients who received more than two previous eradication therapies. Amoxicillin resistance was not detectable in all patients. Conclusion In our region, we observed a stable, but constantly increasing, resistance rate to antibiotics commonly used for the treatment of H. pylori infection. Knowledge of the local antibiotic resistance rates is essential for developing successful treatment strategies for H. pylori eradication.

Role of Helicobacter pylori infection in gastric cancer pathogenesis: a chance for prevention.

Gastric cancer in the absence of strategies implemented for early detection continues to have a dismal prognosis. There are limited options for a curative therapy once patients present with clinical manifestations of this malignant disease. Helicobacter pylori (H. pylori) infection plays a key role in gastric carcinogenesis, supported by epidemiological, preclinical and clinical studies. The recognition of H. pylori infection as a critical risk factor in the development of gastric cancer opens the chance for new venues in prevention strategies.

From gastric inflammation to gastric cancer.

The majority of gastric adenocarcinomas are related to chronic inflammation induced by Helicobacter pylori infection. For intestinal-type gastric cancer, a multistep process of mucosal alterations leading from gastritis via glandular atrophy, intestinal metaplasia and dysplasia to invasive carcinoma is well recognized. Ongoing clinical studies focus on a ‘point of no return’. It is defined as a situation when certain alterations are no longer reversible by H. pylori eradication and progression to gastric cancer may continue. H. pylori affects the mucosal as well as the systemic immune response by secretion of cytokines and the recruitment of distinct inflammatory cells. The immune response is characterized by a balance between a Th1-dominated response and the recruitment of antigen-specific regulatory T cells that allow the bacteria to persist in human gastric mucosa. Besides immune-mediated effects, H. pylori induces cellular alterations as well as genetic alterations in genes that are essential for the epigenetic integrity and mucosal homeostasis. These genetic alterations during gastric cancer development are in focus of intensive research and should ultimately allow the identification of risk factors involved in gastric carcinogenesis. The detection of individuals at high risk for gastric cancer would help to design appropriate strategies for prevention and surveillance.

Characterization and prognosis of patients with hepatocellular carcinoma (HCC) in the non-cirrhotic liver

BackgroundHCC predominantly develops in the condition of chronic inflammation that has led to liver cirrhosis. A small proportion of patients with HCC is diagnosed in the non-cirrhotic liver (NCL). Data on patients with HCC in NCL in advanced stages are scarce.MethodsA retrospective analysis was performed comparing 93 patients with HCC in NCL to 571 patients with HCC in liver cirrhosis (LC) with respect to clinical and demographic characteristics. Also factors influencing survival in patients with HCC in NCL were analyzed.ResultsPatients with HCC in NCL were diagnosed at older age and in more advanced tumor stages than patients with LC. More than 25% of patients with HCC in NCL presented with extrahepatic metastases. Only a minority of patients with HCC in NCL lacked any sign of hepatic damage. Risk factors for LC and risk factors for NAFLD are present in the majority of patients with HCC in NCL. The BCLC classification corresponded with the survival of patients with HCC in NCL although the therapeutic options differ from those for patients with liver cirrhosis.ConclusionsIt will be one of the major challenges in the future to awake awareness of carrying a risk of hepatic malignancies in patients with chronic liver diseases apart from liver cirrhosis, especially in NAFLD. Surveillance programs need to be implemented if these are cost-effective.