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.
Infection with Helicobacter pylori is established as the major risk factor for gastric cancer development. Damage of the mucosal barrier due to H. pylori-induced inflammation enhances the ...carcinogenic effect of other risk factors such as salt intake or tobacco smoking. The genetic disposition of both the bacterial strain and the host can increase the potential towards gastric cancer formation. Genetic variance of the bacterial proteins CagA and VacA is associated with a higher gastric cancer risk, as are polymorphisms and epigenetic changes in host gene coding for interleukins (IL1β, IL8), transcription factors (CDX2, RUNX3) and DNA repair enzymes. Application of high-throughput assays for genome-wide assessment of either genetic structural variance or gene expression patterns may lead to a better understanding of the pathobiological background of these processes, including the underlying signaling pathways. Understanding of the stepwise alterations that take place in the transition from chronic atrophic gastritis, via metaplastic changes, to invasive neoplasia is vital to define the 'point of no return' before which eradication of H. pylori has the potential to prevent gastric cancer. Currently, eradication as preventive strategy is only recommended for high-incidence regions in Asia; large population studies with an adequate follow-up are required to demonstrate the effectiveness of such an approach in Western populations.
Our aim was to evaluate the feasibility of a serological assessment of gastric cancer risk in patients undergoing colonoscopy in countries with low-to-moderate incidence rates.
Serum samples were ...prospectively collected from 453 patients (>50 years old) undergoing colonoscopies. Of these, 279 (61.6%) also underwent gastroscopy to correlate the results for serum pepsinogen I and II (sPG-I and sPG-II), sPG-I/II ratio, and anti-
antibodies with gastric histopathology findings (graded according to the updated Sydney classification and the Operative Link of Gastritis Assessment (OLGA) and the Operative Link for Gastric Intestinal Metaplasia assessment (OLGIM) systems).
was found in 85 patients (30.5%). Chronic atrophic gastritis was diagnosed in 89 (31.9%) patients. High-risk OLGA (III⁻IV) stages were present in 24 patients, and high-risk OLGIM stages were present in 14 patients. There was an inverse correlation of sPG-I with the degree of atrophy and intestinal metaplasia (IM), as well as with the respective OLGA (r = -0.425;
< 0.001) and OLGIM (r = -0.303;
< 0.001) stages. A pathological sPG-I result was associated with a relative risk (RR) of 12.2 (95% confidence interval: 6.29⁻23.54;
< 0.001) for gastric preneoplastic changes.
The assessment of serum pepsinogen allows the identification of patients at increased risk of gastric cancer. A prevention strategy of combining a screening colonoscopy with a serological screening for preneoplastic gastric changes should be considered in the general population.
Non-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.
Histological 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.
Patients 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.
Glandular 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.
AIM:To assess whether antibiotic resistance varies between the antrum and corpus of the stomach of patients that are either Helicobacter pylori(H.pylori)therapy-naive or pre-treated.METHODS:H.pylori ...strains were isolated from antrum and corpus biopsies from 66 patients that received a diagnostic gastroduodenoscopy for variant clinical indications.Antimicrobial susceptibility to amoxicillin,clarithromycin,tetracycline,metronidazole,levofloxacin and rifabutin was tested with the E-test method on IsoSensitest agar with 10 vol%defibrinated horse blood.In patients with a different antibiotic susceptibility pattern between the isolates from the antrum and corpus,DNA fingerprinting via random amplified polymorphic DNA analysis was performed to detect differences among DNA patterns of H.pylori isolates.RESULTS:Primary,secondary and tertiary resistance to clarithromycin was 6.9%,53.8%and 83.3%,retrospectively.Metronidazole and levofloxacin resistance also increased according to the number of previous treatments(17.2%,69.2%,83.3%;13.8%,23.1%,33.3%).Tertiary resistance to rifabutin was detected in12.5%of patients.In none of the 66 patients a resistance against amoxicillin or tetracycline was detectable.Discordant antibiotic susceptibility between antrum and corpus isolates for different antibiotics was seen in 15.2%(10/66)of the patients.Two out of those ten patients were naive to any H.pylori antibiotic treatment.The remaining eight patients previously received at least one eradication therapy.DNA fingerprinting analysis revealed no substantial differences among DNA patterns between antrum and corpus isolates in the majority of patients suggesting an infection with a single H.pylori strain.CONCLUSION:Different antibiotic susceptibility between antrum and corpus biopsies is a common phenomenon and a possible explanation for treatment failure.Resistant H.pylori strains may be missed if just one biopsy from one anatomic site of the stomach is taken for H.pylori susceptibility testing.
Background Despite evidence for the association of distal gastric cancer (GC) with the H. pylori infection, relevance of the infection for proximal GC is uncertain. Aims We analysed the prevalence of ...H.pylori in proximal and distal GC and its association with premalignant mucosal alterations in different gastric locations. Methods We performed a retrospective analysis on 152 patients with GC, stratified according to the location of the main tumor mass into proximal (n = 73) and distal (n = 79) GC. H.pylori prevalence and CagA-status were determined by serology. Intestinal metaplasia (IM), glandular atrophy and mucosal inflammation were diagnosed from histological specimens and graded according to the updated Sydney-classification. Results H.pylori prevalence (78.1 vs. 82.3%) and CagA-status (77.2 vs. 84.6%) were similar in proximal and distal GC as well as in intestinal and diffuse GC. IM (79.8 vs. 60.3%; P = 0.012) and atrophy (50.0 vs. 19.1%; P < 0.001) were more frequent in the mucosa surrounding intestinal tumors. There was a higher degree of surrounding IM in case of distally located compared to proximal tumors (P = 0.001). Overall, IM was more severe in the antrum than the corpus. In contrast, there was more severe active inflammation in the corpus than the antrum (P = 0.017). Conclusion The prevalence of H.pylori is similar in proximal and distal GC if precise allocation of the primary tumor has been performed, especially at the esophagogastric junction. Distal tumors of the intestinal type are more often associated with local IM than proximal and diffuse type carcinomas. This suggests a distinct pathophysiological relevance of these mucosal alterations.
Somatic copy number alterations (SCNAs) are an important class of genomic alteration in cancer. They are frequently observed in cancer samples, with studies showing that, on average, SCNAs affect 34% ...of a cancer cell's genome. Furthermore, SCNAs have been shown to be major drivers of tumour development and have been associated with response to therapy and prognosis. Large-scale cancer genome studies suggest that tumours are driven by somatic copy number alterations (SCNAs) or single-nucleotide variants (SNVs). Despite the frequency of SCNAs and their clinical relevance, the use of genomics assays in the clinic is biased towards targeted gene panels, which identify SNVs but provide limited scope to detect SCNAs throughout the genome. There is a need for a comparably low-cost and simple method for high-resolution SCNA profiling. We present conliga, a fully probabilistic method that infers SCNA profiles from a low-cost, simple, and clinically-relevant assay (FAST-SeqS). When applied to 11 high-purity oesophageal adenocarcinoma samples, we obtain good agreement (Spearman's rank correlation coefficient, r.sub.s=0.94) between conliga's inferred SCNA profiles using FAST-SeqS data (approximately pounds sterling14 per sample) and those inferred by ASCAT using high-coverage WGS (gold-standard). We find that conliga outperforms CNVkit (r.sub.s=0.89), also applied to FAST-SeqS data, and is comparable to QDNAseq (r.sub.s=0.96) applied to low-coverage WGS, which is approximately four-fold more expensive, more laborious and less clinically-relevant. By performing an in silico dilution series experiment, we find that conliga is particularly suited to detecting SCNAs in low tumour purity samples. At two million reads per sample, conliga is able to detect SCNAs in all nine samples at 3% tumour purity and as low as 0.5% purity in one sample. Crucially, we show that conliga's hidden state information can be used to decide when a sample is abnormal or normal, whereas CNVkit and QDNAseq cannot provide this critical information. We show that conliga provides high-resolution SCNA profiles using a convenient, low-cost assay. We believe conliga makes FAST-SeqS a more clinically valuable assay as well as a useful research tool, enabling inexpensive and fast copy number profiling of pre-malignant and cancer samples.
Abstract Background The medial knee contact force may be lowered by modified foot loading to prevent the progression of unilateral gonarthrosis but the real effects of such gait modifications are ...unknown. This study investigates how walking with a more medial or lateral rollover of the foot influences the in vivo measured knee contact forces. Methods Five subjects with telemeterized knee implants walked on a treadmill with pronounced lateral or medial foot loading. Acoustic feedback of peak foot pressure was used to facilitate the weight bearing shift. The resultant contact force, Fres , the medial contact force, Fmed , and the force distribution Fmed /Fres across the tibial plateau were computed from the measured joint contact loads. Findings During lateral foot loading, the two maxima of Fres during the stance phase, Peak 1 and Peak 2, increased by an average of 20% and 12%, respectively. The force distribution was changed by only − 3%/+ 2%. As a result, Fmed increased by + 16%/+ 17%. Medial foot loading, on the other hand, changed Fres only slightly, but decreased the distribution by − 18%/− 11%. This led to average reductions of Fmed by − 18%/− 18%. The reductions were realized by kinematic adaptations, such as increases of ankle eversion, step width and foot progression angle. Interpretation Medial foot loading consistently reduced the medial knee compartment, and may be a helpful gait modification for patients with pronounced medial gonarthrosis. The increase of Fmed during lateral foot loading was most likely caused by muscular co-contractions. Long-term training may lead to more efficient gait and reduce co-contractions.
PDF
