Diagnostic approach to Helicobacter pylori-related gastric oncogenesis.

Helicobacter pylori (H. pylori) is a causative agent of peptic ulcer disease and plays an important role in the development of various other upper and lower gastrointestinal tract and systemic diseases; in addition to carcinogenesis and the development of mucosa-associated lymphoid tissue lymphoma, extragastric manifestations of H. pylori are increasingly being unraveled. Therefore, prompt and accurate diagnosis is essential. Within this narrative review we present an overview of the current trend in the diagnosis of H. pylori infection and its potential oncogenic sequelae, including gastric mucosa atrophy, intestinal metaplasia, dysplasia and gastric cancer. Signs of H. pylori-related gastric cancer risk can be assessed by endoscopy using the Kyoto classification score. New technology, such as optical or digital chromoendoscopy, improves diagnostic accuracy and provides information regarding H. pylori-related gastric preneoplastic and malignant lesions. In addition, a rapid urease test or histological examination should be performed, as these offer a high diagnostic sensitivity; both are also useful for the diagnosis of sequelae including gastric and colon neoplasms. Culture is necessary for resistance testing and detecting H. pylori-related gastric dysbiosis involved in gastric oncogenesis. Likewise, molecular methods can be utilized for resistance testing and detecting H. pylori-related gastric cancer development and progression. Noninvasive tests, such as the urea breath and stool antigen tests, can also be implemented; these are also suitable for monitoring eradication success and possibly for detecting H. pylori-related gastric malignancy. Serological tests may help to exclude infection in specific populations and detect gastric and colon cancers. Finally, there are emerging potential diagnostic biomarkers for H. pylori-related gastric cancer

Widely differing screening and treatment practice for osteoporosis in patients with inflammatory bowel diseases in the Swiss IBD cohort study.

Low bone mineral density (BMD) and osteoporosis remain frequent problems in patients with inflammatory bowel diseases (IBDs). Several guidelines with nonidentical recommendations exist and there is no general agreement regarding the optimal approach for osteoporosis screening in IBD patients. Clinical practice of osteoporosis screening and treatment remains insufficiently investigated.In the year 2014, a chart review of 877 patients included in the Swiss IBD Cohort study was performed to assess details of osteoporosis diagnostics and treatment. BMD measurements, osteoporosis treatment, and IBD medication were recorded.Our chart review revealed 253 dual-energy x-ray absorptiometry (DXA) scans in 877 IBD patients; osteoporosis was prevalent in 20% of tested patients. We identified widely differing osteoporosis screening rates among centers (11%-62%). A multivariate logistic regression analysis identified predictive factors for screening including steroid usage, long disease duration, and perianal disease; even after correction for all risk factors, the study center remained a strong independent predictor (odds ratio 2.3-21 compared to the center with the lowest screening rate). Treatment rates for patients with osteoporosis were suboptimal (55% for calcium, 65% for vitamin D) at the time of chart review. Similarly, a significant fraction of patients with current steroid medication were not treated with vitamin D or calcium (treatment rates 53% for calcium, 58% for vitamin D). For only 29% of patients with osteoporosis bisphosphonate treatment was started. Treatment rates also differed among centers, generally following screening rates. In patients with longitudinal DXA scans, calcium and vitamin D usage was significantly associated with improvement of BMD over time.Our analysis identified inconsistent usage of osteoporosis screening and underuse of osteoporosis treatment in IBD patients. Increasing awareness of osteoporosis as a significant clinical problem in IBD patients might improve patient care

Assessment of hepatic fibrosis and inflammation with look-locker T1 mapping and magnetic resonance elastography with histopathology as reference standard.

PURPOSE To compare the diagnostic performance of T1 mapping and MR elastography (MRE) for staging of hepatic fibrosis and grading inflammation with histopathology as standard of reference. METHODS 68 patients with various liver diseases undergoing liver biopsy for suspected fibrosis or with an established diagnosis of cirrhosis prospectively underwent look-locker inversion recovery T1 mapping and MRE. T1 relaxation time and liver stiffness (LS) were measured by two readers. Hepatic fibrosis and inflammation were histopathologically staged according to a standardized fibrosis (F0-F4) and inflammation (A0-A2) score. For statistical analysis, independent t test, and Mann-Whitney U test and ROC analysis were performed, the latter to determine the performance of T1 mapping and MRE for fibrosis staging and inflammation grading, as compared to histopathology. RESULTS Histopathological analysis diagnosed 9 patients with F0 (13.2%), 21 with F1 (30.9%), 11 with F2 (16.2%), 10 with F3 (14.7%), and 17 with F4 (25.0%). Both T1 mapping and MRE showed significantly higher values for patients with significant fibrosis (F0-1 vs. F2-4; T1 mapping p < 0.0001, MRE p < 0.0001) as well as for patients with severe fibrosis or cirrhosis (F0-2 vs. F3-4; T1 mapping p < 0.0001, MRE p < 0.0001). T1 values and MRE LS were significantly higher in patients with inflammation (A0 vs. A1-2, both p = 0.01). T1 mapping showed a tendency toward lower diagnostic performance without statistical significance for significant fibrosis (F2-4) (AUC 0.79 vs. 0.91, p = 0.06) and with a significant difference compared to MRE for severe fibrosis (F3-4) (AUC 0.79 vs. 0.94, p = 0.03). For both T1 mapping and MRE, diagnostic performance for diagnosing hepatic inflammation (A1-2) was low (AUC 0.72 vs. 0.71, respectively). CONCLUSION T1 mapping is able to diagnose hepatic fibrosis, however, with a tendency toward lower diagnostic performance compared to MRE and thus may be used as an alternative to MRE for diagnosing hepatic fibrosis, whenever MRE is not available or likely to fail due to intrinsic factors of the patient. Both T1 mapping and MRE are probably not sufficient as standalone methods to diagnose hepatic inflammation with relatively low diagnostic accuracy

Assessment of hepatic fibrosis and inflammation with look-locker T1 mapping and magnetic resonance elastography with histopathology as reference standard

Purpose: To compare the diagnostic performance of T1 mapping and MR elastography (MRE) for staging of hepatic fibrosis and grading inflammation with histopathology as standard of reference. Methods: 68 patients with various liver diseases undergoing liver biopsy for suspected fibrosis or with an established diagnosis of cirrhosis prospectively underwent look-locker inversion recovery T1 mapping and MRE. T1 relaxation time and liver stiffness (LS) were measured by two readers. Hepatic fibrosis and inflammation were histopathologically staged according to a standardized fibrosis (F0-F4) and inflammation (A0-A2) score. For statistical analysis, independent t test, and Mann-Whitney U test and ROC analysis were performed, the latter to determine the performance of T1 mapping and MRE for fibrosis staging and inflammation grading, as compared to histopathology. Results: Histopathological analysis diagnosed 9 patients with F0 (13.2%), 21 with F1 (30.9%), 11 with F2 (16.2%), 10 with F3 (14.7%), and 17 with F4 (25.0%). Both T1 mapping and MRE showed significantly higher values for patients with significant fibrosis (F0-1 vs. F2-4; T1 mapping p < 0.0001, MRE p < 0.0001) as well as for patients with severe fibrosis or cirrhosis (F0-2 vs. F3-4; T1 mapping p < 0.0001, MRE p < 0.0001). T1 values and MRE LS were significantly higher in patients with inflammation (A0 vs. A1-2, both p = 0.01). T1 mapping showed a tendency toward lower diagnostic performance without statistical significance for significant fibrosis (F2-4) (AUC 0.79 vs. 0.91, p = 0.06) and with a significant difference compared to MRE for severe fibrosis (F3-4) (AUC 0.79 vs. 0.94, p = 0.03). For both T1 mapping and MRE, diagnostic performance for diagnosing hepatic inflammation (A1-2) was low (AUC 0.72 vs. 0.71, respectively). Conclusion: T1 mapping is able to diagnose hepatic fibrosis, however, with a tendency toward lower diagnostic performance compared to MRE and thus may be used as an alternative to MRE for diagnosing hepatic fibrosis, whenever MRE is not available or likely to fail due to intrinsic factors of the patient. Both T1 mapping and MRE are probably not sufficient as standalone methods to diagnose hepatic inflammation with relatively low diagnostic accuracy. Keywords: Biopsy; Fibrosis; Liver; MR elastography; T1 mappin

Effect of Immune Pressure on Hepatitis C Virus Evolution: Insights From a Single-Source Outbreak

The host's immune response to hepatitis C virus (HCV) can result in the selection of characteristic mutations (adaptations) that enable the virus to escape this response. The ability of the virus to mutate at these sites is dependent on the incoming virus, the fitness cost incurred by the mutation, and the benefit to the virus in escaping the response. Studies examining viral adaptation in chronic HCV infection have shown that these characteristic immune escape mutations can be observed at the population level as human leukocyte antigen (HLA)–specific viral polymorphisms. We examined 63 individuals with chronic HCV infection who were infected from a single HCV genotype 1b source. Our aim was to determine the extent to which the host's immune pressure affects HCV diversity and the ways in which the sequence of the incoming virus, including preexisting escape mutations, can influence subsequent mutations in recipients and infection outcomes. Conclusion: HCV sequences from these individuals revealed 29 significant associations between specific HLA types within the new hosts and variations within their viruses, which likely represent new viral adaptations. These associations did not overlap with previously reported adaptations for genotypes 1a and 3a and possibly reflected a combination of constraint due to the incoming virus and genetic distance between the strains. However, these sites accounted for only a portion of the sites in which viral diversity was observed in the new hosts. Furthermore, preexisting viral adaptations in the incoming (source) virus likely influenced the outcomes in the new hosts. (Hepatology 2011;53:396-405

Whole Genome Pyrosequencing of Rare Hepatitis C Virus Genotypes Enhances Subtype Classification and Identification of Naturally Occurring Drug Resistance Variants

Background. Infection with hepatitis C virus (HCV) is a burgeoning worldwide public health problem, with 170 million infected individuals and an estimated 20 million deaths in the coming decades. While 6 main genotypes generally distinguish the global geographic diversity of HCV, a multitude of closely related subtypes within these genotypes are poorly defined and may influence clinical outcome and treatment options. Unfortunately, the paucity of genetic data from many of these subtypes makes time-consuming primer walking the limiting step for sequencing understudied subtypes. Methods. Here we combined long-range polymerase chain reaction amplification with pyrosequencing for a rapid approach to generate the complete viral coding region of 31 samples representing poorly defined HCV subtypes. Results. Phylogenetic classification based on full genome sequences validated previously identified HCV subtypes, identified a recombinant sequence, and identified a new distinct subtype of genotype 4. Unlike conventional sequencing methods, use of deep sequencing also facilitated characterization of minor drug resistance variants within these uncommon or, in some cases, previously uncharacterized HCV subtypes. Conclusions. These data aid in the classification of uncommon HCV subtypes while also providing a high-resolution view of viral diversity within infected patients, which may be relevant to the development of therapeutic regimens to minimize drug resistanc

Impaired Hepatitis C Virus-Specific T Cell Responses and Recurrent Hepatitis C Virus in HIV Coinfection

BACKGROUND: Hepatitis C virus (HCV)-specific T cell responses are critical for spontaneous resolution of HCV viremia. Here we examined the effect of a lymphotropic virus, HIV-1, on the ability of coinfected patients to maintain spontaneous control of HCV infection. METHODS AND FINDINGS: We measured T cell responsiveness by lymphoproliferation and interferon-γ ELISPOT in a large cohort of HCV-infected individuals with and without HIV infection. Among 47 HCV/HIV-1-coinfected individuals, spontaneous control of HCV was associated with more frequent HCV-specific lymphoproliferative (LP) responses (35%) compared to coinfected persons who exhibited chronic HCV viremia (7%, p = 0.016), but less frequent compared to HCV controllers who were not HIV infected (86%, p = 0.003). Preservation of HCV-specific LP responses in coinfected individuals was associated with a higher nadir CD4 count (r (2) = 0.45, p < 0.001) and the presence and magnitude of the HCV-specific CD8(+) T cell interferon-γ response (p = 0.0014). During long-term follow-up, recurrence of HCV viremia occurred in six of 25 coinfected individuals with prior control of HCV, but in 0 of 16 HIV-1-negative HCV controllers (p = 0.03, log rank test). In these six individuals with recurrent HCV viremia, the magnitude of HCV viremia following recurrence inversely correlated with the CD4 count at time of breakthrough (r = −0.94, p = 0.017). CONCLUSIONS: These results indicate that HIV infection impairs the immune response to HCV—including in persons who have cleared HCV infection—and that HIV-1-infected individuals with spontaneous control of HCV remain at significant risk for a second episode of HCV viremia. These findings highlight the need for repeat viral RNA testing of apparent controllers of HCV infection in the setting of HIV-1 coinfection and provide a possible explanation for the higher rate of HCV persistence observed in this population

PTX3 Polymorphisms and Invasive Mold Infections After Solid Organ Transplant

Donor PTX3 polymorphisms were shown to influence the risk of invasive aspergillosis among hematopoietic stem cell transplant recipients. Here, we show that PTX3 polymorphisms are independent risk factors for invasive mold infections among 1101 solid organ transplant recipients, thereby strengthening their role in mold infection pathogenesis and patients' risk stratificatio

A Viral Dynamic Model for Treatment Regimens with Direct-acting Antivirals for Chronic Hepatitis C Infection

We propose an integrative, mechanistic model that integrates in vitro virology data, pharmacokinetics, and viral response to a combination regimen of a direct-acting antiviral (telaprevir, an HCV NS3-4A protease inhibitor) and peginterferon alfa-2a/ribavirin (PR) in patients with genotype 1 chronic hepatitis C (CHC). This model, which was parameterized with on-treatment data from early phase clinical studies in treatment-naïve patients, prospectively predicted sustained virologic response (SVR) rates that were comparable to observed rates in subsequent clinical trials of regimens with different treatment durations in treatment-naïve and treatment-experienced populations. The model explains the clinically-observed responses, taking into account the IC50, fitness, and prevalence prior to treatment of viral resistant variants and patient diversity in treatment responses, which result in different eradication times of each variant. The proposed model provides a framework to optimize treatment strategies and to integrate multifaceted mechanistic information and give insight into novel CHC treatments that include direct-acting antiviral agents

Genetic Heterogeneity of Hepatitis C Virus in Association with Antiviral Therapy Determined by Ultra-Deep Sequencing

The hepatitis C virus (HCV) invariably shows wide heterogeneity in infected patients, referred to as a quasispecies population. Massive amounts of genetic information due to the abundance of HCV variants could be an obstacle to evaluate the viral genetic heterogeneity in detail.Using a newly developed massive-parallel ultra-deep sequencing technique, we investigated the viral genetic heterogeneity in 27 chronic hepatitis C patients receiving peg-interferon (IFN) α2b plus ribavirin therapy.Ultra-deep sequencing determined a total of more than 10 million nucleotides of the HCV genome, corresponding to a mean of more than 1000 clones in each specimen, and unveiled extremely high genetic heterogeneity in the genotype 1b HCV population. There was no significant difference in the level of viral complexity between immediate virologic responders and non-responders at baseline (p = 0.39). Immediate virologic responders (n = 8) showed a significant reduction in the genetic complexity spanning all the viral genetic regions at the early phase of IFN administration (p = 0.037). In contrast, non-virologic responders (n = 8) showed no significant changes in the level of viral quasispecies (p = 0.12), indicating that very few viral clones are sensitive to IFN treatment. We also demonstrated that clones resistant to direct-acting antivirals for HCV, such as viral protease and polymerase inhibitors, preexist with various abundances in all 27 treatment-naïve patients, suggesting the risk of the development of drug resistance against these agents.Use of the ultra-deep sequencing technology revealed massive genetic heterogeneity of HCV, which has important implications regarding the treatment response and outcome of antiviral therapy