Management of precancerous conditions and lesions in the stomach (MAPS): guideline from the European Society of Gastrointestinal Endoscopy (ESGE), European Helicobacter Study Group (EHSG), European Society of Pathology (ESP), and the Sociedade Portuguesa de Endoscopia Digestiva (SPED)

Atrophic gastritis, intestinal metaplasia, and epithelial dysplasia of the stomach are common and are associated with an increased risk for gastric cancer. In the absence of guidelines, there is wide disparity in the management of patients with these premalignant conditions. The European Society of Gastrointestinal Endoscopy, the European Helicobacter Study Group, the European Society of Pathology, and the Sociedade Portuguesa de Endoscopia Digestiva have therefore combined efforts to develop evidence-based guidelines on the management of patients with precancerous conditions and lesions of the stomach. A multidisciplinary group of 63 experts from 24 countries developed these recommendations by means of repeat online voting and a meeting in June 2011 in Porto, Portugal. The recommendations emphasize the increased cancer risk in patients with gastric atrophy and metaplasia and the need for adequate staging in the case of high-grade dysplasia, and they focus on treatment and surveillance indications and methods.     

Co-ordinated expression of MMP-2 and its putative activator, MT1-MMP, in human placentation

The spatial expression of mRNA for matrix metalloproteinase 2 (MMP-2), its putative activator, the membrane-type 1 matrix metalloproteinase (MT1-MMP), and the MMP-2 substrate type IV collagen was investigated in human placentas of both normal and tubal ectopic pregnancies and in cyclic endometrium using in-situ hybridization. Cytokeratin staining applied to adjacent sections was used to identify epithelial and trophoblast cells. In both normal and tubal pregnancies MT1-MMP, MMP-2 and type IV collagen mRNA were highly expressed and co-localized in the extravillous cytotrophoblasts of anchoring villi, in cytotrophoblasts that had penatrated into the placental bed and in cytotrophoblastic cell islands. In addition, the decidual cells of normal pregnancies in some areas co-expressed MT1-MMP and MMP-2 mRNA, with moderate signals for both components. Fibroblast-like stromal cells in tubal pregnancies were positive for MMP-2 mRNA but generally negative for MT1-MMP mRNA. The consistent co-localization of MT1-MMP with MMP-2 and type IV collagen in the same subset of cytotrophoblasts strongly suggests that all three components co-operate in the tightly regulated fetal invasion process. The co-expression of MT1-MMP and MMP-2 mRNA in some of the decidual cells indicates that these cells are also actively involved in the placentation process.      

T-cell, antibody, and cytokine responses to homologs of the 60-kilodalton heat shock protein in Helicobacter pylori infection.

For Helicobacter pylori, the hsp60 heat shock protein encoded by hspB is being considered as a potential candidate for subunit vaccines. We investigated the humoral and cellular responses to H. pylori hsp60 and its cross-reactivity with the homologous Mycobacterium bovis p65 protein and autologous human hsp60 protein. H. pylori-infected persons had significantly higher levels than uninfected persons of serum immunoglobulin G antibodies recognizing H. pylori hsp60, but not M. bovis p65 or human hsp60, as determined by enzyme-linked immunosorbent assay. In contrast, immunoblotting demonstrated cross-reactivity of H. pylori hsp60 with human hsp60. T-cell recognition of H. pylori hsp60 was found in both infected and uninfected subjects, and there was no recognition of human hsp60. T cells from infected and uninfected subjects that had been activated in response to H. pylori hsp60 or M. bovis p65 were phenotypically similar but appeared to secrete different levels of gamma interferon and interleukin-10. These results demonstrate an apparent difference in the epitopes recognized by the T and B cells responding to H. pylori hsp60 in H. pylori-infected persons. In contrast to the T-cell responses, which were highly variable in all subjects and showed no recognition of autologous proteins, a specific B-cell response that may have cross-reactivity to human hsp60 is evident in some infected subjects.     

Genetic and cellular basis of cerebral cavernous malformations: implications for clinical management

Bacigaluppi S, Retta SF, Pileggi S, Fontanella M, Goitre L, Tassi L, La Camera A, Citterio A, Patrosso MC, Tredici G, Penco S. Genetic and cellular basis of cerebral cavernous malformations: implications for clinical management. Cerebral cavernous malformations (CCMs) are a diffuse cerebrovascular disease affecting approximately 0.5% of the population. A CCM is characterized by abnormally enlarged and leaky capillaries arranged in mulberry‐like structures with no clear flow pattern. The lesion might predispose to seizures, focal neurological deficits or fatal intracerebral hemorrhage. However, a CCM can also remain neurologically silent. It might either occur sporadically or as an inherited disorder with incomplete penetrance and variable expressivity. Due to advances in imaging techniques, the incidence of CCM diagnoses are increasing, and the patient must be managed on a multidisciplinary basis: genetic counselling, treatment if needed, and follow‐up. Advances have been made using radiological and pathological correlates of CCM lesions adding to the accumulated knowledge of this disease, although management of these patients is very variable among centers. This review is aimed at providing an update in genetic and molecular insights of this condition. Included are implications for genetic counselling, and possible approaches to prevention and treatment that derive from the understanding of pathogenetic mechanisms.     

Genomic Comparison of cag pathogenicity island (PAI)-positive and -negative Helicobacter pylori strains: identification of novel markers for cag PAI-positive strains

In an analysis of Helicobacter pylori genomic DNA by macroarray methodology, genomic DNA from a panel of cag pathogenicity island (PAI)-negative H. pylori clinical isolates failed to hybridize with 27 genes located outside the cag PAI in a cag PAI-positive reference strain. PCR analyses confirmed that HP0217 (encoding a lipopolysaccharide biosynthetic protein) and HP1079 (encoding a protein of unknown function) were present significantly more frequently in cagA-positive strains than in cagA-negative strains. A low G+C content of these two genes suggests they were acquired by horizontal transfer events.     

Host cell responses to genotypically similar Helicobacter pylori isolates from United States and Japan.

Associations of Helicobacter pylori genotypes with disease differ between Western countries and Asia. Therefore, we directly compared histopathological and in vitro responses to clinical isolates with similar genotypes. Sixty-three cagA(+) vacAs1/m1 H. pylori isolates (United States, n = 24; Japan, n = 39) and eight cagA-negative vacAs2/m2 strains were incubated with AGS cells, and supernatants were assayed for interleukin-8 (IL-8) and for DNA fragmentation. CagA tyrosine phosphorylation in AGS cells and the sequence of the putative HP0638 (oipA) signal sequence region were determined for 22 representative strains. HP0638 and/or cag island mutant strains were created and examined in IL-8 and CagA tyrosine phosphorylation assays. Levels of IL-8 induction and DNA fragmentation were similar in the U.S. and Japanese cagA(+) vacAs1/m1 isolates. All 10 of the isolates with the highest IL-8 induction and 8 of the 10 isolates with the lowest IL-8 induction had an in-frame oipA open reading frame, and all 10 of the isolates with the highest IL-8 induction and 7 of the 10 isolates with the lowest IL-8 induction induced CagA tyrosine phosphorylation in AGS cells. Eight isolates from gastric ulcer patients induced significantly more apoptosis in vitro, and more severe gastritis and atrophy in vivo, than other Japanese isolates. Disruption of HP0638 did not affect IL-8 induction or CagA tyrosine phosphorylation. Thus, H. pylori cagA(+) vacAs1/m1 isolates from the United States and Japan induce similar IL-8 and apoptosis levels. Inactivation of HP0638 does not alter epithelial responses mediated by the cag island in vitro. Assessment of apoptosis in vitro identified a group of H. pylori isolates that induce more severe gastric inflammation and atrophy.     

Prognostic Bayesian networks I: rationale, learning procedure, and clinical use

Prognostic models are tools to predict the future outcome of disease and disease treatment, one of the fundamental tasks in clinical medicine. This article presents the prognostic Bayesian network (PBN) as a new type of prognostic model that builds on the Bayesian network methodology, and implements a dynamic, process-oriented view on prognosis. A PBN describes the mutual relationships between variables that come into play during subsequent stages of a care process and a clinical outcome. A dedicated procedure for inducing these networks from clinical data is presented. In this procedure, the network is composed of a collection of local supervised learning models that are recursively learned from the data. The procedure optimizes performance of the network’s primary task, outcome prediction, and handles the fact that patients may drop out of the process in earlier stages. Furthermore, the article describes how PBNs can be applied to solve a number of information problems that are related to medical prognosis.     

Local and Systemic Immune and Inflammatory Responses to Helicobacter pylori Strains

Colonization with Helicobacter pylori eventuates in varied clinical outcomes, which relate to both bacterial and host factors. Here we examine the relationships between cagA status, serum and gastric juice antibody responses, and gastric inflammation in dyspeptic patients. Serum, gastric juice, and gastric biopsy specimens were obtained from 89 patients undergoing endoscopy. H. pylori colonization and cagA status were determined by histology, culture, and PCR methods, and acute inflammation and chronic inflammation in the gastric mucosa were scored by a single pathologist. Serum and gastric juice antibodies to H. pylori whole-cell and CagA antigens were determined by enzyme-linked immunosorbent assay. Relationships between variables were sequentially analyzed using univariate and multivariate statistical methods. Of the 89 subjects, 62 were colonized by H. pylori. By univariate analyses, levels of serum immunoglobulin G (IgG) and IgA and gastric juice IgA antibodies against whole-cell and CagA antigens each were significantly higher in the H. pylori-positive group than in the H. pylori-negative group (P < 0.001). H. pylori and CagA seropositivities were both significantly associated with enhanced inflammation in gastric antrum and body (P < 0.02). The presence of gastric juice antibodies to H. pylori antigens was associated with more severe gastric inflammation. However, in multivariate analyses, only the presence of serum antibodies against CagA and, to a lesser extent, whole-cell antigens remained significantly associated with acute and chronic inflammation in antrum and body (P < 0.05). Thus, serum antibody response to CagA correlates with severity of gastric inflammation. Furthermore, given the relationships demonstrated by multivariate analysis, determination of gastric juice antibodies may provide a better representation of serum, rather than secretory, immune response.     

Hairy cell leukemia: a tumor of pre-plasma cells

Monoclonal antibodies defining B-, T-, and myeloid-restricted cell surface antigens were used to characterize the lineage and state of differentiation of tumor cells isolated from 22 patients with hairy cell leukemia (HCL). These tumors were shown to be of B lineage because they strongly expressed the B cell-restricted antigens B1 and B4 and lacked T cell- and monocyte-restricted antigens. Moreover, the strong expression of the plasma cell-associated PCA-1 antigen on the majority of hairy cells suggested that these tumors correspond to later stages of B cell ontogeny. Dual fluorescence experiments further confirmed that HCL splenocytes that coexpressed B1 and PCA-1 demonstrated both the morphology and tartrate-resistant acid phosphatase positivity of hairy cells. The observation that some hairy cells either spontaneously produce immunoglobulin (Ig) or could be induced to proliferate and secrete Ig provides complementary support for the view that HCL is a pre-plasma cell tumor. However, staining of hairy cells with anti-IL2R1 monoclonal antibody, which is directed to the T cell growth factor receptor and/or with the anti-Mo1 reagent, directed to C3bi complement receptor, distinguish these cells from currently identified B cells.