Helicobacter pylori infection and gastric mucosa-associated lymphoid tissue hyperplasia

The association of Helicobacter pylori (Hp) infection with mucosa-associated lymphoid tissue (MALT) hyperplasia in gastric mucosa was investigated. The results showed that the incidence of Hp infection increased as the degree of the mucosal injury was aggravated, but the prevalence of lymphoid follicles in the mucosa with atrophic antritis was much more than in the mucosa without the atrophic and the frequency of detecting Hp and intestinal metaplasia in the mucosa with lymphoid follicles significantly increased, as compared with the mucosa without it. These findings suggest that gastric MALT hyperplasia induced by Hp infection may lead to destruction of gastric glands through hypersensitivity.     

Cure of Helicobacter pylori infection and duration of remission of low-grade gastric mucosa-associated lymphoid tissue lymphoma

BACKGROUND: Low-grade B-cell lymphomas arising in mucosa-associated lymphoid tissue (MALT) are most frequently localized in the gastrointestinal tract. More than 90% of gastric MALT lymphomas are diagnosed in patients with chronic, Helicobacter pylori-associated gastritis. High remission rates for these lymphomas have been observed after the cure of H. pylori infection. Data are lacking, however, with regard to the duration of the remissions. To address this question of remission duration, we have followed 50 patients in whom H. pylori infections were eradicated, and we determined whether the patients in complete remission displayed evidence of residual monoclonal B cells during follow-up. METHODS: Patients were treated with amoxycillin and omeprazole for 2 weeks in an attempt to cure H. pylori infections. Follow-up included endoscopic investigations with biopsy sampling. Monoclonal B cells in biopsy specimens were detected by means of a polymerase chain reaction (PCR)-based assay. RESULTS: H. pylori infections were cured in all 50 patients. The median follow-up for the 50 patients is currently 24 months (729 days; range, 135-1411 days). Forty patients achieved complete remission of their lymphomas, but five have subsequently relapsed. The median time of continuous complete remission for the 40 patients was 15.4 months (468 days; range, 0-1198 days). Among six patients whose Iymphomas did not respond to H. pylori eradication, four revealed high-grade lymphomas upon surgery. PCR indicated the presence of monoclonal B cells during follow-up in 22 of 31 assessable patients in complete remission. CONCLUSIONS: Complete remissions of low-grade gastric MALT Iymphomas after the cure of H. pylori infection appear to be stable, although most patients display evidence of monoclonal B cells during follow-up. Whether these patients are truly cured of their Iymphomas remains to be determined.     

Ongoing somatic mutations and clonal expansions after cure of Helicobacter pylori infection in gastric mucosa-associated lymphoid tissue B-cell lymphoma

PURPOSE: Although most patients with primary gastric low-grade mucosa-associated lymphoid tissue (MALT) B-cell lymphoma experience complete endoscopic and histologic remission after the cure of Helicobacter pylori infection, in many patients, the polymerase chain reaction (PCR) still detects monoclonal B cells in the gastric mucosa. The present study asked whether the lymphoma immunoglobulin VH (IgVH) sequences remained stable in patients with gastric MALT lymphoma after H pylori eradication. PATIENTS AND METHODS: Eight patients with stage EI disease treated with H pylori eradication were analyzed before and at different time points after the cure of the infection. After the amplification of IgVH genes from DNA extracted from gastric biopsy specimens, monoclonal PCR products were cloned and multiple clones (43 to 105) were sequenced per patient. RESULTS: Mutations were detected in all lymphoma VH sequences, which suggested germinal center or postgerminal center origin of the lymphoma B cells. In five of the eight patients, clonal heterogeneity was observed at diagnosis or during follow-up. Genealogical analysis of shared and unshared mutations showed that the process of somatic mutations was ongoing after H pylori eradication in four of the five patients who showed clonal instability. Ongoing mutations were observed in three of the four patients who completely responded to H pylori eradication, but in only one of the four patients who did not respond or who partially responded. CONCLUSION: In low-grade gastric MALT lymphomas, an ongoing process of somatic hypermutation and antigen selection can be detected after the therapeutic removal of the underlying stimulus H pylori. These data point to the relevance of yet unknown antigens that drive this disease. In addition, they challenge the view that these lymphomas may be cured solely by the eradication of H pylori.     

Frequency of vacA genotypes and cytotoxin activity in Helicobacter pylori associated with low-grade gastric mucosa-associated lymphoid tissue lymphoma

The vacA genotypes s1,m1 and s1,m2 were detected in 44 and 30% of Helicobacter pylori isolates, respectively, from patients with gastric mucosa-associated lymphoid tissue lymphoma, compared to 26 and 56% of isolates, respectively, from individuals with gastritis. The vacA s1 genotype was significantly associated with, but not predictive of, the presence of vacuolating cytotoxin activity.     

Helicobacter pylori infection induces gastric cancer in mongolian gerbils

BACKGROUND & AIMS: Although epidemiological studies have indicated that Helicobacter pylori infection plays a crucial role in gastric carcinogenesis in humans, there is no direct proof that H. pylori is actually associated with gastric carcinogenesis. The purpose of this study was to elucidate the relationship between H. pylori infection and gastric carcinogenesis using an animal model of long-term H. pylori infection. METHODS: Mongolian gerbils were orally inoculated with H. pylori, and the sequential morphological changes in the stomach were examined for up to 62 weeks. RESULTS: H. pylori was constantly detected in all infected animals throughout the study. At the 26th week, severe active chronic gastritis, ulcers, and intestinal metaplasia could be observed in infected animals. By the end of the study, adenocarcinoma had developed in the pyloric region of 37% of the infected animals. All tumors consisted of well-differentiated intestinal-type epithelium, and their development seemed to be closely related to intestinal metaplasia. CONCLUSIONS: We have successfully demonstrated that long-term infection with H. pylori induces adenocarcinoma in Mongolian gerbils. The observations are thus highly suggestive of the involvement of H. pylori infection in gastric carcinogenesis in humans.     

Helicobacter pylori infection and gastric secretion

We examined whether an immunosuppressant, FK506, inhibits delayed neuronal death in the gerbil hippocampal CA1 sector after 5-min forebrain ischemia. After reperfusion, gerbils were injected intravenously with FK506. Gerbils in the early injection group were injected with FK506 immediately after reperfusion, and gerbils in the delayed injection group were injected with FK506 1 or 2 h postischemia. The body temperature of the FK506-treated gerbils in the normothermic group was maintained at 37.5-38.0 degrees C for 2 h postischemia. In the chronic survival group, neuroprotection was assessed after recovery for 45 days. Seven or 45 days after reperfusion, neuronal density in the CA1 was assessed following perfusion fixation. FK506 ameliorated cell death in the CA1 in a dose-dependent manner in every group, although it showed a hypothermic effect. FK506 is neuroprotective against forebrain ischemia in gerbils.     

Radiographic and computed tomographic findings of gastric mucosa-associated lymphoid tissue lymphomas

In this paper the complications of colonic diverticulosis are reported, on the basis of two clinical cases personally observed. In the first case, a 68 year-old man, the typical symptomatology with pneumaturia, cloudy urine and watery diarrhea suggested a uro-colonic fistula, therefore a fistula between sigma and bladder, caused by a perforate diverticulum, has been diagnosed by means of cystography and barium enema. In the second case, a 64 year-old woman, the irritative symptomatology, hematuria and endoscopic picture suggested a vesical neoplasia. An accurate examination with abdominal TAC and barium enema, showed a perforate diverticulum between uterus and bladder, without affecting the bladder lumen. The surgical treatment required, in both cases, a left hemicolectomy, a minimal bladder resection in the first case, and a greater one in the second case. During the discussion, the main etiopathogenetic causes of uro-colonic fistulae together with the variants in the onset symptomatology, have been stressed.     

Prevalence and pattern of Helicobacter pylori gastritis in the gastric cardia

OBJECTIVES: Helicobacter pylori has a predilection for antral colonization. Local acid production is the major determinant of colonization. Because production is low in the antrum and cardia, H. pylori should also colonize the cardia. We therefore investigated the histologic pattern of gastritis and the prevalence of H. pylori in the cardia compared with the antrum and corpus. METHODS: From 135 H. pylori-infected patients with gastritis, ulcer disease, or reflux esophagitis, biopsies were obtained from the antrum, corpus, and cardia. The prevalence, topography, and histologic parameters of gastritis were examined. RESULTS: All 135 patients had active antral H. pylori gastritis: in the cardia, 132 of these patients (97.7%) showed active gastritis, and 124 patients (91.9%) had H. pylori visible on staining. Gastritis of the cardia in most patients resembled antral gastritis, but the density of bacteria and the inflammatory responses were less marked. The most striking finding in the cardia of patients with gastroesophageal reflux was a lower density of bacteria compared with antrum and corpus. Intestinal metaplasia was found in 32 patients in antral mucosa (23.7%) versus 28 patients in the cardia (20.7%), versus 11 patients in the corpus (8.1%), and was multifocal in 17 patients (12.6%). CONCLUSIONS: H. pylori gastritis commonly involves the cardia. The histologic density of the bacteria and inflammatory responses are lower than in the antrum. Intestinal metaplasia in the cardia is a common finding in H. pylori gastritis. The cause of the lower bacterial density in the cardia of patients with reflux esophagitis needs further investigation.     

Helicobacter pylori infection and chronic gastric acid hyposecretion

PURPOSE: To evaluate the effects of preirradiation chemotherapy on patterns of failure in children with medulloblastoma. METHODS AND MATERIALS: Fifty-three patients (pts) with medulloblastoma were given preirradiation chemotherapy as initial postoperative treatment at St. Jude Children's Research Hospital from November 1984 to September 1993. Patients < or = 3 years of age (n = 23) received chemotherapy (CH) with delayed craniospinal irradiation (CSI). Children > or = 3 years with more advanced disease (T3b-T4, M+ or measurable residual after resection) were given CH followed by CSI (30 patients). Chemotherapy regimen depended on protocol, but usually included cis- or carboplatin and etoposide, +/- cyclophosphamide and vincristine. RESULTS: Actuarial overall survival and event-free survival rates are 60% (95% confidence interval [41,79]) and 37% [19,55] at 5 years. Children < or = 3 at diagnosis: six of 23 pts completed CH without progression and received consolidative CSI; all six are alive with no evidence of disease (NED) at 2.4-9.1 years. Seventeen patients progressed during CH and were then given CSI. Sites of progression during CH were posterior fossa (PF) in 11 patients, neuraxis (NEUR) in 4, and PF+NEUR in 2. Following CSI, 7 patients are alive NED at 2.0-8.6 years; 10 patients died of progressive disease. Eleven patients had M0 disease at diagnosis; 8 (73%) progressed during CH, 3 in the neuraxis. Children > or = 3 at diagnosis: 20 of 30 patients completed pre-CSI CH without progression; 15 are alive NED at 1.3-9.2 years, and 5 showed post-CSI progression in the PF (n = 3), in the NEUR (n = 1) and in bone marrow (n = 1). Ten of the 30 (33%) patients progressed on CH (6 in NEUR, 4 in PF); 5 are alive and NED or with stable disease. Seventeen patients had M0 disease at diagnosis; 3 out of 17 (18%) progressed during CH, 2 in NEUR and 1 in an extraneural site. In the total group of 30 patients, 11 have had disease recurrence after completion of XRT. The actuarial rate of failure was 23 +/- 9% for the patients < or = 3 years of age and 21 +/- 8% for the older children when evaluated at 4 months after diagnosis (at the completion of chemotherapy in the older children but during the ongoing chemotherapy in the younger children). CONCLUSIONS: In patients presenting with M0 disease and receiving pre-CSI chemotherapy, the risk of neuraxis progression seems to increase with duration of chemotherapy. The sites of progression during preirradiation chemotherapy are nearly equally divided between posterior fossa and other neuraxis sites. CSI salvage of patients progressing on chemotherapy is possible in approximately 50% of patients. Following CSI, neuraxis progression is more frequent than posterior fossa relapse.     

Evaluation of CD23 expression in paraffin-embedded gastric lymphomas of mucosa-associated lymphoid tissue

The CD23 antigen is expressed in a normal subset of B lymphocytes and in some non-Hodgkin's lymphomas. Reactivity for anti-CD23 (BU38) is present in paraffin-embedded tissue in the large majority of nodal small lymphocytic lymphomas, as well as in follicular center cell lymphomas. Most studies of gastric lymphomas of mucosa-associated lymphoid tissue (MALT) reported a lack of CD23, but these studies were performed on frozen tissue. We evaluated CD23 staining in paraffin-embedded tissue in a large series of gastric MALT lymphomas, as well as in cases of chronic gastritis. We assayed 49 well-characterized gastric lymphomas (9 high-grade non-MALT and 40 MALT [20 low grade, 13 mixed low and high grade, and 7 high grade]). High-grade MALT lymphomas without a low-grade component were distinguished from high-grade non-MALT lymphomas by the presence of lymphoepithelial lesions composed of large cells. In addition, we studies nine cases of chronic gastritis containing B-cell aggregates. We used anti-CD23 (BU38) in formalin-fixed, paraffin-embedded tissue. All of our low-grade gastric MALT lymphomas lacked CD23 immunoreactivity. One of the 13 mixed low-grade and high-grade lesions showed CD23 expression in the high-grade component. All of the high-grade MALT and high-grade non-MALT lesions lacked CD23. All of the nine cases of chronic gastritis lacked CD23. CD23 highlighted residual follicular dendritic cells and gastric epithelium. We concluded that gastric MALT lymphomas lacked CD23 (BU38) in paraffin-embedded tissue, with rare exceptions. This lack of CD23 expression might represent a useful feature in small or partially crushed biopsy specimens, particularly in the differential diagnosis with follicular small cleaved cell lymphoma presenting in the gastrointestinal tract.     

Is the polymerase chain reaction or cure of Helicobacter pylori infection of help in the differential diagnosis of early gastric mucosa-associated lymphatic tissue lymphoma?

PURPOSE: The differential diagnosis of early gastric mucosa-associated lymphatic tissue (MALT) lymphoma based on Helicobacter pylori gastritis may be difficult when lymphoepithelial lesions are not detected. The aim of the present study was to investigate the question whether the polymerase chain reaction (PCR) or cure of H pylori infection may be of help in this respect. PATIENTS AND METHODS: Twenty patients with suspected low-grade gastric MALT lymphomas were treated in a double-blinded, randomized, crossover trial with 2,250 mg of either amoxicillin or placebo, both in combination with omeprazole, for 14 days with the aim to cure H pylori infection. PCR was performed using primers specific for the CDR3 region to detect monoclonal B cells. RESULTS: In five of 20 patients, MALT lymphomas were finally diagnosed. Three of these five patients went into complete remission, while two were referred to surgery. In the 15 patients with gastritis, complete regression was observed in all cases. With respect to PCR, monoclonal bands were detected in all four of the analyzed lymphoma patients before histology showed lymphoma. In addition, monoclonal bands were found in three patients with gastritis. In the patients with gastritis and monoclonal PCR, complete regression took longer as compared with the remaining 12 patients with polyclonal PCR and gastritis (P = .0209). Successful H pylori eradication was associated with earlier diagnosis of the MALT lymphoma (P = .0237). CONCLUSION: CDR3-PCR may be of help in the differential diagnosis of early gastric MALT lymphoma. Furthermore, H pylori eradication may lead to earlier diagnosis.     

Relationship between Helicobacter pylori infection, histological gastritis, and functional dyspepsia

BACKGROUND/AIMS: It is still controversial as to whether or not Helicobacter pylori (H. pylori) infection, histological gastritis, and functional dyspepsia (FD) are intercorrelated. We prospectively evaluated patients with functional dyspepsia in an attempt to clarify this issue. METHODOLOGY: Eighty-eight consecutive patients with functional dyspepsia (age range: 18-84 years) who did not show disease(s) other than gastritis were investigated. In a questionnaire they were asked to report the presence or absence of 8 upper gastrointestinal (GI) symptoms and to score them from 0 (absence) to 3 (severe), whereupon a sum score was calculated. Forty age-matched subjects with a sum score of <3 served as controls. Biopsy specimens for histology, bacterial culture, and rapid urease test were taken. A C13-urease breath test was also performed in 122 subjects. RESULTS: H. pylori infection was present in 43% of patients with functional dyspepsia and 35% of control subjects (not significant (n.s.)). None of the symptoms were correlated with H. pylori infection. The median symptom sum score was 8.5 in H. pylori-positive and 9.5 in H. pylori-negative patients with functional dyspepsia (n.s.). Histological gastritis was strongly associated with H. pylori infection but was not correlated with any of the symptoms. CONCLUSIONS: In a prospective population of patients with functional dyspepsia, H. pylori infection or gastritis are not associated with specific or severe symptoms. Our data imply that H. pylori gastritis is not an important condition in the pathogenesis of dyspeptic complaints.     

Gastric mucosal biopsy via a nasogastric tube: a nonendoscopic method for diagnosing fundic and antral mucosal gastritis and Helicobacter pylori infection in man

Synthesis of poly(gamma-glutamate) metabolites of natural folates and antifolates is a critical process. Folypolyglutamates are essential for cell proliferation. Polyglutamates of glutamate (Glu)-containing antifolates are often critical for their cytotoxic action and are relevant to antifolate resistance. However, the role of polyglutamate synthesis in selectivity is less clear. We have undertaken a research program to further define the significance of polyglutamate metabolism and to devise ways to exploit this metabolism to achieve greater therapeutic selectivity in cancer chemotherapy. This article briefly reviews several approaches tested thus far. Inhibition of folypolyglutamate synthesis should lead to cell death. Current ornithine (Orn)-containing folate-based inhibitors of the enzyme responsible for their synthesis, folypolyglutamate synthetase (FPGS), are poorly transported, apparently because of interference by the protonated delta-amine. Replacement of Orn with 4, 4-difluoroOrn, the delta-amine of which has a much lower pKa and is thus less protonated at physiological pH, was explored. Since it is unclear how polyglutamylation contributes to selectivity, we explored generic means either to eliminate or to enhance polyglutamylation. The data indicate that substitution for Glu in an antifolate by some Glu analogs in which the gamma-COOH is either altered or replaced (e.g., gamma-tetrazole-Glu) leads to loss of both FPGS substrate activity and binding; antifolate target specificity is unchanged, while uptake is actually enhanced. Substitution of 3,3-difluoroGlu for Glu leads to enhanced polyglutamylation (although probably only to the diglutamate), retention of target specificity, and at least equal uptake. Comparative studies of the same antifolate containing different replacements for Glu, such as gamma-tetrazole-Glu (no polyglutamylation) or 3,3-difluoroGlu (enhanced polyglutamylation), will be useful in exploring the role and significance of polyglutamylation.     

Superoxide dismutase activity in Helicobacter pylori-positive antral gastritis in children

Reactive oxygen metabolites have been implicated in gastric mucosal injuries. Superoxide dismutase, a scavenger of superoxide radical, is a key enzyme in gastric mucosal protection against several damaging factors. This study was aimed at investigating the relationship of superoxide dismutase activity to Helicobacter pylori-induced antral gastritis in children. Two groups of 11 children each, one positive and the other negative for Helicobacter pylori, were studied. Biopsies from the antrum and corpus were obtained for evaluation of Helicobacter pylori by CLOtest and histology as well as for superoxide dismutase activity (cytochrome c method). Erythrocytic and serum superoxide dismutase levels were determined as well. Superoxide dismutase activity was significantly higher only in the antrum of children with Helicobacter pylori-induced antral gastritis. There was no significant difference in superoxide dismutase activity in the corpus, erythrocytes, or serum of both groups. These findings may suggest a pathogenic relationship between the presence of Helicobacter pylori and oxygen radicals in inducing antral mucosal injury.     

The morphological diagnosis of Helicobacter pylori in the gastric mucosa in chronic gastritis]

JC virus (JCV), a human polyomavirus, is the agent of the demyelinating disease progressive multifocal leukoencephalopathy (PML). JCV exists in four main genotypes in the USA. Type 1, including subtypes Type 1A and Type 1B, makes up about 64% of strains in the USA and is thought to be of European origin. Type 2 is found in Asia, and Type 3 in Africa. A fourth type is found only in the USA. In general, these genotypes differ in 1-2.5% of their DNA sequence. Thirty MS patients and 30 paired controls from Budapest were studied. The clinical course of MS was mainly secondary progressive, and patients were stable at the time of testing. Most of the controls were relatives of the probands: a spouse, parent, or child. Overall, 25 of 60 (42%) of the urines tested positive for JCV by PCR. These included 13 of 30 MS patients, and 12 of 30 controls. Genotyping in the VPI gene showed all 25 JCV strains to be Type 1. Among the MS patients, seven were Type 1A and six were Type 1B. Among the controls, nine were Type 1A and three were Type 1B. In five pairs of MS patients and controls, both were positive for JCV by PCR. Two of these were husband/wife pairs of which one pair was matched for subtype (both Type 1A), and the other was not. Two of them were mother/daughter pairs, and both were matched for subtype (both Type 1B). These findings demonstrate that JCV Type 1 predominates among Hungarians, and suggest that parent/child pairs can be used to trace JCV transmission within the MS family.     

Changes in gastric mucosa and Helicobacter pylori infection in young health volunteers

The effect of microinjection of a GABAB receptor agonist, baclofen, into the ventral tegmental area on the rewarding effect of morphine was investigated using the conditioned place preference paradigm in rats. Morphine (1-8 mg/kg, s.c.) caused a dose-related place preference for the drug-associated place. In contrast, microinjection of baclofen (0.1-1 nmol/side) into the ventral tegmental area did not produce a significant preference for either compartment of the test box. Pretreatment with baclofen (0.1-1 nmol/side) into the ventral tegmental area dose dependently suppressed the morphine (8 mg/kg, s.c)-induced place preference. This suppression of the morphine (8 mg/kg, s.c.)-induced place preference by baclofen (1 nmol/side), but not with the GABAA receptor antagonist bicuculline (1 nmol/side). The present results suggest that a decrease in GABAB neurotransmission in the ventral tegmental area, which may be produced via inhibition of a tonic GABAergic input by morphine, may be involved in the expression of the rewarding effect of morphine.     

Helicobacter pylori and gastric malignancies

Osteolytic lesions of the skull are an unusual complication in patients with AIDS. We report a case of multiple cranial abscesses as the major manifestation of a disseminated infection due to Mycobacterium kansasii in a patient with AIDS.