Normal-appearing Gastric Mucosa Research Articles

S2451 Acute Esophageal Necrosis: A Rarely Encountered Clinical Entity

Introduction: Acute Esophageal Necrosis (AEN), otherwise known as black esophagus for its remarkable appearance during endoscopy, is a rather rare entity in the gastroenterology field. Case Description/Methods: A 51-year-old male with a past medical history of diabetes complicated by peripheral neuropathy presented to the hospital with left lower extremity swelling and pain after a fall. On admission he underwent lower extremity x-ray with subcutaneous air concerning for necrotizing fasciitis. He was taken emergently to the operating room where he underwent 3 compartment exploration with irrigation and drain placement. On day 7 of hospitalization he developed persistent nausea and vomiting for which we were consulted. The following morning he was taken to the endoscopy suite. He was noted to have circumferential black appearance of the esophagus from 28 to 40 cm with abrupt transition to normal-appearing gastric mucosa at the GE junction. This was endoscopically consistent with acute esophageal necrosis He was placed on high-dose intravenous proton pump inhibitor (PPI) therapy as well as sucralfate suspension. Transfer was facilitated to a tertiary care center where repeat endoscopy confirmed the diagnosis. He had a gastrostomy tube placed and ultimately underwent repeat endoscopy 8 weeks later at the same tertiary care center which revealed severe benign appearing esophageal stricturing with inability to pass adult endoscope. It was recommended to continue on PPI therapy with repeat endoscopic evaluation with possible dilation the following month. Unfortunately, in the meantime the patient expired due to unknown causes (Figure). Discussion: AEN is defined by a circumferential, necrotic appearance that almost always affects the distal esophagus with abrupt cessation of the black contour at the GE junction. Incidence is 0.28%, affects men over 4 times more often than women with a mortality near 32%. AEN is usually multifactorial and affects people with many comorbidities. Presenting symptoms varied greatly, with the most prevalent being hematemesis (34%). Injury is related to esophageal ischemia and topical injury. AEN is almost always diagnosed by endoscopy. Biopsy can rule out other similarly appearing pathologies. Management of AEN typically involves treating the underlying cause. Empirical treatment includes IV fluids, PPI, sucralfate, NPO, and TPN in patients with poor nutritional status after 24 hours.Figure 1.: Multiple images showing diffuse esophageal necrosis with abrupt transition to normal mucosa at the GE junction.

Validity of serum amyloid A and HMGB1 as biomarkers for early diagnosis of gastric cancer.

Background and aimGastric carcinomais a frequent neoplasm with poor outcome, and its early detection would improve prognosis. This study was designed to evaluate the possible use of new biomarkers, namely SAA and HMGB1, for early diagnosis of gastric cancer.MethodsA total of 100 patients presenting with gastric symptoms were included. All patients underwent upper endoscopic evaluation, histopathological diagnosis and serum CEA, SAA, and HMGB1 measurements.ResultsPatients were classed endoscopically with neoplastic, inflammatory, and normal-appearing gastric mucosa: 50, 25, and 25 patients, respectively. Histologically, half the patients had chronic gastritis and the remaining cases gastric carcinoma of diffuse (n=28) or intestinal (n=22) type. SAA at cutoff of 18.5 mg/L had the best validity to differentiate gastritis from gastric carcinoma, with AUC, sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) of 0.99, 98%, 100%, 100%, and 98%, respectively, followed by HMGB1 at cutoff of 14.5 pg/μL, with AUC, sensitivity, specificity, PPV, and NPV of 0.91, 70%, 96%, 94.6%, and 76.2%, respectively. Sensitivity, specificity, PPV, and NPV of serum CEA at cutoff of 2.9 ng/mL to differentiate gastritis from gastric carcinoma were 42%, 72%, 60%, and 55.4%, respectively, with AUC of 0.53. Nonetheless, higher serum levels of both SAA and HMGB1 reflected higher tumor grade (P=0.027 and P=0.016, respectively) and advanced tumor stage (P-OBrk-0.001 for both).ConclusionSerum levels of both SAA and HMGB1 could be of great value for early diagnosis of gastric carcinoma, comparable to the diagnostic role of serum CEA, which is not valid for early diagnosis of gastric cancer.

Prevalence and risk factors for fundic gland polyps

The incidence of fundic gland polyps (FGPs) is increasing rapidly and has surpassed hyperplastic polyps to become the most common epithelial gastric polyps in Western countries and China.1, 2 They are usually multiple, small (1-5 mm), transparent, and sessile; the background gastric mucosa is typically normal.3 FGPs are more prevalent among females and are often located in the gastric fundus and body. There are two types of FGPs: sporadic and syndromic (in association with familial adenomatosis polyposis). Although different in their genetic and molecular backgrounds, sporadic and syndromic FGPs are histologically and histochemically indistinguishable. Syndromic FGPs occur in the presence of inherited germline mutation in the adenomatous polyposis coli (APC) gene plus the acquisition of a somatic mutation, leading to complete inactivation of the APC tumor suppressor gene.4 Familial adenomatosis polyposis should be excluded by colonoscopy if FGPs are numerous, large (>1 cm), or dysplasic.3 For sporadic FGPs, up to 23% are associated with proton pump inhibitor (PPI) use.5, 6 A recent review with meta-analysis indicated that long-term use of PPIs (≥12 months) increased the risk of FGPs (pooled odds ratio [confidence interval]: 3.81 [2.78-5.24] for the fixed effects model and 2.88 [0.97-8.55] for the random effects model).7 The risk was even higher if the exposure duration was more than 48 months (pooled odds ratio: 4.02). There is no or inverse association with Helicobacter pylori infection.1, 3 FGPs rarely harbor dysplastic lesions. A study in the USA of 35 372 FGPs found that only 0.3% had low-grade dysplasia.5 Moreover, even syndromic FGPs rarely progress to cancer.8 Once epithelial gastric polyps are found at initial endoscopy, it is important to sample polyps and/or normal-appearing gastric mucosa to establish histological diagnosis and to define who needs surveillance. Biopsies from the background antrum and corpus mucosa could rule out atrophic gastritis, intestinal metaplasia, dysplasia, and H. pylori infection. All these information is important for the management of other epithelial gastric polyps, including hyperplastic polyp, adenoma, and type 1 or 2 gastric neuroendocrine tumors.3 Once sporadic FGPs are diagnosed, routine endoscopic surveillance is not recommended in the absence of dysplasia. There is still no consensus on the indication of endoscopy resection of sporadic FGPs. However, many experts suggest the removal of FGPs larger than 10 mm.3 Few studies have considered risk factors other than age, gender, PPIs, and H. pylori infection for sporadic FGPs. A recent one-center, endoscopy-based retrospective study in Taiwan indicated the incidence of FGPs increased from 0.6% in 2010 to 1.3% in 2015.9 The controls were age- and gender-matched subjects who received upper endoscopy during the similar period with the cases. The authors found the presence of liver cirrhosis, gastric ulcer, duodenal ulcer (adjusted odds ratio: 0.18, 0.28, and 0.35, respectively, all P < 0.001), but not reflux esophagitis, were inversely associated with FGP risk. FGPs are commonly seen in patients with relatively healthy gastric mucosa. This is an interesting finding that implies causative factors to gastric mucosa, including cirrhosis and peptic ulcers, which could reduce the formation of FGPs, probably through the facilitation of glandular outflow. However, more than 30% of H. pylori status was missing, and the information of PPI exposure was less than adequate in this study. Future studies are necessary to support this finding and the proposed mechanism behind it. The author declares no conflict of interest.

Ectopic Tissue in the Stomach Wall Harbors Stunning Diagnosis

Question: A 48-year-old patient was referred for gastroscopy and colonoscopy because of anemia. Personal history was otherwise unremarkable except for Wolf-Parkinson-White syndrome. Gastroscopy showed a submucosal 2 4-cm tumor in the antrum with a central retraction (Figure A, endoscopic finding). On endosonography and MRI, a submucosal tumor was evident, confined to the antral wall, without invasion of the muscularis propria. We performed an endoscopic submucosal dissection (Olympus GIF – H 180). Tumor margins were marked with argon plasma coagulation. For submucosal injection, we used adrenaline (Bichsel, Interlaken, Switzerland), methylene blue (Hanseler, Herisau, Switzerland), and physiogel (gelatine, B. Braun, Melsungen, Germany). In toto resection of the 2 4-cm tumor (Figure B, resection procedure) was done both with dual knife (Olympus, Volketswil, Switzerland) and hook knife (Olympus, Volketswil, Switzerland). Surveillance and 4-day hospitalization were uneventful. Anemia and iron deficiency resolved completely within few days postoperatively after initial iron replacement therapy. Gross pathologic examination showed a well-circumscribed firm submucosal tumor (maximum. 2.5 cm) with a greyish-white cut surface, covered by a normal-appearing gastric mucosa. The histology surprisingly revealed an ectopic lymph node, located in the submucosa, with infiltration of an atypical lymphoid cell population (Figure C, overview). The overlying mucosa was normal, without signs of acute or chronic gastritis. What is the diagnosis? See the Gastroenterology web site (www.gastrojournal.org) for more information on submitting your favorite image to Clinical Challenges and Images in GI.

In vivo assessment of a biological occluder for NOTES gastrotomy closure.

The objective of this study is to evaluate the closure of a transgastric natural orifice transluminal endoscopic surgery (NOTES) access using a multilayer extracellular matrix (ECM) occluder in a canine model. Mongrel dogs (n = 4) underwent a transgastric NOTES peritoneoscopy and the gastrotomy was closed by deploying a 2-sided ECM occluder. Animals were killed at 7 days (n = 2) and 8 weeks (n = 2) for macroscopic and microscopic assessment. All procedures were completed without any complications. No air leaks were detected immediately after the procedure and at 48 hours postoperatively. At 7 days, ECM appeared to be resolved and mild mucosal inflammation was found at the site of gastrotomy. At 8 weeks, the gastrotomy site was macroscopically and microscopically covered with a normal-appearing gastric mucosa. There was an absence of inflammatory cells and no evidence of the ECM. The ECM occluder is safe and effective in this "proof-of-concept" preclinical model.

ENDOSCOPIC IDENTIFICATION OF HELICOBACTER PYLORI GASTRITIS IN CHILDREN

The role of endoscopic findings in deciding whether to biopsy the gastric mucosa of children remains unclear. The present study attempted, for the first time, to identify the value of endoscopic features for diagnosis of Helicobacter pylori (Hp) infection in children. Hp status of consecutive children receiving esophagogastroduodenoscopy (EGD) was established by combinations of histology, (13)C-urea breath test, and serum Hp immunoglobulin (Ig)G antibody. After routine EGD using a conventional endoscope, the presence of RAC (regular arrangement of collecting venules) was scored by close observation, which was carried out at two sites of lower corpus lesser curvature and upper corpus greater curvature. RAC-positive was defined as the presence of minute red points in a regular pattern. Antral nodularity was also scored as present/absent. Eighty-seven consecutive children (38 boys, median age 13 years, range 9-15 years) were evaluated; 25 (29%) were Hp positive. Antral nodularity was seen in 21 (84%) all of whom were Hp positive. The RAC-negative pattern based on examination of the upper and lower corpus yielded a sensitivity, specificity, positive predictive value and negative predictive value for the presence of Hp infection of 100%, 90%, 81%, and 100%. Magnifying endoscopy confirmed that the RAC pattern corresponded to collecting venules in the gastric corpus. The absence of RAC pattern suggests that gastric mucosa biopsies should be taken despite otherwise normal-appearing gastric mucosa for the diagnosis of Hp infection in children.

A Phase II Trial of Darinaparsin in Advanced Lymphomas: Report on Safety and Activity.

Darinaparsin (ZIO-101) is a novel organic arsenic molecule that has a mechanism of action mediated by targeted disruption of mitochondrial function, modified signal transduction, and antiangiogenesis. It is active against diverse cancers in vitro. This Phase II multi-center trial is being conducted in patients diagnosed with advanced lymphomas that have received at least 1 prior therapy and require additional treatment. Patients receive 300 mg/m2 of darinaparsin intravenously for 5 consecutive days every 28 days (1 cycle) and are then evaluated for efficacy and safety by standard criteria. Treatment continues until toxicity or progression. To date the study has accrued 22 patients (15 non-Hodgkin's [NHL], 7 Hodgkin's); 12 are male and 10 are female. Median age at baseline was 60.5 years (range: 28–80), ECOG performance status was ≤2, and median number of prior therapies was 4 (range 2–6). Thirteen subjects have received at least 2 cycles of darinaparsin and are evaluable for efficacy. Of these, 1 (diagnosed with PTCL) has achieved a complete response (CR) and 3 (diagnosed with marginal zone transformed to diffuse large B-cell, marginal zone, and Hodgkin's nodular sclerosis, respectively) have achieved partial responses (PRs). These patients had been heavily pretreated (PTCL: CHOP, ICE, and EPOCH; marginal zone transformed to diffuse B-cell: RCHOP, RICE, RT and autologous bone marrow transplantation; marginal zone: rituximab, RCVP, and gemcitabine; and Hodgkin's: ICE, CBV, gemcitabine+ MDX-060, and stem cell transplant). In the patient with transformed diffuse large B-cell lymphoma who achieved PR, no evidence for macroscopic disease was present, but microscopic low-grade marginal zone lymphoma was detectable in random biopsies from normal-appearing gastric mucosa. In addition, 2 patients (diagnosed with PTCL and Hodgkin's, respectively) have achieved stable disease (SD). The only Grade 3 adverse event (AE) considered drug-related was wheezing. A total of 12 subjects have reported 37 serious adverse events (SAEs) while on study. Of these, only 2 had SAEs that were considered drug-related (neutropenic fever, fall). In conclusion, darinaparsin has been very well tolerated and has demonstrated promising activity in heavily pretreated patients diagnosed with advanced lymphoma. Initial responses (1 CR, 3 PRs, 2 SDs) have been observed among 13 evaluable patients. Accrual continues; additional safety and efficacy data will be reported.

Effects of short-term light to heavy exercise on gastric ulcer development in horses and efficacy of omeprazole paste in preventing gastric ulceration

To determine the effects of 8 days of light to heavy exercise on gastric ulcer development in horses and determine the efficacy of omeprazole paste in preventing gastric ulceration. Randomized, controlled, multicenter clinical trial. 102 horses with normal-appearing gastric mucosa on endoscopic examination that were in light to heavy training. Horses at 4 trial locations were allocated into replicates and sham dosed orally (empty syringe) or treated with a paste formulation of omeprazole (1 mg/kg [0.45 mg/ lb], PO) once daily for 8 days. Training regimens varied among locations and included early training for western performance events; walking, trotting, and cantering in a mechanical exerciser; and race training (2 locations). Prevalences of gastric ulceration at the completion of the 8-day treatment period were compared between groups. At the end of the 8-day treatment period, the proportion of omeprazole-treated horses free from gastric ulceration (88%) was significantly higher than the proportion of sham-dosed horses free from gastric ulceration (27%). Results showed that horses in light to heavy training for as short as 8 days were at risk of developing gastric ulcers and that administration of omeprazole paste decreased the incidence of gastric ulcers.

The epigenetic silencing of LIMS2 in gastric cancer and its inhibitory effect on cell migration

Recent finding has shown that LIMS2 (also known as PINCH2) functions as a natural regulator of the LIMS1– ILK–parvin complex formation and is associated with cell spreading and migration via integrins at focal adhesions. Here, we report for the first time the epigenetic silencing of LIMS2 in gastric tumors. Downregulation of LIMS2 was detected in 91% (10 of 11) of gastric cancer cell lines by real-time quantitative RT-PCR and 80% (8 of 10) of the LIMS2-downregulated cell lines were associated with CpG island hypermethylation at a 5′-upstream region of LIMS2. Furthermore, LIMS2 was restored in its non-expressing cell lines after treatment with 5-Aza-dC and/or trichostatin A. Loss of expression of LIMS2 was also detected in 53% (51 of 96) of primary gastric tumors. This decrease in expression level significantly correlated with an increase of the CpG island hypermethylation. In addition, the methylation status in any normal-appearing gastric tissues was gradually increased in an age-dependent manner, suggesting that the positive methylation in normal-appearing gastric mucosa can be due to ‘field cancerization effect’ as an early event in gastric carcinogenesis. Moreover, the transient transfection of LIMS2-siRNA significantly stimulated cell migration in gastric cancer cells but had no effects on cell growth. These results suggest that the frequent inactivation of LIMS2 by epigenetic alteration in gastric cancer may be important in tumor progression events, such as invasion and metastasis. Thus, LIMS2 may be useful as a molecular biomarker and a therapeutic target by increasing its expression and activity in gastric cancer.

Monoallelic methylation of the APC promoter is altered in normal gastric mucosa associated with neoplastic lesions.

Adenomatous polyposis coli (APC) promoter hypermethylation has been reported frequently in normal gastric mucosa, but it remained to be clarified whether this occurs in every individual. In this study, methylation of the APC promoter was analyzed in histologically normal-appearing gastric mucosa samples by methylation-sensitive single-strand conformation analysis and by a methylation-sensitive dot blot assay. Epithelial cell samples were collected by microdissection from tissue sections. Equal amounts of methylated and unmethylated APC alleles were found in all gastric mucosa samples from patients without any gastric lesions (20 samples). Allele-specific methylation analysis showed that the methylation of the APC promoter was monoallelic; however, which allele was methylated depended on the cell type. Increased or decreased methylation was found in 10 of 36 (28%) normal gastric mucosa samples adjacent to a gastric or esophageal adenocarcinoma. No allelic loss was found at the APC locus. Modification of the methylation status was also found in 3 of 21 (14%) normal-appearing gastric mucosa samples adjacent to intestinal metaplasia. In contrast, all normal mucosa samples in cases with chronic gastritis but without metaplasia or dysplasia showed a monoallelic methylation pattern. Our results indicate the following: (a) In normal gastric mucosa, the APC promoter shows monoallelic methylation, which is not due to imprinting but most likely due to allelic exclusion; (b) the excluded allele differs between foveolar and glandular epithelial cells; (c) the APC methylation pattern is frequently altered in normal-appearing gastric mucosa of gastric or esophageal adenocarcinoma patients; and (d) such alterations also occur in normal gastric mucosa adjacent to intestinal metaplasia.

Discrimination of normal gastric mucosa from Helicobacter pylori gastritis using standard endoscopes and a single observation site: studies in children and young adults.

In the Helicobacter pylori-negative normal stomach, collecting venules are visible in the gastric corpus as numerous minute points. This finding has been termed 'regular arrangement of collecting venules' (RAC). The aim of the present study was to investigate the reliability of the presence of the RAC pattern for discrimination of normal gastric mucosa from H. pylori gastritis in pediatric patients. Fifty-two consecutive children, adolescents and young adults (male:female 24 : 28; median age 15 years, range 8-29 years) referred for endoscopy and assessed for H. pylori infection were prospectively studied. The lower lesser curvature of the corpus near the incisura was evaluated for the RAC pattern using a standard endoscope with the tip close to, but not in contact with, the gastric surface. Gastric biopsies were taken after the endoscopic observation. In all the 29 RAC-positive patients, active H. pylori gastritis was absent, whereas H. pylori gastritis was found in 20 of 23 RAC-negative patients (86.9%). Identification of the RAC pattern at the lower lesser curvature of the corpus using close observation with a standard endoscope proved to be an effective and practical marker to discriminate normal histology from H. pylori gastritis among both children and young adults. Absence of the RAC pattern should prompt gastric mucosal biopsies despite otherwise normal-appearing gastric mucosa.

Gastric intestinal metaplasia on routine endoscopic biopsy

A 50-year-old male recently had an endoscopy by another physician for the indication of dyspepsia. The endoscopy demonstrated no abnormality but biopsy of normal-appearing gastric mucosa demonstrated intestinal metaplasia and infection with H. pylori. The patient comes to you for advice regarding management of gastric intestinal metaplasia.

The effect of a pectin-lecithin complex on prevention of gastric mucosal lesions induced by feed deprivation in ponies.

This study examined whether a product containing a pectinlecithin complex (Pronutrin) (1) could prevent gastric lesions induced in the equine gastric squamous epithelial mucosa using a protocol of intermittent feed deprivation that resulted in prolonged increased gastric acidity (Murray and Eichorn 1996). Eight ponies were used and served as their own controls in 2 trials in which there were 72 h cumulative deprivation (alternating 24 h with no feed, then 24 h free choice hay), with a 4-week interval between trials. Ponies were assigned randomly to receive either 250 g Pronutrin plus 200 g pelleted feed, or 450 g pelleted feed only. Ponies were conditioned to each treatment for 7 days and received Pronutrin and pellets or only pellets once daily during the feed deprivation protocol. Gastroscopy was performed at the beginning and conclusion of the feed deprivation protocol. The endoscopist (MJ.M.) was blinded as to treatments, and lesion severity was scored on a scale of 0-5. Gastroscopy revealed normal-appearing gastric mucosa at the beginning of feed deprivation, with the exception of 2 ponies which had focal squamous mucosal erosion and 1 pony with focal glandular mucosal erosion. After 72 h cumulative feed deprivation, each pony, except 1 pony in one of the trials, developed erosions or ulcers in the gastric squamous mucosa. There was no difference (P = 0.6) in the presence or severity of gastric lesions between treatments. Lesions did not develop in the gastric glandular mucosa as a result of the intermittent feed deprivation with either treatment. In this study, the pectin-lecithin complex in Pronutrin failed to prevent lesions in the gastric squamous mucosa induced by intermittent feed deprivation.

NSAID gastric ulceration: predictive value of gastric pH, mucosal density of polymorphonuclear leukocytes, or levels of IL-8 or nitrite.

NSAID use and Helicobacter pylori both cause damage to the gastric mucosa and can cause peptic ulcers. Our aim was to test the relationship between gastric mucosal polymorphonuclear leukocyte (PMN) infiltration and the severity of NSAID-induced gastric injury. H. pylori density, mucosal interleukin-8 (IL-8), and nitrite levels were assessed after receiving placebo and again after receiving 1000 mg of naproxen daily for three days. Histology was graded using a visual analog scale (0-5). IL-8 levels were assayed by ELISA and nitrite levels by Griess reaction. Eleven healthy volunteers with H. pylori infection entered. All had normal-appearing gastric mucosa after placebo. Postnaproxen gastric damage included three with none, one with mild, three with moderate, two with severe, and three were very severe mucosal injury (including one with an ulcer >5 mm). There was an inverse correlation between endoscopic score and the pH of the gastric juice post-therapy (R = -0.77, P = 0.004). There was no significant change in histologic or biochemical parameters from pretreatment levels. And none of the parameters (eg, PMN density) predicted endoscopic outcome. In conclusion, there was no relation between mucosal PMN density and endoscopic mucosa injury. PMN infiltration, while not predictive, may be a surrogate for an H. pylori infection-related increased risk of NSAID ulcers.

Effects of azoxymethane on X-ray induced intestinal metaplasia in Donryu rats.

The present study was undertaken to determine the effect of azoxymethane (AOM) administration on intestinal metaplasia induced by X-irradiation in male Donryu rats. Five-week-old animals were X-irradiated with two doses of 10 Gy each at a 3-day interval or three X-ray doses of 10 Gy at a 2-day interval and then received AOM injections i.m. at a dose of 15 mg/kg body weight once weekly for 3 weeks, 6 months after irradiation. Alkaline phosphatase positive foci were decreased after AOM treatments, but aberrant crypt like-foci appeared within areas of intestinal metaplasia. In contrast no induction was observed in normal-appearing gastric mucosa.