Helicobacter pylori‐negative gastric cancer: Characteristics and endoscopic findings

Helicobacter pylori (H. pylori) leads to chronic gastritis and eventually causes gastric cancer. The prevalence of H. pylori infection is gradually decreasing with improvement of living conditions and eradication therapy. However, some reports have described cases of H. pylori‐negative gastric cancers (HpNGC), and the prevalence was 0.42–5.4% of all gastric cancers. Diagnostic criteria of HpNGC vary among the different reports; thus, they have not yet been definitively established. We recommend negative findings in two or more methods that include endoscopic or pathological findings or serum pepsinogen test, and negative urease breath test or serum immunoglobulin G test and no eradication history the minimum criteria for diagnosis of HpNGC. The etiology of gastric cancers, excluding H. pylori infection, is known to be associated with several factors including lifestyle, viral infection, autoimmune disorder and germline mutations, but the main causal factor of HpNGC is still unclear. Regarding the characteristics of HpNGC, the undifferentiated type (UD‐type) is more frequent than the differentiated type (D‐type). The UD‐type is mainly signet ring‐cell carcinoma that presents as a discolored lesion in the lower or middle part of the stomach in relatively young patients. The gross type is flat or depressed. The D‐type is mainly gastric adenocarcinoma of the fundic gland type that presents as a submucosal tumor‐like or flat or depressed lesion in the middle and upper part of the stomach in relatively older patients. Early detection of HpNGC enables minimally invasive treatment which preserves the patient's quality of life. Endoscopists should fully understand the characteristics and endoscopic findings of HpNGC.     

Pathological development of the gastric mucosa in Helicobacter pylori‐related diseases

OBJECTIVE : To study the relationship between Helicobacter pylori eradication and the pathological development of the gastric mucosa in H. pylori‐related diseases. METHODS : One hundred and ninety‐one H. pylori‐infected patients were randomly given anti‐H. pylori or non‐anti‐H. pylori medications. Endoscopic examination was carried out 1 year after treatment. Pathological classifications followed the Sydney System. RESULTS : Of the 191 patients, those with chronic inflammation of the gastric mucosa improved (P < 0.05), as did those with atrophy and intestinal metaplasia (P < 0.05). Helicobacter pylori was eradicated in 107 patients, but not in 84 patients. Compared with those patients in whom H. pylori was not eradicated, those with H. pylori eradicated had ameliorated chronic inflammation of the gastric mucosa (P < 0.05) and active inflammation reduced in some cases (P < 0.05). Notwithstanding a stratification of different gastric diseases and different treatments, patients with H. pylori eradicated showed a more marked improvement in mucosal chronic inflammation than did patients in whom H. pylori was not eradicated (P < 0.05). CONCLUSIONS : These results suggest that H. pylori infection is closely related to active inflammation of the gastric mucosa. Helicobacter pylori eradication is beneficial in improving chronic inflammation of the gastric mucosa.     

Diagnosis of Helicobacter pylori‐related chronic gastritis,gastric adenoma and early gastric cancer by magnifying endoscopy

Evaluating the prevalence and severity of gastritis by endoscopy is useful for estimating the risk of gastric cancer (GC). Moreover, understanding the endoscopic appearances of gastritis is important for diagnosing GC due to the fact that superficial mucosal lesions mimicing gastritis (gastritis‐like lesions) are quite difficult to be detected even with optimum preparation and the best technique, and in such cases tissue biopsy is often not very accurate for the diagnosis of gastric epithelial neoplasia. Magnifying endoscopy is a highly accurate technique for the detection of early gastric cancer (EGC). Recent reports have described that various novel endoscopic markers which, visualized by magnifying endoscopy with image‐enhanced system (ME‐IEE), can predict specific histopathological findings. Using ME‐IEE with vessels and surface classification system (VSCS) may represent an excellent diagnostic performance with high confidence and good reproducibility to the endoscopists if performed under consistent conditions, including observation under maximal magnification. The aim of this review was to discuss how to identify high‐risk groups for GC by endoscopy, and how to detect effectively signs of suspicious lesions by conventional white light imaging (C‐WLI) or chromoendoscopy (CE). Furthermore, to characterize suspicious lesions using ME‐IEE using the criteria and classification of EGC based upon VSCS.     

Complete response to multidisciplinary therapy in a patient with primary gastric choriocarcinoma

Primary gastric choriocarcinoma is a rapidly growing neoplasm with an average survival of several months in untreated patients.Gastrectomy with lymph node dissection followed by chemotherapy is the treatment of choice.Regimens used for gastric adenocarcinoma are usually selected.However,median survival remains less than six months.In this case report,we describe a case of primary gastric choriocarcinoma with a clinical complete response to multidisciplinary treatment including surgery,chemotherapy,and radiofrequency ablation(RFA).The patient was originally referred for general malaise.Esophagogastroduodenoscopy demonstrated a large tumor occupying the fornix,and total gastrectomy with lymph node dissection was performed.Seven days later,multiple liver metastatic recurrences with high serum levels of beta-human chorionic gonadotropin(β-hCG) were recognized.Chemotherapy with a gonadal choriocarcinoma regimen consisting of etoposide,methotrexate,actinomycin D,cyclophosphamide,and vincristine(EMA/CO),was initiated.After three cycles,serum β-hCG decreased markedly and the tumors disappeared.Six months later,multiple lung metastatic recurrences were found.After one cycle of EMA/CO,only one nodule remained.Computed tomography-guided RFA was performed for this oligometastatic tumor.The patient has been alive with no evidence of disease for 10 years after the initial diagnosis.To the best of our knowledge,this patient with recurrent primary gastric choriocarcinoma has achieved the longest survival.The present case is the first report of choriocarcinoma metastatic to the lung successfully treated with RFA.From our retrospective analysis of recurrent or unresectable primary gastric choriocarcinoma,we propose that gonadal choriocarcinoma regimens can be considered as first-line for primary gastric choriocarcinoma.     

Proteomic identification of biomarkers related to Helicobacter pylori‐associated gastroduodenal disease: Challenges and opportunities

Helicobacter pylori colonize the stomach of over half the world's population. While 80–90% H. pylori‐infected individuals have clinically asymptomatic gastritis, 10–15% develop peptic ulcer, and 1–2% gastric malignancies. These variable clinical outcomes have led to an interest in prognostic indicators. The current disease paradigm suggests that host genetics and bacterial virulence both play important roles in modulating the final outcome of H. pylori infection. Elucidation of the interaction between host and bacterium is essential to clarify pathogenesis and to develop new strategies for prevention and treatment. Proteomic technology is a powerful tool for simultaneously monitoring proteins and protein variation on a large scale in biological samples. It has provided an unprecedented opportunity to survey a cell's translational landscape comprehensively, and the results may allow in‐depth analyses of host and pathogen interactions. Using this high‐throughput platform and taking advantage of complete sequences for both the H. pylori and the human genome in available databases, we have identified several crucial proteins that have pathogenic and prognostic potential. Among them, antibodies to AhpC and GroEs of H. pylori could be utilized for identification of patients who are at high risk of disease complications after H. pylori infection. Evolving proteomic technologies, together with appropriate clinical phenotyping and genotype information should enhance understanding of disease pathogenesis and lead to more precise prediction of variable disease outcomes. It will also facilitate development of biomarkers for diagnosis, treatment, and prevention of H. pylori infection.     

Helicobacter pylori’s historical journey through Siberia and the Americas

The gastric bacterium Helicobacter pylori shares a coevolutionary history with humans that predates the out-of-Africa diaspora, and the geographical specificities of H. pylori populations reflect multiple well-known human migrations. We extensively sampled H. pylori from 16 ethnically diverse human populations across Siberia to help resolve whether ancient northern Eurasian populations persisted at high latitudes through the last glacial maximum and the relationships between present-day Siberians and Native Americans. A total of 556 strains were cultivated and genotyped by multilocus sequence typing, and 54 representative draft genomes were sequenced. The genetic diversity across Eurasia and the Americas was structured into three populations: hpAsia2, hpEastAsia, and hpNorthAsia. hpNorthAsia is closely related to the subpopulation hspIndigenousAmericas from Native Americans. Siberian bacteria were structured into five other subpopulations, two of which evolved through a divergence from hpAsia2 and hpNorthAsia, while three originated though Holocene admixture. The presence of both anciently diverged and recently admixed strains across Siberia support both Pleistocene persistence and Holocene recolonization. We also show that hspIndigenousAmericas is endemic in human populations across northern Eurasia. The evolutionary history of hspIndigenousAmericas was reconstructed using approximate Bayesian computation, which showed that it colonized the New World in a single migration event associated with a severe demographic bottleneck followed by low levels of recent admixture across the Bering Strait.

The gram-negative gastric bacterium Helicobacter pylori has shared an intimate coevolutionary relationship with humans for the last 100,000 y and possibly longer (1, 2). The greatest genetic diversity in both humans and H. pylori is found in Africa, the ancestral homeland of both species (3). After leaving Africa, H. pylori continued to differentiate in tandem with humans. Unlike its host, the bacterium evolved into multiple distinct geographic populations because it has high mutation and recombination rates, shorter generation times, and lower effective population sizes (4). Human populations expanding along the southern Asia coastal route carried the H. pylori precursors of hpSahul, a divergent, monophyletic population that continues to infect New Guinean Highlanders and Aboriginal Australians (5). The western and central parts of Paeleolithic Eurasia were dominated by hpAsia2, which has differentiated into hspIndia and hspLadakh (6, 7).A Eurasian West–East divide in H. pylori is reflected by the divergence of hpEastAsia, an ancestral East Asian population, into subpopulations hspEAsia (Southeast and East Asians), hspIndigenousAmericas (formerly known as hspAmerind, native North and South Americans), and hspMaori (Austronesian speakers). However, H. pylori’s presence, diversity, and structure in northern Eurasia are still unknown. This vast region, hereafter Siberia, extends from the Ural Mountains in the west to the Pacific Ocean in the east and the Kazakh and Mongolian Steppes in the south. Siberia is inhabited by at least 41 ethnic minorities who often live in small communities of low population densities with a total of <250,000 individuals (8). Notwithstanding often harsh environmental conditions, Siberians subsist through hunter-gathering and/or pastoralism (9), and the diversity of language families spoken in the region (Uralic, Yeniseian, Turkic, Tungusic, Mongolic, Gilyak, and Chukotko-Kamchatkan) hints at a complex history of migration and isolation.The patterns of human diversity between these ethnic groups are also largely understudied, and most genetic studies were based on traditional markers such as mitochondrial or Y chromosome DNA, whose effectiveness is compromised by relatively low mutation rates and incomplete lineage sorting (10–15). Recently, genomic studies of ancient human DNA have offered further insights, confirming that Siberia was the gateway for human migrations into northern America (16, 17) as well as into western Eurasia (18).Two important questions remain unanswered. Firstly, although anatomically modern human hunter-gatherers first appeared in Siberia 45,000 y ago (kya) in the Upper Paleolithic (16), their continued presence in the region throughout the last glacial maximum (LGM, 26.5 to 19 kya) is controversial. One argument suggests that ancient northern Eurasian [ANE (19)] metapopulations in Siberia had already developed adaptive mechanisms that allowed them to persist throughout the LGM, at least in sheltered locations with favorable environments (20). The presence of genetically similar human remains in central Siberia at 24 kya (Ma’lta boy, MA1) and 17 kya (AG2) (17) also hints that the region may have been continuously inhabited by ANEs during the LGM. Conversely, other scientists propose that the LGM paleoclimate resulted in the complete depopulation of central Siberia, driving humans into refugia to the south where they persisted for thousands of years before repopulating northern Siberia during the Holocene (9, 21, 22). Secondly, the peopling of the Americas by anatomically modern humans has long attracted scientific attention. Recent genomic evidence suggests that a single genetically diverse human population migrated across the Bering land bridge into the Americas, followed by subsequent post-LGM gene flow (23, 24). However, the dates of colonization by these migrants, the size of their founder population, and their relationships to other human groups remain unclear.To help answer these and other questions about human movements through Eurasia and the Americas, we undertook large-scale sampling of H. pylori from ethnically diverse aboriginal human populations across Siberia and Mongolia. Genotyping and sequence data were combined with a large reference database of Asian strains to provide an overview of the population structure of their genetic diversity and to infer the demographic and evolutionary histories of the peoples of Siberia and the Americas.     

Stabilizing effect of exenatide in a patient with C‐peptide‐negative diabetes mellitus

Background Exenatide is an incretin mimetic licensed for treatment of Type 2 diabetes poorly controlled despite maximally tolerated doses of oral therapy. Similar in structure to the natural incretin hormone glucagon‐like peptide 1 (GLP‐1), it helps restore underlying pathophysiological abnormalities. Case report We report the successful use of exenatide, combined with insulin, in a 66‐year‐old woman initially diagnosed with Type 2 diabetes in 1989 but now exhibiting a Type 1 phenotype. Diet, lifestyle advice and oral glucose‐lowering agents were commenced but persisting poor control necessitated insulin therapy in 2005. She later presented twice in diabetic ketoacidosis, suggesting conversion to a Type 1 phenotype (postprandial C‐peptide < 94 pmol/l). Despite differing insulin regimens, control remained poor with frequent hyperglycaemic and hypoglycaemic excursions, severely impairing quality of life. Whilst an inpatient in 2007 [glycated haemoglobin (HbA_1c) 10.2%, body mass index (BMI) 31.5 kg/m²] exenatide was commenced in an attempt to stabilize glycaemic control. Dramatic improvements were seen and continued. Eight months later, HbA_1c had fallen by 2% with an 8‐kg weight loss and 10‐unit reduction in daily insulin dose. Quality of life dramatically improved. C‐peptide remains undetectable. Conclusions This patient with features of both Type 1 and Type 2 diabetes benefited greatly from exenatide with insulin therapy. The improvement seen in glycaemic control could not be attributable to enhanced insulin secretion but could be as a result of a combination of the other incretin effects (postprandial glucagon suppression, delayed gastric emptying and weight loss secondary to increased satiety) all improving insulin sensitivity, reducing insulin dose and smoothing control.