We evaluated the efficacy of endoscopic treatment (ET) for gastric neoplastic complications of autoimmune gastritis (AIG). We also assessed the safety of ET and the risk factors for the occurrence of neuroendocrine tumors (NETs) and gastric adenocarcinoma (GA).

This was a retrospective, single-center, observational study. All patients diagnosed with AIG between 1987 and 2019 and had at least 1 upper endoscopy available were included.

The study population comprised 88 patients (68.2% female). The median follow up was 5 years (range 1-28). A total of 132 NETs were diagnosed in 39/88 patients (44.3%) (median age 50.0 years, range 27.0-85.0 years). The mean lesion size was 7.1 mm (range 1-30); there were 80 G1 NETs and 52 G2 NETs. Among the 132 lesions, 86.3% (114/132) were endoscopically resected, mostly by endoscopic mucosal resection (105/114, 92.1%), without complications. Only 1 patient underwent surgery. Twelve patients (13.6%) (7 females; median age, 76.0 years; range, 53.0-90.0 years) presented with GA. Of these, 66.7% (8/12) needed surgery, while 4 patients underwent exclusive endoscopic resection. Only 2 patients presented with NETs and GA (2.8%). Patients who presented with NETs were significantly younger at AIG diagnosis than patients with GA: 52.0 (18.0-85.0) vs. 67.0 (44.0-81.0) years (P=0.008). Patients who presented with GA were significantly older than those who presented with NETs: 76.0 (53.0-90.0) vs. 50.0 (27.0-85.0) years (P<0.001).

ET of NETs for AIG is effective and safe. GA is rarer, occurs in significantly older patients, and usually requires surgery.

Type-A gastritis/autoimmune gastritis (AIG) has gained renewed attention due to declining Helicobacter pylori infection rates and increasing eradication. AIG is associated with pernicious anemia (PA) and is prone to complicate various tumors, such as gastric cancer and neuroendocrine tumors. This report describes a case of AIG with PA in which gastric and esophageal cancers arose simultaneously. An 86-year-old woman had been diagnosed with PA and AIG 9 years earlier. As routine blood tests revealed high levels of carcinoembryonic antigen, she underwent esophagogastroduodenoscopy, which revealed a type 0-IIa lesion in the middle part of the stomach and a type 0-IIa + IIb lesion in the lower esophagus. Endoscopic submucosal dissection was performed on both lesions, since neither distant nor lymph node metastases were identified. Histological examination showed gastric tubular adenocarcinoma and esophageal squamous cell carcinoma. Immunohistology revealed that cells from neither cancer expressed gastrin, gastrin receptor, or p53. Whole-exome sequencing showed 8 gene mutations in the esophageal cancer and 6 mutations in 5 genes in the gastric cancer. The reason for the lack of p53 immunostaining was that TP53 was mutated in these cancers, although TP53 mutations differed. Thus, TP53 mutations may not be detected by immunostaining alone. When treating patients with AIG/PA, clinicians must be aware of the possibility of esophageal cancer coexisting with gastric cancer.

A bibliometric analysis of studies dedicated to autoimmune gastritis (AIG) recently published demonstrated a noteworthy surge in publications over the last three years. This can be explained by numerous publications from different regions of the world reporting the results of several studies that stimulated reassessment of our view of AIG as a precancerous condition. Follow-up studies and retrospective analyses showed that the risk of gastric cancer (GC) in AIG patients is much lower than expected if the patients ever being infected with Helicobacter pylori (H. pylori) were excluded. The low prevalence of precancerous lesions, such as the incomplete type of intestinal metaplasia, may explain the low risk of GC in AIG patients because the spasmolytic polypeptide-expressing metaplasia commonly observed in AIG does not involve clonal reprogramming of the gastric gland and can be considered as an adaptive change rather than a true precancerous lesion. However, changes in gastric secretion due to the progression of gastric atrophy during the course of AIG cause changes in the gastric mic-robiome, stimulating the growth of bacterial species such as streptococci, which may promote the development of precancerous lesions and GC. Thus, Streptococcus anginosus exhibited a robust proinflammatory response and induced the gastritis-atrophy-metaplasia-dysplasia sequence in mice, reproducing the well-established process for carcinogenesis associated with H. pylori. Prospective studies in H. pylori-naïve patients evaluating gastric microbiome changes during the long-term course of AIG might provide an explanation for the enigmatic increase in GC incidence in the last decades in younger cohorts, which has been reported in economically developed countries.

Gastric dysplasia is defined as an unequivocally neoplastic epithelium. Dysplastic lesions are characterized by cellular atypia reflective of abnormal differentiation and disorganized glandular architecture. The last few years have been marked by a refinement of the prognosis and risk of progression of gastric dysplasia and the recognition of novel morphologic patterns of dysplasia. Determination of the correct diagnosis and grade of dysplasia are critical steps since it will be predicting the risk of malignant transformation and help tailor appropriate surveillance strategy. This review describes the morphologic characteristics of conventional dysplasia and nonconventional gastric dysplasia that have been more recently characterized.

Autoimmune metaplastic atrophic gastritis (AMAG) is associated with an increased risk of gastric neoplasms. This study aimed to systematically analyze the incidence rate of gastric cancer (GC), low-grade dysplasia (LGD) and type-1 gastric neuroendocrine tumor (gNETs) development in AMAG adults. Studies on AMAG patients reporting the incidence of gastric neoplasms was identified through a systematic search in PUBMED and EMBASE. Study quality was assessed using the Joanna Briggs Institute quality assessment tool. Incidence rates of GC, LGD and type-1 gNETs were examined by meta-analysis. Thirteen studies met eligibility criteria. Incidence rate of gastric cancer calculated from the pooled data was 0.14% per person-year in both single-center studies and national registration studies. Meta-analysis showed a relative risk of 11.05 (95% CI: 6.39-19.11) for gastric cancer development in AMAG patients. The calculated pooled gastric LGD and type-1 gNETs incidence rates were 0.52% and 0.83% per person-year, respectively. As for experience from our center, we presented three distinctive cases of gastric neoplasm arising from the background of AMAG. This study underscores the potential for malignant transformation of precancerous lesions and reiterates the importance of careful esophagogastroduodenoscopy screening.

The standardized diagnosis and management of gastric precancerous conditions and lesions are important to prevent gastric cancer. This guideline, created by 5 traditional Chinese medicine and Western medicine associations, based on the current morbidity and diagnosis and treatment of gastric precancerous conditions and lesions, provides specific key points and strategies for diagnosis and treatment in the following five aspects: definition and epidemiology, diagnosis and stage, surveillance, treatment and efficacy evaluation. It is hoped that these aspects, assessed by integrating Western medicine and traditional Chinese medicine and involving multidisciplinary participation, will play a guiding role in clinical diagnosis and treatment and achieve effective secondary prevention of gastric cancer.

We aimed to determine the diagnostic value of anti-parietal cell antibodies (anti-PCA), anti-intrinsic factor antibodies (anti-IFA), pepsinogen ratio (PGI/II), and gastrin-17 (G-17) in corpus-restricted atrophic gastritis (CRAG) detected by ELISA (Inova, Biohit). Our study compared 29 CRAG cases against 58 age- and sex-matched controls with mild or no atrophy. Anti-PCA and anti-IFA positive cutoff values were ≥25 units for both. PGI/II value <3 was considered characteristic for atrophy; positive cutoff values for G-17 and anti-H. pylori IgG were >5 pg/L and >30 EIU. Anti-PCA was positive in 65.5% For CRAG cases and 13.8% of the controls (p < 0.0001), anti-IFA was positive in 13.8% and 0% (p = 0.01), respectively. Decreased pepsinogen levels were present in 79.3% of CRAG cases and 10.3% of the controls (p < 0.0001). PGI/II ratio was the best single biomarker, with sensitivity = 79%, specificity = 90%, and AUC 0.90. The combined use of PGI/II and anti-PCA resulted in AUC 0.93 for detecting CRAG. Our study suggests that the best combination of non-invasive biomarkers for detecting CRAG is PGI/II with anti-PCA. The addition of G-17 and anti-IFA is of little utility in clinical application.

Autoimmune gastritis (AIG) is a special type of chronic gastritis characterized by autoimmune disorders caused by cellular immunity, resulting in the destruction of parietal cells and production of antiparietal cell antibodies. Endoscopic findings of AIG are mainly characterized by corpus-dominant advanced atrophy. The antral area is generally considered to have no or mild atrophy; however, there are cases wherein the gastric mucosa is red or faded due to past infection with Helicobacter pylori or bile reflux. Currently, there are no diagnostic criteria for AIG in Japan, and it is important to make a diagnosis based on the presence of gastric autoantibodies and characteristic endoscopic and histological findings. AIG is associated with gastric cancer, neuroendocrine tumors (NETs), and other autoimmune diseases, such as thyroid diseases, anemia, and neurological symptoms due to impaired absorption of iron and vitamin B12 , and thus requires systemic treatment. The significance of diagnosing AIG is to include patients as a high-risk group for the development of gastric cancer and gastric NETs, provide an opportunity to detect autoimmune endocrine diseases, and initiate therapeutic intervention before anemia and neurological symptoms develop. It is important to pay close attention to the occurrence of AIG comorbidities not only at the time of AIG diagnosis but also during follow-up after detection.

Gastric cancer (GC) is one of the most common malignant tumors of the digestive tract, posing a significant risk to human health. Over the past 10 years, the pathological characteristics and the prognosis of GC have been determined based on the locations of the tumors that were then classified into two types-proximal and distal GC. This review focuses on the differences in epidemiology, etiology, cell source, pathological characteristics, gene expression, molecular markers, manifestations, treatment, prognosis, and prevention between proximal and distal GC to provide guidance and a basis for clinical diagnosis and treatment.

Autoimmune gastritis (AIG) is a clinicopathologic diagnosis requiring characteristic histopathology and correlation with laboratory work-up. To better understand how the diagnosis of AIG is made and reported in the pathology community, we conducted an anonymous web-based survey which was circulated among a diverse group of pathologists. Excluding trainees there were 64 respondents: 25 academic gastrointestinal pathologists (AGI, 39%), 22 academic general pathologists (AGP, 34%), 17 private general pathologists (PP, 27%). Our survey results highlighted variations in work-up and sign-out practices. The type of metaplasia needed to diagnose AIG lacked consensus. There was variation in accurate interpretation of immunostains with a trend towards more accurate diagnosis of enterochromaffin-like (ECL) cell hyperplasia by AGI (92%) and AGP (95%) than PP (71%) (p = 0.07). G-cells in antrum on neuroendocrine immunostain, a mimicker of ECL cell hyperplasia, was more frequently misdiagnosed by PP/ AGP (44%), versus AGI (12%) (p = 0.02). A triple immunostain panel (H. pylori, neuroendocrine, gastrin) was used in the work-up of AIG by 72% of AGI versus 23% AGP and 12% PP (p = 0.000061). The less-specific term "atrophic gastritis" was used in the diagnostic line more by respondents with >10 years sign-out experience compared with others (p = 0.04). In conclusion, the survey results highlighted deficiencies in the interpretation of neuroendocrine immunostains which is crucial for AIG diagnosis, as well as variation in reporting practices and definitions. Uniform criteria and terminology are needed in this field to improve communication with clinicians, resulting in appropriate testing and follow-up.

Autoimmune gastritis (AIG) is a chronic immune-mediated, inflammatory condition that involves the destruction of the gastric oxyntic mucosa through the autoimmune-mediated loss of parietal cells, with replacement by atrophic and metaplastic tissue. Diagnosing AIG is important, given the need for ongoing clinical management and vigilance with respect to downstream complications, the most serious of which is gastric adenocarcinoma. Other clinical consequences include gastric neuroendocrine tumors, consequences related to decreased gastric acid and decreased intrinsic factor due to parietal cell destruction and antibodies against intrinsic factor (e.g. micronutrient deficiencies), as well as concomitant autoimmune disorders. Considering the prevalence of AIG and the potential for severe clinical outcomes, it is important to engage in efforts to reduce practice pattern variability related to diagnosis and management. Accordingly, herein, we review of the epidemiology, pathogenesis, clinical presentation of AIG, including both gastric and extragastric manifestations, and provide an overview of clinical management.

Pernicious anemia is a rare condition characterized by vitamin B12 deficiency anemia due to lack of intrinsic factor, often caused by autoimmune gastritis. Patients with pernicious anemia have a higher incidence of other autoimmune disorders, such as type 1 diabetes, vitiligo, and autoimmune thyroid issues. Therefore, the disease has a clear autoimmune basis, although the genetic susceptibility factors have thus far remained poorly studied. We conduct a genome-wide association study meta-analysis in 2166 cases and 659,516 European controls from population-based biobanks and identify genome-wide significant signals in or near the PTPN22 (rs6679677, p = 1.91 × 10-24, OR = 1.63), PNPT1 (rs12616502, p = 3.14 × 10-8, OR = 1.70), HLA-DQB1 (rs28414666, p = 1.40 × 10-16, OR = 1.38), IL2RA (rs2476491, p = 1.90 × 10-8, OR = 1.22) and AIRE (rs74203920, p = 2.33 × 10-9, OR = 1.83) genes, thus providing robust associations between pernicious anemia and genetic risk factors.

Esophageal squamous cell carcinoma (ESCC) is the sixth most common cause of death worldwide. Incidence rates vary internationally, with the highest rates found in Southern and Eastern Africa, and central Asia. Initial observational studies identified multiple factors associated with an increased risk of ESCC, with subsequent work then focused on developing plausible biological mechanistic associations. The aim of this review is to summarize the role of risk factors in the development of ESCC and propose future directions for further research. A systematic search of the literature was conducted by screening EMBASE, MEDLINE/PubMed, and CENTRAL for relevant publications. In total, 73 studies were included that sought to identify risk factors associated with the development of esophageal squamous cell carcinoma. Risk factors were divided into seven subcategories: genetic, dietary and nutrition, gastric atrophy, infection and microbiome, metabolic, epidemiological and environmental and other risk factors. Risk factors from each subcategory were summarized and explored with mechanistic explanations for these associations. This review highlights several current risk factors of ESCC. These risk factors were explored, and explanations dissected. Most studies focused on investigating genetic and dietary and nutritional factors, whereas this review identified other potential risk factors that have yet to be fully explored. Furthermore, there is a lack of literature on the association of these risk factors with tumor factors and disease prognosis. Further research to validate these results and their effects on tumor biology is absolutely necessary.

Pernicious anemia (PA) is an autoimmune disease (AID) which is caused by lack of vitamin B12 (cobalamin) due to its impaired uptake. PA is a multifactorial disease which is associated with a number of other AID comorbidities and which is manifested as part of autoimmune polyglandular syndrome. Due to the shortage of family studies on PA, we planned to address the problem by assessing familial risks for concordant PA between family members and for discordant PA in families of other AID patients.

We collected data on patients diagnosed with AIDs from the Swedish hospitals and family data from a population register. We calculated standardized incidence ratios (SIRs) in families for concordant and discordant risks.

The number of PA patients in the offspring generation (for which the familial risk was calculated) was 7701; 278 (3.6%) patients had a family history of PA. The population prevalence of PA was 0.9/1000. The familial risk for PA was 3.88 when any first-degree relative was the proband, equal for men and women. The familial risk was two times higher between siblings than between offspring and parents which may be due to complex genetic background. Associations of PA with 14 discordant AIDs were significant; these included some AIDs that have previously been described as comorbidities in PA patients and several yet unreported associations, including rheumatoid arthritis and other AIDs.

The familial risks for PA were high suggesting multifactorial genetic etiology. The results call for further population-level studies to unravel mechanisms of familial PA which may help to understand the etiology of this disease.

Globally, a decreasing incidence of male esophageal squamous cell carcinoma (ESCC) has been observed in recent decades. We evaluated the determinants of esophageal distinct iodine-unstained lesions (DIULs), high-cancer-risk lesions and ESCC, among 3858 Japanese alcohol-dependent men (40-79 years) who underwent chromoendoscopic screening between 2003 and 2018. The initial screening detected DIULs ≥ 5 mm in 541 patients (dysplasia in 319 and SCC in 129) and multiple DIULs in 640. The detection rates for DIULs and chronic atrophic gastritis (CAG), pack-years, and the mean corpuscular volume (MCV) decreased over the course of the study period, while the detection of hiatal hernia and/or columnar-lined esophagus (HH/CLE) and the carriers of inactive heterozygous aldehyde dehydrogenase-2 (ALDH2, rs671) increased. Multiple logistic regression analyses showed that an older age, larger number of pack-years, smaller body mass index, larger MCV, presence of a slow-metabolizing alcohol dehydrogenase-1B genotype (rs1229984), presence of an inactive heterozygous ALDH2 genotype, and more advanced degree of CAG increased the odds ratios (ORs) for DIULs, while the 2008-2013 and 2014-2018 screening periods had lower ORs for DIULs than the 2003-2007 screening period. The presence of HH/CLE decreased the OR for multiple DIULs and was associated with a more proximal location of ESCC. In conclusion, the detection of DIULs in an alcohol-dependent population decreased between 2003 and 2018. In addition to reported determinants of ESCC, CAG and HH/CLE were associated with the risk of DIULs. Enigmatically, however, the decline in the detection of DIULs was not adequately explained by these factors and warrants further research.

Autoimmune atrophic gastritis is an organ-specific immune-mediated condition characterized by atrophy of the oxyntic mucosa. Autoimmune atrophic gastritis (AIG) is characterized by a progressive loss of acid-secreting parietal cells leading to hypo-achlorhydria. Due to this peculiar intra-gastric environment, gastric microbiota composition in individuals with autoimmune atrophic gastritis was first supposed and then recently reported to be different from subjects with a normal acidic healthy stomach. Recent data confirm the prominent role of Helicobacter pylori as the main bacterium responsible for gastric disease and long-term complications. However, other bacteria than Helicobacter pylori, for example, Streptococci, were found in subjects who developed gastric cancer and in subjects at risk of this fearful complication, as well as those with autoimmune gastritis. Gastric microbiota composition is challenging to study due to the acidic gastric environment, the difficulty of obtaining representative samples of the entire gastric microbiota, and the possible contamination by oral or throat microorganisms, which can potentially lead to the distortion of the original gastric microbial composition, but innovative molecular approaches based on the analysis of the hyper-variable region of the 16S rRNA gene have been developed, permitting us to obtain an overall microbial composition view of the RNA gene that is present only in prokaryotic cells.

Autoimmune gastritis (AIG) is an increasingly prevalent, organ-specific, immune-mediated disorder characterized by the destruction of gastric parietal cells, leading to the loss of intrinsic factor and reduced acid output. These alterations result in malabsorption of iron, vitamin B₁₂ (pernicious anaemia) and potentially other micronutrients. For several years, most studies have focused on pernicious anaemia only, generating confusion between the two entities. In AIG, the gastric proton pump, H⁺/K⁺ ATPase, is the major autoantigen recognized by autoreactive T cells. The T cell-dependent activation of B cells stimulates the production of anti-parietal cell antibodies, the serological hallmark of AIG. The role of Helicobacter pylori infection in activating or favouring the autoimmune process is still uncertain. Early histopathological alterations allowing a more precise and prompt recognition have recently been described. AIG is burdened by a substantial diagnostic delay as it can present with varied clinical signs including, among others, gastrointestinal symptoms and neuropsychiatric manifestations. In advanced stages, AIG might progress to neuroendocrine tumours and gastric adenocarcinoma. Management includes early detection through a proactive case-finding strategy, micronutrient supplementation and endoscopic surveillance. This Primer comprehensively describes the most important insights regarding the epidemiology, pathophysiology, diagnosis and management of AIG, focusing on the most controversial, outstanding issues and future directions.

Autoimmune gastritis is understudied and possibly associated with gastric noncardia adenocarcinoma (GNCA) and esophageal squamous cell carcinoma (ESCC) in Western populations when it presents as pernicious anemia.

A nested case-control study within a Chinese cohort included 100 ESCC, 200 gastric cardia adenocarcinoma (GCA), and 200 GNCA cases diagnosed between 1986 and 2001 and 400 controls. Serostatus of antiparietal cell antibodies (APCA), Helicobacter pylori antibodies, and pepsinogens were measured using commercial kits and serum collected at baseline. We used logistic regression to calculate odds ratios (OR) and 95% confidence interval (CI) for associations between serologic biomarkers and cancer risk adjusted for numerous potential confounders.

There was an average interval of 8 years between baseline blood draw and cancer diagnosis. The baseline prevalence of APCA seropositivity was 10.0% and 14.5% in subjects who developed GCA and GNCA, respectively. APCA seropositivity was inversely associated with later development of GCA (OR = 0.42; 95% CI, 0.24-0.75), but not significantly associated with later development of GNCA (OR = 0.82; 95% CI, 0.50-1.36) or ESCC (OR = 1.05; 95% CI, 0.58-1.88). APCA seropositivity was significantly associated with low pepsinogen I/II ratios (OR = 3.69; 95% CI, 1.66-8.21), and individuals with low pepsinogen I/II ratios who were seronegative for APCA had the highest risk of both GCA and GNCA.

APCA seropositivity measured years prior to diagnosis was associated with prevalent atrophic gastritis but inversely associated with incident GCA in this Chinese population.

APCA may contribute to a growing list of serologic markers that can improve risk stratification for gastric cancer.

Helicobacter pylori infection of the human stomach is associated with chronic gastritis, peptic ulcer disease or gastric carcinoma, and thus a high burden for the public health systems worldwide. Fortunately, only a small subfraction of up to 15-20% of infected individuals will develop serious complications. Unfortunately, it is not always known upfront, who will be affected by serious diesease outcome. For risk stratifications, it is therefore necessary to establish a common terminology and grading system, that can be applied worldwide to compare population data. The updated Sydney System for classification of gastritis with its semi-quantitative analogue scale is the system, that is currently used worldwide. Additionally, pathologists should always try to classify the etiology of the inflammatory infiltrates in the stomach to instruct the clinicians for choosing a proper treatment regime. Risk factors such as intestinal metaplasia, atrophy and scoring systems to classify these risk factors into a clinical context such as OLGA and OLGIM are discussed. Also, special forms of gastritis like lymphocytic gastritis, autoimmune gastritis and peptic ulcer disease are explained and discussed e.g. how to diagnose and how to treat. Extra-gastric sequelae of H. pylori infections inside and outside the stomach are shown in this chapter as well. Important host and bacterial risk factors such as pathogenicity islands are dicussed to draw a complete landscape around a H. pylori infection, that still can be diagnosed in patients. However, it needs to be noted that some countries have almost no H. pylori infection anymore, while others have still a very high frequency of infections with or without serious complications. The understanding and application of risk assessements may help to save money and quality of life. Extra-gastric H. pylori infections are rarely reported in the literature until today. The pathogenitiy is still under debate, but especially in the bile ducts and gallbladder, several pathological conditions may be also based on H. pylori infection, and will be also discussed.

Pernicious anaemia (PA) is associated with increased gastric cancer risk, but the evidence is conflicting regarding the associated risk of other cancers.

To systematically determine the incidence rates of gastro-intestinal cancers other than gastric cancers (GI-other-than-GC) and non-gastrointestinal cancers (non-GIC) in PA adults, globally and per tumour site, and the risk associated with PA for GI-other than GC and non-GIC.

Studies of PA patients reporting the incidence of GI-other-than-GCs and non-GICs were identified with MEDLINE (PubMed)-EMBASE (from first date available to April 2017). A meta-analysis of annual cancer incidence rates was performed. The outcome was the cumulative incidence of GI-other-than-GCs and non-GICs (ratio between the numbers of new cancer cases identified during the follow-up period and the number of PA patients) and the incidence rate expressed as the rate of events-per-time-unit (person-years).

Of 82,257 PA patients, the pooled incidence rates/100 person-years for non-GCs and non-GICs of 0.27 (95% CI:0.16-0.42) and 0.23 (95% CI:0.22-0.25) were calculated by meta-analysis. Compared to the GLOBOCAN data for the general population from the countries of the included studies, the meta-analysis showed an overall relative risk (RR) of cancer in PA of 0.68 (95% CI:0.48-0.95). PA patients had a lower RR of colorectal, breast, liver, oesophageal, lung, thyroid, ovary, non-melanoma skin and kidney cancers but had a higher RR of biliary tract cancer (1.81:1.21-2.70), multiple myeloma (2.83:1.76-4.55), Hodgkin's lymphoma (3.0:1.35-6.68), non-Hodgkin's lymphoma (2.08: 1.58-2.75), and leukaemia (1.56:1.16-2.12).

An overall lower RR of cancers-other-than-gastric-cancer in PA patients but an increased RR of biliary tract cancers and haematological malignancies was observed.

Hypergastrinemia was shown to stimulate colonic epithelial cell proliferation.

To evaluate the association between pernicious anemia (PA), a disease with hypergastrinemia, and colorectal cancer (CRC) risk.

We conducted a nested case-control study within a large database from the UK. Cases were defined as all individuals in the cohort with at least one medical code for CRC. Controls were selected based on incidence-density sampling. For each case, up to four eligible controls were matched on age at diagnosis, sex, practice-site, and both duration and calendar time of follow-up. Exposure of interest was diagnosis of PA prior to CRC diagnosis date. The primary analysis was a multivariable conditional logistic regression.

Our study included 22,098 CRC cases and 85,969 matched controls. We identified 154 (0.70%) cases and 563 (0.65%) controls with past history of PA. The adjusted OR for the association between PA and CRC risk was 1.02 (95% CI 0.85-1.22). There was no difference in the results after stratification according to sex. In a sensitivity analysis only among individuals without chronic use of proton pump inhibitors (PPIs) the adjusted OR was 1.14 (95% CI 0.90-1.45). There was no association between duration of PA and CRC risk.

PA is not associated with higher CRC risk.

Esophageal cancer (EC) is among the most common malignancies in Eastern Africa, but the occurrence of EC in Sudan has rarely been described in the scientific literature. This paper reports the results of a consecutive case series of all EC patients who visited one of the two public cancer treatment centers in the country in 1999-2012, providing a first description of this disease in a treatment center located in central Sudan.

Clinical and demographic data for all EC patients who visited the Department of Oncology of the National Cancer Institute at the University of Gezira (NCI-UG) from 1999 to the end of 2012 were abstracted and tabulated by sex, tumor type and other characteristics.

A total of 448 EC patients visited NCI-UG in 1999-2012, and the annual number of EC cases increased steadily from 1999. Squamous cell carcinoma (SCC) was the predominant EC tumor type (90%), and adenocarcinoma (ADC) was reported in 9.4% of the EC cases. The overall male-to-female ratio for EC was 1:1.8, but the ratio was tumor type-dependent, being 1:2 for SCC and 2:1 for ADC. Only 20% of EC patients reported having ever used tobacco and/or alcohol, and the vast majority of these patients were male. At the time of EC diagnosis, 47.3% of the patients resided in Gezira State. Some EC patients from Gezira State seek out-of-state treatment in the national capital of Khartoum instead of visiting NCI-UG.

The annual number of EC patients visiting NCI-UG has increased in recent years, approximately half of these patients being from Gezira State. Although this consecutive series of EC patients who visited NCI-UG was complete, it did not capture all EC patients from the state. A population- based cancer registry would provide more complete data required to better understand EC patterns and risk factors.

Health care data holds great promise to be used in clinical decision support systems. However, frequent near-synonymous diagnoses recorded separately, as well as the sheer magnitude and complexity of the disease data makes it challenging to extract non-trivial conclusions beyond confirmatory associations from such a web of interactions. Here we present a systematic methodology to derive statistically valid conditional development of diseases. To this end we utilize a cohort of 5,512,469 individuals followed over 13 years at inpatient care, including data on disability pension and cause of death. By introducing a causal information fraction measure and taking advantage of the composite structure in the ICD codes, we extract an effective directed lower dimensional network representation (100 nodes and 130 edges) of our cohort. Unpacking composite nodes into bipartite graphs retrieves, for example, that individuals with behavioral disorders are more likely to be followed by prescription drug poisoning episodes, whereas women with leiomyoma were more likely to subsequently experience endometriosis. The conditional disease development represent putative causal relations, indicating possible novel clinical relationships and pathophysiological associations that have not been explored yet.

Removal of the appendix might induce physiological changes in the gastrointestinal tract, and subsequently play a role in carcinogenesis. Therefore, we conducted a nationwide register-based cohort study in Sweden to investigate whether appendectomy is associated with altered risks of gastrointestinal cancers.

A population-based cohort study was conducted using the Swedish national registries, including 480,382 eligible patients followed during the period of 1970-2009 for the occurrence of site-specific gastrointestinal cancer (esophageal/gastric/colon/rectal cancer). Outcome and censoring information was collected by linkage to health and demography registers. We examined the incidence of appendectomy in Sweden using data from 1987-2009. We also calculated standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) to estimate the relative gastrointestinal cancer risk through comparison to the general population.

We noted an overall decrease in the age-standardized incidence of appendectomy among the entire Swedish population from 189.3 to 105.6 per 100,000 individuals between 1987 and 2009. Grouped by different discharge diagnosis, acute appendicitis, incidental appendectomy, and entirely negative appendectomy continuously decreased over the study period, while the perforation ratio (18%-23%) stayed relatively constant. Compared to the general population, no excess cancer risk was observed for gastrointestinal cancers under study with the exception of a marginally elevated risk for esophageal adenocarcinoma (SIR 1.32, 95% CI 1.09-1.58).

In Sweden, the incidence of appendectomy and acute appendicitis has decreased during 1987-2009. No excess gastrointestinal cancer risks were observed among these appendectomized patients, with the possible exception of esophageal adenocarcinoma.

Pernicious anemia, a result of autoimmune gastritis, is the most common cause of vitamin B12 deficiency, affecting 2% to 5% of the elderly population. Treatment with vitamin B12 cures the anemia, but not the gastritis. Findings from small studies have indicated that patients with pernicious anemia could have an increased risk of cancer.

We performed a population-based, case-control study of individuals in the Surveillance, Epidemiology, and End Results-Medicare database, comparing 1,138,390 cancer cases (age, 66-99 y) with 100,000 matched individuals without cancer (controls). Individuals with pernicious anemia were identified based on their medical claims within the year before selection for the study. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using unconditional logistic regression, and models were adjusted for sex, age, and calendar year of diagnosis and selection.

Compared with controls, we found individuals with pernicious anemia to be at increased risk for noncardia gastric adenocarcinoma (OR, 2.18; 95% CI, 1.94-2.45) and gastric carcinoid tumors (OR, 11.43; 95% CI, 8.90-14.69). In addition, people with pernicious anemia have an increased risk of developing tonsilar cancer (OR, 2.00; 95% CI, 1.40-2.85), hypopharyngeal cancer (OR, 1.92; 95% CI, 1.35-2.73), esophageal squamous cell carcinoma (OR, 2.12; 95% CI, 1.76-2.55), small intestinal cancer (OR, 1.63; 95% CI, 1.32-2.02), liver cancer (OR, 1.49; 95% CI, 1.28- 1.73), myeloma (OR, 1.55; 95% CI, 1.37-1.75), acute myeloid leukemia (OR, 1.68; 95% CI, 1.46-1.93), and myelodysplastic syndrome (OR, 2.87; 95% CI, 2.53-3.26). People with pernicious anemia have a lower risk of rectal cancer than the general population (OR, 0.82; 95% CI, 0.74- 0.92).

In a population-based, case-control study of individuals in the Surveillance, Epidemiology, and End Results-Medicare database, we found individuals with pernicious anemia to have significantly increased risks of gastric carcinoid tumors, adenocarcinomas, and other cancers located throughout the body.

To classify diseases based on age at peak incidence to identify risk factors for later disease in women's life course.

A cross-sectional baseline survey of participants in the Japan Nurses' Health Study.

A nationwide prospective cohort study on the health of Japanese nurses. The baseline survey was conducted between 2001 and 2007 (n=49,927).

Age at peak incidence for 20 diseases from a survey of Japanese women was estimated using the Kaplan-Meier method with the Kernel smoothing technique. The incidence rate and peak incidence for diseases whose peak incidence occurred before the age of 45 years or before the perimenopausal period were selected as early-onset diseases. The OR and 95% CI were estimated to examine the risk of comorbidity between early-onset and other diseases.

Four early-onset diseases (endometriosis, anaemia, migraine headache and uterine myoma) were significantly correlated with one another. Late-onset diseases significantly associated (OR>2) with early-onset diseases included comorbid endometriosis with ovarian cancer (3.65 (2.16 to 6.19)), endometrial cancer (2.40 (1.14 to 5.04)) and cerebral infarction (2.10 (1.15 to 3.85)); comorbid anaemia with gastric cancer (3.69 (2.68 to 5.08)); comorbid migraine with transient ischaemic attack (3.06 (2.29 to 4.09)), osteoporosis (2.11 (1.71 to 2.62)), cerebral infarction (2.04 (1.26 to 3.30)) and angina pectoris (2.00 (1.49 to 2.67)); and comorbid uterine myoma with colorectal cancer (2.31 (1.48 to 3.61)).

While there were significant associations between four early-onset diseases, women with a history of one or more of the early-onset diseases had a higher risk of other diseases later in their life course. Understanding the history of early-onset diseases in women may help reduce the subsequent risk of chronic diseases in later life.

The human upper digestive tract microbial community (microbiota) is not well characterized and few studies have explored how it relates to human health. We examined the relationship between upper digestive tract microbiota and two cancer-predisposing states, serum pepsinogen I/pepsinogen II ratio (PGI/II; predictor of gastric cancer risk) and esophageal squamous dysplasia (ESD; the precursor lesion of esophageal squamous cell carcinoma; ESCC) in a cross-sectional design.

The Human Oral Microbe Identification Microarray was used to test for the presence of 272 bacterial species in 333 upper digestive tract samples from a Chinese cancer screening cohort. Serum PGI and PGII were determined by ELISA. ESD was determined by chromoendoscopy with biopsy.

Lower microbial richness (number of bacterial genera per sample) was significantly associated with lower PGI/II ratio (P = 0.034) and the presence of ESD (P = 0.018). We conducted principal component (PC) analysis on a β-diversity matrix (pairwise difference in microbiota), and observed significant correlations between PC1, PC3, and PGI/II (P = 0.004 and 0.009, respectively), and between PC1 and ESD (P = 0.003).

Lower microbial richness in upper digestive tract was independently associated with both cancer-predisposing states in the esophagus and stomach (presence of ESD and lower PGI/II).

These novel findings suggest that the upper digestive tract microbiota may play a role in the etiology of chronic atrophic gastritis and ESD, and therefore in the development of gastric and esophageal cancers.

For a few decades the long-term use of proton pump inhibitors has had wide application in the treatment of several gastrointestinal diseases. Since then, however, several studies have called attention to the possible development of anatomical and pathological changes of gastric mucosa, resulting from the long term use of this therapeutic modality. Recent experimental and clinical studies suggest that these changes have connection not only to the development of precancerous lesions, but also of gastric tumors.

To present a qualitative analysis of anatomical and pathological changes of gastric mucosa resulting from the long-term use of proton pump inhibitors.

The headings used were: proton pump inhibitors, precancerous lesions and gastric neoplasms for a non systematic review of the literature, based on Medline, Lillacs and Scielo. Twelve articles were selected from clinical (9) and experimental (3) studies, for qualitative analysis of the results.

The gastric acid suppression by high doses of proton pump inhibitors induces hypergastrinemia and the consequent emergence of neuroendocrine tumors in animal models. Morphological changes most often found in these experimental studies were: enterochromaffin-like cell hyperplasia, neuroendocrine tumor, atrophy, metaplasia and adenocarcinoma. In the studies in humans, however, despite enterochromaffin-like cell hyperplasia, the other effects, neuroendocrine tumor and gastric atrophy, gastric metaplasia and or adenocarcinoma, were not identified.

Although it is not possible to say that the long-term treatment with proton pump inhibitors induces the appearance or accelerates the development of gastric cancer in humans, several authors have suggested that prolonged administration of this drug could provoke the development of gastric cancer. Thus, the evidence demonstrated in the animal model as well as the large number of patients who do or will do a long-term treatment with proton pump inhibitors, justifies the maintenance of this important line of research.

The majority of oesophageal cancer cases occur in developing countries. Globally males predominate.

This study aims to review the clinical aspects of oesophageal carcinoma in Sudanese patients referred to endoscopy in Gezira, Central Sudan.

Data were collected from patients who underwent endoscopy during the period from 2005 to 2007 at The Gezira Centre for Gastroenterology Endoscopies and Laparoscopic Surgery. Demographic and clinical data including; sex, age, locality of residence, clinical presentation, tumour site and morphology were collected and analysed.

Seven hundred and two patients were consecutively referred to our centre for endoscopy. Seventy-three out of 702 patients (9.6%) referred for endoscopy proved to have oesophageal cancer. Fifty-five out of 73 patients (75.3%) were females generating a male to female ratio of 1:3.3. The mean age of females was 52.75±11.66years and that of males was 66.11±9.52. Sixteen (21.9%) patients came from the Managil; 14 (19.2%) from Hasaheesa and Rufaa; 14 (19.2%) from Blue Nile; 10 (13.7%) from Wadmedani (Central Sudan) and 19 (26%) from Elfaw and Kassala. In most cases (75.3%), the tumours were located in the middle third of the oesophagus. 79.5% of the tumours were squamous cell type.

Patients referred for endoscopy to The Gezira Centre for Gastroenterology, Endoscopies and Laparoscopic Surgery in Gezira revealed a greater proportion of women than of men diagnosed with the disease (1:3.3). More studies are needed to investigate the epidemiology of this disease and to identify the reason for the apparent gender uneven manifestation.

A 35-year-old woman with a history of vitiligo, hypothyroidism and amenorrhoea presented with collapse and clinical features of cardiac failure. Laboratory investigations revealed pancytopaenia, the cause of which was found to be vitamin B12 deficiency due to pernicious anaemia. Treatment with intramuscular hydroxycobalamin was commenced and the patient improved steadily with concomitant improvement in her haematological indices. Clinical features of pernicious anaemia which can include marked pancytopaenia, diagnostic approach, associated conditions and approach to treatment are discussed. The importance of surveillance for gastrointestinal malignancy is emphasised.

Many recent studies suggest the immune system plays a significant role in the pathogenesis of autoimmune diseases, chronic inflammatory diseases, and cancer.

Literature published between 2001 and 2011 was reviewed for risk of cancer development in patients with autoimmune and chronic inflammatory diseases. Mode of risk assessment employed did not limit inclusion of studies. Autoimmune conditions developing after diagnosis of a pre-existing cancer were also considered.

We report a pervasive, largely positive association between 23 autoimmune and inflammatory diseases and subsequent cancer development. We discuss associations for celiac disease, inflammatory bowel disease rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis in detail. We also address the less frequently reported development of some autoimmune conditions within the course of some malignancies, such as vitiligo developing in the course of melanoma.

Evidence demonstrates that chronic inflammation and autoimmunity are associated with the development of malignancy. Additionally, patients with a primary malignancy may develop autoimmune like disease. These relationships imply a need for surveillance of patients on immunomodulatory therapies for potential secondary disease processes.

Chronic atrophic gastritis (CAG) is an inflammatory condition characterized by the loss of gastric glandular structures which are replaced by connective tissue (non-metaplastic atrophy) or by glandular structures inappropriate for location (metaplastic atrophy). Epidemiological data suggest that CAG is associated with two different types of tumors: Intestinal-type gastric cancer (GC) and type I gastric carcinoid (TIGC). The pathophysiological mechanisms which lead to the development of these gastric tumors are different. It is accepted that a multistep process initiating from Helicobacter pylori-related chronic inflammation of the gastric mucosa progresses to CAG, intestinal metaplasia, dysplasia and, finally, leads to the development of GC. The TIGC is a gastrin-dependent tumor and the chronic elevation of gastrin, which is associated with CAG, stimulates the growth of enterochromaffin-like cells with their hyperplasia leading to the development of TIGC. Thus, several events occur in the gastric mucosa before the development of intestinal-type GC and/or TIGC and these take several years. Knowledge of CAG incidence from superficial gastritis, its prevalence in different clinical settings and possible risk factors associated with the progression of this condition to gastric neoplasias are important issues. This editorial intends to provide a brief review of the main studies regarding incidence and prevalence of CAG and risk factors for the development of gastric neoplasias.

Recent studies have consistently reported a significant association between gastric atrophy and esophageal squamous cell carcinomas (ESCCs). However, causative factors responsible for the linkage remain to be clarified. Multichannel intraluminal impedance monitoring in conjunction with a pH sensor (MII-pH) is a reliable technique to evaluate gastroesophageal reflux (GER) episodes, independent of the acidity. We investigated the potential roles of GER in the pathogenesis of ESCC with MII-pH.

From August 2008 to May 2010, 14 consecutive inpatients with superficial ESCCs (ESCC group) and 14 age- and sex-matched inpatients without any esophageal dysplastic lesions (non-ESCC group) were enrolled. Twenty-four hour portable MII-pH monitoring was performed under standard hospitalized conditions. The data of MII-pH were used to identify acid reflux (AR: pH drop below 4.0 during a reflux episode) and non-AR (NAR: pH drop above 4.0 during a reflux episode).

The median intragastric pH of the ESCC group was 4.7 (2.3-6.4), implying hypochlorhydria in this patient group. The numbers of total reflux and NAR episodes in the ESCC group were significantly higher than those in the non-ESCC group (56 (43-87) vs. 35.5 (18-47), P=0.016 for total reflux and 46.5 (32-84) vs. 24.5 (8-37), P=0.012 for NAR), whereas the numbers of AR were similar in both groups. In addition, there was significance in the category of percentage time of bolus reflux episodes.

Using MII-pH monitoring, we revealed the clinical significance of GER, especially NAR, in ESCCs. NAR may be a key factor in the link between gastric atrophy and ESCCs.

Dysregulation of the immune function in autoimmune diseases could potentially lead to cancer development and there is definite evidence linking some autoimmune mechanisms with cancer. We analyzed systematically the occurrence of histology-specific digestive tract cancers in patients diagnosed with 33 different autoimmune diseases in order to address the question of shared susceptibility.

Standardized incidence ratios (SIRs) were calculated for subsequent digestive tract cancers up to the year 2008 and in patients hospitalized for autoimmune disease after the year 1964.

Myasthenia gravis associated with five different cancers with SIRs ranging from 1.35 to 2.78. Pernicious anemia, Crohn disease, ulcerative colitis, systemic lupus erythematosis and psoriasis were also associated with cancers at multiple sites. Rheumatoid arthritis associated with no cancer and the standardized incidence ratio was decreased for colon adenocarcinoma, also in ankylosing spondylitis patients.

Increased risks of cancer were observed in patients with several autoimmune diseases. Myasthenia gravis and pernicious anemia were associated with many cancers; this is possibly related to immunosuppressant medication in myasthenia gravis. The decreased risks in colon and rectal adenocarcinomas in rheumatoid arthritis and ankylosing spondylitis suggest underlying inflammatory mechanisms as the risks may have been suppressed by the use of anti-inflammatory medication.

Recent epidemiological studies in Serbia revealed that gastric carcinoma is the third and the fifth main cause of cancer morbidity in men and women, respectively. Despite the declining incidence of gastric cancer, it remains the second most common cause of cancer-related deaths as it is worldwide. A well-defined carcinogenic inflammation-metaplasia-dysplasia-cancer sequence typically precedes the development of most gastric adenocarcinomas. Alterations such as gastric mucosal atrophy and intestinal metaplasia are merely markers of increased risk, while gastric epithelial dysplasia (GED) represent a direct precursor of cancer. DNA damage and increased mucosal proliferation secondary to H pylori infection, combined with a suitable host susceptibility phenotype (eg, genetic polymorphisms in interleukin IL-1B, IL-1RN, and tumor necrosis factor a TNF-alpha genes), are important factors in this progression pathway. However, only a small minority of patients infected with H. pylori eventually develops gastric cancer, and eradication of H pylori in these patients does not seem to eliminate the risk of cancer completely. It has been shown that atrophy may be a better indicator of risk of cancer than intestinal metaplasia, and remains to be validated in routine clinical practice according to recent proposal for new quantitative methods. It is often associated with pseudopyloric gland metaplasia in the gastric corpus mucosa, which expresses a type of trefoil peptide, the spasmolytic polypeptide (termed spasmolytic polypeptide-expressing metaplasia or SPEM) and has been shown to be linked more closely to gastric cancer than intestinal metaplasia. Better histological characterization of adenomatous (or type I), hyperplastic (foveolar or type II) and tubule-neck (mucocellular or type III) GED, two-tiered grading system (low and high grade dysplasia) as well as the introduction of Padova and Vienna international classifications of dysplasia seem to be more helpful in GED surveillance and comparative studies. A combination of histopathological features, serum markers such as pepsinogen I, and molecular tests that analyze host susceptibility polymorphisms and bacterial virulence factors, may allow development of strategies for early detection of cancer in the future. At present, pathobiology of gastric cancerogenesis is far from known, despite the progressive knowledge on predisposing environmental conditions and genetic and epigenetic abnormalities, including tumour suppressor genes, oncogenes, microsatellite instability and hypermethylation or the significance of E-cadherin mutational status association with hereditary diffuse gastric cancer syndrome. Recent evidence regarding the importance of several histopathologically derived prognostic factors, such as resection margin status and lymph node metastases and their implications have also been discussed. We aim to review these aspects, with special relevance to gastric cancer specimen reporting.

Common variable immunodeficiency disorders (CVIDs) are the most frequent symptomatic primary immunodeficiencies in adults. They comprise a heterogeneous group of pathologies, with frequent non-infectious complications in addition to the bacterial infections that usually characterize their presentation. Complications include a high risk of malignancy, especially lymphoma and gastric cancer. Helicobacter pylori infection and pernicious anaemia are risk predictors for gastric cancer in the general population and probably in patients with CVIDs. Screening for gastric cancer in a high-risk population appears to improve survival. Given the increased risk of gastric cancer in patients with CVIDs and prompted by a case of advanced gastric malignancy in a patient with a CVID and concomitant pernicious anaemia, we performed a review of the literature for gastric cancer and conducted a cohort study of gastric pathology in 116 patients with CVIDs under long-term follow-up in Oxford. Regardless of the presence of pernicious anaemia or H. pylori infection, patients with CVIDs have a 10-fold increased risk of gastric cancer and are therefore a high-risk population. Although endoscopic screening of all patients with CVIDs could be considered, a more selective approach is appropriate and we propose a surveillance protocol that should reduce modifiable risk factors such as H. pylori, in order to improve the management of patients with CVIDs at risk of gastric malignancy.

Approximately 9% of gastric carcinomas worldwide are associated with Epstein-Barr virus (EBV), making it the most frequent EBV-associated malignancy. Pernicious anemia, a condition with chronic gastritis and achlorhydria, is strongly associated with gastric carcinoma. Both chronic inflammation and the lack of stomach acid may influence the likelihood of EBV infection of the neoplastic gastric epithelium, but the prevalence of EBV-associated gastric carcinoma among patients with pernicious anemia is unknown. Therefore, we conducted a Danish nationwide case-control study comparing gastric carcinoma patients with pernicious anemia (PA-GC) with those without pernicious anemia (nonPA-GC), frequency matched 1:2. Tumor tissues were reclassified by expert histopathologists blinded to pernicious anemia and EBV status. In total, 186 samples (55 PA-GC and 131 nonPA-GC) were identified. EBV-associated gastric carcinoma (EBV-GC) was more common among PA-GC compared with nonPA-GC, adjusted odds ratio (OR) = 2.53 (CI: 0.88; 7.14), p = 0.08, with further adjustment for lymphocytic infiltrate OR = 2.94 (0.99-8.67), p = 0.05. Gastric carcinomas with signet-ring cell morphology were significantly less common in patients with PA-GC compared with nonPA-GC (OR = 0.05, CI 0.01; 0.24). Although these conditions are rare, we found suggestive evidence that EBV-associated gastric carcinomas are more common among gastric carcinoma patients with pernicious anemia compared with those without.

Acetaldehyde, associated with alcohol consumption, has recently been classified as a group 1 carcinogen in humans. Achlorhydric atrophic gastritis is a well-known risk factor for gastric cancer. Achlorhydria leads to microbial colonization of the stomach. Several of these microbes are able to produce significant amounts of acetaldehyde by oxidation from alcohol. Acetaldehyde can be eliminated from saliva after alcohol intake and during smoking with a semi-essential amino acid, L-cysteine. The aim of this study was to determine whether cysteine can be used to bind acetaldehyde in the achlorhydric stomach after ethanol ingestion.

Seven volunteers with achlorhydric atrophic gastritis were given either slow-release L-cysteine or placebo capsules in a double-blinded randomized trial. Volunteers served as their own controls. A naso-gastric tube was inserted to each volunteer. The volunteers ingested placebo or 200 mg of L-cysteine capsules, and ethanol 0.3 g/kg body weight (15 vol%) was infused intragastrically through a naso-gastric tube. Five-milliliter samples of gastric contents were aspirated at 5-minute intervals.

During the follow-up period, the mean acetaldehyde level of gastric juice was 2.6 times higher with placebo than with L-cysteine (13 vs. 4.7 μM, p < 0.05, n = 7).

L-cysteine can be used to decrease acetaldehyde concentration in the achlorhydric stomach during alcohol exposure. Intervention studies with L-cysteine are needed on reducing acetaldehyde exposure in this important risk group for gastric cancer.

Autoimmune metaplastic atrophic gastritis (AMAG) is an early manifestation of pernicious anemia that precedes the hematologic changes by years to decades. It is associated with metaplastic changes and neoplasms, including pyloric gland adenomas (PGAs). We investigated the frequency of PGAs and other lesions in all nonconsultation gastric biopsies and resections (1988 to 2008) diagnosed as AMAG. We further selected cases confirmed as AMAG by immunohistochemical identification of the gastric body (negative gastrin) and linear and nodular enterochromaffin-like cell hyperplasia (chromogranin). From this subset, all polyps and neoplasms were reviewed. We identified a total of 41,245 patients with gastric biopsies or resections from 46.7% males and 53.3% females comprising patients self-identified as 67.0% white, 23.6% African-American, 1.4% Asian, 0.8% non-White Hispanic, and 7.2% other or unknown. AMAG was diagnosed in 461 patients (1.1%), and had the following percentages based on race: 1.1% White, 1.3% African-American, 1.4% Asian, and 2.7% non-White Hispanic. The female:male ratio was 2:1 with an overall median age at presentation of 67.0 years. Of the 461 patients with AMAG, 143 had endoscopically identifiable lesions. These lesions (n=240) consisted of 179 polyps (138 hyperplastic polyps, 20 oxyntic mucosa pseudopolyps, 18 intestinal-type gastric adenomas, and 3 PGAs), 46 well-differentiated neuroendocrine neoplasms (carcinoid), 1 gastrointestinal stromal tumor, 3 lymphomas, and 11 adenocarcinomas. In summary, AMAG occurred with similar frequency across all racial groups. Although PGAs are associated with AMAG, they remain rare in the setting of AMAG.

Autoimmunity is clearly linked with hematologic malignancies, but less is known about autoimmunity and alimentary tract cancer risk, despite the specific targeting of alimentary organs and tissues by several autoimmune diseases. The authors therefore conducted the first systematic evaluation of a broad range of specific autoimmune diseases and risk for subsequent alimentary tract cancer.

On the basis of 4,501,578 US male veterans, the authors identified 96,277 men who developed alimentary tract cancer during up to 26.2 years of follow-up. By using Poisson regression methods, the authors calculated relative risks (RRs) and 95% confidence intervals.

A history of autoimmune disease with localized alimentary tract effects generally increased cancer risks in the organ(s) affected by the autoimmune disease, such as primary biliary cirrhosis and liver cancer (RR, 6.01; 95% confidence interval [CI], 4.76-7.57); pernicious anemia and stomach cancer (RR, 3.17; 95% CI, 2.47-4.07); and ulcerative colitis and small intestine, colon, and rectal cancers (RR, 2.53; 95% CI, 1.05-6.11; RR, 2.06; 95% CI, 1.70-2.48; and RR, 2.07; 95% CI, 1.62-2.64, respectively). In addition, a history of celiac disease, reactive arthritis (Reiter disease), and systemic sclerosis all were associated significantly with increased risk of esophageal cancer (RR, 1.86-2.86). Autoimmune diseases without localized alimentary tract effects generally were not associated with alimentary tract cancer risk, with the exception of decreased risk for multiple alimentary tract cancers associated with a history of multiple sclerosis.

These findings support the importance of localized inflammation in alimentary tract carcinogenesis. Future research is needed to confirm the findings and improve understanding of underlying mechanisms by which autoimmune diseases contribute to alimentary tract carcinogenesis.

In Orientals, deficient aldehyde dehydrogenase 2 (ALDH2) is associated with an increased risk for esophageal squamous cell carcinoma (ESCC). The local metabolism of carcinogenic acetaldehyde in the upper gastrointestinal tract could be involved in the association, but the underlying mechanism has not been fully elucidated. Since an anacidic stomach can promote bacteria-catalyzed local acetaldehyde production, the gastric acid level could also affect acetaldehyde metabolism. This study investigated whether ALDH2-related susceptibility to ESCC differs depending on the gastric secretion level.

Sixty-two patients with ESCC and sex- and age-matched normal controls were enrolled in this study. ALDH2 polymorphism was analyzed by polymerase chain-restriction fragment length polymorphism, and those with an inactive allele (ALDH2-1/2-2 or ALDH2-2/2-2) were defined as ALDH2 deficient. Gastrin-stimulated acid output was assessed by endoscopic gastrin test and hypochlorhydria was defined as 0.6 mEq/10 min or lower. Multiple logistic regression analyses were used to adjust for other potential confounders.

ALDH2 deficiency or hypochlorhydria was more prevalent in ESCC compared with controls and both showed increased independent associations with ESCC in multivariate analysis. Stratified analysis by the gastric acid secretion level revealed that the associations between the ALDH2 genotype and ESCC differed according to the individual gastric acid secretion levels and that ALDH2 deficiency was a significant risk factor for ESCC exclusively in individuals with hypochlorhydria with an odds ratio (95% confidence interval): 5.0 (1.2-21.2).

Microbial production of carcinogen acetaldehyde in the presence of gastric hypochlorhydria is most probably involved in the mechanism of ALDH2-related susceptibility to ESCC.