Risk stratification of synchronous gastric cancers including alcohol-related genetic polymorphisms.

BACKGROUND AND AIM: We previously identified that ever-smoking and severe gastric atrophy in pepsinogen are risk factors for synchronous gastric cancers (SGCs). This study aimed to determine the association of alcohol drinking status or alcohol-related genetic polymorphism with SGCs and also stratify their risk. METHODS: This multi-center prospective cohort study included patients who underwent endoscopic submucosal dissection for the initial early gastric cancers at 22 institutions in Japan. We evaluated the association of alcohol drinking status or alcohol dehydrogenase 1B (ADH1B) and acetaldehyde dehydrogenase 2 (ALDH2) genotypes with SGCs. We then stratified the risk of SGCs by combining prespecified two factors and risk factors identified in this study. RESULTS: Among 802 patients, 130 had SGCs. Both the ADH1B Arg and ALDH2 Lys alleles demonstrated a significant association with SGCs on multivariate analysis (odds ratio, 1.77), although alcohol drinking status showed no association. The rates of SGCs in 0-3 risk factors in the combined evaluation of three risk factors (ever-smoking, severe gastric atrophy in pepsinogen, and both the ADH1B Arg and ALDH2 Lys alleles) were 7.6%, 15.0%, 22.0%, and 32.1%, respectively. The risk significantly increased from 0 to 3 risk factors on multivariate analysis (P for trend <0.001). CONCLUSIONS: Both the ADH1B Arg and ALDH2 Lys alleles were at high risk for SGCs. The risk stratification by these three factors may be a less invasive and promising tool for predicting their risk.

Long-term endoscopic surveillance for Barrett's esophagus in Japan: Multicenter prospective cohort study.

OBJECTS: Although a recent study showed the cancer incidence of Barrett's esophagus (BE) to be 1.2%/year in 251 patient-years in Japan, the long-term outcomes remain unclear. The present study estimated the cancer risk of BE in Japan using our original prospective multicenter cohort. METHODS: A total of 98 patients with BE of maximum length of ≥2 cm were enrolled during the period of 2010-2012 and received at least one follow-up endoscopy over 5 years thereafter. Cancer incidence rates with 95% confidence interval for occurrence of esophageal adenocarcinoma (EAC) were calculated as the number of events divided by patient-years of follow-up and were expressed as %/year. RESULTS: Overall, the median endoscopic follow-up period was 59.9 (first and third quartiles, 48.5-60.8) months, constituting a total of 427 patient-years of observation. Since two EAC cases developed, the cancer incidence was 0.47% (0.01%-1.81%)/year. The cancer incidence was 0.39% (-0.16% to 2.44%) in 232 patient-years and 0.31% (-0.13% to 1.95%)/year in 318 patient-years for 55 cases with specialized intestinal metaplasia and 70 with BE ≥3 cm (maximum), respectively. At the end of follow-up, 12 of 92 patients (13.0%) died, but none died from EAC. CONCLUSION: This is the largest prospective follow-up study with endoscopy to investigate the incidence of EAC in unequivocal BE with the maximum length of ≥2 cm in Japan. Although a further large-scale study will be required to validate our results, the cancer risk of BE in Japan would be lower than previously reported (0.47% vs 1.2%/year).

Acute Gastric Volvulus Successfully Treated by Endoscopic Reduction in a 6-Year-Old Girl and a Review of the Japanese Literature.

A previously healthy 6-year-old girl suddenly developed severe abdominal pain and nausea. She was diagnosed with acute gastric volvulus, and a nasogastric tube was inserted to decompress the stomach. The volvulus did not reduce spontaneously; therefore, we performed endoscopic reduction on day 3 and were able to treat her successfully. We reviewed the Japanese literature on endoscopic reduction for gastric volvulus in children. Fifteen cases have been reported since 1994. There are no reports of perforation during the procedure. Patients whose general condition is stable and who have no severe anatomic anomalies are good candidates for endoscopic reduction.

Association between the body mass index and the risk of Barrett's esophagus in Japan.

BACKGROUND: We investigated the association between long-segment Barrett's esophagus and obesity in the Japanese population in a multicenter case-control trial. METHODS: One hundred thirteen patients with endoscopically detected Barrett's esophagus with a length of more than 2 cm and the same number of sex- and age-matched controls were prospectively enrolled. Barrett's esophagus was diagnosed based on the Prague C and M criteria. The body mass index (BMI) of the subjects was categorized into the following groups: normal, BMI <22.9; overweight, BMI 23.0-24.9, and obese, BMI >25.0. To determine the association between BMI and the risk of Barrett's esophagus, multivariate logistic regression analyses were performed. RESULTS: The basically adjusted regression model adjusted for smoking and alcohol consumption revealed that overweight and obesity were significantly associated with an elevated risk of Barrett's esophagus (OR 2.4, 95% CI 1.2-4.7, and OR 2.5, 95% CI 1.3-4.6, respectively). The intensity of the association was not attenuated even after adjustment for gastroesophageal reflux disease-related parameters. CONCLUSIONS: An increased BMI was associated with an increased risk for Barrett's esophagus through a gastroesophageal reflux-independent mechanism in the Japanese population. Further, unlike in Caucasian populations, being even slightly overweight with a BMI of 23.0-24.9 was an independent risk factor in the Japanese population.

Smoking history and severe atrophic gastritis assessed by pepsinogen are risk factors for the prevalence of synchronous gastric cancers in patients with gastric endoscopic submucosal dissection: a multicenter prospective cohort study.

BACKGROUND: No studies have evaluated the relationship between lifestyle and synchronous gastric cancers (SGCs) in patients with endoscopic submucosal dissection (ESD) for early gastric cancers (EGCs). Using data from the Tohoku gastrointestinal (GI) study, we aimed to identify factors associated with SGCs. METHODS: Tohoku GI study is a multicenter prospective cohort study investigating the relationship between lifestyle and metachronous gastric cancers. Patients who had a schedule to undergo ESD for primary EGCs were enrolled. We used logistic regression analysis to examine the relationship of 15 candidate factors, including lifestyle, with the prevalence of SGCs in this study. RESULTS: Of 850 patients between 2016 and 2019, 16.0% (136 patients) had SGCs. In multivariate analysis, smoking history (odds ratio [OR], 1.93; p = 0.048) and severe atrophic gastritis assessed by pepsinogen (OR, 1.92; p = 0.004) were risk factors for the prevalence of SGCs. Regarding smoking, current smoking (OR, 2.33; p = 0.021), but not former smoking (OR, 1.76; p = 0.098), was a significant risk factor for its prevalence. In the stratified analysis, severe atrophic gastritis assessed by pepsinogen was a risk factor in patients without Helicobacter pylori (H. pylori) eradication (OR, 2.10; p = 0.002), but not a risk factor in those with H. pylori eradication (OR, 0.75; p = 0.737). CONCLUSION: Smoking history was a risk factor for the prevalence of SGCs in patients with ESD for EGCs, and severe atrophic gastritis assessed by pepsinogen was also a risk factor when H. pylori was not eradicated.

[A case of gastric cancer accompanied by disseminated carcinomatosis of bone marrow with DIC, and subdural hematoma successfully treated with sequential methotrexate and 5-fluorouracil therapy].

A 44-year-old man visited a nearby hospital because of severe headache. Brain MRI revealed a subdural hematoma, and he was transferred to the Department of Neurosurgery of our hospital. Burr hole surgery was performed on the second day of hospitalization because of an enlargement of the hematoma. Laboratory data on admission showed the presence of a disseminated intravascular coagulation(DIC). Bone marrow aspiration revealed metastases of signet ring cell carcinoma, and abdominalCT showed gastric cancer. He was diagnosed as having DIC with bone marrow metastases of advanced gastric cancer. Despite anti-DIC therapy and blood transfusion, his systemic bleeding tendency was not improved. The neurosurgeon therefore consulted with a palliative care team. Since the patient was still young, we considered that he should be treated with anti-cancer drugs. At first, his family did not accept chemotherapy because they were pessimistic about his prognosis. However, after he regained his consciousness, we were able to perform sequential MTX and 5-FU therapy with the consent of the patient and his family. The therapy was successful, and he recovered from DIC and was discharged on the 57th hospital day.

[Autopsy case of abdominal compartment syndrome in a patient with schizophrenia].

A 61-year-old man who had taken several kinds of psychotropic agents for schizophrenia from eighteen was admitted due to acute abdomen. In spite of any treatment he died after arrival. The autopsy revealed marked dilation of gastrointestinal tracts without necrosis through stomach to rectum and pathological examination disclosed hypoganglionosis of whole gastrointestinal wall. We thought that he died of abdominal compartment syndrome as a result of acute on chronic secondary pseudo-obstruction of gastrointestinal tracts due to acquired hypoganglionosis, megacolon, and aerophagia.

[Two cases of primary unresectable and/or recurrent gastrointestinal stromal tumors of small intestine presenting hemoperitoneum caused by administration of imatinib mesylate].

Case1 was a 52-year-old man who had recurrence of postoperative intra-abdominal disseminations from gastrointestinal stromal tumor (GIST) of the jejunum. Case2 was a 66-year-old man who had GIST of the jejunum with multiple liver metastases. Two cases presented hemoperitoneum caused by administration of imatinib mesylate, and we conducted emergent surgery. In spite of surgically non-curative cases, it is suggested that the surgical management for GIST of high grade group with peritoneal exposure should be followed by the administration of imatinib mesylate.

[Examination of the shapes of the end of the common bile ducts after endoscopic sphincterotomy (EST)].

At the treatment of bile duct stones using EST, we sometimes experienced the difficult cases, even if the stones were small. For these cases, we tried endoscopic papillary balloon dilatation, and as a result knoches were made. And after the disappearance of the knoch, we could easily remove the stone. So we prospectively examined how often and at what cases, the knoches were made immediately after EST. As a result, knoches were present for 25% (13/52) of patients even after EST. Narrow distal segments of knoch-present patients were longer than that of knoch-absent patients, significantly. As a result, some function of sphincter was shown to be remained for a quarter of patients even after EST, and for these cases, the treatment of the stones may be difficult.

[Two cases of patients with hepatocellular carcinoma (HCC) that developed in cryptogenic cirrhosis suggestive of nonalcoholic steatohepatitis (NASH) as background liver disease after clinical courses of 26 years].

We report two cases of patients with hepatocellular carcinoma (HCC) that developed in cryptogenic cirrhosis suggestive of nonalcoholic steatohepatitis (NASH) as background liver disease. Case 1 was a 68-year-old woman, and case 2 was a 46-year-old man. They were admitted to our department for evaluation and treatment of HCC. The causes of the underlying liver disease were not determined from blood tests. However, histological analysis of non-tumor tissues of the liver revealed cirrhosis with few fat droplets. Both patients had undergone liver biopsy 26 years before the treatment of HCC. Histological review of the biopsy specimens revealed NASH (case 1) and fatty liver (case 2), respectively. It was suggested that these cases progressed from NASH and fatty liver, respectively, to NASH-related cirrhosis (so called burned-out NASH), eventually, developing HCC. These findings suggest that substantial number of burned-out NASH cases may be included in those with cryptogenic cirrhosis. These two patients are indicative cases that may reveal the long-term natural course of fatty liver and NASH.

Tochu (Eucommia ulmoides) leaf extract prevents ammonia and vitamin C deficiency induced gastric mucosal injury.

The ingestion of dietary antioxidants, including vitamin C (VC), is suggested to play an important role in the prevention of gastric cancer associated with Helicobacter pylori (HP) infection. Recently, water extracts of Tochu (Du-zhong, Eucommia ulmoidea OLIVER) leaves (WETL) have been reported to have potent antioxidant and antimutagenic effects. The present study investigated the effect(s) of VC and WETL on gastric mucosal injury induced by ammonia and a VC deficient diet. Guinea pigs fed the water containing ammonia and/or a VC-deficient diet were simultaneously treated with WETL or VC. Intramucosal levels of thiobarubiturate reactive substances (TBARS), an index of lipid peroxidation, increased significantly in animals fed ammoniated water and VC-deficient diets. This was accompanied by accelerated cell proliferation and increases in immunohistochemical staining indices for oxidative stress-induced DNA adducts and strand breaks (e.g., BrdU-uptake, 8-OhdG, ssDNA and the TUNEL reaction). The administration of either WETL or VC to the ammoniated water and VC-deficient diets ameliorated the increases in intramucosal TBARS levels and labeling indices of BrdU, 8-OHdG, ssDNA and TUNEL, i.e., the levels were similar to those measured in the normal-fed control animals. These data suggest that insufficient VC ingestion may be an important risk factor for gastric cancer development in patients with HP infections. Furthermore, our results suggest that WETL or some constituent may contribute to the prevention of oxidative gastric injury that precedes carcinogenesis.

[Influence of urease activity of the oral cavity and oropharynx on 13C-urea breath test].

We examined whether 13C-urea breath test with powdered 13C-Urea is affected with urease activity in the oral cavity and oropharynx in H. pylori negative cases. We also examined whether the degree of gargling affects the results of 13C-UBT. The results demonstrated that the urease activity not only in the oral cavity, but in the oropharynx may influence the UBT value. Therefore, it is possible that the UBT value may be affected with relic urease activity in the oropharynx if only the oral cavity is gargled. In conclusion, Gargling of the oropharynx in addition to the oral cavity is important to obtain true negative diagnosis with 13C-UBT in patients without Helicobacter pylori infection.

[Reflux esophagitis after H. pylori eradication].

We have reported that prevalence of H. pylori infection and grade of atrophic gastritis were significantly lower, while acid secretion was significantly greater in the patients with reflux esophagitis than those without it. We have also reported that increased gastric acid secretion after H. pylori eradication may explain a reason for developing reflux esophagitis. Therefore, H. pylori is considered to be a protective factor for the development of reflux esophagitis via the induction of gastric hyposecretion. Conversely, according to recent large population-based studies, no evidence was obtained that supports the increased frequency of heartburn symptoms or reflux oesophagitis after the eradication of H. pylori. One reason for the discrepancy may be the difference in the evaluation of gastro-esophageal reflux, another reason may be the difference in acid secretion before the clearance of H. pylori in individual subjects, because the effects of H. pylori on acid secretion vary from patient to patient.

[A case of spontaneous complete necrosis of hepatocellular carcinoma sized 10cm in diameter demonstrated by the resected specimen].

A 68-year-old man with chronic hepatitis C and of a heavy drinker was admitted to our hospital because of a huge liver tumor (10cm in diameter) in segment-5 detected on CT in July 2009. One month later, the size of liver tumor was reduced to 5cm in diameter and another liver tumor of 1cm in segment-3 was detected on CT. AFP and AFP-L3 spontaneously decreased to normal range. In October, a partial hepatectomy was performed. The resected specimen demonstrated complete necrosis with thick capsule. The tumor in segment-3 became equivocal without resection. We considered this is a case of spontaneous complete necrosis of hepatocellular carcinoma.

Long-term outcomes of gastric mucosa-associated lymphoid tissue lymphomas after Helicobacter pylori eradication therapy.

Mucosa-associated lymphoid tissue (MALT) lymphomas are localized primarily in the gastrointestinal tract and are characterized by an indolent nature and favorable outcome with specific therapy. Gastric MALT lymphomas are closely linked to Helicobacter pylori (H. pylori) infection, for which eradication therapy is recognized as an effective primary treatment for the disease. However, there is little information about long-term outcomes after the therapy. In the present study, we elucidated the long-term outcomes of 74 patients (70 H. pylori-positive and 4 negative cases) followed up by endoscopy at least 12 months after exclusive eradication therapy alone. The median follow-up period was 46 months. When the remission status was estimated at the time point of 12 months post-eradication, the numbers of patients with complete remission (CR), histologically residual disease with macroscopic normalization (hRD), partial remission with more than 50% tumor reduction (PR) or no response (NR) were 56, 12, 2 and 4, respectively. During follow-ups of over 12 months post-eradication, 11 of the 12 hRD cases were belatedly induced to CR but one CR case histologically relapsed into hRD. One of the 2 PR cases eventually turned into hRD 20 months later. Therefore, 66 CR, 3 hRD, 1 PR, and 4 NR cases (including 3 H. pylori-negative) were identified at the last follow-up of the present study. All 74 patients were followed up without any second-line therapies, but none exhibited disease progression. Thus, the long-term outcome of localized gastric MALT lymphoma after H. pylori eradication therapy was favorable. A watch and wait strategy may be a reasonable approach for hRD since the majority might be in the process of turning into delayed CR.

Expression of Mg2+-dependent, HCO3- -stimulated adenine triphosphatase in the human duodenum.

BACKGROUND AND AIM: Mg2+-dependent, HCO3- -stimulated adenine triphosphatase (Mg2+-HCO3- -ATPase) is an enzyme that catabolizes ATP in the presence of HCO3- and Mg2+. The activity of this ATPase is known to be present in the duodenum, but its physiological role remains unclear. In the present study, the aim was to study the distribution and biochemical profiles of Mg2+-HCO3- -ATPase in the human duodenum. METHODS: The histochemistry of Mg2+-HCO3- -ATPase, its localization using electron microscopy (EMS), and the measurement of enzyme activity were carried out by using mucosal samples of the bulb, and the second and third portions of the duodenum, obtained from six volunteers by endoscopic biopsy. RESULTS: The Mg2+-HCO3- -ATPase was detected in the brush border along the luminal surface of human duodenal epithelial cells. The EMS confirmed its localization to the surface of microvilli. The activity of Mg2+-HCO3- -ATPase was higher in the distal portions of the human duodenum than in the bulb. Its maximal activity was obtained under a pH of 8.5, and in the presence of 1.0 mmol/L MgCl2 and 50 mmol/L NaHCO3, but the activity was undetectable in pH <7.4 or >9.5. CONCLUSION: The results of the present study suggested that Mg2+-HCO3- -ATPase may work for luminal alkalization in the distal portions of the human duodenum and may contribute to maintaining the activity of pancreatic digestive enzymes.

Contribution of glutamine synthetase to ammonia-induced apoptosis in gastric mucosal cells.

BACKGROUND/AIMS: Glutamine synthetase is a key enzyme necessary for ammonia detoxification in the brain, but excessive activation of this enzyme can be cytotoxic to neural cells as a consequence of excessive consumption of ATP and glutamate. The stomach also expresses high levels of glutamine synthetase and this study aimed to investigate a possible pathophysiological role of glutamine synthetase in ammonia-induced gastric mucosal injury. METHODS: Normal rat gastric mucosal epithelial (RGM-1) cells were treated with ammonia, and a specific glutamine synthetase inhibitor (methionine sulfoximine) was used to assess the action of glutamine synthetase. RESULTS: Treatment with ammonia induced apoptotic cell death. Increased expression of p21 and Bax, decreased expression of Bcl-2, cytochrome C release from the mitochondria into the cytosol and subsequent activation of caspase-9 and -3 were identified in the cells treated with ammonia, although there was no apparent change in p53 expression. On the other hand, pretreatment with various concentrations of methionine sulfoximine reduced the glutamine synthetase activity in ammonia-treated RGM-1 cells, and prevented the induction of apoptosis and the reduction in intracellular ATP levels in a dose-dependent manner. CONCLUSIONS: Our results suggested that the energy exhaustion which resulted from an overload of ammonia to glutamine synthetase may have initiated the apoptotic signaling in gastric mucosal cells.

Oligomycin and antimycin A prevent nitric oxide-induced apoptosis by blocking cytochrome C leakage.

Nitric oxide (NO) is a potent inducer of apoptosis, and its cytotoxicity is closely related to mitochondrial dysfunction. In this study we investigated the effects of a F0F1-ATPase inhibitor, oligomycin, and a mitochondrial respiratory chain complex III inhibitor, antimycin A, on NO-induced apoptosis. We used a normal rat gastric-epithelium cell line, RGM-1, treated with a pure NO donor, NOC-1 -1-hydroxy-2-oxo-3,3-bis(2-aminoethyl)-1-triazene - in the presence or absence of oligomycin or antimycin A. Changes in the expressions of Bax or Bcl-2 proteins, release of cytochrome C from mitochondria into the cytosol, activation of caspase-3, and changes in the mitochondrial membrane potential (DeltaPsi) were measured with the use of Western blotting, c43 lorimetric assays, and a mitochondrial potential sensor, JC-1 dye. Treatment with NOC-18 induced dose-dependent apoptotic cell death in RGM-1 cells. Cell death was accompanied by mitochondrial depolarization, increases in Bax protein expression and cytochrome C leakage, and, subsequently, caspase-3 activation. Oligomycin and antimycin A prevented NO-induced apoptosis in a dose-dependent fashion by preventing cytochrome C release independent of Bcl-2 expression. However, neither compound affected the up-regulation of Bax protein. On the one hand, oligomycin treatment was not accompanied by a decline in DeltaPsi. On the other hand, antimycin A treatment decreased DeltaPsi regardless of NOC-18 treatment. The findings of this study suggest that various functional molecules that constitute the mitochondrial respiratory chain may contribute to cytochrome C release that occurs during NO-induced apoptosis.

High levels of intracellular ATP prevent nitric oxide-induced apoptosis in rat gastric mucosal cells.

Nitric oxide (NO) plays an important role in gastric mucosal injury in the human stomach. Exposure to excessive NO leads to apoptosis; however, the mechanism remains largely unknown in gastric epithelial cells. The apoptotic process is modulated by energy states in cells. This study investigated molecular mechanisms of NO-induced apoptosis in gastric epithelial cells and influence of high glucose on those mechanisms. Normal rat gastric mucosal epithelial (RGM-1) cells were cultured in media containing either 1000 (low) or 4500 mg/l (high) of D-glucose. When the cells were incubated with a chemical NO donor NOC18, apoptosis was induced in a dose-dependent manner. Intracellular adenosine triphosphate (ATP) levels significantly increased in the cells cultured with high glucose in comparison with the low-glucose condition. The cells with high ATP levels were more resistant to NO-induced apoptosis than the cells with low ATP levels. NO-induced apoptosis was followed by mitochondrial depolarization, upregulation of Bax protein, cytochrome C release from mitochondria to the cytosol and subsequent caspases activation. These results suggest that NO inhibition of mitochondrial respiratory system and acute ATP depletion initiate apoptotic signalling in gastric epithelial cells. High glucose may prevent NO-induced apoptosis by leading to high levels of intracellular ATP or other metabolic changes in this cell line.