A multicenter prospective study of the treatment and outcome of patients with gastroduodenal peptic ulcer bleeding in Japan.

Gastroduodenal peptic ulcers are the main cause of nonvariceal upper gastrointestinal bleeding (UGIB). We believe that recent advances in endoscopic techniques and devices for diagnosing upper gastrointestinal tract tumors have advanced hemostasis for UGIB. However, few prospective multicenter studies have examined how these changes affect the prognosis. This prospective study included 246 patients with gastroduodenal peptic ulcers treated at 14 participating facilities. The primary endpoint was in-hospital mortality within 4 weeks, and the secondary endpoints required intervention and refractory bleeding. Subsequently, risk factors affecting these outcomes were examined using various clinical items. Furthermore, the usefulness of the risk stratification using the Glasgow-Blatchford score, rockall score and AIMS65 based on data from the day of the first urgent endoscopy were examined in 205 cases in which all items were complete there are two periods. Thirteen (5%) patients died within 4 weeks; and only 2 died from bleeding. Significant risk factors for poor outcomes were older age and severe comorbidities. Hemostasis was required in 177 (72%) cases, with 20 cases of refractory bleeding (2 due to unsuccessful endoscopic treatment and 18 due to rebleeding). Soft coagulation was the first choice for endoscopic hemostasis in 57% of the cases and was selected in more than 70% of the cases where combined use was required. Rockall score and AIMS65 predicted mortality equally, and Glasgow-Blatchford score was the most useful in predicting the requirement for intervention. All scores predicted refractory bleeding similarly. Although endoscopic hemostasis for UGIB due to peptic ulcer had a favorable outcome, old age and severe comorbidities were risk factors for poor prognosis. We recommend that patients with UGIB should undergo early risk stratification using a risk scoring system.

POGLUT1, the putative effector gene driven by rs2293370 in primary biliary cholangitis susceptibility locus chromosome 3q13.33.

Primary biliary cholangitis (PBC) is a chronic and cholestatic autoimmune liver disease caused by the destruction of intrahepatic small bile ducts. Our previous genome-wide association study (GWAS) identified six susceptibility loci for PBC. Here, in order to further elucidate the genetic architecture of PBC, a GWAS was performed on an additional independent sample set, then a genome-wide meta-analysis with our previous GWAS was performed based on a whole-genome single nucleotide polymorphism (SNP) imputation analysis of a total of 4,045 Japanese individuals (2,060 cases and 1,985 healthy controls). A susceptibility locus on chromosome 3q13.33 (including ARHGAP31, TMEM39A, POGLUT1, TIMMDC1, and CD80) was previously identified both in the European and Chinese populations and was replicated in the Japanese population (OR = 0.7241, P = 3.5 × 10-9). Subsequent in silico and in vitro functional analyses identified rs2293370, previously reported as the top-hit SNP in this locus in the European population, as the primary functional SNP. Moreover, e-QTL analysis indicated that the effector gene of rs2293370 was Protein O-Glucosyltransferase 1 (POGLUT1) (P = 3.4 × 10-8). This is the first study to demonstrate that POGLUT1 and not CD80 is the effector gene regulated by the primary functional SNP rs2293370, and that increased expression of POGLUT1 might be involved in the pathogenesis of PBC.

Bleeding Risk Related to Upper Gastrointestinal Endoscopic Biopsy in Patients Receiving Antithrombotic Therapy: A Multicenter Prospective Observational Study.

BACKGROUND: Although antithrombotic agents are widely used for cardiac and cerebrovascular disease prevention, they increase the risk of gastrointestinal (GI) bleeding. OBJECTIVE: To examine GI bleeding risk in association with an esophagogastroduodenoscopy (EGD) biopsy performed in patients without cessation of antithrombotic therapy. METHODS: This study was prospectively conducted at 14 centers. EGD biopsies were performed in patients receiving antithrombotic agents without cessation, as well as age- and sex-matched controls not receiving antithrombotic therapy. Patients treated with warfarin before the biopsy had a prothrombin time-international normalized ratio level <3.0. The proportion of GI bleeding events was compared between the groups. RESULTS: The patient group (n = 277) underwent a total of 560 biopsies while continuing antithrombotic therapy, of whom 24 were receiving multiple antiplatelet drugs, and 9 were receiving both antiplatelet and anticoagulant agents. The control patients (n = 263) underwent 557 biopsies. The upper-GI bleeding rate within 30 days after the EGD biopsy did not increase in patients without cessation of antithrombotic treatment, regardless of receiving single or multiple antithrombotic agents. CONCLUSIONS: We found no significant increase in upper-GI bleeding risk following an EGD biopsy in patients taking antithrombotic agents, suggesting its safety without the need for antithrombotic treatment interruption.

Clinicopathological and patient characteristics of early gastric neoplasia endoscopically resected with loss of Mlh1 expression.

Hypermethylation of the promoter region of the MLH1 gene leads to loss of Mlh1 protein expression and plays a key role in the development of gastric cancer. Little is known about the association between Mlh1 expression and the clinicopathological and patient characteristics in early gastric neoplasia, particularly in endoscopically resected tumors. Immunohistochemistry was used to examine Mlh1 expression in 140 early gastric neoplasias obtained by endoscopic resection and comprising 31 gastric adenomas (GAs) and 109 early gastric cancers (EGCs), and compared them to corresponding clinicopathological and patient data. P53 expression and phenotypic profiles were also analyzed. The rate of reduced Mlh1 expression and P53 overexpression was 9.6 and 6.5% in GAs, and 27.5 and 27.5% in EGCs, respectively. In elderly patients (≥65 years of age), the aberrant expression of Mlh1 in EGCs was more significant in female than in male patients (59.9 vs. 29.8%; P=0.016). In addition, the frequency of aberrant Mlh1 expression in EGCs increased significantly in patients with oncological family histories and elevated gross type (P=0.033 and P=0.04, respectively). Moreover, a significant correlation was observed among aberrant Mlh1, P53-negative and HGM expression. The present findings suggest that loss of Mlh1 expression is associated with age, gender, oncological family history and tumor growth pattern in EGC. Patient and tumor characteristics are key factors in the screening, surveillance and diagnosis of early gastric neoplasia, particularly in elderly individuals.

Premalignant lesions in gastric cancer.

Despite a plateau in incidence, gastric cancer is one of the most common cancers worldwide and causes considerable morbidity and mortality. Premalignant gastric lesions are well known risk factors for the development of intestinal-type gastric adenocarcinomas. In this multistep model of gastric carcinogenesis, Helicobacter pylori causes chronic active inflammation of the gastric mucosa, which slowly progresses through the premalignant stages of atrophic gastritis, intestinal metaplasia, and adenoma/dysplasia to gastric carcinoma. This progression is paralleled by a stepwise accumulation of multiple genetic and epigenetic abnormalities. Detection, treatment, and molecular analyses of premalignant lesions may thus provide a basis for gastric cancer prevention. This review describes an overview of current knowledge on premalignant gastric lesions. It also reviews the issue of surveillance of patients with premalignant lesions in order to improve the survival of patients with gastric cancer.

[Case of villous tumor of the rectum presenting with severe diarrhea and electrolyte depletion syndrome].

A 83-year-old man with a 2-year history of diarrhea was admitted hospital because of increased diarrhea and general fatigue. He had severe dehydration, hyponatremia, hypokalemia and hypochloremia. Abdominal CT showed tumor and fluid in the rectum. Colonoscopy revealed large tumor with a villous structure in the rectum. Low anterior resection was performed. The histopathological diagnosis was adenocarcinoma with villous adenoma. The immunostaining of the tumor revealed positive COX-2 expression. The diarrhea and electrolyte disturbance disappeared after the resection of tumor.

[A case of splenic abscess in which percutaneous abscess drainage was an effective].

An eighty-six-year-old man was admitted to our hospital for bacterial septic shock due to splenic abscess. He had undergone percutaneous coronary intervention 3 weeks earlier. Percutaneous splenic abscess drainage was urgently performed under ultrasonography, and then the general state of the patient rapidly improved. Staphylococcus hemolyticus was isolated from the splenic abscess. We reported that percutaneous catheter drainage was effective for splenic abscess.

Fhit, Mlh1, P53 and phenotypic expression in the early stage of colorectal neoplasms.

There are two different pathways for the development of colorectal carcinoma (CRC), adenoma-carcinoma sequence (ACS) and de novo (DN) carcinogenesis. To clarify the molecular and clinicopathological characteristics in colorectal carcinogenesis, we examined endoscopically resected specimens of 30 adenomas, 30 carcinoma in adenomas (CIAs), and 18 early pure colorectal carcinomas without any adenoma component (EPCs, so called DN carcinoma) and compared the expression of Fhit, Mlh1, Msh2, P53 and cellular phenotype (HGM, MUC2 and CD10). Markedly reduced or absent Fhit expression was noted in 8 (44%) of 18 EPCs, but none of the adenomas or CIAs (p<0.0001). Six (33%) of 18 EPCs showed loss of Mlh1 expression, but rarely in adenomas and CIAs (p=0.008). This altered Fhit expression was significantly higher in submucosal invasive cancers (p=0.001), lymphatic or venous invasive cancers (p=0.0018), and tumors with altered expression of Mlh1 (p=0.01). The incidence of P53 overexpression was significantly higher in EPCs (39%) and CIAs (27%) than in adenomas (3.3%) (p<0.05). There were significant differences in phenotypic expression between the adenomatous and carcinomatous areas. Moreover, in CIAs and EPCs, the rate of P53 overexpression was significantly higher in the CD10-positive cases (53%) than CD10-negative cases (19%) (p=0.04). The present findings suggested that aberrant Fhit and Mlh1 expression could be related to DN carcinogenesis and that P53 overexpression and changes in phenotypic expression could contribute to the malignant transformation of colorectal precursor lesions.

Expression of Fhit, Mlh1, p16INK4A and E-cadherin in early gastric neoplasia: Correlation with histological grade and gastric phenotype.

An increasing number of tumor suppressor genes (TSGs) that are inactivated by hypermethylation of CpG islands in the promoter have been reported in gastric carcinomas. The aim of this study is to evaluate the clinical significance of TSG protein expression, which correlates with the promoter status, methylated or not, during the early stages of gastric carcinogenesis and to examine its relationship with mucin phenotype. The protein expression of 4 TSGs including Fhit, Mlh1, p16INK4A and E-cadherin was examined using immunohistochemical methods in 103 early gastric neoplasias, comprising 41 adenomas and 62 intramucosal carcinomas, obtained by endoscopic mucosal resection. In addition, phenotypic expression patterns (gastric-, intestinal- and mixed-phenotypes) were also examined. The expression of Fhit, Mlh1, p16 and E-cadherin was lost or reduced in 7.3, 12.2, 12.2 and 9.8% of the adenomas and in 35.5, 29.0, 29.0 and 32.3% of the intramucosal carcinomas, respectively. The absent expression of p16 was significantly associated with the degree of dysplasia in the adenomas (p=0.038). The average number of proteins among the 4 TSGs, whose expression was lost or reduced per sample, was significantly higher in the intramucosal carcinomas (1.35) than in the adenomas (0.41) (p=0.00013). Similarly, the average number was significantly higher in the gastric-type tumors (2.05) than in the intestinal-type tumors (0.49) (p=0.0000019). We demonstrated an increase in the number of TSG proteins whose expression is reduced or lost in the early stages of gastric tumorigenesis, and that this increase is associated with histological grade and gastric phenotype.

[Two cases of primary T cell lymphoma of the small intestine diagnosed by perforated peritonitis].

We encountered 2 cases (a 28-year-old man and a 63-year-old woman) of primary T cell lymphoma of the small intestine diagnosed by perforated peritonitis. T cell lymphoma perforates the small intestine more easily than B cell lymphoma, because T cell lymphoma infiltrates the intestinal tract wall, and forms an ulcerative tumor.

Development of hypoxemia in alcoholic liver disease.

The aim of this study was to investigate the arterial hypoxemia in Japanese patients with alcoholic liver disease (ALD) with regard to alcohol consumption and/or disease severity. Hypoxemia was observed in 78% patients with ALD and in all 46 patients with alcoholic liver cirrhosis (ALC) and 33 (56%) of 59 patients with noncirrhotic alcoholic liver disease (NCALD) (P < 0.0001). The partial pressure of oxygen (PaO2) was 71.1 +/- 5.2 mm Hg in ALC and 78.7 +/- 6.3 mm Hg in NCALD (P < 0.0001). The oxygen consumption in ALD was significantly higher than that in control subjects (P < 0.0001), and a high oxygen consumption was seen in 88% of the patients with ALD, in all 46 ALC patients, and in 46 (78%) of 59 NCALD patients (P < 0.01). Following abstinence from alcohol, the PaO2 and oxygen consumption significantly recovered after day 2 (P < 0.0001), whereas the prothrombin index did not change in either NCALD or ALC patients. Multivariate analysis showed that alcohol consumption and oxygen consumption were significant independent predictors of PaO2. In conclusion, the present findings suggest that increased oxygen consumption due to alcohol ingestion is principally responsible for the hypoxemia in ALD patients.

Expression of Fhit, Mlh1, and P53 protein in human gallbladder carcinoma.

There is limited information on the molecular changes involved in the pathogenesis of gallbladder carcinoma (GBC). The Fragile Histidine Triad (FHIT) gene, encompassing the FRA3B fragile site at chromosome 3p14.2, is a candidate tumor suppressor gene in a variety of human malignancies. Recent studies have suggested that Fhit inactivation can be a consequence of defects in mismatch repair proteins. We analyzed Fhit and Mlh1 protein expressions using immunohistochemical methods in 20 GBCs and three gallbladder adenomas (GBAs) to elucidate the role of Fhit protein in gallbladder carcinogenesis. In addition, we examined whether Fhit and Mlh1 protein expressions correlated with P53 expression and clinicopathological findings. Significant loss or reduction in Fhit expression was noted in nine (45%) of the GBCs and one of the GBAs. Loss of Mlh1 protein expression was detected in six (30%) of the GBCs and one of the GBAs. Reduced Fhit expression was significantly associated with the absence of Mlh1 protein expression in the GBCs and the GBAs (p=0.0186). P53 overexpression was present in 11 (55%) of the GBCs, but none of the GBAs. Fhit and Mlh1 protein expressions were not significantly associated with P53 expression and clinicopathological findings. These results suggested that reduced Fhit expression might be involved in the development of GBC and be correlated with Mlh1 expression.

Hyperendothelinemia and ICG clearance in alcoholic and nonalcoholic cirrhosis.

Plasma endothelin (ET) levels are generally increased in cirrhosis patients in line with the severity of disease; however, the pathophysiological significance remains to be clarified. We evaluated the plasma ET levels in 49 patients with alcoholic cirrhosis and in 53 patients with nonalcoholic cirrhosis of the same disease severity. The plasma ET level was significantly elevated in alcoholic patients (P < 0.0001) and slightly so in nonalcoholic patients (P < 0.01); the difference was significant between the groups (P < 0.0001). The plasma ET level was positively correlated with the Child-Pugh score (P < 0.0001) and negatively correlated with prothrombin index (P < 0.001) and indocyanine green (ICG) clearance (P < 0.0001). The plasma ET level decreased 32% in alcoholic patients after abstinence (P < 0.001), but remained correlated with ICG clearance (P < 0.001) and the Child-Pugh score (P < 0.01), but not with prothrombin index. Regression analysis revealed that the plasma ET level was correlated with estimated hepatic blood flow and alcohol abuse. These findings suggest that hyperendothelinemia in cirrhosis patients is related to alcohol abuse and disease severity, especially to impaired hepatic hemodynamics.