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A 53-year-old woman was admitted because of a giant pancreatic tumor. Hypercalcemia and a high serum parathyroid hormone-related peptide (PTHrP) level were observed. A hypoglycemic attack occurred during pancreatectomy, and the surgical specimen revealed a PTHrP-secreting glucagonoma. Liver metastases developed 1 and 5.5 years later, and bone metastases appeared 6 years after surgery. Her serum PTHrP concentrations remained normal after surgery, despite re-elevation of the serum glucagon concentration after recurrence. The clinical course of this case illustrates the process of development of neuroendocrine tumors secreting two or more hormones.

Two patients developed segmental, diffuse intrahepatic recurrence after percutaneous radiofrequency ablation (RFA) to treat a primary, solitary, and small (2.5 cm) hepatocellular carcinoma (HCC). Despite the size of the HCC, levels of the tumor markers (α-fetoprotein, α-fetoprotein-L3%, and des-γ-carboxyprothrombin) were all elevated before RFA, and tumors in both patients were contiguous with a major branch of the portal vein. Tumor biopsies of both patients revealed moderately differentiated HCC but diagnostic imaging showed an area of reduced tumor blood flow, suggesting a poorly differentiated component. Since early detection of post-RFA malignancies by standard ultrasonography and contrast-enhanced computed tomography was difficult, the most sensitive indicator of recurrence in these two patients was the elevated tumor markers. The diffuse intrahepatic recurrence was thought to be caused by increased intratumoral pressure during RFA, resulting in the dissemination of cancer cells through the contiguous portal vein. The clinical course of these tumors indicate that the choice of RFA should be carefully considered when treating specific subtype of HCC that is adjacent to main portal vein branch and involves a possible poorly differentiated component and that surgical resection or combinations of RFA with other treatment modalities such as transcatheter arterial chemoembolization should be considered as alternative treatment strategies.

To clarify the alterations in lower intestinal microflora induced by gastric acid reduction, the dynamics of 12 major genera or groups of bacteria comprising the microflora in feces and colonic contents were examined by quantitative real-time PCR in proton pump inhibitor-treated rats and in asymptomatic human subjects with hypochlorhydria. In both rat and human experiments, most genera or groups of intestinal microflora (facultative and obligate anaerobes) proliferated by gastric acid reduction, and marked and significant increases in the Lactobacilli group and Veillonella, oropharyngeal bacteria, were observed. In rats, potent gastric acid inhibition led to a marked and significant increase of intestinal bacteria, including the Bacteroidesfragilis group, while Bifidobacterium, a beneficial bacterial species, remained at a constant level. These results strongly indicate that the gastric acid barrier not only controls the colonization and growth of oropharyngeal bacteria, but also regulates the population and composition of lower intestinal microflora.

Congenital portal systemic encephalopathy without liver cirrhosis and/or portal hypertension is rare. An 86-year-old man with senile dementia was admitted due to disturbance of consciousness. His serum ammonia level was high, but there was no evidence of liver cirrhosis or portal hypertension on laboratory tests and upper abdominal enhanced computed tomography (CT). However, on lower abdominal enhanced CT, a meso-caval shunt was found in the right lower abdomen. Superior mesenteric arteriography revealed a shunt flowing into the inferior vena cava via the right gonadal vein. The shunt was closed by balloon occluded retrograde transvenous obliteration, and dementia-like symptoms improved.

A total of 5,209 asymptomatic, middle-aged subjects, whose serum pepsinogen (PG) and Helicobacter pylori antibody levels had been assessed, were followed for 10 years. Subjects with positive serum H. pylori antibodies (>50 U/mL) had an increased cancer risk (HR = 3.48, 95% CI = 1.26–9.64). Risk of gastric cancer increased as the antibody level increased; the H. pylori-positive group with antibody levels >500 U/mL had the highest incidence rate (325/100,000 person-years). Cancer development also increased with a reduced serum PG I level or a reduced PG I/II ratio; the risk was significantly elevated with serum PG I level ≤30 ng/mL (HR = 3.54, 95% CI = 1.95–6.40) or PG I/II ratio ≤3.0 (HR = 4.25, 95% CI = 2.47–7.32). Furthermore, the risk of diffuse-type cancer increased as PG II level increased; it was significantly elevated with PG II level ≥30 ng/mL (HR = 3.81, 95% CI = 1.10–13.21). Using H. pylori antibody and PG levels, subgroups with an especially high or low cancer incidence rate could be identified. H. pylori-negative or indeterminate subjects with low PG level (PG I ≤30 ng/mL or PG I/II ratio ≤2.0) or H. pylori-positive subjects with antibody levels >500 U/mL and a low PG level were among the subgroups with a high cancer incidence rate (over 400/100,000 person-years). In contrast, H. pylori-negative subjects with a PG I level >70 ng/mL or a PG I/II ratio >3.0 had the lowest risk; none of these subjects developed cancer. Thus, serum PG levels and/or H. pylori antibody levels can be used to predict the risk of cancer in individuals with H. pylori-related gastritis from the general population. © 2008 Wiley-Liss, Inc.

Background: Gastric cancer screening using the pepsinogen filter test is receiving wide recognition in Japan owing to convenience, freedom from discomfort or risk, efficiency, and economy. Because the long-term outcomes of cancer development in extensive atrophic gastritis detected by pepsinogen test are unclear, test-positive and test-negative subjects were investigated in a longitudinal cohort study. Methods: Subjects comprised 5,209 middle-aged men with measured serum pepsinogen levels who were followed for 10 years. Cancer development based on “atrophy-positive” and “atrophy-negative” criteria used for cancer screening was investigated. Results: During the study, 63 cases of cancer developed in the cohort, representing an incidence rate of 125 per 100,000 person-years. Pepsinogen test screening using the most widely used atrophy-positive criterion (pepsinogen I, ≤70 ng/mL; pepsinogen I/II ratio, ≤3.0) displayed 58.7% sensitivity, 73.4% specificity, and 2.6% positive predictive value. Cancer incidence rate was 276 per 100,000 person-years for the atrophy-positive group and 70 per 100,000 person-years for the atrophy-negative group. Incidence rate was higher in groups fulfilling stricter positive criteria detecting more extensive atrophy, reaching 424 per 100,000 person-years. In addition, 9.2% of atrophy-negative subjects with pepsinogen I of >70 ng/mL and pepsinogen I/II ratio of ≤3.0 (reflecting putative inflammation-based high pepsinogen II level) are at high risk for cancer, particularly diffuse-type cancer, with a cancer incidence rate comparable with atrophy-positive subjects (216 per 100,000 person-years). Conclusion: Atrophy-positive subjects by pepsinogen filter test, particularly those fulfilling stricter criteria, and atrophy-negative subjects with low pepsinogen I/II ratio reflecting putative extensive active inflammation constitute populations at high risk for gastric cancer, requiring thorough endoscopic examination. (Cancer Epidemiol Biomarkers Prev 2008;17(4):838–45)

We have previously reported that serum pepsinogen (PG) can quantify the level of gastric mucosal atrophy, and that H. pylori eradication reduces cancer development in subjects with mild atrophy identified by serum PG levels. The aim of this study was to elucidate the predictive ability of serum PG levels for the development of metachronous gastric cancer (MGC) after endoscopic resection (ER) of primary cancer in association with H. pylori eradication. A retrospective chart review was performed, and 330 patients who underwent ER for initial early gastric cancer were enrolled. Presence or absence of H. pylori, serum PG levels, and endoscopic atrophy at ER were evaluated. H. pylori eradication was performed at the patient's request after ER. The incidence of MGC in these patients was analyzed. Of 330 patients, 47 developed MGC. Endoscopic extensive atrophy was observed more frequently in patients with MGC (p = 0.001). Although PG I or PG II alone did not significantly differ according to development of MGC, the proportion of PG I/II ≤ 3.0, which is one of the criteria of PG test-positive, was significantly higher in patients with MGC (83 vs. 69%, p = 0.04). H. pylori eradication after ER did not affect MGC development (p = 0.2). On multivariate analysis, serum PG I/II ratio ≤ 3.3 was significantly associated with the development of MGC (hazard ratio: 3.66, 95% confidence interval: 1.47-12.25, p = 0.004). The risk of MGC after ER could be quantitatively predicted by the PG I/II ratio regardless of H. pylori status.

Since the 1990's, the test for serum pepsinogen as a marker for chronic atrophic gastritis has been incorporated into gastric cancer screening programs, on a trial basis, to identify people at high risk for gastric cancer. The addition of the serum test to the cancer screening program has been shown to improve the detection rate of cancer and pepsinogen testing is useful in detecting early-stage gastric cancers arising from atrophic gastric mucosa, which macroscopically tend to be elevated and histologically differentiated. Furthermore, the cost for the detection of a single cancer case is much less than that for conventional screening. Thus, with the introduction of pepsinogen testing, complimenting barium X-ray, a more efficient screening system is available.

Background Both double-balloon enteroscopy (DBE) and video capsule endoscopy (VCE) have similar diagnostic yields for patients with overt obscure gastrointestinal bleeding (OGIB). However, the choice of initial modality is still controversial. The aim of this study was to show the clinical outcome of the strategy of initial VCE, followed by DBE. Methods Eighty-nine consecutive overt OGIB patients who had undergone VCE as the initial examination were analyzed. The interpreters of VCE evaluated the necessity of performing DBE, and the antegrade or retrograde route was chosen, depending on the transit time of the capsule. Results Thirty-seven patients (42 %) underwent DBE depending on the findings of VCE. Of these, bleeding sites in the small bowel were identified in 29 patients with the initially selected route (21 antegrade and 8 retrograde). The remaining 8 later underwent DBE by the other route, but 7 had no bleeding lesion, which was confirmed by second-look VCE. One remaining patient had a jejunal varix found by VCE, but DBE from either side could not reach the lesion. The sensitivity and negative predictive value of VCE were 100 %, both for the presence of small bowel lesions and the requirement of hemostasis in the small bowel; this indicated that VCE never misses relevant findings in the small bowel, and that negative VCE findings correspond to the lack of necessity for further examination. Conclusions VCE as the initial examination can efficiently identify overt OGIB patients who require DBE. The strategy of initial VCE for overt OGIB appears to be reasonable.

OBJECTIVES The role of contrast-enhanced sonography in the diagnosis of recurrent hepatocellular carcinoma is still unclear. This study aimed to clarify the usefulness and limitations of contrast-enhanced sonography with a perfluorobutane microbubble contrast agent (Sonazoid; Daiichi-Sankyo, Tokyo, Japan) after contrast-enhanced computed tomography (CT) for diagnosis of recurrent hepatocellular carcinoma and to establish its optimal use. METHODS A total of 514 patients, who were suspected to have recurrent hepatocellular carcinoma on contrast-enhanced CT, underwent contrast-enhanced sonography. Of 514 suspicious lesions, 484 were diagnosed as recurrent hepatocellular carcinomas, including 142 recurrent hepatocellular carcinomas measuring 1 cm or smaller in diameter. The largest lesion was evaluated in each patient. A final diagnosis of recurrent hepatocellular carcinoma after contrast-enhanced CT was reached on the basis of the typical hallmarks of hepatocellular carcinoma on any of the other contrast imaging modalities or by resected tissue or tumor enlargement during follow-up. RESULTS The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of contrast-enhanced CT were 68%, 93%, 99%, 15%, and 70%, respectively, and the values of contrast-enhanced sonography were 91%, 100%, 100%, 31%, and 91%, excluding 60 unassessable lesions on contrast-enhanced sonography. The diagnostic rate for recurrent hepatocellular carcinoma on contrast-enhanced sonography for lesions with an atypical enhancement pattern on contrast-enhanced CT was 71%. On multivariate analysis of factors contributing to the unassessability of contrast-enhanced sonography, lesion size, location, and abdominal wall thickness were independent factors. CONCLUSIONS Although the assessability of contrast-enhanced sonography depends on lesion size, location, and abdominal wall thickness, contrast-enhanced sonography after contrast-enhanced CT is useful for confirmative diagnosis of small recurrent hepatocellular carcinoma with an atypical enhancement pattern on contrast-enhanced CT, even for lesions measuring 1 cm or smaller in diameter.

To investigate the effects of Japanese apricot (JA) consumption on gastroesophageal reflux disease (GERD)-related symptoms.Participants included individuals living in Minabe-cho, a well-known JA-growing region, who received specific medical check-ups by the local community health service in 2010. GERD-related symptoms were examined in 1303 Japanese individuals using a validated questionnaire, the Frequency Scale for Symptoms of GERD (FSSG), which consists of 7 questions associated with acid reflux symptoms and 5 questions asking about gastrointestinal dysmotility symptoms. Each question was answered using a 4-point scale, with higher scores indicating more severe GERD-related symptoms. Subjects were divided into two groups according to their intake of dried and pickled JA: daily intake (≥ 1 JA daily) (392 subjects) and none or occasional intake (1 JA daily) (911 subjects). FSSG scores were compared between subjects who consumed JA daily and those who did not. Next, subjects were stratified by age, gender and Helicobacter pylori (H. pylori) status for subanalyses.Those who ate JA daily were significantly older than those who did not (60.6 ± 10.5 years vs 56.0 ± 11.0 years, P0.001). Total FSSG scores were significantly lower in subjects with daily JA intake than in those with none or only occasional intake (2.13 ± 3.14 vs 2.70 ± 3.82, P = 0.005). In particular, subjects who consumed JA daily showed significantly improved FSSG dysmotility scores compared with subjects who did not (1.05 ± 1.58 vs 1.46 ± 2.11, P0.001). In contrast, the FSSG reflux score did not differ between subjects with and without daily intake of JA (1.08 ± 1.90 vs 1.24 ± 2.11, P = 0.177). Subanalysis indicated that improvement in dysmotility by JA intake was specifically observed in non-elderly (1.24 ± 1.68 vs 1.62 ± 2.22, P = 0.005) and H. pylori-negative subjects (0.99 ± 1.58 vs 1.57 ± 2.06, P0.001). GERD patients (total FSSG score ≥ 8) were less frequently observed among subjects with daily intake of JA as compared to those without daily intake of JA (6.1% vs 9.7%, P = 0.040).Daily JA intake may improve digestive dysmotility symptoms, resulting in relief of GERD symptoms. The effect is more obvious in non-elderly and H. pylori-negative subjects.

Background and Aim Esophageal varices are usually treated with endoscopic injection sclerotherapy (EIS) or endoscopic band ligation (EBL). However, frequent recurrences of varices after those procedures have been problematic. Argon plasma coagulation (APC) after EIS may be effective for preventing varix recurrence and, in recent years, we have routinely carried out APC after EIS. The aim of the present study was to verify the effectiveness of APC for preventing recurrence of varices after EIS. Methods A case–control study was carried out using a historical control cohort in a single center. The varix recurrence rate in 62 patients (34 men and 28 women, median age; 69 years) who underwent APC after EIS for hemorrhagic or risky esophageal varices (APC group) was compared with that of control patients who did not undergo APC after EIS (control group). Age-, sex-, and liver function-matched two control subjects were selected for one case subject (control group). Recurrence of varices was defined as rupture of varices or reappearance of risky varices. Results The 1-year and 2-year recurrence rates of the APC group were 9.7% and 11.3%, respectively. In contrast, the rates of the control group were 29.0% and 34.7%, respectively. Kaplan–Meier curves showed a significantly lower recurrence rate in the APC group (P = 0.013, log–rank test). No APC-related severe adverse events were observed. Conclusion APC after EIS was safe and could significantly prevent recurrence of esophageal varices. Therefore, the addition of APC should be routinely carried out after EIS.

Serological markers of hepatocellular carcinoma (HCC) indicate its invasiveness. We aimed to investigate whether the prognostic impact of surgical resection (SR) and radiofrequency thermal ablation (RFA) on patients with single nodular HCC ⩽5cm were different regarding positive conditions of the following three HCC markers: alpha-fetoprotein (AFP); lens culinaris agglutinin-reactive fraction of AFP; and des-γ-carboxy prothrombin.This study reviewed 296 patients with single nodular HCC ⩽5cm with Child-Pugh grade A between 2001 and 2011 (SR, n=136; RFA, n=160). Based on positive conditions of previous HCC markers (defined as non-positive, single-positive, double-positive, and triple-positive), overall survival (OS) and prognostic factors were analyzed.Five-year OS rates of SR and RFA among all patients were 70.1% and 69.8%, respectively (p=0.14). However, when stratified by the positive conditions of three HCC markers, their rates of non-, single-, double-, and triple-positive patients were 60.6%, 78.2%, 54.2%, and 75.9% in the SR group, whereas rates were 83.3%, 75.7%, 62.2%, and 47.6% in the RFA group (p values between SR and RFA of each tumor marker condition were 0.45, 0.10, 0.77, and0.01, respectively). Multivariate analyses showed that RFA itself became an independent prognostic factor in the triple-positive group, with an odds ratio of 1.78 (95% confidence interval, 1.16-2.72).Positive conditions of three HCC markers differently influenced survival rates of those who underwent SR and RFA when treating single nodular HCC ⩽5cm. RFA itself became an independent prognostic risk when all three HCC markers were positive. Preoperative evaluation of multiple HCC markers might become an index for selecting treatment modalities.

Objectives An ultrasound contrast agent consisting of perfluorobutane microbubbles (Sonazoid; Daiichi Sankyo, Tokyo, Japan) accumulates in Kupffer cells, which thus enables Kupffer imaging. This study aimed to elucidate the association of defect patterns of hepatocellular carcinoma during the Kupffer phase of Sonazoid contrast-enhanced sonography with outcomes after radiofrequency ablation (RFA). Methods For this study, 226 patients with initial hypervascular hepatocellular carcinoma, who could be evaluated by contrast-enhanced sonography with Sonazoid before RFA, were analyzed. Patients were divided into 2 groups according to the tumor defect pattern during the Kupffer phase. The irregular-defect group was defined as patients with hepatocellular carcinoma that had a defect with an irregular margin, and the no-irregular-defect group was defined as patients with hepatocellular carcinoma that had either a defect with a smooth margin or no defect. Critical recurrence was defined as more than 3 intrahepatic recurrences, vascular invasion, dissemination, or metastasis. Results The irregular-defect and no-irregular-defect groups included 86 and 140 patients, respectively, and had cumulative 5-year critical recurrence rates of 49% and 17% (P < .01). Multivariate analysis indicated that the tumor diameter, lens culinaris agglutinin– reactive α-fetoprotein level, and defect pattern were independent factors related to critical recurrence. The cumulative 5-year overall survival rates for the irregular-defect and no-irregular-defect groups were 46% and 61% (P< .01). Multivariate analysis indicated that the Child-Pugh class, tumor diameter, lens culinaris agglutinin–reactive α-fetoprotein level, and defect pattern were independent factors related to survival. Conclusions The defect pattern of hepatocellular carcinoma during the Kupffer phase of Sonazoid contrast-enhanced sonography is associated with critical recurrence and survival after RFA.

Focal nodular fatty infiltration of the liver is a pseudotumor visualized as a highly echoic lesion on sonography. On computed tomography (CT), focal nodular fatty infiltration is generally characterized by a low-density area with no mass effect. 1 Although focal nodular fatty infiltration must be differentiated from primary liver cancer, a metastatic liver tumor, or hepatic hemangioma, this can be difficult with CT or sonography alone. When differential diagnosis is difficult from imaging investigations alone, biopsy proof of the tumor is necessary before therapy is commenced. The appearance of numerous small multifocal nodular fatty infiltrations in both hepatic lobes may mimic that of metastatic liver disease, leading to incorrect therapy. Particularly if the patient has had malignant disease in the past, multifocal nodular fatty infiltrations may be misdiagnosed, and incorrect therapy may be performed without adequate examination or differential diagnosis of the primary lesion. Although magnetic resonance imaging (MRI) and fine-needle biopsy are reportedly useful in diagnosing focal fatty infiltration of the liver, 2-4 the value of enhanced sonography has not been reported in this situation. We encountered a case of multifocal nodular fatty infiltration in which findings of the late parenchymal phase of enhanced sonography with Levovist (SH U 508A; Schering AG, Berlin, Germany) were useful in ruling out malignancy.

A 77-year-old man hospitalized for epigastric pain showed jaundice of the skin and conjunctivae. Laboratory tests revealed elevated hepatobiliary enzymes and inflammatory markers, and imaging studies demonstrated a 12 cm hepatic cyst compressing the common bile duct. The diagnosis was a giant hepatic cyst causing obstructive jaundice. Cyst drainage and sclerotherapy with 5% monoethanolamine oleate was performed twice, resulting in almost complete disappearance of the cyst. Obstructive jaundice due to a hepatic cyst, as seen in this case, is relatively rare and this report includes a review of other similar cases in Japan.

Received January 19, 2005, from the Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan (H.T., M.O., H.M., N.S., T.K., S.E., T.S., M.I., K.N., K.A., K.Y., Y.S., H.N., M.I.); and Department of Gastroenterology, University of Tokyo, Tokyo, Japan (M.F., N.Y., S.S.). Revision requested February 7, 2005. Revised manuscript accepted for publication March 1, 2005. Address correspondence to Hideyuki Tamai, MD, Second Department of Internal Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama City, Wakayama 640-0012, Japan. Abbreviations CT, computed tomography; HCC, hepatocellular carcinoma; PEIT, percutaneous ethanol injection therapy; RFA, radio frequency ablation; S, segment; TAE, transcatheter arterial embolization ntraperitoneal bleeding due to a ruptured tumor is a serious complication in patients with hepatocellular carcinoma (HCC). According to data compiled by the Liver Cancer Study Group of Japan,1 ruptured HCC accounts for around 10% of deaths in these patients. Clinical features include the sudden onset of abdominal pain and distension and, if bleeding is massive, the presence of shock. Other causes of an acute abdominal emergency must be ruled out. Diagnostic imaging generally includes sonography, contrast computed tomography (CT), and angiography. In patients with ruptured HCC, prompt diagnosis and treatment is essential to avoid hepatocyte necrosis and secondary hepatic failure associated with shock and decreased hepatic perfusion due to bleeding. The underlying liver disease varies in such patients with ruptured HCC. Chronic hepatitis, cirrhosis, or both may be present, and the severity of hepatic dysfunction as well as the size, number, and progression of the neoplastic lesions present varies from case to case. A common feature is the presence of a responsible lesion on or protruding from the surface of the liver. If hemostasis can be achieved early after HCC rupture, then overall prognosis depends on the patient’s liver function and degree of tumor progression. Although there is a risk of intraperitoneal seeding, long-term survival is possible if the tumor can be completely resected by hepatectomy. One study has already reported a good 5-year survival rate after resection of ruptured and nonruptured HCC.2 In another study, rather than performing emergency surgery, Marini et al3 used transcatheter arterial embolization (TAE) to control bleeding; in those patients who could then undergo surgery, elective hepatectomy was associated with long-term survival. Treatment of ruptured HCC involves more than just hemostasis. Subsequent therapy is important, and, whenever possible, complete resection should be performed after bleeding has been controlled.

Background and study aims: Early gastric cancers show gastric and/or intestinal phenotypes with specific mucin production profiles, and the phenotypes can vary with tumor progression. The aim of this study was to evaluate the correlation between tumor invasion patterns and phenotypes in the mucosa and submucosa of early gastric cancers. Methods: Phenotypic expressions of 44 endoscopically resected gastric cancers with submucosal invasion were evaluated immunohistochemically using MUC5AC and MUC6 as gastric and MUC2 and CD10 as intestinal phenotypic markers. Results: Cancers were classified into two patterns by invasion pattern: 19 collapsing pattern (C-pattern) tumors had cancer cells that invaded to the submucosa with expansive destruction of the muscularis mucosae, while 25 passing-through pattern (P-pattern) tumors formed focal cancer cell aggregations in the submucosa without massive destruction of the muscularis mucosae. Cancers with C-pattern invasion were likely to show similar phenotypes between the mucosa and submucosa, while phenotypes of cancers with P-pattern invasion were likely to differ between the two layers (rate of the same phenotypes: C-pattern 68% vs. P-pattern 28%, p = 0.008). Of 22 cancers with P-pattern invasion that included the intestinal phenotype component in the mucosa, 13 (59%) expressed the gastric phenotype alone in the submucosa. Conclusions: Phenotype presentation in the mucosa and submucosa differ by the invasion pattern in early gastric cancer. Tumors with P-pattern invasion are likely to express the gastric phenotype in the submucosa, regardless of phenotype in the mucosa, suggesting that such cancers might achieve submucosal invasion prior to intestinalization occurring in the mucosa.

We report a case of a 16-year-old male who suffered from Crohn's disease (CD) with esophageal involvement, showing remarkable improvement with granulocyte/monocyte adsorption (GMA). The patient had been diagnosed as ileocolic CD and was treated with 5-aminosalicylate. He was admitted to our hospital with symptoms of fever, diarrhea, and odynophagia. Endoscopic examinations revealed that the exacerbation of ileocolic ulcers, and advent of ulcers in esophagus. Because of the patient's refusal to receive corticosteroids, immunomodulators, or biologics, he underwent GMA twice a week. After 10 sessions of GMA, he entered remission with significant decrease in clinical activity. In addition, endoscopic examinations showed remarkable improvement of ileocolic ulcers and disappearance of esophageal lesions. No adverse events were observed. GMA could be effective for manifestations of CD in gastrointestinal tract other than ileum or colon. J. Clin. Apheresis, 2011. © 2011 Wiley-Liss, Inc.

Fatigue crack growth tests using center-cracked [M (T)] specimens and single-edge-cracked (SEC) specimens of SUS304 steel were conducted to examine the behavior of fatigue crack growth in the near-threshold regime at 623 K. Crack closure was eliminated by keeping Kmax constant in ΔK decreasing test in order to obtain easily the threshold value expressed in terms of effective stress intensity factor range, ΔKett. By increasing the value of Kmax and/or ΔK for a crack in a threshold condition, the fatigue crack growth behavior was investigated even in the region below the threshold value obtained by using the conventional ΔK-decreasing test. When the value of Kmax was increased in the conventional threshold condition, crack growth was observed in the lower ΔK region. Crack growth was further observed repeatedly after successive increase in Kmax in the newly established lower region below the conventional threshold value. In the region below a certain value of ΔK, however, crack no longer grew even after the change of Kmax. Discussion was made on the characteristics of threshold.

Lansoprazole is a potent anti-gastric ulcer drug that inhibits gastric proton pump activity. We identified a novel function for lansoprazole, as an inducer of anti-oxidative stress responses in the liver. Gastric administration of lansoprazole (10–100 mg/kg) to male Wistar rats produced a dose-dependent increase in hepatic mRNA levels of nuclear factor, erythroid-derived 2, -like 2 (Nrf2), a redox-sensitive transcription factor, at 3 h and Nrf2 immunoreactivity (IR) in whole hepatic lysates at 6 h. Conversely, the levels of Kelch-like ECH-associated protein (Keap1), which sequesters Nrf2 in the cytoplasm under un-stimulated conditions, were unchanged. Translocation of Nrf2 into the nuclei of hepatocytes was observed using western blotting and immunohistochemistry. Expression of mRNAs for Nrf2-dependent antioxidant and phase II enzymes, such as heme oxygenase 1 (HO-1), NAD (P) H dehydrogenase, quinone 1 (Nqo1), glutathione S-transferase A2 (Gsta2), UDP glucuronosyltransferase 1 family polypeptide A6 (Ugt1a6), were dose-dependently up-regulated at 3 h. Furthermore, the levels of HO-1 IR were dose-dependently increased in hepatocytes at 6 h. Subcutaneous administration of lansoprazole (30 mg/kg/day) for 7 successive days resulted in up-regulation and nuclear translocation of Nrf2 IR in hepatocytes and up-regulation of HO-1 IR in the liver. Pretreatment with lansoprazole attenuated thioacetamide (500 mg/kg)-induced acute hepatic damage via both HO-1-dependent and -independent pathways. Up-stream networks related to Nrf2 expression were investigated using microarray analysis, followed by data mining with Ingenuity Pathway Analysis. Up-regulation of the aryl hydrocarbon receptor (AhR)-cytochrome P450, family 1, subfamily a, polypeptide 1 (Cyp1a1) pathway was associated with up-regulation of Nrf2 mRNA. In conclusion, lansoprazole might have an alternative indication in the prevention and treatment of oxidative hepatic damage through the induction of both phase I and phase II drug-metabolizing systems, i.e. the AhR/Cyp1a1/Nrf2 pathway in hepatocytes.

The aim of the present study was to predict sustained virological response (SVR) to telaprevir with pegylated interferon (PEG-IFN) and ribavirin using viral response within 2 weeks after therapy initiation. Thirty-six patients with genotype 1 hepatitis C virus (HCV) and high viral load were treated by telaprevir-based triple therapy. SVR was achieved in 72% (26/36) of patients. Significant differences between the SVR group and non-SVR group were noted regarding response to prior PEG-IFN plus ribavirin, interleukin (IL)28B polymorphism, amino acid substitution at core 70, cirrhosis, hyaluronic acid level, and HCV-RNA reduction within 2 weeks. Setting 4.56 logIU/mL as the cut-off value for HCV-RNA reduction at 2 weeks, the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for predicting SVR were 77%, 86%, 95%, 50%, and 79%, respectively, and for neither the IL28B minor allele nor core 70 mutant were 80%, 71%, 91%, 50%, and 78%, respectively. In conclusion, evaluation of viral reduction at 2 weeks or the combination of IL28B polymorphism and amino acid substitution at core 70 are useful for predicting SVR to telaprevir with PEG-IFN and ribavirin therapy.

Background The aim of this study was to elucidate the histologic and clinical implications of detection of intratumoral vessels on contrast-enhanced endoscopic ultrasonography (CE-EUS) in gastrointestinal stromal tumors (GISTs). Methods Thirteen patients with a GIST, all of whom were referred for surgery, underwent presurgical CE-EUS. The malignant potential, assessed according to the modified Fletcher risk classification system, and the histologic degree of angiogenesis were compared with the presence or absence of intratumoral vessels on CE-EUS. Results Of the six tumors with intratumoral vessels observed on CE-EUS, five were intermediate- or high-risk GISTs, and the remaining seven negative cases were categorized as very low risk or low risk. The presence of intratumoral vessels on CE-EUS was significantly correlated with a higher-risk classification (p = 0.005). On histologic examination, all GISTs having visualized vessels incorporated vessels of more than 500 μm in diameter. The large intratumoral vessels of the five intermediate- or high-risk GISTs lacked elastic fibers, suggesting that they were neovascular in nature. These higher-risk tumors were also found, by immunohistochemical analysis, to have high expression of vascular endothelial growth factor. Conclusions Intratumoral vessels observed in GISTs on CE-EUS are correlated with a higher degree of angiogenesis, resulting in higher malignant potential. © 2014 Wiley Periodicals, Inc. J Clin Ultrasound, 43:89–97, 2015

Background Pegylated interferon (PEG-IFN) plus ribavirin therapy is still recommended for elderly and/or cirrhotic patients. This study examined whether sustained virological response (SVR) to low-dose PEG-IFN-α2a plus ribavirin therapy for elderly and/or cirrhotic patients could be predicted based on viral reduction within 2 weeks after therapy initiation or interleukin IL-(28B) polymorphism and viral mutations. Methods Participants comprised 115 elderly (≥65 years) and/or cirrhotic patients with genotype-1b and high viral load. Reduced doses of PEG-IFN-α2a (90 μg/kg/week) and ribavirin (400-800 mg/day) were administered for 48-72 weeks based on virological response of each patient. Results SVR was achieved in 34% (39/115), and treatment was discontinued in 15% (17/115). Univariate analysis identified age, α-fetoprotein, fibrosis marker, interferon sensitivity-determining region (ISDR), IL-28B polymorphism and level of viral reduction within 2 weeks as factors contributing significantly to SVR. However, no significant differences were noted in core amino acid substitutions. Multivariate analysis identified age, hyaluronic acid, ISDR and viral reduction as factors independently associated with SVR. Positive predictive value (PPV) and negative predictive value (NPV) of SVR based on the level of viral reduction at 2 weeks (cutoff level, 1.7 log IU/ml) were 83% and 84%, respectively. The PPV of SVR based on IL-28B major and ISDR mutant was 70%, and the NPV of SVR based on IL-28B minor and wild-type ISDR was 89%. Conclusions Evaluations of viral reduction at 2 weeks or both IL-28B and ISDR are useful to predict SVR to low-dose PEG-IFN-α2a plus ribavirin therapy for elderly and/ or cirrhotic patients.

Contrast-enhanced endoscopic ultrasonography (CE-EUS) is a new imaging modality for pancreatic lesions. The aim of this study was to evaluate if CE-EUS is useful for predicting treatment efficacy before pancreatic cancer chemotherapy by assessing intratumoral vessel flow.Thirty-nine patients with unresectable advanced pancreatic cancer underwent CE-EUS before chemotherapy. The patients were divided into 2 groups according to the intratumoral vessel flow observed with CE-EUS: vessel sign-positive and vessel sign-negative groups. Patient prognosis was investigated according to presence or absence of the vessel sign.Two patients were excluded due to poor visualization of CE-EUS images; therefore, 37 patients were analyzed. Contrast-enhanced EUS revealed positive vessel sign in 20 patients, whereas it revealed negative vessel sign in 17 patients. Both progression-free survival and overall survival were significantly longer in the positive- versus negative vessel sign groups (P = 0.037 and P = 0.027, respectively). Multivariate analysis demonstrated that the positive vessel sign was an independent factor associated with longer overall survival (hazard ratio, 0.22; 95% confidence interval, 0.08-0.53).Evaluation of intratumoral vessel flow by CE-EUS could be useful for predicting efficacy of chemotherapy in patients with pancreatic cancer. Contrast-enhanced EUS could be used before chemotherapy for inoperable pancreatic cancer.

Our study investigated the relationship between gastric cancer development and activity of Helicobacter pylori-associated chronic gastritis or the resulting chronic atrophic gastritis (CAG). A cohort of 4,655 healthy asymptomatic subjects, in whom serum pepsinogen (PG) and H. pylori antibody titer had been measured to assess the activity and stage of H. pylori-associated chronic gastritis, was followed for up to 16 years, and cancer development was investigated. In subjects with a serologically diagnosed healthy stomach (H. pylori-negative/CAG-negative), cancer incidence rate was low, at 16/100,000 person-years. With the establishment of H. pylori infection and progression of chronic gastritis, significant stepwise cancer risk elevations were seen from CAG-free subjects (H. pylori-positive/CAG-negative) [hazard ratio (HR) = 8.9, 95% confidence interval (CI) = 2.7-54.7] to subjects with CAG (H. pylori-positive/CAG-positive) (HR = 17.7, 95% CI = 5.4-108.6) and finally to subjects with metaplastic gastritis (H. pylori-negative/CAG-positive) (HR = 69.7, 95% CI = 13.6-502.9). In H. pylori-infected CAG-free subjects, significantly elevated cancer risk was observed in the subgroup with active inflammation-based high PG II level or potent immune response-based high H. pylori antibody titer; the former was associated with a particularly high risk of diffuse-type cancer, and both subgroups showed high cancer incidence rates of around 250/100,000 person-years, comparable to that in subjects with CAG. No such risk elevation was observed in H. pylori-infected subjects with CAG. These results clearly indicate that gastric cancer develops mainly from the gastritis-atrophy-metaplasia-cancer sequence and partly from active inflammation-based direct carcinogenesis, and that serum levels of PG and H. pylori antibody titer provide indices of cancer development in H. pylori-infected subjects.

AIM: To develop a new continuous suction mouthpiece (CSM) and evaluate its usefulness for screening esophagogastroduodenoscopy (EGD). METHODS: A total of 196 patients who were scheduled to undergo screening EGD were assigned to one of two groups: a group using the CSM and a group using a conventional mouthpiece. Extent of salivary flow, frequency of saliva suction, number of choking episodes during the examination, and incidence of aspiration pneumonia after the examination were evaluated and compared between the two groups. Adverse events during and after EGD were also examined. In addition, the oral cavity was meticulously examined after the EGD. RESULTS: The same number of patients was randomly allocated to each group. There were no significant differences between the two groups in sex, age, biopsy procedure, duration of procedure and depth of sedation. Aspiration pneumonia and other significant adverse events were not observed in either group. The grade of extent of salivary flow was significantly lower in patients with the CSM than in patients with the conventional mouthpiece (P < 0.001). Although there was no significant difference, less frequent suctioning and fewer choking episodes were observed in patients with the CSM than in patients with the conventional mouthpiece (P = 0.082 and P = 0.084, respectively). In addition, there were no patients in the CSM group who required saliva suctioning during the procedure. CONCLUSION: Use of the CSM during screening EGD can reduce the extent of salivary flow. The device is expected to reduce complications and contamination with saliva.

Background: Some patients with common bile duct (CBD) stones develop cholangitis requiring drainage, while others do not. The aims of this study were to elucidate the clinical differences among patients with CBD stones who required and did not require emergent drainage, and to identify risk factors for the development of cholangitis requiring emergent drainage in patients with silent CBD stones. Methods: Clinical characteristics of consecutive patients with CBD stones who underwent endoscopic removal of stones or biliary drainage were analyzed retrospectively. Results: Of 101 patients analyzed, 32 had moderate or severe cholangitis as the indication for emergent drainage, and the remaining 69 did not. Patients who required emergent drainage were more likely to have gallstones (P = 0.029), dilated CBD ( > 10 mm) (P = 0.004) and larger CBD stones (P = 0.019). By multivariate analysis, CBD dilation was the only significant differentiating clinical characteristic of the patients who required emergent drainage (OR = 3.75, 95% CI: 1.41-9.96, P = 0.008). Of the 35 patients with silent bile duct stones, eight required emergent endoscopic drainage during the waiting period. CBD dilation was also the only significant risk factor for the development of moderate or severe cholangitis among patients with silent bile duct stones (OR = 10.18, 95% CI: 1.09-94.73, P = 0.042). Conclusions: Dilated CBD ( > 10 mm) was the only risk factor identified for requirement of early drainage in patients with CBD stones. Those who have silent CBD stones with CBD dilatation should undergo early drainage. Gastroenterology Research. 2013;6(6):219-226 doi: http://dx.doi.org/10.4021/gr587w

Objectives The aim of this study was to evaluate the ability of contrast-enhanced endoscopic sonography for discrimination of mural nodules from mucous clots in intraductal papillary mucinous neoplasms of the pancreas. Methods Contrast-enhanced endoscopic sonography was performed in 17 consecutive patients who had an intraductal papillary mucinous neoplasm with mural lesions. To perform contrast-enhanced endoscopic sonography, we used a second-generation sonographic contrast agent. After reconstitution with 2 mL of sterile water for injection, 0.7 mL of the agent was administered through a peripheral vein. From 10 to 30 seconds after injection of the contrast agent, the presence or absence of vascularity in mural lesions was assessed. All cases were referred to surgery, and diagnoses were finally obtained by pathologic examination. Diagnoses of mural nodules versus mucous clots based on the sonographic results were compared with tumor histopathologic findings. Results Pathologic findings revealed 12 cases with mural nodules and 5 cases without. Contrast-enhanced endoscopic sonography depicted vascularity in all 12 cases with pathologically confirmed mural nodules, whereas all 4 cases without vascularity had mucous clots. Only 1 case without a pathologically confirmed mural nodule was overestimated by contrast-enhanced endoscopic sonography as having a mural nodule. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of contrast-enhanced endoscopic sonography for mural nodule detection were 100%, 80%, 92%, 100%, and 94%, respectively. Conclusions Evaluation of vascularity by contrast-enhanced endoscopic sonography could be useful for distinguishing mural nodules from mucous clots in intraductal papillary mucinous neoplasms. Contrast-enhanced endoscopic sonography could be a necessary option to determine surgical indications for intraductal papillary mucinous neoplasms when mural lesions are observed.

Elderly and/or cirrhotic patients with hepatitis C virus (HCV) are at high risk of adverse effects during interferon therapy. The aim of the present study was to evaluate the efficacy, safety and predictive factors for sustained virological response (SVR) of low-dose pegylated interferon-α-2a (PEG IFN-α-2a) monotherapy in elderly and/or cirrhotic patients with HCV genotype-2 or genotype-1 low level infection.Sixty-four elderly (≥65 years) and/or cirrhotic patients with HCV genotype-2 or genotype-1 low level (5 logIU/mL) infection underwent low-dose PEG IFN-α-2a (90 μg/week) monotherapy for 24 weeks. Sixty patients were available for efficacy assessment.SVR was achieved in 78.3%. SVR rates according to genotype-1 low, genotype-2 low and genotype-2 high viral load were 90.0%, 87.1% and 57.9%, respectively. The discontinuation rate was 12.5%. PEG IFN-α-2a was interrupted or discontinued in four patients because of severe thrombocytopenia (25 000/mm(3) ). The baseline platelet counts of all these patients were less than 70 000/mm(3) . On univariate analysis of factors contributing to SVR, significant differences were noted in viral load, platelet count, γ-glutamyltransferase, ferritin, α-fetoprotein level and rapid viral response (RVR). On multivariate analysis, RVR was the only independent factor (P = 0.010, odds ratio = 47.27). The positive and negative SVR-predictive values based on RVR were 95% and 82%, respectively.Low-dose PEG IFN-α-2a monotherapy was effective and tolerable in elderly and/or cirrhotic patients with genotype-2 or genotype-1 low HCV level infection. However, a baseline platelet count of more than 70 000/mm(3) is needed for safety. RVR can predict SVR accurately.

Rapid virological response (RVR), defined as serum hepatitis C virus (HCV) RNA negativity at 4 weeks, is the most useful predictor of sustained virological response (SVR) to standard pegylated interferon (PEG IFN) plus ribavirin therapy for patients infected with genotype 2 HCV. The aim of the present study was to predict SVR using viral response within 2 weeks of therapy initiation.Of 64 HCV genotype 2 patients with a high viral load treated with standard PEG IFN-α-2b plus weight-based ribavirin for 24 weeks, 58 patients whose adherence was more than 67% were analyzed. RNA and core antigen levels were measured at four time points: the day of therapy initiation, the following day, and at 1 and 2 weeks.SVR was achieved in 73% (47/64) of patients. Univariate analysis of SVR contributing factors showed significant differences with age, bodyweight, white blood cell count, platelet count, fibrosis marker levels, baseline core antigen level and viral response. The area under the receiver-operator curve (AUC) of the core antigen level at 1 week (AUC, 0.940) was the highest among the significant SVR predicting factors. Setting 100 fmol/L as the cut-off value for core antigen level at 1 week, the sensitivity, specificity, positive predictive value, negative predictive value and accuracy for predicting SVR were 100%, 86%, 96%, 100% and 97%, respectively, and for predicting RVR were 66%, 93%, 97%, 46% and 72%, respectively.The HCV core antigen level at 1 week after therapy initiation is the most useful predictor for SVR.

Chronic inflammation triggered by Helicobacter pylori causes altered DNA methylation in stomach mucosae, which is deeply involved in gastric carcinogenesis. This study aimed to elucidate the correlation between altered mucosal DNA methylation levels and activity of H. pylori-related gastritis, because inflammatory activity shows particular correlations with the development of diffuse-type cancer.Methylation levels in stomach mucosae of 78 healthy volunteers were determined by real-time methylation-specific PCR or bisulfite pyrosequencing. Examined loci were the promoter CpG islands of six genes (FLNc, HAND1, THBD, p41ARC, HRASLS, and LOX) and the CpG sites of non-coding repetitive elements (Alu and Satα) that are reportedly altered by H. pylori infection. Activity of H. pylori-related gastritis was evaluated using two serum markers: H. pylori antibody titer and pepsinogen II.Methylation levels of the six CpG islands were consistently increased, and those of the two repetitive elements were consistently decreased in a stepwise manner with the activity of gastric inflammation as represented by serum marker levels. Each serum marker level was well correlated with the overall DNA methylation status of stomach mucosa, and these two serologic markers were additive in the detection of the mucosa with severely altered DNA methylation.Alteration in mucosal DNA methylation level was closely correlated with activity of H. pylori-related gastritis as evaluated by serum markers. The observed correlation between altered DNA methylation levels and activity of H. pylori-related gastritis appears to be one of the relevant molecular mechanisms underlying the development of diffuse-type cancer.

Although frequent vomiting reflexes during esophagogastroduodenoscopy (EGD) causes suffering in patients, very few studies have investigated the characteristics of subjects who frequently develop vomiting reflexes. This study examined the incidence of the vomiting reflex and related factors, especially upper gastrointestinal symptoms, among individuals undergoing transoral EGD.Subjects included 488 consecutive adults (mean age, 56.1 ± 8.9 years) who underwent transoral EGD for gastric cancer screening between February 2010 and March 2011. All procedures were performed by an endoscopist with 15 years of experience. Based on a questionnaire survey using the frequency scale for the symptoms of gastroesophageal reflux disease (FSSG), symptoms (dyspepsia and acid reflux symptoms) and the number of vomiting reflexes during EGD were recorded.Of the 488 subjects, 271 (56%) developed vomiting reflexes (mean, 4.2 times). This reflex-positive group was younger (54.3 ± 9.5 years) than the reflex-negative group (58.3 ± 7.7 years, P0.001). The number of subjects in the reflex-positive group with a high FSSG dyspepsia score (2.27 ± 2.57 vs 1.23 ± 1.84; P0.001), acid reflux symptom score (1.96 ± 2.22 vs 1.34 ± 2.14; P0.01) or an esophageal hiatal hernia (14.8% vs 4.6%; P0.001) was significantly higher than in the reflex-negative group. Multivariate analysis also showed a significant correlation between these four factors and the occurrence of vomiting reflexes. Using an FSSG dyspepsia score of 1 as the cut-off offered 68% sensitivity and 57% specificity for predicting the occurrence of vomiting reflexes.Based on FSSG questionnaire responses on upper gastrointestinal symptoms, dyspepsia symptoms, in particular, are related to presence of vomiting reflexes during EGD.

In a previous population-based case-control study, we demonstrated an elevated risk of colorectal neoplasia with Helicobacter pylori (H. pylori) infection. The present study investigated the effects of H. pylori-associated chronic gastritis on the development of colorectal neoplasia by analyzing the recurrence of colorectal neoplasia subsequent to endoscopic resection. Ninety-nine patients who had undergone endoscopic resection of colorectal neoplasia were monitored under colonoscopy, and the recurrence of colorectal neoplasia was prospectively investigated. The stage of H. pylori-associated chronic gastritis in each subject was evaluated using a combination of two serum tests: H. pylori antibody and pepsinogen. In the present cohort, colorectal neoplasia recurred at a rate of 15,296/100,000 person-years during the study period. After adjusting for the confounding factors, chronic atrophic gastritis (CAG) was identified as an independent risk factor [adjusted hazard ratio (HR), 2.72; 95% confidence interval, 1.33–5.57], while H. pylori-infected non-atrophic gastritis was not identified as an independent risk factor for recurrent colorectal neoplasia. Colorectal neoplasia recurred earlier and was significantly more frequent in patients with CAG (22,573/100,000 person-years) compared to patients without CAG (11,089/100,000 person-years; P=0.029, log-rank test). Patients with more extensive CAG showed a higher risk of recurrence. These results demonstrated a significant elevation of the risk of recurrent colorectal neoplasia with the establishment and progression of CAG, indicating the involvement of H. pylori infection in the development of colorectal neoplasia. The two serum tests were useful clinical markers for noninvasively evaluating the risk of each individual for recurrent colorectal neoplasia subsequent to endoscopic resection.

This study aimed to elucidate groups at high risk of developing cancer among patients with serologically identified Helicobacter pylori infection and nonatrophic stomach. Annual endoscopy was performed for a mean of 5.4 years in 496 asymptomatic middle-aged men who were H. pylori antibody-positive and pepsinogen (PG) test-negative. Subjects were stratified according to the activity of H. pylori-associated gastritis measured by serum levels of PG and H. pylori antibody, and/or by endoscopic findings of rugal hyperplastic gastritis (RHG), and cancer development was investigated. During the study period, seven cases of cancer developed in the cohort (incidence rate, 261/100,000 person-years), with 85.7% developing in the group showing a PGI/II ratio ≤ 3.0, reflecting active inflammation-based high PGII levels. Cancer incidence was significantly higher in this group (750/100,000 person-years) than in groups with less active gastritis. Furthermore, cancer incidence for this group was significantly higher in the subgroup with high H. pylori antibody titers than in the low-titer subgroup. Meanwhile, endoscopic findings revealed that 11.7% of subjects showed RHG reflecting localized highly active inflammation, and cancer risk was significantly higher in patients with RHG than in patients without. Combining the two serum tests and endoscopic examination for RHG allowed identification of subjects with more active gastritis and higher cancer risk. No cancer development was observed in these high-risk subjects after H. pylori eradication. Subjects with highly active gastritis identified by the two serological tests and endoscopic RHG constitute a group at high risk of cancer development with H. pylori-infected nonatrophic stomach.

Endoscopic ultrasonography (EUS) was performed on a patient being treated for chronic pancreatitis because a submucosal tumor was observed in the stomach during gastrointestinal endoscopy. As internal pulsatile blood flow on Doppler was present, the diagnosis of an aneurysm was made. The pseudoaneurysm of the left gastric artery was embolized with histoacryl and lipiodol and the splenic artery was embolized with coils at the location of the pseudoaneurysm to prevent hemorrhage. Follow up EUS confirmed the cessation of blood flow from the pseudoaneurysm. Clinicians encountering a gastric submucosal tumor-like protrusion in a patient with chronic pancreatitis should use EUS to investigate the possibility of a pseudoaneurysm, which must be treated as quickly as possible once identified.

Continuation of pegylated interferon (PEG-IFN) plus ribavirin at the recommended dose is difficult in elderly patients and/or patients with cytopenia or complications. Whether the therapeutic efficacy of low-dose PEG-IFN plus ribavirin therapy could be predicted based on virological response within 2 weeks of therapy initiation was evaluated. A total of 106 patients with a high viral load of genotype-1b hepatitis C virus (HCV) underwent low-dose PEG-IFN plus ribavirin therapy. PEG-IFN alpha 2b (0.75 µg/kg per week) and ribavirin (600-800 mg/day) were administered for 48 weeks. Sustained virological response (SVR) was achieved in 37%, and treatment was discontinued in 9%. On univariate analysis of SVR-contributing factors, significant differences were noted in the white blood cell count, platelet count, fibrosis markers, and viral reduction within 2 weeks from therapy initiation. On multivariate analysis, the platelet count and the reduction in the HCV core antigen level at week 2 were independent factors. The positive predictive value (PPV) and the negative predictive value (NPV) for SVR based on a 1-log or greater HCV-RNA level reduction at week 2 were 65% and 90%, respectively, and those based on HCV core antigen level at week 2 were 64% and 97%, respectively. PPV and NPV based on a 2-log or greater reduction of the RNA level were 86% and 67%, respectively, and those based on the core antigen level were 93% and 69%, respectively. Evaluation of viral reduction at week 2 after therapy initiation is useful for predicting SVR to low-dose PEG-IFN plus ribavirin therapy.

Helicobacter pylori (HP) is recognized as a major pathogenic factor for persistent inflammation in the human stomach (Dooley et al., 1989; Marshall & Warren, 1984). In 1994, the International Agency for Research on Cancer (IARC) classified HP infection as a definite class I carcinogen (International Agency for Research on Cancer (IARC), 1994). HP triggers chronic inflammation of the infected stomach mucosa and is considered a major risk factor for gastric cancer (GC) and associated precursor lesions. Long-lasting inflammation in the stomach mucosa leads to a cascade of molecular and morphological changes, representing the gastritis-atrophymetaplasia-dysplasia-cancer sequence (Correa, 1992). The HP infection rate is higher in Japan than in Western countries, with nearly all cases of GC occurring in subjects with underlying HP-related chronic gastritis. HP infection is widely accepted as a major risk factor for the development of GC and its precursor lesions, based on extensive evidence derived from many studies (Blaser et al., 1995; EUROGAST Study Group, 1993; Forman et al., 1991; Hirayama et al., 1999; Honda et al., 1998; Huang et al., 1998; Nomura et al., 1991; Parsonnet et al., 1991; Shimizu et al., 1999; Sipponen et al., 1992; Sugiyama et al., 1998; Talley et al., 1991; Tokieda et al., 1999; Uemura et al., 2001; Watanabe et al., 1998; Zheng et al., 2004). However, in countries such as Japan, where the HP infection rate is high, prediction of GC risk based solely on the presence or absence of HP infection does not offer sufficient specificity. Elucidation of groups at high risk based on the natural history of GC is clearly necessary. The identification of useful markers of GC risk is thus hoped for. Evaluating HPrelated chronic gastritis and determining which subjects are at high risk for developing GC is very important, and would likely increase the efficacy of GC screening by endoscopic or other examinations (Enomoto et al., 2010a; Mukoubayashi et al., 2007; Ohata et al., 2005), and strategic approaches to metachronous multiple GC after endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) performed as minimally invasive treatment for early GC (Gotoda, 2007; Kakushima & Fujishiro, 2008; Nakajima et al., 2006). In addition, in terms of GC prevention, it has become clear that HP-related chronic gastritis cannot be ignored as an origin of carcinogenesis.

To clarify the clinical features of and risk factors for extrahepatic seeding, a major complication following radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC). Our prospective database of 351 nodules in 257 patients with HCC who had undergone RFA between April 2001 and April 2008 was reviewed. The following variables were assessed to identify the risk factors for extrahepatic seeding: age, sex, viral markers, Child-Pugh class, tumor size, number of tumors, RFA indication (tumor size ≤3 cm, number of tumors ≤3), tumor biopsy prior to RFA, degree of histological differentiation, tumor markers, tumor location, number of sessions, and combined transcatheter arterial chemoembolization. The median follow-up period was 36.5 months, during which the rate of seeding after was 5.1% and the 5-year cumulative seeding rate was 8.4%. The survival rate after neoplastic seeding was 21% at 5 years. Univariate analysis of the risk factors for neoplastic seeding showed significant differences in tumor size, RFA indication, subcapsular lesion, number of sessions, tumor biopsy prior to RFA, and des-gamma-carboxy prothrombin value. However, multivariate analysis showed that the only independent risk factor was RFA indication. The prognosis of patients with neoplastic seeding was poor. In particular, RFA performed for HCC not satisfying the RFA indication showed a high risk of seeding, and careful consideration should be given to the optimal treatment method and avoiding direct puncture of subcapsular tumors.

Evaluation of malignant potential is important to determine the treatment strategy for small hepatocellular carcinoma (HCC). The aim of the present study was to establish a method of assessing the malignant potential of small hypervascular HCC using B-mode ultrasonography. One hundred and thirteen arterial hypervascular HCC nodules under 3 cm diagnosed by biopsy or surgical resection (20.5 ± 6.3 mm) were classified into two groups ultrasonographically: type 1 with (n = 27) and type 2 without (n = 86) a halo. Type 2 was categorized into three subgroups: type 2a, homogenous hyperechoic (n = 9); type 2b, hypoechoic with a smooth margin (n = 35); and type 2c, hypoechoic with an irregular or unclear margin (n = 42). The mean diameter of type 2a nodules was significantly smaller than that of other HCC types (P 0.05). Overall, moderately differentiated HCC was the predominant histological type, except for type 2a, all of which were well-differentiated HCC. The percentage of poorly differentiated HCC was significantly higher in type 2c nodules (19%) than in other HCC types (P 0.01). The percentage of Lens culinaris agglutinin-reactive α-fetoprotein (AFP-L3) positivity was significantly higher in type 2c nodules (55%) than in other HCC types (P 0.01). Classification on B-mode ultrasonography was correlated with the histological differentiation and serum level, an indicator of a poor prognosis. The malignant potential of type 2a is the lowest and that of type 2c is the highest, both histologically and serologically. Assessment of the malignant potential of small, hypervascular HCC is possible by B-mode ultrasonography.

Although CD57+ lymphocytes are closely correlated with prognosis in various cancers, the role of subsets of CD57+ cells in hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) is unclear. In the present study, peripheral blood (PB) from HCV-related HCC patients was analyzed. Plasma cytokine levels and in vitro cytokine-producing capabilities were analyzed with enzyme-linked immunosorbent assays, and CD57+ cell subsets were studied using a multi-color FACS system. Interferon (IFN)-γ was undetectable in the plasma of patients with tumors at any stage, whereas the plasma levels of tumor necrosis factor (TNF)-α, interleukin (IL)-10 and IL-18, but not that of IL-12, were significantly higher in stage IV patients compared to patients with earlier-stage tumors. In contrast, the IFN-γ-producing capability of PB was highest in stage I patients and gradually decreased with tumor progression. The IL-10-, IL-18- and IL-12-producing capabilities of PB increased from stage I to III. However, PB-TNF-α, IL-10- and IL-18-producing capabilities were reduced in stage IV patients, probably due to repeated anti-cancer treatments. The percentage of CD4+CD57+αβTCR+ cells (CD4+CD57+ T cells) in peripheral blood lymphocytes (PBLs) increased with tumor progression. Moreover, the percentage of CD4+CD57+ T cells in PBLs and the ratio of CD4+CD57+ T cells to CD4+αβTCR+ cells (CD4+ T cells), but not that of CD4+CD57+ T cells to CD57+αβTCR+ cells (CD57+ T cells), showed a significant inverse correlation with PB-IFN-γ-producing capability. The present results suggest that an increase in CD4+CD57+ T cells controls the capability of PB to produce the anti-tumor cytokine IFN-γ and that PB-IFN-γ production is impaired with HCC tumor progression.

We report a case of a 16-year-old male who suffered from Crohn's disease (CD) with esophageal involvement, showing remarkable improvement with granulocyte/monocyte adsorption (GMA). The patient had been diagnosed as ileocolic CD and was treated with 5-aminosalicylate. He was admitted to our hospital with symptoms of fever, diarrhea, and odynophagia. Endoscopic examinations revealed that the exacerbation of ileocolic ulcers, and advent of ulcers in esophagus. Because of the patient's refusal to receive corticosteroids, immunomodulators, or biologics, he underwent GMA twice a week. After 10 sessions of GMA, he entered remission with significant decrease in clinical activity. In addition, endoscopic examinations showed remarkable improvement of ileocolic ulcers and disappearance of esophageal lesions. No adverse events were observed. GMA could be effective for manifestations of CD in gastrointestinal tract other than ileum or colon.

AIM: To evaluate the association of Helicobacter pylori (H.pylori)-related chronic gastritis stage with upper gastrointestinal symptoms and gastroesophageal reflux disease (GERD). METHODS: Subjects underwent upper gastrointestinal endoscopy, a questionnaire using a frequency scale for symptoms of GERD (FSSG), and measurements of serum H.pylori-antibody and pepsinogen (PG) levels. They were classified into the following 4 groups in terms of H.pylori-related chronic gastritis stage: Group A (n = 219), H.pylori(-)PG(-); Group B (n = 310), H.pylori(+)PG(-); Group C (n = 279), H.pylori(+)PG(+); and Group D (n = 17), H.pylori(-)PG(+). RESULTS: Reflux esophagitis occurred in 30.6% of Group A, 14.5% of Group B, 6.8% of Group C, and 0% of Group D (P < 0.001). Scores for acid reflux symptoms decreased significantly with chronic gastritis stage (from Group A to D) (P < 0.05), while scores for dysmotility symptoms did not differ significantly. The prevalence of non-erosive reflux disease (NERD) did not differ among groups. However, in subjects with GERD, the prevalence of NERD tended to increase with chronic gastritis stage (P = 0.081). CONCLUSION: Acid reflux symptoms and the prevalence of reflux esophagitis can be assessed by measuring both serum H.pylori-antibody and PG levels.

This study investigated correlations between Helicobacter pylori infection or chronic atrophic gastritis (CAG) and risk of colorectal adenoma in a population-based case-control study. Subjects comprised asymptomatic, middle-aged, male Japanese factory workers who participated in an annual health check-up program, including cancer screening with colonoscopy. We selected 239 colorectal adenoma cases based on histological evaluation and 239 age-matched adenoma-free controls, and evaluated colorectal adenoma risk according to stage of H. pylori-related chronic gastritis as determined by serum tests for H. pylori antibody titer and pepsinogen. Subjects with colorectal adenoma were more likely to be smokers and have hypercholesterolemia. H. pylori infection was a risk factor for adenoma as a whole (crude odds ratio [OR]: 2.26, 95% confidence interval [CI]: 1.44-3.55). Analysis of distal adenoma cases showed that adenoma risk was significantly increased in the presence of H. pylori infection, but there was no further increase in risk with CAG. In contrast, proximal adenoma risk increased stepwise with the presence and progression of H. pylori-related chronic gastritis and showed a maximal and significant increase with CAG (crude OR: 4.51, 95% CI: 1.43-14.2). Subjects with more extensive and severe gastritis showed still higher risk not only for proximal but also for distal adenoma. H. pylori-related chronic gastritis is likely to be involved in the development of colorectal neoplasms, and its progression appears to increase the risk, particularly for proximal adenomas. Knowing the H. pylori-related chronic gastritis stage will probably be useful for evaluation of risk for colorectal neoplasia.

We investigated the correlation between Japanese apricot (JA) intake and Helicobacter pylori-related chronic atrophic gastritis (CAG).A questionnaire was administered and serum anti-H. pylori IgG antibodies measured in 1358 asymptomatic adults. The subjects were divided into high-intake and low-intake groups. Histological and serological evaluation of H. pylori-related CAG was performed in 68 non-elderly volunteers.The H. pylori-negative rate did not differ significantly between the high-intake and low-intake groups. Mean antibody titers were lower in the high-intake group, but the difference was not significant. There was no significant difference in the rate of H. pylori infection on the basis of JA intake when subjects were stratified by age. Among H. pylori-positive non-elderly subjects, antibody titers were significantly lower in the high-intake group (P=0.041). Endoscopic tissue biopsy from the 68 volunteers showed less H. pylori bacterial load and mononuclear infiltration irrespective of gastric site in the high-intake group. In the high-intake group, antral neutrophil infiltration was significantly less pronounced and corporal atrophy was less extensive. Serological evaluation using serum PG levels also confirmed these histopathological data.Our findings strongly indicate a preventive effect of JA intake on CAG by inhibiting H. pylori infection and reducing active mucosal inflammation.

The present study investigated the preventive effects of etodolac, a selective cyclo-oxygenase (COX)-2 inhibitor, on metachronous cancer development after endoscopic resection of early gastric cancer. Among 267 early gastric cancer patients who underwent endoscopic resection, 47 patients with extensive metaplastic gastritis were selected based on endoscopic findings and our previously described criteria of serum pepsinogen (PG) test-positive and Helicobacter pylori antibody-negative conditions. Nonrandomized etodolac treatment (300 mg/day) was administered to 26 patients (Group A), while the remaining 21 patients were untreated (Group B). No significant differences in age, sex distribution, lifestyle factors or extent of metaplastic gastritis at baseline were identified between groups. Patients were followed for metachronous cancer development with endoscopy every 6-12 months for up to 5 years. Mean (standard deviation) follow-up period was 4.2 (0.9) years. In Group B, 5 cancers developed (incidence rate = 6,266/100,000 person-years), significantly more than the 1 cancer in Group A (incidence rate = 898/100,000 person-years; p < 0.05). Long-term etodolac treatment did not influence the extent of metaplastic gastritis as revealed by endoscopic findings or by serum PG levels, but effectively reduced metachronous cancer development in patients with extensive metaplastic gastritis. These results strongly suggest that chemoprevention of cancer in the metaplastic stomach is possible by controlling COX-2 expression.

A longitudinal cohort study was conducted in Helicobactor pylori-infected middle-aged Japanese males to evaluate the preventive effects of H. pylori eradication on the development of gastric cancer according to the extent of chronic atrophic gastritis (CAG). The extent of CAG was monitored by baseline serum pepsinogen (PG) levels. We followed 3,656 subjects with persistent H. pylori infection and 473 subjects with successful H. pylori eradication for cancer development for a mean (SD) of 9.3 (0.7) years. Groups with and without extensive CAG were categorized based on PG test-positive criteria to detect extensive CAG of PG I ≤ 70 ng/ml and PG I/II ratio ≤ 3.0. During the study period, 5 and 55 gastric cancers developed in H. pylori-eradicated and the noneradicated subjects, respectively, indicating no significant reduction in cancer incidence after H. pylori eradication. Among the noneradicated subjects, 1,329 were PG test-positive and 2,327 were PG test-negative. Gastric cancer was confirmed in 30 and 25 subjects, respectively. Among subjects whose infection was eradicated, 155 were PG test-positive and 318 were PG test-negative. Of these subjects, gastric cancer was confirmed in 3 and 2 subjects, respectively. Significant reduction in cancer incidence after eradication was observed only in PG test-negative subjects (p < 0.05; log-rank test). The results of this study strongly indicate that cancer development after eradication depends on the presence of extensive CAG before eradication and that H. pylori eradication is beneficial to most PG test-negative subjects with mild CAG as defined by the aforementioned criteria. © 2009 UICC

A total of 5,209 asymptomatic, middle-aged subjects, whose serum pepsinogen (PG) and Helicobacter pylori antibody levels had been assessed, were followed for 10 years. Subjects with positive serum H. pylori antibodies (50 U/mL) had an increased cancer risk (HR = 3.48, 95% CI = 1.26-9.64). Risk of gastric cancer increased as the antibody level increased; the H. pylori-positive group with antibody levels500 U/mL had the highest incidence rate (325/100,000 person-years). Cancer development also increased with a reduced serum PG I level or a reduced PG I/II ratio; the risk was significantly elevated with serum PG I levelor=30 ng/mL (HR = 3.54, 95% CI = 1.95-6.40) or PG I/II ratioor=3.0 (HR = 4.25, 95% CI = 2.47-7.32). Furthermore, the risk of diffuse-type cancer increased as PG II level increased; it was significantly elevated with PG II levelor=30 ng/mL (HR = 3.81, 95% CI = 1.10-13.21). Using H. pylori antibody and PG levels, subgroups with an especially high or low cancer incidence rate could be identified. H. pylori-negative or indeterminate subjects with low PG level (PG Ior=30 ng/mL or PG I/II ratioor=2.0) or H. pylori-positive subjects with antibody levels500 U/mL and a low PG level were among the subgroups with a high cancer incidence rate (over 400/100,000 person-years). In contrast, H. pylori-negative subjects with a PG I level70 ng/mL or a PG I/II ratio3.0 had the lowest risk; none of these subjects developed cancer. Thus, serum PG levels and/or H. pylori antibody levels can be used to predict the risk of cancer in individuals with H. pylori-related gastritis from the general population.