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Translocation (8;21)/AML1-ETO is considered a favorable cytogenetic abnormality in acute myeloid leukemia (AML). However, the outcomes associated with KIT mutations in AML1-ETO have not been elucidated. A 16-year-old boy was diagnosed with recurrent AML. Although he underwent hematopoietic stem cell transplantation (HSCT) twice, the leukemia relapsed and grew resistant to several chemotherapies. We began to treat him with imatinib, but stopped on the 31st day as it did not show any effects. Later, we administered dasatinib. However, we discontinued this because he showed severe nasal hemorrhage 87 days after administration of dasatinib. The therapeutic benefit of tyrosine-kinase inhibitor (TKI) was estimated by quantitative analysis of AML1-ETO and the patient's clinical impression. We did not conduct analyses to determine the effective concentration of TKI. The patient has not yet shown any major molecular response. Therefore, we conclude that TKI may be useful for slight palliation of symptoms in KIT-positive AML. However, patients with refractory AML associated KIT mutations in AML1-ETO should not be considered for TKI monotherapy.

A multiresidue analysis of pesticides in tea using supercritical fluid extraction (SFE) and GC-MS was developed. The preprocessing using SFE shortened the total analysis time. The SFE extract contained less matrices than the extract obtained with organic solvents. However, these matrices disturbed instrumental analysis. So, the extract was cleaned up with ENVI™-Carb/NH2 and InertSep™ SI cartridge. A recovery test was carried out for 245 pesticides spiked in samples at the level of 0.1 μg/g. Recovery rates of 178 pesticides ranged from 70 to 120%, the relative standard deviations (RSDs) were less than 15%, and quantitation limits were between 0.01 and 0.05 μg/g. Based on these results, this method is considered to be useful for multiresidue analysis of pesticides in tea samples.

Recently, it has been shown that approximately 80% of Merkel cell carcinomas harbor a novel polyomavirus named Merkel cell polyomavirus, thought to be a carcinogenic agent. However, it is not fully elucidated whether Merkel cell carcinomas differ with regard to the presence or absence of Merkel cell polyomavirus. To address this, we investigated morphologic differences between Merkel cell polyomavirus-positive and -negative Merkel cell carcinomas by morphometry. Using polymerase chain reaction and real-time quantitative polymerase chain reaction, Merkel cell polyomavirus was detected in 20 (77%) of 26 Merkel cell carcinoma cases, including 4 Merkel cell carcinomas combined with squamous cell carcinomas. Interestingly, Merkel cell polyomavirus was detected only in ordinary (pure) Merkel cell carcinomas; none of the 4 combined Merkel cell carcinomas + squamous cell carcinomas was positive for Merkel cell polyomavirus (P = .001). Morphometric analyses revealed that Merkel cell polyomavirus-negative Merkel cell carcinomas had more irregular nuclei (P < .001) and more abundant cytoplasm (P = .001) than Merkel cell polyomavirus-positive Merkel cell carcinomas, which had uniform round nuclei and scant cytoplasm. Reliability of the morphometry was confirmed using intraobserver and interobserver reliability tests. These results demonstrated statistically significant differences in tumor cell morphology between Merkel cell polyomavirus-positive and -negative Merkel cell carcinomas and reconfirmed the absence of Merkel cell polyomavirus in combined tumors. Furthermore, the results strongly suggest fundamental biological differences between Merkel cell polyomavirus-positive and -negative Merkel cell carcinomas, supporting that Merkel cell polyomavirus plays an important role in the pathogenesis of Merkel cell polyomavirus-positive Merkel cell carcinoma., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: Only a few studies have documented the characteristics of inflammatory bowel disease (IBD) associated with primary sclerosing cholangitis (PSC). We aimed to clarify the clinical and histopathological characteristics of IBD associated with PSC (PSC-IBD)., Methods: Twenty-nine patients with PSC and 60 patients with ulcerative colitis (UC) but without complicating PSC were enrolled in this study. First, the age and sex distribution, affected area, clinical course, number of recurrent attacks, and severity of UC were investigated. Then, mucosal specimens obtained from the right side (cecum and ascending colon), transverse colon, and the left side (descending colon, sigmoid colon, and rectum) during colonoscopy were studied for inflammatory cell infiltration, the presence of crypt abscesses, the degree of goblet cell disappearance, and edema., Results: (1) The incidence of IBD in PSC patients was 68.9% (20/29). There were two peaks in the age distribution of PSC. Male PSC patients demonstrated a first peak and female patients a second peak. Male PSC-IBD patients were in their teens and 20s making the first peak. Female PSC-IBD patients were in their 50s and 60s making the second peak. The PSC-IBD patents were significantly younger than the patients without IBD (33.6 vs. 58.9 years, p < 0.001). (2) PSC-IBD showed a right-sided predominance colonoscopically. (3) None of the patients had a severe clinical course, and a half of them were asymptomatic. (4) Histopathological examination demonstrated severe inflammatory cell infiltration in the cecum and ascending colon, whereas the degree was mild in the rectum/descending colon., Conclusions: PSC-IBD shows characteristic clinical, colonoscopic, and histopathological findings.

Most humans become lifelong carriers of Epstein-Barr virus (EBV) by adulthood. Primary EBV infection in adolescents causes infectious mononucleosis. EBV infection is associated with various diseases, neoplasms and hematological disorders. Recently, we reported that EBV can infect rabbits by intravenous, intranasal and/or peroral inoculation, which caused primary EBV infection in rabbits with heterogeneous host reactions. Some rabbits showed chronic and lifelong EBV infection with hemophagocytosis. In this study, to reveal detailed mechanisms in rabbit EBV infection, an in vitro investigation was performed. We elucidated that: (1) EBV can infect rabbit peripheral blood mononuclear cells and splenic lymphocytes in vitro, because EBV gene expressions were confirmed. (2) It is highly likely that the B cell is the main target cell of rabbit EBV infection and is immortalized similar to humans. (3) CD8+ T cells increased in the rabbit in vivo model after EBV inoculation, whereas an increase of B cells occurred after their transient decrease. These data suggest that EBV-infected B cells were proliferated, while CD8+ T cells increased to recognize and kill them. This system may explain the paths of rabbit EBV infection and host reaction, simulating human EBV infection. In vitro studies will be helpful to reveal the pathogenesis of rabbit EBV infection and EBV-associated diseases., (Copyright © 2010 S. Karger AG, Basel.)

Epstein-Barr virus (EBV) is spread universally in humans, and it causes infectious mononucleosis and sometimes induces serious EBV-associated disease. The detailed mechanism of primary infection in humans has remained unclear, because it is difficult to examine the dynamics of EBV in vivo. In this study, a natural EBV-infection rabbit model by intranasal or peroral inoculation is described. Ten male rabbits were examined for EBV-DNA or mRNA expression and anti-EBV antibodies in blood. Four of 10 rabbits showed the evidence of EBV infection; detection of EBV-DNA or EBV-related genes mRNA in peripheral blood mononuclear cells, increased EBV antibodies in the plasma, and the presence of lymphocytes expressing EBER1 and EBV-related gene proteins in the lymphoid tissues of a rabbit. Three of four infected rabbits were detected transiently EBV-DNA and/or mRNA of EBV-related genes such as EBNA1, EBNA2, BZLF1, and EA in blood, while in one of four, EBV-DNA and/or mRNA were detected for more than 200 days after viral inoculation. The level of EA-IgG increased and its level was maintained in all infected rabbits, whereas those of VCA-IgM and VCA-IgG increased transiently, and EBNA-IgG was not elevated. Pathological examination of a rabbit infected transiently revealed some scattered lymphocytes expressing EBER1, LMP1, and EBNA2 in the spleen and lymph nodes. EA expression was also observed in the spleen. These findings suggest that EBV can infect the rabbit by the intranasal or peroral route, and that this rabbit model is useful for examining the pathophysiology of natural primary EBV infection in humans., ((c) 2010 Wiley-Liss, Inc.)

Background/aims: There have been only a few reports about the clinical course and indications for steroid therapy of autoimmune pancreatitis (AIP). We studied 45 cases of AIP to clarify the clinical course and indications for steroid therapy, from the viewpoint of associated sclerosing cholangitis (SC)., Methodology: Two groups (with and without progression or recurrence) were compared by cholangiographic classification, blood chemistry, initial therapy, presenting symptoms and pancreatic findings., Results: One patient with AIP and no stricture and seven patients with AIP and SC with stricture of the lower common bile duct showed strictures of the intrahepatic bile duct and hilar hepatic lesions during their clinical course. SC patients with intrahepatic stenosis showed higher IgG levels than those with stenosis of the lower common bile duct only. Six of seven cases without steroid therapy and IgG >2000 mg/dL showed significantly greater recurrence or progression of SC., Conclusions: When a patient with SC and AIP with elevated levels of IgG (>2000 mg/dL) is encountered, steroid administration should be initiated immediately.

Background and Aim: The extent of liver drainage for palliative treatment of malignant hilar biliary obstruction is controversial. The aim of this study was to compare endoscopic unilateral versus bilateral drainage in patients with malignant hilar biliary obstruction using a self-expanding metal stent (SEMS)., Methods: We carried out a retrospective review of 46 consecutive patients with malignant hilar biliary obstruction who were treated by endoscopic biliary drainage using SEMS between 1997 and 2005. Unilateral metal stenting (group A) was performed in 17 patients between 1997 and 2000, and bilateral metal stenting (group B) was performed in 29 patients between 2001 and 2005. The successful stent insertion, successful drainage, early complications, late complications, stent patency, and survival rate for groups A and B were evaluated and compared retrospectively., Results: There were no significant differences between the two groups in successful stent insertion (100% vs 90%, group A vs B, respectively), successful drainage (100% vs 96%), early complications (0% vs 10%), or late complications (65% vs 54%). Cumulative stent patency was significantly better in group B than in group A (P = 0.009). In cases of cholangiocarcinoma, cumulative stent patency was significantly better in group B than in group A (P = 0.009), whereas there were no inter-group differences for gallbladder carcinoma. Cumulative survival did not differ significantly between the groups., Conclusions: Endoscopic bilateral drainage using SEMS for malignant hilar biliary obstruction is more effective than unilateral drainage in terms of cumulative stent patency, especially in cases of cholangiocarcinoma.

Background/aims: Lentinan (LNT), a purified beta-glucan, is a biological and immunological modifier and has been used as an anticancer drug in combination with 5-fluorouracil for gastric cancer in Japan. In this prospective randomized study, we evaluated the effects of LNT combination with regard to quality of life (QOL) and LNT binding ratio in monocytes., Methodology: Twenty patients were evaluated for 12 weeks. One cycle was 3 weeks and S-1 (day1-14) and Paclitaxel (days1 and 8) were administered. LNT was used once a week (days 1, 8 and 15) and it was used for all 12 weeks in the LNT 12-wk group and only for the last 6 weeks in the LNT 6-wk group. QOL was evaluated weekly by QOL-ACD, and binding of LNT to monocytes was measured by flow cytometry., Results: There were individual variations in the binding ratio of LNT to monocytes from 0.16% to 11.95%. Toxicity with chemotherapy was not improved in the LNT 12-wk group, however, the total QOL score was significantly elevated in the LNT 12-wk group (p = 0.018) but not in the LNT 6-wk group., Conclusion: LNT combination from the beginning of the chemotherapy may be an important factor for the improvement of patient QOL.

Context: Obstructive jaundice in chronic pancreatitis is generally caused by stenosis of the bile duct in the pancreas. Obstructive jaundice caused by the impaction of a pancreatic stone in the papilla is markedly rare, with only seven cases reported to date., Case Report: We report a case of obstructive jaundice caused by the impaction of a pancreatic stone in the papilla. A 41-year-old male with chronic pancreatitis was admitted because of epigastric pain. Blood analysis revealed increased levels of hepatobiliary system enzymes, mild jaundice and an increase in pancreatic enzymes. Computed tomography revealed a number of pancreatic stones in the main pancreatic duct, and a stone with a diameter of about 1 cm in the pancreatic head. Swelling of the papilla was observed using duodenoscopy while endoscopic ultrasonography revealed a strong echo with acoustic shadows in the papilla. Percutaneous transhepatic biliary drainage was performed for the obstructive jaundice. Contrast medium from the percutaneous transhepatic biliary drainage route regurgitated into the pancreatic duct and revealed the impaction of pancreatic stones in the common channel. The patient was referred to our hospital for treatment of the stone impaction. We performed a needle knife precut papillotomy and extracted a white stone which was diagnosed as a pancreatic stone by composition analysis., Conclusion: Impaction of a pancreatic stone in the papilla is a markedly rare cause of obstructive jaundice in chronic pancreatitis. A needle knife precut papillotomy was effective in removing the impacted pancreatic stone in the papilla.

Background and Aim: Transpapillary bile duct brushing cytology and/or forceps biopsy was performed in the presence of an indwelling guidewire in patients with biliary stricture, and the treatment time, overall diagnosis rate, diagnosis rate of each disease, complications, and influences on subsequent biliary drainage were investigated., Methods: After endoscopic retrograde cholangiography, brushing cytology was performed, followed by forceps biopsy. In patients with obstructive jaundice, endoscopic biliary drainage (EBD) was subsequently performed. To investigate the influences of bile duct brushing cytology and forceps biopsy on EBD, patients who underwent subsequent EBD by plastic stent were compared with patients who underwent EBD alone., Results: The samples for cytology were collected successfully in all cases, and the sensitivity for malignancy/benignity, specificity, and accuracy were 71.6%, 100%, and 75.0%, respectively. The biopsy sampling was successful in 51 patients, and samples applicable to the evaluation were collected in all 51 patients. The sensitivity for malignancy/benignity, specificity, and accuracy were 65.2%, 100%, and 68.6%, respectively. Combination of the two procedures increased the sensitivity and accuracy to 73.5% and 76.6%, respectively. The time required for cytology and biopsy was 11.7 min, which is relatively short. Cytology and biopsy did not affect drainage. Regarding accidents, bile duct perforation occurred during biopsy in one patient (1.9%), but was rapidly improved by endoscopic biliary drainage., Conclusions: Transpapillary brushing cytology and forceps biopsy could be performed in a short time. The diagnosis rate was high, and the incidence of complication was low, having no influence on subsequent biliary drainage.

We evaluated palliative treatment for unresectable malignant stomach pyloric region and the duodenal obstruction using covered self-expandable metallic stent (SEMS). Fifty-seven patients (26 stomach pyloric stenosis, 31 duodenal stenosis) were underwent palliative treatment using covered SEMS. The covered SEMS was Ultraflex stent for esophageal obstruction. The covered SEMS was successfully indwelled in the target region in 56 patients. The patients became able to ingest orally after a mean of 2 days, and 96% of the patients (54/56) became able to eat solid or semi-solid diets later. The SEMS obstruction by tumor ingrowth or hyperplasia was not occurred, so SEMS was maintenance-free. We concluded covered SEMS was useful palliative treatment because it prevented SEMS obstruction by tumor ingrowth or hyperplasia and it was maintenance-free.

Background: It has previously been reported that there is a strong correlation between the expression of glycosylphosphatidylinositol (GPI)-anchored complement membrane inhibitor in gastric epithelium and the severity of inflammation of gastric mucosa. To investigate the regulation of complement activity in gastric epithelium during Helicobacter pylori (H. pylori)-associated gastritis, the expression of GPI-anchored complement membrane inhibitors, decay-accelerating factor (DAF) and 20-kDa homologous restriction factor 20 (HRF20), and membrane cofactor protein (MCP), which is a transmembrane protein, were evaluated after removal of the H. pylori stimulus. Furthermore, the expression of the complement fragment, C3c, was also investigated., Methods: Forty-six patients with epigastric symptoms and endoscopically confirmed peptic ulcer or gastritis who had H. pylori infection of the gastric mucosa were enrolled in the present study. Biopsy specimens were obtained from the gastric antrum and corpus 1 month before and after eradication. Helicobacter pylori infection was determined by the rapid urease test, histology, and culture before eradication, and by histology, culture, and urea breath test after eradication. Gastric biopsy specimens obtained before and after eradication were evaluated for infiltration by neutrophils and mononuclear cells. The expression of complement membrane inhibitors, DAF, HRF20, and MCP and that of the main complement fragment, C3c, was immunohistochemically evaluated., Results: One month after the eradication of H. pylori, the infiltration by neutrophils and mononuclear cells in the gastric mucosa decreased significantly (P < 0.0001) as compared with that before eradication. The expression of DAF, HRF20, and C3c on gastric mucosal epithelium also significantly decreased in both the antrum and the corpus (P < 0.05) 1 month after eradication. However, no change was observed in the expression of MCP., Conclusions: The decrease in the expression of GPI-anchored complement regulator and the complement after removal of a chronic microbial stimulus suggests that the gastric epithelium appears to undergo an aggressive stress of complement during H. pylori infection. Conclusively, DAF and HRF20 may play an important protective role against complement-mediated damage induced by chronic microbial stimuli in such a pathological condition., (Copyright 2005 Blackwell Publishing Asia Pty Ltd.)

Background: Sclerosing cholangitis with autoimmune pancreatitis has a cholangiographic appearance that is similar to that of primary sclerosing cholangitis, but only the former responds well to corticosteroid therapy. It, therefore, is necessary to distinguish between these two diseases. Cholangiography is the reference standard for the diagnosis of primary sclerosing cholangitis. The present study compared the characteristic findings for these two types of sclerosing cholangitis., Methods: Cholangiograms from patients with primary sclerosing cholangitis (n = 29) and sclerosing cholangitis with autoimmune pancreatitis (n = 26) were studied with regard to length and region of stricture formation, and other characteristic findings., Results: Band-like stricture, beaded or pruned-tree appearance, and diverticulum-like formation were significantly more frequent in primary sclerosing cholangitis. In contrast, segmental stricture, long stricture with prestenotic dilatation and stricture of the distal common bile duct were significantly more common in sclerosing cholangitis with autoimmune pancreatitis. Discriminant analysis based on these findings correctly identified 27 of 28 patients with primary sclerosing cholangitis and 25 of 26 patients with sclerosing cholangitis with autoimmune pancreatitis. It also identified a patient with an incorrect diagnosis of primary sclerosing cholangitis who proved, on review of a surgical specimen, to have findings consistent with lymphoplasmacytic sclerosing cholangitis., Conclusions: Characteristic cholangiographic features allow discrimination of sclerosing cholangitis with autoimmune pancreatitis and lymphoplasmacytic sclerosing cholangitis without pancreatitis from primary sclerosing cholangitis.

Intramural injection of peptidoglycan-polysaccharide polymers into the distal colon in rats induces granulomatous colitis associated with extracolonic manifestations. We sought to clarify the effects of Kupffer-cell depletion induced by the intravenous administration of gadolinium on colonic and extracolonic inflammation in this model. The effects of Kupffer-cell depletion on acute and chronic inflammation were evaluated 3 days and 3 weeks after injection of peptidoglycan-polysaccharide, respectively. We assessed the effects of gadolinium on colonic cytokine levels in vivo and the viability of elicited peritoneal macrophages and peptidoglycan-polysaccharide-induced production of nitrite, an indirect index of nitric oxide production, by these cells in vitro. A single injection of gadolinium caused a marked decrease in the number of Kupffer cells stained with antibodies within 3 days. Gadolinium treatment did not alter acute inflammation at 3 days. Repeated treatment with gadolinium dramatically attenuated grossly observed chronic inflammation, including thickening of colon wall, hepatic and splenic nodules, and swelling of foot joints; and significantly reduced the proportional areas occupied by granulomas in the colon, liver, and spleen at 3 weeks. These protective effects were reflected in significant reduction in colon and liver weights; gross scores; colonic myeloperoxidase activity, an indirect quantitative index of granulocyte infiltration; colonic interleukin-1beta levels; plasma nitrite and nitrate levels; and decreased tendency toward arthritis. Although gadolinium did not cause injury in elicited peritoneal macrophages in vitro, the compound dose-dependently attenuated peptidoglycan-polysaccharide-induced production of nitrite by these cells. Chronic Kupffer-cell depletion attenuates peptidoglycan-polysaccharide-induced granulomatous inflammation in the colon, liver, and spleen and reduces the incidence of arthritis, possibly by suppressing the production of interleukin-1beta and nitric oxide.

Background/aims: We examined taurochenodeoxycholic acid-induced hepatotoxicity with reference to Ca2+ and calpain involvement, intracellular bile acid content, and zone specificity in isolated perfused rat liver., Methodology: Taurochenodeoxycholic acid or chenodeoxycholic acid was infused into the portal vein and lactate dehydrogenase release, a marker of hepatocyte injury, in the effluent and bile acid output were measured in the presence and absence of either nickel, a membranous Ca2+ channel blocker, or calpain inhibitor in isolated perfused rat liver., Results: Taurochenodeoxycholic acid induced a significant and transient increase (first peak; 4 min) and subsequent time- and dose-dependent elevation in lactate dehydrogenase release which was proportional to accumulated bile acids in the liver. Although the first peak was significantly suppressed by pretreatment with nickel, the subsequent release was not reduced. Lactate dehydrogenase release at 15, 20, and 25 min was significantly suppressed by the calpain inhibitor. Numbers of damaged hepatocytes stained with trypan blue were significantly increased in the periportal region (zone 1) compared with the pericentral region (zone 3) and these cells were consistently stained with anti-calpain antibody., Conclusions: Taurochenodeoxycholic acid causes both transient damage and subsequent increasing hepatotoxicity which are respectively dependent on Ca2+ influx via membranous Ca2+ channels and calpain, with the periportal region being more susceptible.

A 59-year-old man with bloody stools, and previously diagnosed with sigmoid colon carcinoma, visited our hospital. Preoperative abdominal ultrasonography (US) showed another tumor, with an uneven irregular surface, measuring about 9 x 5 cm, below the left hypochondrium. The tumor consisted of several cysts. Abdominal computed tomography (CT) showed a multicystic tumor attached to the stomach, and its septum and marginal region were intensely stained on contrast imaging. On magnetic resonance imaging (MRI), low and markedly high signals were revealed in the tumor on T1-weighted and T2-weighted sequences, respectively. Contrast imaging of the upper digestive tract showed extramural compression of the greater curvature of the antral stomach by the tumor. The tumor was partially imaged by endoscopic ultrasonography (EUS), but continuity to the stomach was not confirmed. On abdominal angiography, the tumor was slightly stained via the gastroepiploic arteries. Surgical treatment was performed to excise both the gastric tumor and the sigmoid colon carcinoma. The gastric tumor was removed with gastric wall tissue where the tumor was attached to a 2-cm pedicle. It was multicystic, contained watery fluid, and had a smooth outer surface. Histologically, the tumor consisted of multiple irregular cysts without epithelial lining, and solid epitheloid cell nests in between. The tumor cells had clear or eosinophilic cytoplasm and round nuclei. No mitotic figures were seen. The tumor cells in the pedicle were connected with the muscularis propriae of the stomach. Immunohistochemistry showed c-kit-positive, CD34-positive smooth muscle actin (SMA)-negative, and S-100-negative staining of tumor cells. The final diagnosis was gastrointestinal stromal tumor (GIST).