Mannan-binding protein, a C-type serum lectin, recognizes primary colorectal carcinomas through tumor-associated Lewis glycans.

Mannan (mannose)-binding protein (MBP) is a C-type serum lectin that plays a key role in innate immunity. MBP forms large multimers (200-600 kDa) and exhibits broad specificity for mannose, N-acetylglucosamine, and fucose. MBP exhibits high affinity for unique oligosaccharides that have been isolated from human colorectal carcinoma (SW1116) cells and characterized as highly fucosylated high m.w. type 1 Lewis glycans. In this study, we first demonstrated that MBP recognizes human primary colorectal carcinoma tissues through tumor-associated MBP ligands. We performed fluorescence-based histochemistry of MBP in human colorectal carcinoma tissues and showed that MBP clearly stained cancer mucosae in a Ca(2+)-dependent manner. Coincubation with plant (Aleuria aurantia) lectin, but not Con A, blocked MBP staining, indicating that fucose, rather than mannose, is involved in this interaction. The expression of MBP ligands was detected in 127 of 330 patients (38.5%), whereas, most significantly, there was no expression in 69 nonmalignant tissues. The MBP-staining pattern in cancer mucosae significantly overlapped with that of Lewis b [Fucα1-2Galß1-3(Fucα1-4)GlcNAc] staining, but the Lewis b staining in normal tissues was not associated with MBP staining. In addition, the MBP staining correlated inversely with the expression of CA19-9 Ag, and MBP stained 11 of 25 (44%) CA19-9 (sialyl Lewis a [NeuAc(α2-3)Galß1-3(Fucα1-4)GlcNAc])(-) colorectal carcinoma tissues. We found a favorable prognosis in patients with MBP ligand(+) tumors. These results suggest that selective recognition of cancer cells by endogenous MBP seems to be associated with an antitumor effect and that tissue staining with MBP in combination with CA19-9 may serve as a novel indicator of colorectal carcinoma tissues.

Threaded biliary inside stents are a safe and effective therapeutic option in cases of malignant hilar obstruction.

BACKGROUND: Although endoscopic biliary stents have been accepted as part of palliative therapy for cases of malignant hilar obstruction, the optimal endoscopic management regime remains controversial. In this study, we evaluated the safety and efficacy of placing a threaded stent above the sphincter of Oddi (threaded inside plastic stents, threaded PS) and compared the results with those of other stent types. METHODS: Patients with malignant hilar obstruction, including those requiring biliary drainage for stent occlusion, were selected. Patients received either one of the following endoscopic indwelling stents: threaded PS, conventional plastic stents (conventional PS), or metallic stents (MS). Duration of stent patency and the incident of complication were compared in these patients. RESULTS: Forty-two patients underwent placement of endoscopic indwelling stents (threaded PS = 12, conventional PS = 17, MS = 13). The median duration of threaded PS patency was significantly longer than that of conventional PS patency (142 vs. 32 days; P = 0.04, logrank test). The median duration of threaded PS and MS patency was not significantly different (142 vs. 150 days, P = 0.83). Stent migration did not occur in any group. Among patients who underwent threaded PS placement as a salvage therapy after MS obstruction due to tumor ingrowth, the median duration of MS patency was significantly shorter than that of threaded PS patency (123 vs. 240 days). CONCLUSIONS: Threaded PS are safe and effective in cases of malignant hilar obstruction; moreover, it is a suitable therapeutic option not only for initial drainage but also for salvage therapy.

CD8(+) mycosis fungoides with esophageal involvement: A case report.

Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma and is characterized clinically by an indolent course with slow progression. MF is limited to the skin with widespread distribution, however, extracutaneous involvement of MF occurs during the advanced stages of the disease. Esophageal involvement of MF is a rare event. In the present study, we describe the first documented case of CD8(+) MF with esophageal involvement that was endoscopically diagnosed antemortem. A 70-year-old male with a 15-year history of MF presented with difficulty in swallowing. Endoscopic examination revealed a tumorous lesion with ulceration in all regions of the esophagus. Esophagus biopsy demonstrated atypical lymphocytic infiltrates with ulceration. Immunohistochemically, these atypical lymphocytes were positive for CD3, CD8 and cytotoxic granules. Therefore, a diagnosis of CD8(+) MF involving the esophagus was made. Extracutaneous involvement of the esophagus in MF is extremely rare and the majority of previously reported cases have been diagnosed postmortem. Only two cases of MF with esophageal involvement endoscopically diagnosed antemortem have been previously reported and this is the first documented case of CD8(+) MF with esophageal involvement diagnosed by this method. Early detection of extracutaneous involvement of MF is important for accurate treatment and endoscopic examination is a useful tool for detection of this pathology.

Magnifying endoscopy with narrow-band imaging in the differential diagnosis of gastric adenoma and carcinoma and identification of a simple indicator.

BACKGROUND AND AIMS: Discrimination of gastric adenomas from adenocarcinomas by conventional endoscopy is difficult. Therefore, we evaluated the usefulness of magnifying endoscopy combined with narrow-band imaging for this differential diagnosis. METHODS: Forty-nine consecutive gastric lesions were diagnosed as adenomas by conventional endoscopy with forceps biopsy and finally resected by endoscopic submucosal dissection. The findings from magnifying endoscopy with narrow-band imaging were retrospectively classified into five types according to the marginal crypt epithelium and microvascular pattern: Types I and II (clear marginal crypt epithelium combined with regular or unclear microvascular pattern) and Types III, IV, and V (unclear marginal crypt epithelium combined with regular, irregular, or unclear microvascular pattern). RESULTS: Conventional endoscopy showed 39 flat elevated-type lesions (0-IIa) and 10 flat elevated-type lesions with depression (0-IIa+IIc). The patterns on magnifying endoscopy with narrow-band imaging were Type I (n = 8), Type II (n = 8), Type III (n = 2), Type IV (n = 30), and Type V (n = 1). The final histological diagnoses after endoscopic submucosal dissection were adenoma (n = 20), adenocarcinoma in adenoma (n = 22), and adenocarcinoma (n = 7). The cancer-bearing rates were Type I (0%), Type II (0%), Type III (100%), Type IV (89.7%), and Type V (100%). Among the expert endoscopists, intra- and interobserver κ values for each type were 0.85 each, with 92.0% and 88.0% consensus of diagnoses, respectively. CONCLUSIONS: Magnifying endoscopy with narrow-band imaging is a powerful tool for diagnosing gastric borderline lesions.

Magnified endoscopy combined with narrow band imaging of minimal superficial esophageal neoplasia-indicators to differentiate intraepithelial neoplasias.

PURPOSE: Clinical application of narrow band imaging facilitates diagnosis of esophageal neoplasia. However, no previous investigation has been conducted on magnifying endoscopy combined with narrow band imaging in detection of minimal superficial esophageal neoplasia, which is defined as neoplasia <10 mm in diameter. The aim of this retrospective study was to evaluate the usefulness of this combined technique in the differential diagnosis of minimal superficial esophageal neoplasia. METHODS: Between January 2005 and November 2011, 53 minimal superficial esophageal neoplasias in 40 patients were diagnosed by screening upper gastrointestinal endoscopy with narrow band imaging at our hospital. We investigated findings including brownish dots, brownish epithelium, and demarcation line of minimal superficial esophageal neoplasia diagnosed histopathologically as low-grade intraepithelial neoplasia, high-grade intraepithelial neoplasia, and squamous cell carcinoma. RESULTS: Significantly more brownish dots (P < 0.05) and brownish epithelium (P < 0.005) were observed in intraepithelial papillary capillary loops in high-grade neoplasia compared with low-grade neoplasia. When minimal superficial esophageal neoplasia was diagnosed as high-grade intraepithelial neoplasia or squamous cell carcinoma, sensitivity, specificity, positive predictive value, and negative predictive value were 88.9, 42.9, 44.4, and 88.2%, respectively, for brownish dots; 94.4, 51.4, 50.0, and 94.7%, respectively, for brownish epithelium; and 66.7, 62.9, 48.0, and 78.6%, respectively, for demarcation line. CONCLUSIONS: The combined technique was useful in the differential diagnosis of minimal superficial esophageal neoplasia.

Endoscopic submucosal dissection combined with the placement of biodegradable stents for recurrent esophageal cancer after chemoradiotherapy.

We report a case of a patient with esophageal squamous cell carcinoma who presented with obstruction of the esophagus. On endoscopy, a central ulcerating lesion was found spreading to the anterior wall of the middle esophagus. Four courses of chemoradiation therapy successfully produced a complete response for 3 years. A recurrence occurred which consisted of a morphologically flat lesion that occupied the entire circumference of the esophagus. Endoscopic submucosal dissection removed all lesions en bloc. To prevent a post-procedure mucosal defect of the circumference of the esophagus, biodegradable poly-l-lactic acid monofilaments esophageal stents were placed on the same day. One month later, the patient reported a feeling of obstruction. An endoscopic examination revealed food stuck in the stents, this was removed, and balloon dilatation provided good passage which has been maintained for 7 months.

Non-Epstein-Barr virus associated lymphoepithelioma-like carcinoma of the inferior common bile duct.

A carcinoma displaying undifferentiated features with dense lymphoplasmacytic infiltration is defined as a lymphoepithelioma-like carcinoma (LEC), and some of LEC is associated with Epstein-Barr virus (EBV). All of the 13 previously reported cases of LEC of the biliary system were intrahepatic in location. Herein, we describe the first case of LEC of the inferior common bile duct. A 68-year-old Japanese man, who had been previously treated for hepatocellular carcinoma using microwave coagulation therapy, was found to have tumors of the common bile duct and pancreas head. Histopathological study of the resected tumor showed solid or cohesive nests of large undifferentiated cells with irregular large vesicular nuclei and nucleoli. Around the tumor cell nests, dense lymphoplasmacytic infiltration was observed. Focal glandular differentiation (approximately 5%) was also present. These histopathological features corresponded morphologically to LEC. Immunohistochemically, the tumor cells were positive for cytokeratin (CK) 7, CK 19 and CA19-9, but negative for CK 20 and Hep Par 1. In situ hybridization for Epstein Barr virus early small RNAs disclosed no nuclear signal in tumor cells. Therefore, a diagnosis of non-EBV-associated LEC of the inferior common bile duct was made. Although the prognosis of the biliary LEC is thought to be better than that of conventional cholangiocarcinoma, the differences in prognosis between EBV-positive and -negative cases have not yet been established. Therefore, additional case studies will be needed to clarify the clinicopathological features of LEC of the biliary tract.

Comparison of the fecal microbiota profiles between ulcerative colitis and Crohn's disease using terminal restriction fragment length polymorphism analysis.

BACKGROUND: Terminal restriction fragment length polymorphism (T-RFLP) analysis is a powerful tool to assess the diversity of a microbial community. In this study, we performed T-RFLP analysis of the fecal microbiota from patients with ulcerative colitis (UC) and those with Crohn's disease (CD). METHODS: Thirty-one patients with UC, 31 patients with CD, and 30 healthy individuals were enrolled. The polymerase chain reaction (PCR) products obtained from the 16S rRNA genes of fecal samples were digested with BslI, and T-RF lengths were determined. RESULTS: The fecal microbial communities were classified into 5 clusters. Twenty-eight of the 30 healthy individuals and 17 of the 18 patients with inactive UC were classified into clusters I, II, and III, but these clusters included a small number of patients with active UC and inactive/active CD. In contrast, 8 of the 13 patients with active UC and the majority of CD patients (12 of the 16 patients with inactive CD, and 11 of the 15 patients with active CD) were included in clusters IV and V. Based on the BslI-digested T-RFLP database, the bacteria showed a significant decrease in the Clostridium family in patients with active UC and inactive/active CD. In contrast, Bacteroides were significantly increased in CD patients. No significant differences were observed between patients with active UC and those with active CD. CONCLUSION: The fecal microbial communities of IBD patients were different from those of healthy individuals. The gut microbiota of patients with inactive UC tended to be closer to that of healthy individuals, suggesting different roles for the fecal microbiota in the pathophysiology of UC and CD.

Combination of endoscopic submucosal dissection and chemoradiation therapy for superficial esophageal squamous cell carcinoma with submucosal invasion.

The efficacy, safety and clinical outcomes of a combination of endoscopic submucosal dissection (ESD) with subsequent chemoradiation therapy (CRT) for superficial esophageal squamous cell carcinomas (superficial ESCC) remain unclear. We assessed the outcome of the combination of ESD plus CRT for superficial ESCC. Fourteen patients with superficial ESCC invading into the muscularis mucosa or submucosa were treated with ESD plus CRT from 2004 to 2010. En bloc resection of the lesion was successfully performed in all patients. The mean diameter of the lesions was 25 mm (range 10-55). The distribution of the depth of tumor invasion was to the muscularis mucosa in 8 patients, to the upper submucosal third (sm1) in 4 patients and to the middle submucosal third (sm2) in 2 patients. The laterally resected margins and vascular invasion were cancer-negative in all patients, but lymph node involvement was detected in 2 patients. The mean follow-up period after CRT was 45 months (range 19-70). No patients died of esophageal cancer. Recurrence or metastasis of the esophageal cancer was not observed in any of the patients. The combination of ESD plus CRT is effective for superficial ESCC.

Hepatic reactive lymphoid hyperplasia in a patient with primary biliary cirrhosis.

Reactive lymphoid hyperplasia (RLH) of the liver is an extremely rare lesion characterized by the proliferation of non-neoplastic lymphocytes forming follicles. Hepatic RLH is known to be associated with gastrointestinal carcinoma and autoimmune diseases including primary biliary cirrhosis (PBC). We report a case of hepatic RLH in a patient with PBC and gastric cancer. A 68 year old Japanese woman with a 10 year history of liver enzyme abnormality was admitted. Laboratory testing revealed that her anti-mitochondrial antibody was markedly elevated. Five mo after the diagnosis of PBC, she was found to have gastric cancer. Abdominal computed tomography disclosed a liver nodule in S8, suggesting metastatic gastric carcinoma. Histopathologically, the resected liver lesion comprised of a nodular proliferation of small lymphocytes with lymphoid follicles. This is the first reported case of hepatic RLH in a patient with both PBC and gastric cancer. Pre-operative diagnosis of hepatic RLH by clinical imaging is extremely difficult. Therefore, a needle biopsy could be useful to make a diagnosis of hepatic RLH, especially to differentiate from metastatic gastrointestinal carcinoma.

Hepatocellular carcinoma occurring in a Crohn's disease patient.

We report a case of hepatocellular carcinoma (HCC) occurring in a patient with Crohn's disease (CD) without chronic hepatitis or liver cirrhosis, and review the clinicopathological features of HCC in CD patients. A 37-year-old Japanese man with an 8-year history of CD and a medication history of azathioprine underwent resection of a liver tumor. The histopathology of the liver tumor was pseudoglandular type HCC. In the non-neoplastic liver, focal hepatocyte glycogenosis (FHG) was observed, however, there was no evidence of liver cirrhosis or primary sclerosing cholangitis. Only nine cases of HCC in CD patients have been reported previously in the English-language literature. Eight of 10 cases (including the present case) had received azathioprine treatment, and four of these cases also showed FHG, which is considered a preneoplastic liver lesion, within the non-neoplastic liver. Although the precise mechanism of the development of HCC in CD patients is controversial, these results suggest that azathioprine therapy and FHG in the non-neoplastic liver contribute to the development of HCC. These findings also indicate that it is important to survey CD patients treated with prolonged azathioprine therapy for potential liver tumors.

Butyrate stimulates IL-32alpha expression in human intestinal epithelial cell lines.

AIM: To investigate the effects of butyrate on interleukin (IL)-32alpha expression in epithelial cell lines. METHODS: The human intestinal epithelial cell lines HT-29, SW480, and T84 were used. Intracellular IL-32alpha was determined by Western blotting analyses. IL-32alpha mRNA expression was analyzed by real-time polymerase chain reaction. RESULTS: Acetate and propionate had no effects on IL-32alpha mRNA expression. Butyrate significantly enhanced IL-32alpha expression in all cell lines. Butyrate also up-regulated IL-1beta-induced IL-32alpha mRNA expression. Butyrate did not modulate the activation of phosphatidylinositol 3-kinase (PI3K), a mediator of IL-32alpha expression. Like butyrate, trichostatin A, a histone deacetylase inhibitor, also enhanced IL-1beta-induced IL-32alpha mRNA expression. CONCLUSION: Butyrate stimulated IL-32alpha expression in epithelial cell lines. An epigenetic mechanism, such as histone hyperacetylation, might be involved in the action of butyrate on IL-32alpha expression.

Interleukin-33 expression is specifically enhanced in inflamed mucosa of ulcerative colitis.

BACKGROUND: Interleukin (IL)-33 is a cytokine belonging to the IL-1 family. IL-33 has been shown to elicit a Th2-like cytokine response in immune cells. In this study, we investigated IL-33 expression in the inflamed mucosa of patients with inflammatory bowel disease (IBD), and characterized the molecular mechanisms responsible for IL-33 expression in human colonic subepithelial myofibroblasts (SEMFs). METHODS: IL-33 mRNA expression was determined by real-time polymerase chain reaction (PCR). IL-33 expression in the IBD mucosa was evaluated by immunohistochemical methods. RESULTS: IL-33 mRNA expression was significantly elevated in active lesions from patients with ulcerative colitis (UC), but was not detected in inactive lesions from UC patients or in lesions from patients with either active or inactive Crohn's disease. Colonic SEMFs were identified as a major source of IL-33 in the mucosa. IL-1ß and tumor necrosis factor-α (TNF-α) significantly enhanced IL-33 mRNA and protein expression in isolated colonic SEMFs. IL-1ß and TNF-α did not affect IL-33 expression in intestinal epithelial cell lines (HT-29 and Caco-2 cells). This IL-1ß- and TNF-α-induced IL-33 mRNA expression was mediated by p42/44 mitogen activated protein kinase (MAPK) pathway-dependent activation of nuclear factor (NF)-κB and activator protein (AP)-1. CONCLUSIONS: IL-33, derived from colonic SEMFs, may play an important role in the pathophysiology of UC.

The multidrug-resistance protein 4 polymorphism is a new factor accounting for thiopurine sensitivity in Japanese patients with inflammatory bowel disease.

BACKGROUND: Multidrug resistance protein 4 (MRP4) functions as an efflux pump of nucleoside monophosphate analogs, such as 6-mercaptopurine (6-MP) and 6-thioguanine nucleotide (6-TGN). A single-nucleotide polymorphism in human MRP4 (rs3765534) dramatically reduces MRP4 function and results in the intracellular accumulation of 6-TGN. In this study, we investigated the association between MRP4 G2269A polymorphism and thiopurine sensitivity in Japanese IBD patients. METHODS: Direct sequencing of the MRP4 exon 18 was performed. The TPMT A719G and ITPase C94A polymorphisms were determined by polymerase-chain reaction-restriction fragment length polymorphism analyses. RESULTS: Of the 279 samples analyzed (44 healthy volunteers and 235 IBD patients), 68 samples showed a heterozygote of MRP4 G2269A and 7 carried a homozygote. The allelic frequency of MRP4 G2269A was 14.7%. In 130 IBD patients treated with azathioprine/6-MP, the white blood cell count was significantly lower in patients with theMRP4 variant alone (n = 26) than in patients with a wild allelotype (n = 74) (P = 0.014) or in patients with the ITPase variant alone (n = 22) (P = 0.0095). The 6-TGN levels were significantly higher in patients with the MRP4 variant alone than in patients with the wild allelotype(P = 0.049). Of the 15 patients who experienced leucopenia (<3 x 109/l), 7 patients carried the MRP4 variant.The odds ratio of carrying the MRP4 variant alone and having leukopenia was 3.30 (95% confidence interval 1.03­10.57, P = 0.036). CONCLUSIONS: These results suggest that MRP4 G2269A might be a new factor accounting for thiopurine sensitivity in Japanese patients with IBD.

Pneumatosis coli with ulcerative colitis as a rare complication of colonoscopy.

Pneumatosis coli is a relatively rare condition characterized by the presence of gas in the submucosa or subserosa involving mainly the large intestine and, occasionally, the mesenteric attachments. We experienced two cases of pneumatosis coli with ulcerative colitis after colonoscopy that had different clinical courses. Case 1 showed submucosal pneumatosis coli and portal venous air. The air was resolved 30 h later. Case 2 showed subserosal pneumatosis coli and retropneumoperitoneum. The air was eliminated after 3 weeks. The clinical features of pneumatosis coli may depend on the intramural region of the air. Cases 1 and 2 had different air localization, that is, submucosal and subserosal air, and this seems to reflect the differences in the complications. In Case 1 the air expanded to the portal vein, and took only a short time to resolve. In Case 2, however, the air leaked to the retroperitoneal space and took a long time to resolve. In summary, pneumatosis coli as a complication of colonoscopy presented different features depending on the air location. To our knowledge, this is the first report to reveal the difference of air localization and the complications associated with pneumatosis coli after colonoscopy.

Usefulness of bispectral monitoring of conscious sedation during endoscopic mucosal dissection.

AIM: To assess the usefulness of bispectral index (BIS) monitoring in order to carry out endoscopic submucosal dissection (ESD) safely and with patients' satisfaction. METHODS: Three hundred sixty-six patients with an early-stage neoplasm of the digestive tract were enrolled. The BIS monitor (A-1050: Aspect medical systems/NIHON KOHDEN, Tokyo, Japan) was used. The appropriate sedative condition was set at 55 to 75 BIS levels (BIS value) during the endoscopic procedures. RESULTS: Among 366 cases, 13 were accompanied by adverse events during and/or after ESD. All episodes occurred in cases with BIS value between 56 and 65. Hypotension was observed in four cases, and bradycardia in six. Respiratory distress was observed in two cases with chronic pulmonary obstructive disease. All patients with adverse events were able to leave the hospital without extension of the hospitalization. CONCLUSION: BIS monitoring is useful to safely perform ESD. A BIS value of 70 to 75 is suitable for ESD.

Re-evaluation of histogenesis of gastric carcinomas: a comparative histopathological study between Helicobacter pylori-negative and H. pylori-positive cases.

We histopathologically re-evaluated the histogenesis of gastric carcinomas from comparative studies between Helicobacter pylori-positive and H. pylori-negative cases using the gastritis score from the Updated Sydney System. The incidence of H. pylori-negative gastric carcinomas was 3.11% (12/386); they are likely to develop in the fundic gland mucosa, and show a gastric phenotype by mucin immunohistochemistry. Even in cases of completely gastric and predominantly gastric phenotypes, CDX2 protein was expressed in most cases (90.9% of pT1 and 100% of pT2-3), indicating a possibility that intestinalization of carcinoma cells occurs independently of the background mucosa. Regarding the degree of gastritis of background mucosa surrounding 143 H. pylori-positive differentiated-type adenocarcinomas, the mean score ranged from 1.497 to 1.713. Our data support the hypothesis that intestinal metaplasia is not a precancerous but a paracancerous lesion, and most gastric adenocarcinomas develop in mildly to moderately atrophic mucosa with H. pylori-infection, i.e., ongoing atrophy.

Analysis of thiopurine S-methyltransferase genotypes in Japanese patients with inflammatory bowel disease.

BACKGROUND AND AIMS: Myelosuppression observed in patients with inflammatory bowel disease (IBD) treated with azathioprine (AZA) has been attributed to low thiopurine S-methyltransferase (TPMT) activity. TPMT activity is dependent on the genetic polymorphism of high-versus low-metabolizing alleles. We investigated the association between TPMT genotypes and myelosuppression in Japanese IBD patients. METHODS: Forty-one healthy volunteers and 70 IBD patients (UC, n = 50; CD, n = 20) were recruited. All IBD patients were treated with AZA. The TPMT genotypes were determined by polymerase-chain reaction-restriction fragment length polymorphism (PCR-RFLP) analyses. RESULTS: One healthy volunteer showed a heterozygous mutation of TPMT*1/*3C. All other volunteers and the 70 IBD patients were of the wild alleleotype (TPMT*1/*1). In the IBD patients, 7 patients developed leucopenia (<3,000/microL). One of them developed severe leucopenia (<1,000 microL) with agranulocytosis on day 14 after drug initiation. CONCLUSION: TPMT mutations are not associated with myelosuppression in Japanese IBD patients. Even in IBD patients with a wild TPMT genotype, clinicians should pay attention for the possible development of myelosuppression.

Monitoring 6-thioguanine nucleotide concentrations in Japanese patients with inflammatory bowel disease.

BACKGROUND AND AIM: There have been no reports on 6-thioguanine nucleotide (6-TGN) concentrations in Japanese patients with inflammatory bowel disease (IBD) undergoing azathioprine (AZA) or 6-mercaptopurine (6-MP) therapy. The aim of this study was to assess 6-TGN concentrations in Japanese IBD patients. METHODS: Eighty-three patients with Crohn's disease (n = 42) and ulcerative colitis (n = 41) were enrolled. In 69 patients, AZA was prescribed at 50 mg/day, and seven patients were given 75 (n = 5) or 100 mg/day (n = 2). 6-MP was administered at 30 mg/day (n = 7). The 6-TGN concentrations were then assayed by high-performance liquid chromatography. RESULTS: The mean 6-TGN concentrations of the entire study population (n = 83) were 277.9 +/- 179.8 pmol/8 x 10(8) red blood cells (RBC). The mean 6-TGN concentrations in those patients with active disease (n = 38) and those in remission (n = 45) were 232.9 +/- 159.7(mean +/- SD) and 342.8 +/- 184.6 pmol/8 x 10(8) RBC, respectively (P < 0.05). The odds ratio of being in remission and having a 6-TGN value >235 pmol/8 x 10(8) RBC was 2.6 (95% CI 1.05-6.2). A significant inverse correlation was found between the white blood cell (WBC) counts and 6-TGN concentrations (r = -0.301, P < 0.05, n = 83); the mean WBC counts of the active patients (6780 +/- 2412) were significantly higher than the patients in clinical remission (5468 +/- 1920, P < 0.05). Three patients with severe leukopenia and 10 patients with high 6-TGN concentrations had no thiopurine S-methyl transferase mutations. CONCLUSION: The 6-TGN concentrations in Japanese patients with IBD on low-dose AZA and 6-MP therapy were comparable to those reported from Western countries. The monitoring of 6-TGN concentrations may be helpful for developing a therapeutic strategy for Japanese IBD patients.