A multicenter study of the efficacy and safety of leukocytapheresis therapy without concomitant systemic steroid treatment in patients with active ulcerative colitis.

We conducted a multicenter study to investigate the efficacy of leukocytapheresis (LCAP) without concomitant steroid therapy in active ulcerative colitis (UC) patients. Twenty patients were enrolled. LCAP was performed twice a week for 3 weeks. The results revealed a significant decrease of the Lichtiger's clinical activity index (CAI) from 11.7±2.6 at baseline to 6.6±4.1 after the therapy. The endoscopic index and serum C-reactive protein levels also decreased significantly after the therapy. Of the 20 patients, 15 (75%) were assessed as responders (CAI≤4 or ΔCAI≥3), and 7 (35%) achieved complete remission (CAI≤4). No serious adverse reactions were encountered. The results suggest that LCAP is an effective and safe option for patients with active UC who had not received systemic steroid treatment.

Clinical trial: Effects of an oral preparation of mesalazine at 4 g/day on moderately active ulcerative colitis. A phase III parallel-dosing study.

BACKGROUND AND AIMS: Oral mesalazine formulations are effective in the treatment of active ulcerative colitis (UC). It is not clear what induction dose of mesalazine is optimal for treating patients with active UC. We aimed to evaluate the efficacy and safety of 4 versus 2.25 g/day for selected patients with active UC. METHODS: A multicenter, randomized, double-blind, parallel-group clinical study in 39 Japanese medical institutions. A total of 123 patients with moderately active UC received 4 g/day (two divided doses) versus 2.25 g/day (three divided doses) for 8 weeks. Primary endpoint was the ulcerative colitis-disease activity index (UC-DAI) score before and after 8 weeks of treatment. The improvement of each individual UC-DAI variable, remission, and efficacy rates were secondary endpoints. Safety was determined by laboratory data, vital signs, subjective symptoms, and objective findings. RESULTS: Patients receiving 4 g/day achieved a change in UC-DAI score significantly superior to those receiving 2.25 g/day [-3.0 (95% confidence intervals (CI) -3.8 to -2.3) vs. -0.8 (95% CI -1.8 to 0.1), respectively]. There were significant differences in all UC-DAI variables between the groups. Remission rates were 22.0% (4 g/day) and 15.3% (2.25 g/day). The efficacy rate was significantly better with 4 versus 2.25 g/day [76.3 vs. 45.8%, respectively (95% CI 13.8-47.2); P = 0.001]. No difference was seen in adverse events or adverse drug reactions. CONCLUSIONS: A dose of 4 g/day was significantly superior to 2.25 g/day in terms of UC-DAI score for patients with moderately active UC. Safety profiles were similar for both doses.

Infection of sabA-positive H. pylori does not induce anti-Lewis X antibody in host.

BACKGROUND/AIMS: H. pylori uses the sialic acid-binding adhesin (SabA) to recognize Lewis X (LeX) antigen of gastric epithelial cells. SabA is associated with nonopsonic activation of human neutrophils. The aims of this study were to examine the association of bacterial sabA status to the presence of anti-LeX antibody in host and the grade of gastritis. METHODOLOGY: 44 H. pylori strains cultured from gastric biopsies were examined by PCR for presence of 23SrRNA, cagA, and sabA. Serum samples were obtained from all the patients to measure the level of anti-LeX antibody. Histological grade of gastritis was graded according to the updated Sydney System. RESULTS: 23SrRNA gene and the cagA gene were seen in all the samples while 21 strains were sabA positive. The mean titer of anti-LeX antibody was 0.09 and 0.18 in patients infected with sabA-positive and -negative strain, respectively (NS). The grade of inflammatory infiltration was not significantly different between groups in both the corpus and the antral mucosa. CONCLUSIONS: Possession of the sabA gene by infected H. pylori strain might not associate with the presence of anti-LeX antibody in the host. Possession of sabA gene by infected H. pylori might not associate with severity of gastric mucosal inflammation.

Difference of p53AIP1 mRNA expression in gastric mucosa between patients with gastric cancer and chronic gastritis infected with Helicobacter pylori.

GOALS: To examine the significance of alteration of p53-regulated apoptosis-induced protein 1 (p53AIP1) expression in gastric carcinogenesis in patients with Helicobacter pylori infection. BACKGROUND: H. pylori infection induces gastric mucosal inflammation and DNA damage of epithelial cells, which associate with gastric carcinogenesis. p53AIP1 is expressed after DNA damage and induces apoptosis in human cell lines. STUDY: Endoscopic antral and corpus biopsies were obtained from 13 patients with chronic gastritis and 17 with gastric cancer. Expression of p53AIP1 and p53DINP1 mRNA was examined by semiquantitative reverse transcription polymerase chain reaction and mutation of p53 codon-46 was studied by direct sequence analysis. The grade of gastritis was assessed according to the updated Sydney System. Results were compared between patients with gastric cancer and chronic gastritis. RESULTS: In the antrum, p53AIP1 mRNA expression was significantly lower in patients with gastric cancer than in those with chronic gastritis (P<0.05). In patients with chronic gastritis, expression of p53AIP1 mRNA was significantly higher in the antrum than in the corpus (P<0.05). In patients with chronic gastritis, antral mucosa with high p53AIP1 expression tended to have severe intestinal metaplasia. No mutation was found at p53 codon-46. CONCLUSIONS: In H. pylori-infected gastric mucosa expression of p53AIP1 would be higher when the inflammation is severe or intestinal metaplasia is present. Insufficient expression of p53AIP1 may play a role in gastric carcinogenesis in patients infected with H. pylori infection.

[A case of suspected mesenteric panniculitis with a large amount of chylous ascites].

A 79-year-old man was admitted our hospital because of severe abdominal fullness. An abdominal ultrasonography showed a large amount of ascites, and diagnostic puncture detected chylous ascites. An abdominal computed tomography revealed a large amount of ascites and a multinodular mass with calcification in the mesentery of the small intestine. An infectious disease, such as tuberculosis, or malignant tumor was suspected to be the causative disease, but there was no diagnostic evidence in further examinations. Based on clinical features, imaging data and chylous ascites, we searched for case reports and found two similar cases of mesenteric panniculitis. Mesenteric panniculitis was highly suspected in this case, however, histopathological examination was rejected by patient. Therefore, we treated with steroid therapy, which had been reported as effective therapy, and the ascites decreased without recurrence.

[A case of unresectable advanced gallbladder cancer treated by systemic chemotherapy combined with hepatic arterial infusion].

A 53-year-old woman was revealed to have gallbladder cancer with liver metastases (H 1). Since a curative operation is impossible in this case, we started systemic chemotherapy employing S-1 combined with hepatic arterial infusion using epirubicin hydrochloride and mitomycin C. After three months, the primary lesion was reduced in size. The patient has been receiving systemic chemotherapy using S-1 only as an outpatient for 16 months. Although there is not enough evidence to support standard treatment, systemic chemotherapy combined with hepatic arterial infusion would improve the survival time without deterioration of quality of life in patients with advanced gallbladder cancer. This combined therapy should be considered one of the promising strategies for advanced gallbladder cancer.

[A case of unresectable advanced pancreatic cancer treated by S-1 with concurrent radiotherapy].

Chemotherapy (5-FU) with concurrent radiotherapy is recommended as an effective treatment for locally unresectable pancreatic cancer. A phase I study of S-1 with concurrent radiotherapy demonstrated promising results in late years. A 70-year-old man was revealed to have metastatic pancreatic cancer (T 4 N 3 M 1 (PER), Stage IVb). Since a curative operation was impossible in this case, he was treated with systemic chemotherapy using S-1 combined with irinotecan hydrochloride (CPT-11) as first-line chemotherapy. Because the primary lesion was increased in size after two courses,he was then treated by radiotherapy combined with S-1 as second-line treatment. S-1 (80 mg/body/day) was orally administered (2 consecutive weeks, 1-week break), and concurrent radiotherapy was performed at a daily fraction of 1.8 Gy, 5 days/week, total amount 45 Gy. Although in the early period of chemoradiotherapy, transfusion for anemia and morphine hydrochloride for pain control were necessary, his symptoms gradually improved by the reduction of primary lesion. The patient has been receiving systemic chemotherapy as an outpatient for 12 months without deterioration of quality of life.

Blockade of TGF-beta accelerates mucosal destruction through epithelial cell apoptosis.

To clarify the protective role of transforming growth factor (TGF)-beta for the intestinal epithelial injury in vivo, the effect of antibodies against TGF-beta on epithelial destruction and apoptosis was assessed in dextran sulfate sodium (DSS)-induced colitis by histological analysis of colonic sections, account of apoptotic epithelial cells. To evaluate the pathways of epithelial apoptosis, we analyzed the activities of caspases, the level of Fas and cellular FLICE-inhibitory protein (cFLIP) expression in epithelial cells. Apoptotic epithelial cells were increased prior to the onset of ulceration in DSS-induced colitis, and the neutralization of TGF-beta exacerbated epithelial apoptosis and histological damage score. The up-regulation of caspase-8 activity and Fas expression and reduced cFLIP expression were observed in intestinal epithelial cells from anti-TGF-beta antibody-treated mice. The present study revealed that suppression of TGF-beta deteriorated epithelial apoptosis, and the increase of apoptotic epithelial cells may amplify the inflammation in gut mucosa.

Duration of the metronidazole-containing regimen for eradication of Helicobacter pylori infection in northern Japan.

Metronidazole is often used to eradicate clarithromycin-resistant Helicobacter pylori. The aim of this study was to determine the appropriate duration of metronidazole-containing treatment for the eradication of H. pylori infection in northern Japan. We enrolled 83 H. pylori-positive patients in whom first-line triple therapy consisting of a proton pump inhibitor, amoxicillin and clarithromycin had failed. Prior to the second-line therapy, patients underwent endoscopy to obtain H. pylori strains to test the susceptibility to antibiotics. Patients were administered lansoprazole (30 mg b.d.), amoxicillin (750 mg b.d.) and metronidazole (250 mg b.d.) for 5 or 7 days, and the treatment results were tested by (13)C-UBT. None of the isolated H. pylori strains was amoxicillin- or metronidazole-resistant. All the patients completed the regimen without major adverse effects. The eradication rate was 95.1% (39/41; 95% confidence interval [CI], 83.5-99.4%) in the 41 patients who were treated for 5 days and 95.2% (40/42; 95% CI, 83.8-99.4%) in the 42 patients treated for 7 days. The results suggest that 5 days could be a sufficient duration for triple therapy of lansoprazole, amoxicillin and metronidazole as a second-line H. pylori eradication therapy in areas where metronidazole-resistant strains are rare.

[Irritable bowel syndrome in the elderly].

Irritable bowel syndrome (IBS) is a very common gastrointestinal disorder. The prevalence of IBS is about 10-15% of the general population. Epidemiological studies suggested that the prevalence of IBS decreased with age, but IBS remains an important gastrointestinal illness in the aged. But there has been very few research examining on IBS in elderly. Whether advancing age impacts on IBS is largely unknown and how the disorder manifest in the elderly remains unclear. Aging is connected with an increasing prevalence of many chronic neurological difficulties, cardiovascular diseases and mental disabilities. The management of the IBS needs to take the age-related issues into account in elderly. Clinical therapeutic trials should be undertaken in elderly people to ascertain treatment.

Influence of methylated p15 and p16 genes on clinicopathological features in colorectal cancer.

BACKGROUND AND AIM: Genetic silencing by promoter methylation has attracted attention in the carcinogenesis of colorectal cancer. Methylation of the p16(INK4a) gene has been found in primary colorectal cancer. Although the p15(INK4b) gene displays high homology to the p16(INK4a) gene in the amino acid sequence, methylation of p15(INK4b) has not been fully studied. We investigated p15(INK4b) methylation status in patients with colorectal cancer to verify the association between the methylation of p15(INK4b) and clinicopathological features compared with p16(INK4a). METHODS: DNA samples from the tissues of primary colorectal cancer and corresponding adjacent normal colon mucosa were obtained from surgical resections of 88 patients (47 males and 41 females, aged 29-83 years). Methylation-specific polymerase chain reaction was used to analyze p15(INK4b) and p16(INK4a) methylation status after bisulfite modification. Cumulative survival rates (mean follow-up period: 53.2 months) were calculated by the Kaplan-Meier analysis. Methylations of p15(INK4b) and p16(INK4a) genes were detected in 23 (26.1%) and 20 (22.7%) colorectal cancers, respectively. RESULTS: Methylation of p15(INK4b) was not associated with any clinicopathological features. Compared with normal mucosa, the methylation of p15(INK4b) was more prominent in tumor tissue (P < 0.001). Reverse transcription-polymerase chain reaction (RT-PCR) revealed that p15(INK4b) methylaton decreased mRNA expression. Kaplan-Meier analysis showed that patients with stage I-II had a significant difference in survival rate between those with and without methylated p15(INK4b) (P = 0.018). CONCLUSIONS: Our results suggest that methylation of the p15(INK4b) gene contributes to the process of carcinogenesis in colorectal cancer as well as p16(INK4a) and is useful as a prognostic factor in the early stage.

The role of macrophage migration inhibitory factor in lethal Listeria monocytogenes infection in mice.

Macrophage migration inhibitory factor (MIF) has been characterized as a proinflammatory cytokine. Previous studies have indicated that MIF may play a beneficial role or a detrimental role in microbial infections, depending on pathogens. In this study, we investigated the role of MIF in Listeria monocytogenes infection. The MIF titers increased 6h after lethal L. monocytogenes infection but not in the sublethal infection. The elimination of bacteria from the spleens and livers was not affected by anti-MIF antibody (Ab) injection in the sublethal infection, whereas anti-MIF Ab treatment rescued mice from the lethal infection, suggesting that MIF plays a deteriorating role in lethal L. monocytogenes infection. Anti-MIF Ab treatment significantly augmented interleukin (IL)-10 production in the spleens and livers 24h after infection, suggesting that MIF might down-regulate IL-10 production. Although the administration of anti-IL-10 monoclonal Ab showed no significant effect on the bacterial growth in the organs, the bacterial infection was deteriorated by the combined administration of Abs against MIF and IL-10. On the other hand, anti-MIF Ab treatment also increased in the serum cortisol titer 6h after infection compared with the control immunoglobulin G-injected group. Depletion of endogenous IL-10 decreased serum cortisol titers. These results suggested that IL-10 and cortisol might be involved in the deteriorating effect of MIF on lethal L. monocytogenes infection.

Macrophage migration inhibitory factor has a proinflammatory activity via the p38 pathway in glucocorticoid-resistant ulcerative colitis.

Macrophage migration inhibitory factor (MIF) is a cytokine that has potent anti-steroid effects and might be implicated in the pathogenesis of Ulecrative colitis (UC). We defined the functional role of MIF in the glucocorticoid (GC)-resistant inflammatory response in UC. Twenty-four colonic samples were obtained from GC responsive cases, GC refractory cases, Crohn's disease and controls. LPMC were isolated from surgical specimens. MIF was strongly expressed at mRNA levels in refractory cases rather than responsive cases with UC and controls. IL-8 production from LPMC was significantly reduced by GC addition in responsive cases but not in refractory cases. In refractory cases, anti-MIF Ab ameliorated GC-resistant IL-8 production and p38-MAPK activity of LPMC. In addition, p38-MAPK antagonist SB230580 also ameliorated GC-resistant IL-8 production. These results suggest that MIF has an additional proinflammatory activity through the p38-MAPK pathway in GC-resistant UC.

Influence of hepatic impairment on the pharmacokinetics and pharmacodynamics of landiolol hydrochloride, an ultra-short-acting beta1-blocker.

OBJECTIVE: To investigate the effects of mild to moderate hepatic impairment on the pharmacokinetics and pharmacodynamics of landiolol hydrochloride, a new ultra-short-acting beta1-adrenergic antagonist. METHODS: Six patients with hepatic impairment and six healthy volunteers were enrolled in the open-label, parallel-group study. Landiolol hydrochloride was given intravenously with a 1-minute loading infusion of 0.06 mg/kg/min, followed by a 60-minute infusion of 0.02 mg/kg/min using an automated infusion pump. Venous blood was drawn just before (predose) and 1, 2, 5, 15, 30 and 61 minutes after beginning the continuous intravenous infusion (during infusion); 2, 5, 10 and 30 minutes and 1, 4 and 8 hours after the end of the infusion (after infusion); and 24 hours after beginning the infusion (next day). Urine samples were collected up to 24 hours after beginning the infusion. Before subjects were discharged, an indocyanine green elimination test, clinical laboratory testing, physical examination and recording of ECGs and vital signs were performed. RESULTS: The geometric mean maximum plasma concentration and area under the concentration-time curve values for the patients with hepatic impairment were 42% and 44% higher, respectively, than those observed for the healthy volunteers, indicating that hepatic impairment affected the disposition of landiolol hydrochloride. There were no significant changes in the elimination half-life of the drug. There were no clinically significant differences between the two groups in terms of reductions in heart rate or blood pressure. CONCLUSION: The pharmacokinetic and pharmacodynamic characteristics of this ultra-short-acting beta1-blocker were maintained even in the patients with hepatic impairment. Although we did not observe any drug-related adverse events in these patients, hypotension or bradycardia should be considered, necessitating continuous monitoring of both heart rate and BP in patients with hepatic impairment who receive landiolol hydrochloride.

Acute esophageal necrosis caused by alcohol abuse.

Acute esophageal necrosis (AEN) is extremely rare and the pathogenesis of this is still unknown. We report a case of AEN caused by alcohol abuse. In our case, the main pathogenesis could be accounted for low systemic perfusion caused by severe alcoholic lactic acidosis. After the healing of AEN, balloon dilatation was effective to manage the stricture.

Withdrawing method of the stiffening tube incidentally inserted into the descending colon.

We experienced a very rare complication of colonoscopy, a migration of stiffening tube into the colorectum. We herein introduce a withdrawing method of migrating stiffening tube incidentally inserted into the colorectum. A 65-year-old Japanese woman underwent colonoscopy because of abdominal discomfort. We used stiffening tube to insert the scope to the proximal colon because of her redundant sigmoid colon. When withdrawing the scope, we realized that the tube was fully inside the colorectum. We could not remove the tube instantly, and it reached the splenic flexure, finally. We reinserted the scope through the migrating tube, straightened the scope, and withdrew it holding a slight angle of the scope over the proximal end of the tube. Then, we could safely remove the tube along with the scope through the anus.

Study for determination of the optimal cessation period of therapy with anti-platelet agents prior to invasive endoscopic procedures.

BACKGROUND: Anti-platelet agents are widely used for the treatment and prevention of thrombotic diseases. On the other hand, continuation of anti-platelet agents increases the risk of hemorrhagic complications in gastrointestinal endoscopy, and cessation of anti-platelet agents exposes the patient to the risk of thromboembolism. Only a few studies have actually studied the whether a cessation period is required prior to endoscopic procedures and if so, the optional duration of the period. The present study assessed the time course of primary hemostasis after the cessation of anti-platelet agents. METHODS: Eleven healthy men (age range, 19-29 years) were assigned to each of the following regimens: aspirin (ASA; 100 mg/day), ticlopidine (TP; 300 mg/day), and a combination of ASA (100 mg/day) and TP (300 mg/day) for 7 days. There was a washout period of more than 3 weeks between each regimen. A quantitative bleeding time test (QBT test) and platelet aggregation test were performed before the beginning of administration, on the last day of administration, and at 1, 3, and 5 days after cessation, and also at 7 days after cessation for the combination regimen. RESULTS: The average bleeding time (BT) and total bleeding loss volume (Tv) of the 11 subjects after administration of the three regimens were significantly increased compared with those before administration. With the administration of ASA, increases of BT and Tv at 3 days after cessation were not significant. The Tv at 5 days after cessation of TP was not significantly increased. With the combination regimen, the BT and Tv at 7 days after cessation were not significantly increased. CONCLUSIONS: A 3-day cessation period for ASA, a 5-day cessation period for TP, and a 7-day cessation period for ASA+TP administration seem to be sufficient.

Leukocytapheresis in ulcerative colitis: results of a multicenter double-blind prospective case-control study with sham apheresis as placebo treatment.

OBJECTIVE: Leukocytapheresis (LCAP) is a method of therapeutic apheresis that removes peripheral leukocytes. Previous studies showed that in patients with ulcerative colitis (UC), LCAP was more effective than high-dose steroid therapy, and it had few adverse effects. We investigated LCAP in a multicenter study using active and sham devices in a double-blind study in order to elucidate the placebo effect of extracorporeal treatment including anticoagulant medication. METHODS: Twenty-five patients with active UC of severe or moderately severe grade were enrolled and assigned to the active group or the sham group. Six patients were excluded from the study and 19 (10 in the active group and nine in the sham group) were evaluated. LCAP (treatment using an active device or a sham device) was performed once a week for 5 wk, followed by two additional sessions during the next 4 wk at 2-wk intervals. Steroids and other medications were continued at the same dosage for 4 wk, which included a 2-wk pre-observation period and the first 2 wk after the start of the LCAP treatment. New medications or increase in the dosage of previous medication were prohibited until evaluation was conducted. RESULTS: The clinical activity index (CAI) value of UC, indicated that the active group showed a significantly greater improvement (80%, 8/10) than the sham group (33%, 3/9; p<0.05). Adverse effects were observed in five patients (one in the active group and four in the sham group). None of these effects was severe and none of the sessions was terminated as a consequence of the adverse effects. CONCLUSION: The results confirmed that LCAP is a safe and effective therapeutic option for patients with active UC.

Relation of CagA seropositivity to cagPAI phenotype and histological grade of gastritis in patients with Helicobacter pylori infection.

AIM: Infection with Helicobacter pylori (H pylori) possessing the cag pathogenicity island (PAI) has been associated with severe clinical outcome and CagA-antibody has been used to indicate cagPAI-positive infection. The aim of this study was to examine the accuracy of CagA seropositivity to indicate the virulence of the cagPAI in Japan. METHODS: Sixty isolates of H pylori cultured from gastric biopsies were examined by polymerase chain reaction assays for the presence of cagA, cagE and VirD4. Anti-CagA IgG antibody in matching sera was tested by both ELISA and immunoblot assay. Histological grade of gastritis was graded according to the updated Sydney System. RESULTS: Amongst 53 patients infected with cagA+/cagE+/VirD4+ strain, 38 were CagA seropositive. There were four patients infected with strains possessing incomplete cagPAI. Two out of three patients with cagA+/cagE-/VirD4- infection were CagA seropositive, while a patient with cagA-/cagE+/VirD4+ infection was CagA seronegative. Accuracy of ELISA to predict bacterial possession of cagA was 61.7% whereas 58.3% for cagE and VirD4. The immunoblot assay showed relatively higher sensitivity and showed better accuracy. The lower grade of gastric mucosal inflammatory infiltration was seen in false CagA-seronegative patients. CONCLUSION: Some serodiagnosis does not seem to have enough accuracy to indicate virulence of cagPAI, particularly in infection of strains with incomplete cagPAI. The degree of gastric mucosal inflammation may affect the results of CagA serodiagnosis.