Tomoyuki Tsuzuki

Characteristics of Helicobacter pylori-Induced Gastritis and the Effect of H. pylori Eradication in Patients with Chronic Idiopathic Thrombocytopenic Purpura

Background.  The association between Helicobacter pylori infection and idiopathic thrombocytopenic purpura (ITP) has been reported widely. We investigated the prevalence of H. pylori infection, its virulence profile and the effectiveness of its eradication in patients with ITP.

Possible involvement of the interleukin-15 and interleukin-15 receptor system in a heightened state of lamina propria B cell activation and differentiation in patients with inflammatory bowel disease

BackgroundWe investigated the possible roles of the interleukin (IL)-15 and IL-15 receptor (IL-15R) system in a heightened state of B-cell activation and differentiation in intestinal mucosa with inflammatory bowel disease (IBD).MethodsThe expression of IL-15 and IL-15Rα mRNA and protein in inflamed colonic mucosal tissues with IBD, and in control tissues was examined by reverse transcriptase-polymerase chain reaction and immunohistological methods. The effects of recombinant (r)IL-15 on the expression of IL-15Rα on lamina propria B cells and the production of immunoglobulin G (IgG) were analyzed in vitro, using lamina propria mononuclear cells (LPMCs) isolated from control tissues.ResultsThe intensity of IL-15 and IL-15Rα mRNA was greater in the mucosal tissues of patients with IBD, especially in those of patients with ulcerative colitis (UC), than in control tissues. Compared to control tissues, mononuclear cells positive for IL-15Rα protein were observed in greater proportions in tissue sections from patients with IBD, especially in those from patients with UC, where IL-15Rα protein was localized to CD20-positive B cells to a significant degree. There were increases in the proportions of IL-15Rα-positive B cells and IgG-producing cells in rIL-15- or rCD40L-stimulated cultures of LPMCs, with stimulatory effects being greater in the presence of their combination.ConclusionsThese data suggest that the IL-15 and IL-15R system may play important roles in the activation and differentiation of lamina propria B cells in patients with IBD, especially in those with UC.

Possible involvement of neutrophil elastase in impaired mucosal repair in patients with ulcerative colitis

Background. Little information is available on the relative contribution of peptide growth factors and leukocyte-derived proteinases to the repair processes in inflammatory bowel disease (IBD). We investigated their possible roles in epithelial cell restitution and proliferation in patients with IBD. Methods. The expression of hepatocyte growth factor (HGF), keratinocyte growth factor (KGF), transforming growth factor-β (TGF-β), and neutrophil elastase (NE) was examined in colonic mucosal tissues. The effects of organ culture supernatants of mucosal tissues on epithelial cell restitution and proliferation were analyzed in vitro using an intestinal cell line, IEC-6 cells. Results. Most organ cultures detected the presence of measurable levels of HGF, with a relative paucity of KGF and TGF-β activity. Greater levels of HGF were obtained in the mucosa involved with IBD, especially in patients with ulcerative colitis (UC). The mucosa involved with UC also showed higher amounts of NE. The supernatants from the mucosa involved with UC possessed a prominent stimulatory effect on the restitution of IEC-6 cells. By contrast, significant suppression beyond baseline levels was observed for the proliferation of IEC-6 cells when they were incubated with recombinant HGF plus the supernatants from the mucosa involved with UC. This suppression was diminished considerably by preincubation of the supernatants with the anti-NE antibody. Conclusions. HGF produced in the intestinal mucosa may be an important stimulator acting on epithelial cell restitution in patients with IBD. However, NE released in situ may impair mucosal repair through inhibiting epithelial cell proliferation in patients with UC.

A Phase II Multi-Center Study of Triple Therapy with Paclitaxel, S-1 and Cisplatin in Patients with Advanced Gastric Cancer

Objectives: To carry out a phase II multi-center study on the efficacy and safety of triple combination therapy with paclitaxel, S-1, and cisplatin in patients with unresectable/metastatic gastric cancer. Methods: A total of 63 patients from 8 institutions were included in this study. Paclitaxel (160 mg/m2) was administered by infusion for 3 h on the first day. S-1 (70 mg/m2/day) was administered orally for 14 consecutive days from the first day. Cisplatin (60 mg/m2) was administered intravenously over 24 h on day 14 of every 28-day cycle. Results: All 63 patients were assessed for clinical efficacy and safety. A total of 259 cycles of treatment were administered (median 4, range 1–10). Grade 3–4 toxicities included neutropenia in 30.2%, thrombocytopenia in 12.7%, and anemia in 11.1%. There was no grade 3–4 non-hematological toxicity or treatment-related death. Complete response was observed in 6 patients and partial response in 34 patients. The overall response rate was 63.5%. The median progression-free survival and response duration were 8.0 and 8.8 months, respectively, and median survival time was 15 months. Conclusions: Triple combination therapy with paclitaxel, S-1, and cisplatin showed promising safety and efficacy profiles with the potential to become a standard regimen for unresectable/metastatic gastric cancer.

Suppressive effects of cyclosporine A on neutrophils and T cells may be related to therapeutic benefits in patients with steroid-resistant ulcerative colitis

An intravenous infusion of cyclosporine A (CsA) shows clinical benefits in patients with steroid-resistant ulcerative colitis (UC). To clarify its mechanisms, we investigated the ability of CsA to inhibit the functions of neutrophils and T cells. The cytotoxic activity by mucosal T cells was analyzed by anti-CD3-triggered cytotoxicity after lamina propria mononuclear cells were cultured with recombinant interleukin (IL)-2. The chemotactic response, the generation of superoxide, and the production of chemokines, IL-8, and macrophage inflammatory protein-1&agr; by neutrophils were examined using a multiple-well chamber assay, a chemiluminescence method, and an enzyme-linked immunosorbent assay (ELISA), respectively. Mucosal chemokine activity was determined by an ELISA using the organ culture supernatant of mucosal biopsy tissues. Pretreatment with CsA caused consistent inhibitions of cytotoxic activity by mucosal T cells and chemotactic migration, superoxide generation, and chemokine production by neutrophils mostly in a dose-dependent manner. In patients who received an intravenous infusion of CsA, mucosal chemokine activity decreased after therapy in parallel with decreases in the numbers of neutrophils and mononuclear cells in the biopsy tissues. These results suggest that suppressive effects of CsA on neutrophils and T cells may be related to therapeutic benefits in patients with steroid-resistant UC.

Concurrent Chemoradiotherapy with a Novel Fluoropyrimidine, S-1, and Cisplatin for Locally Advanced Esophageal Cancer: Long-Term Results of a Phase II Trial

Objectives: A phase II study was performed to investigate the safety and efficacy of concurrent chemoradiotherapy (CCRT) combined with an orally active fluoropyrimidine, S-1, plus cisplatin for locally advanced esophageal cancer (LAEC). Methods: CCRT comprised 2 courses, a 30-Gy radiotherapy over 3 weeks plus daily oral S-1 (80 mg/m2/day) for 2 weeks and a 24-hour cisplatin infusion (70 mg/m2) on day 8, and an identical course administered after a 2-week break. Results: One hundred and sixteen patients, 12 with stage II, 71 with stage III, and 33 with stage IVa LAEC participated, and 106 of them (91.4%) completed the CCRT course. The most serious toxicity was myelosuppression: grade 3 and 4 neutropenia occurred in 28.4 and 9.5% of patients, respectively. Nonhematologic toxicity was moderate. Complete response rates in patients with stage II, III, and IVa LAEC were 91.7, 67.6, and 36.4%, respectively. The overall median survival time was 2.3 years and that of patients with stage II, III, and IVa cancer was 7.0, 2.6, and 1.3 years, respectively. Conclusions: CCRT combined with S-1 plus cisplatin showed promising safety and efficacy. Potentially, this combination therapy could become a baseline medication for patients with LAEC.

Esophageal cancer with colonic metastasis successfully treated by chemoradiotherapy followed by chemotherapy with S-1 and cisplatin

A 51-year-old man was hospitalized for evaluation of dysphagia and bloody stool. Gastrointestinal endoscopy showed esophageal cancer invading the gastric fundus. A metastatic lesion was demonstrated in the sigmoid colon. The patient agreed to have concurrent chemoradiotherapy for the primary lesion, followed by additional chemotherapy. The first course included 30 Gy of radiotherapy given over 3 weeks, together with daily oral administration of S-1 (80 mg/m2 per day) for 2 weeks, and a 24-h infusion of cisplatin (70 mg/m2) on day 8. After a second course of chemoradiotherapy, four additional courses of chemotherapy with S-1 and cisplatin were administered, at 4-week intervals. After the additional chemotherapy, gastroscopy and colonoscopy showed disappearance of both the primary and the metastatic lesions. One year after his initial hospitalization, no recurrence of either the primary or the metastatic tumor lesions is evident.

Comparison between in vivo and in vitro chemokine production in Helicobacter pylori infection.

Background: Enhanced gastric mucosal chemokine activity has been demonstrated in patients with Helicobacter pylori infection. However, little is known about the mechanisms involved in this phenomenon.

Clarithromycin increases the release of heat shock protein B from Helicobacter pylori

Clarithromycin (CAM) may have certain indirect effects on Helicobacter pylori (H. pylori) other than its inhibitory activity on bacterial growth, as indicated in other infections with Gram‐negative micro‐organisms. In the present study, we examined the effects of lower concentrations of CAM on the release of heat shock protein B (HspB), one of the major antigenic proteins from H. pylori cells, as well as the changes in humoral immune response and histological degree of antral gastritis in patients who received eradication therapy with CAM.

Mucosal expression of matrix metalloproteinases and their tissue inhibitors in ulcerative colitis patients

ruption of the cysteine zinc2 bond associated with conformational change or proteolysis.13 Second, MMP activity is counterbalanced by endogenous inhibitors; a specific tissue inhibitor of MMPs (TIMP) can inhibit active forms of MMPs by 1 : 1 stoichiometric binding where the ratio of active MMPs to TIMPs regulates net enzymatic activity.14 In this issue of the Journal of Gastroenterology, Matsuno and colleagues15 report their investigation of the expression of several MMPs (MMP-1, -2, -3, -7, and -9) and their natural inhibitors (TIMP-1 and -2) in mucosal specimens from patients with UC, using an immunohistochemical method, and confirm the results of earlier studies demonstrating tissue distribution of each MMP and TIMP in colonic mucosa. They also found that the expression of MMPs was increased compared with that of TIMPs in the inflamed mucosa of patients with UC. There was a good correlation between the histological degree of inflammation and the frequency of epithelial expression of MMP-7 at the edge of ulcerative lesions. A similar correlation between MMPs and histological inflammation has been noted previously in the mucosal tissue of patients with UC,7,9 and these results suggest a significant role of the imbalance of MMPs and their natural inhibitors in the pathogenesis of UC. An increase in MMP expression according to the histological degree of inflammation (inflammatory cell density) in the inflamed mucosa of patients with UC probably reflects upregulation of their genes by cytokines and growth factors (e.g., interleukin-1 , tumor necrosis factor-α, transforming growth factor, and epithelial growth factor) produced in situ by inflammatory cells, such as T-lymphocytes, macrophages, endothelial cells, and myofibroblasts.16 In this respect, Salmela and colleagues17 recently reported data showing a functional relationship between MMPs and mucosal injury after T-lymphocyte activation, in their studies using an ex-vivo model with fetal gut explants. Further studies are necessary to dissect the mechanisms Ulcerative colitis (UC) and Crohn’s disease, collectively designated as inflammatory bowel disease (IBD), are chronic intestinal disorders associated with repeated mucosal injury and repair. Chronic intestinal inflammation and subsequent mucosal injury can accompany intensive remodeling of the subepithelial connective tissue, with increased turnover of the extracellular matrix (ECM). Disturbance of the balance between the synthesis and degradation of ECM components is increasingly implicated in the pathological findings of IBD, such as progressive mucosal disintegration and excessive deposition of collagens leading to fibrosis.1,2 Degradation of ECM components is coordinately controlled by the enzymatic activity of several species of metalloproteinase (MMP),3 and current concepts speculate an important role for these enzymes in the process of tissue destruction and remodeling in IBD.4–10 Based on their structure and substrate specificity, the human MMPs can be grouped into five subfamilies; collagenases (MMP-1, -8, and -13), stromelysins (MMP-3, -7, -10, -11, -12, and -26), gelatinases (MMP-2 and -9), membrane-bound MMPs (MMP-14, -15, -16, -17, -24, and -25), and another subfamily (MMP-19, -20, -23, and -28).11 These endopeptidases are released largely from stromal cells, including lymphocytes, polymorphonuclear neutrophils, macrophages, and smooth muscle cells, except for MMP-7 (matrilysin) and MMP-10 (stromelysin-2). The latter two enzymes are produced by epithelial cells and may be involved in epithelial migration through degrading basement membrane components, such as laminin, type IV collagen, casein, proteoglycans, and fibronectin.4,12 The expression of MMPs is strictly controlled under physiological conditions, as expected from their possible harmful nature in vivo. First, they are secreted as latent precursors or zymogens, most of which are activated later by the dis-