Kuniomi Honda

An Inverse Correlation of Human Peripheral Blood Regulatory T Cell Frequency with the Disease Activity of Ulcerative Colitis

Evidence suggests that CD4+CD25+ regulatory T cells play a crucial role in the suppression of intestinal inflammation. However, their role in the suppression of inflammatory bowel disease has not yet been addressed. We examined the proportion of regulatory T cells in inflammatory bowel disease. First, we isolated CD4+CD45RO+CD25+ T cells from the peripheral blood of healthy persons and showed that these cells suppressed T cell proliferation profoundly and expressed FoxP3 abundantly, revealing that they are regulatory cells. Then the proportion of CD45RO+CD25+ in peripheral blood CD4+ T cells was analyzed in patients and healthy controls by flow cytometry. CD4+CD45RO+CD25+ T cell frequency was significantly lower in active ulcerative colitis than in the control and inactive ulcerative colitis. CD4+CD45RO+CD25+ T cell frequency was inversely correlated with the clinical and endoscopic severity of ulcerative colitis. These results suggest that a deficiency of regulatory T cells is associated with the progression of ulcerative colitis.

T helper 1‐inducing property of IL‐27/WSX‐1 signaling is required for the induction of experimental colitis

Background: WSX‐1, a component of the interleukin (IL)‐27 receptor, is a novel class I cytokine receptor with homology to the IL‐12 receptor &bgr;2 chain. Initially, WSX‐1 signaling was reported to play an important role in the promotion of T helper‐1 responses, but recent reports have revealed an anti‐inflammatory property in WSX‐1 signaling. In the present study, we investigated the role of IL‐27/WSX‐1 signaling in a murine colitis model, dextran sulfate sodium (DSS) colitis, by using WSX‐1 knockout (KO) mice. Methods: First, we observed whether WSX‐1 KO mice developed colitis spontaneously. Second, we induced DSS colitis in WSX‐1 KO and wild‐type (WT) mice. Results: WSX‐1 KO mice were observed not to develop colitis spontaneously. The severity of DSS colitis was decreased in WSX‐1 KO mice in comparison with WT mice in association with a reduced production of interferon‐&ggr;, IL‐6, and tumor necrosis factor‐&agr; by lamina propria mononuclear cells from WSX‐1 KO mice and the absence of T‐bet expression in the colon from WSX‐1 KO mice. Conclusions: This study revealed the inflammatory property of IL‐27/WSX‐1 signaling in intestinal inflammation. As a result, IL‐27/WSX‐1 signal pathway may thus be a promising candidate for the therapeutic intervention of human inflammatory bowel diseases such as Crohns disease and ulcerative colitis.

A Critical Role of CD30 Ligand/CD30 in Controlling Inflammatory Bowel Diseases in Mice

BACKGROUND & AIMS A CD30-ligand (CD30L) is a 40-kilodalton, type II membrane-associated glycoprotein belonging to the tumor necrosis factor family. Serum levels of soluble CD30 increased in inflammatory bowel diseases (IBD), suggesting that CD30L/CD30 signaling is involved in the pathogenesis of IBD. In this study, we investigated the role of CD30L in oxazolone (OXA)- and trinitrobenzene sulfonic acid (TNBS)-induced colitis in CD30L knockout (KO) mice. METHODS Colitis was induced by OXA or TNBS in CD30LKO mice with BALB/c or C57BL/6 background, respectively, and diverse clinical signs of the disease were evaluated. Cytokine production from lamina propria T cells of the colon was assessed by enzyme-linked immunosorbent assay. Anti-interleukin (IL)-4 monoclonal antibody (mAb) or agonistic anti-CD30 mAb was inoculated in mice with colitis induced by OXA or TNBS. RESULTS CD30LKO mice were susceptible to OXA-induced colitis but resistant to TNBS-induced acute colitis. The levels of T helper cell 2 type cytokines such as IL-4 and IL-13 in the LP T cells were significantly higher, but the levels of interferon gamma were lower in OXA- or TNBS-treated CD30LKO mice than in wild-type mice. In vivo administration of agonistic anti-CD30 mAb ameliorated OXA-induced colitis but aggravated TNBS-induced colitis in CD30LKO mice. CONCLUSIONS These results suggest that CD30L/CD30 signaling is involved in development of both OXA- and TNBS-induced colitis. Modulation of CD30L/CD30 signaling by mAb could be a novel biologic therapy for IBD.

Impact of double-balloon endoscopy on the diagnosis of jejunoileal involvement in primary intestinal follicular lymphomas: a case series.

In recent years, primary gastrointestinal follicular lymphoma has been increasingly detected in the duodenum on esophagogastroduodenoscopy (EGD). Primary gastrointestinal follicular lymphomas are frequently distributed to multiple sites in the gastrointestinal tract. Therefore, investigation into the spread of follicular lymphomas in the small bowel is important in order to determine the most appropriate treatment strategy. The performance of double-balloon endoscopy (DBE) in the diagnosis of jejunoileal follicular lymphoma lesions has not been fully evaluated. We aimed to investigate the value of DBE in addition to computed tomography (CT) and (18)F-fluorodeoxyglucose positron emission tomography ((18)F-FDG-PET) in the diagnosis of jejunoileal follicular lymphoma. DBE with biopsy was performed in seven patients with primary duodenal follicular lymphoma diagnosed by EGD, in order to investigate jejunoileal involvement. Jejunoileal follicular lymphoma lesions were detected by DBE in six out of the seven patients (three in the jejunum and three in the jejunum and ileum), whereas CT and (18)F-FDG-PET failed to detect the existence of these lesions. Endoscopic findings of the jejunoileal lesions revealed multiple white nodules and white villi, which were similar to those of duodenal lesions. DBE was more useful for the diagnosis of jejunoileal involvement in primary intestinal follicular lymphoma than CT and (18)F-FDG-PET. The use of DBE will become important for determining the most appropriate treatment for gastrointestinal follicular lymphoma.

Endoscopic submucosal dissection by using a grasping-type scissors forceps: a preliminary clinical study (with video).

BACKGROUND Endoscopic submucosal dissection (ESD) with a knife is a technically demanding procedure associated with a high complication rate. The shortcoming of this method is the difficulty of fixing the knife to the target lesion. It can lead to an unexpected incision and result in major complications, such as perforation and bleeding. To reduce the risk of complications related to ESD, we developed a new grasping-type scissors forceps (GSF), which can grasp and incise the targeted tissue by using electrosurgical current. OBJECTIVE To evaluate the efficacy and safety of ESD by using GSF for the removal of gastric neoplasms in human beings. DESIGN Prospective, uncontrolled, single center. SETTING Department of Gastroenterology, Aso Iizuka Hospital, Iizuka, Japan. PATIENTS Four patients with early gastric neoplastic lesions. INTERVENTIONS After marking and injection of a solution into the submucosa, the lesion was separated from the surrounding normal mucosa by complete incision around the lesion by using the GSF. A piece of submucosal tissue was grasped and cut with the GSF by using electrosurgical current to achieve submucosal excision. MAIN OUTCOME MEASUREMENT Technical success and complications. RESULTS All lesions were treated easily and safely, without any unexpected incisions. No delayed hemorrhage and perforation occurred. An en bloc resection and a negative resection margin was obtained in all cases. LIMITATIONS The small number of patients and an uncontrolled study. CONCLUSIONS ESD with GSF appeared to be an easy, safe, and technically efficient method for resecting GI neoplasms.

ENDOSCOPIC SUBMUCOSAL DISSECTION USING A GRASPING-TYPE SCISSORS FORCEPS FOR EARLY GASTRIC CANCERS AND ADENOMAS

Aim:  To reduce the risk of complications related to endoscopic submucosal dissection (ESD) using knives, we developed a new grasping‐type scissors forceps (GSF) that can grasp and incise the target tissue using electrosurgical current. The aim of the present study was to evaluate the efficacy and safety of ESD using GSF for the removal of early gastric cancers and adenomas.

Endoscopic submucosal dissection for superficial esophageal squamous cell neoplasms

Endoscopic resection is an effective treatment for non-invasive esophageal squamous cell neoplasms (ESCNs). Endoscopic mucosal resection (EMR) has been developed for small localized ESCNs as an alternative to surgical therapy because it shows similar effectiveness and is less invasive than esophagectomy. However, EMR is limited in resection size and therefore piecemeal resection is performed for large lesions, resulting in an imprecise histological evaluation and a high frequency of local recurrence. Endoscopic submucosal dissection (ESD) has been developed in Japan as one of the standard endoscopic resection techniques for ESCNs. ESD enables esophageal lesions, regardless of their size, to be removed en bloc and thus has a lower local recurrence rate than EMR. The development of new devices and the establishment of optimal strategies for esophageal ESD have resulted in fewer complications such as perforation than expected. However, esophageal stricture after ESD may occur when the resected area is larger than three-quarters of the esophageal lumen or particularly when it encompasses the entire circumference; such a stricture requires multiple sessions of endoscopic balloon dilatation. Recently, oral prednisolone has been reported to be useful in preventing post-ESD stricture. In addition, a combination of chemoradiotherapy (CRT) and ESD might be an alternative therapy for submucosal esophageal cancer that has a risk of lymph node metastasis because esophagectomy is extremely invasive; CRT has a higher local recurrence rate than esophagectomy but is less invasive. ESD is likely to play a central role in the treatment of superficial esophageal squamous cell neoplasms in the future.

Endoscopic ultrasound-guided fine-needle aspiration for the diagnosis of peripancreatic tuberculous lymphadenitis.

The percentage of patients with atypical extrapulmonary forms of tuberculosis has been increasing. Among extrapulmonary tuberculosis cases, tuberculosis of the pancreas and peripancreatic lymph nodes is a rare clinical entity. Here, we present a case of peripancreatic tuberculous lymphadenitis diagnosed by endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) both cytologically and microbiologically. A 23-year-old man had a 1-week history of epigastralgia and low-grade fever. Subsequently, he was found to have an abnormality on abdominal ultrasound. A computed tomography scan of the abdomen showed a solitary mass consisting of multiple cystic components with rim enhancement in the peripancreatic portion contiguous to the gall bladder. Endoscopic ultrasound-guided fine-needle aspiration was performed to confirm the diagnosis. The cytological examination revealed epithelioid cells with caseous necrosis, indicating tuberculosis. The aspirated fluid was positive by polymerase chain reaction (PCR) analysis and culture for Mycobacterium tuberculosis. Antituberculosis therapy with isoniazid, rifampicin, ethambutol, and pyrazinamide was started based on the PCR and cytology results, and a good response to the treatment was noted. Endoscopic ultrasound-guided fine-needle aspiration cytology with PCR analysis is very useful for the diagnosis of peripancreatic tuberculosis.

Suitability of the expanded indication criteria for the treatment of early gastric cancer by endoscopic submucosal dissection: Japanese multicenter large-scale retrospective analysis of short- and long-term outcomes

Abstract Objective. The criteria for endoscopic resection for early gastric cancer include absolute and expanded indications. Consensus already exists for the absolute indications. However, the suitability of the expanded indications must be validated by long-term outcome analyses since such lesions have only recently become resectable with the development of endoscopic submucosal dissection. The aim of this study is to clarify the suitability of the expanded indications for the treatment of early gastric cancer with endoscopic submucosal dissection. Materials and methods. The medical records of 1161 patients with early gastric cancers (1332 lesions) treated by endoscopic submucosal dissection and meeting the criteria for absolute or expanded indications without additional treatment with gastrectomy were divided into absolute indication group or expanded indication group. Results. Complete resection rates were 96.4% and 93.4% in absolute and expanded indication groups, respectively, with no significant differences between the groups. Delayed bleeding rates were significantly higher in the expanded indication group, whereas all cases were successfully managed conservatively. The 5-year overall survival and recurrence-free rates were 93.7%/99.77% and 90.49%/98.90% in the absolute and the expanded indication groups, respectively, with no significant differences between the groups for either measure. Multivariate analyses revealed that affected horizontal margin and tumor location were independent predictive factors for recurrence. Conclusion. The expanded indication group showed excellent post-endoscopic submucosal dissection short-term and long-term outcomes compared with the absolute indications group, demonstrating that expanded indications are suitable for endoscopic submucosal dissection for early gastric cancer.

Cytotoxic T‐cell lymphoma presenting as secondary myelofibrosis with high levels of PDGF and TGF‐β

To the Editor: Myelo®brosis is often observed in a variety of hematological malignancies including chronic myelogenous leukemia (1), acute megakaryoblastic leukemia (2) and hairy cell leukemia (3). However, malignant lymphoma with diffuse myelo®brosis is rare. We present here a case of cytotoxic T-cell lymphoma presenting as pancytopenia due to diffuse reticulo®brosis of bone marrow. Furthermore, we also discuss the pathogenesis of the ®brosis, and in particular the role of cytokines relative to the ®brosis. A 19-yr-old female was admitted to our hospital to undergo evaluation of pancytopenia in August 1998. Peripheral blood analysis showed a hemoglobin level of 51 g/L, a white blood cell count of 2.7r10/L without abnormal cells, and a platelet count of 35r10/L. Her right cervical lymph nodes were enlarged, and both the liver and spleen were palpable. A systemic computed tomography (CT) scan demonstrated multiple swellings of the bilateral cervical, supraclavicular, para-aortic and mesenteric lymph nodes and marked splenomegaly (Fig. 1). Biopsy of the right cervical lymph node revealed diffuse proliferation of small atypical lymphocytes with some multi-nuclear giant cells. Immunophenotyping revealed that both cells were positive for CD3, CD8, TCRbF1 and TIA-1 and negative for CD4, CD20, CD30 and CD56. Bone marrow aspiration resulted in a dry tap, and its biopsy revealed diffuse reticulo®brosis with lymphoid cells (Fig. 2A). Normal hematopoiesis was severely suppressed. We diagnosed peripheral cytotoxic T-cell lymphoma with myelo®brosis, and the patient subsequently underwent chemotherapy (cyclophosphamide, doxorubicin, vincristine and prednisolone). We performed six courses of chemotherapy. After three courses of chemotherapy, a bone marrow biopsy demonstrated recovery of hematopoiesis and a disappearance of ®brosis (Fig. 2B). However, small lymph nodes 1±2 cm in diameter remained in the neck and abdomen even after all six courses of chemotherapy. The patient underwent alloperipheral blood stem cell transplantation in April 1999, and is alive as of August 2000 with no progression of the disease. We determined the levels of several serum parameters at diagnosis and after three courses of treatment (Table 1). The serum concentration of soluble interleukin-2 receptor and LDH decreased from 14,800 to 502 U/mL, and from 972 to 313 U/ L, respectively. In addition, two serum markers of ®brosis, including procollagen terminal peptide III (4), which was released during the synthesis of type