Takatomi Oku

Fas-mediated apoptosome formation is dependent on reactive oxygen species derived from mitochondrial permeability transition in Jurkat cells

Generation of reactive oxygen species (ROS) and activation of caspase cascade are both indispensable in Fas-mediated apoptotic signaling. Although ROS was presumed to affect the activity of the caspase cascade on the basis of findings that antioxidants inhibited the activation of caspases and that the stimulation of ROS by itself activated caspases, the mechanism by which these cellular events are integrated in Fas signaling is presently unclear. In this study, using human T cell leukemia Jurkat cells as well as an in vitro reconstitution system, we demonstrate that ROS are required for the formation of apoptosome. We first showed that ROS derived from mitochondrial permeability transition positively regulated the apoptotic events downstream of mitochondrial permeability transition. Then, we revealed that apoptosome formation in Fas-stimulated Jurkat cells was clearly inhibited by N-acetyl-l-cysteine and manganese superoxide dismutase by using both the immunoprecipitation and size-exclusion chromatography methods. To confirm these in vivo findings, we next used an in vitro reconstitution system in which in vitro-translated apoptotic protease-activating factor 1 (Apaf-1), procaspase-9, and cytochrome c purified from human placenta were activated by dATP to form apoptosome; the formation of apoptosome was markedly inhibited by reducing reagents such as DTT or reduced glutathione (GSH), whereas hydrogen peroxide prevented this inhibition. We also found that apoptosome formation was substantially impaired by GSH-pretreated Apaf-1, but not GSH-pretreated procaspase-9 or GSH-pretreated cytochrome c. Collectively, these results suggest that ROS plays an essential role in apoptosome formation by oxidizing Apaf-1 and the subsequent activation of caspase-9 and -3.

Argon plasma coagulation for successful treatment of early gastric cancer with intramucosal invasion.

Background: In recent years, there has been an increasing number of cases of early gastric cancer (T1, NX) with intramucosal invasion, which are untreatable by surgical or endoscopic mucosal resection (EMR) because of their high risk. Currently, no adequate treatment is available for such patients. Aim: The main objective of this study was to evaluate whether argon plasma coagulation (APC) is an effective and safe modality for treating early gastric cancer untreatable by surgical resection or EMR. Methods: The study group comprised 20 men and seven women diagnosed with gastric cancer with intramucosal invasion who were considered poor candidates for surgical resection or EMR due to risk factors such as severe cardiac failure or thrombocytopenia. Irradiation conditions for APC treatment were determined using swine gastric mucosa. We used an argon gas flow of 2 l/min at a power setting of 60 W and a maximum irradiation time of 15 s/cm2. The follow up period of the 27 patients ranged from 18 to 49 months (median 30 months). Results: All lesions were irradiated easily, including areas anatomically difficult for EMR such as the gastric cardia or the posterior wall of the upper gastric body. In 26 of 27 patients (96%) there was no evidence of recurrence during the follow up period (median 30 months). One patient showed recurrence six months after the treatment but was successfully retreated. No serious complications were found in any of the 27 patients but three patients (11%) experienced a feeling of abdominal fullness. Interpretation: APC is a safe and effective modality for treatment of early gastric cancer with intramucosal invasion untreatable by surgical resection or EMR. However, further observations are necessary to determine the long term prognosis of patients undergoing this treatment.

Cytomegalovirus cholangitis and pancreatitis in an immunocompetent patient

Cholangitis and pancreatitis associated with cytomegalovirus (CMV) infection in an immunocompetent patient is reported. Endoscopic retrograde cholangiography performed on a 55-year-old man for evaluation of the cause of jaundice and liver dysfunction revealed a distal focal irregular narrowing of the common bile duct. Microscopic findings of the resected specimen showed chronic cholangitis and CMV pancreatitis. Immunohistochemistry disclosed that epithelial cells in the inflamed bile duct were positive for CMV antigen, which was compatible with CMV cholangitis. Inflammation of the biliary tract or pancreas by CMV has been commonly reported as a complication in immunocompromised patients. Our report appears to be a rare case, but suggests that CMV cholangitis or pancreatitis should be considered in the differential diagnoses of common bile duct stenosis or pancreatitis even in immunocompetent individuals.

Clinical and endoscopic features of acute hemorrhagic rectal ulcer

BackgroundAcute hemorrhagic rectal ulcer (AHRU) has increasingly been reported in Japan, whereas it has rarely been reported in the English literature and is not yet established as a disease entity. The aim of this study was to elucidate clinical and endoscopic characteristics of patients with AHRU.MethodsWe enrolled 20 patients with 26 ulcers diagnosed as AHRU in our department between January 2001 and October 2005. Clinical features such as the underlying disorder, Karnofsky performance status (PS), and presence or absence of anticoagulant or antiplatelet therapy, as well as endoscopic findings and type of bleeding, were evaluated. Strategies for hemostasis were also reviewed.ResultsThe most prevalent underlying disorder was diabetes mellitus, and the number of bedridden patients with PS 4 was relatively high. In addition, more than half of the patients had been treated with anticoagulant or antiplatelet agents. Endoscopically, ulcers were characteristically solitary and irregularly shaped, and they did not show any typical localization pattern. As a hemostatic strategy, clipping alone showed a favorable result, with a hemostatic success rate as high as 76.9%.ConclusionsThis study may support the establishment of AHRU as a new clinical entity. In aged patients being treated with anticoagulant or antiplatelet agents, especially bedridden patients using aspirin, the possible appearance of this disease should be kept in mind.

A case of Gardner syndrome with a mutation at codon 1556 of APC: a suggested case of genotype-phenotype correlation in dental abnormality.

A 25-year-old man with suspected Gardner syndrome was introduced to our hospital by a dentist who, during examination of the patient, had found dental dysplasias and multiple osteomas of the jaw. Radiographs, endoscopy and biopsies revealed adenomatous polyposis of the colon. Genetic analysis of peripheral lymphocytes revealed a one-base deletion at codon 1556 in exon 15 of APC, which caused a frame shift and a premature stop at codon 1564. The pedigree analysis demonstrated five patients in his family who presented with dental abnormality and osteomas in addition to adenomatous polyposis of the colon. Although the relationship between the location of APC mutations and dental abnormalities remains controversial, this case supports the hypothesis that a mutation at around codon 1556 of APC is closely associated with dental abnormality and osteomas.

Amelioration of murine dextran sulfate sodium‐induced colitis by ex vivo extracellular superoxide dismutase gene transfer

Background: Although the etiology of inflammatory bowel disease has not been fully clarified, reactive oxygen species is speculated to be involved. Extracellular superoxide dismutase (EC‐SOD), an isozyme of SODs, is known to function mainly in body fluids. We investigated the efficacy of an ex vivo EC‐SOD gene transfer into dextran sulfate sodium (DSS)‐induced colitis mice. Materials and Methods: Experimental colitis was induced by providing Balb/c mice with DSS in sterile distilled water provided as desired. The syngenic fibroblasts were obtained from Balb/c mice embryos and retrovirally transduced with the hEC‐SOD gene. These engineered cells were confirmed to secrete EC‐SOD in culture medium by enzyme‐linked immunosorbent assay and were inoculated subcutaneously in the backs of DSS‐treated mice. Mucosal injury of the colon was evaluated by the disease activity index (DAI: body weight, rectal bleeding, and stool consistency), grading of histologic disease severity, and levels of cytokine (tumor necrosis factor‐&agr;, interleukin‐1&bgr;) production. 8‐Hydroxydeoxyguanosine (8‐OHdG) levels in the mucosal tissue were assessed by immunohistochemical staining. Malondialdehyde (MDA) was measured using a colorimetric assay. Results: A significant improvement was observed in DAI score and histologic severity as well as in mucosal tissue levels of inflammatory cytokines, 8‐OHdG, and MDA of mice treated with the EC‐SOD gene as compared with those without gene therapy, not only in a mild colitis model but also in a severe colitis model. Survival of treated mice in these models was significantly prolonged. Conclusions: Ex vivo transfer of the EC‐SOD gene was feasible for treatment of DSS‐induced colitis.

SUCCESSFUL MANAGEMENT OF METASTASIS-INDUCED PANCREATITIS BY ENDOSCOPIC PANCREATIC DUCT STENTING IN A CASE OF LARGE CELL LUNG CANCER

The prognosis for patients with metastasis‐induced acute pancreatitis (MIAP) is extremely poor. Although chemotherapy has been shown to improve overall survival in patients with MIAP, as well as in patients with small cell lung cancer, it is poorly tolerated by patients with severe pancreatitis. Furthermore, patients with a history of chemotherapy often develop multidrug‐resistant tumors. Here we report a first case of MIAP that was successfully managed by endoscopic pancreatic duct stenting. A 54‐year‐old man with pancreatic metastasis from large cell lung cancer developed acute pancreatitis approximately three times per month, despite a continuous conventional therapy for pancreatitis. As his disease was refractory to chemotherapy, he underwent endoscopic pancreatic duct stenting. The procedure was successful in controlling his pancreatitis, and he survived 7 months after the onset of a first acute pancreatitis. Our experience with this case suggests pancreatic duct stenting as one therapeutic method for MIAP.

A case of true malignant histiocytosis: identification of histiocytic origin with use of immunohistochemical and immunocytogenetic methods

Abstract. We report here an autopsy case of true malignant histiocytosis. The patient was a 67-year-old woman who exhibited fever, wasting, hepatosplenomegaly, and progressive pancytopenia. The bone marrow aspiration disclosed hemophagocytosing cells, which resembled histiocytes. The molecular analysis did not show the clonal gene rearrangement of T-cell receptor or immunoglobulin heavy chain. Although the patient had been started on methylprednisolone pulse therapy and chemotherapy with etoposide, she died from cerebral hemorrhage. The autopsy specimens of spleen and liver showed extensive infiltration of atypical cells, for which histiocytic origin was identified with an immunohistochemical method using monoclonal antibodies against CD11c, CD68, macrophage colony-stimulating factor (M-CSF), M-CSF receptor, lysozyme, antitrypsin and α1-antichymotrypsin. Recent investigations have disclosed that in most cases diagnosed as malignant histiocytosis, hemophagocytosis was reactive and not evoked by histiocytic malignancy. True malignant histiocytosis, for which histiocytic origin is confirmed, is extremely rare.

Adenocarcinoma of the minor duodenal papilla: report of a case.

An 81-year-old male was found to have a duodenal tumor by screening upper gastrointestinal endoscopy. The tumor was located in the minor duodenal papilla. Pathological examination of the biopsy specimen revealed adenocarcinoma, and endoscopic ultrasound showed an elevated hypoechoic mass in the minor duodenal papilla. The preoperative diagnosis was therefore considered to be either adenocarcinoma of the minor duodenal papilla or duodenal cancer. We performed a subtotal stomach-preserving pancreaticoduodenectomy. Histopathological examination of the resected specimen showed the tumor cells to be primarily located in the submucosa of the minor duodenal papilla, with slight invasion into the pancreatic parenchyma through the accessory pancreatic duct. We therefore diagnosed a primary adenocarcima of the minor duodenal papilla. Adenocarcinoma of the minor duodenal papilla is considered to be a rare disease, but it may be underestimated because of the difficulty in distinguishing advanced adenocarcinoma of the minor duodenal papilla from primary duodenal cancer and cancer of the pancreatic head.

Successful treatment of advanced peripheral T-cell lymphoma with an angiocentric growth pattern complicated with hemophagocytic syndrome by high-dose chemotherapy and autologous peripheral blood stem cell transplantation.

Abstract. Peripheral T-cell lymphomas (PTCL) account for about 10% of all lymphomas in Western countries, respond poorly to therapy, and have short survival with no sustained remission. Furthermore, the complication of hemophagocytic syndrome (HPS) sometimes makes the prognosis of this disease extremely worse. We report here a case of PTCL with an angiocentric growth pattern complicated with HPS successfully treated by high-dose chemotherapy and autologous peripheral blood stem cell transplantation. Our case suggests this approach is an excellent candidate for the treatment of this disease.