Hideo Ino

Antitumor effects and drug interactions of the proteasome inhibitor bortezomib (PS341) in gastric cancer cells

The proteasome inhibitor bortezomib (PS341) inhibits the function of the 26S proteasome and has been extensively investigated in the clinical setting of hematologic malignancies. Remarkable efficacy has been reported in the treatment of multiple myeloma, but there have been few studies of its use in the treatment of gastrointestinal malignancy, especially gastric cancer. Here, we demonstrate its efficacy, both alone and in combination with other cytotoxic agents, in gastric cancer cell lines. The human gastric cancer cell lines AZ521, MKN45 and NUGC3 were used as experimental models. Bortezomib produced significant growth inhibition in these cells (mean IC50 values: 1.26, 9.44 and 8.63 μmol/l, respectively) and was also observed to decrease the activity of the extracellular signal-regulated kinase 1/2 and Akt signal pathways, increasing the accumulation of p21. Cell-cycle analysis revealed that a low concentration of bortezomib (10–100 nmol/l) increased accumulation in the G1 phase. Moreover, bortezomib showed synergistic growth inhibition in combination with the conventional cytotoxic agents 5-fluorouracil, paclitaxel, doxorubicin and SN-38, and also downregulates the activity of nuclear factor -κB, which is induced by these agents. Our results demonstrate that bortezomib could be an effective antitumor agent in the treatment of gastric cancer, both as single-agent therapy and in combination with conventional chemotherapeutic agents.

Abnormal fluorine-18-fluorodeoxyglucose uptake in benign esophageal leiomyoma

A benign esophageal leiomyoma with abnormally increased fluorine-18-fluorodeoxyglucose uptake on positron emission tomography (PET) was resected thoracoscopically. The tumor, of which the maximum standardized uptake value of the lesion was 4.7, was well defined and 38 mm in diameter. Neither mitotic activity nor degeneration was found histologically; and immunoreactivity for CD34, CD117, MIB-1, and glucose transporter-1 was negative immunohistochemically. A diagnosis of gastrointestinal stromal tumor was ruled out by an oncogenic kinase gene mutation study. This case cautions against PET-dependent evaluation for malignant potential of esophageal submucosal tumors.

Malignant lymphoma induction of rabbits with oral spray of Epstein-Barr virus-related herpesvirus from Si-IIA cells (HTLV-II-transformed Cynomolgus cell line): A possible animal model for Epstein-Barr virus infection and subsequent virus-related tumors in humans

Malignant lymphoma (ML) was Induced in eight of nine rabbb inoculated by oral spray of the cell‐free pellets from SI‐IIA culture (MLV‐ll‐transformed leukocyte cell line of the Cynomolgus‐producing Epsteln‐Barr virus (EBV)‐related herpesvirus) after 64–141 days. None of the rabbits inoculated with EBV from B‐95–8 cells or HTLV‐II from MOT cells developed ML. Malignant lymphomas were usually of diffuse, large‐cell or mixed type. HTLV‐II infection was excluded by the polymerase chain reaction (PCR) and the particle agglutination test. EBV‐encoded RNA‐1 and EBV‐related DNA were detected in the tumor tissues by In situ hybridization and PCR, respectively. Anti‐viral capsid antigen of EBV antibody (anti‐VCA) was observed 3 weeks after oral inoculation of Si‐IIA cell‐free pellets. Polymerase chain reaction revealed continuous detection of EBV‐related virus DNA in the peripheral blood leukocytes from 3 days after oral inoculation. These results show that ML induced orally wtth SI‐IIA cell‐free pellets was caused by EBV‐related herpesvirus harbored by Si‐IIA cells. Oral spray of EBV from B‐95–8 also induced EBV Infection in rabbits, which was confirmed both by the presence of anti‐VCA and by PCR. These oral infection and mallgnant lymphoma induction systems of rabbit using EBV‐related virus from Si‐IIA or human EBV are useful animal models for the study of EBV infection and EBV‐related lymphomas in humans.

HTLV‐II Non‐integrated Malignant Lymphoma Induction in Japanese White Rabbits Following Intravenous Inoculation of HTLV‐II‐infected Simian Leukocyte Cell Line (Si‐IIA)

Lymphoma induction in rabbits by an unknown factor derived from an HTLV‐II‐producing simian (Cynomolgus) leukocyte cell line (Si‐IIA) is reported. Thirteen of 17 male Japanese white rabbits (76%) inoculated intravenously with Si‐IIA cells developed malignant lymphoma including Hodgkin‐like lymphoma between 62 and 167 days after inoculation. Historically, there was extensive diffuse or nodular infiltration of either large cell type or mixed type lymphoma cells in many organs, frequently involving the spleen, liver, lymph nodes and kidneys, and less frequently the thymus, bone marrow, lungs, heart, skin and gastrointestinal tract. Hodgkin‐like lymphoma was also observed in two rabbits. Chromosomal analysis of five cell lines established from tumor‐bearing rabbits revealed the male rabbit karyotype. The immunophenotype of these tumor cells was usually T‐cell (CD5+or, r RT1+, RT2+or‐, CD45+, CD4−, RABELA− and MHC class II‐DQ+) except for Hodgkin‐like lymphoma cells which expressed only CD45. However, integration of the HTLV‐II provirus genome could not be demonstrated in the tumor tissues or any of the rabbit cell lines by polymerase chain reaction or Southern blot analysis. Moreover, no lymphoma was induced by inoculation of HTLV‐IIC, MOT (other HTLV‐II‐producing human cell lines) or TALL‐1 (control). Two of four rabbits injected with cell‐free pellets from Si‐IIA cultures died of malignant lymphoma (15‐20 days). Five irradiated rabbit cell lines were inoculated but only one (Ra‐SLN) induced lymphoma in 1 of 3 rabbits at 27 days. Neither Herpesvirus saimiri nor Herpesvirus ateles (simian oncogenic viruses) was detected in Si‐IIA cells by immunofluorescence testing. These data suggest that the high rate of lymphoma induction in rabbits may be caused not by only HTLV‐II or well known simian oncogenic viruses, but rather by an unknown passenger agent derived from Si‐IIA or HTLV‐IIA, with which Si‐IIA was established.

A rare primary diaphragmatic hemangioma successfully treated by laparoscopic surgery: Report of a case

This report presents a very rare case of a primary diaphragmatic hemangioma, which was successfully treated by laparoscopic surgery. A 64-year-old man with a left diaphragmatic mass without any significant symptoms was treated by laparoscopic surgery and thus was diagnosed to have a diaphragmatic hemangioma following a pathological examination. Laparoscopic treatment in the deep and narrow abdominal spaces such as the diaphragmatic region is very useful as a less invasive treatment, as well as providing an excellent observation from which to make an accurate diagnosis.

Impact of Endoscopic and Histological Evaluations of Two Different Types of Mesh Plug for a Groin Hernia Model

PurposeThe biological responses to mesh in vivo have been evaluated in some papers, but the in vivo condition of mesh and plugs have not been sufficiently evaluated. This study evaluated the endoscopic observations and histological assessments of mesh plugs using swine models.MethodsAn artificial abdominal hernia was established in the porcine abdomen, and repaired using three different sizes of two types of plug, Proloop (ATRIUM Medical Corporation, Hudson, NH, USA) or Perfix (BARD Medical Division, Covington, GA, USA). The in vivo conditions of each plug were periodically observed using a laparoscope. Moreover, a histological evaluation of the plugs was performed 3 months after implantation.ResultsThe laparoscopic observation revealed that inversion of the plugs occurred in 10 out of 18 cases repaired with Perfix, while no case repaired with Proloop inverted. The large and medium sizes of Perfix plugs were inclined by an average of more than 30°. In addition, the triangular shape of Perfix plugs was broken and the vertical/horizontal ratio was enlarged during the observation period, while Proloop plugs shrank both vertically and horizontally. The inflammatory cell count was significantly lower within the Proloop plugs than within Perfix plugs.ConclusionProloop plugs are apparently superior because they are stable even 3 months after implantation.