Takeshi Sunami

Novel models for human scirrhous gastric carcinoma in vivo

Human scirrhous gastric carcinoma, a diffusely infiltrating type of poorly differentiated gastric carcinoma also known as linitis plastica type carcinoma, is characterized by cancer cell infiltration and proliferation accompanied with extensive stromal fibrosis. We established two new gastric cancer cell lines, designated OUCM‐8 and OCUM‐11, which developed the characteristic biology of scirrhous gastric carcinoma upon orthotopic implantation in mice. Involvement of lymph nodes and liver metastasis was also found in both orthotopic models. Histologically, these orthotopic models showed proliferation with extensive fibrosis, resembling human scirrhous gastric cancer. Both cell lines were derived from ascites of patients with scirrhous gastric cancer. The growth of OCUM‐8 and OCUM‐11 cells following the addition of KGF, FGF, and EGF was increased significantly relative to untreated cells. An increase in the number of attached and spreading cells occurred following the addition of TGF‐β1 in both cell lines. OCUM‐11 cells showed microsatellite instability. Although subcutaneous scirrhous gastric cancer cells show medullary growth, most in vivo studies of scirrhous gastric cancer have used xenografted tumors implanted subcutaneously. Only in a few cases was it confirmed that these scirrhous gastric cancer cell lines retained the original histologic characteristics. Our orthotopic models should contribute to the elucidation of disease progression in situ and to the development of therapy for scirrhous gastric cancer.

ICAM‐1 (Intercellular Adhesion Molecule‐1) Gene Transfection Inhibits Lymph Node Metastasis by Human Gastric Cancer Cells

Lymph node metastasis is one of the prognostic factors in gastric cancer. We have previously reported that decreased intercellular adhesion molecule‐1 (ICAM‐1) expression on cancer cells is associated with lymph node metastasis using a gastric cancer cell. In this study, we transfected ICAM‐1 gene into a gastric cancer cell line, 2MLN, and analyzed the effect on lymph node metastasis in vitro and in vivo. A significantly greater amount of peripheral blood mononuclear cells (PBMC) adhered to ICAM‐1 transfected 2MLN cells, 2MLN/ICAM cells, than to 2MLN/Vector cells. The lysis of 2MLN/ICAM cells by PBMC was significantly increased compared with that of 2MLN/Vector cells. The tumor growth rate of 2MLN/ICAM cells was significantly decreased in vivo. Lymph node metastases caused by 2MLN/ICAM cells were recognized as being fewer in number and smaller, while many lymph node metastases were caused by 2MLN cells. Histologic findings showed that leukocytes were heavily infiltrated in both the 2MLN/ICAM tumors and metastatic lesions, while only a few leukocytes were observed in the lesions associated with 2MLN cells. The above findings indicate that ICAM‐1 gene transduction could prove to be an effective gene therapy for lymph node metastasis of gastric cancer.

ICAM-2 Gene Therapy for Peritoneal Dissemination of Scirrhous Gastric Carcinoma

Purpose: Human scirrhous gastric carcinoma develops peritoneal dissemination with high frequency, and the prognosis of patients with peritoneal metastasis is poor. There have been few reports of an immunogene therapy for peritoneal dissemination. Intercellular adhesion molecule (ICAM)-2 is a second ligand of leukocyte function-associated antigen-1, which functions as a costimulatory molecule for effector cells. In the present study, we examined whether ICAM-2 transfection using adenovirus vector is effective gene therapy for peritoneal metastasis of gastric cancer. Experimental Design: We constructed an adenovirus vector, AdICAM-2, that encodes the full-length human ICAM-2 gene under control of the cytomegalovirus promoter. This vector expresses high levels of ICAM-2 on the human gastric cancer cell line OCUM-2MD3, which has high peritoneal metastatic ability in nude mice. We investigated the antitumor effects of gene transfer of ICAM-2 using the adenovirus vector AdICAM-2 in vitro and in vivo. Results: ICAM-2 expressed on OCUM-2MD3 cells by AdICAM-2 demonstrated significantly high adhesiveness to and cytotoxicity against peripheral blood mononuclear cells in vitro compared with the control adenovirus vector AdlacZ. Intratumoral injection of AdICAM-2 significantly inhibited the growth of s.c. tumor. Mice with peritoneal metastasis survived for a significantly longer time after AdICAM-2 injection, compared with injection of AdlacZ. Histopathological findings revealed that many natural killer cells infiltrated the peritoneal metastatic lesions after AdICAM-2 injection. Conclusions: These findings suggest that transduction of ICAM-2 into cancer cells enhances the adhesion and activation of natural killer cells, resulting in a reduction of peritoneal metastasis. ICAM-2 transfection using adenovirus vector might be an effective form of gene therapy for peritoneal metastasis of gastric cancer.

CD54 expression is predictive for lymphatic spread in human gastric carcinoma.

Even among gastric carcinoma cases with a similar extent of lymphatic invasion, the number of diseased lymph nodes may vary. Other factors might also contribute to the process of lymphangitic metastasis. Primary gastric tumors with the same extent of pathologic lymphatic invasion were studied in 78 patients. We investigated the correlation between CD54 expression on cancer cells and clinicopathologic features. Decreased CD54 expression on cancer cells was significantly correlated with the number of involved lymph nodes and the extent of lymph node spread. The number of diseased lymph nodes was associated with the prognosis of patients with gastric carcinoma. The CD54-negative group had a significantly worse prognosis than the CD54-positive group. These findings suggested that CD54 expression is predictive for lymphatic spread and prognosis in human gastric carcinoma.

Breast metastasis from EGFR-mutated lung adenocarcinoma: A case report and review of the literature

Although lung cancer rarely metastasizes to the breast, we report a case of breast metastasis from lung adenocarcinoma harboring an epidermal growth factor receptor mutation. This breast metastasis was initially considered recurrent breast cancer and was later diagnosed based on histopathological and molecular examinations as metastasis from lung cancer.

Phase I study of nanoparticle albumin-bound paclitaxel, carboplatin and trastuzumab in women with human epidermal growth factor receptor 2-overexpressing breast cancer

Although the concurrent use of anthracycline-containing chemotherapy and taxane with trastuzumab are considered the treatment of choice for the primary systemic therapy of human epidermal growth factor receptor 2 (HER2)-overexpressing early breast cancer, non-anthracycline regimens, such as concurrent administration of docetaxel and carboplatin with trastuzumab, exhibited similar efficacies in a previous study. In addition, tri-weekly treatment with nanoparticle albumin-bound paclitaxel (nab-paclitaxel) resulted in significantly higher response rates and a favorable safety profile compared with standard paclitaxel for metastatic breast cancer patients in another phase III study. Based on these results, a phase I study of combination therapy with nab-paclitaxel, carboplatin and trastuzumab was planned, in order to estimate its efficacy and safety for HER2-overexpressing locally advanced breast cancer. The present study was designed to determine the dose-limiting toxicity (DLT), maximum tolerated dose and recommended dose of this combination treatment in women with HER2-overexpressing locally advanced breast cancer. The starting dose of nab-paclitaxel was 220 mg/m2 (level 1), and the dose was escalated to 260 mg/m2 (level 2). Nab-paclitaxel was administered with carboplatin (area under the curve, 6 mg/ml/min) and trastuzumab tri-weekly. A total of 6 patients were enrolled. Although no DLT was observed during the first cycle, 4 patients developed grade 4 thrombocytopenia, 2 had grade 4 neutropenia and 3 exhibited a grade 4 decrease in hemoglobin levels. In the present phase I study, although no patients experienced DLTs, this regimen was associated with severe hematological toxicities and it was not well tolerated. However, considering the high efficacy and lower risk of cardiotoxicity and secondary carcinogenesis with taxane, platinum and trastuzumab combination therapy, further evaluation of another regimen including weekly administration or a more accurate dose setting should be conducted.