Oxygen-enhanced MR imaging: correlation with postsurgical lung function in patients with lung cancer

PURPOSE: To prospectively determine if lung function as assessed with oxygen-enhanced magnetic resonance (MR) imaging correlates with postsurgical lung function in patients with lung cancer, as compared with quantitative and qualitative findings of computed tomography (CT) and scintigraphy. MATERIALS AND METHODS: Study received institutional review board approval, and informed patient consent was obtained. Thirty consecutive patients (16 men and 14 women, aged 44-81 years; mean age, 65 years) considered candidates for lung resection underwent oxygen-enhanced MR imaging, CT, perfusion scintigraphy, and measurement of forced expiratory volume in 1 second (FEV1). A respiratory-synchronized inversion-recovery half-Fourier single-shot turbo spin-echo MR sequence was used for data acquisition. Correlation of postsurgical lung function (postsurgical FEV1) as determined with oxygen-enhanced MR imaging (FEV1MR), quantitative assessment with CT (FEV1Quant), qualitative assessment with CT (FEV1Qual), and perfusion scintigraphy (FEV1PS) was conducted with actual postsurgical FEV1, and the limits of agreement of each were determined with Bland-Altman analysis. RESULTS: Correlation between postsurgical FEV1MR and actual postsurgical FEV1 values was excellent (r2= 0.81, P < .001); it was better than that of FEV1Qual (r2= 0.76) and FEV1PS (r2= 0.77) and similar to that of FEV1Quant (r2= 0.81) values. The limits of agreement of FEV1MR were between -9.9% and 10.9%. CONCLUSION: Oxygen-enhanced MR imaging can be used to predict posturgical lung function in patients with lung cancer, similar to quantitative CT.     

Combination phase I study of nedaplatin and gemcitabine for advanced non-small-cell lung cancer

To establish the toxicities and maximum tolerated dose (MTD) of nedaplatin with gemcitabine, and to observe their antitumour activity, we conducted a combination phase I study in advanced non-small-cell lung cancer (NSCLC). Patients received nedaplatin (60-100 mg m(-2) given intravenously over 90 min) on day 1, and gemcitabine (800-1000 mg m(-2) given intravenously over 30 min) on days 1, 8, every 3 weeks. In total, 20 patients with locally advanced or metastatic NSCLC who received no prior chemotherapy or one previous chemotherapy regimen were enrolled. The most frequent toxicities were neutropenia and thrombocytopenia; nonhaematological toxicities were generally mild. Three out of six patients experienced dose-limiting toxicities (neutropenia, thrombocytopenia and delayed anaemia) at dose level 4, 100 mg m(-2) nedaplatin with 1000 mg m(-2) gemcitabine, which was regarded as the MTD. There were three partial responses, for an overall response rate of 16.7%. The median survival time and 1-year survival rate were 9.1 months and 34.1%, respectively. This combination is well tolerated and active for advanced NSCLC. The recommended dose is 80 mg m(-2) nedaplatin with 1000 mg m(-2) gemcitabine. This combination chemotherapy warrants a phase II study and further evaluation in prospective randomised trials with cisplatin- or carboplatin-based combinations as first-line chemotherapy for advanced NSCLC.     

Short report: Lethal malaria in cytosolic phospholipase A2- and phospholipase A2IIA-deficient mice

Lipid mediators play important roles in the pathogenesis of malaria. Phospholipase A2s are enzymes involved in the production of these mediators, and they function in inflammation. Among them, cytosolic phospholipase A2 (cPLA2) is a key enzyme in the metabolism of arachidonic acid, the first intermediate in the production of lipid mediators. Plasmodium berghei ANKA causes cerebral malaria in CL57B/6 mice, and we recently produced cPLA2-deficient mice with this background. With the expectation of reduced pathogenicity, we performed experimental infection in these mice. Unexpectedly, the infected mice developed cerebral malaria and died at the same time as the control mice, while the parasitemia progressed similarly in both groups. These observations suggest that secretory PLA2s rather than cPLA2 may be involved in the aggravation, although possible compensation by the induction of other enzymes has not been excluded. The present findings are expected to help clarify the involvement of various phospholipase A2s in malaria.     

Establishment of a new scirrhous gastric carcinoma cell line with microsatellite instability

We report on the establishment of a new scirrhous gastric cancer cell line with microsatellite instability (MSI), designated OCUM-7. This cell line was derived from a primary scirrhous gastric carcinoma. The cells were floating and round shape in culture. Histologic findings of xenografted tumor obtained from OCUM-7 cells showed a poorly differentiated adenocarcinoma with medullary growth. DNA histograms of OCUM-7 cells showed an aneuploid pattern. MSI status of OCUM-7 was analyzed using 8 microsatellite markers. Five of 8 microsatellite loci showed a novel band shift, which demonstrated that OCUM-7 cells were MSI-high. MSI-positive cell lines established from a primary scirrhous gastric carcinoma have not been reported, while several reports of the establishment of a scirrhous gastric cancer cell line are available. OCUM-7 might be beneficial for analyzing the mechanisms of MSI in scirrhous gastric carcinoma.     

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-beta 1 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.     

Lipid-mediated gene transfection of intercellular adhesion molecule-1 suppresses the peritoneal metastasis of gastric carcinoma

We have previously reported that a decreased expression level of ICAM-1 in cancer cells frequently led to the development of lymph node metastasis, and suggested that ICAM-1 gene transfection may inhibit lymph node metastasis. In the present study, we investigated whether ICAM-1 gene therapy for the peritoneal metastasis of gastric carcinoma is useful as a new immuno-gene therapy. ICAM-1 gene was transfected into a gastric cancer cell line, OCUM-2MD3 (2MD3), which has a high metastatic ability to the peritoneum. A transfectant cancer cell line, 2MD3/ICAM-1, had high ICAM-1 expression on the cell surface. The adhesion and cytotoxicity abilities of peripheral blood mononuclear cells were significantly increased against 2MD3/ICAM-1 cells in comparison with 2MD3 cells. Mice inoculated with 2MD3/ICAM-1 cells in the peritoneal cavity had a significantly better survival rate than those inoculated with 2MD3 cells (log-rank test, p<0.05). Histologic findings revealed that more mononuclear cells existed around the metastatic nodules in 2MD3/ICAM-1. Although gastric carcinoma frequently causes peritoneal metastasis, no useful therapy for the metastasis of gastric carcinoma has been developed. These findings revealed that ICAM-1 gene transfection to cancer cells could be a useful immuno-gene therapy for the peritoneal metastasis of gastric carcinoma.     

Analyses of fatal cases of Kawasaki disease in Japan using vital statistical data over 27 years

BACKGROUND: Chronological changes in mortality and case fatality rates from Kawasaki disease covering an extended period in Japan are still unknown. METHODS: We analyzed 679 deaths of patients in Japan whose underlying cause was Kawasaki disease, by using the data of vital statistics between 1972 and 1998. RESULTS: The male-to-female ratio of the number of deaths was 2.07 and the mean age at death in males was higher. Two unusual increases in the epidemic years, 1982 and 1986, were observed in the chronological changes of the number of deaths. The mortality rate of males was higher than that of females, with a few exceptional years, and the annual mortality rates were high in three epidemic years. The age-specific mortality rate was highest in infants under one year of age. Prefectures with high mortality rate clustered in some regions. The case fatality rate decreased annually, declining to as low as 0.2% among those who were born in 1986 and thereafter; and unusual increases in the case fatality rate affected by these three epidemic years were not repeated. CONCLUSIONS: The case fatality rate from Kawasaki disease in Japan decreased during the 27 years of observation: improvements in treatment might account for this.     

Genetic pathways in the evolution of morphologically distinct colorectal neoplasms

Colorectal adenomas can be morphologically classified as exophytic or flat. Polypoid cancers and cancers arising de novo (ie., without any adenomatous component) might be the results of genetic progression from exophytic and flat adenomas, respectively. In this study, we examined 94 morphologically distinct neoplastic specimens for mutations in K-RAS and analyzed 10 microsatellite loci tightly linked to the tumor suppressor genes APC, p53, DCC/SMAD4, hMSH2, and hMLH1. K-RAS mutations were significantly associated with exophytic adenomas [11 of 21 (52%)] compared to flat adenomas [2 of 13(15%), P < 0.03] and polypoid cancers [17 of 25 (68%)] compared to cancers arising de novo [7 of 25 (28%), P < 0.01]. Two polypoid cancer cases demonstrated three and four different K-RAS mutations, respectively, suggesting multiple areas of clonal expansion. Cancers arising de novo were significantly associated with loss of heterozygosity (LOH) at chromosome 3p compared to pol ypoid cancers [6 of 18(33%) versus 1 of 20(5%), P < 0.03], whereas the prevalence of LOH at chromosomes 2p, 5q, 17p, and 18q and microsatellite instability were not different between the groups. For all cancers, LOH at chromosomes 17p and 18q occurred in 47 and 51%, respectively. However, LOH at 17p and 18q occurred in 0 and 16% of benign lesions, respectively, suggesting their role in malignant transformation. There was no difference in LOH at chromosomes 17p and 18q between exophytic and flat lesions. These findings suggest that (a) mutant K-RAS is associated with the exophytic growth of colonic neoplasms, and that (b) some colorectal cancers arising de novo lose chromosome 3p during their evolution, which is not seen in polypoid cancers. Half of all cancers lose chromosomes 17p and 18q at or near the malignant transition of benign lesions as reported previously, irrespective of morphology. There may be more than one genetic avenue for colorectal cancer formation, and this correlates with the morphological characteristics.