Hepatoid adenocarcinomas of the stomach are gastric carcinomas with both adenocarcinomatous and hepatocellular differentiations. They usually produce large amounts of alpha-fetoprotein (AFP) with a Concanavalin A-binding property of hepatic type. In this study, these carcinomas occurred in older persons, with the antrum being a common site. Observed grossly, growth of the tumors was nodular and massive. Prognosis was poor because of frequent liver metastases. In the cytoplasms of tumor cells, various serum proteins were identified, including AFP, alpha-1 antitrypsin (AAT), alpha-1 antichymotrypsin (ACT), albumin, and prealbumin. Localizations of ferritin, prothrombin, and transferrin were demonstrated with less frequency. Adenocarcinomatous foci were composed of well-differentiated, intestinal-type epithelial cells and often contained carcinoembryonic antigen. These adenocarcinomatous and hepatoid areas were often intermingled with each other. There were extensive venous involvements by tumor cells. The poor prognosis of the tumors may be attributed to these involvements as well as to production of AFP and presence of AAT/ACT, which have immunosuppressive and protease-inhibitory properties, respectively.

Although several murine mAbs that have been humanized became useful therapeutic agents against a few malignancies, therapeutic Abs are not yet available for the majority of the human cancers because of our lack of knowledge of which antigens (Ags) can become useful targets. In the present study we established a procedure for comprehensive identification of such Ags through the extensive isolation of human mAbs that may become therapeutic. Using the phage-display Ab library we isolated a large number of human mAbs that bind to the surface of tumor cells. They were individually screened by immunostaining, and clones that preferentially and strongly stained the malignant cells were chosen. The Ags recognized by those clones were isolated by immunoprecipitation and identified by MS. We isolated 2,114 mAbs with unique sequences and identified 21 distinct Ags highly expressed on several carcinomas. Of those 2,114 mAbs 356 bound specifically to one of the 21 Ags. After preparing complete IgG1 Abs the in vitro assay for Ab-dependent cell-mediated cytotoxicity (ADCC) and the in vivo assay in cancer-bearing athymic mice were performed to examine antitumor activity. The mAbs converted to IgG1 revealed effective ADCC as well as antitumor activity in vivo. Because half of the 21 Ags showed distinct tumor-specific expression pattern and the mAbs isolated showed various characteristics with strong affinity to the Ag, it is likely that some of the Ags detected will become useful targets for the corresponding carcinoma therapy and that several mAbs will become therapeutic agents.phage Ab library ͉ therapeutic Ab ͉ tumor-associated antigen S ince the discovery of a method to produce mAbs numerous scientists have been trying to identify and produce mAbs that could be used for immunotherapy against various malignancies. The success for example of alemtuzumab against CD52, trastuzumab against HER2, and rituximab against CD20 for treatment of chronic lymphocytic leukemia, breast cancer, and nonHodgkins lymphoma, respectively (1-3), suggests that mAbs are likely to become very important therapeutic agents also against a wider range of cancers. However, for the majority of the human cancers useful therapeutic Abs are not yet available because of our lack of knowledge of which antigens (Ags) are likely to become useful targets (4). Therefore, several groups of investigators have been trying to identify other potential Ags as targets for immunotherapy using microarray technology (5, 6). Although many differences in transcripts have been revealed between malignant cells and the normal counterpart cells, it will take more time and laborious work to examine which Ags could be targets and to prepare therapeutic Abs against them. Furthermore, the presence of a large amount of transcripts does not always indicate expression of a large amount of the proteins.Our experimental approach was designed in the opposite way to the strategy with the microarray technology mentioned above and was based on the phage-display technology (7). First we isolate...

Adriamycin (ADR) is effective against a wide range of human neoplasms. However, its clinical use is compromised by serious cardiac toxicity, possibly through induction of peroxidation in cardiac lipids. Ascorbic acid, a potent antioxidant, was examined for effect in reducing ADR toxicity in mice and guinea pigs. Ascorbic acid had no effect on the antitumor activity of ADR in mice inoculated with leukemia L1210 or Ehrlich ascites carcinoma, but it significantly prolonged the life of animals treated with ADR. ADR elevated lipid peroxide levels in mouse heart, and ascorbic acid prevented the elevation. The significant prevention of ADR-induced cardiomyopathy in guinea pigs by ascorbic acid was proved by electron microscopy. Ascorbic acid and the derivatives may delay general toxicity of ADR and also prevent the cardiac toxicity. The results also suggest the clinical efficacy of the combined treatment of ADR and ascorbic acid or the derivatives.

756 CLASSLFICATION OF MALIGNANT LYMPHOMA Acta Path. Jap.form no clear-cut pattern but rather monotonous diffuse masses of round cells which appear to differ only in size. It should be a great hazard not only for treatment of the patients but also for statistical, epidemiological and various other studies on lymphomas that the diagnosis on one tumor would vary according to pathologists who examine it or hospitals where a patient is treated.It is therefore very important to evaluate the general situation on lymphoma diagnosis, to investigate the cause of diagnostic diversity, and to find objective measures to improve the accuracy and reproducibility of lymphoma diagnosis.As seen in the other reports of this symposium, new theoretical and technical approaches based on the recently acquired knowledges on basic immunology have greatly advanced the study of malignant lymphoma.50 It is now apparent that the Rappaport classification (AFIP Atlas, 1966)45 whose clinical usefulness had been widely recognized has some theoretical as well as practical drawbacks. Several different new classifications for non-Hodgkin's lymphomas have been proposed by leading scholars of this field in U.S.A. and E~rope,4,~~,16,16,~~35 and they are a t present being critically evaluated in the project for the international classification of non-Hodgkin's lymphoma sponsored by the National Cancer Institute of U.S.A.It was established through the U.S. -Japan seminars on malignant diseases of hematopoetic system held twice in 1967 and 19712, that the geographic difference between U.S.A. and Japan in various aspects of malignant lymphoma notably in the relative incidence of its subtypes was quite a p~a r e n t .~~~~' In order to contribute to the clarification of the problems of lymphoma diagnosis, and to obtain useful findings for a new classification suited for the lymphomas in Japan, a collaborative study was made by organizing a study group consisting of 16 members of different schools and different length of experience in the pathology of lymphoma. This study consisted of two parts namely I) the study of the consistency and reliabily of the histopathological diagnosis, and 11) the correlation between histological appearances and immunological characters of the lymphoma cells.

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