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1. Of immunological phenomena of malignant tumors, I have obseved, by satisfactorily exact experimental methods, the following six cases: immunity in re-transplantation, effects of tumor vaccine, passive immunity, agglutination, precipitation, and cutaneous reaction; and found it clear that antibodies to tumor cells are produced by transplanting tumor cells. Production of antibodies was increased to some degree along with the propagation of tumors, but the productivity was not so strong as seen in the bacteriological field. The most distinctive fact I noticed was the agglutination of tumor cells.
Eaton (15), who tested agglutination of Plasmodium knowlesi by immune serum from chronically infected and superinfected monkeys, reported that the titers of agglutination were given at dilutions of only 1:16 to 1:64± in the acute stages and at dilutions of 1:256 to 1:1, 024± in the chronic stages or after some ten infections of this disease were received.
Agglutinin that operates upon tumor cells is also found, in a small amount (about 1:25), even in normal animals. This gradually increases (1:200) with tumor cells implanted, but not so by the sensitization with other cells, for instance, liver cells or red cells. Therefore I may safely say that this phenmenon is specially confined to tumor cells.
Tumor vaccine forms a subject of interesting study. Successive inoculations of this vaccine were carried out in diverse ways before and after the transplantation of tumors, but the growth of tumors could not be restrained.
In regard to the effects of serum of cured animals, Takeda (16) and his cooperators reported that they transplanted Yoshida Sarcoma in successive generations of white rats of Wister-strain and with 0.5cc of serum from these spontaneously cured animals they were successful in completely preventing tumors from proliferation.
In my experiments serum from cured animals proved effective to some degree in retarding the proliferation of implanted tumors, but not so powerfully as to hinder it.
2. I investigated a cutaneous reaction which was considered as neutralizing phenomenon of tumor toxin.
Recently considerable attention has been paid to such reactions (17) as diagnostic methods of cancer and these methods have a much higher positivity as compared with other means of diagnosis. My method of reaction can be said to be a new one as to obtaining an antigen. Certainly this reaction was produced sooner than several other diagnostic methods I tried, but could not be expected in the early period after transplantation. In other words, even such a reaction requires a certain time in letting the body respond to it. Here lies difficulty of diagnosis of cancer. On the other hand, however, there is a fact that blood sugar increases in amounts describing a certain curve in the early stage after transplantation. With this fact into consideration the decision of positivity may be hastened by judging from cutaneous reaction and blood sugar titer together. That is, in the early period in case the blood sugar titer is high, the cutaneous reaction may safely be judged as certain positive, even though it may by itself be apparently uncertain positive.

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The specific gravity of the liver, spleen kidney, muscle and brain of the rats fed p-dimethylaminoazobenzene was determined by the copper sulphate method. And it was shown that the changes in the specific gravity are most remarkable in the liver and spleen in the course of liver cancer production. The specific gravity of liver decreases strikingly, and that of spleen increases slightly. A little variation in the specific gravity of the kidney and muscle was found. In the case of the brain however, the specific gravity was unchanged throughout the experiment. It appears that these in the specific gravity of the tissue of rats in the process of cancer production are closely related to the content of water and lipids in the tissue.

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To determine the arginine contents in liver, spleen, kidney, muscle and brain of the rats fed p-dimethylaminoazobenzene, Sakaguchi's reaction was followed at various days or stages during the experiment.
The striking fact was that the arginine values of liver and other tissues, except spleen, increased in proportion to the experimental days. Especially the peak of the arginine value in the liver was at the stage of cirrhotic liver.
On the other hand, the single exception was spleen, of which arginine decreased rapidly.

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[in Japanese]

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We have designed a modification of the K. I. K. reaction, which proved also considerably satisfactory results. We believe that our refined method is effetive for early diagnosis of gastric cancer, althouth we have not yet met with a suitable early stage of stomach cancer case to prove it.

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The toxohormone effect, that is, the lowering of liver catalase in tumor bearing animals, can be counteracted by dietary supply not only of dried liver or blood powder but also of excess ferric chloride. This fact was demonstrated in the case of mice bearing transplanted sarcoma and also of normal mice injected with potent toxohormone isolated from human as well as mouse tumors. Injections of ferric chloride mixed with toxohormone in solution also prevented the lowering of liver catalase, which toxohormone alone would bring about.
Based on these experimental results a hypothesis was advanced that it may be through its property of binding available iron that toxohormone interferes with the normal synthesis of catalase, and the possible significance of toxohormone in relation to the whole of iron-containing enzyme systems in cancer was discussed.

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All data were summarized in Table 1 and represented graphically in Figures 1-4.
It was substantiated that esterase activity of the liver was lowered just at the stage when the pathological change was first recognized macroscopically in the liver and was not related to what substrate was used. In the stage of hepatoma its enzyme activity was lowered markedly. Esterase of non-neoplastic part of a liver containing hepatoma nodules had a little higher activity than in liver which has suffered from general cirrhotic change.
Among control groups it is noticeable that the esterase activity of the liver fed rats was higher than that of normal rats. But the inhibitory action of liver feeding on hepatic cancer production may have no correlation to the above fact.
There was no difference between esterase activities of glycerol extract of liver whether DAB was added to it or not in vitro. In these experiments quantitative ratio of added DAB to the amount of tissue was about 1000 times larger than that which was determined by Masayama et al.⁽⁴⁾ in the liver of DAB fed rat. In glycerol extract of hepatoma no difference was also found in vitro whether DAB was added or not.
Whole data were summarized in Table 3 and Figures 5-6. Cathepsin activity of liver increased by DAB feeding exceeding that of normal one and was lowered markedly when hepatoma developed. In the latter case the activity was much lower than the normal. Though the cathepsin activation by cysteine was seen both in normal liver and hepatoma, it was not so distinguishable in liver of rat fed with DAB (except hepatoma), that is, in the macroscopically normal liver or cirrhotic liver. It was thought that these facts might be accounted for if we assume that cathepsin has been already activated in all these cases.
Differing from experiments with esterase, that the occurrence of larger activation than control was already distinguishable even in the stage of macroscopically normal liver, may afford some information on the study of precancerous stage.
Among control experiments activity of cathepsin in the liver of beef liver fed rat was a little higher than that of rats fed with ordinary diet, and in the experiments of activation by cysteine the similar difference was estimated.
Furthermore, as shown in Table 4, there was found no discrepancy of cathepsin activity between original enzyme solution from normal rat liver and the solution added with DAB in vitro.

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In Table 1 average S-N ratio in every group of experimental animals was presented. The S-N ratio was calculated from the result of sulfer and nitrogen determinations in the powdered liver. Therefore maximal and minimal values of S/N do not coincide strictly with those which are calculated from S and N values shown in respective columns of the table, as S/N is determined in every case independently. In Fig. 1 average S mg/N mg×10 of each group was represented graphically and in Fig. 2 mean values of N mg/10mg protein were shown.
Sulfer content in terms of S/N of liver protein of rats fed with DAB was far less than that of normally fed rats. The sulfer content grew higher, the more marked the macroscopical pathological change took place and that of nonneoplastic (cirrhotic) portion of the liver with hepatoma nodules was still larger than the latter and showed closely similar value to that of normal rat liver at this stage. When a hepatoma appeared S-N ratio reached the maximum.
On the contrary S/N in beef liver fed rats, one of the control groups, showed minimal value. Though we can not explain the reason how this remarkable fact had to do with the inhibiting action of beef liver feeding on liver cancer production, we may assume that the addition of certain amount of a readily absorbable and assimilable sulfer compound to the diet may have some influence on production of liver cancer. It may be recalled that there have been studies of many researchers who added on DAB feeding of rats sulfer containing amino acids to the diet.
On observation of nitrogen content of hepatic protein (Fig 2.) though there was no discrepancy between two control groups, we reached also to an assumption that it increased keeping steps with the extent of pathological change. There was seen fair coincidence with the result that Nakano⁴⁾ has obtained in the fraction of hepatic protein precipitated by trichloro-acetic acid.
The fact that a stepwise increase of nitrogen has become demonstrable is due to the above mentioned classification method based on pathological changes, instead of on feeding days with DAB.
It may be added here that a preliminary report on nitrogen determination in water extractable protein of entirely similar materials as used above has been published.⁵⁾ In that study nitrogen content grew lower the more the pathological change developed in hepatic tissue.

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[in Japanese]

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[in Japanese]

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