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A patient with an unresectable hepatocellular carcinoma (HCC) who survived without active treatment 3 years and 8 months after histological diagnosis is described. The size of the liver, which was already quite huge at the time of diagnosis, changed little during the entire clinical observation. However, 2 months before death, his condition deteriorated rapidly following gastrointestinal bleeding due to the direct invasion of the stomach by HCC. A critical reason for the unusually long-term survival of the patient may stem from the facts that a well-differentiated and bile-producing HCC was extent in most encapsulated-tumor tissues and that liver cirrhosis was not present.

In order to increase the accuracy of diagnosis in lung cancer, analysis concerning cytological and histological correlation was attempted. The present study consists of 106 patients, who were seen during the past approximately five years and underwent radical surgery to remove tumors completely; mere biopsy specimens were excluded. These patients were 63 years old on the average, 78 males and 28 females, 29 cases of the hilar type (H) and 77 of the peripheral type (P), and 27 and 76 cases of the clinical stage I in H and P, respectively. Histologically, there were 53 adenocarcinomas (Ad), 38 squamous cell carcinomas (Sq), 4 adenosquamous cell carcinomas (Ad + Sq), 5 large cell carcinomas (LCC), and 6 small cell carcinomas (SCC); among them, 3 Ad and 21 Sq in H, and 50 Ad and 17 Sq in P. The overall positive percentages were 65.5 (H) and 26.0 (P) by combination of spontaneous, airsol-induced and Saccomanno's methods, against 96.6 (H) and 72.8 (P) with inclusion of brushing method. 94.8% of Sq in H and 66.7% of Ad and 70.6% of Sq in P were positive by the brushing. A comparative study of these four methods, performed at least once on the same patient, also confirmed the superiority of brushing. Cyto- and histological agreement was 21/21 (100%) for Sq in H, whereas 30/34 (88.2%) for Ad and 13/15 (86.7%) for Sq in P. In conclusion, cyto- and histological findings in H and P corresponded well, and as far as cytology of peripheral type is concerned, a combined method, especially with brushing, is strongly recommended.

The effects of intravenous infusion of isoproterenol on stenosis resistance were studied in the anesthetized open-chest dog. The circumflex coronary artery (LCx) was isolated near its origin and an electromagnetic flow transducer was placed around the vessel for measuring coronary flow. A polyethylene catheter was inserted into the small branch of LCx for monitoring distal coronary pressure. LCx was constricted with a thick cotton string to a degree of obstruction that eliminated reactive hyperemia following a 20-second coronary occlusion. The coronary resistance across the stenotic segment (RL) was calculated as the pressure gradient across the stenosis divided by coronary flow. Isoproterenol was infused intravenously in a dose to keep the heart rate at a level 25-30% above the control with and without coronary constriction. For maintaining the ascending aortic pressure at the pre-isoproterenol level, the descending thoracic aorta was constricted with a tape. In the absence of coronary constriction, the vascular resistance of large coronary arteries was not affected by isoproterenol with a significant increase in coronary flow. In the presence of coronary stenosis, isoproterenol markedly increased RI regardless of additional aortic constriction. The magnitude of the increase in RL during aortic constriction varied directly with the percent increase in the pressure gradient across the coronary stenosis. Pacing-tachycardia essentially did not affect RL. These results suggest that isoproterenol increased the vascular resistance of the stenotic segment with fixed caliber.

We studied the effects of a splenectomy in combination with immunotherapy on the survival of patients who had undergone a total gastrectomy. It was found that a splenectomy was not effective against advanced gastric cancer at stage III, and that the spleen should be retained for immunotherapy. Splenectomy for gastric cancer at terminal stage IV, particularly in combination with immunotherapy, produced not only augmentation of cellular immunity, but also increased survival.

Characteristics of muscarinic acetylcholine (ACh) receptors were studied in the rat central nervous system (CNS) using 3H-quinuclidinyl benzilate (QNB), an antagonist of muscarinic ACh receptors. Scatchard analysis indicated that the rat CNS had a single 3H-QNB binding site with an apparent dissociation constant (Kd) of 5.0 X 10(-10) M. Li+, Zn++ and Cu++ had strong effects on 3H-QNB binding which indicates that these metal ions might play important roles at muscarinic ACh receptor sites in the brain. Since antidepressants and antischizophrenic drugs displaced the binding of 3H-QNB, the anticholinergic effects of these drugs need to be taken into account when they are applied clinically. The muscarinic ACh receptor was successfully solubilized with lysophosphatidylcholine. By gel chromatography, with a Sepharose 6B column, the solubilized muscarinic ACh receptor molecule eluted at the fraction corresponding to a Stokes' radius of 6.1 nm. With the use of sucrose-density-gradient centrifugation, the molecular weight of the solubilized muscarinic ACh receptor was determined to be about 90,000 daltons. The regional distribution of 3H-QNB binding in rat brain was examined, and the highest level of 3H-QNB binding was found to be in the striatum followed by cerebral cortex and hippocampus, indicating that muscarinic ACh mechanisms affect CNS function mainly through these areas.

A previous study has shown that a single injection of ferric nitrilotriacetate (Fe-NTA) produces hepatic parenchymal iron loading in rats. The present paper reports on iron uptake by rat liver and iron toxicity in the liver after a single injection of Fe-NTA (7.5 mg Fe/kg B.W.). Iron uptake was examined with 59Fe-NTA and Fe-[14C]-NTA. Thirty percent of the injected 59Fe was incorporated in the liver non-heme iron fraction at 3 h and retained for 240 h. Only 1% of the 14C injected as Fe-[14C]-NTA was taken up by the liver at 3 h. Gel filtration with a Sephadex G-25 column of the supernatant fraction of the liver obtained 3 h after the injection showed two peaks of 14C activity. One was eluted in the void volume, and the other corresponded to [14C]-NTA. The former had a molecular weight of 5,000-10,000 as determined with a Sephacryl S-300 column and also had 59Fe activity. The electron spin resonance spectra showed that the generation of a free radical in the liver was initiated within 1 h of the iron administration. The free radical generated in the serum by Fe-NTA was revealed to be superoxide by the spin trapping method. These results suggest that Fe-NTA transfers iron to transferrin in the serum and induces hepatic iron loading. Small amounts of the injected iron were taken up by the liver as Fe-NTA and generated superoxide which may have induced lipid peroxidation of the cellular membranes.

Some cases of early gastric cancer are accompanied with complications of the upper gastro-intestinal tract. The characteristics of these complications were investigated, and the problems of diagnosis and treatment were discussed. Out of 297 cases of early gastric cancer, 18 cases were accompanied with complications of the upper gastro-intestinal tract, including 11 cases of bleeding, a case of perforation and 6 cases of pyloric stenosis. All 18 cases were of the macroscopically depressed type, and about 85 percent of the 297 early gastric cancer cases were of the depressed type. The depressed lesions were often accompanied by ulceration which was an important factor causing the complications, and the mechanism of which appeared to be the same as that of a benign ulcer. There are some cases of early gastric cancer which are discovered by their complications, and it would be more difficult to find an early gastric cancer lesion if there were a benign lesion at the same time. Therefore, it is necessary to take much care when diagnosing and treating cases which have such complications. An endoscopic examination before the operation is especially important, and a biopsy is indispensable.

Metabolism of 3-mercaptopyruvate was investigated using homogenates of rat heart, liver and kidney. When 3-mercaptopyruvate was incubated with heart homogenate, L-cysteine, L-alanine, S-(2-hydroxy-2-carboxyethylthio)-L-cysteine and 3-mercaptolactate were produced. At the same time, a decrease in the amounts of L-glutamate and L-aspartate was demonstrated. These results indicate that 3-mercaptopyruvate was converted to L-cysteine by cysteine aminotransferase (EC 2.6.1.3), to 3-mercaptolactate by lactate dehydrogenase (EC 1.1.1.27), and to pyruvate by 3-mercaptopyruvate sulfurtransferase (EC 2.8.1.2), and that HCETC and L-alanine were formed from these products. In the presence of liver homogenate, 3-mercaptopyruvate was mainly metabolized by 3-mercaptopyruvate sulfurtransferase; production of L-cysteine was small and HCETC was not formed. The metabolism of 3-mercaptopyruvate in the presence of kidney homogenate was intermediate between heart and liver: a fair amount of L-cysteine was formed, but HCETC was not produced. A peak which corresponds to L-cysteine-glutathione disulfide on the chromatogram of amino acid analysis was present when 3-mercaptopyruvate was incubated with heart or liver homogenate, but not with kidney homogenate.

2-Mercaptoethanol increases the optical density of assay solutions at wavelengths between 280 to 400 nm, and therefore interferes with the measurement of protein concentration by the microbiuret method. Protein concentration can be determined in the presence of 2-mercaptoethanol up to 6 mM by modification of the method as follows: after the precipitation of protein by trichloroacetic acid in the presence of deoxycholate, the precipitate is resolubilized with NaOH solution. Dithiothreitol interfered with the protein determinations could by made in the presence of 4 mM of dithiothreitol with the modified microbiuret method. This modified method is time-saving and more reliable than other methods for protein determination, such as Lowry's method, in the presence of sulfhydryl reagents.

Levamisole (LMS) was given to stage III gastric cancer patients starting three days before gastrectomy, at a does of 150 mg/day for three consecutive days every other week. Survival rates of these patients were compared with those of stage III gastric cancer patients previously operated in our Department who had not received levamisole. The background factors of both groups were matched as closely as possible. Both groups were concomitantly treated with mitomycin C and FT-207. The survival rate of the LMS group was significantly higher than that of the control group when the tumor had a diameter of 4.0-8.0 cm, cancer cells infiltrated to the gastric serosa, there were metastases within the regional lymph nodes, cancer cells slightly invaded the venous capillaren and there was moderate infiltration of the stroma.

Active enhancement was induced in inbred rats with cardiac allografts using semisoluble antigens. The optimal time of antigen pretreatment and optimal dose of semisoluble antigens were examined. The presence of serum blocking factors in the sera of rats having had allografts for a long time was examined with a macrophage migration inhibition test and lymphocyte microcytotoxicity assay. Since the blocking factors of macrophage migration inhibition were increasing on the 7th day, that day was determined to be the optimal time of antigen pretreatment. The mean survival time (MST) of cardiac allografts in untreated rats was 17.2 +/- 7.5 days. Semisoluble antigens were administered at 2 mg/kg body weight 7 days before the graft, 4 mg/kg 7 days before the graft and 2 mg/kg divided over three days, 15, 8 and 1 day before the graft, and the MSTs of cardiac allografts of rats receiving these treatments were 71.2 +/- 39.9, 62.6 +/- 42.2 and 79.3 +/- 31.0 days, respectively. The MST in each group of the treated rats was significantly longer than that of the control group (p less than 0.01). Rejection of the allograft, however, was accelerated in a group treated with 8 mg/kg 7 days before the graft (MST: 8.4 +/- 3.2 days). Serum blocking factors were detected in the sera of approximately half of the rats having cardiac allografts which survived a long time.

We investigated the restriction of the host range to infectivity of MSV by helper leukemia virus in vivo. When newborn SD-rats were inoculated intracerebrally, subcutaneously, intraperitoneally or intramuscularly with xenotropic pseudotype Kirsten MSV, Ki-MSV(BV2), either brain tumors or myogenic sarcomas were induced, depending upon the route of inoculation. However, no tumors developed in SW-Icr mice inoculated with Ki-MSV(BV2) either intracerebrally or intramuscularly at birth. Ecotropic Ki-MSV(Ki-MuLV) induced myogenic sarcomas in mice when inoculated intramuscularly and also induced brain tumors and myogenic sarcomas in rats when inoculated intracerebrally and intramuscularly, respectively. Thus, the host range of pseudotype MSV appeared to depend on a helper leukemia virus.

The morphological and biological changes in long term culture cells of normal-appearing trigeminal nerves from 2, 8, and 30-day-old S-D rats administered transplacentaLly with 75 mg ENU/kg were examined. After a marked degeneration of cells, crisscross multiple proliferative foci of transformed spindle cells appeared at the 3rd passage culture from 2 and 8-day-old rats, but not form 30-day-old rats. The transformed cells with S-100 protein and basal lamina had Schwann cell characteristics. Transformed spindle cells continued to form a crisscross pattern more than 700 days and some transformed spindle cells became round in shape 3-6 months after the primary culture. These transformed cells were transplantable to newborn S-D rats and the transplanted tumors were histologically similar to those of malignant Schwannoma of trigeminal nerves induced by ENU. Round-shaped transformed cells were more malignant than spindle-shaped cells and produced rapidly growing transplanted tumors. Spontaneous transformation with multinucleated giant cells occurred in one of the control cultures. These results indicate that the sequential changes of ENU-treated trigeminal nerves in vitro were corresponded to developmental changes of malignant Schwannoma in vivo induced by ENU. This system will be useful for analysis of ENU-carcinogenesis.

The localization of both the large T and small t tumor (T) antigens in cultured cells (Vn 12 cells) of hamster brain tumors induced with BK virus (BKV), a new human papovavirus, was studied by an enzyme labelled antibody method at both the light and electron microscopic levels. Under the light microscope, BKV T antigen was observed in the nucleus, except for the nucleoli, of cells in interphase, and under the electron microscope it was observed in the nucleus except for the nucleoli and nuclear membrane. BKV T antigen appears to be closely associated with nuclear chromatin as previously reported for simian virus 40 tumor antigen (SV40 T antigen). The intracellular localization of BKV T antigen was the same as that of SV40 T antigen. In metaphase, BKV T antigen seems to be distributed diffusely throughout the cytoplasm except for the chromosomes. In telophase, BKV T antigen transfers from the cytoplasm to the nucleus. The migration of BKV T antigen during the cell cycle is thought to be related to the function of T antigen.

Cancer cells obtained from human hepatocellular carcinoma nodules were subjected to primary culture, and a hepatoma cell line was established. The cell clumps obtained by needle puncture were plated directly in plastic tissue culture flasks without any cell dissociation procedures. Cell clusters became attached to flasks in 24 h with an efficiency of about 90%. No fibroblast outgrowth was observed. Primary cultured cells were composed of polygonally shaped epithelial cells with dense cytoplasm and one or more large nuclei. They excreted plasma protein biosynthetic markers of hepatocytes into the culture medium. Plasma protein synthesis of primary cultured hepatoma cells decreased as the age of the primary cultures increased. Cells seeded in September 1980 started to grow continuously after 5 months of cultivation. A new hepatocellular carcinoma cell line (designated as KG55T) was established from these growing cells. KG55T cells have been subcultured for more than 20 passages and form a monolayer of polygonal epithelial cells which pile up after they reach confluence. The cells had a doubling time of 50-60 h and a plating efficiency of 60-65%. Albumin, alpha 1-antitrypsin and alpha 2-macroglobulin syntheses and tyrosine aminotransferase activity were detected. At the 10th passage, KG55T cells were pseudotriploid (mode, 69), and 8q+ and 15q+ translocations were distinctive of this cell line. The morphological characteristics and the capacity for plasma protein synthesis of the primary cultured hepatoma cells and cells of the established hepatoma cell line were compared.

1. An attempt has been made to find the diagnostic criteria for early gastric cancer. It is most important to detect the evidences or suspected features of the malignant growth in incipient stage in order to attain the radical cure by surgical operation. 2. Twelve patients with early gastric cancer (groups A and B) were selected out of 476 patients who had undergone gastrectomy during the past three years in the Okayama Saiseikai General Hospital. The other 6 patients in the "precancerous group" (group C) were also studied, who had abnormal epithelial proliferation in the resected stomach membrane during the same period. 3. The processes of discovery of early cancer have been described. Fairly precise diagnosis can be made in the mucosal carcinoma, but it is not in the ulcer-carcinoma. It was generally difficult to estimate the degree of the malignancy and the extension of the growth preoperatively. 4. The details of the diagnostic aids are as follows. i. Negative occult blood of stool does not always mean the definite diagnostic aid. ii. The malignant gastric change may occur even in non-anacidity. Further investigations should be followed up on gastric ulcer patients if malignant alteration is under the consideration. iii. Minor roentgenological findings, such as the absence or irregularity of mucosal folds, rigid and/or overlapped contour, localized absence or decrease of the peristaltic waves and absence or bow-shaped deformity of the angulus, are of important significance. Such changes should be minutely sought for by X-ray film examination. iv. On gastroscopy and gastrocamera photography, such changes as erosion or irregular granular thickening of the membrane with abnormal reddening and edematous appearance, irregularity of ulcer edge, uneven swelling on ulcer margin with reddening and unsharpness of the edge of adherent coat on ulcer floor, must be noted in the early gastric cancer. v. It is not safe to leave a patient having stomach ulceration under a mere conservative management because it is often quite difficult to dissolve the question of malignancy of the lesion with all sorts of examinations. vi. So far as clinical examinations have indicated malignancy, histological examination must be carried out immediately at the time of operation, even when malignant lesion is absent in inspection and palpation on the exposure of the stomach. vii. On the gross observation of the resected stomach, a particular attention must be paid to erosion, depression or atrophy, irregular granular thickening and abnormal reddening on the restricted areas of the mucosal surface.

For the elucidation of the relationship between the toluene concentration in the air and the amount of hippuric acid excreted in the urine as a metabolite after the work in the workshop where they use toluene, we have succeeded in measuring minute quantities of urinary hippuric acid by a modified method of Gaffney's paperchromatography and also by a simple mass screening examination method devised by us, and obtained the following results. 1. The average concentration of hippuric acid in the urine collected at 2 p. m. from healthy individuals proved to be 184 μg/ ml, and the amount of its excretion was 174 μg/ min. 2. After the three-hour inhalation of toluene whose concentration in the air ranged 20, 50, and 160 ppm, the average concentration of hippuric acid in the urine was found to be 190,863 and 1,930 μg/ml, and the avarage increment of hippuric acid, 33.2, 193.9, and 1060 μg/min respectively. From this results we have found that there is a linear relationship between the toluene concentration in the air on one hand and the concentration of urinary hippuric acid and the increasing amount of its excretion on the other. Thus it has become possible to calculate the toluene concentration in the air even in the workshop where the workers are exposed to toluene discontinuously from the curves of the linear relationships just mentioned. 3. For the control of health in the workshop where they use toluene (such as auto-tricycle factory) we have devised a simple mass screening examination method for the detection of urinary hippuric acid, in which urinary hippuric acid is extracted with ether alcohol, and the coloration of its spots on filter paper is conducted with aroylglycine reagent (DAB and acetic anhydride mixture) in order to find out those excreting 1,000 μg/ml (the maximum allowable concentration) or over.

The effect of the boiled liver extract on the velocity of 4-methyl umbelliferone lucuronide formation by mouse liver homogenate was studied. The results were as follows: 1. Addition of mouse or rat liver boiled extract to the complete system for the glucuronide formation produced an increase in the velocity of the glucuronide formation. 2. The boiled liver extract produced the increase in the velocity of the glucuronide formation not as a substrate but as an activator. 3, The activator in the boiled liver extract was relatively heat stable, acid labile, and precipitated as a fairly ethanol-soluble barium salt. The solution of the activator partially purified by ethanol fractionation of the barium salt indicated its absorption maximum at 262 mμ. These results suggested that the most possible substance in the boiled liver extract responsible for the activation of 4methyl umbelliferone glucuronide formation might be a sugar nucleotide.

The method of identifying human blood is studied from the standpoint of the fibrinolytic enzyme system by means of the "fibrin plate method" and the following results are obtained: 1) "Fibrin plate method" is, in the point of its sensitivity and speciesspecificity, one of the most excellent methods for the identification of human blood. 2) A small amount of the blood stains left standing as long as for 5 to 30 years can serve in the determination of the human blood. 3) Putrefied fluid blood does not demonstrate fibrinolysis. 4) Blood stains absorbed in various objects can also he identified whether they are of the human origin or not. 5) The pieces of cloth stained with human blood give positive fibrinolysis even after four washings with soap or after heating at 100°C for one hour. On the other hand, positive results are obtained with the pieces of cloths after three washings by benzidine test and with the physiological saline-extracted solution obtained after two washings of pieces of cloth, by precipitation test. 6) Proactivator has been found to contain globulin fraction in human serum protein. 7) The blood type can be determined with the same materials previously examined by the "fibrin plate method".

For the purpose to reveal the mechanism of the biological indirect action of X-rays the author has conducted the analysis of the compound lipids of the organs of the rabbits irradiated with X-rays. Silicic acid column chromatography was applied for the fractionation of the compound lipids. Component of each fraction was analyzed by silicic acid-impregnated paper chromatography and infra-red spectrophotometory. The result proved that the compound lipids showed some qualitative and 10+-+ quantitative changes. The changes occurred mainly in glycerophosphatides showing the formation of high level lyso-phosphatidylcholine and lysophosphatidylethanolamine. The fatty acid compositions of the compound lipids were determined by means of gas-liquid chromatography. Further, polyunsaturated fatty acids were analyzed as fatty acid bromide. Major differences found in fatty acid patterns included: in the irradiated group the amount of C18-monoenoic, C18-dienoic, C18-trienoic, C20-tetraenoic and C22-acids were decreased and of C18- and C18-monoenoic acids were increased. It has been elucidated that lysophosphatides not only posesses a strong hemolytic power but also it has an action to induce swelling of the rat liver mitochondria. And it has been suggested that the lysophosphatides and ethanolamine will be responsible, at least partially, for the cell damage induced by X-rays.