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In an attempt to predict the clinical activity of newly developed anthracycline analogues, ME2303, KRN8602, and SM5887 in the treatment of lung cancer, we compared antitumor activity of these drugs with that of adriamycin, using six human lung cancer cell lines and two drug-resistant human lung cancer sublines. Taking the pharmacokinetic data into consideration, we evaluated the relative antitumor activity: the ratio of area under the concentration-time curve of each drug to the 50% inhibitory concentration of the drug. Regarding this ratio, ME2303 was more potent than adriamycin, SM5887, and KRN8602. Cross-resistance of the new analogues to adriamycin was investigated using an adriamycin-resistant small cell lung cancer subline, SBC-3/ADM100 and an etoposide-resistant subline, SBC-3/ETP. SBC-3/ADM100 being 106-fold more resistant to adriamycin than the parent SBC-3 showed less resistance to the analogues: 1.80-fold to KRN8602, 3.80-fold to SM5887, and 8.60-fold to ME2303. SBC-3/ETP which was 52.1-fold more resistant to etoposide and 39.5-fold more resistant to adriamycin were also less resistant to the new analogues: 3.27-fold to KRN8602, 9.07-fold to SM5887, and 17.3-fold to ME2303. In conclusion, ME2303 was found to be the most potent agent among drugs tested for the treatment of lung cancer, and KRN8602 can be expected to be beneficial for the treatment of drug-resistant small cell lung cancer.

Twenty patients with cholelithiasis associated with valvular heart disease were studied to assess the need and the optimal time for cholecystectomy. Twelve patients (11 symptomatic and 1 asymptomatic patients) underwent cholecystectomy. The remaining patients were asymptomatic. The levels of the total bilirubin in 9 patients, and of LDH in 15, were higher than normal. In most of the patients, the serum transaminase levels were higher than normal, but in few cases, the levels were higher than 200 IU/l. These abnormal values, however, were not consistently observed in these patients. No clear association between the type and form of valvular heart disease was demonstrated. The type of prostheses used for valve replacement in these patients were ball, tilting disc and leaflet. No significant differences in efficacy were observed among different types of prostheses. The incidence of silent stones is high in patients with valvular heart disease and heart surgery often causes deterioration in patients with cholelithiasis. The recovery of the patients who underwent cholecystectomy before valve replacement were better than those who underwent cholecystectomy after heart surgery. In conclusion, therefore, patients showing any abnormal results in liver function tests should be assessed in detail by abdominal echography and should receive surgical treatment of biliary tract before heart surgery if necessary.

Since detection of hepatitis C virus RNA by the polymerase chain reaction (PCR) showed that there existed anti-C100-3 (anti-HCV) antibody negative patients infected with HCV, we attempted to find out whether there were any clinical or viral genomic differences between the anti-HCV antibody positive and negative groups. One hundred and fifty-nine patients with chronic liver diseases with hepatitis C virus RNA in their sera were selected. Anti-HCV antibody was tested for anti-C100-3 antibody by an enzyme linked immunosorbent assay. The incidence of anti-HCV antibody was 129/159. The concentration of serum gamma-globulin, the titier of ZTT, and the positive rate of the PCR with the primers of the NS3/4 region (NS3/4PCR) were significantly higher in the anti-HCV antibody positive group than in the negative group. However, the other data such as alanine aminotransferase activity or past history were not significantly different. Nucleotide sequence of the cDNA fragments of NS3/4 region amplified by the PCR did not differ significantly between isolates from anti-HCV antibody positive and negative sera. The sequences observed in the present study did not differ significantly from those reported previously. Although there remains the possibility that the variation of viral genomic sequences may cause the absence of anti-HCV antibody, these results suggested that the individual clinical backgrounds or immunoreactivity of the patients might influence the antibody development.

During the past 15 years we have managed four patients who suffered isolated valvular lesions from blunt chest trauma. Three patients were injured intraffic accidents and another fell from a height. Injured valves were mitral valves in three patients, tricuspid valves in two and aortic valve in one. One individual had a combination of aortic, mitral, and tricuspid valvular lesions.The procedures performed were mitral valve replacement in 2 patients and mitral repair in one, tricuspid valve replacement in one and repair in one, aortic valve replacement in one. The outcome of those patients were fairly well and all returned to their regular jobs．　

To elucidate the relationship between the high concentration of taurine in platelets and platelet aggregation in patients with EPH gestosis (gestosis with edema, proteinuria and hypertension), platelet aggregation and the platelet release response (release of ATP and beta-thromboglobulin) were studied in the washed platelet suspension (PS) obtained from normal pregnant or non-pregnant women and EPH gestosis patients. Platelet aggregation and platelet release response were significantly lower in EPH gestosis patients than in normal pregnant and non-pregnant women. Platelet aggregation, platelet release response induced by ADP and collagen and the aggregation induced by A23187 were inhibited in taurine-loaded PS from non-pregnant women. These results suggest that the decrease of platelet aggregation in EPH gestosis patients was caused by high concentrations of taurine in platelets, which may inhibit the intracellular Ca2+ movement and platelet release response. Therefore, taurine appears to have a protective effect against the hyper-coagulative state in EPH gestosis.

Constitutional lipid peroxidation in randomly selected 32 cases of clinically advanced carcinoma from human gastrointestinal tract (20 cases), breast (8 cases) and kidney (4 cases) was examined histochemically in frozen sections using cold Schiff's reagent. Only two cases of gastrointestinal carcinoma were positive by the reagent. Non-cancerous parenchymal cells were negative. These findings suggest that detectable constitutional lipid peroxidation seldom occurs in either cancerous or normal tissues. The capacity for normal and neoplastic tissues to undergo lipid peroxidation was also studied by incubation with an iron-NADPH pro-oxidant system. Normal parenchymal cells showed, to various degrees, a positive reactivity. In gastrointestinal carcinoma, 6 out of 7 cases of well differentiated adenocarcinoma reacted positively, whereas 2 out of 8 cases of moderately to poorly differentiated adenocarcinoma disclosed weakly positive reactions. Mucinous adenocarcinomas (4 cases) were all negative. Signet-ring cell carcinoma (1 case) was positive. One out of 8 cases of breast cancer also showed positive reaction. Four renal cell carcinomas were all negative. Cancer cells have lower capacity to undergo lipid peroxidation than normal cells, when the iron-NADPH pro-oxidant system was employed. In gastrointestinal carcinoma, the ability to undergo lipid peroxidation by the iron-NADPH pro-oxidant seems to be correlated with their histological differentiation. This fact may suggest that differences in lipid composition or the NADPH enzyme system exist between well differentiated and poorly differentiated gastrointestinal malignancies.

Our initial experience with laparoscopic cholecystectomy for cholecystitis and cholelithiasis was reviewed in 42 patients and the data were compared with those of 21 patients who underwent conventional open cholecystectomy previously. Only one patient required conversion to an open operation. Three of the 42 patients had minor complications without death in laparoscopic cholecystectomy. The mean time for the laparoscopic cholecystectomy was 100 +/- 40 min, as compared with 79 +/- 21 min for the open cholecystectomy. The average postoperative hospital stay was 11.4 +/- 7.1 days for the laparoscopic procedure and 35.5 +/- 15.4 days for the conventional procedure. The laparoscopic cholecystectomy offers the patients shortened hospitalization and lower complications and can replace the conventional open cholecystectomy in large degree, at least in the uncomplicated cases.

The plasma concentration of indomethacin was measured after the rectal administration of water-soluble and fatty base suppositories in rats. The results were compared with the in vitro indomethacin release from suppositories determined by Paddle method using three different types of membranes: cellulose membrane, artificial sausage membrane and natural sausage membrane. The plasma concentrations of indomethacin during the first 4h after the rectal administration were higher in rats that received water-soluble base suppositories than in those that received fatty base types. When either a cellulose membrane or an artificial sausage membrane of cow protein was used in the Paddle method, the amount of indomethacin released from fatty base suppositories was significantly higher than that from water-soluble base ones. However, the results were reversed when a natural sausage membrane of pig colon was used. The discrepancy in the in vitro experiments using water-soluble base suppositories seemed to be due to the difference of pore size of membrane used. Careful consideration should be given to the membrane used in the Paddle method especially when this method is employed to examine the release of poorly soluble drugs like indomethacin in both water-soluble and fatty base suppositories.

We evaluated the surgical problems encountered during treatment of 14 patients with malignant tumors originating in the pelvic region at our department. The tumor involved the iliac bone in 6 patients, the ischial bone in 2, the pubic bone in 2, and the gluteal region in 4. Invasion to the sacrum was observed in 7 patients. Twelve patients underwent surgical procedures consisting of intralesional resection in 6, marginal resection in 3, and wide margin resection in 3. Six of the 7 patients with sacral invasion developed local recurrence. Two patients with chondrosarcoma and one with parosteal osteosarcoma survived for 4 or more years, but the mean survival period in those with high grade malignant tumors was 11 months. These findings indicate the difficulties encountered in the treatment of malignant pelvic tumors.

A cell line of human lung large cell carcinoma (LCC) was established directly from the metastatic skin tumor tissue. The clinical course of the patient who carried this carcinoma was peculiar; generalized lymphadenopathy, histologically resembling Hodgkin's disease, was found as the first clinical symptom. The lung tumor was not discovered until the time of autopsy. This cell line (KaMi) grew adherent to culture vessels with the population doubling time of 20.6h, formed colonies in soft agars with efficiency of 22.6%, and formed tumors in athymic nude mice. The authenticity of KaMi was confirmed by chromosomal analysis and isoenzyme patterns. KaMi cells bore a strong resemblance to the original tumor cells which were composed of small spindle cells, large polygonal cells, and multinucleated giant cells. Immunohistochemically, KaMi cells showed a weak tendency to differentiate to squamous cells, and these immunohistochemical reactivities were almost compatible to those of the original tumor cells, but ultrastructurally, KaMi cells were more immature than the original ones. Treatment with several reagents could not augment a differentiation of KaMi cells. Cytokeratin profiles showed a tendency of squamous cell differentiation. KaMi cells may aid in elucidating the pathogenesis and biology of LCC and its relationship to other lung tumors.

We performed pulmonary artery angioplasty in 19 patients with lung cancer. The procedure consists of segmental or wedge resrection of the infiltrated pulmonary artery stem followed by reconstruction to avoid pneumonectomy and preserve pulmonary function. Among these cases "double sleeve resection" was performed in 10 cases. The 5-year survival of the angioplasty patients was poor at a rate of 11％, but not significantly different from the survival rates for those patients who underwent bronchoplasy alone or pneumonectomy. A promising prognosis may be expected in cases with N0 and N1 lymph node metastasis. However, this procedure may not replace pneumonectmy in patients with intact pulmonary function.

It has been found that the clinical tissue culture method devised in our laboratory for bone marrow is satisfactorily applicable to the in vitro study of human and animal splenic tissues. The present experiments have shown that the growth pattern, migration mode or cellular population of the cultured splenic cells is fairly characteristic of each disease condition, and the technic appears to be a valuable diagnostic aid in the practice of hematology. Direct vision biopsy with the laparoscope is safe and unattended by untoward side effects, enabling us to obtain excellent biopsy material from the enlarged spleen in various blood dyscrasias.

A single subcutaneous injection of 20-methylcholanthrene into newborn AKR mice less than 24 hours old resulted in the acceleration of the development of lymphocytic leukemia, and induction of subcutaneous sarcomas and multiple-lung adenomas. Morphological descriptions of the respective tumors were given. It is suggested that the lungs of newborn mice of strain AKR may prove to be a sensitive organ to evaluate carcinogenicity of certain carcinogenic compounds.

1. When chicken sarcoma virus is serially inoculated on the mouse brain, it loses its carcinogenecity, but when it is inoculated on young chicken, granuloma develops in the liver and lung. When this granuloma is transplanted on adult chicken, a transplantable fibrosarcoma is obtained. 2. According to literature, the originaltumor of the Brown-Pearce cancer is a basal cell cancer, but that imported to Japan in 1953 presented a histological picture of carcinosarcoma. The metastasized tumor of the eye presents a purely cancer tissue, but when this is inoculated on the testis, carcinosarcoma is reproduced. It is therefore considered that the mother cell of the sarcoma is of host origin. 3. MY sarcoma is not a sarcoma, but is a spindle cell cancer. It might be a sarcoma which transformed into a cancer during serial transplantation, but perhaps it was originally a cancer but had been erroneously diagnosed as sarcoma. 4. The tumors we obtained by means of the feeding tests of Yoshida tumor all developed at organs other than those of the digestive tract. They are chiefly reticulo-sarcoma, but others which develop are malignant granuloma in the liver and lung, malignant adenoma in the kidney, papilloma of pelvis, and ependymoma in the cerebral ventricle. Since the discovery of the Yoshida tumor in 1943, serial transplantation has been conducted for 19 years with this tumor not only in Japan but also in foreign countries, but there has been no report to this date that a transformed strain has developed by cell transplantation. It therefore must be considered that the carcinogenesis observed in our feeding tests is a carcinogenesis due to a mechanism completely unlike that of cell transplantation. It has been confirmed by electron microscopy that in the early stage of transplantation of this tumor into the abdominal cavity there was an additional tumor growth due to the anaplastic proliferation of serous cells. 5. During the serial transplantation of viral tumors and/or virus dependent tumors, the tumor sometimes undergoes a morphological change. Though the cause of this is not yet sufficiently elucidated, it is suspected that there is some relationship with virus in the wide sense.

Spontaneous C3Hf lymphatic leukemia maintained in an ascites form was transplanted into newborn Wistar rats less than 24 hours old. Single subcutaneous or intraperitoneal inoculation of the neoplastic cells resulted in progressive tumor growth fatal to the heterologous hosts. Limited serial passage through newborn rats was performed. The intraperitoneally heterografted leukemia grew as massive lymphosarcoma predominantly in the adipose and connective tissue compartments with invasion of the neighboring organs but without leukemic manifestations. The characteristic behavior and histopathologic features of the transplanted disease are presented in comparison with the results of similar experiments reported in the literature.

1. In an attempt to see how fatty acid iron will be absorbed from the intestine, a single administration of fatty acid iron was given and when histological observations were done with lapse of time, it was found that the iron compound was first split into iron and fatty acid and each of them was then absorbed by the intestines by a different mechanism as described in the first report. The present experiment further confirmed these findings. 2. Following the first experiment, another attempt was made to determine how iron was absorbed in the animals given successive oral administration under various conditions or a single intravenous injection of colloidal fatty acid iron, and it was demonstrated that under a certain condition the presence of fat in the feed accelerates the iron absorption from the intestine but its mechanism remains unclarified.

Man bestimmte die Gerinnungszeit einer Mischung von 0.1 ml des frischen Zitratplasmas, 0.1 ml einer Epsilon-Aminokapronsäure-Lösung in Konzentrationen von 0, 02, 0.5, 2.5, 10, 20, 50 und 100 gamma, 0.1 ml CaCl² Lösung und 0.1 ml Michaelis' Puffer. Die erwähnten EACA-Konzentrationen hatten keinen charakteristischen Einfluss auf die Rekalzifikationszeit des frischen und des gelösten lyophilisierten Plasmas.

It has been indicated that, when fatty acid iron is administered orally, the iron compound is split into iron and fatty acid and absorbed by different mechanisms.

The growth inhibitory effect of the fatty acids (OX) from the liver of X-irradiated rabbits on the solid type of Ehrlich ascites tumors has been observed both in gross and histologic observations. OX substance, a fraction of fatty acids extracted from the liver of X-irradiated rabbits has actually been found to inhibit the tumor growth by the local injection, resulting in the disappearance of the tumor after 12 injections for onemonth period, 2.4 ml of 2.5% emulsion in total dosage. Histologic observations reveal degeneration and necrosis of tumor cells, whereas in the control animals always active proliferation of tumor cells can be observed.