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Alpha-1-antitrypsin (alpha 1AT) is present not only in the normal gastrointestine, but in malignant gastrointestinal tissue as well. We studied the expression of alpha 1AT mRNA in 30 cases of esophageal carcinoma using a Northern blot analysis. In addition, we also examined the expression of matrix metalloproteinase 7 (MMP7) mRNA in the latest 15 cases by reverse transcriptase-polymerase chain reaction (RT-PCR) method to clarify the relationship between the alpha 1AT and MMP7. In 25 of the 30, the expression of alpha 1AT mRNA in esophageal carcinomatous tissue (T) was lower than that in the corresponding normal tissue (N) of the esophagus. The T/N ratio of alpha 1AT mRNA expression showed a significant inverse correlation with the depth of tumor invasion, lymph node metastasis and stage of disease (p=0.042, p=0.0001 and p=0.002, respectively). The T/N ratio of alpha 1AT bad a converse correlation with that of MMP7 (p=0.034). The current study thus suggested that i) the lower expression of T/N expression may be a marker for the biological aggressiveness of esophageal carcinoma, and ii) the reduction of alpha 1AT may be partially correlated with the overexpression of MMP7 in tumor tissue.

Prothymosin-alpha (PT-alpha) is a nuclear protein involved in cell proliferation. c-myc is implicated in the carcinogenesis of many human cancers. PT-alpha gene transcription is reported to be regulated by the c-myc gene in vitro. However, little has been reported on the PT-alpha and c-myc mRNA expressions in gastric cancer. We semi-quantitatively determined the PT-alpha and c-myc mRNA expressions in 60 pairs of gastric cancer tissue (T) and corresponding normal tissue (N) using the reverse transcriptase-polymerase chain reaction method. The average of T/N ratio was 1.20 for PT-alpha and 1.30 for c-myc. Cases demonstrating a T/N ratio of more than 1.0 were seen in 33 (55%) and 30 (50%) cases for PT-alpha and c-myc, respectively. No significant correlation was observed between either of these two mRNA expressions and any of the examined clinicopathologic factors for gastric cancer. However, a significant correlation was seen between the expressions of both genes (p<0.0001). The findings support the hypothesis that, regarding human gastric cancer, the transcription of PT-alpha is considered to be under the control of c-myc gene, however, the value of these gene expressions do not reflect biological behavior.

We previously demonstrated that the efficiency of cell transformation by simian virus 40 (SV40) is reduced when proliferating rat 3Y1 cells are inoculated with SV40 as compared with when density-arrested cells are inoculated. In this study, we characterized in more detail the cellular state at the time of virus inoculation that affects the susceptibility to SV40 transformation. When density-arrested 3Y1 cells were stimulated to progress one round of cell cycle by refeeding with medium containing high serum, they began to reduce the susceptibility to SV40 transformation before entering S phase. After re-entry into the non-proliferative state, prolonged maintenance of cells in the non-proliferative state was necessary for restoration of the susceptibility to SV40 transformation. Such dependency of the transformation efficiency on the cellular state at the time of SV40 inoculation paralleled with that of the expression of T antigen in nuclei, while virus adsorption and degradation of the DNA of the adsorbed virus was not dependent on the cellular state. We conclude that after inoculation of proliferating cells with SV40, an unidentified event between the virus adsorption and the accumulation of T antigen protein in nuclei is blocked and that this blockage causes the inhibition of the initiation of transformation.

The multiple tumor suppressor 1 (MTS1) gene is homozygously deleted frequently in cell lines derived from a wide variety of tumors. We investigated the deletion of the MTS1 gene in esophageal cancer cell lines and primary esophageal squamous carcinomas using the polymerase chain reaction. Sixteen and 15 of 23 esophageal cancer cell lines showed homozygous deletion of MTS1 exon 1 and exon 2, respectively, while none of 21 primary esophageal carcinomas showed the deletion. An analysis of MTS1 gene mutations was carried out by direct DNA sequencing in 8 cell lines and 21 primary carcinomas showing no homozygous deletion. In contrast to previous reports of esophageal carcinoma, there were no mutations recognized in the region sequenced. Our study suggests that the inactivation of the MTS 1 gene may play an important role in esophageal carcinoma cell lines but may be less important in primary carcinomas of the human esophagus.

We report on a case of advanced gastric cancer with multiple liver metastasis and lymph node metastases in a 65-year-old Japanese man. He was treated with sequential intravenous administration of moderate-dose methotrexate 1 (MTX) and 5-fluorouracil (5-FU) preoperatively. After eleven cycles of the combination chemotherapy, the findings of liver and lymph node metastases diminished dramatically and the tumor could be resected for a potential cure, using a total gastrectomy and combined hepatectomy. The resected specimen revealed a slightly elevated lesion and a somewhat shallow ulceration due to chemotherapy. Histologically, there was an infiltration of poorly differentiated adenocarcinomas with medullary structure in the muscularis mucosae with fibrous change. The liver was metastasized, but there was no evidence-of lymph node metastasis. We believe that combination chemotherapy of MTX and 5-FU can be effective against gastric cancer.

A human cell line, SiSo, was established from a patient afflicted with uterine cervical adenocarcinoma. The SiSo cell expresses MHC class I antigen, various kinds of adhesion molecules and tumor-associated antigens such as CA125, CEA and GA733. The secretion of CA125 antigen was markedly suppressed by anti-cancer reagents. However, their growth was not affected by any of the anti-cancer reagents tested, suggesting a discrepancy between inhibition of tumor growth and suppression of secretion of tumor-associated antigens after treatment with anti-cancer reagents. The SiSo cell line will provide a tool for investigation of uterine adenocarcinoma.

To screen carcinostatic components in foodstuffs, the toxicity of tea polyphenols was compared between rat 3Y1 diploid fibroblasts and a variety of their virally transformed cells. Among tea polyphenols tested, epigallocatechin gallate killed 3Y1 cells transformed by E1A gene of human adenovirus type 12 (E1A-3Y1 cells) at a 100 times lower concentration than the parental 3Y1 cells. Epigallocatechin gallate also exerted a strong E1A-3Y1 cell-specific toxicity, while epicatechin and epicatechin gallate did not. When the activity of three antioxidant enzymes was compared between 3Y1 and its transformants, catalase activity was markedly low in the latter, especially in E1A-3Y1 cells, and the substrate of the enzyme, hydrogen peroxide, exerted a toxicity specific to this cell line. Then the inhibitory activities of various chemicals on E1A-3Y1 cell-specific toxicity of phospholipids or catechol were examined. Among lipoxygenase inhibitors, all of the polyphenolic compounds inhibited the toxicity of phospholipids, but not a nonpolyphenolic inhibitor (clofibrate). Two phospholipase A,inhibitors (dexamethasone and quinacrine) did not inhibit the toxicity. These results indicate that the triphenol structure of the B ring is essential for the E1A-3Y1 cell-specific toxicity of tea polyphenols, and that the decrease in catalase activity is partially responsible for the higher sensitivity of E1A-3Y1 cells against the polyphenols. The inhibitory effect of polyphenolic lipoxygenase inhibitors is ascribed at least in part to their antioxidant activities.

We treated a 27-year-old pregnant woman with Borrmann type IV gastric cancer and immunohistochemically detected micrometastasis of cancer cells in the bone marrow. Total gastrectomy combined with splenectomy was followed by postoperative chemotherapy. Despite intensive treatment, she died with tumor progression 6 months later. When malignant cells are present in the bone marrow, the prognosis is poor. The literature on gastric cancer associated pregnancy is reviewed.

Alterations of the p53 and Ki-ras genes were examined in 12 human pancreatic cancer-derived cell lines with different metastatic potential. Point mutations of the Ki-ras gene at codon 12 were found in 10 out of 12 cell lines (83%), while abnormalities of the p53 gene were identified in 8 out of 12 cell lines (67%) which included point mutations (n=7) and one base deletion (n=1). The comparison between alterations of the p53 and Ki-ras genes showed that all the 12 cell lines revealed alterations of both genes or one of these genes regardless of the metastatic potential. Further, same alterations of the Ki-ras gene or p53 gene were noted among the cell lines with increased metastatic potential and their parental cell lines. These findings suggest that alterations of the p53 gene, like the Ki-ras gene is a frequent event in pancreatic cancer, and could contribute cooperatively in the oncogenic steps of pancreatic cancer. It is also suggested that the genetic changes of the p53 and Ki-ras genes are not substantially associated with the metastatic potential in pancreatic cancer.

We examined the effect of saturated fatty acids with carbon number from 2 to 10 on proliferation and survival of rat untransformed fibroblast 3Y1 cells and its transformed derivation induced by Simian virus 40 (SV-3Y1). Acetic acid (C2) had no effect on proliferation of these cells. Among medium-chain fatty acids (C6-C10), caproic acid (C6) showed the lowest proliferation inhibitory effect. Caprylic (C8), pelargonic (C9), and capric acid (C10) exerted killing activity to both 3Y1 cells and SV-3Y1 cells, and the toxicity increased with the elongation of their alkyl chains. The toxicity was a little greater to 3Y1 cells than to SV-3Y1 cells. In contrast, short-chain fatty acids caused reversible proliferation arrest in 3Y1 cells at 25 mM in propionic (C3), 5 mM in butyric (C4) and 10 mM in valeric (C5) acids. These short-chain fatty acids arrested 3Y1 cells not only in the GI phase but also in the G2 phase of the cell cycle. To SV-3Y1 cells, however, these short-chain fatty acids were cytotoxic. The cytotoxicity to SV-3Y1 cells was the greatest in butyric acid among short-chain fatty acid tested. These results suggest that short-chain fatty acids exert ploliferation-arresting activity against normal cells while exerting killing activity to the transformed cells.

We report on a case of multiple bone metastasis and disseminated intravascular coagulation (DIG) in a 49-year-old Japanese man. He underwent total gastrectomy for advanced gastric cancer in July 1992, He was diagnosed as a case of multiple bone metastasis in August 1993. Severe anemia, thrombocytopenia, and elevated fibrinogen degradative products were indicative of DIG. He was treated with sequential i.v. administration of methotrexate (MTX) and 5-fluorouracil (5-FU) and continuous i.v. infusion of heparin and gabexate mesilate. After two weeks of treatment with MTX combined with 5-FU, the findings of DIC disappeared and his general condition improved dramatically.

In order to elucidate the relationship between nm23 and metastasis in human gastric cancers, we analyzed gene and protein expression of nm23-H1 using Northern blot and immunohistochemical techniques. nm23-H1 gene expression was identified in 17 out of 19 gastric cancer tissues. The signals in the tumor tissues presenting regional lymph node metastasis seem to be lower than those in the tumor tissues without regional lymph node metastasis, suggesting a role of nm23-H1 in the regional lymph node metastasis in the gastric cancers. However, the protein expression detected immunohistochemically was not correlated to the gene expression, partly because of difficulty in quantifying the amount of protein. Expression of the nm23-H1 gene as well as the nm23-H1 protein in the tumor tissues was higher than those in the corresponding normal mucosae. This suggests a linkage of nm23-H1 in the process of the gastric cancer progression. We also analyzed the sequence abnormalities of the nm23-H1 gene in the gastric cancer tissues using a direct sequencing technique, no mutations were observed.

We investigated the antitumor activity of human natural tumor necrosis factor (n-TNF) either alone or in combination with chemotherapeutic drugs on human glioma cell lines in vitro. Although the cytotoxic effect of n-TNF alone did not exceed 30%, n-TNF, in combination with topoisomerase II-trapping drugs, such as actinomycin D (ACD) and daunomycin (DAM), demonstrated a striking synergistic enhancement of the cytotoxicity, and reached a level of more than 80%, against all the tested cell lines. Thus this new combination therapy is considered to be a promising candidate in developing a new treatment approach to glioma patients.

Lung colonization induced by the intravenous injection of fibrosarcoma cells into syngeneic mice was enhanced by the pretreatment of mice with cyclophosphamide (CPA), adriamycin (ADM), cis-diammine-dichloroplatinum II (DDP) and methotrexate (MTX). At equitoxic levels, CPA showed greater enhancement of the lung colonization than the other drugs treated. After a two-hour pretreatment of an endothelial monolayer culture, the adhesion of fibrosarcoma cells to endothelial cells was enhanced by all drugs, and the greatest enhancement was obtained with CPA. Data from these experiments supports the hypothesis that endothelial cell damag by anticancer drugs may facilitate metastasis of circulating tumor cells.

In rabbit models, the inhibition of proteoglycan (PG) biosynthesis in the epiphyseal growth plate of the ribs was observed in the group given cisplatin both in vitro and in vitro. Serum alkaline phosphatase (ALP) and the bone-derived ALP isoenzyme were observed to decrease in the young rabbits given cisplatin. In rat models, the length of the tibias in both the groups given cisplatin was significantly shorter than that of those in the control rats. The results described may thus suggest that the injury of the epiphyseal growth plate and growth retardation possibly occur due to the use of cisplatin.

In an attempts to increase the antitumor effect and to reduce normal tissue toxicity, the combined cytotoxic effect of cis-Diamminedichloroplatinum (II) (CDDP) and cis-diammine(1,1-cyclobutane dicarboxylate) platinum (II) (CBDCA) was investigated using HeLa and colon 26 cell lines and the combination index (CI). Cytotoxicity of the combination of CDDP and CBDCA on 27 surgically resected specimens of human gastric and colorectal adenocarcinomas was also evaluated using the in vitro succinate dehydrogenase inhibition (SDI) test. The CI values varied with the dose ratio examined (1:1-1:6) of CDDP and CBDCA, with findings that CI<1, synergy, was obtained at fraction affected (Fa)>0.75 for HeLa cells and at Fa<0.9 for colon 26 cells in cases of a dose ratio of 1:1 to 1:2. Of all 27 clinical human adenocarcinomas, the succinate dehydrogenase (SD) activity was significantly lower in cancer cells concomitantly exposed to both CDDP and CBDCA than in those exposed to either drug alone. These positive effects of a combination of two platinum analogues on human malignant tissues have heretofore not been reported, which would warrant the clinical application of this combination for human malignant tumors.

The effect of reduced glutathione (GSH) and ethanol on aflatoxin B1 (AFB1)-induced DNA single strand breaks was studied in primary cultured hepatocytes. Buthionine sulfoximine (BSO) which decreased intracellular GSH to 13% of those of the control levels increased DNA fragmentation of AFB1-treated hepatocytes by over 17% of those without BSO. Thus, a decrease in hepatocyte GSH levels increased AFB1-induced DNA damage. Although ethanol in itself did not induce DNA damage, a combination of BSO and ethanol increased the percentage by over 23% of that with BSO only. Ethanol did not affect the amount of GSH, total cytochrome P-450 (P450), glutathione S-transferase (GST) and epoxide hydrolase (EHase) in cultured hepatocytes. However, GSH-depleted rat hepatocytes exposed to ethanol significantly increased the level of P450IIIA, which activates AFB1. The enhancing effects of ethanol in the presence of BSO are probably due to the induction of this isozyme in rat hepatocytes. The GSH-depleted hepatocytes are more susceptible to chemical carcinogens in the presence of ethanol.

It has become evident that the hepatocyte growth factor (HGF) could be involved in the growth of various epithelial cells. In addition, it has recently been elucidated that the c-met gene, a proto-oncogene, encodes the HGF receptor. We examined the expression of HGF and c-met gene in human gastric cancer, using seven gastric cancer cell lines. The Northern blotting method revealed that, among seven cell lines used, only MKN45 expressed the c-met gene at a high efficiency, while the Southern blotting method demonstrated the amplification of the c-met gene. When the expression of HGF gene was studied by the Northern blot method, the expression of this gene was also observed only in MKN45, which was confirmed by immunostaining with polyclonal antibodies to HGF. The above results suggest the possibility that in MKN45, a gastric cancer cell line, the autocrine mechanism by HGF-met might be involved in its growth.

Eighty-five patients with gastric cancer invading the serosa following curative resection were analyzed with respect to clinicopathological features and prognosis by staining the argyrophilic nucleolar organizer region (AgNOR). The AgNOR was counted in 200 cancer cells per tissue and the mean number per cell was identified as the AgNOR score. The AgNOR count varied from 1.79 to 5.71, while the mean value was 2.92 +/- 0.74 and the median score was 2.95. The patients were divided into two groups: the AgNOR high group (AgNOR count greater-than-or-equal-to 2.95, n=44) and the AgNOR low group (AgNOR count < 2.95, n=41). There were no differences between the two groups with respect to sex, age, tumor size, location of the tumor, macroscopic appearance, histological differentiation, growth pattern and vascular involvement. The lymphatic advancement of tumor cells was prominent and the rate of lymph node metastasis was higher (p<0.01) in patients in the AgNOR high group. The AgNOR high group had a higher rate of recurrence and also had a variety of recurrence styles. The prognosis of the AgNOR high group was poorer, with statistical significance (p<0.01), while the 10-year survival rate was 35.3% for the AgNOR high group and 77.2% for the AgNOR low group. Therefore, the AgNOR count was found to be closely related to tumor advancement and thus is considered to have a predictive value for the prognosis of patients with gastric cancer invading the serosa after curative resection.

To clarify the effect of L-histidinol on hyperthermic killing of cells, HeLa and mouse sarcoma-180 (S-180) cells were exposed to heat in vitro in the presence of L-histidinol and the clonogenic surviving fraction of the cells was examined. After pretreating the cells with L-histidinol for 4 h, exposure of the cells to the combination of heat at 43-degrees-C and L-histidinol for various times (30 min to 4 h) reduced the surviving fraction more prominently than heat alone. Optimal concentrations to confer effective enhancement of heat on HeLa and S-180 cells were 9 mM and 3 mM, respectively. Those concentrations showed little toxicity of L-histidinol alone. Enhancement of the effect of heat by L-histidinol was observed only at 43-degrees-C, but not at 41 and 42-degrees-C. Flow cytometric DNA analysis was used to examine the cell cycle transit effect of L-histidinol. L-histidinol alone arrested the HeLa cells in G1-phase. Heat treatment at 43-degrees-C led to an accumulation of the cells in G2/M-phase and a decrease in the G1-phase fraction. The effect of combined treatment with heat and L-histidinol was complementary, in which L-histidinol attenuated the accumulation of the cells in G2/M-phase and prevented a decrease in the G1-phase fraction. Thus, L-histidinol has the capacity to potentiate hyperthermic cell killing in vitro by a mechanism that may be related to the cell cycle transit effect.

Small cell carcinoma (SC) of the gallbladder is an uncommon tumor, and not enough information of this tumor has been previously reported. The SCs in this series occured in nine women and six men (mean age; 64.5 years). Histologically, they consisted of small atypical cells with scanty cytoplasm, hyperchromatic nuclei and inconspicuous nucleoli growing in sheets and cords. Two tumors contained neoplastic glands similar to those of well-differentiated adenocarcinoma and a histological transition between SC and adenocarcinoma was seen in one of the two tumors. Argyrophil granules were present in 10 tumors. The tumor cells were immunoreactive to epithelial markers (epithelial membrane antigen: 12/14; AE1/AE3: 12/14; CAM 5.2: 9/14; carcinoembryonic antigen: 7/14) and neuroendocrine markers (neuron specific enolase: 11/14; chromagranin A: 4/14; Leu 7: 10/14; adrenocorticotrophic hormone: 6/14). Abnormalities in tumor suppressor gene p53 expression were found in 9 of 14 SCs by using monoclonal antibody PAb 1801. Flow cytometry revealed aneuploidy in 7 (78%) of 9 in the SC and 26 (40%) of 65 in the adenocarcinoma. The survival curve of the SCs was less favorable than that of papillary adenocarcinoma and well differentiated adenocarcinoma in pTNM stage 2-4 (P=0.0027, P=0.0017, respectively). These results suggested that the SCs of the gallbladder arose from common primitive cells capable of endocrine and epithelial differentiation, while most SCs (78%) showed DNA aneuploid by flow cytometry and their prognosis was worse than that of differentiated adenocarcinoma of the gallbladder.

Fifty-eight Japanese patients with secondary adenocarcinoma, which developed in the reconstructed gastric tube after esophagectomy for carcinoma of the esophagus, were reviewed from 20 case reports published over a period of twenty years. Following esophagectomy the gastric tube was replaced through the antesternal route in 32 patients (55.2%), through the retrosternal route in 19 (32.7%) and through the intrathoracic route in 7 (12.1%). Regarding the initial diagnosis of the secondary carcinoma, 28 patients (48.3%) had a self-palpable tumor in the anterior chest, 10 patients (17.2%) had a feeling of dysphagia, and two (3.4%) experienced epigastralgia. In eighteen patients (31.1%), the secondary carcinoma was detected incidentally at follow-up examinations, including two autopsied cases. The interval between esophagectomy and the detection of the secondary carcinoma in the gastric tube ranged from 7 to 255 months (mean 72.4 +/- 54.2 months). In 31 patients (53.4%) the secondary carcinoma was detected more than 5 years after esophagectomy. The mean survival period was 81.2 +/- 54.3 months with a range from 21 to 227 months after esophagectomy. These results thus emphasise the significance of lifetime check-ups for the reconstructed gastric tube, especially when the stomach is used as substitution for the esophagus.

Expression of the c-met proto-oncogene is common iii small cell lung cancer (SCLC) cell lines. The product of this proto-oncogene is the receptor for hepatocyte growth factor (HGF), also known as scatter factor (SF) and hepatopoietin A. We examined the effect of HGF/SF on 8 SCLC cell lines of which six expressed c-Met and 2 control cell lines did not. The effect was monitored by growth curves, in vitro migration in Boyden chambers. and by examination of morphology. Three cell lines responded in one or more of the following ways: Growth inhibition, morphological alterations. and increased migration in Boyden chambers. We conclude that functional c-Met receptors are frequently expressed in SCLC and may contribute to the behaviour of this tumour type.

Toxicity of polyphenols against rat 3Y1 fibroblasts and the cells transformed by human adenovirus (Ad12-3Y1), its EIA gene (EIA-3Y1), or simian virus 40 (SV-3Y1) was examined. Among the diphenol compounds examined, pyrocatechol (o-diphenol) and hydroquinone (p-diphenol) showed selective toxicity against Ad12-3Y1 and EIA-3Y1 cells, while resorcinol (m-diphenol) showed a much weaker non-specific toxicity against these cells. Another o-diphenol (dopamine) and triphenols (gallic acid and pyrogallol) were less toxic but showed selective toxicity. At lower concentrations where they were not toxic, all polyphenols attenuated toxicity of phosphatidylcholine against EIA-3Y1 cells. Among antioxidants examined, ascorbic acid reduced the toxicity of pyrocatechol, but alpha-tocopherol and butyrated hydroxytoluene did not. Oxidation of pyrocatechol was not enhanced in the presence of 3Y1 or EIA-3Y1 cells and their homogenates. These results suggest that the selective toxicity of polyphenols against Ad12-3Y1 and E1A-3Y1 cells is not related to their oxidation velocity but other factors such as the activity of active oxygen-scavenging enzymes.

A case of adenosquamous carcinoma of the liver involving the esophago-gastric junction is reported. The preoperative diagnosis of a submucosal tumor of the cardia of the stomach was made following a barium meal study, gastrofiberscopy, ultrasonography, and computed tomography. At surgery, a tumor was found measuring 6x5 cm in diameter and involving the left lobe of the liver, lower esophagus and cardia of the stomach, and the origin of the tumor was unclear. Post-operative histopathology revealed that the tumor contained two different malignant components of glandular and squamous cells. An adenosquamous carcinoma originating in the liver was suspected, since the cancer cells did not involve the esophago-gastric mucosa and were mainly located in the S2 of the liver. Despite aggressive adjuvant chemotherapy, the patient died of a recurrence in the liver seven months later. This seems to be the first documentation of adenosquamous carcinoma of the liver invading the esophago-gastric junction.

A simple and efficient chemosensitivity assay for human primary tumors has been developed using 96-well microtiter plates covered totally with lethally irradiated 3T3 monolayers termed cell mats, on which the proliferation of normal human fibroblasts is preferentially inhibited. Two days after the inoculation of tumor cells into the microtiter cell mat plates, the cells were treated with various anticancer drugs, and the cell numbers were assessed by radioactivity using a 96-well automatic scintillation counter after subsequent radiolabeling with H-3-deoxyuridine for 24h. In this manner, complete dose response curves of many anticancer drugs were available from one plate within 5 days. Drugs tested in triplicate were adriamycin, mitomycin C, cisplatin, etoposide, and 5-fluorouracil at 0.01, 0.1, and Ix the peak tolerated drug concentrations in serum. Clinically, of the 39 primary tumor specimens of different types received, 4 were contaminated. The remaining 35 samples were successfully cultured, with 5 cultures being abandoned due to an insufficient cpm. As a result, cell survival curves were obtained from 30 (77%) specimens. This high evaluable rate might be due to the feeder effect brought by cell mats. Although optimization of the assay system has yet to be determined, the ability to have multiple drug sensitivity per plate with short-term duration would make this system an efficient assay for chemosensitivity test of human primary tumor cells.

The main treatment of endometrial cancer is surgery. Total abdominal hysterectomy (TAH) and bilateral salpingo-oophorectomy (BSO) is the principal surgery for stage I disease. Recently, pelvic lymph node dissection and para-aortic node biopsy is also being performed. For stage II, many surgeons in Japan prefer to do radical hysterectomy, however, its validity is questioned. For stages III and IV, surgery, radiation, chemotherapy and/or hormone therapy are combined, however, TAH and BSO should be performed at least. In 1988, FIGO changed the endometrial cancer staging system from clinical to surgical. According to this new staging, laparotomy should be done first and treatment plans made depending on the result of surgical finding.

Case-control studies were initiated to investigate possible risk factors (life style, etc.) for hepatocellular carcinoma (HCC) and liver cirrhosis (LC). One hundred and fifty-four patients with HCC and 97 patients with LC who had no evidence of HCC were compared with frequency-matched 298 control subjects. Chronic hepatitis B virus infection and histories of blood transfusion and familial liver diseases were highly and significantly associated with both HCC and LC. Heavy drinkers in their younger years showed about 2 to 3 times risk increase for HCC or LC as compared with non-drinkers. Smoking was suspected as a risk factor, but a dose-response relationship was not clear, and further investigations are needed. To study the factors in the development of HCC from LC, 120 HCC patients with LC were compared with LC patients. No significant factors were observed. Ex-drinkers among LC patients experienced a slightly decreased risk for HCC in contrast to some belief that ex-drinkers with LC have higher risk for HCC.

From 1979-1986, 110 patients with an ovarian cancer have been treated at Kyushu University Hospital. Sixty-eight of these patients with untreated primary adenocarcinoma of the ovary underwent a paraaortic lymph node (PAN) biopsy at the time of their initial surgery. Twenty-two of these 68 patients were found (32.4%) to have a positive PAN. Microscopic PAN metastases were present in 4 patients, who, macroscopically, seemed to have the disease confined to the pelvis. The incidence of a positive PAN was seen to correlate with the clinical stage and degree of differentiation of the primary tumor. Positive PANs were more frequent in cases of a serous rather than a mucinous carcinoma. All 5 patients with a metastatic adenocarcinoma originating from the stomach or the colon had a positive PAN. It thus has been concluded that a PAN evaluation is important for the management of ovarian cancer.

From 1979 to 1986, 355 patients with cervical cancer underwent paraaortic lymph node (PAN) biopsy before the start of initial treatment. Nineteen of these 355 patients (5.4%) had a positive PAN, and the percentage incidence of positive PAN in each clinical stage was as follow: stage Ib, 2.4%; IIa, 0%; IIb, 3.7%; IIIb, 19.0%; and IV, 20%. Eighteen of these 19 patients also had positive pelvic lymph nodes. Positive PANs were found to be more frequent in cases of an adenocarcinoma than in cases of squamous cancer. The palpation of the PANs seemed to be too insufficient to predict the metastasis. Patients with positive PAN who had received paraaortic irradiation survived longer than those who did not receive such treatment. It is concluded that the evaluation of the PAN is important for the management of a cervical cancer.

Results of treatment of 25 Hodgkin's disease patients at Kyushu University Hospital from 1981 to 1985 were reviewed. Total nodal irradiation or MOPP chemotherapy was used mainly. The actuarial 5-year survival rate, 87.2%, was significantly better than the 41.0% of 61 patients treated between 1966 and 1980 (P less than 0.01). However, 12 of the 24 patients in remission eventually relapsed. To further improve the survival rates of patients with Hodgkin's disease, technical improvements in total nodal irradiation and altering Adriamycin-containing chemotherapy protocol from MOPP chemotherapy are advisable.

Incidence of telangiectasia and ulcer among 118 postoperated breast cancer patients, who were tangentially irradiated at Department of Radiology, Kyushu University from 1961 to 1980, followed more than 5 years were evaluated. Telangiectasia occurred in 5% at 20-35 Gy, in 50% at 50-55 Gy. Ulcer occurred in 5% at 50-55 Gy, in 50% at 70-75 Gy. Skin tolerance dose in Rubin's Table (1972) is correct.

The aim of this study is to elucidate the role of "beta-endorphin (beta-End) & beta-lipotropin (beta-LPH)" on the regulation of gonadotropin (Gn) secretion. We investigated the relationships between immunoreactive beta-End plus beta-LPH and Gn in peripheral plasma of normal menstruating women, 1) during periovulatory period, especially at the time of Gn surge, 2) at the estrogen induced Gn surge (positive feedback) and 3) at the time of hypoxic stress. Plasma concentrations of beta-End plus beta-LPH were measured as immunoreactive beta-End (i-beta-End) by RIA after extraction with Sep-Pak C18. First, we assessed pulsatile Gn secretions during periovulatory period in 19 normal women every 10 minutes for 4 hours, some women were at the time of Gn surge in its ascending limb, plateau of the peak, and descending limb of the surge. Meanwhile, circadian variations of plasma i-beta-End levels of these subjects were assessed at 4 hours' interval on the same day. In two subjects, on the day before the onset of LH surge, significantly low (p less than 0.05) basal and peak levels of i-beta-End were observed, although the basic patterns of circadian rhythm were preserved. Secondly, changes of plasma i-beta-End levels during estrogen (estradiol benzoate 1mg i.m.) induced positive feedback tests were evaluated in 16 normal women and 6 hypothalamic amenorrheic women by daily blood sampling. In normal subjects, small but significant increases (p less than 0.05) of plasma i-beta-End were observed when Gn showed initial decreases at 48 hours after injection. Subsequently at 72 hours, however, plasma i-beta-End decreased precipitously at the time of Gn surge. On the other hand, in hypothalamic amenorrheic women who were devoid of Gn surge, no significant changes of plasma i-beta-End levels were observed. The transient decreases of plasma i-beta-End just prior to the Gn surge support the idea that i-beta-End exerts tonic inhibition on the onset of Gn surge and the disappearance of its inhibition might trigger the positive Gn surge. And it was also suggested that release mechanisms of both i-beta-End and Gn are impaired in hypothalamic amenorrhea. Thirdly, in acute hypoxic stress experiment, 5 normal female volunteers were placed in hypobaric (500 mbar) condition in which oxygen supply is a half of atmosphere, simultaneous blood samplings of Gn, prolactin and i-beta-End were performed every 15 minutes for 3 hours.(ABSTRACT TRUNCATED AT 400 WORDS)

A case history of a 39-year-old woman with a follicular, medium-size cell type lymphoma (Nodular poorly differentiated lymphocytic lymphoma) is reported. In spite of receiving no treatment, her lymphoma had changed little for 13 years. This case is regarded as a good example for considering the treatment of low grade malignant lymphomas.

A 55-year-old man underwent an ileocecal resection because of an intestinal obstruction. The resected specimen contained a sessile tumor near the ileal end. This tumor was 9 x 7 cm in size, with a nodular surface of brown tint. Microscopically, it was a well-differentiated adenocarcinoma, the tumor tissue extending into the muscularis propria. The malignant tissue was associated partially with adenomatous areas and, in malignant nests, with foci of lamellar and intracellular cornification. Further, there was focal ossification in the fibrous stroma. Stains for argyrophil and argentaffin cells revealed strong positive reactions, and immunohistochemical studies were positive for calcitonin and CEA. These findings suggest the multi-potentiality of a small intestinal carcinoma.

The incidence of rectal bleeding (Grade II or III) after radiotherapy for carcinoma of uterine cervix were studied. All cases were treated by external irradiation (ERT) and intracavitary irradiation (ICR). The dosage of rectal bleeding at 5% level were as followed; 40 Gy by ERT and 27 Gy at point A by ICR in National Sapporo Hospital, 36-40 Gy by ERT and 24 Gy at point A by ICR in Aichi Cancer Center, 40 Gy by ERT and 27 Gy at point A by ICR in Kyushu Cancer Center.

Variation of the normal tissue response to radiotherapy in animals of a given age, sex and species, and predictive analysis of the post radiotherapy normal tissue injuries for each case were reviewed. The degree of response of mouse hind legs to 25 Gy in a single dose varies from less than 20 Gy equivalent to more than 30 Gy equivalent injuries, implying that there still remains an unknown dose modifying factor whose modification factor is at large. It has been proposed to predict prospectively the post irradiation response of several normal tissues including the lung. Although, it is possible to predict the average degree of normal tissue injuries to a given dose, to predict the response of each case appears to be impossible.

Between 1972 and 1985, 210 patients with nodular poorly differentiated lymphocytic (NPDL), nodular mixed lymphocytic and histiocytic (NM), nodular histiocytic (NH), or diffuse well differentiated lymphocytic (DWDL) lymphoma according to Rappaport classification were treated among the 7 hospitals belonging to JLRTG (Japanese Lymphoma Radiation Therapy Study Group). Age greater than 50 years adversely affected overall survival. But no obvious survival differences were seen by sex and the primary site. Patients with NH had a significantly poorer survival (P less than 0.01), while there were no differences among the other histologic groups. Aggressive combination chemotherapy is advisable for patients with stages II, II and IV NH. But radiotherapy along may be treatment choice for patients with stage I NH. Because among stage I, over all survival and relapse-free survival of patients with NH were similar to those with the other histologic types. Five-year and 10-year relapse-free survival of stage I patients with the other 3 histologic types by radiotherapy alone were 85% and 67%, respectively. Those of stage II patients were both 58%. These data suggest cure of more than 50% of stages I and II patients with favorable lymphoma by radiotherapy alone.

Incidence rate of pulmonary fibrosis with elevation of diaphragma was calculated for 118 postoperated breast cancer patients who were tangentially irradiated at the Department of Radiology Kyushu University from 1961 to 1980 and followed more than 5 years. 5%, 50% occurred at 40-45 Gy, 60-65 Gy, Rubin's Table (1972) is possible correct.

Superior vena cava syndrome (SVCS) is a very rare complication in patients with a gynecologic malignancy. Only 4 cases have been reported in the English literature thus far and, to our knowledge, no such case has been reported in the Japanese literature. We have encountered two cases of SVCS in patients with cervical cancer. In case 1, the SVCS developed secondarily to a metastasis of the cervical cancer to the lungs and mediastinum. In case 2, the cause of the SVCS had been presumed to be due to metastatic cervical cancer, however on autopsy, it turned out to be due to a coexistent malignant lymphoma.

Immunological competence plays an important role in response of patients to radiation therapy and dose of radiation required for tumor control depends also on the immunocompetence of the individual patient. Radiation therapy (even localized irradiation) can, however, cause lymphopenia and induce an immunodeficient state. This may facilitate growth of residual tumor cells or metastatic foci, this negating benefits of the therapy. A brief overview of damage to T and B lymphocytes as well as macrophages and natural killer (NK) cells by radiation therapy was presented. The restoration and potentiation of the immunological competence of the patients by biological response modifiers (BRM) such as OK432 (a bacterial preparation), recombinant interferon (rIFN-gamma) and recombinant interleukin-2 (rIL-2) with or without lymphokine activated killer (LAK) cells, were discussed.

One hundred and one patients of less than seventy years old with T1, T2 and N0 carcinoma of the tongue were graded according to the Jacobson-Yamamoto's grading (1-4 D). All patients were also classified into two groups such as less than fifty years old group and fifty to seventy years old group. Patients with grade 3, 4 C and 4 D carcinoma had more metastases to the cervical lymph nodes than grade 1, 2. Patients with T2N0 carcinoma showed approximately same five year cervical lymph node metastases free survival rate. However, the five year survival rate of less than fifty years old group was significantly lower than that of fifty to seventy years old group. In T2N0, grade 3-4 D carcinoma cases, more dead cases were found in less than fifty years old group than in fifty to seventy years old group.

From 1981, through 1985, 90 patients with primary or recurrent gynecologic malignancies underwent a scalene lymph nodes (SLN) biopsy. Pelvic lymph nodes (PN) and paraaortic lymph nodes (PAN) also were examined for metastasis with CT, lymphography, and palpation or were biopsied after a laparotomy. Twenty-three of these 90 patients (25.6%) were found to have positive SLN. In 5 of these 23 (21.7%), their SLN had not been palpable on physical examination. All signs of PN, PAN and SLN were examined in 42 patients. Twenty-one of these 42 (50%) had positive PN, 14 (66.7%) had positive PAN, and 4 (28.6%) had positive SLN. Seven patients with negative PAN had no SLN metastasis. Of twenty-one patients with negative PN, 2 had positive PAN and none had an SLN metastasis. Thus, it has been concluded that an evaluation of SLN is important for the management of a gynecologic malignancy in patients with positive PAN.

During 1979-1986, 101 patients with an endometrial carcinoma were treated. Eighty-four of these patients underwent a para-aortic lymph node (PAN) biopsy at the time of their initial surgery, eight of whom (9.5%) were found to have a positive PAN. The incidence of positive PAN as per each clinical stage, was as follows: stage I, 2.0%; II, 11.5%; III, 50%; and, IV, 33.3%. Positive pelvic nodes were found in 19.2% of the patients, per the following stages: stage I, 6.1%; II, 32%; and, III & IV, 100%. This finding suggests that PAN metastasis occurs after the pelvic nodes are involved. A 5-year survival rate of approximately 50% is expected even in patients with a positive PAN. Thus our study concludes that an evaluation of para-aortic and pelvic lymph nodes is important for the management of an endometrial carcinoma.

During an 11 year period, from 1976 to 1986, 33 (10.1%) out of 328 patients with oral cancer treated at our clinic had either a scarred pulmonary tuberculosis (TB) or active TB. Four of these 33 patients developed active TB. In two of these cases TB occurred before the therapy of oral cancer commenced and in the other two, after the operation for oral cancer. In one of the 4 cases, a recrudescence of the TB was suspected. Five cases that were suspected of having TB on analysis of their chest X-rays were administered prophylactic anti-tuberculous chemotherapy, after which no recrudescence or onset of TB.

Thyroid function after radiation therapy to the neck was studied in 120 patients, 110 of whom were suffered from malignant lymphomas. No patients had clinical symptoms from thyroid dysfunction, but 9 patients were given thyroid hormone after examination of thyroid function test. TSH elevation rate for 95 patients irradiated to the hole neck by dosage was 0%, 24%, 47% and 47%, for less than 30 Gy, 30-39 Gy, 40-49 Gy and 50 Gy or more, respectively. The effects of lymphangiography and systemic combination chemotherapy on the thyroid function were also discussed.

The dose modifying effects of the age, anatomic location of the normal tissue, positioning of animal during irradiation, preliminary treatment, number of fractions and time interval between doses on response of the normal tissues to radiation were studied, using various kinds of response of mouse hind legs such as early skin reaction, epilation, skin contraction, ulcer formation, leg contraction and growth retardation of femur. The dose modifying factors varied with the kinds and the levels of injuries, meaning that it is very important to define what the critical normal tissue is and its end point first of all, when we discuss the dose modifying factors with respect to the therapeutic gain factors.